MXPA00004940A - Metabotropic glutamate receptor antagonists for treating central nervous system diseases. - Google Patents

Metabotropic glutamate receptor antagonists for treating central nervous system diseases.

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Publication number
MXPA00004940A
MXPA00004940A MXPA00004940A MXPA00004940A MXPA00004940A MX PA00004940 A MXPA00004940 A MX PA00004940A MX PA00004940 A MXPA00004940 A MX PA00004940A MX PA00004940 A MXPA00004940 A MX PA00004940A MX PA00004940 A MXPA00004940 A MX PA00004940A
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adamantyl
carboxamide
quinoxalinecarboxamide
group
ethanone
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MXPA00004940A
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Spanish (es)
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Wagenen Bradford C Van
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Nps Pharma Inc
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Abstract

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

Description

ANTAGONISTS PE METABOTROPICQ GLUTAMATE RECEIVER TO TREAT SYSTEM DISEASES CENTRAL NERVOUS FIELD OF THE INVENTION The present invention provides active compounds in metabotropic glutamate receptors and which are useful for treating neurological and psychiatric diseases and disorders.
BACKGROUND OF THE INVENTION Recent advances in clarifying the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the therapy of neurological and psychiatric diseases and disorders. However, the major challenge for the realization of this promise has been the development of selective subtype compounds of metabotropic glutamate receptor. Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) of mammals. Glutamate produces its effects on central neurons by binding to and thus activating cell surface receptors. These receptors have been divided into two main classes, the ionotropic and metabotropic glutamate receptors based on the structural aspects of the receptor proteins, the means by which the receptors translate signals into the cells and pharmacological profiles. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that activate a variety of secondary intracellular messenger systems after glutamate binding. The activation of mGluRs in intact mammalian neurons produces one or more of the following responses: activation of phospholipase C; increase in the hydrolysis of phosphonositide (Pl); release of intracellular calcium; activation of phospholipase D; activation or inhibition of adenyl cyclase; increase or decrease in the formation of cyclic adenosine monophosphate (cAMP); Activation of guanylyl cliclase; increase in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increase in the release of arachidonic acid; and increases or reductions in the activity of voltage and ligand composite channels. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem, Int. 24: 439 (1994); Pin et al., Neuropharmacology 34: 1 (1995). Eight distinct subtypes of mGluR, called mGluRI to mGluR8, have been identified through molecular cloning. See, for example, Nakanishi, Neuron 13: 1031 (1994); Pin et al., Neuropharmacology 34: 1 (1995); Knoptel and others. J. Med. Chem. 38: 1417 (1995). In addition, a diversity of receptor occurs through the expression of alternately divided forms of certain subtypes of mGluR. See, Pin et al., PNAS 89: 10331 (1992); Minakami et al., BBRC 199: 1136 (1994); Joly et al., J. Neurosci. 15: 3970 (1995). The subtypes of the metabotropic glutamate receptor can be subdivided into three groups, the mGluRs of group I, group II and group III, based on the homology of the amino acid sequence, the second messenger systems used by the receptors, and their pharmacological characteristics. . Nakanishi Neuron 13: 1031 (1994); Pin et al., Neuropharmacology 34: 1 (1995); Knopfel et al., J. Med. Chem. 38: 1417 (1995). The mGluRs of group I comprise mGluRI, mGluR5 and its alternatively divided 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, recombinant Xenopus receptors expressing mGluRI oocytes. See, for example, Masu et al., Nature 349: 760 (1991); Pin et al., PNAS 89: 10331 (1992). Similar results have been obtained with recombinant mGluRd receptors expressing oocytes. Abe et al., J. Biol. Chem. 267: 13361 (1992); Minakani et al., BBRC 199: 1136 (1994); Joly et al., J. Neurosci. 15: 3970). Alternatively, agonist activation of recombinant mGluRI receptors in Chinese hamster ovary (CHO) cells stimulates hydrolysis of Pl, the formation of cAMP and the release of arachidonic acid as measured by standard biochemical assays. Aramori et al., Neuron 8: 757 (1992). In comparison, activation of mGluR5 receptors in CHO cells stimulates the hydrolysis of Pl and the subsequent intracellular calcium passengers, but no stimulation of the cAMP formation or the release of arachidonic acid is observed. i Abe et al., J. Biol. Chem. 267: 13361 (1992). However, the activation of mGluR5 receptors expressed in LLC-PK1 cells results in the hydrolysis of Pl and an increased formation of cAMP. Joly et al., J. Neurosci. 15: 3970 (1995). The profile of the agonist potency for the MgluRs of group I is quiscoalate >; glutamate = ibotenate > (S.1'S.2'S) -2-carboxylicclopropyl) glycine (L-CCG-1) > (1 S, 3R) -1-aminocyclopentan-1,3-dicarboxylic acid (ACPD). Quequicoalate is relatively selective for group I receptors, as compared to the mGluRs of group I II and group III, but it is also a potent receptor activator AMP onotropic Pin et al., Neuropharmacology 34 1, Knopfel et al., Med Chem. 38 1417 (1995). The lack of specific subtype mGluR agonists and antagonists has prevented clarification of the physiological roles of particular mGluRs, and the associated pathophysiological processes that affect the central nervous system that have yet to be defined. However, work with the available unspecified agonists and antagonists has produced some general insights with respect to the mGluRs of group I as compared to the mGluRs of group II and group III The attempts to clarify the physiological roles of the mGluRs of group I suggest that the activation of these receptors produces neuronal excitation. Several studies have shown that ACPD can produce post-cyclic excitement after application to neurons in the hippocampus, cerebral cortex, cerebellum, and thalamus, as well as other regions of the brain. The evidence indicates that this excitation is due to the direct activation of the post-kinaptic mGluRs, but it has also been suggested that the activation of the pre-kinaptic mGluRs occurs, resulting in the elevated release of the neutransmitter. Baskys, Trends Pharmacolo. Sci. 15:92 (1992); Schoepp, Neurochem, Int. 24: 439 (1994); Pin and others, Neuropharmacology 34: 1 (1995). Pharmacological experiments involve the mGluRs of group I as the mediators of this excitation mechanism. The effects of ACPD can be reproduced through low concentrations of quiscoalate in the presence of iGlur agonists.
See, Hu et al., Brain Res. 568: 339 (1991); Greene et al., Eur. J.
Pharmacolo. 226: 279 (1992). It is known that two compounds of fen? Glycine activate mGluRI, mainly (S) -2-hydroxyphenyl glycine ((SJ-3HPG) and (S) -3,5-dihydroxyphenylglycine (fSJ-DHPG), also produce excitation. , Tends Pharmacolo, Sci. 15:33 (1994). In addition, excitation can be blocked through (s) -4-carboxyphenyl glycine ((S) -4CPG), (S) -4-carboxy-3-hydroxyphenylglycine ((SJ-4C3HPG), and (+) - alpha-methyl-4-carboxy * phenylglycine ((+) -MCPG), compounds known to be mGluRI antagonists Eaton et al., Eur. J. Pharmacol. 244: 195 (1993), Wakins et al., Trends i Pharmacol, Sci.15: 333 (1994) Metabotropic glutamate receptors have been implicated in a number of normal processes in the central nervous system of mammals. mGluRs has required the induction of long-term hippocampal enhancement and long-term cerebellar pressure Bashir et al., Nature 363: 347 (1993), Bortolotto et al., Nature 368: 740 (1994); Aiba et al. Cell 79: 365 (1994), Aiba et al, Cell 79: 377 (1994), A role for the activation of mGluR in nociception and analgesia has also been demonstrated, Meller et al., Neuroreport 4: 879 (1993). In addition, it has been suggested that the activation of mGluR plays a modulatory role in a variety of other normal processes, including kináptica transmission, neurological development onal, apoptotic neuronal death, kinápa plasticity, spatial learning, olfactory memory, central control of cardiac activity, the and arousal, motor control, and control of the vestibulo-ocular reflex. For review, see Nakanishi Neuron 13: 1031 (1994); Pin et al., Neuropharmacology 34: 1; Knoprel et al., J. Med. Chem. 38: 1417 (1§95). It has also been suggested that metabotropic glutamate receptors play important roles in a variety of pathophysiological processes and disease states that affect the central nervous system. These include shock, head trauma, anoxic and ischemic damage, hypoglycemia, epilepsy, and neurodegenerative diseases such as Alzheimer's disease. See, Schoepp et al., Trends Pharmacolo. Sci. 14:13 (1993); Cunn? Ngham et al., Life Sci. 54: 135 (1994); Hollman et al., Am. 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 under these conditions is thought to be due to excessive excitation induced by glutamate from the neurons of the central nervous system. Since group I mGluR seem to increase neuronal excitation mediated by glutamate through post-kinetic mechanisms and improved release of pre-kinetic glutamate, its activation probably contributes to the pathology. Accordingly, selective antagonists of mGluR receptors of group I can be therapeutically beneficial, specifically as neuroprotective or anticonvulsant agents. Preliminary studies that determine therapeutic potentials with the available mGluR agonists and antagonists have produced apparently contradictory results. For example, it has been reported that the application of ACPD on hippocampal neurons leads to attacks and neuronal damage (Sacaan et al.
Neurosci. Lett 139: 77 (1992); Lipparu et al., Life Sci. 52:85 (1993).
Other studies indicate, however, that ACPD inhibits activity ', epileptiform, and may also exhibit neuroprotective properties. Taschenberger et al., Neuroreport 3: 629 (1992), Sheardown, Neuroreport 3: 916 (1992); Koh et al., Proc. Nati Acad.
Sci. USA 88: 9431 (1991); Chiamulera et al., Eur. J. Pharmacol. 216: 335 (1992); Síliprandi et al., Eur. J. Pharmacol. 219: 173 (1992); Pizzi et al., J. Neurochem, 61: 683 (1993). It is probably that these conflicting results are due to the lack of selectivity of ACPD, which causes the activation of different subtypes of mGluR. In the neuronal damage finding studies it seems that the mGluRs of group I were activated, thus improving the neurotransmission of undesirable excitation. In the studies that show neuroprotective effects, it seems that the activation of the mGluRs of group II and / or group III occurred, inhibiting the release of pre-kinetic glutamate, and redistributing the neurotransmission of excitation. This interpretation is consistent with the observation that (S) -4C3HPG, a group I mGluR antagonist and group II mGluR agonist protects against audiogenic attacks in mice DBA / 2, while the selective mGluR agonists of group II, DCG-IV and L-CCG-I, protect neurons from the toxicity induced by NMDA and KA, Thomsen et al., J. Neurochem. 62: 2492 (1994); And Bruno and "others, Eur. J. Pharmacol. 256: 109 (1994); Pizzi et al., J. Neurochem. 61: 683 (1993) Based on the foregoing, it is evident that the mGluR agonists currently available and In addition, most of the compounds currently available are amino acids or amino acid derivatives that have limited bioavailability, thus hampering in vivo studies to determine the physiology of mGluR, pharmacology and its therapeutic potential, compounds that selectively inhibit the activation of the group I subtypes of the metabotropic glutamate receptor should be useful for the treatment of neurological disorders and diseases such as senile dementia, Parkinson's disease, Alzheimer's disease, Huntington's Korea, pain, epilepsy, head trauma, anoxic and ischemic injuries, and psychiatric disorders such as schisophrenia and depression. therefore, it is clear that the identification of potent mGluR agonists and antagonists with high selectivity for individual mGluR subtypes, particularly for subtypes of the group I receptor, is greatly desired.
