WO2008113795A1 - Composés potentialisant le récepteur ampa et leurs utilisations en médecine - Google Patents

Composés potentialisant le récepteur ampa et leurs utilisations en médecine Download PDF

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WO2008113795A1
WO2008113795A1 PCT/EP2008/053194 EP2008053194W WO2008113795A1 WO 2008113795 A1 WO2008113795 A1 WO 2008113795A1 EP 2008053194 W EP2008053194 W EP 2008053194W WO 2008113795 A1 WO2008113795 A1 WO 2008113795A1
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Prior art keywords
dihydro
inden
trifluoromethyl
pyrazol
tetrahydro
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PCT/EP2008/053194
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English (en)
Inventor
Nicolas Bertheleme
Daniel Marcus Bradley
Francesca Cardullo
Giancarlo Merlo
Alfonso Pozzan
Jaqueline Sandra Scott
Kevin Michael Thewlis
Simon Edward Ward
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Glaxo Group Limited
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Priority claimed from GB0705330A external-priority patent/GB0705330D0/en
Priority claimed from GB0710874A external-priority patent/GB0710874D0/en
Priority claimed from GB0718199A external-priority patent/GB0718199D0/en
Priority claimed from GB0719000A external-priority patent/GB0719000D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2008113795A1 publication Critical patent/WO2008113795A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds which potentiate the AMPA receptor.
  • the invention also relates to the use of the compounds in treating diseases and conditions wherein the potentiation of the AMPA receptor would be beneficial, compositions containing the derivatives and processes for their preparation.
  • Glutamate receptors which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11 : 25-33).
  • Glutamate receptors can be divided into two distinct families.
  • the G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGlu ⁇ , mGlu7, mGlu ⁇ ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237).
  • the "ionotropic" glutamate receptor family which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).
  • NMDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid
  • KA kainic acid
  • AMPAR Native AMPA receptors
  • GIuRI -4 Native AMPA receptors
  • Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4.
  • GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2.
  • GluR2 is edited in this way.
  • AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198).
  • the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).
  • LTP Long Term Potentiation
  • AMPAR positive allosteric modulators do not activate the receptor directly.
  • AMPAR modulators increase receptor activity.
  • AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.
  • Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559).
  • the present invention provides a compound of formula (I) or a salt thereof:
  • A is selected from CF 3 and CHF 2 ;
  • R 1 is selected from cyclopropyl and pyridyl and R 2 is hydrogen; or R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 ;
  • R is selected from the group consisting of:
  • R 3 is selected from hydrogen and C 1-4 alkyl
  • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, - (CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and Ci -4 alkyl) and -(CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently C 1-6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, hydroxy and oxo.
  • halo refers to fluoro, chloro, bromo or iodo.
  • C 1-6 alkyl refers to an alkyl group having from one to six carbon atoms; and the term “C 1-4 alkyl” refers to an alkyl group having from one to four carbon atoms.
  • Ci -4 alkyl or Ci -6 alkyl may be a straight chain or branched alkyl group.
  • a C 1-4 alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
  • a C 1-6 alkyl group may be selected from the group consisting of a Ci -4 alkyl group, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.
  • C 1-4 alkyl is methyl.
  • Me means methyl.
  • Et means ethyl.
  • C 1-4 alkoxy refers to the group wherein is as defined above.
  • Cs- ⁇ cycloalkyl refers to a cycloalkyl group consisting of from 3 to 6 carbon atoms, ie cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl.
  • haloalkyl refers to an alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • a haloalkyl group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloalkyl group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloC 1-4 alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
  • haloCs- ⁇ cycloalkyl refers to a cycloalkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • a haloC 3-6 cycloalkyl group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloCs- ⁇ cycloalkyl group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloCs-ecycloalkyl groups include fluorocyclopropyl.
  • 5- or 6-membered aromatic heterocyclic ring refers to a monocyclic 5- or 6-membered aromatic carbocyclic group, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur.
  • Examples include furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, oxazepinyl, thiazepinyl, and diazepinyl.
  • nitrogen- containing monocyclic aromatic heterocyclyl groups are pyrrolyl, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, oxazepinyl, thiazepinyl, and diazepinyl.
  • 5- or 6-membered non-aromatic heterocyclic ring refers to a monocyclic 5- or 6-membered non-aromatic carbocyclic group, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur.
  • Examples of monocyclic non-aromatic heterocyclyl groups include 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, 1 ,2oxathiolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, 3- pyrazolinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1 ,4diozanyl, morpholinyl, 1 ,4dithianyl, 1 ,4 oxathianyl, thiomorpholinyl, piperazinyl, 6H-1 ,2,5thiadiazinyl and 2H,6H-
  • nitrogen-containing monocyclic non-aromatic heterocyclyl groups include 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 6H-1 ,2,5thiadiazinyl and 2H,6H- 1 ,5,2-dithiazinyl.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • A is CF 3 . In another embodiment, A is CHF 2 .
