MXPA99009233A - Treatment or prophylaxis of prostatic cancer and benign prostatic hyperplasia with selective estrogen receptor modulators - Google Patents

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 R1 and R2 are independently hydroxy and alkoxy of one to four carbon atoms;and R3 and R4 are independently methyl or ethyl, or R3 and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methyl-pyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.

Description

TREATMENT OR PROPHYLAXIS OF PROSTATIC CANCER AND HIPERP ASIA PROSTATE BENIGNA WITH SELECTIVE RECEIVER MODULATORS ESTROGEN TECHNICAL FIELD The present application relates to the use of a class of biologically active compounds to antagonize the proliferation of benign and malignant prostatic cells. More particularly, the invention relates to the use of a class of substituted benzo Ib-thiophene compounds for the treatment or prophylaxis of prostatic cancer and benign prostatic hyperplasia.

BACKGROUND OF THE INVENTION Mortality due to prostate cancer when the wait-and-see technique is adopted is generally low (9% -15%) in men who have localized tumors. However, these rates belong to patients with localized disease; it does not necessarily apply to younger men with a higher risk. Younger men with tumors in the Aunt stage have a longer projected risk period than older men with the same stage of the disease and are therefore candidates for a REF treatment; 31750 potentially healing. In observational observation studies, the high rates of progression of the disease (34% -80%) indicate that some clinically evident prostate cancers are at rest. Radiation therapy for the TI or T2 stage of clinically localized disease has been widely used, and has been used preferentially in older, less healthy patients and in those with a higher grade of more clinically advanced tumors. However, this treatment does not cure or eradicate all cancer cells in man with hidden metastases. The administration of estrogens to decrease surrounding androgens is an effective hormonal suppressive therapy for disseminated prostate cancer (J. axman, J. R. Soc. Med., 78: 129-135 (1985)). Anti-tumor estrogen responses are mediated primarily through decreases in circulating testosterone resulting from the inhibition of luteinizing hormone secretion. The administration of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-pyrrolidinoethoxy) benzoyl] benzo [b] thiophene (1) / or 6-hydroxy-2- (4-hydroxyphenyl) -3 - [4- (2-piperidinoethoxy) -benzoyl] benzo [£ > ] thiophene, (2), both selective estrogen receptor modulator compounds (SERM) to male Lobund-Wistar rats carrying PAIII tumor has been shown to produce a significant inhibition of tumor metastasis from the primary tumor in the tails and in the gluteal and iliac lymph nodes and in the lungs (see BL Neubauer, et al., Prostate, 27: 220-229 (1995). 1 n = 2 2 n = 3"Selective estrogen receptor modulators" are defined as those compounds that produce estrogen agonism in one or more desired target tissues, together with estrogen antagonism and / or minimal agonism (ie, clinically non-significant) in producer tissues. . Raloxifene possesses, in addition to its antiestrogenic activity, the ability to act as a physiological agonist of androgen action in male int.ict-op animals.

The PAIII adenocarcinoma in Lobund-Wistar rats is a model that is useful for evaluating agents to treat metastatic prostate cancer. When the PAIII cells are injected subcutaneously the tails of male Lobund-Wistar rats, a reproducible, time-dependent, sequential diffusion of the tumor is observed through the gluteal and iliac lymph nodes to the lungs. The morphology of the PAIII tumor recalls the anaplastic lesions in humans, which supports the utility of the tumor as a model to evaluate cytotoxic and metastatic agents for human use. Benign prostatic hyperplasia (BHP) is the most common benign neoplasm in men. It has been estimated that approximately 50% of men in the United States aged over 50 have BPH. BPH is an enlarged prostate gland caused by benign overgrowth of the stromal tissue of the prostate and leads to symptoms which include increased urinary urgency and increased frequency whichWhen untreated, it can lead to associated complications which include damage to the bladder and kidneys. The typical treatment for BPH is "transurethral prostatectomy, a procedure which is expensive and time consuming.The mortality by transurethral resection of the prostate has been reduced to 0.2% in the last 30 years, but the procedure itself has not changed significantly at that time, and the postoperative bite has remained unchanged, with an approximate value of 18% .An estimated 29% of men with benign prostatic hyperplasia will require surgical treatment.This translates into more than 400,000 surgical procedures per year. It has been estimated that, if current rates prevail, a 40-year-old man in the United States will live up to the age of 80 and will have a 29% chance of prostatectomy.The high cost of this procedure, both in time and in money, it has generated a considerable interest in seeking a less expensive and morbid means to deal with BPH.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a method for the treatment or prophylaxis of prostatic cancer or benign prostatic hyperplasia (BPH) in a patient in need of such treatment, which comprises administering a therapeutically effective amount of a selective compound modulator of the Estrogen receptor structure or a pharmaceutically acceptable salt or prodrug thereof. In the above structure, R1 and R2 are independently selected from the group consisting of hydroxy and alkoxy of 1 to 4 carbon atoms. R3 and R4 are independently selected from methyl or ethyl, or R3 and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino ring, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or hexamethyleneimino.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawing: Figure 1 is a graph of the E2Rb binding activity in the human prostatic adenocarcinoma cell line LNCaP.

DETAILED DESCRIPTION Through this specification and the appended claims, the general terms will have their usual meanings. The term "alkyl" denotes a monovalent radical derived by removal of a hydrogen atom from methane, ethane or a straight or branched hydrocarbon, and includes groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso -butyl, tert-butyl and the like. "Alkoxy" means an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom and includes groups such as methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso -butoxy, tert-butoxy and the like. In the present invention, methoxy is the preferred alkoxy group. The term "prodrug" (prodrug), as used herein, means a compound of the present invention that exhibits a group which is metabolically evolved in a human to produce a therapeutically active compound of the present invention. In particular, such prodrug compounds include those in which either or both of the substituent groups R1 and R2 of the structure shown above are hydroxy groups which are protected groups by a pharmaceutically acceptable hydroxy protecting group which is metabolically separated in the body to provide a corresponding monohydroxy or dihydroxy compound of the present invention. The hydroxy protecting groups are described in chapter 2 of T. W. Greene, et al. , "Protective Groups in Organic Synthesis," Second Edition, John Wiley & Sons, Inc., New York, 1991. Simple ether and ester groups are preferred as hydroxy protecting groups of prodrug. Preferred compounds of the present invention include: 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidino-ethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt or prodrug thereof; and 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidino-ethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt or prodrug thereof.

Preparation of the compounds of the invention The starting material for a pathway for preparing compounds of the present invention is prepared essentially as described by C.D. Jones in US Pat. Nos. 4,418,068 and 4,133,814. The initial materials have the formula 1: wherein R5 and R6 are independently -H or a hydroxy protecting group. The hydroxy protecting groups of Rs and R6 are portions which are introduced intentionally during a portion of the synthesis process to protect a group that would otherwise react in the course of chemical manipulations, and are then removed at a later stage of the synthesis . Since the compounds having such protective groups are of importance mainly as chemical intermediates (although some derivatives also show biological activity), their precise structure is not critical. Numerous reactions for the formation, removal and conversion of such protecting groups are described in many standard work including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973).; Greene, T.W. , Protective Groups in Organic Synthesis, Wiley (New York, 1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press, (London and New York, 1965). Representative hydroxy protecting groups include, for example, -C1-C4 alkyl, -C1-C4 alkoxy, -CO- (L- alkyl), -SO ^ - (C4-C6 alkyl) and -CO- Ar, in which Ar is benzyl or optionally substituted phenyl. The term "substituted phenyl" refers to a phenyl group having one or more substituents that are selected from the group consisting of C-, -0 ^ alkyl, C ^ -C ^ alkoxy, hydroxy, nitro, halo and tri ( chlorine or fluoro) methyl. The term "halo" refers to bromine, chlorine, fluorine and iodine. For the compounds of formula 1, the preferred substituents R5 and R6 are methyl, isopropyl, benzyl and methoxymethyl. The compounds in which R5 and Re are each methyl, are prepared via a procedure described in the Jones patent mentioned above. The compounds of formula 1 are also prepared in which the hydroxy protecting group in Rs is selectively removed, which leaves R6 as a hydroxy protecting group as part of the final product. The same is true in the case where the hydroxy protecting group is selectively removed in R6, which leaves the hydroxy protecting group in R5 instead. For example, R5 can be isopropyl or benzyl and R6 methyl. The isopropyl or benzyl moiety is selectively moved by standard procedures, and the methyl protecting group in R6 is left as part of the final product. As shown in Reaction Scheme I, the first steps of the present process for preparing certain compounds of the present invention include selectively placing a leaving group, R7 at the 3-position of a compound of formula 1, to form a compound of formula 2, coupling the product of this reaction with a 4- (protected hydroxy) phenol, 3., to form a compound of formula 4, and selectively removing the hydroxy protecting group on R8 to form a compound of formula 5_. In the sequence of steps shown in Reaction Scheme I, the hydroxy protecting groups, R5, R6 and R8 are chosen such that, in the final stage, the hydroxy protecting group in R8 can be selectively removed in presence of hydroxy protecting groups in R5 and R6.

