CN101084201A - Triazolone, tetrazolone and imidazolone derivatives for use as alpha-2c adrenoreceptor antagonists - Google Patents

Triazolone, tetrazolone and imidazolone derivatives for use as alpha-2c adrenoreceptor antagonists Download PDF

Info

Publication number
CN101084201A
CN101084201A CN 200580043606 CN200580043606A CN101084201A CN 101084201 A CN101084201 A CN 101084201A CN 200580043606 CN200580043606 CN 200580043606 CN 200580043606 A CN200580043606 A CN 200580043606A CN 101084201 A CN101084201 A CN 101084201A
Authority
CN
China
Prior art keywords
compound
alkyl
group
independently
midbody compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN 200580043606
Other languages
Chinese (zh)
Inventor
J·I·安德雷斯-吉尔
M·J·阿尔卡扎-瓦卡
J·帕斯托-弗南德茨
W·H·I·M·德林肯伯格
X·J·M·兰格洛伊斯
J·奥雅扎巴尔－桑塔马里纳
J·A·维加-拉米罗
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of CN101084201A publication Critical patent/CN101084201A/en
Pending legal-status Critical Current

Links

Abstract

The present invention concerns substituted triazolone, tetrazolone and imidazolone derivatives according to the general Formula (I) a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, an N-oxide form thereof or a quaternary ammonium salt thereof, wherein the variables are defined in Claim 1, having selective alpha 2C-adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine. The compounds according to the invention are usefull for the prevention and/or treatment of central nervous system disorders, mood disorders, anxi- ety disorders, stress-related disorders associated with depression and/or anxiety, cognitive disorders, personality disorders, schizoaffective disorders, Parkinson's disease, dementia of the Alzheimer's type, chronic pain conditions, neurodegenerative diseases, addiction disorders, mood disorders and sexual dysfunction.

