CN1259945A - Prevention of breast cancer with selective estrogen receptor modulators - Google Patents

Abstract

The present invention provides a method of preventing breast carcinoma or cancer in a patient comprising administering a therapeutically effective amount of a compound having the structure (I) in which R<1> and R<2> are independently hydroxy or alkoxy of one to four carbon atoms; and R<3> and R<4> are independently methyl or ethyl, or R<3> and R<4>, taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methyl-pyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.

Description

The selective estrogen receptor modulators of Breast Cancer Prevention

Technical field

The present invention relates to drug treatment.Particularly, the present invention relates to substituted benzo [b] thiophenes prevented or prevented mammary cancer in the sufferer of this treatment of need application.

Background of invention

In the U.S., mammary cancer or breast cancer are modal cancer form in the women, and are second causes of disease that causes death.According to estimates 1994 and nineteen ninety-five between, have 46000 examples dead among 182000 mammary cancer new cases that occur among the women approximately.

Usually, infer that optimistically most women develop into this disease at the probability that it has 1/10th in life.Mammary cancer becomes women's main causes of death, and also is the reason that causes DB, psychic trauma and financial loss.In fact most of this sick women of infection dies from the effect of its complication directly or indirectly, for example forfeiture of (cancer) transfer, whole body health, or die from the side effect of intervention treatment as operation, radiation or chemotherapy.

Though done a large amount of investigation, people still understand very few to the epidemiology of this disease.Seemingly substantive hereditary component makes some these diseases of patient's easy infection.Although whether not clear is that this hereditary component is brought out or allowed this disease, or only is to have predicted this lysis.The incidence of having known mammary cancer in some families for a long time is higher, but this analysis can't accurately be predicted other family members and this disease can occur.

Carry out the investigation of a large amount of clinical and pharmacology so far, attempted to illustrate the cause of oestrogenic hormon and mammary cancer, getting in touch between keeping and treating.Though people understand many to the relation of oestrogenic hormon in keeping and treat this disease, but there are a large amount of differences in this sick EPDML influence with regard to oestrogenic hormon, for example oestrogenic hormon is inducer (procarcinogen), still causes the obligate co-factor (admissibility) of this disease.

Described oestrogenic hormon (comprising 17b-estradiol, oestrone and active metabolite thereof) is main sexual hormoue in the women, but in addition, oestrogenic hormon is important homeostasis hormone in its whole adult life in the male sex and women.Under the normal circumstances, each has the oestrogenic hormon of certain level per capita.

Male breast carcinoma is rare disease, and it only accounts for below 1% in all male cancers.American Cancer Society reports have 1000 men to be suffered from mammary cancer by diagnosis approximately in the U.S. in 1994, and its mortality ratio is about 300.

Mammary gland ductal carcinoma in situ (DCIS) is the old model of mammary cancer, and wherein, pernicious epithelial hyperplasia arrives in the ductility system, but does not have penetration to cross the sign that basement membrane arrives the periphery mammary tissue at microscopically.Should in time diagnose the middle aged age of whether suffering from DCIS is 52 years old approximately.Use mammography can earlier check out DCIS more and more widely, this is owing to most cases in asymptomatic women are detected in the mammography generaI investigation.

Recommend premenopausal and postmenopausal women and on the possibility of its increase mammary cancer infection risk, caused great dispute with the Hormone Replacement Therapy (HRT) of alleviating its cardiovascular disorder, osteoporosis and other menopause secondary disease women.As if the conclusion of HRT research usually, (many is later stage research) is that the disease of its demonstration is sent out risk and slightly increased.

Opposite with the detrimental action of oestrogenic hormon in causing mammary cancer, people have obtained in a large number (though incomplete) data about getting in touch between oestrogenic hormon and the mammary cancer that occurred.In the commitment of this disease, many breast cancer cells need oestrogenic hormon as somatomedin.Also definite in addition, but do not recognize fully, why in the process of this disease, the cancer cells forfeiture is to the susceptibility of estrogen effect.In fact, the growth of most cancer cells becomes and is no longer dependent on oestrogenic hormon, and no longer hormonotherapy is responded, comprising " anti--hormone ", GNRH agonist, corpus luteum ketone and male hormone.

Adopt the treatment of hormone-type intervention can obtain very big benefit.Most widely used therapy is to adopt tamoxifen.This therapy has improved the survival rate that the women that suffers from breast cancer was survived 5 years significantly; But, its survival rate at a specified future date (10 years ⁺) be not improved to such degree.Can't improve survival rate at a specified future date is because cancer cells develops to disobeying ly-estrogen gradually from relying on oestrogenic hormon.Therefore, even adopt best combination therapy to regulate method (operation, radiation and/or chemotherapy), the long-term prognosis of sufferer is not good yet, if especially true when the transport property disease exists.Obviously, extremely need to improve treatment, and may the more important thing is and in preliminary investigation, ((de novo) starts anew) to prevent this disease.

Argue that in nearest 10 years reply " estrogen antagonist " therapy is especially used tamoxifen, prevents the possibility of initial mammary cancer to measure.Yet the evidence in part because of the curative effect that lacks tamoxifen, known or genotoxic potential does not also carry out predictability disease prevention test so far in healthy women.

Obviously, extremely need to be applicable to whole crowd's mammary cancer preventive therapy, comprising the high-risk individuality in the masculinity and femininity or there is not the particular risk individuality.

The general speed of invention

The invention provides a kind of method that is used to prevent or prevent mammary cancer in the sufferer of this treatment of need, this method comprises the compound or pharmaceutically acceptable salt thereof with following formula structure or its prodrug of administering therapeutic significant quantity:

The present invention relates to a kind of by in the sufficiently long time, using the formula I compound or pharmaceutically acceptable salt thereof of significant quantity or the method that its prodrug prevents mammary cancer to human body, wherein said human body also mammary cancer do not occurred by diagnosis to be worsened, but has been confirmed as ill danger.

In the last structure of showing, R ¹And R ²Be independently selected from hydroxyl and the alkoxyl group that contains 1-4 carbon atom.

R ³And R ⁴Be independently selected from methyl or ethyl, or R ³And R ⁴Form 1-pyrrolidyl, methyl isophthalic acid-pyrrolidyl, dimethyl-1-pyrrolidyl, piperidino, 4-morpholino or hexamethyleneimino ring jointly with the nitrogen-atoms that is connected.

Compound of the present invention is selective estrogen receptor modulators (SERM ' s), that is to say, in one or more pre-determined target tissues, produce the oestrogenic hormon agonism, in germinal tissue such as mammary gland or uterus, produce oestrogenic hormon antagonistic action and/or faint (promptly not having clinical meaning) agonism simultaneously.

Detailed Description Of The Invention

The present invention relates to the discovery that the compound shown in the following formula I is applicable to Breast Cancer Prevention.Method provided by the invention is to use The compounds of this invention or its pharmacologically acceptable salt or its solvate of doses to this sufferer of need, effectively to prevent mammary cancer.

In present specification and appended claims, conventional term has its its ordinary meaning.

Term " prevention ", " prevention " and " preventing " comprise makes sufferer reduce the possibility that mammary cancer takes place or worsens.

Term used herein " initial (de novo) " is meant that in preliminary investigation the normal breast cell does not change or is deformed into cancer cells or malignant cell.This transformation can betide same cell or daughter cell was gone through in a plurality of stages of evolutionary process, or occurs in one but in the crucial incident.This initial procedure is moved, moves life or spread to new location opposite from former position of tumour with the cell that transforms or worsened.The invention still further relates to and give the sufferer that has initial mammary cancer deterioration danger formula I compound administration.

Do not have specific mammary cancer to worsen dangerous people and be meant that beginning to occur mammary cancer worsens but do not have sign or doubtful point to show that it suffers from this sick possibility and be higher than normal risk, and never be diagnosed as this disease.Causing the greatest danger factor that mammary cancer worsens is personal history or the early stage disease that takes place, even even when the disease alleviation represents that for no sign disease exists.Another Hazard Factor are that this sick family history of suffering from is arranged.

Term " alkyl " representative by sloughing a hydrogen atom deutero-unit price gene, and comprises as groups such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyls on methane, ethane or the straight or branched hydrocarbon.

" alkoxyl group " is meant the abovementioned alkyl that links to each other with parent molecular moiety by a Sauerstoffatom, and comprises for example groups such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert.-butoxy.In the present invention, preferred alkoxyl group is a methoxyl group.

Term used herein " prodrug " is meant and contains the The compounds of this invention that can break to form the group of the active compound of the present invention with therapeutic action the human body metabolism.Especially, drug compound comprises those substituent R in the following formula structure before described ¹And R ²Simultaneously or both one of be hydroxyl through pharmaceutically acceptable hydroxyl protecting group protection, the metabolism fracture in vivo of described hydroxyl protecting group generates corresponding monohydroxy of the present invention or dihydroxy compound.At people's such as T.W.Greene " protecting group in the organic synthesis ", second edition, John Wiley﹠amp; Sons, Inc., New York has described hydroxyl protecting group in 1991, the 2 chapters.Simple ether or ester group are preferred prodrug hydroxyl protecting groups.

Preferred The compounds of this invention comprises:

6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(2-piperidyl-oxyethyl group)-phenoxy group] benzo [b] thiophene or its pharmacologically acceptable salt or its prodrug; With

6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl-oxyethyl group)-phenoxy group] benzo [b] thiophene or its pharmacologically acceptable salt or its prodrug.

The preparation of The compounds of this invention

The starting raw material that is applicable to the The compounds of this invention synthetic route be basically according to C.D.Jones at United States Patent (USP) 4,418, the method preparation of describing in 068 and 4,133,814.Described starting raw material has formula 1: R wherein ⁵And R ⁶Be independently selected from-H or hydroxyl protecting group.

Described R ⁵And R ⁶Hydroxyl protecting group be prepare in a part of building-up process, to introduce and and then the blocking group in the synthetic later stages, sloughed, this protecting group is used for the group of protecting those may react in the chemical operation process.Though contain the compound of this protecting group and be crucial chemical intermediate (though some derivatives also biologically active), strict its precision architecture that limits.Many formation, the reaction that removes and form this protecting group are disclosed in numerous classics, comprising, for example: " protecting group in the organic chemistry ", Plenum Press (London ﹠amp; New York, 1973); Greene, T.W., " protecting group in the organic synthesis ", Wiley (New York, 1981); " peptides ", I volume, Schrooder ﹠amp; Lubke, Academic Press, (London ﹠amp; New Yrk, 1965).

Representational hydroxyl protecting group comprises, for example :-C ₁-C ₄Alkyl ,-C ₁-C ₄Alkoxyl group ,-CO-(C ₁-C ₆Alkyl) ,-SO ₂-(C ₄-C ₆Alkyl) and-CO-Ar, wherein Ar is benzyl or the optional phenyl that replaces.Term " phenyl of replacement " is meant and contains one or more C of being selected from ₁-C ₄Alkyl, C ₁-C ₄The substituent phenyl of alkoxyl group, hydroxyl, nitro, halogen and three (chlorine or fluorine) methyl.Term " halogen " is meant bromine, chlorine, fluorine and iodine.

For formula 1Compound, preferred R ⁵And R ⁶Substituting group is methyl, sec.-propyl, benzyl and methoxymethyl.R wherein ⁵And R ⁶The compound that respectively is methyl can prepare in the method described in its references according to Jones above.