  • R 1 is selected from cyclopropyl and pyridyl, and R 2 is hydrogen.
  • R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 .
  • R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom Or NCH 3 .
  • R 1 and R 2 join together to form a 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom or NCH 3 .
  • R 1 and R 2 join together to form the following group:
  • R is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, optionally substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, haloCi -4 alkyl, halo, hydroxy and oxo.
  • the heterocyclic ring is non- aromatic. In one embodiment, it is 5-membered. In one embodiment, it is selected from morpholine, pyrrolidine and piperidine.
  • the 5- or 6-membered aromatic or non-aromatic heterocyclic ring is attached to the remainder of the molecule through a carbon atom (ie C-linked) or a nitrogen atom (ie N-linked).
  • the ring is substituted with one or more groups selected from Ci -4 alkyl, C(O)Ci -4 alkyl, haloCi -4 alkyl, halo, hydroxy and oxo.
  • the substituent is selected from C 1-4 alkyl, haloC 1-4 alkyl and oxo, for example oxo.
  • R is NH 2 .
  • R is selected from NR 3 SO 2 R 4 , NR 3 C(O)R 4 and OR 4 where R 3 and R 4 are as defined for formula (I).
  • R is selected from NH 2 , NR 3 SO 2 R 4 and NR 3 C(O)R 4 where R 3 and R 4 are as defined for formula (I).
  • R is selected from NR 3 SO 2 R 4 , NR 3 C(O)R 4 and OR 4 wherein:
  • R 3 is selected from hydrogen and C 1-4 alkyl
  • R 4 is selected from Ci -6 alkyl, haloCi -6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl and (CH 2 )qNR 5 R 6 wherein q is O, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl.
  • R 3 is hydrogen.
  • R 4 is selected from and haloC-i- ⁇ alkyl.
  • R 4 is selected from Ci -4 alkyl and haloC 1-4 alkyl.
  • R is selected from NR 3 SO 2 R 4 and NR 3 C(O)R 4 wherein R 3 and R 4 , together with the NC(O) or NSO 2 group to which they are attached, form a 5-membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • R 3 is selected from hydrogen and • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, -(CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C 1-4 alkyl) and -(CH 2 )qNR 5 R 6 wherein q is O, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl; or • R 3 and R 4 , together with the NC(O) group to which they are attached, form a 5- membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from Ci -4 al
  • R 3 is C 1-4 alkyl
  • R 4 is selected from Ci -6 alkyl, haloCi -6 haloalkyl, C 3-6 cycloalkyl and haloC 3-6 cycloalkyl; or • R 3 and R 4 , together with the N(CO) group to which they are attached, form a 5- membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C(O)C 1-4 alkyl, C 1-4 alkyl, halo, haloCi_ 4 alkyl, hydroxy and oxo.
  • NR 3 C(O)R 4 forms a 5-membered non-aromatic heterocyclic ring.
  • NR 3 C(O)R 4 forms a ring selected from pyrrolidinone and piperidinone.
  • NR 3 C(O)R 4 forms a 5-membered or a 6-membered non-aromatic heterocyclic ring that is substituted with one or more groups selected from C 1-4 alkyl, C(O)Ci -4 alkyl, halo, hydroxy and oxo.
  • the substituent is selected from C- ⁇ alkyl, haloCi -4 alkyl and oxo.
  • the present invention also provides a compound of formula (Ib) or a salt thereof:
  • R 1 is cyclopropyl and R 2 is hydrogen, or R 1 and R 2 join together to form a 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom;
  • R is selected from the group consisting of:
  • R 3 is selected from hydrogen and C 1-4 alkyl
  • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, - (CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C 1-4 alkyl) and (CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5-membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • the present invention also provides a compound of formula (Ic) or a salt thereof:
  • A is selected from CF 3 and CHF 2 ;
  • R 1 is selected from cyclopropyl and pyridyl and R 2 is hydrogen; or R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 ;
  • R is selected from the group consisting of:
  • R 3 is selected from hydrogen and Ci -4 alkyl
  • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl and -(CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently C 1- 6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • A is selected from CF 3 and CHF 2 ;
  • R 1 is selected from cyclopropyl and pyridyl and R 2 is hydrogen; or R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 ;
  • R is selected from the group consisting of: (a) a 5- or 6-membered N-linked aromatic or non-aromatic heterocyclic ring, optionally substituted with one, two or three groups selected from Ci -4 alkyl, C(O)Ci -4 alkyl, halo, hydroxy and oxo; and (b) NH 2 , NR 3 SO 2 R 4 and NR 3 C(O)R 4 in which
  • R 3 is selected from hydrogen and Ci -4 alkyl; • R 4 is selected from Ci -6 alkyl, haloCi -6 alkyl, C 3-6 cycloalkyl, haloCs- ⁇ cycloalkyl, -
  • (CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C 1-4 alkyl) and -(CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from Ci -4 alkyl, C(O)Ci -4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • the compounds of the invention may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the level of biological activity may vary between the individual stereoisomers of a given molecule. It is intended that the scope of the invention includes all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, including but not limited to racemic mixtures, which demonstrate appropriate biological activity with reference to the procedures described herein.
