FI120345B - Benzothiophene compounds, intermediates, compositions and procedures - Google Patents

Description

This invention relates to the pharmaceutical field of organic chemistry and to novel benzothiophene compounds useful in the treatment of a variety of medical conditions associated with postmenopausal syndrome and uterine fibroid disease, endometriosis and endometriosis. The present invention relates to intermediate compounds useful for the preparation of pharmaceutically active compounds and pharmaceutical compositions of this invention.

"Post-menopausal syndrome" is a term used to describe pathological conditions that frequently affect women who have or have undergone physiological metamorphosis known as menopause. Although this term is used to describe many diseases, the three main effects of postmenopausal syndrome cause the greatest medical concern over a long period of time: osteoporosis, cardiovascular effects such as ... hyperlipidemia and estrogen-induced cancer; and uterine cancer.

'··· * Osteoporosis describes a group of diseases that are caused by many causes of the disease, but is characterized by a net loss of bone mass per unit volume of · · · ϊ.,. This loss of bone mass: j]: causes bone fractures and the skeleton is unable to provide the necessary structural support to the body. One of the most common types of osteoporosis is menopause. Most women lose 20-60% of bone trap bone mass · · · 30 3 to 6 years after menstruation. This rapid loss of · · * Γ is associated with increased bone resorption and formation of • · • * ··. However, this resorptive cycle is more dominant and

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the result is a net loss of bone mass. Osteoporosis is a common and serious disease in women after menopause.

• · · • • • • • • • • 2

It is estimated that the United States alone has 25 million women affected by these diseases. Osteoporosis causes personal problems and also major financial losses due to its chronic nature and its significant and long-term need for help (hospital and home care) as a result of the disease. This is especially true when talking about older patients. In addition, although osteoporosis is not generally considered a life-threatening disease, 20-30% of mortality is associated with hip fracture-10 in elderly women. A high percentage of this mortality can be directly attributed to postmenopausal osteoporosis.

The altitude tissue in the bone for the effects of post-menopausal osteoporosis is the trap bone. This tissue 15 is often referred to as spongy or lace bone, and is particularly accumulated near the bone ends (near the joints) and vertebrae of the spine. The trap tissue is characterized by small bony structures which are joined together, as well as a firmer and denser bark tissue which forms the outer surface of the bone and the central stem. This interconnected trap network provides * external support for the outer shell structure and is important for the biomechanical strength of the tubular structure. Namely, in post-menopausal osteoporosis, the net resorption and loss of the trap mainly results in impaired bone function and fracture. Given the loss of trap • · · in women after menopause, it is not surprising that the most common fractures are those associated with bones that are highly dependent on trap support, such as the spine, weight-bearing bones such as the femur. • · ”· * bone, and forearm. Indeed, hip fractures, bone fractures, • · I *. ·, And spine fractures are the hallmarks of postmenopausal osteoporosis.

Currently the only generally accepted • • · *. . 35 The method for treating postmenopausal osteoporosis is • 3-estrogen replacement therapy. Although therapy has usually been successful, patient acceptance of this treatment is low, mainly due to the undesirable side effects commonly encountered in estrogen therapy.

5 Throughout the period before menopause, most women have less cardiovascular disease than men of the same age. However, after menopause, the rate of cardiovascular disease in women is slowly increasing to the same extent as in men. This loss of barrier distribution is associated with estrogen loss and, in particular, loss of the ability of estrogens to regulate serum lipid levels. The ability of estrogens to regulate serum lipids is not well understood, but recent evidence indicates that estrogen can stimulate low density lipid 15 (LDL) receptors in the liver to remove excess cholesterol. In addition, estrogen appears to have certain effects on cholesterol biosynthesis and other beneficial effects on cardiovascular health.

It has been reported in the literature that women who undergo estrogen therapy after menopause have serum lipid levels corresponding to pre-menopausal status. Thus, estrogen appears to be an effective treatment against this disease. However, the side effects of estrogen replacement therapy • · · are unacceptable by many women, thus limiting its use. An ideal treatment for this disease would be an agent that would regulate serum lipid: * · *: levels such as estrogen but would avoid the side effects and risks associated with estrogen therapy.

The third major disease associated with menopausal menopause syndrome is estrogen-induced breast cancer and, to a lesser extent, estrogen-dependent cancers in other organs, particularly the uterus. . Although such ··· ί.,. Ί tumors are not only restricted to women after menopause, they are more prevalent in older menopause. 35 years in the population. The current chemotherapy of these cancers involves a large amount of anti-estrogen compounds such as tamoxifen. While such mixed agonist antagonists have beneficial effects in the treatment of these cancers and estrogen side effects are acceptable in life-threatening situations, they are not ideal. For example, these agents may have excitatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and thus may be disadvantageous in some cases. A better treatment for these cancers would be an agent which would be an anti-estrogen compound that lacks estrogen agonist properties in regenerative tissues.

In view of the clear need for novel pharmaceutical agents capable of alleviating the symptoms of postmenopausal syndrome, the present invention relates to novel benzothiophene compounds, their pharmaceutical compositions and methods of using these compounds in the treatment of postmenopausal syndrome and other estrogen mentioned above.

• ♦ · * · * * Uterine fibrosis (uterine fibroid disease) is an old and »« · * ... · ever present clinical disease known by many names, ··· V ·, including uterine fibroid disease, uterine hypertrophy , uterine fibroids, uterine fibroids and fibrotic metritis. Mostly ···. * J *. uterine fibrosis is a disease in which an inappropriate layer of connective tissue is formed on the wall of the uterus. This condition causes menstrual disorders and infertility in women. The exact cause of this disease is poorly understood, but the evidence suggests that there is an inappropriate connective tissue response to the estrogen ··· ϊ. Such conditions were provided by rabbits. in them by daily estrogen administration for three months • · ·. 35 time. In guinea pigs, this condition was achieved by administering daily daily dietary supplementation for 5 months. In addition, estrogen causes similar hypertrophy in rats.

The most common treatment for uterine fibrosis is surgical surgery, which is expensive and in some cases a source of complications such as abdominal adhesions and infections. For some patients, surgery is only a temporary treatment and fibroid continues to grow. In some cases, uterine extraction effectively ends fibroid growth but also renders the patient reproductive-deficient. Gonadotropin releasing hormone antagonists may also be administered, although their use is suppressed by the fact that they may lead to osteoporosis. Thus, there is a need to develop a novel method of treating uterine fibrosis, and the methods of the present invention satisfy this need.

Endometriosis is a severe menstrual disorder with severe pain, bleeding into the endometriosis mass or peritoneal cavity and often leads to infertility. Symptoms of this disease appear to be due to defective endometrial growths that are inappropriately responsive to normal hormone control and are located in • inappropriate tissues. Due to the inappropriate location of endometrial • · ·: ..., V · tissue appears to reverse a local inflammatory-like reaction that does not induce macrophage invasion: and many events leading to a painful reaction ··· . The exact cause of this disease is not well known and its hormone therapy is variegated, ill-defined, and causes many undesirable and potentially dangerous side effects.

One of the treatments for this disease is the use of a low dose of estrogen to suppress endometrial growth by a negative feedback effect against and after the release of cesgonadotropin. 35 estrogen formation; however, in some cases, continuous use of estrogen to control symptoms is necessary. This use of estrogen can often lead to unwanted side effects and even the risk of erdometric cancer.

The second regimen consists of continuous administration of progestin which induces menstrual deficits and suppression of ovarian estrogen production may result in a decrease in endometrial growth. The use of continuous progestin therapy is often accompanied by e ± undesirable progestin-mediated side effects on the central nervous system and often leads to infertility due to suppression of ovarian function.

The third treatment consists of administering weak androgens, which is effective in controlling endometriosis; however, they produce serious masculine effects. Many of these methods of treating endometriosis have also been shown to cause mild bone loss in continuous treatment. Thus, novel methods of treating endometriosis are desirable.

This invention relates to compounds having

... formula I

• · «• · · '• · · 25: · Γ: ···

• · · T

• · · ±. ···. Wherein R 1 is -H, -OH, -O (C 1-4 alkyl), -OCOC 6 H 6, -000 (C 1-6 alkyl), or -OSO 2 (C 2-6 alkyl); R 2 is -H, -OH, -O (C 1-6 alkyl), -OCOC 6 H 5, -000 (C 1-6 alkyl), -OSQ 2 (C 2-5 alkyl), or halogen; · 35 R 3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1 · 4-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, 7-diraethylamino, 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 relates to the following intermediate compounds useful for the preparation of the pharmaceutically active compounds of this invention, some of which are also pharmaceutically active:.

Rla? R11

II

r3- (raa) n-0 — T ^^ jj. ···. z • · f s "fiveK>"

R

··· o • · · • «· • · where • · ·

R 1a is -H or -OR 7 where R 7 is a hydroxy protecting group; 'T1 15 ························································································································· hydroxy-protecting group; R 3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, 5-dimethylamino, di-isopropylamino or 1-hexamethyleneimino; R5 is -H or a hydroxy protecting group which can be selectively removed; R 9 is a leaving group; Rn = = 0 or absent; n is 2 or 3? and Z is -O- or -S-; or pharmaceutically acceptable salts thereof.

The invention also relates to a process for the preparation of compounds 15 having the formula 20?

Il A-R2a ··· / NjS / V --______ i:: ia a * ·· ^ • · · V 1 where ··· * ... · 25 Rla is -H or -OR76 where R7a is - H or a hydroxy protecting group; R 2a is -H, halogen, or -RBBa, wherein R 5a is -H or a hydroxy protecting group; R 3 is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyr- ···. Rolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexahydroxymethylenimine; ··· · ... 1 n is 2 or 3; and J1. Z is -O- or -S-; Or a pharmaceutically acceptable salt thereof, wherein:

a) oxidizing the sulfur atom in the compound of formula IV

5

Rla io rv where

R1a and R2a are as defined above? and R 9 is a leaving group;

b) subjecting the product of step a), a compound of formula XIV

R9 20 °

XIV

To react with a nucleophilic group of the formula 25 (CH3) n- ^ 3

W: MJ

R12 • · · • · · • · Φ. ···. Wherein R 12 is -OH or -SH; · · C) reducing the product of step h), the compound having

: ** · Formula XVI

··· • · · · · · · · · · · · · · · · · · · · · · · · · · ··· ···

Rla il o

XVI

to give a compound of formula 10 R 3 - (CH 2) n -O- \ ΙΓ7- ^ \ "R2a

15V_V

d) optionally removing the hydroxy protecting groups R 1a and / or R 2a, if present, from the product of step c); and e) optionally forming a salt of the product of step c) or step 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 progestogen. 25 rogen or progestin * .ί · Menopause symptoms, especially osteoporosis,

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V 'to alleviate the symptoms of vascular disorders and estrogen dependent cancer. As used herein, the term "estrogen" includes steroid compounds having estrogen: ***: 30, such as, for example, 17b-estradiol, · estrone, conjugated estrogen (Premarin), - • · *, 4 "niestrogen 17b-ethynylestradiol and the like. As used herein, the term "progestin" includes compounds with progestational activity, such as progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like.

The compounds of this invention are also useful for inhibiting human uterine connective tissue disease and endometriosis and aortic smooth muscle cell growth, in particular restenosis, in humans.

This invention relates to compounds having

formula I

R 3 - (O 2) 2 · 1 · 2 · 3 · 4 · 2 → 3 wherein R 1 is -H, -O 2 H, -O (C 1 -C 4 alkyl), -OCOC 1 H 5, -000 (O 2 -alkyl) or -OSO 2 ( R 2 is -H, -OH, -O (C 1-6 alkyl), -OCOC 6 H 5, -OCO (C 1-6 alkyl), -OSO 2 (C 2-6 alkyl), or halogen; R3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-raorpholino, dimethylamino, diethylamino, diisopropylamino or • · * ··· '- 1-hexamethyleneimino; • · · * · * * n is 2 or 3; and «« · * ... · 25 Z is -O- or -S ~; or a pharmaceutically acceptable salt thereof. t * 2 *: Generic terms used to describe the compounds described herein have common meanings. The -; *; * · sign denotes "C1.6 alkyl" branched or unbranched. ···. 30 aliphatic chains of 1 to 6 carbon atoms, including groups such as methyl, ethyl, propyl, isopropyl, • butyl, n-butyl, pentyl, isopentyl, hexyl, iso-

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hexyl and the like. Similarly, the term "C 1-4 alkoxy" is a C 1-4 alkyl group attached through an oxygen molecule and includes groups such as methoxy, ethoxy, • n-propoxy, isopropoxy and the like.

A starting material for one route for the preparation of compounds of formula I of this invention, compounds of formula III, is prepared essentially as described by C. D. Jones in U.S. Patent Nos. 4,418,068 and 4,133,814, each of which is incorporated herein by reference. Formula III has a structure

10 III

wherein R7 and R2a are as defined above.

R7 and Rb hydroxy protecting groups are groups that are not usually found in the final therapeutically active compounds of formula I, but are intentionally added during a certain period of the synthesis process to protect a group that might otherwise react due to chemical reactions and these protecting groups are removed at a later stage. Since compounds containing such protecting groups are of paramount importance ... as chemical intermediates (although some derivatives also have biological activity), their exact structures are • · * ··· * is not important. Many reactions for the formation, removal and, possibly, re-formation of such protecting groups *. * * Have been described in many standard works, including 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, Volume 1, Schrooder and Lubke,. 30 Academic Press (London and New York, 1965).

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

Preferred R 7 and R 8 (R 2a) substituents for compounds of formula III are methyl, isopropyl, benzyl and methoxymethyl. Compounds wherein R 7 and R 7 are both methyl are prepared by the method described in the above-cited Jones patent. Another preferred hydroxy-10 protecting group is methoxymethyl. However, the compound of formula IV, as described below, is first prepared to contain the preferred methyl or other hydroxy protecting group (s). These protecting groups are then removed to form phenol groups which are then re-protected with methoxime-15-style protecting groups.

The compounds of formula III wherein R; the hydroxy protecting groups are selectively removed leaving the R8 (R2a) hydroxy protecting group as part of the final product. The same applies in the case where the R8 (R2a) hydroxy protecting group is selectively removed leaving the R7 hydroxy protecting group in place.

For example, R 7 is isopropyl or benzyl and R 8 (R 2a) is • 1 · 2 · 1 methyl. The isopropyl or benzyl group is selectively removed by standard methods, but the R8 methyl protecting group is retained as part of the final product.

In the first steps of this process, to prepare certain compounds of formula (I), the leaving group · · · is added to the 3-position of compound III, the reaction product of first step is coupled with 4- (protected hydroxy) phenol and the hydroxy protecting group of phenol is removed. This method • · ♦ I .. 30 is illustrated in the following Scheme I.

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 1

Scheme I S

III

Wherein R7 and R2a are Oval; as defined above for R 9

Il | * y— ^ V-R2a, λΑ / ^ // R? O b

15 IV

wherein R9 is a leaving group 'a * 0: ij ^^ T ^ r2b = ::: = 25: · *: ·. · · where Rs is a hydroxy protecting group which can be selectively removed * * * |

* * * V

* · · I. · * ·· 30 1

* * H

* * * f

: ** HO

* · · • · Lv il: 35 ii / = \

Iin / h! '

Ilb 15

In the first step of Scheme I, the appropriate leaving group is selectively brought to the 3-position of the starting material of formula XII by standard methods. Suitable R 9 leaving groups include sulfonates such as 5 methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropane sulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, bromo-2-chloro, other corresponding 10 leaving groups. However, to ensure appropriate substitution of the leaving group, said halogens are preferred and bromine is particularly preferred.

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

The reaction product from the preceding process step, a compound of formula IV, is then reacted with 4- (protected hydroxyl) phenol to form compounds of formula IIa, wherein R e is a selectively removable hydrocarbon. -: Inner protection group. Typically, the 4-hydroxy protecting group 25 of phenol may be any known protecting group which may be · · ·; selectively removes, in this case, the R 7 and, if present, R a groups of the compound of formula Ha. Preferred R6 protecting groups are methoxymethyl when R7 and / or R * are not methoxymethyl, and benzyl. Of these, benzyl · · · 30 is particularly preferred. 4- (protected hydroxy) phenol reagents are commercially available or can be prepared by standard methods.

This coupling reaction is known in the art as the Ullman reaction and is carried out by standard methods [see φ · · \. 35 e.g., Advanced Organic Chemistry: Reactions, Mechanisms, 16 and Structure, Fourth Edition, 3-16 (J. March, John Wiley & Sons, Inc. 1992); Jones, C. D., J. Chem. Soc. Perk. Trans. I, 4: 407 (1992)].

Generally, equivalent amounts of two aryl substituents in the presence of an equimolar amount of a copper (I) oxide catalyst and a suitable solvent are heated to reflux under an inert atmosphere. Preferably, an equivalent amount of a compound of formula IV wherein R 9 is bromine is reacted with an equivalent amount of 10 4-benzyloxyphenol in the presence of an equivalent amount of copper oxide.

Suitable solvents for this reaction are those solvents or mixtures of solvents which remain inert throughout the reaction. Usually, organic bases, especially blocked bases such as 2,4,6-collidine, are preferred solvents.

The temperature used at this stage should be sufficient to complete this coupling reaction and has an effect on the time required for this. When the reaction mixture is heated to reflux under an inert atmosphere such as nitrogen, the time to complete *. * * Is usually from about 20 to about 60 hours.

After coupling to form a compound of formula Ha, the compound of formula Hb is prepared by selectively removing the hydroxy protecting group of the compound of formula Ha from R 6; well known reduction methods. It is necessary that the selected method has no effect on the hydroxy protecting groups of R7 and, if present, R8.

When R 6 is a preferred benzyl group and R 7 and, if present, R 8 are both methyl, this process step is carried out by standard hydrogenolysis methods. In general, the substrate of formula IIa is added to a suitable solvent or mixture of solvents, followed by; the addition of a proton donor to accelerate the reaction and • ·· [· '. 35 convenient hydrogenation catalyst.

• M • · 17

Suitable catalysts include noble metals and oxides such as palladium, platinum and rhodium oxide with a carrier such as carbon or calcium carbonate. Of these, palladium on carbon, especially 10% palladium on carbon, is preferred. Solvents for this reaction are those solvents or mixtures of solvents which remain inert throughout the reaction. Generally, ethyl acetate and C 1-4 aliphatic alcohols, especially ethanol, are preferred.

For this reaction, hydrochloric acid is a sufficient and preferred proton donor.

When conducted at ambient temperature and pressure in the range of about 30 to about 50 psi, the reaction proceeds fairly rapidly. The progress of this reaction can be monitored by standard chromatographic techniques, such as thin layer chromatography.

The compounds of formulas Ha and Hb are novel and described herein as compounds of formula II and are useful for the preparation of pharmaceutically active compounds of formula I.

After the preparation of the compound of formula Hb,

* .1 is reacted with a compound of formula V

ti · • · • · ···

0 '· R3 - (CH2) n - Q V

• ··.

: Where R3 and n are as defined above and Q is bromo or preferably a chlorine group to form a compound of formula VI. The compound of formula VI is then deprotected to form a compound of formula Ia. The steps · · · 30 of this method are shown in the following Scheme II.

•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••··

Diagram 1ϊ HO.

XX

5 o, OvO ~ r: 'r70 h - IXb

10 I

r3- {cHj, "- V ^" Ux o 7j0cK> - 20 R, ° ^.

VI

• · · * * * i

• I

··· I

··· s X: r3-1ch2, „- os ^

s 25 XX

: #:: 0. ·; ·. (| ^ V-R2b. * ··. 30 HO * -1 · · · · · · · · · · · · · · · · · · · · · · · · · · · R 21 'is -H, -OH, or halogen.

• · • · · • 19 ·

In the first step of the process shown in Scheme II, the alkylation is accomplished by standard methods. Compounds of formula V are commercially available or may be prepared by methods well known to those skilled in the art. Preferably, the hydrochloride salt of the compound of formula V, in particular 2-chloroethylpiperidine hydrochloride, is used.

Typically, at least about 1 equivalent of a substrate of formula Hb is reacted with 2 equivalents of 10 compounds of formula V in the presence of at least 4 equivalents of alkali metal carbonate, preferably cesium carbonate, and an appropriate solvent.

Solvents for this reaction are those solvents or mixtures of solvents that remain inert throughout the reaction. N, N-dimethylformamide, in particular its anhydrous form, is preferred.

The temperature used at this stage should be sufficient to complete this alkylation reaction. Usually the ambient temperature is sufficient and inexpensive. This reaction is preferably carried out under an inert atmosphere, especially under a nitrogen atmosphere. Under preferred reaction conditions of · · · * · 1 · l, this reaction is completed in about ··· 16 to 20 hours. Of course, the reaction progress can be followed by standard chromatographic methods.

:: 25 As an alternative to the preparation of compounds of formula VI • · ·: reacting a compound of formula Ilb with an excess of · ·· an alkylating agent of formula. Q - (ch2) „- q1 · · · 30 · · *** where Q and Q1 are both the same or different leaving groups in a basic solution. Suitable leaving groups [1] are the above leaving groups used in the preparation of compounds of formula IV.

• · · · • 20 ·

A preferred base solution for this alkylation reaction is potassium carbonate in an inert solvent such as methyl ethyl ketone (MEK) or DMF. In this solution, the 4-hydroxy group of the benzoyl group of the compound of formula Hb exists as a phenoxide ion which replaces one of the leaving groups of the alkylating agents.

This reaction is at its best when the base solution containing the reactants and reagents is heated to reflux and allowed to run to the end of the wood. When MEK is used as the preferred solvent, the reaction time is about 6 hours to about 20 hours.

The reaction product from this step is then reacted with 1β ± peridine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine or 1-hexamethyleneimine to form compounds of formula VI. Preferably, the hydrochloride salt of piperidine is reacted with an alkylated compound of formula IIb in an inert solvent such as anhydrous DMF and heated to a temperature of about 50 to about 110 ° C. When the mixture is heated to the preferred one

»M

At about 90 ° C, the reaction lasts only about 30 minutes to about 1 hour. However, changes in reaction conditions affect the duration of this reaction, which is required to complete it. Of course, the progress of this reaction step can be followed by standard chromatographic methods.

