EP1660454A1 - Composes azacycliques convenant comme inhibiteurs des canaux specifiques des neurones sensoriels - Google Patents

Composes azacycliques convenant comme inhibiteurs des canaux specifiques des neurones sensoriels

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Publication number
EP1660454A1
EP1660454A1 EP04743288A EP04743288A EP1660454A1 EP 1660454 A1 EP1660454 A1 EP 1660454A1 EP 04743288 A EP04743288 A EP 04743288A EP 04743288 A EP04743288 A EP 04743288A EP 1660454 A1 EP1660454 A1 EP 1660454A1
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EP
European Patent Office
Prior art keywords
alkyl
dihydro
phenyl
defined above
isoquinolin
Prior art date
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EP04743288A
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German (de)
English (en)
Inventor
Richard John Ionix Pharmaceuticals Ltd. Hamlyn
Michael Richard Ionix Pharm. Ltd Huckstep
Rosemary Ionix Pharmaceuticals Ltd Lynch
Stephen Ionix Pharmaceuticals Ltd Stokes
David Christopher Ionix Pharm. Ltd Tickle
Lee Ionix Pharmaceuticals Ltd Patient
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Vernalis R&D Ltd
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Vernalis R&D Ltd
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Priority claimed from GBGB0315872.2A external-priority patent/GB0315872D0/en
Application filed by Vernalis R&D Ltd filed Critical Vernalis R&D Ltd
Publication of EP1660454A1 publication Critical patent/EP1660454A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/10—Quaternary compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to inhibitors of the subtype of mammalian sodium channels known as Na v 1.8 or sensory neurone specific (SNS) channels.
  • the Na v 1.8 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 ⁇ -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.
  • X is -N- or -CH-; n is from 0 to 3; each Ri is the same or different and is a hydroxy, amino, halogen, C ⁇ -C 6 alkyl, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, - haloalkoxy, C ⁇ -C 6 alkylthio, C ⁇ -C 6 haloalkylthio, (C ⁇ C 6 alkyl)amino or di(C ⁇ -C 6 alkyl)amino group; p is 0 or 1 ; R is cyano, -NR / -CO-(C 1 -C 4 alkyl), -NR-S(O) 2 -(C 1 -C 4 alkyl), -CO 2 H, - S(O) 2 OH, -CO 2 -(C C 4 alkyl), -O-S
  • L is a direct bond or a -C ⁇ alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl moiety and A is Ce- o aryl, C 3 -C 6 carbocyclyl, a 5- to 10- membered heteroaryl group or a 5- to 10- membered heterocyclic group,
  • the compounds of the invention are compounds of formula (I), and pharmaceutically acceptable salts thereof, wherein: X is -N- or -CH-; n is from 0 to 3; p is 0; each R ⁇ is the same or different and is a hydroxy, amino, halogen, C ⁇ -C 6 alkyl, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 haloalkoxy, Ci-C ⁇ alkylthio, C ⁇ -C 6 haloalkylthio, (QC ⁇ alkyl)amino or di(C 1 -C 6 alkyl)amino group; m is 1, 2 or 3; and R is either
  • L is a direct bond or a CrC 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl moiety and A is C ⁇ -Cio aryl, C 3 -C 6 carbocyclyl, a 5- to 10- membered heteroaryl group or a 5- to 10- membered heterocyclic group,
  • a d-C 6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as C 1 -C 4 alkyl group or moiety, for example 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.
  • a C 2 -C 6 alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C 2 -C 4 alkenyl group or moiety, for example ethenyl, propenyl and butenyl.
  • an alkenyl group or moiety is saturated except for one double bond.
  • a divalent alkenyl moiety (or alkenylene moiety) can be attached via the same carbon atoms, via adjacent carbon atoms or via non-adjacent carbon atoms.
  • a C 2 -C 6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, such as a C -C alkynyl group or moiety, for example ethynyl, propynyl and butynyl.
  • a C -C alkynyl group or moiety for example ethynyl, propynyl and butynyl.
  • an alkynyl group or moiety is saturated except for one triple bond.
  • a divalent alkynyl moiety (or alkynylene moiety) can be attached via the same carbon atom, via adjacent carbon atoms or via non-adjacent carbon atoms.
  • a C 6 -do aryl group or moiety is typically a phenyl or naphthyl group or moiety. It is preferably a phenyl group or moiety.
  • 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, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl and pyrazolyl groups.
  • Thienyl, triazolyl, pyridyl, thiazolyl and imidazolyl groups are preferred.
  • Pyrrolyl groups are also preferred.
  • a halogen is typically chlorine, fluorine, bromine or iodine - and is preferably chlorine or fluorine.
  • a said d-C 6 alkoxy group is typically a said d-C 6 alkyl group attached to an oxygen atom.
  • a said d-C 6 alkylthio group is typically a said d-C 6 alkyl group attached to a thio group.
  • a d-d haloalkyl group is typically a said d-C 6 alkyl group, for example a C ⁇ -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 3 wherein X is a said halogen atom.
  • Particularly preferred haloalkyl groups are -CF 3 and -CC1 3 .
  • a d-C 6 haloalkoxy group is typically a said d-C 6 alkoxy group, for example a d-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 -OCCI 3 .
  • a d-C 6 haloalkylthio group is typically a said C ⁇ -C 6 alkylthio group, for example a d-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 wherein X is a said halogen atom.
  • Particularly preferred haloalkylthio groups are -SCF 3 and
  • a C 3 -C 6 carbocyclyl group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring, having from 3 to 6 carbon atoms.
  • 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 -do carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a moiety selected from N, O, S, S(O) and S(O) 2 .
  • Preferably, only one carbon atom is replaced with a -S(O)- or -S(O) 2 - moiety.
  • a 5- to 10- membered heterocyclyl group or moiety is a non-aromatic, saturated or unsaturated d-do carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • Saturated heterocyclyl groups are preferred.
  • suitable " heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, 1,4 dioxanyl, 1,3 dioxolanyl and homopiperidinyl groups.
  • heterocyclyl groups include thiomorpholino, S-oxo-thiomorpholino and S,S-dioxo-thiomorpholino groups.
  • Preferred heterocyclyl groups are piperidinyl, morpholinyl, piperazinyl and homopiperidinyl groups.
  • Further preferred heterocyclyl groups are thiomorpholino, S-oxo-thiomorpholino and S,S-dioxo-thiomorpholino groups.
  • a said aryl, carbocyclyl, heteroaryl or heterocyclyl group is fused to two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl and heteroaryl groups
  • said cyclic moieties are fused directly to the aryl, carbocyclyl, heteroaryl or heterocyclyl group.
  • the two cyclic moieties are not fused together.
  • 1 or 2 of the said substituents on an aryl, heteroaryl, carbocyclyl or heterocyclyl group are selected from -NH-CO-(C 1 -C 4 alkyl), -CO-(C -C 4 alkyl), -CO 2 -(d-C 4 alkyl), 5- or 6- membered heteroaryl, phenyl and -CHPh 2 substituents.
