KR100446895B1 - Benzothiophene Compounds, Intermediates, Compositions and Methods - Google Patents

Abstract

The present invention relates to a pharmaceutically active compound of formula (I) or a pharmaceutically acceptable salt thereof:

Where

R ¹ is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), or —OSO ₂ (C ₂ -C ₆ alkyl) ;

R ² is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), —OSO ₂ (C ₂ -C ₆ alkyl) or halo ego:

R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3;

Z is -O- or -S-.

It also relates to a pharmaceutical composition of the compound of general formula (I).

Description

Benzothiophene Compounds, Intermediates, Compositions and Methods

This application is part of US patent application Ser. No. 08 / 396,401, filed February 28, 1995, now pending.

The present invention relates to the field of pharmacy and organic chemistry and provides novel benzothiophene compounds useful for the treatment of postmenopausal syndrome and uterine leiomyoma disease, endometriosis and aortic smooth muscle cell proliferation. The present invention also relates to intermediate compounds and pharmaceutical compositions useful for preparing the pharmaceutically active compounds of the present invention.

"Postmenopausal syndrome" is a term used to describe the various pathological conditions that women often begin or complete with physiological metamorphosis known as menopause. While many lesions are considered using the term, the following three major actions of postmenopausal syndrome have long been the biggest cause of medical concern: osteoporosis, cardiovascular effects (such as hyperlipidemia) and estrogen-dependent cancers (especially breast cancer). And uterine cancer).

Osteoporosis describes a group of diseases resulting from various etiologies, but is characterized by the final loss of bone mass per unit volume. As a result of this loss of bone mass and the resulting fracture, the skeleton that properly supports the body is broken. One of the most common types of osteoporosis is associated with menopause. Most women lose about 20% to about 60% of their bone mass in the shochu compartment of bone within three to six years after menstruation is stopped. This rapid loss is generally associated with increased bone resorption and bone formation. However, bone resorption cycles are more prevalent, and the result is a final loss of bone mass. Osteoporosis is a serious disease commonly seen in postmenopausal women.

There are an estimated 25 million women suffering from these diseases in the United States alone. The consequences of osteoporosis are personally detrimental, and are also the cause of the large economic losses due to the chronicity of the disease from the aftereffects of the disease and the need for prolonged long-term support (hospitalization and home care). This is especially true of older patients. In addition, although osteoporosis is generally not considered a life-threatening disease, mortality associated with hip fractures in older women is 20% to 30%. This large mortality rate may be directly related to postmenopausal osteoporosis.

The most susceptible bone tissue to postmenopausal osteoporosis is bone shochu. This tissue is often referred to as spongy or reticular bone and is particularly concentrated near the distal end of the bone (near the joint) and in the spinal pole. Suzhou tissues are characterized by interosseous bony structures and more tight and dense cortical tissues that make up the outer surface and central bones of the bone. The interconnected suzhou reticulum flanks the outer cortical tissue and is important for the biomechanical strength of the overall structure. In postmenopausal osteoporosis, bone insufficiency and fractures are mainly caused by final bone resorption and loss of shochu. Given the loss of soju in postmenopausal women, it is not surprising that the most common fractures are associated with the soju support, such as bones that are highly dependent on the spine (the neck of the bones that support the weight (eg, the neck of the femur and forearm)). In fact, hip fractures, collis fractures and spinal fracture fractures are characteristic of postmenopausal osteoporosis.

Currently, the only generally accepted method of treating postmenopausal osteoporosis is estrogen therapy. Although treatments are generally successful, few patients adhere to this treatment because estrogen therapy often causes unwanted side effects.

Throughout the premenopausal period, most women have a lower incidence of cardiovascular disease than men of corresponding age. However, after menopause, the incidence of cardiovascular disease in women increases gradually, comparable to the rate seen in men. This loss of protection is associated with loss of estrogen and, in particular, loss of estrogen's ability to regulate the amount of serum lipids. The nature of estrogen's ability to regulate serum lipids is not well known, but evidence to date indicates that estrogen can upregulate liver low density lipid (LDL) receptors to remove excess cholesterol. In addition, estrogens slightly affect the biosynthetic process of cholesterol and other beneficial effects on cardiovascular health.

Postmenopausal women undergoing estrogen replacement have been reported in the literature to concentrate serum lipids and return to premenopausal serum lipids. Thus, estrogen appears to be a suitable treatment for the disease. However, the side effects of estrogen replacement therapy are unbearable for many women and therefore use of this therapy is limited. An ideal therapy for this condition would be a drug that modulates serum lipids like estrogen but without any side effects and risks associated with estrogen therapy.

The third major lesion associated with postmenopausal syndrome is estrogen-dependent breast cancer and, on a smaller scale, estrogen-dependent cancer of other organs, especially the uterus. Such tumors are not limited to postmenopausal women, but tumors are more prevalent in older postmenopausal populations. General chemotherapy for these cancers was highly dependent on the use of anti-estrogen compounds (eg tamoxyphene). Such mixed agonist-antagonists have a beneficial effect on the treatment of the cancer, and estrogen side effects are tolerated but not ideal in an acute life-threatening condition. For example, these agents may be counterproductive for some patients because of their estrogenic (agonist) properties, which may have a stimulating effect on certain cancer cell colonies of the uterus. A better therapy for the treatment of cancer would be a drug which is an anti-estrogen compound that shows little or no estrogen agonist properties for regenerative tissue.

In particular, in response to the obvious need for new agents capable of alleviating postmenopausal syndrome, the present invention provides novel benzothiophene compounds, pharmaceutical compositions thereof, and other post-menopausal syndromes and other estrogen-related pathologies, such as those mentioned below. Provided are methods for using such compounds in treating a condition.

Uterine fibrosis (uterine leiomyoma disease) is an old, always-existing clinical problem, called various names, including leiomyoma, uterine hypertrophy, leiomyoma, uterine myopathy, uterine fibrosis and fibrotic uteritis. In essence, uterine fibrosis is an improper attachment of leiomyoma tissue to the wall of the uterus.

This condition is the cause of menstrual irregularities and infertility in women. The exact cause of this condition is little known, but there is evidence that it is an inappropriate response of leiomyoma tissue to estrogen. This condition was seen in rabbits that had been highly dosed with estrogen for three months. In the case of guinea pigs, the condition was manifested by daily administration of estrogen for 4 months. In the case of rats, estrogen also results in similar hypertrophy.

The most common treatment for leiomyomas is costly and sometimes requires surgery, which is the cause of complications such as abdominal adhesions and the formation of infections. In some patients, early surgery is only a temporary treatment and leiomyomas grow again. In this case, hysterectomy is performed to effectively terminate the fertility of the patient as well as the leiomyoma. It is also possible to administer hormonal antagonists that release gonadotropins, but their use is controlled because they can cause osteoporosis. Therefore, a new method of treating leiomyoma is needed, and the method of the present invention satisfies this need.

Endometriosis is a severe menstrual disorder that involves severe pain, bleeds into the endometrium or peritoneal cavity, and often causes infertility. The cause of this condition appears to be the growth of the ectopic endometrium, which inadequately responds to normal hormonal regulation and is located in inappropriate tissues. Because of the inadequate growth of the endometrium, the tissue appears to initiate a multi-step process that initiates a local inflammatory-like response, and a painful response that causes macrophage infiltration. The exact etiology of the disease is not well known, and the treatment of the disease by hormonal therapy is diverse, poorly defined, and is characterized by various unwanted and potentially dangerous side effects.

One method of treating the disease is to inhibit endometrial growth by using a small amount of estrogen by the negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen; Sometimes it is necessary to use estrogen continuously to suppress symptoms. The use of such estrogens can often lead to unwanted side effects and even the risk of endometrial cancer.

Another therapy consists of continuous administration of progestin, which can induce amenorrhea and inhibit ovarian growth by inhibiting ovarian estrogen production. The use of chronic progestin therapy often involves the unpleasant CNS side effects of progestin and often leads to infertility due to inhibition of ovarian function.

The third treatment consists in administering weak androgens that are effective to inhibit endometriosis; They induce a severe masculine effect. Some of these methods of treating endometriosis have also been associated with minor bone loss if treatment continues. Therefore, a new method of treatment of endometriosis is needed.

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Where

R ¹ is —H, —OH, —O (C ₁ -C ₄ alkyl),-OCOC ₆ H ₅ , -OCO (C ₁ -C ₆ alkyl), or -OSO ₂ (C ₂ -C ₆ alkyl) ;

R ² is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), —OSO ₂ (C ₂ -C ₆ alkyl) or halo ego;

R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3,

Z is -O- or -S-.

The present invention also provides intermediate compounds of the following general formulas (some of which are also pharmaceutically active) or pharmaceutically acceptable salts thereof, useful for preparing pharmaceutically active compounds of the present invention:

Where

R ^1a is —H or —OR ^7, wherein R ⁷ is a hydroxy protecting group;

R ^2a is —H, halo, or —OR ⁸ , wherein R ⁸ is a hydroxy protecting group;

R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diisopropylamino, or 1-hexamethylene Imino;

R ⁶ is —H or an optionally removable hydroxy protecting group;

R ⁹ is a leaving group;

R ¹¹ is absent or = O;

n is 2 or 3;

Z is -O- or -S-.

Also provided is a method for preparing a compound of formula (la ') or a pharmaceutically acceptable salt thereof, comprising the steps a) to e):

Where

R ^1a is —H or —OR ^7a, wherein R ^7a is —H or a hydroxy protecting group;

R ^2a is —H, halo, or —OR ^8a , wherein R ^8a is —H or a hydroxy protecting group;

R ³ is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3;

Z is -O- or -S-]

a) oxidizing a sulfur atom of the general formula (IV)

[Wherein, R ^1a and R ^2a are as defined above and R ⁹ is a leaving group];

b) reacting a compound of formula (XIV), the product of step a), with a nucleophilic group of formula (XV):

[Wherein, R ¹² is -OH or -SH];

c) reducing the compound of formula (XVI) which is the product of step b) to provide formula (Ia ')

d) optionally removing R ^1a and / or R ^2a hydroxy protecting groups (if present) of the product of step c); And

e) optionally preparing a salt of the product of step c) or d).

The present invention also provides a pharmaceutical composition containing a compound of formula (I), optionally estrogen or progestin, and a compound for alleviating the symptoms of postmenopausal syndromes, in particular osteoporosis, cardiovascular related pathological conditions and estrogen-dependent cancer. To use alone or in combination with estrogen or progestin. As used herein, the term "estrogen" refers to a steroidal compound having estrogen activity (e.g. 17b-estradiol, estrone, conjugated estrogen [primarin] (premarin)], equine estrogen 17b-ethynyl estradiol and the like). As used herein, the term "progestin" includes compounds having progestin activity (eg, progesterone, norethyl nodrel, nongestel, megestrol acetate, noretin drone, etc.).

The compounds of the present invention are also useful for inhibiting uterine leiomyoma and endometriosis in women and aortic smooth muscle cell proliferation in humans, especially restenosis.

One aspect of the invention includes a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Where

R ¹ is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), or —OSO ₂ (C ₂ -C ₆ alkyl) ;

R ² is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), —OSO ₂ (C ₂ -C ₆ alkyl) or halo ego;

R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3,

Z is -O- or -S-.

General terms used in the description of compounds described herein have their ordinary meanings. For example, "C ₁ -C ₆ alkyl" is a straight chain of 1 to 6 carbon atoms, which includes residues such as methyl, ethyl, propyl, isopropyl, butyl n-butyl, pentyl, isopentyl, hexyl, isohexyl, etc. Or branched aliphatic chain. Similarly, the term “C ₁ -C ₄ alkoxy” refers to a C ₁ to C ₄ alkyl group bonded by an oxygen molecule and includes residues such as methoxy, ethoxy, n-propoxy, isopropoxy and the like. .

U. S. Patent Nos. 4,418, 068 and 4,133, 814 to CD Jones, in essence, of a route of starting material for the preparation of the compounds of general formula (I), compounds of general formula (III) of the present invention, respectively Manufacture is incorporated herein by reference. Formula (III) has the structure

Wherein R ⁷ and R ^2a are as defined above.

R ⁷ and R ⁸ hydroxy protecting groups are not commonly found in the final therapeutically active compound of formula (I), but are intentionally introduced during some synthetic processes to protect groups that otherwise would react during chemical manipulation, and then Removed in the synthesis step. Since the compounds containing such protecting groups are very important as chemical intermediates (some derivatives also exhibit bioactivity), their detailed structure is not important. Various reactions for the formation, removal and possibly reformation of such protecting groups are described, for example, in Protective Groups in Organic Chemistry , Plenum Press (London and New York, 1973); Green, TW, Protective Groups in Organis Synthesis , Wiley (New York, 1981); And Schrooder Mill Lubke, The Peptides, Vol. I, Academic Press, (London and New York, 1965)].

Representative hydroxy protecting groups include, -C ₁ -C ₄ alkyl I pray to, -C ₁ -C ₄ alkoxy, -CO (C ₁ -C _{6 alkyl), -SO 2 - (C 1} -C 6 alkyl), and - CO-Ar, wherein Ar is benzyl or optionally substituted phenyl. The term "substituted phenyl" means 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 do. The term "halo" refers to bromo, chloro, fluoro and iodo.

In compounds of formula III, preferred R ⁷ and R ⁸ (R ^2a ) substituents are methyl, isopropyl, benzyl and methoxymethyl. Compounds wherein R ⁷ and R ⁸ are each methyl are prepared by the procedure described in the Jones patent referenced above. Another preferred hydroxy protecting group is methoxymethyl. However, the compounds of formula (IV) shown below are first prepared to contain the preferred methyl group or other hydroxy protecting group (s). These protecting groups are then removed to form phenol moieties, which are then reprotected with methoxymethyl protecting groups.

Also prepared are compounds of formula III, wherein the R ⁷ hydroxy protecting group is optionally removed and leaves the R ⁸ (R ^2a ) hydroxy protecting group as part of the final product. Also prepared are compounds of formula III wherein the R ⁸ (R ^2a ) hydroxy protecting group is removed and the R ⁷ hydroxy protecting group is left in place. For example, R ⁷ is isopropyl or benzyl and R ⁸ (R ^2a ) is methyl. Isopropyl or benzyl residues are selectively removed by standard procedures and the R ⁸ methyl protecting group is left as part of the final product.

The first step of the present invention for preparing certain compounds of formula (I) selectively places leaving groups at the 3 position of the compound of formula (III) and the reaction product of the first step is 4- (protected hydroxy). Coupling with phenol and removing the hydroxy protecting group of the phenol. The method of the present invention is shown in the following scheme (I).

Scheme I

Where

R ⁷ and R ^2a are as defined above,

R ⁹ is a leaving group,

R ⁶ is a hydroxy protecting group that may be optionally removed.

In the first step of Scheme (I), a suitable leaving group is optionally placed in the 3-position of general formula (III) (starting material) by standard procedures. Suitable R ⁹ leaving groups include sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate , 2-chlorobenzenesulfonate, triflate, etc.), halogens (eg bromo, chloro and iodo), and other related leaving groups. However, in order to reliably position the leaving group in a suitable position, the above halogen is preferable, and bromo is particularly preferable.

The invention is carried out using the procedures of the standard. For example, when using a preferred halogenating agent, one equivalent of the halogenating agent (preferably bromine) is reacted with one equivalent of the substrate of formula (III) in the presence of a suitable solvent (eg chloroform or acetic acid). . This reaction is carried out at about 40 ° C to about 80 ° C.

The compound of formula (IV), which is a reaction product obtained from the step of the process, is then reacted with 4- (protected hydroxy) phenol, where R ⁶ is a selectively removable hydroxy protecting group of formula (IIa). Prepare the compound. In general, the 4-hydroxy protecting moiety of the phenol is in this case any known protecting group which may be optionally removed without removing the R ⁷ and R ⁸ (if present) residues of the general formula (IIa) compound. Can be. Preferred R ⁶ protecting groups include methoxymethyl and benzyl if R ⁷ and / or R ⁸ is not methoxymethyl. Of these, benzyl is particularly preferred. 4- (protected hydroxy) phenol reagents are commercially available or can be prepared by standard procedures.

This coupling reaction is known in the art as the Ullman reaction and is carried out according to standard procedures [see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 4th edition, 3-16, (J Edited March, John Wiley & Sons, Inc. 1992); see Jones, 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 (I) catalyst and a suitable solvent. Preferably, one equivalent of the compound of formula (IV) wherein R ⁹ 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 solvent mixtures that remain inert throughout the reaction. Typically, organic bases, particularly hindered bases (eg 2,4,6-collidine), are preferred solvents.

The temperature used in this step should be sufficient to complete the coupling reaction and will affect the amount of time required. If the reaction mixture is heated to reflux under an inert atmosphere (eg nitrogen), the time to completion will usually be from about 20 to about 60 hours.

After coupling to form a compound of formula (IIa), a compound of formula (IIb) is prepared by selectively removing the R ⁶ hydroxy protecting group of the compound of formula (IIa) by well known reduction procedures. The procedure chosen should not affect the R ⁷ and R ⁸ (if present) hydroxy protecting groups.

If R ⁶ is the preferred benzyl moiety and R ⁷ and R ⁸ (if present) are each methyl, the steps of the process are carried out by standard hydrolysis processes. Typically, the substrate of formula (IIa) is added to a suitable solvent or solvent mixture, followed by the addition of a proton donor to accelerate the reaction and add the appropriate hydrogenation catalyst.

Suitable catalysts include noble metals and oxides (eg palladium, platinum and rhodium oxide) on supports (eg carbon or calcium carbonate). Of these, palladium on carbon, particularly 10% on carbon, is preferable.

