Triphenylalkene derivatives and their use as selective estrogen receptor modulators

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

 

The scope of the invention

The present invention relates to derivatives triphenylamine and their use as selective modulators of estrogen receptors (SERMs-Sermon).

Rationale inventions

Publications and other materials used to illuminate the study of invention and, in particular, cases to provide additional details related to the practical application, incorporated herein as references.

Estrogen is known as female sexual hormones. However, were later described many tissue-specific characteristics of estrogen in the bodies that classical concepts are not considered to be estrogen-sensitive or estrogen-responsive. During menopause the production of estrogen decreases dramatically. Later in older women usually develop menopausal symptoms, including hot flashes, sweating, insomnia, depression, headache, vaginal dryness, cardiovascular symptoms, incontinence of urine, feeling of swelling, pain mammary glands and fatigue. Long-term estrogen deficiency causes cardiovascular disorders and osteoporosis, which increases the risk of bone fractures and hospitalizations, which are very costly to society. For the treatment of menopausal symptoms increasingly use estrogens. N is, on the other hand, estrogens increase the risk of cancer of the uterus and mammary glands (Lobo, 1995). It is shown that estrogens are also useful for the prevention of Alzheimer's disease (Henderson, 1997) and to reduce LDL-indicators of cholesterol and thereby prevention of cardiovascular disease (Grodstein & Stampfer, 1998). Need new therapeutic methods that would have the benefits of estrogen, but without the risk of cancer. Were developed selective modulators of estrogen receptors (Sarmi)that meets the specified requirements (Maskhadov & Jordan, 1998). However, currently used Sarmy have properties that are far from optimal. For example, the use of raloxifene is limited due to its strong anti-estrogenic properties that cause and exacerbate menopausal symptoms, with a favorable effect on bone (Khovidhunkit & Shoback, 1999). Especially, it is desirable to obtain tissue-specific estrogens, which could be used for the treatment of menopausal symptoms in women, osteoporosis, Alzheimer's disease and/or cardiovascular diseases no cancer risk. In the optimal case, the new Sarmy can be given to men for the prevention of osteoporosis, cardiovascular diseases and Alzheimer's disease without showing adverse effects of estrogen (gynecomastia, reduced the group of libido and so on).

Purpose and brief description of the invention

One of the purposes of the present invention is to create a new selective modulators of estrogen receptors.

Another objective of the present invention is to provide pharmaceutical compositions comprising effective to obtain tissue-specific estrogenic and/or anti-estrogenic actions specified number of new selective modulator of estrogen receptors - link or its non-toxic pharmaceutically acceptable salts and pharmaceutically acceptable compatible media.

Another objective of the present invention is to develop a method of production of tissue-specific estrogenic and/or antiestrogenic effect in a patient for which this effect is desirable, including the introduction of a specified patient of this new selective modulator of estrogen receptors - link or its nontoxic pharmaceutically acceptable salt, in a quantity sufficient to create the desired actions.

Thus, according to one aspect of the present invention concerns new compounds are selective modulators of estrogen receptors, the General formula:

where R1 and R2, which are identical or different and mean

a) H, halogen, co3HE or

b)

where X is O, NH or S; and n means an integer

from 1 to 4; and

R4 and R5, which are identical or different and denote alkyl with 1-4 carbon atoms, N, -CH2CCH or-CH2CH2IT;

or

R4 and R5 form a N-containing five - or six-membered cycle or heteroaromatic cycle; or

C) -Y-(CH2)nCH2-O-R6,

where Y represents O, NH or S, and n means an integer from 1 to 4; and

R6 denotes H, -CH2CH2HE or-CH2CH2Cl; or d) 2, 3 dihydroxypropane, 2-methylsulfonylmethane, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxy-ethoxy or carboxymethoxy, and

R3 denotes H, halogen, HE or-och3; and

their non-toxic, pharmaceutically acceptable salts and esters, and mixtures thereof,

provided that

a) when R2 means

in the 4-position of phenyl,

where R4 and R5

i) the same, or methyl or ethyl; or

ii) form a N-containing five-membered cycle;

then R1 and R3 cannot odnovremenno mean N; and

b) when R2 means

in the 4-position of phenyl,

where R4 and R5 are identical or different and denote methyl

or N; or

when R2 denotes-O-CH2CH2-HE or-O-CH2COOH in 4-position of phenyl,

then R1 and R3 cannot simultaneously denote H or HE in 4 Polo is the situation phenyl; and

if R1 means HE is in the 4-position of phenyl, R3 cannot mean N.

