Benzothiophene compounds or their pharmaceutically acceptable salts

 

(57) Abstract:

The invention relates to benzothiophene compounds of formula I, where R1-H, - OH, -O(C1-C4alkyl), - EA6H5-, OCO(C1-C6alkyl), or-OSO2(C2-C6alkyl);

R2IS-H, -OH, -O(C1-C4alkyl), EA6H5, CCA(C1-C6alkyl) , -OSO2(C2-C6alkyl), or halogen; R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino; n = 2 or 3; Z Is-O - or-S-, or their pharmaceutically acceptable salts. The technical result - the formation of compounds that can be used for treatment of various medical indications associated with postmenstrual syndrome, or fibrous diseases of the uterus, endometrium and proliferation of smooth muscle cells of the aorta. 9 C.p. f-crystals, 3 PL.

The invention relates to the field of pharmaceutical and organic chemistry, more specifically to new benzothiophene compounds that can be used for treatment of various medical indications associated with post-menopausal syndrome, fibroymyalgia relates to intermediate compounds which you can use to obtain the pharmaceutically active compounds of the present invention and pharmaceutical compositions.

"Postmenopausal syndrome" is a term used to describe a variety of pathological conditions, which often occur in women who take, or have expired period of physiological changes, known as menopause. Although this term is used in different pathologies, three main effect of postmenopausal syndrome, leading to the longest diseases include osteoporosis, such cardiovascular manifestations, as hyperlipidemia, and estrogen-dependent cancers, especially breast cancer and uterine cancer.

The term osteoporosis describes a group of diseases of different etiologies, but they all have a net weight loss of bone mass per unit volume. The consequence of this loss of bone mass and the resulting bone fractures is a violation of the functions of the skeleton as a structural support of the body. One of the most common types of osteoporosis associated with menopause. Most women lose from about 20% to 60% of their bone mass in the trabecular part of the bone for 3/6 years after prekrseni the>

However resorptive cycle is dominant, and this leads to net bone loss. Osteoporosis is a common and serious disease in women in the postmenopausal period.

In the USA only there are 25 million women are prone to this disease. The result of osteoporosis are personal damage and it also leads to significant economic losses associated with chronic nature of the disease and the need for intensive and long-term support /hospitalization and home care/ due to subsequent complications. This is especially true for patients of older age. In addition, although osteoporosis is usually not considered as a life-threatening condition, from 20 to 30% of deaths associated with hip fractures in older women. A significant percentage of this mortality can be directly associated with postmenopausal osteoporosis.

The most damaged bone tissue, which acts postmenopausal osteoporosis, is trabecular /sponge/ cloth. This spongy tissue is mainly concentrated near the ends of the bone /near joints in the processes of the spine. Spongy tissue is characterized by a slightly cloth which is the outer layer and the Central core of the bone. This coupled between a spongy mesh provides support for the outer cortical structure and is critical for biochemical strength of the whole structure. In postmenopausal osteoporosis occurs mainly resorption and loss of spongy tissue, which leads to fractures and bone destruction. In light of the loss of spongy tissue in women in the postmenopausal period, it is not surprising that the most common fractures that are associated with the bones, which largely depend on the support of spongy tissue, that is, the spine, the neck is of such weight bearing bones like the femur and forearm. Indeed, femur fractures, fractures collies and compression fractures of the spine are signs of postmenopausal osteoporosis.

To date, the only generally accepted method for the treatment of postmenopausal osteoporosis is estrogensoderjashie therapy. Although this treatment is usually successful, the patient's perception of such treatment is usually low, because estrogen treatment often leads to undesirable side effects.

For premenopausal period atrasta. However, after menopause, the number of cardiovascular disease in women is slowly increasing and is approaching the number of diseases observed in men. This loss of protection was associated with the loss of estrogen, and, in particular, with the loss of estrogen's ability to regulate the levels of lipids in serum. The nature of the ability of estrogen to regulate lipids in the serum is not entirely clear, but current evidence indicates that estrogen can increase the efficiency of receptor low density lipids /ZDZ/ in the liver, resulting in the removal of excess cholesterol. In addition, estrogen, appears to have some effect on cholesterol biosynthesis, and has some other favorable effects on health of the cardiovascular system.

There was a message in the literature that women in the postmenopausal period, who received estrogen treatment, showed the return of the concentrations of lipids in the serum to the values they had in premenopausal. So, pirogen, apparently, is a reasonable treatment of such conditions. However, side effects estrogen-replacement therapy is unacceptable for many women, what about the s to adjust the level of lipids in the serum and estrogen, but who would be deprived of the side effects and risks associated with treatment with estrogen.

The third major pathology associated with postmenopausal syndrome, is an estrogen-dependent cancer of the breast and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasma often associated not only with women in the postmenopausal period, they dominate the population mainly in older, postmenopausal age. Current chemotherapy of such cancers is based mainly on the use of such anti-estrogen compounds, such as tamoxifen. Although such mixed agonist-antagonists and have a favorable effect in the treatment of these cancers and estrogenic side effects tolerated in acute situations, they are not perfect. For example, these agents can have a stimulating effect on some populations of cancer cells in the uterus due to its estrogenic /agonist/ properties, and therefore can be contraproductive in some cases. A more suitable treatment for such cancers would be the agent who would have been anti-estrogen is Tumi/ in relation to reproductive tissues.

In response to a significant need for new pharmaceutical agents that would be able to reduce the symptoms (along with others) of postmenopausal syndrome, in the present invention proposed benzothiophene compounds, pharmaceutical compositions, and methods of using such compounds for the treatment of postmenopausal syndrome and other estrogen pathological conditions that have been stated previously.

The fibrosis of the uterus /or fibrous disease of the uterus/ are old and continuing clinical problem, which is known under various names, including or fibrous disease of the uterus, hypertrophy of the uterus, lamiaa uterus, myometrial hypertrophy, fibrosis of the uterus and fibroid metritis. It is important that the fibrosis of the uterus is a condition in which there is an unacceptable education or fibrous tissue in the walls of the uterus.

This condition is caused by dysmenorrhea and infertility in women. The exact cause of this condition is not entirely clear, but the existing evidence suggests that this is the wrong response or fibrous tissue to estrogen. This state is called in rabbits by daily injection of estrogen in aceeasi. Further, in rats, estrogen also causes similar hypertrophy.

The most common method of treating fibrosis cancer includes surgery, but it is expensive and sometimes causes complications such as the formation of abdominal adhesions and infections. In some patients the initial surgery is only a temporary treatment, and the fibroids grow back. In these cases, perform the hysterectomy, which effectively stops the formation of fibroids, but also the reproductive life of the patient. Next, you can enter antagonists of hormone excretion of gonadotropin, but their use also only temporarily, as they lead to osteoporosis. Thus, there is a need for new methods of treatment of fibrosis of the uterus and methods of the present invention satisfy these requirements.

Endometriosis is a condition serious dysmenorrhea, which is accompanied by severe pain, bleeding endometrial mass or peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition, apparently, is ectopic endometrial growth, which responds inappropriately to normal hormonal control, and are located in inappropriate tissues. Because of napththalene reaction, leading to infiltration of macroview and the cascade of events that leads to the beginning of the painful reactions. The exact etiology of this disease is not fully understood, and its treatment with hormones is ambiguous, poorly motivated and has a number of undesirable and possibly dangerous side effects.

One of the ways of treatment of this disease is the use of low doses of estrogen to suppress endometrial growth due to the negative feedback action on the Central gonadotropin secretion, and subsequent selection by the ovaries of estrogen; however, sometimes it is necessary to continuously use estrogen to control symptoms. Such use of estrogen often leads to undesirable side effects, and even to the risk of endometrial cancer.

Another method of treatment is in the wrong introduction progestins, what causes amenorrhea, and by suppressing the production of estrogen by the ovaries, may slow endometrial growth. The chronic use progestin-only therapy is often accompanied by undesirable actions of progestin on the Central nervous system, and often leads to infertility due to the suppression of ovarian function.

The present invention relates to compounds of the formula I

< / BR>
where R1represents-H, -OH, -O/C1-C4-alkyl/, -OCOC6H5, -OCO/C1-C6-alkyl/ or-OSO2/C2-C6-alkyl/;

R2represents-H, -OH, -O/C1-C4-alkyl/, -OCOC6H5, -OCO/C1-C6-alkyl/, -OSO2/C2-C6alkyl, or halogen;

R3is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1 hexamethyleneimino;

n = 2 or 3;

Z represents-O - or-S-;

or their pharmaceutically acceptable salts.

In addition, in the present invention proposed the following intermediate compounds necessary for obtaining the pharmaceutically active compounds of the present invention, some of which are pharmaceutically active compounds:

2ais-H, halogen, or-OR8where R8is protecting a hydroxyl group;

R3is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diisopropylamino or 1 hexamethyleneimino;

R6is-H or a protecting hydroxyl group, which can selectively delete;

R9is tsepliaeva group;

R11is absent or represents = 0;

n = 2 or 3; and

Z represents-O-or-S-;

or their pharmaceutically acceptable salts.

A method of producing compounds of the formula:

< / BR>
where R1arepresents-H, or-OR7awhere R7ais-H or a protecting hydroxyl group;

R2ais-H, halogen, or-OR8awhere R8ais-H or a protecting hydroxyl group;

R3is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1 hexamethyleneimino;

n represents 2 or 3, and

Z represents-O - or-S-;

or its pharmaceutically acceptable salts, characterized in that it includes

< / BR>
where R
< / BR>
with the nucleophilic group of the formula:

< / BR>
where R12represents-OH or-SH;

c/ restore product from step b/, the compounds of formula XVI:

< / BR>
to obtain the compounds of formula:

< / BR>
d/ optional removal of R1aand/or R2aprotecting hydroxyl groups, if they are present, the product from step c/, and

e/ optional receiving salt of the product from stage c/ d//.

In addition, the present invention relates to pharmaceutical compositions containing a compound of formula I, optionally containing estrogen or progestin, and to the use of these compounds separately, or in combination with estrogen or progestin, for easing symptoms of postmenopausal syndrome, especially osteoporosis, pathological conditions of the cardiovascular system and estrogen-dependent cancers. In the sense used here, the term "estrogen" includes steroidal compounds estradiol, estrone, conjugated estrogen Premarinaquinostraat 17 - ethinylestradiol, etc. In the sense used here, the term "progestin" includes compounds with progesterone activity, such as proges etenia can also be used to suppress or fibrous disease of the uterus and endometriosis in women, proliferation of smooth muscle cells of the aorta, particularly restenosis, in humans.

One aspect of the present invention includes a compound of formula I:

< / BR>
where R1represents-H, -OH, -O/C1-C4alkyl/, -OCOC6H5, -OCO/C1-C6alkyl/ or-OSO2/C4-C6alkyl/;

R2represents-H, -OH, -O/C1-C4alkyl, -OCOC6H5, OCO/C1-C6alkyl/, -OSO2/C2-C6alkyl or halogen;

R3is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino;

n = 2 or 3; and

Z represents-O - or-S-;

or their pharmaceutically acceptable salts.

Common terms used in the description here of the compounds have their usual values. For example, "C1-C6alkyl" refers to branched or unbranched aliphatic chains containing from 1 to 6 atoms, including such parts as methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, etc. Similarly, the term "C1-C4alkoxy" represents C1-C4alkyl group, process the propoxy, etc.

The raw materials for one of the methods of preparing compounds of formula I of the present invention, the compounds of formula III, get almost to the method described by C. D. Johes in U.S. patent N 4418068 and 4133814, which are incorporated here by reference. The compounds of formula III have the following structure:

< / BR>
where R7and R2ahave these values.

R7and R8protecting the hydroxyl group of fragments that are not normally present in the final, therapeutic active compounds of the formula I, but which are intentionally introduced at some stage of the synthesis to protect a group which otherwise might react in chemical reactions, and then removed at later stages of the synthesis. As compounds containing such protective groups are valuable mainly as a chemical intermediate compounds /although some derivatives also exhibit biological activity/, their particular structure is not critical. A number of reactions to create, delete, and possibly re-introduction of such protective groups are described in a number of standard works including, for example, Protective Groups in Organic Chemistry, Plenum Press (London and New Iork, 1973); Green, T. W., Protective Groups in Organic Synthesis, Wi groups include, for example, -C1-C4-alkyl, -C1-C4-alkoxy, -CO-/C1-C6alkyl/, -SO2- A/C4-C6alkyl,- CO-Ar, where Ar represents benzyl or optionally substituted phenyl. The term "substituted phenyl" refers to phenyl group containing one or more of the substituents selected from the group consisting of C1-C4of alkyl, C1-C4alkoxy, hydroxy, nitro, halogen and three/chlorine or fluoride/bromide. The term "halogen" refers to bromine, chlorine, fluorine and iodine.

For compounds of formula III, preferred R7and R8/R2a/ substituents are methyl, isopropyl, benzyl and methoxymethyl. Compounds in which R7and R8each represents methyl, get in the manner described in the aforementioned patent to Jones. Another preferred protecting the hydroxide group is methoxymethyl. However, the compound of formula IV /below/ in the beginning a preferred methyl or other protecting hydroxide groups. Then the protective group is removed, getting phenolic fragments, which then protects ethoxymethylene protective groups.

The compounds of formula II are obtained from R7protecting the hydroxyl groups, the ukta. The same is true when R8/R2aprotecting the hydroxyl group is selectively removed, leaving R7protecting the hydroxyl protective group in place. For example, R7is isopropyl or benzyl, and R8/R2a/ represents methyl. ISO-propyl or benzyl fragment selectively removed in a standard way, and R8methyl protective group leave as part of the final product.

The first stage of the method of the present invention some of the compounds of formula I include selective introduction tseplyaesh groups in position 3 of the compounds of formula III, the implementation of the reactions of addition and the reaction product from the first stage with 4-/ - protected hydroxy and/or phenol, and the removal of the phenolic protecting the hydroxyl group. This method is depicted in scheme I (see the end of the description).

At the first stage of scheme I, the corresponding tsepliaeva group is selectively introduced into position 3 starting compound of the formula III in the standard way. The corresponding R9otsepleniya groups include sulfonates such as methanesulfonate, 4-brabanthallen, toluensulfonate, aconsultant, isopropanolate, 4-methoxybenzenesulfonyl, 4-nitrobenzenesulfonate, 2-Chloraka to provide a suitable introduction tsepliaeva group preferred these halides, and the most preferred bromine.

Consider the reaction of lead using standard methods. So for example, if you use the preferred gaodirelwe agent, the equivalent of such halogenous agent, preferably bromine is subjected to interaction with the equivalent of a substrate of the formula III in the presence of a suitable solvent such as, for example, chloroform or acetic acid. The reaction is conducted at temperatures from about 40oC to about 80oC.

The reaction product from this stage, the compound of formula IV is then subjected to interaction with 4-/ - protected hydroxy and/or phenol to obtain the compounds of formula IIA in which R6is selectively removed to protect the hydroxyl group. Usually 4-hydroxy-protective fragment of phenol may be any known protecting group which can be selectively removed without removing, for example, R7and, if they are present, R8fragments of the compounds of formula IIa. Preferred R6protective groups include methoxymethyl, if R7and/or R8are not methoxymethyl, and benzyl. Of these the most preferred benzyl. Reagents - 4-/ - protected hydroxy/phenols commercially available, or they can get the I /Ullman/ Ullman and it is being carried out in a standard way [see Advanced Organic Chemistry: Reactions, Mechanismg and Structure, Fouth Edition, 3-16, (J. march, ed. , John Wiley & Sons. Inc. 1992); Jones. C. D., J. Chem. Soc. Peck. Trans. I, 4:407 (1992)].

Usually an equivalent amount of two aryl substrates in the presence of up to equimolar amounts of catalyst of copper oxide /1/ and the corresponding solvent, heated to boiling under reflux in an inert atmosphere. It is preferable to expose the interaction equivalent to the compounds of formula IV in which R9is bromine, with an equivalent amount of 4-benzyloxyphenol in the presence of equivalent oxide copper /1/.

Suitable for this reaction solvents are solvents or mixture of solvents which remain inert throughout the reaction. Typically, the preferred solvents are those "employed" basis, as, for example, 2,4,6-kallidin.

The temperature at this stage of the reaction should be sufficient to complete the reaction accession, and affects the time necessary for this. If the reaction mixture is heated to boiling point under reflux in an inert atmosphere, e.g. in nitrogen atmosphere, the time required to complete reacciona formula IIa compounds of formula IIb get selectively removing R6protecting the hydroxyl group of compounds of formula IIa due to the well known reaction of recovery. However, the selected method should not affect R7and, if present, R8protecting the hydroxyl group.

If R6is preferred benzyl fragment, and R7and, if present, R8each are stands, this stage of the method are due to the standard hydrogenolysis.

Typically, the substrate of formula IIa is added to a suitable solvent or mixture of solvents, then adding a donor of protons to accelerate the reaction and the corresponding catalytic hydrogenation.

Suitable catalysts include noble metals, and oxides such as palladium oxide, patina and rhodium in the medium as carbon or calcium carbonate. Which one is preferable palladium on coal, especially 10% palladium on coal.

Solvents for this reaction are those solvents or mixture of solvents which remain inert throughout the reaction. Usually the preferred ethyl acetate and C1-C4-aliphatic alcohols, especially ethanol.

For this reaction, hydrochloric acid is used, where the AI from about 30 psi/2.11 kg/cm2to about 50 psi /3,515 kg/cm2/ she runs very fast. Over the course of the reaction can be monitored using standard chromatographic techniques, for example by means of thin layer chromatography.

The compounds of formula IIa and IIb are new compounds included in the scope of compounds covered by formula II, and can be used to obtain the pharmaceutically active compounds of formula I.

After obtaining the compounds of formula IIb, it is subjected to interaction with the compound of the formula V:

R3-/CH2/n-Q (V)

where R3and n have the previously indicated meanings, and O represents bromine or preferably chlorine, to obtain the compounds of formula VI. Then, the compounds of formula VI removes the protection, to obtain compounds of formula Ia. These stages of the method of the present invention is presented in scheme II (see end of description), where R3, R7, R2aand n have the above significance, and R2represents-H, -OH or halogen.

In the first stage of the method presented in scheme II. alkylation are standard ways. The compounds of formula V are commercially available or they get well known in the art methods. It is preferable to use Sol is th least about 1 equivalent of the substrate of formula IIb is subjected to interaction with 2 equivalents of the compounds of formula V in the presence of at least about 4 equivalents of carbonate of an alkali metal, preferably cesium carbonate, in an appropriate solvent.

Solvents in this reaction can be such solvents or solvent mixtures that remain inert throughout the course of the reaction. Most preferred is N,N-dimethylformamide, especially in its anhydrous form.

The temperature at this stage should be sufficient to have completed this reaction is alkylation. Usually the room temperature is residual and preferred.

Consider the reaction of lead in an inert atmosphere, preferably under nitrogen atmosphere.

In the preferred conditions of reaction it is usually about 16-20 hours. Over the course of the reaction can be monitored using standard chromatographic techniques.