  • the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents R 1 ⁇ R 2 , R 3 and R 4 are 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, hydroxy, amino, (C ⁇ -C 4 alkyl)amino, d-C alkoxy, d-C 4 haloalkyl, C ⁇ -C 4 haloalkoxy, C ⁇ -C 4 alkylthio, d-C 4 haloalkylthio, -NH-CO-(C ⁇ -C 2 alkyl), -CO- (d-C 2 alkyl), -CO 2 -(C !
  • -C 2 alkyl 5- membered heteroaryl, phenyl and -CHPh 2 substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, d-C 2 alkyl groups, d-C 2 alkoxy groups and -NH-CO-(d-C 2 alkyl) groups.
  • substituents are selected from halogen, d-C 4 alkyl, hydroxy, d-C 4 alkoxy, d-C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, d-C 4 haloalkylthio, phenyl and -CHPh 2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms.
  • the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents R 1 ⁇ R 2 , R 3 and R 4 are unsubstituted or are substituted by 1 or 2 substituents which are the same or different and are selected from halogen, d- C alkyl, hydroxy, amino, d-C 2 alkoxy, d-C haloalkyl, d-C 2 haloalkoxy, d-C 2 haloalkylthio, -NH-CO-(d-C 2 alkyl), -CO-(d-C 2 alkyl), -CO 2 -(er-e 2 -alkyl); oxadiazolyl, phenyl and -CHPh 2 substituents, the oxadiazolyl and phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, methyl groups
  • these preferred substituents are selected from halogen, d-d alkyl, hydroxy, d-C 2 alkoxy, d-C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C 2 haloalkylthio, phenyl and -CHPh substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from fluorine and chlorine atoms.
  • X is -CH-.
  • n is 0 or 1.
  • each R ⁇ is the same or different and is a hydroxy, amino, halogen, Cj-C alkyl, d-C haloalkyl, d-C alkoxy, C 2 -C alkenyloxy, C C haloalkoxy, Ci- C 4 alkylthio or d-C 4 haloalkylthio group.
  • each Ri is the same or different and is a hydroxy, halogen, C ⁇ -C 4 alkyl, C 1 -C haloalkyl, d-C alkoxy, C ⁇ -C 4 haloalkoxy, d-C 4 alkylthio or d-C 4 haloalkylthio group.
  • each Ri is the same or different and is C ⁇ -C 2 alkyl, C -C 3 alkenyloxy, amino, hydroxy or C 1 -C 2 alkoxy.
  • each i is the same or different and is Cj-C 2 alkyl, hydroxy or d-C 2 alkoxy.
  • R is cyano, -NH-CO-(C ⁇ -C 4 alkyl), -NH-S(O) 2 -(d-C 4 alkyl), -O-
  • R is cyano, -NH-CO-CH 3 , -NH-S(O) 2 -CH 3 , -O-S(O) 2 -CH 3 , -N-[SO 2 -CH 3 ] 2 or -S(O) 2 OH.
  • p is 0 and Ri is located meta to the fused heterocycle, or on the phenyl carbon atom nearest the N atom.
  • the compound of formula (I) is typically a compound of formula
  • each L moiety in the R substituent is the same or different and represents a direct bond or a d-C 6 alkyl moiety.
  • each L is the same or different and represents a direct bond or a C 1 -C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, for example -CH(CH 3 )- or -CH 2 -CH(CH 3 )-.
  • each L 7 moiety in the R 2 substituent is the same or different and represents a d-d alkyl moiety, preferably a d-C 4 alkyl moiety, for example a methyl, ethyl or propyl moiety, for example -CH(CH 3 )- or -CH 2 -CH(CH 3 )-.
  • each A moiety in the R 2 substituent is the same or different and represents a C -do aryl, C 3 -C 6 cycloalkyl, 5- or 6- membered heterocyclyl or 5- or 6- membered heteroaryl group, which group is (a) unsubstituted or substituted by 1, 2 or 3 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, hydroxy, amino, (C 1 -C 4 alkyl)amino, di(d-C 4 alkyl)amino, C 1 -C4 alkoxy, C ⁇ -C 4 haloalkoxy, C ⁇ -C 4 alkylthio, d-C 4 haloalkylthio, -NH-CO-(d-C 2 alkyl), phenyl and halophenyl substituents and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5-
  • each A moiety in the R 2 substituent is the same or different and represents a C 6 -do aryl, C 3 -C 6 cycloalkyl, 5- or 6- membered heterocyclyl or 5- or 6- membered heteroaryl group, which group is (a) unsubstituted or substituted by 1, 2 or 3 substituents selected from C 1 -C4 alkyl, C 1 -C4 haloalkyl, halogen, hydroxy, d-d alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkylthio, phenyl and halophenyl substituents and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl or heteroaryl groups.
  • each A moiety in the R 2 substituent is typically the same or different and is a phenyl, thienyl, triazolyl, pyridyl, pyrrolyl, pyrrolidinyl, 4-H-pyranyl, cyclopentyl, imidazolyl, thiazolyl or piperidyl group which is (a) unsubstituted or substituted by one or two substituents selected from halogen, d-C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C 2 haloalkylthio, phenyl, d-d alkyl, d-C 2 alkoxy, amino, hydroxy and -NH-CO-(d-C 2 alkyl) groups and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heteroaryl moieties.
  • each A moiety in the R 2 substituent is the same or different and is a phenyl, thienyl, triazolyl, pyridyl, cyclopentyl, imidazolyl, hiazolyl or piperidyl group which is (a) unsubstituted or substituted by one or two substituents selected from halogen, d-C 2 haloalkyl, d-C 2 haloalkoxy, d- haloalkylthio, phenyl, d-d alkyl, d-C 2 alkoxy and hydroxy groups and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heteroaryl moieties.
  • each A moiety in the R 2 substituent is a phenyl, thienyl, triazolyl, pyridyl, fluorenyl, thiazolyl, tetrahydroisoquinolinyl, 9H-carbazolyl, indolinyl, 9H- xanthenyl or benzimidazolyl group, which group is unsubstituted or substituted by one or two substituents selected from halogen, d-C 2 alkyl, hydroxy, amino, d-C 2 alkoxy, d-C 2 haloalkyl, d-C 2 haloalkoxy, d-C 2 haloalkylthio, -NH-CO-CH 3 and phenyl substituents.
  • each A moiety is a phenyl, thienyl, triazolyl, pyridyl, fluorenyl, thiazolyl, tetrahydroisoquinolinyl or benzimidazolyl group, which group is unsubstituted or substituted by one or two substituents selected from halogen, d-d alkyl, hydroxy, d-C 2 alkoxy, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 haloalkoxy, C ⁇ -C haloalkylthio and phenyl substituents.
  • each R substituent in each -CR(A) 2 moiety is the same or different and is hydrogen or methyl.