According to another aspect of the invention relates to pharmaceutical compositions comprising effective to obtain tissue-specific estrogenic and/or antiestrogenic effect the specified number of new selective modulator of estrogen receptors - link or its nontoxic pharmaceutically acceptable salts, and pharmaceutically acceptable compatible media.

Another aspect of the invention relates to a method of producing tissue-specific estrogenic and/or antiestrogenic effect in a patient for which this effect is desirable, including the introduction of a specified patient of this new selective modulator of estrogen receptors - link or its nontoxic pharmaceutically acceptable salt, in a quantity sufficient to create the desired actions.

Detailed description of the invention

The present invention relates to the application of new selective modulators of estrogen receptors (Sermon) and their pharmaceutical products for men and women for the treatment of degenerative diseases and symptoms caused by estrogen deficiency. Usually Sarmy act as estrogen in bone and the cardiovascular system, whereas they are antiestrogenic in breast tissue is elez. Sarmy may have agonistic and antagonistic effects in other tissues. Depending on their chemical structure and hormonal characteristics of some compounds can in particular be suitable for older women to prevent osteoporosis, while non-feminizing estrogens) may also be used by men to prevent osteoporosis, cardiovascular disease and Alzheimer's disease. Some compounds are particularly suited for the treatment of menopausal symptoms in women during menopause. General characteristics of the above compounds is that they are antiestrogenic in breast and prevent the growth of cancerous breast cells. They are weak estrogens in the uterus and do not cause cancer of the uterus (the side effects are well known Sarma, tamoxifen).

New Sarmy of the present invention, therefore, possess tissue-specific estrogenic and/or antiestrogenic effects in vitro and in vivo and are useful for prevention and treatment of osteoporosis, cardiovascular diseases and Alzheimer's disease in men and women, and also for the treatment of menopausal symptoms and breast cancer in women.

The compounds of formula (I) can be obtained by a method that includes vzaimode the op perate the compounds of formula

where R7 has the same meaning indicated above for R1 or R2, or is protected by the specified group, R3’ means of the above R3 or protected, R8 denotes benzyl or tetrahydropyranyl, with an ORGANOMETALLIC compound of the formula

where R9 denotes H, the above R1 and R2, or is protected by the specified group, and M stands-MD-halogen or Li, to obtain the compounds of formula

where r3’, R7, R8 and R9 agree to the above values. R8 means tetrahydropyranyl, when R7 or R9 means-X-(CH2)nCH2-OR6, where X and n take the values specified for (I).

The compound (IV) dehydration using a suitable acid catalyst, preferably with acetic anhydride/acetylchloride, getting derived triphenylethylene formula

where R8’ is H or benzyl, R7’ and R9’ mean R1 and R2 or the benzyl-protected, or the benzyl-protected-CCI2CH2OR6. Possible protective tetrahydropyranyl group in R3, R7, R8 and R9 are removed in this way, receiving the radicals R3, R7’, R8’ and R9’.

Remove possible benzyl group, R8’ may be implemented by processing Zn and acetylchloride in toluene is, that gives triphenylmethanol formula

Gidroksosoedinenii (VI) can be converted into the corresponding chloride by treatment with thionyl chloride or triphenyl-phosphine-carbon tetrachloride in an organic solvent to obtain the formula

The claimed compounds (I) are obtained from compounds of formula (VII), where R7’ and/or R9’ mean benzyl-protected-CCI2CH2OR6, processing Zn and acetylchloride in an organic solvent or by catalytic hydrogenation.

Another method of preparing compounds of the formula (IV) in response to hydroalumination reactions derived “styrene” formula

where R10 means-Cho, -CH2HE, -COOH or the corresponding ester and R3 takes the above values, with benzophenone derivative of the formula

Another method of preparing compounds according to the invention includes O-alkylation of the compounds of formula (V), where R7’ and/or r9’ mean IT, alkylhalogenide derivative of the formula

where m denotes an integer from 1 to 5 and R11 denotes halogen,or6’,

where R6’ means R6 or protected R6, or-COOR,

with the formation of compounds the formula ia

The compound of formula (XI)where R11 denotes halogen, is subjected to the interaction with the amine of the formulareceiving the compound of the formula

Another method of preparing compounds of the formula (VII) involves the reaction of Mac-Marri (McMurry) interaction benzophenone derivative of the formula

where R7’ and R8’ take the above values with the derived 3-chloropropiophenone formula

where R3 takes the above values.