Also can remove R selectively ⁵Hydroxyl protecting group, but retain R ⁶Hydroxyl protecting group is as the part of end product, thereby makes formula 1 compound.Equally, at selectively removing R ⁶In the situation of hydroxyl protecting group, also be really alternatively with R ⁵Hydroxyl protecting group remains.For example, R ⁵Be sec.-propyl or benzyl and R ⁶It is methyl.Remove sec.-propyl or benzyl moiety selectively through standard manner, and keep R ⁶The methyl protecting group is as the integral part of end product.

Shown in reaction scheme I, the first step that is used to prepare this method of some compound of the present invention comprises, optionally in formula 1Go up for 3 of compound and introduce leavings group R ⁷, to form described formula 2 compounds, with the product and 4-(through the hydroxyl of the protection) phenol of this reaction 3The coupling production 4Compound, and optionally slough R ⁸Hydroxyl protecting group forms formula 5Compound.In the sequence of steps of reaction scheme I, select hydroxyl protecting group R ⁵, R ⁶And R ⁸Mode should be, in the end one the step in, optionally with hydroxyl protecting group R ⁸At hydroxyl protecting group R ⁵And R ⁶Existence under slough.

Reaction scheme I

In the first step of reaction scheme I, by standard method optionally in formula 1Introduce a suitable leavings group for 3 of starting raw material.Suitable R ⁷Leavings group comprises: sulphonate base class, for example methylsulfonic acid ester group, 4-bromo-benzene sulfonic acid ester group, toluenesulphonic acids ester group, ethyl sulfonic acid base, different propane sulfonic acid ester group, 4-methoxy benzenesulfonic acid ester group, 4-nitrobenzene-sulfonic acid ester group, 2-chlorobenzenesulfonic acid ester group, trifluoromethane sulfonic acid ester group etc.; Halogen, for example bromine, chlorine and iodine, and other relevant leavings groups.Yet, in order to guarantee to replace suitable leavings group, preferably adopt described halogen, and preferred especially bromine.

This reaction adopts standard method to carry out.For example, when adopting preferred halide reagent, with 1 normal described halide reagent (preferred bromide) and 1 normal formula 1Substrate reacts in The suitable solvent such as chloroform or acetate.This reaction is normally carried out under about 40 ℃-Yue 80 ℃ temperature.

Subsequently with the reaction product in the last preparation process, formula 2Compound is with 4-(through the hydroxyl of protection) phenol 3Reaction forms formula 4Compound, wherein R ⁸It is a hydroxyl protecting group that alternative removes.Usually, do not make formula 3The R of compound ⁵And the R that can exist ⁶Not under the situation that can be removed, the 4-hydroxyl protecting group of phenol can be any known protecting group that can be removed by selectivity.Preferred R ⁸Protecting group comprises: work as R ⁵And/or R ⁶R when being not methoxymethyl ⁸Protecting group can be a methoxymethyl, and benzyl.Wherein, preferred benzyl.Reactant 4-(through the hydroxyl of protection) phenol can be buied or make through standard method.

Formula 2Compound and those formulas 3Coupled reaction between the compound is by well-known to one skilled in the art ullmann reaction, and generally according to standard method carry out [referring to, for example, " modern organic chemistry: reaction, mechanism and structure ", the 4th edition, the 3-16 page or leaf, (J.March, ed., JohnWiley ﹠amp; Sons, Inc.1992); Jones, C.D., The magazine Beijing translation version I of Chemical Society, 4: 407 (1992)].

Usually, in the presence of Red copper oxide (I) catalyzer that waits mole number at the most and appropriate solvent, with two aryl substrates reflux under the rare gas element atmosphere.Preferably with 1 equivalent R wherein ⁷Formula for bromine 2Compound and 1 equivalent 4-benzyloxy phenol react in the presence of 1 equivalent Red copper oxide.

The solvent that is applicable to this reaction is that those keep inert solvent or solvent mixture in entire reaction course.Usually, organic bases, particularly hindered base, for example 2 is preferred solvent.

The temperature that generally should adopt in this step is enough to make this coupled reaction to reach fully, and will influence the required time of reaction.When under inert atmosphere such as nitrogen during with the reaction mixture reflux, the time that reacts completely was generally about 20-about 60 hours.

With formula 2Compound and formula 3Compound coupling production 4Behind the compound, can be through known method of reducing with formula 4R ⁸Hydroxyl protecting group optionally removes, thus the formula of making 5Compound.This selective reaction must not influence R ⁵And the R that may exist ⁶Hydroxyl protecting group.

Work as R ⁸When being preferred benzyl group, and R ⁵And the R that may exist ⁶When being respectively methyl, this step reaction realizes by the standard hydrogen solution.Usually, with formula 4Substrate joins in appropriate solvent or the solvent mixture, adds a kind of protophobe of this reaction and hydrogenation catalyst that is suitable for accelerated subsequently.

The catalyzer that is suitable for comprises precious metal and oxide compound, for example is adsorbed on the oxide compound of palladium, platinum and rhodium on carrier such as charcoal or the lime carbonate.Wherein, preferred palladium charcoal, more preferably 10% palladium charcoal.The solvent that is applicable to this reaction is that those can keep inert solvent or solvent mixture in entire reaction.Usually, ethyl acetate and C ₁-C ₄Fatty Alcohol(C12-C14 and C12-C18), more preferably ethanol.For this reaction, hydrochloric acid serves as suitable and preferred protophobe.

When reaction at room temperature with the pressure range of about 30psi (206.8 kPas)-Yue 50psi (344.7 kPas) in when carrying out, this reaction is carried out comparatively fast.The process of this reaction can be monitored by standard colour chart technology such as thin layer chromatography.

Shown in reaction scheme II, making formula 5Behind the compound, with itself and formula 6The compound reaction:

R ⁴R ⁵N-(CH ₂) ₂-Q

6R wherein ⁴And R ⁵Definition as above, and Q is bromine or chlorine preferably, thus the formula of formation 7Compound.And then with formula 7Compound deprotection production I compound.

Reaction scheme II

Ia，R ⁵＝R ⁶＝H

Ib，R ⁵＝H

Ic，R ⁶＝H

In the first step of route II, reaction is undertaken by standard method.Formula 6Compound can buy or by the preparation of the known method of one skilled in the art.Preferred employing formula 6The hydrochloride of compound.At one of The compounds of this invention more preferably in the situation, adopted 2-chloroethyl piperidine hydrochlorate.

Usually, will be at least about 1 normal formula 5Substrate is at least about 4 equivalent carbonic acid an alkali metal salts, the existence of preferred cesium carbonate and appropriate solvent down with 2 normal formulas 6The compound reaction.

The solvent that is applicable to this reaction is that those keep inert solvent or solvent mixture in entire reaction.Preferred N, dinethylformamide, particularly its anhydrous form.The temperature that adopts in this step reaction is enough to make this alkylated reaction to reach complete.Usually, room temperature condition enough and be preferred temperature.This reaction suits under inert atmosphere, and is concrete as carrying out under the nitrogen atmosphere.

Under suitable reaction conditions, this reaction will be issued at about 16-fully in about 20 hours.This reaction process can be passed through the standard colour chart technical monitoring.

In another route of preparation The compounds of this invention, shown in following reaction scheme III, will be dissolved in the formula in the basic solution 5Compound and excessive formula 8The alkylating reagent reaction:

Q-(CH ₂) _n-Q’

8Wherein Q and Q ' are identical or different leavings groups.Above mentioned the leavings group that is suitable for.

Reaction scheme III

Ia，R ⁵＝R ⁶＝H

Ib，R ⁵＝H

Ic，R ⁶＝H

The preferred basic solution of this alkylated reaction is to contain lime carbonate in inert solvent, and described inert solvent is methyl ethyl ketone (MEK) or DMF for example.In this solution, the hydroxyl without protection of formula 5 compounds is converted into the phenates ion, and it has replaced a leavings group in the alkylating reagent.

When reactant is contained in the described basic solution and reagent is refluxed so that when reacting completely, it is best that this reaction is carried out.When adopting MEK as preferred solvent, the reaction times was at about 6 hours-Yue 20 hours.

Subsequently with the reaction product of this step, formula 9Compound utilizes standard technique and formula 10The compound reaction forms formula 7Compound, described formula 10Compound is selected from piperidino, 1-pyrrolidyl, methyl isophthalic acid-pyrrolidyl, dimethyl-1-pyrrolidyl, 4-morpholinyl, dimethylamine, diethylamine, Diisopropylamine or 1-hexamethylene imine.Preferred employing formula 10The hydrochloride of compound more preferably adopts piperidine hydrochlorate.This reaction generally be in inert solvent such as dry DMF with formula 9Alkylide reaction and be heated to about 60 ℃-Yue 110 ℃ temperature.When with mixture heating up during to about 90 ℃ of preferred temperature, this reaction only use took about 30 minutes-Yue 1 hour.Yet the change reaction conditions will influence this reaction and reach the required time fully.The process of this reactions steps can be passed through the standard colour chart technical monitoring.

Slough formula with currently known methods IThe R of compound ⁵With the R that may exist ⁶Hydroxyl protecting group can make some preferred formula I compound.Many formation and the reaction that removes this type of protecting group have been disclosed in many classics, comprising, for example, " protecting group in the organic chemistry ", PlenumPress (London ﹠amp; New York, 1973); Greene, T.W., " protecting group in the organic synthesis ", Wiley, (New York, 1981); " peptides ", I volume, Schrooder ﹠amp; Lubke, Academic Press (London ﹠amp; New York, 1965).Be used to remove preferred R ⁷And/or R ⁸The method of hydroxyl protecting group, especially methyl and methoxymethyl is described in the following example basically.

Another and be preferably to be used to prepare the method for The compounds of this invention shown in reaction scheme IV.In this route, formula 2The sulphur atom of compound is oxidized into sulfoxide compound 11, subsequently itself and nucleophilic group are reacted, with drawing-in system IThe Sauerstoffatom connecting key.Subsequently with formula 12The sulfoxide partial reduction, obtain some The compounds of this invention.

Reaction scheme IV

Ia，R ⁵＝R ⁶＝H

Ib，R ⁵＝H

Ic，R ⁶＝H

In the first step of this synthetic route, formula 2Compound optionally is oxidized to sulfoxide compound 12Thereby, obtain some The compounds of this invention.Many known methods be applicable to this reaction in step [referring to, for example, Madesclaire, M., Tetrahedron, 42(20); 5459-5495 (1986); Trost, B.M. waits the people, The tetrahedron communication, 22(14); 1280-1290 (1981); Drabowicz, J. waits the people, Synthesising communication, 11(12); 1025-1030 (1981); Kramer, J.B., In the 34th state of people Family's organic chemistry symposiumWilliamsburg, VA., 6 11-15,1995].But the oxygenizement that many oxygenants provide is unfavorable for being converted into required product, and obviously peroxidation forms sulfone compound.Yet described preferred method can be with formula 2Compound is converted into formula with high yield 12Sulfoxide compound, and do not form or only form a small amount of sulfone compound.This method comprises, with formula 2Compound and the about 1.5 equivalent hydroperoxidations of about 1-, described hydrogen peroxide is dissolved in the methylene dichloride mixed solution that contains about 50% trifluoroacetic acid of the 20%-that has an appointment.This reaction is to carry out under about 10 ℃-Yue 50 ℃ temperature, and needs about 1-reach complete in about 2 hours usually.

