HU226326B1 - Benzothiophene compounds, intermediates, process for their production, their use and compositions containing them - Google Patents

Description

The invention in the field of pharmaceutical and organic chemistry provides novel benzothiophene compounds useful for the treatment of various conditions associated with postmenopausal syndrome, uterine fibroid lesions, endometriosis and aortic smooth muscle cell proliferation. The invention further provides intermediates for the preparation of the active compounds of the invention. The invention also relates to pharmaceutical compositions.

The term "postmenopausal syndrome" is used to describe a variety of pathological conditions that often occur in women who have entered or have undergone a physiological transformation known as menopause. Although many ailments deal with this phenomenon, there are three major consequences of the postmenopausal syndrome that cause this major health problem, namely: osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancers, especially breast and m .

They describe a group of osteoporotic diseases which, although of different etiologies, are all characterized by a net loss of bone mass per unit volume. The loss of bone mass and the resultant fractures are the inability of the skeleton to provide proper structural support to the body. One of the most common types of osteoporosis is related to menopause. 3-6 years after cessation of menstruation, most women experience a 20-60% reduction in bone mass in the trabecular bone system. This rapid loss is generally associated with an increase in bone resorption and formation. However, as the resorptive cycle is more dominant, this results in a net loss of bone mass. Osteoporosis is a common and serious condition in post-menopausal women.

In the United States alone, the number of women affected by this disease can be estimated at 25 million. On the one hand, osteoporosis causes individual harm and, on the other hand, represents a major economic expense due to the chronic nature of the disease and the extensive and long-term treatment of its consequences (hospital and home nursing care). This is especially true in older patients. Although osteoporosis is not generally considered a life-threatening condition, 20% to 30% of deaths in older women are related to hip fracture. A high percentage of such deaths is directly related to post-menopausal osteoporosis.

The most valuable bone tissue exposed to post-menopausal osteoporosis is the tissue of the trabecular portion of the bone. This tissue is often referred to as spongy or lattice bone, particularly in the bone ends (near the joints) and in the spinal cord. The trabecular tissue is characterized by interconnected small asteroid structures and a firmer and more dense cortex forming the outer surface and central trunk of the bone. This interconnected network of trabeculae provides lateral support to the outer cortex structure and is a crucial factor in the biomechanical strength of the entire structure. In postmenopausal osteoporosis, it is primarily the net absorption of bone and the reduction of trabeculae that leads to weakening and fracture of the bone. In view of this, it is not surprising that postmenopausal osteoporosis most frequently occurs in bones with trabecular support, such as the spine, in weight-bearing bones such as the femur and forearm. Indeed, hip fractures, bone fractures, and collapse of the spine are hallmarks of post-menopausal osteoporosis.

Currently, the only commonly accepted treatment for post-menopausal osteoporosis is the estrogen replacement method. Although this therapy is generally successful, many patients do not accept it, primarily because estrogenic treatment often has undesirable side effects.

During premenopause, women have a lower incidence of cardiovascular disease than men of the same age. After menopause, however, the incidence of cardiovascular disease in women is slowly rising to that of men. Loss of protection is associated with a decrease in estrogen, more specifically the loss of the ability of the body to regulate serum lipid levels with estrogens. The mechanism by which estrogens regulate serum lipid levels is unknown, but there is evidence that estrogen may increase the function of low-density lipid (LDL) receptors in the liver to remove excess cholesterol. In addition, estrogen also appears to have some effect on cholesterol biosynthesis and other beneficial effects on cardiovascular status.

It is known in the literature that in postmenopausal women receiving estrogen replacement therapy, serum lipid levels return to pre-menopausal levels. Thus, the postmenopausal state could be effectively treated with estrogen. However, many women do not accept the side effects associated with estrogen replacement therapy, which limits the applicability of the therapy. The ideal active ingredient of the treatment would be one that could regulate serum lipid levels like estrogen but would not cause side effects and dangers like estrogenic treatment.

The third major pathological manifestation of postmenopausal syndrome is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancer of other organs, especially the uterus. Although neoplasms are not limited to postmenopausal women, they are more prevalent in the older, postmenopausal generation. Current chemotherapy for such cancers relies heavily on anti-estrogen compounds such as tamoxifen. Although these mixed agonist-antagonist agents are beneficial in the treatment of these cancers and estrogenic side effects can be tolerated in cases of acute life-threatening effects, they are not ideal agents. so for example

These substances may just stimulate certain cancer cell populations of the uterus due to their estrogenic (agonist) nature and are therefore contraindicated in such cases. A better therapeutic treatment of these cancers would be the use of anti-estrogen compounds which have no or negligible estrogen agonist effects on reproductive tissues.

As will be understood, the present invention provides benzothiophene compounds that alleviate, inter alia, postmenopausal syndrome. The present invention also provides pharmaceutical compositions containing benzothiophene compounds and methods of using these compounds for the treatment of postmenopausal syndrome and other estrogen-related pathological conditions mentioned below.

Fibrous degeneration of the uterus (fibrosis, fibroid disease) is an old and eternal clinical problem. It occurs under several names, such as uterine fibroid disease, uterine hypertrophy, uterine fibroids, myometric hypertrophy, uterine fibrosis, and fibrotic metritis. In particular, uterine fibrosis is a disease in which harmful accumulation of fibroid tissue is observed in the uterine wall.

This condition causes menstrual disorders (dysmenorrhea) and infertility in women. The exact cause of the condition is little known, but there is evidence that it is an abnormal response of fibroid tissue to estrogen. Such a condition can be induced in rabbits by the daily administration of estrogen for 3 months or in guinea pigs after similar treatment for 4 months. In rats, estrogen causes similar hypertrophy.

The most common treatment for uterine fibrosis is surgery, which is costly and sometimes a source of complications if it causes, for example, abdominal fusion or infections. For some patients, surgery is only a temporary solution and fibroid tissue grows again. In these cases, the uterus is removed, which ends fibroid tissue outgrowths but also ends the patient's reproductive life. Gonadotropin-releasing hormone antagonists may also be used, but are limited by the fact that this can lead to the development of osteoporosis. Thus, there is a need for a novel method of treating uterine fibrosis, and the method of the present invention satisfies this need.

Endometriosis, which causes severe menstrual disorders, is accompanied by severe pain, bleeding in the lining of the uterus and abdomen, and often infertility. Symptoms of the disease are caused by ectopic endometrial outgrowths, which react abnormally to natural hormonal regulation and appear in abnormal tissue structures. Due to the abnormal location of endometrial outgrowths, the tissue elicits a response similar to local inflammation, resulting in macrophage infiltration and initiation of a cascade of painful events. The exact pathology of the disease is little known, the consequences of hormonal treatment are variable, less well defined and have a number of unwanted, possibly dangerous, side effects. To suppress endometrial tissue growth, the patient is treated with a low dose of estrogen, which has a negative feedback effect on central ganadotropin release and subsequent uterine estrogen production; however, in some cases, continuous estrogen treatment is needed to control symptoms. The use of estrogen can often lead to unwanted side effects and even the risk of developing endometrial cancer.

Another method of treatment involves the continuous administration of progestins, which induce amenorrhea and suppress estrogen production by the ovaries, and may result in regression of endometrial growths. Long-term treatment with progestin often causes unwanted side effects in the central nervous system and often leads to infertility by suppressing ovarian function.

The third treatment is the introduction of weak androgens into the body. Androgens are effective in controlling endometrium but induce severe masculinism. Some of the endometriosis treatments also result in slight bone loss during long-term therapy. For this reason, it is desirable to develop a new method of treating endometriosis.

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein, in formula (I), R ¹ is hydrogen, hydroxy, C 1 -C 4 alkoxy -OCOC ₆ H ₅ , -OCO- (C 1 -C 6). alkyl) or -OSO ₂ - (C 2 -C 6) alkyl;

R ² is hydrogen, hydroxy, C 1 -C 4 alkoxy, -OCOC ₆ H ₅ , -OCO- (C 1 -C 6 alkyl), -OSO ₂ - (C 2 -C 6 alkyl), or halogen;

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

n is 2 or 3; and

Z is oxygen or sulfur.

The invention further provides compounds of formulas II, XIV and XVI useful as intermediates in the preparation of the active ingredient of the present invention, some of which are also pharmaceutically active. In the formulas (II), (XIV) and (XVI), R ^1a is hydrogen or -OR ⁷ , wherein R ⁷ is a hydroxy protecting group;

R ^2a is hydrogen, halogen, or -OR ⁸ , wherein R R is a hydroxy protecting group;

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

R ⁶ is hydrogen or a selectively removable hydroxy protecting group;

R ⁹ is a leaving group;

R ¹¹ is O or absent;

n is 2 or 3; and

Z is oxygen or sulfur.

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The present invention also provides a process for the preparation of a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein R ^1a is hydrogen or -OR ^7a wherein R ^7a is hydrogen or hydroxy protecting group;

R ^2a is hydrogen or halogen, or

-OR ^8a wherein R ^8a is hydrogen or hydroxy protecting group;

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

n is 2 or 3; and

Z is oxygen or sulfur, which process comprises:

(a) a compound of formula IV wherein:

R ^1a and R ^2a are as defined above;

R ⁹ is a sulfur atom of a leaving group compound;

b) reacting the product of formula (XIV) of step a) with a nucleophile of a compound of formula (XXIII) wherein R ¹² is hydroxy or sulfhydryl;

c) reducing the product of formula (XVI) of step b) to a compound of formula (le);

d) optionally removing the hydroxy protecting groups R ^1a and / or R ^{2a on the} product of step c); and

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

The present invention also relates to pharmaceutical compositions comprising a compound of formula I and optionally estrogen or progestin, and the compounds of formula I alone or in combination with estrogen or progestin, for the treatment of symptoms of postmenopausal syndrome, particularly osteoporosis, in the treatment of cardiovascular diseases and estrogen dependent cancers. The term "estrogen" refers to steroids having estrogenic activity, such as 17? -Estradiol, estrone, conjugated estrogen (Premarin®), horse-estrogen, 17? -Ethynyl-estradiol and the like. The term "progestin" refers to compounds that have progestational activity, such as progesterone, noretinodrel, norgestrel, megestrol acetate, norethindrone, and the like.

The compounds of the present invention are useful in the treatment of uterine fibroids, endometriosis, and human aortic smooth muscle cell proliferation, particularly restenosis.

One aspect of the invention is a compound of formula (I) or pharmaceutically acceptable salts thereof, wherein:

R ¹ is hydrogen, hydroxy, C 1-4 alkoxy, -OCOC ₆ H ₅ , -OCO- (C 1-6 alkyl), or -OSO ₂ - (C 2-6 alkyl);

R ² is hydrogen, hydroxy, C 1 -C 4 alkoxy, -OCOC ₆ H ₅ , -OCO (C 1 -C 6 alkyl), -OSO ₂ - (C 2 -C 6 alkyl), or halogen;

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

n is 2 or 3; and

Z is oxygen or sulfur.

The general terms used in the description of the compounds are employed in their usual sense, for example, "C 1-6 alkyl" means a straight or branched C 1-6 aliphatic chain such as methyl, ethyl, propyl, isopropyl, , butyl, η-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. Similarly, "C 1-4 alkoxy" means a C 1-4 alkyl group bonded through an oxygen atom. This includes, for example, methoxy, ethoxy, η-propoxy, isopropoxy and the like.

In one route to the preparation of the compounds of formula (I), the starting material is the compound of formula (III), the preparation of which is described by CD Jones in U.S. Patent Nos. 4,418,068 and 4,133,814, incorporated herein by reference. The meaning of R ⁷ and R ^{2a in the} compound of formula (III) is as defined above.

The hydroxy protecting groups R ⁷ and R ⁸ are generally no longer present in the final compound of formula (I), but at certain stages of the synthetic process protect the group, which would otherwise react in the chemical process. The protecting groups are then removed at a later stage of the synthesis. Since the compounds carrying these protecting groups are primarily chemical intermediates (although some derivatives also show biological activity), the specific structure of the protecting groups is not critical. Reactions of the deprotection, deprotection, or eventual rearrangement of the protecting group have been the subject of several literature studies, for example: "Protective Groups in Organic Chemistry", Plenum Press (London and New York, 1978); Green TW, Protective Groups in Organic Synthesis, Wiley (New York, 1981); "The Peptides," Volume I, Schrooder and Lubke, Academic Press (London and New York, 1965).

Representative hydroxyl protecting groups include, for example, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -CO- (C 1 -C 6 alkyl), -SO ₂ (C 4 -C 6 alkyl) and -CO-Ar wherein Ar is benzyl or optionally substituted phenyl. "Substituted phenyl" means a phenyl group substituted with one or more substituents; the substituent may be C1-C4 alkyl, C1-C4 alkoxy, hydroxy, nitro, trichloromethyl or trifluoromethyl, or halogen. The term "halogen" refers to bromine, chlorine, fluorine or iodine.

HU 226 326 Β1

Preferred R ⁷ and R ⁸ (R ^2a ) substituents for compounds of formula (III) are methyl, isopropyl, benzyl and methoxymethyl. Compounds wherein R ⁷ and R ⁸ are both methyl can be prepared according to the above-mentioned Jones patent. Another preferred protecting group for the hydroxyl group is the methoxymethyl group. However, as shown below, the compound of formula (IV) is first prepared by carrying a preferred methyl (or other) hydroxy protecting group (s). These protecting groups are then removed to form the phenolic moiety and then protected again, but now with methoxymethyl.

Compounds of formula III are also prepared wherein the R ⁷ protecting group is selectively removed, leaving the final R ⁸ (R ^2a ) protecting group in the final product. The same can be done by selectively removing the protecting group R ⁸ (R ^2a ) and leaving the protecting group R ⁷ in place. For example, R ⁷ is isopropyl or benzyl, and R ⁸ (R ^2a ) is methyl. The isopropyl or benzyl group is selectively removed in the usual manner and the R ⁸ methyl group is retained as one of the constituents of the final product.

First steps in the preparation of certain compounds of formula (I): a 3-positioning group is introduced at the 3-position of compound (III): the reaction product of step 1 is reacted with 4-hydroxyphenol protected hydroxyl group; deprotecting the hydroxyl group of the phenol. The reaction is illustrated in Figure 1. In the general formulas in the process, R ⁷ and R ^2a are as defined above, R ⁹ is a leaving group and R ⁶ is a selectively removable protecting group for a hydroxy group.

In the first step of Figure 1, a leaving group is selectively positioned at the 3-position of the starting material of formula (III). Suitable leaving groups R ⁹ include a sulfonate group such as methanesulfonyloxy, 4-bromobenzenesulfonyloxy, tosyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, 4-methoxybenzenesulfonyloxy, 4- nitrobenzenesulfonyloxy, 2-chlorobenzenesulfonyloxy, triflate and the like. -, may be halogen such as bromine, chlorine or iodine - or other similar leaving group. However, for the correct positioning of the leaving group, the above-mentioned halogen atoms, especially bromine, are preferred.

The reaction is carried out according to standard procedures. For example, when the preferred halogenating agent is used, an equivalent weight of a halogenating agent, preferably bromine, is reacted with an equivalent weight of a compound of formula III in a suitable solvent, such as chloroform or acetic acid. The reaction is carried out at 40-80 ° C.

Product of the formula The above reaction step (IV) is reacted with protected hidroxilcsoportú 4-hydroxy-phenol to give (IIIa), a compound wherein R ⁶ represents a selectively removable hydroxy protecting group. The protecting group for the hydroxyl group of phenol 4 may be any known protecting group that can be selectively removed so that in this case R ⁷ and R ⁸ , when present, remain in place. Preferred protecting groups for R ⁶ are methoxymethyl when R ⁷ and / or R ⁸ are not methoxymethyl and benzyl. Of these, benzyl is particularly preferred. The protected hydroxyl-protected 4-hydroxyphenol reagent is commercially available or can be prepared by known methods.

This coupling reaction is known in the art as the Ullman reaction and can be carried out in the conventional manner. See, for example, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 4th Edition, pp. 3-16. page, ed. J. March (John Wiley & Sons, Inc., 1992); Jones C. D., J. Chem. Soc. Perk. Trans. I., 4: 407 (1992)].

Generally, an equivalent weight of the two aryl reagents is refluxed in the presence of a maximum of an equivalent weight of copper (I) oxide catalyst and a suitable solvent in an inert gas space. Preferably, an equivalent weight of a compound of formula (IV) wherein R ⁹ is bromo is reacted with an equivalent weight of 4-benzyloxyphenol in the presence of an equivalent weight of copper (I) oxide.

Solvents or mixtures of solvents which remain unchanged during the reaction are preferred for the reaction. Typical preferred solvents are organic bases, especially blocked bases such as 2,4,6-collidine.

The temperature used for the reaction must be such that the coupling reaction is complete and influences the amount of time required. When the reaction is carried out under reflux in an inert gas such as nitrogen, the reaction takes about 20 to 60 hours to complete.

After coupling, the resulting product of formula (IIa) is converted to the compound of formula (IIb) by removal of the protecting group R ^{6 of} the hydroxyl group using a known reduction procedure. It is necessary that the process is selective and does not touch the hydroxy protecting groups R ⁷ and, if present, R ⁸ .

When R ⁶ is the preferred benzyl group and R ⁷ and, when present, R ⁸ are both methyl, the reaction is carried out by conventional hydrogenolysis procedures. Typically, the compound of formula (IIa) is added to a suitable solvent or solvent mixture, and a proton donor is added to the solution to accelerate the reaction. The hydrogenation is carried out in the presence of a suitable catalyst.

Suitable catalysts include noble metals and their oxides, such as palladium, platinum, and rhodium on a suitable support such as carbon or calcium carbonate. Most preferred of these is palladium on carbon, especially carbon containing 10% palladium.

Suitable solvents for the reaction are those solvents or solvent mixtures which are inert to the reaction. Typical such solvents are ethyl acetate, C 1-4 aliphatic alcohols, ethanol being particularly preferred.

A suitable and preferred proton donor for this reaction is hydrochloric acid.

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The reaction is carried out quickly at room temperature and 30-50 psi. The reaction is monitored by conventional chromatographic techniques, such as thin layer chromatography.

The compounds of formula (IIa) and (IIb) are novel, belong to the group of compounds of formula (II) described herein and may be used in the preparation of a pharmaceutical active ingredient of formula (I).

The process comprises reacting a compound of formula (IIb) with a compound of formula (V): R ³ - (CH ₂ ) ₄ -Q, wherein R ³ and n are as defined above, Q is bromine or, preferably, chlorine. The resulting compound of formula (VI) is deprotected to give compound of formula (Ia). The reaction scheme is illustrated in Figure 2, wherein R ³ , R ⁷ , R ^2a and n are as defined above, R ^2b is hydrogen, halogen or hydroxy.

The first alkylation step of Scheme 2 is carried out according to conventional procedures. The compound of formula (V) is commercially available or can be prepared by methods known to those skilled in the art. Hydrochloride salts of the compounds of formula (V) are preferred, particularly suitable 2-chloroethylpiperidine hydrochloride.

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

Suitable solvents or solvent mixtures are those which remain unchanged during the reaction. Ν, Ν-Dimethylformamide is preferred, especially in the anhydrous state.

The reaction temperature used should ensure that the alkylation is complete. The room temperature is usually sufficient and advantageous for this.

The reaction is carried out in a neutral gas space, preferably under nitrogen.

Under favorable reaction conditions, the reaction is complete within 16-20 hours. The progress of the reaction can, of course, be monitored by chromatography.

