CZ9903554A3 - Treatment method of prophylaxis of prostate cancer and prostate benignant hyperplasia by employing modulators of estrogen selective receptor - Google Patents

Abstract

The present invention provides a method for the treatment or prophylaxis of benign prostate hyperplasia or prostate cancer in a patient it needs this treatment in which selective is administered an estrogen receptor modulator, a compound of Formula I, wherein R 1 and R 2 are independently hydroxy from each other a group or alkoxy of one to four atoms carbon and R3 and R4 are independently of each other methyl or ethyl or R3 and R4 together with the nitrogen atom, k0 they are joining, forming a pyrrolidine, methylpyrrolidine, dimethylpyrrolidine, piperidine, a morpholine or hexamethyleneimine ring.

Description

Method for the treatment or prophylaxis of prostate cancer and benign prostatic hyperplasia with selective estrogen receptor modulators

Technical field

The present invention relates to the use of a group of biologically active compounds as antagonists of the proliferation of benign and malignant prostate cells. More particularly, the invention relates to the use of a group of substituted benzo [b] thiophene compounds for the treatment or prophylaxis of prostate cancer and benign prostatic hyperplasia.

BACKGROUND OF THE INVENTION

Prostate cancer mortality, based on close monitoring in males with localized tumors, is generally low (9% to 15%). However, these values refer to patients with localized disease and do not necessarily apply to younger men at increased risk. Younger men with Tla tumor stages have a longer planned period of risk than older men with the same stage of disease and are therefore candidates for potentially curative treatment. In studies based on careful waiting, high rates of disease progression (34% to 80%) show that only a small proportion of clinically proven prostate cancers are at rest.

Radiation therapy is widely used for stage T1 or T2 of a clinically localized disease and is preferably used in elderly, less healthy patients and in patients with a high degree of clinically more advanced tumors. However, this treatment neither cures nor releases all tumor cells in men with hidden metastases.

The administration of estrogens to reduce circulating androgens is an effective hormonal ablative therapy for disseminated prostate cancer [J. Waxman, J.R. Soc. Med., 78, 129-135 (1985)]. The estrogenic antitumor responses are primarily mediated by a decrease in testosterone in the bloodstream as a result of inhibition of luteinizing hormone secretion.

Administration of 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-pyrrolidinoethoxy) benzoyl] benzo [b] thiophene, 1, or 6-hydroxy-2- (4-hydroxyphenyl) -3- [4] - (2-piperidinoethoxy) benzoyl] benzo [b] thiophene, 2, both compounds selectively modulating estrogen receptors (SERMs), caused tumor inhibition of caustic metastases implanted in the caudal tail into the gluteal and hip lymph nodes by male Lobund-Wistar rats. and into the lungs. [See B. L. Neubauer, et al., Prostate, 27, 220-229 (1995)].

Γ (CH 3 J n NV (1) n = 2 (2) n = 3

Selective estrogen receptor modulators are defined as compounds that produce estrogen agonism in one or more desired target tissues together with estrogen antagonism and / or minimal (i.e., clinically insignificant) agonism in reproductive tissues. Raloxifene, in addition to its antiestrogenic action, has the ability to act as a physiological androgen antagonist in normal males.

PAIII adenocarcinoma in Lobund-Wistar rats is a model useful in evaluating agents for treating metastatic prostate cancer. When PAIII cells are injected subcutaneously into the tails of Lobund-Wistar rats, a reproducible, progressive expansion of tumor cells to the gluteal and hip lymph nodes and to the lungs occurs.

The tumor morphology of PAIII mimics anaplastic injury in humans, allowing the tumor to be useful as a model for evaluating cytotoxic and antimetastatic agents for human use.

Benign prostatic hyperplasia (BPH) is the most common neoplastic process in men. It is estimated that about 50% of American men over the age of 50 suffer from benign prostatic hyperplasia.

Benign prostate hyperplasia is an enlargement of the prostate caused by benign overgrowth of the prostate stromal tissue and leads to symptoms that include increased urgency and frequency, and which, if left untreated, may lead to associated complications including bladder and kidney damage.

Φ · ΦΦ φφφφ

A typical treatment for benign prostatic hyperplasia is transurethral prostatectomy, a procedure that is expensive and time consuming. The mortality of transurethral resection of the prostate has decreased to 0.2% over the past 30 years, but the method itself has not changed over this period and postoperative morbidity remained unchanged at a level of about 18%.

It is estimated that 29% of men with benign prostatic hyperplasia will require surgical treatment. This means more than 400,000 surgical interventions per year. It can be estimated that if a 40-year-old man in the United States lives to an age of 80, the probability of having a prostatectomy is 29%.

The high costs of this method, both in terms of time and money, have generated considerable interest in finding cheaper and more gentle means for treating benign prostatic hyperplasia.

SUMMARY OF THE INVENTION

According to the present invention there is provided a method of treating or prophylaxis of prostate cancer or benign prostatic hyperplasia in a human in need of such treatment comprising administering a therapeutically effective amount of a selective estrogen receptor modulating compound having the structure

or a pharmaceutically acceptable salt or prodrug thereof.

_of 1 9

In the structure shown above, R and R are independently selected from the group consisting of hydroxy and alkoxy of 1 to 4 carbon atoms.

R ³ and R ⁴ are independently selected from methyl or ethyl or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or hexamethyleneimino ring.

A detailed description of the invention follows.

Throughout this description and the appended claims, they have a 9 9 9 9 9 9 9 9 9

9999 999 99 9999 99 99 general terms their common meanings.

The term alkyl refers to a monovalent group derived by the removal of one hydrogen atom from methane, ethane or a straight or branched hydrocarbon, and includes such groups as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl a tert-butyl group and the like.

The term alkoxy means an alkyl group, as defined above, attached to the parent molecular moiety by an oxygen atom and includes such groups as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy. In this invention, the preferred alkoxy group is methoxy.

The term prodrug, as used herein, means a compound of the invention bearing a moiety that is metabolically cleaved in a human organism to provide a therapeutically active agent of the invention. In particular, such prodrugs include compounds wherein one or both of the substituents R ¹ and R ^{2 of} the structure described above are hydroxyl groups which are protected by a pharmaceutically acceptable hydroxyl protecting group that is metabolically cleaved in the body to yield the corresponding monohydroxyl or dihydroxyl compounds according to the invention. The hydroxyl protecting groups are described in Chapter 2 of the monograph TW Green, et al. Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc., New York, 1991. Simple hydroxyl group protecting groups in the prodrug are preferred.

Ether and ester groups.

Preferred compounds of the invention include 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt thereof, or a precursor thereof, and 6-hydroxy-2 - (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt or prodrug thereof.

Preparation of a compound of the invention

The starting material for the process for preparing the compound of the invention is prepared essentially as described by C. D. Jones in U.S. Patent Nos. 4,418,068 and 4,133,814. The starting material has the general formula 1:

(l) in which:

R ⁵ and R ^e are independently hydrogen or a hydroxyl protecting group.

The hydroxyl protecting groups R ⁵ and R ⁶ are radicals which are deliberately introduced at a certain stage of the process. Preparations for protecting a group that might otherwise react during chemical manipulations and then removed at a later stage of preparation. Since the compounds bearing these protecting groups are primarily important as chemical intermediates (although some derivatives also exhibit biological activity), their precise structure is not critical. Numerous reactions for the formation, removal and conversion of these protecting groups are described in a number of standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973), TW Green, 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 protecting groups for hydroxy groups include, for example, -C ^ -C ^ alkyl, C -C alkoxy, -CO- (C _i -C _s alkyl), -SO ₂ - (C ₄ -C ₆ alkyl) group, and a -CO-Ar group in which Ar is a benzyl group or an optionally substituted phenyl group. The term substituted phenyl refers to a phenyl group having one or more substituents selected from the group _χ -0 0 ₄ alkyl, C -C alkoxy, hydroxy, nitro, halo, and tri (chloro) - or tri (fluoro) methyl. The term halogen atom refers to a bromine, chlorine, fluorine and iodine atom.

For the compound of formula (1), R ⁵ and R ^{6 are} preferably methyl, isopropyl, benzyl and methoxymethyl. Compounds in which each R ⁵ and R ^s is methyl, prepared as described in the above-referenced Jones patent.

