RS49886B - BENZOTHOPHENE COMPOUNDS, INTERMEDIATES, COMPOSITIONS AND METHODS - Google Patents

Abstract

A compound of formula I wherein 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 1 -C 6 alkyl), or halogen; R3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino; n is 2 or 3; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof.

Description

This application is in part a continuation of application Serial No. 08/396,401, filed Feb. 28, 1995, now pending.

This invention relates to the fields of pharmaceutical and organic hernia and provides novel benzothiophene compounds useful for the treatment of various medical indications related to post-menopausal syndrome, uterine fibroid disease, erucic-merrinsis, and aortic smooth muscle cell proliferation. The present invention further relates to intermediate compounds, useful in obtaining the pharmaceutically active compounds of the present invention, and pharmaceutical compositions.

"Post-menopausal syndrome" is a term used to describe various pathological conditions that often occur in women who have entered or are completing the physiological transformation known as menopause. Although numerous pathologies are encompassed by the use of this term, three main effects of the post-menopausal syndrome are the sources of the greatest long-term medical occupations: osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer, especially breast and uterine cancer.

Osteoporosis describes a group of diseases originating from different etiologies, but which are characterized by a net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support to the body. One of the most common types of osteoporosis is related to menopause. Most women lose 20% to about 60% of their trabecular bone mass within 3 to 6 years after menopause. This rapid loss is generally associated with increased bone resorption and formation. But the resorptive cycle is more dominant and the result is a pure loss of bone mass. Osteoporosis is a common and serious disease in postmenopausal women.

It has been found that 25 million women in the United States are affected by this disease. The results of osteoporosis are harmful to individuals and also affect a large economic loss due to its chronicity and the necessity for extensive and long-term assistance (hospitalization and home care) in the continuation of the disease. This is especially true in elderly patients. Additionally, although osteoporosis is not generally considered a life-threatening condition, 20% to 30% of mortality is related to hip fracture in older women. A large percentage of mortality is directly related to post-menopausal osteoporosis.

The most vulnerable tissue in bone, according to the effect of post-menopausal osteoporosis, is trabecular bone. This tissue is often referred to as cancellous or mesh bone and is particularly concentrated near the ends

The most vulnerable tissue in bone, according to the effects of post-menopausal osteoporosis, is trabecular bone. This tissue is often referred to as cancellous or mesh bone and is especially concentrated near the ends of the bones (near the junctions) in the spinal vertebrae. Trabecular tissue is characterized by small osteoid structures, which are intertwined with each other, as well as the harder and denser cortical tissue, which forms the outer surface and central axis of the bone. This interlocking network of trabeculae provides lateral support to the outer cortical structure and is critical to the biomechanical strength of the overall image. In post-menopausal osteoporosis, pure resorption and loss of trabeculae is primary, leading to bone damage and fracture. In terms of trabecular loss in post-menopausal women, it is not surprising that the most common fractures are those related to bone, which are highly dependent on the trabecular substrate, e.g. spine, neck of weight-bearing bones, such as the femur and forearm. Early, hip fracture, clavicle fractures, and vertebral crush fractures are the main hallmarks of post-menopausal osteoporosis.

At this time, the only generally accepted treatment for post-menopausal osteoporosis is estrogen-dependent therapy. Although the therapy is generally successful. patient compliance with therapy is poor, primarily because estrogen treatment often causes unwanted side effects.

During the premenstrual period, most women have a lower prevalence of cardiovascular disease than men of the same age. After menopause, however, the proportion of cardiovascular abnormalities in women slowly increases to compare with the proportion in men. This loss of protection is associated with the loss of estrogen, and more specifically, with the loss of estrogen's ability to regulate serum lipid levels. The nature of estrogen's ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen may regulate low-density lipoprotein (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effects on cholesterol biosynthesis, and other beneficial effects on the cardiovascular system.

It is stated in the literature that women in the postmenopausal period with estrogen replacement therapy have a return of serum lipid levels to the concentrations they were in before menopause. In this way, estrogen appears as a rational treatment for this condition. However, the side effects of estrogen replacement therapy are unacceptable to many women, thus limiting the use of this therapy. The ideal therapy for this condition would be an agent that would regulate serum lipid levels like estrogen, but avoid the side effects and risks that come with this therapy.

The third major pathology related to post-menopausal syndrome is estrogen-dependent breast cancer, and to a lesser extent, estrogen-dependent cancers of other organs, especially the uterus. Although such neoplasms are not limited to postmenopausal women, they are more prevalent in the older, postmenopausal population. Current chemotherapy for these cancers relies heavily on the use of anti-estrogenic compounds, such as, for example, tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and estrogenic side effects are tolerable in acute life-threatening™ situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations. In the uterus, due to their estrogenic (agonist) properties, they can also be counterproductive in some cases. A better therapy for treating these cancers would be an agent that is an anti-estrogenic compound with little or no estrogen agonist properties on reproductive tissues.

In response to the clear need for new pharmaceutical agents capable of ameliorating the symptoms of, inter alia, post-menopausal syndrome, the present invention provides novel benzothiophene compounds, pharmaceutical compositions thereof, and methods of using such compounds to treat post-menopausal syndrome and other estrogen-related pathological conditions such as those mentioned below.

Uterine fibrosis (uterine fibroid disease) is an old and ever-present clinical problem, occurring under many names, including uterine fibroid disease, uterine hypertrophy, uterine leiomyomata, myometrial hypertrophy, uterine fibrosis, and fibrotic metritis. Essentially, uterine fibrosis is a condition where there is inappropriate deposition of fibroid tissue on the wall of the uterus.

This condition is the cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood, but evidence suggests that it is an inappropriate response of fibroid tissue to estrogen. Such a condition can be produced in rabbits by daily administration of estrogen for 3 months. In guinea pigs, the condition can be produced by daily administration of estrogen for four months. Furthermore, in rats, estrogen causes similar hypertrophy.

The most common treatment of uterine fibrosis involves surgical procedures, which are expensive and sometimes a source of complications, such as the formation of abdominal adhesions and infections. In some patients, the initial hydrosurgery is only a temporary treatment and the fibroids grow back. In such cases, a hysterectomy is performed, which effectively removes the fibroids, but also the reproductive life of the patient. Gonadotropin-releasing antagonists can also be used, although their use is limited by the fact that they can lead to osteoporosis. Hence, there is a need for new methods of treating uterine fibrosis. and the methods of the present invention satisfy such a need.

Endometriosis is a condition of severe dysmenorrhea, which is associated with severe pain, bleeding into the endometrial masses or the peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition appears to be an ectopic endometrial growth that is responsible for inappropriate to normal hormonal control and is located in inappropriate tissues. Due to inappropriate localization of endometrial growth, the tissue appears to initiate local inflammatory-like responses, causing infiltrating macrophages and a cascade of events leading to the initiation of painful responses. The exact etiology of this disease is not well understood and its treatment with hormonal therapy is different, poorly defined and marked by numerous unwanted and possibly dangerous side effects.

One of the treatments for this coloration is the use of a small dose of estrogen to prevent endometrial growth through a negative feedback effect on the central release of gonadotropin and the subsequent production of estrogen in the ovaries; however, it is sometimes necessary to use continuous estrogen to control symptoms. This use of estrogen can often lead to unwanted side effects and even the risk of endometrial cancer.

Another treatment involves the continuous administration of progestin, which induces amenorrhea and, by preventing the production of estrogen in the ovaries, can cause regression of endometrial growth. The use of chronic progestin therapy is often accompanied by unpleasant CNS side effects of progestin and often leads to infertility due to inhibition of ovarian function.

The third treatment includes the use of weak androgens, which are effective in controlling endometritis; however they induce serious masculinizing effects. Several of these endometritis treatments have also been implicated in causing a mild degree of bone loss with continued therapy. Therefore, new methods of treating endometriosis are desirable.

The present invention relates to compounds of formula I

in which,

R<1> is -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6 alkyl), or -OSO(C2-C alkyl);

R 2 is -H, -OH, -O(C 1 -C 4 alkyl), -OCOC 6 H 5 , -OCO(C 1 -C 6 alkyl), or -OSO(C 2 -C 8 alkyl) or halogen;

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; and

z is -O- or -S-;

or a pharmaceutically acceptable salt thereof.

The present invention further provides the following intermediate compounds, which are useful in obtaining the pharmaceutically active compounds of the present invention, some of which are also pharmaceutically active.

where

R<ia>is -H or -OR<7>, wherein R<7>is a hydroxy protecting group;

R<2a> is -H, halogen, or -OR<8> in which R8 is a hydroxy protecting group;

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

R<6> is -H, or a hydroxy protecting group which can be selectively removed;

R<9> is the leaving group;

R11 does not exist or =0;

n is 2 or 3; and

z is -O- or -S-;

or a pharmaceutically acceptable salt thereof.

Also provided is a procedure for preparing compounds of the formula

where

R<l>is -H or -OR<7a>, wherein R<7a>is -H or a hydroxy protecting group;

R23 is -H, halogen, or -OR<8a> in which R88 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;

R<6> is -H, or a hydroxy protecting group which can be selectively removed;

R<9> is the leaving group;

Ru does not exist or =0;

n is 2 or 3; and

it's-O-or-S-;

or a pharmaceutically acceptable salt thereof.

a) oxidation of the sulfur atom of the compound of formula IV

where

R<1a> and R23 are as previously defined; and

R<9> is the leaving group;

b) reaction of the product of phase a) of the compound of formula XIV

r?

with a nucleophilic group of the formula

where

R<12> is -OH or -SH;

c) reduction of the product of phase b), compound of formula XVI

in order to obtain compounds of formula d) arbitrary removal of R<1a> and/or R<2*> hydroxy protecting groups, when they are present in the product of phase c); and

e) arbitrary formation of salts of compounds of the products of phase c) or phase d).

The present invention further relates to pharmaceutical compositions containing

compounds of formula I, optionally containing estrogen or progestin, and the use of such compounds, alone or in combination with estrogen or progestin, to alleviate the symptoms of post-menopausal syndrome, especially osteoporosis, pathological cardiovascular conditions, and estrogen-dependent cancer. As used herein, the term "estrogen" includes steroidal compounds with estrogenic activity, such as, for example, 17b-estradiol, estrone, conjugated estrogen (Premarin®), equine estrogen 17b-ethynyl estradiol, and the like. As used herein, the term "progestin" includes compounds with progestational activity, such as, for example, progesterone, porethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like.

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

One aspect of the present invention includes compounds of formula I

whereby

R<1> is -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6 alkyl), or -OSO(C2-C6 alkyl);

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

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; and

z is -O- or -S-;

or a pharmaceutically acceptable salt thereof.

General terms used in describing the compounds described herein have their usual meanings. For example, "C 1 -C 8 alkyl" refers to straight or branched aliphatic chains of 1 to 6 carbon atoms, including groups such as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like. Similarly, the term "C 1 -C 4 alkoxy represents a C 1 -C 4 alkyl group attached to an oxygen molecule and includes groups such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The starting materials for one route to the compound of formula I of the present invention, the compound of formula III, are prepared essentially as described by C.D.Jones in U.S.Pat. No. 4,418,068 and 4,133,813 each of which is incorporated herein by reference. Formula III has a structure

wherein , R<7> and R<8> are as previously defined.

R<7> and R<8> hydroxy protecting groups are groups that are not generally found in the final, therapeutically active compounds of formula I, but which are intentionally introduced during part of the synthetic process to protect a group that might otherwise react in terms of chemical change, and which are then removed in the final step of the synthesis. Since compounds having such protecting groups are primarily of importance as chemical intermediates (although some derivatives also exhibit biological activity) their precise structure is not critical. A number of reactions for the formation, removal, and possibly re-formation of such protective groups are described in a number of standard works, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Green, T.W., Protective Groups in Organic Synthesis, Wiley (New York, 1981); and The Peptides, Vol. 1, Schroder and Lubke, Academic Press, (London and New York, 1965).

Representative hydroxy protecting groups include, for example, -C 1 -C 4 alkyl, -C 1 -C 4 alkoxy, -CO-(C 1 -C 6 alkyl), -SO 2 -(C 4 -C 6 alkyl), -CO-Ar wherein Ar is benzyl or optionally substituted phenyl. The term "substituted phenyl" refers to a phenyl group with one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen, nitro, and tri(chloro or fluoro)methyl. The term "halogen" refers to bromine, chlorine, fluorine and iodine.

For compounds of formula III, suitable R<7> and R<8>(R2a) substituents are methyl, isopropyl, benzyl and methoxymethyl. Compounds in which R<7> and R<8> are each methyl are prepared by the procedure described in the aforementioned Jones patent. Another suitable hydroxy protecting group is methoxymethyl. However, the compound of formula IV, as shown below, is first obtained with suitable methyl or other hydroxy protecting groups. These hydroxy protecting groups are then removed, forming phenolic groups, which are then reprotected with methoxymethyl protecting groups.

Compounds of formula III have also been obtained in which the R<7>hydroxy protecting groups are selectively removed, leaving the R<8>(R<2*>) hydroxy protecting groups as part of the final product. For example, R<7> is isopropyl or benzyl and R<8>(R2*) is methyl. The isopropyl or benzyl group is selectively removed by standard procedures and the R<8>methyl protecting group is left as part of the final product.

The first steps of this procedure for obtaining certain compounds of formula I include selective placement of a leaving group at the 3-position of a compound of formula III, purchase of the first step reaction product with 4-(hydroxy protected) phenol, and removal of the phenolic hydroxy protecting group. The given procedure is shown in Scheme I below.

In the first step of Scheme I, the appropriate leaving group is selectively introduced into the 3-position of the starting material of formula III by standard procedures. Suitable R<9> leaving groups include sulfonates, such as methanesulfonate, 4-methoxybenzenesulfonate, 3-nitrobenzenesulfonate, chlorine, and iodine, and other related leaving groups. However, to ensure proper placement of the leaving group, the aforementioned halogens are suitable, and bromine is particularly suitable.

The given reaction is carried out using standard procedures. For example, when suitable halogenating agents are used, an equivalent of such halogenating agent, preferably bromine, is reacted with an equivalent of a substrate of formula III, in the presence of a suitable solvent, such as, for example, chloroform or acetic acid. The reaction is carried out at a temperature of about 40°C to about 80°C.

The reaction product from the preceding procedure step, the compound of formula IV, is then reacted with 4-(hydroxy protected)phenol to form compounds of formula Xa in which R<6> is a hydroxy protecting group that can be selectively removed. In general, the 4-hydroxy protecting group of the phenol can be any known protecting group, which can be selectively removed, without removing in that case, R<7> and when the R<8> group is present, in the compounds of formula Xa. Suitable R<6> protecting groups include methoxymethyl, when R7 and/or R<8> are not methoxymethyl and benzyl. Of these, benzyl is a particularly suitable group. 4-(Hydroxy protected)phenol reactants are commercially available or can be prepared by standard procedures.

This coupling action is known in the art as the Ullman reaction and is performed according to standard procedures [see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition, 3-16, (J. March, ed., John Wiley & Sons, Inc. 1992); Jones, C. D., J. Chem. Soc. Perk. Trans. 1.4:407(1992)].

In general, equivalent amounts of two aryl substrates, in the presence of an equimolar amount of copper(I)-oxide catalyst and a suitable solvent, are heated to reflux under an inert atmosphere. Conveniently, an equivalent of a compound of formula IV wherein R<9> is bromine is reacted with an equivalent amount of 4-benzyloxyphenol in the presence of an equivalent of copper oxide.

Suitable solvents for this reaction are those solvents or solvent mixtures which remain inert during the reaction. Typically, organic bases, especially sterically hindered bases such as, for example, 2,4,6-collidine, are suitable solvents.

The temperature used in this step should be sufficient to allow the completion of this coupling reaction and thus affect the time required. When the reaction mixture is heated to reflux under an inert solvent, such as nitrogen, the time to completion of the reaction will be from about 20 to about 60 hours.

After the coupling, which builds the compound of formula Ha, the compounds of formula IIb are obtained by selective removal of the R<6>hydroxy protecting group of the compound of formula Ha, by means of well-known reduction procedures. The requirement is that the chosen procedure does not act on R<7>i when R<8>hydroxy protecting groups are present.

When R<6> is suitably a benzyl group, and R<7> when present, R<8> is each methyl, the given step of the process being carried out by standard hydrogenolysis procedures. Typically, a substrate of formula Xa is added to a suitable solvent or solvent mixture, followed by the addition of a proton donor to accelerate the reaction and a suitable hydrogenation catalyst.

Suitable catalysts include metals and noble metal oxides, such as palladium, platinum and rhodium oxide, on supports such as carbon or calcium carbonate. Of these, palladium on carbon is suitable, especially 10% palladium on carbon.

Solvents for this reaction are those solvents or solvent mixtures that remain inert during the reaction. Ethyl acetate and C1-C4 aliphatic alcohols, especially ethanol, are typically suitable.

For this reaction, hydrochloric acid serves as an adequate and convenient proton donor.

When carried out at room temperature and pressure in the range of about 2.04 bar to about 3.4 bar, the given reaction takes place quite rapidly. The progress of this reaction can be monitored using standard chromatography techniques, such as thin layer chromatography.

Compounds of formula IIa and IIb are novel, and are included within the class described herein as compounds of formula II, and are useful for the preparation of pharmaceutically active compounds of formula I.

After obtaining the compound of formula IIb, it reacts with the compound of formula V

wherein, R<3> and n are as previously defined, and Q is bromine, or suitably, chlorine, to form compounds of formula VI. Compounds of formula VI are then deprotected to obtain compounds of formula Ia. These stages of the given procedure are shown in Scheme II below.

wherein R 3 , R 7 , R 2 and n are as previously defined, and R< 2b> is -H, -OH, or halogen.

