CN1361782A

CN1361782A - Substituted imidazothiazoles as antidepressant agents

Info

Publication number: CN1361782A
Application number: CN00810593A
Authority: CN
Inventors: P·A·布洛; V·亨斯托克; J·P·瓦茨
Original assignee: Knoll Pharmaceutical Co
Current assignee: Knoll Pharmaceutical Co
Priority date: 1999-05-21
Filing date: 2000-05-11
Publication date: 2002-07-31
Also published as: HUP0201543A2; CZ20014172A3; PL352288A1; AU4565200A; WO2000071548A1; EP1187836A1; TR200200165T2; GB9911881D0; SK16842001A3; BR0010828A; KR20020033625A; NO20015668L; BG106228A; JP2003500409A; CA2374915A1; MXPA01011896A; NO20015668D0; ZA200110021B; IL146541A0

Abstract

The invention discloses compounds of formula (I) including pharmaceutically acceptable salts thereof, in which A is S or O; R1 is H, halogen, a C1-3 alkyl group or a C1-3 alkylthio group; R2 is H or fluoro; and R3 is methyl, ethyl or isopropyl are useful in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, cerebral ischaemia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage.

Description

Imidazothiazoles as the replacement of antidepressive

The present invention relates to new 3-(benzo [b] thiene-3-yl-) imidazo [2,1-b] thiazole compound, it is for 5-HT _1AAcceptor has affinity and suppresses the neurone reuptake of serotonine and/or norepinephrine, relates to the preparation method of these compounds, relates to the pharmaceutical composition that contains this compound, and relate to them in treatment dysthymia disorders, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, dopy, drug abuse, cognitive disorders, presenile dementia, cerebral ischemia, anancastic behavior, panic attack, social phobia, eating disorder, exessive appetite for example, apocleisis, fast food and eat and drink immoderately (binge eating), non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidaemia, the purposes in the anxiety, purposes as the smoking cessation auxiliary, with treating and/or preventing epileptic seizures, nervous disorder, for example epilepsy and/or the symptom of nerve injury is wherein arranged, apoplexy for example, cerebral trauma, cerebral ischemia, head injuries and hemorrhage in purposes.

WO98/41528 discloses the compound of formula A Comprise each enantiomer, racemic modification, perhaps its pharmacologically acceptable salt of other form of mixtures of enantiomer, wherein Ar is a phenyl, naphthyl or benzo [b] thienyl, it separately can be randomly be selected from following substituting group and replaces by one or more: a) halogen, b) alkyl that contains 1-3 carbon atom that is randomly replaced by one or more halogens, c) alkoxyl group that contains 1-3 carbon atom that is randomly replaced by one or more halogens, d) alkylthio that contains 1-3 carbon atom that is randomly replaced by one or more halogens, e) phenoxy group that is randomly replaced, perhaps f by one or more halogens) phenyl that randomly replaced by one or more halogens; R ₁And R ₂Can be identical or different, be a) H independently, b) contain the alkyl of 1-6 carbon atom, c) contain the alkenyl of 3-6 carbon atom, d) contain the cycloalkyl of 3-7 carbon atom, e) wherein encircle the methyl cycloalkyl that contains 3-7 carbon atom, f) randomly by one or more i that are selected from) halogen atom, the ii) alkyl that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, the iii) alkoxyl group that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, the iv) aryl or the heteroaryl that replace of the substituting group of the alkylthio that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, g) wherein contain in the alkyl chain 1-3 carbon atom and wherein aryl or heteroaryl can be randomly by one or more i of being selected from) halogen atom, the ii) alkyl that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, the iii) alkoxyl group that contains 1-3 carbon atom that is randomly replaced, the iv) arylalkyl or the heteroarylalkyl that replace of the substituting group of the alkylthio that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms by one or more halogen atoms; Perhaps R ₁And R ₂Form the alkylidene chain that is randomly replaced, make the atom that it is connected with them form 5 or 6 yuan of rings, R together by one or more alkyl that contain 1-3 carbon atom separately ₃Be a) H, b) randomly by one or more i that are selected from) halogen atom, the ii) alkyl that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, the iii) alkoxyl group that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, the iv) aryl or the heteroaryl that replace of the substituting group of the alkylthio that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, c) wherein aryl is randomly by one or more i of being selected from) halogen atom, the ii) alkyl that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, the iii) alkoxyl group that contains 1-3 carbon atom that is randomly replaced, the iv) arylmethyl that replaces of the substituting group of the alkylthio that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms by one or more halogen atoms; Or d) contains the alkoxyalkyl of 3-6 carbon atom; And R ₄And R ₅, can be identical or different, be the alkyl that contains 1-3 carbon atom, perhaps R independently ₄And R ₅The atom that connects with them forms the cycloalkyl ring that contains 3-6 carbon atom;

Can be used for treating dysthymia disorders, anxiety, Parkinson's disease, obesity, cognitive disorders, epileptic seizures, nervous disorder is for example in the epilepsy and be used as protection and make the neuroprotective of not suffering from the such symptom of apoplexy for example.In the document, do not disclose or hint compound of the present invention.

(pharmaceutical chemistry magazine (Journal ofMedicinal Chemistry) 1971, Vol14 No.10 p977-982) disclose some and have had also [2,1-b] thiazolium compounds of the active glyoxalidine of antidepressive for Sharpe C.J and Shadbolt R.S..And, the document also stated the general activity of these compounds lower and than also in the document disclosed imidazolines have more toxicity.In the document, do not disclose or hint compound of the present invention.

WO97/02269 discloses the compound of formula B Comprise its pharmacologically acceptable salt, wherein A is S (O) _pOr O; P is 0,1 or 2; G is 0,1,2,3 or 4; N is 2 or 3; R ₁It is a) halogen atom, b) alkyl that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, c) alkoxyl group that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, d) alkylthio that contains 1-3 carbon atom separately that is randomly replaced by one or more halogen atoms, alkyl sulphinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkyloyl of 1-6 carbon atom, j) contain the carbalkoxy of 2-6 carbon atom, k) formamyl or the carbamyl ylmethyl that is randomly replaced separately by one or two alkyl N-that contains 1-3 carbon atom separately, l) amino that is randomly replaced sulfamyl or the sulphonamide methyl that is randomly replaced separately, or m) by one or two alkyl that contains 1-3 carbon atom separately by one or two alkyl N-that contains 1-3 carbon atom separately; When g is 2,3 or 4 o'clock, R ₁Be identical or different; R ₂, R ₃And R ₄Be H or the alkyl that contains 1-3 carbon atom that randomly replaced independently by one or more halogen atoms; And R ₅It is a) halogen atom, b) alkyl that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, c) alkoxyl group that contains 1-3 carbon atom that is randomly replaced by one or more halogen atoms, d) alkylthio that contains 1-3 carbon atom separately that is randomly replaced by one or more halogen atoms, alkyl sulphinyl or alkyl sulphonyl, e) hydroxyl, f) contain the acyloxy of 1-3 carbon atom, g) contain the hydroxyalkyl of 1-3 carbon atom, h) cyano group, i) contain the alkyloyl of 1-6 carbon atom, j) contain the carbalkoxy of 2-6 carbon atom, k) formamyl or the carbamyl ylmethyl that is randomly replaced separately by one or two alkyl N-that contains 1-3 carbon atom separately, l) sulfamyl or the sulphonamide methyl that is randomly replaced separately by one or two alkyl N-that contains 1-3 carbon atom separately, or m) amino that is randomly replaced, perhaps n by one or two alkyl that contains 1-3 carbon atom separately) H;

For 5-HT _1AAcceptor has affinity and suppresses the neurone reuptake of serotonine and/or norepinephrine.State that these compounds are useful in treatment CNS disease.But, these compounds show as the active of oxidase inhibitor and/or for other acceptor for example muscarinic receptor have affinity, therefore may cause the side effect of not expecting.Unexpectedly, the invention provides compound with beyond thought superior selectivity and drug effect.In WO97/02269, specifically do not disclose or hint compound of the present invention.

US4160768 discloses 3-(2-benzofuryl)-5, the 6-glyoxalidine also [2,1-b] thiazole as the purposes of anti-inflammatory agent.The document does not have open or hints compound of the present invention.

The invention provides the compound of new formula I Comprise its pharmacologically acceptable salt, wherein A is S or O; R ₁Be H, halogen, C _1-3Alkyl or C _1-3Alkylthio; R ₂Be H or fluorine; And R ₃Be methyl, ethyl or sec.-propyl.

Preferred substituted R ₁Be H, fluorine, chlorine, bromine, methyl and methylthio group.

Preferably, A is S.

Preferably, A is O.

More preferably, R ₃It is methyl.

Formula Ia represents the compound of preferred one group of formula I

Comprise its pharmacologically acceptable salt, wherein R is H or chlorine.

In the preferred compound of the present invention, A is S; R ₁Be H, fluorine or chlorine; R ₂Be H or fluorine; And R ₃It is methyl.

In the preferred compound of the present invention, A is S; R ₁Be H or fluorine; R ₂Be H or fluorine; And R ₃It is methyl.

In the most preferred of the present invention, A is S; R ₁Be H; R ₂Be H; And R ₃It is methyl.

The compound of formula I can exist with the salt with pharmaceutically acceptable acid formation.The present invention includes all such salt.The example of such salt comprises hydrochloride, hydrobromate, vitriol, mesylate, nitrate, maleate, formate, acetate, Citrate trianion, fumarate, tartrate [for example (+)-tartrate, (-)-tartrate or comprise its mixture of racemic mixture], succinate, benzoate, oxalate and with the amino acid salt of L-glutamic acid for example.Such salt can be by well known to a person skilled in the art the method preparation.

The compound of some formula I can exist with different tautomeric forms or exist as different geometrical isomers, and the present invention includes each tautomer and/or the geometrical isomer and their mixture of the compound of formula I.

The compound of some formula I can be can isolating different stable conformation form existing.For example, if there is huge group, then may limit around one or more single bonded rotations owing to steric hindrance.Because the torsion asymmetry of the asymmetric single bonded rotation of restriction is for example because the tension force of steric hindrance or ring can allow to separate different conformers.The present invention includes each conformer of compound of formula I and their mixture.

The compound of some formula I and salt thereof can exist with more than one crystallized form, and the present invention includes each crystallized form and composition thereof.The compound of some formula I and salt thereof also can with solvate for example the form of hydrate exist, and the present invention includes each solvate and composition thereof.

The compound of some formula I contains one or more chiral centres, and exists with different optically active forms.When the compound of formula I contained a chiral centre, compound existed with two kinds of enantiomers, and the present invention includes the mixture of two kinds of enantiomers and enantiomer.By well known to a person skilled in the art method, for example by forming for example isolating diastereomeric salt by crystallization; Formation can be for example by crystallization, gas liquid chromatography or liquid chromatography and isolating diastereomer derivative or mixture; Perhaps under chiral environment, for example for example have on the silicon-dioxide of bonded chiral ligand or gas liquid chromatography or liquid chromatography in the presence of chiral solvent in chiral support, can split enantiomer.Be appreciated that be converted under the situation of another kind of chemical entity, need another step to discharge the enantiomeric forms of hope by the enantiomer of one of above-mentioned separation method with expectation.Perhaps, can use optically-active reagent by asymmetric synthesis, substrate, catalyzer or solvent perhaps by a kind of enantiomer is converted into another kind by asymmetric conversion, can synthesize concrete enantiomer.

When the compound of formula I contained more than one chiral centre, it can exist with diastereomer.Can be by means commonly known in the art for example chromatogram or crystallization to separate diastereomer right, and can separate each enantiomer of each centering as mentioned above.The present invention includes each diastereomer and composition thereof of the compound of formula I.

The compound of concrete formula I is :-3-(benzo [b] thiene-3-yl-)-2-methyl-5, and the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 4-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(benzo [b] thiene-3-yl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 2-methyl-3-(5-methyl benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(benzo [b] thiene-3-yl-)-2-sec.-propyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 2-methyl-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-bromobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; And 3-(benzo [b] furans-3-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; Comprise its pharmacologically acceptable salt.