Alternatively, the compound of formula (VI) may be prepared by reacting the compound of formula (IIb) with an excess of an alkylating agent of formula Q- (CH ₂ ) _n -Q 'in an alkaline solution. Q and Q 'are the same or different leaving groups. Suitable leaving groups are those mentioned above for the preparation of the compound of formula IV.

The preferred alkaline medium for the alkylation reaction contains potassium carbonate in an inert solvent such as methyl ethyl ketone (MEK) or dimethylformamide (DMF). In this solution, the 4-hydroxybenzene moiety of the compound of formula IIb is present as the phenoxide ion and is exchanged with the leaving groups of the alkylating agent.

Preferably, the alkaline solution of the reactant and reagent is refluxed and reacted until the reaction is complete. When MEK is used as the solvent, the reaction time is 6-20 hours.

The reaction product is reacted by standard procedures with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, diisopropylamine or 1-hexamethyleneimine. ).

Preferably, the hydrochloride salt of piperidine is reacted with an alkylated compound of formula IIb in an inert solvent such as anhydrous DMF and heated to 60-110 ° C. When the reaction is carried out at a preferred temperature of 90 ° C, the reaction is complete within 30-60 minutes. However, changing reaction conditions will affect the reaction time required. Of course, the reaction progressed through standard chromatographic techniques.

Compounds of formula VI wherein R ⁷ and R ^{7 are}

when present, each of R ⁸ is C 1 -C 4 alkyl, preferably methyl, and R ^2a is hydrogen or hydroxy, new compounds which are pharmaceutically active in the methods described in the present invention. These compounds are thus covered by the definition of compounds of formula (I).

Preferred compounds of formula (I) are provided when the compound of formula (VI) is R ⁷ and, when present

- The hydroxy protecting groups of R® are cleaved by well known methods. Numerous reactions to the formation and removal of such protecting groups are known, for example, in Protective Groups in Organic Chemistry, Plenum Press (London and New York, 1973); Green TW, Protective Groups in Organic Synthesis, Wiley (New York, 1981); "The Peptides," Volume I, Schrooder and Lubke, Academic Press (London and New York, 1965). Preferred methods for removing the R ⁷ and / or R ⁸ hydroxy protecting groups, in particular the methyl and methoxymethyl groups, are substantially as described in the examples below.

Compounds of formula (Ia) are novel, are pharmaceutically active in the methods of the invention and are included within the scope of compounds of formula (I).

Compounds of formula (I) wherein R ¹ is hydrogen are prepared by the reaction scheme shown in Figure 3. According to this, a commercially available thianaphthenic compound (VII) is replaced by a leaving group to give compound (VIII), which is then reacted with a protected hydroxy group, 4-hydroxyphenol, to give compound (IX). In the formulas of the figure, R @ 3 is a selectively removable hydroxy protecting group, R @ 3 is a leaving group.

The compound of formula (VII) is commercially available. Unless otherwise stated, in the preparation of compounds of formula (VIII) and (IX), R @ 3 and R @ ⁹ are preferred, and the preferred reactants and reaction conditions are the same as those described in the reaction scheme of Figure 1 (see above).

The compound of formula IX is then arylated by a Suzuki coupling reaction [Suzuki, A., Pure

HU 226 326-1 and Appl. Chem., 6 (2): 213-222 (1994)]. Following the Suzuki coupling procedure, the compound of formula IX is selectively halogenated at position 2 and then coupled with the arylboronic acid of formula Xla (path A in Figure 4).

Preferably, however, an arylboronic acid of formula (Xb) is formed from compound of formula (IX) and then reacted with a haloarene compound of formula (XIb) to yield a new intermediate of formula (IIc) (route B). These intermediates are suitable for the preparation of the active compounds of the present invention (compounds of formula (Ib)) by alkylation and deprotection. In the formulas of Figure 4, R ^2a , R ^2b , R ³ , R ⁶ and n are as defined above; X is iodine, bromine or fluorine, in order of preference; and X 'is iodine, bromine, fluorine - in the order of preference or triflate.

In the first step of Figure 4, the compound of formula (IX) at position 2 is iodinated or brominated by conventional means. In general, the compound of formula (IX) is reacted with a small excess of n-butyllithium in hexane in a suitable solvent, in an inert gas such as nitrogen, and a small excess of the desired halogenating agent in a suitable solvent. In this step, the halogenating agent is preferably iodine, but bromine or N-bromosuccinimide may also be used.

Suitable solvents are inert solvents or mixtures of solvents such as diethyl ether, dioxane and tetrahydrofuran (THF). Of these, THF is particularly preferred, especially in the anhydrous state.

The selective halogenation at position 2 is carried out at a temperature in the range of -75 ° C to 85 ° C.

The product of the above reaction is the haloarene compound of formula (Xa) which is reacted with the arylboronic acid of formula (Xla) using the Suzuki coupling reaction. The reaction product is the compound of formula (IIa). The compound of formula (Xla) wherein R ^2a is hydrogen, halogen or -OR ⁸ (wherein R ⁸ is a protecting group as defined above) may be commercially available or may be prepared in a well known manner (e.g., March J .; or Suzuki A; see above).

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

Although Suzuki coupling reactions can be performed with various palladium catalysts, the catalyst selected is usually reaction specific. The use of tetrakis (triphenylphosphine) palladium in the present reaction is highly preferred.

Similarly, various bases may be used for the reaction, but alkali metal carbonates, especially 2N sodium carbonate, are preferred.

The reaction temperature used in the reaction step must be sufficient to complete the coupling reaction. Generally, it is sufficient and preferred to reflux the reaction mixture for 2 to 4 hours.

In Scheme 4, Reaction Route B, the compound of Formula Xb is prepared by well known procedures. In general, the compound of formula IX is reacted with n-butyllithium in a suitable solvent and in an inert gas such as nitrogen under hexane with a slight excess of n-butyllithium. Appropriate trialkyl borate is then added dropwise to the reaction mixture.

Suitable solvents are inert solvents or mixtures of solvents such as diethyl ether, dioxane and tetrahydrofuran, with anhydrous tetrahydrofuran being particularly preferred.

The preferred trialkyl borate for the reaction is triisopropyl borate.

The reaction of the product of formula (Xb) with an aryl halide of formula (Xb) or an aryltriflate is carried out in the usual Suzuki coupling reaction to give the product of formula (IIc). Preferred reaction conditions are described for the reaction of compounds of formula (Xla) and (Xa) (Figure 4), which also yields compounds of formula (IIc).

Conversion of compounds of formula (IIc) to compounds of formula (Ia) has already been described above for the conversion of compounds of formula (IIa) into compounds of formula (Ia).

The compounds of formulas (IIc) and (IId) are novel and suitable for the preparation of the active compounds of the present invention.

The compounds of formula (XII) and (Ib) are also novel and can be used in the methods described herein.

The formula (I) as defined above covers the compounds of formula (XII) and (Ib).

Compounds of formula (I) wherein one of R ¹ and R ² is hydrogen and the other is hydroxy are prepared from a compound of formula (I) wherein both R ¹ and R ² are hydroxy. The dihydroxy compounds of formula (I) are converted into a mixture of 6- and 4'-monotriflates and the triflate group is reduced so that it eventually becomes a hydrogen atom. JM et al., J. Org. Chem., 55: 991 (1990)]. The resulting mixture of monohydroxy derivatives, either as the free base or as a pharmaceutically acceptable salt, preferably as the hydrochloride salt, can be separated by conventional crystallization processes.

Generally, the dihydroxy compound of formula (I) is reacted with 4-6 equivalents of an amine base, such as triethylamine, in an inert solvent, followed by addition of 1 equivalent of trifluoromethanesulfonic anhydride. A statistical mixture of mono- and ditriflates is obtained, which is separated by conventional chromatography. Anhydrous dichloromethane is the preferred solvent for the reaction.

If the reaction is carried out at 0-25 ° C,

It will be complete in 1-5 hours.

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The resulting mixture of monotriflate compounds is then hydrogenated in an inert solvent in the presence of 3-6 equivalents of an amine base, preferably triethylamine, and a hydrogenation catalyst such as palladium on carbon. The preferred solvent for the reaction is ethyl acetate, ethanol or a mixture thereof. The reaction time is 40 psi hydrogen gas at room temperature

2-5 hours.

The monohydroxy derivatives of formula (I) have different solubilities in ethyl acetate and the 6-hydroxy-4'-hydrogen derivative can be preparatively separated from the 6-hydroxy-4'-hydroxy derivative by selective crystallization. The pure monohydroxy compound is obtained by converting the pre-purified mixture to the hydrochloride salt and crystallizing it from ethyl acetate / ethanol.

A more direct method of preparing compounds of formula I wherein one of R ¹ and R ² is hydrogen and the other is hydroxy is based on the compound of formula IIh. This is also an alternative route for the preparation of compounds of formula I wherein one of R ¹ and R ² is hydrogen and the other is C 1 -C 4 -O-alkyl. In the general formula (IIh)

R ³ and n are as defined above;

R ^1c is hydroxy or C 1 -C 4

-O-alkyl;

and

R ^2c is hydroxy or C 1 -C 4

-O-alkyl;

provided that when R ^1c is hydroxy, R ^2c is C 1 -C 4 -alkyl and if R ^1c is C 1 -C 4 -O-alkyl then R ^2c is hydroxy.

In this process, the hydroxyl group of the compound is converted to the triflate derivative by treatment with trifluoromethanesulfonic anhydride. The triflate group is reduced under standard conditions, preferably by catalytic hydrogenation. Then, in a customary manner by removing the protecting group of hydroxyl group to give (I) compound wherein R ¹ and R ² is hydrogen and the other is hydroxy.

Another alternative and preferred method for preparing the compounds of the present invention is shown in Figure 5. The process involves oxidizing the sulfur atom of a compound of formula IV to a sulfoxide group (compound of formula XIV). This derivative is then reacted with a nucleophile to introduce the oxygen or sulfur bond atoms of the compounds of formulas I and II. The sulfoxide group of the compounds of formula (XVI) is reduced to provide the specific compounds of the present invention. In the formulas of Figure 5, each of the general substituents and variables has the same meaning as previously defined.

As a first step in the process, the compound of formula (IV) is selectively oxidized to the sulfoxide. There are many known methods for this [e.g. Madesclaire, M., Tetrahedron, 42 (20): 5459-5495 (1986); Trost, Β. M. et al., Tetrahedron Letters, 22 (14): 1287-1290 (1981); Drabowicz, J., et al

Synthetic Communications, 11 (12): 1025-1030 (1981); Kramer, J. B., et al., 34th National Organic Symposium, Williamsburg, VA, June 11-15, 1995]. However, many oxidants convert only poorly to the desired compound and significant overoxidation to the sulfone. The present new process, in turn, converts the compound of formula (IV) into the compound of formula (XIV) in high yield, with little or no sulfone derivatives being formed. In the process, the compound of formula IV is reacted with 1 to 1.5 equivalents of hydrogen peroxide in methylene chloride containing 20 to 50% trifluoroacetic acid. The reaction is carried out at a temperature of 10-50 ° C and generally takes 1-2 hours to complete.

Subsequently, the leaving group (R ⁹ ) at position 3 is replaced with the desired nucleophile derivative (XV). Such nucleophilic derivatives are prepared in a conventional manner.

In this step of the reaction, the acidic proton of the nucleophile is removed in a polar aprotic solvent, preferably with a small excess of sodium hydride or potassium tert-butoxide. Potassium carbonate and cesium carbonate may also be used as bases. Dioxane and dimethyl sulfoxide may also serve as solvents. The reaction is usually carried out at 0 to 30 ° C and is usually complete within 30 minutes. Compound (XIV) is then added to the solution of the nucleophile component. The substitution reaction was complete at 0-50 ° C in 1-2 hours. The product is recovered by conventional methods.

If the protecting group of the hydroxyl group is a benzyl group, hydrogenolysis of the sulfoxide group can also be performed to remove the benzyl group, so that it is not necessary to selectively remove the protecting group at a later stage.

The new sulfoxides (XVI a, b, c and d) (collectively XVI) are next reduced to benzothlofen (IIg), (le), (Ile) and (le). Prior to reduction, compounds of formula (IIg) and (Ile) may be first alkylated as described herein. The reduction of sulfoxide compounds can be accomplished by any of several methods known in the art. Examples include hydride reduction (with lithium aluminum hydride), catalytic hydrogenation, transfer hydrogenolysis, and trimethylsilyl iodide (TMS-I).

For the reduction, the reagent is selected taking into account the other functional groups in the molecule. Preferred reagents for the compounds of the present invention are lithium aluminum hydride (LiAlH ₄ ) and the transfer hydrogenolysis process (palladium carbon black / ammonium formate). Suitable solvents for lithium aluminum hydride reduction include diethyl ether, dioxane or tetrahydrofuran; anhydrous THF is particularly preferred. Preferred solvents for transfer hydrogenolysis are alcohols, especially ethanol. The reaction was complete at 0-60 ° C for 0.5-2 hours.

If necessary, the hydroxyl protecting groups may be removed from the products of the reaction steps of Figure 5, and salts may be formed at any step. Követke8

Accordingly, the present invention provides a process for the preparation of a compound of formula (le): wherein

R ^1a is hydrogen or -OR ^7a , wherein R ^7a is hydrogen or hydroxy protecting group;

R ^2a is hydrogen, halogen or -OR ^8a , wherein R ^8a is hydrogen or hydroxy protecting group;

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

n is 2 or 3; and

Z is an oxygen or sulfur compound, or a pharmaceutically acceptable salt thereof, which comprises:

(a) a compound of formula IV wherein:

R ^1a and R ^2a are as defined above;

R ⁹ is a sulfur atom of a leaving group compound;

b) reacting the product of formula (XIV) of step a) with a nucleophile of a reagent of formula (XXIII) wherein R ¹² is a hydroxyl or sulfhydryl group;

c) reducing the product of formula (XVI) of step b) to a compound of formula (le);

d) optionally removing the R ^1a and / or R ^2a protecting group of the hydroxyl group from the product of step c); and

e) optionally forming a salt from the reaction product of steps c) or d).

This novel process also provides novel compounds of formulas (XIV) and (XVIa), (XVIb), (XVIc) and (XVId), which can be used as intermediates in the preparation of the pharmaceutical agents of the present invention.

Compounds of formula (I), wherein Z is sulfur, may also be prepared by the reaction of Figure 6, wherein the compound of formula (IVa) may be metallated. The resulting compound of formula (XVII) is reacted with 4-hydroxyphenyl disulfide of protected hydroxy group (XVIII) and the phenolic hydroxy group of formula Ile is deprotected to give compound of formula IIf. Note that in this reaction, R cannot be halogen due to chemical limitations. In the final product of formula (IIf)

R ^1a is hydrogen or -OR ⁷ , wherein R ⁷ is a hydroxy protecting group;

R ^2a is hydrogen or -OR ⁸ , wherein R ⁸ is a hydroxy protecting group;

^R6 is a selectively removable hydroxy protecting group;

R ⁹ is a leaving group; and

M is a metal ion.

In the first two steps of the reaction process of Figure 6, the compound of formula IVa is metallized by a well known process. Most often and most preferably, the compound of formula (IVa) is reacted with a small excess of n-butyllithium in hexane in a suitable solvent, and a solution of the disulfide of formula (XVIII) in a suitable solvent is added dropwise to the reaction mixture.

Both reaction steps are carried out under an inert gas such as nitrogen; the inert solvent may be diethyl ether, dioxane and THF, or a mixture thereof. Most preferred is THF, especially in the anhydrous state. The reactions were carried out at -78 ° C and 85 ° C.

In the first step, the metallized compound of formula (XVII) is obtained which is reacted with a protected hydroxyl group of 4-hydroxyphenyl disulfide (formula (XVIII)) to give the compound of formula (Ile). The compound of formula (XVIII) is prepared from commercially available 4-hydroxyphenylsulfide by protecting the hydroxyl group by known methods. A preferred protecting group for R ⁶ is methoxymethyl, provided that the protecting groups R ⁷ and R ⁸ , when present, are not methoxymethyl. It is important that the protecting group R ^{6 is} different from the protecting groups R ⁷ and R ⁸ so that it can be selectively removed by known methods to give the compound of formula IIf.

The R ⁶ protecting group to remove at least one equivalent of acid, preferably methanesulfonic acid is reacted with the compound of formula (II c) in a protic solvent or mixture of solvents at 25-110 ° C. It takes 6-24 hours for the reaction to complete, which is checked by standard chromatographic techniques.

Suitable solvents for the reaction are, for example, water and methanol.

The compounds of formulas Ile and IIf are novel, useful in the preparation of pharmaceutically active compounds of formula I, and are covered by the above definition of formula II.

Compounds of formula (Id) wherein R ^1b is hydrogen or hydroxy;

R ^2b is hydrogen or hydroxy;

R ³ and n are as defined above in a similar manner to the reaction scheme of Figures 2 and 4. The compounds of formula (Id) are also novel, useful in the methods of the present invention and are covered by the definition of formula (I).

Compounds of formula I wherein R ¹ and R ² are hydroxy protected by different groups or one of R ¹ and R ² is protected hydroxy and the other is hydroxy can be selectively prepared from the modified 2-aryl benzothiophene starting material of formula III assuming that the protecting groups for the R ⁷ and R ⁸ hydroxyl groups are sufficiently different to remove one protecting group so that the other remains in place. Such 2-arylbenzothiophenes can be prepared in a well known manner.

The Suzuki coupling reaction shown above in Figure 4 is particularly preferred for the preparation of compounds of formula I wherein R ¹ and R ² are different hydroxy protected groups. The protected hydroxyl group is 9

The 6-hydroxybenzothiophene-2-boronic acid powder of formula (1b) is reacted with a compound of the formula (Xlb) wherein R ^2a is -OR® and R ⁷ is not the same as R®. As a result of this reaction, compounds of the present invention are obtained wherein R ⁷ and R ⁷ are different hydroxyl protecting groups which allow one to remain selectively removed while the other remains in place in the final product. Preferably, the R ⁷ protecting group, especially benzyl or isopropyl groups, is removed to form the free hydroxy group, while the R ⁷ protecting group, preferably methyl

- stays in place.

The Suzuki coupling reaction can also be used for the above procedure, but the compound of formula Xlb is used instead of the compound of formula XIX

R ^8a is C 1-6 alkyl sulfonate, preferably methanesulfonate or C 4-6 aryl sulfonate; and

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

In this procedure, the protected hydroxy group 6-hydroxybenzothiophene-2-boronic acid is reacted as described above with a compound of formula XIX to give a compound of formula XX which is reacted with boron tribromide in methylene chloride to give the corresponding monohydroxy compound. which is further converted, for example, to the benzylated compound (XXI) by conventional means. The 4'-sulfonate ester group is then selectively removed by alkaline hydrolysis or, preferably, lithium aluminum hydride treatment. The reaction is carried out in a suitable aprotic solvent such as THF. The reaction gives a compound of formula (XII) which is finally methylated at the 4 'site (compound of formula (IIIa)) in a conventional manner. Of course, those skilled in the art will appreciate that various methods may be used to prepare compounds of formula (IIIa) wherein the hydroxyl protecting group is different from that shown in Figure 7, but which can be selectively removed to provide the compound of formula (I) to get monohydroxy compounds. The compounds of formula (IIIa) are subjected to various methods described herein to obtain the compounds of formula (I) and (II) of the present invention.

