Tetracyclic heterocompounds as estrogen receptor modulating agents

FIELD: organic chemistry, medicine, gynecology.

SUBSTANCE: invention relates to novel tetracyclic heterocompounds of the formula (I): wherein X, Y, Z, R1 - R4, n and m has values given in the invention description and used as selective modulating agents for estrogen receptors. Also, invention relates to a method for synthesis of these compounds and pharmaceutical compositions comprising thereof, and their using in treatment and/or prophylaxis of disorders mediated by one or more estrogen receptors. Proposed compounds are useful in treatment and/or prophylaxis of disorders associated with depleting estrogen and comprising such disorders as rush of blood, vaginal dryness, osteopenia and osteoporosis, hormone-dependent cancer and hyperplasia of breast, endometrium, uterus cervix and prostate, endometriosis, uterus fibroma, osteoarthritis that can be used as contraceptive agents both separately and in combination with progestogen or progestogenous antagonist.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

25 cl, 7 tbl, 171 ex

 

The scope of the invention

This invention relates to new, containing heteroatom tetracyclic derivatives containing these compounds, pharmaceutical compositions, their use in the treatment of disorders mediated by one or more estrogen receptors, and methods of obtaining these compounds. Thus, the compounds according to the invention are useful for the treatment and/or prevention of disorders caused by depletion of estrogens (includes, but not in the manner restrictions, hot flashes, vaginal dryness, osteopenia (violation of osteogenesis), osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain disease, cardiovascular and cerebrovascular diseases); for the treatment of 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, uterine fibroids and osteoarthritis and as contraceptives or separately, or in combination with a progestogen or progestogen antagonist.

Background of the invention

Estrogens are a group of female hormones that are required for the reproductive process and development of the uterus, the mammary glands and other physical changes associated with puberty. Ect is ogeny affect various tissues of the entire female body, not only those who are involved in the reproductive process, such as the uterus, Breasts and genitals, but also on the tissues of the Central nervous system, bones, liver, skin, and urinary tract. The ovaries produce the main part 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 an almost complete cessation of the production of estrogen. The transition in the average age for menopause is characterized by decreased levels of estrogen, which causes both short-term and long-term symptoms associated with impaired vasomotor, urogenital, cardiovascular, skeletal and Central nervous systems, such as hot flushes, urogenital atrophy bodies, an increased risk of developing cardiovascular disease, osteoporosis, cognitive and psychological disorders, including increased risk of cognitive impairment and Alzheimer's disease (AD).

Seventy-five percent of all women experience different manifestations of vasomotor symptoms associated with menopause, such as sweating and hot flashes. Such ailments may start several years before menopause and continue for some women more than 10 years, or relatively constant, or as an instant attack without definite is th, the initiating cause.

Urogenital symptoms associated with menopause, affecting the vagina, include dryness, burning, itching, pain during sexual intercourse, minor bleeding and selection, along with atrophy and stenosis. Symptoms affecting the urinary tract, include burning during urination, frequent urination, recurrent urinary tract infections and incontinence. It is reported that these symptoms experiencing up to 50% of all women in the approaching time of menopause and, more often, for several years after menopause. If left untreated, the problem 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 with premature menopause are at greater risk of coronary disease than women of the same age with menstruation. The presence of serum estrogen has a positive effect on serum lipids. The hormone promotes dilation of blood vessels and increases the formation of new blood vessels. Thus, reduced levels of serum estrogen in women in postmenopausal period leads to negative retomo cardiovascular action. In addition, theoretically, the difference in the ability of blood to coagulate can explain the observed difference in prevalence of heart disease before and after menopause.

The skeleton is characterized by a constant process of degeneration and regeneration of bones, carefully regulated interaction at the level of bone cells. These cells are under the direct influence of estrogen. Estrogen deficiency leads to the rarefaction of the bone structure and reduced bone strength. Fast rarefaction of bone mass in the course of the year following immediately after the onset of menopause, leads to menopausal osteoporosis and increases the risk of fractures.

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 studies indicate the relationship between estrogen, menopause and cognitive ability. In particular, it is reported that estrogensensitive therapy and the use of estrogen women can prevent the development of AD and improve cognitive function.

Hormone replacement therapy (HRT) - more specifically, estrogensensitive therapy (ERT) is usually recommended for problems associated with menopause, as well as helps prevent the trouble of taking the breath of osteoporosis and primary cardiovascular complications such as coronary artery disease), as both a preventive and a therapeutic way. As such, HRT is drug therapy to increase the life expectancy of women in the postmenopausal period and ensure a better quality of life.

ERT effectively reduces menopausal symptoms and symptoms involving urinary systemand,as shown, leads to some success in the prevention and treatment of heart disease in women in postmenopausal period. Reports on clinical trials show that ERT reduces the rate of heart attacks and mortality in groups, held ERT, compared to podobnie groups, but without ERT. ERT taken soon after menopause, can also help preserve bone mass over a number of years. Controlled studies have shown that treatment with ERT gives a positive effect even in older women, under the age of 75 years.

However, there are numerous side effects associated with the use of ERT, which affects that patient conditions and treatment regimens. Venous thromboembolism, gallbladder disease, return of menstruation, mastodinia and a possible increase in the risk of uterine cancer and/or breast cancer are at great risk associated with ERT. Up to 30% of women who prescribed ERT, does not meet vorena appointment, and the percentage of the cessation of ERT is from 38 to 70%, while the most important reasons for termination are concerned about the safety of the method and negative effects (swelling and bleeding in the gaps).

Alternatively, HRT is designed and developed a new class of pharmacological agents known as selective receptor modulators estrogen or SERM. Raloxifene, a nonsteroidal benzothiophene SERM sold in the United States and Europe for the prevention and treatment of osteoporosis under the brand name Evista®. It is shown that raloxifene reduces the bone loss and prevents fractures without exerting harmful stimulating effect on the endometrium and breast cancer, although raloxifene is slightly less efficient than ERT for protection from the rarefaction of the bone. 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 also shows a positive impact as an agonist of estrogen on cardiovascular risk factors, in particular through the rapid and prolonged decline in the levels of total cholesterol lipoprotein and lipoprotein low density in patients treated with raloxifene. In addition, it is established that raloxifene reduces the concentration of homocysteine in plasma, zavisimy the risk factor of atherosclerosis and thromboembolic disease.

However, it is reported that raloxifene exacerbates the symptoms associated with menopause, such as hot flashes and vaginal dryness, and does not improve cognitive function of older patients. It is reported that patients taking raloxifene, are more susceptible to the tides than the receiving placebo and those receiving ERT, and suffer more calf muscle cramps than receiving placebo, whereas in women undergoing ERT noted the high frequency of vaginal bleeding and discomfort of breast cancer than those taking raloxifene or placebo.

It is shown that yet either raloxifene or any other currently available SERM-connection does not have the ability to provide all the existing benefits of ERT, such as controlling of postmenopausal syndrome and prevention of AD, without any side effects, such as increasing the risk of endometrial cancer and breast cancer and bleeding. Thus, there is a need for compounds that are selective modulators of estrogen receptor and provide all the benefits of ERT, being directed also on vasomotor, urogenital and cognitive disease or condition caused by reduced levels of systemic estrogen due to menopause.

Brief description of the invention

The crust is ASEE the invention concerns the compounds of formula (I)

wheremeans simple or double bond,

X is chosen from the group comprising O and S, and Y are selected from the group including CRARB, CRARB(CRARB)1-2(preferably CRARB(CRARB)1-2selected from the group including CRARB(CH2)1-2, -CH2CRARBCH2-, -CRARB-CH(OH)-CRARBor CRARB-CH2-CRARB-), CRARBC(O), CRARBC(O)CRARB(preferably CH2C(O)CH2and C(O); alternatively, Y is chosen from the group comprising O and S, and X is chosen from the group including CRARBand C(O);

provided that when X is S, Y is chosen from the group including CRARB, CRARB(CRARB)1-2and CH2C(O)CH2provided also that when Y represents S, then X is chosen from the group including CRARB;

where each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy; provided that each of RAand RBdoes not mean hydroxy;

Z is chosen from the group comprising O and S;

R1selected from the group comprising hydrogen, alkyl, alkenyl, cycloalkyl, aryl, -C(O)-aryl, aralkyl, heteroaryl and hetero is rilastil, where alkyl, cycloalkyl, aryl, kalkilya, heteroaryl or heteroallyl group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -ORc, -C(O)-ORC, -C(O)O-(alkyl)-NRDRE, -C(O)-NRD-(alkyl)-NRDRE, -C(O)-(heteroseksualci)-NRDRE, -C(O)-(heteroseksualci)-RF, -SO2-NRDRE, -NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF, -O-(alkyl)-OSi(alkyl)3, -O-(alkyl)-ORDor-O-(alkyl)formyl;

where Rcselected from the group including alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and geterotsiklicheskikh where cycloalkyl, cycloalkenyl, aryl, kalkilya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents, which independently is ybiraut from the group includes halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -SO2-NRDRE, NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF;

where Q is chosen from the group comprising O, S, NH, N(alkyl) and-CH=CH-;

where each of RDand REindependently selected from the group comprising hydrogen and alkyl; alternatively, RDand REtogether with the nitrogen atom to which they are attached, form a 3-10-membered, preferably 4-to 8-membered ring which is selected from the group including heteroaryl or heteroseksualci, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, oxo, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where RFselected from the group comprising hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and geterotsiklicheskikh where cycloalkyl, rilina, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

R2selected from the group comprising 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 which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -ORc, -C(O)-Rc, -C(O)O-(alkyl)-NRDRE, -C(O)-NRD-(alkyl)-NRDRE, -C(O)-(heteroseksualci)-NRDRE, -C(O)-(heteroseksualci)-RF, -SO2-NRDRE, -NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF, -O-(alkyl)-OSi(alkyl)3, -O-(alkyl)-ORD or-O-(alkyl)formyl;

alternative, R1and R2together with the carbon atom to which they are attached form C(O),

provided that when R1and R2together with the carbon atom to which they are attached form C(O) and X is chosen from the group comprising O and S, then Y is chosen from the group including CRARB, CRARB(CRARB)1-2, CRARBC(O) and CH2C(O)CH2,

provided that when R1and R2together with the carbon atom to which they are attached form C(O) - and Y is chosen from the group comprising O and S, then X is chosen from the group including CRARB;

n means an integer that is chosen in the range from 0 to 4;

each of R3independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -SO2N(RG)2, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG,

where each of RGindependently selected from the group comprising 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 which are independently selected from the group on the waiting alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

alternatively, two RGgroup together with the nitrogen atom to which they are attached, form geterotsyklicescoe group, where heterocytolysine group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

m means an integer that is chosen in the range from 0 to 4;

each of R4independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG-OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -SO2N(alkyl)2, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG;

provided that whenmeans a double bond, X is CH2Y means O, Z denotes O and R1and R2together with the carbon atom to which they are attached form C(O), then at least one of n or m means an integer that is chosen in the range from 1 to 4, preferably n is an integer from 1 to 4 and m is an integer from 1 to 4;

provided also that when means of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen and R2means alkyl, then at least one of n or m means an integer that is chosen in the range from 1 to 4, preferably n is an integer from 1 to 4 and m is an integer from 1 to 4;

provided also that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen, R2means alkyl, n is 1 and m is 1, R3and R4other than methoxy or ethoxy, preferably R3and R4other than alkoxy;

provided also that whenmeans a double bond, X is O, Y represents CH2Z denotes O, R1and R2together with the carbon atom to which they are attached form C(O), n is 0 and m is 2, each R4different from hydroxy or alkoxy,

or its pharmaceutically acceptable salt.

The present invention also relates to the compounds of formula (D)

wheremeans simple or double bond,

A is chosen from the group comprising O and S;

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

each of R10and R11independently selected from the group comprising hydrogen, halogen, hydroxy, alkyl, replacement 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 the alkyl group either by itself or as part of a bóa larger group of substituents, optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, halogen or phenyl, where the aryl group either by itself or as part of a bóa larger group of substituents optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, alkoxy or alkoxycarbonyl, provided that not each of R10and R11means hydrogen or hydroxy;

Z is chosen from the group comprising O and S;

n means an integer that is chosen in the range from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt.

In addition, the present invention relates to compounds of the formula (DI)

wheremeans simple or double bond,

X is chosen from the group comprising O and S, and Y are selected from the group including CRARB, CRARB(CRARB)1-2(preferably CRARB(CRARB)1-2selected from the group including CRARB(CH2)1-2, -CH2CRARBCH2-, -CRARB-CH(OH)-CRARBor CRARB-CH2-CRARB-), CRARBC(O), CRARBC(O)CRARB(preferably CH2C(O)CH2and C(O); alternatively, Y is chosen from the group comprising O and S, and X is chosen from the group including CRARBand C(O);

provided that when X is S, Y is chosen from the group including CRARB, CRARB(CRARB)1-2and CH2C(O)CH2;

provided also that when Y represents S, then X is chosen from the group including CRARB,

where each of RAand RBezavisimo selected from the group including hydrogen, hydroxy, alkyl or alkoxy, provided that not each of RAand RBmeans hydroxy;

T is chosen from the group comprising -(aryl)-O-(alkyl)-NRDREand -(aryl)-O-(alkyl)-OH;

n means an integer that is chosen in the range from 0 to 4;

each of R3independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -SO2N(RG)2, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG,

where Rcselected from the group including alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and geterotsiklicheskikh where cycloalkyl, cycloalkenyl, aryl, kalkilya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -SO2-NRDRE, NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4 0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF,

where Q is chosen from the group comprising O, S, NH, N(alkyl) and-CH=CH-,

where each of RDand REindependently selected from the group comprising hydrogen and alkyl, alternative, RDand REtogether with the nitrogen atom to which they are attached, form a 3-10-membered, preferably 4-to 8-membered ring which is selected from the group including heteroaryl or heteroseksualci, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, oxo, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where RFselected from the group comprising hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and geterotsiklicheskikh where cycloalkyl, aryl, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, Ala the laminitis, dialkylamino, nitro or cyano;

where each of RGindependently selected from the group comprising 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 which are independently selected from the group including alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

alternatively, two RGgroup together with the nitrogen atom to which they are attached, form geterotsyklicescoe group, where heterocytolysine group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

m means an integer that is chosen in the range from 0 to 4;

each of R4independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -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 also concerns a method for obtaining connected the formula I (DX)

wheremeans simple or double bond,

X is chosen from the group comprising O and S;

p is an integer that is chosen in the range from 0 to 2;

each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy, provided that not each of RAand RBmeans hydroxy;

Z is chosen from the group comprising O and S;

n means an integer that is chosen in the range from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt,

including

interaction correspondingly substituted of compounds of formula (VIII)are known compounds or compounds obtained by known methods, where Pg10means a protective group, with an organic base selected from the group including NaHMDS, LiHMDS, KHMDS, LDA go(lower alkyl)aminority, leading to the formation of the corresponding compounds of formula (C), where V denotes the corresponding base cation;

the interaction of the compounds of formula (C) with the correspondingly substituted compound of formula (CI), where E is an electrophile and L is a leaving group, resulting in the formation of the corresponding compounds of formula (CII);

unprotect the compounds of formula (CII), leading to the formation of the corresponding compounds of formula (CIII);

the cyclization of the compounds of formula (III), leading to the formation of the corresponding compounds of formula (DX).

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

wheremeans simple or double bond,

X is chosen from the group comprising O and S;

U is chosen from the group comprising hydrogen and alkyl;

each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy, provided that not each of RAand RBmeans hydroxy;

Z is chosen from the group comprising O and S;

n means an integer that is chosen in the range from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt,

including

interaction correspondingly substituted of compounds of formula (VIII)are known compounds or compounds obtained by known methods, where Pg10means a protective group, with an organic base selected from the group including NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)aminority, leading to the formation of the corresponding compounds of formula (C), where V denotes the corresponding base cation;

the interaction of the compounds of formula (C) with appropriately substituted aldehyde, a compound of formula (CIV), leading to the formation of the corresponding compounds of formula (CV);

unprotect the compounds of formula (CV), leading to the formation of the corresponding compounds of formula (CVI);

the cyclization of the compounds of formula (CIVI), causing the second to the formation of the corresponding compounds of formula (DXI).

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

wheremeans simple or double bond,

X is chosen from the group comprising O and S;

Pg1means a protective group which is selected from the group comprising alkyl, allyl, benzyl, benzoyl, SEM, MOM, BOM, and pivaloyl;

V denotes the cation of the base, which is chosen from the group comprising Li, Na and K;

each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy, provided that not each of RAand RBmeans hydroxy;

Z is chosen from the group comprising O and S;

n is an integer from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt,

including

interaction correspondingly substituted of compounds of formula (VIII), the local connection or the connection obtained by known methods, where Pg1takes values above, with an organic base selected from the group including LiHMDS, LDA, NaHMDS, KHMDS, and di(lower alkyl)aminority, leading to the formation of the corresponding compounds of formula (C).

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

An illustrative example 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 above compounds and a pharmaceutically acceptable carrier. The illustration of the invention is a method of obtaining a pharmaceutical composition comprising mixing any of the above compounds and a pharmaceutically acceptable carrier.

A typical example of the invention are methods of treating disorders mediated by one or more estrogen receptors, in need thereof of a patient, comprising the administration to a patient a therapeutically effective amount of any of the above compounds or the above pharmaceutical compositions.

The illustration of the invention is a method of contraception, including the introduction in need of such joint therapy pale is that therapeutically effective amounts of compounds of formula (I) together with a progestogen or progestogen antagonist.

Another example of the invention is the use of any of the compounds described herein in order to obtain drugs for treating disorders, comprising (a) tides, (b) vaginal dryness, (c) osteopenia (d) osteoporosis, (e) hyperlipidemia, (f) loss of cognitive function, (g) degenerative disease of the brain, (h) cardiovascular disease, (i) cerebrovascular disease, (j) breast cancer, (k) endometrial cancer, (I) cervical cancer (m) prostate cancer, (n) benign prostatic hyperplasia, (o) endometriosis, (p) uterine fibroids, (q) osteoarthritis and (r) for contraception in need of this patient.

Detailed description of the invention

The present invention concerns the compounds of formula (I)

whereX, Y, Z, R1, R2, n, R3, m, and R4take the above values

useful for the treatment and/or prevention of disorders mediated by estrogen receptor. In particular, the compounds of the present invention are useful for the treatment and/or prevention of disorders mediated by estrogen receptors-α and estrogen-β. More preferable compounds of the present invention are tissue selective modulators of estrogen receptors.

Connection nastojasih the invention is also useful for the treatment and/or prevention of disorders, includes impairments caused by depletion of estrogen-sensitive hormones cancer and hyperplasia, endometriosis, uterine fibroids, osteoarthritis, as well as contraceptive devices separately or in combination with a progestogen or progestogen antagonist.

In particular, the compounds of the present invention are useful for the treatment and/or prevention of conditions or disorders selected from the group including hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain disease, 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 prostatic hyperplasia, endometriosis, uterine fibroids and osteoarthritis, and as a method of contraception. Preferably disorders are selected from the group including osteoporosis, hot flashes, 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, it is understood that the two possible orientations of groups with equal probability included in the definition of compounds of formula (I).

In those compounds of formula (I)where Y represents CRARB C(O), the group included in the structure of the nucleus, so that the carbonyl group is linked to the atom X.

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

whereA , D, Z, R10, R11, n, R12, m, and R13take the above values, useful as intermediates in obtaining the compounds of formula (I).

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

whereX, Y, T, n, R3, m, and R4take the above values

useful as intermediates in obtaining the compounds of formula (I).

According to a variant implementation of the present invention represented by the compound of formula (I),

wheremeans simple or double bond,

X is chosen from the group comprising O and S, and Y are selected from the group including CRARB, -CRARB(CH2)1-2, CRARBC(O) C(O); alternatively, Y is chosen from the group comprising O and S, and X is chosen from the group including CRARBand C(O);

provided that when X is S, Y is chosen from the group including CRARBand-CRARB(CH2)1-2; provided that when Y represents S, then X is chosen from the group, what with CR ARB;

where each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy, provided that each of RAand RBdoes not mean hydroxy;

Z is chosen from the group comprising O and S;

R1selected from the group comprising hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaromatic where cycloalkyl, aryl, kalkilya, heteroaryl or heteroallyl group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -ORc, -SO2-NRDRE, -NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF;

where Rcselected from the group including alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and geterotsiklicheskikh where cycloalkyl, cycloalkenyl, aryl, kalkilya, heteroaryl, heteroallyl, Goethe is cycloalkyl or geterotsiklicheskikh group optionally substituted by one or more substituents, are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -SO2-NRDRE, NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF;

where Q is chosen from the group comprising O, S, NH, N(alkyl) and-CH=CH-;

where each of RDand REindependently selected from the group comprising hydrogen and alkyl; alternatively, RDand REtogether with the nitrogen atom to which they are attached, form a 4-8-membered ring which is selected from the group including heteroaryl or heteroseksualci, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where RFselected from the group comprising hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and geterotsiklicheskikh where cycloalkyl the Naya, aryl, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

R2selected from the group comprising hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaromatic where cycloalkyl, aryl, kalkilya, heteroaryl or heteroallyl group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -ORc, -SO2-NRDRE, -NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF;

alternative, R1and R2together with the carbon atom to which they are attached form C(O);

provided that when R1and R2together with the carbon atom to which they are attached, is formed will C(O) and X is chosen from the group including O and S, then Y is chosen from the group including CRARBand CRARB(CH2)1-2;

provided that when R1and R2together with the carbon atom to which they are attached form C(O) - and Y is chosen from the group comprising O and S, then X is chosen from the group including CRARB;

n means an integer that is chosen in the range from 0 to 4;

each of R3independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, SO2, -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -SO2N(RG)2, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG;

where each of RGindependently selected from the group comprising 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 which are independently selected from the group including alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

alternatively, two RGgroup together with the nitrogen atom to which they are attached, form geterotsyklicescoe group, where heterocytolysine group is not necessarily ameena one or more substituents, are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

m means an integer that is chosen in the range from 0 to 4;

each of R4independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, SO2, -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG-OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -SO2N(alkyl)2, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG;

provided that whenmeans a double bond, X is CH2Y means O, Z denotes O and R1and R2together with the carbon atom to which they are attached form C(O), then at least one of n or m means an integer that is chosen in the range from 1 to 4; preferably n is an integer from 1 to 4 and m is an integer from 1 to 4;

provided also that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen and R2means alkyl, then at least one of n or m means an integer that is chosen in the range from 1 to 4; preferably n is an integer from 1 to 4 and m is an integer from 1 to 4;

when the CA is ovii also, whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen, R2means alkyl, n is 1 and m is 1, R3and R4other than methoxy or ethoxy, preferably R3and R4other than alkoxy;

provided also that whenmeans a double bond, X is O, Y represents CH2Z denotes O, R1and R2together with the carbon atom to which they are attached form C(O), n is 0 and m is 2, each R4different from hydroxy or alkoxy,

or its pharmaceutically acceptable salt.

According to a variant implementation of the present inventionmeans of the double bond.

According to a variant implementation of the present invention, when X is S, Y is chosen from the group including CRARB, CRARB(CH2)1-2, CRARBC(O)CRARB(preferably CH2C(O)CH2and CH2CH2CH2; preferably Y represents CRARBor CRARB(CH2)1-2. In another variant implementation of the present invention, when Y represents S, then X is CRARB. According to another variant implementation of the present invention Y is chosen from the group comprising-CRA B-CH2-, -CH2CRARBCH2-, -CRARB-CH(OH)-CRARB- and-CRARB-CH2-CRARB-.

According to a variant implementation of the present inventionmeans a double bond, X is Oh, Z denotes O and Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(lower alkoxy)-, -CH(OH)-, -CH(lower alkyl)-, -CH2C(O)-, -CH2C(O)CH2- and-CH2CH(OH)CH2-; preferably Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH2CH2CH2, -CH(OCH3)-, -CH(OH)-, -CH(CH(CH3)2)-, -CH2C(O)-, -CH2C(O)CH2and CH2CH(OH)CH2-; more preferably Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(OCH3)- and-CH(OH)-; more preferably, Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH2CH2CH2- , and-CH(OH).

In another variant implementation of the present inventionmeans a double bond, X is Oh, Z denotes O and Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH(lower alkoxy)-, -CH(OH)-, -CH(lower alkyl)- and-CH2C(O)-; preferably Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH(OCH3)-, -CH(OH)-, -CH(CH(CH3) )- and-CH2C(O)-; more preferably Y is chosen from the group comprising-CH2-, -CH(OCH3)- and-CH(OH)-; most preferably Y is chosen from the group comprising-CH2- , and-CH(OH)-.

An embodiment of the present invention are the compounds of formula (I), where X is O, Y represents CRARBand Z denotes o to Another embodiment of the present invention are the compounds of formula (I), where X is CRARBY means O, and Z denotes o to Another embodiment of the present invention are the compounds of formula (I), where X is O, Y represents CRARBC(O) -, and Z denotes o to another embodiment of the present invention are the compounds of formula (I), where X is Oh, Z denotes O and Y represents-CH2C(O)CH2-. Another embodiment of the present invention are the compounds of formula (I), where X is O, and Z denotes O and Y is chosen from the group comprising-CH2-, -CH2CH2- and-CH2CH2CH2-.

According to a variant implementation of the present invention X is chosen from the group comprising O and S, preferably X is O. In another variant implementation of the present invention Y is chosen from the group comprising O and S, preferably Y represents O. Preferably Z means O.

According to a variant implementation of the present invention X represents CRA RB. In another variant implementation of the present invention Y is selected from the group including CRARB, CRARBCH2and CRARBC(O).

According to a variant implementation of the present invention, each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl and alkoxy, provided that not each of RAand RBmeans hydroxy. According to a preferred variant implementation of the present invention, each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, isopropyl and methoxy, provided that both RAand RBthat does not mean hydroxy. According to another variant implementation of the present invention, each of RAand RBindependently selected from the group including hydrogen, hydroxy and methoxy.

According to a variant implementation of the present invention R1selected from the group including hydrogen, lower alkyl, lower alkenyl, aryl, -C(O)-aryl, aralkyl, heteroaryl and heteroaryl-(lower alkyl), where lower alkyl, aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO2, NO2CN, -C(O)-(lower al the Il), CO2H, Rc, -SO2-NRDRE, -NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)NRDRE, -C(O)O-(lower alkyl)-NRDRE, -C(O)-NH-(lower alkyl)-NRDRE, -C(O)-(N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom))-NRDRE, -C(O)-(N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom))-RF, -(alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF, -O-(lower alkyl)-OSi(lower alkyl)3, -O-(lower alkyl)-ORDor-O-(lower alkyl)formyl.

According to a variant implementation of the present invention R1selected from the group comprising hydrogen and lower alkyl, preferably R1selected from the group comprising hydrogen and methyl. In another variant implementation of the present invention R1means hydrogen.

According to a variant implementation of the present invention R1means hydrogen and R2is R-stereoconfiguration. In another variant implementation of the present invention R1means hydrogen and R2is S-stereoscop the configuration.

According to a variant implementation of the present invention R1selected from the group including hydrogen, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO2, NO2CN, CO2H, Rc, -SO2-NRDRE, -NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF.

Preferably R1selected from the group including hydrogen, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO2, NO2CN, CO2H, Rcor NRDRE.

More before occhialino R 1selected from the group comprising hydrogen and lower alkyl. Even more preferably R1selected from the group comprising hydrogen and methyl.

According to a variant implementation of the present invention Rcselected from the group comprising lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl(lower alkyl), heteroseksualci and heteroseksualci(lower alkyl), where aryl, kalkilya, heteroaryl, heteroaryl(lower alkyl)other, heterocytolysine or heteroseksualci(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -SO2-NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF.

Preferably Rcselected from the group comprising lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl(lower alkyl), heteroseksualci and heteroseksualci(lower alkyl), where aryl, kalkilya, heteroaryl, heteroaryl(and lower the keel)other, heterocytolysine or heteroseksualci(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rcor NRDRE.

More preferably Rcselected from the group comprising lower alkyl and aralkyl. More preferably Rcselected from the group including methyl, isopropyl and benzyl.

According to a variant implementation of the present invention Q is chosen from the group comprising O, S and-CH=CH-. Preferably Q is chosen from the group comprising O and-CH=CH-, more preferably Q means O.

According to a variant implementation of the present invention, each of RDand REindependently selected from the group comprising hydrogen and lower alkyl. In another variant implementation of the present invention RDand REtogether with the nitrogen atom to which they are attached, form a 4-8-membered ring which is selected from the group including heteroaryl or heteroseksualci, where heteroaryl or heterocytolysine group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, NITR is or cyano. According to a variant implementation of the present inventionRDand REtogether with the nitrogen atom to which they are attached, form a 5-6-membered ring which is selected from the group including heteroaryl or heteroseksualci, where heteroaryl or heterocytolysine group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano.

In another variant implementation of the present invention, each of RDand REindependently selected from the group comprising hydrogen, methyl, ethyl and isopropyl.

According to another variant implementation of the present invention RDand REtogether with the nitrogen atom to which they are attached, form a 5-6-membered ring which is selected from the group including heteroaryl or heteroseksualci, where heteroaryl or heterocytolysine group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, oxo, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano. Preferably RDand REtogether with the nitrogen atom to which they are attached, form a 5-6-membered ring to which e is chosen from the group includes azepane, morpholinyl, pyridyl, piperidinyl, piperazinil, pyrrolidinyl, piperidinyl-2,6-dione and pyrrolidinyl-2,5-dione.

According to a variant implementation of the present invention RFselected from the group including hydrogen, lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl(lower alkyl), heteroseksualci and heteroseksualci(lower alkyl), where aryl, heteroaryl, heteroaryl(lower alkyl)other, heterocytolysine or heteroseksualci(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano. Preferably RFselected from the group including hydrogen, lower alkyl, aryl and heteroaryl, where aryl optionally substituted with halogen. More preferably RFselected from the group comprising hydrogen, methyl, 4-forfinal and 2-pyridyl.

According to a variant implementation of the present invention R2selected from the group comprising hydroxy, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl)other group optionally substituted by one or two substituents that are independently chosen from the group comprising halo is Yong, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO2, NO2CN, CO2H, Rc, -ORc, SO2-NRDRE, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF.

Preferably R2selected from the group comprising hydroxy, lower alkyl, aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO2, NO2CN, CO2H, Rc, -ORcor-NRDRE.

More preferably R2selected from the group comprising hydroxy, aryl, 4-(1-geterotsiklicheskikh)phenyl,

4-(di(alkyl)aminoethoxy)phenyl, 4-(di(alkyl)amino)phenyl and

4-aralkylamines.

More preferably R2selected from the group comprising 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 comprising 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.

More preferably R2selected from the group comprising phenyl,

4-(1-piperidinyloxy)phenyl, 4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl, 4-(1-separators)phenyl,

4-(diethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl and

4-(dimethylamino)phenyl.

Even more preferably R2selected from the group comprising phenyl, 4-(1-piperidinyloxy)phenyl,

4-(1-pyrrolidinyloxy)phenyl, 4-(4-morpholinoethoxy)phenyl,

4-(1-separators)phenyl, 4-(dimethylaminoethoxy)phenyl and

4-(dimethylamino)phenyl.

According to another variant implementation of the present invention R2selected from the group comprising -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDREand -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)ORF. According to another variant implementation of the present invention R2selected from the group comprising -(alkyl)0-4-(Q)0-1-(al is silt) 0-4-NRDREwhere RDand REtogether with the nitrogen atom to which they are attached, form a 5-7-membered ring, which is selected from the group including heteroaryl and heteroseksualci.