·· ΦΦ • · · · · · · ΦΦΦ ·

Also prepared compounds of formula 1, in which the hydroxyl protecting group ^R5 is selectively removed leaving the R groups ^of the hydroxy protecting group as part of the final product. The same applies in the case where the hydroxyl protecting group R ⁶ is selectively removed while leaving the hydroxyl protecting group R ⁵ . For example ^R may be isopropyl or benzyl and ^R6 methyl. The isopropyl or benzyl group is selectively removed by standard methods and the protecting group R ⁶ is retained as part of the final product.

As shown in Reaction Scheme I, the first steps of this process for preparing compounds of the invention include selectively positioning a leaving group, R ¹⁷ at the 3-position of a compound of Formula 1, to form a compound of Formula 2, coupling the product of this reaction 3 with a phenol having protected the hydroxyl group at the 4-position to form a compound of formula 4 and selectively removing the hydroxyl-protecting group R ⁸ to form a compound of formula 5. In the order of steps shown in Reaction Scheme I, the substituents of the hydroxyl protecting groups R ®, R ⁶ and R ® are selected as such. manner that in the final step can be selectively removed substituents R® protecting the hydroxyl group while maintaining the protective substituent R ⁵ and R ^s.

Reaction Scheme I

4 · 4 4 · 44 44 4 · 4 4 • · • 4 4 4 • 4 4 « • • • 4 • 4 4 • • • • • • * • • • • • 4 4 4 4 4 4 4 44 4 4 4 4 44 4 4

In the first step of Reaction Scheme I, the appropriate protecting group is positioned selectively at the 3-position of Formula 1 of the starting material by standard methods. Appropriate leaving groups R ⁷ include sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, triflate and the like, halogens such as chlorine, bromine, iodine, and other related leaving groups. However, halogen atoms are preferred for the correct positioning of the leaving group and bromine is particularly preferred.

This reaction is carried out by standard methods. Eg99 · 99 · 99 ·· ··· 9 · 9 ··· 9 99 9 9999 • 9 · · ····

When using preferred halogenating agents, the equivalent of this halogenating agent, preferably bromine, is reacted with an equivalent of the substrate of Formula 1 in a suitable solvent such as chloroform or acetic acid. The reaction is typically conducted at a temperature of about 40 ° C to about 80 ° C.

The reaction product of the above step, a compound of formula 2, is then reacted with a hydroxyl-protected phenol 3 at the 4-position to form a compound of formula 4 wherein R ⁸ is a selectively removable hydroxyl-protecting substituent. Typically, the phenolic may be a protective radical for a hydroxyl group at position 4 is any known protecting group which can be selectively removed without removing the substituents R ⁵ and, if present, the radicals R ^of the compound of Formula 3. Preferred protecting groups ^R8 include methoxymethyl, when R ⁵ and / or ^R are not methoxymethyl, and benzyl. Of these, a benzyl group is particularly preferred. The hydroxyl-protected phenol reactants at the 4-position are commercially available or can be prepared by standard methods.

The coupling reaction between a compound of Formula 2 and a compound of Formula 3 is known in the art as a Ullman reaction and generally follows standard methods [See, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition, 3-16 (J. March, editors, John Wiley & Sons, Inc. 1992), CD Jones, J.

Chem. Soc. Perk. Trance. 1, 4, 407 (1992)].

Generally, an equivalent amount of two aryl substrates in the presence of up to an equimolar amount of catalyst is frfr. Frfr. The copper (I) iodide and the appropriate solvent are refluxed under an inert atmosphere. Preferably, the equivalent of a compound of formula 2 wherein R ⁷ is bromo is reacted with an equivalent amount of 4-benzyloxyphenol in the presence of an equivalent of cuprous iodide.

Appropriate solvents for this reaction are solvents or solvent mixtures remaining inert throughout the reaction. Typically, preferred solvents are organic bases, especially hindered bases such as, for example

2,4,6-collidine.

The temperature used in this step is generally sufficient to complete this coupling reaction and thus affect the desired time. When the reaction mixture is heated to reflux under an inert atmosphere such as nitrogen atmosphere, the end time is usually from about 20 to about 60 h.

After coupling of the compound of formula 2 with the compound of formula 3 to form the compound of formula 4, the compound of formula 5 is prepared by selectively removing the hydroxyl protecting substituent R ® of the compound of formula 4 by well-known reduction methods. It is imperative that the selected method does not affect the substituent R ⁵ and, if present, the substituent R ⁶ protecting the hydroxyl groups.

If R® is the preferred benzyl moiety, and R ⁵ and in the presence of R ^s is methyl, is carried out by hydrogenolysis standard method. 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 the appropriate hydrogenation catalyst.

• «• ·

Appropriate catalysts include noble metals and oxides such as palladium, platinum and supported rhodium such as carbon or calcium carbonate. Of these, palladium on carbon is preferred, in particular 10% palladium on carbon. Solvents for this reaction are solvents or solvent mixtures remaining inert throughout the reaction. Usually the preferred ethyl acetate and a C, -C ₄ aliphatic alcohols, particularly ethanol. For this reaction, hydrochloric acid serves as a suitable and preferred proton donor.

At an ambient temperature and pressure ranging from about 30 psi to about 50 psi, the reaction proceeds very rapidly. The progress of this reaction can be monitored by standard chromatographic methods, such as thin layer chromatography.

As shown in Reaction Scheme II, the resulting compound of formula 5 is reacted with a compound of formula r ⁴ r ⁵ n- (ch ₂ ) ₂ -q (6) wherein:

R ⁴ and R ⁵ 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 give a compound of formula (7).

- 14 * ··· compounds of formula I.

Reaction Scheme II

R ³

H 1a, R ⁵ = r ⁶ = 1b, R ⁵ = H 1c, R ⁶ = H • φ • φ φ φ

In the first step of the process shown in Reaction Scheme II, the reaction is carried out by standard methods. The compound of formula 6 is commercially available or is prepared by methods well known to one of ordinary skill in the art. Preferably the hydrochloride of the compound of formula 6 is used. In a particularly preferred case of the compound of the invention, 2-chloroethylpiperidine hydrochloride is used.

Generally, at least 1 equivalent of substrate 5 is reacted with 2 equivalents of compound 6 in the presence of at least about 4 equivalents of an alkali metal carbonate, preferably cesium carbonate and the appropriate solvent.

Suitable solvents for this reaction are solvents or solvent mixtures remaining inert throughout the reaction. N, N-dimethylformamide, especially the anhydrous form, is preferred. The temperature used in this step should be sufficient to complete this alkylation reaction. Usually, ambient temperature is sufficient and preferred. This reaction is preferably carried out under an inert atmosphere, in particular under a nitrogen atmosphere.

Under the preferred reaction conditions, this reaction is completed in about 16-20 hours. The progress of this reaction can be followed by standard chromatographic methods.

In an alternative method of preparing a compound of the invention shown in Reaction Scheme III below, a compound of formula 5 is reacted with an alkaline solution in the presence of an alkylating agent of formula 8.

- 16 - ···· · · · · · · · · · · · · · ·

Q- (CH) -Q '

n.

(8) in which

Q and Q ¹ are the same or different leaving groups. The leaving group is that described above.

Reaction Scheme III

1b, R ⁵ = H 1c, R ⁶ = H

A preferred alkaline solution for this alkylation reaction comprises potassium carbonate in an inert solvent such as methyl ethyl ketone (MEK) or dimethylformamide. In this solution, the unprotected hydroxyl group of the compound of formula 5 is converted to a phenoxide ion which displaces one or more leaving groups of the alkylating agent.

• ·

This reaction preferably proceeds with an alkaline solution containing reagents and reagents, which is brought to reflux and allowed to boil until complete. When methyl ethyl ketone is used as the preferred solvent, reaction times range 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 selected from 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine , diisopropylamine or

1-hexamethyleneimine by standard methods to form a compound of formula 7. Preferably, the hydrochloride of the compound of formula 10 is used, and piperidine hydrochloride is particularly preferred. This reaction is typically carried out with an alkylated compound of Formula 9 in an inert solvent such as anhydrous dimethylformamide by heating to a temperature in the range of about 60 ° C to about 110 ° C. When the mixture is heated to a preferred temperature of about 90 ° C, the reaction takes about 30 minutes to 1 hour. However, changes in reaction conditions will affect the amount and time of reaction required to complete. The progress of this reaction step can be monitored by standard chromatographic methods.

Certain preferred compounds of formula I are obtained by cleaving the groups R ^5, and R _g groups present hydroxyl protecting group of the compound of formula I by well known methods. Numerous reactions for the formation and removal of these protecting groups are described in a number of standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973), TW Greene, 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 preferred R '' and / or R ⁸ hydroxy protecting groups, particularly methyl and methoxymethyl groups are essentially described in the Examples.

