EP1037878A2 - 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

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Publication number
EP1037878A2
EP1037878A2 EP98959535A EP98959535A EP1037878A2 EP 1037878 A2 EP1037878 A2 EP 1037878A2 EP 98959535 A EP98959535 A EP 98959535A EP 98959535 A EP98959535 A EP 98959535A EP 1037878 A2 EP1037878 A2 EP 1037878A2
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EP
European Patent Office
Prior art keywords
adamantyl
group
ethanone
compound according
carboxamιde
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98959535A
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German (de)
English (en)
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
NPS Pharmaceuticals Inc
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Publication date
Application filed by NPS Pharmaceuticals Inc filed Critical NPS Pharmaceuticals Inc
Publication of EP1037878A2 publication Critical patent/EP1037878A2/fr
Withdrawn legal-status Critical Current

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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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.

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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.
EP98959535A 1997-11-21 1998-11-20 Antagonistes des recepteurs du glutamate metabotropes, utilises pour le traitement de maladies du systeme nerveux central Withdrawn EP1037878A2 (fr)

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MXPA00004940A (es) 2002-10-17
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IL136250A (en) 2006-12-10
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AU2004202776A1 (en) 2004-07-22
IL136250A0 (en) 2001-05-20
CN1554649A (zh) 2004-12-15
AU2004202776B2 (en) 2008-06-19
CN1285820A (zh) 2001-02-28
JP2001524468A (ja) 2001-12-04
WO1999026927A2 (fr) 1999-06-03
NZ505207A (en) 2003-10-31
WO1999026927A3 (fr) 1999-10-21
AU2004202776A2 (en) 2004-07-22
AU1531799A (en) 1999-06-15

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