CN101238128A - Azabicyclic heterocycles as cannabinoid receptor modulators - Google Patents

Abstract

The present application describes compounds according to Formula: (I) or (II); wherein R<1> and R<2> are aryl or heteroaryl. These compounds are useful as cannabinoid receptor modulators, particulary for the treatment of obesity and smoking abuse.

Description

Azabicyclic heterocycles as Cannibinoid receptor modulators

Background

The main active component delta-9-Tetrahydrocannabinol of hemp (marijuana) or δ-9THC are mediation physiology and mentation, comprise a member in modulation of appetite, immunosuppression, analgesia, inflammation, vomiting, anti-nociception, calmness and intraocular pressure and the big class lipophilic compound (that is cannaboid).Other member of cannaboid family comprises endogenous (arachidonic acid deutero-) part, arachidonic acyl glycollic amide, 2-arachidonic acyl glycerine, 2-arachidonic acyl glyceryl ether.Cannaboid is by selective binding and activate G-albumen coupling Cannabined receptor and work.Two class Cannabined receptors are cloned, comprise CB-1 (L.A.Matsuda etc., Nature, 346,561-564 (1990)) and CB-2 (S.Munro etc., Nature, 365,61-65 (1993)).CB-1 acceptor height is expressed in (M.Glass etc., Neuroscience, 77,299-318 (1997)) in maincenter and the peripheral nervous system, and the CB-2 acceptor then highly is expressed in the immuning tissue, particularly in spleen and tonsilla.The CB-2 acceptor also is expressed in other immune system cell, for example (S.Galiegue etc., Eur J Biochem, 232,54-61 (1995)) on the lymphoidocyte.The agonist activation of Cannabined receptor can cause that inhibition, the map kinase of cAMP accumulation is active to be excited and the closing of calcium channel.

There are a large amount of evidences to show the behavior of cannaboid modulation of appetite.Excite the CB-1 activity at a plurality of species with arachidonic acyl glycollic amide or δ-9THC, comprise the people, causing ingests increases and increase weight (Williamsand Kirkham, Psychopharm., 143,315-317 (1999)).The gene knockout of CB-1 makes mouse descend and more thin and weak (DiMarzo etc., Nature, 410,822-825 (2001)) than wild all tire newborn animal appetite.The ingesting of rat that studies confirm that about CB-1 small molecules antagonist of having delivered reduces (Trillou etc., Am.J.physiol, Regul.Integr.Comp.physiol., R345-R353 (2003)) with body weight.Take for a long time cause in two weeks of CB-1 antagonist AM-251 lose weight significantly and adipose tissue mass reduce (Hildebrandt etc., Eur.J.pharm.462,125-132 (2003)).Have many determined Sanofi CB-1 antagonist SR-141716 subtract appetite effect (Rowland etc., pyschopharm., 159,111-116 (2001); Colombo etc., Life Sci., 63,113-117 (1998)).Have two kinds of CB-1 antagonists at least, the SLV-319 of the SR-141716 of Sanofi company and Solvay company is in the clinical trial of carrying out the modulation of appetite effect.The IIb issue of having delivered is according to the weight reduction effect that has disclosed the dose-dependently of SR-141716 in human subjects in 16 trial periods in week.The CB-1 antagonist also demonstrates the effect that promotes smoking cessation.In September, 2002 Sanofi-Synthelabo information can on showed clinical smoking cessation data of II phase.These data show that the patient of the SR-141716 treatment of consumption maximum dose level has 30.2% to give up smoking, and the person is 14.8% and take the placebo.

Describe in detail

The application has described formula I and formula II compound, contain the pharmaceutical composition of at least a formula I and formula II compound and optional one or more other medicines and jointly use the methods of treatment of formula I and formula III compound individually or with one or more other medicines.This compound has following general formula I and II:

Comprise all prodrugs, pharmaceutically useful salt and steric isomer, R ¹, R ², R ³And R ⁴Explanation in the text.

Definition

In this manual, unless limit in addition, adopt all the time to give a definition for the term that uses in special case.

The term that uses in the literary composition " alkyl " representative contains 1 to 20 carbon in normal chain, preferred 1 to 12 carbon, the more preferably branch of 1 to 8 carbon or unbranched hydrocarbon chain, for example, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl etc.In addition, the alkyl that defines in the literary composition can randomly be replaced by one or more functional groups that are connected with this type of chain usually on any available carbon atom, such as but not limited to, hydroxyl, halogen, alkylhalide group, sulfydryl or thio group, cyano group, alkylthio, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxyl, carbalkoxy, formamido-, carbonyl, thiazolinyl, alkynyl, nitro, amino, alkoxyl group, aryloxy, alkoxy aryl, heteroaryloxy, amido ,-OPO ₃H ,-OSO ₃H etc. are so that form such as alkyl such as trifluoromethyl, 3-hydroxyl hexyl, 2-carboxyl propyl group, 2-fluoro ethyl, carboxymethyl, cyano group butyl.

Unless otherwise indicated, be meant in normal chain, have 1 or 2 to 20 carbon of a plurality of two strandss, preferred 2 to 12 carbon with the form of itself or as the term " thiazolinyl " that the part of another group is used herein, the more preferably straight or branched of 2 to 8 carbon, for example vinyl, 2-propenyl, 3-butenyl, crotyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonene base, 4-decene base, 3-undecenyl, 4-dodecenyl succinic, 4,8,12-14 carbon trialkenyl etc.In addition, Ding Yi thiazolinyl can randomly be replaced by one or more functional groups that are typically connected on this type of chain on any available carbon atom herein, such as but not limited to: halogen, alkylhalide group, alkyl, alkoxyl group, alkynyl, aryl, aralkyl, cycloalkyl, amino, hydroxyl, heteroaryl, the assorted alkyl of ring, alkyl amido, alkyl amido, aryl-amino-carbonyl, nitro, cyano group, thiol, alkylthio and/or described herein any alkyl substituent.

Except as otherwise noted, herein with itself form or as the term " alkynyl " that the part of another group is used be meant one or more triple-linked 2-20 carbon atom are arranged in normal chain, preferably 2-12 carbon atom, the more preferably straight or branched of 2-8 carbon atom, for example 2-propynyl, 3-butynyl, 2-butyne base, 4-pentynyl, 3-pentynyl, 2-hexin base, 3-hexin base, 2-heptyne base, 3-heptyne base, 4-heptyne base, 3-octyne base, 3-n-heptylacetylene base, 4-decynyl, 3-hendecyne base, 4-dodecyne base etc.In addition, Ding Yi alkynyl can randomly be replaced by one or more functional groups that are connected with this type of chain usually on any available carbon atom herein, for example, but be not limited to: halogen, alkylhalide group, alkyl, alkoxyl group, thiazolinyl, aryl, aralkyl, cycloalkyl, amino, hydroxyl, heteroaryl, the assorted alkyl of ring, alkyl amido, alkyl amido, aryl-amino-carbonyl, nitro, cyano group, thiol, alkylthio and/or described herein any alkyl substituent.

Unless otherwise noted, comprise individually or as the term " cycloalkyl " that the part of another group is used herein and contain 1 to 3 additional ring or condense ring filling or fractional saturation (containing one or more pairs of keys) cyclic hydrocarbon group, comprise containing and amount to 3-20, preferred 3-10 monocycle alkyl, bicyclic alkyl and tricyclic alkyl that becomes ring carbon atom, it can condense the described aromatic nucleus of aryl with 1 or 2, comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring decyl and cyclo-dodecyl, cyclohexenyl,

In addition, any cycloalkyl all can randomly be selected from following one or more groups replacements on any available carbon atom: hydrogen, halogen, alkylhalide group, alkyl, alkoxyl group, halogenated alkoxy, hydroxyl, thiazolinyl, alkynyl, aryl, aryloxy, heteroaryl, heteroaryloxy, aralkyl, heteroarylalkyl, alkyl amido, alkyl amide, oxygen, acyl group, aryl-amino-carbonyl, amino, nitro, cyano group, thiol and/or alkylthio and/or any alkyl substituent.

Use separately herein or be meant the alkyl of above definition with naphthenic substituent as the term " cycloalkylalkyl " that the part of another group is used, wherein should " cycloalkyl " and/or " alkyl " can be randomly as above definition be substituted.

Unless otherwise noted, be meant that part at ring contains the monocycle of 6-10 carbon and bicyclic aromatic group (phenyl or naphthyl for example individually or as the term " aryl " that the part of another group is used herein, comprise 1-naphthyl and 2-naphthyl), and can randomly comprise 1-3 and carbocyclic ring or heterocyclic fused other ring, for example

In addition; Ding Yi " aryl " can randomly be replaced by one or more functional groups herein; halogen for example; alkyl; alkylhalide group; alkoxyl group; halogenated alkoxy; thiazolinyl; alkynyl; cycloalkyl; cycloalkylalkyl; heterocyclic radical; Heterocyclylalkyl; aryl; heteroaryl; aralkyl; aryloxy; aryloxy alkyl; alkoxy aryl; carbalkoxy; aryl carbonyl; aryl alkenyl; the aminocarboxyl aryl; arylthio; aryl sulfonyl kia; the arylazo base; heteroarylalkyl; the heteroaryl thiazolinyl; the heteroaryl heteroaryl; heteroaryl oxygen base; hydroxyl; nitro; cyano group; amino; (wherein amino has 1 or 2 substituting group to the amino that replaces; as alkyl; any other aryl compound of narration in aryl or the definition); thiol; alkylthio; arylthio; heteroarylthio; arylthio alkyl; the alkoxy aromatic sulfenyl; alkyl-carbonyl; aryl carbonyl; alkyl amino-carbonyl; aromatic yl aminocarbonyl; alkoxy carbonyl; aminocarboxyl; alkyl carbonyl oxy; aryl-carbonyl oxygen; alkyl-carbonyl-amino; aryl-amino-carbonyl; aryl sulfonyl kia; the aryl sulfonyl kia alkyl; Arenesulfonyl amino or Arenesulfonyl amino carbonyl, with and/or described herein any alkyl substituent.

Unless otherwise noted, be meant individually or as the term " heteroaryl " that the part of another group is used herein and contain 1,2,3 or 4 heteroatoms for example 5 yuan or 6 yuan of aromatic rings of nitrogen, oxygen or sulphur.These rings can condense with aryl, cycloalkyl, heteroaryl or heterocyclic radical, and comprise possible N-oxide compound, as reaching at following document described in the reference wherein: Katritzky, A.R.and Rees, C.W., eds.Comprehensive Heterocyclic Chemistry:TheStructure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, NY; And Katritzky, A.R., Rees, C.W., Scriven, E.F., eds.Comprehensive Heterocyclic Chemistry II:A Review of theLiterature 1982-1995 1996, Elsevier Science, Inc., Tarytowen, NY.In addition, Ding Yi " heteroaryl " can randomly be replaced by one or more substituting groups herein, for example the substituting group that comprises in the definition of above " alkyl of replacement " and " aryl of replacement ".The example of heteroaryl comprises following group etc.:

Be meant to have the substituent above alkyl that defines of heteroaryl separately or as the term " heteroarylalkyl " that the part of another group is used herein, wherein this heteroaryl and/or alkyl can randomly be substituted as defined above.

4 to 7 yuan of stable monocycle systems that term used herein " heterocycle " or " heterocyclic radical " representative do not replace or replace, it can be saturated or unsaturated, form by carbon atom and 1 to 4 heteroatoms that is selected from nitrogen, oxygen or sulphur, and wherein nitrogen and sulfur heteroatom can be randomly oxidized, and nitrogen heteroatom can be randomly quaternized.This heterocycle can be connected on any heteroatoms or carbon atom that can produce rock steady structure.The example of these heterocyclic groups comprises, but be not limited to, piperidyl, piperazinyl, the oxygen piperazinyl, the Oxypertine base, the oxygen pyrrolidyl, oxo azepine _ base, azepine _ base, pyrryl, pyrrolidyl, furyl, thienyl, pyrazolyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, _ azoles base, _ oxazolidinyl, different _ the azoles base, different _ oxazolidinyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, thiadiazolyl group, THP trtrahydropyranyl, the parathiazan base, parathiazan base sulfoxide, parathiazan base sulfone, _ di azoly, and at other heterocycle described in following document and the reference wherein: Katritzky, A.R.and Rees, C.W., eds.Comprehensive HeterocyclicChemistry:The Structure, Reactions, Synthesis and Uses of HeterocyclicCompounds 1984, Pergamon Press, New York, NY; And Katritzky, A.R., Rees, C.W., Scriven, E.F., eds.Comprehensive Heterocyclic ChemistryII:A Review of the Literature 1982-19951996, Elsevier Science, Inc., Tarrytown, NY.

Be meant the alkyl of above definition separately or as the term " Heterocyclylalkyl " that the part of another group is used herein with heterocyclic substituent, wherein this heterocyclic radical and/or alkyl can be randomly as above definition be substituted.

Individually or as term " aralkyl ", " arylalkenyl " and " sweet-smelling alkynyl " that the part of another group is used, be meant alkyl, thiazolinyl and the alkynyl of above definition with aryl substituent.The representative instance of aralkyl includes, but not limited to benzyl, 2-phenylethyl, 3-phenyl propyl, phenylethyl, diphenyl-methyl and menaphthyl etc.

Use or comprise the alkyl or aryl of the above definition that connects via a Sauerstoffatom herein separately as term " alkoxyl group ", " aryloxy ", " heteroaryloxy ", " alkoxy aryl " or " heteroaryl alkoxyl group " that the part of another group is used.

Independent herein use or the term " halogen " or " halogen " that use as the part of another group are meant chlorine, bromine, fluorine and iodine, preferred bromine, chlorine or fluorine.

Term used herein " cyano group " refers to-the CN group.

Term used herein " methylene radical " refers to-CH _2-Group.

Term used herein " nitro " refers to-NO ₂Group.

