WO2007057775A1 - Dérivés de spiropipéridine - Google Patents

Dérivés de spiropipéridine Download PDF

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WO2007057775A1
WO2007057775A1 PCT/IB2006/003320 IB2006003320W WO2007057775A1 WO 2007057775 A1 WO2007057775 A1 WO 2007057775A1 IB 2006003320 W IB2006003320 W IB 2006003320W WO 2007057775 A1 WO2007057775 A1 WO 2007057775A1
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aminopyridin
piperidine
spiro
carboxamide
group
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PCT/IB2006/003320
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English (en)
Inventor
Charlotte Moira Norfor Allerton
Dafydd Rhys Owen
Thomas Ryckmans
Blanda Luzia Christa Stammen
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Pfizer Limited
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/10—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 aromatic rings
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to spiropiperidine derivatives. More particularly, this invention relates to (aminopyridyl)spiropiperidine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
  • the spiropiperidine derivatives of the present invention are delta opioid receptor agonists and have a number of therapeutic applications, particularly in the treatment of pain, especially neuropathic pain.
  • Delta opioid receptors DORs
  • MORs mu opioid receptors
  • KORs kappa opioid receptors
  • GPCRs G-protein coupled receptors
  • Stimulation of DOR induces analgesia in a wide variety of animal models especially inflammatory models (Quock et al, 1999, above).
  • Mouse KO studies have shown that the abuse liability and other CNS risks associated with opiates, such as morphine, are mediated through the mu opioid receptor (Kieffer and Gaveriaux-Ruff 2002 Prog. Neurobio. 66: 285-306).
  • a DOR agonist approach may be devoid of the side effect profiles of mu and kappa opioids (Quock et al., 1999, above). Generally there is good correlation in DOR expression between species with few exceptions e.g. in the spinal cord where, in humans expression is restricted to laminae Ml, an important region for nociception (Mennicken et al., 2003 J. Comparative Neurol. 465: 349-360).
  • Systemic administration of the selective agonist SB-235863 reverses thermal hyperalgesia resulting from sciatic nerve ligation without any effect on gastrointestinal transit or motor coordination (Petrillo et al, above).
  • Systemic administration of DOR agonists has little effect on acute pain but results in potent analgesia following morphine pre-treatment or following inflammatory stimuli (Morinville et al., above). This seems to occur as a consequence of increased trafficking and membrane insertion of DORs located in cytoplasmic vesicles (Cahill et al., above).
  • WO 2004/074273 discloses compounds of formula:
  • WO 2004/004715 describes a method for modulation of conditions associated with the delta opioid receptor, comprising administration of a compound of formula:
  • the present invention provides a compound of formula (I):
  • R 1 represents H, (Ci -10 )alkyl (optionally substituted by one or more substituents ⁇ ), -(CR 2 ) n -
  • (C 3-8 )cycloalkyl (wherein the cycloalkyl part is optionally substituted by one or more substituents ⁇ ), -(CR 2 ) n -Ar, -(CR 2 ) n -Het 1 , -(CR 2 ) n -Het 2 , or -CN, n is O or an integer from 1 to 6;
  • R represents H or (C 1-10 )alkyl; or, when a group R and a group R 1 substitute a nitrogen atom, the groups together with the nitrogen atom form a ring Het 3 ;
  • R 2 and R 3 are the same or different and each represent R or -(CR 2 )-Ar, or R 2 and R 3 , together with the nitrogen atom to which they are attached, form a ring Het 3 ;
  • R 4 represents (C 1-10 )alkyl; a is O, 1 or 2;
  • R 5 represents (C ⁇ iojalkyl, (C 1-10 )haloalkyl, hydroxy-(C 1-10 )alkyl, (C 1-10 )alkoxy(C 1-10 )alkyl, halogen, OH, (C 1-10 )alkoxy, (C ⁇ n ⁇ haloalkoxy, phenoxy, benzyloxy, (C 3-8 )cycloalkyIoxy, (C 3-
  • R 6 , R 7 , R 8 and R 9 are each independently H or (C 1- i 0 )alkyI, or two groups selected from (a) R 6 or R 7 and (b) R 8 or R 9 together form a bond or a (C 1-3 )alkylene group;
  • R 10 represents H, (Ci -10 )alky! (optionally substituted by one or more substituents ⁇ ), -(CR 2 ) q -
  • (C 3-8 )cycloaikyl (wherein the cycloalkyl part is optionally substituted by one or more substituents ⁇ ), -(CR 2 ) q -Ar, -(CR 2 ) q -Het 1 , or -(CR 2 ) q -Het 2 ; q is 0 or an integer from 1 to 6;
  • R 11 represents H, (Ci.i O )alkyl or -(CR 2 )-Ar, or two groups R 11 , together with the nitrogen atom to which they are attached, form a ring Het 3 ;
  • Ar is a phenyl or naphthyl group optionally substituted by one or more substituents ⁇ ;
  • Het 1 is a group selected from (1) a 5- or 6-membered aromatic heterocyclic group having as ring heteroatoms (a) 1 to 4 nitrogen atoms, (b) 1 oxygen or 1 sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, is optionally substituted (i) on carbon by one or more substituents ⁇ and/or (ii) on nitrogen by one or more substituents ⁇ , (2) a bicyclic group comprising an optionally substituted 5- or 6-membered aromatic heterocyclic group, as defined in (1 ) above, fused with a benzene ring (the benzene ring being optionally substituted with one or more substituents ⁇ ) or (3) a bicyclic group comprising two optionally substituted 5- or 6-membered aromatic heterocyclic group, as defined in (1 ) above, fused together
  • alkyl' means a straight or branched monovalent saturated hydrocarbon chain containing from 1 to 10 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • 'alkyl' is (Ci -S )alkyl, more preferably (C 1-4 )alkyl, and most preferably methyl or ethyl.
  • the alkyl group may optionally be substituted by one or more substituents ⁇ , defined below, the number of substituents being limited by the number of substitutable positions (eg a methyl group is limited to 3 substituents).
  • substituents ⁇ there are preferably 1 to 3 substituents ⁇ , more preferably 1 or 2 substituents ⁇ , and most preferably one substituent ⁇ .
  • 'Cycloalkyl' and 'cycloalkane' means a saturated carbocyclic ring having from 3 to 8 carbon atoms, the term 'cycloalkyl' referring to a monovalent group and the term 'cycloalkane ring' referring to a ring completed by two substituents together with the carbon atom to which they are attached, or a ring fused to one of the heterocyclic groups defined below.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • 'cycloalkyl' is (C 3-6 )cycloalkyl.
  • the cycloalkyl group or cycloalkane ring may optionally be substituted by one or more substituents ⁇ , defined below, the number of substituents being limited by the number of substitutable positions. Where the cycloalkyl group or cycloalkane ring is substituted, there are preferably 1 to 3 substituents ⁇ , more preferably 1 or 2 substituents ⁇ , and most preferably one substituent ⁇ .
  • the cycioalkyl group or cycloalkane ring may also be fused with a benzene ring (the benzene ring being optionally substituted with one or more substituents ⁇ ). Examples of such fused groups include indanyl and tetralinyl, of which indanyl is preferred.
  • 'Alkylene' means a straight or branched divalent saturated hydrocarbon chain containing from 1 to 3 carbon atoms.
  • alkyl groups include methylene, ethylene, methylmethylene and propylene.
  • 'alkylene' is methylene or ethylene, more preferably methylene.
  • 'Alkyleneoxy' means a divalent group -alkylene-O-, wherein the alkylene moiety is a straight or branched saturated divalent hydrocarbon chain containing 1 to 4 carbon atoms. The oxygen atom may be attached to the remainder of the molecule at either position.
  • Preferred aikyleneoxy groups include methyleneoxy and ethyleneoxy.
  • alkylenedioxy' means a divalent group -O-alkylene-0-, wherein the alkylene moiety is a straight or branched saturated divalent hydrocarbon chain containing 1 to 4 carbon atoms.
  • Preferred alkylenedioxy groups include methylenedioxy and ethylenedioxy.
  • 'Halogen' means fluoro, chloro, bromo or iodo.
  • 'Oxo' means a doubly bonded oxygen atom.
  • 'Alkoxy' means 'alkyl-O-', wherein 'alkyl' is as defined above (either in its broadest aspect or a preferred aspect).
  • alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, n-hexyloxy, i- hexyloxy, n-heptyloxy, n-octyloxy, n-nonyloxy and n-decyloxy.
  • 'alkoxy' is (C 1-6 )alkoxy, more preferably (C ⁇ alkoxy, and most preferably methoxy or ethoxy.
  • 'Phenoxy' means 'phenyl-O-' and 'benzyloxy' means 'phenyl-CH 2 -O-'.
  • 'Cycloalkyloxy' means 'cycloalkyl-O-', wherein 'cycloalkyl' is as defined above (either in its broadest aspect or a preferred aspect).
  • cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • 'cycloalkyloxy' is (C 3 . 6 )cycloalkyloxy.
  • 'Cycloalkylalkoxy means alkoxy substituted with cycloalkyl, wherein 'alkoxy' and 'cycloalkyl' are as defined above (either in the broadest aspect or a preferred aspect).
  • Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, 1- or 2-cyclopropylethoxy, 1-, 2- or 3- cyclopropylpropoxy, 1-, 2-, 3- or 4-cyclopropylbutoxy, cyclobutylmethoxy, 1- or 2- cyclobutylethoxy, 1-, 2- or 3- cyclobutylpropoxy, 1-, 2-, 3- or 4-cyclobutylbutoxy, cyclopentylmethoxy, 1- or 2-cyclopentylethoxy, 1-, 2- or 3- cyclopentylpropoxy, 1-, 2-, 3- or 4- cyclopentylbutoxy, cyclohexylmethoxy, 1- or 2-cyclohexylethoxy, 1-, 2- or
  • Haloalkyl means an alkyl group, as defined above (either in its broadest aspect or a preferred aspect) substituted by one or more halogen atoms (preferably fluorine or chlorine atoms, more preferably fluorine atoms), the number of halogen atoms being limited by the number of substitutable positions.
  • halogen atoms preferably fluorine or chlorine atoms, more preferably fluorine atoms
  • 'haloalkyl' examples include mono-, di- or trifluoromethyl, mono-, di- or trichloromethyl, bromomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, perfluoroethyl, perfluoropropyl and perfluorobutyl.
  • 'haloaikyi' is (C 1-6 )haloalkyl, more preferably (C 1-4 )haloalkyl, and most preferably mono-, di- or trifluoromethyl, mono-, di- or trichloromethyl, or perfluoroethyl.
  • 'Haloalkoxy' means 'haloalkyl-O-', where 'haloaikyi' is as defined above (either in its broadest aspect or a preferred aspect), the number of halogen atoms being limited by the number of substitutable positions.
  • 'haloalkoxy' include mono-, di- or trifluoromethoxy, mono-, di- or trichloromethoxy, bromomethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloroethoxy, perfluoroethoxy, perfluoropropoxy and perfluorobutoxy.
  • 'haloalkoxy' is (C ⁇ haloalkoxy, more preferably (C ⁇ Jhaloalkoxy, and most preferably mono-, di- or trifluoromethoxy.
  • 'Hydroxyalkyl' means alkyl, as defined above (either in its broadest aspect or a preferred aspect) substituted by a hydroxy (-OH) group.
  • hydroxyalkyl groups include hydroxymethyl, 1- or 2-hydroxyethyl, 1-, 2- or 3-hydroxypropyl, and 1-, 2-, 3- or 4- hydroxybutyl.
  • 'hydroxyalkyl' is (C ⁇ alkyl substituted with hydroxy, more preferably (C 1-4 )alkyl substituted with hydroxy. Hydroxymethyl and 1- or 2-hydroxyethyl groups are especially preferred.
  • alkoxyalkyl means alkyl, as defined above (either in its broadest aspect or a preferred aspect) substituted by an alkoxy group, as defined above (either in its broadest aspect or a preferred aspect).
  • alkoxyalkyl groups include methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, 1- or 2-methoxyethyl, 1- or 2-ethoxyethyl, 1- or 2-propoxyethyl, 1- or 2-butoxyethyl, 1-, 2- or 3-methoxypropyl, 1-, 2- or 3-ethoxypropyl, 1-, 2- or 3- propoxypropyl, 1-, 2- or 3-butoxypropyl, 1-, 2-, 3- or 4-methoxybutyl, 1-, 2-, 3- or 4- ethoxybutyl, 1-, 2-, 3- or 4-propoxybutyl and 1-, 2-, 3- or 4-butoxybutyl.
  • 'alkoxyalkyl means (C 1-6 )alkyl substituted with (C 1-4 )alkoxy, more preferably (C 1-4 )alkyl substituted with (C 1 ⁇ aIkOXy.
  • Methoxymethyl, ethoxymethyl and 2-methoxyethyl groups are especially preferred.
  • R is hydrogen or (Ci -10 )alkyl, as defined above.
  • R is hydrogen or (C 1- 6 )alkyl.
  • R is hydrogen or (C ⁇ alkyl.
  • R 1 represents H, (C 1-10 )alkyl (optionally substituted by one or more substituents ⁇ ), -(CR2)n-(C3-8)cycloalkyl (wherein the cycloalkyl part is optionally substituted by one or more substituents ⁇ ), -(CR 2 ) n -Het 1 , -(CR 2 ) n -Het 2 , -(CR 2 ) n -Ar, or -CN.
  • R 1 represents H, (Ci. 10 )alkyl (optionally substituted by one substituent ⁇ ), -(CR 2 ) n -
  • (C 3 . 8 )cycloalkyl (wherein the cycloalkyl part is optionally substituted by one substituent ⁇ ), - (CR 2 ) n -Het ⁇ -(CR 2 ) n -Het 2 , -(CR 2 ) n -Ar, or -CN.
  • R 1 represents H, (Ci. 10 )alkyl, phenyl, benzyl (wherein the phenyl part is optionally substituted with (C 1-4 )alkyl or (C 1-4 )BIkOXy), -Het 1 , -(CH 2 )-Het 1 or -CN.
  • R 1 is R 1a wherein R 1a represents H, C 1-4 alkyl, phenyl, benzyl (wherein the phenyl part is optionally substituted with (C 1-4 )alkyl or (C 1-4 )alkoxy), pyridyl, -(CH 2 )- pyridyl, oxadiazolyl (optionally substituted with phenyl) or oxazolyl (optionally substituted with C 1-4 alkyl).
  • R 1 is R 1z wherein R 1z represents H, C 1-6 alkyl, -(CR 2 )n-(C 3 . 8 )cycloalkyl, -(CR 2 ) ⁇ -Ar, or -(CR 2 ) n -Het 2 .
  • R 1 is R 1y wherein R 1y represents H, C 1-4 alkyl, C 3-8 cycloalkyl or phenyl.
  • each R may be the same or different.
  • each R is H or methyl. More preferably, each R is H.
  • n is 0, 1 or 2; more preferably 0 or 1.
  • the group Ar is an aryl group selected from phenyl and naphthyl.
  • the group Ar is optionally substituted by one or more substituents ⁇ , defined below, the number of substituents being limited by the number of substitutable positions. Where the group Ar is substituted, there are preferably 1 to 5 substituents ⁇ , more preferably 1 to 3 substituents ⁇ , even more preferably 1 or 2 substituents ⁇ , and most preferably one substituent ⁇ .
  • Ar is phenyl optionally substituted by one substituent ⁇ .
  • Ar is unsubstituted phenyl or phenyl substituted with one substituent selected from (C ⁇ alkyl and (C ⁇ alkoxy.
  • the group Het 1 is selected from (1 ) a 5- or 6-membered aromatic heterocyclic group having as ring heteroatoms (a) 1 to 4 nitrogen atoms, (b) 1 oxygen or 1 sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, is optionally substituted (i) on carbon by one or more substituents ⁇ and/or (ii) on nitrogen by one or more substituents ⁇ , (2) a bicyclic group comprising an optionally substituted 5- or 6-membered aromatic heterocyclic group, as defined in (1 ) above, fused with a benzene ring (the benzene ring being optionally substituted with one or more substituents ⁇ ) or (3) a bicyclic group comprising two optionally substituted 5- or 6-membered aromatic heterocyclic group, as defined in (1) above, fused together.
  • Het 1 examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothienyl, benzpyrazolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, quinolyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, pteridinyl and pyrazolopyrimidiny
  • Het 1 is a group selected from (1 ) and (2) above. Where the group Het 1 is substituted on carbon, there are preferably 1 or 2 substituents ⁇ , and most preferably one substituent ⁇ . In addition, when the group Het 1 is optionally substituted on the one or more ring nitrogen atoms, if present, there is preferably only one substituent ⁇ .
  • Het 1 is thienyl, furanyl, pyrrolyl, imidazolyl, oxadiazolyl, oxazolyl, thiazolyl or pyridyl (these groups being optionally substituted on carbon with one substituent ⁇ , and/or on nitrogen with one substituent ⁇ ).
  • Het 1 is pyridyl, oxadiazolyl or oxazolyl (these groups being optionally substituted with a phenyl group or a (C ⁇ alkyl group).
  • Het 2 include oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxazolidinyl, thiazolidinyi, isoxazolidinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxanyl, oxathianyl, dithianyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl, diazepanyl and azocinyl.
  • Het 2 is a group (4) above. Where the group Het 2 is substituted on carbon, there are preferably 1 or 2 substituents ⁇ , and most preferably one substituent ⁇ . In addition, when the group is optionally substituted on the one or more ring nitrogen atoms, if present, there is preferably only one substituent ⁇ .
  • Het 2 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, these groups being optionally substituted on carbon by one substituent ⁇ and/or on nitrogen by one substituent ⁇ .
  • Het 2 is azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, these groups being optionally substituted on carbon and/or nitrogen by a (C M )alkyl group.
  • the ring is formed by two groups described above together with the nitrogen atom to which they are attached.
  • Specific examples of Het 3 include aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepane, oxazepane, diazepane and azocine.
  • the ring Het 3 is a ring (7) above. Where the ring Het 3 is substituted on carbon, there are preferably 1 or 2 substituents ⁇ , and most preferably one substituent ⁇ . In addition, when the ring is substituted on the one or more ring nitrogen atoms, there is preferably only one substituent ⁇ .
  • Het 3 is azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine, these groups being optionally substituted on carbon by one substituent ⁇ and/or on nitrogen by one substituent ⁇ .
  • Het 3 is azetidine, pyrrolidine, piperidine or piperazine, these groups being optionally substituted on carbon and/or nitrogen by a (C 1-4 )alkyl group.
  • substituents ⁇ are selected from substituents ⁇ 1 comprising halogen, (C 1-6 )alkoxy, phenoxy, (C 1-4 )alkylenedioxy, NR 2 , pyridyl, CN, CONR 2 and NRCOR.
  • substituents a are selected from substituents ⁇ 2 comprising halogen, (C 1-4 )alkoxy, phenoxy, (C 1-2 )alkylenedioxy, CONR 2 and pyridyl.
