MXPA99009228A - Treatment of central nervous system disorders with selective estrogen receptor modulators - Google Patents

Abstract

The present invention provides a method of treating depression, mood swings, or Alzheimer's disease in a patient in need of such treatment by administering a selective estrogen receptor modulating compound of formula (a), 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 OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM WITH SELECTIVE MODULATORS OF THE ESTROGEN RECEIVER TECHNICAL FIELD The present invention relates to medical methods of treatment. More particularly, the present invention relates to the use of a class of substituted benzo [Jb] thiophene compounds for the treatment of depression, mood swings and Alzheimer's disease in patients in need thereof.

BACKGROUND OF THE INVENTION In addition to the well-documented effects of estrogen on reproductive tissue, bone and cholesterol metabolism in postmenopausal women, it is known that estrogen has many actions in the central nervous system with somatic and behavioral consequences. In a climacteric woman, anxiety, depression, tension and irritability begin during perimenopause and can be correlated with reduced estrogen levels. Estrogen replacement therapy has been recommended for the treatment of these symptoms (see J.

REF. ": 31749 Malleson, Lancet, 2: 158 (1953") and R. ilson, et al. , J. Am. Geriatric Soc., 11: 347 (1963)). The mechanism for the protective effects of estrogen against depression in mood swings is not well understood, but may be related to the potential effects of estrogen on biogenic amines such as serotonin (see M. Aylward, Int. Res. Communications System Med Sci .. 1: 30 (1973) In the area of improvement of memory and knowledge, S. Phillips, et al., Psychoneuroendocrinology, 17: 485-495 (1992) has reported that in surgically menopausal women to whom Estrogen is provided, ratings on immediate and delayed memory tests are greater than on similar women who are not given estrogen, in a prospective cohort study in postmenopausal women, AH Paganini-Hill, et al., Am. J. Epidemiol., 140 (3): 256-261 (1994) shows that the risk of Alzheimer's disease is lower in estrogen users compared with women who do not use estrogen. Alzheimer's disease decreases significantly with increasing estrogen doses and increasing the duration of estrogen use. All these studies have led to the growing percon in the literature that estrogen replacement therapy is a promising treatment for central nervous system disorders such as depression, mood swings and Alzheimer's disease in postmenopausal women. These promising uses of estrogen replacement therapy, however, are held back by the disadvantages of long-term estrogen therapy associated with the risks of developing cancers in reproductive tissue. Women on estrogen replacement therapy develop endometrial cancer at rates three to six times higher than nonusers after three to six years of use; After ten years of estrogen replacement therapy, the risk ratio increases tenfold. A growing body of literature suggests that chronicity (ie, 10-15 years) causes thirty to fifty percent in the increased risk of breast cancer. Therefore, there is a need for the development of new compounds which are alternatives to estrogen that have the same beneficial effects on depression and mood changes and in the treatment of Alzheimer's disease, but which lack the harmful effects on reproductive tissue.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a method for treating, in a patient in need of such treatment, a central nervous system disorder that is selected from depression, mood swings and Alzheimer's disease, which comprises administering a therapeutically effective amount of a compound that has the structure: or a pharmaceutically accble salt or prodrug thereof. In the structure shown before, 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, - - methyl pyrrolidino, dimethylpyrrolidino, piperidino, morpholino or hexamethyleneirano. 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 breast or uterus.

