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WO2006082354A1 - Composes azacycliques servant d'inhibiteurs de canaux specifiques aux neurones sensoriels (sns) - Google Patents

Composes azacycliques servant d'inhibiteurs de canaux specifiques aux neurones sensoriels (sns) Download PDF

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Publication number
WO2006082354A1
WO2006082354A1 PCT/GB2006/000040 GB2006000040W WO2006082354A1 WO 2006082354 A1 WO2006082354 A1 WO 2006082354A1 GB 2006000040 W GB2006000040 W GB 2006000040W WO 2006082354 A1 WO2006082354 A1 WO 2006082354A1
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alkyl
group
het
different
same
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PCT/GB2006/000040
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English (en)
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Richard Hamlyn
Mike Huckstep
Christopher Geoffrey Earnshaw
Stephen Stokes
David Tickle
Brigitte Allart
Joseph William Boyd
Lars Jacob Stray Knutsen
Rosemary Lynch
Lee Patient
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Vernalis (R & D) Limited
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Priority to EP06700329A priority Critical patent/EP1833797A1/fr
Publication of WO2006082354A1 publication Critical patent/WO2006082354A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • 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
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to inhibitors of the subtype of mammalian sodium channels known as Na v l .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 SCNlOA.
  • the channel is described in more detail in Akopian et al, (1996), 379, 257-262.
  • Mammalian ion channels are becoming increasingly well characterized, and progress in sodium channel research has been summarized recently in Anger et al, J. Med. Chem. (2001) 44, 115-137.
  • Sodium channels are recognised as valid targets for pain therapeutics, and blockade of sodium channels can be useful in the treatment of a range of pain syndromes (see for example Black et al, Progress in Pain Research and Management (2001), 21 (Neuropathic Pain: Pathophysiology and Treatment), 19- 36).
  • the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body,
  • Ar represents a phenyl ring or a 5- to 6- membered heteroaryl group; n is an integer of from 0 to 3 ;
  • Each Rl is the same or different and is a hydroxy, amino, halogen, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, (C 1 -C 6 alkyl)amino or Oi(C 1 -C 6 alkyl)amino group or a group selected from;
  • R 10 is hydrogen or C1-C4 alkyl
  • R 11 and R 12 can independently be selected from hydrogen, C 1 -C 4 alkyl or taken together as a C 3 -C 6 alkyl chain forming a ring, or taken together forms the group -CR 2 CH 2 -X 1 -CK 2 CH 2 -, where X 1 is O, NH OrNCH 3 ,
  • R 10 is defined as above or taken together any two R 10 groups form a C 3 -C 4 ring forming alkyl chain.
  • R 5 - R 2 and R 3 are the same or different and each represent hydrogen, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, -COR 7 , -CSR 7 , -CO 2 R 77 , -CONR 77 R 777 or oxo, wherein R 7 represents a C 1 -C 6 alkyl group and each R 77 and R 777 are the same or different and represent hydrogen or a C 1 -C 6 alkyl group, provided that at least one of R 2 and R 3 is other than hydrogen; m is 1, 2 or 3; and R 4 is either
  • L is a C 1 -C 6 alkylene group
  • R is hydrogen or a C 1 -C 4 alkyl group
  • each A is the same or different and represents a C 6 -C 10 aryl group or a 5- to 10- membered heteroaryl group
  • Het represents a moiety
  • each R 5 is the same or different and represents halogen, hydroxy, C 1 - C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio,
  • R 7 represents a C 1 -C 4 alkyl group and each R 77 and R 777 are the same or different and represent hydrogen or a C 1 -C 4 alkyl group, and either (i) R 6 and R 7 are the same or different and represent hydrogen, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 6 -C 10 aryl, 5- to 10- membered heteroaryl, -COR 7 , -CSR 7 , -CO 2 R 77 or -CONR 77 R 777 wherein R 7 , R 77 and R
  • a C 1 -C 6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C 1 -C 4 alkyl group or moiety.
  • Examples OfC 1 -C 4 alkyl groups and moieties include methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • a divalent alkyl moiety (or alkylene moiety) can be attached via the same carbon atom, by adjacent carbon atoms or by non-adjacent carbon atoms.
  • a C 6 -C 10 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.
  • heteroatoms for example 1, 2 or 3 heteroatoms, selected from O, S and N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, imidazolyl, pyrrolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl and pyrazolyl groups.
  • a 5- 10- membered heteroaryl group includes a 8- to 10- membered fused bicyclic aromatic system containing at least one heteroatom, for example 1 to 5 heteroatoms selected from O, S and N.
  • heteroatoms for example 1 to 5 heteroatoms selected from O, S and N.
  • examples include indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl and imidazopyrimidinyl.
  • Thienyl groups are preferred.
  • a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine or fluorine.
