EP1037878A2 - Metabotropic glutamate receptor antagonists for treating central nervous system diseases - Google Patents

Metabotropic glutamate receptor antagonists for treating central nervous system diseases

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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Withdrawn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
Other languages
German (de)
French (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
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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Filing date
Publication date
Application filed by NPS Pharmaceuticals Inc filed Critical NPS Pharmaceuticals Inc
Publication of EP1037878A2 publication Critical patent/EP1037878A2/en
Withdrawn legal-status Critical Current

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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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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
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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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    • 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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    • 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
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    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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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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    • C07D233/54—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
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    • 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
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    • 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
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    • 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
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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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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    • 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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    • C07D491/00—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.

Abstract

The present invention provides compounds, and pharmaceutical compositions containing those compounds, that act as antagonists at metabotropic glutamate receptors. The compounds are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.

Description

METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS FOR TREAΗNG CENTRAL NERVOUS SYSTEM DISEASES
FIELD OF THE INVENTION
The present invention provides compounds active at metabotropic glutamate receptors and that are useful for treating neurological and psychiatric diseases and disorders. 5
BACKGROUND OF THE INVENTION Recent advances in the elucidation ot the neurophysiological roles ot metabotropic glutamate receptors have established these receptors as promising drug targets in the therapy of acute and chronic neurological and psychiatric 10 disorders and diseases. However, the major challenge to the realization of this promise has been the development ot metabotropic glutamate receptor subtvpe- selective compounds.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate produces its effects on central neurons
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.
The metabotropic glutamate receptors (mGluRs) are G protein-coupled
20 receptors that activate a variety ot intracellular second messenger systems following the binding ot glutamate. Activation ot mGluRs in intact mammalian neurons elicits one or more of the following responses: activation ot phosphohpase C. 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. Schoepp et al.. Trends Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem. Int. 24:439 (1994); Pm et aL. Neuropharmacology 34: 1 (1995).
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. 267: 13361 (1992); Minakami et al., BBRC 799: 1136 (1994); Joly et al., J. Neurosci. 75:3970 ( 1995). Alternatively, agonist activation of recombinant mGluRl receptors expressed in Chinese hamster ovary (CHO) ceils stimulates PI hydrolysis, cAMP formation, and arachidonic acid release as measured by standard biochemical assavs. Aramoπ et al.. Neuron 8.757 (1992) 99/26927
In comparison, activation of mGluR5 receptors expressed in CHO cells stimulates PI hydrolysis and subsequent intracellular calcium transients, but no stimulation ot cAMP formation or arachidonic acid release is observed. Abe et al.. J. Biol. Chem. 267: 13361 ( 1992). However, activation of mGluR5 receptors expressed in LLC-PK1 ceils results in PI hydrolysis and increased cAMP formation. Joly et al.. J. Neurosci. 15:3970 (1995). The agonist potency profile for Group I mGluRs is quisquaiate > glutamate = lbotenate > (2S,l 'S,2'S)-2- carboxycyciopropyDglycine (L-CCG-I) > (7S,JRj-l-ammocyclopentane-l,3- dicarboxyhc acid (ACPD). 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).
The lack of subtype-specific mGluR agonists and antagonists has impeded elucidation of the physiological roles of particular mGluRs. and the mGIuR- associated pathophysiological processes that affect the CNS have yet to be defined. However, work with the available non-specific agonists and antagonists has yielded some general insights about the Group I mGluRs as compared to the Group II and Group III mGluRs.
Attempts at elucidating the physiological roles of Group I mGluRs suggest that activation of these receptors elicits neuronal excitation. Various studies have demonstrated that ACPD can produce postsynaptic excitation upon application to neurons in the hippocampus, cerebral cortex, cerebellum, and thalamus. as well as other brain regions. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested that activation of presynaptic mGluRs occurs, resulting in increased neurotransmitter release. Baskys, Trends Pharmacol. Sci. 15:92 (1992); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34: 1(1995).
Pharmacological experiments impiicate Group I mGluRs as the mediators of mis excitatory mechanism. The effects of ACPD can be reproduced by low concentrations of quisquaiate in the presence of iGIuR antagonists. Hu et al.. Brain Res. 568:339 (1991), Greene et al., Eur. J. Pharmacol. 226:279 (1992). Two phenylglycine compounds known to activate mGluRl, namely (S)-3- hydroxyphenyiglycine ((S)-3HPG) and rSJ-3,5~dιhydroxyphenylglycιne ( (S)- DHPG), also produce excitation. Waϋαns et al.. Trends Pharmacol. Sci. 15:33 (1994). In addition, the excitation can be blocked by SJ-4-carboxyphenylglycme (rø-4CPG), rø-4-carboxv-3-hydroxyphenyiglycιne ( fSJ-4C3HPG), and ( + )- alpha-methyl-4-carboxyphenyiglycme ((+)-MCPG), compounds known to be mGluRl antagonists. Eaton et al.. Eur. J. Pharmacol. 244: 195 (1993); Watkins et al.. Trends Pharmacol. Sci. 15:333 (1994).
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 potentiaπon 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 nocicepπon and analgesia also has been demonstrated. Meller et ai. Neuroreport 4: 879 (1993). In addition. mGluR activation has been suggested to play a modulatory role in a vaπetv 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. For reviews, see Nakanishi, Neuron 13: 1031 ( 1994); Pin et ai , Neuropharmacology 34: 1; Knopfel et ai, J. Med. Chem. 38: 1417 (1995). 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). Much of the pathology in these conditions is thought to be due to excessive glutamate-induced excitation of CNS neurons. Because 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. Lett. 7J9:77 ( 1992); Lφpara et al.. Life Sci. 52:85 (1993). Other studies indicate, however, that ACPD inhibits epileptiform activity, and also can exhibit neuroprotecπve properties. Taschenberger et ai, Neuroreporτ 3:629 ( 1992): Sheardown, Neuroreport 3:916 (1992); Koh et al., Proc. Natl. Acad. Sci. USA 88:943\ (1991); Chiamulera et al., Eur. J. Pharmacol. 216:335 (1992); Siliprandi et al., Eur. J. Pharmacol. 219: 173 (1992); Pizzi et al., J. Neurochem. 61:683 (1993).
It is likely that these conflicting results are due to the lack of selectivity of ACPD, which causes activation of several different mGluR subtypes. In the studies finding neuronal damage it appears that Group I mGluRs were activated. thereby enhancing undesirable excitatory neurotransmission. In the studies showing neuroprotective effects it appears that activation of Group II and/or Group III mGluRs occurred, inhibiting presynapuc glutamate release, and diminishing excitatory neurotransmission.
This interpretation is consistent with the observation that (S)-4C3UPG. a Group I mGluR antagonist and Group II mGluR agonist, protects against audiogemc seizures in DBA/2 mice, while the Group II mGluR selective agonists DCG-IV and L-CCG-I protect neurons from NMDA- and KA-induced toxicity. Thomsen et ai. J. Neurochem. 62:2492 (1994); Bruno et al.. Eur. J. Pharmacol. 256: 109 ( 1994); Pizzi et al.. J. Neurochem. 67:683 (1993). Based on the foregoing, it is clear that currently available mGluR agonists and antagonists have limited value, due to their lack of potency and selectivity. In addition, most currently available compounds are amino acids or amino acid derivatives that have limited bioavailabilities, thereby hampering in vivo studies to assess mGluR physiology, pharmacology and their therapeutic potential. Compounds that selectively inhibit activation of metabotropic glutamate receptor Group I subtypes should be useful for treatment of neurological disorders and diseases such as senile dementia, Parkinson's disease. Alzheimer's disease. Huntington's Chorea, pain, epilepsy, head trauma, anoxic and ischemic injuries, and psychiatric disorders such as schizophrenia and depression. ,„,„„_, /26927
It is apparent, therefore, that identification of potent mGluR agonists and antagonists with high selectivity for individual mGluR subtvpes. particularly tor Group I receptor subtypes, are greatly to be desired.
SUMMARY OF THE INVENTION
It is an object of the present invention, therefore, to identify metabotopic glutamate receptor-active compounds which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods of making these compounds. It is a further object of this invention to provide pharmaceutical compositions containing compounds which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods of making these pharmaceutical compositions.
It is yet another object of this invention to provide methods of inhibiting activation of an mGluR Group I receptor, and of inhibiting neuronal damage caused by excitatory activation of an mGluR Group 1 receptor.
It is still another object of the invention to provide methods of treating a disease associated with giutamate-induced neuronal damage.
To accomplish these and other objectives, 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. Two heteroatoms in the [linker] may not be adjacent except when those atoms are both N or are both NH. Two adjacent CH2 groups in [linker] also may be replaced by a substituted or unsubstituted alkene or alkyne group. Pharmaceutically acceptable salts of the compounds also are provided. In one embodiment ot the invention. Ar comprises a ring system selected from the group consisting of benzene, thiazole. furyl, pyranvl, 2H-pyrroiyl. thienyl, pyrrolyl, lmidazolyi, pyrazoiyl, pyπdyi. pyrazinyl. pyπmidinyl, pyπdazinyi benzothiazole. benzimidazole. 3H-ιndolyl. indolyl. indazoiyl. puπnyl, quinoiizinyl, isoquinoiyl, quinolyl, phmalizmyl, naphthyπdinyi, qumazoiinyl. ciπnolinyl, isothiazoiyi, quinoxa nyl indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, and chromenyl rings. 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. In another embodiment of the invention, R contains 4, 5, 6, 7, 8, 9, 10 or
11 carbon atoms, where some or all of the hydrogen atoms on two carbon atoms optionally may be replaced with substituents independently selected from the group consisting of F. Cl, OH. OMe, =O, and -COOH.
In yet another embodiment [linker] comprises an amide, ester, or thioester group.
In a preferred embodiment. R comprises a moiety selected from the group consisting of substituted or unsubstituted adamantyi, 2-adamantyl, (1S.2S.3S.5R)- isopinocamphenyl, tπcyclo[4 3.1. l(3,8)]undec-3-yi, (lS.2R.5S)-cu'-myrtany!, (lR,2R.4S)-ιsobornyi, (lR.2R.3R,5S)-ιsopιnocamphenyl, ( lS.2S.5S)-trα/z - myπanyl, (lR,2R.5R)-trα/J5-myrtanyl, (lR,2S,4S)-bornyl, 1-adamantanemethyl. 3-noradamantyl, (lS,2S.3S.5R)-3-pιnanemethyl. cyclooctyl, α.α- dimethylphenethyl. (S)-2-phenyl-l-propyl. cycloheptyl. 4-methyl-2-hexyl groups. 2,2,3,3,4.4,4-heptafluorobutyl. 4-ketoadamantyl, 3-phenyi-2-methylpropyl. 3.5- dimethyladamantyl. trøΛ5-2-phenylcyciopropyi, 2-methylcyclohexyl. 3.3.5- tπmethylcyciohexyl, 2-(ø-methoxyphenyl)ethyl, 2-(l,2,3,4-tetrahydronaphthyi). 4-phenylbutyl, 2-methyl-2-phenyibutyl, 2-(w-fluorophenyl)ethyi, 2-(p- fluorophenyl)ethyl, 2-(3-hydroxy-3-phenyi)propyl, (S)-2-hydroxy-2-phenylethyl, (R)-2-hydroxy-2-phenyiethyl, 2-(3-/w-chlorophenyl-2-methyl)propyl, 2-(3-p- chlorophenyi-2-methyl)propyl, 4-tert-butyl-cyclohexyl, (S)-l-(cyclohexyl)ethyl. 2-(3-(3,4-dιmethylphenyl)-2-methyi)propyl, 3,3-dιmethylbutyl, 2-(5- methyDhexyl, 1-myrtanyi, 2-bornyl, 3-pιnanemethyI, 2.2,3,3,4.4,5.5- octafluoropeπtyl. -fiuoro-α.α-dimethyiphenethyl, 2-naphthyl, 2-bornanyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3.4- dimethylcyclohexyl, 5-chloro-tπcyclo[2.2.1]heptyl, o-α,α-dιmethylphenemyI, 2- mdanyl, 2-spιro[4.5]decyl. 2-phenyiethyl, 1-adamantylethyi. 1-(1- bicyclo[2.2. l]hept-2-yl)ethyl. 2-(2-methyl-2-phenylpropyl), 2-(o- fluoropheny ethyl. l-(cyclohexyi)ethyl, and cyclohexyl.
In a still further embodiment of the invention. Ar comprises a group having the formula
where X'. X2, X'. and X* independently can be N or CH, provided that not more than two of X1. X2. X\ and X4 can be N. In a preferred embodiment. X1 is N. and/or X2 is N. In another embodiment. X3 is N. In still another embodiment. X1 is CH and X2 is N.
