KR20010006215A - Prevention of Breast Cancer with Selective Estrogen Receptor Modulators - Google Patents

Abstract

The present invention provides a method for preventing breast cancer in a patient, comprising administering a therapeutically effective amount of a compound of formula (I)

<Formula I>

Wherein R ¹ and R ² are independently hydroxy or alkoxy having 1 to 4 carbon atoms;

R ³ and R ⁴ are independently methyl or ethyl, or R ³ and R ⁴ together with the nitrogen atom to which they are attached, pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or hexamethylene To form an imino ring.

Description

Prevention of Breast Cancer with Selective Estrogen Receptor Modulators

Breast cancer is the most common form of cancer and the second most common cause of death in American women. In 1994 and 1995, it was estimated that 46,000 deaths out of an estimated 182,000 women with newly diagnosed breast cancer.

At present, it is estimated that most women have a 1/10 chance of developing the disease during their lifetime. Breast cancer is not only a major cause of death for women, but also a cause of physical disability, mental shock and economic loss. A large proportion of women with this disease are either directly or indirectly due to the effects of the disease due to complications, for example metastasis, loss of overall health, or in combination with treatment interventions such as surgery, radiotherapy or chemotherapy. Eventually you die.

The epidemiology of the disease is an intensive research topic, but little is known about it. Some patients appear to have a substantial genetic component that predisposes to the disease. However, it is not clear whether this genetic component is the cause or toleration of the disease or just to predict the course of the disease. For a long time breast cancer has been known to tend to occur more frequently in some families, but this analysis does not accurately predict disease outbreaks in other family members.

Many clinical and pharmacological studies have been conducted to elucidate the relationship between estrogen hormones and the causes, maintenance, and treatment of breast cancer. Although the relationship between estrogens in the maintenance and treatment of the disease is well known, the effects of estrogens on the epidemiology of the disease are related to whether the estrogens are the causative agent (carcinogen) or essential cofactor (tolerant) in the development of the disease. There is much debate.

Estrogens, including 17b-estradiol, estrone, and their active metabolites, are the major sex hormones in women, but also appear to be important homeostatic hormones in both men and women throughout the adult's lifetime. In general, everyone has some level of estrogen.

Male breast cancer is a rare disease that is considered less than 1% of all cancers in men. The American Cancer Society reported that in 1994, 1,000 men were diagnosed with breast cancer in the United States, of which 300 were estimated to have died.

Ductal carcinoma in situ (DCIS) is an early form of breast cancer in which malignant epithelial cells multiply in a linear relationship without microscopic evidence of invading the surrounding breast tissue through the basement membrane. The mean age of DCIS patients at diagnosis is about 52 years. Mammography is becoming more and more widely used, which results in faster detection of DCIS at screening mammography, since most cases are detected in women who otherwise had no subjective symptoms.

Hormone replacement therapy (HRT), which is recommended for alleviating cardiovascular disease, osteoporosis and other postmenopausal effects in postmenopausal women or postmenopausal women, has generated much controversy over the possibility that this therapy increases the risk of developing breast cancer. At present, conclusions from the HRT study, mostly post-observation studies, seem to indicate a slight increase in risk.

In contrast to the questionable role of estrogen in the development of this disease, much (albeit incomplete) knowledge has been gained to relate estrogen to confirmed breast cancer. Estrogen is a growth factor required in most breast cancer cells in the early stages of the disease. In addition, although the reasons are not completely known, it has been demonstrated that cancer cells lose their sensitivity to the effects of estrogen during the course of the disease. As a result, the majority of cancer cells are no longer dependent on estrogens for growth and no longer respond to any hormone-based therapies, including "antiestrogens", GNRH antagonists, progestins and androgens.

Many benefits are gained by using hormone-based therapeutic interventions. The most widely used therapy is the use of tamoxifen. The 5-year survival rate for women with breast cancer has improved dramatically when using this therapy; Long-term survival (more than 10 years) did not improve to the same extent. The long-term survival rate is not improved because the cancer cells gradually progress from estrogen-dependent to independent. Thus, even with the best combination of treatment modalities (surgery, radiotherapy and / or chemotherapy), long-term prognosis for the patient is poor, especially in the presence of metastatic disease. Clearly, there is an urgent need for improved therapies, and perhaps more importantly, firstly (de novo) a method of preventing disease.

It has been argued that in recent decades the use of "antiestrogen" therapies, especially tamoxifen, should be checked for the possibility of preventing de novo breast cancer. However, in part because there is no evidence of benefit and because of the known potential toxicity of tamoxifen, no future preventive trials have been performed on healthy women.

Clearly, there is an urgent need for useful breast cancer prevention methods for the entire human race, including individuals with many risks or no particular risks, including both men and women.

The present invention relates to a method of medical treatment. More specifically, the present invention relates to the use of a group of substituted benzo [b] thiophene compounds for preventing breast cancer in patients in need of prophylactic treatment of breast cancer.

<Summary of invention>

According to the present invention, there is provided a method for preventing breast cancer in a patient in need of prophylactic treatment of breast cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: do.

The present invention also relates to a method of preventing breast cancer by administering to a person having a sufficient time period an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof that has not been diagnosed as breast cancer but determined to be at risk of developing breast cancer. It is about.

In the compound structure shown above, R ¹ and R ² are independently selected from the group consisting of hydroxy and alkoxy having 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 are pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or To form a hexamethyleneimino ring.

Compounds of the invention are selective estrogen receptor modulators (SERM's), e.g. estrogen antagonism and / or minimal (i.e., clinical As non-sensitizing) compounds that cause agonistic action.

<Detailed description of the invention>

The present invention relates to the discovery that the compounds of formula (I) are useful for the prevention of breast cancer. The method provided by the present invention is carried out by administering to a patient in need of a breast cancer prophylactic treatment an amount effective to prevent breast cancer of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof.

Throughout this specification and the appended claims, general terms have common meanings.

The terms "prevention", "prevention" and "prevent" include reducing the likelihood that a patient will develop or develop breast cancer.

As used herein, the term “de novo” means that normal breast cells are not first transformed or modified into cancerous cells or malignant cells. Such modifications can occur through the evolutionary process in the same cell or daughter cell phase, or can occur in a single pivotal event. This de novo process is in contrast to the metastasis, colonization, or spread from an initial tumor location to a new location of already modified or malignant cells. The present invention also relates to administering a compound of formula (I) to a patient at risk of developing de novo breast cancer.