Secondly, with predetermined formula 13Nucleophile derivative displacement 3-position leavings group R ⁷Described nucleophile derivative can prepare through standard method.

In this step reaction of this route, polar aprotic solvent preferably as DMF or tetrahydrofuran (THF) in, by using alkali, preferably slightly excessive sodium hydride or the potassium tert.-butoxide of usefulness handled, to take off the acid proton of nucleophilic group.Other adoptable alkali comprises salt of wormwood and cesium carbonate.In addition, also can adopt other solvent such as dioxane or dimethyl sulfoxide (DMSO).This hydrogenation reaction is normally carried out under about 0 ℃-Yue 30 ℃, and needs to make in about 30 minutes and reach complete.Compound with formula XIV joins in the solution of nucleophilicity reagent subsequently.This replacement(metathesis)reaction is to carry out under about 0 ℃-Yue 50 ℃ temperature, and usually needs about 1-about 2 hours.Isolate product by standard method.

In the next step of this route, formula 14Sulfoxide compound be reduced an accepted way of doing sth IBenzothienyl compounds.

When needed, be positioned at reaction scheme IV product and any one the step product salt on one or more hydroxyl protecting groups all can be sloughed.

Before the ester class of formula I the preparation of drug compound be by, with formula-OCO-(C ₁-C ₆Alkyl) group or-OSO ₂(C ₂-C ₆Alkyl) group is replaced the oh group that 6-and/or 4 '-position may exist by currently known methods, referring to, for example United States Patent (USP) 4 358 593.

For example, as-OCO-(C ₁-C ₆Alkyl) is required group, with single-or the formula of two-hydroxyl ICompound and for example reagent react of acidylate chlorine, bromide, prussiate or trinitride, or with suitable acid anhydrides or mixed anhydride reaction.This reaction is normally carried out in basic solvent such as pyridine, lutidine, quinoline or isoquinoline 99.9, or carries out in tertiary amines solvent such as triethylamine, tributylamine, methyl piperidine etc.This reaction also can be reacted in inert solvent such as ethyl acetate, dimethyl formamide, dimethyl sulfoxide (DMSO), dioxane, glycol dimethyl ether, acetonitrile, acetone, methylethylketone etc., in this type of inert solvent, should add 1 normal acid scavenger (indicating) at least, for example tertiary amine except following.If necessary, can use acylation catalyst, as 4-dimethylaminopyridine or 4-pyrrolidyl pyridine.Referring to, people such as Haslam for example Tetrahedron 36: 2409-2433 (1980).

These reactions are under suitable temperature, carry out in-25 ℃-Yue 100 ℃ approximately, and this type of reaction often are at inert atmosphere, finish as under the nitrogen atmosphere.And room temperature condition generally is enough to make reaction to be carried out.

Acidylate to 6-position and/or 4 '-position hydroxyl also can be that the acid catalyzed reaction by suitable carboxylic acid compound is realized in inert organic solvents.Used acid catalyst for example is sulfuric acid, Tripyrophosphoric acid, methylsulfonic acid etc.

Can also be by making drug compound before the above-mentioned ester class with suitable acid forming activity ester; the ester that forms with known agent for example, described reagent for example is dicyclohexylcarbodiimide, acylimidazole compounds, nitrophenyl phenolic compounds, pentachlorophenol, N-hydroxyl sulfimide and I-hydroxybenzotriazole.Referring to, for example, Japan Chemical Society circular 38: 1979 (1975) and Chem Ber.788﹠amp; 2024 (1970).

Above-mentioned various providing-OCO-(C ₁-C ₆Alkyl) technology of group is to carry out in aforesaid solvent.Certainly, those technology that do not produce the acids product in reaction process just not need be used acid scavenger in reaction mixture.

For example, 6-and/or the 4 '-position hydroxyl of formula I compound is converted into formula-OSO when hope ₂(C ₂-C ₆During alkyl) group, with this is single-or two-oxy-compound and sulphonic acid anhydride or suitable sulfonic acid, for example SULPHURYL CHLORIDE, bromide or sulphonyl ammonium salt react, as King ﹠amp; Monoir exists American Journal of the Chemical Society 97: described in the 2566-2567 (1975).Also can be with described dihydroxy compound with suitable sulphonic acid anhydride or mix the sulphonic acid anhydride reaction.This reaction is to carry out under the condition of being inquired into for example with the reaction of compound such as carboxylic acid halides class the time. The preparation of The compounds of this invention pharmacologically acceptable salt

Though can adopt the free alkali of formula I compound in drug treatment of the present invention, its pharmaceutical acceptable salt suits to prepare and use.The compound that is applicable to the inventive method mainly forms pharmaceutically useful acid salt with multiple organic acid and mineral acid.These salt also within the scope of the invention.

Used term " pharmacologically acceptable salt " represents people such as Berge at document in present specification and appended claims The pharmaceutical science magazine66 (1): the salt of disclosed type among the 1-19 (1977).The pharmacologically acceptable salt that is suitable for comprises: with the salt that typical inorganic acid forms, described mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, sulfuric acid, phosphoric acid, diphosphanetetroic acid etc. for example; With, by organic acid deutero-salt, described organic acid for example be aliphatic series single-and two-carboxylic acid compound, the phenyl paraffinic acid, hydroxyl alkane acid and hydroxyl chain docosandioic acid, aromatic acid compounds, aliphatic series and the aromatic sulfonic acid class that replace.This type of pharmaceutically useful organic acid addition salt comprises: acetate, phenylacetic acid salt, trifluoroacetate, acrylate, ascorbate salt, benzoate, chloro-benzoate, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, tolyl acid salt, neighbour-acetoxy-benzoic acid salt, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyric acid salt, b-hydroxybutyric acid salt, fourth-1, the 4-diacid salt, oneself is-1 years old, 4, diacid salt, caprate, octylate, muriate, cinnamate, citric acid, formate, fumarate, glycollate, enanthate, hippurate, lactic acid salt, malate, maleate, hydroxymaleic acid salt, malonate, mandelate, mesylate, nicotinate, Yi Yansuan salt, nitrate, oxalate, phthalate, terephthalate, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, propiolate, propionic salt, phenylpropionic acid salt, salicylate, sebacate, succinate, suberate, vitriol, hydrosulfate, pyrosulphate, hydrosulphite, sulfonate, benzene sulfonate, right-bromobenzene sulfonate, chlorobenzene sulfonate, esilate, the 2-isethionate, mesylate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, right-toluene-sulfonate, xylenesulfonate, tartrate etc.Preferred salt is hydrochloride and oxalate.

Usually, by with formula I compound with wait mole number or the excessive slightly acid-respons of mole number, thereby form pharmaceutically useful acid salt.General and mutual solvent of reactant such as ether or ethyl acetate are share.Described salt under normal circumstances can be precipitated out from solution in about 1 hour-Yue 10 days, and can obtain separating by filtering or remove in a usual manner to desolvate.

Compare with its deutero-parent compound, pharmacologically acceptable salt generally has the characteristic of high-dissolvability, thereby is more suitable for being formulated as liquid or emulsion. Pharmaceutical preparation

Compound of the present invention can pass through the number of ways administration, comprising oral, rectum, transdermal, subcutaneous, intravenously, intramuscular and intranasal administration.Preferably before administration these compounds are prepared, selected formulation should depend on the attending doctor.So another aspect of the present invention is to contain the formula I compound or pharmaceutically acceptable salt thereof of significant quantity, the oestrogenic hormon of significant quantity or the pharmaceutical composition of progestogen and pharmaceutically acceptable carrier, thinner or vehicle arbitrarily.

In described preparation, the total amount of active ingredient is the 0.1%-99.9% of said preparation (weight).So-called " pharmaceutically acceptable " be meant carrier, thinner, vehicle and salt must with other component compatibility of preparation, and harmless to the recipient.

Pharmaceutical preparation of the present invention can assign to prepare by method and the easy one-tenth that obtains of employing that affiliated field professional knows.For example, formula I compound no matter be to use separately or share with oestrogenic hormon or progestogen, all can be mixed with tablet, capsule, suspensoid, solution, injection, aerosol, pulvis etc. with conventional excipients, diluent or carrier.

In described preparation, the total amount of active ingredient is the 0.1%-99.9% of said preparation (weight).So-called " pharmaceutically acceptable " be meant carrier, thinner, vehicle and salt must with other component compatibility of preparation, and harmless to the recipient.

Preparation specifically can be formulated as the solid or the liquid form of oral administration, be used for the injection of parenterai administration, part or aerosol drug-delivery preparation, or be used for the suppository of rectum or vagina administration mode.

Can with the pharmaceutically acceptable composition of the present invention by in oral, rectum, intravaginal, non-enteron aisle, part (with pulvis, ointment, creme or drops mode), the cheek or hypogloeeis, through the oral cavity or the intranasal spray application give human body or other Mammalss.Term " parenterai administration " be meant at this comprise in intravenously, intramuscular, intraperitoneal, the breastbone, the administering mode of subcutaneous or intra-articular injection or infusion.

The pharmaceutical composition that the present invention is used for parenterai administration comprises moisture or anhydrous solution, dispersion, suspensoid or the emulsion of sterilization, and before use can be molten more at once be the sterilized powder of sterile solution or suspension.Proper sterilization example moisture and anhydrous carrier, thinner, solvent or carrier comprises water, physiological salt solution, ethanol, polyvalent alcohol (for example glycerine, propylene glycol, poly-(ethylene glycol) etc.), and suitable mixture, vegetables oil (for example sweet oil) and injectable organic esters (for example ethyl oleate).For example, keep suitable flowability and can utilize coating material such as Yelkin TTS, can be by keeping suitable granularity in dispersion and suspension agent situation, and can be by adopting tensio-active agent.

Non-enteron aisle composition can also contain auxiliary material, for example sanitas, wetting agent, lubricant and dispersion agent.By containing Bactericide and mycocide, for example parabens, trichloro-butyl alcohol, (benzene) phenol Sorbic Acid wait and guarantee to prevent action of microorganisms.Also can contain isotonic agent, for example sucrose, sodium-chlor etc. as required.Can postpone the absorption of injection formulations by containing slow absorption agent such as aluminum monostearate and gelatin.

In some cases, for the effect of prolong drug, wish that medicine slowly absorbs after subcutaneous or intramuscular injection.This can pass through to use the crystallization or the amorphous material of liquid suspension or low water solubility, or realizes by medicine is dissolved in or is suspended in the oiliness carrier.Contain in a kind of suspension of low water solubility form of medicine in subcutaneous or intramuscular injection, the uptake rate of medicine depends on its dissolution rate.

Can be by in biodegradable polymers, forming injectable " bank " preparation that medicament microcapsule matrix is made The compounds of this invention, described biodegradable polymers for example is the multipolymer of poly-(lactic acid), poly-(oxyacetic acid), lactic acid and oxyacetic acid, poly-(ortho ester) class and poly-(acid anhydride) class, and these materials are that affiliated field professional is known.According to the proportioning of medicine and polymkeric substance and the characteristic of used concrete polymkeric substance, release rate of drugs can be controlled.

