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CN1554649A - Metabotropic glutamate receptor antagonists for treating central nervous system diseases - Google Patents

Metabotropic glutamate receptor antagonists for treating central nervous system diseases Download PDF

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CN1554649A
CN1554649A CNA2004100474998A CN200410047499A CN1554649A CN 1554649 A CN1554649 A CN 1554649A CN A2004100474998 A CNA2004100474998 A CN A2004100474998A CN 200410047499 A CN200410047499 A CN 200410047499A CN 1554649 A CN1554649 A CN 1554649A
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quinoxaline
methane amide
adamantyl
methyl
compound
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Bc
B·C·范瓦格南
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S·T·莫
ʷ
D·L·史密斯
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S·M·舍汉
ж�
I·斯切尔巴科瓦
R·特拉瓦托
R·瓦尔顿
R·巴莫雷
E·G·德马
T·M·斯托曼
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Shire NPS Pharmaceuticals Inc
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Abstract

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

Description

The metabotropic glutamate receptor antagonists that is used for the treatment of central nervous system disease
The application submitted on November 20th, 1998, and application number is dividing an application of application 98813148.X, that denomination of invention is identical with the application.
Invention field
The invention provides has activity to metabotropic glutamate receptor, and is used for the treatment of neural and mental disorder and disorderly compound.
Background of invention
In the acute and chronic nerve and mental disorder and disorder of treatment, illustrate latest developments that the neurophysiology work of metabotropic glutamate receptor uses and established these acceptors as medicine target likely.But the main challenge that realizes this expectation is the exploitation of metabotropic glutamate receptor subtype-selective compound always.
L-glutamic acid is main excitatory neurotransmitter in the mammalian central nervous system (CNS).L-glutamic acid produces its effect to nervus centralis by combination and activating cells surface receptor.The approach that signal transduction is passed through to the cell according to the constitutional features of receptor protein, acceptor and the feature of pharmacy aspect can be divided into these acceptors two big class, the i.e. glutamate receptors of ionotropy (ionotropic) and metabolic effect.
This metabotropic glutamate receptor (mGluRs) is the proteinic acceptor of coupling G-, and it can activate second messenger system in the various born of the same parents, combines with L-glutamic acid then.The activation of mGluRs is brought out below one or more and is reacted in complete mammalian nervous unit: the activation of Phospholipase C; (PI) increase of hydrolysis of phospholipid inositol (phosphoinositide); The release of cellular calcium; The activation of Phospholipase D; The activation of adenylate cyclase or inhibition; Increase or reduction that cyclic amp (cAMP) forms; The activation of guanylate cyclase; The increase that cyclic guanosine monophosphate-Phosphoric acid esterase (cGMP) forms; Phospholipase A 2Activation; Increase that arachidonic acid discharges and voltage-and the increase or the reduction of the ion channel activity of part-control.Schoepp etc., Trends Pharmacol.Sci.14:13 (1993); Schoepp, Neurochem Int.24:439 (1994); Pin etc., neuropharmacology 34:1 (1995).
Identify eight kinds of different mGluR hypotypes by molecular cloning, be called mGluR1-mGluR8.See, for example, Nakanishi. neurone 13:1031 (1994); Pin etc., neuropharmacology 34:1 (1995); Knopfel etc., medicochemistry magazine 38:1417 (1995).The diversity of other acceptor is found in the expression of other montage (spliced) form by some mGluR hypotype.Pin etc., PNAS 89:10331 (1992); Minakami etc., BBRC199:1136 (1994); Joly etc., Journal of Neuroscience 15:3970 (1995).
According to second messenger system that amino acid sequence homology, acceptor utilized and by its pharmacy feature, the metabotropic glutamate receptor hypotype can be further divided into three classes (groups), i.e. I class, II class and III class mGluRs.Nakanishi, neurone 13:1031 (1994); Pin etc., neuropharmacology 34:1 (1995); Knopfel etc., medicochemistry magazine 38:1417 (1995).
I class mGluRs comprises other the variant of montage of mGluR1, mGluR5 and its.Agonist shifts (mobilization) with the activation that combines the generation Phospholipase C of these acceptors and the successive of cellular calcium.Use electrophysiological detection and can confirm these effects, for example the reorganization mGluR1 acceptor that xenopus Xenopus ovocyte is expressed.See Masu etc. for example, natural 349:760 (1991); Pin etc., PNAS 89:10331 (1992).The reorganization mGluR5 acceptor that ovocyte is expressed has also obtained similar results.Abe etc., journal of biological chemistry 267:13361 (1992); Minakami etc., BBRC 199:1136 (1994); Joly etc., Journal of Neuroscience 15:3970 (1995).In addition, measure discovery by the standard biochemical test, the activation energy that is expressed in the agonist of the reorganization mGluR1 acceptor on Chinese hamster ovary (CHO) cell stimulates PI hydrolysis, cAMP to form and arachidonic release.Aramori etc., neurone 8:757 (1992).
As a comparison, activate the mGluR5 that is expressed on the Chinese hamster ovary celI and be subjected to physical efficiency to stimulate PI hydrolysis and the transition (transients) of cellular calcium continuously, but find to stimulate cAMP to form or arachidonic release.Abe etc., journal of biological chemistry 267:13361 (1992).Yet, activate the mGluR5 that is expressed on the LLC-PK1 cell and be subjected to physical efficiency to produce the PI hydrolysis and strengthen cAMP to form.Joly etc., Journal of Neuroscience 15:3970 (1995).Agonist effect distribution pattern (profile) to I class mGluRs: Rangooncreeper Fruit's acid＞L-glutamic acid=ibotenic acid＞(2S, 1 ' S, 2 ' S)-2-carboxyl cyclopropyl) glycine (L-CCG-I)＞(1S, 3S)-1-Aminocyclopentane-1,3-dicarboxylic acid (ACPD).Compare with II class and III class mGluRs, Quisqualic Acid has relative selectivity to the I receptoroid, but it also is effective activator of ionotropy ampa receptor.Pin etc., neuropharmacology 34:1, Knopfel etc., medicochemistry magazine 38:1417 (1995).
The mGluR agonist of hypospecificity and the shortage of antagonist have hindered the elaboration of the physiological action of special mGluRs, and the relevant mGluR of CNS pathophysiological process that has to determine to influence.But, compare with II class and III class mGluRs, the research of the non-specific agonist that had and antagonist has been drawn the common recognition of some relevant I class mGluRs.
Set forth the test of the physiological action of I class mGluRs and think that the activation inducing neural unit of these acceptors is excited.Various researchs have shown that ACPD can produce on the neurone of postsynaptic excitation to hippocampal gyrus, pallium, cerebellum, thalamus blood brain and other brain zone.The fact shows the direct activation of this excitation owing to postsynaptic mGluRs, but shows that also presynaptic mGluRs activated takes place, and it causes the release of the neurotransmitter that increased.Baskys, Trends Pharmacol.Sci.15:92 (1992); Schoepp, Neurochem.Int.24:439 (1994); Pin etc., neuropharmacology 34:1 (1995).
Drug test is about to the medium of I class mGluRs as this excitation mechanism.Can be in the presence of the iGluR antagonist, the Rangooncreeper Fruit's acid by lower concentration produces the ACPD effect again.Hu etc., brain research 568:339 (1991); Greene etc., European pharmacology magazine 226:279 (1992).Two known phenylglycocoll compounds that can activate mGluR1, promptly ((S)-3HPG) and (S)-3, ((S)-DHPG) also can produce activation to 5-dihydroxy phenyl glycine to (S)-3-hydroxy phenyl glycine.Watkins etc., Trends Pharmacol.Sci.15:33 (1994).In addition, known is the compound of mGluR1 antagonist, (S)-and 4-carboxyl phenyl glycine ((S)-4CPG), (S)-4-carboxyl-3-hydroxy phenyl glycine ((S)-4C3HPG) and ((+)-MCPG) this excitation capable of blocking of (+)-Alpha-Methyl-4-carboxyl phenyl glycine.Eaton etc., European pharmacology magazine 244:195 (1993); Watkins etc., Trends Pharmacol.Sci.15:333 (1994).
Found that the many normal processes of metabotropic glutamate receptor and Mammals CNS are relevant.The activate request that has shown mGluRs strengthens and long-term the inducing of constraining of cerebellum hippocampal gyrus is long-term.Bashir etc., natural 363:347 (1993); Bortolotto etc., natural 368:740 (1994); Aiba etc., cell 79:365 (1994); Aiba etc., cell 79:377 (1994).Also confirm mGluR activatory effect in nociception and the pain relieving.Meller etc., Neuroreport 4:879 (1993).In addition, thought that mGluR activation plays regulating effect in various other normal processes, these processes comprise cynapse transmission, neuronal development, the death of programmatic (apoptotic) neuronal cell, synaptic plasticity, space learning, scent-memorizing, the control of heart active maincenter, walk, motion control and oculovestibular reflex control.Consult and see Nakanishi, neurone 13:1031 (1994); Pin etc., neuropharmacology 34:1; Knopfel etc., medicochemistry magazine 38:1417 (1995).
Shown that also metabotropic glutamate receptor works in various pathophysiological processes that influence CNS and disease.They comprise shock, cerebral trauma, anoxic and local ischemic injuries, hypoglycemia, epilepsy and neurodegenerative disease, as the Alzheimer disease.Schoepp etc., TrendsPharmacol.Sci.14:13 (1993); Cunningham etc., life science 54:135 (1994); Hollman etc., Ann.Rev.Neurosci.17:31 (1994); Pin etc., neuropharmacology 34:1 (1995); Knopfel etc., medicochemistry magazine 38:1417 (1995).Think that many pathology of these diseases are owing to the neuronic excitement of the CNS of excessive glutamate induction.Because I class mGluRs can be by the machine-processed release that increases the neuronal excitation of L-glutamic acid mediation and strengthen presynaptic L-glutamic acid of postsynaptic, its activation may be relevant with pathology.Therefore, the selective antagonist of I class mGluR acceptor has the treatment meaning, during especially as neuroprotective or anticonvulsive agent.
As if the preliminary study to existing mGluR agonist and antagonist for treating measures of effectiveness draw the result of contradiction.For example, it is reported that ACPD is used for the hippocampal gyrus neurone can cause epileptic seizures and nerve injury.Sacaan etc., Neurosci.Lett.139:77 (1992); Lipparu etc., life science 52:85 (1993).But other studies show that ACPD can suppress epilepsy type activity, and also can show the character of neuro-protective.Taschenberger etc., Neuroreport3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh etc., Proc.Natl.Acad.Sci.USA 88:9431 (1991); Chiamulera etc., European pharmacology magazine 216:335 (1992); Siliprandi etc., European pharmacology magazine 219:173 (1992); Pizzi etc., J.Neurochem.61:683 (1993).
These contradiction the possibility of result are that it causes the activation of several different mGluRs hypotypes because ACPD lacks selectivity.In the research of finding neuronal damage, show that I class mGluRs is activated, therefore strengthened unwanted excitatory neuron transmission.In the research that presents the neuro-protective effect, show the activation that II class and/or III class mGluRs occur, and suppress presynaptic L-glutamic acid release and reduce the excitatory neuron transmission.
This kind explanation with find consistent; this discovery is (S)-4C3HPG; be I class mGluR antagonist and II class mGluRs agonist; can protect DBA/2 mouse AGS, and II class mGluR selective agonist DCG-IV and L-CCG-I can neuroprotective unit avoid NMDA-and KA inductive toxic action.Thomsen etc., J.Neurochem.62:2492 (1994); Bruno etc., European pharmacology magazine 256:109 (1994); Pizzi etc., J.Neurochem.61:683 (1993).
Describedly clear find out that because existing mGluR agonist and antagonist lack validity and selectivity, so its value is limited according to preceding.In addition, most of existing compounds are amino acid or the amino acid derivative with limited bioavailability, have therefore hindered the research to the evaluation of mGluR physiology, pharmacology and its therapeutic efficacy in vivo.Selectivity suppresses close metabolic (metabotropic) glutamate receptor I class hypotype activatory compound can be used for the treatment of nervous disorders and disease, as senile dementia, Parkinson ' s disease, Alzheimer ' s disease, Huntington ' tarantism, pain, epilepsy, cerebral trauma, anoxic and ischemic injury and mental disorder such as schizophrenia and dysthymia disorders.
Therefore, see obviously being starved of effective mGluR agonist and antagonist that they are to each mGluR hypotype independently, especially I receptoroid hypotype has high selectivity.
Summary of the invention
Therefore, the present invention seeks to identify metabotropic glutamate active acceptor compound, this compound exhibits is to each independently the height validity and the selectivity of metabotropic glutamate receptor hypotype, and the method for these compounds of preparation is provided.
