WO2005005392A1 - Azacyclic compounds as inhibitors of sensory neurone specific channels - Google Patents

Azacyclic compounds as inhibitors of sensory neurone specific channels Download PDF

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WO2005005392A1
WO2005005392A1 PCT/GB2004/002945 GB2004002945W WO2005005392A1 WO 2005005392 A1 WO2005005392 A1 WO 2005005392A1 GB 2004002945 W GB2004002945 W GB 2004002945W WO 2005005392 A1 WO2005005392 A1 WO 2005005392A1
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alkyl
dihydro
phenyl
defined above
isoquinolin
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PCT/GB2004/002945
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French (fr)
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Richard John Hamlyn
Michael Richard Huckstep
Rosemary Lynch
Stephen Stokes
David Christopher Tickle
Lee Patient
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Ionix Pharmaceuticals Limited
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Priority claimed from GBGB0315872.2A external-priority patent/GB0315872D0/en
Application filed by Ionix Pharmaceuticals Limited filed Critical Ionix Pharmaceuticals Limited
Priority to EP04743288A priority Critical patent/EP1660454A1/en
Priority to US10/563,561 priority patent/US20070043024A1/en
Publication of WO2005005392A1 publication Critical patent/WO2005005392A1/en

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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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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    • 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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    • 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
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    • 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
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    • 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
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    • 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

Compounds of the formula (I), and pharmaceutically acceptable salts thereof, are found to be antagonists of SNS sodium channels. They are therefore useful as analgesic and neuroprotective agents wherein: X is -N- or -CH-; n is from 0 to 3.

Description

AZACYCLIC COMPOUNDS AS INHIBITORS OF SENSORY NEURONE SPECIFIC CHANNELS
The present invention relates to inhibitors of the subtype of mammalian sodium channels known as Nav1.8 or sensory neurone specific (SNS) channels. The Nav1.8 channel is a 1,957 amino acid tetrodotoxin-insensitive voltage-gated sodium channel. The sodium channel, nucleic acid sequences coding for the channel, vectors, host cells and methods of identifying modulators, are taught in US-A- 6451554. The α-subunit gene corresponding to this ion channel is referred to as SCN10A. The channel is described in more detail in Akopian et al, (1996), 379, 257-262. Mammalian ion channels are becoming increasingly well characterized, and progress in sodium channel research has been summarized recently in Anger et al, J. Med. Chem. (2001) 44, 115-137. Sodium channels are recognised as valid targets for pain therapeutics, and blockade of sodium channels can be useful in the treatment of a range of pain syndromes (see for example Black et al, Progress in Pain Research and Management (2001), 21 (Neuropathic P'aihfPatnophysiology and Treatment), 19- 36). It has now surprisingly been found that compounds of the general formula (I) set out below act as inhibitors of sensory neurone specific sodium channels. Accordingly, the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof,
Figure imgf000003_0001
wherein: X is -N- or -CH-; n is from 0 to 3; each Ri is the same or different and is a hydroxy, amino, halogen, Cι-C6 alkyl, Cι-C6 haloalkyl, Cι-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, - haloalkoxy, Cγ-C6 alkylthio, Cι-C6 haloalkylthio, (CιC6 alkyl)amino or di(Cι-C6 alkyl)amino group; p is 0 or 1 ; R is cyano, -NR/-CO-(C1-C4 alkyl), -NR-S(O)2-(C1-C4 alkyl), -CO2H, - S(O)2OH, -CO2-(C C4 alkyl), -O-S(O)2-(Cj-C4 alkyl) or -N[S(O)2-(C1-C4 alkyl)]2, wherein Ry is hydrogen or a -C4 alkyl .group; is 1, 2 or 3; and R2 is either
(a) -L-A, wherein L is a direct bond or a -Cβ alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety and A is Ce- o aryl, C3-C6 carbocyclyl, a 5- to 10- membered heteroaryl group or a 5- to 10- membered heterocyclic group,
(b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or C1-C4 alkyl, L is as defined above and each A is the same or different and is as defined above,
(c) -i Het-A7, wherein Het is -O-, -S- or -NR7-, Af is -L-A, -L-CR(A)2 or -L- CH=C(A)2, R is H or -L-A, L; is a C C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above,
(d) -L-CO-NR R4 or -L-CS-NR3. 4, wherein L is as defined above and either (i) R and R , together with the N atom to which they are attached, form a 5- to 10- membered heteroaryl or heterocyclyl group or (ii) R3 represents -L-H or A; wherein L and A' are as defined above, and R4 represents -L'-H, -L'-CO- A7, -L -S(O)-A , -L/-S(O)2-A , -h'-Het-A', -NR-CO-N(A)2, -N(A)2, -A-Het-A, -A , -L-CR(LA)2 or -L-CH=C(LA)2 wherein each L is the same or different, each A is the same or different, and ', L, R, A and A are as defined above,
(e) -CO-L-N jRi or -CS-L-NR R4 wherein L, R3 and R4 are as defined above, (f) -CO- A7 or -CS-A7 wherein A; is as defined above,
(g) -L/-O-N=C(A)2 or -CO-L -O-N=C(A)2 wherein l! is as defined above and each A is the same or different and is as defined above, or
(h) -L -NR-CO-NR3R4 or -L -NR-CS-NR3R4, wherein L1, R, R3 and R are as defined above, wherein said aryl, carbocyclyl, heteroaryl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from C1-C4 alkyl, -C4 haloalkyl, halogen, hydroxy, amino, (d-C4 alkyl)amino, di(Q-C4 alkyl)amino, C C4 alkoxy, C C haloalkoxy, CrC4 alkylthio, C1-C4 haloalkylthio, -NH-CO-(C1-C4 alkyl), -CO-(d-C4 alkyl), -CO2-(Cι-C4 alkyl), 5- or 6- membered heteroaryl, phenyl and -CHPh substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, Cι-C2 alkyl groups, Cι-C2 alkoxy groups and -NH-CO-(C1-C2 alkyl) groups, provided that (a) when R2 is -L-A, A is other than a benzimidazolyl group, and (b) when R is -CO~A! or -CS-A7, A is other than a pyrazolopyrimidinyl or pyrazolyl group. Typically, 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, Cι-C6 alkyl, Cι-C6 haloalkyl, Cι-C6 alkoxy, Cι-C6 haloalkoxy, Ci-Cβ alkylthio, Cι-C6 haloalkylthio, (QCό alkyl)amino or di(C1-C6 alkyl)amino group; m is 1, 2 or 3; and R is either
(a) -L-A, wherein L is a direct bond or a CrC6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety and A is Cβ-Cio aryl, C3-C6 carbocyclyl, a 5- to 10- membered heteroaryl group or a 5- to 10- membered heterocyclic group,
(b) -L-CR(A) or -L-CH=C(A)2 wherein R is hydrogen or C1-C4 alkyl, L is as defined above and each A is the same or different and is as defined above,
(c) -L'-Het-A7, wherein Het is -O-, -S- or -NR;-, A; is -L-A, -L-CR(A)2 or -L- CH=C(A)2, R; is H or -L-A, L7 is a d-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above,
(d) -L-CO-NR3R4 or -L-CS-NR3R-4, wherein L is as defined above and either (i) R3 and R4, together with the N atom to which they are attached, form a 5- to 10- membered heteroaryl or heterocyclyl group or (ii) R3 represents -L-H or A' wherein L and A7 are as defined above, and R4 represents -L -H, -L7-CO-A, A7, -L-CR(LA)2 or -L-CH=C(LA)2 wherein each L is the same or different, each A is the same or different, and L7, L, R, A and A7 are as defined above,
(e) -CO-L-NR3R4 or -CS-L-NR3R4 wherein L, R3 and R4 are as defined above,
(f) -CO-A/ or -CS-A! wherein A is as defined above, or
(g) -L7-O-N=C(A)2 or -CO-L -O-N=C(A)2 wherein L7 is as defined above and each A is the same or different and is as defined above, wherein said aryl, carbocyclyl, heteroaryl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from d-C alkyl, C1-C4 haloalkyl, halogen, hydroxy, d-C4 "alkoxy, Cϊ-C4 haloalkoxy, d-C4 alkylthio, d-C4 haloalkylthio, phenyl and -CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms, provided that (a) when R2 is -L-A, A is other than a benzimidazolyl group and (b) when R2 is -CO-A7 or -CS-A7, A is other than a pyrazolopyrimidinyl or pyrazolyl group. As used herein, a d-C6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as C1-C4 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. As used herein, a C2-C6 alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C2-C4 alkenyl group or moiety, for example ethenyl, propenyl and butenyl. Typically, 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. As used herein, a C2-C6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, such as a C -C alkynyl group or moiety, for example ethynyl, propynyl and butynyl. Typically, 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. As used herein, a C6-do aryl group or moiety is typically a phenyl or naphthyl group or moiety. It is preferably a phenyl group or moiety. As used herein, a 5- to 10- membered heteroaryl group is a 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl and pyrazolyl groups. Thienyl, triazolyl, pyridyl, thiazolyl and imidazolyl groups are preferred. Pyrrolyl groups are also preferred. - As used herein, a halogen is typically chlorine, fluorine, bromine or iodine - and is preferably chlorine or fluorine. As used herein, a said d-C6 alkoxy group is typically a said d-C6 alkyl group attached to an oxygen atom. A said d-C6 alkylthio group is typically a said d-C6 alkyl group attached to a thio group. As used herein, a d-d haloalkyl group is typically a said d-C6 alkyl group, for example a Cι-C4 alkyl group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl groups include perhaloalkyl groups such as -CX3 wherein X is a said halogen atom. Particularly preferred haloalkyl groups are -CF3 and -CC13, As used herein, a d-C6 haloalkoxy group is typically a said d-C6 alkoxy group, for example a d-C4 alkoxy-group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen' atoms. Preferred haloalkoxy groups include perhaloalkoxy groups such as -OCX3 wherein X is a said halogen atom. Particularly preferred haloalkoxy groups are -OCF3 and -OCCI3. As used herein, a d-C6 haloalkylthio group is typically a said Cι-C6 alkylthio group, for example a d-C4 alkylthio group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkylthio groups include perhaloalkylthio groups such as -SCX wherein X is a said halogen atom. Particularly preferred haloalkylthio groups are -SCF3 and
As used herein, a C3-C6 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 C3-C6 cycloalkyl group. Examples include cyclobutyl, cyclopentyl and cyclohexyl. As used herein, a 5- to 10- membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C5-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. More preferably, 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. Examples of suitable " heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, 1,4 dioxanyl, 1,3 dioxolanyl and homopiperidinyl groups. Further examples of suitable 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. Typically, when 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. Typically, the two cyclic moieties are not fused together. Preferably 0, 1 or 2 of the said substituents on an aryl, heteroaryl, carbocyclyl or heterocyclyl group are selected from -NH-CO-(C1-C4 alkyl), -CO-(C -C4 alkyl), -CO2-(d-C4 alkyl), 5- or 6- membered heteroaryl, phenyl and -CHPh2 substituents. Typically, the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents R1} R2, R3 and R4 are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C4 alkyl, hydroxy, amino, (Cι-C4 alkyl)amino, d-C alkoxy, d-C4 haloalkyl, Cι-C4 haloalkoxy, Cι-C4 alkylthio, d-C4 haloalkylthio, -NH-CO-(Cι-C2 alkyl), -CO- (d-C2 alkyl), -CO2-(C!-C2 alkyl), 5- membered heteroaryl, phenyl and -CHPh2 substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, d-C2 alkyl groups, d-C2 alkoxy groups and -NH-CO-(d-C2 alkyl) groups. More typically, the above substituents are selected from halogen, d-C4 alkyl, hydroxy, d-C4 alkoxy, d-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkylthio, d-C4 haloalkylthio, phenyl and -CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms. Preferably, the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents R1} R2, R3 and R4 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-C2 alkoxy, d-C haloalkyl, d-C2 haloalkoxy, d-C2 haloalkylthio, -NH-CO-(d-C2 alkyl), -CO-(d-C2 alkyl), -CO2-(er-e2-alkyl); oxadiazolyl, phenyl and -CHPh2 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, methoxy groups and -NH-CO-CH3 groups. Preferably, these preferred substituents are selected from halogen, d-d alkyl, hydroxy, d-C2 alkoxy, d-C2 haloalkyl, Cι-C2 haloalkoxy, Cι-C2 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. Typically, X is -CH-. Typically, n is 0 or 1. Preferably, each R\ is the same or different and is a hydroxy, amino, halogen, Cj-C alkyl, d-C haloalkyl, d-C alkoxy, C2-C alkenyloxy, C C haloalkoxy, Ci- C4 alkylthio or d-C4 haloalkylthio group. Typically, in this preferred embodiment each Ri is the same or different and is a hydroxy, halogen, Cι-C4 alkyl, C1-C haloalkyl, d-C alkoxy, Cι-C4 haloalkoxy, d-C4 alkylthio or d-C4 haloalkylthio group. More preferably, each Ri is the same or different and is Cι-C2 alkyl, C -C3 alkenyloxy, amino, hydroxy or C1-C2 alkoxy. Typically, in this more preferred embodiment each i is the same or different and is Cj-C2 alkyl, hydroxy or d-C2 alkoxy. Typically, R is cyano, -NH-CO-(Cι-C4 alkyl), -NH-S(O)2-(d-C4 alkyl), -O-
S(O)2-(d-C4 alkyl), -S(O)2-OH or -N-[S(O)2-(C!-C4 alkyl)]2. Preferably, R is cyano, -NH-CO-CH3, -NH-S(O)2-CH3, -O-S(O)2-CH3, -N-[SO2-CH3]2 or -S(O)2OH. Typically p is 0 and Ri is located meta to the fused heterocycle, or on the phenyl carbon atom nearest the N atom. Thus, the compound of formula (I) is typically a compound of formula
Figure imgf000010_0001
Typically, each L moiety in the R substituent is the same or different and represents a direct bond or a d-C6 alkyl moiety. Preferably, each L is the same or different and represents a direct bond or a C1-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, for example -CH(CH3)- or -CH2-CH(CH3)-. Typically each L7 moiety in the R2 substituent is the same or different and represents a d-d alkyl moiety, preferably a d-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, for example -CH(CH3)- or -CH2-CH(CH3)-. Typically, each A moiety in the R2 substituent is the same or different and represents a C -do aryl, C3-C6 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 C1-C4 alkyl, C1-C4 haloalkyl, halogen, hydroxy, amino, (C1-C4 alkyl)amino, di(d-C4 alkyl)amino, C1-C4 alkoxy, Cι-C4 haloalkoxy, Cι-C4 alkylthio, d-C4 haloalkylthio, -NH-CO-(d-C2 alkyl), 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. For the avoidance of doubt, said preferred substituents on the moiety A are themselves unsubstituted. More typically, each A moiety in the R2 substituent is the same or different and represents a C6-do aryl, C3-C6 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 C1-C4 alkyl, C1-C4 haloalkyl, halogen, hydroxy, d-d alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 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. Further, each A moiety in the R2 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-C2 haloalkyl, Cι-C2 haloalkoxy, Cι-C2 haloalkylthio, phenyl, d-d alkyl, d-C2 alkoxy, amino, hydroxy and -NH-CO-(d-C2 alkyl) groups and (b) optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heteroaryl moieties. More typically, each A moiety in the R2 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-C2 haloalkyl, d-C2 haloalkoxy, d- haloalkylthio, phenyl, d-d alkyl, d-C2 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. Preferably, each A moiety in the R2 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-C2 alkyl, hydroxy, amino, d-C2 alkoxy, d-C2 haloalkyl, d-C2 haloalkoxy, d-C2 haloalkylthio, -NH-CO-CH3 and phenyl substituents. More typically, in this preferred embodiment, 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-C2 alkoxy, Cι-C2 haloalkyl, Cι-C2 haloalkoxy, Cι-C haloalkylthio and phenyl substituents. Typically, each R substituent in each -CR(A)2 moiety is the same or different and is hydrogen or methyl. Typically, each Het moiety in the R2 substituent is -O-, -S- or -NR7- wherein R7 is hydrogen, d-C alkyl, phenyl or -(Cι-C alkyl)-phenyl. More preferably, each Het moiety in the R2 substituent is -O- or -NR7- wherein R7 is hydrogen, Cι-C4 alkyl or benzyl. When R3 and R4, together with the N atom to which they are attached, form a heteroaryl or heterocyclyl group, 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. Typically, when R3 and R4, together with the N atom to which they are attached, form a heterocycle, they form a 5- to 7- membered heterocyclyl group. Preferably, they form a 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 C1-C4 alkyl, d-C4 haloalkyl, d-C4 alkoxy, C1-C4 alkylthio, halogen, phenyl, -CHPh2, -CO-(Cι-C2 alkyl), -CO2-(d-C2 alkyl) arid - to 6- membered ' heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, d-C2 alkyl groups, d-C2 alkoxy groups and -NH-CO-(C1-C2 alkyl) groups. More typically, when R3 and R4, 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 C1-C4 alkyl, C1-C4 haloalkyl, halogen, phenyl and -CHPh2 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. Typically, when R3 and R4 do not together form a heterocycle, R3 represents hydrogen, d-d alkyl, phenyl, -(d-d alkyl)-phenyl or -(d-C4 alkyl)-CHPh2. More typically, when R3 and R4 do not together form a heterocycle, R3 represents hydrogen, C1-C4 alkyl, -(d-C4 alkyl)-phenyl or -(C1-C4 alkyl)-CHPh2. Preferably, the phenyl moieties in R3 are unsubstituted or substituted by a hydroxy group. More preferably, R3 is unsubstituted. More preferably, R3 represents hydrogen, d- alkyl or an unsubstituted benzyl, phenyl, hydroxyphenyl or -(C1-C2 alkyl)-CHPh2 group. Most preferably R3 represents hydrogen, d- alkyl or an unsubstituted benzyl or -(Cι-C2 'alkyl)-CHPh2 group. Typically, when R3 and R4 do not together form a heterocycle, R4 represents d-d alkyl, A, -(d-C4 alkyl)-A, -(CH2)m-CH(A)2, -CH[(CH2)mA]2, -(CH2)m-CO-A, -(CH2)m-O-CH(A)2, -(CH2)m-S-CH(A)2,. -(CH2)m-S(O)-CH(A)2, -(CH2)m-S(O)2-
