EP1833797A1

EP1833797A1 - Azacyclic compounds as inhbitors of sensory neurone specific channels (sns)

Info

Publication number: EP1833797A1
Application number: EP06700329A
Authority: EP
Inventors: Richard Ionix Pharmaceuticals Limited HAMLYN; Mike Ionix Pharmaceuticals Limited HUCKSTEP; Christopher G. Ionix Pharm. Limited EARNSHAW; Stephen Ionix Pharmaceuticals Limited STOKES; David Ionix Pharmaceuticals Limited TICKLE; Brigitte Ionix Pharmaceuticals Limited ALLART; Joseph William Ionix Pharm. Limited BOYD; Lars Jacob S. Ionix Pharm. Limited KNUTSEN; Rosemary Ionix Pharmaceuticals Limited LYNCH; Lee Ionix Pharmaceuticals Limited PATIENT
Original assignee: Vernalis R&D Ltd
Current assignee: Vernalis R&D Ltd
Priority date: 2005-01-07
Filing date: 2006-01-06
Publication date: 2007-09-19
Also published as: WO2006082354A1; GB0500300D0

Abstract

Compounds of the formula (I) , and pharmaceutically acceptable salts thereof , are found to be antagonists of SNS sodium channels. They are therefore useful as analgesic and neuroprotective agents. wherein: - Ar represents a phenyl ring or a 5 - to 6- membered heteroaryl group; - m is 1 , 2 or 3 .

Description

AZACYCLIC COMPOUNDS AS INHIBITORS OF SENSORY NEURONE SPECIFIC CHANNELS (SNS )

The present invention relates to inhibitors of the subtype of mammalian sodium channels known as Na_vl .8 or sensory neurone specific (SNS) channels. The Na_v1.8 channel is a 1,957 amino acid tetrodotoxin-insensitive voltage-gated sodium channel. The sodium channel, nucleic acid sequences coding for the channel, vectors, host cells and methods of identifying modulators, are taught in US-A- 6451554. The α-subunit gene corresponding to this ion channel is referred to as SCNlOA. The channel is described in more detail in Akopian et al, (1996), 379, 257-262.

Mammalian ion channels are becoming increasingly well characterized, and progress in sodium channel research has been summarized recently in Anger et al, J. Med. Chem. (2001) 44, 115-137. Sodium channels are recognised as valid targets for pain therapeutics, and blockade of sodium channels can be useful in the treatment of a range of pain syndromes (see for example Black et al, Progress in Pain Research and Management (2001), 21 (Neuropathic Pain: Pathophysiology and Treatment), 19- 36).

It has now surprisingly been found that compounds of the general formula (I) set out below act as inhibitors of sensory neurone specific sodium channels. Accordingly, the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body,

wherein:

Ar represents a phenyl ring or a 5- to 6- membered heteroaryl group; n is an integer of from 0 to 3 ; Each Rl is the same or different and is a hydroxy, amino, halogen, cyano, C₁- C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, (C₁-C₆ alkyl)amino or Oi(C₁-C₆ alkyl)amino group or a group selected from;

-CO₂R¹⁰, -CON(R^π)R¹², -SO₃R¹⁰, -SO₂N(R¹ ^R¹², -N(R^π)R¹², -OSO₂R¹⁰

Where R¹⁰ is hydrogen or C1-C4 alkyl

Where R¹¹ and R¹² can independently be selected from hydrogen, C₁-C₄ alkyl or taken together as a C₃-C₆ alkyl chain forming a ring, or taken together forms the group -CR₂CH₂-X¹ -CK₂CH₂-, where X¹ is O, NH OrNCH₃,

Or a group selected from

-N(R¹⁰)COR¹⁰, -N(R¹⁰)CON(R¹⁰)R¹⁰, -N(R¹⁰)SO₂R¹⁰

Where R¹⁰ is defined as above or taken together any two R¹⁰ groups form a C₃-C₄ ring forming alkyl chain.

Or the group

-X^CH₂)_W-N(R¹ ^R¹², where w can be 2,3 or 4.

5 - R₂ and R₃ are the same or different and each represent hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, -COR⁷, -CSR⁷, -CO₂R⁷⁷, -CONR⁷⁷R⁷⁷⁷ or oxo, wherein R⁷ represents a C₁-C₆ alkyl group and each R⁷⁷ and R⁷⁷⁷ are the same or different and represent hydrogen or a C₁-C₆ alkyl group, provided that at least one of R₂ and R₃ is other than hydrogen; m is 1, 2 or 3; and R₄ is either

(a) -L-CR(A)₂ or -L-Het, wherein L is a C₁-C₆ alkylene group, R is hydrogen or a C₁-C₄ alkyl group, each A is the same or different and represents a C₆-C₁₀ aryl group or a 5- to 10- membered heteroaryl group and Het represents a moiety

wherein p is 0, 1, 2 or 3, Y is N or CH, X is a direct bond, O, S, -S(O)- or -S(O)₂-, each R₅ is the same or different and represents halogen, hydroxy, C₁- C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio,

C₁-C₄ haloalkylthio, -COR⁷, -CSR⁷, -CO₂R⁷⁷ or -CONR⁷⁷R⁷⁷⁷ wherein R⁷ represents a C₁-C₄ alkyl group and each R⁷⁷ and R⁷⁷⁷ are the same or different and represent hydrogen or a C₁-C₄ alkyl group, and either (i) R₆ and R₇ are the same or different and represent hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, -COR⁷, -CSR⁷, -CO₂R⁷⁷ or -CONR⁷⁷R⁷⁷⁷ wherein R⁷, R⁷⁷ and R⁷⁷⁷ are as defined above or (ii) R₆ and R₇, together with the carbon atoms to which they are attached, together form a C₆-C₁₀ aryl or 5- to 10- membered heteroaryl group; (b) -1/-CO-NRsR₉, wherein L⁷ is a direct bond or a C₁-C₆ alkylene group, R₈ is hydrogen, C₁-C₆ alkyl, C₆-C₁₀ aryl or 5- to 10- membered heteroaryl and R₉ is -L⁷-A, -L⁷-CR(A)₂, -L⁷-N(A)₂, -L-Het, -L⁷-CO-Het or Het⁷, wherein R is hydrogen or C₁-C₄ alkyl, L⁷, L, A and Het are as defined above and Het⁷ is a moiety Het, as defined above, in which Y is CH; (c) -L-NR-CO-NR-L⁷-CR(A)₂ or -L-NR-CS-NR-L⁷-CR(A)₂, wherein each R is the same or different and represents hydrogen or C₁-C₄ alkyl and L, L⁷ and A are as defined above; or (d) -L⁷-CO-Het, wherein L⁷ and Het are as defined above, the said aryl and heteroaryl moieties in the R₄ substituent being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,

C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, (C₁-C₆ alkyl)amino or di(C₁-

C₆ alkyl)amino groups.

As used herein, a C₁-C₆ alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C₁-C₄ alkyl group or moiety. Examples OfC₁-C₄ alkyl groups and moieties include methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl and t-butyl. A divalent alkyl moiety (or alkylene moiety) can be attached via the same carbon atom, by adjacent carbon atoms or by non-adjacent carbon atoms. As used herein, a C₆-C₁₀ aryl group or moiety is typically a phenyl or naphthyl group or moiety. It is preferably a phenyl group or moiety.

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

Further, as used herein, a 5- 10- membered heteroaryl group includes a 8- to 10- membered fused bicyclic aromatic system containing at least one heteroatom, for example 1 to 5 heteroatoms selected from O, S and N. Examples include indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl and imidazopyrimidinyl. Thienyl groups are preferred.

As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine or fluorine. As used herein, a said C₁-C₆ alkoxy group is typically a said C₁-C₆ alkyl group attached to an oxygen atom. A said C₁-C₆ alkylthio group is typically a said C₁-C₆ alkyl group attached to a thio group.

As used herein, a C₁-C₆ haloalkyl group is typically a said C₁-C₆ alkyl group, for example a C₁-C₄ alkyl group, substituted by one or more said halogen atoms.

Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl groups include perhaloalkyl groups such as -CX₃ wherein X is a said halogen atom.

Particularly preferred haloalkyl groups are -CF₃ and -CCl₃.

As used herein, a C₁-C₆ haloalkoxy group is typically a said C₁-C₆ alkoxy group, for example a C₁-C₄ alkoxy group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkoxy groups include perhaloalkoxy groups such as -OCX₃ wherein X is a said halogen atom. Particularly preferred haloalkoxy groups are -OCF₃ and -OCCl₃.

As used herein, a C₁-C₆ haloalkylthio group is typically a said C₁-C₆ alkylthio group, for example a C₁-C₄ alkylthio group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkylthio groups include perhaloalkylthio groups such as -SCX₃ wherein X is a said halogen atom. Particularly preferred haloalkylthio groups are -SCF₃ and -SCCI3. Typically, Ar represents a phenyl, thienyl, furanyl or pyrrolyl moieity.

Preferably, Ar represents a phenyl or thienyl moiety. Most preferably, Ar is phenyl.

Typically, n is 0, 1 or 2.

Preferably, each R₁ is the same or different and is a hydroxy, amino, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio or C₁- C₄ haloalkylthio group. More preferably, each R₁ is the same or different and is a C₁-C₂ alkyl, C₁-C₂ haloalkyl, hydroxy, halogen, C₁-C₂ alkoxy or C₁-C₂ haloalkoxy group. Most preferably, each R₁ is the same or different and represents methyl, methoxy, hydroxy, fluorine or chlorine.

Typically, m is 1 or 2. For the avoidance of doubt, when R₂ or R₃ is an oxo (=O) group, it is attached to the nitrogen-containing ring by a double bond, rather than by the single bond depicted.