According to another variant implementation of the present invention R2selected from the group comprising hydroxy, lower alkyl, lower alkenyl, aryl, -C(O)-aryl, aralkyl, heteroaryl and heteroaryl(lower alkyl), where lower alkyl, aryl, kalkilya, heteroaryl or heteroaryl(lower alkyl)other group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, -SH, -S(lower alkyl), SO2, NO2CN, -C(O)-(lower alkyl), CO2H, Rc, -ORc, -SO2-NRDRE, -NRDRE, -(alkyl)0-4-C(O)NRDRE, -C(O)O-(lower alkyl)-NRDRE, -C(O)-NH-(lower alkyl)-NRDRE, -C(O)-(N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom))-NRDRE, -C(O)-(N-containing heteroseksualci bound through the N atom))-RF, -(alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDRE(the al is silt) 0-4-C(O)-(alkyl)0-4-C(O)-ORF, -O-(lower alkyl)-OSi(lower alkyl)3, -O-(lower alkyl)-ORDor-O-(lower alkyl)formyl.

Preferably R2selected from the group comprising hydroxy, lower alkenyl, carboxy-lower alkyl, hydroxy-lower alkyl, aryl, 4-(1-N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom))-alkoxy)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-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom))-(lower alkoxy)carbonyl(lower alkyl), (N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom))(lower alkyl)aminocarbonyl(lower alkyl), (N-containing heteroaryl)-(N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom)))-C(O)-(lower alkyl), (halogen-substituted aryl)-(N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom))carboxy(lower alkyl), 4-((N-containing heteroseksualci)(lower alkoxy))phenylcarbamoyl, 2-hydroxy-2-(4-N-containing heteroseksualci-lower alkoxy)phenyl)ethyl, 4-(three(Nissi is 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 comprising 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-separators)phenyl,

4-(diethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl,

R-4-(dimethylaminoethoxide, 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, piperidinylcarbonyl, pyrrolidinylcarbonyl, morpholinylcarbonyl,

dime is a melamine-n-propoxycarbonyl and morpholinylcarbonyl,

morpholinyl-n-propylenecarbonate, pyrrolidinedithiocarbamate,

4-(2-pyridyl)piperazinylcarbonyl,

4-(4-forfinal)piperazinecarboxamide,

4-(piperidinyloxy)phenylcarbinol,

2-hydroxy-2-(4-(piperidinyloxy)phenyl)ethyl,

4-(2-hydroxyethoxy)phenyl, R-4-(2-hydroxyethoxy)phenyl,

S-4-(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-donatacci)phenyl,

S-4-(pyrrolidinyl-2,5-donatacci)phenyl,

R-4-(pyrrolidinyl-2,5-dione-n-propoxy)phenyl, and

S-4-(pyrrolidinyl-2,5-dione-n-propoxy)phenyl.

More preferably R2selected from the group comprising phenyl, 4-(1-piperidinyloxy)phenyl,

R-4-(piperidinyloxy)phenyl, S-4-(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-4-(dimethylaminoethoxy)phenyl,

S-4-(dimethylaminoethoxy)phenyl,

R-4-(diisopropylaminoethyl)phenyl,

S-4-(diisopropylaminoethyl)FeNi is, 4-(dimethylamino)phenyl,

4-(3-hydroxy-n-propoxy)phenyl and 4-(ethoxycarbonylmethoxy).

More preferably R2selected from the group comprising phenyl, 4-(1-piperidinyloxy)phenyl,

R-4-(piperidinyloxy)phenyl, S-4-(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-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 comprising phenyl, 4-(1-piperidinyloxy)phenyl,

R-4-(piperidinyloxy)phenyl, S-4-(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).

According to another variant implementation of the present invention R2choose the group, including aryl, substituted-O-(alkyl)-NRDRE.

Option execute the present invention are compoundsformula (I), where R1and R2together with the carbon atom to which they are attached form C(O).

In another variant implementation of the present invention R1and R2together with the carbon atom to which they are attached form C(O) - and Y is chosen from the group including CRARB, CRARB(CRARB)1-2, CRARBC(O)CH2C(O)CH2and CH2CRARBCH2preferably CRARB, CRARB(CH2)1-2, CRARBC(O) and CH2C(O)CH2. More preferably, R1and R2together with the carbon atom to which they are attached form C(O) - and Y is chosen from the group comprising CH2CH2CH2CH2CH2CH2CH2C(O) and CH2C(O)CH2.

According to a variant of implementation of the present invention, n means an integer that is chosen in the range from 0 to 2. Preferably n is an integer that is chosen in the range from 0 to 1. In another variant implementation of the present invention n is 1.

According to a variant implementation of the present invention, the substituent R3linked 2-position of the ring structure of the nucleus.

According to a variant the imp is in the present invention, R3selected from the group including halogen, hydroxy, Rc, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro, cyano, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -OSi(RG)3, -ORG, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG.

Preferably R3selected from the group comprising hydroxy, Rc, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -OSi(RG)3, -ORG, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG.

More preferably R3selected from the group including halogen, hydroxy, lower alkoxy, three(lower alkyl)silyloxy, -OC(O)-(lower alkyl), -OC(O)-C(phenyl)-OC(O)-(lower alkyl), -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one) and-OC(O)-C(CH3)(CF3)-phenyl. More preferably R3chosen from the group comprising fluorine, hydroxy, methoxy, tert-butyldimethylsilyloxy, -OC(O)-methyl, -OC(O)-tert-butyl, -OC(O)-C(phenyl)-OC(O)CH3, -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one) and-OC(O)-C(CH3)(CF3)-phenyl. Even more preferably R3selected from the group comprising hydroxy, methoxy, and-OC(O)-tert-butyl. More preferably R3selected from the group comprising hydroxy, and-OC(O)-tert-butyl.

According to a variant implementation of the present invention RGselected from the group including hydrogen, lower alkyl (preferred is methyl equipment), 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 that are independently chosen from the group comprising lower alkyl, halogenated lower alkyl, lower alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-(lower alkyl) and-C(O)O-(lower alkyl).

In another variant implementation of the present invention two RGgroup together with the nitrogen atom to which they are attached, form a 5-6-membered geterotsyklicescoe group, where heterocytolysine group optionally substituted by one or two substituents that are independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro or cyano.

Preferably RGselected from the group comprising lower alkyl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one, where kalkilya group optionally substituted by the substituents, which are selected from the group comprising lower alkyl, halogenated alkyl, or-OC(O)-(lower alkyl). More preferably RGselected from the group comprising 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.

According to a variant implementation of the present invention m means celecia, which is chosen in the range from 0 to 2. Preferably m means an integer that is chosen in the range from 0 to 1. In another variant implementation of the present invention m is 1.

According to a variant implementation of the present invention, the substituent R4connected on 8 - or 9 - position of the ring structure of the nucleus.

According to a variant implementation of the present invention R4selected from the group including halogen, hydroxy, Rc, amino, (lower alkyl)amino, di(lower alkyl)amino, nitro, cyano, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -OSi(RG)3, -ORG, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG.

Preferably R4selected from the group comprising hydroxy, Rc, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -OSi(RG)3, -ORG, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG.

More preferably R4selected from the group comprising hydroxy, lower alkyl, lower alkoxy, three(lower alkyl)silyloxy, -OC(O)-(lower alkyl), -OC(O)-C(phenyl)-OC(O)-(lower alkyl), -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one) and-OC(O)-C(CH3)(CF3)-phenyl. More preferably R4selected from the group comprising hydroxy, methyl, methoxy, tert-butyldimethylsilyloxy, -OC(O)-methyl, -OC(O)-tert-butyl, -OC(O)-C(phenyl)-OC(O)CH3, -OC(O)-(1,7,7-trimethyl-2-oxabicyclo]heptane-3-one) and-OC(O)-C(CH 3)(CF3)-phenyl. Even more preferably R4chosen from the group comprising fluorine, hydroxy, methoxy, and-OC(O)-tert-butyl. Even more preferably R4selected from the group comprising hydroxy, and-OC(O)-tert-butyl.

According to a variant implementation of the present inventionmeans simple or double bond,

X is chosen from the group comprising O and S, and Y are selected from the group including CRARB, CRARB(CRARB)1-2(preferably CRARB(CRARB)1-2selected from the group including CRARB(CH2)1-2, -CH2CRARBCH2-, -CRARB-CH(OH)-CRARBor CRARB-CH2-CRARB-), CRARBC(O) and CRARBC(O)CRARB(preferably CH2C(O)CH2); alternatively, Y is chosen from the group comprising O and S, and X is chosen from the group including CRARBand C(O);

provided that when X is S, Y is chosen from the group including CRARB, CRARB(CRARB)1-2and CH2C(O)CH2; provided that when Y represents S, then X is chosen from the group including CRARB;

where each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alcox is; provided that each of RAand RBdoes not mean hydroxy;

Z is chosen from the group comprising O and S;

R1and R2together with the carbon atom to which they are attached form C(O);

provided that when X is chosen from the group comprising O and S, then Y is chosen from the group including CRARB, CRARB(CRARB)1-2,CRARBC(O) and CH2C(O)CH2;

provided also that when Y is chosen from the group comprising O and S, then X is chosen from the group including CRARB;

n means an integer that is chosen in the range from 0 to 4;

each of R3independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG, -OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -SO2N(RG)2, -O-(alkyl)1-4-C(O)RGand-O-(alkyl)1-4-C(O)ORG;

where Rcselected from the group including alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and geterotsiklicheskikh where cycloalkyl, cycloalkenyl, aryl, kalkilya, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted od is them or more substituents, are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), SO2, NO2CN, CO2H, Rc, -SO2-NRDRE, NRDRE, NRD-SO2-RF, -(alkyl)0-4-C(O)-NRDRE, -(alkyl)0-4-NRD-C(O)-RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)-NRDREor -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)-ORF;

where Q is chosen from the group comprising O, S, NH, N(alkyl) and-CH=CH-;

where each of RDand REindependently selected from the group comprising hydrogen and alkyl, alternative RDand REtogether with the nitrogen atom to which they are attached, form a 3-10-membered, preferably 4-to 8-membered ring which is selected from the group including heteroaryl or heteroseksualci, where heteroaryl or heterocytolysine group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, oxo, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where RFselected from the group comprising hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroaromatic, heteroseksualci and hetaerae cycloalkenyl, where cycloalkyl, aryl, heteroaryl, heteroallyl, heterocytolysine or geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

where each of RGindependently selected from the group comprising 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 which are independently selected from the group including alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, -OC(O)-alkyl or-C(O)O-alkyl;

alternative two RGgroup together with the nitrogen atom to which they are attached, form geterotsyklicescoe group, where heterocytolysine group optionally substituted by one or more substituents which are independently selected from the group including halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

m means an integer that is chosen in the range from 0 to 4;

each of R4independently selected from the group including halogen, hydroxy, Rc, amino, alkylamino, dialkylamino, nitro, cyano, -C(O)RG, -C(O)ORG, -OC(O) G, -OC(O)ORG, -OC(O)N(RG)2, -N(RG)C(O)RG, -OSi(RG)3, -ORG, -SO2N(alkyl)2, -O-(alkyl)0-4-C(O)RGand-O-(alkyl)0-4-C(O)ORG;

provided that whenmeans a double bond, X is CH2Y means O, Z denotes O and R1and R2together with the carbon atom to which they are attached form C(O), then at least one of n or m means an integer that is chosen in the range from 1 to 4, preferably n means an integer from 1 to 4, and m means an integer from 1 to 4;

provided also that whenmeans a double bond, X is O, Y represents CH2Z denotes O, R1and R2together with the carbon atom to which they are attached form C(O), n is 0 and m is 2, each R4different from hydroxy or alkoxy,

or its pharmaceutically acceptable salt.

An embodiment of the present invention are the compounds of formula (D), wheremeans simple or double bond,

A is chosen from the group comprising O and S;

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

each of R10and R11independently selected from the group comprising hydrogen, halogen, hydroxy, alkyl, replacement alkyl, alkoxy, -CH(OH)-aryl, -CHO, -C(O)-aryl, -C(O)O-alkyl, -C(O)O-aryl and pivaloyl, provided that not each of R10and R11means hydroxy;

Z is chosen from the group comprising O and S;

n means an integer that is chosen in the range from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

Option execute the present invention are also the compounds of formula (D), where A denotes O, and Z means Acting

According to a variant implementation of the present invention, each of R10and R11independently selected from the group comprising hydrogen, halogen, replacement alkyl, halogen-substituted alkyl, -CHO, -CH(OH)-phenyl, aryl (which aryl group is optionally substituted by hydroxy, alkoxy or alkoxycarbonyl), -C(O)-Ala is l, -C(O)-(halogen-substituted 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. According to a preferred variant implementation of the present invention R10selected from the group comprising hydrogen and bromine, preferably hydrogen, and R11selected from the group including hydrogen, bromine, iodomethyl, chloromethyl, -CHO, -CH2OH, 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.

According to a variant implementation of the present invention, each of R10and R11independently selected from the group comprising hydrogen, halogen, replacement alkyl, -CHO, -CH(OH)-phenyl, -C(O)-phenyl, -C(O)O-alkyl and-C(O)O-phenyl. According to a preferred variant implementation of the present invention R10means hydrogen and R11selected from the group including hydrogen, bromine, -CHO, -CH2OH, CH(OH)CH2CH2CH3, -CH(OH)-phenyl, -C(O)OCH3and-C(O)O-phenyl.

According to a variant implementation of the present invention, each of R12and R13independently selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, aralkylated, SEM Momoki, pivaloyloxy and-OSi(lower alkyl)3. what according to another variant implementation of the present invention, each of R 12and R13independently selected from the group including halogen, hydroxy, methyl, methoxy, ethoxy, isopropoxy, benzoyloxy, SEM Momoki, pivaloyloxy and tert-butyldimethylsilyloxy. According to another variant implementation of the present invention, each of R12and R13independently selected from the group comprising hydroxy, methoxy, ethoxy, isopropoxy, benzoyloxy, SEM Momoki, pivaloyloxy. In another variant implementation of the present invention, each of R12and R13independently selected from the group comprising hydroxy, methoxy, benzyloxy, benzoyloxy, Momoki, SEM, pivaloyloxy.

According to a variant implementation of the present invention D is chosen from the group comprising hydrogen, methyl, methylcarbamyl, benzoyl, SEM, MOM, and pivaloyl. In another variant implementation of the present invention D is chosen from the group comprising hydrogen, methyl, benzoyl, SEM, MOM and pivaloyl.

Option execute the present invention are the compounds of formula (DI), where Y is chosen from the group comprising-CH2- and-CH2CH2-.

Another variant of implementation of the present invention are the compounds of formula (DI), where T is chosen from the group comprising -(aryl)-O-(alkyl)-NRDREand -(aryl)-O-(alkyl)-OH. Preferably T is chosen from the group comprising 4-(piperidinyloxy)phenyl and 4-(3-hydroxyprop-1 yloxy)FeNi is. According to another variant implementation of the present invention T is chosen from the group comprising -(phenyl)-O-(lower alkyl)-NRDRE.

Option execute the present invention is a method for obtaining compounds of formula (DX), are presented in detail below in scheme 16.

Another variant of implementation of the present invention is a method for obtaining compounds of formula (DXI), are presented in detail below in scheme 17.

Another alternative implementation of the present invention is a method for obtaining compounds of formula (C), are presented in detail below in schemes 16 and 17.

Another alternative implementation of the present invention is a method for obtaining compounds of formula (I), including the interaction of the compounds of formula (DX) or the compounds of formula (DXI) according to the method, schematically represented by the following scheme 3, figure 10, figure 12 or figure 15.

Option execute the present invention is a compound obtained by any of these methods.

Salts of the compounds of the present invention for use in medicine refer to non-toxic "pharmaceutically acceptable salts". However, other salts may be useful for producing compounds of the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid-Additiv the haunted salt, which can for example be 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 according to the invention contain an acidic group, suitable pharmaceutically acceptable salts of such compounds may include alkali metal salts, for example 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, specific examples of pharmaceutically acceptable salts include the following: 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, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, N-methylglucamine salt, oleate, pamoa the (embonate), palmitate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannat, tartrate, teoclate, tosylate, triethiodide and valerate.

In the scope of the present invention also includes prodrugs of the compounds of the present invention. In most cases, these prodrugs are functional derivatives of the compounds, which are easily converted toin vivothe desired connection. Thus, in the treatment methods of the present invention, the term "introduction" covers the treatment of these various disorders specific specified connection or a connection that is not related to the number specified, but turning into the connection specifiedin vivoafter the introduction of the patient. Conventional methods of selecting and obtaining suitable as prodrugs derivatives described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

When the compounds of the present invention have at least one chiral center, such compounds can exist as enantiomers. When compounds contain two or more chiral center, such compounds may additionally exist as diastereomers. It is clear 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 can exist in the form of p is limitow and it is implied that such polymorphs are covered by the present invention. In addition, some compounds may form a solvate with water (i.e. hydrates) or common organic solvents, and implied that such a solvate is also included in the scope of the present invention.

As used here, the term "degenerative disease of the brain" includes cognitive disturbance, dementia, regardless of the underlying causes, and Alzheimer's disease.

As used here, the term "cardiovascular disease" includes elevated levels of blood lipids, coronary arthrosclerosis and coronary heart disease.

As used here, the term "cerebrovascular disease" includes abnormal regional cerebral blood flow and cerebral ischemic disorder.

As used here, the term "antagonist POCs includes mifepristone (RU-486), J-867 (Jenapharm/TAP Pharmaceuticals), J-956 (Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638 (Organon), ORG-31806 (Organon), onapristone (ZK98299) and PRA248 (Wyeth).

As used here, unless otherwise noted, "halogen" means chlorine, bromine, fluorine and iodine.

As used here, unless otherwise noted, the term "alkyl"used alone or as part of a group of substituent include linear or branched chain comprising from one to eight carbon atoms. For example, skinnie radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like. Unless otherwise noted, "lower" as applied to alkyl means carbon chain comprising 1-4 carbon atoms. Similarly, the group "-(alkyl)0-4-"either by itself or as part of a large group substituent, means the absence of the alkyl groups or the presence of alkyl groups containing one to four carbon atoms. Suitable examples include, but are not in the order restrictions, -CH2-, -CH2CH2-, CH2-CH(CH3)- ,- CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2- and the like.

As used here, unless otherwise noted, the term "alkenyl" means a carbon chain comprising one to eight carbon atoms and containing at least one double bond. Suitable examples include, but are not in the order restrictions, allyl, crotyl, 2-butenyl, 2-pentenyl and the like. Except where otherwise indicated, "lower", in relation to alkenyl means alkenylphenol carbon chain containing one to four carbon atoms, such as allyl and the like.

As used here, unless otherwise noted, "alkoxy" means simple oxygen ether radical of the above alkyl groups, linear or branched chain. For example, IU is hydroxy, ethoxy, n-propoxy, sec-butoxy, tert-butoxy, n-hexyloxy and the like. Except where otherwise indicated, a "lower" as applied to alkoxy means alkoxygroup (the above simple oxygen ether radical containing one to four carbon atoms. Suitable examples include, but are not in order of limitation, methoxy, ethoxy, isopropoxy, n-propoxy and the like.

As used here, unless otherwise noted, "aryl" means unsubstituted carbocyclic aromatic groups such as phenyl, naphthyl and the like.

As used here, unless otherwise noted, "aralkyl" means any of the lower alkyl group, a substituted aryl group such as phenyl, naphthyl and the like. Suitable examples include, but are not in order of limitation, benzyl, phenylethyl, phenylpropyl, naphthylmethyl and the like.

As used here, unless otherwise noted, the term "cycloalkyl" means any sustainable 3-8-membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used here, unless otherwise noted, the term "cycloalkenyl" means a lower alkyl group, a substituted cycloalkyl group. Suitable examples include, but are not in the order restrictions, cyclohexylmethyl, acropetally, cyclohexylethyl and the like.

As used here, unless otherwise noted, the term "acyloxy" means a radical of the formula-O-C(O)-R, where R is alkyl, aryl or aralkyl, where the alkyl, aryl or aralkyl optionally substituted. As used here, the term "carboxylate" refers to the group of the radical of the formula-C(O)O-R, where R is alkyl, aryl or aralkyl, where the alkyl, aryl or aralkyl optionally substituted.

As used here, unless otherwise noted, "heteroaryl" means the three-decatizing monocyclic or bicyclic aromatic ring structure containing at least one heteroatom chosen from the group comprising O, N and S, optionally containing one to four additional heteroatoms that are independently selected from the group comprising O, N and S. Preferably, the heteroaryl group means a five or six-membered monocyclic aromatic ring structure containing at least one heteroatom chosen from the group comprising O, N and S, optionally containing one three additional heteroatoms that are independently selected from the group comprising O, N and S; or a nine-decatizing bicyclic aromatic ring structure containing at least one heteroatom chosen from the group comprising O, N and S, optionally containing the DIN-four additional heteroatoms, are independently selected from the group comprising O, N and S. the Heteroaryl group may be attached at any heteroatom or carbon atom of the ring so that when it formed a stable structure.

Examples of suitable heteroaryl groups include, but are not in the order restrictions, 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.

As used here, unless otherwise noted, the term "heteroaromatic" means a lower alkyl group, a substituted heteroaryl group. Suitable examples include, but are not in the order restrictions, pyridylmethyl, izohinolinove, triazolylmethyl, purolater and the like.

As used here, the term "heteroseksualci" means the three-decatizing monocyclic or bicyclic, saturated, partially unsaturated or partially aromatic ring structure containing at least one heteroatom chosen from the group comprising O, N and S, optionally terasul one to four additional heteroatoms, are independently selected from the group comprising O, N and S. Preferably heteroseksualci means five-semicolony monocyclic saturated or partially unsaturated ring structure containing at least one heteroatom chosen from the group comprising O, N and S, optionally containing one to three additional heteroatoms that are independently selected from the group comprising O, N and S; or a nine-decatizing saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom chosen from the group comprising O, N and S, optionally containing one to four additional heteroatoms that are independently selected from the group comprising O, N and S. Heterocytolysine group may be attached at any heteroatom or carbon atom of the ring, provided that it forms a stable structure.

Examples of suitable geterotsiklicheskikh groups include, but are not in the order restrictions, pyrrolidyl, 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 is s include morpholinyl, piperidinyl, piperazinil, pyrrolidinyl, azepane and 2-oxabicyclo[2.2.1]heptane.

As used here, unless otherwise noted, the term "geterotsiklicheskikh" means a lower alkyl group, a substituted geteroseksualnoe group. Suitable examples include, but are not in the order restrictions, piperidinylmethyl, piperazinylmethyl, piperazinylmethyl, morpholinylmethyl and the like.

As used here, the term "N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom)" means the above heteroseksualci containing at least one atom of N, which is connected through the specified atom N. Suitable examples include, but are not in the order restrictions, 1-piperidinyl, 4-piperazinil, 1-pyrrolidinyl, 4-morpholinyl, 1-azepane and the like.

As used here, the symbol "*" indicates the presence of a stereogenic center.

When a particular group is "substituted" (e.g., cycloalkyl, aryl, heteroaryl, heteroseksualci), this 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 that are independently chosen from a specified list of deputies. In addition, when kalkilya, heteroallyl, hetero is Clausiliidae or cycloalkenyl group is substituted, Deputy (deputies) can be in any part of the group (i.e. Deputy (deputies) can be 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 these substituents, such substituents may be the same or different from each other.

According to the standard nomenclature used in this description, the first indicates the end part of the designated side chain with subsequent transfer of the adjacent functionality toward the point of connection. For example, the Deputy "panels1-C6alkylaminocarbonyl1-C6alkyl" means a group of the formula

If not mentioned specifically, when the name of the substituents, such as R3and R4group, use the following numbering structure of the nucleus. Capital letters A, B, C and D are used to denote specific rings tetracyclic structure of the kernel.

As used here, the term "leaving group" means a group, leaving the substrate during the interaction, wherein the substrate is cleaved. Suitable examples include, but are not in the order restrictions, Cl, Br, I, tosylate, mesilate, triplet, hydroxy and the like that is.

As used here, the term "electrophile" refers to the atom or molecule, the carrier electron pair. Suitable examples include, but are not in the order restrictions, 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.

Abbreviations used in the description, in particular on the schemes and examples, are as follows:

Ac = Acetyl group (-C(O)-CH3)

AD = Alzheimer's Disease

AIBN = 2,2'-Azobisisobutyronitrile

BF3·Et2O = Apirat boron TRIFLUORIDE

BOM = Benzoyloxymethyl

BOMCl = Benzyloxyethanol

BOMoxy = Benzyloxyaniline (Amoxi)

Bz = Benzoyl

CSA = Camphorsulfonic acid

DCC = 1,3-Dicyclohexylcarbodiimide

DCE = 1,1-Dichloroethane

DCM = Dichloromethane

DEAD = Diethylazodicarboxylate

DIAD = Diisopropylsalicylic

Dibal-H or DIBAL = Diisobutylaluminum

DIC = Diisopropylcarbodiimide

DIPEA or DIEA = Diisopropylethylamine

DMAP = N,N-Dimethylaminopyridine

DMF = Dimethylformamide (DMF)

DTT = Dithiotreitol

ERT = estrogen replacement therapy

Et = Ethyl (i.e.- CH2CH3)

EtOAc = ethyl Acetate

EtOH = Ethanol

FBS = Fetal calf serum

HEPES = 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

HPLC = liquid XP is matography high resolution (IHVR)

HRT = hormone replacement therapy

IPA or iPrOH = Isopropyl alcohol

iPr2NH = Diisopropylamine

LAH = Socialogical

LDA = Sitedisability

LHMDS or LiHMDS, or

(TMS)2NLi, or LiN(TMS)2= Litigationrelated

KHMDS = Caliphaxisindicative

Me = Methyl (-CH3)

MeOH = Methanol

MOM = Methoxymethyl

MOMCl = Methoxymethane

MOMoxy = Methoxyethoxy (Momoki)

NaHMDS = Matrikelstyrelsen

NBS = N-Bromosuccinimide

n-BuLi = n-Utility

nBu3SnH = n-Tributyltinhydride

NCS = N-Chlorosuccinimide

Oac = Acetoxy

OTBS = tert-Butyldimethylsilyloxy

PBS = Phosphate buffer solution

PCC = Pyridineboronic

PDC = Pyridinediamine

Ph = Phenyl

PIV or Piv = Pivaloyl

PMB = para-Methoxybenzyl

P(Ph)3= Triphenylphosphine

PPTS = Pyridine-p-toluensulfonate

Rochelle solution = an Aqueous solution of Rochelle salt (tetrahydrate potassium-sodium tartrate)

SEM = 2-(Trimethylsilyl)ethoxymethyl

SEMCl = 2-(Trimethylsilyl)ethoxymethylene

SEMoxy = 2-(Trimethylsilyl)ethoxymethylene (SEM)

SERM = Selective modulator of estrogen receptor

TBAF = Tetra(n-Butyl)unmonitored

TBDMS = tert-Butyldimethylsilyl

TBS = tert-Butyldimethylsilyl

TBSCl = tert-Butyldimethylsilyloxy

TEA or Et3N = Triethylamine

TFA = Triperoxonane the acid

THF = Tetrahydrofuran (THF)

TIPSCl = Triisopropylsilane

TIPSOTf = Triisopropylbenzenesulfonyl

TMS = Trimethylsilyl

TMSCHN = Trimethylsilyldiazomethane

TPAP = Tetra-n-Propylammonium

TsOH = n-Toluensulfonate acid

The term "patient", as used here, means an animal, preferably a mammal, most preferably a human, comprising the object of treatment, observation or experiment.

The term "therapeutically effective amount", as used here, refers to an amount of active compound or pharmaceutical agent that elicit the biological or therapeutic response in the system tissues, the animal or human body, they expected the researcher, veterinarian, medical doctor or other Clinician, and includes a partial withdrawal symptoms or disorders that cures. Where the present invention relates to a joint therapy, including the addition of one or more compounds of formula I and a progestogen or progestogennoe antagonist, "therapeutically effective amount" will mean that the number of combinations taken together means such that the combined action causes the desired biological or therapeutic response. For example, therapeutically effective the th number in a joint therapy including the introduction of the compounds of formula I and a progestogen, means the amount of the compounds of formula I and the amount of progestogen, which when combined or sequential introduction have a combined therapeutically effective action. Further, the person skilled in the art it is clear that in the case of joint therapy with the use of the above therapeutically effective amount of individually selected number of compounds of formula I and/or the amount of progestogen or progestogennoe antagonist can match or not match therapeutically effective.

As used here, the term "co-therapy" means treatment need in this patient by introducing one or more compounds of formula I and a progestogen or progestogennoe antagonist, where the connection (connection) of the formula I and progestogen or progestogen antagonist is administered by any suitable means, simultaneously, sequentially, separately or in the same pharmaceutical composition. When the connection (connection) of the formula I and progestogen or progestogen antagonist is administered in separate dosage forms, the number of input per day dose of each compound may be the same or different. Connection (connection) of the formula I and progestogen or progestogen antagonist can be in the Eden one and the same, or different routes of administration. Examples of suitable routes of administration include, but are not in order of limitation, orally, intravenously (iv), intramuscular (im), subcutaneous (sc), percutaneous and pryamokishechnye. Connections can be entered directly into the nervous system, including, but not right restrictions, intracerebrally, intraventricularly, intracerebroventricularly, intrathecal, intracisternally, intraspinally and/or peripherally methods of administration for delivery via intracranial or intravertebral needles and/or catheters with or without the aid of the pumping device. Connection (connection) of the formula I and progestogen or progestogen antagonist can be entered during therapeutic course concurrently or sequentially, at the same time or at different times, at the same timein divided or single forms.

It is implied that the term "composition", as used here, covers the product that contains the specific ingredients in specific amounts, and any product resulting, directly or indirectly, from combinations of the specific ingredients in specific amounts.

The compounds of formula (I), where X represents O or S, Y represents CH2and Z denotes O or S, can be obtained by synthesis via the key intermediate sedimentary (II) or (III)

which in turn can be obtained by means schematically shown in schemes 1 and 2.

Scheme 1

More specifically, the correspondingly substituted compound of formula (IV), where Z denotes O or S, a known compound or compound obtained by known methods, is subjected to the interaction with the correspondingly substituted compound of formula (V), where X represents O or S, a 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 elevated temperatures, in the range of about 80 to 120°C, obtaining the corresponding compound of formula (VI).

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

Alternatively, the compound of formula (VI) is subjected to interaction with demetrious reagent, such as piridinkarboksamid, pyridinediamine, predigitized and things under the tion, not necessarily in an organic solvent, such as xylene, acetic acid and the like, at elevated temperatures, in the range from about 170 to 220°C, obtaining the corresponding compound of formula (VII).

The compound of formula (VII) is subjected to interaction with the respectively selected protective reagent, such as acetylchloride, acetic anhydride, 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, dichloroethane and the like, receiving a corresponding compound of formula (VIII), where Pg1means a protective group. For example, when the compound of the formula (VII) is subjected to interaction with acetylchloride or acetic anhydride, Pg1means acetyl group; when the compound of the formula (VII) is subjected to interaction with the benzoyl chloride, Pg1means benzoyloxy group; when the compound of the formula (VII) is subjected to interaction with BOMCl, MOMCl or SEMCl, Pg1means BOM, MOM or SEM, respectively.

