CN1259944A

CN1259944A - Treatments of prophylaxis of prostatic cancer and benign prostatic hyperplasia

Info

Publication number: CN1259944A
Application number: CN98805956A
Authority: CN
Inventors: B·L·纽保尔
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1997-04-09
Filing date: 1998-04-07
Publication date: 2000-07-12
Also published as: PL336205A1; AU6966198A; ID24358A; HUP0003589A3; EP0975629A4; NO994903L; JP2001518900A; CA2286204A1; WO1998045288A1; NO994903D0; EP0975629A1; ZA982819B; IL132277A0; BR9808515A; KR20010006218A; EA199900914A1; HUP0003589A2; TR199902701T2

Abstract

The present invention provides a method for the treatment or prophylaxis of benign prostatic hyperplasia or prostatic cancer in a patient in need of such treatment comprising administering a selective estrogen receptor modulating compound of formula (I), in which R<1> and R<2> are independently hydroxy and 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

Selective estrogen receptor modulators is used for the treatment of or prevents prostate cancer and benign prostatic hyperplasia

Technical field

The application relates to and uses a class that bioactive compound is arranged, the propagation of and malignant prostate cell optimum in order to antagonism.More particularly, the invention relates to benzo [b] thiophene compound that uses a class to replace, in order to treatment or prevention prostate cancer and benign prostatic hyperplasia.

Background of invention

In the male patient who suffers from regional tumour, when adopting close observation to wait for strategy, the mortality ratio lower usually (9%～15%) that causes because of prostate cancer.Yet these data only limit among the patient of regional disease, and not necessarily are applicable to the high-risk younger male sex.The young male sex who suffers from interim Tla tumour has longer critical days than the older male sex who suffers from the stage tumour, so they may become the candidate of curative therapy.In the research of close observation, the high speed development of disease (34%-80%) shows almost do not have clinical evidence to show that prostate cancer is dormancy.

Radiotherapy has been widely used in stage T ₁And T ₂Clinical region disease, and priority application is the elderly, the patient that physical appearance is relatively poor and those more worsen, clinically more in the tumour in late period.Yet this treatment can not be cured all cancer cells that can not remove the male patient who suffers from hiding property metastases.

Use oestrogenic hormon to reduce the hormone process for stripping (J.Waxman, J.R.Soc.Med., 78:129-135 (1985)) that male sex hormone in the circulation is the prostate cancer sent out of a kind of effective treatment.The antitumor reaction of oestrogenic hormon mainly is to regulate by the testosterone levels that reduces in the circulation, and its reduction is because due to the secretion inhibition of luteotropic hormone.

6-hydroxyl-2-(4-hydroxy phenyl)-3-(4-(pyrrolidyl oxyethyl group) benzoyl) benzo [b] thiophene; 1; or 6-hydroxyl-2-(4-hydroxy phenyl)-3-(4-(2-piperidino-(1-position only) oxyethyl group)-benzoyl) benzo [b] thiophene; (2); all be that selective estrogen receptor is regulated (SERM) compound; use them in the long male Lobund-Wistar rat that the PAIII tumour is arranged, show and obviously to suppress of the transfer of afterbody primary tumo(u)r to stern and ilium lymphatic node and lung.(seeing B.L.Neubauer. etc., Prostate, 27:220-229, (1995)).

The target tissue that " selective estrogen receptor modulators " is defined in one or more hope produces the oestrogenic hormon agonism, and produces the compound of the agonism of oestrogenic hormon antagonism and/or minimum (promptly not obvious clinically) in germinal tissue.Raloxifene, except having its estrogen antagonist activity, it also has the activity of physiology antagonism estrogen effect in complete buck.

PAIII gland cancer in the Lobund-Wistar rat is a useful model, is used to estimate the carcinostatic agent for the treatment of the prostate cancer that shifts.When subcutaneous injection PAIII cell during to male Lobund-Wistar rat tails, can observe repeatably from stern and bone lymphatic node to lung, the tumour of time-dependent manner spreads in proper order.

The form of PAIII tumour is similar to people's degeneration and grows damage.Supported to use this tumour as estimating for the cell toxicant of human and the model of anti-metastasis agent.

Benign prostatic hyperplasia (BPH) is a modal innocent tumor among the male sex.Age among the U.S. man, has 50% to suffer from BPH more than 50 years old approximately according to estimates.

BPH is that frequent micturition if do not treat, may cause related complication, comprising the damage of bladder and kidney because the caused prostate gland of the optimum hypertrophy of prostatic matrix organization increases, and it will cause some symptoms, comprise the increase urgent urination.

To the typical treatment of BPH is prostate excision toward urethra, this not only costliness but also consuming time of performing the operation.In the past thirty years, the mortality ratio of transurethral prostatectomy has been reduced to 0.2%, but operation itself there is no noticeable change at that time, and the postoperative sickness rate remains unchanged and is about 18%.

Have among the male sex of benign prostatic hyperplasia 29% to need operative treatment according to estimates.Have every year in other words greater than 400,000 example operations.If continue present speed, according to estimates, 40 years old man of a U.S. lived by 80 years old, and 29% probability of carrying out prostate removal surgery is just arranged.

No matter on time or money, the cost of the height of this operation has caused the suitable interest of seeking the treatment BPH method that causes that more cheaply and still less the postoperative morbidity is filled.

Brief summary of the invention

The invention provides the method for the treatment of and preventing prostate cancer or benign prostatic hyperplasia (BPH) in the patient of this treatment of needs, this method comprises the selective estrogen receptor modulators with following structure or its pharmaceutically useful salt or the prodrug of administering therapeutic significant quantity.

Show in the structure R last ¹And R ²Be independently selected from a hydroxyl and an alkoxyl group to four carbon atom.

R ³And R ⁴Be independently selected from methyl or ethyl, perhaps R ³And R ⁴Form pyrrolidyl with the nitrogen-atoms that links to each other with them, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidino-(1-position only), morpholino, or hexamethylene imine basic ring.

Be described in detail

In this specification sheets and additional claim, general terms has its ordinary meaning.

Term " alkyl " expression is from methane, ethane, or remove the univalent perssad that a hydrogen atom is derived and obtained in the hydrocarbon of straight or branched, and comprise such group such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl etc.

As above-mentioned definition, " alkoxyl group " refers to that alkyl group links to each other with parent molecular moiety by Sauerstoffatom, comprises such group such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert.-butoxy etc.In the present invention, methoxyl group is preferred alkoxy base.

Term " prodrug " expression The compounds of this invention in this application has a group, and this group produces the compound that therapeutic activity is arranged of the present invention in human body metabolism's cracking.Especially, such prodrug is included in the R in the said structure ¹And R ²One or two is the compound of hydroxyl in the substituting group, and its hydroxyl has been protected by pharmaceutically useful hydroxy-protective group, they in vivo the metabolism cracking to produce monohydroxy or the dihydroxy compound among corresponding the present invention.At T.W.Greene, etc., " blocking group in the organic synthesis " second edition, John Wileg ﹠amp; Sons.Inc.New York, chapter 2 has been discussed the blocking group of hydroxyl in 1991.Simple ether and ester group are preferred prodrug hydroxy-protective groups.

The preferred compound of the present invention comprises: 6-hydroxyl-2-(4-hydroxy phenyl)-3-(4-(2-piperidino-(1-position only)-oxyethyl group) phenoxy group) benzo [b] thiophene or its pharmaceutically useful salt or prodrug; With

6-hydroxyl-2-(4-p-methoxy-phenyl)-3-(4-(2-piperidino-(1-position only)-oxyethyl group) phenoxy group) benzo [b] thiophene or its pharmaceutically useful salt or prodrug.The preparation of The compounds of this invention

Article one, route be used to prepare the initiator of The compounds of this invention mainly be by C.D.Jones at US Patent No ' s 4,418,068 and 4,133, the preparation of method described in 814.This initiator has following formula 1:

R wherein ⁵And R ⁶Be independently-H or hydroxy-protective group.

R ⁵And R ⁶The part of hydroxy-protective group has a mind to introduce in building-up process, is used for protecting those groups that may react in the chemical operation process, is removed in the synthetic later stage then.Because having the compound of these blocking groups is important (though some derivatives equally also show biological activity) as chemical intermediate at first, their accurate structures are unimportant.The existing narration in some classics that is reflected at of such blocking group is removed and is formed in many formation, comprises, for example, the blocking group in the organic chemistry, Plenum Press (London and New York, 1973); Greene, the blocking group in the T.W. organic synthesis, Wileg (New York, 1981); And peptide, I volume, Schrooder and Lubke, Academic Press, (London and New York, 1965).