Alternatively, to obtain the compounds of formula VI, a compound of formula IIb is subjected to interaction with an excess of alkylating agent of the formula:

Q-/CH2/n-Q',

where Q and Q' are the same or different and each represents tsepliaeva group in an alkaline solution. Suitable detachable group, listed previously, usage is helirovanie contains calcium carbonate in an inert solvent, for example, such as methyl ethyl ketone /MEK/ or DMF. In such a solution of 4-hydroxy-group sensornogo fragment of the compounds of formula IIb is phenoxide ion, which replaces one of tseplyaesh groups alkylating agent.

This reaction proceeds best if the alkaline solution containing the reagents, bring to the boiling temperature under reflux, and leave until it is complete. If the preferred solvent used MEK, the reaction time is from about 6 to about 20 hours.

The reaction product from this stage is then subjected to reaction with 1-piperidine, 1-pyrrolidino, methyl-1-pyrrolidino, dimethyl-1-pyrrolidino, 4-morpholine, dimethylamine, diethylamine, Diisopropylamine or 1-hexamethyleneimino standard way to obtain the compounds of formula VI.

Preferably the salt of hydrochloric acid piperidine be interacting with alkilirovanny compound of formula IIb in an inert solvent, such as anhydrous DMF, and heated to a temperature in the range of from about 60oup to about 110oC. If the mixture is heated to a preferred temperature of about 90oC, the reaction takes from about 30 minutes to about 1 hour. However, the course of the reaction at this stage can be monitored using standard chromatographic techniques.

The compounds of formula VI, in which R7and, if present, R8each represents C1-C4alkyl, preferably methyl, and in which R2ais-H or halogen, are new compounds and pharmaceutically active for the methods described here. Accordingly, such compounds are included in the definition of compounds of formula I.

Some preferred compounds of formula I get arseplay R7and, if present, R8protecting the hydroxide group of compounds of formula VI, a well-known ways. Numerous reactions for the introduction and removal of such protective groups are described in many works, including, for example, Protective Groups in Organic Chemistry, Plenum Press, (Lonlon and New York, 1973); Green. T. W. Protective Groups in Organic Synthesis, Wiley. (New York, 1981); and The Peptides, Vol.1, Schroodez and Lubke, Academic Press (London and New York, 1965).

The removal methods are preferred R7and/or R8protecting hydroxyl groups, especially methyl and methoxymethyl are shown below in the examples.

The compounds of formula Ia are new; they are pharmaceutically active in the here described methods, and certain covered here formula I.

The compounds of formula I in which R1is-H receive the CX is archacki available tianeptine /formula VII to obtain a compound of formula VIII, which is then attached to a 4 /protected hydroxy/ phenol, receiving compound of formula IX, where R6is protecting hydroxylgroups, which can selectively remove, and R9is tsepliaeva group.

The compound of the formula VII are commercially available, Obtaining the compounds of formulas VIII and IX, including the definitions for the substituents R6and R9and preferred reagents and reaction conditions, if no other instructions are the same as listed previously for scheme I.

Then the compounds of formula IX arriraw in the reaction accession Suzuki /see Suzuki, A., Pure and Appl. Chem. 6/2/:212-222/ 1994//. Using one of the options of joining Suzuki, the compound of formula IX is selectively halodrol in the 2-position, and then attach to the connection arylboronic acid of the formula XIa (method A in scheme IV, see the end of the description), where R2a, R2b, R3, R6and n have the above meanings, X is iodine, bromine or fluorine, in order of preference; and

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

However, preferably, arylboronic acid of the formula XIb be obtained from compounds of formula IX, and then analyze its interaction with glodariu connection can be used to obtain the pharmaceutically active compounds of the present invention /formula Ib/ in the alkylation and removal of protection.

At the first stage of scheme IV idiot or bromilow the compounds of formula IX in position 2 by known methods. Typically, the compound of formula IX is subjected to interaction with a slight excess of n-utility in hexane, in an appropriate solvent and in an inert atmosphere, e.g. in nitrogen atmosphere, and then was added dropwise a slight excess of the desired halogenous agent in a suitable solvent. Preferably, palodiruyut agent at this stage was iodine, but can also be used and bromine and N-bromosuccinimide.

Suitable solvents include inert solvents or mixture of solvents such as diethyl ether and tetrahydrofuran (THF /THF/. Which one is preferable tetrahydrofuran, especially anhydrous THF.

This reaction selective haloiding in the 2-position normally carried out at a temperature of about -75oC to about 85oC.

In the above reaction get halohydrin formula Xa, which then connect with arylboronic acid of the formula XIa standard way of joining Suzuki, to obtain compounds of the formula IIc. The compounds of formula XIa, in which R2ais-H, halogen or-OR8/where R8is protecting hydroxyle /see March J., and Suzuki, A, Supra).

In this reaction joining a slight excess of the compounds of formula XIa are interacting with each equivalent of the compound of the formula Xa in the presence of a palladium catalyst and an appropriate base such inert solvent like toluene.

Although the reactions proceed Suzuki you can use various palladium catalysts, usually choose specific reaction catalyst. So it is most preferable to use in this reaction tetranitroaniline.

Similarly, in this reaction accession you can use various grounds. However, it is preferable to use a carbonate of an alkali metal, especially 1N sodium carbonate.

The temperature used at this stage should be sufficient to carry out the reaction of accession until the end. Usually sufficient and preferred to heat the reaction mixture to boiling under reflux for from about 2 to about 4 hours.

In method B of scheme IV, a compound of formula Xb with arylboronic the substituent in 2-position get well-known ways. Typically, the compound of formula IX is treated with a small ispytaniyami corresponding trialkylborane.

Suitable solvents include inert solvent or mixture of solvents such as, for example, diethyl ether, dioxin and tetrahydrofuran /THF/. Preferred THF, particularly anhydrous THF.

The preferred trialkylborane used in the present invention is triisopropylsilyl.

The product of this reaction, the compound of formula Xb, then subjected to interaction with arylhalides or aritifical formula XIb due to the standard reaction accession Suzuki, to obtain compounds of the formula IIc. The preferred reaction conditions are the conditions that you specified for the interaction of compounds XIa and Xa in scheme IV, which also lead to the formation of compounds of formula IIc.

The conversion of compounds of formula IIc in the compounds of formula Ia is carried out, as described previously for the conversion of compounds of formula IIa in the compounds of formula Ia.

The compounds of formula IIc and IId are new, and they can be used to obtain the pharmaceutically active compounds of the present invention.

The compounds of formula XII and Ib are also new and can be used in the ways described here, and are included in the definition of formula I.

The compounds of formula I, is also obtained from compounds of the formula I, in which R1and R2represent-OH. Dihydroxy compound of the formula I is converted into a mixture of 6 - and 4'-monotributo and triflates fragment restore the hydrogen /see J. M. et al., J. Org.Chem. 55:991 /1990//. The resulting mixture of monohydroxy derivative, either in the form of free base or pharmaceutically acceptable salt, preferably as a salt of hydrochloric acid, can then be divided by the standard methods of crystallization.

In General, the dihydroxy compound of formula I is treated with from about 4 to about 6 equivalents of amino base such as triethylamine, in directionspanel solvent, followed by addition of 1 equivalent triftormetilfullerenov anhydride. Get a statistical mixture of mono - and di-triflates, and share its standard chromatographic methods. The preferred solvent for this phase is anhydrous dichloromethane.

If the reaction temperature maintained within the range from about 0oC to about 25oC, this reaction is completed within a period of time from about 1 to about 5 hours.

The selected mixture of mono-triflate connections then hydronaut in erectionspeedo is mine, and hydrogenation catalyst, such as palladium on charcoal, which is preferable. Preferred solvents for this reaction include ethyl acetate and ethanol, or in another embodiment, a mixture of the two. If at this stage the reaction is carried out at a pressure of 40 psi /9,84 kg/cm2/ gaseous hydrogen at ambient temperature, the reaction time is from about 2 hours to about 5 hours.

The resulting mixture of monohydroxy derivatives of formula I has different solubilities in ethyl acetate, and 6-hydroxy-4'-hydrogen can be partially separated from the 6-hydrogen-4'-hydroxy by selective crystallization. Further separation, which would ensure the production of clean monohydroxybenzene formula I, can be achieved by turning the choke in the salts of hydrochloric acid, followed by crystallization from a mixture of ethyl acetate/ethanol.

A more direct method of obtaining compounds of the formula I, in which either R1or R2represent-H and the other R1or R2Deputy represents-OH, and an alternative method of preparing compounds of the formula I, in which either R1or R2represent-H and the other R1or R2Deputy represents-O-/C1
R1crepresents-OH or-O-/C1-C4-alkyl/; and

R2crepresents-OH or-O-/C1-C4-alkyl/;

provided that if R1cis-OH, R2crepresents-O-/C1-C4alkyl/ if R1crepresents-O-/C1-C4-alkyl/, then R2cis-OH.

In this way hydroxyprimer this connection turns in triflate derived by processing triftormetilfullerenov anhydride. Then triflates fragment restore under standard conditions, preferably, by catalytic hydrogenation. Then protecting hydroxyl fragment is removed in a standard way, such as those described here, resulting in the receive connection of the formula I, in which either R1or R2is-H and the other R1or R2Deputy represents-OH.

Another option, and preferred is a method of obtaining compounds of the present invention, is presented in scheme V, (see the end of the description), where each of the variables has previously indicated values.

In this method, the sulfur atom of the compounds of formula IV is oxidized to obtain the sulfoxide /formula XIV/, which then podverditi formula I and formula II. Then sulfoxides fragment compounds of formula XVI to restore some of the compounds of the present invention.

In the first stage of this process, the compound of formula IV is selectively oxidized to sulfoxide. To implement this stage of the process, you can use a number of known methods /see Madesclaire. M., Tetrahedron, 42/20/; 5459-5495 /1986/; Trost, B. 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 oxidizing agents only lead to low conversion to the desired product, along with excessive oxidation to the sulfone. However, in this new method is the transformation of compounds of formula IV in the sulfoxide of formula XIV with a high yield with little formation of sulfones /or no education sulfones/. This new method involves the interaction of the compounds of formula IV with from about 1 to about 1.5 equivalents of hydrogen peroxide in a mixture with from about 20% to about 50% triperoxonane acid in methylene chloride. The reaction is conducted at temperatures from about 10oC to about 50oC, and usually requires from about 1 to about 2 hours to complete the reaction. Next, tsepliaeva group in 3-position /R9mi ways.

At this stage of the process, the acidic proton from the nucleophilic group is removed by treatment with base, preferably, a slight excess of sodium hydride or

tert-butoxide potassium, in a polar aprotic solvent, preferably DMF or tetrahydrofuran. You can use other bases including potassium carbonate and cesium carbonate. In addition, you can use and such other solvents, such as dioxane or dimethylsulfoxide. The deprotonation reaction is usually conducted at temperatures from about 0oC to about 30oC, and usually to complete this reaction requires about 30 minutes. Then the compound of formula XIV are added to a solution of the nucleophile. The substitution reaction is conducted at temperatures from about 0oC to about 50oC, and it usually takes from about 1 to about 2 hours. The product distinguish standard ways.

If protecting the hydroxyl group using benzyl fragment, hydrogenolysis sulfoxide fragment will also remove the benzyl protective group, which will eliminate the requirement for selective removal of the group at a later stage of the process.

In the next stage of the process of the present invention new sulfoxy the respectively. Up to this recovery process the compounds of formula IIg and IIe you can alkilirovanii, as is indicated here. Recovery sulfoxide compounds can be performed using one of many known methods, including, for example, the restoration of the hydride /sociallyengaged/, catalytic reduction, transfer hydrogenolysis and trimethylsilylmethyl /TMS/. With this restoration of the choice of the reagent depends on the compatibility of other functional groups of the molecule. For compounds described in the present invention the most preferred reagents are sociallyengaged /LiAlH4/ and transfer hydrogenolysis /palladium mobile/ammonothermal/. For recovery by LiAlH4suitable solvents are, for example, diethyl ether, dioxane and tetrahydrofuran (THF /THF/. Which one is preferable THF, particularly anhydrous THF. For the transfer hydrogenolysis of the most preferred alcohol solvents, particularly ethanol. The reaction is conducted at temperatures from about 0oC to about 60oC, and to complete the reaction may be from about 0.5 hours to about 2 hours.

If desired, you can delete protecting the hydroxyl groups /group/ the products of the method, predstavlennogo obtain compounds of the formula:

< / BR>
where R1arepresents-H or-OR7awhere R7ais-H or a hydroxyl protecting group;

R2ais-H, halogen, or-OR8awhere R8ais-H or a hydroxyl protecting group;

R3is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1 hexamethyleneimino;

n=2 or 3; and

z represents-O - or-S-;

or their pharmaceutically acceptable salts, including:

and/ oxidation of the sulfur atom of the compounds of formula IV:

< / BR>
where R1aand R2ahave the previously indicated meanings; and

R9is tsepliaeva group;

b/ the implementation of the interaction of the product with stage

a/, the compounds of formula XIV:

< / BR>
with the nucleophilic group of the formula:

< / BR>
where R12represents-OH or-SH;

c/ restore product from step b/, the compounds of formula XVI:

< / BR>
to obtain the compounds of formula:

< / BR>
d/ optional removal of R1aand/or R2ahydroxyl protecting group, if present/ product from step c/, and

e/ optional receiving salt of the product from stage c/ d/.

This At an intermediate connection, suitable for the production of pharmaceutically active compounds of the present invention.

The compounds of formula I in which Z represents S, also get using the method of scheme VI (see end of description), where R1arepresents-H or-OR7where R7represents a hydroxyl protecting group; R2arepresents-H, or-OR8where R8is protecting a hydroxyl group; R6is protecting the hydroxyl group, which can selectively remove; R9is tsepliaeva group; and M represents a metal ion, in which the compound IVa metallinou. The resulting product, compound of formula XVII, is subjected to the interaction with the 4/ protected hydroxyl/ phenoldisulfonic formula XVII, and protective phenolic group of compounds of formula IIe are removed, obtaining the compounds of formula IIf. It should be noted that when using this method, R2may not be halogen due to chemical restrictions.

On the first two stages of scheme VI, the compound of formula IVa metallinou by known methods. Usually it is preferable to process the compound of formula IVa slight excess of n-utility in hexano in a suitable solvent, followed by precapitalism solution disulf the ore, as nitrogen, and suitable solvents for both stages include one or more of such inert solvents as diethyl ether, dioxane and THF. Of these the most preferred THF, and especially its anhydrous form. Stage of the considered scheme of the reaction is conducted at temperatures from about -78oC to about 85oC.

In the first stage of this reaction get metallizovannoe compound of formula XVII 4-/protected hydroxide/vinyldimethyl/ compound of formula XVIII/, which is subjected to interaction with such a compound of formula XVII to obtain the compound of formula IIe, get, protecting the hydroxyl group of commercial 4-hydroxyphenylacetic a suitable protecting group by known methods. Preferred R6the protective group is methoxymethyl, provided that R7and R8(if one or both are present), is protecting the hydroxyl group other than methoxymethyl. At the same time necessarily R6the group protecting the hydroxyl, represents the fragment, which is different from R7and R8groups protecting the hydroxyl/ if they are/ to group R66 could be selectively removed by standard methods to obtain compounds of fairytale or solvent mixture is subjected to interaction in an acid medium, containing at least one equivalent of acid, preferably methanesulfonic acid, when heated from about 25oC to about 110oC. Typically, the reaction time is from about 6 to about 24 hours, and over the course of the reaction can be monitored using standard chromatographic techniques.

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

Compounds of formulas IIa and IIf are new, and they can be used to obtain the pharmaceutically active compounds of formula I, and they are included in the definition of formula II.

The compounds of formula Id:

< / BR>
where R1brepresents-H or-OH;

R2brepresents-H or-OH;

R3and n have the previously indicated meanings,

receive, using the above procedure, the corresponding stages of the process illustrated in schemes II and IV. Such compounds of formula Id are also new and can be used in the methods of the present invention, and they are included in the above definition of formula I.

The compounds of formula I in which R1and R2represent different protecting the hydroxyl group, or each R1and R2represents a group protecting snowy source material mentioned above formula III, provided that protects the hydroxyl group denoted by R7and R8different enough for you to remove one protective group and the other when it would have remained intact. Such 2-universityofri get well-known methods.

Most suitable for producing compounds of the formula I, in which R1and R2represent different protective groups, is joining Suzuki presented previously in scheme IV. However, 6/protected hydroxy/benzothiophen-2-Bronevoy acid is subjected to interaction with the compound of the formula XIb in which R2ais-R8and R7not the same with R8. This reaction allows to obtain the compounds of the present invention, in which R7and R8represent different protecting the hydroxyl group, so that one of the protective groups can be selectively removed, while the other remains as a fragment of the final product. Preferably, R7the protective group, especially benzyl or isopropyl, was removed to obtain a hydroxyl fragment, and R8protective group, in particular methyl, remained.

Join Suzuki are also using the above procedures, but alkylsulfonate, preferably, methanesulfonate, or C4-C6-arylsulfonate; and

R10is tsepliaeva group, preferably bromine or triflate.

In this way 6-/ - protected hydroxy/benzothiophen-2-Bronevoy acid, as described previously, is subjected to the interaction with the compound of the formula XIX to obtain the compounds of formula XX, which is subjected to interaction with tribromide boron in methylene chloride to obtain a monohydroxy compound, which is then transformed, for example, benzyl fragment by standard methods /formulas XXI/. 4'-sulphonate ester is then selectively removed through basic hydrolysis or, preferably, by treatment LiAlH4in a suitable aprotic solvent, such as, for example, THF. This reaction leads to the production of the compounds of formula XXII, which in the end, for example, was identified in in position 4 standard way /formula IIIa/. Naturally, professionals should be clear that to obtain the compounds of formula IIIa, in which a group protecting the hydroxyl differ from those presented in scheme VII (see end of description) that can selectively be removed by obtaining monohydroxy compounds of formula I of the present invention can use the to obtain the compounds of formulas I and II of the present invention.

Other preferred compounds of formula I get, due to the replacement of hydroxyl groups in the 6 - and/or 4'-positions /if present/ at the fragment of the formula-O-CO-/C1-C6alkyl/ or-O-SO2- A/C2-C6alkyl/ well-known ways. See, for example, U.S. patent 438593.

So if, for example,- O-CO/C1-C6alkyl/group needs, then mono - or hydroxy-compound of formula I is subjected to interaction with this agent as acylchlorides, bromide, cyanide, or azide, or with an appropriate anhydride or mixed anhydride. Reactions usually lead to something so basic solvent like pyridine, quinoline or isoquinoline, or in such tertiary Amina as triethylamine, tributylamine, methylpiperidin, etc., the Reaction can also be maintained in such an inert solvent as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, etc., to which has been added at least one equivalent of an acid acceptor/exceptions below/, for example, tertiary amine. Optionally, you can use this acylation catalyst, such as 4-dimethylaminopyridine or 4-pyrrolidinedione. See, for example, Haslam et al., Tetrahedzon 36:2409-2433 /1980/.

] The Noah atmosphere, such as gaseous nitrogen. However, usually, to the reaction occurred, enough of the ambient temperature.

The acylation of the hydroxyl group in the 6 - and/or 4'-position can also be due to the reactions catalyzed by the acid in the interaction with the appropriate carboxylic acid in an inert organic solvents. Using such acid catalysts as sulfuric acid, polyphosphoric acid, methanesulfonate acid, etc.

