CZ58896A3 - Benzothiophene compounds, intermediates for their preparation, preparations in which they are comprised and process for preparing thereof - Google Patents

Description

Technical field

This application is a continuation of USSN 08 / 396,401, filed on 28 February 1995 and is still pending.

The present invention relates to the field of pharmacy and organic chemistry and provides novel benzothiophene compounds which are useful in the treatment of various medical indications associated with postmenopausal syndrome, fibroid uterine disease, endometriosis and aortic smooth muscle cell proliferation. The invention further relates to intermediates useful in the preparation of the pharmaceutically active compounds of the invention and pharmaceutical compositions.

Background Art

Postmenopausal syndrome is a term used to describe various pathological conditions that often affect women who enter or are terminated by a physiological metamorphosis known as menopause. Although many pathologies are observed using this term, the three main effects of postmenopausal syndrome are the source of the greatest long-term medical concern: osteoporosis, cardiovascular effects such as hyperlipidemia and estrogen dependent cancer, especially breast cancer and uterine cancer.

Osteoporosis describes a group of diseases that arise from a variety of etiologies, but which are characterized by a net loss of bone mass per unit volume. The consequence of this bone loss and the resulting bone breakdown is skeletal failure that provides adequate structural support to the body. One of the most common types of osteoporosis is associated with menopause. Most women lose from about 20 to about% bone mass in the trabecular part of the bone within 3 to 6 fletes after menstruation. This rapid loss is generally associated with an increase in bone resorption and formation. However, the resorption cycle is more dominant and results in net bone loss. Osteoporosis is a general and serious disease of postmenopausal women.

It is estimated that there are approximately 25 million women in the United States alone who are affected by the disease. The results of osteoporosis are personally harmful and are also considered to be a great economic loss due to their chronicity and the need for extensive and long-term support (hospitalization and nursing home care) for subsequent diseases. This is particularly true in elderly patients. In addition, although osteoporosis is not generally considered a life-threatening condition, a 20-30% mortality rate is related to bone fractures in older women.

A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis.

The most vulnerable tissue in the bone that is affected by postmenopausal osteoporosis is trabecular bone. This tissue is often referred to as a spongy or latticed bone and is particularly accumulated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures that are interconnected with each other, the same as the stiff and dense cortical tissue that forms the outer surface of the bone and the center of the shaft. These interconnected trabuculae provide lateral support to the external cortical structure and is critical to the biomechanical strength of the overall structure. In postmenopausal osteoporosis, net resorption and loss of trabeculae is the primary cause of bone failure and fractures. In the net loss of trabeculae in postmenopausal women, it is not surprising that the most common fractures are those associated with bones that are highly dependent on the trabecular carrier, such as vertebrae, bone bones, as well as the femur and forearm. Indeed, hip fractures, collies fractures and vertebral crush fractures are hallmarks of postmenopausal osteoporosis.

Estrogen replacement therapy is currently only a generally accepted method for treating postmenopausal osteoporosis. Although therapy is generally successful, the patients who prefer this therapy are few, especially since estrogen treatment often produces unwanted side effects.

Throughout the premenopausal period, most women have less symptoms of cardiovascular disease than men of comparable age. However, after menopause, the extent of cardiovascular disease in women is slowly increasing to the corresponding extent apparent in men. This loss of protection is associated with loss of estrogen and, in particular, loss of estrogenic ability to regulate serum lipid levels. The nature of estrogenic ability to regulate serum lipids is not well understood, but evidence shows that estrogen can regulate low density lipid (LDL) receptors in the liver to remove excess cholesterol. In addition, estrogen has been shown to have some efficacy in cholesterol biosynthesis and has other beneficial effects on cardiovascular health.

In the literature it is stated that postmenopausal women following estrogen replacement therapy, on the contrary, reach serum lipid levels approaching those of this substance in the premenopausal state. Thus, estrogen would prove beneficial for treating this condition. However, for many women, the side effects of estrogen replacement therapy are not acceptable μ what limits the use of this therapy. An ideal therapy for this condition would be a preparation that regulates serum lipid levels such as estrogen but which would avoid the side effects and dangers associated with estrogen therapy.

The third major pathology associated with postmenopausal syndrome is estrogen-dependent breast cancer and estrogen-dependent cancer of other organs, such as the uterus, which occurs to a lesser extent. Although such neoplasms are not * self-confined to postmenopausal women, they are more prevalent in the older, postmenopausal population. The current chemotherapy of these cancers to an important extent relies on the use of antiestrogenic compounds such as tamoxifen.

Although such mixed agonist antagonists have beneficial effects on the treatment of these cancers and the side effects of estrogen are tolerable in acute life-threatening situations, they are not ideal. For example, these preparations have stimulatory effects on some cancer cell populations in the uterus, due to their estrogenic (agonistic) properties and may in some cases be counterproductive. Better therapies for treating these cancers would be preparations that would be antiestrogenic compounds that had negligible or no reproductive tissue agonist properties.

In response to a clear need for new pharmaceutical compositions that are capable of alleviating symptoms, including, but not limited to, postmenopausal syndrome, the present invention provides novel benzothiophene compounds, pharmaceutical compositions containing them, and methods for using such compounds to treat postmenopausal syndrome and other estrogen-related pathologies, as the states mentioned below.

Uterine fibrosis (uterine fibroid disease) is an old and still present clinical problem that comes under various names, including uterine fibroid disease, uterine hypertrophy, uterine lieomyomatia, hypertrophic myometry, uterine fibrositis, and fibrous metritis. Basically, uterine fibrosis is a condition where fibroid tissue has been improperly placed on the uterine wall.

This condition causes dysmenorrhea and infertility in women. The exact cause of this condition is misunderstood, but evidence is suggested that it is an inappropriate response of fibroid tissue to estrogen. Such a condition is achieved in rabbits by daily administration of estrogen for 3 months. In guinea pigs, the condition is produced by daily administration of estrogen for 4 months. Further, in rats, estrogen causes similar hypertrophy.

The most common treatment for uterine fibrosis involves surgical procedures that are both costly and sometimes create a source of complications such as abdominal adhesion and infection. In some patients, the initial surgery is only a temporary treatment and the fibroids grow again.

In such cases, a hysterectomy is performed that effectively terminates fibroids, but also the patient's reproductive life. Gonadotrophin-related hormone antagonists may also be administered, but their use is already limited by the fact that they may lead to osteoporosis. Thus, there is a need for new methods for the treatment of uterine fibrosis, and the methods of the invention satisfy this need.

Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial mass or peritoneal cavity, and often leads to infertility. The cause of the symptoms of this condition appears to be in ectopic endometrial growth that inadequately responds to normal hormonal control and is placed in inappropriate tissues.

Due to inappropriate placement of endometrial growth, the tissue shows the onset of local inflammatory-like responses that cause macrophage infiltration and a cascade of events leading to the initiation of a painful response. The exact etiology of this disease is not well known and its treatment of hormonal therapy is detrimental, poorly expressed, and has a number of undesirable and possibly deleterious side effects.

One of the treatments for this disease is the use of a low dose of estrogen to suppress endometrial growth despite the negative rebound effect on central gonadrotropin release and subsequent ovarian estrogen production, but sometimes it is necessary to use a continuous estrogen supply to control symptoms. This use of estrogen can often lead to undesirable side effects as well as the risk of endometrial cancer.

Another treatment is the continuous administration of progestins that induces amenorrhea, and the ovarian estrogen production suppression can cause endometrial regression. The use of sustained progestin therapy is often associated with undesirable side effects of progestins on the central nervous system and often leads to infertility due to suppression of ovarian function.

A third treatment involves the administration of weak androgens that are effective in suppressing endometriosis, but induce a number of serious masculinizing effects. Some of these endometriosis treatments also result in a slight degree of bone loss associated with continuous therapy. Therefore, new methods of treating endometriosis are desirable.

SUMMARY OF THE INVENTION

R ^x

In which -H, -OH, -O (O-C 1-6 alkyl), -OCOC 8 H 8, -OCO (C 1 -C 8 alkyl), or -OSO ₂ (C ₂ -C 8 alkyl) denotes -H, -OH, -O (O-O-R 2 -alkyl), -OCOC 8 H 8, -OCO (C 1 -C 8 alkyl) or -OSO ₂ (C ₂ -C 8 alkyl) or halogen, means 1-piperidyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethylenimino, n is 2 or 3 and

Z is -O- or -S-, and pharmaceutically acceptable salts thereof.

The invention further relates to intermediates which are suitable for the preparation of the pharmaceutically active compounds of the invention, some of which are also pharmaceutically active:

R - _{(CH2) r.-0}

in which

R ^1a represents a hydrogen atom or a group of the formula -OR ⁷ , wherein R represents a hydroxyl group;

R ^2a represents a hydrogen atom, a halogen atom or a group of formula -OR ⁸ wherein R ⁸ represents a hydroxy protecting group, q

R represents 1-piperidyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diisopropylamino or 1-hexamethylenimino, E

R represents a hydrogen atom or a hydroxy protecting group which can be selectively removed,

Q

R means a leaving group

R ¹¹ either does not exist or represents a group of formula = 0, n represents 2 or 3 and

Z is -O- or -S-, or a pharmaceutically acceptable salt thereof.

The invention also provides a process for preparing compounds of formula

in which

R ^1a represents a hydrogen atom or a group of formula -OR ^7a , wherein R ^7a represents a hydrogen atom or a hydroxy protecting group,

R ^2a represents a hydrogen atom, a halogen atom or a group

O-Q and formula -OR wherein R is hydrogen or hydroxy protecting group

R ³ is 1-piperidyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino,

4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethylenimino, n is 2 or 3;

Z is a group of formula -O- or -S-, or a pharmaceutically acceptable salt thereof

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

(IV) in which

R ^{1, 3} and R ^2a are as defined above and

R ⁹ represents a leaving group,

b) allowing the compound of formula (XIV) to regulate the compound from the step, i

(XIV) with a nucleophilic group of a compound of ^ \ ~ _x O (CH _{2) n} -R ² ZU

R- ² in which

Ί O

R represents a group of formula -OH or -SH,

c) reducing the compound of step (b) of formula (XVI) to the compound

(XVI) to give a compound of the formula

d) optionally removing the hydroxy protecting groups to R ^1a and / or R ^2a , if present, from the compound of step c);

e. allowing the salt of the compound of step c) or d) to form.

The invention further relates to pharmaceutical compositions comprising compounds of formula I and optionally comprising an estrogen or progestin, the same as the use of such compounds alone or in combination with an estrogen or progestin, to alleviate the symptoms of postmenopausal syndrome, especially osteoporosis, cardiovascular conditions related to pathological conditions, and estrogen-dependent cancers. As used herein, the term estrogen includes steroidal compounds having estrogenic activity such as 170-estradiol, estrone, conjugated estrogen (Premarin), equine estrogen 170-ethinylestradiol, and the like. As used herein, the term progestin includes compounds having progestational activity such as progesterone, norethylnodrel, nongestrel, megestrol acetate, norethindrone, and the like.

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

In one aspect, the invention includes compounds of Formula I

in which

R ¹ is -H, -OH, -O ((C 1-4 alkyl), -OCOC ₆ H ₅ ,

-OCO (C ₁ -C ₆ alkyl) or -OSO ₂ (C ₂ -C ₆ alkyl),

R ² is -H, -OH, -O (C ₁ -C ₄ alkyl), -OCOC ₆ H ₅ ,

-OCO (C ₁ -C ₆ alkyl), -OSO ₂ (C ₂ -C ₆ alkyl) or halogen,

R ³ is 1-piperidyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethylenimino, n is 2 or 3 and

Z is -O- or -S-, and a pharmaceutically acceptable salt thereof.

The general terms used in the description of the compounds disclosed herein take into account their usual meanings. For example, C 1 -C 6 alkyl refers to straight or branched aliphatic chains of 1 to 6 carbon atoms and includes moieties such as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. Similarly the term ^C l ^-c 4 akoxyskupina represents an alkyl group attached through an oxygen and include moieties such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy and the like.

The starting materials for the single production route of the compounds of formula (I) of the present invention, compounds of formula (III), are essentially prepared as described by CD Jones in U.S. Pat. Nos. 4,418,068 and 4,133,814, each of which is incorporated herein by reference. . The compound of formula III has the structure (III)

in which

R ⁷ and R ^2a are as defined above.

- 7 fl

Hydroxy protecting groups R and R are moieties which are not usually found in the final, therapeutically active compounds of formula I, but which are deliberately introduced during a part of the synthetic process to protect the group which would otherwise react during chemical manipulation and which is then removed at the last stage of the synthesis. Since compounds bearing such protecting groups are particularly important as chemical intermediates (although some derivatives also exhibit biological activity), their exact structure is not critical. A number of responses to the generation, removal and possibly conversion of such protecting groups have been described in a number of basic works, including, for example, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), TW Green, Protective Groups in Organic Synthesis, Wiley , New York (1931) and The Peptides, Vol. I. Schrooder and Lubke, Academic Press, London and New York (1965).

Representative hydroxy protecting groups include, for example, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 6) alkyl, -S ₍ C 2 -C 6) alkyl and -CO-Ar, wherein Ar is benzyl or optionally substituted phenyl. The term substituted phenyl refers to a phenyl group which contains at least one substituent selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, nitro, halogen and trichloromethyl or trifluoromethyl. The term halogen refers to a bromine, chlorine, fluorine and iodine atom.

For compounds of formula III, R ⁷ and R ⁸ (R ^2a ) methyl, isopropyl, benzyl and methoxymethyl are preferred. Compounds in which R ⁷ and R ⁸ each are methyl are prepared by the method described in the aforesaid patent-Jones e. Another preferred hydroxy protecting group is methoxymethyl. However, the compound of formula (IV) shown below is prepared first, preferably bearing a methyl or hydroxy group (s). These protecting groups are then removed to form a phenol moiety which is then protected again with methoxymethyl protecting groups.

Compounds of formula (III) are also prepared in which the hydroxy protecting group of R ⁷ is selectively removed leaving a R ⁸ (R ^2a ) hydroxy protecting group as part of the final compound. The same applies when R ⁸ (R ^2a) hydroxy protecting group seketivně "7 is removed and leaves the spot-protecting group R 7 is hydroxy. For example, R is isopropyl or benzyl and R ⁸ (R ^2a ) is methyl. Isopropyl or benzyl moiety

O is selectively removed by standard procedures and R is retained as part of the final product as a methyl protecting group.

The first steps of this process for producing certain compounds of Formula I include selectively placing a leaving group at the 3-position of Formula III, condensing the first-stage reaction product with 4- (protected hydroxy) phenol, and removing the hydroxy protecting group from phenol. This method is shown in Scheme I below.

Scheme I (III) wherein

R ⁷ and R ^a are as defined above,

R'U

(IV) in which

a bifurcated group

in which of:

R represents a hydroxy protecting group which can be selectively removed,

(lib)

In the first step of Scheme I, a suitable scavenging group is selectively introduced into position 3 of the starting compound of Formula III by conventional methods. Suitable

Q leaving group R includes sulfonates such as methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate, ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, trifluoromethanesulfonate and the like, halogen atoms such as bromine, chlorine and iodine and other related cleavable groups. However, in order to ensure the proper location of the leaving group, said halogen atoms are preferred, with the bromine atom being particularly preferred.

The present invention is carried out using standardized procedures. For example, when preferred halogenating agents are used, the equivalent of such a halogenating agent, preferably bromine, is reacted with an equivalent of a compound of Formula III in the presence of a suitable solvent, for example, chloroform or acetic acid. The reaction proceeds at a temperature of from about 40 ° C to about 80 ° C.

The reaction product of the above-described process step, a compound of formula IV, is then reacted with a 4- (protected hydroxy) phenol to form a compound of formula IIa wherein R ⁸ is a hydroxy-protecting group that is selectively removable. In general, the hydroxy-protecting portion of the 4-position of the phenol may be any known protecting group that can be selectively removed without removal, for example, of R and, if present, without removing part of the R ⁸ compound of Formula IIa. Preferred protecting groups for R ⁶ include methoxymethyl when R ⁷ and / or R ^{8 are} not methoxymethyl, and benzyl. Of course, benzyl is particularly preferred. 4- (Protected hydroxy) phenol reagents are commercially available or can be prepared by standard methods.

This condensation reaction is known in the art as a Ullman reaction and proceeds according to standardized procedures (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., Pp. 3-16, J. March, John Wiley & Sons , Inc. (1992), CD Jones, J. Chem., Soc., Perk, Trans, I, 407 (1992).

Generally, an equivalent amount of two aryl compounds, in the presence of up to equimolar amounts of copper oxide as the catalyst and a suitable solvent, is refluxed under an inert atmosphere. Preferably, the equivalent of a compound of formula IV is reacted in which

Q

R represents a bromine atom with an equivalent amount

4-benzyloxyphenol in the presence of an equivalent amount of copper oxide.

Suitable solvents for this reaction are those solvents or solvent mixtures that remain inert during the reaction. Preferred solvents are usually organic bases, especially hindered organic bases such as 2,4,6-collidine.

The temperature used in this stage should be sufficient to terminate this condensation reaction and will affect the amount of time required for this. If the reaction mixture is refluxed under an inert atmosphere such as nitrogen, the time to completion of the reaction will usually be from about 20 to about 60 hours.

After condensation to form a compound of formula (IIa), a compound of formula (IIb) is produced by selectively removing the hydroxy protecting group of R from the compound of formula (Ia) by well known reduction procedures. It is essential that the selective procedure does not adversely affect the R ⁷ substituent and, if present, the R ⁸ protecting group.

7

When R is preferably a benzyl moiety and when R and when R 1 is always methyl, this process step can be carried out by standardized hydrogenolysis procedures. Typically, a compound of formula IIa is added to a suitable solvent or solvent mixture, then a proton donor is added to accelerate the reaction, and a suitable hydrogenation catalyst is added.

Catalysts include precious metals and their oxides, such as palladium, platinum, and rhodium oxide on a support such as coal or calcium carbonate. Of these, palladium on carbon, especially 10% palladium on carbon, is preferred.

Solvents for this reaction are those solvents or solvent mixtures that remain inert during the reaction. Generally, ethyl acetate and aliphatic alcohols having 1 to 4 carbon atoms, especially ethanol, are preferred.

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

If the reaction proceeds at room temperature and a pressure ranging from about 206 to about 344 kPa, this reaction proceeds very rapidly. The course of this reaction can be monitored by conventional chromatographic techniques such as thin layer chromatography.

Compounds of formula IIa and formula IIb are novel and are included in the group described herein as compounds of formula II. These compounds are useful in the preparation of pharmaceutically active compounds of the formula

AND.

After the compound of formula IIb has been produced, it is reacted with a compound of formula V ^{r 3} - ( ^CH 2> n - Q (V) in which

O

Ran have the meanings given above and

Q represents a bromine atom or, preferably, a chlorine atom to form a compound of formula VI. The compound of formula VI is then deprotected to give a compound of formula Ia. These steps of the present invention are shown in Scheme II below.

Scheme II

VI

R ³ - (CH ₂

R

2b where

Ί 7 7a

R, R, R and n are as defined above and

R ² k represents a hydrogen atom, a hydroxy group or a halogen atom.

In the first step of the process shown in Scheme II, alkylation is carried out by normal procedures. Compounds of formula V are commercially available or are prepared by methods well known to those skilled in the art. Preference is given to using the hydrochloride salt of the compound of formula V, in particular 2-chloroethylpiperidine hydrochloride.

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

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

The temperature used in this step should be sufficient to terminate the alkylation reaction. Usually, room temperature is sufficient and convenient.

The present reaction preferably proceeds under an inert atmosphere, especially under nitrogen.

Preferred reaction conditions are understood to mean that the reaction will continue for about 16 to about 20 hours until complete. Of course, the course of the reaction can be monitored by normal chromatographic techniques.

As an alternative to the preparation of compounds of formula (VI), the case where the compound of formula (IIb) is reacted in an alkaline solution with an excess of an alkylating agent of formula (I) is given as an alternative.

Q - (CH ₂ ) _n --Q 'in which

Q and Q 'each represent the same or different leaving groups.

