AU771358B2 - Metabotropic glutamate receptor antagonists for treating central nervous system diseases - Google Patents
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Description
WO 99/26927 PCT/US98/24833 METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS FOR TREATING 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.
S
BACKGROUND OF THE INVENTION 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 of phospholipase C: increases in phosphoinositide (PI) hydrolysis: intracellular calcium release: activation of phospholipase D: activation or inhibition of adenvl SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -2cyclase: 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 of phospholipase A2: increases in arachidonic acid release: and increases or s 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 er 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 alternatively 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 1. 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 er 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 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 mGluRl 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 mGluR5 receptors. Abe et al., J. Biol. Chem.
267:13361 (1992); Minakami et al., BBRC 199:1136 (1994); Joly er al., J.
Neurosci. 15:3970 (1995). Alternatively, agonist activation of recombinant mGluRl 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).
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCTIUS98/24833 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, carboxycyclopropyl)glycine (L-CCG-I) (IS,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 er 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 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 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 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 (1994). In addition, the excitation can be blocked by 4 -carboxyphenylglycine 4 -carboxy-3-hydroxyphenylglycine ((S)-4C3HPG), and alpha-methyl-4-carboxyphenylglycine compounds known to be mGluRl antagonists. Eaton et al.. Eur. J. Pharmacol. 244:195 (1993): Watkins etal., Trends Pharmacol. Sci. 15:333 (1994).
Metabotropic glutamate receptors have been implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs 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., o1 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 vestibulo-ocular 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 a variety of pathophysiological 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.
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 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 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.
SUBSTITUTE SHEET (RULE 26) It is apparent, therefore, that identification of potent mGluR agonists and antagonists with high selectivity for individual mGluR subtypes, particularly for 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.
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 I receptor.
It is still another object of the invention to provide methods of treating a disease associated with 0 *glutamate-induced neuronal damage.
It is yet another object of the invention to provide use of a metabotropic glutamate receptor-active compound in the treatment of a disease associated with glutamate-induced neuronal damage.
It is another object of the invention to provide use of a metabotropic glutamate receptor-active compound in the manufacture of a medicament used to treat a disease associated with glutamate-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, 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 a quinoxaline moiety with 0-2 substituents, wherein the H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 quinoxaline substituents are selected from the group consisting of F, C1, Br, or I at the 3 position, and C1-C 3 alkyl and F, Cl, Br or I at the 5, 6, 7 and 8 positions, and [linker] is -(CH 2 where n is 2-6, and wherein up to 4 CH 2 groups may independently be replaced with groups selected from the group consisting of C 1
-C
3 alkyl, CHOH, CO, 0, S, SO,
SO
2 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 CH 2 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 of the invention, Ar comprises a ring system consisting of a quinoxalinyl ring. Ar optionally may independently be substituted with up to two
C
1
-C
3 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 7-11 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 and =0.
*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 adamantyl, 2-adamantyl, (lS,2S,3S,5R)isopinocamphenyl, tricyclo[4.3.1.1(3,8)]undec-3-yl, (1S,2R,5S)-cis-myrtanyl, (lR,2R,4S)-isobornyl, (1R,2R,3R,5S)isopinocamphenyl, (1S,2S,5S)-trans-myrtanyl, (1R,2R,5R)trans-myrtanyl, (1R,2S,4S)-bornyl, 1-adamantanemethyl, 3noradamantyl, (1S,2S,3S,5R)-3-pinanemethyl, cyclooctyl, a,a- Sdimethylphenethyl, (S)-2-phenyl-1-propyl, cycloheptyl, 4methyl-2-hexyl groups, 2,2,3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2methylpropyl, 3,5-dimethyladamantyl, trans-2phenylcyclopropyl, 2-methylcyclohexyl, 3,3,5trimethylcyclohexyl, 2-(o-methoxyphenyl)ethyl, 2-(1,2,3,4tetrahydronaphthyl), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2-(m-fluorophenyl)ethyl, 2-(p-fluorophenyl)ethyl, 2-(3- H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 hydroxy-3-phenyl)propyl, -2-hydroxy-2-phenylethyl, -2hydroxy-2 -phenylethyl, 2- (3 -m-chlorophenyl-2 -methyl) propyl, 2- (3-p-chlorophenyl-2-methyl)propyl, 4-tert-butyl-cyclohexyl, (S)-1-(cyclohexyl)ethyl, 2-(3-(3,4-dimethylphenyl)-2methyl) propyl, 3, 3-dimethylbutyl, 2- (5-methyl) hexyl, 1myrtanyl, 2-bornyl, 3-pinanemethyl, 2,2,3,3,4,4,5,5octafluoropentyl, p- fluoro-c, a-dimethylphenethyl, 2 -naphthyl, 2 -bornanyl, cyclohexylmethyl, 3 -methylcyclohexyl, 4methylcyclohexyl, 3, 4-dimethylcyclohexyl, tricyclo heptyl, o-a,a-dimethylphenethyl, 2-indanyl, 2- 2-phenylethyl, 1-adamantylethyl, 1- (1bicyclo[2.2.llhept-2-yl)ethyl, 2-(2-methyl-2-phenylpropyl), 2- (a-fluorophenyl) ethyl, 1- (cyclohexyl) ethyl, and cyclohexyl.
In a still further embodiment of the invention, Ar comprises a group having the formula x
X
where X 1
X
2
X
3 and X 4 independently can be N or CH, provided that not more than two of X 1 Xx, and X 4 c an *be N. In a preferred embodiment, X 1 is N, and/or X2 is N.
20 In another embodiment, X 3 is N. In still another embodiment, X1 is CH and X 2 is N.
In yet another embodiment, the compound is selected from the group consisting of l-Adamantyl-2quinoxalinecarboxylate, N- (2-Adamantyl) -2quinoxalinecarboxamide, N-C (lR, 2R,3R,5S) -3-Pinanemethyl] -2quinoxalinecarboxamide, N- (1-Adamantyl) -2quinoxalinecarboxamide, N- (exo- 2-Norbornanyl) -2quinoxalinecarboxanide, N- [(1R,2S,4S) -Bornyl] -2quinoxalinecarboxamide, N- (3-Noradamantyl) -2quinoxalinecarboxanide, N- 2R,3R,5S)IsopinocamphenylJ -2quinoxalinecarboxamide, N- [(lS,2S,3S,5R) -Isopinocamphenyl] -2quinoxalinecarboxamide, N- (5-Chloro- (2.2.1.O]tricyclo-2, 6 hepta-3-yl) -2-quinoxalinecarboxamide, N- )Tricyclo- 3,8-undeca-3-yl) -2-quinoxalinecarboxamide, N- [(lS,2R,5S) -cis- Myrtanyl] -2-quinoxalinecarboxamide, N- [(1R,2R,4S) Isobornyl] 2-quinoxalinecarboxamide, N- [endo- -2-Norbornanyl] -2- Hz\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 quinoxalinecarboxamide, quinoxalinecarboxamide, quinoxalinecarboxamide, quinoxal inecarboxamide, quinoxal inecarboxaiide, quinoxalinecarboxamide, quinoxal inecarboxamide, quinoxal inecarboxamide, quinoxalinecarboxamide, quinoxal inecarboxamide, quinoxalinecarboxamide, quinoxalinecarboxamide, quinoxal inecarboxamide, quinoxalinecarboxamide, quinoxal inecarboxamide, thereof.
N- 2 -Phenyl 1-propyl]I -2 N- -2 -Phenyl-1-propyl] -2- N- (2 -Indanyl) -2 N- (a,a-Dimethylphenethyl) -2- N- (c,c-Dimethyl-2-chlorophenethyl) -2- N- (a,a-Dimethyl-4-fluorophenethyl) -2- N- (P-Methylphenethyl) -2- N- (3-Methylcyclohexyl) -2- N- (2,3-Dimethylcyclohexyl) -2- N- [(1S,2S,3S,SR) -3-Pinanemethyl] -2- N- (1-Adamantanemethyl) -2- N- (4-Methylcyclohexyl) -2- N- [(1S,2S,5S) -trans-Myrtanyl] -2and N- [(1R,2R,5R) -trans-Myrtanyl] -2or pharmaceutically acceptable salts In a preferred embodiment, the compound is selected from the group consisting of N-(2-Adamantyl)-2quinoxalinecarboxamide, N- [(1R,2R,3R, 5S) -3-PinanemethylJ -2quinoxalinecarboxamide, N- (1-Adamantyl) -2quinoxalinecarboxamide, N- (exo-2 -Norbornanyl) -2quinoxalinecarboxamide, N- 2S,4S) Bornyl] -2quinoxalinecarboxamide, N- (3-Noradamantyl) -2quinoxalinecarboxamide, N- [(lR,2R,3R,5S) -Isopinocamphenyl] -2quinoxalinecarboxamide, N- E(1S,2S, 3S,5R) -Isopinocamphenyl] -2quinoxalinecarboxamide, N- (5-Chioro- [2.2.1.O]tricyclo-2,6hepta-3-yl) -2-quinoxalinecarboxamide, N- Tricyclo- 3,8-undeca-3-yl) -2-quinoxalinecarboxamide, N- [(lS,2R,5S) -cis- Myrtanyl] -2-quinoxalinecarboxanide, N- 2R,4S) Isobornyl) 2-quinoxalinecarboxamide, N- [ondo- -2-NorbornanylJ -2quinoxalinecarboxamide, N- [(lS,2S,3S, 5R) -3-Pinanemethyl] -2quinoxalinecarboxamide, N- (1-Adamantanemethyl) -2quinoxalinecarboxamide, N- 2S, 5S)-trans-MyrtanylJ -2quinoxalinecarboxanide, and N-E[(iR, 2R, 5R) -trans -Myrtanyl] -2quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
In another embodiment, the compound is selected from the group consisting of N-(3-Methylcyclohexyl)-2quinoxalinecarboxamide, N- (2,3 -Dimethylcyclohexyl) -2quinoxalinecarboxamide, N- [(lS,2S,3S,5R) -3-Pinanemethyl] -2- H:\suzanlet\Keep\Speci\15317-99.1 SPECI .doc 10/11/03 quinoxalinecarboxanide, N- (1-Adamantanemethyl) -2quinoxalinecarboxamide, and N- (4 -Methylcyclohexyl) -2quinoxalinecarboxamide or pharmaceutically acceptable salts thereof.