Those who do not have a particular risk of developing breast cancer may develop de novo breast cancer, but have no evidence or signs of disease potential beyond normal risk, and have not previously been diagnosed with the disease. The biggest risk factor contributing to the development of breast cancer is the initial onset of the disease, even if it has been alleviated without evidence of its individual history or its presence. Another risk factor is the family history of the disease.

The term "alkyl" is a monovalent radical with one hydrogen atom removed from methane, ethane or straight or branched chain hydrocarbons, methyl, ethyl, propyl, iso-propyl, n-butyl, secondary-butyl, iso-butyl, tertiary -Groups such as butyl.

"Alkoxy" means an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom and includes methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, secondary-butoxy, iso- Groups such as butoxy, tert-butoxy, and the like. Preferred alkoxy groups in the present invention are methoxy.

As used herein, the term “prodrug” is a compound of the invention comprising a group that is metabolically removed in the human body to form a compound of the invention that is therapeutically active. In particular, such prodrug compounds are hydroxyl groups in which one or both of the R ¹ and R ² substituents in the formulas shown above are protected with a pharmaceutically acceptable hydroxy protecting group such that they are metabolized in the body to correspond to the corresponding It is a compound which becomes a monohydroxy or a dihydroxy compound. Hydroxy protecting groups are described in chapter 2 of TW Greene et al., "Protective Groups in Organic Synthesis," 2nd edition, John Wiley & Sons, Inc., New York, 1991. Simple ether groups and ester groups are preferred as prodrug hydroxy protecting groups.

Preferred compounds of the invention are 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or pharmaceutically acceptable Salts or prodrugs thereof and 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or pharmaceutically acceptable Salts or prodrugs thereof.

<Preparation of the compound of the present invention>

Starting materials for one route for preparing the compounds of the present invention are prepared essentially as described in US Pat. Nos. 4,418,068 and 4,133,814 to C.D. Jones. The starting material is a compound of formula

Wherein R ⁵ and R ⁶ are independently —H or a hydroxy protecting group.

R ⁵ and R ⁶ hydroxy protecting groups are residues that are intentionally introduced during some synthetic procedures and then removed at the end of the synthesis to protect groups that may otherwise react during chemical manipulation. Since compounds with such protecting groups are inherently important as chemical intermediates (although some derivatives also exhibit biological activity), their precise structure is not critical. Numerous reactions for the formation, removal and modification of such protecting groups are described, for example, in Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973; Green, T. Double Oil, Protective Groups in Organic Synthesis, Wiley). (New York, 1981) and in many standards, including The Peptides, Volume I, Schrooder and Lubke, Academic Press, (London and New York, 1965).

Representative hydroxy protecting groups are, for example, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkoxy, -CO- (C ₁ -C ₆ alkyl), -SO _2- (C ₄ -C ₆ alkyl) and -CO-Ar, wherein Ar is benzyl or optionally substituted phenyl. The term “substituted phenyl” denotes a phenyl group having one or more substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, nitro, halo and tri (chloro or fluoro) methyl. The term "halo" is bromo, chloro, fluoro and iodo.

In the compounds of formula 1, preferred R ⁵ and R ⁶ substituents are methyl, isopropyl, benzyl and methoxymethyl. Compounds in which R ⁵ and R ⁶ are each methyl are prepared via the procedure described in the Jones patent referenced above.

A compound of Formula 1 is also prepared that selectively removes the R ⁵ hydroxy protecting group while leaving R ⁶ as a hydroxy protecting group as part of the final product. The same applies to the selective removal of the R ⁶ hydroxy protecting group while leaving the R ⁵ hydroxy protecting group intact. For example, R ⁵ may be isopropyl or benzyl and R ⁶ may be methyl. Isopropyl or benzyl residues can be selectively removed through standard procedures, with the R ⁶ methyl protecting group remaining as part of the final product.

As shown in Scheme I, the first step of the process for the preparation of some compounds of the present invention is by selectively placing a leaving group R ⁷ at position 3 of the compound of formula 1 to form a compound of formula 2, Combining the product of the reaction with 4- (protected-hydroxy) phenol (3) to form a compound of formula 4, optionally removing the R ⁸ hydroxy protecting group to form a compound of formula 5. In the sequence of steps shown in Scheme I, the hydroxy protecting groups R ⁵ , R ⁶ and R ⁸ are selected in such a way that the hydroxy protecting groups R ⁸ can be selectively removed in the presence of the hydroxy protecting groups R ⁵ and R ^{6 in} the final step. do.

In the first step of Scheme I, the appropriate leaving group is optionally placed in the 3-position of the starting material of Formula 1 via standard procedures. Suitable R ⁷ leaving groups are methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfo Sulfonates such as nates, triflate and the like; Halogen, such as bromo, chloro and iodo; And other related leaving groups. However, in order to ensure proper placement of leaving groups, the aforementioned halogens are preferred, and bromo is particularly preferred.

The present invention is carried out using standard procedures. For example, if a preferred halogenating agent is used, such halogenating agent, preferably 1 equivalent of bromine, is reacted with 1 equivalent of the substrate of formula 1 in a suitable solvent such as, for example, chloroform or acetic acid. The reaction typically proceeds at a temperature of about 40 ° C to about 80 ° C.

The compound of formula (2), which is the reaction product of the reaction step, is then reacted with 4- (protected-hydroxy) phenol (3) to yield a compound of formula (4, wherein R ⁸ is a selectively removable hydroxy protecting group) To form. In general, the 4-hydroxy protecting moiety of the phenol in this case, R ^5, when present, and without removing the R ⁶ moieties of the compound of formula 3 can be selectively date any known protection that can be removed. Preferred R ⁸ protecting groups include methoxymethyl (in which case R ⁵ and / or R ⁶ are not methoxymethyl) and benzyl. Of course, benzyl is most preferred. 4- (protected-hydroxy) phenol reactants are commercially available or can be prepared via standard procedures.

The binding reaction between the compound of Formula 2 and the compound of Formula 3 is known in the art as the Ullman reaction and generally proceeds according to standard procedures (see, eg, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, "4th edition, 3-16 (J. March, published by John Wiley & Sons, Inc. 1992); Jones, C. D., J. Chem. Soc. Perk. Trans. I, 4: 407 (1992).

In general, the same amount of two aryl substrates are heated to reflux under an inert atmosphere in the presence of up to equimolar amounts of copper oxide (I) catalyst and a suitable solvent. Preferably, one equivalent of compound of formula 2 wherein R ⁷ is bromo is reacted with the same amount of 4-benzyloxyphenol in the presence of one equivalent of cuprous oxide.