Suitable leaving groups are the leaving groups mentioned above which are used in the preparation of the compound of formula IV.

A preferred alkaline solution for this alkylation reaction comprises potassium carbonate in an inert solvent such as methyl ethyl ketone (MEK) or dimethylformamide.

In this solution, the 4-hydroxy group of the benzoyl moiety of the compound of formula IIb is present as a phenoxide ion, replacing one of the leaving groups of the alkylating agent.

This reaction is best when the alkaline solution contains reagents, the reagents are brought to reflux and the reaction is allowed to proceed to completion. When methyl ethyl ketone is used as the preferred solvent, the reaction time is from about 6 to about 20 hours.

The reaction product of this step is then reacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine or 1-hexamethyleneimine, by a conventional technique, forming compounds of formula VI.

Preferably, the piperidine hydrochloride salt is reacted with an alkylated compound of formula IIb in an inert solvent such as anhydrous dimethylformamide. and all heated to a temperature in the range of about 60 to about 110 ° C. If the mixture is heated to a preferred temperature of about 90 ° C, the reaction to run only needs about 30 minutes to about 1 hour. However, the change in reaction rates will affect the amount of time this reaction takes to complete. Of course, the course of this reaction step can be monitored by normal chromatographic techniques.

Compounds of formula VI wherein R ⁷ and, if present also R ⁸ are each an alkyl group having 1 to 4 carbon atoms, preferably methyl, and R ^2a represents a hydrogen or halogen atom, are new compounds which are pharmaceutically active for the methods described herein. Therefore, such compounds are included in the definition of compounds of Formula I.

Certain preferred compounds of Formula I are

Q is obtained by cleavage of R and, when R is present as the hydroxy protecting group, from the compound of formula VI by well known methods. A number of reactions for the generation and removal of such protecting groups are described in a number of essential works, including, for example, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), TW Green, Protective Groups in Organic Synthesis, Wiley, New York / 1981 / and The Peptides, Vol. I, Schrooder and Lubke, Academic Press, London and New York (1965). Methods for removing the preferred R ⁷ and / or R ⁸ hydroxy protecting groups, especially methyl and methoxymethyl, are described in the Examples below.

The compounds of formula (Ia) are novel compounds which are pharmaceutically active for the methods described herein and are encompassed by formula (I) as defined herein.

Compounds of formula I wherein R ¹ is hydrogen are produced by the synthetic route shown in Scheme III below. Using this route, the leaving group (R ⁹ ) in position 3 is introduced into a commercially available thianaphthalene (formula VII) to form a compound of formula VIII which is then condensed with a 4- (protected hydroxy) phenol to form a compound of formula IX.

Scheme III

IX where

R represents a hydroxy protecting group which can be selectively removed, and

R ⁹ is a leaving group.

Compounds of formula VII are commercially available. The preparation of compounds of formula (VIII) and formula (IX) wherein R ⁶ and R ⁹ are as defined above, as well as the preferred reagents and reaction conditions are as described above and shown in Scheme I above.

The compounds of formula IX are then arylated with Suzuki coupling (see, for example, A. Suzuki, Pure and Appl. Chem., 6 (2), 213-222 (1994)). Choosing the use of the Suzuki coupling reaction, the compound of Formula IX is selectively halogenated at the 2-position and then condensed with an aryl boronic acid of Formula XIa (Route A in Scheme IV below).

Preferably, however, the aryl boronic acid of formula (Xb) is prepared from a compound of formula (IX) and then reacted with a haloarene of formula (XIIb) to form a novel intermediate of formula (IIc) (Route B of Scheme IV below). Such novel intermediates are useful in the preparation of the pharmaceutically active compounds of this invention (compounds of Formula Ib) by alkylation and deprotection.

Scheme IV

IX

II

Xla

R “ ^a

¹ '

where

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

X represents an iodine, bromine or fluorine atom, in order of preference, and

X 'is an iodine, bromine or fluorine atom, respectively, or trifluoromethanesulfonate.

The first step on route A in Scheme IV is iodination or bromination of the compound of formula IX in position 2 using standardized procedures. Generally, a compound of Formula IX is reacted with a slight excess of n-butyllithium in hexane as a suitable solvent and under an inert atmosphere, such as under nitrogen, and then a slight excess of a suitable halogenating agent in a suitable solvent is added dropwise. Preferably, the halogenating agent for this step is iodine, but it is also allowed to use bromine or N-bromosuccinimide.

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

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

The compound of the above reaction, a haloarene of formula Xa, is then coupled with an aryl boronic acid of formula XIa by a Suzuki coupling process to give a compound of formula IIc. Compounds of formula (XIa) wherein R ^2a is a hydrogen atom, a halogen atom or a group of formula -OR ⁸ (wherein R ⁸ is a hydroxy protecting group as defined above) are derived from commercially available compounds by methods well known to those skilled in the art (see e.g. J. March and A. Suzuki, supra).

In the described condensation reaction, a slight excess of the compound of formula (XIa) is reacted with an 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 assist the Suzuki coupling reaction, the selected catalyst is usually specific for the reaction. Thus, the use of tetrakisphenylphosphine palladium for this reaction is highly preferred.

Similarly, different bases may be used in the condensation reaction present. However, it is preferred to use an alkali metal carbonate, particularly a 2-normal sodium carbonate solution.

The temperature used in this step should be sufficient to terminate the condensation reaction. It is usually reasonable and preferred that the reaction mixture is refluxed for about 2 to about 4 hours.

In route B of Scheme IV, arylboronic acid at position 2 of Formula Xb is prepared using well known procedures. Generally, a compound of formula IX is treated with a slight excess of n-butyllithium in hexanes, in a suitable solvent under an inert atmosphere such as nitrogen, and then a suitable trialkyl borate is added dropwise.

Suitable solvents include inert solvents or mixtures of such solvents such as diethyl ether, dioxane and tetrahydrofuran. Tetrahydrofuran is preferred, especially anhydrous tetrahydrofuran.

The preferred trialkyl borate used in this reaction is triisopropyl borate.

The product of this reaction, a compound of formula Xb, is then reacted with an aryl halide or aryl trifluoromethanesulfonate of formula XIIb by conventional Suzuki coupling reaction to form compounds of formula IIc. Preferred reaction conditions for this reaction are described in connection with the reaction of compounds of formula XIa and formula Xa in Scheme IV, where a compound of formula IIc is also obtained.

Conversion of compounds of formula IIc to compounds of formula Ia is carried out as described above for converting compounds of formula IIa to compounds of formula Ia.

The compounds of formula (IIc) and (IId) are novel and are useful in the preparation of the pharmaceutically active compounds of this invention.

Compounds of formula (XII) and formula (Ib) are also novel and are suitable for the methods described herein. These compounds are included under the compounds of formula I as defined herein.

Compounds of formula I wherein R ¹ or R 19 is either

R represents a hydrogen atom and R or R represents a hydroxy group are also prepared from compounds of formula I in which R ¹ and R ² are both hydroxy. The dihydroxy compounds of formula I are converted to a mixture of 6- and 4'-monotrifluoromethanesulfonates and the trifluoromethanesulfonate moiety is reduced to hydrogen (see JM Saa et al., J. Org. Chem. 55. 991 (1990)). The resulting mixture of monohydroxyderivative free base or pharmaceutically acceptable salt, preferably hydrochloride, can then be separated by normal crystallization techniques.

Generally, the dihydroxy compound of formula I is treated with about 4 to about 6 equivalents of an amine base such as triethylamine in a non-reactive solvent, and then 1 equivalent of trifluoromethanesulfonic anhydride is added. A statistical mixture of mono-trifluoromethanesulfonates and di-trifluoromethanesulfonates is prepared and separated by conventional chromatographic techniques. The preferred solvent for this step is anhydrous dichloromethane.

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

The isolated mono-trifluoromethanesulfonate compound mixture is then hydrogenated 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 on carbon is added. Preferred solvents for this reaction include ethyl acetate and ethanol, or alternatively a mixture thereof. If this reaction step is carried out at a hydrogen gas pressure of about 275 kPa at room temperature, the reaction time is from about 2 to about 5 hours.

The resulting mixture of monohydroxy derivatives of formula I has different solubilities in ethyl acetate and the 6-hydroxy-4'-hydrogen derivatives can be partially separated from the 6-hydrogen-4'-hydroxy derivatives by selective crystallization. Further separation, which affords the monohydroxy compounds of formula I, can be achieved by converting the enriched mixtures into hydrochloride salts followed by crystallization from a mixture of ethyl acetate and ethanol.

A more direct process for the preparation of compounds of formula I, I?

wherein either R or R is hydrogen and the other is hydrogen

R 2 or R is hydroxy, as well as an alternative method for preparing compounds of formula I wherein either R ¹ or R ² is hydrogen and the other substituent R ^x or R is -O-alkyl group having 1 to 4 carbon atoms, is used a compound of formula

in which

R ³ and n are as defined above,

Π r

R is hydroxy or -O-alkyl having 1 to 4 carbon atoms and

R is hydroxy or -O-alkyl having 1 to 4 carbon atoms, provided that when ip P *

R is hydroxy, R is -O-alkyl of 1 to 4 carbon atoms, and when and R is -O-alkyl of 1 to 4 carbon atoms, R6c is hydroxy.

In such a process, the hydroxyl portion of such a compound is converted to a trifluoromethanesulfonate derivative by treatment with trifluoromethanesulfonic anhydride. The trifluoromethanesulfonate moiety is then reduced under normal conditions, preferably by catalytic hydrogenation. The hydroxy protecting portion is then removed by conventional means as described herein to give compounds of formula I wherein either R ¹ or R ² is hydrogen and the other R or R is hydroxy.

Another alternative and preferred method for producing the compounds of this invention is shown in Scheme V. In this case, the sulfur atom of the compound of Formula IV below is oxidized to form a sulfoxide of Formula XIV, which is then reacted with a nucleophilic group to introduce an atom oxygen or a sulfur atom as a linker for a compound of formula I and formula II. The sulfoxide moiety of the compounds of formula XVI is then reduced to provide certain compounds of the invention.

Scheme V

^R6 0- (CHn) n ^-R 3 HOV xr ⁵ XVa XVb - 1 XVC 1

- (CH2)

XVd ^R6 ° n

R ₃ - (CH ₂ ) _n -O

Re

R ₃ - (CH ₂ ) _n -O, 1a

O

XVI a

II o

XVI b

2C o

XVIC

II ^R • fi o

XVI d

> 2c in which formulas each substituent is as defined above,

In a first step of the process, a compound of formula IV is selectively oxidized to a sulfoxide. A number of known methods are available for this stage of the process (see, for example, M. Madesclaire, Tetrahedron 42 (20), 5459-5495 (1986), BM Trošt et al., Tetrahedron Letters 22 (14), 1287-1290 (1981), J Drabowicz et al., Synthetic Communications, 11 (12), 1025-1030 (1931), JB Kramer et al., 34th National Organic Symposium, Williamsburg, VA, USA, June 11-15, 1995). However, many oxidants provide only poor conversion to the desired product, the same as leading to significant overoxidation of the sulfone. However, this new process converts a compound of formula IV to a sulfoxide of formula XIV in high yield with or without formation of sulfones. These processes involve reacting a compound of formula IV with about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture of about 20 to about 50% trifluoroacetic acid in methylene chloride. The reaction proceeds at a temperature of from about 10 to about 50 C and usually requires a duration of from about 1 to about 2 hours to allow the reaction to proceed quantitatively.

Further, the cleavable group at position 3 (R ⁹ ) is displaced by a suitable nucleophilic derivative of formula XV. Such nucleophilic derivatives are produced by conventional methods.

In this stage of the process, the acidic proton of the nucleophilic group is removed by treatment with a base, preferably with a slight excess of sodium hydride or potassium tert-butoxide in a polar aporotic solvent, preferably dimethylformamide or tetrahydrofuran. Other bases that may be used include potassium carbonate and cesium carbonate. In addition, other solvents such as dioxane or dimethylsulfoxide may be used. Deprotonization is usually carried out at a temperature of from about 0 ° C to about 30 ° C and typically requires a duration of about 30 minutes to complete. The compound of formula XIV is then added to the solution of the nucleophilic compound. The displacement reaction takes place at a temperature of about 0 to about 50 ° C, and usually takes about 1 to about 2 hours. The product is isolated by standard methods.

When a benzyl moiety is used as the hydroxy protecting group, the hydrogenolysis of the sulfoxide moiety also provides for removal of the benzyl protecting group, eliminating the requirement to selectively remove such a moiety at a later stage of the process.

In the next step of this process, the novel sulfoxides of formulas XVIa, b, c and d (collectively, the compounds of formula XVI) are reduced to a benzothiophene compound of formula IIIa of formula Ic, formula IIIa and Id. Before this reduction process, the compounds of the general formula (IIa) and of the general formula (IIa) can be first alkylated as described herein. Reduction of the sulfoxide compound can be achieved using one of a variety of methods known in the art, for example, hydride reduction (using lithium aluminum hydride), catalytic hydrogenation, transfer hydrogenolysis, and trimethylsilyl iodide (TMS-I). In this reduction, the choice of reagent depends on the compatibility of other functionalities in the molecule. For the compounds described herein, lithium aluminum hydride (LiAlH ₄ formula) and transfer hydrogenolysis (palladium black and ammonium formate) are preferred reagents. Suitable solvents for reduction with lithium aluminum hydride are, for example, diethyl ether, dioxane and tetrahydrofuran. Of course, tetrahydrofuran, especially anhydrous tetrahydrofuran, is preferred. For transfer hydrogenolysis, the solvent is preferably an alcohol, especially ethanol. The reaction takes place at a temperature of from about 0 to about 60 ° C and requires a duration of from about 30 minutes to about 2 hours to complete.

If desired, the hydroxy protecting group or the hydroxy protecting group in the compounds of the process depicted in Scheme V may or may be removed, and the product salt of any process step may be produced. Therefore, the present invention provides a process for the preparation of compounds of the general formula

in which

R ^1a represents a hydrogen atom or a group of the formula -OR ^7a , wherein R ^7a represents a hydrogen atom or a hydroxy protecting group,

R ^2a represents a hydrogen atom, a halogen atom or a group of formula -OR ^8a ,

R a where R represents a hydrogen atom or a hydroxy protecting group,

R ³ is 1-piperidyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino,

4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethylenimino, n is 2 or 3 and

Z represents a group of formula -O- or -S-, or a pharmaceutically acceptable salt thereof;

a) in a compound of formula IV

2a (IV) in which

R ^1a and R ^{2a have the} meanings given above and

R represents a leaving group, the sulfur atom is oxidized,

b) a compound of step a), a compound of formula XIV

R ' ^a : xiv) is reacted with a nucleophilic group of a compound of formula

O- (CH 2) _n -R ³ in which, 12 represents a group of formula -OH or -SH,

c) a compound of step b), a compound of formula XVI

(XVI) is reduced to form a compound of the formula

d) optionally removing a hydroxy protecting group

And from R and / or R 1 ^{and the} compound of step c), if such groups are present, and

e) optionally forming a salt of the compound of step c) or d).

The novel process also provides novel compounds of Formula XIV and Formula XVIa, b, c and d, each of which is an intermediate for the manufacture of the pharmaceutically active compounds of the invention.

Compounds of formula I wherein Z is sulfur is also prepared using the method described below in Scheme VI wherein the compound of formula IVa is metallated. The resulting compound of formula (XVII) is reacted with a 4- (protected hydroxy) phenyl disulfide of formula (XVIII) and the phenol protecting group of formula (Ile) is removed to give compounds of formula (IIf). One of ordinary skill in the art will recognize that when using these methods, R cannot be halogen, due to chemical constraints.

Scheme VI

XVj

Ue

OR ⁶

where

R ^1a represents a hydrogen atom or a group of the formula -OR ⁷ , wherein R represents a hydroxy protecting group,

R represents a hydrogen atom or a group of formula -OR,

Q wherein R is a hydroxy protecting group, E

R represents a hydroxy protecting group which can selectively remove

R ⁹ is a leaving group a

M is a metal ion.

In the first two steps of Scheme VI, a compound of Formula VIa is metallated by well known methods.

Most commonly and preferably, the compound of formula IVa is treated with a slight excess of n-butyllithium in hexanes in a suitable solvent, and then a solution of the disulfide compound of formula XVIII in a suitable solvent is added dropwise.

Both of these reaction steps take place under an inert atmosphere such as nitrogen. Suitable solvents for both steps include one or more solvents such as diethyl ether, dioxane and tetrahydrofuran. Of course, tetrahydrofuran, especially in anhydrous form, is preferred. In addition, these reaction steps take place at a temperature of about -78 to about 85 ° C.

In the first step of this reaction, a metallated compound of formula XVII is obtained. 4- (Protected hydroxy) phenyl disulfide (compound of formula XVIII), which is reacted with such a compound of formula XVII to provide a compound of formula Ile, is prepared by protecting a hydroxy group of a commercially available 4-hydroxyphenyl sulfide with a suitable protecting group by methods known in the art known.

from:

A preferred protecting group for R 0 is methoxymethyl, provided that for R 1 and R 2, if one or both are present, a hydroxy protecting group is different from methoxymethyl. As a rule, the hydroxyl protecting group R is a moiety different from the hydroxy protecting group for R ⁷ and R ³ , if present, so that the R ⁶ moiety can be selectively removed by normal methods to give a compound of formula Uf.

For efficient deprotonation by deprotection

R ⁶ is reacted in a protic solvent or solvent mixture in an acid medium containing at least one equivalent of an acid, preferably methanesulfonic acid, and heated to a temperature of about 25 ° C to about 110 ° C. 24 hours, but the course of the reaction can be monitored by normalized chromatographic methods.

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

The compounds of formula (Ile) and formula (IIf) are novel compounds which are suitable for the preparation of the pharmaceutically active compounds of formula (I) and are included in the above formula (II).

Compounds of formula Id

in which

R ¹ b represents a hydrogen atom or a hydroxy group,

R ^d represents a hydrogen atom or a hydroxy group and

Ran are as defined above, are produced using the methods described above, which are related to the methods characterized by the steps depicted in Schemes II and IV. Such compounds of formula (Id) are also novel substances which are suitable for the methods of the invention and are incorporated herein by reference to formula (I) above.

Compounds of formula (I) wherein R ¹ and R ² are different hydroxy protecting group or either R ¹ or R is a hydroxy protecting group and the other is hydroxy is selectively produced using a modified 2-arylbenzothiophene starting compound of formula III above provided that the hydroxy protecting groups designated for R ⁷ and R ⁸ are sufficiently different such that one protecting group is removable while the other protecting group remains. Such 2-arylbenzothiophenes are prepared by methods well known in the art.

Particularly suitable for the preparation of compounds of formula I in which R and R are different protecting groups is Suzuki coupling as described in Scheme IV above. However, 6- (protected hydroxy) benzothiphene-2-boronic acid is reacted with a compound of formula Xbb as above wherein R is -OR and R is

O is the same as R. This reaction allows the production of the compounds of the invention wherein R and R 0 are different hydroxy protecting groups such that one protecting group can be selectively removed and the other remains as part of the final compound. Preferably, the R ⁷ protecting group, especially the butyl or isopropyl, is removed to form a hydroxyl group

Part, while the R protecting group remains, especially methyl.

Suzuki coupling is also achieved using the methods described above, but substituting the compound of Formula Xb for a compound of Formula XIX

(XIX) in which

R is an alkylsulfonate radical having 1 to 6 carbon atoms, preferably a methanesulfonate, or an arylsulfonate radical of 4 to 6 carbon atoms and

R ¹⁰ is a leaving group, preferably a bromine atom or a trifluoromethanesulfonate residue.

In this process, 6- (protected hydroxy) benzothiophene-2-boronic acid, as described above, is reacted with a compound of formula XIX to form a compound of formula XX which is reacted with boron tribromide in methylene chloride to give the monohydroxy compound which is subsequently converted, for example, to the benzyl moiety by conventional means (compound of formula XXI). The 4'-sulfonate ester is then selectively removed by hydrolysis under basic conditions, or preferably by treatment with lithium aluminum hydride, in a suitable aprotic solvent such as tetrahydrofuran. This reaction provides a compound of formula XXII which is ultimately, for example, methylated at the 4 'position by conventional processes (compound of formula IIIa). It will be appreciated by those skilled in the art that various processes can be used to obtain compounds of Formula IIIa wherein the hydroxy protecting groups are different from those depicted in Scheme VII below but which can be selectively removed to provide the monohydroxy compounds of Formula I of this invention.

