New tetracyclic compounds containing heteroatom, used as selective modulators of oestrogen receptors

FIELD: chemistry, pharmaceutical.

SUBSTANCE: invention pertains to new tetracyclic compounds containing a heteroatom. The compounds can be used in treating and/or prevention of disorders, associated with oestrogen depletion, such as hot flash, vaginal dryness, osteopenia and osteoporosis; sensitive cancerous diseases hormone and hyperplasia of the lacteal gland, endometrium, cervix uteri and prostate; endometriosis, uterus fibrosis and osteoarthritis, and as contraceptive agents, used either separately or combined with progestogen or a progestogen antagonist.

EFFECT: obtaining tetracyclic compounds containing a heteroatom used in treatment and/or prevention of disorders, associated with depletion of oestrogen.

5 cl, 8 tbl, 176 ex

The technical field to which the invention relates

The present invention relates to new, containing heteroatom tetracyclic compounds containing pharmaceutical compositions, their use in the treatment of disorders mediated by one or more estrogen receptors, and methods for their preparation. Compounds of the invention, therefore, are applicable for the treatment and/or prevention of disorders associated with depletion of estrogen (including but not limited to the above, paroxysmal sensation of heat, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain disease, cardiovascular and cerebrovascular diseases); to treat hormone-sensitive cancers and hyperplasia (in tissues including the mammary gland, endometrium, and cervix in women and prostate in men); for the treatment and prevention of endometriosis, fibrosis, cancer and osteoarthritis and as contraceptive agents, used either alone or in combination with a progestogen or progestogen antagonist.

The prior art inventions

Estrogens are a group of female hormones that are essential for the reproductive process and for the development of the uterus, the mammary glands and other physical change in the response associated with puberty. Estrogens have an effect on various tissues in the entire body of women, not only of the tissues involved in the reproductive process, such as tissue of the uterus, the mammary glands and external genitalia, but also the tissues of the Central nervous system, bones, liver, skin and urinary tract. The ovaries produce most of the estrogen in a woman's body.

Menopause is defined as the permanent cessation of menstruation due to loss of ovarian follicular function and almost complete production of estrogen. This change in mid-life menopause is characterized by a decrease in estrogen, which causes both short and long vasomotor symptoms, urogenital, cardiovascular, skeletal and Central nervous systems, such as paroxysmal sensation of heat, urogenital atrophy, increased risk of cardiovascular disease, osteoporosis, cognitive, and psychological distress, including increased risk of impairment of cognitive ability and Alzheimer's disease (AD).

Seventy-five percent of all women experience some occurrence of vasomotor symptoms associated with early menopause, such as paroxysmal sweating and a sensation of heat. These complaints may begin several years before menopause Yiwu some women can last for more than 10 years at a relatively constant or instant attacks without definable calling their causes.

Urogenital symptoms associated with early menopause related to the vagina, include dryness, burning, itching, pain during intercourse, superficial bleeding and highlighting together with atrophy and stenosis. Symptoms related to the urinary tract include burning sensation during urination, frequent need to pass urine, recurrent infectious diseases of the urinary tract and incontinence. States that these symptoms occur in up to 50% of all women around the time of menopause, and more often several years after menopause. If such symptoms are not treated, these problems may become permanent.

Heart attack and stroke are major causes of morbidity and mortality among older women. Female incidence of these diseases increases rapidly after menopause. Women who undergo premature menopause have a greater coronary risk than menstruating women of similar age. The presence of serum estrogen has a positive effect on serum lipids. This hormone stimulates the dilation of blood vessels and increase the formation of new blood vessels. Thus, reduced levels of estrogen in serum posleprodazhnyj women bring the negative cardiovascular effects. In addition, theoretically, it is believed that the difference in the ability of blood to coagulate may explain the observed difference in the prevalence of heart disease before and after menopause.

The skeleton is in a continuous process of degeneration and regeneration of bones at carefully regulated interactions among cells in the bones. These cells are directly affected by estrogen. Estrogen deficiency leads to loss of bone structure and reduces bone strength. Rapid bone loss during the years immediately after menopause leads to polymeropoulos osteoporosis and increased risk of fracture.

Estrogen deficiency is also one of the causes of degenerative changes in the Central nervous system and may lead to Alzheimer's disease (AD) and reduced cognitive abilities. Recent evidence suggests a link between estrogen, menopause and cognitive ability. More specifically, it was indicated that estrogen replacement therapy and the use of estrogen women can prevent the development of AD and improve cognitive function.

Hormone replacement therapy (HRT) - more specifically, estrogen replacement therapy (ERT) is usually prescribed for medical problems associated with menopausal, and to counter the development of osteoporosis and VI is x cardiovascular complications such as coronary arterial disease) as oseltamivir, and therapeutically. As such, HRT is drug therapy to increase life expectancy pokemonporn women and ensuring a better quality of life.

ERT effectively reduces menopausal symptoms and urogenital symptoms and finds some benefits in the prevention and treatment of diseases of the heart in posleprodazhnyj women. Clinical reports have shown that ERT reduces the incidence of heart attacks and the degree of mortality in populations who received ERT, compared with a similar population not treated with ERT. ERT conducted soon after menopause, can also help to maintain bone mass in a few years. Controlled studies have shown that treatment with ERT has a positive effect even on older women up to age 75 years.

However, there are numerous unwanted effects associated with ERT, which reduce the tolerance of therapy by the patient. Venous thromboembolism, gallbladder disease, the resumption of menstruation, mastodinia and possible increased risk of developing uterine cancer and/or breast cancer are the risks associated with ERT. Up to 30% of women who are prescribed ERT, do not execute the instruction, and the degree of cessation of ERT is between 38% and 70%, with concern for the safety and negative actions (what sutie abdomen and bleeding through the gap) are the most important reasons for cessation of ERT.

As an alternative to ERT was conceived and developed a new class of pharmacological agents known as selective receptor modulators estrogen or SERMs. Raloxifene, a nonsteroidal benzothiophene SERM, sold in the United States and Europe for the prevention and treatment of osteoporosis under the trademark evista®. Found that raloxifene reduces and prevents osteoporosis fracture without adverse stimulation of the endometrial tissue and breast tissue, although raloxifene to some extent is less effective than ERT, to protect against osteoporosis. Raloxifene is unique and differs significantly from the ERT that it does not stimulate the endometrium and has the ability to prevent breast cancer. Raloxifene has also demonstrated the beneficial actions of estrogen agonist on the factors of cardiovascular risk, more specifically by means of rapid and continuous decrease in the levels of the General cholesterol and cholesterol of low density lipoprotein in patients being treated with raloxifene. In addition, I found that raloxifene reduces the plasma concentration of homocysteine, an independent risk factor of atherosclerosis and thromboembolic disease.

However, it was stated that raloxifene exacerbates the symptoms associated with menopause, such as paroxysmal feeling garai vaginal dryness, and does not improve cognitive function in elderly patients. Patients receiving raloxifene had a higher frequency of paroxysmal sensations of heat in comparison with consumers or placebo ERT, and large leg cramps than consumers placebo, although women who received ERT, had more cases of vaginal bleeding and discomfort in the chest than consumers of raloxifene or placebo.

It is shown that so far, neither raloxifene nor any of the other currently available compounds SERM is not able to provide all the benefits currently available ERT, such as suppression of polymeropoulos syndrome and prevention of AD, without negative side effects, such as increased risk of endometrial cancer and breast cancer and bleeding. Thus, there is a need for compounds which are selective modulators of estrogen receptors and which provide all the benefits of ERT, while intended for the treatment of vasomotor, urogenital and cognitive disorders or conditions associated with increased systemic levels of estrogen associated with menopause.

Brief description of the invention

The present invention relates to the compound of formula (I)

in which

represents a single or double bond,

X is selected from the group consisting of O and S, and Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2(preferably CR^AR^B(CR^AR^B)_1-2selected from-CR^AR^B(CH₂)_1-2, -CH₂CR^AR^BCH₂-, -CR^AR^B-CH(OH)-CR^AR^Bor CR^AR^B-CH₂-CR^AR^B-), CR^AR^BC(O), CR^AR^BC(O)CR^AR^B(preferably CH₂C(O)CH₂) and With(O); alternatively, Y is selected from the group consisting of O and S, and X is selected from the group consisting of CR^AR^Band(About);

provided that when X represents S, then Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2and CH₂C(O)CH₂; provided further that when Y is S, then X is selected from the group consisting of CR^AR^B;

where each of R^Andand R^Bindependently selected from hydrogen, hydroxy, alkyl or alkoxy, provided that each of R^Andand R^Bis not hydroxy;

Z is selected from the group consisting of O and S;

R¹selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, -C(O)-aryl, aralkyl, heteroaryl and heteroallyl; where the alkyl, the cycle is alkyl, aryl, kalkilya, heteroaryl or heteroallyl group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^c, -OR^c, -C(O)-OR^c, -C(O)O-(alkyl)-NR^DR^E, -C(O)-NR^D-(alkyl)-NR^DR^E, -C(O)-(heteroseksualci)-NR^DR^E, -C(O)-(heteroseksualci)-R^F, -SO₂-NR^DR^E, -NR^DR^E, -NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^E, -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F, -O-(alkyl)-O-Si(alkyl)₃, -O-(alkyl)-OR^Dor-O-(alkyl)-formyl;

where R^Cselected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, cycloalkenyl, aryl, kalkilya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, Ala the La, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^C, -SO₂-NR^DR^E, -NR^DR^E, -NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F;

where Q is selected from the group consisting of O, S, NH, N(alkyl) and-CH=CH-;

where each of R^Dand R^Eindependently selected from the group consisting of hydrogen or alkyl; or R^Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 3-10-membered, preferably 4-to 8-membered ring selected from the group consisting of heteroaryl or geterotsiklicheskie, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, oxo, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where R^Fselected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, aryl, heteroaryl what I heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro - or cyano;

R²selected from the group consisting of hydroxy, alkyl, alkenyl, cycloalkyl, aryl, -C(O)-aryl, aralkyl, heteroaryl and heteroallyl; where alkyl, cycloalkyl, aryl, kalkilya, heteroaryl or heteroallyl group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^c, -OR^c, -C(O)-OR^c, -C(O)O-(alkyl)-NR^DR^E, -C(O)-NR^D-(alkyl)-NR^DR^E, -C(O)-(heteroseksualci)-NR^DR^E, -C(O)-(heteroseksualci)-R^F, -SO₂-NR^DR^E, -NR^DR^E, -NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^E, -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F, -O-(alkyl)-OSi(alkyl)₃, -O-(alkyl)-OR^Dor-O-(alkyl)-formyl;

in alternate who ate R ¹and R²taken together with the carbon atom to which they relate, with the formation of C(O);

provided that when R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O) and X is selected from the group consisting of O and S, then Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2, CR^AR^BC(O) and CH₂C(O)CH₂;

with the additional proviso that, when R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O) - and Y is selected from the group consisting of O and S, then X is selected from the group consisting of CR^AR^B;

n is an integer selected from 0-4;

each R³independently selected from the group consisting of halogen, hydroxy, R^c, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^G, -SO₂N(R^G)₂, -O-(alkyl)_1-4-C(O)R^Gand

-O-(alkyl)_1-4-C(O)OR^G;

where each R^Gindependently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one, where alkyl, aryl or kalkilya group optionally substituted by one or more substituents, independently selected from alkyl, halogenated what Lila, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

in the alternative case, two groups of R^Gtaken together with the nitrogen atom to which they relate, with the formation of geteroseksualnoe group, where heterocytolysine group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

m is an integer selected from 0-4;

each R⁴independently selected from the group consisting of halogen, hydroxy, R^c, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^G, -SO₂N(alkyl)₂, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G;

provided that, whenrepresents a double bond, X represents CH₂, Y is O, Z represents O and R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O), then at least one of n and m is an integer selected from 1-4; preferably n is an integer from 1-4 and m is an integer from 1-4;

with the additional proviso that whenthe stand is made by a single bond, X represents O, Y is CH(alkyl), Z represents Oh, R¹represents hydrogen and R²represents alkyl, then at least one of n and m is an integer selected from 1-4; preferably n is an integer from 1-4 and m is an integer from 1-4;

with the additional proviso that whenrepresents a single bond, X represents O, Y is CH(alkyl), Z represents Oh, R¹represents hydrogen, R²represents alkyl, n is 1 and m is 1, then R³and R⁴are other than methoxy or ethoxy, preferably R³and R⁴is other than alkoxy;

when the additional condition that, whenrepresents a double bond, X represents O, Y is CH₂Z represents Oh, R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O), n is 0 and m is 2, then each R⁴is not hydroxy or alkoxy;

or its pharmaceutically acceptable salt.

The present invention further relates to the compound of formula (D)

in which

represents a single or double bond,

And vibrant group, consisting of O and S;

D is selected from the group consisting of hydrogen, methyl, acetyl, benzyl, benzoyl, SEM, MOM, BOM, TBS, pivaloyl and-C(O)R, where R is selected from alkyl, aryl and substituted aryl; where the substituents on the aryl group are one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, amino, alkylamino, di(alkyl)amino, nitro or cyano;

each of R¹⁰and R¹¹independently selected from hydrogen, halogen, hydroxy, alkyl, replacement of alkyl, alkoxy, -CH(OH)-aryl, -Cho, -C(O)-alkyl, -C(O)-aryl, -C(O)O-alkyl, -C(O)O-aryl, SEM, MOM, BOM, -CH₂CH₂Och₃, -CH₂CH₂-O-benzyl and pivaloyl, where an alkyl group, regardless of whether to take it separately or as part of a larger group-substituent is optionally substituted by one or more substituents independently selected from hydroxy, halogen or phenyl, where aryl group, regardless of whether to take it separately or as part of a larger group-substituent is optionally substituted by one or more substituents independently selected from hydroxy, alkoxy or alkoxycarbonyl;

provided that R¹⁰and R¹¹are not each hydrogen or each hydroxy;

Z is selected from the group consisting of O and S;

n is an integer selected from 0-4;

m is an integer selected from 0-4;

each R¹³independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

or its pharmaceutically acceptable salt.

The present invention further relates to the compound of formula (D1)

in which

represents a single or double bond,

X is selected from the group consisting of O and S, and Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2(preferably CR^AR^B(CR^AR^B)_1-2selected from-CR^AR^B(CH₂)_1-2, -CH₂CR^AR^BCH₂-, -CR^AR^B-CH(OH)-CR^AR^Bor CR^AR^B-CH₂-CR^AR^B-), CR^AR^BC(O), CR^AR^BC(O)CR^AR^Bpreferably, CH₂C(O)CH₂) and With(O)); alternatively, Y is selected from the group consisting of O and S, and X is selected from the group consisting of CR^AR^Band(About);

provided that, when X is present is employed, a S, then Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2and CH₂C(O)CH₂; provided further that when Y is S, then X is selected from the group consisting of CR^AR^B;

where each of R^Andand R^Bindependently selected from hydrogen, hydroxy, alkyl or alkoxy, provided that each of R^Andand R^Bis not hydroxy;

T is selected from the group consisting of -(aryl)-O-(alkyl)-NR^DR^Eand -(aryl)-O-(alkyl) -;

n is an integer selected from 0-4;

each R³independently selected from the group consisting of halogen, hydroxy, R^C, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^G, -SO₂N(R^G)₂, -O-(alkyl)_1-4-C(O)R^Gand

-O-(alkyl)_1-4-C(O)OR^G;

where R^Cselected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, cycloalkenyl, aryl, kalkilya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently is selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^C, -SO₂-NR^DR^E, -NR^DR^E, -NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F;

where Q is selected from the group consisting of O, S, NH, N(alkyl) and-CH=CH-;

where each of R^Dand R^Eindependently selected from the group consisting of hydrogen or alkyl; or R^Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 3-10-membered, preferably 4-to 8-membered ring selected from the group consisting of heteroaryl or geterotsiklicheskie, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, oxo, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where R^Fselected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, arilje is Aya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro - or cyano;

where each R^Gindependently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one, where alkyl, aryl or kalkilya group optionally substituted by one or more substituents, independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

in the alternative case, two groups of R^Gtaken together with the nitrogen atom to which they relate, with the formation of geteroseksualnoe group, where heterocytolysine group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

m is an integer selected from 0-4;

each R⁴independently selected from the group consisting of halogen, hydroxy, R^c, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^{G , -SO₂N(alkyl)₂, -O-(alkyl)_1-4-C(O)RGand-O-(alkyl)_1-4-C(O)ORG;}

or its pharmaceutically acceptable salt.

The present invention further relates to a method for obtaining compounds of formula (DX)

in which

represents a single or double bond,

X is selected from the group consisting of O and S;

p is an integer from 0-2;

R^Aand R^Beach independently selected from hydrogen, hydroxy, alkyl or alkoxy; provided that each of R^Aand R^Bis not hydroxy;

Z is selected from the group consisting of O and S;

n is an integer from 0-4;

each R¹²independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

m is an integer from 0-4;

each R¹³independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

or its pharmaceutically acceptable salt,

contains

the interaction appropriately substituted compounds of formula (VIII), a known compound or compounds, the famous JV the ways, which Pg¹⁰represents a protective group, with an organic base selected from the group consisting of NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)linolite, to obtain the corresponding compounds of formula (C), where V represents the cation of the corresponding base;

the interaction of the compounds of formula (C) with the appropriately substituted compound of formula (CI), in which E represents an electrophilic and L represents a leaving group, to obtain the corresponding compounds of formula (CII);

removing the protection from the compounds of formula (CII) to obtain the corresponding compounds of formula (CIII);

the cyclization of the compounds of formula (III) with the receipt containing the compounds of formula (DX).

The present invention further relates to a method for obtaining compounds of formula (DXI)

in which

represents a single or double bond,

X is selected from the group consisting of O and S;

U is selected from the group consisting of hydrogen and alkyl;

R^Aand R^Beach independently selected from hydrogen, hydroxy, alkyl or alkoxy; provided that each of R^Aand R^Bis not hydroxy;

Z is selected from the group consisting of O and S;

n is an integer from 0-4;

each R¹²independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

m is an integer from 0-4;

each R¹³independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

or its pharmaceutically acceptable salt,

contains

the interaction appropriately substituted compounds of formula (VIII)are known compounds or compounds obtained by known methods, where Pg¹⁰represents a protective group, with an organic base selected from the group consisting of NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)linolite, to obtain the corresponding compounds of formula (C), where V represents the cation of the corresponding base;

the interaction of the compounds of formula (C) With appropriately substituted aldehyde, a compound of formula (CIV), to obtain the corresponding compounds of formula (CV);

remove protection from the compounds of formula (CV) to obtain the corresponding compounds of formula (CVI);

the cyclization of the compounds of formula (CIVI) to obtain the corresponding compounds of formula (DXI).

The present invention further relates to a method for obtaining compounds of formula (C)

in which

represents a single or double bond,

X is selected from the group consisting of O and S;

Pg¹represents a protective group selected from alkyl, allyl, benzyl, benzoyl, SEM, MOM, BOM and pivaloyl;

V represents the cation of a base selected from the group consisting of Li, Na and K;

R^Aand R^Beach independently selected from hydrogen, hydroxy, alkyl or alkoxy; provided that each of R^Aand R^Bis not hydroxy;

Z is selected from the group consisting of O and S;

n is an integer from 0-4;

each R¹²independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

m is an integer from 0-4;

each R¹³independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

or its pharmaceutically acceptable salt,

contains

in aimogasta appropriately substituted compounds of formula (VIII), known compounds or compounds obtained by known methods, where Pg¹has the above significance, with an organic base selected from the group consisting of LiHMDS, LDA, NaHMDS, KHMDS, and di(lower alkyl)linolite, to obtain the corresponding compounds of formula (C).

The present invention further relates to the product obtained by any of the methods described here.

The illustration of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the above compounds. The illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. The illustration of the invention is a method of manufacturing a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.

An example of the invention are methods of treating disorders mediated by one or more estrogen receptors, the subject in need thereof, containing an introduction to the subject a therapeutically effective amount of any of these compounds or pharmaceutical compositions.

The illustration of the invention is a method for introducing to a subject in need of it, tera is efticiency effective amount of the compounds of formula (I) for co-therapy with a progestogen or progestogen antagonist.

Another example of the invention is the use of any of the compounds described herein, upon receipt of a medicinal product for the treatment of (a) paroxysmal feeling the heat, (b) vaginal dryness, (C) osteopenia (d) osteoporosis, (e) hyperlipidemia, (f) loss of cognitive function, (g) degenerative disorders of the brain, (h) cardiovascular disease, (i) cerebrovascular diseases (j) breast cancer, (K) endometrial cancer, (l) cervical cancer (n) benign prostate hyperplasia() endometriosis, (b) fibrosis of the uterus, (q) osteoarthritis and for (r) contraception in a subject in need thereof.

Detailed description of the invention

The present invention relates to the compound of formula (I)

in which, X, Y, Z, R¹, R², n, R³, m, and R⁴have the values defined here are applicable for the treatment and/or prevention of disorders mediated by the estrogen receptor. More specifically, the compounds of the present invention are applicable to treatment and/or prevention of disorders mediated αand/or β-estrogen receptors. More preferably, the compounds of the present invention are selective for tissue receptor modulators estrogen.

Connection this is subramania are further applicable in the treatment and/or prophylaxis of disorders, associated with the depletion of estrogen, the hormone-sensitive cancers and hyperplasia, endometriosis, uterine fibroids, osteoarthritis, and as contraceptive agents, used alone or in combination with a progestogen or progestogen antagonist.

More specifically, the compounds of the present invention are applicable in the treatment and/or prevention of conditions or disorders selected from the group consisting of paroxysmal feeling the heat, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain damage, cardiovascular disease, cerebrovascular disease, cancer or hyperplasia of the breast tissue, cancer or hyperplasia of the endometrium, cancer or hyperplasia of the cervix, cancer or hyperplasia of the prostate, endometriosis, fibrosis of the uterus and osteoarthritis, and as a contraceptive agent. Preferably a disease selected from the group consisting of osteoporosis, paroxysmal feeling the heat, vaginal dryness, breast cancer and endometriosis.

Have in mind that in the compound of formula (I) relative orientation of the groups R¹and R²is not fixed, but rather, it is assumed that in the definition of the compounds of formula (I) included both possible orientations of the groups.

In the case, to the GDS in the compound of formula (I), Y represents CR ^AR^BC(O), this group is included in the structure of the ring so that the carbonyl group is linked to the atom X.

The present invention further relates to compounds of formula (D)

in whichA, D, Z, R¹⁰, R¹¹, n, R¹², m, and R¹³are these values used as intermediates in obtaining the compounds of formula (I).

The present invention further relates to compounds of the formula (DI)

in whichX, Y, T, n, R³, m, and R⁴are these values used as intermediates in obtaining the compounds of formula (I).

In the embodiment, the present invention features a compound of formula (I), whererepresents a single or double bond,

X is selected from the group consisting of O and S, and Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2, CR^AR^BWith(O) and(O); alternatively, Y is selected from the group consisting of O and S, and X is selected from the group consisting of CR^AR^Band(About);

provided that when X represents S, then Y is selected from the group consisting of CR^AR^Band CR^AR^B(CH₂ )_1-2; provided further that when Y is S, then X is selected from the group consisting of CR^AR^B;

where each of R^Andand R^Bindependently selected from hydrogen, hydroxy, alkyl or alkoxy, provided that each of R^Andand R^Bis not hydroxy:

Z is selected from the group consisting of O and S;

R¹selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroallyl; where cycloalkyl, aryl, kalkilya heteroaryl or heteroallyl group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^c, -OR^c, -SO₂-NR^DR^E, -NR^DR^E, -NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, (alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F;

where R^Cselected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, qi is loukolela, aryl, kalkilya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^C, -SO₂-NR^DR^E, NR^DR^E, NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E,

-(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E,

-(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F;

where Q is selected from the group consisting of O, S, NH, N(alkyl) and-CH=CH-;

where each of R^Dand R^Eindependently selected from the group consisting of hydrogen or alkyl; or R^Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 4-to 8-membered ring selected from the group consisting of heteroaryl or geterotsiklicheskie, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where R^Fvibrant group, consisting of hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, aryl, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro - or cyano;

R²selected from the group consisting of hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroallyl; where cycloalkyl, aryl, kalkilya, heteroaryl or heteroallyl group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^c, -OR^c, -SO₂-NR^DR^E, -NR^DR^E, -NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-4-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F;

in the alternative case, R¹and R²taken instead of the e with the carbon atom, with which they are associated, with the formation of C(O);

provided that when R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O) and X is selected from the group consisting of O and S, then Y is selected from the group consisting of CR^AR^Band CR^AR^B(CH₂)_1-2;

with the additional proviso that, when R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O) - and Y is selected from the group consisting of O and S, then X is selected from the group consisting of CR^AR^B;

n is an integer selected from 0-4;

each R³independently selected from the group consisting of halogen, hydroxy, R^c, amino, alkylamino, dialkylamino, nitro, cyano, SO₂-C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^G, -SO₂N(R^G)₂, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G;

where each R^Gindependently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one, where alkyl, aryl or kalkilya group optionally substituted by one or more substituents, independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

in the alternative the positive case, the two groups R ^Gtaken together with the nitrogen atom to which they relate, with the formation of geteroseksualnoe group, where heterocytolysine group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

m is an integer selected from 0-4;

each R⁴independently selected from the group consisting of halogen, hydroxy, R^c, amino, alkylamino, dialkylamino, nitro, cyano, SO₂-C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^G, -SO₂N(alkyl)₂, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G;

provided that, whenis a double bond, X represents CH₂, Y is O, Z represents O and R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O), then at least one of n or m is an integer selected from 1-4; preferably n is an integer from 1-4 and m is an integer from 1-4;

with the additional proviso that whenis a single bond, X represents O, Y is CH(alkyl), Z represents Oh, R¹to depict the place of a hydrogen and R ²represents alkyl, then at least one of n and m is an integer selected from 1-4; preferably n is an integer from 1-4 and m is an integer from 1-4;

with the additional proviso that whenis a single bond, X represents O, Y is CH(alkyl), Z represents Oh, R¹represents hydrogen, R²represents alkyl, n is 1 and m is 1, then R³and R⁴are other than methoxy or ethoxy, preferably R³and R⁴is other than alkoxy;

when the additional condition that, whenis a double bond, X represents O, Y is CH₂Z represents Oh, R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O), n is 0 and m is 2, then each R⁴is not hydroxy or alkoxy;

or its pharmaceutically acceptable salt.

In the embodiment of the present inventionrepresents a double bond.

In the embodiment of the present invention, when X represents S, then Y is selected from the group consisting of CR^AR^B, CR^AR^B(CH₂)_1-2, CR^AR^BC(O)CR^AR^B(preferably ZNS(O)CH ₂) and CH₂CH₂CH₂; preferably Y represents CR^AR^Bor CR^AR^B(CH₂)_1-2. In another embodiment of the present invention, when Y is S, then X represents CR^AR^B. In another embodiment, the present invention Y is selected from the group consisting of CR^AR^B-CH₂-, -CH₂CR^AR^BCH₂-, -CR^AR^B-CH(OH)-CR^AR^B- and-CR^AR^B-CH₂-CR^AR^B-.

In the embodiment of the present inventionrepresents a double bond; X represents O; Z represents O and Y is selected from the group consisting of-CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH(lower alkoxy)-, -CH(OH)-, -CH(lower alkyl)-, -CH₂C(O)-, -CH₂C(O)CH₂- and-CH₂CH(OH)CH₂-; preferably Y is selected from the group consisting of-CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH(och₃)-, -CH(OH)-, -CH((CH(CH₃)₂)-, -CH₂C(O)-, -CH₂C(O)CH₂- and-CH₂CH(OH)CH₂-; more preferably Y is selected from the group consisting of-CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH(och₃)- and-CH(OH)-; more preferably Y is selected from g is PI, consisting of-CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂- , and-CH(OH)-.

In another embodiment, the present inventionrepresents a double bond; X represents O; Z represents O and Y is selected from the group consisting of Y selected from the group consisting of-CH₂-, -CH₂CH₂-, -CH(lower alkoxy)-, -CH(OH)-, -CH(lower alkyl)- and-CH₂C(O)-; preferably Y is selected from the group consisting of-CH₂-, -CH₂CH₂-, -CH(och₃)-, -CH(OH)-, -CH((CH(CH₃)₂)- and CH₂C(O)-; more preferably Y is selected from the group consisting of-CH₂-, -CH(och₃)- and-CH(OH)-; more preferably Y is selected from the group consisting of-CH₂- , and-CH(OH)-.

In the embodiment of the present invention are the compounds of formula (I)in which X represents O; Y represents CR^AR^Band Z represents O. In another embodiment of the present invention are the compounds of formula (I)in which X represents CR^AR^B, Y is O and Z represents O. in Another embodiment of the present invention are the compounds of formula (I)in which X represents O; Y represents CR^AR^BWith(O) and Z represents O. in Another variations is the implementation of the present invention are the compounds of formula (I), in which X represents O, Z represents O and Y is-CH₂C(O)CH₂-. In another embodiment of the present invention are the compounds of formula (I)in which X represents O, Z represents O and Y is selected from the group consisting of-CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-.

In the embodiment of the present invention X is selected from the group consisting of O and S, preferably X represents O. In another embodiment, the present invention Y is selected from the group consisting of O and S, preferably Y is O. Preferably Z represents O.

In the embodiment of the present invention X represents CR^AR^B. In another embodiment, the present invention Y is selected from the group consisting of CR^AR^B, CR^AR^BCH₂and CR^AR^BS(O).

In the embodiment of the present invention R^Aand R^Beach independently selected from the group consisting of hydrogen, hydroxy, alkyl and alkoxy; provided that R^Aand R^Bis not each hydroxy. In a preferred embodiment of the present invention R^Aand R^Beach independently selected from the group consisting of hydrogen, isopropyl and methoxy, priruslovye, as R^Aand R^Bnot represent hydroxy. In another embodiment, the present invention R^Aand R^Beach independently selected from the group consisting of hydrogen, hydroxy and methoxy.

In the embodiment of the present invention R¹selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, -C(O)-aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl); where the lower alkyl, aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO₂, NO₂CN, -C(O)-(lower alkyl), CO₂N, R^c, -SO₂-NR^DR^E, -NR^DR^E, -NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E-C(O)O-(lower alkyl)-NR^DR^E-C(O)-NH-(lower alkyl)-NR^DR^E-C(O)-(N-containing heterocycle (where specified N-containing heterocycle linked through the N atom))-NR^DR^E-C(O)-(N-containing heterocycle (where specified N-containing heterocycle linked through the N atom))-R^f, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)sub> 0-1-(alkyl)_0-4-C(O)-NR^DR^E, -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)OR^F, -O-(lower alkyl)-OSi(lower alkyl)₃, -O-(lower alkyl)-OR^Dor O-(lower alkyl), formyl.

In another embodiment, the present invention R¹selected from the group consisting of hydrogen and lower alkyl, preferably R¹selected from the group consisting of hydrogen and methyl. In another embodiment, the present invention R¹represents hydrogen.

In the embodiment of the present invention R¹represents hydrogen and R²has R-stereoconfiguration. In another embodiment, the present invention R¹represents hydrogen and R²has S-stereoconfiguration.

In the embodiment of the present invention R¹selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO₂, NO₂CN, CO₂N, R^With, -SO₂-NR^DR^E, -NR^DR^E, NR^D-SO₂-R^F, (alkyl)_0-4-C(O)NR^DR^E, -alkyl) _0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor

-(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F.

Preferably R¹selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO₂, NO₂CN, CO₂N, R^Withor NR^DR^E.

More preferably R¹selected from the group consisting of hydrogen and lower alkyl. Even more preferably R¹selected from the group consisting of hydrogen and methyl.

In the embodiment of the present invention R^Cselected from the group consisting of lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl(lower alkyl), geterotsiklicheskie and heteroseksualci(lower alkyl), where aryl, kalkilya, heteroaryl, heteroaryl(lower alkyl), heterocytolysine or heteroseksualci(lower alkyl) group optionally substituted by one or two substituents, n is dependent selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^C, -SO₂-NR^DR^E, NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F.

Preferably R^Cselected from the group consisting of lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl(lower alkyl), geterotsiklicheskie and heteroseksualci(lower alkyl), where aryl, kalkilya, heteroaryl, heteroaryl(lower alkyl), heterocytolysine or heteroseksualci(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^Cor NR^DR^E.

More preferably R^Cselected from the group consisting of lower alkyl and aralkyl. Even more preferably R^Cselected from the group consisting of methyl, isopropyl and benzyl.

In the embodiment of the present invention Q is selected from the group consisting of O, S and-CH=CH-. Preferably Q is selected the C group, consisting of O and-CH=CH-, more preferably Q represents O.

In the embodiment of the present invention R^Dand R^Eeach independently selected from the group consisting of hydrogen and lower alkyl. In another embodiment, the present invention R^Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 4-to 8-membered cycle, selected from the group consisting of heteroaryl or geterotsiklicheskie; where the heteroaryl or heterocytolysine group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano. In another embodiment, the present invention R^Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 5 - or 6-membered cycle, selected from the group consisting of heteroaryl and geterotsiklicheskie; where the heteroaryl or heterocytolysine group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano.

In another embodiment, the present invention R^Dand R^Eeach independently chosen is from the group consisting of hydrogen, methyl, ethyl or isopropyl.

In another embodiment, the present invention R^Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 5 - or 6-membered cycle, selected from the group consisting of heteroaryl and geterotsiklicheskie; where the heteroaryl or heterocytolysine group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, oxo, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano. Preferably R^Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 5-6-membered cycle, selected from the group consisting of azepane, morpholine, pyridyl, piperidinyl, piperazinil, pyrrolidinyl, piperidinyl-2,6-dione and pyrrolidinyl-2,5-dione.

In the embodiment of the present invention R^Fselected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl(lower alkyl), geterotsiklicheskie and heteroseksualci(lower alkyl), where aryl, heteroaryl, heteroaryl(lower alkyl), heterocytolysine or heteroseksualci(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, nor is our alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano. Preferably R^Fselected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; where aryl optionally substituted with halogen. More preferably R^Fselected from the group consisting of hydrogen, methyl, 4-ftoheia and 2-pyridyl.

In the embodiment of the present invention R²selected from the group consisting of hydroxy, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO₂, NO₂CN, CO₂H, R^c, -OR^c, -SO₂-NR^DR^E, -NR^DR^E, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F.

Preferably R²selected from the group consisting of hydroxy, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, Araki the other, heteroaryl or heteroaryl(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO₂, NO₂CN, CO₂H, R^c, -OR^cor-NR^DR^E.

More preferably R²selected from the group consisting of hydroxy, aryl, 4-(1-geterotsiklicheskikh)phenyl, 4-(di(alkyl)aminoethoxy)phenyl, 4-(di(alkyl)amino)phenyl and 4-aralkylamines. Even more preferably R²selected from the group consisting of hydroxy, phenyl, 4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, 4-(diethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl, 4-(dimethylamino)phenyl, 4-benzyloxyphenol and 4-(1-piperidinyl-n-propoxy)phenyl. Even more preferably R²selected from the group consisting of phenyl, 4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, 4-(diethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl, 4-(dimethylamino)phenyl and 4-(1-piperidinyl-n-propoxy)phenyl. Even more preferably R²selected from the group consisting of phenyl, 4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, 4-(di is traminette)phenyl, 4-(dimethylaminoethoxy)phenyl and 4-(dimethylamino)phenyl. Even more preferably R²selected from the group consisting of phenyl, 4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, 4-(dimethylaminoethoxy)phenyl and 4-(dimethylamino)phenyl.

In another embodiment, the present invention R²selected from the group consisting of -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^Eor-(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)OR^F. In another embodiment, the present invention R²selected from the group consisting of -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^Ewhere R^Dand R^Etaken together with the nitrogen atom to which they are connected, forming a 5-7 membered cycle, selected from the group consisting of heteroaryl and geterotsiklicheskie.

In another embodiment, the present invention R²selected from the group consisting of hydroxy, lower alkyl, lower alkenyl, aryl, -C(O)-aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl); where the lower alkyl, aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl) group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(NISS the th alkyl), SO₂, NO₂CN, -C(O)-(lower alkyl), CO₂N, R^c, -OR^c, -SO₂-NR^DR^E, -NR^DR^E, -(alkyl)_0-4-C(O)NR^DR^E-C(O)O-(lower alkyl)-NR^DR^E-C(O)-NH-(lower alkyl)-NR^DR^E-C(O)-(N-containing heteroseksualci (where specified N-containing heteroseksualci connected through the N atom))-NR^DR^E-C(O)-(N-containing heteroseksualci (where specified N-containing heteroseksualci connected through the N atom))-R^f, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^E, -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F, -O-(lower alkyl)-OSi(lower alkyl)₃, -O-(lower alkyl)-OR^Dor-O-(lower alkyl), formyl.

Preferably R²selected from the group consisting of hydroxy, lower alkenyl, carboxy-lower alkyl, hydroxy-lower alkyl, aryl, 4-(1-N-containing heteroseksualci (where specified N-containing heteroseksualci connected through the N atom))phenyl, 4-(di(lower alkyl)aminoethoxy)phenyl, 4-(di(lower alkyl)amino)phenyl, 4-aralkylamines, lower alkoxycarbonyl-lower alkyl, 4-(lower alkoxy-lower alkoxy)phenyl, di(lower alkyl)amino(lower alkoxy)carbonyl(lower alkyl), (N is aderrasi heteroseksualci (where specified N-containing heteroseksualci connected through N-atom)(lower alkoxy)carbonyl(lower alkyl), (N-containing heteroseksualci (where specified N-containing heteroseksualci connected through N-atom)(lower alkyl)aminocarbonyl(lower alkyl), (N-containing heteroseksualci (where specified N-containing heteroseksualci connected through N-atom)-C(O)-(lower alkyl), (halogen-substituted aryl)-(N-containing heteroseksualci (where specified N-containing heteroseksualci connected through the N atom))carboxy(lower alkyl), 4-((N-containing heteroseksualci(lower alkoxy))vinylcarbazole, 2-hydroxy-2-(4-N-containing heteroseksualci-lower alkoxy)phenylethyl, 4-(three(lower alkyl)silyloxy(lower alkoxy)phenyl, 4-(hydroxy-lower alkoxy)phenyl, 4-(formyl-lower alkoxy)phenyl, 4-(carboxy-lower alkoxy)phenyl, 4-(lower alkoxycarbonyl-lower alkoxy)phenyl, 4-(piperidine-2,6-Dion-lower alkoxy)phenyl, 4-(pyrrolidinyl-2,5-dione(lower alkyl)phenyl, R-4-(pyrrolidinyl-2,5-dione(lower alkoxy)phenyl, and S-(4-pyrrolidinyl-2,5-dione(lower alkoxy)phenyl.

