MXPA99009234A

MXPA99009234A - Prevention of breast cancer with selective estrogen receptor modulators

Info

Publication number: MXPA99009234A
Application number: MXPA/A/1999/009234A
Authority: MX
Inventors: Lawrence Glasebrook Andrew
Original assignee: Eli Lilly And Company; Lawrence Glasebrook Andrew
Priority date: 1997-04-09
Filing date: 1999-10-08
Publication date: 2000-06-01

Abstract

The present invention provides a method of preventing breast carcinoma or cancer in a patient comprising administering a therapeutically effective amount of a compound having the structure (I) in which R1 and R2 are independently hydroxy or 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

PREVENTION OF CHEST CANCER WITH SELECTIVE MODULATORS OF ESTRÓGENO RECEPTOR TECHNICAL FIELD The present application relates to medical methods of treatment. More particularly, the present invention relates to the use of a class of benzo compounds [£ > ] thiophene substituted for the prophylaxis or prevention of breast carcinoma in a patient in need of such treatment.

BACKGROUND OF THE INVENTION * Breast carcinoma or breast or breast cancer is the most common form of cancer and the second most common cause of death in women in the United States. In the years of 1994 and 1995, an estimated 182,000 new cases of breast cancer in women occurred, with an estimated mortality of 46,000. It is currently estimated that, statistically, most women have an opportunity in 10 to develop this disease during their lifetime. Breast carcinoma is a leading cause of mortality in women, as well as the cause of disability, psychological trauma and loss REF .: 31746 economic A large percentage of women who acquire this disease eventually die from its effects either directly or indirectly from the complications that arise. "-for example, metastasis, general loss of health or side effects resulting from therapeutic interventions such as surgery, irradiation The epidemiology of this disease, although it has been the object of intense research, is still scarcely understood, and there seems to be a substantial genetic component that predisposes some patients to contract the disease, although it is not clear whether this genetic component is causal. or permissiveness of the disease or only an element of prediction of the disease process.For a long time it has been known that breast carcinoma tends to occur more frequently in some families, although such analysis does not have a predictive nature of accuracy with respect to the presentation of the disease in other members of the A large amount of clinical and pharmacological research has been carried out trying to elucidate the relationship between the hormone estrogen and the cause, maintenance and treatment of carcinoma of the breast. Although there is ample knowledge regarding the relationship of estrogen in the maintenance and treatment of the disease, there is a large amount of controversy associated with the effect of estrogen in the epidemiology of this disease, that is, if the Estrogen is a causative agent (carcinogen) or a mandatory cofactor (permissive) at the onset of the disease. Estrogens, which include 17b-estradiol, estrone and "their active metabolites, are the major hormones related to sex in women, but additionally, they appear to be important homeostatic hormones in both men and women during their adult life. The world has a certain concentration of estrogen Male breast cancer is a rare disease, constituting less than 1% of all cancers in men.The American Cancer Society reported that in 1994 an estimated 1,000 men in the United States were diagnosed with breast cancer, with an estimated mortality of 300. Cutaneous carcinoma in si tu (DCIS) of the chest is an early form of breast cancer in which malignant epithelial cells proliferate in the duct system without microscopic evidence of invasion through the basement membrane within the surrounding breast tissue.The median age of patients with DCIS at the time of the diagnosis is approximately 52 years. The increasing wide dissemination and use of mammography has led to the early detection of DCIS since in the majority of cases it is detected in otherwise asymptomatic women when undergoing screening mammography.

Replacement hormone therapy (HRT) recommended for postmenopausal and perimenopausal women to relieve cardiovascular disease, osteoporosis and other menopausal sequelae, has generated a lot of debate regarding the potential of this therapy to increase the risk of breast cancer. Currently, the findings of the HRT studies, most of which are post-prospective studies, seem to indicate a small increase in risk. In contrast to the problematic role of estrogen in the onset of this disease, a large amount of compression has been obtained (although it is incomplete) with respect to estrogen, with established breast carcinoma. Estrogen is a necessary growth factor for most breast carcinoma cells in the early stages of this disease. It has also been established, although the reason why, during the course of this disease, cancer cells lose this sensitivity to the effects of estrogen has not been fully understood. Finally, most carcinoma cells no longer become estrogen-dependent for growth and no longer respond to any hormone-based therapy, which includes "antiestrogens", GNRH agonists, progestins and androgens. A large amount of benefit has been obtained with the use of hormonally-based therapeutic interventions. The The most widely used therapy is the use of tamoxifen. The five-year survival rate for women with breast cancer has increased markedly with this therapy; however, the long-term survival rate (more than ten years) has not improved to the same extent. This lack of an improvement in the long-term rate has been attributed to the gradual evolution of the carcinoma cells from their dependence to an independence to estrogen. Therefore, even with the best combinations of treatment modalities (surgery, irradiation and / or chemotherapy) the long-term prognosis for patients is poor, especially if present it is a metastatic disease. Clearly, there is a great need for improved therapies and, possibly, more importantly, prevention of the disease in the first instance (de novo) is needed. During the last decade it has been argued that "anti-estrogen" therapy, especially the use of tamoxifen, should be examined to determine its potential to avoid de novo breast carcinoma. However, partially due to the lack of evidence of a benefit and the known and potential toxicity of tamoxifen, prospective prevention trials have not been carried out in healthy women. Clearly, there is a great need for therapy for the prevention of breast cancer useful to the entire population, including individuals at high or no risk. a particular risk, and that includes both men and women.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a method for the prophylaxis or prevention of breast carcinoma in the patient in need of such treatment, which comprises administering a therapeutically effective amount of a compound having the structure: or a pharmaceutically acceptable salt or prodrug thereof.