  • enrichment in a particular in configuration correspond to at least 90% enantiomeric excess.
  • the isomers correspond to at least 95% enantiomeric excess.
  • the isomers correspond to at least 99% enantiomeric excess.
  • Examples of compounds of formula (I) include:
  • the salt of the compound of formula (I) is a pharmaceutically acceptable salt.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • salt refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation.
  • Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alg
  • Salts having a non- pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • the salts may have any suitable stoichiometry.
  • a salt may have 1 :1 or 2:1 stoichiometry.
  • Non-integral stoichiometry ratios are also possible.
  • Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
  • crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
  • prodrugs for certain compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • Certain isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • a compound of formula (I) may be prepared by coupling a compound of formula (II) where X is a leaving group such as a halogen (for example bromine or iodine) with a heterocyclic derivative of formula (III) according to reaction scheme 1.
  • X is a leaving group such as a halogen (for example bromine or iodine)
  • a heterocyclic derivative of formula (III) according to reaction scheme 1.
  • the present invention also provides a process for preparing a compound of the present invention, the process comprising coupling a compound of formula (II):
  • R 1 , R 2 and A are as defined above; and thereafter optionally: a) forming a salt; and/or b) converting a compound of the present invention into another compound of the present invention.
  • Typical coupling conditions comprise heating together for the appropriate time a compound of formula (II), a compound of formula (III), a base (such as potassium carbonate or cesium carbonate), a copper (I) reagent (such as copper (I) iodide or copper (I) oxide) with a ligand (such as N,N-dimethylglycine or frans-1 ,2-diaminocyclohexane) in a suitable solvent such as dimethyl sulfoxide or 1 ,4-dioxane at a suitable temperature such as 180 degC in a microwave reactor or 130 degC by conventional heating.
  • a suitable solvent such as dimethyl sulfoxide or 1 ,4-dioxane
  • R is a secondary or tertiary amide or sulphonamide, or a tertiary amine.
  • R 1 and R 2 are joined together to form a 6-membered non- aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom or NMe.
  • Compounds of formula (II) and (III) are commercially available, described in the literature or may be prepared according to standard synthetic methods.
  • Typical conditions comprise treatment of a compound of formula (V) (or salt thereof) with a compound of formula (XVII) in dimethylformamide in the presence of a suitable base such as diisopropylethylamine or triethylamine, followed by addition of a strong base such as sodium hydride (available as a 60% suspension in mineral oil) to effect cyclisation.
  • Scheme 2 is suitable for enantiomerically pure material or racemates.
  • X is bromine or iodine
  • Y is carbonyl or sulphonyl
  • n is 1 or 2.
  • Compounds of formula (XVII) are commercially available, except when Y is sulphonyl and n is 2.
  • Typical conditions comprise addition of reagent (VII) to a cooled solution of (V) (or salt thereof) in dichloromethane in the presence of a suitable base such as triethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
  • a suitable base such as triethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
  • X is bromine or iodine
  • Y is a carbonyl or sulphonyl
  • R1 is aliphatic.
  • Compounds of formula (VII) are commercially available.
  • Typical conditions comprise addition of reagent (VIII) to a vigorously stirring suspension of the compound of formula (V) (or salt thereof) and base (such as potassium carbonate) in acetonitrile and subsequent heating at reflux for 16 hours.
  • X is bromine or iodine.
  • the compound of formula (VIII) is commercially available.
  • a compound of formula (X) can be prepared from a compound of formula (Xl) by enolate addition to ethyl trifluoroacetate according to reaction scheme 5.
  • Typical conditions comprise treatment of a compound of formula (Xl) with a strong base (such as lithium diisopropylamide (LDA)) under argon in tetrahydrofuran at the appropriate temperature (such as -70 degC) followed by the addition of ethyl trifluoroacetate, mixing for the appropriate time then warming to room temperature.
  • a strong base such as lithium diisopropylamide (LDA)
  • LDA lithium diisopropylamide
  • the appropriate temperature such as -70 degC
  • a compound of formula (XII) can be prepared by condensation of a compound of formula (X) with hydrazine hydrate according to reaction scheme 6. Typical conditions comprise treatment of a compound of formula (X) in ethanol with hydrazine hydrate and heating at the appropriate temperature (such as 70 degC) for the appropriate time (such as 9 hours).
  • Compounds of formula (X) wherein A is CHF 2 are commercially available, described in the literature or may be prepared according to standard synthetic methods.
  • a compound of formula (XIII) can be prepared from a compound of formula (XIV) [prepared according to Liebigs Annalen Der Chemie 1984, 1 1 , 1759-1882;] by enolate addition to ethyl trifluoroacetate followed by condensation with hydrazine hydrate according to reaction scheme 7.