Above-mentioned groups of R1and/or R2compounds of the formula I can also be obtained due to the formation of the active complex ester of the appropriate acid, for example, such a complex ester derived from such known reagents, as dicyclohexylcarbodiimide, illimitably, NITROPHENOL, pentachlorophenol, N-hydroxysuccinimide and 1-hydroxybenzotriazole. See, for example, Bull. Chem. Soc. Japan, 38:1979 /1965/ Chem. Ber., 788 and 2024 /1970/.

Each of the above-mentioned method, which yields a-O-CO-/C1-C6alkyl/ fragments can be carried out, as previously discussed, in solvents. Of course, the ways in which do not get acid product during the reaction, does not require the use in the reaction mixture akts 4'-position of the compounds of formula I is transformed into a group of the formula-O-SO2/C2-C6-alkyl/ mono - or dihydroxy compound is subjected to interaction with, for example, a sulfonic anhydride or a derivative of the appropriate sulfonic acid, as sulphonylchloride, bromide, or sulfonylamino salt, as described in king and Manaira, Y. Amer. Chem. Soc., 97:2566-2567 /1975/.

Dihydroxy compound can also be interaction with the appropriate sulfonic anhydride or mixed sulfonic anhydrides. Such reactions lead to the conditions that were specified earlier in the discussion of reactions with halogenide etc.

Although the methods of the present invention it is possible to use the compounds of formula I in free base form, preferably, to obtain and use the form pharmaceutically acceptable salts. Thus, the compounds used in the methods of the present invention form pharmaceutically acceptable salts joining with a wide range of organic and inorganic acids, and include the physiologically acceptable salts which are often used in the Pharmacopoeia. These salts also form part of the present invention. Typical inorganic acids, which are used for such salts include hydrochloric, promislovogozaliznichnogo acids, as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate and hydroxyalkanoate acids, aromatic acids, aliphatic and aromatic sulfonic acids. So pharmaceutically acceptable salts include the acetate, phenyl acetate, triptorelin, acrolect, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyl-1,4-diet, capret, kaprilat, chloride, cinnamate, citrate, format, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleic, hydroxymet, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, hydrogen phosphate, dihydrophosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, persulfate, sulfite, bisulfite, sulfonate, bansilalpet, p-bromophenylacetate, chlorobenzenesulfonate, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, ecological, tartrate, etc., the Preferred salts are the hydrochloride and oxalate.

Farm with equimolar amount or an excess of acid. The reactants are typically combined in such common solvents as diethyl ether or ethyl acetate. Usually the salt falls out of solution over a period of time from about 1 hour to 10 days, and it can be identified by filtration or solvent can evaporate in the usual way.

Pharmaceutically acceptable salts have a high solubility compared to the compounds from which they are derived, and therefore more convenient for compositions in the form of liquids or emulsions.

The preferred representatives of the compounds of the present invention include the following:

Group I:

[6-methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/;

[6 isopropoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/;

[6-methoxy-2-/4-isopropoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/;

[2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S/-oxide/;

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

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

[6-benzyloxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/;

[6 isopropoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/;

[6-methoxy-2-/4-benzyloxyphenyl/-3-bromo]benzo[b]thiophene-/S-oksioksi] phenoxy] -2- /4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/;

[6 isopropoxy-3-[4-[4-/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-methoxymethylethoxy/thiophenoxy] benzo[b]thiophene;

[6-methoxy-2-/4-methoxyphenyl/-3-/4-hydroxy/thiophenoxy] benzo[b]thiophene;

Group II:

[3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4-hydroxyphenyl/] benzo[b] thiophene;

[3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4-hydroxyphenyl/] benzo[b] difengidramin;

[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-hydroxyphenyl/] benzo[b] difengidramin;

[3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/phenyl/] benzo[b]difengidramin;

[3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-forfinal/] benzo[b]thiophene;

[6-methoxy-2-/4-methoxyphenyl/-3-/4-benzyloxy/phenoxy]benzo[b] thiophene;

[6 isopropoxy-2-/4-methoxyphenyl/-3-/4-b

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

[6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4-methoxyphenyl/] benzo[b]-difengidramin;

[6-methoxy-3-[4-[2-/1-pyrrolidinyl/ethoxy] phenoxy] 2-/4-methoxyphenyl/] benzo[b] thiophene;

[6-methoxy-3-[4-[2-/1-hexamethyleneimino/ethoxy] phenoxy] -2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-N, N-diethylamino/ethoxy] phenoxy]-2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/morpholine/ethoxy]phenoxy]-2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[3-/piperidine/propoxy] phenoxy] -2-/4 - methoxyphenyl/] benzo[b]difengidramin;

[6-methoxy-3-[4-[3-/1-N,N-diethylamino/propoxy]phenoxy]-2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[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]thiophenoxide;

[6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4 - hydroxyphenyl/] benzo[b]difengidramin;

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

[6-hydroxy-3-[4-[2-/1-hexamethyleneimino/ethoxy]phenoxy]-2- /4-hydroxyphenyl/]benzo[b]thiophene;
[6-hydroxy-3-[4-[3-/1-N,N-diethylamino/propoxy]phenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-N, N-diisopropylamino/-ethoxy]phenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[3-/piperidine/propoxy] phenoxy]-2-/4 - hydroxyphenyl/] benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4 - methoxyphenyl/] benzo[b]difengidramin;

[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-hexadecylamine/ethoxy] phenoxy]-2-/4 - methoxyphenyl/]benzo[b]thiophene;

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

[6-benzyloxy-3-[4-[2-/1-morpholino/ethoxy] phenoxy]-2-/4 - methoxyphenyl/] benzo[b]thiophene;

[6 isopropoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4 - methoxyphenyl/]benzo[b]thiophene;

[6 isopropoxy-3-[4-[3-pyrrolidinyl/ethoxy]phenoxy]-2-/4 - methoxyphenyl/] benzo[b]thiophene;

[6 isopropoxy-3-[4-[2-/1-hexadecylamine/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-Neal/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-hexadecylamine/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]difengidramin;

[6-hydroxy-3-[4-[2-/1-pyrrolidinyl/ethoxy]phenoxy]-2-/4 - methoxyphenyl/] benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-hexadecylamine/ethoxy] phenoxy]-2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-N,N-dimethylamino/ethoxy]phenoxy]-2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-morpholino/ethoxy]phenoxy]-2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[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 - benzyloxyphenyl/]benzo[b]thiophene;

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

[6-methoxy-3-[4-enocsi] -2-/4 - isopropoxyphenyl/]benzo[b]thiophene;

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

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

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

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

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

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

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

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

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

[6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/4 - hydroxyphenyl/] benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-pyrrolidinyl/ethoxy]phenoxy]-2-/4 - hydroxyphenyl/] benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-hexamethyleneimino/ethoxy] phenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-N, N-dimethylamino/ethoxy] phenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-dinyl/ethoxy]phenoxy]-2-/4 - benzyloxyphenyl/]benzo[b]difengidramin;

[6 ethylsulfonyl-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy] -2-/4-metilsulfonilmetane/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-4 - ethylsulfonyl/]benzo[b]difengidramin;

[6 ethylsulfonyl-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2- /4-hydroxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4 - triftoratsetilatsetonom/]benzo[b]thiophene;

[3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-benzyloxyphenyl/] benzo[b] difengidramin;

[3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4 - pivaloyloxymethyl/]benzo[b]difengidramin;

[3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/4 - butylcumylperoxide/] benzo[b]difengidramin;

[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/][b]thiophene;

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

[6-benzyloxy-3-[4-[2-/1-piperidinyl/ethoxy]thiophenoxy]-2- /4-about[b]thiophene;

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

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

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

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

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

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

[6 isopropoxy-3-[4-[2-/1-N, N-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-[leinil/ethoxy] thiophenoxy]-2- /4-methoxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-hexamethyleneimino/ethoxy]thiophenoxy]-2- /4-methoxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-N, N-dimethylamino/ethoxy]thiophenoxy]-2- /4-methoxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-morpholino/ethoxy]thiophenoxy]-2- /4-methoxyphenyl/] benzo[b]difengidramin;

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

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

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

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

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

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

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

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

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

[6-methoxy-3-[4-[2-/1-morpholino/ethoxy] thiophenoxy] -2-/4 - isopropoxy is R>
[6-methoxy-3-[4-[2-/1-pyrrolidinyl/ethoxy] thiophenoxy]-2-/4 - hydroxyphenyl/]benzo[b]thiophene;

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

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

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

[6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy]thiophenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-pyrrolidinyl/ethoxy] thiophenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-hexamethyleneimino/ethoxy]thiophenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-N, N-dimethylamino/ethoxy]thiophenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-morpholino/ethoxy]thiophenoxy]-2-/4 - hydroxyphenyl/] benzo[b]difengidramin;

[6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] thiophenoxy]-2-/4 - methoxyphenyl/]benzo[b]difengidramin;

[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-is the site, located between[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]difengidramin;

[6-hydroxy-3-[4-[2-/1-pyrrolidinyl/ethoxy]thiophenoxy]-2- /4-hydroxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-hexamethyleneimino/ethoxy] thiophenoxy] -2- /4-hydroxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-N,N-dimethylamino/ethoxy]thiophenoxy]-2- /4-hydroxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-morpholino/ethoxy] thiophenoxy] -2- /4-hydroxyphenyl/]benzo[b]difengidramin;

[6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2 - phenyl]benzo[b]difengidramin;

Further examples are presented to illustrate the present invention and in no way limit its scope.

These NMR given in these examples, obtained on the GE spectrometer at 300 MHz, and the solvent used is anhydrous d-6 DMSO /if there are no other instructions/.

Example of getting 1. [3-/4-Benzyloxy/phenoxy]benzo[b]thiophene

< / BR>
To a solution of 3-bromobenzo [b] thiophene /69,62 g, 0,325 mol/ 55 ml of anhydrous collidine in nitrogen atmosphere add 4-benzyloxyphenol /97.6 g, 0,488 mol/ and the oxide of mladeni the reaction mixture was diluted with ethyl acetate /200 ml and the crude mixture is filtered through a cake of Celite CeliteAldrich, Milwaukee WI/ to remove inorganic salts. The obtained filtrate was washed with 1N. hydrochloric acid /h ml/. The organic portion is dried over sodium sulfate and concentrated in vacuo to a liquid. Tionately removed by distillation /10 mm RT.art, 115 - 120oC/. The remaining material is processed chromatographic/ silicon dioxide, hexane:ethyl acetate 85:15 to obtain 12.2 g of benzo[b]thiophene and 12.95 g /35% (based on the selected source material/ [3-/4-benzyloxy/phenoxy]benzo[b] thiophene in the form of an off-white solid. So pl. 84-86oC.1H NMR (CDCl3/d: to $ 7.91 - 7,83 /m, 2H/ to $ 7.91 - 7,83 (m, 2H/, 7,47 - 7,34 /m, 7H/,? 7.04 baby mortality /HF, JAB= 9,0 Hz, 4H/, 6,47 /c, 1H/, 5,07 /c, 2H/.

Elemental analysis for C21H16O2S:

Calculated: C 75,88 H 4,85

Found: C 75,75 H 5,00

Example of getting a 2. [2-Iodo-3-/4-benzyloxy/phenoxy]benzo[b]thiophene

< / BR>
To a solution of [3-/4-benzoyloxy/phenoxy]benzo[b]thiophene /6,00 g, 18,1 mmole/ in anhydrous tetrahydrofuran /100 ml in a nitrogen atmosphere at -78oC add n-utility /12,4 ml, to 19.9 mmole, 1.6 M in hexano/ dropwise via syringe. The solution turns from colorless to dark orange. After stirring for 20 minutes at -78oC lithium samples treated with I1/5,03, 19,bedroom mixture becomes light yellow, and leave her to slowly warm to room temperature. The reaction is quenched by adding 0.1 and a solution of sodium sulfate /200 ml/. The layers are separated and the aqueous extracted with ethyl acetate /h ml/. The organic layers are combined, dried over sodium sulfate/ and concentrated in vacuo to obtain an oil, which crystallizes upon standing. After recrystallization from a mixture of hexanol/ethyl ether get 7,10 g /86%/ [2-iodo-3-/4-benzyloxy/phenoxy] benzo[b] thiophene as a white crystalline powder. So melting 87 - 92oC.

1H NMR /CDCl3/d: 7,72/d, J = 8,1 Hz, 1H/, 7,47 - 7,20 /m, 8H/, 6,89 /s, 4H/, 5,01 /C, 2H/.

Elementary analysis for C21H15O2SI:

Calculated: C 55,03 H 3,30

Found: C 55,29 H 3,31

Example of getting a 3. [2-/4-tert-Butylacetyl/-3-/4-benzyloxy/phenoxy] benzo[b]thiophene

< / BR>
To a solution of [2-iodo-3-/4-benzyloxy/phenoxy]benzo[b]thiophene /4,50 g, 9,82 mmole/ in 20 ml of toluene added 4-/tert-butoxy/-phenylboronic acid /2.28 g, 11,75 mmole/ and then tetrakisphosphate /0,76 g of 0.66 mmole/. To this solution was added to 14.5 ml of 2 n sodium carbonate solution. The resulting mixture is heated to boiling under reflux for 3 hours. After cooling, the reaction mixture is diluted with 15 the model. In the concentration receive semi-solid substance that is dissolved in chloroform and passed through a layer of silicon dioxide. After concentrating receive oil, which after a thorough rubbing with hexane gives 4.0 g/91%/ [2-/4-tert-butylacetyl/-3-/4-benzyloxy/phenoxy/benzo[b] thiophene as a white powder. So melting 105-108oC.

1H NMR /CDCl3/d: to 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 /sq JAB= 9,3 Hz, 4H/, 4,99 /C, 2H/, 1,36 /s, 9H/. The mass spectrum with a field desorption: 480 ,

Elemental analysis for C31H28O3S:

Calculated: C 77,47 H by 5.87

Found: C 77,35, H 5,99.

Example 4. In a similar way we obtain [2-/4-methoxyphenyl/-3-/4-benzyloxy/-phenoxy] benzo[b] thiophene, using 4-methoxyphenylalanine acid

< / BR>
Yield = 73%, So melting 115 - 118oC.

1H NMR /CDCl3/d: 7,80 - of 7.90 /m, 3H/, 7,33 - 7,53 /m, 8H/, 6,93 - 7,06 /m, 6H/, 5,00 /C, 2H/, 3,83 /3H/. The mass spectrum with a field disable 483.

Elemental analysis for C28H22O3S:

Calculated: C 76,69, H Is 5.06.

Found: C Of 76.52, H 5,09.

Example of getting a 5. [2-/4-tert-Butylacetyl/-3-/4-hydroxy/phenoxy] benzo[b]thiophene

< / BR>
To a solution of [2-/Amigo 1% concentrated hydrochloric acid, add 0.50 g of 10% palladium on coal. The resulting mixture hydronaut at 40 psi /2,81 kg/cm2/ in for 1 hour, after which according to thin-layer chromatography of the reaction is considered complete. The resulting mixture was filtered through a layer of Celite and the obtained filtrate was concentrated in vacuo. The crude product was dissolved in minimum amount of ethyl acetate and passed through a short column with silica to remove Celite, using as eluent ethyl acetate. In the concentration receive a white solid product, which is thoroughly dissolved with a mixture of hexane/ethyl ether. After filtration receive 868 mg/73%/ [2-/4-tert-butylacetyl/-3-/4-hydroxy/phenoxy]-benzo[b]thiophene. So melting 210-213oC.1NMR /DMCO-d6/d: 9,13 /C, 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 /kV, JAB= a 8.9 Hz, 4H/, 1,28 /s, 9H/.

The mass spectrum with a field desorption: 390.

Elemental analysis for C24H22O3S:

Calculated: C 73,82, H 5,68

Found: C 73,98, H of 5.84

Example of getting a 6. In a similar way we obtain [2-/4-methoxyphenyl/-3-/4-hydroxy/-phenoxy]benzo[b]thiophene

< / BR>
Yield 80%. So melting 120-125oC.

1H NMR /CDCl3/d: 7,80 - of 7.90 ASS="ptx2">

Elemental analysis for C21H16O3S:

Calculated: C 72,39 H 4,63

Found: C 72,68 H 4,82

Example 1. [3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-hydroxyphenyl/] benzo[b]thiophene

< / BR>
To a solution of [2-/4-tert-butylacetyl/-3-/4-hydroxy/phenoxy] benzo[b] thiophene /1,25 g, 3,20 mmol/ in anhydrous N,N-dimethylformamide /10 ml at room temperature add cesium carbonate /5,70 g and 17.6 mmole/. After twenty minutes of stirring in small portions add 2-chloroethylnitrosourea /1,95 g, 10,56 mmole/ received a heterogeneous mixture is intensively stirred for 24 hours. Then the reaction mixture is diluted with 200 ml of water. The aqueous phase is extracted with ethyl acetate three times 100 ml the combined organic layers washed with water /h ml/. After drying the organic layer over sodium sulfate and concentration in vacuo receive oil. After chromatographic processing /5-10% methanol/ chloroform/ obtain 1.47 g/91%/ [3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-tert-butylacetyl/] benzo] [b]thiophene, which is used in the next stage without obtaining analytical data.

[3-[4-[1-/1-Piperidinyl/ethoxy] phenoxy] -2-/4-tert-butylacetyl/]benzo[b] thiophene /1,37 g of 2.72 mmole/ dissolved in triperoxonane Out in vacuum. The residue is dissolved in ethyl acetate /20 ml and washed with saturated sodium bicarbonate solution /3x10 ml/. The organic layer is dried over sodium sulfate and concentrated until, while in the solution is not formed white solid precipitate. The resulting product is recrystallized from a mixture of ethyl acetate/ethyl ether to obtain 1,03 g/85% [3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-hydroxyphenyl/]benzo[b] thiophene as colorless crystals. So melting 169-172oC.

1H NMR /DMSO-d6/d: 9,81 /c, 1H/, 7,93 /d, J = 7.7 Hz, 1H/, 7,54 /d, J = 8.5 Hz, 2H/, of 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/.

Elemental analysis for C27H27NO3S 0,55 CF3CO2H:

Calculated: C 66,40 H 5,46 N WAS 2.76

Found: C 65,99 H 5,49 N 2,61

Example 2 [3-[[4-[2-/1-Piperidinyl/ethoxy]phenoxy]-2-/4-hydroxyphenyl/] benzo[b] thiophene converted into its hydrochloride with 90% yield by treatment of ethyl ether hydrochloric acid in ethyl acetate

Data for the product of example 2: So melting 233-240oC.

1H NMR /DMSO-d6/d: 10,43 /m 1H/, 9,89 /C, 1H/, to 7.93 - 7.95 is /m 1H/, 7,60 - of 7.64 /m, 2H/, 7,35 - 7,50 /m, 3H/, 6,83 - 7,03 /m, 6H/, 4,27 - 4,30 /m, 2H/, 3,40 - 3,60 /m, 4H/, 2,96 - 3,10 /m, 2H/, 1,70 - 1,95 /m, 5H/, 1,40 - 1,53 /m 1H/. The mass spectrum with a field desorption: 446.