An alternative and preferred method of preparing the compound of the invention is shown in Reaction Scheme IV. In the method depicted herein, the sulfur atom of the compound of Formula 2 is oxidized to the sulfoxide, 11, which is then reacted with a nucleophilic group to introduce the oxygen linker into the compound of Formula I. The sulfoxide residue of the compound of Formula 12 is then reduced to give certain compounds of the invention.

• ·

Reaction Scheme IV

R ³

AND

and Ia, ^R5 = ^R6 = H lb, ^R5 = H * Ic, ^R6 = H

In the first step of this preparation, the compound of formula 2 is selectively oxidized to the sulfoxide 12. A number of known methods are available for this step [see, for example, M. Mades.

Claire, Tetrahedron, 42, 5459-5495 (1986), BM Trost et al., Tetrahedron Letters, 22, 1287-1290 (1981), J. Drabowicz et al. , Synthetic Communications, 11, 1025-1030 (1981), JB Kramer et al., 34th National Organic Symposium, Williamsburg, VA. June 1995]. However, many oxidizing agents provide only a low conversion yield to the desired product with a significant proportion of the oxidation to the sulfone. However, the preferred process converts the compound of Formula 2 to the sulfoxide of Formula 12 in high yield and with little or no sulfone formation. The method comprises reacting a compound of Formula 2 with one to 1.5 equivalents of hydrogen peroxide in a mixture of about 20% to about 50% of a mixture of trifluoroacetic acid in methylene chloride. The reaction proceeds at temperatures from about 10 ° C to about 50 ° C and usually requires from about 1 to about 2 hours to complete.

Then the leaving group ^R7 at the 3 position is displaced by the desired nucleophilic derivative of formula 13. Such nucleophilic derivatives are prepared by standard methods.

In this step of the process, the acidic proton of the nucleophilic group is removed by treatment with a base, preferably a small excess of sodium hydride or potassium tetrabutoxide in a polar aprotic solvent, preferably dimethylformamide or tetrahydrofuran. Other useful bases include potassium carbonate and cesium carbonate. In addition, other solvents such as dioxane or dimethyl sulfoxide may be used. Deprotonation typically occurs at temperatures between about 0 ° C and about 30 ° C and typically requires 30 min to complete. A compound of formula XIV is then added to the nucleophilic solution. The displacement reaction takes place at a temperature between 0 ° C and about 50 ° C and usually requires a period of from about 1 to about 2 hours. The product is separated by standard methods.

• ·

In a further step of the process, the sulfoxide 14 is reduced to the benzothiophene compound I.

If desired, the hydroxyl protecting group (s) of the products of the process shown in Reaction Scheme IV and the salts of the products of any step in the process can be removed.

Pro-drug ester compounds of formula I are prepared by substituting the hydroxyl residues at position 6 and / or 4'-position, if present, is the residue of formula -OCO _{(C l} -C _s alkyl), or -OSO ₂ (C ₂ -C _s alkyl) by well known methods. See, for example, U.S. Patent No. 4,358,593.

For example, if a -OCO (C ₁ -C ₆ alkyl) group is desired, the mono- or dihydroxy compound of formula (I) is reacted with a composition such as an acyl chloride, bromide, cyanide or azide or an appropriate anhydride or mixed anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline or in a tertiary amine such as triethylamine, tributylamine, methylpiperidine and the like. The reaction may also be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone and the like to which at least one equivalent of an acid scavenger (except as cited below) such as tertiary amine.

If desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used [see, for example, Haslam et al., Tetrahedron, 36, 2409-2433 (1980)].

·· ·· ► · ·

These reactions can be carried out at moderate temperatures ranging from about -25 ° C to about 100 ° C, often under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually suitable for the reaction.

The acylation of the hydroxyl group at the 6-position and / or the 4-position can also be carried out by reacting the corresponding carboxylic acid in an inert organic solvent catalyzed by an acid. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like are used.

The above-mentioned ester precursor compounds can also be obtained by preparing an active ester of the appropriate acid, such as an ester formed with known reagents such as cyclohexylcarbodiimide, 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 described methods provide -OCO (C _i -C _g alkyl) groups is carried out in solvents as discussed above. However, these processes, which do not produce an acid product during the reaction, do not require the use of an acid scavenger in the reaction mixture.

When it is desired formula I compound in which the hydroxyl group in position 6 or 4 'is converted to -OSO ₂ (C ₂ -C _g alkyl), allowed to react mono- or dihydroxy compound, for example, a sulfonic anhydride or a derivative of the appropriate sulfonic acid such as sulfonyl chloride, sulfonyl bromide, or sulfonylammonium salt as described by King and Monoir, J. Am. Chem. Soc., 97.

·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · ·

2566-2567 (1975). The dihydroxy compound may also be reacted with the appropriate sulfonic anhydride or mixed sulfonic anhydrides. Such reactions are carried out under the conditions described above in the discussion of acid halides and the like.

Preparation of pharmaceutically acceptable salts of the compounds of this invention

While the free base form of the compound of Formula I may be used in the medical methods of the invention, the preparation and use of a pharmaceutically acceptable salt form is preferred. The compounds used in the methods of the invention primarily form pharmaceutically acceptable acid addition salts with a wide range of organic and inorganic acids. These salts are also considered to be part of the invention.

The term pharmaceutically acceptable salts as used throughout this specification and the appended claims refers to salts of the types described in Berge et al., J. Pharmaceutical Science, 66, 1-19 (1977). Suitable pharmaceutically acceptable salts include those formed from typical inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, phosphoric acid, and the like, as well as salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfo acids. These 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, phenylbutyrate. hydroxybutyrate, butin-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malat, maleat, hydroxymaleat, malonate, mandelat, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propioate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulphate, sulphate, bisulphate, bisulphate benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylene sulfonate, tartrate and the like. Preferred salts are the hydrochloride and oxalate salts.

Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of Formula I with an equimolar amount or a slight molar excess of acid. The reactants are generally combined in a co-solvent such as diethyl ether or ethyl acetate. Salts normally precipitate out of solution within about 1 to 10 d and can be separated by filtration, or the solvent can be removed by conventional means.

Pharmaceutically acceptable salts generally have increased solubility compared to the compound from which they are derived and are therefore more suitable for liquid or emulsion formulations.

Pharmaceutical Products

The compound of the invention is administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal administration. The compound is preferably formulated prior to administration, as determined by the attending physician. Accordingly, another aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, which may optionally contain an effective amount of an estrogen or progestin and a pharmaceutically acceptable carrier, diluent or excipient.

The total active ingredients in these compositions are from 0.1 to 99.9% by weight of the composition. By pharmaceutically acceptable is meant a carrier, diluent, excipient and salt compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical composition of the invention is prepared by methods known in the art using well known and readily available ingredients. For example, a compound of formula I, alone or in combination with an estrogen or progestin, is mixed with conventional excipients, diluents or carriers and formulated as tablets, capsules, suspensions, solutions, injectables, aerosols, powders and the like. .

The total amount of active ingredients in these compositions is from 0.1 to 99.9% by weight of the composition. The term pharmaceutically acceptable means a carrier, diluent, excipient and salt compatible with the other ingredients of the composition and does not harm the recipient thereof.

- 27 • · 4

4 4 4 4 4 4 4 9 4 4 4 4 4 4 4 44 44 4 44 444 4 4 C 4 4 4 4 44 4 4

In particular, the compositions may be formulated for oral administration in solid or liquid form for parenteral injection, for topical or aerosol administration, or for rectal or vaginal administration by suppository.

The pharmaceutical compositions of this invention may be administered to humans and other mammals orally, rectally, intravaginally, parenterally, locally (using powders, ointments, creams or drops), buccally or sublingually, or as an oral or nasal spray. The term parenteral administration refers to administration routes including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous or intraarticular injection or infusion.

The pharmaceutical compositions of this invention for parenteral administration include sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions as well as sterile powders that dissolve immediately into sterile solutions or suspensions prior to use. Examples of suitable sterile aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, saline, ethanol, polyols [such as glycerol, propylene glycol, poles (ethylene glycol) and the like] and suitable mixtures thereof, vegetable oils (such as olive oil) and organic esters useful in injection, such as ethyloleate. Proper fluidity is ensured, for example, by the use of coating materials such as lecithin, by maintaining the correct particle size in the case of dispersions and suspensions, and by the use of surfactants.