In yet another embodiment, 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-MethylquιnolyI)]-l- adamantanecarboxamide. Λ'-(6-Quιnolyl)-l-adamantanecarboxamιde. .V-(2- Quinolyl)- 1 -adamantanecarboxamide, yV-(3-Quιnoly 1)- 1 -adamantane-carboxamide. 6-Quιnolyl- 1 -adamantanecarboxyiate. 1 -Adamanty 1-6-quιnolinecarboxylate. 2,2,3.3,4,4,5.5-Octafiuoro-i-pentyl-6-quιnolinecarboxyiate. 1- Adamantanemethyl-6-quιnolιnecarboxylate. l-Adamantyi-2- quinoxalinecar boxy late. ;V-(l-AdamantyI)-3-quιnoiine-carboxarnιde. 7V-( 1 - Adamantyl)-2-quιnoiinecarboxamιde, 7V-(2-Adamantyl)-2- quinoxaiinecarboxamide. .V-[(lR,2R,3R,5S)-3-Pinanemethyl]-2-quιnoxahne- carboxamide, 7V-(1- Adamanty l)-2-quιnoxaIinecarboxamide. 7V-( 1- Adamanty l)-6- quinolinecarboxamide, .V-(e.vo-2-Norbornanyl)-2-quιnoxaIinecarboxamιde. N- [(lR,2S,4S)-Bornyl]-2-quιnoxalinecarboxamide, iV-(3-Noradamantyl)-2- quinoxalinecarboxamide, 7V-[(lR,2R,3R,5S)Iso-pιnocamphenyi]-2- quinoxalinecarboxamide, /V-[(lS,2S,3S.5R)-Isopιnocamphenyl]-2-quιnoxalιne- carboxamide, ;V-(5-Chloro-[2.2.1.0]tπcyclo-2.6-hepta-3-yl)-2- quinoxalinecarboxamide. .V-([4.3.1.1 )Tricyclo-3.8-undeca-3-yl)-2- quinoxalinecarboxamide. Λ'-[(lS.2R,5S)-cw-Myrtanyi]-2- quinoxaiinecarboxamide. Λ'-[( 1 R.2R.4S)Isobornyl]-2-quιnoxalιnecarboxamιde. yV-[endo-( ±)-2-Norbornanyi]-2-quιnoxaiιnecarboxamιde. 7V-[(R)-2-PhenyI-l propyl]-2-quιnoxalιnecarboxamιde, 7V-[(S)-2-Phenyl-l-propyl]-2- quinoxalinecarboxamide, ;V-(2-Indanyi)-2-quιnoxalιnecarboxamιde. 1-Adamantanemethyl 6-quιnolyl ether. 1 -Adamanty l-3-quιnolιnecarboxy late. ,V- (α,α-Dιmethylphenethyl)-2-quιnoxahnecarboxamιde. .'V-(α,α-Dιmethvi-2- chlorophenethyl)-2-quιnoxahnecarboxamιde. 7V-(α,α-Dιmethyl-4- fluorophenethyl)-2-quιnoxalιnecarboxamιde. .V-(β-MedιyIphenethyl)-2- qumoxaimecarboxamide, Λ^3-Methylcyclohexyl)-2-quιnoxalιnecarboxamιde, N- (2,3-Dimethylcyclohexyi)-2-quιnoxalinecarboxamιde. 7V-[(lS,2S,3S,SR)-3- Pinanemethyl]-2-quιnoxaiιne-carboxamιde, N-(l-Adamantanemethyl)-2- quinoxaline-carboxamide. 7V-(4-Methylcyclohexyi)-2-quιnoxalιne-carboxamιde. 7V-[(lS,2S.5S)-trα/w-Myrtanyl]-2-quιnoxaiιne-carboxamιde. and 7V-[(1R.2R.5R)- trø/w-Myπanyl]-2-quιnoxalιnecarboxamιde. and pharmaceutically acceptable salts thereof. In a preferred embodiment, the compound is selected from the group consisting of 7V-(l-Adamantyl)-3-quιnolmecarboxamιde. 7V-(l-Adamantyl)-2- quinohnecarboxamide. /V-(2-Adamantyl)-2-quιnoxalιne-carboxamιde. Λ- [(lR.2R,3R.5S)-3-Pιnanemethyl]-2-quιnoxahne-carboxamιde. Λ-( l-Adamantyi)- 2-qumoxalιne-carboxamιde. .V-( l-Adamantyl)-6-quιnohnecarboxamιde. N-(ew-2- orbornanyl)-2-quιnoxalιne-carboxamιde. .V-[(lR.2S,4S)-Bornyl]-2-quιnoxalιne- carboxamide, Λ-(3-Noradamantyi)-2-quιnoxalιne-carboxamιde. .V- [(lR.2R,3R,5S)-Isopιnocamphenyl]-2-quιnoxaiιne-carboxamιde, N- [(lS.2S,3S,5R)-Isopιnocamphenyl]-2-quιnoxaIιne-carboxamιde. 7V-(5-Chloro- [2.2.1.0]tπcyclo-2,6-hepta-3-yl)-2-quιnoxalιne-carboxamιde. N- ([4.3.1.1]Tπcyclo-3,8-undeca-3-yl)-2-quιnoxahne-carboxamιde. 7V-[(1S.2R.5S)- αϊ-Myrtanyl]-2-quιnoxaiιne-carboxamιde. N-[( 1 R.2R.4S)Isobornyl)-2- quinoxaiine-carboxamide, 7V-[e/jώ>-( ±)-2-Norbornanyl]-2-quιnoxalιne- carboxamide, /V-[(lS,2S,3S,5R)-3-Pinanemethyl]-2-qumoxalinecarboxamιde, 7V- (l-Adamantanemethyl)-2-quιnoxalinecarboxamιde, N-[(lS,2S,5S)-trans- Myrtanyl]-2-quιnoxalιnecarboxamιde, and 7V-[(lR,2R,5R)-tr-zw-Myrtanyl]-2- quinoxalinecarboxamide. and pharmaceutically acceptable salts thereof
In another embodiment, the compound is selected from the group consisting of /V-[6-(2-Methylquιnolyl)]-l-adamantanecarboxamιde. Λ'-(6- Quinoly -l-adamantane-carboxamide. /V-(2-Quιnolyl)-l-adamantanecarboxamιde. and 7V-(3-QuιnolyI)-l-adamantanecarboxamιde. 7V-(3-Methylcyclohexyl)-2- quinoxalinecarboxamide. /V-(2,3-DιmethylcycIohexyi)-2-quιnoxalinecarboxamιde. V-[(lS,2S.3S.5R)-3-Pinanemethyl]-2-quιnoxaiinecarboxamιde. N-(l- Adamantanemethyl)-2-quιnoxalinecarboxamιde, and 7V-(4-Methylcyclohexyi)-2- quinoxaiinecarboxamide. .V-[(R)-2-Phenyi-l-propyi-2-quιnoxaiιnecarboxamιde. N-[(S)-2-Pheny 1- 1 -propyl]-2-quιnoxaiιnecarboxamιde. /V-(2-Indanyl)-2- quinoxaiinecarboxanπde, ΛA(α-α-Dimethylphenethyi)-2-quιnoxaiinecarboxamιde. 7V-(α,α-Dimethyl-2-chlorophenethyl)-2-quinoxaiinecarboxamide. N-( ,a- Dimethyl-4-fIuorophenethyl)-2-quιnoxaline-carboxamιde, and 7V-(β- Methyiphenethyl)-2-quιnoxaline-carboxamide, 1-AdamantanememyI 6-quιnolyl ether, 6-Quιnolyl-l -adamanianecarboxvlate. l-Adamantyl-6-quιnolinecarboxyiate. 2.2,3.3,4,4.5.5-Octafluoro-l-pentyl 6-quιnolιnecarboxylate. 1- Adamantanemethyl 6-quιnolιnecarboxylate. l-Adamantyl-2- quinoxalinecarboxylate. and l-Adamantyl-3-quinolmecarboxylate. and pharmaceutically acceptable salts thereof.
In yet another embodiment, the compound is selected from the group consisting of 3-(l-Adamantanemethoxy)-2-chloroquιnoxaline, 2-(l- Adamantanemethoxy)-3-methylquιnoxaline, 3-(l-Adamantanemethoxy)-2- fluoroquinoxaline. 2-(l-Adamantanemethoxy)-3-tπfluoromethylquιnoxalιne. Λ- [2-(4-Phenylthιazolyl)]- l-adamantanecarboxamιde, .V-[2-(5-Methyl-4- phenylthiazolyl)]-l-adamantanecarboxamιde. 1-( 1 -Adamanty l)-2-(benzothιazol-2- ylsuifany ethanone. 7V-(l-Adamantyl)-2-chloroquιnoxalιne-3-carboxamιde. .V-( l- Adamantyl)-3-methylquιnoxaline-2-carboxamide, and 7V-(1-Adamantyl)-1- oxyquinoxalιne-3-carboxamιde, 4-Chlorophenyl 3-coumaπncarboxyiate, 2-(l- Adamantanemethylsulfany quinoxaline, 3-(l-Adamantanemethoxy)-2- chloropyrazine, l-( l-Adamantyl)-2-(4, 6-dimethylpyπmidin-2- ylsulfany ethanone, l-( l-Adamantyl)-2-(2-anιsylsulfanyl)ethanone. 3-( 1- Adamantanemethoxy) - 1 H-qu ιnoxaiin-2 -one , 1 -( 1 -Adamanty I) -2 -( 3 - anisylsuifanyl)ethanone, 1 -( 1 -Adamanty i)-2-(4-anιsylsulfanyi)ethanone, 1 -( 1 - Adamantyl)-2-(4-chlorophenylsulfanyl)ethanone, l-(l-Adamantyl)-2-(2- naphthylsulfanyl)ethanone, /V-(2-[6-(l-Pipeπdinyl)pyrazιnyl])-l- adamantanecarboxamide. ^V-(2-[6-(l-Piperidinyl)pyrazinyl])adamantan-l- ylmethylcarboxamide. l-( l-Adamantyl)-2-( l-naphthylsulfanyl)ethanone. 1 -( 1- Adamantyl)-2-(8-quιnolylsuifanyl)ethanone hydrochloπde. l-( l-Adamantyl)-2-(4- tπfluoromethoxyphenoxyiethanone. 2-( l-Adamantanemethoxy)quιnoxalιne. 7V- (trα«5-4-Methylcyclohexyl)-2-quιnoxalιnecarboxamιde, N-(cιs-4- Methyicyclohexyl)-2-quιnoxalιnecarboxamιde. Λ (trfl« ,-4-Methylcyciohexyi)-2- qumolinecarboxamide. yV-(tra« -4-Methylcyclohexyl)-3-quιnolιnecarboxamιde. and 7V-(trα/25-4-MethylcyclohexyI)-6-quιnolιnecarboxamιde. 2-(l- Adamantanemethylsulfinv -benzothiazole. /V-(4-Phenylbutyi)-2- quinoxahnecarboxamide. l -( l-Adamantyl)-2-(4, 6-dιmethylpyπmιdιn-2- ylsuIfanyl)eώanol, l-( l-AdamantyI)-2-(3-chloroquιnoxai-2-yl)ethanone. 2-( 1- Adamantanemethylsulfanyi)-3-methylquιnoxalιne, 7V-( l-Adamantyl)-2-anιsamιde, 7 -(l-Adamantanemethyl)-2-amsamιde, l-(l-Adamantyl)-2-(4- chlorophenylsulfany ethanone. 2-( l-Adamantanemethylsuifonyi)-3- methylquinoxalme. l-( l-Adamantyl)-2-(4-fluorophenylsulfanyl)ethanone. l-( 1- Adamantyl)-2-(3-fluorophenvlsulfanyl)ethanone. l -( l-Adamantyl)-2-(2- methoxyphenoxyjethanone. l -(4-AnιsylsuItanyl)butan-2-one. l-( l-Adamantyl)-2- (4-anιsιdmyl)ethanone hvdrochlonde, 3, 3-Dιmethyl-l-(4-anιsylsulfanyl)butan-2- one, l-(4-Biphenyl)-2-(4-anιsylsulfanyl)ethanone. l-(l-Adamantyl)-2-(2- tπfluoromethoxyphenyisulfanyl)ethanone, l-(l-Adamantyl)-2-(3-methylquιnoxal- 2-ylsulfanyl)ethanone, l-( l-Adamantyl)-2-(2-anιsιdιnyl)ethanone hvdrochlonde, 1-(1 -Adamanty l)-2-(4-tπfluoromethoxyphenylamιno)ethanone hvdrochlonde. 1- ( l-Adamantyi)-2-(/V-methyl-4-anιsιdιnyl)ethanone hvdrochlonde. .V-( l-
Adamantyl)-7-tπtluoromethylquιnolιne-3-carboxamιde. .V-( 1 -Adamanty I )-2-( 1- pιperιzιnyl)quιnoxalιne-3-carboxamιde, 7V-(l-Adamantyl)-2-(2- aminoethylamιno)quιnoxalιne-3-carboxamιde, Methyl 7V-(3-quιnolyl)-3- carboxyadamantane- 1 -carboxamide, 1 -( 1 -Adamanty I)-2-[(R)- 1 -( 1 -naphthyl)ethan- l-ylamιno]ethanone. 7V-( l-AdamantyI)-2-methoxyquιnoxalιne-3-carboxamιde. Ethyl 7V-( l-adamantyl)-2-(3-propanoylamιno)quιnoxalιne-3-carboxamιde. .V-(4- Chlorophenyi)-2. 3-dιmethylquιnoxalιne-6-carboxamιde. 7V-( 1 -Adamanty i)-6. 7- dιmethylquιnoxahne-2-carboxamιde, N-((S)- 1 -Tetralmyl)-2- quinoxal ecarboxamide, 7V-(4-Chlorophenethyl)-2-qumoxalιnecarboxamιde. N- (6-Quιnolyl)-2-quιnoxalιnecarboxamιde. 7V-(l-Tetraiιnmethyl)-2- quinoxalinecarboxamide. yV-(l-Indanmethyl)-2-quιnoxalιnecarboxamιde, V-(4, 4- Dimethylcyclohexyl)-2-quιnoxalιnecarboxamιde, and pharmaceutically acceptable salts thereof. In accordance with another embodiment ot the invention, there has been provided a pharmaceutical composition comprising a compound as set forth above, together with a pharmaceutically acceptable diluent or excipient.
In accordance with still another embodiment of the invention, there has been provided a method ot making a compound as set forth above, comprising reacting a compound containing an activated carboxylic acid group with a compound containing an amine, hydroxyi, or thiol group.
In accordance with a still further embodiment of the invention, there has been provided 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.
In yet another embodiment of the invention, there has been provided a method of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, comprising treating neurons with an effective amount of a compound as set forth above.