Suitable solvents for this reaction are solvents or mixtures of solvents that remain inert during the entire reaction. Typically, organic bases, particularly hindered bases such as, for example, 2,4,6-collidine, are preferred solvents.

The temperature used in this step is generally sufficient to complete the coupling reaction and will affect the time required. When the reaction mixture is heated to reflux under an inert atmosphere such as nitrogen, the time to completion is usually about 20 to about 60 hours.

A compound of Formula 5 is prepared by combining a compound of Formula 2 with a compound of Formula 3 to form a compound of Formula 4, followed by selective removal of the R ⁸ hydroxy protecting group of the compound of Formula 4 through well-known reduction procedures. . If the procedure chosen is present with R ⁵ , it is essential not to harm the R ⁶ hydroxy protecting group.

If R ⁸ is the preferred benzyl moiety and R ⁵ and, if present, R ⁶ are each methyl, this reaction step is carried out via standard hydrocracking procedures. Typically, the substrate of Formula 4 is added to a suitable solvent or mixture of solvents, followed by a proton donor and an appropriate hydrogenation catalyst to promote the reaction.

Suitable catalysts include noble metals and oxides such as palladium, platinum and rhodium oxide on supports such as carbon or calcium carbonate. Of course, palladium on carbon, in particular 10% palladium on carbon, is preferred. The solvent for this reaction is a solvent or mixture of solvents that remains inert during the entire reaction. Typically, ethyl acetate and C ₁ -C ₄ aliphatic alcohols, in particular ethanol, are preferred. For this reaction, hydrochloric acid acts as an appropriate and preferred proton donor.

The reaction proceeds very quickly when performed at ambient temperature and pressures ranging from about 30 psi (206.8 kPa) to about 50 psi (344.7 kPa). The reaction process can be monitored by standard chromatography techniques such as thin layer chromatography.

As shown in Scheme II, when a compound of Formula 5 is prepared, it is reacted with a compound of Formula 6 to form a compound of Formula 7. The compound of formula 7 is then deprotected to form a compound of formula I.

Wherein R ⁴ and R ⁵ are as defined above and Q is bromo or preferably chloro.

In the first step of the process shown in Scheme II, the reaction is carried out according to standard methods. Compounds of formula (6) are commercially available or prepared by methods known to those of ordinary skill in the art. Preference is given to using hydrochlorides of the compounds of formula (6). In a particularly preferred embodiment of the compounds of the invention, 2-chloroethylpiperidine hydrochloride is used.

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

Suitable solvents for this reaction are solvents or mixtures of solvents that remain inert during the entire reaction. Preference is given to N, N-dimethylformamide, in particular its anhydride form. The temperature used in this step should be sufficient to complete the alkylation reaction. Typically, the ambient temperature is sufficient and preferred. The reaction is carried out under air, in particular nitrogen.

Under preferred reaction conditions, this reaction will be completed in about 16 to about 20 hours. The progress of the reaction can be monitored through standard chromatography techniques.

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

Wherein Q and Q 'are the same or different leaving groups. Suitable leaving groups are those mentioned above.

Preferred alkaline solutions for this alkylation reaction contain potassium carbonate in an inert solvent such as, for example, methylethyl ketone (MEK) or DMF. In this solution, the unprotected hydroxy group of the compound of formula 5 is converted to phenoxide ions, which substitutes one of the leaving groups of the alkylating agent.

This reaction is best performed when the alkali solution containing the reactants and reactants is refluxed and allowed to proceed until completion. When using MEK as the preferred solvent, the reaction time ranges from about 6 hours to about 20 hours.

The compound of formula 9, the reaction product of this step, is then subjected to standard techniques via 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, A compound of Formula 7 is formed by reacting with a compound of Formula 10 selected from dimethylamine, diethylamine, diisopropylamine or 1-hexamethyleneimine. Preferably, the hydrochloride of the compound of formula 10 is used together with the particularly preferred piperidine hydrochloride. This reaction is typically carried out using an alkylated compound of formula 9 in an inert solvent such as anhydrous DMF and heated to a temperature in the range of about 60 ° C to about 110 ° C. When the mixture is heated to the desired temperature of about 90 ° C., the reaction only takes about 30 minutes to about 1 hour. However, changing the reaction conditions will affect the time required for this reaction to complete. The progress of this reaction step can be monitored by standard chromatography techniques.

Some preferred compounds of formula I are obtained by division by a known method the R ⁶ hydroxy protecting group, if present, and R ⁵ of the compound of formula (I). Numerous reactions for the formation and removal of such protecting groups are described, for example, in Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Green, Protective Groups in Organic Synthesis, Wiley (New York, 1981); And The Peptides, Volume I, Schroeder and Rubke, Academic Press (London and New York, 1965). Preferred methods for removing R ⁷ and / or R ⁸ hydroxy protecting groups, especially methyl and methoxymethyl, are essentially as described in the examples below.

Preferred alternatives for preparing the compounds of the present invention are shown in Scheme IV below. In the method presented here, the sulfur atom of the compound of formula 2 is oxidized to form the sulfoxide of formula 12 and then reacted with a nucleophilic group to introduce the oxygen atom linking group of the compound of formula I. The sulfoxide moiety of the compound of formula 12 is then reduced to provide some compounds of the present invention.

In the first step of the process, the compound of formula 2 is selectively oxidized to the sulfoxide of formula 12. Many known methods can be used for this process step (see, eg, Medesclaire, M., Tetrahedron, 42 (20); 5459-5495 (1986); Lost, BM, etc.). Tetrahedron Letters, 22 (14); 1287-1290 (1981); Drabowicz, J. et al., Synthetic Communications, 11 (12); 1025-1030 (1981); Kramer, JB et al. , 34th National Organic Symposium, Williamsburg, VA., June 11-15, 1995). However, many oxidants are not only poor at converting to the desired product, but also oxidize significant amounts to sulfone. However, a preferred process converts the compound of formula 2 to the sulfoxide of formula 12 in high yield with little or no sulfone formation. The method comprises reacting 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 of about 10 ° C. to about 50 ° C., and usually about 1 to about 2 hours is required for the reaction to complete.

The 3-position leaving group R ⁷ is then substituted with the desired nucleophilic derivative of formula 13. Such nucleophilic derivatives are prepared through standard methods.