Other preferred compounds of formula (I) may be prepared by positioning the 6 and / or 4 '

where present, the hydroxyl group is replaced by -O-CO (C 1 -C 6 alkyl) or -O-SO ₂ - (C 2 -C 6 alkyl) using known procedures. See, for example, U.S. Patent No. 4,358,593.

For example, if -O-C0- (C1-C6) alkyl is desired, the dihydroxy compound of formula (I) is reacted with an acid chloride, an acid bromide, a cyanide, an acid azide, a suitable anhydride or a mixed anhydride. The reaction is preferably carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine. The reaction may also be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, etc., with at least one equivalent weight of acid scavenger (e.g. tertiary as we do. If necessary, an acylation catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, for example, Hasiam et al., Tetrahedron, 36: 2409-2433 (1980).

These reactions are carried out at a moderate temperature, between -25 ° C and 100 ° C, often under an inert gas such as nitrogen. In general, room temperature is sufficient for the reaction to be complete.

Acylation of the hydroxyl group at the 6 and / or 4 'positions with the appropriate carboxylic acid can be accomplished by acid-catalyzed reaction in an inert solvent. Examples of acid catalysts include sulfuric acid, polyphosphoric acid, methanesulfonic acid and the like. used.

The above-mentioned R ¹ and / or R ² groups of the compounds of formula (I) may also be obtained by forming the active ester of the corresponding acid. Such esters may be formed with known reagents such as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide or 1-hydroxybenzotriazole. See, for example, Bull. Chem. Soc. Japan, 38: 1979 (1965); or Chem. Bér., 788 and 2024 (1970).

All of the processes for the above -O-CO- (C 1 -C 6) alkyl are carried out in one of the solvents mentioned above. Where no acid is formed during the process, of course, there is no need for an acid scavenger.

When a compound of formula (I) is required wherein the hydroxyl group at the 6 and / or 4 'positions is replaced by the group -O-SO ₂ - (C 2 -C 6) alkyl, the mono- or dihydroxy compound is, e.g. sulfonic acid anhydride or a corresponding sulfonic acid derivative such as sulfonyl chloride, bromide or sulfonylammonium salt, as described in King and Monoir, J. Med. Chem. Soc., 97: 2566-2567 (1975)]. The dihydroxy compound can be reacted with the appropriate sulfonic anhydride or mixed sulfonic anhydride. Such a reaction is carried out as discussed above for acid halides and the like.

Although the compounds of formula (I) may be used in the free base form in the processes of the present invention, it is preferable to form and use a pharmaceutically acceptable salt. The processes of the present invention employ primarily pharmaceutically acceptable acid addition salts which can be formed using a wide variety of organic and inorganic acids. These salts are often used in pharmaceutical chemistry. Salts are also part of the invention. Inorganic acids used for salt formation: hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Organic sa10 for salt formation

Aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkane mono- and diacids, aromatic acids, aromatic and aliphatic sulfonic acids may also be used. The pharmaceutically acceptable salt may thus be: acetate, phenylacetate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o -acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β- hydroxybutyrate, butin-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxy maleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenyl propionate, salicylate, sebecate pyrosulfate, sulfite, hydrogen sulfite, sulfonate, benzenesulfonate, p-bromophenyl sulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, sulfonate, tartrate, etc. Preferred salts are the hydrochloride and the oxalate.

Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula (I) with an equivalent weight or excess of acid. The reactants are reacted with one another in a common solvent such as diethyl ether or ethyl acetate. The salt is leached from the solution after an hour to 10 days and can be recovered by filtration or removal of the solvent by conventional means.

Pharmaceutically acceptable salts are generally more soluble than the compounds from which they are derived and are therefore often more suitable for the preparation of solutions or emulsions.

The following are preferred examples of compounds of the present invention;

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-bromobenzo [b] thiophene (S-oxide) [2- (4-methoxyphenyl) - 3-Bromo] benzo [b] thiophene (S-oxide) [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene (S-oxide) [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene (S) oxide) [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) [6-isopropoxy-2- (4-methoxyphenyl) - 3-Bromobenzo [b] thiophene (S-oxide) [6-methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) [6-methoxy- 2- (4-Isopropoxyphenyl) -3-bromobenzo [b] thiophene (S-oxide) [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] - 2- (4-methoxyphenyl)] - benzo [b] thiophene (S-oxide) [6-isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4- methoxyphenyl)] - benzo [b] thiophene (S-oxide) [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-benzyloxyphenyl) )] - benzo [b] thiophene (S-oxide) [6-methoxy -3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-isopropoxyphenyl)] benzo [b] thiophene (S-oxide) [6-methoxy-2- ( 4-methoxyphenyl) -3- (4-methoxymethyloxy) thiophenoxy] benzo [b] thiophene [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] hydroxyphenyl) J-benzo [b] thiophene

II. group:

[3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl) benzo [b] thiophene [3- [4- [2- (1-piperidinyl)] -ethoxy] -phenoxy] -2- (4-hydroxy-phenyl) -benzo [b] thiophene hydrochloride [3- [4- [2- (1-pyrrolidinyl) -ethoxy] -phenoxy] -2- (4- hydroxyphenyl) benzo [b] thiophene [3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene [3- [4- [2- (1-N, N-Diethylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [3- [4- [2- (1) piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzophenylthiophene hydrochloride [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene hydrochloride [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-fluorophenyl) benzo [b] thiophene [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene [6-isopropoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) - phenoxy] benzo [b] thiophene [6-methoxy-2- (4-isopropoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene [6-methoxy-3- [4- [ 2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy]] f enoxy] -2 (4-methoxyphenyl) -j-benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2 (4-methoxy) phenyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] -2- (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [ 6-Methoxy-3- [4- [2- (morpholino) -ethoxy] -phenoxy] -2- (4-methoxy-phenyl)] - benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [ 3- (piperidino) propoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [3- (1-N, N-diethyl) amino) propoxy] phenoxy]

2- (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl) ] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene oxalate [ 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy-2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [ 2- (1-Pyrrolidinyl) -ethoxy] -phenoxy] -2 (4-hydroxy-phenyl) -benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-hexamethylene-imino) -ethoxy] ] phenoxy]

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

EN 226 326 Β1 [6-Hydroxy-3- [4- [2- (morpholino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [3- (1-N, N-Diethylamino) propoxy] phenoxy] 2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-N, N-Diisopropylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [3 - (piperidino) propoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] - phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4 -methoxyphenyl)] - benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -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)] benzo [b] thiophene [6-benzyl- oxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-piperidine yl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-pyridinyl) 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)] - benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy] 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1) -pyrrolidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-hexamethylimino) ethoxy] - phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] 2- (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2 (4-methoxyphenyl)] - benzo [b] Thiophene [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy] -3- [4- [2- (1-Pyrrolidine)] -ethoxy] -phenoxy] -2- (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-hexamethylimino) ethoxy] - phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] phenoxy] 2- (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2 (4-methoxyphenyl) )] - benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-benzyloxyphenyl)] - benzo [b] ] thiophene [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2 (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3 - [4- [2- (1-Hexamethyleneimino) ethoxy] phenoxy] 2- (4-benzyloxy-phenyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2 - (1-N, N-Dimethylamino) ethoxy] phenoxy] 2- (4-benzyloxyphenyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2- ( 1-morpholino) ethoxy] phenoxy] -2 (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] ] -phenoxy] -2 (4-isopropoxyphenyl) benzo [b] thiophene [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2 · (4-isopropoxy) phenyl)] - benzo [b] thiophene N [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] ·

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

2- (4-Isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2 · (4-isopropoxyphenyl) ] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 · (4-hydroxyphenyl)] benzo [b] thiophene [6 -methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [ 2- (1-hexamethyleneimino) ethoxy] phenoxy] ·

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

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

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

2- (4-hydroxyphenyl)] - benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] phenoxy] -2 (4-hydroxyphenyl) )] - benzo [b] thiophene hydrochloride [6-benzoyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-benzyloxyphenyl)] - benzo [b] Thiophene hydrochloride [6-ethylsulfonyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy]

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

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

3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzoyloxy-phenyl)] - benzo [b] thiophene hydrochloride [3- [4- [2- (1) piperidinyl) ethoxy] phenoxy] -2- (4-pivaloyloxy phenyl)] benzo [b] thiophene hydrochloride [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] ] -2- (4-butylsulfonyl-oxyphenyl)] - benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 ( 4-methoxyphenyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] - benzo [ b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-methoxy] 3- [4- [2- (1-N, N-Dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4 - [2- (1-Morpholino) ethoxy] thiophenoxy] -2 (2-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-piperidinyl) ) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] - 2- (4-methoxyphenyl)] - benzo [b] thiophene

EN 226 326 Β 1- [6-Benzyloxy-3- [4- [2- (1-hexamethylene-imino) -ethoxy] -thiophenoxy] -2- (4-methoxy-phenyl)] - benzo [b] thiophene [6 Benzyloxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-benzyloxy] -3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [2- ( 1-piperidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) )] - benzo [b] thiophene [6-isopropoxy-3- [4- [2- (1-N, N-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-piperidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1- pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2 - (4-methoxyphenyl)] - benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] - benzo [b] thiophene [6-hydroxy-3- [4- [2-piperidinyl] ethoxy] thiophenoxy] -2 (4-methoxyphenyl) benzo [b] thiophene hydrochloride [6-hydroxy -3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [ 2- (1-Hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [3- [2- (1-N , N-dimethylamino) ethoxy] thiophenoxy] -2- (4-methoxyphenyl) benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] ] -thiophenoxy] -2 (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 ( 4-benzyloxyphenyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-benzyloxyphenyl) ] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-benzyloxy) enyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-benzyloxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2 (4-benzyloxyphenyl)] benzo [b] thiophene [6 -methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2 - (1-Pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] ] thiophenoxy] -2- (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] - 2- (4-isopropoxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2 (4-isopropoxyphenyl)] Benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy] -3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- ( 1-Hexamethylene-imino) -ethoxy-thiophenoxy] -2- (4-hydroxy-phenyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2- (1-N, N-dimethylamino)] ethoxy] t iophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene [6-methoxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2 (4-hydroxy) phenyl)] - benzo [b] thiophene [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] - benzo [b] thiophene- hydrochloride [6-methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [ 4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- ( 1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1- morpholino) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl) )] - benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] - benzo [b] thiophene [6 -hydroxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] thiophenoxy] -2- (4-hydroxy) i-phenyl)] - benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) ethoxy] thiophenoxy] -2- (4-hydroxyphenyl) ] benzo [b] thiophene [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene [6- hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [ 2- (1-Pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-hexamethylenimine) ) -ethoxy-thiophenoxy] -2- (4-hydroxy-phenyl)] - benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-N, N-dimethylamino) -ethoxy] -thiophenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-morpholino) ethoxy] thiophenoxy] -2 (4-hydroxy) phenyl)] - benzo [b] thiophene hydrochloride [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2-phenyl] benzo [b] thiophene hydrochloride.

The effects of the various protocols on the effects of different treatments on circulating lipids are investigated in postmenopausal models.

75-day-old female Sprague-Dawley rats (200-225 g body weight) were obtained from Charles River Laboratories (Portage, MI, USA). The animals were ovariectomized on both sides (OVX) or subjected to Sham surgery at Charles River Laboratories and transported one week later. 3-4 animals are housed in suspended metal cages and can consume any amount of food (calcium content about 0.5%) and water for one week. The room temperature is 22.2 ± 1.7 ° C and the minimum relative humidity is 40%. The animals were exposed to light for 12 hours daily and dark for 12 hours.

Dispensing, tissue sampling

After an acclimation period of one week (i.e. two weeks after ovariectomy), daily dosing of the test compound is started. The animals receive daily13

Orally administered 17a-ethynyl estradiol or test compound, unless otherwise stated, as a suspension in 1% carboxymethylcellulose or 20% in cyclodextrin. Rats receive doses for 4 days. After treatment, the animals were weighed and anesthetized with a 2: 1 mixture of ketamine / xylazine. After blood sampling by cardiac puncture, the animals are sacrificed by carbon dioxide suffocation, the uterus is removed through a midline incision, and the uterine wet weight is measured.

cholesterol Definition

The blood sample is allowed to coagulate at room temperature for 2 hours and centrifuged at 3000 rpm for 10 minutes. Cholesterol in the serum obtained is determined by the Boehringer Mannheim Diagnostics high sensitivity cholesterol assay. Briefly, cholesterol is oxidized to cholest-4-en 3 -ene and hydrogen peroxide. Hydrogen peroxide is reacted with phenol and 4-aminophenazone in the presence of peroxidase. The resulting p-quinone imine dye was measured spectrophotometrically at 500 nm. Cholesterol concentration is calculated using a standard curve. The entire test procedure is automated by the Biomek Automated Workstation.

Study of uterine eosinophil peroxidase (EPO)

The uterus was kept at 4 ° C until enzyme analysis and then homogenized in 50 ml of 50 mM Tris buffer, pH 8.0 containing 0.005% Triton Χ-100. 0.01% Hydrogen Peroxide and 10 mM O-Phenylenediamine (final concentrations) were added to the Tris buffer and the increase in absorbance was measured at 450 nm for one minute. The presence of eosinophils in the uterus indicates the estrogenic activity of the compound. The maximum velocity is determined over a 15 second period of the initial linear portion of the reaction curve.

17? -Ethynyl estradiol was purchased from Sigma Chemical Co., St. Louis, MO, USA.

Effect of compound of formula (I) on serum cholesterol and determination of agonist / non-agonist activity

Table I compares the results of bilaterally removed uterine (OVX) rats, rats treated with 17α-ethinyl estradiol (EE ₂ ; oral estrogen) and the compounds of the present invention. Although EE ₂ causes a decrease in serum cholesterol when administered orally to animals at a dose of 0.1 mg / kg, it also has a stimulatory effect on the uterus, so that the uterus weight of the treated animals is significantly greater than that of the ovariectomized animals. They removed. The response of the uterus to estrogen action is well known in the art.

Not only do the compounds of the invention lower serum cholesterol levels compared to the 20-bee control animals, but most of the test compounds have only a minimal or a slight decrease in uterine weight compared to known estrogenic compounds, a very rare and highly desirable property of a given compound the serum cholesterol level is reduced without adversely affecting uterine weight.

As shown below, estrogenocity was also measured by measuring the infiltration of eosinophils into the uterus. The compounds of the present invention do not cause any increase in the number of eosinophils observed in the connective tissue (stroma) layer of the ovariectomized rats, while estradiol results in a significant, expected increase in eosinophilin filtration.

The data in Table I were obtained from 5-6 animals per treatment.

/. spreadsheet

Compound Dose (mg / kg) Weight of uterus (% increase compared to non-ovarian) Bee EPO (V.max) Serum cholesterol (% increase over non-ovarian) ee ₂ 0.1 229.2 308.1 94.8 Example 9 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 10 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 11 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 14 0.1 32.0 4.8 56.2 1.0 44.3 4.5 42.6 5.0 41.6 4.8 29.5

HU 226 326 Β1

/. Table (continued)

Compound Dose (mg / kg) Weight of uterus (% increase compared to non-ovarian) Bee EPO (V.max) Serum cholesterol (% increase over non-ovarian) Example 19 0.1 19.7 12.0 50.2 1.0 18.4 17.7 59.0 10.0 13.3 4.8 38.9 Example 28 0.01 11.4 2.1 25.1 0.1 24.9 2.4 45.3 1.0 24.7 3.6 53.6 Example 29 0.01 16.9 0.9 29.4 0.05 40.9 3.0 35.9 0.1 30.6 3.0 58.7 Example 30 0.01 21.0 1.2 26.8 0.1 24.8 4.8 47.5 1.0 51.4 9.3 54.4 Example 32 0.01 21.6 3.3 36.2 0.1 33.4 84.3 66.1 Example 33 0.01 9.2 3.6 23.7 0.1 18.2 0.9 46.4 1.0 81.0 29.4 79.3 Example 34 0.01 5.4 3.0 13.1 0.1 16.7 3.3 67.6 1.0 96.6 36.0 73.9 Example 35 0.01 14.0 4.8 29.0 0.1 81.0 29.1 45.2 1.0 117.1 175.1 67.2 Example 36 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 64 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 65 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 75 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 the claimed benefits of the compounds of the present invention, especially when compared to estradiol, the above data clearly demonstrate that the compounds of formula I are not estrogen mimetics.

Osteoporosis examination procedure

The animals described above were treated as described for 35 days and then sacrificed on carbon dioxide for 60 days. There are 6 animals per treatment group. A period of 35 days is sufficient to maximize bone loss. At the time of sacrifice, the uterus is removed, cleansed of foreign tissue, fluid removed, and its mass is determined, which confirms the estrogen deficiency associated with total ovarian removal. The uterine weight is usually reduced by 75% as a result of the removal of the ovaries. The uterus does not continue15

HU 226 326 Β1 was placed in 10% formalin-buffered lumina for subsequent histological analysis.

The right femur is excised and, for distal metaphysis, the x-ray data generated and analyzed by the "image analysis program" (NIH image) are digitized. The proximal portion of the femur is also evaluated by quantitative tomography.

In accordance with the above procedures, the compounds of the present invention and ethinyl estradiol (EE ₃ ) in 20% hydroxypropyl-β-cyclodextrin are administered orally to experimental animals. II. and III. Table I summarizes the data for distal metaphyses of the femur of intact and removed uterine animals treated with compounds of formula (I). Beside the average data, errors of the mean standard are indicated.

II. spreadsheet

Compound / Treatment Dose (kg) Femoral distal metaphysis (X-ray image analysis with graying) Blind (20% cyclodextrin) - 27.2 ± 6.0 Ovariectomy control (20% cyclodextrin) - 8.1 ± 1.8 ee ₂ 0.1 mg 11.5 ± 2.9 * Example 28 0.1 mg 14.7 ± 1.9 1.0 mg 15.0 ± 3.5 * 10.0 mg 15.3 ± 4.0 *

* P <= 0.5 for two Studen T tests on raw data.

III. spreadsheet

Compound / Treatment Dose (kg) Femoral distal metaphysis (X-ray image analysis with graying) Blind (20% cyclodextrin) - 31.1 ± 6.3 Ovariectomy control (20% cyclodextrin) 6.2 ± 1.4 ee ₂ 0.1 mg 17.8 ± 3.5 Example 19 Compound 0.1 mg 15.3 ± 3.0 1.0 mg 15.2 ± 3.7 3.0 mg 18.5 ± 3.2 * Example 33 0.1 mg 19.6 ± 2.3 3.0 mg 17.1 ± 5.5

* P <= 0.005 two Studen T tests on raw data.

In summary, removal of the uterus results in a significant reduction in femoral density compared to intact and vehicle treated control animals. Oral administration of ethinyl estradiol (EE ₂ ) prevents this loss, but there is a perpetual risk that treatment may stimulate goose.

The compounds of the invention also prevent osteoporosis. Their effect is general and dose-dependent. Consequently, the compounds of the present invention are useful in the treatment of postmenopausal syndrome, particularly osteoporosis.