In the first stage of the procedure shown in Section II, the alkylation is carried out using standard procedures. Compounds of formula V are commercially available or are obtained by means well known to those of ordinary skill in the art. The hydrochloride salt of the compound of formula V, especially 2-chloroethylpiperidine hydrochloride, is conveniently used.

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

Solvents for this reaction are those solvents or solvent mixtures that remain inert during the reaction. N,N-dimethylformamide, especially its anhydrous form, is suitable.

The temperature used in this step should be sufficient to complete this alkylation reaction. Typically, the ambient temperature is sufficient and suitable.

The present invention is conveniently carried out under an inert atmosphere, especially nitrogen.

Under suitable reaction conditions, this reaction will proceed to completion in approximately 16 to about 20 hours. Of course, the progress of the reaction can be monitored by standard chromatographic techniques.

As an alternative to preparing a compound of formula VI, a compound of formula IIb is reacted with an excess of an alkylating agent of formula

wherein Q and Q' are the same or different leaving groups, in alkaline solution. Suitable leaving groups are the previously mentioned leaving groups used in the preparation of compounds of formula IV.

A suitable alkaline solution for this alkylation reaction contains potassium carbonate in an inert solvent, such as, for example, methyl ethyl ketone (MEK) or DMF. In this solution, the 4-hydroxy group of the benzoyl group of the compound of formula IIb exists as a phenoxide ion, which displaces one of the leaving groups of the alkylating agent.

This reaction is best when the alkaline solution, containing the reactants and reagents, is brought to reflux and allowed to proceed to completion. When MEK is used as a suitable solvent, the reaction time ranges from about 6 hours to about 20 hours.

The reaction product from this step is then reacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-porfoline, dimethylamine, diethylamine, diisopropylamine, or 1-hexamethyleneamine, using standard techniques, to form compounds of formula VI. Conveniently, the piperidine hydrochloride salt is reacted with the alkylating compound of formula IIb in an inert solvent, such as anhydrous DMF, and heated to a temperature in the range of about 60°C to about 110°C. When the mixture is heated to a suitable temperature of about 90°C, the reaction takes place in only about 30 minutes to about 1 hour. However, changes in the reaction conditions will affect the reaction time necessary for this reaction to take place. Of course, the progress of this reaction phase can be monitored by standard chromatographic techniques.

Compounds of formula VI, wherein R<7>i when R<8> is present, is any C1-C4 alkyl, preferably methyl, and wherein R<2a> is -H or halogen, are novel and pharmaceutically active for the methods described herein. Accordingly, such compounds are encompassed by the definition of compounds of formula I herein.

Certain suitable compounds of formula I are obtained by cleavage of R<7>, and when R<8> hydroxy protecting groups of compounds of formula VI are present. paths of well-known procedures. Numerous reactions for the formation and removal of such protective groups are described in numerous standard works, including, for example, Protective Groups in Organic Chetnisiry, Plenum Press (London and New York, 1973); Green, T.W., Protective Groups in Organic Synthesis, Wiley (New York, 1981); and The Peptides, Vol. I, Schroder and Lubke, Academic Press, (London and New York, 1965). Procedures for removing suitable R<7> and/or R<8> hydroxy protecting groups, preferably methyl and methoxymethyl, are essentially as described in the Examples, below.

Compounds of formula Ia are novel, pharmaceutically active according to the methods described herein, and are encompassed by formula I, as defined herein.

Compounds of formula I, in which R<1>is -H, are obtained by the synthetic procedures shown in Scheme III. Using this procedure, the leaving group in the 3-position (R<9> ) is placed on a commercially available thionaphthene (formula VII) to form a compound of formula VIII, which is then coupled with 4-(hydroxy protected)phenol to give compounds of formula IX.

wherein, R6 is a hydroxy protecting group, which can be selectively removed, and R<9> is a leaving group.

Compounds of formula VII are commercially available. The preparation of compounds of formulas VIII and IX including the definition of the R<6> and R<9> substituents, as well as suitable reactants and conditions, unless otherwise stated herein, is the same as previously described and shown in Scheme I, above.

Compounds of formula IX are then arylated via a Suzuki coupling reaction [see, e.g. Suzuki, A., Pure and Appl. Chem., 6 (2): 213-222 (1994)]. Using one option of the Suzuki coupling, a compound of formula IX is selectively halogenated at the 2- position, and then coupled with an arylboronic acid compound of formula XIa (route A, Scheme IV, below).

Conveniently, however, an arylboronic acid of formula Xb is formed from a compound of formula IX, and then reacted with a halogenated compound of formula XIb to give new intermediates of formula IIc (route B, Scheme IV, below). Such new intermediates are useful for obtaining the pharmaceutically active compounds of the present invention (compounds of formula lb) by alkylation and deprotection.

whereby

R2a, R2b, R<3>, R<6> and n are as previously defined;

X is iodine, bromine, or fluorine, in order of priority; and

X' is iodine, bromine, or fluorine, in order of priority, or triflate.

The first step in pathway A in Scheme IV is the iodination or bromination reaction of the 2- position of the compound of formula IX using standard procedures. In general, compounds of formula IX are reacted with a slight excess of n-butyllithium in hexane, in a suitable solvent and under an inert atmosphere such as nitrogen, then a slight excess of halogenating agent in a suitable solvent is added dropwise. Conveniently, the halogenating agent for this phase is iodine, but the use of bromine, N-bromosuccinimide, is also permitted.

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

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

The product of the previous reaction, a halogenated arene of formula Xa, is then coupled with a rylbrodic acid of formula XIa, using standard Suzuki coupling procedures, to give compounds of formula IIc. Compounds of formula XIa, wherein R<2a> is -H, halogen, or -OR<8> (R<8> is hydroxy protecting as defined, supra) are derived from commercially available compounds by procedures well known to one skilled in the art (see, e.g., March, J., and Suzuki, A., supra).

In a given coupling reaction, a small excess of a compound of formula XIa is reacted with each equivalent of a compound of formula Xa, in the presence of a palladium catalyst and a suitable base, in an inert solvent such as toluene.

Although a variety of palladium catalysts aid in carrying out the Suzuki coupling reaction, the catalyst chosen is usually reaction dependent. Thus, the use of tetrahystriphenylphosphine-palladium, in a given reaction, is very convenient.

Similarly, different bases can be used in a given coupling reaction. However, it is convenient to use alkali metal carbonate, in particular, 2N sodium carbonate.

The temperature used in this step should be sufficient to complete the coupling reaction. Typically, heating the reaction mixture at reflux for a period of about 2 to about 4 hours is adequate and convenient.

In Procedure B, Scheme IV, the 2-, arylboronic acid position of formula Xb is prepared using well-known procedures. In general, the compound of formula IX is treated with a slight excess of n-butyllithium in hexane, in a suitable solvent and under an inert atmosphere, such as nitrogen, followed by the dropwise addition of trialkylborate.

Suitable solvents include an inert solvent or solvent mixture, such as, for example, diethylether, dioxane and tetrahydrofuran (THF). THF, especially anhydrous THF, is suitable.

A suitable trialkylborate used in this reaction is triisopropyl borate.

The product of this reaction, a compound of formula Xb, is then reacted with an aryl halide or aryl triflate of formula XIb, using standard Suzuki coupling procedures, to give a compound of formula Hc. Suitable reaction conditions for this reaction are as described for the reaction of compounds of formula XIa and Xa, in Scheme IV, which also provides compounds of formula Hc.

The transformation of the compound of formula IIc to the compound of formula Ia is carried out as previously described in the coupling of the compound of formula Ha to the compound of formula Ia.

The compounds of formulas IIc and Ud are new, and useful in obtaining the pharmaceutically active compounds of the present invention.

Compounds of formulas XII and lb are also novel, and are useful in the methods described herein, and are encompassed by formula I, as defined herein.

Compounds of formula I, in which either R<1> or R<2> is -H- and the second R<1> or R<2> substituent is -OH, are also obtained from compounds of formula I, in which both R<1> or R<2> are -OH.

The dihydroxy compound of formula I is converted to a mixture of 6- and 4'-monotritlates, and the triflate group is reduced to hydrogen (see, Saa, J.M., et. al., J.Org.Chem., 55 : 991

(1990)). The resulting mixture of monohydroxy derivatives, either as the free base or a pharmaceutically acceptable salt, preferably the hydrochloride salt, can be separated using standard crystallization techniques.

Generally, a dihydroxy compound of formula I is treated with about 4 to about 6 equivalents of an amino base, such as triethylamine, in a non-reactive solvent, followed by the addition of one equivalent of trifluoromethanesulfonic acid anhydride. A static mixture of mono- and di-triflates is formed, and is separated using standard chromatographic techniques. A suitable solvent for this phase is anhydrous dichloromethane.

When carried out in the temperature range of about 0°C to about 25°C, the given reaction is completed in about 1 to about 5 hours.

The isolated mixture of mono-triflate compounds is then hydrogenated, in a non-reactive solvent, in the presence of from about 3 to about 6 equivalents of an amino base, preferably triethylamine, and a hydrogenation catalyst, such as palladium on carbon, which is suitable. Suitable solvents for this reaction are ethyl acetate or ethanol, or, alternatively, a mixture thereof. When this stage of the given reaction is carried out under a hydrogen gas pressure of about 2.7 bar, at room temperature, the reaction time is from about 2 to about 5 hours.

The resulting mixture of monohydroxy derivatives of formula I has different solubilities in ethyl acetate and 6-hydroxy-4'-hydrogen derivatives can be separated from 6-hydrogen-4'hydroxy derivatives by selective crystallization. Further separation, which provides pure monohydroxy compounds of formula I, can be carried out by converting the enriched mixture to the hydrohybrid salts, by means of crystallization from ethyl acetate-ethanol.

A more direct method of preparing a compound of formula I, in which either R<1> or R<2> is -H, and the second substituent of R<1> or R<2> is -OH, as well as an alternative method of preparing a compound of formula I, in which either R<1> or R<2> is -H, and the second R<1> or R<2> substituent is -O-(CrC4alkyl) use a compound of the formula

where

R<3> and n are as previously defined,

R 1c is -OH or -O-(C 1 -C 4 alkyl); and

R<2c>is -OH or -O-(C1C4alkyl); provided that when R<1c>is -OH, R<2c>is -O-(C1C4alkyl); and when R 1c is -O-(C 1 -C 4 alkyl); R 2c is -OH.

In this process, the hydroxy group of such compounds is converted to triflate derivatives by treatment with trifluoromethanesulfonic acid anhydride, the triflate group is then reduced under standard conditions, preferably by catalytic hydrogenation. The hydroxy protecting group is then removed by standard procedures, such as those described herein, to give compounds of formula I wherein either R<1> or R<2> is -H, and the second substituent of R<1> and R<2> is -OH.

Another alternative, and convenient, process for obtaining compounds of the present invention is shown in Scheme V. In this process, the sulfur atom of a compound of formula IV (infra) is oxidized to give a sulfoxide (of formula XIV), which is then reacted with a nucleophilic group to introduce a bound oxygen or sulfur atom of a compound of formula I and formula II. The sulfoxide group of a compound of formula XVI is then reduced to give certain compounds of the present invention, each variable having its previously defined meaning.

In the first stage of this procedure, the compound of formula IV is selectively oxidized to the sulfoxide. A number of known methods are available for the process step [see, Madesclaire, M., Tetrahedron. 42 (20); 5459-5495 (1986); Trost, B.M., et. al, Tetrahedron Letters. 22 (14); 1287-1290 (1981); Drabovitz, J., et. aj., Synthetic Communications, 11 (12); 1025-1030 (1981); Kramer, JB, et. a]., 34th National Organic Symposium, Williamsburg. VA., June 11-15, 1995]. However, many oxidants give only poor conversion to the desired product, as well as significant overoxidation to the sulfone. Given, the new procedure, however, converts the compound of formula IV to the sulfoxide of formula XIV, in high yield, with little or no sulfone formation. This process involves reacting a compound of formula IV with about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture of about 20% to about 50% trifluoroacetic acid in methylene chloride. The reaction is carried out at a temperature of from about 10°C to about 50°C, and typically requires from about 1 to about 2 hours to complete.

Then the leaving group in the 3-(R<9>) position is displaced by the desired nucleophilic derivative of formula XV. Such nucleophilic derivatives are obtained by standard techniques.

In this stage of the procedure, the acidic proton of the nucleophilic group is removed by treatment with a base, preferably a small excess of sodium hydroxide or potassium t-butoxide, in a polar aprotic solvent, preferably DMF or tetrahydrofuran. Other bases that can be used include potassium carbonate and cesium carbonate. Optionally, other solvents, such as dioxane and dimethylsulfoxide, may be used. Deprotonation is typically performed at temperatures between approximately 0°C and about 30°C, and typically requires about 30 minutes to complete. The compound of formula XIV is then added to the nucleophile solution. The displacement reaction is carried out at a temperature between 0°C and about 50°C, and is usually carried out for 1 to about 2 hours. The product is isolated by standard procedures.

When a benzyl group is used as a hydroxy protecting group, hydrogenolysis of the sulfoxide group will also allow removal of the benzyl protecting group, eliminating the requirement for selective removal of such a group at a later stage of the process.

In the following stage of the procedure, new sulfoxides of formulas XVIa, b, c and d (general formula XVI) are reduced to benzothiophene compounds of formulas Ilg, lc, Ue and Id, respectively. Prior to this reduction procedure, compounds of formulas IIg and Ile may first be alkylated as described herein. Reduction of sulfoxide compounds can be performed using one of a number of methods known in the art, including, for example, hydride reduction (lithium aluminum hydride), catalytic hydrogenation, transfer hydrogenolysis, and trimethylsilyl iodide (TMS-I). In this reduction, the choice of reagents is dependent on the compatibility of other functional groups in the molecule. For the compounds described in the present invention, lithium aluminum hydride (LiAlH 4 ) and transfer hydrogenolysis (palladium black/ammonium formate) are suitable reagents. For LiAlH4 reduction, suitable solvents, such as diethylether, dioxane and tetrahydrofuran (THF). Of these, THF, especially anhydrous THF, is suitable. For transfer hydrogenolysis, alcoholic solvents, especially ethanol, are suitable. The reaction is carried out at a temperature of from about 0°C to about 60°C, and requires from about 0.5 hours to about 2 hours to completion.

When desired, the hydroxy protecting group or group of the procedure shown in Semi V, can be removed, and from the product of any product phase. Accordingly, the present invention includes a process for obtaining a compound of the formula

in which,

R<1a >is -H or -OR7a, wherein R7a is -H or a hydroxy protecting group;

R<2a> is -H, halogen, or -OR8a, where R<8a> is -H or a hydroxy protecting group;

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

n is 2 or 3; and

Z is -O- or -S-

or a pharmaceutically acceptable salt thereof which they form

a) oxidation of the sulfur atom of the compound of formula IV

where

RlaiR<2a> are as previously defined; and

R9 is a leaving group;

b) reaction of the product of phase a), compound of formula XIV

with a nucleophilic group of the formula where R 12 is -OH or -SH; c) reduction of the products of phase b), compounds of formula XVI to obtain compounds of formula d) arbitrary removal of R1<a> and/or R<2a> hydroxy protecting groups, when present, in the product of phase c); and

e) arbitrary salt formation of the product of phase c) or phase d).

These new procedures also provide new compounds of formulas XIV, and XVIa, b, c and d,

each intermediate of which is useful for obtaining the pharmaceutically active compounds of the present invention.

Compounds of formula I, wherein Z is S, are also prepared using the procedure described below in Scheme VI, wherein the compound of formula IVa is metalated. The resulting product, a compound of formula XVII, is reacted with a 4-(hydroxy protected) phenyl disulfide of formula XVIII, and the phenolic protecting group of a compound of formula Ile is removed to provide a compound of formula Uf. It can be noted that when using this procedure, R<2> cannot be halogen, due to chemical restrictions.

where

R1a is -H or -OR<7> and R7 is a hydroxy protecting group;

R<2a> is -H or -OR<8> and R<8> is a hydroxy protecting group;

R 6 is a hydroxy protecting group, which can be selectively removed;

R<9> is a leaving group; and

M is a metal ion.

In the first two steps of Scheme VI, the compound of formula IVa is metalated using well-known procedures. Most commonly and conveniently, the compound of formula IVa is treated with a slight excess of n-butyllithium in hexane, in a suitable solvent, followed by the dropwise addition of a solution of the disulfide compound of formula XVIII in a suitable solvent.

Both of these reaction phases are carried out under an inert atmosphere, such as nitrogen, while suitable solvents for both phases include one or more solvents such as diethyl ether, dioxane, and THF. Of these, THF, especially its anhydrous form, is suitable. In addition, given reaction steps are carried out at a temperature of about -78°C to about 85°C.

In the first stage of this reaction, the metalation of the compound of formula XVII is provided. 4-(Hydroxy protected) phenyldisulfide (a compound of formula XVIII), which reacts with such a compound of formula XVII to give a compound of formula Ile, is obtained by protecting the hydroxy group of commercially available 4-hydroxyphenylsulfide, with an appropriate protecting group, by methods known in the art. Suitably the R6 protecting group is methoxymethyl, providing that R<7> and R<8>, if both present, is a hydroxy protecting group other than methoxymethyl. It is imperative that the R<6>hydroxy protecting group is a group different from that formed by the R<7>and R<8>hydroxy protecting groups, when present, so that the R<6> group can be selectively removed, by standard procedures, to provide compounds of formula Uf.

To perform deprotection by removing the R<6> protecting group, the compound of formula Ile is reacted in a practical solvent or solvent mixture in an acidic medium containing at least one equivalent of an acid, preferably methanesulfonic acid, and heated from about 25° to about 110°C. Typically, the reaction time is from about 6 to about 24 hours, but the progress of the reaction can be monitored using standard chromatographic techniques.