Scheme VII

lila

The compounds of formula IIIa are then subjected to the various processes described herein to give compounds of formula I and formula II according to the invention.

Other preferred compounds of formula I are prepared by substituting the 6-position and / or 4'-hydroxyl moieties, when present, for -O-CO-alkyl, wherein the alkyl moiety contains 1 to 6 carbon atoms, or the -O-CO-alkyl moiety. -SO2-alkyl having 2 to 6 carbon atoms, well known in the art, see, for example, U.S. Patent No. 4,358,593.

For example, when a group of formula -O-CO-alkyl, wherein the alkyl moiety contains from 1 to 6 carbon atoms, is desired, the monocydroxy compound or dihydroxy compound of formula I is reacted with a reagent such as an acyl chloride, acyl bromide, cyanide or azide, or an appropriate anhydride or mixed anhydride. The reaction is usually carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine and the like. The reaction may also be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone and the like, to which at least one equivalent of the acid scavenger (except below) may be added such as tertiary amine. If desired, acylation catalysts, such as 4-dimethylaminopyridine or the like, may be used

4-pyrrolidinopyridine (see, e.g., Haslam et al.

Tetrahedron 36., 2409-2433 (1980)].

This reaction is carried out at a slightly elevated temperature, ranging from about -25 to about 100 ° C, often under an inert atmosphere such as under nitrogen. However, the room temperature is usually adequate for the course of the reaction.

Acylation of the hydroxy group at the 6-position and / or at the 4-position can also be carried out by reaction of suitable carboxylic acids in inert organic solvents that are acid catalysed. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like are used.

The above-mentioned R and / or R groups in the compounds of formula I can also be achieved by forming an active ester of a suitable acid, such as esters formed from known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide and 1-hydroxybenzotriazole ( see, for example, Bull. Chem. Soc. Japan, 38, 1979 (1965) and Chem. Ber. 788 and 2024 (1970)).

Each of the abovementioned techniques, which provides 1-C-C 6 alkyl groups having from 1 to 6 carbon atoms in the alkyl group, are carried out in solvents such as those discussed above. Obviously, such techniques, which do not result in the production of acidic products during the course of the reaction, require the use of an acid scavenger in the reaction mixture.

If the desired formula I compound in which the hydroxy group is in position 6 and / or 4 ', a compound of formula I is converted into a group of formula -0-S0 ₂ -alkyl having 2 to 6 carbon atoms and monohydroxy or dihydroxy compound is reacted with, for example, sulfur trioxide or a suitable sulfonic acid derivative, such as a sulfonyl chloride, sulfonyl bromide or ammonium salt of a sulfonyl derivative, as disclosed by King and Monoir in J. Am. Chem. Soc. 97, 2566-2567 (1975).

The dihydroxy compound can also be reacted with a suitable sulfonic anhydride or mixed sulfonic anhydride. Such reactions are carried out under the conditions explained above in the reaction with 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 preferred to prepare and use a pharmaceutically acceptable salt form. Thus, the compounds used in the methods of the invention primarily form pharmaceutically acceptable acid addition salts selected from a wide variety of organic and inorganic acids, and include physiologically acceptable salts, which are often used in pharmaceutical chemistry. Such salts are part of this invention. Conventional inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, phosphoric acid, and the like. Salts derived from organic acids can also be used, such as aliphatic acids of monocarboxylic and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkandiic acids, aromatic acids, aliphatic acids and sulfonic acids. Such pharmaceutically acceptable salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butin- 1,4-dioate, hexine-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymalate, malonate, mandlate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, hydrogen sulphate, pyrosulphate, sulphite, hydrogen sulphite, sulphonate, benzenesulphonate, p- bromophenyl sulfonate, chlorobenzene sulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xyl ensulfonate, tartrate and the like. Preferred salts are the hydrochloride and the oxalate.

Pharmaceutically acceptable acid addition salts are commonly prepared by reacting a compound of Formula I with an equimolar amount of acid or excess thereof. The reactants are usually reacted in a solvent for both reactants, such as diethyl ether or ethyl acetate. The salt normally precipitates out of solution within about 1 hour to 10 days and can be isolated by filtration or the solvent can be stripped in conventional manner.

Pharmaceutically acceptable salts commonly have enhanced dissolution characteristics compared to the compound from which they are derived, and thus are often more capable of forming liquids or emulsions.

Representative preferred compounds of the invention include the following compounds:

Group I:

[6-Methoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene- (S-oxide), 6-isopropoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene- (S-oxide), 6-methoxy-2- (4-isopropoxyphenyl) -3-bromo-benzo [b] thiophene- (S-oxide), [2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene- (S-oxide), [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- (S- oxide), [3- (4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide), 6-benzyloxy-2- ( 4-methoxyphenyl) -3-bromo-benzo [b] thiophene- (S-oxide), 6-isopropoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene (S-oxide), [6-methoxy-2- (4-benzyloxyphenyl) -3-bromo-benzo [b] thiophene- (S-oxide), 6-methoxy-2- (4-isopropoxyphenyl) -3-bromo-benzo [b] thiophene- (S-oxide), [6-benzyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide) [6-isopropoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene (s-oxide), [6-methoxy-3] - [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene- (S-oxide), (6-methoxy-3- [4- [2- (1-piperidyl) ethoxy / phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene- (S-oxide), 6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy / benzo [b] thiophene and [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene.

Group II:

[3- [4- [2- (1-Piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] hydrochloride ] -2- (4-hydroxyphenyl)] benzo [b] thiophene, [3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene, [ 3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene, [3- [4- (2- (1-N, N-diethylamino)] ethoxy / phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [3- [4- (2- (1-piperidyl) ethoxy] phenoxy] -2- 57- (phenyl)] benzo [b] thiophene hydrochloride, [3- [4- [2- (1-piperidyl)] ethoxy / phenoxy] -2- (4-fluorophenyl)] benzo [b] thiophene [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene; isopropoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy / benzo [b] thiophene; 6-methoxy-2- (4-isopropoxyphenyl) -3- (4-benzyloxy) phenoxy / benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride [6-methoxy-3- [4-] 2- (1-piperidyl) ethoxy / phenoxy) -2- ( 4-methoxyphenyl) benzo [b] thiophene [6-methoxy-3- [4- [2- (1-pyrrolodinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo (b) thiophene hydrochloride [6- methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1 -N, N-diethylamino) ethoxy / phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride (6-methoxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [6-methoxy-3- [4- (3- (piperidino) propoxy] phenoxy] -2-hydrochloride hydrochloride

- (4-methoxyphenyl)] benzo (b] thiophene, [6-methoxy-3- [4- [3- (1-N, N-diethylamino) propoxy] phenoxy] -2- (4-methoxyphenyl) benzoic acid hydrochloride (b) thiophene, [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene, oxalate [6-hydroxy-3- [4 - [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene, [6-Hydroxy-3- [4- (2- (1-piperidyl) ethoxy] phenoxy] hydrochloride hydrochloride) 2- (4-hydroxyphenyl)] benzo [b] thiophene, [6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene, [ 6-hydroxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene, (6-hydroxy-3- [4- (2- N, N-diethylamino) ethoxy / phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene [6-hydroxy-3- (4- [2- (morpholino) ethoxy] phenoxy] -2- (4- hydroxyphenyl)] benzo [b] thiophene, [6-Hydroxy-3- [4- (3- (1-N, N-diethylamino) propoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo (b) thiophene hydrochloride [6-Hydroxy-3- [4- [2- (1-N, N-diisopropylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene hydrochloride hydrochloride hydrochloride [6-hydroxy-3- [4- [3- (piperidino) propoxy] phenoxy] 59

-2- (4-hydroxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [6-benzyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene, [6-benzyloxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-hexamethylimino) ethoxy] phenoxy] - 2- (4-methoxyphenyl) benzo [b] thiophene [6-benzyloxy-3-4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzol B] thiophene [6-benzyloxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [6-isopropoxy-3- [4 - [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [6-isopropoxy-3- [4- [2- (1-hexamethylimino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [6-isopropoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzol] thiophene, [6-isopropoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy ] -2- (460

-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene; hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene, [6-hydroxy-3- [4- [2- (1- hexamethylimino) ethoxy / phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] ben of [b] thiophene [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4 - [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-Hydroxy-3- [4- [2- (1-hexamethylimino) ethoxy] phenoxy] hydrochloride ] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] -2- (4-methoxyphenyl) )] benzo [b] thiophene, [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo (b) thiophene hydrochloride, (6-methoxy) -3- [4- [2- (1-piperidine) yl) ethoxy / phenoxy] -2- (461

-benzyloxyphenyl) benzo [b] thiophene [6-methoxy-3- (4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene; methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- (2- N-dimethylamino) ethoxy / phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4 benzyloxyphenyl) benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-isopropoxyphenyl) benzo [b] thiophene, [ 6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- (2- 1-hexamethylenimino) ethoxy / phenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] - 2- (4-isopropoxyphenyl) benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2- (4-isopropoxyphenyl) benzo [b] thiophene [6-methoxy-3- (4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene; - (1-pyrrolidinyl) ethoxy / phenoxy] - 2 - (4 -

-hydroxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene; methoxy-3- [4- [2- (1H, 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-piperidyl) ethoxy] phenoxy] -2- ( 4-hydroxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride hydrochloride hydrochloride [6-methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- / 2] - (1N, 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, [6-benzoyloxy-3- [4- (2- (1-piperidyl) ethoxy] phenoxy] -2- (4-benzoyloxyphenyl)] benzo [b] thiophene hydrochloride [6-ethylsulfonyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-ethylsulfonyloxyphenyl) benzo [b] thiophene, [6-Hydroxy-3- [4- [2- (1-piperidyl) ethoxy] 63-phenoxy] -2- (4-ethylsulfonyloxyphenyl)] benzo [b] thiophene hydrochloride hydrochloride [6- ethylsulfonyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo (b) thiophene, [6-methoxy-3- (4- [2- (1- piperidyl) ethoxy / phenoxy] -2- (4-trifluoromethanesulfonyloxyphenyl) benzo (b) thiophene 3- (4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-benzoyloxyphenyl) benzo [hydrochloride] hydrochloride [ b] thiophene, 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-pivaloyloxyphenyl)] benzo [b] thiophene hydrochloride 3- (4- [2- (1-piperidyl) hydrochloride] hydrochloride) ethoxy / phenoxy] -2- (4-butylsulfonyloxyphenyl)] benzo (b] thiophene, [6-methoxy-3- (4- [2- (1-piperidyl) ethoxy) thiophenoxy] -2- (4-methoxyphenyl) benzo (b) thiophene (6-methoxy-3- (4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy) -2- (4-methoxyphenyl) benzo (b) thiophene (6-methoxy-3) - [4- [2- (1-hexamethylenimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo (b] thiophene, (6-methoxy-3- [4- [2- (1-N, N) -dimethylamino) ethoxy / thiophenoxy] -2- (4-methoxyphenyl)] benzo (b) thiophene, (6-methoxy-3- (4- [2- morpholino) ethoxy / thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene (6-benzyloxy-3- (4- [2- (1-piperidyl) ethoxy] thiophenoxy) -2- (464

-methoxyphenyl) benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene; benzyloxy-3- [4- [2- (1-hexamethylenimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene, [6-benzyloxy-3- [4- (2- N, N-dimethylamino) ethoxy / thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- ( 4-methoxyphenyl) benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene; isopropoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzophenyl] thiophene, [6-isopropoxy-3- [4- [2- (1-hexamethylenimino)] ethoxy / thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene, [6-isopropoxy-3- (4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4 -methoxyphenyl) benzo [b] thiophene, [6-isopropoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene, [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-pyrrolidine yl) ethoxy / thiophenoxy] -2- (465)

-methoxyphenyl) benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-hexamethylenimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene; hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene; - (1-morpholino) ethoxy / thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene [6-Hydroxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] hydrochloride - 2- (4-methoxyphenyl)] benzo [b] thiophene, [6-Hydroxy-3- [4- (2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [hydrochloride] hydrochloride [b] thiophene, [6-hydroxy-3- [4- [2- (1-hexamethylenimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4 - [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy / thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl) benzo [b] thiophene [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-ben zyloxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy] thiophenoxy] -2

- (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl) benzo [ b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene; - [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl) benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl) benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl) benzo [b] thiophene; [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidyl) 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-hexamethylenimino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene; - [2- (1-N, N-dimethyl) mino) ethoxy / thiophenoxy] -2- 67- (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-piperidyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride hydrochloride [ 6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy / thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy hydrochloride [2- (4-hydroxyphenyl)] benzo [b] thiophene, [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo hydrochloride [ b] thiophene, [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride, [6-hydroxy-3- [ 4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy ] - 2- (4-hydroxyphenyl) benzo [b] thiophene, [6-hydroxy-3- [4- (2- xamethylenimino) ethoxy / thiophenoxy] -2- (4-hydroxyphenyl)] benzophenyl thiophene [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2

- (4-hydroxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene, [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4-] 2- (1-pyrrolidinyl) ethoxy / thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene, [6-Hydroxy-3- [4- (2- (1-hexamethylenimino) ethoxy] thiophenoxy] hydrochloride] 2- (4-hydroxyphenyl)] benzo (b] thiophene, [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl) hydrochloride] benzo [b] thiophene, [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride and hydrochloride [6-hydroxy- 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2-phenyl] benzo [b] thiophene.

EXAMPLES OF THE INVENTION

The following examples are presented to further illustrate the production of the compounds of this invention. It is not intended that the present invention be limited to the extent that any of the above examples would cause it.

The NMR spectral data in the examples below are obtained on a GE 300 MHz instrument for NMR spectral analysis. As the solvent, anhydrous d-6 dimethyl sulfoxide is used unless otherwise specified.

Preparation 1

Process for the preparation of [3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene and [3- (4-benzyloxy) phenoxy] benzo [b] thiophene

97.6 g (0.488 mol) of 4-benzyloxyphenol and 23.3 g (0.163 mol) of cuprous oxide are added to a solution of 69.62 g (0.325 mol) of 3-bromo-benzo [b] thiophene in 55 ml of anhydrous collidine under nitrogen. The mixture was refluxed for 24 hours. After cooling, the reaction mixture was diluted with 200 mL of ethyl acetate and the crude mixture was filtered through a pad of p

diatomaceous earths (hereinafter referred to as celite; Celite, Aldrich, Milwaukee, WI, USA) to remove inorganic salts.

The filtrate was washed three times with 150 ml of 1N hydrochloric acid each time. The organic phase is dried over sodium sulfate and evaporated under reduced pressure to a liquid. Thianaphthalene was removed by distillation at 115-120 ° C and 1330 Pa. The remaining material was chromatographed (silica, hexanes / ethyl acetate 85:15) to give 12.2 g of benzo [b] thiophene and 12.95 g (35% based on the recovered starting material) / 3- (4-benzyloxy) phenoxy / benzo (b) thiophene as a volatile solid, mp 84-86 ° C.

- · * Η NMR (CDC1 ₃₎ spectrum δ: 7.91 to 7.83 (m, 2H), 7.47 - 7.34 (m, 7H), 7.04 (q, J _AB = 9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H) ppm.

Analysis for ^{C H} 2i i6 ° 2 ^S: calculated: 75.88% C 4.85% H Found: 75.75% C, 5.00% H.

Preparation 2

Process for preparing [2-iodo-3- (4-benzyloxy) phenoxy] benzo [b] thiophene

To a solution of 6.00 g (18.1 mmol) of 3- (4-benzyloxy) phenoxy / benzo [b] thiophene in 100 ml of anhydrous tetrahydrofuran under nitrogen at -78 ° C was added dropwise 12.4 ml (19, 9 mmol) of a 1.6 molar solution of n-butyllithium in hexanes from a syringe. This solution changes from colorless to dark orange. After stirring at -78 ° C for 20 min, the lithium compound was treated with 5.03 g (19.9 mmol) of iodine added dropwise as a solution in 50 mL of anhydrous tetrahydrofuran. After the addition is complete, the reaction mixture changes color to light yellow and is allowed to slowly warm to room temperature. The reaction was quenched by the addition of 200 mL of 0.1 N sodium sulfite. The layers were separated and the aqueous layer was extracted twice with 150 ml of ethyl acetate each time. The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure to give an oil which crystallized on standing. Recrystallization from hexanes / ethyl ether gave 7.10 g (86%) of 2-iodo-3- (4-benzyloxy) phenoxy / benzophenyl] thiophene as a white crystalline powder. Mp 87-92 ° C.

¹ H NMR (CDCl ₃ ) δ spectrum: 7.72 (d, J = 8.1 Hz, 1H), 7.47-7.20 (m, 8H), 6.89 (s, 4H), 5, 01 (s, 2H) ppm.

Analysis for ^C 21 ^H 15 ° 2 ^SI: Calculated: 55.03% C 3.30% H Found: 55.29% C, 3.31% H.

Preparation 3

Production Method: 2- (4-tert-butoxyphenyl) -3- (4-benzyloxy) phenoxy / benzo [b] thiophene

To a solution of 4.50 g (9.82 mmol) of 2-iodo-3- (4-benzyloxy) phenoxy / benzo (b) thiophene in 20 ml of toluene was added 2.28 g (11.75 mmol) of 4- (tert-butoxy) phenyl boronic acid followed by 0.76 g (0.66 mmol) of palladium tetrakistriphenylphosphine, 14.5 ml of 2 N sodium carbonate solution were added thereto, and the resulting mixture was refluxed for 3 hours. After cooling, the reaction mixture is diluted with 150 ml of ethyl acetate, the organic layer is washed twice with 100 ml of 0.1 N sodium hydroxide solution each time and then dried over sodium sulphate and evaporated to give a semi-solid which is dissolved in chloroform and passed through a layer of carbon dioxide. The solvent was evaporated to give an oil which was triturated with hexanes to give 4.00 g (91%) of (2- (4-tert-butoxyphenyl) -3- (benzyloxy) phenoxy) benzo [b] thiophene as a white powder. mp 105-108 ° C.

¹ H NMR (CDCl 3) spectrum 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, J _AB = 9.3 Hz, 4H), 4.99 (s, 2H), 1.36 (s, 9H) ppm. FD mass spectrum: 480.

Analysis for C ₃₁ H ₂₈ O ₃ S:

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

Preparation 4

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

The yield is 73%. The compound has a melting point of 115 to

118 “C.

¹ H NMR (CDCl ₃ ) spectrum S: 7.30-7.90 (m, 3H), 7.33-7.53 (m, 8H), 6.93-7.06 (m, 6H), 5 .00 (s, 2H), 3.83 (s, 3H) ppm. FD mass spectrum: 433.

Analysis for ^C 28 ^H 22 ° 3 ^S: Calculated: 76.69% C 5.06% H Found: 76.52% C, 5.09% H.

Preparation 5

Method of Production [2- (4-tert-butoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene

To a solution of 1.50 g (3.37 mmol) of [2- (4-tert-butoxy-74-phenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene in 30 ml of absolute ethanol containing 1% concentrated hydrochloric acid, 0.50 g of 10% palladium on carbon is added. The mixture was hydrogenated under a hydrogen pressure of 27 psi for 1 hour. After this time, the reaction was considered complete, based on thin layer chromatography. The mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The crude material was dissolved in a minimal amount of ethyl acetate and passed through a short column of silica to remove celite (ethyl acetate was used as eluent). Evaporation gave a white solid which was triturated with hexanes / ethyl ether. Filtration gave 868 mg (73%) of (2- (4-tert-butoxyphenyl) -3- (4-hydroxy) phenoxy) benzo [b] thiophene. Mp 210-213 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.13 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.35-7.26 (m, 3H), 7.01 (d, J = 8.6 Hz, 2H), 6.70 (q, J _AB = 8.9 Hz,

4H), 1.28 (s, 9H) ppm. FD mass spectrum: 390.