The solvent for this reaction is a solvent or solvent mixture that remains inert throughout the entire reaction. Typically, ethyl acetate and C ₁ -C ₄ aliphatic alcohols, in particular ethanol, are preferred.

In the reaction of the present invention, hydrochloric acid acts as a suitable and preferred proton donor.

When performed at ambient temperature and pressures from about 30 psi to about 50 psi, the reaction of the present invention is carried out at very high speeds. The progress of this reaction can be monitored by standard chromatography techniques such as thin layer chromatography.

Compounds of formula (IIa) and (IIb) are novel and are included in the class described herein as formula (II) and are useful for preparing pharmaceutically active compounds of formula (I).

A compound of formula (IIb) is prepared and reacted with a compound of formula (V) to make a compound of formula (VI):

Where

R ³ and n are as defined above,

Q is bromo or preferably a chloro moiety.

The compound of formula (VI) is then deprotected to prepare a compound of formula (la). The above steps of the process are shown in Scheme II below.

Scheme II

Where

R ³ , R ⁷ , R ^2a and n are as defined above,

R ^2b is -H, -OH or halo.

In the first step of the method shown in Scheme (II), the alkylation reaction is carried out by standard procedures. Compounds of formula (V) are commercially available or prepared by means well known to those skilled in the art. Preferably, hydrochlorides of the general formula (V) compounds are used, in particular 2-chloroethylpiperidine hydrochloride.

Generally, at least about 4 equivalents of alkali metal carbonate (preferably cesium carbonate) and at least about 1 equivalent of substrate of formula (IIb) are reacted with 2 equivalents of formula (V) compound in the presence of a suitable solvent.

The solvent for this reaction is a solvent or solvate that remains inert throughout 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, ambient temperature is sufficient and preferred.

The reaction of the invention is preferably carried out under an inert atmosphere, in particular nitrogen.

Under preferred reaction conditions, the present invention will be completed in about 16 to 20 hours. Of course, the progress of the reaction can be monitored by standard chromatographic techniques.

As another method of preparing a compound of formula (VI), the compound of formula (IIb) in excess of the general formula Q- (CH ₂ ) _n -Q 'in alkaline solution, wherein Q and Q' Or a different leaving group).

Preferred alkaline solutions for this alkylation reaction contain potassium carbonate in an inert solvent such as methylethyl ketone (MEK) or DMF. In this solution, the 4-hydroxy group of the benzoyl moiety in the compound of formula (IIb) is present as a phenoxide ion that replaces one of the leaving groups of the alkylating agent.

This reaction produces the best results when refluxing the alkaline solution and reagents containing the reactants and running until completion. When using MEK as the preferred solvent, the reaction time is from about 6 hours to about 20 hours.

The reaction product obtained from the above step was then subjected to standard techniques by 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, The compound of formula (VI) is prepared by reaction with diethylamine, diisopropylamine or 1-hexamethyleneimine. Preferably, the hydrochloride salt of piperidine is reacted with an alkylated compound of formula IIb in an inert solvent such as anhydrous DMF and heated to 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 amount of time required to complete this reaction. Of course, the progress of this reaction step can be monitored by standard chromatographic techniques.

Compounds of formula (VI) wherein R ⁷ and R ⁸ (if present) are each C ₁ -C ₄ alkyl, preferably methyl and R ^2a is —H or halo are novel and are described in the methods described herein. It is pharmacologically active. Thus, such compounds are included in the compounds of formula (I) described herein.

Preferred specific compounds of formula (I) are obtained by cleaving the R ⁷ and R ⁸ (if present) hydroxy protecting groups of the compound of formula (VI) by well known procedures. Various 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, TW, Protective Groups in Organis Synthesis , Wiley (New York, 1981); And Schrooder Mill Lubke, The Peptides, Vol. I, Academic press, (London and New York, 1965)]. The process for removing the preferred R ⁷ and / or R ⁸ hydroxy protecting groups, in particular methyl and methoxymethyl, is essentially as described in the examples below.

Compounds of formula (Ia) are novel and pharmacologically active with respect to the methods described herein and are included in formula (I) described herein.

The compound of formula (I) wherein R ¹ is -H is prepared by the synthetic route shown in Scheme (III) below. Using this route, the 3-position leaving group (R ⁹ ) is placed in commercial thianaphthalene (formula (VII)) to produce a compound of formula (VIII), followed by 4- (protected hydroxy) ] Phenols are coupled to provide compounds of general formula (IX).

Scheme III

Where

R ⁶ is an optionally removable hydroxy protecting group,

R ⁹ is a leaving group.

Compounds of formula (VII) are commercially available. Preferred reactants and conditions, as well as the preparation of compounds of formula (VIII) and (IX), including the definition of R ⁶ and R ⁹ substituents, are the same as described above and are described in the above scheme (I) unless otherwise stated herein. Is presented in

The compound of formula (IX) was then subjected to the Suzuki coupling reaction (Suzuki A., Pure and Appl. Chem. 6 (2): 213-222 (1994)). Using Suzuki coupling reaction conditions, the compound of formula (IX) is optionally halogenated at 2-position and then coupled with an arylboronic acid compound of formula (XIa) (Path A in Scheme (IV) below) .

Preferably, however, the arylboronic acid of general formula (Xb) is prepared from a compound of general formula (IX) and then reacted with halo-arene of general formula (XIb) to produce a novel intermediate of general formula (IIc). To obtain (Path B of Scheme IV). These novel intermediates are useful for preparing the pharmaceutically active compounds (General Formula (Ib) compounds) of the present invention via alkylation and deprotection.

Scheme IV

Where

R ^2a , R ^2b , R ³ , R ⁶ and n are as defined above;

X is iodo, bromo or fluoro (in preferred order);

X 'is iodo, brobo or fluoro (in preferred order), or triflate.

The first step of route A in FIG. (IV) is the 2-position iodide or bromination of compounds of formula (IX) using standard procedures. In general, in a suitable solvent, the compound of formula (IX) is reacted with a slight excess of n-butyllithium in hexane under an inert atmosphere (eg nitrogen), followed by the dropwise addition of a slight excess of the desired halogenating agent in a suitable solvent. Preferred halogenating agents for this step are iodine, but bromine, N-bromosuccinimide can also be used.

Suitable solvents include, for example, inert solvents or mixtures of solvents such as diethyl ether, dioxane and tetrahydrofuran (THF). Among these, tetrahydrofuran, especially anhydrous THF is preferable.

The 2-position halogenation reaction of the present invention is optionally carried out at about -75 ° C to about 85 ° C.

The halo-aren of formula (Xa), which is the product of the reaction, is then coupled with the arylboronic acid of formula (XIa) by a standard Suzuki coupling reaction procedure to provide a compound of formula (IIc). Procedures well known to those of ordinary skill in the art derive from commercially available compounds of formula (XIa) wherein R ^2a is -H, halo or -OR ⁸ , wherein R ⁸ is a hydroxy protecting group as defined above. (See, eg, March J. and Suzuki, supra).

In the coupling reaction of the present invention, a slight excess of the general formula (XIa) compound is reacted with each equivalent of the general formula (Xa) compound in the presence of a suitable base in a palladium catalyst and an inert solvent such as toluene.

Various palladium catalysts catalyze the Suzuki coupling reaction, but the catalyst of choice is typically reaction specific. Therefore, it is highly desirable to use tetrakistriphenylphosphine palladium in the reaction of the present invention.

Likewise, various bases can be used in the coupling reaction of the present invention. However, preference is given to using alkali metal carbonates, preferably 2N sodium carbonate.

The temperature used in this step should be sufficient to complete the coupling reaction. Typically, it is suitable and preferred to heat the reaction mixture to reflux for about 2 to about 4 hours.

In Route B of Scheme IV, well-known procedures are used to prepare the 2-position arylboronic acid of general formula (Xb). Generally, the compound of formula (IX) is treated with a slight excess of n-butyllithium in hexanes under an inert atmosphere (e.g. nitrogen) in a suitable solvent, followed by the dropwise addition of the appropriate trialkylborate.

Suitable solvents include, for example, inert solvents or mixtures of solvents such as diethyl ether, dioxane and tetrahydrofuran (THF). THF, in particular anhydrous THF, is preferred.

Preferred trialkylborates used in the present invention are triisopropyl borates.

The compound of formula (Xb), the product of the reaction, is then reacted with an aryl halide or aryl triflate of formula (XIb) by standard Suzuki coupling procedures to provide a compound of formula (IIc). Preferred reaction conditions for the reaction of the present invention are as described in the reaction of compounds of formula (XIa) and (Xa) in scheme (IV), which also provides compounds of formula (IIc).

The conversion reaction of the general formula (IIc) compound to the general formula (Ia) compound is carried out as described above for the conversion reaction of the general formula (IIa) compound to the general formula (Ia) compound.

Compounds of formulas (IIc) and (IId) are novel and useful for preparing pharmaceutically active compounds of the invention.

Compounds of Formulas (XII) and (Ib) are also novel and useful for the methods described herein and are included in the compounds of Formula (I) as defined herein.

Compounds of formula (I) wherein R ¹ or R ² is -H and other R ¹ or R ² substituents are -OH, also from compounds of formula (I) wherein R ¹ or R ² are both -OH Manufacture. A dihydroxy compound of formula (I) was converted to a mixture of 6-and 4'-mono-triflate, triflate moieties such as the literature [J. Org. Chem reduced to hydrogen (Saha (Saa, JM) , 55 : 991 (1990). The mixture of monohydroxy derivatives produced as the free base or pharmaceutically acceptable salt (preferably hydrochloride) can then be separated by standard crystallization techniques.

Generally, the dihydroxy compound of formula (I) is treated with about 4 to about 6 equivalents of amine base (e.g. triethylamine) in a non-reactive solvent, followed by one equivalent of trifluoromethanesulfonic anhydride. Add. Statistical mixtures of mono- and di-triplates are prepared and isolated by standard chromatographic techniques. Preferred solvent for this step is anhydrous dichloromethane.

When performed at about 0 ° C. to about 25 ° C., the reaction of the present invention is completed in about 1 to about 5 hours.

Then hydrogenated the isolated mixture of mono-triple compound in an unreactive solvent in the presence of about 3 to about 6 equivalents of an amine base (preferably triethylamine) and a hydrogenation catalyst (preferably palladium on carbon). Let's do it. Preferred solvents for this reaction are ethyl acetate and ethanol, or others, mixtures thereof. When the reaction step of the present invention is carried out at about 40 psi of hydrogen gas at ambient temperature, the reaction time is from about 2 hours to about 5 hours.

The resulting mixture of monohydroxy derivatives of general formula (I) exhibits different solubility in ethyl acetate and the 6-hydroxy-4'-hydrogen derivatives are separated from the 6-hydrogen-4'-hydroxy derivatives by selective crystallization. Partially separable. The thick mixture can be converted to hydrochloride and then further separated by crystallization from ethyl acetate-ethanol to give the pure monohydroxy compound of general formula (I).

A more direct method for preparing a compound of formula (I) wherein one of R ¹ or R ² is -H and the other R ¹ or R ² substituent is -OH and one of R ¹ or R ² is -H, Another method for preparing a compound of formula (I) wherein the other R ¹ or R ² substituent is —O— (C ₁ -C ₄ alkyl) uses a compound of the general formula:

Where

R ³ and n are as defined above;

R ^1c is —OH or —O— (C ₁ -C ₄ alkyl);

R ^2c is —OH or —O— (C ₁ -C ₄ alkyl);

Provided that when R ^1c is -OH, R ^2c is -O (C ₁ -C ₄ alkyl); and if R ^1c is -O- (C ₁ -C ₄ alkyl), R ^2c is -OH.

In this method, the hydroxy moiety of the compound is converted to triflate derivatives by treatment with trifluoromethane sulfonic anhydride. The triflate moiety is then reduced under standard conditions, preferably by catalytic hydrogenation. The hydroxy protecting moiety is then removed by the procedure described in the standard herein so that one of R ¹ or R ² is -H and the other R ¹ or R ² substituent is -OH. Obtain the compound.

Another preferred method for preparing the compounds of the present invention is shown in Scheme (V). In the process of the present invention, sulfoxide (General Formula (XIV)) is prepared by oxidizing the sulfur atom of the general formula (IV) compound (following), and then reacting it with a nucleophilic group to formula (I) and general formula (II). ) Oxygen or sulfur atom linking groups of the compound are introduced. The sulfoxide moiety of the general formula (XVI) compound is then reduced to provide certain compounds of the present invention.

Scheme V

Wherein each variable has a meaning already defined.

In the first step of the process, the compound of formula (IV) is selectively oxidized to sulfoxide. Document of the plurality of available methods known in the steps of the method (e.g., Hadamard's Clare (Madesclaire, M.) [Tetrahedron, 42 (20); 5459-5495 (1986)]; bit roast (Trost, BM Tetrahedron Letters , 22 (14); 1287-1290 (1981); Dr. Drabowicz, J. et al., Synthetic Communications , 11 (12); 1025-1030 (1981); See Kramer, JB et al. 34th National Organic Symposium , Williamsburg, VA., June 11-15, 1995). However, many oxidants have a very poor conversion to the desired product and are excessively oxidized into sulfones. However, the novel process of the invention converts compounds of formula (IV) to sulfoxides of formula (XIV) with little or no production of sulfones. The process of the present invention comprises reacting a general formula (IV) compound with about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture of trifluoroacetic acid in methylene chloride from about 20% to about 50%. The reaction is performed at about 10 ° C. to about 50 ° C., and usually requires about 1 to about 2 hours to complete.

The 3-position leaving group (R ⁹ ) is then substituted with the desired nucleophilic derivative of the general formula (XV). Such nucleophilic derivatives are prepared by standard methods.

In this step of the invention, the acidic protons of the nucleophilic groups are removed by treatment with a base, preferably with a slight excess of sodium hydride or potassium tert-butoxide, in a polar aprotic solvent, preferably DMF or tetrahydrofuran. do. Other bases that may be used include potassium carbonate and cesium carbonate. In addition, other solvents such as dioxane or dimethylsulfoxide may also be used. The deprotonation reaction is usually carried out at 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 nucleophilic solution. The substitution reaction is carried out at 0 ° C. to about 50 ° C. and for about 1 to about 2 hours. The product is isolated by standard procedures.

Using benzyl moieties as hydroxy protecting groups, the hydrogenolysis of sulfoxide moieties also eliminates the need to remove the benzyl protecting groups to selectively remove these groups at later stages of the process.

In the next step of the process of the invention, novel sulfoxides of the general formulas (XVI a, b, c and d) (collectively general formula (XVI)) are substituted with the general formulas (IIg, Ic, IIe and Id), respectively. Reduced to a benzothiophene compound. Prior to the reduction process of the present invention, the compounds of the general formulas (IIg) and (IIe) can first be alkylated as described herein. Reduction of the sulfoxide compound is known in the art, including, for example, hydride reduction methods (lithium aluminum hydride), catalytic hydrogenation methods, transition hydrogenation methods, and trimethylsilyl iodide (TMS-I) methods. By using one of the methods. In this reduction reaction, the choice of reagents depends on the compatibility with other functional groups in the molecule. For the compounds described herein, lithium aluminum hydride (LiAlH ₄ ) and transition hydrogenolysis (palladium black / ammonium formenite) are preferred reagents. For LiAlH ₄ reduction, suitable solvents are, for example, diethyl ether, dioxane and tetrahydrofuran (THF). Among these, THF, especially anhydrous THF is preferable. In the transition hydrogenolysis reaction, alcohol solvents, in particular ethanol, are preferred. The reaction is carried out at about 0 ° C. to about 60 ° C., and requires about 0.5 to about 2 hours to complete.

If necessary, the salt of the hydroxy protecting group or protecting groups in the product of the process shown in Scheme (V) and the product of any step of the process can be removed. Thus, there is provided a process for preparing a compound of the general formula: or a pharmaceutically acceptable salt thereof, comprising the steps a) to e) of the present invention:

[Wherein,

R ^1a is —H or —OR ^7a, wherein R ^8a is —H or a hydroxy protecting group;

R ^2a is —H, halo or —OR ^8a , wherein R ^8a is —H or a hydroxy protecting group;

R ³ is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3,

Z is -O- or -S-]

a) oxidizing a sulfur atom of the general formula (IV)

[Wherein, R ^1a and R ^2a are as defined above and R ⁹ is a leaving group];

b) a compound of formula (XIV) Reacting with a nucleophilic group wherein R ¹² is -OH or -SH:

c) reducing the compound of formula (XVI) which is the product of step b) to provide formula (Ia ')

d) optionally removing R ^1a and / or R ^2a hydroxy protecting groups (if present) of the product of step c); And

e) optionally preparing a salt of the product of step c) or d).

The novel method also provides novel compounds of formulas (XIV) and (XVI a, b, c and d) which are useful intermediates for the preparation of the pharmaceutically active compounds of the present invention.

Compounds of general formula (I) wherein Z is S are also prepared using a method of metallizing a compound of general formula (IVa), described in Scheme (VI) below. The resulting compound of formula (XVII) is reacted with 4- (protected hydroxy) phenyl disulfide of formula (XVIII) and the phenol protecting group of the compound of formula (IIe) is removed to To give a compound. When using this method, it should be noted that R ² cannot be halo due to chemical limitations.

Scheme VI

Where

R ^1a is —H or —OR ⁷ , wherein R ⁷ is a hydroxy protecting group;

R ^2a is —H or —OR ⁸ , wherein R ⁸ is a hydroxy protecting group;

R ⁶ is a hydroxy protecting group which may be optionally removed;

R ⁹ is a leaving group;

M is a metal ion.

In the first two steps of Scheme VI, well-known procedures are used to metallize the general formula (IVa) compounds. Most generally, and preferably, after treating the compound of formula (IVa) with a slight excess of n-butyllithium in hexane in a suitable solvent, a solution of the disulfide compound of formula (XVIII) in a suitable solvent is added dropwise.