Description

As α 2CThe triazolone of-adrenergic receptor antagonist, tetrazole ketone and imidazolone derivatives
Technical field
The present invention relates to have selectivity α 2The active substituted triazole ketone of C-adrenergic receptor antagonist, tetrazole ketone and imidazolone derivatives.The invention still further relates to its preparation method, contain this compound compositions and as the purposes of medicine.
Background of invention
Adrenergic receptor forms the interface between interior living catecholamine suprarenin and norepinephrine, and forms the targeted cells of multiple arrangement in vivo, thereby regulates the neural biological effect of sympathetic nerve.They can be divided into three kinds of main subclass: α 1, α 2And β.Up to now, the adrenergic receptor hypotype of nine kinds of uniquenesses is arranged from several species clonings: α 1A, α 1B, α 1D, α 2A, α 2B, α 2C, β 1, β 2And β 3(Hieble, J.P.; Et al.J.Med.Chem.1995,38,3415-3444).Obtainable α 2Part only has a little marginal subtype-selectives.The factor of a complexity is this α 2-adrenergic receptor part, it is imidazoles or tetrahydroglyoxaline, also arrives non-tetrahydroglyoxaline binding site with the non-adrenergic receptors bind in moderate to the condition of height avidity.
Three kinds of α 2-adrenergic receptor hypotype has the common performance.They are to contain the G-protein coupled receptor of amine in conjunction with 7 transmembrane territories of subtribe.All these three kinds of hypotypes all with the coupling of Gi/o signal transmission system, suppress the Ca at adenylate cyclase, the voltage outpost of the tax office 2+The unlatching of passage and K +The unlatching of passage.Three kinds of acceptors are by genes encoding (Bylund, the D.B. of uniqueness; Et al.Pharmacol.Rev.1994,46,121-136 and Hieble, J.P.et al.Pharmacol.Commun.1995,6,91-97), be positioned at different karyomit(e); The mankind, be used for α 2Gene be found on the karyomit(e) 10 α 2B-gene is positioned on the karyomit(e) 2, and α 2C-gene is positioned on the karyomit(e) 4.This hypotype is preserved between mammalian species well.But in rat and mouse, have an aminoacid replacement base, it has reduced rodent α 2A-adrenergic receptor is to traditional α 2The avidity of-antagonist, Yohimbine and Luo Fusu (rauwolscine).General common recognition is this so-called α 2D-adrenergic receptor hypotype has been represented human α 2AThe rodent homologue of hypotype.
α 2-adrenergic receptor hypotype differently respectively at cell with in organizing, is given acceptor significantly and is had different physiological functions and pharmacologically active situation.Different adjustment in acceptor gene zone also gives different adjusting functions with different protein structures in three kinds of acceptors, all synthesize with acceptor and transcribe after incident relevant.
α 2Originally-adrenergic receptor is feature with the presynaptic receptor, and it regulates the release of norepinephrine as the part of negative feedback loop.Afterwards, it is found that α 2-adrenergic receptor is not limited in the presynaptic position, also has the postsynaptic function.α 2A-adrenergic receptor is the main preceding acceptor (from receptor body) of inhibitory synapse, as the part of negative feedback loop, regulates from sympathetic neuron release norepinephrine.α 2C-adrenergic receptor is extra presynaptic setter in the whole maincenters studied and peripheral nerve tissue.But, α 2AAnd α 2CThe Relative Contribution of-acceptor is different between maincenter and peripheral nerve, α 2C-hypotype compares at the more remarkable (Philipp of maincenter adrenergic neuron at sympathetic nerve terminal, M.et al.Am.J.Physiol.Regul.Integr.Comput.Physiol.2002,283, R287-R295 and Kable, J.W.et al.J.Pharmacol.Exp.Ther.2000,293,1-7).α 2C-adrenergic receptor is particularly suitable for control neurotransmitters release under low action potential frequency.On the contrary, α 2AAs if-adrenergic receptor mainly act on sympathetic neuron under high frequency of stimulation, so relevant (Bucheler of release main and at maximum sympathetic nerve pot-life control norepinephrine, M.M.et al.Neuroscience 2002,109,819-826).α 2B-adrenergic receptor is positioned on the postsynaptic cell, regulates the effect that discharges catecholamine from sympathetic neuron, for example vasoconstriction.α 2-adrenergic receptor not only suppresses the release of itself neurotransmitters, the exocytosis of also regulating multiple other neurotransmitters in maincenter and the peripheral nervous system.In brain, α 2A-and α 2C-adrenergic receptor can suppress the release and the serum secretion of Dopamine HCL in the substrate nervous center in mouse digitation of hippocamps and brain lamina corticalis.On the contrary, α 2-3 adrenergic receptor agonists only may pass through α to the restraining effect of enterogastric peristalsis 2A-subtype.α 2A-and α 2CPartial function difference between the-acceptor can be by unique subcellular location interpretation of scheme.In the time of in being expressed in the rat fibroblast, α 2A-and α 2BBut-adrenergic receptor target plasma membrane.When utilizing agonist to stimulate, has only α 2BThe reverse internalization of-adrenergic receptor is to endosome.α 2C-adrenergic receptor mainly is positioned at intracellular film compartment, be exposed to cooling temperature after, can be transferred to thus cell surface (referring to a.o.Docherty J.R.et.al. Eur.J.Pharmacol.1998,361,1-15).
Lack or overexpression α 2The foundation of the genetically engineered mouse of-adrenergic receptor hypotype, obtained helping to understand the hypotype specific function important information (MacDonald, E.et al.Trends Pharmacol.Sci.1997,18,211-219).
Check the phenotype of these kind mouse, provable α 2AHypotype discharges neurotransmitters and most of α with inhibition from maincenter and tip sympathetic neuron 2The main intermediation effect of-agonist is relevant.α 2B-hypotype main with by α 2The response of the hypertension of tip originally that-agonist causes is relevant, and the hypertension that participates in causing by salt (Link et al. Science 1996,273,803-805 and Makaritsis, K.P.et al.Hypertension 1999,33,14-17).
Clarification α 2CIt is more difficult that the physiological action of-hypotype has been proved to be.Although be distributed in quite widely among the CNS, it is at the non-selective α of media 2Effect in the cardiovascular effect of-agonist does not demonstrate important.Someone proposes, its participated in the reduction body temperature that causes by the U.S. fourth in ground (dexmedetomidine) and the supermotility that causes by the D-amphetamines (Rohrer, D.K.et al.Annu.Rev.Pharmacol Toxicol.1998,38,351-373).α 2CAnother of-adrenergic receptor media may important response be the contraction of skin artery, cause SkBF reduction (Chotani, M.A.et al.Am.J.Physiol.Heart Circ.Physiol.2004,286,59-67).Recently at the dual research proposal that carries out in the confused mouse, the α of striking 2C-adrenergic receptor also is expressed in presynaptic scope, at this and α 2AParticipate in controlling the release of neurotransmitters together actively.Though α 2A-adrenergic receptor is effective especially under high frequency of stimulation, but α 2C-adrenergic receptor is generation effect under low frequency of stimulation on the contrary.Moreover the someone advises, α 2C-hypotype participated in motor behavior and memory process adjusting (Bjorklund, M.et al.Neuroscience 1999,88,1187-1198 and Tanila, H.et al.Eur.J.Neurosci.1999,11,599-603).Other important effect that is caused by this hypotype comprises that also the shock reflection reaches the aggressiveness response (Sallinen to pressure and motion, J.et al.J.Neurosci.1998,18,3035-3042 and Sallinen.J.et al.Neuroscience 1998,86,959-965).At last, the someone points out recently, α 2C-adrenergic receptor can cause α 2The spinal anesthesia of-agonist media and adrenergic-opium synergy (Fairbanks, C.A.etal.J.Pharm.Exp.Ther.2002,300,282-290.
Because it extensively distributes in central nervous system, α 2-acceptor influences multiple behavioral function.The α that changes 2CThe effect that-adrenergic receptor is expressed is assessment (Kable J.W.et al., Journal of Pharmacology and ExperimentalTherapeutics, 2000,293 (1): 1-7), proved α in several different behavior examples 2C-1 adrenergic antagonists has therapeutic value in the mental disorder of treatment and pressure correlation.In the various actions example, unclear is α 2C-hypotype is played the part of the α of some direct roles or change in the media behavior 2C-expression of receptor is regulated and the generation effect because change the downstream of metabolism or other neurotransmitters system.What is interesting is α 2CThe mouse of-receptor deficiency has the shock response of increase, the pulse restraining effect that reduces and the attack latent period of shortening in the isolate attack test.Thus, pass through α 2CThe medicine of-adrenergic receptor effect is responding the disease relevant with sensorimotor gate deficiency with increasing shock, has therapeutic value in retiring as pressure obstacle and medicine after schizophrenia, attention-deficient obstacle, the wound.Except α 2COutside-the hypotype, α 2A-adrenergic receptor also has importance.
α in the increasing gene target mouse 2-adrenergic receptor Physiologic Studies achievement is published, become more complicated than original expection of situation.In fact the α that has only minority 2The biological function of-acceptor is found by single α 2-adrenergic receptor subtype.For other α 2As if the function of-acceptor media has demonstrated two kinds of different strategies and can regulate the adrenergic signal transduction: some biological function is offset α by two kinds 2The control of-receptor subtype, some then needs to have two kinds of receptor subtype controls similar but complementary effect.Because α 2A-subtype α 2The most of classic effect of-2-adrenergic agonist components, people suspect α 2A-selective agonist has substantive better clinical scenarios than existing medicament.At α 2B-or α 2CAs if the medicine of having an effect on-the adrenergic receptor than α 2A-particular agent has classic α still less 2The side effect of-adrenergic.The result demonstrates, α 2CAs if-selectivity medicament can be applied at least some nervous system disorderss, particularly central nervous system disease.
Background technology
The document data base analysis revealed has several adrenergic α on the market 2-antagonist, supplier comprises Akzo Nobel (Organon), Novartis, Pfizer and Schering AG.Not having a kind of in these compounds is to any three kinds of α 2-adrenergic receptor has selectivity.These compound principal indications are dysthymia disorders, high blood pressure disease and the dyskinesia relevant with Parkinson's disease.Have can clinical development α 2The company of-adrenergic receptor antagonist comprises: Britannia Pharmaceuticals, IVAX, Juvantia Pharmaceuticals, MAP Pharmaceuticals, Novartis, Novo Nordisk, Or ganon, Pierre Fabre and Sanofi-Aventis.
As for selectivity α 2CThe development so far of-adrenergic receptor antagonist, OPC-28326 is a compound (Otsuka Pharmaceuticals is used for high blood pressure disease and peripheral blood disease in the 2nd phase) unique in the clinical development.Other α 2CAntagonist is by Oy JuvantiaPharma Ltd (JP 1514 and JP 1302, be disclosed among WO 01/64645 and the WO04/067513) and Novartis AG (NVP-ABE651 and NVP-ABE697, be disclosed in WO 01/55132 and J.Label Compd.Radiopharm 2002,45, in 1180), it is in the clinical preceding development stage, and principal indication is dysthymia disorders and schizophrenia.In addition, several compounds are listed in the very early stage development stage (biological test) by Juvantia and Kyowa Hakko, are used for dysthymia disorders and Parkinson's disease.
Invention description
The object of the present invention is to provide α 2-adrenergic receptor is particularly to α 2C-adrenergic receptor has the compound of binding affinity, particularly as antagonist.
This purpose is passed through by general formula (I) new substituted triazole ketone, imidazolone and terazole derivatives,
Figure A20058004360600121
Medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, and its N-oxide form or its quaternary ammonium salt reach, wherein
Z 1And Z 2Be CH or N independently of one another;
X AAnd X BBe covalent linkage or C independently of one another 1-4Alkyl, one of them divalence-CH 2-unit can be replaced by divalence phenyl unit, and/or each X wherein AAnd X BIn group being selected from halogen, cyano group, hydroxyl, amino, amino, oxo and the formyl radical of one or more hydrogen atoms replace;
Y AAnd Y BIndependently of one another for being selected from the tertiary butyl, NR 1R 2And Pir;
R 1And R 2Be selected from hydrogen independently of one another; Alkyl; Aryl; Aryloxy; Het;-NR aR b,
R wherein aAnd R bBe selected from hydrogen, alkyl, aryl or aralkyl independently of one another; And
Be selected from aryl, aryloxy and-NR aR bIn the alkyl that replaces of one or more groups, R wherein aAnd R bBe selected from hydrogen, alkyl, aryl or aralkyl independently of one another;
Pir is selected from pyrryl; Pyrazolyl; Imidazolyl; Pyridyl; Pyrimidyl; Pyrazinyl; Pyridazinyl; Pyrrolidyl; Imidazolidyl; Pyrazolidyl; Piperidyl; Two azepines bases; Morpholinyl; Thio-morpholinyl; Piperazinyl; Imidazolidyl; The 2H-pyrryl; Pyrrolinyl; Imidazolinyl; Pyrazolinyl; 1,2,3, the 4-tetrahydro isoquinolyl; 7,9-diaza-two ring [4.2.2] last of the ten Heavenly stems-3-thiazolinyl and pseudoindolyl; Wherein each Pir-group can at random be selected from the one or more groups replacements in the following radicals: hydroxyl; Oxo; Alkyl; Alkyl carbonyl; Alkyl sulphonyl; Alkoxy carbonyl; Aryloxyalkyl group; One-Fang aminoalkyl group; Aryl; Aralkyl; Aromatic yl alkenyl; Pyrrolidyl; By the furyl alkyl of 1 or 2 alkyl replacement; The benzofuryl alkyl; 2,3-dihydro-benzo [1,4] dioxy base alkyl; The quinolyl alkyl; Benzothienyl alkyl and indolyl alkyl are at random replaced by halogen;
Het is a ring heterocyclic group that is selected from following radicals: pyrryl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, piperidyl, two azepines bases, morpholinyl, thio-morpholinyl, piperazinyl, imidazolidyl, the 2H-pyrryl, pyrrolinyl, imidazolinyl, pyrazolinyl, furyl, thienyl,  azoles base, different  azoles base, thiazolyl, thiadiazolyl group, isothiazolyl, dioxolyl, the dithiane base, tetrahydrofuran base, triazolyl and triazinyl; Or be selected from the bicyclic heterocycles group of following radicals: quinolyl, isoquinolyl, 1,2,3,4-tetrahydrochysene-isoquinolyl, quinoxalinyl, indyl, pseudoindolyl, benzimidazolyl-, benzoxazol base, benzisoxa  azoles base, benzothiazolyl, benzisothiazole base, benzofuryl, benzothienyl, benzo piperidyl, benzopyranyl and imidazo [1,2-α] pyridyl; Wherein each Het-group is at random replaced by alkyl;
Or two adjacent part X and Y can condense together and form divalent group 1,2,3, and 4-tetrahydrochysene-isoquinolyl is at random replaced by hydrogen, alkyl, aryl, aralkyl, alkyl carbonyl, alkyl sulphonyl and pyrrolidyl alkyl;
Aryl is naphthyl or phenyl, is at random replaced by 1,2 or 3 substituting group that is selected from following radicals independent of each other separately: halogen, cyano group, hydroxyl, amino, alkylamino, alkoxyl group alkylamino, oxo, carboxyl, nitro, sulfenyl, formyl radical and alkoxyl group;
Alkyl is the straight or branched saturated hydrocarbyl that contains 1 to 6 carbon atom; Or contain cyclic saturated hydrocarbon (cycloalkyl) base of 3 to 7 carbon atoms; Or be connected to the cyclic saturated hydrocarbon base that contains 3 to 7 carbon atoms of the straight or branched saturated hydrocarbyl that contains 1 to 6 carbon atom; Each group can at random be replaced by one or more substituting groups that are selected from following radicals: halogen, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfenyl and formyl radical; And
Alkenyl is for further having the alkyl of the above-mentioned definition of one or more pairs of keys.
The invention still further relates to a kind of pharmaceutical composition, said composition contains drug acceptable carrier or thinner, can accept acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt as treatment significant quantity The compounds of this invention, particularly formula (I) compound, its medicine of activeconstituents.
The invention still further relates to The compounds of this invention be used for the preparation prevent and/or treat α 2The antagonism of-adrenergic receptor is particularly to α 2CThe purposes of the obstacle of the antagonism generation response of-adrenergic receptor or the medicine of disease.
Especially, the invention still further relates to the purposes that The compounds of this invention is used to prepare the medicine that prevents and/or treats central nervous system disease, emotional handicap, anxiety disorder, the pressure correlation disease relevant with depression and/or anxiety, cognitive disorder, personality disorder, schizophrenia, Parkinson's disease, alzheimer ' Mu Shi dementia, chronic pain disease, neurodegenerative disease, habit-forming obstacle, emotional handicap and sexual dysfunction.
The compounds of this invention also can combine with the antidepressive, antianxiety agent and/or the antipsychotic drug that have or developing or become future supply at present, be used as additional treatment and/or prevent above-listed disease, thereby the effect of improvement effect and/or effect starts.This can obtain assessment in rodent model, wherein antidepressive, antianxiety agent and/or antipsychotic drug demonstrate activity.For example, in order to alleviate the high heat that causes by pressure, can assess The compounds of this invention with antidepressive, antianxiety agent and/or antipsychotic drug.
Therefore, the invention still further relates to The compounds of this invention and be selected from the purposes of other compounds of antidepressive, antianxiety agent and/or antipsychotic drug as additional use with one or more; Relate to and contain The compounds of this invention and one or more are selected from the pharmaceutical composition of other compound of antidepressive, antianxiety agent and/or antipsychotic drug; And relate to the purposes that this class preparation of drug combination method and this based composition are used to prepare medicine, particularly in treatment dysthymia disorders and/or anxiety disorder, improve action and efficacy and/or effect starts.
Detailed Description Of The Invention
In preferred embodiments, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein Z 1Be CH and Z 2Be N; Or Z 1Be N and Z 2Be N; Or Z 1Be CH and Z 2Be CH; Or Z 1Be CH and Z 2Be CH.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein Z 1Be CH and Z 2Be N.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein each X AAnd X BBe selected from independently of one another: covalent linkage ,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH 2CH 2CH 2CH 2-,-CH (CH 3) CH (CH 3)-,-C (=O) CH 2-,-CH 2C (=O)-,-CH 2CH 2C (=O) CH 2-,-C 6H 4-,-CH 2C 6H 5-,-CH 2CH 2C 6H 5-,-C 6H 5CH 2-,-C 6H 5CH 2CH 2-,-CH 2C 6H 4CH 2-and-CH 2CH 2C 6H 4CH 2CH 2-.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein each X AAnd X BBe selected from independently of one another: covalent linkage ,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH (CH 3) CH (CH 3)-,-C (=O) CH 2-,-CH 2CH 2C (=O) CH 2-,-C 6H 4-,-CH 2C 6H 5-,-C 6H 5CH 2-and-CH 2C 6H 4CH 2-.Preferably, X AAnd X BBe independently of one another-CH 2CH 2-and-CH 2C 6H 5-.More preferably, X AFor-CH 2C 6H 5-, and X BFor-CH 2CH 2-.
In the preferred embodiment of advancing-going on foot, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein Y ABe NR 1R 2And Y BBe Pir; Or Y ABe NR 1R 2And Y BBe NR 1R 2Or Y ABe Pir and Y BBe Pir; Or Y ABe Pir and Y BBe NR 1R 2
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein Y ABe Pir and Y BBe NR 1R 2
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein Pir is selected from pyrrolidyl; Piperidyl; Two azepines bases; Morpholinyl; Piperazinyl; 1,2,3,4-tetrahydrochysene-isoquinolyl; 7,9-diaza-two ring [4.2.2] last of the ten Heavenly stems-3-thiazolinyl and pseudoindolyl; Wherein each Pir-group can at random be selected from the one or more groups replacements in the following radicals: hydroxyl; Oxo; Alkyl; Alkoxy carbonyl; Aryloxyalkyl group, particularly phenoxy group ethyl; One-Fang aminoalkyl group; Aryl; Aralkyl; Aromatic yl alkenyl, particularly 1-(2-methyl-3-phenyl allyl group); Pyrrolidyl; By the furyl alkyl of 1 or 2 alkyl replacement; The benzofuryl alkyl; 2,3-dihydro-benzo [1,4] dioxy base alkyl; The quinolyl alkyl; Benzothienyl alkyl and indolyl alkyl are at random replaced by halogen.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein Pir is a morpholinyl.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein each R 1And R 2Be independently selected from hydrogen; Alkyl; Aryl and be selected from aryl, aryloxy, Het and-NR aR bThe alkyl that replaces of group, R wherein aAnd R bBe selected from hydrogen, alkyl and aralkyl independently of one another.
Preferably, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein Het is selected from pyridyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl and tetrahydrofuran base.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein each R 1And R 2Be selected from hydrogen independently of one another; Methyl; Ethyl; Phenyl; And methyl and ethyl, the group that is selected from phenyl, phenoxy group, dimethylamino, (benzyl) (methyl) amino, (cyclohexyl methyl) (methyl) amino, pyridyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl and tetrahydrofuran base separately replaces.
More preferably, R 1And R 2Be selected from hydrogen and phenoxy group ethyl independently of one another.Most preferably, R 1Be hydrogen and R 2Be the phenoxy group ethyl.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein
Z 1And Z 2Be CH or N independently of one another;
X AAnd X BBe covalent linkage or C independently of one another 1-4Alkyl, one of them divalence-CH 2-unit can be replaced by divalence phenyl unit, and each X wherein AAnd X BOne or more hydrogen atoms in the part are replaced by oxo group;
Y AAnd Y BIndependently of one another for being selected from the tertiary butyl, NR 1R 2And Pir;
R 1And R 2Be selected from hydrogen independently of one another; Alkyl; Aryl and alkyl, be selected from aryl, aryloxy, Het and-NR aR bGroup replace R wherein aAnd R bBe selected from hydrogen, alkyl, aryl or aralkyl independently of one another;
Pir is selected from pyrryl; Piperidyl; Two azepines bases; Morpholinyl; Piperazinyl; 1,2,3, the 4-tetrahydro isoquinolyl; 7,9-diaza-two ring [4.2.2] last of the ten Heavenly stems-3-thiazolinyl and pseudoindolyl; Wherein each Pir-group can at random be selected from the one or more groups replacements in the following radicals: hydroxyl; Oxo; Alkyl; Alkoxy carbonyl; Aryloxyalkyl group; One-Fang aminoalkyl group; Aryl; Aralkyl; Aromatic yl alkenyl; Pyrrolidyl; By the furyl alkyl of 1 or 2 alkyl replacement; The benzofuryl alkyl; 2,3-dihydro-benzo [1,4] dioxy base alkyl; The quinolyl alkyl; Benzothienyl alkyl and indolyl alkyl are at random replaced by halogen;
Het is a ring heterocyclic group that is selected from following radicals: pyridyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl and tetrahydrofuran base;
Or two adjacent part X and Y can condense together and form divalent group 1,2,3, and 4-tetrahydrochysene-isoquinolyl is at random replaced by hydrogen, alkyl, aralkyl, alkyl carbonyl, alkyl sulphonyl and pyrrolidyl alkyl;
Aryl is naphthyl or phenyl, is at random replaced by 1,2 or 3 substituting group that is selected from following radicals independent of each other separately: halogen, cyano group, hydroxyl and alkoxyl group.
In further preferred embodiment, the present invention relates to formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, wherein aryloxyalkyl group is the phenoxy group ethyl, aromatic yl alkenyl is 2-methyl-3-phenyl-allyl group, and pseudoindolyl is partly replaced formation isoindole 1,3-diketo part by two oxos.
The most especially, the present invention relates to 4-(4-morpholine-4-ylmethyl-phenyl)-2-[2-(2-phenoxy group-ethylamino)-ethyl]-2,4-dihydro-[1,2,4] triazole-3-ketone, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt.
In the framework of the application's case, alkyl is that alkyl is the straight or branched saturated hydrocarbyl that contains 1 to 6 carbon atom; Or contain cyclic saturated hydrocarbon (cycloalkyl) base of 3 to 7 carbon atoms; Or be connected to the cyclic saturated hydrocarbon base that contains 3 to 7 carbon atoms of the straight or branched saturated hydrocarbyl that contains 1 to 6 carbon atom; Wherein each group can at random be replaced by one or more substituting groups that are selected from following radicals: halogen, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfenyl and formyl radical.Preferably, alkyl is methyl, ethyl, propyl group sec.-propyl, butyl, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl methyl and cyclohexyl ethyl.