Typically, R₂ and R₃ are the same or different and each represent hydrogen, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, -COR⁷, -CO₂R⁷⁷, -CONR⁷⁷R⁷⁷⁷⁷ or oxo, wherein R⁷ represents a C₁-C₄ alkyl group and each R⁷⁷ and R⁷⁷⁷ are the same or different and represent hydrogen or a C₁-C₄ alkyl group, provided that at least one of R₂ and R₃ is other than hydrogen.

Preferably, R₂ and R₃ are the same or different and each represent hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, -CO₂R⁷, -CONR⁷R⁷⁷Or oxo, wherein R⁷ represents a C₁-C₄ alkyl group and R⁷⁷ represents hydrogen or a C₁-C₄ alkyl group, provided that at least one of R₂ and R₃ is other than hydrogen. More preferably, R₂ represents hydrogen, C₁-C₄ alkyl, -CO₂-(C₁-C₄ alkyl) or oxo and R₃ represents hydrogen, hydroxy, C₁-C₄ alkyl, -CONH-(C₁-C₄ alkyl) or oxo, provided that at least one of R₂ and R₃ is other than hydrogen.

Preferably, either (a) one of R₂ and R₃ is hydrogen or (b) both R₂ and R₃ are oxo. When both R₂ and R₃ are oxo, they are typically present on carbon atoms adjacent to the N atom which carries R₄. Particularly preferred compounds in this latter category are phthalimide derivatives of the formula (I¹)

wherein R₁, n and R₄ are as defined above. Typically, each L moiety in the R₄ substituent is the same or different and represents a C₁-C₄ alkyl moiety. Preferably, each L is the same or different and represents -CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH₂-CH(CH₃)-, -C(CH₃)-CH₂- or -CH(CH₃)-.

Typically, each L moiety in the R₄ substituent is the same or different and represents a direct bond or a C₁-C₄ alkyl moiety. Preferably, each L represents a direct bond or a -(CH₂)-, -(CH₂-CH₂)-, -CH₂-CH₂-CH₂- or -CH(CH₃)- moiety.

Typically, each A moiety in the R₄ substituent is the same or different and represents a phenyl or 5- to 6- membered heteroaryl group. Preferably, each A moiety in the R₄ substituent is a phenyl group. Typically, the aryl and heteroaryl moieties in the R₄ substituent are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy groups.

Preferably, the aryl and heteroaryl moieties in the R₄ substituent are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from hydroxy, halogen, C₁-C₂ alkyl, C₁-C₂ haloalkyl and C₁-C₂ alkoxy groups. Most preferably, the aryl and heteroaryl moieties in the R₄ substituent are unsubstituted or substituted by a single hydroxy, halogen, C₁-C₂ alkyl or C₁-C₂ alkoxy substituent.

For the avoidance of doubt, the moiety Het is attached via the Y atom. Typically, Y in the moiety Het is a N atom.

Typically, X in the moiety Het is a direct bond, O, S or -S(O)-.

Typically, p in the moiety Het is O, 1 or 2. Preferably, p in the moiety Het is O or l.

Typically, each R₅ in the moiety Het is the same or different and represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ haloalkylthio, -COR⁷, -CO₂R⁷ or -CONR⁷R⁷⁷ wherein R⁷ is a C₁-C₄ alkyl group and R⁷⁷ is hydrogen or a C₁-C₄ alkyl group.

Preferably, each R₅ in the moiety Het is the same or different and represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio or -CO-(C₁-C₄ alkyl). More preferably, each R₅ is the same or different and represents halogen, C₁- C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ alkylthio or -CO-(C₁-C₂ alkyl).

Typically, when R₆ and R₇ together form an aryl or heteroaryl group, they form, together with the carbon atoms to which they are attached, a phenyl or 5- to 6- membered heteroaryl group. Preferably they form, together with the carbon atoms to which they are attached, a phenyl group. Most preferably, they form an unsubstituted phenyl group.

Typically, when R₆ and R₇ do not together form an aryl or heteroaryl group, they are the same or different and each represent hydrogen, halogen, C₁-C₄ alkyl, C₁- C₄ haloalkyl, C₁-C₄ alkoxy, phenyl, 5- to 6- membered heteroaryl, -CO₂R⁷ or -CONR⁷R⁷⁷ wherein R⁷ represents a C₁-C₄ alkyl group and R⁷⁷ represents hydrogen or a C₁-C₄ alkyl group.

Preferably, when R₆ and R₇ do not together form an aryl or heteroaryl group, they are the same or different and each represent hydrogen, C₁-C₄ alkyl, phenyl (preferably unsubstituted phenyl), or -CO₂-(C₁-C₄ alkyl). Most preferably, when R₆ and R₇ do not together form an aryl or heteroaryl group, R₆ represents hydrogen, C₁-C₂ alkyl or an unsubstituted phenyl group and R₇ represents hydrogen or -CO₂-(C₁-C₂ alkyl).

Preferably, the moiety Het⁷ is a 9H-xanthenyl group. Typically, when R₄ is defined according to option (a), R is hydrogen. Typically, when R₄ is defined according to option (a), each A is the same or different and represents a phenyl group which is unsubstituted or substituted by a fluorine atom. Typically, when R₄ is defined according to option (a), L is a C₁-C₄ alkylene group.

Typically, when R₄ is defined according to option (b), R₈ is hydrogen, C₁-C₄ alkyl or phenyl. Preferably, R₈ is hydrogen or phenyl.

Typically, R in the moiety R₉ is hydrogen. Preferably, each A moiety in the R₉ substituent is the same or different and represents a phenyl group, which is unsubstituted or substituted as set out above. More preferably, each A moiety in the R₉ substituent is the same or different and represents a phenyl group, which is unsubstituted or substituted by a halogen (preferably fluorine), hydroxy, C₁-C₂ alkyl or C₁-C₂ alkoxy substituent.

Typically, R₉ is -I/-A, -1/-CR(A)₂, -N(A)₂, -L-Het, -l/-CO-Het or Het⁷, wherein R, L⁷, L, A, Het and Het⁷ are as defined above. Preferably, R₉ is -l/-A, -L⁷- CR(A)₂, -N(A)₂, -L-Het, -CO-Het or Het⁷, wherein R, L⁷, L, A, Het and Het⁷ are as defined above. Preferably, R₉ is -L⁷- A, -1/-CR(A)₂, -L-Het, -CO-Het or Her⁷, wherein R, L⁷, L, A, Het and Her⁷ are as defined above.

Typically, when R₄ is defined according to option (b), R₄ is -L-CO-NR₈R₉ wherein, L, R₈ and R₉ are as defined above.

Typically, when R₄ is defined according to option (c), L^ is a direct bond. Typically, when R₄ is defined according to option (c), L is a C₁-C₂ alkylene group. Typically, when R₄ is defined according to option (c), each R is hydrogen. Typically, when R₄ is defined according to option (c), each A is an unsubstituted phenyl group.

Typically, when R₄ is defined according to option (c), R₄ is -L-NR-CS-NR- L⁷-CR(A)₂, wherein L, R, L⁷ and A are as defined above.

Typically, when R₄ is defined according to option (d), L⁷ is a direct bond, -CH₂- or -CH(CH₃)-. More preferably, R₄ is -CH₂- or -CH(CH₃)-. Typically, when R₄ is defined according to option (d), X in the moiety Het is

O, S or -S(O)-. Typically, when R₄ is defined according to option (d), Y in the moiety Het is N. Typically, when R₄ is defined according to option (d) and when R₆ and R₇ in the moiety Het do not together form an aryl or heteroaryl group, R₆ represents hydrogen or an unsubstituted phenyl group and R₇ represents hydrogen or -CO₂-(C₁-C₂ alkyl).

In a further embodiment of the invention, when Ar is a phenyl ring, m is 2 and R₃ is H, R₉ is preferably -1/-CR(A)₂, -L-Het, HetV -l/-CO-Het, more preferably -l/-CR(A)₂. Preferably, in this embodiment, when Ar is a phenyl ring, m is 2 and R₃ is H, R₉ is other than -1/-CO-NR₈R₉.

Further, in another embodiment of the invention, when m is 2, R₂ is other than oxo.