  • Typical conditions comprise treatment of a compound of formula (XIV) with a strong base (such as methyllithium) in tetrahydrofuran at room temperature under argon followed by the addition of ethyl trifluoroacetate at -78 degC, mixing for the appropriate time then warming to room temperature..
  • the isolated product is dissolved in ethanol and treated with hydrazine hydrate and heated at reflux for 6 hours.
  • a compound of formula (XVI) can be prepared by the reduction of a compound of formula (XV) using lithium aluminium hydride according to reaction scheme 8.
  • Typical reduction conditions comprise the addition of lithium aluminium hydride to a cooled solution of a compound of formula (XV) in tetrahydrofuran (THF) followed by heating.
  • Compounds of formula (XV) can be prepared in a manner similar to that described for compounds of formula (XII) in scheme 6.
  • the compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds.
  • Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of the invention.
  • the compounds of the present invention potentiate the AMPA receptor.
  • Compounds which potentiate the AMPA receptor may be useful for treating diseases and conditions which are mediated by or caused by a reduction or imbalance in glutamate receptor function, and which therefore benefit from the potentiation of the AMPA receptor.
  • the present invention provides a compound of formula (I) or a salt thereof for use as a medicament. It will be appreciated that the invention includes the following further aspects. The embodiments described in respect of the first aspect apply equally to each of these further aspects:
  • a compound of the invention in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of the invention for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of the invention; iv) a combination product of a compound of formulathe invention with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient; vi) the use of a combination product as defined in iv) above in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; vii) a combination
  • relevant diseases or conditions are: psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia,
  • Schizophrenia-spectrum disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug-induced psychosis, autism, delerium, mania
  • neurodegenerative diseases including acute mania, manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as
  • Alzheimer's disease substance related disorders (including alcohol-related disorders and nicotine-related disorders); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease,
  • Aids-related dementia or other dementia states as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, stroke, neurodegeneration, drug-induced states, neurotoxic agents), mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, post-electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and
  • psychotic disorder includes :-
  • Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance- Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • Compounds of the invention may also be of use in the treatment of the following disorders:-
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder,
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder
  • Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not
  • Tic Disorders such as Tourette's Disorder (307.23): Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and
  • cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders
  • the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.
  • the present invention provides a method of treatment of schizophrenia or impairment of cognition, comprising administering an effective amount of a compound of the invention.
  • treatment includes prophylaxis as well as alleviation of established symptoms.
  • the mammal to be treated is a human.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).
  • antipsychotics such as olanzapine, risperidone, clozapine, ziprazidone, talnetant
  • drugs for extrapyramidal side effects for example anticholinergics
  • the compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; ii) drugs for treating nicotine addition, for example bupropion.
  • nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches
  • drugs for treating nicotine addition for example bupropion.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; iii) Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; iii) vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon
  • barbiturates for
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations, pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine; vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil, sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion
  • the compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperi
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, parox
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration to mammals including humans.
  • the compositions may be formulated for administration by any route.
  • the compositions may be formulated for oral, topical, or parenteral administration, and may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water.
  • a sterile vehicle for example water.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • Agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • Flash chromatography was carried out using pre-packed lsolute FlashTM or BiotageTM silica-gel columns as the stationary phase and analytical grade solvents as the eluent.
  • NMR spectra were obtained at 298K, at the frequency stated using either a BrukerTM DPX400 or an Oxford InstrumentsTM 250 MHz machine and run as a dilute solution of CDCI3 unless otherwise stated. All NMR spectra were reference to tetramethylsilane (TMS ⁇ H 0, ⁇ c 0). All coupling constants are reported in hertz (Hz), and multiplicities are labelled s (singlet), bs, (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).
  • 2-Aminoindan hydrochloride (5.16 g, 30 mmol, Sigma-Aldrich Company Ltd) was suspended in dry dichloromethane (100 ml), and cooled with stirring under argon to 0 0 C. To the suspension was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (3 eq., about 14ml, about 90 mmol) followed by the dropwise addition of isopropylsulfonyl chloride (6.8ml, 60 mmol). The cooling bath was removed and the mixture stirred at room temperature for 1 h. The reaction mixture was washed with 1 M hydrochloric acid (2 x 50 ml).
  • the title compound was prepared from 5-bromo-2-aminoindane hydrobromide (Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472) using a similar process to that used for description 1.
  • UV WL range 200-400 nm Analysis time 17 min
  • the title compound was prepared from (S)-5-bromo-2-aminoindan (1 R)-(- )-10- camphorsulfonate salt using a similar process to that used for description 7, but using triethylamine as the base instead of diisopropylethylamine. Crude product was purified by flash chromatography on a 5g pre-packed silica column eluting from 20-100% ethyl acetate in petroleum ether.