In accordance with a further embodiment of the invention, there has been provided 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. Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples. while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modificauons within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows illustrative compounds of the invention. „„,, 99/26
DETAILED DESCRIPTION
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-4 Linker]— Ar
where 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.
Structure of the Ar moiety The 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. The ring systems encompassed by
Ar can contain up to tour heteroatoms, independently selected from the group consisting of N. S. and O When Ar is a heteroaryl ring or ring system, it preferably contains one or two heteroatoms. λt 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-ιndoIyl. indolyl. lndazoyl, puπnyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl. naphthyndinyl, quinazoiinyl, cinnolinyl, isothiazolyl, qumoxaiinyl indohzinyl. isoindoiyl, benzothienyl, benzofuranyl, isobenzofuranyl, and chromenyl moieties. Ar preferably is a quinoxa nyl, quinolinyl, or pyndyl moiety.
Other Ar moieties include the 3,4-methylenedιoxy and 3,4-dιoxane 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.
Structure of the R moiety The 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. Preferably, R is optionally substituted alkyl, cycloalkyl, cycloaikylmethyl, or optionally substituted phenylalkyl. Generally, some or all of the hydrogen atoms on up to two methine. methyiene. or methyl groups of R may be replaced by substiments independently selected from the group consisting of F. Cl, OH. OMe. =0. and - COOH groups. However, more than two hydrogen atoms may be repiaced with fluorine, and R may be perfluoπnated. Exemplary R moieties include, but are not limited to: adamantyl, 2- adamantyl, (lS.2S,3S,5R)-ιsopιnocamphenyl, trιcyclo[4.3.1. l(3,8)]undec-3-yl. (lS,2R,5S)- j-myrtanyl, (lR,2R,4S)-ιsobornyl, (1R.2R,3R.5S)- isopinocamphenyl (lS,2S,5S)-trans-myrtanyl (lR,2R,5R)-trans-myrtanyl. (lR.2S,4S)-bornyi, 1-adamantanemethyl, 3-noradamantyI (lS,2S.3S,5R)-3- pinanemethyl, cyclooctyl, dimethylphenethyl, (S)-2-phenyl-l-propyI, cycloheptyl, and 4-methyl-2-hexyi groups. Each ot these exemplary R moieties mav also be substituted in the manner set forth above.
Other preferred R groups include 2.2,3.3.4,4,4-heptafluorobutyl. 4- ketoadamantyl, 3-phenyI-2-methylpropyl, 3,5-dιmethyladamantyi, trans-2- phenylcyclopropyl, 2-medιylcycIohexyI, 3,3,5-tπmethylcyclohexyl, 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. 2-(3- /τι-chlorophenyl-2-methyl)propyI, 2-(3-/>-chlorophenyl-2-medιyi)propyl, 4-t - butyi-cyciohexyl, (S)-l-(cycIohexyl)ethyl, 2-(3-(3,4-dιmethylphenyl)-2- methy propyl, 3.3-dιmethylbutyl, 2-(5-methyl)hexyl, 1-myrtanyl. 2-bornyl. 3- pmanemethyl, 2,2,3,3,4,4,5,5-octafluoropentyl, p-fluoro- 2,2 - dimethylphenethyl, 2-naphthyl. 2-bornanyl. cyclohexyimethyi. 3- methyicyclohexyl, 4-methylcyciohexyi, 3,4-dιmethylcyclohexyl. 5-chloro- tπcyclo[2.2.1]heptyl. o- . -dimethylphenethyl. 2-indanyl. 2-spιro[4.5]decyl. 2- phenylethyl. 1-adamantylethyl. l-( l-bιcyclo[2.2.1 ]hept-2-yl)ethyl. 2-(2-methyi-2- phenylpropyi), 2-(ø-fluorophenyi)ethyl, l-(cyclohexyl)ethyl, cyclohexyl, butan-2- onyl, diphenyiene, 3-carboxyladamantyI, 1-tetrahydronaphtheIenyl, 1-indanyl, 4- methyicyclohexyl, and 4.4-dimethylcyclohexyl moieties. Again, each of these exemplary R moieties may be substituted in the manner set forth above. When compounds may be present in alternative lsomeπc configurations, for example, trans or cύOmethylcyciohexyl, the R moiety may have any of the possible configurations. Similarly, if a compound exists as enantiomers. the R moiety can be either of the enantiomers, or may be a racemate.
Structure of the [linker] moiety
The [linker] moiety generally has the structure -(CH2)n-, where n is 2-6. Up to four 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. N. NH, and NO, provided that two heteroatoms may not be adjacent except when those atoms are both N (forming an -N=N- linkage; or are both NH (forming an -NH-NH- linkage). Any two adjacent CH2 groups also may be replaced by an alkene or alkyne group. In a preferred embodiment, [linker] comprises an amide, ester, thioester. ketomethylene. ether, alkylether, ethylene. ethenyl, acetylenyi, hydroxyalkyl. aikylsulfone. or alkyl aikyisuifoxide group. Preferably, [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. Thus, for example, the invention encompasses compounds having the configuration R-0-(CH2)m-Ar and
Design and synthesis of mGluR Group I antagonists In one embodiment, compounds according to the invention are esters and amides of monocyciic or fused bicyclic aromatic and heteroaromatic carboxylic acids, phenols and amines. In a preferred embodiment, the compounds may be represented by the Formulae II or III: 99/26 2
II III
In Formulae II and III, Y can be either 0, S, NH, or CH2; and X', X2, X3, and X" independently can be N or CH. Preferably, one or two of X', X2, X3, 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 X1 are as defined above.
In another preferred embodiment of the invention, the compounds have me Formulae VI or VII .
VI VII where R and Y are as defined above. In a first embodiment ot the compounds of Formula Vr, Y is N, R is an unsubstituted or monosubstituted 1,1,-dimediylphenylethylamine or 1, 1-dιmethylbenzylamιne moiety, where the substitutuent preferably is an 0-, in-, or -chloπne or p-medioxy group. In a second embodiment of the compounds of Formula VI, Y is N, and 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. In a third embodiment, of the compounds of Formula VI. Y is N, and 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. In yet another preferred embodiment of the invention, the compounds have the Formulae VIII or IX.
VIII IX
wherein X' and R are as defined above. In a first embodiment of compounds of Formula VIII, X1 and X2 are N, X3 and X" are H. R is 1- adamantyl, and a substituent is present on the carbon atom ortho to both the linker and X2. The substituent preferably is a halogen, such as chlorine, or an alkyl group, such as methyl. In a second embodiment of compound IX. R is 1- adamantyl. Compounds ot these first and second embodiments appear to exhibit selectivity tor the mGIuRi receptor.
In still another embodiment, the compounds may have the Formulae X or XI, where Z is a pharmaceutically acceptable substituent. The skilled artisan will recognize that 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.
X XI
In each of the compounds described above, "alkyl" denotes both straight and branched chain alkyl. In other embodiments, R is adamantyl. the linker is -CO- CH2-S-, and Ar is m- or σ-alkyloxyphenyl, or 3,4-methylenedιoxy or 3.4- dioxane.
In general, it appears that selective antagonism of the mGIuRi receptor can be attained with compounds of the formula R-CO-N-An. where An is an aromatic or heteroaromatic group such as a quino nvl. quinoxahnyl. thiazolidinyi, phenyl. benzimidazoyl, or pyndyl group.
The skilled artisan also will recognize that the compounds ot the invention encompass salts of the compounds described above. These salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic. hydroiodic, phosphoric, sulfuπc, tπfluoroacetic, 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 incoφorated herein by reference.
Examples of compounds according to the present invention are set forth in Table 1 below.
Preparation of mGluR Group I antagonists The skilled artisan will recognize that mGluR Group I antagonists according to the invention 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. When 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.
When the [linker] moiety contains an ether linkage, the ether function also can be prepared using standard techniques. For example, eώers 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). Thioeώer 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. When the [linker] moiety contains a ketomethylene group, it can be formed by alkylation ot a ketone enolate. Thus, tor example, a methyl ketone can be deprotonated using a strong base such as lithium dusopropyiamide (LDA). followed by reaction with an alkyl halide. Alternatively, 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. Suitable reagents for oxidizing alcohols to ketones are well known in the art.
[Linker] moieties containing other heteroatom groups also may be prepared using methods that are well known in the art. 7V,7V-Dιsubstιtuted 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. In most cases, the precursor 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.
For example, 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. An illustration of such a transformation is provided below in Example 12.
Testing of compounds for mGluR Group I antagonist activity
The pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art, for example, see Aramoπ et al., Neuron 8:757 (1992); Tanabe et al.. Neuron 8: 169 (1992). The methodology described in those publications is incorporated herein by reference.
Conveniently, 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 incoφorated by reference in their entirety.
Thus, HEK-293 cells (human embryonic kidney cells, available from the American Type Culture Collection, Rockville, MD, Accession Number CRL 1573) are stably transfected with a DNA construct expressing a recombinant receptor. The stably transfected ceils are cultured in high glucose DMEM (Gibco 092) containing 0.8 mM glutamme. 10% FBS, and 200 μM hygromycin B.
A protocol for measuring intracellular calcium mobilization in response to changes in extracellular calcium using the calcium-sensitive dye Fura has been described previously. Briefly, 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 Ca2+ are calculated using a dissociation constant (Kd) of 224 nM and applying equation:
[Ca2 + ]ι = ( F - Fmin /Fmax ) X Kd
where F is fluorescence at any particular time of interest, 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.
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.
In therapeutic and/or diagnostic applications, 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. For example, in the treatment of adult humans, 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.
Pharmaceutically acceptable salts are generally weil 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, hydrochloπde. 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. bromiαe. carbonate, citrate, gluconate. hydrobromide. hvdrochlonde. maieate, mesylate. napsylate. pamoate (embonate), phosphate, saiicyiate. succinate. sulfate. or tartrate.
Depending on the specific conditions being treated, such 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 lntraventπcular. intravenous, lntrapeπtoneal. intranasal. or intraocular injections, just to name a few.
For injection, 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. For such transmucosai administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the 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 weil 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.
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended puφose. 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. In addition to the active ingredients, 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.
Pharmaceutical preparations 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. sodium carboxymethyl-ceiluiose (CMC), and/or polyvinylpyrrolidone (PVP- povidone). If desired, 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. For this puφose. 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. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added. The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
EXAMPLES
General Experimental Methods
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 ninhydπn 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 Aldπch Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (Saint Louis. MO). Fluka Chemical Coφ. (Milwaukee, WI), Fisher Scientific (Pittsburgh. PA), TCI America (Portland. OR), or Lancaster Synthesis (Windham. NH).
EXAMPLE 1: Preparation of Λ46-(2-Methylquinolyl)]-l- adamantanecarboxamide (40)
2-Methyl-6-aminoquinoline
A mixture of 2-merhyi-6-nιtroquιnolιne (1.00 g, 5.31 mmol) and Pearlman's catalyst [palladium dihydroxide on activated charcoal { - 20% palladium); O. lO gj in ethyl acetate (40 mL) was stirred under hydrogen gas (1 atm) at 60°C for 1.5 h. The reaction mixture was filtered and the filtrate was rotary evaporated. This provided 0.81 g (96%) of 2-methyl-6-amιnoquιnoIιne as a yellow solid. /V-[6-(2-Methylquinoiyi)]-l-adamantanecarboxamide (40)
1-Adamantanecarbonvl chloride ( 1.02 g, 5 13 mmol) in pyπdme (2 mL) was added to a solution of 2-methyI-6-ammoquιnolιne (0.81 g, 5.1 mmol) in pyπdine (8 mL). The reaction was stirred for 17 h. To the stirring reaction mixmre was added water ( 100 mL) which caused the product to precipitate..
This precipitate was filtered and then washed with water (3 x 25 mL) and diethyl ether (3 x 25 mL). This provided 1.07 g (65 %) ot (40) as a cream-colored powder: rt= 13.49 mm.; m/z (rel. int.) 320 (M + , 30), 235 (8), 158 (4), 157 (6), 136 ( 11), 135 (100), 130 (11), 107 (7), 93 (15), 91 (8), 79 (18), 77 (11), 67 (6).
In a similar manner, the following V-qumoIyl-l-adamantanecarboxamιdes were prepared:
ιV-(6-Quύιolyl)-l-adarnantanecarboxamide (18)
Prepared from 1 -adamantanecarbonyl chloride ( 1.37 g, 6.90 mmol). 6- aminoquinoline (0.59 g, 4. 1 mmol), pyndine (20 mL), and water (200 L) yielding 1.25 g (100%) of (18): rt= 13.24 mιn.:m/z (rel. int.) 306 (M + ,23), 221 (6), 144 (3), 136 ( 12), 135 (100), 116 (10), 107 (7), 93 (15), 91 (8), 79 (18), 77 (9), 67 (7), 41 (6).
/V-(2-Quinoivl)-l-adamantanecarboxamide hydrochloride (81)
Prepared from 1 -adamantanecarbonyl chloride (0.75 g, 3.8 mmol). 2- aminoquinohne (0.60 g, 4.2 mmol), pyndine ( lO mL), and water ( lOO L). Forming the hydrochloride salt with diethyl ethereal hydrogen chloride yielded
0.19 g (15%) of (81): rt= 12.24 mιn;m/z (rel. int.) 306 (M + ,80), 305 (23), 277 (8), 263 (8), 221 (10), 172 (9), 171 (72), 145 (16), 144 (61), 143 (13), 136 (11), 135 (100), 128 (33), 117 ( 17), 116 (24), 107 (18), 105 (8), 101 (10), 93 (40), 91 (29), 89 ( 13), 81 (14), 79 (55), 77 (35), 67 (18), 65 (10), 55 (12), 53 (10), 41 (20).