COMPENDIUM OF THE INVENTION Therefore, it is an object of the present invention to identify active compounds in the metabotropic glutamate receptor, which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods for making these compounds. Furthermore, it is an object of this invention to provide pharmaceutical compositions containing compounds that exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods for making these pharmaceutical compositions. It is yet another object of this invention to provide methods for inhibiting mGluR group I receptor activation, and for inhibiting neuronal damage caused by excitation activation of a mGluR Group I receptor. It is yet another object of the invention to provide methods for treating a disease associated with neuronal damage induced by glutamate. To achieve these and other objects, the present invention provides potent agonists of metabotropic group I glutamate receptors. These antagonists can be represented by the formula I, R- [linker] -Ar Where R is an alkyl, arylalkyl, cycloalkyl group or straight chain or branched alkylcycloalkyl, optionally substituted, containing 5-12 carbon atoms, Ar is an aromatic, heteroaromatic, optionally substituted arylalkyl or heteroaralkyl moiety containing up to 10 carbon atoms and up to 4 heterogeneous atoms, and [linker] is - (CH 2) n-, wherein n is 2-6 and wherein up to 4 CÍH2 groups independently can be substituted with groups selected from the selected group consisting of Ci-Ca alkyl, CHOH, CO, O, S, SO, S02, N, NH, and DO NOT. Two heterogeneous atoms in the [linker] may not be adjacent, except when those atoms are both N or both are NH. Two adjacent CH2 groups in the [linker] can also be replaced by a substituted or unsubstituted alkene or alkyne group. Pharmaceutically acceptable salts of the compounds are also provided. In one embodiment of the invention, Ar comprises a selected ring system consisting of benzene, thiazole, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, benzothiazole, benzimidazole rings. , 3H-? Ndolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalisinyl, naphthyridinyl, quinazolyl, cinylyl, isothiazolyl, quinoxalinyl, indolizinyl, isoindolyl, benzothienyl, benzofuranyl, izobenzofuranyl, and chromenyl. Ar may optionally be independently substituted with up to two C 1 -C 3 alkyl groups or up to two halogen atoms, wherein the halogen is selected from F, Cl, Br, and I. In another embodiment of the invention, R contains 4, 5 , 6, 7, 8, 9, 10 or 11 carbon atoms, wherein some or all of the hydrogen atoms on two carbon atoms can optionally be replaced with substituents independently selected from the group consisting of F, Cl, OH, OMe , = 0, and -COOH. In yet another embodiment [linker] comprises an amide, ester or thioester group. In a preferred embodiment, R comprises a portion selected from the group consisting of substituted or unsubstituted adamantyl groups, 2-adamantyl, (1S, 2S, 3S, 5R) -? Sopinocamfen? Lo, tricyclo [4, 3, 1, 1 (3.8) undec-3-yl, (1S, 2R, 5S) -c? S-mirtanyl, (1R, 2R, 4S) -isoborn? Lo, (1R, 2R, 3R, 5S) -isop? nocamphenyl, (1S, 2S, 5S) -trans'-myrtanyl, (1R, 2R, 5R) -trans-mirtanyl, (1R.2S.4S) -bornyl, 1 -adamantanmethyl, 3-noradamantyl, ( 1S, 2S, 3S, 5R) -3- \ pinanmethio, cyclooctyl, a, a-d-methylphenyl, (S) -2-phen? I-1-propyl, cycloheptyl, 4-methyl-2-hexyl, 2.2 , 3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethylated, trans-2-phenyl-cyclopropyl, 2-methylcyclohexyl, 3,3,5-trimethylcyclohexyl , 2- (o-methoxyphenyl) ethyl, 2- (1, 2,3,4-tetrahydronaphthyl), 4-phenolbutyl, 2-methyl-2-phenylbutyl, 2- (m-fluorophenyl) ethyl, 2- ( p-fluorophenyl) ethyl, 2- (3-hydroxy-3-phenyl I) propyl, (S) -2-hydroxy-2-p-phenylethyl, (R) -2-hydroxy-2-phenylethyl, 2- ( 3-m-chlorophenyl-2-methyl) propyl, 2- (3-p-chlorof enyl-2-methyl) propyl, 4-tert-butyl-cyclohexyl, (S) -1 - (cyclohexyl) ethyl, 2- (3- (3,4-dimethyl-n-nyl) -2-methy) propyl, 3, 3-dimethylbutyl, 2- (5-methyl) hexyl, 1-mirtanyl, 2-bornyl, 3-pineanthyl, 2,2,3,3,4,4,5,5-octafluorophenyl, p-fluoro-a, a -dimethylphenethyl, 2-naphthyl, 2-bornyanyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4-dimethylcyclohexyl, 5-chloro-trichlor [2,2,1-heptyl, or: a, -d? -methylphenyl] , 2-? Ndan? Lo, 2-spiro [4.5] dec? Io, 2-f enyl eti lo, 1 -admantylethyl, 1- (1-b? Ciclo [2.2.1] hept- 2-yl) ethyl, 2- (2-methyl-2-phenylpropyl), 2- (o-fluorophenyl) ethyl, 1- (cyclohexyl) ethyl, and cyclohexyl. In a further embodiment of the invention, Ar comprises a group of the formula Where X1, X2, and X3 independently can be N or CH, provided that no more than two of X1, X2, X3, and X4 can be N. In a preferred embodiment, X1 is N, and / or X2 is N. In another embodiment, X3 is N. In yet another embodiment, X1 is CH and X2 is N. In another embodiment, Ar is an optionally substituted 2-, 3-, or 4-pyridyl portion, or Ar is a 6-benzothiazolyl portion. . The compound is selected from the group consisting of N- [6- (2-metlinquinolyl)] - 1-adamantanecarboxamine, N- (6-quinolyl) -1-adamantanecarboxamide, N- (2-quinolyl) -1 -adamantanecarboxamide, N - (3-Quinolyl) -1-adamantane-carboxamide, 6-quinolyl-1-adamantanecarboxylate, 1-Adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,55,5-Octafluoro-1-pentyl-6-quinolinecarboxylate, 1 -adamantanmethyl-6-quinolinecarboxylate, 1-Adamantyl-2-quinoxalinecarboxylate, N- (1 -Ada ma nti I) -3-qui nol in -carboxamide, N- (1-Adamantyl) -2-qin or I incarboxamide, N- (2-Adamantyl) -2-quinoxalinecarboxamide, N - [(1R, 2R, 3R, 5S) - 3-Pinanmethyl] -2-quinoxaline-carboxamide, N- (1-Adamantyl) -2-quinoxalinecarboxamide, N- (1-Adamantyl) -6-quinolinecarboxamide, N- (exo-2-Norbornanil) -2-quinoxalinecarboxamine, Ñ - [(1R, 2S, 4S) -Bornyl] -2-quinoxalinecarboxamide, N- (3-Noradamantil) -2-quinoxalinecarboxamide, N - [(1R, 2R, 3RJ5S) lso-pinocamphenyl] -2-quinoxalinecarboxamide, N- [(1S, 2S, 3S, 5R) -lsopinocamphenyl] -2-quinoxalinecarboxamide, N- (5-chloro [2,2,1,0] tricyclo-2,6-hepta-3-yl) -2-quinoxatincarboxanide, N - ([4.3.1.1) Tric? Clo-3,8-undeca-3-yl) -2-qui-oxalincarboxamide, N - [(1S, 2R, 5S) -cis-Mirtanyl] -2-quinoxalin- carboxamide, N - [(1 R, 2R, 4S) lsobornyl] -2-quinolinecarboxamide, N- [endo - (+ J-2-Norbornanil] -2 -quinone xa linca rboxa mide, N - [(R) -2 -phenyl-1-propyl] -2-quinoxaIin ca rboxamide, N - [(S) -2-phenyl-1-propyl] -2-quinoxalinecarboxamide, N- (2-indanyl) -2-quinoxalinecarboxamide, 1 -adamantanmethyl 6-quinolic ether, 1-adamyl-3-quinolinecarboxylate, N- (a, -dimethylphenethyl) -2-quinoxalinecarboxamide, N- (a, -dimethyl-2-chlorophenethyl) -2-quinoxalinecarboxamide, N- (a, a-dimethyl-4-fIuorophenethyl) -2-quinoxalinecarboxamide, N- (β-methylphenethyl) -2-quinoxalincarb oxamide, N- (3-methylcyclohexyl) -2-quinocalin-carboxamide, N- (2,3-dimethylcyclohexyl) -2-quinoxalinecarboxamide, N - [(1S, 2S, 3S , SR) -3-pinanmethyl] -2-quinoxaline-carboxamide, N- (1- Adamantanmethyl) -2-quinoxalinecarboxamide, N- (4-methylcyclohexyl) -2-quinoxaline-carboxamide, N - [(1S, 2S , 5S) -trans-Mirtanil] -2-quinoxaline-carboxamide, and N- [1R, 2R, 5R) -trans-Mirtanyl] -2-quinoxaline-carboxamide, and their pharmaceutically acceptable salts In a preferred embodiment, the The compound is selected from the group consisting of N- (1-adamantyl) -3-quinolinecarboxamide, N- (1- Adamant? l) -2-quinolinecarboxamide, N- (2-Adamant? i) -2-quinoxal? n- carb oxamide, N- [ (1R, 2R, 3R, 5S) -3-Pinanmethyl] -2-quinoXaline-carboxamide, N- (1-Adamantyl) -2-quinoxaline-carboxamide, N- (1- Adam ant?) -6 -quinolinecarboxam ida, N- (exo-2-norbornanil) -2-quinoxal? n-carboxamide, N [(1R, 2S, 4S) -Born? l] -2-quinoxaline-carboxamide, N- (3-Noradamantil) -2-qu? Noxalin-carboxam? Da, N- [1R, 2R, 3R, 5S) - [sop? Nocamfenil] -2-qu? NoxaIin-carboxam? Da, N- i [(1S, 2S, 3S, 5R) -lsop? Nocamfenil] -2-qu? Noxaline-carboxamide, N- (5- chloro- [2, 2, 1,0] tricyclo-2,6-hepta-3-yl) -2-quinocalncarb oxamide, N- ([4,3,1,1] tricyclo-3,8-undeca-3-yl) -2-quinoxalinecarboxamide, N [(1S, 2R, 5S) -cis-Mirtanyl] -2-quinoxalin- carboxamide, N - [(1R, 2R, 4S) -lsobornyl) -2-quinoxaline-carboxamide, N- [endo - (+ j-2-norbornyanil] -2-quinoxalinecarboxamide, N [(1S, 2S, 3S , 5R) -3-Pinanmethyl] -2-quinoxalinecarboxamide, N- (1-Adamantanmethyl) -2-quinonoxycarboxamide, N - [(1S, 2S, 5S) -trans-Mirtanyl] -2-quinoxalinecarboxamide, and N- [ (1 R, 2R, 5R) -trans-Mirtanyl] -2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof. In another embodiment, the compound is selected from the group consisting of N- [6- (2-methylquinolyl] -1-adamancarboxamide, N- (6-quinolyl) -1-adamantane-carboxamide, N- (2-quinolyl) - 1-adamantanecarboxamide, and N- (3-Quinolyl) -1 -adamantancarboxamide, N- (3-methylcyclohexyl) -2-quinoxalinecarboxamide, N- (2,3-Dimethylcyclohexyl) -2-quinocalincarboxamide, N - [(1S, 2S , 2S, 5R) -3- Pinanmethyl] -2-quinoxaIincarboxamide, N- (1-Adamantanmethyl) -2-quinoxalinecarboxamide, and N- (4-methylcyclohexyl- 2, quinoxalinecarboxamide, N- [R] -2-Phenyl-1-propyl-2-q'uinoxali? C'arbbxanim'a , Ñ - [(S) -2-phenyl-1-própil] -2-quinoxalincarboxamida, N- (2-indanil) -2-quinoxalincarboxamida, N- (a, -dimetilfenentil) -2-quinoxalincarboxamida, Ñ- (a , a-dimethyl-2- i chloro fe netiI) -2-quinoxalinecarboxamide, N- (a, a-dimethyl-4-fluoro-phenethyl) -2-quinoxalincabroxamide, and N- (b-methylphenyl) -2-quinoxaline-carboxamide , Ester 1 -adamantanmethyl-6-quinolone, 6-quinolyl-1-adamantancarboxylate, 1-adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,5,5-Octafluoro-1-pentyl 6-quinolinecarboxylate 1 -difant 6-quinolinecarboxylate, 1 -Antimethyl-2-quinbylcarboxylate, and 1-Adamantyl-3-quinolinecarboxylate, and their pharmaceutically acceptable salts In another embodiment, the compound is selected from the group consisting of 3- (1-adamantanemethoxy) ) -2-chloroquinoxaline, 2- (1-Adamantanmethoxy) -3-methylquinoxaline, 3- (1-Adamantanmethoxy) -2-fluoro quinoxaline, 2- (1-Adaman) tanmetoxy) -3-tri-fluoro-methyl-quinoxaline, N- [2- (4-phenylthiazolyl)] -1-adamantanecarboxamide, N- [2- (5-methyl-4-fe-nyl-azolyl)] - 1 -adamantanecarboxamide, 1 - (- Adamantyl) -2- (benzothiazol-2-ylsulfanyl) ethanone, N- (1 -Adama ntil) -2-chloroquinoxalin-3-carboxamide, N- (1 -Adamant il) -3-methylquinoxalin-2- carboxamide, and N- (1-adamantyl) -1-oxiquinoxaline-3-carboxamide, 4-chlorophenyl-3-coumarin carboxylate, 2- (1-adamantanemethylsulfanyl) quinoxaline, 3- (1-Adamantanemethoxy) -2-chloropyrazine, - (1 -Annamantyl) -2- (4,6-dimethyl-pyrimidin-2-ylsulfanyl) ethanone, 1- (Adamantyl) -2- (2-anis) lysufanyl) ethanone, 3- (1-Adamantanemethoxy?) - 1H-qu? Noxal? N-2-one, 1- (1-Adamantyl) -2- (3-anilylsulfonyl) ethanone, 1 - (1 -Amamantyl) -2- (4-anisylsulfanyl) et anona, 1 - ('1 -Adamantil) -2 - (4-chlorophenylsulfanyl) -ethanone, 1- (1-Adamant? L) -2- (2-naphthylsulfan "il) ethanone, N- (2- [6- (1- Piperidinyl) pyrazinyl]) - 1 -adamantancarboxamide, N- (2- [6- (1-. - piperidinyl) pyrazinyl) adamantan-1-ylmethylcarboxamide, 1- (1-Adamantyl) -2- (1-naphthylsulfanyl) ethanone, 1- (1-Adamantyl) -2- (8-quinolyl sulfanyl) ethanone hydrochloride , 1- (1-Adamant? L) -2- (4-tri-fluoro-methoxyphenoxy) ethanone, 2- (1 -Adamantanemethoxy?) Qu? Noxal? Na, N- (trans-4-methylcyclohexyl) -2-quinoxalinecarboxamide, N- (cis-4-mephilyclohexyl) -2-quinoxalinecarboxamide, N- (trans-4-methylcyclohexyl) -2-quinolinecarboxamide, N- (trans-4-methylcyclohexyl) -3-quinoline-1-carboxamide, and N- (trans-4) -methylcyclohexyl) -6-quinolinecarboxamide, 2- (1-adamantanmethylsulfinyl) -benzothioazole, N- (4-phenylbutyl) -2-quinoxalincarb oxamide, 1- (1-styntilyl) -2- (4,6-dimethylpyridinimide- 2-ylsulfanyl) ethanol, 1- (1 -Adamant il) -2- (3-chloroquinoxal-2-yl) ethanone, 2- t (1-Adamantanmethylsulfanyl) -3-methylquinolone, N- (1- Adamanti) -2-anisamide, N- (1-Adamantanmetii) -2-anisamide, 1- (1-Adamantyl) -2- (4-chlorophenylsulfanyl) ethanone, 2- (1-Adamanthamethyl-sulfonyl) -3-methylquinoxaline, 1- (1-Adamantyl) -2- (4-fluorophenylsulfanyl) ethanone, 1 - (1-Ad amantil) -2- (3-fluorophenylisulfanyl) ethanone, 1- (1-Adamantyl) -2- (2-methoxyphenone) ethanone, 1- (4-Anisylsulfanyl) nutan-2-one, 1- (1-Adamantyl) hydrochloride ) -2- (4-anisidinyl) ethanone, 3,3-dimethyl-1- (4-anis? Isulfanyl) butan-2-one, 1- (4- (4-biphenyl) -2- (4-anisyl)! fanyl) ethanone, 1- (1-Adamantyl) -2- (2-trifluoromethoxyphenyl-sulfanyl) ethanone, 1- (1-Adamantyl) -2- (3-methylquinoxal-2-ylsulfanyl) -ethanone, hydrochloride of 1 - ( 1 -Adamantil) -2- (2-antisyl) ethanone, 1- (1-Adamantyl) -2- (4-trifluoromethoxyphenylamino) -ethanone hydrochloride, 1- (1-Adenamant) -2- (N-methyl) hydrochloride -4-anisidyl) -ethanone, N- (1-Adamantyl) -7-tri-fluorine or methi Iqui nolina-3 -carboxamide, N- (1-Adamantyl) -2- (1-pperiodinyl) Quinoxaline-3-carboxamide, N- (1-Adamantyl) -2- (2-aminoethylamino) quinolinyl-3-carboxamide, N- (3-quinolyl) -3-carboxydamantan-1-methylcarboxamide, 1 - (1-Adamantyl) -2 - [(R) -1- (1-naphthyl) ethane-1-u-amino] ethanone, N- (1-Adamantyl) -2-methoxy-quinhoxaline-3-carboxamide, N- (1- adamantyl) -2- (3-propanoylamino) quinoxaline-3-c ethyl arboxamide, N- (4-chlorophenyl) -2,3-dimethylquinoxaline-6-carboxamide, N- (1 -Adamant i I) -6,7-dimethylquinoxaline-2-carboxamide, N - ((S) -1-tetralinyl) -2-quinoxalinecarboxamide, N- (4-chlorophenethyl) -2-quinonoxycarboxamide, N- (6-Quinolyl) -2-quinoxalinecarboxamide, N- (1-TetraIinmethyl) -2-quinoxalinecarboxamide, N- (1-indanmethyl) -2-quinoxylincarboxamide, N- (4,4-dimethylcyclohexyl) -2-quinoxaIincarboxamide, and their pharmaceutically acceptable salts. According to another embodiment of the invention, a pharmaceutical composition comprising a compound as set forth above, together with a pharmaceutically acceptable diluent or excipient, has been provided. . According to yet another embodiment of the invention, there is provided a method for making a compound as set forth above, which comprises reacting a compound containing an activated carboxylic acid group with a compound containing an amine, hydroxyl or thio group In accordance with a further feature of the invention, there has been provided a method for inhibiting the inactivation of a mGluR receptor of group I, which comprises treating a cell containing said mGluR receptor of group I with an effective amount. of a compound as stated above In yet another embodiment of the invention, there has been provided a method for inhibiting neuronal damage caused by activation of excitation of a mGluR receptor of group I which comprises treating neurons with an effective amount of a compound such as It was established earlier. According to a further embodiment of the invention, there has been provided a method for treating a disease associated with glutamate-induced neuronal injury, which comprises administering to a patient suffering from said disease, an effective amount of a composition as set forth above. Other objects, aspects, and advantages of the present invention will be apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. , since various changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art from the following 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 metabotropic glutamate receptors of group I. The compounds contemplated by the invention can be represented by the general formula I R- [linker] -where R is an alkyl group, straight-chain arylalkyl or branched, or optionally alicyclic, and Ar is an aromatic, heteroaromatic, optionally substituted, aryl or heteroaryl alkyl moiety. The [linker] portion is a group that not only covalently binds to the Ar and R portions, but also facilitates the adoption of the correct spatial orientation through Ar and R to allow receptor binding Ar portion structure The Ar portion can generally contain up to 10 carbon atoms, although those skilled in the art will recognize that Ar groups with more than 10 carbon atoms are within the scope of the invention. Ar can be an aplo group. , monocyclic or bicyclic heterocyclic or heteroapyalkyl fused The ring systems encompassed by Ar can contain up to 4 heterogeneous atoms, independently selected from the group consisting of N, S and O When Ar is a hetero ring or a ring system, it contains preferably one or two heterogeneous atoms At least one of the heterogeneous atoms is preferably N The monocyclic Ar groups include, but are not limited to, phenyl, thiazole, fupyl, pyranyl, 2 H-pyrrole, triene, or pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, and • pyrazinyl. Fused bicyclic Ar groups include, but are not limited to: benzothiazole, benzimidazole, 3H-indilyl, indolyl, indazolyl, purinyl, quinocylinyl, isoquinolyl, quinolyl portions, phthalycinyl, naphthyridinyl, quinazolinyl, cinolinylino, izothiazolyl, quinoxalinylindicinyl, isoindonyl, benzothienyl, benzofuranyl, isobenzofuranyl and chromenyl. Ar preferably is a quinoxalinyl, quinolinyl or pyridyl portion. Other Ar portions include the 3,4-methylenedioxy and 3,4-dioxane rings. The Ar moiety can optionally be independently substituted with up to 2 C ^ .3 alkyl groups, or up to two I halogen atoms, wherein the halogen is selected from F, Cl, Br, and I.