In this reaction step, the acidic protons of the nucleophilic group are removed by treatment with a base, preferably slightly excess sodium hydride or potassium tert-butoxide, in a polar aprotic solvent, preferably DMF or tetrahydrofuran. Other bases that may be used include potassium carbonate and cesium carbonate. In addition, other solvents such as dioxane or dimethylsulfoxide may be used. Proton ablation is usually performed at a temperature of about 0 ° C. to about 30 ° C. and usually takes about 30 minutes to complete. The compound of formula XIV is then added to the solution of nucleophiles. The substitution reaction is carried out at 0 to about 50 ° C. and usually proceeds in about 1 to about 2 hours. The product is isolated by standard methods.

In the next step of the process, the sulfoxide of formula 14 is reduced to the benzothiophene compound of formula I.

If desired, the salt of the product of any step of the method and the hydroxy protecting group (s) of the product of the method shown in Scheme IV can be removed.

The prodrug ester compounds of formula (I), if present, may be prepared by formulating 6- and / or 4'-position hydroxy moieties by known methods to formula -OCO (C ₁ -C ₆ alkyl) or -OSO ₂ (C ₂ -C ₆ alkyl) residues. See, for example, US Pat. No. 4,358,593.

For example, if a -OCO (C ₁ -C ₆ alkyl) group is desired, the monohydroxy or dihydroxy compound of formula (I) may be reacted with a reagent such as acyl chloride, bromide, cyanide or azide, or a suitable anhydride or mixed anhydride React with This reaction is conveniently carried out in basic solvents such as pyridine, lutidine, quinoline or isoquinoline or tertiary amine solvents such as triethylamine, tributylamine and methylpiperidine. The reaction is also carried out with addition of at least one equivalent of an acid scavenger (except as noted below), such as tertiary amines, ethyl acetate, dimethylformamide, dimethyl sulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl It may also be carried out in an inert solvent such as ethyl ketone. If desired, an acylation catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine can be used. See, eg, Haslam et al., Tetrahedron, 36: 2409-2433 (1980).

These reactions are often performed under inert atmosphere, such as nitrogen gas, at moderate temperatures ranging from about -25 to about 100 ° C. However, the ambient temperature is usually adequate to proceed with this reaction.

Acylation of 6-position and / or 4'-position hydroxy groups can also be carried out by acid catalyzed reaction of the appropriate carboxylic acid in an inert organic solvent. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like are used.

The ester prodrug compounds mentioned above are also known to known reagents such as dicyclohexylcarbodiimide, acylimidazole, nitrophenol, pentachlorophenol, N-hydroxysuccinimide and 1-hydroxybenzotriazole. It may also be provided by forming an active ester of a suitable acid, such as an ester formed by See, eg, Bull. Chem. Soc. Japan, 38: 1979 (1965) and Chem. Ber., 788 and 2024 (1970).

Each of these techniques to provide -OCO (C ₁ -C ₆ alkyl) residues is carried out in the solvents discussed above. Of course, techniques that do not produce acid products during the reaction do not require the use of acid removers in the reaction mixture.

Compounds of formula (I) in which the hydroxy groups at the 6- and / or 4'-positions of the compounds of formula (I) are converted to the formula -OSO ₂ (C ₂ -C ₆ alkyl) groups are described by King and Mono (Monoir), J. Am. Chem. Soc., 97: 2566-2567 (1975), monohydroxy or dihydroxy compounds may be used, for example, sulfonic anhydrides or derivatives of suitable sulfonic acids such as sulfonyl chloride, bromide or sulfonyl ammonium salts. React with The dihydroxy compound can also be reacted with a suitable sulfonic anhydride or mixed sulfonic anhydride. This reaction is carried out under the conditions described in the discussion of reactions with acid halides above.

<Preparation of a pharmaceutically acceptable salt of the compound of the present invention>

Although the free base form of the compound of formula (I) can be used in the pharmaceutical treatment methods of the present invention, it is preferred to prepare and use pharmaceutically acceptable salt forms. The compounds used in the process of the present invention mainly form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids. Such salts are also contemplated as being within the scope of this invention.

As used throughout this specification and the appended claims, the term “pharmaceutically acceptable salts” is in the form disclosed in Berge et al., J. Pharmaceutical Sciences, 66 (1): 1-19 (1977). Means salt. Suitable pharmaceutically acceptable salts are aliphatic monocarboxylic and dicarboxylic acids, phenyl substituted alkanes, as well as salts formed with conventional inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid, and the like. Salts derived from organic acids such as acids, hydroxyalkanoic acids and hydroxyalkanedic 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, methyl Benzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexin-1,4-dioate, cap Latex, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hiprate, lactate, maleate, maleate, hydroxymaleate, malonate, mandelate, Mesylate, nicotinate, isicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, hydrogen Phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suverate, sulfate, bisulfate, pyrosulfate, sulf Fight, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene- 2-sulfonate, p-toluene-sulfonate, xylenesulfonate, tratarate and the like. Hydrochloride and oxalate are preferred salts.

Pharmaceutically acceptable acid addition salts are usually formed by reacting a compound of formula (I) with an equimolar or slightly excess molar acid. The reaction is generally mixed in a mutual solvent such as diethyl ether or ethyl acetate. Salts usually precipitate in solution within about 1 hour to 10 days and can be separated by filtration or the solvent can be removed by conventional means.

Pharmaceutically acceptable salts generally have improved solubility compared to the compounds from which they are derived, and therefore are often easy to formulate as solutions or emulsions.

<Pharmaceutical formulation>

Compounds of the invention are administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are preferably formulated prior to administration, the choice of which will be determined by the attending physician. Accordingly, another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient, optionally containing an effective amount of estrogen or progestin. will be.

The total amount of active ingredient in such formulations forms from 0.1 to 99.9% by weight of the formulation. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient and salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

Pharmaceutical formulations of the present invention are prepared by methods known in the art using readily available known ingredients. For example, a compound of Formula (I), alone or in combination with an estrogen or progestin compound, may be formulated with conventional excipients, diluents, or carriers to form tablets, capsules, suspensions, solutions, injections, aerosols, powders, and the like. do.

The total amount of active ingredient in such formulations forms from 0.1 to 99.9% by weight of the formulation. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient and salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

The formulations may be formulated in suppositories, in particular in solid or liquid form for oral administration, for parenteral injection, external or aerosol administration, or for rectal or vaginal administration.

The pharmaceutical compositions of the present invention can be administered orally, rectally, intravaginally, parenterally, externally, topically (as powders, ointments, creams or drops), orally or sublingually, or orally or intranasally, to humans and other mammals. Can be administered. As used herein, the term “parenteral administration” refers to a mode of administration that includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous or intraarticular injection or infusion.