When Pg1means acetyl, or the like, the compound of formula (VII) is subjected to interaction with radical brainwashin agent such as NBS, CBrCl3, NaBrO3in combination with NaHSO3and the like, or a radical glorious the m-agent, such as NCS, SO2Cl2, Cl2gas, 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 approximately 50 to 120°C, obtaining the corresponding compound of formula (VIII).

When the compound of the formula (VII) is subjected to interaction with radical brainwashin agent such as NBS, the interaction is carried out in a halogenated organic solvent such as carbon tetrachloride, chloroform, dichloromethane and the like. When the radical pomeroyi reagent means 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 Pg1means benzoyloxy group, pivaloyl, BOM, MOM, SEM or the like, the compound of formula (VII) is subjected to interaction with bromine or a source of bromine, the source for 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 to -78°C, obtaining the corresponding compound of formula (IX).

Remove the protection of the compounds of formula (IX), obtaining the corresponding compound of formula (II). When Pg1means acetyl or benzoyl, protection of the compounds of formula (IX) is removed using a base such as potassium carbonate, sodium carbonate, cesium carbonate and the like, in a solvent such as methanol, ethanol, isopropanol, or mixtures of these solvents, such as methanol : acetone, ethanol : acetone, methanol : acetonitrile, and the like, receiving a corresponding compound of formula (II).

When Pg1means methyl, benzyl, BOM, MOM or SEM, protection of the compounds of formula (IX) is removed using an acid such as TFA, HF, HCl, H2SO4and the like or a Lewis acid such as tin tetrachloride, titanium tetrachloride, trichloride boron, tribromide boron, and the like, or when Pg1means SEM, using an agent to remove the protection, such as LiBF4, TBAF, and the like, in a solvent such as THF, acetonitrile, methylene chloride, chloroform, isopropanol, methanol and the like, at low temperatures in the range of about 0 to 50°C, and then treated with base, such to the to the potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and the like, or an alcoholate of an alkali metal such as sodium ethylate, sodium methylate, tert-butyl sodium, potassium ethylate, potassium methylate, tert-butyl potassium, in a solvent such as methanol, ethanol, isopropanol, THF, or a mixture of these solvents, such as methanol : acetone, ethanol : acetone, methanol : acetonitrile, and the like, receiving a 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 to -78°C, obtaining the corresponding compound of formula (IX).

For the person skilled in the art it is obvious that it may be necessary and/or desirable to protect one or more R3and/or R4groups at any stage of the above method. This can be accomplished by using known protective groups and known reagents and conditions to protect and unprotect, for example, such as described inProtective Groups inOrganic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

The person skilled in the art also understand that the method description the config above scheme 1, can be applied to compounds of the formula (IV) and compounds of formula (V), where R3group (group) substituted by a group (or groups) R12and R4the group (s) substituted by groups R13respectively, where R12and R13take values here, which gives the corresponding compound of formula (IIa)

The compound of formula (IIa) is then optionally may be subjected to interaction by known methods (including, for example, the methods described here) to replace R12and R13group (s) respectively selected, the required groups (group) R3and R4.

The compound of formula (II) can be selectively gidrirovanie 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 of about 20 to 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, receiving a corresponding compound of formula (III) mainly in the form of the CIS isomer.

Alternatively, the compound of formula (III) is subjected to interaction with a hydride, such as LAH, Cu-hydride, Sml2reagent Stryker ([(Ph 3P)CuH]6and the like, in a solvent such as THF, diethyl ether, and the like, at a temperature in the range of about -20 to 60°C, obtaining the corresponding compound of formula (III) mainly in the form of the TRANS-isomer.

Even otherwise, the compound of formula (II) is subjected to interaction with triethylsilane, in the presence of acid, such as TFA, BF3-apirat, alootechie and the like, in an organic solvent such as methylene chloride, toluene and the like, receiving a corresponding compound of formula (III) in the form of a mixture of CIS - and TRANS-isomers.

For the person skilled in the art it is obvious that the method schematically shown above in scheme 2, can be similarly used to obtain compounds of the formula (IIIb)

by replacing the compounds of formula (II) correspondingly substituted compound of formula (IIb)

which is known or obtainable by known methods.

The compounds of formula (I), where X represents O or S, Y represents CRARBand Z denotes O or S, can be obtained from the intermediate compounds of formula (II) according to the method, schematically shown in figure 3.

Scheme 3

Accordingly, the connection forms of the crystals (IIb), well-known compound or compound obtained by known methods, is subjected to the interaction with diisobutylaluminium, L-selectride (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 of about from 0 to -80°C, obtaining the corresponding compound of formula (X).

The compound of formula (X) is subjected to interaction with the correspondingly substituted compound of formula (XII), where MQ denotes 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, which leads to the corresponding compound of formula (XIII).

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

Alternatively, the compound of formula (XIII) is treated with a reagent such as triphenylphosphine, tributylphosphine and the like, or azodicarbon what xamiga, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, receiving a corresponding compound of formula (Ia).

For the person skilled in the art it is obvious that it may be necessary and/or desirable to protect one or more R3and/or R4groups at any stage of the above method. This can be accomplished by using known protective groups and known reagents and conditions to protect and unprotect, for example, such as described inProtective Groups inOrganic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

The person skilled in the art also understand that when the method is schematically presented in the above scheme 3, when Y represents-CH2C(O)CH2and the compound of formula (IIb) is subjected to interaction with containing protective group reagent in order to protect any group of substituent (for example, the group R3or R4), C(O)- CH2C(O)CH2- may also interact with containing protective group reagent with the formation of-CH=C(OPg)CH2-where Pg denotes a protective group. When removing the protection off protection-CH=C(OPg)CH2-getting-CH2C(O)CH2-.

Alternatively, the compound of formula (IIb) in the above scheme 3 is replaced by a compound of the formula (III), obtaining the compound of formula (Ib)

where R2accept above values.

The person skilled in the art it is clear that the compound of formula (Ib), alternatively, can be obtained by selective hydrogenation of correspondingly substituted of compounds of formula (Ia), where Y represents CRARBusing the reagents and conditions described for scheme 2.

The person skilled in the art also understand that the compound of formula (IIb) in the above scheme 3 can be similarly replaced by a compound of the formula (IIIb), which gives the corresponding compound of formula (Iq)

The compounds of formula (I)where one or more R3and/or R4indicate acyloxy can be obtained by the interaction of the correspondingly substituted of compounds of formula (I)where the group (s) R3and/or R4means hydroxy, with appropriately substituted acid chloride, respectively substituted carboxylic acid or substituted anhydride. For example, the compound of formula (I), where R3and R4in 2 - and 8-positions, respectively, indicate acyloxy can be obtained by the method schematically represented in figure 4.

Scheme 4

According to the scheme correspondingly substituted compound of formula (Iaa), obtained according to the scheme (where n denotes 1, R3means hydroxy, m is 1 and R4means hydroxy), is subjected to the interaction with appropriately substituted acid chloride, a compound of formula (XIV), or correspondingly substituted anhydride, a compound of formula (XVI), where RGaccept above values, 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 a hydrocarbon solvent such as benzene, toluene and the like, receiving a 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), where RGthe above values, a known compound or a compound obtained by known methods, in the presence of a binding reagent, such as DCC, DIC, and the like, in an organic solvent, such as DMF, THF, methylene chloride, and the like, receiving a corresponding compound of formula (Ic).

For the person skilled in the art it is obvious that any (any) of the group R3and/or R4ending hydroxy-group, may be subject to podobnoe transformation method, schematically pre is raised above scheme 4. For professionals in this field also it is obvious that when one or more groups R3and/or R4means hydroxy-group-protected silylamines group, such as TBS, the corresponding compound of formula (Ia) is subjected to interaction with tetraalkylammonium, such as TBAF, and the like, and then interact with appropriately substituted acid chloride of formula (XIV) in an organic solvent, such as THF, diethyl ether, and the like, receiving a corresponding compound of formula (Ic).

For the specialist in this field is also clear that the interaction of the compounds of formula (Iaa) from about ≤ 1 equivalent correspondingly substituted of compounds of formula (XIV), correspondingly substituted compounds of formula (XV) or correspondingly substituted of compounds of formula (XVI) will lead to a mixture of compounds, where the group-OC(O)RGturn only R3only R4and as R3and R4. This mixture of compounds is mainly separated by known methods, allocating the requested connection. Further, the interaction of the compounds of formula (Iaa) from about ≥ 2 equivalents correspondingly substituted of compounds of formula (XIV), correspondingly substituted compounds of formula (XV) or correspondingly substituted of compounds of formula (XVI) will lead to the uedineniyu formula (Ic), where the group-OC(O)RGturn both Deputy, R3and R4.

Alternatively, the compound of formula (Iaa) can be replaced by a compound of formula (Iba)(compound of formula (Ib), where n is 1, R3means hydroxy, m is 1 and R4means hydroxy), which is subjected to interaction in the above scheme 4, obtaining the corresponding compound of formula (Id)

For professionals in this field also it is obvious that the above interaction can be used in order to obtain the compounds of formula (I) and (II)where the position of the group R3and R4can be varied within the cycles A and D, respectively, and where the number of groups R3and R4you can vary.

In addition, for the person skilled in the art it is obvious that if desired the presence of various acyloxy in the provisions of R3and R4, alloctype can be sequentially attached to the core structure through the conversion of hydroxy groups according to the above scheme 4, if necessary using a suitable protecting reactive groups and removing the protection.

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

Connect the exclusion of the General formula (XIX) can be obtained according to the method, schematically represented by scheme 5.

Scheme 5

According to the scheme correspondingly substituted compound of formula (XVII), where Pg2means 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 oxidants, such as SeO2, PCC, PDC, and the like, in an organic solvent, such as toluene, xylene, ethyl acetate, dichloromethane and the like, receiving a corresponding compound of formula (XVIII).

The compound of formula (XVIII) further oxidized with an oxidant, such as SeO2, PCC, PDC, and the like, in an organic solvent, such as toluene, xylene, ethyl acetate, dichloromethane and the like, receiving a corresponding compound of formula (XIX).

For the person skilled in the art it is obvious that when the compound of the formula (XVII) is subjected to interaction with 2 or more equivalents of the oxidising agent, the compound of formula (XVII) is converted directly into a compound of formula (XIX) (i.e. there is no need to allocate the intermediate alcohol compound of the formula (XVIII)).

Alternatively, the compound of formula (XIX) can be obtained according to the method, schematically presented in figure 6.

Scheme 6

According to the scheme correspondingly substituted compound of formula (IXa), the compound of formula (IX), where each of RAndand RBmeans hydrogen, where Z denotes O and where Pg1means 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, Cl2gas, 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 approximately 50 to 120°C, obtaining 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, receiving a corresponding compound of formula (XIX).

The compounds of formula (I), where X is O, Y represents CH2or C(O) -, and Z denotes O or S, could the t can be obtained from an intermediate compound of formula (XIX) according to the method, schematically presented in figure 7.

Scheme 7

According to the circuit connection of the formula (XIX) is subjected to interaction with the correspondingly substituted compound of formula (XII), where MQ denotes 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, which leads to the corresponding compound of formula (XXI).

The compound of formula (XXI) is treated with a proton acid, such as HCl, H2SO4p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like or a Lewis acid, such as BF3-apirat, AlCl3, SnCl4and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, receiving a corresponding compound of formula (Ie).

The compound of formula (Ie), optional, can be selectively recovered by using a reducing agent such as LAH/AlCl3and the like, in an organic solvent, such as THF, diethyl ether, dioxane and the like, giving the corresponding compound of formula (If).

For the person skilled in the art it is obvious that it may be necessary and/or desirable to protect one and the and R 3and/or R4groups at any stage of the above method. This can be accomplished by using known protective groups and known reagents and conditions to protect and unprotect, for example, such as described inProtective Groups inOrganic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

For professionals in this field also it is obvious that the compounds (Ie) and/or (If) can be optional, optional selectively gidrirovanny bridge communication cycles B and C, as described previously, using the protection of reactive groups, as necessary, which leads to the corresponding compound of formula (Ig).

Alternatively, the compound of formula (XIX) can be replaced by the appropriate connection that bridge the connection between loops B and C are fully saturated, and then interact in the manner schematically presented in figure 7, receiving a corresponding compound of formula (Ig) or (Ih).

The compounds of formula (I), where X is CRARBY means O, and Z denotes O or S, can be obtained through the synthesis of intermediate compounds of formula (XXIII) and (XXIV)

which, in turn, can be obtained by methods schematice the key presented on figures 8 and 9. Accordingly, the compounds of formula (XXIII), where one or both of RAand RBdifferent from hydrogen, can be obtained according to the method, schematically presented in figure 8.

Scheme 8

According to the scheme correspondingly substituted compound of formula (XXV) is subjected to interaction with an oxidant, such as MnO2PDC, TPAP, and the like, in an organic solvent such as DCM, acetonitrile, DCE, and the like, receiving a corresponding compound of formula (XXVI).

The compound of formula (XXVI) is subjected to interaction with the compound of the formula (XXVII), where MQ denotes 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, which leads to the corresponding compound of formula (XXVIII).

In the compound of formula (XXVIII) to impose protection, interacting with a suitable protecting group, through known chemical transformation, which gives the corresponding compound of formula (XXIX)where Pg3means suitable protective group, such as benzyloxy, methoxy, MOM, SEM, and the like.

Alternatively, the compound of formula (XXVIII) is subjected to interaction with the oxidant, the mayor as MnO 2PDC, TPAP, and the like, in an organic solvent such as DCE, DCM, acetonitrile and the like, receiving a corresponding compound of formula (XXX).

The compound of formula (XXX) is subjected to interaction with the correspondingly substituted compound of formula (XXXI), where MQ denotes 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, which leads to the corresponding compound of formula (XXXII).

The compounds of formula (XXIII), where each of RAand RBmeans hydrogen (i.e. the compounds of formula (XXV)can be obtained by reduction of correspondingly substituted of compounds of formula (XXXIII)

two-stage method. According to the circuit connection of the formula (XXXIII) is subjected to interaction with oxalylamino, in an organic solvent, such as THF, DCM, and the like, and then interact with regenerating agent, such as natrojarosite 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 WMD similar, and then interact with regenerating agent, such as natrojarosite and the like, in an alcohol, such as methanol, ethanol and the like, receiving a corresponding compound of formula (XXIII).

Alternatively, the compound of formula (XXXIII) is transformed into the corresponding compound of formula (XXV), interacting 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 from about -78°C to room temperature.

The compound of formula (XXIV) can be obtained according to the method, schematically presented in figure 9.

Scheme 9

According to the scheme correspondingly substituted compound of formula (XXIII), a known compound or compound obtained by known methods, for example according to the above diagram 8, protects a suitable protecting group by known methods, obtaining the corresponding compound of formula (XXXIV), where Pg4means suitable protective group, such as benzyloxy, methoxy, SEM, MOM, and the like.

The compound of formula (XXXIV) is subjected to interaction with the correspondingly substituted compound of formula (XXXV), a known compound or a compound obtained by known methods, in the presence of organic bases, so the th as LDA, LHMDS, sodium hydride and the like, in an organic solvent, such as diethyl ether, THF and the like, at low temperatures in the range from about -78 to 30°C, obtaining the corresponding compound of formula (XXXVI).

Protection of compounds of formula (XXXVI) is removed by known methods, obtaining the corresponding compound of formula (XXXVII).

The compound of formula (XXXVII) is subjected to interaction with demetrious reagent, such as piridinkarboksamid, pyridinediamine, predigitized and the like, optionally in an organic solvent, such as xylene, acetic acid and the like, at an elevated temperature in the range from about 170 to 220°C, obtaining the corresponding compound of formula (XXIV).

For the specialist in this field is obvious that in order to obtain compounds of formula (I)where one of RAor RBmeans hydrogen, in the manner schematically represented by scheme 9, the compound of formula (XXXIV) can be replaced by a compound of the formula (XXIX).

For professionals in this field also it is obvious that the method is schematically represented by figure 9, when removing the protection of the compounds of formula (XXXVI) with the aim of obtaining the compounds of formula (XXXVII), there is a possibility that the compound of formula (XXXVI) is not completely transformed into a compound of formula (XXXVII), but rather arr is not an 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 RAand/or RBmeans hydrogen, the compound of formula (XXXVIII) is subjected to interaction in the conditions of the Mitsunobu reaction, obtaining the corresponding compound of formula (XXXVII).

Alternatively, if both, RAand RBother than 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 mixtures, such as THF, THF/H2O, dichloromethane, toluene/H2O and the like, receiving a corresponding compound of formula (XXXVII)

which may be subjected to further transformation with the formation of the desired compounds of formula (I) according to the above methods.

The compound of formula (XXIV) is then optionally additionally substituted in position 5 nuclear structure, getting the desired compound of formula (I)according to the method, schematically presented in figure 10.

Scheme 10

More specifically, the correspondingly substituted compound of formula (XXIV) is subjected to interaction with the regenerating agent such as diisobutylaluminium, LAH, and the like, the PR is adicheskim solvent, such as toluene, benzene, THF and the like, at low temperatures in the range of about -50 to -80°C, obtaining the corresponding compound of formula (XXXX).

The compound of formula (XXXX) are oxidized in oxidizing conditions, such as Swern oxidation, in the presence of the reagent Dess-Martin (Dess-Martin periodinane), TPAP, and the like, in an organic solvent, such as dichloromethane, acetonitrile, DCE, and the like, receiving a corresponding compound of formula (XXXXI).

The compound of formula (XXXXI) is subjected to interaction with the correspondingly substituted compound of formula (XII), where MQ denotes 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, which leads to 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, receiving a corresponding compound of formula (Ii).

For the person skilled in the art it is obvious that it may be necessary and/or desirable to protect one or more R3and/or R4groups on any of the stages of Visayas the frame. This can be accomplished by using known protective groups and known reagents and conditions to protect and unprotect, for example, such as described inProtective Groups inOrganic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

When in the compound of formula (Ii) by one or more groups R3and/or R4means hydroxy, hydroxy-group can be optionally converted into the desired group of the above ways, for example by reacting the compounds of formula (Ii) with appropriately substituted acid chloride, respectively substituted carboxylic acid or substituted anhydride as shown in scheme 4.

For the specialist in this field is also apparent that the compound of formula (XXIV), the compound of formula (Ii) or the compound of formula (Ii)where any R3and/or R4hydroxy-group optionally converted into other functional groups can be selectively gidrirovanny on the previously outlined method, which leads to the formation of the corresponding compounds in which the communication bridge group between loops B and C are fully saturated.

The compounds of formula (I), where X is CRARBand Y means S can be obtained by the modification method, schematically presented in schemes 9 and 10. More specifically, with the Association of the formula (XXXVI), obtained according to 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, receiving a corresponding compound of formula (XXXVIa)

The compound of formula (XXXVI) then replace the compound of formula (XXXVIa) and then interact, as described in scheme 9, receiving the corresponding compound of formula (XXIVa)

which, in turn, substituted compound of formula (XXIV) in the method shown in scheme 10, receiving the corresponding compound of formula (I)where Y represents S.

The compounds of formula (I), where X represents O or S, Z denotes O or S and Y represents-CRARBCH2or CRARBCH2CH2where RAand RBother than hydroxy can be obtained by the method, schematically presented in figure 11.

Scheme 11

More specifically, the correspondingly substituted compound of formula (XXXXII), where Pg5means suitable protective group, such as alkyl (such as methyl), benzyl, SEM, MOM, BOM, pivaloyl and the like, a known compound or compound, obtained by the known methods is, subjected to interaction with the correspondingly substituted compound of formula (XXXXIII), where L1means H or alkoxy, such as methoxy, ethoxy and the like, in the presence of a base, such as (TMS)2NLi, LDA, NaHMDS, 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, dioxane and the like, 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, receiving a corresponding compound of formula (XXXXV).

Remove the protection of the compounds of formula (XXXXV) by known methods, obtaining the corresponding compound of formula (XXXXVI).

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

Alternatively, Obedinenie formula (XXXXVI) is treated 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, receiving a corresponding compound of formula (XXXXVII).

The compounds of formula (I), where X is chosen from the group comprising O, Y represents CRARBC(O) -, and Z denotes O or S, can be obtained by the interaction of the correspondingly substituted of compounds of formula (XXXXIV), where L1means phenoxy and where Pg5means SEM or MOM, with acid, such as hydrochloric acid, H2SO4, TFA, and the like, in an organic solvent, such as isopropanol, THF or a mixture of these solvents, such as isopropanol : THF and the like, receiving a corresponding compound of formula (XXXIX)

The compound of formula (XXXIX) are then subjected to further transformation, obtaining the desired compound of formula (I) according to the above methods.

For the person skilled in the art it is obvious that the compound of formula (XXXXVII) may be further subjected to interaction with the corresponding compound of formula (I) or (II) according to the above methods. For example, by replacing the compound of formula (XXXXVII) the compounds of formula (II) in scheme 2 or 3 or replacing the compound of formula (XXXXVII) the compounds of formula (XXIV) in scheme 10.

For when ecialist in this area is obvious, that may be necessary and/or desirable to protect one or more R3and/or R4groups at any stage of the above method. This can be accomplished by using known protective groups and known reagents and conditions to protect and unprotect, for example, such as described inProtective Groups inOrganic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

For professionals in this field also it is obvious that when one or more groups R3and/or R4means hydroxy, hydroxy-group can be optionally converted into the desired group according to the above methods.

For the specialist in this field is also evident that the compounds of formula (I), where connection to a bridge group between loops B and C is unsaturated (i.e. the double bond), can be converted into the corresponding compound of formula (I), where connection to a bridge group between loops B and C is fully saturated (i.e., simple connection), as described above, for example, by selective hydrogenation, for example, gaseous hydrogen using, if necessary, protection of reactive functional groups. Alternatively, the communication bridge group between loops B and C can be selectively gidrirovannah any intermediate connections when the synthetic is E. the compounds of formula (I), provided that the reactive functional group is protected.

The compounds of formula (I), where each of R1and R2different from hydrogen, can be obtained according to the method, schematically presented in figure 12.

Scheme 12

According to the scheme correspondingly substituted compound of formula (XXXXVIII), a known compound or compound obtained by known methods, for example, indicated here by the way, is subjected to the interaction with the correspondingly substituted compound of formula (XXXXIX), where MQ denotes 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, which leads to the corresponding compound of formula (L).

The compound of formula (L) is subjected to interaction with the correspondingly substituted compound of formula (XII), where MQ denotes 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, which leads to the corresponding compound of formula (LI).

The compound of formula (LI) amrabat who provide proton acid, such as HCl, H2SO4p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like or a Lewis acid, such as BF3-apirat, AlCl3, SnCl4and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, receiving a corresponding compound of formula (Ij).

Alternatively, the compound of formula (LI) is treated 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, receiving a corresponding compound of formula (Ij).

The compounds of formula (D) can be obtained from the correspondingly substituted of compounds of formula (VIII), where R3corresponds to R12, R4corresponds to R13and each of RAndand RBmeans 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 subjected to interaction with the respectively selected electrophile, such as alkylhalides, arylamidase, the acid chloride of alkylsilane, methylchloroform, vanillaroma, α-chlorocatechol and the like, receiving a corresponding compound of formula (D).

The compounds of formula (I), where X represents O or S, Z denotes O or S and Y represents-CH2CH 2-can be obtained according to the method, schematically presented in figure 13.

Scheme 13

In more detail, correspondingly substituted compound of formula (LII), where Pg6means suitable protective group such as benzyl, alkyl (such as methyl), SEM, MOM, BOM, substituted benzyl, PMB, and the like, a known compound or compound obtained by known methods, is subjected to the interaction with the correspondingly substituted compound of formula (LIII), where J denotes Cl, Br, iodide or other suitable leaving group and W stands for 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, KHMDS, and the like, receiving a corresponding compound of formula (LIV).

Protection of compounds of formula (LIV) is removed by known methods, for example by treating the 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, receiving a corresponding compound of formula (LV).

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

Alternatively, the compound of formula (LV) is treated 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, receiving a corresponding compound of formula (Ik).

The compounds of formula (I), where X represents O or S, Z denotes O or S and Y represents-CH2CH2CH2-can be obtained according to the method, schematically presented in figure 14.

Scheme 14

In more detail, correspondingly substituted compound of formula (LII), where Pg6means suitable protective group such as benzyl, alkyl (such as methyl), SEM, MOM, BOM, substituted benzyl, PMB, and the like, a known compound or compound obtained by known methods, is subjected to the interaction with the correspondingly substituted compound of formula (LVI), where the two G groups mean leaving group such as Cl, Br, iodide, hydroxy and the like, and where the two G groups are Odinak is new or different, well-known compound or compound obtained by known methods, in the presence of a base, such as (TMS)2NLi, LDA, NaHMDS, KHMDS, and the like, receiving a corresponding compound of formula (LVII).

For the person skilled in the art it is obvious that when the two G groups are different, these groups are chosen so that the relationship G groups with C(O) was more reactive than the relationship G groups with a group of CH2.

Protection of compounds of formula (LVII) is removed by known methods, for example by treating the 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 derivatives of a Lewis acid such as catecholborane, dimethylbenzamide and that podobnie, receiving a 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 an alcoholate of an alkali metal such as sodium ethylate, sodium methylate, tert-butyl sodium, potassium ethylate, potassium methylate, tert-butyl potassium, and the like, in a solvent such as methanol, ethanol, isopropanol, THF, or a mixture of these solvents, such as methanol : acetone, ethanol : acetone, methanol : acetonitrile and the like, receiving a 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, receiving a corresponding compound of formula (Im).

The compound of formula (Im) deoxygenated using the method of Barton or modified Barton way (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 method involves the conversion of alcohol groups of the compounds of formula (Im) to thiocarbonate group, as in compound of formula (LX), with subsequent treatment with tributyltinhydride in the presence of a radical initiator such as benzoyl peroxide, AIBN, and the like), which gives the corresponding compound of formula (In).

For the person skilled in the art it is obvious that the compounds of formula (I), where X represents O or S, Z denotes O or S and Y represents-CRARB-CH(OH)-CRARBor CRARB-CH2-CRARB-can be also obtained by the method, schematically represented above in figure 13, with appropriate substitution of compounds of formula (LII), (LIII) containing suitable substituents of the compounds (LIIa) and (LVIa), respectively.

The compounds of formula (I), where X means Oili S, Y represents CRARBCH2CH2or CH2CH2CH2and Z denotes O or S, can be obtained from the correspondingly substituted of compounds of formula (Xa) in the manner schematically presented in figure 15.

Scheme 15

According to the scheme correspondingly 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, SnCl4, TiCl4Perlina acid and the like, in an organic solvent such as CH2Cl2, CHCl3and the like, receiving a corresponding reactive intermediate compound of formula (LXII).

The compound of formula (LXII) is subjected to interaction with the correspondingly substituted compound of formula (LXIII), where MQ denotes lithium or manygaloherez, such as MgCl, MgBr or MgI (specified 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, which leads to the corresponding compound of formula (Ip).

Alternatively, the compound of formula (LXI) is subjected to interaction with enology ether or allyl reagent such as 1,1-bestemmelse Eloxatin,

1,1-bactrimoralcontraceptives,

(1 methoxybenzyloxy)trimethylsilane, allyltrimethylsilane, allyltrimethylsilane, but-2-entremetier,

but-2-titrimetrically, trimethylphenylammonium and the like, receiving a corresponding compound of formula (Ip).

For the specialist in this field is also evident that the compounds of formula (I), where Y is chosen from the group including CRARB(CRARB)1-2and CRARBC(O)CRARBcan also be obtained by the above methods, by selecting a correspondingly substituted reagents used to replace these compounds.

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

Scheme 16

According to the scheme correspondingly substituted compound of formula (VIII), a known compound or compound obtained by known methods, where RA, RB, n, R3, m, R4and Z agree to the above values, where X represents O or S and where Pg10means suitable protective group, such as alkyl (such as methyl), benzyl, benzoyl, SEM, MOM, BOM, pivaloyl and the like (see, for example,Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene &P.G.M. Wuts,Protective Groups in Orgaic Synthesis , John Wilev & Sons, 1991), is subjected to the interaction with the base, such as LiHMDS, LDA, KHMDS, NaHMDS, and the like, preferably at a temperature below or about equal to room temperature, more preferably at a temperature in the range from about 30 to -100°C, more preferably at low temperature in the range of about -10°C to -30°C, in an aprotic organic solvent such as THF, dioxane, diethyl ether and the like, receiving a corresponding compound of formula (C), where V denotes the corresponding cation of the base, Li, K or Na (i.e., when the base means LiHMDS or LDA, V means Li; when the base means KHMDS, V K means; when the base means NaHMDS, V means Na).

The compound of formula (C) is subjected to interaction with the correspondingly substituted compound of formula (CI), where E is an electrophile (i.e., the atom or the molecule capable of forming a carbon cation or partially carbon cation), such as Br, Cl, I, CH3, SEM, MOM, BOM, Br-CH2CH2-OCH3and the like, and where L2means suitable leaving group such as Cl, Br, I, tosylate, mesilate, and the like, receiving a corresponding compound of formula (CII). The compound of the formula (CI) can also serve as a source of Br or Cl, such as NBS, NCS, and the like.

Protection of compounds of formula (CII) is removed f the mi ( 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 & Sons, 1991), obtaining the corresponding compound of formula (III).

Carry out the cyclization of the compounds of formula (III) by known methods, obtaining the corresponding compound 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 about from 10 to 11, which leads to the corresponding compound of formula DX, where p is 0. When the electrophile E means 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 a Lewis acid, such as BF3-apirat, AlCl3, SnCl4and the like, in a solvent such as toluene, methylene chloride, acetonitrile and the like, with a reagent such as triphenylphosphine, tributylphosphine etc. or azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, receiving a corresponding compound of formula (DX), where p is 1-2.

DL is a specialist in this field is obvious, the compound of formula (C) may be subjected to alternative engagement with the correspondingly substituted compound of formula (CIa), where the electrophile E is-C(O)CH2-OCH3, -C(O)-CH2-Cl, -C(O)-CH2-Br, -C(O)-CH2-(lower alkyl), -CH2-C(O)O-(lower alkyl), giving the corresponding compound of formula (CII), which is then subjected to further interaction with a proton acid, such as HCl, H2SO4p-toluensulfonate acid, camphorsulfonic acid (CSA), TFA, and the like or a Lewis acid, such as BF3-apirat, 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 azodicarboxamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, receiving a corresponding compound of formula (DXa), where the group -(CH2)P- substituted-C(O)-CH2where CH2-the part associated with X.

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

Scheme 17

According to the scheme correspondingly substituted compound of formula (VIII), a known compound or compound obtained by known methods, where R A, RB, n, R3, m, R4and Z agree to the above values, where X represents O or S and where Pg10means suitable protective group, such as alkyl (such as methyl), benzyl, benzoyl, SEM, MOM, BOM, pivaloyl and the like (see, for example,Protective Groups in Organic Synthesis, John Wilev & Sons, 1991), is subjected to the interaction with the base, such as LiHMDS, LDA, KHMDS, NaHMDS, and the like, preferably at a temperature below or about equal to room temperature, more preferably at a temperature in the range from about 30 to -100°C, more preferably at low temperature in the range of about -10 to -30°C, in an aprotic organic solvent such as THF, dioxane, dietilnew ether and the like, receiving a corresponding compound of formula (C), where V denotes the corresponding cation of the base, Li, K or Na (i.e., when the base means LiHMDS or LDA, V means Li; when the base means KHMDS, V K means; when the base means NaHMDS, V means Na).

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

Protection of compounds of formula (CV) is removed 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 & Sons, 1991), obtaining the corresponding compound of formula (CVI).