Portion Structure R The R portion may generally contain between 4 and 11 carbon atoms, although those skilled in the art will recognize that R portions with 12, 13, 14, 15 or 16 carbon atoms will be possible. Although R may have 4, 5 or 6 carbon atoms, preferably R contains at least 7 carbon atoms. Preferably, R is optionally substituted a, cycloa, cycloamethyl or optionally substituted phenyla. In general, some or all of the hydrogen atoms on the two methine, methylene or methyl groups of R may be replaced by substituents independently selected from the group consisting of groups F, Cl, OH, OMe, = O, and -COOH. However, more than two hydrogen atoms can be replaced with fluorine, and R can be perfluorinated. Exemplary R portions 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-mírtanil, (1R.2R.4S) -isobornyl, (1R, 2R, 3R, 5S) -isopinocarmphenyl (1S, 2S, 5S) -trans-mirtanyl, (1 R , 2R, 5R) -trans-mirtanyl, (1R, 2S, 4S) -bornyl, 1-adamantanmethyl, 3-noradamantyl, (1S, 2S, 3S, 5R) -3-pentamethyl, i-cyclooctyl, dimethyl-trynyl, ( S) -2-phenyl-1-propyl, cycloheptyl, and 4-methyl-2-hexyl. Each of these illustrative portions R may also be substituted in the manner stated above. Other preferred R groups include the 2,2,3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethyladamantiio, trans-2-phenylcyclopropyl, 2-methicyclohexyl , 3,3,5-trimethylcyclohexyl, 2- (o-methoxyphenyl) ethyl, 2- (1,2,3,4-tetrahydronaphthyl), "4-phenylbutyl, 2-methyl-2-phenylbutyl, 2- ( m-fluorophenyl) ethylene, 2- (p-fluorophenyl) ethyl, 2- (3-hydroxy-3-phenyl) propyl, (S) -2-hydroxy-2-phenylethyl, (R) -2-h id roxi-2-feh Methyl, 2- (3-m-chlorophenyl-2-methyl) propiio, 2- (3-p-cioophenyl-2-methyl) propyl, 4-tert-butyl-cyclohexyl, (S) -1 - (cyclohexyl) ethyl, 2- (3- (3,4-dimethylphenyl) -2-methyl) propyl, 3,3-dimethylbutyl, 2- (5-methyl) hexyl, 1-mirtyl, 2-bornyl , 3-pipanmethyl, 2,2,3,3,4 ', 4,5,5-octafluoropentyl, p-fluoro-2,2-dimethylphenethyl, 2-naphthyl, 2-bornyanyl, cyclohexylmethyl, 3-methylc? Clohex? lo, 4-meth | lc? clohexyl, 3,4-d? methylcyclohexyl, 5-chloro-tricyclo [2.2-1 jheptyl, o-, -dimethylphenethyl, 2-indanyl, 2-spiro [4,5] decyl , 2-phenylethyl, 1-adamantylethyl, 1- (1-bicyclic) or [2,2,1] hept-2-yl) ethyl, 2- (2-methyl-2-phenylpropyl), 2- (o-fluorophenyl) ethyl, 1- (cyclohexyl) ethyl, cyclohexyl, butan-2- onyl, diphenylene, 3-carboxyladamantyl, 1-tetrahydronaphthylenyl, 1-indanyl, 4-methylcyclohexyl, and 4,4-dimethylcyclohexyl. Again, each of these illustrative portions R may be substituted in the manner set forth above. When the compounds may be present in alternative isomeric configurations, for example, trans or cis-4-methylcyclohexyl), the R portion may have any of the possible configurations. Similarly, if a compound exists as enantiomers, the R portion may be either the enantiomers or may be racemate.
Structure of the portion [linker] The [linker] portion usually has the structure - (CH2) n-, where n is 2-6. Up to four CH2 groups independently can be replaced with groups selected from the group consisting of an a group of Ci-Ca, CHOH, CO, O, S, SO, S02, N, NH, and NO, provided that two heterogeneous atoms can not be adjacent except when those atoms are both N (forming a bond -N = N-) or both are NH (forming a -NH-NH- bond) You can also replace any of the two adjacent CH2 groups through an alkene group or rent.
In a preferred embodiment, [linker] comprises an amide, ester, thioester, ketomethylene, ether, a ether, ethylene, ethenyl, acetylenyl, hydroxya, asulfone or a asulfoxide group. Preferably, [linker] is a group -OH-CH2) m-, -CO-Y- (CH2) m-, pS (O) m- (CH2) m-, where Y is CH2, NH, O or S, and m is 1-4 and n is 0-2. The [linker] portion can have either one of two possible orientations with respect to the R and Ar groups. In this way, for example, the invention encompasses compounds having the configuration R-O- (CH 2) m-Ar and R- (CH 2) m-0-R. 10 Design and synthesis of mGluR antagonists of Group I In one embodiment, the compounds according to the invention are esters and amides of monocyclic or aromatic and heteroaromatic carboxylic acids, bicyclic fused, phenyls and 15 amines. In a preferred embodiment, the compounds can be represented by formulas II or III: II III '20 Formulas II and III, Y can be either O, S, NH, or CH2, and X1, X2, X3 and X4 independently can be N or CH Preferably, one or two of X1, X2, X3 and X4 are N, and the remainder are CH Preferred compounds contemplated by the invention have the formula, 4IV or V wherein R, Y and X1 are as defined above.
IV In another preferred embodiment of the invention, the compounds have the formulas Vio VII.
VI VII wherein R and Y are as defined above In a first embodiment of the compounds of the formula VI, Y is N, R is a 1, 1-dimethylphenylethylamine or 1, 1 -dimethylbenzylamine unsubstituted or mono-substituted, wherein the substituent preferably is an o-, m-, or p-chloride or p-methoxy group. In a second embodiment of the compounds of the formula Vi, Y is N and Y is a phenylethylamine substituted with o-, m- or p-methoxy The compounds of the first and second modalities appear to exhibit selectivity for the mGluR receptor, In a third embodiment, of the compounds of the formula VI, Y is N and R is a phenylethylamine substituted with o, m, or p-fluoro Compounds of the third modality appear not to be deciphered between the mGluRI and mGluR5 receptor subtypes In another preferred embodiment of the invention, the compounds have the formula VIII or IX VIII IX wherein Xt 4 and R are as defined above In a first embodiment of the compounds of formula VIII, X 1 and X 2 are N, X 3 and X 4 are H, R is 1 -admantyl, and a substituent is present on the carbon ortho to both the linker and to X2 The substituent is preferably a halogen, such as chlorine, or an alkyl group such as methyl In a second embodiment of compound IX, R is 1-adamant The compounds of these first and second embodiments appear to exhibit selectivity for the mGluRi receptor. In yet another embodiment, the compounds may have the formulas X or XI, wherein Z is a pharmaceutically acceptable substituent. Those skilled in the art will recognize that pharmaceutically acceptable groups Z are those groups that do not harmfully reduce the binding activity of the compound receptor Suitable groups Z include, but are not limited to, halogen, lower alkyl, oxygen or amine, and their pharmaceutically acceptable derivatives. eptablets including ethers, esters, and amides. Preferably, Z contains 0-4 carbon atoms.
XI In each of the compounds described above, "alkyl" denotes both straight chain and branched alkyl. In other embodiments, R is adamantyl, the linker is -CO-CH2-S-, and Ar is m- or o-alkyloxyphenyl, or 3,4-methylenedioxy or 3,4-dioxane. In general, it seems that a selective mGluR! Receptor antagonist! it can be obtained with compounds of the formula R-CO-N-Art, where Ap is an aromatic or heteroaromatic group, such as a qu? nolinyl, quinoxalinyl, thiazolidinyl, phenyl, benzimidazolyl, or pyridyl group. Those skilled in the art will also recognize that the compounds of the invention encompass salts of the compounds described above. These salts include pharmaceutically acceptable acid salts, pharmaceutically acceptable metal salts, or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydrochloric, phosphoric, sulfuric, trifluoroacetic, malonic, succinic, citric, mandeleic, benzoic, cinnamic, metalsulfonic, and the like, and includes acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Sciences, 66: 2 (1977), incorporated herein by reference. Examples of the compounds according to the present invention are set forth in Table 1 below.
Preparation of the Group I mgluR antagonists Those skilled in the art will recognize that the mGluR antagonists of group I according to the invention can be prepared by methods that are well known in the art, using widely recognized techniques of organic chemistry. Appropriate reactions are described in standard organic chemistry textbooks. See, for example, March, Advanced Organic Chemistry, 2nd. ed., McGraw (1977). For example, the compounds generally can be prepared through the formation of the [linker] portion between two precursor compounds containing suitable portions i of AR and R When the linker contains an amide bond, the amide can be formed using techniques well known, such as reaction between an amine and an acid J chloride, or through the reaction in the presence of a coupling agent such as carbonyldiimidazole, or a corbodiimide such as, for example, 1,3-d-cyclohexylcarbod? im (DCC) The formation of ester and thioester bonds can be achieved in a similar way. When the [linker] portion contains an ether linkage, the ether function can also be prepared using standard techniques. For example, ethers can be formed using the Mitsunobu reaction, wherein one primary alcohol fraction is displaced by another hydroxy group through activation using PPh3 and diethylazodicarboxylate (DEAD). The thioether bonds can be prepared by displacing a leaving group such as halide with a thionate anion, generated by despotonation of a thiol group with the base. When the portion of [linker] contains a ketomethylene group, it can be formed through alkylation or a ketone enolate. Thus, for example, a methyl ketone can be deprotonated using a strong base such as lithium diisopropylamide (LDA), followed by reaction with an alkyl halide. Alternatively, a ketomethylene function can be prepared through the addition of an organometallic compound, such as a Gringnard reagent, to an aldehyde, followed by oxidation of the resulting hydroxyl group to a ketone. Suitable reagents for oxidizing acetone alcohols are well known in the art. [Linker] portions containing other heterogeneous atom groups may also be prepared using methods that are well known in the art. N, N'-disubstituted hydrazine compounds were prepared through reductive amination of hydrazones formed by the reaction of a substituted hydrazone with an aldehyde. The N, N'-disubstituted hazo compounds can be formed, for example, through the oxidation of the corresponding hydrazines. In many cases, the Ar and R portion portions are readily available or can be prepared using direct organic chemistry techniques. Many compounds are commercially available, for example, from Aldrich Chemical Company, Milwaukee, Wl. When the compounds are not commercially available, they can be readily prepared from available precursors using direct transformations that are well known in the art. For example, the carboxylic acids can be converted to the corresponding acid chlorides by reaction with, for example, thionyl chloro or oxalyl chloride. An example of such a reaction is provided below in Example 3. Compounds containing a hydroxy function can be converted to the corresponding amine through (i) conversion of the hydroxyl group to a leaving group, such as a sulfonic acid ester (such as a triflate, mesylate or tosylate) or a haiogenide, (ii) azide ion shift, and (iii) reduction of the resulting azide through, for example, hydrogenation over a platinum oxide catalyst. An illustration of said i transformation is provided later in Example 12.