For example, the sterilization of injection formulations can be passed through the fixed filter paper filtering of bacterium, or by before blending that the component of mixture is pre-sterilized, the time of sterilization can also can (pack as the injection of two chambers) before administration before pharmacy.

The solid dosage that is suitable for oral administration comprises capsule, tablet, pill, pulvis and granule.In this solid dosage, described activeconstituents at least with a kind of inertia, pharmaceutically acceptable carrier (for example Trisodium Citrate or Lin Suanergai) and/or (a) weighting agent or filler, starch based for example, lactose, glucose, mannitol and silicic acid class, (b) tackiness agent, carboxymethyl cellulose for example, alginate, gelatin, poly-(V-Pyrol RC), sucrose and gum arabic, (c) wetting Agent for Printing Inks, glycerine for example, (d) disintegrating agent, agar for example, lime carbonate, potato or tapioca (flour), alginic acid, silicate and yellow soda ash, (e) solution retarding agent, for example paraffin, (f) absorption enhancer, quaternary amines mixture for example, (g) wetting agent, for example hexadecanol and Zerol, (h) absorption agent, for example seminose and bentonite, (i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid-state poly-(ethylene glycol), sodium lauryl sulphate, and composition thereof; Mix.In the situation of capsule, tablet and pill, can also contain buffer reagent in the formulation.

Similarly solids composition also can comprise, is filled with vehicle in soft gelatin capsule or hard gelatin capsule, and for example lactose and high-molecular weight gather (ethylene glycol) class etc.

But the solid dosage of preparation such as tablet, sugar-coat agent, capsule, pill and granule be coating or dressing, for example enteric coating or other dressings of knowing in field of pharmaceutical preparations also.Described dressing can contain the lucifuge agent or discharge the reagent of active ingredient at the digestive tube privileged site, and for example the solubility in acid dressing is suitable for active ingredient is discharged in the stomach, and perhaps, the caustic solubility dressing is suitable to be released to active ingredient in the enteron aisle.

Also can be enclosed in the sustained release coating one or more active ingredients are little, and constituted the part of capsule preparations pill by micro-capsule.

The present invention is suitable for oral liquid dosage form and comprises solution, emulsion, suspension, syrup and elixir.Except active ingredient, liquid preparation can also contain conventional inert diluent such as water or other acceptable solvent in this field, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oils (concrete), glycerine, tetrahydrofuran (THF) alcohol, poly-(ethylene glycol), fatty acid sorbitol ester as Oleum Gossypii semen, peanut oil, Semen Maydis oil, seed oil, sweet oil, Viscotrol C and sesame oil, and composition thereof.

Except thinner, liquid oral medicine can also contain auxiliary material, for example wetting agent, emulsifying agent and suspension agent, and sweeting agent, correctives and flavouring agent.

Liquid suspension also can contain suspension agent except containing active ingredient, for example iso stearyl alcohol compound, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, meta-aluminic acid, bentonite, agar and the tragacanth gum of ethoxylation, and composition thereof.

The composition that is suitable for rectum or intravaginal administration then prepares by one or more The compounds of this invention are mixed with suitable nonirritant excipient, described non-stimulated vehicle is theobroma oil, polyoxyethylene glycol or anyly at room temperature be solid but be the suppository wax of liquid under body temperature for example, can discharge active ingredient in rectum or vaginal canal thus.These compound dissolutions in fused wax, are formed predetermined shape, and allow to be hardened to final suppository formulations.

Compound of the present invention also can be with the liposome form administration.Understand as affiliated field, liposome generally is derived from phospholipids compounds or other lipid matters.Liposomal formulation is by brilliant formation of single or multiple lift aqua liquid that is dispersed in the water-bearing media.Can adopt nontoxic, pharmaceutically useful, metabolizable, as can to form liposome lipid.The composition of liposome form of the present invention can contain stablizer, vehicle, sanitas etc. except containing one or more active substances of the present invention.Preferred lipid compound is natural and synthetic phospholipids compounds and phosphatidylcholine compounds (Yelkin TTS).

The method that is used to form liposome is affiliated field professional's known method, for example, and in " cell biology method " XIV volume that Prescott edits, Academic Press, NewYork, N.Y. (1976), the 33rd page, middle disclosed method. Method of the present invention

By use the rat breast cancer that carcinogens N-nitroso-group-the N-methylurea brings out to rat is the widely accepted animal model that is used to study mammary cancer, and has found that the effect that is applicable to the analytical chemistry preventive.

In two independent tests, before ad libitum access, (experiment 1) or intraperitoneal (experiment 2) are used an all 50mg N-nitroso-groups-N-methylurea/kg body weight in the female Sprague-Dawley rat vein of giving 55 day age, in the food blending a) 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl the oxyethyl group)-phenoxy group of different amounts] benzo [b] thiophene hydrochloride, b) (Z)-2-[4-(1,2-phenylbenzene-1-butylene base) phenoxy group]-N, N-dimethyl amine alkali (tamoxifen alkali), or c) contrast.Contrast comprises the carrier that share with chemical compound.

In experiment 1, with respect to 3mg/kg and the tested animal body restatement of 1mg/kg, the edible dosage in the diet is 60mg/kg and 20mg/kg roughly.

In experiment 2, roughly with respect to 1,0.3,0.1 and the tested animal body restatement of 0.03mg/kg, the edible dosage in the diet is 20,6,2 and 0.6mg/kg.

Observe the poisoning sign of rat and claim its body weight, weekly once the formation palpation of tumour.Animals are put to death in 13 week backs (experiment 1) or 18 week backs (experiment 2), determine tumour and weigh when autopsy.These result of experiment are shown in table 1 (experiment 1) and table 2 (experiment 2).

Table 1 is pair through 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group)-phenoxy group] in the female Sprague-Dawley rat of benzo [b] thiophene hydrochloride (embodiment 15) administration the prevention of tumour do

With

Treatment process	No tumour rat	Tumour mean number/rat	Average tumor weight/rat (g)
				Control group	??3/24(12％)	????3.0	????11.0
60mg embodiment 15 compounds/kg food	??11/12(92％)	????0.08	????0.05
				20mg embodiment 15 compounds/kg food	??11/12(92％)	????0.08	????0.03

Table 2 is pair through 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group)-phenoxy group] in the female Sprague-Dawley rat of benzo [b] thiophene hydrochloride administration (embodiment 15) or tamoxifen alkali

The prophylactic effect of tumour

Treatment process	No tumour rat	Tumour mean number/rat	Average tumor weight/rat (g)
				Control group	??6/23(26％)	????1.8	????9.0
20mg embodiment 15 compounds/kg food	??11/12(92％)	????0.08	????0.43
				6mg embodiment 15 compounds/kg food	??7/12(58％)	????0.50	????1.50
2mg embodiment 15 compounds/kg food	??8/12(67％)	????0.50	????3.40
				0.6mg embodiment 15 compounds/kg food	??6/12(50％)	????0.75	????1.60
2mg tamoxifen alkali/kg food	??7/11(64％)	????0.33	????0.52
				0.6mg tamoxifen alkali/kg food	??7/12(58％)	????09.83	????2.10

Testing data shown in the table 1 shows, compares with control group, and the compound of using the embodiment of the invention 15 can obviously reduce the tumour average number (97%) of the incidence (87%) of tumour, every rat and the weight in average (99%) of every rat tumor.

Testing data shows shown in the table 2, compare with control group, the compound of the embodiment of the invention 15 just can be fully with the dosed administration that is low to moderate 0.6mg/kg food and is reduced the tumour average number of the incidence of tumour, every rat and the weight in average of every rat tumor significantly.Observed curative effect depends on dosage, and can with compare by tamoxifen is viewed.

Because the effect of platform sample appears in two kinds of compounds than low dosage the time, so can't be to by all comparisons of being determined by the observed effect of dose.Yet table 1 and 2 data show, as suppressing or the medicine of Breast Cancer Prevention, the compound of embodiment 15 is effective or more effective as tamoxifen at least.

Therefore, use the The compounds of this invention of significant quantity, concrete as 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group)-phenoxy group] benzo [b] thiophene, be a kind of method that mammary cancer forms that is suitable for preventing, preventing or suppresses.

Be meant that at this used term " significant quantity " The compounds of this invention can suppress or prevent the amount that mammary cancer forms.The specific administration dosage of The compounds of this invention is decided by the residing particular condition of each situation, comprising, for example, give effect, route of administration, the sufferer medical history in the past of drug compound, and pathological condition to be treated.Conventional dosage should contain the The compounds of this invention of the about 600mg/ of the 5mg-that has an appointment days non-toxic level.Preferred dosage generally is the about 80mg/ of about 15mg-days.

Decide accurate dosage according to the cumulative dose regimen of the sufferer in the field of medicaments standard practices; That is to say that described compound and increases dosage till observing desired therapeutic effect gradually with the low dosage administration during beginning.

The following example is used to further specify the preparation of The compounds of this invention.These embodiment do not constitute qualification to scope of the present invention, and protection scope of the present invention is defined by appending claims.

The NMR of the following example is the instrument that produces from GE 300Mhz NMR, and except as otherwise noted, with anhydrous hexadeuterated dimethyl sulfoxide as solvent.

Embodiment 1 [6-methoxyl group-3-[4-[2-(piperidino) oxyethyl group]-phenoxy group]-2-(4-p-methoxy-phenyl)] benzo [b] The preparation of thiophene oxalate Step a:The preparation of [6-methoxyl group-2-(4-methoxyl group-phenyl)-3-bromine] benzo [b] thiophene

Under 60 ℃, (27.0g 100mmol) drips bromine (15.98g, 100mmol) solution that is dissolved in the 200ml chloroform to [6-methoxyl group-2-(4-p-methoxy-phenyl)] benzo [b] thiophene in being dissolved in the 1.10L chloroform in the solution.Behind reinforced the finishing, reaction is cooled to room temperature, and solvent removed in vacuo, obtains the white solid of 34.2g (100%) [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-bromo] benzo [b] thiophene.Mp 83-85 ℃. ¹H NMR (DMSO-d6) d 7.70-7.62 (m, 4H), 7.17 (dd, J=8.6,2.0Hz, 1H), 7.09 (d, J=8.4Hz, 2H) .FD mass spectrums: 349,350. theoretical values: C ₁₆H ₁₃O ₂SBr:C, 55.03; H, 3.75. measured value: C, 54.79; H, 3.76. Step b):The preparation of [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-benzyloxy) phenoxy group] benzo [b] thiophene