Reaction Scheme I In the first step of Reaction Scheme I, an appropriate leaving group is selectively placed at position 3 of formula 1 of starting material via standard procedures. Suitable leaving groups R7 include sulphonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropansul fonate, 4-methylperoxybenzoate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, triflate and the like, halogens such as bromine, chlorine and iodine, and other related outgoing groups. However, to ensure proper placement of the leaving group, the aforementioned halogens are preferred and bromo is especially preferred. The present reaction is carried out using standard or conventional procedures. For example, when the preferred halogenating agent is used, one equivalent of such a halogenating agent, preferably bromine, is reacted with an equivalent of the substrate of formula 1, in a suitable solvent such as, for example, chloroform or acetic acid. The reaction is typically carried out at a temperature from about 40 ° C to about 80 ° C. The reaction product of the above process step, a compound of formula 2., is then reacted with a 4- (protected hydroxy) phenol, 3., to form compounds of formula 4. in which R8 is a protecting group of selectively removable hydroxy. Generally, the 4-hydroxy protecting portion of the phenol can be any known protecting group which can be removed selectively without removing, in this case, the R5 portions and, when present, R6 of the compound of formula 3. The protecting groups of preferred R8 include methoxymethyl, when R5 and / or R6 are not methoxymethyl, and benzyl. Of these, benzyl is especially preferred. Reagents of 4- (hydroxy-protected) phenol are commercially available or can be prepared by standard procedures. The coupling reaction between the compounds of formula 2 and those of formula 3 is known in the art as a Ullman reaction and is generally carried out in accordance with standard procedures [see, for example, "Advanced Organic Chemistry: Reactions , Mechanisms, and Structure, "Fourth Edition, 3-16, (J. March, ed., John Wiley &Sons, Inc. 1992); Jones, C.D., J. Chem. Soc. Perk. Trans. I, 4_: 407 (1992)]. In general, the equivalent amounts of two aryl substrates, in the presence of up to one molar equivalent of copper (I) oxide catalyst and an appropriate solvent, are heated under reflux under an inert atmosphere. Preferably, an equivalent of a compound of formula 2 is reacted in which R7 is bromine, with an equivalent amount of 4-benzyloxyphenol in the presence of a cuprous oxide equivalent. Suitable solvents for this reaction are those solvents or solvent mixtures which remain inert during the reaction. Typically, the preferred solvents are organic bases, particularly a hindered base such as, for example, 2,4,6-collidine. The temperature used in this stage is generally sufficient to carry out the completion of this coupling reaction and will influence the amount of time necessary for it. When the reaction mixture is heated to reflux under an inert atmosphere such as nitrogen, the time to completion is usually from about 20 to about 60 hours. After the coupling of a compound of formula 2 with one of formula I, to form a compound of formula 4, the compounds of formula 5 are prepared by selective removal of the hydroxy protecting group in R8 of a compound of formula 4. means of well-known reduction procedures. It is imperative that the selected procedure does not affect Rs and, when present, the hydroxy protecting groups in R6. When R8 is the preferred benzyl portion, and R5 and, when present, R6 are each methyl, the present process steps are carried out by means of standard hydrogenolysis procedures. Typically, the substrate of formula 4 is added to a suitable solvent or solvent mixture, followed by the addition of a proton donor to accelerate the reaction, and an appropriate hydrogenation catalyst. Suitable catalysts include noble metals and oxides such as palladium, platinum and rhodium oxide on a support such as carbon or calcium carbonate. Of these, palladium on carbon, particularly palladium 10% on carbon, is particularly preferred. The solvents for this reaction are those solvents or mixture of solvents which remain inert through the reaction. Ethyl acetate and C-L-C2 aliphatic alcohols, particularly ethanol, are typically preferred. For the present reaction, hydrochloric acid serves as a suitable and preferred proton donor. When carried out at room temperature and at a pressure ranging from about 206.8 kilopascals (30 psi) to about 344.7 kilopascals (50 psi), the present reaction is carried out very rapidly. The progress of the reaction can be monitored by standard chromatographic techniques such as thin layer chromatography. As shown in Reaction Scheme il, when a compound of formula 5 is prepared, it is reacted with a compound of formula R4R5N- (CH2), - Q wherein R4 and R5 are as defined above, and Q is bromine or preferably chlorine, to form a compound of formula 7. The compound of formula 7. is then deprotected to form a compound of formula I. Reaction scheme II e, R = R = H Ib, R5 = H le, R6 = H In the first stage of the process shown in Reaction Scheme II, the reaction is carried out by standard procedures. The compounds of formula 6 are commercially available or prepared by means well known to one of ordinary skill in the art. Preferably, the hydrochloride salt of the compound of formula 6 is used. In a particularly preferred case of the compounds of the present invention, 2-chloroethylpiperidine hydrochloride is used. Generally, at least about 1 equivalent of a substrate of formula 5 is reacted with two equivalents of a compound of formula 6 in the presence of at least about 4 equivalents of an alkali metal carbonate, preferably cesium carbonate, and a appropriate solvent. Suitable solvents for this reaction are those solvents or mixture of solvents which remain inert during the reaction. N, N-dimethylformamide, especially the anhydrous form thereof, is preferred. The temperature used in this step must be sufficient to carry out the alkylation reaction. Typically, room temperature is sufficient and preferred. The present reaction is preferably carried out under an inert atmosphere, particularly nitrogen. Under preferred reaction conditions, this reaction will be brought to completion for about 16 to about 20 hours. After monitoring the progress of the reaction by means of standard chromatographic techniques. In an alternative process for preparing compounds of the present invention, shown in Reaction Scheme III below, a compound of formula 5 is reacted in an aicaline solution with an excess of an alkylating agent of formula 8 .: Q- (CHa) n-Q ' wherein Q and Q 'are the same or different leaving groups The appropriate leaving groups are those mentioned above.

Reaction Scheme III Ib, R5 = H e, R6 = H A preferred alkaline solution for this alkylation reaction contains potassium carbonate in an inert solvent such as, for example, methyl ethyl ketone (MEK) or DMF. In this solution, the unprotected hydroxy group of the compound of formula 5 is converted to a phenoxide ion which displaces one of the leaving groups of the alkylating agent.This reaction proceeds best when the alkaline solution containing the reactants and the agents is subjected to at reflux and allowed to run to completion When MEK is used as the preferred solvent, the reaction times vary from about 6 hours to about 20 hours The reaction product of this step, a compound of formula 9 then it is reacted with a compound of formula ljO which is selected from 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine, or 1-hexamethyleneimine, via standard techniques, to form compounds of formula 7 Preferably the hydrochloride salt of a compound of formula 1_0 is used with piperidine hydrochloride with particulate preference. The reaction is typically carried out with the alkylated compound of formula 9. in an inert solvent, such as anhydrous DMF, and heated to a temperature in the range of from about 60 ° C to about 110 ° C. When the mixture is heated to a preferred temperature of about 90 ° C, the reaction only requires about 30 minutes to about 1 hour. However, changes in the reaction conditions will affect the amount of time the reaction needs to be carried out completely. The progress of this reaction stage can be monitored via standard chromatographic techniques. Certain preferred compounds of formula I are obtained by separating R5 and, when present, R6 hydroxy protecting groups of compounds of formula by means of well-known procedures. Many reactions are described for formation and removal of such protecting groups in numerous standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Greene, T.W., Protective Groups in Organic Synthesis, Wiley, (New York, 1981); and The Peptides, Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965). Methods for removing hydroxy protecting groups in preferred R7 and / or R8, particularly methyl and methoxymethyl, are essentially as described in the Examples, infra. An alternative and preferred method for the preparation of compounds of the present invention is shown in Reaction Scheme IV. In the process shown there, the sulfur atom of a compound of formula 2 is oxidized to form sulfoxide 11 which then reacts with a nucleophilic group to introduce the binder to the oxygen atom of the compounds of formula I. The sulfoxide portion of the compounds of formula 12 is then reduced to provide certain compounds of the present invention.