All of these reaction steps are carried out under an inert atmosphere such as nitrogen, and suitable solvents for these two steps include one or more inert solvents such as diethyl ether, dioxane and THF. Of these, THF, in particular its anhydrous form, is preferred. In addition, the reaction step of the present invention is carried out at about -78 ℃ to about 85 ℃.

In a first step of the reaction of the present invention, metallized compounds of general formula (XVII) are obtained. 4- (hobo-hydroxy) phenyl disulfide (General Formula (XVIII) compound) which reacts with such a general formula (XVII) compound to give a compound of general formula (IIe) is a compound of commercial 4-hydroxyphenylsulfide. Prepared by protecting hydroxyl groups with suitable protecting groups by procedures known in the art. Preferred R ⁶ protecting groups are methoxymethyl, provided that R ⁷ and R ⁸ are hydroxy protecting groups which are not methoxymethyl when either or both present. R ⁶ protecting group is methoxymethyl, provided that R ⁷ and R ⁸ are hydroxy protecting groups that are not methoxymethyl when either or both present. The R ⁶ hydroxy protecting group must differ from the moiety formed by the R ⁷ and R ⁸ hydroxy protecting groups (if present) to selectively remove the R ⁶ group by standard procedures to provide a compound of formula (IIf). do.

To carry out the deprotection process by removing the R ⁶ protecting group, the general formula (IIe) compound in the proton solvent or solvent mixture is reacted in an acid medium containing at least one equivalent of acid (preferably methanesulfonic acid), and Heat to 25 to about 110 ° C. Typically, the reaction time is about 6 to about 24 hours, but the progress of the reaction can be monitored by standard chromatographic techniques.

Suitable solvents for the present invention include, for example, water and methanol.

Compounds of formulas (IIe) and (IIf) are novel and useful for preparing pharmaceutically active compounds of formula (I) and are included in formula (II) as described above herein.

Using the above procedure relating to the steps of the methods shown in schemes (II) and (IV), compounds of the general formula (Id) are prepared:

Where

R ^1b is -H or -OH;

R ^2b is -H or -OH;

R ³ and n are as described above.

The compounds of formula (Id) are novel and useful in the methods of the invention and are included in formula (I) as described above herein.

By the following formula using a modified 2-aryl-benzothiophene starting material in (III), R ¹ and R ² or a protecting group different from hydroxy, or R ¹ and R ² is a hydroxy protecting group the other of science is hydroxy Optionally preparing a compound of formula (I) which is oxy, the hydroxy protecting groups represented by R ⁷ and R ⁸ must be sufficiently different so that other groups remain while only one protecting group is removed. Such 2-arylbenzothiophenes are prepared by procedures well known in the art.

Particularly useful for preparing compounds of formula (I) wherein R ¹ and R ² are different protecting groups is the Suzuki coupling reaction described above in Scheme (IV). However, 6- (protected hydroxy) benzothiophene-2-boronic acid is reacted with the above general formula (XIb) compound in which R ^2a is —O ^{R 8} and R ⁷ is not equal to R ⁸ . This reaction allows for the selective removal of one protecting group and the preparation of compounds of the invention wherein R ⁷ and R ⁸ are different hydroxy protecting groups so that the other remains as a residue of the final product. Preferably, the R ⁷ protecting group, in particular benzyl or isopropyl, is removed to prepare the hydroxy moiety while leaving the R ⁸ protecting group, especially methyl.

Suzuki coupling reactions are also performed using this procedure except that the compounds of formula (XIb) are replaced with compounds of formula (XIX):

Where

R ^8a is C ₁ to C ₆ alkyl sulfonate (preferably methanesulfonate) or C ₄ to C ₆ aryl sulfonate;

R ¹⁰ is a leaving group, preferably bromo or triflate.

In this reaction, the above-described 6- (protective hydroxy) benzothiophene-2-boronic acid is reacted with a compound of the general formula (XIX) to give a compound of the general formula (XX), which is tribrominated in methylene chloride. Reaction with boron gives a monohydroxy compound which is then converted by standard procedures, for example to a benzyl moiety (formula (XXI)). The 4'-sulfonate ester is then selectively removed by basic hydrolysis or by treatment with LiAlH ₄ , preferably in a suitable aprotic solvent (eg THF). This reaction finally gives a compound of the general formula (XXII) which is methylated by the procedure of the standard, for example at the 4'-position (formula (IIIa)). Of course, one skilled in the art can use a variety of methods to provide compounds of formula (IIIa) in which the hydroxy protecting group is not shown in Scheme (VII) below, but it may be selectively removed to remove the formula (I) of the present invention. It will be appreciated that a monohydroxy compound of may be provided.

Scheme VII

The compounds of formula (IIIa) are then subjected to the various methods described herein to provide compounds of formulas (I) and (II) of the present invention.

If present, the hydroxy moiety at the 6- and / or 4'-positions is prepared by the well-known procedure of the general formula -O-CO- (C ₁ -C ₆ alkyl) or -O-SO _2- (C _2- Other preferred compounds of formula (I) are prepared by replacement with C ₆ alkyl) moieties. See, for example, US Pat. No. 4,358,593.

For example, if a -O-CO (C ₁ -C ₆ alkyl) group is desired, the mono- or dihydroxy compound of formula (I) may be reacted with a reagent such as acyl chloride, acyl bromide, acyl cyanide or acyl azide, Or react with a suitable anhydride or mixed anhydride. Conveniently the reaction is carried out in a basic solvent (eg pyridine, lutidine, quinoline or isoquinoline) or tertiary amine solvent (eg triethylamine, tributylamine, methylpiperidine and the like). The reaction can also be carried out with an inert solvent (e.g. ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile) added with at least one equivalent of an acid scavenger (except as shown below), such as tertiary amine , Acetone, methyl ethyl ketone, etc.). If desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine can be used. See, eg, Haslam et al. , Tetrahedron, 36 : 2409-2433 (1980).

The reaction of the present invention is carried out at an appropriate temperature of about 25 ° C. to about 100 ° C., often under inert atmosphere (eg nitrogen gas). However, ambient temperature is usually adequate for carrying out the reaction.

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

Active esters of suitable acids such as esters formed by known reagents such as dicyclohexylcarbodiimide, acylimidazole, nitrophenol, pentachlorophenol, N-hydroxysuccinimide and 1-hydroxybenzotriazole It is also possible to provide the R ¹ and R ² groups of the general formula (I) mentioned above. See, eg, Bull. Chem. Soc. Japan , 38 : 1979 (1965) and Chem. Ber. , 788 and 2024 (1970).

Each of the techniques that provide -O-CO- (C ₁ -C ₆ alkyl) moieties are carried out in the solvents discussed above. Techniques that do not produce acid products during the reaction, of course, do not require the use of acid scavengers in the reaction mixture.

When a hydroxy group at the 6- and / or 4'-position of the compound of formula (I) is converted to a group of formula -O-SO _2- (C ₂ -C ₆ alkyl) , King and Monoir, J. Am. Chem. Soc. , 97: 2566-2567 (1975), such as mono- or dihydroxy compounds, such as sulfonic anhydrides or derivatives of suitable sulfonic acids, such as sulfonyl chloride, sulfonyl bromide, or sulfonyl ammonium salts. React with The dihydroxy compound can also be reacted with a suitable sulfonic acid anhydride or a mixture of sulfonic anhydrides. This reaction is carried out under the same conditions as described above in the discussion with acid halides and the like.

Although the free-base form of the compound of formula (I) may be used in the process of the invention, it is preferred to prepare and use pharmaceutically acceptable salt forms. Thus, the compounds used in the methods of the present invention first form pharmaceutically acceptable acid addition salts with a wide range of organic and inorganic acids and include physiologically acceptable salts often used in pharmaceutical chemistry. Such salts are also part of the present invention. Typical inorganic acids used to prepare these salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, phosphorous acid and the like. Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Accordingly, such pharmaceutically acceptable 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, hexine-1,4-dioate, cap Latex, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hiprate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, Mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, mono Hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suverate, sulfate, bisulfate, pyosulfate, sulfate Fight, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene- 2-sulfonate, p-toluenesulfonate, kylenesulfonate, tartarate and the like. Preferred salts are the hydrochloride and oxalate salts.

Pharmaceutically acceptable acid addition salts are typically prepared by reacting a compound of formula (I) with an equimolar or excess acid. The reagents are generally mixed in neutral solvents such as diethyl ether or ethyl acetate. Salts usually precipitate from solution within about 1 hour to 10 days and can be isolated by filtration or stripped by conventional means.

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

Representative preferred compounds of the invention include the following compounds:

I group:

[6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

[6-Isopropoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

[6-methoxy-2- (4-isopropoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

[2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide)

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide)

[6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

[6-Isopropoxy-2- (4-benzyloxyphenyl) -3-propo] benzo [b] thiophene- (S-oxide)

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

[6-methoxy-2- (4-isopropoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

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

[6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide )

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

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene- (S-oxide )

[6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy] benzo [b] thiophene

[6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene

II group:

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

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

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

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

[3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

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

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene hydrochloride

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-fluorophenyl)] benzo [b] thiophene

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

[6-isopropoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

[6-methoxy-2- (4-isopropoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

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

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

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) yeethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

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

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

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

[6-methoxy-3- [4- [3- (piperidino) propoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

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

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

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

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

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

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

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

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

[6-hydroxy-3- [4- [3- (1-N, N-diethylamino) propoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

[6-hydroxy-3- [4- [2- (1-N, N-diisopropylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

[6-hydroxy-3- [4- [3- (piperidino) propoxy] phenoxy-2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

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

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

[6-benzyloxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzyl [b] thiophene

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

[6-benzyloxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-benzyloxy-3- [4- [2- (1-N, N-morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

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

[6-isopropoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-isopropoxy-3- [4- [2- (1-hexamethylimino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-isopropoxy-3- [4- [2- (1-N, N-dimethylimino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-isopropoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

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

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

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

[6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

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

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

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

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

[6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

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

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

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene hydrochloride

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

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

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

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

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

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

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

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

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

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

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

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

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

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

[6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene hydrochloride

[6-ethylsulfonyloxy-3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-ethynesulfonyloxyphenyl)] benzo [b] thiophene hydrochloride

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

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

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

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzoyloxyphenyl)] benzo [b] thiophene hydrochloride

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-pivaloyloxyphenyl)] benzo [b] thiophene hydrochloride

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-butylsulfonyloxyphenylyloxyphenyl)] benzo [b] thiophene hydrochloride

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

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

[6-benzyloxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-benzyloxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-benzyloxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-benzyloxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-isopropoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-isopropoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-Isopropoxy-3- [4- [2- (1-N, N-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] Thiophene

[6-isopropoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

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

[6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-hydroxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

[6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

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

[6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

[6-hydroxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

[6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

[6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene

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

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

[6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

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

[6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

[6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

[6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

[6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

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

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

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

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

[6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

[6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

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

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

[6-hydroxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

[6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

[6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

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

The following examples are given to further illustrate the preparation of the compounds of the present invention. It is not intended to limit the invention to the scope of the following examples.

NMR data of the following examples were obtained on a GE 30OMH _z NMR instrument and anhydrous d-6 DMSO was used as solvent unless otherwise indicated.

Preparation Example 1

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)]-benzo [b] thiophene and [3- (4-benzyloxy) Method for preparing phenoxy] benzo [b] thiophene

4-benzyloxyphenol (97.6 g, 0.488 mol) and cuprous oxide (23.3 g, in a solution of 3-bromo-benzo [b] thiophene (69.62 g, 0.325 mol) in 55 mL of anhydrous collidine under N ₂ 0.163 mmol) was added. The mixture was heated to reflux for 24 h. After cooling down, the reaction mixture was diluted with ethyl acetate (200 mL) and the crude mixture was celite. Inorganic salts were removed by filtration through a pad of Celite (Aldrich, Milwaukee, Wisconsin). The filtrate was washed with 1N hydrochloric acid (3x150 mL). The organics were dried (sodium sulfate) and concentrated to liquid in vacuo. Tianaphthene was removed by distillation (10 mmHg, 115-120 ° C.). The remaining material was chromatographed (silicon dioxide, hexane: ethyl acetate 85:15) to give 12.2 g of benzo [b] thiophene and 12.95 g of [3- (4-benzyloxy) phenoxy] benzo [b] thiophene as off-white solid. (35% based on recovered starting material). Melting point 84 to 86 ° C. ¹ H NMR (CDCl ₃ ) d 7.91-7.83 (m, 2H), 7.47-7.34 (m, 7H), 7.04 (q, J _AB = 9.0HZ, 4H), 6.47 (s, 1H), 5.07 (s, 2H). Analytical Calcd for C ₂₁ H ₁₆ O ₂ S: C, 75.88; H, 4.85. Found: C, 75.75; H, 5.00.

Preparation Example 2

[2-iodine-3- (4-benzyloxy) phenoxy] benzo [b] thiophene

N-butyl via syringe in a solution of [3- (4-benzyloxy) phenoxy] benzo [b] thiophene (6.00 g, 18.1 mmol) in anhydrous tetrahydrofuran (100 mL) at -78 ° C, N ₂ 12.4 mL of lithium, 19.9 mmol, 1.6 M in hexane) was added dropwise. The solution turned colorless to dark orange. After stirring at −78 ° C. for 20 minutes, the Lithio species were treated with l ₂ (5.03 g, 19.9 mmol) and added dropwise via cannula as a solution in 50 mL of anhydrous tetrahydrofuran. When the reaction was complete, the reaction turned light yellow and slowly warmed to room temperature. 0.1N sodium sulfite solution (200 mL) was added to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x150 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo to afford an oil which crystallized in a stationary state. Recrystallization from hexane / ethyl ether yielded 7.10 g (86%) of [2-iodo-3- (4-benzyloxy) phenoxy] benzo [b] thiophene as white crystalline powder. Melting point 87-92 ° C., ¹ H, NMR (CDCl ₃ ) d 7.72 (d, J = 8.1 Hz, 1H), 7.47-7.20 (m, 8H), 6.89 (s, 4H), 5.01 (s, 2H). Analytical Calcd for C ₂₁ H ₁₅ O ₂ SI: C, 55.03; H, 3.30. Found: C, 55.29; H, 3.31.

Preparation Example 3

[2- (4-tert-butyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

In a solution of [2-iodo-3- (4-benzyloxy) phenoxy] benzo [b] thiophene (4.50 g, 9.82 mmol) in toluene (20 mL), 4- (tert-butoxy) phenylboronic acid ( 2.28 g, 11.75 mmol), followed by tetrakistriphenylphosphinepalladium (0.76 g, 0.66 mmol). 14.5 mL of 2N sodium carbonate solution was added to this solution. The resulting mixture was heated to reflux for 3 hours. Cool and dilute the reaction with 150 ml of ethyl acetate. The organics were washed with 0.1 N sodium hydroxide (2x100 mL) and then dried (sodium sulfate). When concentrated, it became semisolid, which was dissolved in chloroform and passed through a pad of silicon dioxide. It was concentrated to an oil which was triturated from hexane to yield 4.00 g (91%) of [2- (4-tert-butyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene as a white powder. ) Was obtained. Melting point 105-108 ° C. ¹ H NMR (CDCl ₃ ) d 7.77 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.43-7.24 (m, 8H), 6.98 (d, J = 8.6 Hz, 2H), 6.89 (q, J _AB = 9.3 Hz, 4H), 4.99 (s, 2H), 1.36 (s, 9H). FD mass spectrometry: 480. Analytical calcd. For C ₃₁ H ₂₈ O ₃ S: C, 77.47; H, 5.87. Found: C, 77.35, H, 5.99.

Preparation Example 4

[2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy [b] thiophene was prepared in a similar manner using 4-methoxyphenylboronic acid.

Yield = 73%. Melting point = 115 to 118 ° C. ¹ H NMR (CDCl ₃ ) d 7.80-7.90 (m, 3H), 7.33-7.53 (m, 8H), 6.93-7.06 (m, 6H), 5.00 (s, 2H), 3.83 (s, 3H), FD Mass Spec .: 438. Analytical Calcd for C ₂₈ H ₂₂ H ₃ S: C. 76.69; H, 5.06. Found: C, 76.52; H, 5.09.

Preparation Example 5

[2- (4-tert-butyloxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene

A solution of [2- (4-tert-butoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene (1.50 g, 3.37 mmol) in 30 ml of anhydrous ethanol containing 1% concentrated hydrochloric acid To this was added 0.5 g of 10% palladium on carbon. After the mixture was hydrogenated at 40 psi for 1 hour, the reaction was judged complete by thin layer chromatography. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was dissolved in a minimum amount of ethyl acetate and passed through a short silicon dioxide column to remove celite (ethyl acetate as eluent). Concentration gave a white solid which was triturated from hexane / ethyl ether. Filtration gave 868 mg (73%) of [2- (4-tert-butyloxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene. Melting point 210 to 213 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.13 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.35-7.26 (m, 3H), 7.01 (d, J = 8.6 Hz, 2H) 6.70 (q, J _AB = 8.9 Hz, 4H), 1.28 (s, 9H). FD mass spectrometry: 390. Analytical calcd. For C ₂₄ H ₂₂ O ₃ S: C, 73.82; H, 5.68. Found: C, 73.98; H, 5.84.

Preparation Example 6

[2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene was prepared in a similar manner.

Yield = 80%, Melting Point = 120 to 125 占 폚. ¹ H NMR (CDCl ₃ ) d 7.80-7.90 (m, 3H), 7.48 (m, 1H), 7.30-7.48 (m, 2H), 6.90-7.03 (m, 4H), 6.76-6.86 (m, 2H) , 3.82 (s, 3 H). FD mass spectrometry: 348; Analytical Calcd for C ₂₁ H ₁₆ O ₃ S: C, 72.89; H, 4.63. Found: C, 72.68; H, 4.82.