CH(A)2, -NH-CO-N(A)2, -N(A)2 or -A-O-A, wherein each A is the same or different and is as defined above and m is 0, 1, 2, 3 or 4. More typically, when R3 and j do not together form a heterocycle, R4 represents C1-C4 alkyl, A, -(d-C alkyl)-A, -(CH2)m-CH(A)2, -CH[(CH2)mA]2 or -(CH2)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. Preferably, the A moieties in the 4 substituent are (a) unsubstituted or substituted by 1 or 2 substituents selected from d-C alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, Cι-C2 haloalkyl, d-C2 haloalkoxy and d-C2 haloalkylthio substituents and (b) monocyclic or fused to 1 or 2 phenyl rings. Typically, in this preferred embodiment, 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-C2 haloalkyl, d-C2 haloalkoxy and Cι-C2 haloalkylthio substituents and (b) monocyclic or fused to 1 or 2 phenyl rings. More preferably, when R3 and 4 do not together form a heterocycle, R-4 represents C1-C4 alkyl, fluorenyl, phenyl, pyridyl, -(C1-C4 alkyl)-phenyl, -(C1-C4 alkyl)-(5- to 6- membered heteroaryl), -(CH2)m-(9H-carbazolyl), -(CH2)m-indolinyl, -(CH2)m-(9H-xanthenyl), -(CH2)m-O-CHA7A777, -(CH2)m-S-CHA7A777, -(CH2)m-S(O)- CHA/7A/ , -(CH2)m-S(O)2-CHA A777, -NH-CO-N(phenyl)2, -N(phenyl)2, -A -O-A777, -(CH2)m-CHA77A777, -CH[(CH2)πPh]2 or -(CH2)p-CO-R, wherein m is 0, 1, 2 or 3, A77 and A are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, n is 0, 1 or 2, 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 preferred R4 groups being unsubstituted or substituted by a halogen atom, d-C2 alkyl, hydroxy, amino or Cj-C2 alkoxy group. More preferably, when R3 and R4 do not together form a heterocycle, R4 represents d-C alkyl, fluorenyl, -(d-C alkyl)-phenyl, -(d-d alkyl)-(5- to 6- membered heteroaryl), -(CH2)m-CHA 7A777 wherein m is 0, 1, 2 or 3 and A77 and A777 are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, -CH[(CH2)nPh]2 wherein n is 0, 1 or 2, or -(CH2)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 R4 groups being unsubstituted or substituted by a halogen atom, d-C alkyl or d-C2 alkoxy group. Typically, when R2 is defined according to option (a), A is monocyclic. More typically, A is a monocyclic phenyl or 5- to 6- membered heteroaryl group. Typically, when R2 is defined according to option (a), 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-C4 alkyl, Cι-C4 haloalkyl, halogen, hydroxy, d-C4 alkoxy, d-C4 haloalkoxy, d-C alkylthio, d-C4 haloalkylthio, phenyl and halophenyl substituents. Preferably, when R is defined according to option (a), it is a -(d-C alkyl)- phenyl group, for example benzyl, or a -(C1-C4 alkyl)-(5- to 6- membered heteroaryl) group, for example -CH2-thienyl or -CH2-triazolyl, the phenyl and heteroaryl
• moieties being unsubstituted or substituted'by Lor 2 substituents selected froπrCi-d haloalkyl, halogen, d-C2 haloalkylthio, d-C2 haloalkoxy, d-C2 alkyl and phenyl substituents. Typically, when R2 is defined according to option (b), it is -L-CR(A)2 wherein R and A are as defined above. Preferably, L is d-C4 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, Cι-C2 haloalkyl, d-C2 alkyl, -NH-CO-CH3 and hydroxy substituents. More preferably, 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-C2 haloalkyl, d-C2 alkyl and hydroxy substituents. Typically, when R2 is defined according to option (c), L7 is C -C alkyl, Het is O, NH or -N(benzyl)- and A7 is an unsubstituted -(Cι-C )alkyl-phenyl, -(Cι-C4 alkyl)-CHPh2 or -CH=CHPh2 group. Typically, when R2 is defined according to option (d), L is other than a direct bond. More typically, L is Cι-C6 alkyl. Further, when R2 is defined according to option (d), it is typically -L-CO- NR3R More typically, when R2 is defined according to option (d), R2 is -(CH2)q- CO-lSπE-aR- wherein q is from 1 to 4, and is preferably 1 or 2, and R3 and R4 are as defined above. Preferably, when R2 is defined according to option (d), either (i) R3 and R4, together with the N atom to which they are attached, form a 5- to 7- membered heterocyclyl group or (ii) R3 represents hydrogen, - alkyl, phenyl or -(d-d alkyl)-ρhenyl and R4 represents - alkyl, A, -(C1-C4 alkyl)-A, -(CH2)m-CH(A)2, -CH[(CH2)mA]2, -(CH2)m-O-CH(A)2, -(CH2)m-S-CH(A)2, -(CH2)m-S(O)-CH(A)2, -(CH2)m-S(O)2-CH(A)2, -NH-CO-N(A)2, -N(A)2 or -A-O-A, wherein each A is the same or different and is as defined above and m is 0, 1, 2, 3 or 4. Typically, in this preferred embodiment when R2 is defined according to option (d), either (i) R3 and R4, together with the N atom to which they are attached, form a 5- to 7- membered heterocyclyl group or (ii) R3 represents hydrogen, C1-C4 alkyl or -(C1-C4 alkyl)- phenyl and R-4 represents d-C alkyl, A, -(d-C alkyl)-A, -(CH2)m-CH(A)2 or - CH[(CH2)mA]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 -R2 is defined according- to option (d) either (i) R3-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-C4 alkyl, d-C4 haloalkyl, d-C4 alkoxy, d-C alkylthio, halogen, phenyl, -CHPh2, -CO-(Cι-C2 alkyl), -CO2-(d-C2 alkyl) and 5- to 6- membered heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, C1-C2 alkyl groups, d-C2 alkoxy groups and -NH-CO-(C1-C2 alkyl) groups or (ii) R3 represents hydrogen, d-C4 alkyl or an unsubstituted benzyl, phenyl or hydroxyphenyl group and represents d-C alkyl, fluorenyl, phenyl, pyridyl, -(Cι-C alkyl)-phenyl, -(Cι-C6 alkyl)-(5- to 6- membered heteroaryl), -(CH2)mCHA 7A 7, -CH[(CH2)nPh]2, -(CH2)m-(9H-carbazolyl), -(CH2)m-indolinyl, -(CH2)m-(9H-xanthenyl), -(CH2)m-O-CHA77A777, -(CH2)m-S-
CHA7/A777, -(CH2)m-S(O)-CHA77A777, -(CH2)m-S(O)2-CHA7A777, -NH-CO-N(phenyl)2, -N(phenyl)2 or -A7-O-A777, wherein m is 0, 1, 2 or 3, A77 and A777 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-C2 alkyl, hydroxy, amino or d-C2 alkoxy group. More preferably when R is defined according to option (d) either (i) R3 and R4, 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 -CHPh2 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) R3 represents hydrogen, d-C4 alkyl or an unsubstituted benzyl group and R4 represents C1-C4 alkyl, fluorenyl, -(C1-C4 alkyl)-phenyl, -(Cι-C6 alkyl)-(5- to 6- membered heteroaryl), -(CH2)mCHA 7A777 wherein m is 0, 1, 2 or 3 and A77 and A777 are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, or -CH[(CH2)nPh]2 wherein n is 0, 1 or 2, the cyclic moieties in these groups being unsubstituted or substituted by a d-C2 alkyl group. Typically, when R2 is defined according to option (e), L is a direct bond or a
C1-O4 alkyl moiety, Tor example's, methyl moiety, and R3 and f arenas defined" above. Typically, when R is defined according to option (f), A is a said C6-do aryl group. Typically, when R2 is defined according to option (f), it is -CO-A7. More typically, when R2 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. Preferably, when R2 is defined according to option (f), it is -CO-CH2-CH(R)2 or -CO-R7, wherein each R is the same or different and is a phenyl or halophenyl moiety and R7 is a benzimidazolyl group. Typically, when R2 is defined according to option (g), it is -CO-L -O- N=C(A) , wherein l! is as defined above and each A is the same or different and is as defined above. Preferably, when R2 is defined according to option (g), it is -CO- CH2-O-N=CR77R777 wherein R77 and R777 are the same or different and each represent an unsubstituted phenyl or pyridyl group. Typically, when R2 is defined according to option (h), L7 is d- alkyl. Typically, R is H. Typically, either (i) R3 and R4, together with the N atom to which they are attached, form a phenothiazine or phenoxazine group or (ii) R3 is hydrogen and Rt is -(CH2)m-CHA7A777 or -A7-O-A7 / wherein m is 0, 1, 2 or 3 and A77 and A777 are the same or different and each represent phenyl or a 5- to 6-membered heteroaryl group. Preferably, A77 and A777 are both phenyl. Preferred compounds of formula (I) are those in which: X is -N- or -CH-;
Figure imgf000017_0001
m is 1, 2 or 3; each Ri is the same or different and is a hydroxy, amino, halogen, d-C4 alkyl, C1-C4 haloalkyl, d-C4 alkoxy, Cι-C4 haloalkoxy, C2-C4 alkenyloxy d-C4 alkylthio, or d-d haloalkylthio group; p is 0 or 1; R is cyano, -NH-CO-(Cι-C4 alkyl), -NH-S(O)2-(C C4 alkyl), -O-S(O)2-(d- C4 alkyl), -S(O)2-OH or -N[S(O)2-(d-C4 alkyl]2; and - R2 is either
- (a) - - -L-A wherein L is a direct bond or a d-d alkyl moiety and- Aϊs- a-C^-Cro ' ' aryl, C3-C6 cycloalkyl, 5- or 6- membered heterocyclyl or 5- or 6- membered heteroaryl group, (b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or Cι-C alkyl, L is as defined above and each A is the same or different and is as defined above, (c) -L7-Het-A7, wherein Het is -O-, -S- or -NR7- wherein R7 is hydrogen, d-C4 alkyl, phenyl or -(d-C4 alkyl)-phenyl, A7 is -L-A, -L-CR(A)2 or -L- CH=C(A)2, L7 is a d-C6 alkyl moiety, L is as defined above and each A is the same or different and is as defined above, (d) -L-CO-NRs j or -L-CS-NRaR* wherein L is as defined above and either (i) R3 and R4, together with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl group or (ii) R3 represents hydrogen, d- alkyl, phenyl, -(d-C4 alkyl)-ρhenyl or -(d-C4 alkyl)-CHPh2 and R4 represents Cι-C4 alkyl, A, -(C C4 alkyl)- A, -(CH2)m-CH(A)2, -CH[(CH2)raA]2, -(CH2)m-CO-A, -(CH2)m-O-CH(A)2, -(CH2)ra-S-CH(A)2, -(CH2)m-S(O)-CH(A)2, -(CH2)m-S(O)2-CH(A)2, -NH-CO-N(A)2, -N(A)2 or 7A-O-A, wherein each A is the same or different and is as defined above and m is 0, 1, 2, 3 or 4, (e) -CO-L-NR3R4 or -CS-L-NR3R4 wherein L, R3 and R4 are as defined above,
(f) -CO- A7, or -CS-A7, wherein A7 is as defined above,
(g) . -L7-O-N=C(A)2, -CO-L7-O-N=C(A)2 wherein L7 is as defined above and each A is the same or different and is as defined above, or (h) -L7-NR-CO-NR3R4 or -L7-NR-CS-NR3R4 wherein L7, R, R3 and -Rj are as defined above, wherein said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, C1-C4 alkyl, hydroxy, amino, (d-C4 alkyl)amino, d-C4 alkoxy, d-C4 haloalkyl, d-C4 haloalkoxy, d-C4 alkylthio, d-d haloalkylthio, -NH-CO-(d-C2 alkyl), -CO-(d-C2 alkyl), -CO2-(C C2 alkyl), 5-membered heteroaryl, phenyl "and -CHPh2 suTJstituehts^ the phenyl arid het eϊo'aiyrfhoieties in said substituents being unsubstituted or substituted by one or two further substituents selected from halogen atoms, d-C2 alkyl groups, d-C2 alkoxy groups and -NH-CO- (d-C2 alkyl) groups, provided that (a) when R2 is -L-A, A is monocyclic and (b) when R is -CO-
A7 or -CS-A7, A is a said d-Cio aryl group. Further preferred compounds of formula (I) are those in which X is -CH-;
Figure imgf000018_0001
- p is 0; _ • ■ m is 1, 2 or 3; each Ri is the same or different and is a hydroxy, halogen, C1-C4 alkyl, d- haloalkyl, d-d alkoxy, C1-C4 haloalkoxy, d-d alkylthio, or d-d haloalkylthio group; and - R2 is either
(a) -L-A wherein L is a direct bond or a Cι-C6 alkyl moiety and A is a C6-do aryl, d-C6 cycloalkyl, 5- or 6- membered heterocyclyl or 5- or 6- membered heteroaryl group, (b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or d-C4 alkyl, L is as defined above and each A is the same or different and is as defined above,
(c) -L -Het-A7, wherein Het is -O-, -S- or -NR7- wherein R7 is hydrogen, d-C4 alkyl, phenyl or -(C1-C4 alkyl)-phenyl, A7 is -L-A, -L-CR(A)2 or -L- CH=C(A)2, L7 is a Cj-d alkyl moiety, L is as defined above and each A is the same or different and is as defined above,
(d) -L-CO-N 3R-4 or -L-CS-NR3R- wherein L is as defined above and either (i) R3 and R-*, together with the nitrogen atom to which they are attached, form a 5- to 7- membered heterocyclyl group or (ii) R3 represents hydrogen, d-d alkyl, -(C1-C4 alkyl)-phenyl or -(C1-C4 alkyl)-CHPh2 and R4 represents d-d alkyl, A, -(d-C4 alkyl)-A, -(CH2)m-CH(A)2, -CH[(CH2)mA]2 or -(CH2)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,
(e) -CO-L-NR3R4 or -CS-L-NR3R4 wherein L, R3 and R4 are as defined above, (f) -CO- A7 or -CS-A7 wherein A7 is as defined above, or
(g) " -L7-O-N=C( A)27-CO-L7-O-N=C(A)2 " wherein L7 is as defined above and each "" A is the same or different and is as defined above, wherein said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, C1-C4 alkyl, hydroxy, d-d alkoxy, d-d haloalkyl, d-C4 haloalkoxy, d-C4 alkylthio, Cι-C haloalkylthio, phenyl and -CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by .one or two halogen atoms, provided that (a) when R2 is defined according to option (a), it is a -(Cι-C4 alkyl)-phenyl group or a -(C1-C4 alkyl)-(5- to 6- membered heteroaryl) group, the phenyl and heteroaryl moieties being unsubstituted or substituted by 1 or 2 substituents selected from Cι-C haloalkyl, halogen, Cι-C2 haloalkylthio, Cι-C2 haloalkoxy, Cι-C2 alkyl and phenyl substituents and (b) when R2 is defined according to option (f) it is -CO-CH2-CH(R)2 or -COR, wherein each R is the same or different and is a phenyl or halophenyl moiety and R is a benzimidazolyl group. 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-C2 alkyl, hydroxy or d-C2 alkoxy; p is 0 or 1 ; Ri7 is cyano, -NH-CO-CH3, -NH-S(O)2-CH3, -O-S(O)2-CH3, -N[SO -CH3]2 or -S(O)2-OH; - m is 1, 2 or 3; and R is either
(a) -L-A wherein L represents a direct bond or a C1-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, and 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. or two substituents selected from halogen, C'f-d alkyl," hydroxy, amino, Cι-C2 alkoxy, Cι-C haloalkyl, Cι-C haloalkoxy, d-C2 haloalkylthio, -NH-CO-CH3 and phenyl substituents,
(b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or methyl, L is as defined above and each A is the same or different and is as defined above,
(c) -L -Het-A7 wherein Het is -O- or -NR7- wherein R7 is hydrogen, d-d alkyl or benzyl, A7 is -L-A, -L-CR(A)2 or -L-CH=C(A)2, L7 is a d-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above, (d) -L-CO-NR3R4 wherein L is as defined above and either (i) R3 and j, together with the nitrogen atom to which they are attached, form a 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 one or two substituents selected from Cι-C alkyl, d-C4 haloalkyl, d-d alkoxy, Cι-C4 alkylthio, halogen, phenyl, -CHPh2, -CO-(d-C2 alkyl), -CO2-(d-C2 alkyl) and 5- to 6-membered heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by one or two further substituents selected from halogen atoms, Cι-C2 alkyl groups, d-C alkoxy groups and -NH-CO-(Cι-C2 alkyl) groups, or (ii) R3 represents hydrogen, d-C4 alkyl or an unsubstituted benzyl, phenyl, hydroxyphenyl or -(d-C2 alkyl)-CHPh2 group and P represents d- alkyl, fluorenyl, phenyl, pyridyl, -(d-C4 alkyl)-phenyl, -(Cι-C4 alkyl)-(5- to 6- membered heteroaryl), -(CH2)m-(9H-carbazolyl), -(CH2)m-indolinyl, -(CH2)m-(9H-xanthenyl), -(CH2)m-O-CHA A777, -(CH2)m-S-CHA7A777, -(CH2)m-S(O)-CHA77A777, -(CH2)m- S(O)2-CHA/A /, -NH-CO-N(phenyl)2, -N(phenyl)2 or -A -O-A777, -(CH2)m- CHA7/A7/, -CH[(CH2)nPh]2 or -(CH2)p-CO-R where m is 0, 1 , 2 or 3, A7/ and A are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, n is 0, 1 or 2, p is 1, 2 or 3 and R is 5- or 6-^ membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said R4 groups being unsubstituted or substituted by a halogen atom, d-C2 alkyl, hydroxy, amino or Cι-C2 alkoxy group,
(e) -CO-L-NR3-R4 or -CS-L-NR3R4 wherein L, R3 and t are as defined above,
(f) -CO- A7 or -CS-A where A is as defined above,
(g) -CO-L7-O-N=C(A)2 wherein L7 is as defined above and each A is the same or different and is as defined above; or
(h) -L7-NR-CO-NR3R4 or -L7-NR-CS-NR3R4 wherein L7, R, R3 and R4 are as defined above, provided that when R2 is -L-A, A is monocyclic. Further preferred compounds of formula (I) compounds of formula (la)
Figure imgf000021_0001
wherein n is O or l; each Ri is the same or different and is d-C2 alkyl, hydroxy or Cι-C2 alkoxy; m is 1, 2 or 3; and - R2 is either (a) -L-A wherein L represents a direct bond or a C1-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, and A 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, Cι-C2 alkyl, hydroxy, d-C alkoxy, Cι-C2 haloalkyl, d-C haloalkoxy, d-C2 haloalkylthio and phenyl substituents,
(b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or methyl, L is as defined above and each A is the same or different and is as defined above,
(c) -L -Het-A7 wherein Het is -O- or -NR - wherein R7 is hydrogen, C1-C4 alkyl or benzyl, A is -L-A, -L-CR(A)2 or -L-CH=C(A)2, L7 is a C1-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above,
(d) -L-CO-NR3R4 wherein L is as defined above and either (i) R3 and j, together with the nitrogen atom to which they are attached, form a morpholino, piperazinyl or homopiperidinyl ring which is (a) substituted or unsubstituted by one or two substituents selected from Cι-C4 alkyl, d-C4 haloalkyl, halogen, phenyl and -CHPh2 substituents, the phenyl moieties in said substituents being unsubstituted or substituted by one or two halogen atoms and (b) optionally fused to one or two phenyl rings, or (ii) R3 represents hydrogen, C1-C4 alkyl or an unsubstituted benzyl or -CH2-CH2-CHPh2 group and R4 represents d-d alkyl, fluorenyl, -(C1-C4 alkyl)-phenyl, -(d-d alkyl)-(5- to 6- membered heteroaryl), -(CH2)m-CHA 7A777 where m is 0, 1, 2 or 3 and A77 and A777 are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, -CH[(CH2)nPh]2, wherein n is 0, 1 or 2, or -(CH2)p-CO-R wherein p is 1, 2 or 3 and R is 5- or 6- membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said R4 groups being unsubstituted or substituted by a halogen atom, d-C2 alkyl or d-C2 alkoxy group, (e) -CO-L-NR3R4 or -CS-L-NR3R4 wherein L, R3 and R4 are as defined above,
(f) -CO- A7 or CS-A7 wherein A7 is as defined above, or
(g) -CO-L7-O-N=C(A) wherein L7 is as defined above and each A is the same or different and is as defined above," provided that when R is defined according to option (a) it is a benzyl, -CH - thienyl or -CH2-triazolyl group, the phenyl and heteroaryl moieties being unsubstituted or substituted by 1 or 2 substituents selected from Cι-C2 haloalkyl, halogen, Cι-C2 haloalkylthio, Cι-C haloalkoxy, Cι-C2 alkyl and phenyl substituents. Examples of these particularly preferred compounds of the invention include:
1. 2-(3,5-bis-trifluoromethyl-benzyl)-l,2,3,4-tetrahydro-isoquinolin-6-ol
2. 2-(2-chloro-6-fluoro-benzyl)-l,2,3,4-tetrahydro-isoquinolin-8-ol
3. 2-(2,5-difluoro-benzyl)- 1 ,2,3 ,4-tetrahydro-isoquinolin-8-ol
4. 2-(3,5-difluoro-benzyl)-l,2,3,4-tetrahydro-isoquinolin-8-ol 5. 2-(4-trifluoromethylsulfanyl-benzyl)-l,2,3,4-tetrahydro-isoquinolin-8-ol
6. 2-(3,5-bis-trifluoromethyl-benzyl)-l,2,3,4-tetrahydro-isoquinolin-8-ol
7. 2-(2-dibenzylamino-ethyl)- 1 ,2,3,4-tetrahydro-isoquinolin-8-ol
8. 2-[4,4-bis-(4-fluoro-phenyl)-butyl]- 1 ,2,3 ,4-tetrahydro-isoquinolin-8-ol
9. 2-[4,4-bis-(4-hydroxy-3,5-dimethyl-phenyl)-pentyl]-l,2,3,4-tetrahydro- isoquinolin-8-ol
10. 2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(3-;phenyl-2,3-dihydro- - benzo [1,4] oxazin-4-yl)-ethanone
11. 2-(2-benzyloxy-propyl)-l,2,3,4-tetrahydro-isoquinolin-8-ol
12. 2-(2,2-diphenyl-ethyl)-l,2,3,4-tetrahydro-isoquinolin-8-ol 13. N-benzhydryl-2-(3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
14. 2-(3,4-dihydro-lH-isoquinolin-2-yl)-N-(9H-fluoren-9-yl)-acetamide
15. N-(l-benzyl-2-phenyl-ethyl)-2-(3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
16. 2-(3,4-dihydro-lH-isoquinolin-2-yl)-N-(l,2-diphenyl-ethyl)-acetamide
17. 2-(3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N-(3 ,3-diphenyl-propyl)-acetamide 18. N-benzhydryl-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
19. N-(9H-fluoren-9-yl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
20. N-benzyl-2-(8-memoxy-3,4-dihydro- lH-isoquinolin-2-yl)-N-phenyl- acetamide 21. N-(3,3-diphenyl-propyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
22. N,N-dibenzyl-2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
23. 2-thiophen-2-ylmethyl-l,2,3,4-tetrahydro-isoquinolin-8-ol 24. N-benzhydryl-2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