Suitable solvents for a given reaction include, for example, water and methanol.

Compounds of formulas Ile and Uf are novel, useful in the preparation of pharmaceutically active compounds of formula I and are herein included within the designations of formula II.

Compounds of formula Id

in which,

R1b is -H or -OH;

R2 is -H or -OH; and

R<3> and n, are as previously defined, are obtained by the procedures previously described in connection with the process steps shown in Schemes II and V. Such compounds of formula Id are also novel, useful in the processes of the present invention, and are herein encompassed within the foregoing formula I designation.

Compounds of formula I, in which R<1> and R<2> are different hydroxy protecting groups or one R<1> and R<2> is a hydroxy protecting group and the other is hydroxy, are selectively obtained using the modified 2-arylbenzothiophenoxy starting material of formula III previously, ensuring that the hydroxy protecting groups, designated R<7> and R<8>; different enough so that one protecting group is removed while the others remain. Such 2-arylbenzothiophenes are prepared by procedures well known in the art.

Particularly useful in the preparation of compounds of formula I, is in which R<1> and R<2> are different protecting groups in the Suzuki coupling, as previously described in Scheme

IV. However, 6-(hydroxy protected) benzothiophene-2-boronic acid reacts with a compound of formula XIb, above, wherein R<2a> is -OR8 and R<7> is not equivalent to R<8>. This reaction makes it possible to obtain compounds of the present invention in which R<7> and R<8> are different hydroxy protecting groups, so that one protecting group can be selectively removed and the other remains as a group of the final product. Conveniently, the R<7>protecting group, especially benzyl or isopropyl, is removed to form a hydroxy group, while the R<8>hydroxy protecting group, especially methyl, remains. Suzuki coupling is also performed using the previously described procedures, but by replacing the compound of formula XIb with the compound of formula XIX

where

R 8a is C 1 -C 6 alkyl sulfonate, preferably methanesulfonate or C 4 -C 6 aryl sulfonate; and R<10> is a leaving group; suitably bromine or triflate.

In this procedure, 6-(hydroxy protected) benzothiophene-2-boronic acid, as previously described, reacts with a compound of formula XIX to give a compound of formula XX, which reacts with boron(III)-bromide in methylene chloride to provide a monohydroxy compound, which is then converted to, for example, a benzyl group, by standard procedures (formula XXI). The 4'-sulfonate ester is then selectively removed by base hydrolysis, or conveniently, by treatment with LiAlH 2 , in a suitable aprotic solvent, such as e.g. THF. This reaction yields a compound of formula XXII, which is finally, for example, metalated at the 4'- position by standard procedures (formula III). Of course, one of ordinary skill in the art will recognize that various procedures can be used to provide compounds of formula III, wherein the hydroxy protecting groups are different than shown in Scheme VII below, but which can be selectively removed to provide monohydroxy compounds of formula I, of the present invention.

The compounds of the invention are then subjected to the various procedures described herein to provide the compounds of formulas I and II of the present invention.

Other suitable compounds of formula I are obtained by replacing the hydroxy groups in the 6- and/or 4-position, when present, with a group of the formula -O-CO-(C1-C8 alkyl), or -O-SO2-(C2-C6 alkyl) by well-known procedures. See, e.g. U.S. Pat. No. 4,358,593.

For example, when a -O-CO-(C 1 -C 6 alkyl) group is desired, the mono- or dihydroxy compound of formula I is reacted with an agent such as an acyl chloride, bromide, or azide, or with the appropriate anhydride or mixed anhydride. The reactions are usually carried out in a basic solvent, such as pyridine, lutidine, quinoline, or isoquinoline, or in a tertiary amino solvent, such as triethylamine, tributylamine, methylpiperidine, and the like. The reaction can also be carried out in an inert solvent, such as ethylacetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethyloxyethane, acetone, acetonitrile, acetone, methylethylketone, and usually, to which is added at least one equivalent of an acid acceptor (unless indicated below), such as a tertiary amine. If desired, acylation catalysts such as 4-dimethylaminopyridine and 4-pyrrolidinopyridine can be used. See, e.g., Haslam, et. aj., Tetrahedron. 36: 2409-2403 (1980).

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

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

The previously mentioned R<1> and/or R<2> groups of compounds of formula I can also be provided by forming an active ester of the corresponding acid, such esters being formed using such known reagents as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. See, eg, Buli. Soc. Chem. Japan. 38:1979 (1965), and Chem. Ber.. 788 and 2024 (1970).

Each of the foregoing techniques providing -O-CO-(CrC6alkyl) groups are performed in solvents as previously discussed. These techniques, which do not produce an acid product during the reaction, do not, of course, require the use of an acid acceptor in the reaction mixture.

When a compound of formula I is desired, in which the 6- and/or 4'-hydroxy group of the compound of formula I is converted to a group of the formula -O-SO2-(C2-C6alkyl), the mono- or dihydroxy compound is reacted with, for example, a sulfonic anhydride or a derivative of the appropriate acid, such as a sulfonyl chloride, bromide, or sulfonylammonium salt, as described by King and Monoir, J. Am. Chem. Soc., 97: 2566-2567

(1975). The dihydroxy compound may also react with the corresponding sulfonic anhydride or mixed sulfonic anhydrides. Such reactions are carried out under such conditions as previously described in the discussion of reactions with alkyl halides and the like.

Although the free base form of the compound of formula I may be used in the methods of the present invention, it is preferred to obtain and use the pharmaceutically acceptable salt form. Thus, the compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a variety of organic and inorganic acids, and include physiologically acceptable salts, which are often used in the pharmaceutical industry. Such salts are also part of the present invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkanedic acids, aromatic acids, aliphatic and aromatic sulphonic acids, can also be used. Thus, such pharmaceutically acceptable salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, morbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyram, fembutyrate, p-hydroxybutyrate, butyn-1,4-dioate, hexyl-1,4-gioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylene sulfonate, tartrate and the like. Suitable salts are hydrochloride and oxalate salts.

Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid, the reactants generally being combined in a common solvent such as diethyl ether or ethyl acetate. The salt normally precipitates out of solution in approximately 1 hour to 10 days and can be isolated by filtration or the solvent can be removed by conventional means.

Pharmaceutically acceptable salts generally have increased solubility characteristics compared to the compounds from which they are derived, and thus are more suitable for formulation as liquids or emulsifiers.

Representatives of suitable compounds of the present invention are as follows:

Group I:

[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-methoxyphenyl)-3-brom]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[bithiophene-(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-piperidinii)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]tw [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]benzo[b]thiophene Group II: [3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene [3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzorb]thiophene hydrochloride [3-[4-[2-(l-pyrrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b)thiophene [3-[4-[2-(l-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b] [3-[4-[2-(1-N,N-diethylamino)^^

[3-[4-[2-(1-piperidinyl)ethoxy]phen^^

[3-[4-[2-(1-piperidinyl)ethoxy]pheno

[3-[4-[2-(1-piperidinii)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-(l-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b^

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

[6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phe^

[6-Methoxy-3-[4-[2-(1-hexamethyleneimino)e^^

[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-(morpholine)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b hydrochloride

[6-Methoxy-3-[4-[2-(1-piperidinyl)propoxy]phenoxy]-2-(4-methoxyphenyl)]benzo thiophene hydrochloride

[6-Methoxy-3-[4-[2-(1-N,N-diethylam [b]thiophene hydrochloride)

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

[6-Hydroxy-3-[4-[2-(1-piperidimii)ethoxy]phenoxy]-2-(4-Hydroxyphenyl)]benzo[^oxalate

[64] hydroxy-3-[4-[2-(1-piperidine) hydrochloride

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

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

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

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

[6-hydroxy-3-[4-[2-(1-N,N<liisopropylam benzo{b]thiophene hydrochloride)

[6-Hydroxy-3-[4-[2-(piperidino)propoxy]phenoxy]-2-(4-hydroxyphenyl) hydrochloride

[6-Methoxy-3-[4-[2-(1-piperidimity hydrochloride).

[6-berysyloxy-3-[4-[2-(1-piperidimity^).

[6-benzyloxy-3-[4-[2-(1-pyrohydrin).

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

[6-benzyloxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenox^^

[b]thiophene

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

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

[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-morpholine)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)]beriso(>]thiophene hydrochloride

[6-hydroxy-3-[4-[2-(1-hexamethylimino)e^

[b]thiophene hydrochloride

[6-Hydroxy-3-[4-[2-(1-N,N-dimethylamino)etho^

[b]thiophene hydrochloride

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

[6-methoxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene [6-methoxy-3-{4-[2-( 1 -pyrrolidinyl)ethoxy]phenoxy]-2-(4- benzyloxyphenyl)]benzo[b]thiophene [6-methoxy-3-[4-[2-(1-hexamethylimino)ethoxy)phenoxy]-2-(4-benzyloxyphenyl)]^

[b]thiophene

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

[6-Methoxy-3-[4-[2-(1-morpholine)^

[6-Methoxy-3-[4-[2-(1-piperidine)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)3benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-hexamethylimino)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-morpholine)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)

[b]thiophene

[6-Methoxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene [6-methoxy-3-[4-[2-(l-pyrrolidinyl)ethoxy]phenoxyJ-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-Methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-morpholine)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-hexanethylimino)etho^

[b]thiophene hydrochloride

[6-Methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo [bithiophene hydrochloride

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

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

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

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

[6-ethylsulfonyloxy-3-[4-[2~( 1^

[b]thiophene hydrochloride

[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-trifluoromethanesulfonyloxy-phenyl)[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-butylsulfonyloxyphenyl)]benzo[b]thiophene^hydrochloride

[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-hexamethyleneimmo)ethoxy]thiophenoxy]-2-{4-methoxyphenyl)] benzo[b]thiophene

[6-Methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

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

[6-benzyloxy-3-[4-[2-(1-piperidyl)ethoxy]thiophenolcsiJ-2-(4-methoxyphenyl)

[b]thiophene

[6-benzyloxy-3-[4-[2-(1-pyr^^).

[b]thiophene

[6-benzyloxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-methoxyphene benzoylthiophene

[6-benzyloxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

[6-benzyloxy-3-[4-[2-(1-morpholine)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

[6-Isopropoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

[6-Isopropoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

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

[6-isopropoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)] benzo[bthiophene

[6-isopropoxy-3-[4-[2-(1-morpholine)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy)-2-(4-methoxyphenyl)]benzo [bithiophene

[6-Hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo [bithiophene

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

[6-hydroxy-3-[4-[2-(1-N7N-diethylamino)ethoxy]thiophenoxy]-2-(4-m [b]thiophene

[6-hydroxy-3-[4-[2-(1-morpholine)ethoxy}thiophene^

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

[6-Hydroxy-3-[4-[2-{1-pyrrolidone thiophene hydrochloride

[6-Hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-rnethoxyphenyl)] benzo[bthiophene-hydrochloride

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

[6-hydroxy-3-[4-[2-(1-morpholine)ethoxy]thiophenoxy3-2-(4-rnethoxyphenyl)3benzo[b]thiophene hydrochloride

[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)j^ benzo[bthiophene

[6-Methoxy-3-[4-[2-(1-N,N-dietfamm^benzofjbjthiophene

[6^Methoxy-3-[4-[2-(1-morpho^benzo[bthiophene

[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-(l-hexamethyleneimino)ethoxy]thiophene^ benzo[b]thiophene

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

[6-Methoxy-3-[4-[2-(1-morpholine)ethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]bene [bithiophene

[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo [bithiophene

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

[6-Methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo [bithiophene

[6-Methoxy-3-[4-[2-(1-morpholine)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-pyrrolidyl)etho-thiophene hydrochloride

[6-Methoxy-3-[4-[2-(1-hexamethene) benzo[b}thiophene hydrochloride

[6-Methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo fbthiophene hydrochloride

[6-Methoxy-3-[4-[2-(1-morpholine)ethoxy]thiophenoxy]-2-(4-N hydrochloride

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

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

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

[6-Hydroxy-3-[4-[2-(14hexamethyleneim^ benzo[bjthiophene

[6-hydroxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]thiophenoxy}-2-(4-hydroxyphenyl)]benzophenone

[6-Hydroxy-3-[4-[2-(1-morpholine)etho^

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphen[bithiophene

[6^Hydroxy-3-[4-[2-(1-pyrrolidine^thiophene hydrochloride).

[6-Hydroxy-3-[4-[2-(1-hex^benzothiophene hydrochloride).

[64-Hydroxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)] benzo[bthiophene-hydrochloride

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

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

The following examples are presented to further illustrate the preparation of compounds of the present invention. The invention is not intended to be limited in scope by the reasoning of any of the following examples.

NMR data for the following Examples were generated on a GE 300 MHz instrument, and anhydrous d-6 DMSO was used as the solvent, unless otherwise noted.

Getting 1

Obtaining [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4^

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

To a solution of 3-bromobenzo[bthiophene (69.62 g; 0.325 mol) in 55 ml of anhydrous collidine under N 2 was added 4-benzyloxyphenol (97.6 g; 0.488 mol) and copper oxide (23.3 g; 0.163 mol). The mixture is heated under reflux for 24 hours. After cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and the crude mixture was filtered through a pad of Celite® (Aldrich, Michigan, WI) to remove inorganic salts. The filtrate was washed with IN HCl (3x150 mL). The organic layer is dried (sodium sulfate) and concentrated in vacuo to a liquid. Thianaphthene is removed by distillation (10 mm Hg; 115-120°C). The residue was chromatographed (SiO 2 , hexamethylacetate, 85:15) to give 12.2 g of benzo[b]thiophene and 12.95 g (35% based on regenerated starting material) of [2-(4-benzyloxy)phenoxy]benzo-b]thiophene as an off-white solid. d.p. 84-86°C. <1>H NMR (CDCl 3 ) d 7.91-7.83 (m, 2H), 7.47-7.34 (m, 7H), 7.04 (q, JAB=9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H). Anal. prov. for C2iH16O2S: C, 75.88; H, 4.85. Found: C, 75.75; H, 5.00.

Getting 2

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

To a solution of [3-(4-benzyloxy)phenoxy]benzo[b]thiophene (6.00 g; 18.1 mmol) in anhydrous tetrahydrofuran (100 mL) under N2 at -78°C, n-butyllithium (12.4 g; 19.9 mmol; 16M in hexanes) was added dropwise via syringe. The color of the solution changes from colorless to dark orange. After stirring for 20 minutes at -78°C, the lithium portion is treated with J 2 (5.03; 19.9 mmol) added dropwise via cannula, as a solution in 50 ml of anhydrous tetrahydrofuran. After the addition was complete, the reaction turned bright yellow and was allowed to warm to room temperature. The reaction was quenched by the addition of 0.1N sodium sulfate solution (200 ml). The layers are separated and the aqueous extracted with ethyl acetate (2x150 ml). The organics are combined, dried (sodium sulfate) and concentrated in vacuo to give an oil that crystallizes on standing. Recrystallization from hexane/ethyl ether gave 7.10 g (86%) of [2-iodo-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as a white crystalline powder. d.p. 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). Anal. prov. for C21H|502S: C, 55.03; H, 3.30. Found: C, 55.29; H, 3.31.

Getting 3

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

To a solution of [2-iodo-3-(4-benzyloxy)phenoxy]-benzo[b]thiophene (4.50 g; 9.82 mmol) in toluene (20 ml) was added 4-(tert-butoxy)phenylboronic acid (2.28 g; 11.75 mmol), then tetrakistriphenylphosphine palladium (0.76 g; 0.66 mmol). 14.5 ml of 2N sodium carbonate solution is added to this solution. The resulting mixture is heated under reflux for 3 hours. after cooling, the reaction is diluted with 150 ml of ethyl acetate. The organics were washed with 0.1N sodium hydroxide (2x100 ml) and then dried (sodium sulfate). Concentration gives a semi-solid mass which is dissolved in chloroform and passed through a layer of silica. Concentration gave an oil which triturated from hexane gave 4.00 g (91%) of [2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as a white powder. d.p. 105-108°C<l>HNMR (CDCl3) d 7.77 (d, J=7.7 Hz, IH), 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, Jab=9-3 Hz, 4H), 4.99 (s, 2H), 1.36 (s, 9H). FD mas.spec: 480. Anal. prov. for C₂H₂S: C, 77.47; H, 5.87. Found: C, 77.35; H, 5.99.

Getting 4

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

Yield=73%. d.p. 115-118°C. <!>H NMR (CDCl 3 ) d 7.80-7.90 (m, 3H), 7.33-7.53 (m, 7H), 6.93-7.06 (m, 6H), 5.00 (s, 2H), 3.83 (s, 3H). FD mass spec.: 438. Anal. prov. for C 28 H 22 O 3 S: C, 76.69; H, 5.06. Found: C, 76.52; H, 5.09.

Getting 5

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

To a solution of [2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene (1.5 g; 3.37 mmol) in 30 ml of absolute ethanol, containing 1% concentrated hydrochloric acid, was added 0.50 g of 10% palladium on carbon. The mixture is hydrogenated at 2.75 bar for one hour, after which the reaction is checked for completion by thin layer chromatography. The mixture is filtered through a pad of Celite, and the filtrate is concentrated in vacuo. The crude product is dissolved in a minimum of ethyl acetate and passed through a short SiO2 column to remove Celite (ethyl acetate as eluent). Concentration gave a white solid which was triturated from hexane/ethyl ether. Filtration afforded 868 mg (73%) of [2-(4-tert-butyloxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene. d.p. 210-213°C.<>>H NMR (DMSO-rf6) d 9.13 (s, IH), 7.94 (d, J = 7.7 Hz, IH), 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, JAB=8.9 Hz, 4H), 1.28 (s, 9H). FD mass spec.: 390. Anal. prov. for C24H22O3S: C, 73.82; H, 5.68. Found: C, 73.98; H, 5.84.