Under nitrogen atmosphere, [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-bromine] benzo [b] thiophene (34.00g in being dissolved in the 60ml trimethylpyridine, 97.4mmol) add in the solution 4-benzyloxy phenol (38.96g, 194.8mmol) and Red copper oxide (14.5g, 97.4mmol).The gained mixture heating up was refluxed 48 hours.Be cooled to room temperature, mixture is dissolved in (200mL) in the acetone, and by removing by filter inoganic solids.Vacuum concentrated filtrate, and resistates is dissolved in the methylene dichloride (500mL).With this dichloromethane solution with 3 N(3 * 300mL) washings use 1 to hydrochloric acid again NSodium hydroxide (3 * 300mL) washings.With organic layer drying (sodium sulfate), and vacuum concentration.Resistates is added in the 100mL ethyl acetate, form white solid thus, by filter collecting this white solid [[6-methoxyl group-2-(4-p-methoxy-phenyl)] benzo-[b] thiophene of recovery (4.62g, 17.11mmol].Vacuum concentrated filtrate, subsequently through a short silicagel pad (with methylene dichloride as eluent) to remove the substrate raw material.This filtrate of vacuum concentration, and with resistates in the hexane/ethyl acetate crystallization, obtain the off-white color crystalline solid of [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-benzyloxy) phenoxy group] benzo [b]-thiophene of first batch of 7.19g.Mother liquor concentrated and on silica gel chromatography (hexane/ethyl acetate 80: 20), thereby obtain the product of other 1.81g.The ultimate production of [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-benzyloxy) phenoxy group]-benzo [b] thiophene is 9.00g (24%, in the starting raw material that reclaims).With alkaline extract with 5 NHcl acidifying is pH=4, and collects gained precipitation and dry by filtering, and obtains the 4-benzyloxy phenol that 13.3g reclaims.mp100-103℃。 ¹H NMR (CDCl ₃): d 7.60 (d, J=8.8Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H), 4.98 (s, 2H), 3.86 (s, 3H) 3.81 (s, 3H) .FD mass spectrums: 468. theoretical value C ₂₉H ₂₄O ₄S:C, 74.34; H, 5.16. measured value: C, 74.64; H, 5.29. Step c):The preparation of [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-hydroxyl) phenoxy group] benzo [b] thiophene

Be dissolved in [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-benzyloxy) phenoxy group] benzo [b] thiophene in 1% concentrated hydrochloric acid in the ethanol (1.50g 3.20mmol) adds 10% palladium charcoal (300mg) in the solution to being dissolved in 50mL ethyl acetate and 10mL.With the hydrogenation 20 minutes under 40psi of this mixture, after this judge with thin-layer chromatography whether reaction is complete.Make mixture through diatomite removing catalyzer, and the filtrate vacuum concentration is obtained white solid.Make crude product pass through silicagel pad (chloroform is as eluent).Concentrate the white solid of [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-hydroxyl) phenoxy group] benzo [the b]-thiophene that obtains 1.10g (91%).mp?123-126℃.? ¹H?NMR(DMSO-d6)d?9.10(s，1H)，7.59(d，J＝8.8Hz，2H)，7.52(d，J＝2.1Hz，1H)，7.14(d，J＝8.8Hz，1H)，6.95(d，J＝8.8Hz，2H)，6.89(dd，J＝8.8，2.1Hz，1H)，6.72(d，J＝9.0Hz，2H)，6.63(d，J＝9.0Hz，2H)，3.78(s，3H)，3.72(s，3H)。FD mass spectrum: 378. theoretical values: C ₂₂H ₁₈O ₄S:C, 69.82; H, 4.79. measured value: C, 70.06; H, 4.98. Step d):[6-methoxyl group-3-[4-[2-(piperidino)-oxyethyl group] phenoxy group]-2-(4-p-methoxy-phenyl)] preparation of benzo [b] thiophene oxalate

Under nitrogen atmosphere, to being dissolved in the anhydrous N of 7mL, [6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4 hydroxyl) phenoxy group] benzo [b] thiophene in the dinethylformamide (1.12g, 2.97mmol) add in the solution cesium carbonate (3.86g, 11.88mmol).Stir after 10 minutes, and adding 2-chloroethyl piperidine hydrochlorate (1.10g, 1.48mmol).The gained mixture was at room temperature stirred 18 hours.Make this be reflected at distribute between the chloroform/water (being respectively 100mL).Separate each layer and (3 * 50mL) extract water layers with chloroform.Merge (2 * 100mL) washings of organic layer and water.Dry organic layer (sodium sulfate) and concentrate and obtain oily matter is with its chromatography (2% methyl alcohol/chloroform) on silica gel.With required cut simmer down to oily matter, it is dissolved in the 10mL ethyl acetate, and (311mg 3.4mmol) handles with oxalic acid.Stir after 10 minutes, form white precipitate, collect this precipitation and drying, obtain 1.17g (70%) [6-methoxyl group-3-[4-[2-(piperidino) oxyethyl group]-phenoxy group altogether by filtering]-2-(4-p-methoxy-phenyl)] oxalate of benzo [b] thiophene.Mp 197-200 ℃ (decomposition). ¹H NMR (DMSO-d6) d 7.60 (d, J=8.7Hz, 2H), 7.55 (d, J=1.1Hz, 1H), 7.14 (d, J=8.8Hz, 1H), 7.06 (d, J=8.8Hz, 2H), 6.91 (dd, J=8.8,1.1Hz, 1H), 6.87 (s, 4H), 4.19 (broadband t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broadband t, 2H), 3.12-3.06 (m, 4H), and 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H) .FD mass spectrum: 489. theoretical value C ₂₉H ₃₁NO ₄S0.88HO ₂CCO ₂H:C, 64.95:H, 5.80; N, 2.46. measured value: C, 64.92; H, 5.77; N, 2.54.

Embodiment 2 [6-methoxyl group-3-[4-2-(piperidino) oxyethyl group]-phenoxy group]-2-(4-p-methoxy-phenyl)] benzo [b] The preparation of thiophene hydrochloride

With the oxalate of aqueous bases Processing Example 1 to generate its free alkali, subsequently with by the saturated ether reaction of hydrochloric acid, obtain the salt of this title.mp?216-220℃。 ¹H?NMR(DMSO-d6)d?10.20(bs，1H)，7.64(d，J＝8.7Hz，2H)，7.59(d，J＝1.5Hz，1H)，7.18(d，J＝9.0Hz，1H)，7.00.(d，J＝8.7Hz，1H)，6.96(dd，J＝9.0，1.5Hz，1H)，6.92(q，J _AB＝9.0Hz，4H)，4.31(m，2H)，3.83(s，3H)，3.77(s，3H)，3.43(m，4H)，2.97(m，2H)，1.77(m，5H)，1.37(m，1H)。FD mass spectrum: 489. theoretical value C ₂₉H ₃₁NO ₄S1.0HCl:C, 66.21; H, 6.13; N, 2.66. measured value: C, 66., 46; H, 6.16; N, 2.74.

Embodiment 3 [6-methoxyl group-3-[4-[2-(1-pyrrolidyl) oxyethyl group]-phenoxy group-2-(4-p-methoxy-phenyl)] benzo The preparation of [b] thiophene hydrochloride

Prepare this title compound according to same procedure, mp 95-98 ℃ with embodiment 1 compound. ¹H NMR (DMSO-d6) d 7.64 (d, J=9.0Hz, 2H), 7.58 (d, J=2.0Hz, 1H), 7.18 (d, J=9.0Hz, 1H), 7.00 (d, J=9.0Hz, 2H), 6.94 (dd, J=9.0,2.0Hz, 1H), 6.86 (s, 4H), 3.97 (t, J=6.0Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.73 (t, J=6.0Hz, 2H), 2.51 (m, 4H), 1.66 (m, 4H) .FD mass spectrums: 477.Theoretical value: C ₂₈H ₂₉NO ₄S:C, 70.71; H, 6.15; N, 2.99.Measured value: C, 70.59; H, 6.15; N, 3.01.

Embodiment 4 [6-methoxyl group-3-[4-[2-(1-hexamethyleneimino)-oxyethyl group] phenoxy group-2-(4-anisole Base)] preparation of benzo [b] thiophene hydrochloride

Prepare this title compound according to same procedure, mp 189-192 ℃ with embodiment 1 compound. ¹H NMR (DMSO-d6) d 10.55 (bs, 1H), 7.64 (d, J=9.0Hz, 2H), 7.58 (d, J=2.0Hz, 1H), 7.19 (d, J=9.0Hz, 1H), 7.00 (d, J=9.0Hz, 2H), 6.95 (dd, J=9.0,2.0Hz, H), 6.86 (s, 4H), 3.94 (t, J=6.0Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J=6.0Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H).Theoretical value C ₃₀H ₃₃NO ₄S1.0HCl:C, 66.71; H, 6.35; N, 2.59. measured value: C, 66.43; H, 6.46; N, 2.84.

Embodiment 5 [6-methoxyl group-3-[4-[2-(1-N, N-diethylamino)-oxyethyl group] phenoxy group-2-(4-anisole Base)] preparation of benzo [b] thiophene hydrochloride

Prepare this title compound according to same procedure, mp 196-198 ℃ with embodiment 1 compound. ¹H NMR (DMSO-d6) d 10.48 (bs, 1H), 7.64 (d, J=9.0Hz, 2H), 7.59 (d, J=2.0Hz, 1H), 7.19 (d, J=9.0Hz, 1H), 7.00 (d, J=9.0Hz, 2H), 6.97 (dd, J=9.0,2.0Hz, 1H), 6.87 (q, J _AB=9.0Hz, 4H), 4.25 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.54 (m, 2H), 3.09 (m, 4H), 2.00 (m, 3H), 1.88 (m, 3H).Theoretical value: C ₂₈H ₃₁NO ₄S1.5HCl:C, 63.18; H, 6.15; N, 2.63. measured value: C, 63.46; H, 5.79; N, 2.85.

Embodiment 6 [6-methoxyl group-3-[4-[2-(morpholino) oxyethyl group]-phenoxy group]-2-(4-p-methoxy-phenyl)] benzo [b] The preparation of thiophene hydrochloride

Prepare this title compound according to same procedure, mp 208-211 ℃ with embodiment 1 compound. ¹H NMR (DMSO-d6) d 10.6 (bs, 1H), 7.63 (d, J=9.0Hz, 2H), 7.60 (d, J=2.0Hz, 1H), 7.20 (J=9.0Hz, 1H), 7.00 (d, J=9.0Hz, 2H), 6.97 (dd, J=9.0,2.0Hz, 1H), 6.91 (q, J _AB=9.0Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m, 4H), 3.82 (s, 3H), 3.77 (s, 3H), 3.59-3.42 (m, 4H), 3.21-3.10 (m, 2H).Theoretical value C ₂₈H ₂₉NO ₅S1.0HCl:C, 63.09; H, 5.73; N, 2.65.Measured value: C, 63.39; H, 5.80; N, 2.40.

Embodiment 7 [6-hydroxyl-3-[4-[2-(piperidino) oxyethyl group]-phenoxy group]-2-(4-hydroxy phenyl)] benzo [b] thiophene Preparation

With [6-methoxyl group-3-[4-[2-(piperidino) oxyethyl group] phenoxy group]-2-(4-p-methoxy-phenyl)] (10.00g 19.05mmol) is dissolved in the 500mL anhydrous methylene chloride and is cooled to 8 ℃ benzo [b] thiophene hydrochloride.In this solution, add boron tribromide (7.20mL, 76.20mmol).The gained mixture was stirred 2.5 hours down at 8 ℃.The reaction impouring being stirred and be cooled in 0 ℃ the saturated sodium bicarbonate solution (1L) stops reaction.The separate dichloromethane layer, and the solid of remnants is dissolved in the methanol/ethyl acetate.(3 * 500mL) extract water layer to use 5% methanol/ethyl acetate subsequently.Merge all organic extracting solutions (ethyl acetate and methylene dichloride) and dry (sodium sulfate).Vacuum concentration obtains brown solid, its chromatography (silicon-dioxide, 1-7% methyl alcohol/chloroform) is obtained [6-hydroxyl-3-[4-[2-(piperidino) oxyethyl group] phenoxy group of 7.13g (81%)]-2-(4-hydroxy phenyl)] white solid of benzo [b] thiophene.mp?93℃。 ¹H NMR (DMSO-d6) d 9.73 (bs, 1H), 9.68 (bs, 1H), 7.45 (d, J=8.6Hz, 2H), 7.21 (d, J=1.8Hz, 1H), 7.04 (d, J=8.6Hz, 1H), 6.84 (dd, J=8.6,1.8Hz, 1H (conductively-closed)), 6.81 (s, 4H), 6.75 (d, J=8.6Hz, 2H), 3.92 (t, J=5.8Hz, 2H), 2.56 (t, J=5.8Hz, 2H), 2.36 (m.4H), 1.43 (m, 4H), 1.32 (m, 2H) .FD mass spectrums: 462.Theoretical value C ₂₇H ₂₇NO ₄S:C, 70.20; H, 5.90; N, 3.03 measured values: C, 69.96; H, 5.90; N, 3.14.