  • each Het moiety in the R 2 substituent is -O-, -S- or -NR 7 - wherein R 7 is hydrogen, d-C alkyl, phenyl or -(C ⁇ -C alkyl)-phenyl. More preferably, each Het moiety in the R 2 substituent is -O- or -NR 7 - wherein R 7 is hydrogen, C ⁇ -C 4 alkyl or benzyl.
  • the heteroaryl or heterocyclyl group is typically (a) monocyclic, (b) fused to one or two phenyl rings or (c) a morpholino group which is fused to a phenyl ring and to a lH-pyrazolyl group.
  • R 3 and R 4 together with the N atom to which they are attached, form a heterocycle, they form a 5- to 7- membered heterocyclyl group.
  • morpholino thiomorpholino, S-oxo-thiomorpholino, S,S- dioxo-thiomorpholino, pyrrolidinyl, piperazinyl or homopiperidinyl ring which is (a) optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heteroaryl rings, and (b) unsubstituted or substituted by 1 or 2 substituents selected from C 1 -C 4 alkyl, d-C 4 haloalkyl, d-C 4 alkoxy, C 1 -C 4 alkylthio, halogen, phenyl, -CHPh 2 , -CO-(C ⁇ -C 2 alkyl), -CO 2 -(d-C 2 alkyl) arid - to 6- membered ' heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being
  • R 3 and R 4 together with the N atom to which they are attached, form a heterocycle, they form a morpholino, piperazinyl or homopiperidinyl ring which is (a) unsubstituted or substituted by 1 or 2 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, phenyl and -CHPh 2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms and (b) optionally fused to one or two phenyl rings.
  • R 3 represents hydrogen, d-d alkyl, phenyl, -(d-d alkyl)-phenyl or -(d-C 4 alkyl)-CHPh 2 . More typically, when R 3 and R 4 do not together form a heterocycle, R 3 represents hydrogen, C1-C4 alkyl, -(d-C 4 alkyl)-phenyl or -(C1-C4 alkyl)-CHPh 2 .
  • the phenyl moieties in R 3 are unsubstituted or substituted by a hydroxy group. More preferably, R 3 is unsubstituted.
  • R 3 represents hydrogen, d- alkyl or an unsubstituted benzyl, phenyl, hydroxyphenyl or -(C1-C2 alkyl)-CHPh 2 group. Most preferably R 3 represents hydrogen, d- alkyl or an unsubstituted benzyl or -(C ⁇ -C 2 ' alkyl)-CHPh 2 group.
  • R 4 represents d-d alkyl, A, -(d-C 4 alkyl)-A, -(CH 2 ) m -CH(A) 2 , -CH[(CH 2 ) m A] 2 , -(CH 2 ) m -CO-A, -(CH 2 ) m -O-CH(A) 2 , -(CH 2 ) m -S-CH(A) 2 , . -(CH 2 ) m -S(O)-CH(A) 2 , -(CH 2 ) m -S(O) 2 -
  • R 4 represents C 1 -C 4 alkyl, A, -(d-C alkyl)-A, -(CH 2 ) m -CH(A) 2 , -CH[(CH 2 ) m A] 2 or -(CH 2 ) m -CO-A wherein each A is the same or different and is as defined above and m is 0, 1, 2, 3 or 4.
  • the A moieties in the 4 substituent are (a) unsubstituted or substituted by 1 or 2 substituents selected from d-C alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, amino, C ⁇ -C 2 haloalkyl, d-C 2 haloalkoxy and d-C 2 haloalkylthio substituents and (b) monocyclic or fused to 1 or 2 phenyl rings.
  • the A moieties in the R4 substituent are (a) unsubstituted or substituted by 1 or 2 substituents selected ⁇ from d-C alkyl; Cf-C alkoxy, halogen, d-C 2 haloalkyl, d-C 2 haloalkoxy and C ⁇ -C 2 haloalkylthio substituents and (b) monocyclic or fused to 1 or 2 phenyl rings.
  • R- 4 represents C1-C 4 alkyl, fluorenyl, phenyl, pyridyl, -(C 1 -C 4 alkyl)-phenyl, -(C 1 -C 4 alkyl)-(5- to 6- membered heteroaryl), -(CH 2 ) m -(9H-carbazolyl), -(CH 2 ) m -indolinyl, -(CH 2 ) m -(9H-xanthenyl), -(CH 2 ) m -O-CHA 7 A 777 , -(CH 2 ) m -S-CHA 7 A 777 , -(CH 2 ) m -S(O)- CHA /7 A / , -(CH 2 ) m -S(O) 2 -CHA A 777 , -NH-CO-N(phenyl) 2
  • a phenyl ring for example a tetrahydroisoquinoline group
  • the cyclic moieties in said preferred R 4 groups being unsubstituted or substituted by a halogen atom, d-C 2 alkyl, hydroxy, amino or Cj-C 2 alkoxy group.
  • R 4 represents d-C alkyl, fluorenyl, -(d-C alkyl)-phenyl, -(d-d alkyl)-(5- to 6- membered heteroaryl), -(CH 2 ) m -CHA 7 A 777 wherein m is 0, 1, 2 or 3 and A 77 and A 777 are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, -CH[(CH 2 ) n Ph] 2 wherein n is 0, 1 or 2, or -(CH 2 ) p -CO-R wherein p is 1, 2 or 3 and R is a 5- or 6- membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said most preferred R 4 groups being unsubstituted or substituted by a halogen
  • A is monocyclic. More typically, A is a monocyclic phenyl or 5- to 6- membered heteroaryl group.
  • L is d-d alkyl and A is a phenyl or 5- or 6- membered heteroaryl group, which group is unsubstituted or substituted by 1, 2 or 3 substituents selected from C1-C 4 alkyl, C ⁇ -C 4 haloalkyl, halogen, hydroxy, d-C 4 alkoxy, d-C 4 haloalkoxy, d-C alkylthio, d-C 4 haloalkylthio, phenyl and halophenyl substituents.
  • R is defined according to option (a)
  • it is a -(d-C alkyl)- phenyl group, for example benzyl, or a -(C 1 -C 4 alkyl)-(5- to 6- membered heteroaryl) group, for example -CH 2 -thienyl or -CH 2 -triazolyl, the phenyl and heteroaryl
  • R 2 is defined according to option (b), it is -L-CR(A) 2 wherein R and A are as defined above.
  • L is d-C 4 alkyl
  • R is hydrogen or methyl and each A is the same or different and is a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C ⁇ -C 2 haloalkyl, d-C 2 alkyl, -NH-CO-CH 3 and hydroxy substituents.
  • L is d-d alkyl
  • R is hydrogen or methyl and each A is the same or different and is a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, d-C 2 haloalkyl, d-C 2 alkyl and hydroxy substituents.
  • L 7 is C -C alkyl
  • Het is O, NH or -N(benzyl)-
  • L is other than a direct bond. More typically, L is C ⁇ -C 6 alkyl.