Formula I and formula II compound can exist with the form of salt, and they also within the scope of the invention.Preferred pharmacy acceptable salt (that is, nontoxic physiologically acceptable salt).If formula I and formula II compound contain for example at least one basic center, then they can form acid salt.These salt are and for example inorganic acid that for example mineral acid forms as sulfuric acid, phosphoric acid or haloid acid; Form with organic carboxyl acid, the alkanoic acid of 1 to 4 carbon atom for example, for example unsubstituted or acetate that replaces is as the Mono Chloro Acetic Acid that is replaced by halogen; For example saturated or undersaturated di-carboxylic acid, for example oxalic acid, propylene diester, Succinic Acid, toxilic acid, fumaric acid, phthalic acid or terephthalic acid; For example hydroxycarboxylic acid, for example xitix, carboxyl acetic acid, lactic acid, oxysuccinic acid, tartrate or citric acid; For example amino acid (for example aspartic acid or L-glutamic acid or Methionin or arginine), or phenylformic acid; Or form (C for example with organic sulfonic acid ₁-C ₄) alkyl or aryl sulfonic acid, they are unsubstituted or for example halogen replacement of quilt, as methylsulfonic acid or tosic acid.If be ready, also can form corresponding acid salt with another basic center.Formula I and formula II compound with at least one acidic-group (for example COOH) also can form salt with alkali.The suitable salt that forms with alkali is metal-salt for example, as basic metal or alkaline earth salt, for example sodium, potassium or magnesium salts, or the salt that forms with ammonia or organic amine, the example of organic amine has parathiazan, piperidines, tetramethyleneimine, one, two or three low-grade alkylamines, for example ethamine, TERTIARY BUTYL AMINE, diethylamine, Diisopropylamine, triethylamine, Tributylamine or dimethyl propylamine, perhaps one, two or the trihydroxy-low-grade alkylamine, for example one, two or trolamine.Can further form corresponding inner salt.Also comprise being not suitable for pharmaceutical application, but can be used for for example isolated or purified formula I and the free cpds of formula II or those salt of its pharmacologically acceptable salt.

Preferably contain the formula I of basic group and the salt of formula II compound and comprise a hydrochloride, hydrosulfate, mesylate, phosphoric acid salt, nitrate or acetate.

Preferably contain the formula I of acidic-group and the salt of formula II compound and comprise sodium, potassium and magnesium salts and pharmaceutically useful organic amine salt.

Term " conditioning agent " refers to (for example can strengthen, " agonist " activity) or partly (for example strengthen, " partial agonist " activity), the compound that perhaps suppresses certain function (for example enzymic activity or receptor binding) of (for example " antagonist " active or " inverse agonists " activity) biological activity or process; This enhancing or suppress decide on the concrete incident of generation possibly, for example activation of signal transduction pathway, and/or may in the cell of particular type, show.

Term used herein " bioactive metabolites " is meant that contain any has the functional group who is used for the key point that further replaces in formula I and formula II compound, this can production I and formula II compound when being substituted in bio-transformation.This type of functional group's of biological metabolite example includes, but not limited to-OH ,-NH or hydrogen wherein can by for example-PO ₃H ₂And so on the functional group that replaces of functional group, it when bio-transformation production I and formula II compound-OH or-the NH functional group.

Term used herein " prodrug " comprises the step of utilizing generation acetic ester well known by persons skilled in the art, pivalate, methyl phosphorodithioate, benzoic ether etc.; the acylation reaction that one or more hydroxyls of through type I and formula II compound and alkyl, alkoxyl group or aryl replace, the ester of formation and carbonic ether.Prodrug ester can also include but not limited to phosphoric acid ester, phosphonic acid ester, phosphonic amide acid esters, sulfuric ester, sulphonate and sulphonamide acid esters, wherein this ester can further can be given the group replacement of pharmacy superiority, such as but not limited to, give exposure in favourable water-soluble of biologically active components formula I and formula II compound or the body.

Term used herein " prodrug " comprises the bioactive derivative that contains the formula I of amine or hydroxyl and alkyl, acyl group, alkylsulfonyl, phosphoryl or carbohydrate replacement that formula II compound forms through functionalization.These derivative through type I and formula II compound and alkylation, acylations, sulfonylation or phosphorus esterification reagent form according to step reaction well known by persons skilled in the art.The alkylation of the amine of formula I and formula II can produce (but being not limited to) and comprise with the prodrug other parts at interval unitary derivative, for example alkoxy methyl of Qu Daiing, acyloxy methyl, phosphinylidyne oxygen ylmethyl or sulfonyloxy methyl group are arranged.The alkylation of the amine of formula I and formula II can produce and play the quaternary amine that biologically active agent (that is, formula I and formula II compound) effect is provided in vivo.

Preferred prodrug is made of formula I and formula II compound, and one of them hydroxyl that adheres to is formed a phosphate derivative by phosphorylated.A kind of like this prodrug can also comprise a spacer groups, for example methylene radical oxygen base between formula I and formula II compound and bound phosphate groups.From the method for formula I and a kind of like this prodrug of formula II compound generation is well known by persons skilled in the art, is listed in the following reference.

Preferred prodrug also comprises such formula I and formula II compound, the amine that one of them is attached, and pyridyl for example is with certain group (for example methyl) alkylation, formation quaternary ammonium ion salt.The method that is generated such prodrug by formula I and formula II compound is well known by persons skilled in the art, is listed in the following reference.

Any compound that can transform formation biologically active agent (that is, formula I and formula II compound) in vivo all is the prodrugs in scope and spirit of the present invention.

Various forms of prodrugs are known in the art.Comprehensive description of pair prodrug and prodrug derivant is arranged in the following document:

a)The?Practice?of?Medicinal?Chemistry，Camille?G.Wermuth?et?al.，Ch.31，(Academic?Press，1996)；

b)Design?of?Prodrugs，edited?by?H.Bundgaard，(Elsevier，1985)；

c)A?Textbook?of?Drug?Design?and?Development，P.Krogsgaard-Larsonand?H.Bundgaard，eds.Ch?5，pgs?113-191(Harwood?Academic?Publishers，1991)；

d)Hydrolysis?in?Drug?and?Prodrug?Metabolism，B.Testa?and?J.M.Mayer，(Verlag?Helvetica?Chimica?Acta?AG，Zurich，Switzerland；Wiley-VCH，Weinheim，Federal?Republic?of?Germany，2003)；

e)Ettmayer，P.；Amidon，G.L.；Clement，B.；Testa，B.“Lessons?Learnedfrom?Marketed?and?Investigational?Prodrugs”J.Med.Chem.2004，47(10)，2393-2404；and

f)Davidsen，S.K.et?al.“N-(Acyloxyalkyl)pyridinium?Salts?as?SolubleProdrugs?of?a?Potent?Platelet?Activating?Factor?Antagonist”J.Med.Chem.1994，37(26)，4423-4429.

These reference are all quoted as a reference in this article.

The administration of medicine of the present invention comprises the medicine of the present invention for the treatment of significant quantity.Term used herein " treatment significant quantity " is meant can be treated or prevent by taking the treatment of conditions medication amount that the present composition can be treated.This quantity is the quantity that is enough to show noticeable treatment or prevention or mitigation.Described effect can comprise, for example, treats or prevent illness listed in the text.For treatment target, the significant figure amount depends on the size and the healthy state of this object accurately, the essence of the illness of being treated and degree, and attending doctor's suggestion, and select to be used for the therapy or the therapy combination of administration.

No matter all steric isomers of The compounds of this invention within considering, are form of mixtures or pure or pure basically form all.The compounds of this invention can be included on any one R substituting group at any carbon atom place, has asymmetric center.Therefore, formula I and formula II compound can exist with enantiomorph or diastereomer form or its form of mixtures.The preparation method can use racemoid, enantiomorph or diastereomer as initiator.When preparing diastereomer or enantiomorph product, they can use ordinary method, and for example chromatographic technique, chirality HPLC or fractionation crystallization separate.

Formula I of the present invention and formula II compound can prepare as following reaction scheme and explanation thereof and operable relevant the delivering described in the literature method of those skilled in the art.Reach later and will list exemplary agents and the step that is used for these reactions among the work embodiment.

Abbreviation

The following dummy suffix notation of other local employing in scheme, embodiment and literary composition:

The Ac=ethanoyl

AcOH=acetate

The Boc=tertbutyloxycarbonyl

The DCM=methylene dichloride

DIPEA=N, the N-diisopropylethylamine

DMF=N, dinethylformamide

EDAC=1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride

The EtOAc=ethyl acetate

Et ₃The N=triethylamine

Et ₂The O=ether

The HEX=hexane

The HOBt=1-hydroxy benzotriazole hydrate

The HPLC=high performance liquid chromatography

The LAH=lithium aluminium hydride

The LCMS=liquid chromatography-mass spectrometry

MeOH=methyl alcohol

MS or Mass Spec=mass spectroscopy

NaOH=sodium hydroxide

The PG=protecting group

The rt=room temperature

The TFA=trifluoroacetic acid

The THF=tetrahydrofuran (THF)

The min=branch

Hr (s)=hour

The L=liter

The mL=milliliter

μ L=microlitre

The g=gram

The mg=milligram

The mol=mole

The mmol=mmole

The nM=nmole

The compounds of this invention can prepare with the step that illustrates in the appended scheme.

The preparation method

The compounds of this invention can preparing in the method described in the preparation of embodiment compound with following with explanation in the following scheme 1 to 3 for example.The easy selective solvent of those of ordinary skills, temperature, pressure and other reaction conditions.Initiator is commercially available or can be easily prepared with currently known methods by those of ordinary skills.For following all methods and compound, R ¹, R ², R ³, R ⁴, X ¹And X ²All as described in for formula I and formula II compound.

Below be the definition of the symbol of use all the time in scheme 1 to 3:

PG is independently selected from suitable nitrogen or oxygen blocking group, and the example is benzyl, methoxymethyl [MOM], benzyloxymethyl [BOM], 2-(trimethyl silyl) ethoxyl methyl [SEM], methoxy ethoxy methyl [MEM], the tertiary butyl, tertbutyloxycarbonyl or benzyloxycarbonyl group;

EE S _n2 or S _n1 leavings group, example are halogen (Cl, Br, I) and sulfonate group (OSO ₂-aryl (for example-OSO ₂Ph or-OSO ₂PhCH ₃), or-OSO ₂-alkyl (for example ,-OSO ₂CH ₃Or-OSO ₂CF ₃));

MM boric acid ester or boric acid, or trialkyl stannane; Or the atoms metal of the part of the organometallic compound that uses as the intermediate of linked reaction, for example zinc, magnesium or lithium, this linked reaction can transition metal exist or not in the presence of carry out.

Scheme 1

Wherein EE is for example formula i compound of chlorine, bromine etc. of an activating group, can obtain with method known to those skilled in the art.Formula ii compound, in solvent such as DMF or THF, is obtained with suitable blocking group such as benzyl halide reaction to the high temperature in room temperature under the alkaline condition that uses potassiumphosphate or sodium hydride etc. by formula i compound.Formula iii compound is by formula ii compound and aryl or the preparation of heteroaryl acid reaction.Work as R ¹And R ²When identical, use 2 equivalents or more of aromatic or heteroaryl boric acid.Work as R ¹And R ²Not simultaneously, do not use 1 normal aryl or heteroaryl boric acid.After reaction is finished, the intermediate of formation further with different aryl or heteroaryl acid reactions, obtain formula iii compound.Formula iv compound can be by formula iii compound under the condition of bibliographical information, for example at T.W.Green ﹠amp; P.G.M.Wuts, " Protecting Groups in OrganicSynthesis ", the 3rd edition, Wiley under the condition that can find in 1999, removes protecting group PG and makes.For example, if PG is a benzyl, then formula iii compound obtains formula iv compound with aluminum chloride heat treated in toluene.Formula v compound is under refluxad used chlorizating agent such as POCl by formula iv compound ₃Handle and form.Formula v compound is used for synthesis type I and formula II compound subsequently.

Scheme 2

Formula viii compound is by formula v compound and acylhydrazine prepared in reaction.Use dewatering agent then, for example POCl ₃, at high temperature handle formula viii compound, form formula ix compound.Or formula ix compound is by handling formula v compound with hydrazine, under refluxad reacts with chloride of acid with the formic acid reaction or under alkaline condition subsequently to form.Formula x compound is by formula ix compound and hydroxide source (for example TMSOK or hydroxide four butylamine) prepared in reaction.Formula xi and xii compound are reacted in the presence of alkylating reagent such as bromotoluene, alkylogen etc. in solvent (for example acetonitrile or DMF) by formula x compound and alkali (for example sodium hydride or salt of wormwood) and make.

Scheme 3

Or formula xii compound can be by formula ix compound by preparing with pure condensation under alkaline condition.

In the preparation of compound, can utilize parallel synthetic, the situation that for example has an active reaction center at intermediate, be such as but not limited to, active heteroaryl chlorine for the Suzuki linked reaction, or for the carboxylic acid of acid amides linked reaction, for the active halogen of alkylated reaction, or for for example activation chlorine of the replacement(metathesis)reaction of alcohol.

Embodiment

Following examples are used for illustrating better, but are not to limit embodiment preferred more of the present invention.

The analysis mode HPLC method of in the sign of embodiment, using

Analysis mode HPLC/MS carries out in order to following method on Shimadzu LC 10AS liquid chromatographic system and WatersZMD mass spectrograph:

By 0 to 100% solvent B, linear gradient kept 1 minute at 100%B method A. in 4 minutes.

UV visualization under 220nm

Post: YMC S5 ODS Combiscreen C18,4.6 * 50mm

Flow velocity: 4ml/min

Solvent orange 2 A: 0.2% phosphoric acid, 90% water, 10% methyl alcohol

Solvent B:0.2% phosphoric acid, 90% methyl alcohol, 10% water

Method B.4 minute in by 0 to 100% solvent B, linear gradient kept 1 minute at 100%B.

UV visualization under 220nm

Post: Phenomenex Luna C18,4.6 * 50mm

Flow velocity: 4ml/min

Solvent orange 2 A: 0.1% trifluoroacetic acid, 90% water, 10% methyl alcohol

Solvent B:0.1% trifluoroacetic acid, 90% methyl alcohol, 10% water

Method C.15 minute in by 40% to 95% solvent B, linear gradient

UV visualization under 220nm

Post: Phenomenex Luna Pheny-hexyl 4.6 * 150mm

Flow velocity: 1.2ml/min

Solvent orange 2 A: 0.1% ammonium acetate, 100% water

Solvent B:0.1% ammonium acetate, 100% acetonitrile

The NMR that uses during embodiment characterizes

¹H NMR spectrum is used in the Bruker or the JOEL fourier transformation spectrometer of working down with lower frequency and obtains: ¹H NMR:400MHz (Bruker), 400MHz (JOEL), or 500MHz (JOEL); ¹³C NMR:100MHz (Bruker), 100MHz (JOEL) or 125MHz (JOEL).Spectroscopic data is as chemical shift (multiplicity, number of hydrogen atoms, coupling constant (Hz)) report, be expressed as with respect to ¹The interior mark of H NMR spectrum (tetramethylsilane=0ppm) or with reference to residual solvent peak (for CD ₂HSOCD ₃Be 2.49ppm, CD ₂HOD is 3.30ppm, CHCl ₃Be 7.24ppm, CD ₃SOCD ₃Be 39.7ppm, CD ₃OD is 49.0ppm, CDCl ₃Be 77.0ppm) localized ppm (δ unit).All ¹³C NMR spectrum is proton uncoupling spectrum.