MCF-7 proliferation assay

MCF-7 Breast Adenocarcinoma Cells (ATCC HTB 22) are maintained on MEM medium (minimal essential medium, phenol red, Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (FBS), L-glutamine (2). mM), sodium pyruvate (1 mM), HEPES (N- [2-hydroxyethyl [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid]) (10 mM), non-essential amino acids and bovine- insulin (1 pg / ml) (maintenance medium). Ten days before the assays, the medium of MCF-7 cells was replaced with a maintenance medium containing 10% dextran-coated charcoal-treated fetal bovine serum (DCC-FBS assay medium) to remove intimate steroids. MCF-7 cells are removed from the maintenance vessel in dissociated medium (Ca ²⁺ / Mg ²⁺ -free HBSS without phenol red supplemented with 10 mM HEPES and 2 mM EDTA). The cells are washed twice with assay medium and the cell number is adjusted to 80,000 cells / ml. About 100 μΙ cell suspension (8000 cells) was added to the flat bottom wells of the microtiter plate (Costar 3596) and incubated at 37 ° C for 48 hours. The incubator humidified air contains 5% carbon dioxide. During this time, the cells adhere after transfer. A dilution series of the active compounds and, as a dilution control, DMSO is prepared in the assay medium. In triplicate, 50 ml of the diluted solution and 50 μΙ of assay medium are added to the microcultures to give a final volume of 200 μΙ. The conditions were incubated for an additional 48 hours and the microcultures were pulsed with tritiated thymidine (1 pCi / well) for 4 hours. The cultures were placed at -70 ° C for 24 hours, then thawed and the microcultures were harvested using a Skatron Semiantomatic Cell Harvester. Samples were evaluated with a Wallac Beta Market β-counter. The results are shown in Table IV. We were tabulated, showing some of the compounds of the invention IC ₅₀ -values.

ARC. spreadsheet

Example IC ₅₀ nM Example 9 4.0 Example 19 2.0 Example 28 0,028 Example 30 0.05 Example 32 0.08 Example 75 0.28

HU 226 326 Β1

Inhibition of DMBA-induced breast cancer

Estrogen-dependent breast tumors are induced in female Sprague-Dawley rats (Harlan Industries, Indianapolis, Indiana, USA). At 55 days of age, rats receive a single oral dose of 20 mg of 7,12-dimethylbenzo [a] anthracene (DMBA). Six weeks after DMBA administration, the tumor is examined weekly for tumor appearance. When the tumor appears, the longest and shortest diameters are measured with a metric caliper, the data recorded, and the animal isolated for examination. Animals with different size tumors were divided into the treated and control groups so that the mean size of the two groups was the same. The test and control groups consist of 5-9 animals in each study.

The compounds of the formula I are administered either by intraperitoneal injection in 2% acacia or by oral administration. Oral administration takes the form of a solution or suspension in 0.2 ml corn oil. All treatments, including controls, where acacia or corn oil is administered are administered once daily. Continuing to measure tumors and isolate test animals, the size of tumors was determined weekly using the method described above. Treatments and measurements take 3-5 weeks, during which time the final area of the tumors is determined. The change in mean tumor area for each compound and control treatment was determined.

Uterine fibrosis assays

Test procedure 1

3-20 women with uterine fibrosis are administered the compound of the present invention. The daily dose is 0.1-100 mg and the duration of treatment is 3 months.

During treatment and for 3 months after discontinuation of treatment, the effect on uterine fibrosis is monitored.

Test procedure 2

Identical to Test 1, except that the treatment duration is 6 months.

Test procedure 3

Identical to assay 1, except that the treatment duration is 1 year.

Test procedure 4

A) Induction of fibroid tumor in guinea pig

In sexually mature female guinea pigs, prolonged estrogen stimulation induces leiomyoma (smooth muscle tumor). Animals are injected with estradiol 3-5 times a week for 2 to 4 months or until the tumor appears. Animals are treated daily with the compound of the invention or vehicle for 3 to 16 weeks, then sacrificed, the uterus removed and the tumor examined for regrowth.

B) Transplantation of human uterine fibroid tissue into nude mice

Human leukemia tissue is implanted into the abdominal cavity and / or uterine muscle (myometrium) of sexually mature castrated female nude mice. Exogenous estrogen is added to incubate the graft tissue for growth. In some cases, harvested tumor cells are cultured in vitro before implantation. During treatment, the stomach is flushed daily with formulations of the compound of the invention or vehicle for 3 to 16 weeks, and the implanted tissue is removed and growth or regrowth is measured. When animals are killed, the uterus is removed for examination of the organ.

Test procedure 5

A) Tissue from human fibroid tumor was harvested and maintained in vitro as a primary, untransformed culture. The surgical preparation is passed through a sterile sieve or cleaned of surrounding tissue and a single-cell suspension is prepared. The cells are maintained in media containing 10% serum and antibiotics. The rate of growth in the presence and absence of estrogen is determined. The cells are examined for their ability to produce C3 complement and their response to growth factors and growth hormone. In vitro cultures are evaluated for response to treatment with progestins, GnRH, compounds of the present invention, or vehicle. The levels of steroid hormone receptors are monitored weekly to determine whether important cellular properties are maintained in vitro. A tissue sample from 5 to 25 patients is used.

Activity in at least one of the above assays indicates that the compound of the present invention is a potential treatment for uterine fibrosis.

Test procedure for endometriosis

In Test Methods 1 and 2, the effect of 14 days and 21 days of treatment with compounds of the present invention on growth of implanted endometrial tissue can be examined.

Test procedure 1

20 to 30 adult female C-D rats were used as test animals. The animals are divided into three groups of equal numbers. All animals follow the sex cycle. We perform the surgery on the day of the proestrus. In each group, the right horn is removed, sliced into small rectangular pieces, and the pieces are loosely sutured on different sides near the mesenteric bloodstream. In Group 2 animals, the ovary is removed.

For 14 days from the day following surgery

Animals of Groups 1 and 2 receive water by intraperitoneal injection, animals of Group 3 receive a compound of the present invention at a dose of 1.0 mg / kg body weight. After 14 days, the animals are sacrificed and endometrial implants, adrenal glands, remaining uterus and ovary, where present, are removed and histologically examined. Weigh the ovary and adrenal weights.

Test procedure 2

20-30 female C-D rats were used as test animals. The animals are divided into two equal groups. Each animal is monitored for non-cycling. We perform the surgeries on the day of Proestrus. All animals

The left horn is removed, sliced into small rectangular pieces, and the pieces are loosely sutured at different sides to the mesenteric bloodstream.

Approximately 50 days after surgery, Group 1 animals receive water for intraperitoneal injection for 21 days, Group 2 members receive a compound of the present invention at a dose of 1.0 mg / kg body weight. After 21 days of treatment, all animals are sacrificed, endometrial inserts and adrenal glands removed and weighed. Measuring the implanted pieces, we evaluate their growth. The sex cycle of the animals was followed.

Test procedure 3

A) Surgical induction of endometriosis

Autographic endometrial tissue is used to induce endometriosis in rats and / or rabbits. Mature female females are deprived of both sides of the ovary for reproduction and maintained at a constant level of hormone by exogenous administration of estrogen. Autologous endometrial tissue samples were implanted into the peritoneum of 5-150 animals. The composition of the present invention is used to rinse the animals' stomach daily for 3 to 16 weeks. The removed implanted tissue pieces are measured for growth or regrowth. When animals are sacrificed, the intact horn is removed and the condition of the endometrium examined.

B) Transplantation of human endometrial tissue into a nude mouse

Human endometrial lesions were implanted into the peritoneum of sexually mature, castrated, female nude mice. Exogenous estrogen is used to induce growth of implanted tissue. In some cases, the collected endometrial cells are cultured in vitro before implantation. During treatment, the animals' stomachs are rinsed daily with the compound of the invention for 3 to 16 weeks, and the implanted tissues are removed and their growth or regression is measured. At the time of sacrifice, the uterus is removed and the intact endometrium is assessed.

Test procedure 4

A) Tissue from human endometrial lesions was grown in vitro as primary non-transformed cultures. The surgical preparation is passed through a sterile sieve or cleaned of surrounding tissue to obtain a single cell suspension. The cells are maintained in media containing 10% serum and antibiotics. Growth in the presence and absence of estrogen is determined. Cells are evaluated for their ability to produce C3 complement and their response to growth factors and growth hormone. In vitro cultures are assayed for their proliferative response to treatment with progestins, GnRH, compounds of the invention, or vehicle. The levels of steroid hormone receptors are monitored weekly to determine whether important cellular properties are maintained in vitro. Tissue obtained from 5 to 25 patients is used.

Activity in any of the above assays indicates that the compound of the present invention can be used to treat endometriosis.

The present invention also provides a method of alleviating postmenopausal syndrome in women comprising the use of the aforementioned methods employing a compound of Formula I and administering to the female an effective amount of estrogen or progestin. These methods are particularly suitable for the treatment of osteoporosis and for the reduction of serum cholesterol, because patients can take advantage of the beneficial effects of all the active ingredients while the compounds of the present invention prevent the development of undesirable side effects of estrogen and progestin. The activity of combination therapies in any of the above postmenopausal assays indicates that the combination therapies are useful in alleviating postmenopausal syndrome in women.

Various variants of estrogen and progesterone are commercially available, such as ethinyl estrogen (0.01-0.03 mg / day), mesttranol (0.05-0.15 mg / day), conjugated estrogen hormones, such as Premarin® (Wyeth-Ayerst. 0.3-2.5 mg / day). Examples of progesterone-based agents are medroxyprogesterone such as Provera® (Upjohn; 2.5-10 mg / day), norethylnodrel (1.0-10.0 mg / day) and norethindrone (0.5-2.0 mg / day). ). A preferred estrogen-based compound is Premarin®; preferred progesterone-based agents are norethylnodrel and norethidron.

Both estrogen and progestin-based agents are administered in the same manner as known methods. Most of the compounds of formula (I) of the present invention are administered continuously in doses of 1-3 daily. Cyclic therapy may also be used, particularly for the treatment of endometriosis, or may be applied on a case-by-case basis for painful seizures of the disease. In restenosis, therapy may be limited to a short period (1-6 months) followed by medical intervention such as angioplasty.

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. The particular dose of the compound administered according to the invention will, of course, be determined by the particular circumstances, such as the compound administered, the mode of administration, the condition of the patient, the pathological condition to be treated. A typical daily non-toxic dose is 5-600 mg. Generally, a daily dose of 15 to 80 mg is preferred.

The compounds of the invention may be administered by various routes, including oral, rectal, dermal, subcutaneous, intravenous, intramuscular and nasal. For administration, it is advantageous to make a composition of the compounds and the physician will decide which one to use. Thus, the present invention further provides pharmaceutical compositions comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

They contain an effective carrier, diluent or medium and optionally an effective amount of estrogen or progesterone.

The total amount of active ingredient in the compositions is 0.1 to 99.9% by weight of the composition. The term "pharmaceutically acceptable" means that the carrier, diluent, medium, and salt should be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions of the present invention may be formulated from readily available ingredients such as, for example, the compounds of formula I with or without estrogen or progesterone in the form of tablets, capsules, suspensions, powders, and the like. can be processed. Suitable media, diluents or carriers include: fillers such as starch, sugars, mannitol, and silicon derivatives: binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrants such as calcium carbonate, sodium bicarbonate; solubilizers such as paraffin; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; lubricants such as talc, magnesium stearate, calcium stearate and solid polyethyl glycols.

The pharmaceutical compositions may also be prepared in the form of an elixir or solution for routine oral administration or as a solution for parenteral administration, such as intramuscular, subcutaneous or intravenous administration. The compounds may also be useful in formulating a sustained release dosage form and the like, or formulating a formulation such that the active ingredient is released exclusively or predominantly at a particular physiological site over a period of time. A coating, coating or protective layer can be made, for example, from polymers or waxes.

The compounds of formula I, alone or in combination with other active compounds of the present invention, are administered in the form of conventional formulations. Examples of these formulations are given below.

The following are examples to illustrate what has been said. The examples are provided for illustrative purposes only and are not intended to limit the scope of the invention. NMR data was recorded on a GE 300 MHz NMR apparatus with anhydrous d ₆ -DMSO unless otherwise noted.

Example 1 [3- (4-Benzyloxy) -phenoxy] -benzo [b] thiophene (XXIV)

To a solution of 3-bromobenzo [b] thiophene (69.62 g, 0.325 mol) in anhydrous collidine (55 ml) was added 4-benzyloxyphenol (97.6 g, 0.488 mol) and 23.3 g (0.163 mol). copper (I) oxide. The reaction mixture was refluxed for 24 hours. The cooled reaction mixture was diluted with 200 mL of ethyl acetate and the crude mixture was filtered through a pad of Celite® (Aldrich, Milwakuee, WI) to remove inorganic salts. Wash the filtrate with 3 x 15 mL of hydrochloric acid. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The thianaphthene is removed by distillation (10 mm Hg, 115-120 ° C). The residue was chromatographed (silica, hexane / ethyl acetate, 85:15), 12.2 g of benzo [b] thiophene and 12.95 g of [3- (4-benzyloxy) phenoxy] benzo [b] thiophene. (35% calculated on starting material) as an off-white solid.

Mp 84-86 ° C.

¹ H-NMR (CDCl ₃ ), δ:

7.91-7.83 (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). Elementary analysis for C ₂ H ₁₆ O ₂ S Calcd: C: 75.88, H: 4.85%;

Found: C, 75.75; H, 5.00.

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

To a solution of [3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene (6.00 g, 18.1 mmol) in dry tetrahydrofuran (100 mL) was added dropwise aq. Of a 6 M solution of n-butyllithium in hexane (19.9 mmol). The colorless solution turns to dark orange. After stirring for 20 minutes at -78 ° C, a solution of iodine (5.03 g, 19.9 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise via cannula to the reaction mixture. As the addition is complete, the color of the reaction mixture turns pale yellow. The reaction mixture was allowed to slowly warm to room temperature and quenched by addition of 200 mL of 0.1 N sodium sulfite solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 150 mL). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give an oily residue which crystallized on standing. The product was recrystallized from hexane / ethyl ether to give 7.10 g (86%) of [2-iodo-3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene as a white crystalline powder.

M.p. 87-92 ° C.

¹ H-NMR (CDCl 3), δ:

7.72 (d, J = 8.1 Hz, 1H), 7.47-7.20 (m, 8H), 6.89 (s,

4H), 5.01 (s, 2H).

Elementary analysis of C ₂ - | based H ₁₅ O ₂ SI Calcd: C: 55.03, H: 3.30%;

Found: C, 55.29; H, 3.31.

Example 3 [2- (4-tert-Butyloxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene (XXVI)

To a solution of [2-iodo-3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene (4.50 g, 9.82 mmol) in toluene (20 mL) was added 4- (2.28 g, 11.75 mmol). (tert-butoxy) phenyl boronic acid followed by 0.76 g (0.66 mmol) of tetrakis triphenylphosphine

EN 226 326 Β1 palladium. To this solution is added 14.5 ml of sodium carbonate solution. The resulting reaction mixture was refluxed for 1 hour. The cooled reaction mixture was diluted with 150 mL of ethyl acetate. The organic layer was washed with 0.1 N sodium hydroxide (2 x 100 mL) and dried over sodium sulfate. The concentrated semi-liquid product was dissolved in chloroform and passed through a pad of silica. The oily residue of the filtrate was triturated with hexane to give 4.00 g (91%) of [2- (4-tert-butyloxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene as a white solid. powder.

Melting point: 105-108 ° C.

¹ H-NMR (CDCl ₃ ), δ:

7.77 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H),

7.43-7.24 (m, 8H), 6.98 (d, J = 8.6 Hz, 2H), 6.89 (q,

J _AB = 9.3 Hz, 4H), 4.99 (s, 2H), 1.36 (s, 9H).

FD mass spectrum: 480.

Analysis for C ₃₁ H 8 O ₂ S ₃ Calculated: C, 77.47; H, 5.87%;

Found: C, 77.35; H, 5.99.

Example 4 [2- (4-Matoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] thiophene (XXVII)

The desired product was prepared in a similar manner to Example 3 using 4-methoxyphenylboronic acid. Yield = 73%. 115-118 ° C. ¹ H-NMR (CDCl ₃ ), δ:

7.80-7.90 (m, 3H), 7.33-7.53 (m, 8H), 6.93-7.06 (m, 6H), 5.00 (s, 2H), 3 , 83 (s, 3H).

FD mass spectrum: 438.

Analysis calculated for C ₂₈ H ₂₂ O ₃ S: C, 76.69; H, 5.06;

Found: C, 76.52; H, 5.09.

Example 5 [2- (4-tert-Butyloxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene (XXVIII)

A solution of 1.50 g (3.37 mmol) of [2- (4-tert-butyloxy-phenyl) -3 (4-benzyloxy) -phenoxy] -benzo [b] thiophene in 30 ml of anhydrous ethanol Containing 1% concentrated hydrochloric acid, 0.50 g of 10% palladium on carbon was added. The reaction mixture was hydrogenated at 40 psi for 1 hour and then confirmed to be complete by thin layer chromatography. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude product was dissolved in a minimum amount of ethyl acetate and passed through a short silica column to remove Celite (ethyl acetate as eluent). The solution was evaporated to give a white solid which was triturated with hexane / ethyl ether. Filtration gave 868 mg (73%) of [2- (4-tert-butyloxyphenyl) 3- (4-hydroxy) phenoxy] -benzo [b] thiophene. Melting point: 210-213 ° C.

¹ H-NMR (DMSO-d ₆ ), 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).

FD mass spectrum: 390.

Elemental Analysis for: C ₂₄ H ₂₂ O ₃ S Calculated: C, 73.82; H, 5.68;

Found: C, 73.98; H, 5.84.

Example 6 [2- (4-Methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene (XXIX)

The desired compound was prepared as described in Example 5.

Yield: 80%. Melting point: 120-125 ° C.

¹ H-NMR (DCCl ₃ ), δ:

7.80-7.90 (m, 3H), 7.48 (m, 1H), 7.30-7.48 (m,

2H), 6.90-7.03 (m, 4H), 6.76-6.86 (m, 2H), 3.82 (s,

3H).

FD mass spectrum: 348.

Analysis for C ₂₁ H ₁₆ O ₃ S Calcd: C: 72.39, H: 4.63%;

Found: C, 72.68; H, 4.82.

Example 7 [3- [4- [2- (1-Piperidinyl) atoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene (XXX)

[2- (4-tert-Butyloxyphenyl) -3 (4-hydroxy) phenoxy] -benzo [b] thiophene (1.25 g, 3.20 mmol) in 10 ml of anhydrous Ν, Ν-dimethylformamide 5.70 g (17.6 mmol) of cesium carbonate are added to room temperature solution. After stirring for 20 minutes, 2-chloroethylpiperidine hydrochloride (1.95 g, 10.56 mmol) was added in small portions. The heterogeneous reaction mixture was vigorously stirred for 24 hours. The reaction mixture was diluted with water (200 mL), the aqueous phase was extracted with ethyl acetate (3 x 100 mL), and the combined organic layers were washed with water (2 x 200 mL). After the organic phase was dried over sodium sulfate, it was concentrated under reduced pressure to give an oily residue. This residue was chromatographed (5-10% methanol / chloroform) to give 1.47 g (91%) of [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-tert-butyl). oxyphenyl) benzo [b] thiophene, which is used directly for the next step.

1.37 g (2.73 mmol) of [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-tert-butyloxy-phenyl)] - benzo [b] thiophene was dissolved in 10 ml of trifluoroacetic acid at room temperature. After stirring for 15 minutes, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed with a saturated solution of sodium bicarbonate (3 x 10 mL). The organic layer was dried over sodium sulfate and concentrated until a white solid precipitate formed. The product was recrystallized from ethyl acetate / ethyl ether to give 1.03 g (85%) of [3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl) Benzo [b] thiophene is obtained in the form of a colorless crystal.