  • R 2 when R 2 is defined according to option (d), it is typically -L-CO- NR 3 R More typically, when R 2 is defined according to option (d), R 2 is -(CH 2 ) q - CO-lS ⁇ E-aR- wherein q is from 1 to 4, and is preferably 1 or 2, and R 3 and R 4 are as defined above.
  • R 2 is defined according to option (d), either (i) R 3 and R 4 , together with the N atom to which they are attached, form a 5- to 7- membered heterocyclyl group or (ii) R 3 represents hydrogen, - alkyl, phenyl or -(d-d alkyl)- ⁇ henyl and R 4 represents - alkyl, A, -(C 1 -C 4 alkyl)-A, -(CH 2 ) m -CH(A) 2 , -CH[(CH 2 ) m A] 2 , -(CH 2 ) m -O-CH(A) 2 , -(CH 2 ) m -S-CH(A) 2 , -(CH 2 ) m -S(O)-CH(A) 2 , -(CH 2 ) m -S(O) 2 -CH(A) 2 , -(CH 2 ) m -S(O) 2 -CH(
  • R 2 is defined according to option (d), either (i) R 3 and R 4 , together with the N atom to which they are attached, form a 5- to 7- membered heterocyclyl group or (ii) R 3 represents hydrogen, C1-C4 alkyl or -(C 1 -C 4 alkyl)- phenyl and R- 4 represents d-C alkyl, A, -(d-C alkyl)-A, -(CH 2 ) m -CH(A) 2 or - CH[(CH 2 ) m A] 2 wherein each A is the same or different and is as defined above and m is 0, 1, 2, 3 or 4.
  • -More preferably, when -R 2 is defined according- to option (d) either (i) R 3 -and- • R- 4 , together with the N atom to which they are attached, form a morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, pyrrolidinyl, piperazinyl or homopiperdinyl ring which is (a) optionally fused to 1 or 2 cyclic moieties selected from phenyl rings and 5- to 6- membered heteroaryl rings and (b) unsubstituted or substituted by 1 or 2 substituents selected from d-C 4 alkyl, d-C 4 haloalkyl, d-C 4 alkoxy, d-C alkylthio, halogen, phenyl, -CHPh 2 , -CO-(C ⁇ -C 2 alkyl), -CO 2 -(d-
  • CHA 7/ A 777 -(CH 2 ) m -S(O)-CHA 77 A 777 , -(CH 2 )m-S(O) 2 -CHA 7 A 777 , -NH-CO-N(phenyl) 2 , -N(phenyl) 2 or -A 7 -O-A 777 , wherein m is 0, 1, 2 or 3, A 77 and A 777 are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, and n is 0, 1 or 2, the cyclic moieties in these groups being unsubstituted or substituted by a halogen atom, d-C 2 alkyl, hydroxy, amino or d-C 2 alkoxy group.
  • R is defined according to option (d) either (i) R 3 and R 4 , together with the N atom to which they are attached, form a morpholino, piperazinyl or homopiperdinyl ring which is (a) unsubstituted or substituted by 1 or 2 substituents selected from - alkyl, C1-C4 haloalkyl, halogen, phenyl and -CHPh 2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms and (b) optionally fused to one or two phenyl rings or (ii) R 3 represents hydrogen, d-C 4 alkyl or an unsubstituted benzyl group and R 4 represents C 1 -C 4 alkyl, fluorenyl, -(C 1 -C4 alkyl)-phenyl, -(C ⁇ -C 6 alkyl)-(5- to 6-
  • R 3 and f are n as defined" above.
  • A is a said C 6 -do aryl group.
  • R 2 is defined according to option (f) it is -CO-A 7 .
  • R 2 is defined according to option (f) it is -CO-L-CH(A) 2 or -CO-L- A, wherein L is as defined above and each A is the same or different and is as defined above.
  • R 2 when R 2 is defined according to option (f), it is -CO-CH 2 -CH(R) 2 or -CO-R 7 , wherein each R is the same or different and is a phenyl or halophenyl moiety and R 7 is a benzimidazolyl group.
  • R 2 when R 2 is defined according to option (h), L 7 is d- alkyl.
  • R is H.
  • R3 and R4 together with the N atom to which they are attached, form a phenothiazine or phenoxazine group or (ii) R 3 is hydrogen and R t is -(CH 2 ) m -CHA 7 A 777 or -A 7 -O-A 7 / wherein m is 0, 1, 2 or 3 and A 77 and A 777 are the same or different and each represent phenyl or a 5- to 6-membered heteroaryl group.
  • a 77 and A 777 are both phenyl.
  • Preferred compounds of formula (I) are those in which: X is -N- or -CH-; m is 1, 2 or 3; each Ri is the same or different and is a hydroxy, amino, halogen, d-C 4 alkyl, C 1 -C 4 haloalkyl, d-C 4 alkoxy, C ⁇ -C 4 haloalkoxy, C 2 -C 4 alkenyloxy d-C 4 alkylthio, or d-d haloalkylthio group; p is 0 or 1; R is cyano, -NH-CO-(C ⁇ -C 4 alkyl), -NH-S(O) 2 -(C C 4 alkyl), -O-S(O) 2 -(d- C 4 alkyl), -S(O) 2 -OH or -N[S(O) 2 -(d-C 4 alkyl] 2 ; and - R 2 is either
  • a 7 or -CS-A 7 is a said d-Cio aryl group.
  • Further preferred compounds of formula (I) are those in which X is -CH-; - p is 0; _ • ⁇ m is 1, 2 or 3; each Ri is the same or different and is a hydroxy, halogen, C 1 -C 4 alkyl, d- haloalkyl, d-d alkoxy, C 1 -C 4 haloalkoxy, d-d alkylthio, or d-d haloalkylthio group; and - R 2 is either
  • L is a direct bond or a C ⁇ -C 6 alkyl moiety and A is a C 6 -do aryl, d-C 6 cycloalkyl, 5- or 6- membered heterocyclyl or 5- or 6- membered heteroaryl group
  • -L-CR(A) 2 or -L-CH C(A) 2 wherein R is hydrogen or d-C 4 alkyl
  • L is as defined above and each A is the same or different and is as defined above
  • R 3 represents hydrogen, d-d alkyl, -(C 1 -C 4 alkyl)-phenyl or -(C1-C4 alkyl)-CHPh 2 and R4 represents d-d alkyl, A, -(d-C 4 alkyl)-A, -(CH 2 ) m -CH(A) 2 , -CH[(CH 2 ) m A] 2 or -(CH 2 ) m -CO- A wherein each A is the same or different and is as defined above and m is 0, 1, 2, 3 or 4,
  • More preferred compounds of formula (I) are compounds wherein: X is -N- or -CH-; - n is O or l; each Rj is the same or different and is d-C 2 alkyl, hydroxy or d-C 2 alkoxy; p is 0 or 1 ; Ri 7 is cyano, -NH-CO-CH3, -NH-S(O) 2 -CH 3 , -O-S(O) 2 -CH 3 , -N[SO -CH 3 ] 2 or -S(O) 2 -OH; - m is 1, 2 or 3; and R is either
  • L represents a direct bond or a C 1 -C4 alkyl moiety, for example a methyl, ethyl or propyl moiety
  • A is a phenyl, thienyl, triazolyl, pyridyl, fluorenyl, thiazolyl, tetrahydroisoquinolinyl, 9H-carbazolyl, indolinyl, 9H- xanthenyl or benzimidazolyl group, which group is unsubstituted or ' " substituted ' by one.