• · ·

Compounds of formula VI wherein R 7 and, when present, R 0 are each C 1-6 alkyl, preferably methyl, and wherein R 2 a is -H or halogen are novel and pharmaceutically active for the purposes described herein. Accordingly, such compounds are within the scope of the compounds of formula I.

• · · * · ··. Certain preferred compounds of formula I are obtained from

. By spraying R7 of the compounds of formula VI and, if present, RB

• ·· • ♦ 21 hydroxy protecting groups by well known methods. Many reactions for the formation and removal of such protecting groups have been described in several standard works, including, 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, Part I, by Schrooder and Lubke, Academic Press (London and New York, 1965). Methods for removing the preferred hydroxy protecting groups for R7 and / or Re, especially for methyl and methoxymethyl, are mainly as described in the Examples, infra.

The compounds of formula Ia are novel, are pharmaceutically active methods described herein, and are within the scope of formula I as defined herein.

Compounds of formula I wherein R 1 is -H are prepared via the synthetic route shown in Scheme III. Using this route, the 3-position leaving group (R 9) is combined with commercially available thianaphthene (Formula VII) to form a compound of Formula VIII, which is then coupled with 4- (protected-20-hydroxy) phenol to give compounds of Formula IX.

················································································································ · · · · · · · · · · · · · · · · · ·············································································· · · · ·· • · 22

Scheme III

5

VII

VIII

15 i 'Xx

2 ° J

. ··. ·. f Ly. ···.

Wherein R6 is a hydroxy protecting group which can be selectively removed and R9 is a leaving group.

The compound of formula VII is commercially available.

Preparation of Compounds of Formulas Vili and IX, Including Definition of R6 and R9 Substituents, as well as Preferred Reagents The substances and conditions unless otherwise stated herein are the same as described and illustrated above: *** in Scheme I, supra.

··· · ... · Compounds of formula IX are then arylated via the Suzuki pairing reaction [see, e.g., Suzuki, A., Pure and Appl.

! ·. : 35 Chem., 6 (2): 213-222 (1994)]. Using one of the Suzuki coupling options, the compound of formula IX is selectively halogenated at the 2-position and then coupled with an arylboronic acid compound of formula ixa (route A of the following Scheme IV).

Preferably, however, the arylboronic acid of formula Xb is formed from a compound of formula IX and then reacted with a halogen arene of formula Xlb to provide new intermediates of formula Ile (route B of Scheme IV below). Such novel intermediates are useful for preparing pharmaceutically active compounds of via alkylation and deprotection.

• tlf • • • tlf • • • • tlf • • • • • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 1 1 1 1 1 1 «1 1« 1 1 1 1 · · • · · • · 24

Scheme IV

Oh

IX

10 __j__

Route A „...

- - Route B

ie RS0 p6 {-, ti ccv * 0cVB <0Hh 20 ^ s

Xa ··· Xb • · · • · · S ^ b.oh ,, 25 T R2a - ^ \ ^ y • · · |

f-JX

··· XXcl VTL

::: xib ··· 30 ö6a t tx 'Χχ ***** 0; ..; j 35 CXH> R2a OvO- * ·

They

Ile 25

I__J

V

5 HO _

XX

0 10 CcV-O- * · I Id 15

V

H 3 (CH 2} n-Q

Al: · Τ: GCK> 2 · ..... s \ f • · ···. ·: ·. xii • · · • · · 25 • · · · · · · V: f

30 k ^ -A

T 0 b OK>: * - lb wherein R 2a, R 2b, R 3, R 6 and n are as defined above; X is iodine, bromine or fluorine, in order of preference; X * is iodine, bromine or fluorine, in order of preference, or triflate.

The first step in Route A of Scheme IV is iodination or bromination of the 2-position of the compound of Formula IX using standard methods. Typically, the compound of formula IX is reacted with a small excess of n-butyllithium in hexane in a suitable solvent and an inert atmosphere such as nitrogen, followed by a dropwise addition of a small amount of the desired halogenating agent in the appropriate solvent. The preferred halogenin-15 material for this step is iodine, but the use of bromine, N-bromosuccinimide, is also permitted.

Suitable solvents include an inert solvent or a mixture of solvents such as diethyl ether, dioxane and tetrahydrofuran (THF). Of these, tetra-20 hydrofuran, especially anhydrous tetrahydrofuran, is ... preferred.

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

··· · ... · 25 The product of the preceding reaction, the halogen arene of formula Xa, is then coupled with an arylboronic acid of formula Xla via standard Suzuki coupling reactions to provide compounds of formula Ile. Compounds of formula Xla wherein R 2a is -H, halogen, or -OR 8 (R 8 is a hydroxy protecting group as defined ···. R 30) are derived from commercially available compounds by methods known in the art. (see, e.g., March J .; and Suzuki, A., supra).

In this mating reaction, a small excess of the compound of formula Xa1 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 various palladium catalysts work in Suzuki mating reactions, the catalyst selected is usually reaction-specific. Thus, the use of tetrakistriphenylphosphine palladium in this reaction is very advantageous.

Similarly, different bases can be used in this mating reaction. However, it is preferable to use an alkali metal carbonate, especially 2N sodium carbonate.

At this stage, the rope temperature should be sufficient to complete the pairing reaction. Generally, refluxing the reaction mixture for about 2 to about 4 hours is sufficient and preferred.

In Scheme IV, Route B, the arylburo-15-paronic acid at the 2-position of formula Xb is prepared using well known methods. Typically, the compound of formula IX is treated with a small excess of n-butyllithium in hexanes in the presence of a suitable solvent and in an inert atmosphere such as nitrogen, followed by the dropwise addition of the appropriate trialkyl borate.

Suitable solvents include an inert solvent or a mixture of solvents such as diethyl ether, dioxane and tetrahydrofuran (THF). THF, Erectile · ··: Anhydrous THF is preferred.

The preferred trialkyl borate used in the present invention 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 IXb by standard Suzuki coupling reactions to provide compounds of formula Ile. Preferred reaction conditions for this reaction are as described for the reaction of the compounds of Formulas Xla ······ and Xa in Scheme IV, which also gave ··· compounds of Formula Ile.

·· • · • · · · · · · 28

The conversion of compounds of formula Ile into compounds of formula Ia is accomplished as described above in the conversion of compounds of formula Ha into compounds of formula Ia.

The compounds of formulas Ile and Ild are novel and useful for the preparation of pharmaceutically active compounds of this invention.

The compounds of Formulas XII and Ib are also novel and useful for the methods described herein and are included in the determination of Formula I.

Compounds of formula I wherein either R1 or R2 is -H and the other substituent of R1 or R2 is -OH are also prepared from compounds of formula I wherein both R1 and R2 are -OH. The dihydroxy compound of formula I is converted to a mixture of 6- and 4 * -monotriflates and the triflate group is reduced to hydrogen [see Saa, J.M., et al., J. Org. Chem., 55: 991 (1990)]. The monohydroxy derivatives of the resulting mixture, either as the free base or as a pharmaceutically acceptable salt, preferably the hydrochloride salt, can then be separated by standard crystallization methods.

Typically, the dihydroxy compound of formula I is treated with about 4 to about 6 equivalents of an amine base, such as triethylamine in an ex-reactive solvent, followed by the addition of 1 equivalent of trifluoromethanesulfonic anhydride. A mixture of mono- and di-triflates is formed and separated by standard chromatographic techniques.

; The preferred solvent for this step is anhydrous dichloromethane.

• · ·

When the reaction temperature is in the range of about 0 to about 25 ° C, this reaction is carried out over a period of about 1 to about 5 hours • · · 1: m

The isolated mixture of mono-triflated compounds is then traced in a non-reactive solvent in the presence of about 3 to about 6 equivalents of an amine base, preferably triethylamine, and a hydrogenation catalyst such as palladium / carbon. - • ··; 35, which is preferred. Preferred solvents for this reaction are ethyl acetate and ethanol, or alternatively a mixture thereof. When this step of the reaction is carried out at a pressure of less than about 40 psi of hydrogen gas at ambient temperature, the reaction time is from about 2 hours to about 5 hours,

The resulting mixture of monohydroxy derivatives of formula I has various solubilities in ethyl acetate and the 6-hydroxy-4'-hydrogen derivatives can be partially separated from the 6-hydrogen-4'-hydroxy derivatives by selective crystallization.

Further separation giving pure monohydroxy compounds of formula I can be accomplished by converting the enriched mixtures to the hydrochloride salts followed by crystallization from ethyl acetate-ethanol.

A more direct process for the preparation of compounds of formula I wherein either R1 or R2 is -H and one of the substituents R1 or R2 is -OH, as well as an alternative process for the preparation of compounds of formula I wherein either R1 or R2 is -H and the other Rx or R2 of the substituents is -O-C 1 -C 6 alkyl), a compound of the formula 20 R 3 ~ <CH 2) · ... · ··· L ·. ··· is used. (f τΛ_L \ ~ r2c ···: · 25 · · · · · :::: where R3 and n are as defined above;

R 1c is -OH or -O-C 1-6 alkyl); and. ** ·. R 2c is -OH or -O (C 1 -C 6 alkyl); provided that when R 1c is -OH, R 2c is -O- (C 1 -C 4 alkyl): ** and when R 1c is -O-C 1 -C 4 alkyl), R 2c is -OH.

* ... * In this process, the hydroxy group of such a compound is converted to a triflate derivative by treatment with triflumethane sulphonic anhydride. The triflate group is then reduced under standard conditions, preferably by catalytic hydrogenation. The hydroxy protecting group is then removed by standard methods as described herein to provide compounds of formula I wherein either R1 or R2 is 5-H and the other R1 or R2 substituent is -OH.

Another alternative and preferred method for preparing compounds of this invention is shown in Scheme V. In this process, the sulfur atom (infra) of a compound of formula IV is oxidized to form a sulfoxide (formula XIV), which is then reacted with a nucleophilic moiety to add an oxygen or sulfur atom . The sulfoxide group of the compounds of formula XVI is then reduced to give certain compounds of this invention.

··· • · · »» ··· • · · · · · ·

• M

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · To · Page ··· ·················································································· · · · · · · · · · · ·

• M

• 1 31

Scheme V

Rs JÖC / ~ C «^ ~ R2a

IV

'R R9 p

XIV

_ ί _ rfiX-OR6 rfis-O-ICHjJB-Ra ^ .OR6 rfix, O- (CH2) n-R3 HO- ^ X HCT5 ^ XVa XVI) XVc XVd Y | f v ^; ι · ι "" "οθ0 · '. · 1 2

: ...: O 0 O O

# ... # XVI a XVIfa XVI c 3 ^ {5 • · · ♦ ♦ · • · • ·

: '··: TTT V

: T: R'Vi, Rl-, CH = '»- V>, RVi> W0 UI, s'": iig Ic RU », b„ ··· iC Ile Id ·· • · • · · * ·· • · 5 where each variable is as defined above.

In the first step of this process, the compound of formula IV is selectively oxidized to the sulfoxide. Many known methods are available for this process step [see, e.g., Madesclaire, M., Tetrahedron, 42 (20); 5, 5459-5495 (1986)? Trost, B. M. et al., Tetrahedron Let ters, 22 (14); 1287-1290 (1981); Drabowicz, J. et al., Synthetic Communications, 11 (12); 1025-1030 (1981);

Kramer, J.B. et al., 34th National Organic Symposium, Williamsburg, VA, June 11-15, 1995]. However, many oxidants provide only poor conversion to the desired product, as well as significant over-oxidation to the sulion. However, this novel process converts the compound of formula IV into a sulfoxide of formula XIV in high yields with little or no sulfone formation. In this process, the compound of formula IV is reacted with about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture of about 20 to about 50% tris-fluoroacetic acid in methylene chloride. The reaction is carried out at a temperature of about 10 to about 50 ° C and usually requires from about 1 to about 2 hours to complete.

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

In this preparation step, the acid: poprotone of the nucleophilic group is removed by treatment with a base, preferably · ·· in a small excess of sodium hydride or potassium tert-butoxide in a polar aprotic solvent, preferably · · · DMF or tetrahydrofuran. Other bases which may be used are potassium carbonate and cesium carbonate. In addition, other solvents such as dioxane or ··· * ·· dimethylsulfoxide may be used. Deprotonation is usually carried out at a temperature of about 0 ° C to about 30 ° C and: · * usually requires about 30 minutes to complete.

• · ·. The compound of formula XIV is then added to the nucleophile solution.

• ♦ · • ♦

The substitution reaction is carried out at a temperature of 0 ° C to about 50 ° C

and usually takes from about 1 to about 2 hours. The product is isolated by standard methods.

33

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

In the next step of this process, the new sulfoxides XVIa, b, c and d of the Formulas 10 (collectively Formula XVI) are reduced to the benzothiophene compound of Formulas Ig, Le, Ile and Id, respectively. Prior to this reduction process, the compounds of Formulas Ig and Ile may first be alkylated as described herein. The reduction of sulfoxide compounds can be accomplished using any of a number of methods known in the art, e.g., hydride reduction (lithium aluminum hydride), catalytic hydrogenation, hydrogenolysis, and trimethylsilyl iodide (TMS-I). In this reduction, the choice of reagent depends on compatibility with other functional groups in the molecule. Lithium aluminum hydride *. * * (LiAlH4) and hydrogenolysis (palladium carbon / ammonium formi · · · · ... · acetate) are preferred reagents for the compounds described herein. Suitable solvents for LiAlH4 reduction are diethyl ether, dioxane and tetrahydrofuran (THF). Of these, THF, especially anhydrous THF, is preferred. Hydrogeno- • · ·; * j *; in lysis, alcohol solvents, especially ethanol, are preferred.

Sleep. The reaction is carried out at a temperature of about 0 to about 60 ° C and requires about 0.5 hours to about 2 hours to complete.

If desired, the hydroxy protecting group (s) of the products of the method outlined in Scheme V may be removed and: from the salt of the product of any step. Accordingly, · · ·; ·. The present invention relates to a process for preparing the compounds. 35 r3- (ch2) „- 0 - J ^ jJ ^ 5 pla b where Λ

R 1a is -H or -O R 7a where R 7 is -H or a hydroxy protecting group; R2a is -H, -halogen, or -OR6®, wherein R8 'is -H or a hydroxy protecting group; R 3 is 1-piperidinyl, 1-pyrrolidinyl, 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 process a) oxidizes a sulfur atom in a compound of formula

20 or IV

· * · * · “S C ö O- ·. · Pia • · 25 ···

IV

• · · ··· where

Rle and R2 "are as defined above; and R 9 is a leaving group; • · ·. ···. B) subjecting the product of step a) to a compound having • ·

T is formula XIV

R9? £ xyo- * *. ·: K o

XIV

35 with a nucleophilic group represented by the formula: (-) - (CH 2) n -R 3

O

R 2 wherein R 12 is -OH or -SH;

c) reducing the product of formula b), a compound of formula XVI

R3 - (CH2) n "0 15 Y | T \ V / === \ LJLH} ~ R ~ '

Rla ^ l ^ o

XVI

20 to give a compound of the formula • · · • · · C: R 3 - (CH 2) n -O ~~

^ I

• · · Ov JL

Optionally removing R 1 and / or R 2 * hydroxy-protecting groups, if present, from the product of step c); and ·· • * ·· (e) optionally forming a compound of formula (c) or: ***; (d) salt of the product.

• · ·. · 1 This new method also provides new gas. Compounds XIV and XVIa, b, c and d, each of which is a useful intermediate for the preparation of the pharmaceutically active compounds of this invention.

Compounds of formula I wherein Z is S are also prepared using the method described in Scheme VI below, wherein the compound of formula IVa is metallized. The resulting product, a compound of formula XVII, is reacted with 4- (protected hydroxy) phenyl disulfide of formula XVIII and the phenol protecting group of the compound of formula Ile is removed to give compounds of formula IIf. It should be noted that, when using this manufacturing process 10, R 2 cannot be halogen due to chemical limitations.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · | · • · · · ·· · · 37

Scheme VI

R9 s jQVO- IVa io ¥ „, CcH>" '·

XVII

15 f ^ Ymt fYsXj

| H'0 ^ XVIII

20 Rcy \: T:

·. · S

· * · * · J ™ '"· λ .... Y> - (. YV_ R-" 25 Rla S' f

• · · TT

·.:. · He

• · · I

• * * I

• · · I

• I

• · · • · · 30 · HC · _ K o,

; ···; S

| ···· 1 rV (/ -r2 '• ·

Ilf 38 where

R 1a is -H or -OR 7 and R 7 is a hydroxy protecting group; R 2a is -H or -OR 6 and R 8 is a hydroxy protecting group; R6 is a hydroxy protecting group which can be selectively removed; R3 is a leaving group; and M is a metal ion.

In the first two steps of Scheme VI, the compound of formula IVa is metallized by well known methods 10. Most commonly and most preferably, the compound of formula IVa is treated with a slight excess of n-butyllithium in hexane in an appropriate solvent, followed by the dropwise addition of a solution of the disulfide compound of formula XVIII in an appropriate solvent. Both of these reaction steps are carried out under an inert atmosphere, such as nitrogen, while suitable solvents for both steps are one or more inert solvents such as diethyl ether, dioxane and THF. Of these, THF, especially its anhydrous form 20, is preferred. In addition, these reaction steps are carried out at a temperature of about -78 to about 85 ° C.

In the first step of this reaction, a metallized compound of formula XVII is obtained. 4- (protected hydroxy) phenyl · · ·: disulfide (a compound of formula XVIII) which is reacted with such a compound of formula XVII to give a compound of formula XVII is prepared by protecting the commercially available 4- a hydroxyphenylsulfide ± hydroxy group with a meaning protecting group by methods known in the art. A preferred protecting group for R 6 is methoxymethyl, provided that R 7 and R a, if one or both are present, are a hydroxy protecting group or other methyl group. It is necessary that the R hydroxy protecting group is a group different from the R7 and R8 hydroxy protecting groups, · [if present, so that the R6 group can be selectively · ·· *. . 35 eliminates by standard methods to give compounds of formula Ilf • · · 1.

39

In order to effect deprotonation, the R6 protecting group is removed by reacting a compound of formula Ile in a protic solvent or mixture of solvents with an acid medium containing at least one equivalent acid, preferably methanesulfonic acid, and heating from about 25 ° C to about 110 ° C. The reaction time is usually about 6 to about 24 hours, but the progress of the reaction can be monitored by standard chromatographic techniques.

Suitable solvents for this reaction include, for example, water and methanol.

The novel compounds of formulas lie and IIf are useful for the preparation of pharmaceutically active compounds of formula I and fall within the definition of formula II above.

Compounds of Formula Id R 3 - (CH 2) n -0- ^

S

JD- / 0 ~ r2d ·. · · Rlb S '-f ···

Id · · · V · wherein R R1 b is -H or -OH; · · ·: R 2b is -H or -OH; and ···. * · '· R3 and n are as defined above, prepared using methods described above that are consistent with the steps outlined in Schemes II and IV. Such novel compounds of formula Id are useful for the methods of this invention and are within the definition of formula I.

Compounds of formula I wherein R 1 and R 2 are different hydroxy protecting groups or either R 1 or R 2 is a hydroxy protecting group and the other is hydroxy are prepared selectively using · · ·. 35 modified 2-arylbenzothiophene starting materials of the above Formula III, provided that the hydroxy protecting groups designated by R7 and R8 are sufficiently different that one of the protecting groups is removed while the other remains * Such 2-arylbenzothiophenes are prepared by are well known in the art.

A particularly useful process for the preparation of compounds of formula X wherein R1 and R * are different protecting groups is the Suzuki coupling reaction as described in Scheme IV above. However, 6- (protected hydroxy) benzothiophene-2-boronic acid is reacted with a compound of formula Xlb 10 above wherein R 2a is -O R 8 and R 7 is not the same as R a. This reaction enables the preparation of compounds of this invention wherein R 7 and R 6 are different hydroxy protecting groups so that one protecting group can be selectively removed and the other remaining as part of the final product. Preferably, the R 7 protecting group, and especially benzyl or isopropyl, is removed to form the hydroxy group, while the R 8 protecting group, especially methyl, is retained.

The Suzuki mating reaction is also carried out using the methods described above, but substituting a compound of formula Xlb for a compound of formula XIX.

I JCT

• n 8a ··· I \

25 XXX

wherein: R a is C 1-6 alkyl sulfonate, preferably methanesulfonate or C 4-6 aryl sulfonate; and: * · *: R10 is a leaving group, preferably bromo or tri-. 30 flats.

In this process, 6- (protected hydroxy) benzothio-2-pheneno-2-boronic acid, as described above, is

* .. · * to react with a compound of formula XIX to give formula XX

a compound which is reacted with boron tribromide in 35 methylene chloride to give a monohydroxy compound which is then converted, for example, to a benzyl group 41 by standard methods (formula XXI). The 4'-sulfonate ester is then selectively removed by basic hydrolysis or preferably by treatment with LiAlH4 in a suitable aprotic solvent such as Example 5 in THF. This reaction gives a compound of formula XXII which is finally methylated, for example, at the 4 'position by standard methods (formula IIIa). Of course, one skilled in the art will recognize that various methods may be used to provide compounds of formula IIIa wherein the hydroxy protecting groups are other than those shown in Scheme VII below, but which protecting groups may be removed to provide the monohydroxy compounds of formula I of this invention.

Scheme VII

XXXh * h3cct

XX

20

V

··· * • · * 9. J0CK> “·. · · BzO s -

O 25 XXI

• · · • · · ··· • ··

V · V

Vs f ΤΛ-0H

; ***: 30 '···: ·! xxii? 1 • «'• · ♦.

s * ..: 35 riT ^ \ / 55 ^ ** ** j y— “A OMe purple purple compounds are then exposed to the different

methods of providing Formulas I and II of this invention

compounds.

42

Other preferred compounds of Formula I are prepared by hydroxy groups at the 6- and / or 4'-position of the cor-5, if present, with the -O-CO (C1-C6 alkyl) or -O-SO2- (C2-6 alkyl) group well. by known methods. See, e.g., U.S. Patent No. 4,358,593.