More preferably R²selected from the group consisting of hydroxy, allyl, carboxymethyl, hydroxyethyl, 3-hydroxy-n-propyl, phenyl, 3-(1-piperidinyloxy)phenyl, 4-(1-piperidinyloxy)phenyl, S-4-(piperidinyloxy)phenyl, R-4-(piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, R-4-(1-separators)phenyl, S-4-(1-aseanet the XI)phenyl, 4-(diethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl, R-4-(dimethylaminoethoxy)phenyl, S-4-(dimethylaminoethoxy)phenyl, 4-(diisopropylaminoethyl)phenyl, R-4-(diisopropylaminoethyl)phenyl, S-4-(diisopropylaminoethyl)phenyl, 4-(dimethylamino)phenyl, 4-benzyloxyphenyl, 4-(1-piperidinyl-n-propoxy)phenyl, 4-(tert-butyldimethylsilyloxy)phenyl, 4-(methoxyethoxy)phenyl, methoxycarbonylmethyl, isopropoxycarbonyloxymethyl, dimethylaminocarbonylmethyl, piperidinecarbonitrile, pyrrolidinylcarbonyl, morpholinylcarbonyl, dimethylamino-n-propoxycarbonyl and morpholinylcarbonyl, morpholinyl-n-propylenecarbonate, pyrrolidinedithiocarbamate, 4-(2-pyridyl)piperazinylcarbonyl, 4-(4-forfinal)piperazinylcarbonyl, 4-(piperidinyloxy)phenylcarbamoyl, 2-hydroxy-2-(4-(piperidinyloxy)phenyl)ethyl, 4-(2-hydroxyethoxy)phenyl, R-4-(2-hydroxyethoxy)phenyl, S-4-(2-hydroxyethoxy)phenyl, 4-(3-hydroxy-n-propoxy)phenyl, R-4-(3-hydroxy-n-propoxy)phenyl, S-4-(3-hydroxy-n-propoxy)phenyl, 4-(formulators)phenyl, 4-(carboxymethoxy)phenyl, 4-(carboxymethoxy)phenyl, 4-(ethoxycarbonylmethoxy)phenyl, 4-(ethoxycarbonylmethoxy)phenyl, R-4-(piperidinyl-2,6-donatacci)phenyl, R-4-(pyrrolidinyl-2,5-Dion-ethoxy)phenyl, S-4-(pyrrolidinyl-2,5-Dion-ethoxy)FeNi is a, R-4-(pyrrolidinyl-2,5-dione-n-propoxy)phenyl, and S-4-(pyrrolidinyl-2,5-dione-n-propoxy)phenyl.

Even more preferably R²selected from the group consisting of phenyl, 4-(1-piperidinyloxy)phenyl, R-4-(1-piperidinyloxy)phenyl, S-4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, R-4-(separators)phenyl, S-4-(separators)phenyl, 4-(diethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl, R is 4-(dimethylaminoethoxy)phenyl, S-4-(dimethylaminoethoxy)phenyl, R-4-(diisopropylaminoethyl)phenyl, S-4-(diisopropylaminoethyl)phenyl, 4-(dimethylamino)phenyl, 4-(3-hydroxy-n-propoxy)phenyl and 4-(ethoxycarbonylmethoxy).

Even more preferably R²selected from the group consisting of phenyl, 4-(1-piperidinyloxy)phenyl, R-4-(1-piperidinyloxy)phenyl, S-4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, R-4-(separators)phenyl, S-4-(separators)phenyl, 4-(diethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl, R is 4-(dimethylaminoethoxy)phenyl, S-4-(dimethylaminoethoxy)phenyl, R-4-(diisopropylaminoethyl)phenyl, S-4-(diisopropylaminoethyl)phenyl, 4-(dimethylamino)phenyl, 4-(3-hydroxy-n-propoxy)phenyl and 4-(ethoxycarbonylmethoxy).

Even more preferably R²selected from the group consisting of Anila, 4-(1-piperidinyloxy)phenyl, R-4-(1-piperidinyloxy)phenyl, S-4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl, R-4-(separators)phenyl, S-4-(separators)phenyl, 4-(dimethylaminoethoxy)phenyl, R-4-(dimethylaminoethoxy)phenyl, S-4-(dimethylaminoethoxy)phenyl R-4-(diisopropylaminoethyl)phenyl, S-4-(diisopropylaminoethyl)phenyl, 4-(dimethylamino)phenyl, 4-(3-hydroxy-n-propoxy)phenyl and 4-(ethoxycarbonylmethoxy).

In another embodiment, the present invention R²selected from the group consisting of aryl, substituted-O-(alkyl)-NR^DR^E.

In the embodiment of the present invention are the compounds of formula (I)in which R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O).

In another embodiment, the present invention R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O) - and Y is selected from the group consisting of CR^AR^B, CR^AR^B(CH₂)_1-2, CR^AR^BC(O), CH₂C(O)CH₂and CH₂CR^AR^BCH₂preferably CR^AR^B, CR^AR^B(CH₂)_1-2CR^AR^BWith(O) and CH₂C(O)CH₂. More preferably, R¹and R²taken together with the volume of carbon with which they are associated, with the formation of C(O) - and Y is selected from the group consisting of CH₂CH₂CH₂CH₂CH₂CH₂CH₂With(O) and CH₂C(O)CH₂.

In the embodiment of the present invention n is an integer selected from 0 to 2. Preferably n is an integer selected from 0-1. In another embodiment, the present invention n is 1.

In the embodiment of the present invention, the substituent R³linked 2-position of the cyclic structure.

In the embodiment of the present invention R³selected from the group consisting of halogen, hydroxy, R^C, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro, cyano, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -OSi(R^G)₃, -OR^G, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G.

Preferably R³selected from the group consisting of hydroxy, R^C, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -OSi(R^G)₃, -OR^G, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G.

More preferably, R³selected from the group consisting of halogen, hydroxy, lower alkoxy, three(lower alkyl)silyloxy, -OC(O)-(lower alkyl), -OC(O)-(phenyl)-OC(O)-(lower alkyl), -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.2]heptane-3-one) and-OC(O)-(CH₃)(CFsub> 3)-phenyl. Even more preferably, R³selected from the group consisting of fluorine, hydroxy, methoxy, tert-butyldimethylsilyloxy, -OC(O)-methyl, -OC(O)-tert-butyl, -OC(O)-(phenyl)-OC(O)CH₃, -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one) and-OC(O)-(CH₃)(CF₃)-phenyl. Even more preferably, R³selected from the group consisting of hydroxy, methoxy, and-OC(O)-tert-butyl. Even more preferably, R³selected from the group consisting of hydroxy and-OC(O)-tert-butyl.

In the embodiment of the present invention R^Gselected from hydrogen, lower alkyl (preferably methyl), aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one, where alkyl, aryl or kalkilya group optionally substituted by one or two substituents, independently selected from lower alkyl, halogenated lower alkyl, lower alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-(lower alkyl) or-C(O)O-(lower alkyl).

In another embodiment, the present invention two groups of R^Gtaken together with the nitrogen atom to which they relate, with the formation of 5-6-membered geteroseksualnoe group, where heterocytolysine group optionally substituted by one or two substituents, independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (NISS the th alkyl)amino, di(lower alkyl)amino, nitro or cyano.

Preferably, R^Gselected from the group consisting of lower alkyl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one, where kalkilya group optionally substituted lower alkyl, halogenated alkyl, or-OC(O)-(lower alkyl). More preferably, R^Gselected from the group consisting of methyl, tert-butyl, -C(CH₃)(CF₃)-phenyl, -CH(OC(O)CH₃)phenyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one.

In the embodiment of the present invention m is an integer selected from 0 to 2. Preferably, m is an integer of 0 or 1. In another embodiment, the present invention m is 1.

In the embodiment of the present invention, the substituent R⁴associated with 8 - or 9-position of a cyclic structure.

In the embodiment of the present invention R⁴selected from the group consisting of halogen, hydroxy, R^c, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro, cyano, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -OSi(R^G)₃, -OR^G, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G.

Preferably, R⁴selected from the group consisting of hydroxy, R^c, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -OSi(R^G)₃, -OR^G, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl) _1-4-C(O)OR^G;

More preferably, R⁴selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, three(lower alkyl)silyloxy, -OC(O)-(lower alkyl), -OC(O)-(phenyl)-OC(O)-(lower alkyl), -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one) and-OC(O)-(CH₃)(CF₃)-phenyl. Even more preferably, R⁴selected from the group consisting of hydroxy, methyl, methoxy, tert-butyldimethylsilyloxy, -OC(O)-methyl, -OC(O)-tert-butyl, -OC(O)-(phenyl)-OC(O)CH₃, -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one) and-OC(O)-(CH₃)(CF₃)-phenyl. Even more preferably, R⁴selected from the group consisting of fluorine, hydroxy, methoxy, and-OC(O)-tert-butyl. Even more preferably, R⁴selected from the group consisting of hydroxy and-OC(O)-tert-butyl.

In the embodiment of the present inventionrepresents a single or double bond.

X is selected from the group consisting of O and S, and Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2(preferably CR^AR^B(CR^AR^B)_1-2selected from-CR^AR^B(CH₂)_1-2, -CH₂CR^AR^BCH₂-, -CR^AR^B-CH(OH)-CR^AR^Bor CR^AR^B-CH₂-CR^AR^B-), CR^AR^BWith(O) and CR^A R^BC(O)CR^AR^B(preferably CH₂C(O)CH₂); alternatively, Y is selected from the group consisting of O and S, and X is selected from the group consisting of CR^AR^Band(About);

provided that when X represents S, then Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2and CH₂C(O)CH₂; with the additional proviso that when Y is S, then X is selected from the group consisting of CR^AR^B;

where each of R^Andand R^Bindependently selected from hydrogen, hydroxy, alkyl or alkoxy, provided that each of R^Andand R^Bis not hydroxy;

Z is selected from the group consisting of O and S;

R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O);

provided that when X is selected from the group consisting of O and S, then Y is selected from the group consisting of CR^AR^B, CR^AR^B(CR^AR^B)_1-2, CR^AR^BC(O) and CH₂C(O)CH₂;

with the additional proviso that when Y is selected from the group consisting of O and S, then X is selected from the group consisting of CR^AR^In;

n is an integer selected from 0 to 4;

each R³independently selected from the group consisting of halogen, hydroxy, R^c, amino, alkylamino, dialkylamino, nitro, qi is but -C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^G, -SO₂N(R^G)₂, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G;

where R^Cselected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, cycloalkenyl, aryl, kalkilya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO₂, NO₂CN, CO₂H, R^C, -SO₂-NR^DR^E, NR^DR^E, NR^D-SO₂-R^F, -(alkyl)_0-4-C(O)NR^DR^E, -(alkyl)_0-4-NR^D-C(O)-R^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-NR^DR^E, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-OR^F, -(alkyl)_0-4-(Q)_0-1-(alkyl)_0-4-C(O)-NR^DR^Eor -(alkyl)_0-4-C(O)-(alkyl)_0-4-C(O)-OR^F;

where Q is selected from the group consisting of O, S, NH, N(alkyl) and-CH=CH-;

where each of R^Dand R^Eindependently selected from the group consisting of hydrogen or alkyl; or R Dand R^Etaken together with the nitrogen atom to which they relate, with the formation of 3-10-membered, preferably 4-to 8-membered ring selected from the group consisting of heteroaryl or geterotsiklicheskie, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, oxo, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where R^Fselected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, geterotsiklicheskie and geterotsiklicheskikh where cycloalkyl, aryl, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro - or cyano;

where each R^Gindependently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one, where alkyl, aryl or kalkilya group optionally substituted by one or more substituents, independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

m is an integer selected from 0-4;

each R⁴independently selected from the group consisting of halogen, hydroxy, R^c, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)R^G-C(O)OR^G, -OC(O)R^G, -OC(O)OR^G, -OC(O)N(R^G)₂, -N(R^G)C(O)R^G, -OSi(R^G)₃, -OR^G, -SO₂N(alkyl)₂, -O-(alkyl)_1-4-C(O)R^Gand-O-(alkyl)_1-4-C(O)OR^G;

provided that, whenis a double bond, X represents CH₂, Y is O, Z represents O and R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O), then at least one of n or m is an integer selected from 1-4; preferably n is an integer from 1-4 and m is an integer from 1-4;

with the additional proviso that whenis a double bond, X represents O, Y is CH₂Z made the grants themselves, R¹and R²taken together with the carbon atom to which they relate, with the formation of C(O), n is 0 and m is 2, then each R⁴is not hydroxy or alkoxy.

or its pharmaceutically acceptable salt.

In the embodiment of the present invention are the compounds of formula (D), whererepresents a single or double bond,

And selected from the group consisting of O and S;

D is selected from the group consisting of hydrogen, methyl, acetyl, benzoyl, SEM, MOM, BOM, TBS, pivaloyl and-C(O)R, where R is selected from alkyl, aryl and substituted aryl; where the substituents on the aryl group are one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, amino, alkylamino, di(alkyl)amino, nitro or cyano;

each of R¹⁰and R¹¹independently selected from hydrogen, halogen, hydroxy, alkyl, replacement of alkyl, alkoxy, -CH(OH)-aryl, -Cho, -C(O)-aryl, -C(O)O-alkyl, -C(O)O-aryl and pivaloyl, provided that each of R¹⁰and R¹¹is not hydroxy;

Z is selected from the group consisting of O and S;

n is an integer from 0-4;

each R¹²independently selected from the group consisting of hydroxy, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy;

m is an integer selected the WMD from 0-4;

each R¹³independently selected from the group consisting of hydroxy, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkylated, SEM, Momoki, pivaloyloxy.

In the embodiment of the present invention are the compounds of formula (D)where And represents About and Z represents O.

In the embodiment of the present invention, each of R¹⁰and R¹¹independently selected from hydrogen, halogen, replacement of alkyl, halogen-substituted to the alkyl, -Cho, -CH(OH)-phenyl, aryl (which aryl group is optionally substituted by hydroxy, alkoxy or alkoxycarbonyl), -C(O)-alkyl, -C(O)-(of halogensubstituted alkyl),-C(O)-phenyl, C(O)O-alkyl, -C(O)-(alkyl)-O-(alkyl), -C(O)O-phenyl, -(alkyl)-O-(alkyl) and -(alkyl)-O-(alkyl)-Si(alkyl)₃. In the preferred embodiment of the present invention R¹⁰selected from the group consisting of hydrogen and bromine, preferably hydrogen; and R¹¹selected from the group consisting of hydrogen, bromine, iodmethyl, chlormethyl, -Cho, -CH₂HE, -CH(OH)CH₂CH₂CH₃, -CH(OH)-phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-(methoxycarbonyl)phenyl, -C(O)CH₂-Cl, -C(O)och₃-C(O)-CH₂-O-CH₃-C(O)O-phenyl, -CH₂-O-CH₃and CH₂-O-CH₂CH₂-Si(CH₃)₃.

In another embodiment, assests the of the present invention, each of R ¹⁰and R¹¹independently selected from the group consisting of hydrogen, halogen, replacement of alkyl, -Cho, -CH(OH)-phenyl, -C(O)-phenyl, -C(O)O-alkyl and-C(O)O-phenyl. In a preferred embodiment of the present invention R¹⁰represents hydrogen and R¹¹selected from the group consisting of hydrogen, bromine, -Cho, -CH₂HE, -CH(OH)CH₂CH₂CH₃, -CH(OH)-phenyl, -C(O)och₃and-C(O)O-phenyl.

In the embodiment of the present invention, each of R¹²and R¹³independently selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, aralkylated, SEM, Momoki, pivaloyloxy and-OSi(lower alkyl)₃. In another embodiment of the present invention, each of R¹²and R¹³independently selected from the group consisting of halogen, hydroxy, methyl, methoxy, ethoxy, isopropoxy, benzoyloxy, SEM, Momoki, pivaloyloxy and tert-butyldimethylsilyloxy. In another embodiment of the present invention, each of R¹²and R¹³independently selected from the group consisting of hydroxy, methoxy, ethoxy, isopropoxy, benzoyloxy, SEM, Momoki, pivaloyloxy. In another embodiment of the present invention, each of R¹²and R¹³independently selected from the group consisting of hydroxy, methoxy, benzyloxy, is benzoyloxy, Momoki, SEM, pivaloyloxy,

In the embodiment of the present invention, D is selected from the group consisting of hydrogen, methyl, methylcarbamyl, benzoyl, SEM, MOM and pivaloyl. In another embodiment of the present invention, D is selected from the group consisting of hydrogen, methyl, benzoyl, SEM, MOM and pivaloyl.

In the embodiment of the present invention are the compounds of formula (DI), in which Y is selected from the group consisting of-CH₂- and-CH₂CH₂-.

In another embodiment of the present invention are the compounds of formula (DI), in which T is selected from the group consisting of -(aryl)-O-(alkyl)-NR^DR^Eand -(aryl)-O-(alkyl) -. Preferably T is selected from the group consisting of 4-(piperidinyloxy)phenyl and 4-(3-hydroxyprop-1 yloxy)phenyl. In another embodiment, the present invention T is selected from the group consisting of (phenyl)-O-(lower alkyl)-NR^DR^E.

In the embodiment of the present invention includes a method of obtaining the compounds of formula (DX), described in more detail in scheme 16, which is presented here below.

In another embodiment, the present invention includes a method of obtaining the compounds of formula (DXI), described in more detail in scheme 17, which is presented here below.

In another embodiment, the present and the finding there way to obtain the compounds of formula (C), described in more detail in schemes 16 and 17, which are presented here below.

In another embodiment, the present invention includes a method of obtaining the compounds of formula (I)containing the interaction of the compounds of formula (DX) or the compounds of formula (DXI) according to the method indicated in figure 3, figure 10, figure 12 or figure 15, which are presented here below.

In the embodiment of the present invention include a compound obtained by any of the methods described here.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may be used for obtaining the compounds according to this invention and their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid additive salts, which can be, for example, obtained by mixing a solution of the compound with a solution of the pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds of the invention have acid part, suitable pharmaceutically acceptable salts can vkljucitev yourself alkali metal salts, for example, salts of sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium; and salts formed with suitable organic ligands, e.g. Quaternary ammonium salts. Thus, a typical pharmaceutically acceptable salts include salts: acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calculatedat, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, Hydrobromic, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, synthesis salt, N-methylglucamine, oleate, pamoate (embonate), palmitate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannat, tartrate, teoclate, tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of the compounds of the present invention. In General, such prodrugs will be functional derivatives of the compounds, which are easily transformed in vivo into the required compound. Thus, in the treatment methods of the present invention, the term "introduction" will include the impact of the treatment of various violations described connection specifically described, or in connection, which may not be specifically described, but which turns into a specific compound in vivo after administration to the patient. Conventional procedures for selecting and obtaining the appropriate proletarienne derivatives described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

When the compounds of this invention have at least one chiral center, they may accordingly exist as enantiomers. When the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are included in the scope of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and we mean that as such they are included in the present invention. In addition, some compounds may form a solvate with water (i.e. hydrates) or common organic solvents, and have in mind that such a solvate is also included in the scope of this invention.

Used herein, the term "degenerative disease of the brain" will include impaired cognitive ability, dementia, regardless of its underlying causes, and Alzheimer's disease.

Used herein, the term "cardiovascular ill is the" will include elevated levels of lipids in the blood, coronary arthrosclerosis and coronary heart disease.

Used herein, the term "cerebrovascular disease" will include abnormal regional cerebral blood flow and ischemic brain damage.

Used herein, the term "antagonist of progestogen" will include mifepristone (RU-486), J-867 (Jenapharm/TAP Pharmaceuticals), J-965 (Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638 (Organon), ORG-31806 (Organon), onapristone (ZK98299) and PRA248 (Wyeth).

Used here, unless otherwise noted, the term "halogen" shall mean chlorine, bromine, fluorine and iodine.

Used here, unless otherwise noted, the term "alkyl", regardless if they use it separately or as part of a group of substituent includes an unbranched or branched chain of from one to eight carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. Unless otherwise noted, the term "lower" when used with alkyl means carbon chain composition of 1-4 carbon atoms. Similarly, the group "-(alkyl)_0-4-"regardless of if they use it separately or as part of a large group-Deputy, would be the absence of the alkyl groups or the presence of alkyl groups containing from one to four carbon atoms. P is Rhodesia examples include, but not limited to, -CH₂-, -CH₂CH₂-, -CH₂CH(CH₃)-, -CH₂CH₂CH₂-, -CH₂CH(CH₃)CH₂-, -CH₂CH₂CH₂CH₂- and the like.

Used here, unless otherwise noted, the term "alkenyl" shall mean a carbon chain comprising from one to eight carbon atoms and containing at least one double bond. Suitable examples include, but are not limited to, allyl, crotyl, 2-butenyl, 2-pentenyl and the like. Unless otherwise noted, the term "lower" when used with alkenyl will mean alkenylphenol carbon chain containing from one to four carbon atoms, such as allyl and the like.

Used here, unless otherwise noted, the term "alkoxy" shall mean containing simple oxygen ether radical of the above-described alkyl groups, unbranched or branched chain. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butoxy, n-hexyloxy and the like. Unless otherwise noted, the term "lower" when used with alkoxy means alkoxygroup (simple oxygen ether radical, as described above), containing from one to four carbon atoms. Suitable examples include, but are not limited to read the Lenno methoxy, ethoxy, isopropoxy, n-propoxy and the like.

Used here, unless otherwise noted, the term "aryl" is refers to unsubstituted carbocyclic aromatic groups such as phenyl, naphthyl and the like.

Used here, unless otherwise noted, the term "aralkyl" shall mean any lower alkyl group, a substituted aryl group such as phenyl, naphthyl and the like. Suitable examples include benzyl, phenylethyl, phenylpropyl, naphthylmethyl and the like.

Used here, unless otherwise noted, the term "cycloalkyl" shall mean any stable 3 to 8-membered monocyclic saturated cyclic system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Used here, unless otherwise noted, the term "cycloalkyl" shall mean any lower alkyl group, a substituted cycloalkyl group. Suitable examples include, but are not limited to, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl and the like.

Used here, unless otherwise noted, the term "acyloxy" will mean a radical of the formula-O-C(O)-R in which R represents alkyl, aryl or aralkyl, where the alkyl, aryl or aralkyl is optionally substituted. Used here t is pmin "carboxylate" will mean a radical group of the formula-C(O)O-R, in which R represents alkyl, aryl or aralkyl, where the alkyl, aryl or aralkyl is optionally substituted.

Used here, unless otherwise noted, the term "heteroaryl" shall mean any three-decatizing monocyclic or bicyclic aromatic cyclic structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms, independently selected from the group consisting of O, N and S. Preferably, the heteroaryl group is five - or six-membered monocyclic aromatic cyclic structure containing at least one heteroatom selected from the group consisting of O, N and S not necessarily containing one to four additional heteroatoms, independently selected from the group consisting of O, N and S, or a nine - or deletechannel bicyclic aromatic cyclic structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms, independently selected from the group consisting of O, N and S. the Heteroaryl group may be attached at any heteroatom or carbon atom of the ring, so that the result is a stable structure.

P is emery of suitable heteroaryl groups include, but not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furutani, indolizinyl, indolyl, isoindolyl, indazoles, benzofuran, benzothiazyl, benzimidazolyl, benzothiazolyl, purinol, hemolysins, chinoline, ethenolysis, isothiazolin, cinnoline, phthalazine, hintline, honokalani, naphthyridine, pteridinyl and the like.

Used here, unless otherwise noted, the term "heteroaromatic" shall mean any lower alkyl group, a substituted heteroaryl group. Suitable examples include, but are not limited to, pyridylmethyl, izohinolinove, triazolylmethyl, purolater and the like.

Used herein, the term "heteroseksualci" shall mean any three - decatizing monocyclic or bicyclic, saturated, partially unsaturated or partially aromatic cyclic structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms, independently selected from the group consisting of O, N and S. Preferably heteroseksualci is a five or six-membered monocyclic, saturated or frequent is a rule unsaturated cyclic structure, containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms, independently selected from the group consisting of O, N and S; or a nine-decatizing bicyclic, saturated, partially unsaturated or partially aromatic bicyclic system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms, independently selected from the group consisting of O, N and S. Heterocytolysine group may be attached at any heteroatom or carbon atom of the ring, so that the result is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, pyrrolidinyl, DIOXOLANYL, imidazolines, imidazolidinyl, pyrazolyl, pyrazolidine, piperidine, dioxane, morpholine, dithienyl, thiomorpholine, piperazinil, tritional, indolinyl, bromanil, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuranyl and the like.

Preferred heterocytolysine group include morpholinyl, piperidinyl, piperazinil, pyrrolidinyl, azepane and 2-oxabicyclo[2.2.1]heptane.

Used here, unless otherwise noted, the term "geterotsiklicheskikh" Bud the t to mean any lower alkyl group, substituted geteroseksualnoe group. Suitable examples include, but are not limited to, piperidinylmethyl, piperazinylmethyl, piperazinylmethyl, morpholinylmethyl and the like.

Used herein, the term "N-containing heteroseksualci (where specified N-containing heteroseksualci connected through N-atom)" shall mean any heteroseksualci described above, which contains at least one N-atom and which is connected through the N-atom. Suitable examples include, but are not limited to, 1-piperidinyl, 4-piperazinil, 1-pyrrolidinyl, 4-morpholinyl, 1-azepane and the like.

Used herein, the symbol "*" will denote the presence of a stereogenic center.

When a particular group is "substituted" (e.g., cycloalkyl, aryl, heteroaryl, heteroseksualci), that group may have one or more substituents, preferably from one to five substituents, more preferably one to three substituents, most preferably from one to two substituents independently selected from the list of substituents. In addition, when kalkilya, heteroallyl, geterotsiklicheskikh or cycloalkenyl group is substituted, the substituent(s) may be on any part of the group (i.e. the substituent(s) can be settled and aryl, heteroaryl, geteroseksualnoe, cycloalkyl or the alkyl part of the group).

In relation to substituents, the term "independently" means that when more than one of such substituents, such substituents may be the same or different from each other.

According to the standard nomenclature used throughout this description, the end part of the specified side chain is described first, followed by the neighboring functional group in the direction of the connection point. For example, the Deputy of "phenyl-C₁-C₆-alkylaminocarbonyl-C₁-C₆-alkyl" is a group of the formula

Unless otherwise stated, while naming substituents, such as group R³and R⁴will use the following numbering of a cyclic structure. Capital letters a, b, C and D will be used to denote certain rings tetracyclic structure.

Used herein, the term "leaving group" shall mean any group that is cleaved from the substrate during the reaction in which the substrate is cleaved. Suitable examples include, but are not limited to, Cl, Br, I, tosylate, mesilate, triplet, hydroxy and the like.

Used herein, the term "electrophile" will mean the atom Il the molecule, which accepts a pair of electrons. Suitable examples include, but are not limited to, Br, Cl, I, CH₃, SEM, MOM, BOM, -C(O)CH₂-Och₃-C(O)-CH₂-Cl, -C(O)-CH₂-Br, -C(O)-CH₂-(lower alkyl), -C(O)-CH₂-(benzyl), -C(O)-CH₂-(aryl), -CH₂-C(O)O-(lower alkyl) and the like.

In the description, particularly the schemes and examples, using the following abbreviations:

The term "subject"used herein refers to an animal, preferably a mammal, most preferably the person who was the object of treatment, examination or experiment.

The term "therapeutically effective amount is, used here, refers to an amount of active compound or pharmaceutical agent that causes the biological or medical response system tissue, animal or human that is being studied by the researcher, veterinarian, medical doctor or other Clinician, and this reaction include relieving symptoms being treated diseases or disorders. When the present invention relates to a joint therapy, which includes the introduction of one or more compounds of formula I and a progestogen or progestogen antagonist, "therapeutically effective amount" shall mean that amount of the combination of agents taken together so that the combined action causes the desired biological or medical response. For example, a therapeutically effective amount of joint therapy, which includes the introduction of the compounds of formula I and a progestogen must be a number of the compounds of formula I and the amount of progestogen, which, when used together or sequentially have a combined effect that is therapeutically effective. In addition, the specialist in this area should be clear that in the case of joint therapy with a therapeutically effective amount, as in the example above, the number of connection is of formula I and/or amount of a progestogen or progestogen antagonist individually may be therapeutically effective, or may be therapeutically ineffective.

Used herein, the terms "co-therapy" shall mean treatment of a subject in need thereof, by introducing one or more compounds of formula I with a progestogen or progestogen antagonist, when the compound(I) of formula I and a progestogen or progestogen antagonist is administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical preparation. When the compound(I) of formula I and a progestogen or progestogen antagonist is administered in different dosage forms, the number of doses per day for each compound may be the same or different. The compound(I) of formula I and a progestogen or progestogen antagonist can be entered the same or different routes of administration. Examples of suitable routes of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, and rectal. Connections can also be entered directly into the nervous system of ways, including but not limited to those listed intracerebrally, intraventricularly, intracerebroventricularly, vnutriobolochechnoe, intracavitary, intraspinally and/or peripherally routes of administration by delivery via intracranial or vertebral needles and/or catheters with devices for pumping the sludge is without such devices. The compound(I) of formula I and a progestogen or progestogen antagonist can be entered according to simultaneous or alternating regimens reception, at the same time or at different times during the course of therapy, concurrently in fractional or one-off forms.

It is implied that used here, the term "composition" includes a product containing certain ingredients in certain amounts, as well as any product which is the result of using direct or indirect method, combinations of certain ingredients in certain amounts.

The compounds of formula (I)in which X represents O or S, Y is CH₂and Z represents O or S, can be obtained by synthesis through the formation of key intermediate product, the compounds of formula (II) or (III)

which, in turn, can be obtained according to the methods specified in the scheme 1 and 2.

Scheme 1

More specifically, suitably substituted compound of formula (IV)in which Z represents O or S, a known compound or compound obtained by known methods, is subjected to the interaction with the appropriately substituted compound of formula (V), and when X represents O or S, known compound or a compound obtained by known methods, in the presence of an organic base such as TEA, DIPEA, pyridine, and the like, in an organic solvent, such as acetic anhydride, propionic anhydride, butyric anhydride and the like, at an elevated temperature in the range from about 80°C to about 120°to obtain the corresponding compounds of formula (VI).

The compound of formula (VI) is subjected to interaction with demetrious reagent, such as iodide TMS, BBr₃, AlCl₃with atention and the like, in a chlorinated solvent such as methylene chloride, chloroform, dichloroethane and the like, to obtain the corresponding compounds of formula (VII).

Alternatively the compound of formula (VI) is subjected to interaction with demetrious reagent, such as pyridine hydrochloride, pyridine hydrobromide, hydroiodide pyridine and the like, optionally in an organic solvent, such as xylene, acetic acid and the like, at an elevated temperature in the range from approximately 170°With up to approximately 220°to obtain the corresponding compounds of formula (VII).

The compound of formula (VII) is subjected to interaction with appropriately selected protecting reagent, such as acetylchloride, acetic anhydr is d, the benzoyl chloride, BOMCl, MOMCl, SEMCl and the like, in the presence of a base, such as pyridine, tea, DIPEA, K₂CO₃and the like, in an organic solvent such as methylene chloride, chloroform, acetone, acetonitrile, dihloretan and the like, thus obtaining the corresponding compound of formula (VIII), in which Pg¹represents a protective group. For example, when the compound of the formula (VII) is subjected to interaction with acetylchloride or acetic anhydride, Pg¹represents an acetyl group, when the compound of the formula (VII) is subjected to interaction with benzoyl chloride, Pg¹represents benzoyloxy group when the compound of the formula (VII) is subjected to interaction with BOMCl, MOMCl, SEMCl, Pg¹is the PTO, the PTO or SEM, respectively.

When Pg¹represents acetyl or the like, the compound of formula (VII) is subjected to interaction with radical brainwashin agent such as NBC, CBrCl₃, NaBrO₃in combination with MaHSO₃and the like, or a radical gloriouse agent such as NCS, SO₂Cl₂, gaseous Cl₂, tert-butylhypochlorite and the like, preferably a radical brainwashin agent such as NBC, in the presence of a radical initiator such as benzoyl peroxide, AIBN, and the like, and/or in the presence of a source with the ETA, such as a tungsten lamp, an electric light bulb 120 watt, bright sunlight, and the like, optionally at an elevated temperature in the range from about 50°C to about 120°to obtain the corresponding compounds of formula (VIII).

When the compound of the formula (VII) is subjected to interaction with radical brainwashin reagent such as NBS, the reaction is carried out in a halogenated organic solvent such as carbon tetrachloride, chloroform, dichloromethane and the like. When the radical brainwashin reagent is NaBrO₃the interaction is carried out in an organic solvent such as ethyl acetate, cyclohexane and the like. When the compound of the formula (VII) is subjected to interaction with radical gloriouse reagent, the interaction is carried out in an organic solvent such as ethyl acetate, chloroform, dichloromethane and the like.

When Pg¹represents benzoyloxy group, pivaloyl, PTO, PTO, SEM or the like, the compound of formula (VII) is subjected to interaction with bromine or a source of bromine or chlorine source, such as NBS, NCS, and the like, in the presence of a base such as LHMDS, LDA, KHMDS, NaHMDS, and the like, at low temperatures in the range from about 30°With up to approximately -78°thus the soo is appropriate compound of formula (IX).

The compound of formula (IX) release from protective group, thus obtaining the corresponding compound of formula (II). When Pg¹represents acetyl or benzoyl, the compound of formula (IX) release from protective group base, such as potassium carbonate, sodium carbonate, cesium carbonate and the like, in a solvent such as methanol, ethanol, isopropanol, or mixtures thereof, such as methanol:acetone, ethanol:acetone, methanol:acetonitrile, and the like, thus obtaining the corresponding compound of formula (II).

When Pg¹represents methyl, benzyl, PTO, PTO, SEM, compound of formula (IX) is released from the protective group of the acid, such as TFA, HF, HCl, H₂SO₄and the like or a Lewis acid such as tin tetrachloride, titanium tetrachloride, trichloride boron, tribromide bromine and the like, or when Pg¹represents SEM, protective groups exempt removing the protecting agent such as LiBF₄, TBAF, and the like, in a solvent such as THF, acetonitrile, methylene chloride, chloroform, isopropanol, methanol and the like, at a temperature in the range from approximately 0°50°and then treated with base, such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and the like, or an alkoxide of an alkaline metal is the lia, such as ethoxide sodium, sodium methoxide, tert-piperonyl sodium, atoxic potassium, potassium methoxide, tert-piperonyl potassium in a solvent such as methanol, ethanol, isopropanol, or mixtures of them, such as methanol:acetone, ethanol:acetone, methanol:acetonitrile, and the like, thus obtaining the corresponding compound of formula (II).

Alternatively, the compound of formula (VI) is subjected to interaction with bromine or a source of bromine or chlorine, such as NBS, NCS, and the like, in the presence of a base such as LHMDS, LDA, KHMDS, NaHMDS, and the like, at low temperatures in the range from about 30°With up to approximately -78°C, thus obtaining the corresponding compound of formula (IX).

The person skilled in the art should know that may be necessary and/or desirable to protect one or more of the groups R³and/or R⁴at any stage in the above-described method. This can be accomplished using well-known protective groups and known reagents and conditions protect and unprotect, such as reagents and conditions described inProtective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.

The person skilled in the art should further know that the method described in the above scheme 1, can be used for compounds of formula IV and compounds of the formula (V), in which the group(s) R³is substituted by group(s) R¹²and the group(s) R⁴is substituted by group(s) R¹³respectively, where R¹²and R¹³have values here, to obtain the corresponding compounds of formula (IIa).

The compound of formula (IIa) is then optionally subjected to interaction by known methods (including, for example, the methods described here) to replace the group(s) R¹²and R¹³appropriately selected group(s) R¹²and R¹³.

The compounds of formula (II) can be selectively gidrirovanny with the formation of the corresponding compounds of formula (III), as shown in scheme 2.

Scheme 2

Accordingly, the compound of formula (II) is subjected to interaction with gaseous hydrogen at a pressure in the range from approximately 20 ft/square inch to about 100 pounds per square inch in the presence of a metal catalyst, such as Pd-C, Pt C, Raney Nickel, Pd(OH)₂and the like, thus obtaining the corresponding compound of formula (III) in the form of predominantly the CIS isomer.

Alternatively the compound of formula (III) is subjected to interaction with a hydride, such as LiAH, hydride Cu, SmI₂the reagent of Stricker ([(Ph₃P)CuH]₆and that under the service, in a solvent such as THF, diethyl ether, and the like, at a temperature in the range of from about -20°With up to about 60°C, thus obtaining the corresponding compound of formula (III) in the form of predominantly the TRANS isomer.

In another alternative scenario, the compound of formula (II) is subjected to interaction with triethylsilane in the presence of acid, such as TFU, apirat BF₃, tin tetrachloride and the like, in an organic solvent such as methylene chloride, toluene and the like, thus obtaining the corresponding compound of formula (III) in the form of a mixture of CIS - and TRANS-isomers.

The person skilled in the art should further know that the way shown above in scheme 2, can similarly be used to obtain compounds of the formula (IIIb)

replacement of the compounds of formula (II) suitably substituted compound of formula (IIb)

known compound or a compound obtained by known methods.

The compounds of formula (I)in which X represents O or S, Y represents CR^AR^Band Z represents O or S, can be obtained from the intermediate compounds of formula (II) according to the method indicated in figure 3.

Scheme 3

In line with this, Obedinenie formula (IIb), well-known compound or compound obtained by known methods, is subjected to the interaction with diisobutylaluminium, L-selectride and the like in an organic solvent, such as toluene, benzene, THF, methylene chloride, and the like, at low temperatures in the range from approximately 0°C to about -80°C, thus obtaining the corresponding compound of formula (X).

The compound of formula (X) is subjected to interaction with a suitably substituted compound of formula (XII), where MQ represents a halide of lithium or magnesium, such as MgCl, MgBr or MgI, obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane and the like, thus obtaining the corresponding compound of formula (XIII).

The compound of formula (XIII) is subjected to interaction with a proton acid, such as HCl, H₂SO₄p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like, or a Lewis acid, such as athirat BF₃, AlCl₃, SnCl₄and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, thus obtaining the corresponding compound of formula (Ia).

Alternatively, the compound of formula (XIII) is subjected to treatment is with this reagent, as triphenylphosphine, tributylphosphine and the like, or azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, thus obtaining the corresponding compound of formula (Ia).

