WO2005000309A2 - Composes chimiques - Google Patents

Composes chimiques Download PDF

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Publication number
WO2005000309A2
WO2005000309A2 PCT/GB2004/002697 GB2004002697W WO2005000309A2 WO 2005000309 A2 WO2005000309 A2 WO 2005000309A2 GB 2004002697 W GB2004002697 W GB 2004002697W WO 2005000309 A2 WO2005000309 A2 WO 2005000309A2
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Prior art keywords
alkyl
group
substituents
formula
phenyl
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PCT/GB2004/002697
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English (en)
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WO2005000309A3 (fr
Inventor
Neil Stuart Jennings
Stephen Stokes
Richard John Hamlyn
David Christopher Tickle
Michael Richard Huckstep
Rosemary Lynch
Lars Jacob Stray Knutsen
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Ionix Pharmaceuticals Limited
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Priority claimed from GB0315140A external-priority patent/GB0315140D0/en
Priority claimed from GB0315139A external-priority patent/GB0315139D0/en
Application filed by Ionix Pharmaceuticals Limited filed Critical Ionix Pharmaceuticals Limited
Publication of WO2005000309A2 publication Critical patent/WO2005000309A2/fr
Publication of WO2005000309A3 publication Critical patent/WO2005000309A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a series of inhibitors of the subtype of mammalian sodium channels known as Na v l .S or sensory neurone specific (SNS) channels.
  • the Na v l.S 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 ⁇ -subunit gene corresponding to this ion channel is referred to as SCN10A.
  • the channel is described in more detail in Akopian et al, (1996), 379, 257-262.
  • the present invention therefore provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition where SNS sodium channels are involved in the underlying mechanism of the disease or in producing symptoms that can be treated separately
  • each Ri is the same or different and represents halogen, C C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio, hydroxy, amino, -C 6 alkylamino or di-(Cj-C 6 alkyl)amino; n is 0, 1, 2 or 3; - Xi represents a direct bond, -L-O-L 7 -, -L-S-L 7 - or -L-NR 7 -L 7 - wherein L and L 7 are the same or different and each represent a direct bond or C ⁇ -C 4 alkylene group and R 7 represents hydrogen or C ⁇ -C alkyl; Ar represents a 5- to 6- membered heteroaryl group or a phenyl group which is optionally fused to a 5- membered heteroaryl group; - X 2 represents a direct bond, -L 7 -O-, -L 77 -S-, L 77 -NR 7 -, -CO-,
  • X 2 is a direct bond and Y is a 5- to 10- membered heteroaryl group which contains 1 or 2 heteroatoms selected from N, O and S, the 5- to 10- membered heteroaryl group is attached via a carbon atom which is not adjacent to a N atom, wherein: the alkyl and alkylene groups and moieties in the substituents X 2 and Y are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, hydroxy, amino, C ⁇ -C alkoxy, C ⁇ -C 4 alkylthio, C ⁇ -C alkylamino and di(C ⁇ -C 4 alkyl)amino substituents; and the phenyl, heteroaryl and heterocyclyl groups in the substituents Ari and Y are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from
  • a compound of the formula (II), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or preparation of a condition where SNS sodium channels are involved in the underlying mechanism of the disease or in producing symptoms that can be treated separately
  • Ri represents hydrogen, C1-C 0 alkyl, C 6 -C ⁇ o aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C 3 -C carbocyclyl group; each R 2 is the same or different and represents C ⁇ -C 6 alkyl, halogen, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkythio, hydroxy, nitro, cyano, amino, (C ⁇ -C 6 alkyl)amino or di-(C ⁇ -C 6 alkylamino; R 3 represents hydrogen, C ⁇ -C 6 alkyl, or together with represents a C 2 -C alkylene group; R_ t represents hydrogen, C ⁇ -C 6 alkyl, C 6 -C ⁇ o aryl, C 3 -C 6 carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(C ⁇ -C 6
  • a C ⁇ -C 6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C 1 -C5 alkyl group or Cj-C 4 alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, -CHEt 2 and -CH 2 CHMe 2 .
  • a C ⁇ -C 4 alkylene group or a C 2 -C 4 alkylene group is a linear or branched alkylene group.
  • a propylene group Preferably it is a propylene group.
  • a C 6 -C ⁇ o aryl group or moiety is typically a phenyl or naphthyl group or moiety.
  • it is a phenyl moiety.
  • a 5- to 10- membered heteroaryl group or moiety 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.
  • heteroatoms for example 1, 2 or 3 heteroatoms, selected from O, S and N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, imidazolyl, triazolyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thiazolyl and pyrazolyl groups.
  • Preferred heteroaryl groups and moieties in the formula (I) are 5- membered rings, for example triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrazolyl and furanyl groups and moieties.
  • thienyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, isoxazolyl and furanyl groups are preferred.
  • a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine or fluorine.
  • a said C ⁇ -C 6 alkoxy group is typically a said C ⁇ -C 6 alkyl group attached to an oxygen atom.
  • a said C ⁇ -C 6 alkylthio group is typically a said C ⁇ -C 6 alkyl group attached to a thio group.
  • a C ⁇ -C 6 haloalkyl group is typically a said CpC 6 alkyl group, for example a C 1 -C 4 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 -CX wherein X is a said halogen atom. Particularly preferred haloalkyl groups are -CF 3 and -CC1 3 . As used herein, a C ⁇ -C 6 haloalkoxy group is typically a said -C ⁇ alkoxy group, for example a C 1 -C 4 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 -OCX 3 wherein X is a said halogen atom.
  • haloalkoxy groups are -OCF 3 and -OCCl .
  • a C ⁇ -C 6 haloalkylthio group is typically a said Ci-C ⁇ alkylthio group, for example a C 1 -C 4 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 -SCX 3 wherein X is a said halogen atom.
  • Particularly preferred haloalkylthio groups are -SCF and
  • a C 3 -C 0 carbocyclyl group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 6 carbon atoms. Preferably it is a saturated group, i.e. a C 3 -C 6 cycloalkyl group. Examples include cyclobutyl, cyclopentyl and cyclohexyl.
  • a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C 5 -C ⁇ o carbocyclic ring, for example a 5- or 6- membered ring, in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • Saturated heterocyclyl groups are preferred.
  • suitable heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, 1,4 dioxanyl and 1,3 dioxolanyl.
  • Piperidyl and morpholinyl groups are preferred.
  • the orientation of the Xi moiety in the formula (I) is such that the right hand side of the depicted moieties is attached to the group Ar.