In yet another embodiment, the compound is selected from the group consisting of N-[(R)-2-Phenyl-1propyl-2-quinoxalinecarboxamide, -2-Phenyl-1-propyl] -2quinoxalinecarboxamide, N- (2-Indanyl) -2quinoxalinecarboxamide, N- (a-a-Dimethylphenethyl) -2quinoxalinecarboxamide, N- (c,a-Dimethyl-2-chlorophenethyl) -2quinoxalinecarboxamide, N- (cc, a-Dimethyl-4 -fluorophenethyl) -2quinoxalinecarboxamide, l-Adamantyl-2 -quinoxalinecarboxylate, and N- (P-Methylphenethyl) -2 -quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
In a further embodiment, the compound is selected from the group consisting of 3-(l-Adamantanemethoxy)-2chloroquinoxaline, 3- (1-Adamantanemethoxy) -2fluoroquinoxaline, N- (1-Adainantyl) -2 -chloroquinoxaline-3 carboxanide, or pharmaceutically acceptable salts thereof.
In yet another embodiment, the compound is selected from the group consisting of 2-(1- Adamantanemethylsulfanyl)quinoxaline, 2- (1- Adamantanemethoxy) quinoxaline, N- (trans-4 -Methylcyclohexyl) 2-quinoxalinecarboxamide, N- (cis-4-Methylcyclohexyl) -2quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
In a further embodiment, the compound is selected from the group consisting of N-(4-Phenylbutyl)- 2 quinoxalinecarboxamide, 2- (l-Adamantanemethylsulfonyl) -3methylguinoxaline, 1- (1-Adamantyl) (3-methylquinoxal- 2 ylsulfanyl) ethanone, N- (1-Adamantyl) 7dimethylquinoxaline-2-carboxamide, N- -1-Tetralinyl) -2quinoxalinecarboxamide, N- (4 -Chlorophenethyl) -2quinoxalinecarboxamide, N-U(-Tetralinmethyl) -2quinoxalinecarboxamide, N- (1-Indanmethyl) -2quinoxalinecarboxamide, N- 4-DimethylcycloheXyl) quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
In a preferred embodiment, the compound is N- (trans-4-Methylcyclohexyl) -2-quinoxalinecarboxamide.
H:\suzannet\Keep\Speci\15317-99.l SPECI.doc 10/11/03 -11- In another preferred embodiment, the compound is N-(4,4-Dimethylcyclohexyl)-2-quinoxalinecarboxamide.
In accordance with another embodiment of 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 of making a compound as set forth above, comprising reacting a 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 provided a method of inhibiting activation of an mGluR Group I receptor, comprising treating a cell containing said mGluR Group I receptor with 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 25 disease associated with glutamate-induced neuronal damage, comprising administering to a patient suffering from said disease an effective amount of a compound or composition as set forth above.
In accordance with another embodiment of the 30 invention, there has been provided a use of a compound as set forth above, in the treatment of a disease associated with glutamate-induced neuronal damage.
In yet another embodiment of the invention, there has been provided a use of a compound as set forth above, in 35 the manufacture of a medicament for the treatment of a disease associated with glutamate-induced neuronal damage.
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 H:\suzannet\Keep\Speci\15317-9 9 .1 SPECI.doc 10/11/03 -12indicating preferred embodiments of the invention, are given by way of illustration 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.
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: Linker-Ar where R is an optionally substituted straight or branched chain alkyl, arylalkyl, cycloalkyl or alkylcycloalkyl group containing 5-12 carbon atoms, and Ar is a quinoxaline moiety with 0-2 substituents. The [linker] moiety is a group that not only covalently binds to the Ar and R moieties, but also facilitates adoption of the correct spatial orientation by Ar and R to allow receptor binding.
s eo H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 -13- Structure of the R moiety The R moiety generally may contain between five and twelve carbon atoms, although the skilled artisan will recognize that R moieties with 13, 14, 15, or 16 carbon atoms will be possible. Although R can contain 5 or 6 carbon atoms, preferably R contains at least 7 carbon atoms.
Preferably, R is optionally substituted straight or branched chain aralkyl, alkyl, cycloalkyl, or alkylcycloalkyl.
Generally, some or all of the hydrogen atoms on two carbon atoms may be replaced by substituents independently selected from the group consisting of F, Cl, OH, OMe, and =0.
However, more than two hydrogen atoms may be replaced with fluorine, and R may be perfluorinated. Exemplary R moieties include, but are not limited to: adamantyl, 2-adamantyl, (1S,2S,3S,5R)-isopinocamphenyl, tricyclo[4.3.1.1(3,8)]undec- 3-yl, (1S,2R,5S)-cis-myrtanyl, (1R,2R,4S)-isobornyl, (1R,2R,3R,5S)-isopinocamphenyl (1S,2S,5S)-trans-myrtanyl (1R,2R,5R)-trans-myrtanyl, (1R,2S,4S)-bornyl, 1adamantanemethyl, 3-noradamantyl (1S,2S,3S,5R)-3pinanemethyl, cyclooctyl, dimethylphenethyl, (S)-2-phenyl-1propyl, cycloheptyl, and 4-methyl-2-hexyl groups. Each of these exemplary R moieties may also be substituted in the manner set forth above.
Other preferred R groups include 2,2,3,3,4,4,4heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, trans-2-phenylcyclopropyl, 2methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 2-(omethoxyphenyl)ethyl, 2-(1,2,3,4-tetrahydronaphthyl), 4phenylbutyl, 2-methyl-2-phenylbutyl, 2-(m-fluorophenyl)ethyl, 2-(p-fluorophenyl)ethyl, 2-(3-hydroxy-3-phenyl)propyl, hydroxy-2-phenylethyl, (R)-2-hydroxy-2-phenylethyl, 2-(3-mchlorophenyl-2-methyl)propyl, 2-(3-p-chlorophenyl-2- Smethyl)propyl, 4-tert-butyl-cyclohexyl, H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 -14- (cyclohexyl)ethyl, 2-(3-(3,4-dimethylphenyl)-2-methyl)propyl, 3,3-dimethylbutyl, 2-(5-methyl)hexyl, 1-myrtanyl, 2-bornyl, 3-pinanemethyl, 2,2,3,3,4,4,5,5-octafluoropentyl, p-fluoro- 2,2 -dimethylphenethyl, 2-naphthyl, 2-bornanyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4-dimethylcyclohexyl, 5-chloro-tricyclo[2.2.1]heptyl, o-a, a-dimethylphenethyl, 2-indanyl, 2-spiro[4.5]decyl, 2phenylethyl, 1-adamantylethyl, 1-(1-bicyclo[2.2.1]hept-2yl)ethyl, 2-(2-methyl-2-phenylpropyl), 2-(ofluorophenyl)ethyl, 1-(cyclohexyl)ethyl and cyclohexyl moieties. Again, each of these exemplary R moieties may be substituted in the manner set forth above. When compounds may be present in alternative isomeric configurations, for example, trans or cis-4-methylcyclohexyl, 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
(CH
2 where n is 2-6. Up to four CH 2 groups may independently be replaced with groups selected from the group consisting of a Ci-C 3 alkyl group, CHOH, CO, O, S, SO, SO 2
N,
NH, and NO, provided that two heteroatoms may not be adjacent 25 except when those atoms are both N (forming an linkage) or are both NH (forming an -NH-NH- linkage). Any two adjacent CH 2 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, acetylenyl, hydroxyalkyl, alkylsulfone, or alkyl alkylsulfoxide group. Preferably, [linker] is an -0-
(CH
2
-CO-Y-(CH
2 or -S(O)n-(CH 2 group, where Y is
CH
2 NH, O, or S, and m is 1-4, and n is 0-2. The [linker] 35 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- H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03
(CH
2 )m-Ar and R-(CH 2 )m0'-R.