Analysis for ^C 24 ^H 22 ° 3 ^S: Calculated: 73.82% C 5.63% H Found: 73.93% C, 5.84% H.

Preparation 6

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

The yield was 80%. The compound has a m.p.

125 'C.

1 H NMR (CDCl ₃ ) spectrum S: 7.80-7.90 (m, 3H), 7.48 (m, 1H), 7.30-7.48 (m, 2H), 6.90 - 7.03 (m, 4H), 6.76-6.86 (m, 2H), 3.82 (s, 3H) ppm. FD mass spectrum: 348.

Analysis for C 2 H 4 O 3 S 3 S:

H, 4.63; Found: C, 72.63; H, 4.82.

Example 1

Method of production of [3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

OH

To a solution of 1.25 g (3.20 mmol) of [2- (4-tert-butoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene in 10 mL of anhydrous

Of Ν, Ν-dimethylformamide was added 5.70 g (17.6 mmol) of cesium carbonate at room temperature. After stirring for 20 minutes, 1.95 g (10.56 mmol) of 2-chloroethylpiperidine hydrochloride was added in small portions. The resulting heterogeneous mixture was vigorously stirred for 24 hours. The substances contained in the reaction mixture are then diluted with 200 ml of water. The aqueous phase is extracted three times with 100 ml of ethyl acetate each time. The combined organic layers are then washed twice with 200 ml of water each time. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to an oil. Chromatography (with 5 to 10% methanol in chloroform) affords 1.47 g (91%) of 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-tert-butoxyphenyl) benzoic acid. (b) thiophene, which is used directly in the next step without characterization.

Dissolve 1.37 g (2.73 mmol) of 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-tert-butoxyphenyl)] benzo [b] thiophene in 10 ml of acid trifluoroacetic acid at room temperature. The reaction mixture was stirred for 15 minutes and the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and washed three times with 10 ml of saturated sodium bicarbonate solution each time. The organic layer was dried over sodium sulfate and evaporated to give a white solid in solution. The material was recrystallized from ethyl acetate / ethyl ether. This gave 1.03 g (85%) of 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene as colorless crystals. Mp 169-172 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.81 (s, 1H), 7.93 (d, m)

J = 7.7 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.36-7.26 (m, 3H), 6.86 (s, 4H), 6, 73 (d, J = 8.6 Hz, 2K), 4.10 (m, 2H), 3.29 (m, 2H), 2.95-2.75 (m, 4H), 1.68-1 40 (m, 6H) ppm.

Analysis for ^C 27 ^H 27 ^NO 3 ^S. 0.55 CF ₃ CO ₂ H:

H, 5.46; N, 2.76. Found: C, 65.99; H, 5.49;

Example 2

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

Mp 233-240 ° C.

¹ H NMR (DMSO-d ₆ ) spectrum 5: 10.43 (m, 1H), 9.89 (s, 1H), 7.93-7.95 (m, 1H), 7.60-7.64 (m, 2H), 7.35-7.50 (m, 3H), 6.83-7.03 (m, 6H), 4.27-4.30 (m, 2H), 3.40-3. 60 (m, 4H), 2.96-3.10 (m, 2H), 1.70-1.95 (m, 5H), 1.40-1.53 (m, 1H) ppm. FD mass spectrum: 446.

Analysis for C27H27NO-3S. 1.0 HCl:

H, 5.86; N, 2.91. Found: C, 67.07; H, 5.66; N, 2.96.

The compounds of the following examples were prepared in an analogous manner.

Example 3

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

Mp 150-155 ° C. ¹ H NMR (DMSO-d 6) spectrum S: 9.79 (s, 1H), 7.92 (d, J = 7.8 Hz,

1H), 7.54 (d, J = 8.6 Hz, 2H), 7.36-7.26 (m, 3H), 6.84 (s, 5H)

4H), 6.78 (d, J = 8.6 Hz, 2H), 4.00 (broad triplet, 2H),

2.92 (m, 2H), 2.35 (m, 4H), 1.73 (m, 4H) ppm.

Analysis for ^C 26 ^H 25 ^NO 3 ^S. 0.33 CF ₃ CO ₂ H:

H, 5.44; N, 2.99. Found: C, 68.29; H, 5.46; N, 3.19.

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

Mp 189-191 ° C.

^τ Η NMR (DMSO-dg) spectrum δ: 7.91 (d, J = 7.6 Hz,

1H), 7.52 (d, J = 8.5 Hz, 2H), 7.34-7.25 (m, 3H), 6.81 (s, 4H), 6.75 (d, J = 8 6 Hz, 2H), 3.89 (broad triplet, 2H), 2.75 (broad triplet, 2H), 2.68 (m, 4H), 1.43 (m, 8H) ppm.

Analysis for C ₂₈ H NO ₃ S _{2 g.} 1.50 H ₂ O:

N, 2.88. Found: C, 69.28; H, 6.79; N, 2.58.

Example 5 [3- [4- [2- (1-N, N-Diethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene

The compound has a melting point of 70 ° C.

NMR (DMSO-d6) spectrum δ: 9.91 (broad singlet, 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 (broad triplet, 2H); 76 (broad triplet, 2H), 2.51 (m, 4H), 0.91 (m, 6H) ppm. FD mass spectrum: 434.

Analysis for C ₂ gH -NO ₂ S _3. 0.50 H ₂ O:

H, 6.38; N, 3.16. Found: C, 70.45; H, 6.26; N, 3.20.

Example 6

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

Mp 223-230 ° C.

1 H NMR (DMSO-d 6) spectrum δ: 7.96 (d, J = 7.5 Hz,

1H), 7.66 (d, J = 8.8 Hz, 2H), 7.35-7.50 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H), 6, 86 - 6.90 (m, 4H), 4.28 - 4.31 (m, 2H), 3.74 (s, 3H), 3.37 - 3.45 (m, 4H), 2.92 - 2.96 (m, 2H), 2.46-2.48 (m, 5H), 1.74 (m, 1H) ppm. FD mass spectrum: 459.

Analysis for ^C 28 ^H 29 ^NO 3 ^S. 1.0 HCl:

N, 2.82. Found: C, 68.06; H, 6.38; N, 2.60.

Alternative System (2 - (4-tert-butoxyphenyl)) -3- (4-benzyloxy) phenoxy / benzo [b] thiophene

Preparation 7

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

To a solution of 5.00 g (15.1 mmol) of 3- (4-benzyloxy) phenoxy / benzophenyl] thiophene in 20 mL of anhydrous tetrahydrofuran at -78 ° C was added dropwise 9.90 mL (15.8 mmol) of ) Of 1.6 molar n-butyllithium in hexanes using a syringe. Stir for 15 minutes and then add 3.83 ml (16.6 mmol) of B (OiPr) ₃ and allow the resulting mixture to warm to 0 ° C. The reaction was then quenched with 100 mL of ethyl acetate and 1.0 N HCl. The layers were separated and the organic layer was extracted once with 100 mL of water. The organic layer was dried over sodium sulfate and concentrated in vacuo to a solid which was triturated with ethyl ether / hexanes. Filtration gets

3.96 g (70%) of [3- (4-benzyloxy) phenoxy] benzo (b) thiophene-2-boronic acid as a white solid, mp 115-121 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 8.16 (d, J = 8.5 Hz,

1 H), 7.93 (d, J = 9.0 Hz, 1H), 7.42-7.23 (m, 7H), 6.90 (q, ^J AB ^{= 9.0 Hz} ' ⁰¹ ( ^s , 2H) ppm.

Analysis for ^C 2 H 4 ^H i7 ° ^SB: calculated: 67.04% C 4.55% H Found: 67.17% C, 4.78% H.

[3- (4-Benzyloxy) phenoxy] benzo [b] thiophene-2-boronic acid is reacted with 4- (tert-butoxy) bromobenzene under the conditions described above for [2-iodo-3- (4-benzyloxy)] phenoxy / benzofb] thiophene and 4- (tert-butoxy) phenylboronic acid. There was obtained 2- (4-tert-butoxyphenyl) -3- (4-benzyloxy) phenoxy) benzo [b] thiophene in 81% yield.

The compounds described in the Examples were prepared using this method.

Example 7

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

Mp 223-226 ° C.

¹ H NMR (DMSO-d 6) δ spectrum: 7.99 (d, J = 8.2 Hz,

1H), 7.71 (d, J = 7.3 Hz, 1H), 7.44-7.30 (m, 7H), 6.90 (s, 4H), 4.27 (m, 2H), 3.43-3.35 (m, 4H), 2.97-2.88 (m, 2H), 1.73-1.61 (m, 5H), 1.34 (m, 1H) ppm.

Analysis for C 27 H 27 NO 2 S. 1.0 HCl:

H, 6.06; N, 3.00. Found: C, 69.88; H, 6.11; N, 3.19.

Example 8 [3- [4- [2- (1-Piperidyl) ethoxy] phenoxy] -2- (4-fluorophenyl)] benzo [b] thiophene

Mp 219-226 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 10.20 (broad singlet, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.77 -7.73 (m, 4H), 7.42 - 7.25 (m, 5H), 6.90 (s, 4H), 4.27 (m, 2H), 3.44-3.33 (m, 4H), 2.96-2, 89 (m, 2H), 1.78-1.61 (m, 5H), 1.34 (m, 1H) ppm. FD mass spectrum: 447.

Analysis for ^C 27 ^H 26 ^NO 2 ^SF . 1.0 HCl:

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

Preparation 8

Synthesis Method of [6-Hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene

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

HjCO

Br

OCHj

15.98 g (100 mmol) of bromine are added dropwise to a solution of 27.0 g (100 mmol) of 6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene in 1.10 L of chloroform at 60 ° C. as a solution in 200 ml of chloroform. After the addition was complete, the reaction mixture was cooled to room temperature and the solvent was evaporated. This gave 34.2 g (100%) of 6-methoxy-2- (4-methoxyphenyl) -3H-bromo-benzo [b] thiophene as a white solid. Compound ₃ has a melting point of 83-85 ° C.

and _c ¹ H NMR (DMSO-d 6) spectrum δ: 7.70-7.62 (m, 4H), _τ 7.17 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H) ppm.

FD mass spectrum: 349.350.

and "Analysis for Ο ₁₆ Η ₁₃ Ο ₂ 3Βγ:

H, 3.75; Found: C, 54.79; H, 3.76.

, Example 9 a

- Method of production 6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy / benzo (b) thiophene

S: 7 and ethyl acetate (80:20) to give an additional 1.81 g of product. The total yield of [6-methoxy-2- (4-methoxyphenyl) - 3- (4-benzyloxy) phenoxy] benzo [b] thiophene was 9.00 g (24% based on starting material obtained). The basic extract was acidified to pH 4 with 5N HCl and the resulting precipitate collected by filtration and dried. 13.3 g of 4-benzyloxyphenol are obtained. Mp 100-103 ° C.

1 H NMR (CDCl ₃ ) spectrum: δ 7.60 (d, J = 8.8 Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H) 4.98 (s, 2H); 3.86 (s, 3H); 3.81 (s, 3H) ppm. FD mass spectrum: 468.

Analysis for ^C 29 ^H 24 ° 4 ^S: Calculated: 74.34% C 5.16% H Found: 74.64% C, 5.29% H.

Preparation 9

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

To a solution of 1.50 g (3.20 mmol) of 6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy / benzo [b] thiophene in 50 mL of ethyl acetate and 10 mL of 1% concentrated acid hydrochloric acid in ethanol was added 300 mg of 10% palladium on carbon. The mixture was hydrogenated at 20 psi for 20 minutes and after

At this time, according to thin-layer chromatography, it was judged that a quantitative reaction occurred. The mixture was passed through a pad of celite to remove the catalyst and the filtrate was evaporated under reduced pressure to give a white solid. The crude material was passed through a pad of silica gel (using chloroform as eluent). Evaporation gave 1.10 g (91%) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene as a white solid. Mp 123-126 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.10 (s, 1H), 7.59 (d, m).

J = 8.8 Hz, 2H), 7.52 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8.8, 2.1 Hz, 1H); 6.72 (d, J = 9.0 Hz, 2H); J = 9.0 Hz, 2H),

3.78 (s, 3H), 3.72 (s, 3H) ppm. FD mass spectrum: 378.

Analysis for ^C 22 ^H 18 ° 4 ^S:

calculated: 69.82 % C, 4,79% found: 70.06 % C, 4.98% Example 10

Production method of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene

To a solution of 1.12 g (2.97 mmol) of 6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene in 7 ml of anhydrous β-dimethylformamide under nitrogen 3.86 g (11.88 mmol) of cesium carbonate are added under an atmosphere. Stir for 10 minutes and then add 1.10 g (1.48 mmol) of 2-chloroethylpiperidine hydrochloride. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture is then partitioned between 100 ml of chloroform and water. The layers were separated and the aqueous layer was extracted three times with 50 ml of chloroform each time. The organic layers are combined and washed twice with 100 ml of water each time. The organic layer was dried over sodium sulfate and evaporated to give an oil which was chromatographed on silica gel (2% methanol in chloroform as eluent). The desired fractions were evaporated to an oil which was dissolved in 10 mL of ethyl acetate and treated with 311 mg (3.4 mmol) of oxalic acid. Stir for 10 minutes to form a white precipitate which was filtered off. Drying gave 1.17 g (70%) of total [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene as oxalate salts. Melting point 197 DEG-200 DEG C. (dec.).

¹ H NMR (DMSO-d 6) spectrum 8: 7.60 (d, J = 3.7 Hz,

2H), 7.55 (d, J = 1.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H),

7.06 (d, J = 8.8 Hz, 2H), 6.91 (dd, J = 8.8, 1.1 Hz, 1H),

6.87 (s, 4H), 4.19 (broad triplet, 2H), 3.73 (s, 3H), 3.72 (broad, 3H), 3.32 (broad triplet, 2H), 3.12 - 3.06 (m,

4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H) ppm. FD mass spectrum: 489.

Analysis for C ₃₁ gH ₂ NO ₄ S. 0.83 HO ₂ CCO ₂ H:

H, 5.80; N, 2.46. Found: C, 64.92; H, 5.77;

Example 11

- -Μ

Treatment of the free base with ethyl ether hydrochloric acid affords (6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride

Mp 216-220 ° C.

¹ H NMR (DMSO-d 6) spectrum S: 10.20 (broad singlet, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 1.5 Hz, 1H)

7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.96 (dd, J = 9.0, 1.5 Hz, 1H) 6.92 (q, J _AB = 9.0Kz, 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) ppm. FD mass spectrum: 489.

Analysis for ^C 29 ^H 31 ^NO 4 ^S. 1.0 HCl:

N, 2.66; Found: C, 66.46; H, 6.16; N, 2.74.

The compounds of the Examples below are prepared analogously.

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

Mp 95-98 ° C.

¹ H NMR (DMSO-d 6) spectrum 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 (with, 4H) 3.97 (t, j = = 6.0 Hz, 2H) 3.83 (s, 3H), 3.76 (with, 3H) 2.73 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m

4H) ppm. FD mass spectrum: 477.

Analysis for ^C 28 ^H 29 ^NO 4 ^S:

calculated: 70.71 % C, 6.15 % H, 2.99 % N, found: 70.59 % C, 6.15 % H, 3.01 % N.

Example 13

(6-Methoxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzoylthiophene hydrochloride

Mp 189-192 ° C.

¹ H NMR (DMSO-d ₆ ) spectrum 5: 10.55 (broad singlet,

1H), 7.64 (d, J = 9.0 Hz, 2H ), 7.58 (d, J = 2.0 Hz, 1H) 7.19 (d, J = 9.0 Hz, 1 H), 7, 00 (d, j = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, H), 6.86 (with , 4H), 3.94 (t, j = 6.0 Hz, 2H) 3.83 (s, 3H), 3.76 (s, 3H) / 2.30 (t, J = 6.0 Hz , 2H) , 2.66 (m, 4H), 1.53 (m, 8H) ppm. Analysis p ro C _3Q H ₃₃ NO ₄ S. 1 , 0 HC1: calculated % C, 66.71; 6.35 % H, 2.59% N, found: C, 66.43; % H, 2.84% N.

Example 14

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

- 3 ^V • HCl

OCHj

Mp 196-193 ° C.

1 H NMR (DMSO-d 6) spectrum δ: 10.48 (broad signal, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H)

7.19 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H) 6.37 (q, J _A = 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), 1.83 (m, 3H) ppm.

Analysis for ^C 28 ^H 31 ^NO 4 ^S. 1.5 HCl:

N, 2.63; Found: C, 63.46; H, 5.79; N, 2.85.

Example 15

[6-Methoxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzoylbenzothiophene hydrochloride

- 9 | -

oca ₃

Mp 208-211 ° C.

NMR (DMSO-d6) spectrum δ: 10.6 (broad singlet, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H) ,

7.20 (J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, 1H), 6.91 (q, J _AB = 9.0 Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m, 4H), 3.82 (s, 3H), 3, 77 (s, 3H), 3.59-3.42 (m, 4H), 3.21-3.10 (m, 2H) ppm.

Analysis for ^C 23 ^H 29 ^NO 5 ^S. 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] hydrochloride

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

- 9> -

The compound had a melting point of 195-200 ° C.

NMR (DMSO-d 6) spectrum δ: 9.90 (broad singlet,

1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H),

7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, 1H) ), 6.88 (s, 4H), 3.97 (t, J = 6.0 Hz,

2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.44 (m, 2H), 3.15 (m, 2H),

2.87 (m, 2H); 2.12 (m, 2H); 1.77 (m, 5H); 1.39 (m, 1H) ppm.

Analysis for ^C 30 ^H 33 ^NO 4 ^S. 1.15 HC1:

H, 6.40; N, 2.73. Found: C, 66.01; H, 6.40;

Example 17

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

Mp 164-166 ° C.

1 H NMR (DMSO-d 6) spectrum δ: 9.77 (broad singlet,

1H), 7.64 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H),

7.18 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, 1H) ), 6.89 (s, 4H), 3.99 (t, J = 6.0 Hz,

2H), 3.83 (S, 3H), 3.77 (s, 3H), 3.15 (m, 6H), 2.06 (m, 2H),

1.20 (t, J = 7.0 Hz, 6H) ppm.

Analysis for ^C 29 ^H 33 ^NO 4 ^S. 1.0 HCl:

H, 6.49; N, 2.65. Found: C, 66.25; H, 6.64;

Example 18

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

10.00 g (19.05 mmol) of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene is dissolved in 500 ml of anhydrous methylene chloride and cooled to 8 ° C. To this solution was added 7.20 ml (76.20 mmol) of boron tribromide. The resulting mixture was stirred at 8 ° C for 2.5 hours. The reaction was quenched by pouring into 1 L of saturated saturated sodium bicarbonate solution and cooled to 0 ° C. The methylene chloride layer was separated and the remaining solids were dissolved in a mixture of methanol and ethyl acetate. The aqueous layer was then extracted three times with 500 ml of 5% methanol in ethyl acetate each time. All organic extracts (ethyl acetate and methylene chloride) were combined and dried over sodium sulfate. Evaporation under reduced pressure gave a brown solid which gave 7.13 g (81%) of [6-hydroxy-3- [4- [2- (1-piperidyl)] in silica (silica, 1-7% methanol in chloroform). ethoxy / phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene as a white solid. Mp 93 ° C.

1 H NMR (DMSO-d ₆ ) spectrum 5: 9.7 3 (broad singlet,

1H), 9.68 (broad singlet, 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 = H)

8.6 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.36 (m, 4H), 1 43 (m, 4H), 1.32 (m, 2H) ppm. FD

Mass Spectrum: 462.

Analysis for C27 ^H 27 ^NO 4 ^S: Calculated: 70.20% C 5.90% H 3.03% N Found: 69.96% C, 5.90% H, 3.14% N.