  • Phenothiazine-10-carboxylic acid [2-(8-hydroxy-3 ,4-dihydro- lH-isoquinolin-2- yl)-ethyl]-amide
  • Phenothiazine-10-carboxylic acid [2-(6,7-dimethoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide 162. Phenothiazine-10-carboxylic acid [2-(8-methoxy-3,4-dihydro-lH-isoquinolin- 2-yl)-ethyl]-amide
  • 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 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.
  • 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) 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 10 shown below.
  • Compounds of formula (1) in which m is 2 and X, Rj, n and R are defined as above (reaction scheme 1) maybe prepared from compounds of formula (2) and compounds of formula (3) where X is a leaving group, typically chlorine, using standard methods such as reaction in the presence of a base, for example potassium carbonate.
  • Compounds of formula (2) may be prepared from compounds of formula (4) by standard methods familiar to those skilled in the art such as reduction in the presence of platinum oxide. -Alternatively, compounds of formula (2) may be prepared from compounds of formula (5) and 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 cyclisation of compounds of formula (6) according to the published procedure (Bioorg. Med. Chem. 7 (1999) 2647-2666).
  • Compounds of formula (1) in which m is 1 and X, Rj, n and R 2 are defined as above may be prepared from compounds of formula (2) and compounds of formula (3) where X is a leaving group, typically chlorine, 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 95°C.
  • Compounds of formula (2) may be prepared from compounds of formula (7) where X is a leaving group, preferably bromine, by standard methods familiar to those skilled in the art such as alkylation in the presence of an amine.
  • compounds of formula (2) can be prepared from compounds of formula (7) where X is OH converted into a better leaving group such as a mesylate under standard alkylating conditions familiar to those skilled in the art.
  • Compounds of formula (7) may be prepared from dimethylaryl compounds (8) by bromination using a brominating reagent, for example N-bromosuccinimide.
  • -Alcohols (9) may be prepared from acids (10) by standard methods such as reduction in the presence of lithium aluminium hydride.
  • Compounds of formula (I) in which hi is 3 and X, Ri, n and R are defined as above may be prepared from compounds of formula (2) and compounds of formula (3) where X is a leaving group, typically chlorine, 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 95°C.
  • Compounds of formula (2) where m is 3 may be prepared from compounds of formula (11 ) by reduction in the presence of a metal hydride for example lithium aluminium hydride.
  • Compounds of formula (11) may be prepared from tetralones (12) by standard methods familiar to those skilled in the art such as the Schmidt reaction.
  • compounds of formula (11) may be prepared from tetralones (12) by standard methods familiar to those skilled in the art such as the Beckmann rearrangement or further methods as outlined e.g. in Alicyclic Chemistry, (Martin Grossel, Oxford University Press).
  • Tetralones (12) are either known compounds or can be prepared by analogy with known methods.
  • R 2 is -L-A and L is other than a direct bond, or when R 2 is -L-CR(A) 2 , the reaction between the compounds of formulae (2) and (3) in schemes 1, 2 and 3 is typically performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 80°C.
  • R 2 is -L-A and L is a direct bond
  • the reaction between the compounds of formulae (2) and (3) is typically effected by Buchwald coupling.
  • X in the formula (3) is typically bromine or iodine.
  • the compounds of formula (3) are known compounds, or may be prepared by known methods.
  • compounds of formula (3) in which R 2 is -(CH 2 ) 2 - CH(A) 2 can be prepared by the reduction of compounds of formula (14) in the presence of a reducing agent such as lithium aluminium hydride followed by halogenation in the presence of a halogenating agent such as PBr 3 (reaction scheme 4).
  • a reducing agent such as lithium aluminium hydride
  • a halogenating agent such as PBr 3
  • Compounds of formula (14) may be prepared from diarylethenylacids (15) by reduction in the presence of a reducing agent such as palladium.
  • Diarylethenylacids may be prepared from ketones (16) by standard methods familiar to those skilled in the art such as Wittig reaction. Scheme 4
  • R 2 is -L-CO-NR3R 4
  • the reaction between the compounds of formulae (2) and (3) in schemes 1 to 3 is typically effected in the presence of a base for example triethylamine.
  • a base for example triethylamine.
  • the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 80°C.
  • - - compounds of formula (1) wherein R 2 is -L-CS-NR 3 R- ⁇ may be prepared from compounds of formula (1) where R 2 is -L-CO-NR 3 R 4 by standard methods familiar to those skilled in the art such as sulphonation in the presence of Lawesson's reagent.
  • a further method for preparing compounds of formula (1) wherein X, m, Ri and n are defined as above and R 2 is -CO-L-N B involves the reaction of amides (24) and amines (22) where X is a leavmg group, preferably chlorine, using standard methods such as reaction in the presence of a base for example triethylamine (reaction scheme 8). Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 80°C.
  • Amides (24) may be prepared from amines (2) and acids (23), wherein X 7 is Cl or OH, under standard amide coupling reaction conditions.
  • R 2 is -CO- A 7
  • the reaction between the compounds of formulae (2) and (3) in schemes 1 , 2 and 3 is typically effected in the presence of a coupling agent such as EDC/HOBT, HATU or HBTU.
  • a coupling agent such as EDC/HOBT, HATU or HBTU.
  • Compounds of formula (1) wherein R 2 is -CS-A 7 can, of course, be prepared from compounds of formula (1) where R 2 is -CO- A 7 by standard methods familiar to those skilled in the art such as reaction with Lawesson's reagent.
  • reaction scheme 9 X and X 7 represent leaving groups, for example chlorine.
  • Compounds of formulae (31) and (31 a) may be prepared from amines (2) and compounds of formulae (30) or (30a) under standard amide coupling conditions as previously described.
  • the compounds ofthe invention are found to be inhibitors of sensory neurone specific sodium channels.
  • the compounds ofthe invention are therefore therapeutically useful.
  • the present invention provides a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment ofthe human or animal body.
  • a pharmaceutical composition comprising a compound ofthe 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 ofthe invention. More typically, it contains up to 50 wt% of a compound ofthe invention.
  • Preferred pharmaceutical compositions are sterile and pyrogen free.
  • compositions provided by the invention typically contain a compound ofthe invention which is a substantially pure optical isomer.
  • the compounds ofthe 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 ofthe 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 ofthe invention may also be admimstered 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 ofthe invention therefore include those suitable for inhalation.