The person skilled in the art should know that may be necessary and/or desirable to protect one or more of the groups R³and/or R⁴at any stage in the above-described method. This can be accomplished using well-known protective groups and known reagents and conditions protect and unprotect, such as reagents and conditions described inProtective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.

The person skilled in the art should further know that in the method shown in scheme 3, when Y represents-CH₂C(O)CH₂-, and the compound of formula (IIb) is subjected to interaction with the reagent protective group for the protection of any group-Deputy (for example, the group R³or R⁴), C(O)- CH₂C(O)CH₂-may also interact with the reagent of the protective group with the formation of-CH=C(OPg)CH₂-where Pg represents a protective group. When removing protection-CH=C(OPg)CH₂- also exempt from protection education-CH₂C(O)CH₂-.

In an alternative embodiment, the connection Faure the uly (IIb) is replaced by a compound of the formula (III) in the above scheme 3, thus the compound of formula (Ib).

where R²has the values listed above.

The person skilled in the art should know that the compound of formula (Ib) can be alternatively obtained by selective hydrogenation of appropriately substituted compounds of formula (Ia)in which Y represents CR^AR^Busing the reagents and conditions described in scheme 2.

The person skilled in the art should further know that the compound of formula (IIb) in the above scheme 3 can be similarly replaced by a compound of the formula (IIIb) to obtain the corresponding compounds of formula (1q).

The compounds of formula (I)in which one or more of R³and/or R⁴are acyloxy can be obtained by the interaction of the appropriately substituted compounds of formula (I), in which the group(s) R³and/or R⁴represents hydroxy, acid chloride appropriately substituted acid, appropriately substituted carboxylic acid or an appropriately substituted anhydride. For example, the compound of formula (I)in which R³and R⁴in positions 2 and 8 respectively represent acyloxy, can be obtained by the method indicated in figure 4.

Scheme 4

In line with this, the appropriately substituted compound of formula (Iaa), obtained as described in figure 3 (in which n is 1, R3 represents hydroxy, m is 1 and R4 represents hydroxy), is subjected to the interaction with the acid chloride appropriately substituted acid, a compound of formula (XIV), or appropriately substituted anhydride, a compound of formula (XVI)in which R^Gmatter mentioned above, a known compound or a compound obtained by known methods, in the presence of an organic amine such as tea, DIPEA, pyridine, and the like, in a halogenated organic solvent such as DCM, methylene chloride, chloroform and the like, or in a hydrocarbon solvent such as benzene, toluene and the like, thus obtaining the corresponding compound of formula (Ic).

Alternatively, the compound of formula (Iaa) is subjected to interaction with appropriately substituted carboxylic acid compound of the formula (XV)in which R^Gmatter mentioned above, a known compound or a compound obtained by known methods, in the presence of reagent combinations, such as DCC, DIC, and the like, in an organic solvent, such as DMF, THF, methylene chloride, and the like, thus obtaining the corresponding connection is a group of formula (Ic).

The person skilled in the art should know that any group(s) R³and/or R⁴with terminal hydroxy-group, can be similarly transformed by the method specified above in scheme 4. The person skilled in the art should further know that when one or more of the groups R³and/or R⁴are hydroxy groups protected silyl protecting group, such as TBS, the corresponding compound of formula (Ia) is subjected to interaction of tetraalkylammonium fluoride such as TBAF, and the like, and then the interaction with the acid chloride appropriately substituted acid of the formula (XIV) in an organic solvent, such as THF, diethyl ether, and the like, to obtain the corresponding compounds of formula (Ic).

The person skilled in the art should further know that the interaction of the compounds of formula (Iaa) from about ≤1 equivalent of the appropriately substituted compounds of formula (XIV), appropriately substituted compounds of formula (XV) or a suitably substituted compound of formula (XVI) can be obtained mixture of compounds having R³only R⁴and both of R³and R⁴turn to the group-OC(O)R^G. This mixture of compounds is preferably separated by known methods to highlight the desired connection. In addition, interaction is soedineniya formula (Iaa) from about ≥ 2 equivalents of the appropriately substituted compounds of formula (XIV), appropriately substituted compounds of formula (XV) or a suitably substituted compound of formula (XVI) can be obtained compound of the formula (Ic), in which R³so R⁴turn to the group-OC(O)R^G.

Alternatively, the compound of formula (Iaa) can be replaced by a compound of formula (Iba), the compound of formula (Ib), where n is 1, R³represents hydroxy, m is 1 and R⁴represents hydroxy, and subjected to interaction, as described in scheme 4, to obtain the corresponding compounds of formula (Id)

The person skilled in the art should further know that the above reaction can be conducted with the final stage of preparing compounds of formulas (I) and (II)in which the position of the groups R³and R⁴can be changed in rings a and D, respectively, and in which the number of groups R³and R⁴may change.

In addition, the person skilled in the art should know that, if desirable are different alloctype in the provisions of R³and R⁴, alloctype can be sequentially introduced into the structure of the kernel by transforming the hydroxy-group, as described in the above scheme 4, with suitable protection and unprotect R is actionspane groups, when it is necessary.

The compounds of formula (I)in which X represents O, Y is CH₂or C(O), and Z represents O or S, can be obtained from the intermediate compounds of formula (XIX).

The compound of formula (XIX) can be obtained according to the method indicated in scheme 5.

Scheme 5

In line with this, the appropriately substituted compound of formula (XVII), in which Pg²represents a suitable protective group, such as benzyloxy, methoxy, SEM, MOM, acetoxy and the like, a known compound or compound obtained by known methods, is subjected to the interaction with oxidizing agent such as SeO₂, PCC, PDC, and the like, in an organic solvent, such as toluene, xylene, ethyl acetate, dichloromethane and the like, thus obtaining the corresponding compound of formula (XVIII).

The compound of formula (XVIII) is further oxidized oxidizing agent such as SeO₂, PCC, PDC, and the like, in an organic solvent, such as toluene, xylene, ethyl acetate, dichloromethane and the like, thus obtaining the corresponding compound of formula (XIX).

The person skilled in the art should know that, when the compound of the formula (XVII) interacts with 2 or more equivalents of oxidizing agent, the connection is their formula (XVII) is converted directly into a compound of formula (XIX) (i.e. the intermediate alcohol compound of the formula (XVIII), which does not need to allocate).

Alternatively, the compound of formula (XIX) can be obtained by the method shown in scheme 6.

Scheme 6

In accordance with this appropriately substituted compound of formula (IXa), the compound of formula (IX)in which R^Aand R^Beach represent hydrogen, in which Z represents O and in which Pg¹represents a suitable protective group, such as benzyloxy, methoxy, SEM, MOM, acetoxy and the like, a known compound or compound obtained by known methods, is subjected to the interaction with the radical brainwashin agent such as NBS, CBrCl₃, NaBrO₃in combination with NaHSO₃and the like, or a radical gloriouse agent such as NCS, SO₂Cl₂, gaseous Cl₂, tert-butylhypochlorite and the like, preferably a radical brainwashin agent such as NBS, in the presence of a radical initiator such as benzoyl peroxide, AIBN, and the like, and/or in the presence of a light source such as a tungsten bulb, light bulb 120 watt, bright sunlight, and the like, optionally at an elevated temperature in the range from about 50°C to about 120°S, recip is I while the corresponding compound of formula (XX).

The compound of formula (XX) hydrolyzing with water in the presence of a base such as sodium carbonate, sodium bicarbonate, and the like, thus obtaining the corresponding compound of formula (XIX).

The compounds of formula (I)in which X represents O, Y is CH₂or C(O), and Z represents O or S, can be obtained from the intermediate compounds of formula (XIX) according to the method indicated in figure 7.

Scheme 7

In accordance with this, the compound of formula (XIX) is subjected to interaction with a suitably substituted compound of formula (XII), in which MQ represents lithium or manygaloherez, such as MgCl, MgBr or MgI, obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane and the like, thus obtaining the corresponding compound of formula (XXI).

The compound of formula (XXI) is subjected to interaction with a proton acid, such as HCl, H₂SO₄p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like, or with a Lewis acid, such as athirat BF₃, AlCl₃, SnCl₄and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, receive the I while the corresponding compound of formula (Ie).

The compound of formula (Ie) may be optionally selectively restored by the interaction with the regenerating agent such as LAH/AlCl₃and the like, in an organic solvent, such as THF, diethyl ether, dioxane and the like, to obtain the corresponding compounds of formula (If).

The person skilled in the art should know that may be necessary and/or desirable to protect one or more of the groups R³and/or R⁴at any stage in the above-described method. This can be accomplished using well-known protective groups and known reagents and conditions protect and unprotect, such as reagents and conditions described inProtective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.

The person skilled in the art should further know that the compounds (Ie) and/or (If) can be optionally further selectively gidrirovanny the bridge connection of rings b and C, as previously described, if necessary, protection of reactive groups to obtain the corresponding compounds of formula (Ig).

Alternatively, the compound of formula (XIX) may be replaced with an appropriate compound, which bridge the communication rings In and fully saturated, and then subjected to the interaction of the JV is to own, indicated in figure 7, to obtain the corresponding compounds of formula (Ig) or (Ih).

The compounds of formula (I)in which X represents CR^AR^B, Y is O and Z represents O or S, can be obtained through the synthesis of intermediate compounds of formula (XXIII) and (XXIV)

which, in turn, can be obtained according to the methods specified in schemes 8 and 9. Accordingly the compounds of formula (XXIII), in which one or both of R^Aand R^Bare other than hydrogen, can be obtained by the method indicated in scheme 8.

Scheme 8

In accordance with this appropriately substituted compound of formula (XXV) is subjected to interaction with oxidizing agent such as MnO₂PDC, TPAP, and the like, in an organic solvent such as DCM, acetonitrile, DCE, and the like, thus obtaining the corresponding compound of formula (XXVI).

The compound of formula (XXVI) is subjected to interaction with the compound of the formula (XXVII)in which MQ represents lithium or manygaloherez, such as MgCl, MgBr or MgI, obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane is similar, while receiving a corresponding compound of formula (XXVIII).

The compound of formula (XXVIII) protects interaction with a suitable protecting group by known chemistry, thus obtaining the corresponding compound of formula (XXIX), in which Pg³represents a suitable protective group, such as benzyloxy, methoxy, IOM, SEM, and the like.

Alternatively, the compound of formula (XXVIII) is subjected to interaction with oxidizing agent such as MnO₂PDC, TPAP, and the like, in an organic solvent such as DCE, DCM, acetonitrile and the like, thus obtaining the corresponding compound of formula (XXX).

The compound of formula (XXX) is subjected to interaction with a suitably substituted compound of formula (XXXI), in which MQ represents lithium or manygaloherez, such as MgCl, MgBr or MgI, obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane and the like, thus obtaining the corresponding compound of formula (XXXII).

The compounds of formula (XXIII)in which R^Aand R^Beach represent a hydrogen (i.e. the compounds of formula (XXV)can be obtained by reduction of appropriately substituted compounds of formula (XXXIII)

the two-stage method. In accordance with this, the compound of formula (XXXIII) is subjected to interaction with oxalylamino in an organic solvent, such as THF, DCM, and the like, and then subjected to interaction with the regenerating agent such as sodium borohydride and the like, in an alcohol, such as methanol, ethanol and the like. Alternatively the compound of formula (XXXIII) is subjected to interaction with the anhydride such as acetic anhydride and the like, in an organic solvent, such as THF, DCM, and the like, and then subjected to interaction with the regenerating agent such as sodium borohydride and the like, in an alcohol, such as methanol, ethanol and the like, thus obtaining the corresponding compound of formula (XXIII).

Alternatively the compound of formula (XXXIII) is transformed into the corresponding compound of formula (XXV) by the interaction of the compounds of formula (XXXIII) with a complex of borane:THF in an organic solvent, such as THF and the like, at low temperatures in the range of from about -78°C to about room temperature.

The compound of formula (XXIV) can be obtained by the method shown in scheme 9.

Scheme 9

In accordance with this appropriately substituted compound of formula (XIII), well-known compound or compound obtained by known methods, for example, as in the above scheme 8, protects a suitable protecting group by known methods, thus obtaining the corresponding compound of formula (XXXIV), in which Pg⁴represents a suitable protective group, such as benzyloxy, methoxy, SEM, MOM, and the like.

The compound of formula (XXXIV) is subjected to interaction with a suitably substituted compound of formula (XXXV), a known compound or a compound obtained by known methods, in the presence of a base, such as LDA, LHMDS, sodium hydride and the like, in an organic solvent, such as diethyl ether, THF and the like, at a reduced temperature in the range of from about -78°With up to about 30°C, thus obtaining the corresponding compound of formula (XXXVI).

The compound of formula (XXXVI) freed from the protective groups by known methods, thus obtaining the corresponding compound of formula (XXXVII).

The compound of formula (XXXVII) is subjected to interaction with demetrious reagent, such as pyridine hydrochloride, pyridine hydrobromide, hydroiodide pyridine and the like, optionally in an organic solvent, such as xylene, acetic acid and the like, at an elevated temperature in the range from approximately 170&x000B0; With up to approximately 220°C, thus obtaining the corresponding compound of formula (XXIV).

The person skilled in the art should know that to obtain the compounds of formula (I)in which one of R^Aor R^Brepresents hydrogen, the compound of formula (XXXIV) can be replaced by a compound of the formula (XXIX) in the method shown in scheme 9.

The person skilled in the art should further know that in the method shown in scheme 9, where the compound of formula (XXXVI) is released from the protective group to obtain the compounds of formula (XXXVII), it is possible that the compound of formula (XXXVI) are not fully transformed into a compound of formula (XXXVII), and to some extent is formed intermediate compound of formula (XXXVIII).

The compound of formula (XXXVIII) can then be converted into a compound of formula (XXXVII) by known methods. For example, when R^Aand/or R^Brepresents hydrogen, the compound of formula (XXXVIII) are interaction terms Mitsunobu with the formation of the corresponding compounds of formula (XXXVII).

Alternatively, if both of the R^Aand R^Bare not hydrogen, the compound of formula (XXXVIII) is subjected to interaction with acid, such as HCl, TsOH, PPTS, and the like, in an organic solvent or their mixture, such as THF, THF/H₂Oh, dichloromethane, toluene/N_{2 Oh and the like, thus obtaining the corresponding compound of formula (XXXVII)}

_{which can be further transformed with the formation of the desired compounds of formula (I) according to the methods described here.}

_{The compound of formula (XXIV) is then optionally additionally substituted in position 5, the structure of the nucleus, thus obtaining the desired compound of formula (I)according to the method indicated in scheme 10.}

_{Scheme 10}

_{More specifically, suitably substituted compound of formula (XXIV) is subjected to interaction with the regenerating agent such as diisobutylaluminium, LAH, and the like, in an organic solvent, such as toluene, benzene, THF and the like, at low temperatures in the range from approximately -50°C to about -80°C, thus obtaining the corresponding compound of formula (XXXX).}

_{The compound of formula (XXXX) are oxidized in oxidizing conditions, such as oxidation in Turn, peridinin dess-Martin, TRAR and the like, in an organic solvent, such as dichloromethane, acetonitrile, DCE, and the like, thus obtaining the corresponding compound of formula (XXXXI).}

_{The compound of formula (XXXXI) is subjected to interaction with a suitably substituted compound of formula (XII), in which MQ represents lit the th or manygaloherez, such as MgCl, MgBr or MgI, obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane and the like, thus obtaining the corresponding compound of formula (XXXXII).}

_{The compound of formula (XXXXII) is treated with a reagent such as triphenylphosphine, tributylphosphine and the like, and azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, thus obtaining the corresponding compound of formula (Ii).}

_{The person skilled in the art should know that may be necessary and/or desirable to protect one or more of the groups R³and/or R⁴at any stage in the above-described method. This can be accomplished using well-known protective groups and known reagents and conditions protect and unprotect, such as reagents and conditions described inProtective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.}

_{When in the compound of formula (Ii) one or more of the groups R³and/or R⁴represent hydroxy, hydroxy-group can be optionally converted into the desired group on the methods described previously, for example, the interaction of the compounds of formula (Ii) with the acid chloride approaching the way they substituted acid, appropriately substituted carboxylic acid or an appropriately substituted anhydride, as described in scheme 4.}

_{The person skilled in the art should further know that the compound of formula (XXIV), the compound of formula (Ii) or the compound of formula (Ii)in which any of the hydroxy-group of R³and/or R⁴was further functionalized, can be selectively gidrirovanny with the formation of the corresponding compounds in which the bond of the bridge of the rings b and C is fully saturated, according to the method noted above.}

_{The compounds of formula (I)in which X represents CR^AR^Band Y is S, can be obtained by modification of the methods described in schemes 9 and 10. More specifically, the compound of formula (XXXVI), obtained as in scheme 9, is subjected to the interaction with tianyoude reagent, such as CF3SO3Si(CH3)3/(CH3)3Si-S-Si(CH3)3and the like, in an organic solvent such as methylene chloride, chloroform, dichloromethane and the like, thus obtaining the corresponding compound of formula (XXXVIa).}

The compound of formula (XXXVI) is then substituted for the compound of formula (XXXVIa) and optionally subjected to interaction, as described in scheme 9, thus obtaining the corresponding compound of formula (XXIVa),

which, in turn, replaces the compound of formula (XXIV) in a method described in scheme 10, to obtain the corresponding compounds of formula (I)in which Y is S.

The compounds of formula (I)in which X represents O or S, Z represents O or S and Y is-CR^AR^BCH₂or CR^AR^BCH₂CH₂-where R^Aand R^Bare not hydroxy, can be obtained by the method indicated in scheme 11

Scheme 11

More specifically, suitably substituted compound of formula (XXXXII), in which Pg⁶represents a suitable protective group, such as alkyl (e.g. methyl), benzyl, SEM, MOM, pivaloyl and the like, a known compound or compound obtained by known methods, is subjected to the interaction with the appropriately substituted compound of formula (XXXXIII), in which L¹represents H or alkoxy, such as methoxy, ethoxy and the like, in the presence of a base, such as (TMS)₂NLi, LDA, NaHDS, KHMDS, and the like, in the presence of formuliruiutsia reagent, such as performed, 2,4,6-trichloranisole, BrCH₂COOCH₃, ClCH₂COOCH₃and the like, in an organic solvent, such as THF, diethyl ether, dioxo and the like, while receiving a corresponding compound of formula (XXXXIV).

The compound of formula (XXXXIV) is subjected to interaction with the regenerating agent such as NaBH₄, borane, LAH, and the like, in an organic solvent, such as THF, diethyl ether, dioxane and the like, thus obtaining the corresponding compound of formula (XXXXV).

The compound of formula (XXXXV) freed from the protective groups by known methods, thus obtaining the corresponding compound of formula (XXXXVI).

The compound of formula (XXXXVI) is subjected to interaction with a proton acid, such as HCl, H₂SO₄p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like, or with a Lewis acid, such as athirat BF₃, AlCl₃, SnCl₄and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, thus obtaining the corresponding compound of formula (XXXVII).

Alternatively, the compound of formula (XXXXVI) is subjected to interaction with a reagent such as triphenylphosphine, tributylphosphine and the like, or azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, thus obtaining the corresponding compound of formula (XXXXVII).

The compounds of formula (I)in which X is selected from O, Y represents CR^AR^BC(O) -, and Z of t is made by an O or S, can be obtained by the interaction of the appropriately substituted compounds of formula (XXXXIV), in which L¹represents phenoxy and in which Pg⁵is a SEM or the IOM acid, such as hydrochloric acid, H₂SO₄, TFA, and the like, in an organic solvent, such as isopropanol, THF or a mixture such as isopropanol:THF and the like, with the formation of the corresponding compounds of formula (XXXIX).

The compound of formula (XXXIX) is then optionally subjected to interaction, while receiving the desired compound of formula (I)according to the methods described here.

The person skilled in the art should know that the compound of formula (XXXXVII) may be further subjected to interaction for the conversion into the corresponding compound of formula (I) or formula (II) according to the methods described previously. For example, the replacement of the compounds of formula (II) to the compound of formula (XXXXVII) in scheme 2 or 3, or replacement of the compounds of formula (XXIV) to the compound of formula (XXXXVII) figure 10.

The person skilled in the art should know that may be necessary and/or desirable to protect one or more of the groups R³and/or R⁴at any stage in the above-described method. This can be accomplished using well-known protective groups and known regentova conditions protect and unprotect, for example, such as reagents and conditions described inProtective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.

The person skilled in the art should further know that when one or more of the groups R³and/or R⁴are hydroxy, hydroxy-group can be optionally converted into the desired group on the previously described methods.

The person skilled in the art should further know that the compounds of formula (I), in which the connection of the bridge of the rings b and C is unsaturated (i.e. a double bond), can be converted into the corresponding compound of formula (I), in which the bond of the bridge of the rings b and C is fully saturated (i.e. by a single bond), as previously described, for example, by selective hydrogenation of, for example, gaseous hydrogen, with protection, if necessary, reactive functional groups. In an alternative embodiment, the bond of the bridge of the rings b and C may be selectively gidrirovannah in any intermediate compound in the synthesis of the compounds of formula (I), provided that the reactive functional groups are suitably protected.

The compounds of formula (I), in which each of R¹and R²is not hydrogen, can be obtained by the method indicated in scheme 12.

Therefore the 12

In accordance with this appropriately substituted compound of formula (XXXXVIII), a known compound or compound obtained by known methods, for example, the methods described here, is subjected to the interaction with the appropriately substituted compound of formula (XXXXIX), in which MQ represents lithium or manygaloherez, such as MgCl, MgBr or MgI, obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane and the like, thus obtaining the corresponding compound of formula (L).

The compound of formula (L) is subjected to interaction with a suitably substituted compound of formula (XII), in which MQ represents lithium or manygaloherez, such as MgCl, MgBr or MgI, obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane and the like, thus obtaining the corresponding compound of formula (LI).

The compound of formula (LI) is subjected to interaction with a proton acid, such as HCl, H₂SO₄p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like, or with a Lewis acid, such as athirat BF₃, AlCl₃, SnCl₄and the like, R is storytale, such as toluene, methylene chloride, acetonitrile and the like, thus obtaining the corresponding compound of formula (Ij).

Alternatively, the compound of formula (LI) is subjected to interaction with a reagent such as triphenylphosphine, tributylphosphine and the like, or with azodicarbonamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, thus obtaining the corresponding compound of formula (Ij).

The compound of formula (D) can be obtained from the appropriately substituted compounds of formula (VIII)in which R³corresponds to R¹², R⁴corresponds to R¹³and each of R^Aand R^Brepresents hydrogen. More specifically, the compound of formula (VIII) is subjected to interaction with a strong base, such as LDA, LiN(TMS)₂and the like, and then the interaction with appropriately selected electrophile, such as alkylhalides, arylamidase, the acid chloride of alkylsilane, methylchloroform, vanillaroma, α-chlorocatechol and the like, thus obtaining the corresponding compound of formula (D).

The compounds of formula (I)in which X represents O or S, Z represents O or S and Y is-CH₂CH₂-can be obtained by the method indicated in figure 13.

Scheme 13

More specifically, suitably substituted compound of formula (LII), in which Pg⁶represents a suitable protective group such as benzyl, alkyl (such as methyl), SEM, MOM, BOM, substituted benzyl, RMW and the like, a known compound or compound obtained by known methods, is subjected to the interaction with the appropriately substituted compound of formula (LIII), in which J represents Cl, Br, iodide or other suitable leaving group and W is a group such as alkyl (such as methyl, ethyl and the like), benzyl, -CH₂CH₂TMS, -CH₂CH₂Och₃, -CH₂O-benzyl, and the like, in the presence of a base, such as (TMS)₂NLi, LDA, NaHMDS, RHMDS and the like, thus obtaining the corresponding compound of formula (LIV).

The compound of formula (LIV) is freed from the protective groups by known methods, for example by treatment of compounds of formula (LIV) proton acid, such as HCl, H₂SO₄, TFA, or Lewis acid, such as BCl₃, BBr₃, TiCl₄, SnCl₄or a derivative of such a Lewis acid such as catecholborane, dimethylbenzene and the like, thus obtaining the corresponding compound of formula (LV).

The compound of formula (LV) is treated with a proton acid, such as HCl, H₂SO₄and the like, or an acidic is the Lewis, such as athirat BF₃, AlCl₃, SnCl₄, PCl₃, POCl₃, PCl₅and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, thus obtaining the corresponding compound of formula (Ik).

Alternatively, the compound of formula (LV) is subjected to interaction with a reagent such as triphenylphosphine, tributylphosphine and the like, or with azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, thus obtaining the corresponding compound of formula (Ik).

The compound of formula (I)in which X represents O or S, Z represents O or S and Y is-CH₂CH₂CH₂-can be obtained by the method indicated in figure 14.

Scheme 14

More specifically, suitably substituted compound of formula (LII), in which Pg⁶represents a suitable protective group such as benzyl, alkyl (such as methyl), SEM, MOM, BOM, substituted benzyl, RMW and the like, a known compound or compound obtained by known methods, is subjected to the interaction with the appropriately substituted compound of formula (LVI), in which two groups G represents a leaving group such as Cl, Br, iodide, hydrox and the like, and in which two groups G are the same or different, well-known compound or compound obtained by known methods, in the presence of a base, such as (TMS)₂NLi, LDA, NaHMDS, RHMDS and the like, thus obtaining the corresponding compound of formula (LVII).

The person skilled in the art should know that, when two groups G are different, they are selected so that the group G associated with(About), was more reactive than the group G associated with a group of CH₂.

The compounds of formula (LVII) released from the protecting group by known methods, for example by treatment of compounds of formula (LVII) proton acid, such as HCl, H₂SO₄, TFA, and the like, or a Lewis acid, such as BCl₃, BBr₃, TiCl₄, SnCl₄and the like, or a derivative of such a Lewis acid such as catecholborane, dimethylbenzene and the like, thus obtaining the corresponding compound of formula (LVIII).

The compound of formula (LVIII) is treated with a base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and the like, or alkali metal alkoxide, such as ethoxide sodium, sodium methoxide, tert-piperonyl sodium, atoxic potassium, potassium methoxide, tert-piperonyl potassium and the like, in a solvent such as methanol, ethanol, isopropanol, THF is like, or a mixture of these solvents, such as methanol:acetone, ethanol:acetone, methanol:acetone and the like, thus obtaining the corresponding compound of formula (LIX).

The compound of formula (LIX) is subjected to interaction with the bottom, such as NaBH₄, borane, LAH, and the like, in an organic solvent, such as THF, diethyl ether, dioxane and the like, thus obtaining the corresponding compound of formula (Im).

The compound of formula (Im) toxigenic using Protocol Barton or modified Protocol Barton (see, for example, K.C. Nicolaou, R. A. Daines, J. Uenishi, W.S. Li, D.P. Papahatjis and T.K. Chakraborty, J. Am. Chem. Soc., 1988, 110, pp. 4672-4683; this procedure involves conversion of the alcohol to the compound of formula (Im) in thiocarbonate, as in the compound of formula (LX), the subsequent processing tributyltinhydride in the presence of a radical initiator such as benzoyl peroxide, AIBN, and the like, thus obtaining the corresponding compound of formula (In).

The person skilled in the art should know that the compounds of formula (I)in which X represents O or S, Z represents O or S and Y is-CR^ACR^B-CH(OH)-CR^ACR^Bor CR^ACR^B-CH₂-CR^ACR^B-can be similarly obtained by the method shown above in figure 13, with the replacement of the relevant connected to the second formula (LII), (LIII) appropriately substituted compound (LIIa) and (LVIa), respectively.

The compounds of formula (I)in which X represents O or S, Y represents CR^ACR^BCH₂CH₂or CH₂CH₂CH₂and Z represents O or S, can be obtained from suitably substituted compound of formula (XI) according to the method indicated in figure 15.

Scheme 15

In accordance with this appropriately substituted compound of formula (LXI), a known compound or compound obtained by known methods, is subjected to the interaction with a Lewis acid, such as BF₃OEt₂, SnCl₂, TiCl₄Perlina acid and the like, in an organic solvent such as CH₂Cl₂, CHCl₃and the like, while receiving appropriate reactive intermediate compound of formula (LXII).

The compound of formula (LXII) is subjected to interaction with a suitably substituted compound of formula (LXIII), in which MQ represents manygaloherez, such as MgCl, MgBr or MgI (such manygaloherez can be obtained from the corresponding known alkyl or helgaleena by known methods, in an organic solvent, such as THF, diethyl ether, dioxane, hexane and the like, thus obtaining the corresponding compound of formula (Ip).

In ternatives case, the compound of formula (LXI) is subjected to interaction with simple enol ether or allyl reagent, such as 1,1-bistrimethylammomium, 1,1-bactrimoralcontraceptives, (1 methoxybenzyloxy)trimethylsilane, allyltrimethylsilane, allyltrimethylsilane, but-2-entremetier, but-2-titrimetrically and trimethylphenylammonium and the like, thus obtaining the corresponding compound of formula (Ip).

The person skilled in the art should further know that the compounds of formula (I)in which Y is selected from the group consisting of CR^AR^B(CR^AR^B)_1-2and CR^AR^BC(O)CR^AR^Bcan be similarly obtained according to the methods described herein, the selection and replacement of reagents described herein, suitably substituted reagents.

The present invention further relates to a method for obtaining compounds of formula (DX), described in more detail in scheme 16.

Scheme 16

In accordance with this appropriately substituted compound of formula (VIII), a known compound or compound obtained by known methods, in which R^A, R^B, n, R³, m, R⁴and Z have the meanings given above, in which X represents O or S and which Pg¹⁰represents a suitable protective group, such as alkyl (e.g. methyl), benzyl, benzoyl, SEM, MOM, BOM, pivaloyl and the like (see, nab is emer, Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991), is subjected to the interaction with the base, such as LiHMDS, LDA, KHMDS, NaHMDS, and the like; preferably at a temperature lower than or approximately equal to room temperature, more preferably at a temperature in the range from about 30°With up to approximately -100°S, even more preferably at low temperature in the range from approximately -10°With up to approximately -30°; in an aprotic organic solvent such as THF, dioxane, diethyl ether and the like, thus obtaining the corresponding compound of formula (C), in which V represents the appropriate base cation, Li, K or Na (i.e. when the base is LiHMDs or LDA, V represents Li; when the base is KHMDS, V is a K; when the base is NaHMDS, V represents sodium).

The compound of formula (C) is subjected to interaction with a suitably substituted compound of formula (CI), where E is an electrophile (i.e., the atom or molecule that can form a cation of carbon or partial cation of carbon), such as Br, Cl, I, CH₃, SEM, MOM, BOM, Br-CH₂CH₂-Och₃and the like, and in which L²represents a suitable leaving group is, such as Cl, Br, I, tosylate, mesilate, and the like, thus obtaining the corresponding compound of formula (CII). The compound of the formula (CI) can also be a source of Br or Cl, such as NBS, NCS, and the like.

The compound of formula (CII) released from the protective groups by known methods (Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991), thus obtaining the corresponding compound of formula (III).

The compound of formula (III) cyclist by known methods to obtain the corresponding compounds of formula (DX), where p is an integer from 0 to 2. When the electrophile E is Br, Cl, I, and the like, the compound of formula (IV) is treated with base, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, NaOH, KOH, TEA and the like, preferably to a pH in the range of approximately pH 10 to pH of approximately 11, thus obtaining the corresponding compound of formula DX, where R is 0. When the electrophile E is SEM, MOM, BOM, Br-CH₂CH₂-Och₃and the like, the compound of formula (IV) is subjected to interaction with a proton acid, such as HCl, H₂SO₄p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like, or with a Lewis acid, such as athirat BF₃, AlCl₃, SnCl₄and the fact of podobn is e, in a solvent such as toluene, methylene chloride, acetonitrile and the like, or with a reagent such as triphenylphosphine, tributylphosphine and the like, or with azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, thus obtaining the corresponding compound of formula (DX), where p is 1-2.

The person skilled in the art should know that the compound of formula (C) can be alternatively subjected to the interaction with the appropriately substituted compound of formula (CIa), in which, when the electrophile E represents-C(O)CH₂-Och₃-C(O)-CH₂-Cl, -C(O)-CH₂-Br, -C(O)-CH₂-(lower alkyl), -CH₂-C(O)O-(lower alkyl), to obtain the corresponding compounds of formula (CII), which is then further subjected to interaction with a proton acid, such as HCl, H₂SO₄p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like, or with a Lewis acid, such as athirat BF₃, AlCl₃, SnCl₄and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, or with a reagent such as triphenylphosphine, tributylphosphine and the like, or with azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, to obtain the corresponding the corresponding compounds of formula (DXa), in which -(CH₂)_p- replaced by-C(O)-CH₂where part of CH₂associated with X.

The present invention further relates to a method for obtaining compounds of formula (DXI), as described in more detail in scheme 17.

Scheme 17

In accordance with this appropriately substituted compound of formula (VIII), a known compound or compound obtained by known methods, in which R^A, R^B, n, R³, m, R⁴and Z have the meanings given above, in which X represents O or S and which Pg¹⁰represents a suitable protective group, such as alkyl (e.g. methyl), benzyl, benzoyl, SEM, MOM, BOM, pivaloyl and the like (see, for example, by T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991), is subjected to the interaction with the base, such as LiHMDS, LDA, KHMDS, NaHMDS, and the like; preferably at a temperature lower than or approximately equal to room temperature, more preferably at a temperature in the range from about 30°With up to approximately -100°S, even more preferably at low temperature in the range from approximately -10°With up to approximately -30°; in an aprotic organic solvent such as THF, dioxane, diethyl ether and the like, while receiving appropriate sedimentary (C), in which V represents the appropriate base cation, Li, K or Na (i.e. when the base is LiHMDs or LDA, V represents Li; when the base is KHMDS, V is a K; when the base is NaHMDS, V represents Na).

The compound of formula (C) is subjected to interaction with the appropriately substituted aldehyde, a compound of formula (CIV), in which U represents hydrogen or lower alkyl, while receiving a corresponding compound of formula (CV).

The compound of formula (CV) freed from the protective groups by known methods (Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991), thus obtaining the corresponding compound of formula (CVI).

The compound of formula (CVI) cyclist by known methods, thus obtaining the corresponding compound of formula (DX), in which p is 1. More specifically, the compound of formula (IV) is subjected to interaction with a proton acid, such as HCl, H₂SO₄p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like, or with a Lewis acid, such as athirat BF₃, AlCl₃, SnCl₄and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, or with a reagent such as triphenylphosphine, tributylphosphine and the like, or with and what dicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, to obtain the corresponding compounds of formula (DX), in which p is 1.

When the means of obtaining the compounds according to the invention give a mixture of stereoisomers, these isomers may be separated by conventional methods such as preparative chromatography. The compound can be obtained in racemic form, or individual enantiomers may be obtained either enantiospecific synthesis or by separation. Connections can be, for example, divided into their component enantiomers by standard methods, such as the formation of diastereomeric pairs by obtaining a salt with an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. Compounds can be separated by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary substances. Alternatively the compounds can be separated using chiral HPLC column.

When any of the methods for obtaining the compounds of the present invention may be necessary and/or desirable to protect sensitive or reaktionsmotor the s group on any of the examined molecules. This can be achieved using conventional protective groups such as the groups described inProtective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protective group can be removed by suitable subsequent stage using methods known in this field.

The possibility of using compounds of the present invention for treating disorders mediated by the estrogen receptor, can be installed using the methods described herein in the examples, 172, 173, 174 and 175.

The present invention therefore provides a method of treating disorders mediated by the estrogen receptor, in a subject in need thereof, which includes the introduction of any of the compounds identified here, in an amount effective to treat such violations. The compound can be administered to the patient in any conventional way of introduction, including but not limited to the above, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. The amount of compound that is effective for the treatment of disorders mediated by the estrogen receptor, is between 0.01 mg / kg and 20 mg / kg of body weight of the subject.

The present invention also provides pharmaceutical compositions containing one or n is how many of the compounds of this invention in combination with a pharmaceutically acceptable carrier. These compositions are preferably in a standardized dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, of a device for self-injection or suppositories, for oral, parenteral, intranasal, sublingual or rectal introduction or for introduction of inhalation or insufflate. Alternatively, the composition may be presented in a form suitable for administration once a week or once a month, for example, an insoluble salt of the active compound, such as decanoate salt, may be adapted to receive the drug depot for intramuscular injection. For solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tabletiruemye ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, with formation of a solid composition of the preliminary preparation containing a homogeneous mixture of the compounds of the present invention or its pharmaceutically acceptable salt. When these compositions are pre is the prior of the drug are defined as homogeneous, this means that the active ingredient is dispersed evenly throughout the composition so that the composition can be easily divided into equally effective dosage forms such as tablets, pills and capsules. This solid composition prior drug then divided into uniform dosage forms of the type described above containing from 5 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the new compositions can be coated or prepared by any other means for obtaining a dosage form that provides the advantages of prolonged action. For example, the tablet or pill may contain internal dosed component and an outer dosage component, the latter is in the form of a shell on the ground. Two components can be separated intersolubility layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to slow its release. For such intersolubility layers or coatings can be used a variety of materials, and such materials include a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the new compositions of the present and the gain may be incorporated for administration orally or by injection, include aqueous solutions, syrups, containing the appropriate corrigentov, aqueous or oily suspensions containing a corrigentov emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical excipients. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural gums, such as tragakant, Arabian gum, alginate, dextran, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

A method of treating disorders mediated by estrogen receptor described in the present invention can also be carried out using a pharmaceutical composition containing any of the compounds specified here, and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 5 mg and 1000 mg, preferably about 10-500 mg compounds and can be transformed into any form suitable for the selected method of administration. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to the above, binder, suspendresume agents, lubricants, corrigentov, sweeteners, preservatives, & rsquo; s and coverage. Compositions suitable for oral administration include solid forms, such as pills, tablets, small capsules, capsules (each of which include medicines immediate-release, controlled time release and extended release), granules and powders, and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms applicable for parenteral administration include sterile solutions, emulsions and suspensions.

Compounds of the present invention mainly can be entered as a single daily dose, or the total daily dose may be entered as divided doses for the introduction of a two, three or four times a day. In addition, the compounds of the present invention can be introduced in intranasal form via topical use of suitable intranasal fillers or via transdermal skin patches well known to specialists in this field. For administration in the form of a transdermal delivery system dosed introduction, of course, be continuous rather than intermittent throughout the dosage regimen of the drug.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert the first carrier, such as ethanol, glycerol, water and the like. In addition, when it is desirable or necessary, the mixture may also include suitable binders, lubricants, dezintegriruetsja agents and coloring agents. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as Arabian gum, tragakant, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

Liquid forms may include containing the appropriate corrigentov suspendresume or dispersing agents, such as synthetic and natural gums, for example tragakant, Arabian gum, methylcellulose and the like. For parenteral administration are desirable sterile suspensions and solutions. Isotonic preparations, which usually contain suitable preservatives, used when it is desirable intravenous.