Representational hydroxy-protective group comprises, for example, and-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 optional substituted-phenyl.Term " phenyl of replacement " refers to have one or more C of being selected from ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, hydroxyl, nitro, the substituent phenyl of group of halogen and three (chlorine or fluorine) methyl.Term " halogen " refers to bromine, chlorine, fluorine and iodine.

For the compound of formula 1, preferred R ⁵And R ⁶Substituting group is methyl, sec.-propyl, benzyl and methoxyl methyl.R wherein ⁵And R ⁶The compound that is methyl respectively is to prepare by the method described in the above Jones patent of drawing.

The compound of formula 1 also can be prepared as follows, and optionally removes R ⁵Hydroxy-protective group stays R ⁶Hydroxy-protective group is as the part of the finished product.In the following cases too, optionally remove R ⁶Hydroxy-protective group, and stay R ⁵Hydroxyl protecting group.For example, R ⁵Can be sec.-propyl or benzyl and R ⁶It is methyl.Sec.-propyl or benzyl moiety can optionally be removed by routine operation, and keep R ⁶The methyl blocking group is as the part of the finished product.

As shown in reaction formula I, the first step that is used to prepare some compound of the present invention in present method comprises selectivity configuration leavings group, suc as formula 3 R in 1 compound ⁷, forming the compound of formula 2, with 4-(hydroxyl of protection) phenol, 3, with the coupling mutually of this reaction product, forming the compound of formula 4, and optionally remove R ⁸Hydroxy-protective group is to form formula 5 compounds.In the sequence of steps shown in the reaction formula 1, hydroxy-protective group R ⁵, R ⁶And R ⁸By selecting as follows: in final step, at hydroxyl protecting group R ⁵And R ⁶Exist down, can optionally remove R ⁸Hydroxy-protective group.

Reaction formula I

In the first step of reaction formula I, optionally be configured in suitable leavings group by standard operation on 3 of formula 1 initiator.Suitable R ⁷Leavings group comprises sulphonate, methanesulfonates for example, 4-bromo-benzene sulfonic acid ester, tosylate, esilate, different propanesulfonic acid ester, 4-methoxy benzenesulfonic acid ester, 4-nitrobenzene-sulfonic acid ester, 2-closilate, trifluoromethane sulfonic acid ester etc., halogen for example, bromine, chlorine, and iodine, the leavings group relevant with other.Yet for guaranteeing reasonably to dispose leavings group, preferred above-mentioned halogen is preferably bromine especially.

Under standard operation, carry out this reaction.For example, when preferred use halogenating agent, in appropriate solvent as, for example, in chloroform or the acetate, this halide reagent with monovalent is preferably bromine, with formula 1 substrate reactions of monovalent.Usually reaction is to carry out under from about 40 ℃ to about 80 ℃ in temperature.

Then, with the reactor product of above-mentioned reactions steps, promptly formula 2 compounds with 3 reactions of 4-(hydroxyl of protection) phenol, form formula 4 compounds, wherein R ⁸It is the hydroxy-protective group that alternative is removed.Normally, the 4-hydroxy-protective group of phenol can be any known protecting group, and it can be removed by selectivity, and in the case, R in formula 3 compounds ⁵And R ⁶When group exists, but be not removed.Work as R ⁵And/or R ⁶When not being methoxyl group and benzyl, preferred R ⁸Blocking group comprises methoxymethyl.Wherein more preferred benzyl.4-(hydroxyl of protection) phenol reactant reagent can be buied maybe and can prepare by standard method.

Coupled reaction between formula 2 compounds and formula 3 compounds is known in the industry as Ullman reaction, and is generally undertaken (seeing " Advanced Organic Chemistry: reaction; mechanism and structure " the 4th edition for example, 3-16, (J.March by standard method, ed., John Wiley ﹠amp; Sons, Inc.1992); Jones, C.D., J.Chem.Soc.Perk.Trans.I, 4:407 (1992)).

Usually, in the presence of up to Red copper oxide (I) catalyzer of an equimolar amount and in the suitable solvent, in rare gas element, with two kinds of aromatic substrate reflux of equivalent.Preferably, in the presence of monovalent Red copper oxide, with monovalent R ⁷Be formula 2 compounds of bromine and the 4-benzyloxy phenol reactant of monovalent.

The solvent that this reaction is fit to is that those keep inert solvent or mixed solvent in entire reaction.Be generally organic bases, the big alkali of steric hindrance especially, for example, 2 is preferred solvent.

The temperature that adopts in this step is enough to make this coupled reaction complete usually, and therefore has influence on the required time.When reaction mixture was heated to backflow in rare gas element as in nitrogen, the time that reacts completely was usually from about 20 to 60 hours.

After one of formula 2 compounds and formula 3 compounds linked reaction forms formula 4 compounds,, optionally remove R in formula 4 compounds by well-known method of reducing ⁸Hydroxy-protective group comes preparation formula 5 compounds.But importantly, method selected should not influence R ⁵, and R ⁶The blocking group of hydroxyl (if present).

Work as R ⁸Be preferred benzyl group, R ⁵And R ⁶If (existence) is when being respectively methyl, carry out this step by the hydrogenolysis method of standard.Usually, formula 4 substrates are added in the suitable solvent or mixed solvent, add the hydrogenation catalyst that protophobe is fit to accelerated reaction and adding then.

The catalyzer that is fit to comprises precious metal and metal oxide containing precious metals, and as the palladium on carrier, platinum, and rhodium oxide, carrier for example are carbon or lime carbonate.Wherein, palladium carbon, especially 10% palladium carbon is preferred.The solvent of this reaction or mixed solvent are that those keep inert in entire reaction.Usually, ethyl acetate and C ₁-C ₄Fatty Alcohol(C12-C14 and C12-C18), especially ethanol are preferred.For this reaction, hydrochloric acid can be used as suitable and preferred protophobe.

Extremely about 50psi (344.7 kPas) is when carrying out from about 30 psi (206.8 kPas) when being reflected at room temperature and pressure range, and it is very fast that this reaction is carried out.For example thin-layer chromatography can the monitoring reaction process can to use the standard colour chart technology.

As shown in the reaction formula II, when preparation formula 5 compounds, with itself and formula R ⁴R ⁵N-(CH ₂) ₂-Q 6Reaction, wherein R ⁴And R ⁵As above definition, and Q is bromine or is preferably chlorine, to form formula 7 compounds.With formula 7 compound deprotections, form formula I compound then.

Reaction formula II

In the first step of this process, carry out this reaction shown in the reaction formula II by standard operation.Formula 6 compounds be can buy or with method well known to those of ordinary skill in the art preparation.The hydrochloride of preferably, use formula 6 compounds.In compound more preferred example of the present invention, use 2-chloroethyl piperidine hydrochlorate.

In general,, be preferably under the cesium carbonate existence and in the appropriate solvent at least about 4 normal alkaline carbonates, will be at least about 1 normal formula 5 substrates and the reaction of 2 equivalent formulas, 6 compounds.

Solvent or mixed solvent that this reaction is fit to are that those keep the inert solvent in entire reaction.N, dinethylformamide, especially anhydrous, be preferred.The temperature that adopts in this step should enough make alkylated reaction complete.Usually, room temperature is enough and is preferred.This reaction is preferably carried out under rare gas element, especially under the nitrogen.

Under preferred reaction conditions, after about 16 to 20 hours, reaction will be carried out fully.The monitoring of reaction process available standards chromatographic technique.

Prepare in the method for The compounds of this invention at another, shown in the following reaction formula III, in basic solvent, formula 5 compounds and excessive formula 8 alkylating reagents reacted:

Q-(CH ₂) _n-Q′

8Wherein Q and Q ' are identical or different leavings groups.Suitable leavings group is those above-mentioned mentioning.

The reaction formula III

The preferred alkali solvent of this alkylated reaction is in inert solvent, for example, contains salt of wormwood among methyl ethyl ketone (MEK) or the DMF.In this solution, the unprotected hydroxyl of formula 5 compounds has changed into the phenolate ion, and it has replaced a leavings group in the alkanisation reagent.

When the basic solution that will contain reactant and reagent refluxes and reaction is carried out when complete, it is best that reaction is carried out.When using MEK as preferred solvent, reaction time range was from about 6 hours to about 20 hours.

From the reactor product of this step, i.e. formula 9 compounds, by routine techniques with its be selected from 1-piperidines, 1-tetramethyleneimine, methyl isophthalic acid-tetramethyleneimine, dimethyl-1-tetramethyleneimine, 4-morpholine, dimethylamine, diethylamine, the formula 10 compounds reaction of Diisopropylamine or 1-hexamethylene imine forms formula 7 compounds.Preferably use the hydrochloride of formula 10 compounds, particularly preferably be piperidine hydrochlorate.The reaction normally with formula 9Alkylating compound at inert solvent, as carrying out in the dry DMF.And be heated to temperature range from about 60 ℃ to about 110 ℃.When mixture heating up to preferred temperature was about 90 ℃, reaction only needed 30 minutes to about 1 hour.Yet the variation of reaction conditions will have influence on the length that the required fully time is carried out in this reaction.The process of reactions steps can be monitored by the conventional chromatogram technology.

