CN1158264C - Metabotropic glutamate receptor antagonists for the treatment of central nervous system disorders - Google Patents

Abstract

The present invention provides compounds and pharmaceutical compositions that act as antagonists of metabotropic glutamate receptors. These compounds are useful in treating neurological diseases and disorders. Methods for preparing these compounds are also disclosed.

Description

Metabolic glutamate receptor antagonists for the treatment of central nervous system disorders

field of invention

The present invention provides compounds that are active at metabotropic glutamate receptors and are useful in the treatment of neurological and psychiatric diseases and disorders.

Background of the invention

Recent advances in elucidating the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the treatment of acute and chronic neurological and psychiatric diseases and disorders. However, a major challenge in realizing this expectation has been the development of metabotropic glutamate receptor subtype-selective compounds.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate exerts its effects on the central nervous system by binding to and activating cell surface receptors. According to the structural characteristics of the receptor protein, the pathway through which the receptor transduces the signal to the cell, and the characteristics of the pharmaceutical, these receptors can be divided into two categories, namely, ionotropic and metabolic effects. glutamate receptors.

The metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that activate various intracellular second messenger systems and then bind glutamate. Activation of mGluRs in intact mammalian neurons induces one or more of the following responses: activation of phospholipase C; increased hydrolysis of phosphoinositide (PI); release of intracellular calcium; activation of phospholipase D; Activation or inhibition of cyclic AMP (cAMP) formation; activation or inhibition of cyclic AMP (cAMP); activation of guanylate cyclase; increased cyclic guanylate-phosphatase (cGMP) formation; phospholipase A ₂ Activation; increased release of arachidonic acid and increased or decreased activity of voltage- and ligand-controlled ion channels. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).

Eight distinct mGluR subtypes, termed mGluR1-mGluR8, have been identified by molecular cloning. See, eg, Nakanishi. Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995). Diversity in other receptors is found through the expression of other spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neuroscience 15:3970 (1995).

Metabolic glutamate receptor subtypes can be subdivided into three groups, namely, class I, class II and class III, according to amino acid sequence homology, the second messenger system utilized by the receptor, and its pharmacological characteristics. Class mGluRs. Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995).

Class I mGluRs include mGluR1, mGluR5 and other spliced variants thereof. Binding of agonists to these receptors results in activation of phospholipase C and continuous mobilization of intracellular calcium. These effects can be confirmed using electrophysiological assays, for example on recombinant mGluR1 receptors expressed in Xenopus oocytes. See, eg, Masu et al., Nature 349:760 (1991); Pin et al., PNAS 89:10331 (1992). Similar results have been obtained for recombinant mGluR5 receptors expressed in oocytes. Abe et al., J. Biol. Chem. 267:13361 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neuroscience 15:3970 (1995). In addition, activation of an agonist of the recombinant mGluR1 receptor expressed on Chinese hamster ovary (CHO) cells was found to stimulate PI hydrolysis, cAMP formation, and release of arachidonic acid, as determined by standard biochemical assays. Aramori et al., Neuron 8:757 (1992).

In comparison, activation of the mGluR5 receptor expressed on CHO cells stimulated PI hydrolysis and continuous intracellular calcium transients, but was found not to stimulate cAMP formation or arachidonic acid release. Abe et al., J. Biol. Chem. 267:13361 (1992). However, activation of the mGluR5 receptor expressed on LLC-PK1 cells resulted in PI hydrolysis and enhanced cAMP formation. Joly et al., Journal of Neuroscience 15:3970 (1995). The agonist effect distribution pattern (profile) on class I mGluRs: gentic acid > glutamic acid = ibotenic acid > (2S, 1'S, 2'S)-2-carboxycyclopropyl)glycine (L -CCG-I)>(1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD). Squisquinine is relatively selective for class I receptors compared to class II and class III mGluRs, but is also a potent activator of ionotropic AMPA receptors. Pin et al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417 (1995).

The lack of subtype-specific mGluR agonists and antagonists has hampered elucidation of the physiological roles of specific mGluRs, and mGluRs involved in affecting CNS pathophysiological processes have also had to be identified. However, studies of non-specific agonists and antagonists have yielded some consensus about class I mGluRs compared to class II and class III mGluRs.

Experiments elucidating the physiological role of class I mGluRs suggest that activation of these receptors induces neuronal excitation. Various studies have shown that ACPD can produce postsynaptic excitatory effects on neurons in the hippocampus, cerebral cortex, cerebellum, thalamus blood brain, and other brain regions. The fact that this priming is due to direct activation of the postsynaptic mGluRs, but also suggests that activation of the presynaptic mGluRs occurs, which leads to increased release of neurotransmitters. Baskys, Trends Pharmacol. Sci. 15:92 (1992); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).

Drug trials are targeting class I mGluRs as mediators of this excitatory mechanism. In the presence of iGluR antagonists, the ACPD effect can be regenerated by low concentrations of gentinaic acid. Hu et al., Brain Res. 568:339 (1991); Greene et al., European Journal of Pharmacology 226:279 (1992). Two phenylglycine compounds known to activate mGluR1, namely (S)-3-hydroxyphenylglycine ((S)-3HPG) and (S)-3,5-dihydroxyphenylglycine ((S)-DHPG ) can also be activated. Watkins et al., Trends Pharmacol. Sci. 15:33 (1994). In addition, compounds known to be mGluR1 antagonists, (S)-4-carboxyphenylglycine ((S)-4CPG), (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG) And (+)-α-methyl-4-carboxyphenylglycine ((+)-MCPG) can block the excitatory effect. Eaton et al., European Journal of Pharmacology 244:195 (1993); Watkins et al., Trends Pharmacol. Sci. 15:333 (1994).

Metabolic glutamate receptors have been found to be involved in many normal processes in the mammalian CNS. Activation of mGluRs has been shown to require induction of long-term potentiation in the hippocampus and long-term depression in the cerebellum. Bashir et al., Nature 363:347 (1993); Bortolotto et al., Nature 368:740 (1994); Aiba et al., Cell 79:365 (1994); Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nociception and analgesia has also been demonstrated. Meller et al., Neuroreport 4:879 (1993). In addition, mGluR activation is thought to play a regulatory role in a variety of other normal processes, including synaptic transmission, neuronal development, apoptosistic neuronal cell death, synaptic plasticity, spatial learning, olfactory memory, cardiac activity Central control, walking, motor control, and ocular reflex control. See Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacology 34:1; Knopfel et al., J. Med. Chem. 38:1417 (1995).

Metabolic glutamate receptors have also been shown to play a role in various pathophysiological processes and diseases affecting the CNS. They include shock, brain trauma, hypoxic and ischemic injury, hypoglycemia, epilepsy and neurodegenerative diseases such as Alzheimer's disease. . Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Cunningham et al., Life Sciences 54:135 (1994); Hollman et al., Ann. Rev. Neurosci. 17:31 (1994); Pin et al., Neuropharmacology 34: 1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995). Much of the pathology of these diseases is thought to be due to excess glutamate-induced excitation of CNS neurons. Since class I mGluRs can increase glutamate-mediated neuronal excitation and enhance presynaptic glutamate release through postsynaptic mechanisms, their activation may be involved in pathology. Selective antagonists of class I mGluR receptors are therefore of therapeutic interest, especially as neuroprotective or anticonvulsant agents.

Preliminary studies evaluating the therapeutic efficacy of existing mGluR agonists and antagonists have yielded seemingly contradictory results. For example, administration of ACPD to hippocampal neurons has been reported to cause seizures and neuronal damage. Sacaan et al., Neurosci. Lett. 139:77 (1992); Lipparu et al., Life Sciences 52:85 (1993). However, other studies have shown that ACPD can suppress epileptiform activity and may also exhibit neuronal protective properties. Taschenberger et al., Neuroreport 3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh et al., Proc.Natl.Acad.Sci.USA 88:9431 (1991); Chiamulera et al., European Journal of Pharmacology 216:335( 1992); Siliprandi et al., European Journal of Pharmacology 219:173 (1992); Pizzi et al., J. Neurochem. 61:683 (1993).

These contradictory results may be due to the lack of selectivity of ACPD, which causes the activation of several different subtypes of mGluRs. In studies where neuronal damage was found, class I mGluRs were shown to be activated, thereby enhancing unwanted excitatory neurotransmission. Activation of class II and/or class III mGluRs has been shown in studies showing neuronal protection, inhibiting presynaptic glutamate release and reducing excitatory neurotransmission.

This interpretation is consistent with the finding that (S)-4C3HPG, an antagonist of class I mGluRs and an agonist of class II mGluRs, protects DBA/2 mice from audiogenic seizures, whereas class II mGluRs selectively agonize Agents DCG-IV and L-CCG-I protect neurons from NMDA- and KA-induced toxic effects. Thomsen et al., J. Neurochem. 62:2492 (1994); Bruno et al., European Journal of Pharmacology 256:109 (1994); Pizzi et al., J. Neurochem. 61:683 (1993).

It is clear from the foregoing that existing mGluR agonists and antagonists are of limited value due to their lack of potency and selectivity. In addition, most of the existing compounds are amino acids or amino acid derivatives with limited bioavailability, thus hampering studies on mGluR physiology, pharmacology and evaluation of their therapeutic efficacy in vivo. Compounds that selectively inhibit the activation of metabotropic glutamate receptor class I subtypes are useful in the treatment of neurological disorders and diseases such as senile dementia, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Pain, epilepsy, brain trauma, hypoxic and ischemic injury and psychiatric disorders such as schizophrenia and depression.

Thus, there is clearly a great need for potent mGluR agonists and antagonists that are highly selective for each individual mGluR subtype, especially the class I receptor subtype.

Summary of the invention

Accordingly, it is an object of the present invention to identify metaboglutamate-active receptor compounds which exhibit high potency and selectivity for each individual metabotropic glutamate receptor subtype, and to provide methods for the preparation of these compounds.

Another object of the present invention is to provide pharmaceutical compositions comprising compounds exhibiting high potency and selectivity for the respective subtypes of metabotropic glutamate receptors, and to provide methods for the preparation of these pharmaceutical compositions.

Another object of the present invention is to provide a method for inhibiting the activation of mGluRI receptors and a method for inhibiting neuron damage caused by excitatory activation of mGluRI receptors.

Still another object of the present invention is to provide methods for treating diseases associated with glutamate-induced neuronal damage.

To achieve these objects, the present invention provides potent antagonists of class I metabotropic glutamate receptors. These antagonists can be represented by Formula I.

R-[-linking group-]-Ar

Wherein R is an optionally substituted straight or branched alkyl, aralkyl, cycloalkyl or alkylcycloalkyl containing 5-12 carbon atoms. Ar is an optionally substituted aromatic, heteroaromatic, aralkyl or heteroaralkyl moiety containing up to 10 carbon atoms and up to 4 heteroatoms, and the [linking group] is -( _CH2 ) _n -, wherein n is 2-6, and wherein up to 4 CH ₂ groups can be selected from C ₁ -C ₃ alkyl, CHOH, CO, O, S, SO, SO ₂ , N, NH and The groups of NO are independently substituted. Except when both atoms are N or both NH, the two heteroatoms in the [linking group] are not adjacent to each other. Two adjacent CH ₂ in [Linking Group] may also be substituted by substituted or unsubstituted alkenyl or alkynyl. The present invention also provides a pharmaceutically acceptable salt of the compound.

In one embodiment of the invention Ar comprises a ring system selected from the group consisting of benzene, thiazole, furyl, pyryl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyryl Azinyl, pyrimidinyl, pyridazinyl, benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazolyl, purinyl, quinazinyl, isoquinolyl, quinolinyl, phthalazine Base, 1,5-diazanaphthyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl, indolizyl, isoindolyl, benzothienyl, benzofuryl, Isobenzofuryl and benzopyranyl rings. Ar may be optionally substituted independently with up to two C ₁ -C ₃ alkyl groups or up to two halogen atoms selected from F, Cl, Br and I.

In another embodiment of the present invention, R comprises 4, 5, 6, 7, 8, 9, 10 and 11 carbon atoms, wherein some or all of the hydrogen atoms on two carbon atoms may optionally be independently selected from Substituent substitution of F, Cl, OH, OMe, =O and -COOH.

In another embodiment, the [linking group] includes an amide, ester or thioester group.