DETAILED DESCRIPTION Through this specification and the appended claims, the general terms will present 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 substituent groups R1 and 2 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. The term "patient" refers to a mammal which is in need of treatment to correct mood swings, depression or Alzheimer's disease. It is understood that guinea pigs, dogs, cats, rats, mice, hamsters, rabbits and primates including humans, both males and females, are examples of patients within the scope of the term meaning. 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: RX wherein Re and Rs are independently -H or a hydroxy protecting group. The hydroxy protecting groups of R5 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 then removed at a later stage of the synthesis. . Since the compounds having such protective groups are mainly important 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, d-d alkyl, d-d alkoxy, -C0- (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 d- j alkyl, d-d 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 Rs and Rs substituents 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 RB is selectively removed, which leaves R6 as a hydroxy protecting group as part of the final product. The same is valid in the case in which the hydroxy protecting group is selectively removed in R6, which leaves the hydroxy protecting group in Rs instead. For example, Rs can be isopropyl or benzyl and R6 methyl. The isopropyl or benzyl portion is removed electively by standard procedure, and the methyl protecting group in Rs 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, Rs, R6 and R8 are chosen such that, in the final step, the hydroxy protecting group on R8 can be selectively removed at presence of hydroxy protecting groups in Rs 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 sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, and sopropansul f onat or, 4-methyl-oxybenzenesulfonate, 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 R 8 is a protective hydroxy-removable group 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 Preferred R8 include methoxymethyl, when Rs and / or Rs 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 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 for completion is usually about 20 days approximately 60 hours. After the coupling of a compound of formula 2 with one of formula 3., to form a compound of formula 4, the compounds of formula J5 are prepared by selective removal of the hydroxy protecting group in 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 Rs. When R8 is the preferred benzyl portion, and Rs and, when present, R6 are each methyl, the present process steps are carried out by a standard means of 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 this, palladium on carbon, particularly palladium 10% on carbon, is particularly preferred. The solvent for this reaction are those solvents or mixture of solvents which remain inert through the reaction. Ethyl acetate and Cx-C4 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 kilopaskalee (50 pei), 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 R4RSN- (CH2) 2-Q wherein R4 and Rs are as defined in the above, and Q is bromine or preferably chlorine, to form a compound of formula 1_. The compound of formula 7 is then deprotected to form a compound of formula I.

Reaction scheme II the, R5 = Re = 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 are prepared by means well known to a person usually familiar 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 formula 5 is reacted with equivalent doe 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, 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 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 to prepare the compound of the present invention, shown in the Reaction Scheme III then a compound of formula is reacted in an alkaline solution with an excess of an alkylating agent of. formula 8 .: Q- (CH2) n-Ql in which Q and Q1 are the same or different group ealientee The appropriate outgoing groups are those mentioned above.

Reaction Scheme III 10 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 finish. 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 l-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 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 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 Rs and, when present, hydroxy protecting groups in R6 of the compounds of formula I by means of well-known procedures. Many reactions for the formation and removal of such protecting groups are described 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 the 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 the compound 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 the, R5 _ R6 H Ib, R5 = H le, R6 = H In the first stage of this process, a compound of formula 2 is selectively oxidized to sulfoxide 12 .. Many methods known for the process step are feasible. [see, for example, Madesclaire, M., Tetrahedron, 42 (20); 5459-5495 (1986); Trost, B.M., et al. , Tetrahedron Lettere. 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. Nevertheless, 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 leaving group in position 3, R7, is replaced by the nucleophilic derivative of formula 13. Such nucleophilic derivatives are prepared by means of 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. The 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 1 are prepared by substituting the hydroxy portions at the 6 and / or 4 'positions when present, with a portion of the formula -OCO (Cx-C6 alkyl), or -0S02 (alkyl) of C2-C6) by means of well-known procedures. See, for example, U.S. Patent No. 4,358,593. For example, when a group -OCO (d-Cg alkyl) is desired, a mono- or dihydroxy compound of formula JE is reacted with an agent such as chloride, bromide, cyanide or acyl azide, or with an anhydride or mixed anhydride 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, 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 room temperature is usually adequate for the reaction to take place. The acylation of a hydroxy group in the section 6 and / or in the section 4 'ee can be carried out by reaction 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 ether prodrug compounds can also be provided by forming the active ester of the appropriate acid, such as the esters formed by known reagents such as, for example, 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 (-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 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 sulfonic 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 halide of acid 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 eleates 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 saltse include salts formed by typical inorganic acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like as well as ealee 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, metafoefate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzene sulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-tolue n-sulfonate, xylene sulfonate, tartrate and the like. The preferred saltse 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 intranaeal. Composite groups are preferably formulated before 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 pharmaceutically acceptable carrier, diluent or 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 are formed into tablets, capsules, capsules, 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 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 eupoeitor. 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, vegetale oils. (talee like 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 euepensiones, and by the use of surfactants. • The parenteral compositions may also contain adjuvants such as preservatives or preservatives, wetting agents, emulsifying agents and dispersion improving agents. 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 eubcutaneous or intramuscular injection of an euspension containing a drug form with low water solubility, the absorption rate of the drug 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 in 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 before mixing, either at the time of preparation or before their administration (as in the example of a double-chamber syringe package). The 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) filler materials or fillers such as idonee, 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) agents that retard the solution such as paraffin, (f) agents that accelerate the 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) tallow lubricants such as talc, calcium stearate, magnesium stearate, poly (ethylene glycols), sodium lauryl sulfate and mixtures thereof. In the case of the 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 preparations 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 microcapeulae are 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, the 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, benzoate. of benzyl, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, of cottonseed, ground walnut, corn, germ, olive, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, poly (ethylene glycols), fatty acid esters of sorbitol and mixtures of loe mieme. 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 ethoxylated alcohols, polyoxyethylene sorbitol and eorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite c agar-agar and tragacanth, and mixtures thereof. of the 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 is liquid at room temperature. body temperature and therefore melts in the rectum or vaginal cavity to release the active component or components. The compounds are dissolved in the molten wax, formed into the desired shape and allowed to harden in the finished euphoria 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 ono-or multi-lamellar 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 As discussed above, estrogen has a beneficial effect on mood swings and depression in postmenopausal women and has been shown to also have a beneficial effect on memory and cognition in the elderly and elderly. To be used as a therapeutic agent for such conditions, it may be necessary to administer a medication to a patient for a prolonged period of time. However, the drawbacks associated with chronic estrogen use and the risk of concomitant cancers in reproductive tissue prevent its long-term use of estrogen. A substitute for estrogen should have the beneficial effects of estrogen in the brain, if the harmful effects associated in the breast and uterus. In addition, such a substitute must be able to cross the blood-brain barrier in order to exert the desired effect. The compounds of the present invention possess the desired profile, being selective modulators of the estrogen receptor (SERM) with estrogen-like effects in certain tissues and at the same time lacking (or having a minimal agonistic effect) in the chest and uterus. In addition, as demonstrated by the following data, some compounds of the present invention have been found to cross the blood-brain barrier and exhibit effective brain concentrations after oral administration in laboratory animals.