Example 1

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thio

[2- (4-tert-Butyloxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene (1.25 g, 3.20 in anhydrous N, N-dimethylformamide (10 mL) Cesium carbonate (5.70 g, 17.6 mmol) was added to the solution. After stirring for 20 minutes, a small amount of 2-chloroethylpiperidine hydrochloride (1.95 g, 10.56 mmol) was added. The resulting heterogeneous mixture was stirred vigorously for 24 hours. The reaction contents were then washed with water (200 mL). The aqueous phase was extracted with ethyl acetate (3x100 mL). The combined organic layers were then washed with water (2x200 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo to afford an oil. Chromatography (5-10% methanol / chloroform) to give 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-tert-butyloxyphenyl)] benzo [b] 1.47 g (91%) of thiophene were obtained and used directly in the next step without characterizing.

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-tertbutyloxy-phenyl)] benzo [b] thiophene (1.37 g, 2.73 mmol) around Dissolve in trifluoroacetic acid (10 mL) at temperature. After stirring for 15 minutes, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with saturated sodium bicarbonate solution (3 × 10 mL). The organic layer was dried (sodium sulfate) and concentrated to precipitate a white solid in solution. The product was recrystallized from ethyl acetate-ethyl ether to give 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b as colorless crystals. ] 1.03 g (85%) of thiophene was obtained. Melting point 169 to 172 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.81 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.36-7.26 (m, 3H), 6.86 (s, 4H), 6.78 (d, J = 8.6 Hz, 2H), 4.10 (m, 2H), 3.29 (m, 2H), 2.95-2.75 (m, 4H), 1.68-1.40 (m, 6H) . Analytical calcd. For C ₂₇ H ₂₇ NO ₃ S.0.55CF ₃ Co ₂ H: C, 66.40; H, 5. 46; N, 2.76. Found: C, 65.99; H, 5.49; N, 2.61.

Example 2

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene was treated with ethyl ether hydrochloric acid in ethyl acetate to Converted to hydrochloride (yield 90%).

Data of Example 2: Melting point 233 to 240 ° C. ¹ H NMR (DMSOd ₆ ) d 10.43 (m, 1H); 9.89 (s, 1H), 7.93-7.95 (m, 1H), 7.60-7.64 (m, 2H), 7.35-7.50 (m, 3H), 6.83-7.03 (m, 6H), 4.27-4.30 (m, 2H ), 3.40-3.60 (m, 4H), 2.96-3.10 (m, 2H), 1.70-1.95 (m, 5H), 1.40-1.53 (m, 1H). FD mass spectrometry: 446. Analytical calcd. For C ₂₇ H ₂₇ NO ₃ Cl: C, 67.28; H, 5. 86; N, 2.91. Found: C, 67.07; H, 5. 66; N, 2.96.

Example 3

In a similar manner the following examples were prepared:

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

Melting point 150-155 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.79 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.54 (d, 8.6 Hz, 2H), 7.36-7.26 (m, 3H), 6.84 ( s, 4H), 6.78 (d, J = 8.6 Hz, 2H), 4.00 (bt, 2H), 2.92 (m, 2H), 2.85 (m, 4H), 1.73 (m, 4H). Analytical calcd. For C ₂₆ H ₂₅ NO ₃ S.0.33CF ₃ CO ₂ H: C, 68.25; H, 5. 44; N, 2.99; Found; C, 68.29, H, 5.46; N, 3.19.

Example 4

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

Melting point 189-191 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.91 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.34-7.25 (m, 3H), 6.81 (s, 4H), 6.75 (d, J = 8.6Hz, 2H), 3.89 (bt, 2H), 2.75 (bt, 2H), 2.68 (m, 4H), 1.48 (m, 8H), C ₂₈ H ₂₉ NO ₃ S1.50H Analytical estimate for ₂ O: C, 69.11; H, 6.79; N, 2.88. Found: C, 69.25; H, 6.79; N, 2.58.

Example 5

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

Melting point 70 캜. ¹ H NMR (DMSO-d ₆ ) d 9.91 (bs, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.35-7.24 (m, 3H), 6.82 (s, 4H), 6.78 (d, J = 8.6 Hz, 2H), 2.76 (bt, 2H), 2.51 (m, 4H), 0.91 (m, 6H). FD mass spectrometry: 434. Analytical calcd. For C ₂₆ H ₂₇ NO ₃ S.0.50H ₂ O: C, 70.56; H, 6. 38; N, 3.16. Found: 70.45; H, 6. 26; N, 3.20.

Example 6

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

Melting point = 228 to 230 ° C., ¹ H NMR (DMSO-d ₆ ) d 7.96 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.35-7.50 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H), 6.86-6.90 (m, 4H), 4.28-4.31 (m, 2H), 3.74 (s, 3H), 3.37-3.45 (m, 4H, 2.92-2.96 (m) , 2H), 2.46-2.48 (m, 5H), 1.74 (m, 1H) FD mass spectrometry: 459. Analytical calculation for C ₂₈ H ₂₉ NO ₃ S.1.0HCl: C, 67.80; H, 6.10; N Found: C, 68.06; H, 6.38; N, 2.60.

Another method for synthesizing [2- (4-tert-butyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

Preparation Example 7

[3- (4-benzyloxy) phenoxy] benzo [b] thiophene-2-boronic acid

N-butyllithium (9.90) via syringe into a -78 ° C solution of [3- (4-benzyloxy) phenoxy] benzo [b] thiophene (5.00 g, 15.1 mmol) in 20 mL of anhydrous tetrahydrofuran under N _2. Ml, 15.8 mmol), 1.6 M in hexane) were added dropwise. After stirring for 15 minutes, B (OiPr) ₃ (3.83 mL, 16.6 mmol) was added via syringe and the resulting mixture was warmed to 0 ° C. The reaction was then quenched by partitioning between ethyl acetate and 1.0 N hydrochloric acid (100 mL each). The layers were separated and the organics extracted with water (1 × 100 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo to give a solid which was triturated from ethyl ether / hexanes. Filtration gave 3.96 g (70%) of [3- (4-benzyloxy) phenoxy] benzo [b] thiophene-2-boronic acid as a white solid. Melting point 115 to 121 ° C. ¹ H NMR (DMSO-d ₆ ) d 8.16 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.42-7.23 (m, 7H), 6.90 (q, J _AB = 9.0 Hz, 4H), 5.01 (s, 2H), Analytical calculation for C ₂₁ H ₁₇ O ₄ SB: C, 67.04; H, 4.55 Found: C, 67.17; H, 4.78.

[3- (4-benzyloxy) phenoxy] benzo [b] thiophene-2-boronic acid was reacted with [2-iodo-3- (4-benzyloxy) phenoxy] -benzo [b] thiophene and According to the conditions described for 4- (tert-butoxy) phenyl boronic acid, the reaction was carried out with 4- (tert-butoxy) bromobenzene in 81% yield in [2- (4-tert-butyloxyphenyl) -3- ( 4-benzyloxy) phenoxy] benzo [b] thiophene was obtained.

Example 7

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene hydrochloride

Melting point = 223 to 226 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.99 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.44-7.30 (m, 7H), 6.90 (s, 4H), 4.27 (m, 2H), 3.43-3.35 (m, 4H), 2.97-2.88 (m, 2H), 1.73-1.61 (m, 5H), 1.34 (m, 1H). Analytical Calcd for C ₂₇ H ₂₇ NO ₂ S.1.0HCl: C, 69.59; H, 6.06; N, 3.00. Found: C, 69.88; H, 6. 11; N, 3.19.

Example 8

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-fluorophenyl)] benzo [b] thiophene

Melting point 219 to 226 ° C. ¹ H NMR (DMSO-d ₆ ) d 10.20 (bs, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.77-7.73 (m, 4H), 7.42-7.25 (m, 5H), 6.90 (s , 4H), 4.27 (m, 2H), 3.44-3.31 (m, 4H), 2.96-2.89 (m, 2H), 1.78-1.61 (m, 5H), 1.34 (m, 1H). FD mass spectrometry: 447. Analytical calcd. For C ₂₇ H ₂₆ NO ₂ SF.1.0HCl: C, 67.00; H, 5. 62; N, 2.89. Found: C, 67.26; H, 5.67; N, 3.03.

Preparation Example 8

Synthesis method of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6 -Methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene

To a 60 ° C. solution of [6-methoxy-2- (4-methoxyphenyl)] benzo [b] thiophene (27.0 g, 100 mmol) in 1.10 L of chloroform bromine (15.98 g, 100 mmol) was added dropwise. After the addition was complete, the reaction was cooled to room temperature and the solvent was removed in vacuo to yield [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene as a white solid. 34.2 g (100%) were obtained. Melting point 83 to 85 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.70-7.62 (m, 4H), 7.17 (dd, J = 8.6, 2.0 Hz, 1H, 7.09 (d, J = 8.4 Hz, 2H) .FD mass spectrometry: 349, 350. Analytical calcd. For C ₁₆ H ₁₃ O ₂ SBr: C, 55.03; H, 3.75 Found: C, 54,79; H, 3.76.

Example 9

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

4-benzyloxyphenol in 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 N ₂ (38.96 g, 194.8 mmol) and cuprous oxide (14.5 g, 97.4 mmol) were added. The resulting mixture was heated to reflux for 48 hours. After cooling to room temperature, the mixture was dissolved in acetone (200 mL) and the inorganic solids were removed by filtration. The filtrate was concentrated in vacuo and the residue was dissolved in methylene chloride (500 mL). The methylene chloride solution was washed with 3N hydrochloric acid (3x300 mL) followed by 1N sodium hydroxide (3x300 mL). The organic layer was dried (sodium sulfate) and dried in vacuo. When the residue was taken in 100 ml of ethyl acetate, a white solid was formed, which was collected by filtration to recover [6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene (4.62 g, 17.11 mmol). Harvested. The filtrate was concentrated in vacuo and then passed through a short pad of silica gel (methylene chloride as eluent) to remove material at baseline. The filtrate was concentrated in vacuo and the residue was crystallized from hexane / ethyl acetate to give [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo as an off-white crystalline solid. 7.19 g of [b] thiophene were initially obtained. The mother liquor was concentrated and chromatographed on silica gel (hexane / ethyl acetate 80:20) to give 1.81 g additional product. The total yield of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] -benzo [b] thiophene was 9.00 g (based on recovered starting material) By 24%). 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 to 103 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.60 (d, J = 8.8 Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H), 4.98 (s, 2H), 3.86 (s , 3H); 3.81 (s, 3 H). FD mass spectrometry: 468. Analytical calcd. For C ₂₉ H ₂₄ O ₄ S: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29.

Preparation Example 9

[6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) -phenoxy] benzo [b] thiophene

[6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene (1.50 g, 3.20 mmol) in 50 ml of ethyl acetate and 1% in ethanol Palladium on 105 carbon (300 mg) was added to a solution of 10 mL concentrated hydrochloric acid. After the mixture was hydrogenated at 40 psi for 20 minutes, the completion of the reaction was judged by thin layer chromatography. The mixture was passed through celite to remove the catalyst and the concentrate was concentrated in vacuo as a white vinegar. The crude product was passed through a pad of silica gel (chloroform as solution). 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 캜. ¹ H NMR (DMSO-d ₆ ) d 9.10 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (J = 8.8, 2.1 Hz, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H) , 3.78 (s, 3H), 3.72 (s, 3H). Fd mass spectrometry: 378. Analytical calcd. For C ₂₂ H ₁₈ O ₄ S: C, 69.82; H, 4.79. Found: C, 70.06; H, 4.98.

Example 10

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

[6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene (1.12 g, in 7 ml of anhydrous N, N-dimethylformamide under N ₂ To a solution of 2.97 mmol) cesium carbonate (3.86 g, 11.88 mmol) was added. After stirring for 10 minutes, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) was 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 combined organic layers were washed with water (2x100 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 oil, which was dissolved in 10 ml of ethyl acetate and treated with oxalic acid (311 mg, 3.4 mmol). After stirring for 10 minutes, a white precipitate formed, harvested by filtration and dried to obtain [6-methoxy-3- [4-2- (1-piperidinyl) ethoxy] -phenoxy as the oxalic acid salt. A total of 1.17 g (70%) of ci] -2- (4-methoxyphenyl)] benzo [b] thiophene was obtained. Melting point 197 to 200 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.60 (d, J = 8.7z, 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 (wide t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (wide t, 2H), 3.12-3.06 (m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H), FD Mass spectrometry: 489.C ₂₉ H ₃₁ NO ₄ S.0.88 Analytical Calcd for HO ₂ CCO ₂ H: C, 64.95; H, 5.80; N, 2.46. Found: C, 64.92; H, 5.77; N, 2.54.

Example 11

Treatment of the free base with ethyl ether hydrochloric acid gave [6-methoxy-3- [4-2- (1-perridinyl) ethoxy] -phenoxy] -2- (4-methoxyphenyl)] benzo [b ] Thiophene hydrochloride was obtained.

Melting point 216-220 ° C. ¹ H NMR (DMSO-d ₆ ) d 10.20 (bs, 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 _AB = 9.0 Hz, 4H), 4.31 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.43 (m, 4H), 2.97 (m, 2H), 1.77 (m, 5H), 1.37 (m, 1H). FD mass spectrometry: 489. Analytical calcd. For C ₂₉ H ₃₁ NO ₄ S.1.0HCl: C, 66.21; H, 6. 13; N, 2.66. Found: C, 66.46; H, 6. 16; N, 2.74.

The following examples were prepared in a similar manner.

Example 12

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

Melting point 95-98 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (D, J = 9.0 Hz, 2H), 6.94 (dd, J = 9.0, 2.0 Hz, 1H), 6.86 (s, 4H), 3.97 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.76 ( s, 3H), 2.73 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 4H). FD mass spectrometry: Analytical calcd. For 477 C ₂₈ H ₂₉ NO ₄ S: C, 70.71; H, 6. 15; N, 2.99. Found: C, 70.59; H, 6. 15; N, 3.01.

Example 13

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

Melting point 189-192 ° C. ¹ H NMR (DMSO-d ₆ ) d 10.55 (bs, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, H), 6.86 (s, 4H), 3.94 (t, J = 6.0 Hz, 2H), 3.83 ( s, 3H), 3.76 (s, 3H), 2.80 (t, 6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Analytical calcd. For C ₃₀ H ₃₃ NO ₄ S.1.0HCl: C, 66.71; H, 6. 35; N, 2.59. Found: C, 66.43; H, 6. 46; N, 2.84.

Example 14

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

Melting point 196-198 ° C. ¹ H NMR (DMSO-d ₆ ) d 10.48 (bs, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H), 6.87 (q, J _AB = 9.0 Hz, 4H), 4.25 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.54 (m, 2H), 3.09 (m, 4H), 2.00 (m, 3H), 1.88 (m, 3H). Analytical Calcd for C ₂₈ H ₃₁ NO ₄ S.5HCl: C, 63.18; H, 6. 15; N, 2.63. Found: C, 63.46; H, 5.79; N, 2.85.

Example 15

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

Melting point 208-211 캜. ¹ H NMR (DMSO-d ₆ ) d 10.6 (bs, 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 _AB = 9.0 Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m, 4H), 3.82 (s, 1H), 3.77 (s, 3H), 3.59-3.42 (m, 4H), 3.21-3.10 (m, 2H). Analytical Calcd for C28H ₂₉ NO ₅ S.1.0HCl: C, 63.09; H, 5.73; N, 2.65. Found: C, 63.39; H, 5.80; N, 2.40.

Example 16

[6-methoxy-3- [4- [3-piperidino) propoxy] -phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

Melting point 195-200 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.90 (bs, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0 Hz, 1H), 6.88 (s, 4H), 3.97 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.44 (m, 2H), 3.15 (m, 2H), 2.87 (m, 2H), 2.12 (m, 2H), 1.77 (m, 5H), 1.39 (m, 1H) ). Analytical calcd. For C ₃₀ H ₃₃ NO ₄ S1.15HCl: C, 66.01; H, 6. 40; N, 2.73. Found: C, 66.01: H, 6.40: N, 2.73.

Example 17

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

Melting point 164-166 캜. ¹ H NMR (DMSO-d ₆ ) d 9.77 (bs, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, 1H), 6.89 (s, 4H), 3.99 (t, J = 6.0 Hz, 2H), 3.83 ( s, 3H), 3.77 (s, 3H), 3.15 (m, 6H), 2.06 (m, 2H), 1.20 (t, J = 7.0 Hz, 6H), for C ₂₉ H ₃₃ NO ₄ S.1.0HCl Analytical Calculations: C, 65.96; H, 6. 49; N, 2.65. Found: C, 66.25; H, 6. 64; N, 2.84.

Example 18

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

[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. Boron tribromide (7.20 ml, 76.20 mmol) was added to this solution. The resulting mixture was stirred at 8 ° C. for 2.5 h. The reaction was quenched by pouring into saturated saturated sodium bicarbonate solution (1 L) cooled to 0 ° C and quenched by stirring into saturated sodium bicarbonate solution (1 L) while stirring and cooled to 0 ° C. The methylene chloride layer was separated and the remaining solids were 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 give [6-hydroxy-3- [4- [2- (1-piperidinyl) as a white solid). 7.13 g (81%) of ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene were obtained. Melting point 93 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.73 (bs, 1H), 9.68 (bs, 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 (shielded)), 6.81 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 3.92 (t , J = 5.8Hz, 2H), 2.56 (t, J = 5.8Hz, 2H), 2.36 (m, 4H), 1.43 (m, 4H), 1.32 (m, 2H), FD mass spectrometry: 462 C ₂₇ Analytical Calcd for H ₂₇ NO ₄ S: C, 70.20; H, 5. 90; N, 3.03. Found: C, 69.96; H, 5. 90; N, 3.14.

