[go: up one dir, main page]

WO1999026927A2 - Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central - Google Patents

Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central Download PDF

Info

Publication number
WO1999026927A2
WO1999026927A2 PCT/US1998/024833 US9824833W WO9926927A2 WO 1999026927 A2 WO1999026927 A2 WO 1999026927A2 US 9824833 W US9824833 W US 9824833W WO 9926927 A2 WO9926927 A2 WO 9926927A2
Authority
WO
WIPO (PCT)
Prior art keywords
adamantyl
group
ethanone
compound according
carboxamιde
Prior art date
Application number
PCT/US1998/024833
Other languages
English (en)
Other versions
WO1999026927A3 (fr
Inventor
Bradford C. Van Wagenen
Scott T. Moe
Daryl L. Smith
Susan M. Sheehan
Irina Shcherbakova
Richard Travato
Ruth Walton
Robert Barmore
Eric G. Delmar
Thomas M. Stormann
Original Assignee
Nps Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to NZ505207A priority Critical patent/NZ505207A/en
Priority to JP2000522085A priority patent/JP2001524468A/ja
Priority to CA002311131A priority patent/CA2311131A1/fr
Priority to AU15317/99A priority patent/AU771358B2/en
Priority to IL13625098A priority patent/IL136250A0/xx
Priority to EP98959535A priority patent/EP1037878A2/fr
Priority to MXPA00004940A priority patent/MXPA00004940A/es
Application filed by Nps Pharmaceuticals, Inc. filed Critical Nps Pharmaceuticals, Inc.
Publication of WO1999026927A2 publication Critical patent/WO1999026927A2/fr
Publication of WO1999026927A3 publication Critical patent/WO1999026927A3/fr
Priority to US09/573,347 priority patent/US6429207B1/en
Priority to IL136250A priority patent/IL136250A/en
Priority to US10/211,523 priority patent/US7053104B2/en
Priority to AU2004202776A priority patent/AU2004202776B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
    • 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
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention provides compounds active at metabotropic glutamate receptors and that are useful for treating neurological and psychiatric diseases and disorders. 5
  • Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate produces its effects on central neurons
  • receptors 15 by binding to and thereby activating cell surface receptors.
  • These receptors have been divided into two major classes, the lonotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
  • metabotropic glutamate receptors are G protein-coupled
  • phosphoinosmde (PI) hydrolvsis increases in phosphoinosmde (PI) hydrolvsis; intracellular calcium release: activation ot phosphohpase D: activation or inhibition of adenyl cyclase: increases or decreases in the formation of cyciic adenosme monophosphate (cAMP); activation of guanylyl cyclase: increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phosphohpase A:: increases in arachidonic acid release: and increases or decreases in die activity of voltage- and hgand-gated ion channels.
  • PI phosphoinosmde
  • mGluRl Eight distinct mGluR subtypes, termed mGluRl through mGluR8, have been identified by molecular cloning. See, for example, Nakanishi. Neuron 75:1031 (1994); Pin et al., Neuropharmacology 34: 1 (1995); Knopfel et al., J. Med. Chem. 38: 1417 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al.. PNAS 59: 10331 (1992); Mmakami et al., BBRC 199: 1136 (1994); Joly et al., J. Neurosci. 75:3970 ( 1995).
  • Metabotropic glutamate receptor subtypes may be subdivided into three groups, Group I. Group II, and Group III mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics. Nakanishi. Neuron 13.1031 ( 1994); Pin et al. , Neuropharmacology 34: 1 (1995); Knopfel et al., J. Med. Chem. 38: 1417 (1995).
  • Group I mGluRs comprise mGluRl. mGluR5. and their alternatively spliced variants. The binding of agonists to these receptors results in the activation of phosphohpase C and the subsequent mobilization of intracellular calcium. Electrophysiological measurements have been used to demonstrate these effects in, for example, Xenopus oocytes expressing recombinant mGluRl receptors. See, for example Masu et ai, Nature 349:760 (1991); Pin et al., PNAS ⁇ 9: 10331 (1992). Similar results have been achieved with oocytes expressing recombinant mGluR5 receptors. Abe et al., J. Biol. Chem.
  • Quisquaiate is relatively selective for Group I receptors, as compared to Group II and Group III mGluRs, but it also is a potent activator of ionotropic AMPA receptors. Pin et al.. Neuropharmacology 34: 1, Knopfel et al.. J. Med. Chem. 38: 1417 (1995).
  • Metabotropic glutamate receptors have been implicated in a number of normal processes in the mammalian CNS. Activation ot mGluRs has been shown to be required for induction ot hippocampal long-term potentia ⁇ on and cerebeilar long-term depression. Bashir et al., Nature 363:347 (1993); Bortolotto et al., Nature 368:740 (1994); Aiba et al, Cell 79:365 (1994); Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nocicep ⁇ on and analgesia also has been demonstrated. Meller et ai. Neuroreport 4: 879 (1993).
  • mGluR activation has been suggested to play a modulatory role in a va ⁇ etv ot other normal processes including synaptic transmission, neuronal development. apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waking, motor control, and control of the vestibulo-ocular reflex.
  • apoptotic neuronal death apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waking, motor control, and control of the vestibulo-ocular reflex.
  • Metabotropic glutamate receptors also have been suggested to play roles in a variety ot pathophysiological processes and disease states arfecting the CNS These include stroke, head trauma, anoxic and ischemic injuries, hypogiycemia. epilepsy, and neurodegenerative diseases such as Alzheimer's disease. Schoepp et al.. Trends Pharmacol. Sci. 14: 13 (1993); Cunningham et ai. Life Sci. 54: 135 (1994); Hollman et al., Ann. Rev. Neurosci. 77:31 (1994); Pin et ai , Neuropharmacology 34: ⁇ (1995); Knopfel et al. , J. Med. Chem. 38: 1417 ( 1995).
  • Group I mGluRs appear to increase glutamate-mediated neuronal excitation via postsynaptic mechanisms and enhanced presynapuc glutamate release, their activation probably contributes to the pathology Accordingly, selective antagonists of Group I mGluR receptors could be therapeuticaily beneficial, specifically as neuroprotective agents or anticonvulsants. Preliminary studies assessing therapeutic potentials with the available mGluR agonists and antagonists have yielded seemingly contradictory results. For example, it has been reported that application of ACPD onto hippocampal neurons leads to seizures and neuronal damage (Sacaan et ai, Neurosci.
  • the present invention provides potent antagonists of Group I metabotropic glutamate receptors. These antagonists may be represented by the formula I,
  • R £ ⁇ Linker]— Ar wherein R is an optionally substituted straight or branched chain alkyl. arylalkyl, cycloalkyl, or alkylcycloalkyl group containing 5-12 carbon atoms.
  • Ar is an optionally substituted aromatic, heteroaromatic, arylalkyl, or heteroaralkyl moiety containing up to 10 carbon atoms and up to 4 heteroatoms, and [linker] is -(CH2)n-, where n is 2-6, and wherein up to 4 CH2 groups may independently be substituted with groups selected from the group consisting of GO aikyl, CHOH, CO, 0, S, SO, SO2, N, NH, and NO.
  • Ar comprises a ring system selected from the group consisting of benzene, thiazole. furyl, pyranvl, 2H-pyrroiyl. thienyl, pyrrolyl, lmidazolyi, pyrazoiyl, py ⁇ dyi. pyrazinyl.
  • Ar optionally may independently be substituted wit up to two C1-C3 alkyl groups, or up to two halogen atoms, where halogen is selected from F, Cl, Br, and I.
  • R contains 4, 5, 6, 7, 8, 9, 10 or
  • linker comprises an amide, ester, or thioester group.
  • R comprises a moiety selected from the group consisting of substituted or unsubstituted adamantyi, 2-adamantyl, (1S.2S.3S.5R)- isopinocamphenyl, t ⁇ cyclo[4 3.1.
  • Ar comprises a group having the formula
  • X'. X 2 , X'. and X* independently can be N or CH, provided that not more than two of X 1 . X 2 . X ⁇ and X 4 can be N.
  • X 1 is N. and/or X 2 is N.
  • X 3 is N.
  • X 1 is CH and X 2 is N.
  • Ar is an optionally substituted 2-, 3-, or 4- pyridyl moiety, or Ar is a 6-benzothiazolyl moiety.
  • the compound is selected from the group consisting of 7V-[6-(2-Methylqu ⁇ nolyI)]-l- adamantanecarboxamide. ⁇ '-(6-Qu ⁇ nolyl)-l-adamantanecarboxam ⁇ de. .V-(2- Quinolyl)- 1 -adamantanecarboxamide, yV-(3-Qu ⁇ noly 1)- 1 -adamantane-carboxamide. 6-Qu ⁇ nolyl- 1 -adamantanecarboxyiate.
  • the compound is selected from the group consisting of 7V-(l-Adamantyl)-3-qu ⁇ nolmecarboxam ⁇ de. 7V-(l-Adamantyl)-2- quinohnecarboxamide. /V-(2-Adamantyl)-2-qu ⁇ noxal ⁇ ne-carboxam ⁇ de. ⁇ - [(lR.2R,3R.5S)-3-P ⁇ nanemethyl]-2-qu ⁇ noxahne-carboxam ⁇ de. ⁇ -( l-Adamantyi)- 2-qumoxal ⁇ ne-carboxam ⁇ de. .V-( l-Adamantyl)-6-qu ⁇ nohnecarboxam ⁇ de.
  • the compound is selected from the group consisting of /V-[6-(2-Methylqu ⁇ nolyl)]-l-adamantanecarboxam ⁇ de. ⁇ ' -(6- Quinoly -l-adamantane-carboxamide. /V-(2-Qu ⁇ nolyl)-l-adamantanecarboxam ⁇ de. and 7V-(3-Qu ⁇ nolyI)-l-adamantanecarboxam ⁇ de. 7V-(3-Methylcyclohexyl)-2- quinoxalinecarboxamide. /V-(2,3-D ⁇ methylcycIohexyi)-2-qu ⁇ noxalinecarboxam ⁇ de.
  • the compound is selected from the group consisting of 3-(l-Adamantanemethoxy)-2-chloroqu ⁇ noxaline, 2-(l- Adamantanemethoxy)-3-methylqu ⁇ noxaline, 3-(l-Adamantanemethoxy)-2- fluoroquinoxaline. 2-(l-Adamantanemethoxy)-3-t ⁇ fluoromethylqu ⁇ noxal ⁇ ne. ⁇ - [2-(4-Phenylth ⁇ azolyl)]- l-adamantanecarboxam ⁇ de, .V-[2-(5-Methyl-4- phenylthiazolyl)]-l-adamantanecarboxam ⁇ de.
  • a method of inhibiting activation of an mGluR Group I receptor comprising treaung a cell containing said mGluR Group I receptor wi i an effective amount of a compound as set forth above.