  • the orientation of the X 2 moiety in the formula (I) is such that the right hand side of the depicted moieties is attached to the group Y.
  • X 2 is -CO 2 - it can represent either a -CO-O- or an -O-CO- moiety.
  • the alkyl and alkylene groups and moieties in the substituents Ri, Xi, X 2 and Y in the formula (I) are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, hydroxy, amino, C ⁇ -C 2 alkoxy, C 1 -C2 alkylthio, C ⁇ -C 2 alkylamino and di(C ⁇ -C 2 alkyl)amino substituents.
  • the alkyl and alkylene groups and moieties in the substituents Ri, Xi, X 2 and Y in the formula (I) are unsubstituted or are substituted by 1 or 2 substituents selected from halogen, hydroxy, C ⁇ -C 2 alkoxy and C ⁇ -C 2 alkylthio substituents. More preferably, the alkyl and alkylene groups and moieties in the substituents Ri, Xi, X 2 and Y in the formula (I) are unsubstituted.
  • a said phenyl, heteroaryl or heterocyclyl group or moiety in the formula (I) carries a nitro, cyano, -CONR 7 R 77 , -S(O) 2 -NR 7 R 77 , -CO 2 R 77 , -S(O) 2 R 77 or phenyl substituent
  • only one of the substituents on the phenyl, heteroaryl or heterocyclyl group or moiety is a nitro, cyano, -CONR'R 77 , -S(O) 2 NR 7 R 77 , -CO 2 R 77 , -S(O) 2 R 77 or phenyl group.
  • phenyl, heteroaryl and heterocyclyl groups and moieties in the substituents Ar and Y in the formula (I) are typically unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, C ⁇ -C 4 alkyl, C ⁇ -C alkoxy, C ⁇ -C 4 alkylthio, hydroxy, -NR R 77 , Q-C 4 haloalkyl, C r C 4 haloalkoxy, C ⁇ -C 4 haloalkylthio, -CONR 7 R 77 and phenyl substituents, wherein R 7 and R 77 are the same or different and each represent hydrogen or C ⁇ -C 4 alkyl.
  • the phenyl, heteroaryl and heterocyclyl groups and moieties in the substituents Ar and Y in the formula (I) are unsubstituted or are substituted by 1 or 2 substituents which are the same or different and are selected from halogen, hydroxy, amino, C ⁇ -C 2 alkyl, C ⁇ -C 2 alkoxy, C ⁇ -C 2 alkylthio, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C 2 haloalkylthio, carbamyl and phenyl substituents.
  • each Ri in the formula (I) is the same or different and represents halogen, C 1 -C4 alkyl, C ⁇ -C 4 alkoxy or C ⁇ -C 4 alkylthio.
  • each Ri in the formula (I) is the same or different and represents halogen or an unsubstituted C 1 -C 2 alkyl, C1-C 2 haloalkyl, C ⁇ -C 2 alkoxy, C1-C 2 haloalkoxy, C 1 -C 2 alkylthio or C 1 -C 2 haloalkylthio group. More preferably, each Ri in the formula (I) is the same or different and is a halogen atom. Typically, n in the formula (I) is 0, 1 or 2. Typically, each L and L 7 moiety in the group in the formula (I) is a direct bond or a methylene or ethylene group.
  • each L and L 7 moiety in the formula (I) is unsubstituted.
  • X ⁇ in the formula (I) is -O- or -S-.
  • X ⁇ in the formula (I) is -L- O- or -L-S- wherein L is a C 1 -C4 alkylene group.
  • Xi in the formula (I) is a direct bond.
  • Xi in the formula (I) is unsubstituted.
  • Xi in the formula (I) is a direct bond, -CH 2 -O- or -O-.
  • X ⁇ in the formula (I) is typically not a direct bond when X 2 is a direct bond.
  • Ar in the formula (I) is a 5- membered heteroaryl group, a phenyl group or a phenyl group fused to a 5- membered heteroaryl group.
  • Ar in the formula (I) is a triazolyl, imidazolyl, phenyl, benzofuranyl, benzothienyl or indolyl group. More preferably, Ar in the formula (I) is phenyl, triazolyl or benzofuranyl.
  • the Ar group in the formula (I) is unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, hydroxy, C 1 -C2 alkyl, C1-C2 haloalkyl, C ⁇ -C 2 alkoxy, C1-C2 haloalkoxy, d- C 2 alkylthio and C 1 -C 2 haloalkylthio substituents.
  • the Ar group in the formula (I) is unsubstituted or substituted by a halogen, C 1 -C2 alkyl or C 1 -C 2 alkoxy substituent.
  • each L 77 moiety in the X 2 group in the formula (I) is a methylene or ethylene group.
  • each L 77 moiety in the formula (I) is unsubstituted.
  • X 2 in the formula (I) represents a direct bond, -L 7 -NR 7 -, -CO-, - S(O)-, -S(O) 2 -, -CO-NH 7 - or -S(O) 2 -NR 7 - wherein L 77 is as defined above and R 7 is hydrogen, methyl or ethyl.
  • X 2 in the formula (I) is unsubstituted.
  • X 2 in the formula (I) is a direct bond, -CH 2 -NH-, -S(O) 2 -NH- or -S(O) 2 -.
  • X 2 in the formula (I) is typically not a direct bond when Xi is a direct bond.
  • X 2 in the formula (I) is not a direct bond when X ⁇ is -O-, -S-, -NR 7 - or a direct bond.
  • L 777 in the Y substituent in the formula (I) is an unsubstituted C ⁇ -C alkylene group.
  • Y in the formula (I) represents -(C ⁇ -C alkyl)-N(C ⁇ -C 4 alkyl) 2 , or a -(C ⁇ -C 4 alkyl)-(5- to 10- membered heteroaryl), -(C ⁇ -C 4 alkyl)-(5- to 10- membered heterocyclyl), -(C ⁇ -C 4 alkyl)-phenyl, phenyl, 5- membered heteroaryl or 5- to 10- membered heterocyclyl group, provided that when Xi is -O-, -S- or -NR 7 -, X 2 is a direct bond and Y is a heteroaryl group which contains 1 or 2 heteroatoms selected from N, O or S, Y is attached via a carbon atom which is not adjacent to a N atom.
  • Y in the formula (I) is a 5- membered heteroaryl group
  • either Xi is -O-CH 2 - or X 2 is other than a direct bond.