Example 19

[6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene was subjected to the procedure described above. To oxalate thereof (yield 80%). Data for [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene oxalate As follows.

Melting point 246-249 ° C. (decomposition point). ¹ H NMR (DMSO-d ₆ ) d 7.45 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.87 (dd, J = 8.6, 1.8 Hz, 1H (shielded), 6.84 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 4.08 (bt, 2H), 3.01 (bt, 2H), 2.79 (m , 4H), 1.56 (m, 4H), 1.40 (m, 2H). FD mass spectrometry: 462. Analytical calculation for C ₂₇ H ₂₇ NO ₄ S.0.75HO ₂ CCO ₂ H: C, 64.63; H, 5. 42; N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62.

Example 20

Treatment of the free base in ethyl acetate with ethyl ether hydrochloric acid gave [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) ] Benzo [b] thiophene was converted to its hydrochloride (yield 91%). Data for [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride are given below. Same as

Melting point 158-165 캜. ¹ H NMR (DMSO-d ₆ ) d 9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.04 ( d, J = 8.6 Hz, 1H), 6.86 (q, J _AB = 9.3 Hz, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 4.26 (bt, 2H), 3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5H), 1.25 (m, 1H). FD mass spectrometry: 461, Analytical Calcd for C ₂₇ H ₂₇ NO ₄ S.1.0HCl: C, 65.11; H, 5.67; N, 2.81. Found: C, 64.84; H, 5. 64; N, 2.91.

In a similar manner the following examples were prepared:

Example 21

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

Melting point 99 to 113 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d J = 9.0Hz, 2H), 7.25 (d, J = 2.0Hz, 1H), 7.09 (d , J = 9.0 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 9.0, 2.0 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 (t, J = 7.0 Hz, 4H). Analytical Calcd for C ₂₆ H ₂₅ NO ₄ S.0.5H ₂ O: C, 68.40; H, 5. 74; N, 3.07. Found: C, 68.52; H, 6.00; N, 3.34.

Example 22

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

Melting point 125 to 130 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d J = 9.0 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 7.09 (d , J = 9.0Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 9.0, 2.0Hz, 2H), 6.79 (d, J = 9.0Hz), 3.94 (t, J = 6.0Hz, 2H ), 2.80 (t, J = 6.0 Hz, m, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Analytical Calcd for C ₂₈ H ₂₉ NO ₄ S: C, 70.71; H, 6. 15; N, 2.94. Found: C, 70.67; H, 6. 31; N, 2.93.

Example 23

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

Melting point 137-141 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.75 (s, 1H), 9.71 (s, 1H), 7.49 (d J = 9.0Hz, 2H), 7.25 (d, J = 2.0Hz, 1H), 7.09 (d , J = 9.0 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.95 (t, J = 6.0 Hz , 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H). Analytical Calcd for C ₂₆ H ₂₇ NO ₄ S: C, 69.46; H, 6.05; N, 3.12. Found: C, 69.76; H, 5.85; N, 3.40.

Example 24

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

Melting point 157-162 캜. ¹ H NMR (DMSO-d ₆ ) d 10.60 (bs, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0Hz, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.92 (q, J _AB = 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), 3.51 (m, 4H), 3.18 (m, 2H), C ₂₆ H ₂₅ NO ₄ SHCl Analytical Calcd for: C, 62.46; H, 5. 24; N, 2.80. Found: C, 69.69; H, 5. 43; N, 2.92.

Example 25

[6-hydroxy-3- [4- [3- (1-N, N-diethylamino) propoxy] -phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

Melting point 185-191 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.94 (bs, 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0, 2.0 Hz, 1H ), 3.99 (t, J = 6.0 Hz, 2H), 3.14 (m, 6H), 2.08 (m, 2H), 1.20 (t, J = 6.0 Hz, 6H). Analytical Calcd for C ₂₇ H ₂₉ NO ₄ S.1.30HCl: C, 63.46; H, 5.98; N, 2.74. Found: C, 63.23; H, 6.03; N, 3.14.

Example 26

[6-hydroxy-3- [4- [2- (1-N, N-diisopropylamino) ethoxy] -phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene Hydrochloride

Melting point 128-131 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.81 (bs, 1H), 9.76 (s, 1H), 9.02 (s, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.28 (m, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.90 (s, 4H), 6.79 (m, 3H), 4.19 (m, 2H), 3.68 (m, 2H), 3.50 (m, 2H), 1.31 (m) , 12H). Analytical calcd. For C ₂₈ H ₃₁ NO ₄ S.1.33HCl: C, 63.92; H, 6. 19; N, 2.66. Found: C, 63.82; H, 6.53; N, 2.61.

Example 27

[6-hydroxy-3- [4- [3- (piperidino) phenoxy] -phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

Melting point 258-262 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.85 (bs, 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 3.44 (m, 2H), 3.15 (m, 2H), 2.88 (m, 2H), 2.11 (m, 2H), 1,73 (m, 5H), 1.39 (m, 1 H). Analytical calcd. For C ₂₈ H ₂₉ NO ₄ S.0.75HCl: C, 66.87; H, 5.96; N, 2.78. Found: C, 67.04; H, 5. 90; N, 2.68.

Alternatively, Example 19 was prepared using a methoxymethyl (MOM) protecting group instead of methoxy, as shown in Scheme (III) above. This method is similar to the method described above, but removes the MOM group by acid hydrolysis in the final step.

Preparation Example 10

[6-methoxy-2- (4-methoxymethyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

Melting point 94-96 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.65 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.43-7.32 (m, 5H), 7.23 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 7.04 (dd, J = 8.8, 2.0 Hz, 1H), 6.92 (q, J _AB = 9.2 Hz, 4H), 5.26 (s, 2H) , 5.21 (s, 2H), 5.01 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H). FD mass spectrometry: 528

Preparation Example 11

[6-methoxy-2- (4-methoxymethyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

Melting point 90-91 degreeC. ¹ H NMR (DMSO-d ₆ ) d 9.15 (s, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 2.0 Hz, 1H), 6.72 (q, J _AB = 9.1HZ, 4H), 5.26 (s, 2H), 5.21 (s, 2H), 3.40 (s, 3H) , 3.37 (s, 3 H). FD mass spectrometry: 438. Analytical calcd. For C ₂₄ H ₂₂ O ₆ S: C, 65.74; H, 5.06. Found: C, 65.50; H, 4.99.

Example 28

[6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

50 ml of trifluoroacetic acid was added to a solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (10.0 g, 28.6 mmol) in 50 ml of anhydrous methylene chloride. . After stirring for 5 minutes, hydrogen peroxide (4.0 ml, 28.6 mmol, 30% aqueous solution) was added. The resulting mixture was stirred at ambient temperature for 2 hours. Solid sodium bisulfite (1.25 g) followed by 15 ml of water was added to the dark solution. The mixture was stirred vigorously for 15 minutes and then concentrated in vacuo. The residue was partitioned between chloroform and saturated sodium bicarbonate solution (200 ml each). The layers were separated and the organic layer was extracted with saturated sodium bicarbonate solution. The organic layer was then dried (sodium sulfate) and concentrated to a solid in vacuo, which was triturated from ethyl ether / ethyl acetate. Filtration gave 8.20 g (80%) of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide) as a yellow solid, which was ethyl It can be recrystallized from acetate. Melting point 170-173 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.24 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5, 2.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H). Analytical Calcd for C ₁₆ H ₁₃ NO ₃ SBr: C, 52.62; H, 3.59. Found: C, 52.40; H, 3.55.

Example 29

[2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide) was prepared in a similar manner.

Melting point 120-125 ° C., ¹ H NMR (DMSO-d ₆ ) d 8.06 (D, J = 7.62 Hz, 1H), 7.78-7.59 (m, 5H), 7.13 (d, J = 8.7 Hz, 2H), 3.81 (s, 3 H). FD mass spectrometry: 335. Analytical calcd. For C ₁₅ H ₁₁ O ₂ SBr: C, 53.75; H, 3.31. Found: C, 53.71, H, 3.46.

Preparation Example 12

Method for preparing 4- (2- (1-piperidinyl) ethoxy) -phenol

To a solution of 4-benzyloxyphenol (50.50 g, 0.25 mmol) in 350 ml of anhydrous DMF was added 2-chloroethylpiperidine (46.30 g, 0.25 mol). After stirring for 10 minutes, calcium carbonate (52.0 g, 0.375 mol) and cesium carbonate (85.0 g, 0.25 mol) were added. The resulting heterogeneous mixture was stirred vigorously for 48 hours at ambient temperature. The reaction was then poured into water (500 ml) and extracted with methylene chloride. The organic layer was then extracted several times with 1N sodium hydroxide and finally washed with brine. Extracted several times with 1N sodium hydroxide and finally washed with brine. The organic layer was then dried (sodium sulfate) and concentrated to oil in vacuo. Chromatography (SiO ₂ , 1: 1 hexanes / ethyl acetate) afforded 60.0 g (77%) of 4- [2- (1-piperidinyl) ethoxy] phenoxybenzyl ether as colorless oil. ¹ H NMR (DMSO-d ₆ ) d 7.40-7.27 (m, 5H), 6.84 (q, J _AB = 11.5 Hz, 4H), 4.98 (s, 2H), 3.93 (t, J = 6.0 Hz, 2H) , 2.56 (t, J = 6.0 Hz, 2H), 2.35-2.37 (m, 4H), 1.48-1.32 (m, 6H). FD mass spectrometry: 311. Analytical calcd. For C ₂₀ H ₂₅ NO ₂ : C, 77.14; H, 8.09; N, 4.50. Found: C, 77.34; H, 8. 18; N, 4.64.

4- [2- (1-piperidinyl) ethoxy] phenoxybenzyl ether (21.40 g, 68.81 mmol) was dissolved in 200 ml of 1: 1 EtOH / EtOAc containing 1% concentrated HCl. The solution was transferred to a Parr bottle and 5% palladium on carbon (3.4 g) was added. The mixture was hydrogenated at 40 psi for 2 hours. The mixture was then passed through a plug of celite to remove the catalyst. The filtrate was concentrated to a solid in vacuo and slurried in ethyl ether and filtered to give 12.10 g (83%) of 4- (2- (1-piperidinyl) ethoxy) -phenol. Melting point 148 to 150 ° C. ¹ H NMR (DMSO-d ₆ ) d 8.40 (s, 1H), 6.70 (q, J _AB = 11.5 Hz, 4H), 3.93 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz , 2H), 2.42-2.38 (m, 4H), 1.52-1.32 (m, 6H). FD mass spectrometry: 221. Analytical calcd. For C ₁₃ H ₁₉ NO ₂ : C, 70.56; H, 8.09; N, 4.50. Found: C, 70.75; H, 8.59; N, 6.54.

Example 30

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide )

Sodium hydride (0.57 g, 1.43 mmol, 60% dispersion in inorganic oil) in a solution of 4- (2- (1-piperidinyl) ethoxy) -phenol (0.32 g, 1.43 mmol) in 5 ml of anhydrous DMF at ambient temperature Was added. After stirring for 15 minutes, [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide) (0.50 g, 1.37 mmol) in small amounts Added. After stirring for 1 hour, the completion of the reaction was judged by TLC analysis. The solvent was removed in vacuo and the residue partitioned between water and 10% ethanol / ethyl acetate. The organic layer was washed several times with water and then dried (sodium sulfate). Concentration in vacuo gave an oil which was triturated from ethyl acetate / hexanes to give [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (as a pale yellow solid. 4-methoxyphenyl)] benzo [b] thiophene- (S-oxide) 0.62 g (89%) was obtained. Melting point 97 to 100 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.68 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.06-6.92 (m, 6H), 6.85 (d, J = 8.8 Hz, 2H), 3.94 (t, J = 6.0 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.56 (t, J = 6.0 Hz, 2H), 2.39-2.32 (m, 4H ), 1.47-1.32 (m, 6 H). Analytical Calcd for C ₂₉ H ₃₁ NO ₅ O: C, 68.89; H, 6. 18; N, 2.77. Found: C, 68.95; H, 6.04; N, 2.57.

Example 31

In a similar manner [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide) is prepared It was.

oil. ¹ H NMR (DMSO-d ₆ ) d 8.03 (m, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.53-7.50 (m, 2H), 7.09-6.82 (m, 7H), 3.94 (bt , J = 5.9 Hz, 2H), 3.74 (s, 3H), 2.56 (bt, J = 5.9 Hz, 2H), 2.36-2.33 (m, 4H), 1.45-1.31 (m, 6H), FD mass spectrometry: 475. Analytical calcd. For C ₂₈ H ₂₉ NO ₄ S: C, 70.71; H, 6. 15; N, 2.94. Found: C, 70.44; H, 6. 43; N, 3.20.

Example 32

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

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [200 ° C. in 200 ml of dry THF at 0 ° C. under nitrogen gas. b] A small amount of lithium aluminum hydride (0.34 g, 8.91 mmol) was added to a solution of thiophene- (S-oxide) (Example 30) (3.00 g, 5.94 mmol). After stirring for 30 minutes, the reaction was quenched by the careful addition of 5.0 ml of 2.0N sodium hydroxide. The mixture was stirred vigorously for 30 minutes and additional 2.0 N sodium hydroxide was added to dissolve the salt. The mixture was then partitioned between water and 10% sodium hydroxide. The layers were separated and the aqueous layer was extracted several times with 10% ethanol / ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated to oil in vacuo. The crude product was dissolved in 50 ml of 1: 1 ethyl ether and treated with excess ethyl ether hydrochloride. The resulting precipitate was collected and dried to give [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] as a white solid. 2.98 g (96%) of benzo [b] thiophene hydrochloride were obtained.

Example 6 was also prepared from Example 31 in the same manner.

Preparation Example 13

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

N-butyllithium (76.2 ml, 0.122 mol, 1.6 in hexane through a syringe in a solution of 6-methoxybenzo [b] thiophene (18.13 g, 0.111 mol) in 150 ml anhydrous tetrahydrofuran (THF) at -60 ° C. M solution) was added dropwise. After stirring for 30 minutes, triisopropyl borate (28.2 ml, 0.122 mol) was introduced through a syringe. The resulting mixture was slowly 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. Concentrated in vacuo to a white solid and triturated from ethyl ether hexanes. Filtration gave 16.4 g (71%) of 6-methoxybenzo [b] thiophene-2-boronic acid as a white solid. Melting point 200 ° C. (decomposition point). ¹ H NMR (DMSO-d ₆ ) d 7.83 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.6, 2.0 Hz, 1H), 3.82 (s, 3H), FD mass spectrometry: 208.

Preparation Example 14

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

To a solution of 6-methoxybenzo [b] thiophene-2-boronic acid (3.00 g, 14.4 mmol) in 100 ml of toluene, 4- (methanesulfonyloxy) phenylbromide (3.98 g, 15.8 mmol) followed by 2.0 N sodium carbonate 16 ml of solution was added. After stirring for 10 minutes, tetrakistriphenylphosphinepalladium 0.60 g, 0.52 mmol) was added and the resulting mixture was heated to reflux for 5 hours. Then, the reaction mixture was cooled at ambient temperature, and the product precipitated out of the organic phase. The aqueous phase was removed and the organic layer was concentrated in vacuo to a solid. Trituration from ethyl ether gave a solid which was filtered and dried in vacuo to yield 3.70 g (77%) of [6-methoxy-2- (4-methanesulfonyloxy-phenyl)] benzo [b] thiophene as a tan solid. ) Was obtained. Melting point 197-201 캜. ¹ H NMR (DMSO-d ₆ ) d 7.82-7.77 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 6.98 (dd, J = 8.7, 1.5 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H). FD mass spectrometry: 334. Analytical calcd. For C ₁₆ H ₁₄ O ₄ S ₂ : C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21.

Preparation Example 15

[6-methoxy-2- (4-benzyloxyphenyl)] benzo [b] thiophene was prepared in a similar manner to Preparation Example 14.

Yield = 73%. Melting point 217-221 캜. ¹ H NMR (DMSO-d ₆ ) d 7.63-7.60 (m, 3H), 7.59-7.26 (m, 7H), 7.02 (d, J = 8.7 Hz, 2H), 6.96 (dd, J = 8.8, 2.2 Hz , 1H), 5.11 (s, 2H), 3.88 (s, 3H). FD mass spectrometry: 346. Analytical calcd. For C ₂₂ H ₁₈ O ₂ S: C, 76.27; H, 5.24. Found: C, 76.00; H, 5.25.

Preparation Example 16

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

Boron tribromide in 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 and nitrogen gas 14.20 g, 5.36 ml, 56.8 mmol) was added. The resulting mixture was stirred at ambient temperature for 3 hours. The reaction was poured slowly into excess ice water and quenched. After stirring vigorously for 30 minutes, the white precipitate was collected by filtration, washed several times with water and dried in vacuo to yield [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo as a white solid. 8.92 g (98%) of [b] thiophene were obtained. Melting point 239 to 243 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.70 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.72 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.38 ( d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H), 6.86 (dd, J = 8.7, 1.7 Hz, 1H), 3.38 (s, 3H). FD mass spectrometry: 320. Analytical calcd. For C ₁₅ H ₁₂ O ₄ S ₂ : C, 56.23; H, 3.77. Found: C, 56.49; H, 3.68.