  • a said C 1 -C 6 alkoxy group is typically a said C 1 -C 6 alkyl group attached to an oxygen atom.
  • a said C 1 -C 6 alkylthio group is typically a said C 1 -C 6 alkyl group attached to a thio group.
  • a C 1 -C 6 haloalkyl group is typically a said C 1 -C 6 alkyl group, for example a C 1 -C 4 alkyl group, substituted by one or more said halogen atoms.
  • haloalkyl groups include perhaloalkyl groups such as -CX 3 wherein X is a said halogen atom.
  • Particularly preferred haloalkyl groups are -CF 3 and -CCl 3 .
  • a C 1 -C 6 haloalkoxy group is typically a said C 1 -C 6 alkoxy group, for example a C 1 -C 4 alkoxy group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkoxy groups include perhaloalkoxy groups such as -OCX 3 wherein X is a said halogen atom.
  • Particularly preferred haloalkoxy groups are -OCF 3 and -OCCl 3 .
  • a C 1 -C 6 haloalkylthio group is typically a said C 1 -C 6 alkylthio group, for example a C 1 -C 4 alkylthio group, substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkylthio groups include perhaloalkylthio groups such as -SCX 3 wherein X is a said halogen atom.
  • Particularly preferred haloalkylthio groups are -SCF 3 and -SCCI3.
  • Ar represents a phenyl, thienyl, furanyl or pyrrolyl moieity.
  • Ar represents a phenyl or thienyl moiety. Most preferably, Ar is phenyl.
  • n 0, 1 or 2.
  • each R 1 is the same or different and is a hydroxy, amino, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio or C 1 - C 4 haloalkylthio group. More preferably, each R 1 is the same or different and is a C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, hydroxy, halogen, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy group. Most preferably, each R 1 is the same or different and represents methyl, methoxy, hydroxy, fluorine or chlorine.
  • m is 1 or 2.
  • R 2 and R 3 are the same or different and each represent hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, -COR 7 , -CO 2 R 77 , -CONR 77 R 7777 or oxo, wherein R 7 represents a C 1 -C 4 alkyl group and each R 77 and R 777 are the same or different and represent hydrogen or a C 1 -C 4 alkyl group, provided that at least one of R 2 and R 3 is other than hydrogen.
  • R 2 and R 3 are the same or different and each represent hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, -CO 2 R 7 , -CONR 7 R 77 Or oxo, wherein R 7 represents a C 1 -C 4 alkyl group and R 77 represents hydrogen or a C 1 -C 4 alkyl group, provided that at least one of R 2 and R 3 is other than hydrogen.
  • R 2 represents hydrogen, C 1 -C 4 alkyl, -CO 2 -(C 1 -C 4 alkyl) or oxo and R 3 represents hydrogen, hydroxy, C 1 -C 4 alkyl, -CONH-(C 1 -C 4 alkyl) or oxo, provided that at least one of R 2 and R 3 is other than hydrogen.
  • either (a) one of R 2 and R 3 is hydrogen or (b) both R 2 and R 3 are oxo.
  • both R 2 and R 3 are oxo, they are typically present on carbon atoms adjacent to the N atom which carries R 4 .
  • Particularly preferred compounds in this latter category are phthalimide derivatives of the formula (I 1 )
  • each L moiety in the R 4 substituent is the same or different and represents a C 1 -C 4 alkyl moiety.
  • each L is the same or different and represents -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-, -C(CH 3 )-CH 2 - or -CH(CH 3 )-.
  • each L moiety in the R 4 substituent is the same or different and represents a direct bond or a C 1 -C 4 alkyl moiety.
  • each L represents a direct bond or a -(CH 2 )-, -(CH 2 -CH 2 )-, -CH 2 -CH 2 -CH 2 - or -CH(CH 3 )- moiety.
  • each A moiety in the R 4 substituent is the same or different and represents a phenyl or 5- to 6- membered heteroaryl group.
  • each A moiety in the R 4 substituent is a phenyl group.
  • the aryl and heteroaryl moieties in the R 4 substituent are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy groups.
  • the aryl and heteroaryl moieties in the R 4 substituent are unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from hydroxy, halogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl and C 1 -C 2 alkoxy groups.
  • the aryl and heteroaryl moieties in the R 4 substituent are unsubstituted or substituted by a single hydroxy, halogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy substituent.
  • the moiety Het is attached via the Y atom.
  • Y in the moiety Het is a N atom.
  • X in the moiety Het is a direct bond, O, S or -S(O)-.
  • p in the moiety Het is O, 1 or 2.
  • p in the moiety Het is O or l.
  • each R 5 in the moiety Het is the same or different and represents halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkylthio, -COR 7 , -CO 2 R 7 or -CONR 7 R 77 wherein R 7 is a C 1 -C 4 alkyl group and R 77 is hydrogen or a C 1 -C 4 alkyl group.