Getting 6

Obtained similarly [2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]

benzo[b]thiophene

Yield=80%. d.p. 120-125°C.<l>HNMR (CDCl3) 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, 3H). FD mass spec.: 348. Anal. prov. for C 2 and H 16 O 3 S: C, 72.39; H, 4.63. Found: C, 72.68; H, 4.82.

Example 1

[3-[4-[2-(l-Piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

Cesium carbonate (5.70 g; 17.6 mmol) was added to a solution of [2-(4-tertbutyloxyphenyl)-3-(4-hydroxy)phenoxy]benzo[bithiophene (1.25 g; 3.20 mmol) in anhydrous N,N-dimethylformamide (10 ml) at ambient temperature. After stirring for 20 minutes, 2-chloroethyl-piperidine hydrochloride (1.95 g; 10.56 mmol) was added in small portions. The resulting heterogeneous mixture is vigorously stirred for 24 hours. The contents of the reaction are then diluted with water (200 ml). The aqueous layer was extracted with ethyl acetate (3x100 ml). The combined organic layer is then washed with water (2x200 ml). Drying the organic layer (sodium sulfate) and concentrating in vacuo gives an oil. Chromatography (5-10% methanol/chloroform) gave 1.47 g (91%) of [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene, which was directly introduced into the next step without crystallization.

[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene (1.37 g; 2.73 mmol) was dissolved in trifluoroacetic acid (10 mol) at ambient 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 (3x10 ml). The organic layer is dried (sodium sulfate) and concentrated, after which complex white crystals form in the solution. The product was recrystallized from ethyl acetate-ethylether, giving 1.03 g (85%) of (3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[bthiophene as colorless crystals, mp 169-172°C.<*>H NMR(DMSO^)d 9.81 (s, 1H), 7.93 (d, J=7.7Hz, IH), 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). Anal. prov. for C27H27NO3S0.55 CF3C02H: 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^^^ converted to its hydrochloride salt in 90% yield by treatment with ethyl ether hydrochloric acid in ethyl acetate

Data for Example 2, m.p. 233-240°C. <1>H NMR (DMSCM6) 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 mas.spec: 446. Anal. prov. for C27H27NO3S • 1.0 OHC1: C, 67.28; H, 5.86; N, 2.91. Found: C, 67.07; H, 5.66; N, 2.96.

Example 3

The following examples were obtained analogously: [3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene m.p. 150-155°C.<l>H NMR (DMSO-<i6) d 9.79 (s, IH), 7.92 (d, J=7.8 Hz, IH), 7.54 (d, J=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). Anal. prov. for (^feNO^S • 0.33 CF3CO2H: 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 m.p. 189-191°C. <1>H NMR (DMSO-d6) 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=8.6 Hz, 2H), 3.89 (bt, 2H), 2.75 (bt, 2H), 2.68 (m, 4H), 1.48 (m, 8H). Anal. prov. for C28H29NO3S • 1.5 H2O: 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 m.p. 70°C<*>H NMR (DMSO-^) d 9.91 (bs, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.54 (d, J=8.5Hz, 2H), 7.35-7.24 (m, 3H), 6.82 (s, 4H), 6.78 (d, J=8.6 Hz, 2H), 3.88 (bt, 2H), 2.76 (bt, 2H), 2.51 (m, 4H), 0.91 (m, 6H). FD mass. spec: 434. Anal. prov. for C26H27NO3S - 0.5 H2O: C, 70.56; H, 6.38; N, 3.16. Found: C, 70.45; H, 6.26; N, 3.20. Example 6 [3-[4-[2-(l-Piperidinyl)eU)xy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

d.p. 228-230°C.<*>H NMR (DMSO-rf6) d 7.96 (d, J=7.5Hz, 1H), 7.66 (d, J=8.8Hz, 2H), 7.35-7.50 (m, 3H), 6.98 (d, J=8.7Hz, 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 spec.: 459.. Anal. prov. for C2SH29NO3S ■ 1.0 HC1: C, 67.80; H, 6.10; N, 2.82. Found: C, 68.06; H, 6.38; N, 2.60.

Alternative synthesis of [2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]

benzo[b]thiophene

Getting 7

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

To a solution of [3-(4-benzyloxy)phenoxybenzo[b]thiophene (5.00 g; 15.1 mmol) at -78°C in 20 ml of anhydrous tetrahydrofuran under N2 was added n-butyllithium (9.90 g; 15.8 mmol; 1.6M in hexane) dropwise from a syringe. After stirring for 15 minutes, B(OiPr)3 (3.83 ml; 16.6 mmol) was added with a syringe and the resulting mixture was allowed to warm to 0°C. The reaction was then quenched by partitioning between ethyl acetate and 1.0N HCl (100 mL each). The layers are separated and the organics are extracted with water (1x100 ml). The organic layer was dried (sodium sulfate) and concentrated in vacuo to give a solid, which was taken up in ethyl ether/hexane. Filtration afforded 3.96 g of 70% [3-(4-benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acid as a white solid. d.p. 115-121°C.<*>H NMR (DMSO-d6)d 8.61 (d, J=8.5 Hz, IH), 7.98 (d, J=9.0 Hz, IH), 7.42-7.23 (m, 7H), 6.90 (q, JAB=9.0 Hz, 4H), 5.01 (s, 2H). Anal. prov. for C2iH,704SB: C, 67.04; H, 4.55. Found: C, 67.17; H, 4.78.

[3-(4-Benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acid, reacts with 4-(tertbutoxy)bromobenzene according to the conditions previously described for [2-iodo-3-(4-benzyloxy)phenoxy]-benzo[bthiophene and 4-(tertbutoxy)phenyl boric acid to give [2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[bthiophene in 81% yield.

Examples obtained using this method are:

Example 7 [3-[4-[2-(l-Piperidinyl)ethoxy]phenoxy]-2-phenyl]benzo[b]riophene hydrochloride

U. 223-226°C. *H NMR (DMSO-d6) d 7.99 (d, J=8.2 Hz, IH), 7.71 (d, J=7.3 Hz, IH), 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). Anal. prov. for C27H27NO2S • 1.0 HG1: C, 69.59; H, 6.06; N, 3.00. Found: C, 69.88; H, 6.11; N, 3.19.

Example 8

[3.(442-(1-Piperidinyl)ethoxy]phenoxy]-2-(4-fluorophenyl)]benzob]thiophene

d.p. 219-226°C.<*>H NMR(DMSO-d6)d 10.20 (bs, IH), 7.99 (d, J=8.2 Hz, IH), 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 spec.: 447. Anal. prov. for C27H26N02SF ■ 1.0 HC1: C, 67.00; H, 5.62; N, 2.89. Found: C, 67.26; H, 5.67; N, 3.03.

Getting 8

Synthesis 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 solution of [6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene (27.0 g; 100 mmol) in 1.10 L of chloroform at 60°C was added bromine (15.98 g, 100 mmol), dropwise, as a solution in 200 ml of chloroform. After the addition was complete, the reaction was cooled to room temperature, and the solvent was removed in vacuo to give 34.2 g (100%) of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene as a white solid. d.p. 83-85°C.<*>H NMR (DMSO-40 d 7.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0 Hz, IH), 7.09 (d, J=8.4Hz, 2H). FD mass spec: 349, 350. Anal. pror. for C,6H1302SBr: 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

To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (34.00 g; 97.4 mmol) in 60 ml of collidine, under N2 was added 4-benzyloxyphenol (38.96 g; 194.8 mmol) in copper oxide (14.5 g; 97.4 mmol). The resulting mixture was heated under reflux for 48 hours, after cooling to room temperature, the mixture was dissolved in acetone (200 ml), and 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 HCl (3x300 ml), then with 1N NaOH (3x300 ml). The organic layer is dried (sodium sulfate), and concentrated in vacuo. The residue was taken up in 100 mL of ethyl acetate, whereupon a white solid formed, which was collected by filtration (regenerated [6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene (4.62 g; 17.11 mmol)). The filtrate is concentrated in vacuo and then passed through a thin layer of silica gel (methylene chloride as eluent) to remove basic substances. The filtrate was concentrated in vacuo, and the residue crystallized from hexane/ethyl acetate to give the original 7.19 g of [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as an off-white crystalline mass. The mother liquor was concentrated and chromatographed on silica gel (hexane/ethyl acetate, 80:20) to give an additional 1.81 g of product. The total yield of [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy)]benzo[b]thiophene was 9.00 g (24% based on the regenerated starting material. The base extract was acidified to pH = 4 with 5N HCl and the resulting precipitate was collected by filtration and dried to give 13.3 g of regenerated 4-benzyloxyphenol. m.p. 100-103°C. <1>H NMR (CDCl3) d 7.60 (d, J=8.8, Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H), 4.98 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H). 468. Anal C79H24O4S: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29.

Getting 9

[6-Methoxy-2-(4-nonethoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene

To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene (1.50 g; 3.20 mmol) in 50 ml ethyl acetate and 10 ml 10% concentrated HCl in ethanol, was added 10% Pd/C (300 mg). The mixture is hydrogenated at 2.7 bar for 20 minutes, after which the completeness of the reaction is studied by thin layer chromatography. The mixture is passed through Celite to remove the catalyst, and the filtrate is concentrated in vacuo to white crystals. The crude product is passed through a layer of silica gel (chloroform as eluent). Concentration gave 1.10 g (91%) of [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene as a white solid. d.p. 123-126°C.<*>H NMR(DMSCw/6)d 9.10 (s, IH), 7.59 (d, J=8.8, Hz, 2H), 7.52 (d, J=2.1 Hz, IH), 7.14 (d, J=8.8 Hz, IH), 6.95 (d, J=8.8 Hz, 2H), 6.89 (dd, J=8.8, 2.1 Hz, 1H), 6.72 (d, J=9.0 Hz, 2H), 6.63 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H). FD mas.spec: 378. Anal. prov. for (^HigC^S: C, 69.82; H, 4.79. Found: C, 70.06; H, 4.98.

Example 10

[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy

To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene (1.12 g; 2.97 mmol) in 7 ml of anhydrous N,N-dimethylformamide under N2, was added cesium carbonate (3.86 g; 11.88 mmol). After stirring for 10 min, 2-chloroethylpiperidine hypochloride (1.10 g; 1.48 mmol) was added. The resulting mixture is stirred for 18 hours at room temperature. The reaction mixture was partitioned between chloroform and water (100 ml each). The layers are separated and the aqueous extracted with chloroform (3x50 ml). The organics are combined and washed with water (2x100 ml). Drying orgam (sodium sulfate) and concentration gives an oil which is chromatographed on silica gel (2% methanol/chloroform). The desired fractions were concentrated to an oil, which was dissolved in 10 ml of ethyl acetate and treated with oxalic acid (311 mg; 3.4 mmol). After stirring for 10 minutes, a white precipitate formed and was collected by filtration and drying to give 1.17 g (70%) of total [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy3-2-(4-hydroxyphenyl)]benzo[bthiophene as the oxalate salt. d.p. 197-200°C (dec).<*>H NMR (DMSO-<i6) d 7.60 (d, J=8.7, Hz, 2H), 7.55 (d, J=1.1 Hz, IH), 7.14 (d, J=8.8 Hz, IH), 7.06 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.8,1.1 Hz, IH), 6.87 (s, 4H), 4.19 (broad t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broad t, 2H), 3.12-3.06 (m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H). FD mas.spec: 489. Anal. prov. for C^HsjNC^S - 0.88 H02CC02H: 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 gives [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b3thiophene hydrochloride

d.p. 216-220°C.<*>H NMR(DMSO-J6)d 10.20 (bs, IH), 7.64 (d, J=8.7 Hz, 2H), 7.59 (d, J=1.5 Hz, IH), 7.18 (d, J=9.0 Hz, IH), 7.00 (d, J=8.7 Hz, IH), 6.96 (dd, J=9.0, 1.5 Hz, IH), 6.92 (a, JAB=9.0 Hz, 4H), 4.31 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.43 (m, 4H), 2.97 (m, 2H), 1.77 (m, 5H), 1.37 (m, IH). FD mass spec.: 489. Anal. prov. for C29H31N04S • 1.0 HCl: C, 66.21; H, 6.13; N, 2.66. Found: C, 66.46; H, 6.16; N, 2.74.

The following examples were obtained in an analogous way:

Example 12 [6^Methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-methotheiphenyl)]benzo[b]thiophene-

d.p. 95-98°C.<*>H NMR (DMS0^6) d 7.64 (d, J=9.0 Hz, 2H), 7.58 (d, J=2.0 Hz, IH), 7.18 (d, J=9.0 Hz, IH), 7.00 (d, J=9.0 Hz, 2H), 6.94 (dd, J=9.0, 2.0 Hz, IH), 6.86 (s, 4H), 3.97 (t, J=6.0Hz,2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.73 (t, J=6.0

Hz, 2U), 2.51 (m, 4H), 1.66 (m, 4H). FD mas.spec: 477. Anal. prov. for C2SH2<)NO4S: C 70.71; H, 6.15; N, 2.99. Found: C, 70.59; H, 6.15; N, 3.01.

Example 13

t6-Methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]

benzo[b]thiophene hydrochloride

d.p. 189-192°C. <l>UNMR (DMSO-rf6) d 10.55 (bs, IH), 7.64 (d, J=9.0, Hz, 2H), 7.58 (d, J=2.0 Hz, IH), 7.19 (d, J=9.0 Hz, IH), 7.00 (đ, J=9.0 Hz, 2H), 6.95 (dd, J=9.0, 2.0 Hz, IH), 6.86 (s, 4H), 3.94 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J=6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Anal. prov. for C30H33NO4S -1.0 HCl: C, 66.71; H, 6.35; N, 2.59. Found: C, 66.43; H, 6.46; N, 2.84.

Example 14

[6^Methoxy-3-[4-[2-(1-N,N-diamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]

benzo[b]thiophene hydrochloride

d.p. 196-198°C.<l>KNMR( ĐMSO-d6)d 10.48 (bs, IH), 7.64 (d, J=9.0, Hz, 2H), 7.59 (d, J=2.0 Hz, IH), 7.19 (d, J=9.0 Hz, IH), 7.00 (d, J=9.0 Hz, 2H), 6.97

(dd, J = 9.0, 2.0 Hz, IH), 6.87 (q, JAB=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). Anal. prov. for C3gH31N04S • 1.5 HCl: 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

m.p. 208-211°C.<l>HNMR (DMSO-d6) d 10.6 (bs, IH), 7.63 (d, J=9.0, Hz, 2H), 7.60 (d, J=2.0Hz, IH), 7.20 (d, J=9.0 Hz, IH), 7.00 (d, J=9.0 Hz, 2H), 6.97 (dd, J=9.0, 2.0 Hz, IH), 6.91 (q, 5^ =9. 0 Hz, 4H), 4.29 (m, 2H), 4.08-2.91 (m, 4H), 3.82 (s, 3H), 3.77 (s, 3H), 3.59-3.42 (m, 4H), 3.21-3.10 (m, 2H), 1.88 (at, 3H). Anal. prov. for C28H29N05S • 1.0 HCl: 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-[2-(piperidino)propoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

m.p. 195-200°C. <!>H NMR(DMSO-J6)d 9.90 (bs, IH), 7.64 (d, J=9.0, Hz, 2H), 7.59 (d, J=2.0 Hz, IH), 7.18 (d, J=9.0 Hz, IH), 7.00 (d, J=9.0 Hz, 2H), 6.95 (dd, J=9.0, 2.0 Hz, IH), 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, IH). Anal. prov. for C30H33NO4S - 1.5 HCl: 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-[2-(1-N,N-diethylamino)propoxy]phenoxy]-2-(4-methoxyphenyl)]

benzo[b]thiophene hydrochloride

d.p. 164-166°C.<l>H NMR (DMSCW6) d 9.77 (bs, IH), 7.64 (d, J=9.0, Hz, 2H), 7.59 (d, J=2.0Hz, IH), 7.18 (d, J=9.0 Hz, IH), 7.00 (d, J=9.0Hz, 2H), 6.95 (dd, J=9.0, 2.0 Hz, IH), 6.89 (q, JAb=9.0 Hz, 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). Anal. prov. for C29H33N04S • 1.0 HCl: C, 65.96; H, 6.49; N, 2.65. Found: C, 66.25; H, 6.64; N, 2.84. Example 18 [6-Hydroxy-3-[442-(1-piperidinyl)]

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

Thiophene hydrochloride (10.00 g; 19.05 mmol) was dissolved in 500 ml of anhydrous methylene chloride and cooled to 8°C. To this solution was added boron(III) bromide (7.20 mL; 76.20 mmol). The resulting mixture is stirred at 8°C for 2.5 hours. The reaction was terminated by pouring into the solution with stirring a saturated aqueous solution of sodium bicarbonate (1 h), 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. The aqueous layer was then extracted with 5% methanol/ethyl acetate (3x500 ml). All organic extracts (ethyl acetate and methylene chloride) were combined and dried (sodium sulfate). Concentration in vacuo gave a dark solid which was chromatographed (silica, 1-7% methanol/chloroform) to give 7.13 g (81%) of {6-hydroxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxyJ-2-(4-hydroxyphenyl)]benzo[b]thiophene as a white solid. d.p. 93°C. *H NMR(DMSO-d6)d 9.73 (bs, IH), 0.68 (bs, IH), 7.45 (d, J=8.6, Hz, 2H), 7.21 (d, J=18Hz, IH), 7.04 (d, J=8.6 Hz, IH), 6.84 (dd, J=8.6, 1.8 Hz, IH (masked)), 6.81 (s, 4H), 6.75 (d, J=8.6 Hz, 2H), 3.92 (t, J=5.8 Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.36 (m, 4H), 1.43 (m, 4H), 1.32 (m, 2H). FD mas.spec: 462. Anal. prov. for C27H27NO4S: 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 converted to its oxalate salt in 80% yield, using the procedure described above. Data for [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene oxalate

d.p. 246-249°C (dec).<!>H NMR (DMSO-d6) d 7.45 (d, J=8.6 Hz, 2H), 7.22 (d, J=1.8 Hz, IH), 7.05 (d, J=8.6 Hz, IH), 6.87 (dd, J=8.6,1.8 Hz, IH (masked)), 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. spec.: 462. Anal. prov. for C27H27N04S • 0.75 H02CC02H: C, 64.63; H, 5.42; N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62. Example 20 [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxide^^ was converted to its hydrochloride salt in 91% yield by treatment with the free base in ethyl acetate with ethyl ether HCl. Data for [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride

d.p. 158-165°C (dec).<l>H NMR( DMSO- d6 )d 9.79 (s, IH), 9.74 (s, IH), 7.40 (d, J=8.6 Hz, 2H), 7.23 (d, J=2.0 Hz, IH), 7.04 (d, J=8.6 Hz, IH), 6.86 (q, JAB=9.3 Hz, 4H), 6.76 (dd, J=8.6, 2.0 Hz, 1), 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, IH). FD Mass. spec: 461. Anal. prov. for C27H27NO4S ■ 1.0 H02CC02H: C, 65.11; H, 5.67; N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.