The present invention also comprises the compound that contains the formula I that treats significant quantity or the pharmaceutical composition of its salt and pharmaceutically acceptable diluent or carrier.

As hereinafter employed, term " active compound " refers to compound or its salt of formula I.In treatment is used, can be oral, rectum, non-through intestines or topical application active compound, preferred oral administration.Therapeutic composition of the present invention like this can be taked to be used for oral, rectum, the form of non-any known drug composition through intestines or topical.The pharmaceutically acceptable carrier that is applicable to such composition is that pharmacy field is known.Composition of the present invention can contain the active compound of 0.1-99% (weight).Composition of the present invention generally prepares with unit dosage form.The preferred unit dosage of activeconstituents is the 1-500 milligram.Preparing the vehicle that uses in these compositions is the known vehicle of pharmacy field.

Being used for liquid preparations for oral administration is the preferred present composition, and these are the known pharmaceutical forms that are used for such administration, for example tablet, capsule, syrup and moisture or oil suspension.Preparing the vehicle that uses in these compositions is the known vehicle of pharmacy field.By disintegrating agent for example W-Gum and lubricant for example Magnesium Stearate in the presence of with active compound and inert diluent for example calcium phosphate mix and the mixture compressing tablet can be prepared tablet by currently known methods.Can be with method preparation tablet well known in the art so that compound slowly-releasing of the present invention.If expectation, such tablet can provide enteric coating by currently known methods, for example by using Cellacefate.Similarly, can prepare capsule by ordinary method, for example hard or soft gelatin capsule contains active compound, is with or without the adding vehicle, and if expectation, provide enteric coating with currently known methods.Tablet and capsule generally contain the active compound of 1-500 milligram separately.Other composition that is used for oral administration comprises, for example nontoxic suspension agent for example Xylo-Mucine in the presence of in water-bearing media, contain the aq suspension of active compound and for example contain the oil suspension of compound of the present invention in the peanut oil at suitable vegetables oil.

Can be with well known to a person skilled in the art that method preparation solid oral dosage forms is so that the active compound slowly-releasing.According to the character of active compound, the solid oral dosage forms that contains the enteric coating of composition of the present invention may be useful.Various materials, for example lac and/or sugar can exist as dressing, perhaps modify the physical form of oral dosage form in addition.If expectation can provide enteric coating to for example tablet or pill by currently known methods, for example by using Cellacefate and/or HYDROXY PROPYL METHYLCELLULOSE phthalate.

Capsule and/or the capsule and pill (for example hard or soft gelatin capsule) that contains active compound (vehicle that is with or without adding is fatty oil for example) can be prepared by ordinary method, and if necessary, enteric coating can be provided in a known way.Can prepare the inclusion of capsule and/or capsule and pill so that the active compound slowly-releasing with currently known methods.

The liquid oral dosage form that contains composition of the present invention can be an elixir, suspension and/or syrup (for example at the aq suspension that contains active compound in the presence of the nontoxic suspension agent [for example Xylo-Mucine] in water-bearing media and/or contain the oil suspension of active compound in suitable vegetables oil [for example peanut oil and/or sunflower oil]).Liquid oral dosage form can also contain one or more sweeting agents, correctives, sanitas and/or their mixture.

Active compound can be mixed with particle being with or without under other vehicle situation.These particles can be by directly picked-up or before the picked-up they are being added among the suitable liquid vehicle (for example water) of patient.Particle can contain disintegrating agent (for example pharmaceutically acceptable effervescent mixture that is formed by acid plus carbonate or supercarbonate) and disperse in liquid medium helping.

Preferably, above-mentioned each oral dosage form can contain about 1 milligram to about 1000 milligrams, the active compound of more preferably about 5 milligrams to about 500 milligrams (for example 10 milligrams, 50 milligrams, 100 milligrams, 200 milligrams or 400 milligrams).

The composition of the present invention that is suitable for rectal administration is the known pharmaceutical forms of administration like this, for example contains stearic fat, semi-synthetic glyceryl ester, the suppository of theobroma oil and/or polyoxyethylene glycol alkali.

Pharmaceutical composition also can be non-through enteral administration (for example with known non-pharmaceutical dosage forms (for example sterile suspensions in moisture and/or oily medium and/or the sterile solution in suitable solvent through enteral administration, preferably the blood etc. with the patient of treatment oozes) subcutaneous, intramuscular, intracutaneous and/or intravenously [for example inject and/or infuse] administration).Non-can be (for example by the micro-filtration and/or the use suitable sterile agent [for example oxyethane]) of sterilization through the intestines dosage form.Randomly, can be to the non-pharmaceutically acceptable adjuvant be applicable to below non-through enteral administration one or more that adds through the intestines dosage form: local anesthetic, sanitas, buffer reagent and/or their mixture.Non-ly before using, can in suitable sterile sealed vessel (for example ampoule and/or phial), store the intestines dosage form.Lay up period is for enhanced stability, can be after the container of packing into non-freezing and can under reduced pressure remove liquid (for example water) through the intestines dosage form.

Pharmaceutical composition can be with the known pharmaceutical forms nose administration that carries out this administration (for example sprays, aerosol, atomization solution and/or powder).Can use the dosing system that well known to a person skilled in the art (for example aerosol and/or sucker).

Can be to buccal cavity (for example hypogloeeis) drug administration composition, with the known pharmaceutical forms (for example slow solution tablet, chewing gum, lozenge, lozenge, lozenge, gelifying agent, paste, mouth wass, irrigation and/or powder agent) that is used for administration like this.

Be used for topical application of compositions and can contain a kind of matrix, pharmaceutical active compounds of the present invention disperses wherein, makes for applied dermally compound maintenance compound and skin contact.By with pharmaceutical active compounds with local with vehicle mineral oil for example, Vaseline and/or wax, for example paraffin or beeswax, with effectively through the skin accelerator for example methyl-sulphoxide or propylene glycol be mixed together, can prepare suitable transdermal administration composite.Perhaps active compound can be dispersed in pharmaceutically acceptable emulsifiable paste or the ointment base.The amount of the active compound that is contained in the topical formulations should be that this topical formulations will be administered to the treatment significant quantity of sending the compound of passing in time on the skin.

Compound of the present invention can also by from external source for example by intravenous fluids or from placing intravital compound for the source continuous infusion.In for example comprise the heeling-in storage agent that contains the compound of wanting infusion that discharges continuously by osmosis and implants (a) for example suspension in the acceptable oil of the compound of wanting infusion or the such liquid of solution that can be following two kinds of situations for the source, for example for example dodecanoate exists described compound or (b) solid of the form of heeling-in carrier with the form of the derivative that is insoluble in very much water, for example for the compound of wanting infusion with synthetic resins or wax material.Carrier can be to contain the single object of all compounds or respectively contain the several objects of successive that part is wanted the compound of infusion.Interior amount for the active compound that exists in the source should be to send the amount of the active compound of passing the treatment significant quantity time through a segment length.

In some preparations, can advantageously use the compound of the present invention of the very little particle form of for example passing through the levigate acquisition of liquid energy.

In composition of the present invention, if expectation, active compound can mix with other compatible pharmacologically active principles.

The present invention also comprises the compound of the formula I that is used as medicine.

The pharmaceutical composition that contains the compound of the formula I that treats significant quantity can be used for treating particularly people's dysthymia disorders of Mammals, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, dopy, drug abuse, cognitive disorders, presenile dementia, cerebral ischemia, anancastic behavior, panic attack, social phobia, eating disorder, exessive appetite for example, apocleisis, fast food and eat and drink immoderately non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidaemia, and auxiliary nervous and that conduct is given up smoking to the mankind.Said composition can also be used to treating and/or preventing epileptic seizures, nervous disorder, epilepsy and/or the symptom of nerve injury is wherein arranged for example, apoplexy for example, cerebral trauma, cerebral ischemia, head injuries and hemorrhage.And the accurate amount of the active compound of using in such treatment will depend on several factors, patient's age for example, the severity of disease and medication history in the past, and always depend on the judgement that the medication doctor provides, the amount of the active compound of using every day is in the 1-1000 nanogram range, preferred 5-500 milligram is with one or many single dose or divided dose administration in one day.

On the other hand, the invention provides formula I compound and be used for the treatment of dysthymia disorders in preparation, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, dopy, drug abuse, cognitive disorders, presenile dementia, cerebral ischemia, anancastic behavior, panic attack, social phobia, eating disorder, exessive appetite for example, apocleisis, fast food and eating and drinking immoderately, non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidaemia, and nervous, as the smoking cessation auxiliary, epileptic seizures, nervous disorder, for example epilepsy and/or the symptom of nerve injury is wherein arranged, apoplexy for example, cerebral trauma, cerebral ischemia, the purposes in head injuries and the hemorrhage medicine.

The present invention also provides the treatment dysthymia disorders, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, dopy, drug abuse, cognitive disorders, presenile dementia, cerebral ischemia, anancastic behavior, panic attack, social phobia, eating disorder, for example exessive appetite, apocleisis, fast food and eat and drink immoderately non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidaemia, anxiety, epileptic seizures, nervous disorder, epilepsy and/or the symptom of nerve injury is wherein arranged for example, apoplexy for example, cerebral trauma, cerebral ischemia, head injuries and hemorrhage method, this method comprise the compound to the formula I of patient's administering therapeutic significant quantity of needs treatment.The present invention also provides the method to people's aiding smoking cessation, and this method comprises the compound to the formula I of patient's administering therapeutic significant quantity of needs smoking cessation.

The present invention also provides the method that reduces human craving for tobacco, and this method comprises the compound to the formula I of patient's administering therapeutic significant quantity of needs.The present invention also provides and has reduced people's smoking cessation method of weight increase afterwards, and this method comprises the compound to the formula I of patient's administering therapeutic significant quantity of needs.

In addition, compound of the present invention can be used for the treatment of or prevent metabolic trouble and consequent illness, living heat of for example non-exercise motion and accretion rate are fast, sexual dysfunction, sleep apnea (apnoea), syndromes before menstrual period, the urinary incontinence, the superfunction obstacle, hiatal hernia (hiatial hernia) and reflux esophagitis, pain, neurodynia particularly, the weight increase relevant with pharmacological agent, chronic fatigue syndrome, osteoarthritis and gout, the cancer relevant with weight increase, menstrual function obstacle, cholelith, orthostatic hypotension and pulmonary hypertension.

Compound of the present invention can be used for preventing cardiovascular disease, and reduces adhesiveness of blood platelet, helps lose weight afterwards and help period of pregnancy and loses weight after the smoking cessation.

Compound of the present invention is used in particular for treating obesity and relevant concurrent disease symptoms, for example diabetes, hyperglycemia and hyperlipemia.Known to be used for treating fat monoamine reuptake inhibitors usually relevant with cardiovascular side effects, the heart rate that for example increases and the blood pressure of raising.But compound of the present invention reduces expectability owing to using the particularly cardiovascular side effects that takes place of norepinephrine reuptake inhibitor of monoamine reuptake inhibitors.Do not expect to be bound by theory, it may be 5-HT in the compound of the present invention _1AThe combination of agonism has reduced may be owing to their the monoamine reuptake restraining effect cardiovascular side effects that takes place of its norepinephrine reuptake restraining effect particularly.

On the other hand, the invention provides to reduce to comprise and be incorporated into compound 5-HT _1AThe method of the cardiovascular side effects of the anti-obesity medicine among the agonism.

On the other hand, the invention provides is 5-HT _1AAgonist and be monoamine reuptake inhibitors particularly the compound of norepinephrine reuptake inhibitor in the fat purposes that does not cause cardiovascular side effects with relevant concurrent disease symptoms of treatment.