Another purpose of the present invention provides medicinal compositions, and it comprises each other metabotropic glutamate receptor hypotype is shown the validity of height and compound optionally, and the method for preparing these medicinal compositionss is provided.
Still a further object of the present invention provides the method for the nerve injury that suppresses mGluRI receptoroid activatory method and suppress to be caused by the excited activation of mGluRI receptoroid.
A present invention also purpose provides the method that causes the nerve injury diseases associated with L-glutamic acid for the treatment of.
For realizing these purposes, the invention provides effective antagonist of I class metabotropic glutamate receptor.These antagonists can be represented by formula I.
The R-[-linking group-]-Ar
Wherein R is straight or branched-chain alkyl, aralkyl, cycloalkyl or an alkyl-cycloalkyl optional replacement, that contain 5-12 carbon atom.Ar be optional that replace, contain 10 carbon atoms of as many as and 4 heteroatomic aromatics of as many as, heteroaromatic, aralkyl or heteroaralkyl part, and [linking group] is-(CH 2) n-, wherein n is 2-6, and 4 CH of as many as wherein 2Group can be selected from C 1-C 3Alkyl, CHOH, CO, O, S, SO, SO 2, N, NH and NO group independently replace.Except when two atoms all are N or when all being NH, two heteroatomss in [linking group] are not adjacent one another are.Two adjacent CH in [linking group] 2Also can substituted or unsubstituted alkenyl or alkynyl group replacement.The present invention also provides the pharmacy acceptable salt of this compound.
In an embodiment of the present invention, Ar comprises ring system, it is selected from benzene, thiazole, furyl, pyranyl, the 2H-pyrryl, thienyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, benzothiazole, benzoglyoxaline, the 3H-indyl, indyl, indazolyl, purine radicals, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, the naphthyridine base, quinazolyl, cinnolinyl, isothiazolyl, quinoxalinyl, the indolizine base, pseudoindoyl, benzothienyl, benzofuryl, isobenzofuran-base and chromene basic ring.Ar can choose wantonly by two C of as many as 1-C 3Alkyl or nearly two halogen atoms independently replace, wherein halogen is 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 hydrogen atoms on two carbon atoms can choose wantonly independently be selected from F, Cl, OH, OMe ,=O and-substituting group of COOH replaces.
In another embodiment, [linking group] comprises acid amides, ester or thioester substrate.
In preferred embodiments, R comprises and is selected from following group: replace or unsubstituted adamantyl, the 2-adamantyl, (1S, 2S, 3S, 5R)-different loose amphene base (isopinocamphenyl), three ring [4.3.1.1 (3.8)] undecanes-3-base, (1S, 2R, 5S)-cis-Stenocalyx micheli's alkyl (myrtanyl), (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.
In another embodiment of the present invention, Ar comprises the group with following formula:
Figure A20041004749900151
X wherein 1, X 2, X 3And X 4Can independently be N or CH, condition be X 1, X 2, X 3And X 4In to be no more than two be N.In preferred embodiments, X 1Be N and/or X 2Be N.In another embodiment, X 3Be N.In another embodiment, X 1Be CH and X 2Be N.
In another embodiment, Ar is optional 2-, 3-or the 4-pyridyl part that replaces, and perhaps Ar is a 6-benzothiazole base section.This compound and pharmacy acceptable salt thereof are 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-adamantane esters, 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-quinoline formyl amine, N-(outer-2-removes first Camphanyl (Norbornanyl))-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-fluoro-[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.
In preferred embodiments, this compound and pharmacy acceptable salt thereof are selected from: N-(1-adamantyl)-3-quinoline formyl amine, 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-quinoline formyl amine, 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-[(1S, 2S, 3S, 5R)-3-pinane methyl]-2-quinoxaline methane amide, N-(1-diamantane methyl)-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.
In another embodiment, this compound and pharmacy acceptable salt thereof are 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 and N-(3-quinolyl)-1-diamantane methane amide, N-(3-methylcyclohexyl)-2-quinoxaline methane amide, N-(2, the 3-Dimethylcyclohexyl)-2-quinoxaline methane amide, N-[(1S, 2S, 3S, 5R)-3-pinane methyl]-2-quinoxaline methane amide, N-(1-diamantane methyl)-2-quinoxaline methane amide and N-(4-methylcyclohexyl)-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, 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 and N-(Beta-methyl styroyl)-2-quinoxaline methane amide.6-quinoline-1-diamantane methyl base ether.1-adamantanecarboxylic acid 6-quinoline ester, 6-quinoline first-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 and 3-quinolinecarboxylic acid 1-adamantane esters.
In another embodiment, this compound and pharmacy acceptable salt thereof are selected from: 3-(1-diamantane methoxyl group)-2-chloro-quinoxaline, 2-(1-diamantane methoxyl group)-3-methyl-quinoxaline, 3-(1-diamantane methoxyl group)-2-fluorine quinoxaline, 2-(1-diamantane methoxyl group)-3-trifluoromethyl quinoxaline, N-[2-(4-phenyl thiazole base)]-1-diamantane methane amide, N-[2-(5-methyl-4-phenyl thiazole base)]-1-diamantane methane amide, 1-(1-adamantyl)-2-(benzothiazole-2-base sulfane base) ethyl ketone, N-(1-adamantyl)-2-nitrogen quinoxaline-3-methane amide, N-(1-adamantyl)-3-methyl-quinoxaline-2-methane amide and N-(1-adamantyl)-1-oxo quinoxaline-3-methane amide.3-tonka bean camphor formic acid 4-chloro-phenyl-ester, 2-(1-diamantane methyl sulfane base) quinoxaline, 3-(1-diamantane methoxyl group)-2-chlorine piperazine, 1-(1-diamantane)-2-(4,6-dimethyl pyrimidine-2-base sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(2-anisyl sulfane base) ethyl ketone, 3-(1-diamantane methoxyl group)-1H-quinoxaline-2-ketone, 1-(1-adamantyl)-2-(3-anisyl sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(4-anisyl sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(4-chloro-phenyl-sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(2-naphthyl sulfane base) ethyl ketone, N-(2-[6-(piperidino) pyrazinyl])-1-diamantane methane amide, N-(2-[6-(piperidino) pyrazinyl]) diamantane-1-ylmethyl methane amide, 1-(1-adamantyl)-2-(1-naphthyl sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(8-quinolyl sulfane base) acetophenone hydrochloride, 1-(1-adamantyl)-2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl ketone, 2-(1-diamantane methoxyl group) quinoxaline, N-(trans-the 4-methylcyclohexyl)-2-quinoxaline methane amide, N-(cis-4-methylcyclohexyl)-2-quinoxaline methane amide, N-(trans 4-methylcyclohexyl)-2-quinoline formyl amine, N-(trans-the 4-methylcyclohexyl)-3-quinoline formyl amine and N-(trans-the 4-methylcyclohexyl)-6-quinoline formyl amine.2-(1-diamantane methylsulfinyl) benzothiazole; N-(4-phenyl butyl)-2-quinoxaline methane amide; 1-(1-adamantyl)-2-(4; 6-dimethyl pyrimidine-2-base sulfane base) ethanol; 1-(1-adamantyl)-2-(3-chloro-quinoxaline-2-yl) ethyl ketone; 2-(1-diamantane methyl sulfane base)-3-methyl-quinoxaline; N-(1-adamantyl)-2-anisamide; N-(1-diamantane methyl)-2-anisamide; 1-(1-adamantyl)-2-(4-chloro-phenyl-sulfane base) ethyl ketone; 2-(1-diamantane methyl sulphonyl)-3-methyl-quinoxaline; 1-(1-adamantyl)-2-(4-fluorophenyl sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(3-fluorophenyl sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(2-methoxyl group phenoxy group) ethyl ketone; 1-(4-anisyl sulfane base) fourth-2-ketone; 1-(1-adamantyl)-2-(4-anisidino) acetophenone hydrochloride; 3; 3-dimethyl-1-(4-anisyl sulfane base) fourth-2-ketone; 1-(4-phenylbenzene)-2-(4-anisyl sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(2-Trifluoromethoxyphen-l sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(3-methyl-quinoxaline-2-base sulfane base) ethyl ketone; 1-(1-diamantane)-2-(2-anisidino) acetophenone hydrochloride; 1-(1-adamantyl)-2-(4-Trifluoromethoxyphen-l amino) acetophenone hydrochloride; 1-(1-adamantyl)-2-(N-methyl-4-anisidino) acetophenone hydrochloride; N-(1-adamantyl)-7-Trifluoromethylquinocarboxylic-3-methane amide; N-(1-adamantyl)-2-(1-piperazinyl) quinoxaline-3-methane amide; N-(1-adamantyl)-2-(the amino ethylamino of 2-) quinoxaline-3-methane amide; methyl N-(3-quinolyl)-3-carboxyl diamantane-1-methane amide; 1-(1-adamantyl)-2-[(R)-1-(1-naphthyl) second-1-base is amino] ethyl ketone; N-(1-adamantyl)-2-methoxyl group quinoxaline-3-methane amide; ethyl n-(1-adamantyl)-2-(3-propionamido) quinoxaline-3-methane amide; N-(4-chloro-phenyl-)-2; 3-dimethyl quinoxaline-6-methane amide; N-(1-adamantyl)-6; 7-dimethyl quinoxaline-2-methane amide; N-((S)-1-tetrahydro naphthyl)-2-quinoxaline methane amide; N-(4-chlorobenzene ethyl)-2-quinoxaline methane amide; N-(6-quinolyl)-2-quinoxaline methane amide; N-(1-tetraline methyl)-2-quinoxaline methane amide; (1-(2 for N-; the 3-indanyl) methyl)-2-quinoxaline methane amide; N-(4, the 4-Dimethylcyclohexyl)-2-quinoxaline methane amide.
Another embodiment of the present invention provides medicinal compositions, and it contains the above compound of carrying and pharmaceutically acceptable thinner or vehicle.
Another embodiment of the present invention provides the method for the above compound of putting forward of preparation, and it comprises makes compound that contains activating carboxy acid's group and the compound reaction that contains amino, hydroxyl or thiol group.
Another embodiment of the present invention provides and suppresses mGluRI receptoroid activatory method, and it comprises with the above-claimed cpd of significant quantity handles the cell that comprises described mGluRI receptoroid.
Another embodiment of the present invention provides inhibition to activate the method for caused nerve injury by mGluRI receptoroid excitability, and it comprises with the above-claimed cpd of significant quantity handles the treatment neurone.
Another embodiment of the present invention provides the method for the treatment of the nerve injury diseases associated of being brought out with L-glutamic acid, and it comprises the above composition of carrying of patient's significant quantity of suffering from this disease.
In below describing in detail, will obviously see other purpose of the present invention, feature and advantage.But, should be clear: explanation that these are detailed and the specific embodiment in showing the preferred embodiments of the invention only supply the usefulness of explanation, reason is that the variations and modifications of not leaving in the spirit and scope of the invention are tangible to those those skilled in the art in this detailed specification sheets.
The chart brief introduction
Fig. 1 has shown to be exemplary compounds of the present invention.
                    Describe in detail
Compound provided by the invention is the effective and selective of I class metabotropic glutamate receptor Antagonist. The designed compound of the present invention can be represented by general formula I:
The R-[-linking group-]-Ar
Wherein R is alkyl, aralkyl or the optional alicyclic group that replaces of straight or side chain, Ar is optional aromatics, heteroaromatic, aralkyl or the heteroarylalkyl that replaces. [linking group] is Can not only with Ar and R part covalent bond, can also be easy to take just to establish by Ar and R Body directed and with the group of receptors bind.
The structure of Ar part
Although the person skilled in the art thinks that the Ar group with 10 above carbon atoms is at this Bright range, but the Ar part generally can contain 10 carbon atoms of as many as. Ar can Monocycle or the bicyclic aryl that condenses, alkaryl, heteroaryl or heteroarylalkyl. Ar is included Ring system can contain 4 hetero atoms of as many as, this hetero atom independently is selected from N, S or O. Work as Ar Be hetero-aromatic ring or hetero-aromatic ring when being, preferably contain one or two hetero atom. At least one of them Hetero atom N preferably.
Monocycle Ar group includes, but are not limited to: phenyl, thiazolyl, furyl, pyranose, 2H-pyrrole radicals, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyridine radicals, pyrazinyl, Pyrimidine radicals and pyridazinyl. Condensed-bicyclic Ar group includes, but are not limited to: benzothiazole, benzene And imidazoles, 3H-indyl, indyl, indazolyl, purine radicals, quinolizine base, isoquinolyl, Quinolyl, phthalazinyl, 1,5-phthalazinyl, quinazolyl, cinnoline base, isothiazolyl, Quinoxalinyl, indolizine base, isoindolyl, benzothienyl, benzofuranyl, different benzene And furyl and chromene base section. Ar is quinoxalinyl, quinolyl or pyridine radicals preferably.