  • the present invention also provides an inhalation device containing such a pharmaceutical composition.
  • said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out ofthe 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 ofthe invention without a propellant.
  • 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'ch ' ambers 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. 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 ofthe invention, or a pharmaceutically acceptable salt thereof. Also preferred is sublingual administration.
  • the present invention therefore also provides a sub- lingual tablet comprising a compound ofthe invention or a pharmaceutically acceptable salt thereof.
  • a compound ofthe 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.
  • 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
  • dyesruffs effervescing mixtures
  • sweeteners effervesc
  • 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 ofthe 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.
  • SNS sensory neurone specific
  • 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 ofthe neurone for example at sites of inflammation as a result of inflammatory mediators.
  • Said compounds ofthe 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.
  • SNS sensory neurone specific
  • 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.
  • 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 ofthe symptoms.
  • the compounds ofthe invention may, where appropriate, be used prophylactically to reduce the incidence or severity of said conditions.
  • 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.
  • the compounds ofthe 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 ofthe 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 ofthe 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, Nol.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 ofthe 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 ofthe nociceptive pain system.
  • Examples of chronic pains which can be alleviated with the compounds ofthe 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 HIN, 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 causalgi
  • neurogenic pain Some ofthe 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 neuro genie pain is pain caused by dysfunction ofthe peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease.
  • the compounds ofthe invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain
  • bowel disorders which can be treated or prevented with the compounds ofthe invention include inflammatory bowel syndrome and inflammatory bowel disease, for example Crohn's disease and ulcerative colitis.
  • bladder dysfunctions which can be treated or prevented with the compounds ofthe 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 ofthe invention can also be used to alleviate pain associated with bladder hyper reflexia or bladder inflammation.
  • demyelinating diseases which can be treated or prevented with the compounds ofthe 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 ofthe 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 overstimulatibn of sodium channels:
  • the compounds ofthe 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.
  • affective disorders which can be treated or prevented with the compounds ofthe 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.
  • anxiety disorders which can be treated or prevented with the compounds ofthe 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, post- traumatic stress disorder, anxiety associated with depression, and obsessive compulsive disorder (OCD).
  • GAD generalised anxiety disorder
  • panic disorder panic disorder with agoraphobia
  • simple (specific) phobias e. g. arachnophobia, performance anxiety such as public speaking
  • social phobias e. g. arachnophobia, post- traumatic stress disorder
  • anxiety associated with depression e.g. arachnophobia
  • OCD
  • behavioural disorders which can be treated or prevented with the compounds ofthe 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.
  • cardiovascular disorders which can be treated or prevented with the compounds ofthe 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 ofthe invention include corticobasal degeneration, disseminated sclerosis, Freidrich's ataxia, m ⁇ tomeufone 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 ofthe 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 ofthe invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorfhagic 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 ofthe 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 ofthe 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 ofthe invention include anorexia nervosa, bulimia, Prader-Willi syndrome and obesity.
  • Examples of eye diseases which can be treated or prevented with the compounds ofthe 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.
  • Parkinson's diseases which can be treated or prevented with the compounds ofthe 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.
  • poisoning for example MPTP, manganese or carbon monoxide poisoning
  • Dopa-responsive dystonia-Parkinsonism for example MPTP, manganese or carbon monoxide poisoning
  • posttraumatic Parkinson's disease punch-drunk syndrome
  • Parkinson's with on-off syndrome Parkinson's with freezing (end of dose deterioration)
  • Parkinson's with prominent dyskinesias include drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example
  • Examples of seizure disorders which can be treated or prevented with the compounds ofthe 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 ofthe present invention are also useful in the treatment and prevention of tinnitus.
  • a therapeutically effective amount of a compound of he 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 ofthe specific, compound, the age, weight and conditions ofthe subject to be treated, the type and severity ofthe disease and the frequency and route of administration.
  • daily dosage levels are from 5 mg to 2 g.
  • Example 60 The HPLC analysis of Example 60 was conducted in the following manner: Solvent: MeCN/H 2 O/0.05% NH 3 , 5-95% gradient H 2 O-10min; Column: Xterra 50 x 4.60 i.d., C18 reverse phase; and Flow rate: 1.5mL/min.
  • reaction mixture was heated at 95°C for 7h and cooled to roorh temperature, 'filtered " and the solvent removed in vacuo
  • the residue was dissolved in CH 2 C1 2 (80mL), washed with H 2 O (25mL), dried (Na 2 SO 4 ) and the solvent remove in vacuo .
  • Example 10 2-[4,4-Bis-(4-fluoro-phenyl)-butyl]-8-methoxy-l,2,3,4-tetrahydro- isoquinoline Prepared according to the method described in Example 8. HPLC retention time 8.39min. Mass Spectrum (ES+) m/z 408(M+H).
  • Example 20 N-(9H-Fluorenyl-9-yl)-2-(8-methoxy-3,4-dihydro-lH-isoquinoline- 2-yl)-acetamide Prepared according to the method described in Example 14. HPLC retention time 4.20min. Mass Spectrum (ES+) m z 385(M+H).
  • Example 33 l-(3,4-Dihydro-lH-isoquinoUn-2-yl)-2-[[2-(3,4-dihydro-lH- isoquinolin-2-yl)-2-oxo-ethyl]-(3,3-diphenyl-propyl)-amino]-ethanone
  • Example 34 l-(3,4-Dihydro-lH-isoquinoIin-2-y ⁇ )-2-(3,3-diphe- ⁇ yl-propyIamino)- ethanone
  • Example 36 2- ⁇ (2,2-Diphenyl-ethyl)-[2-8-methoxy-3,4-dihydro-lH-isoquinolin- 2-yl)-2-oxo-ethyl]-amino ⁇ -lH-isoquinolin-2yl)-ethanone
  • Example 37 2- ⁇ Benzhydryl-[2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-2- oxo-ethyl]-amino ⁇ -l-(8-methoxy-3,4-dihydro-lH-isoquinoli- ⁇ -2-yl)-etl ⁇ a ⁇ one
  • Example 39 2-(2,2-Diphenyl-ethylamino)-l-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 31. HPLC retention time 6.65min. Mass Spectrum (ES+) m/z 401 (M+H).
  • reaction mixture was stirred for a further 0.5h and quenched by pouring into a rapidly stirred biphasi solution of 15% potassium dihydrogen phosphate (150 mL) and methyl tert-butyl ether (160 mL). The organic layer was separated and washed with H O (2 xlOO mL).
  • Example 52 8-Methoxy-3,4-dihydro-lH-isoquinolin-2-carbothioic " acid (2,2- diphenyl-ethyl)-amide
  • Example 56 Example 2: N-Benzhydryl-2 ⁇ (4-methoxy-l,3-dihydro-isoindol-2- yl)-acetamide
  • Example 60 2-(3,4-Dihydro-lH-isoquinolm-2-yl)-N-(2,2-diphenyl-ethyl)- acetamide Prepared according to the method described in Example 56. HPLC retention time 6.71min. Mass spectrum (ES+) m/z 371 (M + H).