In the framework of the application's case, alkenyl is for further having the alkyl of the above-mentioned definition of one or more pairs of keys.Preferably, alkenyl is vinyl and propenyl.
In the framework of the application's case, halogen is the substituting group that is selected from fluorine, chlorine, bromine and iodine; And multi-haloalkyl is the cyclic saturated hydrocarbon base that contains the straight or branched saturated hydrocarbyl of 1 to 6 carbon atom or contain 3 to 7 carbon atoms, and wherein one or more carbon atoms are replaced by one or more halogen atoms.Preferably, halogen is bromine, fluorine or chlorine, and preferably, multi-haloalkyl is a trifluoromethyl.
In the framework of the application's case, " The compounds of this invention " is meant that formula (I) compound, its medicine can accept acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt.
Medicine can be accepted acid salt and be defined as the therapeutic activity non-toxic acid additive salt form that formula (I) compound can form.Described salt can obtain by formula (I) compound that utilizes suitable acid treatment alkali form, and this acid is mineral acid for example, as haloid acid, and particularly spirit of salt, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; Organic acid is as acetate, oxyacetic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, ring thionamic acid, Whitfield's ointment, right-aminosallcylic acid and Ba Mo acid.
On the contrary, described acid salt form can be transformed into free alkali form by utilizing suitable alkaline purification.By utilizing suitable organic or inorganic alkaline purification, formula (I) compound that will contain acid proton is transformed into its therapeutic activity is not had noxious metals or amine additive salt form (base addition salt).Suitable base salt forms comprises, as ammonium salt, basic metal and alkaline earth salt, particularly lithium, sodium, potassium, magnesium and calcium salt, salt with organic bases formation, for example amine (hybramine) class salt is clung in second dibenzylamine, N-methyl D-glycosamine, sea, and with amino acids formed salt, for example arginine and Methionin class salt.
On the contrary, by utilizing suitable acid, the acid salt formal transformation can be become free form.
The quaternary ammonium salt of formula (I) compound is defined as the compound that the basic nitrogen of formula (I) compound and suitable quaternizing agent is reacted formation, the wherein alkylogen of quaternizing agent such as any replacement, aryl halide or aralkyl halogen, particularly methyl-iodide and benzyl iodide.Also can use other reactants that contain good leavings group, as trifluoromethanesulfonic acid alkyl ester, methylsulfonic acid alkyl ester and right-toluenesulphonic acids alkyl ester.Quaternary ammonium salt contains positive charge nitrogen.The acceptable counter ion of medicine comprise chlorine, bromine, iodine, trifluoroacetic acid root and acetate ion.
The term additive salt that uses in the application's framework also comprises the solvate that formula (I) compound and salt thereof can form.This kind solvent thing such as hydrate and alcoholate.
Formula (I) N-oxide compound is meant that one of them or several nitrogen-atoms are oxidized to so-called N-oxide compound, and particularly wherein one or more uncle's nitrogen (as piperazinyl or piperidyl group) are by those formulas (I) compound of the N-oxide compound of N-oxidation.This class N-oxide compound can be by need not to go deep into technician's acquisition of skill; They are obvious surrogates of formula (I) compound, and this is because these compounds are metabolite, and it forms by human intake's rear oxidation.Generally known, oxidation normally relates to the first step (Textbook of Organic Medicinal andPharmaceutical Chemistry, 1977, pages 70-75) of drug metabolism.Generally also known, the medication of the also alternative compound of the metabolite of compound own has effect much at one in human body.
According to the present technique field trivalent nitrogen is transformed into the known method of N-oxidised form, formula (I) compound can be transformed into corresponding N-oxide form.Described N-oxidizing reaction generally can be by carrying out formula (I) starting raw material and suitable organic or inorganic peroxide reactions.Suitable inorganic peroxide comprises that as hydrogen peroxide basic metal or alkaline earth metal peroxide are as sodium peroxide, Potassium peroxide.Suitable organo-peroxide can comprise peroxy acid, and for example benzene peroxide carbonic acid or halogeno-benzene peroxide carbonic acid are as 3-chlorobenzene peroxide carbonic acid; The peroxide alkanoic acid is as peracetic acid; Alkyl peroxide is as tertbutyl peroxide.The suitable solvent is, as water; Low-grade alkane alcohol is as ethanol etc.; Hydro carbons is as toluene; Ketone is as 2-butanone; Halohydrocarbon is as methylene dichloride; And the mixture of this kind solvent.
Term used herein " form of three-dimensional chemical isomer " is meant all possible isomeric forms that formula (I) compound has.Unless mention in addition or point out, the chemical name of compound has been represented the mixture of whole possible isomeric forms, and described mixture comprises whole diastereomers and the enantiomorph that contains basic molecular structure.More particularly, three-dimensional center can have R-or S-configuration; Substituting group on the saturated group of bivalent cyclic (part) can have cis-or trans-configuration.The compound that contains two keys can have E or Z-stereochemistry on described pair of key.The form of three-dimensional chemical isomer of formula (I) compound is included within the scope of the invention significantly.
According to the CAS naming rule, when the three-dimensional centers of two of known absolute configuration exist with a molecule in the time, R or S descriptor specify (based on the Cahn-iNgold-Prelog principle of temporal sequence) to lowest number chiral centre, i.e. reference center.Utilize relative descriptors [R *, R *] or [R *, S *] configuration at the expression second three-dimensional center, R wherein *Always be designated as reference center, and [R *, R *] center of expression with identical chirality, and [R *, S *] expression have different chiralitys the center.For example, if the minimum coding chiral centre in the molecule has the S configuration and second center is R, stereo descriptor just is designated as S-[R so *, S *].If use " α " and " β ", contain " α " position that the highest preferential substituent position on the asymmetric c atom in the ring system that minimum ring numbers always is positioned at the determined mean level of the sea of ring system (mean plane) erratically so.With respect to the highest preferential substituent position on referencing atom, the position of the highest preferential substituting group on other asymmetric c atom in the ring system (hydrogen atom in formula (I) compound), if it is positioned at the homonymy of the definite mean level of the sea of ring system, then be designated as " α ", if be positioned at the opposite side of the definite mean level of the sea of ring system, then be designated as " β ".
The present invention also comprises the derivative compound (being commonly referred to " prodrug ") of pharmaceutically active compounds of the present invention, and it can decompose in vivo and obtain The compounds of this invention.Compare with the resulting compound of its decomposition, prodrug will hang down (but not always) usually to the effect of receptor targeted.But, when the physics of required compound or chemical property make its medication difficulty or when invalid, prodrug is particularly useful.For example, required compound may have only bad solvability, and it may poorly transmit by mucous epithelium, perhaps may have the short plasma half-life that need not.Other discussion of prodrug can be referring to Stella, V.J.et al., " Prodrugs ", Drug Delivery Systems, 1985, pp.112-176 and Drugs, 1985,29, pp.455-473.
The prodrug forms of pharmaceutically active compounds of the present invention is generally formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer and N-oxide form thereof, but it contains esterification or amidated acid groups.This class esterification acid groups comprises formula-COOR xBase, wherein R xBe C 1-6Alkyl, phenyl, benzyl or following radicals are arbitrary:
Figure A20058004360600201
The amidation group comprises formula-CONR yR z, R wherein yBe H, C 1-6Alkyl, phenyl or benzyl, and R zFor-OH, H, C 1-6Alkyl, phenyl or benzyl.Containing amino The compounds of this invention can utilize ketone or aldehyde to go into formaldehyde-derived to go out Mannich alkali.This alkali passes through the first order kinetics hydrolysis in the aqueous solution.
In the framework of the application's case, The compounds of this invention is meant that formula (I) compound, its medicine can accept acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form and prodrug thereof.
In the framework of the application's case, a kind of element particularly when mentioning relevant formula (I) compound, comprises the whole isotropic substances and the mixture of isotopes of this element, no matter be natural existence or synthetic the generation, no matter be natural abundant or to be rich in the isotropic substance form.Especially, when mentioning hydrogen, it is meant 1H, 2H, 3H and composition thereof; When mentioning carbon, it is meant 11C, 12C, 13C, 14C and composition thereof; When mentioning nitrogen, it is meant 13N, 14N, 15N and composition thereof; When mentioning oxygen, it is meant 14O, 15O, 16O, 17O, 18O and composition thereof; When mentioning fluorine, it is meant 18F, 19F and composition thereof.
Therefore, The compounds of this invention also comprises one or more isotropic substances of one or more elements and composition thereof, comprises radioactive compound, is also referred to as the reflective markers compound, and wherein one or more radioactive atoms are substituted by a kind of radio isotope.Term " radio-labeled compound " is meant that formula (I) any compound, its N-oxide form, its medicine can accept additive salt or its form of three-dimensional chemical isomer, and it comprises at least one radioactive atom.For example, compound can utilize the labelled with radioisotope of positron or γ radiation.For radioligand-combination technology (membrane receptor assay method) 3The H-atom or 125The I-atom is substituted selection.For imaging, the most frequently used positron emission (PET) radio isotope is 11C, 18F, 15O and 13N, it is all generated by accelerator, and has respectively 20,100,2 and 10 minutes transformation period.Because these radioisotopic transformation period are so short, it is fit to the situation that on-the-spot accelerator is used to produce, so limited its purposes.The most widely used radio isotope is 18F, 99mTc, 201Tl and 123I.These radioisotopic processing, its production, separation and the blending in molecule thereof are conventionally known to one of skill in the art.
Especially, radioactive atom is selected from: hydrogen, carbon, nitrogen, sulphur, oxygen and halogen atom.Preferably, radioactive atom is selected from: hydrogen, carbon and halogen atom.
Especially, radio isotope is selected from: 3H, 11C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br.Preferably, radio isotope is selected from: 3H, 11C and 18F.
Preparation
The compounds of this invention can be usually by some row step preparations, and each step all well known to a person skilled in the art.Especially, triazolone, tetrazole ketone and imdazole derivatives can be according to following synthetic method preparations.
Synthesizing of triazolone derivative
Method A
Figure A20058004360600221
The reaction of initial amino or anilino derivative and [(dimethyl-amino) methylene radical]-hydrazine carboxylic acid's ethyl ester can be under temperature easily, by the routine heating or under microwave irradiation, in polar aprotic solvent such as acetonitrile, carry out for some time, react completely with assurance, typically under microwave irradiation, reacted 20 minutes down in 180 ℃.
Hal-X B-Y BIn the Hal-base be meant halogen atom, as Cl, Br or I.Alkylated reaction a) can exist inorganic or organic bases such as K in aprotic polar solvent such as acetonitrile, DMF or two  alkane 2CO 3, Na 2CO 3, Cs 2CO 3, NaH, Et 3Under N, BTPP or the PS-TBD condition, making things convenient for temperature, carrying out under microwave irradiation or the conventional heating.
Work as X BBe aryl rings, Hal is Br or I atom or suitable group such as CF 3SO 3, palladium coupled reaction b) carry out under the following conditions: in aprotic solvent such as toluene or two  alkane; There are palladium catalyst such as Pd (AcO) 2Or Pd (dba) 3Under the condition; There are alkali such as CS 2CO 3Or under t-BuONa and part such as BINAP or the Xantphos condition; In temperature easily,, react completely guaranteeing by routine heating or microwave irradiation for some time.In addition, the copper coupled reaction also can be used for preparing aryl derivatives.Under latter event, Hal is Br or I atom or suitable group such as B (OH) 2Reaction is carried out under the following conditions: in aprotic solvent such as ethylene dichloride; There are copper compound such as Cu (AcO) 2Under the condition; Catalytic amount or equivalent; Under the condition that has suitable part such as pyridine; And making things convenient for temperature, carry out under microwave irradiation or the conventional heating.In addition, mineral alkali such as K 3PO 4Also can join in the reaction.
Method B
Figure A20058004360600231
In above-mentioned flow process, Z is halogen atom or the oh group among the method A.Alkylated reaction is palladium or copper coupled reaction b a)) can carry out according to the same procedure that method A describes.Under the situation of Z=OH, can use the reaction of Mitsunobu-type and the acquisition required compound.Thus, corresponding pure and mild required triazolone intermediate can exist azepine dimethyl dicarbonate butyl ester, DEAD or DIAD, and is supported on arbitrarily under the condition of the triphenylphosphine on the polymkeric substance, carries out in aprotic solvent such as methylene dichloride.
Synthesizing of tetrazole ketone derivative
Figure A20058004360600232
Above-mentioned required tetrazole ketone intermediate can obtain by one or both methods of describing in the document (Biorg.Med.Chem.Lett.1999,1251-1254 and J.Med.Chem.1986,29,2290-2297).Alkylated reaction then or can under the same terms shown in triazolone-method A, carry out with the palladium/copper coupled reaction of required intermediate.
Synthesizing of imidazolone derivatives
Figure A20058004360600241
Required imidazolone intermediate can obtain in three steps according to the equal known method of any technician in this area.In suitable aprotic solvent such as ethyl acetate or acetonitrile, so that react completely, replace two imidazoles of CDI by reacting by heating thing for some time.Under temperature easily, by the routine heating or shine under microwave, under the hydration acidic conditions, as 10% aqueous hydrochloric acid, the heating product can make the further cyclisation of intermediate.Alkylated reaction then or can under the same terms shown in triazolone-method A, carry out with the palladium/copper coupled reaction of required intermediate.
Formula (I) midbody compound, wherein Y at least AAnd Y BArbitrary being selected from: alkyl; Halogen; Formyl radical; Amino based; Morpholinyl; Alkyl-SO 3-; Cyano group; Hydroxyl; Alkoxy carbonyl, particularly ethoxycarbonyl and tertbutyloxycarbonyl (t-BOC); Aromatic alkoxy carbonyl, particularly carbobenzoxy-(Cbz); And alkoxyl group, particularly methoxyl group, also formed a part of the present invention.
According to the equal known method of any technician in this area, can be with the different Y that are present in the midbody compound AAnd Y BGroups converted becomes to be present in the different Y in the final compound of formula (I) AAnd Y B
Pharmacology
The compounds of this invention, particularly formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, show it surprisingly to α 2-adrenergic receptor is particularly to α 2C-adrenergic receptor has binding affinity, especially can be used as antagonist.
In view of above-mentioned effectiveness, The compounds of this invention is suitable for preventing and/or treating disease, wherein α 2The antagonism of-adrenergic receptor, particularly α 2CThe antagonism of-adrenergic receptor has therepic use.Particularly, The compounds of this invention can be used for treating and/or preventing following disease:
● central nervous system disease comprises:
● emotional handicap comprises main especially dysthymia disorders, have or the melancholy of the feature that is a cup too low, the katatonia feature, melancholy feature, the atypical characteristics that begins postpartum and the situation of showing effect after recurrence have or do not have the melancholia of pattern in season, dysthymic disorder, bipolar I affective disorder, bipolar II affective disorder, the circulation affective disorders, the of short duration dysthymia disorders of recurrent, the mixed type affective disorder, there is not specially appointed bipolar disorder, because the emotional handicap of general health situation, the emotional handicap that material causes, there is not specially appointed emotional handicap, seasonal affective disorder and through preceding dysphoria obstacle.
● the anxiety disorder obstacle comprises the agoraphobia of the panic obstacle medical history of panic obstacle, nothing of panic attack, agoraphobia, no agoraphobia, specific phobia, social phobia, obsessional idea and compulsive obstacle, post-traumatic pressure obstacle, acute pressure obstacle, general anxiety disease, because the anxiety disorder of the anxiety disorder of general health situation, material initiation and do not have specially appointed anxiety disorder.
● the pressure correlation obstacle relevant with melancholy and/or anxiety comprises other reaction of acute stress reaction, adjustment obstacle (of short duration melancholy reaction, long-term melancholy reaction, mixing anxiety and melancholy reaction, the remarkable interferential adjustment of other mood obstacle, the remarkable interferential of behavior are adjusted obstacle, mood and behavior mixing interferential adjustment obstacle, do not had the adjustment obstacle of other specific remarkable sign) and serious pressure.
● dementia, amnesia and do not have other specially appointed identification obstacle, especially by the damage of degenerative obstacle, wound, infection, vascular disease, toxin, ischemia, vitamin b6 usp lack or endocrine disorder causes dementia, perhaps by alcohol or thiamin deficiency cause forgetful, both sides temporal lobe injury that herpes encephalitis and other edge encephalitis cause, anoxia/hypoglycemia/seriously twitch and the dementia that the back neuronal damage of perform the operation, degeneration obstacle, vascular disease or chamber III reasons such as pathology on every side cause.
● because the impaired identification obstacle of identification that other healthy situation causes.
● personality disorder comprises similar Paranoia's personality disorder, schizophrenia personality disorder, schizophrenia type personality disorder, do not arrogate to oneself social personality disorder, peripheral type personality disorder, dramatic personality disorder, autophilia type personality disorder, avoidant property personality disorder, dependency personality disorder, obsessional idea and compulsive behavior personality disorder and does not have specially appointed personality disorder.
● the Schizoaffective mental disorder that causes by different reasons, comprise frame moulding, inhibitable type, mixed type, similar Paranoia's type, entanglement, anxiety, the Schizoaffective mental disorder of differentiation and residual schizophrenia not, schizophreniform obstacle, the Schizoaffective mental disorder, vain hope property mental disorder, of short duration mental disorder, the mental disorder that shared psychotic disorder, material cause and do not have specially appointed mental disorder.
● Parkinson's disease, Gilles de Ia Tourette syndrome and the symptom thereof that can move, can not move-stiff syndrome, dyskinesia and medicine causes, tremble, tarantism, myoclonus, tic and myodystonia.
● attention-deficient/hyperactivity hyperkinesia obstacle (ADHD).
● paralysis on the Parkinson's disease that Parkinson's disease, medicine cause, postencephalitic Parkinson's disease, the carrying out property nuclear, multiple system atrophy, corticobasal degeneration, the dull-witted complication of Parkinson's disease-ALS and basal ganglion calcification.
● the early stage or alzheimer ' Mu Shi disease that begins and have melancholy mood late period.
● behavior interference and behavior disorder that dementia and intelligence are blunt comprise unpeaceful and excited.
● the outer motion obstacle of cone.
● mongolism.
● cathisophobia.
● eating disorder comprises anorexia nervosa, atypia anorexia nervosa, nervosa disease of eating too much at one meal, atypia nervosa disease of eating too much at one meal, the excessive diet relevant with other psychology interference, vomiting and the non-appointment eating disorder relevant with other psychic contagion
● the dementia that AIDS-is relevant.
● the chronic pain situation, comprise neuropathic pain, inflammatory pain, cancer pain and postoperative pain, comprise dental operation.These indications also comprise acute pain skeletal muscle pain, back pain, upper limb body pain, fibromyalgia and facial muscle pain syndrome, actinal surface pain, stomachache, false headache, tic pain and the SARS profile is logical, nerve root damage and arachnoiditis, senile pain, central pain and inflammatory pain.
● neurodegenerative disease comprises alzheimer ' Mu Shi disease, Huntington Chorea, Creutzfeld-Jacob disease, PickShi disease, demyelination obstacle such as multiple sclerosis and ALS, other neuropathy and neurodynia, multiple sclerosis, amyotrophic lateral sclerosis, apoplexy and a wound.
● habit-forming obstacle comprises:
● there are or do not have the substance depilatory or the abuse of Physiological dependence, particularly wherein material is alcohol, Amphetamine, amphetamine-type material, caffeine, hemp, Cocaine, psychedelia, inhalation, nicotine, opium, phencyclidine, phencyclidine compounds, analgesia-soporific, benzodiazepine and/or other material, gives up above-mentioned substance and alcohol withdrawal derangement especially for handling.
● the emotional handicap that causes by alcohol, Amphetamine, caffeine, hemp, Cocaine, psychedelia, inhalation, nicotine, opium, phencyclidine, analgesic agent, soporific, antianxiety agent and other material particularly.
● particularly anxiety disorder that causes by alcohol, Amphetamine, caffeine, hemp, Cocaine, psychedelia, inhalation, nicotine, opium, phencyclidine, analgesic agent, soporific, antianxiety agent and other material and the adjustment disorder that anxiety disorder is arranged.
● smoking cessation.
● weight management comprises obesity.
● somnopathy and interference comprise:
● the somnopathy that parahypnosis and/or the somnopathy that causes based on the somnopathy of parahypnosis, the somnopathy relevant with other intelligence obstacle, by the general health situation and material cause.
● circadian rhythm rhythm obstacle.
● improve sleep quality.
● sexual dysfunction, the sexual dysfunction that comprises dysaphrodisia, property erection problem, orgasm disorder pain obstacle, causes by the general health situation, the sexual dysfunction that material causes and do not have specially appointed sexual dysfunction.
Therefore, the present invention relates to be suitable for formula (I) compound, its medicine of making medicine and can accept acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt.
The present invention also relates to the purposes that The compounds of this invention is used to prepare the medicine that treats and/or prevents central nervous system disease, emotional handicap, anxiety disorder, the pressure correlation disease relevant with depression and/or anxiety, cognitive disorder, personality disorder, schizophrenia, Parkinson's disease, alzheimer ' Mu Shi dementia, chronic pain disease, neurodegenerative disease, habit-forming obstacle, emotional handicap and sexual dysfunction.