Melting point: 169-172 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

9.81 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.54 (d,

J = 8.5 Hz, 2H), 7.36-7.26 (m, 3H), 6.86 (s, 4H),

6.78 (d, J = 8.6 Hz, 2H), 4.10 (m, 2H), 3.29 (m, 2H),

2.95-2.75 (m, 4H), 1.68-1.40 (m, 6H).

HU 226 326 Β1

Elemental analysis based on the formula C ₂₇ H ₂₇ NO ₃ S.0.55 CF ₃ CO ₂ H:

Found: C, 66.40; H, 5.46; N, 2.76.

Found: C, 65.99; H, 5.49; N, 2.61.

Example 8 [3- [3- [2- (1-Piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] - banzo [b] thiophene hydrochloride (XXXI)

The desired compound is prepared by treating the product of Example 7 with ethyl acetate in hydrochloric acid in ethyl acetate. Yield 90%.

Melting point: 233-240 ° C.

¹ H-NMR (DMSO-d 6), δ:

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), 4.27-4.31 (m, 2H) , 3.40-3.60 (m, 4H),

2.96-3.10 (m, 2H), 1.70-1.95 (m, 5H), 1.40-1.53 (m, 1H).

FD mass spectrum: 446.

Analysis for C ₂₇ H ₂₇ NO ₃ S.1,0 HCl Calcd: C: 67.28, H: 5.86, N: 2.91%;

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

The compounds of the following examples can be prepared analogously.

Example 9 [3- [4- [2- (1-Pyrrolidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene (XXXII)

Melting point: 150-155 ° C.

¹ H-NMR (DMSO-d 6), δ:

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, 4H),

6.78 (d, J = 8.6 Hz, 2H), 4.00 (broad, 2H), 2.92 (m,

2H), 2.85 (m, 4H), 1.73 (m, 4H).

Elemental analysis according to the formula C ₂₆ H ₂₅ NO ₃ S.0.33 CF ₃ CO ₂ H:

Found: C, 68.25; H, 5.44; N, 2.99.

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

Example 10 [3- [4- [2- (1-Hexamethyleneimino) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] - banzo [b] thiophene (XXXIII) Melting point: 189-191 ° C C.

¹ H-NMR (DMSO-d 6), δ:

7.91 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H),

7.34-7.25 (m, 3H), 6.81 (s, 4H), 6.75 (d, J = 8.6 Hz,

2H), 3.89 (broad, 2H), 2.75 (broad, 2H), 2.68 (m,

4H), 1.48 (m, 8H).

Analysis calculated for C ₂₈ H ₂₉ NO ₂ S.1.50 H ₂ O: C, 69.11; H, 6.79; N, 2.88.

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

Example 11 [3- [4- [2- (1-N, N-Diethylamino) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene (XXXIV) 70 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.91 (broad, 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, 2H), 2.76 (broad, 2H), 2.51 (m, 4H), 0.91 (m, 6 H).

FD mass spectrum: 434.

Analysis for C ₂₆ H ₂₇ NO ₃ S.0,50 H ₂ O Calcd: C: 70.56, H: 6.38, N: 3.16%;

Found: C, 70.45; H, 6.26; N, 3.20%.

Example 12

3- [4- [2- (1-Piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] - benzo [b] thlophene hydrochloride (XXXV)

Melting point: 228-230 ° C.

¹ H-NMR (DMSO-d 6), 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),

3.73-3.45 (m, 4H), 2.92-2.96 (m, 2H), 2.46-2.48 (m, 5H), 1.74 (m, 1H).

FD mass spectrum: 459.

Analysis calculated for C ₂₈ H ₂₉ NO ₂ S.1.0 HCl: C, 67.80; H, 6.10; N, 2.82.

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

Example 13 [3- (4-Benzyloxy) -phenoxy] -benzo [b] thiophene-2-boronic acid (XXXVI)

To a solution of [3- (4-benzyloxy) phenoxy] -benzoyl] thiophene (5.00 g, 15.1 mmol) in anhydrous tetrahydrofuran (20 mL) at -78 ° C was added dropwise a syringe (9.90 mL) under nitrogen. n-butyllithium in hexane (15.8 mmol). After stirring for 15 minutes, triisopropyl borate (3.83 mL, 16.6 mmol) was added to the reaction mixture and allowed to warm to 0 ° C. The reaction mixture was partitioned between 100 mL of ethyl acetate and 100 mL of 1.0 N hydrochloric acid. The phases are separated and the organic phase is extracted with 100 ml of water. The organic phase was dried over sodium sulfate, concentrated under reduced pressure and the solid residue was triturated with ethyl ether / hexane. Filtration gave 3.96 g (70%) of [3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene-2-boronic acid as a white solid.

115-121 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

8.16 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H),

7.42-7.23 (m, 7H), 6.90 (q, J _AB = 9.0 Hz, 4H), 5.01 (s, 2H).

Analysis for C ₂₁ H ₂₇ O ₄ SB: Calc'd: C, 67.04; H, 4.55%;

Found: C, 67.17; H, 4.78.

Alternatively, from the compound of the above example, [2- (4-tert-butyloxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene can be prepared by treating [3- (4) benzyloxy) phenoxy] benzo [b] thiophene-2-boronic acid is reacted with 4- (tert-butoxy) bromobenzene. The reaction is carried out under conditions similar to those described above for [2-iodo-3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene and 4- (tert-butoxy) -phenylboronic acid. Yield 81%.

This procedure is also used to prepare the compounds of the Examples below.

HU 226 326 Β1

Example 14 [3- [4- [2- (1-Piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene hydrochloride (XXXVII)

Melting point: 223-226 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

7.99 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H),

7.44-7.30 (m, 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).

Analysis for C ₂₇ H ₂₇ NO ₂ S.1,0 HCl Calcd: C: 69.59, H: 6.06, N: 3.00%;

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

Example 15 [3- [4- [2- (1-Piperidinyl) ethoxy] phenoxy] -2- (4-fluorophenyl)] benzo [b] thiophene hydrochloride (XXXVIII)

Melting point: 219-226 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.20 (broad, 1H), 7.99 (d, J = 8.2 Hz, 1H),

7.77-7.73 (m, 4H), 7.42-7.25 (m, 5H), 6.90 (s, 4H),

4.27 (m, 2H), 3.44-3.31 (m, 4H), 2.96-2.89 (m,

2H), 1.78-1.61 (m, 5H), 1.34 (m, 1H).

FD mass spectrum: 447.

Analysis calculated for C ₂₇ H ₂₆ NO ₂ SF.1.0 HCl: C, 67.00; H, 5.62; N, 2.89.

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

Example 16 [6-Methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (XXXIX)

To a solution of [6-methoxy-2- (4-methoxyphenyl)] - benzo [b] thiophene (27.0 g, 100 mmol) in chloroform (1.10 L) was added dropwise 15.98 g (200 mL) of chloroform (60 mL). 100 mmol) of bromine. After the addition was complete, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give 34.2 g (100%) of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene. yielding a white solid.

M.p. 83-85 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.70-7.62 (m, 4H), 7.17 (dd, J = 8.6, 2.0 Hz, 1H),

7.09 (d, J = 8.4 Hz, 2H).

FD mass spectrum 349, 350.

Analysis for C igHi SBR ₃ O ₂ Calcd: C: 55.03, H: 3.75%;

Found: C, 54.79; H, 3.76.

Example 17 [6-Methoxy-2- (4-methoxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene (XL)

To a solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (34.00 g, 97.4 mmol) in collidine (60 mL) was added 38.96 g (194.8 mmol) under nitrogen. 4-benzyloxyphenol and 14.5 g (97.4 mmol) of copper (I) oxide. The reaction mixture was refluxed for 48 hours. After cooling to room temperature, the reaction mixture was diluted with 200 mL of acetone and the inorganic solid was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in methylene chloride (500 mL). The methylene chloride solution was washed with 3 * 300 ml of 3N hydrochloric acid followed by 3 * 300 ml of 1N sodium hydroxide solution. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in 100 mL of ethyl acetate while a white solid was formed which was collected by filtration. There was thus obtained 4.62 g (17.11 mmol) of [6-methoxy-2- (4-methoxyphenyl)] benzo [b] thiophene. The filtrate was concentrated under reduced pressure and passed through a thin layer of silica gel (using methylene chloride as eluent) to remove the baseline material. The filtrate was concentrated under reduced pressure and the residue was crystallized from hexane / ethyl acetate to give 7.19 g of [6-methoxy-2- (4-methoxyphenyl) -3- (4-benzyloxy) phenoxy] benzo [b] of thiophene as an off-white solid crystalline solid. The mother liquor was evaporated and chromatographed on silica gel (hexane / ethyl acetate 80:20) to afford another 1.81 g of the desired product. The total yield of [6-methoxy-2- (4-methoxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene was 9.00 g (24% based on starting material). The alkaline extract was acidified to pH = 4 with 5N hydrochloric acid and the resulting precipitate was collected by filtration and dried to give 13.3 g of 4-benzyloxyphenol.

Melting point: 100-103 ° C.

¹ H-NMR (CDCl ₃ ), 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).

FD mass spectrum: 468.

Analysis for C ₂₄ gH ₂ O ₄ S Calcd: C: 74.34, H: 5.16%;

Found: C, 74.64; H, 5.29.

Example 18 [6-Methoxy-2- (4-methoxy-phenyl) -3- (4-hydroxy) -phenoxy] -benzo [b] thiophene (XLI)

[6-Methoxy-2- (4-methoxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thiophene (1.50 g, 3.20 mmol) in ethyl acetate (50 mL) and 10 mL To a solution of 1% concentrated hydrochloric acid in ethanol was added 300 mg of 10% palladium on carbon catalyst. The reaction mixture was hydrogenated at 40 psi for 20 minutes and then confirmed to be complete by thin layer chromatography. The reaction mixture was filtered through a pad of Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure to give a white solid. The crude product was passed through a pad of silica gel using chloroform as eluent. The solution was evaporated to give 1.10 g (91%) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) phenoxy] benzo [b] thiophene as a white solid.

M.p. 123-126 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.10 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.52 (d,

J = 2.1 Hz, 1H), 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), 6.63 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H),

3.72 (s, 3H).

FD mass spectrum: 378.

HU 226 326 Β1

Analysis calculated for C ₂₂ H ₁₈ O ₄ S: C, 69.82; H, 4.79;

Found: C, 70.06; H, 4.98.

Example 19 [6-Methoxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2 (4-methoxy-phenyl)] - benzo [b] thiophene (XLII)

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 Ν-dimethylformamide cesium carbonate (3.86 g, 11.88 mmol) was added under nitrogen. After stirring for 10 min, 1.10 g (1.48 mmol)

2-Chloroethylpiperidine hydrochloride was added. After stirring at room temperature for 18 hours, the reaction mixture was partitioned between 100 mL of chloroform and 100 mL of water. The layers were separated and the aqueous layer was extracted with chloroform (3 x 50 mL). The organic layers were combined and washed with water (2 x 100 mL). The organic layer was dried over sodium sulfate, evaporated and the oily product was chromatographed on silica gel (eluting with 2% methanol in chloroform). The desired fractions were evaporated and the oily residue was dissolved in ethyl acetate (10 mL) and treated with oxalic acid (311 mg, 3.4 mmol). After stirring for 10 minutes, the white precipitate formed was collected by filtration and, after drying, 1.17 g (70%) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxy) (phenyl)] benzo [b] thiophene oxalate salt is obtained.

Melting point: 197-200 ° C (dec.).

¹ H-NMR (DMSO-d 6), δ:

7.60 (d, J = 8.7 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 Hz, 1.1 Hz, 1H), 6.87 (s, 4H), 4.19 (broad t,

2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broad t, 2H),

3.12-3.06 (m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H).

FD mass spectrum: 489.

Elemental analysis according to the formula C ₂₉ H ₃₁ NO ₄ S.0.88 HO ₂ CCO ₂ H:

Found: C, 64.94; H, 5.80; N, 2.46.

Found: C, 64.92; H, 5.77; N, 2.54.

Example 20 [6-Methoxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2- (4-methoxy-phenyl)] - benzo [b] thiophene hydrochloride (XUII)

The desired compound is prepared by reacting the free base with hydrochloric acid ethyl ether.

Melting point: 216-220 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.20 (broad, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.59 (d,

J = 1.5 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d,

J = 8.7 Hz, 1H), 6.96 (dd, J = 9.0.1.5 Hz, 1H), 6.92 (q,

J _ab = 9.0 Hz, 4H), 4.31 (m, 2H), 3.83 (s, 3H), 3.77 (s,

3H), 3.43 (m, 4H), 2.97 (m, 2H), 1.77 (m, 5H), 1.37 (m, 1H).

FD mass spectrum: 489.

Analysis calculated for C ₂₉ H ₃₁ NO ₄ S.1.0 HCl: C, 66.21; H, 6.13; N, 2.66.

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

The compounds of the following Examples were prepared in an analogous manner to the above.

Example 21 [6-Methoxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2 (4-matoxyphenyl)] benzo [b] thiophene (XUV)

Melting point: 95-98 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7, 00 (d, J = 9.0 Hz, 2H), 6.94 (dd, J = 9.0, 2.0 Hz, 1H), 6.86 (s, 4H), 3.97 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.73 (t, J = 6.0 Hz, 2H), 2.51 (m, 4H) ), 1.66 (m, 4H).

FD mass spectrum: 477.

Analysis calculated for C ₂₈ H ₂₉ NO ₄ S: C, 70.71; H, 6.15; N, 2.99.

Found: C, 70.59; H, 6.15; N, 3.01.

Example 22 [6-Methoxy-3- [4- [2- (1-hexamethylenimino) -ethoxy] -phenoxy] -2- (4-methoxy-fanyl)] - banzo [b] Tlofen hydrochloride (XLV)

Melting point: 189-192 ° C.

¹ H-NMR (DMSO-d 6), δ:

10.55 (broad, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9) , 0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0 Hz, H), 6.86 (s, 4H) ), 3.94 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H) ), 2.66 (m, 4H), 1.53 (m, 8H).

Analysis calculated for C ₃₀ H ₃₃ NO ₄ S.1.0 HCl: 0: 66.71, H: 6.35, N: 2.59;

Found: C, 66.43; H, 6.46; N, 2.84.

Example 23 [6-Methoxy-3- [4- [2- (1-N, N-diethylamino) -ethoxy] -phenoxy] -2- (4-methoxy-fanyl)] - benzo [b] thiophene; hydrochloride (XLVI) ^1H-NMR (DMSO-d₆) δ:

10.48 (broad, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 9) , 0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz, H), 6.87 (q, J _AB = 9.0.4 Hz), 4.25 (m, 2H), 3.83 (3H), 3.77 (s, 3H), 3.54 (m, 2H), 3.09 (m, 4H) ), 2.00 (m, 3H), 1.88 (m, 3H).

Analysis calculated for C ₂₈ H ₃₁ NO ₄ S.1.5 HCl: 0: 63.18, H: 6.15, N: 2.63;

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

Example 24 [6-Methoxy-3- [4- [2- (morpholino) -ethoxy] -phenoxy] -2 (4-methoxy-phenyl)] - benzo [b] thiophene hydrochloride (XLVII)

M.p. 208-211 ° C.

¹ H-NMR (DMSO-d 6), δ:

10.6 (broad 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).

HU 226 326 Β1

Analysis for C ₂₈ H 9 NO ₅ S.1,0 ₂ HCl Calcd: C: 63.09, H: 5.73, N: 2.65%;

Found: C, 63.39; H, 5.80; N, 2.40.

Example 25 [6-Methoxy-3- [4- [3- (piperidino) -propoxy] -phenoxy] -2 (4-methoxy-phenyl)] - benzo [b] thiophene hydrochloride (XLVIII)

Melting point: 195-200 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.00 (broad, 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).

Elemental analysis C3oH 3N0 _{3 4} S.1,15 HCl Calcd: C: 66.01, H: 6.40, N: 7.23%;

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

Example 26 [6-Methoxy-3- [4- [3- (1-N, N-diethylamino) -propoxy] -phenoxy] -2- (4-methoxy-phenyl)] - benzo [b] thiophene hydrochloride XLIX)

Melting point: 164-166 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.77 (broad, 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).

Analysis for C ₃₃ NO ₄ S.1,0 gH ₂ HCl Calcd: C: 65.96, H: 6.49, N: 2.65%;

Found: C, 66.25; H, 6.64; N, 2.84.

Example 27 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] -phanoxy] -2 (4-hydroxyphenyl)] - benzo [b] thiophene (L)

10.00 g (19.05 mmol) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] Thiophene hydrochloride was dissolved in 300 ml of anhydrous methylene chloride and the solution was cooled to 8 ° C. To this solution was added boron tribromide (7.20 mL, 76.20 mmol). The resulting reaction mixture was stirred at 8 ° C for 2.5 hours. The reaction mixture was poured into 1 L of a saturated solution of sodium bicarbonate at 0 ° C with stirring and quenched. The methylene chloride phase was separated and the resulting solid was dissolved in methanol / ethyl acetate. The aqueous phase was extracted with ethyl acetate containing 5% methanol (5 x 500 mL). The ethyl acetate and methylene chloride extracts were combined and dried over sodium sulfate. Concentration of the solution under reduced pressure gave a tan solid which was chromatographed on silica, eluting with 1-7% methanol in chloroform. 7.13 g (81%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene are obtained in white in the form of a solid.

Melting point: 93 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.73 (br, 1H), 9.68 (br, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 1.8 Hz, 1H), 7, 04 (d, 3 = 8.6 Hz, 1H), 6.84 (dd, J = 8.6, 1.8 Hz, 1H (obscured)), 6.81 (s, 4H), 6.75 ( d, J = 8.6 Hz, 2H), 3.92 (t, J = 5.8 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.36 (m, 4H),

1.43 (m, 4H), 1.32 (m, 2H).

FD mass spectrum: 462.

Analysis for C ₂₇ H ₂₇ NO ₄ S: Calcd: C, 70.20; H, 5.90; N, 3.03%;

Found: C, 69.96; H, 5.90; N, 3.14.

Example 28 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy) phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene oxalate (LI)

The oxalate salt was prepared from [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] - benzo [b] thiophene in 80% yield. according to the procedure described above. Melting point: 246-249 ° C.

¹ H-NMR (DMSO-d 6), 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 (obscured)), 6.84 (s, 4H), 6.75 (d, J = 8.6 Hz, 2H), 4.08 (broad, 2H), 3.01 (broad 2H), 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H).

FD mass spectrum: 462.

Elemental analysis based on the formula C ₂₇ H ₂₇ NO ₄ S.0.75 HO ₂ CCO ₂ H:

Found: C, 64.63; H, 5.42; N, 2.64;

Found: C, 64.61; H, 5.55; N, 2.62.

Example 29 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride (III)

[6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] - benzo [b] thiophene was converted to the hydrochloride in 91% yield. by reacting the free base with ethyl acetate in hydrochloric acid in ethyl acetate. Melting point: 158-165 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.86 (q, J _AB = 9.3 Hz, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H);

6.74 (d, J = 8.6 Hz, 2H), 4.26 (broad, 2H), 3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5H), 1.25 (m, 1H).

FD mass spectrum: 461.