For example, when an -O-C 1 -C 1 (alkyl) group is desired, the mono- or dihydroxy compound of Formula I is reacted with an agent such as acyl chloride, faromide, cyanide or azide or a suitable acid anhydride or mixed acid anhydride. The reactions are usually carried out in an alkaline solvent such as pyridine, lutein-dinine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, raethylpiperidine and the like. The reaction may also be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone and the like, to which at least one equivalent of acid has been added. ..: remover (except as shown below) such as • · · ϊ.ί 'tertiary amine. If desired, acylation catalysts such as 4-dimethylaminopyridine or • · ·; 4-pyrrolidinopyridine. See, e.g., Haslam et al., Tetrahedron, 36: 2409-2433 (1980).

These reactions are carried out at moderate temperatures in the range of about -25 ° C to about 100 ° C, most often under an inert atmosphere, such as nitrogen gas. However, the ambient temperature is usually sufficient to allow the reaction to proceed.

• Acylation of the hydroxy group at the 6-position and / or the 4'-position may also be accomplished by appropriate carboxyl • · · *. . 35 by acid-catalyzed reactions of acids in inert or »» »· · ♦ 43 gane solvents. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like are used.

The R 1 and / or R 2 groups of the aforementioned compounds of formula I may also be obtained by formation of an active ester of the appropriate acid, such as esters formed from such known reagents as dicyclohexylcharhodimide, acylimidazoles, nitrophenols, pentachlorophenols, N 10nimide and 1-hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38: 1979 (1965) and Chem. Ber., 788 and 2024 (1970).

Each of the above-described methods for obtaining -O-CO- (C 1-6 -alkyl) groups is carried out in solvents as described above. Of course, those methods which do not obtain the acid product during the reaction do not require the use of an acid scavenger in the reaction mixture.

When a compound of formula I is desired wherein the hydroxy group at the 6- and / or 4'-position of the compound of formula X is converted to the -O-SO 2 - (C 2-6 alkyl) group of formula 20, the mono or dihydroxy compound is reacted with, for example, sulfonic acid anhydride. or a suitable sulfonic acid derivative such as sulfonyl chloride, sulfonyl bromide or sulfonylammonium salt as disclosed by King and Monoir in J. Am. Chem. Soc., 97: 2566-2567 (1975).

· · ·: The dihydroxy compound can also be reacted with the appropriate sulfonic anhydride or mixed sulfonic anhydrides. Such reactions are carried out under the conditions of the ratio as described above for the reaction with the acid halides and the like.

Although the free base form of the compounds of Formula I may be used in the methods of this invention, it is preferable to prepare and use a pharmaceutically acceptable salt form. Thus, the compounds used in the methods of this invention. The formulations primarily form pharmaceutically acceptable acid addition salts with a variety of organic and inorganic acids, and include physiologically acceptable salts that are commonly used in pharmaceutical chemistry. Such salts form part of this invention. Common 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 di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanoedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. Such pharmaceutically acceptable salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o -acetoxybenzoate, o -acetoxybenzoate, o -acetoxybenzoate, b-hydroxybu-20 tyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, · · · * · 11 l formate, fumarate, glycolate, heptanoate, hippo ··· * ... 1 rate, lactate, malate, maleate, hydroxy maleate, · · · V: malonate, mandelate, mesylate, nicotinate, isonic • 1 · 25 cotinate, nitrate, oxalate, phthalate, terephthalate, phosphate , monohydrogen phosphate, dihydrogen phosphate, meta-phosphate, pyro-phosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, substrate, sulfate, bisulfate, pyrosulfate, sulphate · · · 30 f lithium, bisulfite, sulfonate, benzenesulfonate, • · * 1 p-bromophenylsulfonate, chlorobenzenesulfonate, • · · 1 ·· Ethanesulfonate, 2-hydroxyethanesulfonate, meta- • · ·! : nisulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phonate, p-toluenesulfonate, xylene sulfonate, M · 45 tartrate and the like. Preferred salts are the hydrochloride and the oxalate salts.

Pharmaceutically acceptable acid addition salts are usually formed by reacting a compound of formula I with an equimolar amount of acid. The reactants are usually combined in the same solvent such as diethyl ether or ethyl acetate. The salt usually precipitates from the solution over a period of about one hour to ten days and can be isolated by filtration or the solvent 10 can be removed by conventional methods.

Pharmaceutically acceptable salts generally have improved solubility properties compared to the compound from which they are obtained and are thus more susceptible to forming liquids or emulsions.

Representative compounds of the present invention include:

Group I: [6-Methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) 20 [6-isopropoxy-2- {4-methoxyphenyl) -3-bromo] benzo [b] ] thio-phen (S-oxide) · · * * 11 - [6-methoxy-2- {4-isopropoxyphenyl) -3-bromo] benzo [b] thio • · · · · phen (S-oxide) ···: ··· £ 2- (4-roethoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide):) 1): 25 [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] - · · · I. 30 thiophene- (S-oxide) • · 11,11 6 -isopropoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thio-1 ··· phenyl (S-oxide) Z f 6-Methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] -; · 1-thiophene- (S-oxide) · · 46 · 6 - methoxy -2- (4-isopropoxyphenyl) -3-bromo] benzo [b] thiophen {S-oxide) [6-benzyloxy-3- [4- [ 2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxy phenyl)] benzo [b] thiophene (S-oxide) 5- [6-isopropoxy-3- [4- [2- (1-piperidinyl) Jethoxy] 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- (4-10 isopropoxyphenyl)] benzo [ b] thiophene (S-oxide) [6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy] benzo [b] thiophene [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene Group XI: [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxy-phenyl)] benzo [b] Thiophene 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride 20 [3- [4- [2- (1- pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxy-phenyl)] benzo [b] thiophene • [3- [4- [2- (1-hexamethyleneimino)] ethoxy] phenoxy] -2- (4-hyd- • · * ··· 1 roxy phenyl)] benzo [b] thiophene • · · [3- [4- [2- (1H, N-diethylamino) ethoxy] phenoxy] -2- (4-hydroxy-47 [6-methoxy-2- ( 4-Isopropoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl] ethoxy] phenoxy] -2- (4- methoxyphenyl)] benzo [b] thiophene 5 [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy- 3- [4- [2- (1-Pyrolodinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) 3-benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimine)) ethoxy] phenoxy-10] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride 15 [6 -methoxy-3- [4- [3- (piperidino) propoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [3- (1- N, N-diethylamino) propoxy] phenoxy] -2- (4-methoxy) phenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-20 hydroxyphenyl)] benzo [b] thiophene ... [ 6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy 3 phenoxy] -2- (4 - [(1 ']] - hydroxyphenyl)] benzo [b] thiophene oxalate * ··· * [6 -hydroxy-3- [4- [2- (1-piperidinyl) ethoxy 3 phenoxy 3 -2- (4- • · · · · · · · · · · · · · · · hydroxyphenyl)] benzo [b] thiophene hydrochloride · · · Σ ... Σ 25 [6-Hydroxy-3- [4- [2- (1-pyrrolidinyl] ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene: * · *: [6-Hydroxy-3- [4- [2- (1-Hexamethyleneimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-N, N-diethylamino)] ethoxy3 phenoxy] -. ···. 30 2- (4-hydroxyphenyl)] benzo [b] thiophene • · *** [6-hydroxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2- (4-hydroxy · · : *** (hydroxyphenyl)] benzo [b] thiophene hydrochloride ··· [6-hydroxy-3- [4- [3- (1-N, N-diethylamino) propoxy [phenoxy] -2- (4-hydroxyphenyl) enyl)] benzo [b] thiophene hydrochloride · 48 [δ-hydroxy-3- [4- [2- (1-N, N-diisopropylamino) ethoxy [E-noxy]] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [3- (piperidino) propoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride 5 [ 6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-benzyloxy-3- [4- [2- (1) -piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy-10- (4-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-hexamethylimino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6 cyloxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene 15 [6-benzyloxy-3- t -4- [ 2- (1-Morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (6-isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 - (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene. .. [6-Isopropoxy-3- [4- [2- (1-hexamethylimino) ethoxy] phenoxy] · * · [trans] -2- (4-methoxyphenyl)] benzo [b] thiophene • · * ··· '[6-isopropoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxyphenyl] -2- (4-methoxyphenyl)] benzo [b ] thiophene * ·· * ... · 25 [6-isopropoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4- ·, ·, · methoxyphenyl)] benzo [ b] thiophene [6-hydroxy-3- (4- [2- {1-Piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4-] [2- (1-Pyrrolidinyl) ethoxy] phenoxy] -2-. ···. 30 (4-methoxyphenyl)] benzo [b] thiophene • · E 6 -hydroxy-3- [4- [2- (1-hexamethylimino) ethoxy] phenoxy] - · · · ** 2- (4-methoxyphenyl) )] benzo [b] thiophene * ·· * ... · [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] - · * · .. 2- (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- (2- (1-morpholino) ethoxy] phenoxy] -2- (4-methyl - toxiphenyl)] benzo [b] thiophene 49 [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b 31] Phenylhydrochloride 5 [6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3 - [4- (2- (1-Hexamethylimino) ethoxy] phenoxy] -2- (4-methoxy phenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- ( 1N, N-dimethylamino) ethoxy] phenoxy] -10 2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2 - (4-Methoxyphenyl)] benzo [b] thiophene hydroxy hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxy-phenyl)] - benzo [b] thiophene 15 [6-methoxy-3- [4- [2- (1-Pyrrolidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] - si] -2- (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2O-2- (4- benzyloxyphenyl)] benzo [b] thiophene ... [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-benzo · · · * · [' enyl)] benzo [b] thiophene • · * ··· [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4- ··· ·. * 'isopropoxyphenyl)] benzo [b] thiophene ··· 25 [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4- [beta] -isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-Dimethylamino) ethoxy] phenoxy] -. ··· . 30 2- (4-Isopropoxyphenyl)] benzo [b] thiophene • · [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-iso- • ·: * * propoxyphenyl)] benzo [b] thiophene · · · [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene ene [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene 50 [ 6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl) 3 benzo [b] thiophene 5 [6-methoxy-3- [4- [2 - (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-10 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-Hexamethylenimine) ethoxy] phenox si] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride 15 [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl) )] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-benzyloxy] 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -20 2- (4-benzyloxyphenyl)] benzo [b] thiophene hydrochloride [6-ethylsulfonyloxy-3- [4- [2- (1-piperidinyl)] ethoxy] - · · · * · 1 · 1 phenoxy] -2- (4-ethylsulfonyloxyphenyl) 3-benzo [b] thio-3 · phenylene hydrochloride · [6-hydroxy-3- [4- [2- (1-) piperidinyl Jethoxy] phenoxy] -2- (4- • · · 25 ethylsulfonyloxyphenyl)] benzo [b] thiophene hydrochloride [6-ethylsulfonyloxy-3- [4- [2- (1-piperidinyl) ethoxy] -: 1 · 1; phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4- • · · 30 trifluoromethanesulfonyloxyphenyl)] benzo [b] thiophene • · * 3 - [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxy- ·: 1 ··hyphenyl)] benzo [b] Thiophene hydrochloride • · ·: ... [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-pivaloyl; · oxy-phenyl)] benzo [b] thiophene hydrochloride 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-butylsulfonyloxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy] ~ 3- [4- [2- (1-piperidin-1-yl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene 5 [6-methoxy-3- [4- (2- (1) -pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy-10- (4-meth oxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy-3 - [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene 15 [6-benzyloxy-3- (4- (2- (1-pyrrolidinyl) i) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [5-benzyloxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] -thiophenoxy] -2- ( 4-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1N, N-dimethylamino) ethoxy] thlo-phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy ± -3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -: 2- (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [ 2- (1-piperidinyl) ethoxy] thiophenoxy% ··· 1; si] -2- (4-methoxyphenyl)] benzo [b] thiophene. · 1 ·. 25 [6-Isopropoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy, 2 · (4-methoxyphenyl)] benzo [b] thiophene • · · [6- isopropoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thio-4 · * phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4 - [2- (1N, N-Dimethylamino) ethoxy] thio-1,1'-phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene • · · [6-sopropoxy-3- [ 4- (2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene. ··· [6-Hydroxy-3- [4- [2- (1) -piperidinyl) ethoxy] thiophenoxy] -2- · · · (4-methoxyphenyl)] benzo [b] thiophene · [6-hydroxy-3- [4- [2 - (1-Pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene 52 [6-hydroxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophene ] -2- (4-methoxyphenyl)] benzo [b] thiophene 5- [6-hydroxy-3- [4- [2- (1-N, N-diraethylamino} ethoxy] thiophenoxy] -2- (4- methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- (2- (1-m orfolino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy ± -3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2-10 (4- methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-pyrrolidinyl ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-Hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride 15 [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- ( 4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2-20 (4-benzyloxyphenyl)] benzo [b] thiophene [6- methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- • · · * · 11 - (4-benzyloxyphenyl)] benzo [b] thiophene • · · [6-methoxy-3- [4- [2- (1-Hexamethyleneimino) ethoxy] thiophen-4-yl-oxy] -2- (4-benzyloxyphenyl)] benzo [b] t iofen: [2:25 [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene • · · .1 · 1. [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- ( 1-piperidinyl) ethoxy] thiophenoxy] -2- • · 30 (4-isopropoxyphenyl)] benzo [b] thiophene *** [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy ] -2- ··· 1 ·· (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophene- [noxy] 3 -2- (4-isopropoxyphenyl)] benzo [b] thiophene · 53 · 6-methoxy-3- [4- [2- (1-N, N-dimethylamine) ± no) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4 -isopropoxyphenyl)] benzo [b] thiophene 5 [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy -3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene-6-methoxy-3- [4- [2- (1-hexamethyl) tyylene (imino) et ox ] thiophen-10-noxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene? 6-methoxy-3-? 4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy ± -3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- ( 1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-hexamethylenimine imino) ethoxy] thiophene-20-noxy ] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] · # * · 1 1 si] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride ···: ... · [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- ( 4- ··· V (hydroxyphenyl)] benzo [b] thiophene hydrochloride ··· $ ί 25 6-methoxy-3--4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2-: 1j (4-methoxyphenyl)] benzo [b] thiophene hydrochloride ··· 1 · 6 · 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzofb] thiophene £ 6 -hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -? · · 2- (4-hydroxyphenyl)] benzo [b] thiophene • · * 1? 6-hydroxy-3- [4- [2- (1-Hexamethyleneimino) ethoxy] thiophene · · · · · · · · · 1 · · · · · · · · · · · · · - [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy]. si] -2- (4-hydroxyphenyl)] benzo [b] thiophene · [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy ] -2- (4-hydroxyphenyl)] benzo [b] thiophene 54 [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b ] thiophene hydrochloride 5 [6-hydroxy-3- [4- [2- {1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [ 2- (1-Hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3-t4- [2- (1N, N-dimethylamino) ethoxy] ] thiophenoxy-10-si] -2- (4-hydroxyphenyl) 3-benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl) ] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2-phenyl 3 benzo [b] thiophene hydrochloride The following examples are provided to further illustrate the preparation of the compounds of this invention. It is not intended that the following examples limit the scope of the invention in any way.

The NMR results for the following examples were performed on a GE 20 300 MHz NMR apparatus and anhydrous d-6 DMSO was used as the solvent unless otherwise stated.

• • • • • • • • • • • • • • • • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · 55

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

r O

Xr 10

To a solution of S-bromo-benzo [b] thiophene 15 (69.62 g, 0.325 mol) in 55 ml of anhydrous collidine under nitrogen pressure was added 4-benzyloxyphenol (97.6 g, 0.488 mol) and copper (I) oxide (23, 3 g, 0.163 mol). The mixture was heated at reflux for 24 hours. After cooling, the reaction mixture was diluted with ethyl acetate 20 (200 mL) and the crude mixture was filtered through Celite (Aldrich,

Milwaukee, WI) to remove inorganic salts. The filtrate was washed with 1 N hydrochloric acid (3 x * 150 mL). The organics were dried (sodium sulfate) · · · and concentrated in vacuo to a liquid. The tinaphthene was removed by distillation (10 mm Hg, 115-120 ° C). the material was chromatographed (silica, hexane-ethylacetate 85:15) to give 12.2 g of benzo [b] thiophene and 12.95 g (35% based on recovered starting material): 1 · 1: [3- (4 -Benzyloxy) phenoxy 3 benzo [b] thiophene as a white solid, m.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, δB - 9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H) Analyze calculated for C 21 H 16 O 2 S: C 75.88, H 4.85 Found: C 75.75, H 5.00.

· «• • • • • • • • • • • 56

PREPARATION 2 [2-Iodo-3- (4-Benzyloxy) -phenax] benzo [b) Thiophene * -A.

XX

o 10

To a solution of [3- (4-benzyloxy) phenoxy] -benzo [b] thiophene (6.00 g, 18.1 mmol) in anhydrous tetrahydrofuran (100 mL) under nitrogen pressure at -78 ° C, n-butyllithium (12.4 mL, 19.9 mmol, 1.6 M in hexanes) was added dropwise with a hand pump. The solution changed from colorless to clear orange. After stirring for 20 minutes at -78 ° C, the lithium compounds were treated with I 2 (5.03, 19.9 µmol), added dropwise with a hand pump 20 to 50 ml of anhydrous tetrahydrofuran. After complete addition, the reaction turned light yellow and was allowed to slowly warm to room temperature.

• · * ··· * The reaction was quenched by the addition of 0.1 N sodium sulfite.

Preparation 3 [2- (4-tert-Butyloxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene 5 µL.

XX.

* ° co-ck ·

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- (tertbutoxy) phenylboronic acid 15 (2.28 g, 11.75 mmol) followed by tetrakistriphenylphosphine palladium (0.76 g, 0.66 mmol). To this solution was added 14.5 ml of a 2N sodium carbonate solution. The resulting mixture was heated under reflux for three hours. After cooling, the reaction mixture was diluted with 150 mL of ethyl 20 acetate. The organic material was washed with 0.1 N sodium hydroxide (2 x 100 mL) and then dried (sodium sulfate). Concentration of the product gave a semi-solid, which was dissolved in chloroform and allowed to pass through a pad of silica ··· * 1. Concentration gave an oil which was triturated from hexanes to give 4.00 g (91%) of [2- (4-tert-butyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] ] thiophene: 1 · 1 as a white powder. Sp. Mp 105-108 ° C. 1 H NMR (CDCl 3) δ 7.77 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.43 - 7.24 (m, 8H ), 6.98 (d, J = 8.6 Hz, 2H), 6.89 (q,. ···. 30 JB = 9.3 Hz, 4H), 4.99 (s, 2H), 1 , 36 (s, 9H). FD Mass- • ·

spectrometry: 480. Analysis calculated for C 31 H 21 BO 3 S: C

: 77.47, H 5.87. Found: C, 77.35; H, 5.99.

· 58 • • 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58 58

Preparation method

Prepared in the same manner using 4-methoxyphenylboronic acid, [2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene was obtained.

CLV

XX

o OCBi

Yield 73%. Sp. 115-118 ° C. 1 H-NMR (CDCl 3) δ 7.80-7.90 (m, 3H), 7.33-7.53 (m, 8H), 6.93-7.06 (m, 15H), δ 00 (s, 2H), 3.83 (s, 3H). FD Mass Spectrometry: 438. Analysis calculated for C2BH2203S: C, 76.69; H, 5.06. Found: C, 76.52; H, 5.09.

PREPARATION 5 [2- (4-tert-Butyloxyphenyl) -3- (4-hydroxy) phenoxy-20-benzo [b] thiophene: · xx · · · · · · · ·

To a solution of [2- (4-tert-butyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene (1.50 g, ···. 3.37 mmol) in 30 mL of absolute ethanol, containing • · * orid 1% concentrated hydrochloric acid, 0.50 g of *** 10% palladium on carbon was added. The mixture was hydrogenated at 40 psi for one hour, after which the reaction was found to be complete by thin layer chromatography, the mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The crude product was dissolved in a minimum amount of ethyl acetate and passed through a short silica column to remove the diatomaceous earth (ethyl acetate as eluent). Concentration gave a white solid which was triturated with hexane / 5 ethyl ether. Filtration gave 868 mg (73%) of (2- (4-tert-butyloxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene, mp 210-213 ° C .1H NMR (DMSO-d6) d 9.13 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.35 - 7.26 ( m, 3H), 7.01 (d, J = 8.6 Hz, 2H), 6.70 (q, 10-8.9 Hz, 4H), 1.28 (s, 9H). FD mass spectrometry: 390. Analysis calculated for C 24 H 22 O 3 S: C 73.82, H 5.68 Found: C 73.98, H 5.84.

Preparation method

In the same manner was prepared (2- (4-methoxyphenyl) -3- (4-hydroxy} phenoxy) benzo (b] thiophene HO).

XX

o

Cxy-O ~ - ··· • · · · ··· • · · ·:: 80% yield. Sp. = 120-125 ° C. 1 H NMR (CDCl 3) δ 7.80-7.90 (m, 3H), 7.48 (m, 1H), 7.30-7.48 (m, 10H) ), 6.90-7.03 (m, 4H), 6.76-6.86 (m, 2H), 3.82 · · V · (s, 3H). FD mass spectrometry: 348. Analysis calculated For C 21 H 16 O 3 S, C 72.39, H 4.63 Found: C 72.68, H 4.82.

• ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · panel · EN comes 60

Example 1 [3- [4- [2- (1-Piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene?

l // 0H

io

To a solution of [2- (4-tert-butyloxyphenyl) -3- (4-hydroxy) phenoxy] foenzo [b] thiophene (1.25 g, 3.20 mmol) in anhydrous N, N-dimethylformamide (10 mL) was added At room temperature, cesium carbonate (5.70 g, 17.6 mmol) was added. After stirring for 20 minutes, 2-chloroethylpiperidine hydrochloride (1.95 g, 10.56 mmol) was added in small portions. The resulting heterogeneous mixture was stirred vigorously for 24 hours. The reaction medium was then diluted with water (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was then washed with water (2 x 200 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo to give an oil. Chromatography (5-10% methane ··· * · 25 L / chloroform) gave 1.47 g (91%) of 3- [4- [2- (1-piperidinyl) ·. · Li) ethoxy] phenoxy] -2- (4-tert-butyloxyphenyl)] benzo [b] - is: thiophene which was taken directly to the next step without analysis.