Preparation Example 17

[6-benzyloxy-2- (4-methanesulfonyloxyphenyl) -benzo [b] thiophene

To a solution of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (3.20 g, 10.0 mmol) in 75 ml of anhydrous DMF was added to C ₅₂ CO ₃ (5.75 g, 17.7 mmol). Benzyl chloride (1.72 mL, 11.0 mmol) was then 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. Dry in vacuo and the crude product was suspended in 1: 1 hexanes: ethylether. A solid was obtained, yielding 3.72 g (91%) of [6-benzyloxy-2- (4-methanesulfonyloxy-phenyl)] benzo [b] thiophene as a white solid. Melting point 198-202 ° C., ¹ H NMR (DMSO-d ₆ ) d 7.81-7.78 (m, 3H), 7.72 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.47 -7.30 (m, 7H), 5.15 (s, 2H), 3.39 (s, 3H), FD mass spectrometry: 410.

Preparation Example 18

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

Lithium aluminum hydride (2.32 g) in a solution of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (12.50 g, 30.50 mmol) in 300 ml of dry THF at ambient temperature and nitrogen gas , 61.0 mmol) was added in small amounts. The mixture was then stirred at ambient temperature for 3 hours, and then the mixture was quenched by pouring into excess cold 1.0N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phase was then washed several times with water, then dried (sodium sulfate) and concentrated to a solid in vacuo. Chromatography, silicon dioxide, chloroform) yielded 8.75 g (87%) of [6-benzyloxy-2- (4-hydroxyphenyl) benzo [b] thiophene as a white solid. Melting point 212-216 캜. ¹ H NMR (DMSO-d ₆ ) d 9.70 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.51-7.30 (m, 8H), 7.00 (dd, J = 8.7 Hz, 2.2 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 5.13 (s, 2H). FD mass spectrometry: 331. Analytical calcd. For C ₂₁ H ₆ O ₂ S: C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85.

Example 19

[6-benzyloxy-2- (4-methoxyphenyl) -benzo [b] thiophene

Sodium hydride (1.66 g, 41.5 mmol) in a solution of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene (8.50 g, 26.40 mmol) in 200 ml of dry THF at ambient temperature and nitrogen gas. ) Was added in small amounts. When gas evolution stopped, iodomethane (3.25 ml, 52.18 mmol) 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 yield 9.00 g (98%) of [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene as a white solid. Melting point 180 to 185 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J = 8.8, 2.2 Hz 1H), 6.98 (d, J = 8.7 Hz, 2H), 5.13 (s, 2H), 3.76 (s, 3H), FD Mass spectrometry: 346. Analytical calculation for C ₂₂ H ₁₈ O ₂ S: C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43.

Preparation Example 20

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

At ambient temperature [6-benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene (10.0 g, 28.9 mmol) was added to 200 ml of chloroform with 10.0 g of solid sodium bicarbonate. To this suspension bromine (1.50 ml, 29.1 mmol) as a solution in 100 ml of chloroform was added dropwise over 30 minutes. When the addition was complete, water (200 mL) was added and the layers separated. The organic phase was dried (sodium sulfate) and concentrated in vacuo as 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. Melting point 146-150 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.70 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J = 8.8, 2.2 Hz , 1H), 7.06 (D, J = 8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (S, 3H). FD mass spectrometry: 346. Analytical calcd. For C ₂₂ H ₁₇ O ₂ Br: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00.

Preparation Example 21

[6-methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] thiophene was prepared in a similar manner.

Yield = 91%, Melting | fusing point 125-127 degreeC. ¹ H NMR (DMSO-d ₆ ) d 7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3.82 (s, 3H) . FD mass spectrometry; 346. Analytical calcd. For C ₂₂ H ₁₇ O ₂ Br: C, 62.13; H, 4.03. Found: C, 62.33; H, 3.93.

Examples 33 and 34 were prepared in a similar manner to Example 28.

Example 33

[6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide)

Crystallized from ethyl acetate, isolated as a yellow solid. Melting point 202-205 캜. ¹ H NMR (DMSO-d ₆ ) d 7.80 (d, J = 2.2 Hz, 1H), 7.68 (D, J = 8.7 Hz, 2H), 7.55 (D, J = 8.4 Hz, 1H), 7.47-7.32 ( m, 6H), 7.10 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H), 3.80 (S, 3H). FD mass spectrometry: 441. Analytical calcd. For C ₂₂ H ₁₇ O ₃ SBr: C, 59.87; H, 3.88. Found: C, 59.59; H, 3.78.

Preparation Example 34

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

It was isolated by chromatography (SiO ₂ , CHCl ₃ ) as a yellow solid. Melting point 119 to 123 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.73 (D, J = 2.2 Hz, 1H), 7.68 (D, J = 8.8 Hz, 2H), 7.55 (D, J = 8.5 Hz, 1H), 7.46-7.31 ( m, 5H), 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. Analytical calcd. For C ₂₂ H ₁₇ O ₃ SBr: C, 59.87; H, 3.88. Found: C, 60.13; H, 4.10.

Examples 35 and 36 were prepared in a similar manner to Example 30.

Example 35

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

Yellow oil. ¹ H NMR (DMSO-d ₆ ) d 7.76 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J = 8.6 , 2.2 Hz, 1H), 7.03-6.93 (m, 5H), 6.85 (D, J = 8.8 Hz, 2H), 5.18 (s, 2H), 3.91 ((bt, H = 5.8 Hz, 2H), 3.73 ( s, 3H), 2.56 (bt, J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.32m, 6H). FD mass spectrometry: 592. Analytical calcd. For C ₃₅ H ₃₅ NO ₅ S: C, 72.26; H, 6.06; N, 2.41. Found: C, 72.19; H, 5.99; N, 2.11.

Example 36

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

Yellow oil. Melting point 89-93 degreeC. ¹ H NMR (DMSO-d ₆ ) d 7.68 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H ), 6.86 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 3.94 (bt, H = 5.8 Hz, 2H), 3.81 (s, 3H), 2.56 (bt, J = 5.8 Hz, 2H ), 2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H). FD mass spectrometry: 592. Analytical calcd. For C ₃₅ H ₃₅ NO ₅ S.0.25ETOAc: C, 71.62; H, 6. 18; N, 2.32. Found: C, 71.32; H, 5.96; N, 2.71.

Examples 37 and 38 are prepared in a similar manner to Example 11.

Example 37

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

It was isolated in 95% overall yield starting from [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide). Purification by chromatography (SiO ₂ , 1-5% methanol / chloroform) gave an off-white solid. Melting point 105-108 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.62 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J = 8.6 Hz, 1H), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (bt, J = 5.8 Hz, 2H), 3.72 (S, 3H), 2.55 (bt , J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31 (m, 4H). FD mass spectrometry: 565. Analytical calculation for C ₃₅ H ₃₅ NO ₄ S: C, 74.31; H, 6. 24; N, 2.48. Found: C, 74.35; H, 6.07; N, 2.76.

Example 38

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

Yield = 91%. Melting point 106 to 110 ° C. ¹ H NMR (DMSO-d ₆ ) d 7.59 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (bt, J = 5.89 Hz, 2H), 3.78 (s, 3H), 2.55 (bt, J = 5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1.44-1.31 (m, 4H). FD mass spectrometry: 565. Analytical calculation for C ₃₅ H ₃₅ NO ₄ S: C, 74.31; H, 6. 24; N, 2.48. Found: C, 74.26; H, 6. 17; N, 2.73.

Example 39

[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 thiophene (8.50 g, 15.0 mmol) was added palladium black (1.50 g), ammonium formate (3.50 g, 55.6 mmol) and 30 mL of water. The resulting mixture was pulled to reflux and monitored by TLC. After about 3 hours, the completion of the reaction was judged and the solution was cooled to ambient temperature. The reaction was filtered through a pad of celite to remove the catalyst and the filtrate was concentrated to a solid in vacuo. The concentrate was partitioned between saturated sodium bicarbonate and 5% ethanol / ethyl acetate. The layers were separated and the organic phase was dried (sodium sulfate) and concentrated in vacuo. The crude product was chromatographed 9 silicon dioxide, 1-5% methanol / chloroform) to give [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- as foam. 6.50 g (91%) of (4-methoxyphenyl)] benzo [b] thiophene were obtained which were converted to a solid by trituration with hexane. Melting point 174-176 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.77 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (D, J = 2.0 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (s, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H), 3.91 (bt, H = 5.9 Hz, 2H), 3.71 ( s, 3H), 2.55 (bt, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spectrometry: 475. Analytical calcd. For C ₂₈ H ₂₉ NO ₄ S: C, 70.71; H, 6. 15; N, 2.94. Found: C, 70.46; H, 5.93; N, 2.71.

Example 40

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] ti in a similar manner to Example 39 Offen was prepared.

Yield = 88%. Melting point 147 to 150 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.72 (s, 1H), 7.51 (D, J = 2.0 Hz, 1H), 7.48 (D, J = 8.6 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2,2 Hz, 1H), 6.81 (S, 4H), 6,76 (D, J = 8.6 Hz, 2H), 3.91 (bt, J = 5.9 Hz, 2H) , 3.77 (s, 3H), 2.55 (bt, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spectrometry: 475. Analytical calcd. For C ₂₈ H ₂₉ NO ₄ S: C, 70.71; H, 6. 15; N, 2.94. Found: C, 71.00; H, 6. 17; N, 2.94.

Alternatively, [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2-4-benzyloxyphenyl)] benzo [b] thiophene- (S -Oxide) and [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- ( Examples 39 and 40 can be prepared directly from S-oxide) by the same transition hydrogenolysis process (yield 90%).

Example 41

[6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (Example 39) After treatment with ethyl ether / hydrochloride in ethyl acetate, it was crystallized from ethanol / ethyl acetate and converted to its hydrochloride (yield 85%).

Melting point 156 to 160 ° C. ¹ NMR (DMSO-d ₆ ) d 10.28 (bs, 1H), 9.85 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.06 (D , J = 8.7 Hz, 1H), 6.93 (D, J = 8.8 Hz, 2H), 6.87 (q, J _ab = 9.3 Hz, 4H), 4.27 (bt, J = 5.9 Hz, 2H), 3.71 (s, 3H), 3.44-3.31 (m, 4H), 2.98-1.88 (m, 2H), 1.74-1.60 (m, 6H), 1.36-1.29 (m, 1H). FD mass spectrometry: 475. Analytical calcd. For C ₂₈ H ₂₉ NO ₄ S.1.0HCl: C, 65.68; H, 5. 90; N, 2.73. Found: C, 65.98; H, 6. 11; N, 2.64.

Example 42

[6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] ti in a similar manner to Example 41 Offen hydrochloride was prepared.

Melting point 215-217 캜. ¹ H NMR (DMSO-d ₆ ) d 10.28 (bs, 1H), 9.80 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.12 ( d, J = 8.4 Hz, 1H), 6.91-6.80 (m, 5H), 6.78 (D, J = 8.6 Hz, 2H), 4.27 (bt, 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. Analytical calcd. For C ₂₈ H ₂₉ NO ₄ S.1.0HCl: C, 65.68; H, 5. 90; N, 2.73. Found: C, 65.87; H, 5.79; N, 2.99.

Example 43

[6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene hydrochloride

Triethylamine (1.00 mL) was added to a solution of Example 20 (0.50 g, 1.08 mmol) in 20 mL anhydrous tetrahydrofuran at 0 ° C. To this mixture was added benzoyl chloride (0.28 mL, 2.35 mmol). After stirring for 2 hours at 0 ° C., the reaction was quenched by partitioning between ethyl acetate / saturated sodium bicarbonate solution (100 mL each). The layers were separated and the organic layer was dried (sodium sulfate) and concentrated in vacuo as a white solid. The crude product was dissolved in 10 ml of ethyl acetate and treated with ethyl ether hydrochloric acid. The white precipitate formed was collected by filtration. 390 mg of [6-benzoyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy-2- (4-benzoyloxyphenyl)] benzo [b] thiophene hydrochloride as a white solid (50%) was obtained. Melting point 200 to 204 캜. ¹ H NMR (DMSO-d ₆ ) d 9.95 (bs, 1H), 9.18 (m, 1H), 8.16 (m, 2H), 8.12 (dd, J = 10.0, 2.0 Hz, 2H), 7.87 (dd, J = 7.0, 2.0 Hz, 2H), 7.78 (m, 2H), 7.64 (m, 2H), 7.42 (D, J = 7.0 Hz, 2H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (s, 4H), 4.32 (m, 2H), 3.45 (m, 4H), 2.99 (m, 2H), 1.75 (m, 5H), 1.39 (m, 1H). Analytical Calcd for C ₄₁ H ₃₅ NO ₆ S.1.5HCl: C, 67.97; H, 5.08; N, 1.93. Found: C, 68.05; H, 5.24 N, 20 1.

The following examples were made by the same procedure.

Example 44

[6-ethylsulfonyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-ethylsulfonyloxyphenyl)] benzo [b] thiophene hydrochloride

Yield = 72%. Melting point 110-115 ° C. ¹ H NMR (DMSO-d ₆ ) d10.15 (bs, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.85 (d, 1 = 7.0 Hz, 2H), 7.43 (m, 3H), 7.34 (dd, J = 9.0, 2.0 Hz, 1H), 6.97 (m, 4H), 4.31 (m, 2H), 3.57 (m, 4H), 3.44 (m, 4H), 2.97 (m, 2H), 1.76 ( m, 5H), 1.40 (m, 7H). Analytical calcd. For C ₃₁ H ₃₅ NO ₈ S ₃ .1.5HCl: C, 54.57; H, 5. 32; N, 2.05. Found: C, 54.36; H, 5. 37; N, 2.05.

The following examples were prepared by a similar procedure using trifluoromethanesulfonic anhydride.

Example 45

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

Yield = 81%. oil. ¹ H NMR (DMSO-d ₆ ) d 7.82 (D, J = 8.7 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.8 Hz, 1H), 6.93 (dd, J = 8.8, 2.0 Hz, 1H), 6.84 (s, 4H), 3.92 (bt, J = 5.7 Hz, 2H), 3.79 (s, 3H), 2.56 ( bt, J = 5.8 Hz, 2H), 2.36-2.30 (m, 4H), 1.44-1.31 (m, 6H). Mass spectrometry: 607. Analytical calcd. For C ₂₉ H ₂₈ NO ₆ F ₃ S ₂ : C, 57.32; H, 4. 64; N, 2.30. Found: C, 57.16; H, 4.52; N, 2.01.

The following example was prepared from Example 1 by a similar procedure.

Example 46

3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-benzoyloxyphenyl)] benzo [b] thiophene hydrochloride

Yield = 85%. Melting point 190 to 198 ° C. ¹ H NMR (DMSO-d ₆ O d 10.48 (br, s, 1H), 8.00-8.10 (m, 2H), 7.80-8.00 (m, 3H), 7.60-7.53 (m, 4H), 7.40-7.56 ( m, 6H), 6.93 (s, 2H), 4.37-4.43 (m, 3H), 1.40-1.50 (m, 4H) .Analysis calcd for C ₃₄ H ₃₁ NO ₄ S.1.0HCl): C, 74.29, H, 5.68; N, 2.5. Found: C, 74.52; H, 5.80; N, 2.59.

Example 47

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-pivaloyloxyphenyl)] benzo [b] thiophene hydrochloride

Yield = 90%. Melting point 193-197 캜. ¹ H NMR (DMSO-d ₆ ) d 10.10 (br s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.40-7.53 (m, 3H) , 7.15 (d, J = 6.7 Hz, 2H), 7.00 (s, 5H), 4.33-4.40 (m, 2H), 3.45-3.60 (m, 4H), 3.00-3.10 (m, 2H), 1.70-1.90 (m, 6 H), 1.40 (S, 9 H). Mass spectrometry: 529. Analytical calcd. For C ₃₂ H ₃₅ NO ₄ S.1.0HCl: C, 67.89; H, 6. 41; N, 2.47. Found: C, 68.94; H, 6. 61; N, 1.72.

Example 48

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-butylsulfonyloxyphenyl)] benzo [b] thiophene hydrochloride

Yield = 85%. White solid. Melting point 98-104 ° C. ¹ H NMR (DMSO-d ₆ ) d 10.20 (br s, 1H), 8.02 (s, J = 8.0 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.40-7.55 (m, 5H) , 7.00 (S, 4H), 4.30-4.40 (m, 2H), 3.46-3.66 (m, 6H), 3.00-3.10 (m, 2H), 1.70-1.95 (m, 6H), 1.40-1.60 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H). FD mass spectrometry: 565. Analytical calcd. For C ₃₁ H ₃₅ NO ₅ S ₂ .1.0HCl: C, 61.83; H, 6.03; N, 2.33. Found C, 61.55; H, 6. 15; N, 2.25.

Preparation Example 21

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

Method for preparing 4- (methoxymethyloxy) phenyldisulfide:

To a solution of 4-hydroxy phenyldisulfide (650 mg, 2.60 mmol) in 10 mL of anhydrous N, N-dimethylformamide at 10 ° C. was added sodium hydride (230 mg, 5.75 mmol, 60% dispersion nuclei in inorganic oil). After stirring for 15 minutes, chloromethylmethyl ether (0.44 mL, 5.75 mmol) was added via syringe. The reaction was allowed to warm to ambient temperature and stirred for 0.5 h. The mixture was partitioned between brine / ethyl acetate (20 mL each). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL). The organic phase was dried (sodium sulfate) and concentrated to yellow oil (993 mg, 100%). An analytical sample of 4- (methoxymethyloxy) -phenyldisulfide was prepared by chromatography (silicon dioxide, 4% ethyl acetate / hexanes). ¹ H NMR (DMSO-d ₆ ) d 7.40 (d, J = 6.9 Hz, 4H), 7.00 (d, J = 6.9 Hz, 4H), 5.15 (s, 4H), 3.32 (s, 6H). FD mass spectrometry: 338. Analytical calcd. For C ₁₆ H ₁₈ NO ₄ S ₂ : C, 56.78: H, 5.36. Found: C, 57.08; H, 5.44.