The following examples were obtained in an analogous way:

Example 21 [6-Hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

d.p. 99-113°C (dec).<l>H NMR(DMSO-^)d 9.75 (s, IH), 9.71 (s, IH), 7.50 (d, J=9.0 Hz, 2H), 7.25 (d, J=2.0 Hz, IH), 7.09 (d, J=9.0 Hz, IH), 6.85 (s, IH), 6.80 (dd, J=9.0, 2.0 Hz, IH), 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). Anal. prov. for C^H^NG^S • 0.5 H 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

d.p. 125-130°C.<*>H NMR (DMSO-d6) d 9.75 (s, IH), 9.71 (s, IH), 7.50 (d, J=9.0 Hz, 2H), 7.26 (d, J=2.0 Hz, IH), 7.09 (d, J=9.0 Hz, IH), 6.85 (s, IH), 6.80 (dd, J=9.0, 2.0 Hz, IH), 6.79 (d, J=9.0 Hz, 2H), 3.94 (t, J=6.0 Hz, 2H), 2.80 (t, J=6.0Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Anal. prov. for C^^NO^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-(1-N,N-diethylamino)ethoxy}phenoxy]-2-(4-hydroxyphenyl)]

benzo[b]thiophene

d.p. 137-141°C.<*>H NMR(DMSO-d6)d 9.75 (s, IH), 9.71 (s, IH), 7.49 (d, J=9.0Hz, 2H), 7.25 (d, J=2.0 Hz, IH), 7.09 (d, J=9.0 Hz, IH), 6.85 (s, IH), 6.80 (dd, J=9.0, 2.0 Hz, IH), 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). Anal. prov. for C₂₂I₂NC₂S: 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-(morpholine)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride

d.p. 157-162°C.<l>HNMR (ĐMSCwi6) d 10.60 (bs, IH), 9.80 (s, IH), 9.75 (s, IH), 9.71 (s, IH), 7.50 (d, J=9.0 Hz, 2H), 7.28 (d, J=2.0 Hz, IH), 7.10 (d, J=9.0 Hz, IH), 6.92 (q, Jab=9.0 Hz, 4H), 6.81 (dd, J=9.0, 2.0 Hz, IH), 6.80 (d, J=9.0 Hz, 2H), 4.30 (ra, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 (m, 4H), 3.18 (m, 2H). Anal. prov. for C26H25N05S • HCl: 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-[2-(1-N^1-diethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]

benzo[b]thiophene hydrochloride

d.p. 185-19<P>C.<X>H NMR (DMSO-^) d 9.945 (s, IH), 9.811 (s, IH), 9.75 (s, IH), 7.50 (d, J=9.() Hz, 2H), 7.27 (dd, J=2.0 Hz, IH), 7.10 (d, J=9.0 Hz, IH), 6.87 (s, 4H), 6.80 (dd, J=9.0, 2.0 Hz, IH), 6.79 (d, J=9.() Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 3.14 (m, 6H), 2.08 (m, 2H), 1.20 (t, J=6.0 Hz, 6H). Anal. prov. for C27H29N04S ■ 1.30 HCl: 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-diisopropylam).

benzo[b]thiophene hydrochloride

tt. 128-131°C.<*>H NMR (DMSO-^) d 9.81 (bs, IH), 9.76 (s, IH), 9.02 (s, IH), 7.49 (d, J=9.0 Hz, 2H), 7.28 (m, IH), 7.09 (d, J=9.0 Hz, IH), 6.90 (s, 4H), 6.79 (m, 3H), 4.19 (m, 2H), 3.68 (m, 2H), 3.50 (m, 2H), 1.31 (m, 12H). Anal. prov. for C28H31N04S ■ 1.33 HCl: 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)propoxy]phenoxy]-2-(4-hydroxyphenyl)]

benzo[b]thiophene hydrochloride

mp 258-262°C. 1H NMR( ĐMSO-cl6 ) 9.85 (bs, IH), 9.81 (s, IH), 9.75 (s, IH), 7.50 (d, J=9.0 Hz, 2H), 7.27 (d, J=2.0 Hz, IH), 7.10 (d, J=9.0 Hz, IH), 6.87 (s, 4H), 6.80 (dd, J=9.0, 2.0 Hz, IH), 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, IH). Anal. prov. for C28H29NO4S • 0.75 HCl: C, 66.87; H, 5.96; N, 2.78. Found: C, 67.04; H, 5.90; N, 2.68.

Alternatively, as shown in Scheme III above, Example 19 was prepared using a methoxymethyl protecting group (MOM) instead of methoxy. The procedures are directly analogous to those just described, with the difference that the MOM groups are removed in the final step by acid hydrolysis.

Getting 10

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

d.p. 94-96°C.<*>H NMR (DMSO-rf6) d 7.65 (d, J=2.0 Hz, IH), 7.64 (d, J=8.6 Hz, 2H), 7.43-7.32 (m, 5H), 7.23 (d, J=8.8 Hz, IH), 7.08 (d, J=8.6 Hz, 2H), 7.04 (dd, J=8.8,2.0 Hz, IH), 6.92 (q, Jab=9.2 Hz, 4H), 5.26 (s, 2H), 5.21 (s, 2H), 5.01 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H). FR mas.spec: 528. Anal. prov. for C26H25NO4S • 0.5 H2O: C, 68.40; H, 5.74; N, 3.07. Found: C, 68.52; H, 6.00; N, 3.34. Obtaining 11[6-Methoxy-2-(4-methoxymethyloxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene

d.p. 90-91°C.<*>H NMR(DMSO-d6)d 9.15 (s, IH), 7.65 (d, J=8.1 Hz, 2H), 7.63 (d, J=2.0 Hz, IH), 7.22 (d, J=8.8 Hz, IH), 7.05 (dd, J=8.8, 2.0 Hz, IH), 6.72 (q, Jab=9-1 Hz, 4H), 5.26 (s, 2H), 5.21 (s, 2H), 3.40 (s, 3H), 3.37 (s, 3H). FR mass spec.: 438. Anal. prov. 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[b3thiophenyl-(S-oxide)

To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (10.0 g; 23.6 mmol) in 50 ml of anhydrous methylene chloride was added 50 ml of trifluoroacetic acid. After stirring for 5 min, hydrogen peroxide (4.0 g; 28.6 mmol; 30% aqueous solution) was added. The resulting mixture is stirred at room temperature for 2 hours. Solid sodium bisulfate (1.25 g) was added to the dark reaction mixture followed by 15 ml of water. The mixture was stirred vigorously for 15 minutes, then concentrated in vacuo. The residue was partitioned between chloroform and saturated sodium bicarbonate solution (200 ml). The layers were separated and the organic layer was extracted with saturated sodium bicarbonate solution. The organic layers were then dried (sodium sulfate) and concentrated in vacuo to a solid which was treated with 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 recrystallized from ethyl ether. d.p. 170-173°C.<l>H NMR(DMSO-</6)d 7.24 (d, J=2.2 Hz, IH), 7.68 )d, J=8.8 Hz, 2H), 7.54 (d, J=8.5 Hz, IH), 7.26 (dd, J = 8.5, 2.2 Hz, IH), 7.10 (d, J=8.8 Hz, IH). 2H), 3.86 (s, 3H), 3.80 (s, 3H). Anal. prov. for Cl 6 H 13 O 3 SBr: C, 52.62; H, 3.59. Found: C, 52.40; H, 3.55.

Example 29

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

d.p. 120-125°C. <»>H NMR(DMSO-J6)d 8.06 (d, J=7.6 Hz, 1H), 7.78-7.59 (m, 5H), 7.13 (d, J=8.7 Hz, 2H), 3.81 (s, 3H). FD mass spec.: 335. Anal. prov. for Ci5H1102SBr: C, 53.75; H, 3.31. Found: C, 53.71; H, 3.46.

Getting 12

Preparation of 4-(2-(1-piperidinyl)ethoxy)-phenol

To a solution of 4-benzyloxyphenol (50.0 g; 0.25 mol) in 350 ml of anhydrous DMF, 2-chloroethylpiperidine (46.3; 0.25 mol) was added. After stirring for 10 minutes, potassium carbonate (54.0 g; 0.375 mol) and cesium carbonate (85.0 g; 0.25 mol) were added. The resulting heterogeneous mixture is vigorously stirred at ambient temperature for 48 hours. The reaction mixture was then poured into water (500 ml), and extracted with methylene chloride. The organics are then extracted with IN sodium hydroxide, several times and finally washed with sodium chloride solution. The organic layer is then dried (sodium sulfate) and concentrated in vacuo to an oil. Chromatography (SiO 2 , 1:1 hexane/ethyl acetate) afforded 60.0 g (77%) of 4-[2-(1-piperidinyl)ethoxy]phenoxybenzylether as a colorless oil. ?H NMR (DMSO-d6) d 7.40-7.27 (m, 5H), 6-84 (q, JAB=11.5 Hz, 4H), 4.98 (s, 2H), 3.93 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.0Hz, 2H), 2.35-2.37 (m, 4H), 1.48-1.32 (m, 6H). FD mas.spec: 311. Anal. prov. for C20H25N02: 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; 68.80 mmol) was dissolved in 200 ml of 1:1 EtOH/EtOAc, containing 1% conc. HCl. The solution is transferred to a Parr flask, 5% palladium on carbon (3.4 g) is added. The mixture is hydrogenated at 2.75 bar for 2 hours. The mixture is then passed through a bed of Celite to remove the catalyst. The filtrate was concentrated in vacuo to a solid which was suspended in diethyl ether and filtered to give 12.10 g (83%) of 4-(2-(1-piperidinyl)ethoxy)phenol. d.p. 148-150°C

<*>H NMR (DMSO-d6) d 8.40 (s, 1H), 6.70 (q, Jab=H.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 mas.spec: 221. Anal. prov. for C13H19N02: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[bithiophene-(S-oxide)

To a solution of 4-[2-(1-piperidinyl)ethoxy]phenol (0.32 g, 1.45 mmol) in 5 ml of anhydrous DMF at ambient temperature was added sodium hydride (0.57 g; 1.43 mmol; 60% dispersion in mineral oil). After stirring for 15 minutes, [6-methoxy-2-(4-methoxyphenyl)-34o]benzo[b]thiophene-(S-oxide) is added in small portions

(0.50 g; 1.37 mmol). After stirring for 1 hour, the completeness of the reaction is checked by TLC analysis. The solvent was removed in vacuo and the residue partitioned between water and 10% ethanol/ethyl acetate. The organics are washed several times with water and then dried (sodium sulfate). Concentration in vacuo afforded an oil which was treated from ethyl acetate/hexanes to give 0.62 g (89%) of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide) as a pale yellow solid. d.p. 97-100°C. <2>H NMR (DMSO-rf6) 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, 6H). Anal. prov. for C29H3iNO5S: C, 68.89; H, 6.18; N, 2.77. Found: C, 68.95; H, 6.04; N, 2.57.

Example 31

Obtained in an analogous way [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-

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

Oil.<*>H NMR (DMSO-d6) 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), 1.45-1.32 (m, 6H). FD mas.spec: 475. Anal. prov. for C28H29NO4S: 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)ethoyl

hydrochloride

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

Example 6 was also obtained from Example 31, using the same procedure.

Getting 13

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

To a solution of 6-methoxybenzo[b]thiophene (18.13 g; 0.111 mol) in 150 ml of anhydrous tetrahydrofuran (THF) at -60°C, n-butyllithium (76.2 ml; 0.122 mol; 1.6M solution in hexane) was added dropwise via syringe. After stirring for 30 minutes, triisopropyl borate (28.2 mL; 0.122 mol) was added via syringe. The resulting mixture was allowed to slowly warm to 0°C and then partitioned between 1N hydrochloric acid and ethyl acetate (300 ml each). The layers are separated, the organic layer is dried over sodium sulfate. Concentration in vacuo gave a white solid which was triturated from ethyl ether-hexane. Filtration afforded 16.4 g (71%) of 6-methoxybenzo[b]thiophene-2-boronic acid as a white solid. d.p. 200°C (dec). <1>H NMR (DMSO-^) d 7.83 (s, IH), 7.78 (d, J=8.6 Hz, IH), 7.51 (d, J=2.0 Hz, IH), 6.97 (dd, J=8.6,2.0 Hz, IH), 3.82 (s, 3H). FD mas.spec: 208.

Getting 14

[6-Methoxy-2-(4-methanesulfonyloxyoxyphenyl)]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 was added 4-(methanesulfonyloxy)phenylbromide (3.98 g; 15.8 mmol) and then 16 ml of 2.0N sodium carbonate solution. After stirring for 10 minutes, tetrakistriphenylphosphine palladium (0.60 g; 0.52 mmol) was added and the resulting mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature, after which the product settled from the organic layer. The aqueous layer 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 give 3.70 g (77%) of [6-methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[b}thiophene as a brown solid. d.p. 197-201 °C.<*>H NMR (DMSCM6) d 7.82-7.77 (m, 3H), 7.71 (d, J=8.8 Hz, IH), 7.54 (d, J=2.3 Hz, IH), 7.40 (d, J=8.7 Hz, 2H), 6.98 (dd, J=8.7,1.5 Hz, IH), 3.80 (s, 3H), 3.39 (s, 3H). FD mass spec.: 334. Anal. prov. for C16H14O4S2: C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21.

Getting 15

Obtained in a manner analogous to Obtaining 14 is [6-methoxy-2-(4-benzyloxyphenyl)]benzo[b]thiophene

Yield=73%. d.p. 217-221°C<*>H NMR( ĐMSO-d6)d 7.63-7.60 (m, 3H), 7.59-7.26 (m, 7H), 7.02 (d, J=8.7 Hz, 2H), 6.96 (dd, J=8.8,2.2 Hz, IH), 5.11 (s, 2H), 3.88 (s, 3H). FD mas.spec: 346. Anal. prov. for C 22 H 18 O 2 S: C, 76.27; H, 5.24. Found: C, 76.00; H, 5.25.

Getting 16

[6-Hydroxy-2-(4-methanesulfonyloxyphenyl)]ben2o[b]thiophene

Boron(III)-bromide (14.20 g; 5.36 ml; 56.8 mmol) was added to a solution of [6-methoxy-2-(4-meth^ulfo (9.0 g; 28.4 mmol) in anhydrous methylene chloride (200 ml) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by slowly pouring into excess ice water. after stirring for 30 minutes, the white precipitate was collected by filtration, washed several times with water, and then dried in vacuo to give 8.92 g (98%)

[6-Hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene as a white solid. d.p. 239-243°C.<>>H NMR(DMSO-d6)d 7.76 (d, J=8.7 Hz, 2H), 7.72 (s, IH), 7.62 (d, J=8.7Hz, IH), 7.38 (d, J=8.7 Hz, 2H), 7.24 (d, J=1.7 Hz, IH), 6.86 (dd, J=8.7, 1.7 Hz, 1H), 3.38 (s, 3H). FD mas.spec: 320. Anal. prov. for C^H^G^: C, 56.23; H, 3.77. Found: C, 56.49; H, 3.68.

Getting 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, CS2CO3 (5.75 g; 17.7 mmol) was added, followed by benzyl chloride (1.72 mL; 11.0 mmol). The resulting mixture is vigorously stirred for 24 hours. The solvent is removed in vacuo, the solid residue is suspended in 200 ml of water. The white precipitate is collected by filtration and washed several times with water. After drying in a vacuum, the crude product is suspended in a mixture of 1:1, hexane.ethylether. The solid was collected to give 3.72 (91%) of [6-benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene as a white solid. d.p. 198-202°C.<X>H NMR(DMSO-d6)d 7.81-7.78 (m, 3H), 7.72 (d, J=8.7 Hz, IH), 7.64 (d, J=2.2 Hz, IH), 7.47-7.30 (m, 7H), 5.15 (s, 2H), 3.39 (s, 3H). FD mas.spec: 410.