The compound of the present invention can also be introduced in the form of liposomal delivery systems, such as small single bubble is Ki, large single bubbles and multi-layered vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Compounds of the present invention can also be delivered using monoclonal antibodies as individual carriers, which combine molecules of compound. Compounds of the present invention can also be coupled with soluble polymers are used as carriers capable of delivering the target drugs. Such polymers can include polyvinylpyrrolidone, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted residue by Palmitoyl. In addition, the compounds of the present invention can be combined with a class of biodegradable polymers suitable for achieving controlled release of a drug, for example polylactic acid, poly-Epsilon-caprolactone, polyhydroxyalkanoic acid, polyarteritis, polyacetylene, policyidreference, polycyanoacrylate and sewn or amphipatic block copolymers of hydrogels.

The compounds of this invention can be introduced into any of the above compositions in accordance with the scheme of medicines among the STV, established in this area, whenever treatment of disorders mediated by the estrogen receptor.

The daily dosage of the products may vary over a wide range from approximately 1 to approximately 1000 mg per adult human per day. For oral administration the compositions are preferably provided in the form of tablets containing 1,0, 5,0, 10,0, 15,0, 25,0, 50,0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to the treatment of the patient. An effective quantity of a drug is usually injected at the level of the dose from about 0.01 mg/kg to about 20 mg/kg of body weight per day. Preferably the range is from about 0.1 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.5 mg/kg to about 10 mg/kg of body weight per day. Connections can be entered when the mode 1-4 times a day.

The optimal dose, which must be entered, can be easily determined by the person skilled in the art, they may vary depending on the particular compound, the route of administration, the efficacy of the drug, route of administration and success in the treatment of pathological conditions. In addition, factors associated with a particular patient being treated, including the age, a lot of food and time of administration of the drug to the patient, can lead to the need for regulation of the doses.

The following examples are given to aid in understanding the invention and are not intended and should not be construed in any way as limiting the invention which is set forth in the claims that follow thereafter.

EXAMPLE 1

3-(2,4-Acid)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ether acetic acid

A mixture of 2,4-dihydroxyacetophenone (2,233 g, 14,67 mmol, 1 EQ.), 2,4-dimethoxyphenylacetic acid (2,88 g, 14,67 mmol, 1 EQ.), acetic anhydride (7.5 ml, 78 mmol, 5 EQ.) triethylamine (1,49 ml, 2.05 mmol, 1 EQ.) stirred and heated at the boil under reflux in nitrogen atmosphere for 48 hours. After cooling to room temperature the reaction mixture in the form of dark syrup was poured into ice-cold water (˜450 ml). The suspension sticky semi-solid product is neutralized by slow addition to a mixture of solid NaHCO₃. The mixture then allow to harden over night. Dark solid allocate by filtration, washed with water, sucked dry under vacuum and recrystallized from acetic acid, while receiving specified in the title compound in the form of a crystalline solid ivory. The second portion (0.95 g, 18.3 percent) allocate the C stock solution.

TPL: 146-148°C.

MS(Cl) m/z 355 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):to 7.67 (1H, d, J=8.7 Hz), 7,13-7,06 (3H, m), to 6.58 (1H, d, J=12.3 Hz), 6,56 (1H, s), 3,85 (3H, s), 3,76 (3H, s), a 2.36 (3H, s), 2,24 (3H, s)

IR(KBr): 1762, 1731, 1610, 1574, 1506, 1462, 1312, 1264, 1212 cm^-1

Anal. Calc. for C₂₀H₁₈About₆: C, 67,79; N, 5,12. Found: C, 67,75; N, 4,99.

EXAMPLE 2

3-(2,4-Acid)-8-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ether acetic acid

Specified in the header connection receive according to the method described in example 1, replacing 2,4-dihydroxyacetophenone 2,3-dihydroxyacetophenone.

TPL 140-141°C.

MS(Cl) m/z 355 (M+H)⁺, 377 (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):at 7.55 (1H, d, d, J=4,2, 5,32 Hz), 7,29 (1H, d, J=1,29 Hz), 7,27 (1H, d, J=4,37 Hz), was 7.08 (1H, d, J=8,13 Hz), 6,57-6,55 (2H, m), 3,86 (3H, s), 3,76 (3H, s), 2,43 (3H, s), 2,24 (3H, s).

EXAMPLE 3

3-(2,4-Acid)-7-fluoro-4-methyl-2-oxo-2H-chromen-7-silt ether

Specified in the header connection receive according to the method described in example 1, replacing 2,4-dihydroxyacetophenone 4-fluoro-2,4-dihydroxyacetophenone.

TPL 156-157°C.

MS(Cl) m/z 315 (M+H)⁺, 337 (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):to 7.64 (1H, d, d, J=5,98, 8,77 Hz), 7,11-7,01 (3H, m), to 6.58 (1H, d, d, J=2,30, 8,10 Hz), to 6.57 (1H, s), 86 (3H, C)of 3.77 (3H, s), 2,24 (3H, s).

IR(KBr): 1712, 1617, 1527, 1505, 1215, 1118 cm^-1

Anal. Calc. for C₁₈H₁₅About₄: C, 68,78; N, 4,84. Found: C, 68,67; N, 4,70.

EXAMPLE 4

3-(2-Benzyloxy-3-methoxyphenyl)-7-methoxy-4-methylpropan-2-he

Specified in the title compound obtained as a tan foamy solid according to the method described in example 1, with the substitution of 2,3-dimethoxyphenylacetic acid 2-benzyloxy-4-methoxyphenylacetic acid.

MS(Cl) m/z 403 (M+H)⁺, 425 (M+Na), 827 (2M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):7,53 (1H, d, J=9 Hz), 7,30-of 7.23 (5H, m), 7,11 (1H, d, J=8,96 Hz), 6,88-6,85 (2H, m), is 5.06 (2H, d, J=2.00 Hz), 3,88 (3H, s), 3,81 (3H, s), 2,22 (3H, s)

IR(KBr): 1712, 1619, 1603, 1579, 1564, 1509 cm^-1

Anal. Calc. for C₂₅H₂₂About₅/0,1 N₂ABOUT: WITH, 74,28; N, 5,54. Found: C, 74,10; N, 5,38.

EXAMPLE 5

3-(2,4-Dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-he

A mixture of 3-(2,4-acid)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ether acetic acid, obtained as in example 1 (0,177 g, 0.5 mmol, 1 EQ.), and dry pyridine hydrochloride (0.9 g, 8,8 mmol, 16 EQ.) stirred and heated on an oil bath to obtain a melt at 210°C in an atmosphere of nitrogen sealed in a round-bottom flask with free incoming tube within 1 hour. After cooling to room temperature the reaction mixture was triturated with water and the aqueous layer was extracted several times with ethyl acetate until then, until the latter becomes colorless. The combined organic extracts washed with saturated salt solution, dried (anhydrous sodium sulfate), filtered and evaporated, thus obtaining specified in the title compound as a pinkish crystalline solid.

TPL 282-283°C.

MS(Cl) m/z 285 (M+H)⁺, 306 (M+ Na)⁺; scan negative ions 283 (M-H)

¹H-NMR (300 MHz, DMSO-d₆):of 10.47 (1H, Sirs), 9,34 (2H, s), a 7.62 (1H, d, J=8,8 Hz), for 6.81 (2H, d, d, J=2,5, and 8.3 Hz), 6,72 (1H, d, J=2.2 Hz), 6.35mm (1H, d, J=2.1 Hz), 6,27 (1H, d, d, J=2,1, 8,2 Hz)by 2.13 (3H, s)

IR(KBr): 3454, 3264, 1673, 1616, 1562, 1509, 1461, 1379, 1350, 1282, 1157, 1106 cm^-1

Anal. Calc. for C₁₆H₁₂About₅/0,25 H₂ABOUT: WITH, 66,55; N, 4,36. Found: C, 66,63; N, 4.53-In.

EXAMPLE 6

3-(2,3-Dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-he

Specified in the header connection receive according to the method described in example 5, with the substitution of 3-(2,4-acid)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ester of acetic acid 3-(2,4-acid)-8-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ether acetic acid obtained in example 2.

TPL 273-274°C.

MS(Cl) m/z 285 (M+H), 307 (M+Na)⁺that is generowanie negative ions 283 (M-H)

¹H-NMR (300 MHz, DMSO-d₆):10,10 (1H, s), to 9.32 (1H, s), 9,24 (1H, s), 7.23 percent-7,07 (3H, m), 6,85 (1H, d, J=8,23 Hz), 6,37 (1H, d, J=2,27 Hz), 16,29 (1H, d, d, J=2,30, 8,24 Hz), 2,17 (3H, s)

EXAMPLE 7

3-(2,4-Dihydroxyphenyl)-7-fluoro-4-methylpropan-2-he

Specified in the header connection receive according to the method described in example 5, with the substitution of 3-(2,4-acid)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ester of acetic acid 3-(2,4-acid)-7-fluoro-4-methyl-2-oxo-2H-chromen-7-silt ether obtained in example 3.

TPL 266-268°C.

MS(Cl) m/z 287 (M+H)⁺, 309 (M+Na)⁺; scan negative ions 285 (M-H)

¹H-NMR (300 MHz, acetone-d₆):at 8.36 (1H, s)to 8.12 (1H, s), to $ 7.91-a 7.85 (1H, m), 7,37-7,10 (2H, m), 6,98 (1H, d, J=8,24 Hz), 6,50 (1H, d, J=8,32 Hz), 6,46 (1H, d, d, J=2,37, 8,24 Hz), 2,31 (3H, s)

IR(KBr): 3329, 3164, 1685, 1611, 1570, 1272, 1116 cm^-1

Anal. Calc. for C₁₈H₁₁FO₄/0,1 N₂ABOUT: WITH, 66,71; N, TO 3.92. Found: C, 66,63; N, 4,06.

EXAMPLE 8

3-(2-Hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-he

A solution of 3-(2-benzyloxy-3-methoxyphenyl)-7-methoxy-4-methylpropan-2-it (0,98 g of 2.44 mmol), obtained as in example 4, in glacial acetic acid (8 ml) is treated with concentrated hydrochloric acid (3.5 ml) and the mixture is stirred and heated to 60�B0; C for approximately 20 hours. Reaction monitoring mass spectrometry and thin-layer chromatography shows the presence of the source material, so add additional acetic acid (4 ml) and hydrochloric acid (3 ml) and stirring and heating continued for another 20 hours. The reaction mixture was then evaporated to dryness in vacuo and the residue diluted with water. Precipitated crystal pink untreated specified in the title compound are filtered, washed with water and dried. The resulting product is triturated with ether, filtered and optionally washed with ether, thus obtaining specified in the header of the product in the form of solids.

TPL 213-214°C.

MS(Cl) m/z 313 (M+H)⁺; (M-H, scan negative ions)

¹H-NMR (300 MHz, DMSO-d₆):9,40 (1H, Sirs), 7,73 (1H, d, J=8,68 Hz), 7,01-of 6.96 (3H, m), 6,47 (1H, s), 6,46 (1H, d, J=6,60 Hz), 3,88 (3H, s), 3,74 (3H, s)of 2.16 (3H, s)

IR(KBr): 3300, 1669, 1603, 1562 cm^-1

Anal. Calc. for C₁₈H₁₆About₅: C, 69,22; N, 5,16. Found: C, 69,42; N, 5,18.

EXAMPLE 9

3-Acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid

A mixture of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it (0,72 g 2,533 mmol), obtained as in example 5, acetic anhydride (2 m is, approximately 20 mmol) and pyridine (0.2 ml, approximately 2.2 mmol) is heated to 70°C in an atmosphere of nitrogen for 18 hours. The resulting mixture is cooled. Then add water to the mixture and the mixture is stirred at room temperature for 30 minutes, then extracted with dichloromethane. The organic extracts are washed with saturated salt solution, dried (anhydrous sodium sulfate), filtered and evaporated to obtain a foam. The foam is crystallized by rubbing the foam with a mixture of ethyl acetate/ether, thus obtaining specified in title product as a beige crystalline solid.

TPL 145-145°C.

MS(Cl) m/z 411 (M+H)⁺, 432 (M+Na)⁺

¹H-NMR (300 MHz, CDC₃):of 7.70 (1H, d, J=8.7 Hz), 7,26 (1H, d, J=2.3 Hz), 7,16-7,10 (4H, m), is 2.37 (3H, s), 2,32 (3H, s), of 2.28 (3H, s), 2,11 (3H, s)

IR(KBr): 1763, 1726, 1611, 1573, 1501, 1428, 1373, 1202 cm^-1

Anal. Calc. for C₂₂H₁₈About₈: C, 64,39; N, 4,42. Found: C, 64,16; N, 4,23.

EXAMPLE 10

5-Acetoxy-2-(8-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid

Specified in the header connection receive according to the method described in example 9, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-(2,3-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-one, obtained as in example 6.

TPL 119-120°C.

MS m/z 39 [(M-AC)+N] ⁺411(M+H)⁺, 433 (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):to 7.59-rate of 7.54 (1H, m), 7,34-7,29 (2H, m), 7,25 (1H, d, J=to 8.41 Hz), 2,43 (3H, s), 2,32 (3H, s)to 2.29 (3H, s), 2,11 (3H, s)

IR(KBr): 1769, 1720, 1610, 1578, 1501, 1462, 1371, 1202 cm^-1

Anal. Calc. for C₁₈H₁₁FO₄/0,1 N₂ABOUT: WITH, 66,71; N, TO 3.92. Found: C, 66,63; N, 4,06.

EXAMPLE 11

5-Acetoxy-2-(7-fluoro-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid

Specified in the header connection receive according to the method described in example 9, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-(2,4-dihydroxyphenyl)-7-fluoro-4-methylpropan-2-one, obtained as in example 7.

TPL 148-149°C.

MS(Cl) m/z 329 [(M-AC)+N]⁺371 (M+H)⁺, 393 (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):7,70-the 7.65 (1H, m), 7,27 (2H, d, J=8,06 Hz), 7,14-7,05 (3H, m), 2,32 (3H, c), of 2.28 (3H, s), 2,109 (3H, s)

IR(KBr): 1765, 1726, 1706, 1612, 1529, 1500, 1429, 1372, 1273, 1191 cm^-1

Anal. Calc. for C₂₀H₁₅FO₆: C, 64,87; N, 4,08. Found: C, 64,69; N, 3,94.

EXAMPLE 12

3-Methoxy-2-(7-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid

Specified in the title compound obtained as a light pink solid by the procedure described in example 9, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-methylpropan-2-it 3-(2-hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-one, obtained as in example 8.

TPL 125-126°C.

MS(Cl) m/z 355 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):EUR 7.57 (1H, d, J=8,76 Hz), 7,17 (1H, d, J=8.54 in Hz), 6,91-6,86 (3H, m), is 6.78 (1H, d, J=2,52 Hz)to 3.89 (3H, s), of 3.84 (3H, s), 2,24 (3H, s), is 2.09 (3H, s)

IR(KBr): 1765, 1716, 1618, 1605, 1564, 1508, 1206 cm^-1

Anal. Calc. for C₂₀H₁₈About₆: C, 67,79; N, 5,12. Found: C, 67,94; N, 5,14.

EXAMPLE 13

3-Acetoxy-4-(7-acetoxy-4-methyl bromide-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid

A mixture of 3-acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester acetic acid (0,767 g of 1.87 mmol, 1 EQ.), N-bromosuccinimide (0,349 g, 1,962 mmol, of 1.05 equiv.) and benzoyl peroxide (0.035 g, 0,145 mmol) in carbon tetrachloride (30 ml) is stirred and heated at the boil under reflux in a nitrogen atmosphere when illuminated by a tungsten lamp 100 watts for 20 hours. Reaction monitoring MS and TLC shows the presence of unreacted starting material and the reaction mixture is added N-bromosuccinimide (to 0.060 g, 0.34 mmol) and benzoyl peroxide (0.008 g) and the reaction mixture is heated at boiling under reflux in nitrogen atmosphere for an additional 2 hours. The mixture is evaporated to dryness, dissolved in hot dichloromethane and purified column chromatography on silica gel is a blend of 3% ethyl acetate/hexane as eluent, while receiving specified in the title compound as a tan crystalline solid.

TPL 171-172°C.

MS(Cl) m/z 488 (M+H)⁺, 512 (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):7,81 (1H, d, J=8.7 Hz), 7,49 (1H, d, J=8,3 Hz), 7,19-7,13 (4H, m), and 4.40 (1H, d, J=a 10.6 Hz), 4,27 (1H, d, J=10,7 Hz), of 2.38 (3H, s), of 2.33 (3H, s), 2,11 (3H, s)

IR(KBr): 1766, 1725, 1613, 1571, 1499, 1426, 1369, 1194 cm^-1

Anal. Calc. for C₂₂H₁₇BrO₈: C 54,01; N, 3,50. Found: C, 54,03; N, 3,42.

EXAMPLE 14

5-Acetoxy-2-(8-acetoxy-4-methyl bromide-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid

Specified in the title compound obtained as a crystalline solid according to the method described in example 13, with the replacement of 3-acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid 5-acetoxy-2-(8-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ether acetic acid, obtained as in example 10.

EXAMPLE 15

2-(4-methyl bromide-7-methoxy-2-oxo-2H-chromen-3-yl)-5-methoxybenzyloxy ether acetic acid

Specified in the title compound obtained as a crystalline solid according to the method described in example 13, with the replacement of 3-acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid-methoxy-2-(7-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ether acetic acid, obtained as in example 15.

TPL 132-133°C.

MS(Cl) m/z 435 (M+H)⁺, 391 [(M-AC)+N]⁺

¹H-NMR (300 MHz, CDCl₃):to 7.68 (1H, d, J=8,80 Hz), 7,40 (1H, d, J=8,58 Hz), 6,97-6,91 (3H, m), to 6.88 (1H, d, J=2,28 Hz), to 6.80 (1H, d, J=2,40 Hz), 4,39 (1H, d, J=accounted for 10.39 Hz), 4,27 (1H, d, J=10,38 Hz), 3,90 (3H, s), 3,86 (3H, s), is 2.09 (3H, )

IR(KBr): 1785, 1721, 1605, 1564, 1512, 1453, 1289, 1213, 1105 cm^-1

Anal. Calc. for C₂₀H₁₇BrO₆: C, 55,44; N, 3.96 POINTS. Found: C, 55,45; H, Was 4.02.

EXAMPLE 16

3-Acetoxy-4-(4-methyl bromide-7-fluoro-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid

Specified in the title compound obtained as a crystalline solid according to the method described in example 13, with the replacement of 3-acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid 5-acetoxy-2-(7-fluoro-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ether acetic acid, obtained as in example 11.

TPL 230-231°C.

MS(Cl) m/z 451 (M+H)⁺, 471 (M+Na)⁺, 409 [(M-Ac)+H]⁺

¹H-NMR (300 MHz, CDCl₃):7,80 (1H, d, d, J=3,37, 9,62 Hz), 7,49 (1H, d, J=8.35 Hz), 7,21-7,11 (4H, m), 4,39 (1H, d, J=10,61 Hz), 4,27 (1H, d, J=is 10.68), of 2.33 (3H, s)of 2.10 (3H, s)

IR(KBr): 1758, 1727, 1617, 1581, 1371, 1215 cm^-1

EXAMPLE 17

2,8-Dihydroxy-11N-chromeno[4,3-c]chromen-5-he, connection # 1

Method:

To paramashiva is the PTO to the solution of 3-(2-hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-it (0,100 g, 0,204 mmol), obtained as in example 13, in a mixture of methanol (5 ml) and acetone (2 ml) is added at room temperature, anhydrous potassium carbonate (0,08474 g, 0.6 mmol). The solution immediately becomes yellow. The solution is stirred for 2 hours, evaporated to dryness, the residue dissolved in water (15 ml) and then acidified with dilute hydrochloric acid to a pH of approximately 1. The precipitated yellow solid allocate by filtration, washed with water and dried, thus obtaining specified in the header of the connection.

TPL>350°C.

MS(Cl) m/z 283 (M+H)⁺, 305 (M+Na)⁺, 321 (M+K)⁺; scan negative ions 281 (M-H)

¹H-NMR (300 MHz, DMSO-d₆):10,65 (1H, Sirs), 9,85 (1H, Sirs), 8,19 (1H, d, J=8.0 Hz), a 7.62 (1H, d, J=8.1 Hz), PC 6.82 (1H, d, J=8,2 Hz), 6,76 (1H, s), 6,47 (1H, d, J=7,75 Hz), 6,38 (1H, s)5,33 (2H, s)

IR(KBr): 3373, 1699, 1620, 1597, 1508, 1464, 1299, 1264, 1166 cm^-1

Anal. Calc. for C₁₆H₁₀About₅/0,2 H₂O: C, 67,23; N, 3,67. Found: C, 67,31; N, 3,55.

EXAMPLE 18

2,8-Dihydroxy-11N-chromeno[4,3-c]chromen-5-he, connection # 1

Method:

Specified in the header of the product is obtained according to the method described in example 5, with the substitution of 3-(2,4-acid)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ether acetic acid, 2,8-dimethoxy-11N-chromeno[4,3-c]chromen-5-one, obtained as in example 21.

TPL> 360°C.

EXAMPLE 19

2,7-Dihydroxy-11N-chromeno[4,3-c]chromen-5-Oh, compound No. 84

Specified in the header connection receive according to the method described in example 17, replacing 3-(2-hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-5-acetoxy-2-(8-acetoxy-4-methyl bromide-2-oxo-2H-chromen-3-yl)phenyl ether acetic acid, obtained as in example 10.

EXAMPLE 20

8-fluoro-2-hydroxy-11N-chromeno[4,3-c]chromen-5-he, connection # 37

Specified in the header connection receive according to the method described in example 17, replacing 3-(2-hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-acetoxy-4-(4-methyl bromide-7-fluoro-2-oxo-2H-chromen-3-yl)phenyl ether acetic acid, obtained as in example 16.

TPL 259-260°C.

MS(Cl) m/z 285 (M+H)⁺, 307 (M+ Na)⁺; scan negative ions 281 (M-H)

¹H-NMR (300 MHz, DMSO-d₆):9,99 (1H, s), by 8.22 (1H, d, J=8,70 Hz), 7,87 (1H, d, d, J=6,12, of 8.90 Hz), 7,46 (1H, d, d, J=2,52, at 9.53 Hz), 7,31 (1H, d, t, J=2,56, 8,77 Hz), 6,51 (1H, d, d, J=2,45, 8,71 Hz), 6,41 (1H, d, J=2,41 Hz), of 5.40 (2H, )

IR(KBr): 3341, 1697, 1621 1506, 1455, 1275, 1110 cm^-1

Anal. Calc. for C₁₆H₉FO₄: C 67,61; N, 3,19. Found: C, 65,252; N, 3,38.

EXAMPLE 21

2,8-Dimethoxy-11N-chromeno[4,3-c]chromen-5-he, connection # 2

Specified in the title compound obtained as a light yellow solid according to the method described in example 17, replacing 3-(2-hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-it 2-(4-methyl bromide-7-methoxy-2-oxo-2H-chromen-3-yl)phenyl ether acetic acid, obtained as in example 17.

TPL 200-201°C.

MS(Cl) m/z 311 (M+H)⁺, 333 (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):8,49 (1H, d, J=8,83 Hz), 7,37 (1H, d, J=8,46 Hz), make 6.90 (1H, d, d, J=2,67, 8,84 Hz), 6,53 (1H, d, J=2,36 Hz), at 5.27 (2H, s)to 3.89 (3H, s), 3,83 (3H, s)

IR(KBr): 1712, 1621 1573, 1504, 1168 cm^-1

Anal. Calc. for C₁₈H₁₄About₅: C, 69,67; N, 4,55. Found: C, 69,42; N, 4,54.

EXAMPLE 22

2,8-Bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he, connection # 3

Suspension 2,8-dihydroxy-11N-chromeno[4,3-c]chromen-5-it (0,322 g, 1,1412 mmol, 1 EQ.), obtained as in example 17, in dichloromethane (10 ml) is treated with triethylamine (0.8 ml, 5,70 mmol, 5 EQ.) with the subsequent addition of tert-butyldimethylsilyl (0,585 g, 3.88 mmol, 3.4 EQ.). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 18 hours. (Observe that the suspension becomes a clear solution after about 30 minutes of mixing). The reaction mixture was diluted with hexane (˜35 ml) and washed once with saturated Rast is or salt. Water after washing again extracted with hexane. The combined organic extracts are dried (anhydrous sodium sulfate), filtered and evaporated in vacuum, thus obtaining a yellow solid residue. The solid residue is recrystallized them hexane, thus obtaining specified in the title compound as a pale yellow crystalline solid.

TPL 150-151°C.

MS(Cl) m/z 533 (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):8,43 (1H, d, J=8.6 Hz), 7,33 (1H, d, J=8,3 Hz), at 6.84 (1H, s), 6,83 (1H, d, J=9.1 Hz), to 6.57 (1H, d, d, J=2,4, and 8.7 Hz), 6,47 (1H, d, J=2,22 Hz), of 5.26 (2H, s), and 1.00 (9H, s), 0,99 (9H, s), 0,26 (3H, s), 0,23 (6H, s)

IR(KBr): 2957, 2927,2883, 2855, 1713, 1618, 1567, 1498, 1287 cm^-1

Anal. Calc. for C₂₄H₃₈About₅Si₂: C, 65,84; N, 7,50. Found: C, 65,53; N, 7,43.

EXAMPLE 23

2-(tert-Butyldimethylsilyloxy)-8-fluoro-11N-chromeno[4,3-c]chromen-5-he, connection # 85

Specified in the title compound obtained as a colorless crystalline solid following the procedure described in example 22, with the replacement of 2,8-dihydroxy-11N-chromeno[4,3-c]chromen-5-it 8-fluoro-2-hydroxy-11N-chromeno[4,3-c]chromen-5-one, obtained as in example 20.

TPL 197-198°C.

MS(Cl) m/z 399 (M+H)⁺, 421 (M+Na)⁺, 819 (2M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):8,42 (1H, d, J=8,83 Hz), was 7.45 (1H, d, d, J=5,79, 8,46 is C), 7,13? 7.04 baby mortality (2H, m), to 6.58 (1H, d, d, J=2,48, 8,71 Hz), 6.48 in (1H, d, J=2,45 Hz), at 5.27 (2H, s), 0,99 (9H, s)to 0.24 (6H, s)

IR(KBr): 1724, 1619 1503, 1302, 1262, 1173,832 cm^-1

Anal. Calc. for C₂₂H₂₃FO₄Si: C, 66,31; N, Of 5.82. Found: C, 66,05; N, 5,80.

EXAMPLE 24

2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-he, connection # 4

A solution of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he (5,016 g, 9,82 mmol, 1 EQ.) in toluene (525 ml) cooled to -78°With 3-necked round bottom flask of 1 l, equipped with a mechanical stirrer, a hole for the input of nitrogen and addition funnel. To the reaction mixture slowly add a solution of diisobutylaluminium (19 ml of 1,5M, 28,48 mmol, 2.9 EQ.) in toluene while maintaining the temperature of the reaction mixture is lower than -70°C. the Reaction mixture is stirred for 5 hours, quenched by adding methanol (25 ml) followed by addition of 10% citric acid solution (˜140 ml). The resulting solution was diluted with dichloromethane (525 ml), the solution washed with a saturated solution of Rochelle salt (250 ml), then washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered and evaporated, thus obtaining the crude compound as a yellow solid. The solid is recrystallized from a mixture of dichloromethane:hexane (1:1), while receiving at asany the title product as a crystalline solid ivory.

TPL 188-190°C.

MS(Cl) m/z 511 (M+H)⁺, 533 (M+Na)⁺, 495 [(M-H₂O)+H]⁺, 1043 (2M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):to 7.15 (1H, d, J=8,4 Hz), of 6.96 (1H, J=8,4 Hz), 6,59 (1H, d, J=2,24 Hz), is 6.54 (1H, d, d, J=2,31, are 11.62 Hz), 6,46 (1H, d, d, J=2,31, 8.35 Hz), 6,41 (1H, d, J=2,31 Hz), 6,11 (1H, d, J=8,1 Hz, degenerates into a singlet exchange with D₂O)3,01 (1H, d, J=8,2 Hz, able to communicate with D₂O), and 0.98 (18H, s)and 0.22 (6H, s)of 0.21 (6H, s)

IR(KBr): 3407, 2950, 2928, 2857, 1612, 1572, 1496, 1276, 1252, 1166, 1126, 1020, 838, 777 cm^-1

EXAMPLE 25

2-(tert-Butyldimethylsilyloxy)-8-fluoro-5,11-dihydrobromide[4,3-c]chromen-5-Oh, compound No. 86

Specified in the title compound obtained as a colorless crystalline solid following the procedure described in example 24, with the replacement of 2,8-dihydroxy-11N-chromeno[4,3-c]chromen-5-on 2-(tert-butyldimethylsilyloxy)-8-fluoro-11N-chromeno[4,3-c]chromen-5-one, obtained as in example 20.

TPL 166-167°C.

MS(Cl) m/z 401 (M+H)⁺, 423 (M+Na)⁺, 383 [(M-H₂O)+H]⁺

¹H-NMR (300 MHz, CDCl₃):8,42 (1H, d, J=8,83 Hz), was 7.45 (1H, d, d, J=5,79, 8,46 Hz), 7,13? 7.04 baby mortality (2H, m), to 6.58 (1H, d, d, J=2,48, 8,71 Hz), 6.48 in (1H, d, J=2,45 Hz), at 5.27 (2H, s), 0,99 (9H, s)to 0.24 (6H, s)

IR(KBr): 3441, 1616, 1590 1566, 1504, 1294, 1283, 1142, 1028 cm^-1

Anal. Calc. for C₂₂H₂₃FO₄Si/0,4 H₂ABOUT: WITH, 64,81; N, 6,38. Found: C, 64,71; N, To 6.19.

EXAMPLE 26</>

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol

In odnogolosy, round-bottom flask of 50 ml dissolve and mix 4-[2-(piperidine-1-yl)ethoxy]iodobenzoyl (0.828 g, 2.5 mmol, 3 EQ.) in tetrahydrofuran (10 ml) in an argon atmosphere and the mixture is cooled to -22°C. After 5 minutes of mixing with a syringe add an ethereal solution of isopropylacrylamide (1,244 ml, 2,14M solution to 2.65 mmol, 3 EQ.). The reaction mixture is then stirred for 2 hours at approximately -22°C. add the solution in tetrahydrofuran 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol (0,512 g, 1 mmol, 1 EQ. a 10 ml), obtained as in example 24, the cooling bath removed and the reaction mixture was allow to warm to room temperature over night. After approximately 18 hours, the reaction mixture was added a saturated solution of ammonium acetate (15 ml) and extracted with diethyl ether (CH ml). The combined organic extracts washed with saturated salt solution, dried with anhydrous sodium sulfate, filtered and evaporated, thus obtaining a sticky semi-solid residue. Specified in the header of the product isolated in the form of a viscous colorless semi-solid foam chromatography on when likehere when elution with a mixture of 3% methanol/dichloromethane.

MS(Cl) m/z 718 (M+H)⁺scanning negative ions 716 (M-H)]

¹H-NMR (300 MHz, CDCl₃):7,06 (4H, m), 6,62 (2H, d, J=8,4 Hz), 6,45-6,34 (3H, m), 5,38 (1H, Sirs,), to 4.81 (2H, Sirs), of 4.05 (2H, t), 2,80 (2H, t), to 2.57 (4H, Sirs), of 1.47 (4H, m)of 1.46 (2H, m)to 0.96 (9H, s)of 0.93 (9H, s)to 0.19 (6H, s), 0,14 (6H, s).

EXAMPLE 27

2-[4-{[4-(2-Azepin-1 ylethoxy)phenyl]hydroxymethyl}-7-(tert-butyldimethylsilyloxy)-2H-chromen-3-yl]-5-(tert-butyldimethylsilyloxy)phenol

Specified in the header connection receive according to the method described in example 26, with the replacement of the Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium 4-[2-(azepin-1-yl)ethoxy]phenylmagnesium (formed in situ from 4-[2-(azepin-1-yl)ethoxy]odensala and isopropylacrylamide), used as a Grignard reagent.

MS(Cl) m/z 732 (M+H)⁺scanning negative ions 730 (M-H)

¹H-NMR (300 MHz, CDCl₃):to 7.09-7.03 is (4H, m), of 6.66 (2H, d, J=8,32 Hz), 6,45-6,28 (4H, m), the ceiling of 5.60 (1H, Sirs,), to 4.81 (2H, Sirs), a 4.03 (2H, t), of 2.97 (2H, m), and 2.83 (4H, m), 1,61-of 1.53 (8H, m)to 0.96 (9H, s)of 0.93 (9H, s)to 0.19 (6H, s), and 0.15 (6H, C).

EXAMPLE 28

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-morpholine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol

Specified in the header connection receive according to the method described in the example is 26, with the replacement of the Grignard reagent, 4-[2-(piperidine-1-yl)ethoxyphenyl]minibrain, 4-[2-(morpholine-1-yl)ethoxyphenyl]minibrain (formed in situ from 4-[2-(morpholine-1-yl)ethoxy]odensala and isopropylacrylamide), used as a Grignard reagent.

MS(Cl) m/z 720 (M+H)⁺, 742 (M+Na)⁺; scan negative ions 718 (M-H)

¹H-NMR (300 MHz, CDCl₃):7,06-7,02 (4H, m), 6,77 (2H, d, J=7,98 Hz), to 6.43-6,18 (4H, m), 5,67 (1H, Sirs), to 4.81 (2H, Sirs), of 4.05 (2H, t), and 3.72 (4H, m), 2,77 (2H, t), of 2.56 (4H, m)to 0.96 (9H, s)of 0.93 (9H, s)to 0.19 (6H, s), and 0.15 (6H, s).

EXAMPLE 29

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-pyrrolidin-1 ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol

Specified in the header of the product is obtained according to the method described in example 26, with the replacement of the Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium, 4-[2-(pyrrolidin-1-yl)ethoxy]phenylmagnesium (formed in situ from 4-[2-(pyrrolidin-1-yl)ethoxy]odensala and isopropylacrylamide), used as a Grignard reagent.

MS(Cl) m/z 704 (M+H)⁺, 726 (M+Na)⁺scanning negative ions 702 (M-H)

EXAMPLE 30

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-diethylaminoethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol

MS(Cl) m/z 706 (M+H)⁺, 728 (M+Na)⁺scanning negative ions 704 (M-H)

EXAMPLE 31

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-dimethylaminoethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol

Specified in the header of the product is obtained according to the method described in example 26, with the replacement of the Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium, 4-(2-dimethylaminoethoxy)phenylmagnesium (formed in situ from 4-(2-dimethylaminoethoxy)odensala and isopropylacrylamide), used as a Grignard reagent.

MS(Cl) m/z 678 (M+H)⁺, 700 (M+Na)⁺; scan negative ions 706 (M-H)

¹H-NMR (300 MHz, CDCl₃):to 7.09 (4H, m)6,94 (2H, d, J=8,10 Hz), 6,58-6,33 4H, m), of 5.50 (1H, Sirs), 4,82 (2H, Sirs), of 4.00 (2H, t), 2,78 (2H, m), of 2.38 (6H, s), and 0.98 (9H, s)to 0.94 (9H, s)of 0.20 (6H, s), and 0.15 (6H, s).

EXAMPLE 32

5-(tert-Butyldimethylsilyloxy)-2-[7-(tert-butyldimethylsilyloxy)-4-(hydroxyphenyl]methyl)-2H-chromen-3-yl)]phenol

Specified in the header is the product is obtained according to the method described in example 26, with the replacement of the Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium (formed in situ from 4-[2-(piperidine-1-yl)ethoxy]odensala and isopropylacrylamide) phenylmagnesium used as the Grignard reagent.

MS(Cl) m/z 591 (M+H)⁺, 613 (M+Na)*, 573 M-H₂O+H)⁺; scan negative ions, 589 (M-H).

EXAMPLE 33

5-(tert-Butyldimethylsilyloxy)-2-[7-(tert-butyldimethylsilyloxy)-4-[(4-dimethylamino(phenyl)hydroxymethyl]-2H-chromen-3-yl)]phenol

Specified in the header of the product is obtained according to the method described in example 26, with the replacement of the Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium (formed in situ from 4-[2-(piperidine-1-yl)ethoxy]odensala and isopropylacrylamide), 4-(dimethylamino)phenylmagnesium used as the Grignard reagent.

MS(Cl) m/z 634 (M+H)⁺, 616 (M-H₂O+H)⁺,

EXAMPLE 34

2-(7-(tert-Butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl-5-terfenol

Specified in the header connection receive according to the method described in example 26, with the replacement of 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol 2-(tert-butyldimethylsilyloxy)-8-fluoro-5,11-dihydrobromide[4,3-c]chromanol-5th obtained, as in point is the iMER 25.

MS(Cl) m/z 606 (M+H⁺), 648 (M+Na)⁺; scan negative ions 604 (M-H)

EXAMPLE 35

1-(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine, compound No. 8

To a stirred solution of 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol (1,0633 g, 1.48 mmol, 1 EQ.), obtained as in example 26, in tetrahydrofuran (50 ml) in an argon atmosphere at room temperature add powdered molecular sieves (4 Å, 0,250 g) and triphenylphosphine (0,7829 g, 2,99 mmol, 2 EQ.) with the subsequent addition of diethyldithiocarbamate (0.52 g=0,466 ml, 2,96 mmol). The reaction mixture was kept overnight (approximately 18 hours). The reaction mixture is evaporated to dryness, triturated with ether and the resulting colourless solid, triphenylphosphine oxide removed by filtration. The filtrate is evaporated to dryness, thus obtaining a residue, which was purified column chromatography on silica gel using 2% methanol in dichloromethane as the eluent, thus obtaining specified in the header of the product in the form of a viscous semi-solid substance.

MS(Cl) m/z 700 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):7,30 (2H, d, J=8.7 Hz), 6.87 in (1H, d J=8,30 Hz), 6,79 (2H, d, J=1,91, PC 6.82 Hz), 6,70 (1H, d, J=8,42 Hz), to 6.39 (2H, m), of 6.29 (2H, m), 6,14 (1H, s), and 5.30 (1H, d, J=13,90 Hz), 5,10 (1H, d, d, J=1,654, 13,90 Hz), Android 4.04 (2H, t, J=5,97 Hz), 2,48 (2H, t, J=6.0 Hz), 2,48 (4H, m), 1,58 (4H, m), USD 1.43 (2H, m)of 0.95 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s).