Reaction Scheme IV 14 la, R5 = R6 = H Ib, R5 = H le, R6 H In the first step of this process, a compound of formula 2 is selectively oxidized to sulfoxide .12. Many known methods are available for the process step [see, for example, Madesclaire, M., Tetrahedron, 42 (20); 5459-5495 (1986); Trost, B.M., et al. , Tetrahedron Letters, 22 (14); 1287-1290 (1981); Drabowicz, J., et al. , Synthetic Communications, 11 (12); 1025-1030 (1981); Kramer, J.B., et al. , 34th National Oraanic Symposium, Williamsburg, VA. June 11-15, 1995]. However, many oxidants provide only a poor conversion of the desired product as well as significant over-oxidation to the sulfone. However, the preferred process converts a compound of formula 2 to a sulfoxide of formula 12. in a high yield with little or no sulfone formation. This process involves the reaction of a compound of formula 2. with about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture of about 20% to about 50% trifluoroacetic acid in methylene chloride. The reaction is carried out at a temperature from about 10 ° C to about 50 ° C, and usually requires from about 1 to about 2 hours to complete it. Subsequently, the outgoing group in position 3, R7 is displaced by the desired nucleophilic derivative of formula 3. Such nucleophilic derivatives are prepared by standard methods. At this stage of the process, the acid proton of the nucleophilic group is removed by treatment with a base, preferably a slight excess of sodium hydride or potassium terbutoxide, in a polar aprotic solvent, preferably DMF or tetrahydrofuran. Other bases that can be used include potassium carbonate and cesium carbonate. Additionally, other solvents such as dioxane or dimethyl sulfoxide may be used. Deprotonation is usually carried out at a temperature between about 0 ° C and about 30 ° C, and usually requires about 30 minutes for its completion. Then a compound of formula XIV is added to the solution of the nucleophile. The displacement reaction is carried out at a temperature between 0 ° C and about 50 ° C, and is usually carried out for about 1 to about 2 hours. The product is isolated by standard procedures. In the next step of the present process, the sulfoxide of formula 14 is reduced to a benzothiophene compound of formula. When desired, the hydroxy protecting group or groups of the process products shown in Reaction Scheme IV can be removed, and a product salt is formed at any stage of the process. The prodrug ester compounds of formula X are prepared by substituting the hydroxy portions at the 6 and / or 4 'positions when present, with a portion of the formula -OCO (alkyl, or -0S02 (C2-C6 alkyl) ) by means of well-known procedures, see for example, U.S. Patent No. 4,358,593. For example, when a group -OCO (CL-Cg alkyl) is desired, a mono- or dihydroxy compound of formula is reacted with an agent such as chloride, bromide, cyanide or aazide, or with an anhydride or anhydride mixed appropriate. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine and the like. The reaction is also carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethyl sulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone and the like, to which at least one equivalent of an eliminator has been added. acid (except as indicated above), such as a tertiary amine. If desired, ation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine can be used. See, for example, Haslam, et al. , Tetrahedron, 36: 2409-2433 (1980). These reactions are carried out at moderate temperatures, in the range from about -25 ° C to about 100 ° C, often under an inert atmosphere such as nitrogen gas. However, the room temperature is usually adequate for the reaction to take place.The acylation of a hydroxy group in position 6 and / or in the 4 'position can be carried out by reactions catalyzed by acid of the appropriate carboxylic acids in inert organic solvents. Acid catalysts are used such as sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like. The aforementioned ester-promoting compounds can also be provided by forming the active ester of the appropriate acid, such as the esters formed by known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide and 1-hydroxybenzotriazole. See, for example, Bull. Chem. Soc. Japan, 38: 1979 (1965), and Chem. Ber. , 788 and 2024 (1970). Each of the above techniques which provide portions -OCO (C-L-C ^ alkyl) are carried out in solvents as discussed in the above. Those techniques which do not produce an acid product in the course of the reaction, of course, are not needed for the use of an acid scavenger in the reaction mixture. When a compound of formula X is desired in which the hydroxy group in the 6 and / or 4 'position of the compound of formula I is converted to a group of the formula -0S02 (C2-C6 alkyl), the mono- or dihydroxy is reacted with, for example, a sulfonic anhydride or an appropriate sulphonic acid derivative, such as chloride, sulfonyl bromide or ammonium sulphonyl salt, as described by King and Monoir, in J. Am. Chem. Soc., 97: 2566-2567 (1975). The dihydroxy compound can also be reacted with the appropriate sulfonic anhydride or the mixed sulfonic anhydrides. Such reactions are carried out under conditions such as those explained above in the discussion of the reaction with acid halides and the like.

Preparation of pharmaceutically acceptable salts of the compounds of the present invention Although the free base form of the compounds of formula I can be used in medical methods of treatment of the present invention, it is preferred to prepare and use the pharmaceutically acceptable salt form. The compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids. Such salts are also contemplated and considered to be within the scope of the present invention. The term "pharmaceutically acceptable salts" as used in this specification and the appended claims denotes salts of the types described in the Article by Berge, et al. , J. Pharmaceutical Sciences, 66 (1): 1-19 (1977).

Suitable pharmaceutically acceptable salts include salts formed by typical inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like as well as salts derived from organic acids, such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids , hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable organic acid addition salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, b- hydroxybutyrate, butyn-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite , sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylene sulfonate, tartrate and the like. The preferred salts are the hydrochloride and oxalate salts. The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or slightly molar excess of acid. The reagents are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt is usually separated by precipitation from the solution in about 1 hour to 10 days and can be isolated by filtration, or the solvent can be removed by distillation by conventional means. The pharmaceutically acceptable salts generally have characteristics of increased solubility as compared to the compound from which they are derived, and therefore, they are often more susceptible to formulation as liquids or emulsions.

Pharmaceutical formulations The compounds of this invention are administered by various routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are preferably formulated before their administration, the selection of which will be decided by the attending physician. Therefore, another aspect of the present invention is a pharmaceutical composition comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which optionally contains an effective amount of estrogen or progestin, and a carrier, diluent or pharmaceutically acceptable excipient. The total active ingredients in such formulations comprise from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" it is meant that the carrier, diluent, excipients and salts must be compatible with the other ingredients of the formulation, and not be harmful to the reception thereof. The pharmaceutical formulations of the present invention are prepared by methods known in the art using well known and readily available ingredients. For example, the compounds of formula I, either alone or in combination with an estrogen or progestin compound, are formulated with common excipients, diluents or carriers and formed into tablets, capsules, suspensions, solutions, injectables, aerosols, powders and Similar. The total active ingredients in such formulations comprise from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" is meant that the carrier, diluent, excipients and salts, must be compatible with the other ingredients of the formulation, and must not be harmful to the recipient thereof. The formulations may be formulated especially for oral administration, in solid or liquid form, for parenteral injection, topical or aerosol administration or for rectal or vaginal administration by means of a suppository. The pharmaceutical compositions of this invention can be administered to humans or other mammals orally, rectally, intravaginally, parenterally, topically (by means of powders, ointments, creams or drops), buccally or sublingually, or by oral or nasal spray . The term "parenteral administration" refers herein to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous or intraarticular injection or infusion. The pharmaceutical compositions of this invention for parenteral administration comprise sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders which are reconstituted immediately before use in sterile solutions or suspensions. Examples of suitable sterile aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, physiological saline, ethanol, polyols (such as glycerol, propylene glycol, poly (ethylene glycol) and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of appropriate particle size in the case of dispersions and suspensions, and by the use of surfactants. The parenteral compositions may also contain adjuvants such as preservatives or preservatives, wetting agents, emulsifying agents and agents that improve dispersion. The prevention of the action of the microorganisms is ensured by the inclusion of antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid and the like. It is also desirable to include isotonic agents such as sugars, sodium chloride and the like. A prolonged absorption of the injectable formulations can be carried out by the inclusion of agents which retard absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to decrease or slow the absorption of the drug after subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension or a crystalline or amorphous material of low solubility in water or by dissolving or suspending the medicament in an oily vehicle. In the case of subcutaneous or intramuscular injection of a suspension containing a drug form with low solubility in water, the absorption rate of the medication will depend on its rate of dissolution. The injectable "depot" formulations of the compounds of this invention are produced by forming microencapsulated matrices of the medicament into biodegradable polymers such as poly (lactic acid), poly (glycolic acid), copolymers of lactic and glycolic acid, poly (orthoesters) and poly (anhydrides), these materials have been described in the art. Based on the ratio of the drug to the polymer and the characteristics of the particular polymer used, the rate of drug release can be controlled. The injectable formulations are sterilized, for example, by filtration through filters that retain bacteria, or by pre-sterilization of the components or of the mixture before mixing, either at the time of preparation or moments before administration (as in the example of a double-chamber syringe package). Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active component is mixed with at least one inert and pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or fillers such as • starches, lactose, glucose, mannitol and silicic acid, (b) binding agents such as carboxymethylcellulose, alginates, gelatin, poly (vinylpyrrolidine), sucrose and acacia (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, starch of potato or tapioca, alginic acid, silicates and sodium carbonate, (e) solution retarding agents such as paraffin, (f) agents that accelerate absorption such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerin monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid poly (ethylene glycols) s, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form will also contain buffering agents. Solid compositions of a similar type can also comprise the filling material in soft or hard gelatin capsules using excipients such as lactose as well as high molecular weight poly (ethylene glycols) and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can also be prepared with coatings or shells such as enteric coatings or other coatings well known in the pharmaceutical formulating art. The coatings may contain opacifying agents or agents which release the active ingredient or ingredients in a defined part of the digestive tract, such as, for example, acid-soluble coatings for release of the active ingredient or ingredients in the stomach, or soluble coatings in a base for release of the active ingredient or ingredients in the intestinal tract. The active ingredient or ingredients can also be microencapsulated in a sustained release coating wherein the microcapsules form part of a pill or capsule formulation. Liquid dosage forms for oral administration of the compounds of this invention include solutions, emulsions, suspensions, syrups and elixirs. In addition to the active components, liquid formulations may include inert diluents commonly used in the art such as water or other pharmaceutically acceptable solvents, solubilizing agents and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, , 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, ground nut, corn, germ, olive, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, poly (ethylene glycols), sorbitol fatty acid esters and mixtures thereof. In addition to the inert diluents, the liquid oral formulations may also include adjuvants such as wetting agents, emulsifying agents and improving the suspension and sweetening agents, flavors and perfumes. The liquid suspension, in addition to the active ingredient or ingredients may contain suspension-improving agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite clay, agar-agar and tragacanth, and mixtures thereof. same. Compositions for rectal or intravaginal administration are prepared by mixing one or more of the compounds of the present invention with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature, but liquid at room temperature. body and therefore melts in the rectum or vaginal cavity to release the component or active components. The compounds are dissolved in the molten wax, formed into the desired shape and allowed to harden in the finished suppository formulation. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally supplied from phospholipids or other lipid substances. The liposome formulations are made by mono- or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, pharmaceutically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may contain, in addition to one or more active compounds of the present invention, stabilizers, excipients, preservatives and the like. The preferred lipids are phospholipids and the phosphatidylcholines (lecithins), both natural and synthetic. Methods for making liposomes are known in the art and are described, for example, in Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq.