Carry out the cyclization of the compounds of formula (CVI) according to known methods, obtaining the corresponding compound of formula (DX), where p is 1. In particular, 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 a Lewis acid, such as BF3-apirat, 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 azodicarbonamide, such as DEAD, DIAD, and the like, in a solvent such as toluene, THF and the like, receiving a corresponding compound of formula (DX), where p is equal to 1.

When the means of obtaining the compounds according to the invention lead to 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 by enantiospecific synthesis or by separation. Connections can be, for example, separated into their component enantiomers by standard techniques, such as poluchenierazreshenija pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed fractionated crystallization and regeneration of the free base. Compounds can also be separated by obtaining the diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary ingredient. Alternatively, compounds can be separated using chiral GHUR-column.

When implementing any of the methods of obtaining the compounds of the present invention may be necessary and/or desirable to protect sensitive or reactive groups on any of the examined molecules. This can be accomplished by using known protective groups, such as described inProtective Groups inOrganic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene &P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups can be removed at a convenient subsequent stage by applying known from the prior art methods.

The applicability of the compounds of the present invention for treating disorders mediated by the estrogen receptor, can be estimated according to the methods described herein in the examples, 172, 173, 174 and 175.

The present invention also provides a method of treating disorders mediated by receptor benefit of estrogen is, we need this type of treatment of patients, which includes the introduction of any of the above compounds effective for the violation number. The connection can be injected into a patient by any conventional method of administration, including, but not right limitation, intravenous, oral, subcutaneous, intramuscular, transdermal, and parenteral. The number of compounds effective in the treatment of disorders mediated by the estrogen receptor, is in the range from 0.01 mg to 20 mg per 1 kg of body weight of the patient.

The present invention also relates to pharmaceutical compositions comprising one or more compounds according to this invention together with a pharmaceutically acceptable carrier. Preferably such compositions are presented in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, syringes for seminyaks or suppositories, for oral, parenteral, intranasal, sublingual or rectal injection or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for administration once a week or once a month, for example, in the form of insoluble salts of the active compounds, the th as decanoate, can be adapted to receive delayed drug absorption 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, getting a solid composition prior formulation containing a homogeneous mixture of the compounds of the present invention or pharmaceutically acceptable salts of the compounds. When it is mentioned that such compositions prior formulation is homogeneous, we mean that the active ingredient is evenly distributed throughout the composition so that the composition can easily be subdivided into equally effective dosage forms such as tablets, pills and capsules. Such a solid composition prior formulation is then subdivided into unit dosage forms of the above type containing from about 5 to 1000 mg of the active ingredient of the present invention. The tablets or pills of the new compositions can be coated or otherwise formed with the aim of obtaining dosiro the authorized forms, providing the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter in the form of a shell covering the first specified component. Two components can be separated intersolubility layer, which prevents degradation in the stomach and promotes the intake of an internal component in the duodenum or provides slow release. For such intersolubility layers or shells can be used a variety of material, these 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 invention may be presented for administration orally or by injection include aqueous solutions, syrups with appropriate flavoring and aroma additives, aqueous or oil suspensions and emulsions with appropriate flavoring and aroma additives containing edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elexir and similar pharmaceutical solvents. Suitable dispersing or suspendresume means for aqueous suspensions include synthetic grass is e and natural gums, such as tragakant, juice, acacia, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

A method of treating disorders mediated by the estrogen receptor, described in this invention can also be carried out using a pharmaceutical composition containing any of the above compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition can contain in the range of about 5 to 1000 mg, preferably from 10 to 500 mg, connections, and can be presented in any form suitable for the selected method of administration. Carriers include necessary and inert pharmaceutical excipients, including, but not right restrictions, binders, suspendresume tools, lubricants, corrigentov, sweeteners, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, tablets in capsules, capsules (each form includes formulations of immediate release, timed release and sustained release), granules and powders, and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms intended for parenteral administration include sterile solutions, emulsions and suspensions.

<> Conveniently, the compounds of the present invention can be introduced into the single daily dose, or the total daily dose can be administered in divided doses of 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 solvents or by transdermal patch to the skin, is well known to specialists in this field. With the introduction in the form of a transdermal delivery system receiving doses will, of course, be more continuous than in the periodic scheme.

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 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 tools and dyes. Suitable binders include, but are not in order of limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners corn, natural and synthetic gums, such as juice acacia, tragakant or sodium oleate, sodium stearate, magnesium stearate, benzoate n is sodium, sodium acetate, sodium chloride, and the like. The disintegrators include, but are not in order of limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

Liquid forms may include suspendresume or dispersing the funds with the appropriate taste and aroma, such as synthetic and natural gums, for example tragakant, juice, acacia, methylcellulose, and the like. For parenteral administration requires sterile suspensions and solutions. Isotonic preparations usually contain suitable preservatives, used if necessary intravenous injection.

Compounds of the present invention can also be entered in the form of liposomal delivery systems, such as small manelmellado vesicles, large manelmellado vesicles and multilamellar vesicles. Liposomes can be obtained from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Compounds of the present invention may also be delivered through the use of monoclonal antibodies as individual carriers to which are attached molecule compounds. Compounds of the present invention can also be attached to soluble polymers as carriers for targeted drug delivery. Such polymers can in luceti polyvinylpyrrolidone, the copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylene oxide, polylysin,substituted palmitoylated balance. In addition, the compounds of the present invention can be attached to a class of biodegradable polymers useful for achieving controlled release of drugs, including, for example, polyoxypropylene acid, polishlanguage, polyhydroxyalkanoic acid complex poliorcetes, Polyacetals, policyidreference, polycyanoacrylate and sewn or amphipatic block copolymers of hydrogels.

Compounds of the present invention can also be entered in any of the above compositions in accordance with generally accepted regimen of doses when required for the treatment of disorders mediated by the estrogen receptor.

The daily dose can vary within wide limits, from about 1 to 1000 mg, per adult, per day. Compositions for oral administration are preferably produced in the form of tablets containing 1,0, 5,0, 10,0, 15,0, 25,0, 50,0, 100, 250 and 500 milligrams which the active ingredient that provides the ability symptomatic regulation doses for treatment of the patient. An effective quantity of a drug is usually provided at the level doses about is 0.01 to 20 mg/kg of body weight per day, preferably approximately in the range from 0.1 to 10 mg/kg of body weight per day, and particularly preferably from 0.5 to 10 mg/kg of body weight per day. Connections can be entered for receiving from 1 to 4 times a day.

The optimal dose for injection can easily be installed by a person skilled in the art and will vary depending on the specific compound, the route of administration, strength of the drug, the route of administration and the disease progresses. In addition, factors associated with the particular patient being treated, including the patient's age, weight, diet and time of administration, lead to the need for regulation of the doses.

The following examples are given for better understanding of the invention and is not intended and cannot be considered as limiting the invention set forth in the following claims.

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 boiling temperature under reflux in nitrogen atmosphere for 48 hours. the donkey cooling to room temperature the dark syrupy reaction mixture was poured into ice-cold water (˜ 450 ml). The suspension is viscous, semi-solid product is neutralized by slowly adding to a mixture of solid NaHCO3. The mixture is then left to cure over night. Dark produce a solid product by filtration, washed with water, dried with suction and recrystallized from acetic acid, getting mentioned in the title compound in the form of a crystalline solid ivory. The second part of the substance (0.95 g, 18.3 percent) is recovered from the mother liquor.

TPL 146-148°C.

MS (Cl) m/z 355 (M+H)+

1H NMR (300 MHz, CDCl3): δ 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. the calc. C20H18O6: 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, with the replacement of the reagent, 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): δ 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-DIMET xifei)-7-fluoro-4-methyl-2-oxo-2 H-chromen-7-silt ester

Specified in the header connection receive according to the method described in example 1, with the replacement of the reagent, 2,4-dihydroxyacetophenone, 4-fluoro-2-hydroxyacetophenone.

TPL 156-157°C.

MS (Cl) m/z 315 (M+H)+, 337 (M+Na)+.

1H NMR (300 MHz, CDCl3): δ 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), 3,86 (3H, s), of 3.77 (3H, s), 2,24 (3H, s).

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

Anal. the calc., C18H15About4: C 68,78; N 4,84. Found: C 68,67; N 4,70.

EXAMPLE 4

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

Specified in the title compound obtained as a yellowish-brown foamy solid according to the procedure described in example 1, with the replacement of the reagent, 2,4-dimethoxyphenylacetic acid, 2-benzyloxy-4-methoxyphenylalanine acid.

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

1H NMR (300 MHz, CDCl3): δ 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. the calc. C25H22O5·0.1 g2O: C 74,28; N, 5,54. Found: C 74,10; N 5,38.

EXAMPLE 5

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

p>

A mixture of 3-(2,4-acid)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ether acetic acid obtained in example 1 (0,177 g, 0.5 mmol, 1 EQ.), and dry pyridinecarboxamide (0.9 g, 8,8 mmol, 16 EQ.) stirred and heated on an oil bath to melt at 210°C in a closed nitrogen atmosphere in a tightly closed round-bottom flask for 1 hour. After cooling to room temperature the reaction mixture restitut in the powder with water and the aqueous solution is extracted several times with ethyl acetate, until the latter becomes colorless. The combined organic extracts washed with saturated salt solution, dried (anhydrous sodium sulfate), filtered and evaporated, getting mentioned in the title compound as a pinkish crystalline solid.

TPL 282-283°C.

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

1H NMR (300 MHz, DMCO-d6): δ of 10.47 (1H, users), 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) to 2.13 (3H, C).

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

Anal. the calc., C16H12About5·0,25 H2O: C 66,55; N 4,36. Found: C 66,63; N 4,53.

EXAMPLE 6

3-(2,4-Dihydroxyphenyl)-8-hydroxy-4-methylpropan-2-he

Specified the header connection get method described in example 5, replacing 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)+negative loop 283 (M-H).

1H NMR (300 MHz, DMCO-d6): δ 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), of 6.29 (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 outlined in example 5, replacing 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 ester obtained according to example 3.

TPL 266-268°C.

MS (Cl) m/z 287 (M+H)+, 309 (M+Na)+negative loop 285 (M-H).

1H NMR (300 MHz, acetone-d6): δ 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. the calc., With18H11FO4/0,1 N2O: C 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 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°C for about 20 hours. A control reaction using mass spectrum and thin layer chromatography indicates the presence of the source material, so add an additional amount of acetic acid (4 ml) and hydrochloric acid (3 ml), and stirring and heating continued for another 20 hours. Then the reaction mixture is evaporated to dryness in vacuo and the residue diluted with water. Precipitated in the sediment indicated in the title compound in the form of a pinkish crystalline solid crude product produce by filtration, washed with water and dried. The resulting product is ground to powder with diethyl ether, filtered and washed with additional diethyl ether, getting listed in title product in the form of solids.

TPL 213-214°C.

MS (Cl) m/z 313 (M+H)+; (M-H, negative loop).

1H NMR (300 MHz, DMCO-d6): δ 9,40 (1H, users), 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. the calc., With18H16About5: C 69,22; H 5,16. Found: C 69,42; N 5,18.

EXAMPLE 9

3-Acetoxy-4(7-acetoxy-4-methyl-2-oxo-2 H-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 in example 5, acetic anhydride (2 ml, 20 mmol) and pyridine (0.2 ml, 2.2 mmol) is heated to 70°C in nitrogen atmosphere 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 a foamy mass. Foamy product is crystallized, rubbing foamy mass into a powder with a mixture of ethyl acetate/diethyl ether, giving specified in the header of the product in the form of a crystalline solid beige color.

TPL 145°C.

MS (Cl) m/z 411 (M+H)+, 432 (M+Na)+.

1H NMR (300 MHz, CDCl3): δ 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. the calc., C22H18O8: C 64,39; N 4,42. Found: C 64,16; N To 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 on ucaut according to the method described in example 9, replacing 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-(2,4-dihydroxyphenyl)-8-hydroxy-4-methylpropan-2-he obtained in example 6.

TPL 119-120°C.

MS m/z 369 [(M-AC)+N]+, 411(M+H)+, 433 (M+Na)+.

1H NMR (300 MHz, CDCl3): δ 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. the calc., With18H11FO4·0.1 g2O: C 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, replacing 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-(2,4-dihydroxyphenyl)-7-fluoro-4-methylpropan-2-he obtained in example 7.

TPL 148-149°C.

MS (Cl) m/z 329(M-Ac)+H]+, 371(M+H)+, 393 (M+Na)+.

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

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

Anal. the calc., 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 aslight pink solid by the procedure described in example 9, replacing 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-(2-hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-he obtained in example 8.

TPL 125-126°C.

MS (Cl) m/z 355 (M+H)+.

1H NMR (300 MHz, CDCl3): δ 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. the calc., C20H18O6: 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-2N-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 boiling temperature under reflux in a nitrogen atmosphere, in the presence of a tungsten lamp at 100 watts for 20 hours. A control reaction using MS and TLC indicates the presence of starting material so the reaction mixture is added an additional amount of N-bromosuccinimide (to 0.060 g, 0.34 mmol) and benzoyl peroxide (0,00 g) and the reaction mixture is heated at the boiling point under reflux in nitrogen atmosphere for 2 more hours. The mixture is evaporated to dryness, dissolved in hot dichloromethane and purified column chromatography on silica gel using a mixture of 3% ethyl acetate/hexane as eluent, get listed in title product in the form of yellowish-brown crystalline solid.

TPL 171-172°C.

MS (Cl) m/z 488 (M+H)+, 512 (M+Na)+.

1H NMR (300 MHz, CDCl3): δ 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. the calc., With22H17BrO8: 54,01; N 3,50. Found: 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, replacing 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 ester of acetic acid obtained 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 Chris is alicebraga solids by the method, described in example 13, replacing 3-acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid 3-methoxy-2-(7-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid obtained in example 15.

TPL 132-133°C.

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

1H NMR (300 MHz, CDCl3): δ 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), 2, 09 (3H, s).

IR (KBr): 1785, 1721, 1805, 1564, 1512, 1453, 1289, 1213, 1105 cm-1.

Anal. the calc., C20H17BrO6: C 55,44; N 3,96. Found: C 55,45; N 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, replacing 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 ester of acetic acid obtained 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): δ 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 Hz), 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

The way A

To a stirred solution of 3-(2-hydroxy-4-methoxyphenyl)-7-hydroxy-4-methylpropan-2-it (0,100 g, 0,204 mmol)obtained 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 turns yellow. The solution is stirred for 2 hours, evaporated to dryness, the residue dissolved in water (15 ml) and then acidified with diluted hydrochloric acid to approximately pH 1. Precipitated precipitated yellow solid product produce by filtration, washed with water and dried, obtaining specified in the header of the connection.

TPL >350°C.

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

1H NMR (300 MHz, DMCO-d6): δ 10,65 (1H, users), 9,85 (1H, users), 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. the calc., C16H10O5·0,2 H2O: C 67,23; N 3,67. Found: C 67,31; N 3,55.

EXAMPLE 18

2,8-Dihydroxy-11H-chromeno[4,3-c]chromen-5-he

Connection # 1

Method B

Specified in sagola the EC the product is obtained according to the method described in example 5, replacing 3-(2,4-acid)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-silt ether acetic acid, 2,8-dimethoxy-11H-chromeno[4,3-c]chromen-5-he obtained in example 21.

TPL >360°C.

EXAMPLE 19

2,7-Dihydroxy-11H-chromeno[4,3-c]chromen-5-he

Connection # 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-it 5-acetoxy-2-(8-acetoxy-4-methyl bromide-2-oxo-2H-chromen-3-yl)phenyl ester of acetic acid obtained in example 10.

EXAMPLE 20

8-fluoro-2-hydroxy-11H-chromeno[4,3-c]chromen-5-he

Connection # 37

Specified in the title compound obtained as a yellow solid 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 ester of acetic acid obtained in example 16.

TPL 259-260°C.

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

1H NMR (300 MHz, DMCO-d6): δ 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, s).

And The (KBr): 3341, 1697, 1621, 1506, 1455, 1275, 1110 cm-1.

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

EXAMPLE 21

2,8-Dimethoxy-11H-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)-5-methoxybenzyloxy ether acetic acid obtained in example 15.

TPL 200-201°C.

MS (Cl) m/z 311 (M+H)+, 333 (M+ Na)+.

1H NMR (300 MHz, CDCl3): δ 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. the calc., for C18H14About5: 69,67; N 4,55. Found: 69,42; N 4,54.

EXAMPLE 22

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

Connection # 3

Suspension 2,8-dihydroxy-11H-chromeno[4,3-c]chromen-5-it (0,322 g, 1,1412 mmol, 1 EQ.), obtained 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 paramesh what happens at room temperature in a nitrogen atmosphere for 18 hours. (It is observed 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 a saturated solution of salt. Wash water is re-extracted with hexane. The combined organic extracts are dried (anhydrous sodium sulfate), filtered and evaporated in vacuum, obtaining a yellow solid residue. The solid residue is recrystallized from hexane, getting mentioned 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): 6 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, ), of 0.23 (6H, s).

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

Anal. the calc. for C24H38About5Si2: 65,84; N 7,50. Found: 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 header of the product is obtained as a colourless crystalline solid following the procedure described in example 22, replacing 2,8-dihydroxy-11H-chromeno[4,3-c]chromen-5-it 8-fluoro-2-hydroxy-11H-chromeno[4,3-c]chromen-5-he received the output from example 20.

TPL 197-198°C.

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

1H NMR (300 MHz, CDCl3): δ 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): 1724, 1619, 1503, 1302, 1262, 1173, 832 cm-1.

Anal. the calc., 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-ol

Connection # 4

A solution of 2,8-bis(tert-butyldimethylsilyloxy)-11H-chromeno[4,3-c]chromen-5-it (5,016 g, 9,82 mmol, 1 EQ.) in toluene (525 ml) cooled to -78°C 3-necked round bottom flask of 1 l, equipped with a mechanical stirrer, inlet for nitrogen and addition funnel. To the reaction mixture slowly add toluene solution diisobutylaluminium (19 ml 1.5 M, 28,48 mmol, 2.9 equiv.) maintaining the temperature of the reaction mixture below -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 over anhydrous sodium sulfate, filtered and pariva is t, give crude compound as a yellow solid. The solid product is recrystallized from a mixture (1:1) dichloromethane : hexane, getting listed in 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): δ 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, collapsing to D2O-exchange), a 3.01 (1H, d, J=8,2 Hz, capable of D2O-exchange), 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, cm-1.

EXAMPLE 25

2-(tert-Butyldimethylsilyloxy)-8-fluoro-5,11-dihydrobromide[4,3-c]chromen-5-ol. Connection # 86

Specified in the header of the product is obtained as a colourless crystalline solid following the procedure described in example 24, when replacing 2,8-dihydroxy-11H-chromeno[4,3-c]chromen-5-on 2-(tert-butyldimethylsilyloxy)-8-fluoro-11N-chromeno[4,3-c]chromen-5-he obtained 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): δ 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 is C), 6,48 (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. the calc., C22H23FO4Si·0,4 H2O: C 64,81; N 6,38. Found: C 64,71; N Is 6.19.

EXAMPLE 26

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

In odnogolosy round bottom flask 50 ml dissolve and mix 4-[2-(piperidine-1-yl)ethoxy]iadanza (0.828 g, 2.5 mmol, 3 equiv.) in tetrahydrofuran (10 ml)in an argon atmosphere, and the mixture is cooled to -22°C. After 5 minutes stirring with a syringe ethereal solution isopropylacrylamide (1,244 ml, 2,13 M, to 2.65 mmol, 3 EQ.). Then the reaction mixture is stirred for 2 hours at a temperature of about -22°C. then add tertrahydrofuran ring solution of 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 in example 24, the cooling bath removed and the reaction mixture left to warm to room temperature over night. After approximately 18 hours, the reaction mixture is treated by adding a saturated solution of ammonium acetate (15 ml) and extraction with diethyl ether (2 x 25 ml). The combined organic extracts are washed with NASA the military solution of salt and water, dried with anhydrous sodium sulfate, filtered and evaporated, receiving a viscous semi-solid residue. Specified in the header of the product isolated in the form of a viscous colorless semi-solid foamy mass by chromatography on silica gel, elwira a mixture of 3% methanol/dichloromethane.

MS (Cl) m/z 748 (M+H)+negative loop 716 (M-H).

1H NMR (300 MHz, CDCl3): δ 7,06 (4H, m), 6,62 (2H, d, J=8,4 Hz), 6,45-6,34 (3H, m), 5,38 (1H, users), to 4.81 (2H, users), of 4.05 (2H, t), 2,80 (2H, t), to 2.57 (4H, users), of 1.47 (4H, m)of 1.46 (2H, m)to 0.96 (9H, s)of 0.93 (9H, s)to 0.19 (6H, C)of 0.14 (6H, s).

EXAMPLE 27

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

Specified in the header of the product is obtained according to the method described in example 26, replacing Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium, 4-[2-(azepin-1-yl)ethoxy]phenylmagnesium (get in place of 4-[2-(azepin-1-yl)ethoxy]yogashala and isopropylacrylamide) as a Grignard reagent.

MS (Cl) m/z 732 (M+H)+negative loop 730 (M-H).

1H NMR (300 MHz, CDCl3): δ 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, users), to 4.81 (2H, users), 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)are 0.15 (6H).

EXAMPLE 28

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

Specified in the header connection receive according to the method described in example 26, replacing Grignard reagent, 4-[2-(piperidine-1-yl)ethoxyphenyl]minibrain, 4-[2-(morpholine-1-yl)ethoxyphenyl]minibrain (get in place of 4-[2-(morpholine-1-yl)ethoxy]yogashala and isopropylacrylamide) as a Grignard reagent.

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

1H NMR (300 MHz, CDCl3): δ 7,06-7,02 (4H, m), 6,77 (2H, d, J=7,98 Hz), to 6.43-6,18 (4H, m), 5,67 (1H, users), to 4.81 (2H, users), 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), 0,15 (6H, s).

EXAMPLE 29

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

Specified in the header of the product is obtained according to the method described in example 26, replacing Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium, 4-[2-(pyrrolidin-1-yl)ethoxy]phenylmagnesium (get in place of 4-[2-(pyrrolidin-1-yl)ethoxy]yogashala and isopropylacrylamide) as a Grignard reagent.

MS (Cl) m/z 704 (M+H)+, 726 (M+Na)+; negative loop 702 (M-H).

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

Specified in the header of the product is obtained according to the method described in example 26, replacing Grignard reagent, 4-[2-(piperidine-1-yl)ethoxyphenyl]minibrain, 4-(2-diethylaminoethoxy)phenylmagnesium (get in place of 4-(2-diethylaminoethoxy)yogashala and isopropylacrylamide) as a Grignard reagent.

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

EXAMPLE 31

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

Specified in the header of the product is obtained according to the method described in example 26, replacing Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium, 4-(2-dimethylaminoethoxy)phenylmagnesium (get in place of 4-(2-dimethylaminoethoxy)yogashala and isopropylacrylamide) as a Grignard reagent.

MC (Cl) m/z 678 (M+H)+, 700 (M+Na)+; negative loop 706 (M-H).

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

EXAMPLE 32

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

Specified in the header of the product is obtained according to the method described in example 26, replacing Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium (get in place of 4-[2-(piperidine-1-yl)ethoxy]yogashala and isopropylacrylamide), phenylmagnesium as Grignard reagent.

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

EXAMPLE 33

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

Specified in the header of the product is obtained according to the method described in example 26, replacing Grignard reagent, 4-[2-(piperidine-1-yl)ethoxy]phenylmagnesium (get in place of 4-[2-(piperidine-1-yl)ethoxy]yogashala and Isopropylamine-bromide), 4-(dimethylamino)phenylmagnesium as 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, replacing 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol for 2-(tert-butyldimethylsilyloxy)-8-fluoro-5,11-dihydrobromide[4,3-c]chromen-5-ol obtained in example 25.

MS (Cl) m/z 606 (M+H)+, 648 (M+Na)+negative loop 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

Connection # 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 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 is left to perekanatisya overnight (about 18 hours). The reaction mixture is evaporated to dryness, ground to powder with diethyl ether and the resulting colorless solid product consisting of triphenylphosphine, is removed by filtration. The filtrate is evaporated to dryness, obtaining the OS is atok, which is purified column chromatography on silica gel using 2% methanol in dichloromethane as eluent, get listed in title product as a viscous semi-solid substance.

MS (Cl) m/z 700 (M+H)+.

1H NMR (300 MHz, CDCl3): δ 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, m, 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 # 17

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

MS (Cl) m/z 714 (M+H)+.

1H NMR (300 MHz, CDCl3): δ 7,31 (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), 93 (9H, C)to 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

Connection # 12

Specified in the header of the product is obtained according to the method described in example 35, when replacing 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-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)-2N-chromen-3-yl]-5-(tert-butyldimethylsilyloxy)phenol obtained in example 27.

MS (Cl) m/z 702 (M+H)+.

1H NMR (300 MHz, CDCl3): δ 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, users), 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 at 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, when replacing 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chrome is-3-yl)phenol 5-( tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-pyrrolidin-1 ylethoxy)phenyl]methyl}-2N-chromen-3-yl)phenol obtained in example 29.

MS (Cl) m/z 686 (M+H)+.

1H NMR (300 MHz, CDCl3): δ 7,31 (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, users), 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, when replacing 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-diethylaminoethoxy)phenyl]methyl}-2N-chromen-3-yl)phenol obtained in example 30.

MS (Cl) m/z 688 (M+H)+.

1H NMR (300 MHz, CDCl3): δ 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

Connection # 20

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

MS (Cl) m/z 660 (M+H)+.

1H NMR (300 MHz, CDCl3): δ 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), 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, when replacing 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol 5-(tert-butyldimethylsilyloxy)-2-[7-(tert-buildiers is siloxy)-4-(hydroxyphenyl]methyl)-2 N-chromen-3-yl)]phenol obtained in example 32.

MS (Cl) m/z 573 (M+H)+, (M+Na)+.

1H NMR (300 MHz, CDCl3): δ 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

Crude 5-(tert-butyldimethylsilyloxy)-2-[7-(tert-butyldimethylsilyloxy)-4-[(4-dimethylamino(phenyl)hydroxymethyl]-2N-chromen-3-yl)]phenol obtained in example 33, when trying purification using 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): δ 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

Ukazannyj the title product is obtained according to the method described in example 26, replacing 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol for 2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)-5-terfenol obtained in example 34.

MS(Cl) m/z 588 (M+N)+.

1H NMR (300 MHz, CDCl3): δ 7,30 (2H, d, J=8,67 Hz)6,94 (1H, Ab., 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. Connection # 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 in example 35, in tetrahydrofuran (15 ml) under nitrogen atmosphere add Tetra-n-butylammonium (1 M 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). Precipitated precipitated inorganic salts are removed by filtration and washed with ethyl acetate. The combined organic phases ol myauth saturated aqueous sodium bicarbonate (50 ml), dried (anhydrous sodium sulfate), filtered and evaporated to dryness, to give crude product. The crude product is purified column chromatography on silica gel using a mixture (1:1) of hexane and 10% ammoniagenes of methanol containing 10% ammonium hydroxide, get cleaned specified in the header of the product as a brown foamy solid.

MS (Cl) m/z 472 (M+H)+, 470 (M-N); a negative loop.

1H NMR (300 MHz, d-6 acetone): δ 8,46 (2H, user), from 7.24 (2H, d, d, J=1,93, 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

Connection # 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 in example 36.

MS (Cl) m/z 486 (M+H)+; negative loop 484 (M-H).

1H NMR (300 MHz, d-6 acetone): δ 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=1,14 Hz), of 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

Connection # 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 obtained in example 37.

MS (Cl) m/z 474 (M+H)+; negative loop 472 (M-H).

1H NMR (300 MHz, d-6 acetone): δ 8,58 (2H, user), 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), 6,27 (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, users), 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

Connection # 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]chromium is n-5-yl]phenoxy}ethyl)pyrrolidin, obtained according to example 38.

MS (Cl) m/z 458 (M+H)+; negative loop 456 (M-H).

1H NMR (300 MHz, d-6 acetone): δ 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, user), 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

Connection # 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 in example 39.

MS (Cl) m/z 460 (M+H)+; negative loop 458 (M-H).

1H NMR (300 MHz, d-6 acetone): δ 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, user), 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, user), 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

Connection # 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 in example 40.

MS (Cl) m/z 432 (M+H)+; negative loop 430 (M-H).

1H NMR (300 MHz, d-6 acetone): δ 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, users).

EXAMPLE 50

5-[4-Dimethylaminophenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol

Connection # 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-5-yl]phenoxy}ethyl)piperidine 2.8-bis(tert-butyldimethylsilyloxy)-5-(4-dimethylamino)phenyl-5,11-dihydrobromide[4,3-c]chromen obtained in example 42.

MS (Cl) m/z 388 (M+H)+; negative loop 386 (M-H).

1H NMR (300 MHz, d-5 methanol): δ 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

Connection # 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 in example 41.

MS (Cl) m/z 345 (M+N)+; negative loop 343 (M-H).

1H NMR (500 MHz, acetone-d6): δ 8,49 (1H, users), 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, users), 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

Connection # 46

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-[2,8-bis(tert-butyldimethylsilyloxy)-8-fluoro-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine obtained in example 43.

MS (Cl) m/z 474 (M+H)+; negative loop 472 (M-H).

1H NMR (300 MHz, CDCl3): δ from 7.24 (2H, d, J=at 8.36 Hz), 7,19 (1H, user), of 6.90 (1H, Ab., 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, is), 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, users), to 1.60 (4H, osirm), USD 1.43 (2H, osirm).

EXAMPLE 53

8-Fluoro-11-isopropyl-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-ol

Connection # 47

When cleaning compound obtained in example 52, by the method of column chromatography specified in the title compound is isolated in small quantities as the accompanying non-core component formed from similarvideo predecessor [MS (Cl) m/z 630], present as a minor byproduct in the main component, obtained as described in example 52, which in turn is formed from the precursor formed as a minor side product upon receipt specified in the title compound from example 34 in side reactions with isopropylacrylamide.

MS (Cl) m/z 516 (M+H)+; negative loop 514 (M-H).

1H NMR (300 MHz, CDCl3): δ 7,34 (2H, d, J=8.34 per Hz), 7,03 (1H, Ab., J=8.53 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, users), 2,28 (1H, m)of 1.64 (4H, osirm), of 1.46 (2H, osirm), 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-(piperidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid

Connection # 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 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 about 10 minutes, the reaction mixture becomes transparent. Then to the reaction mixture is added slowly (over a period of time of about 5 minutes) 2,2-dimethylpropionic (i.e. pualeilani, of) 0.157 ml, 1.3 mmol, 3.18 EQ.). Then remove the cooling bath and the reaction mixture left to warm to room temperature over night. Then to the reaction mixture is added a 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 re-extracted with dichloromethane (2x20 ml). The combined 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 as eluent a mixture of 2% methanol/dichloromethane, giving specified in the header of the product in the form of a crystalline solid ivory.