Distribution of compounds of the invention among various tissues in female F344 rats Female Fischer 344 rats (approximately twelve weeks old) were read to administer a single oral ingested dose of 5 mg / kg (30 mCi / kg) of 6-hydroxy-2- (4-methoxyphenyl) -3- [-] hydrochloride. 4-piperidinetoxy) phenoxy] benzo- [b] -thiophene in PEG 50% 300 / water 50%. Blood and tissue samples were collected from three rats at each point in time; just before dosing and at 2, 4, 8 and 24 hours after dosing. At each point in time, the animals were sacrificed, blood samples were collected and the heparinized blood and plasma obtained were centrifuged. After the collection of the blood sample in each case, the animals. They were perfused with 0.9% saline solution and the brain, pituitary gland, femurs, ovaries, uterus and liver were surgically removed and placed in separate containers. The brain was further divided into the hypothalamus, hippocampus, cerebellum and cerebral cortex. All samples were stored at -70 ° C. The radioactivity of each sample is determined by liquid scintillation spectrometry. The count is made directly in plasma, while the other tissues were homogenized, digested and oxidized before the count by liquid scintillation. All tissues were weighed before treatment. The liver and brain were homogenized in 0.9% saline and an aliquot of the homogenate is oxidized. The pituitary, hippocampus, hypothalamus, ovaries, uterus and cerebellum are oxidized directly after drying. The femur is digested with a mixture of 30% hydrogen peroxide and concentrated perchloric acid (2/1 v / v) before the liquid scintillation count. The samples are oxidized in a Packard Model 307 Oxidizer and the resulting 14C02 is trapped for liquid scintillation counting. The radioactivity in each tissue sample is converted to equivalent nanograms per gram of tissue (specific activity = 16.3 dpm / ng). The area of 0-24 hours under the curve is calculated for each sample (AUC0_24 h). A liver and cerebral cortex homogenate is analyzed by CLAP and detection of UV radiation at 315 nm to determine whether the radioactivity in these tissues is actually due to the drug dosed initially, to the main metabolite 6-hydroxy-2- (4-hydroxyphenyl) - 3- [4 - (piperidinoethoxy) phenoxy] -benzo [b] thiophene or if glucuronide conjugates exist. A cerebral cortex is obtained eight hours after dosing and the liver samples are collected at four and eight hours after dosing. The proteins in the homogenate are precipitated with acetonitrile and the supernatant is evaporated to dryness. The residue is reconstituted in mobile phase and injected into a SynChropak SCD-100 column with the initial mobile phase constituted by KH2P04 0.05 M 60%, pH 7/17% methanol / 17% acetonitrile (v / v / v). The retention times of the peaks of the homogenate are compared with those obtained from authentic samples of 6-hydroxy-2 - (4-methyl t-oxyfyl) -3- [4 - (piperidinoethoxy) -phenoxy] enzo [b] thiophene and its metabolite 6-hydroxy-2 - (4-hydroxyphenyl) -3- [4 - (piperidinoethoxy) phenoxy] benzo [b] -thifen. Radioactivity is found in all tissues as shown in the data presented in Table 1.