Preferred compounds of formula (I) are those in which: - Ar represents a phenyl ring or a 5- to 6- membered heteroaryl moiety; n is 0, 1 or 2; m is 1 or 2; each R₁ is the same or different and is a hydroxy, amino, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, or C₁-C₄ haloalkylthio group;

R₂ and R₃ are the same or different and each represent hydrogen, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, -COR⁷, -CO₂R⁷, -CONR^//R^/// or oxo, wherein R⁷ represents a C₁-C₄ alkyl group and each R^7/ and R^7// are the same or different and represent hydrogen or a C₁-C₄ alkyl group, provided that at least one of R₂ and R₃ is other than hydrogen; and

R₄ is either (a) -L-CR(A)₂ or -L-Het, wherein L is a C₁-C₄ alkylene group, R is hydrogen or a

C₁-C₄ alkyl group, each A is the same or different and represents phenyl or a

5- to 6- membered heteroaryl group and Het represents a moiety

wherein p is 0, 1 or 2, Y is N or CH, X is a direct bond, O, S or -S(O)-, each R₅ is the same or different and represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ haloalkylthio, -COR⁷, -CO₂R⁷ or -CONR⁷R⁷⁷, wherein R⁷ is a C₁-C₄ alkyl group and R⁷⁷ is hydrogen or a C₁-C₄ alkyl group, and either (i) R₆ and R₇ form, together with the carbon atoms to which they are attached, a phenyl or 5- to 6- membered heteroaryl group, or (ii) R₆ and R₇ are the same or different and each represent hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenyl, 5- to 6- membered heteroaryl, -CO₂R⁷ or -CONR⁷R⁷⁷, wherein R⁷ represents a C₁-C₄ alkyl group and R⁷⁷ represents hydrogen or a C₁-C₄ alkyl group;

(b) -1./-CO-NR₈R₉, wherein L⁷ is a direct bond or a C₁-C₄ alkylene group, R₈ is hydrogen, C₁-C₄ alkyl or phenyl and R₉ is -L⁷-A, -L⁷-CR(A)₂, -L⁷-N(A)₂, -L-

Het, -L⁷-CO-Het or Het⁷, wherein R is hydrogen or C₁-C₄ alkyl, L⁷, L, A and Het are as defined above and Het⁷ is a moiety Het, as defined above, in which Y is CH;

(c) -L-NR-CO-NR-L⁷-CR(A)₂ or -L-NR-CS-NR-L⁷-CR(A)₂, wherein each R is the same or different and represents hydrogen or C₁-C₄ alkyl and L, L⁷ and A are as defined above; or

(d) -L⁷-CO-Het, wherein L⁷ and Het are as defined above, the aryl and heteroaryl moieties in the R₄ substituent being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy groups. Further preferred compounds of formula (I) are those in which

Ar represents a phenyl or thienyl moiety; n is 0, 1 or 2; m is 1 or 2; - each R₁ is the same or different and is a C₁-C₂ alkyl, C₁-C₂ haloalkyl, hydroxy, halogen, C₁-C₂ alkoxy or C₁-C₂ haloalkoxy group;

R₂ represents hydrogen, C₁-C₄ alkyl, -CO₂-(C₁-C₄ alkyl) or oxo and R₃ represents hydrogen, hydroxy, C₁-C₄ alkyl, -CO-NH-(C₁-C₄ alkyl) or oxo, provided that (a) at least one of R₂ and R₃ is other than hydrogen and (b) when m is 2, R₂ is other than oxo; and

R₄ is either: (a) -L-CH(A)₂ or -L-Het, wherein L is a C₁-C₄ alkyl moiety, A represents a phenyl group and Het represents a moiety

wherein p is 0 or 1, X is a direct bond, O, S or -S(O)-, R₅ is halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio or -CO-(C₁-C₄ alkyl), and either (i) R₆ and R₇, together with the carbon atoms to which they are attached, together form a phenyl group or (ii) R₆ and R₇ are the same or different and each represent hydrogen, C₁-C₄ alkyl, phenyl or -CO₂-(C₁-C₄ alkyl);

(b) -L-CO-NR₈R₉ wherein R₈ is hydrogen or phenyl and R₉ is -L'-A, -L^;-CR(A)₂, -N(A)₂, -L-Het, -CO-Het or a 9H-xanthenyl moiety, wherein R is hydrogen or C₁-C₄ alkyl, L⁷ is a direct bond or a C₁-C₄ alkylene group and L, A and Het are as defined above; (c) -L^NH-CS-NH-CH(A)₂, wherein L⁷ is a C₁-C₂ alkylene group and A is as defined above; or (d) -L/-CO-Het wherein L⁷ and Het are as defined above, the phenyl moieties in the R₄ substituent being unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from halogen, hydroxy, C₁-C₂ alkyl, C₁-C₂ haloalkyl, and C₁-C₂ alkoxy groups.

Particularly preferred compounds of formula (I) are compounds of formula (Ia)

wherein R₁, n, Ar, R₂, m, R₃, L⁷, R₅, p, R₆ and R₇ are as defined above, and X is O, S or -SO-.

Preferably, X in the formula (Ia) is O. Preferably, L⁷ in the formula (Ia) is a C₁-C₄ alkylene group.

Preferred definitions for R₁, n, Ar, R₂, m, R₃, L, R₅, p, R₆ and R₇ in the formula (Ia) are the same as those set out above in the context of the formula (I). Examples of compounds of the invention include

1. N-[bis-(4-fluoro-phenyl)-methyl]-2-(6,7-dimethoxy-l-methyl-3,4-dihydro- 1 H-isoquinolin-2-yl)-acetamide

2. N-[bis-(4-fluoro-phenyl)-methyl]-2-(6,7-dimethoxy-3-methyl-3,4-dihydro- 1 H-isoquinolin-2-yl)-acetamide 3. 3-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N-(3 ,3 - diphenyl-propyl)-propionamide 4. 2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinorm-2-yl)-N-(2,2- diphenyl-ethyl)-acetamide

5. 3-(6,7-Dimethoxy-3-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-N-(3,3- diphenyl-propyl)-propionamide 6. 2-(6,7-Dimethoxy-3 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N-(2,2- diphenyl-ethyl)-acetamide

7. N-(3-Carbazol-9-yl-propyl)-2-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide

8. N-[3-(5-Chloro-2-methyl-indol-l-yl)-propyl]-2-(l-methyl-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide

9. N-(3 -Carbazol-9-yl-propyl)-2-(6,7-dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H- isoquinolin-2-yl)-acetamide

10. N-tS-CS-Chloro^-methyl-indol-l-yO-propylJ^-CόJ-dimethoxy-l-methyl- 3,4-dihydro-lH-isoquinolin-2-yl)-acetamide 11. l-Benzhydryl-3-[2-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]- thiourea

12. 1 -Benzhydryl-3 -[2-(6,7-dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2- yl)-ethyl]-thiourea

13. 2-[4,4-Bis-(4-fluoro-phenyl)-butyl]-6,7-dimethoxy-l-methyl-l,2,3,4- tetrahydro-isoquinoline

14. 2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 - phenothiazin- 10-yl-ethanone

15. 2-(6,7-Dimethoxy-3 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 - phenothiazin- 10-yl-ethanone 16. 1 -(2-Chloro-ρhenothiazin- 10-yl)-2-(6,7-dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-ethanone

17. 1 -(2-Chloro-phenothiazin- 10-yl)-2-(6,7-dimethoxy-3 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-ethanone

18. 2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -(5-oxo-5H- 51ambda*4*-phenothiazin-10-yl)-ethanone

19. 2-(6,7-Dimethoxy-3-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-l-(5-oxo-5H- 51ambda*4*-phenothiazin- 10-yl)-ethanone 20. 2-(l-Methyl-3,4-dihydro-lH-isoquinolin-2-yl)-l-(5-oxo-5H-51ambda*4*- phenothiazin- 10-yl)-ethanone

21. 2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -phenoxazin- 10-yl-ethanone 22. 2-(6,7-Dimethoxy-3-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-l -phenoxazin- 10-yl-ethanone

23. 2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -(2- trifluoromethyl-phenothiazin- 10-yl)-eihanone

24. 2-(6,7-Dimethoxy-3-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- trifluoromethyl-phenothiazin- 10-yl)-ethanone

25. 1 -(2-Acetyl-phenothiazin- 10-yl)-2-(6,7-dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H- isoquinolin-2-yl)-ethanone

26. l-(2-Acetyl-ρhenothiazin-10-yl)-2-(6,7-dimethoxy-3-methyl-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone 27. l-(2-Acetyl-phenothiazin-10-yl)-2-(l-methyl-3,4-dihydro-lH-isoquinolin-2- yl)-ethanone

28. 2-(6,7-Dimethoxy-l -methyl-3 ,4-dihydro- lH-isoquinolin-2-yl)-N,N-diphenyl- acetamide

29. 2-(6,7~Dimethoxy-3 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N,N-diphenyl~ acetamide

30. 2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 ~(2- methylsulfanyl-phenothiazin- 10-yl)-ethanone

31. 2-(6,7-Dimethoxy-3-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-l -(2- methylsulfanyl-phenothiazin- 10-yl)-ethanone 32. 2-( 1 -Methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -(2-methylsulfanyl- phenothiazin- 10-yl)-ethanone

33. N-[3,3-Bis-(4-fluoro-phenyl)-propyl]-3-(6,7-dimethoxy-l-methyl-3,4- dihydro- 1 H-isoquinolin-2-yl)-ρropionarnide

34. 4-[2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-acetyl]-3 ,4- dihydro-2H-benzo[l,4]oxazine-2-carboxylic acid ethyl ester

35. 2-(6,7-Dimethoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N-(4-hydroxy- phenyl)-N-phenyl-acetamide 36. 2-(6,7-Dimethoxy-l-methyl-3,4-diliydro-lH-isoquinolin-2-yl)-N-(9H- xanthen-9-yl)-acetamide

37. 2-(8-Methoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -phenoxazin- 10- yl-ethanone 38. 2-(2-Oxo-2-phenoxazin- 10-yl-ethyl)- 1 ,2,3 ,4-tetrahydro-isoquinoline-3 - carboxylic acid tert-butylamide

39. 2-[2-Oxo-2-(3-ρhenyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-ethyl]-l,2,3,4- tetrahydro-isoquinoline-3 -carboxylic acid tert-butylamide

40. 2-(2~Oxo-2~phenoxazin- 10-yl-ethyl)- 1 ,2,3 ,4-tetrahydro-isoquinoline- 1 - carboxylic acid ethyl ester

41. 2-(l -Methyl- 1 ,3 -dihydro-isoindol-2-yl)- 1 -phenoxazin- 10-yl-ethanone

42. 2-(2-Phenoxazin-10-yl-ethyl)-2,3-dihydro-isoindol-l-one

43. 2-(2-Phenoxazin-l 0-yl-propyl)-2,3 -dihydro-isoindol- 1 -one

44. 2-(2-Oxo-2-phenoxazin- 10-yl-ethyl)-2,3 -dihydro-isoindol- 1 -one 45. 2-(l-Methyl-2-oxo-2-phenoxazin-10-yl-ethyl)-2,3-dihydro-isoindol-l-one