Design and synthesis of mGluR Group I antagonists In one embodiment, compounds according to the invention are esters and amides of rnonocyclic 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: 0 9 0 H:\suzannet\Keep\Speci\15317-99.1 SPECI .doc 10/11/03 WO 99/26927 PCT/US98/24833 R- R Y4 II
III
In Formulae II and III. Y can be either 0. S, NH, or CH2; and X 2
X
3 and X' independently can be N or CH. Preferably, one or two 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.
o0 N-
N
IV
V
In another preferred embodiment of the invention, the compounds have the Formulae VI or VII Rs N
N
VI
VII
where R and Y are as defined above. In a first embodiment of the compounds of Formula VI, Y is N, R is an unsubstituted or monosubstituted 1,1,-dimethylphenylethylamine or 1,1-dimethylbenzylamine moiety, where the substintutent preferably is an or p-chlorine or p-methoxy group. In a second embodiment of the compounds of Formula VI, Y is N, and R is an mor p-methoxy substituted phenylethylamine. Compounds of the first and second embodiments appear to exhibit selectivity for the mGluRI receptor. In a third embodiment, of the compounds of Formula VI. Y is N, and R is an o, m, or pfluoro-substituted phenylethylamine. Compounds of the third embodiment appear not to discriminate between the mGluRI and mGluR. receptor subtypes.
SUBSTITUTE SHEET (RULE 26) -17- In yet another preferred embodiment of the invention, the compounds have the Formulae VIII or IX: R 0o1 X VIII IX wherein X1- 4 and R are as defined above. In a first embodiment of compounds of Formula VIII, X1 and X 2 are N, X 3 and X 4 are H, R is 1-adazuantyl, and 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. In a second embodiment of compound IX, R is 1-adamantyl. Compounds of these first and second embodiments appear to exhibit selectivity for the mGluRj receptor.
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-CH 2 and Ar is m- or o-alkyloxyphenyl, or 3,4-methylenedioxy or 3,4dioxane.
4. In still another embodiment, the compound is selected from the group consisting of 1-Adaxnantyl-2quinoxalinecarboxylate, N-(2-Adamantyl)-2quinoxalinecarboxamide, N- [(lR,2R, 3R, 5S) -3-Pinanemethyl] -2quinoxalinecarboxaiide, N- (1-Adamantyl) -2quinoxalinecarboxamide, N- (exo-2 -Norbornanyl) -2quinoxalinecarboxamide, N- [(lR,2S, 4S) Bornyl] -2- 25 quinoxalinecarboxamide, N- (3-Noradamantyl) -2quinoxalinecarboxamide, N- [(1R,2R, 3R, 5S) Isopinocamphenyl] -2quinoxalinecarboxamide, N- [(1S,2S, 3S, 5R) IsopinocamphenylJ -2quinoxaline-carboxamide, N- (5-Chloro- (2.2.1.O]tricyclo-2,6hepta-3-yl) -2-quinoxalinecarboxamide, N- ([4.3.l.1)Tricyclo- 3,8-undeca-3-yl)-2-quinoxalinecarboxamide, Myrtanyl] -2-quinoxalinecarboxamide, N- [(lR,2R,4S) Isobornyl] 2-quinoxalinecarboxamide, N- [endo- -2-Norbornanyl] -2quinoxalinecarboxaiide, N- -2-Phenyl-1-propylJ -2quinoxalinecarboxamide, N- -2-Phenyl-1-propyll -2- H:\suzannet\Keep\Speci\15317-99 .1 SPECI.doc 10/11/03 17aquinoxal inecarboxamide, quinoxalinecarboxamide, quinoxalinecarboxamide, quinoxalinecarboxamide, quinoxalinecarboxamide, quinoxal inecarboxamide, quinoxalinecarboxamide, quinoxal inecarboxamide, quinoxal inecarboxamide, quinoxalinecarboxanide, quinoxalinecarboxamide, quinoxalinecarboxamide, quinoxal inecarboxamide, thereof.
N- (2-Indanyl) -2- N- a-Dimethylphenethyl) -2- N- (a,a-Dimethyl-2-chlorophenethyl) -2- N- (c,c-Dimethyl-4-fluorophenethyl) -2- N- (P-Methylphenethyl) -2- N- (3-Methylcyclohexyl) -2- N- (2,3-Dimethylcyclohexyl) -2- N- ((lS,2S,3S,5R) -3-Pinanemethyl] -2- N- (1-Adamantanemethyl) -2- N- (4-Methylcyclohexyl) -2- N- ((lS,2S, 5S) -trans-MyrtanylJ -2and N- [(1R,2R,5R) -trans-Myrtanyl] -2or pharmaceutically acceptable salts 0 0 *0 OS 0 6 0 0S S 0 0 000*00 0 S. 00 0 0050 *068 0
S
0 0*0005 *05@ 0 0*00 *0S000 0 In a further embodiment, the compound is selected from the group consisting of N-(2-Adamantyl)-2quinoxalinecarboxamide, N- [(lR,2R, 3R,5S) -3-PinanemethylJ -2quinoxalinecarboxamide, N- (1-Adamantyl) -2quinoxalinecarboxamide, N- (exo-2 -Norbornanyl) -2quinoxalinecarboxamide, N- [(1R,2S,4S) -Bornyl] -2quinoxalinecarboxamide, N- (3 -Noradainantyl) -2quinoxalinecarboxamide, N- [(lR,2R, 3R,5S) -IsopinocamphenylJ -2quinoxalinecarboxamide, N- [(lS,2S, 3S,5R) -Isopinocamphenyl] -2quinoxalinecarboxamide, N-(5-Chloro-[2.2.1.O]tricyclo-2,6- 25 hepta-3-yl) -2-quinoxalinecarboxamide, N- ([4.3.1.lJTricyclo- 3,8-undeca-3-yl) -2-quinoxalinecarboxanide, N- [(1S,2R,5S) -cis- MyrtanylJ -2-quinoxalinecarboxanide, N- 2R, 4S) Isobornyl) 2-quinoxalinecarboxamide, N- [endo- -2-NorbornanylJ -2quinoxalinecarboxamide, N- [(lS,2S,3S,5R) -3-PinanemethylJ -2- 30 quinoxalinecarboxamide, N- (1-Adamantanemethyl) -2quinoxalinecarboxamide, N- 2S, 5S) -trans -Myrtanyl] -2quinoxalinecarboxamide, and N- 2R, 5R) -trans -Myrtanyl] -2quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
35 In yet another embodiment, the compound is selected from the group consisting of N-(3-Methylcyclohexyl)- 2-quinoxalinecarboxamide, N- (2,3-Dimethylcyclohexyl) -2quinoxalinecarboxamide, N- [(1S,2S,3S,5R) -3-PinanemethylJ -2quinoxalinecarboxamide, N- (1-Adamantanemethyl) -2quinoxalinecarboxamide, and N- (4-Methylcyclohexyl) -2- H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 -17bquinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
In a further embodiment, the compound is selected from the group consisting of N-[(R)-2-Phenyl-1-propyl-2quinoxalinecarboxamide, N- -2-Phenyl-l-propylj -2quinoxalinecarboxamide, N- Indanyl) -2quinoxalinecarboxamide, N- (a-a-Dimethylphenethyl) -2quinoxalinecarboxamide, N- a-Dimethyl-2-chlorophenethyl) -2quinoxalinecarboxanide, N- a-Dimethyl-4 -fluorophenethyl) -2quinoxalinecarboxamide, l-Adamantyl-2 -quinoxalinecarboxylate, and N- (f-Methylphenethyl) -2 -quinoxaline-carboxamide, or pharmaceutically acceptable salts thereof.
In another embodiment, the compound is selected from the group consisting of 3-(l-Adamantanemethoxy) -2chloroquinoxaline, 3- (1-Adainantanemethoxy) -2fluoroquinoxaline, N- (1-Adamantyl) -2-chloroquinoxaline-3carboxamide, or pharmaceutically acceptable salts thereof.
In still another embodiment, the compound is selected from the group consisting of 2-(l- Adamantanemethylsulfanyl) quinoxaline, 2- (1- Adamantanemethoxy) quinoxaline, N- (trans -4 -Methylcyclohexyl) 2-quinoxalinecarboxamide, N- (cis-4-Methylcyclohexyl) -2quinoxalinecarboxanide, or pharmaceutically acceptable salts thereof.