Testing compounds for the activity of the mGluR antagonist of Group I 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 Aramorti et al., Neuron 8: 757 (1992): Tanabe et al., Neuron 8: 169 (1992). The methodology described in these publications is incorporated herein by reference. Conveniently, the compounds of the invention can be studied using an assay that measures the inhibition of intracellular calcium mobilization in cells expressing recombinant I receptors that can bind the compounds. Suitable receptor constructs are well known in the art and are also described in, for example, Wo 97/05252, the contents of which are hereby incorporated by reference in their entirety. In this manner, HEK-293 cells (human hebrionic kidney cells, available from American Type Culture I Collection, Rockville, MD, MD Accession Number CRL 1573) are stably transfected with a DNA construct expressing a recombinant receptor cells stably transfected, cultured in DMEM with a high glucose content (Gibco 092) containing 0.8 mm glutamine, 10% FBS and 200 μm hydromycin B A protocol to measure intracellular calcium mobilization in response to changes in extracellular calcium Using the calcium-sensitive dye Fura, it has been previously described. In summary, the HEK-293 cells were stably transfected with a DNA construct encoding a recombinant receptor, and loaded with Fura dye. The cells were then washed, returned to suspended and maintained at 37 ° C. The cells were diluted in cuvettes to record the fluorescent signals. s fluorescence at 37 ° C using standard methods, and the concentrations of Ca2 + mtracellular were calculated using a dissociation constant (Kd) of 224 nM and applying the equation [Ca +], = (Fm? n / Fmax) x Kd in where F is fluorescence at any particular time of interest, Fm? n was determined by chelating all available calcium, therefore, no fura 2 was bound to calcium, and Fmax was determined by completely saturating all available fura 2 with calcium. Detailed description for testing the compounds of the invention is given below in Example 15 Preparation of pharmaceutical compositions containing mGluR antagonists, and their use to treat neurological disorders The compounds of the invention are useful for treating disorders or neurological diseases. Although these compounds will typically be used in therapy for humans, they can also be used in veterinary medicine to treat Similar or identical diseases In therapeutic and / or diagnostic applications, the compounds of the invention may be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations can usually be found Remington's Pharmaceutical Sciences: Drug Receptors and Therory Receptor, 18th. Ed. Mack Publishing Co. (1990). The compounds according to the invention are effective on a wide dose scale. For example, in the treatment of humans to adults, doses of about 0.01 to about 1000 mg, preferably about 0.5 to 100 mg per day, may be used. A most preferred dose is from about 2 mg to about 70 mg per day. The exact dose will depend on the route of administration, the manner in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the preference and experience of the attending physician. Pharmaceutically acceptable salts are generally well known to those skilled in the art., and may include, by way of example and not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisilate, estoate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsaminate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hypoxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (mbonate), pantotheta, phosphate / diphosphate, polygalacturonate , salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts can be found in, for example, Remington's Pharmaceutical Sciences: (18. Ed.), Mack Publishing Co., Easton, PA (1990). Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate. Depending on the specific conditions being treated, agents can be formulated in liquid or solid dosage forms and administered systemically or locally. The agents can be supplied, for example, in a release form with I time or sustained as is known to those skilled in the art. Techniques for formulation and administration can be found in Remington's Pharmaceutical Sciences: (18. Ed.), Mack Publishing Co., Easton, PA (1990) Suitable routes may include oral, buccal, sublingual, rectal, transdermal, vaginal transmucosal administration , nasal or intestinal; parenteral delivery, including intramuscular, subcutaneous and intramedullary injections, as well as intraecal, direct intraventricular, intravenous, mtrapeptoneal, intranasal or infraocular injections, just to name a few. For injection, the injection agents can be formulated in aqueous solutions, preferably in physiologically compatible pH regulators such as Hank's solution, Ringer's solution or physiological saline pH regulator. For such mucosal administration, appropriate penetration agents to the barrier that will be permeated are used in the formulation. Such penetrating agents are well known in the art. The use of pharmaceutically acceptable vehicles for formulating the compounds described herein for the practice of the invention in doses suitable for systemic administration is within the scope of the invention. With an appropriate choice of vehicle and proper manufacturing practice, the compositions of the present invention, in particular those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be easily formulated using pharmaceutically acceptable carriers well known in the art in doses suitable for administration. Said vehicles allow 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 their intended purpose. The determination of the effective amounts is within the ability of those skilled in the art, especially in light of the detailed description provided herein. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate the processing of the active compounds into preparations which can be used pharmaceutically. Preparations formulated for oral administration may be in the form of tablets, dragees, capsules or solutions. The 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, then 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, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum , methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents can be added, such as interlaced polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with adequate covers.
For this purpose, concentrated sugar solutions may be used, which optionally may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions and suitable organic solvents or mixtures of solvents. The dyes or pigments may be added to the tablet or dragee coatings for identification or to characterize different combinations of active compound doses. iThe pharmaceutical preparations that can be used orally include skip adjustment capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Jumping adjustment capsules may contain the active ingredients in admixture with a 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 can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers can be added. The present invention, generally so described, will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to limit the present invention.
EXAMPLES General Experimental Methods Capillary gas and mass spectrum chromatographic data were obtained using Hewlett-I Packard (HP) 5890 Series II chromatography coupled to a mass selective detector Series < i No.5971 HP [Ultra-2 Ultra Performance Capillary Column (silicone PnMe interleaver 5%): column length 25 m; internal diameter of the column 0.20 mm; helium flow rate, 60 ml / minute; 250 ° C injector temperature; temperature program, 20 C / min from 125 to 325 ° C for 10 minutes, then remained constant at 325 ° C for 6 minutes]. Thin layer chromatography was performed using 250 μm silica gel TLC HF plates from Analtech Uniplate. UV light was sometimes used together with ninhydrin and spray reagents from Dragendorff (Sigma Chemical Co.) to detect compounds from the TLC plates. Reagents used in reactions were purchased from Aldrich Chemical Co. (Milwaukee, Wl), Sigma Chemical Co. (Saint Louis, MO), Fluka Chemical Corp. (Milwaukee, Wl), Fisher Scientific (Pittsburgh, PA), TCl America (Portland , OR), or Lancaster Sunthesis (Windham, NH) Example 1 Preparation of N- [6- (2-methylquinolyl)] - 1 -adamantancarboximide (40) 2-methyl-6-aminoquinoline A mixture of 2-methyl-6-nitroquinoline (1.00 g, 5.31 mmol) and Pearlman's catalyst [palladium dihydroxide on activated carbon (palladium approximately 20%); 0.10 g] in 40 ml of ethyl acetate was stirred under nitrogen gas (1 atm) at 60 ° C for 1.5 hours. The reaction mixture was filtered and the filtrate was evaporated by rotation. This gave 0.81 g (95%) of 2-methyl-6-aminoquinoline as a yellow solid.
N- [6- (2-methylquinolyl)] -1-adamantanecarboxamide (40). 1-Adamantanecarbonyl chloride (1.02 g, 5.13 mmol) in 2 ml of pyridine was added to a solution of 2-methyl-6-aminoquinoline. (0.81 g, 5.1 mmol) in 8 ml of pyridine The reaction was stirred for 17 hours. To the stirring reaction mixture was added 100 ml of water, which caused the product to precipitate. This precipitate was filtered and then washed with water (2 x 26 ml) and diethyl ether (3 x 25 ml) This provided 1.07 g (65%) of (40) as a cream powder: rt = 13.49 min; m / z (int.risk) 320 (M +, 30), 235 (8), 158 (4), 157 (6), 136 (11), 135 (100), 130 (11), 107 (7 ), 93 (15), 91 (8), 79 (18), 77 (11), 67 (6).
In a similar manner, the following N-quinolyl-1-adamantanecarboxamides were prepared.
N- (6-Quinol il) -1 -adamantancarboxamide (18) Preaparated from 1-adamantanecarbonyl chloride (1.37 g, 6.90 mmol), 6-aminoquinoline (0.5 g, 4.1 mmol), 20 ml pyridine and 200 ml of water, yielding 1.25 g (100%) of (18): rt = 13.24 min; m / z (int. re.) 306 (M +, 23), 221 (6), 144 (3), 136 (12 ), 135 (100), 116 (10), 107 (7), 93 (15), 91 (8), 79 (18), 77 (9), 67 (7), 41 (6) N- (2-quinolyl) -1 -adamantancarboxamide hydrochloride (81) Prepared from 1 -adamantanecarbonyl chloride (0.75 g, 3. 8 mmol), 2-aminoquinolin (0.60 g, 4.2 mmol), 10 ml of pyridine and 100 ml of water. Formation of the hydrochloric acid salt with ethereal diethyl hydrogen chloride yielded 0.19 g (15% of (81) -rt = 1224 min, m / z (int. Re) 306 (M +, 80), 305 (23) , 277 (8), 263 (8), 221 (10), 172 (9), 171 (72), 145 (16), 144 (61), 143 (13), 136 (11), 135 (100), 128 (332), 117 (17), 116 (24), 107 (18), 105 (8), 101 (10), 93 (40), 91 (29), 89 (13), 81 (14), 79 (55), 77 (35), 67 (18), 65 (10), 55 (12), 53 (10), 41 (20).
N- (3-QuinolI) -1-adamantanecarboxanima (86) Prepared from 1-adaminatecarbonyl chloride (0 75 g, 3.8 mmole), 3-aminoquinol none (0.60 g, 4 2 mmole), 10 ml of pyridine and 100 ml of water, yielding 0.33 g (29%) of (86): rt = 13. 01 min; m / z (int. Re) 306 (M +, 22), 136 (11), 135 (100), 116 (11), 107 (8), 93 (15), 91 (8) , 89 (7), 79 (17), 77 (8), 67 (6), 65 (3).
N- (trans-4-methylcyclohexyl) -2-quinoxalinecarboxamide (299) Using the method of Booth (J. Chem. Soc, 1958, 2688; J. Chem. Soc. 1971, 1047: Tetrahedron, 1967, 23, 2421), hydroxylamine (3.8 g, 55 mmol), 50 ml of ethanol, pyridine (4.44 ml, 55 mmol) were stirred at room temperature. methyl-cyclohexanone (6.1 ml, 50 ml), for 16 hours and then heated to reflux for 15 minutes. The ethanol was then removed in vacuo and the residual oil was dissolved in 100 ml of ethyl acetate. The organic layer was washed with water (2X), brine, dried over anhydrous MgSO 4, filtered and concentrated to a clear oil (the oxime product) which crystallized after settling. Without further purification, 1.9 g (15 mmol) of the intermediate oxime was heated in 40 ml of absolute ethanol, refluxed and treated with sodium metal (in small portions) (4 g), the reaction was heated to reflux until the sodium was consumed. The reaction was cooled and treated with 10 ml of water. The reaction was transferred to 1 flask containing ice and concentrated HCl (6 ml). The ethanol was removed in vacuo and the remaining aqueous phase was washed with diethyl ether (3X, to remove the non-reduced oxime). The remaining aqueous phase was concentrated to give 1.8 g of a white crystalline solid (the product of trans-4-methylcyclohexylamine hydrochloride).
Without further purification, 750 mg (5 mmol) of trans-4-methylcyclohexylamine hydrochloride in 10 dichloromethane were 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 room temperature for 16 hours and diluted with 25 ml of chloroform. The organics were washed with 10% HCl (3X), 1 N NaOH (3X), brine, dried over anhydrous MgSO 4, filtered and concentrated to a solid. Chromatography (MPLC) of the crude reaction material through silica (internal diameter 7 x 4 cm, BIOTAGE, KP-SIL, 60 angstroms) using ethyl acetate-hexane (1: 4) gave 470 mg of the desired product, N- (trans-4-methylcyclohexyl) -2-quinoxalin. Thin layer chromatography (TLC, silica) using ethyl acetate-hexane (1: 4) showed a single active UV component of Rf 0.19. GC / EI-MS gave m / z (int. Re.) 269 (M +, 39), EXAMPLE 2 Preparation of 6-quinolyl-1-adamantanecarboxylate (41) 1-Adamantanecarbonyl chloride 1.37 g, 6.90 mmol) in 5 ml of pyridine was added to a solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol) in 15 ml of pyridine. The reaction was stirred for 16 hours. To the stirring reaction mixture was added 200 ml of water, which caused the product to precipitate. This precipitate was filtered, washed with water (3 x 50 ml), and dried under high vacuum. This provided 1.56 g (73.7%) of (41) as a light brown powder. rt = 11.41 min .: m / z (Int. Re.) 307 (M + 2), 136 (11), 135 (100), 116 (11), 107 (7), 93 (14), 92 (2), 91 (8), 89 (7), 79 (16), 77 (8).
EXAMPLE 3 Preparation of 1-adamantyl-6-quinolinecarboxylate (61) 6-quinolinecarbonyl chloride hydrochloride 6-quinolinecarboxylate in thionyl chloride was brought to reflux for 30 minutes. Then, excess thionyl chloride was removed through rotary evaporation (90 ° C) to provide 6-quinolinecarbonyl chloride hydrochloride. 1 - . 1 -adomethyl-6-quinoline carboxylate (61) 6-quinolinecarbonyl hydrochloride (7.76 g, 3.3 mmol) in 2 ml of pyridine was added to a solution of 1-adamantanol (0.60 g, 3.9 mmol) in 8 ml of pyridine. The reaction was stirred at 70 ° C for 16 hours. To the resulting reaction mixture was added 100 ml of water which caused the product to precipitate. This precipitate was filtered and then washed with water (3 x 25 ml). The filter cake was dissolved in 20 ml of ethanol and then water was added to the dark spot (16 ml). The crystallization solution was allowed to stand for 15 hours. Filtration and drying under high vacuum for 7 hours gave 0.32 g (26%) of (61) as light brown needle-like crystals: rt = 11.48 min., M / z (int. Re.) 307 (M) +, 99), 306 (92), 262 (15), 174 (12), 173 (13), 157 (10), 156 (88), 135 (81), 134 (33), 129 (13), 128 (100), 127 (10), 119 (1 I), 107 (18), 102 (16), 101 (37), 93 (51), 92 (76), 91 (35), 81 (14) , 79 (55), 78 (15), 77 (49), 75 (17), 67 (24), 55 (18), 53 (13), 51 (13), 41 (31).
In a similar manner, the following alkyl 6-quinolin- and 2-quinolinecarboxylates were prepared: 2,2,3,3,4,4,5,5-octafluoro-1-pentyl-6-quinolinecarboxylate hydrochloride (68) Prepared from 6-quinolinecarbonyl chloride hydrochloride (0.75 g, 3.3 mmol), 2,2,3,3,4,4,5,5-octafluoro-1-pentanol (0.60 ml, 4.3 mmol), 10 ml pyridine and 100 ml of water.
Formation of the hydrochloride salt with ethereal hydrogen chloride yielded 0.88 g (69% of (68): rt = 7.11 mn; m / z (int.r.) 387 (100), 129 (6), 128 (48), 102 (6), 101 (16), 177 (6), 76 (2), 75 (8), 50 (14). 1-adamantyl-6-quinolinecarboxylate (73). Prepared from 6-quinolinecarbonyl chloride hydrochloride (0.80 g, 3.5 mmol), 1-adamantanemethanol (0.60 g, 3.6 mmol), 10 ml of pyridine and 100 ml of water yielding 0.75 g (65%) of (73) : rt = l 1.90 min; (Int.R.) 321 (M +, 35), 320 (12), 263 (15), 156 (30), 148 (23), 136 (11), 135 (100), 135 (100), 129 (9), 128 (52), 107 (15), 106 (7), 105 (9), 102 (7), 101 (16), 93 (34), 92 (20), 91 (20), 81 (11), 80 (7), 79 (40), 71 8 (6), 77 (24), 75 (7), 67 (14), 55 (9), 53 (6), 51 (6), 41 (14). 1-adamantyl-2-quinoxalinecarboxylate (92) Prepared from 2-quinoxaloyl chloride (0.94 g, 4.4 mmol), 1 -adamantanol (0.60 g, 3.9 mmol), 10 ml of pyridine and 100 ml of water yielding 0.20 g (16%) of (92); rt = 11.21 min; m / z (int. re.) 308 (M +, 26), 264 (6), 136 (11), 136 (11), 10 135 (100), 134 (15), 130 (11), 129 (25), 107 (12), 102 (19), 93 (24), • 92 (9), 91 (1 I), 8 1. (7), 79 (26), 77 (12), 76 (6), 75 (7), 67 (10), 55 (7), 51 (6), 41 (11).