46. 2-(l -Methyl-2-oxo-2-phenoxazin- 10-yl-ethyl)~isoindole- 1 ,3 -dione

47. 2-(2-Phenoxazin- 10-yl-ethyl)-isoindole- 1 ,3 -dione

48. 4-Methyl-2-(2-phenoxazin- 10-yl-ethyl)-isoindole- 1 ,3-dione

49. 4-Methyl-2-(2-phenoxazin-10-yl-propyl)-isoindole-l,3-dione 50. 4-Hydroxy-2-(2-phenoxazin-l 0-yl-propyl)-isoindole-l ,3-dione

51. 4-Methoxy-2-(2 -phenoxazin- 10-yl-propyl)-isoindole- 1 ,3-dione

52. 4-Methyl-2-(2-oxo-2 -phenoxazin- 10-yl-ethyl)-isoindole- 1 ,3-dione

53. 2-( 1 -Methyl-2-phenoxazin- 10-yl-ethyl)-isoindole- 1 ,3-dione

54. 4-Fluoro-2-(2-phenoxazin- 10-yl-ethyl)-isoindole- 1 ,3-dione 55. 5-Fluoro-2-(2-phenoxazin-10-yl-ethyl)-isoindole- 1,3 -dione

56. 4-Fluoro-2-(2-oxo-2-phenoxazin-10-yl-ethyl)-isoindole-l,3-dione

57. 5-Fluoro-2-(2-oxo-2-phenoxazin-10-yl-ethyl)-isoindole-l,3-dione

58. 4-Methoxy-2-(2-oxo-2-phenoxazin- 10-yl-ethyl)-isoindole- 1 ,3-dione

59. 5,6-Dichloro-2-(2-oxo-2-phenoxazm-l 0-yl-ethyl)-isoindole-l ,3-dione 60. 4,7-Difluoro-2-(2-oxo-2-phenoxazin-10-yl-ethyl)-isoindole-l,3-dione

61. 4,7-Dichloro-2-(2-oxo-2-phenoxazin- 10-yl-ethyl)-isoindole- 1 ,3-dione

62. 2-[2-Oxo-2-(3-phenyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-ethyl]-isoindole- 1,3 -dione 63. 2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-N-phenyl-N-(l-phenyl-ethyl)- acetamide

64. 2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-N-(2-methoxy-benzyl)-N-(2- methoxy-phenyl)-acetamide 65. 2-(4-Hydroxy-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl)-l-phenoxazin-10- yl-ethanone

66 6-(2-Oxo-2-phenoxazin-10-yl-ethyl)-6,7-dihydro-5H-thieno[2,3-c]pyridin-4- one

67. 2-(4-Hydroxy-2-methyl-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl)-l- phenoxazin- 1 O-yl-ethanone

68. 2-Methyl-6-(2-oxo-2-phenoxazin-10-yl-ethyl)-6,7-dihydro-5H-thieno[2,3- c]pyridin-4-one

69. 2-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-l-phenoxazin-10-yl-ethanone

70. Phenoxazine-10-carboxylic acid [2-(6,7-dihydro~4H-thieno[3,2-c]pyridin~5- yl)-ethyl] -amide

71. 2-(7-Hydroxy-6,7-dihydro-4H-thieno [3,2-c]pyridin-5-yl)- 1 -phenoxazin- 10- yl-ethanone

72. (6,7-Dimethoxy-l -methyl-3,4-dihydro-lH-isoquinolin-2-yl)-acetic acid N⁷, N^diphenylhydrazide 73. (6,7-Dimethoxy-3-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-acetic acid N⁷, N^diphenyl-hydrazide

74. (6,7-Dimeihoxy- 1 -methyl-3,4-dihydro- 1 H-isoquinolin-2-yl)-phenothiazin- 10- yl-methanone

75. (6,7-Dimethoxy-3 -methyl-3 ,4-dihydro- 1 H-isoqumolin-2-yl)-phenothiazin- 10- yl-methanone

76. (6-Hydroxy-7-methoxy- 1 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- phenoxazin- 10-yl-methanone

77. (6,7-Dimethoxy-3 -methyl-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-phenoxazin- 10- yl-methanone and pharmaceutically acceptable salts thereof.

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, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.

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

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

The compounds of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (3) as shown below, wherein R₁, n, m, R₂, R₃ and R₄ are as defined above and X is a leaving group, typically halogen or mesylate.

Typically, the reaction takes place by standard methods such as reaction in the presence of a base, for example potassium carbonate. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at reflux temperature.

Compounds of formula (2) are known compounds, or can be prepared by analogy with known methods. For example, compounds of formula (2) in which m is 2 and Ar is phenyl can be prepared from isoquinolines as shown in scheme 1 below. Scheme 1

In the reaction scheme depicted as scheme 1, compounds of formula (2) may be prepared from compounds of formula (4) by standard methods familiar to those skilled in the art such as hydrogenation in the presence of a catalyst such as platinum oxide. Alternatively, compounds of formula (2) may be prepared from compounds of formula (5) and a carbonyl compound (for example formaldehyde) by standard methods such as the Pictet-Spengler cyclisation.

Compounds of formula (4) are known compounds or may be prepared by standard methods such as sequential imine formation with derivatised amines such as (7) or by cyclisation of compounds of formula (6), according to the general procedure described by Yoshida et ah, Bioorg. Med. Chem. 1999, 7, 2647-2666.

Compounds of formula (II) in which m is 1 and Ar is phenyl can, for example, be prepared according to scheme 2 set out below.

Scheme 2

In the reaction scheme depicted as scheme 2, compounds of formula (II) may be prepared from compounds of formula (9) where X is a leaving group, preferably bromine or chlorine, by standard methods familiar to those skilled in the art such as a dual alkylation in the presence of either ammonia or a derivatised amine, so that the product of the reaction in the latter case can readily be converted into a compound of formula (II).

Compounds of formula (9) are typically prepared from a substance of formula (10) by standard methods familiar to those skilled in the art, such as radical halogenation using N-bromosuccinimide. Compounds of formula (I) can, of course, be prepared directly from compounds of formula (9) where X is a suitable leaving group, with an amine of formula (13).

Compounds of formula (9) can also be prepared by converting the hydroxyl groups of (11) into leaving groups such as a mesylate or tosylate under standard conditions familiar to those skilled in the art. Alcohol (11) may be prepared from acids (12) by standard methods such as reduction in the presence of lithium aluminium hydride. In cases where the groups R₂ and R₃ are carbonyl, a phthalimide derivative is provided, and such compounds of formula (I) can be conveniently prepared by reaction of the diacid (12) either directly with the amine (13) or by an intermediate anhydride, as described by Iwashima, S. et al, Journal of the Chemical Society, Perkin Transactions 1, 1984, 9, 2177-87. Alternative methods suitable for preparing pthalimides corresponding to formula (1) are illustrated in Yoakim, C. et al, Synlett, 2003, 4, A13-A16, Oelgemoller, M. et al, Heterocycles, 2003, 59, 669- 684 and Luzzio, F.A. et al, Tetrahedron Letters, 1999, 40, 2087-2090.

Compounds of formula (I) in which m is 3 can also be prepared, for example, from compounds of formula (15) by reduction in the presence of a metal hydride for example lithium aluminium hydride. An appropriate reaction scheme is shown below.

Scheme 3

Compounds of formula (15) where m is 3 maybe prepared from compounds of formula (16). Compounds of formula (16) may be prepared from tetralones (m = 2) or related compounds by standard methods familiar to those skilled in the art such as the Schmidt reaction. Alternatively, compounds of formula (16) may be prepared from tetralones (17) by standard methods familiar to those skilled in the art such as the Beckman rearrangement of the corresponding oxime or further methods as outlined e.g. in Alicyclic Chemistry (Martin Grossel, Oxford University Press, December 1997, ISBN 0198501048).

Scheme 4 set out below provides an example of an alternative synthetic approach to compounds of formula (I) in which the group R₄ contains a urea or a thiourea moiety.

Scheme 4

RHN-U-CR(A)₂ (20)

In the reaction scheme depicted above, the amine (8) can be reacted with a compound of formula (18), wherein L, l/, R and A are as defined above, Y is sulphur or oxygen and X is a leaving group, typically chlorine. The procedure is typically performed using standard methods such as reaction in the presence of a base, for example potassium carbonate. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of up to 95⁰C.

Alternatively, an isocyanate or isothiocyanate of formula (19), wherein R₁, R₂, R₃, n, m, L and Y are as defined above, can be reacted with an amine of formula (20) where i/, R and A are as defined above, to provide a desired urea or thiourea derivative of formula (I). Typically this reaction would take place in a suitable solvent such as acetone, toluene, tetrahydrofuran or acetonitrile. Further, although the reaction is illustrated in the case of Ar as phenyl, it is, of course, equally applicable to the case of Ar as a heterocycle, such as thiophene, pyrimidine or pyrrole. Scheme 5 shows a further example of known methods for preparing compounds of formula (I) which are phthalimides (R₂ = an oxo functionality) or close analogues (21).

Scheme 5

(22) (21) Ar = phenyl

Li this reaction scheme, a compound of formula (21) can be prepared by reaction of an amide (22) with an alcohol R₄-OH, under Mitsunobu conditions.

A further method for preparing compounds of formula (I) wherein m, n, R₁, R₂ and R₃ are defined as above and R₄ is -CO-NRsR₉ is shown in scheme 6.