The beneficial property of particularly preferred compound of the present invention in reducing cardiovascular side effects can confirm in the research of rat telemetry, wherein continuous recording heart rate, blood pressure, body temperature and kinematic dexterity in time.Suitable method is described in: Brockway, BP, Mills, PA﹠amp; Azar, SH (1991), by radiotelemetry to rat continuous chronic mensuration blood pressure, heart rate and active novel method.Clinical and experiment hypertension-theory and practice (Clinical andExperimental Hypertension-Theory and Practice) A13 (5), 885-895 and Guiol, C.Ledoussal, C﹠amp; Surg é, J-M (1992) is to the radio telemetry system of unconfined rat chronic mensuration blood pressure and heart rate.Substantive approach.Pharmacology and toxicologic method magazine (Journal of Pharmacological and ToxicologicalMethods) 28,99-105.

Can measure the 5-HT of the particularly preferred compound of the present invention by means commonly known in the art by electrophysiology _1AAgonism.

The preparation method of the compound of formula I will be described now.This method can be carried out with single basis, perhaps by a plurality of parallel synthetic carrying out, also is called the high speed analogue method.This method is preferably carried out under normal pressure.

By disclosed method among the WO97/02269 can preparation formula I compound.In addition, can be by the compound of following method preparation formula I.

Randomly in a kind of acid for example in the presence of acetate or the vitriolic, in 0 ℃ of-200 ℃ of scope preferably in 20 ℃ of-150 ℃ of scopes under the temperature, by compound dehydration with formula II, compound that can preparation formula I A wherein, R ₁, R ₂, R ₃With g as hereinbefore defined.

Under the temperature in 0 ℃ of-200 ℃ of scope, at a kind of solvent for example in the presence of the alcoholic acid, and randomly a kind of acid for example acetate in the presence of; Preferably by under 20 ℃ of temperature to the boiling spread of the solvent that uses, heating, by making the compound of formula III

Compound reaction with formula IV

Wherein Z is a leavings group, halogen for example, bromine for example, A, R ₁, R ₂And R ₃As hereinbefore defined, compound that can preparation formula II.

Under the temperature in 0 ℃ of-200 ℃ of scope, randomly a kind of acid for example acetate in the presence of, and randomly at a kind of solvent for example in the presence of the alcoholic acid, compound by making formula III and the reaction of the compound of formula IV, the also direct compound of preparation formula I is without the intermediate of separate type II; Preferably by heating under the temperature in 20 ℃ of-150 ℃ of scopes.

Randomly a kind of catalyzer for example lewis acid catalyst for example aluminum chloride in the presence of, at a kind of solvent for example in the methylene dichloride, under-20 ℃ of temperature to the boiling spread of the solvent that uses, make the compound of formula V R wherein ₁, R ₂Define R as mentioned with A ₄Be H or methyl,, can prepare wherein R with for example borine/tert-butylamine mixture reaction of a kind of reductive agent ₃It is the formula I compound of methyl or ethyl.

A kind of solvent for example tetrahydrofuran (THF) in the presence of, under-50 ℃ of temperature to the boiling spread of the solvent that uses, make the compound of formula VI Wherein X is a leavings group, bromine for example, and with a kind of metallization reagent tonsilon reactive magnesium for example, then and formylation reagent or for example dimethyl formamide or N-methoxyl group-N-methylacetamide reaction of acylating reagent, compound that can preparation formula V.

A kind of solvent for example methylene dichloride or tetrahydrofuran (THF) in the presence of, under-50 ℃ of temperature to the boiling spread of the solvent that uses, make the compound of formula VII

With for example bromine or the reaction of tribromide phenyltrimethyammonium of a kind of bromizating agent, can preparing wherein, X is the compound of the formula VI of bromine.

By disclosed method among the WO97/02269 can preparation formula VII compound.

By following mensuration compound vitro inhibition in conjunction with the 5-HT acceptor particularly in conjunction with 5-HT _1AThe test of the ability of the tritiate part of acceptor has confirmed the ability of compound and serotonine (5-HT) acceptor interaction of formula I for the product of embodiment 1-17.

Ice-cooled 50mM Tris-HCl damping fluid (when under 25 ℃, 1: when 40w/v measures, pH7.7) in, will be from male Sprague-Dawley rat (Charles River; Weight range 150-250 gram) the hippocampal tissue homogenate of brain, and under 4 ℃ with 40000g centrifugal 10 minutes.With settling homogenate once more in identical damping fluid, under 37 ℃, hatched 10 minutes, and under 4 ℃ with 40000g centrifugal 10 minutes.Final settling is suspended in once more and contains 4mM CaCl ₂, in the 50mMTris-HCl damping fluid (pH7.7) of 0.1%L-xitix and 10 μ M pargyline hydrochlorides (being equivalent to 6.25 milligrams of tissue wet/milliliters), and be used for immediately in conjunction with measuring.

Under 25 ℃, film (400 microlitres; Be equivalent to 2.5 milligrams of tissue wet/pipes) and the single concentration of 50 μ l1nM [ ³H] 8-hydroxyl-2-(dipropyl amino) 1,2,3,4-tetralin ([ ³H] 8-OH-DPAT) and 50 microlitre distilled water (total binding) or 50 microlitre test compounds (with 10 ^-6The single concentration or 10 of M ^-11-10 ^-310 concentration of M scope) or 50 microlitre 5-HT (10 μ M, non-specific binding) hatched 30 minutes.Use the Skatron cell harvester to end to hatch by filtering fast by the Skatron11734 strainer under the vacuum.With ice-cooled 50mMTris-HCl damping fluid, pH7.7 flushing filter (25 ℃, flushing is provided with 9,9,0).Trimmed filter paper dick perforation enters test tube, adds scintillation solution, and measures radioactivity by liquid scintillation counting(LSC).

By following mensuration compound external from 5-HT reuptake site displacement standard part [ ³H] test of ability of citalopram, confirmed the interactional ability of compound and serotonine (5-HT) reuptake site of formula I for the product of embodiment 1-17.

At the ice-cooled 50mM Tris-HClpH7.4 that contains 120mM sodium-chlor and 5mM Repone K (when when measuring down for 25 ℃) (Tris damping fluid; 1: 30w/v), will be from the volume cortical tissue homogenate of the male Charles River rat brain of body weight 150-250 gram, and with 40000g centrifugal 10 minutes.Abandoning supernatant, with settling at the Tris damping fluid with 1: 60w/v is homogenate once more, with 40000g centrifugal 10 minutes.Repeat this step once more.Final settling is suspended in once more among the 50mM Tris-HCl pH7.4 that contains 120mM sodium-chlor and 5mM Repone K and (is equivalent to 3.125 milligrams of tissue wet/milliliters), and is used for immediately in conjunction with measuring.All centrifugally all under 4 ℃, carry out.

Under 27 ℃, film (400 microlitres; Be equivalent to 1.25 milligrams of tissue wet/pipes) and the single concentration of 50 μ l1.3nM [ ³H] citalopram and 50 microlitre distilled water (total binding) or 50 microlitre test compounds are (with 10 ^-6The single concentration or 10 of M ^-11-10 ^-310 concentration of M scope) or 50 microlitre paroxetines (0.5 μ M, non-specific binding) hatched 1 hour.Use the Skatron cell harvester to combine radioactive film by the Skatron11734 strainer recovery of filtering fast under the vacuum by in 0.5%PEI, soaking in advance.With ice-cooled 50mMTris-HCl damping fluid, pH7.4 flushing filter (25 ℃, flushing is provided with 9,9,0).Trimmed filter paper dick perforation enters test tube, adds scintillation solution, and measures radioactivity by liquid scintillation counting(LSC).

By following mensuration compound external from norepinephrine reuptake site displacement standard part [ ³H] test of ability of nisoxetine, confirmed the interactional ability of compound and norepinephrine (NA) reuptake site of formula I for the product of embodiment 1-17.

At the ice-cooled 50mM Tris-HClpH7.4 that contains 120mM sodium-chlor and 5mM Repone K (under 25 ℃) (Tris damping fluid; 1: 60w/v), use the kinematicpolytron (speed is provided with 6, carries out 10 seconds) will be from the volume cortical tissue homogenate of the male Charles River rat brain of body weight 150-250 gram, and with 40000g centrifugal 10 minutes.Abandoning supernatant, with settling in the Tris damping fluid with 1: 60w/v is homogenate once more, with 40000g centrifugal 10 minutes.Repeat this step altogether more than twice, make cerebral tissue all be able to homogenate and centrifugal 4 times.Final settling is suspended in once more among the 50mM Tris-HCl pH7.4 that contains 300mM sodium-chlor and 5mM Repone K and (is equivalent to 18.75 milligrams of tissue wet/milliliters), and is used for immediately in conjunction with measuring.All centrifugally all under 4 ℃, carry out.

Under 4 ℃, film (400 microlitres; Be equivalent to 7.5 milligrams of tissue wet/test tubes) and the single concentration of 50 microlitre 0.6nM [ ³H] nisoxetine and 50 microlitre distilled water (total binding) or 50 microlitre test compounds are (with 10 ^-6The single concentration or 10 of M ^-11-10 ^-310 concentration of M scope) or 50 microlitre Mazindol (1 μ M, non-specific binding) hatched 4 hours.Use the Skatron cell harvester to combine radioactive film by filtering fast by the recovery of Skatron11734 strainer under the vacuum.With the ice-cooled 50mMTris-HCl damping fluid that contains 120mM sodium-chlor and 5mM Repone K, pH7.4 gets filter (flushing is provided with 9,9,0) express developed.Trimmed filter paper dick perforation enters test tube, adds scintillation solution, and measures radioactivity by liquid scintillation counting(LSC).

By following mensuration compound external from muscarinic receptor displacement standard part [ ³H] test of ability of N-methyl scopolamine, confirmed compound and the interactional ability of muscarinic receptor of formula I for the product of embodiment 1-17.

At the ice-cooled 20mM HEPES damping fluid that contains 100mM sodium-chlor and 10mM magnesium chloride, pH7.5 (measuring down) (1: 10w/v) at 25 ℃, (speed is provided with 21700rpm to use Polytron PT3100,3 * 5 seconds) will be from the volume cortical tissue homogenate of the male CharlesRiver rat brain of body weight 150-250 gram, and under 4 ℃ with 49500g centrifugal 30 minutes.Abandoning supernatant is containing the 20mM HEPES damping fluid of 100mM sodium-chlor and 10mM magnesium chloride with settling, homogenate once more among the pH7.5 (being equivalent to 12.5 milligrams of tissue wet/milliliters), and film was stored down at-80 ℃ before needs.

Film is thawed, as indicated abovely dilute among the pH7.5 with 1: 10, use PolytronPT3100 homogenate at the ice-cooled 20mM HEPES damping fluid that contains 100mM sodium-chlor and 10mM magnesium chloride.Under 30 ℃, the film of dilution (200 microlitres; Be equivalent to 0.25 milligram of tissue wet/test tube) contain the 20mMHEPES damping fluid of 100mM sodium-chlor and 10mM magnesium chloride with 200 microlitres, pH7.5 and the single concentration of 50 microlitre 0.15nM [ ³H] N-methyl scopolamine and 50 microlitre distilled water (total binding) or 50 microlitre test compounds are (with 10 ^-6The single concentration or 10 of M ^-11-10 ^-310 concentration of M scope) or 50 microlitre atropine sulfates (1 μ M, non-specific binding) hatched 30 minutes.Use the Skatron cell harvester to combine radioactive film by filtering fast by the recovery of Skatron11734 strainer under the vacuum.With ice-cooled 20mM HEPES damping fluid, pH7.5 gets filter (in that 5,5 flushings 1,2 are set) express developed.Trimmed filter paper dick perforation enters test tube, adds scintillation solution, and measures radioactivity by liquid scintillation counting(LSC).

For each of these tests, the compound of measuring formula I is external from 5-HT _1AThe ability of acceptor and serotonine (5-HT) and norepinephrine (NA) reuptake site and muscarinic receptor displacement standard part, 10 ^-6M test compound specificity is calculated by following method in conjunction with the displacement per-cent of tritiate part.