Found: C 68,29 H 5,46 N 3,19

Example 4. [3-[4-[2-/1-Hexamethyleneimino/ethoxy]phenoxy]-2-/4-hydroxyphenyl/]benzo[b] thiophene

< / BR>
So melting point 189-191oC.1H NMR /DMSO-d6/d: to $ 7.91 /d, J = 7,6 Hz, 1H/, 7,52 /d, J = 8.5 Hz, 2H/, 7,34 - 7,25 /m, 3H/, for 6.81 /s, 4H/, 6,75 /d, J = 8.6 Hz, 2H/, 3,89 /Shir. so , 2H/, 2,75 /Shir. so, 2H/, 2,68 /m, 4H/, 1,48 /m, 8H/. Elemental analysis for C28H29NO3S 1,50 H2O:

Calculated: C 69,11 H 6,79 N 2,88

Found: C 69,25 H 6,79 N 2,58

Example 5. [3-[4-[2-/1-N,N-Dimethylamino/ethoxy]phenoxy]-2- (4-hydroxyphenyl/]benzo[b]thiophene

< / BR>
So melting 70oC.1H NMR /DMSO-d6/d: to 9.91 /Shir. C. 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 /Shir. so, 2H/, was 2.76 /Shir., so, 2H/, of 2.51 /m, 4H/, 0,91 /m, 6H/.

The mass spectrum with a field desorption: 434.

Elemental analysis for C26H27
< / BR>
So melting = 228-23-oC.1H NMR /DMSO-d6/d: of 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 - or 4.31 /m, 2H/, 3,74 /3H/, 3,37 - 3,45 /m, 4H/, 2,92 - 2,96 /m, 2H/, 2,46 - 2,48 /m, 5H/, 1,74 /m 1H/.

The mass spectrum with a field desorption: 459. Elemental analysis for C28H29NO3S 1,0 HCl:

Calculated: C 67,80 H 6,10 N 2,82

Found: 68,06 H 6,38 N 2,60

An alternative way to obtain [2-/4-tert-butylacetyl/-3-/4-benzyloxy/phenoxy]benzo[b]thiophene

Example of getting a 7. [3-/4-Benzyloxy/phenoxy] [b] thiophene-2-baronova acid

< / BR>
To a solution of [3-/4-benzyloxy/phenyloxy] benzo[b] thiophene /5,00 g of 15.1 mmole/ in 20 ml of anhydrous tetrahydrofuran at a temperature of -78oC in nitrogen atmosphere is added dropwise via syringe N-utility /9,90 ml, 15.8 mmole, 1.6 M in hexano/. After fifteen minutes of stirring through a syringe type In/out Pr/3 /a 3.83 ml, of 16.6 mmole/ obtained mixture is allowed to warm to 0oC. the Reaction is quenched by separating the reaction mixture between ethyl acetate and 1.0 and hydrochloric acid /100 ml each/. The organic layer is extracted with water /h ml/. The organic layer is dried over sodium sulfate and concentrated in vacuo to a solid which is triturated with a mixture of atrovividis white solid. So melting 115-121oC. 1H NMR /DMSO-d6/d: 8,16 /d, J = 8.5 Hz, 1H/, 7,98 /d, J = 9.0 Hz, 1H/, 7,42-of 7.23 /m, 7H/, 6,90 per square JAB= 9,0 Hz, 4H/, 5,01 /C, 2H/. Elemental analysis for C21H17O4SB:

Calculated: C 67,04 H 4,55

Found: C 67,17 H 4,78

[3-/4-Benzyloxy/phenoxy] benzo[b] thiophene-2-Bronevoy acid is subjected to interaction with 4-/tert-butoxy/bromantan under the conditions previously described for [2-iodo-3-/4-benzyloxy/phenoxy] benzo[b] thiophene and 4-/tert-butoxy/phenylboronic acid, to obtain [2-/4-tert-butoxyphenyl/-3-/4-benzyloxy/phenoxy]benzo[b]thiophene with 81% yield.

In the following examples used in this way:

Example 7. [3-[4-[2-/1-Piperidinyl/ethoxy] -2-/phenyl/] benzo[b] difengidramin

< / BR>
So melting 223-226oC.1NMR /DMSO-d6/d: 7,99 /d, J = 8,2 Hz, 1H/, 7,71 /d, J = 7,3 Hz, 1H/, 7,44 - 7,30 /m, 7H/, 6,90 /s, 4H/, 4,27 /m, 2H/, of 3.46 - 3,35 /m, 4H/, 2,97 - 2,88 /m, 2H/, 1,73 - 1,61 /m, 5H/, 1,34 /m 1H/.

Elemental analysis for C27H27NO2S 1,0 HCl:

Calculated: C 69,59 H 6,06 N 3,00

Found: C 69,88 H 6,11 N 3,19

Example 8. [3-[4-[2-/1-Piperidinyl/ethoxy]phenoxy]-2-/4-forfinal/]benzo[b]thiophene

< / BR>
So melting 219-226oC.1H NMR /DMSO-d6/d: 10,20 /Shir, C. 1H/, 7,99 /d, J = 8,2 Hz, 1H/, to 7.77 - 7,73 /m, 4H/, 7,42 - 7,25 /m, 5H/, 6,90 /s, 4H/, 4,27 /m, 2H/, 3,44 - 3,31 B>H26NO2SF 1,0 HCl:

Calculated: C 67,00 H 5,62 N 2,89

Found: C 67,26 H 5,67 N 3,03

Example of getting 8. [6-Methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b] thiophene

< / BR>
To a solution of [6-methoxy-2-/4-methoxyphenyl/] benzo[b]thiophene /27,0 g, 100 mmol/ 1,10 l of chloroform at 60oC add bromine /15,98 g, 100 mmol/ added dropwise as a solution in 200 ml of chloroform. After complete addition, the reaction mixture is cooled to room temperature and the solvent is removed in vacuo to obtain a 34.2 g /100%/ [6-methoxy-2-/4-methoxyphenyl/-3-bromo] benzo[b]thiophene in the form of a solid white color. So melting point 83-85oC.

1H NMR /DMSO-d6/d: 7,70 - 7,62 /m, 4H/, 7,17 /DD, J = 8.6 Hz, 2.0 Hz, 1H/, 7,09 /d, J = 8,4 Hz, 2H/. The mass spectrum with a field desorption: 349.

Elemental analysis for C16H13O2SBr;

Calculated: C 55,03 H 3,75

Found: C 54,79 H 3,76

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

< / BR>
To a solution of [6-methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene /34,00 g, 97,4 mmole/ 60 ml collidine in nitrogen atmosphere add 4-benzyloxyphenol /38,96 g, 194,8 mmole/ and copper oxide /14.5 g, 97,4 mmole/. The resulting mixture is heated to boiling point under reflux for 48 hours. Post by filtration. The obtained filtrate was concentrated in vacuo and the resulting residue is dissolved in 500 ml of methylene chloride. Methylenchloride the solution is washed 3 N. hydrochloric acid /h ml/, then 1H. sodium hydroxide /h ml/. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is placed in 100 ml of ethyl acetate, after which the formed white solid, which was collected by filtration. Selected [6-methoxy-2-/4-methoxyphenyl/]benzo[b]thiophene /to 4.62 g, 17.11 per bbl mmole/. The obtained filtrate was concentrated in vacuo, then passed through a thin layer of silica gel/ eluent methylene chloride/ removal of the base material. The obtained filtrate was concentrated in vacuo, and the residue is crystallized from a mixture of hexane/ethyl acetate to obtain first 7,19 g of [6-methoxy-2-/4-methoxyphenyl/-3-/4-benzyloxy/phenoxy] benzo[b] thiophene in the form of off-white crystalline solid. The mother liquor is concentrated and process chromatography on silica gel /hexane/ethyl acetate 80:20 to more of 1.81 g of the product. The total yield [6-methoxy-2-/4-methoxyphenyl/-3-/4-benzyloxy/phenoxy]benzo[b]thiophene is 9.00 g /24% (based on the selected source material/. The basic extract is acidified to pH 4 by 5 N. hydrochloric kislevite 100-103oC. 2H NMR /CDCl3/: d: 7,60 /d, J = 08,0 Hz, 2H/, 7,39 - 7,24 /m, 7H/, 6,90 - 6,85 /m, 7H/, 4,98 /C, 2H/, 3,86 /3H/, 3,81 /3H/. The mass spectrum with a field desorption: 468.

Elemental analysis for C29H24O4S:

Calculated: C 74,34 H 5,16.

Found: C 74,64 H of 5.29,

Example of getting a 9. [6-Methoxy-2-/4-methoxyphenyl/-3-/4-hydroxy/phenoxy] benzo[b]thiophene

< / BR>
To a solution of [6-methoxy-2-/4-methoxyphenyl/-3-/4-benzyloxy/phenoxy] benzo[b] thiophene /1.50 g, 3,20 mmole/ 50 ml ethyl acetate and 10 ml of 1% concentrated hydrochloric acid in ethanol is added 10% palladium on coal /300 mg/. The resulting mixture hydronaut at 40 psi /2,81 kg/cm3/ in for 20 minutes, after which according to thin-layer chromatography of the reaction is terminated. The resulting mixture was passed through Celite to remove the catalyst, and the obtained filtrate was concentrated in vacuo to obtain a solid white color. The crude product is passed through a layer of silica gel /as eluent using chloroform/. After concentrating obtain 1.10 g /91%/. [6-methoxy-2-/4-methoxyphenyl/-3-/4-hydroxy/phenoxy] benzo[b] thiophene in the form of a solid white color. So melting 123-126oC. 1H NMR /DMSO-d6/d: 9,10 /C, 1H/, to 7.59 /d, J = 8,8 Hz, 2H/, 7,52 /d, J = 2.1 Hz, 1H/, 7,14 /d, J = 8,8 Hz, 1H/, what rbla: 378. Elemental analysis for C22H18O4S:

Calculated: C 69,82 H 4,79

Found: C 70,06 H to 4.98

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

< / BR>
To a solution of [6-methoxy-2-/4-methoxyphenyl/-3-/4-hydroxy/phenoxy]benzo[b] thiophene /1.12 g, 2.97 mmole/ in 7 ml of anhydrous N,N-dimethylformamide in a nitrogen atmosphere add cesium carbonate /3,86 g, 11,88 mmole/. After stirring for 10 minutes add 2-chloroethylnitrosourea /1.10 g, 1.48 mmole/. The resulting mixture is stirred for 18 hours at room temperature. The reaction mixture is divided between chloroform and water /100 ml each/. The aqueous layer was extracted with chloroform /h ml/. The organic layers are combined and washed with water /h ml/. After drying the organic portion over sodium sulfate and concentrating receive oil, which chromatographic process on silica gel /2% methanol/ chloroform/. The target fractions are concentrated to an oil, which was dissolved in 10 ml of ethyl acetate is treated with oxalic acid /311 mg, 3.4 mmole/. After stirring for 10 minutes a white precipitate is formed, which is collected by filtration and dried to obtain 1,17 g /70%/ total [6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy the /DMSO-d6/d: 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, 1H/, 6,87 /s, 4H/, 4,19 /Shir.T., 2H/, 3,78 /C, 2H/, 3,72 /3H/, 3,32 /Shir. so, 2H/, 3,12 - 3,06 /m, 4H/, 1,69 - 1,47 /m, 4H/, 1,44 - 1,38 /m, 2H/. The mass spectrum with a field desorption: 489.

Elemental analysis for C29H31NO4S 0,88 HO2CO2H:

Calculated: C 64,95 H 5,80 N 2,46

Found: C 64,92 H 5,77 N 2,54

Example 11. Treatment of the free base with ethyl ether hydrochloric acid leads to the production of [6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy]-phenoxy] -2-/4-methoxyphenyl/]benzo [b]difengidramin

< / BR>
So melting 216 - 220oC.1H NMR (DMSO-d6/d: 10,20 /Shir.S., 1H/, of 7.64 /d, J = 8.7 Hz, 2H/, to 7.59 /d, J = 1.5 Hz, 1H/, 7,18 /d, J = 9.0 Hz, 1H/, 7,00 /d, J = 8.7 Hz, 1H/, of 6.96 /DD, J = 9,0, 1.5 Hz, 1H/, 6,92 /sq JAB= 9,0 Hz, 4H/, or 4.31 /m, 2H/, 3,83 /3H/, of 3.77 /3H/, 3,43 /m, 4H/, 2,97 /m, 2H/, 1,7 /m, 5H/, 1,37 /m 1H/. The mass spectrum with a field desorption: 489. Elemental analysis for C29H31NO4S 1,0 HCl

Calculated: C 66,21 H 6,13 N 2,66

Found: C 66,46 H 6,16 N 2,74

In a similar way we obtain compounds of the following examples:

Example 12. [6-Methoxy-3-[4-[2-/1-pyrrolidinyl/ethoxy]phenoxy]-2-/1-methoxyphenyl/]benzo [b]thiophene

< / BR>
So melting 95-98oC.1H NMR /DMSO-d6/d: to 7.64 /d, J = 9.0 Hz, 2H/, 7,58 /d, J = 2.0 Hz, 1H/, 7,18 /d, J = 9,0/m, 4H/. The mass spectrum with a field desorption: 477.

Elemental analysis for C28H29NO4S:

Calculated: C 70,71 H X 6.15 N 2,99.

Found: C 70,59 H X 6.15 N 3,01.

Example 13. [6-Methoxy-3-[4-[2-/1-hexamethyleneimino/ethoxy]phenoxy]-2-/4-methoxyphenyl/] benzo[b]difengidramin

< / BR>
So melting 189 - 192oC.1H NMR /DMSO-d6/d: 10,55 /Shir. C., 1H/, of 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 /3H/, 3,76 /3H/, 2,80 /t, J = 6.0 Hz, 2H/, 2,66 /m, 4H/, 1,53 /m, 8H/. Elemental analysis for C30H33NO4S 1,0 HCl:

Calculated: C 66,71 H 6,35 N 2,59

Found: C 66,43 H 6,46 N 2,84

Example 14. [6-Methoxy-3-[4-[2-/1-N,N-diethylamino/ethoxy]phenoxy]-2-/4-methoxyphenyl/] benzo[b]difengidramin

< / BR>
So melting point 196-198oC.1H NMR /DMSO-d6/d: 10,48 /Shir. C., 1H/, of 7.64 /d, J = 9.0 Hz, 2H/, to 7.59 /d, J = 2.0 Hz, 1H/, 7,19 /d, J = 9.0 Hz, 1H/, 7,00 /d, J = 9.0 Hz, 2H/, 6,97 /DD, J = 9,0, 2.0 Hz, 1H/, 6,87 /sq JAB= 9,0 Hz, 4H/, of 4.25 (m, 2H/, 3,83 /3H/, of 3.77 /3H/, 3,09 /m, 4H/, 2,00 /m, 3H/, 1,88 /m, 3H/. Elemental analysis for C28H31NO4S 1,5 HCl:

Calculated: C 63,18 H x 6.15 N 2,63

Found: C 63,46 H 5,79 N 2,85

Example 15. [6-Methoxy-3[4-[2-/morpholine/ethoxy]phenoxy] -2-/4-methoxyphenyl/]-benzo[b]difengidramin

< / BR>
T. plale= 9,00 Hz, 2H/, 6,97 /DD, J of 9.0, 2.0 Hz, 1H/, 6,91 /sq, JAB=9,0 Hz, 4H/, 4,29 /m, 2H/, 4,08-3,91 /m, 4H/, 3,82 /3H/, of 3.77 /3H/, 3,59-3,42 /m, 4H/, 3,21-3,10 /m, 2H/. Elemental analysis for C28H29NO5S 1,0 HCl.

Calculated: C 63,09 H 5,73 N 2,65.

Found: C 63,39 H 5,80 N 2,40

Example 16. [6-Methoxy-3-[4-[3-piperidino/proteksi] -phenoxy]-2- /4-methoxyphenyl/]-benzo[b]difengidramin

< / BR>
T. melting 195 - 200oC.1H NMR /DMSO-d6/d: 9,90 Shire.S., 1H/, of 7.64 /e J = 9.0 Hz, 2H/, to 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 = 6,0 Hz, 2 H/ 3,83 /3H/, of 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 for C30H33NO4S 1,15 HCl:

Calculated: C 66,01 H 6,40 N 2,73

Found: C 66,01 H 6,40 N 2,73.

Example 17. [6-Methoxy-3-[4-/1-N,N-diethylamino/propoxy]phenoxy]- 2-/4-methoxyphenyl/]benzo[b]difengidramin

< / BR>
T. melting at 164 - 166oC.1H NMR /DMSO-d6/ d: 9,77 /Shir.S., 1H/, of 7.64 /d, J = 9.0 Hz, 2H/, to 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 /3H/, of 3.77 /3H/, 3,15 /m, 6H, of 2.06 /m, 2H/, 1,20 /t, J = 7.0 Hz, 6H/. Elemental analysis for C29H33NO4S 1,0 HCl:

Calculated: C 65,96 Of 6.49 H N 2,65.

Found: C 66,25 H 6,64 N 2,84.

Example 18 [6 Hydroc the/ethoxy] phenoxy] -2-/4-methoxyphenyl/] benzo[b] difengidramin /10,00 g, 19,05 mmole/ dissolved in 500 ml of anhydrous methylene chloride and cooled to 8oC. To this solution add trichromacy Bor /7,20 ml, 76,20 mmole/. The resulting mixture was stirred at 8oC for 2.5 hours. The reaction is quenched, pouring in a mixed solution of saturated sodium bicarbonate /1 l/ cooled to 0oC. Allocate methylenchloride layer, and the remaining solid portion was dissolved in a mixture of methanol/ethyl acetate. The aqueous layer was then extracted with a mixture of 5% methanol/ethyl acetate /3 x 500 ml/. All organic extracts /an ethyl acetate and methylenchloride/ combined and dried over sodium sulfate. After concentration in vacuo receives a yellow-brown todae substance, which process chromatographic /silica, 1 to 7% methanol/chloroform to obtain 7,13 g /81%/ [6-hydroxy-3-[4- [2-[1-piperidyl/ethoxy]phenoxy]-2-/4-hydroxyphenyl/]benzo[b]thiophene in the form of a solid white color. T. melting in a solid white color. T. melting 93oC.1H NMR /DMSO-d6/ d: 9,73 /Shir.S., 1H/, 7,45 /d, J = 8.5 Hz, 2H/, 7,21 /d, J = 1.8 Hz, 1H/,? 7.04 baby mortality /d, J 8.6 Hz, 1H/, 6,84 /DD, J = 8,6, 1.8 Hz, 1H/ masked//, for 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/, the Mass spectrum with a field desorption: 462.


< / BR>
T. melting 246 - 249oC /s decomposition/.1H NMR /DMSO-d6/ d: 7,45 /d, J = 8.6 Hz, 2H/, 7,22 /d, J = 1.8 Hz, 1H/, 7,05 /d, J = 8.6 Hz, 1H/, 6,87 /DD, J = 8.6 Hz, 1.8 Hz, 1H /masked//, 6,84 S., 4H/, 6,75 /d, J = 8.6 Hz, 2H/, 4,08 /Shir. so, 2H/, 3,01 Shire. so, 2H/, 2,79 /m, 4H/, 1,56 /m, 4H/, 1,40 /m, 2H/. The mass spectrum with a field desorption: 462.