25. N-benzyl-2-(8-hydroxy-3 ,4-dihydro- lH-isoquino lin-2-yl)-N-phenyl- acetamide
26. N-(9H-fluoren-9-yl)-2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
27. N-(3,3-diphenyl-propyl)-2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
28. 2-(5-phenyl-2H-[l,2,3]triazol-4-ylmethyl)-l,2,3,4-tetrahydro-isoquinolin-8-ol
29. 1 -(3 ,4-dihydro- lH-isoquinolin-2-yl)-2-(2,2-diphenyl-ethylamino)-ethanone 30. 1 -(3,4-dihydro-lH-isoquinolin-2-yl)-2-(3,3-diphenyl-propylamino)-ethanone
31. l-(3,4-dihydro-lH-isoquinolin-2-yl)-2-[[2-(3,4-dihydro-lH-isoquinolin-2-yl)- 2-oxo-ethyl] -(3,3 -diphenyl-propyl)-amino] -ethanone
32. 2-dibenzylamino-l-(3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
33. N-(3,3-diphenyl-propyl)-2-(7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
34: " N,N-dibenzyl-2-(7-methoxy-3,4-dihydro- lH-isoquinolin-2-yl)-acetamide dibenzyl-[2-(7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-amine 35. 2-(2,2-diphenyl-ethyl)- 1 ,2,3 ,4-tetrahydro-isoquinoline 36. 2-(2,2-diphenyl-ethyl)-8-methoxy- 1 ,2,3,4-tetrahydro-isoquinoline 37. 2-[4,4-bis-(4-fluoro-phenyl)-butyl]-l ,2,3,4-tetrahydro-isoquinoline
38. 2-[4,4-bis-(4-fluoro-phenyl)-butyl]-8-methoxy-l,2,3,4-tetrahydro- isoquinoline
39. l-(3,4-dihydro-lH-isoquinolin-2-yl)-3,3-bis-(4-fluoro-phenyl)-propan-l-one
40. 2-(3,4-drhιydro-lH-isoquinolin-2-yl)-N-[l-(5-methyl-thiazol-2-yl)-ethyl]- acetamide
41. 2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-[l-(5-methyl-thiazol-2-yl)- ethylj-acetamide
42. (3,3-diphenyl-propyl)-[2-(7-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- ethyl] -amine 43. 2-(benzhydryl-amino)- 1 -(3 ,4-dihydro- lH-isoquinolin-2-yl)-ethanone
44. dibenzyl-[2-(3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-amine
45. [2-(3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-(3,3-diphenyl-propyl)-amine 2-{(2,2-diphenyl-ethyl)-[2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-2- oxo-ethyl]-amino} - 1 -(8-methoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)-ethanone 2-{beιιzhydryl-[2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-2-oxo- ethyl]-amino}-l-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethanone 2-(benzhydryl-amino)- 1 -(8-methoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- ethanone 2-(2,2-diphenyl-ethylamino)-l-(8-methoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethanone (lH-benzoimidazol-5-yl)-(3,4-dihydro-lH-isoquinolin-2-yl)-methanone N-(2,2-diphenyl-ethyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide l-(4-benzhydryl-piperazin-l-yl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethanone . 1 - {4-[bis-(4-fluoro-phenyl)-methyl]-piperazin- 1 -yl} -2-(8-methoxy-3 ,4- dihydro- 1 H-isoquinolin-2-yl)-ethanone: - -l-(4-benzhydryl-piperazin-liyl)-2-(3,4-dihydrό-lH=-isoquinolin-2-yl)- - ethanone, 1 - {4-[bis-(4-fluoro-phenyl)-methyl]-piperazin- 1 -yl} -2-(3,4-dihydro- 1 H- isoquinolin-2-yl)-ethanone 2-(l,3-dihydro-isoindol-2-yl)-N-(2,2-diphenyl-ethyl)-acetamide 1 -(4-benzhydryl-piperazin- 1 -yl)-2-( 1 ,3-dihydrό-isoindol-2-yl)-ethanone 1 - {4-[bis-(4-fluoro-phenyl)-methyl]-piperazin- 1 -yl} -2-( 1 ,3-dihydro-isoindol- 2-yl)-ethanone 2-benzhydrylideneaminooxy-l-(3,4-dihydro-lH-ispquinolin-2-yl)-ethanone 2-(3,4-dihydro-lH-isoquinolin-2-yl)-N-(2,2-diphenyl-ethyl)-acetamide 2-(l,3-dihydro-isoindol-2-yl)-N-(3,3-diphenyl-propyl)-acetamide N-(3,3-diphenyl-propyl)-3r(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- propionamide 2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(phenyl-pyridin-2-yl- methyl)-acetamide 3,4-dihydro-lH-isoquinoline-2-carbothioic acid (2,2-diphenyl-ethyl)-amide N-benzhydryl-2-(l,3-dihydro-isoindol-2-yl)-acetamide 3,4-dihydro-lH-isoquinoline-2-carbothioic acid benzhydryl-amide 67. 8-methoxy-3,4-dihydro-lH-isoquinoline-2-carbothioic acid benzhydryl- a ide
68. 8-methoxy-3,4-dihydro-lH-isoquinoline-2-carbothioic acid (2,2-diphenyl- ethyl)-amide 69. 2-benzhydrylideneaminooxy-l-(8-methoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethanone
70. 2-(di-pyridin-2-yl-methyleneaminooxy)-l-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone
71. 2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(3-phenyl-2,3-dihydro- benzofl ,4]oxazin-4-yl)-ethanone
72. 2-(8-methoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -phenoxazin- 10-yl- ethanone
73. l-(10,ll-dihydro-dibenzo[b,f]azepin-5-yl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone 74. 2-[3-(2,2-diphenyl-vinyloxy)-propyl]-8-methoxy-l,2,3,4-tetrahydro- isoquinoline
75. 4-methoxy-l,3-dihydro-isoindole-2-carbothioic acid benzhydryl-amide
76. 7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepine-2-carbothioic acid benzhydryl-amide 77. 7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepine-2-carbothioic acid (2,2- diphenyl-ethyl)-amide
78. N,N-diisopropyl-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
79. N,N-dibenzyl-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
80. N-benzhydryl-2-(4-methoxy- 1 ,3-dihydro-isoindol-2-yl)-acetamide 81. N-(4,4-diphenyl-butyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
82. N-(4,4-diphenyl-butyl)-2-(4-methoxy- 1 ,3-dihydro-isoindol-2-yl)-acetamide
83. N-benzhydryl-2-(7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl)- acetamide 84. N-(2,2-diphenyl-ethyl)-2-(7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl)-acetamide 85. N-(3 ,3 -diphenyl-propyl)-2-(7-methoxy- 1 ,3 ,4,5 -tetrahydro-benzo [c] azepin-2- yl)-acetamide • 86. N,N-dibenzyl-2-(7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl)- acetamide
87. N,N-dibenzyl-3 -(8-methoxy-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-propionamide
88. N-(3,3-diphenyl-ρropyl)-2-(4-methoxy-l,3-dihydro-isoindol-2-yl)-acetamide
89. N-(2,2-diphenyl-ethyl)-2-(4-methoxy-l,3-dihydro-isoindol-2-yl)-acetamide
90. 2-(l,3-Dihydro-isoindol-2-yl)-N-(2,2-diphenyl-ethyl)-acetamide
91. N,N-Dibenzyl-2-(8-ethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
92. N-(4,4-Diphenyl-butyl)-2-(8-ethoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
93. 2-(8-Ethoxy-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -(3-phenyl-2,3-dihydro- benzo [ 1 ,4]oxazin-4-yl)-ethanone
94. N-(3-Benzhydryloxy-propyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
95. 2-(l,3-Dihydro-isoindol-2-yl)-N-(3,3-diphenyl-propyl)-acetamide
96. N-(2-Benzhydrylsulfanyl-ethyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2- yl)-acetamide
97. 2-(8-AUyloxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(3,3-diphenyl-propyl)- acetamide
98. 2-(4--Amino-l,3-d ydro-isoindol-2-yl)-N-(2,2-diphenyl-ethyl)-acetamide
99. 2-(4- Amino- 1 ,3-dihydro-isoindol-2-yl)-N-(3,3-diphenyl-propyl)-acetamide
100. 2-(4-Amino-l,3-dihydro-isoindol-2-yl)-N-(4,4-diphenyl-butyl)-acetamide
101. 2 -(4- Amino- 1 ,3-dihydro-isoindol-2-yl)-N,N-dibenzyl- acetamide
102. 2-[4,4-Bis-(4-fluoro-phenyi)-butyl]-2,3-dihydro-lH-isoindol-4-ylamine
103. N-[2-(Diphenyl-methanesulfinyl)-ethyl]-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide
104. N-[2-(Diρhenyl-methanesulfonyl)-ethyl]-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide
105. 2-(8-Methoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)-N-(l -phenyl-ethyl)-acetamide
106. 2-(3,4-Dihydro-lH-isoquinolin-2-yl)-N-(l-phenyl-ethyl)-acetamide
107. 2-(Benzhydryl-amino)-l -(1 ,3-dihydro-isoindol-2-yl)-ethanone
108. 2~(8-Amino-3 ,4-dihydro- lH-isoquinolin-2-yl)-N-benzhydryl-acetamide
109. 2-(8--Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4,4-diρhenyl-butyl)- acetamide
110. 2-[4,4-Bis-(4-fluoro-phenyl)-butyl]-l,2,3,4-tefrahydro-isoquinolin-8-ylamine
111. 2-(8-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2,2-diphenyl-ethyl)- acetamide
112. 2-(8-Acetylamino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4,4-diphenyl-butyl)- acetamide
113. N- [3 ,3 -Bis-(4-methoxy-phenyl)-propyl] -2-( 1 ,3 -dihydro-isoindol-2-yl)- acetamide
114. N-[3,3-Bis-(4-methoxy-phenyl)-propyl]-2-(3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
115. N-[3,3-Bis-(4-methoxy-phenyl)-propyl]-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide
116. N-[3-(3,4-Bis-acetylamino-phenyl)-3-phenyl-propyl]-2-(3,4-dihydro-lH- isoquinolin-2-yl)-acetamide
117. N-(4,4-Diphenyl-butyl)-2-(8-methanesulfonylamino-3,4-dihydro-lH- isoquiriolin-2-yl)-acetamide
118. N-[Bis-(4-fluoro-phenyl)-methyl]-2-(l ,3-dihydro-isoindol-2-yl)-acetamide
119. N- [Bis-(4-fluoro-phenyl)-methyl] -2-(3 ,4-dihydro- 1 H-isoquinolin-2-yl)- acetamide
120. N-[Bis-(4-fluoro-phenyl)-methyl] -2 -(8 -methoxy-3 ,4-dihydro- 1 H-isoquinolin-2- yl)-acetamide
121. N-[Bis-(4-fluoro-phenyl)-methyl]-2-(6,7-dimethoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide
122. 3-(5-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(3,3-diphenyl-propyl)- propionamide
123. 2-(5-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2,2-diphenyl-ethyl)- acetamide
124. 2-(Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4,4-diphenyl-butyl)- acetamide
125. 3 -(6,7-Diniethoxy-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N-(3 ,3 -diphenyl-propyl)- propionamide
126. 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2,2-diphenyl-ethyl)- acetamide
127 3-(8-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(3,3-diphenyl-propyl)- propionamide
128 N-(3-Carbazol-9-yl-propyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
129 N-(3-Carbazol-9-yl-propyl)-2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
130 N-[3-(5-Chloro-2-methyl-indol-l-yl)-ρropyl]-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide
131 N-[3-(5-Chloro-2-methyl-indol- 1 -yl)-propyl]-2-(8-hydroxy-3,4-dihydro- 1H- isoquinolin-2-yl)-acetamide
132 2-(8-Methoxy-3,4-dihydro-lH-isoquinoliή-2-yl)-l-phenoxazin-10-yl-ethanone 133 l-Benzhydryl-3-[2-(8Tmethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]- thiourea
134 l-Berιzhydryl-3-[2-(6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]- thiourea
135 l-Benzhydryl-3-[2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-urea 136 l-Benzhydryl-3-[2-(6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]- urea
137 l-(2,2-Diphenyl-ethyl)-3-[2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- ethylj-thiourea
138, l-[2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3-(2,2-diphenyl- ethyl)-thiourea
139 2-(8-Hydroxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -phenothiazin- 10-yl-ethanone 140 2-(8-Methoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -phenothiazin- 10-yl-ethanone 141 1 -(2-Chloro-phenothiazin- 10-yl)-2-(8-hydroxy-3 ,4-dihydro- lH-isoquinolin-2- yl)-ethanone
142 1 -(2-Chloro-phenothiazin- 10-yl)-2-(8-methoxy-3,4-dihydro- 1 H-isoquinolin-2- yl)-ethanone
143 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(5-oxo-5H-51ambda:1;4*- phenothiazin- 10-yl)-ethanone
144 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10-yl-ethanone 145. 2-(8-Hydroxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -(2-trifluoromethyl- phenothiazin- 10-yl)-ethanone
146. 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2-trifluoromethyl- phenothiazin- 10-yl)-ethanone
147. 1 -(2-Acetyl-phenothiazin- 10-yl)-2-(8-hydroxy-3 ,4-dihydro- lH-isoquinolin-2- yl)-ethanone
148. 1 -(2-Acetyl-phenothiazin- 10-yl)-2-(8-methoxy-3 ,4-dihydro- lH-isoquinolin-2- yl)-ethanone
149. 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N,N-diphenyl-acetamide
150. 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N,N-diphenyl-acetamide
151. 2-(6,7-Dimethoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -(5,5-dioxo-5H- 51ambda*6*-phenothiazin-l 0-yl)-ethanone
152. 2-(6,7-Dimethoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)-l -phenothiazin- 10-yl- ethanone
153. l-(2-Chloro-phenothiazin-10-yl)-2-(6,7-dimethoxy-3,4-dihydro-lH- " isoquinolin-2-yl)-ethanone -
154. 2-(6,7-Dimethoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -(2-trifluoromethyl- phenothiazin- 10-yl)-ethanone
155. l-(2-Acetyl-phenothiazin-10-yl)-2-(6,7-dimethoxy-3,4-dihydiO-lH- isoquinolin-2-yl)-ethanone
156. 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2-methylsulfanyl- phenothiazin- 10-yl)-ethanone
157. 2-(6,7-Dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)- 1 -(5-oxo-5H-51ambda*4*- phenothiazin- 10-yl)-ethanone
158. 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2-methylsulfanyl- phenothiazin- 10-yl)-ethanone
159. 2-(8-Methoxy-3,4-dihydro- lH-isoquinolin-2-yl)- 1 -(2-methylsulfanyl- phenothiazin- 10-yl)-ethanone
160. Phenothiazine-10-carboxylic acid [2-(8-hydroxy-3 ,4-dihydro- lH-isoquinolin-2- yl)-ethyl]-amide
161. 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
163. Phenoxazine- 10-carboxylic acid [2-(8-hydroxy-3,4-dihydro- lH-isoquinolin-2- yl)-ethyl] -amide
164. Phenoxazine- 10-carboxylic acid [2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethyl] -amide
165. Phenoxazine-10-carboxylic acid [2-(6,7-dimethoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl] -amide
166. N-[3,3-Bis-(4-fluoro-phenyl)-propyl]-3-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-propionamide
167. (8-Hydroxy-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-acetic acid N',N'-diphenyl- hydrazide
168. (8-Methoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)-acetic acid N',N'-diphenyl- hydrazide
169. (6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetic acid N',N'-diphenyl- hydrazide
170. 4-[2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3,4-dihydiO-2H- benzo[l,4]oxazine-2-carboxylic acid ethyl ester
171. 4-[2-(8-Methoxy-3 ,4-dilιydro- lH-isoquinolin-2-yl)-acetyl]-3 ,4-dihydro-2H- benzo[l,4]oxazine-2 -carboxylic acid ethyl ester
172. 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4-phenoxy-phenyl)- acetamide
173. 2-(5,8-Dihydro-6H-[ 1 ,7]naphthyridin-7-yl)- 1 -phenoxazin- 10-yl-ethanone
174. l-[2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3-(4-phenoxy- phenyl)-urea
175. 2-(8-.Amino-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -phenoxazin- 10-yl-ethanone
176. 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4-hydroxy-phenyl)-N- phenyl-acetamide
177. N-(4-Hydroxy-phenyl)-2-(8-methόxy-3,4-dihydro-lH-isoquinolin-2-yl)-N- phenyl-acetamide
178. 2-( 1 ,3-Dihydro-isoindol-2-yl)- 1 -phenoxazin- 10-yl-ethanone
179. 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(9H-xanthen-9-yl)- acetamide
180. 2-(8-Methoxy-3,4-dihydro- lH-isoquinolin-2-yl)-N-(9H-xanthen-9-yl)- acetamide
181. 2-(5,8-Dihydro-6H-[l,7]naρhthyridin-7-yl)-N,N-diphenyl-acetamide
182 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N,N-bis-(4-methoxy-phenyl)- acetamide
183 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N,N-bis-(4-methoxy-phenyl)- acetamide
184 2-(8-Methoxy-3,4-dihydro-lH-isoqμinolin-2-yl)-N-(2-phenoxy-phenyl)- acetamide
185 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2-phenoxy-phenyl)- acetamide
186 l-[(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetyl]-4,4- diphenylsemicarbazide
187 2-(8-Methoxy-3 ,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -[2-(5-methyl- [l,3,4]dxadiazol-2-yl)-2,3-dihy(3 o-benzo'[l,4]oxa-zih-4- l]-ethanone
188 N-(3-Amino-pyridin-2-yl)-N-(2-hydroxy-phenyl)-2-(8-methoxy-3,4-dihydro- lH-isoquinolin-2-yl)-acetamide
189 3-(8-Methoxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -phenoxazin- 10-yl-propan- 1 - one
190 3-(8-Hydroxy-3,4-dihydro- lH-isoquinolin-2-yl)- 1 -phenoxazin- 10-yl-propan- 1 - one
191 Methanesulfonic acid 2-(2-oxo-2-phenoxazin- 10-yl-ethyl)- 1 ,2,3 ,4-tetrahydro- isoquinolin-8-yl ester
192 l-(2,3-Dihydro-benzo[l,4]oxazin-4-yl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone
193 2-(7-Hydroxy-3 ,4-dihydro- lH-isoquinolin-2-yl)- 1 -phenoxazin- 10-yl-ethanone 194 2-(6-Hydroxy-3,4-dihydro- lH-isoquinolin-2-yl)-l -phenoxazin- 10-yl-ethanone 195 2-(5-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10-yl-ethanone 196 2-(4-Methoxy- 1 ,3 -dihydro-isoindol-2-yl)- 1 -phenoxazin- 10-yl-ethanone 197 N-Methanesulfonyl-N-[2-(2-oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro- isoquinolin-8-yl]-methanesulfonamide 198. N-[2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro-isoquinolin-8-yl]- methanesulfonamide
199. 2-(8-Methoxy-3,4-dihydro- lH-isoquinolin-2-yl)- 1 -( 1 -methyl- lH-4-oxa- 1 ,2,9- triaza-cyclopenta[b]naphthalen-9-yl)-ethanone
200. 2-(8-Methoxy-3,4-dihydro- 1 H-isoquinolin-2-yl)- 1 -phenoxazin- 10-yl-propan- 1 - one
201. Phenoxazine- 10-carboxylic acid [2-(5,8-dihydro-6H-[l,7]naphthyridin-7-yl)- ethyl] -amide
202. 2-(4-Hydroxy- 1 ,3-dihydro-isoindol-2-yl)- 1 -phenoxazin- 10-yl-ethanone
203. . Methanesulfonic acid 2-(2-oxo-2-phenoxazin-10-yl-ethyl)-2,3-dihydro-lH- isoindol-4-yl ester
204. l-Carbazol-9-yl-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
205. 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(3-methyl-2,3-dihydro- benzo[ 1 ,4]oxazin-4-yl)-ethanone
206. 1 -(3 -tert-Butyl-2,3 -dihydro-benzo [1,4] oxazin-4-yl)-2-(8 -methoxy-3 ,4-dihydro- " lH-isoquinolin-2-yl)-ethanone
207. l-(llH-Dibenzo[b,f][l,4]oxazepin-10-yl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone
208. l-(3-Ethyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethanone
209. 2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro-isoquinoline-8-sulfonic acid
210. N-[2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-2,3-dihydro-lH-isoindol-4-yl]- methanesulfonamide
211. l-(3-tert-Butyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-2-(8-hydroxy-3,4-dihydro- 1 H-isoquinolin-2-yl)-ethanone
212. 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-[3-(4-methoxy-phenyl)-2,3- dihydro-benzo[ 1 ,4]oxazin-4-yl]-ethanone
213. l-[3-(2,5-Dimethoxy-phenyl)-2,3-dihydro-benzo[l,4]oxazin-4-yl]-2-(8- methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
214. N-(4-{4-[2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetyl]-3,4-dihydro- 2H-benzo[l,4]oxazin-3-yl}-phenyl)-acetanιide 215. l-[3-(4-Fluoro-phenyl)-2,3-dihydro-benzo[l,4]oxazin-4-yl]-2-(8-methoxy-3,4- dihydro-lH-isoquinolin-2-yl)-ethanone
216. , l-[3-(3,4-Dimethoxy-phenyl)-2,3-dihydro-benzo[l,4]oxazin-4-yl]-2-(8- methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
217. 2-(4-Methoxy- 1 ,3 -dihydro-isoindol-2-yl)- 1 -phenoxazin- 10-yl-propan- 1 -one
218. 1 -( 1 ,3-Dihydro-isoindol-2-yl)-2-phenoxazin- 10-yl-ethanone
219. 2-(4-Chloro- 1 ,3 -dihydro-isoindol-2-yl)- 1 -phenoxazin- 10-yl-ethanone
220. 2-(2-Oxo-2-phenoxazin- 10-yl-ethyl)-2,3-dihydro- 1 H-isoindole-4-carbonitrile and pharmaceutically acceptable salts thereof. As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic,. benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. The compounds of the invention can contain one or more chiral centres. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non- racemic mixtures and pure enantiomers and/or diastereoisomers. Preferred compounds of the invention are optically active isomers. Thus, for example, preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer. or an excess of the S enantiomer. The compounds of formula (I) may be prepared by 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. 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 (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).