Getting 18

[6-Benzyloxy-2-(4-hydroxyphenyl)3benzo[b]thiophene

To a solution of [6-benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene (12.5 g; 30.50 mmol) in 300 ml of anhydrous THF under nitrogen at ambient temperature, lithium aluminum hydride (2.32 g; 61.0 mmol) was added in small portions. The mixture is then stirred at room temperature for 3 hours and then the reaction is terminated by gently pouring the mixture into an excess of cold 1.0N hydrochloric acid. The aqueous layer is extracted with ethyl acetate. The organics are then washed several times with water and then dried (sodium sulfate) and concentrated in vacuo to a solid mass. Chromatography (silica, chloroform) afforded 8.75 g (87%) of [6-benzyloxy-2-(4-hydroxyphenyl)]benzo[bthiophene as a white solid. d.p. 212-216°C.<*>H NMR(DMSO-d6)d 9.70 (s, IH), 7.63 (d, J=8.7 Hz, IH), 7.56 (d, J=2.2 Hz, IH), 7.51-730 (m, 8H), 7.00 (dd, J=8.7, 2.2 Hz, IH), 6.80 (d, J=8.6 Hz, 2H), 5.13 (s, 2H). FD mas.spec: 331. Anal. prov. for O 2 H 2 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

To a solution of [6-benzyloxy-2-(4-hydrolBiphenyl)]benzopyr]thiophene (8.50 g; 26.4 mmol) in 200 mL of anhydrous DMF under nitrogen, sodium hydride (1.66 g; 41.5 mmol) was added in small portions at room temperature. After gas evolution stops, iodomethane (3.25 ml; 52.18 mmol) is added dropwise. The reaction mixture is stirred for 3 hours at ambient temperature. The solvent was then removed in vacuo, and the residue was partitioned between water/ethyl acetate. The layers are separated, and the organic layer is washed several times with water. The organic layer was then dried (sodium sulfate) and concentrated in vacuo to give 9.00 g (98%) of [6-benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene as a white solid. mp 180-185°C.<*>H NMR(DMSO-d6)d 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J=8.8, 2.2 Hz, 1H), 6.98 (d, J=8.7 Hz, 211), 5.13 (s, 2H), 3.76 (s, 3H). FD mas.spec: 346. Anal. prov. for C 22 H 18 O 2 S: C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43.

Getting 20

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

[6-Benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene (1.00 g; 28.9 mmol) was poured into 200 mL of chloroform, along with 10.0 g of solid sodium bicarbonate, at room temperature. To this suspension was added bromine (1.50 mL; 29.1 mmol) dropwise over 30 min as a solution in 100 mL of chloroform. After the addition is complete, water (200 ml) is added and the layers are separated. The organic layer was dried (sodium sulfate) and concentrated in vacuo to give a white solid. Crystallization from methylene chloride/methanol gave 10.50 g (85%) of [6-trimethyloxy-2-(4-methoxyphenyl)-3-bromo]benzothiophene as a white solid. d.p. 146-150°C. <»>H NMR (DMS0^6) d 7.70 (d, J=2.2 Hz, IH), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J=8.8, 2.2 Hz, IH), 7.06 (d, J=8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H). FD mas.spec: 346. Anal. prov. for C 22 H 17 O 2 SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00.

Getting 21

Obtained in an analogous way [6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]

benzo[b]thiophene

Yield=91%. d.p. 125-127°C.<l>UNMR (DMSO-rf6) 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 mas.spec: 346. Anal. prov. for C22H17O3SBr: C, 62.13; H, 4.03. Found: C, 62.33; H, 3.03.

Example 33

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

Isolated as a yellow solid by crystallization from ethyl acetate. d.p. 202-205°C.<*>H NMR (DMS0^6) d 7.80 (d, J=2.2 Hz, IH), 7.68 (d, J=8.7Hz, 2H), 7.55 (d, J=8.4 Hz, IH), 7.47-7.32 (m, 6H), 7.10 (d, J=8.7 Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H). FD mas.spec: 441. Anal. prov. for C22H17O3SBr: C, 59.87; H, 3.88. Found: C, 59.59; H, 3.78.

Example 34

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

Isolated as a yellow solid by chromatography (SiCl2, CHCl3). d.p. 119-123°C.<l>H NMR (DMSO-<i6) d 7.73 (d, J=2.2 Hz, IH), 7.68 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.5 Hz, IH), 7.46-7.31 (m, 5), 7.26 (dd, J=8.5,2.2 Hz, IH), 7.18 (d, J=8.8 Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H). FD mass spec.: 441. Anal. prov. for C22H17O3SBr: C, 59.87; H, 3.88. Found: C, 60.13; H, 4.10.

Example 35

[6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]

benzo[b]thiophene-(S-oxide)

Yellow oil. <l>UNMR (DMSO-^j) d 7.76 (d, J=2.2 Hz, IH), 7.62 (d, J=8.8 Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J=8.6, 2.2 Hz, IH), 7.03-6.93 (m, 5H), 6.85 (d, J=8.8 Hz, 2H), 5.18 (s, 2H), 3.94 (bt, J=5.8 Hz, 2H), 3.73 (s, 3H), 2.56 (bt, J=5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.32 (m, 6H). FD mass spec.: 592. Anal. prov. for C35H35NO5S: 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)

A yellow solid. d.p. 89-93°C.<*>H NMR (DMSO-</6) d 7.68 (d, J=2.2 Hz, IH), 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, J=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 mas.spec: 592. Anal. prov. for C35H35N05S - 0.25 EtOAe: C, 71.62; H, 6.18; N, 2.32. Found: C, 71.32; H, 5.96; N, 2.71.

Obtained in a manner analogous to Example 11 are Examples 37-38:

Example 37 [6-Benyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy-2-(4- methoxyphenU)]benzo[b]thiophene

Isolated in 95% yield, starting from [6-nyloxy-2-(4-methoxynyl)-3-bromo]benzo[b]thiophene-(S-oxide). Purified by chromatography (SiCl>2> 1-5% methanol/chloroform) to give a completely solid white mass. d.p. 105-108°C. Hi NMR (DMSO-</6) d 7.62 (d, J = 2.2 Hz, IH), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J = 8.6 Hz, IH), 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 mas.spec: 565. Anal. prov. for C35H35N04S: 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%. mp 106-110°C. JH NMR (DMSO-^) d 7.59 (d, J=8.8 Hz, 2H), 7.54 (d, J=2.2 Hz, IH), 7.42-7.28 (m, 5H), 7.13 (d, J=8.8 Hz, IH), 7.03 (D, J=8.8 Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (bt, J=5.8 Hz, 2H), 3.92 (bt, J=5.8 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 mas.spec: 565. Anal. prov. for C35H35NO4S: 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-pyriridinyl)ethoxy

To a solution of [6-benzyloxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-methoxy phenyl)]benzo[b]thiophene (8.50 g; 15.0 mmol) in 300 ml of a mixture of 5:1, ethanol/ethyl acetate, was added palladium black (1.50 g), ammonium formate (3.50 g; 55.6 mmol) and 30 ml of water. The resulting mixture is heated to reflux and the reaction is monitored by TLC. After approximately 3 hours, the reaction is completely checked and the solution is cooled to room temperature. The reaction mixture is filtered through a pad of Celite to remove the catalyst, the filtrate is concentrated in vacuo to give a solid. The concentrate is partitioned between saturated sodium bicarbonate solution and 5% ethanol/ethyl acetate. The layers are separated, and the organic layer is dried (sodium sulfate) and concentrated in vacuo. The crude product was chromatographed (silica, 1-5% methanol/chloroform) to give 6.50 g (91%) of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene as a foam which turned into a solid after trituration with hexanes. d.p. 174-176°C. <1>H NMR (DMSCM6) d 9.77 (s, IH), 7.56 (d, J=8.8 Hz, 2H), 7.23 (d, J=2.0 Hz, IH), 7.07 (d, J=8.6 Hz, IH), 6.93 (d, J=8.8 Hz, 2H), 6.81 (s, 4H). 6.76 (dd, J=8.6, 2.0 Hz, IH), 3.91 (bt, J=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 mas.spec: 475. Anal. prov. for C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.46; H, 5.93; N, 2.71.

Example 40

Obtained analogously to Example 39 is [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

Yield=88%. tt. 147-150°C,<*>H NMR( ĐMSO-d6)d 9.72 (s, IH), 7.51 (d, J=2.0 Hz, IH), 7.48 (d, J=8.6 Hz, 2H), 7.11 (d, J=8.8 Hz, IH), 6.88 (dd, J=8.8,2.2

Hz, LH), 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 (ni, 4H), 1.46-1.28 (m, 6H). FD mas.spec: 475. Anal. prov. for C 28 H 2 () NO 4 S: C, 70.71; H, 6.15; N, 2.94. Found: C, 71.00; H, 6.17; N, 2.94.

Alternatively, Examples 39 and 40 can be obtained by the same transfer hydrogenolysis procedure, directly in 90% yield from [6-methoxy-3-[4-[2-(l-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-(S-oxide), respectively.

Example 41

[6-Hydroxy-3-[4-{2-(1-piperidinyl)ethoxy]phene

(Example 39) was converted to its hydrochloride salt in 85% yield by treatment with ethyl ether/hydrochloride in ethyl acetate followed by crystallization from ethanol/ethyl acetate

d.p. 156-160°C.<*>H NMR (DMSO-<26) d 10.28 (bs, IH), 9.85 (s, IH), 7.56 (d, J=8.8 Hz, 2H), 7.25 (d, J=2.0 Hz, IH), 7.06 (d, J=8.7 Hz, IH), 6.93 (d, J=8.8 Hz, IH). 2H), 6.87 (q, Jab=9.3 Hz, 4H), 4.27 (bt, J=5.9 Hz, 2H), 3.71 (s, 3H), 3.44-3.31 (m, 4H), 2.98-2.88 (m, 2H), 1.74-1.60 (m, 5H), 1.36-1.29 (m, IH). FD mas.spec: 475. Anal. prov. for C28H29NO4S • 1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.98; H, 6.11; N, 2.64.

Example 42

Obtained in an analogous manner to Example 41 is [6-hydroxy-3-[4-[2-<1-piperidinyl)ethoxyphenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride

d.p. 215-217°C.<l>UNMR(DMSO-rf6)d 10.28 (bs, IH), 9.80 (s, IH), 7.52 (d, J=2.2 Hz, IH), 7.47 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.4Hz, IH), 6.91-6.80 (m, 5H), 6.78 (d, J=8.6 Hz, 2H), 4.27 (bt, J=5.9 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, IH). FD mass spec.: 475. Anal. prov. for C28H29NO4S • 1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.87; H, 5.79; N, 2.99.

Example 43

[6-Benzoyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzoyloxyphenyl)]

benzo[b]thiophene hydrochloride

To a solution of Example 20 (0.50 g; 1.08 mmol) in 20 ml of anhydrous tetrahydrofuran, at 0°C, was added triethylamine (1.00 ml). Benzoyl chloride 90.28 ml is added to this mixture; 2.35 mmol). After stirring for 2 hours at f<P>C, the reaction is terminated by partitioning between a mixture of ethyl acetate/saturated sodium bicarbonate solution (100 ml each). The layers are separated and the organics are dried (sodium sulfate) and concentrated in vacuo to a white solid. The crude product was dissolved in 10 ml of ethyl acetate and treated with ethyl ether-hydrochloric acid. A white precipitate forms, which is collected by filtration. Drying gave 390 mg (50%) of [6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxyphenoxy]-2-(4-benzyloxyphenyl)]benzo[bithiophene hydrochloride] as a white solid. d.p. 200-204°C.<*>H NMR(DMSO-t/6)d 9.95 (bs, IH), 8.18 (m, IH), 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, IH), 7.00 (s, 4H), 4.32 (m, 2H), 3.45 (m, 4H), 2.99 (m, 2H), 1.75 (m, 5H), 1.39 (m, IH). Anal. prov. for C41H35N06S • 1.5 HCl: C, 67.97; H, 5.08; N, 1.93. Found: C, 68.05; H, 5.24; N, 2.01.

Using the same procedure was obtained:

Example 44 [6-Ethylsulfonyl-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4- ethylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride

Yield=72%. d.p. 110-115°C.<!>H NMR (DMSO-^6) d 10.15 (bs, IH), 8.15 (d, J=2.0 Hz, IH), 7.85 (d, J=7.0 Hz, 2H), 7.43 (m, 3H), 7.34 (dd, J=9.0, 2.0 Hz, IH), 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). Anal. prov. for C^sNO^ • 1.5 HCl: C, 54.57; H, 5.32; N, 2.05. Found: C, 54.36; H, 5.37; N, 2.05.

By a similar procedure using trifluoromethanesulfonic anhydride is: Example 45 [6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4- trifluoromethanesulfonyloxyphenyl)]benzo[b]thiophene

Yield=81%. Oil.<*>H NMR(DMSO-d6)d 7.82 (d, J=8.7 Hz, 2H), 7.60 (d, J=2.0 Hz, IH), 7.54 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.8 Hz, IH), 6.93 (dd, J=8.8, 2.0 Hz, IH), 6.84 (s, 4H), 3.92 (bt, J=5.7 Hz, 2H), 3.79 (s, 3H), 2.56 (bt, J=5.7 Hz, 2H), 2.36-2.30 (m, 4H), 1.44-1.31 (m, 6H). FD mas.spec: 607. Anal. prov. for Cz^gNO^Sz: C, 57.32; H, 4.64; N, 2.30. Found: C, 57.16; H, 4.52; N, 2.01.

Obtained from Example a 1, using similar procedures were:

Example 46

3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-b^).

hydrochloride

Yield=85%. d.p. 190-198°G<l>H NMR (DMSO-d6) 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, 2H), 3.00-3.05 (m, 2H), 2.53-2.63 (m, 6H), 1.75-1.95 (m, 3H), 1.40-1.50 (m, 1H). FD mas.spec: 550. Anal. prov. for C34H3,NO4S ■ 1.0 HCl: C, 74.29; H, 5.68; N, 2.55. 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%. d.p. 193-197°C.<*>H NMR (DMSCM6) d 10.10 (br s, IH), 8.12 (d, J=8.0Hz, IH), 7.85 (d, J=8.6 Hz, IH), 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, 6H), 1.40 (s, 9H). FD ma&spec.: 529. AnaL pror. for C32H35N04S ■ 1.0 HCl: 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]phenol£si3-2-(4-butylsulfono-oxyphenH

hydrochloride

Prmos=85%, white solid. d.p. 98-104°C. <l>HNMR ( ĐMSO- d6 ) d 10.20 (br s, IH), 8.02 (d, J=8.0 Hz, IH), 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 mas.spec: 565. Anal. prov. for C31H35N05S2•1.0 HCl: C, 61.83; H, 6.03; N, 2.33. Found: C, 61.55; H, 6.15; N, 2.25.

Getting 21

[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hyd benzo[l>]thiophene

Preparation of 4-(methoxymethyloxy)phenylsulfide.

Sodium hydride (230 mg; 5.75 mmol; 60% dispersion in mineral oil) was added to a solution of 4-hydroxyphenyldisulfide (650 mg; 2.60 mmol) in 10 ral of anhydrous N,N-dimethylfoimainide at 10°C. After stirring for 15 min, chloromethylmethylether (0.44 mL; 5.75 mmol) was added via syringe. The reaction is warmed to room temperature and stirred for 0.5 hours. The mixture was partitioned between water and brine/ethyl acetate (20 ml each). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x20 ml). The organics were dried (sodium sulfate) and concentrated to a yellow oil (993 mg; 100%). Analytical sample of 4-(methoxymethyloxy)phenyldisulfide, by chromatography (silica, 4% ethyl acetate/hexane). *H NMR (DMSO-^) 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 mas.spec: 338. Anal. prov. for C16H18O4S2: C, 56.78; H, 5.36. Found: C, 57.08; H, 5.44.

Example 49

[6-Methoxy-2-(4-methoxyphenan)-3-(4-metholoxym

To 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 under N2 at -60°C, n-butyllithium (3.15 ml; 5.00 mmol; 1.6 M solution in hexane) was added dropwise via syringe. The resulting mixture is heated to -20°C for 10 minutes, then cooled again to -60°C. 4-(methoxymethyloxy)phenyldisulfide (600 mg; 2.36 mmol) in 5 ml of anhydrous tetrahydrofuran was added to the chthium portion, and the resulting mixture was allowed to warm slowly to 0°C. After stirring for 20 minutes, the reaction was terminated by partitioning between aqueous sodium chloride/ethyl acetate (50 ml each). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2x50 ml). The organic layer was combined, dried (sodium sulfate), and concentrated in vacuo to give an oil. Chromatography (silica, 5% ethyl acetate/hexane) afforded 287 mg (27%) of [6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxy-methyloxy)thiophenoxy]benzo[b]thiophene as a colorless oil.<*>H NMR( ĐMSO- d6 )d 7.59 (d, J=8.4Hz, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.03-6.85 (m, 7H), 5.06 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H). FD mas.spec: 438. Anal. prov. for C24H22O4S2: C, 65.73; H, 5.06. Found: C, 65.93; H, 5.10. Example 50 [6-Methoxy-2-(4-methoxyphenyl)-3-(4-^^

Methanesulfonic acid (0.2 ml; 2.66 mmol) was added to a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxymethyleneoxy)thiophenoxy]benzo[b]thiophene (233 mg; 0.53 mmol) in 10 ml of a mixture, 1:1:2 = methanol : water : tetrahydrofuran. The mixture is heated under reflux for 5 hours. After cooling to ambient temperature, the reaction mixture is diluted with water. The aqueous layer is extracted with ethyl acetate (2x). The organic layer is washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried (sodium sulfate) and concentrated in vacuo to give 206 mg (99%) of [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]benzo[b]thiophene as a colorless oil.<*>H NMR (DMSO-<*6) d 9.43 (s, IH), 7.63 (d, J=8.4 Hz, 2H), 7.61 (d, J=2.0 Hz, IH), 7.59 (d, J=8.8 Hz, IH), 7.08 (d, J=8.4 Hz, 2H), 7.02 (dd, J=8.8,2.0 Hz, IH), 6.90 (d, J=8.6Hz, 2H), 6.63 (d, J=8.6 Hz, 2H). FD mass spec.: 395. Anal. prov. 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

To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]benzo [b]thiophene (242 mg; 0.61 mmol) in 8.0 ml of anhydrous N,N-dimethylformamide, cesium carbonate (820 mg; 2.5 mmol) was added, followed by 2-chloroethylpiperidine hydrochloride (194 mg; 1.05 mmol). The resulting mixture is stirred for 48 hours at ambient temperature and then distributed between an aqueous solution of sodium chloride/ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3x). The organic layer is dried (sodium sulfate) and concentrated in vacuo to an oil. Chromatography (silica, 0.2% methanol/chloroform) afforded 244 mg (92%) of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene as a honey-colored oil.