Embodiment 1

3,6-two chloro-4, the preparation of 5-two (4-chloro-phenyl-) pyridazine

1A.4,5-two chloro-1,2-dihydrogen dazin-3, the preparation of 6-diketone

In a round-bottomed flask, add water (170ml) and hydrazine dihydrochloride (41.9g, 398.8mmol).Solution is refluxed, add in batches two chloro mandelic acid acid anhydrides (66.6g, 38.9mmol).Reaction mixture was stirred 30 fens under refluxing.Be cooled to room temperature then, solid collected by filtration obtains title compound 4,5-two chloro-1, and 2-dihydrogen dazin-3,6-diketone (65g, productive rate 90%) is white solid.MS(M+H)＝181.0。

1B.2-benzyl-6-(benzyloxy)-4, the preparation of 5-dichloro-pyridazine-3 (2H)-ketone

In a round-bottomed flask, add 4,5-two chloro-1,2-dichloro-pyridazine-3, the 6-diketone (20g, 73.8mmol), DMF (200ml), salt of wormwood (20.36g, 147.6mmol) and bromotoluene (15.14g, 88.56mmol).Reaction mixture was stirred 6 hours at 50 ℃, at room temperature stir then and spend the night.After this, reaction mixture is poured into 1: 1 water: in the hexanes mixtures (2000ml).The mixture that forms at room temperature stirred 1 hour.Filter and collect the solid precipitation that forms, obtain title compound 2-benzyl-6-(benzyloxy)-4,5-dichloro-pyridazine-3 (2H)-ketone (23.9g, productive rate 90%) is light yellow solid. ¹H(DMSO-D6)：7.45(m，2H)，7.35(m，4H)，7.30(m，4H)，5.26(s，2H)，5.17(s，2H)。

1C.2-benzyl-6-(benzyloxy)-4, the preparation of 5-two (4-chloro-phenyl-) pyridazine-3 (2H)-ketone

In a round-bottomed flask, add 2-benzyl-6-(benzyloxy)-4, and 5-dichloro-pyridazine-3 (2H)-ketone (20g, 55.4mmol), the 4-chlorophenylboronic acid (19.07g, 121.88mmol), 2N yellow soda ash (124.7ml, 249.3mmol), toluene (200ml) and Pd (PPh ₃) ₄(3.2gm, 2.77mmol).Reaction mixture was stirred 36 hours at 100 ℃, then solution is cooled to room temperature, separate organic layer.This organic layer water (100ml), the saturated NaCl aqueous solution (100ml) are washed.With organic layer drying (MgSO ₄), filter and concentrate.Crude product under-25 ℃ in methyl alcohol (150ml) recrystallization.Solid collected by filtration obtains title compound 2-benzyl-6-(benzyloxy)-4, and 5-two (4-chloro-phenyl-) pyridazine-3 (2H)-ketone (19.5g, productive rate 70%) is light yellow solid.MS(M+H)＝513.1。

1D.4,5-two (4-chloro-phenyl-)-1,2-dihydrogen dazin-3, the preparation of 6-diketone

In a round-bottomed flask, add 2-benzyl-6-(benzyloxy)-4,5-two (4-chloro-phenyl-) pyridazine-3 (2H)-ketone (15.5g, 30.21mmol), toluene (70ml) and aluminum chloride (10.08g, 75.54mmol).Reaction mixture was stirred 2 hours at 90 ℃, be cooled to 0 ℃ then, slowly add water (200ml).This solution extracts with ethyl acetate (3L).Organic layer water (200ml) and NaCl saturated aqueous solution (200ml) are washed.With organic layer drying (MgSO ₄), filter and concentrate.Obtain title compound solid 4,5-two (4-chloro-phenyl-)-1,2-dihydrogen dazin-3, the 6-diketone is not further purified, and is directly used in next reaction.MS(M+H)＝330.9，333.0。

1E.3.6-two chloro-4, the preparation of 5-two (4-chloro-phenyl-) pyridazine

To 4,5-two (4-chloro-phenyl-)-1,2-dihydrogen dazin-3 dropwise adds POCl in the 6-diketone ₃(50ml).The reaction mixture reflux that forms 2 hours, its color blackening.POCl is removed in decompression then ₃, in residue, slowly add water (250g), slowly add water (250ml) subsequently.Filter and collect the solid precipitation that forms, obtain dark solid product.This crude product is dissolved in CH ₂Cl ₂(250ml), solution filters through diatomite (30ml).The filtrate of collecting is concentrated, obtain brown solid.This rough solid is from CH ₂Cl ₂Recrystallization (30ml) and in the hexane (500ml) obtains title compound 3,5-two chloro-4, and 5-two (4-chloro-phenyl-) pyridazine is beige solid (5.0g, 2 step productive rates 45%).MS(M+H)＝368.5，370.5。

Embodiment 2

7,8-two (4-chloro-phenyl-)-3-methyl-5-(4-(trifluoromethyl) benzyl)

Synthesizing of-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone

2A.6-chloro-4,5-two (4-chloro-phenyl-) pyridazine-3-alcohol synthetic

In a round-bottomed flask, add 3,6-two chloro-4,5-two (4-chloro-phenyl-) pyridazine (1000mg, 2.710mmol), THF (20ml) and TMSOK (869mg, 6.775mmol).Reaction mixture was stirred 8 hours at 80 ℃.Then reaction mixture is concentrated residue water (15ml) dilution.With the pH regulator to 4 of 1N HCL with the solution of formation.During adding HCl, be settled out solid.Solid collected by filtration obtains product 6-chloro-4, and 5-two (4-chloro-phenyl-) pyridazine-3-alcohol is white solid (760mg, productive rate 80%).HPLC retention time (method A) 3.535min; LCMS (M+H)=351.1.

2B.6-chloro-4,5-two (4-chloro-phenyl-)-2-(4-(trifluoromethyl) benzyl) pyridazine-3 (2H)-ketone synthetic

In a round-bottomed flask, add 6-chloro-4, and 5-two (4-chloro-phenyl-) pyridazine-3-alcohol (1.5g, 4.26mmol), DMF (15ml) and K ₂CO ₃(1.17g, 8.52mmol).Stirring at room 30 minutes, (1.2g, 5.19mmol), at room temperature restir was 8 hours to add 4-trifluoromethyl benzyl bromine then with reaction mixture.Water (40ml) diluted reaction mixture is poured in the separating funnel with EtOAc extraction (2 * 50ml) subsequently.The organic layer water that merges (4 * 30ml) and NaCl saturated aqueous solution (30ml) wash.Organic layer is used MgSO then ₄To change to remove unnecessary water, filter and concentrate, obtain product 6-chloro-4,5-two (4-chloro-phenyl-)-2-(4-(trifluoromethyl) benzyl) pyridazine-3 (2H)-ketone is pale solid (1.5g, productive rate 65.1%).

2C.7,8-two (4-chloro-phenyl-)-3-methyl-5-(4-(trifluoromethyl) benzyl)-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone synthetic

In burning, round bottom adds 6-chloro-4, and 5-two (4-chloro-phenyl-)-2-(4-(trifluoromethyl) benzyl) pyridazine-3 (2H)-ketone (0.1g, 0.196mmol), propyl carbinol (1ml) and hydrazine hydrate.Reaction mixture is heated to 135 ℃, under this temperature, stirred 24 hours, be cooled to room temperature then, be concentrated into driedly, obtain yellow solid.In formed yellow solid, add CH successively ₂Cl ₂(3ml) and Et ₃N (0.1ml, 0.594mmol).Then to this reaction mixture slowly add diacetyl oxide (24mg, 0.236mmol).With reaction mixture restir 6 hours under room temperature.Water (10ml) dilution then is poured in the separating funnel, uses CH ₂Cl ₂(2 * 15ml) extractions.The organic layer water (10ml) and the saturated NaCl aqueous solution (10ml) that merge are washed.Organic layer is used MgSO then ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains the reaction product of pale solid.In this solid, add POCl ₃(3ml), the solution that forms is heated to 85 ℃, stirred 2 hours in this temperature.Then reaction mixture is cooled off with ice-water bath, slowly add ice-water, be settled out solid.Solid collected by filtration obtains white solid product 7,8-two (4-chloro-phenyl-)-3-methyl-5-(4-(trifluoromethyl) benzyl)-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone, 70mg (67% productive rate) altogether.HPLC retention time (method A) 3.783 minutes; LCMS (M+H)=529.1;

¹HNMR?(MeOD，400Hz)：7.75(2H，d)，7.56(2H，d)，7.39(4H，s)，7.30(2H，d)，7.21(2H，d)，5.85(2H，s)，2.61(3H，s).

Embodiment 3

Synthesizing of 8-(4-chloro-phenyl-)-3-ethyl-5-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-7-(pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone

3A.6-chloro-5-(4-chloro-phenyl-)-4-(pyridin-4-yl) pyridazine-3-alcohol is synthetic

In a round-bottomed flask, add 3, and 6-two chloro-4-(4-chloro-phenyl-)-5-(pyridin-4-yl) pyridazine (1.5g, 4.464mmol), CH ₃CN (5ml), water (1ml) and LiOH-hydrate (0.938g, 22.32mmol).Reaction mixture is heated to 80 ℃, stirred 4 hours in this temperature.Then reaction mixture is cooled to room temperature, concentrating under reduced pressure.Residue water (30ml) dilution.With the pH regulator to 7 of 1N HCl with the aqueous solution, the solution of formation is poured in the separating funnel, with EtOAc (4 * 20ml) extractions.The organic layer that merges is washed with NaCl saturated aqueous solution (30ml).Then with organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains the white solid residue.With this residue at CH ₂Cl ₂Stir 15 minutes after-filtration (10ml), collect solid, obtain product 6-chloro-5-(4-chloro-phenyl-)-4-(pyridin-4-yl) pyridazine-3-alcohol, be white solid (0.70g, productive rate 48%).HPLC retention time (method A) 1.332min.

3B.6-chloro-5-(4-chloro-phenyl-)-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-4-(pyridin-4-yl) pyridazine-3 (2H)-ketone is synthetic

In a round-bottomed flask, add 6-chloro-5-(4-chloro-phenyl-)-4-(pyridyl) pyridazine-3-alcohol (1.1g, 3.47mmol), DMF (10ml), K ₂CO ₃(0.958g, 6.94mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl) pyridine (0.798g, 3.817mmol).Reaction mixture is heated to 80 ℃, under this temperature, stirred 2 hours.Then reaction mixture is cooled to room temperature, with EtOAc (75ml) dilution.The mixture that forms is poured in the separating funnel, water (4 * 10ml) and NaCl saturated aqueous solution (15ml) wash.Organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water.Crude product is with automatic column chromatography system (ISCO, 40g silica gel) purifying, with 40%-100%EtOAc/ hexane gradient wash-out, obtain product 6-chloro-5-(4-chloro-phenyl-)-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-4-(pyridin-4-yl) pyridazine-3 (2H)-ketone, be beige solid (1.35g, productive rate 79%).HPLC retention time (method A) 3.140 minutes; LCMS (M+H)=491.1.

3C.5-(4-chloro-phenyl-)-6-diazanyl-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-4-(pyridin-4-yl) pyridazine-3 (2H)-ketone is synthetic

In a round-bottomed flask, add 6-chloro-5-(4-chloro-phenyl-)-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-4-(pyridin-4-yl) pyridazine-3 (2H)-ketone (900mg, 1.833mmol), 1-BuOH (2ml) and hydrazine hydrate (5ml).Reaction mixture is heated to 130 ℃, under this temperature, stirred 8 hours.Then reaction mixture is cooled to room temperature, concentrating under reduced pressure.Reaction mixture is poured in the separating funnel, be distributed among EtOAc (50ml) and the water (20ml).Separates two, organic layer water (20ml) and NaCl saturated aqueous solution (20ml) are washed.Then with organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains product 5-(4-chloro-phenyl-)-6-diazanyl-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-4-(pyridin-4-yl) pyridazine-3 (2H)-ketone, is yellow solid.HPLC retention time (method A) 1.138min; LCMS (M+H)=487.1.

(3D.5-4-chloro-phenyl-)-6-diazanyl-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-4-(pyridin-4-yl) pyridazine-3 (2H)-ketone

In a round-bottomed flask, add 5-(4-chloro-phenyl-)-6-diazanyl-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-4-(pyridin-4-yl) pyridazine-3 (2H)-ketone (200mg, 0.411mmol), THF (5ml), Et ₃N (124mg, 1.232mmol), add subsequently propionyl chloride (57mg, 0.616mmol).Then reaction mixture was stirred under room temperature 20 minutes.With reaction mixture with EtOAc (30ml) dilution, the solution with water of formation (2 * 10ml) and NaCl saturated aqueous solution (10ml) wash.Organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.Crude product is used 100%EtOAc wash-out 10 minutes with automatic column chromatography system (ISCO, 12g silica gel) purifying, uses 5% MeOH/CH then ₂Cl ₂Wash-out obtains product N '-(4-(4-chloro-phenyl-)-1-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-5-(pyridin-4-yl)-1,6-dihydrogen dazin-3-yl) propionyl hydrazine, is light yellow solid (140mg, productive rate 63%).HPLC retention time (method A) 1.892min; LCMS (M+1)=543.3.