Table 1 Average pharmacokinetic parameters for radioactivity after a single oral dose of 14C-6-hydroxy-2- (4-methoxyphenyl) -3- [4- (piperidinoethoxy) phenoxy] enzo [b] -thiophene in female F344 rats Examination of the data shown in Table 1 indicates that radioactive material is found in all tissues, with peak concentrations reached at 8 hours after dosing, with the exception of the liver, where peak concentrations are reached at 4 hours after dosing. The lowest concentrations are found in plasma and the highest concentrations in the liver. Both the Cmax and AUC0_24 h of radioactivity for the cerebellum, brain, hippocampus and hypothalamus are greater than those observed in plasma, indicating that radioactivity is distributed in areas of the brain after administration of the parent compound, 14C-6-hydroxy -2- (4-methoxyphenyl) -3- [4 - (piperidinoethoxy) phenoxy] benzo [b] thiophene. Analysis of the cerebral cortex homogenate (described above) shows that the radioactivity is due to both the parent compound, 14C-6-hydroxy-2- (4-methoxyphenyl) -3- [4- (piperidinoethoxy) -phenoxy] benzo [b ] thiofen as to its metabolite dihydroxy, 14C-6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (piperidinoethoxy) -phenoxy] benzo [b] thiophene, in a ratio of about 4: 1. The peaks that correspond to the glucuronide conjugates of both the parent compound and its dihydroxy metabolite are not observed in the CLAP chromatogram of the cerebral cortex homogenate. The CLAP chromatogram of the empathic homogenates, however, show peaks whose retention times correspond to the parent compound and its glucuronide conjugate.

Similarity of 6-hydroxy-2- (4-methoxyphenyl) -3- T2- (piperidinoethoxy) phenoxy benzo fbl thiophene with estrogen in the hippocampus Estrogens, such as 17β-estradiol, regulate the transcription of genes by binding to estrogen receptors (ER) which are found in the cytoplasm of certain cell populations. Ligand activation of ER loe is a prerequisite for the nuclear traneport of the complex where it binds to the palindromic DNA consensus sequence of 13 base pairs (estrogen response elements, or ERE) that begins the assembly of an apparatus transcriptional which culminates in the activation of the appropriate target genes. Several genes have been identified which are -regulated by estrogen. These include cytoskeletal proteins, biosynthetic neurotransmitters and metabolic enzymes and receptors, as well as other hormones and neuropeptides. EREs have been identified in many genes that respond to estrogen including vitellogenin, c-fos, prolactin, and luteinizing hormone. Importantly in the central nervous system, sequences similar to ERE have been identified in p75ngr and trkA, both of which serve as signaling molecules for neurotrophins: nerve growth factor (NGF), brain-derived nerve growth factor (BDNGF) ) and neurotrophin-3. It has been shown that BDNF and NGF promote the survival of cholinergic neurons in culture. It has been postulated that if the interactions between neurotrophins and estrogens are important for the development and survival of basal neurons of the anterior brain (which degenerate in Alzheimer's disease) then the clinical conditions in which there is an estrogen deficiency (after the menopause) can contribute to a loss of these neurons. A commonly used model of estrogen suppression is the ovariectomized adult rat. An experiment is conducted in ovariectomized rats using differential mRNA display to determine the similarities and / or differences between a representative compound of the present invention, 6-hydroxy-2- (4-me oxy phenyl) -3- [4- (2 -piperidinoethoxy) phenoxy] -benzo [b] thiophene and estrogen in the alteration of gene expression in various regions of the brain. SpecificallyThey were ovariectomized by the 6-week-old Sprague-Dawley female ratae seller. After a week of acclimatization to laboratory facilities, daily subcutaneous injections of estradiol benzoate (0.03 mg / kg), 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy ) phenoxy] -benzo [b] thiophene (1 mg / kg), or vehicle (control). After five weeks of daily treatment, the animals were sacrificed and their brains were removed and hippocampi were collected by microdissection. The hippocampi were frozen rapidly in nitrogen at -70 ° C. The total RNA is prepared from the accumulated tissue of the appropriate treatment and control groups and subjected to reverse transcription using a 3 'oligonucleotide primer which is selected for specific populations of AR? M (poly-A +). Polymerase chain reactions (PCR) are carried out in a mixture consisting of: random 51 oligonucleotides (10 base pairs in length); total of 150), reaction buffer, Taq polymerase and 32PdTCP. After 40 cycles of amplification, the reaction products were. fractionated by size in a 6% TBE-urea gel, ee eecan and exposed to an X-ray film. The resulting mRNA shows patterns when compared between the treatment groups. 6-hydroxy-2- (4-methoxyphenyl) -3 - [4- (2-piperidinoethoxy) phenoxy] benzo [b] -thiophene produces a parallel pattern of activation or inactivation of genes in the rat hippocampus observed by estrogen. These data indicate that 6-hyd rox i-2 - 8 4 - me t ox ifenil) - 3 - [4 - (2-piperidinoethoxy) phenoxy] benzo [b] -thiophene produces an estrogen-like effect in the hippocampus, a key region in the brain associated with Alzheimer's disease in humans. Therefore, the 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 and its primary metabolite, 6-hydroxy-2 - (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] -thiophene could be useful in the treatment of Alzheimer's disease in a human patient. 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 composition administered in accordance with 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 condition in which the patient is located, 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 be from about 15 mg to about 80 mg / day. The exact dose is determined in accordance with standard practice in the 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 RM instrument? and anhydrous hexadeuterodimethyl sulfoxide was used as the solvent, unless otherwise indicated.