Embodiment 8 [6-hydroxyl-3-[4-[2-(piperidino) oxyethyl group]-phenoxy group]-2-(4-hydroxy phenyl)] benzo [b] thiophene The preparation of oxalate

This title compound is to be prepared by its free alkali, and its yield is 80%, mp 246-249 ℃ (decomposition). ¹H NMR (DMSO-d6) d 7.45 (d, J=8.6Hz, 2H), 7.22 (d, J=1.8Hz, 1H), 7.05 (d, J=8.6Hz, 1H), 6.87 (dd, J=8.6,1.8Hz, 1H (conductively-closed)), 6.84 (s, 4H), 6.75 (d, J=8.6Hz, 2H), 4.08 (bt, 2H), 3.01 (bt, 2H), 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H).FD mass spectrum: 462.Theoretical value: C ₂₇H ₂₇NO ₄S0.75HO ₂CCO ₂H:C, 64.63; H, 5.42; N, 2.64. measured value: C, 64.61; H, 5.55; N, 2.62.

Embodiment 9 [6-hydroxyl-3-[4-[2-(piperidino) oxyethyl group]-phenoxy group]-2-(4-hydroxy phenyl)] benzo [b] thiophene The preparation of hydrochloride

This title compound is to prepare by handling its corresponding free alkali with the saturated ether of hydrochloric acid, and its yield is 91%, mp 158-165 ℃. ¹H NMR (DMSO-d6) d 9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J=8.6Hz, 2H), 7.23 (d, J=2.0Hz, 1H), 7.04 (d, J=8.6Hz, 1H), 6.86 (q, J _AB=9.3Hz, 4H), 6.76 (dd, J=8.6,2.0Hz, 1), 6.74 (d, J=8.6Hz, 2H), 4.26 (bt, 2H), 3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5H), 1.25 (m, 1H) .FD mass spectrums: 461. theoretical value C ₂₇H ₂₇NO ₄S1.0HCl:C, 65.11; H, 5.67; N, 2.81. measured value: C, 64.84; H, 5.64; N, 2.91.

Embodiment 10 [6-hydroxyl-3-[4-[2-(1-pyrrolidyl) oxyethyl group]-phenoxy group]-2-(4-hydroxy phenyl)] benzo [b] The preparation of thiophene

This title compound is by the product of embodiment 3, prepares according to the mode similar to embodiment 7; Mp 99-113 ℃. ¹H NMR (DMSO-d6) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J=9.0Hz, 2H), 7.25 (d, J=2.0Hz, 1H), 7.09 (d, J=9.0Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J=9.0,2.0Hz, 1H), 6.79 (d, J=9.0Hz, 2H), 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 (t, J=7.0H, 4H).Theoretical value: C ₂₆H ₂₅NO ₄S0.5H ₂O:C, 68.40; H, 5.74; N, 3.07. measured value: C, 68.52; H, 6.00; N, 3.34.

Embodiment 11 [6-hydroxyl-3-[4-[2-(1-hexamethyleneimino)-oxyethyl group]-phenoxy group]-2-(4-hydroxy phenyl)] The preparation of benzo [b] thiophene

This title compound is the product by embodiment 4, prepares according to the mode similar to embodiment 7; Mp 125-130 ℃. ¹H NMR (DMSO-d6) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J=9.0Hz, 2H), 7.26 (d, J=2.0Hz, 1H), 7.09 (d, J=9.0Hz, 1H), 6.85 (5,3H), 6.80 (dd, J=9.0,2.0 Hz, 1H), 6.79 (d, J=9.0Hz), 3.94 (t, J=6.0Hz, 2H), 2.80 (t, J=6.0Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). theoretical value: C ₂₈H ₂₉NO ₄S:C, 70.71; H, 6.15; N, 2.94. measured value: C, 70.67; H, 6.31; N, 2.93.

Embodiment 12 [6-hydroxyl-3-[4-[2-(1-N, N diethylamino) oxyethyl group]-phenoxy group]-2-(4-hydroxy phenyl)] benzene And the preparation of [b] thiophene

This title compound is the product by embodiment 5, prepares according to the mode similar to embodiment 7; Mp 137-141 ℃. ¹NMR (DMSO-d6) d 9.75 (s, 1H), 9.71 (5,1H), 7.49 (d, J=9.0Hz, 1H), 7.25 (d, J=2.0Hz, 1H), 7.09 (d, J=9.0Hz, 1H), 6.85 (s, 4H), 6.80 (dd, J=9.0,2.0Hz, 1H), 6.79 (d, J=9.0Hz, 2H), 3.95 (t, J=6.0Hz, 2H), 2.74 (t, J=6.0Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H).Theoretical value: C ₂₆H ₂₇NO ₄S:C, 69.46; H, 6.05; N, 3.12. measured value: C, 69.76; H, 5.85; N, 3.40.

Embodiment 13 [6-hydroxyl-3-[4-[2-(morpholino) oxyethyl group]-phenoxy group]-2-(4-hydroxy phenyl)] benzo [b] thiophene The preparation of hydrochloride

This title compound is the product by embodiment 6, prepares according to the mode similar to embodiment 7; Mp 157-162 ℃. ¹H NMR (DMSO-d6) d 10.60 (bs, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J=9.0Hz, 2H), 7.28 (d, J=2.0Hz, 1H), 7.10 (d, J=9.0Hz, 1H), 6.92 (q, J _AB=9.0Hz, 4H), 6.81 (dd, J=9.0,2.0Hz, 1H), 6.80 (d, J=9.0Hz, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 (m, 4H), 3.18 (m, 2H).Theoretical value: C ₂₆H ₂₅NO ₅SHCl:C, 62.46; H, 5.24; N, 2.80. measured value: C, 69.69; H, 5.43; N, 2.92.

Embodiment 14 [6-hydroxyl-3-[4-[2-(piperidino) oxyethyl group]-phenoxy group]-2-(4-p-methoxy-phenyl)] benzo [b] thiophene The preparation of fen

Step a)The preparation of 6-methoxyl group benzo [b] thiophene-2-boric acid

Under-60 ℃, (18.13g 0.111mol) drips n-Butyl Lithium (76.2mL .122mo1, the hexane solution of 1.6M) in the solution through 6-methoxyl group benzo [b] thiophene of syringe in being dissolved in 150mL anhydrous tetrahydro furan (THF).Stir after 30 minutes, through syringe add tri-isopropylborate (28.2mL .122mol).The gained mixture slowly is warmed to 0 ℃, and subsequently 1 NHydrochloric acid and ethyl acetate (respectively being 300mL) distribute.Separate each layer, and with the organic layer dried over sodium sulfate.Vacuum concentration obtains white solid, and it is ground with the ether hexane.Obtain the white solid of 16.4g (71%) 6-methoxyl group benzo [b] thiophene-2-boric acid after the filtration.200 ℃ of mp (decomposition). ¹H NMR (DMSO-d6) d 7.83 (s, 1H), 7.78 (d, J=8.6Hz, 1H), 7.51 (d, J=2.0Hz, 1H), 6.97 (dd, J=8.6,2.0Hz, 1H), 3.82 (s, 3H) .FD mass spectrums: 208 Step b):The preparation of [6-methoxyl group-2-(4-methylsulfonic acid base phenyl)] benzo [b] thiophene

(3.00g, 14.4mmol) (3.98g 15.8mmol), adds the 2.0N sodium carbonate solution of 16mL to middle adding 4-(methylsulfonic acid base) phenyl-bromide to 6-methoxyl group benzo [b] thiophene-2-boric acid in being dissolved in 100mL toluene subsequently.Stir after 10 minutes, the adding tetrakis triphenylphosphine palladium (0.60g, 0.52mmol), and with gained mixture heating up backflow 5 hours.Subsequently reaction mixture is cooled to room temperature, from organic phase, is settled out product thus.Remove water and vacuum concentration organic layer, obtain solid.Obtain solid with the ether grinding, it is filtered and vacuum-drying, generate the brown solid of [6-methoxyl group-2-(4-methylsulfonic acid base-phenyl)] benzo [b] thiophene of 3.70g (77%).Mp 197-201 ℃. ¹H NMR (DMSO-d6) d 7.82-7.77 (m, 3H), 7.71 (d, J=8.8Hz, 1H), 7.54 (d, J=2.3Hz, 1H), 7.40 (d, J=8.7Hz, 2H), 6.98 (dd, J=8.7,1.5Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H) .FD mass spectrums: 334. theoretical values: C ₁₆H ₁₄O ₄S ₂: C, 57.46; H, 4.21. measured value: C, 57.76; H, 4.21. Step c):The preparation of [6-hydroxyl-2-(4-methylsulfonic acid base-phenyl)] benzo [b] thiophene

Under the condition of room temperature and nitrogen atmosphere, [6-methoxyl group-2-(4-methylsulfonic acid base-phenyl)] benzo [b] thiophene in being dissolved in anhydrous methylene chloride (200mL) (9.50g, 28.40mmol) add in the solution boron tribromide (14.20g, 5.36mL, 56.8mmol).At room temperature the gained mixture was stirred 3 hours.Slowly be poured in the excessive frozen water and make the stopping of reaction.After 30 minutes, collect white precipitate in vigorous stirring after filtration, wash several times and vacuum-drying subsequently with water, obtain the white solid of [6-hydroxyl-2-(4-methylsulfonic acid base-phenyl)] benzo [b] thiophene of 8.92g (98%).mp?239-243℃。 ¹H NMR (DMSO-d6) d 9.70 (s, 1H), 7.76 (d, J=8.7Hz, 2H), 7.72 (s, 1H), 7.62 (d, J=8.7Hz, 1H), 7.38 (d, J=8.7Hz, 2H), 7.24 (d, J=1.7Hz, 1H), 6.86 (dd, J=8.7,1.7Hz, 1H), 3.38 (s, 3H) .FD mass spectrums: 320 theoretical values: C ₁₅H ₁₂O ₄S ₂: C, 56.23; H, 3.77. measured value: C, 56.49; H, 3.68. Step d):The preparation of [6-benzyloxy-2-(4-methylsulfonic acid base-phenyl)] benzo [b] thiophene