Remove R in formula 1 compound with the method for knowing ⁵, and R ⁶Hydroxy-protective group (when existing) obtains some formula 1 preferred compounds.Removing in the many conventional works of being reflected at of these blocking groups of many formation has narration, and this comprises, for example, and the blocking group in the organic chemistry, Plenum Press (London and New York, 1973); Greene, the blocking group in the T.W. organic synthesis, Wileg (New York, 1981); And peptide, I volume, Schrooder and Lubke, Academic Press, (London and New York, 1965).Remove preferred R ⁷And/or R ⁸The method of hydroxy-protective group, especially methyl and methoxymethyl, main described in following example.

Another and be that the preparation method of preferred The compounds of this invention represents in reaction formula IV.Shown in the method, sulphur atom is to form sulfoxide in oxidation-type 2 compounds 11, then itself and nucleophilic group are reacted with the Sauerstoffatom joint in the drawing-in system I compound.With the sulfoxide radicals reduction of formula 12 compounds, obtain compounds more of the present invention then.

Reaction formula IV

In the first step of this method, optionally formula 2 compound oxidations are become sulfoxide 12.Many known methods can be applicable in this method step (see, for example, Madesclaire, M., Tetrahedron, 42 (20); 5459-5495 (1986); Trost, B.M. etc., TetrahedronLetters, 22 (14); 1287-1290 (1981); Drabowicz, J., etc., SyntheticCommunications, 11 (12); 1025-1030 (1981); Kramer, J.B., etc., 34 organic symposials in the whole nation, Williamsburg, VA., June 11-15,1995).Yet it is all relatively poor that many oxygenants are converted into desired product, simultaneously significantly peroxidation to sulfone.But this preferred method transforms the sulfoxide of an accepted way of doing sth 12 with high yield with formula 2 compounds, and only seldom or does not fully generate sulfone.This method comprises the mixture in methylene dichloride with about 1 to about 1.5 normal hydrogen peroxide and about 20% to 50% trifluoroacetic acid, reacts with formula 2 compounds.Reaction be in temperature for carrying out from about 10 ℃ to about 50 ℃, and usually need be complete to carry out from about 1 to about 2 hours.

Then, 3 leavings group R ⁷, replace with required formula 13 nucleophile derivative.Prepare these nucleophile derivative with standard method.

In this step of present method, (preferably DMF or tetrahydrofuran (THF)) removes the acid proton of nucleophilic group by using alkaline purification in polar aprotic solvent, and preferred alkali is excessive slightly sodium hydride or potassium tert.-butoxide.Other spendable alkali comprises salt of wormwood and cesium carbonate.In addition, spendable other solvent such as dioxane or dimethyl sulfoxide (DMSO).Deprotonation is carried out between about 0 ℃ and about 30 ℃ of temperature usually, and needs about 30 minutes usually to finish.Compound with formula XIV joins in the solution of nucleophilic reagent then.Replacement(metathesis)reaction is carried out between 0 ℃ of temperature and about 50 ℃, and carries out usually about 1 to about 2 hours.Use the ordinary method product separation.

In the next step of present method, the sulfoxide of reduction-type 14 is to the benzothienyl compounds of formula I.

When needs, can remove shown in the reaction formula IV one or several hydroxyl protection gene of product in the synthesis technique, and the product salt in the arbitrary step of this technology.

The prodrug ester compound of formula I is by knowing operation with 6 and/or 4 ' position oh group (when existing as them) and formula-OCO (C ₁-C ₆Alkyl), or-OSO ₂(C ₂-C ₆Alkyl) replaces and prepared.See for example U.S. patent No.4,358,583.

For example, when also needing-OCO (C ₁-C ₆Alkyl) during gene, with list or dihydroxyl compound and reagent such as the acyl chlorides of formula I, acylbromide, prussiate, or trinitride, or with suitable acid anhydrides or mixed anhydride reaction.Reaction is carried out in basic solvent usually, as pyridine, and lutidine, quinoline or isoquinoline 99.9, or at the tertiary amine solvent, as triethylamine, tributylamine carries out in the methyl piperidine etc.Reaction also can be carried out in inert solvent, for example in ethyl acetate, and dimethyl formamide, dimethyl sulfoxide (DMSO), dioxane, glycol dimethyl ether, acetonitrile, acetone, methyl ethyl ketone etc., and in this solvent, add the acid scavenger of monovalent (except that following indicating), for example tertiary amine at least.If desired, can be with acylation catalyst for example 4-dimethyl amine yl pyridines or 4-pyrrolidyl pyridine.See, example, Haslam, etc., Tetrahedron, 36:2409-2433 (1980).

These are reflected under the moderate temperature (from-25 ℃ to about 100 ℃ approximately) and carry out, and in the rare gas element of being everlasting as carrying out under the nitrogen.Yet, be suitable for usually reacting under the room temperature.

The acidylate of 6 and/or 4 ' position hydroxyls also can be in inert organic solvents, and the acid catalyzed reaction by suitable carboxylic acid carries out.The acid catalyst such as the sulfuric acid that use, polyphosphoric acid, methylsulfonic acid etc.

Above-mentioned ester prodrugs compound also can be obtained by the active ester that forms appropriate acid, and such ester forms with the reagent of knowing, as dicyclohexylcarbodiimide, and acylimidazole, nitrophenols, pentachlorophenol, N-hydroxy-succinamide and 1-hydroxy benzo triazole.For example see Bull, Chem, Soc, Japan, 38:1979 (1965), and Chem, Ber, 788 and 2024 (1970).

Provide-OCO (C ₁-C ₆Alkyl) the various above-mentioned technology of group is carried out in solvent as discussed above.Those do not produce the technology of acid product in reaction process, certainly, just need not use acid scavenger in reaction mixture.

When 6 and/or 4 in the formula I compound ' position oh group being transformed an accepted way of doing sth-OSO ₂(C ₂-C ₆Alkyl) during group, with list or dihydroxyl compound and, for example, sulphonic acid anhydride or suitable for example SULPHURYL CHLORIDE, sulfuryl bromide or sulfonic acid ammonium salt reaction of sulfonic acid, as by as described in King and the Monoir, J.Am.Chem, Soc, 97:2566-25679 (1975).Dihydroxyl compound also can or mix the sulphonic acid anhydride reaction with suitable sulphonic acid anhydride.Being reflected at like this as carrying out under the condition as illustrated in the discussion of reactions such as above-mentioned and acyl chlorides.The preparation of the pharmacologically acceptable salt of The compounds of this invention

Though in the pharmaceutical methods of the present invention's treatment, can use the free alkali form of formula I compound, preferably prepare and use the form of pharmacologically acceptable salt.The compound that uses in the inventive method mainly is the pharmaceutically useful acid salt with the organic and mineral acid formation of various kinds.Such salt equally within the scope of the invention.

The term that uses in this specification sheets and accessory claim " pharmaceutically useful salt " is meant in Berge etc., J.Pharmaceutical Sciences, 66 (1): the type of disclosed salt in 1-19 (1977) paper.Suitable pharmacologically acceptable salt comprises the salt that is formed by typical mineral acid, hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, nitric acid, sulfuric acid, phosphoric acid, Hypophosporous Acid, 50 etc. and from organic acid deutero-salt.For example aliphatics is single or two carboxylic acids, paraffinic acid, hydroxyl alkane acid and hydroxyl chain docosandioic acid, aromatic acid, fat and aromatic sulphonic acid that phenyl replaces.The pharmaceutically acceptable organic acid additive salt of this kind comprises acetate, phenylacetic acid salt, trifluoroacetate, acrylate, ascorbate salt, benzoate, chloro benzoate, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, tolyl acid salt, acetoxybenzoic acid salt, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyric acid salt, 6-hydroxybutyric acid salt, butine-1, the 4-diacid salt, hexin-1,6-diacid salt, caprate, octylate, muriate, cinnamate, formate, fumarate, glycollate, enanthate, hippurate, lactic acid salt, malate, maleate, hydroxymaleic acid salt, malonate, mandelate, mesylate, nicotinic acid salt, different nicotinic acid salt, nitrate, oxalate, phthalate, terephthalate, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, propine salt, propionic salt, phenylpropionic acid salt, salicylate, sebacate, succinate, suberate, vitriol, hydrosulfate, pyrosulphate, sulphite, hydrosulphite, sulfonate, benzene sulfonate, p-bromobenzenesulfonate, closilate, ethyl sulfonate, 2-hydroxyethyl sulfonate, mesylate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, tosilate, xylenesulfonate, tartrate etc.Preferred salt is hydrochloride and oxalate.