Example 1 Preparation of the oxalate salt of r6-methoxy-3-, 4- [2- (1-piperidinyl) ethoxy-1-phenoxy] -2- (4-methoxyphenyl) benzo rb1 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. NMR (DMSO-dg): 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). Mass spectrum FD: 349, 350. Analysis Calculated for ClsH1302SBr: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76.

Step Preparation of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] enzo [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 ee solution was 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 mmoles.] 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 crystallize from hexanes / ethyl acetate to initially provide 7.19 g of [6-methyl-oxy-2 - (4-methyl-oxy-phenyl) -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 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 initial material recovered). basic 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 recovered 4-benzyloxyphenol, m.p. 100-103 ° C. 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] enzo [b] iofen 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 vacuo to a white solid. The crude product (untreated) is passed through a pad of silica gel (chloroform as eluent). The concentration provides 1.10 g (91%) of [6-m e t o x i-2 - (4-me t o x i f e n i l) -3- (4-hydroxy) phenoxy] benzo [b] thiophene as a white solid, m.p. 123-126 ° C. -I NMR (DMS0-ds) 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 (d, 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- (l-piperidinyl) ethoxy] -phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene A ^ one Solution of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] enzo [b] thiophene (1.12 g, 2.97 mmol) in 7 ml of N, N-dimethylformamide anhydrous under N2 is added cesium carbonate (3.86 g, 11.88 mmol). After stirring for 10 minutes, 2-chloroethylpiperidine hydrochloride is added (1.10 g, 1.48 mmolee). The re-mixing mixture is stirred 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 forms and is 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)] enzo [b] -thiophene X as the oxalate salt. p.f. 197-200 ° C (decomposition). XH NMR (DMSO-ds) 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 t 2H), 3.78 (s, 3H), 3.72 (e, 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- [4- .2- (1-piperidinyl) ethoxyl-phenoxy-2- (4-methoxyphenyl) -1-benzo-T-thiophene Treatment of the oxalate salt of Example 1 with an aqueous base to produce the free bath, followed by reaction with diethyl ether saturated with HCl gives the title salt, m.p. 216-220 ° C. _? NMR (DMS0-d6) 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 (c, JM = 9.0 Hz, 4H), 4. I (m, 2H), 3.83 ( s, 3H), 3 77 (s, 3H), 3.43 (, 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-methoxy-enyl) benzo [b] thiophene The title compound is prepared in the same manner as the compound of Example 1, m.p. 95-98 ° C. 1 H NMR (DMSO-ds) 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. 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. _I 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 (e, 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) enzo [b] thiophene hydrochloride The title compound is prepared in the same manner as the compound of Example 1, m.p. 196-198 ° C. _I NMR (DMS0-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 (c, 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 (, 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. _I NMR (DMSO-dg) 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 (c, JB = 9.0 Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m , 4H), 3.82 (e, 3H), 3.77 (8, 3H), 3.59-3.42 (m, 4H), 3.21-3.10 (m, 2H), Calculated Analysis for C2ßH29N05S -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-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 mmoles). The resulting mixture is stirred at 8 ° C for 2.5 hours. The reaction is effected by pouring it into a stirring solution of edible, bicarbonate of eiodium (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, m.p. 93 ° C. NMR (DMSO-ds) d 9.73 (broad s, 1H), 9.68 (broad e, 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), 6Í84 (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 [6-hydroxy-3 - [4- F2- (l-piperidinyl) ethoxyl phenoxyl-2- (4-hydroxyphenyl) benzo [bl-thiophene] The title compound is prepared in 80% yield from the free base, m.p. 246-249 ° C (decomposition). 1 H NMR (DMSO-d 6) 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 spectrum FD: 462. Analysis Calculated for C27H27NO4S-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 [bl-thiophene] hydrochloride The title compound was prepared in a yield of 91% by treatment of the corresponding free base with diethyl ether, which was saturated with HCl, m.p. 158-165 ° C. XH NMR (DMSO-d6) d 9.79 (s, 1H), 9.74 (s, 1H), 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, 1H). 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) ethoxyphenoxy] -2- (4-hydroxyphenyl) benzo [b] 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. XH NMR (DMS0-d6) d 9.75"(s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.09 (d , J = 9.0 Hz, 1H), 6.85 (8, 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 / 4 ~ H), Calculated Analysis for C2SH2BN04S • 0.5 H20: C, 68.40; H, 5774; N, 3.07. , 68.52; H, 6.00; N, 3.34.