At first, do not have (A) and having the specificity combination of measuring the tritiate part under the situation of (B) test compound: under the situation that does not have compound: there is compound (10 in A (dpm)=total binding (dpm)-non-specific binding (dpm) ^-6M) under the situation: B (dpm)=10 ^-6Combination under the M (dpm)-non-specific binding (dpm)

The specificity that will have the tritiate part of (B) under the situation of compound then is in conjunction with the specificity bonded per-cent that is converted into the tritiate part of (A) under the situation that does not have compound: 10 ^-6Specificity under the M is in conjunction with %=B (dpm)/A (dpm) * 100

By never existing the specificity under the compound situation to deduct the specificity that exists under the compound situation in conjunction with per-cent, obtain test compound (10 then in conjunction with per-cent ^-6M) the specificity bonded of tritiate part is replaced per-cent, with not existing the specificity under the compound situation to think maximum combined, so equal 100%:10 in conjunction with per-cent ^-6Displacement %=100-10 under the M ^-6Specificity under the M is in conjunction with %.

In some cases, utilize the compound of finite concentration scope, for 10 ^-6Displacement % under the M has made displacement curve more than or equal to the compound of the specificity bonded 50% of tritiate part.Then by to the rough non-linear regression of the data of carry out simultaneously three times experiments by bringing following simultaneous equation (from Feldman equation deutero-equation) calculating K into _i: F ₁=[L] _Tot-B

K_{i}^{'} = K_{i} (1 + \frac{F_{1}}{K_{d}})

ab = \frac{C_{k} r_{1} - L + K_{1}^{'}}{2}

F_{2} = - ab + \sqrt{{ab}^{2} + K_{i}^{'} L}

The wherein B of non--specific data others is the concentration of bonded ligand-receptor mixture.The each situation of observing of following calculating: B=DPM/ (specific activity x is hatched volume) L is compound concentrations [L] _AlwaysThe concentration of the tritiate part that is to use, following calculating: [L] _Always=(average DPM * dilution of total DPM of the sample of adding)/(specific activity x is hatched volume) K _dIt is the balance dissociation constant of part.F ₁And F ₂Be respectively the concentration of free ligand and free compound.r ₁It is the total concn of acceptor in the experiment for the first time.Must use C for following experiment _kMultiply by this coefficient (C ₁=1).N _kIt is non-specific binding constant.

Below table 1 provided in the top test for 5-HT for the end product of hereinafter described embodiment 1-17 _1AIn conjunction with and 5-HT and NA picked-up and muscarine (muscarinic) in conjunction with the result of acquisition.K _iThe mean values of representing and be three independent mensuration with nM.% is that each is determined at 10 ^-6Displacement % during M.

Table 1

The embodiment sequence number	????5-HT _1A	The 5-HT picked-up	The NA picked-up	Muscarine
The embodiment sequence number	????5-HT _1A	The 5-HT picked-up	The NA picked-up	Muscarine	????1	????5.6	????266	????3.1	????352
????2	????2.3	????292	????13.2	????268	????1	????5.6	????266	????3.1	????352
????2	????2.3	????292	????13.2	????268	????3	????98％	????48％	????102％	????62％
????4	????3.4	????212	????2.8	????274	????3	????98％	????48％	????102％	????62％
????4	????3.4	????212	????2.8	????274	????5	????3.6	????217	????1.4	????342
????6	????2.8	????113	????1.1	????530	????5	????3.6	????217	????1.4	????342
????6	????2.8	????113	????1.1	????530	????7	????13.6	????194	????1.4	????49
????8	????0.6	????183	????89	????157	????7	????13.6	????194	????1.4	????49
????8	????0.6	????183	????89	????157	????9	????39	????0.28	????3.03	????179
????10	????1.4	????177	????16.6	????147	????9	????39	????0.28	????3.03	????179
????10	????1.4	????177	????16.6	????147	????11	????11.5	????238	????7.3	????342

The embodiment sequence number	??5-HT _1A	The 5-HT picked-up	The NA picked-up	Muscarine
The embodiment sequence number	??5-HT _1A	The 5-HT picked-up	The NA picked-up	Muscarine	????12	????NT	????NT	????NT	????67％
????13	????1.0	????123	????7.5	????194	????12	????NT	????NT	????NT	????67％
????13	????1.0	????123	????7.5	????194	????14	????2.0	????47	????3.3	????8.7
????15	????1.8	????86	????2.8	????230	????14	????2.0	????47	????3.3	????8.7
????15	????1.8	????86	????2.8	????230	????16	????8.8	????33％	????4.6	????39％
????17	????9.0	????12％	????15.1	????231	????16	????8.8	????33％	????4.6	????39％

K _iValue is n=1, the mean value of n=2 or the mean value of n=3.

NT=is test not.

Can confirm that by following test compound of the present invention suppresses the active ability of monoamine oxidase A.

The general method of the wherein tissue-derived people's of the being placenta below using is tested:

Enzyme	Substrate	Hatch	Reaction product	Detection method
Enzyme	Substrate	Hatch	Reaction product	Detection method	MAO-A(h)	Kynuramine ??(0.15mM)	30 minutes/30 ℃	The 4-hydroxyquinoline	Spectrophotometry

Compound under replication 1 and 10 micro-molar concentrations.

Reference: Weyler, W. and Salach, J.I. (1985) is from the purifying and the character of the plastosome A MAO-B B of people's placenta, journal of biological chemistry (J.Biol.Chem.), 260:13199-13207.Acute ingesting zoologizeed and environment

The male Sprague-Dawley rat (body weight 300-450 gram during the experiment beginning) that obtains from Charles River (Margate) is experimentized.Animal is housed in respectively in the polypropylene cage that has the metal grating base plate of 21 ± 1 ℃ of temperature and humidity 55%.Below each cage, place the polypropylene pallet.Animal remains in the anti-phase cycle light and dark.Turned off the light from 09.30 o'clock to 17.30 o'clock, during the room throw light on red light.In institute free in animal ad libitum access powdery rat food and tap water.The mouse food is contained in glass feed cylinder (10 centimetres of the diameters that have aluminium lid; Dark 8 centimetres) lining.Be carved with a hole (3 centimetres of diameters) on each lid and allow to the food of taking food.Before experiment, animal adapts to fortnight at least under these conditions.Test method

Be divided into animal the treatment group that comprises 6-8 rat the day before yesterday in test at random, measures body weight and feed 6 hours.It is unobvious not different before healing with medicine with body weight and the feed of the rat in guaranteeing not on the same group to gather these master datas.In this day of test, animal is used a kind of in the trial drug of vehicle or three kinds of dosage.Orally administered all medicines when dark period begins because during this period rat consume they the major part of food.1,2,4,6 and 24 hours feed cylinders of weighing (being accurate to 0.1 gram) when administration and after the administration.During each reading, the pallet inspection below the cage is spread out the food that takes, it is refunded the feed cylinder.But generally ignore from the food that the feed cylinder spreads out.

All drug doses are represented with free alkali.Medicine dissolution in deionized water or use sound bathe and to be suspended among the 0.4%cellosize.Data analysis

By can calculate the variation (treatment group mean value ± s.e. mean value) of body weight with gram/kilogram rat body weight ecbatic.Utilize special-purpose computer program to calculate ED from the logic sigmoid curve ₅₀Value (ingestion of food being reduced to 50% needed drug dose of control value).The analysis that utilizes variance and Dunnett ' s test (two-tailed) is to carrying out statistics relatively between the average group picked-up.

Unexpectedly, compare with the compound that exemplifies among the WO97/02269, compound of the present invention has higher for 5-HT _1AThe affinity of acceptor.

In addition, unexpectedly, compare with the embodiment of WO97/02269, preferred compound of the present invention has the lower affinity for muscarinic receptor.For example, the embodiment 1 of WO97/02269 has the K of 130nM _iThe muscarine sexual compatibility can cause the side effect of not expecting, dry for example, blurred vision, perspire, palpitaition, the deterioration of constipation and angle closure glaucoma (Blackwell, B., the side effect of antidepressant drug, first part, oxidase inhibitor and tricyclic compound, medicine (Drugs) 21,202-219,1981).Obviously, the compound that muscarinic receptor is had a minimum affinity is an ideal.

In addition, compare with the compound that exemplifies among the WO97/02269, preferred compound of the present invention has the MAO of obvious reduction _ASuppress active.

In above-mentioned test, the product of embodiments of the invention 1 shows the IC of 1600nM ₅₀, and the embodiment 1 of WO97/02269 has the IC of 33nM ₅₀These result's proofs are compared the optionally beat all raising of compound of the present invention with previous disclosed compound.The combination that the inhibition of activity of monoamine oxidase and 5-HT reuptake suppress can cause serotonin syndromes (Sternbach, H., serotonin syndromes, Am.J.Psychiatry148,705-713,1991), and this does not expect very much.

In addition, compare with the compound that exemplifies among the WO97/02269, most preferred of the present invention has the activity of raising in the acute research of ingesting.In the above-mentioned acute research of ingesting, the product of embodiments of the invention 1 had 1.1 mg/kg in the time of 2 hours ED ₅₀, and the embodiment 1 of WO97/02269 had 4.5 mg/kg in the time of 2 hours ED ₅₀

These result's proofs are compared the astonishing raising of the drug effect of compound of the present invention with the disclosed compound of prior art.

Describe the present invention in detail by the following examples, provide these embodiment just for example.Characterize among these embodiment the final product of each by in the following method one or more: high performance liquid chromatography, ultimate analysis, nuclear magnetic resonance spectrum, mass spectrum and infrared spectra.

EXAMPLE Example 1

A)-70 drip two (trimethyl silyl) lithium amide (1M tetrahydrofuran solution in the solution of 3-ethanoyl-benzo [b] thiophene in the tetrahydrofuran (THF) (250 milliliters) that stirs (10 gram) under ℃ following nitrogen; 60 milliliters), then this mixture was stirred 1 hour down at-70 ℃.Methyl iodide (3.54 milliliters) solution dripping in the tetrahydrofuran (THF) (20 milliliters) through 15 minutes under-70 ℃ made stirred mixture be warmed to room temperature through 18 hours, then it was joined in the saturated aqueous ammonium chloride solution (300 milliliters).Product is extracted in the ethyl acetate (3 * 100 milliliters), and water (2 * 50 milliliters) and saturated sodium chloride aqueous solution (50 milliliters) wash the extraction liquid that merges then, and dry (sodium sulfate), vacuum is removed solvent.By the silicon-dioxide purifying resistates of flash chromatography method in BiotageFlash 400i  device, use sherwood oil (boiling point 40-60 ℃) and 99: 1 mixture of ethyl acetate to be eluent.Merge suitable fraction and vacuum and remove solvent, obtain 3-propionyl benzo [b] thiophene (2.7 gram) of colorless solid, it just need not be further purified and be used.

B) 3-propionyl-benzo [b] thiophene (6.75 grams in the tetrahydrofuran (THF) (100 milliliters) that 30 fens clockwise stirs under 0-5 ℃ of following nitrogen; with similar method for preparing) solution in add tribromide phenyltrimethyammonium (13.35 gram) in batches, then this mixture was stirred 20 minutes down and at room temperature stirred 4 hours at 0 ℃.Filter to remove solid and with tetrahydrofuran (THF) (30 milliliters) washing, merging filtrate and washings then, and vacuum removal solvent.Resistates is dissolved in methylene dichloride (200 milliliters), water (3 * 30 milliliters) and saturated sodium chloride aqueous solution (30 milliliters) wash this solution then, dry (sodium sulfate), remove solvent, obtain 1-(benzo [b] thiene-3-yl-)-2-bromo third-1-ketone, be brown oil (9.2 gram), it at room temperature slowly solidifies, and just need not be further purified and used.

