AU2004202776B2 - Metabotropic glutamate receptor antagonists for treating central nervous system diseases - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: NPS PHARMACEUTICALS, INC.

Invention Title: METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS FOR TREATING CENTRAL NERVOUS SYSTEM DISEASES The following statement is a full description of this invention, including the best method of performing it known to us: -2- METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS AND THEIR USE FOR TREATING CENTRAL NERVOUS SYSTEM DISEASES

FIELD

The present invention provides compounds active at metabotropic glutamate receptors and that are useful for treating neurological and psychiatric diseases and disorders.

BACKGROUND

Recent advances in the elucidation of the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the therapy of acute and chronic neurological and psychiatric disorders and diseases. However, the major challenge to the realization of this promise has been the development of metabotropic glutamate receptor subtypeselective compounds.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate produces its effects on central neurons by binding to and thereby activating cell surface receptors. These receptors have been divided into two major classes, the ionotropic 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 receptors that activate a variety of intracellular second messenger systems following the binding of glutamate. Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation ofphospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation ofphospholipase A 2 increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).

Eight distinct mGluR subtypes, termed mGluR1 through mGluR8, have been identified by molecular cloning. See, for example, Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med.

Chem. 38:1417 (1995). Further receptor diversity occurs via expression of H:\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -3alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosci. 15:3970 (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 mGluR1, mGluR5, and their alternatively spliced variants. The binding of agonists to these receptors results in the activation of phospholipase C and the subsequent mobilization of intracellular calcium.

Electrophysiological measurements have been used to demonstrate these effects in, for example, Xenopus oocytes expressing recombinant mGluR1 receptors. See, for example Masu et al., Nature 349:760 (1991); Pin et al., PNAS 89:10331 (1992).

Similar results have been achieved with oocytes expressing recombinant receptors. Abe et al., J. Biol. Chem. 267:13361 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosci. 15:3970 (1995). Alternatively, agonist activation of recombinant mGluR1 receptors expressed in Chinese hamster ovary (CHO) cells stimulates PI hydrolysis, cAMP formation, and arachidonic acid release as measured by standard biochemical assays. Aramori et al., Neuron 8:757 (1992).

In comparison, activation of mGluR5 receptors expressed in CHO cells stimulates PI hydrolysis and subsequent intracellular calcium transients, but no stimulation of 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 cells 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 quisqualate glutamate ibotenate (2S,1 carboxycyclopropyl)glycine (L-CCG-I) (1S,3R)-1-aminocyclopentane-1,3dicarboxylic acid (ACPD). Quisqualate 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 mGluRassociated pathophysiological processes that affect the CNS have yet to be defined.

However, work with the available non-specific agonists and antagonists has yielded H,\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -4some 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 implicate Group I mGluRs as the mediators of this excitatory mechanism. The effects of ACPD can be reproduced by low concentrations of quisqualate in the presence of iGluR antagonists. Hu et al., Brain Res. 568:339 (1991); Greene et al., Eur. J. Pharmacol. 226:279 (1992). Two phenylglycine compounds known to activate mGluR1, namely hydroxyphenylglycine ((S)-3HPG) and (S)-3,5-dihydroxyphenylglycine DHPG), also produce excitation. Watkins et al., Trends Pharmacol. Sci. 15:33 (1994). In addition, the excitation can be blocked by (S)-4-carboxyphenylglycine (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG), and (+)-alphamethyl-4-carboxyphenylglycine compounds known to be mGluR1 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 ofmGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar 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 nociception and analgesia also has been demonstrated. Meller et al., Neuroreport 4: 879 (1993). In addition, mGluR activation has been suggested to play a modulatory role in a variety of 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 vestibuloocular reflex. For reviews, see Nakanishi, Neuron 13: 1031 (1994); Pin et al., Neuropharmacology 34:1; Knopfel et al., J. Med. Chem. 38:1417 (1995).

Metabotropic glutamate receptors also have been suggested to play roles in H,\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 a variety ofpathophysiological processes and disease states affecting the CNS.

These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, and neurodegenerative diseases such as Alzheimer's disease. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Cunningham et al., Life Sci. 54:135 (1994); Hollman et al., Ann. Rev. Neurosci. 17:31 (1994); Pin et al., Neuropharmacology 34:1 (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 presynaptic glutamate release, their activation probably contributes to the pathology. Accordingly, selective antagonists of Group I mGluR receptors could be therapeutically 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 al., Neurosci. Lett. 139:77 (1992); Lipparti et al., Life Sci. 52:85 (1993). Other studies indicate, however, that ACPD inhibits epileptiform activity, and also can exhibit neuroprotective properties. Taschenberger et al., Neuroreport 3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh et al., Proc. Natl. Acad. Sci. USA 88:9431 (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 presynaptic glutamate release, and diminishing excitatory neurotransmission.

This interpretation is consistent with the observation that (S)-4C3HPG, a Group I mGluR antagonist and Group II mGluR agonist, protects against audiogenic 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 al., J. Neurochem. 62:2492 (1994); Bruno et al., Eur. J. Pharmacol.

256:109 (1994); Pizzi et al., J. Neurochem. 61:683 (1993).

Based on the foregoing, it is clear that currently available mGluR agonists H:\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 06/05 2008 17:51 FAX 61 3 92438333 GRIFFITH HACK 4. IPAUSTRALIA 1aOO6 00 -6- 0 0- and antagonists have limited value, due to their lack of potency and selectivity. In addition, most currently available compounds are amino ac ds or amino acid derivatives that have limited bioavailabilities, thereby hampering in vi o studies to assess mGluR physiology, pharmacology and their therapeutic potential. pompounds that selectively inhibit activation of metabotropic glutamate receptor Grou4 I subtypes should be useful for treatment of neurological disorders and diseases such as senile dementia, N 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.

It is apparent, therefore, that identification of potent mGluR agonists and 1 antagonists with high selectivity for individual mGluR subtpes, particularly for Group SI receptor subtypes, are greatly to be desired.

SUMMARY

1s 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 s btypes, and to provide methods of making these compounds.

It is a further object of this invention to provide phatmaceutical compositions containing compounds which exhibit a high degree ofpote cy and selectivity for individual metabotropic glutamate receptor subtypes.

It is yet another object of this invention to provide n ethods of inhibiting activation of an mGluR Group I receptor, and of inhibiting :euronal damage caused by excitatory activation of an mGluR Group I receptor.

It is still another object of the invention to provide methods of treating a disease associated with glutamate-induced neuronal damage.

It is a further object of the invention to provide use 4f a metabotropic glutamate receptor-active compound in the treatment of a disease associated with glutamateinduced neuronal damage.

It is yet another object of the invention to provide u~e of a metabotropic glutamate receptor-active compound in the manufacture of medicament used to treat a disease associated with glutamate-induced neuronal damage.

To accomplish these and other objectives, the preset application relates to potent antagonists of Group I metabotropic glutamate receptors. These antagonists may be represented by the formula I, N:Melboume\CaseslPatentl38000-a38999P38405.AU.1pec 3840 U1 Speccalion 2008-4-30 doc 605/08 COMS ID No: ARCS-189488 Received by IP Australia: Time 17:55 Date 2008-05-06 04/06 2008 17:42 FAX 61 3 92438333 GRIFFITH HACK 4IPAUSTRALIA Id005 -7- R4 Linker 4-A wherein R is an optionally substituted straight or branched cycloalkyl, or alkylcycloalkyl group containing 5-12 carbo moiety and [linker] is -(CH 2 where n is 2-6, and whereit independently be replaced with groups selected from the gr alkyl, CHOH, CO, O, S, SO, S02, N, NH, and NO. Two he may not be adjacent except when those atoms are both N o-

CH

2 groups in [linker] also may be replaced by a substitute alkyne group. Pharmaceutically acceptable salts ofthe com More specifically, the present invention provides a the formula

I,

R-+LinkerAr wherein R is an optionally substituted cycloalkyl or containing 5-12 carbon atoms, wherein Ar is a quinolinyl moiety substituted with a wherein [linker] is -(CH 2 )n-CO-NH-, where n is 0-4; or a pharmaceutically acceptable salt thereof In one embodiment of the invention, R contains 7, 8, where some or all of the hydrogen atoms on two carbon atoi replaced with substituents independently selected from the E OH, OMe and =0.

In yet another embodiment [linker] comprises an am group.