  • a method of treating a disease associated with glutamate-induced neuronal damage comprising administering to a patient suffering from said disease an effective amount of a composition as set forth above.
  • Figure 1 shows illustrative compounds of the invention.
  • the invention provides compounds that are potent and selective antagonists of Group I metabotropic glutamate receptors.
  • the compounds contemplated by the invention can be represented by the general formula I:
  • R is a straight or branched chain alkyl. arylalkyl, or optionally substituted alicyclic group, and Ar is an optionally substituted aromatic, heteroaromatic. arylalkyl, or heteroaralkyl moiety.
  • the [linker] moiety is a group that not only covalently binds to the Ar and R moieties, but also facilitates adoption of die correct spatial orientation by Ar and R to allow receptor binding.
  • Ar moiety generally may contain up to ten carbon atoms, although the skilled artisan will recognize that Ar groups with more than ten carbon atoms are widiin the scope of the invention.
  • Ar can be a monocyciic or fused bicvclic aryl. alkaryi, heteroaryl or heteroarylalkyl group.
  • Ar can contain up to tour heteroatoms, independently selected from the group consisting of N. S. and O
  • Ar When Ar is a heteroaryl ring or ring system, it preferably contains one or two heteroatoms. ⁇ t least one of the heteroatoms preferably is N.
  • Monocyciic Ar groups include, but are not limited to: phenyl. thiazoyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrroyl, imidazoyl, pyrazoyl, pyndyl, pyrazinyl. pynmidinyl, and pyridazinyl moieties.
  • Fused bicvclic Ar groups include, but are not limited to: benzothiazole, benzimidazole. 3H- ⁇ ndoIyl. indolyl. lndazoyl, pu ⁇ nyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl.
  • Ar preferably is a quinoxa nyl, quinolinyl, or pyndyl moiety.
  • Ar moieties include the 3,4-methylened ⁇ oxy and 3,4-d ⁇ oxane rings.
  • the Ar moiety optionally may independently be substituted with up to two G-G alkyl groups, or up to two halogen atoms, where halogen is selected from F. Cl. Br. and I.
  • R moiety generally may contain between four and eleven carbon atoms, although the skilled artisan will recognize that R moieties with 12, 13, 14, 15, or 16 carbon atoms will be possible.
  • Aldiough R can contain 4. 5 or 6 carbon atoms, preferably R contains at least 7 carbon atoms.
  • R is optionally substituted alkyl, cycloalkyl, cycloaikylmethyl, or optionally substituted phenylalkyl.
  • R is optionally substituted alkyl, cycloalkyl, cycloaikylmethyl, or optionally substituted phenylalkyl.
  • R may be perfluo ⁇ nated.
  • R moieties include, but are not limited to: adamantyl, 2- adamantyl, (lS.2S,3S,5R)- ⁇ sop ⁇ nocamphenyl, tr ⁇ cyclo[4.3.1. l(3,8)]undec-3-yl.
  • R groups include 2.2,3.3.4,4,4-heptafluorobutyl. 4- ketoadamantyl, 3-phenyI-2-methylpropyl, 3,5-d ⁇ methyladamantyi, trans-2- phenylcyclopropyl, 2-med ⁇ ylcycIohexyI, 3,3,5-t ⁇ methylcyclohexyl, 2-(o- methoxyphenyl)ethyl, 2-(l,2,3,4-tetrahydronaphthyl), 4-phenyIbutyi, 2-methyl-2- phenylbutyl, 2-(/w-fluorophenyl)ethyl, 2-(p-fluorophenyl)ethyl, 2-(3-hydroxy-3- pheny propyl, (S)-2-hydroxy-2-phenylethyl, (R)-2-hydroxy-2-phenyiethyl.
  • the R moiety may have any of the possible configurations.
  • the R moiety can be either of the enantiomers, or may be a racemate.
  • the [linker] moiety generally has the structure -(CH2)n-, where n is 2-6.
  • CH2 groups may independently be replaced with groups selected from the group consisting of a G-G alkyl group, CHOH, CO, 0, S. SO. SO2.
  • [linker] comprises an amide, ester, thioester. ketomethylene. ether, alkylether, ethylene.
  • [linker] is an -O-(CH:)m- , -CO-Y-(CH2) m -, or -S(O CH2)m- group, where Y is CH2. NH, 0. or S. and m is 1-4, and n is 0-2.
  • the [linker] moiety may have either one of two possible orientations with respect to the R and Ar groups.
  • the invention encompasses compounds having the configuration R-0-(CH2)m-Ar and
  • compounds according to the invention are esters and amides of monocyciic or fused bicyclic aromatic and heteroaromatic carboxylic acids, phenols and amines.
  • the compounds may be represented by the Formulae II or III: 99/26 2
  • Y can be either 0, S, NH, or CH2; and X', X 2 , X 3 , and X" independently can be N or CH. Preferably, one or two of X', X 2 , X 3 , and X* are N, and the remainder are CH.
  • Preferred compounds contemplated by the invention have the formula TV or V, where R, Y and X 1 are as defined above.
  • the compounds have me Formulae VI or VII .
  • R and Y are as defined above.
  • Y is N
  • R is an unsubstituted or monosubstituted 1,1,-dimediylphenylethylamine or 1, 1-d ⁇ methylbenzylam ⁇ ne moiety, where the substitutuent preferably is an 0-, in-, or -chlo ⁇ ne or p-medioxy group.
  • Y is N
  • R is an 0-, m- , or /7-methoxy substituted phenyiethylamine.
  • Compounds of the first and second embodiments appear to exhibit selectivity for the mGIuRi receptor.
  • Y is N
  • R is an 0, m, or p- fluoro-substituted phenyiethylamine.
  • Compounds of the third embodiment appear not to discriminate between the mGIuRi and mGluRs receptor subtypes.
  • the compounds have the Formulae VIII or IX.
  • X' and R are as defined above.
  • X 1 and X 2 are N
  • X 3 and X" are H.
  • R is 1- adamantyl
  • a substituent is present on the carbon atom ortho to both the linker and X 2 .
  • the substituent preferably is a halogen, such as chlorine, or an alkyl group, such as methyl.
  • R is 1- adamantyl. Compounds ot these first and second embodiments appear to exhibit selectivity tor the mGIuRi receptor.
  • the compounds may have the Formulae X or XI, where Z is a pharmaceutically acceptable substituent.
  • Z is a pharmaceutically acceptable substituent.
  • pharmaceutically acceptable Z groups are those groups that do not deletenously reduce the receptor binding activity of the compound. Suitable Z groups include, but are not limited to halogen, lower alkyl, oxygen or amine. and their pharmaceutically acceptable derivatives including ethers, esters, and amides. Preferably. Z contains 0-4 carbon atoms.
  • alkyl denotes both straight and branched chain alkyl.
  • R is adamantyl.
  • the linker is -CO- CH2-S-, and Ar is m- or ⁇ -alkyloxyphenyl, or 3,4-methylened ⁇ oxy or 3.4- dioxane.
  • salts of the compounds described above include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic. hydroiodic, phosphoric, sulfu ⁇ c, t ⁇ fluoroacetic, maionic, succinic. citric, mande c, benzoic, cinnamic, methanesuifonic and similar ones, and include acids related to the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Sciences, 66:2 (1977) and inco ⁇ orated herein by reference.
  • pharmaceutically acceptable acid addition salts such as hydrochloric, hydrobromic. hydroiodic, phosphoric, sulfu ⁇ c, t ⁇ fluoroacetic, maionic, succinic. citric, mande c, benzoic, cinnamic, methanesuifonic and similar ones, and include acids related to the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Sciences, 66:2 (1977
  • mGluR Group I antagonists may be prepared by methods that are well known in the art, using widely recognized techniques of organic chemistry. Suitable reactions are described in standard textbooks of organic chemistry. For example, see March, Advanced Organic Chemistry, 2d ed., McGraw Hill (1977). For example, the compounds generally may be prepared by formation of the [linker] moietv between two precursor compounds containing suitable Ar and R moieties.
  • the linker contains an amide linkage
  • the amide may be formed using well known techniques, such as reaction between an amine and an acid chloride, or by reaction in the presence of a coupling reagent such as carbonyldiimidazoie, or a carbodiimide such as, for example, 1,3- dicyclohexyicarbodiimide (DCC). Formation of ester and thioester linkages can be achieved in similar fashion.
  • the ether function also can be prepared using standard techniques.
  • e ⁇ ers can be formed using the Mitsunobu reaction, where a primary alcohol function is displaced by another hydroxy group via activation using PPh3 and diethylazodicarboxylate (DEAD).
  • Thioe ⁇ er linkages may be prepared by displacement of a leaving group such as hahde with a thiolate anion. generated by deprotonation ot a thiol group with base.
  • the [linker] moiety contains a ketomethylene group, it can be formed by alkylation ot a ketone enolate.
  • a methyl ketone can be deprotonated using a strong base such as lithium dusopropyiamide (LDA). followed by reaction with an alkyl halide.
  • a ketomethylene function can be prepared via addition of an organometailic compound, such as a Grignard reagent, to an aldehyde, followed by oxidation of the resultant hydroxyl group to a ketone.
  • organometailic compound such as a Grignard reagent
  • [Linker] moieties containing other heteroatom groups also may be prepared using methods that are well known in the art.
  • 7V,7V-D ⁇ subst ⁇ tuted hydraz e compounds may be prepared via reductive amination of hydrazones formed by reaction of a monosubstituted hydrazone widi an aldehyde.
  • N.N- Disubstituted azo compounds can be formed, for example, by oxidation of the corresponding hydrazines.
  • Ar and R moieties are readily available, or may be prepared using straightforward techniques of organic chemistry. Many compounds are commercially available, for example, from Aldnch Chemical Company, Milwaukee. WI. When the compounds are not commercially available, they may readily prepared from available precursors using straightforward transformations that are well known in the art.
  • carboxyiic acids may be converted into the corresponding acid chlorides by reaction with, tor example, thionyi chloride or oxalyl chloride.