  • each R 5 in the moiety Het is the same or different and represents halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or -CO-(C 1 -C 4 alkyl). More preferably, each R 5 is the same or different and represents halogen, C 1 - C 2 alkyl, C 1 -C 2 haloalkyl, C 1 -C 2 alkylthio or -CO-(C 1 -C 2 alkyl).
  • R 6 and R 7 together form an aryl or heteroaryl group, they form, together with the carbon atoms to which they are attached, a phenyl or 5- to 6- membered heteroaryl group. Preferably they form, together with the carbon atoms to which they are attached, a phenyl group. Most preferably, they form an unsubstituted phenyl group.
  • R 6 and R 7 do not together form an aryl or heteroaryl group, they are the same or different and each represent hydrogen, halogen, C 1 -C 4 alkyl, C 1 - C 4 haloalkyl, C 1 -C 4 alkoxy, phenyl, 5- to 6- membered heteroaryl, -CO 2 R 7 or -CONR 7 R 77 wherein R 7 represents a C 1 -C 4 alkyl group and R 77 represents hydrogen or a C 1 -C 4 alkyl group.
  • R 6 and R 7 do not together form an aryl or heteroaryl group, they are the same or different and each represent hydrogen, C 1 -C 4 alkyl, phenyl (preferably unsubstituted phenyl), or -CO 2 -(C 1 -C 4 alkyl).
  • R 6 and R 7 do not together form an aryl or heteroaryl group, R 6 represents hydrogen, C 1 -C 2 alkyl or an unsubstituted phenyl group and R 7 represents hydrogen or -CO 2 -(C 1 -C 2 alkyl).
  • the moiety Het 7 is a 9H-xanthenyl group.
  • R is hydrogen.
  • each A is the same or different and represents a phenyl group which is unsubstituted or substituted by a fluorine atom.
  • L is a C 1 -C 4 alkylene group.
  • R 8 is hydrogen, C 1 -C 4 alkyl or phenyl.
  • R 8 is hydrogen or phenyl.
  • R in the moiety R 9 is hydrogen.
  • each A moiety in the R 9 substituent is the same or different and represents a phenyl group, which is unsubstituted or substituted as set out above. More preferably, each A moiety in the R 9 substituent is the same or different and represents a phenyl group, which is unsubstituted or substituted by a halogen (preferably fluorine), hydroxy, C 1 -C 2 alkyl or C 1 -C 2 alkoxy substituent.
  • a halogen preferably fluorine
  • R 9 is -I/-A, -1/-CR(A) 2 , -N(A) 2 , -L-Het, -l/-CO-Het or Het 7 , wherein R, L 7 , L, A, Het and Het 7 are as defined above.
  • R 9 is -l/-A, -L 7 - CR(A) 2 , -N(A) 2 , -L-Het, -CO-Het or Het 7 , wherein R, L 7 , L, A, Het and Het 7 are as defined above.
  • R 9 is -L 7 - A, -1/-CR(A) 2 , -L-Het, -CO-Het or Her 7 , wherein R, L 7 , L, A, Het and Her 7 are as defined above.
  • R 4 is -L-CO-NR 8 R 9 wherein, L, R 8 and R 9 are as defined above.
  • L ⁇ is a direct bond.
  • L is a C 1 -C 2 alkylene group.
  • each R is hydrogen.
  • each A is an unsubstituted phenyl group.
  • R 4 is -L-NR-CS-NR- L 7 -CR(A) 2 , wherein L, R, L 7 and A are as defined above.
  • L 7 is a direct bond, -CH 2 - or -CH(CH 3 )-. More preferably, R 4 is -CH 2 - or -CH(CH 3 )-.
  • R 4 is defined according to option (d)
  • X in the moiety Het is
  • R 4 is defined according to option (d)
  • Y in the moiety Het is N.
  • R 6 and R 7 in the moiety Het do not together form an aryl or heteroaryl group, R 6 represents hydrogen or an unsubstituted phenyl group and R 7 represents hydrogen or -CO 2 -(C 1 -C 2 alkyl).
  • R 9 is preferably -1/-CR(A) 2 , -L-Het, HetV -l/-CO-Het, more preferably -l/-CR(A) 2 .
  • R 9 is other than -1/-CO-NR 8 R 9 .
  • R 2 is other than oxo.