The claimed compound of formula (I)where R1 or R2 means 2,2-diethyl-2-hydroxyethoxy can be obtained by the coupling of compounds of formula (XI), where m is 1 and R11 means-COOR, ethylmagnesium.

The claimed compound of formula (I)where R1 or R2 is 1-ethyl-2-hydroxyethoxy, can be obtained by O-alkylation of the compounds of formula (V), where R7’ or R9’ IT means, ethyl-α-bromobutyrate and recovery of ester obtained by lydialydia.

Experimental part

Methods

Evaluation of estrogenic and antiestrogenic properties of compounds in experiments on the growth of MCF-7 cells in vitro

Estrogen-sensitive human cancer cells breast cancer, MCF-7 (McGrath clone), kept in RPMI-1640 medium, d is complete with 10% serum, amniotic calf, 2 mm L-glutamine, 10 μg/ml insulin and 10 μg/ml gentamicin. Cells are grown as a single layer culture in 75 cm2plastic flask for tissue culture (Nunc, Roskilde, Denmark) in 25 ml of medium at 37°C in an atmosphere of 95% air, 5% CO2and Passepartout twice a week.

For experiments involving hormone treatment or antihormonal, cells in exponential growth phase will precultured in the absence of estradiol one day. Cells plated on plates at a density of 3.5×103cells/well in 96-well plates for micrometrology (Nunclon, Roskilde, Denmark) and incubated for 24 hours at 37°C, 95% air, 5% CO2Wednesday , RPMI-1640 (with L-glutamine and gentamicin as above) with 5% serum amniotic calf (twice desorbed coal, covered with a layer of dextran to remove steroids) and in the absence of phenol red. Upon completion of the incubation period remove the environment. Exposure to study drug start immediately, adding fresh medium with 5% desorbed whey. Half of the cells are grown with estradiol, half - without estradiol. Add the studied compounds (dissolved in ethanol at a concentration of 0.01 M and accordingly the diluted nutrient medium). The final concentration of compounds is equal to 1, 10 and 100 nm, and 1 and 10 μm. Cells incubated for four days.

Live to etoc determined after 4 days using a luminometer based on the amount of ATP and interaction luciferase, as described Kangas'Ohm et al, 1984. This method allows assessment of extragenetic on the basis of the ability of compounds to stimulate the growth of estrogen-dependent cells in the absence of estradiol. Astrogenetix compares the maximum incentive growth (at any concentration) of the target compound as a percentage of the growth stimulus under the influence of estradiol (100% stimulus). In the present study antagonism appreciate at a concentration of 1 µmol/l as a percentage of theoretically complete (100%) of the antagonism, which means complete inhibition of estradiol-stimulated. At high concentrations of the molecule can also be toxic. Toxicity measured as the fraction of dead cells (i.e. 100% means that all the cells during exposure were killed). The results are presented in table 2.

Evaluation of estrogenicity and antiestrogenicity in vivo

The classical way to assess estrogenic and antiestrogenic actions is the use of immature females mice or rats (Terenius, 1971). Animals at the age of 18 days exposed to these compounds for 3 days. On the fourth day cause asphyxia animals with CO2and record body weight and weight of the uterus. Estrogens increase the size and weight of females (heterotrophy effect), whereas antiestrogens inhibit the specified action. Connection t is thus, give alone or with estradiol to assess both agonistic and antagonistic actions. Both results are shown in table 3 as percentage stimulation by estrogen (100%) and as the inhibition of estrogen (full inhibition is 100%). Values are given at two dose levels, low, i.e. 3-5 mg/kg, and high, i.e. 10-50 mg/kg Estrogenic activity may also be assessed after a 4-week treatment undergone oophorectomy rats on the basis of the size of the uterus. The specified test is performed with the compounds of structures listed in table 4.