In a preferred embodiment, R comprises a moiety se consisting of adamantyl, 2-adamantyl, (1 S,2S,3S,5R)-isopinj tricyclo[4.3.1.1(3,8)]undec-3-yl, (1 S,2R,5S)-cis-myrtanyl, (1R,3R,5S)-isopinocamphnyl, (1S,2S,5S)-trans-myrtan myrtanyl, (1R,2S,4S)-boyl, 1-adamantanemethyl, 3-norad pinanemethyl, cyclooctyl, t,at-dimethylphenethyl, (S)-2-ph 4 -methyl-2-hexyl groups, 2 2 3 ,3,4,4,4-heptafluorobutyl, 4methylpropyl, 3 ,5-dimethyladamantyl, trans-2-phenylcyclo hain alkyl, arylalkyl, I atoms. Ar is a quinoline Sup to 4 CH 2 groups may up consisting of C 1

-C

3 eroatoms in the [linker] are both NH. Two adjacent or unsubstituted alkene or ounds also are provided.

ompound represented by

(I)

ycloalkylmethyl group methyl group, and 9, 10 or 11 carbon atoms, optionally may be up consisting ofF, Cl, de, ester, or thioester ected from the group ocamphenyl, .R,2R,4S)-isobomyl 4, unantyl, (1S,2S,3S,5R)-3nyl- I -propyl, cycloheptyl, etoadamantyl, 3-phenyl-2ropyl, 2-methylcyclohexyl, N:W boumeCases\PalentI3800-3599P3 8406-AU-1SpedS\ 406&.AU.1 SpeclRcalon 2008-4-30.doc a3Sc/08 COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 06/05 2008 17:51 FAX 61 3 92438333 GIF~ AK- PUTAI 0 GRIFFITH HACK IPAUSTRALIA Q 008 00 0 0 ci 0 7A 3,3 ,5-arimethylcyclohexyl, 2-(o-methoxyphenyl)ethyl, 1 2,3,4-tetrahydronaphthy1), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2-(m-fluoropbenylfkthyl, 2-(pfluorophenyl)ethyl, 2-(3-hydroxy-3-phenyi)propyl, (S)-2-h~droxy-2-phenylethyI, hydroxy-2-phenylethyl, 2-(3-m-chloropheny1-2-methy)pro~,yI, 2-(3-p-chlorophenyl-2mnethyl)propyl, 4-tert-bulyl-cyclohexyl, -(cyclohexyl){hyl, dimethylphenyl)-2-methyl)propyl, 3,3-methylbutyl, 2-(5-lethyl)hexyl, I -'nyrtanyl, 2bornyl, 3-pinaneniethyl, 2,2,3,3,4,4, 5,5-octafluoropentyl, p' fluoro-axczdimethyiphenethyl, 2-naphthyi, 2-bornanyl, cyclohexylmelyl, 3-methylcyclohexyl, 4methylcyclohexyl, 3,4- N:WiboumeCasuPtitenLt38OO-38909P3640O6AU. 1lSpodiP30o6.AU1 Specification 2008-4-30.dov 01008B COMS ID No: ARCS-i 89488 Received by IP Australia: Time 17:55 Date 2008-05-06 04/06 2008 17:42 FAX 61 3 92438333 GRIFFITH HACK 4IPAUSTRALIA amoo6 -8dimethylcyclohexyl, 5-chloro-tricyclo[2.2. 1 heptyl, o-ct,a-lhnethylphenethyl, 2indanyl, 2-spiro[4.5]decyl, 2-phenylethyl, 1 -adanantylethy 1, 1 -bicyclo[2.2.] Jhept-2yl)ethyl, 2 -(2-methyl-2-phenylpropyl), 2-(o-fluorophenyl)e thyl, I -(cyclohexyl)ethyl, and cyclohexyl.

In yet another embodiment, the compound is selected from the group consisting of N-[6-(2-Methylquinolinyl)]-1-adamantanecarboxamide, N-(6-Quinolinyl)-ladamantanecarboxamide, N-(2-Quinolinyl)-1 -adanantanec uboxamide, N-(3- Quinolinyl)-1 -adamantane-carboxamide, 6-Quinolinyl- 1-a amantanecarboxylate, 1- Adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,5,5-Octafin ro-1 -pcntyl-6quiholinecarboxylate, 1 -Adamantanemethyl-6-quinolinecaijboxylat, N-(1-adamantyl)- 3-quinoline-carboxamide, N-(1 -Adamantyl)-2-quinolinecaroxamide, N-(l- Adanantyl)-6-quinolinecarboxamide, 1 -Adamantyl-3-quinbilinecarboxylate, and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the compound is selected from the group consisting is of N-(1-Adamantyl)-3-quinolinecarboxamide, N-(1-Adamantyl)-2quinolinecarboxamide and pharmaceutically acceptable sal s thereof.

In another embodiment, the compound is selected fiom the group consisting of N-[6-(2-Methylquinolinyl)] -l-adamantanecarboxamide, AT- 6-Quinolinyl)-ladamantanecarboxanide, N-(2-Quinolinyl)-1 -adanantanecarboxamide, and N-(3- Quinolinyl)-1-adaniantanecarboxamide and pharmaceutica y acceptable salts thereof In yet another embodiment, the compound is 1-Adai antanemethyl 6-quinolinyl ether, or a pharmaceutically acceptable salt thereof.

In another embodiment the compound is selected fom the group consisting of 6-Quinolinyl-1 -adamantanecarboxylate, -Adamantylted m the grop c 2 2 3 3 ,4,4,5,5-Octafluoro- I-penty 6-quinolinecarboxylate,j I-Adamantanemethyl 6quinolinecarboxylate, and pharmaceutically acceptable salt thereof In still another embodiment, the compound is selected from the group consisting of N-(trans-4-Methylcyelohexyl)-2-quinolinecarboxamide, hV-(trans-4- Methylcyclohexyl)-3-quinoljnecarboxamide and N-(trans-f-Methylcyclohexyl)-6quinolinecarboxamide, and pharmaceutically acceptable salfs thereof.

In yet another embodiment, the compound is seiecteh from the group consisting of Methyl N-(3-quinoliny)-3 -carboxyadamantane- 1 -carbox uide, and pharmaceutically acceptable salts thereof.

In yet another embodiment, the compound is -Methylquinolinyl)]-1 adamantanecarboxamide or a pharmaceutically acceptable 4 ilt thereof N:MeIlboumeasasatenaeeaOOO-a991P384eeAu1ssped "'3S40.AU.1 Specification 2008-4-3doc 4JDBEBa COMS ID No: ARCS-i93213 Received by IP Australia: Time 17:46 Date 2008-06-04 04/06 2008 17:42 FAX 61 3 92438333 GRIFFITH HACK 1PAUSTRALIA Q007 00 O -9- C- In accordance with another embodiment of the inve tion, there has been provided a pharmaceutical composition comprising a comound as set forth above, together with a pharmaceutically acceptable diluent or exci ient.

SIn accordance with still another embodiment of the invention, there has been provided a method of making a compound as set forth abo e, comprising reacting a ,NO compound containing an activated carboxylic acid group with a compound containing an amine, hydroxyl, or thiol group.

In accordance with a still further embodiment of the invention, there has been 0 provided a method of inhibiting activation of an mGluR Or Gmup I receptor, comprising o treating a cell containing said mGluR Group I receptor witL an effective amount of a -compound or a pharmaceutical composition as set forth ab ve.

C, In yet another embodiment of the invention, there h s been provided a method of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, comprising treating neurons with an effective amo unt of a compound or a pharmaceutical composition 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 glulamate-induced neuronal damage, comprising administering to a patient suffering fromn said disease an effective amount of a composition or a pharmaceutical composition as set forth above.

In accordance with another embodiment of the inve ition, there has been provided use of a compound or a pharmaceutical compositi n as set forth above, in the treatment of a disease associated with glutamate-induced n uronal damage.

In accordance with still another embodiment of the invention, there has been provided use of a compound or a pharmaceutical composition as set forth above, in the 2 5 manufacture of a medicament for the treatment of a disease associated with glutamateinduced neuronal damage.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should ke understood, however, that the detailed description and the specific examples, whie indicating preferred embodiments of the invention, are given by way of illustrat on only, since various changes and modifications 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.

N:olelboume\CasePatent3BO0oo-389P3B406.AU.1SpedP384M06,AU .1Spec licaUction200e-43Bdoc4/05 COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 04/06 2008 17:42 FAX 61 3 92438333 GRIFFITH HACK 4 1 IPAUSTRALIA Z008o DETAILED DESCRIPTION The invention provides compounds that are potent Group I metabotropic glutamate receptors. The compounc application can be represented by the general formula I: s where R is an optionally substituted straight or branched cl cycloalkyl or alkylcycloalkyl group, and Ar is a quinoline is a group that not only covalently binds to the Ar and R m adoption of the correct spatial orientation by Ar and R to a More specifically, the present invention provides a the formula I, R- Linker--Ar wherein R is an optionally substituted cycloalkyl or containing 5-12 carbon atoms, wherein Ar is a quinolinyl moiety substituted with wherein [linker] is -(CH 2 )n-CO-NH-, where n is 0-4 or a pharmaceutically acceptable salt thereof.

nd selective antagonists of s contemplated by the ain alkyl, arylalkyl, oiety. The [linker] moiety >ieties, but also facilitates ow receptor binding.

ompound represented by

(I)

cycloalkylmethyl group methyl group, and ad twelve carbon atoms, th 12, 13, 14, 15, or 16 6 carbon atoms, preferably lly substituted alkyl, ylalkyl. Generally, some or or methyl groups of R may group consisting ofF, Cl, en atoms may be replaced :adamantyl, 2-adamantyl, c-3-yl, (1S,2R,5S)-cisphenyl (1S,2S,5S)-transadamantanemethyl, 3methylphenethyl, 1 Each of these exemplary bove.