  • the phenyl, heteroaryl and heterocyclyl groups and moieties in the Y substituent in the formula (I) are unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, amino, C1-C 2 alkyl, C1-C2 alkoxy, -C 2 alkylthio, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C2 haloalkylthio, carbamyl and phenyl substituents.
  • Y is other than a phenyl substituted thiazolyl group. More typically, in this embodiment, the Y substituent is not substituted by a phenyl group.
  • Preferred compounds of formula (I) are those in which: each Rj is the same or different and represents halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 1 -C 4 alkylthio; n is 0, 1 or 2; - Xi represents a direct bond, -O-, -S-, -L-O- or -L-S- wherein L is a C 1 -C 4 alkylene group; Ar represents a 5- membered heteroaryl group, a phenyl group or a phenyl group fused to a 5- membered heteroaryl group; X 2 represents a direct bond, -L 77 -NR 7 -, -CO-, -S(O)-, -S(O) 2 -
  • X 2 is as defined above; and Y is -(C 1 -C4 alkyl)-N(C ⁇ -C 4 alkyl) 2 or a -(C1-C4 alkyl)-(5- to 6- membered heteroaryl), -(C 1 -C 4 alkyl)-(5- to 10- membered heterocyclyl), 5- membered heteroaryl or 5- to 10- membered heterocyclyl group, provided that when X 2 is a direct bond and Y is a heteroaryl group containing 1 or
  • each Ri in the formula (la) is other than an amino group. More preferably, each Ri in the formula (la) is the same or different and is a halogen atom.
  • n in the formula (la) is 0, 1 or 2.
  • X 2 in the formula (la) is -CH 2 -N ⁇ -, -S(O) 2 -NH- or -S(O) 2 -.
  • each R 2 in the formula (la) is the same or different and is C 1 -C 2 alkyl or C 1 -C 2 alkoxy.
  • m in the fo ⁇ nula (la) is 0 or 1.
  • Y in the formula (la) is -(C ⁇ -C 2 alkyl)-N(C ⁇ -C 2 alkyl) 2 or a -(C C2 alkyl)-(5- to 6- membered heteroaryl), -(C ⁇ -C 2 alkyl)-(5- to 6- membered heterocyclyl), 5- membered heteroaryl or 5- to 6- membered heterocyclyl group, provided that when X 2 is a direct bond and Y is a heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S, Y is attached via a carbon atom which is not adjacent to a nitrogen atom.
  • Y in the formula (la) is -(C ⁇ -C 2 alkyl)-N(C ⁇ -C 2 alkyl) 2 or a triazolyl, pyrazolyl, thiazolyl, thiadiazolyl, piperidyl, -methyl-piperidyl or -methyl-triazolyl group, the triazolyl, pyrazolyl, thiazolyl, thiadiazolyl and piperidyl groups and moieties being unsubstituted or substituted by an amino, C ⁇ -C 2 alkyl, C ⁇ - C 2 alkoxy, C 1 -C 2 alkylthio, carbamyl or phenyl substituent, provided that when Y is a pyrazolyl or thiazolyl group it is attached via a carbon atom which is not adjacent to a nitrogen atom.
  • Y in the formula (la) is not a phenyl substituted thiazolyl group.
  • Ri, R 2 , n, m and X 2 are as defined in the formula (la); and Y is -(C1-C4 alkyl)-N(C,-C 4 alkyl) 2 or a -(C C 4 alkyl)-(5- to 6- membered heteroaryl), -(C 1 -C 4 alkyl)-(5- to 10- membered heterocyclyl), 5- membered heteroaryl or 5- to 10- membered heterocyclyl group, wherein: the alkyl and alkylene groups and moieties in the substituents Ri, R 2 , X 2 and Y are unsubstituted; and the heteroaryl and heterocyclyl groups and moieties in the substituent Y are unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen, hydroxy, amino, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C2 alky
  • each Ri in the formula (lb) is other than an amino group. More preferably, each Ri in the formula (lb) is the same or different and is a halogen atom.
  • n in the formula (lb) is 0, 1 or 2.
  • X 2 in the formula (lb) is
  • each R 2 in the formula (lb) is the same or different and is C1-C2 alkyl or C 1 -C 2 alkoxy.
  • m in the formula (lb) is 0 or 1.
  • Y in the formula (lb) is -(C1-C2 alkyl)-N(C C 2 alkyl) 2 or a -(Q-
  • Y in the formula (lb) is -(C1-C2 alkyl)-N(C ⁇ -C2 alkyl) 2 or a triazolyl, pyrazolyl, thiazolyl, thiadiazolyl, piperidyl, -methyl-piperidyl or -methyl- triazolyl group, the triazolyl, pyrazolyl, thiazolyl, thiadiazolyl and piperidyl groups and moieties being unsubstituted or substituted by an amino, C 1 -C2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, carbamyl or phenyl substituent.
  • Y in the formula (lb) is not a phenyl substituted thiazolyl group.
  • Further preferred compounds of the formula (I) are compounds of formula (I)
  • each Ri in the formula (lc) is the same or different and is a halogen atom.
  • n in the formula (lc) is 0.
  • L in the fo ⁇ nula (lc) is n-butyl or -CH(CH 3 )-.
  • Ar in the formula (lc) is an unsubstituted triazolyl, imidazolyl, phenyl, benzofuranyl, benzothienyl or indolyl group. More preferably, Ar in the formula (lc) is an unsubstituted triazolyl or benzofuranyl group.
  • R 3 in the formula (lc) is a phenyl or 5- membered heteroaryl group which is unsubstituted or substituted by a C 1 -C2 alkyl substituent. More preferably, R 3 is a phenyl or thiazolyl group which is unsubstituted or substituted by a C 1 -C 2 alkyl group. Examples of the particularly preferred compounds of formulae (la), (lb) and (lc) are:
  • the alkyl and alkylene groups and moieties in the substituents Ri to R4 in the formula (II) are unsubstituted or are substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen, hydroxy, amino, Ci- C 2 alkoxy, C1-C2 alkylthio, C 1 -C 2 alkylamino and di(C ⁇ -C 2 alkyl)amino substituents.
  • the alkyl and alkylene groups and moieties in the substituents Ri to R 4 in the formula (II) are unsubstituted or are substituted by 1 or 2 substituents selected from hydroxy, C1-C2 alkoxy and C ⁇ -C 2 alkylthio substituents. More preferably, the alkyl and alkylene groups and moieties in the substituents Ri to R 4 in the formula (II) are unsubstituted.