(28)

The reaction scheme depicted above involves the reaction of amides (25) and amines (23) where X is a leaving group, preferably chlorine, using standard methods such as reaction in the presence of a base, for example triethylamine. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 8O⁰C. Amides (25) may be prepared from amines (8) and acids (24), wherein X^; is Cl or OH, under standard amide coupling reaction conditions. Typically, where X⁷ is Cl, the reaction is effected in the presence of triethylamine. Alternatively, compounds of formula (I) where R₄ is -CO-NR₈R₉, maybe prepared from amines (2) by standard methods familiar to those skilled in the art, such as acylation with isocyanates (27). An alternative is the reaction of the amine (2) with an acid halide of formula (28).

Compounds of formula (I) in which Ar is a heterocycle can be prepared by analogy with the methods set out above, or by other conventional techniques. One such technique is shown in scheme 7 below.

Scheme 7

Thus, when Ar is thiophene, the method shown in scheme 7 involves the use of a Pictet Spengler reaction, as described for example in Mach, U.R. et al., ChemBioChem, 2004, 5, 508-518, whereby a substituted thiophen-2-yl-ethylamine is reacted with formaldehyde or ethoxymethoxyethane in the presence of a mineral acid such as hydrochloric acid, and a solvent such as 2-propanol or tetrahydrofuran. Compounds in which Ar represents other heteroaryl groups can be prepared by analogous methods, as can compounds in which m (in formula I) is other than 2.

Another example of a method for preparing compounds of formula (II) wherein Ar is a thiophene heterocycle is shown in scheme 8. Scheme 8

This reaction scheme involves a method described by Kikuchi, C. et ah, Bioorganic & Medicinal Chemistry Letters, 2002, 12, 2549-2552, by which a 4-keto piperidine is reacted with phosphorus oxychloride and DMF to provide a formylated intermediate, which is reacted with a substituted thioacetic acid ester to provide a substituted 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine. Once the N-protecting group is removed and the substance decarboxylated, the desired compound of formula (1) can be prepared by reactions described above.

Other methods for preparing the 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine ring system are known to those familiar with the art, and include Warm, A., Heterocycles 1992, 34, 2263-2267 as well as Maffrand, J.P.; Eloy, F. Journal of Heterocyclic Chemistry, 1976, 13, 1347-1349. A further example for preparing compounds of formula (II) in which the fused heterocyclic system is 4,5,6,7-tetrahydrothieno[2,3-c]pyridine is shown in scheme 9.

Scheme 9

This reaction involves the reaction of a 2-formylthiophene with a 2,2- dimethoxyethylamine derivative, as described for example in Maffrand, J.P.; Eloy, F. Journal of Heterocyclic Chemistry, 1976, 13, 1347-1349. Subsequent reduction and hydrolysis yields a compound of formula (28). The starting materials used in the above reaction schemes are known compounds, or may be prepared by analogy with known methods.

As will be evident to those of skill in the art, compounds of formula (II) in which Ar represents a heterocycle other then those depicted in the schemes shown above can also be prepared by known techniques. Examples of suitable techniques include the methods for preparing pyrrolo-fused cyclic amines set out in Haginoya, N. et al, Journal of Medicinal Chemistry, 2004, 47, 5167-5182, the methods for preparing thiazolo-fused cyclic amines set out in WO 04/58728 and WO 00/09480 and the methods for preparing the corresponding pyridine analogues set out in Dukat, M. et al, European Journal of Medicinal Chemistry, 1996, 31, 875-888. The compounds of the invention are found to be inhibitors of sensory neurone specific sodium channels. The compounds of the invention are therefore therapeutically useful. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free. Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer. The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules. Compositions suitable for oral administration may, if required, contain a colouring or flavoring agent. Typically, a said capsule or tablet comprises from 5 to 500 mg, preferably 10 to 500 mg, more preferably 15 to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories. One preferred route of administration is inhalation. The major advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed. Preferred pharmaceutical compositions of the invention therefore include those suitable for inhalation. The present invention also provides an inhalation device containing such a pharmaceutical composition. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler. Typically, said propellant is a fluorocarbon.

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

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

Typically, said inhalation device contains a spacer. A spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device. Spacers with withholding chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended. Another preferred route of administration is intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. Drugs can be delivered nasally in smaller doses than medication delivered in tablet form. By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter-patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses. Thus, the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.

A further preferred route of administration is transdermal administration. The present invention therefore also provides a transdermal patch containing a compound of the invention, or a pharmaceutically acceptable salt thereof. Also preferred is sublingual administration. The present invention therefore also provides a sublingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof.

A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.

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

Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The compounds of the present invention are therapeutically useful in the treatment or prophylaxis of conditions involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone. Said condition may be one of hypersensitivity for example resulting from a concentration of SNS channels at the site of nerve injury or in axons following nerve injury, or may be sensitisation of the neurone for example at sites of inflammation as a result of inflammatory mediators. Said compounds of the invention are therefore most preferred for their use in the treatment or prophylaxis of any condition involving hypersensitivity or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone.

Accordingly, the present invention also provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of a condition involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone, more specifically hypersensitivity of a sensory neurone or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone. Also provided is a method of treating a patient suffering from or susceptible to a condition involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone, more specifically hypersensitivity of a sensory neurone or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The term treatment in this context is deemed to cover any effect from a cure of said condition to alleviation of any or all of the symptoms. The compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence or severity of said conditions.

Specific conditions in which SNS channels are present and believed to be involved include pain, for example chronic and acute pain, hypersensitivity disorders such as bladder dysfunction and bowel disorders which may or may not also have associated pain, and demyelinating diseases.

SNS sodium channels are known to mediate pain transmission. Typically, the compounds of the invention are therefore used as analgesic agents. SNS specific sodium channels have been identified as being particularly important in the transmission of pain signals. The compounds of the invention are accordingly particularly effective in alleviating pain. Typically, therefore, said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain. The compounds of the invention are effective in alleviating both chronic and acute pain. Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease. A discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol.7, p.147. Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system. Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.

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

Examples of bowel disorders which can be treated or prevented with the compounds of the invention include inflammatory bowel syndrome and inflammatory bowel disease, for example Crohn's disease and ulcerative colitis.

Examples of bladder dysfunctions which can be treated or prevented with the compounds of the invention include bladder hyper reflexia and bladder inflammation, for example interstitial cystitis, overactive (or unstable) bladder (OAB), more specifically urinary incontinence, urgency, frequency, urge incontinence and nocturia. The compounds of the invention can also be used to alleviate pain associated with bladder hyper reflexia or bladder inflammation. Examples of demyelinating diseases which can be treated or prevented with the compounds of the invention are those in which SNS channels are known to be expressed by the demyelinated neurones and which may or may not also have associated pain. A specific example of such a demyelinating disease is multiple sclerosis. The compounds of the invention can also be used to alleviate pain associated with demyelinating diseases such as multiple sclerosis.

The compounds of the invention have additional properties as they are capable of inhibiting voltage dependent sodium channels. They can therefore be used, for example, to protect cells against damage or disorders which results from overstimulation of sodium channels. The compounds of the invention are useful in the treatment and prevention of peripheral and central nervous system disorders. They can therefore additionally be used in the treatment or prevention of an affective disorder, an anxiety disorder, a behavioural disorder, a cardiovascular disorder, a central or peripheral nervous system degenerative disorder, a central nervous system injury, a cerebral ischaemia, a chemical injury or substance abuse disorder, a cognitive disorder, an eating disorder, an eye disease, Parkinson's disease or a seizure disorder.

Examples of affective disorders which can be treated or prevented with the compounds of the invention include mood disorders, bipolar disorders (both Type 1 and Type II) such as seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease, schizophrenia, psychotic disorders, mania and paranoia.

Examples of anxiety disorders which can be treated or prevented with the compounds of the invention include generalised anxiety disorder (GAD), panic disorder, panic disorder with agoraphobia, simple (specific) phobias (e. g. arachnophobia, performance anxiety such as public speaking), social phobias, posttraumatic stress disorder, anxiety associated with depression, and obsessive compulsive disorder (OCD). Examples of behavioural disorders which can be treated or prevented with the compounds of the invention include behavioural and psychological signs and symptoms of dementia, age-related behavioural disorders, pervasive development disorders such as autism, Asperger's Syndrome, Retts syndrome and disintegrative disorder, attention deficit disorder, aggressivity, impulse control disorders and personality disorder.

Examples of cardiovascular disorders which can be treated or prevented with the compounds of the invention include cardiac arrthymia, atherosclerosis, cardiac arrest, thrombosis, complications arising from coronary artery bypass surgery, myocardial infarction, reperfusion injury, intermittant claudication, ischaemic retinopathy, angina, pre-eclampsia, hypertension, congestive cardiac failure, restenosis following angioplasty, sepsis and septic shock.

Examples of central and peripheral nervous system degenerative disorders which can be treated or prevented with the compounds of the invention include corticobasal degeneration, disseminated sclerosis, Freidrich's ataxia, motorneurone diseases such as amyotrophic lateral sclerosis and progressive bulbar atrophy, multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathies such as diabetic neuropathy, tabes dorsalis, drug-induced neuropathy and vitamin deficiency, systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy and spasticity.

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

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

Examples of chemical injuries and substance abuse disorders which can be treated or prevented with the compounds of the invention include drug dependence, for example opiate dependence, benzodiazepine addition, amphetamine addiction and cocaine addiction, alcohol dependence, methanol toxicity, carbon monoxide poisoning and butane inhalation.

Examples of cognitive disorders which can be treated or prevented with the compounds of the invention include dementia, Alzheimer Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body Dementia, Senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome and dementia pugilans.