7V-(3-Quinolyl)-l-adamantanecarboxamide (86)
Prepared from 1 -adamantanecarbonyl chloride (0.75 g, 3.8 mmol), 3- aminoquinohne (0.60 g, 4.2 mmol), pyndine ( 10 mL), and water ( lOO mL) yielding 0.33 g (29%) ot (86): rt= 13.01 mm. m/z ( rel. int. ) 306 (M + .22), 136 ( 11), 135 ( 100), 116 ( 11), 107 (8), 93 ( 15), 91 (8), 89 (7), 79 ( 17), 77 (8), 67 (6), 65 (3). -(trαπs-4-MethyIcyclohexyl)-2-quinoxalinecarboxamide (299)
Using the method of Booth (J. Chem. Soc. 1958, 2688: J. Chem. Soc. 1971, 1047: Tetrahedron. 1967, 23, 2421), hydroxylamine (3.8 g, 55 mmol), ethanol (50 mL), pyndine (4.44 mL, 55 mmol), and 4-methyl cyclohexanone (6.1 mL, 50 mmol) were stirred at ambient temperature for 16 hours and then heated at reflux for 15 minutes. The ethanol was then removed in vacuo and d e residual oil dissolved in ethylacetate (100 mL). The organic layer was washed with water (2X), brine, dried over anhydrous MgSO . filtered, and concentrated to a clear oil (die oxime product), which crystallized upon standing.
Without further purification 1.9 g (15 mmol) of the intermediate oxime in absolute ethanol (40 mL) was heated to reflux and treated with (in small portions) sodium metal (4 g). The reaction was heated at reflux until the sodium was consumed. The reaction was cooled and treated with water (10 mL). The reaction was transferred into a flask containing ice and concentrated HCI (6 mL). The ethanol was removed in vacuo and the remaining aqueous phase washed with diethyl ether (3X, to remove unreduced oxime). The remaining aqueous phase was concentrated to afford 1.8 g of a white crystalline solid (the ιrans-4- methylcyclohexylamine hydrochloride product). Without furdier purification 750 mg (5 mmol) of trans-4- methylcyclohexyl amme hydrochloride in dichloromethane (10 mL) was treated with pyndine ( 1.62 mL. 20 mmol) followed by the addition of 2-quιnoxaloyl chloride (963 mg, 55 mmol). The reaction was stirred at ambient temperature for 16 hours and diluted with chloroform (25 mL). The organics were washed with 10% HCI (3X), 1 N NaOH (3X), brine, dried over anhydrous MgSO-4, filtered and concentrated to a solid. Chromatography (MPLC) of the crude reaction material through silica (7 x 4 cm i.d., BIOTAGE, KP-SIL, 60 angstroms) using ethylacetate-hexane (1:4) afforded 470 mg of the desired product, iV-(trα/j5-4-methylcyciohexyl)-2-quinoxaiιnecarboxamide. Thin-layer chromatography (TLC. silica) using ethylacetate-hexane ( 1:4) showed a single UV active component at R 0.19. GC/EI-MS gave m/z (rel. int.) 269 (M\ 39), 212 (8), 198 (6), 174 (15), 157 (21), 129 (100), 112 (43), and 102 (46). EXAMPLE 2: Preparation of 6-Quinolyl 1-adamantanecarboxylate (41)
1 -Adamantanecarbonyl chloride (1.37 g, 6.90 mmol) in pyndine (5 mL) was added to a solution ot 6-hydroxyquιnolιne ( l .OO g, 6.89 mmol) in pyndine
(15 mL). The reaction was stirred for 16 h. To the stirring reaction mixmre was added water (200 mL) which caused the product to precipitate. This precipitate was filtered, washed with water (3 x 50 mL), and dried under high vacuum.
This provided 1.56 g (73.7%) of (41) as a light-brown powder: rt= 11.41 ram.: m/z (rel. int.) 307 (M + ,2), 136 (11), 135 (100), 116 (11), 107 (7), 93 (14), 92 (2), 91 (8), 89 (7), 79 (16), 77 (8).
EXAMPLE 3: Preparation of 1- Adamanty I 6-quinoIinecarboxylate (61)
6-Quinolinecarbonyl chloride hydrochloride
6-QuιnoIιnecarboxylιc acid was refluxed in thionyl chloride for 30 mm. The excess thionyl chloride was then removed by rotary evaporation (90° C) to provide 6-quιnolιnecarbonyi chloride hydrochloride.
1-Adamantyl 6-quinolinecarboxylate (61)
6-Quιnoiιnecarbonyl chloride hydrochloride (0.76g, 3.3 mmol) in pyndine (2 mL) was added to a solution of 1 -adamantanol (0.60 g, 3.9 mmol) in pyndine (8 mL). The reaction was stirred at 70°C for 16 h. To the stirring reaction mixture was added water ( 100 L) which caused the product to precipitate. This precipitate was filtered and then washed with water (3 x
25 mL). The filter cake was dissolved in ethanol (20 mL) and water was then added to the cloud point (16 mL). The crystallizing solution was allowed to stand for 15 h. Filtering and drying under high vacuum for 7 h provided 0.32 g (26%) of (61) as light brown needle-like crystals: rt= l 1.48 ram.; m/z (rel. int.) 307 (M + ,99), 306 (92), 262 (15), 174 (12), 173 (13), 157 (10), 156 (88), 135 (81), 134 (33), 129 (13), 128 (100), 127 (10), 119 (11), 107 (18), 102 (16), 101 (37), 93 (51), 92 (76), 91 (35), 81 (14), 79 (55), 78 (15), 77 (49), 75 (17), 67 (24), 55 (18), 53 (13), 51 (13), 41 (31).
In a similar manner, the following alkyl 6-quιnolιne- and 2- quinoxalinecarboxylates were prepared: 2.2,3.3.4.4.5.5-Octafluoro-l-pentyl-6-quinoline-carboxylate hydrochloride (68)
Prepared from 6-quιnoIιnecarbonyl chloride hydrochloride (0.75 g,
3.3 mmol), 2.2.3.3,4.4,5,5-octafluoro-l-pentanol (0.60 mL. 4 3 mmol), pyndine (10 mL), and water ( lOO mL). Forming the hydrochloride salt with ethereal hydrogen chloride yielded 0.88 g (69%) of (68): rt=7.11 mm.; m/z (rel. int.) 387 (M + ,26), 156 (100), 129 (6), 128 (48), 102 (6), 101 (16), 77 (6), 76 (2), 75 (8), 50 (14).
1-AdamantanemethyI 6-quinolinecarboxyiate (73)
Prepared from 6-quιnoiιnecarbonyl chloride hydrochloride (0.80 g,
3.5 mmol), 1 -adamantanemethanol (0.60 g, 3.6 mmol), pyndine (10 mL), and water (100 mL) yielding 0.75 g (65%) of (73): rt= 11.90 mιn.; (rel. int.) 321 (M + , 35), 320 (12), 263 ( 15), 156 (30), 148 (23). 136 (11), 135 (100), 135 (100), 129 (9), 128 (52), 107 (15), 106 (7), 105 (9). 102 (7), 101 (16), 93 (34), 92 (20), 91 (20), 81 (11), 80 (7), 79 (40), 78 (6), 77 (24), 75 (7), 67 (14), 55 (9), 53 (6), 51 (6), 41 (14).
1-AdamantyI 2-quinoxalinecarboxylate (92) Prepared from 2-quιnoxaloyl chloride (0.84 g, 4 4 mmol), 1 -adamantanol
(0.60 g, 3.9 mmol), pyndine ( 10 mL), and water (100 mL) yielding 0 20 g
(16%) of (92): rt= 11.21 mm.; m/z (rel. int.) 308 (M + .26), 264 (6), 136 ( 11), 136 ( 1 1), 135 (100). 134 (5), 130 (11), 129 (25), 107 (12), 102 (19), 93 (24), 92 (9). 91 ( 11), 81 (7), 79 (26), 77 (12), 76 (6), 75 (7), 67 (10), 55 (7), 51 (6), 41 ( 11).
EXAMPLE 4: Preparation of /V-(l-Adamantyl)-3- quinoiinecarboxamide (72) l, -Carbonyldiimιdazole (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-dιmethyIformamιde (0.5 mL) was added in one portion. The reaction mixture was stirred at 60 °C for 2 h. The reaction was then diluted with chloroform and washed with water (3 x 30 mL) The organic layer was dried (anhydrous magnesium sulfate), filtered through silica gel, and rotary evaporated. This provided 73 mg (24%) of (72) as a crystalline solid: rt= 11.02 mm.: m/z (rel. int.) 306 (M + ,78), 305 (42), 250 (19), 249 (100), 213 (7), 173 (5), 157 (10).156 (89), 129 (12), 128 (92), 102 (5), 101 (36).94 (6), 93(10).92(12), 91 (14).79(10), 77(14), 77(14), 75 (10), 67(7), 41 (11).
In a similar manner, the following /V-alkyl-2-quinohne- and 2- quinoxalinecarboxamides were prepared:
V-(l-Adamantyl)-2-quinoIinecarboxamide (74)
Prepared from l.l'-carbonyldnmidazole (160 mg, 0.987 mmol), quinaldic acid (173 mg, 1.00 mmol), and 7V,N-dιmethylformamιde (2.5 mL) yielding
77 mg (25%) of (74): rt= 10.53 mm.; m/z (rel. int.) 306 (M + ,91), 305 (26), 277 (9), 263 (9).221 (11), 172 (9), 171 (73), 145 (15), 144 (60), 143 (15), 136 (11), 135 (100). 128 (36), 117 (19), 116 (27).107 (20), 105 (8), 101 (10).93 (42), 91 (30).89 (14), 81 (13), 79 (55), 77 (37), 67 (18), 65 (11), 55 (12), 53 (10), 41 (18).
/V-(2-AdamantyI)-2-quinoxalinecarboxamide (144) Prepared from l.l'-carbonyldiimidazoie (161 mg, 1.00 mmol), 2- quinoxalinecarboxy c acid (174 mg, 1.00 mmol), 2-adamantanamιne (136 mg,
0.90 mmol), and dichloromediane (3.5 mL) yielding 98 mg (35%) of (144): rt= 11.79 mm.: m/z (rel. int.) 307 (M + .33), 151 (12).150 (100).130 (24).129 (35), 103 (11), 102(20).91 (13), 79(11), 77(8), 76(6), 75 (5), 70(6).67(5). 41 (6).
Λ^-[(lΛ,2R.3R.5S)-3-PinanemethyI]-2-quinoxalinecarboxamide (151)
Prepared from l,l'-carbonyldiimιdazoIe (161 mg, 1.00 mmol), 2- quinoxalinecarboxylic acid (174 mg, 1.00 mmol), (-)-3-pιnanemethyiamιne (150 mg, 0.90 mmol), and dichloromediane (3.5 mL) yielding 50 mg (17%) of
(151): rt= 11.46 mm.; m/z (rel. int.) 323 (M + ,7), 187 (76), 186 (10), 174 (25). 166 (15), 158 (44), 157 (20).144 (6), 131 (10), 130 (78), 129 (100), 107 (8), 103 (21), 102 (44), 95 (15), 93 (10), 91 (9), 81 (11), 79 (13), 77 (12), 76 (14), 75 (11), 69(8), 67 (17), 55 (20), 53 (10), 51 (7), 43 (10), 41 (30). EXAMPLE 5: Preparation of V-(l-Adamantyl)-2- quinoxaiinecarboxamide (91)
2-Quιnoxaioyl chloride (0.84 g, 4.4 mmol) was added to a soiution of 1- adamantanamine (0.60 g, 4.0 mmol) in pyndine ( 10 mL). The reaction was then stirred for 30 mm. To the stirring reaction mixmre was added water ( 100 mL) which caused the product to precipitate. This precipitate was filtered, washed with water (3 x 25 mL), and dried under high vacuum for 16 h. This provided
1.00 g (82%) of (91): rt= 11.73 mm.; m/z (rel. int.) 307 (M + ,39), 279 (5), 157 (5), 151 (11), 150 (100), 130 (21), 129 (58), 103 (12), 102 (24), 94 (7), 93 (8), 91 (10), 79 (9), 77 (9), 76 (7), 75 (6), 67 (5), 41 (8), 41 (8).
In a similar manner, the following iV-substituted 6-quιnolιne- and 2- quinoxalinecarboxamides were prepared:
7V-(l-Adamantyl)-6-quinoIinecarboxamide (42)
Prepared from 6-quιnolιnecarbonyi chloride hydrochloride ( 1.51 g,
10 mmol), 1 -adamantanamine (1.73 g, 10 mmol), pyndine (5 mL), and water (200 mL) yielding 330 mg (11 %) ot (42): rt= 11.04 mm.; m/z (rel. int.) 306 (M + ,34), 305 (15), 250 (11), 249 (56), 156 (11), 155 (100), 130 (5), 128 (10), 127 (69), 126 (5), 102 (8), 101 (16), 93 (8), 92 (9), 91 (12), 79 (10), 77 (16), 67 (6), 41 (11), 41 (11).
^-(exo^-Norbornany ^-quinoxalinecarboxamide (148)
Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol), exo-2- aminonorbornane (133 mg, 0 90 mmol), pyndine (5 mL), and water (50 mL) yielding 35 mg (15%) ot (148): rt= 10.22 mm.; m/z (rel. int.) 267 (M + ,36), 198 (10), 158 (7), 157 (9), 131 (7), 130 (47), 129 (78), 111 (8), 111 (8), 110 (100), 103 (16), 102 (39), 77 (5), 76 (12), 75 (11), 67 (11), 51 (7), 41 (10).
jΛ/-[(lR.2S,4S)-Bornyl]-2-quinoxaϋnecarboxamide (150)
Prepared from 2-quιnoxaloyl chloride ( 193 mg, 1.0 mmol), (/?)-( + )- bornylamine ( 138 mg, 0.90 mmol), pyndine (5 mL), and water (50 mL) yielding
140 mg (50%) ot (150): rt= 10.79 mm.; m/z (rel. int. ) 309 (M + ,27), 199 (8), 187 (10), 174 (10), 158 (11), 157 (14), 153 (10), 152 (82), 144 (9), 135 (11), 131 (7), 130 (51), 129 (100), 109 (20), 103 (18), 102 (43), 95 (38), 93 (12).91 (7), 79 (9), 77 (11), 76 (13), 75 (11), 67 (17), 55 (14), 53 (8).51 (8).43 (8), 41 (25).