Assessment of effects on cholesterol and bone

Connections give r.o. (per os) - P.O. female rats for 4 or 5 weeks daily. At the end take a blood sample. The serum is separated by centrifugation and frozen until analysis for total cholesterol. The bone samples taken from the spine and tibia. The physical strength of the bones studied, as described Peng'Ohm et al, 1994. Assessment of bone includes:

Ash mass tibial epiphysis

Epiphysis one tibia carefully separated and burned. The sample is burned to remove water and organic material. Ash mass corresponds to the mineral content of bone. In addition, take samples of bone for the study of histomorphometry. In some cases, osteogenesis study by wpri the swinging tetracycline (50 mg/kg R(V.B.) 10 days prior to autopsy) and calcein (20 mg/kg century B. 3 days prior to autopsy). The method is based on the irreversible binding of tetracycline to the growing bone and its determination by fluorescence (Peng et al, 1994).

Mechanical testing of bones

Mechanical testing of bone is carried out using the apparatus for testing material, designed at the University of Oulu (Technical support Department at the medical faculty). The testing device is based on the principle of lever. One end of the steel arm is fixed. Plunger rod and a motor drive connected with the lever arm when the ratio of the moments of 12.5 cm/50 cm = 1/4. As a motor with a drive to achieve continuous vertical movement of 0.62 cm/s) using a linear mechanism (SEY 10 Magnetic Elektromotoren AG, Switzerland). On pressing rod set interchangeable compression nozzle for various tests, transmitting compressive force to the sample and moving with constant speed 0,155 mm/s to maximum full load 1200 N. The RAM rod is directed through the axial bearing to provide vertical movement. The compressive force measured by the sensor temperature-compensated effort, which is connected with a fixed part of the compression platform. Electronic measuring devices include sensor calibration and adjustment.

Strength W is s femur

The maximum stress on the neck of the femur is determined using test cantilever bending. Tripod for bone is a thick plate of polymethyl methacrylate, in which is drilled a few holes of various sizes. On one side of each hole slotted groove for the third trochanter of the femur. Femoral bone saw through exactly between the middle and lower third of the body of the femur. Bone is inserted perpendicular to and tightly into the appropriate hole on the tripod. Small skewer each bone comes into contact with the surface of the plate. This method allows for fast and stable fixation of bone without the use of any additional materials. Concave compression cylinder, 2.5 mm in diameter made of aluminum. Complex head-neck of the femur is subjected to test to destruction, creating parallel to the body burden of the crown.

Evaluation of antitumor activity in vivo

Antitumor activity assessed by applying the model of DMBA - DMBA (dimethylbenz[a]anthracene). A single oral dose of DMBA (12 mg) initiate carcinogenesis of the mammary gland. New connections is administered for 5 weeks, before the appearance of palpable tumors. The size of tumors and the number of new tumors closely evaluate once a week before the deadline. The model describes in detail what about the Kangas'om et al., 1986. Tumor growth was measured once a week. All the tumors are classified, according to their abilities to growth, progressive, stable and regressing. Disappeared tumors are counted separately. Tumors are considered to be progressive if the tumor volume increased more than 8 times for a 5-week period dosed introduction of medicines, and regressing, if the tumor volume was reduced to one-fourth or less than the value of the initial volume. If the volume of the tumor has changed less than or remained unchanged, the tumor is considered to be stable.

Results

In total, the above methods evaluated 46 compounds, which are included in the list of examples of typical compounds are numbered and listed in table 1.