  • a said aryl, heteroaryl, heterocyclyl or carbocyclyl group or moiety in the formula (II) carries a nitro or cyano substituent, only one of the substituents on the aryl, heteroaryl, heterocyclyl, or carbocyclyl group is a nitro or cyano group.
  • aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Rj, R 4 and Het in the formula (II) are typically unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, C 1 -C 4 alkyl, C1-C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy and C 1 -C 4 haloalkylthio substituents.
  • the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Ri , R 4 and Het in the formula (II) are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, C 1 -C2 alkyl, C 1 -C2 alkoxy, hydroxy, cyano, C1-C2 haloalkyl, C 1 -C 2 haloalkoxy and C 1 -C 2 haloalkylthio substituents.
  • Ri in the formula (II) is hydrogen, C ⁇ -C 6 alkyl, C 6 -C ⁇ 0 aryl, a 5- to 10- membered heteroaryl group or a C 3 -C 6 cycloalkyl group.
  • Ri in the formula (II) is hydrogen, an unsubstituted C ⁇ -C 6 alkyl group, an unsubstituted C 3 -C 6 cycloalkyl group or a C 6 to C 10 aryl or 5- to 10- membered heteroaryl group, which aryl or heteroaryl group is unsubstituted or substituted with 1 , 2 or 3 substituents which are the same or different and are selected from halogen, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C 1 -C0 alkylthio, hydroxy, nitro, cyano, amino, C ⁇ -C 6 alkylamino, di-(C ⁇ -C 6 alkyl)amino, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 haloalkoxy and C ⁇ -C 6 haloalkylthio substituents.
  • Ri in the formula (IT) is hydrogen, an unsubstituted C ⁇ -C 6 alkyl group, an unsubstituted C 3 -C 6 cycloalkyl group or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents, preferably 1 or 2 substituents, selected from halogen, cyano, C1-C2 alkyl, C ⁇ -C 2 alkoxy, C1-C 2 haloalkyl, C 1 -C 2 haloalkoxy and C ⁇ -C 2 haloalkylthio substituents.
  • Ri in the formula (II) is hydrogen, an unsubstituted C 1 -C 4 alkyl group, an unsubstituted cyclohexyl group or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents, preferably 1 or 2 substituents, selected from halogen, cyano, C1-C2 alkoxy, C 1 -C2 haloalkyl, C 1 -C 2 haloalkoxy and C 1 -C 2 haloalkylthio substituents.
  • n in the formula (II) is more than 1
  • not more than one R 2 substituent represents a group selected from nitro and cyano.
  • each R 2 substituent in the formula (II) is the same or different and represents C 1 -C 4 alkyl, halogen, d-C 4 alkoxy, C 1 -C 4 alkylthio, hydroxy, nitro, cyano, amino, (C 1 -C 4 alkyl)amino or di(C ⁇ -C 4 alkyl)amino.
  • the or each R 2 substituent in the formula (II) is unsubstituted.
  • each R 2 substituent in the formula (II) is the same or different and represents halogen, hydroxyl, amino, nitro or an unsubstituted C 1 -C 2 alkyl, C ⁇ -C 2 alkoxy, (C ⁇ -C 2 alkyl)amino or di(C ⁇ -C 2 alkyl)amino group.
  • each R 2 substituent in the formula (II) is the same or different and represents halogen, nitro, or an unsubstituted C1-C 2 alkyl or C1-C2 alkoxy group.
  • n in the formula (II) is 0, 1 or 2.
  • X in the formula (II) represents -CO-, -SO 2 - or -CH 2 -.
  • X in the formula (II) represents -CH 2 -.
  • R in the formula (II) represents hydrogen or -C 4 alkyl or, together with R 4 , represents an unsubstituted C 2 - alkylene group.
  • the R 3 substituent in the formula (II) is unsubstituted. More preferably, R 3 in the formula (II) is hydrogen.
  • R 4 in the formula (II) represents hydrogen, C ⁇ -C 6 alkyl, C 6 -C ⁇ o aryl, C 3 -C 6 carbocyclyl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -(C1-C2 alkyl)-(C 6 -C ⁇ o aryl), -(C ⁇ -C 2 alkyl)-(C 3 -C carbocyclyl), -(C 1 -C 2 alkyl)-(5- to 10- membered heteroaryl), -( -C 2 alkyl)-(5- to 10- membered heterocyclyl) or, together with R , represents a C 2 -C 4 alkylene group.
  • R 4 in the formula (II) represents hydrogen, Cj-C alkyl, phenyl, C 3 -C 6 cycloalkyl, a 5- or 6- membered heteroaryl group, -(C ⁇ -C 2 alkyl)-phenyl or, together with R , represents an unsubstituted C 2 -C 4 alkylene group.
  • the R 4 substituent in the formula (II) is unsubstituted or substituted with 1 or 2 substituents selected from hydroxy, methoxy and methylthio substituents. More preferably, the R4 substituent in the formula (II) is unsubstituted.
  • R 4 in the formula (II) is hydrogen or an unsubstituted C 1 -C 4 alkyl, phenyl or benzyl group.
  • Het in the formula (II) represents a 5- membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S.
  • the Het moiety in the formula (II) is unsubstituted or is substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, C ⁇ -C 4 alkyl, C ⁇ -C alkoxy, C1-C 4 alkylthio, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy and C ⁇ -C 4 haloalkylthio substituents.
  • the Het moiety in the formula (II) is unsubstituted or is substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, C 1 -C 2 alkyl and C 1 -C 2 haloalkyl substituents. More preferably, the Het moiety in the formula (II) is unsubstituted or is substituted by 1 , 2 or 3 substituents which are the same or different and are selected from methyl and ethyl substituents.
  • Het in the formula (II) represents a thiazolyl, oxazolyl, imidazolyl, pyrrolyl, thienyl, pyrazolyl, furanyl or isoxazolyl moiety which is unsubstituted or substituted by 1, 2 or 3 methyl or ethyl substituents.
  • Het in the formula (II) is other than furanyl.