Other Ar comprises 3,4-methylene-dioxy and 3,4-dioxane ring system. The Ar part can be appointed Choosing is by two C of as many as1-C 3Alkyl or nearly two halogen atom independently replace, wherein halogen selects From F, Cl, Br and I.
The R part-structure
Although the person skilled in the art thinks that the R part may have 12,13,14,15 or 16 Individual carbon atom, but R generally can contain 4-11 carbon atom. Although R can contain 4,5 or 6 Individual carbon atom, but R preferably contains at least 7 carbon atoms. R is the optional alkane that replaces preferably Base, cycloalkyl, methyl cycloalkyl or the optional phenylalkyl that replaces. Usually, R's Some or all hydrogen atoms on methine below two or two, methylene or the methyl all Can independently be selected from F, Cl, OH, OMe ,=O and-substituting group of COOH replaces. But Be, plural hydrogen atom can be replaced by F, and R can be that perfluor replaces.
Example R partly includes, but are not limited to: adamantyl, 2-adamantyl, (1S, 2S, 3S, 5R)-different loose amphene base, three ring [4.3.1.1 (3.8)] hendecanes-3-base, (1S, 2R, 5S)-Cis-hill gooseberry's alkyl, (1R, 2R, 4S)-isobornyl, (1R, 2R, 3R, 5S)-different loose amphene base, (1S, 2S, 5S)-trans-hill gooseberry's alkyl, (1R, 2R, 5R)-trans-hill gooseberry's alkyl, (1R, 2S, 4S)-bornyl, 1-adamantane methyl, 3-remove first adamantyl (1S, 2S, 3S, 5R)-3-Pinane methyl, ring octyl group, dimethyl benzene ethyl, (S)-2-phenyl-1-propyl group, suberyl and 4-Methyl-2-hexyl. Each of these examples R part can be got by the above mode of carrying Generation.
Other preferred R comprises 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, 2-methyl Cyclohexyl, 3,3,5-trimethylcyclohexyl, 2-(o-methoxyphenyl) ethyl, (1,2,3,4-four for 2-The hydrogen naphthyl), 4-phenyl butyl, 2-methyl-2-phenyl butyl, 2-(fluorophenyl) ethyl, 2-are (right Fluorophenyl) ethyl, 2-(3-hydroxyl-3-phenyl) propyl group, (S)-2-hydroxyl-2-phenylethyl, (R)-2-Hydroxyl-2-phenylethyl, 2-(chlorphenyl between 3--2-methyl) propyl group, 2-(3-rubigan-2-methyl) Propyl group, 4-tert-butylcyclohexyl, (S)-1-(cyclohexyl) ethyl, 2-(3-(3,4-3,5-dimethylphenyl)-2-Methyl) propyl group, 3,3-dimethylbutyl, 2-(5-methyl) hexyl, 1-hill gooseberry's alkyl, 2-borneol Base, 3-pinane methyl, 2,2,3,3,4,4,5,5-octafluoro amyl group, to fluoro-2,2-dimethyl benzene ethyl, 2-naphthyl, 2-bornanyl, cyclohexyl methyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4-Dimethylcyclohexyl, 5-chloro-three encircle [2.2.1] heptyl, neighbours-.-dimethyl benzene ethyl, (2,3-two for 2-The hydrogenation indenyl), 2-spiral shell [4.5] decyl, 2-phenylethyl, 1-adamantyl ethyl, 1-(1-two rings [2.2.1] heptan-the 2-yl) ethyl, 2-(2-methyl-2-phenyl propyl), 2-(adjacent fluorophenyl) ethyl, 1-(ring Hexyl) ethyl, cyclohexyl, fourth-2-acyl group (butan-2-only), diphenylene, 3-carboxyl gold Firm alkyl, 1-tetralyl, 1-(2,3-indanyl), 4-methylcyclohexyl and 4,4-diformazan Basic ring hexyl part. In these examples R part each can be by the above mode of carrying Be substituted. When there is other isomery configuration in these compounds, for example, cis-or trans-The 4-methylcyclohexyl, the R part can have any possible configuration. Similarly, if compound Have enantiomer, R can be enantiomer or raceme.
The structure of [linking group] part
[linking group] generally has structure-(CH2) n-, wherein n is 2-6. 4 CH of as many as2C can be selected from1-C 3Alkyl, CHOH, CO, O, S, SO, SO2, N, NH and NO group independently replace, condition is: except when these two atoms all are N (formation-N=N-keys) Or when all being NH (NH-NH-key), two hetero atoms can not be adjacent one another are. Any two phases Adjacent CH2Group also can be replaced by alkenyl or alkynyl group.
In preferred embodiments, [linking group] comprises acid amides, ester, thioesters, ketone group Asia Methyl (ketomethylene), ether, alkyl ether, 1,2-ethylidene, vinyl, acetenyl, Hydroxy alkyl, alkyl sulfone or alkyl-alkyl sulfoxide. [linking group] preferably-O-(CH2) m-、 -CO-Y-(CH 2) m-or-S (O)n-(CH 2) m-, wherein Y is CH2, NH, O or S, m is 1-4, n are 0-2. For two kinds of directed things of possibility of Ar and R, [linking group] can have Wherein any. Therefore, for example, the present invention includes and have configuration R-O-(CH2) m-Ar and R-(CH2) mThe compound of-O-R.
The design of MGluRI class antagonist is with synthetic
In one embodiment, The compounds of this invention be monocycle or the bicyclic ring system aromatics that condenses and The ester of heteroaromatic carboxylic acids, phenol and amine and acid amides. In preferred embodiments, this chemical combination Thing can be represented by formula II or III:
In formula II or III, Y can be O, S, NH or CH2；X 1、X 2、X 3And X4Can independently be N or CH. Preferred X1、X 2、X 3And X4In one or two be N, its That surplus is CH. The designed preferred compound of the present invention has formula IV or V, wherein R, Y And X1Define the same.
Figure A20041004749900232
In another preferred embodiment of the present invention, compound has formula VI or VII:
Figure A20041004749900233
Wherein R and Y definition is the same. In first embodiment of formula VI compound, Y Be N, R does not replace or mono-substituted 1,1-phenpromethamine or 1,1-dimethyl benzene methylamine Part, wherein this substituting group preferably adjacent-,-or right-chlorine or to methoxyl group. In formula VIization In second embodiment of compound, Y is N, R be adjacent-,-or the benzene of right-methoxy substitution Ethamine. As if the compound of first and second embodiments demonstrate selection to the mGluR acceptor The property. In the 3rd embodiment of formula VI compound, Y is N, R be adjacent-,-or right-The phenyl ethylamine that fluorine replaces. The compound of the 3rd embodiment is at mGluR1And mGluR5Acceptor Do not demonstrate difference between the hypotype.
In another preferred embodiment of the present invention, compound has formula VIII or IX:
Figure A20041004749900241
X wherein 1-4The same with the R definition.In first embodiment of formula VIII compound, X 1And X 2Be N, X 3And X 4Be H,, R is the 1-adamantyl, and with linking group and X 2There is substituting group on all adjacent carbon atom.This substituting group is halogen preferably, as chlorine, or alkyl, as methyl.In second embodiment of formula IX compound, R is the 1-adamantyl.The compound of first and second embodiments is to mGluR 1As if acceptor demonstrate selectivity.
In another embodiment, compound can have formula X or XI, and wherein Z is pharmaceutically acceptable substituting group.The person skilled in the art should be appreciated that these pharmaceutically acceptable Z groups are those groups that do not reduce the receptor-binding activity of this compound nocuously.Suitable Z group includes, but are not limited to halogen, low alkyl group, oxygen or amine, with and pharmaceutically acceptable derivates, comprise ether, ester and acid amides.Z preferably contains 0-4 carbon atom.
In above-described each compound, " alkyl " refers to the alkyl of straight chain and side chain.In other embodiments, R is an adamantyl, and this linking group is-CO-CH 2-S-, Ar be between the position or the ortho position alkoxyl phenyl, 3,4-methylene-dioxy or 3,4-dioxane.
In a word, use formula R-CO-N-Ar 1Compound can obtain mGluR 1The selective antagonist of acceptor, wherein Ar 1Be aromatics or heteroaromatic group, as quinolyl, quinoxalinyl, thiazolidyl, phenyl, benzimidazolyl-or pyridyl.
The person skilled in the art knows that compound of the present invention comprises the salt of the above compound.These salt comprise pharmaceutically-acceptable acid addition, pharmaceutically acceptable metal-salt or optional alkylation amine salt, the salt of example hydrochloric acid salt, hydrobromate, hydriodate, phosphoric acid salt, vitriol, trifluoroacetate, malonate, succinate, citrate, mandelate, benzoate, cinnamate, mesylate or class acidoid, comprise and the pharmaceutical science magazine, the salt that the relevant acid of listed pharmacy acceptable salt forms among the 66:2 (1977) is incorporated among the present invention as a reference.
Following table 1 is listed the example of The compounds of this invention.
The preparation of mGluRI class antagonist
The person skilled in the art knows: use well-known technique of organic chemistry, by method well known in the art, can prepare mGluRI class antagonist of the present invention.Illustrate in the suitable standard that the is reflected at organic chemistry textbook.For example, see March, Advanced Organic Chemistry, second edition, McGraw Hill (1977).
For example, this compound generally forms and should [linking group] prepare by containing between suitable Ar and the R precursor compound partly at two.When this linking group contains amido linkage, the available technology of knowing forms this acid amides, for example by prepared in reaction between amine and the acyl chlorides, or passes through at coupler, there is prepared in reaction down as carbonyl dimidazoles or carbodiimide (as 1,3-dicyclohexyl carbodiimide (DCC)).Can form ester bond or thioester bond in a similar manner.
When this [linking group] when containing ehter bond, also the available standards technology prepares this ether functional group.For example use the Mitsunobu reaction and form ether, wherein by using PPh 3And diethylazodicarboxylate (DEAD) activation, primary alcohol functions is replaced with another hydroxyl.Thioether bond can be by the anionic replacement(metathesis)reaction preparation of the thiolate that leavings group (as halogen) and thiol group and alkali deprotonation effect are produced.
When this [linking group] contained the ketone group methylene radical, it can form by the alkylation of ketone enol ester.For example use highly basic such as di-isopropyl lithamide (LDA) with the methyl ketone deprotonation, then with the alkylogen prepared in reaction.In addition, can then make resulting hydroxyl oxidize reaction generate ketone and prepare this ketone group methylene radical functional group by organometallic compound (as Grignard reagent) is joined in the aldehyde.The suitable reagent that in this area alcohol is oxidized to ketone is well-known.
Contain the also available method preparation well known in the art of other heteroatomic [linking group] part.N, N '-two replace hydrazine compound can be by will singly replacing the hydrazone reduction amination effect preparation that hydrazone and aldehyde reaction form.N, N '-two replace azo-compound can be passed through, as the oxidizing reaction formation of corresponding hydrazine.
In most cases, precursor Ar and R partly are easy to obtain, and perhaps can use the simple technology preparation of organic chemistry.Chemical compound lot is commercially available, as by Aldrich ChemicalCompany, and Milwaukee, WI provides.When these compounds can not be by commercially available acquisition, they can be prepared with simple transformation well known in the art by existing precursor.
For example, by reacting, carboxylic acid can be changed into corresponding acyl chlorides with for example thionyl chloride or oxalyl chloride.This reaction example provides in following examples 3.The compound that contains hydroxy functional group can be changed into corresponding amine by following 3 methods and hydroxyl be changed into leavings group by (i), as sulphonate (as triflate, methanesulfonates or tosylate) or halogenide, (ii) replace by azides ion (azide ion), (iii) with the trinitride reduction that obtains, by, for example, through the platinum-oxide catalyst hydrogenation.This conversion explanation is provided in following examples 12.
Measure the antagonistic activity of compound to mGluR class I
Available standards function activity experiment is analyzed the pharmacological properties of The compounds of this invention.The embodiment of glutamate receptor experiment knows in this area, for example, sees Aramori etc., neurone 8:757 (1992); Tanabe etc., neurone 8:169 (1992).Methodology described in these publications is attached to the present invention as a reference.
Usually, application can be measured the migration inhibition test research The compounds of this invention of cellular calcium in the cell of express recombinant acceptor, and this receptor can combine with The compounds of this invention.Suitable receptor structure is known in this area, and also explanation in as WO 97/05252, and document full content is attached among the present invention as a reference.
Therefore, the DNA component stability ground transfection HEK-293 cell of available expression recombinant receptor (HEKC, American Type Culture Collection.Rockville, MD, number of registration CRL 1573).In the high glucose DMEM (Gibco 092) that comprises 0.8mM L-glutamic acid, 10%FBS and 200 μ M hygromycin B, cultivate this stable transfection cell.