The invention further relates to a method for preventing breast cancer by administering to a human for a sufficient term an effective dose of a compound of formula I or a pharmaceutically acceptable salt or prodrug thereof where the human is not yet He has been diagnosed with, but it has been determined that he is at risk of developing breast cancer. In the structure shown above, 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. The compounds of the present invention are selective estrogen receptor modulators (SERM), that is, compounds which produce estrogen agonism in one or more of the desired target tissues and at the same time produce minimal antagonism and / or agonism (i.e. , clinically insignificant) of estrogen in reproductive tissue such as the chest or uterus.

DETAILED DESCRIPTION The present invention relates to the discovery that the compounds of formula I above are useful for preventing breast cancer. The methods provided by this invention are practiced by administering to a patient in need thereof, a dose of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, which is effective in preventing cancer. of chest In this specification and in the appended claims, the general terms have their usual meanings. The terms "prevention of", "prophylaxis" and "avoid" include reducing the likelihood that a patient will develop or develop breast cancer. The term "de novo", as used in the present invention, means a lack of transformation or metamorphosis of normal breast cells to cancerous or malignant cells in the first instance. Such a transformation can occur in stages in the same cells or in fixed cells by means of an evolutionary process or they can occur in a single pivotal event This de novo process contrasts with the metastasis, colonization or diffusion of already transformed or malignant cells of the site of the tumor to new positions. This invention is also related to the administration of a compound of formula I to a patient who is at risk of developing de novo breast cancer. ~~~ rA person who is not at particular risk of developing breast cancer is a person who can develop de novo breast cancer and who has no evidence or suspicion of the potential of the disease above normal risk, and who has never had a diagnosis of presenting the disease. The biggest risk factors that contribute to the development of carcinoma of the breast are the antecedents or personal clinical history of suffering from the disease, or a previous presentation of the disease, even if it is in remission without evidence of its presence. Another risk factor is a family history of the disease. The term "alkyl" denotes a monovalent radical derived by removal of a hydrogen atom from methane, ethane or a linear 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 -butoxi, ter- 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; Y 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 R5 and R6 are portions which are intentionally introduced 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 process. 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 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). Representative hydroxy protecting groups include, for example, -Ci-C ,,, alkyl-C ^ -C ^ alkoxy, -CO- (C6-C6 alkyl), -S02- (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 C4-C4 alkoxy, hydroxy, nitro, halo and tri (chloro or fluoro) methyl. The term "halo" refers to bromine, chlorine, fluorine and iodine. For the compounds of formula 1, the preferred substituents R5 and Re "" are methyl, isopropyl, benzyl and methoxymethyl. The compounds in which R5 and R6 are each methyl, are prepared via a process described in the Jones patent mentioned above. The compounds of formula 1 are also prepared in which the hydroxy protecting group in R5 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 portion is selectively removed 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 in R8 to forming 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 step, the "protective group" of hydroxy in R8 can be removed selectively in the 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, isopropansulphonate, 4-methoxybenzenesulphonate, 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 bromine 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 R 8 is a hydroxy protecting group removable selectively. 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 & amp;; 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 in which R7 is bromine is reacted with an amount equivalent of 4-benzyloxyphenol in the presence of an equivalent cuprous oxide. 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 step 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 for completion is usually from about 20 to about 60 hours.After coupling a compound of formula 2. with one of formula 3_, to form a compound of formula 4, the compounds of formula 5 are prepared by selective removal of the hydroxy protecting group on R8 of a compound of formula 4 by means of well known reduction methods. It is imperative that the selected procedure does not affect R5 and, when present, the hydroxy protecting groups in R6. When R8 is the preferred benzyl moiety, and R5 and, when present, R6 are each methyl, the present process steps are carried out by means of standard procedures of hydrogenolysis. 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.The appropriate 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 are particularly preferred.The solvents for this reaction are those solvents or mixture of solvents which Typically, ethyl acetate and aliphatic alcohols of C.sub.j, particularly ethanol, are preferred.For the present reaction, hydrochloric acid serves as a suitable and preferred proton donor when it is carried out at room temperature. environment and at a pressure that varies from approximately 206.8 kilopascals (30 psi) to approximately 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 II, when a compound of formula 5 is prepared, it is reacted with a compound of formula R4R5N- (CH2) 2-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 la, R5 = R6 = H Ib, Rs = 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 an appropriate solvent. Suitable solvents for this reaction are those solvents or mixture of solvents which remain inert during the reaction. N is preferred, N-dimethylformamide, especially the anhydrous form thereof. 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 an end during approximately 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 the Reaction Scheme III then a compound of formula is reacted 5_ in an alkaline solution with an excess of an alkylating agent of formula 8 .: Q- (CH2) n-Q ' which Q and Q1 are the same or different outgoing groups. Appropriate outposts are those mentioned above.