  • This intermediate (32.7g, 167mmol) was dissolved in ethanol (570ml) and to the solution hydrazine hydrate (16.7g, 16.6ml, 334mmol) was added at room temperature. The resulting mixture was stirred at reflux temperature for 6 hours, then it was allowed to cool down to room temperature and the solvent was removed by rotary evaporation. The residue was partitioned between dichloromethane (400ml) and water (200ml). The aqueous layer was extracted twice with dichloromethane (each with 150ml). The combined organic layers were washed with water (200ml), brine (150ml) and dried over sodium sulphate. The solvent was removed by rotary evaporation to obtain 20.47g of a yellow solid.
  • Coloumn Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 urn.
  • Mobile phase A: Water + 0.1 % formic acid, B: CH 3 CN + 0.06 % formic acid Gradient: 3% to 6% (B) in 0.1 min., 6% to 70% (B) in 0.5 min., 70% (B) to 99% (B) in
  • UV range 210-350 nm
  • Example 1 ⁇ /- ⁇ (2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide
  • reaction mix was cooled and added to a 5g pre-packed silica column which was then eluted from 50% ethyl acetate in petroleum ether to give a dark oil which was further purified by mass directed auto-prep to give a pure crop of the title compound as a yellow oil (103mg, 48%).
  • Example 2 1 - ⁇ (2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-pyrrolidinone
  • Example 3 1 - ⁇ (2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone
  • the title compound was prepared from 1-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole using a similar process to that used for Example 2, except the reaction was heated at 19O 0 C in a microwave reactor for 1 h.
  • Example 4 1 - ⁇ (2/?)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone
  • the title compound was prepared from 1-[(2/?)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole using a similar process to that used for Example 2, except the reaction was heated at 19O 0 C in a microwave reactor for 1 h.
  • Typical procedure The title compounds reported in table 1 were prepared by parallel synthesis. 0.12M DMSO solutions of each 5-bromoindane scaffold (YY) and of each pyrazole scaffold (WW) were prepared. Then the necessary scaffold solutions (1.5ml, 0.18mmol) and pyrazole solutions (1.5ml, 0.18mmol) were dispensed into 5ml microwave tubes. To the resulting DMSO mixtures, N,N-dimethylglycine (0.021 g, 0.207mmol), potassium carbonate (0.05Og, 0.360mmol) and copper (I) iodide (0.038g, 0.198mmol) were added.
  • the resulting suspensions were heated at 190 0 C in a microwave reactor for 30 min, then they were filtered and the solvent removed by vacuum centrifuge overnight.
  • the obtained crude products were partitioned between dichloromethane (3ml) and aqueous saturated ammonium chloride (2ml), then the organic layers were separated and the solvent removed by blowing down in air.
  • the obtained crude products were purified by preparative HPLC/MS to give the title compounds (YW) as reported in table 1.
  • Example 8 ⁇ /- ⁇ (2S)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol- 1(5H)-yl]-2,3-dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide
  • Example 23 i- ⁇ PJ-S-IS-cyclopropyl-S-ttrifluoromethylJ-IH-pyrazol-i-yll ⁇ .S- dihydro-1H-inden-2-yl ⁇ -2-pyrrolidinone
  • Example 27 W 2 ,W 2 -c//mefA?y/-yV 7 - ⁇ 2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazol-1 -yl]-2,3-dihydro-1H-inden-2-yl ⁇ glycinamide formic acid salt
  • Example 27 ⁇ / 2 , ⁇ / 2 -dimethyl- ⁇ / 1 - ⁇ 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]- 2,3-dihydro-1 H-inden-2-yl ⁇ glycinamide formic acid salt LC/MS (ES): Found 407 (ES+), retention time 2.10 mins C 2 i H 2 SF 3 N 4 O requires 406.
  • Example 28 ⁇ /- ⁇ (2/?)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide
  • Example 29 1-[(2/?S)-2-(1,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1H-inden-5-yl]-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole And Description 22: 2-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]isothiazolidine 1 ,1- dioxide
  • 3-Chloro-1-propanesulfonyl chloride (40 ⁇ l, 0.33mmol) was added in one portion to a stirring solution of diisopropylethylamine (50 ⁇ l, 0.29mmol), and a mixture of 5-[3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-amine and 5- bromo-2-aminoindane (48.2mg - combined mass of both indane amines) in DMF (1 ml).
  • Example 30 ⁇ /- ⁇ (2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ acetamide
  • Description 23 ⁇ /-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]acetamide
  • Acetyl chloride (50 ⁇ l, 0.70mmol) was added in one portion to a room temperature stirring mixture of DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) (80 ⁇ l, 0.53mmol), and a mixture of 5-[3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-amine and 5-bromo-2-aminoindane (77.0mg - combined mass of both indane amines) in DCM (1.5ml).