  • An example of such a reaction is provided below in Example 3.
  • Compounds containing a hydroxy function may be converted into the corresponding amine by (i) conversion of the hydroxyl group into a leaving group, such as a sulfonic acid ester (such as a triflate, mesylate, or tosylate) or a halide, (ii) displacement with azide ion, and (iii) reduction of the resulting azide by, for example, hydrogenation over a platinum oxide catalyst.
  • a leaving group such as a sulfonic acid ester (such as a triflate, mesylate, or tosylate) or a halide
  • displacement with azide ion such as a triflate, mesylate, or tosylate
  • reduction of the resulting azide by, for
  • the pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity.
  • glutamate receptor assays are well known in the art, for example, see Aramo ⁇ et al., Neuron 8:757 (1992); Tanabe et al.. Neuron 8: 169 (1992). The methodology described in those publications is incorporated herein by reference.
  • the compounds of the invention may be studied using an assay that measures inhibition of intracellular calcium mobilization in cells expressing recombinant receptors that can bind the compounds.
  • Suitable receptor constructs are well known in the art and are also described, for example, in WO 97/05252, the contents of which are hereby inco ⁇ orated by reference in their entirety.
  • HEK-293 cells human embryonic kidney cells, available from the American Type Culture Collection, Rockville, MD, Accession Number CRL 15763
  • the stably transfected ceils are cultured in high glucose DMEM (Gibco 092) containing 0.8 mM glutamme. 10% FBS, and 200 ⁇ M hygromycin B.
  • HEK-293 cells stably transfected with a DNA construct encoding a recombinant receptor, are loaded with Fura dye. The ceils then are washed, resuspended. and maintained at 37 °C. The cells are diluted into cuvettes for recording fluorescent signals. Measurements of fluorescence are performed at 37 °C using standard methods, and concentrations of intracellular Ca 2+ are calculated using a dissociation constant (Kd) of 224 nM and applying equation:
  • Fimn is determined by chelating all calcium available, therefore, no fura 2 is bound to calcium, and Fm « is determined by fully saturating all the fura 2 available with calcium.
  • Example 15 A detailed protocol for testing the compounds of the invention is provided below at Example 15. Preparation of pharmaceutical compositions containing mGluR antagonists, and their use in treating neurological disorders
  • the compounds of the invention are useful for treating neurological disorders or diseases. While these compounds will typically be used in therapy tor human patients, they may also be used in veterinary medicine to treat similar or identical diseases.
  • the compounds of the invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences: Drug Receptors and Receptor Theory, 18th ed.. Mack Publishing Co. ( 1990).
  • the compounds according to the invention are effective over a wide dosage range.
  • dosages from about 0.01 to about 1000 mg, preferably from about 0.5 to about 100 mg, per day may be used.
  • a most preferable dosage is about 2 mg to about 70 mg per day.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight ot the subject to be treated, and the preference and experience of the attending physician.
  • salts are generally well known to those of ordinary skill in the art. and may include, by way of example but not limitation, acetate, benzenesulfonate. besylate, benzoate, bicarbonate, bitartrate. bromide, calcium edetate. camsylate. carbonate, citrate, edetate. edisylate. estolate. esylate, fumarate, gluceptate, gluconate, glutamate. glycollylarsanilate. hexylresorcinate. hydrabamine. hydrobromide, hydrochlo ⁇ de. hydroxynaphthoate.
  • iodide iseduonate, lactate, lactobionate, malate.
  • maieate mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/disphosphate, polygalacturonate, saiicyiate, stearate, subacetate, succinate, sulfate. tannate, tartrate, or teoclate.
  • Other pharmaceutically acceptable salts may be found in, for example, Remington s Pharmaceutical Sciences: ( 18th ed.), Mack Publishing Co.. Easton.PA ( 1990).
  • Preferred pharmaceutically acceptable salts include, tor example, acetate, benzoate. bromi ⁇ e. carbonate, citrate, gluconate. hydrobromide. hvdrochlonde. maieate, mesylate. napsylate. pamoate (embonate), phosphate, saiicyiate. succinate. sulfate. or tartrate.
  • agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
  • the agents may be delivered, for example, in a timed- or sustained- release form as is known to those skilled in the art.
  • Techniques for formulation and administration may be found in Remington's Pharmaceutical Sciences: (18th ed.), Mack Publishing Co., Easton, PA (1990).
  • Suitable routes may include oral, buccal, sublinguai. rectal, transdermal, vaginal, transmucosai, nasal or intestinal administration: parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal. direct lntravent ⁇ cular. intravenous, lntrape ⁇ toneal. intranasal. or intraocular injections, just to name a few.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer ' s soiution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer ' s soiution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present invention in particular, those formulated as solutions, may be administered parenteraily, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended pu ⁇ ose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees. capsules, or solutions.
  • compositions tor oral use can be obtained by combining the active compounds widi solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol. or sorbitol: cellulose preparations, tor example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth. methyl cellulose, hydroxypropylmethyl-ceilulose.
  • CMC carboxymethyl-ceiluiose
  • PVP- povidone polyvinylpyrrolidone
  • disintegrating agents may be added, such as the cross- linked polyvinylpyrrolidone. agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this pu ⁇ ose. concentrated sugar solutions may be used, which may optionally contain gum arable, talc, polyvinylpyrrolidone, carbopoi gel, polyethvlene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made ot gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the acuve ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and. optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and. optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • Capillary gas chromatographic and mass spectral data were obtained using a Hewlett-Packard (HP) 5890 Series II Gas Chromatograph coupled to an HP 5971 Series Mass Selective Detector [Ultra-2 Ultra Performance Capillary Column (cross nked 5% PhMe siiicone); column length, 25 m; column i.d., 0.20 mm: helium flow rate. 60 mL/mm: injector temp., 250 °C; temperature program. 20 C/min from 125 to 325 °C for 10 min. then held constant at 325 °C for 6 mm]. Thin-layer chromatography was performed using Analtech Uniplate 250-um silica gel HF TLC plates.
  • UV light sometimes in conjunction with ninhyd ⁇ n and Dragendorff's spray reagents (Sigma Chemical Co.) were used for detecting compounds on the TLC plates.
  • Reagents used in reactions were purchased from the Ald ⁇ ch Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (Saint Louis. MO). Fluka Chemical Co ⁇ . (Milwaukee, WI), Fisher Scientific (Pittsburgh. PA), TCI America (Portland. OR), or Lancaster Synthesis (Windham. NH).
  • 6-Qu ⁇ noI ⁇ necarboxyl ⁇ c acid was refluxed in thionyl chloride for 30 mm.
  • the excess thionyl chloride was then removed by rotary evaporation (90° C) to provide 6-qu ⁇ nol ⁇ necarbonyi chloride hydrochloride.
  • EXAMPLE 4 Preparation of /V-(l-Adamantyl)-3- quinoiinecarboxamide (72) l, -Carbonyldiim ⁇ dazole (161 mg, 1.00 mmol) in N.N- dimethylformamide (1 mL) was added in one portion to a suspension ot 3- quinoiinecarboxyhc acid (173 mg, 1.00 mmol) in TV.TV-dimethylformamide (1 mL). The resulting reaction solution was stirred for 2.5 h. 1- Adamantanamine (151 mg, 1.00 mmol) in 7V,7V-d ⁇ methyIformam ⁇ de (0.5 mL) was added in one portion.
  • N-[(S)-2-PhenyI-l-propyl]-2-quinoxalinecarboxamide (173) Prepared from 2-qu ⁇ noxaloyl chloride (0.47 g, 2.4 mmol), (5)-2-phenyl-l- propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yieldmg
  • Trifluoroacetic anhydride (5.50 mL, 39.0 mmol) was added to (-)-trans- myrtanol (5.10 mL. 32.5 mmol) in dry tetrahydroluran ( 100 mL). This reaction mixmre was stirred for 1 h. The reaction mixmre was rotary evaporated. This provided 7 60 g (94%) or ( ⁇ S,2S.5S)-trans-my ⁇ a.nvl t ⁇ fluoroacetate.
  • the aqueous layer was made basic with 0.1 M sodium hydroxide (50 mL) and extracted with dichloromethane (2 x 50 mL). The organic layer was then dried (anhydrous sodium sulfate) and rotary evaporated. This provided 78 mg (7%) ot (15.2S.5S)-tra «J-my ⁇ anylam ⁇ ne as a light yellow oil.
  • HEK-293 cells expressing a recombinant receptor as described in WO 97/05252 were loaded with 2 ⁇ M Fura-2 acetoxymethylester by incubation for 30-40 minutes at 37 °C in SPF-PCB (126 mM NaCI, 5 mM KG, 1 mM MgCh.
  • the cells were washed 1-2 times in SPF-PCB. resuspended to a density ot
  • the cells were diluted five-told into a quartz cuvette with BSA-free 37 °C SPF-PCB to achieve a final BSA concentration of 0.1 % (1.2 mL of 37 °C BSA-free SPF-PCB + 0.3 mL cell suspension).
  • Measurements ot fluorescence were performed at 37 °C with constant stirring using a custom-built spectrofluonmeter (Biomedical Instrumentation Group, University ot Pennsylvania). Excitation and emission wavelengths were 340 and 510 nm. respectively.
  • digitonin Sigma Chemical Co., St.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Quinoline Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