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-tert-butyl-oxy-phenyl)] -benzo [b] thiophene (1.37 g, 2.73 mmol) • · ··· • was dissolved in trifluoroacetic acid (10 mL) at ambient temperature. After stirring for 15 minutes, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate · 1 · # ι (20 mL) and washed with saturated sodium bicarbonate solution (3 × 10 mL). The organic layer was dried (sodium sulfate) and concentrated to precipitate a white precipitate in solution. The product was recrystallized from ethyl acetate-ethyl ether to give 1.03 g (85%) of 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [5] [b] thiophene as colorless crystals. Sp. 169-172 "C.

1 H-NMR (DMSO-d 6) δ 9.81 (s, 1H>, 7.93 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H). , 7.36-7.26 (m, 3H), 6.86 (s, 4H), 6.78 (d, J = 8.6 Hz, 2H), 4.10 (m, 2H), 3, 29 (m, 2H), 2.95-2.75 (m, 4H), 1.68-1.40 (m, 6H) Analysis calcd for C27H27NO3S 10.55 CF3CO2H: C, 66.40 H, 5.46; N, 2.76 Found: C, 65.99; H, 5.49; N, 2.61.

Example 2 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene was converted to its hydrochloride salt in 90% yield by treatment with ethyl ether hydrochloride acid in ethyl acetate. .

, 2HC1 0 ··· ^ £ »··· • · · · · ··· · ... · 25 Results of Example 2. Sp. 233-240 eC.

···: (DMSO-d 6) δ 10.43 (m, 1H), 9.89 (s, 1H), 7.93 - 7.95 (m, T: 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).

. ···. 30 FD mass spectrometry: 446. Analysis calculated

H, 5.86; N, 2.91. C CHHJ7NO3S. Found: C

H, 5.66; N, 2.96.

· 1 ·

The following examples were prepared in an analogous manner: 62 2 · 2 · 3 · 62

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

O

10 O

Sp. 150-155 ° C. 1 H NMR (DMSO-d 5) δ 9.79 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.54 (d, J 8.6 Hz, 2H), δ , 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). Ana-15 lysis calculated for C 26 H 25 NO 3 S-0.33 CF 3 CO 2 H: C 68.25, H 5.44, N 2.99. Found: C, 68.29; H, 5.46; N, 3.19.

Example 4 [3- [4- [2- (1-Hexamethyleneimino) ethoxy] -enoxy] -2- (4-hydroxyphenyl)] benzo {b] thiophene 20.0-¾

= Ϊ́! O ^ O ° H

• · · • · · I ·

Sp. 189-191 ° C. 1 H NMR (DMSO-d 6) δ 7.91 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.34-7.25 (m , .1 ♦ ·. 30 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). Analysis: 'Calculated for C2BH2, NO3S, 1.50 H2O: C, 69.11; H, 6.79; N, 2.88.

Found: C, 69.25; H, 6.79; N, 2.58.

· · • • • • • • • • • 63

EXAMPLE 5 [3- [4- [2- (3-Dimethylamino) Ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

Yeah

o 10

Sp. 70 eC. 1 H-NMR (DMSO-d 6) δ 9.91 (bs, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H). , 7.35-7.24 (m, 3H), 6.82 (s, 4H), 6.78 (d, J = 8.6 Hz, 2H), 3.88 (bt, 2H), 2, 76 (bt, 2H), 2.51 (m, 4H), 0.91 (m, 6H). FD mass-15 spectrometry: 434. Analysis calculated for C 26 H 27 NO 3 S.0, 50 H 2 O: C 70.56, H 6.38, N 3.16. Found: C, 70.45; H, 6.26; N, 3.20.

Example 6 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-grain-20-phenoxyphenyl)] benzo [b] thiophene hydrochloride.1: ·. _ .Hey

S Cr-Q

25 _ ***** Il «J-OCHs; 1: 1: \ -l

Sp. = 228-230 ° C. 1 H-NMR (DMSO-d 6) δ 7.96 (d, J = 7.5 DEG, 1H), 7.66 (d, J = 8.8 Ha, 2H), 7.35-7 , 50 (m, **: 23H), 6.98 (d, J = 8.7 Hz, 2H), 6.86 - 6.90 (m, 4H), 4.28 - Γ1 ···, 31 (m, 2H), 3.74 (s, 3H), 3.37 - 3.45 (m, 4H), 2.92 - s' [: 2.96 (m, 2H), 2.46 - 2.48 (m, 5H), 1.74 (m, 1H). FD-mass- ··. sas spectrometry: 459. Analysis calculated -1.0% · · · · · · · · · · · · · ·/ 64 · · · · · · · · · · · · · · · · · · · · Found: C, 68.06; H, 6.38; N, 2.60.

Alternative Preparation of [2- (4-tert-Butyloxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene 5 Preparation 7 [3- (4-Benzyloxy) -enoxy] benzo [b] thiophene-2- boronic acid

Q

XX

o 1) -B (OH) j at -78 ° C in a solution of [3- (4-benzyloxy) phenoxy] benzo [b] thiophene (5.00 g, 15.1 mmol) in 20 mL: of anhydrous tetrahydrofuran under nitrogen pressure, n-butyllithium (9.90 mL, 15.8 mmol, 1.6 M in hexane-20) was added dropwise with a hand pump. After stirring for 15 minutes, B (0iPr) 3 (3.83 mL, 16.6 mmol) was added via a hand pump and the resulting mixture was allowed to warm to 0 ° C.

The reaction was then quenched by addition of ethyl acetate and 1.0 N hydrochloric acid (100 ml each). The layers were separated and the organic layer was extracted with water (1 x 100 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo to a solid which was triturated from ethyl ether / hexanes. Filtration gave 3.96 g (70%) of [3- (4-benzyloxy) -enoxy] benzo [b] thio, ···. 30 Phenyl-2-boronic acid as a white solid.

• ·

Sp. 115-121 ° C. ΧΗ-ΝΜΗ (DMSO-d 6) δ 8.16 (d, J 8 8.5 Hz, 1 1 ··· 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.42 - 7 , 23 (m, 7H), 6.90 · · · (g, JB = 9.0 Hz, 4H), 5.01 (s, 2H). Analysis calculated for C 21 H 17 O 4 SB: C, 67.04; H, 4.55. Found: C, 67.17; H, 4.78.

55- [3- (4-Benzyloxy) -phenoxy] -benzo [b] thiophene-2-boronic acid was reacted with 4- (tert-butoxy) bromo-benzene as described above [2-iodo-3- ( 4-benzyloxy) phenoxy] benzo [b] thiophene and 4- (tert-butoxy) phenylboronic acid-5-ol under the conditions described to give [2- (4-tert-butyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene in 81% yield.

Examples where this method was used are: Example 7 [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene hydrochloride. * HC1 15 ^ Xx 20 Sp. 223 - 226 "C. 1 H NMR (DMSO-d 6) δ 7.99 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.44 - 7.30 (m Δ: 7H), 6.90 (s, 4H), 4.27 (m, 2H), 3.43 - 3.35 (m, 4H), λ = 2.97 - 2.88 (m, 2H). ), 1.73-1.61 (m, 5H), 1.34 (m, 1H).

: Analysis calculated for C 27 H 27 NO 2 S · 1.0 HCl: C 69.59, H 6.06, O 25 N 3.00. Found: C, 69.88; H, 6.11; N, 3.19.

: Example 8 • · · [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-fluorophenyl)] benzo [b] thiophene · · · · · * * HCl

ί: ° XX

***** / °

! · :; 35 Ccy-O

• · 66

Sp. 219-226 ° C. 1 H-NMR (DMSO-d 6) δ 10.20 (bs, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.77-7.73 (ra, 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). 5 FD Mass Spectrometry: 447. Analysis calculated for c27h26no2sf.

1.0 HCl: C, 67.00; H, 5.62; N, 2.89. Found: C, 67.26; H, 5.67; N, 3.03.

PREPARATION 8 [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 ramol) in 1.10 L of chloroform at 60 ° C was added bromine (15.98 g, 100 mmol) was added dropwise as a 200 mL chloroform solution. When the addition was * .12 complete, the reaction was cooled to room temperature and the solvent was removed in vacuo to give 34.2 g (100%) of [6- • · · ί.ί · methoxy-2- (4- methoxyphenyl) -3-bromo] benzo [b] thio £ ene

: 3! 25 as a white solid. Sp. 83-85 ° C. 1 H-NMR

• j1! (DMSO-d 6) d 7.70-7.62 (m, 4H), 7.17 (dd, J 8.6, 2.0 Hz, 1H), 7.09 (d, J = 8.4). Hz, 2H). FD-mass spectrometry; 349, 350. Analysis calculated for 016H13O2SBr: C 55.03, H 3.75.

··· Found: C, 54.79; H, 3.76.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • • • •

IM

·· • · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 67 · 67

Example 9 [6-Methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene CL.

XX

o ^ ~ ° ch3

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 nitrogen pressure was added 4-benzyloxyphenol (38.96 g, 194.8 mmol) and copper (I) 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 the inorganic solids were removed by filtration. The filtrate was concentrated in vacuo and the residue was dissolved in methylene chloride (500 mL). The methylene chloride solution was washed with 3N hydrochloric acid (3 x 300 mL) followed by 1N sodium hydroxide (3 x 300 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo. The residue was taken up in 100 mL of ethyl acetate and then the formed white solid was collected by filtration [[6-methoxy-2- (4-methoxyphenyl)] benzo [b] -; thiophene (4.62 g, 17.11 mmol]. The filtrate was concentrated in vacuo. ···. Hexane / ethyl acetate to give initially 7.19 g of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] - · ·: 35 benzo [b] thiophene as a pale crystalline solid The solid was concentrated and chromatographed on silica gel (80:20 hexane: ethyl acetate) to give 1.81 g of additional product. [6-methoxy-2- (4-methoxyphenyl) -3- ( The total yield of 4-benzyloxy) phenoxy] benzo [b] thlophene was 5.00 g (24% based on recovered starting material).

The basic extract was acidified to pH 4 with 5 N hydrochloric acid and the resulting precipitate was collected by filtration and dried to give 13.3 g of the recovered 4-benzyloxyphenol. Sp. 100 - 103 "C. 1 H-NMR (CDCl 3) δ 7.60 (d, 3 = 8.8 10 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). FD mass spectrometry: 468, Analysis calculated for C29 H24 O4 S: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29.

Preparation 9 [6 * -methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene

HO

XX

20 φ XXH> - ... HjCCT v • • • «· • | | | | | * To a solution of [6-methoxy-2- (4-methoxyphenyl * ··· * 25,11) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene (1.50 g, ·:. · 3.20 mmol) in 50 ml of ethyl acetate and 10 ml of 1% · concentrated hydrochloric acid in ethanol, 10% palladium on carbon (300 mg) was added. The mixture was hydrogenated at 40 psi for 20 minutes, after which the reaction was found to be complete by thin layer chromatography. The mixture was allowed to pass through diatomaceous earth to remove the catalyst and the filtrate was concentrated in vacuo to give a white solid.

The crude product was allowed to pass through a pad of silica gel; * · .. (chloroform as eluent). Concentration gave 1.10 g (91%) of? 35 [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] -? 69 benzo [b] thiophene as a white solid. Sp. 123-126 ° C. 1 H-NMR (DMSO-d 6) δ 9.10 (s, 1H), 7.59 (d, J 8.8 Hz, 2H), 7.52 (d, J - 2.1 Hz, 1H), δ , 14 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8.8, 2.1 Hz, 5 1H ), 6.72 (d, J * 9.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H) ). FD mass spectrometry: 378. Analysis calculated for C 22 H 18 O 4 S: C, 69.82; H, 4.79. Found: C, 70.06; H, 4.98.

Example 10 10 [6-Methoxy-3- (4- [2- (1-piperidinyl) ethoxy) phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

»BOjCCOaH

o

H 2 CO 3 - 20 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 nitrogen pressure, cesium carbonate (3.86 g, 11.88 * · *;). * mmol) was added. After stirring for 10 minutes, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) was added.

The resulting mixture was stirred for 18 hours at ambient temperature. The reaction mixture was partitioned between chloroform and water (100 mL each). The layers were separated and the aqueous: layer was extracted with chloroform (3 x 50 mL). Organic: ***; The substances were combined and washed with water (2 x 100 mL). Drying of the organic material (sodium sulfate) and concentration gave an oil which was 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 • 70, a white precipitate was formed and collected by filtration and dried to give 1.17 g. (70%) total yield (6-methoxy-3 '- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene as the oxalate salt. 197 DEG-200 DEG C. (dec.) .1H NMR (DMSO-d6) d 7.60 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 1.1 Hz) 1 H), 7.14 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.91 (dd, J = 8.8, 1.1) Hz, 1H), 6.87 (s, 4H), 4.19 (broad t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broad t, 2H) ), Δ 3.12 ~ 3.06 (m, 4H), 1.69 ~ 1.47 (m, 4H), 1.44-1.38 (m, 2H), FD mass spectrometry; 489, Analysis calculated For C 29 H 31 NO 4 S-0.88 H 2 CO 2 H: C 64.95, H 5.80, N 2.46, Found: C 64.92, H 5.77, N 2.54.

Example 11 Treatment of the free base with ethyl ether hydrochloride gave [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] ] thiophenehydro-chloride • BCl ° ^ xx ° ♦ ♦ ♦ • · · «·«

Sp. 216-220 ° C. 1 H-NMR (DMSO-d 6) δ 10.20 (bs, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 1.5 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.96 (dd, 30 J = 9.0, 1.5 Hz) , 1H), 6.92 (q, JM = 9.0 Hz, 4H), 4.31 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H) , 3.43 (m, 4H), 2.97 (m, 2H), 1.77 (m, 5H), 1.37 (m, 1H). FD-mass spectrometry:

* ··· * 489. Analysis calculated for C29 H31 NO4 S · 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 prepared in an analogous manner:

Example 12 [6-Methoxy-3 '- [4- [2- (1-pyrrolodinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene *

It jT / —C ocH3 10

Sp. 95-98 eC. 1 H-NMR (DMSO-d 6) δ 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9 , 0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.94 {dd, J = 9.0, 2.0 Hz, 1H), 6.86 (s, 4H) ), 3.97 (t, J = 6.0Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.73 (t, J = 6.0Hz, 2H), 2.51 (m, 4H), 1.66 (m, 4H). FD mass spectrometry: 477. Analysis calculated for C 29 H 29 NO 4 S: C 70.71, H 6.15, N 2.99. Found: C, 70.59; H, 6.15; N, 3.01.

Example 13 20 [6-Methoxy-3- [4- [2- (1-hexamethylene-imino) -ethoxy] -phenoxy] -2- (4-methoxy-phenyl)] - benzo [b] thiophene-N · hydrochloride 'χχ • · · 0

• · · I

· '· · R / ^ \ ΙΧΗ-Γ0' "

SjCO3 ·· »• * · 30 Sp. 189 - 192 eC. 1 H-NMR (DMSO-d 6) δ 10.55 (bs, 1H), δ · · · · · · 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J - 2). , 0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J * 9.0) , 2.0 Hz, H), 6.86 (s, 4H), 3.94 (t, J = 6.0 Hz,

• M

2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H), 35 2.66 (m, 4H), 1 , 53 (m, 8H). For C C3H H33NOSS 1.0 · · · · · · · · · · · · · · · · · · · · · · · · · · · Found: C, 66.43; H, 6.46; N, 2.84.

Example 14 [6-Methoxy-3- [4- [2- (1-N, N-diethylamino) -ethoxy] -phenoxy] -2- (4-methoxy-phenyl) -benzo [b] thiophene-hydrochloride • HClO

Jt - / \ —QCSi 15 Sp. 196-198 ° C. 1 H-NMR (DMSO-d 6) δ 10.48 (bs, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, 3 = 2.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H ), 6.87 (q, = 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). Analysis calculated for C 28 H 31 NO 4 S · 1.5 HCl: C 63.18, H 6.15, N 2.63. Found: O ': C 63.43, H 5.79, N 2.85.

Example 15 ··· [6-Methoxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2- (4- [**] 25-methoxyphenyl)] benzo [b] thiophene hydrochloride ··· • · 1 · ν'1 j0 ^ v1 \

Q

*: ·· 1 30 J

·· 1 Jv / \} - ° ca3 • 1 ··· • · • ·

Sp. Mp 208-211 ° C. 1 H-NMR (DMSO-d 6) δ 10.6 (bs, 1H), δ δ 7.63 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 2.0 Hz) , 1H), 7.20 (J = 9.0 Hz, 1H), 7.00 (d, J »9.0 Hz, 2H), 6.97 (dd, J) = 9.0, 2.0 Hz, 1H), 6.91 (q, JM = 9.0 Hz, 4H), 4.29 (m, 2H), 4.08 - 3.91 (m, 4H) , 3.82 (s, 3H), 3.77 (s, 3H), 3.59 - 3.42 (m, 4H), 3.21 - 3.10 (m, 2H), Analysis calculated for C22 H29 NO5 S » 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- [3- (piperidino) propoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride

O

»HC1 15 o ΧΧ3ΧΓ / ~ 0” ·

Sp. 175-200 ° C. 1 H NMR (DMSO-d 6) δ 9.90 (bs, 1H), δ 7.64 (d, J = 9.0 Hz, 2H), 7.59 <d, J = 2.0 Hz, 1H). , 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, 1H), 6.88 (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 (in, 5H), 1.39 (m, f; 25 1H). Analysis calculated for 1.15 HCl: C, 66.01. H, 6.40; N, 2.73. Found: C, 66.01; H, 6.40; N, 2.73.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · • ♦ · 1 · • · ♦ • ·· • · 74

Example 17 [6-Methoxy-3- [4- ~ 3 - (1N, N-diethylamino) propoxy; i-phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride \ ^ - H * HCl

Xx 10 ° jT jC / - \ y ~ ° cBj

Sp. 164-166 ° C. 1 H-NMH (DMSO-d 6 d 9.77 (bs, 1H), δ 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J * 2.0 Hz, 1H). , 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, 1 H), 6/89 (s, 4H), 3.99 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.15 ( m, 6H), 2.06 (tn, 2H), 1.20 (t, J = 7.0 Hz, 6H) Analysis calculated for 20 C 29 H 33 NO 4 S · 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- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- {4-hydroxyphenyl) -3-benzo [b] thiophene 0 Xx 0 ·. · 30 · X · H · · · · HO · · · · · · · · · · · · · · · · · · E 6-Methoxy-3-C4- [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 * 35 methylene chloride and cooled to 8 ° C. To this solution was added boron tribromide (7.20 ml, 76.20 mraol), and the resulting mixture was stirred at 8 ° C for 2.5 hours. The reaction was quenched by pouring saturated sodium bicarbonate into the stirred solution. (1 L) and cooled to 50 [deg.] C. The methylene chloride layer was separated and the remaining solids were dissolved in methanol / ethyl acetate, then the aqueous layer was extracted with 5% methanol / ethyl acetate (3 x 500 mL) All organic extracts (ethyl acetate) and methylene chloride ) were combined and dried (sodium sulfate). Concentration in vacuo gave a tan solid which was chromatographed (silica, 1-7% methanol / chloroform) to give 7.13 g (81%) of [6-hydroxy-3- [4- [2- (1-piperidinyl)] ethoxy] phenoxy 3- (4-hydroxyphenyl) benzo [b] thiophene as a white solid. Sp. 93 ° C. 1 H-NMR (DMSO-d 6) δ 9.73 (bs, 1H), 9.68 (bs, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.84 (dd, J = 8.6, 1.8 Hz, 1H (masked)), 6 , 81 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 2.56 20 (t, J = 5 , 8 Hz, 2H), 2.36 (m, 4H), 1.43 (m, 4H), 1.32 ... (m, 2H). FD mass spectrometry: 462. Analysis calculated 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) 3-benzo [b] ] thiophene is converted to its ok-::: saline salt in 80% yield by the method described above. Details of [6-hydroxy-3- [4- [2- (1-piperidinyl) -: *; * ethoxy] phenoxy] -2- (4-hydroxyphenyl) -benzo [b] thiophenoxy] ···. 30 Salads • · • · ·

.. *. * BO3CCQ3H

?

• O

: 35 76

Sp. 246-249 ° C (dec.). 1 H-NMR (DMSO-d 6) δ 7.45 (d, J 1 8.6 Hz, 2H), 7.22 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.6) Hz, 1H), 6.87 (dd, J = 8.6, 1.8 Hz, 1H (covered)), 6.84 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 4.08 (bt, 2H), δ 3.01 (bt, 2H), 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H).

FD mass spectrometry: 462. Analysis calculated for C27H27NO4S1 0.75 HO2CO3H1; Found: C, 64.63; H, 5.42; N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62.

Example 20 10 [6-Hydroxy-3- [4- [2- (1-piperidinyl] ethoxy] texoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene was converted to its hydrochloride salt in 91% yield by treatment with the free base in ethyl acetate. with ethyl ether hydrochloride Information on [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride • HCl o

= "·: JCCVO-M

... BCT 3 ··· 2w • «• · · · · · · · · · · · · · · · · · · · · · · · · · · · · 25 25 25 25 Sp 158-165 ° C 1 H NMR (DMSO-d s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = ···: T: 2.0 Hz, 1H), 7.04 (d, J - 8.6 Hz, 1H), 6.86 (q, = 9.3 Hz, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 4.26 (bt, 2H), 3.37 (m, 4H), 2.91 (m, 2H), · · · 30 1/72 (m, 5H), 1, 25 (m, 1H) FD mass spectrometry: 461.

Analysis calculated for C 37 H 27 NO 4 S 1.0 HCl: C, 65.11; H, 5.67; 1.2 ··· N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.