Parenteral compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms is guaranteed by the use of antibacterial and anti-bacterial agents. fungal agents such as paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to use isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of injectables can be ensured by the introduction of devices which delay absorption such as aluminum monostearate and gelatin.

In some cases, to prolong the effect of a drug, it is desirable to slow the absorption of the drug after subcutaneous or intramuscular injection. This may be accomplished by using a liquid suspension or crystalline or amorphous material of low water solubility, or by dissolving or suspending the drug in an oil vehicle. In the case of subcutaneous or intramuscular injection, a suspension containing a low water solubility form of the drug depends on the rate of absorption of the drug.

Injectable depot preparations of a compound of the invention are prepared by forming microencapsulated drug matrices in biodegradable polymers such as polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, and polyorthoesters and polyanhydrides, materials which can be found in the art. Depending on the ratio of drug to polymer and the properties of the polymer used, the rate of drug release can be controlled.

The injectable compositions are sterilized, for example, by passing bacteria-retaining filters or by pre-sterilizing the ingredients of the mixture prior to mixing, either during preparation or just prior to preparation (as is the case in two compartments containing a syringe).

Solid dosage forms for oral administration include: - - - - - - - - - - - - - - - - 5 capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is admixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, glucose, mannitol and silicic acid, (b) with a binder such as carboxymethylcellulose, alginates, gelatin, poles (vinylpyrrolidone), sucrose and acacia gum; (c) moisture-retaining agents such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch , alginic acid, silicates and sodium carbonate; (e) delaying agent solutions such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) humectants such as cetyl alcohol and glycerol monostearate; (h) absorbents such as kaolin and diatomaceous earth; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid poles (ethylene glycols), laurels sodium ylsulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain buffers.

Solid formulations of a similar type may also contain a fill in soft or hard gelatin capsules using excipients such as lactose as well as high molecular weight poles (ethylene glycols) and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can also be prepared with coatings or coatings, such as enteric coatings or other coatings well known in the pharmaceutical art. The coatings may contain opacifying agents or agents releasing the active ingredient (s) in a given part of the gastrointestinal tract, such as acid-soluble coatings to release the active ingredient (s) in the stomach or alkaline-soluble coatings30.

dilutes to release the active ingredient (s) in the intestinal tract.

The active ingredient (s) may also be microencapsulated in a sustained release coating, wherein the microcapsules form part of the composition in a pill or capsule.

Liquid dosage forms for oral administration of a compound of the invention include solutions, emulsions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid compositions may contain inert diluents commonly used in the art such as water or other pharmaceutically acceptable solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,

1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, crushed nuts, corn, germ, olives, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyesters (ethylene glycols), sorbitol fatty acid esters and mixtures thereof.

In addition to inert solvents, liquid oral compositions may also contain adjuvant compositions such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The liquid suspension may contain, in addition to the active ingredient (s), suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite clay, agar and tragacanth, and mixtures thereof.

Compositions for rectal or intravaginal administration of the compositions of the invention. They are prepared by mixing one or more of the compounds of the invention with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or any suppository wax that is solid at room temperature but liquid at the human body temperature so that it melts in the rectum or vaginal cavity with the release of the active ingredient (s). The compounds are dissolved in the molten wax, formed into the desired shape and allowed to cure to the final suppository state.

The compound of the invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposome formulations are prepared as monolamellar or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any pharmaceutically acceptable and metabolizable lipid capable of forming liposomes can be used. The liposome formulation may additionally contain, in addition to one or more of the active ingredients of the present invention, stabilizing agents, excipients, preservatives and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic.

Methods for preparing liposomes are well known in the art, as described, for example, by Prescott, editors, Methods in Cell Biology, Vol. XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

The method of the invention

Benign prostatic hyperplasia

Fibromuscular stroma of the male accessory sex organs in several species is sensitive to the stimulatory effects of androgens and estrogens. This tissue is thought to play an important role in the initial development and further progression of benign prostatic hyperplasia. The target organ of estrogenic responses may be inhibited by certain non-steroidal antagonists, such as tamoxifen or clomifene, but the use of these agents in men may be limited by their feminizing effects related to their innate properties of estrogen agonists.

Pharmacological antagonism of estrogen action may be useful in the treatment of benign prostatic hyperplasia. Tamoxifen administered to human patients with benign prostatic hyperplasia is relatively ineffective in altering the relative distribution of prostatic glandular and stromal tissue, but these results may result from partial agonist activity of the compound with stimulation of prostatic fibromuscular stroma.

Prostate cancer

Recently, G. G. Kuiper et al., Proc. NAt'1. Acad. Sci. USA, 93. 5925-5930 (1996) described a gene sequence for a novel estrophil protein when cloning from rat prostate and ovarian tissue. This new estrophilic substance, called ERb, shares> 95% of the binding domain homology and about 55% of the ligand binding domain homology with the uterine estrogen receptor ER. ERb may be a basic receptor mediating estrogenic action in the prostate. Interestingly, ERb mRNA expression is demonstrated in the human prostate carcinoma cell line LNCaP in our laboratories. This observation that human prostate tumor cells express ERb indicates that the selective receptor-modulating compound of the invention is useful in the treatment and prevention of prostate cancer.

The selective estrogen receptor modulating compounds of the present invention have a relatively pure antagonistic profile with high estrogen receptor activity but lack the deleterious cardiovascular and feminizing effects of estrogen agonists. Administration of an effective amount of a compound of the invention is effective in the management or treatment of both hormone-sensitive benign and malignant urogenital neoplasias.

In the experiments described below, the ability of the compounds of the invention to bind to estrogen receptors in several prostate cancer cell lines was evaluated.

LNCaP, DU-45 and PC-3 human prostate cancer cell lysates are prepared in TEG medium containing 50 nM Tris.HCl, pH 7.4, 1.5 mM ethylenediaminetetraacetic acid (EDTA), 0.4 M KCl, 10% glycerol, 0.5 mM 2-ME and 10 mM sodium molybdate and further containing protease inhibitors pepstatin (1 mg / ml), leupeptin (2 mg / ml), aprotinin (5 mg / ml) and phenylmethylsulfonyl fluoride (PMSF, 0.1 mM) (TEGP).

Cell lysates are centrifuged and the pellets are resuspended in cold TEGP (1 ml TEGP / 100 mg pellets) and sonicated for 30 s (70% power cycle, output 1.8) on a Branson Model 450 sonication apparatus. Lysates are pelleted by centrifugation at 10,000 g for 15 min at 4 ° C after which the supernatants were collected and either used immediately or stored at -70 ° C.

Competitive Binding Analysis • · • ·

The binding buffer is TEG in which 0.4 M KCl is replaced with 50 mM NaCl and to which 1 mg / ml ovalbumin (TEGO) is further added. The selected compound of the invention is diluted to 20 nM in TEGO from which three-fold serial dilutions are prepared. Assays were performed on round bottom polypropylene microplates in triplicate microwells. 35 ml of tritiated 17b-estradiol (0.5 nM, specific activity 60.1 Ci / mmol, DuPont-New England Nuclear, Boston, MA) and 35 ml of cold competitive test substance (0.1 nM to 5) are placed in each well. mM) or TEGO followed by incubation for 5 min at 4 ° C with shaking, 70 ml of MCF-7 cell line lysate.

The plates are incubated for 24 h at 4 ° C and then 70 ml of dextran coated charcoal (DCC) is added to each well followed by vigorous shaking for 8 min at 4 ° C. Then the plates are centrifuged at 1500 g for 10 min at 4 ° C. Supernatant is collected from each well into a flexible polystyrene microplate for scintillation counting on a Wallac Micobeta Model 1450 computer. Radioactivity is expressed as counts per minute (DPM) after correction for detection efficiency (35-40%) and background. Additional controls are total counts and total counts + DCCs to define the lower limit of activity extractable with DCCs. The results of these competitive binding assays are expressed as mean bound percentages (percent binding) +/- standard deviation using the ^DPM formula.

DPM without testing. substances

D ^p M _CE ikova activity ^{+ D} <^"C _ ^ x 100 Total Activity ^{PM + DCC} • ·

In this study, LNCaP cell cultures demonstrate a high activity [i.e., a dissociation constant = 6.5 nM, a saturable (B = 160 fmol / mg) cell protein or about 37000 receptors per cell] of tritiated E ₂ binding.