Pharmaceutical compositions for parenteral administration of the present invention include sterile aqueous solutions or non-aqueous solutions, dispersants, suspensions or emulsions, as well as sterile powders which are reconstituted with sterile solutions or suspensions immediately before use. Examples of suitable sterile aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, physiological saline solutions, ethanol, polyols (e.g. glycerol, propylene glycol, poly (ethylene glycol), etc.) and suitable mixtures thereof, edible oil ( Injectable organic esters such as, for example, olive oil) and ethyl oleate. Proper fluidity is maintained, for example, by using coating materials such as lecithin, by maintaining appropriate particle sizes in the case of dispersants and suspending agents and by using surfactants.

Parenteral compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like are included to prevent the action of microorganisms. It may be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Inclusion of agents that delay absorption, such as aluminum monostearate and gelatin, can result in delayed absorption of the injectable formulation.

In some cases, to delay drug effects, it is desirable to slow drug absorption after subcutaneous or intramuscular injection. This can be accomplished by using liquid suspensions, crystalline or amorphous materials with low water solubility, or by dissolving or suspending the drug in an oil vehicle. In the case of subcutaneous or intramuscular injection of suspensions containing drug forms with low water solubility, the rate of absorption of the drug depends on its rate of dissolution.

Injectable "depot" formulations of the compounds of the present invention include poly (lactic acid), poly (glycolic acid), copolymers of lactic acid and glycolic acid, poly (orthoesters) and poly ( Anhydrous) to form a microencapsulated matrix of the drug in a biodegradable polymer. Depending on the ratio of drug to polymer and the nature of the specific polymer used, the rate of drug release can be controlled.

Injectable preparations are sterilized (such as in the example of a double chamber syringe package), for example by filtration with a bacterial filter or by pre-sterilizing and then mixing the components of the mixture at the time of preparation or immediately before administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. For solid dosage forms, the active ingredient may be selected from one or more pharmaceutically acceptable inert carriers such as sodium citrate or dicalcium phosphate and / or (a) fillers or swelling agents such as starch, lactose, glucose, mannitol and silicic acid, ( b) binders such as carboxymethylcellulose, alginate, gelatin, poly (vinylpyrrolidine), sucrose and acacia, (c) humectants such as glycerol, (d) agar-agar, calcium carbonate, potatoes or Disintegrants such as tapioca starch, alginic acid, silicate and sodium carbonate, (e) solution retardants such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerin monostearate (h) adsorbents such as kaolin and bentonite clay, and (i) talc, calcium stearate, magnesium stearate, solid poly (ethylene glycol), sodium lauryl sulfate and Of mixed with the bow takje such as a mixture. For capsules, tablets and pills, the dosage form may contain a buffer.

Solid compositions of a similar type may also include fillers in soft or hard gelatin capsules using excipients such as lactose as well as high molecular weight poly (ethylene glycol) and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules may also be prepared using coatings or shells such as enteric coatings or other coatings known in the pharmaceutical art. The coating may be used to release the active ingredient (s) at a specific site of the digestive tract, such as, for example, an acid soluble coating to release the active ingredient (s) in the stomach or a base soluble coating for releasing the active ingredient (s) in the intestine. It may contain an opacifying agent.

The active ingredient (s) can also be microencapsulated with a sustained release coating using microcapsules made as part of the filler of the capsule formulation.

Liquid dosage forms for oral administration of a compound of this invention include solutions, emulsions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid preparations may be prepared by inert diluents commonly used in the art, such as water or other pharmaceutically acceptable solvents, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, perme oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, poly (ethylene glycol), sorbitol Solubilizers and emulsifiers such as fatty acid esters and mixtures thereof.

In addition to inert diluents, liquid oral formulations may also include auxiliaries such as wetting agents, emulsifying and dispersing agents and sweetening, flavoring and fragrances.

Liquid suspending agents, in addition to the active ingredient (s), such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta hydroxide, bentonite clay, agar-agar, tragacanth and mixtures thereof It may contain a suspending agent.

Compositions for rectal or vaginal administration are those such as cocoa butter, polyethylene glycol or any suppository waxes that cause one or more compounds of the invention to be solid at room temperature but liquid at body temperature to melt in the rectum or vagina to release the active ingredient (s). Prepared by mixing with a suitable non-irritating excipient. The compounds are dissolved in molten wax to be shaped into the desired shape and cured into the final suppository formulation.

Compounds of the invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipids. Liposomal formulations are formed by mono- or multi-layer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, metabolic lipid that is pharmaceutically acceptable that can form reformosomes can be used. Compositions of the present invention in liposome form may contain, in addition to one or more active compounds of the present invention, stabilizers, excipients, preservatives, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl choline (ricetin).

Methods of forming liposomes are described in the art, for example, as described in Prescott, Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 and below. Known in

<Method of the present invention>

Carcinogenicity N-nitroso-N-methylurea to induce carcinoma in rats is a recognized animal model for breast cancer research and has been found to be suitable for analyzing the effects of chemoprophylactic agents.

In two separate studies, 55-day-old female Sprague-Dawley rats were treated with varying amounts of a) 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinyl Ethoxy) phenoxy] benzo [b] thiophene hydrochloride, b) (Z) -2- [4- (1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethylethanamine base (Tamoxifen base) or c) a dose of 50 mg / kg body weight of N-nitroso-N-methylurea intravenously (study 1) or intraperitoneally (study) a week prior to providing free access to the diet containing the control. 2). Controls included vehicles used in combination with the active compound.

In Study 1, the dietary dose of 60 mg / kg feed and 20 mg / kg was interpreted as a rough comparative dose of 3 and 1 mg / kg body weight for test animals.

In Study 2, the dietary amounts of 20, 6, 2 and 0.6 mg / kg feed are interpreted as the rough comparative doses of 1, 0.3, 0.1 and 0.03 mg / kg body weight for the test animals.

Rats were observed for evidence of toxicity and weighed and promoted tumor formation once a week. After 13 weeks (study 1) or 18 weeks (study 2) animals were sacrificed and necropsied to identify and weigh tumors. The results of these studies are shown in Table 1 (Study 1) and Table 2 (Study 2).