Usually with formula I compound with wait the mole or the acid-respons of molar excess slightly, form pharmaceutically useful acid salt.Reactant usually in mutual solvent as carrying out in ether or the ethyl acetate.Salt in about one hour to 10 days from solution spontaneous nucleation separate out, and can by filtering separation to or remove solvent with ordinary method.

Pharmaceutically useful salt generally has stronger dissolution characteristics than their compound of deriving, and therefore often is more suitable in being mixed with liquid or emulsion.Pharmaceutical preparation

The compounds of this invention can be by the number of ways administration, comprise oral, rectum, transdermal, subcutaneous, intravenously, intramuscular and intranasal administration.Before administration, preferably compound is mixed with preparation, by the selection of physician's decision to them.Therefore, another aspect of the present invention is a pharmaceutical composition, and it contains the formula I compound of significant quantity, or its pharmaceutically useful salt, also can randomly contain oestrogenic hormon or urine hormone and pharmaceutically useful carrier, thinner or the vehicle of significant quantity.

In such prescription, total active constituent accounts for 0.1%～99.9% of weight of formulation." pharmaceutically useful " is meant carrier, thinner, vehicle and salt must be with preparation in other composition compatible, and can not be harmful to its experimenter.

Pharmaceutical preparation of the present invention is by the method known to this field, is prepared with the composition of knowing and easily obtain.For example, separately with formula I compound, or with the combination of oestrogenic hormon or urine hormone, with common vehicle, thinner, or carrier prepared, and makes tablet, capsule, suspension agent, solution, injectable agent, aerosol, pulvis etc.

In such preparation, total activeconstituents accounts for 0.1% to 99.9% of weight of formulation." pharmaceutically useful " is meant carrier, thinner, vehicle and salt must be with preparation in other composition compatible, and can not be harmful to the recipient.

Also preparation can be deployed into solid or liquid form especially, for oral administration, parenteral injection, part or aerosol drug delivery.Or be used for rectum or vagina administration in the suppository mode.

Pharmaceutical composition of the present invention can be applied to people or other Mammals, mode has oral, rectum, and transvaginal, non-stomach and intestine, local (with pulvis, ointment, emulsifiable paste, or drops) buccal or sublingual administration, or for oral cavity or nose spraying.Here term " parenteral introduction " refers to comprise intravenously, intramuscular, and intraperitoneal, subcutaneous in the breastbone, or the administering mode of intra-articular injection or infusion.

The pharmaceutical composition that the present invention is used for parenteral introduction comprises aseptic water or non-aqueous solution, dispersion agent, and suspension agent or emulsion and aseptic powder agent, it is mixed with sterile solution or suspension agent before use immediately again.Suitable sterilized water and nonaqueous carrier, thinner, the example of solvent or vehicle comprises water, normal saline solution, ethanol, and polyvalent alcohol (as glycerine, propylene glycol, poly-(ethylene glycol), Deng) and its suitable mixture, vegetables oil (as sweet oil) and injectable organic ester platform such as ethyl oleate.Keep suitable flowability,, in dispersion agent and suspension agent, keep the granular size that is fit to and use tensio-active agent for example by using coating substance such as lecithin.

Non-stomach and intestine composition also can comprise auxiliary such as sanitas, wetting agent, emulsifying agent, and dispersion agent.Prevent microbial process by adding antibiotic and the anti-mycotic agent assurance, for example, parabens, butylene-chlorohydrin, the phenol sorbyl alcohol, etc.Sometimes also need add for example sugar of isotonic agent, sodium-chlor etc.Prolong the injectable formulation that absorbs and to prolong the reagent that absorbs by adding, make as aluminum monostearate and gelatin.

In some cases, for the prolong drug effect, the absorption of the medicine that slows down after subcutaneous or intramuscular injection is suitable.This can be by using liquid suspension, or the crystal of low water solubility or non-setting material, or by medicine being dissolved in oily vehicle or suspending and realized.Contain in the situation of suspension agent of drugs of low aqueous solubility form in subcutaneous or intramuscular injection, the uptake rate of medicine depends on its dissolved speed.

The injectable of The compounds of this invention " long-acting type " preparation is to make by form the matrix of medicament microcapsule in biodegradable polymer, this polymer is for example poly-(lactic acid), poly-(oxyacetic acid), the multipolymer of lactic acid and oxyacetic acid, poly-(urate) and poly-(acid anhydrides), these materials have narration in the art.According to the character of the concrete polymer of the ratio of medicine and polymer and use, speed that can control drug release.

Injectable formulation is through aseptically process, for example, is detained the filtration of strainer by bacterium, or handles by before mixing the component of mixture being carried out pre-sterilizing, aborning or before facing administration (as in the example of double-chamber syringe packing).

The solid dosage that is used for oral administration comprises capsule, tablet, pill, pulvis and granule.In such solid dosage, active ingredient at least with a kind of inertia, but the carrier of hyoscine mixes mutually, for example Trisodium Citrate, or Lin Suanergai, and/or (a) weighting agent or supplement such as starch, lactose, glucose, mannitol, and silicic acid, (b) tackiness agent such as carboxymethyl cellulose, alginate, gelatin, poly-(ethene tetramethyleneimine), sucrose and gum arabic, (c) wetting agent such as glycerine, (d) disintegrating agent such as agar, lime carbonate, yam starch or tapioca (flour), alginic acid, silicate and yellow soda ash, (e) solution retarding agent such as paraffin, (f) absorb accelerator such as quaternary ammonium compound, (g) wetting agent such as cetyl alcohol and glyceryl monostearate, (h) absorption agent such as kaolin and wilkinite, (i) lubricant talcum for example, calcium stearate, Magnesium Stearate, solid gathers (ethylene glycol), Sodium Lauryl Sulphate BP/USP and their mixture.At capsule, in the example of tablet and pill, formulation also can contain buffer reagent.

The solids composition of similar type also can comprise the use vehicle, fills soft or hard gelatin capsule as lactose and high-molecular-weight poly (ethylene glycol) etc.

Solid dosage such as tablet, drageeing, capsule, pill and granule also can be prepared with dressing or shell, for example enteric coating or other dressing of knowing in the medicament field.This dressing can contain the lucifuge agent or at the reagent of digestive tube privileged site release of active ingredients, for example, the acid-solubility dressing is used for release of active ingredients under one's belt, or the alkali-soluble dressing is used at the enteron aisle release of active ingredients.

Also activeconstituents can continued to discharge microencapsulation in the dressing, the micro-capsule of making is as the piller part in the capsule preparations.

The liquid dosage form that The compounds of this invention is used for oral administration comprises solution, emulsion, suspension agent, syrup and elixir.Except active ingredient, liquid preparation can comprise inert diluent in the art commonly used, for example water or other pharmaceutically useful solvent, solubility promoter and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzyl alcohol, phenylformic acid benzyl ester, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (especially, cottonseed, peanut, corn, plumule, olive, castor-oil plant, and sesame oil), glycerine, tetrahydrofurfuryl alcohol, poly-(ethylene glycol), fatty acid sorbitol ester and their mixture.

Except inert diluent, liquid oral medicine can also comprise auxiliary such as wetting agent, emulsification and suspension agent, and sweeting agent, seasonings, and perfuming agent.

Except activeconstituents, liquid is that suspension agent can comprise suspensoid such as ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar and tragacanth gum and their mixture.

Rectum or vagina administration composition are by one or more compounds of the present invention are mixed with suitable non-irritating excipient.As theobroma oil, polyoxyethylene glycol or any be solid in room temperature, but under human temperature, be the suppository wax of liquid, thereby therefore discharge activeconstituents at rectum or intravaginal fusion.With compound dissolution in the wax of fusing, the shape of wanting, and make it hardening and form final suppository.

The also available liposome form administration of The compounds of this invention.As known in the art, liposome is from phosphide or other lipid material usually.Liposomal formulation is disperseed in aqueous medium by list or multilayer hydration liquid crystal and forms.Can use any nontoxic, pharmaceutically acceptable, metabolizable lipoid that can form liposome.Except one or more active ingredient beyond the region of objective existences of the present invention, the liposome formulation of this composition can comprise stablizer, vehicle, sanitas etc.Preferred lipoid is natural or synthetic phosphide and phosphatidylcholine (Yelkin TTS).