25 In yet another embodiment, the compound is Go 0 0:064:selected from the group consisting of N-(4-Phenylbutyl)-2quinoxalinecarboxamide, 2- (l-Adamantanemethylsulfonyl) -3methylguinoxaline, 1- (1-Adamantyl) (3-methylquinoxal- 2 ylsulfanyl) ethanone, N- (1-Adaxnantyl) 7dimethylquinoxaline-2-carboxamide, N- -1-Tetralinyl) -2quinoxalinecarboxamide, N- (4 -Chlorophenethyl) -2- 0696.quinoxalinecarboxamide, N-U(-Tetralinxnethyl) -2- 000 0 quinoxalinecarboxamide, N- (1-Indarnmethyl) -2- 0:60:quinoxalinecarboxamide, N- 4 -Dimethylcyclohexyl) -2- 0 00 35 quinoxalinecarboxamide, or pharmaceutically acceptable salts 0 0: 0 0 thereof.
In a further embodiment, the compound is selected from the group consisting of N-(trans-4-Methylcyclohexyl)- 2 quinoxalinecarboxamide.
H.\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 -17c- In yet another embodiment, the compound is selected from the group consisting of N-(4,4- Dimethylcyclohexyl) -2 -quinoxalinecarboxamide.
In general, it appears that selective antagonism of the mGluRj receptor can be attained with compounds of the formula R-CO-N-Arl, where Ar 1 is an Hz\suzannet\Keep\Speci\15317-9 9 .l SPECIdoc 10/11/03 WO 99/26927 PCT/US98/24833 aromatic or heteroaromatic group such as a quinolinyl. quinoxalinvl.
thiazolidinyl, phenyl. benzimidazoyl, or pyridyl group.
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 I 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.
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -19- When the [linkerl 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 ketomethvlene function can be prepared via addition of an organometallic 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. N,N-Disubstiitued hydrazine compounds may be prepared via reductive amination of hydrazones formed by reaction of a monosubstituted hydrazone with an aldehyde.
N.AN-
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 oxalvl 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..
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 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.
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 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" are calculated using a dissociation constant (Kd) of 224 nM and applying equation: [Ca- 2 li (F Fmi x Kd where F is fluorescence at any particular time of interest. Fm is determined by chelating all calcium available, therefore, no fura 2 is bound to calcium, and Fn.x 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 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -21- Preparation of pharmaceutical compositions containing mGluR antagonists, and their use in treating neurological disorders The compounds of the invention are useful for treating neurological S 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 will 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.
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -22maleate, 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 sustainedrelease form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington's Pharmaceutical Sciences: (18th 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. intraperitoneai, 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 and 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.
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 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 crosslinked 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, 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.
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 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 (crosslinked 5% PhMe silicone); column length, 25 m; column i.d., 0.20 mm: helium flow rate. 60 mL/min: injector temp., 250 oC; temperature program. 20 C/min from 125 to 325 °C for 10 min. then held constant at 325 'C for 6 mini. Thin-layer chromatography was performed using Analtech Uniplate 25 0-um silica gel HF TLC plates. UV light sometimes in conjunction with ninhydrin 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 Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (Saint Louis. MO). Fluka Chemical Corp. (Milwaukee, WI), Fisher Scientific (Pittsburgh. PA). TCI America (Portland. OR). or Lancaster Synthesis (Windham.
NH).
EXAMPLE 1: Preparation of N-[6-(2-Methylquinolvl)]-ladamantanecarboxamide 2 -Methyl-6-aminoquinoline A mixture of 2 -methyl-6-nitroquinoline (1.00g, 5.31 mmol) and Pearlman's catalyst [palladium dihydroxide on activated charcoal palladium); 0.10 gJ in ethyl acetate (40 mL) was stirred under hydrogen gas (1 atm) at 60 0 C for 1.5 h. The reaction mixture was filtered and the filtrate was rotary evaporated. This provided 0.81 g of 2 -methyl-6-aminoquinoline as a yellow solid.
SUBSTITUTE SHEET (RULE 26) WO 99/26927 WO 9926927PCT/US98/24833 /V4[6-(2-,Nrlethvlquinoviy) J- I-adamantanecarboxarnide '-Adamantanecarbonyf chloride 1.02 g. 5.13 mmoh in p yridine (2 iniL) was added to a solution of 2 -methyl-6-aminoquinoline (0.81 g, 5. 1 Inmol) in pyridine (8 mL The reaction was stirred for 17 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) and diethyl ether (3 x 25 mnL). This provided 1.07 g of (40) as a cream-colored powder: rt 13.49 min.: mlz (rel. int.) 320 (M 30), 235 158 157 136 (11), 135 (100), 130 107 93 91 79 77 67 In a similar manner, the following N-quinolvl- I -adamantanecarboxamides were prepared:
N-(
6 .Quinolyl-.adamantanecabaide (18) Prepared from l-adamantanecarbonyl chloride (1.3 7 6.90 mmofl. 6aminoquinoline (0.59 4. 1 inmol), pyridine (20 mL), and water (200 mL) yielding 1.25 g (100%) of (18): rt= 13.24 min.:m/z (rel. inE.) 306 221 144 136 135 (100), 116 107 93 91 79 67 41
N-(
2 Quinolvi-l.adamantanecarboxamid hydrochloride (81) Prepared from I -adamantanecarbonvi chloride (0.75 a, 3.8 mmol). 2 aminoquinoline (0.60 g, 4.2 mmol), pyridine (10 mL), and water (100 mL).
Forming the hydrochloride salt with diethyl ethereal hydrogen chloride yielded 0.19 g of (81): rt= 12.24 min;m/z (rel. int.) 306 (M 305 277 263 221 172 171 145 144 143 136 135 (100), 1 28 (33), 117 116 107 105 101 93 91 89 81 79 77 67 65 55 53 41
N-(
3 Quinol l).1adamtaecabaide (86) Prepared from l-adamantanecarbonyl chloride (0.75 g, 3.8 mmol), 3aminoquinomne (0.60 g, 4.2 mmol), pyridine (10 mL), and water (100 rnL) yielding 0.33 g of (86): rt= 13.01 min., m/z (rel. init.) 306 (M 136 135 (100), 116 107 93 91 89 79 77 67 65 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -26- N-(trans-4-Methylcyclohexyl)-2-quinoxainecarboxamide (299) Using the method of Booth Chem. Soc.. 1958, 2688: J. Chem. Soc..
1971, 1047; Tetrahedron. 1967. 23, 2421), hydroxylamine (3.8 g, 55 mmol).
ethanol (50 mL), pyridine (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 the residual oil dissolved in ethylacetate (100 mL). The organic layer was washed with water brine, dried over anhydrous MgSO4. filtered, and concentrated to a clear oil (the 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 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 trans-4methylcyclohexylamine hydrochloride product).
Without further purification 750 mg (5 mmol) of trans-4methylcyclohexyl amine hydrochloride in dichloromethane (10 mL) was treated with pyridine (1.62 mL. 20 mmol) followed by the addition of 2-quinoxaloyl 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 1 N NaOH brine, dried over anhydrous MgSO4, filtered and concentrated to a solid. Chromatography (MPLC) of the crude reaction material through silica (7 x 4 cm BIOTAGE, KP-SIL, angstroms) using ethylacetate-hexane afforded 470 mg of the desired product, N-(trns-4-methylcycohexyl)-2-quinoxaliecarboxamide. Thin-layer chromatography (TLC. silica) using ethylacetate-hexane showed a single UV active component at R 0.19. GC/EI-MS gave m/z (rel. int.) 269 39), 212 198 174 157 129(100), 112 and 102 (46).
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -27- EXAMPLE 2: Preparation of 6-Quinolyl 1-adamantanecarboxylate (41) l-Adamantanecarbonyl chloride (1.
3 7 g, 6.90 mmol) in pyridine (5 mL) was added to a solution of 6 -hydroxyquinoline (1.00 g, 6.89 mmol) in pyridine mL). The reaction was stirred for 16 h. To the stirring reaction mixture 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 of (41) as a light-brown powder: rt= 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 thionvl chloride for 30 min.
The excess thionyl chloride was then removed by rotary evaporation (90° 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 l-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 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=11.48 min.; m/z (rel. int.) 307 306 262 174 173 157 156 135 134 129 128 (100), 127 119 107 102 101 93 92 91 81 79 78 77 75 67 55 53 51 41 (31).
In a similar manner, the following alkyl 6-quinoline- and 2 quinoxalinecarboxylates were prepared: SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 2 2 3 3 .4.4.5.5-Octafluoro-I -pentvl.- 6 -quinoline.carboxvjate hydrochloride (68) Prepared from 6 -quinol inecarbonyl chloride hydrochloride (0.75 g, 3.3 mmol), 2 2 3 3 ,4.4,5,5-octltuorolpenmnoI (0.60 mL. 4.3 mmol). pyridine s (10 mL), and water (100 mL). Forming the hydrochloride salt with ethereal hydrogen chloride yielded 0.88 g of (68): rt=7.1l minl.; mlz (rel. int.) 387 156 (100), 129 128 102 101 77 76 75 50 (14).
l-Adamantanemethyl 6 -qwnolinecarboxyjate (73) Prepared from 6 -quinolinecarbonyl chloride hydrochloride (0.80 g, mmol), Il-adarnantanemethanol (0.60 g, 3.6 rmcl), pyridine (10 mL), and water (100 ml-) yielding 0. 75 g (65 of (73): rt= 11.90 min.; (rel. int.) 321 320 263 156 148 (23).