The compounds of this invention can combine with the antidepressive, antianxiety agent and/or the antipsychotic drug that have or developing or become future supply at present, is used as additional treatment and/or prevents above-listed disease, and particularly the effect of improvement effect and/or effect start.The compounds of this invention and other medicament can combination preparation mode exist, for simultaneously, separately or successively use, be used to prevent and/or treat melancholy and/or anxiety.This combination preparation can exist as the double pack form.Certainly, The compounds of this invention and other medicament can be used as the separated drug composition, while or medication successively.
Therefore, the present invention also relates to other other compound that is selected from antidepressive, antianxiety agent and antipsychotic drug of The compounds of this invention and one or more and combine, as the purposes of additional treatment.
Suitable antidepressive type comprises: NRI, the selective serotonin reuptake inhibitor (SSRI ' s), oxidase inhibitor (MAOI ' s), the monoamine oxidase reverse inhibitor (RIMA ' s), thrombotonin and NRI (SNRI ' s), norepinephrine activation and specific thrombotonin activation antidepressive (NaSSA ' s), corticotropin releasing factor(CRF) (CRF) antagonist, alpha-2-adrenoceptor antagonists and atypia antidepressive.
The suitable example of NRI comprises: amitriptyline, clomipramine, P-3693A, imipramine, trimeproprimine, A Moping (amoxapine), desmethylimipramine, maprotiline, nortriptyline, Pood woods (protriptyline), Rui Boding (reboxetine) and drug acceptable salt thereof.
The suitable example of selective serotonin reuptake inhibitor comprises: chlorobenzene oxygen propylamine, fluorine watt amine (fluvoxamine), Ba Ruiding (paroxetine), Saite woods (sertraline) and drug acceptable salt thereof.
The suitable example of oxidase inhibitor comprises: isocarboxazid, Phenelzine, tranylcypromine, Sai Lielin (selegiline) and drug acceptable salt thereof.
The suitable example of monoamine oxidase reverse inhibitor comprises: not Luoping (moclobemide) and drug acceptable salt thereof.
The suitable example of thrombotonin and NRI comprises Wella expense (venlafaxine) and drug acceptable salt thereof.
The suitable example of atypia antidepressive comprises: bupropion, lithium, Nie Fadong (nefazodone), Te Luodong (trazodone), vicilan, western Boot (sibutramine) and drug acceptable salt thereof.
Other suitable antidepressive comprises: that orchid of Ah Di (adinazolam), I is general (alaproclate), A Miding (amineptine), amitriptyline/zeisin combination, Ah Di clings to (atipamezole), A Ruimi (azamianserin), Ba Xinna (bazinaprine), shellfish forint (befuraline), must Finland (bifemelane), Bi Nuolin (binodaline), Bi Benmo (bipenamol), Pu Faluo (brofaromine), Bu Puping (bupropion), Ka Ruilong (caroxazone), Sai Ruilan (cericlamine), Xi Napu (cianopramine), west not many (cimoxatone), west general greatly (citalopram), restrain go out general (clemeprol), gram watt amine (clovoxamine), greatly must Buddhist nun (dazepinil), dimethylethanolamine, the ground woods (demexiptiline) of going out, ground this flat (dibenzepin), many absorption units (dothiepin), ground DOPA (droxidopa), Ying Niexin (enefexine), Yi Dalan (estazolam), Yi Duodong (etoperidone), Fen Moding (femoxetine), fragrant (fengabine) on the rocks, take Lip river amine (fezolamine), Ford new (fluotracen), Yi Da (idazoxan), Ying Dabing (indalpine), Ying Luoxin (indeloxazine), Yi Puduo (iprindole), Lie Pulin (levoprotiline), benefit fourth (litoxetine), Luo Feipu (lofepramine), ground amine (medifoxamine) goes out, general greatly (metapramine) goes out, Te Lin (metralindole) goes out, Mi Sailing (mianserin), Mi Naxi (milnacipran), Mi Napu (minaprine), Mi Tebing (mirtazapine), not Rayleigh (monirelin), alunite Pood (nebracetam), Nie Fupan (nefopam), niaguitil (nialamide), Nuo Mifen (nomifensine), Novolten (norfluoxetine), Ou Luolin (orotirelin), Ou Fuxin (oxaflozane), Bi Napan (pinazepam), than woods many (pirlindone), must ground woods (pizotyline), Rui Tanxin (ritanserin), Luo Lipu (rolipram), celo wheat (sercloremine), venue of sports event woods (setiptiline), west Boot (sibutramine), crisp cloth amine (sulbutiamine), crisp than auspicious (sulpiride), Brittany Lip river (teniloxazine), match Rayleigh (thozalinone), Sai Moling (thymoliberin), ground alunite fourth (tianeptine), ground card ice (tiflucarbine), Dove new (tofenacin), many Su Ping (tofisopam), many Luo Dong (toloxatone), fourth (tomoxetine) how not, Wa Ruili (veralipride), tie up fast woods (viqualine), flat (zometapine) and drug acceptable salt thereof go out for auspicious fourth of going out (zimelidine) and Lip river, and St.John ' s wort herb, or Hypericumperforatum, or its extract.
Suitable antianxiety agent comprises: benzodiazepine and 5-HT 1AReceptor stimulant or antagonist, particularly 5-HT 1APartial agonist, corticotropin releasing factor(CRF) (CRF) antagonist, having the muscarine cholinomimetic can active compound and act on the compound of cationic channel.Except benzodiazepine, other suitable antianxiety agent is that non-benzodiazepine calmness-soporific such as Lip river must (zolpidem); Mood stabilizer such as Ke Balan (clobazam), Jia Bading (gabapentin), Rameau Ji (lamotrigine), Luo Ruili (loreclezole), Ou Kabing (oxcarbamazepine), benzodiazole base dimethyl-penten enol and Wei Jiaba (vigabatrin); And barbiturate(s).
Suitable major tranquilizer is selected from: acetyl azophenlyene, particularly its malate; A Lan ground is (alentemol), particularly hydrobromate not; A Pading (alpertine); Suicalm; Shellfish is evened up (batelapine), particularly maleate; R-4584; Conscience many (benzindopyrine), particularly hydrochloride; Bromobenzene  piperazine ketone; General group many (bromperidol); Butaclamol, particularly hydrochloride; Rolectil; Propionyl azophenlyene, particularly maleate; Ka Telin (carvotroline), particularly hydrochloride; Chlorpromazine; Ke Puli (chlorprothixene); New School auspicious (cinperene); New special acid amides (cintriamide); Clo horse (clomacran), particularly phosphoric acid salt; Clopenthixol; The chlorine ratio is (clopimozide) not; Chlorine is than blue (clopipazan), particularly mesylate; Chlorine is than ketone (cloroperone), particularly hydrochloride; W-130; Diuril acid amides (clothixamide), particularly maleate; Leoponex; Encircle third azophenlyene, particularly hydrochloride; The fluorine piperidines; Etazolate, particularly hydrochloride; Pfennig close (fenimide); The fluorine heart many (flucindole); Fluorine goes out flat (flumezapine); Fluphenazine, particularly caprate, enanthate and/or hydrochloride; Fluorine must swell (fluspiperone); Fluorine is than woods (fluspirilene); The special woods (flutroline) of fluorine; Ji Fotelin (gevotroline), particularly hydrochloride; Fluperamide; R-1625; Yi Luobidong (iloperidone); Yi Miduolin (imidoline), particularly hydrochloride; Lan Pailong (lenperone); Ke Saiping; Marseille fourth (mazapertine), particularly succinate; Suo Da (mesoridazine) goes out; Horizon (metiapine) goes out; (milenperone) swells in Milan; Mi Liding (milipertine); Mo Lidong (molindone), particularly hydrochloride; Na Ruinuo (naranol), particularly hydrochloride; Buddhist nun's fluorine is (neflumozide), particularly hydrochloride not; Ou Kabidong (ocaperidone); Ou Lanping (olanzapine); Ou Sipairui (oxiperomide); Ben Fuduo (penfluridol); This Horizon (pentiapine), particularly maleate; Trilifan; Pimozide; Bi Nuoping (pinoxepin), particularly hydrochloride; Bi Panlong (pipamperone); Piperacetazine; The general piperazine of piperazine (pipotiazine), particularly palmitate; Soon the winter (piquindone), particularly hydrochloride; Prochlorperazine, particularly edetate; Chloropyrazine, particularly maleate; Promazine, particularly hydrochloride; Fast Horizon (quetiapine); Auspicious not (remoxipride); Rui Bidong (risperidone); Auspicious Carlow (rimcazol), particularly hydrochloride; Clofluperol, particularly hydrochloride; Match fourth many (sertindole); Sai Duolong (setoperone); Si Bipailong (spiperone); Sulpiride; Thioridazine; Thiothixene; The auspicious heart of shuttle (thorazine); Ground is than winter (tioperidone), particularly hydrochloride; Ground Si Bilong (tiospirone), particularly hydrochloride; Trifluoperazine, particularly hydrochloride; Triperidol; Triflupromazine; Rui Puxidong (ziprasidone), particularly hydrochloride; And their mixture.
Pharmaceutical composition
The present invention also relates to a kind of pharmaceutical composition, it comprises drug acceptable carrier or thinner and can accept acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt as The compounds of this invention, particularly formula (I) compound, its medicine of activeconstituents.
The compounds of this invention, particularly formula (I) compound, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt, or its any subgroup or its combination, can be made into the various medicament forms that are suitable for the administration purpose.The suitable composition that can all enumerate normally is used to be administered systemically.
In order to prepare pharmaceutical composition of the present invention, will be as the significant quantity specific compound of activeconstituents, at random be its additive salt form, mix closely that wherein said carrier can have multiple different form according to the required dosage form of taking medicine with drug acceptable carrier.These pharmaceutical compositions are suitably the unit form of medication, are particularly suitable for oral, rectum, through skin, the injection of non-enteron aisle or inhaled medication.For example, when the composition of preparation oral administration form, under oral liquid such as suspension, syrup, elixir, emulsion and solution situation, can use any common drug media, as water, ethylene glycol, oils, alcohols etc.; Under pulvis, pill, capsule and tablet situation, can use solid carrier such as starch, sucrose, kaolin, thinner, lubricant, binding agent, disintegrating agent etc.Because medication is convenient, tablet and capsule have been represented best oral administration unit form, obviously are to use solid pharmaceutical carriers this moment.For non-enteron aisle composition, carrier generally includes sterilized water, is most of at least, although can comprise that other composition is as helping dissolving.As preparing injection solution, carrier can comprise the mixture of salt brine solution, glucose solution or salt solution and glucose solution.The preparation injection emulsion can use appropriate liquid carrier, suspension agent etc.Also comprise the solid form preparation that can before using, can change into liquid form preparation rapidly.In being suitable for the composition of percutaneous dosing, carrier at random comprises penetration enhancer and/or suitable wetting agent, at random mixes with a spot of suitable additive, and wherein additive can not cause tangible deleterious effect on skin.Described additive can promote medication to skin and/or to help preparation be to need compositions.The administration in many ways of these compositions is as through skin patch, some agent, ointment.
Easy and dosage is consistent for medication, be particularly conducive to aforementioned pharmaceutical compositions is made the unit form of medication.Unit used herein form of medication is meant the physical sepn unit that is applicable to unitary dose, and each unit contains predetermined active principle, and it makes it combine the back with required pharmaceutical carrier as calculated and produces required result of treatment.The example of this class unit form of medication comprises tablet (comprising indentation or coated tablet), capsule, pill, pulvis bag, eye disc, suppository, injection solution or suspension etc., with and isolating multiple formulation.Because The compounds of this invention is effective oral medication dopamine antagonist, is particularly conducive to oral administration so contain the pharmaceutical composition of this compound.
The present invention also relates to a kind of pharmaceutical composition, said composition comprises The compounds of this invention and one or more are selected from other compound of resist melancholy agent, antianxiety agent and major tranquilizer; The invention still further relates to said composition is used to prepare and particularly treat the purposes that melancholy and/or anxiety start with the effect and/or the effect of improvement effect.
The following example is used for explanation rather than will limits the scope of the invention.
Experimental section
A. the preparation of midbody compound
Hereinafter " RT " represents room temperature, " CDI " expression 1,1 '-carbonyl dimidazoles, " DBPE " represents Di Iso Propyl Ether, " MIK " represents methyl iso-butyl ketone (MIBK), " BINAP " expression [1,1 '-dinaphthalene]-2,2 '-two bases two [diphenylphosphine], " NMP " represents 1-Methyl-2-Pyrrolidone, " Pd 2(dba) 3" expression three (dibenzalacetones) two palladiums, " BTTP " expression 1,1 '; 1 "-[(1, the 1-dimethyl ethyl) phosphinimylidyne] three-pyrrolidone, " Xantphos " expression (9,9-dimethyl-9H-xanthene-4,5-two bases) two [phenylbenzene-phosphine, two (dimethylamino) methylene radical of " HATU " expression 1-[]-1H-1,2,3-triazolo [4,5-b] pyridine  3-oxide compound hexaflarate hydrochlorate, and " DMF " expression N, dinethylformamide.
Embodiment A 1
A-1. prepare midbody compound 1
With 4-(4-bromophenyl)-2,4-dihydro-3H-1,2,1 of 4-triazole-3-ketone (0.002mol), 4-iodo-1-piperidine carboxylic acid, 1-dimethyl ethyl ester (0.003mol) and Cs 2CO 3(0.004mol) in CH 3Mixture heated 10 minutes down at 150 ℃ under microwave irradiation among the CN (7ml), and is following 10 minutes at 180 ℃ again.Filter gained solid and evaporating solvent.Utilize CH 2Cl 2, utilize CH again 2Cl 2/ CH 3OH (98/2) through filter paper purifying residue, collects the gained solid.Output: 0.25g midbody compound 1 (30%).
B. prepare midbody compound 2
Figure A20058004360600331
With midbody compound 1 (0.00106mol), zinc cyanide (0.00064mol) and Pd (PPh 3) 4(0.000088mol) mixture in deoxidation DMF (5ml) heated 10 minutes down in 150 ℃ under microwave irradiation, filtered gained solid and evaporating solvent then.Utilize CH 2Cl 2/ CH 3OH (98/2) and CH 2Cl 2/ CH 3OH (96/4) collects required solid then at silica gel upper prop chromatography purification residue.Output: 0.235g midbody compound 2 (60%).
C. prepare midbody compound 3 (removing t-BOC)
With midbody compound 2 (0.00064mol) in trifluoroacetic acid (0.5ml) and CH 2Cl 2Mixture (2ml) at room temperature stirred 1 hour, added saturated Na 2CO 3Solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 0.124g midbody compound 3 (72%).
D. prepare midbody compound 4
Figure A20058004360600341
With midbody compound 3 (making) according to A1.c (0.00046mol), 2-methyl-3-phenyl-2-propionic aldehyde (0.00092mol) and NaBH (OAc) 3(0.00092mol) in 1, the mixture in the 2-ethylene dichloride (3ml) heated 10 minutes down in 100 ℃ under microwave irradiation, added saturated NH then 4Cl solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Manifold is collected (vacuum) purifying residue (gradient: CH 2Cl 2/ CH 3OH 98/2,96/4), by capturing and be discharged into single step purification.Collect product cut and evaporating solvent.Output: 0.014g midbody compound 4 (8%).
E. prepare midbody compound 5
The mixture of midbody compound 4 (0.0005mol) in Trifluoromethanesulfonic anhydride (1ml) and ethanol (4ml) stirred and refluxed 18 hours, then reaction mixture is injected into saturated Na 2CO 3In the solution (10ml), utilize CH 2Cl 2Extraction.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Utilize manifold (gradient: CH 2Cl 2/ EtOAc 4/1,1/1) filtered residue.Collect product cut and evaporating solvent.Output: 0.079g midbody compound 5 (35%).
F. prepare midbody compound 6
Figure A20058004360600351
Under-78 ℃ with DIBAL (0.00045mol; 1.0M, in toluene) join in the mixture of midbody compound 5 (0.00018mol) in dry toluene (2ml), then reaction mixture is cooled to room temperature, at room temperature stirred 30 minutes.Add CH 2Cl 2/ CH 3OH (1/1) utilizes saturated NH 4The starting raw material DIBAL-H that Cl solution (0.5ml) quenching is excessive.Diatomite filtration gained solid, dry then (Na 2SO 4) organic filtrate, evaporating solvent.Output: 0.078g midbody compound 6 (100%, under need not to be further purified, use it for next reactions steps).
Embodiment A 2
A. prepare midbody compound 27
Figure A20058004360600352
With 1,1-dimethyl ethyl-4-piperidyl amino manthanoate (0.0349mol), 2-methyl-3-phenyl-2-propionic aldehyde (0.0268mol) and NaBH (OAc) 3(0.0349mol) at room temperature stir in ethylene dichloride (130ml) and molecular sieve (4 ) mixture in (q.s.) and spend the night, then filter reaction mixture on diatomite.Utilize 10%NH 4Cl solution-treated filtrate is utilized the EtOAc extraction.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 11.44g midbody compound 27 (99%).
B. prepare midbody compound 28
Trifluoroacetic acid (23.6ml) is added drop-wise to midbody compound 27 (0.014mol) in ice-water bath refrigerative CH 2Cl 2In the solution (100ml).At 0 ℃ of stirred reaction mixture 2 hours to the room temperature, utilize 50%NaOH solution basic metalization then, and extraction.Separate organic layer, dry (Na 2SO 4), filtration and evaporating solvent are to doing.Output: 2.72g midbody compound 28 (84%).
C. prepare midbody compound 7
Figure A20058004360600362
Under microwave irradiation, with midbody compound 28 (0.005mol) and [(dimethylamino) methylene radical]-hydrazine carboxylic acid's ethyl ester (0.010mol) in CH 3Mixture among the CN (20ml) heated 20 minutes down at 180 ℃, and evaporating solvent utilizes Anaesthetie Ether washing gained residue then.Output: 1.400g midbody compound 7 (94%).
D. prepare midbody compound 8
Under microwave irradiation, with midbody compound 7 (0.00084mol), 4-methyl-bromobenzoate (0.00126mol), Pd 2(dba) 3(0.000042mol), BINAP (0.000126mol) and the mixture of t-BuONa (0.00126mol) in deoxidation toluene (3ml) be 175 ℃ of heating 15 minutes down, adds CH then 2Cl 2And 10%NH 4Cl solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Utilize manifold (vacuum) (gradient: CH 2Cl 2/ EtOAc 4/1,2/1) the purifying residue.Collect product cut and evaporating solvent.Output: 0.107g midbody compound 8 (29%).
Embodiment A 3
Preparation midbody compound 9
Figure A20058004360600371
Under microwave irradiation, the midbody compound that will make according to A1.f
Figure A20058004360600372
(0.0001 0mol) and MnO 2(0.00050mol) mixture in ethylene dichloride (1ml) heated 10 minutes down at 120 ℃.On diatomite, cross filter solid, utilize CH 2Cl 2Washing, evaporating solvent then.Output: 0.037g midbody compound 9 (92%).
Embodiment A 4
A. prepare midbody compound 13
Figure A20058004360600373
Under microwave irradiation, the midbody compound that will make according to embodiment A 1.c
Figure A20058004360600374
(0.0015mol), (2-bromine oxethyl) benzene (0.00165mol) and K 2CO 3(0.0030mol) in CH 3Mixture among the CN (10ml) heated 10 minutes down at 120 ℃, added CH then 2Cl 2Filter the gained solid, evaporating solvent.At last, utilize ether washing gained residue.Output: 0.392g midbody compound 13 (57%).
B. prepare midbody compound 10
Figure A20058004360600381
With CO (gas) be blown into midbody compound 13 (making) according to A4.a (0.00022mol), NaHCO 2(0.00033mol) and Cl 2Pd (PPh 3) 2(0.000009mol) in the mixture in DMF (5ml), reaction mixture is heated to 110 ℃ then, CO this moment (gas) continues to be blown into.Add extra NaHCO 2(2 x q.s.) and Cl 2Pd (PPh 3) 2(2 xq.s.), mixture heated 2 hours down at 110 ℃, and CO this moment (gas) continues to be blown into.Evaporating solvent is collected in CH with residue 2Cl 2In.On diatomite, cross filter solid, evaporating solvent.Manifold (vacuum) (gradient: CH 2Cl 2/ CH 3OH 96/4) purifying gained residue.Collect product cut and evaporating solvent.Output: 0.081g midbody compound 10 (91%).
Embodiment A 5
A. prepare midbody compound 11
Figure A20058004360600382
With N-[4-[4-(4-p-methoxy-phenyl)-1-piperazinyl] phenyl] Hydrazinecarboxamidederivatives (, comprising its content) at this according to the explanation of WO94/18978 preparation (0.001mol) and the mixture of formyl imines (0.029mol) in DMSO (10ml) 160 ℃ of heating 2 hours down.After the cooling, reaction mixture is injected in the mixture of MIK and DIPE.Filtering-depositing is used in the activated carbon treatment among the DMF.After the filtration, the product crystallization, filtration product is also dry.Output: 1g midbody compound 11 (28%).
B. prepare midbody compound 12
Figure A20058004360600391
Under microwave irradiation, with midbody compound 11 (making) (0.001mol) according to A5.a, 4-iodo-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (0.002mol) and BTPP (0.002mol) are in CH 3Mixture among the CN (3.5ml) heated 20 minutes down at 120 ℃, utilized CH 3The solid that the CN washing is collected is then by short open tubular column purification by chromatography (elutriant 1:CH 2Cl 2/ EtOAc4/1,1/1; Elutriant 2:CH 2Cl 2/ 2-acetone 1/1).Collect product cut and evaporating solvent.Output: 0.12Og midbody compound 12 (22%).
Embodiment A 6
A. prepare midbody compound 26
Figure A20058004360600392
To 1,2-dihydro-5H-1,2, add α in the 4-triazole-mixture of 3-ketone (5.74mmol) in toluene (70ml), α-diphenyl benzene methyl alcohol (4.7mmol) and right-toluenesulphonic acids (1.91mmol).Under nitrogen atmosphere, utilize Dean-Stark separator reflux reaction 20 hours.Cooling solution, and utilize 2%NaHCO 3Aqueous solution quenching utilizes CH 2Cl 2(3x100ml) extraction.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Column chromatography purifying (elutriant: CH 2Cl 2/ MeOH 9/1) residue.Output: 925mg midbody compound 26 (60%).
B. prepare midbody compound 39
Figure A20058004360600401
In the mixture of midbody compound 26 (2.446mmol) in DMF (2ml), add NaH (4.077mmol).At room temperature stirring reaction was 30 minutes, adds 2-(3-bromopropyl)-1H-isoindole-1,3 (2H)-diketone (2.70mmol) then, 90 ℃ of following reacting by heating 20 hours.Evaporating solvent, column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH 9/1) product.Collect the cut of selecting, and evaporate its solvent.Output: 940mg midbody compound 39 (75%).
C. prepare midbody compound 58
Figure A20058004360600402
With midbody compound 39 (0.972mmol) in TFA/H 2O/CH 2Cl 2(1: 1: 1) mixture in (10ml) stirred 20 hours down at 60 ℃.Remove solvent, column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH 9/1) product.Collect the cut of selecting, and evaporate its solvent.Output: 265mg midbody compound 58 (100%).This crude product can be used for next step under need not to be further purified.
D. prepare midbody compound 59
Figure A20058004360600411
To midbody compound 58 (0.0367mmol) in CH 2Cl 2Add PS-PPh in the mixture (4ml) 3(0.0734mmol) with 1,1-dimethyl ethyl 4-(methylol)-1-piperidine carboxylic acid ester (0.5505mmol).Stirring reaction 5 minutes.Add two (1, the 1-dimethyl ethyl) diazane dicarboxylic esters (0.05505mmol) then, reaction was at room temperature stirred 3 hours.Filter resin and evaporated filtrate solvent.Column chromatography purifying (elutriant: CH 2Cl 2/ MeOH 9/1) product.Collect the cut of selecting, and evaporate its solvent.Utilize CH 2Cl 2/ trifluoroacetic acid 8/2 is handled residue, evaporating solvent.Output: 25mg midbody compound 59 (100%).This crude product can be used for next step under need not to be further purified.
Embodiment A 7
A. prepare midbody compound 29
Figure A20058004360600412
Under microwave irradiation, with 1-(phenyl methyl)-4-piperylhydrazine (0.0125mol) and 2-[(dimethylamino) methylene radical] hydrazine carboxylic acid's methyl esters (0.025mol) is in CH 3Mixture among the CN (50ml) heated 20 minutes down at 180 ℃, then evaporating solvent.Utilize CH at last 3CN/ ether (1/9) washing gained residue.Output: 2.6g midbody compound 29 (81%).
B. prepare midbody compound 30
Figure A20058004360600413
Under microwave irradiation, with midbody compound 29 (0.003mol), ethyl bromoacetate (0.0045mol) and K 2CO 3(0.006mol) in CH 3Mixture among the CN (10ml) heated 15 minutes down at 120 ℃, added CH then 2Cl 2Cross filter solid, evaporating solvent.Column chromatography purifying (elutriant 1:CH 2Cl 2/ EtOAc 1/1; Elutriant 2:CH 2Cl 2/ CH 3OH 96/4) product.Collect the product cut, and evaporate its solvent.Output: 1.01g midbody compound 30 (98%).
C. prepare midbody compound 31
Figure A20058004360600421
Midbody compound 30 (0.0029mol) and 1-chloroethyl carbonochloride acidester (0.0087mol) mixture in THF (10ml) stirred and reflux 1 hour, add extra 1-chloroethyl carbonochloride acid ester (0.939ml) then, reacting by heating mixture 1 hour.Add saturated NaHCO 3Solution utilizes CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.By short opening silica gel chromatography purifying (elutriant 1:CH 2Cl 2/ EtOAc 1/0,1/1; Elutriant 2:CH 2Cl 2/ CH 3OH 9/1) residue.Collect product cut and evaporating solvent.Output: 0.28g midbody compound 31.
D. prepare midbody compound 32
Figure A20058004360600422
With midbody compound 31 (0.00078mol) in CH 3Mixture stirring among the OH (10ml) and reflux 1 hour add CH then 2Cl 2With saturated Na 2CO 3Solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 0.200g midbody compound 32.