L'invention concerne des composés et des compositions pharmaceutiques contenant lesdits composés, qui agissent comme antagonistes au niveau des récepteurs du glutamate métabotropes. Lesdits composés sont utiles pour le traitement de maladies et de troubles neurologiques. Des procédés de préparation desdits composés sont également décrits.
PCT/US1998/024833 1997-11-21 1998-11-20 Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central WO1999026927A2 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
JP2000522085A JP2001524468A (ja) 1997-11-21 1998-11-20 中枢神経系疾患を治療するための代謝調節型グルタミン酸受容体アンタゴニスト
CA002311131A CA2311131A1 (fr) 1997-11-21 1998-11-20 Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central
AU15317/99A AU771358B2 (en) 1997-11-21 1998-11-20 Metabotropic glutamate receptor antagonists for treating central nervous system diseases
IL13625098A IL136250A0 (en) 1997-11-21 1998-11-20 Metabotropic glutamate receptor antagonist compounds
EP98959535A EP1037878A2 (fr) 1997-11-21 1998-11-20 Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central
NZ505207A NZ505207A (en) 1997-11-21 1998-11-20 Metabotropic glutamate receptor antagonists for treating central nervous system diseases
MXPA00004940A MXPA00004940A (es) 1997-11-21 1998-11-20 Antagonistas de receptor de glutamato metabotropico para tratar enfermedades del sistema nervioso central.
US09/573,347 US6429207B1 (en) 1997-11-21 2000-05-19 Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
IL136250A IL136250A (en) 1997-11-21 2000-05-21 Metabotropic glutamate receptor antagonist compounds
US10/211,523 US7053104B2 (en) 1997-11-21 2002-08-05 Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
AU2004202776A AU2004202776B2 (en) 1997-11-21 2004-06-17 Metabotropic glutamate receptor antagonists for treating central nervous system diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6675897P 1997-11-21 1997-11-21
US60/066,758 1997-11-21