Example 19

6-Hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene was converted to its oxalate salt in 80% yield as described above. The following are the parameters for oxalate of [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene

Melting point: 246 DEG-249 DEG C. (decomposition) ^. @ ¹ H NMR (DMSO-d6) spectrum δ: 7.45 (d, J = 8.6 Hz,

2H), 7.22 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H),

6.87 (dd, J = 8.6, 1.8 Hz, 1H (masked)), 6.84 (s, 4H),

6.75 (d, J = 8.6 Hz, 2H), 4.08 (broad triplet, 2H), 3.01 (broad triplet, 2H), 2.79 (m, 4H), 1.56 (m , 4H), 1.40 (m,

2H) ppm. FD mass spectrum: 462.

Analysis for C27 ^H 27 ^NO 4 ^S. 0.75 HO ₂ CCO ₂ H: Calculated: 64.63% C 5.42% H 2.64% N Found: 64.61% C, 5.55% H, 2.62% N.

Example 20

6-Hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene was converted to its hydrochloride salt in 91% yield by treating the free base in ethyl acetate with ethyl ether hydrochloric acid. Following are the parameters for [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene hydrochloride

• aci

Mp 158-165 ° C.

¹ H NMR (DMSO-d ₆ ) δ spectrum: 9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23 ( d, J = 2.0 Hz, 1 H),

7.04 (d, J = 8.6 Hz, 1H), 6.86 (q, J _AB = 9.3 Hz, 4H), 6.76 (dd, J = 8.6 Hz, 2.0 Hz) 1H), 6.74 (d, J = 8.6 Hz, 2H), 4 _; 26 (broad triplet, 2H), 3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5H), 1.25 (m, 1H) ppm. FD mass spectrum: 461.

Analysis for C27 ^H 27 ^N0 4 ^S. 1.0 HCl:

H, 5.67; N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.

The compounds of the Examples below are prepared analogously.

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

Mp 99-113 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.25 (d , J = 2.0 Hz, 1 H),

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) ppm.

Analysis for ^C 26 ^H 25 ^NO 4 ^S * ° ^{'5 H} 2 ^0: Calculated: 68.40% C 5.74% H 3.07% N Found: 68.52% C, 6.00% H , 3.34% N.

Example 22 [6-Hydroxy-3- [4- [2- (1-hexamethylenimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene

- ιοΟ -

Mp 125-130 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.75 (s, 1H), 9.71 (s, s);

1H), 7.50 (d, J = 9.0 Hz , 2H), 7, 26 (d, J = 2 , 0 Hz, IH) 7.09 (d, J = 9.0 Hz, 1H) , 6.85 (s , 3H), 6.80 (dd, j = 9.0, 2.0 Hz, 1H), 6.79 (d, J) 9.0 Hz) , 3.94 (t, J = 6.0 Hz, 2H) 2.80 (t, J = 6.0 Hz, 2H) , 2.66 (m) , 4H), 1.53 (m, 8H) ppm. Analysis for ^C 28 ^H 29 ^NO 4 ^S: calculated: 70.71% C, 6; 15% H 2 , 94% N, Found: 70.67% C, 6; 31% H 2 , 93% N.

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

Mp 137-141 ° C.

NMR (DMSO-d 6) spectrum δ: 9.75 (s, 1H), 9.71 (s, s);

1H) 7.49 (d, J = 9.0 Hz, 1H) 7.25 (d, J = 2.0 Hz, 1 H), 7.09 (d, J = 9.0 HZ, 1H) 6.85 (s, 4H), 6.80 (dd, J = 9.0, 2.0 HZ, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H)

ppm.

Analysis for ^C 26 ^H 27 ^NO 4 ^S:

calculated: 69.46 % C, 6.05 % H, 3,12 % N found: 69.76 o, 0 C, 5.85 % H, 3.40 % N

Example 24

[6-Hydroxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2-hydrochloride

- (4-hydroxyphenyl)] benzo [b] thiophene

- οχ_-

Mp 157-162 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 10.60 (broad singlet, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.92 (q, ^J AB ^{= 9} ' ^{Hz) '4H)' 6 '81 (dd', J = 9 '0' 2} '° ^{Hz' 1 H) '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) ppm.

Analysis for ^C 26 ^H 25 ^NO 5 ^S. HCl:

H, 5.24; N, 2.80. Found: C, 69.69; H, 5.43; N, 2.92.

Example 25

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

Mp 185-191 ° C.

^T H NMR (DMSO-d6) spectrum δ: 9, 94 (wide sing flight, 1H) 9.81 (s, 1 H), 9.75 (s, 1 H), 7, 50 (d, J = 9.0 Hz, 2H), 7.27 (dd, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1 H), 6.87 (p 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) , 14 (m , 6H), 2.03 (m, 2H), 1.20 (t, J = 6.0 Hz, 6H) ppm.

Analysis for ^C 27 ^H 29 ^NO 4 ^S. H, 5.98; H, 2.74; Found: C, 63.23; H, 6.03; N, 3.14.

Example 26

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

Mp 128-131 ° C.

^{Χ Η} NMR (DMSO-d₆) spectrum?: 9.81 (br s, 1H), 9.76 (s, 1H), 9.02 (s, 1H), 7.49 (d, J = 9.0 7.28 (m, 1H); 7.09 (d, J = 9.0 Hz, 1H); 6.90 (s, 4H); 6.79 (m, 3H); 19 (m, 2H), 3.63 (m, 2H), 3.50 (m, 2H), 1.31 (m, 12H) ppm.

Analysis for ^C 28 ^H 31 ^NO 4 ^S. 1.33 HCl:

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] hydrochloride

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

- ¹⁰ Γ-

Mp 258-262 ° C.

NMR (DMSO-d 6) spectrum δ: 9.85 (broad singlet, 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80 (dd, 1H), 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) ppm .

Analysis for ^C 28 ^H 29 ^NO 4 ^S. H, 5.96; H, 2.78; Found: C, 67.04; H, 5.90;

In another embodiment, as shown in Scheme III above, the compound of Example 19 is prepared using a methoxymethyl (MOM) protecting group instead of a methoxy group. The methods are directly analogous to the method just described except that the methoxymethyl groups are removed in the final step by hydrolysis under acidic conditions.

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

Mp 94-96 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 7.65 (d, J = 2.0 Hz,

1H), 7.64 (d, J = 3.6 Hz, 2H), 7.43-7.32 (m, 5H), 7.23 (d, J = 8.8, 1H), 7.08 (d, J = 8/6 Hz, 2H), 7.04 (dd, J = 8.8, 2.0 Hz, 1H), 6.92 (q, J _AB = 9.2 Hz, 4H), 5.26 (s, 2H), 5.21 (s, 2H), 5.01 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H) ppm. FD mass spectrum: 528.

Preparation of 11/6-Methoxy-2- (4-methoxymethyloxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene

Mp 90-91 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.15 (s, 1H), 7.65 (d, 1H);

J = 8.1 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H); 22 (d, j = 8.8 HZ, 1H), 7, 05 (dd, j = 8.8, 2.0 Hz, 1H), 6.72 (<3 / ^j and b ⁼ 9.1 HZ, 4H), 5, 26 (s, 2H). 5.21 (s, 2H); 3H), 3.37 (with, 3H) ppm. FD weight Spectrum: 438.

Analysis for C24 ^H 22 ° 6 ^S: Calculated: 65.74% C 5.06% H Found: 65.50% C, 4.99% H.

Example 28

Method of Production 6-Methoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene (S-oxide)

To a solution of 10.0 g (23.6 mmol) of 6-methoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene in 50 ml of anhydrous methylene chloride was added 50 ml of trifluoroacetic acid. Stir for 5 minutes and then add 4.0 mL (28.6 mmol) of 30% aqueous hydrogen peroxide. The resulting mixture was stirred at room temperature for 2 hours. 1.25 g of solid sodium bisulfite and then 15 ml of water are added to the dark solution. The mixture was stirred vigorously for 15 minutes and then evaporated under reduced pressure. The residue was partitioned between 200 ml of chloroform and saturated sodium bicarbonate solution. The layers were separated and the organic layer was extracted with saturated sodium bicarbonate solutions. The organic layer was then dried over sodium sulfate and concentrated in vacuo to a solid which was triturated with a mixture of ethyl ether and ethyl acetate. Filtration afforded 8.20 g (80%) of 6-methoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene (S-oxide) as a yellow solid which can be recrystallized from ethyl acetate. Mp 170-173 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 7.24 (d, J = 2.2 Hz,

1H), 7.68 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H),

7.26 (dd, J = 8.5, 2.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H),

3.86 (s, 3H), 3.80 (s, 3H) ppm.

Analysis for C ^ gHjgOgSBr:

H, 3.59; Found: C, 52.40; H, 3.55.

Example 29

Analogously, 2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene (S-oxide) was prepared.

The compound has a melting point of 120 DEG-125 DEG.

¹ H NMR (DMSO-d 6) spectrum δ: 8.06 (d, J = 7.6 Hz,

1H), 7.78-7.59 (m, 5H), 7.13 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H) ppm. FD mass spectrum: 335.

Analysis for C-j_ ₅ H ₁₁ O ₂ SBr:

H, 3.31; Found: C, 53.71; H, 3.46.

Preparation 12

Process for preparing 4- [2- (1-piperidyl) ethoxy] phenol

To a solution of 50.50 g (0.25 mol) of 4-benzyloxyphenol in 350 ml of anhydrous dimethylformamide was added 2.30 g (0.25 mol) of 2-chloroethylpiperidine. Stir for 10 minutes and then add 52.0 g (0.375 mol) of potassium carbonate and 85.0 g (0.25 mol) of cesium carbonate. The resulting heterogeneous mixture was stirred vigorously at room temperature for 48 hours. The reaction mixture is then poured into 500 ml of water and extracted with methylene chloride. The organic layer was extracted several times with 1 N sodium hydroxide solution and then washed with saturated sodium chloride solution. The organic layer was then dried over sodium sulfate and evaporated under reduced pressure to an oil. Chromatography (silica, 1: 1 hexanes / ethyl acetate) afforded 60.0 g (77%) of 4- [2- (1-piperidyl) ethoxy] phenoxybenzyl ether as a colorless oil.

¹ H NMR (DMSO-d 6) spectrum δ: 7.40-7.27 (m, 5H),

6.84 (q, J _AB = 11.5 Hz, 4H), 4.98 (s, 2H), 3.93 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.0 Hz, 2H), 2.35-2.37 (m, 4H), 1.48-1.32 (m, 6H) ppm. FD mass spectrum: 311.

Analysis for ^C 20 ^H 25 ^{NO 2:} Calculated: 77.14% C 8.09% H 4.50% N Found: 77.34% C, 8.18% H, 4.64% N.

21.40 g (68.81 mmol) of 4- [2- (1-piperidyl) ethoxy] -1H-phenoxybenzyl ether are dissolved in 200 ml of a 1: 1 mixture of ethanol and ethyl acetate containing 1% concentrated hydrochloric acid. The solution was transferred to a Parr hydrogenator and 3.4 g of 5% palladium on carbon was added. The mixture was hydrogenated at 2 psi for 2 hours. The reaction mixture was then passed through a pad of celite to remove the catalyst. The filtrate was evaporated under reduced pressure to give a solid which was suspended in ethyl ether and filtered to give 12.10 g (83%) of 4- [2- (1-piperidyl) ethoxy] phenol. Mp 148-150 ° C.

¹H NMR (DMSO-d₆) spectrum δ: 8.40 (s, 1H), 6.70 (q, ^J AB ^{= Χ1 '5Hz' 4H) '3' 93 (t 'J 6'} ° ^{Hz '2H ) '2' 59 (t 'J =} 6.0 Hz, 2H), 2.42 to 2.38 (m, 4H), 1.52 - 1.32 (m, 6H) ppm.

FD mass spectrum: 221.

Analysis for C ₁₃ H ₁₉ NO ₂ :

H, 8.09; N, 4.50. Found: C, 70.75; H, 8.59; N, 6.54.

Example 30

Method of preparation [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide)

To a solution of 0.32 g (1.43 mmol) of 4- [2- (1-piperidyl) -122-ethoxy / phenol in 5 mL of anhydrous dimethylformamide at room temperature was added 0.57 g (1.43 mmol) of a 60% dispersion sodium hydride in mineral oil. The reaction mixture is stirred for 15 minutes and then 0.50 g (1.37 mmol) of 6-methoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene (S) is added in small portions. -oxide). Stir for 1 hour at which point the reaction was judged complete by thin layer chromatography. The solvent was evaporated under reduced pressure and the residue was partitioned between water and 10% ethanol in ethyl acetate. The organic phase is washed several times with water and then dried over sodium sulfate. Evaporation under reduced pressure gave an oil which was triturated with a mixture of ethyl acetate and hexanes. 0.62 g (89%) of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-) was obtained. oxide) as a pale yellow solid. Mp 97-100 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 7.68 (d, J = 2.1 Hz,

1 H), 7.62 (d, J = 8.8 Hz, 2H), 7.06-6.92 (m, 6H), 6.85 (d, 6H)

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) ppm.

Analysis for ^C 29 ^H 3i ^N0 5 ^S: Calculated: 68.89% C 6.13% H 2.77% N Found: 68.95% C, 6.04% H, 2.57% N.

Example 31

Analogously, [3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide) was prepared

- llt-

The compound is an oil.

¹ H NMR (DMSO-d 6) spectrum δ: 8.03 (m, 1H), 7.65 (d, d)

J = 8.7 Hz, 2H), 7.53-7.50 (m, 2H), 7.09-6.82 (m, 7H), 3.94 (broad triplet, J = 5.9 Hz, 2H), 3.74 (s, 3H), 2.56 (broad triplet, J = 5.9 Hz, 2H), 2.36-2.33 (m, 4H), 1.45-1.31 ( m, 6H) ppm. FD mass spectrum: 475.

Analysis for C ₂ 8 ^H 29 ^NO 4 ^S: Calculated: 70.71% C 6.15% H 2.94% N Found: 70.44% C 6.43% H 3.20% N .

Example 32

Process for the preparation of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride

- lil -

To a solution of 3.00 g (5.94 mmol) of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene- ( S-oxide (Example 30) in 200 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere at 0 ° C was added in small portions 0.34 g (8.91 mmol) of lithium aluminum hydride. After stirring for 30 minutes, the reaction was quenched by the careful addition of 5.0 mL of 2.0 N NaOH. The mixture was stirred vigorously for 30 minutes and then another 2.0 N sodium hydroxide solution was added to dissolve the salts. The mixture was then partitioned between water and 10% sodium hydroxide solution. The layers were separated and the aqueous layer was extracted several times with 10% ethanol in ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to an oil. The crude material was dissolved in 50 mL of a 1: 1 mixture of ethyl acetate and ethyl ether and treated with excess hydrogen chloride in ethyl ether. The resulting precipitate is collected and dried. This gave 2.93 g (96%) of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo (b) thiophene hydrochloride as a white solid. solids.

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

Preparation 13

111

Process for preparing 6-methoxybenzo [b] thiophene-2-boronic acid

To a solution of 18.13 g (0.111 mol) of 6-methoxybenzo [b] thiophene in 150 ml of anhydrous tetrahydrofuran at -60 DEG C. 76.2 ml (0.122 mol) of a 1.6 molar solution of n-butyllithium in hexanes is added by injection syringe. After stirring for 30 minutes, the syringe is introduced

28.2 ml (0.122 mol) of triisopropyl borate. The resulting mixture was allowed to gradually warm to 0 ° C and then partitioned between 300 ml of 1N hydrochloric acid and ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate. Evaporation under reduced pressure gave a white solid which was triturated with a mixture of ethyl ether and hexanes.

Filtration gave 16.4 g (71%) of 6-methoxybenzo [b] thiophene-2-boronic acid as a white solid. The compound has a melting point of 200 DEG C. (decomposition).

¹ H NMR (DMSO-d ₆ ) δ spectrum: 7.83 (s, 1H), 7.78 (d, 1H);

J = 8.6 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.97 (dd, J =

8.6, 2.0 Hz, 1H), 3.82 (s, 3H) ppm. FD mass spectrum: 208.

Preparation 14

Method of production 6-methoxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene h ₃ Co

- ii5 -

OSOjCHj

To a solution of 3.00 g (14.4 mmol) of 6-methoxybenzo [b] thiophene-2-boronic acid in 100 mL of toluene was added 3.98 g (15.8 mmol) of 4- (methanesulfonyloxy) phenyl bromide followed by 16 mL 2.0-normal sodium carbonate solution. After stirring for 10 min, 0.60 g (0.52 mol) of palladium tetrakistriphenylphosphine was added and the resulting mixture was refluxed for 5 h. The reaction mixture is then allowed to cool to room temperature, whereupon the substance precipitates out of the organic phase. The aqueous phase was removed and the organic layer was evaporated under reduced pressure to give a solid. Trituration from ethyl ether gave a solid which was filtered off and dried under reduced pressure. 3.70 g (77%) of 6-methoxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene were obtained as a brown solid. M.p. 197 DEG-201 DEG.

¹ H NMR (DMSO-d 6) δ spectrum: 7.82-7.77 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2, 3 Hz, 1 H), 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) ppm. FD mass spectrum: 334.

Analysis for C ₁₆ H ₁₄ O ₄ S ₂ :

C, 57.46; H, 4.21; Found: C, 57.76;

Preparation 15

In an analogous manner to Preparation 14, 6-methoxy-2- (4-benzyloxyphenyl) benzo b] thiophene was prepared.

H ₃ co

OBn

The yield was 73%. Mp 217-221 ° C.

^T H NMR (DMSO-d₆) spectrum δ: 7.63 to 7.60 (m, 3H), 7.59 - 7.26 (m, 7H), 7.02 (d, J = 8.7 Hz, 2H), 6.96 (dd, J = 8.8,

2.2 Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H) ppm. FD mass spectrum: 346.

Analysis for ^C 22 ^H 18 ° ^{S 2:} Calculated: 76.27% C 5.24% H Found: 76.00% C, 5.25% H.

Preparation 16

Process for the preparation of 6-hydroxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene

To a solution of 9.50 g (23.40 mmol) of 6-methoxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene in 200 mL of anhydrous methylene chloride at room temperature under a nitrogen atmosphere is added 14.20 g (5%). , 36 ml, 56.3 mmol) of boron tribromide. The resulting mixture was stirred at room temperature for 3 hours. The reaction is quenched by slowly pouring the reaction mixture into excess ice. After vigorous stirring for 30 minutes, the white precipitate was filtered off, washed several times with water and then dried under reduced pressure to give 8.92 g (98%) of 6-hydroxy-5Si. -2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene as a white solid. Mp 239-243 ° C.

^{Χ Η} NMR (DMSO-d₆) spectrum?: 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) ppm. FD mass spectrum: 320.

Analysis for ^{C H} i2 i5 ° 4 ^{S 2:} Calculated: 56.23% C 3.77% H Found: 56.49% C, 3.68% H.

Preparation 17

Method of Production 6-Benzyloxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene

To a solution of 3.20 g (10.0 mmol) of 6-hydroxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene in 75 ml of anhydrous dimethylformamide is added 5.75 g (17.7 mmol) of cesium carbonate and then 1.72 ml (11.0 mmol) of benzyl chloride. The resulting mixture was stirred vigorously for 24 hours. The solvent was evaporated under reduced pressure and the solid residue was suspended in 200 mL of water. The white precipitate was filtered off and washed several times with water. After drying under reduced pressure, the crude material was suspended in a 1: 1 mixture of hexanes and ethyl ether. The solid was collected to give 3.72 g (91%) of 6-benzyloxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene as a white solid.

- 110 fabric. The compound had a melting point of 198-202 ° C.

¹ H NMR (DMSO-d 6) δ spectrum: 7.81-7.78 (m, 3H), 7.72 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2, 2 Hz, 1H), 7.47-7.30 (m, 7H), 5.15 (s, 2H), 3.39 (s, 3H) ppm. FD mass spectrum: 410.

Preparation 18

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

To a solution of 12.50 g (30.50 mmol) of 6-benzyloxy-2- (4-methanesulfonyloxyphenyl) benzo [b] thiophene in 300 ml of anhydrous tetrahydrofuran at room temperature under a nitrogen atmosphere was added in small portions 2.32 g (61.0 mmol) lithium aluminum hydride. The mixture was then stirred at room temperature for 3 hours and then quenched by carefully pouring the mixture into excess cold 1.0 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phase is washed several times with water and then dried over sodium sulfate. Evaporation under reduced pressure gave a solid which was chromatographed (silica, chloroform). 8.75 g (87%) of 6-benzyloxy-2- (4-hydroxyphenyl) benzo [b] thiophene are obtained as a white solid. Mp 212-216 ° C.