The term "effective amount" as used herein means an amount of a compound of the invention that is capable of alleviating the symptoms of the conditions described herein. The specific dose of a compound administered according to the invention is determined by the particular conditions of the case, for example, the efficacy of the compound administered, the route of administration, the patient's condition and the pathological condition to be treated. A typical daily dose will contain a non-toxic dosage level of from about 5 mg to about 600 mg / d of a compound of the invention. Preferred daily doses will generally be from about 15 mg to about 80 mg / d.

The exact dose is determined in accordance with standard medical practice in the field of dose titration for a patient, i.e., starting with a low dose of the compound and gradually increasing until the desired therapeutic effect is achieved.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are given to further illustrate the preparation of a compound of the invention. The examples are not to be construed as limiting the scope of the invention as defined in the appended claims.

NMR data for the following examples are obtained on a GE 300 MHz NMR instrument and unless otherwise stated, dimethylsulfoxide with six deuterium atoms is used as the solvent.

Example 1

Preparation of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene oxalate salt

Step a

Preparation of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene

of thiophene (27.0 g, 100 mmol) in 1.10 L chloroform at 60 ° C was added dropwise bromine (15.98 g, 100 mmol) as a solution in 200 mL chloroform. After the addition was complete, the reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo to give 34.2 g (100%) of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene as white solids, m.p. 83-85 ° C.

¹ H NMR (DMSO-d _e) δ 7.70-7.72 (m, 4H), 7.17 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H).

FD mass spectrometry: 349, 350.

• ·

Calcd. For C ₁₆ H _{x 3} O ₂ SBr (%): C 55.03, H 3.75. Found% (%): C 54.79, H 3.76.

Step b

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 a nitrogen atmosphere was added 4-benzyloxyphenol (38, 96 g, 194.8 mmol) and copper (I) iodide (14.5 g, 97.4 mmol). The resulting mixture was refluxed for 48 h. On cooling to room temperature, the mixture was dissolved in acetone (200 mL) and the inorganic solids were removed by filtration. The filtrate was evaporated in vacuo and the residue was dissolved in methylene chloride (500 mL). The methylene chloride solution was washed with 3N hydrochloric acid solution (3 x 300 mL), followed by 1 N sodium hydroxide solution (3 x 300 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was taken up in 100 mL of ethyl acetate and the resulting white solid collected by filtration was [6-methoxy-2- (4-methoxyphenyl)] benzo [b] thiophene (4.62 g, 17.11 mmol). The filtrate was evaporated in vacuo and passed through a short pad of silica gel (with methylene chloride as eluent) to remove the starting material. The filtrate was evaporated in vacuo and the residue was crystallized from hexane / ethyl acetate to give 7.19 g of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene as off-white. crystalline solids. The mother liquor was evaporated and purified by silica gel chromatography (hexane / ethyl acetate 80:20) to give an additional 1.81 g of product. The overall yield of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene is 9.00 g (24% based on starting material). The basic extract was acidified to pH 4 with a 5N hydrochloric acid solution and the resulting precipitate was collected by filtration and dried to give 13.3 g of 4-benzyloxyphenol, mp 100-103 ° C.

H NMR (CDC1J : δ 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 (WITH, 3H).

FD mass spectrometry: 468.

The calculated amount for C _g H OS (%): 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

OCH.

To a solution of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyl39 oxy) phenoxy] benzo [b] thiophene (1.50 g, 3.20 mmol) in 50 mL ethyl acetate and 10 mL 1% of concentrated hydrochloric acid in ethanol was added 10% palladium on carbon (300 mg).

The mixture is hydrogenated at 40 psi for 20 min and then the reaction is complete as judged by thin layer chromatography. The mixture was passed through Celite to remove the catalyst and the filtrate evaporated in vacuo to a white solid. The crude product was passed through a pad of silica gel (with chloroform as eluent). Evaporation gave 1.10 g (91%) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene as a white solid, m.p. 123-126 ° C. .

^{Σ Η} NMR _(DMSO-d) δ 9.10 (s, 1 H), 7.59 (d, J = 8.8Hz, 2H), 7.52 (d, J = 2.1Hz, 1H), 7.14 (d, J = 8.8 Hz, 1 H), 6.95 (d, J = 8.8Hz, 2H) 6.89 (dd, J = 8.8, 2.1 Hz, 1H), 6.72 (d, J = 9.0Hz, 2H) 6.63 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H).

FD mass spectrometry: 378.

The calculated amount for ^C 22 ^H IE0 ₄ S (%): C 69.82, H 4.79. Found% (%): C 70.06, H 4.98.

Step d

Preparation of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene oxalate salt

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 cesium carbonate (3.86 g, 11.88 mmol) was added under nitrogen. After stirring for 10 min, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) was added. The resulting mixture was stirred for 18 h at ambient temperature. Separate between chloroform / water (100 ml of each of these solvents). The layers were separated and the aqueous layer was extracted with chloroform (3 x 50 mL). The organic layers were combined and washed with water (2 x 100 mL). Drying of the organic layer (sodium sulfate) and evaporation gave an oil which was chromatographed on silica gel (2% methanol / chloroform). The desired fractions were evaporated to an oil which was dissolved in 10 mL of ethyl acetate and treated with oxalic acid (311 mg, 3.4 mmol). After stirring for 10 min, a white precipitate formed, which was collected by filtration and dried to give 1.17 g (70%) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] - 2- (4-methoxyphenyl)] benzo [b] thiophene as the oxalate salt, m.p. 197-200 ° C (dec.).

¹ H NMR (DMSO-d) δ 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 (s, 3H), 3.32 (broad t, 2H), 3.12-3.06 (m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m,

2H).

FD mass spectrometry: 489.

H, 5.80; N, 2.46. Amount found (%):

C 64.92, H 5.77, N 2.54.

Example 2

Preparation of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride ··············································································· ·· «·» ·

Treatment of the oxalate salt of Example 1 with an aqueous base to give the free base followed by treatment with diethyl ether saturated with hydrochloric acid affords the title compound, m.p. 216-220 ° C.

¹H NMR _(DMSO-dg) δ (10.20 (br 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 (q, J = 9.0 AB Hz, 4H), 4.31 (m, 2H), 3.83 (with, 3H), , 3.ΊΊ (S, 3H) 3.43 (m, 4H), 2.97 (m, 2H), 1.77 (m, 5H), 1.37 (m, 1H)

FD mass spectrometry: 489.

Calculated for C _{2 g} amount of H _{3 R 4} NO S.1,0 HC1 (%): 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-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene · • d r r r r r r r r r r r r r r r r r r r r r r r r r r r ··

The title compound was prepared in the same manner as Example 1. The melting point was 95-98 ° C.

^{Χ Η} NMR (DMSO-d _e) δ 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).

FD mass spectrometry: 477.

Calculated mass for ^c 2e ^H 29 ^N 0 ₄ S (%): 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-hexamethylenimino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

9 9 9 9 9 9

9 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9

999 99 99 99 99

The title compound was prepared in the same manner as Example 1. Its melting point was 189-192 ° C.

^{Χ Η} NMR (DMSO-d ₆₎ δ 10.55 (br 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, Η), 6.86 (s, 4H), 3.94 (t, J = 6.0 Hz, 2H), 3.83 (s,

3H), 3.76 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H).

Calculated amount for C ₃₀ H ₃₃ NO ₄ S · 1.0 HCl (%) C 66.71, H 6.35, N 2.59. Found% (%): C 66.43, H 6.46, N 2.84.

Example 5

Preparation of [6-methoxy-3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride φ · φ · · · · ·· φ e ·· <

φ · · φ · · ·

The title compound was prepared in the same manner as Example 1. Its melting point was 196-198 ° C.

^X H NMR (DMSO-d _e) δ 10.48 {br s, 1H), 7.64 (d,

J = 9.0 Hz, 2H), 7.59 (d, J = 2.0Hz, 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 (q, J = 9.0 Hz, 4H), 4.25 (m, 2H), 3.83 (with, 3H), 3.77 (s, 3H), 3, 54 (m, 2H), 3.09 (m, 4H), 2.00 (m, 3H), 1.88 (m, 3H).

The calculated amount for C _2s H _3i S.1,5 NO ₄ 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 9 9 9 9

9 9 9 9 9 9 9

9 9 9 9 9 9 9

999 9 «99 99 9 · 999 · ·« V

9999 999 99 99 9999 99 'HCl, ¹ &apos; N-

H ₃ CO

OCH ·

The title compound was prepared in the same manner as Example 1. Its melting point was 208-211 ° C.