EXAMPLE 36

1-(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)ASEAN, connection # 16

Specified in the header of the product is obtained according to the method described in example 35, with the substitution of 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol and 5-(tert-butyldimethylsiloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-diethylaminoethoxy)phenyl]methyl}-2H-chromenes-2-yl)phenol, obtained as in example 27.

MS(Cl) m/z 714 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):731 (2H, d, J=8,72 Hz), 6.87 in (1H, d, J=8,32 Hz), 6,79 (2H, d, J=8,70 Hz), 6,70 (1H, d, J=8,44 Hz), 6,14 (1H, s), and 5.30 (1H, d, J=13,88 Hz), 5,10 (1H,d, d, J=1,55, 13,88 Hz to 4.01 (2H, t, J=6,20 Hz), only 2.91 (2H, t, J=6,20 Hz), 2,81--by 2.73 (4H, m), 1.70 to to 1.60 (8H, m)of 0.95 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s)

EXAMPLE 37

1-(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)morpholine, compound No. 12

Specified in the header of the product is obtained according to the method described in example 35, with the substitution of 5-(tert-butyldimethylsilyloxy)-2-(7-(the pet-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol 2-[4-{[4-(2-azepin-1 ylethoxy)phenyl]hydroxymethyl}-7-(tert-butyldimethylsilyloxy)-2H-chromenes-3-yl]-5-(tert-butyldimethylsilyloxy}phenol, obtained as in example 28.

MS(Cl) m/z 702 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):7,31 (2H, d, J=8,65 Hz), to 6.88 (1H, d, J=8,33 Hz), 6,79 (2H, d, J=a total of 8.74 Hz), 6,70 (1H, d, J=8,43 Hz), 6,41-6,27 (4H, m), x 6.15 (1H, Sirs), and 5.30 (1H, d, J=13,77 Hz), 5,10 (1H, d, d, J=1,52, 13,77 Hz), Android 4.04 (2H, t) 3,74-of 3.69 (4H, m)of 2.75 (2H, t), 2,55-2,52 (4H, m)of 0.95 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s).

EXAMPLE 38

1-(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)pyrrolidin, connection # 10

Specified in the header of the product is obtained according to the method described in example 35, with the substitution of 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol and 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-{4-(2-pyrrolidin-1 ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol, obtained as in example 29.

MS(Cl) m/z 686 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):731 (2H, d, J=8,59 Hz), 6.87 in (1H, d, J=8,32 Hz), to 6.80 (2H, d, J=8,70 Hz), 6,70 (1H, d, J=to 8.41 Hz), x 6.15 (1H, s), and 5.30 (1H, d, J=13,88 Hz), 5,10 (1H, d, J=14,04 Hz), of 4.05 (2H, t, J=5,88 Hz), 2,87 (2H, t, J=5,98 Hz), 2,61 (4H, Sirs), of 0.95 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s).

EXAMPLE 39

(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)diethylamine, connection # 18

Specified in the header of the product is obtained according to the method described in example 35, with the substitution of 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol and 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-diethylaminoethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol, obtained as in example 30.

MS(Cl) m/z 688 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):7,31 (2H, d, J=8,59 Hz), 6.87 in (1H, d, J=8,32 Hz), 6,77 (2H, d, J=8,70 Hz), 6,70 (1H, d, J=8,42 Hz), 6,41-6,27 (4H, m), x 6.15 (1H, s), and 5.30 (1H, d, J=13,85 Hz), 5,10 (1H, d, J=13,89 Hz), of 3.97 (2H, t, J=6,41 Hz), 2,82 (2H, t, J=6,39 Hz), 2,60 (4H, square, J=7,14 Hz)of 1.03 (6H, t, J=7,14 Hz)to 0.96 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s).

EXAMPLE 40

(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)dimethylamine, compound No. 20

Specified in the header of the product is obtained according to the method described in example 35, with the substitution of 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol and 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-dimethylaminoethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol, obtained as in example 31.

MS(Cl) m/z 660 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃): 7,31 (2H, d, J=8,69 Hz), 6.87 in (1H, d, J=8,32 Hz), for 6.81 (2H, d, J=8,68 Hz), 6,70 (1H, d, J=8,42 Hz), 6,41-6,27 (4H, m), 6,14 (1H, s), and 5.30 (1H, d, J=13,83 Hz), 4,91 (1H, d, d, J=1,50, 13,88 Hz)to 3.99 (2H, t, J=5,79 Hz), 2,68 (2H, t, J=5,79 Hz)to 2.29 (6H, s)of 0.95 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s).

EXAMPLE 41

2,8-Bis(tert-butyldimethylsilyloxy)-5-phenyl-5,11-dihydrobromide[4,3-c]chromen, connection # 5

Specified in the header of the product is obtained according to the method described in example 35, with the substitution of 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol and 5-(tert-butyldimethylsilyloxy)-2-[7-(tert-butyldimethylsilyloxy)-4-(hydroxyphenyl]methyl)-2H-chromen-3-yl)]phenol obtained as in example 32.

MS (Cl) m/z 573 (M+H)⁺, (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):7,41 (2H, m), 7,28 (2H, m), 6.87 in (1H, d, J=8,30 Hz), is 6.54 (1H, d, J=8,40 Hz), 6,41 (1H, d, J=2.30 Hz), 6,40 (1H, d, d, J=2,34, 7,94 Hz), 6,21 (s, 1H, C), 5,31 (1H, d, J=13,90 Hz), 5,10 (1H, d, d, J=1,44, 13,90 Hz)to 0.96 (9H, s)of 0.93 (9H, s)to 0.19 (6H, s), 0,16 (6H, s).

EXAMPLE 42

2,8-Bis(tert-butyldimethylsilyloxy)-5-(4-dimethylamino)phenyl-5,11-dihydrobromide[4,3-c]chromen, connection # 23

The crude 5-(tert-butyldimethylsilyloxy)-2-[7-(tert-butyldimethylsilyloxy)-4-[(4-dimethylamino(phenyl)hydroxymethyl]-2H-chromen-3-yl)]phenol obtained as in example 34, when cleaning with what ispolzovaniem chromatography on silica gel and a mixture of ethyl acetate/hexane as eluent gives specified in the title compound in the form of cyclodehydration product.

MS(Cl) m/z 573 (M+H)⁺, (M+Na)⁺

¹H-NMR (300 MHz, CDCl₃):7,41 (2H, m), 7,28 (2H, m), 6.87 in (1H, d, J=8,30 Hz), is 6.54 (1H, d, J=8,40 Hz), 6,41 (1H, d, J=2.30 Hz), 6,40 (1H, d, d, J=2,34, 7,94 Hz), 6,21 (s, 1H, C), 5,31 (1H, d, J=13,90 Hz), 5,10 (1H, d, d, J=1,44, 13,90 Hz), 2,89 (6H, s)to 0.96 (9H, s)of 0.93 (9H, s)to 0.19 (6H, s), 0,16 (6H, s).

EXAMPLE 43

1-(2-{4-{2-(tert-Butyldimethylsilyloxy)-8-fluoro-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine, compound No. 87

Specified in the header of the product is obtained according to the method described in example 26, with the replacement of 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol 2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl-5-tortenelem obtained as in example 34.

MS(Cl) m/z 588 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):7,30 (2H, d, J=8,67 Hz)6,94 (1H, Awkw., J=8,49 Hz), to 6.80 (2H, d, J=8,68 Hz), 6,70 (1H, d, J=8,42 Hz), 6,59 (1H, d, t, J=2,55, of 8.47 Hz), 6,51 (1H, d, d, J=of 2.51, 9,82 Hz), 6,41 (1H, d, J=2,34 Hz), 6,23 (1H, d, d, J=2,36, of 8.37 Hz), 6,18 (1H, s), 5,31 (1H, d, J=14,07 Hz), to 5.08 (1H, d, d, J=1,37, 13,87 Hz), Android 4.04 (2H, t, J=6,02 Hz), 2,73 (2H, t, J=6,03 Hz), 2,47 (4H, m), a 1.88 (4H, m), USD 1.43 (2H, m)to 0.96 (9H, s)to 0.19 (6H, s).

EXAMPLE 44

5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 9

To a stirred solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (0,19 g, 0,2714 mmol, 1 EQ.), obtained as in example 35, in tetrahydrofuran (15 ml) under nitrogen atmosphere add fluoride, Tetra-n-butylamine (1M in tetrahydrofuran, of 1.36 ml of 1.36 mmol, 5 EQ.) and the mixture is stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and then washed with saturated aqueous ammonium chloride (35 ml). The precipitated inorganic salts are removed by filtration and washed with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium bicarbonate (50 ml), dried (anhydrous sodium sulfate), filtered and evaporated to dryness, thus obtaining the crude product. The crude product is purified column chromatography on silica gel using 1:1-mixture of hexane and 10% ammonium hydroxide in methanol, thus obtaining purified specified in the title product as a brown foamy solid product.

MS(Cl) m/z 472 (M+H)+, 470 (M-H, scan negative ions)

¹H-NMR (300 MHz, d-6 acetone):8,46 (2H, W), from 7.24 (2H, d, d, J=1,93, and 6.6 Hz), 6,91 (1H, d, J=8,40 Hz), of 6.71 (3H, d, J=6.6 Hz), of 6.29 (1H, d, d, J=2,43, to 8.34 Hz), and 6.25 (1H, d, J=2,40 Hz), of 6.20 (1H, d, d, J=2,43, 8,32 Hz), 6,13 (2H, d, J=2,36 Hz in), 5.25 (1H, d, J=14,15 Hz), is 4.93 (1H, d, d, J=1,66, 14,13 Hz)to 3.89 (2H, t, J=6,02 Hz), of 2.51 (2H, t, J=6,02 Hz), 2,30 (4H, m)to 1.37 (4H, m)of 1.26 (2H, m)

EXAMPLE 45

5-[4-(2-Azepin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, the connection is their No. 17

Specified in the header of the product is obtained according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)ASEAN obtained as in example 36.

MS(Cl) m/z 486 (M+H)⁺; scan negative ions 484 (M-H)

¹H-NMR (300 MHz, d-6 acetone):to 7.32 (2H, d, J=8,70 Hz), 7,03 (1H, d, J=of 8.37 Hz), at 6.84 (3H, d, J=at 8.60 Hz), to 6.43-6,26 (5H, m), lower than the 5.37 (1H, d, J=14,14 Hz), is 5.06 (1H, d, d, J=1,67, 14,14 Hz), of 4.00 (2H, t, J=6,14 Hz), 2,85 (2H, t, J=6,11 Hz), and 1.56 (8H, m).

EXAMPLE 46

5-[4-(2-Morpholine-4-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 13

Specified in the header of the product is obtained according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)morpholine was obtained as in example 37.

MS(Cl) m/z 474 (M+H)⁺; scan negative ions 472 (M-H)

¹H-NMR (300 MHz, d-6 acetone):8,58 (2H, W), 7,37 (2H, d, J=8,68 Hz),? 7.04 baby mortality (1H, d, J=8,73 Hz), at 6.84 (3H, d, J=8,73 Hz), 6.42 per (1H, d, d, J=2,37, to 8.34 Hz), 6,38 (2H, d, 2.37 Hz), 6,33 (1H, d, d, J=2,41, of 8.33 Hz), 6,2 (2H, d, J=2,33 Hz), 6,27 (1H, s)5,38 (1H, d, J=14,11 Hz), is 5.06 (1H, d, d, J=1,56, 14,13 Hz)4,06 (2H, t, J=5,81 Hz), of 3.57 (4H, t, J=4,01 Hz), of 2.92 (4H, Sirs), 2,69 (2H, t, J=3,45).

EXAMPLE 47

5-[4-(2-Pyrrolidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 11

Specified in the header of the product is obtained according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)pyrrolidin obtained as in example 38.

MS(Cl) m/z 458 (M+H)⁺; scan negative ions 456 (M-H)

¹H-NMR (300 MHz, d-6 acetone):of 7.36 (2H, d, J=8,63 Hz), 7,01 (1H, d, J=8.34 per Hz), 6,84-6,79 (3H, m), 6,44-6,26 (5H, m), are 5.36 (1H, d, J=14,14 Hz), of 5.05 (1H, d, d, J=1,22,14,13 Hz), 4,82 (2H, W), a 4.03 (2H, t, J=5,85 Hz), of 2.81 (2H, t, J=of 5.83), of 2.54 (4H, m) 1,71 by 1.68 (4H, m).

EXAMPLE 48

5-[4-(2-Diethylaminoethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 19

Specified in the header of the product is obtained according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)diethylamine obtained as in example 39.

⁺; scan negative ions 458 (M-H)

¹H-NMR (300 MHz, d-6 acetone):of 7.36 (2H, d, J=8,65 Hz), 7,02 (1H, d, J=at 8.36 Hz), PC 6.82 (3H, d, d, J=2,34, 8,47), 6,43-6,26 (5H, m), of 5.50 (2H, W), lower than the 5.37 (1H, d, J=14,12 Hz), is 5.06 (1H, d, d, J=1,46, 14,12 Hz), 4,82 (2H, W), to 3.99 (2H, t, J=6,23 Hz), of 2.81 (2H, t, J=6,16 Hz), 2.57 m (4H, square, J=7,12 Hz), 0,99 (6H, t, J=7,11).

EXAMPLE 49

5-[4-(2-Dimethylaminoethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 21

Specified in the header of the product is obtained according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)dimethylamine obtained as in example 40.

MS(Cl) m/z 432 (M+H)⁺; scan negative ions 430 (M-H)

¹H-NMR (300 MHz, d-6 acetone):7,37 (2H, d, J=8,63 Hz), 7,03 (1H, d, J=at 8.36 Hz), at 6.84 (3H, d, J=8,49 HZ), to 6.43-6,27 (5H, m), 5,38 (1H, d, J=14,11 Hz), is 5.06 (1H, d, d, J=1,39, 14,11 Hz), was 4.02 (2H, t, J=5,88 Hz), 2,63 (2H, t, J=5,85 Hz), of 2.23 (6H, Sirs).

EXAMPLE 50

5-[4-Dimethylaminophenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 26

Specified in the header of the product is obtained according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen--yl]phenoxy}ethyl)piperidine 2.8-bis(tert-butyldimethylsilyloxy)-5-(4-dimethylamino)phenyl-5,11-dihydrobromide[4,3-c]chromen, obtained as in example 42.

MS(Cl) m/z 388 (M+H)⁺; scan negative ions 386 (M-H)

¹H-NMR (300 MHz, d-5 methanol):7,21 (2H, d, J=8,79 Hz), 6,92 (1H, d, J=at 8.36 Hz), of 6.71 (1H, d, J=to 8.41 Hz), only 6.64 (2H, d, J=8,83 Hz), 6,33 (1H, d, d, J=2,42, of 7.70 Hz), 6,30 (1H, d, J=2,39 Hz), 6,23 (1H, d, d, J=2,43, at 8.36 Hz), 6,12 (1H, d, J=2,41 Hz), between 6.08 (1H, s), of 5.26 (1H, d, J=13,95 Hz), to 5.03 (1H, d, d, J=1,62, to 13.95 Hz), of 2.86 (6H, s).

EXAMPLE 51

5-Phenyl-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 6

Specified in the header of the product is obtained according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine 2.8-bis(tert-butyldimethylsilyloxy)-5-phenyl-5,11-dihydrobromide[4,3-c]chromen obtained as in example 41.

MS(Cl) m/z 345 (M+H)⁺; scan negative ions 343 (M-H)

¹H-NMR (500 MHz, acetone-d6):8,49 (1H, Sirs), of 8.47 (1H, s), 7,46 (2H, d, d, J=1,76, 8,10 Hz), 7,31-7,26 (3H, m),? 7.04 baby mortality (1H, d, J=scored 8.38 Hz), 6.87 in (1H, d, J=scored 8.38 Hz), 6,47 (1H, d, d, J=2,43, scored 8.38 Hz), 6,38 (1H, d, d, J=2,43, scored 8.38 Hz), 6,33 (1H, Sirs), of 6.29 (1H, d, J=2,43), 5,38 (1H, d, J=14,08), is 5.06 (1H, d, d, J=1,67, 14,08 Hz).

EXAMPLE 52

8-Fluoro-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-ol, compound No. 46

Specified in the header connection receive according to the method described in example 44, replacing -(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-8-fluoro-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine, obtained as in example 42.

MS(Cl) m/z 474 (M+H)⁺; scan negative ions 472 (M-H)

¹H-NMR (300 MHz, CDCl₃):from 7.24 (2H, d, J=at 8.36 Hz), 7,19 (1H, W), make 6.90 (1H, Awkw., J=to 8.45 Hz), to 6.67 (2H, d, J=8,66 Hz), 6,62 (2H, d, 8,43), to 6.57 (1H, d, d, J=2,53, 8,49 Hz), of 6.49 (1H, d, d, J=2,47, 9,79 Hz), 6,33 (1H, d, J=2,24 Hz), 6,14 (1H, s), of 5.24 (1H, d, J =13,86 Hz), to 5.03 (1H, d, 13,19 Hz), of 4.00 (2H, t, J=5,69 Hz), 2,70 (2H, m), of 2.54 (4H, Sirs), to 1.60 (4H, SIRM), USD 1.43 (2H, SIRM).

EXAMPLE 53

8-Fluoro-11-isopropyl-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-ol, compound No. 47

During the cleaning compound obtained in example 52, column chromatography specified in the title compound is isolated in a small amount as a companion smaller component formed from similarvideo predecessor [MS (CI) m/z 630]present as a smaller side product in the main component, obtained as in example 52, which, in turn, is formed from the precursor formed as a smaller side-product in the process of obtaining specified in the header of the compound of example 34 through side reactions with isopropylacrylamide.

MS(Cl) m/z 516 (M+H)⁺; scan negative ions 514 (M-H)

¹H-NMR (300 MHz, CDCl₃):7,34 (2H, d, J=8.34 per Hz), 7,03 (1H, Awkw., J=853 Hz), to 6.75 (2H, d, J=8,79 Hz), is 6.61 (2H, d, J=8.34 per Hz), to 6.57 (1H, d, 2,40 Hz), 6,50 (1H, d, d, J=2,61, 6,12 Hz)6,429 (1H, d, J=2,40 Hz), 6,24 (1H, d, d, J=2,42, to 8.34 Hz), 6,04 (1H, s)to 4.92 (1H, d, 7,30 Hz), 4,08 (2H, t, J=5,79 Hz), and 2.83 (2H, m), 2,59 (4H, Sirs), 2,28 (1H, m)of 1.64 (4H, SIRM), of 1.46 (2H, SIRM), 1,25 (1H, s)of 1.07 (3H, d, J=6,90 Hz)of 1.03 (3H, d, J=6,54 Hz)

EXAMPLE 54

8-(2,2-Dimethylpropionic-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 22

To a cooled with ice and stirred suspension of 5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol (0,200 g, 0,424 mmol), obtained as in example 44, in dichloromethane (10 ml) in an atmosphere of nitrogen was added triethylamine (0.2 ml, was 1.43 mmol, 3.5 EQ.). After approximately 10 minutes to see what the reaction mixture becomes transparent. To the reaction mixture is then added slowly (over about 5 minutes) 2,2-dimethylpropionic (i.e. pualeilani, of) 0.157 mmol, 1.3 mmol, 3.18 EQ.). The cooling bath is then removed and the reaction mixture was allow to warm to room temperature over night. To the reaction mixture and then add saturated solution of NaHCO₃(20 ml) and the resulting solution was stirred at room temperature for 1 hour. The organic layer is separated and the aqueous layer was again extracted with dichloromethane (2 x 20 ml). Together the major organic extracts washed with saturated salt solution, dried (anhydrous sodium sulfate), filtered and evaporated in vacuum. The residue is purified by chromatography on silica gel using 2% solution of methanol/dichloromethane as the eluent, thus obtaining specified in the header of the product in the form of a crystalline solid ivory.

MS (Cl) m/z 640 (M+H)⁺

¹H-NMR (300 MHz, CDCl₃):7,30 (2H, d, J=8.7 Hz), 7,01 (1H, d, J=8,4 Hz), 6,83-of 6.78 (3H, m), only 6.64 (1H, d,d, J=2,3, 8.5 Hz), 6,63 (1H, d, J=2.3 Hz), 6,54-of 6.49 (2H, m), 6,21 (1H, s), lower than the 5.37 (1H, d, J=14 Hz), 5,16 (1H, d, J=14 Hz), of 4.05 (2H, t, J=6.0 Hz), is 2.74 (1H, t, J=6.0 Hz), 2.49 USD (4H, Sirs), to 1.59 (4H, m)to 1.37 (2H, m)of 1.32 (9H, s)of 1.30 (9H, s)

IR(KBr): 2972, 2934, 2872, 1754, 1611, 1585, 1510, 1498, 1220, 1175, 1157, 1127, 1109, 1026 cm^-1

Anal. Calc. for C₃₉H₄₅NO₇/0.6 N₂ABOUT: WITH, 73,22; N, TO 7.09, N, 2,19. Found: C, 72,25; N, 7,06, N, 2,08.

EXAMPLE 55

8-(2,2-Dimethylpropionic)-5-methyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 30

STAGE A: 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(2-pyrrolidin-1 ylethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol

To a solution of 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (331 mg, 1,22 mmol) in THF (7.5 ml) at -78°add n-utility (2.5m in hexane, 478 μl, 1,19 mmol). The mixture was stirred at -78°C for 0.5 hour. It is the mixture then add 2,8-bis-(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he (153 mg, 0.30 mmol) in THF (3 ml), obtained as in example 22. The reaction mixture was then stirred at -78°C for 1.5 hours. To this mixture add methylanisole (3M in diethyl ether, 1 ml, 2,99 mmol) at -78°and the reaction mixture was stirred at room temperature over night. The reaction mixture was quenched with aqueous NH₄Cl and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO₄. The solvent is evaporated, thus obtaining the crude product as a yellow oil. The crude product is transferred to the next stage without additional purification.

MS m/z (M⁺)=719.

STAGE b: 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)pyrrolidin

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(2-pyrrolidin-1 ylethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol obtained as in the above stage And dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of 1:2, vol/about., concentrated HCl:H₂About). The reaction mixture was vigorously stirred at room temperature for 1.5 hours. The mixture is then diluted with water and ethyl acetate. The layers are separated and the organic layer washed successively with saturated NaHCO₃saturated salt solution and dried over MgSO₄. The desiccant AHP crystal growth is litrovuyu and the filtrate concentrated. Flash chromatography using a mixture of 49:49:2 ethyl acetate: hexane:CH₃HE (containing 1% NH₄OH as eluent gives specified in the title compound in the form of light oil.

¹H-NMR (300 MHz; CDCl₃):0,80 (s, 30H), 1,72 to 1.76 (m, 4H), of 1.97 (s, 3 H), 2,59-2,61 (m, 4H), 2,84 (t, 2H, J=5,9), a 4.03 (t, 2H, J=5,9), 5,04 (Avcv., 2H, Δν_AB=13,8; Δν_AB=22 Hz), of 6.29 (DD, 1 H, J=2,4, 8.6 Hz), 6,41 (d, 1 H, J=2.2 Hz), 6,52-to 6.57 (m, 3H), 6,78 (d, 2 H, J=8,8 Hz), 6.89 in (d, 1H,J= 8,4 Hz), 7,38 (d, 2H, J=8,8 Hz)

MS m/z (M⁺)=700

STAGE C: 5-methyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol

To a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)pyrrolidine (84,5 mg, 0.12 mmol) in THF (7 ml) is added tetrabutylammonium fluoride (1M in THF, 241.4 M. μl, 0.24 mmol). The mixture is stirred at room temperature for 40 minutes Then add saturated NH₄Cl followed by the addition of ethyl acetate. The resulting layers separated, the organic layer was washed with saturated salt solution and dried over MgSO₄. The solvent is evaporated and the residue is dried in vacuum for 2 hours at room temperature, while receiving specified in the title compound, which is transferred to the next stage without additional purification.

MS m/z (M⁺)=472, (M^-)=470.

Stage D: 8-(2,2-dimethylpropionic and-5-methyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid

To a suspension of 5-methyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained as in the above stage, in dichloromethane (5 ml) (DCM) at 5°With add triethylamine (Et₃N) (67 mg, 0.66 mmol) and stirred for 5 minutes To the reaction mixture and then add trimethylacetylchloride (75,7 mg, 0,63 mmol) and the mixture is stirred at room temperature over night. To the reaction mixture and then add saturated NaHCO₃(10 ml) and the mixture is stirred for 1 hour. The reaction mixture was then extracted with DCM, washed with saturated salt solution and dried over MgSO₄. After removal of the drying agent, the solution is concentrated and the resulting residue elute through a short column with silica using 2% methanol in DCM. The solvent is evaporated, thus obtaining specified in the title compound as a thick yellow oil.

¹H-NMR (300 MHz; CDCl₃):of 1.23 (s, 18H), 1,52-to 1.59 (m, 8H), of 1.97 (s, 3H), 2,72 is 2.75 (m, 4H), 2,90 (t, 2H, J=6.0 Hz), 3,99 (t, 2 H, J=6.0 Hz), 5,04 (Avcv., 2H, Δν_AB=13,8; Δν_AB=22 Hz), of 6.29 (DD, 1 H, J=2,4, 8.6 Hz), 6,41 (d, 1H, J=2.2 Hz), 6,51-6,56 (m, 3H), 6,77 (d, 2H, J=8,8 Hz), to 6.88 (d, 1H, J=8,4 Hz), 7,38 (d, 2H, J=8,8 Hz).

MS m/z (M⁺)=640, 662.

EXAMPLE 56

11-[4-(2-Azepin-1 ylethoxy)phenyl]-8-(2,2-dimethylpropionic)-11-methyl-5,11-dihydrobromide[4,3-c]chromen-2-silt ether, compound No. 33

STAGE A: 2-[4-{1-[4-(2-azepin-1 ylethoxy)phenyl]-1-hydroxyethyl}-7-(tert-butyldimethylsilyloxy)-2H-chromen-3-yl]-5-(tert-butyldimethylsilyloxy)phenol

To a solution of 1-[2-(4-bromophenoxy)ethyl]azepane (356 mg, 1,19 mmol) in THF (7.5 ml) at -78°add n-utility (2.5m in hexane, 466 μl, of 1.17 mmol). The reaction mixture was stirred at -78°C for 0.5 hour. To the mixture were then added 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-Oh, obtained as in example 22 (149 mg, 0.29 mmol)in THF (3 ml) and the reaction mixture stirred at -78°C for 1.5 hours. To the mixture then add methylanisole (3M in diethyl ether, 1 ml, 3 mmol) at -78°and the mixture is then stirred at room temperature over night. The reaction is quenched with aqueous NH₄Cl and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO₄. The remaining solvent is evaporated, thus obtaining the crude specified in the title product as a yellow oil, which is used in the next stage without additional purification.

MS m/z (M⁺)=746.

STAGE b: 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)ASEAN

2-[4-{1-[4-(2-Azepin-1 ylethoxy)phenyl]-1-hydroxyethyl}-7-(tert-butyldimethylsilyloxy)-2H-chromen-3-yl]-5-(tert-butyltin is telelinks)phenol, obtained, as indicated in stage a above, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of 1:2, vol/about., concentrated HCl:H₂About). The reaction mixture was vigorously stirred at room temperature for 1.5 hours, then diluted with water and ethyl acetate. The resulting layers are separated and the organic layer washed successively with saturated NaHCO₃saturated salt solution and dried over MgSO₄. The drying agent is filtered off and the filtrate concentrated. Flash chromatography using a mixture of 49:49:2 ethyl acetate:hexane:CH₃HE (containing 1% NH₄OH as eluent gives specified in the title compound as a pale yellow oil.

¹H-NMR (300 MHz; CDCl₃):of 0.77 (s, 30H), 1,52-to 1.59 (m, 8H), of 1.97 (s, 3H), 2.71 to a 2.75 (m, 4H), 2,90 (t, 2H, J=6.0 Hz), 3,99 (t, 2H, J=6.0 Hz), 5,04 (Avcv., 2H, ΔνAB=13,8; Δν_AB=22 Hz), of 6.29 (DD, 1H, J=2,4, 8.6 Hz), 6,41 (d, 1 H, J=2.2 Hz), 6,53 (m, 3H), 6,77 (d, 2 H, J=8,8 Hz), to 6.88 (d, 1 H, J=8,4 Hz, 7,38 (d, 2H, J=8,8 Hz)

MS m/z (M⁺)=728.

STAGE C: 5-[4-(2-azepin-1 ylethoxy)phenyl]-5-methyl-5,11-dihydrobromide[4,3-c]chromen-2,8-diol

To a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)azepane (77,5 mg, 0.11 mmol) in THF (7 ml) is added tetrabutylammonium fluoride (1M in THF, 213 μl, 0.21 mmol). The mixture is stirred at room temperature for 40 minutes the ATEM add saturated NH ₄Cl followed by the addition of ethyl acetate. The resulting layers separated, the organic layer was washed with saturated salt solution and dried over MgSO₄. The remaining solvent is evaporated and the residue is dried in vacuum for 2 hours at room temperature, while receiving specified in the title compound, which is transferred to the next stage without additional purification.

MS m/z (M⁺)=472, (M^-)=470.

STAGE D: 11-[4-(2-Azepin-1 ylethoxy)phenyl]-8-(2,2-dimethylpropionic)-11-methyl-5,11-dihydrobromide[4,3-c]chromen-2-silt ether

To a suspension of 5-[4-(2-azepin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained as in the above stage, in dichloromethane (5 ml) (DCM) at 5°With add triethylamine (tea) (59 mg, 0.59 mmol) and stirred for 5 minutes To the reaction mixture and then add trimethylacetylchloride (66,7 mg, 0.55 mmol) and the mixture is then stirred at room temperature over night. To the reaction mixture and then add saturated NaHCO₃(10 ml) and the mixture is stirred for 1 hour. The reaction mixture was then extracted with DCM, washed with saturated salt solution and dried over MgSO₄. After removal of the desiccant organic solution is concentrated and the residue purified by chromatography on silica gel using 2% methanol in DCM as eluent, thus obtaining specified in sagola the ke compound as a thick yellow oil.

¹H-NMR (300 MHz; CDCl₃):of 1.23 (s, 18H), 1,52-to 1.59 (m, 8H), of 1.97 (s, 3H), 2,72 is 2.75 (m, 4H), 2,90 (t, 2H, J=6.0 Hz), 3,99 (t, 2 H, J=6.0 Hz), 5,04 (Avcv., 2H, Δν_AB=13,8; Δν_AB=22 Hz), of 6.29 (DD, 1 H, J=2,4, 8.6 Hz), 6,41 (d, 1H, J=2.2 Hz), 6,51-6,56 (m, 3H), 6,77 (d, 2H, J=8,8 Hz), to 6.88 (d, 1H, J=8,4 Hz), 7,38 (d, 2H, J=8,8 Hz).

EXAMPLE 57

8-(2,2-Dimethylpropionic)-11-methyl-11-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 41

STAGE A: 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(2-piperidine-1-yl)ethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol

To a solution of 1-[2-(4-bromophenoxy)ethyl]piperidine (360 mg, of 1.27 mmol) in THF (7.5 ml) at -78°add n-utility (1.6 m in hexane, 773 μl, of 1.24 mmol). The reaction mixture was stirred at -78°C for 0.5 hour. To the reaction mixture were then added 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-Oh, obtained as in example 22 (158 mg, 0.31 mmol)in THF (3 ml) and the reaction mixture stirred at -78°C for 1.5 hours. Then to the reaction mixture add methylanisole (3M in diethyl ether, 1 ml, 3 mmol) at -78°and the reaction mixture was stirred at room temperature over night. The reaction is quenched with aqueous NH₄Cl and the reaction mixture is extracted with ethyl is the Etat. The organic layer was washed with saturated salt solution and dried over MgSO₄. The organic layer is concentrated, thus obtaining the crude specified in the title product as a yellow oil, which is transferred to the next stage without additional purification.

MS m/z (M⁺)=732.

STAGE b: 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(2-piperidine-1-yl)ethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol (obtained as described in stage a above, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of 1:2, vol/about., concentrated HCl:H₂O). The reaction mixture was vigorously stirred at room temperature for 1.5 hours, then diluted with water and ethyl acetate. The layers are separated and the organic layer washed successively with saturated NaHCO₃saturated salt solution and then dried over MgSO₄. The drying agent is filtered off and the filtrate concentrated. Flash chromatography using a mixture of 49:49:2 ethyl acetate:hexane:CH₃HE (containing 1% NH₄OH as eluent gives specified in the title compound as a pale yellow oil.

¹H-NMR (300 MHz; CDCl₃):0,78 (s, 30H), of 1.33 and 1.35 (m, 2H), 1,57-to 1.63 (m, 4H), of 2.05 (s, 3H), 2.49 USD is 2.51 (m, 4H), was 2.76 (who, 2H, J=6.0 Hz), 4,08 (t, 2H, J=6.0 Hz), 5,11 (Avcv., 2 H, ΔνAB=13,8; Δν_AB=31 Hz), 6,37 (DD, 1H, J=2,4, 8.6 Hz), 6.48 in (d, 1 H, J=2.2 Hz), 6,60-only 6.64 (m, 3H), at 6.84 (d, 2H, J=8,8 Hz), of 6.96 (d, 1H, J=8,4 Hz), 7,44 (d, 2H, J=8,8 Hz)

MS m/z(M⁺)=716, 739.

STAGE C: 5-methyl-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol

To a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (54 mg, 0,076 mmol) in THF (7 ml) is added tetrabutylammonium fluoride (1M in THF, 151 μl, 0.15 mmol). The mixture is stirred at room temperature for 40 minutes Then add saturated NH₄Cl followed by the addition of ethyl acetate. The resulting layers separated, the organic layer was washed with saturated salt solution and dried over MgSO₄. After concentration of the organic layer, the residue is dried in vacuum for 2 hours at room temperature, while receiving specified in the title compound, which is used in the next stage without additional purification.

MS m/z (M⁺)=486, (M^-)=484.

STAGE D: 8-(2,2-dimethylpropionic)-11-methyl-11-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid

To a suspension of 5-methyl-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained as in the above stage, in dichloromethane (5 ml) (DCM) p is 5° With added tea (42 mg, 0.42 mmol) and the reaction mixture is stirred for 5 minutes To the reaction mixture and then add trimethylacetylchloride (47 mg, 0,39 mmol) and the mixture is stirred at room temperature over night. To the reaction mixture and then add saturated NaHCO₃(10 ml) and the mixture is stirred for 1 hour. The reaction mixture is extracted with DCM, washed with saturated salt solution and dried over MgSO₄. The organic layer is concentrated and the residue purified on silica gel using 2% methanol in DCM as eluent, thus obtaining specified in the title compound as a thick yellow oil.

¹H-NMR (300 MHz; CDCl₃):of 1.31 (s, 18H), of 1.33 and 1.35 (m, 2H), 1,57-to 1.63 (m, 4H), of 2.05 (s, 3H), 2.49 USD is 2.51 (m, 4H), was 2.76 (t, 2H, J=6.0 Hz), 4,08 (t, 2H, J=6.0 Hz), 5,11 (Avcv., 2H, Δν_AB=13,8 Hz; Δν_AB=31 Hz), 6,37 (DD, 1H, J=2,4, 8.6 Hz), 6.48 in (d, 1H, J=2.2 Hz), of 6.26 (m, 3H), at 6.84 (d, 2H, J=8,8 Hz), of 6.96 (d, 1H, J=8,4 Hz), 7,44 (d, 2H, J=8,8 Hz)

MS m/z (M⁺)=654, 667.

EXAMPLE 58

8-(2,2-dimethylpropionic)-11-methyl-11-[4-(3-piperidine-1-ylpropionic)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, connection # 43

STAGE A: 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(3-piperidine-1-ylpropionic)phenyl]ethyl}-2H-chromen-3-yl)phenol

To a solution of 1-[3(4-bromophenoxy)propyl]piperidine (393 mg, of 1.32 mmol) in THF (7.5 ml) at -78°add n-utility (1.6 m in hexane, 804 μl, 1,29 mmol). The reaction mixture was then stirred at -78°C for 0.5 hour. To the mixture were then added 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-Oh, obtained as in example 22 (164 mg, 0.32 mmol)in THF (3 ml) and the reaction mixture stirred at -78°C for 1.5 hours. Then to the reaction mixture add methylanisole (3M in diethyl ether, 1 ml, 3 mmol) at -78°and the reaction mixture is then pereshivayut at room temperature over night. The reaction is quenched with aqueous NH₄Cl and the mixture is then extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO₄. After removal of the drying agent, the remainder of the concentrate, while receiving untreated specified in the title product as a yellow oil, which was used in the next stage without additional purification.

MS m/z (M⁺)=746.

STAGE b: 1-(3-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}propyl)piperidine

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(3-piperidine-1-yl)propoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol (obtained as described in stage a above, dissolved in toluene (8 ml) and then treated with diluted HCl (0.4 ml mixture of 1:2, vol/about., koncentrira the fair HCl:H ₂O). The reaction mixture was vigorously stirred at room temperature for 1.5 hours. The mixture is then diluted with water and ethyl acetate. The resulting layers are separated and the organic layer washed successively with saturated NaHCO₃saturated salt solution and then dried over MgSO₄. The drying agent is filtered off and the filtrate concentrated. Flash chromatography using a mixture of 49:49:2 ethyl acetate:hexane:CH₃HE (containing 1% NH₄OH as eluent gives specified in the title compound as a pale yellow oil.

¹H-NMR (300 MHz; CDCl₃):0,78 (s, 30H), 1,51-of 1.53 (m, 2H), 1,78-to 1.82 (m, 4H), of 2.05 (s, 3H), 2,14-2,19 (m, 2H), 2,74-and 2.79 (m, 4H), 2,86 of 2.92 (m, 2H), 4.00 points (t, 2H, J=5,9 Hz), 5,14 (Avcv., 2H, Δν_AB=13,8 Hz; Δν_AB=21 Hz), 6,37 (DD, 1H, J=2,4, 8.6 Hz), 6.48 in (d, 1H, J=2.2 Hz), 6,59-only 6.64 (m, 3H), PC 6.82 (d, 2H, J=8,8 Hz), 6,97 (d, 1H, J=8,4 Hz), 7,46 (d, 2H, J=8,8 Hz)

STAGE C: 5-methyl-5-[4-(3-piperidine-1-ylpropionic)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol

To a solution of 1-(3-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}propyl)piperidine (97,5 mg, 0,134 mmol) in THF (7 ml) is added tetrabutylammonium fluoride (1M in THF, 268 μl, 0.27 mmol). The reaction mixture was stirred at room temperature for 40 minutes Then the reaction mixture is added saturated NH₄Cl followed by the addition of ethyl acetate. Arr is zovastina layers separated, the organic layer was washed with saturated salt solution and dried over MgSO₄. After concentration of the organic layer, the residue is dried in vacuum for 2 hours at room temperature, while receiving specified in the title compound, which is transferred to the next stage without additional purification.