¹ H NMR (DMSO-d ₆ ) δ spectrum: 9.70 (s, 1H), 7.63 (d, 6H);

J = 8.7 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.51-7.30 (m, 8H), 7.00 (dd, J = 8.7) , 2.2 Hz, 1H), 6.80 (d, J = 8.6 Hz,

3 '] 2Η), 5.13 (s, 2Η) ppm. FD mass spectrum: 331.

Analysis for ^{C H} 2i i6 ° 2 ^S: calculated: 75.88% C 4.85% H Found: 75.64% C, 4.85% H.

Example 19

Process for the preparation of 6-benzyloxy-2- (4-methoxyphenyl) benzo (b) thiophene

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

¹ H NMR (DMSO-d 6) spectrum δ: 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J = 8.8, 2) , 2 Hz, 1 H), 6.93 (d,

J = 8.7 Hz, 2H), 5.13 (s, 2H), 3.76 (s, 3H) ppm. FD mass spectrum: 346.

- 120 Analysis for ^C 22 ^H 13 ° ^{S 2:} Calculated: 76.27% C 5.24% H Found: 76.54% C, 5.43% H.

Preparation 20

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

10.0 g (23.9 mmol) of 6-benzyl-oxy-2- (4-methoxyphenyl) benzo [b] thiophene were added to 200 ml of chloroform together with 10.0 g of solid sodium bicarbonate at room temperature. To this suspension was added dropwise 1.50 ml (29.1 mmol) of bromine over 30 minutes as a solution in 100 ml of chloroform. After the addition is complete, 200 ml of water are added to the reaction mixture and the layers are separated. The organic phase was dried over sodium sulfate and evaporated under reduced pressure 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. Mp 146-150 ° C.

¹ H NMR (DMSO-d ₆ ) δ spectrum: 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) ppm. FD mass spectrum: 346.

Analysis for ^c 22 ^H 17 ° 2 ^SBr:

% C, 62.13; H, 4.03; Found: C, 61.87; H, 4.00.

Preparation 21

Analogously, 6-methoxy-2- (4-benzyloxyphenyl) -3-bromo-benzo [b] thiophene was prepared

Yield 91%. The compound has a melting point of 125 to

127 'C.

¹ H NMR (DMSO-d 6) δ spectrum: 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) ppm. FD mass spectrum: 346.

Analysis for C 2 ^H _2] _7 ^O 2 ^SBr: Calculated: 62.13% C 4.03% H Found: 62.33% C, 3.93% H.

Similarly to Example 28, the compounds described in Examples 33 and 34 were prepared.

Example 33

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

- 12 ^ -

It was isolated as a yellow solid by crystallization from ethyl acetate. Mp 202-205 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 7.80 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.55 (d, J 7.47-7.32 (m, 6H), 7.10 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H), 3.80. (s, 3H) ppm. FD mass spectrum: 441.

Analysis for ^C 22 ^H 17 ° 3 ^SBr: Calculated: 59.87% C 3.88% H Found: 59.59% C, 3.78% H.

Example 34

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

It is isolated as a yellow solid by chromatography (silica, chloroform). Mp 119-123 ° C.

¹ H NMR (DMSO-d 6) δ spectrum: 7.73 (d, J = 2.2 Hz, 1H),

37.68 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 3.5 Hz, 1H), 7.46-7.31 (m, 5H), 7.26 (dd) , J = 8.5, 2.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H) ppm. FD mass spectrum: 441.

Analysis for C ₂₂ H ₁₇ O ₃ SBr:

H, 3.83; Found: C, 60.13; H, 4.10.

Similar to Example 30, the compounds described in Examples 35 and 36 were prepared.

Example 35 [6-Benzyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide)

oca-.

The compound is a yellow oil.

¹ H NMR (DMSO-d 6) spectrum S: 7.76 (d, J = 2.2 Hz, 1H),

7.62 (d, J = 3.8 Hz, 2H); 7.44-7.30 (m, 5H);

J = 8.6, 2.2 Hz, 1H), 7.03-6.93 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H) ), 3.94 (broad triplet, J = 5.8 Hz,

2H), 3.73 (s, 3H), 2.56 (broad triplet, J = 5.8 Hz, 2H),

IN

2.37-2.34 (m, 4H), 1.45-1.32 (m, spectrum: 592).

Analysis for C ₃₅ H ₃₅ NO ₅ S:

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

Example 36

6H) ppm. FD mass [6-Methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene (S-oxide)

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

¹ H NMR (DMSO-d 6) δ spectrum: 7.68 (d, J = 2.2 Hz, 1H),

7.62 (d, J = 8.8 Hz, 2H), 7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H), 6.86 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 3.94 (broad triplet, J = 5.8 Hz, 2H), 3.81 (s, 3H), 2.56 (broad triplet, J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H) ppm. FD mass spectrum: 592.

Analysis for C ₃₅ H ₃₅ NO ₅ S. 0.25 CH ₃ COOC ₂ H ₅ :

H, 6.18; N, 2.32;

Found: C, 71.32; H, 5.96; N, 2.71.

Similarly to Example 11, the compounds described in Examples 37 and 33 were prepared.

Example 37

Production method of [6-benzyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene

BnO o

OCH

The compound was isolated in 95% overall yield starting from 6-benzyloxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene (S-oxide). Purification is carried out by chromatography (silica, 1-5% methanol in chloroform) to give an off-white solid. The compound has a melting point of 105-108 ° C.

NMR (DMSO-d 6) spectrum 5: 7.62 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.30 (m , 5H), 7.15 (dd,

J = 8.6 Hz, 1H), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (broad triplet, J = 5.8 Hz, 2H), 3.72 (s, 3H), 2.55 (broad triplet, J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44 1.31 (m, 4H) ppm. FD mass spectrum: 565.

Analysis for C ₃₅ H ₃₅ NO ₄ S:

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

Example 38 [6-Methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl) benzo [b] thiophene

The yield was 91%. Mp 106-110 ° C.

¹ H NMR (DMSO-d 6) δ spectrum: 7.59 (d, J = 8.8 Hz, 2H),

7.54 (d, J = 2.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (d, J =

8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (s, 4H), 5.08 (s 2H), 3.92 (broad triplet, J = 5.8 Hz, 2H), 3.78 (s, 3H),

2.55 (broad triplet, J = 5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1.44-1.31 (m, 4H) ppm. FD mass spectrum: 565.

Analysis for C ₃₅ H ₃₅ NO ₄ S:

H, 6.24; N, 2.48. Found: C, 74.26; H, 6.17; N, 2.73.

Example 39 r

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

To a solution of 8.50 g (15.0 mmol) of [6-benzyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene in 300 ml of a 5: 1 mixture of ethanol and ethyl acetate, 1.50 g of palladium black, 3.50 g (55.6 mmol) of ammonium formate and 30 ml of water were added. The resulting mixture was refluxed and monitored by thin layer chromatography. After approximately 3 hours, the reaction was judged to be quantitative and the solution was cooled to room temperature. The reaction mixture was filtered through a pad of celite to remove the catalyst and the filtrate was evaporated under reduced pressure to give a solid. The concentrate was partitioned between saturated sodium bicarbonate solution and 5% ethanol in ethyl acetate.

The layers were separated and the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The crude material was chromatographed (silica, 1-5% methanol in chloroform) to give 6.50 g (91%) of [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] - 2- (4-methoxyphenyl)] benzo [b] thiophene as a foam which is converted to a solid after trituration with hexanes. Mp 174-176 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.77 (s, 1H), 7.56 (d, d).

J = 8.8 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 8.6)

Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (s, 4H), 6.76 (dd, 2H),

J = 8.6, 2.0 Hz, 1H), 3.91 (broad triplet, J = 5.9 Hz, 2H), 3.71 (s, 3H), 2.55 (broad triplet, J = 5) 9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H) ppm. FD mass spectrum: 475.

Analysis for C ₂₈ H _2g NO ₄ S:

H, 6.15; N, 2.94. Found: C, 70.46; H, 5.93;

Example 40

In an analogous manner to Example 39, [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4'-hydroxyphenyl)] benzo [b] thiophene was prepared.

OH

Yield 88%. The compound has a melting point of 147 to

150 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.72 (s, 1H), 7.51 (d, m).

J = 2.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 Hz, 1H), 6.81 (s, 4H), 6.76 (d, J = 8.6 Hz, 2H), 3.91 (broad triplet, J = 5.9 Hz) , 2H),

3.77 (s, 3H), 2.55 (broad triplet, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H) ) ppm. FD mass spectrum: 475.

Analysis for ^C 28 ^H 29 ^NO 4 ^S: Calculated: 70.71% C 6.15% H 2.94% N Found: 71.00% C, 6.17% H, 2.94% N.

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

Example 41 [6-Hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (Example 39) was converted to its hydrochloride in 85% yield. % by treatment with ethyl ether solution of hydrogen chloride in ethyl acetate and then crystallized from a mixture of ethanol and ethyl acetate.

Mp 156-160 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 10.28 (broad singlet,

- 13 # 1H), 9.85 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.87 (q, J _AB = 9.3 Hz, 4H), 4.27 ( wide triplet, J =

5.9 Hz, 2H), 3.71 (s, 3H), 3.44-3.33 (m, 4H), 2.98-2.88 (m, 2H), 1.74-1.60 (m, 5H), 1.36-1.29 (m, 1H) ppm. FD mass spectrum: 475.

Analysis for ^C 28 ^H 29 ^NO 4 ^S. 1.0 HCl:

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

Example 42

In an analogous manner to Example 41, [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride was prepared.

The compound has a melting point

215 to 217 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 10.28 (broad singlet, 1H), 9.80 (S, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.47 ( d, J =

8.6 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.91-6.80 (m, 5H),

6.78 (d, J = 8.6 Hz, 2H), 4.27 (broad triplet, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.43-3.33 (m, 4H), 2.97-2.91 (m, 2H),

1.78-1.61 (m, 5H), 1.36-1.29 (m, 1H) ppm. FD weight

13, spectrum: 475.

Analysis for ^C 28 ^H 29 ^NO 4 ^S. 1.0 HCl:

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

Example 43

Process for the preparation of [6-benzoyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-benzoyloxyphenyl) benzo [b] thiophene hydrochloride

To a solution of Example 20 (0.50 g, 1.08 mmol) in dry tetrahydrofuran (20 mL) at 0 ° C was added triethylamine (1.00 mL). To this mixture was added 0.28 mL (2.35 mmol) of benzoyl chloride. Stir for 2 hours at room temperature and quench the reaction rapidly by partitioning between 100 mL of ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the organic layer was dried over sodium sulfate and evaporated under reduced pressure to a white solid. The crude material was dissolved in 10 mL of ethyl acetate and treated with ethyl ether hydrochloric acid. The resulting white precipitate was collected by filtration and dried to give 390 mg (50%) of [6-benzoyloxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-benzoyloxyphenyl) benzoic acid hydrochloride. [b] thiophene as a white solid. The compound had a melting point of 200 DEG-204 DEG.

1 H NMR (DMSO-d 6) spectrum δ: 9.95 (broad singlet,

1 H), 8.18 (m, 1H), 8.16 (m, 2H), 8.12 (dd, J = 10.0, 2.0 Hz, 2H), 7.87 (dd, J = 7 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) ppm.

Analysis for C ₄₁ H ₃₅ NO 8 S. 1.5 HCl:

H, 5.08; N, 1.93. Found: C, 68.05; H, 5.24; N, 2.01.

In the same way:

Example 44

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

The yield is 72%. Mp 110-115 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 10.15 (broad singlet, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 7.0 Hz, 2H),

- X3J -

7.43 (m, 3H), 7.34 (dd, J = 9.0, 2.0 Hz, 1H), 6.97 (m, 4H), 4.31 (m, 2H). 3.57 (m, 4H), 3.44 (m, 4H), 2.97 (m, 2H), 1.76 (m, 5H), 1.40 (m, 7H) ppm.

Analysis for ^C 35 ^H 3i ^NO 8 ^with the third 1.5 HCl:

H, 5.32; N, 2.05. Found: C, 54.36; H, 5.37;

In a similar manner, compounds described below were prepared using trifluromethanesulfonic anhydride.

Example 45 [6-Methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-trifluoromethanesufonyloxyphenyl) benzo [b] thiophene

Yield 81%. The compound is in the form of an oil.

¹ H NMR (DMSO-d 6) spectrum δ: 7.82 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (d, J 7.17 (d, J = 8.8 Hz, 1H); 6.93 (dd, J = 3.8, 2.0 Hz, 1H); , 4H), 3.92 (broad triplet, J = 5.7 Hz, 2H), 3.79 (s, 3H), 2.56 (broad triplet, J = 5.7 Hz, 2H), 2.36 2.30 (m, 4H), 1.44-1.31 (m, 6H) ppm. FD mass spectrum: 607.

Analysis for ^C 29 ^H 23 ^NO 6 ^F 3 ^S 2 ^: Calculated: C, 57.32; H, 4.64; N, 2.30.

Found: 57.16% C, 4.52% N.

% H, 2.01

The compounds of Example 1 were prepared similarly to the compounds below.

Example 46

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

HCl

The yield was 85%. M.p.

198 ° C.

1 H), (m, 2H), (m,

550.

^{Σ Η} NMR (DMSO-d from 8.00 to 8.10 (m, 4H), 7.40 to 7.56 3.00 to 3.05 (m, 3H), 1.40 to 1.50 ₆₎ spectrum δ: 10.43 (broad singlet, 2H), 7.80-8.00 (m, 3H), 7.60-7.53 (m, 6H), 6.93 (s, 2H), 4.37 4.43 (m, 2H), 2.53-2.63 (m, 6H), 1.75-1.95 (m, 1H) ppm., FD mass spectrum Analysis for C ₃₄ H ₃₁ NO ₄ S . 1.0 HCl:

H, 5.68; N, 2.55. Found: C, 74.52; H, 5.80;

Example 47

Yield 90%. M.p.

197 ° C.

1 H NMR (DMSO-d 6) spectrum δ: 10.10 (broad singlet, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H)

7.40 - 7.53 (m, 3H), 7.15 (d, J = 6 ', 7 Hz, 2H), 7.00 (s, 5H)

4.33-4.40 (m, 2H), 3.45-3.60 (m, 4H), 3.00-3.10 (m,

2H), 1.70-1.90 (m, 6H), 1.40 (s, 9H) ppm. FD mass spectrum: 529.

Analysis for ^C 32 ^H 35 ^NO 4 ^S · 1.0 HCl:

H, 6.41; N, 2.47. Found: C, 68.94; H, 6.61; N, 1.72.

Example 48

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

-

The yield was 85% white solid. Mp 98-104 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 10.20 (broad singlet, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H),

7.40 - 7.55 (m, 5H), 7.00 (s, 4H), 4.30 - 4.40 (m, 2H), 3.46

3.66 (m, 6H), 3.00-3.10 (m, 2H), 1.70-1.95 (m, 6H),

1.40-1.60 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H) ppm. FD mass spectrum: 565.

Analysis for ^c 3iH ₃ gNO ₅ S ₂ · 1.0 HCl:

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

Preparation 21

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

13 H-CO ₃ CO ₃ CO

with

OCH ₂ OCH ₃

Process for preparing 4- (methoxymethyloxy) phenyl disulfide

To a solution of 650 mg (2.60 mmol) of 4-hydroxyphenyl disulfide in 10 mL of anhydrous .beta. Stir for 15 minutes and then add 0.44 mL (5.75 mmol) of chloromethyl methyl ether. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The mixture was partitioned between 20 ml of brine and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with 20 ml of ethyl acetate each time. The organic layer was dried over sodium sulfate and evaporated to a yellow oil (993 mg, 100%). An analytical sample of 4- (methoxymethyloxy) phenyl disulfide was prepared by chromatography (silica, 4% ethyl acetate and hexanes).

¹ H NMR (DMSO-d 6) spectrum 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) ppm.

FD mass spectrum: 338.

Analysis for ^C 18 ^H i6 ° 4 ^{S 2:} Calculated: 56.78% C 5.36% H Found: 57.03% C, 5.44% H.

Example 49

Method of Production 6-Methoxy-2- (4-methoxyphenyl) -3- (4-methoxy-13-methyleneoxy) thiophenoxy / benzo [b] thiophene

To a solution of 1.82 g (5.2 mmol) of 6-methoxy-2- (4-methoxyphenyl) -3-bromo-benzo [b] thiophene in 10 ml of anhydrous tetrahydrofuran under nitrogen at -60 ° C was added dropwise. 3.15 ml (5.0 mmol) of a 1.6 molar solution of n-butyllithium in hexanes by syringe. Heat the resulting mixture at -20 ° C for 10 minutes, then cool again to -60 ° C, add 800 mg (2.36 mmol) of 4- (methoxymethyloxy) phenyl disulfide in -5 mL of anhydrous tetrahydrofuran to the lithium compound and The resulting mixture was allowed to gradually warm to 0 ° C. The mixture was stirred for 20 minutes and then quenched with 50 mL of brine and ethyl acetate. The layers were separated and the aqueous phase was extracted twice with 50 ml of ethyl acetate each time. The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure to an oil. Chromatography (silica, 5% ethyl acetate in hexanes) afforded 287 mg (27%) of 6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy / benzo [b] thiophene as a colorless oil.

1 H NMR (DMSO-d 6) spectrum S: 7.59 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (d, J 8.03 (6.8H, 7H), 5.06 (s, 2H), 3.79 (s, 3H), 3.76 (s, 3H) ppm. FD mass spectrum: 438.

^Analysis: Calculated: 65.73% C 5.06% H Found: 65.93% C, 5.10% H.

Example 50

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

To a solution of 233 mg (0.53 mmol) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy] benzo [b] thiophene in 10 ml of a 1: 1 mixture of methanol, water and tetrahydrofuran : 1: 2 0.2 ml (2.66 mmol) of methanesulfonic acid is added. The mixture was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water. The aqueous phase is extracted twice with ethyl acetate. The organic layer was washed several times with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. So get it?

206 mg (99%) of 6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy / benzo [b] thiophene as a colorless oil.

¹ H NMR (DMSO-d 6) spectrum δ: 9.43 (s, 1H), 7.63 (d, d)

J = 8.4 Hz, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 3.4 Hz, 2H), 7.02 (dd, J = 8.8, 2.0 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H); J = 3.6 Hz, 2H) ppm.

14 FD mass spectrum: 395.

Analysis for ^C 22 ^H 18 ° 3 ^{S 2:} Calculated: 66.98% C 4.60% H Found: 67.26% C, 4.78% H.

Example 51

Production method of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene

To a solution of 242 mg (0.61 mmol) of 6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxybenzo [b] thiophene in 8.0 ml of anhydrous N, N-dimethylformamide cesium carbonate (820 mg, 2.5 mmol) was added followed by chloroethylpiperidine hydrochloride (194 mg, 1.05 mmol). The resulting mixture was stirred at room temperature for 48 hours and then partitioned between brine and ethyl acetate. The layers were separated and the aqueous layer was washed three times with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to an oil. Chromatography (silica, 0-2% methanol in chloroform) afforded 244 mg (92%) of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene as an amber colored oil.

Example 52

A sample of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene was converted to its hydrochloride in a normal manner in 72% yield.

M.p. 193 DEG-201 DEG.

¹ H NMR (DMSO-d 6) spectrum 5: 7.63 (d, J = 8.6 Hz, 2H),

7.62 (d, J = 2.0 Hz, 1H); 7.58 (d, J = 8.2 Hz, 1H);

J = 8.6 Hz, 2H), 7.02 (dd, J = 8.2, 2.0 Hz, 1H), 6.92 (q, J _AB = 9.0 Hz, 4H), 4.24 (broad triplet, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.49-3.39 (m, 4H), 2.93 (m, 2H), 1.82 1.62 (m, 5H), 1.38 (m, 1H) ppm.