Reaction Scheme III Ib, R5 = H le, 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 reagents and agents is refluxed and allowed to run until 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. is then reacted with a compound of formula 10 which is selected from 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, -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 10 is used with piperidine hydrochloride being particularly preferred. 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 go to full completion. 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, hydroxy protecting groups in R6 of the compounds of formula by means of well-known procedures Many reactions for the formation and removal of such groups are described. protectors in numerous standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973), Greene, TW, Protective Groups in Organic Synthesis, Wiley, (New York, 1981), and The Peptides , Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965) The 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 compue Sto of formula 2 is oxidized to form the sulfoxide 11 which then reacts with a nucleophilic group to introduce the binder to the oxygen atom of the compounds of formula X. The sulfoxide portion of the compounds of formula 12 then * is reduced to provide certain compounds of the present invention.

Reaction Scheme IV the, 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 1_2. 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. S nthetic Communications, 11 (12); 1025-1030 (1981); Kramer, J.B., et al. , 34th National Organic Svmposium, 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. with 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 leaving group in position 3, R7, is displaced by the desired nucleophilic derivative of formula 13 .. Such nucleophilic derivatives are prepared by means of standard methods. In 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 X4 is reduced to a benzothiophene compound of formula X. When desired, the hydroxy protecting group or groups of the products of the process shown in Reaction Scheme IV are they can remove, 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 in the 6 and / or 4 'positions when present, with a portion of the formula "-OCO (C ^ Cg alkyl), or -0S02 ( C2-C6 alkyl) by means of well-known processes, see for example, U.S. Patent No. 4,358,593, For example, when an -OCO group (CL-Cg alkyl) is desired, a compound is reacted mono- or dihydroxy of formula X with an agent such as chloride, bromide, cyanide or acyl azide, or with a suitable mixed anhydride or anhydride 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, aceto na, methyl ethyl ketone and the like, to which has been added at least one equivalent of an acid scavenger (except as indicated above), such as a tertiary amine. If desired, acylation 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 ambient 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 Suitable carboxylic acids in inert organic solvents Acid catalysts such as sulfuric acid are used, 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_-C6 alkyl) are carried out in solvents as discussed in the foregoing. 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 1 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 -OS02 (C2-C6 alkyl)' "the mono compound - 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 as 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 mainly form pharmaceutically acceptable acid addition salts with a wide variety of organic acids and inorganic 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 in 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, 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, benzeneTTfonate, 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, 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 excipients, diluents or common carriers and are formed into tablets, capsules, suspensions, solutions, injectables, aerosols, powders and the like. "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 should not be harmful to the recipient thereof Formulations can 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. 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 injection or infusion. n intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous or intraarticular. The pharmaceutical compositions of this invention for parenteral administration comprise aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, sterile, 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 and diluents, solvents, and vehicles include water, physiological saline, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, oils. vegetables (such as olive oil) and injectable organic esters such as ethyl oleate The 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.Parential compositions may also contain adjuvants such as preservatives or preservatives, wetting agents, emulsifying agents and agents that improve dispersion.Prevention of the action of microorganisms is ensured by the inclusion of antibacterial and antifungal agents, for example, paraben, chlorobutanol, acid f Enolsorbic and similar. 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 bacteria-retaining filters, or by pre-sterilization of the components or of the mixture prior to mixing, either at the time of mixing. 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 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) , 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. microencapsular in a sustained release coating wherein the microcapsules form part of a pill or capsule formulation. The "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, the formulations liquids 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, 1, 3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, poly (ethylene glycols), sorbitol fatty acid esters and mixtures of the same. 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 temperature environment, but liquid at body temperature 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.Liposome formulations are made by mono- or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium.Any nontoxic, pharmaceutically acceptable and metabolizable lipid can be used. of forming liposomes 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 The methods for making liposomes are known in the technique 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 The induction of mammary tumors in rats by administration of the carcinogen N-nitoso-N-methylurea is a well accepted animal model for the study of breast cancer and has been found adequate for the analysis of the effects of chemopreventive agents. In two separate studies, 55-day-old female Sprague-Dawley rats were given an intravenous (study 1) or intraperitoneal (study 2) dose of 50 mg of N-nitroso-N-methylurea per kilogram of body weight a week earlier of feeding them with a diet ad Ubi tum into which variable amounts of: a) 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinyletoxy) -phenoxy] benzo hydrochloride were mixed [Jb ] thiophene, bj (Z) -2 - [4- (1, 2-diphenyl-1-butenyl) phenoxy] -N, N-dimethylethanamine base (tamoxifen base), or c) control. The control consisted of the vehicle used in combination with the active compounds. In study 1, the dietary doses of 60 mg / kg of diet and 20 mg / kg of diet are translated into generally comparable doses with 3 and 1 mg / kg of body weight for the test animals. In study 2, the dietary doses of 20, 6, 2 and 0.6 mg / kg of diet are generally translated into doses comparable of 1, 0.3, 0.1 and 0.03 mg / kg of body weight per test animal. The rats were observed for evidence of toxicity and weighed and palpated to determine tumor formation once a week. The animals were sacrificed after thirteen weeks (study 1) or eighteen weeks (study 2) and the tumors were confirmed and weighed at autopsy. The results of these studies are shown in table 1 (study 1) and table 2 (study 2) below.