Below narrated the scheme of measuring the cellular calcium transfer that changes with the outer calcium of born of the same parents with calcium sensitive dye Fura.Saying simply, is with HEK-293 cell (the DNA component stability cells transfected of the recombinant receptor of promptly encoding) load Fura dyestuff.Then with cell washing, resuspending, and remain under 37 ℃.With these cell dilutions to the cup (cuvettes) that is used for writing down fluorescent signal.Under 37 ℃, measure fluorescence with standard method, and use the dissociation constant (Kd) under the 224nM and use Ca in the following Equation for Calculating born of the same parents 2+Concentration:
[Ca 2+] i＝(F-F min/F min)×Kd
Wherein F is at any required time point place fluorescence, F MinBe the measured value of all the obtained calcium of chelating, therefore do not have Fura 2 and combine with calcium, and F MaxIt is the measured value under complete saturated all Fura 2 of calcium.
The following example 15 provides the detailed protocol of test The compounds of this invention.
Preparation contains the mGluR antagonist and can be used for treating the medicinal compositions of sacred disease
The compounds of this invention is used for the treatment of nervous disorders or disease.Though generally use these compounds for treating human patientses, also can be used as the similar or identical disease of veterinary drug treatment.
When being used for the treatment of and/or diagnose, The compounds of this invention can be mixed with and be used for various administering modes, comprise whole body and part or site-specific delivery of drugs.Technology and formulation are generally seen Remington Pharmaceutical Sciences: Drug Receptors and Receptor Theory, the 18th edition, Mack Publishing Co. (1990).
The compounds of this invention is effective in very wide dosage range.For example, in the treatment adult, the about 0.01-1000mg of doses available every day, preferred 0.5-100mg.Most preferred dosage about 2-70mg every day.Accurately dosage is decided according to route of administration, the form that gives compound, the patient who receives treatment, patients receiving treatment's body weight and doctor in charge's preference and experience.
Those this areas common person skilled in the art generally understand for pharmacy acceptable salt very much, this salt can comprise following example, but is not limited to: acetate, benzene sulfonate, besylate, benzoate, supercarbonate, bitartrate, bromide, Ca-EDTA, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutaminate, bismuth glycolyl arsanilate salt, hexyl resorcin(ol) salt, hydrabamine, hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, isethionate, lactic acid salt, Lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/phosphor acid hydrogen salt, Polygalacturonate, salicylate, stearate, alkali formula acetate, succinate, vitriol, tannate, tartrate or teoclate.Other pharmacy acceptable salt as seen, for example, Remington Pharmaceutical Sciences: (the 18th edition) Mack Publishing Co., Easton, PA (1990).
The salt of preferred pharmaceutical compositions comprises: as acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromate, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphoric acid salt, salicylate, succinate, vitriol or tartrate.
According to the disease specific of being treated, these medicines can be made the liquid or solid formulation and carry out whole body or topical.For example, with known timing of those skilled in the art or slowly-releasing form, transmit this medicine.The technology and the administering mode of preparation are seen Remington Pharmaceutical Sciences: (the 18th edition) Mack Publishing Co., Easton, PA (1990).That suitable approach comprises is oral, in the cheek, hypogloeeis, rectum, through skin, vagina, through mucous membrane, nasal cavity or enterally administering; Non-enteron aisle transmission comprises intramuscular, subcutaneous, intramedullary injection, and in the sheath, directly in the ventricle in (direct intraventricular), vein, intraperitoneal, the nose or intraocular injection, just lists a little.
For injecting, medicine of the present invention can be made the aqueous solution, the damping fluid of preferred physical compatibility is as Hank solution, Ringer solution or physiological saline.For mucosal, should in this formulation, use the suitable permeate agent that can see through barrier.In the art, these permeate agents are generally known.
Use pharmaceutically acceptable carrier, this is mixed with suitable formulation for the invention process disclosed compound is also included within the scope of the invention for the method for whole body administration.Correct carrier and the suitable preparation method of selecting can be with composition of the present invention (especially those pharmaceutical solutionses) through parenterai administration, as intravenous injection.Use pharmaceutically acceptable carrier well known in the art, can easily this compound be made and be suitable for oral formulation.These carriers can make The compounds of this invention be made into tablet, pilule, capsule, liquid, gelifying agent, syrup, paste, suspension agent etc. and supply patient's oral absorption of being treated.
The medicinal compositions that is suitable among the present invention comprises that those wherein contain the composition of this active ingredient of the significant quantity that can reach its intended purposes.Determine that this significant quantity is fully within those person skilled in the arts' of this area ability, particularly by means of after the detailed description mentioned herein.
Except that activeconstituents, these medicinal compositionss can comprise suitable pharmaceutically acceptable carrier, and it comprises vehicle and auxiliary, and they help active compound is processed into can be at the preparation that pharmaceutically uses.The preparation of making oral administration can be the form of tablet, lozenge, capsule or solution.
The preparation of oral administration can be by mixing active compound with solid excipient, the resulting mixture of optional grinding adds after the suitable auxiliary then, makes granular mixture and obtains, if requirement can be made into tablet or lozenge.Appropriate excipients is that especially, weighting agent such as sugar comprise lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulosics is as W-Gum, wheat starch, rice starch, yam starch, gelatin, tragacanth gum, methylcellulose gum, HPMC, Xylo-Mucine (CMC) and/or polyvinylpyrrolidone (PVP; Povidone).If requirement can add disintegrating agent, as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, as sodiun alginate.
Lozenge can carry out suitable dressing.For this reason, can use priming, its optional Sudan Gum-arabic, talcum powder, polyvinylpyrrolidone, carbopol glue, polyoxyethylene glycol (PEG) and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture of comprising.Dyestuff or pigment can be joined and be used to prove or illustrate that the difference of active compound doses forms in the dressing of tablet or lozenge.
The seal capsule and the softening agent that can be used for sucking fit (push-fit) capsule that oral medicinal preparations comprises that gelatin is made and soft capsule, be made by gelatin are as glycerine or sorbyl alcohol.The sucking fit capsule can comprise activeconstituents, and the weighting agent that is mixed with is as lactose, tackiness agent, as starch and/or lubricant, as talcum powder or Magnesium Stearate and optional stablizer.In soft capsule, active compound can be dissolved in or be suspended in the suitable liquid, as fatty oil, whiteruss or liquid macrogol (PEGs).In addition, can add stablizer.
Can easier understanding so lead to the present invention who states with reference to following examples, these embodiment only for explanation, do not limit the scope of the invention.
Embodiment
General experimental technique
Capillary gas chromatography and mass-spectrometric data record with Hewlett-Packard (HP) 5890II type gas-chromatography, the coupled HP 5971 type Series Mass Selector Detector (mass selective detector) of this chromatographic instrument [the super performance capillary column of Ultra-2 (crosslinked 5%PhMe polysiloxane); Column length, 25m; Column internal diameter, 0.20mm; Helium flow speed, 60mL/min; Injector temperature, 250 ℃; Temperature program(me) from 125-325 ℃, was carried out 10 minutes with 20C/min, kept 6 minutes at 325 ℃ then].Thin-layer chromatography carries out with Analtech Uniplate 250 μ m silica gel H F TLC plates.With measuring compound on the TLC plate in conjunction with the UV lamp of ninidrine and Dragendorff streak reagent (Sigma Chemical Co.) sometimes.Agents useful for same is 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) locates to buy.
Embodiment 1: preparation N-[6-(2-toluquinoline base)]-1-diamantane methane amide (40)
2-methyl-6-quinolylamine
Under 60 ℃ and hydrogen, with 2-methyl-6-nitroquinoline (1.00g, 5.31mmol) and Pearlman ' s catalyzer [be stated from two palladium hydroxides (about 20% palladium) on the gac; 0.10g] ethyl acetate (40ml) mixture stirred 1.5 hours.Filter this reaction mixture, with the filtrate rotary evaporation.Obtain 2-methyl-6-quinolylamine of 0.81g (96%), be yellow solid.
N-[6-(2-toluquinoline base)]-1-diamantane methane amide (40)
(1.02g, pyridine 5.13mmol) (2mL) liquid join 2-methyl-6-quinolylamine, and (0.81g is in pyridine 5.1mmol) (8mL) solution with 1-diamantane formyl chloride.This reaction solution was stirred 17 hours.In the reaction mixture of this stirring, add entry (100mL), cause the product precipitation.With sedimentation and filtration, water (3 * 25mL) and ether (3 * 25mL) washing.Obtain 1.07g (65%) (40), be the lacteous 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).
By similar method, N-quinolyl-1-diamantane methane amide that preparation is following
N-(6-quinolyl)-1-diamantane methane amide (18)
With 1-diamantane formyl chloride (1.37g, 6.90mmol), the 6-quinolylamine (0.59g 4.1mmol), the preparation of pyridine (20mL) and water (200mL), obtains (18) of 1.25g (100%):
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-diamantane carboxamide hydrochloride (81)
With 1-diamantane formyl chloride (0.75g, 3.8mmol), the 2-quinolylamine (0.60g, 4.2mmol), the preparation of pyridine (10mL) and water (100mL).Hydrogenchloride with etherization forms hydrochloride, obtains (81) of 0.19g (15%):
Retention time=12.24min.; 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-diamantane methane amide (86)
With 1-diamantane formyl chloride (0.75g, 3.8mmol), the 3-quinolylamine (0.60g 4.2mmol), the preparation of pyridine (10mL) and water (100mL), obtains (86) of 0.33g (29%):
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-the 4-methylcyclohexyl)-2-quinoxaline methane amide (299)
Use Booth (J.Chem.Soc., 1958,2688; J.Chem.Soc., 1971,1047; Tetrahedron .1967,23,2421) method, at room temperature, with azanol (3.8g, 55mmol), ethanol (50mL), pyridine (4.44mL, 55mmol) and the 4-methylcyclohexanone (6.1mL 50mmol) stirred 16 hours, and reflux is 15 minutes then.Vacuum is removed ethanol again, then residual oily matter is dissolved in the ethyl acetate (100mL).With organic layer water (2X), salt water washing, through anhydrous MgSO 4Drying is filtered, and concentrates and obtains clarifying oily matter (this oxime product), places crystallization.
To use (branch small portion) sodium metal (4g) to handle again without dehydrated alcohol (40mL) reflux of this intermediate oxime of the 1.9g that is further purified (15mmol).The reaction solution reflux is exhausted until sodium.With this reactant cooling, water (10mL) is handled.With this reactant transfer to comprising in ice and the flask of dense HCl (6mL).Vacuum is removed ethanol, and residual water is washed (3X removes the oxime that is not reduced) with ether.With the concentrated 1.8g white crystalline solid (trans-4-methyl cyclohexylamine hydrochloride product) that obtains of residual water.
Methylene dichloride (10mL) liquid that will-4-methyl cyclohexane amine hydrochlorate trans without the 750mg that is further purified (5mmol) with pyridine (1.62mL 20mmol) handles, then add 2-quinoxaline acyl chlorides (963mg, 55mmol).Under the room temperature, should react and stir 16 hours, use chloroform (25mL) dilution then.With organic layer 10%HCl (3X), 1N NaOH (3X), salt water washing, through anhydrous MgSO 4Drying is filtered, and concentrates and obtains solid.This crude reaction material through silica gel (7 * 4cm internal diameter, BIOTAGE, KP-SIL, 60 dusts), is obtained the desired product of 470mg with ethyl acetate-hexane (1: 4) stratographic analysis (MPLC), N-(trans-the 4-methylcyclohexyl)-2-quinoxaline methane amide.Thin-layer chromatography (TLC, silica gel) with ethyl acetate-hexane (1: 4) demonstrates at R f0.19 single UV active ingredient of locating.GC/EI-MS obtains 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 6-quinolyl 1-adamantanecarboxylic acid ester (41)
(1.37g, pyridine 6.90mmol) (5mL) liquid join the 6-hydroxyquinoline, and (1.00g is in pyridine 6.89mmol) (15mL) solution with 1-diamantane formyl chloride.This reaction solution was stirred 16 hours.In the reaction mixture of this stirring, add entry (200mL), cause the product precipitation.With sedimentation and filtration, water (3 * 50mL) washings, high vacuum dry.Obtain 1.56g (73.7%) (41), be 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 6-quinolinecarboxylic acid 1-adamantane esters (61)
6-quinoline formyl villaumite hydrochlorate
In thionyl chloride, the 6-quinolinecarboxylic acid was refluxed 30 minutes.By rotary evaporation (90 ℃), remove excessive thionyl chloride and obtain 6-quinoline formyl villaumite hydrochlorate then.