  • Preferred compounds of fo ⁇ nula (II) are those in which: - Ri is hydrogen, C ⁇ -C 6 alkyl, C 6 -C ⁇ o aryl, a 5- to 10- membered heteroaryl group or a C 3 -C 6 cycloalkyl group; n is i, 2, 3 or 4; each R 2 is the same or different and represents C 1 -C 4 alkyl, halogen, C 1 -C 4 alkoxy, C1-C4 alkylthio, hydroxy, nitro, cyano, amino, (C 1 -C 4 alkyl)amino or di(C ⁇ -C 4 alkyl)amino, provided that not more than one R 2 substituent represents a group selected from nitro or cyano; X represents -CH2-, -CO- or -S(O) 2 -; R represents hydrogen or C1-C4 alkyl or, together with R 4 , represents -(CH 2 ) r - wherein r is
  • Ri is hydrogen, an unsubstituted C 1 -C 4 alkyl group, an unsubstituted cyclohexyl group or a phenyl group which is unsubstituted or substituted by 1 , 2 or 3 substituents, preferably 1 or 2 substituents, selected from halogen, cyano, C 1 -C 2 alkoxy, C1-C2 haloalkyl, C1-C2 haloalkoxy and C1-C2 haloalkylthio substituents; each R 2 is the same or different and represents halogen, hydroxyl, amino, nitro or an unsubstituted C1-C2 alkyl, C1-C2 alkoxy, (C1-C2 alkyl)amino or di(C ⁇ -C 2 alkyl)amino group, provided that not more than one R 2 substituent is nitro; R 4 represents hydrogen or an unsubstituted C 1 -C 4 alkyl,
  • each R 2 is the same or different and represents halogen, nitro or an unsubstituted C1-C2 alkyl or d-C 2 alkoxy group, provided that not more than one R 2 substituent is nitro.
  • Examples of the compounds of formula (II) are: (S)-(4-Benzyloxy-benzyl)-[ 1 -(5-methyl-thiazol-2-yl)-ethyl]-amine (S)-3-(4- ⁇ [ 1 -(5-Methyl-thiazol-2-yl)-ethylamino]-methyl ⁇ -phenoxymethyl) benzonitrile
  • 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 p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.
  • the compounds of the invention can contain one or more chiral centre.
  • 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.
  • preferred compounds of formula (I) or formula (II) 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 conventional routes, for example those set out in any of schemes 1 to 4 shown below.
  • Ri, n, Xi, Ar, X 2 and Y are as defined above for the formula (I), unless otherwise indicated.
  • Compounds of formula (1) in which R ls n, Xi and Ar are defined as above and X 2 is CH 2 NH may be prepared from compounds of formula (2) by cyclisation in the presence of an amine, for example hydrazine hydrate.
  • Compounds of formula (2) may be prepared by treating compounds of formula (3), in which n is 1, with diphenyl cyanocarbonimidate.
  • Ar and Y are defined as above and X 2 is -L 7 -NR 7 -, -L -O- or -L 7 -S-, wherein L 77 is a C 1 -C4 alkylene group, may be prepared from compounds of formula (3) in which n is from 1 to 4 and Z is a leaving group, preferably chlorine, and compounds of formula (6) where L is NHR 7 , OH or SH and Y is as defined above, using standard methods familiar to those skilled in the art. Such methods include alkylation in the presence of a base, for example triethylamine.
  • Compounds of formula (3) in which Ar is defined as above and Xi is -L-O- L 7 -, -L-NR 7 -L 7 - or -L-S-L 7 - wherein L 7 is as defined above and L is a C 1 -C 4 alkylene group may be prepared from compounds of formula (4) in which A is -L 7 -OH, -L -SH or -L 7 -NHR 7 and compounds of formula (5) in which L is a C 1 -C 4 alkylene group and B is a leaving group, preferably a halogen such as bromine, by standard methods familiar to those skilled in the art. Such methods include alkylation in the presence of a base.
  • L 7 is as defined above and L represents a direct bond
  • L represents a direct bond
  • compounds of formula (4) where A is -L 7 OH and compounds of formula (5) wherein L is a direct bond and B is OH by standard methods familiar to those skilled in the art. Such methods include the Mitsunobu reaction.
  • compounds may be prepared from compounds of formula (4) where A is -L 7 OH and compounds of formula (5) where L is a direct bond and B is a halogen such a bromine, by standard methods familiar to those skilled in the art.
  • Such methods include ' the Ullman reaction.
  • Compounds of formula (3) in which Ar is defined as above and Xi is -L-S-L 7 - wherein L 7 is as defined above and L represents a direct bond may be prepared from compounds of fo ⁇ nula (4) where A is -L 7 SH and compounds of formula (5) where L is a direct bond and B is a halogen such as bromine, by standard methods familiar to those skilled in the art. Such methods include alkylation as described above.
  • Compounds of formula (3) in which Ar is defined as above and Xi is a direct bond may be prepared from compounds of formula (4) where A is bromine and compounds of formula (5) where B is a boronic acid residue (-B(OH) 2 ), by standard methods familiar to those skilled in the art. Such methods include the Suzuki reaction.
  • Compounds of formulae (4), (5) and (6) are known compounds or may be prepared from known compounds by analogy with known methods.
  • Compounds of formula (1) in which X 2 is -CONR 7 -, -SONR 7 - or -S(O) 2 NR 7 - may be prepared by treating compounds of formula (7), in which X 2 is -CO-, -SO-, or -S(O) 2 - and L is OH or CI, with compounds of formula (9) in which Y is defined as above, under standard amide coupling reaction conditions. Typically, when L is CI, the reaction is effected in the presence of a base such as triethylamine.
  • the compounds of formula (7) are known compounds, or can be prepared from known compounds by analogy with known methods.
  • compounds of formula (7) in which X2 is SO2 and L is CI can be prepared from corresponding compounds of formula (8) in which Z is H, in the presence of chloro sulphonic acid.
  • Compounds of formula (1) in which X 2 is -CO- may be prepared from compounds of formula (8) in which Z is H and compounds of formula (10) where Y is as defined above and A is COC1 by standard methods. Such methods include the Friedel Crafts reaction.
  • Compounds of formula (1) in which X 2 is -CO2- may be prepared from compounds of formula (S) in which Z is OH and compounds of formula (10) in which Y as defined above and A is CO 2 H by standard methods familiar to those skilled in the art.
  • compounds of formula (14) in which Ar is defined as above and Xi is -L-O-L 7 -, -L- NR-L 7 - or -L-S-L 7 - wherein ! is as defined above and L represents a C ⁇ -C 4 alkylene group may be prepared from compounds of formula (13) in which A is L 7 -OH, L -SH or L / NHR / and compounds of formula (5) in which B is a leaving group, preferably a halogen such as bromine, by standard methods familiar to those skilled in the art. Such methods include alkylation in the presence of a base.
  • compounds of formula (1) in which Ri, n, Xi, Ar and Y are as defined above and X 2 is a direct bond can be prepared from compounds of formula (15) and compounds of formula (16), in which B is a boronic acid residue (B(OH) 2 ) by standard methods such as the Suzuki reaction.