¹ H NMR (DMSO-d ₆₎ δ 10.6 (br 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 (q, J = 9.0 Hz (4H), 4.29 (m, 2H), 4,08-3,91 (m, 4H), 3.82 (with, 3H), 3.77 (s, 3H), 3.59-3.42 (m, 4H), 3.21 -3.10 (m, 2H).

Calculated amount for C ^ HH ^NO ^S. 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

[6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride (10.00 g, 19.05 mmol) was dissolved in 500 ml of anhydrous methylene chloride and cooled to 8 ° C. To this solution was added boron tribromide (7.20 mL, 76.20 mmol). The resulting mixture was stirred at 8 ° C for 2.5 h. The reaction was quenched by adding 1 L of saturated sodium bicarbonate solution to the stirred solution cooled to 0 ° C. The methylene chloride layer was removed and the remaining solids were dissolved in methanol / ethyl acetate. The aqueous layer was then extracted with 5% methanol / ethyl acetate (3 x 500 mL). All organic extracts (ethyl acetate and methylene chloride) were combined and dried over sodium sulfate. Evaporate in vacuo and brown solid is chromatographed (silica gel 1% to 7% methanol / chloroform) to give 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.

¹ H NMR (DMSO-d ₆ ) δ 9.73 (br s, 1H), 9.68 (br

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), 1.32 (m, 2H).

FD mass spectrometry: 462.

Calculated amount for C ^ HH ^NO ^S (%): C, 70.20,

H, 5.90; N, 3.03. Found% (%): C 69.96, H 5.90,

N, 3.14.

Example 8

Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene oxalate salt

HIM

OH

The title compound was prepared in 80% yield. And the yield was 80%. · · 9 9 ·

- 48 - ···· ........ * ·· ·· from free base. Its melting point is 246-249 ° C (with decomposition).

^{Χ Η} NMR (DMSO-dJ δ 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 1.01 (broad t, 2H), 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H).

FD mass spectrometry: 462.

H, 5.42; N, 2.64. Amount found (%):

C 64.61, H 5.55, N 2.62.

Example 9

Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

• ·

The title compound was prepared in 91% yield by treating the corresponding free base with diethyl ether saturated with hydrochloric acid. Its melting point is 158-165 ° C.

1 H NMR (DMSO-d 6) δ 9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 2) 0.1 Hz, 1H), 7.04 (d,

J = 8.6 Hz, 1H), 6.86 (q, J _{and ab} = 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, IH).

FD mass spectrometry: 461.

Calculated amount for C ^ HH ^NO ^S. 1.0 HCl (%):

C 65.11, H 5.67, N 2.81. Quantity found (%): C 64,84,

H, 5.64; N, 2.91.

Example 10

Preparation of [6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

HIM

OH ·· * and • * · and • · a *

0 0 0

0 0 ·

0 0 «

The title compound was prepared from the product of Example 3 in a manner similar to that used in Example 7 above. Its melting point is 99-113 ° C.

NMR (DMSO-d _e) δ 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 (s, 1H), 6.80 (dd, J = 9.0, 2.0 Hz,

1H), 6.79 (d, J = 9.0Hz, 2H), 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 ( t, J = 7.0 Hz, 4H).

Calculated quantity for C H NO S.0,5 H 0 (%):

26254 2

C 68.40, H 5.74, N 3.07. Quantity found (%): C 68,52,

H, 6.00; N, 3.34.

Example 11

Preparation of [6-hydroxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

OH «« · · · · 1 · · · t <<

• ·

The title compound was prepared from the product of Example 4 in a manner similar to that used in Example 7 above. Its melting point is 125-130 ° C.

¹ H NMR (DMSO-d 6) 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 7.09 (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).

Calculated quantity for ^c 2e ^H 23 ^N ° ₄ S (%): C 70.71,

H, 6.15; N, 2.94. Found% (%): C 70.67, H 6.31,

N, 2.93.

Example 12

Preparation of [6-hydroxy-3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

• · · · ·

About · · · · · · · · · · · ···

The title compound was prepared from the product of Example 5 in a manner similar to that used in Example 7 above. Its melting point is 137-141 ° C.

¹ H NMR (DMSO-d 6) δ 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 = 9.0Hz, 2H), 3.95 (t, J = 6.0Hz, 2H), 2.74 (t, J = 6.0Hz, 2H) 2.51 (m, 4H), 1.66 (m, 6H).

Calculated quantity for ^c 26 ^H 27 ^N 0 ₄ S (%): 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) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

HIM

OH

The title compound was prepared from the product of Example 6 in a manner similar to that used in Example 7 above. Its melting point is 157-162 ° C.

^X H NMR (DMSO-d _s) O 10.60 (br 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 (q, = 9.0 Hz, 4H) , 6.81 (dd, J = 9.0, 2,0 Hz, 1H) 6.80 (d, J = 9.0 Hz, 2H) , 4.30 (m, 2H) , 3.95 (m, 2H), 3 75 (m, 2H); 51 (m, 4H), 3, 18 (m, 2H).

Calcd for C, ^H HN .O množstvíSHCl (%): 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) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

OCH · 9 · 9 · 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9

9999 999 99

Step a

Preparation of 6-methoxybenzo [b] thiophene-2-boronic acid

H ₃ CO with ^A B- ^OH

Oh

To a solution of 6-methoxybenzo [b] thiophene (18.13 g, 0.111 mol) in 150 mL of anhydrous tetrahydrofuran at 60 ° C was added dropwise a syringe of n-butyllithium (76.2 mL, 0.122 mol, 1.6 M solution in hexane). After stirring for 30 min, triisopropyl borate (28.2 mL, 0.122 mol) was added via syringe. The resulting mixture was allowed to gradually warm to 0 ° C and then partitioned between 1N hydrochloric acid and ethyl acetate (300 mL each). The layers were separated and the organic layer was dried over sodium sulfate. Evaporation in vacuo gave a white solid which was treated with a mixture of ethyl ether and hexane. Filtration gave 16.4 g (71%) of 6-methoxybenzo [b] thiophene-2-boronic acid as a white solid, mp 200 ° C (dec.).

¹ H NMR (DMSO-d6) δ 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).

FD mass spectrometry: 208.

Step b ί · 9 · 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 • • 9 9 9 9 9 9 9

9999 999 99

Preparation of [6-methoxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene

OSO ₂ CH ₃

6-methoxybenzo [b] thiophene-2

To a solution of boronic acid (3.00 g, 14.4 mmol) in 100 mL of toluene was added 4- (methanesulfonyloxy) phenyl bromide (3.98 g, 15.8 mmol) followed by 16 mL of 2.0 N sodium carbonate solution. . After stirring for 10 min, tetrakistriphenylphosphine palladium (0.60 g,

0.52 mmol) and the resulting mixture was refluxed for 5 h. The reaction mixture was then allowed to cool to room temperature at which the product precipitated from the organic phase. The aqueous phase was removed and the organic layer was evaporated in vacuo to a solid. Trituration from ethyl ether gave a solid which was filtered off and evaporated in vacuo to give 3.70 g (77% of [6-methoxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene as a brown solid, mp 197 to 201 ° C.

1 H NMR (DMSO-d) δ 7.82-7.77 (m, 3H), 7.71 (d, J = o

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).

ΦΦ · ΦΦ ·· ΦΦ φ φφφ φ · φ φ φ · ·

9 Φ ·· Φ · 9 Φ

Φ · ΦΦΦ ·

ΦΦ ΦΦΦ ΦΦ ΦΦΦΦ ΦΦ

FD mass spectrometry: 334.

Calculated quantity for C 11 H 13 S 4 4.21. Found% (%): C = 57.76, (%): C 57.46, H 4.21.

Step c

Preparation of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene

OSO ₂ CH ₃

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 was added boron tribromide (14 mL). , 20 g, 5.36 mL, 56.8 mmol). The resulting mixture was stirred at ambient temperature for 3 h. The reaction was quenched by slow pouring into excess ice water. After vigorous stirring for 30 min, the white precipitate was collected by filtration, washed several times with water and then dried in vacuo to give 8.92 g (98%) of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene as a white solid, m.p. 239-243 ° C.

^X H NMR (DMSO-d _e) δ 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 = 0 · 0 · 0 · 000 000)

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).

FD mass spectrometry: 320.