6-quinolinecarboxylic acid 1-adamantane esters (61)
(0.76g, pyridine 3.3mmol) (2mL) liquid join the 1-adamantanol, and (0.60g is in pyridine 3.9mmol) (8mL) solution with 6-quinoline formyl villaumite hydrochlorate.Under 70 ℃, this reaction solution was stirred 16 hours.In the reaction mixture of this stirring, add entry (100mL), cause the product precipitation.With sedimentation and filtration, water (3 * 50mL) washings again.Filter cake is dissolved in the ethanol (20mL), adds entry then to cloud point (16mL).Place and made solution crystallization in 15 hours.Filter, high vacuum dry obtained (61) of 0.32g (26%) in 7 hours, was light brown needle crystal:
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).
By similar method, prepare following 6-quinoline and 2-quinoxaline alkyl ester:
2,2,3,3,4,4,5,5-octafluoro-1-amyl group-6-quinoline-manthanoate hydrochloride (68)
With 6-quinoline formyl villaumite hydrochlorate (0.75g, 3.3mmol), 2,2,3,3,4,4,5,5-octafluoro-1-amylalcohol (0.60mL, 4.3mmol), pyridine (10mL) and water (100mL) preparation.Hydrogenchloride with etherificate forms hydrochloride, obtains (68) of 0.88g (69%):
Retention time=7.11min.; 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).
6-quinolinecarboxylic acid 1-diamantane methyl esters (73)
With 6-quinoline formyl villaumite hydrochlorate (0.80g, 3.5mmol), 1-diamantane methyl alcohol (0.60mL, 3.6mmol), the preparation of pyridine (10mL) and water (100mL).Obtain 0.75g (65%) (73):
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).
2-quinoxaline formic acid 1-adamantane esters (92)
With 2-quinoxaline acyl group (quinoxaloyl) villaumite hydrochlorate (0.84g, 4.4mmol), 1-diamantane methyl alcohol (0.60mL, 3.9mmol), the preparation of pyridine (10mL) and water (100mL).Obtain 0.20g (16%) (92):
Retention time=11.21min.; 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).
Embodiment 4:N-(1-adamantyl)-3-quinoline formyl amine (72)
With 1, (161mg, N 1.00mmol), dinethylformamide (1mL) liquid once join the 3-quinolinecarboxylic acid, and (173mg, N 1.00mmol) is in dinethylformamide (1mL) suspension for 1 '-carbonyl dimidazoles.The reaction soln that obtains was stirred 2.5 hours.Once add 1-amantadine (adamantanamine) (151mg, N 1.00mmol), dinethylformamide (0.5mL) liquid.Under 60 ℃, reaction mixture was stirred 2 hours.Then this reaction solution is diluted water (3 * 30mL) washings with chloroform.With organic layer drying (anhydrous magnesium sulfate), through filtered through silica gel, rotary evaporation again.Obtain 73mg (24%) (72), be crystalline solid:
Retention time=11.02min.; 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).
By similar approach, prepare following N-alkyl-2-quinoline-and 2-quinoxaline methane amide:
N-(1-adamantyl)-2-quinoline formyl amine (74)
With 1,1 '-carbonyl dimidazoles (160mg, 0.987mmol), quinaldinic acid (173mg, 1.00mmol) and N, dinethylformamide (2.5mL) preparation obtains 77mg (25%) (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 methane amide (144)
With 1,1 '-carbonyl dimidazoles (161mg, 1.00mmol), the 2-quinoxaline carboxylic acid (174mg, 1.00mmol), the 2-amantadine (136mg 0.90mmol) and methylene dichloride (3.5mL) preparation, obtains (144) of 98mg (35%):
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-pinane methyl]-2-quinoxaline methane amide (151)
With 1,1 '-carbonyl dimidazoles (161mg, 1.00mmol), the 2-quinoxaline carboxylic acid (174mg, 1.00mmol), (-)-3-pinane methylamine (150mg 0.90mmol) and methylene dichloride (3.5mL) preparation, obtains (151) of 50mg (17%):
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).
Embodiment 5:N-(1-adamantyl)-2-quinoxaline methane amide (91)
(0.84g, (0.60g is in pyridine 4.0mmol) (10mL) solution 4.4mmol) to join the 1-amantadine with 2-quinoxaline acyl chlorides.Then this reactant was stirred 30 minutes.In the reaction mixture of this stirring, add entry (100mL), cause the product precipitation.With this sedimentation and filtration, water (3 * 25mL) washings, high vacuum dry 16 hours.Obtain 1.00g (82%) (91):
Retention time=11.73min.; 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).
By similar approach, prepare the 6-quinoline that following N-replaces-and 2-quinoxaline methane amide:
N-(1-adamantyl)-6-quinoline formyl amine (42)
With 6-quinoline acyl chloride hydrochloride (1.51g, 10mmol), the 1-amantadine (1.73g 10mmol), the preparation of pyridine (5mL) and water (200mL), obtains (42) of 330mg (11%):
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-(outer-2-removes the first Camphanyl)-2-quinoxaline methane amide (148)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), outer-2-amino go the first camphane (133mg, 0.90mmol), pyridine (5mL) and water (50mL) prepares, and obtains (148) of 35mg (15%):
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-quinoxaline methane amide (150)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), (R)-(+)-bornyl amine (138mg 0.90mmol), the preparation of pyridine (5mL) and water (50mL), obtains (150) of 140mg (50%):
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-removes the first adamantyl)-2-quinoxaline methane amide (152)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), 3-removes the first amantadine (157mg 0.90mmol), the preparation of pyridine (5mL) and water (50mL), obtains (152) of 167mg (63%): 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)-different loose amphene base]-2-quinoxaline methane amide (165)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), (1R, 2R, 3R, 5S)-(-)-different loose camphane alkenyl amine (138mg 0.90mmol), the preparation of pyridine (5mL) and water (50mL), obtains (165) of 230mg (83%):
Retention time=10.88min.; 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)-different loose amphene base]-2-quinoxaline methane amide (166)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), (1S, 2S, 3S, 5R)-(+)-different loose camphane alkenyl amine (138mg 0.90mmol), the preparation of pyridine (5mL) and water (50mL), obtains (166) of 208mg (75%):
Retention time=10.88min.; 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-chlorine three ring [2.2.1.0 (2,6)] heptane-3-yl)-2-quinoxaline methane amide (167)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), 5-chlorine three ring [2.2.1.0 (2,6)] heptane-3-base amine (129mg, 0.90mmol), pyridine (5mL) and water (50mL) prepares, and obtains (167) of 100mg (37%):
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-(three ring [4.3.1.1 (3,8)] undecanes-3-yl)-2-quinoxaline methane amide (168)
With 2-quinoxaline acyl chlorides (135mg, 0.70mmol), three ring [4.3.1.1 (3,8)] undecanes-3-base amine hydrochlorates (100mg, 0.60mmol), pyridine (5mL) and water (50mL) prepares, and obtains (168) of 110mg (57%):
Retention time=12.52min.; 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-Stenocalyx micheli's alkyl]-2-quinoxaline methane amide (169)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), (-)-cis-Stenocalyx micheli's alkylamine (138mg 0.90mmol), the preparation of pyridine (5mL) and water (50mL), obtains (169) of 224mg (81%):
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-quinoxaline methane amide (170)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), (138mg 0.90mmol), the preparation of pyridine (5mL) and water (50mL), obtains (170) of 130mg (81%): retention time=10.76min. in (R)-(-)-iso-borneol amine; 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).
In the N-[(-(±)-2-removes the first Camphanyl)-2-quinoxaline methane amide (171)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), interior-(±)-2-amino go the first camphane (133mg 0.90mmol), the preparation of pyridine (5mL) and water (50mL), obtains (171) of 175mg (73%):
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 group]-2-quinoxaline methane amide (172)
With 2-quinoxaline acyl chlorides (0.47g, 2.4mmol), (R)-2-phenyl-1-propylamine (0.30g 2.2mmol), the preparation of pyridine (5mL) and water (50mL), obtains (172) of 0.49g (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 group]-2-quinoxaline methane amide (173)
With 2-quinoxaline acyl chlorides (0.47g, 2.4mmol), (S)-2-phenyl-1-propylamine (0.30g 2.2mmol), the preparation of pyridine (5mL) and water (50mL), obtains (173) of 0.48g (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, the 3-indanyl)]-2-quinoxaline methane amide (221)
With 2-quinoxaline acyl chlorides (0.32g, 1.7mmol), 2-amino-1, the 2-indane (0.20g 1.5mmol), pyridine (3mL) and water (30mL) preparation, obtains (221) of 0.23g (53%):
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-encircles octyl group-2-quinoxaline methane amide (228)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), the ring octyl amine (123 μ L, 114mg, 0.90mmol), pyridine (5mL) and water (100mL) prepares, and obtains (228) of 100mg (39%):
Retention 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), 1 03 (20), 102 (50), 76 (13), 75 (12), 67 (6), 56 (7), 55 (9), 51 (6), 43 (6), 41 (16).
N-suberyl-2-quinoxaline methane amide (229)
With 2-quinoxaline acyl chlorides (193mg 1.0mmol), cycloheptylamino (115 μ L, 102mg, 0.90 mmol), pyridine (5mL) and water (100mL) preparation, obtains (229) of 30mg (12%):
Retention 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-spiral shell (4,5) decyl]-2-quinoxaline methane amide (236)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), amino spiral shell (4, the 5) decane of 2-(150mg, 0.79mmol), pyridine (5mL) and water (100mL) prepares, and obtains (236) of 206mg (74%):
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 1-diamantane methyl 6-quinolyl ether (94)
(5.00g, 30.0mmol) (13.1g, the mixture of tetrahydrofuran (THF) 90.2mmol) (75mL) stirred 15 minutes with the 6-hydroxyquinoline with 1-diamantane methyl alcohol.Add then triphenyl phosphine (10.2g, 39.0mmol), then add diethyl azodiformate (6.14mL, 39.0mmol).This reaction mixture was refluxed 18 hours.Rotary evaporation removes and desolvates then.(3 * 25mL) pass through filter paper filtering with the jelly that obtains with ether.With the filtrate rotary evaporation, (3 * 25mL passes through filter paper filtering with the jelly that obtains to use hexane again.Again with the filtrate rotary evaporation, use then hexane (3 * 25mL) with the jelly that obtains by filter paper filtering, rotary evaporation filtrate again.Obtain the crude product of 3.8g (43%), be red oil.This oil reservoir is analysed (94) that (2: 1 hexane/ethyl acetate) obtains 1.6g (18%):
Retention time=11.29min.; 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).
Embodiment 7: preparation 3-quinolinecarboxylic acid 1-adamantane esters (101)
With 1-adamantanol (152mg, 1.0 mmol), 3-quinoline carboxylic acid (173mg, 1.0mmol) and dimethylamino pyridine (mixture in the dinethylformamide (2mL) is cooled to 0 ℃ for 122mg, methylene dichloride 1.0mmol) (2mL) and N.Once add 1,3-dicyclohexyl carbodiimide (227mg, methylene dichloride 1.1mmol) (1mL) liquid.Under 25 ℃, this reaction mixture was stirred 20 hours.Then this reaction mixture is diluted with methylene dichloride (40mL), with (3 * 30mL) washings of 1M sodium hydroxide.With organic layer drying (anhydrous magnesium sulfate), filter by Celite, again rotary evaporation.The material that obtains is through rotary thin layer chromatogram (chloroform solution of 3% methyl alcohol) purifying.With the purest partial rotation evaporation, again with the material ethyl alcohol recrystallization that obtains.Obtain 42mg (14%) (101):
Retention time=7.78min.; 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).
Embodiment 8: preparation N-(α, alpha-alpha-dimethyl styroyl)-2-quinoxaline methane amide (108)
(207mg, methylene dichloride 1.07mmol) (1mL) liquid join the PHENTERMINE that is cooled to 0 ℃, and (160mg is in methylene dichloride 1.07mmol) (3mL) solution with 2-quinoxaline acyl chlorides.With reaction solution temperature to 25 ℃.After 5 minutes, this reaction mixture with ethyl acetate (40mL) dilution, is used (2 * 40mL) washings of 1M sodium hydroxide.With organic layer drying (anhydrous magnesium sulfate), by filtered through silica gel, rotary evaporation again.Obtain 51mg (16%) (108):
Retention time=9.31min.; 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-benzyl chloride base)-2,4,6-triphenyl pyridinium tetrafluoroborate salt
(2.0g 14mmol) is added drop-wise to 2,4, and (5.1g is in the suspension of methylene dichloride 13mmol) (40mL) for 6-triphenyl pyridinium tetrafluoroborate salt with the 2-Histol.This reaction mixture was stirred 16 hours.Add ethanol (4mL) and excessive ether with precipitated product.With sedimentation and filtration, drying.Obtain the N-(2-benzyl chloride base)-2,4 of 6.14g (92%), 6-triphenyl pyridinium tetrafluoroborate salt.