Analysis calculated for C ₂₇ H ₂₇ NO ₄ S.1.0 HCl: 0: 65.11, H: 5.67, N: 2.81;

Found: 0, 64.84; H, 5.64; N; 2.91%.

The following compounds were prepared analogously to the above.

Example 30 [6-Hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene (Lili)

Melting point: 99-113 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H),

7.25 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J = 9) , 0, 2.0 Hz, 1H), 6.79 (d,

HU 226 326 Β1

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).

Analysis for C _{2 4} S.0,5 5NO 6H ₂ O H ₂ O: 0, 68.40, H, 5.74, N, 3.07%;

Found: C, 68.52; H, 6.00; N, 3.34.

Example 31 [6-Hydroxy-3- [4- [2- (1-hexamethyleneimino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene (UV)

Melting point: 125-130 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H),

7.26 (d, 3 = 2.0 Hz, 1H), 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).

Analysis calculated for C ₂₈ H ₂₉ NO ₄ S: 0: 70.71, H: 6.15, N: 2.94;

Found: 0: 70.67, H: 6.31, N: 2.92.

Example 32 [6-Hydroxy-3- [4- [2- (1-N, N-diethylamino) ethoxy] phenoxyl] -2- (4-hydroxyphenyl)] benzo [b] thiophene LV)

137-141 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.75 (s, 1H), 9.71 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 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).

Elemental analysis O ₂₈ H ₂₇ NO ₄ S Calcd: 0: 69.46, H: 6.05, N: 3.12%;

Found: C, 69.76; H, 5.85; N, 3.40.

Example 33 [6-Hydroxy-3- [4- [2- (morpholino) atoxy] phenoxy] -2 (4-hydroxyphenyl) -benzo [b] thiophene hydrochloride (LVI)

Melting point: 157-162 ° C.

¹ H-NMR (DMSO-d 6), δ:

10.60 (broad, 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 _A b = 9.0 Hz, 4H), 6.81 (dd, J = 9.0, 2.0 Hz, 1H), 6.80 (d, J = 9.0 Hz, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 (m, 4H), 3.18 (m, 2H).

Analysis for C ₂₅ NO ₅ S.HCI gH ₂ O: Calculated: C, 62.46; H, 5.24; N, 2.80%;

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

Example 34 [6-Hydroxy-3- [4- [3- (1-N, N-diethylamino) -propoxy] -phenoxy] -2- (4-hydroxy-phenyl)] - benzo [b] thiophene; hydrochloride (LVII)

Melting point: 185-191 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.94 (broad 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27 (dd, J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J = 9.0.2.0 Hz, 1 H), 6.79 (d, J = 9.0 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.14 (m, 6 H), 2.08 (m , 2H), 1.20 (t, J = 6.0 Hz, 6 H).

Analysis for C ₂₇ H ₂₉ NO ₄ S.1,30 HCl Calcd: C, 63.46; H, 5.98; N, 2.74%;

Found: 0: 63.23, H: 6.03, N: 3.14%.

Example 35 [6-Hydroxy-3- [4- [2- (1-N, N-diisopropylamino) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] - benzo [b] thiophene. hydrochloride (LVIII)

128-131 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.81 (broad, 1H), 9.76 (s, 1H), 9.02 (s, 1H), 7.49 (d,

J = 9.0 Hz, 2H), 7.28 (m, 1H), 7.09 (d, J = 9.0 Hz, 1H),

6.90 (s, 4H), 6.79 (m, 3H), 4.19 (m, 2H), 3.68 (m,

2H), 3.50 (m, 2H), 1.31 (m, 12H).

Analysis for C ₂₈ H ₃₁ NO ₄ S.1,33 HCl Calcd: 0: 63.92, H: 6.19, N: 2.66%;

Found: 0: 63.82, H: 6.53, N: 2.61.

Example 36 [6-Hydroxy-3- [4- [3- (piperidino) propoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride (LIX) Melting point: 258- 262 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.85 (broad, 1H), 9.81 (s, 1H), 9.75 (s, 1H), 7.50 (d,

J = 9.0 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.10 (d,

J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J = 9.0, 2.0 Hz,

1 H), 6.79 (d, J = 9.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H),

3.44 (m, 2H), 3.15 (m, 2H), 2.88 (m, 2H), 2.11 (m,

2H), 1.73 (m, 5H), 1.39 (m, 1H).

Analysis for C ₂₈ H ₂₉ NO ₄ S.0,75 HCl Calcd: C: 66.87, H: 5.96, N: 2.78%;

Found: C, 67.04; H, 5.90; N, 2.68.

Alternatively, as shown in Figure 3 above, the compound of Example 28 can be prepared using a methoxymethyl group as a protecting group instead of a methoxy group. The process is a direct analogue to that described, except that the methoxymethyl group is removed by acid hydrolysis at the final step.

Example 37 [6-Methoxy-2- (4-methoxy-methyloxy-phenyl) -3- (4-benzyloxy) -phenoxy] -benzo [b] thlophene (LX)

Melting point: 94-96 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.65 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H),

7.43-732 (m, 5H), 7.23 (d, J = 8.8 Hz, 1H), 7.08 (d,

J = 8.6 Hz, 2H), 7.04 (dd, J = 8.8, 2.0 Hz, 1H), 6.92 (q,

J _ab = 9.2 Hz, 4H), 5.26 (s, 2H), 5.21 (s, 2H), 5.01 (s,

3H), 3.40 (s, 3H), 3.37 (s, 3H).

FD mass spectrum: 528.

Example 38 [6-Matoxy-2- (4-methoxy-1-methyloxy-phenyl) -3- (4-hydroxy) -phenoxy] -benzo [b] thiophene (LXI)

Melting point: 90-91 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.15 (s, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.63 (d,

J = 2.0 Hz, 2H, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.05 (dd,

J = 8.8 Hz, 1H), 6.72 (q, J _AB = 9.1 Hz, 4H), 5.26 (s,

2H), 5.21 (s, 2H), 3.40 (s, 3H), 3.37 (s, 3H).

HU 226 326 Β1

FD mass spectrum: 438.

Elemental analysis according to the formula C ₂₄ H ₂₂ O ₆ S:

Found: C, 65.74; H, 5.06;

Found: C, 65.50; H, 4.99.

Example 39 [6-Methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) (LXII)

To a solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (10.0 g, 28.6 mmol) in dry methylene chloride (50 mL) was added trifluoroacetic acid (50 mL). After stirring for 5 minutes, 30% aqueous hydrogen peroxide (4.0 mL, 28.6 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. To the dark solution was added 1.25 g of solid sodium bisulfite and 15 ml of water. The reaction mixture was stirred vigorously for 15 minutes and then concentrated under reduced pressure. The residue was partitioned between chloroform (200 mL) and a saturated solution of sodium bicarbonate (200 mL). The phases are separated and the organic phase is extracted with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to a solid residue which was triturated with ethyl ether / ethyl acetate. Filtration gave 8.20 g (80%) of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) as a yellow solid which was ethyl acetate. recrystallized from acetate.

Melting point: 170-173 ° C.

¹ H-NMR (DMSO-d ₆ ), 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) ). Analysis calculated for C ₁₆ H ₁₃ O ₃ SBr: C, 52.62; H, 3.59;

Found: C, 52.40; H, 3.55.

Example 40 [2- (4-Methoxy-phenyl) -3-bromo] -benzo [b] thiophene (S-oxide) (LXIII)

The desired compound was prepared in an analogous manner to the above.

Melting point: 120-125 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

8.06 (d, J = 7.6 Hz, 1H), 7.78-7.59 (m, 5H), 7.13 (d,

J = 8.7 Hz, 2H), 3.81 (s, 3H).

FD mass spectrum: 335.

Analysis calculated for C ₁₅ H ₁₁ O ₂ SBr: C, 53.75; H, 3.31;

Found: C, 53.71; H, 3.46.

Example 41

4- (2- (1-Piperidinyl) ethoxy) phenol (LXIV)

To a solution of 50.50 g (0.25 mol) of 4-benzyloxyphenol in 350 ml of anhydrous dimethylformamide is added 46.30 g (0.25 mol) of 2-chloromethylpiperidine. After stirring for 10 minutes, 52 g (0.375 mol) of potassium carbonate and 85.0 g (0.25 mol) of cesium carbonate are added. The heterogeneous mixture was vigorously stirred at room temperature for 48 hours. The reaction mixture was poured into 500 ml of water and extracted with methylene chloride. The organic layer was treated several times with 1N sodium hydroxide solution and washed with brine. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to an oily residue. Chromatography (silica, hexane / ethyl acetate, 1: 1) gave 4- [2- (1-piperidinyl) ethoxy] phenoxybenzyl ether (60.0 g, 77%) as a colorless oil.

¹ H-NMR (DMSO-d 6), 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).

FD mass spectrum: 311.

Analysis for C ₂₀ H ₂₅ NO _2: Calc'd: C, 77.14; H, 8.09; N, 4.50%;

Found: C, 77.34; H, 8.18; N, 4.64.

4- (2- (1-Piperidinyl) ethoxy] phenoxy) benzyl ether (21.40 g, 68.81 mmol) was dissolved in ethanol / ethyl acetate (200 mL, 1: 1) containing 1% concentrated hydrochloric acid. The solution was transferred to a Parr flask and 3.4 g of 5% palladium on carbon catalyst were added and the reaction mixture was hydrogenated at 40 psi for 2 hours. The reaction mixture was passed through a pad of Celite to remove the filtrate under reduced pressure. The residue was evaporated to a solid residue which was triturated with ethyl ether and filtered to give 12.10 g (83%) of 4- (2- (1-piperidinyl) ethoxyphenol).

Melting point: 148-150 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

8.40 (s, 1H), 6.70 (q, J _AB = 11.5 Hz, 4H), 3.93 (t,

J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.42-2.38 (m,

4H), 1.52-1.32 (m, 6H).

FD mass spectrum: 221

Analysis for C ₁₃ H NO _{2 to} O: Calculated: C, 70.56; H, 8.09; N, 4.50%;

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

Example 42 [6-Methoxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2- (4-methoxy-phenyl)] - benzo [b] thiophene (S-oxide) ( LXV)

To a solution of 4- (2- (1-piperidinyl) ethoxy) phenol (0.32 g, 1.43 mmol) in anhydrous dimethylformamide (5 mL) was added a solution of 0.57 g of 60% sodium hydride in mineral oil at room temperature. (1.43 mmol). After stirring for 15 minutes, [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) (0.50 g, 1.37 mmol) was added in small portions to the reaction mixture. . After stirring for 1 hour, the reaction is monitored by TLC analysis. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate containing 10% ethanol. The organic layer was washed several times with water and then dried over sodium sulfate. Concentrated under reduced pressure, the oily residue was triturated with ethyl acetate / hexane to give 0.62 g (89%) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 4-methoxyphenyl) benzo [b] thiophene (S-oxide) is obtained in the form of a pale yellow solid.

Melting point: 97-100 ° C.

HU 226 326 Β 11 ¹ H-NMR (DMSO-dg), δ:

7.68 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H),

7.06-6.92 (m, 6H), 6.85 (d, J = 8.8 Hz, 2H), 3.94 (t,

J = 6.0 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.56 (t,

J = 6.0 Hz, 2H), 2.39-2.32 (m, 4H), 1.47-1.32 (m,

6H).

Analysis calculated for C ₂₉ H ₃₁ NO ₅ S: C, 68.89; H, 6.18; N, 2.77.

Found: C, 68.95; H, 6.04; N, 2.57.

Example 43 [3- [4- [2- (1-Piperidinyl) atoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide) (LXVI)

The desired compound was prepared in an analogous manner to the above.

Oil.

¹ H-NMR (DMSO-d ₆ ), δ:

8.03 (m, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.53-7.50 (m,

2H), 7.09-6.82 (m, 7H), 3.94 (broad, J = 5.9 Hz,

2H), 3.74 (s, 3H), 2.56 (broad, J = 5.9 Hz, 2H),

2.36-2.33 (m, 4H), 1.45-1.31 (m, 6H).

FD mass spectrum: 475.

Analysis for C ₂₉ gH ₂ NO ₄ S: Calcd: C, 70.71; H, 6.15; N, 2.94%;

Found: C, 70.44; H, 6.43; N, 3.20%.

Example 44 [6-Methoxy-3- [4- [2- (1-piparidinyl) atoxy] phenoxy] -2- (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride ()

3.00 g (5.94 mmol) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene To a solution of (S-oxide) (Example 42) in anhydrous tetrahydrofuran (200 mL) was added lithium aluminum hydride (0.34 g, 8.91 mmol) in small portions at 0 ° C and under nitrogen. After stirring for 30 minutes, the reaction is quenched by careful addition of 5.0 ml of 2.0 N sodium hydroxide solution. The reaction mixture was vigorously stirred for 30 minutes and an additional 2.0 N sodium hydroxide solution was added to dissolve the salt. The reaction mixture was partitioned between water and 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted several times with ethyl acetate containing 10% ethanol. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to an oily residue. The crude product was dissolved in ethyl acetate / ethyl ether (50 mL, 1: 1) and triturated with excess ethyl ether hydrochloride. The resulting precipitate was collected and dried (2.98 g, 96%) [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] Thiophene hydrochloride was obtained as a white solid.

Example 12 was also prepared from Example 43 using the same procedure.

Example 45

6-Matoxybenzo [b] thiophene-2-dermic acid (LXVII)

To a solution of 6-methoxybenzo [b] thiophene (18.13 g, 0.111 mol) in anhydrous tetrahydrofuran (150 ml) at -60 ° C was added 76.2 ml of a solution of 1.6 M n-butyllithium in hexane (0.122 mol). Dosing is carried out dropwise through a syringe. After stirring for 30 minutes, 28.2 ml (0.122 mol) of triisopropyl borate are added via syringe to the reaction mixture. The reaction mixture was allowed to gradually warm to 0 ° C and partitioned between 300 mL of 1N hydrochloric acid and 300 mL of ethyl acetate. The phases are separated, the organic phase is dried over sodium and concentrated under reduced pressure to give a white solid which is triturated with ethyl ether / hexane. Filtration of the solid gave 16.4 g (71%) of 6-methoxybenzo [b] thiophene-2-boronic acid as a white solid.

Melting point: 200 ° C (dec.).

¹ H-NMR (DMSO-d 6), δ:

7.83 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.51 (d,

J = 2.0 Hz, 1H), 6.97 (dd, J = 8.6, 2.0 Hz, 1H), 3.82 (s,

3H).

FD mass spectrum; 208th

Example 46 [6-Methoxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (LXIX)

To a solution of 6-methoxybenzo [b] thiophene-2-boronic acid (3.00 g, 14.4 mmol) in toluene (100 mL) was added 4- (methanesulfonyloxy) phenyl bromide (3.98 g, 15.8 mmol). and 16 ml of 2.0 N sodium carbonate solution. After stirring for 10 minutes, tetrakis triphenylphosphine palladium (0.60 g, 0.52 mmol) was added to the reaction mixture, and the resulting mixture was refluxed for 5 hours. The reaction mixture is then allowed to warm to room temperature while the product precipitates from the organic phase. The aqueous phase is removed and the organic phase is concentrated under reduced pressure. The resulting solid was triturated with ethyl ether, filtered and dried under reduced pressure to give 3.70 g (77%) of [6-methoxy-2- (4-methanesulfonyloxyphenyl)] - benzo [b] thiophene as a tan solid. in the form of a solid. Melting point: 199-201 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.82-7.77 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d,

J = 2.3 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 6.98 (dd,

J = 8.7 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H).

FD mass spectrum: 334.

Elemental Analysis for CigH | Based on ₄ O ₄ S _2: Calcd: C, 57.46; H, 4.21%;

Found: 0: 57.76; H: 4.21%.

Example 47 [6-Methoxy-2- (4-benzyloxyphenyl)] - benzo [b] thiophene (LXX)

The desired compound was prepared as described in Example 46.

Yield: 73%.

Melting point: 217-221 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.63-7.60 (m, 3H), 7.59-7.26 (m, 7H), 7.02 (d,

J = 8.7 Hz, 2H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 5.11 (s,

2H), 3.88 (s, 3H).

FD mass spectrum 346.

HU 226 326 Β1

Analysis for C 2 H ₁₈ O ₂ S ₂ O: Calculated: C, 76.27; H, 5.24%;

Found: C, 76.00; H, 5.25.

Example 48 [6-Hydroxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (LXXI)

To a solution of [6-methoxy-2- (4-methanesulfonyloxyphenyl)] - benzo [b] thiophene (9.50 g, 28.40 mmol) in dry methylene chloride (200 mL) was added 14.20 g (5.36 mL) at room temperature and under nitrogen. 56.8 mmol) of boron tribromide. The reaction mixture was stirred at room temperature for 3 hours and then quenched by slowly pouring the mixture into excess ice water. After vigorous stirring for 30 minutes, the white precipitate was collected by filtration, washed several times with water and dried under reduced pressure.

8.92 g (98%) of [6-hydroxy-2- (4-methanesulfonyloxyphenyl) -benzo [b] thiophene are obtained in the form of a white solid. Melting point: 239-243 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

9.70 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.72 (s, 1H),

7.62 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 1.7 Hz, 1H), 6, 86 (dd, J = 8.7.1.7 Hz, 1H), 3.38 (s, 3H).

FD mass spectrum: 320.

Elemental Analysis for: C ₁₅ H ₁₂ O ₄ S ₂ Calculated: C, 56.23; H, 3.77.

Found: C, 56.49; H, 3.68.

Example 49 [6-Banyloxy-2- (4-methanesulfonyloxyphenyl)] benzo [b] thiophene (LXII)

To a solution of 3.20 g (10.0 mmol) of [6-hydroxy-2- (4-methanesulfonyloxyphenyl) -benzo [b] thiophene in 75 ml of dry dimethylformamide is added 5.75 g (17.7 mmol) of cesium chloride. carbonate followed by 1.72 mL (11.0 mmol) of benzyl chloride The reaction mixture was stirred vigorously for 24 hours, the solvent was removed under reduced pressure and the solid residue was suspended in 200 mL of water. After drying under reduced pressure, the crude product was suspended in hexane / ethyl ether (1: 1) to give the solid product (3.72 g, 91%) [6-benzyloxy-2- (4-methanesulfonyloxy). phenyl)] - benzo [b] thiophene as a white solid.

Melting point: 198-202 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.81-7.78 (m, 3H), 7.72 (d, J = 8.7 Hz, 1H), 7.64 (d,

J = 2.2 Hz, 1H), 7.47-7.30 (m, 7H), 5.15 (s, 2H),

3.39 (s, 3H).

FD mass spectrum: 410.

Example 50 [6-Benzyloxy-2- (4-hydroxy-phenyl)] - benzo [b] thiophene (LXIII)

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 is added 2.32 g of nitrogen in small portions at room temperature. (61.0 mmol) of lithium aluminum hydride. The reaction mixture was stirred at room temperature for 3 hours and then carefully quenched by pouring the mixture into cold 1.0N 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 and concentrated under reduced pressure to a solid. The product was chromatographed (silica, chloroform) to give 8.75 g (87%) of [6-benzyloxy-2- (4-hydroxyphenyl)] - benzo [b] thiophene as a white solid.

Melting point: 212-216 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.70 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (d,

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

2.2 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 5.13 (s, 2H).

FD mass spectrum: 331.

Analysis for C ₂₁ H ₁₆ O ₂ S Calcd: C: 75.88, H: 4.85%;

Found: C, 75.64; H, 4.85.