  • B is a boronic acid residue
  • Such compounds can also be prepared from compounds of fo ⁇ nula (15) and compounds of formula (16) where L is tributyl tin (Sn(C 4 H 9 ) 3 ) by standard methods. Such methods include the Stille reaction.
  • Compounds of formula (16) in which B is -B(OH) 2 can be prepared from the co ⁇ esponding bromo-substituted compound of formula (17) in the presence of triethylborate ester.
  • Compounds of formula (16) where L is Sn(C 4 H 9 ) 3 can be prepared from the corresponding bromo-substituted compound of formula (17) and tributyl tin chloride in the presence of butyl lithium.
  • Compounds of formula (17) are known compounds or may be produced from known compounds by analogy with known methods. They may, for example, be prepared by processes similar to those set out above for the preparation of compounds of fo ⁇ nula (3). Further, compounds of formulae (13) and (15) are also known compounds or can be prepared by analogy with known methods.
  • Compounds of formula (1) in which Ar is a heterocycle, X2 is CH 2 NH and Y is as defined above may be prepared from compounds of formulae (18) and (19) by standard methods. Such methods include reductive animation in the presence of a reducing agent, for example sodium cyanoborohydride.
  • Compounds of formula (18) in which Ar is as defined above are known compounds or can be prepared from known compounds by analogy with known methods.
  • a compound of formula (18) in which Xi is a direct bond and Ar is 2H-[l,2,3]-triazole may be prepared from compounds of formula (20) as described in M. Journet et al, Tetrahedron Letters, 42, 2001.
  • Compounds of formula (18) in which Ar is defined as above and Xi is -L-O- L 7 -,,-L-NR-L 7 - or -L-S-L 7 - wherein L 7 is as defined above and L is a C ⁇ -C 4 alkylene group, may be prepared from compounds of formula (21) in which A is -L 7 -OH, -L 7 - SH or -LNHR 7 and compounds of formula (5) where B is a leaving group, preferably a halogen such as bromine, by standard methods familiar to those skilled in the art. Such methods include alkylation in the presence of base.
  • Compounds of formula (18) where Ar is defined as above and Xi is -L-NR -L wherein L is as defined above and L represents a direct bond may be prepared from compounds of formula (21) where A is -LNHR 7 and compounds of formula (5) where L is a direct bond and B is bromine, by standard methods familiar to those skilled in the art. Such methods include palladium-mediated cross coupling as per the Buchwald reaction.
  • Compounds of formula (18) in which Ar is defined as above and Xi is -L-O- L 7 wherein L is as defined above and L represents a direct bond may be prepared from compounds of formula.
  • Compounds of formula (IS) in which Ar is defined as above and Xi is a direct bond may be prepared from compounds of formula (21) where A is bromine and compounds of formula (5) where B is a boronic acid residue (-B(OH) 2 ), by standard methods familiar to those skilled in the art. Such methods include the Suzuki reaction.
  • Compounds of formulae (20), (21) and (19) are known compounds or can be prepared by analogy with known methods.
  • compounds of formula (19) in which Y is a heterocycle are known compounds or can be prepared from known compounds by analogy with known methods as described in 'Heterocyclic Chemistry', 4 th Edition, J. A. Joule and K. Mills, Blackwells, Oxford, 2000.
  • the thus obtained compounds of formula (I) may be salified by treatment with an appropriate pharmaceutically acceptable acid or base to form a pharmaceutically acceptable salt, as described above. Racemic mixtures obtained by any of the above processes can be resolved by standard techniques, for example elution on a chiral chromatography column.
  • the compounds of formula (II) may also be prepared by conventional routes, for example those set out in any of schemes A to H shown below. In the reaction schemes shown below, R ls n, R 2 , R 3 , R 4 , X and Het are as defined above for the formula (II), unless otherwise indicated.
  • reaction scheme A Compounds of formula (II) where X is CH 2 and Ri to i and Het are defined as above (reaction scheme A) may be prepared from aldehydes (2) and heterocyclic amines (3) using standard methods such as reductive amination in the presence of a reducing agent, for example sodium cyanoborohydride. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or dichloromethane at room temperature in a "one pot" reaction.
  • Aldehydes (2) are known compounds or can be prepared by analogy with known methods.
  • aldehydes (2) may be prepared by reaction of hydroxybenzaldehydes (4) and compounds of formula (5) in which L is a leaving group, for example chloride, by standard methods familiar to those skilled in the art such as alkylation in the presence of a base.
  • the aldehydes (2) may also be prepared from hydroxybenzaldehydes (4) and compounds of formula (5) in which L is OH converted into a better leaving group by standard methods such as mesylation.
  • aldehydes (2) may be prepared from hydroxybenzaldehydes (4) and compounds of formula (5) in which L is OH by standard methods such as Mitsunobu reaction.
  • Compounds of formula (3) are known compounds, or can be prepared by analogy with known methods. Schemes 2 to 4 detail examples of appropriate synthetic techniques for preparing the compounds of formula (3).
  • Scheme B details an example of the preparation of a heterocyclic amine (3) wherein Het is as depicted above and Z is O or S.
  • X in the formula (7) is of course also O or S.
  • R and R ⁇ . in scheme (B) represent substituents on the Het moiety. Accordingly, they can represent any of the groups mentioned above as appropriate substituents for the moiety Het.
  • the synthesis is effected by analogy with known methods, (see, for example, "Heterocyclic Chemistry", 4 th Edition, J. A. Joule and K. Mills, Blackwells, Oxford, 2000).
  • the heterocyclic amines may be prepared from a ketone (6), where L is a leaving group, preferably bromide, and an amide (7), where X is O or S by standard methods familiar to those skilled in the art.
  • Scheme C details an example of the preparation of a heterocyclic amine (3) wherein Het is as depicted in the formula (3) above and Z is NH, O or S.
  • Such amines may be prepared from amines (8) where P is a protecting group. Examples of suitable protecting groups can be found in 'Protecting Groups' PJ Kocienski, Thieme - Medical Publishers 2000. P is preferably CBz.
  • the amines (3) can be prepared from the amines (8) by cyclisation in the presence of ammonium acetate, acetonitrile or Lawesson's reagent.
  • the amines (8) may be prepared from compounds of formula (9) by standard methods such as oxidation using Dess-Martin periodinane.
  • Compounds of formula (9) may be prepared from amino acids (10) and amino alcohols (11) under suitable standard amide coupling reaction conditions.