Elemental analysis for C27H27NO4S 0,75 HO2CO2H:

Calculated: C 64,63 H 5,42 N 2,64.

Found: C 64,61 H 5,55 N 2,62.

Example 20. [6-Hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/4-hydroxyphenyl/] benzo[b] thiophene converted into its hydrochloride with 91% of outputs, treating the free base with ethyl acetate ethyl ether, hydrochloric acid. Data for [6-hydroxy-3-/4-[2-/1-piperidinyl/ethoxy]- phenoxy]-2-/4-hydroxyphenyl/]benzo[b]difengidramin:

< / BR>
T. pl. 158 - 165oC.1H NMR /DMSO-d6/ d: 9.97 /C, 1H/, 9,74 /c, 1H/, 7,40 /d, J = 8.6 Hz, 2H/, of 7.23 /d, J = 2.0 Hz, 1H/,? 7.04 baby mortality /d, J = 8.6 Hz, 1H/, 6,86 /sq JAB= 9,3 Hz, 4H/, 6,76 /DD, J = 8,6, 2.0 Hz, 1H/, 6,74 /d, J = 8.6 Hz, 2H/, 4.26 deaths /Shir.T., 2H/, 3,37 /m, 4H/, 2,91 /m, 2H/, 1,72 /m, 5H/, 1,25 /m 1H/. The mass spectrum with a field desorption: 461.

Elemental analysis for C27H27NO4S 1,0 HCl:

Calculated: C 65,1

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

< / BR>
T. melting 99 - 113oC. 1H NMR /DMCO-d6/ d: 9,75 /C, 1H/, 9,71 /C, 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 /C, 1H/, 6,80 /DD, J = 9,0, 2.0 Hz, 1H/, 6,79 /d, J = 9.0 Hz, 2H/, 3,93 /m, 2H/, 2,73 /m, 2H/, 2,53 /m, 4H/, 0,96 /t, J = 7,0 Hz, 4H/.

Elemental analysis for C26H25NO4S 0,5 H2O

Calculated: 68,40 H 5,74 N 3,07

Found: C 68,52 H 6,00 N 3,34

Example 22. [6-Hydroxy-3-[4-[2-/1-hexamethyleneimino/ethoxy] phenoxy]-2-/4-hydroxyphenyl/]benzo[b]thiophene

< / BR>
T. melting point 125 - 130oC.1H NMR /DMCO-d6/ d: 9,75 /C, 1H/, 9,71 /C, 1H/, 7,50 /d, J = 9.0 Hz, 2H/, 7,26 /d, J = 2.0 Hz, 1H/, 7,09 /d, J = 9.0 Hz, 1H/, 6,85 /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/. Elemental analysis for C28H29NO4:

Calculated: C 70,71 H x 6.15 N 2,94

Found: C 70,67 of 6.31 H N 2,93

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

< / BR>
T. melting 137 - 141oC. 1H NMR /DMSO-d6/ d: 9,75 /C, 1H/, 9,71 /C, 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 /so J = 6.0 Hz, 2H/, 2,74 /t, J = 6.0 Hz, 2H/, of 2.51 /m, 4H/, 1,66 /m, 6H/. Elemental analysis for C
< / BR>
T. melting 157 - 162oC.1H NMR /DMSO-d6/ d: or 10.60 /Shir. C., 1H/, 9,80 /C, 1H/, 9,75 /C, 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 /sq JAB= 9,0 Hz, 4H/, for 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 per m, 2H/, 3,51 /m, 4H/, 3,18 /m, 2H/. Elemental analysis for C26H25NO5S HCl

Calculated: C 62,46 H a 5.25 N 2,80

Found: C 69,69 H 5,43 N 2,92

Example 25. [6-Hydroxy-3-[4-[3-/1-N,N-diethylamino/propoxy] phenoxy]-2-/4-hydroxyphenyl/]benzo[b]difengidramin

< / BR>
So melting 185-191oC.1H NMR /DMSO-d6/ d 9,94 /Shir.S., 1H/, 9,81 /C, 1H/, 9,75 /C, 1H/, 7,50 /d, J = 9.0 Hz, 2H/, 7,27 /DD, J = 2.0 Hz, 1H/, 7,10 /d, J = 9.0 Hz, 1H/, 6,87 /s, 4H/, 6,80 /DD, J = 9,0 2,0 Hz, 1H/, 6,79 /d, J = 9.0 Hz, 2H/, 3,99 /t, J = 6.0 Hz, 2H/, 3,14 /m, 6H/, 2,08 /m, 2H/, 1,20 /t, J = 6.0 Hz, 6H/. Elemental analysis for C27H29NO4S 1,3 HCl

Calculated: C 63,46 H 5,98 N 2,74

Found: C 63,23 H 6,03 N 3,14

Example 26. [6-Hydroxy-3-[4-[2-/1-N,N-diethylamino/ethoxy] phenoxy]-2-/4-hydroxyphenyl/]benzo[b]difengidramin

< / BR>
So melting 128-131oC.1H NMR /DMSO-d6/d: 9,81 /Shir. C., 1H/, 9,76 /C, 1H/, 9,02 /C, 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/. Elemental analysis for C28H31NO4S 1,33 HCl:
< / BR>
So melting 258-262oC.1H NMR /DMSO-d6/ d: 9,85 /Shir. C., 1H/, 9,81 /C, 1H/, 9,75 /C, 1H/, 7,50 /d, J = 9.0 Hz, 2H/, 7,27 /d, J = 2.0 Hz, 1H/, 7,10 /d, J = 9.0 Hz, 1H/, 6,87/s, 4H/, 6,80 /DD, J = 9,0, 2.0 Hz, 1H/, 6,79 /d, J = 9.0 Hz, 2H/, 3,97 /t, J = 6.0 Hz, 2H/, 3,44 /m, 2H/, 3,15 /m, 2H/, 2,88 /m, 2H/, 2,11 /m, 2H/, 1,73 /m, 5H/, 1,39 /m 1H/.

Elemental analysis for C28H29NO4S 0,75 HCl:

Calculated: C 66,87 H 5,96 N 2,78

Found: C 67,04 H 5,90 N 2,68

In another embodiment, as shown in scheme III, compound of example 19, receive, using ethoxymethylene /IOM/ protective groups instead of methoxy. How exactly similar to the one used previously, except that the PTO group is removed at the final stage of acid hydrolysis.

Example 10. [6-Methoxy-2-/4-methoxyethoxymethyl/-3-/4-benzyloxy/phenoxy] benzo[b]thiophene

< / BR>
So melting 94-96oC1H NMR /DMSO-d6/ d: 7,65 /d, J = 2.0 Hz, 1H/, of 7.64 /d, J = 8.6 Hz, 2H/, 7,43-7,32 /m, 5H/, of 7.23 /d, J = 8,8 Hz, 1H/, 7,08 /d, J = 8.6 Hz, 2H/,? 7.04 baby mortality /DD, J = 8,8, 2.0 Hz, 1H/, 6,92 /sq JAB= 9,2 Hz, 4H/, 5,26 /C, 2H/, to 5.21 /C, 2H/, 5,01 /3H/, 3,40 /3H//, 3,37 /3H/. The mass spectrum with a field desorption: 528

Example of getting 11. [6-Methoxy-2-/4-methoxyethoxymethyl/-3-/4-hydroxy/phenoxy] benzo[b]thiophene

< / BR>
So melting 90 - 91oC.1H NMR /DMSO-d6/d: 9,15 /C, 1H/, 7,65 /40 /s, 3H/, 3,37 /3H/. The mass spectrum with a field desorption: 438.

Elemental analysis for C24H22O6S: C 65,74 H 5,06

Found: C 65,50 H 4,99

Example 28. [6-Methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S oxide

< / BR>
To a solution of [6-Methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene /10.0 g, 28.6 mmole/ in 50 ml of anhydrous methylene chloride are added 50 ml triperoxonane acid. After stirring for 5 minutes add the hydrogen peroxide /4,0 ml, 28.6 mmole, 30% aqueous solution. The resulting mixture was stirred at room temperature for 2 hours. The dark solution was added solid sodium bisulfite /1,25 g/, and then 15 ml of water. The resulting mixture was intensively stirred for 15 minutes, then concentrated in vacuo. The remainder is divided between chloroform and saturated sodium bicarbonate solution /200 ml each/. The organic layer is extracted with saturated sodium bicarbonate solution. Then the organic layer is dried over sodium sulfate and concentrated in vacuo to obtain a solid product, which was triturated with ethyl ether/ethyl acetate. After filtration gain of 8.2 g /80%/ [6-methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/ in a solid yellow color, which MOC, 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 /3H/, 3,80 /3H/.

Elemental analysis for C16H13O3SBr:

Calculated: C 52,62 H 3,59

Found: C 52,40 H 3,55

Example 29. In a similar way we obtain [2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S oxide/

< / BR>
So melting 120-125oC.1H NMR /DMSO-d6/d: 8,06 /d, J = 7,6 Hz, 1H/, 7,78 - to 7.59 /m, 5H/, 7,13 /d, J = 8.7 Hz, 2H/, 3,81 /3H/. The mass spectrum with a field desorption: 335. Elemental analysis for C15H11O2SBr:

Calculated: C 53,75 H 3,31.

Found: C 53,71 H of 3.46

Example 12. Getting 4-[2-/1-piperidinyl/ethoxy]phenol

< / BR>
To a solution of 4-benzyloxyphenol /50,50 g of 0.25 mol/ 350 ml anhydrous DMF is added 2-chlorethylene /46,30 g of 0.25 mol/. After ten minutes of stirring the potassium carbonate /52,0 g 0,375 mol/ and cesium carbonate /85,0 of 0.25 mol/. The obtained heterogeneous mixture is intensively stirred at room temperature for 48 hours. Then the reaction mixture is poured into 500 ml of water and extracted with methylene chloride. Then the organic part is extracted several times with 1H. sodium hydroxide, and finally washed with brine. Then the organic layer is dried over sodium sulfate and concentrate the g/77%/ 4-/2-/1-piperidinyl/-etoxy/phenoxybenzyl ether as a colourless oil.

1H NMR /DMSO-d6/d: 7,40 - 7,27 /m, 5H/, 6,84 /sq JAB= 11.5 Hz, 4H/, 4,98 /C, 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/. The mass spectrum with a field desorption: 311. Elemental analysis for C20H25NO2:

Calculated: C 77,14 H 98,0 N 4,50.

Found: C 77,34 H 8,18 N WITH 4.64

4-[2-/1-piperidinyl/ethoxy] phenoxybenzyl ether /21,40 g, 68,81 mol/ dissolved in 200 ml 1:1 EtOH:EtOAc containing 1% conc. HCl. This solution is transferred into a Parr flask and added 3.4 g of 5% palladium-on-charcoal grill. The resulting mixture hydronaut at a pressure of 40 psi /2,81 kg/cm2/, for 2 hours, and then passed through a layer of Celite to remove the catalyst. The obtained filtrate was concentrated in vacuo to obtain a solid substance, which is then suspended in ethyl ether, and filtered to obtain 12,10 g/83%/ 4-[2-/1-piperidinyl/ethoxy] phenol. So melting 148 - 150oC.1H NMR /DMSO-d6/d: 8,40 /C, 1H/, 6,70 /sq JAB= 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/. The mass spectrum with a field desorption: 221. Elemental analysis for C13H19NO2.

Calculated: C 70,56 H 8,09 N 4,50

Found: C 70,75 H 8,59 N 6,54.

Example 30. [6-Methoxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2- /4-methoxyphenyl/]-benzo[b]thiophene/S-the temperature is added sodium hydride /0,57 g, of 1.43 mmole, 60% dispersion in mineral oil/. After stirring for 15 minutes [6-methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene/S-oxide/ /0,50 g of 1.37 mmole/ add in small portions. After stirring for 1 hour, on the completion of the reaction is judged according to TLC. The solvent is removed in vacuum and the residue is divided between water and 10% ethanol/ethyl acetate. The organic portion is washed several times with water and then dried over sodium sulfate. After concentration in vacuo receive oil, which is triturated in ethyl acetate/hexane until receipt of 0.62 g /89%/ [6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2- /4-methoxyphenyl/]-benzo[b] thiophene/S-oxide/ form solid of light yellow color. So melting 97 - 100oC. 1H NMR /DMSO-d6/d: 7,68 /d, J = 2.1 Hz, 1H/, 7,62 /d, J = 8,8 Hz, 2H/, 7,06 - 6,92 /m, 6H/, 6,85 /d, J = 8,8 Hz, 2H/, 3,94 /t, J = 6.0 Hz, 2H/, 3,81 /3H/,

3,72 /3H/, 2,56 /t, J = 6.0 Hz, 2H/, 2,39 - 2,32 /m, 4H/, 1,47 - 1,32 /m, 6H/. Elemental analysis for C29H31NO5S :

Calculated: C 68,89 H 6,18 N 2,77

Found: C 68,95 H 6,04 N TO 2.57

Example 31. In a similar way we obtain[3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/4-methoxyphenyl/] benzo[b]thiophene/S-oxide/

< / BR>
Oil.1H NMR /DMSO-d6/d : 8,03 /m 1H/, 7,65 /d, J = 8.7 Hz, 2H/, 7,53 - 7,50 /m, 2H/, 7,09 rbla: 475. Elemental analysis for C28H29NO4S : C 70,71 H X 6.15 N 2,94. Found: C 70,44 To 6.43 H N 3,20.

Example 32. [6-Methoxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2- /4-methoxyphenyl/]-benzo[b]difengidramin

< / BR>
To a solution of 6-methoxy-[3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/4-methoxyphenyl/] benzo[b]thiophene/S-oxide/ 30/ /3.00 g, 5,94 mmole/ in 200 ml of anhydrous SDOF in nitrogen atmosphere at 0oC add sociallyengaged /0.34 g 8,91 mmole/ small portions. After ten minutes of stirring the reaction quenched carefully by adding 5.0 ml of 2.0 n sodium hydroxide. The resulting mixture was intensively stirred for 30 minutes and added dropwise addition of 2.0 n sodium hydroxide to dissolve the salts. Then the resulting mixture was partitioned between water and 10% sodium hydroxide. The layers are separated and the aqueous extracted several times with 10% ethanol/ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to an oil. The crude product is dissolved in 50 ml 1:1 ethyl acetate/ethyl ether and treated with excess ethylethylenediamine. The precipitate is collected and dried to obtain 2,98 /96%/ [6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2- /4-methoxyphenyl/] -benzo[b]difengidramin in the form of a white solid.


< / BR>
To a solution of 6-methoxybenzo[b] thiophene /18,13 g, 0,111 mol/ 150 ml anhydrous tetrahydrofuran at -60oC add n-utility /76,2 ml, 0,122 mol, 1.6 M solution in hexano/ dropwise via syringe. After stirring for 30 minutes via a syringe injected triisopropylsilyl /28,2 ml, 0,122 mol/. The resulting mixture was left to slowly warm to 0oC, and then share between 1 N. hydrochloric acid and ethyl acetate /300 ml each/. The organic layer is dried over sodium sulfate. After concentration in vacuo get a solid white product, which was triturated with ethyl ether/hexane. After filtration gain of 16.4 g /71%/ 6 methoxybenzo[b] thiophene-2-Bronevoy acid in a solid white color. So melting 200oC /decomposition/.

1H NMR /DMSO-d6/d: 7,83 /c, 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 /3H/. The mass spectrum with a field desorption: 208.

Example of getting a 14. [6-Methoxy-2-/4-methysulfonylmethane/]benzo[b] thiophene

< / BR>
To a solution of 6-methoxybenzo[b] thiophene-2-Bronevoy acid /3.00 g, 14.4 mmole/ 100 ml of toluene added 4-/methansulfonate/phenylboronic/ 3,98 g, 15.8 mmole/ and then 16 ml of the s /0,60 g, of 0.52 mol/ and the resulting mixture is heated to boiling under reflux for 5 hours. Then the reaction mixture is allowed to cool to room temperature, whereupon the product precipitates from the organic phase. The aqueous phase was removed and the organic layer was concentrated in vacuo to obtain a solid product. After a thorough trituration in ethyl ether to obtain a solid product, which is filtered off and dried in vacuo to obtain 3,70 g /77%/ [6-methoxy-2-/4-methysulfonylmethane/] benzo[b] thiophene in the form of product yellow-brown color. So melting 197 -201oC. 1H NMR /DMSO-d6/d: 7,81-to 7.77 /m, 3H/, 7,71 /d, J = 8,8 Hz, 1H/, 7,54 /d, J = 2.3 Hz, 1H/, 7,40 /d, J = 8.7 Hz, 2H/, 6,98 /DD, J = 8,7, 1.5 Hz, 1H/, 3,80 /3H/, 3,39 /3H/. The mass spectrum with a field desorption: 334. Elemental analysis for C16H14O4S2:

Calculated: C 57,46 H 4,21

Found: C 57,76 H 4,21.

Example of receipt 15. Analogously to example getting 14 receive [6-Methoxy-2-/4-benzyloxyphenyl/]benzo[b]thiophene

< / BR>
The yield was 73%. So melting 217 - 221oC.1H NMR /DMSO-d/ d: 7,63 - 7,60 /m, 3H/, to 7.59 - 7,26 /m, 7H/, 7,02 /d, J = 8.7 Hz, 2H/, of 6.96 /DD, J = 8,8, 2.2 Hz, 1H/, 5,11 /C, 2H/, 3,88 /3H/. The mass spectrum with a field desorption: 346. Elemental analysis for C22H18O2S:

Calculated: C 76,27 the Hairdryer

< / BR>
To a solution of [6-methoxy-2-/4-methysulfonylmethane/]benzo[b]thiophene /9,50 g, 28,40 mmole/ in anhydrous methylene chloride /200 ml at room temperature in a nitrogen atmosphere add trichromacy Bor /14,40 g, are 5.36 ml, 56,8 mmole/. The resulting mixture was stirred at room temperature for 3 hours. The reaction is quenched slowly pouring the reaction mixture into an excess of ice water. After thirty minutes of intense mixing white precipitate is collected by filtration, washed several times with water and then dried in vacuum to obtain 8,92 /98%/ [6-hydroxy-2-/4-methysulfonylmethane/]benzo[b]thiophene in the form of a solid white color. So melting 239 - 243oC.

1H NMR /DMSO-d6/d: 9,70 /C, 1H/, 7,76 /d, J = 8.7 Hz, 2H/, 7,72 /C, 1H/, 7,62 /d, J = 8,7, 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 /3H/. The mass spectrum with a field desorption 320. Elemental analysis for C15H12O4S2:

Calculated: C 56,23 H of 3.77

Found: C 56,49 H 3,68

Example of receipt 17. [6-Benzyloxy-2-/4-methysulfonylmethane/]benzo[b]thiophene

< / BR>
To a solution of [6-hydroxy-2-/4-methysulfonylmethane/] benzo[b] thiophene /3,20 g, 10.0 mmole/ 75 ml anhydrous DMF add C2CO3/5.75 g of 17.7 mmole/ and then benzylchloride is, the solid residue is suspended in 200 ml of water. A white precipitate is collected by filtration and washed several times with water. After drying in vacuum the crude product is suspended in a mixture of 1:1 hexane:ethyl ether. The hard part is collected to obtain and 3.72 g /91%/ [6-benzyloxy-2-/4-methysulfonylmethane/] benzo[b] thiophene in the form of a solid white color. So melting 198 - 202oC.1H NMR /DMSO-d6/d: 7,81 - 7,78 /m, 3H/, 7,72 /d, J = 8.7 Hz, 1H/, of 7.64 /d, J = 2.2 Hz, 1H/, 7,47 - 7,30 /m, 7H/, 5,15 /C, 2H/, 3,39 /3H/. The mass spectrum with a field desorption: 410.