  • substituents ⁇ are selected from substituents ⁇ 1 comprising (C 1-6 )alkyl, (C 1- 6 )haloalkyl, phenyl, halogen, (C 1-6 )alkoxy, phenoxy, CN, CONR 2 , NRCOR, and COOR. More preferably, substituents ⁇ are selected from substituents ⁇ 2 comprising (C 1-4 )alkyl, halogen, (C 1-4 )haloaikyl (especially CF 3 ) and (C ⁇ alkoxy.
  • substituents ⁇ are selected from substituents ⁇ 1 comprising (C 1-6 )alkyl, phenyl and pyridyl.
  • substituents ⁇ are selected from substituents ⁇ 2 comprising (C 1-4 )alkyl.
  • the group NR 2 R 3 is present at the 4-position of the pyridine ring (the pyridine ring nitrogen being the 1 -position).
  • the bond to the left of the groups is connected to the spiro ring and the bond to the right is connected to the group R 1 .
  • the bond between X and Y is a single bond.
  • X represents C(L-R 1 ) 2
  • preferably one group (L-R 1 ) is H and the other group (L-R 1 ) is other than H.
  • both groups (L-R 1 ) are H.
  • R, R 1 and Het 1 are as defined above, either in its broadest aspect or in a preferred aspect; or a group R and a group R 1 , together with the nitrogen atom to which they are attached, together form a group Het 3 wherein Het 3 is as defined above, either in its broadest aspect or in a preferred aspect.
  • X represents C(L C -R 1a ) 2> N(L b '-R 1a ) or O, wherein
  • R 1a represents H, Ci -4 alkyl, phenyl, benzyl, pyridyl, oxadiazolyl (optionally substituted with phenyl) or oxazolyl (optionally substituted with Ci -4 alkyl).
  • Y represents C(L-R 1 ) 2
  • preferably one group (L-R 1 ) is H and the other group (L-R 1 ) is other than H.
  • both groups (L-R 1 ) are H.
  • R and R 1 are as defined above, either in its broadest aspect or in a preferred aspect; or a group R and a group R 1 , together with the nitrogen atom to which they are attached, together form a group Het 3 wherein Het 3 is as defined above, either in its broadest aspect or in a preferred aspect.
  • R and Het 2 are as defined above either in its broadest aspect or in a preferred aspect; or a group R and a group R 1 , together with the nitrogen atom to which they are attached, together form a piperidine, piperazine or azepine group which is optionally fused with a benzene ring.
  • m may be 0 or 1.
  • Z represents C(L-R 1 ) 2 (wherein L and R 1 are as defined above, either in its broadest aspect or in a preferred aspect) or O.
  • Z represents CH 2 or O, even more preferably CH 2 .
  • R 2 and R 3 are the same or different and each represent R (as defined above, either in its broadest aspect or in a preferred aspect) or benzyl, or R 2 and R 3 , together with the nitrogen atom to which they are attached, form a group Het 3 (as defined above, either in its broadest aspect or in a preferred aspect).
  • R 2 and R 3 are the same or different and each represent H, C 1-4 alkyl or benzyl.
  • R 2 and R 3 each represent H.
  • a is 0 or 1 , suitably 0.
  • b is 0, 1 or 2, suitably 0 or 1.
  • n is 0 or 1 , suitably 0.
  • R 5 represents (C 1-6 )alkyl, F, Cl, Br, OH, (C 1-6 JaIkOXy, CN,
  • R 5 represents methyl, OH or methoxy.
  • p is O or 1 , more preferably 1.
  • R 6 , R 7 , R 8 and R 9 are each independently H or (C 1-4 )alkyl. More preferably, R 6 , R 7 , R 8 and R 9 are all H.
  • R 10 represents H, (C 1-6 )alkyl (optionally substituted by one or more substituents ⁇ ), (C 3 . 6 )cycloalkyl (wherein the cycloalkyl part is optionally substituted by one or more substituents ⁇ ), benzyl (wherein the phenyl part is optionally substituted by one or more substituents ⁇ 1 ), or -Het 1 .
  • R 10 represents H, (C 1-4 )alkyl, benzyl (wherein the phenyl part is optionally substituted by one or more substituents ⁇ 2 ), or pyridyl.
  • q is O, 1 or 2, more preferably 0 or 1.
  • R 11 represents H or (C 1-6 )alkyl.
  • the compounds of formula (I) are preferably compounds of formulae (1-1), (I-2), (I-3), (I-4), (I- 5), (I-6), (I-7) or (I-8):
  • L, L', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , a and b are as defined above, either in the broadest aspect or a preferred aspect.
  • Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from the suitable and/or preferred groups for each variable. Even more preferred compounds of the invention include those where each variable in Formula (I) is selected from the more preferred or most preferred groups for each variable.
  • R 1 represents H, (C 1-10 )alkyl (optionally substituted by one or more substituents ⁇ ), -(CR 2 ) n - (C 3-8 )cycloalkyl (wherein the cycloalkyl part is optionally substituted by one or more substituents ⁇ ), -(CR 2 ) n -Ar, -(CR 2 ) n -Het 1 , -(CR 2 ) n -Het 2 , or -CN, n is O or an integer of from 1 to 6;
  • R represents H or (C 1-10 )alkyl; or, when a group R and a group R 1 substitute a nitrogen atom, the groups together with the nitrogen atom form a ring Het 3 ;
  • R 2 and R 3 are the same or different and each represent R or -(CR 2 )-Ar, or R 2 and R 3 , together with the nitrogen atom to which they are attached, form a ring Het 3 ;
  • R 4 represents (C 1-10 )alkyl; a is O, 1 or 2;
  • b is O or an integer from 1 to 4;
  • R 6 , R 7 , R 8 and R 9 are hydrogen;
  • Ar is a phenyl or naphthyl group optionally substituted by one or more substituents ⁇ ;
  • Het 1 is a 5- or 6-membered aromatic heterocyclic group having as ring heteroatoms (a) 1 to 4
  • Het 3 is a 3- to 8-membered saturated heterocyclic ring containing 1 or 2 heteroatoms of which one heteroatom is a nitrogen atom and the other heteroatom, if present, is selected from nitrogen, oxygen and sulphur, is optionally substituted on carbon by one or more substituents ⁇ and/or on nitrogen by one or more substituents ⁇ and/or on sulphur by one or two oxo groups and is optionally fused with a benzene ring (the benzene ring being optionally substituted by one or more substituents ⁇ ) or a (C 3 .
  • substituents ⁇ are selected from (C 1-10 )alkyI, phenyl, halogen, CF 3 , OR, O-phenyl,
  • substituents ⁇ are selected from (C 1-1o )alkyl, phenyl, pyridyl, CONR 2 and COOR; or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds of the invention are delta opioid receptor agonists.
  • they show an affinity for the delta opioid receptor which is greater than their affinity for the mu and kappa opioid receptors.
  • Preferred compounds of the invention show at least a 10-fold selectivity for the delta opioid receptor as compared with the mu opioid receptor.
  • the compounds of formula (I), being delta opioid receptor agonists, are potentially useful in the treatment of a range of disorders.
  • the present invention also comprises a compound of formula (I), as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
  • the present invention also comprises use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of diseases or conditions mediated by the delta opioid receptor.
  • the present invention also comprises a method for the treatment of a disease mediated by the delta opioid receptor, comprising administering to a mammal an effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt or solvate thereof.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review).
  • These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
  • A-delta fibres myelinated
  • C fibres non-myelinated
  • the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated. Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain.
  • Acute pain does not generally result in any persistent psychological response.
  • chronic pain is long- term pain, typically persisting for more than three months and leading to significant psychological and emotional problems.
  • Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
  • Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13- 44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44).
  • the activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-deita fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, postoperative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
  • Back pain may be due to herniated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal • muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • Pain associated with osteoarthritis or rheumatoid arthritis includes joint pain associated with osteoarthritis or rheumatoid arthritis and soft tissue (e.g., muscle) pain due to change in gait or other body movement in response to joint pain.
  • Joint pain associated with rheumatoid arthritis may be due to inflammation in the joint or degradation of cartilage of the joint.
  • Joint pain associated with osteoarthritis is usually due to degradation of cartilage of the joint, although such pain may be due to episodic flares of inflammation in osteoarthritic joints.
  • Preferred joints are knee, hip, and joints of hands.
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • Gl gastrointestinal
  • FBD functional bowel disorder
  • IBD inflammatory bowel disease
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
  • musculoskeletal disorders including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis; • heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;
  • head pain such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and
  • orofacial pain including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.
  • the compounds of formula (I) are also useful in the treatment of conditions other than pain.
  • the compounds of formula (I) are useful in the treatment of conditions of lower urinary tract dysfunction including but not exclusively restricted to overactive bladder, increased daytime frequency, nocturia, urgency, urinary incontinence (any condition in which there is an involuntary leakage of urine), including stress urinary incontinence, urge urinary incontinence and mixed urinary incontinence, overactive bladder with associated urinary incontinence, enuresis, nocturnal enuresis, continuous urinary incontinence, situational urinary incontinence such as incontinence during sexual intercourse, and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).
  • LUTS benign prostatic hyperplasia
  • PE premature ejaculation
  • PE is a relatively common sexual dysfunction in men. It has been defined in several different ways but the most widely accepted is the Diagnostic and Statistical Manual of Mental Disorders IV one which states: "PE is a lifelong persistent or recurrent ejaculation with minimal sexual stimulation before, upon or shortly after penetration and before the patient wishes it. The clinician must take into account factors that affect duration of the excitement phase, such as age, novelty of the sexual partner or stimulation, and frequency of sexual activity. The disturbance causes marked distress of interpersonal difficulty.”