Table 1

The list of rooms (no.) and the names of typical connections
No.Connection
1(E)-(2-{4-[4-Chloro-1-(4-forfinal)-2-phenylbut-1-enyl]phenoxy}-ethyl)dimethylamine
2(Z)-(2-{4-[4-Chloro-1-(4-forfinal)-2-phenylbut-1-enyl]phenoxy}-ethyl)dimethylamine
3(E)-(2-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}-ethyl)dimethylamine
4(E)-(2-{4-[4-Chloro-1,2-bis(4-chlorophenyl)is ut-1-enyl]phenoxy}ethyl)-dimethylamine
5(Z)-(2-{4-[4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethyl)-dimethylamine
6(E)-4-Chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)-but-1-EN
7(Z)-4-Chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)-but-1-EN
8(E)-2-{4-[4-Chloro-2-phenyl-1-(4-forfinal)buta-1-enyl]phenoxy}-ethanol
9(E)-2-{4-[4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethanol
10(E)-3-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenyl-but-1-enyl]phenoxy}-propane-1,2-diol
11(Z)-4-Chloro-1-[4-(2-methylsulfonylmethane)phenyl]-1,2-di-phenyl-but-1-EN
12(E)-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}-acetic acid
13(Z)-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}-acetic acid
14(E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-chlorophenyl)-2-phenyl-but-1-EN
15(E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-forfinal)-2-phenyl-but-1-EN
162-(4-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}-phenoxy)-1-ethanol
17(E)-2-{4-[4-Chloro-2-phenyl-1-(4-chlorophenyl)but-1-enyl]phenoxy}ethanol
18(Z)-2-[3-(4-chlorine is -1,2-diphenyl-but-1-enyl)phenoxy]ethanol
19(Z)-2-{2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethoxy}ethanol
20(Z)-3-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]propane-1,2-diol
21(Z)-1-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethyl}-1H-imidazol
22(Z)-2-({2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethyl}methylamino)ethanol
23(Z)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)dimethylamine
24(E)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)dimethylamine
25(Z)-(2-{4-[4-Chloro-2-(4-forfinal)-1-phenylbut-1-enyl]phenoxy}-ethyl)dimethylamine
26(Z)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)buta-1-enyl]-phenoxy}ethyl)dimethylamine
27(E)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)buta-1-enyl]-phenoxy}ethyl)dimethylamine
28(z)-1-(2-{4-[4-Chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl] phenoxy}-ethyl) - piperidine

(Table 1 continued)
No.Connection
29(E)-1-(2-{4-[4-Chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl) - piperidine
30(Z)--(2-{4-[4-Chloro-2-{2-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl) - piperidine
31(E)-1-(2-{4-[4-Chloro-2-(2-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl) - piperidine
32(Z)-1-[4-(2-Dimethylaminoethanol)phenyl]-1,2-diphenyl-4-chloro-but-1-EN
33(Z)-{2-[3-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethyl}dimethylamine
34(E)-3-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenylbut-1-enyl}-phenol
35(Z)-3-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]propane-1-ol
36(Z)-2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenylsulfanyl]ethanol
37(Z)-2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)buta-1-enyl]-phenoxy}ethanol
38(Z)-1-(2-{4-[4-Chloro-2-(2-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl) - piperidine
39(E)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}phenol
40(Z)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}phenol
41(Z)-2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamino]ethanol
42(Z)-4-{1-(2-Chloroethyl)-2-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-vinyl}phenol
43(E)-4-{1-(2-Chloroethyl)-2-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-vinyl}phenol
44(Z)-{2-[4-(4-Chloro-1,2-diphenylbuta-1-e is Il)phenoxy]ethyl}methylprop-2-ynylamine
45(Z)-3-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxymethyl] pentane-3-ol
46(Z)-2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]butane-1-ol
47N-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenyl]-N’,N’-dimethylated-1,2-diamine

Patterns characteristic of the compounds presented below:

Connect dimethylaminoethoxy fragments

R1R3No.
4-FH1 and 2
4-ClH3
4-Cl4-Cl4 and 5
H4-Cl23 and 24
H4-F25
4-OSS4-Cl26 and 27

Connection dimethylaminoethoxy fragment

R1R3RNo.
NNCH2CH2imidazolyl21
NNCH2 CH2N(CH3)CH2CH2OH22
N3-och3CH2CH2piperidinyl28 and 29
N4-och3CH2CH2piperidinyl30 and 31
N2-CLCH2CH2piperidinyl38
3-HeNCH2CH2imidazolyl39 and 40
NNCH2CH2N(CH3)CH2CCH44

Alcohols

R1R3No.
4-FN8
4-CL4-CL9
4-och2CH2HEN16
4-CLN17
C-HEN34
4-och34-CL37
N4-HE42 and 43

R1R3RNo.
4-CL4-CLCH2CH2Cl6 and 7
4-CLNCH2CH(OH)CH2HE10
NNCH2CH2S311
4-CLNCH2SOON12 and 13
4-CLNCH2CH2Och2CH2CL14
4-FNCH2CH2Och2CH2CL15
NNCH2CH2Och2CH2HE19
NNCH2CH(OH)CH2HE20
NNCH2CH2CH2HE35
NNSNA(HE)(CH2CH3)245
NNCH(CH2CH3)CH2HE46

Estrogenic and anti-estrogenic and cytotoxic activity of some compounds in vitro in table 2, from which one can see that the spectrum of hormonal activity of the compounds varies, and this creates the possibility of application of compounds with different clinical diseases.