Example obtain 18. [6-Benzyloxy-2-/4-hydroxyphenyl/]benzo[b]thiophene

< / BR>
To a solution of [6-benzyloxy-2-/4-methysulfonylmethane/]benzo[b]thiophene /12,50 g, 30,50 mmole/ in 300 ml of anhydrous THF under nitrogen atmosphere at room temperature add sociallyengaged /2,32 g, 61,0 mmole /small portions. Then the resulting mixture was stirred at room temperature for 3 hours and then quenched carefully pouring into an excess of cold 1.0 and hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The organic portion is washed several times with water and then dried over sodium sulfate and concentrated in vacuo to obtain a solid substance. After chromatographic processing /dioxide logo color. So melting 212 - 216oC.1H NMR /DMSO-d6/d: 9,70 /C, 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 /C, 2H/. The mass spectrum with a field desorption 331. Elemental analysis for C21H16O2S:

Calculated: C 75,88 H 4,85

Found: C 75,64 H 4,85.

Example obtain 19. [6-benzyloxy-2-/4-methoxyphenyl/]benzo[b]thiophene

< / BR>
To a solution of [6-benzyloxy-2-/4-hydroxyphenyl/] benzo[b]thiophene /8,50 g, 26,40 mmole/ in 200 ml of anhydrous DMF under nitrogen atmosphere at room temperature is added sodium hydride /1.66 g, 41.5 mmole/ small portions. After the evolution of gas ceases, was added dropwise iodomethane /of 3.25 ml, 52,18 mmole/. The reaction mixture is stirred for 3 hours at room temperature. Then the solvent is removed in vacuum and the residue is divided between water and ethyl acetate. The organic phase is washed several times with water. Then the organic portion is dried over sodium sulfate and concentrated in vacuo to obtain 9.00 g /98%/ [6-benzyloxy-2-/4-methoxyphenyl/]benzo[b]thiophene in the form of a solid white color tones of melting point 180 - 185oC. 1H NMR /DMSO-d6/d: to 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 /C, 2H/, 3,76 /3H/. The mass spectrum of the paragraph is Found: C 76,54 H 5,43.

An example of obtaining 20. [6-Benzyloxy-2-/4-methoxyphenyl/]-3-bromo]benzo[b] thiophene

< / BR>
[6-Benzyloxy-2-/4-methoxyphenyl/] benzo[b] thiophene /10.0 g, of 28.9 mmole/ placed in 200 ml of chloroform with 10.0 g of solid sodium bicarbonate at room temperature. To this suspension is added bromine /1,50 ml of 29.1 mmole/ dropwise over 30 minutes in the form of a solution in 100 ml of chloroform. When you are finished adding, add 200 ml water and the layers separated. The organic phase is dried over sodium sulfate and concentrated in vacuo to obtain a solid white color. After crystallization from a mixture of methylene chloride/methanol receive 10,50 g /84%/ [6-benzyloxy-2-/4-methoxyphenyl/]-3-bromo]benzo[b]thiophene in the form of a solid white color. So melting 146 - 150oC. 1H NMR /DMSO-d6/d: 7,70 /d, J = 2.2 Hz, 1H/, 7,65 - 7,60 /m, 3H/, 7,47 - 7,30 /m, 5H/, 7,19 /DD, J = 8,8, 2.2 Hz, 1H/, 7,06 /d, J = 8.7 Hz, 2H/, 5,17 /C, 2H/, 3,78 /3H/. The mass spectrum with a field desorption: 346.

Elemental analysis for C22H17O2SBr:

Calculated: C 62,13 H Is 4.03.

Found: C 61,87 H 4,00

Example of getting a 21. In a similar way we obtain [6-methoxy-2-/4-benzisoxazol/]-3-bromo]benzo[b]thiophene

< / BR>
Yield 91%. So melting 125 - 127oC.1H NMR /DMSO-d6/d: to 7.64 - to 7.61 /m, 4H/, 7,46-7,31 /m, 5H/, 7,15-7,09 / O2SBr:

Calculated: C 62,13 H 4,03

Found: C 62,33 H 3,93.

Similar to the method of example 28 to obtain the compounds of examples 33 and 34.

Example 33. [6-Benzyloxy-2-/4-methoxyphenyl/]-3-bromo]benzo[b]thiophene-/S-oxide/

< / BR>
Isolated in a solid yellow color due to crystallization from ethyl acetate. So melting 202 - 205oC.1H NMR /DMSO-d6/d: 7,80 /d, J = 2.2 Hz, 1H/, 7,68 /d, J = 8.7 Hz, 2H/, 7,55 /d, J = 8,4 Hz, 1H/, 7,47 - 7,32 /m, 6H/, 7,10 /d, J = 8.7 Hz, 2H/, 5,23 /C, 2H/, 3,80 /3H/. The mass spectrum of the salt desorption: 441. Elemental analysis for C22H17O3SBr,

Calculated: C 59,87 H 3,88.

Found: C 59,59 H Of 3.78.

Example 34. [6-Methoxy-2-/4-benzyloxyphenyl/]-3-bromo]benzo[b]thiophene-/S-oxide/

< / BR>
Isolated in a solid yellow color due to chromatographic treatment /silicon dioxide, CHCl3/. So melting 119-123oC1H NMR /DMSO-d6/d: 7,73 /d, J= 2.2 Hz, 1H/, 7,68 /d, J=8,8 Hz, 2H/, 7,55 /d, J=8.5 Hz, 1H/, 7,46 - 7,31 /m, 5H/, 7,26 /DD, J = 8,5, 2.2 Hz, 1H/, 7,18 /d, J= 8,8 Hz, 2H/, 5,16 /C, 2H/, 3,86 /3H/. The mass spectrum with a field desorption: 441. Elemental analysis for C22H17O3SBr:

Calculated: C 59,87 H 3,88.

Found: C 60,13 H 4,10.

Similar to the method of example 30 get connection examples 35-36.

A yellow oil.1H NMR /DMSO-d6/d: 7,76 /d, J = 2.2 Hz, 1H/, 7,62 /d, J= 8,8 Hz, 2H/, 7,44-7,30 /m, 5H/, 7,12 /DD, J = 8,6, 2.2 Hz, 1H/, 7,03-6,93 /m, 5H/, 6,85 /d, J = 8,8 Hz, 2H/, 5,18 /C, 2H/, 3,94 /Shir.T., J = 5.8 Hz, 2H/, to 3.73 /3H/, 2,56 /Shir.T. J = 5.8 Hz, 2H/, 2,37 - 2,34 /m 4H/, 2,37-2,34 /m, 4H/, 1,45 - 1,32 /m, 6H/. The mass spectrum with a field desorption: 592. Elementary analysis for C35H35NO5S:

Calculated: C 72,26 H 6,06 N, 2,41.

Found: C 72,19 H 5,99 N 2,11

Example 36. [6-Methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2- /4-benzyloxyphenyl/]benzo[b]thiophene-/S-oxide/

< / BR>
Solid yellow color. So melting 89-93oC.1H NMR /DMSO-d6d: 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 /C, 2H/, 3,94 /Shir.t, J = 5.8 Hz, 2H/, 3,81 /3H/, 2,56 /Shir., J = 5.8 Hz, 2H/, 2,37-2,34 /m, 4H/, 1,45 - 1,31 /m, 6H/. The mass spectrum with a field desorption 592. Elemental analysis for C35H35NO5S. of 0.25 EtOAc:

Calculated: C 71,62 H 6,18 N, 2,32.

Found: C 71,32 H 5,96 N 2,71

similar to the method of example 11 receive connection examples 37-38.

Example 37. [6-Benzyloxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/methoxyphenyl/] benzo[b]thiophene

< / BR>
Highlighted with 95% yield based on [6-benzyloxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene-/S-oxide/. After chromatographic purification /silica, 1-5% methanol/PI = 2.2 Hz, 1H/, to 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 /C, 2H/, 3,92 /Shir.T. K, J = 5.8 Hz, 2H/, 3,72 /3H/, 2,55 /Shir.T. J = 5.8 Hz, 2H/, 2,37-2,34 /m, 4H/, 1,44 - 1,31 /m, 4H/. The mass spectrum with a field desorption 565. Elemental analysis for C35H35NO4S:

Raschitano: C 74,31 H 6,24 N, 2,48.

Found: C 74,35 H 6,07 N Was 2.76.

Example 38. [6-Methoxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2- /4-benzyloxyphenyl/]benzo[b]thiophene

< / BR>
Yield 91%. So melting 106-110oC. 1H-NMR /DMSO-d6/d: to 7.59 /d, J = 8,8 Hz, 2H/, 7,54 /d, J = 2.2 Hz, 1H/, 7,42-7,28 /m, 5H/, 7,13 /d, J = 8,8 Hz, 1H/, 7,03 /d, J=8,8 Hz, 2H/, 6,82 /s, 4H/, 5,08 /C, 2H/, 3,92 /Shir.T. J = 5.8 Hz, 2H/, 3,78 /c, 3H/, 2,55 /Shir.T. J = 5.8 Hz, 2H/, 2,37 - 2,33 /m, 4H/, 1,44 - 1,31 /m, 4H/. The mass spectrum with a field desorption 565.

Elemental analysis for C35H35N)4S:

Calculated: C 74,31 H 6,24 N 2,48

Found: C sampled at 74.25 H 6,17 N 2,73

Example 39. [6-Hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2- /methoxyphenyl/]benzo[b]thiophene

< / BR>
To a solution of [6-benzyloxy-3-[4-[2-/1-piperidinyl/ethoxy] phenyl]-2- /4-methoxyphenyl/] benzo[b] thiophene /8,50 g, 15,0 mmole/ in 300 ml of a mixture of 5:1 ethanol/ethyl acetate added palladium black /1.50 g/ format ammonium /3.50 g, 55,6 mmole/ and 30 ml of water. The resulting mixture is heated to boiling under reflux and the reaction course is monitored with the temperature. The reaction mixture was filtered through a layer of Celite to remove catalyst and the filtrate was concentrated in vacuo to solids. This concentrate is shared between a saturated solution of sodium bicarbonate and 5% ethanol/ethyl acetate. The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product is treated with chromatographic /silica, 1-5% methanol/chloroform to obtain 6.50 g /91%/ [6-hydroxy-3-[4- [2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-methoxyphenyl/] benzo[b] - thiophene in the form of foam, which turns into solid connection after a thorough rubbing with hexane. So melting point 174-176oC1H NMR /DMSO-d6/d: 9,77 /C, 1H/, 7,56/, J = 8,8 Hz, 2H/, of 7.23 /d, J = 2.0 Hz, 1H/, 7,07 /d, J = 8.6 Hz, 1H/, 6,93 /d, J = 8,8 Hz, 2H/, for 6.81 /s, 4H/, 6,76 /DD, J = 8,7, 2.0 Hz, 1H/, 3,91 /Shir.T. J = 5,9 Hz, 2H/, 3,71 /3H/, 2,55 /Shir. so J = 5,9 Hz, 2H/, 2,38 - 2,33 /m, 4H/, 1,46 of 1.28 /m, 6H/. The mass spectrum with a field desorption 475.

Elemental analysis:

Calculated for C28H29NO4S: C 70,71 H X 6.15 N 2,94.

Found: C 70,46 H 5,93 N 2,71.

Example 40. Similar to the method of example 39 receive [6-methoxy-3-[4-[2-/1-piperidyl/ethoxy]phenoxy]-2-/4-hydroxyphenyl/] benzo[b]thiophene

< / BR>
Yield = 88%. So melting point 148-150oC.1H NMR /DMSO-d628H29NO4S:

C 70,71 H X 6.15 N 2,94

Found: C 71,00 H 6,17 N 2,94.

In another embodiment, the compounds of examples 39 and 40 can be obtained directly in the same way transterritorial with a 90% yield of [6-methoxy-3-[4-[2-/1-piperidyl/ethoxy]phenoxy]-2-2/4-benzyloxyphenyl/] benzo[b] thiophene-/S-oxide/ and [6-benzyloxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4 - methoxyphenyl/]benzo[b]-thiophene-/S-oxide/, respectively.

Example 41. [6-Hydroxy-3-[4-[2-/1-piperidyl/ethoxy]phenoxy]-2- /4-methoxyphenyl/] benzo[b] thiophene /example 39/ converted into hydrochloride with 85% yield by treatment of ethyl ether/hydrochloride in ethyl acetate followed by crystallization from ethanol/ethyl acetate.

< / BR>
So melting 156 to 160oC1H NMR /DMSO-d6/d: 10,28 /Shir.S., 1H/, 9,85 /C, 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 /kV, JAB= 9,3 Hz, 4H/, 4,27 /Shir., so, 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/. The mass spectrum with a field desorption: 475.

Elemental analysis for C28H29NO4S. 1,0 HCl

Calculated: C 65,68 H 5,90 N 2,73.
< / BR>
So melting 215 - 217oC.1H NMR /DMSO-d6/d: 10,28 /Shir.S., 1H/, 9,80 /C, 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 /Shir., so, J = 5.8 Hz, 2H/, 3,78 /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), Mass spectrum with a field desorption: 475.

Elemental analysis for Ct28H29NO4S1,0 HCl Calculated: C 65,68 H 5,90 N 2,73

Found: C 65,87 H 5,79 N 2,99.

Example 43. [6-Benzyloxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/4 - benzyloxyphenyl/]benzo[b]difengidramin

< / BR>
To a solution of example 20 /0.50 g, a 1.08 mmole/ in 20 ml of anhydrous tetrahydrofuran at 0oC add triethylamine /1,00 ml/. To this mixture add the benzoyl chloride /0,28 ml of 2.35 mmole/. After stirring for 2 hours at 0oC the reaction is quenched by distributing between ethyl acetate/ saturated sodium bicarbonate solution /100 ml each/. The layers are separated and the organics dried over sodium sulfate and concentrated in vacuo to a solid white color. The crude product is dissolved in 10 ml ethyl acetate and treated with ethyl ether hydrochloric acid. A white precipitate is formed, which is collected by filtration. After drying obtain 390 mg /50%/ [6-benzyloxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/4 - BAA/SUP>H NMR /DMSO-d6/d: 9,95 /Shir.s, 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/, of 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/.

Elemental analysis for C41H35NO6S 1,5 HCl:

Calculated C 67,97 H 5,08 N 1,93.

Found: C 68,05 H a 5.25 N 2,01

In the same way get:

Example 44. [6 Ethylsulfonyl-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4-metilsulfonilmetane/]benzo[b]difengidramin

< / BR>
Yield = 72%. So melting 110-115oC.1H NMR /DMSO-d6/d: 10,15 /Shir.S., 1H/, 8,15 /d, J = 2.0 Hz, 1H/, a 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/, or 4.31 /m, 2H/, 3,57 /m, 4H/, 3,44 /m, 4H/, 2,97 /m, 2H/, 1,76 /m, 5H/, 1,40 /m, 7H/. Elemental analysis for C31H35NO8S31,5 HCl

Calculated: C 54,57 H 5,32 N 2,05.

Found: C 54,36 Lower Than The 5.37 H N 2,05.

In a similar way, using triftormetilfullerenov anhydride get:

Example 45. [6-Methoxy-3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4 - triftoratsetilatsetonom/]benzo[b]thiophene

< / BR>
Yield = 81%. Oil.1H NMR /DMSO-d6/d: 7,82 /d, J = 8.7 Hz, 2H/, 7,60 /d, J = 2.0 Hz, 1H/, 7,54 /d, J = 8.7 Hz, 2H/, 7,17 /d, J = 8,8 Hz, 1H/, 6,93 /DD, J = 8,8, 2.0 Hz, 1H/, 6,84 /s, 4H/, 3,92 /Shir.T., J = 5.7 Hz, 2H/, 3,79 /3H/, 2,56 /Shir., so, J = 5.7 Hz, 2H/, 2,36 >
S2:

Calculated: C 57,32 H With 4.64 N 2,30.

Found: C 57,16 to 4.52 H N 2,01

Example 1 in a similar way get:

Example 46. [3-[4-[2-/1-Piperidinyl/ethoxy]phenoxy]-2-/4-benzyloxyphenyl/]benzo [b]difengidramin

< / BR>
Yield 85%. So melting 190-198oC.1H NMR /DMSO-d6/d: 10,48 /Shir.art., 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 /c, 2H/, 4,37 - 4,43 /m, 2H/, 3,0 - 3,05 /m, 2H/, 2,53 - 2,63 /m, 6H/, a 1.75 - 1,95 /m, 3H/, of 1.40 - 1.50 /m 1H/. The mass spectrum with a field desorption: 550.

Elemental analysis for C34H31NO4S 1,0 HCl:

Calculated: C 74,29 H 5,68 N, 2,55.

Found: C 74,52 H 5,80 N 2,59.

Example 47. [3-[4-[2-/1-Piperidinyl/ethoxy]phenoxy]-2-/4 - pivaloyloxymethyl/]benzo[b]difengidramin

< / BR>
Yield = 90%. So melting 193-197oC.1H NMR /DMSO-d6/d: 10,10 /Shir.S., 1H/, 8,12 /d, J = 8.0 Hz, 1H/, 1H/, a 7.85 /d, J = 8.6 Hz, 1H/, 7,40 - 7,53 /m, 3H/, 7,15 /d, J = 6,7 Hz, 2H/, 7,00 /s, 5H/, 4,33 - 4,40 /m 2H/, 3,45 - 3,60 /m, 4H/, 3,00 - 3,10 /m, 2H/, 1,70 - 1,90 /m, 6H/, 1,40 /s, 9H/. The mass spectrum with a field desorption: 529. Elemental analysis for C32H35NO4S 1,0 HCl

Calculated: C 67,89 H 6,41 N 2,47.

Found: C 68,94 H 6,61 N 1,72

Example 48. [3-[4-[2-/1-Piperidinyl/ethoxy]phenoxy]-2-/4-butylcumylperoxide/] benzo[b]difengidramin

< / BR>
Yield = 85% tordo,82 /d, J = 8.7 Hz, 2H/, 7,40 - 7,55 /m, 5H/, 7,00 /s 4H/, 4,30 - 4,40 /m, 2H/, of 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/. The mass spectrum with a field desorption: 565.

Elemental analysis for C31H35NO5S21,0 HCl

Calculated: C 61,83 H 6,03 N, 2,33.

Found: C 61,55 H X 6.15 N 2,25.

Example of getting a 21. [6-Hydroxy-3-[4-[2-/1-piperidinyl/ethoxy]thiophenoxy]-2-/4-hydroxyphenyl/] benzo[b]thiophene

< / BR>
Getting 4-/methoxyethoxy/phenoldisulfonic.