EXAMPLE 4 Preparation of N- (1 -Adamantyl) -3-quinolinecarboxamide (72) 1,1 '- Carbonyldiimisazole / 161 mg, 1.00 mmol) in 1 ml of N, N-dimethylformamide was added in one portion in a portion of a 4fc 3-quinolinecarboxylic acid suspension (173 mg, 1.00 mmol) in 1 ml of N, N-dimethylformamide. The resulting reaction solution is 20 stirred for 2.5 hours. 1 -adamantamine (1.51 mg, 1.00 mmol) in 0.5 ml of N, N-dimethylformamide was added in one portion. The reaction mixture was stirred at 60 ° C for 2 hours. The reaction was then diluted with chloroform and washed with water (3 x 30 ml) The organic layer was dried (anhydrous magnesium sulfate), filtered 25 through silica gel and rotating evaporated. This resulted in 73 mg (24%) of (72) as the crystalline solid: rt = 11.2 min; m / z (int. Re) 306 (M +, 78), 305 (42), 250 (19), 249 (100), 213 (7), 173 (5), 157 (10), 156 (89), 129 (12), 128 (92), 102 (5), 101 (36), 94 (6), 93 (10), 92 (12), 91 (14), 79 (10), 77 (14), 77 (14), 5 (10), 67 (7), 41 (11).
In a similar manner, the following N-alkyl-2-qu? Nolin- and 2-quinolinecarboxamides were prepared.
N- (1-adamantyl) -2-quinolinecarboxamide (74) Prepared from 1,1'-carbonyldiimidazole (160 mg, 0.987 mmol), quinaldic acid (173 mg, 1.00 mmol) and 2.5 ml of N, N-dimethylformamide producing 77 mg (25%) of (74): rt = 10.53 min; m / z (int. Re) 306 (M +, 91) t 305 (26), 277 (9), 263 (9), 221 (11), 172 (9), 171 (73), 145 (15), 144 (60), 143 (15), 136 (11), 135 (100), 128 (36), 117 (19), 1 , 16 (27), 107 (20), 105 (8), 101 (10), 93 (42), 91 (30), 89 (14), 81 (13), 79 (55), 77 (37) , 67 (18), 65 (11), 55 (12), 53 (10), 41 (18).
N- (2-adamantyl) -2-quinoxalinecarboxamide (144) Prepared from 1,1 '-carbonyldimidazole (161 mg, 1.00 mmol), 2-quinoxalincarboxylic acid (174 mg, 1.00 mmol), 2-adamantanamine (136 mg) 0.90 mmoles) and 3.5 ml of dichloromethane yielding 98 mg (35%) of (144): rt = 11.79 min; m / z (int. Re.) 307 (M +, 33), 151 (12), 150 (100), 130 (24), 129 (35), 103 (11), 102 (20), 91 (13), 79 (11), 77 (8), 76 (6), 75 (5), 70 (6), 67 (5), 41 (6).
N - [(1R, 2R, 3R, 5S) -3-pinanmethyl] -2-quinoxalinecarboxamide (151) Prepared from 1,1-carbonyldiimidazole (161 mg, 1.00 mmol), 2-quinoxalinecarboxylic acid (174 mg, 1.00 mmoles), (-) - 3-pinanmet? lamina (150 mg, 0.90 mmol), 3.5 ml dichloromethane * * • producing 50 mg (17%) of (151): rt = 11.46 min; m / z (int. Re) 323 (M +, 7), 187 (76), 186 (10), 174 (25 ), 166 (15), 158 (44), 157 (20), 144 (6), 131 (10), 130 (78), 129 (100), 107 (8), 103 (21), 102 (44 ), 95 (15), 93 (10), 91 (9), 81 (11), 79 (13), 77 (12), 76 (14), 75 (11), 69 (8), 67 (17 ), 55 (20), 53 (10), 51 (7), 43 (10), 41 (30).
EXAMPLE 5 Preparation of N- (1 -Adamantyl) -2-q ui noxal incarboxamide (91) 2-Quinoxaloyl chloride (0.84 g, 4.4 mmol) was added to a solution of 1-adamantamine (0.6 O g, 4.0 mmol) in 10 ml of pyridine. The reaction was then stirred for 30 minutes. To the stirring reaction mixture was added 100 ml of water which caused the product to precipitate. This precipitate was filtered, washed with water (3 x 25 ml), and dried under high vacuum for 16 hours. This provided 1.00 g (82%) of (91) rt = 11.73 min; m / z (re int) 307 (M +, 39), 279 (5), 157 (5), 151 (11), 150 ( 100), 130 (21), 129 (58), 103 (12), 102 (24), 94 (7), 93 (8), 91 (10), 79 (9), 77 (9), 76 ( 7), 75 (6), 67 (5), 41 (8), 41 (8).
In a similar manner, the following N-substituted 6-quinolin- and 2-quinoxaline carboxamides were prepared.
N- (1-adamantyl) -6-quinolinecarboxamide (42) Prepared from 6-quinolinecarbonyl chloride hydrochloride (1.51 g, 10 mmol), 1-adamantamine (1.73 g, 10 mmol), 5 ml pyridine and 200 mg. ml of water yielding 330 mg (11%) of (42): rt = 11.04 min; m / z (int. re) 306 (M +, 34), 305 (15), 250 (11), 249 ( 56), 156 (11), 155 (100), 130 (5), 128 (10), 127 (69), 126 (5), 102 (8), 101 (16), 93 (8), 92 ( 9), 91 (12), 79 (10), 77 (16), 67 (6), 41 (11), 41 (11).
N- (Exo-2-Norbornyanil) -2-quinoxalinecarboxamide (148) Prepared from 2-quinoxaxolyl chloride (193 mg, 1.0 mmol), exo-2-aminorborne (i3 mg, 90 mmoles), 5 ml of pyridine and 50 ml of water, yielding 35 mg (15%) of (148): rt = 10.22 min; m / z (int. Re) 267 (M +, 36), 198 (10), 158 (7), 157 (9), 131 (7), 130 (47), 129 (78), 111 (8), 111 (8), 110 (100), 103 (16), 102 (39), 77 (5), 76 (12), 75 (11), 67 (11), 51 (7), 41 (10).
N - [(1R, 2S, 4S) -bornyl] -2 -quinoxalinecarboxamide (150) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (R) - (+) - boronamine (138 mg, 0.90 mmoles), 5 ml of pyridine and 50 ml of water yielding 140 mg (50%) of (150): rt = 10.79 min; m / z (int.r.) 309 (M + .27), 199 ( 8), 187 (10), 174 (10), 158 (11), 157 (14), 153 (10), 152 (82), 144 (9), 135 (11), 131 (7), 130 ( 51), 129 (100), 109 (20), 103 (18), 102 (43), 95 (38), 93 (12), 91 (7), 79 (9), 77 (11), 76 ( 13), 715 (11), 67 (17), 55 (14), 53 (8), 51 (8), 43 (8), 41 (25).
N (-3-Noradamantil) -2-quinoxalinecarboxamide (152) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 3-noradamantamine (157 mg, 0.90 mmol), 5 ml of pyridine, and 150 ml of water yielding 167 mg (63%) of (152): rt = 11.00 min; m / z (int.risk) 293 (M +, 50), 265 (12), 250 (18), 232 (6), 222 (20), 157 (12), 144 (6), 137 (7), 136 (64), 131 (6), 130 (35), 130 (35), 129 (100), 103 (19), 102 (35), 94 (15), 91 (6), 80 (6), 79 (11), 77 (11), 76 (12), 75 (9), 67 (6), 53 (6), 51 (6), 41 (13).
N - [(1 R, 2R, 3R, 5S) -isopinocamphenyl] -2-quinoxalinecarboxamide (165) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (1 R, 2R, 3R, 5S) - (-) - isopinocamphenylamine (138 mg, 0.90 mmol), 5 ml of pyridine and 50 ml of water yielding 230 mg (83%) of (165): rt = 10.88 min; m / z (int. re) 309 (M +, 4), 226 (19), 200 (17), 199 (5), 198 (7), 186 (9), 175 (7), 174 (116), 158 (6), 157 ( 14), 152 (6), 130 (42), 129 (100), 103 (16), 102 (42), 102 (42), 95 (13), 93 (10), 79 (6), 77 ( 7), 76 (11), 75 (9), 67 (7), 55 (12), 53 (6), 51 (5), 43 (5), 41 (18).
N - [(1S, 2S, 3S, 5R) -isopinocam phen il] -2 -quinoxalinecarboxamide (166) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (1 S, 2S, 3S, 5R ) - (+) -isopinocamphenylamine (138 mg, 0.90 mmol), 5 ml of pyridine in 50 ml of water yielding 208 mg (75%) of (166): rt = 10.88 min; m / z (int. ) 309 (M +, 4), 226 (16), 200 (14), 198 (7), 186 (8), 175 (6), 174 (14), 158 (5), 156 (13), 130 (42), 130 (42), 129 (100), 103 (18), 102 (46), 95 (11), 93 (10), 91 (5), 79 (5), 77 (8), 76 (12), 75 (11), 67 (8), 55 (13), 53 (6), 51 (6), 43 (6), 41 (20).
N- (5-chlorotricyclo [2.2.2.0 (2,6)] hept-3-yl) -2-quinoxaline-carboxamide (167) Prepared from 2-quinocaloyl chloride (193 mg, 1.0 mmol), 5- Chlorotricyclo [2.2.1.0 (2.6)] hept-3-ylamine (129 mg, 0.90 mmol), 5 ml of pyridine and 50 ml of water yielding 100 mg (37%) of (167): rt = 11.29 min.; m / z (int. re) 299 (M +, 2), 264 (76), 246 (12), 199 (7), 198 (47), 186 (16), 185 (6), 144 (6), 142 (16), 130 (30), 129 (100), 106 (15), 103 (20), 102 (55), 102 (55), 91 (24), 80 (7), 79 (18), 78 (6), 77 (18), 76 (19), 75 (19), 65 (10), 53 (6), 52 (6), 51 (14), 50 (7).
N- (Tricyclo [4.3.1.1 (3, 8)] undec-3-yl) -2-quinoxal incarboxamide (168) Prepared from 2-quinoxaloyl chloride (135 mg, 0.70 mmol), tricycle [4.3.1.1 (3, 8)] undec-3-Mamin, hydrochloride (100 mg, 0.60 mmol), 5 ml of pyridine, and 50 ml of water yielding 110 mg (57%) of (168): rt = 12.52 min .; m / z (int.risk) 321 (M +, 48), 165 (13), 164 (100), 157 (9), 131 (8), 130 (32), 130 (32), 129 (79 ), 107 (5), 106 (5), 105 (11), 103 (17), 102 (31), 94 (9), 93 (8), 92 (9), 91 (15), 81 (6 ), 80 (7), 79 (16), 77 (10), 76 (9), 75 (7), 67 (8), 55 (5), 53 (5), 41 (10).
N [(1 S, 2 R, 5S) -cis-m i rta ni I] -2-qu i noxal incarboxamide (169) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (-) -cis-mirtanylamine (138 mg, 0.90 mmol), 5 ml of pyridine, and 50 ml of water yielding 224 mg (81%) of (169): rt = 11.32 min; m / z (int. ) 309 (M +, 18), 186 (30), 1714 (20), 158 (12), 157 (27), 152 (16), 131 (6), 130 (47), 130 (47), 129 (100), 121 (5), 103 (17), 102 (45), 93 (121), 91 (6), 81 (11), 79 (12), 77 (10), 76 (13), 75 (11), 69 (13), 67 (15), 55 (8), 54 (6), 53 (8), 51 (7), 43 (6), 41 (26).
N- £ (1R, 2R, 4S) -isobornyl-2-quinoxalinecarboxamine (170) Prepared from 2-quinoxaloyl chloride (193 mg, 10 mmol), (R) - (-) - isobornylamine (138 mg, 0.90 mmol, 5 ml of pyridine, and 50 ml of water yielding 130 mg (81%) of (170): i rt = 10.76 min; m / z (int. Re) 309 (M +, 24), 199 (7), 197 (6), 187. (8), 174 (8), 158 (9), 157 (12), 153 (7), 152 (58), 144 (9), 135 (8), 130 (46), 129 (100), 109 (14), 103 (21), 102 (48), 95 (31), 93 (10), 91 (7), 79 (8), 77 (10), 76 (13), 75 (12), 67 (15), 55 (12), 53 (7), 51 (6), 43 (6), 41 (18).
N- [endo - (+ J-2-norbornyanil] -2-quinoxalinecarboxamide (171) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), endo- (+ _) - 2-aminorbornane (133 mg 0.90 mmoles), 5 ml of pyridine, and 50 ml of water yielding 175 mg (73%) of (171): rt = 10.15 min; m / z (int. Re) 267 (M +, 35), 198 (11), 185 (6), 158 (7), 157 (11), 144 (5), 131 (7), 130 (55), 129 (100), 111 (6), 110 (81), 103 (24), 102 (56), 77 (7), 76 (19), 75 (17), 75 (17), 67 (13), 55 (5), 53 (7), 51 (9), 50 (5), 41 (14).
N - [(R) -2-phenyl-1-propyl] -2-quinoxalinecarboxamide (172) i Prepared from 2-quanoxaloyl (0.47 g, 2.4 mmol), (R) -2-phenyl-1-propylamine ( 10.30 g, 2.2 mmoles), 5 ml of pyridine, and 50 m of water yielding 0.49 g (76%) of (172): rt = 10.63 min; m / z (m.t. re.) 291 (M +, 14 ), 186 (9), 158 (5), 157 (32), 130 (25), 129 (100), 118 (22), 105 (24), 104 (5), 103 (31), 102 (48) ), 91 (9), 79 (11), 78 (6), 77 (18), 76 (13), -75 (13), 75 (13), 51 (9) N - [(S) -2 phenyl-1-propyl-2-quinoxalincarboxamide (173) Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (S) -2-phenyl-1-propylamine (0.30 g, 2.2 mmol), ml of pyridine and 50 ml of water, 5 ml of pyridine and 50 ml of water yielding 0.48 g (74% of (173): rt = 10.72 min; m / z (int. re) 291 (M +, 13 ), 186 (68), 158 (5), 157 (37), 130 (21), 129 (100), 118 (29), 105 (21), 103 (16), 102 (37), 91 (7 ), 79 (10), 77 (15), 76 (11), 75 (10), 51 (9), 51 (9).