  • Example 62 l-(4-benzhydryI-piperazin-l-yI)-2-(8-methoxy ⁇ 3 ? 4-dihydro-lH- isoquinolin-2-yl)-ethanone l-(4-Benzhydryl-piperazin-l-yl)-2-chloro-ethanone: '
  • Example 63 l- ⁇ 4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-l-yl ⁇ -2-(8-methoxy- 3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
  • Example 64 l-(4-Benzhydryl-piperazin-l-yl)-2-(3,4-dihydro-lH-isoquinolin-2- yl)-ethanone
  • Example 65 l- ⁇ 4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-l-yI ⁇ -2-(3,4-dihydro- lH-isoquinolin-2-yl)-ethanone
  • Example 68 l- ⁇ 4-[Bis-(4-fluoro-phenyl)-methyl]-piperazm-l-yl ⁇ -2-(l,3-dihydro- isoindol-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time - -4:5-2min. IH NMR (400 MHz (CD 3 ) 2 SO)D H 2:20-2.25 (4H),3.40-3.55-(6H), 3.90" (4H), 4.40 (IH), 7.05-7.20 (8H), 7.35-7.45 (4H). Mass spectrum (ES+) m/z 448 (M + H). ' Example 69: 2-(8-methoxy-3 5 4-dihydro-lH-isoquinolin-2-yl)-N-(phenyl-pyridin- 2-yl-methyl)-acetamide
  • Example 70 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(3-phenyl-2,3- dihydro-benzo[l,4]oxazin-4-yI)-ethanone
  • Example 74 N,N-Dibenzyl-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide Prepared according to the method described in Example 56. HPLC retention time 4.57min. Mass spectrum (ES+) m/z 401 (M + H).
  • Example 79 2-[3-(2,2-Diphenyl-vinyloxy)-propyl]-8-methoxy-l,2,3,4- tetrahydro-isoqumoline l-(3-Bromopropyloxy)-2,2-diphenylethene:
  • Example 82 N-(3,3-Diphenyl-propyl)2-(7-methoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl)-acetamide Prepared according to the method described in Example 56. HPLC retention time 4.47min. Mass spectrum (ES+) m/z 429 (M + H).
  • Phosphorous pentoxide (Fisher, P/3000/53) (14.2g, 50mmol) was added in portions to methanesulphonic acid (Avocado, 13565) (25mL), and the mixture was heated to 130°C [2-(4-Methoxy-phenyl)-ethyl]-carbamic acid methyl ester (5.23g, 25mmol) was added in portions and the mixture was heated at 140°C for a further lhr. The reaction was allowed to cool to ca.80°C and it was carefully added to ice with rapid stirring.
  • Lithium aluminium hydride 1.0M solution in THF (Aldrich, 21,277-6) (0.42mL, 0.42mmol) was added drop wise to N,N-Dibenzyl-2-(7-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide (140mg, 0.35mmol). After addition the reaction was refluxed for 3hrs. The reaction was cooled to 0°C and quenched by the careful addition of deionised H 2 O (lmL), 10% NaOH solution (lmL) and deionised H 2 O (3mL).
  • Example 102 2-(l ,3-Dihydro-isoindol-2-yl)-N-(3,3-diphenyl-propyl)acetamide
  • Example 104 2-(8-AHyIoxy-3,4-dihydro-lH-isoqumolra-2-yl)-N-(3,3-diphenyl- propyl)acetamide
  • Example 106 2-(4-Amino-l,3-dihydro-isoindol-2-yl)-N-(3,3-diphenyl- propyl)acetamide Prepared according to the method described in Example 14. HPLC retention time 4.02min. Mass Spectrum (ES+) m/z 386(M+H).
  • N-[2-(Diphenylmethanesulphinyl)-ethyl]-2-(8-methoxy-3,4-dihydro-lH-isoquinolin- 2-yl)acetamide was prepared from N-(2-benzhydrylsulphanyl-ethyl)-2-(8-methoxy- 3,4-dihydro-lH-isoquinolin-2-yl)acetamide (leq) and mCPBA (leq) in CH 2 C1 2 to afford the title compound.
  • Mass Spectrum (ES+) m/z 463(M+H).
  • Example 111 N-[2- ⁇ iphenylmethanesulphonyl)-ethyl]-2-(8-methoxy ⁇ 3,4- dihydro-lH-isoqumolin-2-yl)acetamide N-[2-(Diphenyhnethanesulphonyl)-ethyl]-2-(8-methoxy-3,4-dihydro-lH-isoquinolin- 2-yl)acetamide was prepared from N-(2-benzhydrylsuIphanyl-ethyl)-2-(8-methoxy- 3,4-dihydro-lH-isoquinolin-2-yl)acetamide (leq) and mCPBA (2eq) in CH 2 C1 2 to afford the title compound. HPLC retention time 3.26min. Mass Spectrum (ES+) m/z 479(M+H).
  • Example 117 2-[4,4-Bis-(4-fluorophenyl)-butyl]-l,2,3,4-tetrahydro-isoquinolin- 8-yIamine Prepared according to the method described in Example 14. HPLC retention time 4.60min. Mass Spectrum (ES+) m/z 393(M+H).
  • Example 118 2-(8-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2,2-dipkenyI- ethyl)acetamide- Prepared according to the method described in Example 14. HPLC retention time. 4.11 min. Mass Spectrum (ES+) m z 386(M+H).
  • Example 120 N-[3,3-Bis-(4-methoxyphenyl)-propyl]-2-(l,3-dihydro-isoindol-2- yl)acetamide
  • Example 122 N-[3,3-Bis-(4-methoxyphenyl)-propyl]-2-(8-methoxy-3,4-dihydro- lH-isoquinoIin-2-yI)acetamide
  • N-(4,4-Diphenyl-butyl)-2-(8-methanesulphonylamino-3 ,4-dihydro- 1 H-isoquinolin-2- yl)acetamide was prepared from 2-(8-amino-3 ,4-dihydro- lH-isoquinolin-2-yl)-N- (4,4-diphenyl-butyl)acetamide (1 eq), methanesulphonylchloride (1 eq) and triethylamine (leq) in CH 2 C1 2 to afford the title compound. HPLC retention time 3.99min. Mass Spectrum (ES+) m/z 492(M+H).
  • Example 127 N-[Bis-(4-fluorophenyl)methyl]-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl) acetamide
  • Example 128 N-[Bis-(4-fluorophenyl)methyl]-2-(6,7-dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)acetamide
  • Example 132 3-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinoUn-2-yl)-N-(3,3- diphenyl-propyI)propionamide Prepared according to the method described in Example 14. HPLC retention time 4.01min. Mass Spectrum (ES+) m z 459(M+H).