To a solution of 4-hydroxyphenylacetic /650 mg, 2,60 mmole/ in 10 ml of anhydrous N,N-dimethylformamide at 10oC add sodium hydride /230 mg of 5.75 mmole/, 60% dispersion in mineral oil. After stirring for 15 minutes added via syringe chloromethylation ether /of 0.44 ml, 5.75 mmol/. The reaction mixture is allowed to warm to room temperature and stirred for 0.5 hour. The resulting mixture was partitioned between brine and ethyl acetate /20 ml each/. Selected aqueous layer was extracted with ethyl acetate /2 x 20 ml/. The organic portion is dried over sodium sulfate and concentrated to a yellow oil /993 mg, 100%/. An analytical sample of 4-/methoxyethoxy/phenoldisulfonic get in the chromatographic processing /silicon dioxide, 4% of those who Eva desorption: 338. Elemental analysis for C16H18O4S2.

Calculated: C, 56.78 Has H Are 5.36.

Found: C 57,08 H 5,44.

Example 49. [6-Methoxy-2-/4-methoxyphenyl/-3-/4-methoxymethylethoxy/thiophenoxy] benzo[b]thiophene

< / BR>
To a solution of [6-methoxy-2-/4-methoxyphenyl/-3-bromo]benzo[b]thiophene /1,82 g, 5.2 mmole/ in 10 ml of anhydrous tetrahydrofuran under nitrogen atmosphere at -60oC add n-utility /3,15 ml, 5.0 mmole, of 1.6 M solution in hexano/ dropwise via syringe. The resulting mixture was heated to -20oC for 10 minutes, then cooled to -60oC. To lithium sample type 4/methoxyethoxy/-vinyldimethyl /800 mg of 2.36 mmole/ in 5 ml of anhydrous tetrahydrofuran, and the mixture was left to slowly warm to 0oC. After twenty minutes of stirring the reaction quenched by spreading the mixture between brine and ethyl acetate /50 ml each/. The layers are separated and the aqueous phase extracted with ethyl acetate /2 x 50 ml/. The organic layers are combined, dried over sodium sulfate and concentrated in vacuo to an oil. In the chromatographic processing /silica, 5% ethyl acetate /hexane/ receive 287 mg /27%/ [6-methoxy-2-/4-methoxyphenyl/-3-/4-methoxymethylethoxy/thiophenoxy] benzo[b]thiophene in the form of bestv the,79 /s, 3H/, 3,76 /3H/. The mass spectrum with a field desorption: 438. Elemental analysis for C24H22O4S2:

Calculated: C 65,73 H 5,06

Found: C 65,93 H 5,10

Example 50. [6-Methoxy-2-/4-methoxyphenyl/-3-/4-hydroxy/thiophenoxy] benzo[b]thiophene

< / BR>
To a solution of [6-methoxy-2-/4-methoxyphenyl/-3-/4-methoxymethylethoxy/thiophenoxy] benzo[b]thiophene /233 mg, of 0.53 mmole/ in 10 ml of a mixture 1:1:2 methanol: water: tetrahydrofuran add methansulfonate acid /0.2 ml, of 2.66 mmole/. The resulting mixture is heated to boiling under reflux for 5 hours. After cooling to room temperature the reaction mixture is diluted with water. The aqueous phase is extracted twice with ethyl acetate. The organic layer is washed several times with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo to obtain 206 mg /99%/ [6-methoxy-2-/4-methoxyphenyl/-3-/4-hydroxy/thiophenoxy]benzo[b] thiophene as a colorless oil.1H NMR /DMSO-d6/d: 9,43 /C, 1H/, 7,63 /d, J = 8,4 Hz, 2H/, to 7.61 /d, J = 2.0 Hz, 1H/, to 7.59 /d, J = 8,8 Hz, 1H/, 7,08 /d, J = 8,4 Hz, 2H/, 7,02 /DD, J = 8,8 Hz, 2.0 Hz, 1H/, 6,90 /d, J = 8.6 Hz, 2H/, 6,63 /d, J = 8.6 Hz, 2H/. The mass spectrum with a field desorption: 395. Elemental analysis for C22H18O3S2: C 66,98 H 4,60 calculated;

the]thiophene

< / BR>
To a solution of [6-methoxy-2-/4-methoxyphenyl and 3-/4-hydroxy/thiophenoxy]benzo [b] thiophene /242 mg, and 0.61 mmole/ 8.0 ml of anhydrous N, N-dimethylformamide added cesium carbonate /820 mg, 2.5 mmole/ and then 2-chloroethylnitrosourea /194 mg, 1.05 mmole/. The resulting mixture is stirred for 48 hours at room temperature, and then partitioned between brine and ethyl acetate. The layers are separated and the aqueous phase extracted with ethyl acetate three times. The organic layer is dried over sodium sulfate and concentrated in vacuo to an oil. In the chromatographic processing /silicon dioxide, 0-2% methanol /chloroform/ receive 244 mg /92% [6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy]thiophenoxy]-2-/4-methoxyphenyl/] benzo[b]thiophene in the form of oil of amber.

Example 52. Sample [6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy]thiophenoxy] -2-/4-methoxyphenyl/] benzo[b] thiophene converted into the hydrochloride in the standard way with 72% yield.

< / BR>
So melting 198-201o.1H NMR /DMSO-d6/d: 7,63 /d, J = 8.6 Hz, 2H/, 7,62 /d, J = 2.0 Hz, 1H/, 7,58 /d, J = 8,2 Hz, 1H/, 7,07 /d, J=8.6 Hz, 2H/, 7,02/DD, J=8,2, 2.0 Hz, 1H/, 6,92 /sq JAB=9,0 Hz, 4H/, 4,24 /Shir. so, 2H/, 3,82 /3H/, 3,80 /3H/, 3,49-3,39 /m, 4H/, 2,93 /m, 2H/, 1,82-1,62 /m, 5H/, 1,38 /m 1H/, Elemental analysis for C29H32NO3S21,0 HCl


< / BR>
To a solution of

6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy]thiophenoxy]-2-/4 - methoxyphenyl/] benzo[b] difengidramin /160 mg, 0,29 mmole/ in 15 ml of anhydrous methylene chloride at 0oC in nitrogen atmosphere add trichromacy Bor /0.15 ml/. The obtained dark solution is stirred for 1 hour at 0oC, and then immediately pour into a mixed solution of ethyl acetate saturated solution of sodium bicarbonate /50 ml/ each. The layers are separated and the aqueous phase washed with ethyl acetate /3 x 30 ml/. The organic portion is dried over sodium sulfate and concentrated in vacuo to obtain a solid white color. In the chromatographic processing /silicon dioxide 0-5% methanol/chloroform/ get 91 mg /60%/ [6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] -2-/4-hydroxyphenyl/] benzo[b] thiophene in the form of a solid white color. So melting 123-127oC.1H NMR /DMSO-d6/d: 9,79 /C, 1H/, 9,71 /C, 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 a /m, 4H/, 1,41 of 1.28 /m, 6H/. The mass spectrum with a field desorption: 478. Elemental analysis for C27H27NO3S2:

Calculated: C 67,90 H 5,70 N 2,93

Found: C 68,14 of 5.84 H N 2,65

Example 54. [6-Hydroxy-3-[4-[2-1-piperidinyl/e is Mr /DMSO-d6/d: 9,86 /C, 1H/, 9,79 /C, 1H/, 7,46 /l, J=8.5 Hz, 2H/, 7,42 /d, J=8.7 Hz, 1H/, 7,29 /dB J=2.0 Hz, 1H/, of 6.96 /d, J= 8.7 Hz, 2H/, 6,86-for 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/, 13,5-1,28/m 1H/. The mass spectrum with a field desorption: 477. Elemental analysis for C27H27NO3S22,2 HCl

Calculated: C 58,13 H 5,28 N Of 2.51.

Found: C 58,11 H 5,10 N, 2,61.

In the same way get a connection:

Example 55. [6-Methoxy-3-[4-[2-/1-pyrrolidinyl/ethoxy] thiophenoxy]- 2-/4-methoxyphenyl/]benzo[b]difengidramin

< / BR>
So melting 215-218oC.1H NMR /DMSO-d6/d to 7.61-7,58 /m, 3H/, 7,52 /d, J= 8,8 Hz, 1H/,? 7.04 baby mortality-6,95 /m, 5H/, 6,86 /d, J=8,8 Hz, 2H/, 4,22 /Shir. so, 2H/, 3,79 /3H/, 3,76 /3H/, 3,47-3,42 /m, 4H/, 3,01 /m, 2H/, 1,94-1,80 /m, 4H/. The mass spectrum with a field desorption: 491. Elemental analysis for C28H29NO3S21,0 HCl.

Calculated: C, 63, 67 H 5,73 N 2,65.

Found: C, 63.47 Per H 5,78 N 2,65.

Example 56. [6-Hydroxy-3-[4-[2-/1-pyrrolidinyl/ethoxy]thiophenoxy]-2-/4 - hydroxyphenyl/]benzo[b]difengidramin

< / BR>
So melting 137-140oC /decomposition/.1H NMR /DMSO-d6/d: 9,86/C, 1H/, 9,80 /C, 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/, of 6.96 /d, J= 8.7 Hz, 2H/, 6,87-for 6.81 /m, 5H/, 4,21 /Shir. so, 2H/, 3,53-3,41 /m, 4H/, 3,01 /m, 2H/, 1,95-1,82 /m, 4H/. The mass spectrum with a field desorption: 464. Elemental analysis for C26
From the product of example 45 by hydrogenolysis of the triflate as set forth in example 58, receive [6-methoxy-3-[4-[2-/1-piperidinyl/-ethoxy]phenoxy]-2-/phenyl/]benzo [b]difengidramin

< / BR>
So melting 187-195oC.1H NMR/DMSO-d6/d: 7,66 /d, J =2,8 Hz, 2H/, 7,58 /d, J=2.0 Hz, 1H/, 7,39 /t, J=7.5 Hz, 2H/, 7,28 /m 1H/, 7,17 /d, J=8,8 Hz, 1H/, 6,91 /DD, = 8,8 Hz, 2.0 Hz, 1H/, 6,89 /s, 4H/, 4,23 /Shir. so, J=5.7 Hz, 2H/, 3,79/3H/, 3,45-3,38/m, 4H/, 2,98 /m, 2H/, 1,77-1,61 /m, 5H/, 1,31 /m 1H/. The mass spectrum with a field desorption: 460. Elemental analysis for C28H29NO3S1,0 HCl:

Calculated: C 67,80 H 6,10 N 2,84.

Found: C 67,62 Of 5.89 H N 2,67.

Example 58

[6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/phenyl/] benzo[b] difengidramin

< / BR>
To a solution of [6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4-hydroxyphenyl /benzo[b] difengidramin (5.0 g, 10.0 mmol) in 100 ml of anhydrous methylene chloride at 0oC in an atmosphere of N2add triethylamine /scored 8.38 ml, 60,0 mmole/ and then triftormetilfullerenov anhydride /1,69 ml, 10.0 mmole/. The resulting mixture was left to slowly warm to room temperature and stirred for 1.5 hours. The reaction mixture is quenched, pouring it into 200 ml of saturated sodium bicarbonate solution. Then the aqueous phase is extracted with ethylacetate tographically processing /0-3% methanol /chloroform/ get 2,82 g /39%/ [6-triftorbyenzola-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4 - triftormetilfosfinov/] benzo[b] thiophene, /1,82 g, 31%/ 1:1-mixture of [6-triftorbyenzola-3-[4-[2-/1-piperidinyl/ethoxy] -phenoxy] -2-/4-phenyl/] benzo[b] thiophene and[3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-triftormetilfosfinov/] benzo [b] thiophene and 1.48 g /36%/ selected source material in the form of free base.

To the solution mixture 1:1 triflate derived from the last reaction /0.50 g, from 0.84 mmole/ in 60 ml of a mixture of ethanol: ethyl acetate /5:1/ added triethylamine /2.0 ml/ 5% palladium-on-coal /0.50 g/. The resulting mixture hydronaut at 40 psi /2,81 kg/cm2/ within 2 hours. Then the resulting mixture was filtered through Cellit /Celite/ to remove the catalyst. The resulting filtrate concentrated to oil. The resulting mixture of monohydroxy derivatives dissolved in ethyl acetate, which is deposited[3-[4-[2-/1-piperidinyl/ethoxy]phenoxy]-2-/4-hydroxyphenyl/] benzo[b] thiophene. The obtained filtrate consists of a mixture of 4:1 monohydroxy derivative, in which [6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy]-2-/phenyl/[benzo[b]thiophene is a major component. The obtained filtrate was concentrated in vacuo and the resulting solid portion was dissolved in minimum amount of ethyl acetate and treated with ethyl ether hydrochloric acid. The hard part of paracrystalline/]benzo[b]difengidramin. T. melting 217 - 219oC.1H NMR /DMCO-d6/d: 9,87 /C, 1H/, of 7.64 /d, J = 7.5 Hz, 2H/, 7,39-7,26 /m, 4H/, 7,10 /d, J = 8,6, 1H/, 6,89 /s, 4H/, 6,78 /DD, J = 8,6, 2.0 Hz, 1H/. 4,22 /Shir.T., 2H/, 3,39-3,37 /m, 4H/, 2,97-2,90 /m, 2H/, 1,74-1,60 /m, 5H/, 1,39 /m 1H/.

The mass spectrum with a field desorption: 466.

Elemental analysis for C27H27NO3S 1,0 HCl

Calculated: C 67,28 H 5,86 N 2.91 In.

Found: C 67,00 H 5,59 N 2,87.

In another embodiment, the compound of example 58 produced by demethylation of the product of example 57, as indicated in example 18.

Example 59.

[6 isopropoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4 - methoxyphenyl/] benzo[b] thiophene-/S/-oxide/ receive as specified for [6-methoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4-methoxyphenyl/] benzo[b]thiophene-/S-oxide/. /30/.

< / BR>
A yellow oil.1H NMR /DMSO-d6/d: 7,69 /d, J = 2,0 1H/, to 7.67 /d, J = 8.6 Hz, 2H/. 7,09-6,99 /m, 5H/, of 6.96-6.87 in /m, 3H/, 4,76 /septet, J = 6.0 Hz, 1H/, 3,99 /Shir. so, J = 6.0 Hz, 2H/, 3,78 /3H/, 2,61 /Shir. so 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/. Mass spectrum (field desorption: 533. Elemental analysis for C31H35NO5S 0,67 H2O:

Calculated: C 68,23 H Of 6.71 N To 2.57.

Found: C 67,90 H Of 6.31 N, 2,53.

[6 isopropoxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy] -2-/4 - methox the oxy]-2-/4 - methoxyphenyl/]benzo[b]thiophene /example 32/

< / BR>
T. melting 168 - 170oC1H NMR /DMSO-d6/d: 10,37 /C, 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/, with 4.64 /septet, J = 6.0 Hz, 1H/, 4,28 /Shir. so , J = 6.0 Hz, 2H/, 3,72 /3H/, 3,44-3,37 /m, 4H/, 2,95-2,89 /m, 2H/, 1,73-1,60 /m, 5H/, 1,36 of 1.28 /m 1H/, 1,25 /d, J = 6.0 Hz, 6H/.

The mass spectrum with a field desorption: 517. Elemental analysis for C31H35NO4S HCl

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] difengidramin make [6-hydroxy-3-[4-[2-/1-piperidinyl/ethoxy] phenoxy/-2-/4-methoxyphenyl/] benzo[b]thiophene due to processing 2.0 equivalents BCl3at a temperature of 0 to 10oC in anhydrous dichloromethane /in these conditions the methyl ether does not split/.

Example 60

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

< / BR>
Data for (IA): C27H27NO4S HCl

Elemental analysis:

Calculated,%: C 65,12 H 5,67 N 2,81

Found,%: C 65,28 H 5,74 N 2,89

Mass spectrum (DD+) (field desorption+) : 462

The compound of formula (IA) are obtained on the basis of [6 isopropoxy-2-(4-methoxyphenyl)-3-bromo] [b]thiophene, synthesized according to example paleologou [6 isopropoxy-2-(4 - methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide). At the same time, according to the method of example 12, but using 2-charityproviding, receive a 4-(2-(1-pyrrolidinyl)-ethoxy)phenyl. Then 4-(2-(1-pyrrolidinyl)-ethoxy)phenyl subjected to interaction with [6-isopropoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b] thiophene-(S-oxide) in accordance with the method of example 30. Sulfoxide group then restore according to the method of example 32, receiving hydrochloric salt [6 isopropoxy-3-[4-[2-(1-pyrrolidinyl)-ethoxy]phenoxy]-2-(4-methoxyphenyl) benzo[b]thiophene.

Finally, ISO-propyl protective group is removed according to the method of example 59, receiving hydrochloric salt of [6-hydroxy-3-[4-[2-(1- pyrrolidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)-benzo[b]thiophene.

Test procedure

General procedure for preparation of

In the examples, which illustrate the method used postmenopausal model, which determine the effectiveness of different treatments in relation to circulating lipids.

Semidesyatipyatiletiyu female rats strain Spaque Dawley /weighing 200 to 225 g/ is obtained from Charles River Laborotories (portoge, MI). In animals, or remove both ovaries /O X/ or perform the operation according to the method of shamaa at Charles river laboratories, and then put later time what uranium calcium approximately 0.5%/ and water for one week. The temperature in the room support when 22,2o1,7oC with a minimum relative humidity of 40%. The photoperiod in the room is 12 hours of light and 12 hours of darkness. The metering mode. The selection of fabrics.

After a week of acclimatization period /i.e. two weeks after oophorectomy/ begin daily administration of the test compounds. 17-ethinylestradiol or test compound is administered orally /the/ in the form of a suspension in 1% carboxymethylcellulose or dissolved in 20% cyclodextrin. Animals injected in the dose daily for 4 days. After completion of the scheme dosage animals are weighed and anaesthetize with a mixture of ketamine : xylazine /2:1 volume/volume/ and blood samples taken, taking the puncture of the heart. Then kill animals with CO2, remove the uterus through an incision of the peritoneum. Then determine the wet weight of the uterus.

Analysis for cholesterol

The blood samples are allowed to clot at room temperature for 2 hours and the serum obtained after centrifugation for 10 minutes at 3000 rpm Syaratnya cholesterol was determined by high-performance analysis for cholesterol Boehringer Mannheim Diagnostike. Cholesterol to oxidize the cholesterol-4-EN-3-one and hydrogen peroxide water is p-hinolinovogo dye, which is determined spectrophotometrically at a wavelength of 500 nm. Then calculate the content of cholesterol from the standard curve. The entire analysis is carried out automatically using a Biomek Automated Workstation/

Peroxidase analysis of the contents in the uterus of sotiropulos /EPO/

Uterine contain at 4oC until enzyme analysis. Then the uterus homogenized in 50 volumes mm Tris buffer /pH 8.0/ containing 0.005% Triton X-100. After the addition of Tris buffer, 0.01% hydrogen peroxide and 10 mm O-phenylenediamine /final concentration for one minute followed by the increase of absorption at 450 nm. The presence of sotiropulos in Queens is an indicator extragenic the activity of the connection. Maximum speed with 15 second intervals determined relative to the initial, linear portion of the curve of reaction.