3E.8-(4-chloro-phenyl-)-3-ethyl-5-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-7-(pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone is synthetic

In a round-bottomed flask, add N '-(4-(4-chloro-phenyl-)-1-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-5-(pyridin-4-yl)-1,6-dihydrogen dazin-3-yl) propionyl hydrazine (130mg, 0.239mmol) and toluene (5ml).Reaction mixture is heated and stirred 1 hour at 130 ℃.Add POCl subsequently ₃(1.3ml), 130 ℃ of restir 4 hours.Then reaction mixture is cooled to room temperature, under reduced pressure concentrates.Residue is dissolved among the EtOAc (30ml).Formed solution is poured in the separating funnel, washed with 0.5N NaOH (10ml), water (15ml) and NaCl saturated aqueous solution (10ml).Organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.With crude product with automatic column chromatography system (ISCO, 4g silica gel) purifying, with 65%-100%EtOAc/ hexane wash-out, obtain product 8-(4-chloro-phenyl-)-3-ethyl-5-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-7-(pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone (80mg), be pale solid, productive rate 64%.HPLC retention time (method A) 2.110min;

LCMS(M+H)＝525.2； ¹HNMR(CDCl ₃，500Hz)：8.59(2H，d，J＝4.4Hz)，7.56(1H，d，J＝7.7Hz)，7.44，(1H，d，J＝7.7Hz)，7.3417(4H，m)，7.18(2H，d，J＝4.4Hz)，5.64(2H，s)，2.82(2H，q)，2.79(3H，s)，1.46(3H，t). ¹³C-NMR(CDCl ₃，500Hz)158.3，154.4，148.9，144.0，140.8，138.2，136.2，133.3，131.8，131.6，129.0，128.8，126.8，125.8，118.3，49.1，22.4，20.8，12.3.

Embodiment 4

Synthesizing of 4-(8-(4-chloro-phenyl-)-3-ethyl-5-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-5,6-dihydro-[1,2,4] triazolo [4,3-b] pyridazine-7-yl) cyanobenzene

4A.2-benzyl-4,5-dichloro-pyridazine-3 (2H)-ketone synthetic

In a round-bottomed flask, add 4, and 5-dichloro-pyridazine-3 (2H)-ketone (50g, 303.03mmol), DMF (150ml), K ₂CO ₃(46g, 333.33) and bromotoluene (51.83g, 303.03mmol).Reaction mixture stirring at room 16 hours, slowly into is poured it in water (500ml) then, formed solid precipitation.With this slurry in stirring at room 1 hour, solid collected by filtration then.With this solid vacuum-drying, obtain product 2-benzyl-4,5-dichloro-pyridazine-3 (2H)-ketone is pale brown look solid (74g, productive rate 97%).HPLC retention time (method A) 2.788min; LCMS (M+1)=255.1.

4B.2-benzyl-5-chloro-4-methoxyl group pyridazine-3 (2H)-ketone is synthetic

Add 2-benzyl-4 in a round-bottomed flask, (7.14g is 27.99mmol) with two _ alkane (125ml, anhydrous) for 5-dichloro-pyridazine-3 (2H)-ketone.In the reaction mixture that forms, slowly add 25%NaOMe/MeOH solution (6.98ml, 30.51mmol).Reaction mixture was at room temperature stirred 70 minutes.Water (200ml) dilution is subsequently poured the solution that forms in the separating funnel into, uses CH ₂Cl ₂(2 * 100ml) extractions.The organic layer that merges is washed with NaCl saturated aqueous solution (10ml).Organic layer is used MgSO then ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.This crude product is used 0-5%MeOH/CH with automatic column chromatography system (ISCO, 120g silica gel) purifying ₂Cl ₂Wash-out obtains product 2-benzyl-5-chloro-4-methoxyl group pyridazine-3 (2H)-ketone, is colorless oil (6.5g, productive rate 93%).HPLC retention time (method A) 3.090min; LCMS (M+H)=251.2.

4C.2-benzyl-5-(4-chloro-phenyl-)-4-methoxyl group pyridazine-3 (2H)-ketone is synthetic

In a round-bottomed flask, add 2-benzyl-5-chloro-4-methoxyl group pyridazine-3 (2H)-ketone (25.1g, 0.1mmol), the 4-chlorophenylboronic acid (17.215g, 0.11mmol), Pd (PPh ₃) 4 (9.24g, 0.008mmol), toluene (200ml), EtOH (200ml) and 2.0N Na ₂CO ₃(200ml, 0.4mmol).Reaction mixture is used argon gas purge 10 minutes, is heated to 120 ℃ then, stirs 18 hours in this temperature.After this reaction mixture is cooled to room temperature, pours in the separating funnel separates two into.Water layer extracts with EtOAc (50ml).The organic layer that merges is washed with 1N NaOH (200ml), water (200ml) and NaCl saturated aqueous solution (200ml).Organic layer is used MgSO then ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.This crude product is used 0-30%EtOAc/CH with automatic column chromatography system (ISCO, 330g, silica gel) purifying ₂Cl ₂Gradient elution obtains product 2-benzyl-5-(4-chloro-phenyl-)-4-methoxyl group pyridazine-3 (2H)-ketone (33g, productive rate 99%), is light yellow solid.HPLC retention time (method A) 3.740min; LCMS (M+H)=327.2.

4D.2-benzyl-4-chloro-5-(4-chloro-phenyl-) pyridazine-3 (2H)-ketone is synthetic

In a round-bottomed flask, add 2-benzyl-5-(4-chloro-phenyl-)-4-methoxyl group pyridazine-3 (2H)-ketone (32.7g, 0.1mmol) and POCl ₃(80ml).Reaction mixture is heated to 80 ℃, and under this temperature, stirred 3 hours.Solution is cooled to room temperature, and concentrating under reduced pressure is to remove POCl ₃The residue that forms cools off with ice-water bath, and slowly adds ice-water (50ml) in 15 minutes in reaction flask, adds water (400ml) then, is settled out solid.Reaction mixture is filtered, collect solid.Crude product with 0-40%EtOAc/ hexane gradient wash-out, obtains beige solid product (30g, productive rate 91%) with automatic column chromatography system (ISCO, 330g silica gel) purifying.HPLC retention time (method A) 3.491min; LCMS (M+H)=331.2.

4E.4-(2-benzyl-5-(4-chloro-phenyl-)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene is synthetic

In tube sealing, add 2-benzyl-4-chloro-5-(4-chloro-phenyl-) pyridazine-3 (2H)-ketone (3.31g, 10.0mmol), 4-cyano-phenyl boric acid (2.94g, 20mmol), Pd (dppf) Cl ₂The methylene dichloride complex compound (0.817g, 1.0mmol), potassiumphosphate (6.36g, 30mmol) and THF (10ml).

Reaction soln is used argon-degassed 5 minutes, be enclosed in the reaction tubes then.With reactant heat to 90 ℃, under this temperature, kept 4 hours then.Subsequently reaction mixture is cooled to room temperature, with EtOAc (50ml) dilution.Then reaction mixture is poured in the separating funnel, separated each layer.Organic layer water (20ml) and NaCl saturated aqueous solution (20ml) are washed.This organic layer is used MgSO subsequently ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.This crude product is with automatic column chromatography system (ISCO, 330g silica gel) purifying, and the EtOAc/ hexane wash-out with the 0-70% gradient obtains 3.65g (productive rate 92%) 4-(2-benzyl-5-(4-chloro-phenyl-)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene.HPLC retention time (method B) 3.81min; LCMS (M+H)=398.0.

4F.4-(2-benzyl-5-(4-chloro-phenyl-)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene is synthetic

Under room temperature and argon gas, (3.62g, 9.12mmol) suspension in toluene (50ml) adds AlCl to 4-(2-benzyl-5-(4-chloro-phenyl-)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene ₃(3.65g, 27.4mmol).Reaction mixture is heated to 80 ℃, stirred 4 hours in this temperature.Then solution is cooled to room temperature, concentrating under reduced pressure.Add frozen water (100ml) to reaction residue, the slurry that forms was stirred 20 minutes.Then with EtOAc with solution dilution, separate each layer.(2 * 50ml) extract water layer with EtOAc.The organic layer that merges is washed with 1N NaOH (50ml).Subsequently with organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.This crude product obtains 2.21g (productive rate 79%) 4-(5-(4-chloro-phenyl-)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene with the development of EtOAc/ hexane.HPLC retention time (method B) 3.22min; LCMS (M+H)=308.0.

4G.4-(6-bromo-5-(4-chloro-phenyl-)-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene is synthetic

At room temperature to 4-(5-(4-chloro-phenyl-)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene (2.21g, 7.2mmol) suspension in 30ml methyl alcohol add the LiOH monohydrate (0.45g, 10.8mmol).With the mixture heating up to 70 that forms ℃, under this temperature, stirred 15 minutes.In reaction mixture, dropwise add Br then carefully ₂(2.3g, 14.4mmol).After adding, Br ₂Color after 2 minutes, disappear.The HPLC Indicator Reaction has finished 40%.Add successively then the bromine add (～0.8g, 5mmol) and the LiOH monohydrate (0.21g, 5mmol).It is depleted to add in back 2 minutes bromine.Then reaction mixture is cooled to room temperature, removal of solvent under reduced pressure, the residue of formation is from acetone (reconcentration in 2 * 20ml).In the light brown residue that obtains, add 20ml DMF, under room temperature and Ar gas, add subsequently a hydration LiOH (0.612g, 14.40mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl) pyridine (1.65g, 7.91mmol).Reaction mixture is heated to 70 ℃, stirred 1 hour under this temperature, be cooled to room temperature then, water (50ml) and EtOAc (50ml) dilution were stirred 10 minutes.Separate each layer, organic phase is washed with NaCl saturated aqueous solution (100ml).Then with organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.This crude product with 20-80%EtOAc/ hexane gradient wash-out, obtains pale solid product (3.27g, productive rate 81%) with automatic column chromatography system (ISCO, 120g silica gel) purifying.HPLC retention time (method B) 3.91min; LCMS (M+H)=561.0.

4H.4-(5-(4-chloro-phenyl-)-6-diazanyl-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene is synthetic

In the microwave flask, add 4-(6-bromo-5-(4-chloro-phenyl-)-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene (105mg, 0.187mmol), pyridine (10ml) and anhydrous nitrile (60mg, 1.87mmol).With reaction mixture microwave heating to 200 ℃, under this temperature, continue to keep 1.5 hours.Then reaction mixture is cooled to room temperature, removes and desolvate, obtain yellow solid product.This product is used for next reaction, is not further purified.

4I.N '-(4-(4-chloro-phenyl-)-5-(4-cyano-phenyl)-1-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-1,6-dihydrogen dazin-3-yl) the propionyl hydrazine is synthetic

In a round-bottomed flask, add 4-(5-(4-chloro-phenyl-)-6-diazanyl-2-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-3-oxygen-2,3-dihydrogen dazin-4-yl) cyanobenzene (96mg, 0.187mmol), THF (3ml), Et ₃N (37.8mg, 0.374mmol) and propionyl chloride (17.3mg, 0.187mmol).The reaction mixture that forms was at room temperature stirred 20 minutes, use EtOAc (30ml) dilution then.Pour the solution that forms in separating funnel layering.The organic layer water (2 * 10ml) and NaCl saturated aqueous solution (10ml) wash.Then with organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.This crude product is with automatic column chromatography system (ISCO, 4g silica gel) purifying, with 20-80%EtOAc/ hexane gradient wash-out, obtain product N '-(4-(4-chloro-phenyl-)-5-(4-cyano-phenyl)-1-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-1,6-dihydrogen dazin-3-yl) propionyl hydrazine, be light yellow solid, 50g (two step productive rates 40%).HPLC retention time (method A) 2.941min; LCMS (M+H)=567.3.

4J.4-(8-(4-chloro-phenyl-)-3-ethyl-5-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-5,6-dihydro-[1,2,4] triazolo [4,3-b] pyridazine-7-yl) cyanobenzene is synthetic

In round-bottomed flask, add N '-(4-(4-chloro-phenyl-)-5-(4-cyano-phenyl)-1-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-1,6-dihydrogen dazin-3-yl) propionyl hydrazine (45mg, 0.0794mmol) and toluene (3ml).Reaction mixture is heated to 130 ℃, under this temperature, stirred 1 hour, add POCl then ₃(1ml), 130 ℃ of restir 4 hours.Subsequently reaction mixture is cooled to room temperature, concentrating under reduced pressure.Residue is dissolved among the EtOAc (30ml), and the solution of formation is washed with 0.5N NaOH (10ml), water (15ml), NaCl saturated aqueous solution (10ml).Organic layer MgSO ₄Pulp is filtered and is concentrated to remove unnecessary water, obtains crude product.This crude product is with automatic column chromatography system (ISCO, 4g silica gel) purifying, with 65-100%EtOAc/ hexane wash-out, obtain product 4-(8-(4-chloro-phenyl-)-3-ethyl-5-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-6-oxygen-5,6-dihydro-[1,2,4] triazolo [4,3-b] pyridazine-7-yl) cyanobenzene (30mg), be pale solid, productive rate 69%.HPLC retention time (method A) 3.110min;

LCMS(M+H)＝549.4. ¹HNMR(CDCl ₃，500Hz)：7.49-7.53(3H，m)，7.35-7.37(1H，m)，7.22-7.24(6H，m)，5.57(2H，s)，2.73(2H，q)，2.65(3H，s)，1.38(3H，t)； ¹³CNMR(CDCl ₃，500Hz)159.8，155.7，148.6，147.5(q)，143.9，138.0，137.1，136.6，133.5，131.9，131.8，128.9，120.8(q)，118.6，118.2，112.6，49.2，22.2，20.5，12.4.

Embodiment 5

7,8-two (4-chloro-phenyl-)-6-(4-methoxyl group benzyloxy base)

Synthesizing of-[1,2,4] triazolos [4,3-b] pyridazine

5A.6-fluoro-7,8-two (4-chloro-phenyl-)-[1,2,4] triazolo [4,3-b] pyridazine synthetic

In round-bottomed flask, add 3,6-two chloro-4,5-two (4-chloro-phenyl-) pyridazine (1.55g, 4.201mmol), pyridine (10ml) and hydrazine hydrate (617mg, 12.602mmol).Reaction mixture was stirred 4 hours at 120 ℃.Then reaction mixture is concentrated near dry, in the residue that forms, adds water (50ml), form solid.Solid collected by filtration obtains beige solid product 3-chloro-4,5-two (4-chloro-phenyl-)-6-diazanyl pyridazine (1.53g, productive rate 99%).HPLC retention time (method A) 2.740min; LCMS (M+H)=365.1.