Structure of the R moiety The R moiety generally may contain between five a although the skilled artisan will recognize that R moieties v carbon atoms will be possible. Although R can contain 5 o: R contains at least 7 carbon atoms. Preferably, R is optiona cycloalkyl, cycloalkylmethyl, or optionally substituted phei all of the hydrogen atoms on up to two methine, methylene, be replaced by substituents independently selected from the OH, OMe and =0 groups. However, more than two hydrog with fluorine, and R may be perfluorinated.

Exemplary R moieties include, but are not limited tc (1 S, 2

S,

3 S,5R)-isopinocamphenyl, tricyclo[4.3.1.1 (3,8)]und myrtanyl, (IR,2R,4S)-isobornyl, (1R,2R,3R,5S)-isopinocan myrtanyl (1R,2R,5R)-trans-myrtanyl, (1R,2S,4S)-boryl, 1noradamantyl S,2S,3S,5R)-3-pinanemethyl, cyclooctyl, di phenyl-l-propyl, cycloheptyl, and 4-methyl-2-hexyl groups R moieties may also be substituted in the manner set forth a N:WelboumeaCaseePatenti3000-38999P384DS6AU. 1Spei P38408.AU.1 Specication 2008-4-30.doc 4/06/08 COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 04/06 2008 17:43 FAX 61 3 92438333GRFIhHC-.PASALAi09 GRIFFUTH HACK 4.IPAUSTRALIA Z009 Other preferred R groups include 2,2,3,3 3 4,4,4-hept ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethylada phenyleyclopropyl, 2-methylcyclohexyl, 3,3,5-triinethylcy methoxyphenyl)ethyl, 2-(I ,2,3,4-tetrahydronaphthyl), 4-ph s phenylbutyl, 2-Qn-fl-uorophenyl)ethyl, 2-(jp-JluorophenyIeI ifluorobutyl, 4nantyl, trans-2- :lohexyl, 2-(o- 3nylbutyl, 2-methyl-2hyl, 2-(3-hydroxy-3- N:Wefbcurretases\PateMtk38OD3B9B9%P3B40&AU).1SpecjsW35408BAU.1 specdricatlon ZQDB-4-3Odcc 4/0W8B COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 06/05 2008 17:52 FAX 61 3 92438333 GRIFFITH HACK -,IPAUSTRALIA Roil 00 0

O

-11phenyl)propyl, (S)-2-hydroxy-2-phenylethyl, (R)-2-hydrox -2-phenylethyl, 2-(3-mchlorophenyl-2-methyl)propyl, 2-(3-p-chlorophenyl-2-metl yl)propyl, 4-tert-butylcyclohexyl, (S)-l-(cyclohexyl)ethyl, 2-(3-(3,4-dimethylphe iyl)-2-methyl)propyl, 3,3dimethylbutyl, 2-(5-methyl)hexyl, 1-myrtanyl, 2-bornyl, 3- inanemethyl, 2,2,3,3,4,4,5,5-octafluoropentyl, p-fluoro- 2,2 -dimethylphenethyl, 2-naphthyl, 2boranyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methyl yclohexyl, 3,4dimethylcyclohexyl, 5-chloro-tricyclo[2.2.1]heptyl, o-a,a- imethylphenethyl, 2indanyl, 2-spiro[4.5]decyl, 2-phenylethyl, 1-adamantylethy, 1-(l-bicyclo[2.2.1]hept-2yl)ethyl, 2-(2-methyl-2-phenylpropyl), 2-(o-fluorophenyl)e hyl, 1-(cyclohexyl)ethyl and cyclohexyl moieties. Again, each of these exemplary R mcieties may be substituted in the manner set forth above. When compounds may be presn t in alternative isomeric configurations, for example, trans or cis-4-methylcyclohex rl, 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 race ate.

Structure of the [linker] moiety The [linker] moiety generally has the structure -(CI where n is 2-6. More specifically, the [linker] moiety has the structure -(CH2)-C3-NH-, where n=0-4. Up to four CH 2 groups may independently be replaced with groups selected from the group consisting of a Ci-C3 alkyl group, CHOH, CO, O, S, SO, S)2, N, NH, and NO, provided that two heteroatoms may not be adjacent except fvhen those atoms are both N (forming an linkage) or are both NH (forming an -N H-NH- linkage). Any two adjacent CH2 groups also may be replaced by an alkene or alkyne group.

In a preferred embodiment, [linker] comprises an arlide, ester, thioester, ketomethylene, ether, alkylether, ethylene, ethenyl, acetylelyl, hydroxyalkyl, alkylsulfone, or alkyl alkylsulfoxide group. Preferably, [li ker] is an -O-(CH 2

-CO-

or 2 group, where Y is CH 2 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-O-(CH 2 )m-Ar and (CH2)m-O-R.

Design and synthesis of mGluR Group I antagonists In one embodiment, compounds according to the in ention are esters and amides ofmonocyclic or fused bicyclic aromatic and heteroaroma c carboxylic acids, phenols and amines. In a preferred embodiment, the compounds my be represented by the Formulae II or III: N:VMelboume\CasB\Patent3B00O-36999\P30406AU.11Spe W\P3640.AU.1 Specificalion 2008-4-30.doc 60508 COMS ID No: ARCS-189488 Received by IP Australia: Time 17:55 Date 2008-05-06 -12-

O

R X X4 R Y X1 4 II III In Formulae II and III, Y can be either O, S, NH, or CH 2 and X 2

X

3 and X 4 independently can be N or CH. Preferably, one of X 2

X

3 and X 4 are N, and the remainder are CH. Preferred compounds contemplated by the invention have the formula IV or V, where R, Y and X' are as defined above.

0 R Y X1 R X1 O N

N

IV V In yet another preferred embodiment of the invention, the compounds have the Formulae VIII or IX: R

O

0 X0X4 R 0 X2 X3 N VIII

IX

wherein X1- 4 and R are as defined above. In a second embodiment of compound IX, R is 1-adamantyl. Compounds of these first and second embodiments appear to exhibit selectivity for the mGluRi receptor.

In each of the compounds described above, "alkyl" denotes both straight and branched chain alkyl. In other embodiments, R is adamantyl and the linker is -CO-

CH

2 In general, it appears that selective antagonism of the mGluRi receptor can be attained with compounds of the formula R-CO-N-Arl, where Arl is a quinolinyl group.

H:\ShonalKeep\Speci\P53408 Divisional speci 17/06/04 -13- The skilled artisan also will recognize that the compounds of 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, sulfuric, trifluoroacetic, malonic, succinic, citric, mandelic, benzoic, cinnamic, methanesulfonic and similar ones, and include acids related to the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Sciences, 66:2 (1977) and incorporated 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] moiety 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 carbonyldiimidazole, or a carbodiimide such as, for example, 1,3dicyclohexylcarbodiimide (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, ethers can be formed using the Mitsunobu reaction, where a primary alcohol function is displaced by another hydroxy group via activation using PPh 3 and diethylazodicarboxylate (DEAD). Thioether linkages may be prepared by displacement of a leaving group such as halide with a thiolate anion, generated by deprotonation of a thiol group with base.

When the [linker] moiety contains a ketomethylene group, it can be formed by alkylation of a ketone enolate. Thus, for example, a methyl ketone can be deprotonated using a strong base such as lithium diisopropylamide (LDA), followed by reaction with an alkyl halide. Alternatively, a ketomethylene function can be prepared via addition of an organometallic compound, such as a Grignard H:\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -14reagent, 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. N,N-Disubstituted hydrazine compounds may be prepared via reductive amination of hydrazones formed by reaction of a monosubstituted hydrazone with 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 Aldrich 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, carboxylic acids may be converted into the corresponding acid chlorides by reaction with, for example, thionyl 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 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 Aramori 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 incorporated by reference in their entirety.

HI\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 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 cells are cultured in high glucose DMEM (Gibco 092) containing 0.8 mM glutamine, 10% FBS, and 200 pM 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 cells then are washed, resuspended, and maintained at 37 OC. 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: [Ca 2 ]i (F Fmin /Fmax) x Kd where F is fluorescence at any particular time of interest, Fmin is determined by chelating all calcium available, therefore, no fura 2 is bound to calcium, and Fmax 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 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 for 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 H:\ShonaI\Keep\Speci\P53408 Divisional speci 17/06/04 -16will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

Pharmaceutically acceptable 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, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/disphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found in, for example, Remington's Pharmaceutical Sciences; (18th Mack Publishing Co., Easton,PA (1990).

Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, 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.), 2 5 Mack Publishing Co., Easton, PA (1990). Suitable routes may include oral, buccal, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, 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 solution, or physiological saline buffer. For such transmucosal 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 H.\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -17and suitable manufacturing practice, the compositions of the present invention, in particular, those formulated as solutions, may be administered parenterally, 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.

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 purpose. 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 for oral use can be obtained by combining the active compounds with 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, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (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 purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene 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 of 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 active ingredients in admixture with filler such as lactose, binders such as starches, H!\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 04/06 2008 17:43 FAX 61 3 92438333 GRIFFITH HACK ZPAUSTRALIA Q010 -18and/or lubricants such as talc or magnesium stearate and, o soft capsules, the active compounds may be dissolved or si liquids, such as fatty oils, liquid paraffin, or liquid polyeth, addition, stabilizers may be added.

s The present invention, thus generally described, wi readily by reference to the following examples, which are j illustration and are not intended to be limiting of the prese

EXAMPLES

General Experimental Methods Capillary gas chromatographic and mass spectral d Hewlett-Packard (HP) 5890 Series II Gas Chromatograph Series Mass Selective Detector [Ultra-2 Ultra Performance (crosslinked 5% PhMe silicone); column length, 25 m; co helium flow rate, 60 mL/min; injector temp., 250 tem C/min from 125 to 325 °C for 10 min, then held constant a Thin-layer chromatography was performed using Analtech gel HF TLC plates. UV light sometimes in conjunction wi Dragendorffs spray reagents (Sigma Chemical Co.) were t compounds on the TLC plates. Reagents used in reactions Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Fluka Chemical Corp. (Milwaukee, WI), Fisher Scientific America (Portland, OR), or Lancaster Synthesis (Windhan ptionally, stabilizers. In spended in suitable 'lene glycols (PEGs). In 1 be understood more rovided by way of t invention.

ita were obtained using a -oupled to an HP 5971 Capillary Column lumn 0.20 nnm; perature program, S325 °C for 6 min].

Uniplate 250-tm silica th ninhydrin and sed for detecting were purchased from the (Saint Louis, MO), Pittsburgh, PA), TCI

,NH).

holinyl)]-l- 1 mmol) and Pearlman's palladium); 0.10 g] in n) at 60°C for 1.5 h.

evaporated. This rellow solid.

amide in pyridine (2 mL) was EXAMPLE 1: Preparation of N-[6-(2-Methylqui adamantanecarboxamide 2-Methyl-6-aminoquinoline A mixture of 2-methyl-6-nitroquinoline (1.00 g, 5.: catalyst [palladium dihydroxide on activated charcoal (~2C ethyl acetate (40 mL) was stirred under hydrogen gas (1 at The reaction mixture was filtered and the filtrate was rotar provided 0.81 g of 2-methyl-6-aminoquinoline as a N-[6-(2-Methylquinolinyl)]-l-adamantanecarbo: 1-Adamantanecarbonyl chloride (1.02 g, 5.13 mmo 1 1

I\

N:Welboume\CasesPattW%3a -389 P340.AU-1SpedsP38 4I)AU.1 Specifloaton 2008-4-30doc 4A)6=0 COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 04/06 2008 17:43 FAX 61 3 92438333 GRIFFITH HACK 4.IPAUSTRALIA 0011l -19added to a solution of 2 -methyl-6-aminoquinoline (0.81 g, (8 mL). The reaction was stirred for 17 h. To the stirring i added water (100 mL) which caused the product to precipit filtered and then washed with water (3 x 25 mL) and diethy This provided 1.07 g of(40) as a cream-colored po rt=13.49 min.; m/z (rel. int.) 320 235 158 (100), 130 107 93 91 79 77 6 In a similar manner, the following N-quinolinyl-l-ai were prepared: 5.1 mmol) in pyridine :action mixture was ate. This precipitate was 1 ether (3 x 25 mL).

der: 157 136 135 7(6).

lamantanecarboxamides

N-(

6 -Quinolinyl)-l-adamantanecarboxamide (18 Prepared from 1-adamantanecarbonyl chloride (1.31 g, 6.90 mmol), 6aminoquinoline (0.59 g, 4.1 mmol), pyridine (20 mL), and vater (200 mL) yielding 1.25 g (100%) of (18): rt=13.24 min.;m/z (rel. int.) 306 221 144 i36 135 (100), 116 107 93 91 79 77 67 41

N-(

2 -Quinolinyl)-l-adamantanecarboxamide hyd Prepared from 1-adamantanecarbonyl chloride (0.75 aminoquinoline (0.60 g, 4.2 mmol), pyridine (10 mL), and Forming the hydrochloride salt with diethyl ethereal hydrog 0.19 g of(81): rt=12.24 min;m/z (rel. int) 306 305 277 171 145 144 143 136 135 (11 116 107 105 101 93 91 89 (1 67 65 55 53 41

N-(

3 -Quinolinyl)-l-adamantanecarboxamide (86) Prepared from 1-adamantanecarbonyl chloride (0.75 aminoquinoline (0.60 g, 4.2 mmol), pyridine (10 mL), and v 0.33 g of (86): rtl13.01 min.; m/z (rel. int.) 306 136 135 (10 93 91 89 79 77 67 65 N-(trans- 4 -Methyleyclohexyl)-2-quinoxalinecarbo Using the method of Booth Chem. Soc., 1958, 26 1971, 1047; Tetrahedron, 1967, 23, 2421), hydroxylamine (3 rochloride (81) g, 3.8 mmol), 2vater (100 mL).

n chloride yielded 263 221 172 128 117 (17), 81(14), 79 77 g, 3.8 mmol), 3- 'ater (100 mL) yielding 116 107 Iamide (299) 8; J. Chem. Soc., .8 g, 55 mmol), N:\MelboumelCasesPatenl38000-38999P38400.AU.1\Speci\P384 AU.1 SpeldBcatlon 2008-4-30.doc 4106/0 COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 04/06 2008 17:43 FAX 61 3 92438333 GRIFFITH HACK .IPAUSTRALIA 1012 ethanol (50 mL), pyridine (4.44 mL, 55 mmol), and 4-met mmol) were stirred at ambient temperature for 16 hours minutes. The ethanol was then removed in vacuo and tl ethylacetate (100 mL). The organic layer was washed witi over anhydrous MgSO 4 filtered, and concentrated to a clea which crystallized upon standing.

Without further purification 1.9 g (15 mmol) of the absolute ethanol (40 mL) was heated to reflux and treated v sodium metal (4 The reaction was heated at reflux until The reaction was cooled and treated with water (10 mL). T into a flask containing ice and concentrated HCI (6 mL). T vacuo and the remaining aqueous phase washed with diethy unreduced oxime). The remaining aqueous phase was cone white crystalline solid (the trans-4-methylcyclohexylamine Without further purification 750 mg (5 mmol) of tre amine hydrochloride in dichloromethane (10 mL) was treat mmol) followed by the addition of2-quinoxaloyl chlori reaction was stirred at ambient temperature for 16 hours an mL). The organics were washed with 10% HCI 1 over anhydrous MgSO4, filtered and concentrated to a solid of the crude reaction material through silica (7 x 4 cm id., angstroms) using ethylacetate-hexane afforded 470 mr (trans-4-methylcyclohexyl)-2-quinoxalinecarboxamide.

T

(TLC, silica) using ethylacetate-hexane showed a sing R 0.19. GC/EI-MS gave m/z (rel. int.) 269 (Mv, 39), 212 129 (100), 112 and 102 (46).

yl cyclohexanone (6.1 mL, and then heated at reflux for ie residual oil dissolved in water brine, dried roil (the oxime product), intermediate oxime in ith (in small portions) the sodium was consumed.

he reaction was transferred e ethanol was removed in I ether (3X, to remove entrated to afford 1.8 g of a hydrochloride product).

ns-4-methylcyclohexyl d with pyridine (1.62 mL, .e (963 mg, 55 mmol). The I diluted with chloroform NNaOH brine, dried Chromatography

(MPLC)

IIOTAGE, KP-SIL, Sof the desired product, Nin-layer chromatography [e UV active component at 198 174 157 EXAMPLE 2: Preparation of 6-Quinolinyl 1-ada]antanecarboxylate (41) 1-Adamantanecarbonyl chloride (1.37 g, 6.90 mmolj added to a solution of 6-hydroxyquinoline (1.00 g, 6.89 mm The reaction was stirred for 16 h. To the stirring reaction m (200 mL) which caused the product to precipitate. This pred with water (3 x 50 mL), and dried under high vacuum. This (41) as a light-brown powder: in pyridine (5 mL) was in pyridine (15 mL).

xture was added water ipitate was filtered, washed provided 1.56 g of N:AMelboumeasesPatent\3Cooo-3899sP30e46.AU.1 Sp~ s40o.AU.1 Specfcadon 2008-4-3.doc s/oweR COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 -21rt=11.41 min.; m/z (rel. int.) 307 136 135 (100), 116 107 93 92 91 89 79 77 EXAMPLE 3: Preparation of 1-Adamantyl 6-quinolinecarboxylate (61) 6-Quinolinecarbonyl chloride hydrochloride 6-Quinolinecarboxylic acid was refluxed in thionyl chloride for 30 min.