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/573,347 Continuation-In-Part US6429207B1 (en) 1997-11-21 2000-05-19 Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases

Publications (2)

Publication Number Publication Date
WO1999026927A2 true WO1999026927A2 (fr) 1999-06-03
WO1999026927A3 WO1999026927A3 (fr) 1999-10-21

Family

ID=22071510

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/024833 WO1999026927A2 (fr) 1997-11-21 1998-11-20 Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central

Country Status (9)

Country Link
EP (1) EP1037878A2 (fr)
JP (1) JP2001524468A (fr)
CN (2) CN1158264C (fr)
AU (2) AU771358B2 (fr)
CA (1) CA2311131A1 (fr)
IL (2) IL136250A0 (fr)
MX (1) MXPA00004940A (fr)
NZ (1) NZ505207A (fr)
WO (1) WO1999026927A2 (fr)

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026198A1 (fr) * 1998-11-02 2000-05-11 Eli Lilly And Company Limited Derives d'oxazine (3,6-dihydro)-2h-1,2- n-substitues, leur preparation et leur utilisation comme antagonistes de mglur1 selectifs
WO2000026199A3 (fr) * 1998-11-02 2000-08-17 Lilly Co Eli Composes pharmaceutiques
WO2000073283A1 (fr) * 1999-06-02 2000-12-07 Nps Pharmaceuticals, Inc. Antagonistes du recepteur de glutamate metabotropique et leur utilisation pour le traitement de maladies du systeme nerveux central
WO2001012627A1 (fr) * 1999-08-19 2001-02-22 Nps Pharmaceuticals, Inc. Composes heteropolycycliques et leur utilisation en tant qu'antagonistes des recepteurs du glutamate metabotrope
WO2001010846A3 (fr) * 1999-08-05 2001-11-08 Igt Pharma Inc Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers
WO2001029011A3 (fr) * 1999-10-15 2001-11-08 Hoffmann La Roche Derives de benzodiazepines
WO2001029012A3 (fr) * 1999-10-15 2001-11-08 Hoffmann La Roche Derives de benzodiazepines
WO2001072291A3 (fr) * 2000-03-25 2002-02-21 Univ Manchester Traitement de troubles des mouvements
EP1059090A4 (fr) * 1998-03-03 2002-02-27 Yamanouchi Pharma Co Ltd Medicaments contre l'infarcissement du cerveau
WO2002028837A1 (fr) * 2000-10-02 2002-04-11 Janssen Pharmaceutica N.V. Antagonistes du récepteur métabotrope du glutamate
WO2002064545A1 (fr) 2001-02-13 2002-08-22 Aventis Pharma Deutschland Gmbh Amines indanyle acyles et leurs utilisation comme agents pharmaceutiques
US6660753B2 (en) 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
WO2003082350A3 (fr) * 2002-03-29 2004-03-04 Janssen Pharmaceutica Nv Derives radiomarques de quinoline et de quinolinone et leur utilisation en tant que ligands du recepteur metabotropique du glutamate
WO2003027068A3 (fr) * 2001-09-24 2004-04-08 Elan Pharm Inc Amines substituees pour le traitement de la maladie d'alzheimer
WO2004014881A3 (fr) * 2002-08-09 2004-05-27 Astrazeneca Ab Nouveaux composes
WO2004058754A1 (fr) * 2002-12-24 2004-07-15 Euro-Celtique S.A. Derives de benzoazolylpiperazine presentant une activite antagoniste vis-a-vis de mglur1 et de mglur5
WO2004069813A1 (fr) * 2003-01-31 2004-08-19 Astrazeneca Ab Derives de quinoxaline satures et leur utilisation en tant que ligands du recepteur du glutamate metabotropique
WO2004056745A3 (fr) * 2002-12-23 2004-11-11 Janssen Pharmaceutica Nv Acetamides d'adamantyle utiles comme inhibiteurs de la deshydrogenase 11-beta hydroxysteroide
EP1582519A3 (fr) * 1999-08-19 2005-12-21 Nps Pharmaceuticals, Inc. Composes heteropolycycliques et leur utilisation comme antagonistes des recepteurs glutamiques metabotropes
WO2006020879A1 (fr) * 2004-08-13 2006-02-23 Astrazeneca Ab Composes a base d'isoindolone et leur utilisation comme potentialisateurs du recepteur metabotropique du glutamate
WO2007021308A1 (fr) * 2005-08-12 2007-02-22 Astrazeneca Ab Isoindolones potentiateurs du récepteur glutamate métabotropique
WO2007037543A1 (fr) * 2005-09-29 2007-04-05 Banyu Pharmaceutical Co., Ltd. Dérivé de biarylamide
WO2007045876A1 (fr) * 2005-10-21 2007-04-26 Merz Pharma Gmbh & Co. Kgaa Chromenones et leur utilisation en tant que modulateurs des recepteurs metabotropes au glutamate
WO2007071358A1 (fr) * 2005-12-20 2007-06-28 Novartis Ag Dérivés d'acide nicotinique en tant que modulateurs des récepteurs métabotropiques du glutamate
WO2006138660A3 (fr) * 2005-06-17 2007-07-19 Apogee Biotechnology Corp Inhibiteurs de la sphingosine kinase
WO2007095024A1 (fr) 2006-02-16 2007-08-23 Astrazeneca Ab Isoindolones activant le récepteur métabotropique du glutamate
WO2006024627A3 (fr) * 2004-08-30 2007-09-13 Janssen Pharmaceutica Nv Derives d'acetamides n-2 adamantanyl-2-phenoxy utilises en tant qu'inhibiteurs de la deshydrogenase 11-beta hydroxysteroide
US7408065B2 (en) 2003-06-02 2008-08-05 Astrazeneca Ab P2X7 receptor antagonists and their use
US7476399B2 (en) 2003-08-06 2009-01-13 Senomyx Inc. Flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
US7501416B2 (en) 2004-02-06 2009-03-10 Bristol-Myers Squibb Company Quinoxaline compounds and methods of using them
US7511033B2 (en) 2007-04-19 2009-03-31 Hoffmann-La Roche Inc. Dihydro-benzo[B][1,4]diazepin-2-one sulfonamide derivatives
EP2064959A1 (fr) 2007-10-31 2009-06-03 Symrise GmbH & Co. KG Néomenthylamides aromatiques en tant qu'agents aromatisants
US7622589B2 (en) 2005-03-17 2009-11-24 Pfizer Inc. Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as VR1 receptor antagonists
WO2010101648A1 (fr) * 2009-03-06 2010-09-10 Wood Richard D Modulateurs des récepteurs au glutamate et agents thérapeutiques
US7807706B2 (en) 2005-08-12 2010-10-05 Astrazeneca Ab Metabotropic glutamate-receptor-potentiating isoindolones
US7842324B2 (en) 2005-06-15 2010-11-30 Senomyx, Inc. Bis-aromatic amides and their uses as sweet flavor modifiers, tastants, and taste enhancers
US7868008B2 (en) 2005-08-12 2011-01-11 Astrazeneca Ab Substituted isoindolones and their use as metabotropic glutamate receptor potentiators
US7947689B2 (en) 2006-08-04 2011-05-24 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-a]pyrimidines as metabotropic glutamate receptor modulators
US7964616B2 (en) 2007-03-22 2011-06-21 Astrazeneca Ab Compounds 679
US7964732B2 (en) 2006-11-17 2011-06-21 Pfizer Inc. Substituted bicyclocarboxyamide compounds
WO2011109398A2 (fr) 2010-03-02 2011-09-09 President And Fellows Of Harvard College Procédés et compositions pour le traitement du syndrome d'angelman et des troubles du spectre autistique
WO2011150380A1 (fr) 2010-05-28 2011-12-01 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et des troubles associés
WO2012009646A1 (fr) 2010-07-15 2012-01-19 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et de troubles associés
US8106073B2 (en) 2007-11-30 2012-01-31 Astrazeneca Ab Quinoline derivatives 057
US8148372B2 (en) 2008-06-06 2012-04-03 Astrazeneca Ab Metabotropic glutamate receptor isoxazole ligands and their use as potentiators—286
WO2012072547A1 (fr) * 2010-11-30 2012-06-07 Bayer Cropscience Ag Dérivés pyrimidiques et leur utilisation comme agents de lutte antiparasitaire
US8377939B2 (en) 2007-06-07 2013-02-19 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators 842
EP2567696A1 (fr) 2006-11-22 2013-03-13 Seaside Therapeutics, Inc. Procédés de traitement du retard mental, du syndrome de Down, du syndrome de l'X fragile et de l'autisme
US8415333B2 (en) 2009-02-24 2013-04-09 Respiratorious Ab Bronchodilating diazaheteroaryls
US8563591B2 (en) 2004-08-30 2013-10-22 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US8784782B2 (en) 2005-02-04 2014-07-22 Senomyx, Inc. Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions
US9012494B2 (en) 2004-05-07 2015-04-21 Janssen Pharmaceutica N.V. Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9072313B2 (en) 2006-04-21 2015-07-07 Senomyx, Inc. Comestible compositions comprising high potency savory flavorants, and processes for producing them
US9150512B2 (en) 2004-08-30 2015-10-06 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
CN114539170A (zh) * 2021-12-31 2022-05-27 华南农业大学 一种用于同时检测金刚烷胺、喹乙醇、氯霉素的半抗原、人工抗原及其制备方法和应用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100357283C (zh) * 2002-04-02 2007-12-26 中国科学院上海药物研究所 一类甲硫氨酰氨肽酶抑制剂
SE0302192D0 (sv) * 2003-08-08 2003-08-08 Astrazeneca Ab Novel compounds
GB0506133D0 (en) * 2005-03-24 2005-05-04 Sterix Ltd Compound
TW200817385A (en) * 2006-07-04 2008-04-16 Organon Nv Heterocyclic derivatives
CN101348461B (zh) * 2007-07-17 2011-10-05 西安利君制药有限责任公司 用于老年痴呆症治疗的n-(3-吡啶甲酰氧基)-3,5-二甲基-1-金刚烷胺或其可药用盐
WO2012006760A1 (fr) * 2010-07-14 2012-01-19 Merck Sharp & Dohme Corp. Composés tricycliques comme modulateurs allostériques des récepteurs métabotropes au glutamate
KR102529578B1 (ko) * 2014-08-29 2023-05-09 (주)아모레퍼시픽 신규 아다만탄 유도체 화합물