  • the International Classification of Diseases 10 definition states: "There is an inability to delay ejaculation sufficiently to enjoy lovemaking, manifest as either of the following: (1) occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is required: before or within 15 seconds of the beginning of intercourse); (2) ejaculation occurs in the absence of sufficient erection to make intercourse possible. The problem is not the result of prolonged abstinence from sexual activity"
  • Ejaculation is dependent on the sympathetic and parasympathetic nervous systems. Efferent impulses via the sympathetic nervous system to the vas deferens and the epididymis produce smooth muscle contraction, moving sperm into the posterior urethra. Similar contractions of the seminal vesicles, prostatic glands and the bulbouretheral glands increase the volume and fluid content of semen.
  • Expulsion of semen is mediated by efferent impulses originating from a population of lumber spinothalamic cells in the lumbosacral spinal cord (Coolen & Truitt, Science, 2002, 297, 1566) which pass via the parasympathetic nervous system and cause rhythmic contractions of the bulbocavernous, ischiocavernous and pelvic floor muscles.
  • Cortical control of ejaculation is still under debate in humans.
  • the medial pre-optic area and the paraventricular nucleus of the hypothalamus seem to be involved in ejaculation.
  • Ejaculation comprises two separate components - emission and ejaculation.
  • Emission is the deposition of seminal fluid and sperm from the distal epididymis, vas deferens, seminal vesicles and prostrate into the prostatic urethra. Subsequent to this deposition is the forcible expulsion of the seminal contents from the urethral meatus.
  • Ejaculation is distinct from orgasm, which is purely a cerebral event. Often the two processes are coincidental.
  • Premature female orgasm may be defined as: a) Persistent or recurrent orgasm with minimal sexual stimulation, occurring before, upon or shortly after penetration and generally before the person/couple wishes it. b) Interpersonal difficulties arise from female lack of motivation for/discomfort with continued sexual stimulation, c) The disturbance gives rise to negative psychosocial consequences where arousal occurs in inappropriate situations, d) The disturbance itself causes marked distress or interpersonal difficulty.
  • WSCDI means ⁇ S-dimethylaminopropyO-S-ethylcarbodiimide hydrochloride
  • DCC means N.N'-dicyclohexylcarbodiimide
  • HOBT means 1 -hydroxybenzotriazole hydrate
  • HOAT means 1-hydroxy-7-azabenzotriazole
  • PyBOP® means benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate
  • PyBrOP® means bromotrispyrrolidinophosphonium hexafluorophosphate
  • CDI means 1 ,1 '-carbonyldiimidazole
  • HBTU means 0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIAD diisopropyl azodicarboxylate
  • AIBN 2,2'-azobis-(2-methylpropionitrile)
  • Pd(dppf) 2 means 1 ,1 '-bis[(diphenylphosphino)ferrocene]palladium;
  • Pd 2 (dba) 3 means tris(dibenzylideneacetone)dipailadium (0)
  • NMM 4-methylmorpholine
  • H ⁇ nig's base means N-ethyldiisopropylamine
  • Et 3 N means triethylamine
  • BOC means terf-butoxycarbonyl
  • CBz means benzyloxycarbonyl
  • MeOH means methanol
  • EtOH means ethanol
  • EtOAc means ethyl acetate
  • Et 2 O means diethyl ether
  • THF means tetrahydrofuran
  • DMSO means dimethyl sulfoxide
  • DCM dichloromethane
  • AcOH acetic acid
  • TFA means trifluoroacetic acid
  • STAB means sodium triacetoxyborohydride
  • NaHMDS means sodium hexamethyldisilazane
  • DMF means dimethylformamide
  • TLC means thin layer chromatography
  • DMA means dimethylacetamide
  • Bu 3 SnH means tributyltin hydride
  • (Me 3 Si) 3 SiH means tris(trimethylsilyl)si!yl hydride
  • Pd(OAc) 2 means palladium diacetate; and TfO means trifluoromethanesulfonyloxy.
  • R a represents (N-R)-R 1 or 0-R 1 and PG represents a protecting group, suitable examples of which are described in "Protecting Groups in Organic Synthesis” by T. W. Greene and P. Wuts, Wiley and Sons, 1991.
  • PG is preferably BOC.
  • Compounds of formula (II) may be obtained commercially or from published methods (eg as described in WO 97/36873, step E) unless their synthesis is described in this specification.
  • Single enantiomers of (II) (e.e. > 95%) may be obtained by conventional chiral separation methods, preferably by repeated crystallisation in the presence of chiral amines, preferably (S)- or (R)- ⁇ -methyl- benzylamine, in toluene.
  • Step a): Compounds of formula (III) may be synthesised by coupling an amine, HNRR 1 or alcohol R 1 OH with an acid (II), in the presence of a conventional coupling agent, optionally in the presence of a catalyst, with an excess of base in a suitable solvent.
  • the preferred conditions are: 1-hydroxybenzotriazole monohydrate (1 eq.), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide HCI (1.2 eq.), and N-methylmorpholine (1.5 eq.) and the appropriate amine/aicohol (1.1 eq.) in dichloromethane at room temperature for up to
  • Step b): Deprotection of compounds of formula (III) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions when PG is BOC are TFA in DCM for about 4 hrs at room temperature.
  • an alcohol solvent preferably 2-methyl-2-butanol
  • Step d): Compounds of formula (Ia) may be prepared by reduction of the crude reaction mixture, or the isolated product, of step c). Typically, reduction is carried out in the presence of a suitable catalyst, e.g. palladium on carbon or palladium hydroxide on carbon, under an atmosphere of hydrogen or with a suitable hydrogen transfer reagent (e.g. cyclohexene or ammonium formate), or in the presence of a reducing agent, typically iron powder, in organic acid at room temperature to 65 0 C for 2 to 18 hours.
  • a suitable catalyst e.g. palladium on carbon or palladium hydroxide on carbon
  • a suitable hydrogen transfer reagent e.g. cyclohexene or ammonium formate
  • a reducing agent typically iron powder
  • Preferred conditions are ammonium formate (6 eq.) and 20% palladium hydroxide on carbon (10% by weight) at 65 0 C until conventional methods of detection, preferably TLC, indicate complete conversion.
  • the isolated product from step c) may be dissolved in an organic acid, preferably acetic acid, and stirred in the presence of iron powder at room temperature for 2-10 hours, preferably 2-4 hours.
  • Compounds of formula (Vl) may be obtained from published methods (eg as described in WO 2004/028459, example 21 , compound xxii). Steps a) to c): Compounds of formula (Ic) may be obtained from compounds of formula (Vl) using the conditions described in steps c), d) and b) for compounds of formula (Ia) depicted in Scheme 1.
  • Step d): Compounds of formula (Ib) may be synthesised by coupling a sulphonyl chloride, R 1 SO 2 CI, with an amine (Ic), in the presence of an excess of base in a suitable solvent.
  • the preferred conditions are: 1 eq. of R 1 SO 2 CI, 1.5 eq. triethylamine in dichloromethane at room temperature for 4-16 hours.
  • R b represents (C 1-10 )alkyl or Het 1 (as defined above)
  • R c represents (C ⁇ ojalkyl
  • PG represents a suitable protecting group, suitable examples of which are described in "Protecting Groups in Organic Synthesis” (referred to above), preferably BOC.
  • Compounds of formula (VII) may be obtained from published methods (eg as described in US 5578593, compound 21 , scheme 10).
  • Step a): Deprotection of compounds of formula (VII) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis” (referred to above).
  • PG is BOC 1
  • preferred conditions are 4M hydrochloric acid in dioxane at room temperature.
  • the imine is hydrolysed during work up.
  • Preferred conditions are 1 eq. diamine (VIII), 3.5 eq. sodium carbonate in methyl isobutyl ketone at 110 0 C for 3 hours, then (V) at 8O 0 C overnight and finally 2-propanol at room temperature for 4 hours.
  • the intermediate nitro compound can then be reduced according to the conditions described in the synthesis of compounds of formula (Ia), step d), Scheme 1.
  • Step d): Compounds of formula (Ie) may be prepared by coupling the amine of formula (If) with the appropriate sulphonyl chloride R 1 SO 2 CI optionally in the presence of a base.
  • the conditions are amine and sulphonyl chloride R 1 SO 2 CI, optionally with an excess of tertiary amine such as triethylamine, H ⁇ nig's base or NMM, in DCM or THF, at room temperature for 1 to 24 hours.
  • the preferred conditions are amine and 1.1 eq. of R 1 SO 2 CI, 3 eq. triethylamine in dichioromethane at room temperature for up to 18 hours.
  • Step e): Compounds of formula (IX) may be obtained by coupling the amine of formula (VII) with the appropriate acid or acid derivative. The reaction may be undertaken using either:
  • amine and anhydride (R 1 CO) 2 O optionally with an excess of tertiary amine such as Et 3 N, H ⁇ nig's base or NMM, in DCM or THF, without heating for 1 to 24 hours.
  • Preferred conditions are: Amine and 1eq. acid R 1 COOH, 1.1 eq. 1-hydroxybenzotriazole monohydrate, 1.1 eq. 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide HCI, and 3 eq. triethylamine in dichloromethane at room temperature for up to 18 hrs.
  • a base e.g. sodium tert-butoxide or sodium methoxide
  • a suitable catalyst e.g. palladium (II) acetate or Pd 2 (dba) 3
  • a ligand e.g.