  • Preferred compounds of formula (I) are those in which: - Ar represents a phenyl ring or a 5- to 6- membered heteroaryl moiety; n is 0, 1 or 2; m is 1 or 2; each R 1 is the same or different and is a hydroxy, amino, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, or C 1 -C 4 haloalkylthio group;
  • R 2 and R 3 are the same or different and each represent hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, -COR 7 , -CO 2 R 7 , -CONR // R /// or oxo, wherein R 7 represents a C 1 -C 4 alkyl group and each R 7/ and R 7// are the same or different and represent hydrogen or a C 1 -C 4 alkyl group, provided that at least one of R 2 and R 3 is other than hydrogen; and
  • R 4 is either (a) -L-CR(A) 2 or -L-Het, wherein L is a C 1 -C 4 alkylene group, R is hydrogen or a
  • each A is the same or different and represents phenyl or a
  • each R 5 is the same or different and represents halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkylthio, -COR 7 , -CO 2 R 7 or -CONR 7 R 77 , wherein R 7 is a C 1 -C 4 alkyl group and R 77 is hydrogen or a C 1 -C 4 alkyl group, and either (i) R 6 and R 7 form, together with the carbon atoms to which they are attached, a phenyl or 5- to 6- membered heteroaryl group, or (ii) R 6 and R 7 are the same or different and each represent hydrogen, halogen, C 1 -
  • Het, -L 7 -CO-Het or Het 7 wherein R is hydrogen or C 1 -C 4 alkyl, L 7 , L, A and Het are as defined above and Het 7 is a moiety Het, as defined above, in which Y is CH;
  • Ar represents a phenyl or thienyl moiety; n is 0, 1 or 2; m is 1 or 2; - each R 1 is the same or different and is a C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, hydroxy, halogen, C 1 -C 2 alkoxy or C 1 -C 2 haloalkoxy group;
  • R 2 represents hydrogen, C 1 -C 4 alkyl, -CO 2 -(C 1 -C 4 alkyl) or oxo and R 3 represents hydrogen, hydroxy, C 1 -C 4 alkyl, -CO-NH-(C 1 -C 4 alkyl) or oxo, provided that (a) at least one of R 2 and R 3 is other than hydrogen and (b) when m is 2, R 2 is other than oxo; and
  • R 4 is either: (a) -L-CH(A) 2 or -L-Het, wherein L is a C 1 -C 4 alkyl moiety, A represents a phenyl group and Het represents a moiety
  • R 5 is halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or -CO-(C 1 -C 4 alkyl), and either (i) R 6 and R 7 , together with the carbon atoms to which they are attached, together form a phenyl group or (ii) R 6 and R 7 are the same or different and each represent hydrogen, C 1 -C 4 alkyl, phenyl or -CO 2 -(C 1 -C 4 alkyl);
  • Particularly preferred compounds of formula (I) are compounds of formula (Ia)
  • R 1 , n, Ar, R 2 , m, R 3 , L 7 , R 5 , p, R 6 and R 7 are as defined above, and X is O, S or -SO-.
  • X in the formula (Ia) is O.
  • L 7 in the formula (Ia) is a C 1 -C 4 alkylene group.
  • R 1 , n, Ar, R 2 , m, R 3 , L, R 5 , p, R 6 and R 7 in the formula (Ia) are the same as those set out above in the context of the formula (I).
  • Examples of compounds of the invention include
  • 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.
  • 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 reacting a compound of formula (II) with a compound of formula (3) as shown below, wherein R 1 , n, m, R 2 , R 3 and R 4 are as defined above and X is a leaving group, typically halogen or mesylate.
  • reaction takes place by standard methods such as reaction in the presence of a base, for example potassium carbonate.
  • a base for example potassium carbonate.
  • reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at reflux temperature.
  • compounds of formula (2) may be prepared from compounds of formula (4) by standard methods familiar to those skilled in the art such as hydrogenation in the presence of a catalyst such as platinum oxide.
  • compounds of formula (2) may be prepared from compounds of formula (5) and a carbonyl compound (for example formaldehyde) by standard methods such as the Pictet-Spengler cyclisation.
  • Compounds of formula (4) are known compounds or may be prepared by standard methods such as sequential imine formation with derivatised amines such as (7) or by cyclisation of compounds of formula (6), according to the general procedure described by Yoshida et ah, Bioorg. Med. Chem. 1999, 7, 2647-2666.
  • compounds of formula (II) may be prepared from compounds of formula (9) where X is a leaving group, preferably bromine or chlorine, by standard methods familiar to those skilled in the art such as a dual alkylation in the presence of either ammonia or a derivatised amine, so that the product of the reaction in the latter case can readily be converted into a compound of formula (II).
  • X is a leaving group, preferably bromine or chlorine
  • Compounds of formula (9) are typically prepared from a substance of formula (10) by standard methods familiar to those skilled in the art, such as radical halogenation using N-bromosuccinimide.
  • Compounds of formula (I) can, of course, be prepared directly from compounds of formula (9) where X is a suitable leaving group, with an amine of formula (13).
  • Compounds of formula (9) can also be prepared by converting the hydroxyl groups of (11) into leaving groups such as a mesylate or tosylate under standard conditions familiar to those skilled in the art.