Method of the present invention BHP - The fibromuscular stroma of male sex accessory organs of various species are sensitive to the stimulatory effects of androgens and estrogens. It is considered that this tissue plays an important role both in the initial development and in the subsequent progress of benign prostatic hyperplasia (BPH). The estrogenic responses of organs can be inhibited by certain non-steroidal antagonists such as tamoxifen or clomiphene, but the usefulness of these compounds in men can be limited to their feminizing effects related to their inherent properties of estrogen agonists. The pharmacological antagonism of the action of estrogen may be useful in the treatment of BPH. Tamoxifen administered to human patients with BPH is relatively ineffective in altering the relative distribution of glandular and stromal prostatic tissue, but these results may be the result of a partial agonistic activity of the compound with concomitant stimulation of the prostatic fibromuscular stroma.

Prostate Carcinoma - Recently, G. G. Kuiper, et al., Proc. Nati Acad. Sci. USA, 93: 5925-5930 (1996) have reported the cloning of the gene sequence for rat prostatic and ovarian tissue for a novel stromal protein. This new estrophile, which has been termed ERb, shares a homology of DNA binding domain > 95% and approximately 55% homology of ligand-binding domain with the uterine estrogen receptor (ER). ERb can be the main receptor that mediates the action of estrogen in the prostate. Interestingly, the expression of mRNA for ERb has also been shown in the human prostate cancer cell line LNCaP in our laboratories. This observation that human prostate cancer cells express ERb indicates that the selective estrogen receptor modulator compound of the present invention is useful in the treatment and prevention of prostate cancer. The selective compounds that modulate the estrogen receptor of the present invention have a relatively pure antagonist profile with a high affinity for estrogen receptors, but lack the dangerous cardiovascular and feminizing susceptibilities of estrogen agonists. The administration of an effective amount of a compound of the present invention is effective for the administration or treatment of urogenital neoplasms sensitive to both benign and malignant hormones. In the experiments described below, the capabilities of the compounds of the present invention to bind to estrogen receptors in various human prostate cancer cell lines were evaluated. Lysates are prepared from the human prostate cancer cell lines LNCaP, DU-45 and PC-3 in a TEG medium comprising 50 nM Tris-HCl, pH 7.4, 1.5 mM ethylenediaminetetraacetic acid (EDTA), 0.4 M KCl, glycerol 10 %, 2 -ME 0.5 mM and 10 mM sodium molybdate, which also contains the protease inhibitors pepstatin (1 mg / ml), leupeptin (2 mg / ml), aprotinin (5 mg / ml) and phenylmethylsulfonyl fluoride (PMSF) , 0.1 mM) (TEGP).

The used cells are centrifuged and the pellets are resuspended in cold TEGP (1 ml of TEGP / 100 mg of sediment) and subjected to sonication for 30 seconds (duty cycle 70%, output 1.8) in a Branson Model 450 sonicator. lysates are pelleted by centrifugation at 10,000 x G for 15 minutes at 4 ° C after which the supernatants are removed and used immediately or stored at -70 ° C Competitive Union Test The binding buffer is TEG in which 0.4 M KCl is replaced by 50 mM NaCl and to which 1 mg / ml ovalbumin (TEGO) has been added. The selected compounds of the present invention are diluted to 20 nM in TEGO from which triple serial dilutions are prepared. The tests are carried out in microplates of round bottom polypropylene in triplicate microwells. Each well receives 35 ml of tritiated 17b-estradiol (0.5 nM, specific activity, 60.1 Ci / mmol, DuPont-New England Nuclear, Boston, MA) and 35 ml of cold competition test compound (0.1 nM - 5 mM) or TEGO, and after incubation for 5 minutes at 4 ° C with shaking, 70 ml of cell line lysate MCF-7. The plates are incubated for 24 hours at 4 ° C, after which 70 ml of dextran-coated activated charcoal (DCC) is added to each well, followed by vigorous stirring for 8 minutes at 4 ° C. The plates are then centrifuged at 1500 x G for 10 minutes at 4 ° C. The supernatant is collected from each well in a flexible polystyrene microplate for scintillation counting in a Wallac Micobeta model 1450 counter. Radioactivity is expressed in disintegrations per minute (DPM) after correcting for counting efficiency (35-40%) and the background. The additional controls were the total accounts and the total accounts + DCC to define the lower limit of withdrawable accounts by DCC. The results of these competitive binding assays are expressed as the average percent binding (% bound) +/- standard deviation using the formula: ? i ^ JP- 1M1cop? test case - nJPJ-M L 1subccount total% X 100 linked? 1JPrlMl? N composed of test- nUPJ: M1 'total subaccount + DCC A graph of E2Rb binding activity in a human prostatic adenocarcinoma cell line LNCaP is shown in Figure 1. In this study, high affinity binding (ie, dissociation constant (Kp = 6.5 nM), saturable (Bmax = 160 fmol / mg of cellular protein or approximately 37,000 receptors per cell) of tritiated E2 in cell cultures is demonstrated LNCaP.

As the term "effective amount" means an amount of compound of the present invention which is capable of alleviating the symptoms of the conditions described herein. The specific dose of a compound administered according to this invention is determined by the particular circumstances surrounding the case and including, for example, the potency of the compound administered, the route of administration, the constitution or the condition in which it is found. the patient and the pathological condition in question. A typical daily dose will contain a non-toxic dosage level from about 5 mg to about 600 mg / day of a compound of the present invention. The preferred daily doses will generally be from about 15 mg to about 80 mg / day. The exact dose is determined in accordance with standard practice in medical techniques of dose titration for the patient; that is, a low dose of the compound is initially administered, and the dose is gradually increased until the desired therapeutic effect is observed. The following examples are presented to further illustrate the preparation of compounds of the present invention. The examples should not be read as limiting the scope of the invention as defined by the appended claims.

The NMR data of the following examples were generated on a GE 300 MHz NMR instrument and anhydrous hexadeuterodimethyl sulfoxide was used as the solvent, unless otherwise indicated.

Example 1 Preparation of the oxalate salt of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxyl-phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene Step a): Preparation of [6-methoxy-2- (4-methoxy-phenyl) -3-bromo] benzo [b] thiophene To a solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (27.0 g, 100 mmol) in 1.10 1 of chloroform at 60 ° C is added bromine (15.98 g, 100 mmoles) dropwise as a solution in 200 ml of chloroform. After the addition is completed, the reaction is cooled to room temperature, and the solvent is removed in vacuo to provide 34.2 g (100%) of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene as a white solid, mp 83-85 ° C. 1 H NMR (DMSO-d 6): d 7.70-7.62 (m, 4H), 7.17 (dd, J = 8.6, 2.0 Hz, ÍH), 7.09 (d, J = 8.4 Hz, 2H). Mass spectrum FD: 349, 350. Analysis Calculated for C16H1302SBr: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76T.