Example 49

[6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) -thiophenoxy] benzo [b] thiophene

A solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (1.82 g, 5.2 mmol) in 10 mL of anhydrous tetrahydrofuran at -60 ° C., N ₂ . N-butyllithium (3.15 mL, 5.0 mmol, 1.6 M in hexane) was added dropwise via syringe. The resulting mixture was warmed to -20 ° C for 10 minutes and then cooled to -60 ° C. 4- (methoxymethyloxy) -phenyldisulfide (800 mg, 2.36 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the Lithio species and the resulting mixture was slowly cooled to 0 ° C. After stirring for 20 minutes, the reaction was quenched by partitioning between brine / ethyl acetate (50 mL each). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried (sodium sulfate) and concentrated to oil in vacuo. Chromatography (silicon dioxide, 5% ethyl acetate / hexanes) to yield [6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethylbenoxy) thiophenoxy] benzo as colorless oil. [b] 287 mg (27%) of thiophene were obtained. _{^{1 H NMR (DMSO- d 6)}} d 7.59 (d, J = 8.4Hz, 2h), 7.58 (d, J = 2.0Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.03-6.85 ( m, 7H), 5.06 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H). Mass Spec .: 438. Analytical Calcd for C ₂₄ H ₂₂ O ₄ S ₂ : C, 65.73; H, 5.06. Found: C, 65.93; H, 5.10.

Example 50

[6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) -thiophenoxy] benzo [b] thiophene

Methanol: Water: Tetrahydrofuran 1: 1: 2 [6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy] benzo [b in 10 ml of a mixture ] To a solution of thiophene (233 mg, 0.53 mmol) methanesulfonic acid (0.2 mL, 2.66 mmol) was added. The mixture was heated to reflux for 5 hours. Cool to ambient temperature and dilute the reaction mixture with water. The aqueous phase was extracted with ethyl acetate (× 2). The organic layer was washed several times with saturated sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated in vacuo to afford [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene as a colorless oil. 206 mg (99%) were obtained. _{^{1 H NMR (DMSO- d 6)}} d 9.43 (s, 1H), 7.63 (d, J = 8.4Hz, 2H), 7.6 (d, J = 2.0Hz, 1H), 7.59 (d, J = 8.8Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.02 (dd, J = 8.8, 2.0 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H). FD mass spectrometry: 395. Analytical calcd. For C ₂₂ H ₁₈ O ₃ S ₂ : C, 66.98; H, 4.60. Found: C, 67.26, H, 4.78.

Example 51

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [[b] thiophene

[6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene (242 mg, 0.61 in 8.0 ml of anhydrous N, N-dimethylformamide. To the solution of mmol) cesium carbonate (820 mg, 2.5 mmol) was added followed by 2-chloroethylpiperidine hydrochloride (194 mg, 1.05 mmol). The resulting mixture was stirred at ambient temperature for 48 hours and then partitioned between brine / ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate (3 ×). The organic layer was dried (sodium sulfate) and concentrated to oil in vacuo. Chromatography (silicon dioxide, 0-2% methanol / chloroform) gave [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- as an amber oil. 244 mg (92%) of (4-methoxyphenyl)] benzo (b) thiophene were obtained.

Example 52

Samples of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene are standard It was converted to its hydrochloride according to the procedure (yield 72%).

Melting point 198 to 201 캜. ¹ H NMR (DMSO-d ₆ ) d 7.63 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H), 7.02 (dd, J = 8.2, 2.0 Hz, 1H), 6.92 (q, J _AB = 9.0 Hz, 4H), 4.24 (bt, 2H), 3.82 (s, 2H), 3.80 (S, 3H), 3.49-3.39 (m <4H), 2.93 (m, 2H), 1.82-1.62 (m, 5H), 1.38 (m, 1H). Analytical calcd. For C ₂₉ H ₃₂ NO ₃ S 2 .1.0HCl: C, 64.28; H, 5.95; N, 2.58. Found: C, 64.09; H, 6.08; N, 2.78.

Example 53

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

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) in 15 mL of anhydrous methylene chloride at 0 ° C. and N ₂ . )] Benzo [b] thiophene hydrochloride (160 mg, 0.29 mmol) was added boron tribromide (0.15 mL). The resulting dark solution was stirred at 0 ° C. for 1 hour and then immediately poured into a stirring solution of ethyl acetate / saturated sodium bicarbonate solution (50 mL each). The layers were separated and the aqueous phase washed with ethyl acetate (3 x 30 mL). The organic phase was dried (sodium sulfate) and concentrated in vacuo to a white solid. Chromatography (silicon dioxide, 0-5% methanol / chloroform) gave [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- as a white solid. 91 mg (60%) of (4-hydroxyphenyl)] benzo [b] thiophene were obtained. Melting point 123-127 ° C. ¹ H NMR (DMSO- d ₆ ) d 9.79 (s, 1H), 9.71 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.9 Hz, 1H), 7.26 ( d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.82-6.76 (m, 5H), 3.91 (t, J = 8.8 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.40 (m, 4H), 1.41-1.28 (m, 6H), FD mass spectrometry: 478. Analytical calculation for C ₂₇ H ₂₇ NO ₃ S ₂ : C, 67.90; H, 5. 70; N, 2.93. Found: C, 68.14; H, 5. 84; N, 2.65.

Example 54

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

Melting point 180 to 190 ° C. ¹ H NMR (DMSO-d ₆ ) d 9.86 (s, 1H), 9.79 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.7 Hz, 1H), 7.29 ( d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.86-6.81 (m, 5H), 4.27 (m, 2H), 3.41-3.37 (m, 4H), 2.96-2.84 (m, 2H), 1.77-1.60 (m, 5H), 1.35-1.28 (m, 1H). FD mass spectrometry: 477. Analytical calcd. For C ₂₇ H ₂₇ NO ₃ S ₂ .2.2HCl: C, 58.13; H, 5. 28; N, 2.51. Found: C, 58.11, H, 5.10; N, 2.61.

The following examples were made by the same method.

Example 55

[6-methoxy-3- [4- [2- (1-pyrrolodinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride

Melting point 215-218 캜. ¹ H NMR (DMSO-d ₆ ) D 7.61-7.58 (m, 3H), 7.52 (d, J = 8.8 Hz, 1H), 7.04-6.95 (m, 5H), 6.86 (d, J = 8.8 Hz, 2H ), 4.22 (bt, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.47-3.42 (m, 4H), 3.01 (m, 2H), 1.94-1.80 (m, 4H). FD mass spectrometry: 491. Analytical calcd. For C ₂₈ H ₂₉ NO ₃ S ₂ .1.0HCl: C, 63.67; H, 5.73; N, 2.65. Found: C, 63.47; H, 5.78; N, 2.65.

Example 56

[6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

Melting point 137-140 ° C. (decomposition point). _{^{1 H NMR (DMSO- d 6)}} d 9.86 (s, 1H), 9.80 (s, 1H), 7.46 (d, J = 8.6Hz, 2H), 7.42 (D, J = 8.7Hz, 1H), 7.29 ( D, J = 2.0Hz, 1H), 6.96 (D, J = 8.7Hz, 2H), 6.87-6.81 (m, 5H), 4.21 (bt, 2H), 3.53-3.41 (m, 4H), 3.01 (m , 2H), 1.95-1.82 (m, 4H). FD Mass Spectrometry: Analytical Calcd for 464. C ₂₆ H ₂₅ NO ₃ S ₂ .1.0HCl: C, 62.45; H, 5. 24; N, 2.80. Found: C, 62.36; H, 5. 37; N, 2.61.

Example 57

From the product of Example 45, triflate was hydrolyzed as described below in Example 58 to 6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (Phenyl)] benzo [b] thiophene hydrochloride was prepared.

Melting point 187-195 ° C. ¹ H NMR (DMSO- d ₆ ) d 7.66 (d, J = 2.8 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.28 (m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.0 Hz, 1H), 6.89 (s, 4H), 4.23 (bt, J = 5.7 Hz, 2H), 3.79 ( s, 3H), 3.45-3.38 (m, 4H), 2.98 (m, 2H), 1.77-1.61 (m, 5H), 1.3 (m, 1H), FD Mass spectrometry: 460 C ₂₈ H ₂₉ NO ₃ S ₂ Analytical calculation for 1.0HCl: C, 67.80; H, 6. 10; N, 2.84. Found: C, 67.62; H, 5.89; N, 2.67.

Example 58

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

100 ml to 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzoic anhydride at 0 ° C. and N ₂ . To a solution of [b] thiophene hydrochloride (5.00 g, 10.0 mmol) was added triethylamine (8.38 mL, 60.0 mmol) followed by trifluoromethanesulfonic anhydride (1.69 mL, 10.0 mmol). The resulting mixture was allowed to slowly warm up to room temperature and stirred for 1.5 h. The reaction was then quenched by pouring into 200 mL of saturated sodium bicarbonate solution. The aqueous phase was then extracted with ethyl acetate (3 x 100 mL). The organic layer was dried (sodium sulfate) and concentrated to oil in vacuo. 6-trifluoromethanesulfonate-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-tri by chromatography (0-3% methanol / chloroform) Fluoromethane-sulfonatephenyl)] benzo [b] thiophene 2.82 g (39%), 6-trifluoromethanesulfonate-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy Cy-2- (4-phenyl)] benzo [b] thiophene and 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-trifluoromethanesulfonate 1.82 g (31%) of a 1: 1 mixture of phenyl)] benzo] b] thiophene and 1.48 g (36%) of recovered starting material as free base were obtained.

Triethylamine (2.0 mL) and 5% palladium on carbon (0.50 g) in a solution of a 1: 1 mixture (0.50 g, 0.84 mmol) of the monotriplate derivative of the last reaction in 60 mL of ethanol-ethyl acetate (5: 1) ) Was added. The resulting mixture was stirred at 40 psi for 2 hours. The mixture is then celite The catalyst was removed by filtration. The filtrate was concentrated to oil. The resulting mixture of monohydroxy derivatives was dissolved in ethyl acetate, which resulted in 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl] benzo [b ] Thiophene precipitated The filtrate was composed mainly of 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene Consisting of a 4: 1 mixture of phosphorus monohydroxy derivatives, the filtrate was concentrated in vacuo, the resulting solid was dissolved in a minimum amount of ethyl acetate and treated with ethyl ether hydrochloric acid, the resulting solid was recrystallized from ethanol, 69 mg (18%) of isotopically pure 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (phenyl)] benzo [b] thiophene hydrochloride Melting point 217-219 ° C. ¹ H NMR (DMSO- d ₆ ) d 9.87 (s, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.39-7.26 (m, 4H), 7.10 (d , J = 8.6 Hz, 1H), 6.89 (S, 4H), 6.78 (dd, J = 8.6, 2.0 Hz, 1H), 4.22 (bt, 2H), 3.39-3.37 (m, 4H), 2.97-2.90 (m, 2H), 1.74-1.60 (m, 5H), 1.39 (m, 1H) FD mass spectrometry: 446. Analytical calculation for C ₂₇ H ₂₇ NO ₃ S.1.0HCl: C, 67.28; H, 5.86; N, 2.91. Found: C, 67.00; H, 5.59; N, 2.87.

Alternatively, Example 58 is prepared by demethylating the product of Example 57 as described in Example 18.

Example 59

[6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S-oxide) [6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo as described for Example 30 [b] thiophene- (S-oxide) was prepared.

A yellow _{^{oil, 1 H NMR (DMSO- d 6}} ) d 7.69 (d, J = 2.0Hz, 1H), 7.67 (d, J = 8.6Hz, 2H), 7.09-6.99 (m, 5H), 6.96-6.87 ( m, 3H), 4.76 (seven line, J = 6.0 Hz, 1H), 3.99 (bt, J = 6.0 Hz, 2H), 3.78 (S, 3H), 2.61 (bt, J = 6.0 Hz, 2H), 2.44 -2.37 (m, 4H), 1.53-1.43 (m, 4H), 1.40-1.32 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H). FD mass spectrometry: 533. Analytical calcd. For C ₃₁ H ₃₅ NO ₅ S.0.67H ₂ O: C, 68.23; H, 6.71; N, 2.57. Found: C, 67.90; H, 6. 31; N, 2.53.

To [6-methoxy-3- [4- [2- (1-piperidinyl) methoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (Example 32) [6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride as described for Was prepared.

Melting point 168-170 ° C. ¹ H NMR (DMSO-d ₆ ) d 10.37 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.52 (D, J = 1.3 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.92-6.85 (m, 5H), 4.64 (seven line, J = 6.0 Hz, 1H), 4.28 (bt, J = 6.0 Hz, 2H), 3.72 (s, 3H), 3.44-3.37 (m, 4H), 2.95-2.89 (m, 2H), 1.73-1.60 (m, 5H), 1.36-1.28 (m, 1H), 1.25 (d, J = 6.0 Hz , 6H). FD mass spectrometry: 517. Analytical calcd. For C ₃₁ H ₃₅ NO ₄ S.HCl: C, 67.19; H, 6.55; N, 2.53. Found: C, 67.15; H, 6. 29; N, 2.62.

[6-isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride at 0 to 10 ° C Was treated with 2.0 equivalents of BCl ₃ in anhydrous dichloromethane (methyl ether was not cleaved under these conditions) [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene.

Examination process

General manufacturing process

In the examples illustrating the method, postmenopausal models were used to determine the different therapeutic effects while circulating lipids.

75-day-old female Spraque Dawley rats (200-225 g body weight) were obtained from Charles River Laboratories, Portage, Mich. Animals were left and right identically at Charles River Laboratories. After ovulation or Sham surgery procedures, they were shipped one week later.When they arrived, they were trapped in groups of three or four birds per cage in metal cages suspended in the air and fed with food (calcium-containing drugs). 0.5%) and water for 1 week, room temperature was maintained at 22.2 ± 1.7 ° C., minimum relative humidity was 40%, and the photoperiod in the room was 12 hours-light and 12 hours-shaded.

Dosing Scheme Tissue Collection . After 1 week, a compliance period in which the test compound is administered daily (ie, 2 weeks after OVX) was initiated. Unless stated otherwise, 17a-ethynyl estradiol or test compound was given orally as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. Animals were administered daily for four days. After completing the dosing schedule, animals were weighed and anesthetized with a ketamine: xylazine (2: 1, V: V) mixture and blood samples were collected by cardiac puncture. Animals were then choked with CO ₂ to kill, the midline was dissected to remove the uterus, and the wet weight of the uterus was determined.

Cholesterol Analysis : Blood samples were coagulated for 2 hours at room temperature and centrifuged at 3000 rpm for 10 minutes to obtain serum. Serum cholesterol was determined using Boehringer Mannheim diagnostics high performance cholesterol assay. Simply cholesterol was oxidized with choles-4-en-3-one and hydrogen peroxide. Hydrogen oxide was then reacted with phenol and 4-aminophenazone in the presence of peroxidase to obtain a p-quinone imine dye which was read by spectrometer at 500 nm. Next, the cholesterol concentration was calculated for the calibration curve. The entire assay was automated using the Biopek automated Workstation.

Uterine eosinophil peroxidase (EPO) assay . The uterus was kept at 4 ° C. until enzymatic analysis. The uterus was then homogenized to 50 volumes of 50 mM Tris buffer (pH-8.0) containing 0.005% Triton X-100. 0.01% hydrogen peroxide and 10 mM O-phenylenediamine (final concentration) in Tris buffer were added and the increase in absorbance was monitored for 1 minute at 450 nm. The presence of eosinophils in the uterus is an indicator of the estrogen activity of the compound. The maximum velocity at 15 second intervals was determined for the initial linear portion of the response curve.

Compound Source : 17a-ethynyl estradiol from Sigma Chemical Co., St. Louis, Missouri.

Effect of Formula (I) Compounds on Serum Cholesterol and Determination of Agonist / Non-Agonist Activity

The data presented in Table 1 below show a comparison of ovarian rats, rats treated with 17a-ethynylestradiol (EE ₂ ; orally available forms of estrogen) and rats treated with certain compounds of the invention. . EE ₂ decreased serum cholesterol when administered orally at 0.1 mg / kg / day, but the EE ₂ uterine weight was much greater than the uterine weight of ovarian-extracted test animals because it also stimulated the uterus. This uterine response to estrogen is widely recognized in the art.

Compounds of the present invention generally reduced serum cholesterol as compared to ovarian-extracted control animals, as well as increasing the uterine weight to a very minimal level with a slight decrease in most test compounds. Compared to the estrogen compounds known in the art, the advantage of reducing serum cholesterol without adversely affecting uterine weight is very rare and desirable.

As shown in the data below, estrogenicity was also determined by evaluating the adverse reaction that eosinophils invade into the uterus. Compounds of the present invention did not increase the number of eosinophils found in the interstitial layer of ovarian isolated rats, while estradiol almost increased the infiltration rate of eosinophils as expected.

The data shown in Table 1 below reflects the response of 5 to 6 rats to treatment.

Table 1

Table 1 (continued)

In addition to the proven advantages of the compounds of the present invention, particularly when compared to estradiol, the data clearly show that the compounds of formula (I) are not estrogen pseudogenic. In addition, no toxic effects (survival) are observed in any treatment.

Osteoporosis Test Course

Rats were treated daily for 35 days (6 rats per treatment group) and suffocated with carbon dioxide on day 36, following the general manufacturing procedure below. The 35 day period was sufficient to maximize bone density (measured as described herein). Wetness was removed, the uterus was removed to dissect without extraneous tissue, and the wet weight was determined after discarding the fluid contents to determine the estrogen deficiency associated with complex ovarian extraction. In response to ovarian extraction, uterine weight usually decreased by about 75%. The uterus was then placed in 10% neutral buffered formalin and then histologically analyzed.