In a preferred embodiment, R comprises a group selected from the group consisting of substituted or unsubstituted adamantyl, 2-adamantyl, (1S, 2S, 3S, 5R)-isopinocamphenyl (isopinocamphenyl), Tricyclo[4.3.1.1(3.8)]undec-3-yl, (1S,2R,5S)-cis-myrtanyl, (1R,2R,4S)-isobornyl, (1R, 2R, 3R, 5S)-isopine camphenyl, (1S, 2S, 5S)-trans-myrtleyl, (1R, 2R, 5R)-trans-myrtleyl, (1R, 2S, 4S)-bornyl, 1-adamantylmethyl, 3-noradamantyl, (1S, 2S, 3S, 5R)-3-pinanemethyl, cyclooctyl, α, α -Dimethylphenethyl, (S)-2-phenyl-1-propyl, cycloheptyl, 4-methyl-2-hexyl, 2,2,3,3,4,4,4-heptyl Fluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethyladamantyl, trans-2-phenylcyclopropyl, 2-methyl Cyclohexyl, 3,3,5-trimethylcyclohexyl, 2-(o-methoxyphenyl)ethyl, 2-(1,2,3,4-tetrahydronaphthyl), 4-phenylbutyl Base, 2-methyl-2-phenylbutyl, 2-(m-fluorophenyl)ethyl, 2-(p-fluorophenyl)ethyl, 2-(3-hydroxy-3-phenyl)propyl , (S)-2-hydroxyl-2-phenylethyl, (R)-2-hydroxyl-2-phenylethyl, 2-(3-m-chlorophenyl-2-methyl)propyl, 2 -(3-p-chlorophenyl-2-methyl)propyl, 4-tert-butylcyclohexyl, (S)-1-(cyclohexyl)ethyl, 2-(3-(3,4-dimethylbenzene base)-2-methyl)propyl, 3,3-dimethylbutyl, 2-(5-methyl)hexyl, 1-myrtyl, 2-bornyl, 3-pinanemethyl , 2,2,3,3,4,4,5,5-octafluoropentyl, p-fluoro-α,α-dimethylphenethyl, 2-naphthyl, 2-bornyl, cyclohexylmethyl Base, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4-dimethylcyclohexyl, 5-chloro-tricyclo[2.2.1]heptyl, o-α,α-dimethylbenzene Ethyl, 2-(2,3-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-fluorophenyl)ethyl, 1-(cyclohexyl)ethyl and cyclohexyl.

In another embodiment of the invention Ar comprises a group having the formula:

wherein X ¹ , X ² , X ³ and X ⁴ can independently be N or CH, provided that no more than two of X ¹ , X ² , X ³ and X ⁴ are N. In a preferred embodiment, ^X1 is N and/or ^X2 is N. In another embodiment, ^X3 is N. In another embodiment, ^X1 is CH and ^X2 is N.

In another embodiment, Ar is an optionally substituted 2-, 3- or 4-pyridyl moiety, or Ar is a 6-benzothiazolyl moiety. The compound and its pharmaceutically acceptable salts are selected from: N-[6-(2-methylquinolyl)]-1-adamantanecarboxamide, N-(6-quinolyl)-1-adamantane Formamide, N-(2-quinolyl)-1-adamantanecarboxamide, N-(3-quinolyl)-1-adamantanecarboxamide, 6-quinoline 1-adamantanecarboxylate, 6 -1-adamantyl quinolinecarboxylate, 2,2,3,3,4,4,5,5-octafluoro-1-pentyl-6-quinolinecarboxylate, 6-quinolinecarboxylate 1- Adamantyl methyl ester, 1-adamantyl 2-quinoxalinecarboxylate, N-(1-adamantyl)-3-quinoline-carboxamide, N-(1-adamantyl)-2-quinoline Formamide, N-(2-adamantyl)-2-quinoxaline formamide, N-[(1R, 2R, 3R, 5S)-3-pinanemethyl]-2-quinoxaline formamide, N-(1-adamantyl)-2-quinoxaline carboxamide, N-(1-adamantyl)-6-quinoline carboxamide, N-(exo-2-norbomanyl) )-2-quinoxaline formamide, N-[(1R,2S,4S)-bornyl]-2-quinoxaline formamide, N-(3-noradamantyl)-2-quinoxaline Formamide, N-[(1R, 2R, 3R, 5S)-isopine camphenyl]-2-quinoxaline carboxamide, N-[(1S, 2S, 3S, 5R)-isopine camphenyl] -2-quinoxaline formamide, N-(5-chloro-[2.2.1.0]tricyclo-2,6-hept-3-yl)-2-quinoxaline formamide, N-([4.3.1.1 ]tricyclo-3,8-undecyl-3-yl)-2-quinoxaline carboxamide, N-[(1S,2R,5S)-cis-myrtle alkyl]-2-quinoxaline Phenylcarboxamide, N-[(1R,2R,4S)-isobornyl]-2-quinoxalinecarboxamide, N-[endo-(±)-2-norbornyl]-2-quinoxaline Phenylcarboxamide, N-[(R)-2-phenyl-1-propyl]-2-quinoxalinecarboxamide, N-[(S)-2-phenyl-1-propyl]-2- Quinoxaline carboxamide, N-[2-(2,3-indanyl)]-2-quinoxaline carboxamide, 1-adamantylmethyl 6-quinolyl ether, 1-adamantyl- 3-quinoline formate, N-(α,α-dimethylphenethyl)-2-quinoxaline carboxamide, N-(α,α-dimethyl-2-chlorophenethyl)- 2-quinoxaline formamide, N-(α, α-dimethyl-4-fluorophenethyl)-2-quinoxaline formamide, N-(β-methylphenethyl)-2-quinone Oxaline formamide, N-(3-methylcyclohexyl)-2-quinoxaline formamide, N-(2,3-dimethylcyclohexyl)-2-quinoxaline formamide, N-[( 1S, 2S, 3S, SR)-3-pinenemethyl]-2-quinoxaline formamide, N-(1-adamantylmethyl)-2-quinoxaline formamide, N-(4-form Cyclohexyl)-2-quinoxaline carboxamide, N-[(1S, 2S, 5S)-trans-myrtyl]-2-quinoxaline carboxamide and N-[(1R, 2R, 5R)-trans-myrtyl]-2-quinoxalinecarboxamide.

In a preferred embodiment, the compound and its pharmaceutically acceptable salts are selected from: N-(1-adamantyl)-3-quinoline carboxamide, N-(1-adamantyl)-2-quinoline Phenylcarboxamide, N-(2-adamantyl)-2-quinoxaline-carboxamide, N-[(1R, 2R, 3R, 5S)-3-pinanemethyl]-2-quinoxaline- Formamide, N-(1-adamantyl)-2-quinoxaline-formamide, N-(1-adamantyl)-6-quinoline formamide, N-(exo-2-norbornane Base)-2-quinoxaline-carboxamide, N-[(1R,2S,4S)-bornyl]-2-quinoxaline-carboxamide, N-(3-noradamantyl)-2- Quinoxaline-carboxamide, N-[(1R, 2R, 3R, 5S)-isopine camphenyl]-2-quinoxaline-carboxamide, N-[(1S, 2S, 3S, 5R)-iso Pine camphenyl]-2-quinoxaline-carboxamide, N-(5-chloro-[2.2.1.0]tricyclo-2,6-hept-3-yl)-2-quinoxaline-carboxamide, N-([4.3.1.1]tricyclo-3,8-undec-3-yl)-2-quinoxaline-carboxamide, N-[(1S,2R,5S)-cis-myrtle Alkyl]-2-quinoxaline-carboxamide, N-[(1R,2R,4S)-isobornyl]-2-quinoxaline-carboxamide, N-[inside-(±)-2-de Formyl]-2-quinoxaline-carboxamide, N-[(1S, 2S, 3S, 5R)-3-pinanemethyl]-2-quinoxalinecarboxamide, N-(1-adamant Alkylmethyl)-2-quinoxaline carboxamide, N-[(1S, 2S, 5S)-trans-myrtyl]-2-quinoxaline carboxamide and N-[(1R, 2R, 5R)-trans-myrtyl]-2-quinoxalinecarboxamide.

In another embodiment, the compound and its pharmaceutically acceptable salts are selected from: N-[6-(2-methylquinolyl)]-1-adamantanecarboxamide, N-(6-quinoline Base)-1-adamantanecarboxamide, N-(2-quinolyl)-1-adamantanecarboxamide and N-(3-quinolyl)-1-adamantanecarboxamide, N-(3-form Cyclohexyl)-2-quinoxaline carboxamide, N-(2,3-dimethylcyclohexyl)-2-quinoxaline carboxamide, N-[(1S,2S,3S,5R)-3- Pinanemethyl]-2-quinoxaline carboxamide, N-(1-adamantylmethyl)-2-quinoxaline carboxamide and N-(4-methylcyclohexyl)-2-quinoxaline carboxamide amides. N-[(R)-2-phenyl-1-propyl]-2-quinoxaline carboxamide, N-[(S)-2-phenyl-1-propyl]-2-quinoxaline carboxamide Amide, N-[2-(2,3-indanyl)]-2-quinoxaline formamide, N-(α,α-dimethylphenethyl)-2-quinoxaline formamide, N-(α,α-Dimethyl-2-chlorophenethyl)-2-quinoxaline carboxamide, N-(α,α-Dimethyl-4-fluorophenethyl)-2-quinoxaline phenoline carboxamide and N-(β-methylphenethyl)-2-quinoxaline carboxamide. 6-Quinoline-1-adamantyl methyl ether. 6-quinoline 1-adamantanecarboxylate, 6-quinolinemethyl-1-adamantyl ester, 2,2,3,3,4,4,5,5-octafluoro-1-pentyl-6-quinoline phenoline carboxylate, 1-adamantyl methyl 6-quinoline carboxylate, 1-adamantyl 2-quinoxaline carboxylate and 1-adamantyl 3-quinoline carboxylate.