C) under the nitrogen with crude product 1-(benzo [b] thiene-3-yl-)-2-bromo third-1-ketone (9.2 gram), the heating 17 hours under refluxing of 2-imidazolidine thioketones (3.5 gram), the mixture of ethanol (200 milliliters) and acetate (100 milliliters), vacuum removal solvent then.Resistates and ether (100 milliliters) grind, and collect solid and the crystallization from ethanol that obtains by filtering then, obtain 3-(benzo [b] thiene-3-yl-)-2-methyl-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt, be white solid (4.9 gram), m.p.277-278 ℃.Alternative preparation A

A) under about 5 ℃, bromine (20 milliliters) solution in the mixture of benzo [b] thiophene in the methylene dichloride (500 milliliters) that stirs (50 gram) and anhydrous sodium acetate (46 gram) in the drip dichloromethane (100 milliliters), this mixture at room temperature stirred 72 hours, then solvent was removed in its filtration and vacuum.Distillation residue obtain 3-bromo benzo [b] thiophene (51.3 gram) of light yellow oil, under the 53Pa b.p.93-104 ℃.

B) N in the water of Jiao Baning (500 milliliters), the solution of O-dimethyl hydroxyl amine hydrochlorate (50 gram) cools off in ice, adds salt of wormwood (125 gram) through 10 minutes in batches.Add toluene (500 milliliters), stirred mixture is cooled to 0 ℃, drip propionyl chloride (43 milliliters) at 0-5 ℃ then.After adding, this mixture stirred 5 minutes down at 0 ℃, removed cooling bath, continued again to stir 1 hour.Water phase separated and wash with toluene (2 * 100 milliliters), toluene solution water of He Binging (200 milliliters) and saturated sodium chloride aqueous solution (200 milliliters) washing then, dry (sodium sulfate), vacuum is removed solvent, obtain colorless oil N-methoxyl group-N-methyl propanamide (19.9 gram), it just need not be further purified and be used.The further separated product of water by then extracting from merging with methylene dichloride (2 * 100 milliliters) with ether (2 * 100 milliliters).The dry extraction liquid (sodium sulfate) that merges, vacuum is removed solvent, obtains colorless oil N-methoxyl group-N-methyl propanamide (14.2 gram), and it just need not be further purified and be used.

C) add a little iodine crystal to the magnesium chips (5.05 gram) and the mixture of tetrahydrofuran (THF) (25 milliliters), add 10 milliliters of the solution of 3-bromo benzo [b] thiophene (42.1 restrain) in the tetrahydrofuran (THF) (200 milliliters) then.This mixture of heating causes and forms green reagent under nitrogen, removes heating source then, and adds remaining 3-bromo benzo [b] thiophene solution with the speed that keeps gentle reflux under stirring.When adding (about 35 minutes), with this mixture restir 35 minutes under not heating, heating 10 minutes under refluxing then, and make and be cooled to room temperature.The solution that added the N-methoxyl group-N-methyl propanamide (23.1 gram) in the tetrahydrofuran (THF) (100 milliliters) through 2 minutes, this mixture at room temperature stirred 20 minutes and stirred 5 hours under reflux temperature, in ice, cool off then, and drip 2M hydrochloric acid (125 milliliters).This mixture stirred 30 minutes, filtered (Celite), and vacuum concentrated filtrate is to remove tetrahydrofuran (THF).Product is extracted in the ethyl acetate (2 * 300 milliliters), and water (2 * 200 milliliters) and saturated sodium chloride aqueous solution (2 * 200 milliliters) wash the extraction liquid that merges then, and dry (sodium sulfate), vacuum is removed solvent.Resistates grinds with sherwood oil (boiling point 60-80 ℃) (100 milliliters), filters and collects the solid that obtains, and 45 ℃ of following vacuum-dryings 6 hours, obtain cream-coloured solid 3-propionyl benzo [b] thiophene (23.3 gram), m.p.73-75 ℃.

D) add tribromide phenyltrimethyammonium (8.6 gram) in the solution of 3-propionyl benzo [b] thiophene (4.34 gram) in the tetrahydrofuran (THF) (80 milliliters) that 10 fens clockwise stirs under 0-5 ℃ of following nitrogen in batches, then this mixture was at room temperature stirred 4 hours.Filter to remove the solid that obtains and wash with tetrahydrofuran (THF) (30 milliliters), merging filtrate and washings then, and vacuum removes solvent, obtains 1-(benzo [b] thiene-3-yl-)-2-bromo third-1-ketone, be brown oil, it just need not be further purified and be used.

E) under the nitrogen with crude product 1-(benzo [b] thiene-3-yl-)-2-bromo third-1-ketone, 2-imidazolidine thioketones (2.33 gram), and the mixture of ethanol (120 milliliters) heated 15 minutes under refluxing, add acetate (60 milliliters) then, heating is after 24 hours under refluxing for this mixture, and vacuum is removed solvent.Resistates crystallization from ethanol (125 milliliters) obtains 3-(benzo [b] thiene-3-yl-)-2-methyl-5, and the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also, is white solid (4.4 gram), m.p.272-274 ℃.Alternative preparation B

A) under the room temperature with 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (200 the gram; With the similar approach preparation of describing among the WO97/02269), the mixture vigorous stirring of saturated aqueous sodium carbonate (1000 milliliters) and methylene dichloride (2000 milliliters) 1.5 hours is separated organic layer then, water (500 milliliters) washing, dry (sal epsom), and vacuum is removed solvent.Repeat this method with identical scale, merge twice product, obtain light yellow solid 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole (264.3 gram) also, and it just need not be further purified and be used.

B) under 0-5 ℃ through 1.75 hours 3-(benzo [b] thiene-3-yl-)-5 in the methylene dichloride that stirs, 6-glyoxalidine also [2,1-b] the solution dripping bromine (55.5 milliliters) of thiazole (264.3 gram), stir this mixture 30 minutes down and at room temperature stirred 1 hour at 0 ℃ then.Filter and collect the solid that obtains, with methylene dichloride (300 milliliters) washing and 70 ℃ of following vacuum-dryings, obtain light yellow solid 3-(benzo [b] thiene-3-yl-)-2-bromo-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (431 gram), it just need not be further purified and be used.

C) in the solution of 1 hour ethyl-magnesium-chloride [2.0M diethyl ether solution (620 milliliters)] in the tetrahydrofuran (THF) (1700 milliliters) that stirs, add 3-(benzo [b] thiene-3-yl-)-2-bromo-5 under 0-8 ℃ under the nitrogen in batches, 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (170 gram), stir this mixture 1.5 hours down at 3 ℃ then.Added dimethyl formamide (136 milliliters) through 30 minutes under 3-8 ℃, then this mixture was at room temperature stirred 2 hours, be cooled to 8 ℃ and add saturated aqueous ammonium chloride solution (600 milliliters) and water (350 milliliters) and stopped reaction by careful.Add ethyl acetate (1500 milliliters), this mixture was at room temperature stirred 18 hours, filter and collect the solid (fraction 1) that obtains.The organic layer of separating filtrate, with saturated sodium chloride aqueous solution (500 milliliters) washing, dry (sal epsom), vacuum is removed solvent.Resistates is dissolved in the propan-2-ol (1000 milliliters) of heat, at room temperature leaves standstill behind the filtered while hot solution 20 hours.Filter and collect the solid that obtains, with propan-2-ol (100 milliliters) washing, and 70 ℃ of following vacuum-dryings, obtain yellow solid 3-(benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (19.4 gram) also, m.p.206 ℃.Under the room temperature with solid fraction 1, methylene dichloride (2100 milliliters), the mixture of 2M hydrochloric acid (250 milliliters) and water (1000 milliliters) stirred 15 minutes, added triethylamine (80 milliliters) then.The separate dichloromethane layer is by being extracted in the methylene dichloride (500 milliliters) and from other product of aqueous phase separation.The dry dichloromethane solution (sal epsom) that merges, vacuum is removed solvent, and the yellow solid 3-that gets back (benzo [b] thiene-3-yl-)-5,6-glyoxalidine be [2,1-b] thiazole-2-formaldehyde (63.0 gram) also, m.p.208 ℃.

D) suspension of the aluminum chloride fine powder in the methylene dichloride (330 milliliters) of ice-cooled stirring (14 gram) adds borine/tert-butylamine mixture (18.3 gram) in batches, then this mixture is stirred 55 minutes down at 0 ℃.3-in 0 ℃ of following drip dichloromethane (70 milliliters) (benzo [b] thiene-3-yl-)-5,6-glyoxalidine be the solution of [2,1-b] thiazole-2-formaldehyde (10 gram) also, then this mixture was stirred 15 minutes and at room temperature stirred 21 hours down at 0 ℃.End mixture by carefully adding entry (1000 milliliters) back adding 2.5M hydrochloric acid (175 milliliters), by adding the 5M aqueous sodium hydroxide solution its alkalization is pH10 then.Water phase separated, and with methylene dichloride (300 milliliters) washing, the dry then dichloromethane solution (sal epsom) that merges, vacuum is removed solvent.Half (5 gram) resistates is dissolved in ethanol (12 milliliters) and adds 48% Hydrogen bromide (3.5 milliliters).Dilute this mixture and filter the solid that collection obtains with ether (100 milliliters), then it is suspended in the ethanol (46 milliliters).This mixture was heated 15 minutes under refluxing, in ice, cool off, filter and collect the solid that obtains, with ether (40 milliliters) washing and vacuum-drying, obtain white solid 3-(benzo [b] thiene-3-yl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (3.54 gram) also, m.p.273-276 ℃.

Embodiment 2

A)-70 n-Butyl Lithium (the 2.5M hexane solution in the ether (46 milliliters) that stirs under ℃ following nitrogen; The solution of 3-bromo-5-chloro benzo [b] thiophene 4.14 drips of solution milliliter) adds diethyl ether in (20 milliliters) (2 gram) stirs mixture 30 minutes down at-70 ℃ then.Once add 2-bromo propionyl chloride (1.67 gram), mixture was stirred 4 hours down at-70 ℃, make it be warmed to 0 ℃ then.With mixture 0 ℃ of following restir 30 minutes, then by adding saturated aqueous ammonium chloride solution (50 milliliters) stopped reaction.Separate the waterbearing stratum, and, use saturated sodium chloride aqueous solution (2 * 30 milliliters) to wash ethereal solution and the drying (sodium sulfate) that merges then with ether (2 * 30 milliliters) washing.Vacuum is removed solvent, through silicon-dioxide purifying resistates, uses sherwood oil (boiling point 60-80 ℃) and 9: 1 mixture of ethyl acetate to be eluent by the flash chromatography method.Merge suitable fraction and vacuum and remove solvent, obtain 1-(5-chloro benzo [b] thiene-3-yl-)-2-bromo third-1-ketone (0.32 gram) of white solid, it just need not be further purified and be used.

B) under the nitrogen with 1-(5-chloro benzo [b] thiene-3-yl-)-2-bromo third-1-ketone (0.3 gram), the 2-imidazolidine thioketones (0.12 gram) and the mixture of ethanol (10 milliliters) heated 15 minutes under refluxing, add acetate (4 milliliters) then, this mixture heated 24 hours under refluxing, and vacuum is removed solvent then.Resistates is dissolved in the water of minimum volume, by adding the 5M aqueous sodium hydroxide solution this solution alkalization is pH12, and product is extracted in the methylene dichloride (3 * 30 milliliters).Dry extraction liquid (sodium sulfate) and vacuum are removed solvent.By the silicon-dioxide purifying resistates of flash chromatography method in Biotage Flash 40i  device, use methylene dichloride to use 20: 1 mixture of methylene dichloride and methyl alcohol to be eluent then.Merge suitable fraction and vacuum and remove solvent, obtain yellow solid 3-(5-chloro benzo [b] thiene-3-yl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole (0.1 gram) also, m.p.264-267 ℃.