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 -q uino xalinecarboxy late (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=lI1 211 min.. m/z (rel. in.) 308 (M 26), 264 136 136 135 (100). 134 130 129 107 102 93 92 91(1 1).
8 79 77 76 75 67 55 51 41 (11).
EXAMPLE 4: Preparation of N-(1-Adamantvl)-3quiinolinecarboxamide (72) 1,lI'-Carbonvidiimidazole (161 mg, 1.00 mmol) in N.Ndimethylformamjde (I mL) was added in one portion to a suspension of 3quinolinecarboxylic acid (173 mg, 1.00 mmcl) in NN-dimethyformammde (1 mL). The resulting reaction solution was stirred for 2.5 h. I- Adamantanammne (151 mg, 1 .00 mmol) in NN-dimethylformamide (0.5 mL) was added in one portion. The reaction mixture was stirred at 60 CC 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 SUBSTITUTE SHEET (RULE 26) WO 99/26927 WO 9926927PCTIUS98/24833 -29silica gel, and rotary evaporated. This provided 73 mg of (72) as a crystalline solid: rt 11. 02 min.: m/z (rel. mtE.) 306 (M 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-alkvl-2-quinoline- and 2quinoxalinecarboxamides were prepared: N-(l dmny)--unlneabxmd (74) Prepared from 1. l-carbonyldiimidazole 160 mg, 0. 987 mmol), quinaldic acid (173 mg, 1.00 mmol), and NN-dimethylformamide (2.5 ml-) yielding 77 mg (25 of (74): rt=l0.53 min.; m/z (rel. it.) 306 305 277 263 221 1s 172 171 145 144 143 136 135 (100). 128 117 116 107 105 101 93 91 89 (14), 81 79 77 67 65 55 53 41 (18).
N-2Aaati--uioaieabxmd (144) Prepared from [.lI'-carbonyldiimidazole (161 mg, 1.00 rumol), 2quinoxalinecarboxylic acid (174 rug, 1.00 mmol), 2 -adamantanamine (136 mug, 0.90 mmol), and dichloromethane (3.5 mL) yielding 98 mg of (144): rt~= 1.79 min.: m/z (rel. int.) 307 151 150 (100). 130 129 103 102 91 79 77 76 75 70 67 2S 41 N-(R2 R5)3Pnaeehl--unoaieabxmd (151) Prepared from 1,lI'-carbonydiimidazole (161 mng, 1.00 mmol), 2quinoxalinecarboxylic acid (174 mg, 1.00 mmol), (-)3-pinanemethylamine (150 mg, 0.90 mmcl), and dichloromethane (3.5 ml-) yielding 50 mg of (151): rt 1.46 min.; mlz (rel. int.) 323 (M 187 186 174 166 158 157 144 131 130 129 (100), 107 103 102 95 93 91 81 79 77 76 (11),.69 67 55 53 51 43 41 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 EXAMPLE 5: Preparation of d-(-Adamnantyl) -2.
quinoxalinecarboxamide (91) 2 -Quinoxalovl chloride (0.84 g, 4.4 mmol) was added to a solution of Iadamantanamine (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 (82 of (9 1): rt=11.73 min.: m/z (rel. mnt.) 307 279 157 151 150 (100), 130 129 103 102 94 93 91 79 77 76 75 67 41 41 In a similar manner, the following N-substituted 6 -quinoline- and 2quinoxainecarboxamides were prepared: N-IAanny)6qioieabxmd (42) Prepared from 6 -quinolinecarbonyj chloride hydrochloride 1.51 g, mmol), I-adamananamine (1.73 g, 10 mmol), pyridine (5 mL), and water (200 mL) yielding 330 mg (11I%) of (42): rt= 11.04 min.; mlz (rel. mtE.) 306 305 250 249 156 155 (100), 130 128 127 126 102 101 93 92 91 79 77 67 41 41 (11).
N-eo2Nronni--unxiieabxmd (148) Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmol). exo-2aminonorbornane (133 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 35 mg of (148): rt 10. 22 min.; mlz (rel. int.) 267 (M 36), 198 158 157 131 130 129 111 111 110 (100), 103 102 77 76 75 67 51 41 Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmob., bornylamine (138 mg, 0.90 Inmol), pyridine (5 mLU, and water (50 mL) vielding 140mig of (150): rt= 10.79 min.; m/z (rel. int.) 309 199 187 174 158 157 153 152 144 135 131 130 129 SUBSTITUTE SHEET (RULE 28) WO 99/26927 PCT/US98/24833 -31- (100), 109 103 102 95 93 91 79 77 76 75 67 55 53 51 43 41 /V-(3-Noradamantyl)- 2 -quinoxalinecarboxamide (152) Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmol), 3noradamanianamine (157 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 167 mg of (152): rt=11.00 min.: m/z (rel. int.) 293 265 250 232 222 157 144 137 136 131 130 130 129 10 (100), 103 102 94 91 80 79 77 76 67 53 51 41 (13).
N-[(IR,2R,3R,SS)-Isopinocamphenyl]-2-quinoxalinecarboxamide (165) Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmol), (1R, 2
R,
3 R,5S)-(-)-isopinocamphenylamine (138 mg, 0.90 mmol), pyridine mL), and water (50 mL) yielding 230 mg of (165): rt= 10.88 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-[(IS,2S,3S,5R)-Isopinocamphenyl]-2-quinoxalinecarboxamide (166) Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmol), (1S,2S,3S,5R)-(+)-isopinocamphenylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 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 (18).
102 95 93 91 79 77 76 75 67 53 51 43 41 N-(5-Chlorotricyclo[2.2.1.0(2,6)]hept-3-yl)-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=I1.29 min.: m/z (rel. int.) 299 264 246 199 198 186 185 144 142 130 129 (100), 106 103 102 102 91 80 79 78 77 76 65 53 52 51(14), 50 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -32- N-(Tricyclo[4.3.1.1(3,8)]undec-3-i)-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 (5 mL), and water (50 mL) yielding 110 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 (31), 94 93 92 91(15), 81 80 79 77 76 75 67 55 53 41 N-[(1S,2R,S)-cis-Myrtanyl]-2-quinoxalecarboxamide (169) Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmol), myrtanylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 224 mg of (169): rt= 11.32 min.: m/z (rel. int.) 309 186 174 158 157 152 131 130 130 129 (100), 121 103 102 93 91 81 79 77 76 75 69 67 55 54 53 51 43 41 (26).
N-(1R,2R,4S)-Isobornyl]-2-quinoxalinecarboxamide (170) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol). isobornylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 130 mg 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 67 55 53 51 43 41 (18).
N-[endo-()-2-Norbornanyl]-2-quinoxalinecarboxamide (171) Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmol), endo-(+)-2aminonorbornane (133 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 1 7 5 mg of (171): rt=10.15 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).
SUBSTITUTE SHEET (RULE 26) WO 99/26927 WO 9926927PCTIUS98/24833 -23- N-()2Pev--rpi-2qioaieabxmd (172) Prepared from 2 -quinoxalovi chloride (0.47 g, 2.4 mmol), (R)-2-phenvi- Il-propyiaxnine 30 g, 2.2 mmol), pyridine (5 mnL), and water (50 mL) yieldingy 0.49 g of (172): s rt= 10.63 min. r/z (rel. int.) 291 186 158 157 130 129 (100), 118 105 104 103 102 91 79 (11).
78 77 76 75 75 51 N-()2Pey--rpl-2qioaieabxmd (173) Prepared from 2 -qumnoxaloyl chloride (0.47 g, 2.4 mniol), (S)-2-phenyl-l..
propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 ml-) yielding 0.48 g of (173): rt= 10.72 min.: m/z (rel. int.) 291 186 158 157 130 129 (100), 118 105 103 102 91 79 77 is 76 75 51 51 N-2Idnl--unxfncroand (221) Prepared from 2 -quinoxaloyl chloride (0.32 g, 1.7 mmol), 2 -aininoindan (0.20 g, 1.5 mmol), pyridine (3 mL), and water (30 ml-) yielding 0.23 g(53%) of (22 1): rE=11.33 min.; m/z (rel. int.) 289 132 130 129 117 116 (100), 115 104 103 102 91 78 77 (13), 76 75 51 51 50 N-yloti2qioaieabxmd (228) Prepared from 2 -quinoxaloyl chloride (193 mg, 1.0 mmol), CYCIOOCEylamine (123 JIL, 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-ylhpy--unoaieabxmd (229) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol).
cycloheptylamine (115 uLL. 102 mg, 0.90 mmol), pyridine (5 mL), and water (100 ml-) yielding 30mig of (229): SUBSTITIUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -34rt=10.30 min.: m/z (rel. int.) 269 212 198 185 174 174 157 131 130 129 (100), 112 103 102 76 75 56 55 51 42 41 -[2-Spiro(4.5)decl-2-quinoxalinecarboxamide (236) Prepared from 2 -quinoxaloyv chloride (193 mg, 1.0mmol). 2- (150mg, 0.79mmol), pyridine (5mL). 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 41 (14).