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3632581A (en) * 1968-10-08 1972-01-04 American Home Prod Schiff bases of quinoxaline-2-carboxal-dehydes and their reduction products
GB1329447A (en) * 1969-10-27 1973-09-05 Squibb & Sons Inc 4-adamantylaminoalkylamino-2-styryl-quinolines salts and derivatives thereof
FR2355829A1 (fr) * 1976-06-24 1978-01-20 Debat Lab Nouveaux derives de la nitroxoline utile en therapeutique
IL53440A0 (en) * 1977-11-22 1978-01-31 Teva Pharma 2-adamantyl hydrazines their preparation and pharmaceutical compositions containing them
FR2509728A1 (fr) * 1981-07-17 1983-01-21 Roussel Uclaf Nouveaux derives de la quinoleine, leurs sels, procede de preparation, application a titre de medicaments et compositions les renfermant
US5346907A (en) * 1988-04-05 1994-09-13 Abbott Laboratories Amino acid analog CCK antagonists
IE902295A1 (en) * 1989-07-07 1991-01-16 Abbott Lab Amino acid analog cck antagonists
EP0407192B1 (fr) * 1989-07-07 1997-03-05 Meiji Seika Kabushiki Kaisha Dérivés acyloxy-4-quinoléine et compositions insecticides et acaricides les contenant
DE69128682T2 (de) * 1990-03-28 1998-06-04 Otsuka Pharma Co Ltd Chinolinderivat, antiulcus-mittel das dieses derivat enthält und darstellung dieses derivates
JPH0441425A (ja) * 1990-06-07 1992-02-12 Tanabe Seiyaku Co Ltd ５―リポキシゲナーゼ阻害剤
ATE152443T1 (de) * 1992-07-10 1997-05-15 Glaxo Lab Sa Anilide-derivate
JPH07179371A (ja) * 1993-12-21 1995-07-18 Canon Inc 液晶性化合物、それを含む液晶組成物、それを用いた液晶素子、それらを用いた表示方法、及び表示装置
US5716944A (en) * 1994-07-04 1998-02-10 Takeda Chemical Industries, Ltd. Phosphonic acid compounds, their production and use
WO1996005818A1 (fr) * 1994-08-19 1996-02-29 Nps Pharmaceuticals, Inc. Procedes et composes actifs au niveau des recepteurs de glutamate metabotropiques, destines au traitement d'affections et de troubles neurologiques
US5707985A (en) * 1995-06-07 1998-01-13 Tanabe Seiyaku Co. Ltd. Naphthyl-, quinolyl- and isoquinolyl- sulfonamide derivatives as cell adhesion modulators
AU725491B2 (en) * 1997-05-03 2000-10-12 Smithkline Beecham Plc Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors

Cited By (118)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1059090A4 (fr) * 1998-03-03 2002-02-27 Yamanouchi Pharma Co Ltd Medicaments contre l'infarcissement du cerveau
WO2000026199A3 (fr) * 1998-11-02 2000-08-17 Lilly Co Eli Composes pharmaceutiques
WO2000026198A1 (fr) * 1998-11-02 2000-05-11 Eli Lilly And Company Limited Derives d'oxazine (3,6-dihydro)-2h-1,2- n-substitues, leur preparation et leur utilisation comme antagonistes de mglur1 selectifs
US6482824B1 (en) 1998-11-02 2002-11-19 Eli Lilly And Company Use of n-substituted (3,6-dihydro)-2h-1,2-oxazine derivatives as selective mglur1 antagonists
WO2000073283A1 (fr) * 1999-06-02 2000-12-07 Nps Pharmaceuticals, Inc. Antagonistes du recepteur de glutamate metabotropique et leur utilisation pour le traitement de maladies du systeme nerveux central
EP1595871A3 (fr) * 1999-06-02 2005-11-30 Nps Pharmaceuticals, Inc. Antagonistes du recepteur metabotrope duglutamate et leur utilisation pour le traitement des maladies du systeme nerveux central.
WO2001010846A3 (fr) * 1999-08-05 2001-11-08 Igt Pharma Inc Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers
EP1582519A3 (fr) * 1999-08-19 2005-12-21 Nps Pharmaceuticals, Inc. Composes heteropolycycliques et leur utilisation comme antagonistes des recepteurs glutamiques metabotropes
WO2001012627A1 (fr) * 1999-08-19 2001-02-22 Nps Pharmaceuticals, Inc. Composes heteropolycycliques et leur utilisation en tant qu'antagonistes des recepteurs du glutamate metabotrope
US7112595B2 (en) 1999-08-19 2006-09-26 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US6660753B2 (en) 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
WO2001029011A3 (fr) * 1999-10-15 2001-11-08 Hoffmann La Roche Derives de benzodiazepines
US6407094B1 (en) 1999-10-15 2002-06-18 Hoffmann-La Roche Inc. Glutamate receptor antagonists
US6509328B1 (en) 1999-10-15 2003-01-21 Hoffmann-La Roche Inc. Glutamate receptor antagonists
US7018998B2 (en) 1999-10-15 2006-03-28 Hoffmann-La Roche Inc. Glutamate receptor antagonists
WO2001029012A3 (fr) * 1999-10-15 2001-11-08 Hoffmann La Roche Derives de benzodiazepines
US6960578B2 (en) 1999-10-15 2005-11-01 Hoffmann-La Roche Inc. Glutamate receptor antagonists
RU2259360C2 (ru) * 1999-10-15 2005-08-27 Ф.Хоффманн-Ля Рош Аг Производные бензодиазепина и лекарственное средство, их содержащее
US7151098B2 (en) 1999-10-15 2006-12-19 Hoffmann-La Roche Inc. Glutamate receptor antagonists
RU2257382C2 (ru) * 1999-10-15 2005-07-27 Ф.Хоффманн-Ля Рош Аг Производные бензодиазепина, лекарственное средство, содержащее их, и способ их получения
WO2001072291A3 (fr) * 2000-03-25 2002-02-21 Univ Manchester Traitement de troubles des mouvements
EA007464B1 (ru) * 2000-10-02 2006-10-27 Янссен Фармацевтика Н.В. Антагонисты метаботропных рецепторов глутамата
JP2004510764A (ja) * 2000-10-02 2004-04-08 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 代謝共役型グルタミン酸受容体拮抗剤
US7629468B2 (en) 2000-10-02 2009-12-08 Janssen Pharmaceutica Nv Metabotropic glutamate receptor antagonists
US7115630B2 (en) 2000-10-02 2006-10-03 Janssen Pharmaceutica N.V. Metabotropic glutamate receptor antagonists
WO2002028837A1 (fr) * 2000-10-02 2002-04-11 Janssen Pharmaceutica N.V. Antagonistes du récepteur métabotrope du glutamate
US7179839B2 (en) 2001-02-13 2007-02-20 Sanofi-Aventis Deutschland Gmbh Acylated indanyl amines and their use as pharmaceuticals
US8163751B2 (en) 2001-02-13 2012-04-24 Sanofi-Aventis Deutschland Gmbh Acylated indanyl amines and their use as pharmaceuticals
JP2004518719A (ja) * 2001-02-13 2004-06-24 アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング アシル化インダニルアミンおよび医薬としてのその使用
US7713963B2 (en) 2001-02-13 2010-05-11 Sanofi-Aventis Deutschland Gmbh Acylated indanyl amines and their use as pharmaceuticals
WO2002064545A1 (fr) 2001-02-13 2002-08-22 Aventis Pharma Deutschland Gmbh Amines indanyle acyles et leurs utilisation comme agents pharmaceutiques
WO2003027068A3 (fr) * 2001-09-24 2004-04-08 Elan Pharm Inc Amines substituees pour le traitement de la maladie d'alzheimer
US7517517B2 (en) 2002-03-29 2009-04-14 Janssen Pharmaceutica N.V. Radiolabelled quinoline and quinolinone derivatives and their use as metabotropic glutamate receptor ligands
JP2005524679A (ja) * 2002-03-29 2005-08-18 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 放射能標識付きキノリンおよびキノリノン誘導体および代謝向性グルタメート受容体リガンドとしてのそれらの使用
EA009334B1 (ru) * 2002-03-29 2007-12-28 Янссен Фармацевтика Н.В. Меченные радиоактивными изотопами производные хинолина и их применение в качестве лигандов метаботропного глутаматного рецептора
AU2003226737B2 (en) * 2002-03-29 2008-09-04 Janssen Pharmaceutica N.V. Radiolabelled quinoline and quinolinone derivatives and their use as metabotropic glutamate receptor ligands
WO2003082350A3 (fr) * 2002-03-29 2004-03-04 Janssen Pharmaceutica Nv Derives radiomarques de quinoline et de quinolinone et leur utilisation en tant que ligands du recepteur metabotropique du glutamate
KR101061561B1 (ko) * 2002-03-29 2011-09-02 얀센 파마슈티카 엔.브이. 대사자극성 글루타메이트 수용체 리간드로서 방사능표지된 퀴놀린 및 퀴놀리논 유도체 및 그의 용도
WO2004014881A3 (fr) * 2002-08-09 2004-05-27 Astrazeneca Ab Nouveaux composes
RU2352568C9 (ru) * 2002-08-09 2009-06-27 Астразенека Аб [1,2,4]оксадиазолы (варианты), способ их получения, фармацевтическая композиция и способ ингибирования активации метаботропных глютаматных рецепторов-5
RU2352568C2 (ru) * 2002-08-09 2009-04-20 Астразенека Аб [1,2,4]оксадиазолы (варианты), способ их получения, фармацевтическая композиция и способ ингибирования активации метаботропных глютаматных рецепторов-5
US7456200B2 (en) 2002-08-09 2008-11-25 Astrazeneca Ab Compounds
EA009710B1 (ru) * 2002-12-23 2008-02-28 Янссен Фармацевтика Н.В. Адамантилацетамиды как ингибиторы 11-бета гидроксистероиддегидрогеназы
US7968601B2 (en) 2002-12-23 2011-06-28 Janssen Pharmaceutica N.V. Adamantyl acetamides as 11-β hydroxysteroid dehydrogenase inhibitors
WO2004056745A3 (fr) * 2002-12-23 2004-11-11 Janssen Pharmaceutica Nv Acetamides d'adamantyle utiles comme inhibiteurs de la deshydrogenase 11-beta hydroxysteroide
US7332524B2 (en) 2002-12-23 2008-02-19 Janssen Pharmaceutica N.V. Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors
HRP20050666B1 (hr) * 2002-12-24 2009-05-31 Euro-Celtique S.A. Benzoazolilpiperazinski derivati koji imaju aktivnost vr1 antagonista
US9434721B2 (en) 2002-12-24 2016-09-06 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8604037B2 (en) 2002-12-24 2013-12-10 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
US8536177B2 (en) 2002-12-24 2013-09-17 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8008300B2 (en) 2002-12-24 2011-08-30 Purdue Pharma L.P. Therapeutic agents useful for treating pain
WO2004058754A1 (fr) * 2002-12-24 2004-07-15 Euro-Celtique S.A. Derives de benzoazolylpiperazine presentant une activite antagoniste vis-a-vis de mglur1 et de mglur5
US7582635B2 (en) 2002-12-24 2009-09-01 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
WO2004069813A1 (fr) * 2003-01-31 2004-08-19 Astrazeneca Ab Derives de quinoxaline satures et leur utilisation en tant que ligands du recepteur du glutamate metabotropique
US7408065B2 (en) 2003-06-02 2008-08-05 Astrazeneca Ab P2X7 receptor antagonists and their use
US7476399B2 (en) 2003-08-06 2009-01-13 Senomyx Inc. Flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
US8124121B2 (en) 2003-08-06 2012-02-28 Senomyx, Inc. Flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
US10060909B2 (en) 2003-08-06 2018-08-28 Senomyx, Inc. Flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
US10557845B2 (en) 2003-08-06 2020-02-11 Firmenich Incorporated Flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
US11268952B2 (en) 2003-08-06 2022-03-08 Firmenich Incorporated Flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
US7501416B2 (en) 2004-02-06 2009-03-10 Bristol-Myers Squibb Company Quinoxaline compounds and methods of using them
US9776965B2 (en) 2004-05-07 2017-10-03 Janssen Pharmaceutica Nv Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9302987B2 (en) 2004-05-07 2016-04-05 Janssen Pharmaceutica N.V. Pyrrolidinyl derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9012494B2 (en) 2004-05-07 2015-04-21 Janssen Pharmaceutica N.V. Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
WO2006020879A1 (fr) * 2004-08-13 2006-02-23 Astrazeneca Ab Composes a base d'isoindolone et leur utilisation comme potentialisateurs du recepteur metabotropique du glutamate
US7968570B2 (en) 2004-08-13 2011-06-28 Astrazeneca Ab Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
EA012263B1 (ru) * 2004-08-30 2009-08-28 Янссен Фармацевтика Н.В. Производные n-2-адамантанил-2-феноксиацетамида в качестве ингибиторов 11-бета-гидроксистероид-дегидрогеназы
US9630921B2 (en) 2004-08-30 2017-04-25 Janssen Pharmaceutica Nv Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
WO2006024627A3 (fr) * 2004-08-30 2007-09-13 Janssen Pharmaceutica Nv Derives d'acetamides n-2 adamantanyl-2-phenoxy utilises en tant qu'inhibiteurs de la deshydrogenase 11-beta hydroxysteroide
US8563591B2 (en) 2004-08-30 2013-10-22 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9150512B2 (en) 2004-08-30 2015-10-06 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US8344181B2 (en) 2004-08-30 2013-01-01 Janssen Pharmaceutica N.V. N-2 adamantanyl-2-phenoxy-acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9422284B2 (en) 2004-08-30 2016-08-23 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US8968708B2 (en) 2005-02-04 2015-03-03 Senomyx, Inc. Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions
US8784782B2 (en) 2005-02-04 2014-07-22 Senomyx, Inc. Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions
US7915448B2 (en) 2005-03-17 2011-03-29 Pfizer Inc. Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as VR1 receptor antagonists
US7622589B2 (en) 2005-03-17 2009-11-24 Pfizer Inc. Substituted sulfonylaminoarylmethyl cyclopropanecarboxamide as VR1 receptor antagonists
US7842324B2 (en) 2005-06-15 2010-11-30 Senomyx, Inc. Bis-aromatic amides and their uses as sweet flavor modifiers, tastants, and taste enhancers
USRE49811E1 (en) 2005-06-17 2024-01-23 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
RU2447060C2 (ru) * 2005-06-17 2012-04-10 Эпоуджи Биотекнолоджи Корпорейшн Ингибиторы сфингозинкиназы
EP2314574A1 (fr) * 2005-06-17 2011-04-27 Apogee Biothechnology Corporation Inhibiteurs de la sphingosine kinase
US8557800B2 (en) 2005-06-17 2013-10-15 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
US7338961B2 (en) 2005-06-17 2008-03-04 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
WO2006138660A3 (fr) * 2005-06-17 2007-07-19 Apogee Biotechnology Corp Inhibiteurs de la sphingosine kinase
AU2006261327B2 (en) * 2005-06-17 2012-07-05 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
US8063248B2 (en) 2005-06-17 2011-11-22 Apogee Biotechnology Corporation Sphingosine kinase inhibitors
US8153638B2 (en) 2005-08-12 2012-04-10 Astrazeneca Ab Metabotropic glutamate-receptor-potentiating isoindolones
US7868008B2 (en) 2005-08-12 2011-01-11 Astrazeneca Ab Substituted isoindolones and their use as metabotropic glutamate receptor potentiators
WO2007021308A1 (fr) * 2005-08-12 2007-02-22 Astrazeneca Ab Isoindolones potentiateurs du récepteur glutamate métabotropique
US7807706B2 (en) 2005-08-12 2010-10-05 Astrazeneca Ab Metabotropic glutamate-receptor-potentiating isoindolones
WO2007021309A1 (fr) * 2005-08-12 2007-02-22 Astrazeneca Ab Isoindolones substitués et leur utilisation comme potentiateurs métabotropiques du récepteur glutamate
WO2007037543A1 (fr) * 2005-09-29 2007-04-05 Banyu Pharmaceutical Co., Ltd. Dérivé de biarylamide
WO2007045876A1 (fr) * 2005-10-21 2007-04-26 Merz Pharma Gmbh & Co. Kgaa Chromenones et leur utilisation en tant que modulateurs des recepteurs metabotropes au glutamate
WO2007071358A1 (fr) * 2005-12-20 2007-06-28 Novartis Ag Dérivés d'acide nicotinique en tant que modulateurs des récepteurs métabotropiques du glutamate
WO2007095024A1 (fr) 2006-02-16 2007-08-23 Astrazeneca Ab Isoindolones activant le récepteur métabotropique du glutamate
US9072313B2 (en) 2006-04-21 2015-07-07 Senomyx, Inc. Comestible compositions comprising high potency savory flavorants, and processes for producing them
US7947689B2 (en) 2006-08-04 2011-05-24 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-a]pyrimidines as metabotropic glutamate receptor modulators
US7985753B2 (en) 2006-08-04 2011-07-26 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-A]pyrimidines as metabotropic glutamate receptor modulators
US7964732B2 (en) 2006-11-17 2011-06-21 Pfizer Inc. Substituted bicyclocarboxyamide compounds
EP2578216A1 (fr) 2006-11-22 2013-04-10 Seaside Therapeutics, Inc. Procédés de traitement du syndrome de l'X fragile
EP2567696A1 (fr) 2006-11-22 2013-03-13 Seaside Therapeutics, Inc. Procédés de traitement du retard mental, du syndrome de Down, du syndrome de l'X fragile et de l'autisme
US7964616B2 (en) 2007-03-22 2011-06-21 Astrazeneca Ab Compounds 679
US7511033B2 (en) 2007-04-19 2009-03-31 Hoffmann-La Roche Inc. Dihydro-benzo[B][1,4]diazepin-2-one sulfonamide derivatives
US8377939B2 (en) 2007-06-07 2013-02-19 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators 842
US8377940B2 (en) 2007-06-07 2013-02-19 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators—842
EP2064959A1 (fr) 2007-10-31 2009-06-03 Symrise GmbH & Co. KG Néomenthylamides aromatiques en tant qu'agents aromatisants
US8106073B2 (en) 2007-11-30 2012-01-31 Astrazeneca Ab Quinoline derivatives 057
US8148372B2 (en) 2008-06-06 2012-04-03 Astrazeneca Ab Metabotropic glutamate receptor isoxazole ligands and their use as potentiators—286
US8415333B2 (en) 2009-02-24 2013-04-09 Respiratorious Ab Bronchodilating diazaheteroaryls
WO2010101648A1 (fr) * 2009-03-06 2010-09-10 Wood Richard D Modulateurs des récepteurs au glutamate et agents thérapeutiques
WO2011109398A2 (fr) 2010-03-02 2011-09-09 President And Fellows Of Harvard College Procédés et compositions pour le traitement du syndrome d'angelman et des troubles du spectre autistique
WO2011150380A1 (fr) 2010-05-28 2011-12-01 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et des troubles associés
WO2012009646A1 (fr) 2010-07-15 2012-01-19 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et de troubles associés
EA023763B1 (ru) * 2010-11-30 2016-07-29 Байер Интеллектчуал Проперти Гмбх Производные пиримидина и их применение в качестве пестицидов
AU2011335158B2 (en) * 2010-11-30 2016-09-15 Bayer Intellectual Property Gmbh Pyrimidine derivatives and use thereof as pesticides
WO2012072547A1 (fr) * 2010-11-30 2012-06-07 Bayer Cropscience Ag Dérivés pyrimidiques et leur utilisation comme agents de lutte antiparasitaire
US9241487B2 (en) 2010-11-30 2016-01-26 Bayer Intellectual Property Gmbh Pyrimidine derivatives and use thereof as pesticides
CN114539170A (zh) * 2021-12-31 2022-05-27 华南农业大学 一种用于同时检测金刚烷胺、喹乙醇、氯霉素的半抗原、人工抗原及其制备方法和应用