MS m/z (M⁺)=500, (M^-)=498.

STAGE D: 8-(2,2-dimethylpropionic)-11-methyl-11-[4-(3-piperidine-1-ylpropionic)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid

To a suspension of 5-methyl-5-[4-(2-piperidine-1-ylpropionic)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained as in the above stage, in dichloromethane (5 ml) (DHM) at 5°add Et₃N (74,5 mg of 0.74 mmol) and the reaction mixture is stirred for 5 minutes To the reaction mixture and then add trimethylacetylchloride (84 mg, 0.70 mmol) and the reaction mixture was stirred at room temperature over night. To the reaction mixture and then add saturated NaHCO₃(10 ml) and the mixture is then stirred for 1 hour. The reaction mixture was then extracted with DHM, washed with saturated salt solution and dried over MgSO₄. After removal of the desiccant organic layer is concentrated and the resulting residue purified by chromatography on silica gel using 2% methanol in DHM as the eluent, thus obtaining at asanee the title compound as a thick yellow oil.

MS m/z (M+H) 668

¹H-NMR (300 MHz; CDCl₃):of 1.30 (s, 18H), 1,51-of 1.53 (m, 2H), 1,78-to 1.82 (m, 4H), of 2.05 (s, 3H), 2,14-2,19 (m, 2H), 2,74-and 2.79 (m, 4H), 2,86 of 2.92 (m, 2H), 4.00 points (t, 2H, J=5,9 Hz), 5,14 (Avcv., 2H, Δν_AB=13,8 Hz; Δν_AB=21 Hz), 6,37 (DD, 1H, J=2,4, 8.6 Hz), 6.48 in (d, 1H, J=2.2 Hz), 6,59-only 6.64 (m, 3H), PC 6.82 (d, 2H, J=8,8 Hz), 6,97 (d, 1H, J=8,4 Hz), 7,46 (d, 2H, J=8,8 Hz)

EXAMPLE 59

8-(2,2-dimethylpropionic)-11-methyl-11-[3-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 38

STAGE A: 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[3-(2-piperidine-1-yl)ethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol

To a solution of 1-[3-(4-bromophenoxy)ethyl]piperidine (343 mg, to 1.21 mmol) in THF (7.5 ml) at -78°add n-utility (2.5m in hexane, 471 μl, 1.18 mmol) and the reaction mixture stirred at -78°C for 0.5 hour. To the reaction mixture and then add a solution of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-it is obtained as in example 22 (150 mg, 0.29 mmol)in THF (3 ml). The reaction mixture was stirred at -78°C for 1.5 hours. Then to the reaction mixture add methylanisole (3M in diethyl ether, 1 ml, 3 mmol) at -78°and then the reaction mixture was stirred at room temperature over night. The reaction is quenched with aq is m NH ₄Cl and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO₄. After removal of the desiccant organic layer is concentrated, thus obtaining the crude specified in the title compound as a yellow oil, which was used in the next stage without additional purification.

MS m/z (M⁺)=732.

STAGE b: 1-(2-{3-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine

5-(tert-Butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[3-(2-piperidine-1-yl)ethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol (obtained as described in stage a above, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of 1:2, vol/about., concentrated HCl:H₂O) and the reaction mixture is vigorously stirred at room temperature for 1.5 hours. The reaction mixture is then diluted with water and ethyl acetate. The resulting layers are separated and the organic layer washed successively with saturated NaHCO₃saturated salt solution and dried over MgSO₄. The drying agent is filtered off and the filtrate concentrated. Flash chromatography using a mixture of 49:49:2 ethyl acetate:hexane:CH₃HE (containing 1% NH₄OH as eluent gives specified in the title compound as a pale yellow oil.

MS m/z (M ⁺) 715, 736.

STAGE C: 5-methyl-5-[3-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol

To a solution of 1-(2-{3-[2,8-bis(tert-butyldimethylsilyloxy)-5-methyl-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (34 mg, 0,048 mmol) in THF (7 ml) is added tetrabutylammonium fluoride (1M in THF, 95 μl, 0,095 mmol). The mixture is stirred at room temperature for 40 minutes To the reaction mixture and then add saturated NH₄Cl followed by the addition of ethyl acetate. The resulting layers separated, the organic layer was washed with saturated salt solution and dried over MgSO₄. The drying agent is filtered off, the organic layer is concentrated and the resulting residue is dried in vacuum for 2 hours at room temperature, while receiving specified in the title compound, which is used in the next stage without additional purification.

MS m/z (M⁺)=486, (M^-)=484.

STAGE D: 8-(2,2-dimethylpropionic)-11-methyl-11-[3-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid

To a suspension of 5-methyl-5-[3-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained as in the above stage, in dichloromethane (5 ml) (DHM) at 5°add Et₃N (27 mg, 0.26 mmol) and the reaction mixture is stirred for 5 minutes Then add trimethyl shall Cotillard (30 mg, 0.25 mmol) and the reaction mixture was stirred at room temperature over night. To the reaction mixture and then add saturated NaHCO₃(10 ml) and the mixture is stirred for 1 hour. The reaction mixture was then extracted with DHM, washed with saturated salt solution and dried over MgSO₄. Dessicant removed and the organic layer concentrated. The resulting residue is purified by means of chromatography on silica gel using 2% methanol in DHM as the eluent, thus obtaining specified in the title compound as a thick yellow oil.

MS m/z (M⁺) 654.

EXAMPLE 60

4-methyl bromide-3-(2,4-dibenzyline)-7-benzoylamino-2-he

LiHMDS (1.0m, 378 μl, 2.5 EQ., 0,378 mmol) in THF is added dropwise via syringe to a solution of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-she (90 mg, 1.0 EQ., 0,151 mmol) in THF (1 ml) at -78°C in an atmosphere of N₂. Note that the reaction mixture acquires a reddish color. After the addition, the reaction mixture is stirred for an additional 0.5 hour at -78°C. To the reaction mixture were then added at 78°With bromine (12 μl, 1.5 EQ., 0,227 mmol). Note that the color of the mixture turns from red to light yellow. The reaction mixture was then stirred for an additional 0.5 hour at -78°C. the Reaction is quenched with saturated of rest the rum NaHCO ₃the reaction mixture is heated to room temperature and vigorously stirred at room temperature for 15 min THF is removed on a rotary evaporator under vacuum. The remainder of the reaction mass added ethyl acetate (20 ml) and water (5 ml), while receiving two phases. The aqueous phase is extracted twice with ethyl acetate. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na₂SO₄, filtered and concentrated, thus obtaining the crude specified in the title compound as a yellow solid. The crude substance is purified column flash chromatography using a mixture of 3:1 hexanol and ethyl acetate as the eluent, thus obtaining specified in the title compound as a pale yellow solid.

Determine that the product contains a compound 3-benzoyloxy-4-(7-benzoyloxy-4-methyl bromide-2-oxo-2H-chromen-3-yl)phenyl ester of benzoic acid and 3-benzoyloxy-4-(7-benzoyloxy-4-dibromomethyl)-2-oxo-2H-chromen-3-yl)phenyl ester of benzoic acid.

R_f=0,60 mixture in 3:1 hexane:ethyl acetate (UV).

¹H-NMR (CDCl₃, TMS standard), by 8.22 (m, J=14,4 Hz, 5H), of 8.04 (d, J=6,9 Hz, 1H), a 7.85 (d, J=9.6 Hz, 1H), 7,69 (m, 4H), 7,42 (m, 5H), 7,30 (m, 5H), 4,48 (Avcv., J=10,8 Hz, 2H)

MS (M+1), 699, 697.

EXAMPLE 61

2,8-Dihydroxy-11N-chromeno[4,3-c]chromen-5-he, connection # 1

The method:

4-methyl bromide-3-(2,4-dibenzyline)-7-benzoylamino-2-he (67 mg, 1.0 EQ., 0,099 mmol) dissolved in acetone (1 ml) and methanol (0.5 ml) in an atmosphere of N₂. Then in one portion to the solution add the powder To₂FROM (41 mg, 3.0 EQ., 0,298 mmol). The reaction mixture was stirred at room temperature over night. Note that the color of the reaction mixture turns from light yellow to orange. The solvent is removed, the residue is dissolved in water and the resulting mixture is acidified to approximately pH 1 by adding dropwise 6 N. HCl. The reaction mixture was added CH₂Cl₂and the aqueous phase is extracted twice CH₂Cl₂. The combined organic layer was washed with water and saturated salt solution, dried over anhydrous Na₂SO₄, filtered and concentrated, thus obtaining specified in the title compound as a brown solid. To the crude product add a mixture of 5:1 hexane:ethyl acetate. The supernatant is removed with a pipette and the remaining insoluble solid is dried under vacuum, thus obtaining specified in the title compound in the form of solids.

R_f=0,2, hexane:ethyl acetate=3:1, UV.

EXAMPLE 62

3-[2,4-Bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-he

A mixture of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-she (4.7 g, 16.5 mmol), SEMCl (14.6 ml of 82.9 mmol) and K₂CO₃(18.6 g, 367,1 mmol) in acetone (600 ml) is heated to 50°C in nitrogen atmosphere for 1 hour. The resulting mixture is cooled, filtered and evaporated to a thick oil. Oil cleanse SiO₂using a mixture of 5-10% ethyl acetate/hexane as the gradient of the solvent, thus obtaining specified in the title compound in the form of oil.

MS(Cl) m/z 675 (M+H)⁺, 697 (M+Na)⁺

¹H-NMR (CDCl₃, 300 MHz)(h/m) and 7.6 (d, J=6 Hz, 1H), 7,2-to 6.8 (m, 5H), of 5.1 and 5.4 (m, 6H), 3,6-3,9(m, 6H), of 2.25(s, 3H), 0,2-0,1 (m, 27H).

EXAMPLE 63

3-[2,4-Bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl bromide-7-(2-trimethylsilylamodimethicone)chromen-2-he

3-Necked round bottom flask 250 ml provide a magnetic stir bar, a rubber stopper and an adapter for the intake/release of argon. This flask is charged with THF (20 ml) with a syringe, iPr₂NH (1.8 ml, 14.0 mmol) with a syringe and cooled to -10°in a bath of ice/methanol. With a syringe added dropwise n-utility (1,85M (m), 6.3 ml, 11.7 mmol) in hexane at -10°and the mixture is stirred for 15 min at -10°C. To the solution is added dropwise with a syringe 3-[2,4-bis-(2-trimethylsilylamodimethicone)phenyl]-4-IU the Il-7-(2-trimethylsilylamodimethicone)chromen-2-he (5,1 g, 7.8 mol) in THF (20 ml). The mixture was stirred at -10°C for 2.5 hours. This mixture is added dropwise via syringe to a solution of Br₂(0,76 ml, 2 EQ.) in THF (100 ml), cooled at -78°and 3-necked round bottom flask of 1 l, equipped with a mechanical stirrer and a membrane for carrying out the reaction in an atmosphere of N₂. After complete addition, the mixture is stirred for 5 min at -78°and then diluted with EtOAc (0.5 l), fed with a syringe, NaHCO₃(50 ml), fed with a syringe, and saturated Na₂SO₃(100 ml), fed with a syringe. Bath of dry ice/acetone is removed and the mixture allow to warm to room temperature with stirring. The organic phase is separated and the aqueous phase back extracted with EtOAc (2x0,2 l). The combined organic phase was washed with a saturated solution of salt (2x0,5 l) and concentrated in vacuo, while receiving specified in the title compound in the form of the crude semi-solid substance.

MS m/z M+H=770; M+Na=793

¹H-NMR (CDCl₃, 300 MHz)(h/m): 7,8-to 6.8 (m, 6H), 5,6-5,1 (m, 6H), 4,4-4,2 (Ab., J=16 Hz, 2H), 3,8-3,6 (m, 6H), 0.8 to 0,11 (m, 6H)

EXAMPLE 64

3-[2,4-Bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-he

1 N. HCl (10 ml) (1 HCl solution are obtained from the COI is whether the concentrated HCl in a mixture of 1:1 THF:IPA) dissolve 3-[2,4-bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl bromide-7-(2-trimethylsilylamodimethicone)chromen-2-he (200 mg, 0,544 mmol) and the resulting mixture is stirred for 24 hours at room temperature. The reaction mixture was then diluted with EtOAc (100 ml) and the organic layer washed with water (2 x 20 ml) and saturated salt solution (30 ml). The organic layer is dried over Na₂SO₄, filtered and the organic solvent is evaporated, thus obtaining specified in the title compound, 3-[2,4-bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-it is in the form of a crude solid.

MS(Cl) m/z 362 (M+H⁺); 384 (M+Na⁺)

¹H-NMR (CDCl₃, 300 MHz)(h/m): 7,8-to 6.8 (m, 6H), 4,8-4,6 (Ab., J=14.6 Hz, 2H).

EXAMPLE 65

2,8-Dihydroxy-11N-chromeno[4,3-c]chromen-5-he, connection # 1

The way D:

2,8-Dihydroxy-11N-chromeno[4,3-c]chromen-5-he (90 mg, 0.25 mmol) dissolved in Meon (2.5 ml). Add To₂CO₃(35 mg, 0.2 mmol) and the resulting mixture is stirred for 10 min at room temperature. The reaction mixture was diluted with EtOAc (50 ml), filtered and the organic solvent is evaporated to dryness. The obtained semi-solid substance cleanse SiO₂using 50% EtOAc in hexano, while receiving specified in the title compound in the form of solids.

MS(Cl) m/z 283 (M+N⁺), 306 (M+Na⁺).

EXAMPLE 66

1-(2-{4-(2,-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine

Method:

1-[2-(4-Iodinase)ethyl]piperidine (1,656, 5 mmol) is dissolved in THF and cooled to -78°C. To the reaction mixture and then slowly add n-utility (2M solution in pentane, 2.5 ml, 10 mmol) over 5 minutes the Resulting solution is stirred for 1 hour at -78°C. 2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol (1 g, 1,953 mmol) dissolved in THF (20 ml) and then the solution is added slowly to the reaction mixture containing 1-[2-(4-iodinase)ethylpiperidine and n-utillity for 10 minutes the Reaction mixture is stirred for an additional hour. The reaction is quenched Meon (1 ml) and then the reaction mixture was treated with a saturated solution of ammonium chloride (30 ml) and then diluted with diethyl ether (150 ml). The organic layer is separated and washed with saturated salt solution (100 ml). The organic layer is dried over anhydrous Na₂SO₄, filtered and the solvent is evaporated, thus obtaining the crude oil. The crude oil was diluted with toluene (150 ml) and HCl (37%, 6,0 ml) and stirred for 30 min at room temperature. The solution was diluted with EtOAc (300 ml), the organic layer washed twice with water (100 ml) and then with saturated solution of NaHCO₃(150 ml). The organic layer is separated and dried over anhydrous Na₂SO₄, filtered and evaporated, the of learn when it is mentioned in the title compound in the form of a foamy material.

MS(Cl) m/z 700 (M+N⁺), 723 (M+Na⁺).

¹H-NMR (300 MHz, CDCl₃): 7,30 (2H, d, J=8.7 Hz), 6.87 in (1H, d, J=8,30 Hz), 6,79 (2H, d, J=1,91, PC 6.82 Hz), 6,70 (1H, d, J=8,42 Hz), to 6.39 (2H, m), of 6.29 (2H, m), 6,14 (1H, s), and 5.30 (1H, d, J =13,90 Hz), 5,10 (1H, d, d, J=1,654, 13,90 Hz), Android 4.04 (2H, t, J=5,97 Hz), 2,48 (2H, t, J=6.0 Hz), 2,48 (4H, m), 1,58 (4H, m), USD 1.43 (2H, m)of 0.95 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s).

EXAMPLE 67

8-(2,2-Dimethylpropionic)-5S^*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid

1M TBAF (in THF, 17 ml, 17 mmol, 3 EQ.) added dropwise into a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (4.0 g, 5.7 mmol) in THF (40 ml) at -10°C. the Reaction mixture is stirred for 15 minutes. To the reaction mixture and then add the acid chloride 2,2-dimethylpropionic acid (2.5 ml, 20 mmol, 3.5 EQ.). The reaction mixture was diluted with ethyl acetate and washed with 5% sodium bicarbonate and then with saturated salt solution. The organic layer is dried over anhydrous Na₂SO₄and concentrated, thus obtaining a mixture of 1:2 manipulat:dipivalat. To the crude product dissolved in CH₂Cl₂add the acid chloride 2,2-dimethylpropionic acid (4.3 ml) and triethylamine (5 ml) and the reaction mixture is stirred for 30 minutes Reacts the mixture was diluted with ethyl acetate (300 ml) and then washed with a saturated solution of salt. Flash chromatography on a Biotage column, eluruumi 2%-5% Meon in CH₂Cl₂gives specified in the header of the product in the form of a racemic mixture of 8-(2,2-dimethylpropionic)-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid.

The racemic compound (8-(2,2-dimethylpropionic)-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid) (2.5 g) is loaded into the column chiral HPLC ChiralPak AD (5 cm (EXT. diameter) x 50 cm (length)) and elute with 20% Meon in IPA at a flow rate of 90 ml/min Two peaks are removed under vacuum, thus obtaining: (8-(2,2-dimethylpropionic)-5R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid in the form of a first peak and (8-(2,2-dimethylpropionic)-5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid in the form of the second peak.

MS m/z 640 (M+H⁺), 663 (M+Na⁺)

¹H-NMR (300 MHz, CDCl₃): 7,30 (2H, d, J=8.7 Hz), 7,01 (1H, d, J=8,4 Hz), 6,83-of 6.78 (3H, m), only 6.64 (1H, d, d, J=2,3, 8.5 Hz), 6,63 (1H, d, J=2.3 Hz), 6,54-of 6.49 (2H, m), 6,21 (1H, s), lower than the 5.37 (1H, d, J=14 Hz), 5,16 (1H, d, J=14 Hz), of 4.05 (2H, t, J=6.0 Hz), is 2.74 (1H, t, J=6.0 Hz), 2.49 USD (4H, Sirs), to 1.59 (4H, m)to 1.37 (2H, m)of 1.32 (9H, s)of 1.30 (9H, s)

EXAMPLE 68

8-((1S)-(-)-Campanil)-5S^*-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-digitar the Meno[4,3-c]chromen-2-silt ether (1S)-(-)-campanulas acid, connection # 49

1M TBAF (in THF, 8.5 ml, 8.5 mmol, 3 EQ.) added dropwise into a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (2.00 g, to 2.85 mmol) in THF (30 ml) at -10°and the reaction mixture is stirred for 15 minutes. To the reaction mixture and then add the acid chloride (1S)-(-)-campanulas acid (1,69 g, 8.6 mmol, 3 EQ.). The reaction mixture was then diluted with ethyl acetate (300 ml) and washed with 5% sodium bicarbonate and then washed with a saturated solution of salt. The organic layer is dried over anhydrous Na₂SO₄and concentrated, thus obtaining a mixture of 1:3 monocomponent derived: Giampaolo derived.

To the crude product in CH₂Cl₂(55 ml) was added the acid chloride (1S)-(-)-campanulas acid (1.5 g) and tea (2.0 ml) and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was then diluted with ethyl acetate (250 ml) and then washed with a saturated solution of salt. Flash chromatography on a column of SiO₂, eluruumi 2%-5% Meon in CH₂Cl₂gives specified in the title compound in the form of diastereomers a mixture of 8-((1S)-(-)-campanil)-5S^*-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether (1S)-(-)-campanulas acid and 8-((1S)-(-)-campanil)-5R^*-[4-(2-piperidine-1-ilato the si)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether (1S)-(-)-campanulas acid.

The mixture of diastereomers is suspended in hot ethanol (110 ml) in the presence of (R)-(-)-10-camphorsulfonic acid (0.6 EQ.) and the suspension is stirred at 70°C for 4 hours before until the solution is clear. The solution is filtered and cooled down to room temperature. The solid formed after 64 hours, the solid is filtered off and dried in vacuum, obtaining mentioned in the title compound as a solid (84% di).

MS m/z 832 (M+H⁺); 854 (M+Na⁺)

¹H-NMR (CDCl₃, 300 MHz)(h/m): 7,3 (d, J=8,3 Hz, 2H), and 7.1 (d, J= 8.7 Hz, 2H), 7,7-to 7.8 (m, 3H), 6,7-6,5 (m, 4H), 6,21 (s, 1H), 5,4-5,2 (Ab., J =14,4 Hz, 2H), 4,1 (t, J=3 Hz, 2H), 2,75 (t, J=6 Hz, 2H), 2,29-1,5 (m, 18H), 1,2-0,8 (m, 18H)

EXAMPLE 69

3-(2,4-Biotoxicity)-7-methoxyethoxy-4-methylpropan-2-he

MOMCl (6,62 ml of 82.9 mmol) is added to the mixture To₂CO₃(18.6 g, approximately 367,1 mmol) and 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-she (4.7 g, 16.5 mmol) in acetone (600 ml) at 0°C in nitrogen atmosphere for 1 hour. The reaction mixture is then stirred for 4 hours, during this time give her the opportunity to come to room temperature. The reaction mixture was then filtered and evaporated to obtain a viscous oil. Oil cleanse SiO₂using 5-10% solution of ethyl acetate:hexane is as a gradient solvent, while receiving 3-(2,4-biotoxicity)-7-methoxyethoxy-4-methylpropan-2-it is in the form of solids.

MS m/e 417 (M+N) and 439 (M+Na⁺)

¹H-NMR (CDCl₃, 300 MHz)(ppm): 7.7 (d, 6,7 Hz, 1H), 7,1-6,6 (m, 5H), 5,3-5,1 (m, 6H), 3,411 (s, 3H), 3,41 (s, 3H), and 3.3 (s, 3H), 2,2 (s, 3H)

EXAMPLE 70

[3-(2,4-Biotoxicity)-7-methoxyethoxy-2-oxo-2H-chromen-4-yl]acetaldehyde

In a clean, dry flask of 200 ml, purged with nitrogen, download Diisopropylamine (2.7 ml of 19.5 mmol, 3 equiv.) anhydrous THF (50 ml) and 3-(2,4-biotoxicity)-7-methoxyethoxy-4-methylpropan-2-he (8.1 ml, 16,25 mmol, 2.5 EQ.) at -78°C. After 30 minutes, to this solution is added dropwise a solution of 3-(2,4-biotoxicity)-7-methoxyethoxy-4-methylpropan-2-she (2.7 g, 6.5 mmol, 1 EQ.) in anhydrous THF (13 ml). The solution is heated to -10°C and stirred at this temperature for 30 minutes. In the reaction mixture is then slowly add performed (3.6 ml, 33 mmol, 5 EQ.). The reaction mixture was then stirred for 30 min, quenched with saturated aqueous NH₄Cl, extracted with ethyl acetate and then concentrated, thus obtaining specified in the header of the product in the form of a crude solid, which was purified flash chromatography with elution 30% ethyl acetate in hexane, thus obtaining specified in sagalevitch in the form of solids.

MS: 443,0, M-H;

¹H-NMR (300 MHz, CDCl₃):(h/m) a 9.7 (s, 1H), 6,8-7,4 (m, 6H), a 5.25 (s, 2H), and 5.2 (s, 2H), 5,1 (s, 2H), of 3.7-3.9 (m, 2H), 3,49 (s, 3H), 3,5 (s, 3H), 3,4 (s, 3H)

EXAMPLE 71

3-(2,4-Biotoxicity)-4-(2-hydroxyethyl)-7-methoxyethoxide-2-he

Sodium borohydride (17 mg, 0.45 mmol, 0.5 EQ.) dissolved in ethanol (5 ml), then added to a solution of [3-(2,4-biotoxicity)-7-methoxyethoxy-2-oxo-2H-chromen-4-yl]acetaldehyde (400 mg, 0.90 mmol, 1 EQ.) in ethanol (10 ml) at -10°and the reaction mixture is stirred for 30 minutes. The solvent is evaporated and the resulting residue is dissolved in ethyl acetate (100 ml) and washed twice with a saturated solution of salt. The organic layer is dried over anhydrous sodium sulfate, and then concentrated to obtain the crude product, which was purified flash chromatography with elution with 50% ethyl acetate, thus obtaining specified in the title compound, 3-(2,4-biotoxicity)-4-(2-hydroxyethyl)-7-methoxyethoxide-2-it, in the form of solids.

MS: 447,1, M+H; 469,1, M+Na; 445,1 M-H

¹H-NMR (300 MHz, CDCl₃):(h/mn) of 6.8 to 7.7 (m, 6H), to 5.3 (s, 2H, in), 5.25 (s, 2H), and 5.2 (s, 2H), and 3.8 (m, 2H), 3,51 (s, 3H), 3,50 (s, 3H), 3,4 (s, 3H), 3.0 a (m, 2H), 1,75 (t, 1H).

EXAMPLE 72

3-(2,4-Dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-he

In the flask, purged with nitrogen, download 3-(2,4-biotoxicity)-4-(2-hydroxyethyl)-7-methoxyethoxide-2-he (200 mg) and 1 N. HCl (10 ml) in a mixture of 1:1 isopropanol:THF. The reaction mixture was stirred overnight, then diluted with ethyl acetate (200 ml) and washed three times with a saturated solution of salt. The organic layer is dried over anhydrous sodium sulfate and then concentrated. The residue is purified flash chromatography with elution with 10% methanol in dichloromethane, while receiving 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it is in the form of solids.

MS: 313,0 M-H; 315,1 M+H, 337,0, mina;

¹H-NMR (300 MHz, CD₃OD):(h/m) for 6.3 to 7.8 (m, 6H), of 3.65 (m, 2H), 2,9 (m, 2H).

EXAMPLE 73

2,8-Dihydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 56

In a dry, clean flask, purged with nitrogen, download 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-he (50 mg, 0.16 mmol, 1 EQ.), triphenylphosphine (176 mg, 0.67 mmol, 4.2 equiv.) molecular sieves 4 Å (50 mg) and dry THF (10 ml) and the reaction mixture is stirred for 30 minutes. To the reaction mixture were then added DEAD (of 0.11 ml, 0.67 mmol, 4.2 EQ.) and the reaction mixture was stirred at room temperature for 1 hour. The insoluble residue is filtered off and the filtrate conc is so The residue is purified flash chromatography with elution with 2% methanol in dichloromethane, while receiving specified in the header of the product in the form of solids.

MS: 295,0 M-H; 297 M+H; 319 mina;

¹H-NMR (300 MHz, THF-d8):(h/mn) of 6.5 to 7.8 (m, 6H), 4,6 (t, 2H), 3,0 (t, 2H).

EXAMPLE 74

2,8-Dihydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he

2,8-Dihydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he (30 mg) dissolved in THF (1 ml). To the reaction mixture then add triethylamine (0.2 ml) and 1M TBSCl (0.2 ml) in dichloromethane and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 ml) and then twice washed with a saturated solution of salt. The organic layer is dried over anhydrous sodium sulfate and concentrated. The crude product is purified flash chromatography with elution with a mixture of 100:10:2 hexane/dichloromethane/ethyl acetate, thus obtaining 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-it is in the form of solids.

MS m/z 525(M+H⁺), 547(M+Na⁺)

¹H-NMR (CDCl₃, 300 MHz)(ppm): of 6.6 to 7.8 (m, 6H), 4,6 (t, 2H), 3,0 (t, 2H), 1,1 (2s, 18H), 10,2-0,1(2s, 12H)

EXAMPLE 75

2,8-Bis(tert-butyldimethylsilyloxy)-11,12-digit the-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol

2,8-Bis(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he (35 mg, of 0.066 mmol) dissolved in toluene (5 ml) and the resulting solution cooled to -78°C. To the above reaction mixture at -78°then add a solution of Dibal-H (70 μl, 1.5m solution in toluene). The reaction mixture was stirred at -78°C for 3 hours. To the reaction mixture were then added methanol (0.5 ml) and then a solution of Rochelle salt (2 ml, 1M solution). The reaction mixture was gradually warmed to room temperature. The reaction mixture was diluted with CH₂Cl₂(30 ml), the organic layer separated and dried over Na₂SO₄. The solution is filtered and evaporated, thus obtaining the crude product, which was purified on SiO₂while this is mentioned in the title compound in the form of solids.

MS m/z 527(M+H+), 550(M+Na⁺)

¹H-NMR (300 MHz, CDCl₃):to 7.15 (1H, d, J=8,4 Hz), of 6.96 (1H, J=8,4 Hz), 6,59 (1H, d, J=2,24 Hz), is 6.54 (1H, d, d, J=2,31, are 11.62 Hz), 6,46 (1H, d, d, J=2,31, 8.35 Hz), 6,41 (1H, d, J=2,31 Hz), 6,11 (1H, d, J=8.1 Hz), 4,6 (2H, m), and 3.0 (2H,, m) and 0.98 (18H, s)and 0.22 (6H, s)of 0.21 (6H, s)

EXAMPLE 76

1-(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)piperidine

1-[2-(4-Iodinase)ethyl]piperidine (150 m is, 0,453 mmol) is dissolved in THF and cooled to -78°C. To the reaction mixture and then slowly over 5 min add n-utility (2M solution in pentane, 266 μl). The reaction mixture is stirred for 1 hour at -78°C. In a separate flask 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol (28 mg, 0,053 mmol) dissolved in THF (1 ml) and the solution slowly over 5 min is added to the reaction mixture containing 1-[2-(4-iodinase)ethyl]piperidine and n-utillity. The reaction mixture was stirred for additional 1 hour. The reaction mixture was quenched Meon (0.5 ml), treated with a saturated solution of ammonium chloride (30 ml) and then diluted with diethyl ether (25 ml). The organic layer is separated and washed with saturated salt solution (15 ml). The organic layer is dried over anhydrous Na₂SO₄, filtered and the solvent is evaporated, thus obtaining the crude oil. The crude oil was diluted with toluene (30 ml) and 1 N. HCl (6.0 ml) and then stirred for 30 min at room temperature. The reaction mixture was diluted with EtOAc (20 ml) and the organic layer washed twice with water (20 ml) and a saturated solution of NaHCO₃(10 ml). The organic layer is separated, dried over anhydrous Na₂SO₄, filtered and evaporated, thus obtaining 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H6,13 dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)piperidine in the form of oil.

MS m/z 714(M+H⁺)

¹H-NMR (300 MHz, CDCl₃): 7,46 (2H, d, J=8.7 Hz), 6.87 in (1H, d, J=8,30 Hz), 6,79 (2H, d, J=1,91, PC 6.82 Hz), 6,70 (1H, d, J=8,42 Hz), to 6.39 (2H, m), of 6.29 (2H, m), 6,14 (1H, s), and 5.30 (1H, d, J =13,90 Hz), 5,10 (1H, d, d, J=b1,654, 13,90 Hz), and 4.6 (m, 2H), Android 4.04 (2H, m), 3.0 a (m, 2H), 2,48 (2H, t, J=6.0 Hz), 2,48 (4H, m), 1,58 (4H, m), USD 1.43 (2H, m)of 0.95 (9H, s)of 0.93 (9H, s)of 0.18 (6H, s), 0,16 (6H, s)

EXAMPLE 77

5-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol, compound No. 55

To a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)piperidine (1.6 mg, 0,0022 mmol), obtained as in example 76, in THF (0.1 ml) is added TBAF (10 μl, 1M solution in THF, 0,010 mmol) at -10°C. the Color of the solution changed to light yellow. The solution is stirred at -10°C for 30 minutes the solution is then added saturated aqueous NH₄Cl (0.1 ml) to extinguish the reaction. The reaction mixture was extracted with ethyl acetate (100 ml), the organic solution is dried over anhydrous Na₂SO₄organic solution is filtered and concentrated in vacuo, while receiving the oil, which is purified HPLC with reversed phase, while receiving specified in the header of the connection.

¹H-NMR (300 MHz, CD₃OD): 7,4(d, J=10 Hz, 2H), 7,15 (d, J=10 Hz, 1H), 7,0 (d, J=10 Hz, 1H), 6,85 (d, J=10 Hz, 2H), 6,5 (m, 2H), 6.35mm (DD, 1H), x 6.15 (d, J=3 is C, 1H), equal to 6.05 (s, 1H), 4,6 (m, 2H), 4,3 (t, J=5 Hz, 2H), 3,55 (d, J=12 Hz, 2H), 3.45 points (t, J=5 Hz, 2H), 3,3 (m, 2H), 3.0 a (m, 2 H), and 2.8 (m, 2H), and 1.9 (m, 2H), of 1.75 (m, 2H);

MS(Cl) m/z: 485(M+H⁺).

EXAMPLE 78

5R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol and 5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 14, No. 15

The racemic mixture of 5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol (50 mg) is loaded into the column chiral HPLC ChiralPak AD (EXT. diameter 21 mm x 250 mm long) and elute with 50% methanol in isopropyl alcohol with a flow rate of 4 ml/min Two peaks are collected separately and removed under vacuum, thus obtaining 5R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol in the form of the first peak, MS (CI) m/z 472 (M+N⁺), and 5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol in the form of the second peak, MS (CI) m/z 472 (M+N⁺).

EXAMPLE 79

8-Hydroxy-11-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid and 8-hydroxy-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 51, No. 52

TBAF (1M in THF, 850 μl, 0.85 mmol, 3 EQ.) added dropwise into a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy and)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (200 mg, 0,285 mmol) in THF (10 ml) at -10°C. the Reaction mixture is stirred for 15 minutes. To the reaction mixture and then add the acid chloride 2,2-dimethylpropionic acid (714 μl, 0,285 mmol, 1 EQ.). The reaction mixture was diluted with ethyl acetate and washed with 5% sodium bicarbonate and then with saturated salt solution. The organic layer is dried over anhydrous Na₂SO₄and concentrated, thus obtaining the crude oil, which is purified HPLC (using a Luna C18 column, 1% TFA in acetonitrile (ACN) and 1% TFA in H₂About as a gradient of solvent). Two peaks are collected separately and evaporated to dryness under vacuum, thus obtaining 8-hydroxy-11-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid in the form of the first peak, MS (CI) m/z 556 (M+N⁺), and 8-hydroxy-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid in the form of the second peak, MS (CI) m/z 556 (M+N⁺).

MS(Cl) m/z: 556(M=H⁺)

¹H-NMR (300 MHz, CDCl₃):7,42 (2H, d, J=8.7 Hz), 7,03 (1H, d, J=8,4 Hz), 6,83-6,79 (3H, m), only 6.64 (1H, d, d, J=2,3, 8.5 Hz), only 6.64 (1H, d, J=2.3 Hz), 6,54-of 6.49 (2H, m), 6,51 (1H, s), vs. 5.47 (1H, d, J=14 Hz), to 5.17 (1H, d, J=14 Hz), of 4.05 (2H, t, J=6.0 Hz), 2,74-2,49 (5H, Sirs), to 1.59 (4H, m)to 1.37 (2H, m)of 1.32 (9H, s)

EXAMPLE 80

3-[2,4-Bis-(2-trimethylsilylamodimethicone)phenyl]-4-(3-chloro-2-oxopropyl)-7-(2-t is ametissenimetamiseks)chromen-2-he

At room temperature to 3-[2,4-bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-ONU (1.6 g, is 2.37 mmol) in THF (10 ml) is slowly added LiHMDS (2,9 ml, 2,84 mmol). The reaction mixture is stirred for 10 minutes and then add in chlorocatechol (of 0.28 ml, 1.5 EQ.) in THF (20 ml) at -20°C. the Reaction mixture was kept at -20°C for 1 hour, then diluted with diethyl ether (200 ml), washed with aqueous NH₄Cl (100 ml), saturated salt solution and the organic layer dried over anhydrous MgSO₄. The resulting product is then concentrated in vacuo to dryness and purified column chromatography on silica gel, thus obtaining specified in the title compound as a colourless oil.

¹H-NMR (CDCl₃):-0,1˜0,2 (m, N), 3,52˜4,12 (m, 10H), to 5.08 (s, 2H), 5,26 (s, 2H), 5,27 (s, 2H), 6,74 (m, 1H), 6,95-to 7.18 (m, 4H), 7,31 (m, 1H)

MS (m/z): MNa⁺(773)MH^-(749).

EXAMPLE 81

4-(3-Chloro-2-oxopropyl)-3-(2,4-dihydroxyphenyl)-7-hydroxypropan-2-he

3-[2,4-Bis-(2-trimethylsilylamodimethicone)phenyl]-4-(3-chloro-2-oxopropyl)-7-(2-trimethylsilylamodimethicone)chromen-2-he (0,846 g, 1.13 mmol) in HCl (1 N. in 40 ml of a mixture of 1:1 THF:iPrOH) was stirred overnight at 25°C. the Reaction mixture was then diluted with uh what ilaclama (10 ml) and washed with a saturated solution of salt (g ml). The organic layer is extracted with ethyl acetate (CH ml). The organic layers are combined, dried, concentrated and purified column chromatography on silica gel (5% Meon/DCM), while receiving specified in the title compound as white crystals.

¹H-NMR (CDCl₃)3,71 (d, 1H, J=15,0 Hz), 4,12 (d, 1H, J=15,0 Hz)to 4.52 (m, 2H), and 6.25 (m, 2H), 6.75 in (m, 3H), 7.5 (m, 1H), 9,35 (s, 1H), to 9.45 (s, 1H), 10,50 (s, 1H)

MS (m/z): MH⁺(361), MNa⁺(383), MN^-(359).

EXAMPLE 82

6,12-Dihydroxy[1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione, compound No. 211

4-(3-Chloro-2-oxopropyl)-3-(2,4-dihydroxyphenyl)-7-hydroxypropan-2-he (356 mg, 0.86 mmol) is stirred with K₂CO₃(356 mg, 2.57 mmol) in a mixture of acetone (40 ml) and Meon (20 ml) for 2 h at 25°C. Note that the color of the reaction mixture becomes yellow-green. Add aqueous HCl (2 N. 20 ml) and volatile organic solvents are removed by evaporation. The residue is washed with water and filtered, thus obtaining specified in the title compound as a pale yellow powder.

¹H-NMR (CDCl₃):of 2.08 (m, 2H), 2,68 -2,92 (m, 2H), 4.95 points (m, H), 5,02 (m, 1H), 5,62 (d, 1H, J=9.8 Hz), 5,96 (d, 1H, J=9.8 Hz), 7,03 (s, 1H), 7,51 (s, 1H)

MS (m/z): MH^-(323).