1-(2-chloro-phenyl-)-2-methyl-2-nitropropane
(3.19mL, (0.85g is in methyl alcohol 35mmol) (15mL) mixed solution 35.5mmol) to join sodium hydride with the 2-nitropropane.Then this reaction mixture is stirred and temperature to 25 ℃ 10 minutes.The rotary evaporation solvent obtains white solid.Under logical nitrogen, with this solid and N-(2-benzyl chloride base)-2,4, (mixture stirred 16 hours 6-triphenyl pyridinium tetrafluoroborate salt among the 6.14g, methyl-sulphoxide 11.8mmol) (45mL).Add this reaction of entry quencher then.(3 * 100mL) extract with ether with this mixture again.Organic layer is washed with saturated sodium-chloride water solution, and dry (anhydrous sodium sulphate) filters.This filtrate was stirred 4 hours in strongly-acid Amberlyst 15 ion exchange resin (1g/mmol).This mixture is filtered rotary evaporation.Obtain 1-(2-the chloro-phenyl-)-2-methyl-2-nitropropane of 2.35g (93%).
α, alpha-alpha-dimethyl-2-chlorobenzene ethamine
Under hydrogen (60psig), (weight ratio is 50% the aqueous solution with Raney nickel; 2.3g) and 1-(2-chloro-phenyl-)-2-methyl-2-nitropropane (2.35g, ethanol 11mmol) (35mL) mixture jolting 3.5 hours.Then this reaction mixture is filtered, again with the filtrate rotary evaporation.Obtain the α of 2.3g (110%), alpha-alpha-dimethyl-2-chlorobenzene ethamine.
N-(α, alpha-alpha-dimethyl-2-chlorobenzene ethyl)-2-quinoxaline methane amide (197)
By (108) similar method, with 2-quinoxaline acyl chlorides (158mg, 0.82mmol), α, alpha-alpha-dimethyl-2-chlorobenzene ethamine (151mg, 0.82mmol) and methylene dichloride (3mL) prepare (197), obtain (197) of 196mg (70%):
Retention time=10.04min.; 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).
Embodiment 9: preparation N-(α, alpha-alpha-dimethyl-4-fluorobenzene ethyl)-2-quinoxaline methane amide (129)
To 1-(4-fluorophenyl)-2-methyl-2-propylamine (105mg, add in pyridine 0.628mmol) (2mL) solution 2-quinoxaline acyl chlorides (133mg, 0.691mmol).Then this reaction solution was stirred 30 minutes.In the mixed solution of this stirring, add entry (20mL), make product be separated into oily matter.(1 * 10mL) extracts, and (rotary evaporation placed high vacuum following 15 hours to water again for 2 * 5mL) washings, dry (anhydrous magnesium sulfate) with ethyl acetate with this mixed solution.Obtain 146mg (71.9%) (129):
Retention time=10.45min.; 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).
By similar method, prepare the 2-quinoxaline methane amide that following N-replaces:
N-(Beta-methyl styroyl)-2-quinoxaline methane amide (131)
With 2-quinoxaline acyl chlorides (193mg, 0.84mmol), the Beta-methyl phenylethylamine (103mg 0.76mmol) and pyridine (2mL) preparation, obtains (131) of 154mg (69%):
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 methane amide (161)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), the 3-methyl cyclohexylamine (119mg 0.90mmol) and pyridine (5mL) preparation, obtains (161) of 190mg (78%):
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, the 3-Dimethylcyclohexyl)-2-quinoxaline methane amide (163)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), 2, the 3-dimethylcyclohexylamine (115mg 0.90mmol) and pyridine (5mL) preparation, obtains (163) of 150mg (59%):
Retention time=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-pinane methyl]-2-quinoxaline methane amide (207)
With 2-quinoxaline acyl chlorides (193mg, 1.0mmol), (+)-3-pinane methylamine (150mg 0.90mmol) and pyridine (5mL) preparation, obtains (207) of 229mg (79%):
Retention time=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).
Embodiment 10: preparation N-(1-diamantane methyl)-2-quinoxaline methane amide (146)
(429mg, (500mg is in chloroform 2.6mmol) (5mL) solution 2.6mmol) to join the 1-adamantane methylamine with 2-quinoxaline acyl chlorides.This reaction mixture is heated to all substances dissolving.Under 25 ℃, this reaction mixture was stirred 1 hour.Add entry (100mL) to the reaction mixture Shen of this stirring, so that the product precipitation.With sedimentation and filtration, water (2x) washing, dry under the high vacuum.Obtain 375mg (45%) (146):
Retention time=12.27min.; 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).
Embodiment 11: preparation N-(4-methylcyclohexyl)-2-quinoxaline methane amide (162)
To the 4-methyl cyclohexylamine (119mg, add in pyridine 0.90mmol) (2mL) solution 2-quinoxaline acyl chlorides (193mg, 1.0mmol).Then this reaction solution was stirred 1 hour.In the reaction mixture of this stirring, add entry (20mL), make product be precipitated as oily matter.With ether (2 * 25mL) liquid extraction, water (2 * 25mL) washings, dry (anhydrous sodium sulphate), the then rotary evaporation of this mixture with 30% methylene dichloride.Obtain 123mg (51%) (162): retention time=10.00min.; 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).
Embodiment 12: preparation N-[(1S, and 2S, 5S)-trans-Stenocalyx micheli's alkyl]-2-quinoxaline methane amide (225)
(1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl trifluoro-acetate
(5.50mL, (5.10mL is in dry tetrahydrofuran 32.5mmol) (100mL) 39.0mmol) to join (-)-trans-myrtanol with trifluoroacetic anhydride.This reaction mixture was stirred 1 hour.This reaction mixture of rotary evaporation.Obtain 7.60g (94%) (1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl trifluoro-acetate.
(1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl trifluoro-acetate
By similar method, with trifluoroacetic anhydride (5.40mL, 38.0mmol, 1.2 equivalents), (+)-trans-myrtanol (5.00mL, 4.90g, 31.7mmol) and tetrahydrofuran (THF) (100mL) prepare (1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl trifluoro-acetate.Obtain 7.60g (94%) (1R,, 2R, 5R)-trans-Stenocalyx micheli's alkyl trifluoro-acetate.
(1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl azide
Under 80 ℃, will (1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl trifluoro-acetate (1.0g, 4.0mmol), (0.39g, 6.0mmol) and N, the mixture of dinethylformamide (50mL) stirred 24 hours folded sodium-chlor.After being cooled to 25 ℃, add entry (100mL), (2 * 50mL) extract with ether with this mixture again.Then with organic layer drying (anhydrous sodium sulphate), rotary evaporation.Obtain 1.12g (100%) (1S, 2S 5S)-trans-Stenocalyx micheli's alkyl azide, are colorless oil.
(1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl azide
By similar method, with (1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl trifluoro-acetate (7.60g, 30.4mmol), sodiumazide (3.00g, 45.6mmol) and N, dinethylformamide (100mL) preparation (1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl azide, obtain 4.10g (48.2%) (1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl azide.
(1S, 2S, 5S)-trans-Stenocalyx micheli's alkylamine
Under hydrogen (50psig), will (1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl azide (1.12g, 7.32mmol) and ethanol (50mL) the mixed solution jolting of platinum oxide (IV) hydrate (0.34g) 2 hours.Then by this reaction mixture of filter paper filtering, again with the filtrate rotary evaporation.The material that obtains is joined in the 0.12M hydrochloric acid (100mL), and (2 * 50mL) extract with ether with this aqueous solution then.(50mL) makes the water layer alkalize with 0.1M sodium hydroxide, and (2 * 50mL) extract to use methylene dichloride again.Then with organic layer drying (anhydrous sodium sulphate), rotary evaporation.Obtain 78mg (7%) (1S, 2S 5S)-trans-Stenocalyx micheli's alkylamine, are light yellow oil.
(1R, 2R, 5R)-trans-Stenocalyx micheli's alkylamine
By similar method, with (1R, 2R, 5R)-trans-Stenocalyx micheli's alkyl azide (4.10g, 26.8mmol), platinum oxide (IV) hydrate (0.41g) and ethanol (75mL) prepare (1R, 2R, 5R)-trans-Stenocalyx micheli's alkylamine.Obtain 2.00g (48.8%) (1R, 2R, 5R)-trans-Stenocalyx micheli's alkylamine.
N-[(1S, 2S, 5S)-trans-Stenocalyx micheli's alkyl]-2-quinoxaline methane amide (225)
By and (162) similar method, with 2-quinoxaline acyl chlorides (49mg, 0.25mmol), (1S, 2S, 5S)-trans-Stenocalyx micheli's alkylamine (35mg, 0.23mmol) and pyridine (5mL) prepare (225), obtain (225) of 8mg (10%):
Retention time=11.23min.; 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-Stenocalyx micheli's alkyl]-2-quinoxaline methane amide (226)
By similar method, with 2-quinoxaline acyl chlorides (193mg, 1.0mmol), (1R, 2R, 5R)-trans-Stenocalyx micheli's alkylamine (138mg, 0.90mmol) and pyridine (5mL) prepare (226), obtain (226) of 27mg (10%);
Retention time=11.19min.; 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).
Embodiment 13: preparation N-[N '-(R)-α-Jia Jibianji-2-acetamido]-3-quinolylamine dihydrochloride (156)
N-(R)-α-Jia Jibianji-2-chlor(o)acetamide
(2.4g, methylene dichloride 20mmol) (50mL) liquid join chloroacetyl chloride, and (2.25g is in methylene dichloride 20mmol) (70mL) and pyridine (10mL) liquid with (R)-Alpha-Methyl benzylamine.Reaction mixture is stirred, use ether (500mL) dilution again, water (3 * 30mL) washings, dry (anhydrous magnesium sulfate), rotary evaporation then.Obtain N-(R)-α-Jia Jibianji-2-chlor(o)acetamide of 3.60g.
N-(R)-α-Jia Jibianji-2-iodo-acid amide
(10.37g, dry acetone solution 69mmol) slowly join N-(R)-α-Jia Jibianji-2-chlor(o)acetamide, and (3.39g in dry acetone solution 17mmol), refluxes this reaction mixture 16 hours with sodium iodide.Then this reaction mixture is filtered, again with the filtrate rotary evaporation.Add ether, this mixed solution was stirred 20 minutes.Again this mixed solution is filtered, rotary evaporation filtrate then, high vacuum dry obtains N-(R)-α-Jia Jibianji-2-iodo-acid amide again.
N-[N '-(R)-α-Jia Jibianji-2-acetamido]-3-quinolylamine dihydrochloride (156)
(0.15g is 1.0mmol) with the Potassium monofluoride (50%) (0.30g, acetonitrile 2.5mmol) (20mL) the mixed solution stirring 1 hour that load on the Celite with the 3-quinolylamine.(0.31g, acetonitrile liquid 1.0mmol) reflux this reaction mixture 64 hours then to add N-(R)-α-Jia Jibianji-2-iodo-acid amide.Filter this mixed solution, again with this filtrate rotary evaporation.The material that obtains is dissolved in the ether, with (3 * 30mL) washings of 1M sodium hydroxide.The water layer that merges is saturated with sodium-chlor, use chloroform (4x) to extract then.With the organic layer drying (anhydrous magnesium sulfate) that merges, rotary evaporation.The material that obtains is dissolved in the chloroform (10mL), adds the ether solution (5ml) of 1M hydrogenchloride, again with this solution rotating evaporation.The material that obtains is dissolved in the chloroform (5mL), filters this filtrate of rotary evaporation by 0.45 μ m filter disc.Obtain 13mg (3%) (156):
Retention time=10.43min.; 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).
Embodiment 14: preparation 1-(1-adamantyl)-2-(benzothiazole-2-base sulfane base) ethyl ketone (273)
Sodium hydride (36.5mg, 1.52mmol, 60% Dormant oils liquid) is washed with pentane (4X), at N 2Following dry, be suspended in dimethyl formamide (DMF, 10mL) in, be cooled to 0 ℃ again.Stir down, be added dropwise to 2-mercaptobenzothiazole (253.3mg, DMF 1.52mmol) (5mL) solution.Under 0 ℃, this reactant was stirred 20 minutes, with 1-diamantane brooethyl ketone (389.8mg, DMF 1.52mmol) (8mL) solution-treated.Under the room temperature, this reactant was stirred 30 minutes, with ether (100mL) dilution.(5 * 30mL) washings, remaining organic solution is through anhydrous MgSO with the solution with water that obtains 4Drying is filtered the simmer down to solid.The product that requires: the GC/EI-MS that obtains 287mg (55%) with the hot ethanol recrystallize obtains m/z (relative intensity) 343 (M +, 10), 315 (2), 180 (2), 148 (10), 135 (100), 107 (9), 93 (17) and 79 (20).