In another embodiment, the compound and its pharmaceutically acceptable salts are selected from: 3-(1-adamantylmethoxy)-2-chloro-quinoxaline, 2-(1-adamantylmethoxy )-3-methylquinoxaline, 3-(1-adamantanemethoxy)-2-fluoroquinoxaline, 2-(1-adamantanemethoxy)-3-trifluoromethylquinoxaline , N-[2-(4-phenylthiazolyl)]-1-adamantanecarboxamide, N-[2-(5-methyl-4-phenylthiazolyl)]-1-adamantanecarboxamide, 1-(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-oxoquinoxaline-3-carboxamide. 4-chlorophenyl 3-coumarin formate, 2-(1-adamantylmethylsulfanyl)quinoxaline, 3-(1-adamantylmethoxy)-2-chloropiperazine, 1- (1-adamantyl)-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)ethanone, 1-(1-adamantyl)-2-(2-anisylsulfanyl) Ethanone, 3-(1-adamantylmethoxy)-1H-quinoxalin-2-one, 1-(1-adamantyl)-2-(3-anisylsulfanyl)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-ylmethylformamide, 1-(1-adamantyl)-2-(1-naphthylsulfane base) ethanone, 1-(1-adamantyl)-2-(8-quinolylsulfanyl)ethanone hydrochloride, 1-(1-adamantyl)-2-(4-trifluoro Methoxyphenoxy)ethanone, 2-(1-adamantanemethoxy)quinoxaline, N-(trans-4-methylcyclohexyl)-2-quinoxalinecarboxamide, N-( Cis-4-methylcyclohexyl)-2-quinoxalinecarboxamide, N-(trans-4-methylcyclohexyl)-2-quinolinecarboxamide, N-(trans-4-methyl Cyclohexyl)-3-quinolinecarboxamide and N-(trans-4-methylcyclohexyl)-6-quinolinecarboxamide. 2-(1-adamantylmethylsulfinyl)benzothiazole, N-(4-phenylbutyl)-2-quinoxaline carboxamide, 1-(1-adamantyl)-2-(4 , 6-dimethylpyrimidin-2-ylsulfanyl)ethanol, 1-(1-adamantyl)-2-(3-chloroquinoxalin-2-yl)ethanone, 2-(1-adamantane Methylsulfanyl)-3-methylquinoxaline, N-(1-adamantyl)-2-anisamide, N-(1-adamantylmethyl)-2-anisamide, 1-(1 -Adamantyl)-2-(4-chlorophenylsulfanyl)ethanone, 2-(1-adamantylmethylsulfonyl)-3-methylquinoxaline, 1-(1-adamantyl )-2-(4-fluorophenylsulfanyl)ethanone, 1-(1-adamantyl)-2-(3-fluorophenylsulfanyl)ethanone, 1-(1-adamantyl )-2-(2-methoxyphenoxy)ethanone, 1-(4-anisylsulfanyl)butan-2-one, 1-(1-adamantyl)-2-(4-fennel Amino)ethanone hydrochloride, 3,3-dimethyl-1-(4-anisylsulfanyl)butan-2-one, 1-(4-diphenyl)-2-(4-anisyl Sulfanyl)ethanone, 1-(1-adamantyl)-2-(2-trifluoromethoxyphenylsulfanyl)ethanone, 1-(1-adamantyl)-2-(3 -Methylquinoxalin-2-ylsulfanyl)ethanone, 1-(1-adamantane)-2-(2-anisylamino)ethanone hydrochloride, 1-(1-adamantyl)- 2-(4-trifluoromethoxyphenylamino)ethanone hydrochloride, 1-(1-adamantyl)-2-(N-methyl-4-anisidineamino)ethanone hydrochloride, N -(1-adamantyl)-7-trifluoromethylquinoline-3-carboxamide, N-(1-adamantyl)-2-(1-piperazinyl)quinoxaline-3-carboxamide , N-(1-adamantyl)-2-(2-aminoethylamino)quinoxaline-3-carboxamide, methyl N-(3-quinolyl)-3-carboxyadamantane-1-methyl Amide, 1-(1-adamantyl)-2-[(R)-1-(1-naphthyl)eth-1-ylamino]ethanone, N-(1-adamantyl)-2-methanone Oxyquinoxaline-3-carboxamide, ethyl N-(1-adamantyl)-2-(3-propionylamino)quinoxaline-3-carboxamide, N-(4-chlorophenyl) -2,3-Dimethylquinoxaline-6-carboxamide, N-(1-adamantyl)-6,7-dimethylquinoxaline-2-carboxamide, N-((S)- 1-tetrahydronaphthyl)-2-quinoxaline carboxamide, N-(4-chlorophenethyl)-2-quinoxaline carboxamide, N-(6-quinolyl)-2-quinoxaline Formamide, N-(1-tetrahydronaphthylmethyl)-2-quinoxalinecarboxamide, N-(1-(2,3-indanyl)methyl)-2-quinoxalinecarboxamide, N-(4,4-Dimethylcyclohexyl)-2-quinoxalinecarboxamide.

One embodiment of the present invention relates to a compound represented by formula V or IX or its pharmaceutical

Acceptable salts on:

Wherein R includes a group selected from the group consisting of adamantyl, 2-adamantyl, (1S, 2S, 3S, 5R)-isopine camphenyl, tricyclo[4.3.1.1(3.8)]undecane- 3-yl, (1S, 2R, 5S)-cis-myrtyl, (1R, 2R, 4S)-isobornyl, (1R, 2R, 3R, 5S)-isopine camphenyl, ( 1S, 2S, 5S)-trans-myrtyl, (1R, 2R, 5R)-trans-myrtyl, (1R, 2S, 4S)-bornyl, 1-adamantylmethyl , 3-noradamantyl, (1S,2S,3S,5R)-3-pinenemethyl, cyclooctyl, α,α-dimethylphenethyl, (S)-2-phenyl- 1-propyl, cycloheptyl, 4-methyl-2-hexyl, 2,2,3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl- 2-methylpropyl, 3,5-dimethyladamantyl, trans-2-phenylcyclopropyl, 2-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 2- (o-methoxyphenyl) ethyl, 2-(1,2,3,4-tetrahydronaphthyl), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2-( m-fluorophenyl) ethyl, 2-(p-fluorophenyl) ethyl, 2-(3-hydroxy-3-phenyl) propyl, (S)-2-hydroxy-2-phenylethyl, ( R)-2-Hydroxy-2-phenylethyl, 2-(3-m-chlorophenyl-2-methyl)propyl, 2-(3-p-chlorophenyl-2-methyl)propyl, 4-tert-butylcyclohexyl, (S)-1-(cyclohexyl)ethyl, 2-(3-(3,4-dimethylphenyl)-2-methyl)propyl, 3,3-dimethyl butylbutyl, 2-(5-methyl)hexyl, 1-myrtyl, 2-bornyl, 3-pinanemethyl, 2,2,3,3,4,4,5,5- Octafluoropentyl, p-fluoro-α,α-dimethylphenethyl, 2-naphthyl, 2-bornyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3 , 4-dimethylcyclohexyl, 5-chloro-tricyclo[2.2.1]heptyl, o-α,α-dimethylphenethyl, 2-(2,3-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-fluorophenyl)ethyl, 1-(cyclohexyl)ethyl and cyclohexyl,

wherein Y is O, S, NH or _CH2 , and,

Wherein, X ¹ is N or CH.

Another embodiment of the present invention provides a pharmaceutical composition comprising the above-mentioned compound together with a pharmaceutically acceptable diluent or excipient.

Another embodiment of the present invention provides a process for the preparation of the above-mentioned compounds, which comprises reacting a compound containing an activated carboxylic acid group with a compound containing an amino, hydroxyl or thiol group.

Another embodiment of the present invention provides a method for inhibiting the activation of mGluRI-like receptors, which comprises treating cells containing the mGluRI-like receptors with an effective amount of the above compound.

Another embodiment of the present invention provides a method for inhibiting nerve damage caused by excitatory activation of mGluRI receptors, which comprises treating neurons with an effective amount of the above compound.

Another embodiment of the present invention provides a method of treating a disease associated with glutamate-induced nerve damage, which comprises administering an effective amount of the above-mentioned composition to a patient suffering from the disease.

Other objects, features and advantages of the present invention will be apparent from the following detailed description. It should be understood, however, that this detailed description and the specific examples, which indicate preferred embodiments of the invention, are illustrative only, since changes can be made within the detailed description without departing from the spirit and scope of the invention. and modifications will be apparent to those skilled in the art.

Introduction to Charts

Figure 1 shows exemplary compounds of the present invention.

Detailed description

The compounds provided by the present invention are potent and selective antagonists of class I metabotropic glutamate receptors. The designed compound of the present invention can be represented by general formula I:

R-[-linking group-]-Ar

Wherein R is straight or branched alkyl, aralkyl or optionally substituted alicyclic group, and Ar is optionally substituted aromatic, heteroaromatic, aralkyl or heteroaralkyl. [Linking group] is a group that can not only be covalently bonded to Ar and R, but also easily bind to the receptor through Ar and R adopting the correct stereo orientation.

Structure of the Ar part

Ar moieties generally may contain up to 10 carbon atoms, although those skilled in the art consider Ar groups having more than 10 carbon atoms to be within the scope of the invention. Ar can be a monocyclic or fused bicyclic aryl, alkaryl, heteroaryl or heteroaralkyl group. The ring system encompassed by Ar may contain up to 4 heteroatoms independently selected from N, S or O. When Ar is a heteroaromatic ring or heteroaromatic ring system, it preferably contains one or two heteroatoms. At least one of the heteroatoms is preferably N.

Monocyclic Ar groups include, but are not limited to: phenyl, thiazolyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidine group and pyridazinyl group. Fused bicyclic Ar groups include, but are not limited to: benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazolyl, purinyl, quinazinyl, isoquinolyl, quinolinyl, Phthalazinyl, 1,5-diazinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl, indolizinyl, isoindolyl, benzothienyl, benzofuran base, isobenzofuryl and benzopyranyl moieties. Ar is preferably quinoxalinyl, quinolinyl or pyridyl.

Other Ar include 3,4-methylenedioxy and 3,4-dioxane ring systems. The Ar moiety may be optionally substituted independently with up to two C ₁ -C ₃ alkyl groups or up to two halogen atoms selected from F, Cl, Br and I.

R part structure

Typically R may contain 4-11 carbon atoms, although those skilled in the art recognize that the R moiety may have 12, 13, 14, 15 or 16 carbon atoms. While R may contain 4, 5 or 6 carbon atoms, preferably R contains at least 7 carbon atoms. R is preferably optionally substituted alkyl, cycloalkyl, cycloalkylmethyl or optionally substituted phenylalkyl. Generally, some or all of the hydrogen atoms on two or less methine, methylene or methyl groups of R can be independently selected from F, Cl, OH, OMe, =O and -COOH Substituents replace. However, two or more hydrogen atoms may be substituted by F, and R may be perfluoro-substituted.

Example R moieties include, but are not limited to: adamantyl, 2-adamantyl, (1S,2S,3S,5R)-isopine camphenyl, tricyclo[4.3.1.1(3.8)]undecane-3 -yl, (1S, 2R, 5S)-cis-myrtyl, (1R, 2R, 4S)-isobornyl, (1R, 2R, 3R, 5S)-isopine camphenyl, (1S , 2S, 5S)-trans-myrtleyl, (1R, 2R, 5R)-trans-myrtleyl, (1R, 2S, 4S)-bornyl, 1-adamantylmethyl, 3-Noradamantyl (1S, 2S, 3S, 5R)-3-pinanemethyl, cyclooctyl, dimethylphenethyl, (S)-2-phenyl-1-propyl, cyclo Heptyl and 4-methyl-2-hexyl. Each of these example R moieties can be substituted in the manner noted above.

Other preferred R includes 2,2,3,3,4,4,4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethyl Adantyl, trans-2-phenylcyclopropyl, 2-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 2-(o-methoxyphenyl)ethyl, 2- (1,2,3,4-tetrahydronaphthyl), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2-(m-fluorophenyl)ethyl, 2-(p-fluoro Phenyl)ethyl, 2-(3-hydroxy-3-phenyl)propyl, (S)-2-hydroxy-2-phenylethyl, (R)-2-hydroxy-2-phenylethyl , 2-(3-m-chlorophenyl-2-methyl)propyl, 2-(3-p-chlorophenyl-2-methyl)propyl, 4-tert-butylcyclohexyl, (S)-1-( Cyclohexyl) ethyl, 2-(3-(3,4-dimethylphenyl)-2-methyl)propyl, 3,3-dimethylbutyl, 2-(5-methyl)hexyl , 1-myrtyl, 2-bornyl, 3-pinanemethyl, 2,2,3,3,4,4,5,5-octafluoropentyl, p-fluoro-2,2-di Methylphenethyl, 2-naphthyl, 2-bomanyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4-dimethylcyclohexyl, 5-chloro-tricyclic [2.2.1] Heptyl, o-.-dimethylphenethyl, 2-(2,3-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-fluorophenyl ) ethyl, 1-(cyclohexyl) ethyl, cyclohexyl, butan-2-acyl (butan-2-only), diphenylene, 3-carboxyadamantyl, 1-tetrahydronaphthyl, 1- (2,3-indanyl), 4-methylcyclohexyl and 4,4-dimethylcyclohexyl moieties. Each of these example R moieties can be substituted as noted above. When these compounds exist in an additional isomeric configuration, eg, cis- or trans-4-methylcyclohexyl, the R moiety can have any possible configuration. Similarly, if a compound exists as an enantiomer, R may be the enantiomer or the racemate.

Structure of the [Linking Group] part

[Linking group] generally has the structure -(CH ₂ ) _n -, where n is 2-6. Up to 4 CH ₂ may be independently substituted by a group selected from C ₁ -C ₃ alkyl, CHOH, CO, O, S, SO, SO ₂ , N, NH and NO, with the proviso that: except when the two When the atoms are both N (forming a -N=N-bond) or both NH (-NH-NH-bond), two heteroatoms cannot be adjacent to each other. Any two adjacent _CH2 groups may also be substituted by alkenyl or alkynyl groups.

In preferred embodiments, the [linking group] includes amide, ester, thioester, ketomethylene, ether, alkyl ether, ethylene, vinyl, ethynyl, hydroxyl Alkyl, alkyl sulfone or alkyl alkyl alum. [Linking group] is preferably -O-(CH ₂ ) _m -, -CO-Y-(CH ₂ ) _m - or -S(O) _n -(CH ₂ ) _m -, wherein Y is CH ₂ , NH , O or S, m is 1-4, n is 0-2. [Linking group] can have either of the two possible directors of Ar and R. Thus, for example, the invention includes compounds having the configurations RO-( _CH2 ) _m -Ar and R-( _CH2 ) _m -OR.