  • Heterocyclic amines (3) where Z is substituted N may be prepared from heterocyclic amines (3) where Z is NH by standard methods familiar to those skilled in the art such as alkylation in the presence of a base, for example sodium hydride.
  • Scheme D depicts a further example of an appropriate process for preparing a compound of formula (II) where X is CH 2 , Ri to R 4 are as defined above, Het is as depicted above and Z is O or S.
  • Such compounds may be prepared from compounds of formula (12) and ⁇ -haloketones (6) where L is a leaving group, preferably bromide, by cychsation in the presence of base.
  • the amides (12) may be prepared from compounds of formula (13) and aldehydes (2) by standard methods such as reductive amination using in the presence of a reducing agent.
  • Compounds of formula (II) wherein X is -CH 2 - and Ri to j and Het are defined as above may also be prepared from amides (15) by standard methods such as reduction with borane.
  • Amides (15) may be prepared from heterocyclic amines (3) and compounds with the formula (16), in which Li represents OH or CI, under standard amide coupling reaction conditions. Typically, where Lj is OH, the reaction is effected in the presence of a coupling agent such as EDCHOBT, HATLT or HBTU.
  • the amines (3) are known compounds or can be prepared by analogy with known methods.
  • Compounds with the general formula (16) in which Li is a leaving group, for example a chlorine atom may be prepared by standard methods, such as alkylation of compounds (17) as described previously.
  • Compounds of formula (II) wherein X is CH 2 and ⁇ to Ri and Het are defined as above may also be prepared from alcohols (18) by standard methods such as Mitsunobu reaction in the presence of an appropriate amine.
  • compounds of formula (II) may be prepared from alcohols (18) by standard methods such as converting the alcohol into a better leaving group such as a mesylate followed by alkylation in the presence of the appropriate amine.
  • Alcohols (18) may be prepared from aldehydes (2) by standard methods familiar to those skilled in the art such as reduction in the presence of borane.
  • compounds of formula (II) may be prepared from compounds of formula (19) wherein L is a leaving group, for example chlorine, by standard methods such as alkylation with an appropriate amine. Appropriate reaction conditions for such alkylations are given above.
  • Compounds of formula (19), wherein L is a leaving group may be prepared from alcohols (18) by standard methods such as halogenation in the presence of a thionyl halide for example thionyl chloride.
  • Compounds of formula (II) where X is CH 2 , R 3 is hydrogen, R ⁇ , R 2 and R( are as defined above and Het is as depicted in scheme B may also be prepared from compounds of formula (22), in which A is a direct bond or a Ci-Cs-alkyl group (reaction scheme G).
  • the reaction can be effected by standard methods familiar to those skilled in the art (see for example those set out in reaction scheme 2 for the preparation of compounds of formula (3)).
  • Compounds of formula (22) may be prepared from amines (21) by standard methods such as alkylation with haloacids in the presence of base.
  • Amines of formula (21) may be prepared from nitriles (20) by standard methods such as reduction with borane. The preparation of nitriles (20) is described in the literature.
  • amines (21) may be prepared from alcohols (18) by standard methods such as Mitsunobu reaction with phthalimide followed by deprotection with hydrazine.
  • reaction scheme H Compounds of formula (II) in which X is -CO-, -SO- or -S(O) 2 - and Ri to R and Het are defined as above (reaction scheme H) can be prepared by reacting compounds of formula (23), in which L is OH or CI, with heterocyclic amines (3) under standard amide coupling reaction conditions. Typically, when L is OH, the reaction is effected in the presence of a coupling agent such as EDC/HOBT, HATU or HBTU.
  • the compounds of formula (23) are known compounds, or can be prepared by analogy with known methods. For example, they can be prepared from corresponding compounds of formula (24) by standard methods, such as those set out in reaction scheme 1 for the preparation of compounds of formula (2).
  • the thus obtained compounds of formula (II) may be salified by treatment with an appropriate acid or base. Racemic mixtures obtained by any of the above processes can be resolved by standard techniques, for example elution on a chiral chromatography column.
  • the compounds of the invention are therapeutically useful.
  • the present invention therefore also provides a compound of formula (D or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body
  • each Ri is the same or different and represents halogen, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C alkylthio, hydroxy, amino, C ⁇ -C 6 alkylamino or di-(C ⁇ -C 6 alkyl)amino;
  • - n is 0, 1, 2 or 3;
  • Xi represents a direct bond, -L-O-L 7 -, -L-S-L 7 - or -L-NR 7 -L 7 - wherein L and L 7 are the same or different and each represent a direct bond or C ⁇ -C 4 alkylene group and R 7 represents hydrogen or C ⁇ -C alkyl;
  • Ar represents a 5- to 6- membered heteroaryl group or a phenyl group which is optionally fused to a 5- membered heteroaryl group;
  • X 2 represents a direct bond, -L 7 -O-, -L 7 -S-, L 77 -NR 7 -,
  • each Ri is the same or different and represents halogen, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkylthio, hydroxy, C ⁇ -C 6 alkylamino or di-(C ⁇ -C 6 alkyl)amino; n is 0, 1, 2 or 3;
  • X ⁇ represents a direct bond, -L-O-L 7 -, -L-S-L 7 - or -L-NR 7 -L 7 - wherein L and L 7 are the same or different and each represent a direct bond or C1-C 4 alkylene group and R 7 represents hydrogen or C 1 -C4 alkyl;
  • Ar represents a 5- to 6- membered heteroaryl group or a phenyl group which is optionally fused to a 5- membered heteroaryl group;
  • X 2 represents a direct bond, -L 7 -O-, -L 77 -S-, L 7 -NR 7 -, -
  • Preferred compounds of formulae (Y) and (I") are the same as the preferred compounds of formula (I) set out above.
  • the compound of formula T) or (I") may be a compound of formula (la), (lb) or (lc) as defined above, as long as it is not 4-[4-(benzyloxy)phenyl]-lH-pyrazole.
  • Xi is -O- or
  • Y is other than a phenyl-substituted thiazolyl group. More preferably, Y is other than a phenyl-substituted thiazolyl group whatever X ⁇ represents. Most preferably, Y in the formulae (Y) and (I") is other than a phenyl-substituted heteroaryl group.
  • the present invention also provides a compound of the formula (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body. Further, certain compounds of the formula (II) are believed to be novel.
  • the present invention therefore also provides a compound of formula (II), as defined above, or a pharmaceutically acceptable salt thereof, provided that Het in the formula (II) is other than furanyl.