  • 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl in a suitable solvent, typically toluene, 1 ,4- dioxane or DMF ' with heating.
  • Preferred conditions are: 1 eq. of amine, 1 eq. of 2- chloropyridine, 1.4 eq. of sodium tert-butoxide in the presence of 0.1 eq. palladium (II) acetate and 0.1 eq. 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl in toluene at 80 0 C for up to 4 hours.
  • a base e.g. sodium hydride or NaHMDS
  • a suitable solvent e.g. tetrahydrofuran or DMF at room temperature
  • Preferred conditions are: 1 eq. of compound (VII), 3.7 eq. of iodomethane, 1.2 eq. of sodium hydride in tetrahydrofuran at room temperature for up to 3 hours.
  • Step h): Deprotection of compounds of formula (IX) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis” (referred to above).
  • PG is BOC
  • preferred conditions are 4M hydrochloric acid in dioxane at room temperature or TFA in DCM at room temperature.
  • Step k): Reaction of compounds of formula (Ie) wherein L is -NH-C( O)- and R 2 and R 3 are H with a compound of formula R C -LG, wherein LG is a suitable leaving group, eg Cl, Br, I, OTf, in the presence of a base, eg sodium hydride or NaHMDS in a suitable solvent, eg THF or DMF.
  • a base eg sodium hydride or NaHMDS in a suitable solvent, eg THF or DMF.
  • the preferred conditions are sodium hydride and R c -I in THF at room temperature for 18 hours.
  • Steps c) and d): Reaction of the ketone of formula (Ik) with a homochiral sulfinamide of formula R d S( O)N H 2 (wherein R d represents (C 1-10 )alkyl), preferably in the presence of titanium ethoxide in a suitable organic solvent, e.g. THF or toluene at reflux followed by reduction at low temperature with a suitable reducing agent, e.g sodium borohydride or sodium triacetoxyborohydride, may provide compounds of formula (Ij).
  • Preferred conditions are: 1 eq. of compound (Ik), 1.5 eq. of sulfinamide, 3.5 eq. of titanium ethoxide in THF at reflux for 18 hours, followed by 4 eq. of sodium borohydride at -48 0 C to room temperature over 18 hours.
  • Step e): The sulfinamide may be cleaved to give compounds of formula (Ii) under acidic conditions, typically HCI or trifluoromethanesulfonic acid in an appropriate solvent, e.g. methanol, ethanol, DCM.
  • acidic conditions typically HCI or trifluoromethanesulfonic acid in an appropriate solvent, e.g. methanol, ethanol, DCM.
  • the preferred conditions are: 1 eq. of compound (Ij) in methanol with an excess of a 4M solution of hydrogen chloride in dioxane at room temperature for about 30 minutes.
  • Step f): Compounds of formula (Ih) may be prepared by coupling amines of formula (Ii) with the appropriate acid or acid derivative using conditions described in step e) for compounds of formula (Ie) depicted in Scheme 3.
  • the preferred conditions are amine (Ii), 1eq. acid R 1 COOH, 1.1 eq. 1-hydroxybenzotriazole monohydrate, 1.1 eq. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide HCI, and 3 eq. triethylamine in dichloromethane at room temperature for up to i ⁇ hrs.
  • Step a): Compounds of formula (XIV) may be prepared by methods analogous to those described in "Comprehensive Heterocyclic Chemistry", A.R. Katritzky, CW. Rees, Pergamon Press, Oxford, 1984.
  • compounds of formula (XIV) where Het 1 is oxadiazolyl may be prepared by coupling an acid with the appropriate hydrazide of formula R 6 CONHNH 2 , followed by ring closure with an appropriate dehydrating reagent, e.g. phosphorus oxychloride, thionyl chloride or 2-chloro-1 ,3-dimethyl-2-imidazolinium tetrafluoroborate.
  • dehydrating reagent e.g. phosphorus oxychloride, thionyl chloride or 2-chloro-1 ,3-dimethyl-2-imidazolinium tetrafluoroborate.
  • the preferred conditions are: 1 eq.
  • Step b): Deprotection of compounds of formula (XIV) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions when PG is BOC are TFA in DCM for about 3 hrs at room temperature.
  • Steps c) and d): Compounds of formula (I/) may be obtained from compounds of formula (XV) using conditions described in steps c) and d) for compounds of formula (Ia) depicted in Scheme 1.
  • PG represents a protecting group, suitable examples of which are described in "Protecting Groups in Organic Synthesis” (referred to above).
  • PG is preferably BOC.
  • Step a): Compounds of formula (XVII) may be synthesised by coupling the appropriate amine of formula NH 2 CHR 1 CH 2 OH, with acid (XVI), in the presence of a conventional coupling agent, optionally in the presence of a catalyst, with an excess of base in a suitable solvent.
  • Preferred conditions are 1eq. acid of formula (XVI), 2 eq. triethylamine, 1.1 eq NH 2 CHR f CH 2 OH, 1 eq. 2-chloro-1 ,3-dimethyl-2-imidazolinium tetrafluoroborate in DCM at room temperature for 72 hours.
  • Step b): Compounds of formula (XVIII) may be prepared by methods analogous to those described in "Comprehensive Heterocyclic Chemistry" (referred to above). For example, oxidation of the alcohol of formula (XVII) with a suitable oxidising reagent, e.g. 1 ,1 ,1- triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3(1 H)-one, standard Swern conditions (typically oxalyl chloride, DMSO and triethylamine) or pyridinium chlorochromate, followed by cyclisation of the intermediate aldehyde with a suitable dehydrating reagent e.g.
  • a suitable dehydrating reagent e.g.
  • Step c): Deprotection of compounds of formula (XVIII) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions when PG is BOC are TFA in DCM for about 3 hrs at room temperature.
  • a suitable catalyst and solvent typically platinum oxide or palladium on carbon in methanol or ethanol at 1-4 atmospheres of hydrogen, preferably platinum oxide in ethanol at room temperature under 3 atmospheres of hydrogen.
  • Step b): Deprotection of compounds of formula (XXI) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis” (referred to above). Preferred conditions are 1 eq. methyl piperidine (XXI), 3 eq. 1-chloroethylchloroformate, 1 eq. 1 ,8-bis-(dimethylamino)naphthalene in 1 ,2-dichIoroethane at reflux for 3 hours.
  • Step c): Protection of compounds of formula (XXII) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis” (referred to above). Preferred conditions when PG is BOC are 1 eq. piperidine (XXII) 1 1.1 eq. triethylamine, 1 ,1 eq. di-'butyl-dicarbonate in dichloromethane at room temperature for 18 hours.
  • Step d): Debenzylation of compounds of formula (XXIV) followed by protection may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions when PG is BOC are 1 eq. (XXIV), palladium on carbon, in ethanol at 4O 0 C under hydrogen for 6 hours, followed by 1 eq. triethylamine, 1eq. di-'butyl dicarbonate in dichloromethane at room temperature for 3 hours.
  • Step e): Hydrolysis of esters of formula (XXIII) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions are 1 eq. ester (XXIII), 1.5 eq. 1 M aqueous sodium hydroxide in methanol at room temperature for 18 hours.
  • Single enantiomers of acids of formula (XXV) (e.e. > 95%) may be obtained by conventional chiral separation methods, preferably by repeated crystallisation in the presence of chiral amines, preferably (S)- or (R)- ⁇ -methyl- benzylamine, in toluene.
  • Step f): Compounds of formula (XXVI) may be prepared by coupling the acid of formula (XXV) with the appropriate amine of formula NHRR 1 in the presence of a conventional coupling agent, optionally in the presence of a catalyst, with an excess of base in a suitable solvent.
  • Preferred conditions are 1 eq. acid (XXIV), 1 eq. HOBT, 1.1 eq. WSCDI, 2- 10 eq. NHRR 1 , in dimethylformamide or dichloromethane at room temperature for 18 hours.
  • Steps h) and i) and I) and m) Compounds of formula (In) and (lo) may be obtained from compounds of formula (XXVII) and (XXIX) respectively using conditions described in steps c) and d) for compounds of formula (Ia) depicted in Scheme 1.
  • Step j): Esters of general formula (XXVIII) may be obtained using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions are 1 eq. acid (XXV), 1 eq. HOBT, 1 eq. WSCDI, in dichloromethane with excess R 1 OH.
  • Step n): Hydrolysis of esters of formula (lo) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions are 1 eq. ester (lo), 1.2 eq. lithium hydroxide in tetrahydrofuran at room temperature for 7 hours.
  • Step o): Compounds of formula (In) may be prepared by coupling the acid of formula (Ip) with the appropriate amine of formula NHRR 1 using conditions described in step f) for compounds of formula (In) above.
  • the preferred conditions are 1 eq. acid (Ip), 1.5 eq. HBTU, 1.2 eq. NHRR 1 , 14 eq. triethylamine in N-methylpyrrolidine at room temperature for 18 hours.
  • Scheme 8 In Scheme 8, PG represents a suitable protecting group, preferably benzyl.
  • PG represents a suitable protecting group, preferably benzyl.
  • Compounds of formula (XXX) may be obtained by methods described in this specification (e.g Preparation 52).
  • Step a): Compounds of formula (XXXII) may be obtained from alcohols of formula (XXXI) by a Mitsunobu reaction with the appropriate phenol, using standard methodology.
  • a suitable phosphine such as tri- "butylphosphine or triphenylphosphine
  • a suitable dehydrating agent typically an azo compound such as diisopropyl azodicarboxylate or di-terf- butyl azodicarboxylate, in a solvent such as dichloromethane, tetrahydrofuran or N 1 N- dimethylformamide, at temperatures between 25-115 0 C, for 1-48 hours, optionally in the absence of light.