The mensuration of embodiment 15:mGluRI class antagonistic activity
By under 37 ℃, at SPF-PCB (126mM NaCl, 5mM KCl, 1mMMgCl 2, 20mM Na-HEPES, 1.0mM CaCl 2, 1mg/mL glucose and 0.5%BSA, pH7.4) middle incubation 30-40 minute, with 2 μ M Fura-2 acetoxyl group methyl esters, will be at the HEK-293 cell loading of the express recombinant acceptor described in the WO 97/05252.
This cell is washed 1-2 time in SPF-PCB, and it is 4-5 * 10 that resuspending becomes density 6Cell/mL under 37 ℃, remains in the plastic cup then.Be the record fluorescent signal, with the SPF-PCB of 37 ℃ no BSA this cell dilution placed quartz curette for five times, obtaining final BSA concentration is 0.1% (the SPF-PCB+0.3mL cell suspending liquid of the no BSA that 1.2mL is 37 ℃).Under 37 ℃, constant agitation, measure fluorescence with the spectrophotofluorometer (BiomedicalInstrumentation Group, University of Pennsylvania) of customization.Excite with emission wavelength and be respectively 340 and 510nm.For the calibration fluorescent signal, add digitonin (Sigma Chemical Co., St.Louis, MO; Catalogue #D-5628; Final concentration 50 μ g/mL) obtain maximum fluorescence (F Max), and by adding TRIS alkali/EGTA (10mM, pH8.3, finally) the apparent minimum fluorescence (F of mensuration Min).Use the dissociation constant (Kd) of 224nM and use Ca in the following Equation for Calculating born of the same parents 2+Concentration:
[Ca 2+] i＝(F-F min/F min)×Kd；
Wherein F is the fluorescence of surveying in any required time point place, and F is at F MaxAnd F MinBetween.
Measuring adding 5mM Ca in the cup in addition 2+(the outer calcium concn of final born of the same parents, contrast response 6mM).In this experiment whole process, measure the contrast response that changes in the outer calcium of born of the same parents.Under the single concentration of every glass of cell, measure compound, and all compounds prepare in DMSO.Carry out suitable dilution so that add the 10 μ l (final DMSO is not more than 0.67%) that the volume of compound is not more than per 1500 μ l cumulative volumes, and reach specific mensuration concentration.
Once obtaining stable cellular calcium baseline, be about to this compound and join in this cup.Make the response that adds this compound or do not have response and stablized 1-3 minute, add 5mM calcium then and measure of the influence of this compound this follow-up calcium response.Once the peak that obtains this follow-up calcium response, promptly add digitonin and EGTA to measure F respectively in successively mode MaxAnd F MinWith nM is unit, with the variation of data representation cellular calcium concentration.These variations and the contrast of contrast (no compound) calcium response of compound being added the back calcium response.The response normalization method (normalized) of calcium is the percent change to the response of this contrast when measuring compound and exist.Data are inserted the Levenberg-Marquardt analysis draw non-linear least squares, and measure the IC of each compound 50With its fiducial interval of 95%.
Therefore, the present invention has been carried out all sidedly openly, and be illustrated with reference to above-described representative example.Those skilled in the art are with cognition: when not leaving the spirit and scope of the present invention, can carry out various modifications to the present invention.

Claims (27)

1. compound or its pharmacy acceptable salt of formula I representative:
The R-[-linking group-]-Ar
Wherein R is straight or branched-chain alkyl, aralkyl, cycloalkyl or an alkyl-cycloalkyl optional replacement, that contain 5-12 carbon atom,
Wherein Ar be optional that replace, contain 10 carbon atoms of as many as and 4 heteroatomic aromatics of as many as, heteroaromatic, aralkyl or heteroaralkyl part,
Wherein [linking group] is-(CH 2) n-, wherein n is 2-6, and 4 CH of as many as wherein 2C can be selected from 1-C 3Alkyl, CHOH, CO, O, S, SO, SO 2, N, NH and NO group independently replace, condition is: unless these two atoms all are N or when all being NH, otherwise two heteroatomss are not adjacent one another are, and wherein any two adjacent CH 2Can substituted or unsubstituted alkenyl or alkynyl group replacement.
2. according to the compound of claim 1, wherein Ar comprises and is selected from following ring system: benzene, thiazole, furyl, pyranyl, the 2H-pyrryl, thienyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, benzothiazole, benzoglyoxaline, the 3H-indyl, indyl, indazolyl, purine radicals, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, 1, the 5-phthalazinyl, quinazolyl, cinnolinyl, isothiazolyl, quinoxalinyl, the indolizine base, pseudoindoyl, benzothienyl, benzofuryl, isobenzofuran-base and chromene basic ring
Wherein Ar can choose wantonly by two C of as many as 1-C 3Alkyl or nearly two halogen atoms independently replace, wherein halogen is selected from F, Cl, Br and I.
3. 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.
4. according to the compound of claim 1, wherein [linking group] comprises acid amides, ester or thioesters.
5. according to the compound of claim 3, 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.
6. according to the compound of claim 1, wherein Ar comprises the group with following formula:
X wherein 1, X 2, X 3And X 4Can independently be N or CH, condition be X 1, X 2, X 3And X 4In to be no more than two be N.
7. according to the compound of claim 6, X wherein 1Be N.
8. according to the compound of claim 7, X wherein 2Be N.
9. according to the compound of claim 6, X wherein 3Be N.
10. according to the compound of claim 6, X wherein 1Be CH and X 2Be N.
11. according to the compound of claim 1, wherein Ar is optional 2-, 3-or the 4-pyridyl that replaces.
12. according to the compound of claim 1, wherein Ar is the 6-benzothiazolyl.
13. comprise according to the compound of claim 1 and the medicinal compositions of pharmaceutically acceptable thinner or vehicle.
14. preparation is according to the method for the compound of claim 4, it comprises makes compound that contains active carboxylic acid's group and the compound reaction that contains amino, hydroxyl or thiol group.
15. suppress mGluR I receptoroid activated method, it comprises the cell that contains this receptor with the compound treatment according to claim 1 of significant quantity.
16. suppress to be activated by the excitability of mGluR I receptoroid the method for the nerve injury that causes, it comprises the compound treatment neurone according to claim 1 with significant quantity.
17. the method for the nerve injury diseases associated that treatment and L-glutamic acid bring out, it comprises the composition according to claim 13 of patient's significant quantity of suffering from this disease.
18. 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.
19. compound and pharmacy acceptable salt thereof according to claim 1, wherein this compound is selected from: N-(1-adamantyl)-3-quinoline formyl amine, 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-quinoline formyl amine, 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-[(1 S, 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-[(1S, 2S, 3S, 5R)-3-pinane methyl]-2-quinoxaline methane amide, N-(1-diamantane methyl)-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.
20. according to the compound and the pharmacy acceptable salt thereof of 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 and N-(3-quinolyl)-1-diamantane methane amide.
21. compound and pharmacy acceptable salt thereof according to claim 1, wherein this compound is selected from: N-(3-methylcyclohexyl)-2-quinoxaline methane amide, N-(2, the 3-Dimethylcyclohexyl)-2-quinoxaline methane amide, N-[(1S, 2S, 3S, 5R)-3-pinane methyl]-2-quinoxaline methane amide, N-(1-diamantane methyl)-2-quinoxaline methane amide and N-(4-methylcyclohexyl)-2-quinoxaline methane amide.
22. compound and pharmacy acceptable salt thereof according to claim 1, wherein this compound is selected from: N-[(R)-and 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, 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 and N-(Beta-methyl styroyl)-2-quinoxaline methane amide.
23. according to the compound or the pharmacy acceptable salt of claim 1, wherein this compound is a 1-diamantane methyl 6-quinolyl ether.
24. compound and pharmacy acceptable salt thereof according to claim 1, wherein this compound is selected from: 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 and 3-quinolinecarboxylic acid 1-adamantane esters.
25. according to the compound and the pharmacy acceptable salt thereof of claim 1, wherein this compound is selected from: 3-(1-diamantane methoxyl group)-2-chloro-quinoxaline, 2-(1-diamantane methoxyl group)-3-methyl-quinoxaline, 3-(1-diamantane methoxyl group)-2-fluorine quinoxaline, 2-(1-diamantane methoxyl group)-3-trifluoromethyl quinoxaline, N-[2-(4-phenyl thiazole base)]-1-diamantane methane amide, N-[2-(5-methyl-4-phenyl thiazole base)]-1-diamantane methane amide, 1-(1-adamantyl)-2-(benzothiazole-2-base sulfane base) ethyl ketone, N-(1-adamantyl)-2-chloro-quinoxaline-3-methane amide, N-(1-adamantyl)-3-methyl-quinoxaline-2-methane amide and N-(1-adamantyl)-1-oxygen base quinoxaline-3-methane amide.
26. compound and pharmacy acceptable salt thereof according to claim 1, wherein this compound is selected from: 3-tonka bean camphor formic acid 4-chloro-phenyl-ester, 2-(1-diamantane methyl sulfane base) quinoxaline, 3-(1-diamantane methoxyl group)-2-chlorine piperazine, 1-(1-adamantyl)-2-(4,6-dimethyl pyrimidine-2-base sulfane base) ethyl ketone, 1-(1-diamantane)-2-(2-anisyl sulfane base) ethyl ketone, 3-(1-diamantane methoxyl group)-1H-quinoxaline-2-ketone, 1-(1-adamantyl)-2-(3-anisyl sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(4-anisyl sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(4-chloro-phenyl-sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(2-naphthyl sulfane base) ethyl ketone, N-(2-[6-(piperidino) pyrazinyl])-1-diamantane methane amide, N-(2-[6-(piperidino) pyrazinyl]) diamantane-1-ylmethyl methane amide, 1-(1-adamantyl)-2-(1-naphthyl sulfane base) ethyl ketone, 1-(1-adamantyl)-2-(8-quinolyl sulfane base) acetophenone hydrochloride, 1-(1-adamantyl)-2-(4-Trifluoromethyl phenyl ether oxygen base) ethyl ketone, 2-(1-diamantane methoxyl group) quinoxaline, N-(trans-the 4-methylcyclohexyl)-2-quinoxaline methane amide, N-(cis-4-methylcyclohexyl)-2-quinoxaline methane amide, N-(trans-the 4-methylcyclohexyl)-2-quinoline formyl amine, N-(trans-the 4-methylcyclohexyl)-3-quinoline formyl amine and N-(trans-the 4-methylcyclohexyl)-6-quinoline formyl amine.
27. compound and pharmacy acceptable salt thereof according to claim 1; wherein this compound is selected from: 2-(1-diamantane methylsulfinyl) benzothiazole; N-(4-phenyl butyl)-2-quinoxaline methane amide; 1-(1-adamantyl)-2-(4; 6-dimethyl pyrimidine-2-base sulfane base) ethanol; 1-(1-adamantyl)-2-(3-chloro-quinoxaline-2-yl) ethyl ketone; 2-(1-diamantane methyl sulfane base)-3-methyl-quinoxaline; N-(1-adamantyl)-2-anisamide; N-(1-diamantane methyl)-2-anisamide; 1-(1-adamantyl)-2-(4-chloro-phenyl-sulfane base) ethyl ketone; 2-(1-diamantane methyl sulphonyl)-3-methyl-quinoxaline; 1-(1-adamantyl)-2-(4-fluorophenyl sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(3-fluorophenyl sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(2-methoxyl group phenoxy group) ethyl ketone; 1-(4-anisyl sulfane base) fourth-2-ketone; 1-(1-adamantyl)-2-(4-anisidino) acetophenone hydrochloride; 3; 3-dimethyl-1-(4-anisyl sulfane base) fourth-2-ketone; 1-(4-phenylbenzene)-2-(4-anisyl sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(2-Trifluoromethoxyphen-l sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(3-methyl-quinoxaline-2-base sulfane base) ethyl ketone; 1-(1-adamantyl)-2-(2-anisidino) acetophenone hydrochloride; 1-(1-adamantyl)-2-(4-Trifluoromethoxyphen-l amino) acetophenone hydrochloride; 1-(1-adamantyl)-2-(N-methyl-4-anisidino) acetophenone hydrochloride; N-(1-adamantyl)-7-Trifluoromethylquinocarboxylic-3-methane amide; N-(1-adamantyl)-2-(1-piperazinyl) quinoxaline-3-methane amide; N-(1-adamantyl)-2-(the amino ethylamino of 2-) quinoxaline-3-methane amide; methyl N-(3-quinolyl)-3-carboxyl diamantane-1-methane amide; 1-(1-adamantyl)-2-[(R)-1-(1-naphthyl) second-1-base is amino] ethyl ketone; N-(1-adamantyl)-2-methoxyl group quinoxaline-3-methane amide; ethyl n-(1-adamantyl)-2-(3-propionamido) quinoxaline-3-methane amide; N-(4-chloro-phenyl-)-2; 3-dimethyl quinoxaline-6-methane amide; N-(1-adamantyl)-6; 7-dimethyl quinoxaline-2-methane amide; N-((S)-1-tetrahydro naphthyl)-2-quinoxaline methane amide; N-(4-chlorobenzene ethyl)-2-quinoxaline methane amide; N-(6-quinolyl)-2-quinoxaline methane amide; N-(1-tetraline methyl)-2-quinoxaline methane amide; (1-(2 for N-; the 3-indanyl) methyl)-2-quinoxaline methane amide; N-(4, the 4-Dimethylcyclohexyl)-2-quinoxaline methane amide.