Step Preparation of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene To a solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (34.00 g, 97.4 mmol) in 60 ml of collidine under N2 is added 4-benzyloxyphenol (38.96 g, 194.8 mmoles) and cuprous oxide (14.5 g, 97.4 mmol). The resulting mixture is heated to reflux for 48 hours. Upon cooling to room temperature, the mixture is dissolved in acetone (200 ml), and the inorganic solids are removed by filtration. The filtrate is concentrated in vacuo, and the residue is dissolved in methylene chloride (500 ml). The methylene chloride solution is washed with 3 N hydrochloric acid (3 x 300 ml), followed by 1 N sodium hydroxide (3 x 300 ml). The organic layer is dried (sodium sulfate) and concentrated in vacuo. The residue is taken up in 100 ml of ethyl acetate, whereby a white solid is formed which is collected by filtration [6-methoxy-2- (4-methoxyphenyl)] benzo- [b] thiophenone recovered (4.62 g)., 17.11 mmol]. The filtrate is concentrated in vacuo and then passed through a short pad of silica gel (methylene chloride as eluent) to remove the baseline material. The filtrate is concentrated in vacuo, and the residue crystallizes from hexanes / ethyl acetate to initially provide 7.19 g of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b. ] -thiophene as a whitish crystalline solid. The mother liquor is concentrated and subjected to chromatography on silica gel (hexanes / ethyl acetate 80:20) to give 1.81 g of additional product. The total yield of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene is 9.00 g (24% based on the recovered starting material). The basic extract is acidified to pH = 4 with 5N hydrochloric acid, and the resulting precipitate is collected by filtration and dried to provide 13.3 g of 4-benzyloxyphenol recovered, m.p. 100-103 ° C. XH NMR (CDC13): d 7.60 (d, J = 8.8 Hz, 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), Mass Spectrum FD: 468. Analysis Calculated for C29H2404S: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29.

Step c): Preparation of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene To a solution of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene (1.50 g, 3.20 mmol) in 50 ml of ethyl acetate and 10 ml of acid Concentrated hydrochloric acid 1% in ethanol is added 10% palladium carbon (300 mg). The mixture is hydrogenated at 2.8 kg / cm2 (40 psi) for 20 minutes, time after which the reaction is considered complete by thin layer chromatography. The mixture is passed through Celite to remove the catalyst, and the filtrate is concentrated in. Vacuum to a white solid. The crude product (untreated) is passed through a pad of silica gel (chloroform as eluent). The concentration affords 1.10 g (91%) of [6-ethoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene as a white solid, m.p. 123-126 ° C. XH NMR (DMSO-d6) d 9.10 (s, ÍH), 7.59 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.1 Hz, ÍH), 7.14 (d, J = 8.8 Hz, ÍH), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8. 8, 2.1 Hz, ÍH), 6.72 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), Mass Spectrum FD: 378. Analysis Calculated for C22H1804S: C, 69.82; H, 4.79. Found: C, 70.06; H, 4.98.

Step d): Preparation of the oxalate salt of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-methoxy-enyl) benzo [b] thiophene To a solution of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene (1.12 g, 2.97 mmol) in 7 ml of anhydrous N, -dimethylformamide under N 2 carbonate is added of cesium (3.86 g, 11.88 mmol). After stirring for 10 minutes, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) is added. The resulting mixture is stirred for 18 hours at room temperature. The reaction is distributed between chloroform / water (100 ml of each). The layers are separated and the aqueous phase is extracted with chloroform (3 x 50 ml). The organic phase is combined and washed with water (2 x 100 ml). Drying of the organic phase (sodium sulfate) and concentration gives an oil which is subjected to chromatography on silica gel (2% methanol / chloroform). The desired fractions are concentrated to an oil which is dissolved in 10 ml of ethyl acetate and treated with oxalic acid (311 mg, 3.4 mmol). After stirring for 10 minutes, a white precipitate is formed and collected by filtration and dried to provide 1.17 g (70%) total of [6-methoxy -3- [4- [2- (1-pyridinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] -thiophene, as the oxalate salt. p.f. 197-200 ° C (decomposition). XR NMR (DMS0-d6) d 7.60 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 1.1 Hz, ÍH), 7.14 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.91 (dd, J = 8.8, 1.1 Hz, ÍH), 6.87 (s, 4H), 4.19 (broad t 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 ( t broad, 2H), 3.12-3.06 (m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H), Mass Spectrum FD: 489. Analysis Calculated for C29H31N04S -0.88 H02CC02H: C, 64.95; H, 5.80; N, 2.46. Found: C, 64.92; H, 5.77; N, 2.54.

Example 2 Preparation of the hydrochloride salt of [6-methoxy-3- T4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene Treatment of the oxalate salt of Example 1. with an aqueous base to produce the free base, followed by reaction with diethyl ether saturated with HCl gives the title salt, m.p. 216-220 ° C. * H NMR (DMSO-d6) d 10.20 (s broad, ÍH), 7.64 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 1.5 Hz, ÍH), 7.18 (d, J = 9.0 Hz, ÍH), 7.00 (d, J = 8.7 Hz, ÍH), 6.96 (dd, J = 9.0, 1.5 Hz, ÍH), 6.92 (c, J? = 9.0 Hz, 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, ÍH), Mass spectrum FD: 489.

Analysis Calculated for C2gH31N04S • 1.0 HCl: C, 66.21; H, 6.13; N, 2.66. Found: C, 66.46; H, 6.16; N, 2.74.

Example 3 Preparation of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene The title compound is prepared in the same manner as the compound of Example 1, m.p. 95-98 ° C. XH NMR (DMSO-dg) d 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, ÍH), 7.18 (d, J = 9.0 Hz, ÍH), 7.00 (d, J = 9.0 Hz , 2H), 6.94 (dd, J = 9.0, 2.0 Hz, ÍH), 6.86 (s, 4H), 3.97 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.73 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 4H), Mass Spectrum FD: 477. Analysis Calculated for C28H29N04S: C, 70.71; H, 6.15; N, 2.99. Found: C, 70.59; H, 6.15; N, 3.01.

Example 4 Preparation of [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride The title compound is prepared in the same manner as the compound of Example 1, m.p. 189-192 ° C. 1H NMR (DMSO-d6) d 10.55 (broad s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7. 58 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, ÍH), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, H), 6.86 (s, 4H), 3.94 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H), 2.66 (m, 4H) ), 1.53 (m, 8H), Calculated Analysis for C30H33NO4S • 1.0 HCl: C, 66.71; H, 6.35; N, 2.59. Found: C, 66.43; H, 6.46; N, 2.84.

Example 5 Preparation of [6-methoxy-3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [bl-iofen] hydrochloride The title compound is prepared in the same manner as the compound of Example 1, m.p. 196-198 ° C. XH NMR (DMSO-d6) d 10.48 (s broad, ÍH), 7.64 (d, J = 9.0 Hz, 2H), 7. 59 (d, J = 2.0 Hz, ÍH), 7.19 (d, J = 9.0 Hz, ÍH), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, ÍH), 6.87 (c, J? = 9.0 Hz, 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). Analysis Calculated for C28H31N04S • 1.5 HCl: C, 63.18; H, 6.15; N, 2.63. Found: C, 63.46; H, 5.79; N, 2.85.

Example 6 Preparation of [6-methoxy-3 - [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride The title compound is prepared in the same manner as the compound of Example 1, m.p. 208-211 ° C. ^? NMR (DMSO-d6) d 10.6 (broad s, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7. 60 (d, J = 2.0 Hz, 1H), 7.20 (J = 9.0 Hz, ÍH), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, ÍH), 6.91 (c, JM = 9.0 Hz, 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), Calculated Analysis for C28H29N05S • 1.0 HCl: C, 63.09; H, 5.73; N, 2.65. Found: C, 63.39; H, 5.80; N, 2.40.