Calculated quantity for ^C 15 ^H X 2 ° ₄ ^S 2 (%): 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

Cl ^^ axis ₂ ch ₃

To a solution of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (3.20 g, 10.0 mmol) in 75 mL of anhydrous dimethylformamide was added cesium carbonate (5.75 g, 17.7 mmol). ) followed by benzyl chloride (1.72 mL, 11.0 mmol). The resulting mixture was stirred vigorously for 24 h. The solvent was evaporated in vacuo and the solid residue was suspended in 200 mL of water. The white precipitate was collected by filtration and washed several times with water. After drying in vacuo, the crude product was suspended in hexane / ethyl ether 1: 1. The solid was 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.

¹ H NMR (DMSO-d _e) δ 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).

FD mass spectrometry: 410.

Step e

Preparation of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene

To a solution of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (12.50 g, 30.50 mmol) in 300 mL anhydrous tetrahydrofuran was added lithium aluminum hydride (2, 32 g (61.0 mmol) in small portions. The mixture was stirred at ambient temperature for 3 h and quenched by carefully pouring the mixture into an excess of cold 1.0 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic layer was then washed several times with water and dried (sodium sulfate) and evaporated in vacuo to give a solid. Chromatography (chloroform on sulfur) 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

9 9 · 99 g of lica gel) gives 8.75 g (87%) of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [ b] thiophene as a white solid, m.p. 212-216 ° C.

¹ H NMR (DMSO-d 6 δ 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).

FD mass spectrometry: 331.

Calculated quantity for C ₂₁ H ₁₆ OS (%): 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

Frfrfr frfr frfr frfr frfr frfr frfrfr frfr frfrfr frfrfr frfr frfrfr frfr frfr frfr frfr

To a solution of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [f] thiophene (8.50 g, 26.40 mmol) in 200 mL of anhydrous dimethylformamide was added sodium hydride in small portions at room temperature under nitrogen flow. (1.66 g, 41.5 mmol). When gas evolution ceased, iodomethane (3.25 mL, 52.18 mmol) was added dropwise. The reaction mixture was stirred for 3 h at ambient temperature. Then the solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed several times with water. The organic layer was dried over sodium sulfate and evaporated in vacuo to give 9.00 g (98%) of [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene as a white solid, mp 180-185 Deň: 32 ° C.

^X H NMR _(DMSO-d) δ 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).

FD mass spectrometry: 346.

Calculated quantity for ^c 22 ^H ie O ₂ S (%): 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

[6-Benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene (10.0 g, 28.9 mmol) was added to 200 mL of chloroform along with 10.0 g of solid sodium bicarbonate at ambient temperature. To this suspension was added bromine (1.50 mL, 29.1 mmol) dropwise over 30 min as a solution in 100 mL of chloroform.

Water (200 ml) was then added and the layers were separated. The organic phase was dried over sodium sulfate and evaporated in vacuo to a white solid. Crystallization from methylene chloride / methanol gave 10.50 g (85%) of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene as a white solid, m.p. 146-150 ° C. .

¹ H NMR (DMSO-d _e) δ 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 spectrometry: 346.

Calculated amount for C ^ H ^ O ^ SBr (%):

H, 4.03. Found% (%): C 61.87, H 4.00.

C 62.13,

44 · ·· ·· • 4 ·· • · ·· • 4 • 4 • • 4 • • • • • • • • • • • • • • • • 4 • 4 • • •• 4 • 44 · * ·· «< 44 ··

Step h

Preparation of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] -

The title compound was prepared by oxidizing the product of step g with 1.5 equivalents of hydrogen peroxide in a mixture of trifluoroacetic acid and methylene chloride. The product is isolated as a yellow solid by crystallization from ethyl acetate and its melting point is 202-205 ° C.

^T H NMR (DMSO-d _e) 5 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 mass spectrometry: 441.

Calculated quantity for C ₂₂ H _iv O ₃ SBr (%): C 59.87,

H, 3.88. Found% (%): C 59.59, H 3.78.

Step i

Preparation of [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] 63

-2-4- (methoxyphenyl)] benzo [b] thiophene (S-oxide)

Reaction of the product of step i) above with 4- (2-piperidinoethoxy) phenol in the base affords the title compound as a yellow oil.

^{Χ Η} NMR (DMSO-d _s) δ 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).

FD mass spectrometry: 592.

Calculated amount for C ^ HH ^N ^O ^S (%): C, 72.26,

H, 6.06; N, 2.41. Found% (%): C 72.19, H 5.99,

N, 2.11.

Step j

Preparation of [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

OCH,

Reduction of the product of step i) above provides the title compound isolated in a total yield of 95%. Purification on silica gel with 1 to 5% methanol / chloroform gave an off-white solid, m.p. 105-108 ° C.

¹ H NMR (DMSO-d 6) δ 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).

FD mass spectrometry: 565.

Calculated quantity for ^C 3 S ^H 3 S ^N ° ₄ ^{1 * * * S} (%): C 74.31,

H, 6.24; N, 2.48. Found% (%): C 74.35, H 6.07,

N, 2.76.

Step to

Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

OCH

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 Palladium black (1.50 g), ammonium formate (3.50 g, 55.6 mmol) and 30 mL of water were added to 300 mL of 5: 1 ethanol / ethyl acetate. The resulting mixture was refluxed and monitored by thin layer chromatography. After about 3 h, the reaction was deemed complete and the solution was cooled to ambient temperature. The mixture was filtered through a pad of Celite to separate the catalyst and the filtrate evaporated in vacuo to a solid. The concentrate was partitioned between saturated sodium bicarbonate solution and 5% ethanol / ethyl acetate. The layers were separated and the organic phase was dried over sodium sulfate and evaporated in vacuo. The crude product is purified by chromatography (1 to 5% methanol / chloroform on silica gel) to give 6.50 g (91%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] - 2- (4-methoxyphenyl)] benzo [b] thiophene in the form of a foam which is formed

converted to solid by trituration with hexane. Its melting point is 174-176 ° C.

¹H NMR (DMSO-d _e) δ 9.77 (s, 1H), 7.56 (d, J = 8); 8 Hz, 2H), 7.23 (d, J = 2.0Hz, 1H), 7.07 (d, J = 8.6Hz, 1H) / 6.93 (d, J = 8.8Hz, 2H) 6.81 (s, 4H), 6.76 (dd, J = 8) , 6, 2,0 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).

FD mass spectrometry: 475.

The calculated amount for C _2s H _{2 g} NO ₄ S (%): C 70.71, H 6.15, N 2.94. Found% (%): C 70.46, H 5.93, N 2.71.

Example 15

Preparation of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

OCH

The product of Example 14 was converted to the corresponding hydrobromide

rochloride in 85% yield by treatment with diethyl ether saturated with hydrogen chloride in ethyl acetate followed by crystallization from ethanol / ethyl acetate. Melting point: 156-160 ° C.

^{Χ Η} NMR _(DMSO-dg) δ 10.28 (br s, 1H), 9.85 (s,

1H), 7.56 (d, J = 8.8Hz, 2H), 7.25 (d, J = 2.0Hz, 1H),

7.06 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.87 (q, J _{and ab} = 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).

FD mass spectrometry: 475.

Calculated quantity for C ₂ H 2 _g NO ₄ S.1,0 HCl (%):

H, 5.90; N, 2.73. Quantity 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-hydroxyphenyl)] benzo [b] thiophene 9 9 9 9 9 9 99 9999 99 99

Step a

Preparation of [6-methoxy-2- (4-benzyloxyphenyl)] benzo [b] thiophene

Following the general methods of steps a) to g) of Example 14, the title compound was obtained in 73% yield and had a melting point of 217-221 ° C.

1 H NMR (DMSO-d 6 δ 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).

FD mass spectrometry: 346.

The calculated amount for ^C 22 ^H IE ° ₂ S (%): C 76.27, H 5.24. Found% (%): C 76.00, H 5.25.

Step b [6-Methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] thiophene

The title compound is obtained in a yield of 91% and has a melting point of 125-127 ° C.

1 H NMR (DMSO-d 6) δ 7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3.82 (s, 3H).

FD mass spectrometry: 346.

Calculated amount for C ^ H ^ C ^ SBr (%): C 62.13,

H, 4.03. Found% (%): C 62.33, H 3.93.

Step c [6-Methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide)

The title compound is isolated as a yellow solid by chromatography (chloroform on silica gel) and has a melting point of 119-123 ° C.