Embodiment 3

A) drip Methyl Thioglycolate (62.87 milliliters) in the solution of the triethylamine (244.85 milliliters) in the dimethyl formamide (400 milliliters) that stirs under 110 ℃ of following nitrogen, then this mixture was stirred 30 minutes down at 110 ℃.Add 2 in the dimethyl formamide (100 milliliters) fast, 6-difluorobenzaldehyde (100 gram) solution heats this mixture 4 hours under refluxing then.Make this mixture be cooled to room temperature, then it is added in the mixture of ice and water (4000 milliliters).Filter and collect product and vacuum-drying, obtain white solid 4-fluoro benzo [b] thiophene-2-carboxylic acid methyl esters (110 gram), it just need not be further purified and be used.

B) add 2M aqueous sodium hydroxide solution (1000 milliliters) in the suspension of 4-fluoro benzo [b] the thiophene-2-carboxylic acid methyl esters in the methyl alcohol (1500 milliliters) that stirs (110 gram) under the nitrogen under the room temperature.Under the room temperature this mixture was stirred 4 hours, then separation solution phase by being decanted in the 2M hydrochloric acid (3000 milliliters) and from unreacted 4-fluoro benzo [b] thiophene-2-carboxylic acid methyl esters.Filtration is collected the solid that obtains and 60 ℃ of following vacuum-dryings, is obtained white solid 4-fluoro benzo [b] thiophene-2-carboxylic acid (77 gram) from acidic mixture, it just need not be further purified and be used.Residual unreacted 4-fluoro benzo [b] thiophene-2-carboxylic acid methyl esters is dissolved in the hot methanol (500 milliliters), at room temperature adds 2M aqueous sodium hydroxide solution (250 milliliters) then.Under the room temperature this mixture was stirred 8 hours, join then in the 2M hydrochloric acid (1000 milliliters).Filter and collect solid and the vacuum-drying that obtains, obtain white solid 4-fluoro benzo [b] thiophene-2-carboxylic acid (33 gram).

C) add ketone powder (40 gram) in the solution of 4-fluoro benzo [b] thiophene-2-carboxylic acid in the quinoline (500 milliliters) that stirs (77 gram), then this mixture is stirred under 180-200 ℃ and heated 2 hours.Make this mixture be cooled to room temperature, then it is added in the 2M hydrochloric acid (1500 milliliters).Add ethyl acetate (1000 milliliters), mixture filters by Celite , then with ethyl acetate (500 milliliters) washing, and the dry then organic layer (sal epsom) that merges, and vacuum is removed solvent.Through silicon-dioxide purifying resistates, use sherwood oil (boiling point 40-60 ℃) then to be eluent by the flash chromatography method with sherwood oil (boiling point 40-60 ℃) and 25: 1 mixture of ethyl acetate.Merge suitable fraction and vacuum and remove solvent, obtain colorless oil 4-fluoro benzo [b] thiophene (50.46 gram).

D)-25 the solution of the bromine (18.7 milliliters) in the mixture drip dichloromethane (200 milliliters) of 4-fluoro benzo [b] thiophene in the methylene dichloride (400 milliliters) that stirs (50.46 gram) and anhydrous sodium acetate (40 restrain) under ℃ following nitrogen, this mixture was at room temperature stirred 18 hours, then solvent is removed in its filtration and vacuum.Resistates is dissolved in methylene dichloride (about 50 milliliters), under nitrogen, adds entry (300 milliliters) and zinc powder (about 40 grams) then.The heating under refluxing of this mixture at room temperature left standstill them 20 hours after 4 hours.Add ethyl acetate (300 milliliters), continued reflux 15 minutes, make mixture be cooled to room temperature then.Filtering mixt (Celite ) and with ethyl acetate (3 * 100 milliliters) washing leaching cake, water phase separated and wash with ethyl acetate (200 milliliters), the dry then organic solution (sal epsom) that merges, vacuum is removed solvent, obtain light brown solid 3-bromo-4-fluoro benzo [b] thiophene (59.4 gram), it just need not be further purified and be used.

E) under 0 ℃ of nitrogen in the tetrahydrofuran (THF) (800 milliliters) that stirs the solution of ethyl-magnesium-bromide [2.0M diethyl ether solution (190 milliliters)] add the solution of 3-bromo-4-fluoro benzo [b] thiophene (59.4 gram) in the tetrahydrofuran (THF) (250 milliliters), then this mixture was heated 1.5 hours and made under refluxing and be cooled to room temperature.Add N-methoxyl group-N-methyl propanamide (33.5 gram) and with the heating 2 hours under refluxing of this mixture.Make mixture be cooled to room temperature, then it is joined in the saturated aqueous ammonium chloride solution (1000 milliliters).Product is extracted in the ethyl acetate (2 * 500 milliliters), the dry then extraction liquid (sal epsom) that merges, vacuum is removed solvent.Through silicon-dioxide purifying resistates, use sherwood oil (boiling point 40-60 ℃) then to be eluent by the flash chromatography method with methylene dichloride.Merge suitable fraction and vacuum and remove solvent, obtain reddish-brown solid 4-fluoro-3-propionyl benzo [b] thiophene (22 gram).

F) solution of 4-fluoro-3-propionyl benzo [b] thiophene in the tetrahydrofuran (THF) (300 milliliters) that stirs (22 gram) adds tribromide phenyltrimethyammonium (39.5 gram) under 0 ℃ of following nitrogen, then this mixture is at room temperature stirred 3 hours.Remove the solid that obtains and use washed with dichloromethane by the silicon-dioxide filtration, merging filtrate and washings then, and vacuum removes solvent, obtains 2-bromo-1-(the 4-fluorobenzene is [b] thiene-3-yl-also) third-1-ketone, be brown oil (about 40 grams) that it just need not be further purified and be used.

G) under the nitrogen with crude product 2-bromo-1-(the 4-fluorobenzene is [b] thiene-3-yl-also) third-1-ketone (about 40 gram), 2-imidazolidine thioketones (10.71 gram), the mixture of ethanol (150 milliliters) and acetate (75 milliliters) heated 2 hours under refluxing, and then add 2-imidazolidine thioketones (2.2g), and continued reflux 2 hours.Mixture is cooled to 0 ℃, filter to collect the solid that obtains and with ethanol (2 * 100 milliliters) washing, then by with the mixture stirring of saturated sodium bicarbonate aqueous solution (500 milliliters) and methylene dichloride (500 milliliters) 30 minutes with its alkalization.Separate organic layer, contain water and vibrate with methylene dichloride (2 * 250 milliliters), the dry then dichloromethane solution (sal epsom) that merges, and vacuum is removed solvent.Resistates is dissolved in ethanol (200 milliliters), adds concentrated hydrochloric acid (6 milliliters) down at 0 ℃ then.Vacuum is removed solvent, and resistates crystallization from ethanol (about 100 milliliters) then obtains 3-(the 4-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, and the 6-glyoxalidine is [2,1-b] thiazole hydrochloride also, is white solid (17.5 gram), m.p.259-262 ℃.

Embodiment 4

Under 0 ℃ in the ethanol (10 milliliters) that stirs 3-(benzo [b] thiene-3-yl-)-2-methyl-5,6-glyoxalidine also [2,1-b] (5 grams are with embodiment 1: the solution that adds the fumaric acid (2.13 gram) in the ethanol (40 milliliters) in the solution similarity method preparation that alternative preparation B describes) for thiazole.This mixture is stirred 15 minutes after-filtration down at 0 ℃ collect solid and the vacuum-drying that obtains, obtain white solid 3-(benzo [b] thiene-3-yl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole fumarate (4.71 gram) also, m.p.179-181 ℃.

Embodiment 5

3-in ethanol (45 milliliters) (benzo [b] thiene-3-yl-)-2-methyl-5,6-glyoxalidine also [2,1-b] thiazole (4.27 grams, with embodiment 1: add concentrated hydrochloric acid (4 milliliters) in the solution similarity method preparation that alternative preparation B describes), add this mixture in ether (250 milliliters) then and stirred 15 minutes.Filter and collect the solid that obtains, with ether (50 milliliters) washing and 70 ℃ of following vacuum-dryings, obtain white solid 3-(benzo [b] thiene-3-yl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrochloride (3.50 gram) also, m.p.254-256 ℃.

Embodiment 6

3-(benzo [b] thiene-3-yl-)-2-methyl-5 in the ethanol (28 milliliters) that stirs, 6-glyoxalidine also [2,1-b] thiazole (2.66 grams, with embodiment 1: the solution similarity method preparation that alternative preparation B describes) adds the D in the ethanol (30 milliliters), the solution of L-tartrate (1.43 gram).The suspension stirring that obtains was added ether (80 milliliters) after 5 minutes.Solid collected by filtration with ether (50 milliliters) washing and 70 ℃ of following vacuum-dryings, obtains white solid 3-(benzo [b] thiene-3-yl-)-2-methyl-5, and the 6-glyoxalidine is [2,1-b] thiazole D also, L-tartrate (4.00 gram), m.p.204-205 ℃.

Embodiment 7

With with embodiment 1: the similarity method that alternative preparation B describes, at first with benzo [b] thiophene bromination, then with reactive magnesium, then with N-methoxyl group-N-methylbutyryl amine reaction, preparation 3-(benzo [b] thiene-3-yl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also, be colorless solid, m.p.219-221 ℃.

Embodiment 8

A)-70 n-Butyl Lithium (the 1.6M hexane solution in the ether (20 milliliters) that stirs under ℃ following nitrogen; 7 milliliters) solution in drip 3-bromo-5-methyl benzo [b] thiophene in the ether (5 milliliters) (2.5 grams; With embodiment 1: the similarity method that alternative preparation A describes prepares by bromination 5-methyl benzo [b] thiophene) solution, then with this mixture-70 ℃ of stirrings 30 minutes down.Dripped the solution of the N-methoxyl group-N-methyl propanamide (1.3 gram) in the ether (5 milliliters) through 20 minutes, stirring the mixture under-70 ℃ 3 hours and making through 20 hours is warmed to room temperature, adds 2M hydrochloric acid (25 milliliters) stopped reaction then.Separate the ether layer, water (25 milliliters) and saturated sodium chloride aqueous solution (25 milliliters) washing, dry (sal epsom), vacuum is removed solvent.Through silicon-dioxide purifying resistates, use sherwood oil (boiling point 60-80 ℃) and 40: 1 mixtures of ethyl acetate to be eluent by the flash chromatography method.Merge suitable fraction and vacuum and remove solvent, obtain 5-methyl-3-propionyl benzo [b] thiophene of pale solid and 20: 1 mixture of 5-methyl-2-propionyl benzo [b] thiophene (1.2 gram), it just need not be further purified and be used.

B) (1.2 grams of 5-methyl-3-propionyl-benzo [b] thiophene in the tetrahydrofuran (THF) (20 milliliters) that stirs under 0 ℃; as above-mentioned preparation) solution in add tribromide phenyltrimethyammonium (2.25 gram) in batches, then this mixture was stirred 1 hour down and at room temperature stirred 20 hours at 0 ℃.Filtering mixt and vacuum are removed solvent.Resistates is dissolved in the methylene dichloride (50 milliliters), water (2 * 50 milliliters) washing then, dry (sal epsom), vacuum is removed solvent, obtains the burgundy solid, and itself and sherwood oil (b.p.60-80 ℃) (50 milliliters) are developed.Vacuum is removed solvent, obtains 2-bromo-1-(5-methyl benzo [b] thiene-3-yl-) third-1-ketone (0.75 gram), its under refluxing under the nitrogen with 2-imidazolidine thioketones (0.27 gram), the mixture heating up of ethanol (30 milliliters) and acetate (15 milliliters) 24 hours.Vacuum is removed solvent, resistates and ether (20 milliliters) development, and filter and collect solid and the vacuum-drying that obtains, obtain 2-methyl-3-(5-methyl benzo [b] thiene-3-yl-)-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt, be white solid (0.52 gram), m.p.266-269 ℃.