Example 7 Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-hydroxy-enyl) -benzo [b] thiophene Dissolve [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride. (10.00 g, 19.05 mmol) in 500 ml of anhydrous methylene chloride and cooled to 8 ° C. To this solution is added boron tribromide (7.20 ml, 76.20 mmoles). The resulting mixture is stirred at 8 ° C for 2.5 hours. The reaction is suspended by pouring it into a stirred solution of saturated sodium bicarbonate (11), cooled to 0 ° C. The methylene chloride layer is separated, and the remaining solids are dissolved in methanol / ethyl acetate. The aqueous layer is subsequently extracted with 5% methanol / ethyl acetate (3 x 50 ml). All organic extracts (ethyl acetate and methylene chloride) are combined and dried (sodium sulfate). Concentration in vacuo gives a solid cinnamon which is subjected to chromatography (silicon dioxide, 1-7% methanol / chloroform) to provide 7.13 g (81%) of [6-hydroxy-3- [4- [2- (1 -piperidinyl) ethoxy] -phenoxy] -2- (4-hydroxyphenyl) -benzo [b] thiophene as a white solid, mp 93 ° C. ^? NMR (DMSO-d6) d 9.73 (s broad, ÍH), 9.68 (s broad, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.21 (D, J = 1.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, ÍH), 6.84 (dd, J = 8.6, 1.8 Hz, ÍH (masked)), 6.81 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 2. 56 (t, J = 5.8 Hz, 2H), 2.36 (m, 4H), 1.43 (m, 4H), 1.3 (m, 2H). Mass spectrum FD: 462. Analysis Calculated for C27H27N04S: C, 70. twenty; H, 5 90; N, 3 03 Found: C, 69 96; H, 5 90; N, 3 14 Example 8 Preparation of the oxalate salt of [6-hydroxy-3-4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene The title compound is prepared in 80% yield from the free base, m.p. 246-249 ° C (decomposition). * H NMR (DMSO-d6) d 7.45 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 1.8 Hz, HH), 7.05 (d, J = 8.6 Hz, HH), 6.87 (dd, J) = 8.6, 1.8 Hz, ÍH (masked)), 6.84 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 4.08 (broad t, 2H), 3.01 (broad t, 2H), 2.79 (m , 4H), 1.56 (m, 4H), 1.40 (m, 2H). Mass spectrum FD: 462. Analysis Calculated for C27H27N04S • 0.75 H02CC02H: C, 64.63; H, 5.42; N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62.

Example 9 Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxyl-phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene hydrochloride The title compound is prepared in a yield of 91% by treatment of the corresponding free base with diethyl ether saturated with HCl, m.p. 158-165 ° C. X H NMR (DMSO-dg) d 9.79 (s, ÍH), 9.74 (s, ÍH), 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.86 (c, Jm = 9.3 Hz, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1), 6.74 (d, J = 8.6 Hz, 2H), 4.26 (broad t , 2H), 3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5H), 1.25 (m, ÍH). Mass spectrum FD: 461. Analysis Calculated for C27H27N04S • 1.0 HCl: C, 65.11; H, 5.67; N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.

Example 10 Preparation of 6-hydroxy-3-T4- [2- (1-pyrrolidinyl) ethoxy] -f-noxy] -2- (4-hydroxyphenyl) benzo Tb] iofen The title compound is prepared from the product of Example 3 in the same manner as that used in Example 7 above; p.f. 99-113 ° C. 2H NMR (DMS0-d6) d 9.75 (s, ÍH), 9.71 (s, ÍH), 7.50 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, ÍH), 6.85 (s, 1H), 6.80 (dd, J = 9.0, 2.0 Hz, ÍH), 6.79 (d, J = 9.0 Hz, 2H ), 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 (t, J = 7.0 Hz, 4H), Calculated Analysis for C26H25N04S • 0.5 H20: C, 68.40; H, 5.74; N, 3.07. Found: C, 68.52; H, 6.00; N, 3.34.

Example 11 Preparation of r6-hydroxy-3-T4 - [2 - (1-hexamethyleneimino) ethoxyl phenoxyl -2- (4-hydroxyphenyl) benzo [bl-thiophene] The title compound is prepared from the product of Example 4 in the same manner as that used in Example 7 above; p.f. 125-130 ° C. NMR (DMS0-d6) d 9.75 (s, ÍH), 9.71 (s, ÍH), 7.50 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 2.0 Hz, HH), 7.9 (d, J = 9.0 Hz, ÍH), 6.85 (s, 3H), 6.80 (d, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz), 3.94 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Analysis Calculated for C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.67; H, 6.31; N, 2.93.

Example 12 Preparation of [6-hydroxy-3- [4- [2- (1-N, N-diethylamino) -ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene The title compound is prepared from the product of Example 5 in the same manner as that used in Example 7 above; p.f. 137-141 ° C. XH NMR (DMSO-d6) d 9.75 (s, ÍH), 9.71 (s, ÍH), 7.49 (d, J = 9.0 Hz, ~ LK), 7.25 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, ÍH), 6.85 (s, 4H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H ), 3.95 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H). Analysis Calculated for C26H27N04S: C, 69.46; H, 6.05; N, 3.12. Found: C, 69.76; H, 5.85; N, 3.40.

Example 13 Preparation of [6-hydroxy-3- [4- [2- (morpholino) ethoxyl-phenoxy] -2- (4-hydroxyphenyl) benzo [bl-thiophene] hydrochloride The title compound is prepared from the product of Example 6 in the same manner as that used in Example 7 above; p.f. 157-162 ° C. XH NMR (DMS0-d6) d 10.60 (s broad, ÍH), 9.80 (s, 1H), 9.75 (s, ÍH), 7.50 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 2.0 Hz , ÍH), 7.10 (d, J = 9.0 Hz, ÍH), 6.92 (c, JAB = 9.0 Hz, 4H), 6.81 (dd, J = 9.0, 2.0 Hz, "ÍH), 6.80 (d, J = 9.0 Hz, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 (m, 4H), 3.18 (m, 2H) Analysis Calculated for C26H25N05S • HCl: C, 62.46; H, 5.24; N, 2.80, Found: C, 69.69; H, 5.43; N, 2.92.

Example 14 Preparation of [6-hydroxy-3- T4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-methoxyphenyl) benzo [bl-thiophene] Step a): preparation d l á (3 6-methoxybenzo [b] thiof en-2-boronic, To a solution of 6-methoxybenzo [b] iofen (18.13 g, 0.111 mol) in 150 ml of anhydrous tetrahydrofuran (THF) at -60 ° C is added dropwise, via a syringe, N-butyllithium (76.2 ml, 0.122 moles, 1.6 M solution in hexane). After stirring for 30 minutes, triisopropyl borate (28.2 ml, 0.122 mol) is introduced via a syringe. The resulting mixture is allowed to warm gradually to 0 ° C and then distributed between 1 N hydrochloric acid and ethyl acetate (300 ml each). The layers are separated and the organic layer is dried over sodium sulfate. Concentration in vacuo produces a white solid which is triturated from ethyl ether and hexanes. Filtration provides 16.4 g (71%) of 6-methoxybenzo [b] -thiophene-2-boronic acid as a white solid. p.f. 200 ° C (decomposition). XH NMR (DMSO-d6) d 7.83 (s, ÍH), 7.78 (d, J = 8.6 Hz, ÍH), 7.51 (d, J = 2.0 Hz, ÍH), 6.97 (dd, J = 8.6, 2.0 Hz, ÍH), 3.82 (s, 3H). Mass spectrum FD: 208.

Stage . l Preparation of [6-methoxy-2-methanesulfonyl-oxyphenyl)] benzo [b] thiophene To a solution of 6-methoxybenzo [b] -thiophene-2-boronic acid (3.00 g, 14.4 mmol) in 100 ml of toluene is added 4- (methanesulfonyloxy) phenyl bromide (3.98 g, 15.8 mmol) followed by 16 ml of a 2.0 N solution of sodium carbonate. After stirring for 10 minutes, tetrakistriphenylphosphine palladium (0.60 g, 0.52 mmole) is added and the resulting mixture is heated to reflux for 5 hours. The reaction mixture is then allowed to cool to room temperature after which the product precipitates from the organic phase. The aqueous phase is removed and the organic layer is concentrated in vacuo in a solid. Trituration from ethyl ether provides a solid which is filtered and dried in vacuo to give 3.70 g (77%) of [6-methoxy-2- (4-methanesulfonyloxy-phenyl)] benzo [b] thiophene as a solid cinnamon, pf 197-201 ° C. ? NMR (DMSO-d6) d 7.82-7.77 (m, 3H), 7.71 (d, J = 8.8 Hz, ÍH), 7.54 (d, J = 2.3 Hz, ÍH), 7. 40 (d, J = 8.7 Hz, 2H), 6.98 (dd, J = 8.7, 1.5 Hz, ÍH), 3 . 80 (s, 3H), 3. 39 (s, 3H). Mass spectrum FD: 334.

Analysis Calculated for C16HX404S2: C, 57. 46; H, 4 twenty-one . Found: C, 57.76; H, 4.21.

Step _ £ l Preparation of [6-methoxy-2- (4-methanesulfonyl-oxyphenyl)] benzo [b] thiophene To a solution of [6-methoxy-2- (4-methanesulfonyl-oxyphenyl)] benzo [b] thiophene (9.50 g, 28.40 mmol) in anhydrous methylene chloride (200 ml) at room temperature, under nitrogen gas is added tribromide of boron (14.-20 g, 5.36 ml, 56.8 mmol). The resulting mixture is stirred at room temperature for 3 hours. The reaction is suspended by pouring it slowly in ice water in excess. After stirring vigorously for 30 minutes, the white precipitate is collected by filtration, washed several times with water, and then dried in vacuo to give 8.92 g (98%) of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene as a white solid, m.p. 239-243 ° C. XH NMR (DMS0-d6) d 9.70 (s, ÍH), 7.76 (d, J = 8.7 Hz, 2H), 7.72 (s, ÍH), 7.62 (d, J = 8.7 Hz, ÍH), 7.38 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.7 Hz, ÍH), 6. 86 (dd, J = 8.7, 1.7 Hz, ÍH), 3.38 (s, 3H). Mass spectrum FD: 320. Analysis Calculated for C15H1204S2: C, 56.23; H, 3.77. Found: C, 56.49; H, 3.68.