The excess thionyl chloride was then removed by rotary evaporation (900 C) to provide 6-quinolinecarbonyl chloride hydrochloride.

1-Adamantyl 6-quinolinecarboxylate (61) 6-Quinolinecarbonyl chloride hydrochloride (0.76g, 3.3 mmol) in pyridine (2 mL) was added to a solution of 1-adamantanol (0.60 g, 3.9 mmol) in pyridine (8 mL). The reaction was stirred at 70 0 C for 16 h. To the stirring reaction mixture was added water (100 mL) 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 of(61) as light brown needle-like crystals: rt=11.48 min.; m/z (rel. int.) 307 306 262 174 173 (13), 157 156 135 134 129 128 (100), 127 119 107 102 101 93 92 91 81 79 78 77 (49), 67 55 53 51 41 (31).

In a similar manner, the following alkyl 6-quinoline- and 2quinoxalinecarboxylates were prepared: 2,2,3,3,4,4,5,5-Octafluoro-l-pentyl-6-quinoline-carboxylate hydrochloride (68) Prepared from 6-quinolinecarbonyl 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), pyridine mL), and water (100 mL). Forming the hydrochloride salt with ethereal hydrogen chloride yielded 0.88 g of (68): rt=7.11 min.; m/z (rel. int.) 387 156 (100), 129 128 102 101 77 76 75 50 (14).

H,\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -22- 1-Adamantanemethyl 6-quinolinecarboxylate (73) Prepared from 6-quinolinecarbonyl chloride hydrochloride (0.80 g, mmol), 1-adamantanemethanol (0.60 g, 3.6 mmol), pyridine (10 mL), and water (100 mL) yielding 0.75 g of(73): rt=11.90 min.; (rel. int.) 321 320 263 156 148 136 135 (100), 135 (100), 129 128 107 106 105 102 101 93 92 91 81 80 79 78 77 75 67 55 53 51 41 (14).

1-Adamantyl 2-quinoxalinecarboxylate (92) Prepared from 2-quinoxaloyl chloride (0.84 g, 4.4 mmol), 1-adamantanol (0.60 g, 3.9 mmol), pyridine (10 mL), and water (100 mL) yielding 0.20 g of (92): rt=11.21 min.; m/z (rel. int.) 308 264 136 136 135 (100), 134 130 129 107 102 93 92 91 81 79 77 76 75 67 55 51 41 (11).

EXAMPLE 4: Preparation of N-(1-Adamantyl)-3-quinolinecarboxamide (72) 1,1 '-Carbonyldiimidazole (161 mg, 1.00 mmol) in N,N-dimethylformamide (1 mL) was added in one portion to a suspension of 3-quinolinecarboxylic acid (173 mg, 1.00 mmol) in N,N-dimethylformamide (1 mL). The resulting reaction solution was stirred for 2.5 h. 1-Adamantanamine (151 mg, 1.00 mmol) in N,Ndimethylformamide (0.5 mL) was added in one portion. The reaction mixture was stirred at 60 OC 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 of (72) as a crystalline solid: rt=11.02 min.; m/z (rel. int.) 306 305 250 249 (100), 213 173 157 156 129 128 102 101 94 93 92 91 79 77 77 75 67 41 (11).

In a similar manner, the following N-alkyl-2-quinoline- and 2quinoxalinecarboxamides were prepared: N-(1-Adamantyl)-2-quinolinecarboxamide (74) Prepared from 1,1'-carbonyldiimidazole (160 mg, 0.987 mmol), quinaldic H:\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -23acid (173 mg, 1.00 mmol), and N,N-dimethylformamide (2.5 mL) yielding 77 mg of (74): rt=10.53 min.; m/z (rel. int.) 306 305 277 263 221 172 171 145 144 143 136 135 (100), 128 117 (19), 116 107 105 101 93 91 89 81 79 77 67 65 55 53 41 (18).

N-(2-Adamantyl)-2-quinoxalinecarboxamide (144) Prepared from 1,1'-carbonyldiimidazole (161 mg, 1.00 mmol), 2quinoxalinecarboxylic acid (174 mg, 1.00 mmol), 2-adamantanamine (136 mg, 0.90 mmol), and dichloromethane (3.5 mL) yielding 98 mg of (144): rt=11.79 min.; m/z (rel. int.) 307 151 150 (100), 130 129 103 102 91 79 77 76 75 70 67 41 N-[(1R,2R,3R,5S)-3-Pinanemethyl]-2-quinoxalinecarboxamide (151) Prepared from 1,1'-carbonyldiimidazole (161 mg, 1.00 mmol), 2quinoxalinecarboxylic acid (174 mg, 1.00 mmol), (-)-3-pinanemethylamine (150 mg, 0.90 mmol), and dichloromethane (3.5 mL) yielding 50 mg of (151): rt=11.46 min.; m/z (rel. int.) 323 187 186 174 166 158 157 144 131 130 129 (100), 107 103 102 95 93 91 81 79 77 76 75 69 67 55 53 51 43 41 EXAMPLE 5: Preparation of N-(1-Adamantyl)-2 quinoxalinecarboxamide (91) 2-Quinoxaloyl chloride (0.84 g, 4.4 mmol) was added to a solution of 1adamantanamine (0.60 g, 4.0 mmol) in pyridine (10 mL). The reaction was then stirred for 30 min. To the stirring reaction mixture 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 of (91): rt=11.73 min.; m/z (rel. int.) 307 279 157 151 150 (100), 130 129 103 102 94 93 91 79 77 76 67 41 41 In a similar manner, the following N-substituted 6-quinoline- and 2- H:\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -24quinoxalinecarboxamides were prepared: N-(1-Adamantyl)-6-quinolinecarboxamide (42) Prepared from 6-quinolinecarbonyl chloride hydrochloride (1.51 g, 10 mmol), I1-adamantanamine 73 g, 10 mmol), pyridine (5 mL), and water (200 mL) yielding 330 mg of (42): rt=l 1.04 min.; m/z (rel. int.) 306 305 250 249 156 (11), 155 (100), 130 128 127 126 102 101 93 92 91 79 77 67 41 41 (11).

N-(exo-2-Norbornanyl)-2-quinoxalinecarboxamide (148) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), exo-2aminonorbomnane (133 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 35 mg of (148): rt=1 0.22 minl.; m/z (rel. int.) 267 198 158 157 131 130 129 111 111 110 (100), 103 102 77 76 N-[IR,2S,4S)-Bornyl]-2-quinoxalinecarboxamide (150) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), bomnylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 140 mg of (150): rt=l 0.79 min.; m/z (rel.- int.) 309 199 187 174 158 (11), 157 153 152 144 135 131 130 129 (100), 109 103 102 95 93 91 79 77 76 75 (11), 67 55 53 51 43 41 N-(3-Noradamantyl)-2-quinoxalinecarboxamide (152) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 3noradamantanamine (157 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 167 mg of (152): rt=1 1.00 min.; m/z (rel. int.) 293 265 250 232 222 157 144 137 136 131 130 130 129 (100), 103 102 94 91 80 79 77 76 75 67 53 51 41 (13).

H,\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 N- [(1R,2R,3R,5S)-Isopinocamphenyl]-2-quinoxalinecarboxamide (165) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (1R,2R,3R,5S)- (-)-isopinocamphenylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water mL) yielding 230 mg of (165): rt=1 0.88 min.; m/z (rel. int.) 309 226 200 199 198 186 175 174 158 157 152 130 129 (100), 103 102 102 95 93 79 77 76 75 67 55 53 51 43 41 (18).