Scheme 1
Figure imgf000035_0001
(6) (4) (2) (3)
Figure imgf000035_0002
(5) (1)
Compounds of formula (1) in which m is 1 and X, Rj, n and R2 are defined as above (reaction scheme 2) 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. -Alternatively, 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.
Scheme 2
Figure imgf000036_0001
(10) (9) (1)
Compounds of formula (I) in which hi is 3 and X, Ri, n and R are defined as above (reaction scheme 3) 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. Alternatively, 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.
Scheme 3
Figure imgf000037_0001
Figure imgf000037_0002
(1) When R2 is -L-A and L is other than a direct bond, or when R2 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. When R2 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. Thus, 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. For example, compounds of formula (3) in which R2 is -(CH2)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 PBr3 (reaction scheme 4). 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
Figure imgf000038_0001
(16) (15) (14) (13)
Compounds of formula (3) in which R is -L-CH=C(A)2 where L and A are defined as above (reaction scheme 5) may be prepared from corresponding carboxylic acids by reduction in the presence of a reducing agent, for example lithium aluminium hydride, followed by halogenation in the presence of a halogenating reagent for example PBr3.
Scheme 5
Figure imgf000038_0002
(IS) (17) Compounds of formula (3) wherein R2 is -L7-Het-A7 can, for example, be prepared from compounds of formula (19) where Y is a leaving group, by reaction with compounds of formula (20) (reaction scheme 6). Compounds of formula (18) in which A7 is -CH2(A)2 may also be prepared from compounds of formula (16) and compounds of formula (20) by standard methods familiar to those skilled in the art. Thus, when Het is O or S, compounds (16) and (20) can be condensed in the presence of an acid catalyst, for example PTSA. When Het is NH the reaction between compounds (16) and (20) can be effected by standard methods such as reductive animation in the presence of a reducing agent, for example sodium borohydride. Scheme 6
A -Λ. Het-L'-X (20) X-L'-Het-A (18)
A O (16) Het-L'-X (20)
A'-Y (19)
When R2 is -L-CO-NR3R4 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. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 80°C. Further, - - compounds of formula (1) wherein R2 is -L-CS-NR3R-} may be prepared from compounds of formula (1) where R2 is -L-CO-NR3R4 by standard methods familiar to those skilled in the art such as sulphonation in the presence of Lawesson's reagent. Compounds of formula (3) in which R2 is -L-CO-NR3R4 can be prepared from amines (22) and compounds of formula (23), in which X7 is Cl or OH, under standard amide coupling reaction conditions (reaction scheme 7). Typically, where X7 is Cl, the reaction is effected in the presence of triethylamine.
Scheme 7
Figure imgf000039_0001
(22) (23) A further method for preparing compounds of formula (1) wherein X, m, Ri and n are defined as above and R2 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 X7 is Cl or OH, under standard amide coupling reaction conditions. Typically, where X7 is Cl, the reaction is effected in the presence of triethylamine. Alternatively, compounds of formula (1) where R2 is -CO-L-NRs i, L is a direct bond and i is hydrogen may be prepared from amines (2) by standard methods familiar to those skilled in the art such as alkylation with isocyanates (25). Similarly, compounds of formula (1) where R2 is -CS-L-N aRj and L is a direct bond may be prepared from amines (2) by standard methods such as alkylation with isothiocyanates (26). Compounds of formula (1) wherein R2 is -CS-L-NRs can, of course, be prepared from compounds of formula (1) where RNs ^L-CO-NR^R by standard methods familiar to those skilled in the art such as sulphonation using Lawesson's reagent.
Scheme 8
Figure imgf000040_0001
R,. NH S=C=NR3 I R3 (26) (22)
Figure imgf000040_0002
When R2 is -CO- A7, 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. Compounds of formula (1) wherein R2 is -CS-A7 can, of course, be prepared from compounds of formula (1) where R2 is -CO- A7 by standard methods familiar to those skilled in the art such as reaction with Lawesson's reagent. Compounds of formula (3), wherein R2 is -CO-L7-O-N=C(A)2 or -L-O- N=C(A) may be prepared from ketones (16) and hydroxylamine by standard methods familiar to those skilled in the art (reaction scheme 9). In reaction scheme 9, X and X7 represent leaving groups, for example chlorine. Further, an additional method of preparing compounds of formula (I) in which R2 is -CO-L7-O-N=C(A)2 or -L7-O-N=C(A)2 involves the reaction of a compound of formula (31) or (31a), wherein X is a leaving group, typically chlorine, and oximes (29) by standard methods as previously described. 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.
Scheme 9
Figure imgf000041_0001
(31a) The compounds ofthe invention are found to be inhibitors of sensory neurone specific sodium channels. The compounds ofthe invention are therefore therapeutically useful. Accordingly, 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. Also provided is 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. Further, the pharmaceutical 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. Typically, a said capsule or tablet comprises from 5 to 500 mg, preferably 10 to 500 mg, more preferably 15 to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds 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. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out ofthe inhaler. Typically, said propellant is a fluorocarbon. Further preferred inhalation devices include nebulizers. Nebulizers are devices capable of delivering fine liquid, mists of medication through a "mask" that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages. Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound ofthe 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'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. Thus, the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition. A further preferred route of administration is transdermal administration. The present invention therefore also provides a transdermal patch containing a compound 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. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyesruffs; 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, of " 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 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. 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. Accordingly, the present invention also provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of a condition involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone, more specifically hypersensitivity of a sensory neurone or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone. Also provided is a method of treating a patient suffering from or susceptible to a condition involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone, more specifically hypersensitivity of a sensory neurone or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone, which method comprises aidministerihg to" said patient an effective amount of a compound of formula (ϊ),'oϊ a " pharmaceutically acceptable salt thereof. The term treatment in this context is deemed to cover any effect from a cure of said condition to alleviation of any or all ofthe symptoms. The compounds ofthe invention may, where appropriate, be used prophylactically to reduce the incidence or severity of said conditions. Specific conditions in which SNS channels are present and believed to be involved, include pain, for example chronic and acute pain, hypersensitivity disorders such as bladder dysfunction and bowel disorders which may or may not also have associated pain, and demyelinating diseases. SNS sodium channels are known to mediate pain transmission. Typically, the compounds 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. Typically, therefore, 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. 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 Examples of 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. Examples of 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. Examples of 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. Examples of 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. Examples of 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). Examples of 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. Examples of 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, mόtomeufone 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. Examples of 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. 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. Preferably, daily dosage levels are from 5 mg to 2 g. The following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting SNS specific sodium channels. A negative result in any one particular assay is not determinative.
EXAMPLES
The HPLC analysis of Examples 1 to 8, 14 to 29, 32 to 35, 40 to 44 and 98 to 223 was conducted in the following manner: Solvent: MeCN/H2O/0.05% NH3, 5-95% gradient H2O-6 min; Column: Phenomenex 50 x 4.6 mm i.d., C18 reverse phase; and Flow rate: 1.5 mL/min, unless indicated otherwise.
The HPLC analysis of Examples 9 to 13, 30, 31, 36 to 39 and 45 to 48 was conducted in the following manner: Solvent: MeCN/H2O/0.05% NH3, 5-95% gradient H2O-10min; Column: Phenomenex 50 x 4.6 mm i.d., Cl 8 reverse phase; and Flow rate: 1.5mL/min, unless indicated otherwise.
The HPLC analysis of Examples 49 to 56, 58, 59 and 61 to 97 was conducted in the following manner: Solvent: MeCN/H2O/0.05% NH3, 5-95% gradient H2O-6min; Column: Xterra 50 x 4.60 i.d., Cl 8 reverse phase; and Flow rate: 1.5mL/min, unless indicated otherwise. -
The HPLC analysis of Example 60 was conducted in the following manner: Solvent: MeCN/H2O/0.05% NH3, 5-95% gradient H2O-10min; Column: Xterra 50 x 4.60 i.d., C18 reverse phase; and Flow rate: 1.5mL/min.
Example 1: N-Benzhydryl-2-chloro-acetamide
To a stirred solution of aminodiphenylmethane (Aldrich A5,360-5) (4.36g, 25.3 mmol) in CH2C12 (50 mL) was added Et3N (Aldrich 47, 128-3) (2.81 g, 27.77 mmol). The reaction mixture was cooled to approximately 10°C and chloroacetylchloride (Aldrich 10,449-3) (3.14g, 27.83 mmol) was added drop-wise over 5 min. The reaction mixture was stirred for 2h and quenched by the addition of distilled H2O (50 mL). The layers were separated and the organic layer washed with brine (50 mL), dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography to afford the title compound as a white solid (0.78g, 12%): HPLC retention time 3.67min. Mass Spectrum (ES+) m/z 260 (M+H). The following compounds were synthesized from the appropriate diphenylalkylamine and chloroacetylchloride according to the method described above:
2-Chloro-N-(2,2-diphenyl-ethyl)-acetamide;
2-Chloro-N-(3,3-diphenyl-propyl)-acetamide;
N-Benzyl-2-chloro-N-phenyl-acetamide;
N,N-Dibenzyl-2-chloro-acetamide;
2-Chloro-N-(9H-flurenyl-9-yl)-acetamide; N,N-Dibenzyl-3-chloro-propionamide;
2-Chloro- 1 -(3 ,4-dihydro- 1 H-isoquinolin-2-yl)-ethanone; and
2-Chloro-l-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethanone.
Example 2: 2-Chloro-N-(4,4-diphenyl-butyl)-acetamide
To a stirred solution of l-Bromo-3,3-diphenylpropane (Acros 27191231) (2g, 7.27mmol) in dimethyl sulphoxide (5 mL) was added potassium cyanide (Aldrich 20,781-0) (0.57g, 8.73mmol). The reaction mixture was stirred at room temperature for 19h and quenched by the addition of distilled H2O (20 mL). The resulting solution was extracted with EtOAc (3 x 20 mL) the combined organic layers dried (Na2SO4), filtered and the solvent removed in vacuo. The resulting residue was dissolved in anhydrous tetrahydrofuran (25 mL) and borane-tetrahydrofuran complex (Aldrich 17,619-2) (IM, 27 mL, 27mmol) was added drop wise over 5min. The reaction mixture was heated at reflux for 2h, cooled to 0°C and quenched with CH3OH (10 mL). The solvent was removed in vacuo and the residue azeotroped with CH3OH (3 x 15 mL). The residue was dissolved in CH2C12 (20 mL) and Et3N (1.39g, 13.69mmol) was added. The reaction mixture was cooled to approximately 10°C and chloroacetylchloride (Aldrich 10,449-3) (1.55g, 12.44mmol) was added drop-wise over 5min. The reaction mixture was stirred for 4h and quenched with distilled H2O (20 mL). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo The residue was purified by flash column chromatography to afford the title compounds a viscous oil (1.8g, 85%): HPLC retention time 4.04min. Mass Spectrum (ES+) m/z 302 (M+H). Example 3: 3-Chloro-N-(3,3-diphenyl-propyl)-propioπamide
To a stirred solution of 3,3 Diphenylpropylamine (Acros 15948-0250) (6.5g, 30.7mmol) in CH2C12 (50 mL) was added Et3N (Aldrich 47,128-3) (2.81g, 27.77 mmol). The reaction mixture was cooled to approximately 10°C and 3- chloropropionyl chloride (Aldrich C6,912-8) (4.29g, 30.7mmol) was added drop- wise over 5 min. The reaction mixture was stirred for 2h and quenched by the addition of distilled H2O (50 mL). The layers were separated and the organic layer washed with brine (50 mL), dried (Na2SO4) and the solvent remove in vacuo . The residue was purified by flash column chromatography and recrystallisation from EtOAc to afford the title compound as a white solid (3.1g, 33%): HPLC retention time 3.98min. Mass Spectrum (ES+) m/z 302 (M+H).
Example 4: 8-Methoxyisoquinoline
Ref: Y. Yoshida et al Bioorg. Med. Chem. 7 (1999) 2647-2666.
To a 1 L round bottom flask, equipped with a Dean-Stark trap, was added 2- methoxybenzaldehyde (Aldrich 10,962-2) (23.8g, 175mmol) in benzene (850 mL). To this stirred solution was added 2,2-dimethoxyethylamine (Aldrich 12,196-7) (18.3g, 175 mmol). The reaction mixture was refluxed for 5h, cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in tetrahydrofuran (238 mL) and cooled to c.a.-10°C, (external temperature maintained between -8°C to - 10°C with acetone/card-ice). To this cooled solution was added ethyl chloroformate (Aldrich 18,589-2) (18.9g, 174 mmol) over c.a, 5 min. The reaction mixture was allowed to warm to room temperature and treated with trimethyl phosphite (Aldrich T7,970-7) (25 mL, 212 mmol). The reaction mixture was stirred at room temperature for 60h, and evaporated in vacuo to give an oil. This oil was dissolved in CH C12 (238 mL) and cooled to 0°c (external temperature), treated with titanium tetrachloride (Aldrich 20,856-6) (200 g, 1.0 mol) over c.a. 8min, warmed to room temperature, heated at reflux for 3h, cooled to room temperature and stirred, overnight. The reaction mixture was diluted with CH2C12 (800mL) and cooled to c.a. 0°C and basified with 30% sodium hydroxide solution. The neutralised mixture was filtered through celite/sand diluting with c.a. 5 L of CH2C12. The CH2C12 layer was separated and dried over MgSO4, filtered and the solvent removed in vacuo. The resulting brown oil is purified by flash column chromatography using CH2Cl /CH3OH,.90/10, v/v as mobile phase to give the title compounds a red oil (19.7 g, 70%). 1H NMR (400MHz, DMSO-d6) δ 4.02 (3H), 7.12 (IH), 7.55 (IH), 7.75 (IH, ), 7.8 (IH), 8.50 (IH), 9.55 (IH).
Example 5: Isoquinolin-8-ol
Ref: Y. Yoshida et al Bioorg. Med. Chem. 7 (1999) 2647-2666.
To a stirred solution of 8-methoxyisoquinoline (7.0g, 44mmol) in anhydrous CH2C12 (60 mL) cooled in an ice bath, was added over 0.5h, boron tribromide, IM in CH2C12 (Aldrich 21 , 122-2) (219 mL, 219 mmol) . The reaction mixture was warmed to room temperature, heated at reflux for 2h, cooled to -78°C, and decomposed by the addition of CH3OH (150 mL). The reaction mixture was warmed to room temperature, heated at reflux for 0.5h and the solvent removed in vacuo. The residue was azeotroped with CH3OH (3 x 100 mL) and suspended in H2O (150 mL). To this suspension was added CH2C12 (300 mL) and with vigorous stirring neutralised to c.a. 7.0 with ammonia (0.88). The CH2C1 layer was separated and the aqueous layer extracted with CH C12 (2 x 200 mL). The combined layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography to give the title compoundas a pale yellow solid. (6.87g, 98%). 1H NMR (400MHz, DMSO- ) δ 7.10 (IH), 7.45 (IH), 7.65 (IH, ), 7.75(1H), 8.50 (IH), 9.50 (IH), 10.90 (IH).
Example 6: l,2,3,4-Tetrahydro-isoquinolin-8-ol acetate salt
US Patent 3,575,983
To a stirred solution of Isoquinolin-8-ol (2.0g, 13.8mmol) in ethanol (120 mL) was added acetic acid (2 mL) and platinum (IN) oxide (Aldrich 45,992-5) (0.2g). The . reaction mixture was hydrogenated at ca. 4bar for 18h. The catalyst was filtered off and the solvent removed in vacuo to give the title compound as a tan solid (5.2g, 92%): HPLC retention time 2.0min. Mass Spectrum (ES+) m z 150 (M+H). Example 7: 8-Methoxy-l,2,3,4-tetrahydro-isoquinoline acetate salt
Prepared according to the method described in Example 6: HPLC retention time 3.33min. Mass Spectrum (ES+) m/z 164 (M+H). Example 8: 2-(2-DibenzyIamino-ethyI)l,2,3,4-tetrahydro-isoquinoIm-8-ol)
To a stirred suspension of l,2,3,4-Tetrahydro-isoquinolin-8-ol acetate salt (l.Og, 4.78mmol) in MeCN (50mL) was added N-(chloroethy)dibenzylamine hydrochloride (Aldrich 29,136-6) (1.42g, 4.78mmol), tetrabutylammonium iodide (Aldrich 14,077- 5) (0.29g, 0.79mmol) and potassium carbonate (Acros ) (0.66g, 4.78mmol). The " 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 CH2C12 (80mL), washed with H2O (25mL), dried (Na2SO4) and the solvent remove in vacuo . The residue was purified by flash column chromatography using CH2Cl2/CH3OH/ ammonia, 95/5/0.2, v/v/v, as mobile phase to give the title compoundzs a low melting solid (0.71g, 39%) : IH NMR (400MHz, CDC13) δH 2.6-2.9 (8H), 3.55 (2H), 3.65(4H), 6.5(1H), 6.95(1H), 7.2-7.5(1 IH). HPLC retention time 7.27min. Mass Spectrum (ES+) m/z 373 (M+H). Example 9 : 2-[4,4-Bis-(4-fluoro-phenyl)-butyl]-l,253,4-tetrahydro-isoquinoline
Prepared according to the method described in Example 8. HPLC retention time 8.29min. Mass Spectrum (ES+) m/z 378(M+H). 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 11 : 2-(2,2-Diphenyl-ethyl)-l,2,3,4-tetrahydro-isoq inoline-8-ol
To a stirred solution of l,2,3,4-Tetrahydro-isoquinolin-8-ol acetate salt (0.120g, 0,57mmol) in CH3OH (5mL) was added Et3N (Aldrich 47,128-3) (0.058g, 0.57mmol). The reaction mixture was stirred for 0.5h , diphenylacetaldehyde (Aldrich D20-245-0) (0.113g, 0.57mmol) in CH3OH (5mL), and sodium cyanoborohydride (Aldrichl 5,615-9) (0.036g, 0.57mmol) was added. The reaction mixture was stirred for 18h. The solvent was removed in vacuo and the residue was purified by flash column chromatography using CH2Cl2/CH3OH, 95/5 w to afford the title compound as a white solid (0.032g, 17%). HPLC retention time 3.21min. Mass Spectrum (ES+) m/z 330(M+H).
Example 12: 2-(2,2-DiphenyI-ethyl)l,2,3,4-tetrahydro-isoquinolme
Prepared according to the method described in Example 11 but with CH2C12 as the reaction solvent. HPLC retention time 4.96min. Mass Spectrum (ES+) m/z 314(M+H).
Example 13: 2-(2,2-Diphenyl-ethyl)-8-methoxy-l,2,3,4-tetrahydro-isoquinoline
Prepared according to 'the method described in Example 11 but with CH2C12 as the reaction solvent. HPLC retention time 4.96min. Mass Spectrum (ES+) m/z 344(M+H).
Example 14: N-Benzyhydryl-2-(3,4-dihydro-lH-isoquinolin-2-yl)-acetamide
To a stirred solution of l,2,3,4-Tetrahydroisoquinoline (AldrichA5,5560-8) (0.133g, lmmol) in MeCN (15mL) was added potassium carbonate (Acros P/4120/50) 0.138g, lmmol) ), tetrabutlylammonium iodide (Aldrich 14,077-5) (0.074g, 0.02mmoι). To this suspension was added N-Benzhydryl-2-chloro-acetamide (0.259g, lmmol) in MeCN (lOmL). The reaction mixture was heated at reflux for 8h, cooled to room temperature and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography using iso-hexane.EtOAc as mobile phase to afford the title compound as a clear oil (0.256g, 72%). HPLC retention time 4. Mass Spectrum (ES+) m/z 357(M+H).