EXAMPLE 83

6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy][1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dio is, compound No. 212, and

2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9(1H)-he

6,12-Dihydroxy[1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione (obtained as described in example 82) (283 mg, 0.87 mmol), TBSCl (1.0m in DCM, and 2.6 ml, 3 EQ.) and Thea (0,36 ml, 3 EQ.) in DCM (10 ml) was stirred at 25°C for 30 minutes Method LC-MS showed the presence of only 2,8-di(OTBS)-product. The reaction mixture was then stirred overnight at 25°after this time, the method LC-MS showed the presence of a second, 2,8,12-three(OTBS)substituted product. The reaction mixture was then diluted with diethyl ether (50 ml), washed with water (50 ml), saturated salt solution and dried over MgSO₄. The product was then purified on silica gel, thus obtaining mentioned in the title compound as a yellow foam.

6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy][1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione:

¹H-NMR (CDCl₃):0,10˜0,19 (m, 18H), 0,84, to 0.92 (d, 27H), 4,22 (d, 1H, J=13.2hz), 4,79 (d, 1H, J=13,2 Hz), 5,72 (s, 1H), 6,51 (s, 1H), only 6.64 (m, 1H), 6,72 (m, 1H), 6,76 (m, 1H), 7,32 (d, 1H, J=10.5 Hz), 7,41 (d, 1H, J=10.5 Hz)

MS(m/z): MH^-(551)

EXAMPLE 84

2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro[1]benzopyrano[4,3-e][1]benzoxazin-9-ol

2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9(1H)-he obtained, as in the example above 83 (208 mg, 0.31 mmol)in toluene (5 ml) at -78°subjected to interaction with DIBAL (of 0.21 ml, 1.5 m in toluene, 1 EQ.). 3 hours later to the reaction mixture add 1 EQ. DIBAL. The reaction mixture was then diluted with ethyl acetate (100 ml), washed three times with a solution of Rochelle salt and twice subjected to back extraction with ethyl acetate (25 ml). The organic layers are dried and concentrated. The residue is purified on silica gel (5% ethyl acetate in hexane), while receiving specified in the title compound as a yellow foam.

¹H-NMR (CDCl₃):0,10-0,23 (m, 18H), 0,86-1,25 (m, 27H), and 3.16 (d, 1H, J=8,8 Hz), 4,25 (d, 1H, J=14,8 Hz), free 5.01 (d, 1H, J=17.7 and Hz), to 5.57 (s, 1H), 6,02 (d, 1H, J=8.0 Hz), 6,53˜6,70 (m, 4H), to 7.15 (m, 1H), 7.23 percent (m, 1H)

MS (m/z): MH^-(667)

EXAMPLE 85

2-(3,9-Bis(tert-butyldimethylsilyloxy)-6-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-benzo[b]oxazin-5-yl)-5-(tert-butyldimethylsilyloxy)phenol

Iodine (634 mg, at 1.91 mmol, 5 EQ.) in THF (5 ml) at -78°subjected to interaction with n-BuLi (0,76 ml, 2.5m in hexano) within 15 minutes the Mixture was then added to the solution 2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro[1]benzopyrano[4,3-e][1]benzoxazin-9(1H)-ol, compound, receive the tion, as in the example above 84 (256 mg, 0.38 mmol)in THF (5 ml) at -78°and the resulting reaction mixture is stirred for 1 hour. The reaction mixture was quenched Meon (0.1 ml) and then aqueous NH₄Cl. The resulting mixture is extracted with ethyl acetate (200 ml). The organic layers are dried and concentrated and subjected to azeotropic distillation with benzene (50 ml), while receiving specified in the header of the product in the form of crude oil.

MS (m/z): MN⁺(874), MN^-(872).

EXAMPLE 86

1-[2-[4-[2,6,12-Tris-[[(1,1-dimethylethyl)dimethylsilane]oxy]-3,9-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9-yl]phenoxy]ethyl]piperidine and

6,12-bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,9-dihydro-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e]benzoxazin-2(3H)-he, compound No. 95

The crude 2-(3,9-bis(tert-butyldimethylsilyloxy)-6-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-benzo[b]oxazin-5-yl)-5-(tert-butyldimethylsilyloxy)phenol obtained as in example 85 (0.38 mmol)in DCM (10 ml) at -10°mix with BF₃·Et₂O (0,32 ml, 2,47 mol, 6.5 EQ.) within 30 minutes the Resulting reaction mixture is quenched with water (5 ml) and stirred for 10 minutes, the Reaction mixture was then diluted with ethyl acetate (100 ml), washed twice with 5% HCl and then twice with a saturated solution of salt. The resulting residue with the shat and concentrate, while receiving specified in the title compound in the form of a mixture in the form of oil.

The oil is divided into the following components flash chromatography.

1-[2-[4-[2,6,12-Tris-[[(1,1-dimethylethyl)dimethylsilane]oxy]-3,9-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9-yl]phenoxy]ethyl]piperidine:

MS (m/z): MN⁺(856);

6,12-bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,9-dihydro-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e]benzoxazin-2(3H)-he:

MS (m/z): MN^-(740).

EXAMPLE 87

1,9-Dihydro-6,12-dihydroxy-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e]benzoxazin-2(3H)-he, compound No. 96

A mixture of the crude product, 1-[2-[4-[2,6,12-Tris-[[(1,1-dimethylethyl)dimethylsilane]oxy]-3,9-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9-yl]phenoxy]ethyl]piperidine, and 6,12-bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,9-dihydro-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e][1]benzoxazin-2(3H)-she received, as described above in example 86 (0.38 mmol), dissolved in THF (4 ml). Add a pre-prepared solution of TBAF (1.50 ml, 1.5 mmol, 4.0 EQ.) and acetic acid (0,043 ml, from 0.76 mmol, 2.0 EQ.) in THF (2.0 ml) and the reaction mixture is stirred for 14 hours. The reaction mixture was then diluted with ethyl acetate (10 ml) and washed with saturated salt solution (2 x 30 ml). The aqueous layer was extracted with ethyl acetate (2 x 50 ml). Organically the layers combine, dried, concentrated and purified column chromatography on silica gel (50-100% hexane/ethyl acetate), obtaining mentioned in the title compound as a white powder.

MS (m/z): MN⁺(514).

EXAMPLE 88

6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro-2-hydroxy[1]benzopyrano[4,3-e][1]benzoxazin-9(1H)-he, compound No. 216

The solution 6,12-bis[[(1,1-dimethylethyl)dimethylsilane]oxy][1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione, obtained in example 83 (216 mg, 0.4 mmol), in ethanol (4 ml) are added to NaBH₄(7.4 mg, 0.5 EQ.) at -10°C. the Reaction mixture was kept at this temperature with stirring for 2 hours. At this time add additional NaBH₄(12 mg) and the reaction mixture is stirred for another hour. The reaction mixture was quenched with aqueous NH₄Cl (5 ml) and then extracted with ethyl acetate (50 ml). The organic layers separated, dried over anhydrous Na₂SO₄concentrate and purify on silica gel with 15% ethyl acetate in hexane), while receiving specified in the title compound as a solid foam.

MS (m/z): MN⁺(554).

EXAMPLE 89

0-[6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro-9-oxo[1]benzopyrano[4,3-e]benzoxazin-2-yl]-O-phenyl ester cynogale acid

6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro-2-hydroxy[1]benzopyrano[4,3-e][1]benzoxazin-9(1H)-he obtained as in the above example 88 (215 mg, 0,388 mmol), mixed with thionyl chloride (80,081 ml, 0,582 mmol, 1.5 equiv.) pyridine (0,082 ml, 1 mmol, 2.6 EQ.) and DMAP (2.4 mg, 0.02 mmol, 5 EQ.) in DHM (4 ml) and the reaction mixture was stirred at room temperature over night. The reaction mixture was then diluted with ethyl acetate (50 ml), washed twice with saturated CuSO₄and then washed twice with a saturated solution of salt. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil purified flash column (5% ethyl acetate/hexane), while receiving specified in the title compound as colorless foamy solid.

MS (m/z): MN⁺(691), MNa⁺(713).

EXAMPLE 90

6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro-[1]benzopyrano[4,3-e][1]benzoxazin-9(1H)-he, compound No. 214

Through O-[6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro-9-oxo[1]benzopyrano[4,3-e][1]benzoxazin-2-yl]-O-phenyl ester cynogale acid, obtained as in the above example 89 (236 mg, 0.34 mmol), AIBN (2.8 mg, of 0.05 EQ.) and n-Bu₃SnH (0,137 ml, 1.5 EQ.) in toluene (4 ml) for 5 min bubbled N₂, heated to 80°C and stirred over night. The reaction mixture was then diluted with ethyl acetate (50 ml) and prom is live water CuSO ₄and a saturated solution of salt. The organic layer is concentrated and purified by silica gel, thus obtaining specified in the title compound as white crystals.

MS (m/z): MN⁺(539).

EXAMPLE 91

6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro[1]benzopyrano[4,3-e][1]benzoxazin-9-ol, compound No. 94

The connection is obtained, as in the example above 90 (227 mg, 0.42 mmol), restore the procedure described in example 84, while receiving specified in the title compound as a white solid.

MS (m/z): MNa⁺(563), MN⁺(539).

EXAMPLE 92

5-(tert-Butyldimethylsilyloxy)-2-(9-(tert-butyldimethylsilyloxy)-6-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-3,4-dihydro-2H-benzo[b]oxazin-5-yl)phenol, compound No. 291

Specified in the header connection receive according to the method described in the above example 85, with replacement 2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro[1]benzopyrano[4,3-e][1]benzoxazin-9-ol at 6,12-bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro[1]benzopyrano[4,3-e]benzoxazin-9-ol, and indicated in the title compound obtained as a yellow oil.

MS (m/z): MN⁺(746).

EXAMPLE 93

1-[2-[4-[6,12-Bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-those whom rehydro[1]benzopyrano[4,3-e][1]benzoxazin-9-yl]phenoxy]ethyl]piperidine, connection # 282

Specified in the header connection receive according to the method described in the above example 86, with the substitution of 2-(3,9-bis(tert-butyldimethylsilyloxy)-6-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-benzo[b]oxazin-5-yl)-5-(tert-butyldimethylsilyloxy)phenol 5-(tert-butyldimethylsilyloxy)-2-(9-(tert-butyldimethylsilyloxy)-6-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-3,4-dihydro-2H-benzo[b]oxazin-5-yl)phenol, and indicated in the title compound obtained as foam.

MS (m/z): MN⁺(728).

EXAMPLE 94

1,2,3,9-Tetrahydro-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e][1]benzoxazin-6,12-diol, compound No. 97

Specified in the header connection receive according to the method described in the example above 87, replacing the mixture of the crude product of 1-[2-[4-[6,12-bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro[1]benzopyrano[4,3-e][1]benzoxazin-9-yl]phenoxy]ethyl]piperidine, and is listed in the title compound obtained as a pink solid.

MS (m/z): MN⁺(500).

Racemic 1,2,3,9-Tetrahydro-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e]benzoxazin-6,12-diol (1.0 g) load on the column for chiral chromatography ChiralPak AS (EXT. the diameter of 5 cm x length 50 cm) and elute with 20% Meon in IPA with a flow rate of 9 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 2: 1,2,3,9-tetrahydro-9R*-(-)-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e][1]benzoxazin-6,12-diol,

[α]=-57°, (=0,302, Meon)

¹H-NMR (CD₃OD)1,49 (broad s, 2H), 1.69 in (broad s, 4H), 1.91 a (broad m, 2H), 2,08 (broad m, 2H), 2,71 (broad m, 4H), 2,92 (broad m, 2H), 3,74 (wide c, 1H), 4,12 (broad m,2H), 4,56 (broad s, 1H),5,95(s, 1H), between 6.08 and the 7.65(m, 10H)

MS (m/z): MH⁺(500)

Peak 1: 1,2,3,9-tetrahydro-9S*-(+)-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e]benzoxazin-6,12-diol,

[α]=+66°, (=0,402, Meon)

¹H-NMR (CD₃OD)1,49 (broad s, 2H), 1.69 in (broad s, 4H), 1.91 a (broad m, 2H), 2,08 (broad m, 2H), 2,71 (broad m, 4H), 2,92 (broad m, 2H), 3,74 (broad s, 1H), 4,12 (broad m, 2H), 4,56 (broad s, 1H), 5,95 (s, 1H), between 6.08 -7,65 (m, 10H)

MS (m/z): MH⁺(500)

EXAMPLE 95

[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, compound No. 98

To a solution of 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol (obtained as in example 24) (2,87 g, 5.6 mmol) in DHM (50 ml) is added BF₃·apiret (1,42 ml, and 11.2 mmol). The reaction mixture was then stirred and find that the mixture becomes dark red. After 20 min slowly add 1,1-bistrie elciliklerin (2 ml, 8.4 mmol, 1.5 EQ.). After 15 minutes add another portion of 1,1-bistrimethylammomium (1 g), and the solution becomes yellow after 10 minutes the Reaction mixture was diluted with ethyl acetate (200 ml) and then washed with aqueous solution of NH₄Cl and saturated salt solution. Flash chromatography (20% ethyl acetate/hexane) gives specified in the title compound as a yellow solid.

¹H-NMR (CDCl₃) to 0.10 (s, 12H), to 0.72 (s, 18H), 2,31 (d, 1H, J=11.7 Hz), 2,68 (m, 1H), 4,69 (d, 1H, J=13,6 Hz), to 4.98 (d, 1H, J=13,6 Hz), the ceiling of 5.60 (d, 1H, J=11.8 Hz), 6,18˜of 6.26 (m, 3H), 6,62 (d, 1H, J=7.8 Hz), 6,72 (d, 1H, J=7,8 Hz)

MS (m/z): MH⁺(555), MNa⁺(577), MH^-(553).

EXAMPLE 96

Methyl ester [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, compound No. 101

At room temperature to a solution of [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, the compound obtained as described above in example 95 (56 mg, 0.10 mmol)in benzene (0.7 ml) and Meon (0.2 ml) is added TMSCHN₂(0.075 ml, 2.0m in hexano) and the reaction mixture is stirred for 15 minutes the Solvent is removed and the residue purified flash chromatography, thus obtaining specified in the title compound as a yellow oil.

¹H-NMR (CDCl₃)of 0.08 (s, 12H), 0,78 (s, 18H), and 2.26 (d, 1H, J=15,5 Hz), 3,51 (s, 3H), 469 (d, 1H, J=13,8 Hz), to 4.98 (d, 1H, J=13,8 Hz)to 5.56 (d, 1H, J=10.5 Hz), 6,17˜6,24 (m, 4H), 6,63 (d, 1H, J=6.6 Hz), 6,74 (d, 1H, J=6,6 Hz)

MS (m/z): MH⁺(569), MNa⁺(591), MH^-(567),

EXAMPLE 97

Methyl ether (2,8-dihydroxy-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, compound No. 102

By the same procedure as described in example 87, methyl ester [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, a compound obtained as in example 96, is subjected to the interaction with TBAF, while receiving specified in the title compound as a yellow solid.

¹H-NMR (CDCl₃)2,47 (m, 1H), 2,72 (m, 1H), 3,69 (s, 3H), 4,88 (d, 1H, J=14,5 Hz), 5,27 (d, 1H, J=14,5 Hz), 5,74 (d, 1H, J=10.5 Hz), 6,34 (m, 2H), 6,44 (m, 2H), 7,00 (m, 2H)

MS (m/z): MNa⁺(363), MH^-(339)

EXAMPLE 98

2-Dimethylaminoethyl ether (2,8-dihydroxy-5,11-dihydrobromide[4,3-c]chromen-5-yl)acetic acid, compound No. 104

Stage A:

A mixture of [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid compounds obtained as in the above example 95 (56 mg, 0.1 mmol), 2-dimethylaminoethanol (30 μl, 27 mg, 3.0 EQ.), DIC (14 mg, 18 μl) and DMAP (12 mg) in DHM (2 ml) is stirred for 13 hours. The reaction mixture was then concentrated, while it is 2-dimethylaminoethyl ether [2,8-bis(tert-butyl)dimethylsiloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid in the form of a crude foam.

Stage:

According to the method described in example 87, the crude 2-dimethylaminoethyl ether [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, the compound obtained in the above stage And, dissolved in THF (1 ml) at -10°and then treated with TBAF, while receiving specified in the title compound as a yellow solid.

MS (m/z): MN⁺(398), MNa⁺(420), MN^-(396).

EXAMPLE 99

(2,8-Dihydroxy-5,11-dihydrobromide[4,3-c]chromen-5-yl)acetic acid, compound No. 107

According to the method described in example 87, [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, a compound obtained as in example 95 (56 mg, 0.1 mmol), subjected to interaction with TBAF, while receiving specified in the title compound as a yellow solid.

¹H-NMR (acetone-d₆)2,39 (m, 1H), 2,75 (m, 1H), 4,91 (m, 1H), 5.25 in (m, 1H), 5,78 (m, 1H), 6,41 (m, 2H), 6,50 (m, 2H), 7,00 (m, 2H)

MS (m/z): MH^-(325), (M+OAc)^-(385).

EXAMPLE 100

[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetaldehyde

At -78°to a solution of methyl ester [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, is soedineniya, obtained as in example 96 (120 mg, 0.21 mmol)in toluene (2 ml) is added DIBAL (of 0.28 ml, 1.5 m in toluene, 2 EQ.) at -78°C and stirred for 6 hours at -78°C. the Reaction mixture was then quenched at -78°chilled Meon. Purification of the residue HPLC gives specified in the title compound as a thick oil.

¹H-NMR (CDCl₃)of 0.05 (s, 12H), of 0.79 (s, 18H), to 2.29 (m, 1H), 2,85 (m, 1H), 4.72 in (d, 1H, J=13,7 Hz)5,08 (d, 1H, J=13,7 Hz), of 5.75 (d, 1H, J=10.0 Hz), and 6.25 (m, 4H), 6,69 (d, 2H, J=9.6 Hz), being 9.61 (s, 2H)

MS (m/z): MH⁺(561), MNa⁺(593)

A by-product, 2-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]ethanol, also provide HPLC in the form of oil.

¹H-NMR (CDCl₃)of 0.05 (s, 12H), of 0.79 (s, 18H), of 3.56 (m, 1H), 3,71 (m, 1H), 4.72 in (d, 1H, J=13,7 Hz), 4,96 (d, 1H, J=13,7 Hz), 5,31 (d, 1H), 6,21˜is 6.78 (m, 6H), being 9.61 (s, 2H)

MS (m/z): MH⁺(563).

EXAMPLE 101

5-(2-Hydroxyethyl)-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, compound No. 122

According to the method described in example 87, [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]ethanol is subjected to interaction with TBAF, while receiving specified in the title compound as a yellow solid.

¹H-NMR (CD₃OD)5 is 0.05 (s, 12H), of 0.79 (s, 18H), of 3.56 (m, 1H), 3,71 (m, 1H), 4.72 in (d, 1H, J=13,8 Hz), 4,96 (d, 1H, J=13,8 Hz), 5,31 (d, 1H, J=98 Hz), 6,21-of 6.78 (m, 6H), being 9.61 (s, 2H)

MS (m/z): MH⁺(313), MH^-(311)

EXAMPLE 102

8-(tert-Butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 220

At room temperature a mixture of 8-hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-it is obtained as in example 74 (2.0 g of the crude product, 7.0 mmol), and TBSCl (5.34 g, 35 mmol), triethylamine (5 ml) in DHM (80 ml) is stirred over night. The reaction mixture was then washed with water and saturated salt solution. The organic layers dried over anhydrous sodium sulfate and concentrated and purified flash chromatography, thus obtaining specified in the title compound as a white solid.

¹H-NMR (CD₃OD)to 0.19 (s, 6H), of 0.95 (s, 9H), 2,85 (m, 2H), 4,59 (m, 2H), 6,76-7,72 (m, 6H).

MS (m/z): MH⁺(395), MNa⁺(417), 2MNa⁺(811).

EXAMPLE 103

2-(tert-Butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 221

According to the method described in the example above, 102, 2-hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, obtained as in example 74 (11.2 g, 40 mmol), subjected to interaction, while receiving specified in the title compound in the form of below the powder.

¹H-NMR (CD₃OD)to 0.19 (s, 6H), of 0.95 (s, 9H), 2,85 (m, 2H), 4,60 (m, 2H), 6,55-of 7.55 (m,6H)

MS (m/z): MH⁺(395), MNa⁺(417), 2MNa⁺(811), MH^-(393).

EXAMPLE 104

8-(tert-Butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, compound No. 138

To a solution of 8-(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-she, compounds obtained as in the above example 102 (3.0 g, 7.56 mmol), at -78°slowly added DIBAL (5,10 ml, 1.5m in toluene, 1.0 EQ.). After 3 hours the reaction mixture was diluted with ethyl acetate (100 ml), washed three times with a solution of Rochelle salt and twice subjected to back extraction with ethyl acetate (25 ml). The organic layers are dried and concentrated. The residue is purified on silica gel (5% ethyl acetate in hexane), while receiving specified in the title compound as a white solid.

¹H-NMR (CD₃OD)of 0.21 (s, 6H), and 0.98 (s, 9H), 2,72˜of 3.12 (m, 3H), 4,58 (m, 2H), 6,12 (m, 1H), 6,61 (m, 2H), 7,02˜7,58 (m, 6H).

MS (m/z): MNa⁺(419).

EXAMPLE 105

2-(tert-Butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, compound No. 139

According to the method described in the above example 104, 2-(tertBUTYLPEROXY)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he the compound obtained as in the above example 103 (4.0 g, 10.1 mmol), subjected to interaction, while receiving specified in the title compound as a white solid.

¹H-NMR (CD₃OD)of 0.26 (s, 6H), of 1.05 (s, 9H), 2,85˜of 3.48 (m, 3H), 4,58 (m, 2H), 6,12 (m, 1H), 6,61˜of 6.73 (m, 2H), 7,05˜7,42 (m, 6H)

MS (m/z): MNa⁺(419), MH^-(395).

EXAMPLE 106

5-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, compound No. 140

According to the method described in example 76, 2-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, the compound obtained as in the above example 105, is subjected to the interaction with 1-[2-(4-iodinase)ethyl]piperidine, thus obtaining 2-(8-(tert-butyldimethylsilyloxy)-5-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2,3-dihydrobenzo[b]oxepin-4-yl)phenol in the form of crude oil. The crude 2-(8-(tert-butyldimethylsilyloxy)-5-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2,3-dihydrobenzo[b]oxepin-4-yl)phenol is then further treated with HCl (12 N. 4 EQ., of 0.67 ml) in toluene (100 ml)to give 1-(2-{4-[2-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)piperidine in the form of crude oil. The crude 1-(2-{4-[2-(tert-is utilimetrics)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)piperidine is then further processed by a complex of HF· pyridine (70% HF, 30% pyridine, 0.5 ml) in CH₃CN (20 ml) at room temperature for 30 minutes, the Reaction mixture was diluted with a mixture of ethyl acetate:THF (1:1) and then washed with 5% NaHCO₃and a saturated solution of salt. The reaction mixture was dried, concentrated and purified flash chromatography with elution 5% Meon in DHM, while receiving specified in the title compound as a pale yellow solid.

¹H-NMR (Acetone-d₆)of 1.35 (m, 2H), 1,49 (m, 4H), 2,42 (Sirs, 4H), of 2.64 (m, 2H), 2,71˜2,98 (m, 3H), 3,91 (m, 2H), 4,59˜4,74 (m, 2H), 6,21 (s, 1H), 6,55 was 7.45 (m, 11H)

MS (m/z): MH⁺(470)

Racemic compound, 5-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol (800 mg), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 100% IPA with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 1: 5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

¹H-NMR (DMSO-d₆)of 1.36 (m, 6H), 2,28˜at 2.59 (m, 6H), to 2.65 (m, 1H), 2,89 (m, 1H), 3,91 (t, 2H, J=6.6 Hz), 4,59 (m, 2H), 6,16-7,38 (m, 12H), 9,65 (s, 1H)

MS (m/z): MH⁺(470)

[α]_D=+39 (C=0,23, Meon)

Peak 2: 5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

[α]_{D =-37 (C=0,43, Meon)}

_{MS (m/z): MN⁺(470).}

_{EXAMPLE 107}

_{5-[4-(2-Azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, compound No. 141}

_{According to the method described in the example above, 105, 2-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol (0.8 g, 2.0 mmol), the compound obtained as in the example above 105, is subjected to the interaction with 1-[2-(4-iodinase)ethyl]azepane, while receiving specified in the title compound as a yellow solid.}

_{¹H-NMR (Acetone-d6)and 1.54 (m, 8H), 2,58-2,95 (m, 8H), 3,95 (m, 2H), 4,59-4,74 (m, 2H), 6,21 (s, 1H), 6,51˜was 7.45 (m, 11H)}

MS (m/z): MH⁺(484).

Racemic compound, 5-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol (950 mg), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 100% IPA with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 2: 5S*-(-)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

[α]_D=-28 (C=0,12, Meon)

¹H-NMR (DMSO-d₆)1,51 (broad s, 8H), of 2.45 (broad m, 4H), 2,70 (broad m, 2H), up 3.22 (broad s, 2H), 3,91 (t, 2H, J=6.6 Hz), 4,56 (m, 2H), x 6.15 (s, 1), 6,39˜of 7.36 (m, 11H), 9,67 (s, 1H)

MS (m/z): MH⁺(484)

Peak 1: 5R*-(+)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

[α]_D=+38 (C=0,25, Meon)

MN⁺(484).

EXAMPLE 108

5-[4-(2-Dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, compound No. 142

According to the method described in the example above, 106, 2-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, compound, obtained as in example 105, subjected to sequential interaction with [2-(4-iodinase)ethyl]dimethylamine HCl and then the complex HF·pyridine, while receiving specified in the title compound as a yellow solid.

¹H-NMR (CDCl₃)of 2.28 (s, 6H), of 2.72 (m, 2H), 2,82 (m, 2H), 3,95 (m, 2H), 4,59 (m, 2H), 6,02 (s, 1H), 6,41˜7,29 (m, 11N)

MS (m/z): MH⁺(430)

Racemic compound, 5-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol (890 mg), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute with 20% Meon and 80% IPA with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 1: 5R*-(+)-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohe the TA[1,2-a]naphthalene-2-ol

[α]_D=+38 (C=0.3, and Meon)

¹H-NMR (DMSO-d₆)to 2.13 (s, 6H), 2,43 of 2.92 (m, 4H), of 3.95 (t, 2H, J=6.6 Hz), 4,59 (m, 2H), x 6.15 (s, 1H), 6,38˜7,39 (m, 11H), RS 9.69 (s, 1H)

MS (m/z): MH⁺(430)

Peak 2: 5S*-(-)-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

[α]_D=-36 (C=0,32, Meon)

MS (m/z) MH⁺(430).

EXAMPLE 109

5-[4-(2-Azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol, compound No. 143

According to the method described in example 106, 8-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, the compound obtained in example 105, is subjected to interact sequentially with 1-[2-(4-iodinase)ethyl]azepane, HCl, and then with a complex of HF·pyridine, while receiving specified in the title compound as a yellow solid.

¹H-NMR (Acetone-d₆)and 1.54 (m, 8H), 2,58-2,95 (m, 8H), 3,95 (m, 2H), 4,59-4,74 (m, 2H), 6,21 (s, 1H), 6,51˜was 7.45 (m, 11H)

MS (m/z): MH⁺(484).

Racemic compound, 5-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol (840 mg), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 40% Meon and 80% IPA with a flow rate of 100 ml/min Two peaks are removed in vacuum, obtaining the ri following enantiomers.

Peak 1: 5R*-(+)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol

[α]_D=+37 (C=0.11, the Meon)

¹H-NMR (DMSO-d₆)of 1.55 (broad s, 8H), 2,68 of 2.92 (m, 8H), to 3.92 (t, 2H, J=6.6 Hz), br4.61 (m, 2H), 6,14˜7,38 (m, 12H), of 9.56 (s, 1H)

MS (m/z): MH⁺(484)

Peak 2: 5S*-(-)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol

[α]_D=-39 (C=0,51, Meon)

¹H-NMR (DMSO-d₆)of 1.55 (broad s, 8H), 2,68˜2,92 (m, 8H), to 3.92 (t, 2H, J=6.6 Hz), br4.61 (m, 2H), 6,14˜7,38 (m, 12H), of 9.56 (s, 1H)

MS (m/z): MH⁺(484)

EXAMPLE 110

5-[4-(2-Dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol, compound No. 144

According to the method described in the above example 106, 8-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, compound, obtained as in example 104, subjected to sequential interaction with [2-(4-iodinase)ethyl]dimethylamine HCl and then the complex HF·pyridine, while receiving specified in the title compound as a yellow solid.

MS (m/z): MN⁺(430).

Racemic compound, 5-[4-(2-dimethylaminoethoxy)phenyl]-1,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol (800 mg), load the column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 100% IPA with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 1: 5R*-(+)-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol

[α]_D=+42 (C=0,34, Meon)

¹H-NMR (DMSO-d₆)a 2.12 (s, 6H), 2.49 USD˜2,90 (m, 4H), of 3.95 (t, 2H, J=6.6 Hz), br4.61 (m, 2H), 6,09˜of 7.23 (m, 11H), 9,54 (s, 1H)

MS (m/z): MH⁺(430)

Peak 2: 5S*-(-)-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol

[α]_D=-42 (C=0,34, Meon)

MS (m/z) MH⁺(430).

EXAMPLE 111

5-[4-(2-Azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol, compound No. 159

According to the method described in example 106, 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, obtained as in example 75 (1.5 g, 2,85 mmol), subjected to interact sequentially with 1-[2-(4-iodinase)ethyl]azepane, HCl, and then with a complex of HF·pyridine, while receiving specified in the title compound in the form of foam.

¹H-NMR (CDOD₃)of 1.65 (m, 4H), of 1.84 (m, 4H), 2,78 (m, 2H), 3,35 (m, 4H), of 3.48 (m, 2H), 4,18 (m, 2H), br4.61 (m, 2H), 6,02 (s, 1H), 6,18-to 7.35 (m,10 H)

MS (m/z): MH⁺(500), MH^-(498).

Racemic compound, 5-[4-(2-AZE is EN-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (1,02 g), load into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 100% IPA with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 1: 5R*-(+)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol

[α]_D=+33 (C=0.11, the Meon),

MS (m/z) MH⁺(500), MN^-(498).

Peak 2: 5S*-(-)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol

[α]_D=-39 (C=0,51, Meon)

MS (m/z) MH⁺(500), MN^-(498).

EXAMPLE 112

5-[4-(2-Diisopropylaminoethyl)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol, compound No. 160

According to the method described in example 106, 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, obtained as in example 75 (1.5 g to 2.85 mmol), subjected to sequential interaction with [2-(4-iodinase)ethyl]diisopropylamino, HCl, and then the complex HF·pyridine, while receiving specified in the title compound as a pink solid.

¹H-NMR (CDOD₃)of 1.28 (d, 12H, J=5.3 Hz), 2,78 (m, 2H), 3,25 (m, 2H), 3,52 (m, 2H), of 4.05 (m, 2H), 4,56 (m, 2H), 6,05˜7,35 (m, 11H)

MS (m/z): MH⁺(502), MH^-(500),

Racemic compound, 5-[4-(2-diisopropylamino is ethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (1.4 g), load into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 80% IPA and 20% of hexanol with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 1: 5R*-(+)-[4-(2-diisopropylaminoethyl)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol

[α]_D=+43 (=0,112, Meon)

MS (m/z) MH⁺(502), MN^-(500).

Peak 2: 5S*-(-)-[4-(2-diisopropylaminoethyl)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol

[α]_D=-69 (C=0,812, Meon)

MS (m/z): MH⁺(502), MN^-(500).

EXAMPLE 113

5-[4-(2-Dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol, compound No. 161

According to the method described in example 106, 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, obtained as in example 75 (2.8 g, 5.3 mmol), subjected to sequential interaction with [2-(4-iodinase)ethyl]dimethylamine HCl and then the complex HF·pyridine, while receiving specified in the title compound as a yellow solid.

¹H-NMR (CDOD₃)to 2.85 (s, 6H), of 3.28 (m, 2H), 3,54 (m, 2H), 4,28 (m, 2H), br4.61 (m, 2H), the 6.06 (s, 1H), 6,15˜7,41 (m, 10H)

MS (m/z): MH⁺(446), MH^-(444)

Racemic compound, 5-[4-(2-dimethyl what minoletti)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (1.7 g), load into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 80% IPA and 20% of hexanol with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 1: R*-(+)-5-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol.

[α]_D=+39 (C=0,14, Meon),

MS (m/z) MH⁺(446), MN^-(444).

Peak 2: S*-(-)-5-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol.

[α]_D=-49 (C=0,4, Meon),

MS (m/z) MH⁺(446), MN^-(444).

EXAMPLE 114

9-Methyl-5-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, compound No. 283

According to the method described in example 106, 2-(tert-butyldimethylsilyloxy)-9-methyl-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, obtained as in example 106 (0,80 g of 1.95 mmol), subjected to sequential interaction with [2-(4-iodinase)ethyl]morpholine, HCl, and then the complex HF·pyridine, while receiving specified in the title compound as a yellow solid.

MS (m/z): MN⁺(484).

EXAMPLE 115

8-Fluoro-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 87

Specified in the header connection receive according to the method described in example 54, when replacing 5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol 8-fluoro-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-I, and the compound obtained as foam.

¹H-NMR (CDCl₃)1,18, 1,32 (D, 2C), of 1.42 (2H, m), and 1.63 (4H, m)of 2.64 (4H, Sirs), 2,87 (2H, t, J=5.5 Hz), 4,11 (2H, t, J=5.5 Hz), further 5.15 (1H, d, J=14,0 Hz), 5,38 (1H, d, J=14,0 Hz), 6,18 (1H, s), 6.48 in˜7,31 (10H, m)

MS (m/z): MH⁺(558)

Racemic compound, 5-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (1.7 g), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 100% IPA with a flow rate of 100 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 2: 8-Fluoro-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid.

TPL 182˜183°C

[α]_D=+160 (C=0,225, CHCl₃)

Peak 1: 8-Fluoro-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid.

TPL 178˜179°C

[α]_D=-173 (=0,205, CHCl₃).

EXAMPLE 116

3-(2,4-Acid)-4-methylpropan-2, compound No. 239

Specified in the header is Obedinenie get method described in example 1, replacing 2,4-dimethoxyacetophenone 2-hydroxyacetophenone, and get the product as yellow solid.

MS(m/z): MH⁺(297), MNa⁺(319), 2MNa⁺(615)

¹H-NMR (CDCl₃)6,65˜of 7.69 (m, 7H), 3,83 (s, 3H), of 3.73 (s, 3H), 2,32 (s, 3H)

EXAMPLE 117

4-methyl bromide-3-(2,4-acid)chroman-2, compound No. 240

Specified in the header connection get the procedure described in example 63, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-(2,4-acid)-4-methylpropan-2-one and replacing the bromine NBS, and get the product as yellow solid.

¹H-NMR (CDCl₃)7,08-to 7.61 (m, 5H), 6,41 (m, 2H),4,39 (1H, d, J=10.1 Hz), 4,12 (1H,d,J=10.1 Hz).

MS (m/z): MNa⁺(399), 2MNa⁺(773)

EXAMPLE 118

2-Hydroxy-11N-chromeno[4,3-c]chromen-5-Oh, compound No. 218

To a mixture of 4-methyl bromide-3-(2,4-acid)-2H-chromene (25,8 g, 68,76 mmol) in CH₂Cl₂(1,27 l) under nitrogen atmosphere is added slowly BBr₃(1.0m in CH₂Cl₂, 310 ml, 4.5 equiv.) at 25°C. After 16 h stirring the reaction mixture was poured into a cold solution of saturated NaHCO₃(700 ml) and water (700 ml). Then to the reaction mixture is added aqueous NaOH solution (75 ml, 10 BC). The aqueous layer is tdelay and then acidified water (10 BC) to pH ˜ 1.0, which leads to the formation of a yellow solid, which was filtered, washed with water and air-dried in vacuum over night, while receiving specified in the title compound as a yellow solid.

¹H-NMR (CDCl₃)for 9.95 (1H, s), 8,24 (d, 1H, J=8.7 Hz), 7,79 (1H, J=7.9 Hz), a 7.62 (1H, t, J=7.2 Hz), 7,41 (m, 2H), 6,55˜6.42 per (2H, m), 5,42 (2H, s)

MS (m/z): MH⁺(267), MNa⁺(289)

EXAMPLE 119

2-(tert-Butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-Oh, compound No. 219

2-Hydroxy-11N-chromeno[4,3-c]chromen-5-Oh (0.5 g)obtained as in example 118, dissolved in THF (5 ml). To the reaction mixture then add triethylamine (1.5 ml) and 1M TBSCl (2.0 ml) in dichloromethane and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 ml) and then washed twice with a saturated solution of salt. The organic layer is dried over anhydrous sodium sulfate and concentrated. The crude product is purified flash chromatography with elution with a mixture of 100:10:2 hexane/dichloromethane/ethyl acetate, thus obtaining specified in the title compound in the form of solids.

¹H-NMR (CDCl₃)8,43 (1H, d, J=8.7 Hz), 7,58˜7,28 (m, 4H), 6,59˜to 6.43 (m, 2H), 5,31 (2H, s),

MS (m/z): MH⁺(381), MNa⁺(403)

u> EXAMPLE 120

2-(tert-Butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-he, connection # 135

Specified in the header connection receive according to the method described in example 24, with the replacement of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-on 2-(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-it, and receive the product in the form of solids.

¹H-NMR (CDCl₃)7,28˜7,02 (m, 4H), 6.48 in˜6,32 (m, 3H), 5,32˜5,13 (t, 2H), 3,09 (1H, d, J=7,6 Hz)

MS (m/z): MNa⁺(405)

EXAMPLE 121

3-(2,4-Acid)-5,7-dimethoxy-4-methylpropan-2-he, connection # 284

Specified in the header connection receive according to the method described in example 1, replacing 2,4-dihydroxyacetophenone 1-(2-hydroxy-4,6-acid)atenonol, with the specified connection receive in the form of a yellow solid.

¹H-NMR (CDCl₃)7,08-6,28 (m, 6H), 3,86 (6H, s), of 3.84 (3H, s), 3,76 (3H, s), of 2.34 (s, 3H)

MS (m/z): MH⁺(357), MNa⁺(379)

EXAMPLE 122

3-Acetyl-5,7-dimethoxy-4-methylpropan-2-he

Specified in the header connection produce as a byproduct in the synthesis described above in example 123.