  • Example 33 1 -[(2/?S)-2-(1 -piperidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazole formic acid salt
  • Example 35 ⁇ /- ⁇ (2/?S)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)- yl]-2,3-dihydro-1H-inden-2-yl ⁇ acetamide
  • Example 36 The following compounds were synthesised from ⁇ /-[(2/?S)-5-bromo-2,3-dihydro-1 H- inden-2-yl]methanesulfonamide (Example 36) and 2-[(2/?S)-5-bromo-2,3-dihydro-1 H- inden-2-yl]isothiazolidine 1 ,1-dioxide (Example 37) in a manner similar to that described for Example 35.
  • Example 40 1 - ⁇ (2R)-5-[6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[3,4-c]pyridin-1-yl]-2,3-dihydro-1 H-inden-2-yl ⁇ -2-pyrrolidinone
  • the resulting suspensions were heated at 190 0 C in a microwave reactor for 30 min, then they were filtered and the solvent removed by vacuum centrifuge overnight.
  • the obtained crude products were dissolved in MeOH (3ml) and eluted through a 2g SCX cartridge (MeOH then 2M solution of NHg in MeOH as eluent). The solvent was then removed by blow down.
  • Example 46 4- ⁇ 5-[5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1 -yl]-2,3-dihydro-1H- inden-2-yl ⁇ morpholine
  • Example 48 4- ⁇ (2/?)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ morpholine, hydrochloride salt
  • the reaction mixture was diluted with ethylacetate then filtered through a pad of kieselguhr to remove the catalyst.
  • the organic solution was washed with water, dried with sodium sulphate and evaporated.
  • the resultant material was purified by MDAP.
  • the resulting material was dissolved in methanol and treated with ethereal hydrochloride. Solvent was removed to give the title compound as a HCI salt (35mg).
  • Example 50 4- ⁇ (2/?)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ morpholine, hydrochloride salt
  • Example 51 4- ⁇ (2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ morpholine, hydrochloride salt
  • Example 52 4- ⁇ (2S)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-1 -yl]- 2,3-dihydro-1H-inden-2-yl ⁇ morpholine, formate salt
  • reaction mixture was partitionned between water (20ml) and DCM (40ml). The aqueous was further extracted with DCM (40ml). The organics were combined, washed with water (20ml), dried over MgSO 4 and concentrated to give a black oil which was purified by reverse phase chromatography using the MDAP to afford 20mg of a brown oil which was purified again using the MDAP. Relevant fractions were combined and concentrated to afford 4mg of the title compound as a clear oil and as the formate salt.
  • Example 54 ⁇ /- ⁇ (2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide, hydrochloride salt
  • Example 55 1 - ⁇ (2/?)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]- 2,3-dihydro-1H-inden-2-yl ⁇ -2-pyrrolidinone
  • Example 56 1 - ⁇ (2/?)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone, hydrochloride salt
  • Example 57 1 - ⁇ (2/?)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone, hydrochloride salt
  • Coloumn Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 urn.
  • Mobile phase A: Water + 0.1 % formic acid, B: CH 3 CN + 0.06 % formic acid
  • the generic method used has a 2 minute runtime.
  • UV range 210-350 nm
  • the UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
  • HPLC analysis was conducted on a Sunfire C18 column (30mm x 4.6mm i.d. 3.5 ⁇ m packing diameter) at 30 degrees centigrade.
  • the UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
  • UV range 210-350 nm
  • UV range 210-350 nm
  • the column used is Waters X-bridge, the dimensions of which are 30mm x
  • the stationary phase particle size is 5 ⁇ m.
  • Aqueous solvent 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.
  • the ability of the compounds of the invention to potentiate AMPA receptor-mediated response may be determined by using fluorescent calcium-indicator dyes such as FLUO4.
  • fluorescent calcium-indicator dyes such as FLUO4.
  • the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).
  • 384 well plates are prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells form functional homotetrameric AMPA receptors.
  • tissue culture medium in the wells are discarded and the wells are each washed three times with standard buffer (80 ⁇ l_) for the stable cell line (145 mM NaCI, 5 mM KCI, 1 mM MgCI 2 , 2 mM CaCI 2 , 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI).
  • standard buffer 80 ⁇ l_
  • the plates are then incubated for 60 minutes in the dark with 2 ⁇ M FLUO4-AM dye (20 ⁇ l_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well is washed three times with buffer (80 ⁇ l_) (30 ⁇ l_ of buffer remained in each well after washing).
  • DMSO dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • a Biomek FX Beckman Coulter
  • Each dilution (1 ⁇ l_) is transferred to another compound plate and buffer (50 ⁇ l_) is added.
  • An agonist stimulus (glutamate) plate is prepared by dissolving sodium glutamate in water to give a concentration of 100 mM.
  • This solution is diluted with buffer to give a final concentration of 500 ⁇ M and dispensed into another 384-well plate (50 ⁇ l_/well) using a Multidrop (Thermolabsystems).
  • the cell plate is then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)].
  • a baseline fluorescence reading is taken over a 10 to 240 second period, and then 10 ⁇ L from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 ⁇ M to 10 pM) is added (to give a final concentration in the range 30 ⁇ M to 3 pM).
  • the fluorescence is read over 5 minute period.