Table 1 Prevention of breast cancer in female Sprague-Dawley rats by administration of 6-hydroxy-2- (4-methoxyphenyl) -4- [4- (2-piperidinylethoxy) -phenoxy] benzo [Jb] thiophene hydrochloride (Example 15 ) Table 2 Prevention of breast cancer in female Sprague-Dawley rats by administration of 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinylethoxy) -phenoxy] benzo [Jb] thiophene hydrochloride (Example 15 ) or Tamoxifen base Examination of the data in Table 1 shows that administration of the compound of Example 15 of the present invention results in a significant decrease in tumor incidence (87%), average number of tumors per rat (97%) and average load of tumor by rats (97%) compared to the control. The examination of the data shown in Table 2 shows that the administration of doses as low as 0. 6 mg / kg of the diet of the compound of example 15 of the present invention is sufficient to significantly reduce the incidence of tumor formation, number of tumors per rat, and load by means of tumors per rat suar are compared with the control. The effects observed depend on the dose and are comparable with those observed are tamoxifen.

The observation of an efesto at all the doses tested prevents a definitive somatosis between the two compounds, since a similar effect to lower plateau has been observed for both compounds. However, the data in Tables 1 and 2 indicate that the compound of Example 15 is at least in cash, or more effective than tamoxifen as an agent for the inhibition or prevention of breast tumor. Therefore, administration of an effective amount of a compound of the present invention, especially 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] -thiophene is a useful method for the prophylaxis, prevention or inhibition of the formation of breast cancer. As used herein, the term "effective amount" means an amount of the 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 partial synapses that surround the saso and which, for example, include the potency of the administered substance, the route of administration, the state in which the patient is found, and the pathological condition in question. A typical daily dose will be a non-toxic dosifisation level from about 5 mg to about 600 mg / day of a compound of the present invention. Preferred daily doses will be from about 15 mg to about 80 mg / day. "" The exact dose is determined in accordance with standard practice in medical techniques. Of patient dosing determination; 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. - 4 * 7 - Example 1 Preparation of the oxalate salt of r6-methoxy-3-f4-Í2- (1- piperid? Ni-1) ethoxyl-phenoxy-1-2- (4-methoxyphenyl) benzo Tbl 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) -benzo [b] thiophene (27.0 g, 100 mmol) in 1.10 1 of sloroform at 60 ° C, bromine (15.98 g, 100 mmol) was added dropwise. We are a solution in 200 ml of sloroform. After the admission 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 blast solid, mp 83-85 ° C. 1 H NMR (DMS0-6): d 7.70-7.62 (m, 4H), 7.17 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), FD mass spectrum: 349, 350. Calsulated analysis for C16H1302SBr: C, 55.03; H, 3.75, Sound: C, 54.79; H, 3.76.