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Publication number Priority date Publication date Assignee Title
WO1999044639A1 (en) * 1998-03-03 1999-09-10 Yamanouchi Pharmaceutical Co., Ltd. Remedies for brain infarction
GB9823847D0 (en) * 1998-11-02 1998-12-23 Lilly Co Eli Pharmaceutical compounds
GB9823845D0 (en) 1998-11-02 1998-12-23 Lilly Co Eli Pharmaceutical compounds
DE60022050C5 (en) * 1999-06-02 2007-10-11 NPS Pharmaceuticals, Inc., Salt Lake City METABOTROPE GLUTAMATE RECEPTOR ANTAGONISTS FOR THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM
EP1210338A2 (en) * 1999-08-05 2002-06-05 IGT Pharma Inc. 1,4-diazepine derivatives for the treatment of diseases related to the central nervous system
EP1582519A3 (en) * 1999-08-19 2005-12-21 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
NZ517221A (en) * 1999-08-19 2004-01-30 Nps Pharma Inc Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US6660753B2 (en) 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
HUP0203142A3 (en) 1999-10-15 2003-03-28 Hoffmann La Roche Benzodiazepine derivatives, process for preparation of the compounds, pharmaceutical compositions containing them and their use
KR100481386B1 (en) 1999-10-15 2005-04-08 에프. 호프만-라 로슈 아게 Benzodiazepine derivatives
GB0007193D0 (en) * 2000-03-25 2000-05-17 Univ Manchester Treatment of movrmrnt disorders
IL155163A0 (en) 2000-10-02 2003-10-31 Janssen Pharmaceutica Nv Metabotropic glutamate receptor antagonists
TWI243164B (en) * 2001-02-13 2005-11-11 Aventis Pharma Gmbh Acylated indanyl amines and their use as pharmaceuticals
JP2005514330A (en) * 2001-09-24 2005-05-19 イーラン ファーマスーティカルズ、インコーポレイテッド Substituted amines for the treatment of Alzheimer's disease
UA78548C2 (en) * 2002-03-29 2007-04-10 Janssen Pharmaceutica Nv Radiolabelled quinoline and quinolinone derivatives and use thereof as metabotropic ligands of glutamate receptor
CN100357283C (en) * 2002-04-02 2007-12-26 中国科学院上海药物研究所 Methionyl aminopeptidase inhibitor
CN1894241A (en) * 2002-08-09 2007-01-10 阿斯利康(瑞典)有限公司 '1,2,4' oxadiazoles as modulators of metabotropic glutamate receptor-5
WO2004056744A1 (en) 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
US7582635B2 (en) * 2002-12-24 2009-09-01 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
AU2004209540A1 (en) * 2003-01-31 2004-08-19 Astrazeneca Ab Saturated quinoxaline derivatives and their use as metabotropic glutamate receptor ligands
GB0312609D0 (en) 2003-06-02 2003-07-09 Astrazeneca Ab Novel compounds
RU2006106920A (en) 2003-08-06 2007-09-20 Синомикс Инк. (Us) T1R HETERO-OLIGOMER TASTE RECEPTORS, CELL LINES THAT EXPRESS THE SPECIFIED RECEPTORS AND TASTE COMPOUNDS
SE0302192D0 (en) * 2003-08-08 2003-08-08 Astrazeneca Ab Novel compounds
US7501416B2 (en) 2004-02-06 2009-03-10 Bristol-Myers Squibb Company Quinoxaline compounds and methods of using them
EP1747199B1 (en) 2004-05-07 2014-09-17 Janssen Pharmaceutica NV Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
TW200613272A (en) 2004-08-13 2006-05-01 Astrazeneca Ab Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
WO2006024627A2 (en) * 2004-08-30 2006-03-09 Janssen Pharmaceutica N.V. N-2 adamantanyl-2-phenoxy-acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
DE602005017159D1 (en) 2004-08-30 2009-11-26 Janssen Pharmaceutica Nv OXYSTEROID DEHYDROGENASE INHIBITORS
KR101197672B1 (en) 2004-08-30 2012-11-07 얀센 파마슈티카 엔.브이. Tricyclic Lactam Derivatives as 11-Beta Hydroxysteroid Dehydrogenase Inhibitors
US8968708B2 (en) 2005-02-04 2015-03-03 Senomyx, Inc. Compounds comprising linked heteroaryl moieties and their use as novel umami flavor modifiers, tastants and taste enhancers for comestible compositions
WO2006097817A1 (en) 2005-03-17 2006-09-21 Pfizer Japan Inc. N- (n-sulfonylaminomethyl) cyclopropanecarboxamide derivatives useful for the treatment of pain
GB0506133D0 (en) * 2005-03-24 2005-05-04 Sterix Ltd Compound
TW200715993A (en) 2005-06-15 2007-05-01 Senomyx Inc Bis-aromatic amides and their uses as sweet flavor modifiers, tastants, and taste enhancers
MX2007015863A (en) * 2005-06-17 2008-04-02 Apogee Biotechnology Corp Sphingosine kinase inhibitors.
US7868008B2 (en) 2005-08-12 2011-01-11 Astrazeneca Ab Substituted isoindolones and their use as metabotropic glutamate receptor potentiators
US7807706B2 (en) 2005-08-12 2010-10-05 Astrazeneca Ab Metabotropic glutamate-receptor-potentiating isoindolones
WO2007021309A1 (en) * 2005-08-12 2007-02-22 Astrazeneca Ab Substituted isoindolones and their use as metabotropic glutamate receptor potentiators
WO2007037543A1 (en) * 2005-09-29 2007-04-05 Banyu Pharmaceutical Co., Ltd. Biarylamide derivative
EP1957475A1 (en) * 2005-10-21 2008-08-20 Merz Pharma GmbH & Co.KGaA Chromenones and their use as modulators of metabotropic glutamate receptors
KR20080076962A (en) * 2005-12-20 2008-08-20 노파르티스 아게 Nicotinic Acid Derivatives as Metabolic Glutamate Receptor Modulators
TW200804281A (en) 2006-02-16 2008-01-16 Astrazeneca Ab New metabotropic glutamate receptor-potentiating isoindolones
DK2010009T3 (en) 2006-04-21 2017-10-02 Senomyx Inc PROCEDURES FOR THE PREPARATION OF SOLID FLAVOR COMPOSITIONS
TW200817385A (en) * 2006-07-04 2008-04-16 Organon Nv Heterocyclic derivatives
US7947689B2 (en) 2006-08-04 2011-05-24 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-a]pyrimidines as metabotropic glutamate receptor modulators
JP2010510202A (en) 2006-11-17 2010-04-02 ファイザー株式会社 Substituted bicyclocarboxamide compounds
RS55585B1 (en) 2006-11-22 2017-06-30 Clinical Research Associates LLC Methods of treating down's syndrome, fragile x syndrome and autism
AR065806A1 (en) 2007-03-22 2009-07-01 Astrazeneca Ab DERIVATIVES OF QUINOLINA, PROCESSES FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USES FOR THE TREATMENT OF Rheumatoid ARTHRITIS.
WO2008128889A1 (en) 2007-04-19 2008-10-30 F. Hoffmann-La Roche Ag Dihydro-benzo[b][1,4]diazepin-2-one sulfonamide derivatives
TWI417100B (en) 2007-06-07 2013-12-01 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators-842
CN101348461B (en) * 2007-07-17 2011-10-05 西安利君制药有限责任公司 N-(3-pyridine formyloxy)-3,5-dimethyl-1-amantadine for curing senile dementia or pharmaceutical salt thereof
EP2064959B1 (en) 2007-10-31 2012-07-25 Symrise AG Aromatic Neomenthylamides as flavouring agents
US8106073B2 (en) 2007-11-30 2012-01-31 Astrazeneca Ab Quinoline derivatives 057
US8211882B2 (en) * 2008-03-08 2012-07-03 Richard Delarey Wood Glutamate receptor modulators and therapeutic agents
SA109300358B1 (en) 2008-06-06 2012-11-03 استرازينيكا ايه بي Isoindolone Metabotropic Glutamate receptor Potentiators
WO2010097410A1 (en) 2009-02-24 2010-09-02 Respiratorius Ab Novel bronchodilating diazaheteroaryls
EP2544688B1 (en) 2010-03-02 2016-09-07 President and Fellows of Harvard College Methods and compositions for treatment of angelman syndrome
WO2011150380A1 (en) 2010-05-28 2011-12-01 Xenoport, Inc. Methods of treatment of fragile x syndrome, down's syndrome, autism and related disorders
WO2012006760A1 (en) * 2010-07-14 2012-01-19 Merck Sharp & Dohme Corp. Tricyclic compounds as allosteric modulators of metabotropic glutamate receptors
US20120016021A1 (en) 2010-07-15 2012-01-19 Xenoport, Inc. Methods of treating fragile x syndrome, down's syndrome, autism and related disorders
MX2013005948A (en) 2010-11-30 2013-07-03 Bayer Ip Gmbh Pyrimidine derivatives and use thereof as pesticides.
KR102529578B1 (en) * 2014-08-29 2023-05-09 (주)아모레퍼시픽 Novel adamatan derivative compound
CN114539170B (en) * 2021-12-31 2023-05-16 华南农业大学 Hapten and artificial antigen for simultaneously detecting amantadine, olaquindox and chloramphenicol, and preparation method and application thereof

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3632581A (en) * 1968-10-08 1972-01-04 American Home Prod Schiff bases of quinoxaline-2-carboxal-dehydes and their reduction products
GB1329447A (en) * 1969-10-27 1973-09-05 Squibb & Sons Inc 4-adamantylaminoalkylamino-2-styryl-quinolines salts and derivatives thereof
FR2355829A1 (en) * 1976-06-24 1978-01-20 Debat Lab Esters of nitroxoline with (poly)carboxylic or (poly)sulphonic acids - useful as antibacterials and antifungals
IL53440A0 (en) * 1977-11-22 1978-01-31 Teva Pharma 2-adamantyl hydrazines their preparation and pharmaceutical compositions containing them
FR2509728A1 (en) * 1981-07-17 1983-01-21 Roussel Uclaf NOVEL QUINOLINE DERIVATIVES, THEIR SALTS, PREPARATION METHOD, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME
US5346907A (en) * 1988-04-05 1994-09-13 Abbott Laboratories Amino acid analog CCK antagonists
DE69033636T2 (en) * 1989-07-07 2001-05-03 Meiji Seika K.K., Tokio/Tokyo Use of 4-acyloxyquinoline derivatives as insecticides and acaricides
IE902295A1 (en) * 1989-07-07 1991-01-16 Abbott Lab Amino acid analog cck antagonists
EP0480052B1 (en) * 1990-03-28 1998-01-14 Otsuka Pharmaceutical Co., Ltd. Quinoline derivative, antiulcer drug containing the same, and production of said derivative
JPH0441425A (en) * 1990-06-07 1992-02-12 Tanabe Seiyaku Co Ltd 5-lipoxygenase inhibitor
DK0649410T3 (en) * 1992-07-10 1997-09-15 Glaxo Lab Sa Anilide.
JPH07179371A (en) * 1993-12-21 1995-07-18 Canon Inc Liquid crystal compound, liquid crystal composition containing the compound, liquid crystal element using the composition, displaying method and displaying apparatus using the element
EP0769015B1 (en) * 1994-07-04 2001-03-14 Takeda Chemical Industries, Ltd. Phosphonic acid compounds, their production and use
WO1996005818A1 (en) * 1994-08-19 1996-02-29 Nps Pharmaceuticals, Inc. Methods and compounds active at metabotropic glutamate receptors useful for treatment of neurological disorders and diseases
US5707985A (en) * 1995-06-07 1998-01-13 Tanabe Seiyaku Co. Ltd. Naphthyl-, quinolyl- and isoquinolyl- sulfonamide derivatives as cell adhesion modulators
TR199902724T2 (en) * 1997-05-03 2000-04-21 Smithkline Beecham P.L.C. Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors.

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