The right femur was cut out, the resulting x-rays were digitized and analyzed by a shape analysis program (NIH shape) at the terminal metaphyseal. The basal pattern of the tibia of these animals was also scanned by quantitative computed tomography.

According to the procedure, the compound of the present invention and ethynyl estradiol (EE ₂ ) in 20% hydroxypropyl b-cyclodextrin were administered orally to the test animals. The terminal femoral interosseous data shown in Tables 2 and 3 below are the results of general formula (I) compound therapeutics compared to complete ovarian isolated test animals. The results are reported as the standard error of the mean ± mean.

TABLE 2

TABLE 3

In summary, the extraction of ovaries from test animals resulted in a much lower femoral density compared to the vehicle-treated complete control. Orally administered ethynyl estradiol (EE ₂ ) prevents this loss, but there is always a risk of uterine irritation by the therapeutic agent.

The compounds of the present invention also prevented bone loss in a general dose-dependent manner. Accordingly, the compounds of the present invention are useful for treating postmenopausal syndromes, in particular osteoporosis.

MCF-7 proliferation assay

10% fetal bovine serum (FBS) (V / V), L-glutamine (2 mM), sodium pyruvate (1 mM), HEPES {(N- [2-hydroxyethyl] piperazine-N '[2-ethanesulfonic acid ] 10 mM, MCF-7 breast adenocarcinoma cells (ATCC) in MEM (minimum essential medium, red phenol free, Sigma, St. Louis, MO) (maintenance medium) with non-essential amino acids and bovine insulin (1 μg / ml) HTB 22) 10 days prior to the assay, MCF-7 cells were added with fetal bovine serum (DCC-FBS) assay medium stripped with 10% dextran coated charcoal stripped instead of 10% FBS. MCF-7 cells were removed from the maintenance flasks using cell separation media (Ca ++ / Mg ++ free HBSS (without red phenol) with 10 mM HEPES and 2 mM EDTA). Wash twice with and adjust to 80,000 cells / ml Approximately 100 μl (8,000 cells) was added to a flat bottom microculture well [Costa (C ostar) 3596] and incubated for 48 hours in a 37 ° C. incubator immersed with 5% CO ₂ to allow cell adhesion and transfer and equilibrate.Sequential dilutions of DMSO as a pharmaceutical or control diluent were measured. 50 ml was transferred to three microincubators, and then 50 ml of assay medium was added to a final volume of 200 ml. After further incubation for 48 hours in a 37 ° C. incubator with 5% CO ₂ , The microcultures were pulsed with tritiated thymidine (1 μCi / well) for 4 hours The cultures were frozen at −70 ° C. for 24 hours, then thawed and Skatron semi-automatic cells. Microcultures were harvested using a harvester Samples were counted by liquid scintillation using a Wallac BetaPlace b counter. IC ₅₀ of the specific compound of the invention is shown.

Table 4

DMBA-Induced Breast Tumor Inhibition

Estrogen-dependent breast tumors were generated in female Sprague-Dawley rats purchased from Harlan Industries, Indianapolis, Indiana. After about 55 days of breeding, rats were orally administered once with about 20 mg of 7,12-dimethylbenz [a] anthracene (DMBA). About 6 weeks after DMBA administration, the mammary glands were promoted against the appearance of tumors every week. Each time one or more tumors appeared, the longest and shortest diameters of each tumor were measured with a metric caliper and the measurements recorded and the animals selected for the experiment. Attempts were made to uniformly distribute tumors of various sizes to the treatment and control groups so that tumors of average size were equally distributed within the test group. For each experiment, the control group and the test group contained 5 to 9 animals.

The compound of formula (I) is administered orally orally as an intraperitoneal injection in 2% gum arabic. Orally administered compounds are dissolved or suspended in 0.2 ml of corn oil. Each treatment, including the Arabic gum and corn oil control treatment, is administered once daily to each test animal. After initial tumor measurement and selection of test animals, tumors are measured weekly by the above-mentioned method. Treatment and measurement of animals continues for 3 to 5 weeks until the final area of the tumor is determined. For each compound and treatment, the change in the average tumor area is determined.

Smooth myopathy test process

Test 1

Three to twenty women with leiomyomas are administered a compound of the present invention. The amount of dosing compound is 0.1-1000 mg / day and the dosing period is 3 months.

The woman is observed for effects on leiomyoma during the administration period and up to 3 weeks after discontinuation.

Test 2

The same procedure as in Trial 1 is used, except that the dosing period is 6 months.

Test 3

The same procedure as in test 1 is used, except that the dosing period is one year.

Test 4

A. Introduction of Fibroma Tumors to Guinea Pigs

Uterine leiomyoma is introduced into sexually mature female guinea pigs using prolonged estrogen stimulation. Animals are administered by injection of estradiol 3 to 5 times weekly for 2 to 4 months or until tumors grow. Therapeutic agents consisting of the compounds or vehicles of the invention are administered daily for 3 to 16 weeks, after which the animals are killed, the uterus is harvested and analyzed for tumor regression.

B. Transplantation of Human Uterine Leiomyoma Tissues to Nude Mice

Tissue from human leiomyoma is implanted into the abdominal cavity or uterine muscle of sexually mature ovarian depleted female nude mice. Exogenous estrogen is supplied to induce growth of explanted tissue. In some cases, harvested tumor cells are cultured in vitro and then transplanted. Therapeutic agents consisting of the compounds or vehicles of the present invention are supplied by gavage daily for 3 to 16 weeks, the grafts are removed and measured for growth or degeneration. At death, the uterus is harvested to assess the condition of the organs.

Test 5

A. Tissues of human uterine leiomyoma tumors are harvested and maintained in vitro as the primary non-transforming culture. Surgical specimens are pushed through a sterile mesh or sieve or otherwise removed from surrounding tissue to form a single cell suspension. The cells are maintained in medium containing 10% serum and antibiotics. Growth of rats is determined in the presence and absence of estrogen. Cells are assayed for their ability to produce complement component C3 and their response to growth factors and growth hormone. In vivo cultures are treated with progestin, GnRH, a compound of the invention and vehicle, followed by evaluation of the response to the proliferative response. The amount of steroid hormone receptor is evaluated weekly to determine if important cellular characteristics are maintained in vitro. Tissues from 5 to 25 patients are used.

By showing activity in one or more of these tests, the compounds of the present invention are identified as likely to treat leiomyomas.

Endometriosis Test Process

In trials 1 and 2, the effects of 14 and 21 days of administration of the compounds of the present invention on the growth of explanted endometrial tissue can be examined.

Test 1

12 to 30 mature CD strain female rats are used as test animals. Divide them into three groups of equal numbers. The estrus cycle of all animals is monitored. During estrus, surgery is performed for each female. The left uterine angle of the females in each group is removed and cut into small squares, and the squares are loosely sutured to various sites adjacent to the mesenteric blood stream. In addition, the ovaries of females of group 2 are removed.

After surgery, animals in groups 1 and 2 were intraperitoneally injected with water for 14 days, while animals in group 3 were intraperitoneally injected with 1.0 mg of the compound of the present invention per kg of body weight for the same period. After 14 days of treatment, each female is killed and the endometrial explants, adrenal glands, residual uterus and ovary (if applicable) are removed and prepared for histological examination. Weigh the ovaries and adrenal glands.

Test 2

12 to 30 mature CD strain female rats are used as test animals. Divide them into two groups of equal numbers. The estrus cycle of all animals is monitored. During estrus, surgery is performed for each female. The left uterine angle of the females in each group is removed and cut into small squares, and the squares are loosely sutured to various sites adjacent to the mesenteric blood stream.

About 50 days after surgery, animals assigned to Group 1 were intraperitoneally injected with water for 21 days, while animals of Group 2 were injected 1.0 mg intraperitoneally with compounds of the present invention per kilogram of body weight for the same period. After 21 days of treatment, each female is killed and the endometrial explants and adrenal glands are removed and weighed. Explants are measured as indicators of growth. Monitor the heat cycle.

Test 3

A. Introduction of Endometriosis by Surgery

Autografts of endometrial tissue are used to induce endometriosis in rats and / or rabbits. Reproductiveally mature female animals are subjected to ovarian extraction on the left and right sides, and estrogen is externally supplied to provide a certain amount of hormone. Autograft endometrial tissue is implanted into the peritoneum of 5 to 150 animals and estrogen is fed to induce growth of explanted tissue. Therapeutic agents comprised of the compounds of the invention are fed daily by gavage for 3-16 weeks, and the grafts are removed and measured for growth or degeneration. At death, the complete angle of the uterus is harvested to assess the condition of the endometrium.

B. Transplantation of Human Endometrial Tissue into Nude Mice

Tissues of human endometrial lesions are implanted into sexually mature, deovarian female nude mice. Exogenous estrogen is supplied to induce growth of transplanted tissue. In some cases, harvested endometrial cells are cultured ex vivo and then transplanted. Therapeutic agents consisting of the compounds of the present invention are fed daily by gavage for 3 to 16 weeks, and the grafts are removed to determine growth or regression. At death, the uterus is harvested to assess the condition of the complete endometrium.

Test 4

A. Tissues of human endometrial lesions are harvested and maintained in vitro as primary nontransformation culture. Surgical specimens are pushed through a sterile mesh or sieve or otherwise removed from surrounding tissue to form a single cell suspension. The cells are maintained in medium containing 10% serum and antibiotics. Growth of rats is determined in the presence and absence of estrogen. Cells are assayed for their ability to produce complement component C3 and their response to growth factors and growth hormone. The in vivo culture is treated with progestin, GnRH, a compound of the invention and the vehicle, and then the response is assessed for the proliferative response. The amount of steroid hormone receptor is evaluated weekly to determine if important cellular characteristics are maintained in vitro. Tissues from 5 to 25 patients are used.

By showing activity in one or more of these tests, the compounds of the present invention are found to be useful for treating endometriosis.

The invention also provides a method for alleviating menopausal syndrome in women, comprising the above-mentioned method using a compound of formula (I), and also comprising administering to the woman an effective amount of estrogen or progestin. These therapies provide the patient with the benefit of each agent while the compounds of the present invention inhibit the unwanted side effects of estrogen and progestin and are therefore particularly useful for treating osteoporosis and reducing serum cholesterol. Any of the following postmenopausal tests demonstrates that the therapeutic agent of the mixture is active, thereby confirming that the combination therapy is useful for alleviating the symptoms of postmenopausal syndrome in women.

Various forms of estrogen and progestin are commercially available. Estrogen agents include, for example, ethynyl estrogen (0.01 to 0.03 mg / day), mestranol (0.05 to 0.15 mg / day), and primarin [Wyeth-Ayerst; 0.3 to 2.5 mg / day). Progestin-based drugs, for example, Provera Provera (Upjohn); 2.5 to 10 mg / day], such as hydroxyprogesterone, noretil nodrel (1.0 to 10.0 mg / day) and nonettin drone (0.5 to 2.0 mg / day). Preferred estro-based compounds are primarin, and noretil nodrel and noretin drone are preferred progestin-based drugs.

Methods of administering each of the estrogen-based and progestin-based agents are the same as those known in the art. For most of the methods of the present invention, the compound of general formula (I) is administered continuously one to three times daily. However, circulating therapies are particularly useful for the treatment of endometriosis or may be used acutely during painful attacks due to disease. In restenosis, treatment is limited to short (1-6 month) intervals after medical procedures such as angioplasty.

As used herein, the term "effective amount" refers to an amount of a compound of the present invention that can alleviate the syndromes of the various pathological conditions described herein. The particular amount of compound administered according to the invention will, of course, be determined by the particular environment around the patient, including the compound to be administered, the route of administration, the condition of the patient and the pathological condition to be treated. A typical daily dose will contain a nontoxic dose of about 5 mg to about 600 mg / day of a compound of the present invention. Preferred daily dosages are generally from about 15 mg to about 80 mg / day.

The compounds of the present invention can be administered by a number of routes, including rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Preferably, these compounds are formulated and administered, and the choice will be determined by the attending physician. Accordingly, another aspect of the invention is a pharmaceutical comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally an effective amount of estrogen or progestin, and a pharmaceutically acceptable carrier, diluent or excipient. Composition.

The total active ingredient in the formulation comprises 0.1 to 99.9% by weight of the formulation. "Pharmaceutically acceptable" means a carrier, excipient and salt that is compatible with the other ingredients of the formulation and should not be harmful to its receptor.

Pharmaceutical formulations of the present invention can be prepared by readily available ingredients that are well known by procedures known in the art. For example, in the presence or absence of an estrogen or progestin compound, the compound of formula (I) is formulated with conventional excipients, diluents or carriers and prepared into tablets, capsules, suspensions, powders and the like. Examples of excipients, diluents and carriers suitable for such formulations include: fillers and weighting agents (eg, starches, sugars, mannitol and silicic acid derivatives); Binders such as carboxymethyl cellulose and other cellulose derivatives, alginate gelatin and polyvinylpyrrolidone; Humectants (eg glycerol); Disintegrants such as calcium carbonate and sodium bicarbonate; Dissolution retardants such as paraffin; Absorption accelerators such as quaternary ammonium compounds; Surfactants (eg cetyl alcohol, glycerol monostearate); Adsorptive carriers such as kaolin bentonite; And lubricants such as talc calcium stearate, magnesium stearate and solid polyethylglycol.

The compounds may also be formulated as a solution for elixirs or convenient oral administration, for example by intramuscular, subcutaneous or intravenous routes or as a solution suitable for oral administration. In addition, this compound can be formulated as an extended dosage form or the like. In addition, this compound is well suited to formulate as an extended dosage form and the like. The formulation may be configured to release only the active ingredient, preferably to certain physiological lesions, possibly over a period of time. For example, coatings, encapsulants and protective matrices can be prepared from polymeric materials or waxes.

Compounds of formula (I) are administered either alone or in admixture with the agents of the invention in generally convenient formulations. The following formulations are illustrative only and are not intended to limit the scope of the invention.

1st brother

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

Formulation 1 : Gelatin Capsule

The formulation can be changed according to the appropriate modifications provided.

Tablet formulations are prepared using the following ingredients:

Formulation 2: Tablet

The ingredients are blended and compressed to make tablets.

Alternatively, tablets each containing 2.5 to 1000 mg of the active ingredient are prepared as follows:

Formulation 3 : Tablet

45 mesh milk with active ingredient, starch and cellulose. Pass the U. S. sieve and mix thoroughly. The polyvinylpyrrolidone solution was mixed with the resulting powder and then 14 mesh of oil. s. Pass the sieve. The granules thus prepared were dried at 50 to 60 ° C., and 18 mesh of milk. s. Pass the sieve. Then, 60 mesh in advance. s. Sieve passed through sodium carboxymethyl starch, magnesium stearate and talc is added to the granules, mixed and compressed in a tableting machine to obtain tablets.

Suspensions containing 0.1 to 1000 mg of the drug per 5 ml of dose each are prepared as follows.

Formulation 4 : Suspension

The drug is 45 mesh. s. Pass the sieve and mix with sodium carboxymethyl cellulose and syrup to make a soft paste. The benzoic acid solution, flavor and pigment are diluted with some water and added with stirring. Then sufficient water is added to make the desired volume.

An aerosol solution is prepared to contain the following ingredients:

Formulation 5 : Aerosols

The active ingredient is mixed with ethanol and the mixture is added to a portion of promoter 22, cooled to 30 ° C. and then transferred to a fill container. Then, the required medicine is supplied to the stainless steel container and diluted with the residual accelerator. Then, the valve device is placed in the container.

Suppositories are prepared as follows:

Formulation 6 : Suppositories

The active ingredient is 60 mesh milk. s. The sieve is passed through and suspended in saturated fatty acid glycerides which have been previously melted with the minimum required heat. The mixture is then poured into suppository molds of nominal 2 g capacity and cooled.

Intravenous preparations are prepared as follows:

Formulation 7 : Intravenous Solution

The solution of these components is administered intravenously to the patient at a rate of about 1 ml per minute.

Formulation 8 : Mixed Capsule I

Formulation 9 : Mixed Capsule II

Formulation 10 : Mixed Tablets

Claims (11)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Where R ¹ is —H, —OH, —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), or —OSO ₂ (C ₂ -C ₆ alkyl) ; R ² is —H, —OH —O (C ₁ -C ₄ alkyl), —OCOC ₆ H ₅ , —OCO (C ₁ -C ₆ alkyl), —OSO ₂ (C ₂ -C ₆ alkyl) or halo ; R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; Z is -O- or -S-. The method of claim 1, R ¹ is -OH; R ² is -OCH ₃ ; R ³ is 1-piperidinyl; n is 2; Z is -O- Compound or a pharmaceutically acceptable salt thereof. The method of claim 1, R ¹ is -OH; R ² is -OH; R ³ is 1-piperidinyl; n is 2; Z is -O- Compound or a pharmaceutically acceptable salt thereof. The compound [6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo according to claim 1, represented by the following formula: [b] thiophene or a pharmaceutically acceptable salt thereof. The compound of claim 4, wherein said salt is a hydrochloride salt. A symptom of postmenopausal syndrome, comprising as an active ingredient a compound according to any one of claims 1 to 3, 4 and 5 together with one or more pharmaceutically acceptable carriers, excipients or diluents. Pharmaceutical formulations for alleviation. The pharmaceutical formulation of claim 6 for alleviating osteoporosis. The pharmaceutical formulation of claim 6 for alleviating cardiovascular disorders. The pharmaceutical formulation of claim 6 for alleviating hyperlipidemia. The pharmaceutical formulation of claim 6 for alleviating hormone dependent breast cancer. The pharmaceutical formulation according to claim 6, wherein the active ingredient is a compound according to any one of claims 1 to 3, 4 and 5 and estrogen or progestin.