Step _bl 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 slurry solution is washed with 3 N hydrochloric acid (3 x 300 ml), followed by 1 N sodium hydroxide (3 x 300 ml). The sapa organelle is dried (sodium sulfate) and concentrated in vacuo. The residue is taken up in 100 ml of ethyl acetate, resulting in a white solid which is collected by filtration [6-methoxy-2- (4-methoxyphenyl)] benzo- [b] thiophene, recovered (4.62 g, 17.11 mmol) .The filtrate is concentrated in vacuo and then is passed through a short pad of silica gel (methylene slurry as eluent) to remove the baseline material.The filtrate is concentrated in vacuo, and the residue crystallizes from hexanes / ethyl acetate to provide Initially 7.19 g of [6-me t oxy-2 - (4-me t ox if eni 1) - 3 - (4-benzyloxy) phenoxy] benzo [b] -thiophene as a whitish crystalline solid. and are subjected to silica gel chromatography (hexanes / ethyl acetate 80:20) to provide 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 anhydrous 5 N slurry, and the resulting precipitate is resolered by filtration and dried to provide 13.3 g of 4-benzyloxyphenol resuperated. p.f. 100-103 ° C. XK 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 masses FD: 468. Analisys 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-bensyloxy) phenoxy] benzo [b] thiophene (1.50 g, 3.20 mmol) in 50 ml of ethyl acetate and 10 ml of aceide The mixture is hydrogenated at 2.8 kg / cm2 (40 psi) for 20 minutes, time after the sual phase, it is considered somatic by chromatography thin sapa The mixture is passed through Celite to remove the catalyst, and the filtrate is concentrated in vacuo to a white solid.The crude product (untreated) is passed through a pad of silica gel (chloroform) as eluent) The consentration provides 1.10 g (91%) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene as a white solid, mp 123-126 ° C. ""? NMR (DMS0-.d6) d 9.10 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8. 8, 2.1 Hz, 1H), 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, N-dimethylformamide under N2 Cesium sarbonate (3786 g, 11.88 mmol) is added. 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 one sada). The sapas are separated and the puffy phase is extracted is sloroformo (3 x 50 ml). The organic phase is combined and washed with water (2 x 100 ml). The solidification of the organelle phase (sodium sulfate) and the sonsension yield an oil that 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 a very 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). XH NMR (DMS0-d6) d 7.60 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 1.1 Hz, 1H), 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, 1H), 6.87 (s, 4H), 4.19 (broad 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 [6-methoxy-3 - [4- \ 2- (1-piperidinyl) ethoxyl-phenoxy-2- (4-methoxyphenyl)] benzo fb] iofen hydrochloride salt 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. "? NMR (DMSO-ds) d 10.20 (broad s, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 1.5 Hz,1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.96 (dd, J = 9.0, 1.5 Hz, 1H), 6.92 (s, JAB = 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, 1H), Mass Spectrum FD: 489. Analysis Calculated for C29H31N04S • 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 3 The title package is prepared in the same manner as the package of Example 1, p.f. 95-98 ° C. 1 H NMR (DMSO-d 6) d 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.94 (dd, J = 9.0, 2.0 Hz, 1H), 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. Sound: 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. "" H NMR (DMSO-dg) 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, 1H), 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 =?: 0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H), Calsulated 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-methoxy phenyl) benzo [b] thiophene hydrochloride The title compound is prepared in the same manner as the compound of Example 1, m.p. 196-198 ° C. 1H NMR (DMSO-d6) d 10.48 (broad s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H), 6.87 (s, JM = 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- (- 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 (DMS0-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, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H), 6.91 (s, 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. Sound: C, 63.39; H, 5.80; N, 2.40.