Embodiment 9

With with embodiment 1: the similarity method that alternative preparation A describes, at first with benzo [b] thiophene bromination, then with reactive magnesium, with N-methoxyl group-3, the reaction of N-amide dimethyl butyrate prepares 3-(benzo [b] thiene-3-yl-)-2-sec.-propyl-5 then, 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt, be the light brown solid, m.p.208-210 ℃.

Embodiment 10

A)-70 the solution of the 4-fluorophenyl methyl sulfide in the tetrahydrofuran (THF) that stirs (22.0 gram) drips s-butyl lithium (1.25M92: 8 hexanaphthenes: hexanes mixtures solution under ℃ following nitrogen; 100 milliliters), then this mixture was stirred 65 minutes down at-70 ℃.-68 ℃ to-70 ℃ drip dimethyl formamide (13.2 milliliters) down, through 20 hours this stirred mixture slowly are warmed to room temperature then, then it are added the solution of the acetate (10 milliliters) in the entry (500 milliliters).Product is extracted in the ether (3 * 150 milliliters), the extraction liquid of using the washing of 2M hydrochloric acid (200 milliliters) and saturated sodium-chloride water solution (200 milliliters) to merge then, dry (sodium sulfate), vacuum is removed solvent.Identify that by nuclear magnetic resonance spectrum this resistates (25 gram) (just need not be further purified and be used) is estimated mainly to be made up of 2: 3 mixture of 4-fluorophenyl methyl sulfide and 2-fluoro-5-(methylthio group) phenyl aldehyde respectively.

B) under 140-150 ℃ of following nitrogen with the Methyl Thioglycolate (8.9 milliliters) that stirs, crude product 2-fluoro-5-(methylthio group) phenyl aldehyde (25 grams; As above preparation), the mixture heating up of N,N-DIMETHYLACETAMIDE (250 milliliters) and ethyl diisopropyl amine (42 milliliters) 3.5 hours, vacuum is removed solvent then.Add entry (650 milliliters) to resistates, then product is extracted in the methylene dichloride (3 * 150 milliliters).The extraction liquid that water (3 * 150 milliliters) washing merges, dry (Na ₂SO ₄), and vacuum is removed solvent.By grinding the purifying resistates, collect the solid that obtains by filtering then, with ether (2 * 50 milliliters) washing with ether (250 milliliters), vacuum-drying, obtain 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid methyl esters (13.3 gram), be light yellow solid, m.p.89.7-90.4 ℃.

C) sodium hydroxide (8 gram) is dissolved in water (100 milliliters), then this solution is added 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid methyl esters (23.8 grams in the methyl alcohol (300 milliliters) that stirs; With the preparation of above-mentioned similar approach) solution.This mixture heating up refluxed 10 minutes and made at room temperature leave standstill 3 days.By heating suspension is concentrated into about 250 milliliters cumulative volume, add entry (100 milliliters) then, and the heat filtering mixture is to remove undissolved material.Add the solution of the concentrated hydrochloric acid (40 milliliters) in the entry (20 milliliters) to filtrate, filter and collect the solid that obtains, and wash with water, then 80 ℃ of following vacuum-dryings, obtain 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid (21 gram), be light yellow solid, m.p.186-186.5 ℃.

D) under the nitrogen with copper powder (5.3 gram), the mixture of 5-(methylthio group) benzo [b] thiophene-2-carboxylic acid (20 gram) and quinoline (100 milliliters) stirred also reflux 30 minutes, then heat filtering.Filtrate is added concentrated hydrochloric acid (100 milliliters), in the mixture of ice (500 gram) and ether (200 milliliters), filter solid that collection obtains then and wash with ether.Separation contains water and other product is extracted in the ether (2 * 150 milliliters).The ether layer that merges washs with 2M hydrochloric acid (200 milliliters) and water (200 milliliters), and dry (sodium sulfate), vacuum is removed solvent, obtains 5-(methylthio group) benzo [b] thiophene, is light brown solid (14.7 gram), and it just need not be further purified and be used.

E) be lower than the aluminum bromide (26.2 gram) that under 0 ℃ of following nitrogen the solution of 5-(methylthio group) benzo [b] thiophene in the methylene dichloride (180 milliliters) (14.7 gram) is joined stirring; in the mixture of acetyl bromide bromide (7.12 milliliters) and methylene dichloride (120 milliliters), be lower than under 0 ℃ the reddish dark brown solution stirring 30 minutes that will obtain then and at room temperature stirred 20 hours.This solution is added in the mixture of ice (600 gram) and concentrated hydrochloric acid (50 milliliters), add methylene dichloride (300 milliliters) then, and filter (Celite ) and remove insoluble substance.Separate and contain water, and therefrom other product is extracted into methylene dichloride (300 milliliters), the dry then dichloromethane solution (sal epsom) that merges, vacuum is removed solvent.Add acetate (200 milliliters) and methylene dichloride (200 milliliters) to resistates, then add the solution of 2-imidazolidine thioketones in the acetate (200 milliliters) (5.29 gram), methylene dichloride is removed in distillation then.Residual mixture heated 2 hours under refluxing, and by heating under vacuum cumulative volume was reduced to about 200 milliliters then.By coming heat of dissociation solution, make its cooling then from the insoluble substance decant.Remove other insoluble substance as before, remove solvent in 50 ℃ of following vacuum then.Resistates mixes with water (300 milliliters) and 5M aqueous sodium hydroxide solution (300 milliliters), then product is extracted in the methylene dichloride (300 milliliters).Dry extraction liquid (sodium sulfate), vacuum is removed solvent.Through silicon-dioxide partial purification resistates, use ethyl acetate then to use ethyl acetate by the flash chromatography method, 8: 1: 1 mixtures of methyl alcohol and triethylamine are eluent.Merge suitable fraction and vacuum and remove solvent, obtain yellowish brown jelly (3.6 gram) 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole also, and it just need not be further purified and be used.

F) solution with bromine in the methylene dichloride (10 milliliters) (1.87 gram) adds 3-[5-(methylthio group) benzo [b] thiene-3-yl-in the methylene dichloride (80 milliliters) that stirs]-5, the 6-glyoxalidine is [2,1-b] thiazole (3.55 grams also; As above preparation) solution keeps internal temperature to be lower than 20 ℃, then by coming separate dichloromethane and vacuum concentration from the insoluble substance decant simultaneously.Resistates grinds with methylene dichloride (10 milliliters), filters then and collects the solid that obtains, and obtains 2-bromo-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt, be yellowish brown solid (2.97 gram), m.p.260-265 ℃.

G) 2-bromo-3-[5-(methylthio group) benzo [b] thiene-3-yl-in the tetrahydrofuran (THF) (40 milliliters) that stirs under-10 ℃ under the nitrogen]-5,6-glyoxalidine also [2,1-b] suspension of thiazole hydrobromide salt (2.90 gram) adds the solution of ethyl-magnesium-chloride [2.8M tetrahydrofuran solution (8.76 milliliters)], and then this mixture was at room temperature stirred 90 minutes and be cooled to-5 ℃.Add dimethyl formamide (5 milliliters), then the suspension that obtains was at room temperature stirred 2 hours, add ethyl acetate (200 milliliters) and saturated aqueous ammonium chloride solution (200 milliliters) then.The separating ethyl acetate layer, dry (sodium sulfate), vacuum is removed solvent, obtain solid 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (1.4 gram) also, m.p.157-158.5 ℃, it just need not be further purified and be used.

H) add borine/tert-butylamine mixture (1.04 gram) under 0 ℃ of following nitrogen in the suspension of the aluminum chloride fine powder in the methylene dichloride (20 milliliters) that stirs (0.80 gram), then this mixture was stirred 1 hour down at 0 ℃.Add 3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (0.66 gram also; As above preparation), then this mixture was stirred 15 minutes and at room temperature left standstill 20 hours down at 0 ℃.End mixture by carefully adding entry (25 milliliters) back adding 2M hydrochloric acid (25 milliliters), then all borane complexes of thermal degradation.Filter this suspension, then by adding the 5M aqueous sodium hydroxide solution with filtrate alkalization (pH14).Product is extracted in the methylene dichloride (2 * 50 milliliters), the dry then extraction liquid (sodium sulfate) that merges, vacuum is removed solvent.The solution of the anhydrous oxalic acid in the ethyl acetate (10 milliliters) (0.12 gram) is joined in the solution of the safran resistates (0.39 gram) in the mixture of methylene dichloride (25 milliliters) and ethyl acetate (50 milliliters), then distillation removal methylene dichloride.Filter and collect the solid that obtains, wash vacuum-drying then with ethyl acetate (2 * 10 milliliters), obtain white solid 2-methyl-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5,6-glyoxalidine also [2,1-b] thiazole oxalate (0.36 gram), m.p.197 ℃.

Embodiment 11

A) [b] thiophene (2.8 grams: with the similarity methods of embodiment 3 and 10 descriptions from 2 also of the 5-fluorobenzene in the drip dichloromethane (27 milliliters) in the mixture of aluminum chloride in the methylene dichloride (70 milliliters) that stirs (7.34 gram) and 2-bromo propionyl chloride (4.73 gram) under the nitrogen, the preparation of 5-two fluoro-phenyl aldehydes) solution, mixture was at room temperature stirred 2.5 hours, then it is added in the ice-cooled water (250 milliliters) and stirred 1 hour.Separate and contain water, and therefrom other product is extracted in the methylene dichloride (100 milliliters), dichloromethane solution water of He Binging (2 * 100 milliliters) and saturated sodium chloride aqueous solution (2 * 100 milliliters) washing then, dry (sodium sulfate), vacuum is removed solvent.By flash chromatography method twice resistates of silicon-dioxide purifying in Biotage Flash 40i  device, use 9: 1 mixture of sherwood oil (b.p.60-80 ℃) and ether to be eluent.Merge suitable fraction and vacuum and remove solvent, obtain 9: 1 mixtures (2.1 gram) of 2-bromo-1-(the 5-fluorobenzene is [b] thiene-3-yl-also) third-1-ketone and 2-bromo-1-(the 5-fluorobenzene is [b] thiophene-2-yl also) third-1-ketone, it just need not be further purified and be used.

B) with crude product 2-bromo-1-(the 5-fluorobenzene is [b] thiene-3-yl-also) third-1-ketone (2.1 grams; As above-mentioned preparation), the 2-imidazolidine thioketones (0.75 gram) and the mixture of ethanol (60 milliliters) heated 10 minutes under refluxing, and added acetate (30 milliliters) then, and this mixture heated 20 hours under refluxing, make and at room temperature leave standstill 60 hours, vacuum is removed solvent then.Resistates grinds with ethanol (100 milliliters), and the solid that obtains is dissolved in hot ethanol (100 milliliters).By distillation cumulative volume is reduced to about 60 milliliters, makes the mixture cool to room temperature then.Filter to collect the solid that obtains, vacuum-drying, and with ethanol (75 milliliters) recrystallization, obtain 3-(the 5-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also, be white solid (0.45 gram), m.p.268-271 ℃.

Embodiment 12

A) pass through 3-(the 5-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt and 3-(the 5-fluorobenzene is [b] thiophene-2-yl also)-2-methyl-5,6-glyoxalidine also [2,1-b] 58: 42 mixture (the similarity method preparation of describing with the embodiment 11) alkalization of thiazole hydrobromide salt, prepare 3-(the 5-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also.By obtaining this pure free alkali behind the silicon-dioxide purifying of flash chromatography method in BiotageFlash 40i  device, 9: 1 the mixture that uses methylene dichloride and methyl alcohol then is eluent with 1: 1 mixture, and the mixture that perhaps uses 97: 3 mixture of methylene dichloride and methyl alcohol to follow with 9: 1 is eluent.

B) 3-in ethanol (250 milliliters) (the 5-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5,6-glyoxalidine also [2,1-b] solution of thiazole (4.6 gram) adds 5.5M hydrochloric acid (4.3 milliliters), under stirring this mixture is added drop-wise in the ether (400 milliliters), adds ether (2000 milliliters) then.This suspension was at room temperature left standstill 3 days, filter then and collect the solid that obtains, wash with ether (200 milliliters), and 40 ℃ of following vacuum-dryings, obtain 3-(the 5-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrochloride also, be white solid (3.6 gram), m.p.243-244 ℃.