5B.6-chloro-7,8-two (4-chloro-phenyl-)-[1,2,4] triazolo [4,3-b] pyridazine synthetic

In round-bottomed flask, add 3-chloro-4, and 5-two (4-chloro-phenyl-)-6-diazanyl pyridazine (3.0g, 8.2mmol) and formic acid (15ml).Reaction mixture 120 ℃ of heating 2 hours, is cooled to room temperature then, pours into (100ml) in the water, be settled out solid.Solid collected by filtration obtains product 6-chloro-7, and 8-two (4-chloro-phenyl-)-[1,2,4] triazolo [4,3-b] pyridazine is gray solid (2.8g, productive rate 91%).LCMS(M+H)＝376.9； ¹H?NMR(CDCl ₃，400Hz)：9.16(1H，s)，7.38-7.40(4H，m)，7.37(2H，d)，7.15(2H，d)。

5C.7,8-two (4-chloro-phenyl-)-6-(4-methoxyl group benzyloxy base)-[1,2,4] triazolo [4,3-b] pyridazine synthetic

In round-bottomed flask, add 6-chloro-7,8-two (4-chloro-phenyl-)-[1,2,4] triazolo [4,3-b] pyridazine (37.6mg, 0.10mmol), 4-anisole methyl alcohol (0.15mmol), THF (1ml) and 2-tertbutylimido-2-diethylamino-1,3-dimethyl perhydro-1,3, and 2-diaza phosphorus heterocycle hexene (BEMP) (30mg, 0.11mmol).Reaction mixture is heated to 50 ℃, under this temperature, stirred 40 hours.Remove and desolvate, residue preparation HPLC purifying obtains pure products 7, and 8-two (4-chloro-phenyl-)-6-(4-methoxyl group benzyloxy base)-[1,2,4] triazolo [4,3-b] pyridazine is solid product.HPLC retention time (method C) 7.91min; LCMS (M+H)=477.10.

Embodiment 6

7,8-two (4-chloro-phenyl-)-3-(trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone synthetic

Title compound is by 6-chloro-7, and 8-two (4-chloro-phenyl-)-3-(trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazine and TMSOK synthesizes according to the above-mentioned steps reaction.

¹HNMR(DMSO，400Hz)：7.48(2H，d)，7.38-7.7.42(4H，?m)，7.25(2H，d). ¹³CNMR(DMSO，400Hz)16；0.88，145.91，137.00，135.11，133.90，132.94，132.10，131.07，129.98，128.00?127.13，118.30(q).

Following compound utilization and embodiment 2 are for 7, and the synthetic described similar step of 8-two (4-chloro-phenyl-)-3-methyl-5-(4-(trifluoromethyl) benzyl)-[1,2,4] triazolo [4,3-b] pyridazines-6 (5H)-ketone is synthetic.

HPLC retention time (method A) 3.836min HPLC retention time (method A) 3.580min

LCMS(M+H)＝515.0 LCMS(M+N)＝516.2

， ，

HPLC retention time (time A) 3.783min HPLC retention time (method A) 3.918min

LCMS(M+H)＝529.1 LCMS(M+H)＝583.1

， ，

HPLC retention time (method A) 3.856min HPLC retention time (method A) 3.886min

LCMS(M+H)＝543.2 LCMS(M+H)＝557.1

， 。

Following compound utilization and embodiment 3 are for 8-(4-chloro-phenyl-)-3-ethyl-5-((2-methyl-6-(trifluoromethyl) pyridin-3-yl) methyl)-7-(pyridin-4-yl)-[1,2,4] the synthetic described similar step of triazolo [4,3-b] pyridazines-6 (5H)-ketone is synthetic.

HPLC retention time (method A) 2.27min HPLC retention time (method A) 2.26min

LCMS(M+H)＝497.2 LCMS(M+H)＝511.2

’ ，

HPLC retention time (method A) 2.32min HPLC retention time (method A) 2.41min

LCMS(M+H)＝511.3 HRMS(M+H)＝476.1283

， ，

HPLC retention time (method A) 2.680min HPLC retention time (method A) 2.110min

LCMS(M+H)＝525.2 LCMS(M+H)＝525.2

， ，

HPLC retention time (method A) 2.295min HPLC retention time (method A) 2.363min

LCMS(M+H)＝539.3 LCMS(M+H)＝511.2

， ，

HPLC retention time (method A) 2.603min HPLC retention time (method A) 1.816min

LCMS(M+H)＝520.1 LCMS(M+H)＝467.2

， ，

HPLC retention time (method A) 1.625min HPLC retention time (method A) 2.548min

LCMS(M+H)＝453.2 LCMS(M+H)＝593.3

， 。

Following compound utilization and embodiment 5 are for 7, and the synthetic described similar step of 8-two (4-chloro-phenyl-)-6-(4-methoxyl group benzyloxy base)-[1,2,4] triazolo [4,3-b] pyridazine is synthetic.

HPLC retention time (method A) 4.11min HPLC retention time (method A) 4.09min

LCMS(M+H)＝529.0 LCMS(M+H)＝515.1

， ，

HPLC retention time (method A) 2.84min HPLC retention time (method A) 4.16min

LCMS(M+H)＝497.2 LCMS(M+H)＝543.1

， ，

HPLC retention time (method A) 4.21min HPLC retention time (method A) 3.75min

LCMS(M+H)＝557.0 LCMS(M+H)＝516.1

， ，

HPLC retention time (method A) 4.19min

LCMS(M+H)＝583.1

，

HPLC retention time (method C) 7.91min HPLC retention time (method C) 8.71min

MS(M+H)＝477.10 MS(M+H)＝531.09

， ，

HPLC retention time (method C) 7.97min HPLC retention time (method C) 6.72min

MS(M+H)＝500.13 MS(M+H)＝471.13

， ，

HPLC retention time (method C) 8.33min HPLC retention time (method C) 6.09min

MS(M+H)＝511.16 MS(M+H)＝488.10

， ，

HPLC retention time (method C) 8.04min HPLC retention time (method C) 5.57min

MS(M+H)＝477.10 MS(M+H)＝448.11

， ，

HPLC retention time (method C) 5.50min HPLC retention time (method C) 6.25min

MS(M+H)＝448.11 MS(M+H)＝476.14

， ，

HPLC retention time (method C) 6.53min HPLC retention time (method C) 9.01min

MS(M+H)＝462.13 MS(M+H)＝544.22

， ，

HPLC retention time (method C) 7.75min HPLC retention time (method C) 8.31min

MS(M+H)＝491.10 MS(M+H)＝505.13

， 。

Biological assessment

The cannabinoid receptor binding test

The research of radioligand associativity is carried out in the cytolemma that Chinese hamster ovary (CHO) cell (CHO-CB-1 cell) by overexpression recombinant human CB-1 prepares.The overall test volume of associativity research is 100 μ l.5 μ g films are with testing damping fluid (25mM HEPES, 150mMNaCl, 2.5mM CaCl ₂, 1mM MgCl ₂, 0.25%BSA) being supplemented to final volume is 95 μ l.The film of dilution is with compound or the preincubation of DMSO carrier.Adding ultimate density is 2nM's ³H-CP-55,940 (120Ci/mmol) make the reaction beginning, at room temperature carry out 2.5 hours.This association reaction stops by with the Packard cell harvester reactant transfer being gone up to GF/B 96 orifice plates (soaking with 0.3% polymine in advance).Filter is washed with 0.25 * PBS, adds 30 μ l MicroScint in every hole, utilizes scintillation counting technique quantitative assay bonded radioactively labelled substance on Packard TopCount scintillometer.The test of CB-2 radioligand associativity is carried out equally, only is to use the film that derives from the CHO-CB-2 cell.

For the compound of thinking the CB-1 antagonist, the CB-1 receptor affinity Ki of this compound must be less than 13000nM.With above-mentioned test determination the time, the CB-1 receptor affinity Ki value of work embodiment 1-63 is in the scope of 0.01nM to 10000nM.

The test of Cannabined receptor functionally active

The functional CB-1 inverse agonists activity of test compound accumulates test determination with cAMP in the CHO-CB-1 cell.The CHO-CB-1 cell grows in 96 orifice plates near merging.Siphoned away growth medium the same day in function test, and (PBS adds 2mM HEPES/0.1mM 3-isobutyl-1-methylxanthine/0.1%BSA) to add 100 μ l test damping fluid.Compound is added to in 1: 100 the test damping fluid of 100%DMSO dilution, and preincubation 10 minutes adds 5 μ M forskolins then.This mixture was at room temperature placed 15 minutes, added 0.1N HCl termination reaction then.Quantitatively determine cAMP total concn in the born of the same parents with Amersham cAMP SPA test kit.

Use and associating

Use

The compounds of this invention is a Cannibinoid receptor modulators, comprises as for example compound of selective agonist, partial agonist, inverse agonists, antagonist or the partial antagonist of Cannabined receptor.Therefore, The compounds of this invention can be used for active diseases associated of treatment or prevention and G-albumen coupling Cannabined receptor and obstacle.Preferably, The compounds of this invention has the activity as the antagonist or the inverse agonists of CB-1 acceptor, and can be used for treating active diseases associated or obstacle with the CB-1 acceptor.

Therefore, The compounds of this invention can be to Mammals, preferably to people's administration, be used for the treatment of various disease conditions and obstacle, include but not limited to: metabolism and eating disorder, and the illness relevant with metabolic disturbance (for example, obesity, diabetes, arteriosclerosis, hypertension, PCOD, cardiovascular diseases, osteoarthritis, tetter, insulin resistant, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and somnopathy, hyperlipidaemia, bulimia nervosa and mandatory eating disorder) or mental disorder, for example substance abuse, dysthymia disorders, anxiety, mania and schizophrenia.These compounds also can be used to improve cognitive function (for example, treatment is dull-witted, comprises alzheimer's disease, short-term memory forfeiture and attention deficit); Neurodegenerative disease (for example, Parkinson's disease, cerebral crisis and craniocerebral trauma) and ypotension (for example ypotension of hemorrhagic or endotoxin induced).These compounds also can be used for treating the katabolism relevant with the respirator dependence with suboptimal pulmonary function; Treatment heart function bad (for example with valvular heart disease, myocardial infarction, megalocardia or congestive heart failure are relevant); Improve whole pulmonary function; Transplant rejection; Rheumatoid arthritis; Multiple sclerosis; Inflammatory bowel; Lupus; Graft versus host disease (GVH disease); The supersensitivity that T is cell-mediated; Psoriasis; Asthma; Hashimoto thyroiditis; Ji-Ba syndromes, cancer, contact dermatitis, rhinallergosis, and ischemia or reperfusion injury.

Can be used for treating the compound of desire or motivation obstacle, regulate the hope of consumption sugar, carbohydrate, alcohol or medicine, more generally is the consumption of regulating the composition with pleasant sensation value.In this explanation and claim, the desire obstacle is understood as that and means: with material, and the relevant obstacle of substance abuse and/or substance depilatory particularly; The feed behavior disorder particularly causes overweight feed behavior disorder easily, no matter how it originates from, for example: bulimia nervosa, sugar craving.Therefore the present invention also relates to use CB-1 receptor antagonist or inverse agonists treatment exessive appetite and obesity, comprise and the relevant obesity of type ii diabetes (non-insulin-dependent diabetes mellitus (NIDDM)), perhaps more generally, the disease that any patient of causing becomes overweight.Said herein obesity is defined as body surface index (kg/m ²) be at least 26.It can be caused by any reason, no matter be reason heredity or environment, comprise and surfeiting and voracity, PCOD, craniopharyngioma, Pu-Wei syndromes, the Froechlich syndromes, type ii diabetes, tethelin defective, Tener syndromes and reduce or energy expenditure is reduced to other pathological state of feature with metabolic activity.The term " treatment " that uses in application facet as herein described comprise prevent, part alleviation or cure diseases or obstacle.In addition, the treatment expection of obesity can stop the fat related indication progress of medical science, for example arteriosclerosis, type ii diabetes, PCOD, cardiovascular diseases, osteoarthritis, tetter, hypertension, insulin resistance, hypercholesteremia, hypertriglyceridaemia, cholelithiasis and somnopathy.

Compound of the present invention also can be used for therapeutant abuse obstacle, comprises substance depilatory or does not have the abuse of physical dependence.The material of abuse comprises alcohol, Amphetamine (or amphetamine-type material), caffeine, hemp, Cocaine, halluoinogen, inhalation, Nicotine, opioid, phencyclidine (or Phencyclidines material), calmness-soporific or benzodiazepine _ class, and the material of other (or unknown) or the combination of above material." substance abuse obstacle " speech comprises that also medicine or alcohol gives up syndromes and material brings out during giving up anxiety or emotional handicap outbreak.

Compound among the present invention can be used for treating memory impairment and cognitive disorder.It is impaired and/or can not recall the information of before having learned that the symptom of memory impairment is shown as the ability of study fresh information.Memory impairment is dull-witted initial stage symptom, also can be with such as alzheimer's disease, schizophrenia, Parkinson's disease, Huntington Chorea, Pick's disease, Ke-Ya Shi disease, HIV, cardiovascular diseases, head trauma and with the age relevant relevant symptoms of disease such as cognitive function decline.Dementia comprises other intellectual damage outside the loss of memory and the memory.Cannibinoid receptor modulators also can be used for treating the cognitive impairment relevant with attention deficit, for example attention deficit disorder (ADD).

The compounds of this invention also can be used for treatment and brain dopaminergic system dysfunction diseases associated, for example Parkinson's disease and substance abuse obstacle.Parkinson's disease are that a kind of trembling with the mitigation of moving is the neurodegeneration dyskinesia of feature.

As the conditioning agent of Cannabined receptor, The compounds of this invention also can be used for treatment and prevention respiratory disease and obstacle.The respiratory disease that Cannibinoid receptor modulators can be used for includes but not limited to: chronic respiratory blocks sick, pulmonary emphysema, asthma and bronchitis.In addition, Cannibinoid receptor modulators blocking-up pulmonary epithelial cells is by activation such as for example allergic test, inflammatory cytokine or cigarettes, thus restriction Saliva Orthana, cytokine and chemotactic because of release, or optionally suppress the pulmonary epithelial cells activation.

In addition, the compound that uses among the present invention can activated cell in, particularly white corpuscle, pulmonary epithelial cells or the inhibition passage in the two, thus can be used for treating this type of disease." leukocyte activation " is defined as any or all cell proliferation, cytokine generation in this article, adhesion protein is expressed and inflammatory mediator produces." epithelial cell activation " is defined as the generation that any or all Saliva Orthanas, cytokine, chemokine and adhesion protein are expressed.