EXAMPLE 6: Preparation of 1-Adamantanemethvl 6 -quinolvl ether i 5 (94) A mixture of 1-adamantanemethanol (5.00 g, 30.0 mmol) and 6hydroxyquinoline (13.1 g. 90.2 mmol) in tetrahydrofuran (75 mL) was stirred for 15 min. Then, triphenylphosphine (10.2 g, 39.0 mmol) was added, followed by diethyl azodicarboxylate (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 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.) 293 149 (100), 145 128 121 116 116 107 93 91 89 81 79 77 67 65 55 53 41 (14).
EXAMPLE 7: Preparation of l-Adamantyl 3 -quinolinecarboxylate (101) A mixture of 1-adamantanol (152 mg, 1.0 mmol), 3 -quinolinecarboxylic acid (173 mg, 1.0 mmol), and dimethylaminopyridine (122 mg, 1.0 mmol) in dichloromethane (2 mL) and NN-dimethylformamide (2 mL) was cooled to 0 °C.
1.
3 -Dicyclohexylcarbodiimide (227 mg, 1.1 mmol) in dichloromethane (I mL) was added in one portion. The reaction mixture was stirred at 25 oC for 20 h.
SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 The reaction mixture was then diluted with dichloromethane (40 mL) and washed with IM 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 thin-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.) 307 306 (100), 173 155 135 127 119 106 100 93 92 91 78 77 76 74 67 54 41(12).
EXAMPLE 8: Preparation of N-(a,ca-Dimethylphenethvl)-2quinoxalinecarboxamide (108) 2 -Quinoxaloyl 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 OC. The reaction was allowed to warm to 25 OC. After min. the reaction mixture 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 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 of 2 ,4, 6 -triphenylpyrylium tetrafluoroborate (5.1 g, 13 mmol) in dichloromethane (40 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 6.14g of N-(2chlorobenzyl)-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 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -36was 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 rmmol) 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 diethvi s 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-( 2 -chlorophenyl)-2-methyl-2-nitropropane.
a,a-Dimethyl-2-chlorophenethylamine A mixture of Raney nickel (50% by weight in water: 2.3 g) and 1-(2chlorophenyl)-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.ca-dimethyl-2-chlorophenethylamine.
N-(a,a-Dimethyl-2-chlorophenethyl)-2quinoxalinecarboxamide (197) In a similar manner to (108), (197) was prepared from 2-quinoxaloyl chloride (158 mg, 0.82 mmol), c,a-dimethyl-2-chlorophenethylamine (151 mg, 0.82 mmol). and dichloromethane (3 mL) yielding 1 96 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 (18).
75 75 62 50 41 EXAMPLE 9: Preparation of N-(a,a-Dimethyl-4-fluorophenethyl)-2quinoxalinecarboxamide (129) To a solution of l-( 4 -fluorophenyl)-2-methyl-2-propylamine (105 mg.
0.628 mmol) in pyridine (2 mL) was added 2-quinoxaloyl chloride (133 rmg.
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 5 mL), dried (anhydrous magnesium sulfate), rotary evaporated, and put under high vacuum for 15 h. This provided 1 4 6 mg of(129): SUBSTITUTE SHEET (RULE 26) WO 99/26927 PTU9143 PCT/US98/24833 -37- 45 min.: M/z (rel. Inc.) 323 (M 2 14 186 157 135 130 129 (100). 1 09 103 102 83 76 75 42 In a similar manner, the following N-substitured 2quinoxaliecarboxamides were prepared: Prepared from 2-quinoxaloyl chloride (193 mg, 0.84 mmol). g methylphenethyjamine (103 mg, 0.76 mmol), and pyridine (2 ml-) yielding 154 mg of (131): rt= 10.71 min.; m/z (rel. int.) 291 (M 12), 186 158 157 130 129 (100), 118 105 103 102 91 79 78 77 76 75 51 51 Prepared from 2 "-quinoxaloyl chloride (193 mng, 1.0 mmoi), 3methvlcyclohexylamine H119 mg, 0.90 mmol), and pyridine (5 mL) yielding 190Omg 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
IV-(
2 3 -Dimrethvlcyclohexyl) 2 -quinoxainecarboxmide (163) Prepared from 2 -quinoxaioyl chloride (193 mng, 1.0 mmo). 2.3dimechylcyclohexylamine (115 mg, 0.90 mmol). and pyridine (5 ml-) vieidinsi 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-(S2,S5)3Pnnmty]2qioaieabxmd (207) Prepared from -1-quinoxaloyl chloride (193 mg, 1.0 mmol). 3S pinanemethylarnine (150 mg, 0.90 mmol), and pyridine (5 mL) vielding 229 Ing of (207): rt 12 .07 min.: mlz (rel. int.) 323 (M 12). 187 (100). 186 174 166 159 158 157 150 144 131 1.30 129 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -38- 107 103 102 95 93 91 83 81 79 (11), 77 76 69 67 55 43 41 EXAMPLE 10: N-(l-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 OC 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 9 1 81 79 77 76 (16), 67 65 55 53 51 41 (13).
EXAMPLE 11: Preparation of N-(4-Methylcyclohexyl)-2quinoxalinecarboxamide (162) To a solution of 4 -methylcyclohexylamine (119mg, 0.90 mmol) in pyridine (2 mL) was added 2 -quinoxaloyl chloride (193 mg, 1.0 mmol). The reaction was then stirred for I 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 SUBSTITUTE SHEET (RULE 26) WO 99/26927 WO 9926927PCTIUS98/24833 -319mixture was stirred for I h. The reaction mixture was rotary evaporated. This provided 7.60 g of (lS.
2 S.5S)-rrans-myvrtan yl trifluoroacetate.
(1R.2R.5R)-trans-Mvrtanyl trifluoroacetate In a similar manner. (IR, 2 R,5R)-trans-myrtanvl trifluoroacetate was prepared from trifluoroacetic anhydride (5.40 ml-. 38.0 mmol, 1.2 equiv) trans-myrtanol (5.00 mL. 4.90 g, 31.7 mmol), and tetrahvdrofuran (100 mL) yielding 7.60 g of (lR, 2 R,SR)-trans-myrtanyl trifluoroacetate.
A mixture of (lS, 2 S,5S)-trans-myrtanyl trifluoroacetate (1.0 g, mmol), sodium azide (0.39 g, 6.0 mmol), and N.N-dimethylformamide mL) was stirred at 80 'C 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 laver was then dried (anhydrous sodium sulfate) and rotary evaporated.
This provided 1. 12 g (100%) of (IS,2S.5S)-rrans-mnyrtanylazide as a colorless oil.
(lR.
2 In a similar manner. (lR.
2 R,5R)-trans-myrtanylazide was prepared from tritluoroacetate (7.60 g, 30.4 rnmol), sodium azide (3.00 g, 45.6 mmol), and N.N-dimethylformamide (100 mL) yielding 4. 10 g of (IR.
2 (lS, 2 A mixture of (lS.
2 S,5S)-trans-myrtanylazide 12 g, 7.32 mmol) and platinum(IV) 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 mQ. 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 SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCTIUS98/24833 evaporated. This provided 78 mg of (IS.2S.5S)-trans-myrtanylamine as a light yellow oil.
(lR.
2 In a similar manner. (lR.
2 R.5R)-trans-myrtanylamine was prepared from
(IR,
2 R,5R)-trans-myrtanylazide 10 g, 26.8 inmol), platinum(IV) oxide hydrate (0.41 and ethanol (75 mL) yielding 2.00 g of trans-myrtanylamine.
N-(S2.S-rn-vtnl]2qioaieabxmd (225) In a similar manner to (162), (225) was prepared from 2-quinoxalovl chloride (49 mg, 0.25 mmol), (lS.
2 S.5S)-trans-myrranylamine (35 ME, 0.23 mmol), and pyridine (5 mL) yielding 8 mg of (225): rt= 11.23 min.: m/z (rel. int.) 309 (M 187 186 174 158 157 152 131 130 130 129 (100), 103 102 93 91 81 79 77 76 75 69 67 (17).
54 53 51 43 41 R2.R-rn-ytnl-2qioaieabxmd (226) In a similar manner. (226) was prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (lR, 2 R.5R)-trans-myrtanylamne (138 mg, 0.90 mmol).
and pyridine (5 mL) yielding 27 mg of (226): rt= 11. 19 min.. m/z (rel. mnt.) 309 (M 186 186 174 158 157 152 131 130 130 129 (100), 121 103 102 93 91 81 79 77 76 75 69 (14).