Examples of eating disorders which can be treated or prevented with the compounds of the invention include anorexia nervosa, bulimia, Prader-Willi syndrome and obesity. Examples of eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrhage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, retinal artery occlusion and retinitis.

Examples of Parkinson's diseases which can be treated or prevented with the compounds of the invention include drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese or carbon monoxide poisoning), Dopa-responsive dystonia-Parkinsonism, posttraumatic Parkinson's disease (punch-drunk syndrome), Parkinson's with on-off syndrome, Parkinson's with freezing (end of dose deterioration) and Parkinson's with prominent dyskinesias. Examples of seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonicclonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).

The compounds of the present invention are also useful in the treatment and prevention of tinnitus. A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of body weight, for example 0.01 to 10 mg, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.

Certain compounds of the invention are believed to be novel. The present invention therefore also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, provided that the compound of formula (I) is other than 2-(2-phenoxazin-10-yl-ethyl)-isoindole-l,3-dione. The following Examples illustrate the invention. They do not, however, limit the invention in any way. hi this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting SNS specific sodium channels. A negative result in any one particular assay is not determinative. Examples

Example 1 : l-(2-Chloro-phenothiazm-10-yl)-2-(6,7-dimethoxy-l-methyl-3,4- dihydro-lH-isoquinolin-2-yl)ethanone

A solution of 6,7-dimethoxy-l -methyl- 1,2,3, 4-tetrahydroisoquinoline hydrochloride (79 mg, 0.32 mmol), K₂CO₃ (87mg, 0.62mmol) and tetra-n-butylammonium iodide (Aldrich, 14,077-5) (24mg, O.Oόmmol) in CH₃CN (5 mL) was stirred at room temperature (r.t.) for 30 min. 2-Chloro-l-(2-chlorophenothiazin)-10-yl-ethanone (100 mg, 0.32 mmol) was added and the reaction was heated at reflux for 5 hrs. The reaction mixture was allowed to cool, diluted with CH₃CN (5 mL), and the solids removed by filtration. The solvent was removed in vacuo and the residue purified via flash chromatography eluting with EtOAc/isohexane (1:4) to afford the title compound as a yellow oil.

Yield 100 mg (65%): HPLC retention time, 4.58min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 481 (M + H). ¹H NMR (CDCl₃) δ 7.71-7.68 (IH, d, Ar-H), 7.57-7.57 (IH, d, Ar-H), 7.42-7.40 (IH, d, Ar-H), 7.35- 7.16 (4H, m, Ar-H), 6.53 (IH, s, Ar-H), 6.48 (IH, s, Ar-H), 4.16-4.11 (IH, q, CH), 3.84 (3H, s, -OCH₃), 3.84 (3H, s, -OCH₃), 3.63-3.46 (2H, m, -COCH₂), 3.07-3.00 (IH, m, CH₂), 2.82-2.73 (2H, m, CH₂), 2.55-2.51 (IH, m, CH₂), 1.29-1.25 (3H, t, CH₃)

The following compounds were synthesised according to the method described for Example 1 using the appropriately substituted cyclic amine starting material and alkyl chloride:

The following compound was synthesised according to the method described in Example 1 with the following modification: Et₃N was used as base. For synthesis of Example 70 the starting amine was 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Maffrand, J.P. and Eloy, F., Journal of Heterocyclic Chemistry, (1976), 13, 1347-9.

Example 74: (6,7-Dimethoxy-l-methyl-3,4-dihydro-lH-isoquinoIin-2-yl)- phenothiazin-10-yl-methanone

To a stirred solution of 6,7-dimethoxy-l-methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride (70mg, 0.29mmol) in dichloromethane (5mL) was added phenothiazine-10-carbonyl chloride (75mg , 0.29mmol) and Et₃N (60μl, 0.43mmol) and the reaction stirred at r.t. for 14 hours. The reaction mixture was filtered, concentrated in vacuo and purified via flash chromatography eluting with EtOAc/isohexane (1 :4) to afford the title compound as a white crystalline solid. Yield 90mg (72%) : HPLC retention time, 4.32min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 477 (M + H).

The following compounds were prepared by the method described for Example 74:-

Example 38: 2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid tert-butylamide To a stirred solution of ((3S)-3-(l,2,3,4-tetrahydroisoquinolyl)-N-(^tBu)carboxamide (0.52g, 2.3mmol) and 2-chloro-l-phenoxazin-lO-yl-ethanone (0.65g, 2.5mmol) in CH₃CN was added Et₃N (0.35mL, 2.5mmol) and the reaction heated to reflux for 14 hours. The reaction was allowed to cool, quenched with 5% K₂CO₃ (water) and extracted with ethyl acetate ( 3 x 10OmL). The organic extracts were combined, dried (MgSO₄) and concentrated in vacuo. The residue was purified via flash chromatography eluting with 1.5% methanol/DCM to afford the title compound as a brown foam. Yield 0.85g (83%) : HPLC retention time, 4.54min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 456 (M + H). ¹H NMR (CDCl₃) δ 7.48-7.44 (2H₅ m, Ar-H), 7.38 (IH, bs, Ar-H), 7.27-7.21 (2H, m, Ar-H), 7.19-7.12 (7H, m, Ar-H), 7.06-7.02 (IH, m, -NH), 3.92 (IH, d, -CH₂), 3.86 (IH₅ d, -CH₂), 3.78 (IH, d, -CH₂), 3.07 (IH₅ dd, -CH₂), 1.22 (9H₅ s, -(CH₃)₃). The following compounds were prepared by the method described for Example 38:

Example 72: 5,6-Dichloro-2-(2-oxo-2-phenoxazin-10-yl-ethyl)-isoindole-l,3- dione

A solution of 4,5-dichlorophthalic anhydride (70mg, 0.29mmol) and 2- aminophenoxazin-10-yl-ethanone (63mg, 0.29mmol) in toluene (4mL) was heated to reflux for 4 hours. The reaction was cooled to r.t. and the solvent removed in vacuo. The residue was purified via flash chromatography eluting with 5% EtOAc/isohexane to afford the title compound as a white solid. Yield lOmg (8%) : HPLC retention time, 4.56min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 439 (M + H). ¹H NMR (DMSO) δ 8.23 (2H, s, Ar-H), 7.74-7.72 (2H, m, Ar-H), 7.36-7.28 (4H, m, Ar-H), 7.25-7.21 (2H, m, Ar-H), 4.78 (2H, s, CH₂)

The following compounds were prepared by the method described for Example 72:

Example 62: 2-[2-Oxo-2-(3-phenyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-ethyl]- isoindole-l,3-dione

To a stirred solution of potassium phthalimide (60mg, 0.32mmol) and 2-chloro-l-(3- phenyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-ethanone (102mg, 0.35mmol) in CH₃CN (5 mL) was added Et₃N (50μl, 0.36mmol) and the reaction heated at 8O⁰C for 5 hours. The reaction was cooled to r.t. and concentrated in vacuo. The residue was purified via flash chromatography eluting with 100% DCM to afford the title compound as a white solid. Yield 106mg (82%) : HPLC retention time, 3.99min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 Ld., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 399 (M + H). ¹H NMR (CDCl₃) δ 7.92-7.86 (2H₅ m, Ar-H), 7.77-7.72 (2H, m, Ar-H), 7.54 (IH, bs, Ar-H), 7.35-7.19 (5H, m, Ar-H), 7.08 (IH, dt, Ar-H), 6.95-6.90 (2H, m, Ar-H), 5.95 (IH, bs, -CHAr), 5.01 (IH, bd, -CH2), 4.84 (IH, bd, -CH₂), 4.59-4.52 (2H, m, -CH₂).

The following compounds were prepared by the method described for Example 62:

Example 43: 2-(2-Phenoxazin-10-yl-propyl)-2,3-dihydro-isoindol-l-one

To a solution of l-amino-2- aminophenoxazin-10-yl-propane (144mg, 0.6mmol) in DCE (5mL) was added 2-carboxybenzaldehyde (90mg, 0.6mmol), Et₃N (109μl, 0.78mmol), sodium triacetoxyborohydride (90mg, 0.6mmol) and the reaction stirred at r.t. for 16 hours. The reaction was diluted with DCM (2OmL) then washed with water and 10% aqueous HCl. The organic extracts were combined, dried (MgSO₄) and concentrated in vacuo. The residue was purified via flash chromatography eluting with 40% EtOAc/isohexane to afford the title compound as a beige solid. Yield 90mg (42%): HPLC retention time, 4.15min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 357 (M + H).