The following compounds were prepared analogously. valla: • · · · • · t · · 2 • · 77

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

O

10 O

Sp. 99 - 113 "C. 1 H NMR (DMSO-d 6) δ 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 2) , 0 Hz, 1H), 7.09 <d, J = 9.0 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H ), 6.79 {d, J = 9.0 Hz, 2H), 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 < t, J = 7.0 Hz, 4H). H, 5.74; N, 3.07. Found: C, 68.40; H, 5.74; Found: C, 68.52; H, 6.00; N, 3.34. Example 22 [6-Hydroxy-3- [4- [2- (1-hexamethylenimine) ethoxy-phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene I ° ^ Xx ·. · * O: =: = jOcyx'y · 0 "·» »• ·« • · ·

Sp. 125-130 ° C. 1 H-NMR (DMSO-d 6) δ 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J <= 9.0 Hz, 2H), 7.26 (d, J =. ···. 30 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.85 (s, 3H), 6.80 ′ ** (dd, 0) = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz), 3.94 (t, ♦ ♦: J = 6.0 Hz, 2H), 2.80 ( t, J = 6.0 Hz, 2H), 2.66 (m, 4H), · 1.53 (m, 8H). Analysis calculated for C ^ HH ^ NCN ^O S; C, 70.71; H, 6.15; N, 2.94. Found: C, 70.67; H, 6.31; H, 2.93.

• · • · · · · · · · 78

Example 23 [6-Hydroxy-3- [4- ~ [2- (1-N, N-diethylamino) ethoxy] -phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

Sp. 137-141 ° C. 1 H NMR (DMSO-d 6) δ 9.75 (s, 1H), 9.71 (a, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.25 (d, J - 2.0 Hz, 1H), 7.09 (d, 3 = 9.0 Hz, 1H), 6.85 (s, 4H), 6.80 (dd, J = 9.0, 2.0 Hz) , 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.95 (t, 15 J - 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H). Analysis calculated for C 26 H 27 NO 4 S: C, 69.46; H, 6.05; N, 3.12. Found: C, 69.76; H, 5.85; N, 3.40. Example 24 [6-Hydroxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2-20 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride • HClO.

* · * * O

· ** · cxS — C V ~ ° H

··· * ·· \ Jr ... HO v ® • · · • · ·

Sp. 157-162 ° C. 1 H-NMR (DMSO-d 6) δ 10.60 (bs, 1H), δ; 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.28 * 30 (d, J = 2.0) Hz, 1H), 7.10 (d, J * 9.0 Hz, 1H), 6.92 (q, **: * JM m 9.0 Hz, 4H), 6.81 (dd, 3 = 9.0, 2.0 Hz, 1H), 6.80 (d,: **. J = 9.0 Hz, 2H), 4.30 (m, 2H), 3.95 (m, 2H) , 3.75 (m, 2H),

3.51 (m, 4H), 3.18 (m, 2H). Analysis calculated for C26H25NO5S ·; ·. HCl: C, 62.46; H, 5.24; N, 2.80. Found: C, 69.69; H

35 5.43, N 2.92.

• t »• · 79

Example 25 [6-Hydroxy-3- [4- [3- (1-N, N-diethylamino) propoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride

5 N

V / v HCl

'XX

10 o

Sp. 185-191 ° C, 1 H NMR (DMSO-d 6) δ 9.94 (bs, 1H), δ 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27

(dd, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 <d, J = 9.0 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.14 (m, 6H), 2 , 08 (m, 2H), 1.20 (t, J = 6.0 Hz, 6H). Analysis calculated for C 27 H 29 NO 4 S ♦ 1.30 for 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- (1H, N-diisopropylamino) - · · · · · · · · · · · · · · · · · · · · · (4-Hydroxyphenyl) 3-benzo [b] thio-· · · 25 phenol hydrochloride ·.: J * Hcl • · · vx ^ η, τ, A xx. ** ·. 30 o

• · · HO

• · • · ···: · *. Sp. 128-131 ° C. 1 H NMR (DMSO-d 6) δ 9.81 (bs, 1H), · ··· · · · 35 9.76 (s, 1H), 9.02 (s, 1H), 7.49 (d, J = 9.0 Hz, 2H), 7.28 · 80 (m, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.90 (s, 4H), 6.79 (m, 3H), 4.19 (m, 2H), 3.68 (m, 2H), 3.50 (ro, 2H>, 1.31 (in, 12H). Analysis calculated for C20H31NO4S11, 33 for 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 * 3 Cl

X

o

liv-C /) -OH

is ho ^ s

Sp. 258-262 eC. 1 H-NMR (DMSO-d 6) δ 9.85 (bs, 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J 19.0 Hz, 2H ), 7.27 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 20 4H), 6.80 (dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 3.44 ( m, 2H), 3.15 (m, 2H), 2.88 (m, 2H), 2.11 (m, 2H), 1.73 (m, 5H), 1.39 (m, 1H).

• ··

Analysis calculated for C20 H29 NO4 S10.75 HCl: C, 66.87; H, 5.96; O: 2.78. Found: C, 67.04; H, 5.90; N, 2.68.

Alternatively, as shown in Scheme III: supra, Example 19 was prepared using methoxymethyl: 1 · 1 · (Μ0Μ) protecting groups instead of methoxy. The methods are directly analogous to those recently described, except that the MOM groups are finally removed by acid hydrolysis.

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 81

Preparation 10 (6-Methoxy-2- (4-methoxymethyloxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene

Sp. 94 - 96 ttC. 1 H NMR (DMSO-d 6) δ 7.65 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.43 - 7.32 (m , 15 5H), 7.23 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 7.04 (dd, J = 8.8, 2) , 0 Hz, 1H), 6.92 (q, 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). FD Mass Spectrometry: 528. Preparation 11 [6-Methoxy-2- (4-methoxymethyloxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene • · ·:: ho

W, XX

• o C .: 25 / - \: jl J 7 — ζ. Λ — ochsochj * ··> 1v. · \\ ΛΤ e · .. HaCOB ^ CO ^ ^ 1S V-1f • · ·

Sp. 90-91 eC. 1 H-NMR (DMSO-d 6) δ 9.15 (s, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.22 30 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 2.0 Hz, 1H), 6.72 * ·: 2 (q, JA8 = 9 , 1 Hz, 4H), 5.26 (s, 2H), 5.21 (s, 2H), 3.40 (s, · 1 ··· 3H), 3.37 (s, 3H). FD mass spectrometry: 438. Analysis calculated for C24H2206S: C 65.74, H 5.06. Found: C, 65.50; H, 4.99.

• · # • ·· · • · · · · · 2 • ♦

Example 28 82 [6-Methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide)

Br 5 ocb3

O

To a solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (10.0 g, 28.6 mmol) in 50 mL of anhydrous methylene chloride was added 50 mL of tri- -fluoro. After stirring for 5 minutes, hydrogen peroxide (4.0 mL, 28.6 mmol, 30% aqueous solution) was added. The resulting mixture was stirred at ambient temperature for two hours. Solid sodium bisulfite 15 (1.25 g) was added to the dark solution followed by 15 mL of water. The mixture was stirred vigorously for 15 minutes and then concentrated in vacuo. The residue was partitioned between chloroform and saturated sodium bicarbonate solution (200 mL). The layers were separated and the organic layer was extracted with 20 saturated sodium bicarbonate solutions. The organic layer was then dried (sodium sulfate) and concentrated in vacuo to a solid which was triturated from ethyl ether / ethyl acetate. Filtration gave 8.20 g (80%): T: [6-methoxy-2- (4-methoxyphenyl) -3-bromo) benzo [b] thiophene: ***; 25 (S-oxide) as a yellow solid which can be · · ·

. recrystallize from ethyl acetate. Sp. 170-173 ° C. 1 H-NMR

. ·! ·. (DMSO-dJ d 7.24 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, · 2H), 7.54 (d, J = 8, 5 Hz, 1H), 7.26 (dd, J 8.5, 2.2 Hz, 1H), 7.10 (d, J = 8.8 H, 2H), 3.86 (s, 3H) , 3.80 (s, 3H.

Anal. Calcd for C16H1303SBr: C, 52.62; H, 3.59. Observed •• 1 * ·; · 'tu: C 52.40, H 3.55.

··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·yst bat Page

Example 29 83

Prepared in an analogous manner to [2- (4-methoxy-phenyl) -3-bromo] benzo [b] thiophene (S-oxide)

Br 5 C ° cH * fl o

Sp. 120-125 ° C. 1 H-NMR (DMSO-d 6) δ 8.06 (d, J = 7.6 Hz, 1H), 7.78 - 7.59 (m, 5H), 7.13 (d, J = 8.7 Hz) , 10 2H), 3.81 (s, 3H). FD mass spectrometry: 335. Analysis calculated for C15H102O2SBr: C, 53.75; H, 3.31. Found: C, 53.71; H, 3.46.

PREPARATION 12 Preparation of 4- {2- (1-piperidinyl) ethoxy) -enol

j0 ~ O

To a solution of 4-benzyloxyphenol (50.50 g, 0.25 mol) in 350 ml of anhydrous DMF was added 20-2-chloroethylpiperidine (46.30 g, 0.25 mol). After stirring for 10 minutes, potassium carbonate (52.0 g, 0.375 mol) and cesium carbonate (85.0 g, · · · · ... · 0.25 mol) were added. The resulting heterogeneous mixture was stirred butter vigorously at ambient temperature for 48 hours. The reaction mixture was then poured into water (500 mL) and extracted with methylene chloride. The organics were then extracted with 1 N sodium hydroxide several times and finally washed with brine. The organic layer was then dried (sodium sulfate) and concentrated in vacuo to give an oil. Chromatography of 30 graphs (SiO 2, 1: 1 hexane / ethyl acetate) gave 60.0 g · ** (77%) of 4- [2- (1-piperidinyl) ethoxy] phenoxybenzyl ether ** ··· colorless as an oil. 1 H NMR (DMSO-d 6) δ 7.40-7.27 s ”] s (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 = 6.0 Hz, 2H), 2.35-2.37 · · ·. 35 (m, 4H), 1.48-1.32 (m, 6H). FD mass spectrometry: 311.

• ·· • · 84

Analysis calculated for C 20 H 5 NO 2: C 77.14, H 8.09, N 4.50. Found: C, 77.34; H, 8.18; N, 4.64.

4- [2- (1-piperidinyl) ethoxy] phenoxybenzyl ether (21.40 g, 68.81 mmol) was dissolved in 200 mL of 1: 15 EtOH / EtOAc containing 1% concentrated HCl. The solution was transferred to a Parr flask and 5% palladium on carbon (3.4 g) was added. The mixture was hydrogenated at 40 psi for two hours. The mixture was then allowed to pass through a pad of diatomaceous earth to remove the catalyst. The filtrate was concentrated in vacuo to give a solid which was taken up in ethyl ether and filtered to give 12.10 g (83%) of 4- (2- (1-piperidinyl) ethoxy) phenol, m.p. 148-150 ° C. 1 H NMR (DMSO-d 6) δ 8.40 (s, 1H), 6.70 (q, JfB * 11.5 Hz, 4H), 3.93 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.42-2.38 (m, 4H), 1.52-1.32 (m, 6H). FD mass spectrometry: 221. Analysis calculated

For C 13 H 19 NO 2: C 70.56, H 8.09, N 4.50. Found: C, 70.75; H, 8.59; N, 6.54.

Example 30 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide) s

; .T; ^ Q

2 p

: .i · I j3 "'C ^) _ Da! ·: T: o

To a solution of 4- (2- (1-piperidinyl) ethoxy) -? · 30 phenol (0.32 g, 1.43 mmol) in 5 mL of anhydrous DMF at ambient temperature was added sodium hydride (0.57 g, ··· * ·· 1.43 mmol, 65% dispersion in mineral oil). After stirring for 15 min, [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thlophene (S-oxide) (0.50 g, 1, 37 [·. 35 mmol) was added in small portions. After stirring for 1 h, the reaction was found complete by thin layer chromatography analysis. The solvent was removed in vacuo and the residue partitioned between water and 10% ethanol / ethyl acetate. The organics were washed several times with water 5 and then dried (sodium sulfate). Concentration in vacuo gave an oil which was triturated from ethyl acetate / hexanes to give 0.62 g (89%) of [6-methoxy-13- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)]. benzo [b] thiophene (S-oxide) as a pale yellow solid. Sp. 97-100 ° C. 1 H NMR (DMSO-d 6) d 7.68 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.06 - 6.92 (m , 6H), 6.85 (d, J = 8.8 Hz, 2H), 3.94 (t, J = 6.0 Hz, 2H), 3.81 (s, 3H), 3.72 (s) , 3H), 2.56 (t, J = 6.0 Hz, 2H), 2.39-2.32 (m, 4H), 1.47-1.32 (m, 6H). Calcd for C29H31NO5S: C, 68.89; H, 6.18; N, 2.77. Found: C, 68.95; H, 6.04; N, 2.57.

Example 31

In a similar manner, [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo-20 [b] thlophene (S-oxide) was prepared. ΐίΐΛ ^ ÖCHj il

Example 32 86 (6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride

• SCI

O

f — C /) - och3

HjCO ^ s '-'

To a solution of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophen (S- oxide) (Example 30) (3.00 g, 5.94 mmol) in 200 mL of anhydrous THF under nitrogen pressure at 0 ° C was added lithium aluminum hydride (0.34 g, 8.91 mmol) in small portions. After stirring for 30 minutes, the reaction was quenched by the careful addition of 5.0 mL of 2.0 N sodium hydroxide. The mixture was stirred vigorously for 30 minutes and additional 2.0 N sodium hydroxide was added to dissolve the salts. The mixture was then partitioned between water and 10% sodium hydroxide. The layers were separated and the aqueous layers were extracted several times with 10% ethyl acetate. ·! ! phenol / ethyl acetate. The organic layer was dried (nat: [ϊ 25 sulfur sulfate) and concentrated in vacuo to an oil. The crude product was dissolved in 50 ml of 1: 1 ethyl acetate / ethyl ether and then treated with excess 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] -4,5-phenoxy] -2- ( 4-methoxyphenyl)] benzo [b] thiophene hydrochloride as a white solid.

Example 6 was also prepared from Example 31 by the same method.

• · t • · • · · · · · 1 1 • · · • · 87

Preparation 13 6-Methoxybenzo [b] thiophene-2-boronic acid

J-B (OH) a 5

To a solution of 6-methoxybenzo [b] thiophene (18.13 g, 0.111 mol) in 150 mL of anhydrous tetrahydrofuran (THF) at -60 ° C was added n-butyllithium (76.2 mL, 0.122 mol, 1 mL). , 6M solution in hexanes) drop by hand with a 10 mm pump. After stirring for 30 minutes, triisopropylborate (28.2 mL, 0.122 mol) was added by hand pump. The resulting mixture was allowed to slowly warm to 0 ° C and then partitioned between 1 H hydrochloric acid and ethyl acetate (300 mL each). The layers were separated and the organic layer was dried over sodium sulfate.

Concentration in vacuo gave a white solid which was triturated from ethyl ether-hexanes. Filtration gave 16.4 g (71%) of 6-methoxybenzo [b] thiophene-2-boronic acid as a white solid, m.p. 200 ° C (dec.). 1 H NMR δ (DMSO-d 6) δ 7.83 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H). , 6.97 (dd, J = 8.6, 2.0 Hz, 1H), 3.82 * n *, Σ (s, 3H). FD mass spectrometry: 208, 11 Preparation 14 ··· [6-Methoxy-2- (4-methanesulfonyloxyphenyl)] - benz -; ***: 25-bis-thiophene; HiCO 3 CO 4 G 4 ° C '... To a solution of 6-methoxybenzo [b] thiophene-2- • 3 · *, 30 boronic acid (3.00 g, 14.4 mmol) in 100 mL of toluene, 4- (methanesulfonyloxy) phenyl bromide (3.98 g, 15.8 mmol) was added followed by 16 mL of 2.0 N sodium carbonate; carbonate solution. After stirring for 10 minutes, tetra- · · · / cistriphenylphosphine palladium (0.60 g, 0.52 mmol) was added. , 35 were adjusted and the resulting mixture was heated at reflux for 88 hours. The reaction mixture was then allowed to cool to ambient temperature, after which the product was chelated from the organic phase. The aqueous phase was removed and the organic layer was concentrated in vacuo to give 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 tan solid. Sp. 197 -201 'C. Ή-ΝΜΙΙ (DMSO-d6) δ 7.82-7.77 (m, 3H), 7.71 (d, 10 J = 8.8 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 6.98 (dd, J = 8.7, 1.5 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H). FD mass spectrometry: 334. Analysis calculated for C 16 H 14 O 4 S 2: C 57.46, H 4.21. Found: C, 57.76; H, 4.21.

Preparation 15 [6-Methoxy-2- (4-benzyloxyphenyl) -benzophenyl] thiophene was prepared in a similar manner to Preparation 14.

Il y — OBn 20 ^ V1! Yield 73%. Sp. 217-221 eC. 1 H-NMR (DMSO-d 6) δ 7.63-7.60 (m, 3H), 7.59-7.26 (m, 7H), 7.02 (d, J = 8.7).

Hz, 2H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 5.11 (s, 2H), 1 · 25 · 3.88 (s, 3H). FD mass spectrometry: 346. Analysis calcd. . ·. tu C, 2HiaO2S: C, 76.27; H, 5.24. Found: C, 76.00,. ···. H, 5.25.

• · ·

Preparation 16 ... [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] - · · · 30 benzo [b] thiophene · ·: ·. [j \ - osq, cH,: "πηΛΑ / V- / ··· HO ^» 5 ^ o and • · • «···

To a solution of [6-methoxy-2- (4-methanesulfon-35-yloxy-phenyl) -benzophen] -thiophene (9.50 g, 28.40 mraol) · · · · · · 89 in anhydrous methylene chloride (200 mL) at room temperature under nitrogen pressure, boron tribromide (14.20 g, 5.36 mol, 56.8 nunol) was added. The resulting mixture was stirred at ambient temperature for three hours. The reaction mixture was quenched by slowly pouring off excess ice water. After vigorous stirring for 30 minutes, the white precipitate was collected by filtration, washed several times with water, and then dried under vacuum to give 8.92 g (98%) of [6-hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene-10 as a white solid. Sp. 239-243 ° C. 1 H-NMR (DMSO-d 6) δ 9.70 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.72 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H), 6.86 (dd, J = 8 , 7, 1.7 Hz, 1H), 3.38 (s, 3H). FD mass spectrometry: 320. Ana-15 lysate calculated for C 18 H 18 Z 4 S 2: C 56.23, H 3.77. Found: C, 56.49; H, 3.68.

Preparation 17 [6-Benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene

To a solution of [6-hydroxy-2- (4-methanesulfonyl * * '* phenyloxyphenyl)] benzo [b] thiophene (3.20 g, 10.0 mmol) · ··· ... · 25 in 75 mL anhydrous DMF, Cs 2 CO 3 (5.75 g, 17.7 mmol) was added followed by benzyl chloride (1.72 mL, 11.0 mmol).

The resulting mixture was stirred vigorously for 24 hours. Solvent

was removed in vacuo and the solid residue was suspended in 20

: '! * Ml of water. The white precipitate was collected by filtration and%. * ··. 30 were washed several times with water. After drying in vacuo, the crude product was suspended in 1: 1 hexane: ethyl ether. The solid was collected to give 3.72 g (91%) of [6- [4] benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b], [b] thiophene as a white solid. Sp. 198 -: 3520 ° C. 1 H NMR (DMSO-d 6) δ 7.81-7.78 (m, 3H), 7.72 (d, • 90 J = 8.7 Hz, 1H), 7.64 (d, J = 2 , 2 Hz, 1H), 7.47-7.30 (in, 7H), 5.15 (s, 2H), 3.39 (s, 3H). FD mass spectrometry: 410.

Preparation 18 5 [6-Benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene A solution of [6-benzyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (12, 50 g, 30.50 mmol) in 300 ml of anhydrous THF under nitrogen pressure at ambient temperature, lithium aluminum hydride (2.32 g, 61.0 mmol) was added in small portions. The mixture was then stirred at ambient temperature for 3 hours and then quenched by carefully adding an excess of cold 1.0 N hydrochloric acid. The aqueous phase was then extracted with ethyl acetate. The organic material was then washed several times with water and then dried (sodium sulfate 20) and concentrated in vacuo to a solid. Chromatography (silica, chloroform) gave 8.75 g (87%) of [6-benzyloxy-2- (4-hydroxyphenyl)] benzo [b] thiophene • ·

* ··· 1 as a white solid. Sp. 212-216 ° C. H NMR

· «1: (DMSO-d 6) δ 9.70 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 ··· 25 (d, J = 2, 2 Hz, 1H), 7.51 - 7.30 (m, 8H), 7.00 (dd, J = 8.7, 2.2 Hz, 1H), 6.80 (d, J = 8.6) Hz, 2H), 5.13 (s, 2H).

: FD mass spectrometry: 331. Analysis calculated for C 21 H 16 O 2 S: C 75.88, H 4.85. Found: C, 75.64; H, 4.85.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · leave · risk send end 34 · • · 91

Example 19 [6-Benzyloxy-2- (4-methoxyphenyl)] benzo [b] thiophene

To a solution of [6-benzyloxy-2- (4-hydroxy-enenyl)] benzo [b] thiophene (8.50 g, 26.40 mmol) in 200 mL of anhydrous DMF under nitrogen pressure at ambient temperature , sodium hydride (1.66 g, 41.5 mmol) was added in small portions. After the evolution of gas was complete, iodomethane (3.25 mL, 52.18 mmol) was added dropwise. The reaction mixture was stirred for 3 hours at ambient temperature. The solvent was then removed in vacuo and the residue partitioned between water and ethyl acetate. The layers were separated and the organic phase was 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. Sp. 180-185 ° C. 1 H-NMR (DMSO-d 6) δ 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J =? · *):]. * 8.8, 2.2 Hz, 1H), 6.98 (d, 3 = 8.7 Hz, 2H), 5.13 (s, 2H), · · * ··· * 3.76 (s) , 3H). FD Mass Spectrometry: 346. Analysis calculated for C 22 H 11 CO 2 S: C 76.27, H 5.24. Found: C 76.54, · · ·: ...: 25 H 5.43.