Form the method for liposome, be well known in the art, and be described in, for example, Prescott, the method in the Ed. cytobiology, volume XIV, Academic Press, NewYork, N.Y. (1976), p 33 et seq.The inventive method

The male accessory sex organ's of some kinds of BPH-fiber flesh matrix is responsive to male sex hormone and estrogenic hormesis.It is believed that in initial development that this is organized in benign prostatic hyperplasia (BPH) and the follow-up process and play an important role.Some non-steroidal antagonists such as tamoxifen or Clomiphene can suppress the estrogenic reaction of target organ, but these compounds of use limit in the relevant effect of feminizing of estrogen agonist character in being subjected to them in male body.

The pharmacology antagonism of estrogen effect comes in handy in treatment BPH.Being applied to people BPH patient's tamoxifen, is being relative nullity aspect the relative distribution that changes body of prostate and matrix organization, but these the possibility of result are from the PAA of this compound, due to the stimulation that the musculus prostaticus fibre substrate is followed.Prostate cancer-nearest G.G.Kuiper etc. have reported among the 93:5925-5930 (1996) the close oestrogenic hormon albumen of cloning from the gene order of rat prostate and ovary tissue or one new at Proc.NAt ' l.Acad.Sci.USA.This new close oestrogenic hormon body is named as ERb, enjoys with uterine estrogen receptor (ER)＞95%DNA binding domains homology and about 55% aglucon binding domains homology.ERb might be the principal recipient of mediation estrogen effect in the prostate gland.What is interesting is, in our laboratory, in the LNCaP PC-3, also demonstrate the expression of ERb mRNA.Human Prostate Cancer Cells is expressed this observations of ERb and show that the compound of selective estrogen receptor regulating effect of the present invention is useful in treatment and prevention prostate cancer.

Selective estrogen receptor of the present invention is regulated compound and is had single relatively antagonistic action, and estrogen receptor is had high avidity, but the tendency that does not have the deleterious cardiovascular of estrogen agonist and feminize.The The compounds of this invention of using significant quantity is effective in the urogenital tumour of controlling and treating optimum and pernicious hormone-sensitive.

In following experiment, in some prostate cancer cell lines, estimated The compounds of this invention bonded ability on estrogen receptor.

LNCaP DU-45 and PC-3 PC-3's lysate prepares in the TEG medium; this medium comprises 50nM TrisHCl pH 7.4; 1.5mM ethylenediamine tetraacetic acid (EDTA) (EDTA) 0.4M KCl; 10% glycerine, 0.5mM2-ME and 10mM Sodium orthomolybdate; and also contain proteinase inhibitor pepstatin (1mg/mL); leupeptin (2mg/mL) presses down white enzyme peptide of dawn (5mg/mL) and phenyl methyl fluorosulfonyl (PMSF, 0.1mM) (TEGP).

Cell pyrolysis liquid is centrifugal, and will be deposited in resuspension among the cold TEGP (1mL TEGP/100 mg sheet), and in Bramson type 450 ultrasonoscopes (Sonifier) supersound process 30 seconds (work period 70%, output 1.8).With lysate centrifugal 15 minutes, take out supernatant liquor then and exist side by side and promptly use or in-70 ℃ of storages at 4C 10,000 * G.Competition is in conjunction with test

The binding buffer agent is TEG, wherein replaces 0.4 M KCl with 50mM NaCl and to the ovalbumin (TEGO) that wherein adds 1mg/mL again.The The compounds of this invention of selecting is diluted to 20nM in TEGO, from 3 times of serial dilutions of its preparation.Carry out in the little dish of round bottom polypropylene of test in three parts of little wells.Add the 35mL tritium in every well for 17b-estradiol (0.5nM specific activity 60.1 Ci/mmol, DuPont-New England Nuclear.Boston, and hatched 5 minutes under 4 ℃ of joltings with the 70mLMCF-7 cell pyrolysis liquid MA) and cold competition test compounds (0.1nM-5mM) or the TEGO of 35mL, thereupon.

At 4 ℃ flat board was hatched 24 hours, in each well, add the gac (DCC) of 70mL dextran dressing then, and in 4 ℃ of violent joltings 8 minutes.Then with flat board at 4 ℃, centrifugal 10 minutes of 1500 * G.With supernatant liquor from each and collect and be transferred in the plasticity-polystyrene microplate scintillation counting on Wallac Micobeta 1450 type registers.Radioactivity is represented with per minute decay (DPM) after having proofreaied and correct counting efficiency (35-40%) and background.Additional contrast is total counting and grand total+DCC, to determine the lower bound of DCC extractabke counting.These emulative results in conjunction with test with average percentage in conjunction with (% in conjunction with)+/-standard deviation represents, uses following formula:

In the research, in the LNCaP cell cultures, shown high affinity (that is dissociation constant (K, _p=6.5nM), tritium is for E ₂Saturable (B _Max=160fmol/mg cell protein or every cell 37,000 acceptors) combination.

The amount that refers to alleviate the symptom The compounds of this invention under the condition described here at this used term " significant quantity ".According to the administration given dose of The compounds of this invention is that particular case by example is determined, for example, comprises the action intensity of administered compound, route of administration, patient's state of health and the pathological condition of being treated.Usually every day, dosage comprised the The compounds of this invention of non-toxic level, from about 5mg extremely about 600mg/ days.Preferred every day, dosage was usually from about 15mg extremely about 80mg/ days.

According in field of medicaments the conventional experience to patient's " dose titration " determine dosage accurately, that is, and the compound of initial application low dosage, and gradually increased dosage amount until the result of treatment of observing hope.

Following example is the preparation that is used for further illustrating The compounds of this invention.These examples can not be interpreted as restriction to the scope of the invention of claims definition.

The NMR data of following example are measured on GE 300 MHz NMR instruments, use anhydrous hexadeuterated dimethyl sulfoxide to be solvent, except as otherwise noted.

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

(27.0g 100mmol) in the solution of 1.10 liters of chloroforms, is added dropwise to bromine (15.98g, 100mmol) solution in the chloroform to (6-methoxyl group-2-(4-p-methoxy-phenyl)) benzo [b] thiophene in 60 ℃.After being added dropwise to complete, reaction is cooled to room temperature, and under vacuum, removes and desolvate, obtain (6-methoxyl group-2-(4-p-methoxy-phenyl)-3-bromine) benzo [b] thiophene of 34.2g (100%), be white solid.mp 83-85℃。 ¹H?NMR(DMSO-d ₆)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 spectrum: 349,350.Ultimate analysis theoretical value 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

At N ₂Under the atmosphere, to (6-methoxyl group-2-(4-p-methoxy-phenyl)-3-bromine) benzo [b] thiophene (34.00g, 97.4mmol) in the solution of 60mL collidine, add 4-benzyloxy phenol (38.96g, 194.8mmol) and Red copper oxide (14.5g, 97.4mmol).The gained mixture heating up was refluxed 48 hours.After being cooled to room temperature, mixture is dissolved in the acetone (200mL), removes by filter inoganic solids.Concentrated filtrate under the vacuum, and residuum is dissolved in (500mL) in the methylene dichloride.Dichloromethane solution can be used 3N hydrochloric acid, and (3 * 300mL), (3 * 300mL) wash to use 1N sodium hydroxide afterwards.Dry organic layer (sodium sulfate), and concentrate under the vacuum.Residuum is handled with the 100mL ethyl acetate, filtered and collect the white solid that forms, and (6-methoxyl group-2-(4-p-methoxy-phenyl)) benzo [b] thiophene of recovery (4.62g, 17.11mmol).Concentrated filtrate under the vacuum, then by silica gel short column (methylene dichloride is as eluent) to remove alkaline matter.Vacuum concentrated filtrate, and, obtain initial 7.19g (6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-benzyloxy) phenoxy group) benzo [b] thiophene with surplus materials crystallization in hexane/ethyl acetate, be near-white crystalline solid.Concentrated mother liquor and on silica gel chromatography (hexane/ethyl acetate 80: 20), obtain other 1.81g product.The total recovery of (6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-benzyloxy) phenoxy group) benzo [b] thiophene is that 9.00g is 24% based on the starting raw material that reclaims., and filter and collect the gained precipitation to pH=4 with 5N hcl acidifying alkalescence extract, drying obtains the 4-benzyloxy phenol that 13.3g reclaims.mp?100-103℃。 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 spectrum: 468.Ultimate analysis theoretical value C ₂₉H ₂₄O ₄S:C, 74.34; H, 5.16.Measured value: ℃, 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

To (6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-benzyloxy) phenoxy group) benzo [b] thiophene (1.50g, 3.20mmol) at the concentrated hydrochloric acid of 50mL ethyl acetate and 10mL 1% in alcoholic acid solution, add 10% palladium carbon (300mg).This mixture of hydrogenation is 20 minutes under 40psi, is finished by thin-layer chromatography judgement reaction after this time.With mixture by diatomite removing catalyzer, and under vacuum concentrated filtrate to obtaining white solid.Crude product is by silica gel (is eluent with the chloroform).Obtain (6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-hydroxyl) phenoxy group) benzo [b] thiophene of 1.10g (91%) after concentrating, be white solid.mp?123-126℃。 ¹H NMR(DMSO-d ₆) 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.Ultimate analysis theoretical value C ₂₂H ₁₈O ₄S:C, 69.82; H, 7.79.Measured value: C, 70.06; H, 4.98.Step d): the preparation of (6-methoxyl group-3-(4-(2-(piperidino)-oxyethyl group) phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene oxalate