  • Step b): Compounds of formula (XXXIII) may be prepared by a radical initiated cyclisation of the compound of formula (XXXII), in the presence of a suitable radical initiator (e.g. AIBN) and radical carrier source (e.g. Bu 3 SnH, (Me 3 Si) 3 SiH) in a suitable solvent (e.g. toluene) at 60- 8O 0 C for 4 hours.
  • a suitable radical initiator e.g. AIBN
  • radical carrier source e.g. Bu 3 SnH, (Me 3 Si) 3 SiH
  • solvent e.g. toluene
  • Step c): The compound of formula (XXXIV) may be obtained by removal of the N-protecting group using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above).
  • PG represents benzyl
  • this may be achieved by catalytic hydrogenation in the presence of a suitable catalyst e.g. Pd/C or Pd(OH) 2 in a suitable alcoholic solvent, e.g. H 2 O, MeOH, or EtOH at between room temperature and 6O 0 C under an atmosphere of H 2 .
  • a suitable catalyst e.g. Pd/C and Pd(OH) 2 and a hydrogen donor, e.g.
  • a suitable solvent e.g. EtOH or MeOH
  • deprotection can be achieved using 1-chloroethylchloroformate in an appropriate organic solvent, e.g 1 ,2- dichloroethane followed by hydrolysis with, for example, sodium hydroxide or methanol.
  • Preferred conditions 1eq. compound (XXXIII), 5 eq. NH 4 CO 2 H, 10% Pd/C in EtOH at the reflux temperature of the reaction solvent for about 1.5 hrs, Or, 1 eq. compound (XXXIII), 1 eq. 1-chloroethylchloroformate, 1eq. triethylamine in 1 ,2- dichloroethane at O 0 C to reflux for 2 hours followed by methanol at reflux for 45 minutes.
  • Steps d) and e): Compounds of formula (Iq) may be obtained from compounds of formula (XXXIV) using conditions described in steps c) to d) for compounds of formula (Ia) depicted in Scheme 1.
  • Steps f) and g): Hydrolysis of esters of formula (Iq) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions are 1 eq. ester (Iq) with 2M hydrochloric acid in THF at 35 0 C for 20 hours.
  • Compounds of formula (Ir) may be prepared by coupling the intermediate acid with the appropriate amine using conditions described in step f) for compounds of formula (In) depicted in Scheme 7.
  • Preferred conditions are 1 eq. acid, 1 eq. HOBT, 1.2 eq. WSCDI 1 3 eq. amine NHRR 1 in DMF at room temperature for 16 hours.
  • PG represents a suitable protecting group, suitable examples of which are described in "Protecting Groups in Organic Synthesis” (referred to above).
  • PG is preferably BOC.
  • Compounds of formula (XXXV) may be obtained by reacting an N-protected 4-piperidone with an amine of formula R 1 NH 2 in an appropriate organic solvent, e.g. trimethylorthoformate followed by reaction with an appropriately substituted 2-bromobenzoyl chloride in the presence of a base e.g. triethylamine or H ⁇ nig's base in an appropriate organic solvent e.g. dichioromethane, THF.
  • Preferred conditions are 1 eq. N-protected 4-piperidone, 1 eq. R 1 NH 2 in trimethylorthoformate at room temperature for 72 hours followed by 1 eq. 2- bromobenzoyl chloride, 2 eq. triethylamine in dichloromethane at O 0 C to room temperature for 18 hours.
  • Step c): Compounds of formula (XXXVI) may be obtained by cyclising alkenes of formula (XXXV) under standard Heck conditions.
  • compounds of formula (XXXV) are cyclised in the presence of a suitable catalyst, e.g. PdCI 2 or Pd(OAc) 2 , a phosphine ligand, e.g. triphenylphosphine and a base, e.g. triethylamine in a suitable organic solvent, e.g. dimethylformamide or acetonitrile at room temperature to 100 0 C.
  • Preferred conditions are 1 eq. (XXXIV), 1 eq.
  • Step d): Deprotection of compounds of formula (XXXVI) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions when PG is BOC, are TFA in DCM for about 18 hours at room temperature.
  • a suitable catalyst e.g. palladium on carbon or palladium hydroxide
  • a solvent e.g. ethyl acetate, methanol or ethanol
  • Preferred conditions are 10% palladium on carbon in ethyl acetate and acetic acid at room temperature under 4 atmospheres of hydrogen for 18 hours.
  • an appropriate reducing reagent eg sodium borohydride or lithium aluminium hydride in a suitable organic solvent, eg methanol or tetrahydrofuran.
  • Preferred conditions are 1 eq. ketone (Ik), 1.3 eq. sodium borohydride or lithium aluminium hydride in tetrahydrofuran at room temperature for 18 hours.
  • a base e.g. sodium hydride
  • Preferred conditions are 1 eq. alcohol (Iu), 1.1 eq. sodium hydride, 1.1 eq. R 1 I in tetrahydrofuran at room temperature for 18 hours. .
  • Step b): Compounds of general formula (Iv) may be obtained from the reaction of compounds of formulae (XXXIX) and (XL) under Buchwald reaction conditions. These are typically the reaction of a compound of formula (XXXIX) with an amine of formula (XL) in the presence of a metal catalyst e.g. Pd(OAc) 2 , Pd(dppf) 2 , and a base, e.g. sodium tert-butoxide, in an appropriate solvent, e.g. dioxane or toluene. Preferred conditions are 1 eq. (XL), 1 eq.
  • acidic conditions e.g. hydrochloric acid or sulphuric acid
  • an appropriate solvent e.g. dioxane or water.
  • the preferred conditions are 1 eq. nitrile (Iy) in dioxane and 6N hydrochloric acid at 15O 0 C for 15 hours.
  • Step b): Compounds of formula (Iw) may be prepared by coupling the acid of formula (Ix) with the appropriate amine of formula RNHR using conditions described in step f) for compounds of formula (In) depicted in Scheme 7.
  • Preferred conditions are 1 eq. acid (Ix), 1.1 eq. WSCDI, 1.3 eq. HOBT, 11 eq. RNHR in dimethylformamide at room temperature for 72 hours.
  • Step a): Compounds of formula (XLII) may be obtained from acid (XLI) and R 9 -LG wherein R 9 is (C ⁇ ojalkyl and LG is a suitable leaving group, e.g. Br, I, with a base, eg lithium diisopropylamide or sodium hydride, in an appropriate organic solvent, eg THF.
  • Preferred conditions are 1 eq. acid (XLI), 3 eq. lithium diisopropylamide, 3 eq. R 9 -LG in THF at O 0 C to room temperature for 18 hours.
  • Step b): Compounds of formula (XLIII) may be prepared by coupling the acid of formula (XLII) with the appropriate amine using conditions described in step e) for compounds of formula (Ie) depicted in scheme 3. Preferred conditions are 1 eq. acid (XL), excess NHRR 1 , 1.5 eq. HBTU in THF at 5O 0 C for 18 hours.
  • Step c): Deprotection of compounds of formula (XLIII) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions when PG is BOC are 4M hydrochloric acid in dioxane for about 2 hours at room temperature.
  • PG represents a suitable protecting group, suitable examples of which are described in "Protecting Groups in Organic Synthesis” (referred to above).
  • PG is preferably benzyloxycarbonyl.
  • Compounds of formula (XLV) may be obtained from published methods (eg as described in Xie et al, Tetrahedron, 2004, 60, 4875-4878).
  • Step b): Deprotection of compounds of formula (XLVI) may be undertaken using standard methodology, as described in "Protecting Groups in Organic Synthesis" (referred to above). Preferred conditions when PG is benzyloxycarbonyl are 1-methyl-1 ,4-cyclohexadiene and catalytic Pd(OH) 2 on carbon in ethanol at 5O 0 C for 30 minutes.
  • Step c) Compounds of formula (laa) may be obtained from compounds of formula (XLVII) using the conditions described in steps c), d) for compounds of formula (Ia) depicted in Scheme 1.
  • the present invention also comprises a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier or diluent.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X- ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition')-
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks.
  • Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • references to compounds of formula (I) include references to pharmaceutically acceptable salts and solvates thereof.
  • the compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).
  • Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereo isomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-Iabelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • intermediate compounds of formula (I)I as hereinbefore defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I).
  • the invention includes all polymorphs of the aforementioned species and crystal habits thereof.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • excipients may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981- 986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent.
  • Some components of the formulation may perform more than one function.
  • the compound of formula (I) may be water-soluble or insoluble.
  • a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • the compound of formula (I) may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma ef a/ (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug- loaded poly( ⁇ 7-lactic-coglyco!ic)acid (PGLA) microspheres.
  • PGLA poly( ⁇ 7-lactic-coglyco!ic)acid
  • the compounds of the invention may also be administered topically, (intra)dermally, or transdermal ⁇ to the skin or mucosa.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellent, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, gels, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • two or more pharmaceutical compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions. .
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compounds of the invention is typically in the range 1 mg to 5000 mg, preferably 10 mg to 2000 mg depending, of course, on the mode of administration.
  • oral administration may require a total daily dose of from 50 mg to 1000 mg; an intravenous dose may require from 50 mg to 1000 mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the ability of the compounds of the formula (I) to bind to the delta opioid receptor may be measured using the assay described below.