Example 11 Preparation of [6-hydroxy-3 - [4- [2- (1-hexamethyleneimino) ethoxyphenoxy] -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. _I NMR (DMS0-ds) 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). Analysis Calculated for C28H29N04S: C, 70. 71; H, 6. fifteen; 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) -ethoxyphenoxy-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. XE NMR (DMS0-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, 4HJ 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-T4- [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. 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 (c, J ^ = 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) X 3.75 (m, 2H), 3.51 (m, ~ 4H), 3.18 (m, 2H). Analysis Calculated for C2SH2SN0SS • 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 - [4- [2- (1-piperidinyl) ethoxyl phenoxy] -2- (4-methoxyphenyl) benzo [bl-thiophene] Step a): preparation of 6-methoxybenzo [b] thiophen-2-boronic acid.

To 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 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, m.p. 200 ° C (decomposition). _? NMR (DMSO-ds) d 7.83 (s, 1H), 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.

Step b): Preparation of [6-methoxy-2- (4-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 gives 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. 1 H 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), 3.8O (s, 3H), 3.39 (s, 3H). Mass spectrum FD: 334. Analysis Calculated for C1SH1404S2: C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21. " Step c) .- Preparation of [6-methoxy-2- (4-methanesulfonyl-oxyphenyl)] benzo [b] thiophene To a solution of [6-methoxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (9.50 g, 28.40 mmol) in anhydrous methylene chloride (200 ml) at room temperature, under nitrogen gas, boron tribromide is added (14.20 g, 5.36 ml, 56.8 mmol). The resulting mixture is stirred at room temperature for 3 hours. The reaction is delayed by slowly pouring it into 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, mp 239-243 ° C. NMR (DMS0-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). Mass spectrum FD: 320. Analysis Calculated 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-methanesulfonyl-oxyphenyl)] 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 chloride of benzyl (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. After allowing to dry in vacuo, the crude product is suspended in 1: 1 hexanes: ethyl ether. The solid is collected to give 3.72 g (91%) of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene as a white solid, m.p. 198-202 ° C. -I NMR (DMSO-dg) 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 (e, 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 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 hydrochloric acid 1. The aqueous phase is extracted with ethyl acetate.The organic fraction is subsequently washed several times. The mixture is then dried with water and then dried (sodium sulfate) and concentrated in vacuo to a solid, chromatography (silicon dioxide, chloroform) yielding 8.75 g (87%) of [6-benzyloxy-2- (4-hydroxyphenyl)). ] benzo [b] thiophene as a white solid, mp 212-216 ° C. 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 (e, 2H). FD masses: 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 add sodium hydride (1.66 g, 41.5 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. -I NMR (DMSO-ds) 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). Mass spectrum FD: 346. Analysis Calculated for C22H1802S: C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43.