Female Sprague by Administration of 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinylethoxy) phenoxy] benzo [b] thiophene hydrochloride (Example 15) -Cancer prevention of Dawley rats process Non-Tumor Rats Average number of tumors per rat Average amount of tumors per rat (gm) Reference substance 3/24 (12%) 3.0 11.0 60 mg of compound of Example 15 / kg feed 11/12 (92%) 0.08 0.05 20 mg of the compound of Example 15 / kg feed 11/12 (92%) 0.08 0.03

By administration of 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinylethoxy) phenoxy] benzo [b] thiophene hydrochloride (Example 15) or tamoxifen base Cancer Prevention in Female Sprague-Dawley Rats process Non-Tumor Rats Average number of tumors per rat Average amount of tumors per rat (gm) Reference substance 6/23 (26%) 1.8 9.0 20 mg of the compound of Example 15 / kg feed 11/12 (92%) 0.08 0.43 6 mg of compound of Example 15 / kg feed 7/12 (58%) 0.50 1.50 2 mg compound / kg feed of Example 15 8/12 (67%) 0.50 3.40 0.6 mg of the compound / kg feed of Example 15 6/12 (50%) 0.75 1.60 2 mg tamoxifen base / kg feed 7/11 (64%) 0.33 0.52 0.6 mg tamoxifen base / kg feed 7/12 (58%) 0.983 2.10

The data in Table 1 showed that tumor administration (87%), the average number of tumors per rat (97%) and the average amount of tumors per rat (99%) were compared to the control when the compound of Example 15 of the present invention was administered. Shows a decrease.

The data in Table 2 significantly reduced tumor incidence, number of tumors per rat, and average amount of tumors per rat, compared to the control, even with a low dose of 0.6 mg / kg feed of the compound of Example 15 of the present invention. It was shown to be sufficient to reduce. The effect observed is dose dependent and comparable to the results observed with tamoxifen.

Observation of the effect at all doses tested prevented a clear comparison between the two compounds, since a plateau effect was observed at lower doses of the two compounds. However, the data in Table 1 and Table 2 show that the compounds of Example 15 are at least as effective as or more effective than tamoxifen as agents for inhibiting or preventing breast cancer.

Thus, an effective amount of a compound of the invention, in particular 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene, is administered Doing so is a useful way to prevent, arrest or inhibit breast cancer formation.

As used herein, the term “effective amount” means an amount of a compound of the present invention that can inhibit or prevent breast cancer formation. The specific dosage of a compound administered according to the invention is determined by the specific circumstances surrounding each condition, including, for example, the potency of the compound administered, the route of administration, the medical history of the patient, and the pathology being treated. A typical daily dosage will contain a nontoxic dosage level of about 5 mg to about 600 mg / day of a compound of the present invention. Preferred daily dosages will generally be from about 15 mg to about 80 mg / day.

The exact dosage is determined according to standard practice in the medical arts for titrating dosages for a patient; That is, initially a low dose of the compound is administered and the dose is gradually increased until the desired therapeutic effect is observed.

The following examples are provided to further illustrate the preparation of the compounds of the present invention. The examples should not be construed as limiting the scope of the invention as defined in the appended claims.

NMR data in the following examples were generated on a GE 300 MHz NMR apparatus and anhydrous hexadeuterodimethylsulfoxide was used as solvent unless otherwise indicated.

Example 1

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

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

To a solution of 27.0 g (100 mmol) of [6-methoxy-2- (4-methoxyphenyl)] benzo [b] thiophene in 1.10 L of chloroform at 60 ° C., add 15.98 g (100 mmol) of bromine in 200 mL of chloroform. It was added dropwise as a solution. After completion of the dropwise addition, the reaction was cooled to room temperature and the solvent was removed in vacuo to give 34.2 g of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (100 %) Was obtained as a white solid. Melting point 83-85 ° C.

Step b): Preparation of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

38.96 g of 4-benzyloxyphenol in a solution of 34.00 g (97.4 mmol) of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene in 60 ml of collidine under nitrogen (194.8 mmol) and 14.5 g (97.4 mmol) of cuprous oxide were added. The resulting mixture was heated to reflux for 48 hours. After cooling to room temperature, the mixture was dissolved in 200 ml of acetone and filtered to remove inorganic solids. The filtrate was concentrated in vacuo and the residue was dissolved in 500 ml of methylene chloride. The methylene chloride solution was washed with 3N hydrochloric acid (3 × 300 mL) followed by 1N sodium hydroxide (3 × 300 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate, at which time a white solid formed, which was collected by filtration (4.62 g (17.11 mmol) of [6-methoxy-2- (4-methoxyphenyl)] benzo [b] thiophene. )). The filtrate was concentrated in vacuo and then passed through a thin layer of silica gel (methylene chloride as eluent) to remove the base material. The filtrate was concentrated in vacuo and the residue was crystallized in hexane / ethyl acetate to first give [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo as an off-white crystalline solid. 7.19 g of [b] thiophene were obtained. The mother liquor was concentrated and chromatographed on silica gel (hexanes / ethyl acetate 80:20) to give further 1.81 g of product. The total yield of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene is 9.00 g (24% based on recovered starting material) ). The basic extract was acidified to pH = 4 with 5N hydrochloric acid, and the resulting precipitate was collected by filtration and dried to give 13.3 g of recovered 4-benzyloxyphenol. Melting point 100-103 ° C.

Step c): Preparation of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene

1.50 g of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene in 50 ml of ethyl acetate and 10 ml of concentrated 1% solution of concentrated hydrochloric acid in ethanol To a solution of (3.20 mmol) 300 mg of 10% palladium on carbon was added. After the mixture was hydrogenated at 40 psi for 20 minutes, the completion of the reaction was determined by thin layer chromatography. The mixture was passed through celite to remove the catalyst and the filtrate was concentrated in vacuo to yield a white solid. The crude product was passed through a layer of silica gel (chloroform as eluent). Concentration gave 1.10 g (91%) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene as a white solid. Melting point 123-126 ° C.

Step d): [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene oxalate Produce

1.12 g (2.97 of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene in 7 ml of anhydrous N, N-dimethylformamide under nitrogen. 3.86 g (11.88 mmol) cesium carbonate was added to the solution. After stirring for 10 minutes, 1.10 g (1.48 mmol) of 2-chloroethylpiperidine hydrochloride were added. The resulting mixture was stirred at ambient temperature for 18 hours. The reaction was partitioned between chloroform / water (100 mL each). The layers were separated and the aqueous layer was extracted with chloroform (3 × 50 mL). The organic layers were combined and washed with water (2 × 100 mL). The organic layer was dried (sodium sulfate) and concentrated to give an oil, which was chromatographed on silica gel (2% methanol / chloroform). The desired fractions were concentrated to give an oil, which was dissolved in 10 ml of ethyl acetate and treated with 311 mg (3.4 mmol) oxalic acid. After stirring for 10 minutes, a white precipitate formed which was collected by filtration and dried to give 1.17 g (70%) of [6-methoxy-3- [4- [2- (1-piperidi) in total as oxalate. Yl) -ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene. Melting point 197-200 ° C.