Example 15: 2-(3,4-Dihydro-lH-isoquinolm-2-yl)-N-(9H-fluorenyl)-acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.34min. Mass Spectrum (ES+) m/z 355(M+H).
Example 16: N,N-Dibenzyl-2-(3,4-dihydro-lH-isoquinolin-2yl)-acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.41min. Mass Spectrum (ES+) m/z 371(M+H).
Example 17: N-Benzyl-2-(3,4-dihydro-lH-isoquinolin-2-yl)-N-phenyl-acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.24min. Mass Spectrum (ES+) m/z 357(M+H).
Example 18: 2-(3,4-Dihydro-lH-isoquinolin-2yl)-N-(3,3-diphenyl-propyl)- acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.35min. Mass Spectrum (ES+) m/z 385(M+H).
Example 19 : N-Benzhydryl-2-(8-methoxy~3,4-dihy dro-lH-isoquinolin-2-yl)- acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.30min. Mass Spectrum (ES+) m/z 387(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 21: N-Benzhydryl-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N- phenyl-acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.15min. Mass Spectrum (ES+) m/z 387(M+H).
Example 22 : N-(3,3-Diphenyl-propyl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.22min. Mass Spectrum (ES+) m/z 415(M+H).
Example 23 : N,N-Dibenzyl-2-(8-hydroxy-3,3-dihydro-lH-isoqumolin-2-yl)- acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.21min. Mass Spectrum (ES+) m/z 387(M+H).
Example 24: N-Benzhydryl-2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.03min. Mass Spectrum (ES+) m/z 373(M+H).
Example 25: N-Benzyl-2-(8-hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N- phenyl-acetamide
Prepared according to the method described in Example 14. HPLC retention time 3.99min. Mass Spectrum (ES+) m/z 373(M+H). Example 26: N-(9H-fluoren-9-yl)-2-(8-hydroxy-3,4-dihydro-lH-isoquinoIin-2- yl)-acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.02min. Mass Spectrum (ES+) m/z 371 (M+H).
Example 27: N-(3,3-Diphe-αyl-propyl)-2-(8-hydroxy-3,4-dihydro-lH-isoqumolin- 2-yl)-acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.10min. Mass Spectrum (ES+) m/z 401 (M+H).
Example 28: 2-(3,4-Dihydro-lH-isoqumolin-2-yl)-N-[l-(5-methyl-thiazol-2-yl)- ethyl]-acetamide
Prepared according to the method described in Example 14. HPLC retention time 3.73min. Mass Spectrum (ES+) m/z 316(M+H).
Example 29: 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolm-2-yl)-N-[l-(5-methyI- thiazol-2-yl)-ethyl] -acetamide
Prepared according to the method described in Example 14. HPLC retention time 3.21min. Mass Spectrum (ES+) m/z 332(M+H).
Example 30: l-(3,4-Dihydro-lH-isoquinoline-2-yI-3,3-bis-(4-fluoro-phenyI)- propan-1-one
To a stirred solution of 1,2,3,4-Tetrahydroisoquinoline (AldrichA5,5560-8) (0.102g, 0.76mmol) in CH2C1 (5mL) was added 3,3-Bis-(4-fluro-phenyl)-propionyl chloride (0.107g, 0.33mmol). The reaction mixture was stirred for 5h and the solvent removed in vacuo. The residue was purified by flash column chromatography using CH Cl2as mobile phase followed by preparative HPLC to give the title compound as an oil (3.4mgs, (2%). HPLC retention time 4.39min. Mass Spectrum (ES+) m/z 378(M+H).
Example 31 : 2-(Benzhydryl-amino)-l-(3,4-dihydro-lH-isoquinolin-2-yl)- ethanone
To a stirred solution of 2-Chloro-l-(3,4-dihydro-lH-isoquinolin-2-yl)-ethanone (0.150g, 0.71mmol) in acetonitril was added of aminodiphenylmethane (Aldrich A5,360-5) (0.131g, 0.7l'ππnol), tetrabutlylammonium iodide (Aldrich 14,077-5) (0.53g, 0.14mmol) and potassium carbonate (Acros ) (0.99g, 0.71mmol). The reaction mixture was heated at reflux for 5h and cooled to room temperature and the solvent removed in vacuo. The residue was purified by column chromatography using EtOAc/iso-hexane, 1/1, v/v, to give the title compound as a colourless oil (O.lOg, 39%). HPLC retention time 6.65min. Mass Spectrum (ES+) m/z 357(M+H>.
Example 32 : l-(3,4-Dihydro-lH-isoquinolin-2-yl)-2-(2,2-diphenyl-ethylami-αo)- ethanone
To a stirred solution of 2-Chloro-l-(3,4-dihydro-lH-isoquinolin-2-yl)-ethanone (0.209g, l.Ommol) was added (0.197g, l.Ommol), 2,2-Diphenylpropyamine (Aldrich D20-670-9)(0.2113g, l.Ommol) tetrabutlylammonium iodide (Aldrich 14,077-5) (0.369g, 0.074mmol) and potassium carbonate (Acros ) (0.99g, 0.71mmol). The reaction mixture was heated at reflux for 18h, cooled to room temperature and the solvent removed in vacuo. The residue was purified by column chromatography using EtOAc/iso-hexane, 1/3, v/v, to give the title compound as a colourless oil (0.047g, 12 %). HPLC retention time 4.24min. 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
Prepared according to the method described in Example 31. HPLC retention time 4.70min. Mass Spectrum (ES+) m/z 558(M+H). Example 34: l-(3,4-Dihydro-lH-isoquinoIin-2-yϊ)-2-(3,3-diphe-αyl-propyIamino)- ethanone
Prepared according to the method described in Example 31. HPLC retention time 4.30min. Mass Spectrum (ES+) m/z 385(M+H).
Example 35: 2-Dibenzylamino-l-(3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
Prepared according to the method described in Example 31. HPLC retention time 4.72min. Mass Spectrum (ES+) m/z 371 (M+H).
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
Prepared according to the method described in Example 31.' HPLC retention-time - 4.75min. Mass Spectrum (ES+) m/z 604(M+H).
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-α-2-yl)-etlιaιιone
Prepared according to the method described in Example 31. HPLC retention time 7.57min. Mass Spectrum (ES+) m z 560(M+H).
Example 38: 2-(Benzhydryl-amino)-l-(8-methoxy-3,4-dihydro-lH-isoquinolme- 2-yl)-ethanone
Prepared according to the method described in Example 31. HPLC retention time 6.18min. Mass Spectrum (ES+) m/z 387(M+H).
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).
Example 40: 2-(l,3-Dihydro-isomdol-2-yl)-N-(3,3-diphenyl-propyl)-acetamide
To a stirred solution of isoindoline (Aldrich 51,557-4) (0.25g, 2.1mmol) in MeCN (15mL) was added 2-Chloro-N-(3,3-diphenyl-propyl)-acetamide (0.60g, 2.1mmol), tetrabutlylammonium iodide (Aldrich 14,077-5) (0.16g, 0.42mmol) and Et3N ) (Aldrich 47,128-3) (600μl, 2. lmmol). The reaction mixture was heated at reflux for 4h and cooled to room temperature, and the solvent removed in vacuo The residue was dissolved in CH2C1 (lOOmL), washed with H O (20mL), dried (Na2SO4) and the solvent remove in vacuo . The residue was purified by flash column chromatography using EtOAc/iso-hexane, 1/1 as mobile phase to give the title compounds, a tan solid (0.25g, 32%). HPLC retention time 4.33min. Mass Spectrum (ES+) m/z 371 (M+H).
Example 41 : N-Benzhydryl-2-(l,3-dmydro-isoindol-2-yl)-acetamide
Prepared according to the method described in Example 40. HPLC retention time 4.32min. Mass Spectrum (ES+) m z 343(M+H).
Example 42: 2-Benzhydrylideneaminooxy-l-(3,4-dihydro-lH-isoquinoline-2-yl)- ethanone
To a suspension of sodium hydride 60% dispersion in mineral oil (Aldrich 2,344-1) in dimethyl foramide (2mL) cooled in an ice bath was added benzophenone oxime (Lancaster 0817) (0.47g, 2.39mmol). The reaction mixture was removed from the ice bath and stirred at room temperature for 0.5h. To this solution was added 2-Chloro-l- (3,4-dihydr -lH-isoquinolin-2-yl)-ethanone (0.5g, 2.39mmol) in dimethyl formamide (lmL). The reaction was stirred for 18h, diluted with H2O (30mL), extracted with Et2O (50mL), dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by preparative HPLC (Solvent: MeCN/H2O/0.05% NH3, 5-95% gradient H2O-6min. Column: Phenomenex 50 x 4.6 mm i.d., C18 reverse phase. Flow rate: 15mL/min.) to give the title compound as a glass (0.44g, 55%). HPLC retention time 4.53min. Mass Spectrum (ES+) m/z 371 (M+H).
Example 43: 2-BenzhydryIideneaminooxy-l-(8-methoxy-3,4-dihydro-lH- isoquinoli-αe-2-yl)-ethanone
Prepared according to the method described in Example 42. HPLC retention time 4.48min. Mass Spectrum (ES+) m/z 401(M+H).
Example 44: 2-(Di-pyridin-2-yl-methyleneaminooxy)-l-(8-methoxy-3,4-dihydro- lH-isoquinoline-2-yl)-ethanone
Prepared according to the method described in Example 42. HPLC retention time 3.50min. Mass Spectrum (ES+) m/z 403(M+H).
Example 45: 2-(5-Phe-Qyl-2H-[l,2,3]triazol-4-ylmethyl)-l,2,3,4-tetrahydro- isoquinolin-8-ol
5-Phenyl-2H-[l, 2, 3]-triazole-4-carbaldehyde:
To a stirred solution of phenylacetylene (Aldrich 11,770-6) (5.1g, 50 mmol) in anhydrous tetrahydrofuran (125 mL) at - 40°C under nitrogen was added dropwise over c.a 2 min nButyl lithium (Aldrich 18,617-1) (31.3 mL, -50 mmol) whilst maintaining the temperature (internal) between -35°C to - 40°C with external cooling. To this solution was added anhydrous dimethyl formamide (7.75 mL) and the reaction mixture allowed to warm to room temperature, stirred for 0.5h and quenched by pouring into a rapidly stirred biphasic solution of 10% potassium dihydrogen phosphate (270 mL) and methyl tert-butyl ether (250 mL), cooled to c.a. -5°C. The layers were separated and the aqueous layer back extracted with methyl tert-butyl ether (100 mL). The combined organic layers were washed with H2O (2 x 200 mL), dried (MgSO4) and evaporated to dryness in vacuo to give a yellow oil which was purified by flash column chromatography to give 6.1 g of a pale yellow oil. A solution of this oil (3.1g in dimethyl sulphoxide (17.5 mL) was added to a vigorously stirred solution of sodium azide (Aldrich 19,993-1) (1.79g, 27.5 mmol) over c.a. 10 min whilst maintaining the temperature (internal) between 20 to 25°C. The 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). The aqueous layers were re-extracted with methyl tert-butyl ether (100 mL) and the combined organic layers dried over (MgSO4) and evaporated in vacuo to afford the title compound as an off white solid (3.1g, 65%): 1H NMR (400MHz, CDC13) δH 7.46-7.59 (3H), 7.66-7.89 (2H), 10.14 (IH), 16.08 (IH, ).
2-(5-Phenyl-2H-[l , 2, 3]triazol-4-ylmethyl)-l, 2, 3, 4-tetrahydro-isoquinolin-8-ol:
To a stirred solution of 1 ,2,3,4-Tetrahydro-isoquinolin-8-ol acetate salt (0.120g, 0,57mmol) in CH3OH (5mL) was added Et3N (Aldrich 47,128-3) (0.058g, 0.57mmol). The reaction mixture was stirred for 0.5h, 5-phenyl-2H-[l,2,3]-triazole- 4-carbaldehyde (0.025g, 0.14mmol) in CH3OH (5mL), and sodiύm cyanoborohydride (Aldrichl 5,615-9) (0.009g, 0.14mmol) was added. The reaction mixture was heated at reflux for 5h, cooled to room temperature and the solvent removed in vacuo . The residue was purified by flash column chromatography using EtOAc/iso-hexane 1/1, v/v as mobile phase to afford the title compound as a viscous oil (0.004g, 10%). HPLC retention time 2.54min. Mass Spectrum (ES+) m/z 306(M+H).
Example 46: [2-(3,4-Dihydro-lH-isoquinolin-2-yl)-ethyl]-(3,3-diphenyϊ-propyl)- amine
To a stirred solution of 2-(3,4-Dihydro-lH-isoquinolin-2yl)-N-(3,3-diphenyl-propyl)- acetamide : (0.184g, 0.047mmol) in tetrahydrofuran (lOmL) was added lithium aluminium hydride IM in Et2O (Aldrich 21,279-2) (lOmL, lO mol). The reaction mixture was heated at reflux 8h, cooled to room temperature and stirred for 18h. The reaction mixture was quenched with CH2C12 (30mL) and sodium hydroxide solution (2M, 4mL). The CH2C12 layer was separated, washed with H2O dried (Na2SO ) and the solvent removed in vacuo. The residue was purified by preparative HPLC (Solvent: MeCN/H2O/0.05% NH3, 5-95% gradient H2O-10min. Column: Phenomenex 50 x 19 mm i.d., C18 reverse phase. Flow rate: 15mL/min.), to give the title compound as a pale yellow oil (0.007g, 3.9%). HPLC retention time 7.76min. Mass Spectrum (ES+) m/z 371 (M+H).
Example 47: Dibenzyl-[2-(3,4-dihydro-lH-isoquinoIm-2-yl)-ethyI]-amine
Prepared according to the method described in Example 46. HPLC retention time 8.48min. Mass Spectrum (ES+) m/z 357(M+H).
Example 48: 2-(2-Benzyloxy-propyl)~l,2,3,4-tetrahydro-isoquinolin-8-ol
To a stirred solution of 2-Benzyloxypropionic acid (0.318g, 1.76mmol) in CH2C1 (3mL) was added oxalyl chloride (Aldrich O-880-1) (1.12g, 8.83mmol). The reaction mixture was stirred at room temperature for 5h and the solvent and excess reagent removed inNacuo. The residue was dissolvedϊn CΗ2C12 (2mL) and added to a- stirred solution of l,2,3,4-Tetrahydro-isoquinolin-8-ol acetate salt (0.367g, 3.52mmol), Et3N (Aldrich 47,128-3) (0.356g, 3.52mmol) in CH2C12 (2mL) and the reaction mixture was stirred overnight. The reaction mixture was diluted with 5% hydrochloric acid (5mL), separated and the organic layer washed with H2O (5mL), brine (5mL), dried, (Na2SO4) and the solvent remove in vacuo. The residue (0.147g) was dissolved in tetrahydrofuran (2mL) and Lithium aluminium hydride (Aldrich 21,277-6). (IM in THF, lmL, lmmol). The reaction mixture was heated at reflux for 2h, cooled to room temperature and diluted with CH2C1 (lOmL). The mixture was extracted with H2O (5mL x 2), brine (5mL), dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography. to afford the title compound as a oil (0.073g, .52%).. HPLC retention time 3.1 lmin. Mass Spectrum (ES+) m/z 298 (M+H).
Example 49: 4-Methoxy-l,3-dihydro-lH-isoindole-2-carbothioic acid benzhydryl-amide
2-Benzyl-4-methoxy-2, 3-dihydro-2H-isoindole: 2,3-Dimethylanisole (Acros, 15999) (12.5 g, 91.8 mmol), N-bromosuccinimide (Aldrich, B8.125-5) (32.6 g, 183.5 mmol) and benzoyl peroxide (Lancaster, 13174) (300 mg) were refluxed in CC1 (200 mL) for 20 hrs. The reaction was cooled and the insoluble material removed by filtration. The solid was washed with CC1 and the combined filtrate concentrated in vacuo to afford a yellow solid which was used without further purification. The yellow solid and benzyltriethylammonium chloride (Acros, 16402) (0.75 g, 3.3 mmol) were dissolved in a mixture of 50%aqs NaOH (40 mL) and toluene (175 mL). To the solution was added drop-wise, benzylamine (Aldrich, 18,570-1) (91.8g, 101 mmol) over 15mins at ambient temperature. Once addition was complete, the reaction was stirred for 24hrs at rt. The organic layer was separated, washed with brine (3 x 100 L), dried (MgSO4) and concentrated in vacuo. The residue was purified via flash chromatography, eluting with EtOAc/ isohexane (1:15) to afford 2-benzyl-4-methoxy-2,3-dihydro-lH-isoindole as a red oil. Yield 6.5g (30%o). HPLC retention time 4.2 lmin. Mass spectrum (ES+) m/z 240 (M + H).
4-Methoxy-2, 3-dihydro-lH-isoindole: 2-Benzyl-4-methoxy-2,3-dihydro-lH-isoindole (1.9g, 7.94mmol) was dissolved in CH3OH (50mL) and placed in a 250mL autoclave. 10% Palladium on activated charcoal (Acros, 19503) (300mg) was added and the reaction was hydrogenated at 3.5bar for 24hrs. When complete, the catalyst was separated via filtration, and the solvent was removed in vacuo. The residue was purified via flash chromatography • eluting with MeOH/CH2Cl2 (1 :4) to afford 4-methoxy-2,3-dihydro-lH-isoindole as a beige solid. Yield 0.720g (61 %). HPLC retention time, 3.07min. Mass spectrum (ES+) m/z 150 (M + H).
4-Methoxy-l, 3-dihydro-lH-isoindole-2-carbothioic acid benzhydryl-amide
2-Benzyl-4-methoxy-2,3-dihydro-lH-isoindole (50mg, 0.335mmol) and benzhydryl isothiocyanate (Fluorochem, 18194) (75mg, 0.335mmol) were stirred in toluene (2mL) for 24hrs at ambient temperature. The solvent was removed in vacuo and the residue was purified via flash chromatography eluting with EtOAc/isohexane (1 :4) to afford the title compound as a white solid. Yield 95mg (76%). HPLC retention time 4.50min. Mass spectrum (ES+) m/z 375 (M + H).
5 Example 50: 3,4-Dihydro-lH-isoquinpline-2-carbothioic acid benzhydryl-amide
Prepared according to the method described in Example 49. HPLC retention time, 4.49min. Mass spectrum (ES+) m/z 359 (M + H). .
10 Example 51: 3,4-Dihydro-lH-isoquinoline-2-carbothioic acid (2,2-diphenyl- ethyl)-amide
Prepared according to the method described in Example 49 : HPLC retention time, 4.59min. Mass spectrum (ES+) m/z 373 (M + H). " 15 Example 52: 8-Methoxy-3,4-dihydro-lH-isoquinolin-2-carbothioic "acid (2,2- diphenyl-ethyl)-amide
Prepared according to the method described in Example 49. HPLC retention time 20 4.53min. Mass spectrum (ES+) m/z 403 (M + H).
Example 53: 3,4-Dihydro-lH-isoquinoline-2-carbothioic acid benzhydryl-amide
Prepared according to the method described in Example 49. HPLC retention time 25 4.51min. Mass spectrum (ES+) m/z 389 (M + H).
Example 54: 7-Methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-carbothioic acid benzhydryl-amide
30 Prepared according to the method described in Example 49. HPLC retention time 4.46min. Mass spectrum (ES+) m/z 403 (M + H). Example 55: 7-Methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-carbothioic acid (2,2-diphenyI-ethyI)-amide
Prepared according to the method described in Example 49. HPLC retention time 4.53min. Mass spectrum (ES+) m/z 417 (M + H).
Example 56: Example 2: N-Benzhydryl-2~(4-methoxy-l,3-dihydro-isoindol-2- yl)-acetamide
A solution of 2-benzyl-4-methoxy-2,3-dihydro-lH-isoindole (75 mg, 0.50 mmol), K2CO3 (69mg, 0.50mmol) and tetrabutylammonium iodide (Aldrich, 14,077-5) (37mg, 0. lmmol) in MeCN (3 mL) was stirred at rt for 30 mins. N-Benzhydryl-2- chloro-acetamide (130 mg, 0.5 mmol) was added and the reaction was refluxed for 5 hrs. The reaction mixture was allowed- to cool, diluted with MeCN (5 mL), and the solids removed by filtration. The solvent was removed in vacuo and the residue purified via flash chromatography eluting with EtOAc/isohexane (1 :2)"to afford the title compound as a pale green solid. Yield 60 mg (32%). HPLC retention time 4.24min. Mass spectrum (ES+) m/z 373 (M + H).