/V-(3-Noradamantvl)-2-quinoxaIinecarboxamide (152) Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol), 3- noradamantanamine (157 mg, 0.90 mmol), pyndine (5 mL), and water (50 mL) yielding 167 mg (63%) of (152): rt= 11.00 mm.: m/z (rel. int.) 293 (M + .50), 265 (12), 250 (18), 232 (6), 222 (20), 157 (12), 144 (6), 137 (7), 136 (64), 131 (6), 130 (35), 130 (35), 129 (100), 103 (19), 102 (35), 94 (15), 91 (6), 80 (6), 79 (11), 77 (11), 76 (12).75 (9), 67(6), 53(6), 51(6), 41 (13).
iV-[(lR.2Λ.3R,5S)-Isopinocamphenyl]-2-quinoxaiinecarboxamide (165)
Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol), (lR,2R,3R,5S)-(-)-ιsopιnocamphenylamιne (138 mg, 0.90 mmol), pyndine
(5 mL), and water (50 mL) yielding 230 mg (83%) of (165): rt= 10.88 mm.: m/z (rel. int.) 309 (M + ,4), 226 (19), 200 (17), 199 (5), 198 (7), 186(9), 175(7), 174(16), 158(6), 157(14), 152(6), 130(42), 129(100), 103 (16), 102 (42), 102(42), 95(13), 93(10), 79(6), 77(7), 76(11), 75 (9).67(7), 55 (12), 53 (6), 51 (5), 43 (5), 41 (18).
Λ^-[(lS.2S.3S,5R)-Isopinocamphenyl]-2-quinoxalinecarboxamide (166)
Prepared from 2-qumoxaloyI chloride (193 mg, 1.0 mmol),
(15,25,3S,5R)-(+)-isopinocamphenylamine (138 mg, 0.90 mmol), pyndine (5 mL), and water (50 mL) yielding 208 mg (75%) of (166) : rt= 10.88 mm.: m/z (rel. int.) 309 (M + ,4), 226 (16), 200 (14), 198 (7), 186 (8). 175 (6), 174 (14), 158 (5), 156 (13), 130 (42), 130 (42), 129 (100). 103 (18). 102 (46), 95 (11), 93 (10), 91 (5), 79 (5), 77 (8), 76 (12), 75 (11), 67 (8), 55 (13), 53(6), 51(6), 43(6), 41 (20).
N-(5-Chlorotricyclo[2.2 .0(2,6)]hept-3-yI)-2-quinoxalinecarboxamide
(167)
Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol), 5- chlorotncyclo[2.2.1.0(2,6)]hept-3-ylamιne (129 mg, 0.90 mmol), pyndine (5 mL), and water (50 mL) yielding 100 mg (37%) of (167): rt= 11.29 mm.: m/z (rel. int.) 299 (M + .2), 264 (76), 246 (12), 199 (7). 198 (47), 186 (16), 185 (6), 144 (6), 142 (16), 130 (30), 129 (100), 106 (15), 103 (20), 102 (55), 102 (55), 91 (24), 80 (7), 79 (18), 78 (6), 77 (18), 76 (19), 75 (19), 65 (10), 53 (6), 52 (6), 51 (14), 50 (7). jV-(Tricyclo[4.3.1.1(3,8)]undec-3-yl)-2-quinoxalinecarboxamide (168)
Prepared from 2-quιnoxaioyl chloride (135 mg, 0.70 mmol). tricyclo[4.3.1.1(3,8)]undec-3-yiamιne hydrochloride (100 mg, 0.60 mmol). pyndine (5 mL), and water (50 mL) yielding 110 mg (57%) of (168): rt=12.52 mm.: m/z (rel. int.) 321 (M + ,48), 165 (13), 164 (100), 157 (9), 131 (8), 130(32), 130(32), 129(79), 107(5), 106(5), 105(11), 103(17), 102(31), 94 (9), 93 (8), 92 (9), 91 (15), 81 (6), 80 (7), 79 (16), 77 (10), 76 (9), 75 (7), 67 (8), 55 (5), 53 (5), 41 (10).
7V-[(lS,2R,5S)-cw-Myrtanyl]-2-quinoxalinecarboxamide (169)
Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol), (-)-cύ- myrtanylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 224 mg (81%) of (169): rt=11.32 mm.: m/z (rel. int.) 309 (M + ,18), 186 (30), 174 (20), 158 (12), 157 (27), 152 (16), 131 (6), 130 (47), 130 (47), 129 (100), 121 (5), 103 (17), 102 (45), 93 (12), 91 (6), 81 (11), 79 (12), 77 (10), 76 (13), 75 (11), 69 (13), 67 (15), 55 (8), 54 (6), 53 (8), 51 (7), 43 (6), 41 (26).
/V-[(lR,2R.4S)-Isobornyl]-2-quinoxalinecarboxamide (170) Prepared from 2-quιnoxaioyl chloride (193 mg, 1.0 mmol). (7?)-(-)- isobornylamme (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 130 mg (81%) of ( 170): rt= 10.76 mm.: m/z (rel. int.) 309 (M + ,24), 199 (7), 197 (6), 187 (8), 174 (8), 158 (9), 157 (12), 153 (7), 152 (58), 144 (9), 135 (8), 130 (46), 129 (100), 109 (14), 103 (21), 102 (48), 95 (31), 93 (10), 91 (7), 79 (8), 77 (10), 76 (13).75 (12), 67 (15), 55 (12), 53 (7), 51 (6), 43 (6), 41 (18).
/V-[ertdo-(+)-2-NorbomanyI]-2-quinoxalmecarboxamide (171)
Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol), endo-(±)-2- aminonorbornane (133 mg, 0.90 mmol), pyndine (5 mL), and water (50 mL) yielding 175 mg (73%) of (171): rt=10.15 min.: m/z (rel. int.) 267 (M+,35), 198 (11), 185 (6), 158 (7), 157 (11), 144 (5), 131 (7), 130 (55), 129 (100), 111 (6), 110 (81), 103 (24), 102 (56), 77 (7), 76 (19), 75 (17), 75 (17), 67 (13), 55 (5), 53 (7), 51 (9), 50 (5), 41 (14). 9/26927
-33- V-[(R)-2-Phenyl-l-propyl]-2-quinoxalinecarboxamide (172)
Prepared from 2-quιnoxaIoyi chloride (0.47 g, 2.4 mmol), (R)-2-phenyl-
1-propylamιne (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yieldmg
0.49 g (76%) of (172): rt= 10.63 mm.: m/z (rel. int.) 291 (M + .14), 186 (9), 158 (5), 157 (32). 130 (25), 129(100), 118(22).105 (24), 104(5), 103 (21), 102 (48), 91 (9), 79(11). 78 (6), 77 (18), 76 (13), 75 (13), 75 (13), 51 (9).
N-[(S)-2-PhenyI-l-propyl]-2-quinoxalinecarboxamide (173) Prepared from 2-quιnoxaloyl 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
0.48 g (74%) of (173): rt= 10.72 mm.: m/z (rel. int.) 291 (M + ,13), 186 (68), 158 (5). 157 (37). 130 (21), 129(100), 118 (29).105(21), 103 (16), 102 (37), 91 (7), 79(10), 77(15). 76(11), 75(10), 51 (9), 51 (9).
N-(2-IndanyI)-2-quinoxalinecarboxamide (221)
Prepared from 2-quιnoxaloyl chloride (0.32 g, 1.7 mmol), 2-amιnoιndan
(0.20 g, 1.5 mmol), pyndine (3 mL), and water (30 mL) yielding 0.23 g (53%) of (221): rt=11.33 mm.; m/z (rel. int.) 289 (M + .10), 132 (6), 130 (28), 129 (41). 117 (15), 116 (100), 115 (37), 104 (7), 103 (26), 102 (37), 91 (7), 78 (7), 77 (13), 76 (16), 75 (14), 51 (9), 51 (9), 50 (5).
N-CyclooctyI-2-quinoxalinecarboxamide (228)
Prepared from 2-quιnoxaIoyi chloride (193 mg, 1.0 mmol), cyclooctylamme (123 μL, 114mg, 0.90 mmol), pyndine (5 mL), and water
(100 mL) yielding 100 mg (39%) of (228): rt= 10.86 rain.; m/z (rel. int.) 283 (M + ,27), 212 (6), 199 (9), 198 (20), 198 (20), 185 (16), 184 (6), 174 (8), 157 (15), 144 (7), 131 (6), 130 (48), 129 (100), 126 (42), 103 (20), 102 (50), 76 (13), 75 (12), 67 (6), 56 (7), 55 (9), 51 (6), 43 (6), 41 (16).
N-Cycloheptyl-2-quinoxalinecarboxamide (229) Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol). cycioheptylamine (115 uL. 102 mg, 0.90 mmol), pyndine (5 mL), and water (100 mL) yielding 30 mg (12%) of (229): rt= 10.30 mm. : m/z (rel. int. ) 269 (M + ,39). 212 (6), 198 (20). 185 ( 13). 174 ( 14), 174 ( 14), 157 (20), 131 (7), 130 (49), 129 ( 100), 1 12 (44), 103 (23). 102 (51), 76 (15), 75 (13), 56 (6), 55 (8), 51 (7), 42 (5), 41 (15).
jV-[2-Spiro(4.5)decyl]-2-quinoxalinecarboxamide (236)
Prepared from 2-quιnoxaloyi chionde (193 mg, 1.0 mmol). 2- amιnospιro(4.5)decane ( 150 mg, 0.79 mmol), pyridine (5 mL), and water
(100 mL) yielding 206 mg (74%) of (236): rt= 10.94 mm. : m/z (rel. int.) 282 (M + ,25), 199 (7), 186 (6), 157 (10), 130 (32), 129 (96), 125 (40), 110 (10), 109 (100), 108 (15), 103 (14), 102 (55), 98 (6), 97 (27), 96 (25), 84 (9), 82 (18), 76 (15), 75 (16), 70 (55), 69 (7), 68 (13), 56 (7), 55 (8), 53 (6), 51 (9), 43 (8), 42 (36), 41 (14).
EXAMPLE 6: Preparation of 1-Adamantanemethyl 6-quinolyl ether (94)
A mixture of 1 -adamantanemethanol (5.00 g, 30.0 mmol) and 6- hydroxyquino ne ( 13.1 g, 90.2 mmol) in tetrahydrofuran (75 mL) was stirred for 15 min. Then, tnphenylphosphine (10.2 g, 39.0 mmol) was added, followed by die iyl azodicarboxyiate (6.14 mL, 39.0 mmol). The reaction mixture was refluxed for 18 h. The solvent was then removed by rotary evaporation. The resulting gel was filtered through paper with diethyl ether (3 x 25 mL). The filtrate was rotary evaporated, and the resulting gel was filtered through paper with hexanes (3 x 25 mL). Again the filtrate was rotary evaporated, the resulting gel was filtered through paper with hexanes (3 x 25 mL), and the filtrate was rotary evaporated. This provided 3.8 g (43% ) of crude product as a red oil.
This oil was chromatographed (2: 1 hexanes/ethyl acetate) to provide 1.6 g (18%) of (94): rt= 11.29 min. ; m/z (rel. int.) 293 (M + , 15), 149 (100), 145 (6), 128 (13), 121 (6), 116 (12), 1 16 (12), 107 ( 17), 93 (29), 91 (18), 89 ( 10), 81 (16), 79 (25), 77 (17), 67 (14), 65 (5), 55 (8), 53 (6), 41 (14).
EXAMPLE 7: Preparation of 1-Adamantvl 3-quinolinecarboxylate
(101)
A mixmre of 1 -adamantanol (152 mg, 1.0 mmol), 3-quinolinecarboxylic acid (173 mg, 1.0 mmol), and dimethylaminopyridine (122 mg, 1.0 mmol) in dichloromediane (2 mL) and /VN-dimethylformamide (2 mL) was cooled to 0 °G 1.3-Dicyciohexylcarbodiimιde (227 mg, 1. 1 mmol) in dichloromethane ( 1 mL) was added in one portion. The reaction mixture was stirred at 25 °C for 20 h. The reaction mixture was then diluted with dichloromethane (40 mL) and washed with 1 M sodium hydroxide (3 x 30 mL). The organic layer was dried
(anhydrous magnesium sulfate), filtered through Celite, and rotary evaporated.
The resulting material was purified by spinning thm-layer chromatography (3% methanol in chloroform). The purest fraction was rotary evaporated, and the resulting material was recrystallized from ethanol. This provided 42 mg (14%) of (101): rt=7.78 min.; m/z (rel. int.) 307 (M + ,96), 306 (100), 173 (11), 155 (38), 135 (6), 127 (55), 119 (6), 106 (9), 100 (23), 93 (25), 92 (33), 91 (14), 78 (23), 77 (6), 76 (13), 74 (8), 67 (9), 54 (7), 41 (12).
EXAMPLE 8: Preparation of /V-(α,α-DimethyIphenethyi)-2- quinoxaiinecarboxamide (108)
2-Quιnoxaloyl chloride (207 mg, 1.07 mmol) in dichloromethane ( 1 mL) was added to a solution of phentermine (160 mg, 1.07 mmol) in dichloromethane (3 mL) cooled to 0 °C. The reaction was allowed to warm to 25 °C. After 5 min. the reaction mixmre was diluted with ethyl acetate (40 mL) and washed with I M sodium hydroxide (2 x 40 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through silica gel, and rotary evaporated.