N-[(lS,2S,3S,5R)-Isopinocamphenyl]-2-quinoxalinecarboxamide (166) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (1S,2S,3S,SR)- (+)-isopinocamnphenylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water mL) yielding 208 mg of (166): rt=10.88 min.; m/z (rel. int.) 309 226 200 198 186 175 174 158 156 130 130 129 (100), 103 102 (46), 93 91 79 77 76 75 67 55 53 51 43 41 12.2.1.0(2,6)] hept-3-yI)-2-quinoxalinecarboxamide (167) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), chlorotricyclo[2.2. 1.0(2,6)]hept-3-ylamine (129 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 100 mg of (167): rt= 1.29 min.; mlz (rel. int.) 299 264 246 199 198 186 185 144 142 130 129 (100), 106 103 102 102 91 80 79 78 77 76 75 65 53 52 51 50 N-(Tricyclo undec-3-yI)-2-quinoxalinecarboxamide (168) Prepared from 2-quinoxaloyl chloride (135 mg, 0.70 mmol), tricyclo[4.3. 1. 1(3,8)]undec-3-ylamine hydrochloride (100 mg, 0.60 mmol), pyridine mL), and water (50 mL) yielding 1 10 mg of (168): rt=12.52 min.; m/z (rel. int.) 321 165 164 (100), 157 131 130 130 129 107 106 105 103 102 94 93 92 91 81 80 79 77 76 75 67 55 53 41 Ht\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -26- N-[(1S,2R,5S)-cis-Myrtanyll-2-quinoxalinecarboxamide (169) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), myrtanylamine (13 8 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 224 mg of (169): rt=1 1.32 min.; m/z (r el. int.) 309 186 174 158 157 (27), 152 131 130 130 129 (100), 121 103 102 (45),.93 91 81 79 77 76 75 69 67 5 5 54 53 51 43 41 (26).

N- I(1R,2R,4S)-Isobornylj-2-quinoxalinecarboxamide (170) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), isobomnylamine (13 8 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 13 0mg (8 of (170): rt=10.76 min.; m/z (rel. int.) 309 199 197 187 174 158 157 153 152 144 135 130 129 (100), 109 103 102 95 93 91 79 77 76 75 67 5 3 51 43 41 (18).

N- [endo-(±)-2-NorbornanyJ -2-quinoxalinecarboxamide (171) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), endo-(+)-2aminonorbomnane (133 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 175 mg of (171): rt=1 0. 15 min.; m/z (rel. int.) 267 198 185 158 157 144 131 130 129 (100), 111 110 103 102 77 76 75 75 67 55 53 51 50 41 (14).

N-[(R)-2-Phenyl-1-propyl]-2-quinoxalinecarboxamide (172) Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (R)-2-phenyl-1Ipropylamnine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.49 g of (172): rt=10.63 min.; m/z (rel. int.) 291 186 158 157 130 129 (100), 118 105 104 103 102 91 79 78 77 76 75 75 51 N-[(S)-2-Phenyl-1 -propylj-2-quinoxalinecarboxamide (173) Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (S)-2-phenyl-1Ipropylamnine (0.30 g, 2.2 mmol), pyridine, (5 mL), and water (50 mL) yielding H.\Shona1\Keep\Speci\P53408 DiVisional speci 17/06/04 -27- 0.48 g of (173): rt=1O.72 min.; m/z (rel. int.) 291 186 158 157 130 (21), 129 (100), 118 105 103 102 91 79 77 76 (11), 51 51 N-(2-Indanyl)-2-quinoxalinecarboxamide (221) Prepared from 2-quinoxaloyl chloride (0.32 g, 1.7 mmol), 2-aminoindan (0.20 g, 1.5 mmol), pyridine (3 mL), and water (30 mL) yielding 0.23 g of (221): rt=1 1.33 min.; m/z (rel. int.) 289 132 130 129 117 116 (100), 115 104 103 102 91 78 77 76 51 51 50 N-Cyclooctyl-2-quinoxalinecarboxamide (228) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), cyclooctylamine (123 [t1, 114 mg, 0.90 mmol), pyridine (5 mL), and water (100 mL) yielding 100 mg of (228): rt=10.86 min.; m/z (rel. int.) 283 212 199 198 198 185 184 174 157 144 131 130 129 (100), 126 103 102 76 75 67 56 55 51 43 41 (16).

N-Cycloheptyl-2-quinoxalinecarboxamide (229) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), cycloheptylamine (115 [tL, 102 mg, 0.90 rnmol), pyridine (5 mL), and water (100 mL) yielding 30 mg of (229): rt=10.30 min.; m/z (rel. int.) 269 212 198 185 174 (14), 174 157 131 130 129 (100), 112 103 102 76 75 56 55 51 42 41 N-[2-Spiro(4.5)decyl]-2-quinoxalinecarboxamide (236) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2- (150 mg, 0.79 mmol), pyridine (5 mL), and water (100 mL) yielding 206 mg of (236): rt=10.94 min.; m/z (rel. int.) 282 199 186 157 130 129 125 110 109 (100), 108 103 102 98 97 96 84 82 76 75 70 69 68 56 55 53 51 43 42 (36),41 (14).

H.\Shonal\Keep\Speci\PS3408 Divisional speci 17/06/04 04/06 2008 17:44 FAX 61 3 92438333 GRIFFITH HACK IPAUSTRALIA @013 -28- EXAMPLE 6: Preparation of 1-Adamantanemetnyl 6-quinolinyl ether (94) A mixture of 1 -adamantanemethanol (5.00 g, 30.01 hydroxyquinoline (13.1 g, 90.2 mmol) in tetrahydrofuran 15 min. Then, triphenylphosphine (10.2 g, 39.0 mmol) wa azodicarboxylate (6.14 mL, 39.0 mmol). The reaction mix The solvent was then removed by rotary evaporation. The through paper with diethyl ether (3 x 25 mL). The filtrate the resulting gel was filtered through paper with hexanes (3 filtrate was rotary evaporated, the resulting gellwas filtered (3 x 25 mL), and the filtrate was rotary evaporated. This pt product as a red oil. This oil was chromatographed (2:1 he provide 1.6 g of (94): rt=11.29 min.; m/z (rel. int.) 293 149 (100), 145 116 107 93 91 89 81 (16), 55 53 41 (14).

knmol) and 6- 75 mL) was stirred for i added, followed by diethyl ure was refluxed for 18 h.

resulting gel was filtered vas rotary evaporated, and x 25 mL). Again the through paper with hexanes ovided 3.8 g of crude 'anes/ethyl acetate) to 128 121 116 79 77 67 iolinecarboxylate (101) EXAMPLE 7: Preparation of 1-Adamantyl 3-qui A mixture of -adamantanol (152 mg, 1.0 mmol), 3 quinolinecarboxylic acid (173 mg, 1.0 mmol), and dimethylaminopyridine (122 mg, .0 mmol) in dichloromethane (2 mL) and N,N-dimethylformamide (2 m) was cooled to 0 1,3- Dicyclohexylcarbodiimide (227 mg, 1.1 mmol) in dichloro ethane (1 mL) was added in one portion. The reaction mixture was stirred at 25 °C f r 20 h. The reaction mixture was then diluted with dichloromethane: (40 mL) an washed with 1 M sodium hydroxide (3 x 30 mL). The organic layer was dried (anhy ous magnesium sulfate), filtered through Celite, and rotary evaporated. The resultin material was purified by spinning thin-layer chromatography methanol in chlor form). The purest fraction was rotary evaporated, and the resulting material was recrytallized from ethanol This provided 42 mg of (101): rt=7.78 min.; m/z (rel. int.) 307 306 (100), 173 (1 155 135 127 119 106 100 93 92 91 7 77 76 74 67 54 41 (12).

N:kMelbne Casacs~atenlQBOC)03BR9P3e46.U0\6 ed P38406AU.1 Spedficaion 20084-3.dc 3/06t08 COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 -29- EXAMPLE 8: Preparation of N-(a,a-Dimethylphenethyl)-2quinoxalinecarboxamide (108) 2-Quinoxaloyl chloride (207 mg, 1.07 mmol) in dichloromethane (1 mL) was added to a solution ofphentermine (160 mg, 1.07 mmol) in dichloromethane (3 mL) cooled to 0 OC. The reaction was allowed to warm to 25 After 5 min, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with 1 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 of(108): rt=9.31 min.; m/z (rel. int.) 305 214 186 157 130 129 (100), 103 102 92 91 76 75 65 N-(2-Chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate 2-Chlorobenzylamine (2.0 g, 14 mmol) was added dropwise to a suspension of2,4,6-triphenylpyrylium tetrafluoroborate (5.1 g, 13 mmol) in dichloromethane mL). The reaction mixture 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 of N-(2-chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate.

1-(2-Chlorophenyl)-2-methyl-2-nitropropane 2-Nitropropane (3.19 mL, 35.5 mmol) was added to a mixture of sodium hydride (0.85 g, 35 mmol) in methanol (15 mL) cooled to 0 OC. The reaction mixture was then stirred and allowed to warm to 25 OC for 10 min. The solvent was rotary evaporated to provide a white solid. A mixture of this solid and N-(2chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate (6.14 g, 11.8 mmol) in dimethyl sulfoxide (45 mL) was stirred under nitrogen gas for 16 h. Water was then 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/mmol) for 4 h. The reaction mixture was filtered and rotary evaporated. This provided 2.35 g of 1-(2chlorophenyl)-2-methyl-2-nitropropane.

a,a-Dimethyl-2-chlorophenethylamine A mixture of Raney nickel (50% by weight in water; 2.3 g) and 1-(2- Hi\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 chlorophenyl)-2-methyl-2-nitropropane (2.35 g, 11 mmol) in ethanol (35 mL) was shaken under hydrogen gas (60 psig) for 3.5 h. The reaction mixture was then filtered, and the filtrate was rotary evaporated. This provided 2.3 g (110%) of a,adimethyl-2-chlorophenethylamine.