The The compounds of this invention treatment comprises with the example of the application of leukocyte activation diseases associated, but be not limited to, the treatment various diseases is for example: graft (organ graft for example, acute graft, xenotransplant thing or heterograft or homotransplant (for example in burn treatment, adopting)) repel; Protection ischemia or reperfusion injury, for example ischemia or the reperfusion injury that in organ transplantation, myocardial infarction, apoplexy or other reason, takes place; The transplantation tolerance introducing; Sacroiliitis (for example rheumatoid arthritis, psoriatic arthritis or osteoarthritis); The multiple sclerosis disease; Respiratory tract and pulmonary disorder include but not limited to, chronic obstructive pulmonary disease (COPD), pulmonary emphysema, bronchitis and acute respiratory distress syndrome (ADRS); Inflammatory bowel comprises ulcerative colitis and Crohn's disease; Lupus (systemic lupus erythematous); Graft versus host disease (GVH disease); The hypersensitization venereal disease that T-is cell-mediated comprises the contact-type supersensitivity, delaying type supersensitivity and seitan susceptibility enteropathy (celiac disease); Psoriasis; Contact dermatitis (comprise and causing) by toxicodendron; Hashimoto thyroiditis; House Glenn syndromes; From autoimmune thyroid hyperfunction, for example Graves disease; Addison disease (' suprarenal gland is from immunological disease); Polyadenous systemic autoimmune disease (being also referred to as polyadenous systemic autoimmune syndromes); The autoimmunity baldness; Pernicious anemia, vitiligo, from the immunity hypopituitarism, Ji-Ba syndromes, other autoimmune disease, glomerulonephritis, serum sickness, urticaria; Allergic disease, for example respiratory allergies (asthma, spring fever, allergic rhinitis) or skin allergic reaction; Scleroderma, mycosis fungoides, acute inflammation and breathing response (for example acute respiratory distress syndrome and ischemia/reperfusion injury); Dermatomyositis, alopecia circumscripta, chronic actinic dermatitis, eczema, Behchet's syndromes, palm toe pustulosis, PG, Sai Zeli syndromes, atopic dermatitis, systemic sclerosis and morphea.Term used herein " relevant with leukocyte activation " or " the leukocyte activation mediation " disease comprise above-mentioned various diseases or obstacle.In a specific embodiment, The compounds of this invention can be used for treating above-mentioned exemplary disease, no matter its cause of disease how.The present invention does exercises monocyte, scavenger cell, T-cell etc. be can be used for treating any above-mentioned disease in conjunction with activity.

Cannabined receptor is important for the Fc-γ acceptor response of regulating monocyte and scavenger cell.Depend on the production of the TNF α of Fc-γ in The compounds of this invention inhibition people's the monocyte/macrophage.The ability of this inhibition Fc γ acceptor dependency monocyte and scavenger cell response has caused the extra antiphlogistic activity of The compounds of this invention.This activity is for the treatment inflammatory diseases, and for example sacroiliitis or inflammatory bowel are valuable especially.Particularly, The compounds of this invention can be used for treating autoimmunization glomerulonephritis and brightic other situation of being brought out in the deposition in kidney by immunocomplex, and this mixture triggers the response of Fc-γ acceptor, causes injury of the kidney.

Cannabined receptor is expressed in the pulmonary epithelial cells.These cells are the excretory reasons that cause Saliva Orthana and inflammatory cytokine/chemokine in the lung, thereby are involved in the generation and the progress of respiratory tract disease intricately.Cannibinoid receptor modulators is regulated the spontaneous and generation that be excited of Saliva Orthana and cytokine.Therefore, these compounds can be used for treating respiratory tract and pulmonary disorder, comprise COPD, ARDS and bronchitis.

In addition, Cannabined receptor can be expressed on the intestinal epithelial cells, and therefore regulates cytokine and Saliva Orthana production, may in the treatment inflammatory diseases relevant with intestines clinical application be arranged.Cannabined receptor also is expressed on the lymphocyte as a subsystem of white corpuscle.Therefore, Cannibinoid receptor modulators can suppress B and T cell activation, propagation and differentiation.So these compounds can be used for treating the autoimmune disease that relates to antibody or cell-mediated response, for example multiple sclerosis and lupus.

In addition, Cannabined receptor is also regulated the mastocyte that Fc-epsilon receptor and chemokine bring out and the flailing action of basophilic leukocyte.This plays an important role in asthma, rhinallergosis and other allergic disease.The Fc-epsilon receptor is excited by the IgE-antigenic compound.The compounds of this invention suppresses the threshing response that Fc-ε brings out, and comprises basophilic leukocyte system, RBL.The ability of this inhibition Fc-epsilon receptor dependent mast cells and basophilic leukocyte response has caused the extra anti-inflammatory and the anti-allergic activity of The compounds of this invention.Particularly, The compounds of this invention can be used for treating the allergic disease of asthma, rhinallergosis and other situation.

Associating

The present invention comprises pharmaceutical composition in its scope, contain at least a formula I compound as the treatment significant quantity of activeconstituents in the composition, it can Individual existence or with a kind of pharmaceutical carrier or thinner associating.Randomly, The compounds of this invention can use separately or share with other the suitable medicine that can be used for treating above-mentioned illness, comprising: diet pill, and antidiabetic drug reduces the appetite medicine; Decreasing cholesterol/fat medicine improves the HDL medicine, strengthens the cognitive ability medicine, treats neurodegenerative medicine, the medicine of treatment respiratory symptom, the medicine of treatment enteropathy, antiphlogistic drug; Anxiolytic; Thymoleptic; Depressor; Cardiac glycoside; And antitumor drug.

Other these medicines can be before taking Cannibinoid receptor modulators of the present invention, simultaneously or administration afterwards.

The diet pill that suitable and The compounds of this invention is united use comprise novel melanocortin receptor (MC4R) agonist, melanin concentrating hormone receptor (MCHR) antagonist, secretagogue receptor (GHSR) antagonist, the galanin receptors conditioning agent, orexin antagonists, the CCK agonist, GLP-1 agonist and other preceding former hyperglycemic-glycogenolytic factor derived peptide; NPY1 or NPY5 antagonist, NPY2 and NPY4 conditioning agent, the corticotropin releasing factor agonist, Histamine Receptors-3 (H3) conditioning agent, aP2 inhibitor, PPAR gamma modulators, PPAR δ conditioning agent, acetyl-CoA carboxylase (ACC) inhibitor, 11-β-HSD-1 inhibitor, adiponectin receptor conditioning agent; 'beta '3 adrenergic agonists, for example AJ9677 (Takeda/Dainippon), L750355 (Merck) or CP331648 (Pfizer) or in U.S. Patent No. 5,541,204,5,770,615,5,491,134,5,776, disclosed other known β 3 agonists in 983 and 5,488,064; Thryoid receptor β conditioning agent, for example disclosed ligands for thyroid receptor in WO 97/21993 (U.Cal SF), WO 99/00353 (KaroBio) and WO 00/039077 (KaroBio); Lipase inhibitor, for example Ao Lisitai or ATL-962 (Alizyme); Serotonin receptor agonist (for example BVT-933 (Biovitrum)), monoamine reuptake inhibitors or releasing agent, for example Phenfluoramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, Sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, Dextrofenfluramine, phentermine, Phenylpropanolamine or Mazindol; Appetite-inhibiting agent, for example topiramate (Johnson﹠amp; Johnson), CNTF (ciliary neurotrophic factor)/Axokine_ (Regeneron), BDNF (neurotrophic factor derived from brain), Leptin and Leptin receptor modulators, perhaps cannaboid-1 receptor antagonist, for example SR-141716 (Sanofi) or SLV-319 (Solvay).

The example that suitable and The compounds of this invention is united the antidiabetic drug of use comprises: Regular Insulin succagoga or insulin sensitizer, comprise biguanides, sulfonylurea, glucosidase inhibitor, aldose reductase inhibitor, PPAR gamma agonist (for example thiazolidinedione), PPAR alfa agonists (for example fiber acid derivative), PPAR delta antagonist or agonist, PPAR α/γ dual agonists, 11-β-HSD-1 inhibitor, DPP IV (DP4) inhibitor, SGL T2 inhibitor, glycogen phosphorylase inhibitors, and/or meglitinides, and Regular Insulin, and/or glucagon-like-peptide-1 (GLP-1), GLP-1 agonist and/or PTP-1B inhibitor (Protein-tyrosine-phosphatase-1B inhibitor).

This antidiabetic drug can be oral antihyperglycemic, preferably a kind of biguanides, for example N1,N1-Dimethylbiguanide or phenformin or its salt, preferably Metformin.At antidiabetic drug is a kind of situation of biguanides, the consumption of The compounds of this invention and the weight ratio of biguanides at about 0.001: 1 to about 10: 1 scope, preferably from about 0.01: 1 to about 5: 1.

Antidiabetic drug is sulfonylurea preferably also, Glyburide for example, glimepiride (is disclosed in United States Patent (USP) 4,379,785), Glipizide, gliclazide or P-607, other known sulfonylurea or other the antihyperglycemic that influences β cell ATP dependency passage, preferred Glyburide and Glipizide, they can be same or divide administration in other oral dosage form.Oral antidiabetic drug also can be a kind of glucosidase inhibitor, and for example acarbose (is disclosed in United States Patent (USP) 4,904,769) or miglitol (be disclosed in United States Patent (USP) 4,639,436), they can be same or divide administration in other oral dosage form.

The compounds of this invention can be united use with the PPAR gamma agonist, for example thiazolidinedione oral antidiabetic or other insulin sensitizer (NIDDM patient is had the insulin sensitivity effect), for example the MCC-555 of Rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi company (is disclosed in United States Patent (USP) 5,594,016), the GL-262570 of Glaxo-Well-come company, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), Yi Shalie ketone (MIT/J﹠amp; J), JTT-501 (JPNT/P﹠amp; U), L895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN) or YM-440 (Yamanouchi), preferred Rosiglitazone and pioglitazone.

The compounds of this invention can be united use with PPAR α/γ dual agonists, for example (Merck/Kyorin is as at Yajima etc., Am.J.Physiol.Endocrinol.Metab. for MK-767/KRP-297, described in the 284:E966-E971 (2003)), AZ-242 (tesaglitazar; Astra-Zeneca; As at Ljung etc., J.Lipid Res., 43, described in the 1855-1863 (2002)); Muraglitazar; Or at United States Patent (USP) 6,414, the compound described in 002.

The compounds of this invention can or be used for treating arteriosclerotic medication combined use with antihyperlipidemic.An example of hypolipidemic is a HMG CoA reductase inhibitor, includes but not limited to mevastatin and United States Patent (USP) 3, the related compound of describing in 983,140, lovastatin and United States Patent (USP) 4, disclosed related compound in 231,938, Pravastatin and for example United States Patent (USP) 4, disclosed related compound in 346,227, Simvastatin and United States Patent (USP) 4,448, disclosed related compound in 784 and 4,450,171.Operable other HMG CoA reductase inhibitor, include but not limited to, United States Patent (USP) 5,354, disclosed fluvastatin in 772, United States Patent (USP) 5,006,530 and 5,177, disclosed Cerivastatin in 080, United States Patent (USP) 4,681,893,5,273,995,5,385,929 and 5,686, disclosed atorvastatin in 104, United States Patent (USP) 5,011, disclosed pitavastatin in 930 (Buddhist nun of Nissan/Sankyo company cut down him spit of fland (NK-104) or itavastatin), United States Patent (USP) 5,260,440 disclosed Shionogi-Astra/Zeneca superstatins, and United States Patent (USP) 5, disclosed relevant statin compound in 753,675, United States Patent (USP) 4,613, the pyrazole analogs of disclosed methyl dihydroxy pentanone derivative in 610, the indenes analogue of disclosed methyl dihydroxy pentanone derivative among the PCT application WO86/03488, United States Patent (USP) 4,647, disclosed 6-[2-in 576 (pyrroles of replacement-1-yl) alkyl) pyran-2-one and derivative thereof, the SC-45355 of Searle company (glutaric acid derivatives that a kind of 3-replaces) dichloro acetic acid ester, the imidazoles analogue of disclosed methyl dihydroxy pentanone among the PCT application WO 86/07054, French Patent 2, disclosed 3-carboxylic acid in 596,393-2-hydroxyl propyl-phosphine acid derivative, disclosed furans and thiophene derivant among the european patent application No.0221025, United States Patent (USP) 4, the naphthyl analogue of disclosed methyl dihydroxy pentanone in 686,237, United States Patent (USP) 4,499, disclosed octahydro naphthalene compound in 289, european patent application No.0,142, the keto analog of disclosed lovastatin among the 146A2, with United States Patent (USP) 5,506,219 and 5, disclosed quinoline and pyridine derivate in 691,322.In addition, in GB 2205837, disclose and be suitable for the phospho acid that are used for suppressing HMG CoA reductase enzyme of the present invention.

Be suitable for inhibitor for squalene synthetic enzyme of the present invention and include but not limited to, United States Patent (USP) 5,712; disclosed alpha-phosphonosulfonate in 396, Biller etc. be at J.Med.Chem., and 31; those disclosed among the 1869-1871 (1998) comprises isoprenoid (phosphinyl methyl) phosphonic acid ester and other known inhibitor for squalene synthetic enzyme, for example at United States Patent (USP) 4; 871; 721 and 4,924,024 and Biller; S.A.; Neuenschwander, K., Ponpiom; M.M.; and Poulter, C.D., Current Pharmaceutical Design; 2, those that disclose among the 1-40 (1996).

In addition, be suitable for other inhibitor for squalene synthetic enzyme of the present invention and also comprise P.Ortizde Montellano etc., J.Med.Chem.20, disclosed terpenoid pyrophosphate among the 243-249 (1977); Corey and Volante, J.Am.Chem.Soc., 98, disclosed bisphosphate farnesol ester analogs A and preceding squalene pyrophosphate (PSQ-PP) analogue among the 1291-1293 (1976); McClard, R.W. etc. be at J.Am.Chem.Soc., and 109, the phosphinyl phosphonic acid ester of report in 5544 (1987), and Capson, T.L., PhD dissertation, June, 1987, Dept.Med.Chem.U of Utah, Abstract, Table of Contents, pp 16,17,40-43,48-51, the cyclopropane compound of Summary report.