  • Example 138 N-[3-(5-Chloro-2-methyI-indoI-l-yI)-propyl]-2-(8-hydroxy-3,4- dihydro-lH-isoquinolin-2-yI)acetamide
  • Example 140 l-Benzhydryl-3-[2-(6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethyl]-thiourea
  • Example 142 l-Benzhydryl-3-[2-(6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethyl]-urea
  • Example 144 l-[2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3- (2,2-diphenyl-ethyl)-thiourea
  • Example 147 l-(2-Chloro-phenothiazin-10-yl)-2-(8-hydroxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4.33min. Mass Spectrum (ES+) m/z 4.23(M+H).
  • Example 148 l-(2-Chloro-phenothiazin-10-yl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone
  • Example 151 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- trifluoromethyl-phenothiazin-10-yl)-ethanone
  • Example 152 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- trifluoromethyl-phenothiazin-10-yl)-ethanone
  • Example 153 l-(2-Acetyl-phenothiazm-10-yl)-2-(8-hydroxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone
  • Example 154 1 -(2-Acetyl-phenothiazin-l 0-y l)-2-(8-methoxy-3,4-dihy dro-1 H- isoquinolin-2-yl)-ethanone
  • Example 158 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l- phenothiazin-10-yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 4.19min. Mass Spectrum (ES+) m/z 433(M+H).
  • Example 159 l-(2-Chloro-phenothiazin-10-yl)-2-(6,7-dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)-ethanone
  • Example 162 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- methylsulphanyl-phenothiazm-l 0-yl)-ethanone
  • Example 164 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- methylsulphanyl-phenothiazin-l 0-yl)-ethanone
  • Example 170 Phenoxazine-10-carboxylic acid [2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide
  • Example 172 Phenoxazine-10-carboxylic acid [2-(6,7-dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)-ethyl]-amide
  • Example 175 (8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yI)-acetic acid N',N'- diphenyl-hydrazide
  • Example 176 (6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetic acid N',N'-diphenyl-hydrazide
  • Example 177 4-[2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3,4- dihydro-2H-benzo[l,4]oxazine-2-carboxylic acid ethyl ester
  • Example 178 4-[2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3,4- dihydro-2H-benzo[l,4]oxazine-2-carboxylic acid ethyl ester
  • Example 180 2-(5,8-Dihydro-6H-[l,7]naphthyridin-7-yl)-l-phenoxazin-10-yl- ethanone Prepared according to the method described in Example 56 with the following modification: triethylamine was used as base. HPLC retention time 3.1min. Mass Spectrum (ES+) m/z 358(M+H).
  • Example 181 l-[2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3-(4- phenoxyphenyl)-urea
  • Example 186 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(9H-xanthen-9- yl)acetamide
  • Example 191 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2- phenoxyphenyl)acetamide Prepared according to the method described in Example 56. HPLC retention time 4.77min. Mass Spectrum (ES+) m/z 389(M+H).
  • Example 196 3-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-l 0- yl-propan-1-one
  • Example 200 2-(7-Hydroxy-3,4 ⁇ dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10- yl-ethanone
  • Example 201 2-(6-Hydroxy-3,4 ⁇ dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10- yl-ethanone
  • Example 202 2-(5-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10- yl-ethanone Prepared according to the method described in Example 56. HPLC retention time 3.89min. Mass Spectrum (ES+) m/z 373(M+H).
  • Example 203 2-(4-Methoxy-l,3-dihydro-isoindol-2-yl)-l-phenoxazin-l 0-yl- ethanone
  • Example 204 N-Methanesulphonyl-N- [2-(2-oxo-2-phenoxazin-l 0-yl-ethyI)- l,2,3,4-tetrahydro-isoquinoIin-8-yl]-methanesulphonamide
  • Example 205 N-[2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro- isoquinoIin-8-yl]-methanesuIphonamide
  • Example 206 2-(8-Methoxy-3,4-dihydro-lH-isoquinoIin-2-yl)-l-(l-methyl-lH-4- oxa-l,2,9-triaza-cyclopenta[b]naphthalen-9-yl)-ethanone
  • Example 207 2-(8- ethoxy-3,4-dihydro-lH-isoquinolm-2-yl)-l-phenoxazin-10- yl-propan-1-one
  • Example 208 Phenoxazine-10-carboxylic acid [2-(5,8-dihydro-6H- [l,7]naphthyridin-7-yl)-ethyl]-amide
  • Example 212 2-(8-Methoxy-3,4-dihydro-lH-isoquinoIin-2-yl)-l-(3-methyl-2,3- dihydro-benzo[l,4]oxazin-4-yl)-ethanone
  • Example 213 l-(3-tert-Butyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-2-(8-methoxy- 3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
  • Example 214 l-(HH-Dibenzo[b,f][l,4]oxazepin-10-yl)-2-(8-methoxy-3,4- dihydro-lH-isoquinolin-2-yI)-ethanone
  • Example 215 l-(3-Ethyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-2-(8-methoxy-3,4- dihydro-lH-isoquinolin-2-yl)-ethanone
  • Example 218 l-(3-tert-Butyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-2-(8-hydroxy- 3,4-dihydro-lH-isoquinolin-2-yl)-ethanone Prepared according to the method described in Example 56. HPLC retention time 4.1 lmin. Mass Spectrum (ES+) m/z 381 (M+H).
  • Example 220 l-[3-(2,5-Dimethoxyphenyl)-2,3-dihydro-benzo[l,4]oxazin-4-yl]-2- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
  • Example 222 l-[3-(4-Fluorophenyl)-2,3-dihydro-benzo[l,4]oxazin-4-yl]-2-(8- methoxy-3,4-dihydro-lH-isoqumolin-2-yl)-ethanone
  • Example 223 l-[3-(3,4-Dimethoxyphenyl)-2,3-dihydro-benzo[l,4]oxazin-4-yI]-2- (8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
  • SH-SY-5Y hNa v 1.8 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 50,000cells.weir " 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 tetiamethylahnnbrnurh 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 pyrethroid 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.
  • Baseline fluorescence levels are first determined before the addition of a sodium containing buffer (220mM sodium chloride; 2mM calcium chloride; 0.8mM magnesium chloride hexahydrate; lOmM HEPES; lOmM glucose; 5mM potassium chloride.

Abstract

La présente invention concerne des composés représentés par la formule générale (I) et certains de leurs sels pharmaceutiquement admis. Ces produits, qui s'avèrent des antagonistes des canaux sodium des neurones sensoriels, conviennent donc comme analgésiques et neuroprotecteurs. Dans cette formule, X est -N- ou -CH-, et 'n' vaut de 0 à 3.
EP04743288A 2003-07-07 2004-07-07 Composes azacycliques convenant comme inhibiteurs des canaux specifiques des neurones sensoriels Withdrawn EP1660454A1 (fr)

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PCT/GB2004/002945 WO2005005392A1 (fr) 2003-07-07 2004-07-07 Composes azacycliques convenant comme inhibiteurs des canaux specifiques des neurones sensoriels

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