  • Alcohol (11) may be prepared from acids (12) by standard methods such as reduction in the presence of lithium aluminium hydride.
  • a phthalimide derivative is provided, and such compounds of formula (I) can be conveniently prepared by reaction of the diacid (12) either directly with the amine (13) or by an intermediate anhydride, as described by Iwashima, S. et al, Journal of the Chemical Society, Perkin Transactions 1, 1984, 9, 2177-87.
  • Compounds of formula (15) where m is 3 maybe prepared from compounds of formula (16).
  • compounds of formula (16) may be prepared from tetralones (17) by standard methods familiar to those skilled in the art such as the Beckman rearrangement of the corresponding oxime or further methods as outlined e.g. in Alicyclic Chemistry (Martin Grossel, Oxford University Press, December 1997, ISBN 0198501048).
  • the amine (8) can be reacted with a compound of formula (18), wherein L, l/, R and A are as defined above, Y is sulphur or oxygen and X is a leaving group, typically chlorine.
  • the procedure is typically performed using standard methods such as reaction in the presence of a base, for example potassium carbonate.
  • a base for example potassium carbonate.
  • the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of up to 95 0 C.
  • an isocyanate or isothiocyanate of formula (19), wherein R 1 , R 2 , R 3 , n, m, L and Y are as defined above, can be reacted with an amine of formula (20) where i/, R and A are as defined above, to provide a desired urea or thiourea derivative of formula (I).
  • this reaction would take place in a suitable solvent such as acetone, toluene, tetrahydrofuran or acetonitrile.
  • a suitable solvent such as acetone, toluene, tetrahydrofuran or acetonitrile.
  • the reaction is illustrated in the case of Ar as phenyl, it is, of course, equally applicable to the case of Ar as a heterocycle, such as thiophene, pyrimidine or pyrrole.
  • a compound of formula (21) can be prepared by reaction of an amide (22) with an alcohol R 4 -OH, under Mitsunobu conditions.
  • the reaction scheme depicted above involves the reaction of amides (25) and amines (23) where X is a leaving group, preferably chlorine, using standard methods such as reaction in the presence of a base, for example triethylamine. Typically the reaction is performed in a solvent such as methanol, tetrahydrofuran or acetonitrile at a temperature of 8O 0 C.
  • Amides (25) may be prepared from amines (8) and acids (24), wherein X ; is Cl or OH, under standard amide coupling reaction conditions. Typically, where X 7 is Cl, the reaction is effected in the presence of triethylamine.
  • compounds of formula (I) where R 4 is -CO-NR 8 R 9 maybe prepared from amines (2) by standard methods familiar to those skilled in the art, such as acylation with isocyanates (27).
  • An alternative is the reaction of the amine (2) with an acid halide of formula (28).
  • the method shown in scheme 7 involves the use of a Pictet Spengler reaction, as described for example in Mach, U.R. et al., ChemBioChem, 2004, 5, 508-518, whereby a substituted thiophen-2-yl-ethylamine is reacted with formaldehyde or ethoxymethoxyethane in the presence of a mineral acid such as hydrochloric acid, and a solvent such as 2-propanol or tetrahydrofuran.
  • a mineral acid such as hydrochloric acid
  • a solvent such as 2-propanol or tetrahydrofuran.
  • Compounds in which Ar represents other heteroaryl groups can be prepared by analogous methods, as can compounds in which m (in formula I) is other than 2.
  • This reaction scheme involves a method described by Kikuchi, C. et ah, Bioorganic & Medicinal Chemistry Letters, 2002, 12, 2549-2552, by which a 4-keto piperidine is reacted with phosphorus oxychloride and DMF to provide a formylated intermediate, which is reacted with a substituted thioacetic acid ester to provide a substituted 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine.
  • the desired compound of formula (1) can be prepared by reactions described above.
  • This reaction involves the reaction of a 2-formylthiophene with a 2,2- dimethoxyethylamine derivative, as described for example in Maffrand, J.P.; Eloy, F. Journal of Heterocyclic Chemistry, 1976, 13, 1347-1349. Subsequent reduction and hydrolysis yields a compound of formula (28).
  • the starting materials used in the above reaction schemes are known compounds, or may be prepared by analogy with known methods.
  • compounds of formula (II) in which Ar represents a heterocycle other then those depicted in the schemes shown above can also be prepared by known techniques.
  • suitable techniques include the methods for preparing pyrrolo-fused cyclic amines set out in Haginoya, N. et al, Journal of Medicinal Chemistry, 2004, 47, 5167-5182, the methods for preparing thiazolo-fused cyclic amines set out in WO 04/58728 and WO 00/09480 and the methods for preparing the corresponding pyridine analogues set out in Dukat, M. et al, European Journal of Medicinal Chemistry, 1996, 31, 875-888.