This provided 51 mg (16%) of (108): rt=9.31 min.: m/z (rel. int.) 305 (M + ..0), 214 (96), 186 (30), 157 ( 16), 130 (22), 129 (100). 103 (10), 102 (31), 92 (4), 91 (47), 76 (5), 75 (5), 65 ( 10).
V-(2-Chlorobenzyl)-2,4,6-triphenyipyridinium tetrafluoroborate
2-Chlorobenzylamιne (2.0 g, 14 mmol) was added dropwise to a suspension of 2,4,6-trιphenylpyryiium tetrafluoroborate (5.1 g, 13 mmol) in dichloromethane (40 mL). The reaction mixmre was stirred for 16 h. Ethanol (4 mL) and excess diethyl ether were added to precipitate the product. The precipitate was filtered and dried. This provided 6.14 g (92%) ot V-(2- chlorobenzyl)-2,4,6-trιphenylpyπdιnium tetrafluoroborate.
l-(2-ChlorophenyI)-2-methyl-2-nitropropane
2-Nitropropane (3.19 mL, 35.5 mmol) was added to a mixmre of sodium hydride (0.85 g, 35 mmol) in methanol ( 15 mL) cooled to 0 °C. The reaction mixmre was then stirred and allowed to warm to 25 °C for 10 min. The solvent was rotary evaporated to provide a white solid. A mixture of this solid and N-(2- chlorobenzyI)-2.4.6-trιpnenvlpyπdιπιum tetrafluoroborate (6. 14 g, 11.8 mmol) in dimethyl suifoxide (45 mL) was stirred under nitrogen gas for 16 h. Water was men added to quench the reaction. This mixture was then extracted with diethyl ether (3 x 100 mL). The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), and filtered. The filtrate was stirred in strongly acidic Amberlyst 15 ion-exchange resin (1 g/mmoi) for 4 h. The reaction mixmre was filtered and rotary evaporated. This provided 2.35 g (93%) of l-(2-chlorophenyl)-2-methyl-2-nιtropropane.
,α-Dimethyl-2-chlorophenethy!amine
A mixmre of Raney nickel (50% by weight in water: 2.3 g) and l-(2- chlorophenyl)-2-methyl-2-nιtropropane (2.35 g, 11 mmol) in ethanol (35 mL) was shaken under hydrogen gas (60 psig) for 3.5 h. The reaction mixmre was then filtered, and the filtrate was rotary evaporated. This provided 2.3 g ( 1 10%) of α,α-dιmethyl-2-chlorophenethylamιne.
/V-(α,α-Dimethyl-2-chlorophenethyl)-2-quinoxalinecarboxamide (197)
In a similar manner to (108), (197) was prepared from 2-quιnoxaloyl chloride ( 158 mg, 0.82 mmol), ,α-dimethyl-2-chlorophenethylamme ( 151 mg,
0.82 mmol), and dichloromethane (3 mL) yielding 196 mg (70%) of (197): rt= 10.04 mm.: m/z (rel. int.) 339 (M + ..0). 213 (58). 186 (24). 156 ( 12). 129 (25), 128 ( 100). 126 ( 14), 124 (44), 102 ( 14), 101 (38), 98 (5), 90 (5). 88 ( 18). 75 ( 10), 75 (10), 75 (9), 62 (5), 50 (5), 41 (9).
EXAMPLE 9: Preparation of N-(α,α-Dimethyl-4-fluorophenethyl)-2- quinoxalinecarboxamide (129)
To a solution of l-(4-fIuorophenyl)-2-methyl-2-propylamιne (105 mg, 0.628 mmol) in pyndine (2 mL) was added 2-quιnoxaloyl chloride ( 133 mg, 0.691 mmol). The reaction was then stirred for 30 mm. To the stirring reaction mixmre was added water (20 mL) which caused the product to separate as an oil. This mixmre was extracted with ediyl acetate (1 x 10 mL), washed with water (2 x 5 mL), dried (anhydrous magnesium sulfate), rotary evaporated, and put under high vacuum for 15 h. This provided 146 mg (71.9%) of (129): 9/26927
- 37 - rt= 10.45 min.: m/z (rel. int.) 323 (M + , . l), 214 (73), 186 (22), 157 (14), 135 (4), 130 ( 19), 129 (100). 109 (22), 103 (9), 102 (30), 83 (7), 76 (9). 75 (8). 42 (6).
In a similar manner, the following <V-substιtuted 2- quinoxaiinecarboxamides were prepared:
N-(β -Methylphenethyl)-2-quinoxaϋnecarboxamide (131)
Prepared from 2-quιnoxaloyl chloride (193 mg, 0.84 mmol). β- mediylphenethylamine ( 103 mg, 0.76 mmol), and pyndine (2 mL) yielding
154 mg (69%) of (131): rt= 10.71 mm.; m/z (rel. int.) 291 (M+,12), 186 (66), 158 (5), 157 (37), 130 (20), 129 (100), 118 (28), 105 (21), 103 (17), 102 (37), 91 (7), 79 (10), 78 (5), 77 (15), 76 (11), 75 (10), 51 (10), 51 (10).
V-(3-MethylcyclohexyI)-2-quinoxalinecarboxamide (161)
Prepared from 2-quιnoxaloyl chloride (193 mg, 1.0 mmol), 3- methylcyclohexylamine ( 1 19 mg, 0.90 mmol), and pyndine (5 mL) yielding
190 mg (78%) of (161): rt=9.99 mm.; m/z (rel. int.) 269 (M + ,37), 226 (6), 198 (11), 174 (23), 157 (23), 131 (7), 130 (44), 129 (100), 113 (5), 112 (59), 103 (20), 102 (41), 95 (5), 81 (6), 76 (15), 75 (12), 56 (5), 55 (9), 51 (7), 41 (15), 41 (15).
7V-(2 ,3 -Dimethy Icyclohexy 1) -2-quinoxalinecarboxamide ( 163) Prepared from 2-quιnoxaioyl chloride (193 mg, 1.0 mmol). 2.3- dimethylcyclohexylamine ( 115 mg, 0.90 mmol), and pyndine (5 mL) yielding
150 mg (59%) of (163): rt=10.12 mm.; m/z (rel. int.) 283 (M + ,35), 212 (6), 198 (14), 175 (6), 174 (39), 158 (7), 157 (22), 131 (6), 130 (46), 129 (100), 126 (44), 109 (8), 103 (20), 103 (20), 102 (45), 76 (13), 75 (11), 67 (7), 56 (10), 55 (12), 51 (6), 43 (6), 41 (16).
A/-[(lS,2S,3S,5R)-3-PinanemethyI]-2-quinoxalinecarboxamide (207)
Prepared from 2-quιnoxaloyl chloride ( 193 mg, 1.0 mmol). ( +)-3- pmanemethylamine (150 mg, 0.90 mmol), and pyndine (5 mL) yielding 229 mg
(79%) of (207): rt= 12.07 mm.: m/z (rel. int.) 323 (M + , 12). 187 (100). 186 (12), 174 (33), 166 (24), 159 (8), 158 (66), 157 (26). 150 (9), 144 (7), 131 (11), 130 (80), 129 (85), - 36 -
107 (10), 103 (14), 102 (31), 95 (22), 93 (11), 91 (8), 83 (7), 81 (11), 79 (11), 77 (8), 76 (8), 69 (8), 67 (13), 55 (17), 43 (9), 41 (25).
EXAMPLE 10: /V-(l-Adamantanemethyl)-2-quinoxalinecarboxamide (146)
2-Quιnoxaloyl chloride (429 mg, 2.6 mmol) was added to a solution ot 1- adamantanemethylamine (500 mg, 2.6 mmol) in chloroform (5 mL). The reaction mixmre was heated unul everything had dissolved. The reaction mixmre was stirred at 25 °C for 1 h. To the stirring reaction mixmre was added water
(100 mL) which caused the product to precipitate. The precipitate was filtered, washed with water (2x), and dried under high vacuum. This provided 375 mg
(45%) of (146): rt= 12.27 mm.; m/z (rel. int.) 321 (M + .101), 186 (7), 174 (6), 164 (34), 158 (6), 157 (8), 136 (11), 135 (100), 131 (7), 130 (46), 129 (75), 107 (23), 105 (6), 103 (20), 102 (53), 93 (44), 92 (6), 91 (23), 81 (13), 79 (47), 77 (24), 76 (16), 75 (13), 67 (16), 65 (6), 55 (9), 53 (8), 51 (8), 41 (13).
EXAMPLE 11: Preparation of V-(4-MethyIcycIohexyi)-2- quinoxalinecarboxamide (162)
To a solution ot 4-methylcyciohexyIamιne (119 mg, 0.90 mmol) in pyndine (2 mL) was added 2-quιnoxaloyl chloride (193 mg, 1.0 mmol). The reaction was then stirred for 1 h. To the stirring reaction mixmre was added water (20 mL) which caused the product to precipitate as an oil. This mixmre was extracted with 30% dichloromethane in diethyl ether (2 x 25 mL), washed with water (2 x 25 mL), dried (anhydrous sodium sulfate), and rotary evaporated.
This provided 123 mg (51 %) ot (162): rt= 10.00 min.: m/z (rel. int.) 269 (M+,53), 212 (15), 212 (15), 198 (7), 174 (25), 158 (6), 157 (36), 131 (7), 130 (44), 129 (100), 113 (6), 112 (66). 103 (18), 102 (36), 95 (9), 81 (6), 76 (12), 75 (9), 56 (5), 55 (10), 51 (6), 41 (12).
EXAMPLE 12: Preparation of V-[(lS,2S,5S)-trα/w-Myrtanyl]-2- quinoxalinecarboxamide (225)
(lS,2S,5S)-trα«.ϊ-Myrtanyl trifluoroacetate
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-myτιa.nvl tπfluoroacetate.
(lR.2R.5i?)-trøns-Myrtanyl trifluoroacetate In a similar manner, (lR,2R,5R)-trø/w-myrtanyI trifluoroacetate was prepared from tnfluoroacetic anhydride (5.40 mL, 38.0 mmol, 1.2 equιv) (+)- trørcy-myrtanol (5.00 mL. 4.90 g, 31.7 mmol), and tetrahydrofuran ( 100 mL) yielding 7.60 g (94%) of (lR,2R,5R)-trα u-myrtanyl trifluoroacetate.
(15,2S,55)-trα/u-Myrtanyiazide
A mixmre of (lS,2S,5S)-trα«5-myrtanyl trifluoroacetate (1.0 g, 4.0 mmol), sodium azide (0.39 g, 6.0 mmol), and /V.N-dimethylformamide (50 mL) was stirred at 80 °C for 24 h. After cooling to 25 °C, water ( 100 mL) was added, and this mixmre was extracted with diethyl ether (2 x 50 mL). The organic layer was then dried (anhydrous sodium sulfate) and rotary evaporated. This provided 1. 12 g ( 100%) of (lS,2S,5S)-trα/u-myrtanylazιde as a colorless oil.
(l/?,2R,5R)-trα/ιs-Myrtanylazide In a similar manner. (lR.2R,57?)-trα/w-myrtanyiazιde was prepared from
(lR.2R.5R)-trα/! -myrtanyl trifluoroacetate (7 60 g, 30.4 mmol), sodium azide (3.00 g, 45.6 mmol), and TV.TV-dimethylformamide (100 mL) yielding 4 10 g (48.2%) of ( lR,2R.5R)-tra/w-myrtanyIazιde.
(lS,2S,5S)-trα/w-MyrtanyIamine
A mixmre of (lS,2S,5S)-trα/u-myrtanylazιde (1.12 g, 7.32 mmol) and platιnum(IV) oxide hydrate (0.34 g) in ethanol (50 mL) was shaken under hydrogen gas (50 psig) for 2 h. The reaction mixmre was then filtered through paper, and the filtrate was rotary evaporated. The resulting material was taken up in 0.12 M hydrochloric acid (100 mL), and the aqueous solution was washed with diethyl ether (2 x 50 mL). 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-myπanylamιne as a light yellow oil.
(lR.2R.5R)-trans-Myrtanylamine In a similar manner. ( 17?.2R.5R)-trα/w-myrtanyiamιne was prepared from
(lR,2R,5R)-trα w-myrtanylazιde (4.10 g, 26.8 mmol), platιnum(IV) oxide hydrate (0.41 g), and ethanol (75 mL) yielding 2.00 g (48.8%) ot ( IR.2R.5R)- trα/w-myrtanylamme .
7V-[(lS,2S.5S)-trαns-MyrtanyI]-2-quinoxalinecarboxamide (225)
In a similar manner to ( 162), (225) was prepared from 2-quιnoxaloyl chloride (49 mg, 0.25 mmol), (lS,2S.5S)-tra/w-myrtanylamιne (35 mg,
0.23 mmol), and pyndine (5 mL) yielding 8 mg (10%) of (225): rt= l 1.23 min.; m/z (rel. int.) 309 (M + ,25), 187 (15), 186 (39), 174 ( 12), 158 (14), 157 (29), 152 (20), 131 (6), 130 (47), 130 (47), 129 (100), 103 (15), 102 (41), 93 (9), 91 (6), 81 (12), 79 (12), 77 (9), 76 (11), 75 (10), 69 (14). 67 (17). 55 (8), 54 (5), 53 (7), 51 (7), 43 (6), 41 (25).
/V-[(lR.2 ?.5Λ)-trαns-Myrtanyl]-2-quinoxalinecarboxamide (226) In a similar manner. (226) was prepared from 2-quιnoxaloyl chloride
(193 mg, 1.0 mmol), (lR,2R.5R)-trα^-myrtanylamme (138 mg, 0.90 mmol). and pyridine (5 mL) yielding 27 mg (10%) of (226): rt= 1 1.19 min.: m/z (rel. int.) 309 (M + ,21), 186 (47), 186 ( 18), 174 ( 17), 158 ( 16), 157 (34), 152 (30), 131 (6), 130 (47), 130 (47), 129 ( 100), 121 (6), 103 (15), 102 (40), 93 ( 1 1), 91 (6), 81 (12), 79 (1 1), 77 (8), 76 (10). 75 (9), 69 ( 14), 67 (17), 55 (7), 53 (6), 51 (5), 43 (5), 41 (18).