E. prepare midbody compound 33
With midbody compound 32 (0.00079mol), 2-methyl-3-phenyl-2-propionic aldehyde (0.00119mol) and NaBH (Oac) 3(0.00119mol) mixture in ethylene dichloride (4ml) heated 10 minutes down at 105 ℃, added NH then 4OH (38%NH 3, in H 2Among the O).Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.By the short opening silica gel chromatography of manifold purifying (elutriant 1:CH 2Cl 2/ EtOAc 9/1; Elutriant 2:CH 2Cl 2/ CH 3OH96/4) residue.Collect product cut and evaporating solvent.Output: 0.055g midbody compound 33 (18%).
F. prepare midbody compound 14
Figure A20058004360600432
With NaBH 4(0.00035mol) join intermediate 33 (0.00014mol) in CH 3In the mixture among OH (150ml) and the THF (0.750ml), stirred reaction mixture 1 hour at room temperature then.Add 10%NH 4Cl solution utilizes CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 0.038g midbody compound 14 (79%).
G. prepare midbody compound 15
Figure A20058004360600433
Under 0 ℃, Methanesulfonyl chloride (0.00017mol) is joined midbody compound 14 (according to A7.a preparation) (0.00011mol) and Et 3N (0.00022mol) is in CH 2Cl 2In the solution (1ml), stirred reaction mixture 1 hour at room temperature adds saturated NaHCO then 3Solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.With residue manifold (5g tube) purifying (elutriant: CH 2Cl 2/ CH 3OH 97/3).Collect product cut and evaporating solvent.Output: 0.033g midbody compound 15 (71%).
Embodiment A 8
A. prepare midbody compound 16
Figure A20058004360600441
Under 0 ℃, two (1, the 1-dimethyl ethyl) two carbonic ethers (0.0094mol) are joined intermediate (making according to B8.a) (0.0094mol) and CH 2Cl 2(0.0094mol) in Et 3In the solution of N (25ml), earlier under 0 ℃, stirred reaction mixture at room temperature again.Evaporating solvent is by the short opening silica gel chromatography of manifold purifying (gradient: CH 2Cl 2/ EtOAc 1/0,1/1) residue.Collect product cut and evaporating solvent.Output: 3.5g midbody compound 16 (74%).
B. prepare midbody compound 17
Figure A20058004360600451
With midbody compound 16 (making) according to A8.a (5.5mmol), NaHCO 2(16.5mmoD, PdCl 2(PPh 3) 2(0.28mmol) and DMF (50ml) be incorporated in the PARR container.Seal this system, utilize CO (gas) pressurization (40bars).120 ℃ of following reacting by heating 20 hours.Open system then.Evaporating solvent is with CH under the solid collection 2Cl 2, pass through diatomite filtration.Evaporated filtrate is by chromatography purification (gradient: CH 2Cl 2/ EtOAc 9/1,4/1) residue.Collect product cut and evaporating solvent.Output: 1.1g midbody compound 17 (27%).
C. prepare midbody compound 18
Figure A20058004360600452
With midbody compound 17 (making) according to A8.b (0.00029mol), morpholine (0.00044mol) and NaBH (OAc) 3(0.00044mol) mixture in ethylene dichloride (2ml) stirred 10 minutes down at 100 ℃, added then to concentrate NH 4OH solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue filters (elutriant 1:CH by silica gel tube (5g) 2Cl 2/ EtOAc 4/1; Elutriant 2:CH 2Cl 2/ CH 3OH 96/4).Collect product cut and evaporating solvent.Output: 0.122g midbody compound 18 (80%).
Embodiment A 9
A. prepare midbody compound 19
Figure A20058004360600461
Under 0 ℃, with NaBH 4(0.00031mol) join midbody compound 17 (making) (0.00031mol) in CH according to A8.b 3In the solution among the OH (2ml), reaction mixture at room temperature stirred 1 hour.Add 10%NH 4Cl solution utilizes CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue utilizes Sep-Pak silica gel tube (5g) manifold purifying (elutriant 1:CH 2Cl 2/ EtOAc 4/1; Elutriant 2:CH 2Cl 2/ 2-acetone 2/1).Collect product cut and evaporating solvent.Output: 0.054g midbody compound 19 (38%).
B. prepare midbody compound 20
Figure A20058004360600462
At N 2Following reaction: under 0 ℃, with midbody compound 19 (making) according to A9.a (0.00012mol) mixture in anhydrous THF (1ml) join 60%NaH (0.00024mol) in the mixture of anhydrous THF (1ml), stir the gained mixture 15 minutes, and added CH down at 0 ℃ then 3I (0.00048mol), at room temperature stirred reaction mixture is 90 minutes.Add extra CH 3I (0.00048mol), at room temperature stirred reaction mixture is 90 minutes, adds 10%NH then 4Cl solution utilizes CH 2Cl 2Extraction gained mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue utilizes Sep-Pak silica gel tube (5g) manifold purifying (gradient: CH 2Cl 2/ EtOAc 1/0,4/1).Collect product cut and evaporating solvent.Output: 0.047g midbody compound 20 (84%).
Embodiment A 10
A. prepare midbody compound 21
Figure A20058004360600471
Under 0 ℃, with NaBH 4(0.0170mol) be added drop-wise to midbody compound
Figure A20058004360600472
(making according to A7.e) is (0.0068mol) in CH 3Among OH (7ml) and the anhydrous THF (35ml) in the mixture, stirred reaction mixture 1 hour at room temperature then.Add 10%NH 4Cl solution utilizes CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 2.13g midbody compound 21 (87%).
B. prepare midbody compound 22
Figure A20058004360600473
Under 0 ℃, Methanesulfonyl chloride (0.0087mol) is added drop-wise to midbody compound 21 (making according to A10.a) (0.0058mol) and Et 3N (0.0116mol) is in CH 2Cl 2In the mixture (35ml), stirred reaction mixture 1 hour at room temperature then.Add saturated NaHCO 3Solution utilizes CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Be settled out residue by DIPE, collect the gained solid then.Output: 2.5g midbody compound 22 (98%).
C. prepare midbody compound 23
Figure A20058004360600481
Under microwave irradiation, with midbody compound 22 (making) according to A10.b (0.0055mol), 2-phenoxyethylamine (0.0110mol), Cs 2CO 3(0.0110mol) and molecular sieve 4 (0.5g) in CH 3Mixture among the CN (40ml) heated 20 minutes down at 150 ℃, added CH then 2Cl 2, filter reaction mixture on diatomite.Evaporating solvent, with the gained residue by short opening column chromatography purification (elutriant: CH 2Cl 2/ (CH 3OH/NH 3) 97/3).Collect product cut and evaporating solvent.Output: 2.330g midbody compound 23 (88%).
D. prepare midbody compound 24
Figure A20058004360600482
At N 2Down, with midbody compound 23 (making) according to A10.c (0.0045mol) and NaH (60%) (0.0068mol) mixture in THF (25ml) at room temperature stirred 3 hours, add benzyl chloroformate (0.0068mol) then, at room temperature stirred reaction mixture is 3 hours.Add EtOAc, utilize water and salt water washing organic layer, dry then (Na 2SO 4), filter and evaporating solvent.With the gained residue by short opening column chromatography purification (elutriant: CH 2Cl 2/ EtOAc 4/1,2/1).Collect product cut and evaporating solvent.Output: 2.14g midbody compound 24 (78%).
E. prepare midbody compound 25
Figure A20058004360600491
Trifluoroacetic acid (20ml) is added drop-wise to midbody compound 24 (making according to A10.d) (0.0034mol) in CH 2Cl 2In the mixture (240ml), stirred reaction mixture 1 hour at room temperature then, evaporating solvent.Utilize saturated Na 2CO 3Solution with gained residue basic metalization, utilizes CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 1.78g midbody compound 25.
F. prepare midbody compound 34
Under microwave irradiation, with the TBD (2.9mmol/g) of midbody compound 25 (0.0002921mol), 1-(chloromethyl)-4-fluorobenzene (0.0008763mol) and polymer support (0.0008763mol) in CH 3Mixture among CN (2ml) and the DMF (0.15ml) was 170 times reactions 20 minutes, and filter reaction mixture utilizes CH then 2Cl 2The residue of washing and filtering.Evaporating solvent, residue utilize Sep-Pak silica gel tube manifold (vacuum) purifying (elutriant: CH 2Cl 2/ (CH 3OH/NH 3) 99/1).Collect product cut and evaporating solvent.Output: 0.140g midbody compound 34 (77%).
Embodiment A 11
Preparation midbody compound 35
Figure A20058004360600501
With midbody compound 8 (making) according to A8.a (0.0002mol), N, N-dimethyl-1 (0.0003mol), Pd (Oac) 2(0.00001mol), Xantphos (0.00002mol) and Cs 2CO 3(0.0003mol) mixture in deoxidation two  alkane (1ml) heated 15 minutes down at 150 ℃, and is following 10 minutes at 170 ℃ then.Filter gained solid and evaporating solvent.With residue by manifold purifying (elutriant 1:CH 2Cl 2/ CH 3OH 96/4; Elutriant 2:CH 2Cl 2/ (CH 3OH/NH 3) 95/5).Collect product cut and evaporating solvent.Output: 0.040g midbody compound 35 (39%).
Embodiment A 12
A. prepare midbody compound 36
Figure A20058004360600502
Under 0 ℃, with NaBH 4(50.0085mol) join 4-(4-bromophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazole-1-ethyl acetate (0.0034mol) is in CH 3In the mixture among OH (3ml) and the THF (15ml), reaction mixture at room temperature stirred 2 hours then.Add 10%NH 4Cl solution utilizes CH 2Cl 2Extraction gained mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue utilizes the DIPE washing, collects required product.Output: 0.78g midbody compound 36 (81%).
B. prepare midbody compound 37
Figure A20058004360600511
Under 0 ℃, methylsulfonyl chloride (0.015mol) is joined midbody compound 36 (making according to A12.a) (0.01mol) and Et 3N (0.02mol) is in CH 2Cl 2In the mixture (50ml), reaction mixture at room temperature stirred 1 hour then, added saturated NaHCO 3Solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Then, utilize ether wash residual thing.Output: 3.39g midbody compound 37 (94%).
C. prepare midbody compound 38
Figure A20058004360600512
With midbody compound 37 (making) according to A12.b (0.0094mol), 2-phenoxyethylamine (0.0188mol), N, N, N-tributyl-1-butyl brometo de amonio (0.0094mol) and K 2CO 3(0.0188mol) in CH 3Mixture among the CN (40ml) heated 20 minutes down at 120 ℃, added CH then 2Cl 2Cross filter solid, residue is by column chromatography purifying (elutriant 1:CH 2Cl 2/ EtOAc 1/1; Elutriant 2:CH 2Cl 2/ CH 3OH 96/4).Collect product cut and evaporating solvent.Output: 5.9g midbody compound 38 (quantitative output, it can be used for next reactions steps under not being further purified).
D. prepare midbody compound 40
Figure A20058004360600513
With midbody compound 39 (0.001518mol), 2-phenoxyethylamine (0.0030mol) and Cs 2CO 3(0.0030mol) in anhydrous CH 3Mixture among the CN (10ml) heated 20 minutes down in 150 ℃ in microwave oven (Milestone), filtered refrigerative reaction mixture, evaporated filtrate then on diatomite.Residue is by opening silica gel column chromatography purifying (elutriant 1:CH 2Cl 2/ EtOAc 1/1; Elutriant 2:CH 2Cl 2/ CH 3OH 96/4).Collect product cut and evaporating solvent.Output: 0.52g midbody compound 40 (85%).
Embodiment A 13
Preparation midbody compound 41
Figure A20058004360600522
With midbody compound 11 (making) according to A5.a (0.0014mol), 4-(brooethyl)-methyl benzoate (0.0021mol) and K 2CO 3(0.028mol) in CH 3Mixture among the CN (10ml) heated 15 minutes down in 150 ℃ in microwave oven, added CH then 2Cl 2, filter reaction mixture on diatomite.The evaporated filtrate solvent utilizes EtOAc washing gained residue.Output: 0.335g midbody compound 41 (49%).
Embodiment A 14
A. prepare midbody compound 43
Figure A20058004360600531
In microwave oven, react.With 1-(4-bromophenyl)-1,3-dihydro-2 H-imidazol-2-one (, comprising its content) at this according to the explanation of WO2003042188 preparation (0.0058mol), 2-ethyl bromoacetate (0.0070mol) and K 2CO 3(0.0087mol) in CH 3Mixture among the CN (20ml) heated 15 minutes down at 130 ℃.Add CH 2Cl 2By diatomite filtration precipitation, evaporated filtrate solvent.Output: 2.0g midbody compound 43 (quantitative output, it can be used for next reactions steps under not being further purified).
B. prepare midbody compound 44
Figure A20058004360600532
With NaBH 4(0.0145mol) be added drop-wise to midbody compound 43 (0.0058mol) in CH 3In the solution of OH (4ml) and THF (20ml), stir down at 0 ℃.At room temperature stirred reaction mixture is 1 hour.Add 10%NH 4The Cl aqueous solution.Utilize CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 1.28g midbody compound 44 (78%).
C. prepare midbody compound 45
Figure A20058004360600533
Methylsulfonyl chloride (0.0050mol) is added drop-wise to midbody compound 44 (0.0045mol) and Et 3N (0.0068mol) is in CH 2Cl 2In the solution (15ml), stir down at 0 ℃.At room temperature stirred the gained reaction mixture 1 hour.Add saturated NaHCO 3The aqueous solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Utilize ether to handle residue, filtering-depositing is also dry.Output: 1.43g midbody compound 45 (88%).
D. prepare midbody compound 46
Figure A20058004360600541
In microwave oven, react.With midbody compound 45 (0.0037mol), 2-phenoxyethylamine (0.0074mol), Cs 2CO 3(0.0074mol) and 4  molecular sieves (0.330g) in CH 3Mixture among the CN (25ml) heated 20 minutes down at 170 ℃.By diatomite filtration precipitation, evaporated filtrate solvent.Residue is by short opening silica gel column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH94/6).Collect product cut and evaporating solvent.Output: 1.4g midbody compound 46 (94%).
E. prepare midbody compound 47
Figure A20058004360600542
At midbody compound 46 (0.0035mol) and Et 3N (0.0035mol) is in CH 2Cl 2Add two (1, the 1-dimethyl ethyl)-two carbonic ethers (0.0035mol) in the mixture (15ml), stir down at 0 ℃.Then, reaction mixture at room temperature stirred 1 hour.Product is by short opening silica gel column chromatography purifying (elutriant: CH 2Cl 2/ EtOAc 100/0, and then 3/1).Collect product cut and evaporating solvent.Utilize DIPE to handle residue, dry then.Output: 1.23g midbody compound 47 (70%).
F. prepare midbody compound 48
Figure A20058004360600551
In microwave oven, react.At N 2React under the atmosphere.With midbody compound 47 (0.00033mol), 1-methylpiperazine (0.0005mol), Pd (Oac) 2(0.000017mol), Xantphos (0.000033mol) and Cs 2CO 3(0.0005mol) mixture in deoxidation two  alkane/DMF 9/1 heated 15 minutes down at 175 ℃.Add CH 2Cl 2, diatomite filtration solid, evaporated filtrate solvent.Residue carries out column chromatography purifying (elutriant: CH on 10-g silica gel tube 2Cl 2/ CH 3OH 97/3; Elutriant: CH then 2Cl 2/ (CH 3OH/NH 3) 96/4 and 95/5).Collect product cut and evaporating solvent.Output: 0.085g midbody compound 48 (49%).
Embodiment A 15
A. prepare midbody compound 49
Figure A20058004360600552
At N 2React under the atmosphere.With N-(1, the 1-dimethyl ethyl)-N-ethyl-2-methyl-2-propylamine (0.0024mol) join midbody compound 47 (making) according to A14.e (0.0012mol), ethanoyl formyl acid anhydride (0.0024mol), PdCl 2(PPh 3) 2(0.00012mol) and triethyl silicane (0.0018mol) in anhydrous CH 3In the mixture among the CN (12ml).In sealed tube, reaction mixture heated 24 hours down at 60 ℃.Add extra ethanoyl formyl acid anhydride, PdCl 2(PPh 3) 2, triethyl silicane and N-(1, the 1-dimethyl ethyl)-N-ethyl-2-methyl-2-propylamine.Reaction mixture heated 24 hours down at 60 ℃.By the diatomite filtration precipitation, utilize CH 2Cl 2Flushing, the evaporated filtrate solvent.The short opening silica gel column chromatography of residue purifying (elutriant: CH 2Cl 2/ EtOAc 100/0, and then 4/1).Collect product cut and evaporating solvent.Output: 0.400g midbody compound 49 (74%).
B. prepare midbody compound 50
Figure A20058004360600561
In microwave oven, react.With midbody compound 49 (0.00044mol), morpholine (0.00075mol) and NaBH (OAc) 3(0.00075mol) in 1, the mixture in the 2-ethylene dichloride (2ml) heated 15 minutes down at 80 ℃.Add 32%NH 3The aqueous solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is by manifold column chromatography purifying (elutriant: CH 2Cl 2/ EtOAc 1/1, then CH 2Cl 2/ CH 3OH 95/5).Collect product cut and evaporating solvent.Output: 0.160g midbody compound 50 (70%).
Embodiment A 16
A. prepare midbody compound 51
Figure A20058004360600562
With carbonic acid trichlorine methyl alcohol ester (0.008mol) in anhydrous CH 2Cl 2Drips of solution (25ml) is added to 2, and 2-dimethoxy methylamine (0.022mol) is in anhydrous CH 2Cl 2In the solution (50ml), stir down at 0 ℃.Divide three times and add Et 3N (0.044mol) stirs down at 0 ℃ simultaneously.Reaction mixture at room temperature stirred 5 minutes.Add 1-(phenoxy group ethyl)-4-piperidines methylamine (0.011mol) in anhydrous CH 2Cl 2Solution (25ml), gained reaction mixture at room temperature stirred 1 hour.Add saturated Na 2CO 3The aqueous solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Output: 5.6g midbody compound 51 (quantitative output, it can be used for next reactions steps under not being further purified).
B. prepare midbody compound 52
Figure A20058004360600571
In microwave oven, react.With midbody compound 51 (0.011mol) in 2N HCl (20ml) and CH 3Mixture among the OH (50ml) heated 10 minutes down at 120 ℃.Mixture is injected into saturated Na 2CO 3Go in the aqueous solution.Utilize CH 2Cl 2Extract this mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.The short opening silica gel column chromatography of residue purifying (elutriant: CH 2Cl 2/ (CH 3OH/NH 3) 96/4, then 90/10).Collect product cut and evaporating solvent.Utilize ether to handle residue, collect then and drying.Output: 1.35g midbody compound 52 (41%).
C. prepare midbody compound 53
Figure A20058004360600572
In microwave oven, react.With midbody compound 52 (0.0010mol), ethyl chloroacetate (0.0015mol) and K 2CO 3(0.0015mol) in CH 3Mixture among the CN (4ml) heated 15 minutes down at 120 ℃, and is following 15 minutes at 150 ℃ then.Filtering-depositing is then by manifold column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH 95/5).Collect product cut and evaporating solvent.Output: 0.243g midbody compound 53 (63%).
D. prepare midbody compound 54
Figure A20058004360600573
With LiOH (0.00076mol) in H 2Solution among the O (1ml) joins in the solution in midbody compound 53 (0.00063mol) and the two  alkane (10ml).At room temperature stirred the gained reaction mixture 24 hours, evaporating solvent.Utilize ether to handle residue, collect then and drying.Output: 0.190g midbody compound 54 (83%).
Embodiment A 17
A. prepare midbody compound 42
Figure A20058004360600581
In microwave oven, react.With 1-(4-bromophenyl)-1,2-dihydro-5H-tetrazolium-5-ketone (0.0058mol), 4-(iodomethyl)-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (0.0070mol) and BTTP (0.0070mol) are in CH 3Mixture among the CN (20ml) heated 30 minutes down at 120 ℃, evaporating solvent.Residue is by short opening silica gel column chromatography purifying (elutriant: CH 2Cl 2/ EtOAc 100/0, and then 4/1).Collect product cut and evaporating solvent.Output: 2.58g midbody compound 42.
B. prepare midbody compound 55
Trifluoroacetic acid (10ml) is joined midbody compound 42 (making according to A17) (0.0058mol) in CH 2Cl 2In the solution (40ml).Reaction mixture at room temperature stirred 2 hours.Add saturated Na 2CO 3The aqueous solution (pH=8).Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Utilize ether to handle residue, collect then and drying.Output: 0.85g midbody compound 55 (45%).
C. prepare midbody compound 56
Figure A20058004360600591
In microwave oven, react.With midbody compound 55 (making) according to A17.b (0.0025mol), 2-bromine oxethyl benzene (0.00275mol) and K 2CO 3(0.0050mol) in CH 3Mixture among the CN (10ml) heated 10 minutes down at 120 ℃, added CH 2Cl 2By diatomite filtration precipitation, evaporated filtrate solvent.Utilize ether to handle residue, collect then and drying.Output: 0.85g midbody compound 56 (74%).
D. prepare midbody compound 57
At N 2React under the atmosphere.With N-ethyl-N-(1-methylethyl)-2-propylamine (0.0030mol) join midbody compound 56 (making) according to A17.d (0.0015mol), two (triphenylphosphine) palladiums (0.00015mol) of formic acid acetonyl ester (0.0030mol), dichloro and triethyl silicane (0.00225mol) be in anhydrous CH 3In the mixture among the CN (15ml).In sealed tube, reaction mixture heated 24 hours down at 60 ℃.Add extra formic acid acetonyl ester, two (triphenylphosphine) palladiums of dichloro, triethyl silicane and N-ethyl-N-(1-methylethyl)-2-propylamine.Reaction mixture heated 24 hours down at 60 ℃.Filtering-depositing, the evaporated filtrate solvent.Residue is by short opening silica gel column chromatography purifying (elutriant: CH 2Cl 2/ EtOAc 4/1, then CH 2Cl 2/ CH 3OH9/1).Collect product cut and evaporating solvent.Output: 0.660g midbody compound 57.
This midbody compound 57 is as the starting raw material of the final compound 104 of preparation.
The intermediate structure of tabulating down in 1 prepares according to the foregoing description.
Table 1:
Figure A20058004360600601
Figure A20058004360600621
Figure A20058004360600631
Figure A20058004360600641
Figure A20058004360600651
Figure A20058004360600661
Figure A20058004360600671
According to general reaction process, above-mentioned intermediate can change into the final compound of the present invention
Figure A20058004360600681
At least one Y wherein A' and Y B' for being selected from halogen, Br particularly; Formyl radical; Alkyl SO 3-; Cyano group; Hydroxyl; And alkoxyl group, particularly methoxyl group and oxyethyl group; Or at least one Y wherein A' and Y B' be NR 1L B, NL AR 2Or NL AL B, it is characterized in that L AAnd L BBe selected from alkoxy carbonyl, particularly tert-butoxycarbonyl (t-BOC) independently of one another; And aromatic alkoxy carbonyl, particularly phenyloxycarbonyl.The method of conversion type (I) compound is well known to a person skilled in the art, has hereinafter enumerated many kinds of methods.The specific detail of these methods does not limit its general application.
The present invention also relates to formula (I ') midbody compound
At least one Y wherein A' and Y B' for being selected from halogen, Br particularly; Formyl radical; Alkyl SO 3-; Cyano group; Hydroxyl; And alkoxyl group, particularly methoxyl group and oxyethyl group; Or at least one Y wherein A' and Y B' be NR 1L B, NL AR 2Or NL AL B, it is characterized in that L AAnd L BBe selected from alkoxy carbonyl, particularly tert-butoxycarbonyl (t-BOC) independently of one another; And aromatic alkoxy carbonyl, particularly phenyloxycarbonyl.
B. prepare final compound
Embodiment B 1
A. prepare final compound 109
Figure A20058004360600691
With midbody compound 6 (0.000087mol), phthalic imidine (0.000261mol), diethylazodicarboxylate (0.000261mol) and PS-triphenylphosphine (0.000348mol; 3mmol/g) mixture in anhydrous THF (1ml) reacted 30 minutes down at 90 ℃, filtered the gained solid then.The filter paper residue is captured in the ISOLUTE SCX-2 tube, and utilizes CH 3OH/NH 3Discharge.The final compound 109 (39%) of output: 0.018g.
B. prepare final compound 34
Figure A20058004360600692
Stir final compound 109 (0.000034mol) and the mixture of hydrazine (0.000068mol) in ethanol (1ml), and refluxed 24 hours, add saturated Na then 2CO 3Solution and CH 2Cl 2Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is by manifold purifying (elutriant 1:CH 2Cl 2/ CH 3OH 96/4; Elutriant 2:CH 2Cl 2/ (CH 3OH/NH 3) 96/4).Collect product cut and evaporating solvent.The final compound 34 (44%) of output: 0.006g.
Embodiment B 2
A. prepare final compound 56
Figure A20058004360600701
With final compound 114 (0.00006mol), 2,3-dihydro-1,4-benzo dioxin-6-formaldehyde (0.00012mol) and NaH (OAc) 3(0.00012mol) mixture in ethylene dichloride (1ml) heated 10 minutes down at 100 ℃, added CH then 2Cl 2/ CH 3OH (1/1).Utilize ISOLUTE SCX-2 tube, required product is captured from mixture.Utilize CH 2Cl 2/ CH 3OH (1/1) washed product is utilized CH 2Cl 2/ (CH 3OH/NH 3) (1/1) discharge from resin.Evaporating solvent utilizes CH 3OH wash residual thing is collected then.The final compound 56 (43%) of output: 0.015g.
B. prepare final compound 80
Figure A20058004360600702
In microwave oven, with midbody compound 9 (making) according to A3 (0.00009mol), morpholine (0.00018mol) and NaBH (OAc) 3(0.00014mol) mixture in ethylene dichloride (1ml) heated 10 minutes down at 100 ℃, added 31%NH then 3The aqueous solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is by manifold (vacuum) purifying (elutriant 1:CH 2Cl 2/ EtOAc 1/1; Elutriant 2:CH 2Cl 2/ CH 3OH 96/4).Collect the product cut, evaporating solvent, and freeze-drying gained residue.The final compound 80 (18%) of output: 0.0077g.
Embodiment B 3
Prepare final compound 7
Figure A20058004360600711
Under 140 ℃, utilize Pd/C 10% (3g), with midbody compound as catalyzer
Figure A20058004360600712
(, comprising its content) at this according to the explanation of WO99/58530 preparation (0.025mol) and the mixture of 2-phenoxyethylamine (0.036mol) in THF (300ml) had under the condition of thiophene solution (3ml) hydrogenation 16 hours.Consuming H 2After (1 equivalent), filtering catalyst, and evaporated filtrate.Residue grinds in the 2-propyl alcohol.Filtering-depositing is also dry.The final compound 7 (94%) of output: 12.4g.
Embodiment B 4
A. prepare final compound 37
Figure A20058004360600713
In microwave oven, with compound
Figure A20058004360600714
(0.00017mol), (2-bromo-oxyethyl group) benzene (0.00011mol) and CH 3CN (0.00034mol) is in K 2CO 3Mixture (0.5ml) heated 10 minutes down at 120 ℃, added entry then, utilized CH 2Cl 2The extractive reaction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is by the high perfomance liquid chromatography purifying.Collect product cut and evaporating solvent.The final compound 37 (2%) of output: 0.0015g.