  • the present invention provides a pharmaceutical composition comprising a compound of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention.
  • Preferred pharmaceutical compositions are sterile and pyrogen free.
  • the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
  • the compounds of the invention may be administered in a variety of dosage forms.
  • compositions suitable for oral administration are compositions suitable for oral administration, for example tablets and capsules.
  • Compositions suitable for oral administration may, if required, contain a colouring or flavoring agent.
  • a said capsule or tablet comprises from 5 to 500 mg, preferably 10 to 500 mg, more preferably 15 to 100 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.
  • inhalation One preferred route of administration is inhalation.
  • the major advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.
  • Preferred pharmaceutical compositions of the invention therefore include those suitable for inhalation.
  • the present invention also provides an inhalation device containing such a pharmaceutical composition.
  • said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler.
  • said propellant is a fluorocarbon.
  • Nebulizers are devices capable of delivering fine liquid mists of medication through a "mask" that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.
  • Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound of the invention without a propellant.
  • said inhalation device contains a spacer.
  • a spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device. Spacers with withholding chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended. Another preferred route of administration is intranasal administration.
  • the nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form.
  • Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. Drugs can be delivered nasally in smaller doses than medication delivered in tablet form. By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter-patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses.
  • the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.
  • a further preferred route of administration is transdermal administration.
  • the present invention therefore also provides a transdermal patch containing a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • Also preferred is sublingual administration.
  • the present invention therefore also provides a sublingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
  • 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.
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the compounds of the present invention are therapeutically useful in the treatment or prophylaxis of conditions involving sodium ion flux through a sensory neurone specific (SNS) channel of a sensory neurone.
  • Said condition may be one of hypersensitivity for example resulting from a concentration of SNS channels at the site of nerve injury or in axons following nerve injury, or may be sensitisation of the neurone for example at sites of inflammation as a result of inflammatory mediators.
  • Said compounds of the invention are therefore most preferred for their use in the treatment or prophylaxis of any condition involving hypersensitivity or sensitisation of a sensory neurone specific (SNS) channel of a sensory neurone.
  • 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
  • treatment in this context is deemed to cover any effect from a cure of said condition to alleviation of any or all of the symptoms.
  • the compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence or severity of said conditions.
  • SNS channels 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 of the invention are therefore used as analgesic agents.
  • SNS specific sodium channels have been identified as being particularly important in the transmission of pain signals.
  • the compounds of the invention are accordingly particularly effective in alleviating pain.
  • said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain.
  • the compounds of the invention are effective in alleviating both chronic and acute pain.
  • Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease.
  • a discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol.7, p.147.
  • Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system.
  • Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.
  • Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal. A discussion of chronic pain can be found in the Halpern reference given above. Chronic pain is sometimes a result of persistent dysfunction of the nociceptive pain system.
  • Examples of chronic pains which can be alleviated with the compounds of the invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia, "phantom limb” pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIV, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia.
  • trigeminal neuralgia a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease
  • diabetic neuropathy causalgia
  • neurogenic pain Some of the chronic pains set out above, for example, trigeminal neuralgia, diabetic neuropathic pain, causalgia, phantom limb pain and central post-stroke pain, have also been classified as neurogenic pain.
  • One non-limiting definition of neurogenic pain is pain caused by dysfunction of the peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease.
  • the compounds of the invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain.
  • Examples of bowel disorders which can be treated or prevented with the compounds of the invention include inflammatory bowel syndrome and inflammatory bowel disease, for example Crohn's disease and ulcerative colitis.
  • bladder dysfunctions which can be treated or prevented with the compounds of the invention include bladder hyper reflexia and bladder inflammation, for example interstitial cystitis, overactive (or unstable) bladder (OAB), more specifically urinary incontinence, urgency, frequency, urge incontinence and nocturia.
  • the compounds of the invention can also be used to alleviate pain associated with bladder hyper reflexia or bladder inflammation.
  • demyelinating diseases which can be treated or prevented with the compounds of the invention are those in which SNS channels are known to be expressed by the demyelinated neurones and which may or may not also have associated pain.
  • a specific example of such a demyelinating disease is multiple sclerosis.
  • the compounds of the invention can also be used to alleviate pain associated with demyelinating diseases such as multiple sclerosis.
  • the compounds of the invention have additional properties as they are capable of inhibiting voltage dependent sodium channels. They can therefore be used, for example, to protect cells against damage or disorders which results from overstimulation of sodium channels.