N- (2-indanyl) -2-quinoxalinecarboxamide (221) Prepared from 2-quinoxaloyl chloride (0.32 g, 1.7 mmol), 2-aminoindan (0.2 μg, 1.5 mmol), 3 ml pyridine, and 30 ml of water yielding 0.23 g (53%) of (221): rt = 11.33 min; m / z (int. Re) 289 (M +, 10), 132 (6), 130 (28), 129 (41), 1 17 (15), 116 (100), 115 (37), 104 (7), 103 (26), 102 (37), 91 (7), 78 (7), 77 (13) , 76 (16), 75 (14), 51 (9), 51 (9), 50 (5) N-Cyclooctyl-2-quinoxalinecarboxamide (228) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmoies), cyclooctylamine (123 μL, 114 mg, 0 90 mmol), 5 ml pyridine, and 100 ml water producing 100 mg (39%) of (228): rt = 10.86 min; m / z (int re.) 283 (M +, 27), 212 (6), 199 (9), 198 (20), 198 (20), 185 (16), 184 (6), 174 (8), 157 (15), 144 (7), 131 (6), 130 (48), 129 (100), 126 (42), 103 (20), 102 (50), 76 (13), 75 (12), 67. { (6), 56 (7), 55 (9), 51 (6), 43 (6), 41 (16) N-Cycloheptyl-2-quinoxalinecarboxamide (229) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), cycloheptylamine (115 μl, 192 mg, 0.90 mmol), 5 ml of pyridine and 100 ml of water, yielding 30 mg (12%) of (229): rt = 10.30 min; m / z (re. int.) 269 (M +, 39), 212 (6), 198 (20), 185 (13), 174 (14), 174 (14), 157 (20), 131 (7), 130 (49) , 129 (100), 112 (44), 103 (23), 102 (51), 76 (15), 75 (13), 56 (6), 55 (8), 51 (7), 42 (5), 41 (15).
N- [2-Spiro (4.5) decyl] -2-quinoxalinecarboxamide (236) Prepared from 2.quinoxaloyl chloride (193 mg, 1.0 mmol), 2-aminospiro (4.5) decane (150 mg, 0.79 mmol) ), 5 ml of pyridine, and 100 ml of water yielding 206 mg (74%) of (236: rt = 10.94 min .: m / z (int.r.) 282 (M +, 25), 199 (7) , 186 (6), 157 (10), 130 (32), 129 (96), 125 (40), 110 (10), 109 (100), 108 (15), 103 (14), 102 (55) , 98 (6), 97 (27), 96 (25), 84 (9), 82 (18), 76 (15), 75 (16), 70 (155), 69 (7), 68 (13) , 56 (7), 55 (8), 53 (6), 51 (9), 43 (8), 42 (36), 41 (14).
EXAMPLE 6 Preparation of 1-diemantanmethyl-6-quinolone ether (94) A mixture of 1-adamantanemethanol (5.00 g, 30.0 mmol) and 6-hydroxyquinoline (13.1 g, 90.2 mmol) in 75 ml of tetrahydrofuran was stirred for 15 minutes. minutes Then, tphenylphosphine 10 2 g, 30.0 mmol) was added, followed by diethyl azodicarboxylate (6.14 ml, 30.0 mmol). The reaction mixture was refluxed for 18 hours. The solvent was then removed by gaseous evaporation. The resulting gel was filtered through paper with diethyl ether (3 x 25 ml). The filter was rotary evaporated, and the resulting gel was filtered through paper with hexane (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 resulted in 3.8 g (43%) of crude product as a red oil. This oil is chromatographed (2: 1 hexane / ethyl acetate) to provide 1.6 g (18%) of 94-rt = 11.29 min; m / z (int.r.) 293 (M +, 15), 149 ( 100), 145 (6), 128 (13), 121 (6), 116 (12), 116 (12), 107 (17), 93 (29), 91 (18), 89 (10), 81 ( 16), 79 (25), 77 (17), 67 (14), 65 (5), 55 (S), 53 (6), 41 (14).
EXAMPLE 7 Preparation of 3-quinolinecarboxylate 1-adamantyl (101) A mixture of 1 -adamantanol (152 mg, 1.0 mmol), 3-quinolylcarboxylic acid (173 mg, 1.0 mmol), and dimethylaminopyridine (122 mg, 1.0 mmol) in 2 ml of dichloromethane and 2 ml of N, N-dimethylformamide was cooled to 0 ° C. 1,3-dicyclohexylcarbodiimide (227 mg, 1.1 mmol) in 1 ml of dichloromethane was added in one portion. The reaction mixture was stirred at 25 ° C for 20 hours. The reaction mixture was then diluted with 40 ml of dichloromethane and washed with 1 M sodium hydroxide (3 x 30 ml) The organic layer was dried (anhydrous magnesium sulfate), filtered through celite and rotary evaporated . The resulting material was purified through spin thin layer chromatography (3% methanol in chloroform). The purest fraction was rotary evaporated and the resulting material was recrystallized from ethanol. This yielded 42 mg (14%) of (101): rt = 7.78 m? N; m / z (int. Re.) 307 (M +, 96), 306 (100), 173 (11), 155 ( 38), 135 (6), 127 (55), 119 (6), 106 (9), 100 (23), 93 (25), 92 (33), 91 (14), 78 (23), 77 (6), 76 (13), 74 (8), 67 (.9), 54 (71), 41 (12).
EXAMPLE 8 Preparation of N- (a, a-dimethylphenyl) -2-quinoxalinecarboxamide i (108) 2-Quinoxaloyl chloride (207 mg, 1.07 mmol) was added in 1 ml of dichloromethane to a solution of phentermine (160 mg, 1.07 mmol) in 3 ml of dichloromethane cooled to 0 ° C. The mixture was allowed to warm to 25 ° C. After 5 minutes, the reaction mixture was diluted with 40 ml of ethyl acetate and washed with 1 M sodium hydroxide (2 x 40 ml). The organic layer was dried (anhydrous magnesium sulfate) filtered through silica, and rotary evaporated. This yielded 51 mg (16%) of (108): rt = 9.31 min; m / z (int. Re) 305 (M + ..0), 214 (96), 186 (30), 157 (16 ), 130 (22), 129 (100), 103 (10), 102 (31), 92 (4), 91 (47), 76 (5), 75 (5), 65 (10). i N- (2-chlorobenzyl) -2,4,6-triphenylpyridinium tetrafluoroborate 2-Chlorobenzylamine (2.0 g, 14 mmol) was added dropwise to a suspension of tetrafluoroborate of 2,4,6-triphenylpyridinium (5.1 g, 13 mmol) in 40 ml of dichloromethane. The reaction mixture was stirred for 16 hours. 4 ml of ethanol and an excess of diethyl ether were added to precipitate the product. The precipitate was filtered and dried. This provided 6.14 g (92%) of N- (2-cyclobenzyl) -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 15 ml of cooled methanol. 0 ° C. The reaction mixture was then stirred and allowed to warm to 25 ° C for 10 minutes. The solvent was rotary evaporated to provide a white solid. A mixture of this solid and n (2-c! Orobenzyl) -2 tetrafluoroborate4,6-trifluoride (6.14 g, 11.8 mmol) in 45 ml of dimethyl sulfoxide was stirred under nitrogen gas for 16 hours. Then water was added to quench the reaction. This mixture was then extracted with diethyl ether (3 x 100 ml). The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), and filtered. The filtrate was stirred in a strongly acidic Amberlist 15 ion exchange resin (1 g / mmoles) for 4 hours. The reaction mixture was filtered and rotary evaporated. This provided 2.35 g (93%) 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- (2-chlorophenyl) -2-methyl-2-nitropropane (2.35 g, 11 mmol) in 35 g. ml of ethanol was stirred under hydrogen gas (4,218 kg / cm2m) for 3.5 hours. The reaction mixture was then filtered, and the filtrate was rotary evaporated. This afforded 2.3 g (110%) of a, a-dimetii-2-cyprophenethylamine.
N- (a, a-Dimethyl-2-chlorophenethyl) -2-quinoxaNncarboxamide (197) In a manner similar to (108), (197) was prepared to 2-quinoxaloyl chloride (158 mg, 0.82 mmol), oc, a-dimethyl-2-chlorophenethylamine (151 mg, 0.82 mmol) and 3 ml of dichloromethane producing 196 mg (70%) of (197): rt = 10.04 min., M / z (int. Re.) 339 (M + .0), 213 (58), 186 (24), 156 (12), 129 (25), 128 (100), 126 (14), 124 (44), 102 (14), 101 (38), 98 (5), 90 (5), 88 (18), 75 (10), 75 (10), 75 (9), 62 (5), 50 (5), 41 (9).
EXAMPLE 9 Preparation of N- (a, a-dimethyl-4-fluorofenethyl) -2-quinoxalinecarboxamide (129). To a solution of 1- (4-fluorophenyl) -2-methyl-2-propylamine (105 mg, 0.628 mmol) in 2 ml of pyridine was added 2-quinonoxaloyl chloride (133 mg, 0.691 mmol). The reaction mixture was then stirred for 30 minutes. To the stirring reaction mixture was added 20 ml of water, 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 placed under high vacuum for 15 hours. This provided 146 mg (71.9%) of (129): rt = 10.45 min; m / z (Int.R.) 323 (M + .1), 214 (73), 186 (22), 157 (14), 135 ( 4), 130 (19), 129 (100), 109 (22), 103 (9), 102 00), 83 (7), 76 (9), 75 (8), 42 (6).
In a similar manner, the following N-substituted 2-quinoxalinecarboxamides were prepared.
N- (β-methylphenethyl) -2-quinoxalinecarboxamide (131) Prepared from 2-quinoxaloyl chloride (193 mg, 0 84 mmol, β-methylphenethylamine (103 mg, 0.76 mmol), and 2 ml of pyridine producing 15 mg (69%) of (131): rt = 10.71 min; m / z (int.risk) 291 (M +, 12), 186 (66), 158 (5), 157 (37), 130 (20), 129 (100), 118 (28), 105 (21), 103 (17), 102 (37), 91 (7), 79 '(10), 78 (5), 77 (15), 76 (.11), 75 (I0), 51 (10), 51 (10) N- (3-methylcyclohexyl) -2-quinoxalinecarboxamide (163) Prepared from 2-qunoxaloyl chloride (193 mg, 10 mmol), 3-methyl-chlorhexyl amine (119 m, 0 90 mmol) ) and 5 ml of pyridine yielding 190 mg (78%) of (161): rt = 9.99 min; m / z (int. re) 269 (M +, 37), 226 (6), 198 (11 ), 174 (23), 157 (23), 131 (7), 130 (44), 129 (100), 113 (5), 112 (59), 103 (20), 102 (41), 95 (5 ), 81 (6), 76 (15), 75 (12), 56 (5), 55 (9), 51 (7), 41 (15), 41 (15).
N- (2,3-dimethylcyclohexyl) -2-quinoxalinecarboxamide (163) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 2,3-dimethylcyclohexylamine (115 mg, 0.90 mmol), and 5 ml pyridine yielding 150 mg (59%) of (163): rt = 10.12 min; m / z (int.r.) 283 (M +, 35), 212 (6), 198 (14), 175 (6) , 174 (39), 158 (7), 157 (22), 131 (6), 130 (46), 129 (100), 126 (44), 109 (8), 103 (20), 103 (20), 102 (45), 76 (13), 75 (11), 67 (7), 56 i (10), 55 (12), 51 (6) , 43 (6), 41 (16). i - N - [(1S, 2S, 3S, 5R) -3-pinanmethyl] -2-quinoxalinecarboxamide (207) Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (+) - 3-phenylammelamine (150 mg, 0.90 mmol), and 5 ml of pyridine yielding 229 mg, (79%) of (207) -rt = 121.07 min; m / z (int.r.) 323 (M +, 12), 187 (100 ), 186 (12), 174 (39), 166 (24), 159 (8), 158 (66), 157 (26), 150 (9), 144 (7), 131 (11), 130 (80 ), 129 (85), 107 (10), 103 (14), 102 (31), 95 (22), 93 (11), 91 (8), 83 (7), 81 (11), 79 (11) ), 77 (8), 76 (8), 69 (8), 67 (13), 55 (17), 43 (9), 41 (25).
EXAMPLE 10 N- (1-adamantanemethyl) -2-quinoxalinecarboxamide (146) 2-Quinoxaloyl chloride (429 mg, 2.6 mmol) was added to a solution of 2-adamantanmetimamine (500 mg, 2.6 mmol) in 5 ml of chloroform. The reaction mixture was heated until everything dissolved. The reaction mixture was stirred at 25 ° C for 1 hour. To the stirring reaction mixture was added 10 ml of water, which caused the product to precipitate. The precipitate was filtered, washed with water (2X) and dried under high vacuum. This was given 375 mg (45% of (146): rt = 12.27 min.m / z (Int.R.) 321 (M +, 101), 186 (7), 174 (6), 164 (34), 158 (6), 157 (8), 136 (11), 135 ( 100), 131 (7), 130 (46), 129 (75), 107 (23), 105 (6), 103 (20), 102 (53), 93 (44), 92 (6), 91 ( 23), 81 (13), 79 (47), 77 (24), 76 (16), 75 (13), 67 (16), 65 (6), 55 (9), 53 (8), 51 ( 8), 41 (13).
EXAMPLE 11 Preparation of N- (4-methylcyclohexyl) -2-quinoxalinecarboxamide (162) To a solution of 4-methylcyclohexylamine (119 mg, 0.90 mmol) in 2 ml of pyridine was added 2.quinoxaloyl chloride (193 mg. , 1.0 mmol). The reaction was then stirred for 1 hour. To the stirring reaction mixture was added 20 ml of water, 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 (51%) of (162): irt = 10.00 min; m / z (re., Nt.) 269 (M +, 53), 212 (15), 212 (15), 198 (7), 174 (25), 158 (6), 157 (36), 131 (7), 130 (44), 129 (100), 113 (6), 112 (66), 103 (18), 102 (36), 95 (9), 81 (6), 76 (12), 75 (9), 56 (5), 55 (10), 51 (6), 41 (12).