Example 7 Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-hydroxyphenyl) 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 mmol) .The resulting mixture is stirred at 8 ° C for 10 minutes. 2.5 hours The reaction is suspended by pouring it into a stirred solution of saturated sodium bisarbonate (11), cooled to 0 ° C. The methylene chloride layer separates, and the remaining solids are dissolved in methanol / ethyl acetate. The asparous sap is subsequently extracted, 5% methanol / ethyl acetate (3 x 500 ml), all the organic extracts (ethyl acetate and methylene chloride) are combined and dried (sodium sulfate). consentrasión in vacuo provides a solid sanela that is subjected to chromatography (silisium dioxide, methanol 1-7% / sloroformo) 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. 1 H NMR (DMSO-d6) d 9.73 (broad s, 1H), 9.68 (broad s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.21 (D, J = 1.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.84 (dd, J = 8.6, 1.8 Hz, 1H (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, 70.20; H, 5.90; N, 3.03. Found: C, 69.96; H, 5.90; N, 3.14. '"- Example 8 Preparation of the oxalate salt of r6-hydroxy-3- [4- (2- (1- piperidinyl) ethoxyphenoxy) -2- (4-hydroxyphenyl) benzo [b] iofen The title compound is prepared in 80% yield from the free base, m.p. 246-249 ° C (decomposition) "? RMN d 7.45 (d, J = 8.6 Hz, 2H), 7. 22 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.87 (dd, J = 8.6, 1.8 Hz, 1H (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 layer 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 f6-hydroxy-3- [4 - [2- (1-piperidinyl) ethoxyl-phenoxy] -2- (4-hydroxyphenyl) benzo [bl-thiophene] slorhydrate 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. 1 H NMR (DMSO-d 6) d 9.79 (s, 1 H), 9.74 (s, 1 H), 7.40 (d, J = 8.6 Hz, 2 H), 7.23 (d, J = 2.0 Hz, 1 H), 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, 1H), FD mass spectrum: 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 r6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxyl-phenoxy] -2- (4-hydroxyphenyl) benzo [bl-thiophene] 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. 1 H NMR (DMSO-d 6) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.25 (d, = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.85 ( s, 1H), 6.80 (dd, J = '"9.-0, 2.0 Hz, 1H), 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 C26H2sN04S • 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 [6-hydroxy-3 - [4- \ 2- (1-hexamethyleneimino) ethoxyphenoxy] -2- (4-hydroxyphenyl) benzo-1-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. XH NMR (DMS0-d6) d 9.75 (s, 1H), "" 9".71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 7.9 (d, J = 9.0 Hz , 1H), 6.85 (s, 3H), 6.80 (dd, 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). Calsulated Analysis for C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Sound: C, 70.67; H, 6.31; N, 2.93.

Example 12 Preparation of T6-h: idroxy-3 - [4-- \ 2-- (1-N, N-diethylamino) -ethoxy] phenoxy-2- (4-hydroxy} <1> benzo [bl-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. "? NMR (DMSO-d6) d 9.75 (s, 1H), -9.71 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H ), 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 hydrochloride Tbl thiophene 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. R NMR (DMS0-d6) d 10.60 (broad s, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 2.0 Hz , 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.92 (s, JM = 9.0 Hz, 4H), 6.81 (d, J = 9.0, 2.0 Hz, 1H), 6.80 (d, J = 9.0 Hz , 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3. 15 (m, 2H), 3.51 (m, 4H), 3.18 (m, 2H). Calcined Analisys for C26H25NOsS • HCl: C, 62.46; H, 5.24; N, 2.80. Sound: C, 69.69; H, 5.43; N, 2.92.

Example 14 Preparation of r6-hydroxy-3-T4- [2- (1-pjperidinyl) ethoxyphenoxy] -2- (4-methoxyphenyl) benzo ib] thiophene Step a): preparation of 6-methoxybenzo [b] thiophene-2-boronic acid.

A solution of 6-methoxybenzo [b] thiophene (18.13 g, 0.111 mol) in 150 ml of anhydrous tetrahydrofuran (THF) at -60 ° C is added dropwise, by means of a syringe, N-butyllithium (76.2 ml, 0.122). moles, 1.6 M solvation in hexane). After stirring for 30 minutes, triisopropyl borate (28.2 ml, 0.122 mol) was introduced via 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 yields a white solid which is ground from ethereal ether and hexanes. The filtration yields 16.4 g (71%) of 6-methoxybenzo [b] -thiophene-2-boronisolate as a solid solid. p.f. 200 ° C (desomposition). X H NMR (DMSO-d 6) d 7.83 (s, 1 H), 7.78 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.97 (dd, J 8.6, 2.0 Hz, 1H), 3.82 (s, 3H). Mass spectrum FD: 208.

"" ^ Stage b): Preparation of [6-methoxy-2- (4-methanesulfonyl-oxyphenyl)] benzo [b] thiophene To a solution of 6-methoxybenzo [b] -thiophene-2-boroniso 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 layer Organic is concentrated in vacuo in a solid. Trituration from ethyl ether gives a solid which is filtered and dried in vacuo to provide 3.70 g (77%) of [6-methoxy-2"(4-methanesulfonyloxy-phenyl)] benzo [b] thiophene as a solid. Sanela, mp 197-201 ° C. "? NMR (DMS0-d6) d 7.82-7.77 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H ), 6.98 (dd, J = 8.7, 1.5 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H). Mass spectrum FD: 334. Analysis Calculated for C16H1404S2: C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21.

Step 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 slurry (200 ml) at room temperature, under gaseous nitrogen is added boron tribromide (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 crude 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 solid solid. p.f. 239-243 ° C. XH NMR (DMSO-d6) d 9.70 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.72 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H), 6.86"(dd, J = 8.7, 1.7 Hz, 1H), 3.38 (s, 3H). Massive mass FD: 320. Analysis Calsulated for C1SH1204S2: 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 slurry. "of bensyl (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 plump grass is collected by filtration and washed several times with water. When left to 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. ? RMN (DMSO-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.