TPL 166˜167°C.

Anal. Calculated for sub> 14H₁₄About₅: C, 64,12; N; 5,38;

Measured: C, 64,20; N; 5,43.

¹H-NMR (CDCl₃)6.42 per (1H, d, J=2.3 Hz), 6,37 (1H, d, J=2.3 Hz), with 3.89 (s, 3H), 2,61 (s, 3H), 2,41 (s, 3H)

MS (m/z): MH⁺(263), MNa⁺(285), 2MNa⁺(547)

EXAMPLE 123

2-(7-(tert-Butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol

Specified in the header connection receive according to the method described in example 26, with the replacement of 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol for 2-(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol, and receive the product in the form of oil.

¹H-NMR (CDCl₃)7,24˜x 6.15 (m, 11N), 5,46 (s, 1H), 4.92 in (m, 2H), 4,18 (Sirs, 2H), 3,02 (Sirs, 2H), 2,78 (Sirs, 4H), 1,78 (Sirs, 4H), 1,52 (Sirs, 2H), to 0.92 (s,9H), of 0.14 (s, 6H)

MS (m/z): MH⁺(588), MH^-(586)

EXAMPLE 124

1-(2-{4-[2-(tert-Butyldimethylsilyloxy)5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine, compound No. 158

Specified in the header connection receive according to the method described in example 35, with the substitution of 5-(tert-butyldimethylsilyloxy)-2-(7-tert-butyldimethylsilyloxy)-4-{hydroxy-[4-[2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromenes-3-yl)phenol 1-(2-{4-[2-(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-a]chromen-5-yl]phenoxy}ethyl)piperidine, and receive the product in the form of foam.

¹H-NMR (CDCl₃)7,16˜6,12 (m, 11N), equal to 6.05 (s, 1H), further 5.15 (1H, d, J=14.1 Hz), of 4.95 (1H, d, J=14.1 Hz), 4,16 (2H, Sirs), 3,05 (Sirs, 4H), 1,72 (Sirs, 4H), 1,38 (Sirs, 2H), of 0.79 (s, 9H)

MS (m/z): MH⁺(570).

EXAMPLE 125

5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-ol, compound No. 133

Specified in the header connection receive according to the method described in example 44, replacing 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine 1-(2-{4-[2-(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine, and receive the product in the form of solids.

¹H-NMR (CDCl₃)7,39 of 6.31 (m, 12H), the 5.45 (1H, d, J=14,2 Hz), further 5.15 (1H, d, J=14,2 Hz), was 4.02 (t, 2H, J=6.2 Hz), to 2.65 (t, 2H, J=6.2 Hz), 2,45 (Sirs, 4H), 2.05 is (Sirs, 4H)and 1.51 (m, 2H).

MS (m/z):MH⁺(456)

EXAMPLE 126

5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 134

Specified in the header connection receive according to the method described in example 54, when replacing 5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol 5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-olo is, obtained as in example 127, and receive the product in the form of solids.

¹H-NMR (CDCl₃)7,38˜6,38(m, 11H), 6,21 (s, 1H), of 5.40 (1H, d, J=14,0 Hz), 5,18 (1H, d, J=14,0 Hz), of 4.13 (2H, t, J=5.5 Hz), 2,95 (2H, t, J=5.4 Hz), 2,71 (Sirs, 4H), 1,68 (SIRM, 4H), of 1.47 (m, 2H), 1,32 (s, 9H).

MS (m/z): MH⁺(539).

EXAMPLE 127

7-Fluoro-3-(2-methoxyphenyl)-4-methylpropan-2-he, connection # 284

Specified in the header connection receive according to the method described in example 1, replacing 2,4-dihydroxyacetophenone 1-(4-fluoro-2-hydroxyphenyl)Etalon and replacement of 2,4-dimethoxyphenylacetic acid 2-methoxyphenylazo acid, and the product is obtained in the form of solids.

¹H-NMR (CDCl₃)7,65˜6,94 (m, 6H), 3,79 (s, 3H), of 2.23 (s, 3H)

MS (m/z): MH⁺(285), MNa⁺(307).

EXAMPLE 128

3-(2-Methoxyphenyl)-4-methylpropan-2, compound No. 241

Specified in the header connection receive according to the method described in example 1, replacing 2,4-dihydroxyacetophenone 1-(2-hydroxyphenyl)Etalon and 2,4-dimethoxyphenylacetic acid 2-methoxyphenylazo acid, and the product is obtained in the form of solids.

¹H-NMR (CDCl₃)7,68˜of 6.96 (m, 8H), 3,79 (s, 3H), of 2.25 (s, 3H)

MS (m/z): MH⁺(267), MNa +(289).

EXAMPLE 129

4-methyl bromide-3-(2,4-acid)-5,7-dimethoxyfuran-2, compound No. 242

Specified in the header connection get the procedure described in example 63, with the replacement of 3-[2,4-bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-it 3-(2,4-acid)-5,7-dimethoxy-4-methylpropan-2-he and bromine at NBS (1.1 EQ.), moreover, the product is obtained in the form of solids.

¹H-NMR (CDCl₃)7,28˜6,38 (m, 5H), of 4.49 (d, 1H, J=8,8 Hz), or 4.31 (d, 1H, J=8,8 Hz), of 3.94 (s, 3H), a 3.87 (s, 3H), 3,85 (s, 3H), of 3.75 (s, 3H)

MS (m/z): MH⁺(436, 438), MNa⁺(457, 459)

EXAMPLE 130

4-methyl bromide-3-(2-methoxyphenyl)chromen-2, compound No. 243

Specified in the header connection get the procedure described in example 63, with the replacement of 3-[2,4-bis-(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-it 3-(2-methoxyphenyl)-4-methylpropan-2-he and replacement of bromine by NBS (1.1 EQ.), moreover, the product is obtained in the form of solids.

¹H-NMR (CDCl₃)7,82˜7,01 (m, 8H), of 4.44 (d, 1H, J=10,2 Hz), 4,25 (d, 1H, J=10,2 Hz)

MS (m/z): MH⁺(347), MNa⁺(369)

EXAMPLE 131

4-methyl bromide-3-(2-hydroxyphenyl)chromen-2, compound No. 244

Specified in the header of the connection receives the same procedure as described in example 120, with the replacement of 4-methyl bromide-3-(2,4-acid)-2H-chromene 4-methyl bromide-3-(2-methoxyphenyl)chromen-2-it, and the product is obtained in the form of solids.

TPL 213˜215°C.

¹H-NMR (CDCl₃)7,82-7,01 (m, 8H), 5,02 (s, 1H), 4,50 (1H, d, J=10,2 Hz), 4,30 (1H, d,J=10,2 Hz)

MS (m/z): MH⁺(333), MNa⁺(355)

EXAMPLE 132

11N-Chromeno[4,3-c]chromen-5-he

Specified in the header connection get the procedure described in example 61, on the basis of 4-methyl bromide-3-(2-hydroxyphenyl)chromen-2-it instead of 4-bromoethyl-3-(2,4-dibenzyline)-7-benzoylamino-2-it, and the product is obtained in the form of solids.

Anal. Calculated for C₁₆H₁₁BrO₃: C 58,03; N; 3,35;

Measured: C, 58,02; N; 3,29.

TPL 201,5˜202,0°C.

¹H-NMR (CDCl₃) δ 8,61-7,01 (m, 8H), of 5.34 (s, 2H).

MS (m/z): MN⁺(333), MNa⁺(355).

EXAMPLE 133

5,11-Dihydrobromide[4,3-c]chromen-5-ol, compound 136

Specified in the header connection receive according to the method described in example 24, from 11N-chromeno[4,3-c]chromen-5-it instead of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-it, and the product is obtained in the form of solids.

Ana is. Calculated for C₁₆H₁₂About₃: C, 76,18; N; 4,79;

Measured: C, 75,86; N; 4,70.

¹H-NMR (CDCl₃) δ 7,34˜6,86 (m, 8H), 6,41 (d, 1H, J=6.3 Hz), with 5.22 (m, 2H), 3,12 (d, 1H, J=7,8 Hz).

MS (m/z): MN⁺(253), MNa⁺(275).

EXAMPLE 134

2-(4-{Hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol, compound No. 246

Specified in the header connection receive according to the method described in example 26, from 2-(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol, replacement 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol, and the product is obtained in the form of solids.

Anal. Calculated for C₂₉H₃₁NO₄.0,75 H₂About:

WITH, 73,94; N; OF 4.95; N, 2,97.

Measured: C, 73,98; N; 6,92, N, 2,97.

¹H-NMR (DMSO-d₆)9,80 (s, 1H), of 7.48˜6,59 (m, 12H), by 5.87 (Sirs, 1H), 5,58 (Sirs, 1H), 5,01 (shirt, 1H), with 4.64 (shirt, 1H), 3,98 (Sirs, 2H), 2,58 (Sirs, 2H), 2,37 (Sirs, 4H), 1,42 (Sirs, 4H), 1,34 (Sirs, 2H)

MS (m/z): MH⁺(458)

EXAMPLE 135

1-{2-[4-(5,11-Dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}piperidine, compound No. 137

Specified in the header connection receive according to the method described in example 35, from 2-(4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol instead of 5-(tert-buildiers is siloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol, and receive the product in the form of solids.

Anal. Calculated for C₂₉H₂₉NO₃:

WITH, 79,24; N; OF 6.65; N, 3,19.

Measured: C, 78,96; N; 6,57, N, 3,11.

¹H-NMR (CDCl₃)7,38-of 6.71 (m, 12H), to 6.22 (s, 1H), 5,38 (d, 1H, J=14,0 Hz), 5,15 (d, 1H, J=14.1 Hz), a 4.03 (t, 2H, J=6,1 Hz), a 2.71 (t, 2H, J=6,1 Hz), 2,45 (Sirs, 4H), 1.55V (Sirs, 4H), 1,45 (SIRM, 2H),

MS (m/z): MH⁺(440)

Example 136

1-(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-11-methoxy-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine, compound No. 162

Specified in the title compound emit flash chromatography as a by-product of the reaction described in example 35.

¹H-NMR (CDCl₃)7,38˜6,10 (m, 11H), 5,91 (s, 1H), to 4.41 (Sirs, 2H), 3,61 (s, 3H), 3,21 (Sirs, 2H), 3.15 in (SIRM, 4H), 1,95 (Sirs, 4H), and 1.54 (Sirs, 2H), 0,91 (m, 18H), 0,21 (m, 12H)

MS (m/z): MH⁺(730)

EXAMPLE 137

5R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 172, and

5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 171

Racemic compound, 5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt e is Il-2,2-dimethylpropionic acid, obtained as in example 126 (400 mg), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 80% IPA and 20% of hexanol with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following two enantiomers.

Peak 1: 5R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid.

[α]=-91 (c=0,21, CHCl₃).

Peak 2: 5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid.

[α]=+102 (c=0,31, CHCl₃).

EXAMPLE 138

5R*-(-)-1-{2-[4-(5,11-Dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}piperidine, compound No. 170, and

5S*-(+)-1-{2-[4-(5,11-dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}piperidine, compound No. 169

Racemic compound, 5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, obtained as in example 135, (900 mg), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute with 50% IPA and 50% of hexanol at a flow rate of 200 ml/min. Two peaks are removed under vacuum, thus obtaining the following two enantiomers.

Peak 1: 5R*-(-)-1-{2-[4-(5,11-dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}piperidine.

[α]=-135 (c=0,27, CHCl₃).

Peak 2: 5S*-(+)-1-{2-[4-(5,11-dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}PI is Eridan.

[α]=+146 (c=0,27, CHCl₃).

EXAMPLE 139

2-(tert-Butyldimethylsilyloxy)-8-fluoro-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol, compound No. 286

A solution of 2-(tert-butyldimethylsilyloxy)-8-fluoro-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-it (1.56 g, 3.7 mmol) in toluene (40 ml) was treated with DIBAL (2,53 ml, 1.5m in toluene, 1.0 EQ.) at -78°C for 3 hours. The reaction mixture was then quenched with chilled Meon at -78°and the solvent is removed under reduced pressure. The residue is purified flash chromatography (10% EtOAc in hexano), while receiving specified in the title compound as a white solid.

MS (m/z): MN⁺(416).

EXAMPLE 140

5-[4-(2-Azepin-1 ylethoxy)phenyl]-8-fluoro-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, compound No. 174

Specified in the header connection get the procedure described in example 106, with the substitution of 2-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol for 2-(tert-butyldimethylsilyloxy)-8-fluoro-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol (1.1 g), and the product is obtained as a yellow solid.

¹H-NMR (CDCl₃)to 1.61 (m, 8H), 2,71˜2,99 (m, 8H), to 3.92 (t, 2H, J=6.6 Hz), of 4.66 (m, 2H), 6,8 (s, 1H), 6,46˜of 7.36 (m, 10H)

MS (m/z): M+H=502

Racemic compound, 5-[4-(2-azepin-1 ylethoxy)phenyl]-8-fluoro-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, (700 mg), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 80% IPA and 20% of hexanol with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following two enantiomers.

Peak 1: 5R*-(+)-[4-(2-azepin-1 ylethoxy)phenyl]-8-fluoro-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol.

[α]_D=+24,2 (c=0,305, Meon).

MS (m/z): M+H=502.

Peak 2: 5S*-(-)-[4-(2-azepin-1 ylethoxy)phenyl]-8-fluoro-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

[α]=-28,2 (c=0.5, Meon).

MS (m/z): M+H=502.

EXAMPLE 141

8-Hydroxy-11S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 89, and

8-hydroxy-5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound No. 90

8-(2,2-Dimethylpropionic)-5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromelalumel ether of 2,2-dimethylpropionic acid, obtained as in example 67 (10 g), suspended in the Meon (200 ml) in a resealable tube and added 1.2 equivalent of diethylamine. The resulting solution is heated to 150°in ECENA 3 hours. The reaction mixture was concentrated in vacuo and purified on SiO₂thus the mixture.

A mixture of (3.1 g) are loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 100% IPA with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following two regioisomer.

Peak 1: 8-hydroxy-5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid.

¹H-NMR (CDCl₃)of 1.35(s, 9H), 1,45 (broad s, 2H), 1,62 (broad s, 4H), 2,61 (broad s, 4H), 2,82 (broad s, 2H), 3,92 (t, 2H, J=6.0 Hz), of 5.05 (d, 1H, J=14,7 Hz in), 5.25 (d, 1H, J=14,7 Hz), 6,12˜7,22 (m, 11H)

MS (m/z): MH+ (556)

Peak 2: 8-hydroxy-11S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid.

¹H-NMR (CDCl₃)1,19(d, 9H, J=7,0 Hz)of 1.42 (broad s, 2H), 1,61 (broad s, 4H), 2,59 (broad s, 4H), of 2.72 (broad s, 2H), 4,06 (m, 2H), of 5.05 (d, IH, J=13,2 Hz), 5,24 (d, 1H, J=13,2 Hz), 6,16-of 7.23 (m, 11H)

MS (m/z): MH+(556)

EXAMPLE 142

8-Methoxy-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-ol, compound No. 176

8-Hydroxy-5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid (330 mg), the compound obtained in the above example 145, dissolved in MESI CH ₃CN/MeOH (3:1) (8 ml), add TMSCHN₂(2M in hexane, 3.3 ml) and the mixture is stirred over night. The reaction mixture is concentrated to dryness. The resulting crude oil is suspended in the Meon (5 ml) and TEA (0.800 to ml) and heated in a sealed tube at 150°With during the night. The reaction mixture was concentrated and purified on SiO₂using 5-10% Meon in CH₂Cl₂while this is mentioned in the title compound as a yellow foam.

¹H-NMR (CDOD₃)to 1.48 (m, 2H), 1.61 of (m, 4H), 2,59 (broad s, 4H), and 2.79 (t, 2H, J=5.6 Hz), 4,08 (t, 2H, J=5.6 Hz), 5,02 (d, 1H, J=13,8 Hz), 5,31 (d, 1H, J=13,6 Hz)

MS (m/z): MH⁺(486)

EXAMPLE 143

8-Methoxy-11S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-ol, compound No. 181

8-Hydroxy-11S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid (300 mg), the compound obtained as in example 145, dissolved with a mixture of CH₃CN/MeOH (3:1) (8 ml), add TMSCHN₂(2M in hexane, 3.3 ml) and the mixture is stirred over night. The reaction mixture is concentrated to dryness. The resulting crude oil is suspended in the Meon (5 ml) and TEA (0.8 ml) and heated in a sealed tube at 150°With during the night. The reaction mixture was concentrated and purified on SiO₂used the eat 5-10% Meon in CH ₂Cl₂while this is mentioned in the title compound as a yellow foam.

MS (m/z): MN⁺(486).

EXAMPLE 144

5S*-(+)-1-{2-(4-(2,8-Dimethoxy-5,11-dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}piperidine, compound No. 173

5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol (290 mg), obtained as in example 78, dissolved in CH₃CN/Meon (3:1) (5 ml). Add TMSCHN₂(2M in hexane, 4 ml) and the mixture is stirred over night. The reaction mixture is concentrated to dryness and purified on SiO₂using 5% Meon in CH₂Cl₂while this is mentioned in the title compound as a colourless oil.

¹H-NMR (CDCl₃)of 1.41 (broad s, 2H), 1,62 (broad s, 4H), 2,53 (broad s, 4H), and 2.79 (s, 2H), 3,81 (s, 3H), of 3.84 (s, 3H), 4,08 (t, 2H, J=5.5 Hz), 5,12 (d, 1H, J=13,6 Hz), 5,41 (d, 1H, J=13,6 Hz), 6,18 (s, 1H), 6,32-7,38 (m, 10H)

MS (m/z): MH⁺(500)

EXAMPLE 145

5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol, compound No. 99, and

5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol, compound No. 100

Racemic compound, 5-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-the IOL, obtained in example 77 (1.18 g), loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 80% IPA and 20% Meon with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following two enantiomers.

Peak 1: 5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol.

¹H-NMR (CD₃OD)of 1.46 (m, 2H), 1,59 (m, 4H), to 2.55 (m, 4H), of 2.72 (M, 2H), 2,81 (m, 2H), was 4.02 (t, 2H, J=5.4 Hz), 4,60 (m, 2H), equal to 6.05 (s, 1H), 6,14˜7,34 (m, 10H),

TPL 147˜149°C.

[α]=+57° (c=0,302, Meon).

Anal. Calculated for C₃₀H₃₁NO₅.0,95 N₂About:

WITH, 71,68; N, 6,60; N, 2,79.

Found: C, 71,67; N, Of 6.52; N, 2.57 M).

MS (m/z): MN⁺(486).

Peak 2: 5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol.

[α]=-59° (c=0,41, Meon).

MS (m/z): MN⁺(486).

EXAMPLE 146

5S*-(-)-1-{2-[4-(2,8-Dimethoxy-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl)phenoxy]ethyl}piperidine, compound No. 156

5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (1 g), obtained as in example 145, dissolved in CH₃CN/Meon (3:1) (28 ml). Add TMSCHN₂(2M in hexane, 3.3 ml) and the mixture is stirred over night. The reaction mixture is concentrated of Dosh and purified on SiO ₂using 5% Meon in CH₂Cl₂while this is mentioned in the title compound as a yellow oil.

¹H-NMR (CDCl₃)of 1.40 (m, 2H), 1,59 (m, 4H), 2.49 USD (broad s, 4H), of 2.72 (m, 2H), 2.91 in (m, 2H), 3,71 (s, 3H), 3,78 (C #H)of 4.05 (m, 2H), 4,69 (m, 2H), equal to 6.05 (s, 1H), 6,36-7,39 (m, 10H)

MS (m/z): MH+ (514)

EXAMPLE 147

2-Methoxy-5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol, compound No. 196, and

8-Methoxy-5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol, compound No. 195

5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (10 g), obtained as in example 145, dissolved in a mixture of CH₃CN/MeOH (3:1) (280 ml). Add 1.1 equivalent TMSCHN₂(2M in hexane, to 10.2 ml) and the mixture is stirred over night. The reaction mixture is concentrated to dryness and purified on SiO₂using 5-10% Meon in CH₂Cl₂while this mixture is listed in the title compounds as a yellow foam.

A mixture of compound (2.9 g) is loaded into a column for chiral HPLC ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute 100% IPA with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following two listed in the connection header.

Peak 1: 2-labels and-5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol.

¹H-NMR (DMSO-d₆)of 1.42 (s, 2H), 1.61 of (s, 4H), 2,41˜3,14 (m, 8H), to 3.67 (s, 3H), 4,24 (s, 2H), 4,59 (m, 2H), 6,14˜7,28 (m, 11H)

MS (m/z): MH⁺(500)

Peak 2: 8-methoxy-5S*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol

¹H-NMR (CD₃OD)of 1.41 (broad s, 2H), 1,59 (broad s, 4H), 2,50 (broad s, 4H), 2,68 (m, 2H), 2,81 (m, 2H), 3,78 (m, 2H), br4.61 (t, 2H, J=6,0 Hz), of 6.02 (s, 1H), 6.22 per 7,29 (m, 10H)

MS (m/z): MH+ (500)

EXAMPLE 148

3-(2,4-Acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2, compound No. 258

In odnogolosy flask of 200 ml download bis(trimethylsilyl)amide lithium ((TMS)₂NLi, 16 ml of 1M solution in THF). To the reaction mixture for 10 min add 3-(2,4-acid)-7-methoxy-4-methylpropan-2-he (3,45 g) in anhydrous THF and the mixture is stirred at -20°C for 45 minutes To the reaction mixture for 10 min add (2 chloromethoxy)ethyl)trimethylsilane (1,95 g) and stirring is continued at -10°C for 6 hours. The reaction mixture was quenched with saturated NH₄Cl (200 ml) and extracted with EtOAc (200 ml). The organic phase is concentrated in vacuo at 60°thus the crude product, which was purified with flash chromatography to obtain specified in the title compound as a white solid.

MS (/z): MH ⁺(457), MNa⁺(479).

EXAMPLE 149

7-Methoxy-3-(2-methoxyphenyl)-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-he, connection # 262

Specified in the header connection receive according to the method described in the example above, 148, with the replacement of 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 7-methoxy-3-(2-methoxy-3-(2-methoxyphenyl)-4-methylpropan-2-one, and the product is obtained in the form of a white solid.

MS (m/z): MN⁺(427), MNa⁺(449).

EXAMPLE 150

3-(2,4-Acid)-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2, compound No. 259

Specified in the header connection receive according to the method described in the example above, 148, with the replacement of 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 3-(2,4-dimethoxyphenyl)-4-methylpropan-2-one, and the product is obtained in the form of a white solid.

MS (m/z): MN⁺(427), MNa⁺(449).

EXAMPLE 151

3-(2,4-Acid)-7-fluoro-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2, compound No. 264

Specified in the header connection receive according to the method described in the example above, But replacing 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 3-(2,4-dimethoxyphenyl)-4-fluoro-4-methylpropan-2-one, and the product is obtained in the form of a solid is the first substance.

MS (m/z): MN⁺(445), MNa⁺(467).

EXAMPLE 152

3-(2,4-Acid)-6-methyl-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2, compound No. 267

Specified in the header connection receive according to the method described in the example above, 148, with the replacement of 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 3-(2,4-dimethoxyphenyl)-4,6-dimethyl-4-methylpropan-2-one, and the product is obtained in the form of solids.

MS (m/z): MN⁺(441), MNa⁺(463).

EXAMPLE 153

3-(2,4-Dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2, compound No. 62

Flask of 1 l load CH₂Cl₂(200 ml) and 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chromen-2-one, obtained as in example 148 (5 g). The solution was stirred at room temperature in an atmosphere of N₂and in an atmosphere of N₂over a period of 20 min add BBr₃(8 ml). The reaction mixture was then stirred for 36 hours. The reaction mixture was cooled to 0°and the reaction mixture is poured into pre-cooled 1 N. NaOH (200 ml, 5°). The resulting solution is neutralized 1 N. HCl to pH 4 and extracted with EtOAc (2 l). The organic layer is separated and concentrated in vacuo to dryness, then purified flash chromatography, thus obtaining specified in the header is the connection in the form of a yellow solid.

MS (m/z): MN⁺(315), MNa⁺(337).

EXAMPLE 154

3-(2,4-Dihydroxyphenyl)-4-(2-hydroxyethyl)chromen-2, compound No. 269

Specified in the header connection receive according to the method described in the above example 153, with the replacement of 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-it 3-(2,4-acid)-4-[2-(2-trimethylsilyloxy)ethyl]chromen-2-one, obtained as in example 150, and the product is obtained in the form of solids.

MS (m/z): MN⁺(299), MNa⁺(321).

EXAMPLE 155

7-Hydroxy-4-(2-hydroxyethyl)-3-(2-hydroxyphenyl)chromen-2, compound No. 271

Specified in the header connection receive according to the method described in the above example 153, with the replacement of 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-it 7-methoxy-3-(2-methoxyphenyl)-4-[2-(2-trimethylsilyloxy)ethyl]chromen-2-one, obtained as in example 149, and the product is obtained in the form of solids.

MS (m/z): MN⁺(299), MNa⁺(321).

EXAMPLE 156

3-(2,4-Dihydroxyphenyl)-7-fluoro-4-(2-hydroxyethyl)chromen-2, compound No. 270

Specified in the header connection receive according to the method described in the above example 153, with the replacement of 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)the Teal]chromen-2-it 3-(2,4-acid)-7-fluoro-4-[2-(2-trimethylsilyloxy)ethyl]chromen-2-one, obtained as in example 151, the product is obtained in the form of solids.

MS (m/z): MN⁺(317), MNa⁺(339).

EXAMPLE 157

3-(2,4-Acid)-4-(2-hydroxyethyl)-6-methylchromone-2, compound No. 268

Specified in the header connection receive according to the method described in the above example 153, with the replacement of 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-it 3-(2,4-acid)-6-methyl-4-[2-(2-trimethylsilyloxy)ethyl]chromen-2-one, obtained as in example 152, and the product is obtained in the form of solids.

MS (m/z): MN⁺(313), MNa⁺(335).

EXAMPLE 158

2,8-Dihydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 56

A suspension of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it, obtained as in example 153 (2.5 g), and anhydrous THF (40 ml) is cooled to a temperature of approximately -5 to 0°C. To the reaction mixture and then add diisopropylethylamine (DIAD, 6,64,5 ml) for 35 min and the mixture was stirred at -5°C for 30 minutes Then during 30 min add a solution of triphenylphosphine (to 8.41 g) in THF (160 ml), the reaction mixture is heated to 20°C and stirred for 18 hours. The solvent is distilled off in vacuum at 60°the resulting residue was dissolved in CH ₂Cl₂(300 ml) and washed with 2 N. solutions of NaOH three times (200 ml, 100 ml and 50 ml). The aqueous phase are combined and subjected to back extraction with CH₂Cl₂(50 ml). The aqueous phase is cooled to 0°and acidified to pH˜1-2 with concentrated HCl (37%) and the resulting suspension stirred at 10°C for 1 hour. Solid allocate by filtration and the filter residue is washed with N₂About (50 ml). This solid is dried under vacuum, thus obtaining specified in the title compound in the form of solids.

MC: 295,0 M-N; 297 M+N; 319 M+Na

¹H-NMR (300 MHz, THF-d8):(h/mn) of 6.5 to 7.8 (m, 6H), 4,6 (t, 2H), 3,0 (t, 2H).

EXAMPLE 159

2-Hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he, connection # 225

Specified in the header connection receive according to the method described in the above example 153, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it 3-(2,4-dihydroxyphenyl)-4-(2-hydroxyethyl)chromen-2-one, obtained as in example 158, and the product is obtained in the form of solids.

MS (m/z): M+H=281, M+Na=283.

EXAMPLE 160

8-Hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 223

Specified in the header connection receive is eodice, described in the above example 153, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it 7-hydroxy-4-(2-hydroxyethyl)-3-(2-hydroxyphenyl)chromen-2-one, obtained as in example 158, and the product is obtained in the form of solids.

MS (m/z): M+H=281, M+Na=283.

EXAMPLE 161

8-fluoro-2-hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 226

Specified in the header connection receive according to the method described in the above example 153, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it 3-(2,4-dihydroxyphenyl)-7-fluoro-4-(2-hydroxyethyl)chromen-2-one, obtained as in example 158, and the product is obtained in the form of solids.

MS (m/z): M+H=299, M+Na=321.

EXAMPLE 162

2-Hydroxy-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 287

Specified in the header connection receive according to the method described in the above example 153, with the replacement of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it 2-hydroxy-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one, obtained as in example 158, and the product is obtained in the form of solids.

MS (m/z): M+H=295, M+Na=317.

EXAMPLE 163

2-(tert-Butyldimethylsilyl the si)-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he connection # 228

Specified in the header connection receive according to the method described in example 22, with the replacement of 2,8-dihydroxy-11N-chromeno[4,3-c]chromen-5-it 2-hydroxy-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one, and the product is obtained in the form of solids.

MS (m/z): M+N=409, M+Na=431.

EXAMPLE 164

2-(tert-Butyldimethylsilyloxy)-8-fluoro-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, compound No. 288

Specified in the header connection receive according to the method described in 22, with the replacement of 2,8-dihydroxy-11N-chromeno[4,3-c]chromen-5-it 8-fluoro-2-hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one, and the product is obtained in the form of solids.

MS (m/z): M+H=413, M+Na=435.

EXAMPLE 165

2-(tert-Butyldimethylsilyloxy)-8-fluoro-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, compound No. 205

Specified in the header connection receive according to the method described in 84, with replacement 2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro[1]benzopyrano[4,3-e]benzoxazin-9(1H)-she 2-(tert-butyldimethylsilyloxy)-8-fluoro-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one, and the product is obtained in the form of solids.

MS (m/z): M+H=415, M+Na=437.

<> EXAMPLE 166

2-(tert-Butyldimethylsilyloxy)-9-methyl-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, compound No. 207

Specified in the header connection receive according to the method described in 84, with replacement 2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9(1H)-she 2-(tert-butyldimethylsilyloxy)-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one, and the product is obtained in the form of solids.

MS (m/z): M+N=411, M+ Na=433.

EXAMPLE 167

7-Methoxy-3-(2-methoxyphenyl)-4-methylpropan-2, compound No. 289

Specified in the header connection receive according to the method described in example 1, replacing 2,4-dihydroxyacetophenone and 4-dimethoxyphenylacetic acid commercially available 2,4-dimethoxyacetophenone and 2-methoxyphenylacetic acid, respectively, and receive the product as a yellow solid.

MS (m/z): M+H=297, M+ Na=319.

EXAMPLE 168

3-(2-Methoxyphenyl)-4,6-dimethylamino-2, compound No. 290

Specified in the header connection receive according to the method described in example 1, replacing 2,4-dihydroxyacetophenone and 4-dimethoxyphenylacetic acid 4-methyl-2-hydroxyacetophenone and 2,4-methoxyphenylalanine sour is Oh, respectively, and get the product as yellow solid.

MS (m/z): M+H=281, M+Na=303.

Example 169

2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethanol, compound No. 186

To a transparent solution of 2-(4-iodinase)ethanol (400 mg, 5 EQ.) in THF (10 ml) add isopropylacrylamide (3.0 ml, ˜1.0m, 10 EQ.). After 10 min at 25°add 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol (example 75) (162 mg, 0.30 mmol) in THF (2 ml) and the mixture stirred for 30 min before quenching the reaction mixture of aqueous saturated solution of NH₄Cl. After blanking add EtOAc (200 ml), the organic layer separated and dried over anhydrous Na₂SO₄and concentrate under reduced pressure, thus obtaining the crude oil. The crude oil was dissolved in toluene (10 ml) and then treated with TFA (0,023 ml, 1 EQ.) when 0°C. the Reaction mixture was then diluted with EtOAc (200 ml) and washed with water (200 ml). The organic layer is separated and dried over Na₂SO₄, then concentrate under reduced pressure, thus obtaining the crude oil. This crude oil is purified column flash chromatography, thus obtaining specified in the title compound in the form of foam.

¹H-NMR (CDCl_{3 )7,35˜6,29 (m, 10H), of 6.02 (s, 1H), to 4.62 (t, 2H, J=6.5 Hz), 4,01-a 3.83 (m, 4H), of 2.86 (m, 2H), 0,93 (d, 18H, J=13,7 Hz), 0,17 (d, 12H, J=15.2 Hz)}

_{MS (m/z): MH+ (647), MNa+ (669).}

_{Racemic product, 2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethanol (950 mg), loaded into a column for chiral chromatography ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute with 50% IPA and 50% of hexanol with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.}

_{Peak 1: 5R*-(+)-2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethanol.}

_{[α]D ²⁰=+33,5° (0,30, CHCl3).}

Peak 2: 5S*-(-)-2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethanol.

[α]_D ²⁰=-33,5° (0,36, CHCl₃).

EXAMPLE 170

3-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}propanol-1, connection # 191

By the same procedure as described in example 169, replacing 2-(4-iodinase)ethanol 3-(4-iodinase)propane-1-I (2,78 g, 10 mmol, 5 EQ.) get listed in the title compound as a white solid.

Anal. Calculated for C₃₈H₅₂About Si₂: C 69,05; 7,93, Si, 8,50.

Found: C, 68,68; N, 8,00, Si, 8,90.

¹H-NMR (CDCl₃)7,19 to 6.35 (m, 10H), 5,63 (s, 1H), 4,49 (t, 2H, J=6.6 Hz), 3,99 (m, 2H), 3,66 (m, 2H), 2,42 (m, 2H), 1.93 and (m, 2H), were 0.94 (d, 18H, J=13,7 Hz), 0,16 (d, 12H, J=15.2 Hz).

MS (m/z): MH+ (661)

Racemic product, 3-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}propanol-1-ol (850 mg), loaded into a column for chiral chromatography ChiralPak AD (EXT. the diameter of 5 cm x 50 cm) and elute with 50% IPA and 50% of hexanol with a flow rate of 150 ml/min Two peaks are removed under vacuum, thus obtaining the following enantiomers.

Peak 1: 5R*-(+)-3-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}propan-1-ol.

[α]_D ²⁰=29,5° (0,36, CHCl₃).

Peak 2: 5S*-(-)-3-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}propanol-1-ol.

[α]=-29,5° (0,36, CHCl₃).

EXAMPLE 171

5S*-(+)-1-{2-[4-(2,8-Digidance-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl)phenoxy]ethyl}pyrrolidin-2,5-dione, compound No. 277

Stage A:

To a solution 5S*-(-)-2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethanol (323 mg, 0.5 mmol)obtained, ka is in example 169, and succinamide (49.5 mg) in CH₂Cl₂(5 ml) is added triphenylphosphine (132 mg) and DEAD (0.8 ml) and the reaction mixture is stirred for 12 hours. The reaction mixture was then quenched by adding 50 ml of water and diluted with EtOAc (100 ml). The organic layer is separated and dried over anhydrous Na₂SO₄. Connection purified flash chromatography, thus obtaining 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)pyrrolidin-2,5-dione in the form of solids.

MS (m/z): MN⁺(729); M-N (727).

[α]_D ²⁰=-35,5°, (0,36, CHCl₃).

Stage:

1-(2-{4-[2,8-Bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)pyrrolidin-2,5-dione, obtained as described in stage A (220 mg), dissolved in a mixture of acetonitrile:pyridine (10:1). Add HF·pyridine (0.5 ml) and the reaction mixture is stirred for 12 hours at room temperature. The reaction mixture was quenched with aqueous saturated solution of NaHCO₃(100 ml) and then diluted with ethyl acetate (200 ml). The organic layer was separated and then concentrated under reduced pressure, thus obtaining the crude oil. The crude oil is purified flash chromatography, thus obtaining specified in the title compound in the form of solids.

MS (m/z): MN⁺(500); M-N (48).

EXAMPLE 177

5R*-(+)-1-{2-[4-(2,8-Dimethoxy-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl)phenoxy]ethyl}piperidine, compound No. 300

5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (10 g)obtained in example 145, dissolved in CH₃CN/Meon (3:1) (340 ml). Add TMSCHN₂(2M in hexane, to 30.3 ml) and the mixture is stirred for 36 hours. The reaction mixture is concentrated to dryness and purified on SiO₂using 5% Meon in CH₂Cl₂while this is mentioned in the title compound as a yellow foam.

¹H-NMR (CDCl₃)of 1.40 (m, 2H), 1,59 (m, 4H), 2.49 USD (broad s, 4H), of 2.72 (m, 2H), 2.91 in (m, 2H), 3,71 (s, 3H), of 3.78 (s, 3H), of 4.05 (m, 2H), 4,69 (m, 2H), equal to 6.05 (s, 1H), 6,36˜7,39 (m, 10H)

[α]=+7.2V (c=0,38 g/100 ml CHCl₃, 25°C)

MS (m/z): MH+ (514)

EXAMPLE 178

2-Methoxy-5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol, compound 301, and

8-methoxy-5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, compound 302

5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (10 g), obtained as in example 145, dissolved in CH₃CN/MeOH (3:1) (286 ml). Add 1,1 equivalent is Alanta TMSCHN ₂(2M in hexane, to 10.2 ml) and the mixture is stirred over night. The reaction mixture is concentrated to dryness and purified on SiO₂using 5-10% Meon in CH₂Cl₂while this mixture is listed in the title compounds as a yellow foam.

A mixture of compound (250 mg) is loaded into the column chiral HPLC ChiralPak AD (5 cm (inner diameter)X50 cm (length)) and elute with 15% IPA in hexano with a flow rate of 100 ml/min Two peaks are removed under vacuum, thus obtaining the following listed in the connection header.

Peak 1: 2-methoxy-5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-8-ol

¹H-NMR (DMSO-d₆)1,42 (c, 2H), 1.61 of (c, 4H), 2,41-3,14 (m, 8H), to 3.67 (s, 3H), 4,24 (s, 2H), 4,59 (s, 2H), 6,14˜7,28 (m, 11H)

MS (m/z): MH+ (500)

Peak 2: 8-methoxy-5R*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

¹H-NMR (DMSO-d₆)of 1.41 (broad s, 2H), 1,59 (broad s, 4H), 2,50 (broad s, 4HO), 2,68 (m, 2H), 2,81 (m, 2H), 3,78 (m, 2H), br4.61 (t, 2H, J=6.0 Hz), of 6.02 (s, 1H), 6.22 per˜7,29 (m, 10H)

MS (m/z): MH+ (500)

EXAMPLE 179

8-Hydroxy-11R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, compound 92, and

8-hydroxy-5R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-DIMET propionovoi acid, connection 91