Step d): Preparation of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene To a solution of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (3.20 g, 10.0 mmol) in 75 ml of anhydrous DMF is added Cs2CO3 (5.75 g, 17.7 mmol) followed by benzyl chloride (1.72 ml, 11.0 mmol). The resulting mixture is stirred vigorously for 24 hours. The solvent is removed in vacuo and the solid residue is suspended in 200 ml of water. The white precipitate is collected by filtration and washed several times with water. By letting it dry in vacuo, the crude product is suspended in 1: 1 hexanes: ethyl ether. The solid is collected to provide 3.72 g (91%) of [6-benzyloxy-2- (4-methanesulfonyl-oxyphenyl)] benzo [b] thiophene as a white solid, m.p. 198-202 ° C. NMR (DMS0-d6) d 7.81-7.78 (m, 3H), 7.72 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.47-7.30 (m, 7H), 5.15 (s, 2H), 3.39 (s, 3H). Mass spectrum FD: 410. - 6§ - Step e): Preparation of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene To a solution of [6-methanesulfonyl-phenyl)] benzo [b] thiophene (12.50 g, 30.50 mmol) in 300 ml of anhydrous THF under nitrogen gas at room temperature is added lithium aluminum hydride (2.32 g, 61.0 mmol) in small portions. The mixture is then stirred at room temperature for 3 hours and then suspended by carefully pouring the mixture into an excess of cold 1.0 N hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The organic fraction is subsequently washed several times with water and then dried (sodium sulfate) and concentrated in vacuo to a solid. Chromatography (silicon dioxide, chloroform) provides 8.75 g (87%) of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene as a white solid, m.p. 212-216 ° C. X H NMR (DMS0-d6) d 9.70 (s, HH), 7.63 (d, J = 8.7 Hz, HH), 7.56 (d, J = 2.2 Hz, HH), 7.51-7.30 (m, 8H), 7.00 ( dd, - 6 $ -J = 8.7, 2.2 Hz, ÍH), 6.80 (d, J = 8.6 Hz, 2H), 5.13 (s, 2H). Mass spectrum FD: 331. Analisys Calculated for C21H1602S: C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85.

Step f): Preparation of [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene To a solution of L6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene (8.50 g, 26.40 mmol) in 200 ml of anhydrous DMF under nitrogen gas at room temperature is added sodium hydride (1.66 g, 41.5 g). mmoles) in small portions. Once the gas production has ceased, iodomethane (3.25 ml, 52.18 mmoles) is added dropwise. The reaction is stirred for 3 hours at room temperature. The solvent is then removed in vacuo and the residue is distributed between water / ethyl acetate. The layers are separated, and the organic phase is washed several times with water. The organic layer is subsequently dried (sodium sulfate) and concentrated in vacuo to provide 9.00 g (98%) of [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene as a white solid, m.p. 180-185 ° C. ^ -NMR (DMSO-d6) d 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J = 8.8, 2.2 Hz, ÍH), 6.98 (d, J = 8.7 Hz, 2H), 5.13 (s, 2H), 3.76 (s, 3H). Mass spectrum FD: 346. Analysis Calculated for C22H1802S: C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43.

Step a): Preparation of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene S e c o l o c a [6-b enc i l ox i-2 - (4-methoxyphenyl)] benzo [b] thiophene (10.0 g, 28.9 mmol) in 200 ml of chloroform together with 10.0 g of solid sodium bicarbonate at room temperature. To this suspension, bromine (1.50 ml, 29.1 mmol) is added dropwise over 30 minutes as a solution in 100 ml of chloroform. When the addition is complete, water (200 ml) is added and the layers are separated. The organic phase is dried (sodium sulfate) and concentrated in vacuo to a white solid. Crystallization from methylene chloride / methanol gives 10.50 g (85%) of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene as a white solid, m.p. 146-150 ° C. H NMR (DMS0-d6) d 7.70 (d, J = 2.2 Hz, ÍH), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J = 8.8, 2.2 Hz, ), 7.06 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H). Mass spectrum FD: 346. Analysis Calculated for C22H1702SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00.

Step h): Preparation of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophenon- (S-oxide) The title compound is prepared by oxidation of the product of step g) with 1.5 equivalents of hydrogen peroxide in a mixture of trifluoroacetic acid in methylene chloride. The product is isolated as a yellow solid by crystallization from ethyl acetate, m.p. 202-205 ° C. 1 H NMR (DMS0-d6) d 7.80 (d, J = 2.2 Hz, HH), 7.68 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.4 Hz, HH), 7.47-7.32 (m, 6H), 7.10 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H).

Mass spectrum FD: 441. Analysis Calculated for C22H1703SBr: C, 59.87; H, 3.88. Found: C, 59.59; H, 3.78.

Step i): Preparation of [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide) Reaction of the product from step i) above with 4- (2-piperidinoethoxy) phenol in base gives the title compound as a yellow solid. XH NMR (DMS0-d6) d 7.76 (d, J = 2.2 Hz, HH), 7.62 (d, J = 8.8 Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J = 8.6, 2.2 Hz, ÍH), 7.03-6.93 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 3.94 (broad t, J = 5.8 Hz, 2H), 3.73 (s, 3H), 2.56 (broad t, J = 5.8 hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.32 (m, 6H). Mass spectrum FD: 592. Analisys Calculated for C3SH35NOsS: _ C_, 72_.26 H, 6.06; N, 2.41. Found: C, 72.19; H, 5.99; N, 2.11.

Step j): Preparation of [6-benzyloxy-3 - [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene The reduction of step i) above gives the title compound, isolated with a total yield of 95%. Purification by chromatography (SiO2, 1-5% methanol / chloroform) gives an off white solid, m.p. 105-108 ° C. XH NMR (DMSO-d6) d 7.62 (d, J = 2.2 Hz, HH), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J = 8.6 Hz, ÍH), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (broad t, J = 5.8 Hz, 2H), 3.72 (s, 3H), 2.55 (broad t , J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31 (m, 4H). Mass spectrum FD: 565. Analysis Calculated for C35H35N04S: C, 74.31; H, 6.24; N, 2.48. Found: C, 74.35; H, 6.07; N, 2.76.

Step k): Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene To a solution of [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (8.50 g, 15.0 mmol) in 300 ml of ethanol / ethyl acetate : 1 palladium black (1.50 g), ammonium formate is added (3.50 g, 55.6 mmol) and 30 ml of water. The resulting mixture is heated to reflux and monitored by TLC. After about 3 hours, the reaction is considered complete and the solution is cooled to room temperature. The reaction is filtered through a pad of Celite to remove the catalyst, and the filtrate is concentrated in vacuo to a solid. The concentrate is distributed between a saturated solution of sodium bicarbonate and 5% ethanol / ethyl acetate. The layers are separated, and the organic phase is dried (sodium sulfate) and concentrated in vacuo. The crude product is subjected to chromatography (silicon dioxide, 1-5% methanol / chloroform) to give 6.50 g. (91%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-ethoxyphenyl)] benzo [b] thiophene as a foam that is converted to a solid when it is crushed with hexanes. p.f. 174-176 ° C. ^? NMR (DMSO-d6) d 9.77 (s, HH), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 2.0 Hz, HH), 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (s, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H), 3.91 (broad t, J = 5.9 Hz, 2H), 3.71 (s, 3H), 2.55 (broad t, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). Mass spectrum FD: 475. Analysis Calculated for C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.46; H, 5.93; N, 2.71.

Example 15 Preparation of the hydrochloride salt of [6-hydroxy -3 - [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [bl-thiophene] The product of Example 14 is converted to the corresponding hydrochloride salt in a yield of 85% by treatment with a mixture of diethyl ether saturated with HC1_ in ethyl acetate followed by crystallization from ethanol / ethyl acetate; p.f. 156-160 ° C. X H NMR (DMSO-d 6) d 10.28 (broad s, ÍH), 9.85 (s, ÍH), 7.56 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 2.0 Hz, ÍH), 7.06 (d , J = 8.7 Hz, ÍH), 6.93 (d, J = 8.8 Hz, 2H), 6.87 (c, JM = 9.3 Hz, 4H), 4.27 (broad t, J = 5.9 Hz, 2H), 3.71 (s, 3H), 3.44-3.31 (, 4H), 2.98-2.88 (m, 2H), 1.74-1.60 (m, 5H), 1.36-1.29 (m, ÍH). Mass spectrum FD: 475. Analysis Calculated for C28H29N04S • 1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.98; H, 6.11; N, 2.64.