Under N2, to (6-methoxyl group-2-(4-p-methoxy-phenyl)-3-(4-hydroxyl) phenoxy group) benzo [b] thiophene (1.12g, 2.97mmol) at the anhydrous N of 7mL, in the solution of dinethylformamide, add carbonate palladium (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.Reactant is distributed in chloroform/water (each 100mL).Separate two-layer and with chloroform (3 * 50mL) aqueous layer extracted.Merge organic layer and wash (2 * 100mL) with water.Dry organism (sodium sulfate) also concentrates, and obtains oily matter, it is purified on silica gel chromatography (2% methyl alcohol/chloroform).Concentrate the elutriant part of wanting, obtain oily matter, will be dissolved in the 10mL ethyl acetate also the usefulness oxalic acid treatment (311mg, 3.4mmol).Stir after 10 minutes, form white precipitate and filter collection and drying, obtain total its 1.17g (70%) (6-methoxyl group-3-(4-(2-(piperidino) oxyethyl group)-phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene, be oxalate.Mp 197-200 ℃ (decomposition). ¹H NMR (DMSO-d ₆) 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 (wide t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (wide 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.Ultimate analysis 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.

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

To produce free alkali from the water-soluble alkaline purification of the oxalate of example 1, react then with the saturated ether of HCl, obtain title salt, mp 216-220 ℃.

¹H?NMR(DMSO-d ₆)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＝8.7?Hz，1H)，6.96(dd，J＝9.0，1.5?Hz，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.Ultimate analysis 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.

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

Title compound prepares with quadrat method with compound in the example 1, mp 95-98 ℃. ¹HNMR(DMSO-d ₆)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 spectrum 477.Ultimate analysis 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.

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

Title compound is with the same method preparation of the compound of example 1.mp?189-192℃。 ¹H?NMR(DMSO-d ₆)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)。Ultimate analysis 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.

The preparation of example 5 (6-methoxyl group-3-(4-(2-(1-N, N-diethyl amido)-oxyethyl group) phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene hydrochloride

Title compound is with the same method preparation of the compound of example 1, mp 196-198 ℃. ¹H?NMR(DMSO-d ₆)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)。Ultimate analysis 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.

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

Title compound is with the same method preparation of example 1 compound, mp 208-211 ℃. ¹H?NMR(DMSO-d ₆)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)。Ultimate analysis 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.

The preparation of example 7 (6-hydroxyl-3-(4-(2-(piperidino) oxyethyl group)-phenoxy group)-2-(4-hydroxy phenyl)) benzo [b] thiophene

(10.00g, 19.05mmol) dissolving is descended in the 500mL anhydrous methylene chloride and is cooled to 8 ℃ with (6-methoxyl group-3-(4-(2-(piperidino) oxyethyl group)-phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene hydrochloride.In this solution, add boron tribromide (7.20mL, 76.20mmol).At 8 ℃ the gained mixture was stirred 2.5 hours.And impouring to the saturated sodium bicarbonate that is stirring (1L) with termination reaction, be cooled to 0 ℃.The separate dichloromethane layer, and remaining solid is dissolved in the methanol/ethyl acetate.Use 5% methanol/ethyl acetate (3 * 500mL) aqueous layer extracted then.Merge all organic extract liquids (ethyl acetate and methylene dichloride) and dry (sodium sulfate).Concentrate in the vacuum, obtain brown solid, its chromatogram purification (silicon-dioxide, 1-7% methyl alcohol/chloroform) is obtained (6-hydroxyl-3-(4-(2-(piperidino) oxyethyl group)-phenoxy group)-2-(4-hydroxy phenyl)) benzo [b] thiophene of 7.13g (81%), be white solid.mp?93℃。 ¹H?NMR(DMSO-d ₆)d9.73(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(masked))，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 spectrum: 462.Ultimate analysis theoretical value C ₂₇H ₂₇NO ₄S:C, 70.20; H, 5.90; N, 3.03.Measured value: C, 69.96; H, 5.90; N, 3.14.

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

Title compound prepares from free alkali with 80% yield, mp 246-249 ℃ (decomposition). ¹H?NMR(DMSO-d ₆)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(masked))，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.Ultimate analysis 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.

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

Title compound is to prepare by handling corresponding free alkali with the saturated ether of HCl, and yield is 91%, mp 158-165 ℃. ¹H?NMR(DMSO-d ₆)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 spectrum: 461.Ultimate analysis 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.

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

Title compound is from example 3 products, prepares by above-mentioned example 7 similar methods; Mp 99-113 ℃. ¹H?NMR(DMSO-d ₆)d?9.75(s，1H)，9.71(s，1H)，7.50(d，J＝9.0Hz，2H)，7.25(d，J＝2.0?Hz，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＝7.0Hz，4H)。Ultimate analysis theoretical value C ₂₆H ₂₅NO ₄S0.5 H ₂O:C, 68.40; H, 5.74; N, 3.07.Measured value: C, 68.52; H, 6.00; N, 3.34.

The preparation of example 11 (6-hydroxyl-3-(4-(2-(1-hexamethylene imine base)-oxyethyl group) phenoxy group)-2-(4-hydroxy phenyl)) benzo [b] thiophene

Title compound is from example 4 products, and the similarity method that uses by above-mentioned example 7 prepares; Mp 125-130 ℃. ¹H?NMR(DMSO-d ₆)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(s，3H)，6.80(dd，J＝9.0，2.0Hz，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)。Ultimate analysis 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.

The preparation of example 12 (6-hydroxyl-3-(4-(2-(1-N, N-diethyl amido) oxyethyl group) phenoxy group)-2-(4-hydroxy phenyl)) benzo [b] thiophene

Title compound is from example 5 products, and the similarity method that uses by above-mentioned example 7 prepares; Mp 137-141 ℃. ¹H NMR (DMSO-d ₆) d 9.75 (s, 1H), 9.71 (s, 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). ultimate analysis 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.

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

Title compound is from example 6 products, and the similarity method that uses by above-mentioned example 7 prepares; Mp 157-162 ℃. ¹H?NMR(DMSO-d ₆)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，JAB＝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)。Ultimate analysis 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.

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

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

In the time of 60 ℃, (18.13g 0.111mol) is added dropwise to n-Butyl Lithium (76.2mL .122mol, 1.6M hexane solution) by syringe in the solution of 150mL anhydrous tetrahydro furan (THF) to 6-methoxyl group benzo [b] thiophene.Stir after 30 minutes, with syringe add the triisopropyl boric acid ester (28.2mL .122mol).The gained mixture is warmed to 0 ℃ gradually, in 1N hydrochloric acid and ethyl acetate (each 300mL), distributes then.Tell each layer, use the dried over sodium sulfate organic layer.Concentrate in the vacuum, the development of ether hexanaphthene obtains white solid.Obtain 6-methoxyl group benzo [b] thiophene-2-boric acid of 16.4g (71%) after the filtration, be white solid.200 ℃ of mp (decomposition). ¹H?NMR(DMSO-d ₆)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)。Mass spectrum: 208.Step b): the preparation of (6-methoxyl group-2-(4-methylsulfonyl-oxygen phenyl)) benzo [b] thiophene

(3.00g, (3.98g 15.8mmol), adds the sodium carbonate solution of 16mL 2.0 N then 14.4mmol) to add 4-(methylsulfonyl oxygen) phenyl bromide in the solution of 100mL toluene to 6-methoxyl group benzo [b] thiophene-2-boric acid.Stir after 10 minutes, adding four (triphenyl) phosphine palladium (0.60g, 0.52mmol), and with gained mixture heating up backflow 5 hours.Then reaction mixture is cooled to room temperature, be settled out product from organic phase this moment.Divide and remove water and under vacuum, concentrate organic phase, obtain solid.Development obtains solid from ether, and filtration is also dry under vacuum, obtains (6-methoxyl group-2-(4-methylsulfonyl oxygen-phenyl)) benzo [b] thiophene of 3.70g (77%), is brown solid.mp?197-201℃。 ¹H?NMR(DMSO-d ₆)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)。Mass spectrum: 334.Ultimate analysis theoretical value 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-methylsulfonyl-oxygen phenyl)) benzo [b] thiophene