MC (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, users), 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. the calc. With39H45NO7·0,6 H2ABOUT: WITH 73,22; H TO 7.09; N 2,19. Found: 72,25; H 7,06; N Of 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

Connection # 30

STAGE A: 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)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°C add n-utility (2.5 M in hexane, 478 μl,1,19 mmol). The mixture was stirred at -78°C for 0.5 hours. Then to this mixture is added 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he (153mg, 0.30 mmol) in THF (3 ml)obtained in example 22. Then the reaction mixture was stirred at -78°C for 1.5 hours. To this mixture add methylanisole (3 M in diethyl ether, 1 ml, 2,99 mmol) at -78°C and the reaction mixture was AC who're asked at room temperature over night. The reaction is quenched with aqueous NH4Cl and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO4. The solvent is evaporated, give crude product as a yellow oil. The crude product used in 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 earlier stage And, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of concentrated HCl : H2O = 1:2 vol./vol.). 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 drying agent is filtered off and the filtrate concentrated. Flash chromatography using a mixture of ethyl acetate : hexane : CH3OH (containing 1% NH4OH) = 49:49:2 as eluent gives specified in the title compound in the form of low-viscosity oils.

1H NMR (300 MHz, CDCl3): δ 0,80 (s, 30H), 1,72 to 1.76 (m, 4H), 1,7 (s, 3H), 2,59-2,61 (m, 4H), 2,84 (t, 2H, J=5,9 Hz), a 4.03 (t, 2H, J=5,9 Hz), 5,04 (Ab., 2H, JAB=13,8 Hz; ΔνAB=22 Hz), of 6.29 (DD, 1H, J=2,4, 8.6 Hz), 6,41 (d, 1H, J=2.2 Hz), 6,52-to 6.57 (m, 3H), 6,78 (d, 2H, 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) add tetrabutylammonium (1 M in THF, 241.4 M. μl, 0.24 mmol). The mixture is stirred at room temperature for 40 minutes 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, obtaining mentioned in the title compound, which is used in the next stage without additional purification.

MS m/z (M+) = 472,(M-) = 470.

STAGE D: 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.

To a suspension of 5-methyl-5-[4-(2-pyrrolidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained earlier stage C, in dichloromethane (5 ml) (DCM) at 5° C add triethylamine (Et3N) (67 mg, 0.66 mmol) and stirred for 5 minutes Then to the reaction mixture add trimethylacetylchloride (75,7 mg, 0,63 mmol) and the mixture is stirred at room temperature overnight. Then to the reaction mixture is added saturated NaHCO3(10 ml) and the mixture stirred for 1 h Then the reaction mixture is extracted with DCM, washed with saturated salt solution and dried over MgSO4. After removing the drying agent, the solution is concentrated and the resulting residue passed through a short column with silica, elwira 2% methanol in DCM. The solvent is evaporated, getting mentioned in the title compound as a viscous yellow oil.

1H NMR (300 MHz, CDCl3): δ of 1.23 (s, N), 1,72 to 1.76 (m, 4H), of 1.97 (s, 3H), 2,59-2,61 (m, 4H), 2,84 (t, 2H, J=5,9 Hz), a 4.03 (t, 2H, J=5,9 Hz), 5,04 (Ab., 2H, JAB=13,8 Hz; ΔνAB=22 Hz), of 6.29 (DD, 1H, J=2,4, 8.6 Hz), 6,41 (d, 1H, J=2.2 Hz), 6,52-to 6.57 (m, 3H), 6,78 (d, 2H, 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+)=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 ester

Connection # 33

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

To a solution of 1-[2-(4-bromophenoxy)ethyl]azepane (356 mg, 1,19 mmol) in THF (7.5 ml) at -78°C add n-utility (2.5 M in hexane, 466 μl,at 1.17 mmol). The reaction mixture was stirred at -78°C for 0.5 hours. Then added to the mixture of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he obtained in example 22, (149mg, 0.29 mmol) in THF (3 ml) and the reaction mixture stirred at -78°C for 1.5 hours. Then to the mixture add methylanisole (3 M in diethyl ether, 1 ml, 3 mmol) at -78°C and then stirred at room temperature overnight. The reaction is quenched with aqueous NH4Cl and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO4. The remaining solvent is evaporated, give crude specified in 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-butyldimethylsilyloxy)phenol obtained earlier stage And, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml of a mixture of kontsentrirovano what I HCl : H 2O = 1:2 vol./vol.). The reaction mixture was vigorously stirred at room temperature for 1.5 h, 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 dried over MgSO4. The drying agent is filtered off and the filtrate concentrated. Flash chromatography using a mixture of ethyl acetate : hexane : CH3OH (containing 1% NH4OH) = 49:49:2 as eluent gives specified in the title compound in the form of low viscous yellow oil.

1H NMR (300 MHz, CDCl3): δ 0,77 (s, N), 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 (Ab., 2H, JAB=13,8 Hz; ΔνAB=22 Hz), of 6.29 (DD, 1H, J=2,4, 8.6 Hz), 6,41 (d, 1H, J=2.2 Hz), 6,53 (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+)=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) add tetrabutylammonium (1 M in THF, 213 μl, 0.21 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 washed the t saturated salt solution and dried over MgSO 4. The remaining solvent is evaporated and the residue is dried in vacuum for 2 hours at room temperature, obtaining mentioned in the title compound, which is used in 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 ester.

To a suspension of 5-[4-{2-azepin-1 ylethoxy)phenyl]-5-methyl-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained earlier stage C, in dichloromethane (5 ml) (DCM) at 5°C add triethylamine (TEA) (59 mg, 0.59 mmol) and stirred for 5 minutes After which the reaction mixture add trimethylacetylchloride (66,7 mg, 0.55 mmol) and the mixture is then stirred at room temperature for night. Then to the reaction mixture is added saturated NaHCO3(10 ml) and stirred for 1 h, the Reaction mixture is 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, get mentioned in the title compound as a viscous yellow oil.

1H NMR (300 MHz, CDCl3): δ of 1.23 (s, N), 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, 2H, J=6.0 Hz), 5,04 (Ab., 2H, JAB =13,8 Hz; ΔνAB=22 Hz), of 6.29 (DD, 1H, 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).

MC m/z (M+)=668.

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

Connection # 41

STAGE A: 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[4-(2-piperidine-1-ylethoxy)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°C add n-utility (a 1.6 M in hexane, 773 ál,to 1.24 mmol). The reaction mixture was stirred at -78°C for 0.5 hours. Then to the reaction mixture of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he obtained in example 22, (158mg, 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 (3 M in diethyl ether, 1 ml, 3 mmol) at -78°C and the reaction mixture was stirred at room temperature overnight. The reaction is quenched with aqueous NH4Cl and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO 4. The organic layer is concentrated, give crude specified in title product as a yellow oil, which is used in 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-ylethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol obtained earlier stage And, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of concentrated HCl : H2O = 1:2 vol./vol.). The reaction mixture was vigorously stirred at room temperature for 1.5 h, 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 drying agent is filtered off and the filtrate concentrated. Flash chromatography using a mixture of ethyl acetate : hexane : CH3OH (containing 1% NH4OH) = 49:49:2 as eluent gives specified in the title compound in the form of low viscous yellow oil.

1H NMR (300 MHz, CDCl3): δ 0,78 (s, N), 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 (Ab., 2H, JAB=13,8 Hz; ΔνAB=31 Hz), 6,37 (DD, 1H, J=2,4, 8.6 Hz), 6,8 (d, 1H, 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).

MC 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)pyrrolidine (54 mg, 0,076 mmol) in THF (7 ml) add tetrabutylammonium (1 M in THF, 151 μl, 0.15 mmol). The mixture is stirred at room temperature for 40 minutes 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 h at room temperature, obtaining mentioned 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-pyrrolidin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, obtained earlier stage C, in dichloromethane (5 ml) (DCM) at 5°C add TEA (42 mg, 0.42 mmol) and the reaction mixture is stirred for 5 minutes Then to the reaction mixtures and add trimethylacetylchloride (47 mg, 0,39 mmol) and the mixture is stirred at room temperature overnight. Then to the reaction mixture is added saturated NaHCO3(10 ml) and stirred for 1 h the resulting mixture was 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, get mentioned in the title compound as a viscous yellow oil.

1H NMR (300 MHz, CDCl3): δ 1,31 (s, N), 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 (Ab., 2H, JAB=13,8 Hz; ΔνAB=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°C add n-utility (a 1.6 M in hexane, 804 μl,1,29 mmol). The reaction mixture p is remediat at -78° C for 0.5 hours. Then to the reaction mixture of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he obtained in example 22, (164mg, 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 (3 M in diethyl ether, 1 ml, 3 mmol) at -78°C and then stirred at room temperature overnight. The reaction is quenched with aqueous NH4Cl and then the reaction mixture was 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, give crude specified in title product as a yellow oil, which is 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-ylpropionic)phenyl]ethyl}-2H-chromen-3-yl)phenol obtained earlier stage And, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of concentrated HCl : H2O = 1:2 vol./vol.). The reaction mixture was vigorously stirred at room temperature for 1.5 hours the mixture is Then diluted in the Oh 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 ethyl acetate : hexane : CH3OH (containing 1% NH4OH) = 49:49:2 as eluent gives specified in the title compound in the form of low viscous yellow oil.

1H NMR (300 MHz, CDCl3): δ 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 (Ab., 2H, JAB=13,8 Hz; ΔνAB=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) add tetrabutylammonium (1 M 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. 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 su is at vacuum for 2 h at room temperature, getting listed in the title compound, which is used in 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 earlier stage C, in dichloromethane (5 ml) (DCM) at 5°C add Et3N (74,5 mg of 0.74 mmol) and stirred for 5 minutes Then add trimethylacetylchloride (84 mg, 0.70 mmol) and the reaction mixture was stirred at room temperature overnight. Then to the reaction mixture is added saturated NaHCO3(10 ml) and then stirred for 1 h After which the reaction mixture is extracted with DCM, 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 DCM as eluent, get mentioned in the title compound as a viscous yellow oil.

MS m/z (M+H) 668.

1H NMR (300 MHz, CDCl3): δ of 1.30 (s, N)and 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 (Ab., 2H, JAB=13,8 Hz; ΔνAB=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

Connection # 38

STAGE A: 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{1-hydroxy-1-[3-(2-piperidine-1-ylethoxy)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°C add n-utility (2.5 M in hexane, 471 μl,1.18 mmol) and the reaction mixture stirred at -78°C for 0.5 hours. Then to the reaction mixture of 2,8-bis(tert-butyldimethylsilyloxy)-11N-chromeno[4,3-c]chromen-5-he obtained in example 22, (150mg, 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 (3 M in diethyl ether, 1 ml, 3 mmol) at -78°C and then stirred at room temperature overnight. The reaction is quenched with aqueous NH4Cl and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over MgSO4. After removal of the desiccant organic layer conc the Ute, getting wet is listed 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-ylethoxy)phenyl]ethyl}-2H-chromen-3-yl)phenol obtained earlier stage And, dissolved in toluene (8 ml) and treated with diluted HCl (0.4 ml mixture of concentrated HCl : H2O = 1:2 vol./about.) and the reaction mixture is vigorously stirred at room temperature for 1.5 hours Then the reaction mixture was 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 ethyl acetate : hexane : CH3OH (containing 1% NH4OH) = 49:49:2 as eluent gives specified in the title compound in the form of low viscous 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-d is hydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine (34 mg, 0,048 mmol) in THF (7 ml) add tetrabutylammonium (1 M in THF, 95 μl, 0,095 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. 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 h at room temperature, obtaining mentioned 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 earlier stage C, in dichloromethane (5 ml) (DCM) at 5°C add Et3N (27 mg, 0.26 mmol) and the reaction mixture is stirred for 5 minutes Then add trimethylacetylchloride (30 mg, 0.25 mmol) and the reaction mixture was stirred at room temperature overnight. Then to the reaction mixture is added saturated NaHCO3(10 ml) and stirred for 1 h Then the reaction mixture extrag the shape DCM, washed with saturated salt solution and dried over MgSO4. The desiccant is removed and the organic layer concentrated. The resulting residue is purified by chromatography on silica gel using 2% methanol in DCM as eluent, get mentioned in the title compound as a viscous yellow oil.

MS m/z (M+) 654.

EXAMPLE 60

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

LiHMDS (1.0 in M, 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. Redness of the reaction mixture. After the addition, the reaction mixture was stirred for further 0.5 h at -78aboutC. Then the reaction mixture is added bromine (12 ál,1.5 EQ., 0,227 mmol) at 78°C. Observe the change in color of the mixture from red to light yellow. Then the reaction mixture was stirred for further 0.5 h at -78aboutC. the Reaction is quenched with saturated solution of NaHSO3the reaction mixture is heated to room temperature and vigorously stirred at room temperature for 15 min THF is removed by rotary evaporation under vacuum. Then to the reaction residue add ethyl acetate (20 ml) and water (5 ml), which leads to the formation of two phases. Water FA is the extracted twice with ethyl acetate. The combined organic layer was washed with saturated salt solution, dried over anhydrous Na2SO4, filtered and concentrated give crude specified in the title compound as a yellow solid. The crude product is purified column flash chromatography, using as eluent a mixture of hexane and ethyl acetate at a dilution of 3:1, get mentioned in the title compound as a pale yellow solid.

It is established that the product contains a mixture of 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.

Rf= 0,60 in a mixture (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 (Ab., J=10,8 Hz, 2H).

MC (M+H), 699, 697.

EXAMPLE 61

2,8-Dihydroxy-11H-chromeno[4,3-c]chromen-5-he

Connection # 1

The method C

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 to the solution was added a powder of K2CO3(41 mg, 3.0 EQ., 0,298 mmol) in one portion. The reaction mixture was stirred at room t is mperature during the night. Observe the change in color of the reaction mixture 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. To the reaction mixture are 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 give crude specified in the title compound as a brown solid. To the crude product add a mixture (5:1) hexane : ethyl acetate. The supernatant solution was removed by pipette and the remaining insoluble solid product is dried in vacuum, obtaining specified in the title compound in the form of solids.

Rf= 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, receiving a viscous oil. The oil is purified with SiO2using the gradient of RA is the maker of 5-10 to a mixture of ethyl acetate/hexane, get listed in the title compound in the form of oil.

MS (Cl) m/z 675 (M+H)+, 697 (M+Na)+.

1H NMR (300 MHz, CDCl3): δ to 7.6 ppm (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. In specified flask is charged with a syringe THF (20 ml), iPr2NH (1.8 ml, 14.0 mmol)with a syringe, and the contents cooled to -10°C in a bath of a mixture of ice/methanol. Added dropwise via syringe n-utility (1,85 M (m), syringe, 6.3 ml, 11.7 mmol) in hexane at a temperature of -10°C, stirred for 15 min at -10°C. To the solution is added dropwise with a syringe 3-[2,4-bis(2-trimethylsilyloxy-methoxy)phenyl]-4-methyl-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 with a syringe to a cooled to -78°C solution Br2(0,76 ml, 2 EQ.) in THF (100 ml)contained in a 3-necked round bottom flask of 1 l, equipped with a mechanical stirrer and a membrane for N2. After d is bauleni the mixture is stirred for 5 min at -78° C and then diluted with EtOAc (0.5 l), adding syringe, saturated NaHCO3(50 ml), adding syringe, and saturated Na2SO3(100 ml), adding syringe. Remove bath with a mixture of dry ice/acetone and the reaction mixture left to warm to room temperature with stirring. The organic phase is separated and the aqueous phase is subjected to back extraction with EtOAc (2 × 0.2 l). The combined organic phase was washed with saturated salt solution (2 × 0.5 l) and concentrated in vacuo, obtaining mentioned in the title compound as a crude semi-solid product.

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

1H NMR (300 MHz, CDCl3): δ (ppm) of 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) (get 1 HCl solution, using 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 was stirred for 24 h at room temperature. Then the reaction mixture was diluted with EtOAc (100 ml) and the organic layer washed with water (2 × 20 ml) and saturated salt solution (30 ml). The organic layer is dried over Na2SO4 , filtered and the organic solvent is evaporated, getting mentioned in the title compound, 3-[2,4-bis(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-it, in the form of crude solid product.

MS (Cl) m/z 362 (M+H+); 384 (M+Na+).

1H NMR (300 MHz, CDCl3): δ (ppm) of 7.8 to 6.8 (m, 6H), 4,8-4,6 (Ab., J= 14.6 Hz, 2H).

EXAMPLE 65

2,8-Dihydroxy-11H-chromeno[4,3-c]chromen-5-he

Connection # 1

The way D:

2,8-Dihydroxy-11H-chromeno[4,3-c]chromen-5-he (90 mg, 0.25 mmol) dissolved in MeOH (2.5 ml). Add K2CO3(35 mg, 0.2 mmol) and the resulting mixture stirred for 10 min at room temperature. The reaction mixture was diluted with EtOAc (50 ml), filtered and the organic solvent evaporated to dryness. The obtained semi-solid product was then purified SiO2using 50% EtOAc in hexane, get mentioned in the title compound in the form of solids.

MS (Cl) m/z 283 (M+H+), 306 (M+Na+).

EXAMPLE 66

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

The way B:

1-[2-(4-iodinase)ethyl]piperidine (1,656 g, 5 mmol) is dissolved in THF and cooled to -78°C. Then, to the reaction mixture slowly over 5 min, to relax the Ute n-utility (2 M solution in pentane, 2.5 ml, 10 mmol). The resulting solution was stirred for 1 h 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 added to the reaction mixture containing 1-[2-(4-iodinase)ethyl]piperidine and n-utillity slowly for 10 minutes, the Reaction mixture was stirred for further one hour. The reaction mixture was quenched with MeOH (1 ml), then 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, receiving 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, getting mentioned in the title compound in the form of a foamy substance.

MS (Cl) m/z 700 (M+N+), 723 (M+Na+).

1H NMR (300 MHz, CDCl3): δ 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)was 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

1 M TBAF (in THF, 17 ml, 17 mmol, 3 EQ.) added dropwise to 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. Then to the reaction mixture 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, obtaining a mixture (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, the Reaction 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% MeOH 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)FeNi is]-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) load on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute with 20% MeOH in IPA at a flow rate of 90 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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, corresponding to the peak one 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, corresponding to the peak of the two.

MS m/ z 640 (M+H+), 663 (M+Na+).

1H NMR (300 MHz, CDCl3): δ 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, users), 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)-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether (1S)-(-)-campanulas acid

Connection # 49

1 M TBAF (in THF, 8.5 ml, 8.5 mmol, 3 EQ.) added dropwise to a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}-ethyl)piperidine (2.0 g, to 2.85 mmol) in THF (30 ml) at -10°C and the reaction mixture is stirred for 15 minutes Then the reaction mixture is added the acid chloride (1S)-(-)-campanulas acid (1,69 g, 8.6 mmol, 3 EQ.). Then the reaction mixture was diluted with ethyl acetate (300 ml) and washed with 5% sodium bicarbonate, then washed with a saturated solution of salt. The organic layer is dried over anhydrous Na2SO4and concentrated, obtaining a mixture (1:3) manokaran- : disimpan-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 is stirred for 30 minutes at room temperature. Then the reaction mixture was diluted with ethyl acetate (250 ml) and then washed with a saturated solution of salt. Flash chromatography on a column with SiO2, eluruumi 2%-5% MeOH in CH2Cl2gives specified in the title compound in the form of diastereomers a mixture of 8-((1S)-(-)-campanil)-5S(or R)-[4-(2-piperidine-1-ylethoxy)phenyl)-5,11-dihydrobromide[4,3-c]chromen-2-silt ether (1S)-(-)-campanulas acid and 8-((1S)-(-)-campanil)-5-[4-(2-piperidine-1-ylethoxy)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 stirred at 70°C for 4 h until the solution not the Thanet transparent. The solution is filtered and cooled down to room temperature. The solid product formed after 64 h, the solid product is filtered and dried in vacuum, obtaining mentioned in the title compound as a solid (84% de).

MS m/z 832 (M+N+); 854 (M+Na+).

1H NMR (300 MHz, CDCl3): δ (ppm) of 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) are added to a mixture of K2CO3(18.6 g, about 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. Then the reaction mixture was stirred for 4 h, during the specified time, solution, allow to warm to room temperature. Then the reaction mixture is filtered and evaporated, receiving a viscous oil. The oil is purified on SiO2using a mixture of ethyl acetate : hexane with gradient of solvent 5-10, receive 3-(2,4-biotoxicity)-7-methoxyethoxy-4-methylpropan-2-it is in the form of solids.

MS m/e 417 (M+H+) and 439 (M+Na+).

1H NMR (CDCl3, 300 MHz): δ (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 (who, 3H).

EXAMPLE 70

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

Into a clean dry flask of 200 ml, purged with nitrogen, add Diisopropylamine (2.7 ml of 19.5 mmol, 3 equiv.) dry THF (50 ml) and 3-(2,4-biotoxicity)-7-methoxyethoxy-4-methylpropan-2-she (8.1 ml, 16,25 mmol, 2.5 EQ.) at -78°C. After 30 minutes to the specified 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 dry THF (13 ml). The solution is heated to -10°C and stirred at the same temperature for 30 minutes. Then to the reaction mixture slowly add performed (3.6 ml, 33 mmol, 5 EQ.). Then the reaction mixture was stirred for 30 min, quenched with saturated aqueous NH4Cl, extracted with ethyl acetate and then concentrated, getting listed in title product as a crude solid, which was purified flash chromatography, elwira 30% ethyl acetate in hexane, get listed in title product in the form of solids.

MS: 443,0, M-H.

1H NMR (300 MHz, CDCl3): δ (ppm) 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)-(2-hydroxyethyl)-7-methoxyethoxide-2-he

Natrojarosite (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°C 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 give crude product, which was purified flash chromatography, elwira 50% ethyl acetate, get mentioned 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): δ (ppm) 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, add 3-(2,4-biotoxicity)-4-(2-hydroxyethyl)-7-methoxyethoxide-2-he (200 mg) and 1 N. HCl (10 ml) in a mixture (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. Organic closeout over anhydrous sodium sulfate and then concentrated. The residue is purified flash chromatography, elwira 10% methanol in dichloromethane, to obtain 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, (M+Na).

1H-NMR (300 MHz, CD3OD): δ (ppm) 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-he

Connection # 56

Into a clean dry flask, purged with nitrogen, add 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-he (50 mg, 0.16 mmol, 1 equiv.),triphenylphosphine (176 mg, 0.67 mmol, 4.2 equiv.) molecular sieves 4 Å (50 mg)anddry THF (10 ml) and the reaction mixture is stirred for 30 minutes. Then to the reaction mixture are 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 product is filtered and the filtrate concentrated. The residue is purified flash chromatography, elwira 2% methanol in dichloromethane, get listed in title product in the form of solids.

MS: 295,0 (M-H); 297 (M+H); 319 (M+Na).

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

EXAMPLE 74

2,8-Bis(tert-butyldimethylsilyloxy)-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). Then the reaction mixture is added triethylamine (0.2 ml) and 1 M 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 washed twice with a saturated solution of salt. The organic layer is dried over anhydrous sodium sulfate and concentrated. The crude product was purified flash chromatography, elwira mixture (100:10:2) hexane/dichloromethane/ethyl acetate, receive 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 (300 MHz, CDCl3): δ (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-dihydro-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. Then, to the above reaction mixture is added a solution of Dibal-H (70 μl, 1.5 M solution in toluene) at -78°C. the Reaction mixture was stirred at -78°C for 3 hours After which the mixture reaktsionnoi methanol (0.5 ml) and then a solution of Rochelle salt (2 ml, 1 M 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, to give crude product, which was purified on SiO2getting listed in the title compound in the form of solids.

MS m/z 527 (M+H+), 550 (M+Na+).

1H NMR (300 MHz, CDCl3): δ 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=2,31,11,62 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), a 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 mg, 0,453 mmol) is dissolved in THF and cooled to -78°C. Then, to the reaction mixture slowly for 5 minutes, add n-utility (2 M solution in pentane, 226 μl). The reaction mixture was stirred for 1 h at -78°C. In a separate flask dissolve 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) in THF (1 ml) and added dropwise to the reaction mixture containing 1-[2-(4-iodinase)ethyl]piperidine and n-utillity slowly for 5 minutes. The reaction mixture peremeshivajutsa 1 hour. The reaction mixture was quenched with MeOH (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, receiving 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, 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)piperidine in the form of oil.

MS m/z 714 (M+H+).

1H NMR (300 MHz, CDCl3): δ 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

Connection # 55

To a solution of 1-(2-{4-[2,8-bis(Tr is t-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 in example 76, in THF (0.1 ml) is added TBAF (10 ál, 1 M solution in THF, 0,010 mmol) at -10°C. the Solution becomes light yellow. The solution is stirred at -10°C for 30 minutes Then to the solution was added saturated aqueous NH4Cl (0.1 ml)to quench the reaction. The reaction mixture was extracted with ethyl acetate (100 ml), the organic solvent is dried over anhydrous Na2SO4, an organic solvent, filtered and concentrated in vacuo, receiving oil that cleans GHUR with reversed phase, 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 Hz, 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, 2H), 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) download on ChiralPak AD chiral GHUR-column (21 mm and x 250 mm length.) and elute 50% MeOH in isopropyl alcohol at a flow rate of 4 ml/min Fraction, corresponding to two peaks are collected separately and the solvent is removed under vacuum, getting 5R*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, corresponding to the peak one,

MS (Cl) m/z 472 (M+H+),

and 5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol, corresponding to the peak of the two,

MC (Cl) m/z 472 (M+H+).

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 (1 M in THF, 850 μl, 0.85 mmol, 3 EQ.) added dropwise to a solution of 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-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. Then to the reaction mixture 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 concentrate give crude oil, which is purified GHUR (using Luna C18 column, 1% TFA in acetonitrile (ACN) and 1% TFA in H2O as a gradient solvent system). Faction responsible TLD the peaks, collected separately and evaporated to dryness in a vacuum, getting 8-hydroxy-11-[4-(2-piperidine-1-ylethoxy)phenyl)-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid, corresponding to the peak one,

MC (Cl) m/z: 556 (M+H+),

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, corresponding to the peak of the two,

MC (Cl) m/z: 556 (M+H+).

1H NMR (300 MHz, CDCl3): δ 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, users), 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-trimethylsilylamodimethicone)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 was stirred for 10 min and then added to chloroacetanilide (of 0.28 ml, 1.5 EQ.) in THF (20 ml) at -20°C. the Reaction mixture was kept at -20°C within 1 hour,then diluted with diethyl ether (200 ml), washed with aqueous NH4Cl (100 ml), saturated salt solution and the organic layer dried over without the one MgSO 4. Then the obtained product was concentrated in vacuo to dryness and purified column chromatography on silica gel, getting mentioned in the title compound as a colourless oil.

1H NMR (CDCl3): δ -0,1˜0,2 (m, 27H), 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., 40 ml of a mixture of 1:1 THF : iPrOH) is stirred overnight at 25°C. Then the reaction mixture was 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). The organic layers are combined, dried, concentrated and purified column chromatography on silica gel (5% MeOH/DCM)to give specified in the title compound as white crystals.

1H NMR (CDCl3): δ 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), MH-(359).

EXAMPLE 82

6,12-Dihydroxy[1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione

Connection # 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 MeOH (20 ml) for 2 h at 25°C. 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, obtaining mentioned in the title compound as a slightly yellowish powder.

1H NMR (CDCl3): δ of 2.08 (m, 2H), 2,68˜of 2.92 (m, 2H), 4.95 points (m,N), 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]-a[1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione,

connection # 212

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

and

6,12-Dihydroxy[1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione (obtained in the above example 82) (283 mg, 0.87 mmol), TBSCl (1,0 M in DCM, and 2.6 ml, 3 EQ.) and TEA (of 0.36 ml, 3 EQ.) in DCM (10 ml) was stirred at 25°C for 30 min LC-MS shows the presence of only 2,8-di(OTBS)-product. Then the reaction mixture was stirred overnight at 25°C, after a specified time LC-MS shows the presence of vtoro what about 2,8,12-three(OTBS)-substituted product. Then the reaction mixture was 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, getting listed in the title compound as a yellow foamy mass.

6,12-bis[[(1,1-Dimethylethyl)dimethylsilane]oxy]-a[1]benzopyrano[4,3-e][1]benzoxazin and 2.9(1H,3H)-dione

1H NMR (CDCl3): δ 0,10˜0,19 (m, 18H), 0,84, to 0.92 (d, N), 4,22 (d, 1H, J=13,2 Hz), 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(1N)-he obtained in the above example 83, (208 mg, 0.31 mmol) in toluene (5 ml) at -78°C is 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. Then the reaction mixture was diluted with ethyl acetate (100 ml), washed three times with a solution of Rochelle salt (Rocheile) and double-spend 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)to give specified in the title compound as a yellow foamy mass is s.

1H NMR (CDCl3): δ 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): MN-(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°C is subjected to interaction with nBuLi (0,76 ml, 2.5 M in hexane) within 15 minutes the mixture is 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-ol, the compound obtained in the above example 84, (256 mg, 0.38 mmol) in THF (5 ml) at -78aboutC and the resulting reaction mixture is stirred for 1 h, the Reaction mixture was quenched with MeOH (0.1 ml) and then aqueous NH4Cl. The resulting mixture was extracted with ethyl acetate (200 ml). The organic layers are dried, concentrated and azeotropic distillation with benzene (50 ml), getting listed in title product in the form ofthe crude oil.

MS (m/z): MH+(874), MH-(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][1]benzoxazin-2(3H)-he compound No. 95

and

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 from example 85 (0.38 mmol) in DCM (10 ml) at -10°C is mixed with BF3·Et2On (0,32 ml, 2,47 mol, 6.5 EQ.) within 30 minutes the reaction mixture is quenched with water (5 ml) and stirred for 10 min. Then the reaction mixture was diluted with ethyl acetate (100 ml), washed twice with 5% HCl and then twice with a saturated solution of salt. The resulting residue is dried and concentrated, obtaining a mixture specified in the header of the compounds in the form of oil.

The oil is divided into the following components using 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): MH+(856),

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)-he,

MS (m/z): MH-(740).

EXAMPLE 87

1,9-Dihydro-6,12-dihydroxy-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e][1]benzoxazin-2(3H)-he

Connection # 96

The crude mixture of products, 1-[2-[4-[2,6,12-Tris[[(1,1-dimethylethyl)dimethylene is]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)-it, obtained in the above example 86, (0.38 mmol), dissolved in THF (4 ml). Add (2.0 ml) pre-obtained 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 and the reaction mixture is stirred for 14 hours. Then the reaction mixture was 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). The organic layers are combined, dried, concentrated and purified column chromatography on silica gel (50-100% hexane/etelaat), getting mentioned in the title compound as a white powder.

MS (m/z): MH+(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

Connection # 216

The solution 6,12-bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-a[1]benzopyrano[4,3-e][1]benzoxazin-2,9(1N,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 the same temperature under stirring for 2 hours. At the end of the specified time add an additional amount of NaBH4(12 mg ) and the reaction mixture stirred for further one hour. The reaction mixture was quenched with aqueous NH4Cl (5 ml) is then extracted with ethyl acetate (50 ml). The organic layers separated and dried over anhydrous Na2SO4concentrate and purify on silica gel (15% ethyl acetate in hexane)to give specified in the title compound as a solid foam-like mass.

MS (m/z): MH+(554).

EXAMPLE 89

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 etherTopolino 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 in the above example 88, (215 mg, 0,388 mmol) is 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 DCM (4 ml) and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was 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 is purified on a flash column (5% ethyl acetate/hexane)to give specified in the title compound as colorless foamy solid.

MS (m/z): MH+(691), MNa+(713).

EXAMPLE 90

6,12-Bis[[(1,1-dimethyle the l)dimethylsilane]oxy]-2,3-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9(1 H)-he

Connection # 214

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 Topolino acid obtained in the above example 89, (236 mg, 0.34 mmol), AIBN (2.8 mg, of 0.05 EQ.) and nBu3SnH (0,137 ml, 1.5 EQ.) in toluene (4 ml) Tegaserod for 5 min with N2, heated to 80°C and stirred overnight. Then the reaction mixture was diluted with ethyl acetate (50 ml) and washed with aqueous CuSO4and a saturated solution of salt. The organic layer is concentrated and purified on silica gel, getting mentioned in the title compound as white crystals.