Example 57: N-(2,2-Diphenyl-ethyl)-2-(4-methoxy-l53-dihydro-isoindol-2-yl)- acetamide
Prepared according to the method described in Example 56. HPLC retention time 3.10min (Solvent: MeCN/H2O/0.05% HCOOH, 5-95% gradient H2O-6min. Column: Xterra 50 x 4.60 i.d., C18 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 387 (M + H).
Example 58: N-(3,3-Diphenyl-propyl)-2-(4-methoxy-l,3-dihydro-isoindol-2-yl)- acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.32min. Mass spectrum (ES+) m/z 401 (M + H). Example 59 : N-(4,4-Diphenyl-butyl)-2-(4-methoxy-l ,3-dihydro-isoindol-2-yl)- acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.41min. Mass spectrum (ES+) m/z 415 (M + H).
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 61 : N-(2,2-Dipheuyl-ethyl)-2-(8-methoxy-3;,4-dilιydro-lH-isoquinolin- 2-yl)-acetamide
" Prepared according to he method described in Example 56. HPLC retention time 4.57min. Mass spectrum (ES+) m/z 401 (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: '
A solution of 1-benzhydryl-piperazine (Acros, 12293) (5.05g, 20mmol) and Et3N (2.22g, 22mmol) in CH2C12 (20 mL) was cooled to 5°C using an ice/H2O cooling. Chloroacetyl chloride (Aldrich, 10,449-3) (2.5g, 22mmol) in CH2C12 (5mL) was added drop wise such that the temperature remained below 20°C. Once addition was complete, the reaction was stirred for for a further 18hrs at ambient temperature. Deionised H O (50 mL) was added and stirring continued for a further lhr. The organic layer was separated, washed with brine (3 x 100 mL), dried (MgSO4) and concentrated in vacuo to afford l-(4-benzhydryl-piperazin-l-yl)-2-chloro-ethanone as a brown oil, which was used without further purification. Yield 6.8g (95%). HPLC retention time, 4.22min. Mass spectrum (ES+) m/z 329 (M + H). l-(4-Benzhydryl-piperazin-l-yl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- ethanone:
Prepared according to the method described in Example 55. HPLC retention time, 4.77min. Mass spectrum (ES+) m/z 456 (M + H).
Example 63 : l-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-l-yl}-2-(8-methoxy- 3,4-dihydro-lH-isoquinolin-2-yl)-ethanone
l-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-l-yl}-2-chloro-ethanone:
Prepared according to the method described in Example 62. HPLC retention time 4.26min. Mass spectrum (ES+) m/z 365 (M + H).
l-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-l -yl}-2-(8-methOxy-3,4-dihydro-lΗ- - isoquinolin-2-yl)-ethanone:
Prepared according to the method described in Example 55. HPLC retention time 4.74min. Mass spectrum (ES+) m z 492 (M + H).
Example 64: l-(4-Benzhydryl-piperazin-l-yl)-2-(3,4-dihydro-lH-isoquinolin-2- yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.71min. Mass spectrum (ES+) m/z 426 (M + H).
Example 65: l-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-l-yI}-2-(3,4-dihydro- lH-isoquinolin-2-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.66min. Mass spectrum (ES+) m/z 461 (M + H). Example 66: 2-(l,3-Dihydro-isoindol-2-yl)-N-(2,2-diphenyI-ethyl)-acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.28min. Mass spectrum (ES+) m/z 357 (M + H). .
Example 67: l-(4-Benzhydryl-piperazin-l-yl)-2-(l,3-dihydro-isoindol-2-yl)- ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.50min. Mass spectrum (ES+) m/z 412 (M + H).
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 (CD3)2SO)DH 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-354-dihydro-lH-isoquinolin-2-yl)-N-(phenyl-pyridin- 2-yl-methyl)-acetamide
2-Chloro-N-(phenyl-pyridin-2-yl-methyl)-acetamide: ■ Prepared according to the method described in Example 1. Yield 600mg (98%). HPLC retention time 3.40min. Mass spectrum (ES+) m/z 261 (M + H).
2-(8-methoxy~3,4-dihydro-lH-isoquinolin-2-yl)-N-(phenyl-pyridin-2-yl-methyl)7 acetamide:
Prepared according to the method described in Example 56. HPLC retention time 4.15min. Mass spectrum (ES+) m/z 388 (M + H). 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
2-(2-Nitro-phenoxy)-l-phenyl-ethanone:
A solution of 2-nitrophenol (Aldrich, NI ,970-2) (13.9 g, 100 mmol) and K2CO3 (15.2 g, 10 mmol) was stirred in MeCN (50 mL) at rt for 30mins. KI (1.83 g, 11 mmol) was added in one portion followed by phenacyl bromide (Lancaster, 6260) (19.9g, lOOmmol) in portions. After addition the reaction was stirred for 24hrs at RT, and poured onto ice/H2O (lltr) with stirring. The solid was separated via filtration and washed with H2O. The solid was dried and recrystallized ex IPA (300mL) to afford 2-(2-nitro-phenoxy)-l-phenyl-ethanone as cream coloured crystals. Yield 20g (80%). HPLC retention time 3.83min. Mass spectrum (ES+) m/z 258 (M + H).
3-Phenyl-3,4~dihydro-2H-betιzo[l ,4] oxazine:
To a stirred solution of sodium hypophosphite (Aldrich, 24,366-3) (50g) in deionised H2O (200mL) and THF (200mL) containing 2-(2-nitro-phenoxy)-l-phenyl-ethanone (lOgj 39mmol) was added 10% Palladium on activated charcoal (Acros,19503) (lg). The reaction was stirred at RT for 18hrs sodium hypophosphite (Aldrich, 24,366-3) (50g) and 10% Palladium on activated charcoal (Acros,19503) (lg) was added and the reaction was stirred for a further 18hrs at RT. The catalyst was filtered off and the two phase mixture was diluted with deionised H2O and extracted with Et2O (x3). The combined extracts were washed with H2O and dried over MgSO4. The solvent was removed in vacuo to afford 3 -phenyl-3,4-dihydro-2H-benzo[ 1,4] oxazine as a red oil which was used without further purification. Yield 8.2g (100%).
2-Chloro-l-(3-phenyl-2,3-dihydro-benzo[l,4]oxazin-4-yl)-ethanone:
Prepared according to the method described in Example 62. HPLC retention time 3.91min (Solvent: MeCN/H2O/0.05% HCOOH, 5-95% gradient H2O-6min. Column: Xterra 50 x 4.60 i.d., C18 reverse phase. Flow rate: 1.5mL/min.). IH NMR (400 MHz (CD3)2SO)DH4.45-4.55 (2H), 4.80 (IH), 4.95 (IH), 5.80 (IH), 6.80 (IH), 6.90 (IH), 7.00 (IH), 7.20-7.25 (IH), 7.30-7.35 (4H), 7.80 (IH). Mass spectrum (ES+) m/z 288 (M + H).
2-(8-Hydroxy-3, 4-dihydro-lH-isoquinolin-2-yl)-l -(3-phenyl-2, 3-dϊhydro- benzofl ,4] 'oxazin-4-yl)-ethanone:
Prepared according to the method described in Example 56. HPLC retention time 6.30min (Solvent: MeCN/H2O/0.05% NH3, 5-95% gradient H2O-10min. Column: Xterra 50 x 4.60 i.d., C18 reverse phase. Flow rate: 1.5mL/min.). IH NMR (400 MHz (CD3)2SQ)DH 2.60-2.70 (4H), 3.45-3.65 (4H), 4.35 (IH), 4.90 (IH), 5.95 (IH), 6.50 (IH), 6.55 (IH), 6.75 (IH), 6.85-6.90 (2H), 6.95-7.00 (IH), 7.15 (IH), 7.20- 7.30 (4H), 8.00 (IH), 9.30 (IH). Mass spectrum (ES+) m/z 401 (M + H).
Example 71 : 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(3-phenyl-2,3- dihydro-benzo [1,4] oxazin-4-yl)-etIianone
Prepared according to the method described in Example 56. HPLC retention time 4.49min. Mass spectruni (ES+) m/z 415 (M + H).
Example 72: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10- yl-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.53min. Mass spectrum (ES+) m/z 387 (M + H).
Example 73: l-(10,ll-Dihydro-dibenzo[b,f]azepin-5-yl)-2-(8-methoxy-3,4- dihydro-lH-isoquinolin-2-yI)~ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.37min. Mass spectrum (ES+) m/z 399 (M + H).
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 75: N,N-Diisopropyl-2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.26min. Mass spectrum (ES+) m/z 305 (M + H).
Example 76: N-(4,4-Diphenyl-butyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin- 2-yl)-acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.55min. Mass spectrum (ES+) m/z 429 (M + H).
Example 77: N-(3,3-Diphenyl-propyl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yI)-propionamide
Prepared according to the method described in Example 56 with the following modification: the reaction was refluxed for 24hrs. HPLC retention time 4.36min. Mass spectrum (ES+) m/z 429 (M + H).
Example 78: N,N-Dibenzyl-3-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- propionamide
Prepared according to the method described in Example 56 with the following modification: the reaction was refluxed for 24hrs. HPLC retention time 4.45min. Mass spectrum (ES+) m/z 415 (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:
Dipehenyl-acetaldehyde (Aldrich, D20,425-0) (lg, 5. lmmol) was dissolved in CH2C12 (lOmL) and tetrabutylammonium bromide (Aldrich, 19,311-9) (161mg, 0.5mmol) was added followed by 1.2-MNaOH solution (lOmL) and 1,3- dibromopropane (Aldrich, 12,590-3) (5.14g, 25.5mmol) with vigorous stirring. The reaction was stirred at RT for 18hrs and acidified with 2M HCI (lOmL). The organic phase was separated and washed well with H O, before being dried (MgSO4). The solvent was removed in vacuo and the residue was purified via flash chromatography eluting with EtOAc/isohexane (3:97) to afford a colourless oil. Yield 890mg (55%>).
2-[3-(2, 2-Diphenyl-vinyloxy)-propyl] -8-methoxy-l , 2, 3, 4-tetrahydro-isoquinoline:
Prepared according to the method described in Example 5. HPLC retention time 5.02min. IH NMR (400 MHz CDCI^DH 2.0 (2H), 2.65-2.70 (4H), 2.85-2.90 (2H), 3.55 (2H), 3.80 (3H), 4.00-4.05 (2H), 6.55 (IH), 6.65 (IH), 6.70 (IH) 7.10 (ffl), 7.18-7.24 (4H), 7.25-7.35 (4H), 7.38-7.44 (2H). Mass spectrum (ES+) m/z 400 (M + H).
Example 80: N-Benzhydryl-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 4.40min. Mass spectrum (ES+) m/z 401 (M + H).
Example 81: N-(2,2-Diphenyl-ethyl)2-(7-methoxy-l,3,4,5-tetrahydro- benzo[c]azepm-2-yl)-acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.39min. Mass spectrum (ES+) m/z 415 (M + H).
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).
Example 83: N,N-Dibenzyl-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 415 (M + H).
Example 84: 2-Thiophen-2-ylmethyl-l,2,3,4-tetrahydro-isoqumolin-8-ol
A solution of l,2,3,4-tetrahydro-isoquinolin-8-ol acetic acid salt (75 mg, 0.358 mmol) andEt3N (36mg, 0.358mmol) in CH3OH (2 mL) was stirred at ambient temperature for 30mins. 2-Thiophenecarboxaldehyde (Aldrich T3,240-9) (40mg, 0.358mmol) was added and the reaction was stirred for 2hrs-at room temperature. Sodium cyanoborohydride (Aldrich, 15,615-9) (23mg, 0.358mmol) was added and the reaction was stirred at RT for 18hrs. The solvent was removed in vacuo and the residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (2:98) to afford the title compound™ a white solid. Yield 28mg (32%). HPLC retention time, 3.43min. IH NMR (400 MHz (CD3)2SO)DH 2.70-2.75 (2H),2.85-2.90 (2H), 3.60 (2H), 3.95 (2H), 6.50-6.60 (2H), 6.90-6.95 (IH), 6.95-7.0 (IH), 7.05 (IH), 7.35 (IH). Mass spectrum (ES+) m/z 246 (M + H).
Example 85: (lH-Benzoimidazol-5-yl)-(3,4-dihydro-lH-isoquinotin-2-yl)- methanone
To a solution of 5-benzimidazolecarboxylic acid (Aldrich, 29,678-3) (324mg, 2mmol) in CH2C12/DMF (9:1) (lOmL) was added: 1,2,3,4-tetrahydro-isoquinoline (Aldrich, Tl,300-5) (320mg, 2.4mmol), Et3N (404mg, 4mmol), 1- hydroxybenzotriazole (Acros, 16916) (405mg, 3mmol) and l-[3-(dimethylamino)- proρyl]-3-ethyl-carbodiimide (ACT, RC8102) (460mg, 2.4mmol) and the reaction was stirred at RT for 18hrs. The reaction mixture was diluted with EtOAc (10 mL), washed (5% citric acid), (sat. sodium bicarbonate), and (brine). The organic layer was dried (MgSO ) and concentrated in vacuo. The residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (5:95) to afford the title compound as a brown oil. Yield 15mg (3%). HPLC retention time 3.09min. Mass spectrum (ES+) m/z 278 (M + H).
Example 86: N-(3,3-Diphenyl-propyl)-2-(7-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-acetamide [2-(4-methoxy-phenyl)-ethyl]-carbamic acid methyl ester:
4-Methoxyphenethylamine (Aldrich, 18,730-5) (25.8g, 17 lmmol) and Et3N (20.7g, 205mmol) were dissolved in anhydrous THF (lltr) and cooled to 0°C. Methyl chloroformate (Aldrich, M3,530-4) 80.8g, 855mmol) was added drop wise keeping the temperature at 0°C. After addition the reaction was stirred at 0°C for a further " 2hrs and at RT for 18hrs. Deionised H2O (250mL) was added aήdihe resulting-" solution was extracted into Et2O (400mL) and EtOAc (2x300mL). The combined extracts were washed with brine (3x500mL) and IM HCI (3x400mL). The organic layer was dried over dried MgSO4 and the solvent was removed in vacuo to afford a yellow oil which quickly solidified. This was slurried in isohexane, filtered and washed with isohexane to afford [2-(4-methoxy-phenyl)-ethyl]-carbamic acid methyl ester as a white solid, which was used without further purification. Yield 29g (83%).
7-Methoxy-3,4-dihydro-2H-isoquinolin-l-one:
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. This solution was extracted with CH2C1 (3x50mL) and the combined extracts were washed with brine (2x50mL), dried (MgSO ) and the solvent removed in vacuo. The residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (10:90) to afford 7-methoxy-3,4-dihydro-2H-isoquinolin-l-one. Yield 3.3g (75%). HPLC retention time 3.41min (Solvent: MeCN/H2O/0.05% HCOOH, 5-95% gradient H2O-10min. Column: Xterra 50 x 4.60 i.d., C18 reverse phase. Flow rate: 1.5mL/min.). Mass spectrum (ES+) m/z 178 (M + H).
7 -Methoxy- 1, 2, 3, 4-tetrahydro-isoquinoline hydrochloride:
Lithium aluminium hydride, 1.0M solution in THF (Aldrich, 21,277-6) (22mL, 22mmol) was added drop wise to 7-methoxy-3,4-dihydro-2H-isoquinolin-l-one (3.0g, 17mmol) in THF (25mL) at RT. After addition the reaction was refluxed for 3hrs. The reaction was cooled to 0°C and quenched by the careful addition of deionised H O (lmL), 10% NaOH solution (lmL) and deionised H2O (3mL). The basic suspension was filtered through celite and extracted into EtOAc (3xl50mL). The combined extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified via flash chromatography eluting with
MeOH/CH2Cl2 (10:90) to afford T-nιethoxy-l,2,3 4-tetrahydr -lso"quinoline. This was dissolved in EtOAc (lOmL) and hydrogen chloride, 2.0m solution in Et2O (Aldrich, 45,518-0) (lOmL) was added drop wise, which formed a white ppte. The solid was filtered off and washed with Et2O to afford 7-methoxy- 1,2,3, 4-tetrahydro- isoquinoline hydrochloride as a wliite solid. Yield 1.4g (42%). HPLC retention time, 3.05min. Mass spectrum (ES+) m/z 164 (M + H).
Η-(3,3-Diphenyl-propyl)-2-(7 -methoxy-3, 4-dihydro-lH-isoquinolin-2-yl)-acetamide:
7-Methoxy-l,2,3,4-tetrahydro-isoquinoline hydrochloride (200mg, lmmol) was • stirred in MeCN (lOmL) with K2CO3 (276mg, 2mmol) and TBAI (Aldrich, 14,077- 5) (74mg, 0.2πimoι) for 30mins. 2-Chloro-N-(3,3-diphenyl-ρropyI)-acetamide (288mg, lmmol) was added and the reaction was refluxed- for 24hrs. The reaction was cooled, diluted with MeCN (lOmL) and the insoluble material was removed via filtration. The solvent was removed in vacuo and the residue was purified via flash chromatography eluting with EtoAc/isohexane (1:4) to afford the title compound as an orange oil. Yield 150mg (36%) HPLC retention time, 4.45min. Mass spectrum (ES+) m/z 415 (M + H). Example 87: N,N-DibenzyI-2-(7-methoxy-3,4-dihydro-lH-isoquinolm-2-yl)- acetamide
Prepared according to the method described in Example 86. HPLC retention time 4.53min. Mass spectrum (ES+) m/z 401 (M + H).
Example 88: DibenzyI-[2-(7-methoxy-3,4-dihydro-lH-isoquinolm-2-yl)-ethyl]- amine
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 H2O (lmL), 10% NaOH solution (lmL) and deionised H2O (3mL). The basic suspension was filtered "through'celϊte "and exfraϋte'd mfo'EtOAc" (3xl50mL). The combined extracts were dried over MgSO and the solvent was removed in vacuo. The residue was purified via flash chromatography eluting with MeOH/CH2Cl2 (10:90) to afford Dibenzyl-[2-(7-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amine. HPLC retention time 5.13min. Mass spectrum (ES+) m/z 387 (M + H).
Example 89: (3,3-Diphenyl-propyl)-[2-(7-methoxy-3,4-dihydro-lH-isoquinolin- 2-yl)-ethyl] amine
Prepared according to the method described in Example 88. HPLC retention time, 4.91min. Mass spectrum (ES+) m/z 401 (M + H).
Example 90: 2-(3,5-Bis-trifluoromethyl-benzyl)-l ,2,3,4-tetrahydro-isoquinolin- 6-ol
A solution of l,2,3,4-Tetrahydro-isoquinolin-6-ol (0.05 g, 0.13 mmol), 1- bromomethyl-3,5-bis-trifluoromethyl-benzene (0.041 g, 0.13 mmol) and K2CO3 (0.018 g, 0.13 mmol) in MeCN ( 2 mL) was shaken at ambient temperature for 16 hours. The reaction was filtered through a plug of cotton wool, concentrated in vacuo and purified by flash chromatography to afford the title compound. HPLC retention time, 1.26 min. Mass spectrum (ES+) m/z 376 (M + H).
Example 91 : 2-(2-Chloro-6-fluoro~benzyl)-l,2,3,4-tetrahydro-isoquinoIin-8-ol
Prepared according to the method described in Example 90. HPLC retention time 0.97 min. Mass spectrum (ES+) m/z 292 (M + H).
Example 92 : 2-(2,5-Difluoro-benzyI)-l,2,3,4-tetrahydro-isoquinoIin-8-ol
Prepared according to the method described in Example 90. HPLC retention time,
1.26 min. Mass spectrum (ES+) m/z 276 (M + H).
Example 93 : 2-(3,5-Difluoro-benzyl)-l ,2,3,4-tetrahydro-isoquinolin-8-ol
Prepared according to the method described in Example 90. HPLC retention time 0.97 min. Mass spectrum (ES+) m/z 276 (M + H).
Example 94 : 2-(4-Trifluoromethylsulfanyl-benzyI)-l ,2,3,4-tetrahydro- isoquinolin-8-ol
Prepared according to the method described in Example 90. HPLC retention time 1.24 min. Mass spectrum (ES+) m/z 340 (M + H),
Example 95: 2-(3,5-Bis-trifluoromethyl-benzyI)-l,2,3,4-tetrahydro-isoquinoIin- S-ol
Prepared according to the method described in Example 90. HPLC retention time,
1.27 min. Mass spectrum (ES+) m/z 376 (M + H). Example 96 : 2-[4,4-Bis-(4-fluoro-phenyl)-butyl]-l,2,3,4-tetrahydro-isoquinolin- 8-oI
Prepared according to the method described in Example 90. HPLC retention time 1.46 min. Mass spectrum (ES+) m/z 394 (M + H).
Example 9 : 2-[4,4-Bis-(4-hydroxy-3,5-dimethyl-phenyl)-pentyl]-l,2,3,4- tetrahydroisoquinoIin-8-ol
Prepared according to the method described in Example 90. HPLC retention time 1.41 min. Mass spectrum (ES+) m/z 460 (M + H).