Analysis for ^C 29 ^H 32 ^NO 3 ^S 2. 1.0 HCl:

H, 5.95; N, 2.58. Found: C, 64.09; H, 6.03;

Example 53

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

- 14t-

To a solution of 160 mg (0.29 mmol) of [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride in 15 mL of anhydrous methylene chloride at 0 ° C under nitrogen was added 0.15 ml of boron tribromide. The resulting dark solution was stirred at 0 ° C for 1 hour and then immediately poured into 50 mL of stirred ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was washed three times with 30 ml of ethyl acetate each time. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a white solid. Chromatography (silica, 0 to 5% methanol in chloroform) affords 91 mg (60%) of [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl) ] benzo [b] thiophene as a white solid. Mp 123-127 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.79 (s, 1H), 9.71 (s, 1H);

1H), 7.46 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 3.9 Hz, 1H),

7.26 (d, J = 2.0 Hz, 1H); 6.91 (d, J = 8.8 Hz, 2H); 6.82-6.76 (m, 5H); , J = 8.3 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.40 (m, 4H), 1.41-1.28 (m, 6H) ppm. FD mass spectrum: 473.

Analysis for C ₂₇ H ₂₇ NO ₃ S ₂ :

H, 5.70; N, 2.93. Found: C, 68.14; H, 5.84;

Example 54

Process for the preparation of [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene hydrochloride

Mp 180-190 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 9.86 (s, 1H), 9.79 (s, s);

1H), 7.46 (d, J = 3.5 Hz, 2H), 7.42 (d, J = 8.7 Hz, 1H),

7.29 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.86

6.81 (m, 5H), 4.27 (m, 2H), 3.41-3.37 (m, 4H), 2.96

2.84 (m, 2H), 1.77-1.60 (m, 5H), 1.35-1.28 (m, 1H) ppm FD mass spectrum: 477.

Analysis for ^C 27 ^H 27 ^N0 3 ^S 2 · ^{2.2 HCl:} Calculated: 58.13% C 5.28% H 2.51% N Found: 58.11% C, 5.10% H, 2.61% N.

The following compounds are prepared by the same methods:

Example 55

IN

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

Mp 215-218 ° C.

¹ H NMR (DMSO-d 6) spectrum δ: 7.61-7.58 (m, 3H), 7.52 (d, J = 8.8 Hz, 1H), 7.04-6.95 (m, 5H), 6.86 (d, J = 8.8 Hz, 2H), 4.22 (broad triplet, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.47 3.42 (m, 4H), 3.01 (m, 2H), 1.94-1.80 (m, 4H) ppm. FD mass spectrum: 491.

Analysis for ^C 28 ^H 29 ^NO 3 ^S 2 · 1 +. ^{θ HC1 Calculated:} 63.67% C 5.73% H 2.65% N Found: 63.47% C, 5.78% H, 2.65% N.

Example 56

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

- 14 <· -

Mp 137-140 ° C (dec.).

¹ H NMR (DMSO-d 6) spectrum δ: 9.86 (s, 1H), 9.80 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.42 (d , J = 8.7 Hz, 1 H),

7.29 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.87-6.81 (m, 5H), 4.21 (broad) triplet, 2H), 3.53-3.41 (m, 4H), 3.01 (m, 2H), 1.95-1.82 (m, 4H) ppm. FD mass spectrum: 464.

Analysis for C26 ^H 25 ^NO 3 ^S 2 ^'1/0: calculated: 62.45% C 5.24% H 2.30% N Found: 62.36% C, 5.37% H, 2.61 % N.

Example 57

[6-Methoxy-3- [4- [2- (1-piperidyl) ethoxy phenoxy] -2- (phenyl)] benzo [b] thiophene hydrochloride was prepared from Example 45 by hydrogenolysis of trifluoromethanesulfonate as described below 58.

The compound has a melting point

187 to 195 ° C.

¹ H NMR (DMSO-d 6) δ spectrum: 7.66 (d, J = 2.8 Hz, 2H),

7.58 (d, j = 2.0 Hz, 1H), 7.39 (t, J = 7 5 Hz, 2H), 7.28 (m, 1H) 7.17 (d, J = 8.8 Hz, 1H), 6.91 (dd, J ⁼ 8.8, 2.0 Hz 1H) 6.89 (s, 4H), 4, 23 (wide triplet, J = 5.7H, 2H), 3.79 (s, 3H), 3.45 - 3.38 (m, 4H), 2.93 (m, 2H), 1.77-1.61 (m, 5H), 1.31 (m, 1 H) ppm. FD weight Spectrum: 460.

Analysis for ^C 28 ^H 29 ^NO 3 ^S. H, 6.10; N, 2.84. Found: C, 67.62; H, 5.89; N, 2.67.

Example 58

Process for the preparation of [6-hydroxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (phenyl) benzo [b] thiophene hydrochloride

To a solution of 5.00 g (10.0 mmol) of (6-hydroxy-3- (4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride in Triethylamine (8.38 ml, 60.0 mmol) and then trifluoromethanesulfonic anhydride (1.69 ml, 10.0 mmol) were added to 100 ml of anhydrous methylene chloride at 0 ° C under a nitrogen atmosphere. The reaction was then quenched by pouring into 200 mL of saturated sodium bicarbonate solution, then extracting the aqueous phase three times with 100 mL of ethyl acetate each time, drying the organic phase over sodium sulfate and evaporating under reduced pressure to an oil. methanol in chloroform) affords 2.82 g (39%) of 6-trifluoromethanesulfonate-3- (4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-trifluoromethanesulfonatphenyl) benzo (b) thiophene; , 82 (31%) of the 1: 1 mixture

3- [4- (2- (1-piperidyl) ethoxy) ethoxy] phenoxy] -2- (4-phenyl)] benzo (b) thiophene; (phenoxy) -2- (4-trifluoromethanesulfonatphenyl) benzo [b] thiophene and 1.48 g (36%) of the starting material obtained as the free base.

To a solution of 0.50 g (0.84 mmol) of the monotrifluoromethanesulfonate derivative in a 1: 1 mixture from the latter reaction in 60 ml of a 5: 1 mixture of ethanol and ethyl acetate, 2.0 ml of triethylamine and 0.50 g of 5 are added. % palladium on carbon. The resulting mixture was hydrogenated at 2 psi for 2 hours. The reaction mixture is then filtered through a pad of celite to remove the catalyst. The filtrate was evaporated to an oil. The resulting monohydroxy derivative mixture was dissolved in ethyl acetate to precipitate 3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene. The filtrate consists of a 4: 1 mixture of monohydroxy derivatives where 6-hydroxy-3- [4- (2- (1-piperidyl) ethoxy) phenoxy] -2- (phenyl) benzo [b] thiophene is the major component. The filtrate was evaporated under reduced pressure and the resulting solid dissolved in a minimal 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-piperidyl) ethoxy] phenoxy] -2- (phenyl) benzo [b] hydrochloride. ] thiophene having a melting point of 217-219 ° C.

¹ H NMR (DMSO-d 6) δ spectrum: 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 (broad triplet) , 2H), 3.39-3.37 (m, 4H), 2.97-2.90 (m,

2H), 1.74-1.60 (m, 5H), 1.39 (m, 1H) ppm. FD mass spectrum: 446.

Analysis for ^C 27 ^H 27 ^NO 3 ^S. 1.0 HCl:

H, 5.86; N, 2.91. Found: C, 67.00; H, 5.59; N, 2.87.

In another embodiment, the compound of Example 58 is prepared by demethylating the compound of Example 57 as described in Example 18.

Example 59 v

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

The compound is a yellow oil.

NMR (DMSO-d6) spectrum δ: 7.69 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.09-6.99 (m , 5H), 6.96-6.87 (m, 3H), 4.76 (septet, J = 6.0 Hz, 1H), 3.99 (broad triplet, J = 6.0 Hz, 2H), 3.78 (s, 3H), 2.61 (broad triplet, J = 6.0 Hz, 2H), 2.44-2.37 (m, 4H), 1.53-1.43 (m, 4H) ), 1.40-1.32 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H) ppm. FD mass spectrum: 533.

Analysis for C ₃₁ H ₃₅ NO ₅ S. 0.67 H ₂ 0:

N, 2.57. Found: C, 67.90; H, 6.31; N, 2.53.

(6-Isopropoxy-3- [4- (2- (1-piperidyl) ethoxy) phenoxy] -2- (4-methoxyphenyl) benzo (b) thiophene (S-oxide) hydrochloride was prepared as described for [6-methoxy-3- [4- [2- (1-piperidyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo (b] thiophene (Example 32).

- 15Ú-

Mp 168-170 ° C.

¹ H NMR (DMSO-d 6) spectrum S: 10.37 (s, 1H), 7.58 (d, m).

J = 8.6 Hz, 2H), 7.52 (d, J = 1.3 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.92-6.85 (m, 5H), 4.64 (septet, J = 6.0 Hz, 1H), 4.28 (broad triplet, J = 6.0 Hz) (2H), 3.72 (s, 3H), 3.44-3.37 (m, 4H), 2.95-2.88 (m, 2H), 1.73-1.60 (m, 5H ), 1.36-1.28 (m, 1H), 1.25 (d, J = 6.0 Hz, 6H) ppm. FD mass spectrum: 517.

Analysis for C ₃₁ H ₃₅ NO ₄ S. HC1:

H, 6.55; N, 2.53. Found: C, 67.15; H, 6.29;

(6-Isopropoxy-3- [4- (2- (1-piperidyl) ethoxy) phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride is converted to 6-hydroxy-3- [4- 2- (1-piperidyl) ethoxy / phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene by treatment with 2.0 equivalents of boron trichloride at 0-10 ° C in anhydrous dichloromethane (the methyl ether does not cleave under these conditions) ).

¹⁵ Ί '

Test procedure

General preparation procedure

In the examples illustrating the methods, a post-menopausal model is used to determine the effects of various treatments on circulating lipids.

days old female Sprague Dawley rats (weighing from 200 to 225 g) are obtained from Charles River Laboratories (Portage, MI, USA). The animals were either bilateral ovariectomized (OVX) or Sham's surgical procedure at Charles River Laboratories and then transported after 1 week. Upon delivery, the rats are placed in metal suspension cages in groups of 3 or 4 animals per cage and allowed access to ad libidum (calcium content of about 0.5%) and water for 1 week. The room temperature is maintained at 22.2 ± 1.7 ° C with a minimum relative humidity of 40%. The photoperiod in the room is 12 hours light and 12 hours dark.

Dosage regimen for tissue collection

After a one week acclimation period (therefore, two weeks after varicectomization), daily dosing of the test compound is started. 17-α-Ethinylestradiol or test compound is administered orally, unless otherwise indicated, as a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. Animals receive a dose for 4 days per day.

After dosing regimen the weight of the animals is determined. The animals are anesthetized with a 2: 1 mixture of ketam and xylazine and blood samples are collected by cardiac puncture.

The animals are then sacrificed by carbon dioxide asphyxiation, uterus

Except for the midline incision, the wet uterine weight is determined.

Cholesterol Analysis

Blood samples are allowed to coagulate at room temperature for 2 hours and serum is obtained by centrifugation for 10 minutes at 3000 rpm. Serum cholesterol is determined using a high resolution test of Boehringer Mannheim Diagnostics. Briefly, cholesterol is oxidized to cholest-4-en-3-one and hydrogen peroxide. The hydrogen peroxide is then reacted with phenol and 4-aminophenazone in the presence of peroxidase to form a p-quinone imine dye, the concentration of which is then read spectrophotometrically at 500 nm. The cholesterol concentration is then calculated against a standard curve. The entire test is automated using Biomek Automated Workstation.

Dermal Eosinophil Peroxidase (EPO) Test

The uteri are maintained at 4 ° C until enzyme analysis. The uteri are then homogenized in a 50-fold volume of 50 mM Tris buffer (pH 8.0) containing 0.005% Triton X-100. After the addition of 0.01% hydrogen peroxide and 10 mM O-phenylenediamine (final concentration) in Tris buffer, the increase in absorbance was monitored for 1 minute at 450 nm. The presence of eosonophils in the uterus indicates the estrogenic activity of the compound. The maximum velocity of the 15 second interval is determined during the initial, linear portion of the reaction curve.

Compound source

15I, 17-α-Ethinylestradiol is obtained from Sigma Chemical Co., St. Petersburg. Louis, MO, USA.

Effect of Compounds of Formula I on Serum Cholesterol and Determination of Agonist / Neagonist Activity

The data in Table I below show comparable results between ovariectomized rats, 17α-ethinylestradiol-treated rats (EE ₂ , orally available estrogen form) and rats treated with certain compounds of the invention. Although 17α-ethinylestradiol is the cause of a decrease in serum cholesterol when administered orally at 0.1 mg / kg per day, the uterine stimulating effect is also such that the weight of the uterus treated with 17α-ethinylestradiol is significantly greater than the uterine weight of the ovariectomized test animals . This uterine response to estrogen is well known in the art.

Not only are the compounds of the invention generally lowering serum cholesterol compared to ovariectomized control animals, but uterine weight is only minimally increased with poorly reduced amounts in most test compound compositions. Compared to estrogenic compounds known in the art, a preferred reduction in serum cholesterol without adverse effects on uterine weight is quite rare and desirable.

As expressed below, estrogenicity is also determined by evaluating the adverse response of eosinophilic infiltration to the uterus. The compounds of this invention do not cause any increase in the number of eosinophils observed in the ovariectomized rat stromal layer, while estradiol

15 (causing substantial, expected increase in eosinophilic infiltration.

The data presented in Table 1 below express 6 rats per treatment. Table 1 Response 5 or Serum Cholesterol (% decrease against OVX) Compound Dose mg / kg Uterine weight (% increase against OVX) EPO Uterus (V. max) ee ₂ 0.1 229.2 308.1 94.8 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 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 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 Example 10 0.1 19.7 12.0 50.2 1.0 18.4 17.7 59.0 10.0 13.3 4.8 38.9

Table 1 - Continuation

Weight of uterus Uterus

Compound Dose mg / kg (% increase against OVX) EPO (V. max Example 19 0.01 11.4 2.1 0.1 24.9 2.4 1.0 24.7 3.6 Example 20 0.01 16.9 0.9 0.05 40.9 3.0 0.1 30.6 3.0 Example 21 0.01 21.0 1.2 0.1 24.3 4.8 1.0 51.4 9.3 Example 23 0.01 21.6 3.3 0.1 33.4 84.3 1.0 148.9 150.6 Example 24 0.01 9.2 3.6 0.1 18.2 0.9 1.0 81.0 29.4 Example 25 0.01 5.4 3.0 0.1 16.7 3.3 1.0 96.6 36.0 Example 26 0.01 14.0 4.8 0.1 81.0 29.1 1.0 117.1 175.1

Serum cholesterol (% decrease against OVX)

25.1

45.3

53.6

29.4

35.9

58.7

26.8

47.5

54.4

36.2

47.2 66.1

23.7

46.4

79.3

13.1

67.6

73.9

29.0

45.2

62.7 ¢ Table 1 - continued

Compound Dose mg / kg Uterine weight (% increase against OVX) EPO Uterus (V. max) Serum cholesterol (% decrease against OVX Example 27 0.01 2.2 3.3 12.2 0.1 49.2 4.8 50.8 1.0 86.4 52.5 76.5 Example 43 0.01 0.0 3.3 9.2 0.1 17.2 4.8 43.8 1.0 31.0 6.0 39.4 Example 44 0.01 43.8 3.6 12.6 0.1 80.5 88.5 43.8 1.0 74,8- 94.5 67.4 Example 53 0.1 40.6 0.9 62.7 1.0 24.1 1.3 57.5 10.0 32.0 4.8 58.7

In addition, to demonstrate the utility of the compounds of this invention, particularly compared to estradiol, the data presented above clearly demonstrate that the compounds of Formula I do not mimic estrogen. Malignant toxicological effects (survival) are seen cervically in any treatment.

Osteoposis Testing Procedure

According to the general preparation procedure set forth below, rats are tested daily for 35 days (6 rats per treatment group) and carbon dioxide asphyxiation on day 36.

The 35 day period is sufficient to allow maximum reduction in bone hostility as measured herein. At the time of sacrifice, the uterus is removed, the free outer tissue is separated and the liquid content is expelled prior to determination of the weight, to confirm estrogen deficiency associated with complete ovariectomy. Usually, the weight of the uterus decreases by about 75% in response to ovariectomy. The uterus is then placed in 10% neutral buffered formalin and left for subsequent histological analysis.

The right femur is excised, induced by digitilized X-rays and analyzed by an imaging analysis program (NIH imaging) in the distal metaphysis. Proximal tibia from these animals is also serially examined by quantitative computed tomography.

According to the above procedures, the compounds of this invention and 17α-ethinylestradiol (EE ₂ ) in 20% hydroxypropyl-β-cyclodextrin are orally administered to the test animals. The femoral distal metaphysis values shown in Tables 2 and 3 below are the results of treatment with the compound of Formula I compared to intact and ovariectomized test animals. Results are reported as mean ± standard error of mean.

Table 2

Compound / Treatment

Distal femur metaphysis (X-ray imaging analysis)

Batch / kg spokes, gray scratches

Sham (20% cyclodextrin) 27.2 + 6.0 Overiektom control - 3.1 + 1.8 determination (20% cyclo- dextrin) ee ₂ 0.1 mg 11.5 + 2.9 * Example 19 0.1 mg 14.7 + 1.9 1.0 mg 15.0 + 3.5 * 10.0 mg 15.3 + 4.0 * * P < = 0.5 two-tailed Student's T test to gross values

Table 3

Distal femur metaphysis (X-ray imaging analysis)

Compound / Treatment Dose / kg beams , gray Sham (20% cyclodextrin) - 31.1 ± 6.3 Overiectomy Control - 6.2 ± 1.4 determination (20% cyclo- dextrin) ee ₂ 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 13.5 ± 3.2 ' Example 24 0.1 mg 18.3 ± 2.6 ' 1.0 mg 19.6 ± 2,3 ' 3.0 mg 17.1 ± 5.5

P <= 0.5 two-tailed Student's T test for gross values.

In summary, the ovariectomy of the test animals causes a significant reduction in femur density compared to intact vehicle-treated control animals. Orally administered 17α-ethinylestradiol prevents this loss, but the risk of delayed stimulation in this treatment is always present.

The compounds of the invention also prevent bone

Therefore, the compounds of this invention are useful in the treatment of postmenopausal syndrome, especially osteoporosis.

MCF-7 proliferation assay

MCF-7 adenocarcinoma breast cells (ATCC HTB 22) are kept in minimal essential medium (MEM, phenol red free, Sigma, St. Louis, MO, USA) supplemented with 10% by volume fetal calf (FBS), 2 mM L-glutamine , 1 mM sodium pyruvate, 10 mM N - (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic) / (HEPES), non-essential amino acids and 1 µg / ml bovine insulin (nutrient medium). Ten days prior to the assay, MCF-7 cells are transferred to nutrient medium supplemented with 10% charcoal coated dextran stripped fetal bovine serum (DCC-FBS, assay medium) in place of 10% FBS to deplete the sterosphere internal stores. MCF-7 cells are removed from the flask containing nutrient medium using cell dissociation medium (Ca ⁺⁺ / Mg ⁺⁺ depleted of HBSS (phenol red free), supplemented with 10 ml of acid (N- (2-hydroxyethyl) piperazine-N ¹ - ( 2-ethanesulfonic acid) and 2 mM EDTA). The cells were washed twice with assay medium and adjusted to 80,000 cells per milliliter. Approximately 100 ml (8000 cells) are added to a flat bottom microculture cell (Costar 3596) and incubated at 37 ° C in a humidified 5% carbon dioxide incubator for 48 hours to allow the cells to adhere and evil after transfer. Serial dilutions of drug or dimethylsulfoxide as diluent for control are prepared in assay medium and 50 ml of sample is transferred to triplicate microcultures and then 50 ml of test medium is added to a final volume of 200 ml. After a further 48 hours at 37 ° C, tritiated thymidine microcultures (activity 37 kBq per well) are regularly added to a humidified 5% carbon dioxide incubator for 4 hours. The culture is stopped by freezing at -70 ° C for 24 hours, then the meat is thawed and the microcultures are collected using a Skatron Semiautomatic Cell Harvester. The samples are counted by liquid scintillation counting using a Wallac BetaPlace β-counter. The results in Table 4 below show IC ₅₀ values for certain compounds of the invention.