  • 500 ⁇ M glutamate solution (10 ⁇ l_) is added (to give a final concentration of 100 ⁇ M).
  • the fluorescence is then read over a 4 minute period.
  • the activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by cyclothiazide at their maximum response (i.e. greater than 30 ⁇ M).
  • 384 well plates are prepared containing confluent monolayer of HEK 293 cells stably expressing human GluR2 flip (unedited) AMPA receptor subunit.
  • culture medium are discarded and the cells washed three times with standard buffer (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) and 20 ⁇ l_ of buffer remained in each well after washing.
  • standard buffer 145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3
  • the plates are then incubated at room temperature for 60 minutes in the dark with 2 ⁇ M FLUO-4AM dye to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cells. After incubation cells are washed three times with buffer and 30 ⁇ l_ of buffer remained in each well after washing. Compounds of the invention are tested in a final assay concentration range from 100 ⁇ M to 1 nM.
  • DMSO dimethylsulfoxide
  • the cell plate is then transferred into a fluorescence imaging plate based reader (such as the FLIPR384 - Molecular Devices).
  • a fluorescence imaging plate based reader such as the FLIPR384 - Molecular Devices.
  • a baseline fluorescence reading is taken over a 5 to 10 second period, and then 10 ⁇ L of 500 ⁇ M glutamate solution is added (to give a final concentration of 100 ⁇ M).
  • the fluorescence is then read over a 4-5 minute period.
  • the activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by 150 ⁇ M cyclothiazide at their maximum response.
  • the assay described above is believed to have an effective limit of detection of a pEC 50 in the region of 3.5-4.0 due to the limitations of compound solubility.
  • the pEC 5 o result is generally considered to be accurate +/- 0.3.
  • Example compounds were screened using at least one of the assays described above and gave an average pEC 50 equal to or greater than 3.5 and/or demonstrated an activity of on average at least 20% that of the reference compound (at its maximal response).

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Abstract

L'invention concerne un composé représenté par la formule (I), ainsi que ses sels. Dans ladite formule, A, R1, R, R2 correspondent à leur définition du descriptif. Elle concerne également des procédés de préparation, des compositions pharmaceutiques et leurs utilisations sous forme de médicament, par exemple, pour traiter une maladie ou un état résultant d'une diminution ou d'un déséquilibre de la fonction du récepteur de glutamate, tels que la schizophrénie ou le déficit cognitif.
PCT/EP2008/053194 2007-03-20 2008-03-18 Composés potentialisant le récepteur ampa et leurs utilisations en médecine WO2008113795A1 (fr)

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WO2010066658A1 (fr) * 2008-12-09 2010-06-17 Glaxo Group Limited Composés de potentialisation du récepteur ampa et leurs utilisations en médecine
WO2012137982A2 (fr) 2011-04-05 2012-10-11 Takeda Pharmaceutical Company Limited Dérivé de sulfonamide et son utilisation
WO2016176457A1 (fr) * 2015-04-29 2016-11-03 Janssen Pharmaceutica Nv Imidazopyrazines et pyrazolopyrimidines et leur utilisation comme modulateurs des récepteurs ampa
WO2018080917A1 (fr) * 2016-10-26 2018-05-03 Janssen Pharmaceutica Nv Composés de pyridine bicyclique fusionnés et leur utilisation comme modulateurs des récepteurs ampa
WO2018080916A1 (fr) * 2016-10-26 2018-05-03 Janssen Pharmaceutica Nv Composés azahétérocycliques fusionnés et leur utilisation en tant que modulateurs des récepteurs ampa
US10604484B2 (en) 2015-04-29 2020-03-31 Janssen Pharmaceutica Nv Indolone compounds and their use as AMPA receptor modulators
US10611730B2 (en) 2015-04-29 2020-04-07 Janssen Pharmaceutica Nv Benzimidazolone and benzothiazolone compounds and their use as AMPA receptor modulators
US11312712B2 (en) 2015-04-29 2022-04-26 Janssen Pharmaceutica Nv Azabenzimidazoles and their use as AMPA receptor modulators