Example 98: N,N-Dibenzyl-2-(8-ethoxy-3,4-dihydro-lH-isoquinolin-2- yl)acetamide
Prepared according to he method described in Example 14. _HPLC retention time^ 4.72min. Mass Spectrum (ES+) m/z 415 (M+H).
Example 99 : N-(4,4-Diphenyl-butyl)-2-(8-ethoxy-3,4-dihydro-lH-isoquinoIin-2- yl)aeetamide
Prepared according to the method described in Example 14: HPLC retention time 4.68min. Mass Spectrum (ES+) m/z 443(M+H).
Example 100: 2-(8-Ethoxy-3,4-dihydro-lH-isoqumolm-2-yl)-l-(3phenyI-2,3- dihydro-benzo[l,4]oxazin-4-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.60min. Mass Spectrum (ES+) m/z 429(M+H). Example 101 : N-(3-Benzhydryloxy-propyl)-2-(8-methoxy-3,4-dihydro~lH- isoquinolin-2-yI)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.43min. Mass Spectrum (ES+) m/z 445 (M+H).
Example 102 : 2-(l ,3-Dihydro-isoindol-2-yl)-N-(3,3-diphenyl-propyl)acetamide
Prepared according to the method described in Example 40. HPLC retention time 4.33min. Mass Spectrum (ES+) m/z 371 (M+H).
Example 103: N-(2-Benzhydrylsulphanyl-ethyl)-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.55minr Mass Spectram-(ES+)-m z 47(M+H).-
Example 104: 2-(8-AHyIoxy-3,4-dihydro-lH-isoqumolra-2-yl)-N-(3,3-diphenyl- propyl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.59min. Mass Spectrum (ES+) m/z 441(M+H).
Example 105 : 2-(4-Amino-l ,3-dihydro-isoindol-2-yl)-N-(2,2-diphenyl- ethyl)acetamide
Prepared according to the method, described in Example 14. HPLC retention time 3.93min. Mass Spectrum (ES+) m/z 373 (M+H).
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).
Example 107: 2-(4-Amino-l,3-dihydro-isomdol-2-yl)-N-(4,4-diphenyl- butyl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.14min. Mass Spectrum (ES+) m/z 400(M+H).
Example 108: 2-(4-Amino-l,3-dihydro-isomdol-2-yl)-N,N-dibenzylacetamide
Prepared according to the method described in Example 14. HPLC retention time 4.03min. Mass Spectrum (ES+) m/z 372(M+H).
Example 109: 2-[4,4-Bis-(4-fluorophenyl)-butyl]-2,3-dihydro-lH-isoindol-4- ylamine
Prepared according to the method described in Example 14. HPLC retention time 4.50min. Mass Spectrum (ES+) m/z 379(M+H).
Example 110: N-[2-(Diphenylmethanesulphinyl)-ethyl]-2-(8-methoxy-3,4- dihydro-lH-isoquinoIin-2-yl)acεtamide
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 CH2C12 to afford the title compound. HPLC retention time 3.85min. Mass Spectrum (ES+) m/z 463(M+H).
Example 111: N-[2-φiphenylmethanesulphonyl)-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 CH2C12 to afford the title compound. HPLC retention time 3.26min. Mass Spectrum (ES+) m/z 479(M+H).
Example 112: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(lphenyl- ethyl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.04min. Mass Spectrum (ES+) m/z 325(M+H).
Example 113: 2-(3,4-Dihydro-lH-isoquinolin-2-yl)-N-(lphenyl-ethyl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 3.99min. "Mass Spectrum (ES+) m/z 295(M+H).
Example 114: 2-(Benzhydryl-amino)-l-(l,3-dihydro-isoindol-2-yl)-ethanone
Prepared according to the method described in Example 14. HPLC retention time 4.12min. Mass Spectrum (ES+) m/z 343(M+H).
Example 115: 2-(8-Amino-3,4-dihydro-lH~isoqumolin-2-yl)-N- benzhydrylacetamide
Prepared according to the method described in Example 14. HPLC retention time 3.99min. Mass Spectrum (ES+) m/z 372(M+H).
Example 116: 2-(8-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4,4-diphenyl- butyl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.13min. Mass Spectrum (ES+) m/z 414(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 119: 2-(8-Acetylamino-3,4-dihydro-lH-isoquinolin-2-yI)-N-(4,4- diphenyl-butyl)acetamide
2-(8-Acetylamino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4,4-diphenyl- butyl)acetamide was prepared from 2-(8-amino-3,4-dihydro-lH-isoquinolin-2-yl)-N- (4,4-diphenyl-butyl)acetamide (1 eq.) and acetylchloride (1 eq) in CH2C12 to afford the title compound. HPLC retention time 4.2 lmin. Mass Spectrum (ES+) m/z 456(M+H).
Example 120: N-[3,3-Bis-(4-methoxyphenyl)-propyl]-2-(l,3-dihydro-isoindol-2- yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.30min. Mass Spectrum (ES+) m/z 431 (M+H).
Example 121 : N-[3,3-Bis-(4~methoxyphenyl)-propyl]-2-(3,4-dihydro-lH- isoquinolin-2-yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time ' 4.42min. Mass Spectrum (ES+) m/z 445 (M+H). Example 122: N-[3,3-Bis-(4-methoxyphenyl)-propyl]-2-(8-methoxy-3,4-dihydro- lH-isoquinoIin-2-yI)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.31min. Mass Spectrum (ES+) m/z 475(M+H).
Example 123: N-[3-(3,4-Bis-acetylaminophenyl)-3phenyl-propyl]-2-(3,4- dihydro-lH-isoquinolin-2-yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 3.67min. Mass Spectrum (ES+) m/z 499(M+H).
Example 124: N-(4,4-Diphenyl-butyl)-2-(8-methanesulphonylamino-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 CH2C12 to afford the title compound. HPLC retention time 3.99min. Mass Spectrum (ES+) m/z 492(M+H).
Example 125: N-[Bis-(4-fluorophenyl)methyl]-2-(l,3-dihydro-isoindol-2- yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.28min. Mass Spectrum (ES+) m/z-379(M+H).
Example 126: N-[Bis-(4-fluorophenyl)methyl]-2-(3,4-dihydro-lH-isoquinolin-2- yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.42min. Mass Spectrum (ES+) m/z 393(M+H). Example 127: N-[Bis-(4-fluorophenyl)methyl]-2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl) acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.44min. Mass Spectrum (ES+) m/z 423(M+H).
Example 128: N-[Bis-(4-fluorophenyl)methyl]-2-(6,7-dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.13min. Mass Spectrum (ES+) m/z 453 (M+H).
Example 129: 3-(5-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(3,3-diphenyl- propyl)propionamide
Prepared according to the method described in Example 14. HPLC retention time 3.87min. Mass Spectrum (ES+) m/z 414(M+H).
Example 130: 2-(5-Amino-3,4-dihydro-lH-isoqumolin-2-yl)-N-(2,2-dip-henyl- ethyl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 3.90min. Mass Spectrum (ES+) m/z 386(M+H).
Example 131 : 2-(Dimethoxy-3,4-dihydro-lH-isoquinoIin-2-yl)-N-(4,4-diphenyl- butyl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.25min. Mass Spectrum (ES+) m/z 459(M+H).
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 133: 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2,2- diphenyl-ethyl) acetamide
Prepared according to the method described in Example 14: HPLC retention time 4.07min. Mass Spectrum (ES+) m/z 431 (M+H).
Example 134: 3-(8-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-N-(3,3-diphenyl- propyl)propionamide
Prepared according to the method described in Example 14. HPLC retention time 3.97min. Mass Spectrum (ES+) m/z 414(M+H).
Example 135: N-(3-Carbazol-9-yl-propyl)-2-(8-methoxy-3,4-dihydro-lH- isoquinoIin-2-yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.47min. Mass Spectrum (ES+) m/z 428(M+H).
Example 136: N-(3-Carbazol-9-yl-propyl)-2-(8-hydroxy-3,4-dihydro-lH- isoquinolin-2-yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.07min. Mass Spectrum (ES+) m/z 414(M+H).
Example 137: N-[3-(5-Chloro-2-methyl-indoI-l-yl)-propyl]-2-(8-methoxy-3,4- dihydro-lH-isoquinolin-2-yl)acetamide
Prepared according to the method described in Example 14. HPLC retention time 4.48min. Mass Spectrum (ES+) m/z 426(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
Prepared according to the method described in Example 14. HPLC retention time 4.06min. Mass Spectrum (ES+) m/z 413(M+H).
Example 139: l-Benzhydryl-3-[2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- ethyl]-thiourea
1 -Benzhydryl-3 -[2-(8-methoxy-3 ,4-dihydro- 1 H-isoquinolin-2-yl)-ethyl]-thiourea was prepared from 2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)ethylamine (leq) and benzhydryl isothiocyanate (leq) in CH2C12 to afford the title compound. HPLC retention time 4.55min. Mass Spectrum (ES+) m/z 432(M+H).
Example 140: l-Benzhydryl-3-[2-(6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethyl]-thiourea
Prepared according to the method described in Example 139. HPLC retention time 4.23min. Mass Spectrum (ES+) m/z 462(M+H).
Example 141 : l-Benzhydryl-3-[2-(8-methoxy-3,4-dihydro-lH-isoquinolin-2-yl)- ethyl]-urea
Prepared according to the method described in Example 139. HPLC retention time 4.18miή. Mass Spectrum (ES+) m/z 416(M+H). Example 142: l-Benzhydryl-3-[2-(6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2- yl)-ethyl]-urea
Prepared according to the method described in Example 139. HPLC retention time 3.86min. Mass Spectrum (ES+) m/z 446(M+H).
Example 143: l-(2,2-Diphenyl-ethyl)-3-[2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl]-thiourea
Prepared according to the method described in Example 139. HPLC retention time 4.55min. Mass Spectrum (ES+) m/z 446(M+H).
Example 144: l-[2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-3- (2,2-diphenyl-ethyl)-thiourea
Prepared according to the method described in Example 139: HPLC retentiontime" 4.23mm. Mass Spectrum (ES+) m/z 476(M+H).
Example 145: 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenothiazin- 10-yl-ethanone
Prepared according to the method described in Example 56. HPLC retention time - 4.06min. Mass Spectrum (ES+) m/z 389(M+H).
Example 146: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenothiazin- 10-yI-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.56min. Mass Spectrum (ES+) m/z 403(M+H).
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
Prepared according to the method described in Example 56. HPLC retention time 4.82min. Mass Spectrum (ES+) m/z 438(M+H).
Example 149: 2-(8-Methoxy-3,4-dihydro-lH-isoqumolin-2-yl)-l-(5-oxo-5H- 5Iambda*4*-phenothiazm-10-yl)-ethanone
Prepared according to the method described in Example 110. HPLC retention time 3.94min. Mass Spectrum (ES+) m/z 419(M+H).
Example 150: 2-(8-Hydroxy-374-dihydro-lΗ-isoquinolin=2^yl)-l-phenoxazin-l 0- yl-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.12min. Mass Spectrum (ES+) m/z 373(M+H).
Example 151 : 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- trifluoromethyl-phenothiazin-10-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.40min. Mass Spectrum (ES+) m/z 457(M+H).
Example 152: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- trifluoromethyl-phenothiazin-10-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.83min. Mass Spectrum (ES+) m/z 471 (M+H). Example 153: l-(2-Acetyl-phenothiazm-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 3.93min. Mass Spectrum (ES+) m/z 431 (M+H).
Example 154: 1 -(2-Acetyl-phenothiazin-l 0-y l)-2-(8-methoxy-3,4-dihy dro-1 H- isoquinolin-2-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.37min. Mass Spectrum (ES+) m/z 445(M+H).
Example 155: 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N,N- diphenylacetamide
Prepared according to the method described in Example 56. HPLC retention time 3.75min. Mass Spectrum (ES+) m/z 359(M+H).
Example 156: 2-(8-Metkoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N,N- diphenylaeetamide
Prepared according to the method described in Example 56. HPLC retention time 4.22min. Mass Spectrum (ES+) m/z 373(M+H).
Example 157: 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(5,5-dioxo- 5H-5Iambda*6*-phenothiazin-10-yI)-ethanone
Prepared according to the method described in Example 111. HPLC retention time 3.76min. Mass Spectrum (ES+) m/z 465(M+H).
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
Prepared according to the method described in Example 56. HPLC retention time 4.46min. Mass Spectrum (ES+) m/z 468(M+H).
Example 160: 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinoIm-2-yI)-l-(2- trifluoromethyl-phenothiazin-10-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.53min. Mass Spectrum (ES+) m/z 501 (M+H).
Example 161 : l=(2-Acetyl-phenothiazin-10-yl)-2-(6,7-dimethoxy-3,4-dihydro-~ lH-isoquinolm-2-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.06min. Mass Spectrum (ES+) m z 475 (M+H).
Example 162: 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- methylsulphanyl-phenothiazm-l 0-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.40min. Mass Spectrum (ES+) m/z 479(M+H).
Example 163: 2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(5-oxo-5H- 51ambda*4*-phenothiazin-10-yl)-ethanone
Prepared according to the method described in Example 110. HPLC retention time 3.56min. Mass Spectrum (ES+) m/z 449(M+H). Example 164: 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- methylsulphanyl-phenothiazin-l 0-yl)-ethanone
Prpeared according to the method described in Example 56. HPLC retention time 4.26min. Mass Spectrum (ES+) m/z 435(M+H).
Example 165: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-(2- methylsulphanyl-phenothiazin-10-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.70min. Mass Spectrum (ES+) m/z 449(M+H).
Example 166: Phenothiazine-10-carboxylic acid [2-(8-hydroxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl] -amide
Prepared according to the method described in Example 56 "with" the following* modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 3.86min. Mass Spectrum (ES+) m/z 418(M+H).
Example 167: Phenothiazine-10-carboxylic acid [2-(6,7-dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)-ethyl] -amide
Prepared according to the method described in Example 56 with the following modification: tetrabutylammom'um iodide was not used and triethylamine was used as a base. HPLC retention time 4.04min. Mass Spectrum (ES+) m/z 357(M+H).
Example 168: Phenothiazine-10-carboxylic acid [2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide
Prepared according to the method described in Ex;ample 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 4.62min. Mass Spectrum (ES+) m/z 357(M+H). Example 169: Phenoxazine-10-carboxylic acid [2-(8-hydroxy-3,4-dihydro-lH- isoquinolin-2-yI)-ethyl]-amide
Prepared according to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 4.61min. Mass Spectrum (ES+) m/z 432(M+H).
Example 170: Phenoxazine-10-carboxylic acid [2-(8-methoxy-3,4-dihydro-lH- isoquinolin-2-yl)-ethyl]-amide
Prepared according to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 3.84min. Mass Spectrum (ES+) m/z 402(M+H).
Example 172: Phenoxazine-10-carboxylic acid [2-(6,7-dimethoxy-3,4-dihydro- lH-isoquinolin-2-yl)-ethyl]-amide
Prepared according to the method described in Example 56 with the following modification: tetrabutylammonium iodide was not used and triethylamine was used as a base. HPLC retention time 4.26min. Mass Spectrum (ES+) m/z 416(M+H).
Example 173 : N-[3,3-Bis-(4-fluorophenyl)-propyl]-3-(8r-methoxy-3,4-dihydro- lH-isoquinolin-2-yl)propionamide
Prepared according to the method described in Example 56. HPLC retention time 3.9min. Mass Spectrum (ES+) m/z 465(M+H).
Example 174: (8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetic acid N',N'- diphenyl-hydrazide
Prepared accordmg to the method described in Example 56. HPLC retention time 3.42min. Mass Spectrum (ES+) m/z 374(M+H). Example 175: (8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yI)-acetic acid N',N'- diphenyl-hydrazide
Prepared according to the method described in Example 56. HPLC retention time 3.85min. Mass Spectrum (ES+) m/z 388(M+H).
Example 176: (6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetic acid N',N'-diphenyl-hydrazide
Prepared according to the method described in Example 56. HPLC retention time 3.55min. Mass Spectrum (ES+) m/z 418(M+H).
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
Prepared according to the method described in "Example 56. "HPLC retention ime ~ 4.01min. Mass Spectrum (ES+) m/z 397(M+H).
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
Prepared according to the method described in Example 56. HPLC retention time 4.22min. Mass Spectrum (ES+) m/z 411 (M+H).
Exampe 179: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(4- phenoxyphenyl)acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.18min. Mass Spectrum (ES+) m/z 389(M+H).
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
Prepared according to the method described in Example 139. HPLC retention time 3.5min. Mass Spectrum (ES+) m/z 418(M+H).
Example 182: 2-(8-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10-yl- ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.09min. Mass Spectrum (ES+) m/z 372(M+H).
Example 183 : 2-(8-Hydroxy-3,4-dikydro-lH-isoquinolin-2-yl)-N-(4- hydroxyphenyl)-Nphenylacetamide
Prepared according to the method described in Example 56. HPLC retention time 3.98min. Mass Spectrum (ES+) m/z 375(M+H).
Example 184: N-(4-Hydroxyphenyl)-2-(8-methoxy-3,4-dihydro-lH-isoquinolin- 2-yl)-Nphenylacetamide
Prepared according to the method described in Example 56. HPLC retention time 4.54min. Mass Spectrum (ES+) m/z 433(M+H).
Example 185: 2-(l,3-Dihydro-isoindol-2-yl)-l-phenoxazin-10-yl-ethanone
Prepared according to the, method described in Example 56. HPLC retention time 4.44min. Mass Spectrum (ES+) m/z 343 (M+H). Example 186: 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(9H-xanthen-9- yl)acetamide
Prepared according to the method described in Example 56. HPLC retention time 3.96min. Mass Spectrum (ES+) m/z 387(M+H).
Example 187: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(9H-xanthen-9- yl)acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.56min. Mass Spectrum (ES+) m/z 401 (M+H).
Example 188: 2-(5,8-Dihydro-6H-[l,7]naphthyridin-7-yl)-N,N- diphenylacetamide
Prepared according to the method described in Example 56" with" the following - modification:- triethylamine was used as base. HPLC retention time 3.44min. Mass Spectrum (ES+) m/z 344(M+H).
Example 189: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yϊ)-N,N-bis-(4- methoxyphenyl)acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.22min. Mass Spectrum (ES+) m/z 433(M+H).
Example 190: 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N,N-bis-(4- methoxyphenyl)acetamide
Prepared according to the method described in Example 56. HPLC retention time . 3.63min. Mass Spectrum (ES+) m/z 419(M+H).
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 192: 2-(8-Hydroxy-3,4-dihydro-lH-isoquinolin-2-yl)-N-(2- phenoxyphenyl)acetamide
Prepared according to the method described in Example 56. HPLC retention time 4.17min. Mass Spectrum (ES+) m/z 375(M+H).
Example 193 : l-[(8-Methoxy-3,4-dihydro-lH-isoquinoIin-2-yI)-acetyl]-4,4- diphenylsemicarbazide
Prepared according to the method described in Example 56. HPLC retention time 3.76min. Mass Spectrum (ES+) m/z 431 (M+H).
Example 194: 2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-[2-(5-methyl- [l,3,4]oxadiazol-2-yl)-2,3-dihydro-benzo[l,4]oxazin-4-yI]-ethanone
Prepared according to the method described in Example 56. HPLC retention time 3.76min. Mass Spectrum (ES+) m/z 431 (M+H).
Example 195: N-(3-Amino-pyridin-2-yl)-N-(2-hydroxyphenyl)-2-(8-methoxy-3,4- dihydro-lH-isoquinolin-2-yl)acetamide
Prepared according to the method described in Example 56. HPLC retention time 3.79min. Mass Spectrum (ES+) m/z 405(M+H).
Example 196: 3-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-l 0- yl-propan-1-one
Prepared according to the method described in Example 56. HPLC retention time 4.52min. Mass Spectrum (ES+) m/z 401 (M+H). Example 197: 3-(8-Hydroxy-3,4-dihydro-lH-isoquinoIin-2-yl)-l-phenoxazin-l 0- yl-propan-l-one
Prepared according to the method described in Example 56. HPLC retention time 3.93min. Mass Spectrum (ES+) m/z 387(M+H).
Example 198: Methanesulphonic acid 2-(2-oxo-2-phenoxazin-10-yI-ethyl)- 1 ,2,3,4-tetrahydro-isoquinolin-8-yl ester
Prepared according to the method described in Example 124. HPLC retention time 4.23min. Mass Spectrum (ES+) m/z 452(M+H).
Example 199: l-(2,3-Dihydro-benzo[l,4]oxazin-4-yl)-2-(8-methoxy-3,4-dihydro- lH-isoquinolin-2-yl)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.07min. Mass Spectrum (ES+) m/z 339(M+H).