Table 4

Compound ^IC 50

Example 3 4.0 Example 10 2.00 Example 19 0.023 Example 21 0.05 Example 23 0.08 Example 53 0.23

DMBA-induced breast tumor inhibition

Estrogen-dependent breast tumors are produced in female Sprague-Dawley rats purchased from Harlan Industries, Indianapolis, Indiana, USA. At approximately 55 days of age, rats receive a single oral dose of 20 mg of 7,12-dimethylbenz [a] anthracene (DMBA). About 6 weeks after administration of 7,12-dimethylbenz [ajanthracene], the mammary gland is examined by palpation at weekly intervals for tumor appearance. Whenever one or more tumors are shown, the longest and shortest diameters of each tumor are measured using a metric scale, measurements are made and animals are

- ¹⁶ 1Select for experiments. Testing is performed to evenly distribute different tumor sizes to the treated and control groups such that mid-sized tumors are evenly distributed among the test groups. The contiguous groups and test groups for each experiment contain 5 to 9 animals.

The compounds of formula I are administered either by intraperitoneal injections in 2% acacia or orally. Orally administered compounds are either dissolved or suspended in 0.2 ml of corn oil. Each preparation, including a preparation containing gum arabic and corn oil, is administered once a day to each test animal. After initial tumor measurement and selection of test animals, tumors are measured weekly by the above-mentioned method. Treatment and measurement of animals is continued for 3-5 weeks, at which time the final tumor area is determined. For each compound and control treatment, the change in mean tumor area is determined.

Procedure for testing uterine fibrosis

A test of 1 to 20 women suffering from uterine fibrosis is administered a compound of the invention. The amount of compound administered is from 0.1 to 1000 mg per day and the administration period is 3 months.

Women are observed during the administration period and up to 3 months after discontinuation of treatment, to have uterine fibrosis for effects.

Test 2

The same procedure as in Test 1 is used except that the administration period is 6 months.

Test 3

The same procedure as in Test 1 is used except that the administration period is 1 year.

Test 4

A. Induction of fibroid tumors in guinea pigs

Prolonged estrogen stimulation is used to induce leiomyomatides in sexually mature female guinea pigs. Animals are administered estradiol three to five times per week by injection for 2 to 4 months or until tumors appear. Treatment involves administering a compound of this invention or vehicle daily for 3 to 16 weeks, and then killing, taking the uterus and testing for tumor regression.

B. Implantation of human uterine fibroid tissue with nude mice

Human leiomyomase tissue is implanted into the peritoneal cavity or uterine myometrium of sexually mature, castrated female nude mice. ³ is introduced exogenous estrogen are supplied to induce growth of the explanted tissue. In some cases, the harvested tumor cells are cultured in vitro prior to implantation. Treatment with a compound of the invention or vehicle promotes gastric lavage daily for 3-16 weeks, implants are removed and measured for growth or regression. At the time of sacrifice, uteri are taken to determine organ status.

Test 5

A. Tissue is obtained from human uterine fibroid tumors and maintained in vitro as the primary untransformed culture. Surgical specimens are squeezed with sterile mesh or sieve or alternatively separated into small pieces from the surrounding tissue to produce a uniform cell suspension. Cells are maintained in medium containing 10% serum and antibiotic. Growth rate is determined in the presence or absence of estrogen. Cells are assayed for their ability to produce complementary component C3 and their response to growth factors and growth hormones. In vitro cultures are tested for their proliferative response after progestin treatment, GnRH, compounds of the invention, and vehicle. Steroid hormone receptor levels are tested weekly to determine whether important cellular characteristics are maintained in vitro. Tissue from 5 to 25 patients is used.

Activity in at least one of the above assays indicates that the compounds of this invention are effective in the treatment of uterine fibrosis.

Procedure for Texting Endometriosis

In Tests 1 and 2, the effects of the biweekly and three-weekly administration of the compounds of this invention on the growth of examined endometrial tissue can be tested.

Test 1

20 to 30 adult female CD rats are used as test animals. The animals are divided into 3 groups

the same number of individuals and the estrous cycle of all animals is followed. Surgery is performed on each female on the day of proestra. Females from each group retain the left uterine horn, cut into small squares, and the squares are freely stapled at various sites adjacent to the mesenteric blood stream. In addition, females from Group 2 have ovaries removed.

On the days following surgery, Group 1 and 2 animals received intraperitoneal injections of water for 14 days, while Group 3 animals received intraperitoneal injections of 1.0 mg of a compound of this invention per kilogram of body weight during the same time period. After treatment for 14 days, each female is sacrificed and the endometric explants, adrenals, remaining uterus and ovaries, if practicable, are removed and prepared for histological examination. Also, the weight of the ovaries and adrenal glands is determined.

Test 2

20 to 30 adult female CD rats are used as test animals. The animals are divided into two groups and the estrous cycle of all animals is followed. Surgery is performed on each female on the day of proestra. Females from each group retain the left uterine horn, cut into small squares, and the squares are freely stapled at various sites adjacent to the mesenteric blood stream.

Approximately 50 days after surgery, animals labeled Group 1 receive intraperitoneal injections of water for 21 days, while Group 2 animals receive intraperitoneal injections of 1.0 mg of a compound of this invention per kilogram of body weight during the same období time period. After treatment for 21 days, each female is sacrificed and endometric explants and adrenals are removed. Explants are measured to determine growth. The estrous cycle is followed.

Test 3

A. Surgical induction of endometriosis

Endometrial tissue autographs are used to determine endometriosis in rats and / or rabbits. Female animals of reproductive maturity undergo bilateral surgical ovarian withdrawal and estrogen is delivered exogenously to obtain a specific and constant level of hormone. Autologous endometrial tissue is implanted into the peritoneum in 5 to 150 animals and the estrogen is delivered to induce growth of the explanted tissue. The treatment of administering the compound of the invention is promoted by gastric lavage daily for 3-16 weeks, and then the implants are removed and their growth or regression is measured. At the time of sacrifice, the intact horn of the uterus is removed to determine the endometrial condition.

B. Implantation of human endometrial tissue with nude mice

Tissue from human damaged lining is implanted into the peritoneum of sexually mature, castrated female nude mice. Exogenous estrogen is supplied to induce growth of explanted tissue. In some cases, the captured endometric cells are cultured in vitro prior to implantation. The treatment of administering the compound of the invention is promoted by gastric lavage daily for 3-16 weeks and then the implants are removed and their growth or regression measured. At the time of sacrifice, uteri are removed to determine the intact endometrial condition.

Test 4

A. Tissue from human damaged uterine mucosa is obtained and maintained in vitro as primary non-transformed culture. Surgical specimens are squeezed with sterile mesh or sieve or alternatively separated into small pieces from the surrounding tissue to produce a uniform cell suspension. Cells are maintained in medium containing 10% serum and antibiotic. Growth rate is determined in the presence or absence of estrogen. Cells are assayed for their ability to produce complementary component C3 and their response to growth factors and growth hormones. In vitro cultures are tested for their proliferative response after progestin treatment, GnRH, compounds of the invention, and vehicle. Steroid hormone receptor levels are tested weekly to determine whether important cellular characteristics are maintained in vitro. Tissue from 5 to 25 patients is used.

Activity in any of the above assays indicates that the compounds of this invention are effective in the treatment of endometriosis.

The invention also provides a method of alleviating postmenopausal syndrome in women, comprising the above method using compounds of Formula I and further comprising administering to the woman an effective amount of estrogen or progestin. This treatment is particularly useful for treating osteoporosis and lowering serum cholesterol because the patient benefits from each pharmaceutical composition, although the compounds of the invention are intended to inhibit the undesirable side effects of estrogen and progesterin. The activity of these combination treatments in any of the postmenopausal assays listed below shows that combination treatments are useful for alleviating symptoms in women suffering from postmenopausal syndromes.

Various forms of estrogen and progestin are commercially available. Estrogen-based compositions include, for example, ethynyl estrogen (0.01 to 0.03 mg per day), mestranol (0.05 to 0.15 mg per day) and conjugated estrogen hormones such as Premarin ^R (Wyeth-Ayerst, 0.3). up to 2.5 mg per day). Progestin-based compositions include, for example, medroxyprogesterone such as Provera (Upjohn, 2.5 to 10 mg per day), norethylnodrel (1.0 to 10.0 mg per day) and norethindrone (0.5 to 2.0 mg per day) ). A preferred estrogen based compound is

Premarin. Norethylnodrel and norethindrone are preferred progestin-based compositions.

The method of administering each estrogen and progestin-based composition is in accordance with methods known in the art. In most methods of the present invention, the compounds of Formula I are administered continuously one to three times daily. However, cyclic therapy may be particularly useful in the treatment of endometriosis or may be urgently used during painful disease. In the case of restenosis, therapy may be limited to short intervals (1 to 6 months) after treatment procedures such as angioplasty

As used herein, the term effective amount means an amount of a compound of the invention that is capable of alleviating the symptoms of the various pathological conditions described herein. Of course, a particular dose of the compound administered according to the invention will depend upon the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the condition of the patient, and the pathological condition to be treated. A conventional daily dose will contain a non-toxic level of the compound of the invention dosed from about 5 to about 600 mg per day. Preferred daily doses will usually be from about 15 to about 80 mg per day.

The compounds of this invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal routes.

These compounds are preferably formulated prior to administration, which will be decided by the attending physician. Another aspect of the invention is a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally containing an effective amount of estrogen or progestins, and a pharmaceutically acceptable carrier, diluent or vehicle.

All active ingredients in such compositions comprise from 0.1 to 99.9% by weight of the composition. The term pharmaceutically acceptable means that the carrier, diluent, vehicle and salt must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The compounds may also be formulated as elixirs or solutions for conventional oral administration or as solutions suitable for parenteral administration, for example by intramuscular, subcutaneous or intravenous routes. In addition, the compounds are well suited for formulating sustained-release compositions and the like. Resources can be

They are constructed to release the active agent only or preferably in a particular physiological site, advantageous over a period of time. Coatings, coatings and protective materials, for example, polymeric substances or waxes, can be made on the compositions.

The compounds of formula (I), alone or in combination with the pharmaceutical compositions of this invention, will generally be administered in conventional formulations. The following examples of compositions are illustrative only and are not intended to limit the scope of the invention.

Pharmaceutical compositions

In the pharmaceutical compositions described below, the active ingredient is a compound of formula I or a salt thereof, or a solvate thereof.

Composition 1: Gelatin capsules

Hard gelatin capsules are Amount (mg / capsule) prepared using active ingredient ingredients 0.1 - 1000 starch, NF 0 - 650 starch, liquid powder 0 - 650 silicone liquid, 0 - 15,350 cSt (3.50 cm ² .s ^-1 )

The device described above may change provided that it is in accordance with reasonable deviations.

A tablet formulation is prepared using the following ingredients.

Formulation 2: Tablets

Component Amount (mg / tablet) active substance 2.5 - 1000 cellulose, microcrystalline 200-650 silica, sublimed 10-650 stearic acid 5-15

The ingredients are mixed and compressed into tablet. In another embodiment, each tablet containing 2.5 to 1000 mg of the active ingredient is prepared as follows • Formulation 3: Tablets Ingredient Amount (mg / tablet) active substance 25 - 1000 starch 45 cellulose, microcrystalline 35 polyvinylpyrrolidone 4 (as a 10% solution in water) sodium carboxymethyl cellulose 4.5 magnesium stearate 0.5 talc 1

The active ingredient, starch and cellulose are passed through a 45 mesh screen and mixed thoroughly. The resulting powder is mixed with polyvinylpyrrolidone and then passed through a No. 14 US sieve. The granules so produced are dried at 50-60 ° C and passed through a No. 18 US sieve. Sodium carboxymethylcellulose, starch, magnesium stearate and talc are previously passed through a 60 US sieve and then added to the granules with which they are compressed on a tabletting machine to obtain tablets.

Prepare a suspension containing 0.1 to 1000 mg of drug per 5 ml dose as follows:

Formulation 4: Suspension

Component Quantity (mg / 5 ml) active substance sodium carboxymethylcellulose syrup benzoic acid solution flavor dye purified water

0.1-1000 mg 50 mg 1.25 mg 0.10 ml if necessary up to 5 ml

The drug is passed through a 45 US sieve and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. To this paste is added a benzoic acid solution, a flavoring agent and a dye diluted with a small amount of water, with stirring. Then add sufficient water to the required volume.

Prepare an aerosol solution containing these

folders:

Formulation 5: Aerosol

Ingredient Quantity (% by weight) active substance 0.25 ethanol 25.75 propellant 22 70.00 (chlorodifluoromethane)

The active substance is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C and transferred to a filling apparatus. The desired amount is then metered into a stainless steel container and diluted with the remaining propellant. The container is then fitted with valve units.

Suppositories are prepared as follows:

Means 6: Suppositories

Ingredient Quantity (mg / suppository) active substance 250 glycerides saturated fatty acids 2000

The active substance is passed through a 60 US sieve and suspended in glycerides of saturated fatty acids pre-melted using the minimum necessary heat. The mixture is then poured into suppository molds of 2 g nominal size and allowed to cool.

The intravenous formulation is prepared as follows:

Formulation 7: Intravenous solution

Ingredient Amount Active substance 50 mg isotonic saline 1000 ml

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

Formulation 8: Combination Capsules I

Component Quantity (mg / capsule) Active substance 50

Premarin 1

Avicel pH 101 50 Starch 1500 117,50 Silicone Oil 2

Tween 80 0.50

Cab-O-Sil 0.25

Formulation 9: Combination Capsules II

Component Quantity (mg / capsule) active substance norethylnordel Avicel pH 101

82.50

Starch 1500 Tween 80 Silicone Oil

0.50

Composition 10: Combined tablets Component Amount (mg / tablet) active substance 50 Premarin 1 corn starch, NF 50 Povidone, K29-32 6 Avicel pH 101 41.50 Avicel pH 102 136,50 crosslinked povidone XL10 2.50 magnesium stearate 0.50 Cab-O-Sil 0.50

Claims (20)

PATENTOVÉ A compound of formula I R ² (I) wherein R ¹ represents -H, -OH, -O (C 1 -C ₄ alkyl), -OCOC ₉ H ₅ , -OCO 2 C 1 -C 6 alkyl) or -OSO ₂ (C ₂ -C 8 alkyl), R ² represents -H, -OH, -O (C £ _C4 alkyl) -OCOCgHg, -OCO (C ₁ -C 6 alkyl), -OSO ₂ (C ₂ -C 6 alkyl) or a halogen atom, R ³ is 1-piperidyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino, n is 2 or 3 and Z is -O- or -S-, 2. A compound according to claim 1, wherein ^J is R And n is 2, or a pharmaceutically acceptable salt thereof. A compound according to claim 2, wherein Z is -O-, or a pharmaceutically acceptable salt thereof. The compound of claim 3, wherein R ¹ is hydroxy and R ² is -O (C 1 -C ₄ alkyl), or a pharmaceutically acceptable salt thereof. The compound of claim 4, wherein R ² is methoxy, or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the salt is the hydrochloride. A compound according to claim 3, wherein R ¹ and R ² are each hydroxy, or a pharmaceutically acceptable salt thereof. The compound of claim 7, wherein the salt is the hydrochloride. 9. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 8 and optionally an estrogen or progestin, together with at least one pharmaceutically acceptable carrier, vehicle or diluent thereof. A compound of formula XIV (XIV) wherein: 1 * 7 R is a hydrogen atom or a group of the formula -OR, wherein R is a hydroxy protecting group, R ^2a represents a hydrogen atom, a halogen atom or a group of the formula -OR ⁸ , Where R is a hydroxy protecting group, R ⁹ is a leaving group, or a pharmaceutically acceptable salt thereof. A compound according to claim 10, wherein R ^1a and R ^2a are each methoxy and R ⁹ is bromine, or a pharmaceutically acceptable salt thereof. A compound of the general formula wherein: 1a - 7 R represents a hydrogen atom or a group of the formula -OR, wherein R ⁷ represents a hydroxy protecting group, R ^2a represents a hydrogen atom, a halogen atom or a group of the formula -OR ⁸ , Where R is a hydroxy protecting group, R represents a hydrogen atom or a hydroxy protecting group which may be selectively removed, R ¹¹ either does not exist or is = O and Z is -O- or -S-, or a pharmaceutically acceptable salt thereof. A compound of the formula according to claim 12, wherein R ^1a and R ^2a are each methoxy, R ⁶ is hydrogen, R ¹¹ does not exist and Z is -O-, or a pharmaceutically acceptable salt thereof. - $ 18 A compound of the formula according to claim 12, wherein R ^1a and R ^2a are each methoxy, R ⁶ is hydrogen, R ¹¹ is = O and Z is -O-, or a pharmaceutically acceptable salt thereof. A compound of the general formula wherein: R ^1a represents a hydrogen atom or a group of the formula -OR ⁷ , wherein R ⁷ represents a hydroxy protecting group, R ^2a represents a hydrogen atom, a halogen atom or a group of the formula -OR ⁸ , Where R is a hydroxy protecting group, R is 1-piperidyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino, n is 2 or 3 and Z is -O- or -S-, or a pharmaceutically acceptable salt thereof. A compound of the formula according to claim 15, wherein R ^1a and R ^2a are each methoxy, R ³ is 1-piperidyl, n is 2, Z is -O-, or a pharmaceutically acceptable salt thereof. A process for the preparation of compounds of formula I in which R ^1a represents a hydrogen atom or a group of the formula -OR ^7a , wherein R ^7a represents a hydrogen atom or a hydroxy protecting group, R ^2a represents a hydrogen atom, a halogen atom or a group of the formula -OR ^8a , Q wherein R represents a hydrogen atom or a hydroxy protecting group, R ³ is 1-piperidyl, 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, characterized in that: a) oxidizes the sulfur atom in the compound of formula IV R 2a (IV) wherein R ^a and R ^3a are as defined above and Q R represents a leaving group, b) regulating the compound of step a), a compound of formula XIV - ¹⁸ 3 - (XIV) with a nucleophilic group of a compound of formula wherein is a group of formula -OH or -SH, c) reducing the compound of step b), a compound of formula XVI to form a compound of formula (XVI) 18, d) optionally removing the hydroxy protecting groups on R ^1a and / or R ^2a from the compound of step c), if present, and e) optionally forming a salt of the compound of step c) or d). A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, characterized in that: and) A) reduces a compound of formula XVI (xvi) in which R ^1a represents a hydrogen atom or a group of the formula -OR ^7a , wherein R ^7a represents a hydrogen atom or a hydroxy protecting group, R ^2a represents a hydrogen atom, a halogen atom or a group of the formula -OR ^6a , Q-a wherein R represents a hydrogen atom or a hydroxy protecting group, R ³ is 1-piperidyl, 1-pyrrolidino, methyl-1 -pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino, n is 2 or 3 and is -O- or -S-, or a pharmaceutically acceptable salt thereof, B) reacting a compound of formula IIb in which R is a hydroxy protecting group and R ^2a and Z are as defined above, with a compound of formula V R ³ - (CH ₂ ) _n - Q (V) in which Q is a leaving group and R ³ and n are as defined above, C) reacting a compound of formula IIb wherein * 1 c * R ^{A represents a} hydroxy or -O-alkyl group having 1 to 4 carbon atoms and O / - « R is hydroxy or -O-alkyl of 1 to 4 carbon atoms, with the proviso that when 1 c R is hydroxy, R is -O-C 1 -C 4 -alkyl, and when and R ^1c is -O-C 1 -C 4 -alkyl, R is hydroxy, R ³ is 1-piperidyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino, n is 2 or 3 and Z is -O- or -S-, or a pharmaceutically acceptable salt thereof, and ii) reduces the resulting trifluoromethanesulfonate moiety, (b) optionally removing the remaining hydroxy protecting group (s); and c) optionally, forming a salt of the compound of step or (b). A compound of formula I, anywhere transportable by the method of claim 17. A compound of formula I, anywhere transportable by the method of claim 18.