Preparation 20: [6-Benzyloxy-2- (4-methoxy-phenyl) -3-bromo] -benzo [b] thiophene ··· ···

Bncr s · · · · · ·: ... · [6-Benzyloxy-2- (4-methoxyphenyl)] benzo [b] -thlophene (10.0 g, 28.9 mmol) was added to 200 mL of chloro . ·. : 35 Form with 10.0 g of solid sodium bicarbonate at ambient temperature. To this suspension, bromine (1.50 mL, 29.1 nunol) was added dropwise over 30 minutes as a solution in 100 mL of chloroform. After complete addition, water (200 mL) was added and the layers were separated. The organic phase 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-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene as a white solid. Sp. 146-110 ° C. 1 H-NMR (DMSO-d 6) δ 7.70 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H). , 7.19 (dd, J = 8.8, 2.2 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 3.78 ( s, 3H). FD Mass Spectrometry: 346. Analysis calculated for C22H1702SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00. Preparation 21 21 C 6 -methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] thiophene was prepared in an analogous manner.

br

20 She. JC / C ° BD

BjCCT S.V. (/ ··· Σ Yield 91%. Mp 125-127 ° C. 1 H NMR (DMSO-d 6) δ 7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, ··· *. · · 3H), 5.15 (s, 2H), 3.82 (s, 3H) FD mass spectrometry: 25,346 Analysis calculated for C 22 H 17 O 2 SBr: C 62.13, H 4.03, Found: C 62.33, H 3.93.

···; 1 · 1: Examples 33 to 34 were prepared by a method analogous to Example 28.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · to– • to · • ·

Example 33 93 [6-Benzyloxy-2- (4-methoxy-phenyl) -3-bromo] -benzo [b] thiophene (S-oxide)

Br jf y / -00153

Bno | \ —— · / o

Isolated as a yellow solid by crystallization from ethyl acetate. Sp. Mp 202-205 ° C. 1 H NMR (DMSO-d 6) δ 7.80 {d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.4) Hz, 1H), 7.47-7.32 (m, 6H), 7.10 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H) ). FD mass spectrometry: 441. Analysis calculated for C22H17703SBr: 15C 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)

Br JC ^ 3 C ~ ^ - ~ o8a ί · i h, co "^ nn?;:> ^ 'S v y li:: o ··· ♦ ♦♦ • · ·

Isolated as a yellow solid by chromatography (SiO 2, CHCl 3). Sp. 119 - 123 “C. 1 H NMR (DMSO-d 6) δ 7.73 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.5) Hz, 1H), 7.46 - 7.31 (m, 5H), 7.26 (dd, J = 8.5, 2.2 Hz, 1H), 7.18 (d, J = 8.8 Hz) , 2H), 5.16 (s,: 1 · 2H), 3.86 (s, 3H). FD mass spectrometry: 441. Analysis. Calc'd for C22H1703SBr: C, 59.87; H, 3.88. Found: a / 1 C 60.13, H 4.10.

Examples 35 to 36 were prepared by a method analogous to Example 30.

·· • 1 • · · · * · »• ·· 2 • · 94

Example 35 [6-Benzyloxy * -3- [4- [2- (1-piperidinyl) ethoxy] -phenoxy] -2- (4-raethoxyphenyl)] - benzo [b] iodo-ene (S-oxide) - ¾

O

- / \ —och3 10 ΛΛ / '-'

BdO H

o

Yellow oil. 1 H-NMR (DMSO-d 6) δ 7.76 (d, J = 2.2)

Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.44 - 7.30 (m, 5H), 7.12 (dd, J = 8.6, 2.2) Hz, 1H), 7.03 - 6.93 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 3.94 (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 spectrometry: 592.

Analysis calculated for C 35 H 35 NO 5 S; Found: 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 • · · · · · · · · · · · · 3 - 3- (4-benzyloxyphenyl). ) 3 benzo [b] thiophene- * · [* (S-oxide) * 0 Xx o 30 r7V \ _ / = ^ OBn: ·. Haccr v f.

: ·· Il ... <3 1

Yellow solid. Sp. 89 - 93 "C. 1 H-NMR

φ: * · .. (DMSO-d 6) δ 7.68 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, J J 2 2H), δ, 42 - 7.28 (m, 5H), 7.08 - 6.92 (m, 6H), 6.86 (d, ·95 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, B Hz, 2H), 2.37 - 2.34 (m, 4H), 1.45-1.31 (m, 6H). FD Mass Spectrometry: 592. Analysis calculated for C 35 H 35 NO 5 S 10.25 EtOAc: C 71.62, H 6.18, N 5 2.32, Found: C 71.32, H 5.96, N 2.71.

Examples 37-38 were prepared by a method analogous to Example 11.

Example 37 [6-Benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] -10-phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene]

Isolated in 95% overall yield from [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thio-20-phen (S-oxide). Purified by chromatography (SiO 2, 1-5% methanol / chloroform) to give a faint solid. Sp. 105 - 108 1C. 1 H NMR (DMSO-d 6) δ 7.62 (d, J = 2.2 ···

Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.30 (m, 5H), T: 7.15 (dd, J = 8.6 Hz, 1 H), 7.00-6.94 (m, 3H), 6.82 (s, O 25 4H), 5.13 (s, 2H), 3.92 (bt, J 1 5.8 Hz, 2H). ), 3.72 (s, 3H), 2.55 (bt, J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31 (m , 4H). FD mass spectrometry: 565. Analysis calculated for C 35 H 35 NO 4 S: C, 74.31; H, 6.24; N, 2.48. Found: C, 74.35; H, 6.07; N, 2.76.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 1996 · 1996 · 1996

Example 38 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene-o ^ ·

Yield 91%. Sp. Mp 106-110 ° C. 1 H-NMR (DMSO-d 6) δ 7.59 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.42 - 7.28 ( m, 5H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8

Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (bt, J = 5.8 Hz, 15 2H), 3.78 (s, 3H), 2 , 55 (bt, J = 5.8 Hz, 2H), 2.37 - 2.33 (m, 4H), 1.44 - 1.31 (m, 4H). FD mass spectrometry: 565. Analysis calculated for C 35 H 35 NO 4 S: C, 74.31; H, 6.24; N, 2.48. Found: C, 74.26; H, 6.17; N, 2.73.

Example 39 20 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-raethoxyphenyl)] benzo [b] thiophene O 25 w. A solution of [6-benzyloxy-3- [4- [2- (1- • · * * 30 piperidinyl) ethoxy] phenoxy] -2- {4-methoxyphenyl) ] benzo [b] thiophene (8.50 g, 15.0 mxnol) in 300 mL of 5: 1 ethyl • ethyl acetate / ethyl acetate, palladium on carbon (1) was added. , 50 g), ammonium formate (3.50 g, 55.6 nunol) and 30 ral ···. / Water. The resulting mixture was heated to reflux temperature. 35 and followed by thin layer chromatography. After about 3 hours, the reaction was complete and the solution was cooled to ambient temperature. The reaction was filtered through a pad of diatomaceous earth to remove the catalyst and the filtrate was concentrated in vacuo to give a solid. The conc-5 concentrate was partitioned between saturated sodium bicarbonate solution and 5% ethanol / ethyl acetate. The layers were separated and the organic phase was dried (sodium sulfate) and concentrated in vacuo. The crude product was chromatographed (silica, 1-5% methanol / chloroform) to give 6.50 g (91%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy ] -2- (4-methoxyphenyl) 3-benzo [b] thiophene as a foam which solidified after trituration in hexanes. Sp. 174-176 "C. 1 H NMR (DMSO-d 6) δ 9.77 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.07 δ (d, J * 8.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (s, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H), 3.91 (bt, 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 mass spectrometry: 475. Analysis calculated for C28 H29 NO4 S: C 70.71, H 6.15, N 2.94. 20 Observed; C, 70.46; H, 5.93; N, 2.71.

... Example 40 • · · [6-Methoxy-3- [4- (2- (1-piperidinyl) ethoxy] phenoxy · · * ··· * s] -2- (4-hydroxyphenyl)] benzo [ b] thiophene was prepared by a · · · V * method analogous to Example 39.

• · · 25 ^ ¥ O χχ o

: ***: 30 j0C / C ^ ~ 0B

··: *** Yield 88%. Sp. 147-150 ° C. 1 H-NMR (DMSO-d 6) δ: 9.72 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.48 (d, J * 8.6). δ Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 δ: 35 Hz, 1H), δ , 81 (s, 4H), 6.76 (d, J = 8.6, 2H), 3.91 (bt, · 98 J = 5.9 Hz, 2H), 3.77 (s, 3H). , 2.55 (bt, J = 5.9 Hz, 2H),

2.38 - 2.33 (m, 4H), 1.46 - 1.28 (in, 6H). FD mass spectra: 475. Analysis calculated for C 28 H 29 NO 4 S: C 70.71, H

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

Alternatively, Examples 39 and 40 can be prepared directly by hydrogenation in 90% yield of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy]] phenoxy] -2- (4-benzyloxy). siphenyl)] benzo [b] thiophene (S-oxide) and [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) ] of benzo [b] thiophene (S-oxide), the corresponding ti.

Example 41 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-raethoxyphenyl)] benzo [b] thiophene (Example 39) was converted to its hydrochloride salt in 85% yield by treatment ethyl ether / hydrogen chloride in ethyl acetate followed by crystallization from ethanol / ethyl acetate

• HC

I .. 0: T:, ···. 'S /' ... · 25 \ .V Sp. 156-160 ° C. 1 H NMR (DMSO-d 6) δ 10.28 (bs, 1H), δ: 9.85 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.25 (d , J = 2.0

Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.87 (q, JM = 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 (ro, 2H), .. 1.74 - 1.60 (ro, 5H) ), 1.36-1.29 (ro, 1H). FD Mass Spectral • ·

meters: 475. Analysis calculated for C 20 H 29 NO 4 S 1.0 HCl: C

65.68, H 5.90, N 2.73. Found: C, 65.98; H, 6.11; N, 2.64.

• • • • • • • • 99

Example 42 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride was prepared by a procedure analogous to Example 41. with. -HCl

O

Sp. 215-217 ° C. 1 H NMR (DMSO-d 5) δ 10.28 (bs, 1H), 9.80 (s, 1H), 7.52 (d, 3 = 2.2 Hz, 1H), 7.47 (d, J = 8.6 15 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.91 - 6.80 (m, 5H), 6.78 (d, J = 8.6) Hz, 2H), 4.27 (bt, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.43 - 3.34 (m, 4H), 2.97 - 2.91 (m, 2H), 1.78-1.61 (m, 5H), 1.36-1.29 (m, 1H). FD-mass spectrometry:

475. Analysis calculated for C 29 H 29 NO 4 S * 1.0 HCl: C 65.68, H

N, 2.73. Found: C, 65.87; H, 5.79; N, 2.99.

... Example 43 • · {m * [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] - • · * ··· * phenoxy] -2- (4- benzoyloxyphenyl)] benzo [b] thio ~ · · · * * * phenol hydrochloride

-S

s Ο -'- 'φ o 30 i XYy-0 - \ _ y ^ \

'-' f ~ \ _J

S s • · · j \. To a solution of Example 20 (0.50 g, 1.08 mmol) in 20: 35 mL of anhydrous tetrahydrofuran at 0 ° C was added? 100 triethylamine (1.00 mL). To this mixture was added Bentoyl chloride (0.28 L, 2.35 mmol). After stirring at 0 ° C for 2 hours, the reaction was quenched by partitioning between ethyl acetate / saturated sodium bicarbonate solution (100 mL each). The layers were separated and the organic material was 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 formed which was collected by filtration. Drying gave 390 mg (50%) of [6-benzoyloxy-3 '- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- {4-benzoyloxyphenyl)} benzo [b] thiophene hydrochloride as a white solid. as a solid. Sp. 200-204 ° C. 1 H-D (DMSO-d 6) δ 9.95 (bs, 1H), 8.18 (m, 1H), 8.16 (m, 15 2H), 8.12 (dd, J = 10.0, 2.0 Hz, 2H), 7.87 {dd, J = 7.0, 2.0 Hz, 2H), 7.78 (m, 2H), 7.64 (m, 2H), 7.42 { d, J = 7.0 Hz, 2H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (s, 4H), 4.32 (m, 2H), 3.45 (m, 4H), 2.99 (m, 2H), 1.75 (m, 5H), 1.39 (m, 1H). Analysis calculated for C 41 H 35 NO 6 S 1 1.5 HCl: 20 C 67.97, H 5.08, N 1.93. Found: C, 68.05; H, 5.24; N, 2.01.

··· * · 1 1 By the same method were prepared: ··· • »• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · · · · · · · · · 101

Example 44 [6-Ethylsulfonyloxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2- (4-ethylsulfonyloxyphenyl)] - benzo [b] thiophene hydrochloride 5

10 \ -OS (0) JEC

Yield 72%. Sp. 110-115 ° C, 1 H NMR (DMSO-d 6) δ 10.15 (bs, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 7, 15 Hz, 2H), 7.43 (m, 3H), 7.34 (dd, 3 = 9.0, 2.0 Hz, 1H), 6.97 (m, 4H), 4.31 (m, 2H) ), 3.57 (m, 4H), 3.44 (m, 4H), 2.97 (m, 2H), 1.76 (m, 5H), 1.40 (m, 7H), Analysis calculated for C31H35NOaS3 · 1 HCl: C, 54.57; H, 5.32; N, 2.05. Found: C, 54.36; H, 5.37; N, 2.05.

By the same method, using trifluoromethanesulfonic anhydride, the following was obtained: • · · *. * * Example 45 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-trifluororethanesulfonyloxyphenyl). )] - 25 benzo [b] thiophene

• · · O

30 r / = \:: - £ Λ — osojcp, ·: · \ J / .. b3cct v a • · • Il

Yield 81%. Oil. 1 H NMR (DMSO-d 6) δ 7.82 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.7! 35 Hz, 2H), 7.17 (d, J 8 8.8 Hz, 1H), 6.93 (dd, J = 8.8, 2.0 Il · 102

Hz, 1H), 6.84 (s, 4H), 3.92 (bt, J1 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-mass spectrometry; 607. Analysis calculated for C 29 H 29 NO 2 F 3 S 2: C 57.32, H 4.64, N 2.30. Found: C, 57.16; H, 4.52; N, 2.01.

Example 46 was prepared by the same methods: Example 46 3- [4- [2- (1-piperidinyl) ethoxy [phenoxy] -2- {4-benzyloxy-phenyl)] benzo [f] thiophene hydrochloride V0

Yield 85%. Sp. 190-198 "C. 1 H NMR (DMSO-d 6) δ 10.48 (br s, 1H), 8.00-8.10 (m, 2H), 7.80-8.00 (m, 20H) ), 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 gas ··· saspectrometry; 550, Analysis calculated for C34H31NO4S · 1.0 ···: HCl: C 74.29, H 5.68, N 2.55 Found: C 74.52 , 25 H 5.80, N 2.59.

•••••••••••••••••••••••••••••••••••••••••••••••••••••• · • · «• · • • 1 · • m 1 • · · • ♦ 103

Example 47 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- {4-pivaloyloxyphenyl)] benzo [b] thiophene hydrochloride »HCl

O

ao OS-Cty / O »

Yield 90%. Sp. 193-197 ° C. 1 H NMR (DMSO-d 6) δ 10.10 (br s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H). , 7.40 - 7.53 (m, 3H), 7.15 (d, J = 6.7 Hz, 15 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 mass spectrometry: 529. Analysis calculated for C 32 H 35 NO 4 S · 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, [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-butoxybenzylsulfonyloxyphenyl)] benzo [b] thiophene hydro- .. * chloride • · ·::: »hci I" 0 v '\ ä ·. · · o \ ^ —a part (o) jhbu ··· 30 • · “* Yield 85% white solid. Sp. * 98 - ···: 104 ″ C. 1 H NMR (DMSO-d 6) δ 10.20 (br s, 1H), 8.02 (d, J = 8.0 Hz, 1H), δ , 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,! ·: 35 6H), 3.00 - 3.10 (m, 2H), 1.70 - 1.95 (m, 6H), 1.40 - 1, 60 • · · • · 104

(m, 4H), 0.87 (t, J = 7.3 Hz, 3H). FD mass spectrometry: 565. Analysis calculated for C31H35NO5S2 · 1.0 HCl: C, 61.83, H

6.03, N, 2.33. Found: C, 61.55; H, 6.15; N, 2.25.

Preparation 21 21 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene.

Preparation of HjCOBjCO1-4- (methoxymethyloxy) phenyl disulfide. To a solution of 4-hydroxyphenyl disulfide (650 mg, 2.60 nunol) in 10 ml of colorless N, N-dimethylform-15 amide at 10 ° C was added sodium hydride (230 mg, 5.75 mmol at 60%). dispersion in mineral oil). After stirring for 15 minutes, chloromethyl methyl ether (0.44 mL, 5.75 mmol) was added by hand pump. The reaction mixture was warmed to ambient temperature and stirred for 0.5 to 20 hours. The mixture was partitioned between saline / ethyl acetate ... (20 mL each). The layers were separated and the aqueous »1 * 1 phase was extracted with ethyl acetate (2 x 20 mL). The organic phase was dried (sodium sulfate) and concentrated to a yellow oil (993 mg, 100%). An analytical sample of 4- (methoxymethyl-25-yloxy) phenyl disulfide was prepared by chromatography (silica, 4% ethyl acetate / hexane). 1 H-NMR (DMSO-d 6) δ 7.40 (d, J = 6.9 Hz, 4H), 7.00 (d, J =

6.9 Hz, 4H), 5.15 (s, 4H), 3.32 (s, 6H). FD Mass Spectrometer: 338. Analysis calculated for C 16 H 16 O 4 S 2: C 56.78, H

• · ·, ···. 30 5.36. Found: C, 57.08; H, 5.44.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · English

Example 49 [6-Methoxy-2- (4-methoxyphenyl) -3- (4-methoxyacetylenoxy) thiophenoxy] benzofb} thiophene

BjCOB 3CO v

XX

s jCO'O- ™ ·

HjCO ^ h - '10

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 nitrogen pressure "60" At C, n-butyllithium (3.15 mL, 5.0 15 mmol, 1.6 M solution in hexanes) was added dropwise via a hand pump. The resulting mixture was heated at -20 ° C for 10 minutes and cooled back to -60 ° C. 4- (Methoxymethyloxy) phenyl disulfide (800 mg, 2.36 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the lithium compounds and the resulting mixture was allowed to gradually warm to 0 ° C. After stirring for 20 ... minutes, the reaction was quenched with brine / ethyl acetate (50 mL in each tank). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to an oil. Chromatography (silica, 5%: ethyl acetate / hexane) gave 287 mg (27%) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy *. si3benzo [b] thiophene as a colorless oil. ^ -NMR (DMS0 ~ d6). ···. 30 d 7.59 (d, J = 8.4 Hz, 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 mass spectrometry: 438.

Analysis calculated for C CZ4HHl2Oi, S2: C 65.73, H 5.06. Found: C, 65.93; H, 5.10.

• · • · * * · · 106

Example 50 [6-Methoxy ± -2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene

To a solution of [6-methoxy ± -2- (4-methoxyphenyl) -1- (4-methoxymethyleneoxy) thiophenoxy] benzo [b] thiophene (233 mg, 0.53 mmol) in 10 mL of methanol water: tetrahydrofuran 1: 1: 2, methanesulfonic acid 15 (0.2 mL, 2.66 mmol) was added. The mixture was refluxed for a further 5 hours. After cooling to ambient temperature, the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (2x). The organic layer was washed with saturated sodium bicarbonate solution several times. The organic layer was dried (sodium sulfate) and concentrated in vacuo to give 206 mg (99%) of [6-meth ··· V1-toxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benz-: ... · so [b] thiophene as a colorless oil. 1 H-NMR (DMSO-d 6) δ 9.43: T: (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.61 (d, J 2,0 2.0 Hz, 25 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), ···: 7.02 (dd, J = 8, Δ 2.0 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H). FD Mass Spectrometry: 395. Anal. Calcd for C 22 H 17 O 3 Na: C 66.98, H 4.60. Found: C, 67.26; H, 4.78.

• • »» »» »» »» »107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107 107

Example 51 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] "2" (4-methoxyphenyl)] benzo [b 3 thiophene]

Jl jT / -1 V-OCHj

To a solution of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene (242 mg, 0.51 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 was stirred for 48 hours at ambient temperature and then partitioned between brine / ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (3x). The organic layer was dried (sodium sulfate) and concentrated in vacuo to give an oil.

Chromatography (silica, 0-2% methanol / chloroform) gave 244 mg (92%) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] -: T: thiophene as a tan oil.

: ***: 25 Example 52 • · ·. . *. A sample of [6-methoxy-3- [4- (2- (1-piperidinyl) ethoxy] thiophenyl] -2- (4-methoxyphenyl)] benzo [b] thiophene was converted to its hydrochloride salt according to the standard method. - ... in 72% yield • · · • · · • 30. ···. , t; Xl

. *. · 'S

35 jccvO— 108

Sp. 198-201 ° C. 1 H-NMR (DMSO-d 6) δ 7.63 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8 , 2 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H), 7.02 (dd, J = 8.2, 2.0 Hz, 1H), 6.92 (q, JM) = 9.0 Hz, 4H), 4.24 (bt, 2H), 3.82 δ (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, 1H). Analysis calculated for C 29 H 32 NO 3 S 2 · 1.0 HCl; C, 64.28; H, 5.95; N, 2.58. Found: C, 64.09; H, 6.08; N, 2.78.

Example 53 10 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

To a solution of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-raethoxyphenyl) benzo [b] tm-thiophene hydrochloride (160 mg, 0.29 mmol) in 15 ml of anhydrous methylene chloride at 0 ° C under nitrogen pressure was added boron tribromide (0.15 ml). The resulting dark solution ··· * was stirred for 1 hour at 0 ° C and then poured immediately into a stirred solution of ethyl acetate / saturated sodium bicarbonate solution: * · *: (50 mL each). The layers were separated and the aqueous phase was washed with ethyl acetate (3 x 30 mL). The organic phase was dried (sodium sulfate) and concentrated in vacuo. 30 to a white solid. Chromatography (silica, 0.5% methanol / chloroform) gave 91 mg · 60% (60%) of [6-hydroxy-3- (4- [2- (1 (piperidinyl) ethoxy] thiophene ··· noxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene as a white solid, mp 123-127 ° C. 1 H-NMR (DMSO-d 6) d: 35 δ, 79 (s, 1H), 9.71 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.42 · · · 109 (d, 3 = 8.9 Hz) , 1H), 7.26 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.8 HZ, 2H), 6.82-6.76 (m, 5H), 3 , 91 (t, J = 8.8 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.40 (m, 4H), 1.41 - 1.28 (m, 6 H) FD mass spectrometry: 478. Analysis calculated for C 27 H 27 NO 3 S 2: C 67.90, H 5.70, N 2.93 Found: C 68.14, H 5.84, N 2.65.