  • Stimulation buffer was made at 2x concentrated to allow for 1 in 2 dilution with compound as follows:
  • Stimulation buffer Final concentration: 5mM HEPES pH 7.4, HBSS, 0.1 % BSA, 1OmM MgCI 2 .6H 2 O and 0.5mM IBMX in purified H 2 O:
  • Detection buffer 5mM HEPES pH 7.4, HBSS, 0.1 % BSA and 0.3% Tween-20 in purified H 2 O: 50ml 10x HBSS, 600mg HEPES, 500mg BSA, 1.5ml Tween-20 and 450ml purified H 2 O.
  • Acceptor beads 3.75mg/ml stock.
  • Cell suspension 20 ⁇ l acceptor beads/ml cells
  • cAMP curve 1 ⁇ l acceptor beads/500 ⁇ l stimulation buffer
  • Detection mix 2 ⁇ l biotin-cAMP + 800 ⁇ l detection buffer.
  • the assay protocol dictates that compounds will be diluted by a factor of 2 when the final assay mix is assembled.
  • Compounds were made as 4mM stocks in 100% DMSO and 10 ⁇ l transferred to a v-bottom 96-well plate for further dilutions to generate 11 pt concentration effect curves with Vz log dilutions. Test compounds were evaluated in the range of 0.03nM - 10 ⁇ M (final assay concentration).
  • DOR cells were cultured in T225 flasks in DMEM/nutrient mix F12 supplemented with 2mM L- glutamine, 500 ⁇ g/ml hygromycin and 10% heat inactivated foetal bovine serum. Media was changed every 3 days. Cells were kept in an incubator at 37 0 C, with 95% O 2 and 5% CO 2 . Cell culture took place under sterile conditions in a Class Il Microbiological Safety Cabinet. Cells were split by removing the media, washing twice with 1OmIs PBS and adding 3mls of cell dissociation solution. The usual split ratio is 1 :5 to 1 :30. Cell dissociation solution was inactivated after approximately 5 minutes with supplemented media.
  • DOR cells are harvested and a viable cell count performed (Trypan Blue exclusion to identify non-viable cells). The cells were then centrifuged and resuspended in 2x stimulation buffer to the required cell density (1.6E06 cells/ml equates to 8000/well in 5 ⁇ l).
  • the plate was then read on a Fusion reader and EC 50 values calculated for the test compounds.
  • the delta opioid receptor agonists of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain.
  • a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • NSAID nonsteroidal antiinflammatory drug
  • NSAID nonsteroidal antiinflammatory drug
  • diclofenac diflusinal, etodolac
  • fenbufen fenoprofen
  • flufenisal flurbiprofen
  • ibuprofen indomethacin
  • ketoprofen ketorolac
  • meclofenamic acid mefenamic acid
  • meloxicam nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac
  • NSAID nonsteroidal antiinflammatory drug
  • a barbiturate, sedative e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • an Hi antagonist having a sedative action e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyciizine; • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g.
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido- 1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoIine;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g. ( ⁇ R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4- methylphenyl)-7H-[1 ,4]diazocino[2,1-g][1 ,7]-naphthyridine-6-13-dione (TAK-637), 5- [[(2R,3S)-2-[(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4- morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]
  • a muscarinic antagonist e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium
  • a COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or iumiracoxib;
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan; • a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g. capsazepine);
  • a beta-adrenergic such as propranolol
  • a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HTI B /ID agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
  • a 5-HT 2A receptor antagonist such as (R)-(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1- methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil),
  • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (1 ⁇ ,3 ⁇ ,5 ⁇ )(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S.5R)- 3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-f!uorobenzyl)-proline, [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6- yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one,
  • mGluRI metabotropic glutamate subtype 1 receptor
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
  • a noradrenaline (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S 1 S)- reboxetine;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1- iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo- L-cysteine, S-[2-[(1 -iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2- methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1 R,3S)-3-amino-4-hydroxy-1-(5- thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitri!e; 2-[[(1 R,3S)-3-amino-4-hydroxy-1- (5-thiazo
  • an acetylcholinesterase inhibitor such as donepezil
  • a prostaglandin E 2 subtype 4 (EP4) antagonist such as ⁇ /-[( ⁇ 2-[4-(2-ethyl-4,6- dimethyl-I H-imidazo ⁇ . ⁇ -clpyridin-i-yOpheny ⁇ ethylJaminoJ-carbonyll ⁇ -methyl- benzenesulfonamide or 4-[(1S)-1-( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]- carbonyl ⁇ amino)ethyl]benzoic acid;
  • a leukotriene B4 antagonist such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7- yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4- methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870, • a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5- trimethyl-6-(3-pyridylmethyl),1 ,4-benzoquinone (CV-6504);
  • a leukotriene B4 antagonist such as 1-(3-biphenyl-4-yl
  • a sodium channel blocker such as lidocaine
  • a 5-HT3 antagonist such as ondansetron
  • Optical Rotation is measured on a Perkin Elmer 341 Polarimeter. This high-resolution instrument has an accuracy of ⁇ 0.0020°. The rotation can be measured at 5 wavelengths, 589nm, 578nm, 546nm, 436nm and 365nm and the Polarimeter cell is temperature controlled with a Peltier unit, normally operated at 25°C.
  • Example 30 The ketone of Example 30 (400mg, 1.36mmol) was dissolved in tetrahydrofuran.
  • the reaction mixture was cooled to -48 0 C then added via a cannula to a suspension of sodium borohydride (205mg, 5.4mmol) in tetrahydrofuran (5ml) stirring at -48 0 C.
  • the reaction mixture was allowed to slowly warm to room temperature overnight.
  • reaction mixture was quenched with water then extracted from water into dichloromethane, dried over magnesium sulphate filtered and evaporated in vacuo.
  • residue was purified by column chromatography using an ISCO ® silica cartridge eluting a linear gradient from dichloromethane - 90/10/1 dichloromethane/ methanoi/0.880 ammonia.
  • the product was collected as a white solid (320mg, 0.8mmol,
  • step (a) The sulfinamide of step (a) (384mg, 0.96mmol) was dissolved in methanol (600 ⁇ L). 4M Hydrogen chloride in dioxane (560 ⁇ L) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was diluted with ether and the resultant precipitate collected by filtration. The product was collected as a pale pink solid (340mg, 0.96mmol, 100%).
  • step (b) The title compound was obtained as a cream solid in 80% yield from the sulfanamide of step (a), following the procedure described in Example 1 , step (b).
  • Example 9 The alcohol of Example 9 (70mg, 0.24mmol) was dissolved in tetrahydrofuran (5ml). Sodium hydride (10mg, 0.26mmol) was added and the reaction mixture stirred for 15 minutes before the addition of iodomethane (16 ⁇ l_, 0.26mmol, 1.1eq). The reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was quenched with water then extracted from water into dichloromethane, dried over magnesium sulphate, filtered and evaporated in vacuo. The residue was purified by column chromatography using an ISCO ® silica cartridge eluting with a linear gradient from dichloromethane - 90:10:1 dichloromethane/methanol/0.880 ammonia.
  • Example 13 1'-[4-(Dimethylamino)pyridin-2-yl1-N,N-dimethyl-2,3-dihvdrospirorindene-1.4'-piperidine1-3- carboxamide
  • the crude material was purified by column chromatography using an ISCO ® silica cartridge eluting with dichloromethane/ methanol/0.880 ammonia (95:5:0.5). The product was obtained as a white solid (42mg, 0.09mmol, 39%).
  • step (a) The ester of step (a) (336mg, 0.985mmol) was dissolved in water: dioxane (4ml:5ml). 2M sodium hydroxide (0.6ml, 1.2mmol) was added and the reaction mixture stirred at room temperature for 1 hour. The solution was neutralised with 2M hydrochloric acid. The reaction was concentrated in vacuo to yield the title compound in quantitative yield.
  • Example 19 The nitrile of Example 19 (35mg, 0.113mmol) was dissolved in 1,4-dioxane (0.5ml) and 6N aqueous hydrochloric acid (5.0ml) added. The reaction mixture was stirred at 15O 0 C for 15 hours. The reaction mixture was concentrated in vacuo to yield the title compound as a yellow gum.
  • step (a) The acid of step (a) (50mg, 0.138mmol), 1-hydroxybenzotriazole monohydrate (26mg, 0.180mmol), 1-(3-dimethylaminopropyl)-3-ethyIcarbodiimide HCI (31 mg, 0.160mmol) and ethyipiperazine (200 ⁇ L, 1.57mmol) were combined in dimethylformamide (3ml) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo then redissolved in ethyl acetate (20ml). The solution was washed with 3% aqueous sodium hydrogen carbonate (2x1 OmI), dried over sodium sulphate, filtered and evaporated in vacuo.
  • the crude product was purified by column chromatography using an ISCO ® silica cartridge eluting with dichloromethane - 90:10:1 dichloromethane/methanol/0.880 ammonia. (7mg, 0.015mmol, 12%).
  • Example 132 The amine of Example 132 (110mg, 0.373mmol), benzenesulphonyl chloride (73mg, 0.411mmol) and triethylamine (156 ⁇ l_, 1.12mmol) were combined in dichloromethane and stirred at room temperature overnight. Benzenesulphonyl chloride (2.0 ⁇ L, 15mmol) was added and the reaction mixture stirred for a further 20 minutes. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography using an ISCO ® silica cartridge eluting with dichloromethane - 90:10:1 dichloromethane/methanol/0.880 ammonia.
  • Example 132 and methanesulphonyl chloride, following a similar procedure to that described in Example 27.