Design and synthesis of MGluR class I antagonists

In one embodiment, the compounds of the invention are esters and amides of monocyclic or fused bicyclic aromatic and heteroaromatic carboxylic acids, phenols and amines. In a preferred embodiment, the compound may be represented by formula II or III:

In formula II or III, Y can be O, S, NH or CH ₂ ; X ¹ , X ² , X ³ and X ⁴ can independently be N or CH. Preferably one or two of X ¹ , X ² , X ³ and X ⁴ are N, and the rest are CH. Preferred compounds contemplated by the present invention have formula IV or V, wherein R, Y and ^X1 are as defined above.

In another preferred embodiment of the invention, the compound has formula VI or VII:

Wherein R and Y are as defined above. In a first embodiment of the compound of formula VI, Y is N, R is unsubstituted or monosubstituted 1,1-dimethylphenethylamine or a 1,1-dimethylbenzylamine moiety, wherein the substituent Preference is given to o-, m- or p-chloro or p-methoxy. In a second embodiment of the compounds of formula VI, Y is N and R is ortho-, meta- or p-methoxy substituted phenethylamine. The compounds of the first and second embodiments appear to exhibit selectivity for mGluR receptors. In a third embodiment of the compounds of formula VI, Y is N and R is ortho-, meta- or para-fluoro substituted phenethylamine. The compounds of the third embodiment show no distinction between mGluR ₁ and mGluR ₅ receptor subtypes.

In another preferred embodiment of the invention, the compound has formula VIII or IX:

wherein X ^1-4 and R are as defined above. In a first embodiment of the compound of formula VIII, X ^{and X} are N, X ^{and X} are H, R is 1-adamantyl, and carbon atoms adjacent to both the linking group and X ^are Substituents are present. The substituent is preferably halogen, such as chlorine, or alkyl, such as methyl. In a second embodiment of the compounds of formula IX, R is 1-adamantyl. The compounds of the first and second embodiments appear to exhibit selectivity for the mGluR ₁ receptor.

In another embodiment, the compound may have formula X or XI, wherein Z is a pharmaceutically acceptable substituent. Those skilled in the art will appreciate that such pharmaceutically acceptable Z groups are those that do not deleteriously reduce the receptor binding activity of the compound. Suitable Z groups include, but are not limited to, halogen, lower alkyl, oxygen or amine, and pharmaceutically acceptable derivatives thereof, including ethers, esters and amides. Z preferably contains 0-4 carbon atoms.

In each of the compounds described above, "alkyl" refers to straight chain and branched chain alkyl groups. In other embodiments, R is adamantyl, the linking group is -CO-CH ₂ -S-, Ar is meta or ortho alkoxyphenyl, 3,4-methylenedioxy or 3 , 4-dioxane.

In conclusion, selective antagonists of the mGluR ₁ receptor can be obtained with compounds of the formula R-CO-N-Ar ₁ , where Ar ₁ is an aromatic or heteroaromatic group such as quinolinyl, quinoxalinyl, thiazolidine phenyl, benzimidazolyl or pyridyl.

Those skilled in the art will appreciate that the compounds of the present invention include salts of the compounds described above. These salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated amine salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate , trifluoroacetate, malonate, succinate, citrate, mandelate, benzoate, cinnamate, mesylate, or salts of similar acids, including those associated with the Journal of Pharmaceutical Sciences, The pharmaceutically acceptable salts listed in 66:2 (1977) form the salts of the relevant acids, which are incorporated herein by reference.

Table 1 below lists examples of compounds of the present invention.

Preparation of mGluRI antagonists

Those skilled in the art know that the mGluRI antagonists of the present invention can be prepared by methods well known in the art using well-known organic chemistry techniques. Appropriate reactions are described in standard organic chemistry textbooks. See, eg, March, Advanced Organic Chemistry , 2nd ed., McGraw Hill (1977).

For example, the compound is generally prepared by forming the [linking group] between two precursor compounds containing the appropriate Ar and R moieties. When the linking group contains an amide bond, the amide can be formed using well-known techniques, such as by reaction between an amine and an acid chloride, or by reacting an amide with a coupling agent such as carbonyldiimidazole or carbodiimide (such as 1,3-diimide prepared by reaction in the presence of cyclohexylcarbodiimide (DCC). Ester linkages or thioester linkages can be formed in a similar manner.

When the [linking group] contains an ether linkage, the ether functionality can also be prepared using standard techniques. For example the Mitsunobu reaction is used to form ethers in which the primary alcohol function is replaced with another hydroxyl group by activation with PPh ₃ and diethyl azodicarboxylate (DEAD). Thioether linkages can be prepared by displacement of a leaving group such as a halogen with the thiolate anion resulting from deprotonation of the thiol group and base.

When the [linking group] contains a ketomethylene group, it can be formed by alkylation of a ketoenol ester. Prepared, for example, by deprotonation of methyl ketones with a strong base such as lithium diisopropylamide (LDA), followed by reaction with an alkyl halide. Alternatively, the ketomethylene functionality can be prepared by adding an organometallic compound, such as a Grignard reagent, to an aldehyde, followed by oxidation of the resulting hydroxyl to form a ketone. Suitable reagents for the oxidation of alcohols to ketones are well known in the art.

[Linker] moieties containing other heteroatoms may also be prepared by methods well known in the art. N,N'-disubstituted hydrazine compounds can be prepared by reductive amination of hydrazones formed by reacting monosubstituted hydrazones with aldehydes. N,N'-disubstituted azo compounds can be formed, for example, by oxidation of the corresponding hydrazines.

In most cases, the precursor Ar and R moieties are readily available or can be prepared using simple techniques of organic chemistry. Many compounds are available commercially, such as from Aldrich Chemical Company, Milwaukee, WI. When these compounds are not commercially available, they can be prepared from existing precursors by simple transformations well known in the art.

For example, carboxylic acids can be converted to the corresponding acid chlorides by reaction with, for example, thionyl chloride or oxalyl chloride. An example of this reaction is provided in Example 3 below. Compounds containing hydroxyl functionality can be converted to the corresponding amines by (i) converting the hydroxyl group into a leaving group such as a sulfonate (e.g. triflate, mesylate or tosylate ester) or halide, (ii) displacement by an azide ion, (iii) reduction of the resulting azide by, for example, hydrogenation over a platinum oxide catalyst. An illustration of this transformation is provided in Example 12 below.

Determination of antagonistic activity of compounds against mGluR class I

The pharmacological properties of the compounds of the invention can be analyzed using standard functional activity assays. Examples of glutamate receptor assays are well known in the art, see, eg, Aramori et al., Neuron 8:757 (1992); Tanabe et al., Neuron 8:169 (1992). The methodologies described in these publications are incorporated herein by reference.

In general, compounds of the invention are studied using assays that measure inhibition of intracellular calcium mobilization in cells expressing recombinant receptors to which the compounds of the invention bind. Suitable acceptor structures are well known in the art and are also described, for example, in WO 97/05252, the entire contents of which are incorporated herein by reference.

Therefore, HEK-293 cells (human embryonic kidney cells, American Type Culture Collection. Rockville, MD, Accession No. CRL 1573) can be stably transfected with DNA constructs expressing recombinant receptors. The stably transfected cells were cultured in high glucose DMEM (Gibco 092) containing 0.8 mM glutamate, 10% FBS and 200 [mu]M hygromycin B.

The protocol for measuring intracellular calcium mobilization as a function of extracellular calcium using the calcium sensitive dye Fura has been described above. Briefly, HEK-293 cells (ie, cells stably transfected with a DNA construct encoding a recombinant receptor) were loaded with Fura dye. Cells were then washed, resuspended, and kept at 37°C. These cells were diluted into cuvettes for recording fluorescent signals. Fluorescence was measured by standard methods at 37°C and the concentration of intracellular Ca2 ⁺ was calculated using the dissociation constant (Kd) at 224 nM and applying the following equation:

[Ca ²⁺ ] _i = (FF _min /F _min ) x Kd where F is fluorescence at any desired time point and F _min is a measure of sequestration of all available calcium, thus no Fura 2 binds calcium , while F _max is the measured value at all Fura 2s with full calcium saturation.

Example 15 below provides a detailed protocol for testing compounds of the invention.

Preparation of pharmaceutical compositions containing mGluR antagonists and useful for treating neurological diseases

The compounds of the invention are useful in the treatment of neurological disorders or diseases. Although these compounds are generally used to treat human patients, they may also be used as veterinary medicines to treat similar or identical diseases.

For therapeutic and/or diagnostic use, the compounds of the invention may be formulated for various modes of administration, including systemic and localized or localized administration. Techniques and formulations are generally found in Remington Pharmaceutical Sciences : Drug Receptors and Receptor Theory, 18th Ed., Mack Publishing Co. (1990).

The compounds of the present invention are effective over a wide dosage range. For example, in the treatment of an adult, a daily dose of about 0.01-1000 mg, preferably 0.5-100 mg may be used. The most preferred dosage is about 2-70 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the patient being treated, the weight of the patient being treated, and the preference and experience of the attending physician.

Those of ordinary skill in the art are generally well aware of pharmaceutically acceptable salts, which may include the following examples, but are not limited to: acetate, besylate, besylate, benzoate, bicarbonate salt, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edylate, edisylate, estolate, esylate, fumarate, gluceptate, dextrose salt, glutamate, glycolyl asanate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactic acid Salt, lactobionate, malate, maleate, mandelate, methanesulfonate, mucate, napsylate, nitrate, embonate, pantothenate, phosphate/hydrogenphosphate , polygalacturonate, salicylate, stearate, sub-acetate, succinate, sulfate, tannin, tartrate, or teoclate. Other pharmaceutically acceptable salts can be found, eg, in Remington Pharmaceutical Sciences : (18th Edition) Mack Publishing Co., Easton, PA (1990).

Preferred pharmaceutically acceptable salts include: such as acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate , mesylate, napsylate, embonate, phosphate, salicylate, succinate, sulfate or tartrate.

Depending on the particular disease being treated, these drugs are formulated as liquid or solid dosage forms and administered systemically or topically. For example, the drug is delivered in a timed or sustained release form well known to those skilled in the art. For formulation techniques and modes of administration, see Remington Pharmaceutical Sciences : (18th Edition) Mack Publishing Co., Easton, PA (1990). Appropriate routes include oral, buccal, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or enteral administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct cardiac Intravenous (direct intraventricular), intravenous, intraperitoneal, intranasal, or intraocular, to name a few.

For injection, the drug of the present invention can be prepared in aqueous solution, preferably in a physiologically compatible buffer, such as Hank's solution, Ringer's solution or physiological saline. For transmucosal administration, suitable penetrants that penetrate the barrier should be used in the dosage form. These penetrants are generally well known in the art.

It is also within the scope of this invention to formulate the compounds disclosed for the practice of this invention in suitable dosage forms for systemic administration using a pharmaceutically acceptable carrier. With proper choice of carrier and appropriate method of preparation, the compositions of the present invention (especially those formulated in solution) can be administered parenterally, such as intravenously. The compounds can be conveniently formulated into dosage forms suitable for oral administration using pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pellets, capsules, liquids, gels, syrups, slurries, suspensions and the like for oral absorption by the patient to be treated.

Pharmaceutical compositions suitable for use in the present invention include those containing the active ingredient in an effective amount to achieve its intended purpose. Determining such an effective amount is well within the ability of those skilled in the art, particularly with the aid of the detailed description provided herein.

These pharmaceutical compositions may contain, in addition to the active ingredients, suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Formulations made for oral administration may be in the form of tablets, lozenges, capsules or solutions.

Formulations for oral administration can be obtained by mixing the active compound with a solid excipient, optionally grinding a resulting mixture, and then, after adding suitable auxiliaries, forming a mixture of granules, if desired, into tablets or lozenges. agent. Suitable excipients are, inter alia, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose products, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, formazan cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and/or polyvinylpyrrolidone (PVP; povidone). If desired, disintegrants, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, may be added.

Tablets may be suitably coated. For this purpose, concentrated sugar solutions may be used, optionally including gum arabic, talc, polyvinylpyrrolidone, carbopol gum, polyethylene glycol (PEG) and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be incorporated into the tablets or lozenges for proof or to illustrate different compositions of the active compound doses.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft capsules, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). Additionally, stabilizers may be added.