Step g): Preparation of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene S is col oca [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 suepeneion 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. NMR (DMS0-de) 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). 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. p.f. -202-205 ° C. NMR (DMSO-dsJ 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), FD masae spectrum: 441. Analysis Calculated for C22H1703SBr: C, 59.87; H, 3.88. 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 bae affords the title compound as a yellow solid. 1 H NMR (DMSO-d 6) d 7.76 (d, J = 2.2 Hz, 1 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.44-7.30 (m, 5 H), 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 (, 4H), 1.45-1.32 (m, 6H). FD masae spectrum: 592. Analysis Calculated for C3SH35N05S: C, 72.26; H, 6.06; N, 2.41. Found: "C, 72.19; H, 5.99; N, 2.11.

Step i): 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 (Si02, 1-5% methanol / chloroform) gives an off white solid, m.p. 105-108 ° C. _ NMR (DMSO-ds) 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 (e, 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). Spectrum of masae FD: 565. Analysis Calculated for C3SH35N04S: C, 74.31; H, 6X24; 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)] enzo [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 5: 1 palladium black (1.50 g), ammonium formate (3.50 g, 55.6 mmol) and 30 ml of water are added. 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 provide 6.50 g (91%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4- methoxyphenyl)] benzo [b] thiophene as a foam that is converted to a solid when triturated with hexanes. p.f. 174-176 ° C. _? NMR (DMS0-d6) d 9.77 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 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 (e, 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) phenoxyl-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 HCl in ethyl acetate followed by crystallization from ethanol / ethyl acetate; p.f. 156-160 ° C. XH NMR (DMSO-ds) 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 Hz, 2H), 6.87 (c, J ^ = 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. 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 Preparation of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl) -1 benzo [bl-thiophene] Step a): Preparation of [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. NMR (DMSO-ds) 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 compote with a yield of 91%, p.f. 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 (e, 2H), 3.82 (s, 3H). Mass spectrum FD: 346. Analysis Calculated for C22H1702SBr: C, 62.13; H, 4.03. Found: C, 62.33; H, 3.93.

Step _cl: [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. NMR (DMSO-ds) 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. Analysis 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. 1 H NMR (DMSO-ds) 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 (, 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 C3SH35NOsS -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 with a yield of 91%, m.p. 106-110 ° C. _í NMR (DMSO-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 (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 C3SH3SN04S: C, 74.31; H, 6.24; N, 2.48 Found: C, 74.26; H, 6.17; N, 2.73.

Step f): Preparation of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] • benzo [b] thiophene The title compound is obtained with a yield of 88%, m.p. 147-150 ° C. NMR (DMS0-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 [6-methoxy-3- {4- \ 2- (1- ~ piperidinyl) ethoxy-1-phenoxy-2- (4-hydroxyphenyl) -1-benzo [bl-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 (DMS0-d6) d 10.28 (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 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, 2.9-9.

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 made 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 small amount of 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 diepoeitive. 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 United States sieve and suspended in the saturated fatty acid glycerides which have previously been melted using the minimum necessary heat. 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 (20)

CLAIMS Having described the invention as above, the property contained in the following claims is claimed as property:

1. A method for treating, in a patient in need of such treatment, a central nervous system disorder that is selected from depression, mood swings and Alzheimer's disease, 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 one to four carbon atoms, and R3 and R4 are independently selected from methyl or ethyl, or R3 and R4, taken together with the nitrogen atom at which are bound together form a pyrrolidino ring, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or hexamethinimino.

2. The method according to claim 1, characterized in that the method comprises treating, in a patient in need of such treatment, depression or mood changes.

3. The method according to claim 1, characterized in that the method comprises treating, in a patient in need of such treatment, Alzheimer's disease.

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 one to four carbon atoms.

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

9. The method according to claim 3, characterized in that R1 is hydroxy and R2 is alkoxy of one to four 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 treating, in a patient in need of such treatment, depreesion or mood swings, the method is 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-methyloxy) -3- [4- (2-piperidinoet oxy) -phenoxy] benzo [b] iofen 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 thereof

16. A method for treating, in a patient in need of such treatment, the disease of Alzheimer's, 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-methoxy-enyl) -3- [4- (2-piperidinoethoxy) -phenoxy] benzo [b] thiophene or a salt pharmaceutically acceptable thereof.

18. 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 salt acceptable of it. The method according to claim 13, characterized in that the salt is the hydrochloride salt 20. The method according to claim 16, characterized in that the salt is the hydrochloride salt.