  • the compounds of the invention are useful in the treatment and prevention of peripheral and central nervous system disorders. They can therefore additionally be used in the treatment or prevention of an affective disorder, an anxiety disorder, a behavioural disorder, a cardiovascular disorder, a central or peripheral nervous system degenerative disorder, a central nervous system injury, a cerebral ischaemia, a chemical injury or substance abuse disorder, a cognitive disorder, an eating disorder, an eye disease, Parkinson's disease or a seizure disorder.
  • affective disorders examples 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 of the invention include generalised anxiety disorder (GAD), panic disorder, panic disorder with agoraphobia, simple (specific) phobias (e. g. arachnophobia, performance anxiety such as public speaking), social phobias, posttraumatic stress disorder, anxiety associated with depression, and obsessive compulsive disorder (OCD).
  • 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, performance anxiety such as public speaking
  • posttraumatic stress disorder e.g. arachnophobia
  • anxiety associated with depression e.g. arachnophobia
  • OCD obsessive compulsive disorder
  • behavioural disorders which can be treated or prevented with the compounds of the invention include behavioural and psychological signs and symptoms of dementia, age-related behavioural disorders, pervasive development disorders such as autism,
  • cardiovascular disorders which can be treated or prevented with the compounds of the invention include cardiac arrthymia, atherosclerosis, cardiac arrest, thrombosis, complications arising from coronary artery bypass surgery, myocardial infarction, reperfusion injury, intermittant claudication, ischaemic retinopathy, angina, pre-eclampsia, hypertension, congestive cardiac failure, restenosis following angioplasty, sepsis and septic shock.
  • central and peripheral nervous system degenerative disorders which can be treated or prevented with the compounds of the invention include corticobasal degeneration, disseminated sclerosis, Freidrich's ataxia, motorneurone diseases such as amyotrophic lateral sclerosis and progressive bulbar atrophy, multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathies such as diabetic neuropathy, tabes dorsalis, drug-induced neuropathy and vitamin deficiency, systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy and spasticity.
  • central nervous system injuries which can be treated with the compounds of the invention include traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injuries, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury.
  • cerebral ischaemias which can be treated or prevented with the compounds of the invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke or lacunar stroke, subarachnoid haemorrhage, cerebral vasospasm, peri-natal asphyxia, drowning, cardiac arrest and subdural haematoma.
  • Examples of chemical injuries and substance abuse disorders which can be treated or prevented with the compounds of the invention include drug dependence, for example opiate dependence, benzodiazepine addition, amphetamine addiction and cocaine addiction, alcohol dependence, methanol toxicity, carbon monoxide poisoning and butane inhalation.
  • drug dependence for example opiate dependence, benzodiazepine addition, amphetamine addiction and cocaine addiction, alcohol dependence, methanol toxicity, carbon monoxide poisoning and butane inhalation.
  • Examples of cognitive disorders which can be treated or prevented with the compounds of the invention include dementia, Alzheimer Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body Dementia, Senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome and dementia pugilans.
  • Examples of eating disorders which can be treated or prevented with the compounds of the invention include anorexia nervosa, bulimia, Prader-Willi syndrome and obesity.
  • Examples of eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrhage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, retinal artery occlusion and retinitis.
  • Parkinson's diseases which can be treated or prevented with the compounds of the invention include drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese or carbon monoxide poisoning), Dopa-responsive dystonia-Parkinsonism, posttraumatic Parkinson's disease (punch-drunk syndrome), Parkinson's with on-off syndrome, Parkinson's with freezing (end of dose deterioration) and Parkinson's with prominent dyskinesias.
  • 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
  • seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonicclonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).
  • partial epilepsy simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures
  • generalised seizures including generalised tonicclonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox Gastaut, West Syndome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).
  • the compounds of the present invention are also useful in the treatment and prevention of tinnitus.
  • a therapeutically effective amount of a compound of the invention is administered to a patient.
  • a typical dose is from about 0.001 to 50 mg per kg of body weight, for example 0.01 to 10 mg, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 5 mg to 2 g.
  • the present invention therefore also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, provided that the compound of formula (I) is other than 2-(2-phenoxazin-10-yl-ethyl)-isoindole-l,3-dione.
  • the following Examples illustrate the invention. They do not, however, limit the invention in any way. hi this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting SNS specific sodium channels. A negative result in any one particular assay is not determinative. Examples
  • Example 1 l-(2-Chloro-phenothiazm-10-yl)-2-(6,7-dimethoxy-l-methyl-3,4- dihydro-lH-isoquinolin-2-yl)ethanone
  • reaction mixture was allowed to cool, diluted with CH 3 CN (5 mL), and the solids removed by filtration. The solvent was removed in vacuo and the residue purified via flash chromatography eluting with EtOAc/isohexane (1:4) to afford the title compound as a yellow oil.
  • Example 70 The following compound was synthesised according to the method described in Example 1 with the following modification: Et 3 N was used as base.