The invention thus generally described may be better understood by reference to the following examples, which are provided for illustration only and do not limit the scope of the invention.

Example

General Experimental Method

Capillary gas chromatography and mass spectrometry data were measured by a Hewlett-Packard (HP) 5890 II gas chromatograph coupled to a HP 5971 Series Mass Selector Detector (mass selective detector) [Ultra-2 super performance capillary column (cross-linked 5% PhMe polysiloxane); column length, 25m; column inner diameter, 0.20mm; helium flow rate, 60mL/min; , and then held at 325°C for 6 minutes]. Thin layer chromatography was performed on Analtech Uniplate 250 μm silica gel HF TLC plates. Compounds on TLC plates were assayed with UV light sometimes in combination with ninhydrin and Dragendorff spray developer (Sigma Chemical Co.). Reagents used were purchased from Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (SaintLouis, MO), Fluka Chemical Corp. (Milwaukee, WI), Fisher Scientific (Pittsburgh, PA), TCI America (Portland, OR) or Lancaster Synthesis (Windham, NH).

Embodiment 1: Preparation of N-[6-(2-methylquinolyl)]-1-adamantanecarboxamide (40)2-methyl-6-aminoquinoline

2-Methyl-6-nitroquinoline (1.00 g, 5.31 mmol) and Pearlman's catalyst [palladium dihydroxide (approximately 20% palladium) on activated carbon; 0.10 g ] in ethyl acetate (40ml) was stirred for 1.5 hours. The reaction mixture was filtered and the filtrate was rotovapped. This gave 0.81 g (96%) of 2-methyl-6-aminoquinoline as a yellow solid.

N-[6-(2-Methylquinolinyl)]-1-adamantanecarboxamide (40)

1-Adamantanecarbonyl chloride (1.02 g, 5.13 mmol) in pyridine (2 mL) was added to a solution of 2-methyl-6-aminoquinoline (0.81 g, 5.1 mmol) in pyridine (8 mL). The reaction was stirred for 17 hours. Water (100 mL) was added to the stirred reaction mixture causing precipitation of the product. The precipitate was filtered, washed with water (3 x 25 mL) and diethyl ether (3 x 25 mL). 1.07 g (65%) of (40) were obtained as a cream powder:

Retention time = 13.49min.; m/z (relative intensity) 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-adamantanecarboxamide was prepared

N-(6-quinolyl)-1-adamantanecarboxamide (18)

Preparation from 1-adamantanecarbonyl chloride (1.37 g, 6.90 mmol), 6-aminoquinoline (0.59 g, 4.1 mmol), pyridine (20 mL) and water (200 mL) afforded 1.25 g (100%) of (18) : retention time=13.24min.; m/z (relative intensity) 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-adamantanecarboxamide hydrochloride (81)

Prepared from 1-adamantanecarbonyl chloride (0.75 g, 3.8 mmol), 2-aminoquinoline (0.60 g, 4.2 mmol), pyridine (10 mL) and water (100 mL). Hydrochloride formation with etherified hydrogen chloride afforded 0.19 g (15%) of (81): retention time = 12.24 min.; m/z (relative intensity) 306 (M+, 80), 305 (23), 277 ( 8), 263(8), 221(10), 172(9), 171(72), 145(16), 144(61), 143(13), 136(11), 135(100), 128( 33), 117(17), 116(24), 107(18), 105(8), 101(10), 93(40), 91(29), 89(13), 81(14), 79( 55), 77(35), 67(18), 65(10), 55(12), 53(10), 41(20).

N-(3-quinolyl)-1-adamantanecarboxamide (86)

Preparation from 1-adamantanecarbonyl chloride (0.75 g, 3.8 mmol), 3-aminoquinoline (0.60 g, 4.2 mmol), pyridine (10 mL) and water (100 mL) afforded 0.33 g (29%) of (86) : retention time=13.01min.; m/z (relative intensity) 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)

Hydroxylamine (3.8 g, 55 mmol), Ethanol (50 mL), pyridine (4.44 mL, 55 mmol) and 4-methylcyclohexanone (6.1 mL, 50 mmol) were stirred for 16 hours, then heated to reflux for 15 minutes. Further ethanol was removed in vacuo and the residual oil was dissolved in ethyl acetate (100 mL). The organic layer was washed with water (2X), brine, dried over anhydrous _MgSO4 , filtered and concentrated to give a clear oil (the oxime product) which crystallized on standing.

Without further purification 1.9 g (15 mmol) of this intermediate oxime in absolute ethanol (40 mL) was heated to reflux and treated (in small portions) with sodium metal (4 g). The reaction solution was heated to reflux until the sodium was consumed. The reaction was cooled and treated with water (10 mL). The reaction was transferred to a flask containing ice and cone. HCl (6 mL). Ethanol was removed in vacuo and the residual aqueous phase was washed with ether (3X, to remove unreduced oxime). The remaining aqueous phase was concentrated to give 1.8 g of a white crystalline solid (trans-4-methylcyclohexylamine hydrochloride product).

Without further purification, 750 mg (5 mmol) of trans-4-methylcyclohexylamine hydrochloride in dichloromethane (10 mL) was treated with pyridine (1.62 mL, 20 mmol), followed by the addition of 2-quinoxaline acid chloride ( 963 mg, 55 mmol). The reaction was stirred at room temperature for 16 hours, then diluted with chloroform (25 mL). The organic layer was washed with 10% HCl (3X), 1N NaOH (3X), brine, dried over anhydrous _MgSO4 , filtered, and concentrated to a solid. The crude reaction mass was chromatographed (MPLC) on silica gel (7 x 4 cm id, BIOTAGE, KP-SIL, 60 Angstroms) with ethyl acetate-hexane (1:4) to give 470 mg of the desired product, N-( trans-4-methylcyclohexyl)-2-quinoxalinecarboxamide. Thin layer chromatography (TLC, silica gel) with ethyl acetate-hexane (1:4) showed a single UV active component at R _f 0.19. GC/EI-MS obtained m/z (relative intensity) 269(M ⁺ , 39), 212(8), 198(6), 174(15), 157(21), 129(100), 112(43) and 102 (46).

Embodiment 2: Preparation of 6-quinolyl 1-adamantanecarboxylate (41)

1-Adamantanecarbonyl chloride (1.37 g, 6.90 mmol) in pyridine (5 mL) was added to a solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol) in pyridine (15 mL). The reaction was stirred for 16 hours. Water (200 mL) was added to the stirred reaction mixture causing precipitation of the product. The precipitate was filtered, washed with water (3 x 50 mL), and dried under high vacuum. 1.56 g (73.7%) of (41) were obtained as a light brown powder:

Retention time = 11.41min.; m/z (relative intensity) 307(M+, 2), 136(11), 135(100), 116(11), 107(7), 93(14), 92(2) , 91(8), 89(7), 79(16), 77(8).

Embodiment 3: Preparation of 1-adamantyl 6-quinoline carboxylic acid ester (61)

6-Quinolinecarbonyl chloride hydrochloride

In thionyl chloride, 6-quinolinecarboxylic acid was refluxed for 30 minutes. Then by rotary evaporation (90° C.), excess thionyl chloride was removed to obtain 6-quinolineformyl chloride hydrochloride.

1-adamantyl 6-quinolinecarboxylate (61)

6-Quinolineformyl chloride hydrochloride (0.76 g, 3.3 mmol) in pyridine (2 mL) was added to a solution of 1-adamantanol (0.60 g, 3.9 mmol) in pyridine (8 mL). The reaction was stirred at 70°C for 16 hours. Water (100 mL) was added to the stirred reaction mixture causing precipitation of the product. The precipitate was filtered and washed with water (3 x 50 mL). The filter cake was dissolved in ethanol (20 mL), then water was added to cloud point (16 mL). The solution was left to crystallize for 15 hours. Filtration and high vacuum drying for 7 hours gave 0.32 g (26%) of (61) as light brown needle crystals:

Retention time=11.48min.; m/z (relative intensity) 307(M+, 99), 306(92), 262(15), 174(12), 173(13), 157(10), 156(88) , 135(81), 134(33), 129(13), 128(100), 127(10), 119(11), 107(18), 102(16), 101(37), 93(51) , 92(76), 91(35), 81(14), 79(55), 78(15), 77(49), 75(17), 67(24), 55(18), 53(13) , 51(13), 41(31).

In a similar manner, the following 6-quinoline and 2-quinoxaline alkyl esters were prepared:

2,2,3,3,4,4,5,5-Octafluoro-1-pentyl-6-quinoline-carboxylate hydrochloride (68)

With 6-quinolineformyl chloride hydrochloride (0.75g, 3.3mmol), 2,2,3,3,4,4,5,5-octafluoro-1-pentanol (0.60mL, 4.3mmol), pyridine (10 mL) and water (100 mL). Hydrochloride formation with etherified hydrogen chloride afforded 0.88 g (69%) of (68): retention time = 7.11 min.; m/z (relative intensity) 387 (M+, 26), 156 (100), 129 ( 6), 128(48), 102(6), 101(16), 77(6), 76(2), 75(8), 50(14).

1-Adamantyl methyl 6-quinolinecarboxylate (73)

Prepared from 6-quinolinecarbonyl chloride hydrochloride (0.80 g, 3.5 mmol), 1-adamantanemethanol (0.60 mL, 3.6 mmol), pyridine (10 mL) and water (100 mL). 0.75 g (65%) of (73) was obtained:

Retention time=11.90min.; m/z (relative intensity) 321(M+, 35), 320(12), 263(15), 156(30), 148(23), 136(11), 135(100) , 135(100), 129(9), 128(52), 107(15), 106(7), 105(9), 102(7), 101(16), 93(34), 92(20) , 91(20), 81(11), 80(7), 79(40), 78(6), 77(24), 75(7), 67(14), 55(9), 53(6) , 51(6), 41(14).

1-adamantyl 2-quinoxalinecarboxylate (92)

Prepared from 2-quinoxaloyl chloride hydrochloride (0.84 g, 4.4 mmol), 1-adamantanemethanol (0.60 mL, 3.9 mmol), pyridine (10 mL) and water (100 mL). 0.20 g (16%) of (92) was obtained:

Retention time = 11.21 min.; m/z (relative intensity) 308(M+, 26), 264(6), 136(11), 136(11), 135(100), 134(5), 130(11) , 129(25), 107(12), 102(19), 93(24), 92(9), 91(11), 81(7), 79(26), 77(12), 76(6) , 75(7), 67(10), 55(7), 51(6), 41(11).

Example 4: N-(1-adamantyl)-3-quinoline carboxamide (72)

Add 1,1'-carbonyldiimidazole (161 mg, 1.00 mmol) in N, N-dimethylformamide (1 mL) to 3-quinolinecarboxylic acid (173 mg, 1.00 mmol) in N, N-dimethylformamide in methyl formamide (1 mL) suspension. The resulting reaction solution was stirred for 2.5 hours. A solution of 1-adamantanamine (151 mg, 1.00 mmol) in N,N-dimethylformamide (0.5 mL) 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 through silica gel, and rotovapped. Obtained 73 mg (24%) of (72) as a crystalline solid: retention time = 11.02 min.; m/z (relative intensity) 306 (M+, 78), 305 (42), 250 (19), 249 (100) , 213(7), 173(5), 157(10), 156(89), 129(12), 128(92), 102(5), 101(36), 94(6), 93(10) , 92(12), 91(14), 79(10), 77(14), 77(14), 75(10), 67(7), 41(11).

In a similar manner, the following N-alkyl-2-quinoline- and 2-quinoxaline carboxamides were prepared:

N-(1-adamantyl)-2-quinolinecarboxamide (74)

Prepared from 1,1'-carbonyldiimidazole (160 mg, 0.987 mmol), 2-quinolinecarboxylic acid (173 mg, 1.00 mmol) and N,N-dimethylformamide (2.5 mL) to give 77 mg (25%) of (74): retention time=10.53min.; m/z (relative intensity) 306(M+, 91), 305(26), 277(9), 263(9), 221(11), 172(9) , 171(73), 145(15), 144(60), 143(15), 136(11), 135(100), 128(36), 117(19), 116(27), 107(20) , 105(8), 101(10), 93(42), 91(30), 89(14), 81(13), 79(55), 77(37), 67(18), 65(11) , 55(12), 53(10), 41(18).