MS (m/z): MH+(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

Connection # 94

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

MS (m/z): MNa+(563), MH-(539).

EXAMPLE 92

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

Connection # 291

Specified in the header connection receive according to the method described in the above example 85, substituting 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][1]benzoxazin-9-ol, which gives specified in the title compound as a yellow oil.

MS (m/z): MH+(746).

EXAMPLE 93

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

Connection # 282

Specified in the header connection receive according to the method described in the example above, 86, substituting 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, which gives specified in the title compound in the form of frothy mass.

MS (m/z): MH+(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

The connection is 97

Specified in the header connection receive according to the method described in the example above, 87, replacing the crude mixture of products 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, which gives specified in the title compound as a pink solid.

MS (m/z): MH+(500).

Racemic 1,2,3,9-tetrahydro-9-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e][1]benzoxazin-6,12-diol (1.0 g) load on a ChiralPak AS chiral GHUR-column (5 cm VND x 50 cm length.) and elute with 20% MeOH in IPA at a flow rate of 90 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, obtaining the following two enantiomers.

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

[α]=-57° (c=0,302, MeOH).

1H NMR (CD3OD): δ 1,49 (user. s, 2H), 1.69 in (users, 4H), 1.91 a (osirm, 2H), 2,08 (osirm, 2H), 2,71 (osirm, 4H), 2,92 (osirm, 2H), 3,74 (users, 1H), 4,12 (osirm, 2H), 4,56 (users, 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-9-S*-(+)-[4-[2-(1-piperidinyl)ethoxy]phenyl][1]benzopyrano[4,3-e][1]benzoxazin-6,12-diol.

[α]=+ 66° ( C=0,402, Meon).

1H NMR (CD3OD): δ 1,49 (users, 2H), 1.69 in (users, 4H), 1.91 a (osirm, 2H), 2,08 (osirm, 2H), 2,71 (osirm, 4H), 2,92 (osirm, 2H), 3,74 (users, 1H), 4,12 (osirm, 2H), 4,56 (users, 1), 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

Connection # 98

To a solution of 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol (obtained in example 24) (2,87 g, 5.6 mmol) in DCM (50 ml) is added BF3•apiret (1,42 ml, and 11.2 mmol). Then the reaction mixture is stirred, the mixture becomes dark red. After 20 min slowly add 1,1-bistrimethylammomium (2 ml, 8.4 mmol, 1.5 EQ.). After 15 minutes add another portion of 1,1-bistrimethylammomium (1 g) and the solution turns yellow for 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): δ 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

Connection # 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 in the above example 95, (56 mg, 0.10 mmol) in benzene (0.7 ml) and MeOH (0.2 ml) is added TMSCHN2(0.075 ml, 2.0 M in hexane) and the reaction mixture is stirred for 15 minutes the Solvent is removed and the residue purified by flash chromatograph, getting mentioned in the title compound as a yellow oil.

1H NMR (CDCl3): δ 0,08 (s, 12H), 0,78 (s, 18H), and 2.26 (d, 1H, J=15,5 Hz), 3,51 (s, 3H), 4,69 (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

Connection # 102

Following the same method described in example 87, methyl ester [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, the compound obtained in example 96, is subjected to the interaction with TBAF, which gives specified in the title compound as a yellow solid.

1H NMR (CDCl3): δ 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

Connection # 104

Stage A

A mixture of [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid compounds obtained 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 DCM (2 ml) is stirred for 13 hours. Then the reaction mixture was concentrated, obtaining 2-dimethylaminoethyl ether [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid as a crude foam product.

Stage B

Following the procedure 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 A is dissolved in THF (1 ml) at -10°C and then treated with TBAF, getting mentioned in the title compound as a yellow solid.

MS (m/z): MH+(398), MNa+(420), MH-(396).

EXAMPLE 99

(2,8-Dihydroxy-5,11-dihydrobromide[4,3-c]chromen-5-yl)acetic acid

Connection # 107

Following the procedure described in example 87, [2,bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid, the compound obtained in example 95, (56 mg, 0.1 mmol) is subjected to interaction with TBAF, getting mentioned in the title compound in the form ofyellow solid.

1H NMR (acetone-d6): δ 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): MM-(325), (M +OAc)-(385).

EXAMPLE 100

[2,8-Bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetaldehyde

At -78°C to a solution of methyl ester [2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]acetic acid compounds obtained from 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. Then the reaction mixture was quenched at -78°C chilled MeOH. Purification of the residue by the method GHUR network specified in the title compound as a viscous oil.

1H NMR (CDCl3): δ 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 a method GHUR in the form of oil.

1H NMR (CDCl3): δ 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 -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

Connection # 122

Following the procedure described in example 87, 2-[2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]ethanol is subjected to interaction with TBAF, getting mentioned in the title compound as a yellow solid.

1H NMR (CD3OD): δ 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=13,8 Hz), 4,96 (d, 1H, J=13,8 Hz), 5,31 (d, 1H, J=9.8 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-he

Connection # 220

At room temperature a mixture of 8-hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-she obtained in example 74, (2.0 g crude product, 7.0 mmol) and TBSCl (5.34 g, 35 mmol), triethylamine (5 ml) in DCM (80 ml) is stirred over night. Then the reaction mixture is washed with water and saturated salt solution. The organic layers dried over anhydrous sodium sulfate and concentrated and purified flash chromatography, getting mentioned in the title compound as a white solid.

1H NMR (D 3OD): δ 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): MHT (395), MNa+(417), 2MNa+(811).

EXAMPLE 103

2-(tert-Butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he

Connection # 221

Following the procedure described in the example above 102, is subjected to the interaction of 2-hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he obtained in example 74, (11.2 g, 40 mmol), get mentioned in the title compound as a white powder.

1H NMR (CD3OD): δ 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, the compounds obtained in the above example 102, (3.0 g, 7.56 mmol) at -78°C slowly added DIBAL (5,10 ml, 1.5 M in toluene, 1.0 EQ.). After 3 h the reaction mixture was diluted with ethyl acetate (100 ml), washed three times with a solution ofRochelle salt(Rochelle) and twice does the opposite extraction with ethyl acetate (25 ml). The organization is practical layers are dried and concentrated. The residue is purified on silica gel (5% ethyl acetate in hexane)to give specified in the title compound as a white solid.

1H NMR (CD3OD): δ 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

Connection # 139

Following the procedure described in the example above 104, is subjected to the interaction of 2-(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-Oh, the compound obtained in the above example 103, (4.0 g, 10.1 mmol), get mentioned in the title compound as a white solid.

1H NMR (CD3OD): δ 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)MN-(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

Connection # 140

Following the procedure 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 in the above example 105, experience the t interaction with 1-[2-(4-iodinase)ethyl]piperidine, getting 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. Crude 2-(8-(tert-butyldimethylsilyloxy)-5-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2,3-dihydrobenzo[b]oxepin-4-yl)phenol in further treated with HCl (12 N., 4 EQ., of 0.67 ml) in toluene (100 ml), giving 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. Then the crude 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 optionally treated with 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, elwira 5% MeOH in DCM, get mentioned in the title compound as a slightly yellowish solid.

1H NMR (acetone-d6): δ of 1.35 (m, 2H), 1,49 (m, 4H), 2,42 (user. s, 4H), of 2.64 (m, 2H), 2.71 to 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-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol (800 mg) download on ChiralPa AD chiral GHUR-column (5 cm and x 50 cm length.) and elute with 100% IPA at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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-ol.

1H NMR (DMCO-d6): δ 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, MeOH).

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]=-37, (c=0,43, MeOH).

MS (m/z): MH+(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

Following the procedure 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, the compound obtained in the above example 105, (0.8 g, 2.0 mmol) is subjected to interaction with 1-[2-(4-iodinase)ethyl]azepane, getting mentioned in the title compound as a yellow solid.

1H NMR (acetone-d6): δ 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-diox the benzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol, (950 mg) download on ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute with 100% IPA at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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, MeOH).

1H NMR (DMCO-d6): δ 1,51 (user. s, 8H), 2,45 (user. m, 4H), 2,70 (user. m, 2H), 3,22 (users, 2H), 3,91 (t, 2H, J=6.6 Hz), 4,56 (m, 2H), x 6.15 (s, 1H), 6,39 and 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, MeOH).

MH+(484).

EXAMPLE 108

5-[4-(2-Dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol

Connection # 142

Following the procedure described in example 106, 2-(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol, the compound obtained in example 105, sequentially subjected to interaction with [2-(4-iodinase)ethyl]dimethylamine HCl and then HF·pyridine, getting mentioned in the title compound as a yellow solid.

1H NMR (CDCl3): δ 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, 11H).

MS (m/z): MH+(40).

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) download on ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute with 20% MeOH and 80% IPA at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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-2-ol.

[α]D=+38 (c=0.3, and Meon).

1H NMR (DMCO-d6): δ to 2.13 (s, 6H), 2,43˜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, 11N), 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

Following the procedure 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, sequentially treated with 1-[2-(4-iodinase)ethyl]azepane, HCl, and then HF·pyridine, getting mentioned in the title compound as a yellow solid.

1H NMR (acetone-d6): &x003B4; and 1.54 (m, 8H), 2,68˜2,95 (m, 8H), 3,98 (m, 2H), 4,74 (m, 2H), 6,18 (s, 1H), 6,21˜7,39 (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) download on ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 40% MeOH and 60% IPA at a flow rate of 100 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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-8-ol.

[α]D=+37 (c=0,11, MeOH).

1H NMR (DMCO-d6): δ 1.55V (users, 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).

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 or=0.51, MeOH).

1H NMR (DMCO-d6): δ 1.55V (users, 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

Following the procedure 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 104, the sequence is correctly subjected to interaction with [2-(4-iodinase)ethyl]dimethylamine, HCl and then HF·pyridine, getting mentioned in the title compound as a yellow solid.

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-8-ol, (800 mg) download on ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute with 100% IPA at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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, MeOH).

1H NMR (DMCO-d6): δ 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, MeOH).

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

Connection # 159

Following the procedure 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 in example 75, (1.5 g, 2,85 mmol) sequentially subjected to interaction with 1-[2-(4-iodinase)ethyl]azepane,HCl, and then HF· pyridine, getting mentioned in the title compound in the form of a frothy mass.

1H NMR (CDOD3): δ 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-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta-[1,2-a]naphthalene-2,8-diol (1,02 g), loaded on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute with 100% IPA at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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, MeOH).

MS (m/z): MH+(500), MH-(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 or=0.51, MeOH).

MS (m/z): MH+(500), MH-(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

Connection # 160

Following the procedure 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 in example 75, (1.5 g, 2,85 mmol) sequentially subjected interaction is the influence of [2-(4-iodinase)ethyl]diisopropylamino, HCl and then HF·pyridine, getting mentioned in the title compound as a pink solid.

1H NMR (CDOD3): δ 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), MN-(500).

Racemic compound, 5-[4-(2-diisopropylaminoethyl)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (1.4 g), loaded on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 80% IPA and 20% hexane at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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 (c=0,112, MeOH).

MS (m/z): MH+(502), MH-(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, MeOH).

MS (m/z): MH+(502), MH-(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

Connection # 161

Following the procedure 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 in example 75, (2.8 g, 5,3 shall mol) successively subjected to interaction with [2-(4-iodinase)ethyl]dimethylamine, HCl and then HF·pyridine, getting mentioned in the title compound as a yellow solid.

1H NMR (CDOD3): δ 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-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2,8-diol (1.7 g), loaded on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 80% IPA and 20% hexane at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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, MeOH).

MS (m/z): MH+(446), MH-(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, MeOH).

MS (m/z): MH+(446), MH-(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

Connection # 283

Following the procedure 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 in example 106, (0,80 g, 1,95mmol) of p is therefore subjected to interaction with [2-(4-iodinase)ethyl]morpholine, HCl and then HF·pyridine, getting mentioned in the title compound as a yellow solid.

MS (m/z): MH+(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, substituting 5-[4-(2-piperidine-1-yl-ethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol 8-fluoro-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3c]chromen-2-ol, which gives a foamy mass.

1H NMR (CDCl3): δ 1,18, of 1.32 (9H, two s)of 1.42 (2H, m), and 1.63 (4H, m)of 2.64 (4H, users), 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 on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute with 100% IPA at a flow rate of 100 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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] = + 160°(c = 0,225, CHCl3).

Peak 1: 8-FPO is-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] = - 173°(c = 0,205, CHCl3).

EXAMPLE 116

3-(2,4-Acid)-4-methylpropan-2-he

Connection # 239

Specified in the header connection receive according to the method described in example 1, substituting 2,4-dihydroxyacetophenone 2-hydroxyacetophenone, which gives a yellow solid.

MS (m/z): MH+(297), MNa+(319), 2MNa+(615).

1H NMR (CDCl3): δ 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)chromeen-2-he

ConnectionNo. 240

Specified in the header connection get the procedure described in example 63, substituting 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-methylpropan-2-it 3-(2,4-acid)-4-methylpropan-2-he and replacing the bromine on the NBS, which gives a yellow solid.

1H NMR (CDCl3): δ 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-11H-chromeno[4,3-c]chromen-5-he

Connection # 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 BBr3of (1.0 M in CH2 Cl2, 310 ml, 4.5 equiv.) at 25°C. After 16 h stirring the reaction mixture was poured into a cooled 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 was separated and then acidified 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, getting mentioned in the title compound as a yellow solid.

1H NMR (CDCl3): δ 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 (21).

MS (m/z): MH+(267), MNa+(289).

EXAMPLE 119

2-(tert-Butyldimethylsilyloxy)-11H-chromeno[4,3-c]chromen-5-he

Connection # 219

2-Hydroxy-11H-chromeno[4,3-c]chromen-5-Oh (0.5 g)obtained in example 118, dissolved in THF (5 ml). Then the reaction mixture is added triethylamine (1.5 ml) and 1 M TBSCl (2.0 ml) in dichloromethane and the reaction mixture was stirred at room temperature for 1 h, 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 was purified flash chromatography, elwira mixture (100:10:2) hexane/dichloromethane/ethyl acetate, ucaut specified in the title compound in the form of solids.

1H NMR (CDCl3): δ 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).

EXAMPLE 120

2-(tert-Butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-ol

Connection # 135

Specified in the header connection receive according to the method described in example 24, substituting 2,8-bis(tert-butyldimethylsilyloxy)-11H-chromeno[4,3-c]chromen-5-he 2-(tert-butyldimethylsilyloxy)-11H-chromeno[4,3-c]chromen-5-it, get a solid substance.

1H NMR (CDCl3): δ 7,28 ˜ 7,02 (m, 4H), 6.48 in-6,32 (m, 3H), 5,32 ˜ 5,13 (m, 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, substituting 2,4-dihydroxyacetophenone 1-(2-hydroxy-4,6-acid), Etalon receive a yellow solid.

1H NMR (CDCl3): δ 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 of the connection marked out as a by-product of what intese, described in the above example, 123.

TPL 166-167°C.

Anal. Calculated for C14H14O5: 64,12; N 5,38.

Defined: 64,20; N 5,43.

1H NMR (CDCl3): δ 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

Connection # 245

Specified in the header connection receive according to the method described in example 26, substituting 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, get the oil.

1H NMR (CDCl3): δ 7,24-x 6.15 (m, 11H), 5,46 (s, 1H), 4.92 in (m, 2H), 4,18 (users, 2H), 3,02 (users, 2H), 2,78 (users, 4H), 1,78 (users, 4H), 1,52 (users, 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, substituting 5-(tert-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-elecoxiban]methyl}-2H-chromen-3-yl)phenol 1-(2-{4-[2-( tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-yl]phenoxy}ethyl)piperidine, get foamy mass.

1H NMR (CDCl3): δ 7,16-6,12 (m, 11H), 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, users), 3,05 (users, 2H), 2,81 (users, 4H), 1,72 (users, 4H), 1,38 (users, 2H), of 0.79 (s, 9H), to 0.19 (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, substituting 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, get a solid substance.

1H NMR (CDCl3): δ 7,39 of 6.31 (m, 12H), the 5.45 (1H, d, J=14,2 Hz), 5,1 (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 (users, 4H), 2.05 is (users, 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

Connection # 134

Specified in the header connection receive according to the method described in example 54, substituting 5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2,8-diol 5-[4-(2-p is peridin-1 ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-ol, obtained in example 127, get a solid substance.

1H NMR (CDCl3): δ 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 (users, 4H), 1,68 (osirm, 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 # 285

Specified in the header connection receive according to the method described in example 1, substituting 2,4-dihydroxyacetophenone 1-(4-fluoro-2-hydroxyphenyl)Etalon and substituting 2,4-dimethoxyphenylacetic acid 2-methoxyphenylazo acid, get a solid substance.

1H NMR (CDCl3): δ the 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-he

Connection # 241

Specified in the header connection receive according to the method described in example 1, substituting 2,4-dihydroxyacetophenone 1-(2-hydroxyphenyl)Etalon and 2,4-dimethoxyphenylacetic acid 2-methoxyphenylazo acid, get a solid substance.

1H NMR (CDCl3): δ 7,68˜of 6.96 (m, 8H), 3,79 (s, 3H), of 2.25 (s, 3H).

MS (m/z): MH+(267), MNa+(289).

EXAMPLE129

4-methyl bromide-3-(2,4-acid)-5,7-dimethoxyfuran-2-he

Connection # 242

Specified in the header connection get the procedure described in example 63, substituting 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.), get a solid substance.

1H NMR (CDCl3): δ 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-he

Connection # 243

Specified in the header connection get the procedure described in example 63, substituting 3-[2,4-bis(2-trimethylsilylamodimethicone)phenyl]-4-methyl-7-(2-trimethylsilylamodimethicone)chromen-2-it 3-(2-methoxyphenyl)-4-methylpropan-2-he and substituting bromine for NBS (1.1 EQ.), get a solid substance.

1H NMR (CDCl3): δ 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-he

Connection # 245

Specified in the header of the connection will receive the same method described in example 120, substituting 4-methyl bromide-3-(2,4-dimethoxy the Nile)-2H-chromen 4-methyl bromide-3-(2-methoxyphenyl)chromen-2-it, get a solid substance.

TPL 213˜215°C.

1H NMR (CDCl3): δ 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

11H-Chromeno[4,3-c]chromen-5-he

Specified in the header connection receive according to the method described in example 61, on the basis of 4-methyl bromide-3-(2-hydroxyphenyl)chromen-2-it instead of 4-methyl bromide-3-(2,4-dibenzyline)-7-benzoylamino-2-it, get a solid substance.

Anal. Calculated for C16H11BrO3: 58,03; N 3,35.

Defined: 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): MH+(333), MNa+(355).

EXAMPLE 133

5,11-Dihydrobromide[4,3-c]chromen-5-ol

Connection # 136

Specified in the header connection receive according to the method described in example 24, from 11H-chromeno[4,3-c]chromen-5-it instead of 2,8-bis(tert-butyldimethylsilyloxy)-11H-chromeno[4,3-c]chromen-5-it, get a solid substance.

Anal. Calculated for C16H12O3: 76,18; N 4,79.

Defined: 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): MH+(253), MNa+(275).

EXAMPLE 134

2-(4-{Hydroxy-[4-(2-piperid the n-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 instead of 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide [4,3-c]chromen-5-ol, get a solid substance.

Anal. Calculated for C29H31NO4·0,75 H2O:

WITH 73,94; N 6,95, N 2,97.

Defined: 73,98; N 6,92, N 2,97.

1H NMR (DMCO-d6): δ 9,80 (s, 1H), of 7.48 ˜ 6,59 (m, 12H), by 5.87 (users, 1H), 5,58 (users, 1H), 5,01 (userd, 1H), with 4.64 (userd, 1H), 3,98 (users, 2H), 2,58 (users, 2H), 2,37 (users, 4H), 1,42 (users, 4H), 1,34 (users, 2H).

MS (m/z): MH+(458).

EXAMPLE 135

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

Connection # 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-butyldimethylsilyloxy)-2-(7-(tert-butyldimethylsilyloxy)-4-{hydroxy-[4-(2-piperidine-1-ylethoxy)phenyl]methyl}-2H-chromen-3-yl)phenol get a solid substance.

Anal. Calculated for C29H29NO3: 79,24; N. OF 6.65, N 3,19.

Defined: 78,96; N 6,57, N 3,11.

1H NMR (CDCl3): δ 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 (users, 4H), 1.55V (users, 4H), 1,45 (osirm, 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

Connection # 162

Specified in the title compound emit method flash chromatography as a by-product of the reaction described in example 35.

1H NMR (CDCl3): δ 7,38˜6,10 (m, 11H), 5,91 (s, 1H), to 4.41 (users, 2H), 3,61 (s, 3H), 3,21 (users, 2H), 3.15 in (osirm, 4H), 1,95 (users, 4H), and 1.54 (users, 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

connection # 171

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. 172

and

Racemic compound, 5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether of 2,2-dimethylpropionic acid obtained in example 126, (400 mg) download on ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 80% IPA and 20% hexane at a flow rate of 150 ml/mi is. Fractions corresponding to two peaks, evaporated in vacuum, obtaining the following 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,

connection # 169

and 5S*-(+)-1-{2-[4-(5,11-dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}piperidine,

connection # 170

Racemic compound, 1-{2-[4-(5,11-dihydrobromide[4,3-c]chromen-5-yl)phenoxy]ethyl}piperidine obtained in example 135, (900 mg) download on ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 50% IPA and 50% hexane at a flow rate of 200 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, obtaining the following 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}piperidine.

[α] = +146° (c = 0,27, CHCl3).

EXAMPLE 139

2-(tert-Butyldimethylsilyloxy)-ftor-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-ol

Connection # 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, 1.5 M in toluene, 1.0 EQ.) at -78°C for 3 hours. Then the reaction mixture was quenched with chilled MeOH at -78°C and the solvent is removed under reduced pressure. The residue is purified flash chromatography (10% EtOAc in hexane)to give specified in the title compound as a white solid.

MC (m/z): MH+(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, substituting 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), receiving a yellow solid.

1H NMR (CDCl3): δ 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), between 6.08 (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), download ChiralPak AD chiral GHUR-column (5 cm and x 50 cm length.) and elute 80% IPA and 20% hexane at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, obtaining the following 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, MeOH).

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]D=-28,2, (c=0.5, MeOH).

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. 90

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

connection # 89

8-(2,2-Dimethylpropionic)-5S*-(+)-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-c]chromen-2-silt ether dimethylpropionic acid obtained in example 67, (10 g) is suspended in MeOH (200 ml) and hermetically sealed ampoule added 1.2 equivalent of diethylamine. The resulting solution was heated to 150°C for 3 hours, the Reaction mixture was concentrated in vacuo and purified on SiO2getting the mix specified in the header connections.

A mixture of (3.1 g) C is Gruaud on ChiralPak AD chiral GHUR-column (5 cm and x 50 cm length.) and elute with 100% IPA at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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): δ to 1.35 (s, 9H), 1,45 (users, 2H), 1,62 (users, 4H), 2,61 (users, 4H), 2,82 (users, 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): δ 1,19 (d, 9H, J=7,0 Hz), 1,42 (users, 2H), 1,61 (users, 4H), 2,59 (users, 4H), 2,72 (users, 2H), 4,06 (m, 2H), of 5.05 (d, 1H, 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

Connection # 181

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 141, dissolved in a mixture of CH3CN/MeOH (3:1) (8 ml). Add TMSCHN2(2 M in hexane, 3.3 ml) and stirred over night. The reaction mixture is concentrated to dryness. The resulting crude oil su is ponderous in MeOH (5 ml) and TEA (0.800 to ml) and heated in hermetically sealed vial at 150° C during the night. The reaction mixture was concentrated and purified on SiO2using 5-10% MeOH in CH2Cl2get listed in the title compound as a yellow foamy mass.

1H NMR (CDOD3): δ to 1.48 (m, 2H), 1.61 of (m, 4H), 2,59 (users, 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. 195

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 in example 141, dissolved in a mixture of CH3CN/MeOH (3:1) (8 ml). Add TMSCHN2(2 M in hexane, 3.3 ml) and stirred over night. The reaction mixture is concentrated to dryness. The resulting crude oil is suspended in MeOH (5 ml) and TEA (0.8 ml) and heated in hermetically sealed vial at 150°C during the night. The reaction mixture was concentrated and purified on SiO2using 5-10% MeOH in CH2Cl2get listed in the title compound as a yellow foamy mass.

MS (m/z): MH+(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 in example 78, dissolved in a mixture of CH3CN/MeOH (3:1) (5 ml). Add TMSCHN2(2 M in hexane, 4 ml) and stirred over night. The reaction mixture is concentrated to dryness and purified on SiO2using 5% MeOH in CH2Cl2get listed in the title compound as a colourless oil.

1H NMR (CDCl3): δ 1,41 (users, 2H), 1,62 (users, 4H), 2,53 (users, 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,

connection # 125

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. 126

and

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-diol obtained in example 77, (1.18 g) load on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 80% IPA and 20% MeOH at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, obtaining the following two enantiomers.

p> 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): δ 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, MeOH).

Anal. Calculated for C30H31NO5·0,95 H2O:

WITH 71,68; N 6,60; N 2,79.

Found: 71,67; N. Of 6.52, N To 2.57.

MS (m/z): MH+(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, MeOH).

MS (m/z): MH+(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. 157

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 in example 145, dissolved in a mixture of CH3CN/MeOH (3:1) (28 ml). Add TMSCHN2(2 M in hexane, 3.3 ml) and stirred over night. The reaction mixture is concentrated to dryness and purified on SiO2using 5% MeOH in CH2Cl2get listed in the title compound as a yellow oil.

1H NMR (CDCl3): δ of 1.40 (m, 2H), 1,59 (m, 4H), 2.49 USD (users, 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), 6,05 (who, 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. 195

and 8-methoxy-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. 196

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 (10 g)obtained in example 145, dissolved in a mixture of CH3CN/MeOH (3:1) (280 ml). Add 1.1 equivalent TMSCHN2(2 M in hexane, to 10.2 ml) and stirred over night. The reaction mixture is concentrated to dryness and purified on SiO2using 5-10% MeOH in CH2Cl2get the mixture specified in the title compounds as a yellow foamy substance.

A mixture of compound (2.9 g) load on a ChiralPak AD chiral GHUR-column(5 cm and x 50 cm length.) and elute with 100% IPA at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, obtaining the following two listed in the connection header.

Peak 1: 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.

1H NMR (DMCO-d6): δ 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-2-ol.

1H NMR (CD3OD): δ 1,41 (users, 2H), 1,59 (users, 4H), 2,50 (users, 4HO, of 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-he

Connection # 258

In odnogolosy flask of 200 ml download letibit(trimethylsilyl)amide ((TMS)2NLi, 16 ml of 1 M solution in THF). 3-(2,4-Acid)-7-methoxy-4-methylpropan-2-he (3,45 g) in anhydrous THF is added to the reaction mixture over a 10 minute period and stirred at -20°C for 45 minutes (2-Hermeticity)trimethylsilane (1,95 g) are added to the reaction mixture over a 10 minute period 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 was concentrated in vacuoat 60°C give crude product, which was purified flash chromatography, giving specified in the title compound as a white solid.

MS (m/z): MH+(457), MNa+(479).

EXAMPLE 149

7-Methoxy-3-(2-methoxyphenyl)-4-[2-(2-trimethylsilyloxy)e is Il]chromen-2-he

Connection # 262

Specified in the header connection receive according to the method described in the example above, 148, substituting 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 7-methoxy-3-(2-methoxyphenyl)-4-methylpropan-2-it, get a white solid.

MS (m/z): MH+(427), MNa+(449).

EXAMPLE 150

3-(2,4-Acid)-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-he

Connection # 259

Specified in the header connection receive according to the method described in the example above, 148, substituting 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 3-(2,4-acid)-4-methylpropan-2-it, get a white solid.

MS (m/z): MH+(427), MNa+(449).

EXAMPLE 151

3-(2,4-Acid)-7-fluoro-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-he

Connection # 264

Specified in the header connection receive according to the method described in the example above, 148, substituting 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 3-(2,4-acid)-7-fluoro-4-methylpropan-2-it, get a solid substance.

MS (m/z): MH+(445), MNa+(467).

EXAMPLE 152

3-(2,4-Acid)-6-methyl-4-[2-(2-trimethylsilyloxy)ethyl]XP is Myung-2-he

Connection # 267

Specified in the header connection receive according to the method described in the example above, 148, substituting 3-(2,4-acid)-7-methoxy-4-methylpropan-2-it 3-(2,4-acid)-4,6-dimethylamino-2-it, get a solid substance.

MS (m/z): MH+(441), MNa+(463).

EXAMPLE 153

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

Connection # 231

Into a flask of 1 l load CH2Cl2(200 ml) and 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-he obtained in example 148, (5 g). The solution was stirred at room temperature in an atmosphere of N2and add BBr3(8 ml)in an atmosphere of N2for a 20-minute period. Then the reaction mixture is stirred for 36 hours. The reaction mixture was cooled to 0°C and the reaction mixture is poured into pre-cooled 1 N. NaOH (200 ml, 5°C). The resulting solution was neutralized with 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, getting mentioned in the title compound as a yellow solid.

MS (m/z): MH+(315), MNa+(337).

EXAMPLE 154

3-(2,4-Dihydroxyphenyl)-4-(2-guide the oxyethyl)chromen-2-he

ConnectionNo. 269

Specified in the header connection receive according to the method described in the example above, 153, substituting 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-it 3-(2,4-acid)-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-he obtained in example 150, get a solid substance.

MS (m/z): MH+(299), MNa+(321).

EXAMPLE 155

7-Hydroxy-4-(2-hydroxyethyl)-3-(2-hydroxyphenyl)chromen-2-he

Connection # 271

Specified in the header connection receive according to the method described in the example above, 153, substituting 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-it 7-methoxy-3-(2-methoxyphenyl)-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-he obtained in example 149, get a solid substance.

MS (m/z): MH+(299), MNa+(321).

EXAMPLE 156

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

Connection # 270

Specified in the header connection receive according to the method described in the example above, 153, substituting 3-(2,4-acid)-7-methoxy-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-it 3-(2,4-acid)-7-fluoro-4-[2-(2-trimethylsilyloxy)ethyl]chroman-2-he received oprimary 151, get a solid substance.

MS (m/z): MH+(317), MNa+(339).

EXAMPLE 157

3-(2,4-Dihydroxyphenyl)-4-(2-hydroxyethyl)-6-methylchromone-2-he

Connection # 268

Specified in the header connection receive according to the method described in the example above, 153, substituting 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]chroman-2-he obtained in example 152, get a solid substance.

MS (m/z): MH+(313), MNa+(335).

EXAMPLE 158

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

Connection # 56

A suspension of 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-she obtained in example 153, (2.5 g) and anhydrous THF (40 ml) is cooled to a temperature of approximately -5 to 0°C. Then, to the reaction mixture add diisopropylethylamine (DIAD, 64,5 ml) in a 35-minute period and the mixture was stirred at -5°C for 30 minutes Then add a solution of triphenylphosphine (to 8.41 g) in THF (160 ml) for a 30-minute period, the reaction mixture is heated to 20°C and stirred for 18 hours. The solvent concentrate thein the vacuumat 60°C and the resulting residue is dissolved is in CH 2Cl2(300 ml) and washed three times with 2 n.NaOH solution (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°C and acidified to pH ˜1-2 using concentrated HCl solution (37%), the resulting suspension is stirred at 10°C for 1 hour. The solid product produce by filtration and dense precipitate on the filter was washed with H2O (50 ml). Specified solid product is dried in vacuum, obtaining specified in the title compound in the form of solids.