Example 200: 2-(7-Hydroxy-3,4~dihydro-lH-isoquinolin-2-yl)-l-phenoxazin-10- yl-ethanone
Prepared according to the metiiod described in Example 56. HPLC retention time 3.88min. Mass Spectrum (ES+) m/z 373(M+H).
Example 201 : 2-(6-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 3.83min. Mass Spectrum (ES+) m/z 373(M+H).
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
Prepared according to the method described in Example 56. HPLC retention time 4.36min. Mass Spectrum (ES+) m/z 373(M+H).
Example 204 : N-Methanesulphonyl-N- [2-(2-oxo-2-phenoxazin-l 0-yl-ethyI)- l,2,3,4-tetrahydro-isoquinoIin-8-yl]-methanesulphonamide
Prepared according to the method described in Example 124. HPLC retention time 4.04min. Mass Spectrum (ES+) m/z 528(M+H).
Example 205: N-[2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro- isoquinoIin-8-yl]-methanesuIphonamide
Prepared according to the method described in Example 124. HPLC retention time 2.95min. Mass Spectrum (ES+) m/z 450(M+H).
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
Prepared according to the method described in Example 56. HPLC retention time 4.1 lmin. Mass Spectrum (ES+) m/z 391(M+H).
Example 207 : 2-(8- ethoxy-3,4-dihydro-lH-isoquinolm-2-yl)-l-phenoxazin-10- yl-propan-1-one
Prepared according to the method described in Example 56. HPLC retention time 4.98min. Mass Spectrum (ES+) m/z 401 (M+H). Example 208: Phenoxazine-10-carboxylic acid [2-(5,8-dihydro-6H- [l,7]naphthyridin-7-yl)-ethyl]-amide
Prepared according to the method described in Example 56 with the following modification: triethylamine was used in place of potassium carbonate. HPLC retention time 4.98min. Mass Spectrum (ES+) m/z 401 (M+H).
Example 209: 2-(4-Hydroxy-l,3-dihydro-isoindol-2-yl)-l-phenoxazin-10-yl- ethanone
Prepared according to the method described in Example 56. HPLC retention time 3.73min. Mass Spectrum (ES+) m/z 359(M+H).
Example 210: Methanesulphonic acid 2-(2-oxo-2-phenoxazin-10-yl-ethyl)-2,3- "dihydno-lH-isoindol-4-yl ester
Prepared according to the method described in Example 124. HPLC retention time 4.18min. Mass Spectrum (ES+) m/z 437(M+H).
Example 211 : l-Carbazol-9-yl-2-(8-methoxy-3,4~dihydro-lH-isoquinolin-2-yl)- ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.86min. Mass Spectrum (ES+) m/z 371(M+H).
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
Prepared according to the method described in Example 56. HPLC retention time 4.26min. Mass Spectrum (ES+) m/z 353(M+H). 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
Prepared according to the method described in Example 56. HPLC retention time 4.79min. Mass Spectrum (ES+) m/z 395(M+H).
Example 214: l-(HH-Dibenzo[b,f][l,4]oxazepin-10-yl)-2-(8-methoxy-3,4- dihydro-lH-isoquinolin-2-yI)-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.44min. Mass Spectrum (ES+) m/z 401 (M+H).
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
Prepared according to the method described in Example 56. HPLC'fetention time 4.40min. Mass Spectrum (ES+) m/z 367(M+H).
Example 216: 2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro- isoqumoline-8-sulphonic acid
Prepared according to the method described in Example 56. HPLC retention time 2.39min. Mass Spectrum (ES+) m/z 437(M+H).
Example 217: N-[2-(2-Oxo-2-phenoxazin-10-yI-ethyl)-2,3-dihydro-lH-isoindol- 4-yl]-methanesulphonamide
Prepared according to the method described in Example 124. HPLC retention time 2.86min. Mass Spectrum (ES+) m/z 436(M+H).
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 21 : 2-(8-Methoxy-3,4-dihydro-lH-isoqumolin-2-yl)-l-[3-(4- methoxyphenyl)-2,3-dihydro-benzo[l,4]oxazin-4-yl]-ethanone
Prepared according to the method described in Example 56. HPLC retention time 4.5 lmin. Mass Spectrum (ES+) m/z 445(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
Prepared according to the method described in Example 56. HPLC retention time 4.69min. Mass Spectrum (ES+) m/z 475(M+H).
Example 221 : N-(4-{4-[2-(8-Methoxy-3,4-dihydro-lH-isoquinolin-2-yl)-acetyl]- 3,4-dihydro-2H-benzo[l,4]oxazin-3-yl}phenyl)acetamide
Prepared according to the method described in Example 56. HPLC retention time 3.88min. Mass Spectrum (ES+) m/z 472(M+H).
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
Prepared ^according to the method described in Example 56. HPLC retention time 4.57min. Mass Spectrum (ES+) m/z 433(M+H).
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
Prepared according to the method described in Example 56. HPLC retention time 4.29min. Mass Spectrum (ES+) m/z 475(M+H).- Biological Screening
Inhibition of Human Nav1.8 stably expressed in SH-SY-5Y cells A SH-SY-5Y neuroblastoma cell line stably expressing the human Nayl .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 hNavl-8 channel. SH-SY-5Y hNav1.8 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 δOOμg.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 (FLIPR™ membrane potential dye, Molecular Devices Corporation), containing lOμM 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 lOOμM - 0.05μM. 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. pH 7.4) to cause membrane depolarisation in those cells where channel block has not been effected (final sodium concentration = 72.5mM). Membrane depolarisation is registered by an increase in fluorescence emission at 565nm. The change in fluorescence seen in each test well upon the addition of sodium containing buffer is calculated relative to the baseline fluorescence for that well. This figure is then used for calculating the IC50 for each test compound. The results are set out in Tables 1 and 2 below.
TABLE 1
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
TABLE 2
The compound numbers in Table 2 refer to those set out at pages 21 to 32 ofthe description.
Figure imgf000110_0001
Figure imgf000110_0002
Figure imgf000111_0001
1.10
Figure imgf000112_0001
Figure imgf000112_0002

Claims

1. Use of a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof in the manufacture.of a medicament for use in the treatment or prevention of a condition involving sodium ion flux througli a sensory neurone specific channel of , a sensory neurone
Figure imgf000113_0001
wherein: - X is -N- or -CH-; n is from 0 to 3; . each Ri is the same or different and is a hydroxy, amino, halogen, Cι-C6 alkyl, Cj-C6 haloalkyl, Cι-C6 alkoxy, Cz-Cβ alkenyloxy, C2-C6 alkynyloxy, Cι-C6 haloalkoxy, C]-C6 alkylthio, Cι-C6 haloalkylthio, ( Cβ alkyl)amino or di(Cι-C6 alkyl)amino group; p is 0 or 1 ; R is cyano, -NR -CO-(C1-C4 alkyl), -NR -S(O)2-(C1-C4 alkyl), -CO2H, - S(O)2OH, -CO2-(C C4 alkyl), -O-S(O)2-(C!-C4 alkyl) or -N[S(O)2-(CrC4 alkyl)]2, wherein R/ is hydrogen or a Q- alkyl group; - m is 1, 2 or 3; and - . R2 is either (a) -L-A, wherein L is a direct bond or a C C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety and A is Cβ- o aryl, C3-C6 carbocyclyl, a 5- to 10- membered heteroaryl group or a 5- to 10- membered heterocyclic group, (b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or Cι-C alkyl, L is as defined above and each A is the same or different and is as defined above, (c) -L'-Het-A , wherein Het is -O-, -S- or -MR'-, A' is -L-A, -L-CR(A)2 or -L- CH=C(A)2, R is H or -L-A, L is a C C6 'alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above, (d) -L-CO-N ^ or -L-CS-NR R , wherein L is as defined above and either (i) R3 and R4, together with the N atom to which they are attached, form a 5- to 10- membered heteroaryl or heterocyclyl group or (ii) R3 represents -L-H or A7 wherein L and A' are as defined above, and R4 represents -L'-H, -L'-CO- A7, -L -S(O)-A/, -L/-S(O)2-A , -l -Het-A', -NR-CO-N(A)2, -N(A)2, -A-Het-A, -A', -L-CR(LA) or -L-CH=C(LA)2 wherein each L is the same or different, each A is the same or different, and L , L, R, A and A' are as defined above,
(e) -CO-L-NR R4 or -CS-L-NR3R- wherein L, R3 and R-4 are as defined above,
(f) -CO-A or -CS-A/ wherein A' is as defined above, (g) -L/-O-N=C(A)2 or -CO-L/-O-N=C(A)2 wherein L; is as defined above and each A is the same or different and is as defined above, or
(h) -L -NR-CO-NR3R4 or -L -NR-CS-NR3R4, wherein L1, R, R3 and R4 are as defined above, •■ wherein - said aryl, carbocyclyl, heteroaryl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from d-C alkyl, d-C4 haloalkyl, halogen, hydroxy, amino, (Cι-C4 alkyl)amino, di(d-C4 a-tkyl)amino, C1-C4 alkoxy, d-C4 haloalkoxy, C1-C4 alkylthio,
C1-C4 haloalkylthio, -NH-CO-(Cι-C4 alkyl), -CO-(Cι-C4 alkyl), -CO2-(d-C4 alkyl),
5- or 6- membered heteroaryl, phenyl and -CHPh2 substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms, d-C2 alkyl groups, d-C2 alkoxy groups and -NH-CO-(Cι-C2 alkyl) groups, provided that (a) when R is -L-A, A is other than a benzimidazolyl group, and (b) when R2 is -CO-A7 or -CS-A7, A is other than a pyrazolopyrimidinyl or pyrazolyl group.
Use according to claim 1, wherein: X is -N- or -CH-; n is from 0 to 3; p is 0; each i is the same or different and is a hydroxy, amino, halogen, d-C6 ' alkyl, Cι-C6 haloalkyl, Cι-C6 alkoxy, Ci-Ce haloalkoxy, Cι-C6 alkylthio, Cι-C6 haloalkylthio, (CιC6 alkyl)amino or di(d-C6 alkyl)amino group; m is 1, 2 or 3; and R2 is either (a) -L-A, wherein L is a direct bond or a d-C-6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety and A is C6-Cιo aryl, C -C6 carbocyclyl, a 5- to 10- membered heteroaryl group or a 5- to 10- membered heterocyclic group, (b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or d-C4 alkyl, L is as defined above and each A is the same or different and is as defined above, (c) -L7-Het-A7, wherein Het is -O-, -S- or -NR -, A1 is -L-A, -L-CR(A)2 or -L- CH=C(A)2, R7 is H or -L-A, L7 is a d-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above, (d) . -L-CO-NR3Rt or -L-CS-NR^, wherein L is as defined above and either (i) R3 and R4, together with the N atom to which they are attached, form a 5- to 10- membered heteroaryl or heterocyclyl group or (ii) R3 represents -L-H or A! wherein L and A are as defined above, and R-4 represents -L7-H, -L7-CO-A, A1, -L-CR(LA)2 or -L-CH=C(LA)2 wherein each L is the same or different, each A is the same or different, arid L1, L, R, A and A1 are as defined above, (e) -CO-L-NR3R-4 or -CS-L-NRjRt wherein L, R and R4 are as defined above, (f) -CO- A7 or -CS-A wherein A7 is as defined above, or (g) -L-O-N=C(A)2 or -CO-L -O-N=C(A)2 wherein L7 is as defined above and each A is the same or different and is as defined above, wherein said aryl, carbocyclyl, heteroaryl and heterocyclyl groups are optionally fused to one or two cyclic moieties selected from phenyl rings and 5- to 6- membered heterocyclyl and heteroaryl groups, and said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are unsubstituted or are substituted by 1,
2 or 3 substituents which are the same or different and are selected from Cι-C4 alkyl, d-C haloalkyl, halogen, hydroxy, C C4 alkoxy, Cι-C haloalkoxy, C1-C4 alkylthio, Cι-C haloalkylthio, phenyl and -CHPh substituents, the phenyl moieties in said substituents being unsubstituted or substituted by 1 or 2 halogen atoms, provided that (a) when R is -L-A, A is other than a benzimidazolyl group and (b) when R is -CO- A7 or -CS-A , A. is other than a pyrazolopyrimidinyl or pyrazolyl group.
3. Use according to claim 1 or 2, wherein the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents Rl5 R2, R3 arid R4 are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cι-C alkyl, hydroxy, amino, (C1-C4 alkyl)amino, C\- C4 alkoxy, Cι-C4 haloalkyl, d-C haloalkoxy, d-C4 alkylthio, d-C4 haloalkylthio, -NH-CO-(d-C2 alkyl),. -CO-(Cι-C2 alkyl), -CO2-(d-C2 alkyl), 5- membered heteroaryl, phenyl and -CHPh2 substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by one or two further substituents selected from halogen atom,"C1-C2 alkyl groups, d-C2 alkoxy groups and -NH-CO- ' (d-C alkyl) groups.
4. Use according to any one ofthe preceding claims, wherein each Ri is the same- or different and is a hydroxy, amino, halogen, Cι-C4 alkyl, d-C4 haloalkyl, d- C alkoxy, C2-C4 alkenyloxy, C1-C4 haloalkoxy, C1-C4 alkylthio or C1-C4 haloalkylthio group.
5. Use according to any one ofthe preceding claims, wherein each L moiety in the R2 substituent is the same or different and represents a direct bond or a C1-C4 alkyl moiety and/or each L7 moiety in the R2 substituent is the same or different and represents a d-C4 alkyl moiety.
6. Use according to any one ofthe preceding claims, wherein each A moiety in the R2 substituent is the same or different and represents a C6-Cιo aryl, C3-C6 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 Cι-C4 alkyl, d-C4 haloalkyl, halogen, hydroxy, amino, (Cι-C4 alkyl)amino, di(Cι-C alkyl)amino, d-C4 alkoxy, d-C4 haloalkoxy, Ci-C4 alkylthio, Cι-C4 haloalkylthio, -NH-CO-(C1-C alkyl), 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.
7. Use according to any one ofthe preceding claims, wherein each R substituent in each -CR(A)2 moiety is the same or different and is hydrogen or methyl.
8. Use according to any one ofthe preceding claims, wherein each Het moiety iinn tthhee RR22 ssuubbssttiittuueenntt iiss --CO-, -S- or -NR7- wherein R7 is hydrogen, Cι-C4 alkyl, phenyl or -(d-C4 alkyl)-ρhenyl.
9. Use according to any one ofthe preceding claims, wherein, when R3 and Rj, together with the nitrogen atom to which they are attached, form a heterocycle, they form a 5- to 7- membered heterocyclyl group.
10. Use according to claim 9, wherein, when R3 and R4, together with the nitrogen atom to which they are attached, form a heterocycle, they form a 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 Cι-C4 alkyl, d-C haloalkyl, d-C4 alkoxy, C C4 alkylthio, halogen, phenyl, -CHPh2, -CO-(d-C2 alkyl), -CO2-(Cι-C2 alkyl) and 5- to 6- membered heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by 1 or 2. further substituents selected from halogen atoms, d-C2 alkyl groups, C1-C2 alkoxy groups and -NH-CO(d-C2 alkyl) groups.
11. Use according to any one of the preceding claims, wherein, when R3 and -R4 do not together form a heterocycle, R3 represents hydrogen or a Cj-C4 alkyl, phenyl,
-(Cι-C alkyl)-phenyl or -(C1-C4 alkyl)-CHPh2 group in which the phenyl moieties are unsubstituted or substituted by a hydroxy group and j represents C1-C4 alkyl, A, -(d-C4 alkyl)-A, -(CH2)m-CH(A)2, -CH[(CH2)mA]2, -(CH2)m-CO-A, -(CH2)m-O- CH(A)2, -(CH2)m-S-CH(A)2, -(CH2)m-S(O)-CH(A)2, -(CH2)m-S(O)2-CH(A)2, -NH- CO-N(A)2, -N(A)2 or -A-O-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 R- substituent being (a) unsubstituted or substituted by one or two substituents selected from d-C4 alkyl, d- C4.alkoxy, halogen, hydroxy, amino, d-C haloalkyl, Cj-C2 haloalkoxy and Cι-C2 haloalkylthio substituents and (b) monocyclic or fused to one or two phenyl rings.
12. Use according to any one ofthe preceding claims, wherein, when R2 is defined according to option (a), A is monocyclic.
13. Use according to any one ofthe preceding claims, wherein, when R2 is defined according to option (f), A is a said Cδ-do aryl group.
14. Use according to any one ofthe preceding claims, wherein - X is -N- or -CH-; n is'O or l; each Ri is the same or different and is Cι-C2 alkyl, hydroxy or C1-C2 alkoxy; p is O or l; R is cyano, -NH-CO-CH3, -NH-S(O)2-CH3, -O-S(O)2-CH3, -N[SO2-CH3]2 or -S(O)2-OH; . m is 1, 2 or 3; and R2 is either (a) -L-A wherein L represents a direct bond or a d-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, and 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 or two substituents selected from halogen, d-C2 alkyl, hydroxy, amino, d-C2 alkoxy, Cι-C2 haloalkyl, C1-C2 haloalkoxy, Cι-C2 haloalkylthio, -NH-CO-CH3 and phenyl substituents, (b) -L-CR(A)2 or -L-CH=C(A)2 wherein R is hydrogen or methyl, L is as defined above and each A is the same or different and is as defined above, (c) -L7-Het-A7 wherein Het is -O- or -NR7- wherein R7 is hydrogen, C1-C4 alkyl or benzyl, A7 is -L-A, -L-CR(A)2 or -L-CH=C(A)2, L7 is a C1-C4 alkyl moiety, for example a methyl, ethyl or propyl moiety, L is as defined above, R is as defined above and each A is the same or different and is as defined above,
(d) -L-CO-NR3R-4 wherein L is as defined above and either (i) R3 and R-4, together with the nitrogen atom to which they are attached, form a 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 one or two substituents selected from d-C4 alkyl, d-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, halogen, phenyl, -CHPh2, -CO-(d-C2 alkyl), -CO2-(d-C2 alkyl) and 5- to 6-membered heteroaryl substituents, the phenyl and heteroaryl moieties in said substituents being unsubstituted or substituted by one or two further substituents selected from halogen atoms, Cj-C2 alkyl groups, C1-C2 alkoxy groups and -NH-CO-(C1-C2 alkyl) groups, or (ii) R3 represents hydrogen, C1-C4 alkyl or an unsubstituted benzyl, phenyl, hydroxyphenyl or -(C1-C2 alkyl)-CHPh2 group and 4 represents -G1-C alkyl, -fluorenyl, phenyl, pyridyl, -(C1-C4 alkyl)-ρhenyl, -(Cι-C4 alkyl)-(5- to 6- membered heteroaryl), -(CH2)m-(9H-carbazolyl), -(CH2)m-indolinyl, -(CH2)m-(9H-xanthenyl), -(CH2)m-O-CHA77A/77, -(CH2)m-S-CHA7A//, -(CH2)m-S(O)-CHA77A//, ' -(CH2)m-S(O)2-CHA77A777, -NH-CO-N(phenyl)2, -N(phenyl)2 or -A77-O-A777, -(CH2)m-CHA 7A777, -CH[(CH2)„Ph]2 or -(CH2)p-CO-R where m is 0, 1 , 2 or 3, A77 and A777 are the same or different and each represent phenyl or a 5- or 6- membered heteroaryl group, n is 0, 1 or 2, p is 1, 2 or 3 and R is 5- or 6- membered heterocyclic group fused to a phenyl ring, for example a tetrahydroisoquinoline group, the cyclic moieties in said i groups being unsubstituted or substituted by a halogen atom, Cι-C alkyl, hydroxy, amino or d-d alkoxy group,
(e) -CO-L-NR3Ri or -CS-L-NR3R-4 wherein L, R3 and Ri are as defined above, (f) . -CO-A7 or -CS-A7 where A is as defined above, (g) -CO-L -O-N=:C(A) wherein L7 is as defined above and each A is the same or different and is as defined above; or . (h) -L -NR-CO-NR3R4 or -L -NR-CS-NR3R4 wherein L7, R, R3 and R are as defined above, provided that when R2 is -L-A, A is monocyclic.
15. Use according to any one of the preceding claims, wherein said condition is chronic or acute pain, a bowel disorder, a bladder dysfunction, tinnitus or a demyelinating disease.
16. A compound ofthe formula (I), as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound ofthe formula (I), as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
18. A composition according to claim 17 which is a capsule or tablet comprising from 10 to 500 mg of a compound ofthe formula (I), as defined in any one of claims ϊ'-to 1 ~ or a pharmaceutically acceptable salt thereof.
19. An inhalation device comprising a pharmaceutical composition according to claim 18.
20. An inhalation device according to claim 19' which is a nebulizer.
21. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment ofthe human or animal body.
22. A method of treating a patient suffering from or susceptible to a condition as defined in claim 1 or 15, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined in any of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
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