The following compounds were prepared by the method described for Example 43 :

Example 47: 2-(2-Phenoxazin-10-yl-ethyl)-isoindole-l,3-dione

To a solution of phthalimide (lOOmg, 0.68mmol), 2-phenoxazin-lO-yl-ethanol (200mg, 0.88mmol) and Ph₃P (250mg, 0.85mmol) in dry THF (1OmL) was added DIAD (187μl, 0.95mmol) at O⁰C. The reaction was allowed to warm to r.t. and stirred for 16 hours. The reaction was concentrated in vacuo and purified via flash chromatography eluting with 10% EtOAc/isohexane to afford the title compound as a yellow solid. Yield 130mg (54%): HPLC retention time, 4.52min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 357 (M + H). ¹H NMR (CDCl₃) δ 7.92-7.90 (2H, m, Ar-H), 7.79-7.77 (2H, m, Ar-H), 6.92-6.85 (4H, m, Ar-H), 6.73-6.66 (4H, m, Ar-H), 4.00-3.95 (2H₅ m, CH₂), 3.80-3.76 (2H, m, CH₂)

The following compound was prepared by the method described for Example 47:

Example 52 : 4-Methoxy-2-(2-phenoxazin-10-yl-propyl)-isoiudole-l,3-dione A solution OfCH₃CN (5 ml) containing 4-hydroxy~2-(2-oxo-2-phenoxazm-10-yl- ethyl)-isoindole-l,3-dione (lOOmg. 0.26mmol), potassium carbonate (54mg, 0.39mmol) and methyl iodide (73mg, 0.52mmol) was stirred at reflux for 5 hours. The reaction was cooled to r.t, filtered, concentrated in vacuo and the residue purified via flash chromatography eluting with 30% EtOAc/isohexane to afford the title compound as a yellow solid. Yield lOOmg (96%): HPLC retention time, 4.39min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 401 (M + H). ¹H NMR (CDCl₃) δ 7.74-7.70 (IH, dd, Ar-H), 7.51-7.49 (IH, d, Ar-H), 7.27-7.25 (IH, d, Ar-H), 7.09-7.06 (2H, dd, Ar-H), 6.97-6.93 (2H, dt, Ar-H), 6.83-6.76 (4H, m, Ar-H), 4.42-4.36 (IH, m, CH), 4.27-4.21 (IH, dd, CH₂), 4.08-4.03 (IH, dd, CH₂), 4.07 (3H, s, OCH₃), 1.47-1.45 (3H, d, CH₃).

The following compound was prepared by the method described for Example 52:

Example 65: 2-(4-Hydroxy-4,7~dihydro-5H~thieno[2,3-c]pyridin-6-yl)-l- phenoxazin-10-yl-ethanone

(2,2-Dimethoxy-ethyl)-thiophen-2-ylmethylamine

A solution of 2-thiophenecarboxaldehyde (Ig, 8.93mmol) and aminoacetaldehyde dimethylacetal (1.4g, 13.4mmol) in DCM (23OmL) was stirred at 35⁰C for 1 h.

Sodium triacetoxyborohydride (5.68g, 27mmol) was added and the reaction stirred at r.t. for 5 hours. NaHCO₃ (saturated solution, 10OmL) was added and the organics were collected, washed (brine), dried (MgSO₄) and concentrated in vacuo. The residue was purified via flash chromatography eluting with 50% EtOAc/isohexane to afford the title compound as a yellow oil. Yield 1.6g (90%): HPLC retention time, 2.76min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 202 (M + H).

4,5,6,7-Tetrahydrothieno[2,3-c]pyridin-4-ol

To a solution of (2,2-dimethoxy-ethyl)-thiophen-2-ylmethylamine (1.6g, 7.96mmol) in dioxane (5mL) was added 6N HCl (solution in dioxane) and the reaction stirred at r.t. for 17 hours. The reaction volume was reduced to 10 mL and the solution dissolved in DCM (5OmL). The mixture was washed with 2N NaOH solution (4OmL), the organic layer was separated, dried (MgSO₄) and concentrated in vacuo. The residue was purified via flash chromatography eluting with 10% methanol/DCM to afford the title compound as an orange solid. Yield 1.17g (70%): HPLC retention time, 1.86min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.).

2-(4-Hydroxy-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl)-l-phenoxazin-10-yl- ethanone

To a solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (935mg, 6mmol) in CH₃CN (3 OmI) was added Et₃N ( 1.7mL 12mmol) followed by 2-chloro- 1 - phenoxazin-10-yl-ethanone (2.35g, 9mmol) and the reaction heated to reflux for 4 hours. The reaction mixture was cooled to r.t. and concentrated in vacuo to afford a brown residue. The residue was partitioned between DCM/Bicarb (10OmL) and the organics collected, washed (brine), dried (MgSO₄) and concentrated in vacuo. The residue was purified via flash chromatography eluting with 20% EtOAc/isohexane to afford the title compound as pale brown solid. Yield 1.4g (62%) : HPLC retention time, 3.84min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 379 (M + H). ¹H NMR (CDCl₃) δ 7.62-7.59 (IH, dd, Ar-H), 7.27-7.24 (IH₅ dd, Ar-H), 7.25-7.22 (2H, m, Ar-H), 7.20-7.13 (5H, m, Ar-H), 7.03- 7.02 (IH, d, Ar-H), 4.63-4.60 (IH, broad d, OH), 4.03-3.99 (IH, d) and 3.75-3.72 (IH, d, AB system, CH₂), 3.84-3.80 (IH, d) and 3.72-3.68 (IH, d) (AB system, CH₂), 3.08-3.04 (IH, dd), 2.96-2.93 (IH, dd, ABX system, CH₂), 2.47-2.44 (IH, broad d, CH).

Example 66: 6-(2-Oxo-2-phenoxazin-10-yl-ethyl)-6,7-dihydro-5H-thieno[2,3- c] pyridin-4-one

To a solution of 2-(4-hydroxy-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl)-l- phenoxazin-10-yl-ethanone (5.4g, 14.27mmol) in DCM (30OmL) was added pyridinium chlorochromate (PCC) (3.6g, 14.27mmol) and the reaction stirred at r.t. for 2 hours. The reaction was filtered through a pad of silica eluting with 50% EtOAc/isohexane. The fractions were combined and concentrated in vacuo. The solid was purified by preparative HPLC chromatography (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-I Omin. Column: Xterra 50 x 19 i.d., Cl 8 reverse phase) to afford the title compound as a beige solid. Yield 0.3 g (6%): HPLC retention time, 3.86min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-OmUi. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 377 (M + H). ¹H NMR (CDCl₃) δ 7.58- 7.56 (2H, m, Ar-H), 7.43-7.42 (IH, d, Ar-H), 7.27-7.23 (3H, m, Ar-H), 7.19-7.15 (5H, m, Ar-H), 4.26 (2H, s, CH₂), 3.74 (2H, s, CH₂), 3.56 (2H, s, CH₂).

The following compound was prepared by the method described for Example 66:

Example 12: l-Benzhydryl-3-[2-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)- ethyl] thiourea

[2-(l-Methyl-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester

A solution of 1,2,3,4-tetrahydro-l-methylisoquinoline (300 mg, 2.04 mmol), K₂CO₃ (564mg, 4.08mmol) and tetrabutylaimnonium iodide (Aldrich, 14,077-5) (151mg, 0.4mmol) in CH₃CN (50 mL) was stirred at r.t. for 30 mins. 2-Boc- aminoethylbromide (457 mg, 2.04 mmol) was added and the reaction was heated at reflux for 17 hrs. The reaction mixture was allowed to cool, diluted with CH₃CN (5 mL), and the solids removed by filtration. The solvent was removed in vacuo and the residue purified via flash chromatography on silica gel, eluting with EtOAc/isohexane (1 :9), to afford the title compound as a white solid. Yield 104mg (18%): HPLC retention time, 4.33min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.).

2-(l-Methyl-3,4-dihydro-lH-isoquinoIin-2-yl)-ethylamine

To a solution of [2-(l-Methyl-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (0.16g, 0.55mmol) in methanol (1OmL) was added 2M HCl (5.5mL Ether) and stirred at r.t. for 2 hours. The reactions mixture was concentrated in vacuo to afford the title compound as a white solid. Yield 82mg (78%): HPLC retention time, 3.54min (Solvent: CH3CN/H₂O/0.05% NH₃, 5-95% gradient H₂O- 6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.).

l-Benzhydryl-3-[2-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-thiourea

To a solution of 2-(l-methyl-3,4-dihydro-lH-isoquinolin-2-yl)ethylamine (76mg, 0.3mmol) in DCM (4mL) was added Et₃N (0.6mmol), benzhydryl isothiocyanante (75mg, 0.33mmol) and the reaction stirred at r.t. for 17 hours. The reaction was concentrated in vacuo and the residue was purified by solid phase extraction (Amberlyst 15) to afford the title compound as a white solid. Yield 88mg (62%): HPLC retention time, 4.61min (Solvent: CH₃CN/H₂O/0.05% NH₃, 5-95% gradient H₂O-6min. Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 416 (M + H).

The following compound was prepared by the method described for Example 12 with the following modification: in the case of Example 71 , phenothiazine- 10- carbonyl chloride was used in place of benzhydryl isothiocyanate.

Biological Screening

Inhibition of Human Na_v1.8 stably expressed in SH-SY-5Y cells

A SH-SY- 5Y neuroblastoma cell line stably expressing the human Nayl .8

(hNaγl.8) ion channel was constructed. This cell line has been used to develop a medium to high throughput assay for determining the ability of test compounds to inhibit membrane depolarisation mediated via the hNayl .8 channel.

SH-SY- 5Y hNaγl.8 are grown in adherent monolayer culture using 50:50 Ham's F-12 / EMEM tissue culture medium supplemented with 15% (v/v) foetal bovine serum; 2mM L-glutamine, 1% NEAA and βOOμg.ml^"1 Geneticin sulphate. Cells are removed from the tissue culture flask using trypsin/EDTA and re-plated into black walled, clear bottom 96-well assay plates at 50,000CeIIs-WeIl^"1 24 hours prior to assay. On the day of assay the cell assay plates are washed to remove cell culture medium using a sodium free assay buffer (145mM tetramethyl ammonium chloride; 2mM calcium chloride; 0.8mM magnesium chloride hexahydrate; 1OmM HEPES; 1OmM glucose; 5mM potassium chloride, pH 7.4). Fluorescent membrane potential dye solution (FLIPR™ membrane potential dye, Molecular Devices Corporation), containing 1 OμM of a pyrethroid to prevent channel inactivation and 25OnM tetrodotoxin (TTX) to reduce interference from TTX-sensitive sodium channels present in the cell line. Test compound, initially dissolved in dimethyl sulfoxide but further diluted in sodium free buffer, is added to achieve the final test concentration range of lOOμM - 0.05 μM. Cell plates are incubated for 30 minutes at room temperature to allow equilibration of dye and test compound. Plates are then transferred to a fluorescence plate reader for fluorescence measurement using an excitation wavelength of 530nm whilst measuring fluorescence emission at 565nm. Baseline fluorescence levels are first determined before the addition of a sodium containing buffer (22OmM sodium chloride; 2mM calcium chloride; 0.8mM magnesium chloride hexahydrate; 1OmM HEPES; 1OmM glucose; 5mM potassium chloride. pH 7.4) to cause membrane depolarisation in those cells where channel block has not been effected (final sodium concentration = 72.5mM). Membrane depolarisation is registered by an increase in fluorescence emission at 565nm.