EXAMPLE 13: Preparation of 7V-[/V'-(Λ)-α-MethyIbenzyl-2-acetamido]-
3-aminoquinoline dihydrochloride (156)
N-(R)-α-Methylbenzyl-2-chloroacetamide
(R)-α-MethyΙbenzylamιne (2.4 g, 20 mmol) in dichloromethane (50 mL) was added to chloroacetyl chloride (2.25 g, 20 mmol) in dichloromethane (70 mL) and pyndine ( 10 mL). The reaction solution was stirred, then diluted with diethyl ether (500 mL), washed with water (3 x 30 mL), dried (anhydrous magnesium sulfate), and rotary evaporated. This provided 3.60 g of N-(R)-a- methylbenzyl-2-chloroacetamιde. /V-( ?)-α-MethylbenzyI-2-iodoacetamide
A solution or sodium iodide ( 10.37 g, 69 mmol) in dry acetone was slowly added to a solution of /v-(Λ)-α-methylbenzyi-2-chioroacetamιde (3.39 g, 17 mmol) in dry acetone, and the reaction mixmre was refluxed for 16 h. The reaction mixmre was then filtered, and the filtrate was rotary evaporated. Diethyl ether was added, and the mixmre was stirred for 20 min. The mixmre was then filtered, and the filtrate was rotary evaporated and then put under high vacuum to provide N-(R)- -methyIbenzyl-2-iodoacetamιde.
Λ^[Λ^'-(R)-α-Methylbenzyl-2-acetamido]-3-ammoquinoline dihydrochloride (156)
A mixmre of 3-amιnoquιnolιne (0.15 g, 1.0 mmol) and potassium fluoride on Celite (50%) (0.30 g, 2.5 mmol) in acetonitnle (20 mL) was stirred for 1 h. iV-(R)-α-Medιylbenzyl-2-ιodoacetamιde (0.31 g, 1.0 mmol) in acetonitnle was added, and the reaction mixture was refluxed tor 64 h. The mixmre was filtered. and the filtrate was rotary evaporated. The resulting material was taken up in diethyl ether and washed wim 1 M sodium hydroxide (3 x 30 mL). The combined aqueous layers were samrated with sodium chloride and were then extracted with chloroform (4x). The combined organic layer were dried
(anhydrous magnesium sulfate) and rotary evaporated. The resulting material was dissolved in chloroform ( 10 mL), 1 M hydrogen chloride in diethyl ether
(5 mL) was added, and the solution was rotary evaporated. The resulting material was dissolved m chloroform (5 mL) and filtered through a 0.45 μm filter disc, and the filtrate was evaporated. This provided 13 mg (3%) ot (156): rt= 10.43 min.; m/z (rel. int.) 328 (M + , 11), 182 (12), 181 (86), 180 (37), 167
(22), 166 (25), 165 (17), 162 (53), 161 (95), 160 (37), 148 (32), 145 ( 18), 135
(21), 132 (16), 122 (9), 120 (22), 119 (20), 107 (19), 106 (13), 105 ( 100). 104 (22), 103 (19), 90 (12), 79 (25), 78 (11), 77 (38), 51 (10), 44 (10), 41 ( 1 1)
EXAMPLE 14: Preparation of l-(l-Adamantyl)-2-(benzothiazol-2- y!sulfanyl)ethanone (273)
Sodium hydride (36.5 mg, 1.52 mmol. 60% in mineral oil) was washed with pentane (4X), dried under N2, suspended in dimethylformamide (DMF. 10 mL) and cooled to 0 °C With stirring, a solution of 2-mercaptobenzothιazoie (253.3 mg, 1.52 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred 20 minutes at 0°C and treated with a solution of 1- adamantanebromomethyl ketone (389.8 mg, 1 52 mmol) in DMF (8 mL). The reaction was stirred 30 minutes at ambient temperamre and diluted with diethyl ether (100 mL). The resulting solution was washed with water (5 x 30 mL) and the remaining organic solution dried over anhydrous MgSO4, filtered, and concentrated to a solid. Recrystallization from hot ethanol afforded 287 mg (55%) of the desired product: GC/EI-MS gave m/z (rel. int.) 343 (M+. 10), 315 (2), 180 (2), 148 (10), 135 (100), 107 (9), 93 (17), and 79 (20).
EXAMPLE 15: Assay of mGluR Group I antagonist activity
HEK-293 cells expressing a recombinant receptor as described in WO 97/05252 were loaded with 2 μM Fura-2 acetoxymethylester by incubation for 30-40 minutes at 37 °C in SPF-PCB (126 mM NaCI, 5 mM KG, 1 mM MgCh.
20 mM Na-HEPES, 1.0 mM CaCh, 1 mg/mL glucose, and 0.5% BSA. pH 7 4).
The cells were washed 1-2 times in SPF-PCB. resuspended to a density ot
4-5 million cells/mL and kept at 37 °C in a plastic beaker. For recording fluorescent signals, 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. To calibrate fluorescence signals, digitonin (Sigma Chemical Co., St. Louis, MO; catalog # D-5628; 50 μg/mL, final) was added to obtain maximal fluorescence (Fmaxi, and the apparent minimal fluorescence (Fmm) was determined by adding TRIS-Base/EGTA (10 mM, pH 8.3, final). Concentrations of intracellular Ca2+ were calculated using a dissociation constant (Kd) of 224 nM and applying the equation:
[Ca2 ~]. = (F - Firun F a ) x Kd; where F is fluorescence measured at any particular time of interest and F falls between Fm-x and Fmm.
Control responses to the addition ot 5 mM Ca2τ (final extracellular calcium concentration. 6 mM) were determined in separate cuvettes. Control responses to changes in extracellular calcium were determined throughout the length of the experiment. Compounds were tested at a single concentrauon per cuvette of cells, and all compounds were prepared in DMSO. Appropriate dilutions were made such mat compounds were added in no greater volume man 10 μl per a total volume of 1500 μl (final DMSO not greater than 0.67%) to achieve any particular testing concentration.
Once a stable intracellular calcium baseline was achieved, the compound was added to the cuvette. The response or lack ot response to the compound addition was allowed to stabilize for 1-3 minutes and then 5 mM calcium was added to determine the effect of the compound on the subsequent calcium response. Once the peak for the subsequent calcium response was obtained, digitionm and EGTA were added in a sequential manner to determine FH A and Fmin respectively. Data were expressed as changes in intracellular calcium concentrations in nM. These changes in the calcium response post compound addition were compared to the control (no compound) calcium response. Responses to calcium in the presence of test compounds were normalized as a percent change from that of controls. Data were entered into a Levenberg- Marquardt analysis for non-linear least squares and an IGo and 95% confidence intervals thereof were determined for each compound. The invention thus has been disclosed broadly and illustrated in reference to representative embodiments described above. Those skilled in the art will recognize that various modifications can be made to the present invention without departing from the spirit and scope thereof.

Claims

What is claimed is:
1. A compound represented by the formula I.
R- Linker]— Ar wherein R is an optionally substituted straight or branched chain alkyl. aralkyl, cycioalkyl, or alkylcycloalkyl group containing 5-12 carbon atoms. wherein Ar is an optionally substituted aromatic, heteroaromatic. aralkyl, or heteroaralkyl moiety containing up to 10 carbon atoms and up to 4 heteroatoms, and wherein [linker] is -(CH2V, where n is 2-6, and wherein up to 4 CH2 groups may independently be substituted with groups selected from the group consisting of G-G alkyl. CHOH. CO. O. S, SO. SO2. N. NH. and NO. provided that two heteroatoms may not be adjacent except when those atoms are both N or are both NH. and wherein any two adjacent CH2 groups may be replaced by a substituted or unsubstituted alkene or alkyne group, or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein Ar comprises a ring system selected from the group consisting of benzene, thiazole, turyl, pyranyl. 2H-pyrrolyl. ihienyl, pyroilyl, lmidazolyl, pyrazolyl, pyndyl. pyrazinyl. pynmidinyl, pyridazinyl benzothiazole. benzimidazole. 3H-ιndolyI, indolyl. indazoiyi, puπnyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyπdinyl, quinazo nyl, cinnolinyl, isothiazolyl, quinoxa nyl indolizinyl, isoindolyl, benzothienyl. benzofuranyl, isobenzofuranyi, and chromenyl rings, wherein Ar 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.
3. The compound according to claim 1, wherein R contains 7-11 carbon atoms, wherein some or all of the hydrogen atoms on two carbon atoms optionally may be replaced with substiments independently selected from the group consisting of F. Cl. OH. OMe, and =0. - - 5 -
4. The compound according to claim 1 , wherein [linker] comprises an amide, ester, or thioester group.
5. The compound according to claim 3, wherein R comprises a moiety selected from the group consisting of adamantyl, 2-adamantyl, (lS,2S,3S,5R)-ιsopιnocamphenyl, tncyclo[4.3.1. l(3,8)]undec-3-yl, ( 1S.2R.5S)- -myrtanyl, ( lR.2R.4S)-isobornyl (lR,2R.3R.5S)-ιsopιnocamphenyl, (lS.2S.5S)-trα w-myrtanyl, (lR,2R,5R)-trc/w-myrtanyl, (lR.2S,4S)-bornyl. 1- adamantanemethyl, 3-noradamantyl, (lS,2S,3S,5R)-3-pinanemethyl, cyclooctyl, α, -dimedιylphenethyl, (S)-2-phenyl-l-propyl, cycioheptyi, 4-methyl-2-hexyl groups, 2,2,3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2- methylpropyl. 3.5-dimethyladamantyl, tra/7i,-2-phenyicyclopropyl, 2- methyicyclohexyl, 3,3,5-tnmethylcyclohexyl, 2-(ø-methoxyphenyl)ethyl. 2- (1,2,3,4-tetrahydronaphthyl), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2-(m- fluorophenyl)ethyl, 2-(p-fluorophenyi)ethyl, 2-(3-hydroxy-3-phenyl)propyl, (S)- 2-hydroxy-2-phenylethyl , (R)-2-hydroxy-2-phenylethyI , 2-(3- -chloropheny 1-2- methyl)propyl, 2-(3-p-chlorophenyl-2-methyi)propyl, 4-tert-butyl-cyclohexyl. (S)- 1 -(cyclohexyl)ethyl , 2 -(3-(3 , 4-dimethylphenyl)-2-methyl)propyl , 3,3- dimethylbutyl, 2-(5-methyl)hexyl, l-myrtanyl, 2-bornyl, 3-pιnanemethyl. 2,2,3,3,4,4,5,5-octafluoropentyl, -fluoro- ,α-dimethylphenethyl, 2-naphthyl. 2- bornanyi, cyclohexylmethyl. 3-methylcyclohexyl. 4-methylcyclohexyI. 3.4- dimediylcyclohexyl. 5-chloro-tπcyclo[2.2.1]heptyl, o-α.α-dimethylphenethyl, 2- indanyl, 2-spιro[4.5]decyl, 2-phenylethyI, 1 -adamanty lethyl, 1-(1- bicycio[2.2. l]hept-2-yl)ethyl, 2-(2-methyl-2-phenylpropyl), 2-(o- fluorophenyl)ethyl, l-(cyclohexyl)ethyl, and cyclohexyl.
6. The compound according to claim 1 , wherein Ar comprises a group having the formula
wherein X1, X2, X5, and X4 independently can be N or CH. provided that not more than two of X1, X2, X5, and X" can be N. -46 -
7. The compound according to claim 6. wherein X1 is N.
8. The compound according to claim 7. wherein X2 is N.
9. The compound according to claim 6, wherein X^ is N.
10. The compound according to claim 6. wherein X1 is CH and X2 is
N.
11. The compound according to claim 1 , wherein Ar is an optionally substituted 2-, 3-. or 4-pyπdyl moiety.
12. The compound according to claim 1. wherein Ar is a 6- benzothiazoiyl moiety.
13. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent or excipient.
14. A method ot making a compound according to claim 4. comprising reacting a compound containing an activated carboxylic acid group with a compound containing an amine. hydroxyl, or thiol group.
15. A method of inhibiting activation of an mGluR Group I receptor, compπsmg treating a cell contammg said receptor with an effective amount of a compound according to claim 1.
16. A method of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, comprising treating neurons with an effective amount of a compound according to claim 1.
17. A method of treating a disease associated with giutamate-induced neuronal damage, comprising administering to a patient sutfermg from said disease an effective amount ot a composition according to claim 13.