67 55 53 51 43 41 (18).
EXAMPLE 13: Preparation of N-[N'-(R)-a-Methylbenzl.2acetamidol.
3 -arninoquinotiie dihydrochloride (156) N-(R)a-Methybenz2choroacetmide (R)-c-Methylbenzyiamine (2.4 g, 20 tniol) in dichloromethane (50 mL) was added to chloroacetyl chloride (2.25 g, 20 mmol) in dichloromnethane mL) and pyridine (10 mnL). The reaction solution was stirred, then diluted with diethyl ether (500 imL), washed with water (3 x 30 mL), dried (anhydrous magnesium sulfate), and rotary evaporated. This provided 3.60 g of -R-x me~hvibenzy-2-choroaceamide SUBSTITUTE SHEET (RULE 28) WO 99/26927 PCT/US98/24833 -41- 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-IN'-(R)-c-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)-c-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 (10 mL), 1 M hydrogen chloride in diethyl ether mL) was added, and the solution was rotary evaporated. The resulting material was dissolved in chloroform (5 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.) 328 182 181 180 167 166 165 162 161 160 148 145 135 132 122 120 119 107 106 105 (100). 104 103 90(12), 79 78 77 51 44 41 (11).
EXAMPLE 14: Preparation of 1-(l-Adamantvl)-2-(benzothiazol-2ylsulfanyl)ethanone (273) Sodium hydride (36.5 mg, 1.52 mmol. 60% in mineral oil) was washed with pentane dried under N2. suspended in dimethylformamide (DMF. SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -42mL) 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 20 minutes at 0°C and treated with a solution of 1adamantanebromomethyl ketone (389.8 mg, 1.52 mmol) in DMF (8 mL). The reaction was stirred 30 minutes at ambient temperature and diluted with diethvl 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 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 u.M Fura-2 acetoxymethylester by incubation for 30-40 minutes at 37 oC in SPF-PCB (126 mM NaCI, 5 mM KCI, 1 mM MgCl2.
mM Na-HEPES. 1.0 mM CaClh, I 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 BSA-free 37 OC 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 oC with constant stirring using a custom-built spectrofluorimeter (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 .g/mL, final) was added to obtain maximal fluorescence (Fmn), and the apparent minimal fluorescence 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: [Ca"Ji (F F,n x Kd; SUBSTITUTE SHEET (RULE 26) WO 99/26927 PCT/US98/24833 -43where F is fluorescence measured at any particular time of interest and F falls between Fmx and Frn.
Control responses to the addition of 5 mM Ca 2 (final extracellular S 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 Al per a total volume of 1500 j/l (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 and Fmi 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 ICso 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.
SUBSTITUTE SHEET (RULE 26) -43a- For the purposes of this specification it will be clearly understood that the word "comprising" means "including but not limited to", and that the word "comprises" has a corresponding meaning.
H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03
Claims (15)
1. A compound represented by the formula I, R-Linker Ar wherein R is an optionally substituted straight or branched chain alkyl, aralkyl, cycloalkyl, or alkylcycloalkyl group containing 5-12 carbon atoms, wherein Ar is a quinoxaline moiety with 0-2 substituents, wherein the quinoxaline substituents are selected from the group consisting of F, Cl, Br, or I at the 3 position, and C 1 -C 3 alkyl and F, Cl, Br, or I at the 5, 6, 7, and 8 positions, and wherein [linker] is -(CH 2 where n is 2-6, and wherein up to 4 CH 2 groups may independently be replaced with groups selected from the group consisting of Ci-C 3 alkyl, CHOH, CO, O, S, SO, SO 2 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 CH 2 groups may be replaced by a substituted or unsubstituted S: 20 alkene or alkyne group, or a pharmaceutically acceptable salt thereof.
2. 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 substituents independently selected from the group consisting of F, Cl, OH, OMe, and =0. *0
3. The compound according to claim 1 or claim 2, 30 wherein [linker] comprises an amide, ester, or thioester group.
4. The compound according to any one of claims 1 to 3, wherein R comprises a moiety selected from the group consisting of adamantyl, 2-adamantyl, (1S,2S,3S,5R)- H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 45 isopinocamphenyl, tricyclo[4.3.l.l(3,8)]undec-3-yl, -cis-myrtanyl, (lR,2R,4S) -isobornyl (lR,2R,3R,5S) -isopinocamphenyl, (lS,2S,5S) -trans-myrtanyl, (1R,2R,5R) -trans-myrtanyl, (lR,2S,4S) -bornyl, 1- adamantanemethyl, 3-noradamantyl, (1S,2S,3S,5R) -3- pinanemethyl, cyclooctyl, a,a-dimethylphenethyl, -2- phenyl-1-propyl, cycloheptyl, 4-methyl-2-hexyl groups, 2,2,3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl- 2-methyipropyl, 3 ,5-dimethyladamantyl, trans-2 phenylcyclopropyl, 2 -methylcyclohexyl, 3,3,5- trimethylcyclohexyl, 2- (o-methoxyphenyl) ethyl, 2- (1,2,3,4- tetrahydronaphthyl), 4 -phenylbutyl, 2-methyl -2- phenylbutyl, 2-(rn-f luorophenyl) et hyl, 2- (p- fluorophenyl)ethyl, 2- (3-hydroxy-3-phenyl)propyl, -2- hydroxy-2-phenylethyl, -2-hydroxy-2-phenylethyl, 2- (3- m-chlorophenyl-2-methyl)propyl, 2- (3-p-chlorophenyl-2 methyl)propyl, 4-tert-butyl-cyclohexyl, -1- (cyclohexyl)ethyl, 2- (3,4-dimethylphenyl) -2- methyl)propyl, 3, 3-dimethylbutyl, 2- (5-methyl)hexyl, 1- myrtanyl, 2-bornyl, 3-pinanemethyl, 2,2,3,3,4,4,5,5- octafluoropentyl, p-fluoro-a,a-dimethylphenethyl, 2- naphthyl, 2 -bornanyl, cyclohexylmethyl, 3- ~.methylcyclohexyl, 4-methylcyclohexyl, 3,4- 000:dimethylcyclohexyl, 5-chloro-tricyclo[2.2.1]heptyl, O-a'a- dimethylphenethyl, 2-indanyl, 2-spiro[4.5]decyl, 2- phenylethyl, 1-adamantylethyl, 1- (1-bicyclo[2.2.llhept-2- yl)ethyl, 2- (2-methyl-2-phenylpropyl), 2- (a- fluorophenyl) ethyl, 1- (cyclohexyl) ethyl, and cyclohexyl. 0..60. 0.06 30 5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable diluent or excipient. o. A method of making a compound according to any one of claims 1 to 4, comprising reacting a compound containing an activated carboxylic acid group with a compound containing an amine, hydroxyl, or thiol group. H:\suzannet\Keep\Speci\15317-99.1 SPECI.dOC 10/11/03 46
7. A method of inhibiting activation of an mGluR Group I receptor comprising treating a cell containing said receptor in vitro with an effective amount of a compound according to any one of claims 1 to 4.
8. A method of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 4.
9. 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 compound according to any one of claims 1 to 4 or a composition according to claim The compound according to any one of claims 1 to 4, wherein said compound is selected from the group 20 consisting of l-Adamantyl-2-quinoxalinecarboxylate, N-(2- Adamantyl)-2-quinoxalinecarboxamide, N-[(1R,2R,3R,5S)-3- Pinanemethyl]-2-quinoxalinecarboxamide, N- (1-Adamantyl) -2- quinoxalinecarboxamide, N-(exo-2-Norbornanyl)-2- quinoxalinecarboxamide, N-[(1R,2S,4S)-Bornyl]-2- quinoxalinecarboxamide, N-(3-Noradamantyl)-2- quinoxalinecarboxamide, N-[(1R,2R,3R,5S)Isopinocamphenyl]- 2-quinoxalinecarboxamide, N-[(1S,2S,3S,5R)- Isopinocamphenyl]-2-quinoxalinecarboxamide, [2.2.1.0]tricyclo-2,6-hepta-3-yl)-2- S 30 quinoxalinecarboxamide, N-([4.3.1.1)Tricyclo-3,8-undeca-3- yl)-2-quinoxalinecarboxamide, N-[(lS,2R,5S)-cis-Myrtanyl] 2-quinoxalinecarboxamide, N-[(1R,2R,4S)Isobornyl]-2- quinoxalinecarboxamide, N-[endo-(±)-2-Norbornanyl]-2- quinoxalinecarboxamide, N-[(R)-2-Phenyl-1 propyl]-2- quinoxalinecarboxamide, N-[(S)-2-Phenyl-l-propyl]-2- quinoxalinecarboxamide, N-(2-Indanyl)-2- quinoxalinecarboxamide, N-(a,a-Dimethylphenethyl)-2- H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 47 quinoxalinecarboxamide, N- (c,a-Dimethyl-2- chiorophenethyl) -2-quinoxalinecarboxamide, N- a- Dimethyl-4-fluorophenethyl) -2-quinoxalinecarboxanide, N- (P-Methylphenethyl) -2-quinoxalinecarboxamide, N- (3- Methylcyclohexyl) -2-quinoxalinecarboxaiide, N- (2,3- Dimethylcyclohexyl) -2-quinoxalinecarboxanide, N- [(1S,2S,3S,5R) -3-Pinanemethyl] -2-quinoxalinecarboxamide, N- (l-Adainantanemethyl) -2-quinoxalinecarboxanide, N- (4- Methylcyclohexyl) -2-quinoxalinecarboxamide, N- trans-Myrtanyl] -2-quinoxalinecarboxamide, and NV- 2R, 5R) -trans-Myrtanyl] -2-quinoxalinecarboxamide, or pharmaceutically acceptable saits thereof.