Embodiment 13

5-chloro-3-propionyl benzo [b] thiophene (5.8 grams under 0-5 ℃ of following nitrogen in 2 minutes clockwise tetrahydrofuran (THF) (100 milliliters); the similarity method of describing with embodiment 2 by with n-Butyl Lithium reaction back and N-methoxyl group-N-methyl propanamide reaction from also [b] thiophene preparation of 3-bromo-5-chlorobenzene) solution add tribromide phenyltrimethyammonium (9.7 gram) in batches, then this mixture was at room temperature stirred 2.5 hours.Filter and remove the solid that obtains, vacuum is removed solvent from filtrate then.Resistates, the 2-imidazolidine thioketones (2.65 gram) and the mixture of ethanol (120 milliliters) heated 15 minutes under refluxing, and added acetate (60 milliliters) then.Mixture is heating 24 hours and vacuum removal solvent under refluxing.Add ethanol (50 milliliters) to resistates, vacuum is removed solvent then, obtain a kind of solid, it is recrystallization from hot ethanol (250 milliliters), then 50 ℃ of following vacuum-dryings, obtains 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-2-methyl-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt, be pink solid (6.25 gram), m.p.283-286 ℃.

Embodiment 14

Similarity method with embodiment 11 descriptions, with the 5-chlorobenzene also [b] thiophene [to be similar to heterocyclic chemistry magazine (J.Heterocycl Chem) (1988), 25 (4), the preparation of 1271 method] and the 2-bromobutanoylchloride initial, preparation 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also, be pale solid, m.p.285-289 ℃ (240 ℃ of contractions).

Embodiment 15

Similarity method with embodiment 11 descriptions, also [b] thiophene [to be similar to method that embodiment 3 describes from the preparation of 5-bromo-2-fluorobenzaldehyde] and 2-bromo propionyl chloro are initial with the 5-bromobenzene, preparation 3-(the 5-bromobenzene is [b] thiene-3-yl-also)-2-methyl-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt, be brown solid, m.p.272-275 ℃.

Embodiment 16

(54 restrain with crude product 2-bromo-1-(the 4-fluorobenzene is [b] thiene-3-yl-also) third-1-ketone under the nitrogen, to be similar to the method preparation that embodiment 3 describes), 2-imidazolidine thioketones (19.4 gram), the mixture of ethanol (200 milliliters) and acetate (100 milliliters) heated 2 hours under refluxing, add other 2-imidazolidine thioketones (2 gram) then, and under refluxing, continue heating 30 minutes.This mixture is cooled to 0 ℃, filters and collect the solid vacuum-drying then that obtains, obtain 3-(the 4-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also, is light yellow solid (52.1g), m.p.264-266 ℃.

Embodiment 17

3-(benzo [b] thiene-3-yl-)-5 under-70 ℃ of following nitrogen in 20 minutes clockwise tetrahydrofuran (THF) (80 milliliters), the 6-glyoxalidine is [2,1-b] thiazole (6.7 grams also; Method preparation with the embodiment 3 of WO97/02269) drips n-Butyl Lithium (2.5M hexane solution in the suspension; 14 milliliters), then this mixture was stirred 30 minutes down at-70 ℃.Add dimethyl formamide (2.7 milliliters), make mixture be warmed to room temperature, add saturated aqueous ammonium chloride solution (200 milliliters) stopped reaction then.Product is extracted in the methylene dichloride (3 * 200 milliliters), uses saturated sodium chloride aqueous solution (100 milliliters) washing extraction liquid then, dry (sodium sulfate), vacuum is removed solvent.Through silicon-dioxide purifying resistates, use 9: 1 mixture of methylene dichloride and methyl alcohol to be eluent by the flash chromatography method.Merge suitable fraction and vacuum and remove solvent, obtain resistates (4.3 gram), it uses 20: 1 mixture of methylene dichloride and methyl alcohol to be eluent by the silicon-dioxide purifying of flash chromatography method in Biotage Flash 40i  device.Merge suitable fraction and vacuum and remove solvent, obtain brown solid 3-(benzo [b] furans-3-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (3.3 gram) also, and it just need not be further purified and be used.

To be similar to embodiment 1: the alternative method for preparing the B description is from 3-(benzo [b] furans-3-yl)-5, and the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde (3.0 grams also; To be similar to method for preparing) and borine/tert-butylamine mixture prepare 3-(benzo [b] furans-3-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole crude product (1.6 gram) also.This crude product is dissolved in methylene dichloride (50 milliliters), adds ether (50 milliliters) then.Filter and remove the solid that obtains, vacuum is removed solvent from filtrate then.By the silicon-dioxide purifying resistates of flash chromatography method in JonesFlashmaster II  device, use methylene dichloride to use methylene dichloride and 9: 1 mixture of methyl alcohol to be eluent then.Merge suitable fraction and vacuum and remove solvent, obtain resistates (4.3 gram), it uses 19: 1 mixture of methylene dichloride and methyl alcohol to be eluent by the silicon-dioxide purifying of flash chromatography method in BiotageFlash 40i  device.Merge suitable fraction and vacuum and remove solvent, obtain resistates (0.28 gram), it is dissolved in methyl alcohol (5 milliliters).Add entry (5 milliliters), and this mixture is acidified to pH1 by adding 2M hydrochloric acid.From cotton-shaped solution removal methyl alcohol, filter then and remove insoluble substance under the vacuum.By adding the 2M aqueous sodium hydroxide solution filtrate is alkalized to pH12, filter then and collect the solid that obtains, water (10 milliliters) washing, vacuum-drying, obtain white solid 3-(benzo [b] furans-3-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole (0.18 gram) also, m.p.119-122 ℃.Embodiment A

Describe the purposes of compound of the present invention in pharmaceutical compositions in detail by following description.Term in this explanation " active compound " refers to any compound of the present invention, but any compound of the final product of front embodiment particularly.A) capsule

In capsular preparation, separate coalescent the active compound of 10 parts of weight and the lactose of 240 parts of weight and mixing.With this mixture hard gelatin capsule of packing into, each capsule contains unitary dose or part unit dose of active compound.B) tablet

Prepare tablet with following composition.

Parts by weight

Active compound 10

Lactose 190

W-Gum 22

Polyvinylpyrrolidone 10

Magnesium Stearate 3

With active compound, it is coalescent that lactose and some starch are separated, mix, and with the ethanolic soln of polyvinylpyrrolidone with the mixture pelleting that obtains.Dry granules is mixed with Magnesium Stearate and remaining starch.This mixture of compacting provides tablet on tabletting machine, its each sheet contains unitary dose or part unit dose of active compound.C) enteric coated tablet

Prepare tablet with the method for describing in top (b).With ordinary method, with the ethanol of 20% Cellacefate and 3% diethyl phthalate: the solution of methylene dichloride (1: 1) is with the tablet enteric coating.D) suppository

In the preparation of suppository, in the triglyceride level suppository base of 1300 parts of weight, mix the active compound of 100 parts of weight, this mixture is made suppository, each suppository contains the treatment effective amount of actives.

Claims

1. the compound of formula I

Comprise its pharmacologically acceptable salt, wherein A is S or O; R ₁Be H, halogen, C _1-3Alkyl or C _1-3Alkylthio; R ₂Be H or fluorine; And R ₃Be methyl, ethyl or sec.-propyl.

2. according to the compound of claim 1, wherein A is S.

3. according to the compound of claim 1, wherein A is O.

4. according to the compound of each claim of front, R wherein ₁Be H, fluorine, chlorine, bromine, methyl and methylthio group.

5. according to the compound of each claim of front, R wherein ₃It is methyl.

6. the compound according to the formula I of claim 1 of formula Ia representative

Comprise its pharmacologically acceptable salt, wherein R is H or chlorine.

7. according to the compound of claim 1, wherein A is S; R ₁Be H, fluorine or chlorine; R ₂Be H or fluorine; And R ₃It is methyl.

8. according to the compound of claim 1, wherein A is S; R ₁Be H or fluorine; R ₂Be H or fluorine; And R ₃It is methyl.

9. according to the compound of claim 1, wherein A is S; R ₁Be H; R ₂Be H; And R ₃It is methyl.

10. according to the compound of claim 1, it is selected from 3-(benzo [b] thiene-3-yl-)-2-methyl-5, and the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 4-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(benzo [b] thiene-3-yl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 2-methyl-3-(5-methyl benzo [b] thiene-3-yl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(benzo [b] thiene-3-yl-)-2-sec.-propyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 2-methyl-3-[5-(methylthio group) benzo [b] thiene-3-yl-]-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-fluorobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-chlorobenzene is [b] thiene-3-yl-also)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; 3-(the 5-bromobenzene is [b] thiene-3-yl-also)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; And 3-(benzo [b] furans-3-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also; Comprise its pharmacologically acceptable salt.

11. pharmaceutical composition, it comprises each compound and the pharmaceutically acceptable diluent or the carrier of formula I of claim 1-10 for the treatment of significant quantity.

12. be used as the compound of the formula I of medicine.

13. the compound of formula I, it is used for the treatment of dysthymia disorders, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, dopy, drug abuse, cognitive disorders, presenile dementia, cerebral ischemia, anancastic behavior, panic attack, social phobia, eating disorder, exessive appetite for example, apocleisis, fast food and eating and drinking immoderately, non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidaemia, anxiety, epileptic seizures, nervous disorder, epilepsy and/or the symptom of nerve injury is wherein arranged for example, apoplexy for example, cerebral trauma, cerebral ischemia, head injuries and hemorrhage and conduct smoking cessation auxiliary.

14. the compound of formula I is used for the treatment of dysthymia disorders in preparation, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, dopy, drug abuse, cognitive disorders, presenile dementia, cerebral ischemia, anancastic behavior, panic attack, social phobia, eating disorder, for example exessive appetite, apocleisis, fast food and eat and drink immoderately non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidaemia, anxiety, epileptic seizures, nervous disorder, for example epilepsy and/or the symptom of nerve injury is wherein arranged, apoplexy for example, cerebral trauma, cerebral ischemia, purposes in the medicine of head injuries and hemorrhage and conduct smoking cessation auxiliary.

15. the treatment dysthymia disorders, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, obesity, dopy, drug abuse, cognitive disorders, presenile dementia, cerebral ischemia, anancastic behavior, panic attack, social phobia, eating disorder, for example exessive appetite, apocleisis, fast food and eat and drink immoderately non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia, hyperlipidaemia and nervous method, this method comprise the compound to the formula I of patient's administering therapeutic significant quantity of needs treatment.

16. reduce the method for human craving for tobacco, this method comprises each the compound of formula I to the claim 1-10 of patient's administering therapeutic significant quantity of needs.

17. reduce the method for human smoking cessation back weight increase, this method comprises each the compound of formula I to the claim 1-10 of patient's administering therapeutic significant quantity of needs.

14. each the compound of formula I of claim 1-10, it is used for the treatment of or prevents metabolic trouble and consequent illness, be that living heat of non-exercise motion and accretion rate are fast especially, sexual dysfunction, sleep apnea, syndromes before menstrual period, the urinary incontinence, hyperfunction disease, hiatal hernia and reflux esophagitis, pain, neurodynia particularly, the weight increase relevant with pharmacological agent, chronic fatigue syndrome, osteoarthritis and gout, the cancer relevant with weight increase, menstrual function obstacle, cholelith, orthostatic hypotension and pulmonary hypertension.

15. each the compound of formula I of claim 1-10, it is used for preventing cardiovascular disease, reduces adhesiveness of blood platelet, helps to lose weight after period of pregnancy, or helps to lose weight after the smoking cessation.

16. the preparation method of the compound of formula I described herein.