  • the nitro-pyridine N-oxide of Preparation 103 (100mg, 0.3mmol) was dissolved in ethyl acetate (20ml), 10% palladium on carbon (10mg, 10% by weight) was added and the reaction mixture stirred at room temperature under 3.4 atmospheres of hydrogen overnight. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography using an ISCO ® silica cartridge. Dichloromethane/methanol/0.880 ammonia (90:10:1 ) was used as the eiuent. The title compound was obtained as a white solid (10mg, 0.03mmol, 11%).
  • the nitro-pyridine N-oxide of Preparation 115 (500mg, 1.5mmol) was dissolved in acetic acid (5ml), iron powder (491 mg, 8.8mmol) was added and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue extracted from 2M sodium hydroxide into dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and evaporated to yield the crude amino pyridine. The material was purified by column chromatography on silica gel using dichloromethane/methanoI/0.880 ammonia as eluent. The title compound was obtained as a white solid (260mg, 0.88mmol, 59%).
  • the nitro-pyridine N-oxide of Preparation 105 (11mg, 0.023mmoi) was dissolved in acetic acid (2ml), iron powder (8mg, 0.143mmol) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue extracted from 2M sodium hydroxide into dichloromethane. The combined organic extracts were dried over sodium sulphate, filtered and evaporated to yield the crude amino pyridine. The material was purified by column chromatography using an ISCO ® silica cartridge, eluting with dichloromethane/methanol/0.880 ammonia. The title compound was obtained as a colourless gum (5mg, 0.012mmol, 52%).
  • Example 110 following a similar procedure to that described in Example 31.
  • the product was purified by crystallisation from dich!oromethane:methanol.
  • the crude product was purified by column chromatography on silica gel using dichloromethane/ methanol/0.880 ammonia (90:10:1) as eluent to afford the title compound as a brown solid (560mg, 1.65mmol, 72%).
  • step (a) The ester of step (a) was dissolved in tetrahydrofuran (7ml). A solution of lithium hydroxide (47mg, 1.95mmol) in water (20ml) was added and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was acidified to pH 3 with 2N hydrochloric acid and then extracted into ethyl acetate, dried over magnesium sulphate, filtered and evaporated to yield the title compound as a powder (442mg, 1.3mmol, 78%).
  • LCMS was performed using a Phenomenex Luna C18, 5 ⁇ m, 30 x 4.6 mm id column with a flow rate of 2.5 ml/min.
  • the solvent was evaporated and the residue dissolved in dimethylsulphoxide: water (3:1 ).
  • The-material was purified by HPLC on a Phenomenex Luna C18, 10 ⁇ m, 150 x 10 mm id column using acetonitrile: 0.05% aqueous diethylamine as the mobile phase.
  • LCMS was performed using a Phenomenex Luna C18, 5 ⁇ m, 30 x 4.6 mm id column with a flow rate of 2.5 ml/min.
  • Detection is performed at 225nm. Retention times are quoted for ELSD detection.
  • the reaction mixture was decanted, discarding the catalyst and the methanol evaporated.
  • the material was purified by HPLC on a Phenomenex Luna C18, 10 ⁇ m, 150 x 10 mm id column using acetonitrile: 0.05% aqueous diethylamine as the mobile phase.
  • LCMS was performed using a Phenomenex Luna C18, 5 ⁇ m, 30 x 4.6 mm id column with a flow rate of 2.5 ml/min.
  • the amide was redissolved in dichloromethane (2ml) and treated with trifluoroacetic acid (1ml). The solution was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was extracted from 2M sodium hydroxide (2ml) into dichloromethane (3x2ml) and the combined organic extracts dried over sodium sulphate, filtered and evaporated.
  • the nitro-pyridine N-oxide of Preparation 106 (65mg, 0.16mmol) was dissolved in ethanol (3ml), cyclohexene (0.4ml, 3.2mmol) and 10% palladium on carbon (15mg) were added and the reaction mixture heated at 7O 0 C for 8 hours. 10% Palladium on carbon (10mg) and cyclohexene (0.3ml) were added and the reaction heated for a further 2.5 hours. The catalyst was removed by filtration through Arbocel ® and the filtrates concentrated in vacuo. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol as the eluent (18mg, O. ⁇ mmol, 30%).
  • step (a) The ester of step (a) (23mg, 0.068mmol) and lithium hydroxide (2.5mg, 0.102mmol) were dissolved in tetrahydrofuran (0.2ml). Water (0.2ml) was added and the reaction mixture stirred at room temperature overnight. 2N hydrochloric acid (0.034ml, 0.102mmol) was added, then the reaction mixture evaporated in vacuo. The residue was triturated with ether. to yield the title compound as a beige solid (25mg, 0.07mmol).
  • Example 131 The ester of Example 131 (70mg, 0.2mmol) was dissolved in tetrahydrofuran (2ml) and treated with 2M hydrochloric acid (2mi). The reaction mixture was stirred at 35 0 C for 20 hours. The solvent was evaporated in vacuo. The intermediate acid was dissolved in dimethylformamide (3ml) and treated with 1-hydroxybenzotriazole monohydrate (31 mg,
  • the reaction mixture was concentrated in vacuo and the residue extracted from 2M sodium hydroxide into dichloromethane.
  • the combined organic extracts were dried over sodium sulphate, filtered and evaporated to yield the crude aminopyridine.
  • the material was purified by column chromatography over silica gel eluting with dichloromethane: methanol: 0.88 ammonia (95:5:0.5) to yield the title compound (155mg, 0.52mmol).
  • nitro-pyridine N-oxide was dissolved in methanol. Palladium hydroxide (10% by weight) and ammonium formate (6eq) were added and the reaction mixture heated at reflux for 2-18 hours. The reaction mixture was allowed to cool to room temperature and the catalyst removed by filtration through Arbocel ® . The combined filtrates were concentrated in vacuo and the residue extracted from saturated sodium hydrogen carbonate into dichloromethane, dried over magnesium sulphate, filtered and evaporated to yield the crude amino pyridine. The material was purified by column chromatography on silica gel using dichIoromethane/methanol/0.880 ammonia as eluent to afford the title compounds. ⁇

Abstract

La présente invention concerne des composés de formule (I) : où la ligne pointillée représente une liaison covalente éventuelle entre X et Y, et X, Y, Z, m, R2, R3, R4, R5, R6, R7, R8, R9, a et b ont les valeurs données dans la description de l'invention, ainsi que les sels et les solvates de qualité pharmaceutique desdits composés. Les composés sont des agonistes du récepteur opioïde delta et présentent plusieurs applications thérapeutiques, en particulier dans le traitement de la douleur.
PCT/IB2006/003320 2005-11-21 2006-11-16 Dérivés de spiropipéridine WO2007057775A1 (fr)

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CN102464663A (zh) * 2010-11-11 2012-05-23 上海药明康德新药开发有限公司 1‘-叔丁氧羰基-螺[苯并二氢吡喃-4,4‘-哌啶]-2-甲酸的合成方法
WO2012168162A1 (fr) 2011-06-06 2012-12-13 F. Hoffmann-La Roche Ag Acide acétique de benzocylcoheptène
WO2012172043A1 (fr) 2011-06-15 2012-12-20 Laboratoire Biodim Dérivés de purine et leur utilisation comme produits pharmaceutiques pour prévenir ou traiter les infections bactériennes
WO2014072903A1 (fr) 2012-11-06 2014-05-15 Actelion Pharmaceuticals Ltd Nouveaux dérivés d'aminométhylphénol en tant qu'agents antipaludiques
EP3601239A4 (fr) * 2017-03-23 2020-05-13 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
US11535632B2 (en) 2019-10-31 2022-12-27 ESCAPE Bio, Inc. Solid forms of an S1P-receptor modulator
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US10807991B2 (en) 2010-07-09 2020-10-20 Abbvie B.V. Spiro-cyclic amine derivatives as S1P modulators
WO2012004378A1 (fr) 2010-07-09 2012-01-12 Abbott Healthcare Products B.V. Dérivés d'amines spiro-cycliques en tant que modulateurs de s1p
JP2013535412A (ja) * 2010-07-09 2013-09-12 アブビー・ベー・ブイ Ｓ１ｐモジュレーターとしてのスピロ環状アミン誘導体
US11427598B2 (en) 2010-07-09 2022-08-30 AbbVie Deutschland GmbH & Co. KG Spiro-cyclic amine derivatives as S1P modulators
EP3144312A1 (fr) 2010-07-09 2017-03-22 AbbVie B.V. Dérivés d'amines spiro-cycliques comme modulateurs de s1p
CN102464663A (zh) * 2010-11-11 2012-05-23 上海药明康德新药开发有限公司 1‘-叔丁氧羰基-螺[苯并二氢吡喃-4,4‘-哌啶]-2-甲酸的合成方法
WO2012168162A1 (fr) 2011-06-06 2012-12-13 F. Hoffmann-La Roche Ag Acide acétique de benzocylcoheptène
WO2012172043A1 (fr) 2011-06-15 2012-12-20 Laboratoire Biodim Dérivés de purine et leur utilisation comme produits pharmaceutiques pour prévenir ou traiter les infections bactériennes
WO2014072903A1 (fr) 2012-11-06 2014-05-15 Actelion Pharmaceuticals Ltd Nouveaux dérivés d'aminométhylphénol en tant qu'agents antipaludiques
EP3601239A4 (fr) * 2017-03-23 2020-05-13 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
US11535632B2 (en) 2019-10-31 2022-12-27 ESCAPE Bio, Inc. Solid forms of an S1P-receptor modulator
WO2023284833A1 (fr) * 2021-07-14 2023-01-19 宜昌人福药业有限责任公司 Dérivé de pipéridine spirocyclique, composition pharmaceutique de celui-ci, procédé de préparation s'y rapportant et utilisation associée

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