N-(a,a-Dimethyl-2-chlorophenethyl)-2-quinoxalinecarboxamide (197) In a similar manner to (108), (197) was prepared from 2-quinoxaloyl chloride (158 mg, 0.82 mmol), a,a-dimethyl-2-chlorophenethylamine (151 mg, 0.82 mmol), and dichloromethane (3 mL) yielding 196 mg of (197): rt=10.04 min.; m/z (rel. int.) 339 213 186 156 129 128 (100), 126 124 102 101 98 90 88 75 75 62 50 41 EXAMPLE 9: Preparation of N-(a,a-Dimethyl-4-fluorophenethyl)-2quinoxalinecarboxamide (129) To a solution of 1-(4-fluorophenyl)-2-methyl-2-propylamine (105 mg, 0.628 mmol) in pyridine (2 mL) was added 2-quinoxaloyl chloride (133 mg, 0.691 mmol). The reaction was then stirred for 30 min. To the stirring reaction mixture was added water (20 mL) which caused the product to separate as an oil.

This mixture was extracted with ethyl acetate (1 x 10 mL), washed with water (2 x mL), dried (anhydrous magnesium sulfate), rotary evaporated, and put under high vacuum for 15 h. This provided 146 mg of(129): rt=10.45 min.; m/z (rel. int.) 323 214 186 157 135 130 129 (100), 109 103 102 83 76 75 42 In a similar manner, the following N-substituted 2-quinoxalinecarboxamides were prepared: N-(p-Methylphenethyl)-2-quinoxalinecarboxamide (131) Prepared from 2-quinoxaloyl chloride (193 mg, 0.84 mmol), 3methylphenethylamine (103 mg, 0.76 mmol), and pyridine (2 mL) yielding 154 mg of(131): rt=10.71 min.; m/z (rel. int.) 291 186 158 157 130 129 (100), 118 105 103 102 91 79 78 77 76 75 51 51 H.\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -31- N-(3-Methylcyclohexyl)-2-quinoxalinecarboxamide (161) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 3methylcyclohexylamine (119 mg, 0.90 mmol), and pyridine (5 mL) yielding 190 mg of(161): rt=9.99 min.; m/z (rel. int.) 269 226 198 174 157 131 130 129 (100), 113 112 103 102 95 81 76 75 56 55 51 41 41 N-(2,3-Dimethylcyclohexyl)-2-quinoxalinecarboxamide (163) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2,3dimethylcyclohexylamine (115 mg, 0.90 mmol), and pyridine (5 mL) yielding 150 mg of (163): rt=10.12 min.; m/z (rel. int.) 283 212 198 175 174 158 157 131 130 129 (100), 126 109 103 103 102 76 75 67 56 55 51 43 41 (16).

N-[(1S,2S,3S,5R)-3-Pinanemethyl]-2-quinoxalinecarboxamide (207) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), pinanemethylamine (150 mg, 0.90 mmol), and pyridine (5 mL) yielding 229 mg of (207): rt=12.07 min.; m/z (rel. int.) 323 187 (100), 186 174 166 (24), 159 158 157 150 144 131 130 129 107 103 102 95 93 91 83 81 79 77 76 69 67 55 43 41 EXAMPLE 10: N-(1-Adamantanemethyl)-2-quinoxalinecarboxamide (146) 2-Quinoxaloyl chloride (429 mg, 2.6 mmol) was added to a solution of 1adamantanemethylamine (500 mg, 2.6 mmol) in chloroform (5 mL). The reaction mixture was heated until everything had dissolved. The reaction mixture was stirred at 25 °C for 1 h. To the stirring reaction mixture was added water (100 mL) which caused the product to precipitate. The precipitate was filtered, washed with water and dried under high vacuum. This provided 375 mg of(146): rt=12.27 min.; m/z (rel. int.) 321 186 174 164 158 157 136 135 (100), 131 130 129 107 105 103 102 93 92 91 81 79 77 76 75 67 Hs\Shonal\Keep\Speci\PS3408 Divisional speci 17/06/04 -32- 65 55 53 51 41 (13).

EXAMPLE 11: Preparation of N-(4-Methylcyclohexyl)-2quinoxalinecarboxamide (162) To a solution of 4-methylcyclohexylamine (119 mg, 0.90 mmol) in pyridine (2 mL) was added 2-quinoxaloyl chloride (193 mg, 1.0 mmol). The reaction was then stirred for 1 h. To the stirring reaction mixture was added water (20 mL) which caused the product to precipitate as an oil. This mixture 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 of (162): rt=10.00 min.; m/z (rel. int.) 269 212 212 198 174 158 157 131 130 129 (100), 113 112 103 102 95 81 76 75 56 55 51 41 (12).

EXAMPLE 12: Preparation of N-[(1S,2S,5S)-trans-Myrtanyl]-2quinoxalinecarboxamide (225) (1S,2S,5S)-trans-Myrtanyl trifluoroacetate Trifluoroacetic anhydride (5.50 mL, 39.0 mmol) was added to (-)-transmyrtanol (5.10 mL, 32.5 mmol) in dry tetrahydrofuran (100 mL). This reaction mixture was stirred for 1 h. The reaction mixture was rotary evaporated. This provided 7.60 g of (1S,2S,5S)-trans-myrtanyl trifluoroacetate.

(1R,2R,5R)-trans-Myrtanyl trifluoroacetate In a similar manner, (1R,2R,5R)-trans-myrtanyl trifluoroacetate was prepared from trifluoroacetic anhydride (5.40 mL, 38.0 mmol, 1.2 equiv) (+)-transmyrtanol (5.00 mL, 4.90 g, 31.7 mmol), and tetrahydrofuran (100 mL) yielding 7.60 g of (1R,2R,5R)-trans-myrtanyl trifluoroacetate.

(1S,2S,5S)-trans-Myrtanylazide A mixture of (1S,2S,5S)-trans-myrtanyl trifluoroacetate (1.0 g, 4.0 mmol), sodium azide (0.39 g, 6.0 mmol), and N,N-dimethylformamide (50 mL) was stirred at 80 OC for 24 h. After cooling to 25 water (100 mL) was added, and this mixture 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 H:\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -33- (100%) of (1S,2S,5S)-trans-myrtanylazide as a colorless oil.

(1R,2R,5R)-trans-Myrtanylazide In a similar manner, (lR,2R,5R)-trans-myrtanylazide was prepared from (lR,2R,5R)-trans-myrtanyl trifluoroacetate (7.60 g, 30.4 mmol), sodium azide (3.00 g, 45.6 mmol), and NN-dimethylformamide (100 mL) yielding 4. 10 g of (1S,2S,5S)-trans-Myrtanylamine A mixture of (I1S,2S,5S)-trans-myrtanylazide (1.12 g, 7.32 mmol) and platinum(JV) oxide hydrate (0.34 g) in ethanol (50 mL) was shaken under hydrogen gas (50 psig) for 2 h. The reaction mixture 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 of (1S,2S,5S)-trans-myrtanylamine as a light yellow oil.

(1R,2R,5R)-trans-Myrtanylamine In a similar manner, (1R,2R,5R)-trans-myrtanylamnine was prepared from (1R,2R,5R)-trans-myrtanylazide (4.10 g, 26.8 mmol), platinum(IV) oxide hydrate (0.41 and ethanol (75 mL) yielding 2.00 g of (1R,2R,5R)-transmyrtanylamine.

N- I(1S,2S,5S)-trans-Myrtanyl]-2-quinoxalinecarboxamide (225) In a similar manner to (162), (225) was prepared from 2-quinoxaloyl chloride (49 mg, 0.25 mmol), (1S,2S,5S)-trans-myrtanylamine (35 mg, 0.23 mmol), and pyridine (5 mL) yielding 8 mg of (225): rt=1 1.23 min.; m/z (rel. int.) 309 187 186 174 158 (14), 157 152 131 130 130 129 (100), 103 102 93 91 81 79 77 76 75 69 67 55 54 53 51 43 41 N- [(1R,2R,5R)-trans-Myrtanyl]-2-quinoxalinecarboxamide (226) In a similar manner, (226) was prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (1R,2R,5R)-trans-myrtanylamine (138 mg, 0.90 mmol), and H:\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -34pyridine (5 mL) yielding 27 mg of (226): rt=11.19 min.; m/z (rel. int.) 309 186 186 174 158 (16), 157 152 131 130 130 129 (100), 121 103 102 93 91 81 79 77 76 75 69 67 53 51 43 41 (18).