  • the present invention also provides a pharmaceutical composition comprising (a) a compound of the formula (I'), as defined above, a compound of the formula (II), as defined above, or a pharmaceutically acceptable salt thereof, and (b) 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.
  • 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.
  • 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).
  • MDI metered dose inhaler
  • inhalation devices which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
  • 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.
  • the pharmaceutical compositions of the invention are typically suitable for intranasal administration.
  • 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.
  • 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.
  • 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 sensitization 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 sensitization of a sensory neurone specific (SNS) channel of a sensory neurone.
  • the present invention also provides the use of a compound of formula (I) or (II), 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.
  • SNS sensory neurone specific
  • SNS sensory neurone specific
  • 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.
  • SNS channels Specific conditions in which SNS channels are present and believed to be involved include pain namely chronic or 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.
  • 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.
  • 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 Tlierapy, 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.
  • trigeminal neuralgia a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease
  • diabetic neuropathy causalgia
  • 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.
  • the compounds of the invention can also be used to alleviate pain associated with inflammatory disease or inflammatory bowel syndrome.
  • bladder dysfunctions which can be treated or prevented with the compounds of the invention include bladder hyper reflexia, bladder inflammation, for example interstitial cystitis, overactive (or unstable) bladder (OAB), more specifically urinary incontinence, urgency, frequency, urge incontinence, nocturia and bladder hyper reflexia.
  • the compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.
  • 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 present invention are also useful in the treatment or 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.
  • daily dosage levels are from 5 mg to 2 g.
  • the following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting SNS specific sodium channels. A negative result in any one particular assay is not determinative. EXAMPLES
  • Example 3 (Preparation Example): l-(5-Methyl-4,5-dihydro-oxazol-2-yl)- ethylamine trifluoroactetate
  • reaction mixture was partitioned using diethyl ether (2 x 100 mL) and the organics extracts were combined, washed (brine), dried (magnesium sulphate) and concentrated in vacuo at 20°C.
  • the resulting oil was dissolved in dry methanol (100 mL) and molecular sieves (4A) (5 g) were added.
  • pyruvic aldehyde (40% solution in H 2 O) (0.78 g, 4.3 mL), ammonium acetate (3.3 g, 43 mmol) and the reaction heated to 60°C for 16 hours.
  • Example 26 (S)-(4-Cyclohexylmethoxy-benzyl)-[l-(5-methyl-thiazol-2-yl)- ethyl]-amme (S)-4-(Cyclohexylmethoxy-benzyl)-[l-(5-methyl-thiazol-2-yl)-ethyl]-amine was prepared from 4-cyclohexylmethoxy benzaldehyde and l-(S)-(5-methyl-thiazol-2- yl)-ethylamine hydrochloride salt according to the method described in Example 10 : HPLC retention time, 4.93 min (Solvent: MeCNH 2 O/0.05% NILOH, 5-95% gradient H 2 O - 6 min. Column: Xterra SO x 4.60 mm i.d., CI 8 reverse phase. Flow rate: 1.5 ml/min.). Mass spectrum (ES+) m/z 345 (M + H).
  • Example 42 (S)-[4-(2-Chloro-6-fluoro-benzyIoxy)-2-methoxy-benzyl]-(3- methyl-thiophen-2-ylmethyl)-amine
  • S)-[4-(2-Chloro-6-fluoro-benzyloxy)-2-methoxy-benzyl]-(3-methyl-thiophen-2- ylmethyl)-amine was prepared from 4-(2-chloro-6-fluoro-benzyloxy)-2,-methoxy- benzaldehyde and C-(3-methyl-thiophen-2-yl)-methylamine according to the method described in Example 10 : IH NMR (400 MHz, CDC1 3 ) ⁇ H 2.17 (3H), 3.80-3.90 (7H), 5.21 (2H), 6.54-6.64 (2H), 6.S2 (IH), 7.10-7.20 (3H), 7.24-7.36 (2H). Mass spectrum (ES+) m/z 406 (M + H).
  • Example 60 4-(4-Fluoro-phenoxy)-N-(5-methylsulphanyl-[l,3,4]-thiadiazol-2- yl)-benzenesulfonamide
  • 4-(4-Fluoro-phenoxy)-N-(5-methylsulphanyl-[l,3,4]-thiadiazol-2-yl)- benzenesulfonamide was prepared from 4-(4-fluoro-phenoxy)-benzenesulfonyl chloride (0.23g, 0.79mmol) and 2-amino-5-(methylthio)-l,3,4 thiadiazole (Aldrich, 49,421-6) (0.1 lg, 0.75mmol) according to the method described in example 4 with the following modification.
  • Example 65 3-[4-(2,6-Difluoro-benzyloxy)-3-methoxy-phenyl]-pyrazole-l- carboxylic acid amide
  • SH-SY-5Y neuroblastoma cell line stably expressing the human Na ⁇ l.8 (hNavl.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 hNa ⁇ l .8 channel.
  • SH-SY-5Y hNa ⁇ l.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 ⁇ OO ⁇ g.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 SOjOOOcells.well "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; lOmM HEPES; lOmM glucose; 5mM potassium chloride, pH 7.4).
  • a sodium free assay buffer 145mM tetramethyl ammonium chloride; 2mM calcium chloride; 0.8mM magnesium chloride hexahydrate; lOmM HEPES; lOmM glucose; 5mM potassium chloride, pH 7.4
  • Fluorescent membrane potential dye solution (FLIPRTM membrane potential dye, Molecular Devices Corporation), containing lO ⁇ M of a pyretliroid to prevent channel inactivation and 250nM 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 lOO ⁇ M - 0.05 ⁇ M. 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.
  • 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 IC 5 o for each test compound. The results are set out in the Table below.

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Abstract

L'invention concerne des composés de formules (I) et (II) et des sels associés acceptables pharmaceutiquement, lesdits composés étant des inhibiteurs des canaux de sodium spécifiques des neurones sensoriels. Ces composés sont utilisés en tant qu'agents analgésiques et neuroprotecteurs. Dans la formule (I), R1 représente un substituant organique, X1 et X2 représentent des liaisons directes ou des groupes caractéristiques d'espaceurs, Ar représente un aryle ou un hétéroaryle et Y représente un groupe aminoalkyle substitué ou un groupe caractéristique contenant un hétéroaryle, un hétérocyclyle ou un phényle, et dans la formule (II), R1, R2, R3, Ar et R4 représentent des substituants organiques, X représente un groupe caractéristique d'espaceur et Het représente un groupe hétéroaryle ou hétérocyclyle à 5 éléments.
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