18. The compound according to claim 1 , wherein said compound is selected from me group consisting of 7V-[6-(2-MedιylquιnolyI)]-l- adamantanecarboxamide, /V-(6-QuιnoIyl)-l-adamantanecarboxamιde. 7V-(2- QuιnolyI)-l-adamantanecarboxamιde, N-(3-Quιnolyl)-l-adamantane-carboxamιde. 6-Qumoiyl-l-adamantanecarboxylate, l-Adamantyl-6-qumoIιnecarboxylate. 2,2,3,3,4,4,5,5-Octafluoro-l-pentyl-6-qumolιnecarboxylate. 1- Adamantanemethyl-6-quιnolιnecarboxylate, 1 -Adamantyi-2- quinoxaiinecarboxylate, 7V-( 1 -AdamantyI)-3-quιnolιne-carboxamιde, 7V-( 1 - AdamantyI)-2-qumolιnecarboxamιde, 7V-(2-Adamantyl)-2- qumoxalmecarboxamide. N-[(lR.2R,3R,5S)-3-Pιnanemethyl]-2-quιnoxalιne- carboxamide. N-( 1 -Adamantyl)-2-qumoxaimecarboxamιde, 7V-( 1 - Adamanty 1) -6- quinoiinecarboxamide, 7V-( ro-2-Norbornanyl)-2-quinoxahnecarboxamide. 7V- [(lR,2S.4S)-Bornyl]-2-quιnoxalιnecarboxamιde, V-(3-Noradamantyl)-2- quinoxaiinecarboxamide, 7V-[( 1 R,2R.3R,5S)Iso-pιnocamphenyi]-2- qumoxaiinecarboxamide. /V-[(lS,2S.3S,5R)-Isopιnocamphenyl]-2-qumoxalιne- carboxamide, /V-(5-Chloro-[2.2.1.0]tπcyclo-2,6-hepta-3-yl)-2- qumoxa necarboxamide, 7V-([4.3.1.1 )Tπcyclo-3,8-undeca-3-yl)-2- quinoxahnecarboxamide, yV-[(lS,2R,5S)-cιs-Myπanyl]-2- qumoxalinecarboxamide. /V-[(lR.2R,4S)Isobornyl]-2-quιnoxalιnecarboxamιde. jV-[endo-( ±)-2-Norbornanvl]-2-quιnoxalιnecarboxamιde. 7V-[(R)-2-Phenyl- 1 propyl]-2-quιnoxalιnecarboxamιde. 7V-[(S)-2-Phenyl-l-propyl]-2- quinoxalinecarboxamide, V-(2-Indanyl)-2-quιnoxalιnecarboxamιde. 1-Adamantanemethyl 6-quιnolyl e er, l-Adamantyl-3-quιnolιnecarboxyIate. 7V- (α,α-Dιmethyiphenedιyl)-2-quιnoxalmecarboxamιde, 7V-(α,α-Dιmethyl-2- chlorophenethyl)-2-quιnoxaiιnecarboxamιde, 7V-( ,α-Dιmethyl-4- fluorophenethyl)-2-quιnoxahnecarboxamιde, N-(β-MethylphenethyI)-2- quinoxahnecarboxamide, 7V-(3-Methyicyclohexyl)-2-quιnoxalιnecarboxamιde. 7V- (2,3-Dιmethylcyclohexyl)-2-quιnoxahnecarboxamιde, /V-[(lS,2S.3S,SR)-3- PmanemethyI]-2-quinoxaline-carboxamide, 7V-( l-Adamantanemethyl)-2- qumoxaline-carboxamide, .V-(4-MethylcycIohexyl)-2-quιnoxalιne-carboxamιde, 7V-[(lS,2S,5S)-trfl/2- -Myrtanyl]-2-quιnoxalιne-carboxamιde, and 7V-[(lR.2R,5R)- trc ,-MyrtanyI]-2-quinoxalinecarboxamide. and pharmaceutically acceptable salts thereof.
19. The compound according to claim 1, wherein said compound is selected from the group consisting of 7V-( l-Adamantyl)-3-quιnolιnecarboxamιde. N-(l-Adamantyi)-2-quinohnecarboxamide, Λr-(2-Adamantyl)-2-quιnoxaiιne- carboxamide, Λ-[(lR,2R.3R,5S)-3-Pinanemethyl]-2-quιnoxaIιne-carboxamιde, N- (l-Adamantyi)-2-quιnoxaline-carboxamide. 7V-(l-Adamantyi)-6- quinolinecarboxamide, N-(erø-2-Norbornanyl)-2-quιπoxaiine-carboxamιde, N- [(lR,2S,4S)-Bornyl]-2-quιnoxaline-carboxamιde, 7V-(3-Noradamantyl)-2- quinoxaiine-carboxamide, 7V-[(lR,2R,3R,5S)-Isopιnocamphenyl]-2-quιnoxaiine- carboxamide, 7V-[(lS,2S.3S.5R)-Isopιnocamphenyl]-2-quιnoxaiine-carboxamιde. 7V-(5-Chloro-[2.2.1.0]tncyclo-2,6-hepta-3-yI)-2-quιnoxalιne-carboxamιde. N- ([4.3.1. l]Tricycio-3,8-undeca-3-yl)-2-qumoxaline-carboxamιde, /V-[(1S.2R,5S)- y-Myrtanyi]-2-quιnoxaiine-carboxamιde, N-[(lR,2R.4S)Isobornyi)-2- quinoxaline-carboxamide. N-[endo-( +)-2-Norbornanyi]-2-quιnoxaline- carboxamide, 7V-[(lS,2S,3S,5R)-3-Pinanemethyl]-2-quinoxaIinecarboxamide. 7V- (l-AdamantanemethyI)-2-quιnoxalιnecarboxamιde, N-[(lS.2S,5S)-trans- Myrtanyl]-2-quιnoxalιnecarboxamιde, and 7V-[( 1 R.2R,5R)-trα^-Myrtany 11-2- quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
20. The compound according to claim 1 , wherein said compound is selected from the group consisting of 7V-[6-(2-Methylquιnolyl)]-l- adamantanecarboxamide, 7V-(6-Quιnolyl)- 1 -adamantanecarboxamide. /V-(2- Quinoiyl)-l-adamantanecarboxamide. and 7V-(3-QumolyI)-l- adamantanecarboxamide, and pharmaceutically acceptable salts thereof
21. The compound according to claim 1, wherein said compound is selected from the group consisting of N-(3-MethylcycIohexyl)-2- qumoxaiinecarboxamide, 7V-(2,3-Dimethylcyclohexyl)-2-quιnoxalinecarboxamide. 7V-[(lS.2S,3S,5R)-3-Pinanemethyl]-2-quιnoxalinecarboxamιde, 7V-(1- Adamantanemethyl)-2-quιnoxahπecarboxamιde, and 7V-(4-Methylcyclohexyl)-2- quinoxaiinecarboxamide. and pharmaceutically acceptable salts thereof.
22. The compound according to claim 1, wherein said compound is selected from the group consisting of 7V-[(R)-2-Phenyl-l-propyl-2- qumoxaiinecarboxamide. iV-[(S)-2-Phenyl-l-propyl]-2-quιnoxalmecarboxamιde. /V-(2-Indanyl)-2-quιnoxahnecarboxanπde, 7V-(α-α-DιmethyIphenethyl)-2- quinoxahnecarboxamide. .V-(α,α-Dιmethyl-2-chlorophenethyl)-2- quinoxalinecarboxamide. .V-(a,a-Dimethyl-4-fluorophenethyl)-2-quinoxaline- carboxamide, and N-(β-Methyiphenethyl)-2-quιnoxalιne-carboxamιde, and pharmaceuucally acceptable salts thereof.
23. The compound according to claim 1, wherein said compound is 1- Adamantanemethyl 6-quιnolyl ether, or a pharmaceutically acceptable salt thereof.
24. The compound according to claim 1 , wherein said compound is selected from the group consisting of 6-Quιnolyl-l-adamantanecarboxylate. 1- Adamantyl-6-quιnolιnecarboxylate. 2,2,3,3,4,4,5,5-Octafluoro-l-pentyl 6- quinoiinecarboxyiate, 1 -Adamantanemediyl 6-quιnolιnecarboxyiate, 1-Adamantyi- 2-quιnoxaiιnecarboxyiate. and l-Adamantyl-3-quιnolιnecarboxylate. and pharmaceutically acceptable salts thereof.
25. The compound according to claim 1 , wherein said compound is selected from the group consisting of 3-(l-Adamantanemethoxy)-2- chloroquinoxaline. 2-(l-Adamantanemethoxy)-3-methyiquιnoxalιne. 3-(l- Adamantanemethoxy)-2-fluoroquιnoxalιne. 2-( l-Adamantanemethoxy)-3- tπfluoromemylquinoxaline, 7V-[2-(4-PhenyIthιazoiyI)]- 1 -adamantanecarboxamide. 7V-[2-(5-Methyl-4-phenylthιazolyI)]-l -adamantanecarboxamide. l-(l-Adamantyl)- 2-(benzothιazol-2-ylsulfanyi)ethanone, 7V-(l-Adamantyl)-2-chloroquιπoxaiιne-3- carboxamide, 7V-(1- Adamanty l)-3-methylquιnoxalιne-2-carboxamιde. and 7V-(1- Adamantyl)-l-oxyquinoxahne-3-carboxamide, and pharmaceutically acceptable salts thereof.
26. The compound according to claim 1, wherein said compound is selected from the group consisting of 4-Chlorophenyl 3-coumarmcarboxylate. 2- (l-Adamantanemethylsuifanyl)quιnoxalιne, 3-(l-Adamantanemethoxy)-2- chloropyrazine. 1-( 1- Adamanty I)-2-(4, 6-dιmethylpyπmιdιn-2- ylsulfanyl)ethanone, l-(l-Adamantyl)-2-(2-anιsylsulfanyl)ethanone, 3-(l- Adamantanemethoxy)- 1 H-quιnoxaiin-2-one, 1 -( 1 -Adamantyl)-2-(3- anisylsulfanyl)ethanone. l-(l-Adamantyl)-2-(4-anisylsulfanyl)ethanone, 1-(1- Adamantyl)-2-(4-chIorophenylsulfanyl)ethanone, l-(l-AdamantyI)-2-(2- naphthylsulfanyl)ethanone, N-(2-[6-( 1 -Pipeπdiny pyrazinyl])- 1 - adamantanecarboxamide, 7V-(2-[6-( 1-Pipeπdinyl)pyrazιnyl])adamantan- 1 - ylmethylcarboxamide, l-(l-Adamantyl)-2-(l-naphthylsulfanyI)ethanone, 1-(1- Adamantyl)-2-(8-quinolylsulfanyi)ethanone hydrochloride, 1 -( 1 -Adamanty I)-2 -(4- trifluoromethoxyphenoxy)ethanone, 2-(l-Adamantanemethoxy)quinoxaline, 7V- (trα/w-4-Med ylcyclohexy l)-2-quinoxalinecarboxamide , N-(cis-4- Methylcyclohexyl)-2-quιnoxalinecarboxamide, 7V-(trαnj,-4-Methylcyclohexyl)-2- quinolinecarboxamide, 7V-(trα/w-4-Methylcyclohexyl)-3-quιnolinecarboxamιde. and N-(tra«i'-4-Methyicyciohexyi)-6-quinolinecarboxamide. and pharmaceutically acceptable saits thereof.
27. The compound according to claim 1, wherein said compound is selected from the group consisting of 2-(l-AdamantanemethylsulfinyI)- benzothiazole, ;V-(4-Phenylbutyl)-2-quιnoxalmecarboxamide. l-( l-Adamantyl)-2- (4, 6-dimethylpyπmidin-2-ylsulfanyl)ethanol, l-(l-Adamantyl)-2-(3- chloroquinoxal-2-yl)ethanone, 2-(l-Adamantanemethylsulfanyl)-3- methylquinoxaline. 7V-(l-Adamantyl)-2-anιsamide, 7V-(l-Adamantanemethyl)-2- anisamide. l-(l-Adamantyl)-2-(4-chlorophenyisulfanyl)ethanone, 2-(l- Adamantanemethylsulfonyl)-3-methylquinoxaiine. l-(l-Adamantyl)-2-(4- fluorophenylsulfanyl)ethanone. l-(l-Adamantyl)-2-(3- fluorophenylsulfanyOethanone. 1-(1 -Adamanty I)-2-(2-methoxyphenoxy)ethanone. l-(4-Anisylsulfanyl)butan-2-one, l-(l-Adamantyl)-2-(4-anisidinyl)ethanone hydrochloride, 3, 3-Dimethyl-l-(4-anisylsulfanyl)butan-2-one, l-(4-Biphenyl)-2- (4-anisylsulfanyl)ethanone, 1 -( 1- Adamanty l)-2-(2- trifluoromethoxyphenyIsulfanyi)ethanone, l-(l-AdamantyI)-2-(3-methylquinoxai- 2-ylsulfanyI)ethanone, l-( l-Adamantyl)-2-(2-anisidinyl)ethanone hydrochloride, l-(l-Adamantyl)-2-(4-tnfluoromethoxyphenylamino)ethanone hydrochloride. 1- ( l-Adamantyl)-2-(7V-methyl-4-amsidinyl)ethanone hydrochloride, 7V-( 1- Adamantyl)-7-trifluoromethylquιnoline-3-carboxamide. 7V-( 1- Adamanty l)-2-( 1- piperizinyl)quinoxaline-3-carboxamιde. 7V-( l-Adamantyl)-2-(2- ammoedιylamιno)quιnoxaline-3-carboxamιde, Memyl 7V-(3-qumoiyI)-3- carboxyadamantane- 1 -carboxamide. 1-(1 -Adamanty l)-2-[(R)-l-( l-naphthyl)ethan- l-yiamιno]ethanone. 7V-(l-Adamantyl)-2-methoxyquιnoxaiιne-3-carboxamιde, Ethyl 7V-( l-adamantyl)-2-(3-propanoylammo)quιnoxaline-3-carboxamιde. 7V-(4- Chlorophenyl)-2, 3-dimethylquιnoxaline-6-carboxamιde. N-(l-Adamantyl)-6, 7- dimethylqumoxaline-2-carboxamιde, N-((S)- 1 -Tetraiιnyl)-2- quinoxalinecarboxamide, 7V-(4-Chlorophenethyl)-2-quιnoxalιnecarboxamιde. 7V- (6-Quinolyl)-2-quιnoxalinecarboxamιde, 7V-(l-Tetraiinmethyl)-2- qumoxaiinecarboxamide, 7V-(l-Indanmethyl)-2-quinoxaiinecarboxamide, 7V-(4, 4- Dimethylcyclohexyl)-2-quιnoxaiinecarboxamide, and pharmaceuucally acceptable salts thereof.
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