B. prepare final compound 58
Figure A20058004360600721
In microwave oven, with midbody compound
Figure A20058004360600722
(making) according to Al.c (0.00006mol), (2-bromine oxethyl) benzene (0.000072mol) and K 2CO 3(0.00012mol) in CH 3Mixture among the CN (0.5ml) is 120 ℃ of down heating 10 minutes, add then resin-connection-N=C=O and CH 2Cl 2, reaction mixture at room temperature stirred 1 hour.By diatomite filtration gained solid, utilize ISO-LUTE SCX-2 tube from solution, to capture required product.Utilize CH 2Cl 2/ CH 3OH (1/1) washed product, and utilize CH 2Cl 2/ (CH 3OH/NH 3) (1/1) discharge from resin.Evaporation residue utilizes CH 2OH wash residual thing is collected then.Output: 0.0206g final product 58 (62%).
Embodiment B 5
Prepare final compound 79
Figure A20058004360600723
In microwave oven, with midbody compound 7 (making) according to A2.c (0.00017mol), 1-(2-chloroethyl)-piperidine hydrochlorate (0.00051mol) and PS-TBD (2.70mmol/g) be (0.00051mol) in CH 3Mixture among the CN (2ml) heated 20 minutes down at 130 ℃, added extra PS-TBD (2.70mmol/g) then (0.00051mol), and reaction mixture heated 20 minutes down in 130 ℃ in microwave oven.Cross filter solid, utilize CH 2Cl 2Washing.The evaporated filtrate solvent, residue is by the high perfomance liquid chromatography purifying.Collect product cut and evaporating solvent.Output: 0.0069g fi-nal compound 79 (10%).
Embodiment B 6
Prepare final compound 38
Figure A20058004360600731
Under microwave irradiation, with midbody compound 13 (making) according to A4.a (0.00011mol), N, N-dimethyl-1 (0.00017mol), Pd 2(dba) 3(0.000006mol), BINAP (0.000017mol) and t-BuOK (0.00017mol) 170 ℃ of heating 15 minutes down, cross filter solid in the mixture of toluene (deoxidation) in (0.5ml) then, utilizes CH 2Cl 2Washing.The evaporated filtrate solvent, the gained residue filters (elutriant 1:CH by manifold 2Cl 2/ CH 3OH 95/5; Elutriant 2:CH 2Cl 2/ (CH 3OH/NH 3) 95/5).Collect product cut and evaporating solvent.Utilize the SCX-2 tube to capture required product, utilize CH then 3OH/NH 3Discharge.Evaporating solvent, and freeze-drying gained residue.The final compound 38 (65%) of output: 0.033g.
Embodiment B 7
Prepare final compound 51
Figure A20058004360600741
In microwave oven, with midbody compound 13 (making) according to A4.a (0.437mmol), 1-methylpiperazine (0.65mmol), Pd (OA) 2(0.021mmol), Xantphos (0.0437mmol), Cs 2CO 3(0.65mmol) mixture in two  alkane/DMF 9/1 (2.96ml) heated 15 minutes down at 170 ℃.The diatomite filtration solid is evaporated to filtrate dried.Residue is by HPLC purifying (elutriant: CH 3CN/NH 4HCO 3).Collect the cut of selecting, evaporate its solvent.Utilize the diisopropyl ether crystalline residue.Output: the final compound 51 (40%) of 82.5mg of f.
Embodiment B 8
A. prepare final compound 28
Figure A20058004360600742
In microwave oven, with midbody compound 15 (making) according to A7.g (0.000078mol), 2-phenoxyethylamine (0.000156mol), N, N, N-tributyl-1-butyl brometo de amonio (0.000078mol) and K 2CO 3(0.000156mol) in CH 3Mixture among the CN (0.5ml) is 120 ℃ of down heating 15 minutes, add then resin-connection-CHO (0.000312mol) and CH 2Cl 2(1ml).In microwave oven, reaction mixture was heated 20 minutes down at 100 ℃, cross filter solid.Evaporating solvent, residue is by manifold purifying (elutriant 1:EtOAc; Elutriant 2:CH 2Cl 2/ CH 3OH 96/4).Collect the product cut, be further purified, utilize CH by being captured in the ISOLUTE SCX-3 tube 3OH/NH 3Discharge.At last, required cut is collected product cut and evaporating solvent by the high performance liquid chromatography purifying.The final compound 28 (18%) of output: 0.0066g.
Prepare final compound 8 thus, but do not add resin-connection-CHO.
B. prepare final compound 29
Figure A20058004360600751
Final compound 28 (making according to B8.a) is collected the product cut then (0.00061mol) by the high performance liquid chromatography purifying, utilizes HCl/2-propyl alcohol (q.s.) place of settling HCl-salt (1: 2) in EtOH.Evaporating solvent utilizes 2-propyl alcohol washing gained residue.The final compound 29 (40%) of output: 0.129g.
Embodiment B 9
A. prepare final compound 23
Figure A20058004360600752
Trifluoroacetic acid (0.5ml) is joined midbody compound 18 (making according to A8.c) (0.00023mol) in CH 2Cl 2In the mixture (2ml), reaction mixture at room temperature stirred 1 hour, added saturated Na then 2CO 3Solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is collected in CH 3Among the OH, be captured in then in the ISOLUTE SCX-2 tube, utilize CH 3OH/NH 3Discharge.The final compound 23 (53%) of output: 0.052g.
B. prepare final compound 24
At room temperature, utilizing HCl/ Virahol (35ml) to handle midbody compound 18 (making according to A8.c) (5.5mmol) spends the night.Collect solid, utilize pure washing with alcohol, and dry.The final compound 24 (70%) of output: 1.9g.
C. prepare final compound 21
Figure A20058004360600761
Under microwave irradiation, with midbody compound 17 (making) according to A8.b (0.0008mol), 4-(1-pyrrolidyl) piperidines (0.0012mol) and NaBH (OAc) 3(0.0012mol) in 1, the mixture in the 2-ethylene dichloride (10ml) heated 10 minutes down at 100 ℃, added 37%NH then 4OH solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Utilize silica gel tube (10g) manifold (vacuum) purifying residue (elutriant 1:CH 2Cl 2/ EtOAc 2/1; Elutriant 2:CH 2Cl 2/ CH 3OH 95/5; Elutriant 3:CH 2Cl 2/ (CH 3OH/NH 3) 95/5 → 9/1).Collect product cut and evaporating solvent.Utilize HCl/2-propyl alcohol (3ml) to handle gained residue (precipitation), add the 37%HCl aqueous solution then.At room temperature stir the gained mixture 24 hours, and added pure EtOH, and collect solid.The final compound 21 of output: 0.1701g.
D. prepare final compound 93
Figure A20058004360600762
Under microwave irradiation, with midbody compound 17 (making) according to A8.b (0.00011mol), tetrahydrochysene-2-furylamine (0.00017mol) and resin-be connected-BH (OA) 3(0.00033mol; 2.07mmol/g) in 1, the mixture in the 2-glycol dimethyl ether (1ml) is 140 ℃ of down heating 10 minutes, add then extra tetrahydrochysene-2-furylamine (2 * 0.0175ml) with resin-be connected-BH (OA) 3(2 x 0.159g) crosses filter solid.The evaporation organic solvent adds 37%HCl in the hydration concentrated solution) reaction mixture at room temperature stirred 24 hours, added EtOH (3ml), collected the gained solid then, and dry.The final compound 93 (36%) of output: 0.020g.
Embodiment B 10
Prepare final compound 99
Figure A20058004360600771
Pd/C 10% (0.5ml) is joined intermediate 34 (according to A10.f preparation) (0.00023mol) in the mixture in 1 (2ml), and reaction mixture at room temperature stirred 1 hour.Filter then, utilize saturated Na 2CO 3Solution-treated filtrate solvent.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is collected in CH 3Among the OH, be captured in then in the ISOLUTE SCX-2 tube, utilize CH 3OH/NH 3Discharge.The final compound 99 (53%) of output: 0.052g.
Embodiment B 11
Figure A20058004360600772
In microwave oven, with final compound 8 (making) according to B8.a (0.00020mol), CHO (37%) (0.00030mol), NaBH 3CN (0.00030mol) and ZnBr 2(0.00010mol) in CH 3Mixture among the OH (2ml) heated 5 minutes down at 140 ℃, added NH then 4OH solution (37%NH 3, in H 2Among the O), utilize CH 2Cl 2The extraction mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Utilize silica gel tube (5g), manifold purifying residue (gradient: CH 2Cl 2/ CH 3OH 98/2,97/3).Collect the product cut, utilize the ether washing then, and evaporating solvent.The final compound 9 (51%) of output: 0.054g.
B. prepare final compound 30
Figure A20058004360600781
Under microwave irradiation, with final compound 28 (making) according to B8.a (0.00022mol), H 2CO (37%) (0.00033mol), NaBH 3CN (0.00033mol) and Zn 2Br 2(0.00011mol) in CH 3Mixture among the OH (2ml) heated 5 minutes down at 140 ℃, heated 10 minutes down at 150 ℃ then.Add extra H 2CO (37%) (0.00033mol) and NaBH 3CN (0.00033mol), reaction mixture heated 5 minutes down at 150 ℃.Required product is captured in the SCX-2 tube, utilizes CH 3OH/NH 3Discharge, then manifold purifying (gradient: CH 2Cl 2/ CH 3OH 98/2,96/4), by the high performance liquid chromatography purifying.Collect the product cut, and evaporating solvent.The final compound 30 (35%) of output: 0.0371g.
Embodiment B 12
Prepare final compound 4,5 and 6
Figure A20058004360600782
By chiral separation method (Chiralpak AD) (elutriant: CH 3OH 100%), separate final compound 7 (making) (q.s.) according to B3.Collect two kinds of cuts: cut (I) (compound 4 and 5 mixture) and cut (II).The final compound 6 of cut (II) output: 0.119g (enantiomorph B-CIS).Cut (I) is by chiral separation method (Chiralpak AD) (elutriant: EtOH/ heptane 70/30) further separate, collect two kinds of product cuts then.The final compound 4 of cut (III) output: 0.110g (enantiomorph A-CIS).The final compound 5 of cut (IV) output: 0.260g (TRANS, racemoid).
Embodiment B 13
Prepare final compound 120
Figure A20058004360600791
With HATU (0.00068mol) join midbody compound 54 (making) according to A16.d (0.00052mol), 1-methylpiperazine (0.00047mol) and N-(1, the 1-dimethyl ethyl)-N-ethyl-2-methyl-2-propylamine (0.00068mol) be in CH 2Cl 2(10ml) and in the mixture among the DMF (2.5ml).Reaction mixture at room temperature stirred 4 hours.Add entry.Utilize CH 2Cl 2Extract this mixture.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is by manifold column chromatography purifying (10g silica gel tube; Elutriant: CH 2Cl 2/ CH 3OH 95/5; CH then 2Cl 2/ (CH 3OH/NH 3) 95/5 and 90/10).Collect the product cut, and evaporating solvent.Utilize ether wash residual thing, dry then.The final compound 120 (58%) of output: 0.1375g.
Embodiment B 14
Prepare final compound 116
Figure A20058004360600792
With midbody compound
Figure A20058004360600801
(making) according to A 15.a (0.0005mol), 4-piperidines alcohol (0.00075mol) and NaBH (OAc) 3(0.00075mol) in 1, the reaction mixture in the 2-ethylene dichloride (2ml) heated 15 minutes down at 80 ℃.Add 32%NH 3The aqueous solution.Separate organic layer, dry (Na 2SO 4), filter and evaporating solvent.Residue is by manifold column chromatography purifying (elutriant: CH 2Cl 2/ CH 3OH 95/5, then CH 2Cl 2/ (CH 3OH/NH 3) 95/5, then 90/10).Collect product cut and evaporating solvent.Residue is dissolved in the 2-propyl alcohol, utilizes the HCl/2-propyl alcohol to change into hydrochloride (1: 2).Filtering-depositing is also dry.The final compound 116 of output: 0.018g.
Embodiment B 15
Prepare final compound 106
Figure A20058004360600802
Will be in the midbody compound in the HCl/2-propyl alcohol (2ml)
Figure A20058004360600803
(making according to A15.b) (0.0003mol) at room temperature stirred 24 hours.Filtering-depositing is also dry.The final compound 106 of output: 0.063g.
Table 2 is to 8 arbitrary formula (I) compounds of having enumerated according to the foregoing description description that make of method.
Table 2
Figure A20058004360600811
Figure A20058004360600821
Figure A20058004360600851
Figure A20058004360600871
Figure A20058004360600891
Table 3
Figure A20058004360600911
Figure A20058004360600921
Figure A20058004360600931
Table 4
Figure A20058004360600941
Figure A20058004360600951
Figure A20058004360600961
Figure A20058004360600971
Figure A20058004360600981
Figure A20058004360600991
Figure A20058004360601021
Figure A20058004360601041
Figure A20058004360601051
Figure A20058004360601061
Table 5
Figure A20058004360601071
Figure A20058004360601081
Figure A20058004360601091
Table 6
Figure A20058004360601101
Table 7
Figure A20058004360601121
Table 8
Figure A20058004360601131
Table 9
Figure A20058004360601151
C. pharmacology embodiment
General rule
Formula (I) compound and α 2CInteraction between the-adrenergic receptor at the external beam radiotherapy part in conjunction with measuring.Usually, will have the lower concentration radioligand of high binding affinity to special receptor or transmission body, be rich in special receptor or transmission body organize the preparation sample, or in buffer medium, cultivate with cloning by expression human receptor's cell preparation.In culturing process, radioligand combines with acceptor or transmission body.When reaching balance, with the active acceptor of binding radioactivity with do not have the acceptor of binding radioactivity to be separated, and counting is in conjunction with active acceptor or transmission body.In competition combination experiment, measure the interaction between tested compound and the acceptor.The tested compound of various concentration is joined in the culturing mixt that contains acceptor or transmission system agent and radioligand.Its binding affinity has suppressed combining of radioligand with the proportional tested compound of its concentration.Be used for h α 2C, h α 2CAnd h α 2CThe radioligand of receptors bind be [ 3H]-raulwolscine.
Embodiment C 1: α 2CThe combination experiment of-adrenergic receptor
Cell culture and membrane prepare
With the human suprarenin-α of stable transfection 2A-,-α 2BOr α 2CThe Chinese hamster ovary celI of receptor cdna is at additional 10% heat-inactivated fetal bovine serum (Life Technologies, Merelbeke-Belgium) and Dulbecco ' s ModifiedEagle ' s Medium (the DMEM)/Nutrient mixture Ham ' s F12 (ratio: 1: 1) of microbiotic (100IU/ml penicillin G, 100 μ g/ml streptomycin sulfates, 110 μ g/ml pyruvic acid and 100 μ g/ml L-glutaminates) (Gibco cultivates in Gent-Belgium).In the day before yesterday of collecting cell, utilize the 5mM Sodium propanecarboxylate to bring out, after 80-90% merges, cell scraped do not containing Ca 2+And Mg 2+Phosphate buffered saline (PBS) in, and collect down centrifugal 10 minutes of 1500 * g.Utilize the Ultraturrax homogenizer and under 23,500 * g centrifugal 10 minutes, equal cell plastid in Tris-HCl 50mM.By resuspending and homogeneous again, wash pill again, final pill is resuspended among the Tris-HCl, be divided into the 1ml sample aliquot and be stored under-70 ℃.
α 2The combination experiment of-adrenergic receptor hypotype
Film is thawed, cultivating in the damping fluid (glycylglycine 25 mM, pH 8.0) at homogeneous.In the cumulative volume of 500 μ l, under 25 ℃, utilize contain or do not contain competitor [ 3H] raulwolscine (NET-722) (New England Nuclear, USA) (1nM ultimate density) cultivated 2-10 μ g protein 60 minutes, then utilized Filtermate 196 collectors (Packard, Meriden, CT), on GF/B filter paper, filter fast.Utilize ice-cold cleaning buffer solution (Tris-HCl 50mM pH 7.4) fully to clean.(Packard, Meriden CT) go up by scintillation counting mensuration filter paper bonded radioactive activity, with count number (cpm) expression of result with per minute at Topcount.In the presence of 1 μ M hazol, measure for h α 2A-and h α 2BThe nonspecific combination of acceptor, and in the presence of 1 μ M spi roxatrine, measure h α 2CThe nonspecific combination of acceptor.
Data are divided new and result
With the total binding percentage ratio that does not exist tested compound to record, calculate the data that the mensuration when having compound obtains.Suppress curve, promptly total binding can generate automatically to the chart of percentage comparison of tested compound concentration logarithmic value, and uses non-linear regression can obtain S shape and suppress curve.Can obtain the pIC of tested compound by curve separately 50Value.
Under concentration dependent mode, formula (I) all compound is 10 in test concentrations -6M and 10 -9Between the M at h α 2CThe position (but also usually is positioned at h α 2AWith h α 2B-on) inhibition that produces is greater than 50% (pIC 50).
For the several compounds of selecting, it has covered most different embodiments of formula (I) compound, and results of in vitro studies is shown in table 8.
Table 8. the pharmacological datum of The compounds of this invention (n.d.=does not measure)
pIC 50
The compound sequence number α 2A α 2B α 2C
62 7.4 8.0 9.3
64 7.3 7.9 9.2
84 7.6 7.7 9.2
90 7.7 7.3 9.2
40 8.4 9.2 9.1
17 7.5 7.2 9.1
42 7.6 8.1 9.0
82 7.9 7.8 9.0
86 7.4 7.5 9.0
13 7.2 7.2 9.0
27 7.6 7.1 9.0
14 7.3 7.1 9.0
61 7.2 8.0 8.9
65 7.1 7.7 8.9
87 7.5 7.5 8.9
93 7.3 6.9 8.9
41 8.2 8.9 8.8
38 7.6 8.4 8.8
43 7.6 8.2 8.8
124 7.2 n.d. 8.8
73 6.8 7.4 8.8
pIC 50
The compound sequence number α 2A α 2B α 2C
1 7.0 7.2 8.8
21 7.4 7.1 8.8
12 6.9 7.0 8.8
95 7.8 6.9 8.8
18 7.3 6.9 8.8
60 7.4 8.3 8.7
129 7.3 n.d. 8.7
109 7.5 7.4 8.7
88 7.4 7.4 8.7
89 6.6 6.9 8.7
97 7.3 6.6 8.7
125 7.5 n.d. 8.6
68 7.4 8.1 8.6
66 7.4 7.3 8.6
130 7.3 n.d. 8.6
48 6.7 7.6 8.5
94 7.5 6.9 8.5
96 7.4 6.7 8.5
19 7.2 6.6 8.5
102 7.1 6.6 8.5
23 6.8 6.6 8.5
127 7.2 n.d. 8.4
49 7.2 8.2 8.4
37 7.4 7.6 8.4
pIC 50
The compound sequence number α 2A α 2B α 2C
47 7.1 7.4 8.4
20 7.0 7.0 8.4
29 7.0 6.9 8.4
28 6.9 6.7 8.4
132 7.2 n.d. 8.3
53 7.0 8.4 8.3
52 7.0 7.7 8.3
63 6.8 7.5 8.3
83 6.5 7.3 8.3
91 7.5 7.1 8.3
104 7.2 7.1 8.3
92 7.6 6.7 8.3
24 6.6 6.6 8.3
85 6.9 6.9 8.2
46 6.9 6.8 8.2
4 5.6 6.7 8.2
125 7.4 n.d. 8.1
131 6.9 n.d. 8.1
51 6.8 8.1 8.1
72 6.8 7.6 8.1
7 6.9 6.9 8.1
101 6.2 6.6 8.1
39 7.2 8.1 8.0
34 7.4 7.3 8.0
pIC 50
The compound sequence number α 2A α 2B α 2C
99 6.6 6.7 8.0
100 6.2 6.4 8.0
5 6.3 6.3 8.0
16 6.8 5.8 8.0
44 6.9 5.4 8.0
128 7.1 n.d. 7.9
126 6.7 n.d. 7.9
50 6.6 7.8 7.9
31 7.3 7.6 7.9
32 6.9 7.3 7.9
36 7.4 7.1 7.9
108 6.1 6.6 7.9
54 6.8 7.5 7.8
55 5.9 7.3 7.8
33 7.8 7.2 7.8
8 6.2 6.8 7.8
30 6.4 6.7 7.8
3 6.4 6.6 7.8
10 6.2 6.3 7.8
45 6.5 6.7 7.7
71 6.6 6.6 7.7
98 6.3 6.6 7.7
107 6.3 6.4 7.7
67 6.4 7.0 7.6
pIC 50
The compound sequence number α 2A α 2B α 2C
2 6.7 6.7 7.6
103 6.3 6.1 7.6
69 6.8 n.d. 7.6
79 6.4 6.2 7.5
80 7.2 n.d. 7.4
70 6.4 n.d. 7.4
106 6.4 n.d. 7.4
35 6.9 n.d. 7.3
22 6.1 n.d. 7.3
58 5.9 n.d. 7.3
25 5.6 n.d. 7.3
105 6.5 n.d. 7.2
81 6.2 n.d. 7.1
57 ＜5 n.d. 7.1
15 6.1 n.d. 7.0
74 6.1 n.d. 6.8
6 5.1 n.d. 6.7
77 5.5 n.d. 6.6
59 5.8 n.d. 6.2
11 5.1 n.d. 6.1
9 ＜5 n.d. 6.1
75 ＜5 n.d. 6.1
76 ＜5 n.d. 6.1
56 ＜5 n.d. 6.0
D. composition embodiment
" activeconstituents " of Shi Yonging (a.i.) is meant that formula (I) compound, its medicine can accept acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form, its quaternary ammonium salt and prodrug thereof in these embodiments.
Embodiment is D.1: oral drops
Under 60-80 ℃, 500g a.i. is dissolved in 0.5 liter of 2 hydroxy propanoic acid and the 1.5 liters of polyoxyethylene glycol.After being cooled to 30-40 ℃, add 35 liters of polyoxyethylene glycol, mixture stirs.Add the solution of 1750g soluble saccharin in 2.5 liters of pure water then, when stirring, add 2.5 liters of cocoa seasoningss, and utilize polyoxyethylene glycol quantitatively to volume be 50 liters, obtain containing the oral drops solution of 10mg/mla.i..Gained solution is filled to suitable container.
Embodiment is D.2: oral liquid
9g 4-methyl hydroxybenzoate and 1g4-nipasol are dissolved in 4 liters of ebullient pure water.In 3 liters of these solution, dissolve the 10g 2,3 dihydroxybutanedioic acid earlier, dissolve 20g a.i. subsequently.The latter solution is combined with the remainder of former solution, to wherein adding 12 liter 1,2,3-glycerol and 3 liter of 70% sorbitol solution.The 40g soluble saccharin is dissolved in 0.5 premium on currency and 2ml immature fruit of Juteleaf Raspberry, adds 2ml gooseberry essence.The latter solution is mixed with the former, add water quantitatively to volume be 20 liters, obtain the oral liquid that every (5ml) contains the 5mg activeconstituents.Gained solution is filled to suitable container.
Embodiment is D.3: film-coated tablets
Preparation tablet core
With 100g a.i., 570g lactose and 200g starch thorough mixing, utilize 5g sulfuric acid dodecane ester sodium and the 10g Polyvinylpyrolidone (PVP) solution humidifying in about 200ml water then.Wet powdered mixture is sieved, and drying is after sieve.Add 100g Microcrystalline Cellulose and 15g hydrogenated vegetable oil then.All mix, be pressed into tablet, obtain 10,000 tablets, respectively contain the 10mg activeconstituents.
Dressing
In the solution of 10g methylcellulose gum in the 75ml Denatured alcohol, add the solution of 5g ethyl cellulose in the 150ml methylene dichloride.Add 75ml methylene dichloride and 2.5ml1 then therein, 2, the 3-glycerol.With the fusing of 10g polyoxyethylene glycol, be dissolved in the 75ml methylene dichloride.The latter solution is added in the former solution, adds 2.5g Dolomol, 5g Polyvinylpyrolidone (PVP) and 30ml therein and concentrate color suspension, make its whole homogenizing.In coating device, utilize the mixture that so obtains with tablet core pericardium clothing.
Embodiment is D.4: injection solution
1.8g 4-methyl hydroxybenzoate and 0.2g 4-nipasol are dissolved in about 0.5 liter of water for injection.After being cooled to about 50 ℃, under agitation condition, add 4g acetate, 0.05g propylene glycol and 4g a.i..Solution is cooled to room temperature, replenishes water for injection, obtain containing the solution of 4mg/ml a.i. quantitatively to about 1 liter.Solution by filter sterilization, is filled to sterile chamber.
E. physical-chemical data
E.1 LCMS
The HPLC gradient is HP 1100 supplies by Agilent, and its post well heater is set in 40 ℃.Flow through light diode array (PDA) detector in the tubing string, branch to the MS detector then, ZQ that this MS detector can be Waters-Micromass or ToF (Timeof Flight) mass spectrograph.The former also is equipped with photoscanning detector (ELSD).According to applied MS method, this MS detector is equipped with electronic atomized particle source, can be simultaneously at just (1 or 2 volt of voltage) and negative electricity from pattern or only work in positive ionization pattern.
Among the anti-phase HPLC LC method be the XDB-C18 of Agilent tube (3.5 μ m finish in 4.6 * 30mm), flow velocity be 1ml/ minute (for the HPLC of ToF coupling, called after " S2011 "; For with the HPLC of ZQ coupling, called after " S3011 ").(mobile phase A: 0.5g/ rises ammonium acetate solution, Mobile phase B: acetonitrile to use three kinds of moving phases; Moving phase C: control gradient condition methyl alcohol), it controlled to 50%B and 50%C by 80%A, 10%B, 10%C in the time of 6.0 minutes, controlled to 100%B in the time of 6.5 minutes, was retained to 7.0 minutes, and in the time of 7.6 minutes, utilize 80%A, 10%B and 10%C reequilibrate, be retained to 9.0 minutes.Inject the sample of 5 μ L volumes.
The standard MS method of ToF:, be scanned up to 750, acquisition high-res mass spectrum from 100 by in 1 second.Adopt nitrogen as atomizing gas.For positive and negative ionization pattern, its awl voltage is 20V.Source temperature remains on 140 ℃.The reference substance that is used to lock spraying is leucine-brain coffee.
The standard MS method of ZQ:, be scanned up to 1000, the acquisition mass spectrum from 100 by in 1 second.Adopt nitrogen as atomizing gas.For positive and negative ionization pattern, its awl voltage is 20V.Source temperature remains on 140 ℃.The reference substance that is used to lock spraying is leucine-brain coffee.
In both cases, all utilize Waters-Micromass MassLynx-Openlynx data system to carry out data gathering.
Table 9. the physical-chemical data
The compound sequence number Fusing point (C) LCMS
R t(purity %) MW (MH) + Fragmentation/adducts
1 249.8
8 4.9(100.00) 514 515
9 5.36(87.56) 528 529
10 5.41(97.44) 542 543
11 3.36(99.05) 470 471
15 5.61(92.66) 499 500
16 ＞300 3.05(99.60) 359 360
17 263.3
18 222.8 2.83(97.92) 437.24 438
23 3.45(95.55) 423 424
The compound sequence number Fusing point (C) LCMS
R t(purity %) MW (MH) + Fragmentation/adducts
24 260.6 3.55(97.24) 423.23 424 446(MNa) +
25 268.4 3.68(97.30) 441 442
28 5.19(97.19) 461 462
29 246.8 5.25(100) 461.28 462 484(MNa) +
30 5.71(98.59) 475.29 476
31 4.54(89.43) 460.30 461 331(MH +-130)
32 3.74(99.51) 417.25 418
33 4.22(98.82) 403.24 404
34 4.34(88.27) 403.53 404 131(MH +-273)
35 3.38(88.60) 464 465
36 2.75(85.83) 393 394
37 2.94(94.81) 423 424
40 214.4 2.97(100.00) 478.31 479
41 228.3 3.62(95.82) 488.33 489
42 5.78(93.60) 546 547
43 5.41(97.75) 540 541
44 2.83(95.35) 359 360
45 259.7 3.92(96.85) 423 424
51 220.8 3.74(93.58) 476.29 477 259(MH +-218)
The compound sequence number Fusing point (C) LCMS
R t(purity %) MW (MH) + Fragmentation/adducts
52 122.9
55 4.85(91.66) 568 569
56 5.16(96.00) 582 583
57 6.1(93.54) 564 565
58 5.4(99.12) 554 555
59 4.79(87.34) 540 541
69 5.2(84.33) 473 474
75 ＞300
79 4.8(88.71) 409.28 410
80 5.6(96.43) 473.28 474 387(MH +-87)
81 5.19(88.69) 487.29 488 358(MH +-130)
82 4.06(94.86) 489.24 490 393(MH +-97)
83 5.21(94.47) 485.24 486 508(MNa) +
84 4.06(92.44) 489.57 490
85 1.72(98.90) 367 368
86 2.47(87.86) 410 411
97 1.95(99.48) 379.2 380
98 5.87(97.84) 475 476
99 5.17(96.54) 487.58 488 510(MNa) +
The compound sequence number Fusing point (C) LCMS
R t(purity %) MW (MH) + Fragmentation/adducts
100 3.16(95.98) 421.50 422
101 3.46(97.45) 457 458
102 2.85(100.00) 476 477
103 3.46(99.23) 421 422
105 5.22(100.00) 399 400
106 4.91(79.49) 442 443
108 3.7(99.42) 368.18 369
123 4.95(91.82) 560 561
124 4.11(99.44) 572 573
125 4.8(98.56) 554 555
126 3.42(98.02) 555 556
127 3.8 1(96.82) 548 549
128 4.12(98.27) 543 544
130 4.81(99.5) 560 561
131 5.79(96.55) 592 593
132 3.8(96.6) 400 401