11. The compound according to any one of claims 1 to 4, wherein said compound is selected from the group consisting of N- (2-Adamantyl) -2-quinoxalinecarboxanide, N- 2R,3R, 5S) -3-Pinanemethyl] -2-quinoxalinecarboxanide, N- (l-Adamantyl) -2-quinoxalinecarboxamide, N- (exo-2- Norbornanyl) -2-quinoxalinecarboxanide, N- 2S,4S) Bornyl] -2-quinoxalinecarboxamide, NV-(3-Noradamantyl) -2- quinoxalinecarboxanide, N- 2R, 3R, *.pncmhnyl2qioaincroaie 9. Ispinocamphenyl]amhnyl-2-quinoxalinecarboxammiddeN N- (5-Chloro- tricyclo-2, 6-hepta-3-yl) -2- quinoxalinecarboxamide, N- ([4.3.l.lJTricyclo-3,8-undeca-3- yl) -2-quinoxalinecarboxamide, N- [(lS,2R,5S) -cis-MyrtanylJ 2-quinoxalinecarboxamide, N- [(lR,2R,4S)Isobornyl) -2- quinoxalinecarboxamide, N- [endo- -2-Norbornanyl] -2- 9 9 quinoxalinecarboxanide, N- 2S, 3S, 5R) -3-Pinaneinethyl] 30 2-quinoxalinecarboxamide, N- (-Adamantanemethyl)-2 quinoxalinecarboxamide, N- [(lS,2S, 5S)-trans-Myrtanyl] -2- quinoxalinecarboxanide, and N- 2R, 5R) -trans-Myrtanyl] 2 -quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
12. The compound according to any one of claims 1 to 4, wherein said compound is selected from the group H:\suzainet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 48 consisting of N- (3-Methylcyclohexyl) -2- quinoxalinecarboxamide, N- (2,3-Dimethylcyclohexyl) -2- quinoxalinecarboxamide, N- 2,3S, 5R) -3-Pinanemethyl] 2-quinoxalinecarboxamide, N- (1-Adamantanemethyl) -2- quinoxalinecarboxamide, and N- (4-Methylcyclohexyl) -2- quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
13. The compound according to any one of claims 1 to 4, wherein said compound is selected from the group consisting of N- -2-Phenyl-1-propyl-2- quinoxalinecarboxamide, N- US) -2-Phenyl-1-propylJ -2- quinoxalinecarboxamide, N- (2-Indanyl) -2- quinoxalinecarboxamide, N- (a-a-Dimethylphenethyl) -2- quinoxalinecarboxamide, N- (a,c-Dimethyl-2- chiorophenethyl) -2-quinoxalinecarboxamide, N- a- Dimethyl-4-fluorophenethyl) -2-quinoxaline-carboxamide, 1- Adamantyl-2-quinoxalinecarboxylate, and N- (P- Methyiphenethyl) -2-quinoxaline-carboxamide, or pharmaceutically acceptable salts thereof. *14. The compound according to any one of claims 1 to 4, wherein said compound is selected from the group consisting of 3- (1-Adamantanemethoxy) -2-chlorocpuinoxaline, 3- (1-Adamantanemethoxy) -2-f luoroquinoxaline, N- (1- Adamantyl) -2 -chloroquinoxaline-3-carboxamide, or pharmaceutically acceptable salts thereof. .15. The compound according to any one of claims i to 30 4, wherein said compound is selected from the group consisting of 2- (1-Adamantanemethylsulfanyl)quinoxalile, 2- (1-Adamantanemethoxy) quinoxaline, N- (trans-4- Mehlyloey)2qunx..cabxmd,.-cs4 Methylcyclohexyl) -2-quinoxalinecarboxanide, N-or s4 pharmaceutically acceptable salts thereof.
16. The compound according to any one of claims 1 to H:\suzannet\Keep\Speci\15317-99.1 SPECI .doc 10/11/03 49 4, wherein said compound is selected from the group consisting of N-(4-Phenylbutyl)-2-quinoxalinecarboxamide, 2-(1-Adamantanemethylsulfonyl)-3-methylquinoxaline, 1-(1- Adamantyl)-2-(3-methylquinoxal-2-ylsulfanyl)ethanone, N- (1-Adamantyl)-6, 7-dimethylquinoxaline-2-carboxamide, N- ((S)-l-Tetralinyl)-2-quinoxalinecarboxamide, N-(4- Chlorophenethyl)-2-quinoxalinecarboxamide, N-(1- Tetralinmethyl)-2-quinoxalinecarboxamide, N-(1- Indanmethyl)-2-quinoxalinecarboxamide, 4- Dimethylcyclohexyl)-2-quinoxalinecarboxamide, or pharmaceutically acceptable salts thereof.
17. The compound according to any one of claims 1 to 4, wherein said compound is N-(trans-4-Methylcyclohexyl)- 2-quinoxalinecarboxamide.
18. The compound according to any one of claims 1 to 4, wherein said compound is N-(4,4-Dimethylcyclohexyl)-2- quinoxalinecarboxamide. :i 19. Use of a compound according to any one of claims 1 to 4 in the treatment of a disease associated with a glutamate-induced neuronal damage.
20. Use of a compound according to any one of claims 1 to 4 in the manufacture or a medicament for the treatment of a disease associated with glutamate-induced neuronal damage. ooot *ooftt ft ft ftftftf H:\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03 50
21. A compound represented by formula I, pharmaceutical compositions comprising them, methods of making them, methods of treatment involving them or uses involving them, substantially as herein described with reference to any one of the accompanying examples. Dated this 10th day of November 2003 NPS PHARMACEUTICALS INC By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia 0 0 o o C o *e H;\suzannet\Keep\Speci\15317-99.1 SPECI.doc 10/11/03
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| US6675897P | 1997-11-21 | 1997-11-21 | |
| US60/066758 | 1997-11-21 | ||
| PCT/US1998/024833 WO1999026927A2 (en) | 1997-11-21 | 1998-11-20 | Metabotropic glutamate receptor antagonists for treating central nervous system diseases |
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| AU2004202776A Division AU2004202776B2 (en) | 1997-11-21 | 2004-06-17 | Metabotropic glutamate receptor antagonists for treating central nervous system diseases |
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| AU2004202776A Ceased AU2004202776B2 (en) | 1997-11-21 | 2004-06-17 | Metabotropic glutamate receptor antagonists for treating central nervous system diseases |
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| JP (1) | JP2001524468A (en) |
| CN (2) | CN1158264C (en) |
| AU (2) | AU771358B2 (en) |
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| MX (1) | MXPA00004940A (en) |
| NZ (1) | NZ505207A (en) |
| WO (1) | WO1999026927A2 (en) |
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- 1998-11-20 AU AU15317/99A patent/AU771358B2/en not_active Ceased
- 1998-11-20 CA CA002311131A patent/CA2311131A1/en not_active Abandoned
- 1998-11-20 NZ NZ505207A patent/NZ505207A/en unknown
- 1998-11-20 CN CNA2004100474998A patent/CN1554649A/en active Pending
- 1998-11-20 MX MXPA00004940A patent/MXPA00004940A/en active IP Right Grant
- 1998-11-20 EP EP98959535A patent/EP1037878A2/en not_active Withdrawn
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2000
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2004
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| EP1037878A2 (en) | 2000-09-27 |
| NZ505207A (en) | 2003-10-31 |
| WO1999026927A3 (en) | 1999-10-21 |
| AU2004202776A1 (en) | 2004-07-22 |
| IL136250A0 (en) | 2001-05-20 |
| AU2004202776A2 (en) | 2004-07-22 |
| IL136250A (en) | 2006-12-10 |
| CA2311131A1 (en) | 1999-06-03 |
| JP2001524468A (en) | 2001-12-04 |
| CN1285820A (en) | 2001-02-28 |
| MXPA00004940A (en) | 2002-10-17 |
| CN1554649A (en) | 2004-12-15 |
| AU1531799A (en) | 1999-06-15 |
| AU2004202776B2 (en) | 2008-06-19 |
| WO1999026927A2 (en) | 1999-06-03 |
| CN1158264C (en) | 2004-07-21 |
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