Example 52

Sample [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-

methoxypheniI)]benzo [bjthiophene translated to its hydrochloride salt acc

standard procedure in yield 72%

d.p. 198-201°C. *H NMR (DMSO-^j) d 7.63 (d, J=8.6 Hz, 2H), 7.62 (d, J=2.0 Hz, IH), 7.58 (d, J=8.2 Hz, IH), 7.07 (d, J=8.6 Hz, 2H), 7.02 (dd, 3=82, 2.0 Hz, IH), 6.92 (q, JAJ3=9.0 Hz, 4H), 4.24 (bt, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.49-3.39 (m, 4H), 2.93 (m, 2H), 1.82-1.62 (m, 5H), 1.38 (m, IH). Anal. prov. for C29H32NO3S2• 1.0 HCl: 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

Boron(III) bromide (0.15 ml) was added to a solution of [6-methoxy-3-[4-[2-( 1 -piperidinyl)ethoxy]thiophenoxy i-2-(4-methoxyphenyl)]benzo[bithiophene hydrochloride (160 mg; 0.29 mmol) in 15 ml of anhydrous methylene chloride at 0°C under nitrogen. The resulting dark solution is stirred for 1 hour at 0°C, and then immediately poured with stirring into a solution of ethyl acetate and aqueous sodium bicarbonate solution (50 ml each). The layers were separated, and the aqueous layer was washed with ethyl acetate (3x30ml). The organics are dried (sodium sulfate) and concentrated in vacuo to a white solid. Chromatography (silica, 0-5% methanol/chloroform) afforded 91 mg (60%) of [6-hydroxy-3-[4-[2-(l-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene as a white solid. d.p. 123-127°C.<*>H NMR( ĐMSO- d6 )d 9.79 (s, IH), 9.71 (s, IH), 7.46 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.9 Hz, IH), 7.26 (d, J=2.0 Hz, IH), 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 spec.: 478. Anal. prov. for C27H27NO3S2: 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

d.p. 180-190°alVLNMR (DMSCM6) d 9.86 (s, IH), 9.79 (s, IH), 7.46 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.7 Hz, IH), 7.29 (d, J=2.0 Hz, IH), 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 mas.spea: 477. Anal. prov. for C27H27NO3S2• 2.2 HCl: C, 58.13; H, 5.28; N, 2.51. Found: C, 58.11; H, 5.10; N, 2.61.

I get the same procedures are:

Example55

[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenir)j

benzo[b]thiophene hydrochloride

d.p. 215-218°C.<*>H NMR (DMSOd6) d 7.61-7.58 (m, 3H), 752 (d, J=8.8 Hz, IH), 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 mas.spec: 491. Anal.

prov. for C28H29NO3S2• 1.0 HCl: C, 63.67; H, 5.73; N, 2.65. Found: C, 63.47; R 5.78; N, 2.65.

Example56

[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy-3thiophenoxy]-2-(4-

hydroxyphenyl)]benzo[b]thiophene hydrochloride

d.p. 137-140°C.<*>H NMR(DMSO-d6)d 9.86 (s, IH), 9.80 (s, IH), 7.46 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.7 Hz, IH), 7.29 (d, J=2.0 Hz, IH), 6.96 (d, J=8.7 Hz, 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 spec.: 464. Anal. prov. for C26H25NO3S2• 1.0 HCl: C, 62.45; H, 5.24; N, 2.80. Found: C, 62.36; H, 5.37; N, 2.61.

Example 57

Obtained from the product of Example 45 by hydrogenolysis of the triflate as described

below in Example 58 is 6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)J

Benzoylthiophene hydrochloride

d.p. 187-195°C.<l>HNMR(DUSO-d6)d 7.66 (d, J = 2.8 Hz, 2H), 7.58 (d, J = 2.0 Hz, IH), 7.39 (t, J=7.5 Hz, 2H), 7.28 (m, IH), 7.17 (d, J=8.8 Hz, IH), 6.91 (dd, J=8.8, 2.0 Hz, IH), 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), 1.31 (m, IH). FD mas.spec: 460. Anal. prov. for C28H29N03S • 1.0 HCl: 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

To a solution of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxy-phenyl)]benzo[b]thiophene hydrochloride (5.00 g; 10.0 mmol) in 100 ml of anhydrous methylene chloride at 0°C, under nitrogen, was added triethylamine (8.38 ml; 60.0 mmol), followed by trifluoromethanesulfonic acid anhydride. (1.69 ml; 10.0 mmol). The resulting mixture is gradually heated to room temperature and stirred for 1.5 hours. The reaction is terminated by pouring into 200 ml of saturated sodium bicarbonate solution. The aqueous layer was then extracted with ethyl acetate (3x100 ml). The organic layer was dried (sodium sulfate and concentrated in vacuo to give an oil. Chromatography 90-3% methanol/chloroform) gave 2.82 g (39%) of trifluoromethanesulfonate-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-trifluoromethanesulfonatephenyl)]benzo[b]thiophene, 1.82 g (31%) of a 1:1 mixt. 6-trifluoromethanesulfonate-3-[4-[2-(l-piperithiophene and 3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-trifluoromethanesulfonatephenyl)] benzo [b]thiophene, and 1.48 g (30%) of regenerated starting material as free base.

Triethylamine (2.0 ml) and 5% palladium on carbon (0.50 g) were added to a solution of a 1:1 mixture of monotriflate serivates from the last reaction (0.50 g; 0.84 mmol) in 60 ml of ethanol-ethyl acetate (5:1). The resulting mixture is hydrogenated at 2.75 bar for 2 hours. The mixture is then filtered through Celite to remove the catalyst. The filtrate is concentrated to an oil. The resulting mixture of monohydroxy derivatives is dissolved in ethyl acetate from which 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene precipitates. The filtrate consisted of a 4:1 mixture of monohydroxy derivatives, where 6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)benzo[b]thiophene was the major product. The filtrate is concentrated in vacuo, and the resulting solid is dissolved in a minimum amount of ethyl acetate and treated with ethyl ether-hydrochloric acid. The resulting solid was recrystallized from ethanol to give 69 mg (10%) of isomeric pure [6-hydroxy-3-[4-[2-(l~piperidinyl)ethoxy]phenoxy]-2-(phenyl)]benzo[b]thiophene hydrochloride m.p. 217-219°C. <J>H NMR (DMSO-d6) d 9.87 (s, IH), 7.64 (d, J=7.5 Hz, 2H), 7.39-7.26 (m, 4H), 7.10 (d, J=8.6 Hz, IH), 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 mas.spec: 446. Anal. prov. for C^H^NC^S • 1.0 HCl: C, 67.28; H, 5.86; N, 2.91. Found: C, 67.00; H, 5.59; N, 2.87.

Alternatively, Example 58 was obtained by demethylation of the product of Example 57, as described in Example 18.

Example 59

[6-isopropoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)

benzo[b]thiophene-(S-oxy) was prepared as described in [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxy)

(Example 30)

Yellow oil.1*! NMR (DMSO-^) 7.69 (d, J=2.0 Hz, IH), 7.67 (d, J=8.6 Hz, 2H), 7.09-6.99 (m, 5H), 6.96-6.87 (m, 3H), 4.76 (septet, J=6.0 Hz, IH), 3.99 (bt, 1=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 spec.: 533. Anal. prov. for C31H35N05S • 0.67 H2O: C, 68.23; H, 6.71; N, 2.57. Found: C, 67.90; H, 6.31; N, 2.53.

[6-Isopropoxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)] benzo[b]thiophene hydrochloride was prepared as described for [6-methoxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene.

(Example 32)

d.p. 168-170°C.<1>H NMR (DMSO-^6) d 10.37 (s, IH), 7.58 (d, J=8.6 Hz, 2H), 7.52 (d, J=1.3 Hz, IH), 7.12 (d, J=8.8 Hz, IH), 6.95 (d, J=8.6 Hz, 2H), 6.92-6.85

(m, 5H), 4.64 (septet, J=6.0 Hz, IH), 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, IH), 1.25 (d, J=6.0 Hz, 6H). FD mas.spec: 517. Anal. prov. for C31H35N03S • 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-(l-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)] benzo[b]thiophene hydrochloride was converted to [6-hydroxy-3-[4-[2-(l-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo{b]thiophene by treatment with 2.0 equivalents of anhydrous BC13 at 0°C to 10°C. dichloromethane (methyl ether is not cleaved under these conditions).

Testing procedure

General preparation procedure

In the examples to illustrate the method, a postmenopausal model was used in which the effects of different treatments on lipid circulation were determined.

Seventy-five day old female Sprague Dawley rats (weight 200 to 225 g) were obtained from Charles River Laboratories (Portage, MI). Animals underwent bilateral ovariectomy (OVX) or sham surgery at Charles River Laboratories and then delivered one week later. After arrival, the animals were placed in metal cages, in groups of 3 or 4 per cage, and subjected to ad libitum diet (calcium content of about 03%) and water for a week. The room temperature is set at 22.2° ±1.7 °C, with a minimum relative humidity of 40%. The photoperiod in the room was 12 hours light and 12 hours dark.

Determination of tissue collection regime. After a one-week incubation period (two weeks after OVX), daily dosing of the test compound was started. 17α-ethynyl estradiol or the test compound were given orally, unless otherwise specified, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. Animals were dosed daily for 4 days. Following a certain regimen, the animals were weighed and anesthetized with a mixture of ketamine:xylazine (2:1; V:V), and blood samples were collected by cardiac puncture. The animals were then sacrificed by asphyxiation with CO2, the uteri were removed through a midline incision, and the wet weights of the uteri were determined.

Cholesterol analysis. Blood samples were allowed to clot at room temperature for 2 hours and serum was obtained by centrifugation for 10 minutes at 3000 rpm. Serum cholesterol was determined using the Boehringer Mannheim Diagnostics cholesterol test method. In a short time, cholesterol is oxidized to cholest-4-en-3-one and hydrogen peroxide. Hydrogen peroxide was then reacted with phenol and 4-aminophenazone in the presence of peroxidase to produce a p-quinone imine dye, which was read spectrophotometrically at 500 nm. Cholesterol concentration was then calculated according to the standard curve. The entire method is automated using the Biomek Automated VWorkstation.

Test of uterine eosinophilic peroxidase (EPO). The uteri were kept at 4°C until the time of enzymatic analysis. Uteri were homogenized in 50 volumes of 50 mM Tris buffer (pH - 8.0) containing 0.005% Triton X-100. After adding 0.01% hydrogen peroxide and 10 mM o-phenylenediamine (final concentration) to Tris buffer, the increase in absorbance was monitored for one minute at 450 nm. The presence of eosinophils in the uterus is an indication of the estrogenic activity of the compound. The maximum speed was determined in an interval of 15 seconds from the beginning of the linear part of the reaction curve.

Origin of the compound. 17α-ethynyl estradiol was obtained from Sigma Chemical Co., St. Louis,

MO.

Effect of Formula I compounds on serum cholesterol i

determination of agonistic/non-agonistic activity

The data in Table 1 show the comparative results of ovariectomized rats and rats treated with 17a-ethinyl estradiol (EE2; a form of estrogen for oral use) and rats treated with compounds from this study. Although EE2 causes a decrease in serum cholesterol when administered orally at 0.1 mg/kg/day, it also shows a stimulating effect on the uterus, so that the weight of the EE2uterus is significantly greater than the weight of the uterus of ovariectomized test animals. This uterine response to estrogen is well known in the art.

The compounds from this study not only generally reduce the level of cholesterol in the serum, compared to control, ovariectomized animals, but their use (most of the tested compounds) slightly changes the weight of the uterus. The action of estrogenic compounds known in this field to reduce serum cholesterol, without adversely affecting the weight of the uterus, is very rare and desirable.

As shown in the data below, estrogenicity was also determined by evaluating the unfavorable response by infiltration of eosinophils into the uterus. The compounds of this study do not show any increase in the number of eosinophils in the stromal layer of ovariectomized rats, while estradiol causes a significant, expected increase in eosinophil infiltration.

The data given in Table 1 show the response of 5 to 6 rats per treatment.

In addition to the demonstrated advantages of the compounds of this study, especially in comparison to estradiol, the above data clearly indicate that the compounds of Formula I are not estrogen mimetic. Furthermore, no deleterious toxicological effects (survival) were observed in any treatment.

Osteoporosis testing procedure

According to the general preparation procedure outlined above, rats were treated daily for a period of 35 days (6 rats per treatment group) and sacrificed by asphyxiation with CO 2 on the 36th day. A period of 35 days was sufficient to allow maximal reduction in bone density, which was measured in the manner described herein. At the time of sacrifice, the uteri were removed, freed of the surrounding tissue by dissection and the liquid content was expelled, before determining the wet weight, in order to confirm the estrogen deficit caused by the complete ovariectomy. The uteri were then placed in 10% neutral buffered formalin to allow for subsequent histological analysis.

Right femurs were excised and digitized x-rays were passed through the distal metaphysis and then analyzed by imaging (NIH imaging). The proximal aspect of the tibia of these animals was also scanned by quantitative computed tomography.

According to the above procedure, the compounds from this research and ethinyl estradiol (EE2) in a 20% solution of hydroxypropyl b-cyclodextrin were administered orally to the test animals. The data for the distal femoral metaphysis, shown below in Tables 2 and 3, are the result of the comparative treatment of compounds of Formula I and intact ovariectomized test animals. Results are presented as mean ± standard error of the mean.

In summary, ovariectomy in test animals causes a significant reduction in femoral density compared to intact, capsule-treated controls. Orally administered ethinyl estradiol (EE2) prevents this loss, but the risk of uterine stimulation with this treatment is present.

The compounds from this study also prevent bone loss in general, depending on the administered dose. Therefore, the compounds from this research are useful for treating post-menopausal syndromes, especially osteoporosis.

MCF-7 proliferation assay

MCF-7 breast adenocarcinoma cells (ATCC HTB 22) were maintained in MEM medium (phenol red-free minimum essential medium, Sigma, St. Louis, MO) containing 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}, non-essential amino acids and bovine insulin (1 mg/mL) (maintenance medium). Ten days before the assay, MCF-7 cells were transferred to maintenance medium containing 10% DCC-FBS (assay medium), in order to deplete residual internal stores of steroids. MCF-7 cells were removed from the maintenance flasks using cell separation medium (Ca<++>čMg<++>free HBSS (released phenol red) with 10 mM HEPES and 2 mM EDTA). cells were washed twice with assay medium and adjusted to 80,000 cells/mL. About 100 pX (8,000 cells) were added to flat-bottom microculture wells (Costar 3596) and incubated at 37°C in an incubator, in a stream of humidified 5% CO2, for 48 hours to allow cell attachment and equilibration after transfer. A dilution series of drugs or DMSO - control solution was prepared in test medium and 50 µL was transferred to microcultures with 50 pL of pure test medium, to a final volume of 200 pL. After an additional 48 hours of incubation under the same conditions, the microcultures were stimulated with thyrtinium-containing thymidine pulses (1 uCi/well) for 4 hours. Cultivation is completed by freezing at -70°C for 24 hours and then thawing and collecting the microcultures, using a Skatron semi-automatic cell harvester. Samples were counted with a liquid scintillation counter, using a Vallac Beta Place b-counter. The results in Table 4 show the IC50 for some compounds from this study.

Inhibition of DMBA-induced breast tumorigenesis

Estrogen-dependent mammary tumors were produced in female Sprague Dawley rats, which were purchased from Harlan Industries, Indianapolis, Indiana. At about 55 days of age, rats received a single oral dose of 20 mg of 7,12-dimethylbenz[anthracene (DMBA). About 6 weeks after DMBA administration, the mammary glands were palpated, at weekly intervals, to determine the appearance of tumors. At the appearance of one or more tumors, the largest and smallest diameters of each tumor were measured with a caliper and scaled, and based on this, the animals were selected for the experiment. In doing so, an attempt was made to uniformly distribute different tumor sizes in the treated and control groups, so that the mean tumor size was equally distributed among the tested groups. Control and test groups for each experiment contain 5 to 9 animals.

Formula I compounds were administered either by intraperitoneal injection of 2% acacia or orally. Orally administered compounds were either diluted or suspended in 0.2 mL of corn oil. Each treatment, including acacia and corn oil-control treatments, were administered once daily to each tested animal. Following initial tumor measurements and selection of test animals, tumors were measured weekly using the method described above. Treatment and measurements of the animals were continued for 3 to 5 weeks, during which the final tumor involvement was determined. For each compound and control treatment, the mean change in tumor involvement was determined.

Uterine fibrosis test procedure

Test 1

Between 3 and 20 women, who have uterine fibrosis, applied the compound from this study. The amount of compound that was applied was from 0.1 to 1000 mg/day, and the period of application was 3 months.

The women were followed during the administration and for more than 3 months after the cessation of the administration of the compound, in order to determine its effect on uterine fibrosis.