Example 51 [6-Benzyloxy-2- (4-methoxy-phenyl)] - benzo [b] thiophene (LXXIV)

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

Melting point: 180-185 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd,

J = 8.8, 2.2 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 5.13 (s,

2H), 3.76 (s, 3H).

FD mass spectrum 346.

Analysis calculated for C ₂₂ H ₁₈ O ₂ S: C, 76.27; H, 5.24;

Found: C, 76.54; H, 5.43.

Example 52 [6-Benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (LXXV)

[6-Benzyloxy-2- (4-methoxyphenyl)] - benzo [b] thiophene (10.0 g, 28.9 mmol) was added to chloroform (200 mL) together with 10.0 g of solid sodium bicarbonate at room temperature. Bromine (1.50 mL, 29.1 mmol) in chloroform (100 mL) was added dropwise over 30 minutes. After the addition was complete, 200 ml of water were added to the reaction mixture and the phases were separated

EN 226 326 Β1. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a white solid. The product was crystallized from methylene chloride / methanol to give 10.50 g (85%) of [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene as a white solid.

Melting point: 146-150 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.70 (d, J = 2.2 Hz, 1H), 7.65-7.60 (m, 3H),

7.47-7.30 (m, 5H), 7.19 (dd, J = 8.8, 2.2 Hz, 1H),

7.06 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H). FD mass spectrum 346.

Elemental Analysis: Calculated for C ₂₂ H ₁₇ O ₂ SBr: 0: 62.13; H: 4.03;

Found: 0: 61.87, H: 4.00%.

Example 53 [6-Methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] thiophene (LXXVI)

The desired compound was prepared in an analogous manner to the above.

Yield: 91%.

Melting point: 125-127 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3 , 82 (s, 3H).

FD mass spectrum 346.

Analysis calculated for C ₂₂ H ₁₇ O ₂ SBr: 0: 62.13, H: 4.03;

Found: C, 62.33; H, 3.93.

The compounds of Examples 54 and 55 were prepared as described in Example 39.

Example 54 [6-Banyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) (LXXVII)

The product was recovered as a yellow solid by recrystallization from ethyl acetate.

Mp 202-205 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

7.80 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7, 47-7.32 (m, 6H), 7.10 (d,

J = 8.7 Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H).

FD mass spectrum: 441.

Analysis calculated for C ₂₂ H ₁₇ O ₃ SBr: C, 59.87; H, 3.88;

Found: C, 59.59; H, 3.78.

Example 55 [6-Methoxy-2- (4-benzyloxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) (LXXVIII)

Chromatography (silica, chloroform) gave the product as a yellow solid. 119-123 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.73 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.5 Hz, 1H), 7, 46-7.31 (m, 5H), 7.26 (dd,

J = 8.5, 2.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 5.16 (s,

2H), 3.86 (s, 3H).

FD mass spectrum: 441.

Elemental analysis according to the formula C ₂₂ H ₁₇ O ₂ SBr:

Found: C, 59.87; H, 3.88;

Found: C, 60.13; H, 4.10%.

The compounds of Examples 56 and 57 were prepared as described in Example 42.

Example 56 [6-Banyloxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2 (4-methoxy-phenyl)] - benzo [b] thiophene (S-oxide) ) (LXXIX) Yellow oil.

¹ H-NMR (DMSO-d ₆ ), δ:

7.76 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H),

7.44-7.30 (m, 5H), 7.12 (dd, J = 8.6, 2.2 Hz, 1H),

7.03-6.93 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 5.18 (s,

2H), 3.94 (br, J = 5.8 Hz, 2H), 3.73 (s, 3H), 2.56 (br, J = 5.8 Hz, 2H), 2.37-2, 34 (m, 4H),

1.45-1.32 (m, 6H).

FD mass spectrum: 592.

Elemental analysis for C 5 H ₃₅ NO ₅ S ₃ calculated: 0: 72.26, H: 6.06, N: 2.41%;

Found: 0: 72.19, H: 5.99, N: 2.11.

Example 57 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-benzyloxyphenin)] - benzo [b] thiophene (S-oxide) ) (LXXX) Yellow solid.

Melting point: 89-93 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

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, J = 5.8 Hz)

2H), 3.81 (s, 3H), 2.56 (broad, J = 5.8 Hz, 2H),

2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H).

FD mass spectrum: 592.

Analysis for C ₃₅ H ₃₅ NO ₅ S.0,25 EtOAc Calcd: 0: 71.62, H: 6.18, N: 2.32%;

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

The compounds of Examples 58 and 59 were prepared as described in Example 20.

Example 58 [6-Benzyloxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2 (4-methoxy-phenyl)] - benzo [b] thiophene (LXXXI)

The product was isolated in 95% yield from [6-benzyloxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide). Purification was by chromatography (silica, 1-5% methanol / chloroform) to give an off-white solid.

Melting point: 105-108 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

7.62 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H),

7.45-7.30 (m, 5H), 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, J = 5.8 Hz, 2H), 3.72 (s, 3H), 2.55 (wide,

J = 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31 (m,

4H).

FD mass spectrum: 565.

Analysis calculated for C ₃₅ H ₃₅ NO ₄ S: 0: 74.31, H: 6.24, N: 2.48;

Found: C, 74.35; H, 6.07; N, 2.76.

HU 226 326 Β1

Example 59 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-benzyloxyphenyl)] - benzo [b] thiophene (LXXXII)

Yield: 91%.

Melting point: 106-110 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

7.59 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (d) , J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (d, J = 8, 8Hz, 1H), 7.03 (d, J = 8.8Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (broad, J = 5, 8 Hz, 2H), 3.78 (s, 3H), 2.55 (broad, J = 5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1.44-1. 31 (m, 4H).

FD mass spectrum: 565.

Analysis: Calculated for C35H35NO4S: 0: 74.31, H: 6.24, N: 2.48;

Found: 0: 74.26, H: 6.17, N: 2.73%.

Example 60 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzyl [b] thiophene (LXXXIII)

8.50 g (15.0 mmol) of [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] - benzo [ b) Thiophene A solution of palladium on carbon (1.50 g), ammonium formate (3.50 g) and water (30 ml) was added to a solution of ethanol / ethyl acetate (5: 1, 300 ml). The reaction mixture is refluxed and the progress of the reaction is monitored by thin layer chromatography. After 3 hours, the reaction was complete and the solution was cooled to room temperature. The reaction mixture was filtered through Celite, the catalyst was removed and the filtrate was evaporated under reduced pressure to a solid residue. The residue was partitioned between saturated sodium bicarbonate solution and 5% ethanol in ethyl acetate. The phases are separated, the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed (silica 1-5% methanol / chloroform) to give 6.50 g (91%) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- ( 4-methoxyphenyl) benzo [b] thiophene is obtained in the form of a foam which is triturated with hexane to give a solid.

Melting point: 174-176 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.77 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 8) , 6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.81 (s, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H ), 3.91 (br, J = 5.9 Hz, 2H), 3.71 (s, 3H), 2.55 (br, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H),

1.46-1.28 (m, 6H).

FD mass spectrum: 475.

Analysis for C ₂₈ H ₂₉ NO ₄ S: Calc: C, 70.71; H, 6.15; N, 2.94%;

Found: C, 70.46; H, 5.93; N, 2.71.

Example 61 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene (LXXXIV)

The desired compound was prepared as described in Example 60.

Yield: 88%.

M.p. 147-150 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

9.72 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.48 (d,

J = 8.6 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 (br, J = 5.9 Hz, 2H), 3.77 (s, 3H), 2.55 (br, J = 5.9 Hz, 2H), 2.38-2, 33 (m, 4H),

1.46-1.28 (m, 6H).

FD mass spectrum: 475.

Analysis calculated for C28 H29 NO4 S: C, 70.71; H, 6.15; N, 2.94.

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

Alternatively, the compounds of Examples 60 and 61 can be prepared directly by the same transfer hydrogenolysis method in 90% yield using [6-methoxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2- (4) benzyloxyphenyl)] benzo [b] thiophene (S-oxide) and [6-benzyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 - (4-methoxyphenyl)] - benzo [b] thiophene (S-oxide) from.

Example 62 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride (LXXXV)

The compound of Example 60 was converted to the hydrochloride salt in 85% yield by treatment with ethyl ether / hydrochloric acid in ethyl acetate followed by crystallization from ethanol / ethyl acetate.

156-160 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.28 (broad, 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 (broad, J = 5.9 Hz, 2H), 3.71 (s, 3H), 3.44-3.31 (m, 4H), 2.98-2.88 (m, 2H) , 1.74-1.60 (m, 5H),

1.36-1.29 (m, 1H).

FD mass spectrum: 475.

Analysis for C _{2 4} 8 H 9 NO ₂ S.1,0 HCl Calcd: C: 65.68, H: 5.90, N: 2.73%;

Found: 0: 65.98, H: 6.11, N: 2.64.

Example 63 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy) -3-phenoxy] -2- (4-methoxycarbonyl)] - benzo [b] thiophene hydrochloride (LXXXVI)

The hydrochloride salt was prepared as described in Example 62.

Melting point: 215-217 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.28 (broad, 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, J = 5.8 Hz, 2H), 3.78 (s) , 3H), 3.43-3.34 (m,

4H), 2.97-2.91 (m, 2H), 1.78-1.61 (m, 5H),

1.36-1.29 (m, 1H).

FD mass spectrum: 475.

Analysis calculated for C ₂₈ H ₂₉ NO ₄ S.1.0 HCl: C, 65.68; H, 5.90; N, 2.73.

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

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Example 64 [6-Benzoyloxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2- (4-benzoyloxy-phenyl)] - benzo [b] thiophene hydrochloride. LXXXVII)

To a solution of the compound of Example 29 (0.50 g, 1.08 mmol) in dry tetrahydrofuran (20 mL) was added triethylamine (1.00 mL) at 0 ° C. Benzoyl chloride (0.28 mL, 2.35 mmol) was added to the reaction mixture, stirred at 0 ° C for 2 hours, and the reaction mixture was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL). The phases were separated, the organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a white solid. The crude product was dissolved in ethyl acetate (10 mL) and treated with ethyl ether in hydrochloric acid. A white precipitate formed which was collected by filtration. After drying, 390 mg (50%) of [6-benzoyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-benzoyloxyphenyl)] - benzo [b] Thiophene hydrochloride was obtained as a white solid.

Melting point: 200-204 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

9.95 (broad, 1H), 8.18 (m, 1H), 8.16 (m, 2H), 8.12 (dd, J = 10.0, 2.0 Hz, 2H), 7.87 (dd, J = 7.0, 2.0 Hz,

2H), 7.78 (m, 2H), 7.64 (m, 2H), 7.42 (d, J = 7.0 Hz,

2H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (s, 4H), 4.32 (m, 2H), 3.45 (m, 4H), 2.99 (m, 2H), 1.75 (m, 5H),

1.39 (m, 1H).

Analysis for C ₄₁ H ₃₅ NO _this S.1,5 HCl Calcd: C: 67.97, H: 5.08, N: 1.93%;

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

Example 65 [6-Ethylsulfonyloxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-ethylsulfonyloxyphenyl) -benzo [b] thiophene hydrochloride (LXXXVIII)

The desired compound is prepared according to the above procedure. Yield: 71%.

Melting point: 110-115 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.15 (broad, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.85 (d,

J = 7.0 Hz, 2H), 7.43 (m, 3H), 7.34 (dd, J = 9.0,

2.0 Hz, 1H), 6.97 (m, 4H), 4.31 (m, 2H), 3.57 (m,

4H), 3.44 (m, 4H), 2.97 (m, 2H), 1.76 (m, 5H), 1.40 (m, 7H).

Calcd for C ₃ H ₃₅ NO ₈ S ₃ .1,5 HCl Calcd: C: 54.57, H: 5.32, N: 2.05%;

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

Example 66 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-trifluoromethanesulfonyloxy-phenyl)] - benzo [b] thiophene (LXXXIX)

The desired compound was prepared according to the above procedure using trifluoromethanesulfonic anhydride.

Yield: 81% (oil).

¹ H-NMR (DMSO-D ₆ ), δ:

7.82 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7, 17 (d, J = 8.8 Hz, 1H), 6.93 (dd,

J = 8.8, 2.0 Hz, 1H), 6.84 (s, 4H), 3.92 (broad,

J = 5.7 Hz, 2H), 3.79 (s, 3H), 2.56 (broad, J = 5.7 Hz,

2H), 2.36-2.30 (m, 4H), 1.44-1.31 (m, 6H).

FD mass spectrum: 607.

Analysis for C ₂ F ₆ gH28NO ₃ S ₂ Calculated: C: 57.32, H: 4.64, N: 2.30%;

Found: 0: 57.16, H: 4.52, N: 2.01.

The following compounds were prepared as described in Example 7.

Example 67

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

Yield: 85%.

Melting point: 190-198 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.48 (br, s, 1H), 8.00-8.10 (m, 2H), 7.80-8.00 (m, 3H), 7.60-7.53 (m, 4H), 7.40-7.56 (m, 6H),

6.93 (s, 2H), 4.37-4.43 (m, 2H), 3.00-3.05 (m, 2H), 2.53-2.63 (m, 6H), 1, 75-1.95 (m, 3H), 1.40-1.50 (m, 1H).

FD mass spectrum: 550.

H, 5.68; N, 2.66 Found: C, 74.29; H, 5.68;

Found: C, 74.52; H, 5.80; N, 2.59.

Example 68

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

Yield: 90%.

Melting point: 193-197 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.10 (s broad, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.40-7.53 ( m, 3H), 7.15 (d, J = 6.7 Hz, 2H), 2.00 (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), 1.41 (s, 9H).

FD mass spectrum 529.

Analysis calculated for C ₃₂ H ₃₅ NO ₄ S.1.0 HCl: 0: 67.89, H: 6.41, N: 2.47;

Found: 0, 68.94; H, 6.61; N, 1.72.

Example 69

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

Yield: 85%.

Melting point: 98-104 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.20 (broad s, 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).

FD mass spectrum: 565.

Analysis for C ₃₁ H ₃₅ NO ₅ S ₂ A solution of 1.0 HCl Calcd: 0: 61.83, H: 6.13, N: 2.33%;

Found: 0: 61.55, H: 6.15, N: 2.25.

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Example 70

4- (Methoxymethyloxy) phenyl disulfide (XCili)

To a solution of 4-hydroxyphenyl disulfide (650 mg, 2.60 mmol) in anhydrous Ν, Ν-dimethylformamide (10 mL) is added a 60% sodium hydride suspension in mineral oil (230 mg, 5.75 mmol). . After stirring for 15 minutes, chloromethyl methyl ether (0.44 mL, 5.75 mmol) was added via syringe and the temperature was allowed to rise to room temperature. After stirring for half an hour, the reaction mixture was partitioned between 20 mL of brine and 20 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layer was dried over sodium sulfate and evaporated to give 993 mg (100%) of the desired product as a yellow oil. Part of the product is purified by chromatography to give analytically pure 4- (methoxymethyloxy) phenyl disulfide. Chromatography on silica, eluting with 4% ethyl acetate in hexane.

¹ H-NMR (DMSO-d ₆ ), δ:

7.40 (d, J = 6.9 Hz, 4H), 7.00 (d, J = 6.9 Hz, 4H), 5.15 (s, 4H), 3.32 (s, 6H).

FD mass spectrum: 338.

Analysis calculated for C ₆ H ₁₈ O ₄ S _2: Calcd: C, 56.78; H, 5.36%;

Found: C, 57.08; H, 5.44.

Example 71 [6-Methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy] benzo [b] thiophene (XCIV)

To a solution of [6-methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (1.82 g, 5.2 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen and at -60 ° C using a syringe of a solution of 1.6 M n-butyllithium in hexane (3.15 mL, 5.0 mmol) was added dropwise. The reaction mixture was heated to 20 ° C for 10 minutes and then cooled to -60 ° C. In anhydrous tetrahydrofuran (5 mL), 4- (methoxymethyloxy) phenyl disulfide (800 mg, 2.36 mmol) was added to the lithium compound and the reaction mixture was allowed to gradually warm to 0 ° C. After stirring for 20 minutes, the reaction was partitioned between 50 mL of brine and 50 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The oily residue was chromatographed (silica); 5% ethyl acetate in hexane), 287 mg (27%) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyleneoxy) thiophenoxy] benzo [b] thiophene are obtained. oil.

¹ H-NMR (DMSO-D ₆ ), δ:

7.59 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7, 03-6.85 (m, 7H), 5.06 (s, 2H),

3.79 (s, 3H), 3.76 (s, 3H).

FD mass spectrum: 438.

Analysis for C ₂₄ H ₂₂ O ₄ S ₂ ratings O: Calculated: C, 65.73, H, 5.06%;

Found: C, 65.93; H, 5.10%.

Example 72 [Methoxy-2- (4-methoxyphenyl) -3- (4-hydroxy) thiophenoxy] benzo [b] thiophene (XCV)

233 mg (0.53 mmol) of [6-methoxy-2- (4-methoxyphenyl) -3- (4-methoxymethyloxy) thiophenoxy] benzo [b] thiophene in methanol / water / tetrahydrofuran 1: 1 Methanesulfonic acid (0.2 mL, 2.66 mmol) was added to a solution of 1: 1 (10 mL). The reaction mixture was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layer was washed several times with a saturated solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure to give 2.6 mg (99%) of [6-methoxy-2- (4-methoxyphenyl) 3- (4-hydroxy) thiophenoxy] benzo [b] Thiophene was obtained as a colorless oil.

¹ H-NMR (DMSO-d ₆ ), δ:

9.43 (s, 1H), 7.63 (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 = 8.4 Hz, 2H), 7.02 (dd, J = 8.8, 2.0 Hz, 1H), 6.90 (d,

J = 8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H).

FD mass spectrum: 395.

Analysis calculated for C ₂₂ H ₁₈ O ₃ S ₂ : C, 66.98; H, 4.60;

Found: C, 67.26; H, 4.78.

Example 73 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene (XCVI)

A solution of [6-methoxy-2- (4-methoxyphenyl) -3 (4-hydroxy) thiophenoxy] benzo [b] thiophene (242 mg, 0.61 mmol) in 8.0 mL of Ν, Ν-dimethylformamide was added. 820 mg (2.5 mmol) of cesium carbonate followed by 194 mg (1.05 mmol) of 2-chloroethylpiperidine hydrochloride. The reaction mixture was stirred for 48 hours at room temperature and then partitioned between brine and ethyl acetate. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to an oily residue. The residue was chromatographed (silica, 0-2% methanol / chloroform) to give [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (244 mg, 92%). (4-Methoxyphenyl)] benzo [b] thiophene was obtained as a yellow oil.

Example 74 [6-Methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride salt (XCVII)

Melting point: 198-201 ° C.

¹ H-NMR (DMSO-d 6), δ:

7.63 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7, 07 (d, J = 8.6 Hz, 2H), 7.02 (dd,

J = 8.2, 2.0 Hz, 1H), 6.92 (q, J _AB = 9.0 Hz, 4H), 4.24 (broad, 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).

Analysis for C ₃₂ gH ₂ NO ₂ S ₂ A solution of 1.0 HCl Calcd: C: 64.28, H: 5.95, N: 2.58%;

Found: C, 64.09; H, 6.08; N, 2.78.