(3.20g 10.0mmol) adds Cs to benzo [b] thiophene to [6-hydroxyl-2-(4-methylsulfonic acid base phenyl)] in being dissolved in the 75mL dry DMF in the solution ₂CO ₃(5.75g, 17.7mmol), add subsequently benzyl chloride (1.72mL, 11.0mmol).With gained mixture vigorous stirring 24 hours.Remove under the vacuum and desolvate, and solid residue is suspended in the 200mL water.Collect white precipitate after filtration and wash several with water.After the vacuum-drying, crude product is suspended in 1: 1 hexane: in the ether.Collect solid, obtain the white solid of 3.72g (91%) [6-benzyloxy-2-(4-methylsulfonic acid base-phenyl)] benzo [b] thiophene.mp?198-202℃。 ¹H NMR (DMSO-d6) d 7.81-7.78 (m, 3H), 7.72 (d, J=8.7Hz, 1H), 7.64 (d, J=2.2Hz, 1H), 7.47-7.30 (m, 7H), 5.15 (s, 2H), 3.39 (s, 3H) .FD mass spectrums: 410. Step e):The preparation of [6-benzyloxy-2-(4-hydroxy phenyl)] benzo [b] thiophene

Under nitrogen atmosphere and room temperature, [6-benzyloxy-2-(4-methylsulfonic acid base-phenyl)] benzo in being dissolved in the anhydrous THF of 300mL [the bJ thiophene (and 12.50g, 30.50mmol) add on a small quantity in the solution repeatedly lithium aluminium hydride (2.32g, 61.0mmol).At room temperature will make the stopping of reaction in the cold 1.0N hydrochloric acid that this mixture stirred 3 hours and impouring carefully is excessive.Use the ethyl acetate extraction water.Subsequently organic phase is washed with water several and dry (sodium sulfate), and vacuum concentration is a solid.Chromatography (silicon-dioxide, chloroform) obtains the white solid of 8.75g's (87%) [6-benzyloxy-2-(4-hydroxy phenyl)] benzo [b] thiophene.Mp 212-216 ℃ ¹H NMR (DMSO-d6) d 9.70 (s, 1H), 7.63 (d, J=8.7Hz, 1H), 7.56 (d, J=2.2Hz, 1H), and 7.51-7.30 (m, 8H), 7.00 (dd, J=8.7,2.2Hz, 1H), 6.80 (d, J=8.6Hz, 2H), 5.13 (s, 2H) .FD mass spectrums: 331. theoretical values: C ₂₁H ₁₆O ₂S:C, 75.88; H, 4.85. measured value: C, 75.64; H, 4.85. Step f):The preparation of [6-benzyloxy-2-(4-p-methoxy-phenyl)] benzo [b] thiophene

Under nitrogen atmosphere and room temperature, [6-benzyloxy-2-(4-hydroxy phenyl)] benzo [b] thiophene in being dissolved in the 200mL dry DMF (8.50g, 26.40mmol) add on a small quantity in the solution repeatedly sodium hydride (1.66g, 41.5mmol).When gas stops to emit, and the dropping methyl iodide (3.25mL, 52.18mmol).At room temperature reactant was stirred 3 hours.Solvent removed in vacuo subsequently, and make resistates between water/ethyl acetate, distribute.Separate each layer, and organic phase is washed with water for several times.And then dry organic layer (sodium sulfate) and vacuum concentration, obtain the white solid of 9.00g (98%) [6-benzyloxy-2-(4-p-methoxy-phenyl)] benzo [b] thiophene.Mp 180-185 ℃. ¹H NMR (DMSO-d6) d 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J=8.8,2.2Hz, 1H), 6.98 (d, J=8.7Hz, 2H), 5.13 (s, 2H), 3.76 (s, 3H) .FD mass spectrums: 346. theoretical value C ₂₂H ₁₈O ₂S:C, 76.27; H, 5.24. measured value: C, 76.54; H, 5.43. Step g):The preparation of [6-benzyloxy-2-(4-p-methoxy-phenyl)-3-bromine] benzo [b] thiophene

At room temperature, (10.0g 28.9mmol) places the 200mL chloroform that contains the 10.0g solid sodium sulfate with [6-benzyloxy-2-(4-p-methoxy-phenyl)] benzo [b] thiophene.In 30 minutes, in this suspension, drip bromine (1.50mL, 29.1mmol) solution that is dissolved in the 100mL chloroform.Behind reinforced the finishing, add entry (200mL) and separate each layer.With organic phase drying (sodium sulfate) and vacuum concentration, obtain white solid.Crystallization in methylene chloride obtains the white solid of 10.50g (85%) [6-benzyloxy-2-(4-p-methoxy-phenyl)-3-bromine] benzo [b] thiophene.Mp 146-150 ℃. ¹H NMR (DMSO-d6) d 7.70 (d, J=2.2Hz, 1H), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J=8.8,2.2Hz, 1H), 7.06 (d, J=8.7Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H) .FD mass spectrums: 346. theoretical values: C ₂₂H ₁₇O ₂SBr:C, 62.13; H, 4.03. measured value: C, 61.87; H, 4.00. Step h):The preparation of [6-benzyloxy-2-(4-p-methoxy-phenyl)-3-bromine] benzo [b] thiophene-(S-oxide compound)

This title compound is in the mixture of trifluoroacetic acid and methylene dichloride, and the product of the step g) hydrogen peroxide oxidation with 1.5 equivalents is made.By the separable product that goes out yellow solid of crystallization in ethyl acetate.Mp 202-205 ℃. ¹H NMR (DMSO-d6) d 7.80 (d, J=2.2Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.55 (d, J=8.4Hz, 1H) 7.47-7.32 (m, 6H), 7.10 (d, J=8.7Hz, 2H), 5.23 (S, 2H), 3.80 (s, 3H) .FD mass spectrums: 441. theoretical values: C ₂₂H ₁₇O ₃SBr:C, 59.87; H, 3.88. measured value: C, 59.59; H, 3.78. Step I):[6-benzyloxy-3-[4-[2-(piperidino) oxyethyl group] phenoxy group]-2-(4-p-methoxy-phenyl)]-preparation of benzo [b] thiophene-(S-oxide compound)

In alkali with step I) product and 4-(2-piperidyl oxyethyl group) phenol reactant obtain this title compound of yellow oily. ¹H NMR (DMSO-d6) d 7.76 (d, J=2.2Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J=8.6,2.2Hz, 1H), and 7.03-6.93 (m, 5H), 6.85 (d, J=8.8Hz, 2H), 5.18 (s, 2H), 3.94 (bt, J=5.8Hz, 2H), 3.73 (s, 3H), 2.56 (bt, J=5.8Hz, 2H), and 2.37-2.34 (m, 4H), 1.45-1.32 (m, 6H) .FD mass spectrum: 592. theoretical values: C ₃₅H ₃₅NO ₅S:C, 72.26; H, 6.06; N, 2.41. measured value: C, 72.19; H, 5.99; N, 2.11. Step j):[6-benzyloxy-3-[4-[2-(piperidino) oxyethyl group] phenoxy group]-2-(4-p-methoxy-phenyl)] preparation of benzo [b] thiophene

With step I) product reduction obtain this title compound, the total recovery after the separation is 95%.By chromatogram purification (SiO ₂, 1-5% methyl alcohol/chloroform), obtain the off-white color solid, mp 105-108 ℃. ¹H NMR (DMSO-d6) d 7.62 (d, J=2.2Hz, 1H), 7.59 (d, J=8.8Hz, 2H), and 7.45-7.30 (m, 5H), 7.15 (dd, J=8.6Hz, 1H), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (bt, J=5.8Hz, 2H), 3.72 (s, 3H), 2.55 (bt, J=5.8Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31 (m, 4H) .FD mass spectrum: 565. theoretical values: C ₃₅H ₃₅NO ₄S:C, 74.31; H, 6.24; N, 2.48. measured value: C, 74.35; H, 6.07; N, 2.76. Step k):[6-hydroxyl-3-[4-[2-(piperidino) oxyethyl group] phenoxy group]-2-(4-p-methoxy-phenyl)] preparation of benzo [b] thiophene

[6-benzyloxy-3-[4-[2-(piperidino) oxyethyl group] phenoxy group in being dissolved in 5: 1 ethanol/ethyl acetate of 300mL]-2-(4-p-methoxy-phenyl)] benzo [b] thiophene (8.50g, 15.0mmol) add in the solution palladium black (1.50g), ammonium formiate (3.50g, 55.6mmol) and 30mL water.Monitor with the backflow of gained mixture heating up and with TLC.After about 3 hours, judge that reaction has reached fully, is cooled to room temperature with this solution.To react through Celite pad and filter to remove catalyzer, be solid with the filtrate vacuum concentration.Make enriched material between saturated sodium bicarbonate solution and 5% ethanol/ethyl acetate, distribute.Separate each layer, and dry organic phase (sodium sulfate) and vacuum concentration.With crude product chromatography (silicon-dioxide, 1-5% methyl alcohol/chloroform), obtain 6.50g (91%) [6-hydroxyl 3-[4-[2-(piperidino) oxyethyl group) phenoxy group]-2-(4-p-methoxy-phenyl)] foam of benzo [b] thiophene, be converted into solid after foam ground with hexane.Mp 174-176 ℃. ¹H NMR (DMSO-d6) d 9.77 (s, 1H), 7.56 (d, J=8.8Hz, 2H), 7.23 (d, J=2.0Hz, 1H), 7.07 (d, J=8.6Hz, 1H), 6.93 (d, J=8.8Hz, 2H), 6.81 (s, 4H), 6.76 (dd, J=8.6,2.0Hz, 1H), 3.91 (bt, J=5.9Hz, 2H), 3.71 (s, 3H), 2.55 (bt, J=5.9Hz, 2H), and 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H) .FD mass spectrum: 475. theoretical values: C ₂₈H ₂₉NO ₄S:C, 70.71; H, 6.15; N, 2.94. measured value: C, 70.46; H, 5.93; N, 2.71.

Embodiment 15 [6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidines-1-base oxethyl) phenoxy group] benzo [b] thiophene The preparation of hydrochloride

In ethyl acetate, by product with the saturated ether mixture process embodiment 14 of HCl, crystallization in ethanol/ethyl acetate subsequently, thus being translated into corresponding hydrochloride, its yield is 85%.Mp 156-160 ℃. ¹H NMR (DMSO-d6) d 10.28 (bs, 1H), 9.85 (s, 1H), 7.56 (d, J=8.8Hz, 2H), 7.25 (d, J=2.0Hz, 1H), 7.06 (d, J=8.7Hz, 1H), 6.93 (d, J=8.8Hz, 2H), 6.87 (q, J _AB=9.3Hz, 4H), 4.27 (bt, J=5.9Hz, 2H), 3.71 (s, 3H), 3.44-3.31 (m, 4H), 2.98-2.88 (m, 2H), 1.74-1.60 (m, 5H), 1.36-1.29 (m, 1H) FD mass spectrum: 475. theoretical values: C ₂₈H ₂₉NO ₄S1.0HCl:C, 65.68; H, 5.90; N, 2.73. measured value: C, 65.98; H, 6.11; N, 2.64.