Being suitable for other hypolipidemic of the present invention includes but not limited to, fiber acid derivative, for example fenofibrate, gemfibrozil, chlorine Bei Te, bezafibrate, Win-35833, S-8527 etc., probucol, and United States Patent (USP) 3, disclosed related compound in 674,836, preferred probucol and gemfibrozil; Cholic acid chelating agent, Colestyramine for example, colestipol and DEAE-sephadex (SECHOLEX, POLICEXIDE) and Cholestagel (Sankyo/Geltex), and phosphatidylcholine (Rhone-Poulenc), Eisai E-5050 (ethanolamine derivant that a kind of N-replaces), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), amino cyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivatives), linolexamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivativess), nicotinic acid, acipimox, Acifran, Xin Meisu, para-aminosalicylic acid, Asprin, United States Patent (USP) 4,759, disclosed poly-(diallyl methylamine) derivative in 923, United States Patent (USP) 4,027, poly-(diallyldimethylammonium chloride) and ionene of disclosed quaternary amine in 009, and other known serum cholesterol lowering agent.

Other hypolipidemic can be ACAT inhibitor (it also has the atherosclerosis activity), and is for example disclosed in following document: Drugs of the Future, and 24,9-15 (1999), (Avasimibe); " The ACAT inhibitor; C1-1011 is effective in the prevention andregression of aortic fatty streak area in hamsters ", Nicolosi et al., Atherosclerosis (Shannon, Irel), 137 (1), 77-85 (1998); " The pharmacological profile of FCE 27677:anovel ACAT inhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB 100-containing lipoprotein '; Ghiselli; Giancarlo; Cardiovasc.Drug Rev.; 16 (1), 16-30 (1998); " RP 73163:a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor ", Smith, C., et al., Bioorg.Med.Chem.Lett, 6 (1), 47-50 (1996); " ACAT inhibitors:physiologic mechanisms forhypolipidemic and anti-atherosclerotic activities in experimental animals ", Krause etal., Editor (s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation:Mediators Pathways, 173-98 (1995), Publisher:CRC, Boca Raton, Fla.; " ACATinhibitors:potential anti-atherosclerotic agents ", Sliskovic et al., Curr.Med.Chem., 1 (3), 204-25 (1994); " Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) ashypocholesterolemic agents.6.The first water-soluble ACAT inhibitor with lipid-regulating activity.Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) .7.Development of a series of substituted N-phenyl-N '-[(1-phenylcyclopentyl)-methyl] ureas with enhanced hypocholesterolemic activity '; Stout et al.; Chemtracts:Org.Chem.; 8 (6); 359-62 (1995); perhaps TS-962 (Taisho PharmaceuticalCo.Ltd), and F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

Hypolipidemic can be the up-regulator of ldl receptor live body, for example MD-700 (TaishoPharmaceutical Co.Ltd) and LY295427 (Eli Lilly).Hypolipidemic can be a kind of cholesterol absorption inhibitor, and the SCH48461 of preferred Schering-Plough company (Yi Ze is for a rice shellfish) is with at Atherosclerosis 115,45-63 (1995) and J.Med.Chem.41, those that disclose in 973 (1998).

It can be cholestery ester transfer protein inhibitors (CETP) that other lipid lowerers or lipid are regulated medicine, the CP-529 of Pfizer for example, 414 reach those disclosed in WO/0038722 and EP 818448 (Bayer) and EP 992496, with SC-744 and the SC-795 of Pharmacia, and CETi-1 and JTT-705.

Hypolipidemic can be a kind of ileum Na ⁺/ cholic acid cotransporter inhibitor, for example at Drugs of the Future, 24, disclosed among the 425-430 (1999).The ATP citrate lyase inhibitor that can be used for Combined Preparation of the present invention for example comprises those disclosed in the United States Patent (USP) 5,447,954.

Other lipid lowerers also comprises phytoestrogen compound, for example disclosed in WO 00/30665, comprise isolating soybean protein, soybean protein enriched material or bean powder, and isoflavones, for example Sophoricol, daidzin, Daidezin or Equol, perhaps disclosed plant sterol, phytostanols or tocotrienols in WO 2000/015201; Disclosed beta-lactam cholesterol absorption inhibitor among the EP 675714; The agent of HDL incremental adjustments, lxr agonist for example, PPAR α-agonist and/or FXR agonist; Disclosed LDL katabolism promotor among the EP 1022272; Sodium-proton exchange inhibitors, for example disclosed among the DE 19622222; Ldl receptor inductor or steroidal glycosides, for example United States Patent (USP) 5,698,527 and GB 2304106 in disclosed; Antioxidant, for example disclosed beta-carotene, xitix, alpha-tocopherol or vitamin A among the WO 94/15592, and vitamins C and a kind of anti-homocysteine medicine, for example folic acid, folate, vitamin B6, vitamin B12 and vitamin-E; Disclosed vazadrine among the WO 97/35576; Disclosed a kind of cholesterol absorption inhibitor among the WO 97/48701, a kind of HMG-CoA synthetase inhibitors, or a kind of lanosterol demethylase inhibitor; The PPAR delta agonists that is used for the treatment of dyslipidemia; Or as conjugated protein-1 (SREBP-1) of disclosed a kind of sterol regulatory element among the WO 2000/050574, sphingolipid for example, as ceramide, or neutral sphingomyelinase enzyme (N-SMase) or its segment.Preferred hypolipidemic is Pravastatin, lovastatin, Simvastatin, atorvastatin, fluvastatin, pitavastatin and superstatin, and nicotinic acid and/or Cholestagel.

The compounds of this invention can be united use with antihypertensive drug.The example that suitable and The compounds of this invention is united the antihypertensive drug of use comprises the Beta-3 adrenergic blocker, calcium channel blocker (L type and/or T type; For example, diltiazem _, verapamil, nifedipine and mybefradil), hydragog(ue) (for example, chlorothiazide, hydrochlorothiazide, flumethiazide, Hydroflumethiazide, Hydrex, methyl chlorothiazide, trichloromethiazide, polythiazide, benzothiazine, Ethacrynic Acid, tricrynafen, chlorthalidone, Furosemide, musolimine, bumetanide, the phenalgin butterfly is fixed, guanamprazine, spironolactone), renin inhibitor, ACE inhibitor (for example, captopril, zofenopril, fosinopril, enalapril, ceranopril, Yipingshu, delapril, pentopril, quinapril, Ramipril, lisinopril), the AT-1 receptor antagonist (for example, losartan, irbesartan, the figured silk fabrics yarn is smooth), the ET receptor antagonist (for example, sitaxentan, atrasentan and United States Patent (USP) 5,612,359 and 6,043, disclosed compound in 265), ET/AII dual antagonist (for example disclosed compound among the WO 00/01389), neutral endopeptidase (NEP) inhibitor, vasopeptidase inhibitors (NEP-ACE double inhibitor) (for example, omapatrilat and gemopatrilat), and nitrate esters.

Cannibinoid receptor modulators can be used for treating and other fat relevant disease, comprises somnopathy.Therefore, the medicine that can be used for and treat somnopathy of the compound described in the present invention is united use.The suitable associating with The compounds of this invention uses the example of the medicine for the treatment of somnopathy to comprise the melatonin analogue, the melatonin receptor antagonist, ML 1B agonist, the GABA receptor modulators, the nmda receptor conditioning agent, histamine-3 (H3) receptor modulators, dopamine agonist and orexin receptor conditioning agent.

Cannibinoid receptor modulators can reduce or alleviate substance abuse or habituation obstacle.Therefore, Cannibinoid receptor modulators can reduce the required dosage of present habituation treating dysfunction medicine or improve its effectiveness with the medication combined use that is used for treating the habituation obstacle.Being used for the example of medicine of therapeutant abuse and habituation obstacle is: selective serotonin reuptake inhibitor (SSRI), methadone, Lepetan, Nicotine and Bupropion.

Cannibinoid receptor modulators can anxiety reduction or depression; Therefore, the compound described in the application can be used to unite use with anxiolytic or thymoleptic.The example that is fit to unite the anxiolytic of use with The compounds of this invention comprises benzodiazepine _ (for example stable, lorazepam, oxazepam, alprazolam, zeisin, clonazepam, chlorine nitrogen _, halazepam and prazepam), 5HT1A receptor stimulant (buspirone for example, flesinoxan, gepirone and ipsapirone), and corticotropin releasing factor (CRF) antagonist.

The example that suitable and The compounds of this invention is united all kinds of thymoleptic of use comprises norepinephrine reuptake inhibitor (tertiary amine and secondary amine tricyclic antidepressant), selective serotonin reuptake inhibitor (SSRIs) (fluoxetine, fluvoxamine, paroxetine and Sertraline), oxidase inhibitor (MAOIs) (Isocarboxazid, Phenelzine, Tranylcypromine, selegiline), the reversible inhibitor of monoamine oxidase (RIMAs) (moclobemide), serotonin and norepinephrine reuptake inhibitor (SNRIs) (Venlafaxine), corticotropin releasing factor (CRF) receptor antagonist, alpha-2-adrenoceptor antagonists, with atypical antidepressive (Bupropion, lithium, nefazodone, trazodone and viloxazine).

Conventional antipsychotics and the associating of CB-1 receptor antagonist can strengthen the sx effect in psychosis or the mania treatment.In addition, such associating energy example is sx fast, reduces the needs that carry out long-term treatment with antipsychotic drug.Uniting so also can reduce needed antipsychotic effective dose, makes to take place that the common bad probability of motor function reduces in the long-term antipsychotic treatment.

The example that suitable and The compounds of this invention is united the antipsychotic drug of use comprises thiodiphenylamine (chlorpromazine, mesoridazine, thioridazine, Acetophenazine, Fluphenazine, trilafon and trifluoperazine), thioxanthene (chlorprothixene, tiotixene), heterocycle dibenzo azepine _ (leoponex, olanzapine and Aripiprazole), butyrophenone (haloperidol), diphenylbutylpiperidand (Mo Qiding) and indolone (molindolone) class antipsychotic drug.Have other antipsychotic drug of uniting the potential medical value of use and comprise loxapine, Sulpiride and risperidone with The compounds of this invention.

The compounds of this invention is united also with conventional antipsychotics schizoid treatment is produced the enhanced curative effect, as above to as described in the mania.Here said schizophrenia comprises bigoted property, entanglement, tonus, branch voltinism and residual schizophrenia, schizophrenia-like disorder, schizoaffective disorder, vain hope property mental disorder, brief psychotic disorders and undetermined mental disorder.The example that suitable and The compounds of this invention is united the antipsychotics of use comprises above-mentioned antipsychotics, and dopamine-receptor antagonist, muscarinic receptor agonist, 5HT2A receptor antagonist and 5HT2A/ dopamine-receptor antagonist or partial agonist (for example, olanzapine, Aripiprazole, risperidone, Ziprasidone).

The compound of describing among the present invention can be used for strengthening the effect of cognition enhancer, for example acetylcholinesterase inhibitor (as, tacrine), M-ChR-1 agonist (as, Milameline), nicotinic agonist, glutamate receptor (AMPA and NMDA) conditioning agent, and nootropics (as, piracetam, Levetiracetam).The suitable associating with The compounds of this invention uses the example of the medicine for the treatment of alzheimer's disease and cognitive disorder to comprise E2020, tacrine, revastigraine, 5HT6, inhibitors of gamma-secretase, beta-secretase inhibitors, SK channel blocker, Maxi-K blocker and KCNQ blocker.

Compound described in the present invention can be used for improving the curative effect of the medicine that uses in the treatment Parkinson's disease.The example that is used for treating Parkinsonian medicine comprises: the levodopa that adds or do not add the COMT inhibitor, antiglutamic acid energy medicine (amantadine, Riluzole), alpha-2 adrenergic antagonist (as Racemic idazoxan), the opiate antagonist (as, TREXUPONT), other dopamine agonist or transporter conditioning agent (as, Ropinirole), perhaps clarke rope or neurotrophic factor are as glial cell line derived neurotrophic factor (GDNF).

The compounds of this invention can be united use with suitable anti-inflammation drugs.The example that suitable and The compounds of this invention is united the anti-inflammation drugs of use comprises prednisone, dexamethasone, cyclooxygenase-2 inhibitors (promptly, COX-1 and/or cox 2 inhibitor, for example NSAID, Asprin, indomethacin, Ibuprofen BP/EP, piroxicam, Naproxen Base, celecoxib, ten thousand networks), the CTLA4-Ig agonist/antagonist, the CD40 ligand antagonists, IMPDH inhibitor (Mycophenolate Mofetil (Cell Cept for example ^_)), integrin antagonists, α-4 β-7 integrin antagonists, cell adhension inhibitors, the interferon-gamma antagonist, ICAM-1, tumour necrosis factor (TNF) antagonist is (for example, infliximab, OR1384 comprises the TNF-alpha inhibitor, for example tenidap, anti-THF antibody or soluble TNF acceptor, for example etanercept (Enbrel ^_), rapamycin (sirolimus or rapamycin) and leflunomide (Arava)), prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonist (for example Priliximab), P38 mitogen-activated protein kinase (PTK) inhibitor, IKK inhibitor, and the medicine (Zelnorm for example that is used for the treatment of irritable bowels syndrome ^_And Maxi-K ^_Opener, as United States Patent (USP) 6,184, those disclosed among the 231B1).

Can comprise with the example that Cannibinoid receptor modulators is united other medicine of use: ciclosporin class (for example ciclosporin A), anti--IL-2 acceptor (Anti-Tac), anti--CD45RB, anti--CD2, anti-CD-3 (OKT-3), anti--CD4, anti--CD80, anti--CD86, monoclonal antibody OKT3, interactional medicament between blocking-up CD40 and the gp39 is as to CD40 and/or the specific antibody of gp39 (promptly, CD154), the fusion rotein that constitutes by CD40 and gp39 (CD401g and CD8gp39); The NF-xB depressant of functions, as the nuclear translocation inhibitor, Gusperimus (DSG) for example; Gold compound, anti-proliferative agent, methotrexate for example, FK506 (tacrolimus, Prograf), Mai Kaofen acid ethyl ester, cytotoxic drug such as azathioprine and endoxan, antibacterial agent such as anti-IL-4 or IL-4 receptor fusion protein and PDE4 inhibitor (as Ariflo), and in following U.S. Patent application disclosed ptk inhibitor, these applications all are incorporated herein by reference in full: the Ser.No.09/097 that on June 15th, 1998 submitted to, 338, the Ser.No.09/094 that on June 15th, 1998 submitted to, the Ser.No.09/173 that on October 15th, 797,1998 submitted to, 413, with the Ser.No.09/262 that submitted on March 4th, 1999,525.Also referring to following document and the document wherein quoted, they are merged in this paper as a reference:

Hollenbaugh，D.，et?al.，“Cleavable?CD40Ig?Fusion?Proteins?and?theBinding?to?Sgp39”，J.Immunol.Methods?(Netherlands)，188(1)，pp.1-7(Dec.15，1995)；Hollenbaugh，D.，et?al.，“The?Human?T?Cell?Antigen?Gp39，A?Member?of?theTNF?Gene?Family，Is?a?Ligand?for?the?CD40?Receptor：Expression?of?a?Soluble?Formof?Gp39?with?B?Cell?Co-Stimulatory?Activity”，EMBO?J(England)，11(12)，pp.4313-4321(December?1992)；and?Moreland，L.W.et?al.，“Treatment?of?RheumatoidArthritis?with?a?Recombinant?Human?Tumor?Necrosis?Factor?Receptor(P75)-FcFusion?Protein，”New?England?J.of?Medicine，337(3)，pp.141-147(1997)。

Other above medicine, when uniting when using with The compounds of this invention, can according to for example in Physicians ' Desk Reference (PDR), point out or use by the quantity that those of ordinary skills determine.