Example 54 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzotb] thiophene hydro-chloride C-HG1

S

Sp. 180-190 ° C. 1 H-NMR (DMSO-d 6) δ 9.86 (s, 1H), 9.79 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.7 20 Hz, 1H), 7.29 (d, 3 = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.86 ~ 6.81 ( m, 5H), 4.27 (m, 2H), 3.41 - 3.37 (m, 4H), 2.96 - 2.84 (m, 2H), 1.77 - 1.60 (m, 5H), 1.35 - 1.28 .1 ··. (m, 1H). FD mass spectrometry: 477. Analysis calculated for C 27 H 27 NO 3 S 2 · 2.2 HCl: G 58.13, H 5.28, N 2.51. Found: 25 C 58.11, H 5.10, N 2.61.

• ♦ **! By the same methods, the following were prepared: · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

IM

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 55 [6-Methoxy-3- [4- [2- (1-pyrrolodinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride • ac

S

10 JJÖ ~ O ~ 0C''1

HjCCT ^ S> - <

Sp. 215-218 "C. 1 H-NMR (DMSO-d 6) δ 7.61 - 7.58 (m, 3H), 7.52 (d, J - 8.8 Hz, 1H), 7.04 - 6.95 (in, 5H) , 6.86 (d, J = 8.8 Hz, 2H), 4.22 (bt, 2H), 3.79 (s, 3H), 3.76 (s, 15 3H), 3.47 - 3 , 42 (m, 4H), 3.01 (m, 2H), 1.94-1.80 (m, 4H). FD mass spectrometry: 491. Analysis calculated for C 29 H 29 N 3 O 2 S 1.0 HCl: C 63.67, H 5.73, N 2.65, Found: C 63.47, H 5.78, N 2.65.

Example 56 20 [6-Hydroxy-3- [4- [2- (1-pyrrolodinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene * · · • • · * ··· * »HCl 1 - σ '" Ό ... s jCcH> ™ • · · 30 * “. · * Mp 137-140 ° C (dec). Hi-NMR (DMSO-d6) d 9.86 (s, 1H), 9.80 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.7 Hz, 1H ), 7.29 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.87-6.81 (m, 5H), 4.21 (bt, 2H), 3.53 - 3.41

«M

; 35 (m, 4H), 3.01 (m, 2H), 1.95-1.82 (m, 4H). FD Mass- • ·· • ·

EI spectrometry: 464. Analysis calculated for C 26 H 28 NO 3 S 2 · 1.0 HCl: C 62.45, H 5.24, N 2.60. Found: C, 62.36; H, 5.37; N, 2.61.

Example 57 6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene hydrochloride was prepared from the product of Example 45 by triflate hydrogenolysis as described in Example 58 below.

• BCl o 15.

H3ecr ^ s '-'

Sp. 187-195 ° C. 1 H-NMR (DMSO-d 6) 7.66 (d, J = 2.8 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.39 (t, J = 7). 5 Hz, 2H), 7.28 (m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.91 (dd, 20 J = 8.8, 2.0 Hz, 1H ), 6.89 (s, 4H), 4.23 {bt, J (5.7 Hz, ... 2H), 3.79 (s, 3H), 3.45 - 3.38 (m, 4H). ), 2.98 (m, 2H), λ max 1.77-1.61 (m, 5H), 1.31 (m, 1H). FD-mass spectrometry:

460. Analysis calculated for C 28 H 29 NO 3 S · 1.0 H 2 O: C 67.80, H

V; 6.10, N, 2.84. Found: C, 67.62; H, 5.89; N, 2.67.

• * »• • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

• M

•••••••••••••••••••••••••••••••• 112

Example 58

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

V-Xx

O

io ao jOC / -

To a solution of 6-hydroxy-3- (4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzophb] -thiophene hydrochloride (5.00 g, 10 0 mmol) in 100 mL of anhydrous methylene chloride at 0 ° C under nitrogen pressure, add -15 mL of triethylamine (8.38 mL, 60.0 mmol) followed by trifluoromethanesulfonic anhydride (1.69 mL, 10.0 mmol). the mixture was allowed to slowly warm to room temperature and stirred for 1.5 h, then quenched by pouring 200 mL of saturated sodium bicarbonate solution, then the aqueous phase was extracted with ethyl acetate (3 x 100 mL). Chromatography (0-3% methanol / chloroform) an- ··· · * · * · gave 2.82 g (39%) of 6-trifluoromethanesulfonate-3- [4- [2-. ···. 25 (1-piperidinyl) ethoxy] phenoxy] -2- (4-trifluoromethanesulfonylphenyl) benzo [b] thiophene, 1.82 g (39%) · · · 6-trifluoro -m ethanesulfonate 3- [4- [2- (1-piperidinyl) -4,5-ethoxy] phenoxy] -2- (4-phenyl)] benzo [b] thiophene; and 3- [4-. #, [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-fluorophenyl) methanesulfonylphenyl]] benzo [b] thiophene 1: 1 mixture and • · * ... * 1.48 g (36%) of the recovered starting material as free base. Sena.

. · **. To a solution of the monotroph plate in a ··· 1: 1 mixture of derivatives (0.50 g, 0.84 mmol) in 60 mL · 35 mL of ethanol-ethyl acetate (5: 1) was added triethyl • · ·

• M

• · 113 liamines (2.0 mL) and 5% palladium on carbon (0.50 g). The resulting mixture was hydrogenated at 40 psi for two hours. The mixture was then filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated to an oil. The resulting mixture of monohydroxy derivatives-5 was dissolved in ethyl acetate from which 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene was precipitated. The filtrate consisted of a 4: 1 mixture of monohydroxy derivatives with 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene 10 as the major component. The filtrate was concentrated in vacuo and the resulting solid was dissolved in a minimum amount of ethyl acetate and treated with ethyl ether / hydrochloric acid. The resulting solid was recrystallized from ethanol to give 69 mg (18%) of isomerically pure 6-hydroxy-3- [4- [2- (1-piperidin-15-ridinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene -hydrokloridla. Sp. Mp 217-219 ° C. 1 H NMR (DMSO-d 6) δ 9.87 (s, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.39-7.26 (m, 4H), 7.10 (d, J = 8.6 Hz, 1H), 6.89 (s, 4H), 6.78 (dd, J = 8.6, 2.0 Hz, 1H), 4.22 (bt, 2H) , 3.39-3.37 (m, 4H), 2.97 -20 2.90 (m, 2H), 1.74-1.60 (m, 5H), 1.39 (m, 1H). FD mass spectroscopy: 446. Analysis calculated for C27H27NO3S 1.0 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 prepared by derivatizing 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-oxide) • 1 ·. ···. 30 was prepared as described in [6-methoxy-3- [4- (2- (1-piperidin-1-yl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [1]: [b] thiophene (S-oxide) (Example 30).

• · · · · · · · · · 2 · · 114

Cr-Q

O

5 λΌ ^ Ο-οοη * ° 11 ο

Yellow oil. 1 H NMR (DMSO-d 6) δ 7.69 (d, J = 2.0 Hz, 1H), 7.67 <d, J = 8.6 Hz, 2H), 7.09 - 6.99 (m , 5H), δ 6.96-6.87 (m, 3H), 4.76 (septet, J * 6.0 Hz, 1H), 3.99 (bt, J = 6.0 Hz, 2H), 3.78 (s, 3H), 2.61 (bt, J = 6.0 Hz, 2H), 2.44-2.37 (m, 4H), 1.53-1.43 (m, 4H). , 1.40-1.32 (ra, 2H), 1.29 (d, J * 6.0 Hz, 6H). FD mass spectrometry: 533. Analysis calculated for C 31 H 35 NO 5 S-0.67 H 2 O: C 68.23, 15 H 6.71, N 2.57. Found: C, 67.90; H, 6.31; N, 2.53.

[6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride was prepared as described in [6-methoxy-3- [ 4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo-20 [b] thiophene (Example 32).

• ··., Ä.

C.HCI

j:.: O

* ·. ·· 25 j Λ li - £ V-O CH3 oAAs7 V /: T: Sp. 168-170 ° C. 1 H-NMR (DMSO-d 6) δ 10.37 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 1.3 Hz, 1H). , 7.12 · · · (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H,, 6.92 - 6.85 (bb SH), 4 , 64 (septet, J = 6.0 Hz, 1H), 4.28 (bt, J = **: * 6.0 Hz, 2H), 3.72 (s, 3H), 3.44-3 , 37 (m, 4H), 2.95 - 2.89 (in, 2H), 1.73 - 1.60 (m, 5H), 1.36 - 1.28 (m, 1H), 35 L, 25 (d, J = 6.0 Hz, 6H). FD mass spectrum analysis: 517. Analysis 115 calculated for C 31 H 35 NO 4 S · HCl: C 67.19, H 6.55, N 2.53 Found: C 67 , 15, H 6.29, N 2.62.

[6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydro-5 chloride was converted to C6-hydroxy-3- [4- [2 - (1-piperidinyl) -ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene by treatment with 2-0 equivalents of BC13 at 0-10 ° C in anhydrous dichloromethane (methyl ether was not cleaved under these conditions).

10 Test Method

General, manufacturing method

In the method illustrative examples, a post-menopausal model was used to determine the effects of different treatments on circulating lipids.

Female Sprague Dawley rats (weighing 200 to 225 g), 75 days old, were obtained from Charles River Laboratory (Portage, MI). The animals were either bilaterally ovariectomized (OVX) or subjected to Sham surgery on Charles River Laborato-20 and then removed one week later. When the rats arrived, they were housed in metal cages in groups of three or four · · · · cages and received food ad libitum (cal: [**: serum concentration about 0.5%) and water for one week. Room: * · *: The temperature was maintained at 22.2 ° C + 1.7 ° C relatively. ***. 25 with a minimum humidity of 40%. Light periods in a room with • · ·. . ·. floods for 12 hours of light and 12 hours of darkness.

• · ·

Dosage, tissue collection. After a one week adaptation period (i.e., two weeks after OVX) ... the daily dose of the test compound was started. 17a-Ethyl • · · **] # * 30 Nylestradiol or test compound was administered orally, unless otherwise stated, as a 1% carboxymethylcellulose suspension or dissolved in 20% cyclodextrin; ***; so. The animals received doses daily for four days.

• · · .. * After the dosing period, the animals were weighed and anesthetized • · “35 ketamine? xylazine (2: 1, v: v) mixture and water were collected by heart injection. The animals were then sacrificed by choking with CO 2, the uterus was removed by a midline opening, and the weight of the womb was determined.

Cholesterol Analysis. Blood samples were allowed to clot at room temperature for two hours and serum was obtained after centrifugation for 10 minutes at 3000 rpm. Serum cholesterol was determined using the Boehringer Mannheim Diagnostics High Resolution Cholesterol Assay. Cholesterol was rapidly oxidized to cholest-4-en-3-one and hydrogen-10 peroxide. Hydrogen peroxide was then reacted with phenol and 4-aminophenazone in the presence of peroxidase to give the p-quinone imine dye, which was spectrophotometrically interpreted at 500 nm. Cholesterol levels were then calculated relative to the standard curve. The entire experiment was programmed using a Biomek Automated Workstation.

Uterine eosinophilic peroxidase (EPO) assay. The uterus was maintained at 4 ° C until enzymatic analysis. The uterus was then homogenized in 50 volumes of 50 mM Tris buffer (pH 8.0) containing 0.005% Triton 20 X-100. After the addition of 0.01% hydrogen peroxide and 10 mM O-Phenylenediamine (final concentrations), the increase in absorbance for one minute at 450 nm määrit * ··· 1 nm was determined. The presence of eosinophils in the uterus is a sign of the estrogenic activity of ··· ·. ·. The maximum speed of 15 ··· every 25 seconds was determined relative to the linear portion of the original reactance: # i1J.

The compound Source. 17? -Ethynyl estradiol was obtained from Sigma Chemical Co., St. Louis, MO.

Effect of compounds of formula I on serum cholesterol ···. Determination of 30 lineage and agonist / non-agonist activity ··· ** The results in Table 1 represent comparative results between • ovarian rats and rats treated with 17a-ethynylestradiol (EE, oral estrogen form) and rats treated with certain compounds of this invention. Although EE2 caused a decrease in serum cholesterol when administered orally at 0.1 rag / kg / day, it also induced stimulation of the uterus with the uterine weight of EE2 being essentially higher than that of the non-ovarian test animals. This uterine response to estrogen is well known in the art.

The compounds of the present invention not only generally lower serum cholesterol compared to non-ovarian control animals, but the uterine weight increased only to a minimal extent or slightly decreased in the testing of compounds of the formula. Compared to estrogen compounds known in the art, the benefit of lowering serum cholesterol without adversely affecting uterine weight is quite rare and desirable.

As seen in the following results, estrogenicity was also determined by evaluating the adverse effect of eosinophil absorption on the uterus. The compounds of the present invention did not induce any increase in the number of eosinophils observed in the basal tissue of ovarian rats, whereas estradiol caused a significant expected increase in eosinophil absorption.

• · »**! / The results in Table 1 illustrate the reaction / treatment of 5-6 rats • · '···'.

I i i i i i i i i i i i i i i i i i ·•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• () (Table) 1 118

Dose Uterine Weight Uterine EPO Serum Cholesterol

Compound mg / kg (% increase vs. OVX) (V. max. <% Reduction vs. OVX) EE2 0.1 229.2 308.1 94.8 5

Example 3 0.01 29.1 1.8 50.6 0.1 55.4 4.8 47.8 1.0 61.9 5.4 49.2

Example 4 0.1 33.2 3.9 53.7 10 1.0 35.6 4.8 62.1 10.0 34; 7 3.0 65.3

Example 5 0.1 66.7 7.2 67.2 1.0 106.9 54.6 67.7 25 10.0 109.8 59.4 60.2

Example 7 0.1 32.0 4.8 56.2 1.0 44.3 4.5 42.6 5.0 41.6 4.8 29.5 7Ω 'Example 10 0.1 19.7 12.0 50.2 1.0 18.4 17 7 59.0 • · · 1 10.0 13, 3 4.8 38.9 «· • · · · ·: Example 19 0.01 11, 4 2, J 25.1 · /”: 25 ° »a 24.9 2.4 45.3: · /: M 2V 3.6 53.6 • · · · · · · 1’ 2 1 Example 20 0.01 16.9 0.9 29, 4 0.05 40.9 30 35.9 • · · 'f: 0.1 30.6 3.0 58.7 ··· 30 • · • ··

Example 21 0.01 21.0 1.2 26.8 • 3 0.1 24.8 4.8 47.5 110 51.4 9.3 54/4 • · · · · · · · 3 • · 119

Table 1 (continued)

Dose Uterine Weight Uterine EPO Serum Cholesterol

Compound mg / kg (% increase vs. OVX) (V. max. <% Reduction vs. OVX)

Example 23 0.01 21.6 3.3 36.2 5 0.1 33.5 84.3 47.2 1.0 148.9 150.6 66.1

Example 24 0.01 9.2 3.6 23.7 0.1 18.2 0.9 46.4 1.0 81.0 29.4 79.3 10

Example 25 0, 01 5.5 3.0 13.1 0.1 16.7 3.3 67.6 1.0 96.6 36.0 73.9

Example 26 0.01 14.0 4.8 29.0 0.1 81.0 29.1 45.2 1.0 117.1 175.1 62.7

Example 27 o, 01 2.2 3.3 12.2 0.1 49.2 4.8 50.8 20 1.0 86.4 52.5 76.5 • · · * .1 1 Example 43 0, 01 0.0 3.3 9.2

0.1 17.2 4.8 43, B

* 1.0 6, o 39.4 • · · 25 1 Example 44 0.01 43.8 3.6 12.6 * · 1 · 1 0.1 80.5 88.5 43 .8: 1.0 74.8 94.5 67.4

Example 53 o, l 40.6 0.9 62.7 ···. 30 1.0 24.1 1 3 57.5 _10,0_32,0_4J3_5B, 7_ • · ..... '' ...... '' '"4 .....- Γ-ΓΓΓΓ-. In addition to the claimed advantages of the compounds of the present invention, especially when compared to estradiol, the preceding results clearly show: that the compounds of formula I are not estrogen-mimicking compounds, and no toxicological effects were observed.

Osteoporosis test method

Following the general experimental protocol infra, rats were treated daily for 35 days (6 rats / treatment group) and killed by carbon dioxide suppression for 36 days-10. The 35 day period was sufficient to achieve maximal decrease in bone density as determined herein. At slaughter, the uterus was removed, non-body tissue was removed, and fluids were removed prior to determination of wet weight to determine estrogen deficiency associated with complete ovarian removal. The uterine weight was routinely reduced by about 75% in response to ovarian removal. The uterus was then placed in a 10% neutral buffered formalin solution, followed by tissue analysis.

The right femur was removed and x-rayed ... using the Image Analysis Program (NIH image) from the outer bone growth area. The tibia of these animals was analyzed by quantitative computer tomography.

In accordance with the foregoing methods, the compounds of this invention and ethynyl estradiol (EE2) were administered orally in 20% hydroxypropyl? -Cyclodextrin to an

»M

ί for animals. The data in the following Tables 2 and 3 for the femoral bone area are the results of treatment · 1 · 1; Compound of Formula I Compared to Intact and Ovarian ···. 30 animal animals. Results are presented as mean + • · · tm · standard error of the mean.

• · • · ·

• M

• · • · · · · · ·

• M

· · · · · · · ·

Table 2 121

Compound / Treatment Armos / kg Outer femoral growth medium (5 gray reading of X-ray analysis)

Sham (20% cyclodextrin - 27/2 ± 6.0)

Removed Ovarian Scooter 10 (20% Cyclodextrin - 8.1 ± 1.8 EE2 0/1 mg 11.5 ± 2.9 *

Example 9 0.1 mg 14.7 ± 1.9 1.0 mg 15.0 ± 3.51 15 10.0 mg 15.3 ± 4.0 * * P <= 0.05 Two-tailed Student's T test raw results

Table 3 20 Compound / Treatment Dose / kg Outer femoral growth medium (Gray reading of X-ray imaging) V: Share (20% Cyclo-11 '*: 25 Dextrin - 31.1 + 6.3: 1 · *: Egg deleted -; ***: serial control ···. (20% cyclodextrin - 6.2 + 1.4 30 EE2 0.1 mg 17.8 ± 3.5 ... Example 10 0.1 mg 15 , 3 ± 3.0 • · · *:!. * 1.0 mg 15.2 ± 3.7: ··· * ’3.0 mg 18.5 ± 3.2 *

Example 24 0.1 mg 18.3 ± 2.6 * · 35 1.0 mg 19.6 ± 2.3 * ./ 3.0 mg 17.1 ± 5.5 * · *. * P <= 0.05 from the untreated two-tailed Student's T-test 122

In summary, ovariectomy of experimental animals caused a significant reduction in femoral density compared to vehicle-treated controls. Orally administered ethynyl estradiol (EEa) prevented this loss, but the risk of uterine excitation in this treatment is always present * The compounds of this invention also generally inhibited bone loss, depending on dose. Accordingly, the compounds of this invention are useful in the treatment of postmenopausal syndrome, particularly osteoporosis.

MCF-7 Proliferation Assay MCF-7 Breast Cancer Cells (ATCC HTB 22) were maintained in MEM (Minimum Essential Medium, Phenol Red, Sigma, St. Louis, MO) supplemented with 10% to 10% fetal bovine serum (FBS) (vol / vol), L-glutamine (2 mM), sodium pyruvate (1 mM), HEPES {(N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid] mM}, non-essential amino acids and bovine insulin (1 pg / ml) (medium) 10 days prior to experiment 20 MCF-7 cells were supplemented with fetal bovine serum (DCC-FBS) ... purified with 10% dextran-coated with carbon to replace 10% FBS to deplete steroid-depleted stores • MCF-7 cells were removed from the flasks using cell dissociation fluid (Ca ++ / Mg ++ ···

* ... · 25 free HBSS (phenol red-free) supplemented with 10 mM

HEPES and 2 mM EDTA). Cells were washed twice with test medium and adjusted to 80,000 cells / ml. about 100 mL (8,000 cells) was added to flat-bottomed microplate wells; silicon (Costar 3596) and incubated at 37 ° C in 5% CO 2 **. 30 hours in a humidified incubator for 48 hours to allow cell binding and • · ··· post-transplantation.

• ·: ** Serial dilutions of drugs or DMSO, as solvent control • · · * ... * was prepared in assay medium and 50 ml was transferred · * · .. triplicate into micro cultures followed by 50 ml of assay medium *. ml. At 48 ° C for an additional 48 hours at 37 ° C in a 5% CO 2 humidified incubator, microcultures were pulsed with tritiated thymidine (1 µCi / well) for 4 hours. The cultures were treated by cooling at -70 ° C for 24 hours, followed by thawing and recovery of the micro cultures using a Skatro semiautomatic cell harvester. Samples were counted by liquid scintillation analysis using a Wallac BetaPlace b counter. The results shown in Table 4 below show the IC50 values for certain compounds of this invention.

10

Table 4

Compound ICSft nM

Example 3 4.0

Example 10 2.00 Example 19 0.028

Example 21 0.05

Example 23 0.08

Example 53 Inhibition of Breast Tumor Induced by 0.28 DMBA; 11a ... Estrogen-dependent breast tumors were induced in female Sprague-Dawley rats obtained from Harlan Industries, Indianapolis, Indiana. At approximately 55 days, rats received a single oral dose of 20 mg of 7,12-dimethylbenz [a] anthracene (DMBA).

:.:. About six weeks after DMBA administration, mammary glands were manually palpated weekly to detect tumors. Whenever one or more tumors occurred, each; the largest and smallest diameter of the tumor were determined in meters · 1 ·. 30, the assays were recorded and the animal was selected for the experiment. Thereafter, an attempt was made to · · ί 2 uniformly distribute the different tumor sizes in the treated and

«M

· ... · roll groups so that the average tumor sizes were evenly distributed between these test groups.