EXAMPLE 12 Preparation of N - [(1 S, 2S, 5S) -trans-m-triethyl] -2-q uinoxal i-carboxamide (225) (1S, 2S, 5S) -trans-Mirtanyl Trifluoroacetate Trifluoroacetic anhydride was added (5.50 ml), 39.0 mmol) a (-) - trans-mirtanol (5.10 ml, 32.5 mmoles) in dry tetrahydrofuran. The reaction mixture was stirred for 1 hour. The reaction mixture was rotary evaporated. This provided 7.60 g (94%) of (1S, 2S, 5S) -trans-mirtanyl trifluoroacetate. (1 R, 2R, 5R) -trans-mirtanyl trifluoroacetate In a similar manner, (1R, 2R, 5R) -trans-mirtanyl trifluoroacetate was prepared from trifluoroacetic anhydride (5.40 ml, 38.0 mmol, 1.2 equiv) (+) -trans-mirtanol (5.00 ml, 4.90 g, 31.7 mmol), and 10 ml of tetrahydrofuran yielding 7.60 g (94%) of trifluoroacetate (1R, 2R, 5R) -trans-mirtanil. (1S, 2S, 5S) -trans.Mirtanilazide A mixture of (1S, 2S, 5S ^ -trans-mirtanyl trifluoroacetate (1.0g, 4.0mmol), sodium azide (0.39g, 6.0mmol), and 50ml of N, N-dimethylformamide was stirred at 80 ° C for 24 hours, after cooling to 25 ° C, 100 ml of water was added, and this mixture was extracted with diethyl ether (2 x 50 ml). dried (anhydrous sodium sulfate) and rotary evaporated This yielded 1.12 g (100%) of (1S, 2S, 5S) -trans-myrtanylazide as a colorless oil. (1R, 2R, 5R) -trans-mirtanilazide In a similar manner, (1R, 2R, 5R) -trans-myrtanylazide was prepared from (1R, 2R, 5R) -trans-mirtanyl trifluoroacetate (7.60 g) , 30.4 mmol), sodium azide (3.00 g, 45.6 mmol), and 100 ml of N, N-dimethylformamide yielding 4.10 g, (48.2% of (1R, 2R, 5R) -trans-mirtanylazide. (1S, 2S, 5S) -trans-myrtanylamine A mixture of (1S, 2S, 5S) -trans-myrtanylazide (1.12 g, 7.32"mmoles) and platinum (IV) hydrate (0 34 g) in 50 ml of ethanol was stirred under hydrogen gas (3.515 kg / cm2m for 2 hours.) The reaction mixture was then filtered through paper and the filter was rotary evaporated. The resulting material was taken up in 12 M hydrochloric acid (100 ml). The aqueous solution was washed with diethyl ether (2 x 50 ml), the brine layer was made basic with 0.1 M sodium hydroxide (50 ml) and extracted with 2 x 50 ml dichloromethane. dried (anhydrous sodium sulfate) and rotary evaporated: This afforded 78 mg (75%) of (1S, 2S, 5S) -> trans-myrtanylamine as a light yellow oil. (1R, 2R, 5R) -trans-Mirtanylamine In a similar manner, (1R, 2R, 5R) -trans-im? Rtan? Lamina was prepared from (1R, 2R, 5R) -trans-mirtanylazide ( 4.10 g, 26. 8 mmoles), platinum oxide hydrate (IV) (0.41 g) and ethanol (75 ml) yielding 2.00 g (48.8%) of (1 R, 2R, 5R) -trans-mirtanylamine.
N - [(1 S, 2S, 5S) -trans-rn i rta nil] -2-qu i noxa! incarboxamide (225) In a manner similar to (162), (225) was prepared from 2-quinoxaloyl chloride (49 mg, 0.25 mmol), (1 S, 2S, 5S) -trans-mirtanylamine (35 mg, 0.23 mmole) and pyridine (5 ml) yielding 8 mg (10%) of (225): rt = 11.23 min .: m / z (int.r.) 309 (M + 25), 187 (15), 186 (39), 174 (12), 158 (14), 157 (29), 152 (20), 131 (6), 130 (47), 130 (47), 129 (100), 103 (15), 102 (41), 93 (9), 91 (6), 81, (12), 79 (12), 76 (11), 75 (10), 69 (14), 67 (17), 55 (8), 54 (5), 53 (7), 51 (7), 43 (6), 41 (25) • N - [(1 R, 2R, 5R) -trans-mirtanyl] -2-quinoxalinecarboxamide (226) In a similar manner, (226) was prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (1 R, 2RJ, 5R) -trans-m? Rtan? Lam? Na (138 mg, 0.90 mmol) ) and pyridine (5 ml) yielding 27 mg (10%) of (226): rt = 11.19 min .: m / z (int. re) 309 (M + .21), 186 (47), 186 (18) , 174 (17), 158 (16), 157 (34), 152 (30), 131 (6), 130 (47), 130 (47), 129 (100), 121 (6), 103 (15), 102 (40), 93 (11), 91 (6), 81 (12), 79 (11), 77 (8), 76 (10), 75 (9), 69 (14), 67 (17), 55 (7), 53 (6), 51 (5), 43 (5), 41 (18).
EXAMPLE 13 I Preparation of N-rN '- (R) -a-methylbenzyl-2-acetamidol-3-aminoquinoline dihydrochloride (156) N- (R) -methylbenzyl-2-chloroacetamide. (R) -a-Methylbenzylamine (2.4 g, 20 mmol) in 50 ml of dichloromethane was added to chloroacetyl chloride (2.25 g, 20 mmol) in 70 ml of dichloromethane and 10 g. ml of pyridine. The reaction solution was stirred, then diluted with 500 ml of diethyl ether, washed with water (3 x 30 ml), dried (anhydrous magnesium sulfate) and rotary evaporated. This provided 3.60 g of N- (R) -a-methylbenzyl-2-chloroacetamide.
N- (R) -a-Methylbenzyl-2-iodoacetamide A solution of sodium iodide (10 37 g, 69 mmol) in dry acetone was added slowly to a solution of N- (R) -a-meth? Ibencii-2 chloroacetamide (3.39 g, 7 mmol) in dry acetone, and the reaction mixture was refluxed for 16 hours. The reaction mixture was then filtered, and the filtrate was rotary evaporated. Diethyl ether was added, and the mixture was stirred for 20 minutes. The mixture was then filtered, and the filtrate was rotary evaporated and then placed under high vacuum to provide N- (R) -methylbenzyl-2-iodoacetamide.
N- [N '- (R) -a-methylbenzyl-2-acetamido] -3- i aminoquinoline dihydrochloride (156) A mixture of 3-aminoquinolin (0.15 g, 1.0 mmol) and potassium fluoride in celite (50%) ) (0.3 g, 2.5 mmol) in 20 ml of acetonitrile, was stirred for 1 hour. N- (R) -a-Methylbenzyl-2-iodoacetamide (0.31 g, 1.0 mmol) in acetonitrile was added, and the reaction mixture was refluxed for 64 hours. 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 aqueous layers were saturated with sodium chloride and then extracted with chloroform (4x). The combined organic layer was dried (anhydrous magnesium sulfate and rotary evaporated). The resulting material was dissolved in 10 ml of chloroform, 1 M of hydrogen chloride in 5 ml of diethyl ether was added and the solution was rotary evaporated. The resulting material was dissolved in 5 ml of chloroform and filtered through a 0.44 μm filter disk and the filtrate was evaporated. This yielded 13 mg (3% of (156): rt = 10.43 min; m / z (int. Re) 328 (M +, 11), 182 (12), 181 (86), 180 (37), 167 (22), 166 (25), 165 (17), 162 (53), 161 (95), 160 (37), 148 i (32), 145 (18), 135 (21), 132 (16) , 122 (9), 120 (22), 119 (20), 107 (19), 106 (13), 105 (100), 104 (22), 103 (19), 90 (12), 79 (25) , 78 (11), 77 (38), 51 (10), 44 (10), 41 (11).
EXAMPLE 14 Preparation of 1- (1-Amontilyl) -2- (benzothiazol-2-isulfanyl) eta none (273) Sodium hydride (36.5 mg, 1.52 mmol), 60% in mineral oil) was washed with pentane ( 4X), dried under N2, suspended in dimethylformamide (DMF, 10 ml) and cooled to 0 ° C. With stirring, a solution of 2-mercaptobenzothiazole (253.3 mg, 1.52 mmoles) in 5 ml of DMF was added dropwise. The reaction was stirred for 20 minutes at 0 ° C and treated with a solution of 1-adamantanbromomethyl ketone (389.8 mg, 1.52 mmole) in 8 ml of DMF. The reaction was stirred for 30 minutes at room temperature and diluted with 100 ml of diethyl ether. The resulting solution was washed with water (5 x 30 ml) and the remaining organic solution was dried over anhydrous MgSO, filtered and concentrated to a solid. Recrystallization from hot ethanol afforded 287 mg (55%) of the desired product-GC / El-MS gave m / z (re .mt) 343 (M +, 10), 315 (2), 180 (2), 148 (10), 135 (100), 107 (9), 93 (17) and 79 (20).
EXAMPLE 15 Assay of the activity of the mGluR agonist of Group I HEK-293 cells were loaded by expressing a recombinant recpetor, as described in WO 97/05252, with 2 μM of fura-2-acetoxymethi | ester by incubation for 30-40 minutes at 37 ° C in SPF-PCB (126 mM NaCl, 5 mM KCl? 1 mM MgCl2, 20 mM Na-HEPES, 1.0 mM CaCl2 1 mg / mL glucose, and 0.5% BSA, pH 7.4). • 5 The cells were washed 1-2 times in SPF-PCB, resuspended at a density of 4-5 million cells / ml and kept at 38 ° C in a plastic beaker. To record the fluorescent signals, the cells were diluted 5 times in a quartz cuvette with BSA-free SPF-PCB at 37 ° C 10 to obtain a final BSA concentration of 0.1% (1.2 ml of • SPF-PCB free of BSA at 37 ° C plus 0.3 ml of cell suspension) Fluorescence measurements were made at 37 ° C with constant agitation using a common development spectrometer (Biomedical Instrumentation Group, University of Pennsylvania). The 15 excitation and emission wavelengths were 340 and 510 nm, respectively. To calibrate the fluorescence signals, digitonin (Sigma Chemical Co., St. Louis, MO; catalog # D-5628; 50 μg / ml, final) was added to obtain maximum fluorescence (Fma > (), and fluorescence apparent minimum (Fm, n) was determined using 20 TRIS-Base / EGTA (10 mM, pH 8.3 final) '. The intracellular Ca2 + concentrations were calculated using a dissociation constant (Kd) of 224 nM and applying the equation: [Ca2 +] 1 = (F-Fm '? N / Fmax) xKd; where F is the fluorescence measured at any time 25 of interest and F falls between Fmax and Fm? N.
The control responses to the addition of 5 mM Ca2 + (final extracellular calcium concentration, 6 mM) were determined in separate cuvettes. The control responses to changes in extracellular calcium were determined throughout the experiment. The compounds were probed at a single concentration per cell cell, and all compounds were prepared in DMSO. Appropriate dilutions were made so that the compounds were added in a volume not greater than 10 μl for a total volume of 1,500 μl (final DMSO not greater than 067%) to obtain any particular test concentration. Once the stable intracellular calcium baseline was achieved, the compound was added to the beaker. The response or lack of response to the addition of the compound 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, digitionine and EGTA were added in a sequential manner to determine Fma and Fmm, respectively. The data were expressed as changes in intracellular calcium concentrations in nM. These changes in the calcium response after the addition of the compound were compared with the control calcium response (without compound). Responses to calcium in the presence of test compounds were normalized as a percentage change for those in controls. Data were entered into a Levenberg-Marquardt analysis for non-linear least squares and an IC50 and intervals of 95% confidence were determined for each compound. The invention in this manner has been described extensively and illustrated with reference to the representative embodiments described above. Those skilled in the art will recognize that various modifications can be made to the present invention without departing from the spirit and scope thereof.

Claims (9)

1. - A compound represented by the formula I: R- [linker] -Ar wherein R is an optionally substituted straight or branched alkyl, arylalkyl, cycloalkyl or I alkylcycloalkyl group, containing 5-12 carbon atoms, wherein Ar is an aromatic, heteroaromatic, optionally substituted arylalkyl or heteroaralkyl moiety containing i to 10 carbon atoms and up to 4 heterogeneous atoms, and wherein [linker] is - (CH2) n-, where n is 2-6 and where up to 4 CH 2 groups independently can be substituted with groups selected from the group consisting of C 1 Ca alkyl, CHOH, CO, O, S, SO, S02, N, NH, and NO; ! provided that two heterogeneous atoms may not be adjacent, except when those atoms are both N or both are NH, and where two adjacent CH2 groups may be replaced by a substituted or unsubstituted alkene or alkyne group, or a pharmaceutically acceptable salt of the same.