Also Published As

Publication number Publication date
AU2004202776A2 (en) 2004-07-22
EP1037878A2 (fr) 2000-09-27
CN1158264C (zh) 2004-07-21
WO1999026927A3 (fr) 1999-10-21
IL136250A (en) 2006-12-10
NZ505207A (en) 2003-10-31
AU2004202776A1 (en) 2004-07-22
AU2004202776B2 (en) 2008-06-19
CN1285820A (zh) 2001-02-28
IL136250A0 (en) 2001-05-20
AU771358B2 (en) 2004-03-18
MXPA00004940A (es) 2002-10-17
JP2001524468A (ja) 2001-12-04
AU1531799A (en) 1999-06-15
CA2311131A1 (fr) 1999-06-03
CN1554649A (zh) 2004-12-15

Similar Documents

Publication Publication Date Title
EP1037878A2 (fr) Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central
US6429207B1 (en) Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
AU778063B2 (en) Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
US10899714B2 (en) 6-aminoisoquinoline compounds
AU2005200634A1 (en) Tumor necrosis factor receptor-derived peptide analogues
US8034943B2 (en) 6-aminoisoquinoline compounds
DE60033689T2 (de) Inhibitoren von serinproteasen
AU2006239547B2 (en) Acetylene derivatives
JP2020524158A (ja) Ｓｓａｏ阻害剤
NZ323387A (en) Quinoline derivatives having neurokinin antagonist activity, preparation and use thereof
US6392053B2 (en) Process for preparing arylacetylaminothiazoles
DE69132689T2 (de) Biologisch aktive amine
AU2001257493A1 (en) Process for preparing arylacetylaminothiazoles
MXPA00000940A (en) Haze free polyether polyol compositions and a method for their preparation
WO2019154380A1 (fr) Inhibiteur de la voie de la kynurénine
HK1052929B (en) Process for preparing arylacetylaminothiazoles

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 136250

Country of ref document: IL

Ref document number: 98813148.X

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

ENP Entry into the national phase

Ref document number: 2311131

Country of ref document: CA

Ref document number: 2311131

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/004940

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: KR

ENP Entry into the national phase

Ref document number: 2000 522085

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15317/99

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 505207

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1998959535

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1998959535

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 15317/99

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 178023

Country of ref document: IL