• · · · • • »• · ♦ 2 • · 124

The control and experimental groups each had 5-9 animals.

Compounds of formula I were administered either by intraperitoneal injection in 2% acacia or orally.

The compounds for oral administration were either dissolved or suspended in 0.2 of any corn oil. Each treatment, including acacia and corn oil control treatments, was performed once daily for each test animal. After initial tumor assay and selection of test animals, 10 tumors were measured weekly by the above method. The treatment and measurement of the animals continued for 3-5 weeks at which time the final tumor areas were determined. For each compound and control treatment, the mean change in tumor area was determined.

15 Uterine Fibrosis Testing Procedures

Experiment 1 3-20 women with uterine fibrosis were administered a compound of the present invention. The amount of compound administered was from 0.1 to 1000 mg / day and the administration time was three months.

Women were observed during the administration period and always until: · l., One month after stopping administration:

H1 to find out the uterine fibroids.

** Experiment 2 ♦ ·· · · * ··. * 25 The same procedure as in Experiment 1 was used except that the administration period was 6 months.

Experiment 3 The same procedure as in Experiment 1 was used except that the administration period was one year.

. ···. 30 Experiment 4 • · ♦ ·· • A. Induction of connective tissue tumors in guinea pigs ··! ** Prolonged estrogen stimulation was used to induce smooth M · muscle tumor in sexually mature female. you guinea pigs. The animals were given estradiol 3-5 times

• M

. 35 weeks by injection for 2-4 months or until tumors • ♦ * • · 125 were formed. The treatments consisted of daily administration of a compound or adjuvant of the invention for 3 to 16 weeks and then the animals were sacrificed and the uterus was harvested and analyzed for tumor regression.

B. Implantation of human uterine connective tissue in nude mice

Human smooth muscle tumor tissue was implanted into the peritoneal cavity or uterine muscle layer of mature castrated female nude mice, Exterior estrogen was administered to induce growth of tissue culture. In some cases, harvested tumor cells were cultured in vitro before implantation. The treatment consisting of administering a compound or excipient of the present invention was performed by gastric lavage daily for 3 to 16 weeks and the grafts were removed and growth or regression was measured. At the time of killing, the uterus was recovered to determine the condition of the organ.

Experiment 5 A. Tissue from human uterine connective tissue tumors was harvested and maintained as primary non-transformed cultures in vitro. Surgical specimens were extruded through a sterile screen or strainer or alternatively • · · disassembled into small portions of surrounding tissue to obtain a single cell suspension. The cells · 25 were maintained in nutrient medium containing 10% serum and antibiotics. Growth rates in the presence or absence of estrogen: 1 · 1 · without it were determined. The ability of cells to produce complement component C3 and their response to growth factors and growth hormone was determined. The proliferation reaction of in vitro cultures was determined after treatment with progestins, GnRH, a compound of the present invention and excipient.

• ·: 1 ·· Steroid hormone receptor levels were determined weekly ···: .. # Σ to determine if important cellular properties are maintained: ·. neet in vitro. Tissues of 5-25 patients were used.

• ♦ · ♦ • · ♦ • ♦ · • ♦ 126

Activity in at least one of the preceding experiments of the present invention demonstrates efficacy in the treatment of uterine fibrosis.

Endometriosis Test Method 5 In tests 1 and 2, the effects of the compounds of this invention on the growth of implanted endometrial tissue after 14 days and 21 days may be investigated.

Experiment 1 12 to 30 adult CD female rats 10 were used as experimental animals. They were divided into three equal groups. The sheep cycle of all animals was followed. The day before the ridge, each female was subjected to surgery. The females in each group were removed from the uterus, cut into small squares, and the squares were sewn loosely at different locations near the mesenteric blood flow. In addition, females in Group 2 had their ovaries removed.

After the day after surgery, animals in Groups 1 and 2 received intraperitoneal injections of water on day fourteen, while animals in Group 3 received 1.0 mg of a compound of this invention / kg body weight per day for a continuous period of time. After 14 days of treatment, each female was killed and endometrial tissue cultures, adrenal glands, residual uterus and ovaries were preserved, removed, and prepared for histoplasty. ·: ...: 25 for logical research. Ovaries and Adrenal Glands J.j .: Weighed.

Experiment 2 12 to 30 adult CD female rats were used as experimental animals. They were divided into two equal sizes. 30 groups. The sheep cycle of all animals was followed. On the previous day, each female underwent surgery.

• ·: · * The uterus was removed from the females in each group, cut into small squares, and the stitches were loosely sutured at various sites near the mesenteric blood flow. About 50 days ·. : 35 males after surgery, Group 1 animals received intraperitoneal injections of water for 21 days, whereas Group 2 animals received 1.0 mg of a compound of this invention / kg body weight for a similar period of time. At 21 days post-treatment, each female was sacrificed and endo-5 metric tissue cultures and adrenal glands were removed and weighed. Tissue cultures were monitored as growth indicators. The cycle of Kiima was followed.

Experiment 3 A. Surgical induction of endometriosis Endometrial tissue self-grafts were used to induce endometriosis in rats and / or rabbits. Mature females underwent biliary ovariectomy and estrogen was administered externally, thereby producing a specific and constant hormone-15 level. Autologous endometrial tissue was implanted into the peritoneum of 5-150 animals and estrogen was administered to induce tissue culture growth. In treatment, the compounds of this invention were administered by gastric lavage daily for 3 to 16 weeks and the grafts were removed and growth or regression was determined. At killing, the intact ... uterine horn was recovered to determine the endometric state.

B. · Implantation of Human Endometrial Tissue • · · · · · * * in Hairless Mice ··· · ... · 25 Tissue from Human Endometrial Injury Area «: Implanted Female Castrated Female Hair::: in the peritoneal cavity of nude mice. The external estrogen gene was administered to induce growth of tissue culture. In some cases, the recovered tumor cells are lysed ···. 30 in vitro before implantation. A treatment consisting of administering a compound or excipient of the present invention was performed by gastric lavage daily for 3 to 16 weeks, and the hen and grafts were removed and growth or regression occurred. * · Φ> was tatted. At the time of the killing, the uterus was recovered by an organ ·. : 35 to determine the status of the men.

• · ♦ • · 128

Experiment 4 A. Tissue from the human endometrial lesion area was harvested and maintained as primary non-transformed cultures in vitro. Surgical specimens were sputtered through a sterile screen or strainer or alternatively dissected in small portions of surrounding tissue to obtain a single cell suspension. The cells were maintained in nutrient medium containing 10% serum and antibiotics. Growth rates in the presence or absence of estrogen were determined. The ability of cells to produce complement component C3 and their response to growth factors and growth hormone was determined. The in vitro culture proliferation reaction was determined after treatment with progestins, GnRH, a compound of the present invention and excipient. Steroid hormone receptor levels were determined weekly to determine whether important cellular properties were maintained in vitro. Tissues of 5-25 patients were used.

Activity in at least one of the preceding assays of this invention indicates that the compounds of this invention are useful in the treatment of endometriosis. The present invention also relates to a method for relieving postmenopausal syndrome in a woman comprising administering a compound of formula I and additionally administering to the woman an effective amount of estrogen or progestin. These treatments are particularly useful in the treatment of osteoporosis and in lowering serum cholesterol, since the patient benefits from the benefits of the pharmaceutical agent while the compounds of this invention inhibit the undesirable side effects of estrogen and progestin. The combination of these ···. The activity of telemedicine therapy in any menopause menstrual • • infrared demonstrates that the treatment combination is useful in alleviating postmenopausal syndromes in women.

There are various forms of estrogen and progestin. : Available from 35 balls. Estrogen-based substances include, for example, ethynyl estrogen (0.01-0.03 mg / day), mestranol (0.05-0.15 mg / day) and conjugated estrogen hormones such as Premarin * (Wyeth-). Ayerst; 0.3-2.5 mg / day). Frogestin-based agents include, for example, 5 medroxyprogesterone such as Provera * (Upjohn; 2.5-10 mg / day), norethylnodrel (1.0-10.0 mg / day) and nonetnin drone (0.5-2.0 mg / day). day). The preferred estrogen based compound is Premarin and norethylnodrel and norethindrone are preferred progestin based agents.

The method of administering each estrogen and progestin based agent is consistent with what is known in the art. In most of the methods of this invention, the compounds of Formula I are administered continuously, 1 to 3 times daily. However, cyclic therapy may be particularly useful in the treatment of endometriosis or may be used during acute pain episodes. In the case of restenosis, treatment can be performed for short periods (1-6 months) following medical procedures such as re-shaping the blood vessels.

As used herein, the term "effective amount" means an amount of a compound of this invention capable of ameliorating the symptoms of the various pathological diseases described herein. The specific dose of the compound of this invention to be administered will, of course, be determined depending upon the particular circumstances of the case, e.g., the compound administered, the route of administration, the condition of the patient and the subject being treated. pathological condition. The usual daily dose contains a non-toxic dose of the compound of this invention from about 5 mg to about 600 mg / day. Cheap daily ···. The daily dose is usually from about 15 mg to about 80 mg / day.

The compounds of this invention may be administered by a variety of routes, including oral, rectal, and oral administration. subcutaneous, transdermal, intravenous, intramuscular ·. : 35 Inner or Nasal Route. These compounds are preferably formulated prior to a dosage form selected by the physician in charge. Thus, another object of the present invention is a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally containing an effective amount of estrogen or progestin and a pharmaceutically acceptable carrier, diluent or excipient.

The total amount of active ingredients in such formulations is from 0.1 to 99.9% by weight of the formulation. "Pharmaceutically acceptable" means that the carrier, diluent, excipients and salt must be compatible with the other ingredients of the formulation and not deleterious to the patient.

The pharmaceutical formulations of the present invention may be prepared by methods known in the art and from readily available ingredients. For example, compounds of Formula I, with or without an estrogen or progestin compound, may be formulated with common excipients, diluents, or carriers ... and form into tablets, capsules, suspensions, powder, · · · * · * and the like. Examples of fillers, diluents, and carriers suitable for such formulations include the following: fillers such as starch, sugar, mannitol, and silica derivatives; binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate? • · ·. ···. Agents for retarding dissolution, such as paraffin, re- sorption accelerators, such as quaternary anunonium compounds; surfactants, such as cetyl alcohol, glycerol, • ... · serol monostearate; adsorbing carriers such as kaolin and bentonite; and lubricants such as talc, bleach and magnesium stearate and solid polyethyl glycols.

The compounds may be formulated as elixirs or solutions for standard oral administration or as solutions for parenteral administration, e.g., intramuscular, subcutaneous or intravenous. In addition, the compounds are well suited as formulations for sustained release and the like. Formulations may be such that they release the active ingredient only, or preferably, at a specific physiological site, possibly over a period of time. Coatings, capsules, and protective matrices may be made, for example, of polymeric substances or waxes.

Compounds of formula I, alone or in combination with a pharmaceutical agent of this invention, are usually administered in a preferred formulation. The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.

20 Formulations

In the following formulations, "active ingredient" V 1 represents a compound of formula I or a salt or solvate thereof.

···: .ϊ: Formulation 1: Gelatin Capsules: 25 Hard gelatin capsules are prepared using:; 1: Ingredient Quantity (mg / capsule) .1ί1. Active ingredient 0.1-1,000 • · · 'Starch NF 0-650 Starch powder 0-650 • · · 30 Silica liquid 350 centistokes 0-15 • · · · *! ic spread.

• · ·

The tablet formulation is prepared using the following ingredients: 132

Formulation 2: Tablets

Ingredient Amount (mg / tabletl)

Active ingredient 2.5-1,000

Cellulose, fine crystalline 200 - 650 5 Silica 10 - 650

Stearic acid 5-15

The ingredients are mixed and compressed into tablets. Alternatively, tablets each containing 2.5 to 1000 g of the active compound are prepared as follows:

Formulation 3: Tablets

Ingredient Amount (mg / tablet)

Active ingredient 25-1 000 Starch 45 15 Cellulose, fine crystalline 35

Polyvinylpyrrolidone 4 (as a 10% solution in water)

Sodium carboxymethylcellulose 4.5

Magnesium Stearate 0.5 20 Talc 1 ... The active ingredient, starch, and cellulose are passed through a No. 45 mesh U, S. sieve and thoroughly mixed, the polyvinylpyrrolidone solution is mixed with the powder obtained. which then pass through a 14 mesh US sieve. The granules so formed are dried at 50-60 ° C and allowed to pass through a No. 18 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate and talc, previously allowed to pass through a No. 60 U.S sieve, are added .1 ···. 30 then granulated, which, after mixing, are compressed in a tablet machine to give tablets.

Suspensions, each containing 0.1-1000 mg ··· medicine / 5 ml dose, are prepared as follows:

Formulation 4: Suspension

Component Amount (mg / 5 ml)

The active ingredient is 0.1-1000 mg

Sodium carboxymethylcellulose 50 mg 5 Syrup 1.25 mg

Benzoic acid solution 0.10 ml

Flavor q.v.

Dye q.v.

Purified Water to 5ml 10 The drug is passed through a No. 45 mesh U.S. sieve and mixed with sodium carboxymethylcellulose and syrup to give a smooth paste. The benzoic acid solution, flavor and coloring agent are diluted with a little water and added with stirring. Sufficient water is added to provide the required volume.

Prepare an aerosol solution containing the following ingredients:

Formulation 5: Aerosol

Ingredient Quantity (% by weight) 20 Active ingredient 0.25

Ethanol 25.75 Propellant 22 (Chlorofluoromethane) 70.00 ···

The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant gas 22, cooled to a temperature of 30 ° C and transferred to a filling device. Required: The amount is then fed into a stainless steel tank and diluted with the remaining propellant gas. The valve units are then • placed in the container.

The suppositories are prepared as follows:. 30 Formulation 6: Suppositories • · [· * Ingredient Quantity (mg / suppository): '** Active ingredient 250 ···

Saturated fatty acid glycerides 2000; The active ingredient is allowed to pass through No. 60 mesh • ··. ·. : 35 through a U.S. sieve and suspended in saturated fatty acid glycerides, previously thawed using a minimum amount of heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

5 The intravenous formulation is prepared as follows:

Formulation 7: Intravenous solution Component Quantity

Active ingredient 50 mg 10 Isotonic saline 1000 ml

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

Formulation 8: Combination capsule I Component Quantity (mg / capsule) 15 Active ingredient 50

Premarin 1

Avicel pH 101 50 Starch 1500 117.50

Silicone Oil 2 20 Tween 80 0.50

Cab-O-Sil 0.25 • · · # · ·

'·' 1 Formulation 9; Compound capsule II

• · ·

Component Quantity (mg / capsule) ··· V: Active ingredient 50 25 Norethylnodrel 5: Avicel pH 101 82.50 • · · Starch 1500 90

Silicone oil 2

Tween 80 0.50 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ● ● ● ● ● ● • • • • • • • · 135

Formulation 10: Combination tablet Ingredient amount (mg / capsule)

Active ingredient

Premarin 1 5 Cornstarch NF 50

Povidone, K29-32 6

Avicel pH 101 41.50

Avicel pH 102 136.50

Crospovidone XL10 2.50 10 Magnesium stearate 0.50

Cab-0-Sil 0.50 • · · * «« • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·’s {under fast back 1 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · · · · · · ·

Claims (22)

136 Patents and Inventions A compound of formula I wherein R 1 is -H, -OH, -O (C 1-4 alkyl), -OCOC 6 H 5, -OCO (C 1-6 alkyl), or -OSO 2 (C 1-6 alkyl); R 2 is -H, -OH, -O (C 1-4 alkyl), -OCOC 6 H 5, -OCO (C 1-6 alkyl), -OSO 2 (C 2-6 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 tax 3; and '15 is -O-tax -S-; : j: tax its pharmaceutically acceptable salt. : * · *: A compound according to claim 1, characterized by .1 ·. The compound is determined to be [6-hydroxy-3- [4- [2- (1-. pyrimididinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [3 · 5] yl] [b] thiophene of formula a: * · .. I | I)> - C /) - 0CHa:: HO s - '..., • ♦ • ♦♦ • · J. * ·· or a pharmaceutically acceptable salt thereof. 137 Compound according to Claim 2, characterized in that said salt is the hydrochloride salt. Compound according to claim i, characterized in that it is [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b ] thiophene or its hydrochloride salt. Compound according to Claim 1, characterized in that R 3 is 1-piperidinyl and n is 2, or a pharmaceutically acceptable salt thereof. A compound according to claim 5, characterized in that Z is -O-, or a pharmaceutically acceptable salt thereof. Compound according to claim 6, characterized in that R 1 is -OH and R 2 is -O (C 1-4 alkyl), or a pharmaceutically acceptable salt thereof. The compound of claim 7, wherein R a is -OCH 3, or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 8, wherein said salt is the hydrochloride salt. A compound according to claim 6, characterized in that R 1 and R 2 are each -OH, or a pharmaceutically acceptable salt thereof. A compound according to claim 10, characterized in that said salt is the hydrochloride salt: 7: ··· A pharmaceutical formulation, characterized in that it contains as active ingredient a compound according to any one of claims 1 to 11 and optionally estrogen or progestin together with one or more pharmaceutically acceptable carriers, ··· 1 ·· or diluent. ··· • · · · ··· ··· 138 A compound of the formula 'XX / 0C ^ O ~ r 3' R 11 wherein R 11 is -H or -OR 7 where R 'is a hydroxy protecting group; R6a is -H, halogen or -OR8, wherein R6 is a hydroxy protecting group; R6 is -H or a hydroxy protecting group which can be selectively removed; R11 is = O or absent; and 10 Z is -O- or -S-? or a pharmaceutically acceptable salt thereof. A compound according to claim 13, characterized in that R 1a and R 2a are each -OCH 3, R 6 is -H, R 11 is not present and Z is -O-, or a pharmaceutically acceptable salt thereof. salt. The compound of claim 13, characterized in that R1a and R2a are each -OCH3 / Re * · '··· * is -H, Ru is = 0 and Z is - 0, or a pharmaceutically acceptable salt thereof. • · · *. * · 20. 16. A compound of the formula R3- (CH2) n-0 ^; ^ · · · r i ·. ··: ···. f-y-X} -r2 ': wherein R139 is -H or -OR7 where R' is a hydroxy protecting group; R 2a is -H, -halogen, or -OR 8 where R 8 is a hydroxy protecting group; and Pv3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-5 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. A compound according to claim 16, characterized in that R 1a and R 2a are each -OCH 3, R 3 is 1-piperidinyl, n is 2 and Z is -O-, or a pharmaceutically acceptable salt thereof. A process for the preparation of compounds of the formula I R 3 - (CH 2) n -O- - - - - - - - - - - - where R 1 is - H or -O-R 7a wherein R 7a is -H or a hydroxy protecting group; R2a is -H, halogen or -OR5a, where R8a is -H or ... hydroxy protecting group; and ♦ · · R 3 is 1-piperidinyl, 1-pyrrolidino, methyl-1 · · * ··· * pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, di- isopropylamino or 1-hexamethyleneimino; n is 2 or 3; and • · «. Z is -O- or -S-; For the preparation of 140 or a pharmaceutically acceptable salt thereof, characterized in that: a) oxidizing a sulfur atom in a compound of formula IV R 9 χχκ> R 10 IV 5 wherein R 1a and R 2a are as defined above; and R 9 is a leaving group; b) reacting the product of step a), a compound of Formula XIV R9: T: ... Rla | jO xiv • · · · * · 1 with a nucleophilic group of formula «• · \ 0 0 0 • (CH2) n-R R, τ, O • 9 · p 2 · 1 ′ · T 15 · 1 · .. wherein R 12 is -OH or -SH; · .2. c) reducing the product of step b), a compound of the formula XVI to provide the compound XVI. d) optionally removing the R 1a and / or R 2a hydroxy-5 inner protecting groups, if present, from the product of step c); and e) optionally forming a salt of the product of step c) or step d). A process for the preparation of a compound of formula I according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, characterized in that: ··; ϊ that ···: a) ··· (A) is reduced to a compound of the formula XVI R3 - (CHj) π-0 :: ί: / z I '··· f V-R2a ·: · Ri » y 11: ·. o «·· *. . XVI wherein 142 R11a is -H or -OR7a wherein R7a is -H tax hydroxy protecting group; R 2a is -H, halogen or -OR 8a, wherein R 8a is -H or a hydroxy protecting group; R3 is 1-piperidinyl, 1-pyrrolidino, 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; (B) providing a compound of formula Hb HO-n z Hb wherein .1 ··. R7 is a hydroxy protecting group; and R 2a and Z are as defined above; • · · with a compound of the formula * · · · r3 - (0Η2) η - q v • · 20 where • · V · Q is a leaving group; and R 3 is as defined above; 143 (C) is carried out by reacting a compound of the formula Hb HCL ^ XX z Ilb wherein R 2a, R 7 and Z are as defined above, with an alkylating agent of formula Q- (CH 2) n Q 'where Q and Q 1 are the same or different leaving groups, the product of which is then reacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine or 1-hexamethylenimine · 1 · 1 ·; this. · 2. (D) for the preparation of a compound of formula I wherein R1 or R2 is -H and the other substituent of R1 or R2 is -OH, i) forming a triflate of a hydroxy group from a compound of formula • ♦ · • · ·: F: R3- (CH2) n-cx ^ Xk * ·· z • · · f ·: · t / · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · « Wherein R 3c is -OH or -O- (C 1-4 alkyl); and R 2c is -OH or -O- (C 1-4 alkyl); provided that when R 1c is -OH, R 2c is -O- (C 1 -C 4 alkyl), and when R 1c is -O- (C 1 -C 4 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; 10. is 2 or 3; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof; and ii) reducing the resulting triflate group; b) optionally removing the remaining hydroxy protecting group (s); and c) optionally forming a salt of the product of step a) or step b). A compound of formula I as claimed in any one of claims 1 to 11 for use in ameliorating symptoms of postmenopausal syndrome. The compound of claim 20, characterized in that said postmenopausal syndrome is osteoporosis, cardiovascular disease, hyperlipidemia, or a hormone. due to cancer. A compound of formula I as claimed in any one of claims 1 to 11 for use as an agent for inhibiting uterine fibroid disease, endometriosis, aortic smooth muscle cell proliferation or restenosis. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· 145