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WO2007107539A1 (fr) * 2006-03-20 2007-09-27 Glaxo Group Limited Composés qui potentialisent le récepteur ampa et leurs utilisations en médicine

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WO2006015828A1 (fr) * 2004-08-09 2006-02-16 Glaxo Group Limited Composés potentialisateurs de récepteur de glutamate et utilisations de ceux-ci en médecine
WO2007107539A1 (fr) * 2006-03-20 2007-09-27 Glaxo Group Limited Composés qui potentialisent le récepteur ampa et leurs utilisations en médicine

Cited By (27)

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WO2010066658A1 (fr) * 2008-12-09 2010-06-17 Glaxo Group Limited Composés de potentialisation du récepteur ampa et leurs utilisations en médecine
WO2012137982A2 (fr) 2011-04-05 2012-10-11 Takeda Pharmaceutical Company Limited Dérivé de sulfonamide et son utilisation
US9527807B2 (en) 2011-04-05 2016-12-27 Takeda Pharmaceutical Company Limited Sulfonamide derivative and use thereof
WO2016176457A1 (fr) * 2015-04-29 2016-11-03 Janssen Pharmaceutica Nv Imidazopyrazines et pyrazolopyrimidines et leur utilisation comme modulateurs des récepteurs ampa
US11312712B2 (en) 2015-04-29 2022-04-26 Janssen Pharmaceutica Nv Azabenzimidazoles and their use as AMPA receptor modulators
US10611730B2 (en) 2015-04-29 2020-04-07 Janssen Pharmaceutica Nv Benzimidazolone and benzothiazolone compounds and their use as AMPA receptor modulators
JP2018514537A (ja) * 2015-04-29 2018-06-07 ヤンセン ファーマシューティカ エヌ．ベー． イミダゾピラジン及びピラゾロピリミジン、並びにａｍｐａ受容体調節物質としてのこれらの使用
US10604484B2 (en) 2015-04-29 2020-03-31 Janssen Pharmaceutica Nv Indolone compounds and their use as AMPA receptor modulators
US10513523B2 (en) 2015-04-29 2019-12-24 Janssen Pharmaceutica Nv Imidazopyrazines and pyrazolopyrimidines and their use as AMPA receptor modulators
CN109963851A (zh) * 2016-10-26 2019-07-02 詹森药业有限公司 融合的双环吡啶化合物及其作为ampa受体调节剂的用途
EA036903B1 (ru) * 2016-10-26 2021-01-13 Янссен Фармацевтика Нв Соединения конденсированных бициклических пиридинов и их применение в качестве модуляторов ampa-рецептора
KR20190067239A (ko) * 2016-10-26 2019-06-14 얀센 파마슈티카 엔.브이. 융합된 바이사이클릭 피리딘 화합물 및 ampa 수용체 조절제로서의 이들의 용도
KR20190066068A (ko) * 2016-10-26 2019-06-12 얀센 파마슈티카 엔.브이. 융합된 아자헤테로사이클릭 화합물 및 ampa 수용체 조절제로서의 이들의 용도
JP2019532981A (ja) * 2016-10-26 2019-11-14 ヤンセン ファーマシューティカ エヌ．ベー． 融合アザヘテロ環状化合物、及びａｍｐａ受容体調節因子としてのそれらの使用
JP2019536760A (ja) * 2016-10-26 2019-12-19 ヤンセン ファーマシューティカ エヌ．ベー． 縮合二環ピリジン化合物、及びａｍｐａ受容体調節因子としてのそれらの使用
US10155769B2 (en) 2016-10-26 2018-12-18 Janssen Pharmaceutica Nv Fused azaheterocyclic compounds and their use as AMPA receptor modulators
US10087185B2 (en) 2016-10-26 2018-10-02 Janssen Pharmaceutica Nv Fused bicylic pyridine compounds and their use as AMPA receptor modulators
WO2018080916A1 (fr) * 2016-10-26 2018-05-03 Janssen Pharmaceutica Nv Composés azahétérocycliques fusionnés et leur utilisation en tant que modulateurs des récepteurs ampa
CN109890823A (zh) * 2016-10-26 2019-06-14 詹森药业有限公司 稠合氮杂环化合物及其作为ampa受体调节剂的用途
AU2017350688B2 (en) * 2016-10-26 2021-04-01 Rapport Therapeutics, Inc. Fused azaheterocyclic compounds and their use as AMPA receptor modulators
EA037731B1 (ru) * 2016-10-26 2021-05-14 Янссен Фармацевтика Нв Конденсированные азагетероциклические соединения и их применение в качестве модуляторов ampa-рецептора
CN109890823B (zh) * 2016-10-26 2021-11-30 詹森药业有限公司 稠合氮杂环化合物及其作为ampa受体调节剂的用途
CN109963851B (zh) * 2016-10-26 2021-11-30 詹森药业有限公司 融合的双环吡啶化合物及其作为ampa受体调节剂的用途
JP6994029B2 (ja) 2016-10-26 2022-01-14 ヤンセン ファーマシューティカ エヌ．ベー． 融合アザヘテロ環状化合物、及びａｍｐａ受容体調節因子としてのそれらの使用
WO2018080917A1 (fr) * 2016-10-26 2018-05-03 Janssen Pharmaceutica Nv Composés de pyridine bicyclique fusionnés et leur utilisation comme modulateurs des récepteurs ampa
KR102416798B1 (ko) 2016-10-26 2022-07-04 얀센 파마슈티카 엔.브이. 융합된 바이사이클릭 피리딘 화합물 및 ampa 수용체 조절제로서의 이들의 용도
KR102417483B1 (ko) 2016-10-26 2022-07-05 얀센 파마슈티카 엔.브이. 융합된 아자헤테로사이클릭 화합물 및 ampa 수용체 조절제로서의 이들의 용도

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