2. A compound according to claim 1, wherein Ar comprises a ring system selected from the group consisting of benzene, thiazole, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl rings. , pyrimidyl, pyrdazinyl, benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, ftalizinyl, naphthyridinyl, quinazolyl, cinolinyl, isothiazolyl, quinoxalinyl, indolizinyl, isoindolyl, benzothienyl, benzofuranyl, izobenzofuranyl, and chromenyl, wherein Ar optionally independently can be substituted with up to two C 1 Cs alkyl groups, or up to two I halogen atoms, wherein the halogen is selected from F, Cl, Br, and I. 3.- The compound according to claim 1, wherein R contains 7-11 carbon atoms, wherein some or all of the hydrogen atoms on two carbon atoms can optionally be replaced with substi listeners independently selected from the group consisting of F, Cl, OH, OMe, and = O. 4. The compound according to claim 1, wherein [linker] comprises an amide, ester or thioester group. 5. The compound according to claim 3, wherein R comprises a portion selected from the group consisting of adamantyl, 2-adamantyl, (1S, 2S, 3S, 5R) -isopinocamphenyl, tricyclo [4.3.1] , 1 (3.8) undec-3-yl, (1S, 2R, 5S) -cis-mirtanyl, (1R, 2R, 3R, 5S) -isopinocamphenyl, (1S, 2S, 5S) -trans-mirtanyl, (1R, 2R, 4S) -isobornyl, (1R, 2R, 3R, 5S) -isopinocamphenyl, (1S, 2S, 5S) trans-mirtanyl, (1R, 2R, 5R) -trans-mirtanyl, (1R.2S.4S) -bornyl, 1 -adamantanmethyl, 3-noradamantyl, (1S, 2S, 3S, 5R) ) -3-p-nanometry, cyclooctyl, a, a-dimethylphenyl, (S) -2-phenyl-1-propyl, cycloheptyl, 4-methyl-2-hexyium, 2,2,3,3,4,4, 4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethyladamantyl, trans-2-phenecyclopropyl, 2-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 2- (o-methoxyphenyl) ethyl 2- (1, 2,3,4-tetrahydronaphthyl), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2- (m-fluorophenyl) ethyl, 2- (p-fluorophenyl) ethyl, 2- (3- hydroxy-3-phenM) pro pyl, (S) -2-h id roxy-2-phen Methyl, i (R) -2-hydroxy-2-p-phenylethyl, 2- (3-m-chlorophenyl-2-methyl) ) propyl, 2- (3-p-chlorophenyl-2-ylmethyl) propMo, 4-tert-butyl-cyclohexyl, (S) -1- (cyclohexyl) ethyl, 2- (3- (3,4-dimethylphenyl)) -2-methyl) propyl, 3,3-dimethylbutyl, 2- (5-methyl) hexyl, 1-myrtanyl, 2-bornyl, 3-pineanthyl, 2,2,3,3,4,4,5,5- octafluoropentyl, p-fluoro-a, a-dimethylphenethyl, 2-naphthyl, 2-bornyanyl, cyclohexylmethyl, and 3-methyl Cyclohexyl, 4-methylcyclohexyl, 3,4-dimethylcyclohexyl, 5-chloro-tricyclic, or [2,2,1-heptyl, or, a-dimethylphenyl, 2-indanyl, 2-spiro [4,5] decyl, 2-phenylethyl, 1-adamantylethyl, 1- (1-bicyclo [2.2.1] hept-2-yl) ethyl, 2- (2-methyl-2-phenylpropyl), 2- (o-phlorophenyl) etiyl , 1 - (cyclohexyl) ethyl, and cyclohexyl. I 6. The compound according to claim 1, wherein Ar comprises a group having the formula: where X1, X2, X3 and X4 independently can be N or CH, provided that no more than two of X1, X2, X3 and X4 may be N. 1. The compound according to claim 6, wherein X1 is N. 8. The compound according to claim 7, in where X2 is N. 9. The compound according to claim 6, wherein X3 is N. 10. The compound according to claim 6, wherein X1 is CH and X2 is N. 11.- The compound according to claim 1, wherein Ar is an optionally substituted 2-, 3-, or 4-pyridyl portion. 12. The compound according to claim 1, wherein Ar is a 6-benzothiazolyl moiety. 1
3. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable diluent. 1
4. A method for making a compound according to claim 4, which comprises reacting a compound containing an active carboxylic acid group with a compound containing an amine, hydroxyl or thiol group. 1
5. A method for inhibiting the activation of a mGluR receptor of group I, which comprises treating a cell containing said receptor with an effective amount of a compound according to claim 1. 16.- A method to inhibit the damage neuronal caused by activation of excitation of a mGluR receptor of group I, which comprises treating neurons with an effective amount of a compound according to claim 1. 17.- A method for treating a disease associated with neuron damage induced by glutamate , comprising administering to a patient suffering from said disease, an effective amount of a composition according to claim 13. 18. The compound according to claim 1, wherein said compound is selected from the group consisting of N- [6- (2-m ethylquinolyl I)] - 1 -adamantan carboxamine, N- (6-quinolyl) -1-adamantanecarboxamide, N- (2-quinolyl) -1 -adamantanecarboxamide, N- (3- Quinolyl) -1-adamantan-carbox amide, 6-quinolyl-1-adamantanecarboxylate, 1-Adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,5,5-Octafluoro-1-pentyl-6-quinolinecarboxylate, 1 -adamantanmethyl-6-quinolinecarboxylate, 1-Adamantyl-2-quinoxalinecarboxylate, N- (1 -Adamantil) - 3-quinoline-carboxamide, N- (1-Adamantyl) -2-quinolinecarboxamide, N- (2-Adamantyl) -2-quinoxalinecarboxamide, N - [(1R, 2R, 3R, 5S -3-Pinanmethyl) -2 -quinoxaline-carboxamide, N- (1 -Adamantyl) -2-quinoxalinecarboxamide, N- (1-Adamantyl) -6-quinolinecarboxamide, N- (exo-2-Norbornanil) -2-quinoxalinecarboxamine, N - [(1R, 2S, 4S) -Bornyl] -2-quinoxaline-carboxamide, N- (3-Noradamantil) -2-quinoxalinecarboxamide, N - [(1R, 2R, 3R, 5S) lso-pinocam fe nyl] -2-quinoxalincarb oxamide, N - [(1S, 2S, 3S, 5R) -isopinocamphenyl] -2-quinoxaIincarboxamine, N- [(1Sl2S, 3S, 5R) -lsopinocamphenyl] -2-quinoxalinecarboxamide, N- (5-chloro [2.2 , 1.0] tricyclo-2,6-hepta-3-yl) -2-quinoxalinecarboxanide, N- ([4,3,1,1) Tricyclo-3,8-undeca-3-M) -2-quinoxalinecarboxamide , N- [(1S, 2R, 5S) -cis-Myrtanyl] -2-quinoxalinecarboxamide, N - [(1R, 2R, 4S) lso'bornyl] -2-quinolinecarboxamide, N- [endo - (+.) - 2-Norbornanil] -2-quinoxal inc arboxamide, N - [(R) -2-phenyl-1-propyl] -2-quinoxaline-carboxamide, N - [(S) -2-phenyl-1-propyl] -2-quinoxalinecarboxamide, N- (2-indanyl ) -2-quinoxalinecarboxamide, ether 1 -adamantanmethyl 6-quinolone, i 1-adamantyl-3-quinolinecarboxylate, N- (a, a-dimethemethyl) -2-quinoxaline carboxamide, N- (a, ad? Methyl-2-chlorophenethyl) ) -2-quinoxalinecarboxamide, N- (a, a-dimethyl-4-fluorofenethyl) -2-quinoxalinecarboxamide, N- (β-methylphenethyl) -2-quinoxal? Ncarb oxamide, N- (3-methylcyclohexyl) -2-quinocalincarboxamide , N- (2,3-dimethylcyclohexyl) -2-quinoxaI'ncarboxamide ~ N - [(1S, 2S, 3S, SR) -3-pinanmethyl] -2-quinoxaline-carboxamide, N- (1-Adamantanmethyl) -2 -quino xa lin carboxamide, N- (4-methylcyclohexyl) -2-q uinoxaline-carboxamide, N - [(1 S, 2S, 5S) -trans-Mirtan? l] -2-quinoxaline-carboxamide, and N- [1 R, 2R, 5R) -trans-Mirtanyl] -2-quinoxaline-carboxamide, and pharmaceutically acceptable salts thereof. 19. The compound according to claim 1, wherein said compound is selected from the group consisting of N- (1-adamantyl) -3-quinolinecarboxamide, N- (1-Adamantyl) -2-quinolinecarboxamide, N - (2-Adamantyl) -2-quinoxalinecarboxamide, N- [(1R, 2R, 3R, 5S) -3-Pinanmethi] -2-quinoxalinecarboxamide, N- (1-Adamantyl) -2-quinoxalinecarboxamide, N- (1- Adamantyl) -6-quinolinecarboxamide, N- (exo-2-norbornaniI) -2-quinoxaIincarboxamide, N [(1R, 2S, 4S) -Bornyl] -2-quinoxaline-carboxamide, 'N- (3 - Noradamantil) -2-quinoxaline-carboxamide, N- [1R, 2R, 3R, 5S) - [sopinocamfenylJ-2-quinoxaline-carboxamide, N - [(1S, 2S, 3S, 5R) -lsopinocamfeniI] -2-quinoxaline -carboxamide, N- (5-chloro- [2,2,1, 0] tricyclo-2,6-hepta-3-yl) -2-quinocalincarboxamide, N - ([4,3,1,1] tricyclo- 3,8-undeca-3-yl) -2-quinoxalinecarboxamide, N [(1S, 2R, 5S) -cis-Mirtanyl] -2-quinoxaline-carboxamide, N - [(1R, 2R, 4S) -sobornyl) - 2-quinoxaline-carboxamide, N- [endo - (+.) - 2-norbornyanil] -2-quinoxaline carboxamide, N [(1S, 2S, 3S, 5R) -3-Pinanmethyl] -2-qu? Noxalincarb oxami da, N- (1 -Ada nmethyl blanket) -2-qu inoxyl i n-carboxamide, N - [(1S, 2S, 5S) -trans-M i rtanyl] -2-quinoxalincarb oxamide, and N - [(1 R, 2R, 5R) -trans-Mirtanyl] -2-quinoxalinecarboxamide, and their pharmaceutically acceptable salts. 20. The compound according to claim 1, wherein said compound is selected from the group consisting of N- [6- (2-methylquino] - 1-adamantanecarboxamine, N- (6-Quinoxy) -1- i adamantanecarboxamide, N- (2-quino -1-adamantanecarboxamide, and i N- (3-quino -1 -adamantanecarboxamide, and their pharmaceutically acceptable salts. 21. The compound according to claim 1, wherein said compound is selected from the group consisting of N- (3-methylcyclohexyl) -2-quinocainecarboxamide, N- (2,3-dimethylcyclohexyl) -2-quinoxalinecarboxamide, N - [(1S, 2S, 3S, SR) -3-pinanmethyl] -2-quinoxalinecarboxamide, N- (1-Adamantanmethyl) -2-quinoxalinecarboxamide, and N- (4-methylcyclohexyl) -2-qu? Noxalin- carboxamide, and pharmaceutically acceptable salts thereof. % e 78 22. The compound according to claim 1, wherein said compound is selected from the group consisting of N- [R] -2-Phenyl-1-propyl-2-quinoxalinecarboxanima, N - [(S) -2-phenyl-1-propyl] -2-quinoxalinecarboxamide, N- (2-indanyl) -2-quinoxaline-5-carboxamide, N- (a, a-dimethylfenentil) -2-quinoxalinecarboxamide, N- (a, a-dimethyl-2-chlorophenethyl) -2-quinoxalinecarboxamide, N- (α, α-dimethyl-4-fluorophenethyl) -2-quinoxalincabroxamide, and N- (β-methylphenethyl) -2- and quinoxaline carboxamide, and their pharmaceutically acceptable salts. 23. The compound according to claim 1, wherein said compound is 1-diemantanmethyl 6-quinolyl ester or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 1, wherein said compound is selected from the group consisting of 6- quinoli! -1-adamantancarboxylate, 1-adamantyl-6-quinolinecarboxylate, 2,2,2,3,4 , 4,5,5-Octafluoro-1-pentyl-6-quinolinecarboxylate, 1- adamantabmetl-6-quinolinecarboxylate, 1-Adamantyl-2-quinoxylcarboxylate, and 1-Adamantyl-3-quinoline incarboxylate, and their pharmaceutically acceptable salts . 25. The compound according to claim 1, in Wherein said compound is selected from the group consisting of 3- (1-adamantanemethoxy) -2-chloroquinoxaline, 2- (1-Adamantanemethoxy) -3-methoxyquinoline, 3- (1-Adamantanemethoxy) -2-fluoro quinoxaline , 2- (1-Adamantanmethoxy) -3-trifluoromethylquinoxaline, N- [2- (4-phenylthiazolyl)] -1-adamantanecarboxamide, N- [2- (5-methyl-4-phenylthiazolyl)] - 1-adamantanecarboxamide, 1 - (- Adamantyl) -2- (benzothiazol-2-ylsulfanyl) ethanone, N- (1-Adamantyl) -2-chloroquinoxaline-3- Carboxamide, N- (1-Adamantyl) -3-methylquinoxaline-2-carboxamide, and N- (1-adamantyl) -1-oxy-oxyhexalin-3-carboxamide, and their pharmaceutically acceptable salts. 2
6. The compound according to claim 1, wherein said compound is selected from the group consisting of 4-chlorophenyl-3-coumarincarboxylate, 2- (1 -adamantanmethylsulfanyl) quinoxaline, 3- (1 -damantanemethoxy) -2-chloropyrazine , 1- (1- Adamantyl) -2- (4,6-dimethylpyrimidin-2-ylsuiphenyl) ethanone, 1- (Adamantyl) -2- (2-anisylsulfanyl) ethanone, 3- (1-Adamantanmethoxy) -1H-quinoxane -2-one, 1- (1 -Adamantil) -2- (3-annylsulfanyl) ethanone, 1- (1-Adamantyl) -2- (4-anisylsulfanyl) ethanone, 1- (1-Adamantyl) -2- ( 4-Chlorophenylsulfanyl) ethanone, 1- (1-Adamantyl) -2- (2-naphthylsulfanyl) ethanone, N- (2- [6- (1-Piperidinyl) pyrazinyl]) - 1-adamantanecarboxamide, N- ( 2- [6- (1-piperidinyl) pyrazinyl) adamantan-1-ylmethylcarboxamide, 1- (1-Adamantyl) -2- (1-naphthylsulfanyl) ethanone, 1- (1-Adamantyl) -2- (8-) hydrochloride quinolysulfanyl) ethanone, 1- (1-Adamantyl) -2- (4-trifluoromethoxyphenoxy) ethanone, 2- (1-Adamantan-methoxy) quinoxaline, N- (trans-4-methylcyclohexyl) -2-quinoxaline-carboxamide, N- (cis-4-methylcyclohexyl) -2-quinoxalinecarboxamine da, N- (trans-4-methylcyclohexyl) -2-quinolinecarboxamide, N- (trans-4-methylcyclohexyl) -3-quinolinecarboxamide, and N- (trans-4-methylcyclohexyl) -6-quinolinecarboxamide, and their pharmaceutically acceptable salts of the same. 2
7. The compound according to claim 1, wherein said compound is selected from the group consisting of 2- (l-Adamantanmethylsulfinyl) -benzothioazole, N- (4-f in i I butyl) -2-quinoxalinecarboxamide, - (1-mannylnyl) -2- (4,6-dylmethylpyrimidin-2-Msulfanyl) ethanol, 1- (1-Adenamant) -2- (3-chloroquinoxal-2-yl) ethanone, 2- (1 - Adamantanmethylsulfanyl) -3-methylquinoxaline, N- (1-Adamantyl) -2-anisamide, N- (1-Adamamnomethyl) -2-anisamide, 1- (1-Adamantyl) -2- (4-chlorophenylsulfanyl) ethanone, 2- (1-Adamantanmethylsulfonyl) -3-methylquinoxaline, 1- (1-Adamantyl) -2- (4-fluorophenylsulfanyl) ethanone, 1- (1-Adamantyl) -2- (3-fluorof in ilsulf anil) ethanone, 1- (1-Adamantyl) -2- (2-methoxyphenone) ethanone, 1- (4-Anisylsulfanyl) butan-2-one, 1- (1-Adamantyl) -2- (4-anisidinyl) ethanone hydrochloride, 3 , 3-dimethyl-1- (4-anis? LsuIfanyl) butan-2-one, 1- (4- (4-biphenyl) -2- (4-anis? Isulfanyl) ethanone, 1- (1 -A-styllin) -2- (2-trifluoromethoxy fe nyl-su! Fanyl) ethanone, 1- (1-Adamantyl) -2- (3-metMquinoxal-2-ylsulfanyl) -ethanone, chlor hydrate of 1 - (1 -Adamantil) -2- (2-anis-sil) ethanone, > 1- (1-Adamantyl) -2- (4-trifluoromethoxyphenylamino) -i ethanone hydrochloride, 1- (1-Adenamant) -2- (N-methyl-4-anisidyl) ethanone hydrochloride, N- (1 -A mild) -7-tri fluoro methylinoline-3-carboxamide, N- (1-Adamantyl) -2- (1-piperizinyl) quinoxaline-3-carboxamide, N- (1-Adamantl) -2- (2- aminoethylamino) quinoxylin-3-carboxamide, N- (3-quinolyl) -3-carboxydamantan-1-methylcarboxamide, 1- (1-Adamantyl) -2 - [(R) -1- (1-naphthyl) ethan-1-ylamino] ethanone, N- (1-Adamantyl) -2-methoxyquinhoxaline-3-carboxamide, ethyl N- (1-adamantyl) -2- (3-propanoylamino) quinoxaline-3-carboxamide , N- (4- "chlorophenyl) -2,3-dimethylquinoxaline-6-carboxamide, N- (1-Adenamant) -6,7-dimethylquinoxaline-2-carboxamide, N - ((S) -1-tetralinM) - 2-quinoxalinecarboxamide, N- (4-Clorophenethe I) -2-quinoxylin carboxamide, N- (6-quinolyl) -2 -quinoxalinecarboxamide, N- (1 -tetramethylmethyl) -2-quinoxalinecarboxamide, N- (1- Ndanmethyl) -2-quinolinylcarboxamide, N- t (4,4-dimethylcyclohexyl) -2-quinoxalinecarboxamide, and its pharmaceutically acceptable salts bles of it.
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