N-(2-adamantyl)-2-quinoxaline carboxamide (144)

Prepared from 1,1'-carbonyldiimidazole (161 mg, 1.00 mmol), 2-quinoxalinecarboxylic acid (174 mg, 1.00 mmol), 2-adamantanamine (136 mg, 0.90 mmol) and dichloromethane (3.5 mL) , yielding 98 mg (35%) of (144):

Retention time = 11.79min.; m/z (relative intensity) 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-pinenemethyl]-2-quinoxaline carboxamide (151)

With 1,1'-carbonyldiimidazole (161mg, 1.00mmol), 2-quinoxalinecarboxylic acid (174mg, 1.00mmol), (-)-3-pinanemethylamine (150mg, 0.90mmol) and dichloromethane (3.5 mL) was prepared to give 50 mg (17%) of (151):

Retention time = 11.46min.; m/z (relative intensity) 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: N-(1-adamantyl)-2-quinoxaline carboxamide (91)

2-Quinoxaline acid chloride (0.84 g, 4.4 mmol) was added to a solution of 1-adamantanamine (0.60 g, 4.0 mmol) in pyridine (10 mL). The reaction was then stirred for 30 minutes. Water (100 mL) was added to the stirred reaction mixture causing precipitation of the product. The precipitate was filtered, washed with water (3 x 25 mL), and dried under high vacuum for 16 hours. 1.00 g (82%) of (91) was obtained: retention time=11.73 min.; m/z (relative intensity) 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-quinoline- and 2-quinoxaline carboxamides were prepared:

N-(1-adamantyl)-6-quinolinecarboxamide (42)

Preparation from 6-quinolinoyl chloride hydrochloride (1.51 g, 10 mmol), 1-adamantanamine (1.73 g, 10 mmol), pyridine (5 mL) and water (200 mL) afforded 330 mg (11%) of (42): Retention time = 11.04min.; m/z (relative intensity) 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-norbornyl)-2-quinoxaline carboxamide (148)

Preparation from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), exo-2-aminonorbornane (133 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) afforded 35 mg (15%) of (148 ):

Retention time=10.22min.; m/z (relative intensity) 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-quinoxaline acid chloride (193 mg, 1.0 mmol), (R)-(+)-bornylamine (138 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) to give 140 mg (50%) of (150): retention time=10.79min.; m/z (relative intensity) 309(M+, 27), 199(8), 187(10), 174(10), 158(11), 157(14), 153(10), 152(82), 144(9), 135(11), 131(7), 130(51), 129(100), 109(20), 103(18), 102(43), 95(38), 93(12), 91(7), 79(9), 77(11), 76(13), 75(11), 67(17), 55(14), 53(8), 51(8), 43(8), 41(25).

N-(3-noradamantyl)-2-quinoxaline carboxamide (152)

Preparation from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), 3-noramantadine (157 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) afforded 167 mg (63%) of (152): Retention time=11.00min.; m/z (relative intensity) 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-[(1R, 2R, 3R, 5S)-isopine camphenyl]-2-quinoxaline carboxamide (165)

With 2-quinoxaline acid chloride (193 mg, 1.0 mmol), (1R, 2R, 3R, 5S)-(-)-isopine camphenylamine (138 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) Preparation yielded 230 mg (83%) of (165): retention time = 10.88 min.; m/z (relative intensity) 309 (M+, 4), 226 (19), 200 (17), 199 (5), 198 (7), 186(9), 175(7), 174(16), 158(6), 157(14), 152(6), 130(42), 129(100), 103(16), 102 (42), 102(42), 95(13), 93(10), 79(6), 77(7), 76(11), 75(9), 67(7), 55(12), 53 (6), 51(5), 43(5), 41(18).

N-[(1S, 2S, 3S, 5R)-isopine camphenyl]-2-quinoxaline carboxamide (166)

With 2-quinoxaline acid chloride (193 mg, 1.0 mmol), (1S, 2S, 3S, 5R)-(+)-isopine camphenylamine (138 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) Preparation yielded 208 mg (75%) of (166): retention time = 10.88 min.; m/z (relative intensity) 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[2.2.1.0(2,6)]heptane-3-yl)-2-quinoxalinecarboxamide (167)

With 2-quinoxaline acid chloride (193 mg, 1.0 mmol), 5-chlorotricyclo[2.2.1.0(2,6)]heptane-3-ylamine (129 mg, 0.90 mmol), pyridine (5 mL) and water ( 50mL) to obtain 100mg (37%) of (167): retention time = 11.29min.; m/z (relative intensity) 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-quinoxaline carboxamide (168)

With 2-quinoxaline acid chloride (135mg, 0.70mmol), tricyclo[4.3.1.1(3,8)]undec-3-ylamine hydrochloride (100mg, 0.60mmol), pyridine (5mL) and water (50 mL) prepared to give 110 mg (57%) of (168): retention time = 12.52 min.; m/z (relative intensity) 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-[(1S,2R,5S)-cis-myrtyl]-2-quinoxalinecarboxamide (169)

Prepared from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), (-)-cis-myrtylamine (138 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) to give 224 mg (81% ) of (169): retention time=11.32min.; m/z (relative intensity) 309 (M+, 18), 186 (30), 174 (20), 158 (12), 157 (27), 152 (16 ), 131(6), 130(47), 130(47), 129(100), 121(5), 103(17), 102(45), 93(12), 91(6), 81(11 ), 79(12), 77(10), 76(13), 75(11), 69(13), 67(15), 55(8), 54(6), 53(8), 51(7 ), 43(6), 41(26).

N-[(1R,2R,4S)-isobornyl]-2-quinoxalinecarboxamide (170)

Prepared from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), (R)-(-)-isobornylamine (138 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) to give 130 mg (81%) of (170): retention time=10.76min.; m/z (relative intensity) 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-(±)-2-norbornyl)-2-quinoxaline carboxamide (171)

Prepared from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), endo-(±)-2-aminonorbornane (133 mg, 0.90 mmol), pyridine (5 mL) and water (50 mL) to give 175 mg (73% ) of (171): retention time=10.15min.; m/z (relative intensity) 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)

Prepared from 2-quinoxaline acid chloride (0.47 g, 2.4 mmol), (R)-2-phenyl-1-propanamine (0.30 g, 2.2 mmol), pyridine (5 mL) and water (50 mL) to give 0.49 g ( (172) of 76%): retention time=10.63min.; m/z (relative intensity) 291 (M+, 14), 186 (9), 158 (5), 157 (32), 130 (25), 129 (100), 118(22), 105(24), 104(5), 103(21), 102(48), 91(9), 79(11), 78(6), 77(18), 76 (13), 75(13), 75(13), 51(9).

N-[(S)-2-phenyl-1-propyl]-2-quinoxalinecarboxamide (173)

Prepared from 2-quinoxaline acid chloride (0.47 g, 2.4 mmol), (S)-2-phenyl-1-propanamine (0.30 g, 2.2 mmol), pyridine (5 mL) and water (50 mL) to give 0.48 g ( (173) of 74%): retention time=10.72min.; m/z (relative intensity) 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-(2,3-Indanyl)]-2-quinoxalinecarboxamide (221)

Prepared from 2-quinoxaline acid chloride (0.32 g, 1.7 mmol), 2-amino-1,2-indane (0.20 g, 1.5 mmol), pyridine (3 mL) and water (30 mL) to give 0.23 g of (53 %) of (221): retention time=11.33min.; m/z (relative intensity) 289 (M+, 10), 132 (6), 130 (28), 129 (41), 117 (15), 116 ( 100), 115(37), 104(7), 103(26), 102(37), 91(7), 78(7), 77(13), 76(16), 75(14), 51( 9), 51(9), 50(5).

N-Cyclooctyl-2-quinoxaline carboxamide (228)

Prepared from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), cyclooctylamine (123 μL, 114 mg, 0.90 mmol), pyridine (5 mL) and water (100 mL) afforded 100 mg (39%) of (228): retained Time=10.86min.; m/z (relative intensity) 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-quinoxaline carboxamide (229)

Prepared from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), cycloheptylamine (115 μL, 102 mg, 0.90 mmol), pyridine (5 mL) and water (100 mL) afforded 30 mg (12%) of (229): retained Time=10.30min.; m/z (relative intensity) 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-quinoxaline acid chloride (193 mg, 1.0 mmol), 2-aminospiro(4,5)decane (150 mg, 0.79 mmol), pyridine (5 mL) and water (100 mL) to give 206 mg (74%) of (236): retention time=10.94min; m/z (relative intensity) 282(M+, 25), 199(7), 186(6), 157(10), 130(32), 129(96), 125 (40), 110(10), 109(100), 108(15), 103(14), 102(55), 98(6), 97(27), 96(25), 84(9), 82 (18), 76(15), 75(16), 70(55), 69(7), 68(13), 56(7), 55(8), 53(6), 51(9), 43 (8), 42(36), 41(14).

Embodiment 6: Preparation of 1-adamantyl methyl 6-quinolyl ether (94)

A mixture of 1-adamantanemethanol (5.00 g, 30.0 mmol) and 6-hydroxyquinoline (13.1 g, 90.2 mmol) in tetrahydrofuran (75 mL) was stirred for 15 minutes. Triphenylphosphine (10.2 g, 39.0 mmol) was then added followed by diethyl azodicarboxylate (6.14 mL, 39.0 mmol). The reaction mixture was refluxed for 18 hours. The solvent was then removed by rotary evaporation. The resulting gum was filtered through filter paper with diethyl ether (3 x 25 mL). The filtrate was rotovapped and the resulting gum was filtered through filter paper with hexanes (3 x 25 mL). The filtrate was rotovapped again, then the resulting gum was filtered through filter paper with hexanes (3 x 25 mL), and the filtrate was rotovapped again. Obtained 3.8 g (43%) of crude product as a red oil. Chromatography (2:1 hexane/ethyl acetate) of the oil gave 1.6 g (18%) of (94): retention time = 11.29 min.; m/z (relative intensity) 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(8), 53(6), 41(14).

Example 7: Preparation of 1-adamantyl 3-quinolinecarboxylate (101)

1-Adamantanol (152mg, 1.0mmol), 3-quinolinecarboxylic acid (173mg, 1.0mmol) and dimethylaminopyridine (122mg, 1.0mmol) in dichloromethane (2mL) and N, N-di The mixture in methylformamide (2 mL) was cooled to 0°C. 1,3-Dicyclohexylcarbodiimide (227 mg, 1.1 mmol) in dichloromethane (1 mL) was added in one portion. The reaction mixture was stirred at 25°C for 20 hours. The reaction mixture was then diluted with dichloromethane (40 mL) and washed with 1M sodium hydroxide (3 x 30 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through Celite, and rotovaped. The resulting material was purified by spin thin layer chromatography (3% methanol in chloroform). The purest fractions were rotovaped and the resulting material recrystallized from ethanol. Obtained 42 mg (14%) of (101): retention time = 7.78 min.; m/z (relative intensity) 307 (M+, 96), 306 (100), 173 (11), 155 (38), 135 (6 ), 127(55), 119(6), 106(9), 100(23), 93(25), 92(33), 91(14), 78(23), 77(6), 76(13 ), 74(8), 67(9), 54(7), 41(12).

Example 8: Preparation of N-(α,α-dimethylphenethyl)-2-quinoxaline formamide (108)

2-Quinoxaline acid chloride (207 mg, 1.07 mmol) in dichloromethane (1 mL) was added to a solution of phentermine (160 mg, 1.07 mmol) in dichloromethane (3 mL) cooled to 0°C. The reaction solution was warmed to 25 °C. After 5 minutes, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with 1M sodium hydroxide (2 x 40 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through silica gel, and rotovapped. 51 mg (16%) of (108) was obtained: retention time = 9.31 min.; m/z (relative intensity) 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).

N-(2-chlorobenzyl)-2,4,6-triphenylpyridinium tetrachloroborate

2-Chlorobenzylamine (2.0 g, 14 mmol) was added dropwise to a suspension of 2,4,6-triphenylpyridinium tetrachloroborate (5.1 g, 13 mmol) in dichloromethane (40 mL) . The reaction mixture was stirred for 16 hours. Ethanol (4 mL) and excess diethyl ether were added to precipitate the product. The precipitate was filtered and dried. 6.14 g (92%) of N-(2-chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate were obtained.