In room temperature nitrogen, to (6-methoxyl group-2-(4-methylsulfonyl oxygen phenyl)) benzo [b] thiophene (9.50g, 28.40mmol) in the solution of anhydrous methylene chloride (200mL), add boron tribromide (14.20g, 5.36mL, 56.8mmol).The gained mixture was at room temperature stirred 3 hours.Slowly impouring to the excessive frozen water with termination reaction.The vigorous stirring reaction was filtered and collected white depositions after 30 minutes, washed with water for several times, and is dry in a vacuum then, obtains (6-hydroxyl-2-(4-methylsulfonyl oxygen phenyl)) benzo [b] thiophene of 8.92g (98%), is white solid.mp?239-243℃。 ¹H?NMR(DMSO-d ₆)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 spectrum: 320.Ultimate analysis theoretical value 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-methylsulfonyl-oxygen phenyl)) benzo [b] thiophene

(3.20g 10.0mmol) in the solution of 75mL dry DMF, adds Cs to (6-hydroxyl-2-(4-methylsulfonyl oxygen phenyl)) benzo [b] thiophene ₂CO ₃(5.75g, 17.7mmol), add then benzyl chloride (1.72mL, 11.0mmol).Vigorous stirring gained mixture 24 hours.Remove in the vacuum and desolvate, and solid residue is suspended in the 200mL water.Filter and collect white precipitate and wash several with water.Dry in the vacuum, crude product is suspended in 1: 1 hexane: in the ethyl acetate.Collect (6-benzyloxy-2-(4-methylsulfonyl oxygen phenyl)) benzo [b] thiophene that solid obtains 3.72g (91%), be white solid.mp?198-202℃。 ¹H?NMR(DMSO-d ₆)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 spectrum: 410.Step e): the preparation of (6-benzyloxy-2-(4-hydroxy phenyl))-benzo [b] thiophene

At room temperature in the nitrogen, to (6-benzyloxy-2-(4-methylsulfonyl oxygen phenyl)) benzo [b] thiophene (12.50g, 30.50mmol) in the solution of the anhydrous THF of 300mL, divide add in a small amount lithium aluminum hydride (2.32g, 61.0mmol).Then this mixture was at room temperature stirred 3 hours, in the careful afterwards cold 1.0N hydrochloric acid that the reaction mixture impouring is excessive with termination reaction.Use the ethyl acetate extraction water.Then organism is washed with water for several times, dry (sodium sulfate) afterwards, and under vacuum, concentrate, obtain solid.Chromatogram purification (silicon-dioxide, chloroform) obtains (6-benzyloxy-2-(4-hydroxy phenyl))-benzo [b] thiophene of 8.75g (87%), is white solid.mp?212-216℃。

¹H?NMR(DMSO-d ₆)d?9.70(s，1H)，7.63(d，J＝8.7Hz，1H)，7.56(d，J＝2.2Hz，1H)，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 spectrum: 331.Ultimate analysis theoretical value 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

At room temperature in the nitrogen, to (6-benzyloxy-2-(4-hydroxy phenyl)) benzo [b] thiophene (8.50g, 26.40mmol) in the solution of 200mL dry DMF, divide add in a small amount sodium hydride (1.66g, 41.5mmol).After gas is produced, be added dropwise to methyl iodide (3.25mL, 52.18mmol).At room temperature reaction stirred is 3 hours.Under vacuum, remove then and desolvate, residuum is distributed in water/ethyl acetate.Layering, and water is with the organic layer washing for several times.Dry then (sodium sulfate) organic layer also concentrates under vacuum, obtains (6-benzyloxy-2-(4-p-methoxy-phenyl)) benzo [b] thiophene of 9.00g (98%), is white solid.mp?180-185℃。 ¹H?NMR(DMSO-d ₆)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 spectrum: 346.Ultimate analysis 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-bromo) benzo [b] thiophene

At room temperature, (10.0g 28.9mmol) places the 200mL chloroform with the 10.0g solid sodium bicarbonate with (6-benzyloxy-2-(4-p-methoxy-phenyl)) benzo [b] thiophene.(1.50mL is 29.1mmol) to this suspension to be added dropwise to bromine solutions in the 100mL chloroform in 30 minutes.After being added dropwise to complete, adding entry (200mL) and separate each layer.Concentrate with organic phase drying (sodium sulfate) and under vacuum white solid.Crystallization from methylene chloride obtains 10.50g (85%) (6-benzyloxy-2-(4-p-methoxy-phenyl)-3-bromo) benzo [b] thiophene, is white solid.mp?146-150℃. ¹H?NMR(DMSO-d ₆)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(5，2H)，3.78(s，3H)。FD mass spectrum: 346.Ultimate analysis theoretical value 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-bromo) benzo [b] thiophene-(S-oxide compound)

With of the product oxidation of the mixture of 1.5 normal hydrogen peroxide in the methylene dichloride of trifluoroacetic acid with step g), the preparation title compound.Product is isolated in crystallization from ethyl acetate, is yellow solid.mp?202-205℃。 ¹H?NMR(DMSO-d ₆)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 spectrum: 441.Ultimate analysis theoretical value C ₂₂H ₁₇O ₃SBr:C, 59.87; H, 3.88.Measured value: C, 59.59; H, 3.78.Step I): the preparation of (6-benzyloxy-3-(4-(2-(piperidino) oxyethyl group) phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene-(S-oxide compound)

In alkali, with above-mentioned steps i) product and 4-(2-piperidino-(1-position only) oxyethyl group) phenol reactant, obtain title compound, be yellow oil.

¹H?NMR(DMSO-d ₆)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)，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)，2.37-2.34(m，4H)，1.45-1.32(m，6H)。FD mass spectrum: 592.Ultimate analysis theoretical value 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): the preparation of (6-benzyloxy-3-(4-(2-(piperidino) oxyethyl group) phenoxy group)-2-(4-p-methoxy-phenyl))-benzo [b] thiophene

Reduction above-mentioned steps i) product, the total recovery separation with 95% obtains title compound.Chromatogram purification (SiO ₂, 1-5% methyl alcohol/chloroform), obtain the near-white solid.mp?105-108℃。 ¹H?NMR(DMSO-d ₆)d?7.62(d，J＝2.2Hz，1H)，7.59(d，J＝8.8Hz，2H)，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.Ultimate analysis theoretical value 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): the preparation of (6-hydroxyl-3-(4-(2-(piperidino) oxyethyl group) phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene

To (6-benzyloxy-3-(4-(2-(piperidino) oxyethyl group) phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene (8.50g, 15.0mmol) in the solution of 5: 1 ethanol/ethyl acetate of 300mL, add palladium black (1.50g), ammonium formiate (3.50g, 55.6mmol) and the water of 30mL.The gained mixture heating up is monitored to backflow and with the TLC method.After about 3 hours, judge that reaction finishes, and is cooled to room temperature with solution.With reactant filtration over celite pad with remove catalyzer and under vacuum concentrated filtrate, obtain solid.Enriched material is distributed in saturated sodium bicarbonate solution and 5% ethanol/ethyl acetate.Separate each layer, and concentrate with organic phase drying (sodium sulfate) and under vacuum.Chromatogram (silicon-dioxide, 1-5% methyl alcohol/chloroform) purifying crude product, obtain (6-hydroxyl-3-(4-(2-(piperidino) oxyethyl group) phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene of 6.50g (91%), be spumescence, change into solid with the hexane development.mp?174-176℃。 ¹H?NMR(DMSO-d ₆)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)，2.38-2.33(m，4H)，1.46-1.28(m，6H)。FD mass spectrum: 475.Ultimate analysis theoretical value C ₂₈H ₂₉NO ₄S:C, 70.71; H, 6.15; N, 2.94.Measured value: C, 70.46; H, 5.93; N, 2.71.

The preparation of example 15 (6-hydroxyl-3-(4-(2-(piperidino) oxyethyl group)-phenoxy group)-2-(4-p-methoxy-phenyl)) benzo [b] thiophene hydrochloride

Product with the saturated mixture process example 14 of ether in ethyl acetate of HCl changes into corresponding hydrochloride with 85% yield, crystallization from ethanol/ethyl acetate then, mp 156-160 ℃. ¹H?NMR(DMSO-d ₆)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.Ultimate analysis theoretical value 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.

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

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

According to the general operation from step a) to step g) in the example 14, obtain title compound with 73% yield, mp 217-221 ℃.