Example 16 Pration of r6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy-2- (4-methoxyphenyl) -1-benzo-T-thiophene [6-methoxy-2- (4-benzyloxyphenyl)] benzo [b] thiophene Following the general procedures of steps a) to g) of Example 14, the title compound is obtained with a yield of 73%, m.p. 217-221 ° C. XH 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, 2.2 Hz, ), 5.11 (s, 2H), 3.88 (s, 3H). Mass spectrum FD: 346. Analysis Calculated for C22H1802S: C, 76.27; H, 5.24. Found: C, 76.00; H, 5.25.

Step sL [6-methoxy-2- (4-benzyloxy f-enyl) -3-bromo)] benzo [b] iofen The title compound is obtained with a yield of 91%, m.p. 125-127 ° C. XH 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). Mass spectrum FD: 346. Analysis Calculated for C22H1702SBrí C, 62.13; H, 4.03. Found: C, 62.33; H, 3.93.

Step c] _: [6-methoxy-2- (4-benzyloxyphenyl) -3-bromo)] benzo [b] thiophenon- (S-oxide) The title compound is isolated as a yellow solid by chromatography (SiO2, CHC13). p.f. 119-123 ° C. XH NMR (DMSO-dg) d 7.73 (d, J = 2.2 Hz, HH), 7.68 (d, J = 8.8 Hz ~ 2H), 7.55 (d, J = 8.5 Hz, HH), 7.46-7.31 (m, 5), 7.26 (dd, J = 8.5, 2.2 Hz, ÍH), 7.18 (d, J = 8.8 Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H). Mass spectrum FD: 441. Analisys Calculated for C22H1703SBr: C, 59.87; H, 3.88. Found: C, 60.13; H, 4.10.

Step d): [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene- (S-oxide) The title compound is obtained as a yellow solid, m.p. 89-93 ° C. XH NMR (DMSO-d6) d 7.68 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H), 6.86 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 3.94 (broad t, J = 5.8 Hz, 2H), 3.81 (s, 3H), 2.56 (broad t, J = 5.8 Hz, 2H ), 2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H). Mass Spectrum FD: 592. Analysis Calculated for C35H35N05S • 0.25 EtOAc: C, 71.62; H, 6.18; N, 2.32. Found: C, 71.32; H, 5.96; N, 2.71.

Step e): [6-methoxy -3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene The title compound is obtained in a yield of 91%, pf 106-110 ° C. XH NMR (DMSO-d6) d 7.59 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, ÍH), 7.42-7.28 (m, 5H), 7.13 (d, J = 8.8 Hz, ÍH), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (broad t, J = 5.8 Hz, 2H), 3.78 (s, 3H), 2.55 (broad t, J = 5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1. 44-1.31 (m, 4H). Mass spectrum FD: 565. Analysis Calculated for C35H35N04S: C, 74.31; H, 6.24; N, 2.48.

Found: C, 74.26; H, 6.17; N, 2.73.

Step f): Pration of [6-methoxy-3 - [4 - [2 - (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyl) phenyl)] - benzo [b] thiophene The composed of the title with a yield of 88%, pf 147-150 ° C. XH NMR (DMS0-d6) d 9.72 (s, HH), 7.51 (d, J = 2.0 Hz, HH), 7.48 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.8 Hz, HH) , 6.88 (dd, J = 8.8, 2.2 Hz, ÍH), 6.81 (s, 4H), 6.76 (d, J = 8.6 2H), 3.91 (broad t, J = 5.9 Hz, 2H), 3.77 (s, 3H ), 2.55 (broad t, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). Mass spectrum FD: 475. Analysis Calculated for C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Found: C, 71.00; H, 6.17; N, 2.94.

Example 17 Pration of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxyl-phenoxy-2- (4-hydroxyphenyl) -1-benzo] -bothiophene hydrochloride The title compound is pred in a manner analogous to that used in Example 15 to provide the title compound, m.p. 215-217 ° C. XH NMR (DMSO-d6) d 10.28 (broad s, 1H), 9.80 (s, ÍH), 7.52 (d, J = 2.2 Hz, ÍH), 7.47 (d, J = 8.6 Hz, 2H), 7.12 (d , J = 8.4 Hz, ÍH), 6.91-6.80 (m, 5H), 6.78 (d, J = 8.6 Hz, 2H), 4.27 (broad t, J = 5.8 Hz, 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, ÍH). Mass spectrum FD: 475. Analysis Calculated for C28H29N04S • 1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.87; H, 5.79; N, 2.99.

Formulation Examples In the formulations which follow, the term "active ingredient" means a compound of formula I, or a salt or solvate thereof.

Formulation Example 1 Gelatin Capsules Formulation Example 2 Tablets Formulation Example 3 Tablets The active ingredient, starch and cellulose are passed through a No. 45 mesh US sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders which are then passed through a US No. 14 mesh screen. The granules produced in this way are dried at 50 ° -60 ° C and passed through through a United States No. 18 mesh screen. Sodium carboxymethylstarch, magnesium stearate and talc are prewired through a US No. 60 sieve and then added to the granules which, after mixing, are compressed in a tabletting machine to produce tablets.

Formulation Example 4 Suspensions The medicament is passed through a No. 45 mesh US sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a uniform paste. The benzoic acid solution, flavor and color are diluted with a little water and added, with stirring. Then enough water is added to produce the required volume.

Formulation Example 5 Aerosol The active ingredient is mixed with ethanol and the mixture is added to a proportion of the propellant 22, cooled to 30 ° C and transferred to a filling device. The required amount is then fed to a stainless steel vessel and diluted with the remaining propellant. The valve units are then placed in the container.

Formulation Example 6 Suppositories The active ingredient is passed through a No. 60 mesh US sieve and suspended in the saturated fatty acid glycerides that have previously been melted using the minimum heat required. The mixture is then poured into a suppository mold of nominal capacity 2 g and allowed to cool.

Formulation Example 7 Injectable Formulations The solution of the above ingredients is administered intravenously to a patient at a rate of about 1 ml per minute. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (18)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A method for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient in need of such treatment, characterized in that it comprises administering a therapeutically effective amount of a compound having the structure: or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R1 and R2 are independently selected from the group consisting of hydroxy and alkoxy of 1 to 4 carbon atoms; and R3 and R4 are independently methyl or ethyl, or R3 and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino ring, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or hexamethyleneimino. 2. The method according to claim 1, characterized in that the method comprises the treatment or prophylaxis of prostate cancer in a patient in need of such treatment.

3. The method according to claim 1, characterized in that the method comprises the treatment or prophylaxis of benign prostatic hyperplasia in a patient in need of such treatment.

4. The method according to claim 1, characterized in that R1 and R2 are both hydroxy.

5. The method according to claim 2, characterized in that R1 and R2 are both hydroxy.

6. The method according to claim 3, characterized in that R1 and R2 are both hydroxy.

7. The method according to claim 1, characterized in that R1 is hydroxy and R2 is alkoxy of 1 to 4 carbon atoms.

8. The method according to claim 2, characterized in that R1 is hydroxy and R2 is alkoxy of 1 to 4 carbon atoms.

9. The method according to claim 3, characterized in that R1 is hydroxy and R2 is alkoxy of 1 to 4 carbon atoms.

10. The method according to claim 1, characterized in that R3 and R4 are combined with the nitrogen atom to which they are attached to form a piperidino ring.

11. The method according to claim 2, characterized in that R3 and R4 are combined with the nitrogen atom to which they are attached to form a piperidino ring.

12. The method according to claim 3, characterized in that R3 and R4 are combined with the nitrogen atom to which they are attached to form a piperidino ring.

13. A method for the treatment or prophylaxis of prostate cancer in a patient in need of such treatment, characterized in that it comprises administering a therapeutically effective amount of a compound having the structure: or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 is hydroxy or methoxy.

14. The method according to claim 13, characterized in that the compound is 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) -phenoxy] -benzo [b] thiophene or a pharmaceutically acceptable salt thereof.

15. The method according to claim 13, characterized in that the compound is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) -phenoxy] -benzo [b] thiophene or a pharmaceutically acceptable salt of the same .

16. A method for treating benign prostatic hyperplasia in a patient in need of such treatment, characterized in that it comprises administering a therapeutically effective amount of a compound having the structure: or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 is hydroxy or methoxy.

17. The method according to claim 16, characterized in that the compound is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) -phenoxy] -benzo [b] thiophene or a pharmaceutically acceptable salt of the same . The method according to claim 116, characterized in that the compound is 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) -phenoxy] -benzo [b] thiophene or a salt pharmaceutically acceptable thereof.