1-(2-Chlorophenyl)-2-methyl-2-nitropropane

2-Nitropropane (3.19 mL, 35.5 mmol) was added to a mixture of sodium hydride (0.85 g, 35 mmol) in methanol (15 mL). The reaction mixture was then stirred and warmed to 25°C for 10 minutes. The solvent was rotovapped to give a white solid. Under nitrogen, this solid and N-(2-chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate (6.14 g, 11.8 mmol) in dimethyl sulfoxide (45 mL) The mixture was stirred for 16 hours. Water was then added to quench the reaction. The 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 on strongly acidic Amberlyst 15 ion exchange resin (1 g/mmol) for 4 hours. The mixture was filtered and rotovaped. 2.35 g (93%) of 1-(2-chlorophenyl)-2-methyl-2-nitropropane were obtained.

α,α-Dimethyl-2-chlorophenethylamine

A solution of Raney nickel (50% by weight in water; 2.3 g) and 1-(2-chlorophenyl)-2-methyl-2-nitropropane (2.35 g, 11 mmol) was mixed under hydrogen (60 psig). The ethanol (35 mL) mixture was shaken for 3.5 hours. The reaction mixture was then filtered and the filtrate was rotovapped. 2.3 g (110%) of α,α-dimethyl-2-chlorophenethylamine are obtained.

N-(α,α-Dimethyl-2-chlorophenethyl)-2-quinoxaline carboxamide (197)

Prepared in a similar manner to (108) using 2-quinoxaline acid chloride (158 mg, 0.82 mmol), α,α-dimethyl-2-chlorophenethylamine (151 mg, 0.82 mmol) and dichloromethane (3 mL) (197), obtained 196 mg (70%) of (197): retention time = 10.04 min.; m/z (relative intensity) 339 (M+, .0), 213 (58), 186 (24), 156 (12 ), 129(25), 128(100), 126(14), 124(44), 102(14), 101(38), 98(5), 90(5), 88(18), 75(10 ), 75(10), 75(9), 62(5), 50(5), 41(9).

Example 9: Preparation of N-(α,α-dimethyl-4-fluorophenethyl)-2-quinoxaline carboxamide (129)

To a solution of 1-(4-fluorophenyl)-2-methyl-2-propanamine (105 mg, 0.628 mmol) in pyridine (2 mL) was added 2-quinoxaline acid chloride (133 mg, 0.691 mmol). The reaction was then stirred for 30 minutes. Water (20 mL) was added to the stirred mixture and the product separated as an oil. The 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 h. 146 mg (71.9%) of (129) were obtained: retention time = 10.45 min.; m/z (relative intensity) 323 (M+, .1), 214 (73), 186 (22), 157 (14), 135 ( 4), 130(19), 129(100), 109(22), 103(9), 102(30), 83(7), 76(9), 75(8), 42(6).

In a similar manner, the following N-substituted 2-quinoxaline carboxamides were prepared:

N-(β-methylphenethyl)-2-quinoxaline carboxamide (131)

Prepared from 2-quinoxaline acid chloride (193mg, 0.84mmol), β-methylphenethylamine (103mg, 0.76mmol) and pyridine (2mL) to give 154mg (69%) of (131): retention time = 10.71min .; m/z (relative intensity) 291 (M+, 12), 186 (66), 158 (5), 157 (37), 130 (20), 129 (100), 118 (28), 105 (21) , 103(17), 102(37), 91(7), 79(10), 78(5), 77(15), 76(11), 75(10), 51(10), 51(10) .

N-(3-Methylcyclohexyl)-2-quinoxaline carboxamide (161)

Preparation from 2-quinoxaline acid chloride (193mg, 1.0mmol), 3-methylcyclohexylamine (119mg, 0.90mmol) and pyridine (5mL) afforded 190mg (78%) of (161): retention time = 9.99min .; m/z (relative intensity) 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-quinoxaline carboxamide (163)

Preparation from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), 2,3-dimethylcyclohexylamine (115 mg, 0.90 mmol) and pyridine (5 mL) afforded 150 mg (59%) of (163): RT =10.12min.; m/z (relative intensity) 283(M+, 35), 212(6), 198(14), 175(6), 174(39), 158(7), 157(22), 131 (6), 130(46), 129(100), 126(44), 109(8), 103(20), 103(20), 102(45), 76(13), 75(11), 67 (7), 56(10), 55(12), 51(6), 43(6), 41(16).

N-[(1S, 2S, 3S, 5R))-3-pinenemethyl]-2-quinoxaline carboxamide (207)

Preparation from 2-quinoxaline acid chloride (193 mg, 1.0 mmol), (+)-3-pinanemethylamine (150 mg, 0.90 mmol) and pyridine (5 mL) afforded 229 mg (79%) of (207): RT =12.07min.; m/z (relative intensity) 323(M+, 12), 187(100), 186(12), 174(33), 166(24), 159(8), 158(66), 157 (26), 150(9), 144(7), 131(11), 130(80), 129(85), 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: Preparation of N-(1-adamantylmethyl)-2-quinoxaline carboxamide (146)

2-Quinoxaline acid chloride (429 mg, 2.6 mmol) was added to a solution of 1-adamantylmethylamine (500 mg, 2.6 mmol) in chloroform (5 mL). The reaction mixture was heated until all material dissolved. The reaction mixture was stirred at 25°C for 1 hour. Water (100 mL) was added to the stirred reaction mixture to precipitate the product. The precipitate was filtered, washed with water (2x) and dried under high vacuum. Obtained 375 mg (45%) of (146): retention time = 12.27 min.; m/z (relative intensity) 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-quinoxaline carboxamide (162)

To a solution of 4-methylcyclohexylamine (119 mg, 0.90 mmol) in pyridine (2 mL) was added 2-quinoxaline acid chloride (193 mg, 1.0 mmol). The reaction was then stirred for 1 hour. Water (20 mL) was added to the stirred reaction mixture, causing the product to precipitate as an oil. The mixture was extracted with 30% dichloromethane in ether (2 x 25 mL), washed with water (2 x 25 mL), dried (anhydrous sodium sulfate), and rotovapped. Obtained 123 mg (51%) of (162): retention time = 10.00 min.; m/z (relative intensity) 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-[(1S,2S,5S)-trans-myrtle alkyl]-2-quinoxaline carboxamide (225)(1S,2S,5S)-trans-myrtle Alkyl trifluoroacetate

Trifluoroacetic anhydride (5.50 mL, 39.0 mmol) was added to (-)-trans-myrtanol (5.10 mL, 32.5 mmol) in dry tetrahydrofuran (100 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was rotovaped. 7.60 g (94%) of (1S,2S,5S)-trans-myrtyl trifluoroacetate were obtained.

(1R,2R,5R)-trans-myrtle alkyl trifluoroacetate

In a similar manner, ( 1R,2R,5R)-trans-myrtleyl trifluoroacetate. 7.60 g (94%) of (1R,2R,5R)-trans-myrtyl trifluoroacetate were obtained.

(1S,2S,5S)-trans-Myrtle alkyl azide

At 80°C, (1S, 2S, 5S)-trans-aurinyl trifluoroacetate (1.0g, 4.0mmol), sodium azide (0.39g, 6.0mmol) and N, N - A mixture of dimethylformamide (50 mL) was stirred for 24 hours. After cooling to 25°C, water (100 mL) was added and the mixture was extracted with ether (2 x 50 mL). The organic layer was then dried (anhydrous sodium sulfate) and rotovaped. Obtained 1.12 g (100%) of (1S,2S,5S)-trans-myrtleyl azide as a colorless oil.

(1R,2R,5R)-trans-Myrtle Alkyl Azides

In a similar manner, (1R, 2R, 5R)-trans-myrtle alkyl trifluoroacetate (7.60g, 30.4mmol), sodium azide (3.00g, 45.6mmol) and N, N - Preparation of (1R,2R,5R)-trans-myrtle alkyl azide from -dimethylformamide (100 mL) afforded 4.10 g (48.2%) of (1R,2R,5R)-trans-myrtle Auryl Alkyl Azides.

(1S, 2S, 5S)-trans-myrtle alkylamine

Under hydrogen (50 psig), (1S,2S,5S)-trans-myrtle alkyl azide (1.12 g, 7.32 mmol) and platinum(IV) oxide hydrate (0.34 g) in ethanol (50 mL ) and shake the mixture for 2 hours. The reaction mixture was then filtered through filter paper and the filtrate was rotovapped. The resulting material was added to 0.12M hydrochloric acid (100 mL), and the aqueous solution was extracted with ether (2 x 50 mL). The aqueous layer was made basic with 0.1M sodium hydroxide (50 mL) and extracted with dichloromethane (2 x 50 mL). The organic layer was then dried (anhydrous sodium sulfate) and rotovaped. Obtained 78 mg (7%) of (1S,2S,5S)-trans-Argentylamine as a pale yellow oil.

(1R,2R,5R)-trans-Myrtle Alkylamine

Prepared in a similar manner using (1R,2R,5R)-trans-myrtle alkyl azide (4.10 g, 26.8 mmol), platinum(IV) oxide hydrate (0.41 g) and ethanol (75 mL) (1R,2R,5R)-trans-myrtylamine. Obtained 2.00 g (48.8%) of (1R,2R,5R)-trans-myrtylamine.

N-[(1S,2S,5S)-trans-myrtleyl]-2-quinoxalinecarboxamide (225)

In a similar manner to (162), 2-quinoxaline acid chloride (49 mg, 0.25 mmol), (1S, 2S, 5S)-trans-myrtylamine (35 mg, 0.23 mmol) and pyridine (5 mL ) to prepare (225), to obtain 8 mg (10%) of (225): retention time = 11.23 min.; m/z (relative intensity) 309 (M+, 25), 187 (15), 186 (39), 174 ( 12), 158(14), 157(29), 152(20), 131(6), 130(47), 130(47), 129(100), 103(15), 102(41), 93( 9), 91(6), 81(12), 79(12), 77(9), 76(11), 75(10), 69(14), 67(17), 55(8), 54( 5), 53(7), 51(7), 43(6), 41(25).

N-[(1R,2R,5R)-trans-myrtyl]-2-quinoxalinecarboxamide (226)

In a similar manner, (226 ), to obtain 27 mg (10%) of (226): retention time = 11.19 min.; m/z (relative intensity) 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: Preparation of N-[N'-(R)-α-methylbenzyl-2-acetamido]-3-aminoquinoline dihydrochloride (156)

N-(R)-α-Methylbenzyl-2-chloroacetamide

Add (R)-α-methylbenzylamine (2.4g, 20mmol) in dichloromethane (50mL) to chloroacetyl chloride (2.25g, 20mmol) in dichloromethane (70mL) and pyridine (10mL) . The reaction mixture was stirred, diluted with diethyl ether (500 mL), washed with water (3 x 30 mL), dried (anhydrous magnesium sulfate), and rotovapped. 3.60 g of N-(R)-α-methylbenzyl-2-chloroacetamide were obtained.

N-(R)-α-Methylbenzyl-2-iodoacetamide

A dry acetone solution of sodium iodide (10.37g, 69mmol) was slowly added to a dry acetone solution of N-(R)-α-methylbenzyl-2-chloroacetamide (3.39g, 17mmol), and the The reaction mixture was refluxed for 16 hours. The reaction mixture was then filtered and the filtrate was rotovapped. Diethyl ether was added and the mixture was stirred for 20 minutes. Then the mixture was filtered, and then the filtrate was rotovapped and dried under high vacuum to obtain N-(R)-α-methylbenzyl-2-iodoacetamide.