Example 2

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

The free base was prepared by treating the oxalate of Example 1 with an aqueous base, followed by reaction with HCl saturated diethyl ether to give the title salt. Melting point 216-220 ° C.

Example 3

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

The title compound was prepared in a similar manner to the compound of Example 1. Melting point 95-98 ° C.

Example 4

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

The title compound was prepared in a similar manner to the compound of Example 1. Melting point 189-192 ° C.

Example 5

Of [6-methoxy-3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride Produce

The title compound was prepared in a similar manner to the compound of Example 1. Melting point 196-198 ° C.

Example 6

Preparation of [6-methoxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

The title compound was prepared in a similar manner to the compound of Example 1. Melting point 208-211 ° C.

Example 7

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

10.00 g (19.05 mmol) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride ) Was dissolved in 500 mL of anhydrous methylene chloride and cooled to 8 ° C. To this solution was added 7.20 mL (76.20 mmol) of boron tribromide. The resulting mixture was stirred at 8 ° C. for 2.5 h. The reaction was poured into 1 L of a saturated solution of saturated sodium bicarbonate, quenched and cooled to 0 ° C. The methylene chloride layer was separated and the remaining solid was dissolved in methanol / ethyl acetate. The aqueous layer was then extracted with 5% methanol / ethyl acetate (3 × 500 mL). All organic extracts (ethyl acetate and methylene chloride) were combined and dried (sodium sulfate). Concentration in vacuo gave a tan solid which was chromatographed (silicon dioxide, 1-7% methanol / chloroform) to [6-hydroxy-3- [4- [2- (1-piperidinyl) as white solid). 7.13 g (81%) of methoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene were obtained. Melting point 93 ° C.

Example 8

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

The title compound was prepared in 80% yield from the free base. Melting point 246-249 ° C. (decomposition).

Example 9

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

The corresponding free base was treated with HCl saturated diethyl ether to give the title compound in 97% yield. Melting point 158-165 ° C.

Example 10

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

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

Example 11

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

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

Example 12

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

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

Example 13

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

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

Example 14

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

Step a): Preparation of 6-methoxybenzo [b] thiophene-2-boronic acid

To a solution of 18.13 g (0.111 mol) of 6-methoxybenzo [b] thiophene in 150 mL of anhydrous tetrahydrofuran (THF) at -60 ° C., add 76.2 mL (0.112 mol, 1.6M solution in hexane) of n-butyllithium. Dropwise via syringe. After stirring for 30 minutes, 28.2 ml (0.122 mol) of triisopropyl borate were introduced through a syringe. The resulting mixture was gradually warmed 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. Concentration in vacuo gave a white solid, which was triturated with ethyl ether hexane. Filtration gave 16.4 g (71%) of 6-methoxybenzo [b] thiophene-2-boronic acid as a white solid. Melting point 200 ° C. (decomposition).

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

To a solution of 3.00 g (14.4 mol) of 6-methoxybenzo [b] thiophene-2-boronic acid in 100 ml of toluene, followed by 3.98 g (15.8 mmol) of 4- (methanesulfonyloxy) phenylbromide followed by 2.0N sodium carbonate solution 16 ml was added. After stirring for 10 minutes, 0.60 g (0.52 mmol) of tetrakistriphenylphosphinepalladium was added and the resulting mixture was heated to reflux for 5 hours. The reaction mixture was then cooled to ambient temperature and the product precipitated out of the organic phase. The aqueous phase was removed and the organic layer was concentrated to solid under vacuum. Trituration from ethyl ether gave a solid, which was filtered and dried under vacuum to afford 3.70 g (77%) of [6-methoxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene as a tan solid. Got it. Melting point 197-201 ° C.

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

In a solution of 9.50 g (28.40 mmol) of [6-methoxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene in 200 ml of anhydrous methylene chloride, 14.20 g of boron tribromide under nitrogen gas at room temperature ( 5.36 mL, 56.8 mmol) was added. The resulting mixture was stirred at ambient temperature for 3 hours. The reaction was slowly quenched by pouring into excess ice water. After vigorous stirring for 30 minutes, the white precipitate was collected by filtration, washed several times with water and dried under vacuum to afford [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene 8.92 g (98%) was obtained as a white solid. Melting point 239-243 ° C.

Step d): Preparation of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene

To a solution of 3.20 g (10.0 mmol) of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene in 75 mL of anhydrous DMF followed by 5.75 g (17.7 mmol) of Cs ₂ CO ₃ 1.72 mL (11.0 mmol) benzylchloride was added. The resulting mixture was stirred vigorously for 24 hours. The solvent was removed 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. The crude product was suspended in 1: 1 hexanes: ethyl ether while drying in vacuo. The solid was collected to give 3.72 g (91%) of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene as a white solid. Melting point 198-202 ° C.

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

2.32 g of lithium aluminum hydride at ambient temperature under nitrogen gas in a solution of 12.50 g (30.50 mmol) of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene in 300 ml of dry THF 61.0 mmol) was added in small portions. The mixture was then stirred at ambient temperature for 3 hours and then quenched by carefully pouring the mixture into excess cold 1.0N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic layer was then washed several times with water, then dried (sodium sulfate) and concentrated to a solid under vacuum. Chromatography (silicon dioxide, chloroform) gave 8.75 g (87%) of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene as a white solid. Melting point 212-216 ° C.

Step f): Preparation of [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene

1.66 g (41.5 mmol) sodium hydride at ambient temperature under nitrogen gas in a solution of 8.50 g (26.40 mmol) [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene in 200 mL of anhydrous DMF. Was added in small portions. Once gas evolution ceased, 3.25 mL (52.18 mmol) of iodomethane was added dropwise. The reaction was stirred at ambient temperature for 3 hours. The solvent was then removed in vacuo and the residue partitioned between water / ethyl acetate. The layers were separated and the organic phase washed several times with water. The organic layer was then dried (sodium sulfate) and concentrated in vacuo to afford 9.00 g (98%) of [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene as a white solid. Melting point 180-185 ° C.

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

At ambient temperature 10.0 g (28.9 mmol) of [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene were placed in 200 ml of chloroform with 10.0 g of solid sodium bicarbonate. To this suspension 1.50 mL (29.1 mmol) bromine was added dropwise over 30 minutes as a solution in 100 mL chloroform. When the addition was complete, 200 mL of water was added and the layers were separated. The organic phase was dried (sodium sulfate) and concentrated to a white solid under vacuum. 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. Melting point 146-150 ° C.