Formula of the present invention (I) compound can oral or parenterai administration, for example subcutaneous or intravenous administration, and with the administering mode in intranasal, rectum or hypogloeeis, be administered to the known various Mammalss that suffer from this type of disease, people for example, effective dose is up to 1g, preferably is up to 200mg, more preferably be up to 100mg, with once a day, the mode medication of secondary or four divided doses.

Formula (I) compound can be used for any purposes as herein described in any suitable manner with the form of the dosage device formulation that contains pharmaceutically useful carrier of nontoxicity or thinner, for example, and with the form oral administration of tablet, capsule, granula or powder agent; Sublingual administration; The buccal administration; With subcutaneous, intravenously, intramuscular or breastbone inner injection or the infusion techniques form of aseptic injectable water or non-aqueous solution or suspension (for example with) parenterai administration; Nose administration comprises being applied to the nose film, for example sucks spraying; Topical is for example with the form of emulsifiable paste or ointment; Or rectal administration, for example with the form of suppository.The compounds of this invention can be for example to be fit to discharge immediately or prolong the form administration that discharges.Discharge immediately or prolong the form that can contain the suitable pharmaceutical compositions of The compounds of this invention that discharges, perhaps, particularly prolonging the situation that discharges, realize by for example using device such as hypodermic implant or osmotic pump by use.The compounds of this invention also can be with the liposome form administration.

Be used for the liquid preparations for oral administration example and comprise suspensoid, it can contain the Microcrystalline Cellulose that for example is used for increment, as the alginic acid or the sodiun alginate of suspension agent, as the methylcellulose gum of viscosity enahncers with such as those sweeting agents known in the art or flavour agent; Quick-release tablet, it can contain for example Microcrystalline Cellulose, Lin Suanergai, starch, sodium stearate and/or lactose with and/or other vehicle, tackiness agent, extender, disintegrating agent, thinner and lubricant, for example as known in the art those.Formula I compound also can include the clothes administration by hypogloeeis and/or oral cavity, discharges via the oral cavity.Molded tablet, compacting and tablet or cryodesiccated tablet are operable form examples.Exemplary compositions comprises The compounds of this invention and rapidly-soluble thinner, for example N.F,USP MANNITOL, lactose, sucrose and/or cyclodextrin, composition prepared together.Can also comprise the high-molecular weight vehicle in these preparations, for example Mierocrystalline cellulose (Microcrystalline Cellulose) or polyoxyethylene glycol (PEG).This class preparation also can comprise a kind of vehicle that promotes that mucous membrane adheres to, for example hydroxypropylcellulose (HPC), Vltra tears (HPMC), Xylo-Mucine (SCMC), copolymer-maleic anhydride (for example Gantrez), and the reagent of sustained release, for example acrylic copolymer (as Carbopol 934).Can also add lubricant, glidant, flavour agent, tinting material and stablizer so that preparation and use.

Be used for nose and be included in the solution of salt solution with the composition example of aerosol or inhalation, it can contain for example phenylcarbinol or other suitable sanitas, strengthens the absorption enhancer and/or other the solubilizing agent or the dispersion agent known in the art of bioavailability.

The composition example that is used for the enteron aisle external administration comprises injectable solution or suspension, they can contain for example suitable nontoxicity, the outer acceptable diluent of enteron aisle or solvent, for example, N.F,USP MANNITOL, 1,3 butylene glycol, water, Ringer solution, isoosmotic sodium chloride solution, or other suitable dispersion or wetting agent and suspension agent, comprise synthetic monoglyceride or diester, and lipid acid, comprise oleic acid, or polyoxyethylenated castor oil.

The composition example that is used for rectal administration comprises suppository, and it can contain for example suitable nonirritant excipient, for example theobroma oil, synthetic glyceryl ester or polyoxyethylene glycol, and they are solid at normal temperatures, but liquefaction and/or dissolving in rectal cavity discharges medicine.

Be used for the topical drug delivery composition example and comprise topical vehicle, for example Plastibase (mineral oil of polyethylene gelling).

Should be clear, for any specific object, concrete dosage level and medicine frequency can change, and depend on multiple factor, comprise the activity of used particular compound, the metabolic stability of this compound and action time length, the species of treatment target, age, body weight, general health situation, sex and diet, the mode of administration and time, drainage rate, medication combined, and the severity of concrete illness.

Should be clear, though the invention has been described by the specific embodiments described in detail, these embodiments are for General Principle of the present invention is described, the present invention needn't be subjected to its restriction.For any given material, process steps or chemical formula, some modifications and variations will be conspicuous for those skilled in the art, and can not depart from true spirit of the present invention and scope.And all such modifications and change all should be thought and belong within the scope of following claim.

Claims (24)

1. a formula I compound or its prodrug, or pharmaceutically useful salt, or solvate, or steric isomer:

Wherein:

R ¹And R ²Be independently selected from aryl and heteroaryl;

R ³Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, the heterocyclic radical alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl and-(CH ₂) _nC (O) NR ⁵R ⁶

N is 1 or 2;

R ⁵And R ⁶Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aryl, heteroaryl, aralkyl and heteroarylalkyl; And R5 and R6 can form a 4-7 unit ring altogether; With

R ⁴Be selected from hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl and heteroarylalkyl.

2. the compound of claim 1, wherein:

R ³Be selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, the heterocyclic radical alkyl, aralkyl, heteroarylalkyl and-(CH ₂) _nC (O) NR ⁵R ⁶

N is 1 or 2;

R ⁵And R ⁶Be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aralkyl and heteroarylalkyl; And R ⁵And R ⁶Can form a 4-7 unit ring altogether.

3. the compound of claim 1, wherein:

R ⁴Be selected from hydrogen, alkyl, cycloalkyl and heterocyclic radical.

4. the compound of claim 1, wherein:

R ¹And R ²Be independently selected from aryl and heteroaryl;

R ³Be selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, the heterocyclic radical alkyl, aralkyl, heteroarylalkyl and-(CH ₂) _nC (O) NR ⁵R ⁶

N is 1 or 2;

R ⁵And R ⁶Be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aralkyl and heteroarylalkyl; And R ⁵And R ⁶Can form a 4-7 unit ring altogether; With

R ⁴Be selected from hydrogen, alkyl, cycloalkyl and heterocyclic radical.

5. the compound of claim 1, wherein:

R ¹Be selected from phenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-fluorophenyl, 4-cyano group-3-pyridyl and 4-methyl-3-pyridyl;

R ²Be selected from the 4-chloro-phenyl-, 4-cyano-phenyl, 4-fluorophenyl, 4-pyridyl, 3-methyl-4-pyridyl, 3-ethyl-4-pyridyl, 4-methyl-3-pyridyl, 4-ethyl-3-pyridyl, 4-sec.-propyl-3-pyridyl, 4-chloro-2-pyridyl, 4-methyl-2-pyridyl and 4-cyano group-3-pyridyl;

R ³Be selected from 4-cyano group benzyl, 4-benzyl chloride base, the 4-luorobenzyl, the 4-trifluoromethyl benzyl, 4-trifluoromethyl-3-pyridylmethyl, 2-methyl-4-trifluoromethyl-3-pyridylmethyl, 2-ethyl-4-trifluoromethyl-3-pyridylmethyl, 2-sec.-propyl-4-trifluoromethyl-3-pyridylmethyl, 2-cyclopropyl-4-trifluoromethyl-3-pyridylmethyl, 2-cyano group-4-trifluoromethyl-3-pyridylmethyl, 2-trifluoromethyl-3-pyridylmethyl, 2-methyl-3-pyridylmethyl, 2-sec.-propyl-3-pyridylmethyl, 2-cyano group-3-pyridylmethyl and 4-trifluoromethyl-2-pyridylmethyl; With

R ⁴Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, trifluoromethyl and trifluoroethyl.

6. a formula II compound or its prodrug, or its pharmaceutically useful salt, or solvate, or steric isomer

Wherein:

R ¹And R ²Be independently selected from aryl and heteroaryl;

R ³Be selected from alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, the heterocyclic radical alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl and-(CH ₂) _nC (O) NR ⁵R ⁶

N is 1 or 2;

R ⁵And R ⁶Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aryl, heteroaryl, aralkyl and heteroarylalkyl; R ⁵And R ⁶Can form a 4-7 unit ring altogether; With

R ⁴Be selected from hydrogen, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl and heteroarylalkyl.

7. the compound of claim 6, wherein:

R ³Be selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aralkyl, heteroarylalkyl ,-(CH ₂) _nC (O) NR ⁵R ⁶

N is 1 or 2;

R ⁵And R ⁶Be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aralkyl and heteroarylalkyl; And R ⁵And R ⁶Can form a 4-7 unit ring altogether.

8. the compound of claim 6, wherein:

R ⁴Be selected from hydrogen, alkyl, cycloalkyl and heterocyclic radical.

9. the compound of claim 6, wherein:

R ¹And R ²Be independently selected from aryl and heteroaryl;

R ³Be selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, the heterocyclic radical alkyl, aralkyl, heteroarylalkyl and-(CH ₂) _nC (O) NR ⁵R ⁶

N is 1 or 2;

R ⁵And R ⁶Be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aralkyl and heteroarylalkyl; And R ⁵And R ⁶Can form a 4-7 unit ring altogether; With

R ⁴Be selected from hydrogen, alkyl, cycloalkyl and heterocyclic radical.

10. the compound of claim 6, wherein:

R ¹Be selected from phenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-fluorophenyl, 4-cyano group-3-pyridyl and 4-methyl-3-pyridyl;

R ²Be selected from the 4-chloro-phenyl-, 4-cyano-phenyl, 4-fluorophenyl, 4-pyridyl, 3-methyl-4-pyridyl, 3-ethyl-4-pyridyl, 4-methyl-3-pyridyl, 4-ethyl-3-pyridyl, 4-sec.-propyl-3-pyridyl, 4-chloro-2-pyridyl, 4-methyl-2-pyridyl and 4-cyano group-3-pyridyl;

R ³Be selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, the heterocyclic radical alkyl, aralkyl, heteroarylalkyl and-(CH ₂) _nC (O) NR ⁵R ⁶

N is 1 or 2;

R ⁵And R ⁶Be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical alkyl, aralkyl and heteroarylalkyl; And R ⁵And R ⁶Can form a 4-7 unit ring altogether; With

R ⁴Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, trifluoromethyl and trifluoroethyl.

11. the compound of claim 1, wherein this compound is selected from:

12. the compound of claim 6, wherein this compound is selected from:

13. a pharmaceutical composition wherein contains at least a claim 1 compound and at least a pharmaceutically useful carrier or thinner.

14. the pharmaceutical composition of claim 13 wherein also contains another kind of at least medicine.

15. a medication combined body, comprising a kind of pharmaceutical composition and a kind of medicine of claim 13, this medicine is selected from: antiadipositas drug, appetite-inhibiting agent, antidiabetic drug, hyperlipidemia medicine, hypolipidemic, pravastatin, lipid regulating agent, cholesterol reducing agent, lipid lowerers, the medicine of raising HDL, antihypertensive drug, the medicine of treatment somnopathy, the medicine of therapeutant abuse and habituation obstacle, anxiolytic, thymoleptic, antipsychotic drug, cognitive enhancer, the medicine that overstocks obstacle is recognized in treatment, the medicine of treatment alzheimer's disease is treated Parkinsonian medicine, antiphlogistic drug, treat neurodegenerative medicine, treat arteriosclerotic medicine, the medicine of treatment respiratory symptom, the medicine of treatment enteropathy, cardiac glycoside, and antitumour drug.

16. the pharmaceutical composition of claim 15, wherein should the another kind medicine can be before the administration of the pharmaceutical composition of claim 13, simultaneously or administration afterwards.

17. treat fat method for one kind, comprise Cannabined receptor 1 antagonist at least a claim 1 of patient's administering therapeutic significant quantity of needs.

18. the method for a smoking cessation comprises Cannabined receptor 1 antagonist at least a claim 1 of patient's administering therapeutic significant quantity of needs.

19. a pharmaceutical composition is comprising compound and at least a pharmaceutically useful carrier or the thinner of at least a claim 6.

20. the pharmaceutical composition of claim 19 wherein also comprises at least a other medicine.

21. a medication combined body wherein comprises pharmaceutical composition and a kind of medicine of claim 19, this medicine is selected from: antiadipositas drug, appetite-inhibiting agent, antidiabetic drug, hyperlipidemia medicine, hypolipidemic, pravastatin, lipid regulating agent, cholesterol reducing agent, lipid lowerers, the medicine of raising HDL, antihypertensive drug, the medicine of treatment somnopathy, the medicine of therapeutant abuse and habituation obstacle, anxiolytic, thymoleptic, antipsychotic drug, cognitive enhancer, the medicine that overstocks obstacle is recognized in treatment, the medicine of treatment alzheimer's disease is treated Parkinsonian medicine, antiphlogistic drug, treat neurodegenerative medicine, treat arteriosclerotic medicine, the medicine of treatment respiratory symptom, the medicine of treatment enteropathy, cardiac glycoside, and antitumour drug.

22. the medication combined body of claim 21, wherein another kind of medicine can be before the pharmaceutical composition administrations of claim 19, simultaneously or administration afterwards.

23. treat fat method for one kind, comprise Cannabined receptor 1 antagonist at least a claim 6 of patient's administering therapeutic significant quantity of needs.

24. the method for a smoking cessation comprises the antagonist to the Cannabined receptor 1 of at least a claim 6 of patient's administering therapeutic significant quantity of needs.