  • Et 3 N was used as base.
  • the starting amine was 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Maffrand, J.P. and Eloy, F., Journal of Heterocyclic Chemistry, (1976), 13, 1347-9.
  • Example 38 2-(2-Oxo-2-phenoxazin-10-yl-ethyl)-l,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid tert-butylamide
  • ((3S)-3-(l,2,3,4-tetrahydroisoquinolyl)-N-( t Bu)carboxamide 0.52g, 2.3mmol
  • 2-chloro-l-phenoxazin-lO-yl-ethanone 0.65g, 2.5mmol
  • Et 3 N 0.35mL, 2.5mmol
  • Example 52 4-Methoxy-2-(2-phenoxazin-10-yl-propyl)-isoiudole-l,3-dione
  • Example 65 2-(4-Hydroxy-4,7 ⁇ dihydro-5H ⁇ thieno[2,3-c]pyridin-6-yl)-l- phenoxazin-10-yl-ethanone
  • Example 71 The following compound was prepared by the method described for Example 12 with the following modification: in the case of Example 71 , phenothiazine- 10- carbonyl chloride was used in place of benzhydryl isothiocyanate.
  • hNa ⁇ l.8 ion channel was constructed. This cell line has been used to develop a medium to high throughput assay for determining the ability of test compounds to inhibit membrane depolarisation mediated via the hNayl .8 channel.
  • SH-SY- 5Y hNa ⁇ l.8 are grown in adherent monolayer culture using 50:50 Ham's F-12 / EMEM tissue culture medium supplemented with 15% (v/v) foetal bovine serum; 2mM L-glutamine, 1% NEAA and ⁇ OO ⁇ g.ml "1 Geneticin sulphate. Cells are removed from the tissue culture flask using trypsin/EDTA and re-plated into black walled, clear bottom 96-well assay plates at 50,000CeIIs-WeIl "1 24 hours prior to assay.
  • a sodium free assay buffer 145mM tetramethyl ammonium chloride; 2mM calcium chloride; 0.8mM magnesium chloride hexahydrate; 1OmM HEPES; 1OmM glucose; 5mM potassium chloride, pH 7.4.
  • Fluorescent membrane potential dye solution FLIPRTM membrane potential dye, Molecular Devices Corporation, containing 1 O ⁇ M of a pyrethroid to prevent channel inactivation and 25OnM tetrodotoxin (TTX) to reduce interference from TTX-sensitive sodium channels present in the cell line.
  • Test compound initially dissolved in dimethyl sulfoxide but further diluted in sodium free buffer, is added to achieve the final test concentration range of lOO ⁇ M - 0.05 ⁇ M.
  • Cell plates are incubated for 30 minutes at room temperature to allow equilibration of dye and test compound. Plates are then transferred to a fluorescence plate reader for fluorescence measurement using an excitation wavelength of 530nm whilst measuring fluorescence emission at 565nm.
  • Membrane depolarisation is registered by an increase in fluorescence emission at 565nm.

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Abstract

La présente invention concerne des composés de formule (I), ainsi que des sels de ceux-ci, acceptables d'un point de vue pharmaceutique, qui se sont avérés être des antagonistes de canaux sodiques SNS. Ces composés sont utilisés comme analgésiques et comme agents neuroprotecteurs. - Ar représente un noyau phényle ou un groupe hétéroaryle à 5 ou 6 éléments, - m vaut 1, 2 ou 3.
PCT/GB2006/000040 2005-01-07 2006-01-06 Composes azacycliques servant d'inhibiteurs de canaux specifiques aux neurones sensoriels (sns) WO2006082354A1 (fr)

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WO2008120761A1 (fr) * 2007-03-30 2008-10-09 Nippon Shinyaku Co., Ltd. Dérivé hétéroarylé
WO2009101917A1 (fr) 2008-02-13 2009-08-20 Eisai R & D Management Co., Ltd. Dérivé de bicycloamine
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WO2008120761A1 (fr) * 2007-03-30 2008-10-09 Nippon Shinyaku Co., Ltd. Dérivé hétéroarylé
US8217031B2 (en) 2007-03-30 2012-07-10 Nippon Shinyaku Co., Ltd. Heteroaryl derivatives
JP5206669B2 (ja) * 2007-03-30 2013-06-12 日本新薬株式会社 ヘテロアリール誘導体
WO2009101917A1 (fr) 2008-02-13 2009-08-20 Eisai R & D Management Co., Ltd. Dérivé de bicycloamine
US8252810B2 (en) 2008-02-13 2012-08-28 Eisai R&D Management Co., Ltd. Bicycloamine derivatives
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
US12162868B2 (en) 2016-08-18 2024-12-10 Vidac Pharma Ltd.. Piperazine derivatives, pharmaceutical compositions and methods of use thereof

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