The change in fluorescence seen in each test well upon the addition of sodium containing buffer is calculated relative to the baseline fluorescence for that well. This figure is then used for calculating the IC₅₀ for each test compound. The results are set out in Tables 1 below.

Claims

1. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body,

wherein:

Ar represents a phenyl ring or a 5- to 6- membered heteroaryl group; n is an integer of from 0 to 3 ; - Each Rl is the same or different and is a hydroxy, amino, halogen, cyano, C₁-

C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, (C₁-C₆ alkyl)amino or di(Ci-C₆ alkyl)amino group or a group selected from; -CO₂R¹⁰, -CON(R¹ ^R¹², -SO₃R¹⁰, -SO₂N(R^{1 J})R¹², -N(R¹ ^R¹², -OSO₂R¹⁰ Where R¹⁰ is hydrogen or C1-C4 alkyl

Where R and R can independently be selected from hydrogen, C₁-C₄ alkyl or taken together as a C₃-C₆ alkyl chain forming a ring, or taken together forms the group

-O^CHrX^CI^CEb-, where X¹ is O, NH OrNCH₃,

Or a group selected from -N(R¹⁰)COR¹⁰, -N(R¹⁰)CON(R¹⁰)R¹⁰, -N(R¹⁰)SO₂R¹⁰

Where R¹⁰ is defined as above or taken together any two R¹⁰ groups form a C₃-C₄ ring forming alkyl chain. Or the group

-X^CH₂VN(R^{1 !})R¹², where w can be 2,3 or 4.

R₂ and R₃ are the same or different and each represent hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, -COR⁷, -CSR⁷, -CO₂R⁷⁷, -CONR⁷⁷R⁷⁷⁷ or oxo, wherein R⁷ represents a C₁-C₆ alkyl group and each R⁷⁷ and R⁷⁷⁷ are the same or different and represent hydrogen or a C₁-C₆ alkyl group, provided that at least one of R₂ and R₃ is other than hydrogen; m is 1, 2 or 3; and - R₄ is either

(a) -L-CR(A)₂ or -L-Het, wherein L is a C₁-C₆ alkylene group, R is hydrogen or a C₁-C₄ alkyl group, each A is the same or different and represents a C₆-C₁O aryl group or a 5- to 10- membered heteroaryl group and Het represents a moiety

C₁-C₄ haloalkylthio, -COR⁷, -CSR⁷, -CO₂R⁷⁷ or -CONR⁷⁷R⁷⁷⁷ wherein R⁷ represents a C₁-C₄ alkyl group and each R and R are the same or different and represent hydrogen or a C₁-C₄ alkyl group, and either (i) R₆ and R₇ are the same or different and represent hydrogen, hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₆-C₁₀ aryl, 5- to 10- membered heteroaryl, -COR⁷, -CSR⁷, -CO₂R⁷⁷ or -CONR⁷⁷R⁷⁷⁷ wherein R⁷, R⁷⁷ and R⁷⁷⁷ are as defined above or (ii) R₆ and R₇, together with the carbon atoms to which they are attached, together form a C₆-C₁₀ aryl or 5- to 10- membered heteroaryl group; (b) -L^CO-NR₈R₉, wherein L⁷ is a direct bond or a C₁-C₆ alkylene group, R₈ is hydrogen, C₁-C₆ alkyl, C₆-C_1O aryl or 5- to 10- membered heteroaryl and R₉ is -L⁷-A, -1/-CR(A)₂, -1/-N(A)₂, -L-Het, -l/-CO-Het or Het⁷, wherein R is hydrogen or C₁-C₄ alkyl, i/, L, A and Het are as defined above and Het⁷ is a moiety Het, as defined above, in which Y is CH;

(c) -L-NR-CO-NR-IZ-CR(A)₂ or -L-NR-CS-NR-L^CR(A)₂, wherein each R is the same or different and represents hydrogen or C₁-C₄ alkyl and L, L⁷ and A are as defined above; or

(d) ~L⁷-CO-Het, wherein L⁷ and Het are as defined above, the said aryl and heteroaryl moieties in the R₄ substituent being unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, (C₁-C₆ alkyl)amino or di(Q- C₆ alkyl)arnino groups.

2. A compound accordingly to claim 1, wherein Ar represents a phenyl or thienyl moiety.

3. A compound according to claim 1 or 2, wherein n is 0, 1 or 2.

4. A compound according to any one of the preceding claims, wherein each R₁ is the same or different and is a hydroxy, amino, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio or C₁-C₄ haloalklthio group.

5. A compound according to claim 4, wherein each R₁ is the same or different and is a C₁-C₂ alkyl, C₁-C₂ haloalkyl, hydroxy, halogen, C₁-C₂ alkoxy or C₁-C₂ haloalkoxy group.

6. A compound according to any one of the preceding claims, wherein m is 1 or 2.

7. A compound according to any one of the preceding claims, wherein R₂ and R₃ are the same or different and each represent hydrogen, halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, -COR⁷, -CO₂R⁷⁷, -CONR⁷⁷R⁷⁷⁷ or oxo, wherein R⁷ represents a C₁- C₄ alkyl group and each R⁷⁷ and R⁷⁷⁷ are the same or different and represent hydrogen or a C₁-C₄ alkyl group, provided that at least one of R₂ and R₃ is other than hydrogen.

8. A compound according to any one of the preceding claims, wherein each L moiety in the R₄ substituent is the same or different and represents a C₁-C₄ alkyl moiety.

9. A compound according to any one of the preceding claims, wherein each L moiety in the R₄ substituent is the same or different and represents a direct bond or a C₁-C₄ alkyl moiety.

10. A compound according to any one of the preceding claims, wherein each A moiety in the R₄ substituent is the same or different and represents a phenyl or 5- to 6- membered heteroaryl group.

11. A compound according to claim 10, wherein each A moiety in the R₄ substituent is a phenyl group.

12. A compound according to any one of the preceding claims, wherein the aryl and heteroaryl moieties in the R₄ substituent are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy and C₁-C₄ haloalkoxy groups.

13. A compound according to any one of the preceding claims, wherein X in the moiety Het is a direct bond, O, S or -S(O)- and/or Y in the moiety Het is a nitrogen atom.

14. A compound according to any one of the preceding claims, wherein p in the moiety Het is 0, 1 or 2.

15. A compound according to any one of the preceding claims, wherein each R₅ in the moiety Het is the same or different and represents halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,

C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ haloalkylthio, -COR⁷, -CO₂R⁷ or -CONR⁷R⁷⁷ wherein R⁷ is a C₁-C₄ alkyl group and R⁷⁷ is hydrogen or a C₁-C₄ alkyl group.

16. A compound according to any one of the preceding claims, wherein when R₆ and R₇ together form an aryl or heteroaryl group they form, together with the carbon atoms to which they are attached, a phenyl or 5- to 6- membered heteroaryl group.

17. A compound according to any one of the preceding claims wherein, when R₆ and R₇ do not together form an aryl or heteroaryl group, they are the same or different and each represent hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenyl, 5- to 6- membered heteroaryl, -CO₂R⁷ or -CONR⁷R⁷⁷ wherein R⁷ represents a C₁-C₄ alkyl group and R⁷⁷ represents hydrogen or a C₁-C₄ alkyl group.

18. A compound according to any one of the preceding claims, wherein R₉ represents -L⁷-A, -1/-CR(A)₂, -N(A)₂, -L-Het, -CO-Het or Het⁷.

19. A compound according to any one of the preceding claims, which is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof,

wherein R₁, n, Ar, R₂, m, R₃, L⁷, R₅, p, R₆ and R₇ are as defined in any one of the preceding claims, and X is O, S or -SO-.

20. A compound according to claim 19 wherein X is O and/or L⁷ is a C₁-C₄ alkylene group.

21. A compound according to any one of the preceding claims, wherein when Ar is a phenyl ring, m is 2 and R₃ is H, R₉ is -L⁷-CR(A)₂, -L-Het, Het⁷ or -L⁷-CO-Het.

22. A compound according to any one of the preceding claims, wherein, when m is 2, R₂ is other than oxo.

23. A pharmaceutical composition comprising a compound of the formula (I), as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

24. A composition according to claim 23 which is a capsule or tablet comprising from from 10 to 500 mg of a compound of the formula (I), as defined in any one of claims 1 to

22, or a pharmaceutically acceptable salt thereof.

25. An inhalation device comprising a pharmaceutical composition according to claim 23.

26. Use of a compound of the formula (I), as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of a condition involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone.

27. Use according to claim 27 wherein the medicament is for use in alleviating pain.

28. A method of treating a patient suffering from or susceptible to a condition as defined in claim 26 or 27, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

29. A compound of formula (I), as defined in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, provided that the compound of formula (I) is other than 2-(2-phenoxazin-l 0-yl-ethyl)-isoindole-l ,3-dione