HU 226 326 Β1

Example 75 [6-Hydro-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2 (4-hydroxy-fanyl)] - banzo [b] thlophene (XCVIII)

160 mg (0.29 mmol) of [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene hydrochloride To a solution of 15 ml of anhydrous methylene chloride is added 0.15 ml of boron tribromide at 0 ° C and under nitrogen. The resulting dark solution was stirred for 1 hour at 0 ° C and then immediately poured into a mixture of 50 ml of ethyl acetate and 50 ml of a saturated solution of sodium bicarbonate with stirring. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a white solid. This product was chromatographed (silica, 0-5% methanol / chloroform), 91 mg (60%) [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy)] - thiophenoxy] -2- (4-Hydroxy-phenyl) -benzo [b] thiophene was obtained as a white solid. M.p. 123-127 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

9.79 (s, 1H), 9.71 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H),

7.42 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6, 82-6.76 (m, 5H), 3.91 (t, J = 8.8 Hz, 2H), 2.56 (t, J = 5.8 Hz, 2H), 2.40 (m, 4H),

1.41-1.28 (m, 6H).

FD mass spectrum: 478.

H, 5.70; N, 2.93 Found: C, 67.90; H, 5.70;

Found: C, 68.14; H, 5.84; N, 2.65.

Example 76 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] thiophenoxy] -2 (4-hydroxyphenyl)] benzo [b] thiophene hydrochloride (XCIX)

Melting point: 180-190 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

9.86 (s, 1H), 9.79 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H),

7.42 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6, 86-6.81 (m, 5H), 4.27 (m, 2H),

3.41-3.37 (m, 4H), 2.96-2.84 (m, 2H), 1.77-1.60 (m, 5H), 1.35-1.28 (m, 1H).

FD mass spectrum: 477.

Calcd for C2 _{7 3} H27NO S2.2,2 HCl Calcd: C: 58.13, H: 5.28, N: 2.51%;

Found: C, 58.11; H, 5.10; N, 2.61.

The following compounds are also prepared by the above procedures.

Example 77 [6-Methoxy-3- [4- [2- (1-pyrrolidinyl) -ethoxy] -phenoxy] -2 (4-methoxy-fanyl)] - benzo [b] thiophene hydrochloride (C)

Melting point: 215-218 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

7.61-7.58 (m, 3H), 7.52 (d, J = 8.8 Hz, 1H), 7.04-6.95 (m, 5H), 6.86 (d, J = 8.8 Hz, 2H), 4.22 (broad, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.47-3.42 (m, 4H), 3, 01 (m, 2H), 1.94-1.80 (m, 4H).

FD mass spectrum: 491.

Elemental analysis for C28H29NO2S2. 1.0 HCl Calculated: C, 63.67; H, 5.73; N, 2.65.

Found: C, 63.47; H, 5.78; N, 2.65.

Example 78 [6-Hydroxy-3- [4- [2- (1-pyrrolidinyl) ethoxy] thiophenoxy] -2 (4-hydroxy-phenyl) -N-benzo [b] thiophene hydrochloride (Cl)

137-140 ° C (dec.).

¹ H-NMR (DMSO-d 6), δ:

9.86 (s, 1H), 9.80 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H),

7.42 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6, 87-6.81 (m, 5H), 4.21 (broad, 2H), 3.53-3.41 (m, 4H), 3.01 (m, 2H), 1.95-1.82 ( m, 4H).

FD mass spectrum: 464.

Elemental analysis C2gH ₂ S2.1,0 5NO ₂ HCl Calcd: C: 62.45, H: 5.24, N: 2.80%;

Found: C, 62.36; H, 5.37; N, 2.61.

Example 79 [6-Methoxy-3- [4- [2- (1-piperidinyl) -ethoxy] -phenoxy] -2-phenyl] -benzo [b] thiophene hydrochloride (Cll)

The desired compound is obtained from the product of Example 66 by hydrogenolysis of triflate as described in Example 80.

Melting point: 187-195 ° C.

¹ H-NMR (DMSO-d 6), δ:

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 (broad, J = 5.7 Hz, 2H), 3.79 (s, 3H), 3.45-3.38 (m, 4H), 2.98 (m, 2H), 1 , 77-1.61 (m, 5H), 1.31 (m, 1H).

FD mass spectrum: 460.

Analysis calculated for C28H H9 _NO2 S.1,0 ₂ HCl Calcd: C: 67.80, H: 6.10, N: 2.84%;

Found: C, 67.62; H, 5.89; N, 2.67.

Example 80 [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (fanyl) -benzo [b] thiophene hydrochloride (Cili)

5.00 g (10.0 mmol) of [6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene To a solution of hydrochloric acid in 100 ml of anhydrous methylene chloride is added 8.38 ml (60.0 mmol) of triethylamine at 0 ° C and under nitrogen, followed by 1.69 ml (10.0 mmol) of trifluoromethanesulfonic anhydride. The reaction mixture was allowed to gradually warm to room temperature and stirred for 1.5 hours. The reaction mixture was poured into a saturated solution of sodium bicarbonate (200 mL) and quenched. The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The organic phase is dried over sodium sulfate and concentrated under reduced pressure to an oily residue. The residue was chromatographed (0-3% methanol / chloroform) to give 2.82 g (39%) of [6-trifluoromethanesulfonate-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4- trifluoromethanesulfonate ethyl)] - benzo [b] thiophene, 1.82 g (31%) [6-trifluoromethanesulfonate-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-phenyl)] - benzo [b] thiophene and 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-trifluoromethanesulfonate phenyl)] - benzo [b] thiophene 1 A mixture of 1: 1 and 1.48 g (36%) of the free base is recovered.

0.50 g (0.84 mmol) of a 1: 1 mixture of monotriflate derivatives obtained in the latter reaction

The reaction mixture was treated with 60 ml of ethanol / ethyl acetate (5: 1) and 2.0 ml of triethylamine and 0.50 g of 5% palladium on carbon were added. The reaction mixture was hydrogenated at 40 psi for 2 hours. The reaction mixture was filtered through Celite to remove the catalyst and the filtrate was evaporated to an oily residue. The resulting mixture of monohydroxy derivatives was dissolved in ethyl acetate and precipitated from 3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-hydroxyphenyl)] benzo [b] thiophene. The precipitate contains a 4: 1 mixture of monohydroxy derivatives, with 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl)] benzo [b] thiophene being the major components. The filtrate was evaporated under reduced pressure and the resulting solid was dissolved in a minimum amount of ethyl acetate and treated with ethyl ether in hydrochloric acid. The resulting solid was recrystallized from ethanol to give 6-hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (phenyl) benzo [b] thiophene hydrochloride (69 mg, 18%). isomer is obtained. Melting point: 217-219 ° C.

¹ H-NMR (DMSO-d 6), δ:

9.87 (s, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.39-7.26 (m,

4H), 7.10 (d, J = 8.6 Hz, 1H), 6.89 (s, 4H), 6.78 (dd,

J = 8.6, 2.0 Hz, 1H), 4.22 (broad, 2H), 3.39-3.37 (m,

4H), 2.97-2.90 (m, 2H), 1.74-1.60 (m, 5H), 1.39 (m, 1H).

FD mass spectrum: 446.

Analysis calculated for C 7 H ₂₇ NO _{2 3} S.1,0 HCl Calcd: C: 67.28, H: 5.86, N: 2.91%;

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

Alternatively, the product of Example 80 may be obtained by demethylating the product of Example 79 as described in Example 27.

Example 81 [6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene (S-oxide) ( CIV)

The desired compound is obtained from [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene (S-oxide). is prepared as described in Example 42.

Yellow oil.

¹ H-NMR (DMSO-d 6), δ:

7.69 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H),

7.09-6.99 (m, 5H), 6.96-6.87 (m, 3H), 4.76 (septet, J = 6.0 Hz, 1H), 3.99 (broad, J = 6.0 Hz, 2H),

3.78 (s, 3H), 2.61 (broad, J = 6.0 Hz, 2H), 2.44-2.37 (m, 4H), 1.53-1.43 (m, 4H) , 1.40-1.32 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H).

FD mass spectrum: 533.

Analysis for C ₃₁ H ₃₅ NO ₅ S.0,67 H ₂ O Calcd: 0: 68.23, H: 6.71, N: 2.57%;

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

Example 82 [6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2 (4-methoxyphenyl)] benzo [b] thiophene hydrochloride (CV)

The title compound was prepared in Example 44 from [6-methoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] -2- (4-methoxyphenyl)] benzo [b] thiophene. . Melting point: 168-170 ° C.

¹ H-NMR (DMSO-d ₆ ), δ:

10.37 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.52 (d,

J = 1.3 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.95 (d,

J = 8.6 Hz, 2H), 6.92-6.85 (m, 5H), 4.64 (septet,

J = 6.0 Hz, 1H), 4.28 (broad, J = 6.0 Hz, 2H), 3.72 (s,

3H), 3.44-3.37 (m, 4H), 2.95-2.89 (m, 2H),

1.73-1.60 (m, 5H), 1.36-1.28 (m, 1H), 1.25 (d,

J = 6.0 Hz, 6H).

FD mass spectrum: 517.

Analysis for C ₃₁ H ₃₅ NO ₄ S.HCI O: Calculated: C, 67.19; H, 6.55; N, 2.53%;

Found: C, 67.15; H, 6.29; N, 2.62.

[6-Isopropoxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] 2- (4-methoxyphenyl)] - benzo [b] thiophene hydrochloride with 2.0 equivalents of boron trichloride by reaction at 0-10 ° C in anhydrous dichloromethane to give [6-hydroxy-3- [4- [2- (1-piperidinyl-ethoxy] -phenoxy] -2- (4-methoxy-phenyl)] - benzo [b] thiophene (Methyl ether does not decompose under these conditions).

Examples of pharmaceutical compositions are given below. The term "active ingredient" in the examples refers to a compound of formula I, a salt or solvate thereof.

Example 83

gelatin capsules

Ingredient Quantity (mg / capsule) of active ingredient 0.1-1000 starch, NF 0-650 starch, liquid powder 0-650 silicone oil, 350 centistock 0-15.

The mixture of ingredients is filled into solid gelatin capsules. The composition may vary according to the intended purpose.

Example 84

tablets

Ingredient Quantity (mgfiabletta)

agent 2.5-1000 cellulose, microcrystalline 200-650 silica, colloidal 10-650 stearic 5-15. The ingredients are ground and crushed into tablets. push. Example 85 tablets component Quantity (mg / tablet) agent 2.5-1000 starch 45 cellulose, microcrystalline 35 polyvinylpyrrolidone (10% aqueous solution) 4 sodium carboxymethylcellulose 4.5 magnesium stearate 0.5 talc First

The drug, starch and cellulose were passed through a 45 mesh U.S. sieve and blended thoroughly. The resulting powder is mixed with the polyvinylpyrrolidone solution and passed through a 14 mesh U.S. sieve. The resulting granulate was 50-60 ° C

It is dried at a temperature of 18 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate and talc were passed through a 60 mesh U.S. sieve, added to the granulate, mixed and compressed into tablets.

Example 86: Suspension

component Quantity (mg / 5 ml) agent 0.1-1000 mg sodium carboxymethyl cellulose 50 mg syrup 1.25 mg Benzoic acid solution 0.10 ml flavoring substance optionally color material optionally with purified water Make up to 5 ml.

The drug is passed through a 45 mesh U.S. sieve and mixed with sodium carboxymethylcellulose and syrup to form a homogeneous paste. The benzoic acid solution, flavoring and coloring agents are diluted in all water and added to the paste. Make up to volume with water.

Example 87

Aerosol

Ingredient Quantity (% w / w) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00.

The active ingredient is mixed with ethanol and added to a portion of the propellant 22, cooled to -30 ° C and introduced into the filler. The desired amount is added to a stainless steel tank and diluted with the remaining propellant. Finally, place the valve on the container.

Example 88

Cone

Ingredient Quantity (mg / suppository) active ingredient 250 Saturated Fatty Acid Glycerides 2000.

The drug is passed through a 60 mesh U.S. sieve and resuspended in a melt of saturated fatty acid glycerides at the minimum required temperature. The suspension is poured into a mold with a nominal capacity of 2 g and allowed to cool.

Example 89 Intravenous solution

Contains isotonic saline active ingredient

The above solution was administered intravenously at a rate of ml / min.

Amount 50 mg

1000 mg.

administered to the patient

Example 90

Combination capsule Active ingredient Quantity (mg / capsule) Active ingredient 50 premazine 1

Avicel pH = 101 50 starch 1500 117.50 silicone oil 2 Tween 80 0.50 Cab-O-Sil 0.25. Example 91 Combination capsule component Quantity (mg / capsule) agent 50 norethynodrel 5 Avicel pH = 101 82.50 starch 1500 90 silicone oil 2 Tween 80 0.50.

Example 91

Combination capsule

component Quantity (mg / capsule) agent 50 premazin 1 cornstarch 50 In Povidone, K29-32 6 Avicel pH = 101 41.50 Avicel pH = 102 136.50 Crospovidone XL10 2.50 magnesium stearate 0.50 Cab-O-Sil 0.50.

Claims (25)

PATENT CLAIMS CLAIMS 1. Compounds of formula I wherein R ¹ is -H, -OH, -O (C 1 -C 4 alkyl), -OCOC 6 H 5, -OCO (C 1 -C 6 alkyl), or -OSO ₂ (C 2 -C 6 alkyl); R ² is -H, -OH, -0 (1-4C group -0C0C ₆ H ₅ group, -OCO (1-6C 40 alkyl, -OSO ₂ (C 2 -C 6 alkyl) or halogen; R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 45 1-hexamethyleneimino; n is 2 or 3; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof. Compounds according to claim 1, wherein R ³ denotes 1-piperidinyl and n represents 2 or a pharmaceutically acceptable salt thereof. Compounds according to claim 2, wherein Z is -O- or a pharmaceutically acceptable salt thereof. 4. The compound of claim 3 wherein R ¹ je55 Lentes -OH and ^R2 is -0 (1-4C group or a pharmaceutically acceptable salt thereof. Compounds according to claim 4, wherein R ² is -OCH 3 or a pharmaceutically acceptable salt thereof. HU 226 326 Β1 The compound of claim 5, wherein said salt is the hydrochloride salt. Compounds according to claim 3, wherein R ¹ and R ² are both -OH or a pharmaceutically acceptable salt thereof. The compound of claim 7, wherein said salt is the hydrochloride salt. 9. [6-Methoxy-2- (4-methoxyphenyl) -3-bromo] benzo [b] thiophene (S-oxide) represented by the formula (LXII). 10. A pharmaceutical composition comprising the active compounds of claims 1-8. A compound according to any one of claims 1 to 6, and optionally further comprising estrogen or progestin, together with one or more suitable pharmaceutically acceptable carriers, excipients or diluents. Compounds of formula II wherein R ^1a is -H or -OR ⁷ wherein R ⁷ is a hydroxy protecting group; R ^2a is -H, -halogen, or -OR ⁸ , wherein R ² is a hydroxy protecting group; ^R6 is-H or a selectively removable hydroxy protecting group; R ^{11 is} either absent or = O; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof. Compounds according to claim 11, wherein R ^1a and R ^2a is both -OCH ₃ , R ⁶ is -H, R ¹¹ is absent, and Z is -O-, or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 11, wherein R ^1a and R ^2a is both -OCH ₃ , R ⁶ is -H, R ¹¹ is = O, and Z is -O-, or a pharmaceutically acceptable salt thereof. 14. A compound of formula XVI wherein: R ^1a is -H or -OR ⁷ wherein R ⁷ is a hydroxy protecting group; R ^2a is -H, -halogen, or -OR ⁸ , wherein R ⁸ is a hydroxy protecting group; R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino -group; n is 2 or 3; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof. Compounds according to claim 14, wherein R ^1a and R ^2a is both -OCH ₃ , R ³ is 1-piperidinyl, n is 2, and Z is -O-, or a pharmaceutically acceptable salt thereof. A process for the preparation of a compound of formula (le) wherein: R ^1a is -H or group -0R ^7a wherein R ^7a is a hydroxy group or hydrogen; R ^2a is -H, -halogen, or -OR ^8a , wherein R ^8a is a hydroxy protecting group or hydrogen; R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino; n is 2 or 3; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof a) oxidizing the sulfur atom of a compound of formula IV wherein R ^1a and R ^2a are as defined above and R ⁹ is a leaving group; b) reacting the product of step a), i.e. a compound of formula XIV, with a nucleophile of formula XXIII wherein R ¹² is -OH or -SH; c) reducing the product of step b), i.e. a compound of formula XVI, to a compound of formula le; d) optionally removing any hydroxy protecting groups R ^1a and / or R ^2a from the product obtained in step c); and e) optionally converting the product of steps c) or d) to a salt. 17. Procedure 1-8. 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 3, wherein A) a compound of Formula XVI wherein: R ^1a is -H or group -0R ^7a wherein R ^7a is a hydroxy group or hydrogen; R ^2a is -H, -halogen, or -OR ^8a , wherein R ⁸³ is a hydroxy protecting group or hydrogen; R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethyleneimino -group; n is 2 or 3; and Z is -O- or -S-; or pharmaceutically acceptable salts thereof; B) a compound of formula IIb wherein R ⁷ is a hydroxy protecting group; and R ^2a is reacted with a compound of formula V wherein Q is a leaving group and R ³ is as defined above; C) a compound of formula (IIb) wherein R ^2a , R ⁷ and Z are as defined above, with an alkylating agent of formula Q- (CH ₂ ) _n -Q 'wherein Q and Q' are the same or different leaving groups, reacting the product of the reaction with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, dlethylamine, diisopropylamine or 1-hexamethyleneimine; obsession D) for the preparation of compounds of formula I wherein one of the substituents R ¹ or R ² is -H and the remaining R ¹ or R ² substituent is -OH, the) i) a compound of formula IIh wherein R ^1c is -OH or -O- (C 1 -C 4 alkyl); HU 226 326 Β1 R ^2c is -OH or -O- (C 1 -C 4 alkyl), provided that when R ^1c is -OH, R ^2c is -O- (C 1 -C 4 alkyl), and R ^1c is -O- (C 1 -C 4 alkyl), then R ^2c is -OH, R ³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1-hexamethylene imino group; n is 2 or 3; and Z is -O- or -S-; or forming a triflate from the hydroxyl chain of its pharmaceutically acceptable salts; and ii) reducing the resulting triflate chain. b) optionally removing the remaining hydroxy protecting group or groups; and c) optionally forming a salt from the product of step a) or b). 18. A compound according to any one of claims 1 to 6 for use in ameliorating the symptoms of postmenopausal syndrome. The compound of claim 18, wherein the postmenopausal condition is osteoporosis, a related cardiovascular disease, hyperlipidemia, or hormone-dependent cancer. 20. A compound according to any one of claims 1 to 6 for use in the inhibition of uterine fibroid disease, endometriosis, aortic malignant cell proliferation or restenosis. 21. A compound according to any one of claims 1 to 4 for use in therapy. 22. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the alleviation of symptoms of postmenopausal syndrome. 23. Figures 1-8. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the alleviation of symptoms of postmenopausal syndrome, wherein the postmenopausal syndrome is osteoporosis, a related cardiovascular disease, hyperlipidemia or hormone dependent cancer. 24. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the inhibition of uterine fibroid disease, endometriosis, aortasimus muscle proliferation or restenosis. 25. [6-Hydroxy-3- [4- [2- (1-piperidinyl) ethoxy] phenoxy] 2- (4-methoxyphenyl)] - benzo [b] thiophene, and pharmaceutically acceptable salts thereof.