Source connection: 17 - ethinylestradiol get from the Sigma Chemical Co., Article Louis, MO.

The influence of compounds of formula I on serum cholesterol and determination of agonist/non-agonistic activity

The data presented in the following table 1, pokazat the results obtained when comparing rats after oophorectomy, rats treated with 17 - levonorgestrel /EE2; and oral is 2
causes a reduction in serum cholesterol in oral introduction in doses of 0.1 mg/kg/day, it also has a stimulating effect on the uterus, so that the weight EE2females is significantly higher than the weight of females in the test animals after oophorectomy. This reaction of the uterus to estrogen is well known to specialists.

The compound of the present invention not only lead to a General reduction in serum cholesterol compared to the control animals after oophorectomy, but the weight of the uterus only minimally increased or slightly decreased for most of the tested compounds of formula I. In comparison with well-known specialists estrogenic compounds, the favorable effect of reducing serum cholesterol without undesirable influence on the weight of the uterus is very rare and desirable.

As can be seen from the following results, astrogenetix can also be evaluated, determining feedback infiltration sotiropulos in the uterus. Compounds of the present invention do not cause any increase in the number of sotiropulos observed in the construction layer at ovariectomized rats, although estradiol causes a significant expected increase infiltration sotiropulos.

Test procedure for the determination of osteoporosis

In accordance with the General procedure of preparation rats were treated daily for 35 days /6 rats per group/ and slew improved carbon dioxide on day 36. It turned out that period of 35 days is enough to ensure maximum recovery of bone density, which was determined as shown here. At the time of killing the uterus is removed, freed from the outer fabric and the contained liquid is removed before determining the wet weight to confirm the deficiency of estrogen associated with full oophorectomy. The weight of the uterus is usually reduced and is about 75% as a reaction to ovariectomy. Then the uterus was placed in 10% neutral superyoung formalin for subsequent histological analysis.

Excised first femur and conduct x-ray examination and analysis program image-analysis /NIH image/ from the distal metaphysis. Prox tomography.

In accordance with the above procedure, compounds of the present invention and levonorgestrel /EE2/ in 20% hydroxypropyl -- cyclodextrin is administered orally to the test animals. Data relative to the distal metaphysis of the tibia below in tables 2 and 3, and present the results of processing the compound of the formula I as compared with intact and ovariectomized test animals. The results are presented as mean average standard error.

In conclusion we can say that oophorectomy text animals causes a significant decrease in the density of bone as compared with intact animals, which impose only media. Oral introduction of levonorgestrel /EE2/ prevents this loss, but there is always the risk of stimulation of the uterus under this treatment.

Compounds of the present invention also prevent the total loss of bone tissue in a dose-dependent manner. Accordingly, the compounds of the present invention can be used for the treatment of postmenopausal syndrome, in particular osteoporosis.

Analysis of proliferation of MCF-7

The cells of the adenocarcinoma group MCF-7 /ATCC NTV 22/ Podgornoe calf serum /FBS/ /amount of/volume of/, L-glutamine /1 mm, sodium pyruvate /1 mm, HEPES //N-/2-hydroxyethyl/piperazine-N'/2-econsultancy acid/ 10 mm/, unsubstituted amino acids and bovine insulin /1 ug/ml/ /support environment/. 10 days before analysis, cells MCF-7 was transferred to maintenance medium supplemented with 10% dextran-coated charcoal treated fetal calf serum /BCA-FBS/ analytical environment/instead of 10% FBS, in order to exhaust domestic reserves of steroids. Cells MCP-7 removed from the flasks, using a medium for dissociation of cells /Ca++/Mg++free HBSS/ not containing phenol red/, supplemented with 10 mm HEPES and 2 mm EDTA/. Cells are washed twice analytical environment and bring the concentration up to 8000 cells/ml to About 100 ml /8000 cells/ add in flat-bottomed microcultural cells /Costar 3596/ and incubated at 37oC in 5% CO2humidified incubator for 48 hours to allow the cells to adhere and be balanced after migration. Prepare serial dilutions of drugs for DMSO as a control diluent in the analytical environment and 50 ml transferred into three overlapping micro cultures, and then 50 ml of analytical environment to a final volume of 200 ml After an additional 48 hours at 37other /1 microcurie/cell/ within 4 hours. Treatment of cultures complete, freezing at -70oC for 24 hours and then Ottawa and collecting micro cultures using a semi-automated compilation of the cells Scarton /Skarron/. Samples are counted using a liquid scintillation counter Wallac BetaPlace b. The results are presented in table 4 further demonstrate IR50for some compounds of the present invention.

Inhibition of mammary tumor-induced DMBA

Estrogen-dependent tumors of the breast cancer cause in female rats strain Sprague-Dole, which is obtained from Harlan industries, Indianapolis, Indiana. At the age of about 55 days to rats administered orally and once 20 mg 7,12-dimethylbenz/a/anthracene /DMA/. After approximately 6 weeks after the introduction of DMBA Breasts alperujo with weekly intervals for the appearance of tumors. As soon as one or more of the tumor, the largest and smallest diameters of each tumor was measured with a caliper, measure, record, and these animals are selected for experiments. An attempt to evenly distribute animals with different sizes of tumors in the treated and control groups, so that the average size of tumors were equally the lo 5 9 animals.

The compounds of formula I is administered either by intraperitoneal injection in 2% acacia or orally. Those compounds that are injected oral, injected or dissolved or suspended in 0.2 ml of corn oil. In each treatment, including the control processing acacia and corn oil, the drug is administered once daily to each test animal. After the initial measurement of the tumor and selection of test animal dimensions, the sizes of tumors determined weekly by the above method. Processing and control animals continue for 3 to 5 weeks, and then determine the final size of the tumors. To determine the changes in average size of tumors for each of the compounds and for control animals.

Test for fibrosis of the uterus

Test 1. Three-twenty women with fibrosis of the uterus enter the compound of the present invention. The number of input connections is the amount of from 0.1 to 1000 kg/day, and the period of treatment is 3 months.

During the time of admission and for up to 3 months after discontinuation of medications for women are observed regarding the effect on the fibrosis of the uterus.

Test 2. Use the procedure t is the period of injection is 1 year.

Test 4.

A. or fibrous tumors induced in Guinea pigs

In order to cause leiomyoma in sexually Mature females Guinea pigs, use of prolonged stimulation by estrogen. Animals injected dose estradiol 3-5 times a week by injection within 2-4 months or until the tumor. Processing, which consists of the compounds of the present invention or the media, is carried out daily for 3-16 weeks, and then animals wortlaut, uterus gather and analyze on the subject of regression of the tumor.

B. Implantation or fibrous tissue of the uterus women naked mice

Tissue from leiomyoma women implanted in the peritoneal cavity and/or myometrium uterus of sexually Mature, castrated females naked mice. Supply of exogenous estrogen to cause growth explantions tissue. In some cases, the collected tumor cells cultured in vitro before implantation. Treatment consisting of compounds of the present invention or media carried out by lavage of the stomach daily for 3-16 weeks, the implants were removed and determine the growth or regression. At the time of conciliation of the uterus selected and inspected to assess the condition of the body.

Activity in at least one of the above tests indicates that the compounds of the present invention is effective for the treatment of fibrosis of the uterus.

Test for endometriosis

In tests 1 and 2 the effects of 14 and 21 day introduction compounds of the present invention on the growth explantions endometrial tissue can be investigated.

Test. 1.

As test animals use from 12 to 30 adult females krisu female operate, females in each group remove the left horn of the uterus is divided into small squares, and these squares are freely attached at various points, the connection with mesentericus blood flow. In addition, females of group 2 remove the ovaries.

The next day after surgery the animals of groups 1 and 2 intraperitoneally injected water within 14 days, whereas animals of group 3 injected intraperitoneally injection of 1.0 mg of the compound of the present invention per 1 kg of body weight during the same period of time. After 14 days of treatment all females kill and endometrial explants, the adrenal glands, the remains of the uterus and ovaries, where possible, remove and prepare for histological studies. The ovaries and adrenal glands weighed.

Test. 2.

As test animals use from 12 to 30 adult female rats strain SD. They are divided into two equal groups. Control of the estrous cycle of all animals. On the day of proestrus all females operate. Females of all groups remove the left uterine horn, cut into small squares, and these squares are freely attached at various points near mesentericus the blood stream.

After about 50 days after surgery, the animals of group 1 enter EDINENIE of the present invention per kg of body weight during the same period of time. After 21 days of treatment each of the females kill and endometrial explants and adrenal glands were removed and weighed. These explants was measured as indicators of growth. Write cycles of extras.

Test 3.

A. Surgical induction of endometriosis

The autotransplants endometrial tissue is used for induction of endometriosis in rats and/or rabbits. In female animals in the reproductive age remove both ovaries and estrogen is administered exogenously, thus providing a specific and constant level of hormone. Autologous endometrial tissue implanted in the peritoneum 5 - 150 animals and injected estrogen to induce growth explantions tissue. Processing, comprising the compound of the present invention is carried out by lavage of the stomach daily for 3 to 16 weeks, the implants are removed and measured to determine growth or regression. At the time of killing selected intact horn of the uterus to assess the condition of the endometrium.

B. Implantation of endometrial tissue of women naked mice

Tissue from ulcers endometrial women implanted in the peritoneum of sexually Mature castrated females naked mice. Introduce exogenous estrogen induction of growth Explant the Oia. Treatment consisting of compounds of the present invention is administered by lavage of the stomach daily for 3 to 16 weeks, the implants are removed and measured to determine growth or regression. At the time of killing selected the uterus to determine the status of the endometrium.

Test 4.

A. Collect endometrial tissue ulcers women and retain in vitro as a primary nontransgenic crops. Obtained surgical specimens push through a sterile mesh or sieve, or in another embodiment, pinch off from the surrounding tissue to obtain a unicellular suspension.

The support cells in medium containing 10% serum and antibiotics. The rate of growth in the presence of estrogen or without him determine. Cells assessed on their ability to produce the complement component C3 and their response to growth factors and growth hormones. Culture in vitro assessed for their proliferative response after treatment protestingly, early warning system, the connection of the present invention and a carrier. Levels of steroid hormone receptors evaluated weekly to determine whether to store important cell characteristics in vitro. Using tissue from 5 - 25 patients.

In the present invention a method of alleviating postmenopausal symptoms in women, which includes the above-mentioned method of using compounds of formula I and further includes the introduction of women effective amount of estrogen or progestin. Such treatments are particularly suitable for the treatment of osteoporosis and reduction of serum cholesterol, as it ensures that the patient benefits from each pharmaceutical agent, and compounds of the present invention will inhibit unwanted side effects of estrogen and progestin. The activity of these combinations of treatment in any of the post-test shows that this combination treatment can be used to relieve symptoms of postmenopausal symptoms in women.

Commercially available various forms of estrogen and progestin. Agents on the basis of estrogen include, for example, etinilestradiol /0.01 - 0.03 mg/day, mestranol /0.05 - 0.15 mg/day and conjugated estrogenic hormones, such as premarin/Wyest-Ayerst; 0.3 to 2.5 mg/day. Agents on the basis of progestin include, for example, medroxyprogesterone, such as provera/Cleared; 2,5-10 mg/day, norethynodrel /1,0 - 10,0 mg /day and Norat ortengren are the preferred agents based on progestin.

The method of administration of each agent on the basis of estrogen or progestin correspond to those known in the art. For most of the methods of the present invention the compounds of formula I is administered continuously, from 1 to 3 times a day. However, cyclic therapy may be particularly useful in the treatment of endometriosis or can be actively used during painful episodes of the disease. In the case of restenosis treatment may be limited to a short /1-6 monthly/ intervals after such medical procedures such as angioplasty.

In the sense used here, the term "effective amount" means an amount of compound of the present invention, which is able to alleviate the symptoms of the various pathological conditions herein described. The specific dose of a compound that is entered by the method of the present invention should, of course, be determined by the specific circumstances related disease, including, for example, entered the compound, route of administration, the condition of the patient and the pathological condition to be treated. The usual daily dose contains a non-toxic level dose from about 5 mg to about 600 mg/day of the compounds of the present invention. Usually pribretenie can be entered in various ways, including oral, rectal, subcutaneous, intravenous, intramuscular, through the skin and through the nose. These compounds are preferably formulated prior to introduction to the method determined by the doctor. Thus, another aspect of the present invention is a pharmaceutical composition comprising an effective amount of the compounds of formula I, or its pharmaceutically acceptable salt, optionally containing an effective amount of estrogen or progestin, and a pharmaceutically acceptable carrier, diluent, or excipient.

The full amount of the active ingredients in such compositions is from 0.1% to 99.9% by weight of the composition. The term "pharmaceutically acceptable" is meant the carrier, diluent, excipient and salt that is compatible with other ingredients of the composition, and do not render harmful influence on the recipient.

The pharmaceutical compositions of the present invention can be obtained, known in the art methods, using well known and readily available ingredients. For example, the compounds of formula I, together with estrogen or progestin, can be prepared with conventional excipients, diluents or carriers, in the form of tablets, capsules, suspensions, then, is the following: such fillers and increasing volume of the agents, as starch, sugars, mannitol, and derivatives of silicon; such binding agents, as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; moisturizing agents such as glycerol; such loosening agents like calcium carbonate and sodium bicarbonate; agents for delaying dissolution as paraffin; such accelerators resorbtive as Quaternary ammonium compounds; surface active agents, as cetyl alcohol, glycerol monostearate; such adsorbing media as kaolin and bentonite; and such moving as talc, calcium and magnesium stearate, and solid polyethylene glycol.

Compounds can also be prepared in the form of Alexiou or solutions for conventional oral administration or as solutions for parenteral injection, for example, intramuscularly, subcutaneously or intravenously. In another embodiment, these compounds are well suited for the preparation of compositions in dosage forms with delayed release of active agent, etc., These compositions can be prepared to release the active ingredient only or preferably in a particular physiological environment, it is possible for some period of time. P>

The compounds of formula I alone or in combination with a pharmaceutical agent of the present invention typically can be entered in the form of conventional compositions. The following examples of such compositions are merely illustrative and in no way should limit the scope of the present invention.

Songs

In the following examples, the compositions of the "active ingredient" means a compound of formula I or its salt or MES.

Form 1: Gelatin capsules

Hard gelatin capsules get using:

The ingredient Quantity (mg/capsule

The active ingredient is 0.1 - 1000

Starch /NF-national guide/ - 0 - 650

Presuposes powder starch - 0 - 650

Silicone fluid, 350 cSt - 0 - 15

The above composition can be changed in accordance with reasonable options.

Form 2: Tablets

Composition of tablets get, using the following ingredients:

The ingredient Quantity (mg/tablet

Active ingredient - 2,5 - 1000

Microcrystalline cellulose - 200 - 650

Silicon dioxide (white carbon black) - 10 - 650

Stearic acid - 5 - 15

All the components are mixed and pressed into tablet form.

In dbrt:

3rd Form: Tablets.

The ingredient Quantity (mg/tablet

Active ingredient - 25 - 1000

Starch - 45

Microcrystalline cellulose - 35

Polyvinylpyrrolidone (10% solution in water) - 4

The sodium carboxymethyl cellulose is 4.5

Magnesium stearate and 0.5

Talc - 1

The active ingredient, starch, and cellulose are passed through sieve No. 45 mesh U.S. and mix thoroughly. With the obtained powders are mixed solution of polyvinylpyrrolidone all this passed through sieve No. 14 mesh U.S. dollars. The obtained granules were dried at 50 - 60oC and passed through sieve No. 18 mesh U.S. dollars. The sodium carboxymethyl cellulose, magnesium stearate and talc, missed first through sieve # 60 mesh U.S., added to the granules which, after mixing the components, pressed into tablets.

The following provides a suspension, each of which contains 0.1 to 1000 kg of drug per 5 ml dose:

Form 4: Suspension.

The ingredient Quantity (mg/5 ml:

The active ingredient is 0.1-1000

The sodium carboxymethyl cellulose - 50

Syrup - 1,25

A solution of benzoic acid, ml - 0,10

Flavoring agent - q.v.

Dye - q.v.

Purified water To 5 ml

Drug transport the paste. Add with stirring a solution of benzoic acid, flavoring agent and dye, diluted with a little water, then add water to the desired volume.

Aerosol solution containing the following ingredients was prepared as follows:

Form 5: Aerosol.

Ingredient: Amount, wt.%:

Active ingredient - 0,25

Ethanol - 25,75

Propellant 22 /Chlorodifluoromethane/ - 70,00

The active ingredient is mixed with ethanol, the mixture is added to a part of propellant 22, cooled to 30oC, and transferred to a filling device. Then enter the desired number in the stainless steel container and diluted with the remaining amount of propellant. Then the container is provided with a valve.

As follows is prepared suppositories:

Form 6: Suppositories.

The ingredient Quantity (mg/suppository:

Active ingredient: 250

Glycerides of saturated fatty acids - 2000

The active ingredient is passed through sieve # 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, which previously melted using the minimum heat. Then the obtained mixture is then poured into molds for suppouse way.

Form 7: Solution for intravenous administration.

Ingredient - Number

Active ingredient: 50 mg

Isotonic saline solution - 1000 ml

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

Form 8: Combined capsule I.

The ingredient Quantity (mg/capsule:

Active ingredient - 50

Premarin - 1

Avicel pH 101 - 50

Starch 1500 - 117,50

Silicone oil - 2

Twin 80 - 0,50

Cab-o-Sil - 0,25

Form 9: Combined capsule II.

The ingredient Quantity (mg/capsule:

Active ingredient - 50

Norethynodrel - 5

Avicel pH 101 - 82,50

Starch 1500 - 90

Silicone oil - 2

Twin 80 - 0,50

The form 10. Combined pills.

The ingredient Quantity (mg/capsule:

Active ingredient - 50

Premarin - 1

Corn starch NF - 50

Povidone, K29-32 - 6

Avicel pH 101 - 41,50

Avicel pH 102 - 136,50

Crosspovidone XZ10 - 2,50

Magnesium stearate - 0,50

Cab-O-Sil - 0,50 p

1. Benzothiophene the compounds of formula I

< / BR>
where R1IS-H, -OH, -O(C1- C4alkyl), -OCOC6H5, -OCO(C1- C4alkyl), or-OSO2C6alkyl), -OSO2(C2- C6alkyl), or halogen;

R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino;

n = 2 or 3;

Z is-O - or-S-;

or their pharmaceutically acceptable salts.

2. Connection on p. 1, where R3- 1-piperidinyl, n = 2, or their pharmaceutically acceptable salts.

3. Connection on p. 2, where Z Is-O-, or their pharmaceutically acceptable salts.

4. Connection on p. 3, where R1- HE, R2- -O(C1- C4alkyl), or their pharmaceutically acceptable salts.

5. Connection on p. 4, where R2- -OCH3or their pharmaceutically acceptable salts.

6. Connection on p. 5, where this salt is hydrochloric salt.

7. Connection on p. 3, where R1and R2everyone-HE, or their pharmaceutically acceptable salts.

8. Connection on p. 7, where this salt is hydrochloric salt.

9. Connection on p. 1 representing [6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)benzo[b]thiophene of the formula

< / BR>
or its pharmaceutically acceptable salt.


 

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