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

1H-NMR (300 MHz, THF-d8): δ (ppm) 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 example above, 153, substituting 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it 3-(2,4-dihydroxyphenyl)-4-(2-hydroxyethyl)chromen-2-he obtained in example 158, get a solid substance.

MC (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-he

Connection # 223

Specified in the header connection receive methods is e, described in the example above, 153, substituting 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-he is 7-hydroxy-4-(2-hydroxyethyl)-3-(2-hydroxyphenyl)chromen-2-he obtained in example 158, get a solid substance.

MC (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-he

Connection # 226

Specified in the header connection receive according to the method described in the above example 158, substituting 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it 3-(2,4-dihydroxyphenyl)-7-fluoro-4-(2-hydroxyethyl)chromen-2-he obtained in example 156, get a solid substance.

MC (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-he

Connection # 287

Specified in the header connection receive according to the method described in the above example 158, substituting 3-(2,4-dihydroxyphenyl)-7-hydroxy-4-(2-hydroxyethyl)chromen-2-it 3-(2,4-dihydroxyphenyl)-4-(2-hydroxyethyl)-6-methylchromone-2-he obtained in example 157, get a solid substance.

MC (m/z): M+H= 295, M+Na= 317.

EXAMPLE 163

2-(tert-Butyldimethylsilyloxy)-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthas the Lin-5-he

Connection # 228

Specified in the header connection receive according to the method described in example 22, replacing 2,8-dihydroxy-11H-chromeno[4,3-c]chromen-5-he 2-hydroxy-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-it, get a solid substance.

MC (m/z): M+H= 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-he

Compound No. 288

Specified in the header connection receive according to the method described in example 22, replacing 2,8-dihydroxy-11H-chromeno[4,3-c]chromen-5 is 8-fluoro-2-hydroxy-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-it, get a solid substance.

MC (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 example 84, substituting 2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9(1N)-2-(tert-butyldimethylsilyloxy)-8-fluoro-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he receives a yellow solid.

MC (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

Connection # 207

Specified in the header connection receive according to the method described in example 84, substituting 2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-2,3-dihydro[1]benzopyrano[4,3-e][1]benzoxazin-9(1N)-2-(tert-butyldimethylsilyloxy)-9-methyl-11,12-dihydro-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-he receives a yellow solid.

MC (m/z): M+H= 411, M+Na= 433.

EXAMPLE 167

7-Methoxy-3-(2-methoxyphenyl)-4-methylpropan-2-he

ConnectionNo. 289

Specified in the header connection receive according to the method described in example 1, substituting 2,4-dihydroxyacetophenone and 4-dimethoxyphenylacetic acid respectively of industrially produced 2,4-dimethoxyacetophenone and 2-methoxyphenylazo acid, receives a yellow solid.

MC (m/z): M+H=297, M+Na = 319.

EXAMPLE 168

3-(2-Methoxyphenyl)-4,6-dimethylamino-2-he

Connection # 290

Specified in the header connection receive according to the method described in example 1, substituting 2,4-dihydroxyacetophenone and 4-dimethoxyphenylacetic acid the meet is but 4-methyl-2-hydroxyacetophenone and 2,4-dimethoxyphenylacetic acid, receives a yellow solid.

MC (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

Connection # 186

To a transparent solution of 2-(4-iodinase)ethanol (400 mg, 5 EQ.) in THF (10 ml) add isopropylacrylamide (3.0 ml, ˜1,0 M, 10 EQ.). After 10 min 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) at 25°C and stirred for 30 min, after which the reaction mixture is quenched with saturated aqueous NH4Cl. After blanking add EtOAc (200 ml), the organic layer separated and dried over anhydrous Na2SO4concentrate under reduced pressure to give crude oil. The crude oil was dissolved in toluene (10 ml) and then treated with TFA (0,023 ml, 1 EQ.) when 0°C. then the reaction mixture was 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 to give crude oil. Crude oil is purified column flash chromatography, getting mentioned in the title compound in the form of a frothy mass.

1H NMR (CDCl3): δ 7,35-of 6.29 (m, 10H), of 6.02 (s, 1H), to 4.62 (t, 2H, J=6.5 Hz), 4,01-3,83 (who, 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 on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 50% IPA and 50% hexane at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, 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]20D= +33,5° (c 0,36, 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]20D= -33,5° (c 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}propan-1-ol

Compound No. 191

Following the same methodology described in example 169, replacing 2-(4-iodinase)ethanol 3-(4-iodinase)propan-1-ol (2,78 g, 10 mmol, 5 EQ.) get listed in the title compound as a white solid.

Anal. Calculated for C38H52O6Si2:

WITH 69,05; N 7,93, S 8,50.

Found: 68,68; N 8,00, Si 8,90.

1H NMR (CDCl3): δ 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}propan-1-ol (850 mg), loaded on a ChiralPak AD chiral GHUR-column (5 cm VND x 50 cm length.) and elute 50% IPA and 50% hexane at a flow rate of 150 ml/min Fraction, corresponding to two peaks, evaporated in vacuum, obtaining the following two 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]20D= 29,5° (c 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}propan-1-ol.

[α]20D= -29,5° (c 0,36, CHCl3).

EXAMPLE 171

5S*-(+)-1-{2-[4-(2,8-Dihydroxy-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-5-elfenix]ethyl}pyrrolidin-2,5-dione

Connection # 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), according to the scientists to example 169, and succinamide (49.5 mg) in CH2Cl2(5 ml) add triphenylphosphine (132 mg) and DEAD (0.8 ml) and the reaction mixture is stirred for 12 hours. Then the reaction mixture was 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, 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): MH+(729); M-H (727).

[α]20D= -35,5° (c 0,36, CHCl3).

Stage B

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 in the above stage A, (220 mg) is dissolved in a mixture of acetonitrile : pyridine (10:1). Add HF·b

Beaupied (0.5 ml) and the reaction mixture is stirred for 12 hours at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3(100 ml) and then diluted with ethyl acetate (200 ml). The organic layer was separated and then concentrated under reduced pressure to give crude oil. Crude oil is purified flash chromatography, getting mentioned in the title compound in the form of solids.

MS (m/z): MH+ (500); M-H (498).

Following the techniques described is shown above schemes and the examples, get typical compounds of the present invention, are listed in tables 1-3. For stereoconfiguration group, R2R* - ( -) - and S*-(+) symbols indicate that the exact orientation is not installed.

Typical examples of intermediate compounds for preparing compounds of formula (I) are listed in the following tables 4 and 5.

Table 4
ID

No
R12(R13)nDR11Est. MW
608-benzyloxy2-benzyloxybenzoyl-CH(OH)-phenyl702,71
618-hydroxy2-hydroxy H-CH(OH)-phenyl390,38
628-hydroxy2-hydroxyH-CH2OH314,29
638-(2-SEM)2-(2-SEM)SEM-CH(OH)-phenyl781,17
648-(2-SEM)2-(2-SEM)SEM-CH(OH)-CH2CH2CH3747,16
658-benzoyloxy2-Benzyloxybenzoyl-C(O)-phenyl596,58
668-(2-SEM)2-(2-SEM)SEM-CH2OH705,07
678 Momoki2 MomokiMOM-CHO444,43
688 Momoki2 MomokiMOM-CH OH446,44
698-(2-SEM)2-(2-SEM)SEM-C(O)OCH3733,08
708-(2-SEM)2-(2-SEM)SEM-C(O)O-phenyl796,15
718-hydroxy2-hydroxyH-C(O)O-phenyl404,37
728-(2-SEM)2-(2-SEM)SEM-CHO703,06
738-methoxy2-methoxymethylH326,34
748-methoxy2-methoxymethylBr405,24
758-(2-SEM)2-(2-SEM)SEMH675,05
768-(2-SEM) 2-(2-SEM)SEMBr753,94
778-hydroxy2-hydroxyHBr363,16
788 Momoki2 MomokiMOMH416,42
798 Momoki2 MomokiMOMBr495,32
808-benzyloxy2-benzyloxybenzoylH596,58
818 pivaloyloxy2 pivaloyloxythe pivaloylH536,61
828-hydroxy2-hydroxyHH284,07
838-benzyloxy2-benzyloxybenzil Br674,06
2292-trimethyl-ciliatoxic-methoxy8-trimethyl-ciliatoxic-methoxytrimethylsilyl-ethoxymethyliodomethyl814,99
2302-trimethyl-ciliatoxic-methoxy8-trimethyl-ciliatoxic-methoxytrimethylsilyl-ethoxymethylchloromethyl723,53
2312-hydroxy8-hydroxyHchloromethyl332,74
2322-hydroxy8-hydroxyHiodomethyl424,19
2332-trimethyl-ciliatoxic-methoxy8-trimethyl-ciliatoxic-methoxytrimethylsilyl-ethoxymethylphenoxy-carbonyl797,19
2342-hydroxy8-hydroxyHchloromethyl-carbonyl 360,75
2362-hydroxy8-hydroxyH1-phenyl-1-hydroxy-methyl392,41
2372-methoxy-methoxy8-methoxy-methoxymethoxymethylchloromethyl-carbonyl492,91
2382-trimethyl-ciliatoxic-methoxy8-trimethyl-ciliatoxic-methoxytrimethylsilyl-ethoxymethylchloromethyl-carbonyl751,55
2392-methoxy-methylH296,33
2402-methoxy-methylbromine375,22
241--methylH266,3
2422-methoxy8,10-dimethoxymethyl bromine435,27
243--methylbromine345,2
244--Hbromine331,17
2472-methoxy7-methoxymethylH326,35
2482-methoxy8-methoxymethylchloromethyl-carbonyl402,83
251--methyl4-methoxy-phenyl372,42
252--H4-hydroxy-phenyl344,37
254--methylcarbamylbromo and 4-methoxy-carbonyl-phenyl507,34
2552-methoxy 8-methoxymethylmethoxy-methyl-carbonyl398,42
2562-trimethyl-ciliatoxic-methoxy8-trimethyl-ciliatoxic-methoxytrimethyl-ciliatoxic-methyltrimethyl-silyl-ethoxy-methyl805,33
2572-methoxy-methoxy8-methoxy-methoxymethoxymethyltrimethyl-silyl-ethoxy-methyl546,7
2582-methoxy8-methoxymethyltrimethyl-silyl-ethoxy-methyl456,62
2592-methoxy-methyltrimethyl-ciliatoxic-methyl426,59
2602-methoxy-methylmethoxy-methyl340,38
261-8-methoxymethyl methoxy-methyl340,38
262-8-methoxymethyltrimethyl-silyl-ethoxy-methyl426,59
263-8-fluoromethyltrimethyl-silyl-ethoxy-methyl414,55
2642-methoxy8-fluoromethyltrimethyl-silyl-ethoxy-methyl444,58
2652-methoxy8-fluoromethylmethoxy-methyl358,37
2662-methoxy9-methylmethylmethoxy-methyl354,41
2672-methoxy9-methylmethyltrimethyl-silyl-ethoxy-methyl440,62
2682-hydroxy9-methylH hydroxy-methyl312,33
2692-hydroxy-Hhydroxy-methyl298,3
2702-hydroxy8-fluoroHhydroxy-methyl316,29
271-8-hydroxyHhydroxy-methyl298,3
284-8-fluoromethylH
2852-methoxy8,10-dimethoxyHH
289-8-methoxymethylH
290-9-methylmethylH
The symbol "-" means that the substituent R12 or R 13no
Table 5
ID

No
R3R4YTEst. MW
2492-(tert-butyl-dimethyl-silyloxy)8-(tert-butyl-dimethyl-silyloxy)-CH2CH2-4-(hydroxy-n-propoxy)-phenyl679,02
2452-(tert-butyl-dimethyl-silyloxy)8-(tert-butyl-dimethyl-silyloxy)-CH2CH2-4-(Piperi-dinyl-ethoxy)phenyl587,84
246---CH2-4-(Piperi-dinyl-ethoxy)-phenyl457.57
2352-(tert-butyl-dimethyl-silyloxy)8-(tert-butyl-dimethyl-silyloxy)-CH2CH2-4-(Piperi-dinyl-ethoxy)phenyl732,13
291 8-(tert-butyl-dimethyl-silyloxy)-CH2CH2-CH2-4-(Piperi-dinyl-ethoxy)-phenyl
The symbol "-" means that the substituent R3or R4no

Other compounds obtained as an intermediate in the synthesis of the compounds of the present invention, include the following:

also known as 2,8-bis(tert-butyldimethylsilyloxy)-5,11-dihydrobromide[4,3-c]chromen-5-carbonitrile;

also known as 4-[4-(4-acetoxyphenyl)-2-oxo-2H-chromen-3-yl]phenyl ester of acetic acid;

also known as 2,6,12-Tris[[(1,1-dimethylethyl)dimethylsilane]oxy]-3,9-dihydro-[1]benzopyrano[4,3-e][1]benzoxazin-9-ol;

also known as 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;

also known as 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 thiocarbonic acids;

also known as O-[6,2-bis[[(1,1-dimethylethyl)dimethylsilane]oxy]-1,2,3,9-tetrahydro-9-oxo[1]benzopyrano[4,3-e][1]benzoxazin-2-yl]-S-methyl ether dithiocarbonic acid;

also known as 11H-chromeno[4,3-c]chromen-5-he, and

also known as 3-acetyl-7-methoxy-2-methylpropan-4-one.

Example 172

Analysis of estrogen receptor-α using tablet Flash

This test is used to control the binding of radiolabelled estrogen with estrogen receptor. The test is carried out on a BioMek 2000 (Beckman). Tablets read using a scintillation counter (Packard TopCount) with reduced single pulse, receiving the characteristic binding of the compound to the receptor. The analysis is performed according to the method described in Allan et al.,Anal. Biochem.(1999),275(2), 243-247.

On the first day of 100 ál of estrogen-screening buffer (ESB, Panvera)containing 5mm of dithiothreitol (DTT, Panvera), 0.5 μg mouse anti-estrogenic receptor monoclonal antibodies (SRA-1010, Stressgen) and 50 ng of purified estrogen receptor-α person (Panvera), add to each cell 96-well Flash Plate Plus tablet containing sewngoat antimurine antibodies (NEN Life Sciences). The tablet is sealed and incubated at 4°C during the night.

On the second day of each of the wells washed three times with 200 µl PBS, pH of 7.2, at room temperature. Then to each of the wells was added to 98 μl ofradiolabelled estrogen (0.5 nm, Thu is equivalent to 6 NCI at 120 CI/mmol party, Amersham), diluted ESB and 5mm of dithiothreitol (DTT). Then to specific cells added to 2.5 μl ofthe test compounds diluted in 30% (V/V) mixture of dimethyl sulfoxide/50 mm HEPES, pH 7.5. The contents of the cells thrice mixed by aspiration, tablet, sealed and incubated at room temperature for one hour. Then the cell is considered for 1 min atTopCount scintillation counter (Packard).

EXAMPLE 173

Fluorescence polarization analysis of estrogen receptor-β

This analysis controls the binding of a fluorescent analogue of estrogen (Fluormone ES2, Panvera) with estrogen receptor. Tablets read using fluorimetry installed in the polarization mode. The decrease in fluorescence compared to the control with the solvent indicates the binding of the compound to the receptor.

It is important during this experiment to avoid getting air bubbles in the reaction mixture in each of the cells in the 96-well plate. (Bubbles on the surface of the reaction mixture violate luminous flux, affecting polarization data). In addition, it is also important to thoroughly mix the reaction components adding to the cell.

Ice get 2X the standard mixture of analytical buffer (Panvera), 10 nm DTT and 40 nm ES2. Ice also get 2X p is a promotional mix of analytical buffer (Panvera) and 20 nm ehr-β (Panvera) and 40 nm ES2.

Diluted samples of the test compounds receive a 30% (V/V) mixture of dimethyl sulfoxide/50 mm HEPES, pH 7.5. Here perform breeding 40X desired final concentration.

Then for each cell add 50 ál of standard mixture. All cells add 48 ál of the reaction mixture. To the corresponding cells add 2.5 μl of the diluted sample connection. The reaction mixture is stirred using a manual pipette, tablet cover the adhesive coating from a roll of aluminum foiland incubatedat room temperature for 1 hour.

Each of the cells read on the LjL Analyst at a wavelength of 265 nm excitation and wavelength emission 538.

Illustrative compounds of the present invention analyzed by the method described above for binding to the estrogen receptor-α and binding to estrogen receptor-βthe results are shown in table 6.

td align="center"> 173
TABLE 6
ID NoEstrogen receptor-α μm (No.)Estrogen receptor-β μm (No.)
1worn : 0.505 (4)0,061
2>10K(4)>10K(4)
60,013(2)0,016 (4)
90,0023(2) 0,084 (2)
110,009 (2)0,7 (6)
130,006 (2)0,026 (2)
140,0074 (4)0,15(4)
150,017(4), 0,00640,017(4), 0,028
170,0014 (2)0,031 (2)
190,0019(2)0,099 (2)
210,015(2)0,011 (2)
223,45 (2)>10K(2)
245,95 (4)>10K(2)
251,2(2)>10K(2)
260,014 (5)of 0.02 (4)
270,69 (2)>10K(2)
280,14(2)6,25 (2)
290,004 (4)0,017(4)
30>10K(4)>10K(4)
33NANA
411,9(2)>10K(2)
430,62 (2)0,165(2)
89>1,00>1000
900,006690
990,003910
1000,002620
1250,07928
1260,004230
1310,061220
1320,004866
1460,006299
1470,180190
1480,003626
1490,01534
1500,019110
1510,01425
1520,0086110
1530,006623
1540,004235
1550,088140
1630,01312
1640,002824
1650,001611
1660,001820
1670,007013
1680,004228
1690,0721000
1700,160460
1710,1401000
172is 0.2601000
0,1701000
1740,0015, 0,001329,18
1750,6601000
1760,0241000
1770,040330
1780,0064, 0,0076181,5,360
1791,001000
1801,001000
1810,001110
1830,0149,1
1900,008916
1950,125200
1960,055595
2760,024260
NA means redetection activity for the tested concentration

EXAMPLE 174

The test on the proliferation of MCF-7 cells

This test is carried out according to the method described in Welshons et al., (Breast Cancer Res. Treat,1987, 10(2), 169-75), with minor changes.

Briefly, MCF-7 cells (from Dr. C. Jordan, Northwestern University) support in not containing phenol red RPMI 1640 medium (Gibco) with 10% FBS (Hyclone), supplemented bovine insulin and non-essential amino acids (Sigma). Initially, cells treated with 4-guide what oxfamamerica (10 -8M) and left to stand at 37°C within 24 hours. After such incubation with tamoxifen cells treated with compounds at various concentrations.

The investigated method agonist compounds added to the culture mediain various concentrations. Compounds analyzed by the method of antagonists, bred in a similar way and to a cultural environments also add 10 nm 17β-estradiol. Cells incubated for 24 hours at 37°C. After this incubation to a cultural environments add14C-thymidine activity of 0.1 µci (56 MCI/mmol, Amersham) and the cells incubated a further 24 hours at 37°C. the cells are Then washed twice buffered saline Hanks (HBSS) (Gibco) and carry out the expense on the scintillation counter. The increase in the content of14C-thymidine processed in connection cells compared with cells treated as a control solvent, represents the percentage increase of cell proliferation.

Illustrative compounds of the present invention investigated according to the method described above, the obtained results are presented in table 7.

TABLE 7
ID Noagonist (No.) (nm)antagonist (No.) (nm)
11200(1)&t; 10K(1)
2>10K(1)>10K(1)
697(1)>10K(1)
9>10K(12)777 (6)
11>10K(1)246 (3)
13>10K(1)1400(1)
14>10K(7)5600 (2)
15>10K(7)6,25 (2)
17>10K(1)3580(1)
19>10K(6)713(4)
21>10K(4)970 (4)
22>10K(8)662 (7)
24>10K(6)672 (6)
25>10K(10)1393(6)
2664,3 (3)>10K(3)
27NANA
28NANA
29NANA
30>10K(1)2200(1)
33>10K(1)4800(1)
41>10K(1)>10K(1)
43>10K(1)>1K(1)
89845
901670
99182
10075
1254700
126245
131>10000
1321280
1461123
147>10000
148997
1491360
1502940
1512760
1522612
1531274
1541437
155>10000
163687
164293
165401
166217
167424
168220
169 10000
17010000
1715100
1722280
173>10000
1741744
1755000
176>10000, 4000
1773000
1781476
1791866
180655
1811335
18310000
190>10000
195>1000
196>1000
2764680
NA means redetection activity for the tested concentration

EXAMPLE 175

The test for alkaline phosphatase in human endometrial Ishikawacells

This test is carried out according to the method described in Albert et al.,Cancer Res,(9910),50(11), 330-6-1, with minor changes.

Ishikawa cells (from ATCC) support in DMEM/F12 (1:1), not containing phenol red medium (Gibco), supplemented with 10% calf serum (Hyclone). 24 hours before the test medium is replaced by DMEM/F12 (1:1), not containing phenol red medium with 2% calf serum.

The investigated method agonist compounds added to the culture mediain various concentrations. Compounds analyzed by the method of antagonists, bred in a similar way and to a cultural environments also add 10 nm 17β-estradiol. The cells are then incubated at 37°C for 3 days. On the fourth day, the medium is removed, to a cell add 1 volume of 1X dilution buffer (Clontech), followed by addition of 1 volume of analytical buffer (Clontech). The cells are then incubated at room temperature for 5 minutes. Add 1 volume of freshly prepared chemiluminescent buffer (1 volume chemiluminescent substrate (CSPD) in 19 volumes chemiluminescent enhancer at a final concentration of 1.25 mm CSPD; Sigma Chemical Co.). Cells are incubated at room temperature for 10 minutes and then quantify luminometer. Enhancing chemiluminescence compared to the control solvent used for calculating the increase of alkaline phosphatase activity.

Illustrative compounds of the present invention ISS is adavani according to the method described above, the results are presented in table 8.

TABLE 8
ID Noagonist (No.) (nm)antagonist (No.) (nm)
1130(1)>10K(1)
2>10K(1)>10K(1)
633(2)>10K(1)
9>10K(12)110(7)
1180(1)
13>10K(2)228 (2)
14>10K(11)149 (6)
15>10K(11)112(7)
17>10K(6)513 (5)
19>10K(1)250(1)
21>10K(9)830 (8)
22>10K(11)53,5(11)
24>10K(9)66(10)
25>10K(11)235 (10)
26>10K(5)180(1)
27NANA
28NANA
29NANA
30>10K(1)630(1)/td>
33>10K(1)1000(1)
41>10K(1)550(1)
43>10K(1)1600(1)
8910
9057
99130
10019
1251620
12678
1314940
132548
146154
147>10000
148138
1491020
150850
151605
152324
153509
154167
1553770
163405
16461
15 128
16641
16735
168287
169830
1702664
17156,7
17268,4
173>10000
174135
175300
176>10000, 793
177259
178125
1799
1800,9
18134
1833000
190>10000
195>739
196>229
276481
NA means redetection activity to test the end of the ation

EXAMPLE 176

As a specific variant of oral composition, 100 mg of compound No. 22 obtained in example 54, are mixed to obtain a composition with a sufficiently finely powdered lactose, receiving a total amount of 580 to 590 mg used for filling hard gelatin capsules of size O.

Although in the above description sets forth the main provisions of this invention, involving examples for purposes of illustration, it is obvious that almost the invention covers all modifications, improvements and/or changes as included in the scope of the attached points and cash equivalents.

1. The compound of formula (I),

wheremeans simple or double bond,

X is O and Y is chosen from the group including: CRARB, CRARB(CRARB)1-2, CRARBC(O), CRARBC(O)CRARBand C(O); alternatively, Y means O and X are selected from the group including CRARBand C(O); where each of RAand RBindependently selected from the group comprising: hydrogen, hydroxy, alkyl or alkoxy; provided that not each of RAand RBmeans hydroxy;

Z means About;

R1selected from the group consisting of Dort, alkyl, alkenyl, cycloalkyl, aryl, -C(O)-aryl, where the alkyl or aryl group optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, alkoxy, CO2H, RC, -ORC, -C(O)-ORC, -C(O)O-(alkyl)-NRDRE, -NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -O-(alkyl)-ORD;

where RCselected from the group including alkyl and geterotsiklicheskikh; where geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, alkyl, alkoxy or NRDRE;

where Q means About;

where each of RDand REindependently selected from the group comprising hydrogen and alkyl;

alternative, RDand REtogether with the nitrogen atom to which they are attached, form a 3-10-membered ring which is selected from the group including heteroaryl or heteroseksualci;

R2selected from the group comprising hydroxy, alkyl, alkenyl, cycloalkyl, aryl, -C(O)-aryl, where the alkyl or aryl group optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, alkoxy, CO2H, RC, -ORC, -C(O)-ORC-C(O)O-(alkyl)-NRDRE, -NR DRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -O-(alkyl)-ORD;

alternative, R1and R2together with the carbon atom to which they are attached form C(O);

provided that when R1and R2together with the carbon atom to which they are attached form C(O) and X is O, Y is chosen from the group including CRARB, CRARB(CRARB)1-2, CRARBC(O) and CH2C(O)CH2;

provided that when R1and R2together with the carbon atom to which they are attached form C(O) and Y represents Oh, then X is chosen from the group including CRARB;

n means an integer that is chosen in the range from 0 to 4;

each of R3independently selected from the group including halogen, hydroxy, RC, -C(O)RG, -C(O)ORG, -OC(O)RG, -OSi(RG)3, -ORG;

where each of RGindependently selected from the group comprising hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one;

m means an integer that is chosen in the range from 0 to 4;

each of R4independently selected from the group including halogen, hydroxy, RC, -C(O)RG, -C(O)ORG, -OC(O)RG, -OSi(RG)3, -ORG;

when the service is provided whenmeans a double bond, X is CH2Y means O, Z denotes O and R1and R2together with the carbon atom to which they are attached form C(O), then at least one of n or m means an integer that is chosen in the range from 1 to 4;

provided also that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen and R2means alkyl, then at least one of n or m means an integer that is chosen in the range from 1 to 4;

provided also that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen, R2means alkyl, n is 1 and m is 1, R3and R4other than methoxy or ethoxy;

provided also that whenmeans a double bond, X is O, Y represents CH2Z denotes O, R1and R2together with the carbon atom to which they are attached form C(O), n is 0 and m is 2, each R4different from hydroxy, or alkoxy;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wheremeans simple or double bond, X is O;

Y wybir the t group, includes: CRARB, CRARB(CRARB)1-2, CRARBC(O)CH2C(O)CH2C(O) and CH2CRARBCH2; where each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, lower alkyl or lower alkoxy; provided that not each of RAand RBmeans hydroxy;

Z means About;

R1selected from the group comprising: hydrogen, lower alkyl, lower alkenyl, aryl, -C(O)-aryl, where the lower alkyl group or aryl group optionally substituted by one or two substituents that are independently chosen from the group comprising: hydroxy, lower alkoxy, CO2H, RC, -NRDRE-C(O)O-(lower alkyl)-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -O-(lower alkyl)-ORD;

where RCselected from the group comprising lower alkyl and heteroseksualci(lower alkyl); where heteroseksualci(lower alkyl)other group optionally substituted by one or two substituents that are independently chosen from the group comprising hydroxy, lower alkyl, lower alkoxy or NRDRE;

where each of RDand REindependently selected from the group comprising hydrogen and lower alkyl; alternatively, RDand REtogether with the nitrogen atom to which they shall uedineny, form a 5-6-membered ring which is selected from the group including heteroaryl or heteroseksualci;

R2selected from the group comprising hydroxy, lower alkyl, lower alkenyl, aryl or-C(O)-aryl, where the lower alkyl group or aryl group optionally substituted by one or two substituents that are independently chosen from the group comprising hydroxy, lower alkoxy, -C(O)-O(lower alkyl), CO2H, RC, -ORC, -NRDRE-C(O)O-(lower alkyl)-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -O-(lower alkyl)-ORD;

alternative, R1and R2together with the carbon atom to which they are attached form C(O);

provided that when R1and R2together with the carbon atom to which they are attached form C(O) and X is O, Y is chosen from the group including CRARB, CRARB(CRARB)1-2, CRARBC(O)CH2C(O)CH2and CH2CRARBCH2;

n means an integer that is chosen in the range from 0 to 2;

each of R3independently selected from the group including halogen, hydroxy, RC, -OC(O)RG, -OSi(RG)3and-ORG;

where each of RGindependently selected from the group including hydrogen, lower alkyl, and the sludge, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one;

m means an integer that is chosen in the range from 0 to 2;

each of R4independently selected from the group including halogen, hydroxy, RC, -OC(O)RG, -OSi(RG)3and-ORG;

provided that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen and R2means lower alkyl, then at least one of n or m means an integer that is chosen in the range from 1 to 4;

provided also that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen, R2means alkyl, n is 1 and m is 1, R3and R4other than methoxy or ethoxy;

provided also that whenmeans a double bond, X is O, Y represents CH2Z denotes O, R1and R2together with the carbon atom to which they are attached form C(O), n is 0 and m is 2, each R4different from hydroxy, or alkoxy;

or its pharmaceutically acceptable salt.

3. The compound according to claim 1, where

means simple or double bond,

X is chosen from the group including CR ARBand C(O);

Y means Of;

where each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, lower alkyl or lower alkoxy; provided that not each of RAand RBmeans hydroxy;

Z means About;

R1selected from the group including hydrogen, lower alkyl, lower alkenyl, aryl or-C(O)-aryl, where the lower alkyl group or aryl group optionally substituted by one or two substituents that are independently chosen from the group comprising: hydroxy, lower alkoxy, CO2H, RC, -NRDRE-C(O)O-(lower alkyl)-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -O-(lower alkyl)-ORD;

where Rcselected from the group comprising lower alkyl and heteroseksualci(lower alkyl); where heteroseksualci(lower alkyl)other group optionally substituted by one or two substituents that are independently chosen from the group comprising: hydroxy, lower alkyl, lower alkoxy, or NRDRE;

where each of RDand REindependently selected from the group comprising hydrogen and lower alkyl;

alternative, RDand REtogether with the nitrogen atom to which they are attached, form a 5-6-membered ring which is selected from the group including heteroaryl and the and heteroseksualci;

R2choose from a group including: hydroxy, lower alkyl, lower alkenyl, aryl and-C(O)-aryl, where the lower alkyl group or aryl group optionally substituted by one or two substituents that are independently chosen from the group comprising: hydroxy, lower alkoxy, CO2H, RC, -ORC, -NRDRE, -C(O)O-(lower alkyl)-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -O-(lower alkyl)-ORD;

alternative, R1and R2together with the carbon atom to which they are attached form C(O);

provided that when R1and R2together with the carbon atom to which they are attached form C(O) and Y represents Oh, then X is chosen from the group including CRARB;

n means an integer that is chosen in the range from 0 to 2;

each of R3independently selected from the group comprising: halogen, hydroxy, RC, -OC(O)RG, -OSi(RG)3and-ORG;

where each of RGindependently selected from the group comprising: hydrogen, lower alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one;

m means an integer that is chosen in the range from 0 to 2;

each of R4independently selected from the group comprising: halogen, hydroxy, RC, -OC(O)RG, -OSi(R G)3, -ORG;

provided that whenmeans a double bond, X is CH2Y means O, Z denotes O and R1and R2together with the carbon atom to which they are attached form C(O), then at least one of n or m means an integer that is chosen in the range from 1 to 4;

or its pharmaceutically acceptable salt.