Embodiment 16 [6-methoxyl group-3-[4-[2-(piperidino)-oxyethyl group] phenoxy group]-2-(4-hydroxy phenyl)] benzo [b] thiophene The preparation of fen

Step a):The preparation of [6-methoxyl group-2-(4-benzyloxy phenyl)] benzo [b] thiophene

According to the step a) of embodiment 14 ordinary methods-g), obtain this title compound, yield is 73%.Mp 217-221 ℃. ¹H NMR (DMSO-d6) d 7.63-7.60 (m, 3H), 7.59-7.26 (m, 7H), 7.02 (d, J=8.7 Hz, 2H), 6.96 (dd, J=8.8,2.2Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H) .FD mass spectrums: 346. theoretical value C ₂₂H ₁₈O ₂S:C, 76.27; H, 5.24. measured value: C, 76.00; H, 5.25. Step b):[6-methoxyl group-2-(4-benzyloxy phenyl)-3-bromine] benzo [b] thiophene

The yield of this title compound is 91%.Mp 125-127 ℃. ¹H NMR (DMSO-d6) d 7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3.82 (s, 3H) .FD mass spectrums: 346. theoretical values: C ₂₂H ₁₇O ₂SBr:C, 62.13; H, 4.03. measured value: C, 6233; H, 3.93. Step c):[6-methoxyl group-2-(4-benzyloxy phenyl)-3-bromine] benzo [b] thiophene-(S-oxide compound)

Go out this title compound (SiO of yellow solid by chromatographic separation ₂, CHCl ₃) .mp 119-123 ℃. ¹H NMR (DMSO-d6) d 7.73 (d, J=2.2Hz, 1H), 7.68 (d, J=8.8Hz, 2H), 7.55 (d, J=8.5Hz, 1H) 7.46-7.31 (m, 5), 7.26 (dd, J=8.5,2.2Hz, 1H), 7.18 (d, J=8.8Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H) .FD mass spectrums: 441. theoretical value C ₂₂H ₁₇O ₃SBr:C, 59.87; H, 3.88. measured value: C, 60.13; H, 4.10. Step d):[6-methoxyl group-3-[4-[2-(piperidino) oxyethyl group] phenoxy group]-2-(4-benzyloxy phenyl)] benzo [b] thiophene-(S-oxide compound)

This title compound that obtains is a yellow solid.Mp 89-93 ℃. ¹H NMR (DMSO-d6) d 7.68 (d, J=2.2Hz, 1H), 7.62 (d, J=8.8Hz, 2H), and 7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H), 6.86 (d, J=8.8Hz, 2H), 5.09 (s, 2H), 3.94 (bt, J=5.8Hz, 2H), 3.81 (s, 3H), 2.56 (bt, J=5.8Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H) .FD mass spectrum: 592. theoretical values: C ₃₅H ₃₅NO ₅S0.25EtOAc:C, 71.62; H, 6.18; N, 2.32. measured value: C, 71.32; H, 5.96; N, 2.71. Step e):[6-methoxyl group-3-[4-[2-(piperidino) oxyethyl group] phenoxy group] 2-(4-benzyloxy phenyl)] benzo [b] thiophene

The compound yield of this title is 91%, mp 106-110 ℃. ¹H NMR (DMSO-d6) d 7.59 (d, J=8.8Hz, 2H), 7.54 (d, J=2.2Hz, 1H), and 7.42-7.28 (m, 5H), 7.13 (d, J=8.8Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (bt, J=5.8Hz, 2H), 3.78 (s, 3H), 2.55 (bt, J=5.8Hz, 2H), and 2.37-2.33 (m, 4H), 1.44-1.31 (m, 4H) .FD mass spectrum: 565. theoretical values: C ₃₅H ₃₅NO ₄S:C, 74.31; H, 6.24; N, 2.48. measured value: C, 74.26; H, 6.17; N, 2.73. Step f):[6-methoxyl group-3-[4-[2-(piperidino) oxyethyl group] phenoxy group]-2-(4-hydroxy phenyl)] preparation of benzo [b] thiophene

The compound yield of this title is 88%, mp 147-150 ℃. ¹H NMR (DMSO-d6) d 9.72 (s, 1H), 7.51 (d, J=2.0Hz, 1H), 7.48 (d, J=8.6Hz, 2H), 7.11 (d, J=8.8Hz, 1H), 6.88 (dd, J=8.8,2.2Hz, 1H), 6.81 (s, 4H), 6.76 (d, J=8.6,2H), 3.91 (bt, J=5.9Hz, 2H), 3.77 (S, 3H), 2.55 (bt, J=5.9Hz, 2H), and 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H) .FD mass spectrum: 475. theoretical values: C ₂₈H ₂₉NO ₄S:C, 70.71; H, 6.15; N, 2.94. measured value: C, 71.00; H, 6.17; N, 2.94.

Embodiment 17 [6-methoxyl group-3-[4-[2-(piperidino) oxyethyl group] phenoxy group]-2-(4-hydroxy phenyl)] benzo [b] thiophene The preparation of fen hydrochloride

Prepare this title compound according to mode similar to Example 15, mp 215-217 ℃. ¹H NMR (DMSO-d6) d 10.28 (bs, 1H), 9.80 (s, 1H), 7.52 (d, J=2.2Hz, 1H), 7.47 (d, J=8.6Hz, 2H), 7.12 (d, J=8.4Hz, 1H), and 6.91-6.80 (m, 5H), 6.78 (d, J=8.6Hz, 2H), 4.27 (bt, J=5.8Hz, 2H), 3.78 (s, 3H), and 3.43-3.34 (m, 4H), 2.97-2.91 (m, 2H), 1.78-1.61 (m, 5H), 1.36-1.29 (m, 1H), FD mass spectrum: 475. theoretical values: C ₂₈H ₂₉NO ₄S1.0HCl:C, 65.68; H, 5.90; N, 2.73. measured value: C, 65.87; H, 5.79; N, 2.99. Example of formulations

In following series preparation, " active ingredient " is meant the compound of formula I, or its salt or solvate.

Example of formulations 1

Gelatine capsule

Constituent mass (mg/ capsule)

Active ingredient 0.1-1000

Starch, NF 0-650

Flow starch powder 0-650

Siloxane fluid 350 centistoke 0-15

Example of formulations 2

Tablet

Constituent mass (mg/ sheet)

Active ingredient 2.5-1000

Microcrystalline Cellulose 200-650

Fumed silica 10-650

Stearic acid 5-15

Example of formulations 3

Tablet

Constituent mass (mg/ sheet)

Active ingredient 25-1000

Starch 45

Microcrystalline Cellulose 35

Polyvinylpyrrolidone (as 10% water-soluble 4

Liquid)

Xylo-Mucine 4.5

Magnesium Stearate 0.5

Talcum 1

Active ingredient, starch and Mierocrystalline cellulose are sieved and thorough mixing through No. 45 mesh sieves of the U.S..With the solution and the gained powder mixes of polyvinylpyrrolidone, with after No. 14 mesh sieves of the U.S. sieve.The gained particle sieves 50-60 ℃ of drying and through No. 18 mesh sieves of the U.S..Make Xylo-Mucine, Magnesium Stearate and talcum at first pass through No. 60 mesh sieves of the U.S., join subsequently in the particle, after this mix, and then on tabletting machine, compress, obtain tablet.

Example of formulations 4

Suspension

Constituent mass (mg/5ml)

Active ingredient 0.1-1000mg

Xylo-Mucine 50mg

Syrup 1.25mg

Benzoic acid solution 0.10Ml

Correctives is an amount of

Tinting material is an amount of

Pure water 5mL

Make medicine pass through No. 45 mesh sieves of the U.S. and mix, form slick paste, under agitation add some water benzoic acid solution, correctives and tinting material dilution with Xylo-Mucine and syrup.Add the water of q.s subsequently, reach pre-determined volume.

Example of formulations 5

Aerosol

Constituent mass (% weight)

Active ingredient 0.25

Ethanol 25.75

Propellent 22 (chloro two fluoro methane) 70.00

Active ingredient is mixed with ethanol, and this mixture is joined in the part propellent 22, be cooled to 30 ℃, transfer in the tamping unit.In stainless steel vessel, charge into predetermined amount subsequently and with the dilution of remaining propellent.Mounted valve element on container subsequently.

Example of formulations 6

Suppository

Constituent mass (mg/ bolt)

Active ingredient 250

Saturated fatty acid glyceride class 2000

Make active ingredient by No. 60 mesh sieves of the U.S. and be suspended in the saturated fatty acid glyceride compounds that melts in advance, when the fusion saturated fatty acid glyceride, provide necessary but minimum heat.Subsequently mixture is poured in the 2g chamber suppository mold of standard and cooling.

Example of formulations 7

Injection formulations

Constituent mass

Active ingredient 50mg

Deng oozing salts solution 1000mL

Give the solution of sufferer intravenous infusion said components with about 1mL/ minute speed.

Claims (16)

1. the method for a Breast Cancer Prevention in the sufferer of this treatment of need, this method comprises compound or pharmaceutically acceptable salt thereof or its prodrug of the following formula structure of administering therapeutic significant quantity:

Wherein, R ¹And R ²Be hydroxyl or the alkoxyl group that contains 1-4 carbon atom independently; And R ³And R ⁴Be methyl or ethyl independently, or R ³And R ⁴Form 1-pyrrolidyl, methyl isophthalic acid-pyrrolidyl, dimethyl-1-pyrrolidyl, piperidino, 4-morpholinyl or hexamethyleneimino ring jointly with the nitrogen-atoms that is connected.

2. the process of claim 1 wherein that sufferer also do not suffered from mammary cancer by diagnosis, but be confirmed as suffering from the danger of this disease.

3. the process of claim 1 wherein R ¹And R ²Be hydroxyl.

4. the process of claim 1 wherein R ¹Be hydroxyl and R ²It is the alkoxyl group that contains 1-4 carbon atom.

5. the method for claim 4, wherein R ²Be methoxyl group.

6. the method for claim 2, wherein R ¹And R ²Be hydroxyl.

7. the method for claim 2, wherein R ¹Be hydroxyl and R ²For containing the alkoxyl group of 1-4 carbon atom.

8. the method for claim 7, wherein R ²Be methoxyl group.

9. the process of claim 1 wherein R ³And R ⁴Form the 1-piperidine ring jointly with the nitrogen-atoms that is connected.

10. the method for claim 2, wherein R ³And R ⁴Form the 1-piperidine ring jointly with the nitrogen-atoms that is connected.

11. the process of claim 1 wherein compound or pharmaceutically acceptable salt thereof or its prodrug of the following formula structure that comprises the administering therapeutic significant quantity:

R wherein ²Be hydroxyl or methoxyl group.

12. the method for claim 2, comprising compound or pharmaceutically acceptable salt thereof or its prodrug of the following formula structure of administering therapeutic significant quantity:

R wherein ²Be hydroxyl or methoxyl group.

13. the method for claim 11, wherein said compound are 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group) phenoxy group] benzo [b] thiophene or its pharmacologically acceptable salt.

14. the method for claim 11, wherein said compound are 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(2-piperidyl oxyethyl group) phenoxy group] benzo [b] thiophene or its pharmacologically acceptable salt.

15. the method for claim 12, wherein said compound are 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-[4-(2-piperidyl oxyethyl group) phenoxy group] benzo [b] thiophene or its pharmacologically acceptable salt.

16. the method for claim 12, wherein said compound are 6-hydroxyl-2-(4-hydroxy phenyl)-3-[4-(2-piperidyl oxyethyl group) phenoxy group] benzo [b] thiophene or its pharmacologically acceptable salt.