Step h): Preparation of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

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

Step i): [6-Benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- ( Preparation of S-oxides

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

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

The product of step i) was reduced to afford the title compound, isolated in 95% overall yield. Purification by chromatography (SiO ₂ , 1-5% methanol / chloroform) gave an off-white solid. Melting point 105-108 ° C.

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

[6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [300] in 300 ml of 5: 1 ethanol / ethyl acetate. b] To a solution of 8.50 g (15.0 mmol) of thiophene, 1.50 g of palladium black, 3.50 g (55.6 mmol) of ammonium formate and 30 ml of water were added. The resulting mixture was heated to reflux and monitored by TLC. After about 3 hours, the reaction was judged complete and the solution was cooled to ambient temperature. The reaction was filtered through a layer of celite to remove crystals and the filtrate was concentrated to a solid in vacuo. The concentrate was partitioned between saturated sodium bicarbonate solution and 5% ethanol / ethyl acetate. The layers were separated and the organic layer was dried (sodium sulfate) and concentrated in vacuo. The crude product was chromatographed (silicon dioxide, 1-5% methanol / chloroform) to give [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4 6.50 g (91%) of -methoxyphenyl)] benzo [b] thiophene was obtained as a foam which was triturated with hexane to convert to a solid. Melting point 174-176 ° C.

Example 15

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

The product of Example 14 was treated with a mixture of HCl saturated diethyl ether in ethyl acetate and then crystallized from ethanol / ethyl acetate to convert to the corresponding hydrochloride in 85% yield. Melting point 156-160 ° C.

Example 16

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

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

The title compound was obtained in 73% yield following the general procedure of steps a) to g) of Example 14. Melting point 217-221 ° C.

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

The title compound was obtained in 91% yield. Melting point 125-127 ° C.

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

The title compound was isolated by chromatography (SiO ₂ , CHCl ₃ ) as a yellow solid. Melting point 119-123 ° C.

Step d): [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene- ( S-oxide)

The title compound was obtained as a yellow solid. Melting point 89-93 ° C.

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

The title compound was obtained in 91% yield. Melting point 106-110 ° C.

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

The title compound was obtained in 88% yield. Melting point 147-150 ° C.

Example 17

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

Prepared in a similar manner to the method used in Example 15, to obtain the title compound. Melting point 215-217 ° C.

<Formulation example>

"Active ingredient" in the following formulations means a compound of formula (I) or a salt or solvate thereof.

Formulation Example 1

Gelatin capsules

ingredient Amount (mg / capsules) Active ingredient 0.1-1000 Starch, NF 0-650 Starch fluid powder 0-650 Silicone Fluid 350 Centistox 0-15

Formulation Example 2

refine

ingredient Amount (mg / tablet) Active ingredient 2.5-1000 Cellulose, microcrystalline 200-650 Fired silicon dioxide 10-650 Stearic acid 5-15

Formulation Example 3

refine

ingredient Amount (mg / tablet) Active ingredient 25-1000 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone (10% aqueous solution) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 talc One

The active ingredient, starch and cellulose were passed through a 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone was mixed with the obtained powder and then passed through a 14 mesh U.S. sieve. The granules thus prepared were dried at 50-60 ° C. and passed through an 18 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate and talc were first passed through a 60 U.S. sieve, then added to granules, mixed and compressed in a tablet machine to obtain a tablet.

Formulation Example 4

Suspension

ingredient Volume (mg / 5 ml) Active ingredient 0.1-1000 mg Sodium carboxymethyl cellulose 50 mg syrup 1.25 mg Benzoic acid solution 0.10 ml Flavor q.v. coloring agent q.v. Purified water Volume to make 5 ml

The medicine was passed through a 45 mesh U.S. sieve and mixed with sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, flavor and colorant were diluted with some water and added with stirring. Subsequently, a sufficient amount of water was added to obtain the desired volume.

Formulation Example 5

Aerosol

ingredient Volume (wt%) Active ingredient 0.25 ethanol 25.75 Propellant 22 (chlorodifluoromethane) 70.00

The active ingredient was mixed with ethanol, the mixture was added to a portion of the propellant 22, cooled to 30 ° C. and transferred to the filling apparatus. The desired amount was then supplied to a stainless steel vessel and diluted with the remaining propellant. The valve unit was then mounted to the vessel.

Formulation Example 6

Suppository

ingredient Amount (mg / suppository) Active ingredient 250 Saturated Fatty Acid Glyceride 2000

The active ingredient was passed through a 60 mesh U.S. sieve and suspended in pre-melted saturated fatty acid glycerides with minimal required heat. The mixture was then poured into suppository molds of nominal 2 g capacity and cooled.

Formulation Example 7

Injection preparations

ingredient amount Active ingredient 50 mg Appearance saline 1000 ml

The solution of this component was administered intravenously to the patient at a rate of about 1 ml per minute.

Claims (16)

A method for preventing breast cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof. <Formula I> Wherein R ¹ and R ² are independently selected from hydroxy and alkoxy having 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 are pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino or To form a hexamethyleneimino ring. The method of claim 1, wherein the patient is not diagnosed with breast cancer but is determined to be at risk of breast cancer. The method of claim 1, wherein R ¹ and R ² are both hydroxy. The method of claim 1, wherein R ¹ is hydroxy and R ² is alkoxy having 1 to 4 carbon atoms. The method of claim 4, wherein R ² is methoxy. The method of claim 2, wherein R ¹ and R ² are both hydroxy. The method of claim 2, wherein R ¹ is hydroxy and R ² is alkoxy having 1 to 4 carbon atoms. 8. The method of claim 7, wherein R ² is methoxy. The method of claim 1, wherein R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperidino ring. The method of claim 2, wherein R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperidino ring. The method of claim 1 comprising administering a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof. Wherein R ² is hydroxy or methoxy. The method of claim 2 comprising administering a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof. # 67 Wherein R ² is hydroxy or methoxy. The compound of claim 11, wherein the compound is 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or pharmaceutical Which is a salt thereof. The compound of claim 11, wherein the compound is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or pharmaceutical Which is a salt thereof. 13. The compound of claim 12 wherein the compound is 6-hydroxy-2- (4-methoxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or pharmaceutical Which is a salt thereof. 13. The compound of claim 12 wherein the compound is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) phenoxy] benzo [b] thiophene or pharmaceutical Which is a salt thereof.