Claims (30)

1. formula (I) compound,
Figure A2005800436060002C1
Medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, and its N-oxide form or its quaternary ammonium salt reach, wherein
Z 1And Z 2Be CH or N independently of one another;
X AAnd X BBe covalent linkage or C independently of one another 1-4Alkyl, one of them divalence-CH 2-unit can be replaced by divalence phenyl unit, and/or each X wherein AAnd X BIn group being selected from halogen, cyano group, hydroxyl, amino, amino, oxo and the formyl radical of one or more hydrogen atoms replace;
Y AAnd Y BIndependently of one another for being selected from the tertiary butyl, NR 1R 2And Pir;
R 1And R 2Be selected from hydrogen independently of one another; Alkyl; Aryl; Aryloxy; Het;-NR aR b, R wherein aAnd R bBe selected from hydrogen, alkyl, aryl or aralkyl independently of one another; And be selected from aryl, aryloxy and-NR aR bIn the alkyl that replaces of one or more groups, R wherein aAnd R bBe selected from hydrogen, alkyl, aryl or aralkyl independently of one another;
Pir is selected from pyrryl; Pyrazolyl; Imidazolyl; Pyridyl; Pyrimidyl; Pyrazinyl; Pyridazinyl; Pyrrolidyl; Imidazolidyl; Pyrazolidyl; Piperidyl; Two azepines bases; Morpholinyl; Thio-morpholinyl; Piperazinyl; Imidazolidyl; The 2H-pyrryl; Pyrrolinyl; Imidazolinyl; Pyrazolinyl; 1,2,3, the 4-tetrahydro isoquinolyl; 7,9-diaza-two ring [4.2.2] last of the ten Heavenly stems-3-thiazolinyl and pseudoindolyl; Wherein each Pir-group can at random be selected from the one or more groups replacements in the following radicals: hydroxyl; Oxo; Alkyl; Alkyl carbonyl; Alkyl sulphonyl; Alkoxy carbonyl; Aryloxyalkyl group; One-Fang aminoalkyl group; Aryl; Aralkyl; Aromatic yl alkenyl; Pyrrolidyl; By the furyl alkyl of 1 or 2 alkyl replacement; The benzofuryl alkyl; 2,3-dihydro-benzo [1,4] dioxy base alkyl; The quinolyl alkyl; Benzothienyl alkyl and indolyl alkyl are at random replaced by halogen;
Het is a ring heterocyclic group that is selected from following radicals: pyrryl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, piperidyl, two azepines bases, morpholinyl, thio-morpholinyl, piperazinyl, imidazolidyl, the 2H-pyrryl, pyrroles's beautiful jade base, imidazoles beautiful jade base, pyrazolinyl, furyl, thienyl,  azoles base, different  azoles base, thiazolyl, thiadiazolyl group, isothiazolyl, dioxolyl, the dithiane base, tetrahydrofuran base, triazolyl and triazinyl; Or be selected from the bicyclic heterocycles group of following radicals: quinolyl, isoquinolyl, 1,2,3,4-tetrahydrochysene-isoquinolyl, quinoxalinyl, indyl, pseudoindolyl, benzimidazolyl-, benzoxazol base, benzisoxa  azoles base, benzothiazolyl, benzisothiazole base, benzofuryl, benzothienyl, benzo piperidyl, benzopyranyl and imidazo [1,2-α] pyridyl; Wherein each Het-group is at random replaced by alkyl;
Or two adjacent part X and Y can condense together and form divalent group 1,2,3, and 4-tetrahydrochysene-isoquinolyl is at random replaced by hydrogen, alkyl, aryl, aralkyl, alkyl carbonyl, alkyl sulphonyl and pyrrolidyl alkyl;
Aryl is naphthyl or phenyl, is at random replaced by 1,2 or 3 substituting group that is selected from following radicals independent of each other separately: halogen, cyano group, hydroxyl, amino, alkylamino, alkoxyl group alkylamino, oxo, carboxyl, nitro, sulfenyl, formyl radical and alkoxyl group;
Alkyl is the straight or branched saturated hydrocarbyl that contains 1 to 6 carbon atom; Or contain cyclic saturated hydrocarbon (cycloalkyl) base of 3 to 7 carbon atoms; Or be connected to the cyclic saturated hydrocarbon base that contains 3 to 7 carbon atoms of the straight or branched saturated hydrocarbyl that contains 1 to 6 carbon atom; Each group can at random be replaced by one or more substituting groups that are selected from following radicals: halogen, cyano group, hydroxyl, amino, oxo, carboxyl, nitro, sulfenyl and formyl radical; And
Alkenyl is for further having the alkyl of the above-mentioned definition of one or more pairs of keys.
2. according to the compound of claim 1, it is characterized in that Z 1Be CH and Z 2Be N; Or Z 1Be N and Z 2Be N; Or Z 1Be CH and Z 2Be CH; Or Z 1Be CH and Z 2Be CH.
3. according to the compound of claim 2, it is characterized in that Z 1Be CH and Z 2Be N.
4. the compound arbitrary according to claim 1 to 3 is characterized in that each X AAnd X BBe selected from independently of one another: covalent linkage ,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH 2CH 2CH 2CH 2-,-CH (CH 3) CH (CH 3)-,-C (=O) CH 2-,-CH 2C (=O)-,-CH 2CH 2C (=O) CH 2-,-C 6H 4-,-CH 2C 6H 5-,-CH 2CH 2C 6H 5-,-C 6H 5CH 2-,-C 6H 5CH 2CH 2-,-CH 2C 6H 4CH 2-and-CH 2CH 2C 6H 4CH 2CH 2-.
5. according to the compound of claim 4, it is characterized in that each X AAnd X BBe selected from independently of one another: covalent linkage ,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH (CH 3) CH (CH 3)-,-C (=O) CH 2-,-CH 2CH 2C (=O) CH 2-,-C 6H 4-,-CH 2C 6H 5-,-C 6H 5CH 2-and-CH 2C 6H 4CH 2-.
6. according to the compound of claim 5, it is characterized in that X AFor-CH 2C 6H 5-, and X BFor-CH 2CH 2-.
7. the compound arbitrary according to claim 1 to 6 is characterized in that Y ABe NR 1R 2And Y BBe Pir; Or Y ABe NR 1R 2And Y BBe NR 1R 2Or Y ABe Pir and Y BBe Pir; Or Y ABe Pir and Y BBe NR 1R 2
8. according to the compound of claim 7, it is characterized in that Y ABe Pir and Y BBe NR 1R 2
9. the compound arbitrary according to claim 1 to 8 is characterized in that Pir is selected from: pyrrolidyl; Piperidyl; Two azepines bases; Morpholinyl; Piperazinyl; 1,2,3,4-tetrahydrochysene-isoquinolyl; 7,9-diaza-two ring [4.2.2] last of the ten Heavenly stems-3-thiazolinyl and pseudoindolyl; Wherein each Pir-group can at random be selected from the one or more groups replacements in the following radicals: hydroxyl; Oxo; Alkyl; Alkoxy carbonyl; Aryloxyalkyl group, particularly phenoxy group ethyl; One-Fang aminoalkyl group; Aryl; Aralkyl; Aromatic yl alkenyl, particularly 1-(2-methyl-3-phenyl allyl group); Pyrrolidyl; By the furyl alkyl of 1 or 2 alkyl replacement; The benzofuryl alkyl; 2,3-dihydro-benzo [1,4] dioxy base alkyl; The quinolyl alkyl; Benzothienyl alkyl and indolyl alkyl are at random replaced by halogen.
10. according to the compound of claim 9, it is characterized in that Pir is a morpholinyl.
11. the compound arbitrary according to claim 1 to 10 is characterized in that each R 1And R 2Be independently selected from hydrogen; Alkyl; Aryl and be selected from aryl, aryloxy, Het and-NR aR bThe alkyl that replaces of group, R wherein aAnd R bBe selected from hydrogen, alkyl and aralkyl independently of one another.
12., it is characterized in that each R according to the compound of claim 11 1And R 2Be selected from hydrogen independently of one another; Methyl; Ethyl; Phenyl; And methyl and ethyl, the group that is selected from phenyl, phenoxy group, dimethylamino, (benzyl) (methyl) amino, (cyclohexyl methyl) (methyl) amino, pyridyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl and tetrahydrofuran base separately replaces.
13. according to the compound of claim 12, its feature is at R 1And R 2Be selected from hydrogen and phenoxy group ethyl independently of one another.
14. the compound arbitrary according to claim 1 to 10 is characterized in that Z 1And Z 2Be CH or N independently of one another;
X AAnd X BBe covalent linkage or C independently of one another 1-4Alkyl, one of them divalence-CH 2-unit can be replaced by divalence phenyl unit, and each X wherein AAnd X BOne or more hydrogen atoms in the part are replaced by oxo group;
Y AAnd Y BIndependently of one another for being selected from the tertiary butyl, NR 1R 2And Pir;
R 1And R 2Be selected from hydrogen independently of one another; Alkyl; Aryl and alkyl, be selected from aryl, aryloxy, Het and-NR aR bGroup replace R wherein aAnd R bBe selected from hydrogen, alkyl, aryl or aralkyl independently of one another;
Pir is selected from pyrryl; Piperidyl; Two azepines bases; Morpholinyl; Piperazinyl; 1,2,3, the 4-tetrahydro isoquinolyl; 7,9-diaza-two ring [4.2.2] last of the ten Heavenly stems-3-thiazolinyl and pseudoindolyl; Wherein each Pir-group can at random be selected from the one or more groups replacements in the following radicals: hydroxyl; Oxo; Alkyl; Alkoxy carbonyl; Aryloxyalkyl group; One-Fang aminoalkyl group; Aryl; Aralkyl; Aromatic yl alkenyl; Pyrrolidyl; By the furyl alkyl of 1 or 2 alkyl replacement; The benzofuryl alkyl; 2,3-dihydro-benzo [1,4] dioxy base alkyl; The quinolyl alkyl; Benzothienyl alkyl and indolyl alkyl are at random replaced by halogen;
Het is a ring heterocyclic group that is selected from following radicals: pyridyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl and tetrahydrofuran base;
Or two adjacent part X and Y can condense together and form divalent group 1,2,3, and 4-tetrahydrochysene-isoquinolyl is at random replaced by hydrogen, alkyl, aralkyl, alkyl carbonyl, alkyl sulphonyl and pyrrolidyl alkyl;
Aryl is naphthyl or phenyl, is at random replaced by 1,2 or 3 substituting group that is selected from following radicals independent of each other separately: halogen, cyano group, hydroxyl and alkoxyl group.
15. the compound arbitrary according to claim 1 to 10 is characterized in that aryloxyalkyl group is the phenoxy group ethyl, aromatic yl alkenyl is 2-methyl-3-phenyl-allyl group, and pseudoindolyl is partly replaced formation isoindole 1,3-diketo part by two oxos.
16., it is characterized in that this compound is any compound of table 2 to table 8 according to the compound of claim 1.
17. compound according to claim 1, it is characterized in that this compound is 4-(4-morpholine-4-ylmethyl-phenyl)-2-[2-(2-phenoxy group-ethylamino)-ethyl]-2,4-dihydro-[1,2,4] triazole-3-ketone, its medicine can be accepted acid or base addition salt, its form of three-dimensional chemical isomer, its N-oxide form or its quaternary ammonium salt.
18. according to the purposes of the arbitrary compound of claim 1 to 17 as medicine.
19. compound and one or more antidepressive, antianxiety agent and psychotolytic other compound of being selected from as additional treatment arbitrary according to claim 1 to 17 make up.
20. a pharmaceutical composition, said composition comprise medicine acceptable carrier or thinner and as the arbitrary compound of treatment significant quantity claim 1 to 17 of activeconstituents.
21., it is characterized in that it comprises that further one or more are selected from antidepressive, antianxiety agent and psychotolytic other compound according to the pharmaceutical composition of claim 20.
22., it is characterized in that it is the form that is suitable for oral administration according to claim 20 and 21 arbitrary pharmaceutical compositions.
23. a method for preparing the pharmaceutical composition of claim 20 is characterized in that the compound that the medicine acceptable carrier and the claim 1 to 17 of treatment significant quantity is arbitrary mixes closely.
24. a method for preparing the pharmaceutical composition of claim 21 is characterized in that the compound that the medicine acceptable carrier and the claim 1 to 17 of treatment significant quantity is arbitrary and one or more are selected from antidepressive, antianxiety agent and psychotolytic other compound and mix closely.
25. being used for preparation according to the arbitrary compound of claim 1 to 17 prevents and/or treats α 2The antagonism of-adrenergic receptor is particularly to α 2CThe antagonism of-adrenergic receptor has the purposes of medicine of the disease of therapeutic action.
26. be used to prepare the purposes of the medicine that prevents and/or treats central nervous system disease, emotional handicap, anxiety disorder, the pressure correlation disease relevant, cognitive disorder, personality disorder, schizophrenia, Parkinson's disease, alzheimer ' Mu Shi dementia, chronic pain disease, neurodegenerative disease, habit-forming obstacle, emotional handicap and sexual dysfunction according to the arbitrary compound of claim 1 to 17 with depression and/or anxiety.
27. the compound according to claim 25 and 26 is selected from the purposes of antidepressive, antianxiety agent and psychotolytic other compound combination as additional treatment and one or more.
28. a method for preparing the compound of claim 1 is characterized in that formula (I ') compound is transformed an accepted way of doing sth (I) compound
Figure A2005800436060007C1
The definition of wherein all variablees such as claim 1, and at least one Y wherein A' and Y B' for being selected from halogen, Br particularly; Formyl radical; Alkyl SO 3Cyano group; Hydroxyl; And alkoxyl group, particularly methoxyl group and oxyethyl group; Or at least one Y wherein A' and Y B' be NR 1L B, NL AR 2Or NL AL B, it is characterized in that L AAnd L BBe selected from alkoxy carbonyl, particularly tert-butoxycarbonyl (t-BOC) independently of one another; And aromatic alkoxy carbonyl, particularly phenyloxycarbonyl.
29. formula (I ') midbody compound
Figure A2005800436060007C2
It is characterized in that at least one Y A' and Y B' for being selected from halogen, Br particularly; Formyl radical; Alkyl SO 3Cyano group; Hydroxyl; And alkoxyl group, particularly methoxyl group and oxyethyl group.
30. formula (I ') midbody compound, wherein at least one Y A' and Y B' be NR 1L B, NL AR 2Or NL AL B, it is characterized in that L AAnd L BBe selected from alkoxy carbonyl, particularly tert-butoxycarbonyl (t-BOC) independently of one another; And aromatic alkoxy carbonyl, particularly phenyloxycarbonyl.
CN 200580043606 2004-12-21 2005-12-20 Triazolone, tetrazolone and imidazolone derivatives for use as alpha-2c adrenoreceptor antagonists Pending CN101084201A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP04106817 2004-12-21
EP04106817.2 2004-12-21
EP05104873.4 2005-06-03