4. The compound according to claim 2, wheremeans of the double bond,

X is O;

Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(lower alkoxy)-, -CH(OH)-, -CH2CH(OH)CH2-, -CH(lower alkyl)-, -CH2C(O)- and-CH2C(O)CH2-;

Z means About;

R1selected from the group comprising hydrogen and lower alkyl;

R2selected from the group comprising hydroxy, lower alkenyl, carboxy-lower alkyl, hydroxy-lower alkyl, aryl, 4-(1-N-containing heteroseksualci (where specified N-containing heteroseksualci bound through the N atom)alkoxy)-phenyl, 4-(di(lower alkyl)aminoethoxy)phenyl, 4-(di(lower alkyl)amino)phenyl, lower alkoxy-carbonyl-lower alkyl, 4-(lower alkoxy-lower alkoxy)-phenyl, di(lower alkyl)amino(lower alkoxy)carbonyl(lower alkyl), (N-containing heteroseksualci (where specified N-containing heterocy loukil bound through the N atom))-(lower alkoxy)carbonyl(lower alkyl), 4-((N-containing heteroseksualci)(lower alkoxy))phenylcarbamoyl, 4-(hydroxy-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;

alternative R1and R2together with the carbon atom to which they are attached form C(O);

n is an integer from 0 to 1;

R3selected from the group including halogen, hydroxy, lower alkoxy, three(lower alkyl)silyloxy, -OC(O)-(lower alkyl), or-OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one);

m is an integer from 0 to 1;

R4selected from the group including halogen, hydroxy, lower alkyl, lower alkoxy, three(lower alkyl)silyloxy, -OC(O)-(lower alkyl), and-OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one);

or its pharmaceutically acceptable salt.

5. The compound according to claim 4, where

Y is chosen from the group comprising-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(OCH3)-, -CH(OH)-, -CH2CH(OH)CH2-, -CH((CH(CH3)2)- ,- CH2C(O)- and-CH2C(O)CH2-;

R1selected from the group comprising hydrogen and methyl;

R2selected from the group comprising hydroxy, allyl, carboxymethyl, hydroxyethyl, 3-hydroxy-npropyl, 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-separators)phenyl, 4-(diethylaminoethoxy)phenyl,

4-(dimethylaminoethoxy)phenyl, R-4-(dimethylaminoethoxide,

S-4-(dimethylaminoethoxy)phenyl, 4-(diisopropylaminoethyl)phenyl,

R-4-(diisopropylaminoethyl)phenyl, S-4-(diisopropylaminoethyl)phenyl, 4-(dimethylamino)phenyl, 4-(1-piperidinyl-n-propoxy)phenyl, 4-(methoxyethoxy)phenyl, methoxycarbonylmethyl, isopropoxycarbonyloxymethyl, dimethylaminocarbonylmethyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, morpholinylcarbonyl, dimethylamino-n-propoxycarbonyl, 4-(piperidinyloxy)phenylcarbamoyl, 4-(2-hydroxyethoxy)phenyl, R-4-(2-hydroxyethoxy)phenyl, S-4-(hydroxyethoxy)phenyl, 4-(3-hydroxy-n-propoxy)phenyl, R-4-(3-hydroxy-n-propoxy)phenyl, S-4-(3-hydroxy-n-propoxy)phenyl, R-4-(piperidinyl-2,6-donatacci)phenyl, R-4-(pyrrolidinyl-2,5-donatacci)phenyl, S-4-(pyrrolidinyl-2,5-donatacci)phenyl, R-4-(pyrrolidinyl-2,5-dione-n-propoxy)phenyl, and S is 4-(pyrrolidinyl-2,5-dione-n-propoxy)phenyl;

alternative R1and R2together with atmosphered, to which they are attached form C(O);

R3chosen from the group comprising fluorine, hydroxy, methoxy, tert-butyldimethylsilyloxy, -OC(O)-methyl, -OC(O)-tert-butyl or-OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one);

R4chosen from the group comprising fluorine, hydroxy, methyl, methoxy, tert-butyldimethylsilyloxy, -OC(O)-methyl, -OC(O)-tert-butyl, -OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one);

or its pharmaceutically acceptable salt.

6. The compound according to claim 5, where

Y is chosen from the group comprising-CH2-, -CH2CH2- -CH2CH2CH2-, -CH(OCH3)- and-CH(OH)-;

R2selected from the group comprising phenyl, 4-(1-piperidinyloxy)phenyl, R-4-(piperidinyloxy)phenyl, S-4-(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-4-(dimethylaminoethoxy)phenyl, S-4-(dimethylaminoethoxy)phenyl, R-4-(diisopropylaminoethyl)phenyl, S-4-(diisopropylaminoethyl)phenyl, 4-(dimethylamino)phenyl and 4-(3-hydroxy-n-propoxy)phenyl;

alternative R1and R2together with the carbon atom to which they are attached form C(O);

R3selected from the group comprising hydroxy, methoxy, and-OC(O)-tre is butyl;

R4chosen from the group comprising fluorine, hydroxy, methoxy, and-OC(O)-tertbutyl;

or its pharmaceutically acceptable salt.

7. The connection according to claim 6, where Y is chosen from the group comprising: -CH2-, -CH2CH2- -CH2CH2CH2- , and-CH(OH)-;

R2selected from the group comprising phenyl, 4-(1-piperidinyloxy)phenyl, R-4-(piperidinyloxy)phenyl, S-4-(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-4-(dimethylaminoethoxy)phenyl, S-4-(dimethylaminoethoxy)phenyl, R-4-(diisopropylaminoethyl)phenyl, S-4-(diisopropylaminoethyl)phenyl, 4-(dimethylamino)phenyl and 4-(3-hydroxy-n-propoxy)phenyl;

or its pharmaceutically acceptable salt.

8. The connection according to claim 7, where R1selected from the group comprising hydrogen and methyl;

R2selected from the group comprising phenyl, 4-(1-piperidinyloxy)phenyl, R-4-(piperidinyloxy)phenyl, S-4-(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, S4(diisopropylaminoethyl)phenyl, 4-(dimethylamino)-phenyl and 4-(3-hydroxy-n-propoxy)phenyl;

R3selected from the group comprising hydroxy, and-OC(O)-tertbutyl;

or its pharmaceutically acceptable salt.

9. The compound according to claim 5, where the compound of formula (I) are selected from the group including

2-(2,2-dimethyl-propionyloxy)-8-(2,2-dimethylpropionic)-5-[4-(2-piperidine-1-yl-ethoxy)phenyl]-5,11-dihydrobromide[4,3-C]chromen-2-silt ether of 2,2-dimethylpropionic acids;

2-(2,2-dimethylpropionic)-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 acids;

2-(2,2-dimethylpropionic)-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 acids;

8-fluoro-5-[4-(2-piperidine-1-yl-n-propoxy)phenyl]-5,11-dihydrobromide[4,3-C]chromen-2-ol;

8-(2,2-dimethylpropionic)-5-hydroxy-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalene-2-silt ether of 2,2-dimethylpropionic acids;

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

5R-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-C]chromen-2,8-diol;

5S-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-C]chromen-2,8-diol;

8-hydroxy-5-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-C]XP is Myung-2-silt ether

2,2-dimethylpropionic acids;

8-hydroxy-11-[4-(2-piperidine-1-ylethoxy)phenyl]-5,11-dihydrobromide[4,3-C]chromen-2-silt ether

2,2-dimethylpropionic acids;

5-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol;

5S*-(-)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol;

5R*-(+)-[4-(2-azepin-1 ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol;

5-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol;

5R*-(+)-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol;

5S*-(-)-[4-(2-dimethylaminoethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[3,4]cyclohepta[1,2-a]naphthalene-2-ol;

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;

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;

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;

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;

8-methoxy-5*-(-)-[4-(2-piperidine-1-ylethoxy)phenyl]-11,12-dihydro-5H-6,13-dioxobenzo[34]cyclohepta[1,2-a]naphthalene-2-ol,

and its pharmaceutically acceptable salts.

10. The compound of formula (I),

wheremeans simple or double bond,

X is Oh and Y is chosen from the group including CRARB, -CRARB(CH2)1-2, CRARBC(O) C(O); alternatively, Y means O, and X is chosen from the group including CRARBand C(O);

where each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy; provided that not each of RAand RBmeans hydroxy;

Z means About;

R1selected from the group comprising hydrogen, alkyl, cycloalkyl or aryl; where the aryl group is optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, alkoxy, CO2H, RC, -ORCor-NRDRE;

where RCselected from the group including alkyl and geterotsiklicheskikh; where geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, alkyl, alkoxy, NRDREor -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE;

where each of RDand REindependently in baraut from the group including hydrogen and alkyl; alternatively, RDand REtogether with the nitrogen atom to which they are attached, form a 4-8-membered ring which is selected from the group including heteroaryl or heteroseksualci;

Q means About;

R2selected from the group comprising hydroxy, alkyl, cycloalkyl or aryl, where the aryl group is optionally substituted by one or more substituents which are independently selected from the group comprising: hydroxy, alkoxy, CO2H, RC, -ORC, -NRDREor -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE;

alternative, R1and R2together with the carbon atom to which they are attached form C(O);

provided that when R1and R2together with the carbon atom to which they are attached form C(O) and X is O, Y is chosen from the group including CRARBand CRARB(CH2)1-2;

provided that when R1and R2together with the carbon atom to which they are attached form C(O) and Y represents Oh, then X is chosen from the group including CRARB;

n means an integer that is chosen in the range from 0 to 4;

each of R3independently selected from the group including halogen, hydroxy, RC, -C(O)RG, -C(O)ORG, -OC(O)Rsup> G, -OSi(RG)3or ORG;

where each of RGindependently selected from the group comprising hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one;

m means an integer that is chosen in the range from 0 to 4;

each of R4independently selected from the group including halogen, hydroxy, RC, -C(O)RG, -C(O)ORG, -OC(O)RG, -OSi(RG)3orG;

provided that whenmeans a double bond, X is CH2Y means O, Z denotes O and R1and R2together with the carbon atom to which they are attached form C(O), then at least one of n or m means an integer that is chosen in the range from 1 to 4;

provided also that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen and R2means alkyl, then at least one of n or m means an integer that is chosen in the range from 1 to 4;

provided also that whenmeans of a simple bond, X is O, Y represents CH(alkyl), Z denotes O, R1means hydrogen, R2means alkyl, n is 1 and m is 1, R3and R4other than methoxy or ethoxy;

provided as is, whenmeans a double bond, X is O, Y represents CH2Z denotes O, R1and R2together with the carbon atom to which they are attached form C(O), n is 0 and m is 2, each R4different from hydroxy, or alkoxy;

or its pharmaceutically acceptable salt.

11. The compound of formula (D)

where

means simple or double bond,

And means On;

D is chosen from the group comprising hydrogen, methyl, acetyl, benzyl, benzoyl, SEM, MOM, BOM, TBS, TMS, pivaloyl;

each of R10and R11independently selected from the group comprising hydrogen, halogen, hydroxy, alkyl, alkoxy, -C(O)-alkyl, where alkyl group, either by itself or as part of a large group of substituents optionally substituted by one or more substituents which are independently selected from the group comprising hydroxy, halogen;

provided that not each of R10and R11means hydrogen or hydroxy;

Z means About;

n means an integer that is chosen in the range from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt.

12. The compound of formula (DI),

where

means simple or double bond,

X is Oh and Y is chosen from the group including CRARB, CRARB(CRARB)1-2, CRARBC(O), CRARBC(O)CRARBand C(O); alternatively Y represents O, and X is chosen from the group including CRARBand C(O);

where each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy; provided that not each of RAand RBmeans hydroxy;

T is chosen from the group comprising -(aryl)-O-(alkyl)-NRDREand -(aryl)-O-(alkyl) -;

n means an integer that is chosen in the range from 0 to 4;

each of R3independently selected from the group including halogen, hydroxy, RC, -C(O)RG, -C(O)ORG, -OC(O)RG, -OSi(RG)3, -ORG;

where RC selected from the group including alkyl and geterotsiklicheskikh; where geterotsiklicheskikh group optionally substituted by one or more substituents which are independently selected from the group comprising: hydroxy, alkyl, alkoxy or NRDRE;

where each of RDand REindependently selected from the group comprising hydrogen and alkyl; alternatively, RDand REtogether with the nitrogen atom to which they are attached, form a 3-10-membered ring which is selected from the group including heteroaryl or heteroseksualci;

where each of RGindependently selected from the group comprising hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-one;

m means an integer that is chosen in the range from 0 to 4;

each of R4independently selected from the group including halogen, hydroxy, RC, -C(O)RG, -C(O)ORG, -OC(O)RG, -OSi(RG)3, -ORG;

or its pharmaceutically acceptable salt.

13. Pharmaceutical composition having the effect of a modulator of estrogen receptors containing a pharmaceutically acceptable carrier and a compound according to claim 1.

14. Pharmaceutical composition having the effect of a modulator of estrogen receptors, obtained by mixing the compound according to claim 1 and pharmaceutically acceptable nose is the body.

15. A method of obtaining a pharmaceutical composition, comprising mixing the compound according to claim 1 and a pharmaceutically acceptable carrier.

16. The use of compounds according to claim 1 for the manufacture of a medicinal product for the treatment of disorders mediated by the estrogen receptor.

17. The application of article 16, where the breach is mediated by estrogen receptor, selected from the group including hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain disease, cardiovascular disease, cerebrovascular disease, cancer of the breast tissue, hyperplasia of the breast tissue, endometrial cancer, endometrial hyperplasia, cervical cancer, hyperplasia, cervical cancer, prostate cancer, prostatic hyperplasia, endometriosis, uterine fibroids, osteoarthritis and for the purposes of contraception.

18. The application of article 16, where the breach is mediated by estrogen receptor, selected from the group including osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.

19. The use of a composition according to 13 for the manufacture of a medicinal product for the treatment of disorders mediated by the estrogen receptor.

20. The use of the compounds of formula (I) and a progestogen or progestogen antagonist for drug production is about money, used for contraception.

21. The method of obtaining the compounds of formula (DX),

where

means simple or double bond,

X is O;

p is an integer that is chosen in the range from 0 to 2;

each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy; provided that not each of RAand RBmeans hydroxy;

Z means About;

n is an integer ranging from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt;

including,

interaction correspondingly substituted of compounds of formula (VIII)are known compounds or compounds obtained by known methods, where Pg10about the means of the protective group, with an organic base selected from the group including NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)aminority, leading to the formation of the corresponding compounds of formula (C), where V denotes the corresponding base cation;

the interaction of the compounds of formula (C) with the correspondingly substituted compound of formula (CI), where E means the electrophile and L is a leaving group, resulting in the formation of the corresponding compounds of formula (CII);

unprotect the compounds of formula (CII), leading to the formation of the corresponding compounds of formula (CIII);

the cyclization of the compounds of formula (III), leading to the formation of the corresponding compounds of formula (DX).

22. The method of obtaining the compounds of formula (DXI),

where

means simple or double bond,

X is O;

U is chosen from the group comprising hydrogen and alkyl;

each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy; provided that not each of RAand RBmeans hydroxy;

Z means About;

n is an integer, to the / establishment, which is chosen in the range from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt;

including,

interaction correspondingly substituted of compounds of formula (VIII)are known compounds or compounds obtained by known methods, where Pg10means a protective group, with an organic base selected from the group including NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)aminority, leading to the formation of the corresponding compounds of formula (C), where V denotes the corresponding base cation;

the interaction of the compounds of formula (C) with appropriately substituted aldehyde, a compound of formula (CIV), leading to the formation of the corresponding compounds of formula (CV);

unprotect the compounds of formula (CV),leading to the formation of the corresponding compounds of formula (CVI);

the cyclization of the compounds of formula (CVI), leading to the formation of the corresponding compounds of formula (DXI).

23. The method of obtaining the compounds of formula (Sa),

where

means simple or double bond,

X is O;

Pg11means a protective group which is selected from the group comprising alkyl, allyl, benzyl, benzoyl, SEM, MOM, BOM, and pivaloyl;

V is chosen from the group comprising Li, Na and K;

each of RAand RBindependently selected from the group comprising hydrogen, hydroxy, alkyl or alkoxy; provided that not each of RAand RBmeans hydroxy;

Z means About;

n is an integer from 0 to 4;

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

m means an integer that is chosen in the range from 0 to 4;

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

or its pharmaceutically acceptable salt;

< num="2371"> including,

interaction correspondingly substituted of compounds of formula (VIlla), known compounds, or compounds obtained by known methods, with an organic base selected from the group including NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)aminority, leading to the formation of the corresponding compounds of formula (Sa).

24. The compound obtained by the method according to item 21.

25. The compound obtained by the method according to item 22.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, oncology.

SUBSTANCE: invention relates to a method for isolation of epotilons used in medicine in treatment of cancer diseases. Method for desorption of epotilons A, B, D and/or E from synthetic resin is based on using low-polar or nonpolar solvent chosen from the group comprising (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Used aromatic solvent is chosen from the group including naphthalene, benzene or naphthalene and benzene substituted with one or some substitutes chosen from the following group: (lower)-alkyl, (lower)-alkoxy-group, halogen atom, nitro-group and (lower)-alkoxy-(lower)-alkyl wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Solvent is removed to the required level but up to preparing a dry residue preferably. If necessary, residue is dissolved in mixture alcohol/hydrocarbon in the corresponding volume ratio. Alcoholic phase is evaporated until dry and then alcoholic extract is crystallized from mixture alcohol and hydrocarbon. Then formed crystallized product is dissolved in mixture nitrile/water but preferably in mixture acetonitrile/water taken in the ratio = 2:3 (vol./vol.). Formed solution is applied on column (if necessary, after separation for some distillates) for preparative chromatography in reversed phase followed by elution with mixture nitrile/water, removing nitrile and extraction of an aqueous phase with ester. Ester extract is evaporated and formed product is subjected for crystallization. Method for preparing epotilons A, B, D and/or E from resin or reaction mixture involves the following steps: (a) desorption of epotilons with low-polar or nonpolar solvent chosen from the group including (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents being the desorption step can be repeated up to achievement of the more complete desorption; (b) removal of solvent used in desorption from formed solutions by evaporation; (c) optional crystallization of epotilon(s) after desorption and first of all for crystallization of epotilon B by addition of mixture of alcohol with hydrocarbon and the following evaporation of alcoholic phase until dry and crystallization of epotilon B from the corresponding mixture of solvents; (d) (obligatory step) separation of epotilons by method of chromatography in reversed phase and the following dissolving a residue obtained in previous step in suitable solvent, elution with mixture nitrile/water and removing nitrile from epotilon-containing fractions by evaporation. If necessary, water remained with epotilon is extracted with ester followed by evaporation of epotilon-containing ester phase until dry; (e) optional purification by adsorption chromatography method, and final recrystallization of purified epotilon from corresponding solvents or mixture of solvents. If necessary, in this process between each step formed solutions or suspensions are concentrated, and/or liquid or solid components are separated of one another. Separation of epotilons A and B is carried out by chromatography method based on a mobile layer modeling. Invention provides simplifying methods for preparing large amounts of epotilons for satisfying requirement in these agents.

EFFECT: improved isolating method.

12 cl, 2 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to a novel crystalline form of (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)ethylideneoxy]-5,20-epoxy-1-hydroxytax-11-ene-13-yl-(2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate that shows the diffraction picture of roentgen rays in powder with characteristic peaks at diffraction angles (θ)= 6.2o, 10.3o, 10.7, 11.4o and 12.0, and a method for its preparing. Method involves carrying out the crystallization step by using organic solvent chosen from group consisting of ketone type solvent, nitrile solvent type and their mixture, or mixture of said solvent and water. Also, invention relates to an antitumor agent based on the prepared crystalline form. Invention provides the stable quality of a medicinal agent based on its lower hygroscopicity.

EFFECT: improved and valuable properties of compounds.

8 cl, 5 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for synthesis of new compounds, namely, 1,11-dialkyl-3,5-dihydrofuro-[2',3':3,4]-cyclohepta[c]isochromens of the formula: (Ia-f): wherein (Ia): R means hydrogen atom (H); R1 means hydrogen atom (H); (Ib): R means bromine atom (Br); R1 means hydrogen atom (H); (Ic): R means chlorine atom (Cl); R1 means hydrogen atom (H); (Id): R means hydrogen atom (H); R1 means bromine atom (Br): (Ie): R means hydrogen atom (H); R1 means chlorine atom (Cl); (If): R means methoxy-group (-OCH3); R1 means hydrogen atom. Method involves formation of condensed tetracyclic system as result of the successive recyclization reactions of furan ring of derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol and the secondary cyclization of formed isochromen ketone in boiling of solution containing derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol of the formula: in ethanol medium in the presence of hydrogen chloride alcoholic solution for 15-40 min. Invention provides synthesis of new derivatives of isochromens possessing the potential anti-inflammatory activity.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

1 cl, 2 tbl, 5 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a novel method for preparing 14β-hydroxy-1,4-carbonate-desacetylbaccatin III and intermediate substances used in preparing new derivatives of taxane and possessing an antitumor activity. Method involves the following stages: a) protection of hydroxyls at positions 7 and 10 in 10-desacetylbaccatin III wherein R and R1 are taken among hydrogen atom, (C1-C10)-alkyl or aryl, (C1-C10)-alkyl- or aryl-carbonyl, trichloroacetyl, (C1-C4)-trialkylsilyl; preferably, when R and R1 are similar then they represent trichloroacetyl; when they are different then, preferably, R represents trichloroacetyl and R1 represents acetyl; or R represents triethyl or trimethylsilyl and R1 represents acetyl; b) two-stage oxidation to yield a derivative oxidized to carbonyl at position 13 and hydroxylated at position 14; c) carboxylation of vicinal hydroxyls at positions 1 and 14 to yield 1,14-carbonate derivative; d) reduction of carbonyl at position 13; e) removal of protective groups at positions 7 and 10. Also, invention relates to intermediate substances. Invention provides preparing intermediate substances used in synthesis of taxane.

EFFECT: improved preparing method.

8 cl, 8 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-tetrahydrofuranbenzodioxolyl sulfonamide compounds of the formula (I): , its salts, stereoisomers and racemates that are effective inhibitors of protease activity. Also, invention relates to pharmaceutical preparations, methods for inhibition of retrovirus proteases, in particular, to resistant retrovirus proteases, to many drugs, methods for treatment and prophylaxis of infection or disease associated with retrovirus infection in mammals and to methods for inhibition of retrovirus replication. Invention provides preparing new derivatives of bis-tetrahydrofuranbenzodioxalyl sulfonamides eliciting the valuable pharmaceutical properties.

EFFECT: valuable medicinal properties of compound and composition, improved treatment method.

16 cl, 2 dwg, 3 tbl

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

The invention relates to a method for producing 1,4:3,6-dianhydro-D-sorbitol, which is an intermediate in the production of lekarstvennyh drugs on the basis of its mono - or dinitropropane

The invention relates to a method for epoxidation prehiring of olefin, which includes the interaction prehiring of the olefin with oxygen source in the presence of salt catalyst

The invention relates to powder clarifier number sorbitol-xylitol-acetaline connections for clarification of a semicrystalline polyolefin resins and compositions based on it

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel crystalline modifications of 1-[4-(5-cyanoindole-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)-piperazine hydrochloride, crystalline modification of 1-[4-(5-cyanoindole-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)-piperazine hydrochloride hydrate (forms V, VI, VIII) and 1-[4-(5-cyanoindole-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)-piperazine hydrochloride anhydrate (forms IV, III, VII, IX). Proposed forms can be used in preparing solid medicinal formulations for treatment of or prophylaxis of depressive states, anxiety disorders, maniacal-depressive disorders, maniacal syndrome, dementia, disorders associated with substrates deficiency, disorder in sexual function, alimentary disorders, obesity, fibromyalgia, insomnia, psychiatric disorders, brain infarction, hypertension, in treatment of adverse effects in treatment of hypogonadism, secondary amenorrhea, premenstrual syndrome and undesirable post-delivery lactation. Also, invention relates to methods for synthesis of forms V and IV and to pharmaceutical compositions and pharmaceutical preparation based on thereof. Invention provides the improved solubility, reduced hygroscopicity and increased storage time of synthesized compounds and the preparation based on thereof.

EFFECT: improved and valuable properties of forms.

13 cl, 46 dwg, 2 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved preparing method.

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to hydroxamate derivatives described by general formula I: , in which R1 represents H or linear C1-C6-alkyl; R2 hydrogen, С110-alkyl optionally substituted by 1-5 constituents selected from hydroxy, amino, hydroxyalkyl; C4-C9-cycloalkyl; aryl; C4-C9-heterocycloalkyl, C4-C9-heterocycloalkylalkyl containing 2 heteroatoms (nitrogen and/or oxygen); C4-C9-cycloalkylalkyl; arylalkyl; heteroarylalkyl containing 1-4 nitrogen atoms as heteroatoms; -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl, and (CH2)nR7; R3 and R4, identical or different, independently denote hydrogen, optionally OH-substituted C1-C6-alkyl; C(O)-O-W, or -N(R12)C(O)W; or R3 and R4 together with carbon atom, to which they are linked, represent C=O; or R2 together with carbon atom, to which it is linked, and R3 together with carbon atom, to which it is linked, can form C4-C9-heterocycloalkyl containing 2 nitrogen atoms as heteroatoms; or mixed aryl or non-aryl polyheterocyclic ring; R5 is selected from hydrogen; C1-C6-alkyl; C4-C9-cycloalkyl; C(O)-W; aryl optionally substituted by 1-2 constituents selected from halogen and hydroxyalkyl; heteroaryl containing nitrogen as heteroatom; arylalkyl; aromatic polycycle; polyheteroaryl containing 1-2 nitrogen atoms as heteroatoms and optionally substituted by 1-2 substituents selected from hydroxyalkyl, halogen, alkyl, and aryl; mixed aryl-nonaryl polyheterocycle containing nitrogen or oxygen atom as heteroatom and optionally substituted by groups -N-OH, =N-OH; n, n1, n2, and n3, identical or different, are independently selected from within a range of 0-6; X and Y, identical or different, are independently selected from hydrogen, halogen, and nitro group; or pharmaceutically acceptable salt thereof. Invention also relates to a pharmaceutical composition showing inhibitory activity toward hydroxamate derivative of general formula I in combination with one or several pharmaceutically acceptable carriers. Hydroxamate derivative of general formula I are also appropriate for treating proliferative disease and regulating p21 promoter.

EFFECT: enabled use of hydroxamate derivatives as deacetylase inhibitors.

42 cl, 6 tbl, 272 ex

Prucaloprid n-oxide // 2301806

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel benzamide derivative of the formula (I) , its stereochemical isomeric forms, its pharmaceutically acceptable acid-additive salts and pharmaceutical compositions containing the indicated novel compound. Also, invention relates to methods for synthesis of indicated compounds, preparing compositions and their using as a medicinal agent use in treatment of digestive tract motor system disorders.

EFFECT: valuable medicinal property of compound and pharmaceutical compositions.

8 cl, 1 tbl, 3 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes substituted benzoylpyrazoles of the general formula (I): wherein Q means oxygen atom (O); R1 means alkyl with 1-6 carbon atoms; R2 means hydrogen atom; R3 and R4 mean independently of one another hydrogen atom, halogen atom, alkyl with 1-4 carbon atoms substituted with halogen atom; R5 means hydrogen atom, alkyl with 1-6 carbon atoms; Y means hydrogen atom; Z means alkoxyamino-group with 1-6 carbon atoms, alkylamino-group with 1-6 carbon atoms, substituted alkoxy-group with 1-4 carbon atoms, N-alkylalkoxyamino-group with 1-4 carbon atoms, phenyl substituted with halogen atom, monocyclic heterocyclyl, heterocyclylamino-group, group -N=(heterocyclyl) chosen from the group: furyl, tetrahydrofurylmethylamino-group, isoxazolyl, dihydroisoxazolyl (isoxazolinyl), tetrahydroisoxazolyl (isoxazolidinyl), tetrahydro-(2H)-1,2-oxazine-2-yl, dihydrothiazolyl (thiazolinyl), oxadiazolylamino-, thiadiazolylamino-group, piperidinyl, piperidinylamino-group, 2-oxo-1,3-diazacyclohexyl, morpholinyl, morpholinylamino-group, respectively, and substituted if necessary with alkyl with 1-4 carbon atoms, halogenalkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms involving their all possible tautomeric forms and possible salts. Also, invention describes a herbicide agent based in proposed compounds. Proposed compounds possess herbicide activity.

EFFECT: valuable properties of compounds and agent.

4 cl, 5 tbl, 77 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of cyclic amine of the general formula (1): , their pharmaceutically acceptable salts or hydrates wherein each among R1, R2 and R3 represents independently hydrogen atom, halogen atom, hydroxy-group, (C1-C8)-alkoxy-group; each among W1 and W2 represents independently nitrogen atom (N) or -CH; X represents oxygen atom (O), -NR4, -COONR4 or -NR4CO; R4 represents hydrogen atom, (C1-C8)-alkyl, (C3-C6)-alkynyl, substituted or unsubstituted phenyl, unsubstituted benzyl, unsubstituted indanyl wherein substitute(s) of phenyl represent(s) 1-3 groups or atoms chosen from (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkoxy-group substituted with 1-3 halogen atoms, (C1-C8)-alkylthio-group, (C1-C8)-alkylsulfonyl, halogen atom, trifluoromethyl group and (C1-C3)-alkylenedioxy-group; each among l, m and n represents number 0 or 1. Proposed compounds possess inhibitory effect on cell adhesion and/or cell infiltration and can be used as a medicinal agent and pharmaceutical composition based on thereof.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 439 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of 1H-imidazole-4-carboxamide of the formula (I): wherein R represents phenyl, 2-pyridinyl, 3-pyridinyl that can be substituted; R1 means phenyl, 5-membered aromatic heterocyclic ring comprising one nitrogen atom (N) as a heteroatom that can be substituted; R2 means hydrogen atom (H), (C1-C8)-alkyl; R3 represents (C2-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, benzyl group, aromatic ring that can be substituted; R4 means hydrogen or halogen atom, cyano-group, sulfamoyl, methanesulfonyl, methylsulfanyl or (C1-C4)-alkyl. Also, invention describes methods for synthesis of these compounds and pharmaceutical compositions. Derivatives of 1H-imidazole-4-carboxamide are effective agonists, partial agonists or antagonists of cannabinoid CB1-receptors that can be useful in treatment of psychic and neurological diseases and other diseases with involving cannabinoid neurotransmission.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical compositions.

11 cl, 1 tbl, 113 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

The invention relates to a method of transforming isoflavonoid conjugates in isoflavonones the aglycones by processing a mixture containing isoflavone conjugates and water at a pH of about 6-13,5, a temperature of about 2-121oWith over a period of time sufficient to convert most of the conjugates in isoflavone conjugates, then contact with the enzyme capable of decomposing due isoflavonoid glycoside with isoflavonoid the glikona at pH of about 3 to 9 and a temperature of about 5-75oWith over a period of time sufficient to convert these isoflavonoid of glikona in isoflavonones the aglycones, as well as way of turning isoflavonoid conjugates and isoflavonoid of glikona in isoflavonones the aglycones after removal isoflavonoid conjugates and isoflavonoid of glikona from material of vegetable protein
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