EXAMPLE 13: Preparation of N-[N'-(R)-a-Methylbenzyl-2-acetamido]- 3-aminoquinoline dihydrochloride (156) N-(R)-ot-Methylbenzyl-2-chloroacetamide (R)-a-Methylbenzylamine (2.4 g, 20 mmol) in dichloromethane (50 mL) was added to chloroacetyl chloride (2.25 g, 20 mmol) in dichloromethane (70 mL) and pyridine (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-2chloroacetamide.

N-(R)-a-Methylbenzyl-2-iodoacetamide A solution of sodium iodide (10.37 g, 69 mmol) in dry acetone was slowly added to a solution of N-(R)-a-methylbenzyl-2-chloroacetamide (3.39 g, 17 mmol) in dry acetone, and the reaction mixture was refluxed for 16 h. The reaction mixture was then filtered, and the filtrate was rotary evaporated. Diethyl ether was added, and the mixture was stirred for 20 min. The mixture was then filtered, and the filtrate was rotary evaporated and then put under high vacuum to provide -methylbenzyl-2-iodoacetamide.

N-[N'-(R)-a-Methylbenzyl-2-acetamido]-3-aminoquinoline dihydrochloride (156) A mixture of 3-aminoquinoline (0.15 g, 1.0 mmol) and potassium fluoride on Celite (0.30 g, 2.5 mmol) in acetonitrile (20 mL) was stirred for 1 h. N- (R)-a-Methylbenzyl-2-iodoacetamide (0.31 g, 1.0 mmol) in acetonitrile was added, and the reaction mixture was refluxed for 64 h. The mixture was filtered, and the filtrate was rotary evaporated. The resulting material was taken up in diethyl ether and washed with 1 M sodium hydroxide (3 x 30 mL). The combined aqueous layers were saturated with sodium chloride and were then extracted with chloroform The combined organic layer were dried (anhydrous magnesium sulfate) and rotary evaporated. The resulting material was dissolved in chloroform H\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 mL), 1 M hydrogen chloride in diethyl ether (5 mL) was added, and the solution was rotary evaporated. The resulting material was dissolved in chloroform mL) and filtered through a 0.45 [tm filter disc, and the filtrate was evaporated.

This provided 13 mg of(156): rt=10.43 min.; m/z (rel. int.) 328 182 181 180 167 (22), 166 165 162 161 160 148 145 135 132 122 120 119 107 106 105 (100), 104 103 (19), 79 78 77 51 44 41 (11).

EXAMPLE 14: Preparation of 1-(1-Adamantyl)-2-(benzothiazol-2ylsulfanyl)ethanone (273) Sodium hydride (36.5 mg, 1.52 mmol, 60% in mineral oil) was washed with pentane dried under N 2 suspended in dimethylformamide (DMF, 10 mL) and cooled to 0 OC. With stirring, a solution of 2-mercaptobenzothiazole (253.3 mg, 1.52 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred 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 temperature 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 MgSO 4 filtered, and concentrated to a solid.

Recrystallization from hot ethanol afforded 287 mg of the desired product: GC/EI-MS gave m/z (rel. int.) 343 10), 315 180 148 135 (100), 107 93 and 79 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 jtM Fura-2 acetoxymethylester by incubation for 40 minutes at 37 °C in SPF-PCB (126 mM NaC1, 5 mM KC1, 1 mM MgCl 2 20 mM Na-HEPES, 1.0 mM CaCl 2 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 of million cells/mL and kept at 37 °C in a plastic beaker. For recording fluorescent signals, the cells were diluted five-fold into a quartz cuvette with BSAfree 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 of fluorescence were performed at 37 °C with constant stirring using a custom-built H.\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 -36spectrofluorimeter (Biomedical Instrumentation Group, University of 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 itg/mL, final) was added to obtain maximal fluorescence (Fmax), and the apparent minimal fluorescence (Fmin) was determined by adding TRIS-Base/EGTA (10 mM, pH 8.3, final). Concentrations of intracellular Ca 2 were calculated using a dissociation constant (Kd) of 224 nM and applying the equation: [Ca2+]i (F Fmin/Fmax) x Kd; where F is fluorescence measured at any particular time of interest and F falls between Fmax and Fmin.

Control responses to the addition of 5 mM Ca 2 (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 concentration per cuvette of cells, and all compounds were prepared in DMSO. Appropriate dilutions were made such that compounds were added in no greater volume than 10 gl per a total volume of 1500 ul (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 of 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, digitionin and EGTA were added in a sequential manner to determine Fmax 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 3 0 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 IC5o 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.

H~\Shonal\Keep\Speci\P53408 Divisional speci 17/06/04 06/05 2008 17:52 FAX 61 3 92438333 GRIFFITH HACK IPAUSTRALIA U012 00 0 0 0 -37- In the claims which follow and in the preceding descriptio of the invention, except where the context requires otherwise due to express langua e or necessary implication, the word "comprise" or variations such as "comprises" or 'comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodid ents of the invention.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any cther country.

N:\MelboumelGasesPtern3000-3699BP38406.AU.1 Spe( isP340S.AU.1 Specification 200-4-30.doo o/iD 8 COMS ID No: ARCS-189488 Received by IP Australia: Time 17:55 Date 2008-05-06

Claims (7)

1. 5-12 carbon atoms, wherein Ar is a quinolinyl moiety substituted with a wherein [linker] is -(CH 2 where n is 0-4 or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R cont wherein some or all of the hydrogen atoms on two carbon at with substituents independently selected from the group con and =0. 3. The compound according to any one of claims 1 to 3 moiety selected from the group consisting of adamantyl, 2-a isopinocamphenyl, tricyclo[4.3.1.1(3,8)Jundec-3-yl, (1S,2R, (1R,2R,4S)-isobornyl (1,2R, 3 R,5S)-isopinocamphenyl, (1 (1R, 2 R,5R)-trans-myrtanyl, (lR,2S,4S)-bornyl, 1-adamantax (IS, 2 S,3S,5R)-3-pinanemethyl, cyclooctyl, cycloheptyl, 4-k dimniethyladamantyl, 2 -methylcyclohexyl, 3 3 ,5-trimethylyc cyclohexyl, 1-myrtanyl, 2 -bornyl, 3-pinanemethyl, 2-bornan methylcyclohexyl, 4 -methylcyclohexyl, 3 ,4-dimethylcyclohe tricyclo[2.2.ljheptyl, 2 -spiro[4.5decyl and cyclohexyl. 4. The compound according to any one of claims 1 to 3, N-[ 6 2 -Methylquinolinyl)y--adamantanecarboxamide or a acceptable salt thereof. A pharmaceutical composition comprising a compo claims 1 to 4 and a pharmaceutically acceptable diluent or ex
2. 6. A method of making a compound according to any on comprising reacting a compound containing an activated carb N: ielbouneCasse\atentl300D-39991P3B406.Atj.11SpecsP ycloalkylmethyl group methyl group, and s 7-11 carbon atoms, ms optionally are replaced isting ofF, Cl, OH, OMe, wherein R comprises a amantyl, (IS,2S,3S,5R)- iS)-cis-myrtanyl, 2 S,SS)-trans-myrtanyl, temethyl, 3 -noradamantyl, toadamantyl, ohexyl, 4-tert-butyl- cyclohexylmethyl, 3- cyl, wherein said compound is harmaceutically I according to any one of ipient. of claims 1 to 4, xylic acid group with a 40SAU. 1 Specification 2008-4-30-d- COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04 04/06 2008 17 :44 FAX 61 3 92438333 GRIFFITH HACK -39- compound containing an amine, hydroxyl, or thiol group.
3. 7. A method of inhibiting activation of an mGluR Gr( treating a cell containing said receptor with an effective an s according to any one of claims 1 to 4 or a pharmaceutical claim
4. 8. A method of inhibiting neuronal damage caused by mGluR Group I receptor, comprising treating neurons witi compound according to any one of claims 1 to 4 or a phan according to claim
5. 9. A method of treating a disease associated with glut damage, comprising administering to a patient suffering fri is amount of a compound according to any one of claims 1 tc composition according to claim Use of a compound according to any one of claims composition according to claim 5 in the treatment of a dise glutamate-induced neuronal damage.
6. 11. Use of a compound according to any one of claims composition according to claim 5 in the manufacture ofa of a disease associated with glutamate-induced neuronal d IPAUSTRALIA ]015 )up I receptor, comprising iount of a compound Tomposition according to excitatory activation of an an effective amount of a Laceutical composition nmate-induced neuronal )m said disease an effective 4 or a pharmaceutical 1 to 4 or a pharmaceutical ase associated with 1 to 4 or a pharmaceutical hedicament for the treatment image.
7. 12. A compound represented by formula I as defined ii claim 1, a pharmaceutical composition comprising it, a method of making it, or a me hod or use involving it, substantially as herein described with reference to example 1. N:\MelboumelCaseslPatentLOO0-38999\P38406AU.1Sp sIP3B406.AU.1 Specificallon 200B-4-30.doc 4106/08 COMS ID No: ARCS-193213 Received by IP Australia: Time 17:46 Date 2008-06-04