^{Χ Η} NMR (DMSO-dJ δ 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).

FD mass spectrometry: 441.

Calculated amount for C ^ HH ^O ^SBr (%): 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- (471 &lt; - &gt;)

-benzyloxyphenyl)] benzo [b] thiophene (S-oxide)

The title compound is obtained as a yellow solid, m.p. 89-93 ° C.

¹ H NMR (DMSO-d 6 δ 7.68 (d, J = 2.2 Hz, 1H), 7.62 J = 8.8 Hz, 2H), 7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H), 6 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 3.94 (broad t, J = 5 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).

FD mass spectrometry: 592.

Calculated amount for C H NO S.0,25 EtOAc (%)

5 3 5 5

C 71.62, H 6.18, N 2.32. Found% (%): C 71.32, H 5.96, N 2.71.

here (d,

Step e • [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

The title compound is obtained in a yield of 91% and has a melting point of 106-110 ° C.

1 H-NMR (DMSO-d 6) δ 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, 4 H).

FD mass spectrometry: 565.

The calculated amount for C _3s H ₃₅ NO ₄ S (%): 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-hydroxyphenyl)] benzo [b] thiophene 9 9 9 9 99 9

9 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9 · 99

9999 999 99

The title compound was obtained in 88% yield and had a melting point of 147-150 ° C.

¹ H NMR (DMSO-d 6 δ 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, 1 H),

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).

FD mass spectrometry: 475.

Calculated quantity for C H NO S (%): C 70,71,

H, 6.15; N, 2.94. Found% (%): C 71.00, H 6.17,

N, 2.94.

Example 17

2:

·· · ·

Preparation of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

The title compound was prepared in a manner analogous to that used in Example 15 to give the title compound, m.p. 215-217 ° C.

1H), ^l H NMR (DMSO-d _e) δ 10.28 (br s, 1H), 9.80 (s, 7.52 (d, J = 2.2Hz, 1H), 7.47 (d, J = 8.6Hz, 2H) 7.12 (D, J = 8.4Hz, 1H) 6.91-6.80 (m, 5H), 6.78 (d, J = • 8.6 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) ).

FD mass spectrometry: 475.

Calculated amount for C ₂ H 2 _g NO S.1,0 HCl (%):

H, 5.90; N, 2.73. Found% (%): C 65.87, H 5.79, N 2.99.

- 75 φ · · · • · · 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

Examples of resources

In the following compositions, the term active ingredient means a compound of formula (I) or a salt or solvate thereof.

Example of composition 1

Gelatin capsules

Component Amount (mg / capsule) Active ingredient 0.1 - 1000 Starch, NF 0 - 650 Starch, flowable powder 0 - 650 Liquid silicone, 3.5.10 ^-4 m ² s ^-1 (350 cSt) 0-15 Example of device 2 Tablets Component Quantity (mg / tablet) Active ingredient 2.5 - 1000 Microcrystalline cellulose 200 - 650 Fumed silica 10 - 650 Stearic acid 5-15

Device example 3 »···

9 9 9 9 9 ·

99,999 · 99 ··

Tablets

Component

Quantity (mg / tablet)

Active ingredient 25 - 1000

Starch 45

Microcrystalline cellulose 35

Polyvinylpyrrolidone 4 (as a 10% solution in water)

Carboxymethylcellulose sodium 4.5

Magnesium stearate 0,5

Talc 1

The active ingredient, starch and cellulose are passed through a 45 mesh U.S. sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders and then passed through a 14 mesh U.S. sieve and mixed thoroughly. The obtained granules are dried at 50-60 ° C and passed through a 18 mesh U.S. sieve. Carboxymethyl starch sodium, magnesium stearate and talc that have previously passed a 60 mesh U.S. sieve are added to the granules which are compressed after mixing on a tabletting machine to obtain tablets.

Example of device 4

Suspension

Ingredient Amount (mg / 5 ml)

Active ingredient

Carboxymethylcellulose sodium

0.1 - 1000 mg mg ·· «♦

Syrup 1.25 mg Benzoic acid solution 0,10 ml Flavor according to wish Dye according to wish Purified water to 5 ml

The drug is passed through a 45 mesh U.S. sieve and mixed with carboxymethylcellulose sodium and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a small amount of water and added with stirring. Sufficient water is then added to obtain the desired volume.

Example of device 5

Aerosol

Component Quantity (% by weight)

Active Ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00

The active ingredient is mixed with ethanol, and the mixture is added to a propellant portion 22 cooled to 30 ° C and transferred to a filling machine. The required amount is then filled into a stainless steel container and diluted with the remaining propellant. The valve unit is then connected to the vessel.

Example of composition 6

Suppositories • 9 · 99 99 9 9 9 9 9 9 9 9

9 9 · 9 9 * 9 * ····

9 9 9 9 9

- 78 - * 9 9 9 9 9 9 9 9 9999 999 99 Component Amount (mg / suppository) Active ingredient Glycerides saturated fatty acids 250 2000 The active ingredient is passed through a 0.25 mm (60 mesh U.S.) sieve and suspended in saturated fatty acid glycerides that have previously been melted using the minimum necessary heat. The mixture is then poured into a suppository mold having a nominal content of 2 g and allowed to cool. Example of device 7 Injectable preparations Component Amount Active ingredient Isotonic saline 50 mg 1000 ml

The solution of the ingredients enumerated above is administered intravenously to the patient at a rate of about 1 ml / min.

Claims (18)

PATENT CLAIMS Use of a compound of structure R ³ in which R ¹ and R ² are independently selected from the group consisting of hydroxy and alkoxy of 1 to 4 carbon atoms, and R ³ and R ⁴ are independently selected from methyl or ethyl or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or hexamethyleneimino ring or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient in need thereof. Use of a compound according to claim 1 having the structure in this claim, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of prostate cancer in a patient in need thereof. Use of a compound according to claim 1 having the structure in this claim, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia in a patient in need thereof. Use of a compound according to claim 1 having the structure in this claim, wherein both R ¹ and R ² are hydroxy, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient in need thereof. The use of a compound according to claim 2 having the structure set forth in claim 1, wherein both R ¹ and R ² are hydroxy, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient in need thereof. The use of a compound according to claim 3 of the structure set forth in claim 1, wherein both R ¹ and R ² are hydroxy, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient in need thereof. 7. Use of a compound according to claim 1 of the structure mentioned in this claim wherein R is a hydroxyl group and R is alkoxy of 1-4 carbon atoms, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a _patient, - that it needs. Use of a compound according to claim 2 of the structure as claimed in claim 1, wherein R ¹ is hydroxy and R ² is C 1 -C 4 alkoxy, for the manufacture of a medicament for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient needs. Use of a compound according to claim 3 of the structure as claimed in claim 1, wherein R ¹ is hydroxy and R ² is C 1 -C 4 alkoxy, for the manufacture of a medicament for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient needs. The use of a compound according to claim 1 of the structure, wherein said R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperidine ring, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in patient who needs it. Use of a compound according to claim 2 having a structure of> 34> as set forth in claim 1, wherein R and R 'together with the nitrogen atom to which they are attached form a piperidine ring, to produce * a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia or prostate cancer in a patient in need thereof. Use of a compound according to claim 3 of the structure as claimed in claim 1, wherein R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperidine ring, for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of benign prostatic hyperplasia or cancer prostate in a patient in need of it. Use of a compound of the structure wherein R ² is hydroxy or methoxy, or a pharmaceutically acceptable salt or prodrug, for the manufacture of a medicament for the treatment or prophylaxis of prostate cancer in a patient in need thereof. The use of a compound according to claim 13 having the structure in this claim which is 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt thereof , for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of prostate cancer in a patient in need thereof. The use of a compound according to claim 13 having the structure in this claim which is 6-hydroxy-2- (4-methoxy) phenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis of prostate cancer in a patient in need thereof. 16. Use of a compound of structure _# ³ R * in which R ² is hydroxy or methoxy, or a pharmaceutically acceptable salt or prodrug, for the manufacture of a medicament for treating benign prostatic hyperplasia in a patient in need thereof. Use of a compound according to claim 16 having the structure in this claim which is 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or a pharmaceutically acceptable salt thereof , for the manufacture of a medicament for treating benign prostatic hyperplasia in a patient in need thereof. The use of a compound according to claim 16 having the structure of 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] as claimed in this claim. benzo [b] thiophene or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating benign prostatic hyperplasia in a patient in need thereof.