Publications (1)

Publication Number Publication Date
CN101084201A true CN101084201A (en) 2007-12-05

Family

ID=38913137

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200580043606 Pending CN101084201A (en) 2004-12-21 2005-12-20 Triazolone, tetrazolone and imidazolone derivatives for use as alpha-2c adrenoreceptor antagonists

Country Status (1)

Country Link
CN (1) CN101084201A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103459379A (en) * 2011-02-21 2013-12-18 大正制药株式会社 Glycine transport inhibitor
CN109153663A (en) * 2016-05-27 2019-01-04 百时美施贵宝公司 Triadimefon compound and tetrazolium ketone compounds as ROCK inhibitor

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103459379A (en) * 2011-02-21 2013-12-18 大正制药株式会社 Glycine transport inhibitor
CN103459379B (en) * 2011-02-21 2015-04-01 大正制药株式会社 Glycine transport inhibitor
CN109153663A (en) * 2016-05-27 2019-01-04 百时美施贵宝公司 Triadimefon compound and tetrazolium ketone compounds as ROCK inhibitor
CN109153663B (en) * 2016-05-27 2021-08-13 百时美施贵宝公司 Triazolones and tetrazolones as ROCK inhibitors

Similar Documents

Publication Publication Date Title
CN101341135B (en) Substituted pyrazinone derivatives for use in MCH-1 mediated diseases
CN100549014C (en) Triazolopyrimidine derivative as the Glycogen Synthase kinase 3 inhibitor
AU2007328979B2 (en) Novel substituted diaza spiro pyridinone derivatives for use in MCH-1 mediated diseases
TW200811146A (en) Novel N-aryl and N-heteroaryl substituted pyridinone derivatives for use in MCH-1 mediated diseases
ES2339998T3 (en) PIRAZINONA DERIVATIVES SUBSTITUTED FOR USE AS A MEDICINAL PRODUCT.
US20100029620A1 (en) Substituted triazoline, tetrazolone and imidazolone derivatives for use as a medicine
CN101448795A (en) Substituted pyrazinone derivatives for use as a medicine
CN101084201A (en) Triazolone, tetrazolone and imidazolone derivatives for use as alpha-2c adrenoreceptor antagonists
ES2342116T3 (en) DERIVATIVES OF PIRAZINONA SUBSTITUTED AS ANTAGONISTS OF THE ADRENORRECEPTORS ALFA2C.
CN101426788A (en) Substituted pyrazinone derivatives for use as a medicine
CN1329396C (en) C-substituted tricyclic isoxazoline derivatives and their use as anti-depressants

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20071205