Test 2

The same procedure was used as in Test 1, with the exception that the application period was 6 months.

Test 3

The same procedure was used as in Test 1, with the fact that the application period was 1 year.

Test 4

A. Induction of fibroid tumors in guinea pigs

Prolonged estrogen stimulation has been used to induce leiomyomata in sexually mature female guinea pigs. The animals were dosed with estradiol 3-5 times a week, through injections, for a period of 2 to 4 months or until the appearance of tumors. Treatment consisting of the compounds of this study or the vehicle was administered daily for a period of 3-16 weeks, after which the animals were sacrificed and the uteri were collected to examine for tumor regression.

B. Implantation of human uterine fibroid tissue into nude mice

Tissues from human leiomyomas (smooth muscle tissue tumors) were implanted into the peritoneal cavity or uterine myometrium of sexually mature, castrated female nude mice. Exogenous estrogen induced tissue culture growth. In some cases, the harvested tumor cells are cultured in vitro, prior to implantation. Treatment consisting of compounds from this study or carrier was provided by daily gastric lavage for a period of 3-16 weeks, after which the implants were removed and their growth or regression was measured. At the time of sacrifice, the uteri were harvested to determine organ status.

Test 5

A. Human uterine fibroid tumor tissue was collected and maintained, in vitro, as a primary, untransformed culture. Surgical specimens were passed through a sterile mesh or sieve, or separated from the surrounding tissue by alternating rubbing, to obtain a suspension of single cells, cells were maintained in a medium containing 10% serum and antibiotics. Growth was determined in the presence and absence of estrogen. cells were examined for their ability to produce complement components C3 and their response to growth factors and growth hormones. Cultures were evaluated in vitro for the proliferative response following treatment with progestins, GnRH, the study compound, and transporters. Steroid hormone receptor levels were assessed weekly to determine whether important cell characteristics were maintained in vitro. Tissue from 5-25 patients was used.

Activity in at least one of the above tests indicates that the application of the compounds from this research is possible in the treatment of uterine fibrosis.

Procedure for testing for endometriosis

Tests 1 and 2 can examine the effects of 14-day and 21-day administration of compounds from this study on the growth of endometrial tissue explants.

Test

Twelve to thirty adult female CD rats were used as test animals. They are divided into three groups with equal numbers. The estrus cycle was monitored in all animals. On the day of proestrus, surgical interventions were performed on each of the females. Females in each group had their left uterine tube removed, dissected into small squares, which were lightly sewn to different places attached to the mesenteric blood vessels. In addition, females from group 2 had their ovaries removed.

One day after the surgical intervention, animals from groups 1 and 2 received intraperitoneal injections of water for 14 days, while animals from group 3 received intraperitoneal injections of 0.1 mg of the compound from this study, per kilogram of body weight, for the same duration. After 14 days of treatment, all females were sacrificed and endometrial explants, adrenals, removed uteri and ovaries, where appropriate, were removed and dissected for histological examination. Ovaries and adrenals were measured.

Test 2

Twelve to thirty adult female CD rats were used as test animals. They are divided into two groups with equal numbers. The estrus cycle was monitored in all animals. On the day of proestrus, surgical interventions were performed on each of the females. Females in each group had their left uterine tube removed, dissected into small squares, which were lightly sewn to different places attached to the mesenteric blood vessels.

About 50 days after the surgical intervention, animals from group 1 received intraperitoneal injections of water for 21 days, while animals from group 2 received intraperitoneal injections with 0.1 mg of the compound from this study, for the same duration. After 21 days of treatment, all females were sacrificed and endometrial explants and adrenals were removed and weighed. Explants were measured as an indication of growth. The estrus cycle was monitored.

Test 3

A. Surgical induction of endometriosis

Autography of endometrial tissue was used to induce endometriosis in rats or rabbits. Female animals at reproductive maturity were subjected to bilateral oophorectomy and supplied with exogenous estrogen, which provided a specific and constant hormone level. Autologous endometrial tissue was implanted into the peritoneum of 5 to 150 animals and estrogen was used to induce growth of the explanted tissue. Treatment consisting of the compounds of this study was provided by gastric lavage during the day for a period of 3-16 weeks, after which the implants were removed and measured, to determine growth or regression. At the time of sacrifice, the intact fallopian tube was harvested to determine the state of the endometrium.

B. Implantation of human endometrial tissue into nude mice

Human endometrial lesion tissue was implanted into the peritoneum of sexually mature, castrated female nude mice. Exogenous estrogen was used to induce the growth of explanted tissue. In some cases, harvested endometrial cells are cultured in vitro prior to implantation. Treatment consisting of the compounds of this study was provided by gastric lavage during the day for a period of 3-16 weeks, after which the implants were removed and measured to determine growth or regression. At the time of sacrifice, uteri were collected to determine the state of intact endometria.

Test 4

A. Tissue from a human endometrial lesion was harvested and maintained, in vitro, as a primary, untransformed culture. Surgical specimens were passed through a sterile mesh or sieve, or separated from the surrounding tissue by alternating rubbing, to obtain a suspension of single cells, cells were maintained in a medium containing 10% serum and antibiotics. Growth was determined in the presence and absence of estrogen. cells were examined for their ability to produce complement components C3 and their response to growth factors and growth hormones. Cultures were evaluated in vitro for the proliferative response following treatment with progestins, GnRH, the study compound, and transporters. Steroid hormone receptor levels were assessed weekly to determine whether important cell characteristics were maintained in vitro. Tissue from 5-25 patients was used.

Activity in at least one of the above tests indicates that the application of the compounds from this study is possible in the treatment of endometriosis.

This research also provided a method for alleviating postmenopausal syndrome in women which includes the previously mentioned method of using a Formula I compound and administering an effective amount of estrogen or progestin. These treatments are particularly useful for treating osteoporosis and reducing blood cholesterol levels, as the compounds from this research can inhibit the unwanted side effects of estrogen and progestin. The activities of these combination treatments, in all of the post-menopausal tests mentioned earlier, indicate that the combination treatments are useful for alleviating post-menopausal symptoms in women.

Various forms of estrogen and progestin are commercially available. Estrogen-based preparations include, for example, ethinyl estrogen (0.01 - 0.03 mg/day), mestranol (0.05 - 0.15 mg/day) and conjugated estrogenic hormones such as Premarin®

(Wyeth-Ayerst; 0.3 - 2.5 mg/day). Progestin-based preparations include, for example, medroxyprogesterone such as Provera® (Upjohn; 2.5 - 10 mg/day), norethylnodrel (1.0 - 10.0 mg/day), and nonethindrone (0.5 - 2.0 mg/day). The most preferred estrogen-based compound is Premarin, and norethylnodrel and norethindrone are preferred as progestin-based preparations.

Methods of administration of preparations based on estrogen and progestin are consistent with those otherwise known in the field. In most of the methods from this research, Formula I compounds are applied continuously, 1 to 3 times a day. Cycle therapy can be particularly useful in the treatment of endometriosis or can be used during painful attacks of the disease. In cases of restenosis, therapy may be limited to shorter (1 to 6 months) intervals, following medical procedures such as angioplasty.

As used herein, the term ±effective amount<2>refers to the amount of a compound of this study that is capable of ameliorating the symptoms of the various pathological conditions described herein. The specific dose of a compound administered according to this study may, of course, be determined by the specific circumstances, including, for example, the compound being administered, the routes of administration, the condition of the patient, and the pathological condition being treated. A typical daily dose consists of a non-toxic level, from about 5 mg to about 600 mg/day, of the compounds of this study. The most preferred daily dose, in general, is about 15 mg to about 80 mg/day.

The compounds of this study can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are formulated before administration and selected, which is decided by the respective doctor. Another aspect of this research is pharmaceutical formulation, which comprises an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt of the compound, an amount of an optional estrogen or progestin, and pharmaceutically acceptable carriers, solvents or excipients.

The amount of active ingredients in such a recipe ranges from 0.1% to 99.9% by weight of the total weight. "Pharmaceutically acceptable" means carriers, solvents, excipients and salts, which must be compatible with other ingredients from the recipe and which are not harmful to the recipients themselves.

The pharmaceutical formulation of this research can be prepared by procedures known in the art, using well-known and readily available ingredients. For example, the compounds of Formula I, with or without estrogen or progestin, can be formulated with general excipients, solvents or carriers and can be formed into tablets, capsules, suspensions, powders and the like. Examples of excipients, solvents and carriers suitable for such formulation include the following: fillers and extenders such as starch, sugars, mannitol and silicone derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; retarding agents such as paraffin; agents for accelerated resorption such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorbent carriers such as kaolin and bentonite and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols.

The compounds may also be formulated as elixirs and solutions for conventional oral administration or as solutions suitable for parenteral administration, for example intramuscularly, subcutaneously or intravenously. Also, the compounds may well be formulated in sustained release dosage forms and the like. The formulation can be so constructed that only the active ingredients are released or, preferably, that they are released in specific physiological locations over a period of time. Covers, sleeves and protective matrices can be produced, for example, from polymeric substances or wax.

The compounds of Formula I, alone or in combination with the pharmaceutical agents of this study, will generally be used in conventional formulations. The following formulation examples are only illustrative and do not limit the scope of this research.

Formulations

In the following formulations given under the term "active ingredient" is meant the compound of formula I or its salts.

Formulation 1: Gelatinous Capsules

The above formulation can be modified in various ways according to the initial formulation.

Further, the formulation for the preparation of tablets using the following ingredients is given:

Formulation 2: Tablets

The compounds were mixed and compressed to form tablets.

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

Formulation 3: Tablets

The active ingredient, starch, and cellulose are sieved through a U.S. No. 45 mesh sieve and then mixed. The polyvinylpyrrolidone solution is mixed with the resulting powder, which is then passed through a U.S. No. 14 mesh sieve. The granules obtained in this way are dried at 50-60°C and passed through a U.S. sieve No. 18, mixed. Sodium carboxymethyl cellulose, starch, magnesium stearate and talc previously sieved through U.S. No. 60 sieves are mixed and then added to the granules, which after mixing are compressed in a machine for

tableting whereby tablets are obtained.

Suspensions containing from 0.1 to 1000 mg of medication in 5 ml doses are made as follows.

Formulation 4: Suspensions

The active ingredient is sieved through a U.S. No. 45 sieve, mixed and then mixed with sodium carboxymethyl cellulose and syrup to form a paste. Benzoic acid solution, fragrance, color are diluted with a small amount of water and added to the previous paste while mixing. The remaining water is then added to the desired volume.

The aerosol solution being prepared contains the following ingredients:

Formulation 5: Aerosol

The active ingredient is mixed with ethanol and propellant 22 is added in portions to the mixture, cooled to 30°C and transferred to a sensitive atomizer. The required amount is then placed in stainless steel containers and diluted with the remaining propellant. After this, the required quantity that was placed in the container is closed.

Suppositories are prepared as follows:

Formulation 6: Suppositories

The active ingredient is sieved through U.S. No. 60 sieves, mixed and then suspended in glycerides of saturated fatty acids which have been heated to the melting point using the least amount of heat necessary. The mixture is then placed in 2 g suppositories and allowed to cool.

The intravenous dose is prepared as follows:

Formulation 7: Intravenous solution

The solution with the above formulation is given to patients at a rate of 1 ml per minute.

Formulation 8: Combined Capsules I

Formulation 9: Combined Capsules II

Formulation 10: Combination Tablets

Claims (23)

1. Compound of formula I indicated by that R<1> is -H, -OH, -O(C1-C4 alkyl), -OCOC6HS, -OCO(C1C6 alkyl), or -OSO1CCrOs alkyl; R 2 is -H, -OH, -O(C 1 -C 4 alkyl), -OCOC 6 H 5 , -OCO(d -C 6 alkyl), -OSO 4 C 1 -C 4 alkyl), or halogen; R 3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino; her 2 or 3; and Zje-O- or-S-; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, characterized in that R<3> is 1-piperidinyl and n is 2, or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, wherein Z is -O- or a pharmaceutically acceptable salt thereof. 4. a compound according to claim 3, characterized in that R<1> is -OH and R2 is -O(C1-C4alkyl), or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4, characterized in that R<2>-OCH3, or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 5, characterized in that said hydrochloride salt thereof is. 7. A compound according to claim 3, characterized in that R<1> and R<2> are each -OH or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 7, characterized in that said hydrochloride salt thereof is. 9. A pharmaceutical formulation, characterized in that it consists of an active ingredient compound according to any one of claims 1 to 8, and, optionally, estrogen or progestin, which are associated with one or more pharmaceutically acceptable carriers, excipients, or diluents thereof. 10. Compound of the formula indicated by that R<1> is -H or -OR<7>, where R<7> is a hydroxy protecting group; R2a is -H, halogen, or -OR<8>, where R<8> is a hydroxy protecting group; R 6 is -H or a hydroxy protecting group which may be selectively removed; R11 does not exist or is =0; and Zje-O-or-S-; or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 10, wherein R1a and R<2a> are each -OCH3, R6 is -H, R11 is absent, and Z is -O-, or a pharmaceutically acceptable salt thereof. 12. A compound according to claim 10, characterized in that R and R<2a> are each, -OCH3, R$ is - H, R<11> is =O, and Z is -O-, or a pharmaceutically acceptable salt thereof. 13. Compound of the formula indicated by that R1a is -H or -OR<7>, where R<7> is a hydroxy protecting group; R2* is -H, halogen or -OR<8>, where R<8> is a hydroxy protecting group; R3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; her 2 or 3; and Zje-O- or -S-; or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 13, characterized in that R1a and R<2*> are each ~OCH3, R<3> is 1-piperidinyl, it is 2, and Z is -O-, or a pharmaceutically acceptable salt thereof. 15. Process for obtaining compounds of the formula indicated by that R,a is -H or -OR<7a>, where R<7a> is -H or a hydroxy protecting group; R2a is -H, halogen or -OR<8a>, where R8a is -H or a hydroxy protecting group; R 3 is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; her 2 or 3; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof, comprising a) oxidation of the sulfur atom of the compound of formula IV where: R1a and R<2a> are as previously defined; and R<9>represents the leaving group; b) reaction of the product of phase a), compound of formula XIV with a nucleophilic group of the formula where R 12 is -OH or -SH; c) reduction of the product of phase b), the compound of formula XVI to obtain the compound of formula d) optional removal of the R<la> and/or R<2a> hydroxy protecting groups, when present, in the product of phase c); and e) optional salt formation of the compound of the product of phase c) or phase d). 16. A process for obtaining a compound of formula I, or its pharmaceutically acceptable salt, according to any of claims 1 to 8, characterized in that it includes A) reduction of a compound of formula XVI in which R 1a is -H or -OR 7 where R 7a is -H or a hydroxy protecting group; R2* is -H, halogen or -OR<8>a, where R8 is -H or a hydroxy protecting group; R 3 is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; her 2 or 3; and Zje -O- or-S-; or a pharmaceutically acceptable salt thereof; (B) reacting compounds of formula IIb whereby, R7 is a hydroxy protecting group; and R<2a> and Z are as defined previously; with a compound of formula V whereby, Q is the outgoing group; and R<3> is as previously defined; (C) reacting compounds of formula IIb whereby, R<2a>, R<7> and Z are as previously defined, with an alkylating agent of the formula where Q and Q' are the same or different leaving group, the product of which is then reacted with 1-piperidine, 1-pyrrolidine methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, morpholine, dimethylarthylamine, diethylamine, diisopropylamine, 1-hexamethyleneimine; or (D) for the compound of formula I, where R<1>R2 is -H and the second R<1>or R<2>substituent is -OH, i) formation of the triflate hydroxy group of the compound of the formula whereby, RIC-OH or -O-(CrC4 alkyl) R<2C>-OH or -O-(C1-C4alkyl); provided that R1C is -OH, R<2C> is -O-(C1-C4 alkyl) and when R<1C> is -O-(C1-C4 alkyl) R<2C> is -OH; R 3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino; her 2 or 3; and Zje-O- or-S-; or their pharmaceutically acceptable salt and ii) reduction of the resulting triflate group; b) optional removal of the remaining hydroxy protecting group or groups; and c) optional salt formation of the product of phase a) or phase b). 17. A compound of formula I according to any one of claims 1 to 8, for use as an agent for alleviating symptoms of postmenopausal syndrome. 18. The compound according to claim 17, characterized in that the condition of the postmenopausal syndrome is osteoporosis, a corresponding cardiovascular disease, hyperlidemia or hormone-dependent cancer. 19. The compound of formula 1 according to any one of claims 1 to 8, characterized in that it is used as an agent for inhibiting uterine fibroid disease, endometriosis, aortic smooth muscle cell proliferation or restenosis. 20. The compound of formula 1 according to any one of claims 1 to 8, characterized in that it is used in therapy. 21. Use of a compound of formula I according to any one of claims 1 to 8 for the manufacture of a medicament for alleviating the symptoms of postmenopausal syndrome. 22. Use of a compound of formula I according to any one of claims 1 to 8 for the manufacture of a medicament for alleviating symptoms of postmenopausal syndrome when the condition of the postmenopausal syndrome is osteoporosis, corresponding cardiovascular disease, hyperlidemia or hormone-dependent cancer. 23. Use of a compound of formula I according to any one of claims 1 to 8 for the manufacture of a medicament for use as an agent for inhibiting uterine fibroid disease, endometriosis, aortic smooth muscle cell proliferation or restenosis. Continued from page 1. Z is -O- or -S-; or a pharmaceutically acceptable salt thereof, which are useful intermediates for the preparation of compounds of formula I. Further provided are pharmaceutical compositions of compounds of formula I for, inter alia, alleviating symptoms of post-menopausal syndrome and hormonally dependent cancer, especially breast cancer.