Step e): Preparation of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene To a solution of [6-methanesulfonyloxy-phenyl)] benzo [b] thiophene (12.50 g, 30.50 mmol) in 300 ml of anhydrous TFH under nitrogen gas at room temperature is added lithium aluminum hydride (2.32 g, 61.0 g. mmoles) 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 organza frassion is subsequently washed several times with water and then dried (sodium sulfate) and sonsentrated in vacuo to a solid. The chromatography (silicon dioxide, chloroform) provides 8.75 g (87%) of [6-bensyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene as a white solid. p.f. 212-216 ° C. XH NMR (DMSO-d6) d 9.70 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.51-7.30 (m, 8H), 7.00 ( dd, J = 8.7, 2.2 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 5.13 (s, 2H). Mass spectrum FD: 331. Analysis 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 [6-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 mmoles) in small portions After the gas produssion has bent, 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 partitioned 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-bensyloxy-2 -. (4-methoxyphenyl)] benzo [b] thiophene as a white solid, mp 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, 1H), 6.98 (d, J = 8.7 Hz, 2H) , 5.13 (s, 2H), 3.76 (s, 3H). Spectrum of FD masses: 346. Analysis Calculated for C22H1802S: C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43.

Step Preparation of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene Place [6-benzyl] oxy-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) was added dropwise during 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 is a white solid, m.p. 146-150 ° C. "-H-NMR (DMSO-d6) d 7.70 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J = 8.8, 2.2 Hz, 1H) ,: "" 7.06 (d, J = 8.7 Hz ~, 2H), 5.17 (s, 2H), 3.78 (s, 3H) .FD mass spectrum: 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. XH NMR (DMSO-d6) d 7.80 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.47-7.32 (m, 6H), 7.10 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H). Mass density FD: 441. Calibrated analysis for C22H1703SBr: C, 59.87; H, 3.88. Sound: C, 59.59; H, 3.78.

Step i): Preparation of [6-bensyloxy-3 - [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide) Removal of the product from step i) above with _4- (2-piperidinoethoxy) phenol in base gives the title compound as a yellow solid. 1 H NMR (DMS0-d6) d 7.76 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.44- 7. 30 (m, 5H), 7.12 (dd, J = 8.6, 2.2 Hz, 1H), 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. Analysis Calculated for C35H3SN05S: C, 72.26; H, 6.06; N, 2.41, Found: C, 72.19; H, 5.99; N, 2.11.

Step): 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, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J = 8.6 Hz, 1H), 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 solder 7 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 5: 1 is added palladium black (1.50 g), ammonium formate (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 to be somatic and the solution cooled to room temperature. The reassum is filtered through a pad of Celite to remove the catalyst, and the filtrate is concentrated in vacuo to a solid. The soncinate 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 provide 6.50 g. (91%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene is a foam that is converted to a solid suando is crushed are hexanes. p.f. 174-176 ° C. 1 H NMR (DMSO-d 6) d 9.77 (s, 1 H), 7.56 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 2.0 Hz, 1H), 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 density 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) -1 benzo [b] 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 HCl in ethyl acetate followed by crystallization from ethanol / ethyl acetate; p.f. 156-160 ° C. XH NMR (DMSO-d6) d 10.28 (broad s, 1H), 9.85 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.06 (d , J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 ÍTz-, 2H), 6.87 (s, JM = 9.3 Hz, 4H), 4.27 (broad t, J = 5.9 Hz, 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). Mass Spectrum FD: 475. Calsulated Analysis for C28H29N04S • 1.0 HCl: C, 65.-68; H, 5.90; N, 2.73. Sound: C, 65.98; H, 6.11; N, 2.64.

Example 16 Preparation of [6-methoxy-3 - [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxy-enyl) -1-benzo [bl-thiophene] Step a___: Preparation of [6-methoxy -2- (4-bensyloxyphenyl)] benzo [b] thiophene Following the general requirements of steps a) to g) of Example 14, the title compound is obtained with a yield of 73%, m.p. 217-221 ° C. ? H 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, 1H), 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.

Etepa b): [6-methoxy-2- (4-benzyloxyphenyl) -3-bromo)] benzo [b] thiophene The title compound is obtained with a yield of 91%, m.p. 125-127 ° C. "? 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. Calsulated Analysis for C22H1702SBr: C, 62.13; H, 4.03, Found: C, 62.33; H, 3.93.