¹H?NMR(DMSO-d ₆)d?7.63-7.60(m，3H)，7.59-7.26(m，7H)，7.02(d，J＝8.7Hz，2H)，6.96(dd，J＝8.8，2.2Hz，1H)，5.11(s，2H)，3.88(s，3H)。FD mass spectrum: 346.Ultimate analysis theoretical value C ₂₂H ₁₈O ₂S:C, 76.27; H, 5.24.Measured value: C, 76.00; H, 5.25.Step b): the preparation of (6-methoxyl group-2-(4-benzyloxy phenyl)-3-bromo) benzo [b] thiophene

Obtain title compound, yield 91%, mp 125-127 ℃. ¹H?NMR(DMSO-d ₆)d?7.64-7.61(m，4H)，746-7.31(m，5H)，7.15-7.09(m，3H)，5.15(s，2H)，3.82(s，3H)。FD mass spectrum 346.Ultimate analysis theoretical value C ₂₂H ₁₇O ₂SBr:C, 62.13; H, 4.03.Measured value: C, 62.33; H, 3.93.Step c): (6-methoxyl group-2-(4-benzyloxy phenyl)-3-bromo) benzo [b] thiophene-(S-oxide compound)

Chromatogram (SiO ₂, CHCl ₃) purify title compound, be yellow solid.mp?119-123℃。 ¹H?NMR(DMSO-d ₆)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 spectrum 441.Ultimate analysis 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)

Obtain title compound, be yellow solid, mp 89-93 ℃.

¹H?NMR(DMSO-d ₆)d?7.68(d，J＝2.2Hz，1H)，7.62(d，J＝8.8Hz，2H)，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.Ultimate analysis theoretical value 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

Obtain title compound, yield is 91%, mp 106-110 ℃.

¹H?NMR(DMSO-d ₆)d?7.59(d，J＝8.8Hz，2H)，7.54(d，J＝2.2Hz，1H)，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)，2.37-2.33(m，4H)，1.44-1.31(m，4H)。FD mass spectrum 565.Ultimate analysis theoretical value 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): the preparation of (6-methoxyl group-3-(4-(2-(piperidino)-oxyethyl group) phenoxy group)-2-(4-hydroxy phenyl)) benzo [b] thiophene

Obtain title compound, yield is 88%, mp 147-150 ℃.

¹H NMR (DMSO-d ₆) 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), (m, 4H), (m, 6H) the .FD mass spectrum 475 for 1.46-1.28 for 2.38-2.33.Ultimate analysis theoretical value C ₂₈H ₂₉NO ₄S:C, 70.71; H, 6.15; N, 2.94.Measured value: C, 71.00; H, 6.17; N, 2.94.

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

By being similar to method used in the example 15, preparing and obtain title compound, mp 215-217 ℃. ¹H?NMR(DMSO-d ₆)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)，6.91-6.80(m，5H)，6.78(d，J＝8.6Hz，2H)，4.27(bt，J＝5.8Hz，2H)，3.78(s，3H)，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.Ultimate analysis theoretical value 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.Formulation examples

In following prescription, " activeconstituents " is meant formula I compound, or its salt or solvate.

Formulation examples 1

Gelatine capsule component content (mg/ capsule) activeconstituents 0.1-1000 starch, but NF 0-650 starch flowing powder 0-650350 centistoke siloxane fluid 0-15

Formulation examples 2

Ingredient in tablets content (mg/ sheet) activeconstituents 2.5-1000 Microcrystalline Cellulose 200-650 silicon-dioxide, fiery cigarette (fumed) 10-650 stearic acid 5-15

Formulation examples 3

Ingredient in tablets content (mg/ sheet) active component 25-1000 starch 45 microcrystalline celluloses, 35 polyvinylpyrrolidones 4 (being 10% aqueous solution) sodium carboxymethylcellulose 4.5 dolomols 0.5 talcum 1

With activeconstituents, starch and Mierocrystalline cellulose are by No.45 order U.S. sieve and thorough mixing.The gained powder is mixed with polyvinylpyrrolidone, then by No.14 order U.S. sieve.With the particle that obtains like this 50 ° of-60 ℃ of dryings and passed through No.18 order U.S. sieve.With sodium starch glycolate, Magnesium Stearate and talcum by No.60 order U.S. sieve, are added in the above-mentioned particle earlier then, after the mixing, are pressed into tablet on tabletting machine.

Formulation examples 4

Suspending agent component content (mg/5mL) active component 0.1-1000mg sodium carboxymethylcellulose 50mg syrup 1.25mg benzoic acid solution 0.10ml spices adds pure water to 5mL in right amount with toner in right amount

Medicine is mixed to form even mashed prod by No.45 order U.S. sieve and with carboxymethyl cellulose sodium and syrup, with benzoic acid solution, spices and dilute with some water, and adding while stirring with toner.Add enough water gagings then to reach required volume.

Formulation examples 5

Aerosol component content (weight %) activeconstituents 0.25 ethanol 25.75 propellants 22 (chlorodifluoromethane) 70.00

Activeconstituents is mixed with ethanol, and the gained mixture is added in the propellant 22 of part, be cooled to 30 ℃, and be transferred in the container.Then aequum is added in the stainless container and and dilutes with the residue propellant.Then valve system is filled in the container.

Formulation examples 6

Suppository component content (mg/ suppository) activeconstituents 250 saturated fatty acid glycerides 2,000

Activeconstituents is suspended in advance by No.60 order U.S. sieve and with it makes in the saturated fatty acid glyceride of fusing with minimum institute heat requirement.Then the mixture impouring is also cooled off to the suppository mould that is denoted as the 2g capacity.

Formulation examples 7

Injectable formulation component content activeconstituents 50mg isotonic saline solution 1,000mL

The solution intravenous injection of above composition is administered to the patient, the about 1mL per minute of speed.

Claims

1. to a kind of method of treatment among the patient of this treatment of needs or prevention benign prostatic hyperplasia or prostate cancer, it comprises the compound with following structure of administering therapeutic significant quantity,

Compound or its pharmaceutically useful salt or prodrug, wherein R ¹And R ²Be independently selected from hydroxyl or from an alkoxy base to four carbon atom; And R ³And R ⁴Be independently selected from methyl or ethyl, or R ³And R ⁴Form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidino-(1-position only), morpholino or hexamethylene imine basic ring with the nitrogen-atoms that they link to each other.

2. the process of claim 1 wherein that this method is included in treatment or prevention prostate cancer among the patient who needs this treatment.

3. the process of claim 1 wherein that this method is included in treatment or prevention benign prostatic hyperplasia among the patient who needs this treatment.

4. the process of claim 1 wherein R ¹And R ²It all is hydroxyl.

5. the method for claim 2, wherein R ¹And R ²It all is hydroxyl.

6. the method for claim 3, wherein R ¹And R ²It all is hydroxyl.

7. the process of claim 1 wherein R ¹Be hydroxyl and R ²It is an alkoxyl group to four carbon atom.

8. the method for claim 2, wherein R ¹Be hydroxyl and R ²It is an alkoxyl group to four carbon atom.

9. the method for claim 3, wherein R ¹Be hydroxyl and R ²It is an alkoxyl group to four carbon atom.

10. the process of claim 1 wherein R ³And R ⁴Form the piperidino-(1-position only) ring with the nitrogen-atoms that links to each other with them.

11. the method for claim 2, wherein R ³And R ⁴Form the piperidino-(1-position only) ring with the nitrogen-atoms that links to each other with them.

12. the method for claim 3, wherein R ³And R ⁴Form the piperidino-(1-position only) ring with the nitrogen-atoms that links to each other with them.

13. to a kind of method of treatment among the patient of this kind of needs treatment or prevention prostate cancer, it comprises the compound with following structure of administering therapeutic significant quantity Or its pharmaceutically useful salt or prodrug,

R wherein ²Be hydroxyl or methoxyl group.

14. the method for claim 13, wherein said compound are 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-(4-(2-piperidino-(1-position only) oxyethyl group)-phenoxy group) benzo [b] thiophene or its pharmaceutically useful salt.

15. the method for claim 13, wherein said compound are 6-hydroxyl-2-(4-hydroxy phenyl)-3-(4-(2-piperidino-(1-position only) oxyethyl group)-phenoxy group) benzo [b] thiophene or its pharmaceutically useful salt.

16. to a kind of method of treatment benign prostatic hyperplasia among the patient of this kind of needs treatment, what it comprised the administering therapeutic significant quantity has a following formula structural compounds

Or its pharmaceutically useful salt or prodrug, wherein R ²Be hydroxyl or methoxyl group.

17. the method for claim 16, wherein said compound are 6-hydroxyl-2-(4-hydroxy phenyl)-3-(4-(2-piperidino-(1-position only) oxyethyl group)-phenoxy group) benzo [b] thiophene or its pharmaceutically useful salt.

18. the method for claim 13, wherein said compound are 6-hydroxyl-2-(4-p-methoxy-phenyl)-3-(4-(2-piperidino-(1-position only) oxyethyl group)-phenoxy group) benzo [b] thiophene or its pharmaceutically useful salt.