N-[N'-(R)-α-methylbenzyl-2-acetamido]-3-aminoquinoline dihydrochloride (156)

A mixture of 3-aminoquinoline (0.15 g, 1.0 mmol) and potassium fluoride (50%) on Celite (0.30 g, 2.5 mmol) in acetonitrile (20 mL) was stirred for 1 hour. N-(R)-[alpha]-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 rotovapped. The resulting material was dissolved in ether and washed with 1M sodium hydroxide (3 x 30 mL). The combined aqueous layers were saturated with sodium chloride, then extracted with chloroform (4x). The combined organic layers were dried (anhydrous magnesium sulfate) and rotovaped. The resulting material was dissolved in chloroform (10 mL), 1M hydrogen chloride in ether (5 mL) was added, and the solution was rotovapped. The resulting material was dissolved in chloroform (5 mL), filtered through a 0.45 μm filter pad, and the filtrate was rotovapped. Obtained 13 mg (3%) of (156): retention time = 10.43 min.; m/z (relative intensity) 328 (M+, 11), 182 (12), 181 (86), 180 (37), 167 (22 ), 166(25), 165(17), 162(53), 161(95), 160(37), 148(32), 145(18), 135(21), 132(16), 122(9 ), 120(22), 119(20), 107(19), 106(13), 105(100), 104(22), 103(19), 90(12), 79(25), 78(11 ), 77(38), 51(10), 44(10), 41(11).

Example 14: Preparation of 1-(1-adamantyl)-2-(benzothiazol-2-ylsulfanyl)ethanone (273)

Sodium hydride (36.5 mg, 1.52 mmol, 60% in mineral oil) was washed with pentane (4X), dried under _N2 , suspended in dimethylformamide (DMF, 10 mL), and cooled to 0 °C . With stirring, a solution of 2-mercaptobenzothiazole (253.3 mg, 1.52 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred at 0°C for 20 minutes and treated with 1-adamantanylbromomethyl ketone (389.8 mg, 1.52 mmol) in DMF (8 mL). The reaction was stirred at room temperature for 30 minutes and diluted with ether (100 mL). The resulting solution was washed with water (5 x 30 mL), and the remaining organic solution was dried over anhydrous MgSO ₄ , filtered, and concentrated to a solid. Recrystallization from hot ethanol gave 287 mg (55%) of the desired product: GC/EI-MS gave m/z (relative intensity) 343 (M ⁺ , 10), 315(2), 180(2), 148(10 ), 135(100), 107(9), 93(17) and 79(20).

Example 15: Determination of activity of mGluRI antagonists

By incubating at 37°C for 30-40 minutes in SPF-PCB (126mM NaCl, 5mM KCl, 1mMMgCl ₂ , 20mM Na-HEPES, 1.0mM CaCl ₂ , 1mg/mL glucose and 0.5% BSA, pH 7.4), with HEK-293 cells expressing recombinant receptors described in WO 97/05252 were loaded with 2 μM Fura-2 acetoxymethyl ester.

The cells were washed 1-2 times in SPF-PCB, resuspended to a density of 4-5×10 ⁶ cells/mL, and then kept in plastic cups at 37°C. To record the fluorescent signal, the cells were diluted five-fold with 37°C BSA-free SPF-PCB and placed in a quartz cuvette to obtain a final BSA concentration of 0.1% (1.2mL 37°C BSA-free SPF-PCB+0.3mL cells suspension). Fluorescence was measured with a custom spectrofluorometer (Biomedical Instrumentation Group, University of Pennsylvania) at 37°C under constant agitation. The excitation and emission wavelengths are 340 and 510 nm, respectively. To calibrate the fluorescence signal, digitonin (Sigma Chemical Co., St. Louis, MO; catalog #D-5628; final concentration 50 μg/mL) was added to obtain maximum fluorescence (F _max ), and by adding TRIS base/EGTA (10 mM , pH 8.3, final) to determine the apparent minimum fluorescence (F _min ). A dissociation constant (Kd) of 224 nM was used and the concentration of intracellular Ca2 ⁺ was calculated using the following equation:

[Ca ²⁺ ] _i = (FF _min /F _min ) x Kd; where F is the measured fluorescence at any desired time point and F is between F _max and F _min .

Control responses to the addition of 5 mM Ca2 ⁺ (final extracellular calcium concentration, 6 mM) were determined in separate cups. Control responses to changes in extracellular calcium were measured throughout the experiment. Compounds were assayed at a single concentration per cup of cells and all compounds were prepared in DMSO. Appropriate dilutions were made so that the volume of compound added was no greater than 10 μl per 1500 μl total volume (no greater than 0.67% final DMSO) to achieve the specified assay concentration.

Once a stable baseline of intracellular calcium is obtained, the compound is added to the cup. The response or lack of response to the addition of the compound was allowed to stabilize for 1-3 minutes before the addition of 5 mM calcium to determine the effect of the compound on the subsequent calcium response. Once the peak of this subsequent calcium response was obtained, digitonin and EGTA were added in a sequential fashion to determine _Fmax and _Fmin , respectively. Data express changes in intracellular calcium concentration in nM. These changes in calcium response following compound addition are compared to control (no compound) calcium response. Responses to calcium in the presence of assay compounds were normalized to the percent change in response to controls. Data were entered into a Levenberg-Marquardt analysis to generate non-linear least squares and the _IC50 and 95% confidence intervals for each compound were determined.

Having thus been fully disclosed, the invention has been described with reference to the representative examples set forth above. Those skilled in the art will recognize that various modifications can be made in the present invention without departing from the spirit and scope of the invention.

Claims (12)

1. Formula V or IX the representative compound or its pharmacy acceptable salt:

   

   Wherein R comprises and is selected from following group: adamantyl, the 2-adamantyl, (1S, 2S, 3S, 5R)-different loose amphene base, three ring [4.3.1.1 (3.8)] undecanes-3-base, (1S, 2R, 5S)-cis-Stenocalyx micheli's alkyl, (1R, 2R, 4S)-isobornyl, (1R, 2R, 3R, 5S)-different loose amphene base, (1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl, (1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl, (1R, 2S, 4S)-bornyl, 1-diamantane methyl, 3-removes the first adamantyl, (1S, 2S, 3S, 5R)-3-pinane methyl, the ring octyl group, α, the alpha-alpha-dimethyl styroyl, (S)-2-phenyl-1-propyl group, suberyl, 4-methyl-2-hexyl, 2,2,3,3,4,4,4-seven fluorine butyl, 4-ketone group adamantyl, 3-phenyl-2-methyl-propyl, 3,5-dimethyladamantane base, trans-the 2-phenycyclopropyl, the 2-methylcyclohexyl, 3,3, the 5-trimethylcyclohexyl, 2-(o-methoxyphenyl) ethyl, 2-(1,2,3, the 4-tetralyl), the 4-phenyl butyl, 2-methyl-2-phenyl butyl, 2-(fluorophenyl) ethyl, 2-(to fluorophenyl) ethyl, 2-(3-hydroxyl-3-phenyl) propyl group, (S)-2-hydroxyl-2-phenylethyl, (R)-2-hydroxyl-2-phenylethyl, 2-(chloro-phenyl-between 3--2-methyl) propyl group, 2-(3-rubigan-2-methyl) propyl group, the 4-tert-butylcyclohexyl, (S)-1-(cyclohexyl) ethyl, (3-(3 for 2-, the 4-3,5-dimethylphenyl)-and the 2-methyl) propyl group, 3, the 3-dimethylbutyl, 2-(5-methyl) hexyl, 1-Stenocalyx micheli's alkyl, the 2-bornyl, 3-pinane methyl, 2,2,3,3,4,4,5,5-octafluoro amyl group, to fluoro-α, the alpha-alpha-dimethyl styroyl, the 2-naphthyl, bornyl, cyclohexyl methyl, the 3-methylcyclohexyl, the 4-methylcyclohexyl, 3, the 4-Dimethylcyclohexyl, 5-chloro-three ring [2.2.1] heptyl, neighbour-α, the alpha-alpha-dimethyl styroyl, 2-(2, the 3-indanyl), 2-spiral shell [4.5] decyl, the 2-phenylethyl, 1-adamantyl ethyl, 1-(1-two ring [2.2.1] heptan-2-yl) ethyl, 2-(2-methyl-2-phenyl propyl), 2-(adjacent fluorophenyl) ethyl, 1-(cyclohexyl) ethyl and cyclohexyl

   Wherein, Y is O, S, NH or CH ₂, and,

   Wherein, X ¹Be N or CH.
2. 2. the compound of claim 1, wherein this compound is the compound of formula IX.
3. 3. the compound of claim 1, wherein this compound is the compound of formula V.
4. 4. according to the compound of claim 1, wherein R comprises 7-11 carbon atom, wherein some or all hydrogen atoms on two carbon atoms can independently be selected from F, Cl, OH, OMe and=optional replacement of substituting group of O.
5. 5. the compound of claim 3, wherein Y is NH, O or S.
6. 6. according to the compound of claim 3, X wherein ¹Be N.
7. 7. according to the compound of claim 3, X wherein ¹Be CH.
8. 8. comprise according to the compound of claim 1 and the medicinal compositions of pharmaceutically acceptable thinner or vehicle.
9. 9. the application of the compound of claim 1 in suppressing mGluRI receptoroid activated product preparation.
10. 10. according to the application in suppressing the product preparation that excitability by the mGluRI receptoroid activates the neuronal damage that causes of the compound of claim 1.
11. 11. the application of the compound of claim 1 in the product preparation that is used for the treatment of the neuronal damage diseases associated of bringing out with L-glutamic acid.
12. 12. compound and pharmacy acceptable salt thereof according to claim 1, wherein this compound is selected from: N-[6-(2-toluquinoline base)]-1-diamantane methane amide, N-(6-quinolyl)-1-diamantane methane amide, N-(2-quinolyl)-1-diamantane methane amide, N-(3-quinolyl)-1-diamantane methane amide, 6-quinoline-1-adamantanecarboxylic acid ester, 6-quinolinecarboxylic acid 1-diamantane ester, 2,2,3,3,4,4,5,5-octafluoro-1-amyl group-6-quinoline methyl ester, 6-quinolinecarboxylic acid 1-diamantane methyl esters, 2-quinoxaline formic acid 1-adamantane esters, N-(1-adamantyl)-3-quinoline-carboxamide, N-(1-adamantyl)-2-quinoline formyl amine, N-(2-adamantyl)-2-quinoxaline methane amide, N-[(1R, 2R, 3R, 5S)-3-pinane methyl]-2-quinoxaline methane amide, N-(1-adamantyl)-2-quinoxaline methane amide, N-(1-adamantyl)-6-quinoxaline methane amide, N-(outer-2-removes the first Camphanyl)-2-quinoxaline methane amide, N-[(1R, 2S, 4S)-bornyl]-2-quinoxaline methane amide, N-(3-removes the first adamantyl)-2-quinoxaline methane amide, N-[(1R, 2R, 3R, 5S)-different loose amphene base]-2-quinoxaline methane amide, N-[(1S, 2S, 3S, 5R)-different loose amphene base]-2-quinoxaline methane amide, N-(5-chloro-[2.2.1.0] three rings-2,6-heptan-3-yl)-2-quinoxaline methane amide, N-([4.3.1.1] three rings-3,8-undecane-3-yl)-2-quinoxaline methane amide, N-[(1S, 2R, 5S)-cis-Stenocalyx micheli's alkyl]-2-quinoxaline methane amide, N-[(1R, 2R, 4S)-isobornyl]-2-quinoxaline methane amide, in the N-[-(±)-2-removes the first Camphanyl]-2-quinoxaline methane amide, N-[(R)-2-phenyl-1-propyl group]-2-quinoxaline methane amide, N-[(S)-2-phenyl-1-propyl group]-2-quinoxaline methane amide, N-[2-(2, the 3-indanyl)]-2-quinoxaline methane amide, 1-diamantane methyl 6-quinolyl ether, 1-adamantyl-3-quinoline methyl ester, N-(α, the alpha-alpha-dimethyl styroyl)-2-quinoxaline methane amide, N-(α, alpha-alpha-dimethyl-2-chlorobenzene ethyl)-2-quinoxaline methane amide, N-(α, alpha-alpha-dimethyl-4-fluorobenzene ethyl)-2-quinoxaline methane amide, N-(Beta-methyl styroyl)-2-quinoxaline methane amide, N-(3-methylcyclohexyl)-2-quinoxaline methane amide, N-(2, the 3-Dimethylcyclohexyl)-2-quinoxaline methane amide, N-[(1S, 2S, 3S, SR)-3-pinane methyl]-2-quinoxaline methane amide, N-(1-diamantane methyl)-2-quinoxaline methane amide, N-(4-methylcyclohexyl)-2-quinoxaline methane amide, N-[(1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl]-2-quinoxaline methane amide and N-[(1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl]-2-quinoxaline methane amide.

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