Stage ±: [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. 1 H NMR (DMSO-dg) d 7.73 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7.46-7.31 (m, 5), 7.26 (dd, J = 8.5, 2.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H). Mass spectrum FD: 441. Analis Calsulated 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. "? NMR (DMSO-d6) d 7.68 (d, J = 2.2 Hz," lH), 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. Calsulated Analysis for C35H35N05S - 0.25 EtOAs: C, 71.62; H, 6.18; N, 2.32. Sound: C, 71.32; H, 5.96; N, 2.71.

Step e): [6-methoxy-3- [4 - [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-bensyloxyphenyl)] benzo [b] thiophene The title compound is obtained with a yield of 91%, m.p. 106-110 ° C. 1 H NMR (DMS0-d6) d 7.59 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (t "- broad, 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 density FD: 565. Analysis Calulated for C35H35N04S: C, 74.31; H, 6.24; N, 2.48 Sound: C, 74.26; H, 6.17; N, 2.73.

"Step f): Preparation of [6-methoxy-3 - [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxy-enyl)] -benzo [b] thiophene The title compound is obtained with a yield of 88%, m.p. 147-150 ° C. XH NMR (DMSO-d6) d 9.72 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H) , 6.88 (dd, J = 8.8, 2.2 Hz, 1H), 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 Preparation of r6-methoxy-3 - [4-l "2- (1-piperidinyl) ethoxyl-phenoxy] -2- (4-hydroxyphenyl) -1-benzo-ib] thiophene hydrochloride The title compound is prepared 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 . 28 (broad s, 1H), 9.80 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H) , 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, 1H). Mass layer FD: 475 .. Analysis calculated for C28H29N04S • 1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Sound: C, 65.87; H, 5.79; N, 2.99.

Formulasión examples In the formulas that follow, the term "astivo 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 manner are blended 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 medisamento is passed through a US No. 45 mesh screen and mixed with sodium carboxymethyl cellulose and syrup to form a uniform paste. The benzoic acid solution, the taste and the color are diluted with a little water and added, with agitation. Then enough water is added to produce the required volume.

Formulation Example 5 Aerosol The astivo 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 are the remaining propellant. The valve units are then placed in the container.

Formulation Example 6 Suppositories The astivo ingredient is passed through a 60 mesh No. 60 mesh US sieve and suspended in the saturated fatty acid glycerides which have previously been melted using the minimum required salor. 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 approximately 1 ml per minute. "It is noted that in relation to this date, the best method conosido by the applicant to implement the aforementioned invention, is the convensional for the manufastura of objects or produtos to which it refers.

Claims

CLAIMS The invention having been described as an antesede, the content of the following claims is resigned as property:

1. The use of a structure that has the structure:

Or a pharmaceutically acceptable salt or prodrug thereof, wherein R- or R 2 are independently selected from the group consisting of hydroxy and alkoxy of 1 to 4 carbon atoms, and

R3 and R4 are independently selected from methyl or ethyl, or R and R4, taken together with the nitrogen atom to which they are attached, form a pyrrolidino ring, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino in the preparation of a medicament useful for the prevention of a carcinoma of the chest in a patient, 2. The use according to claim 1, characterized in that the patient has not yet been diagnosed, but it has been determined that he is at risk of breast cancer. 3. The use according to claim 1, characterized in that R -1 and R2 are both hydroxy. -

4. The use according to claim 1, characterized in that R 1 is hydroxy and R 2 is alkoxy of 1 to 4 carbon atoms.

5. The use according to claim 1, characterized in that R is methoxy.

6. The use according to claim 2, characterized in that R 1 and R 2 are both hydroxy.

7. The use according to claim 2, characterized in that R is hydroxy and R2 is alkoxy of 1 to 4 carbon atoms.

8. The use according to claim 7, characterized in that R is methoxy.

9. The use according to claim 1, characterized in that R3 and R4 combine with the nitrogen atom to which they are attached to form a piperidino- ring.

10. The use 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.

11. The use according to claim 1, characterized in that it comprises administering a therapeutically effective amount of a compound having the structure - or a salt or a pharmaceutically assimilable salt thereof, wherein R2 is hydroxy or methoxy.

12. The use according to claim 2, characterized in that the administration of a therapeutically effective amount of a compound having the structure or a pharmaceutically acceptable salt or prodrug thereof, wherein R2 is hydroxy or methoxy.

13. The use in accordance with claim 11, sarasterized because the compound is 6- hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) -phenoxy] -benzo [b] thiophene or a pharmaceutically acceptable salt thereof. The use according to claim 11, characterized in that the compound is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] -benzo [b] thiophene or a pharmaceutically salt acceptable of it. 15. The use according to claim 12, characterized in that the compound is 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] -benzo [b] thiophene or a pharmaceutically salt acceptable of it. 16. The use according to claim 12, wherein the somatic compound is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) -phenoxy] -benzo [b] thiophene or a pharmaceutically acceptable salt thereof.