Compounds with weak hormonal activity, which effectively destroy the cells MCF-7 (human breast cancer cells cancer) at the highest investigated concentration (10 μm) preferably can be used in the treatment of breast cancer. These compounds amongst the compounds belong rooms№1, 3, 16, 19, 26, 27, 39 and 40 (table 2). These compounds and others are less effective estrogens and antiestrogens than the well-known drugs against breast cancer, tamoxifen and toremifene (table 3). Of particular interest is the connection # 19, because it is more effective antitumor agent in vivo in models of DMBA-induced mammary gland tumors in rats, even at very low doses than clinically used tamoxifen and toremifene (table 6).

Compounds with weak estrogenic and antiestrogenic activity may be particularly useful for the prevention and treatment of osteoporosis and menopausal symptoms. To these compounds (among others) include compounds№3, 10, 11, 18, 19, 20, 25, 32, 36 and 44 (table 2, 3 and 4).

Compounds that reduce the surrounding cholesterol, can be useful as a cardiovascular drug. For women some valid astrogenetix of these compounds, and compounds that are not estrogen, or a very weak estrogen, and lower cholesterol, can also be used by men for the prevention and treatment of cardiovascular diseases. To these compounds include (among others) connection No. 3, 19, 20 (also for men) and 33 (for women) (table 4). It is also assumed that the same compounds are useful for treating or preventing Alzheimer's disease. In the latter case, the cytotoxic effect of the compounds should be weak, as in the case of compound No. 33 (table 2). It should be noted that the compound No. 19 has no estrogenic effect on the weight of the prostate in doses that are active in models of DMBA-induced mammary gland tumors (tables 6 and 7). Therefore, it can be particularly successful with men and can have the advantage, in addition to treatment of the above conditions, in the treatment of prostate cancer.

The hormonal profile of the compounds may be in some cases, different in vitro and in vivo, for example, compound No. 1 has estrogenic effects in vitro (table 2), but has weak estrogenic activity in vivo (table 3). Thus, above the s examples should be considered as examples of useful applications in various diseases. These examples should not be construed as limiting the possible use of these compounds in different clinical indications.

Table 2. Estrogenic, anti-estrogenic and cytotoxic activity of the studied compounds in the MCF-7 cells.

Details of the estimates are given in the text. The maximum estrogenic agonist in the absence of estradiol calculated as a percentage from estradiol stimulus (100%). Antiestrogenic property is assessed at a concentration of 1 µmol/l, theoretically taking full antagonism 100%. Toxicity at a concentration of 10 µmol/l measured as the fraction of dead cells compared to control (i.e. 100 means that all cells were killed). As standards used known antiestrogens.

Connection

No.
Without estradiol (E2)With estradiol (E2)
 The maximum agonism (% E2)Maximum cell death (% fraction of dead cells)Antagonism at 1 μm (% of full antagonism)Maximum cell death (% fraction of dead cells)
111008100
210032 39100
31100194
4109010100
51110031100
60471640
83129252

(Table 2 continued)
Connection

No.
Without estradiol (E2)With estradiol (E2)
 The maximum agonism (% E2)Maximum cell death (% fraction of dead cells)Antagonism at 1 μm (% of full antagonism)Maximum cell death (% fraction of dead cells)
91445962
10347035
111426055
1412102757
157482 59
1622902396
170441738
183010140
1914142150
20852560
21580091
221151241
231489593
244689498
251742627
260971198
270995100
283861892
30591492
321186090
3320058 80
340000
3545501450
368171337
37439041
3809968100
390681778
40063346
415401047
429231354
437880622

(Table 2 continued)
Connection

No.
Without estradiol (E2)With estradiol (E2)
 The maximum agonism (% E2)Maximum cell death (% fraction of dead cells)Antagonism at 1 μm (% of full antagonism)Maximum cell death (% faction is dead cells)
442478895
45156319
4618152351
Tamoxifen3110043100
Toremifene3710044100
FC-a23502180
ICI 1643849100100100

Table 3. Heterotropia (for example, estrogen and estrogen-antagonistic effect of the studied compounds in the 3-day heterotropia test undeveloped uterus of rats.

Estrogenic activity is assessed as the percentage of the maximum, the estrogen-induced actions. Antiestrogenic action expressed as a percentage of theoretically complete inhibition of the actions of estrogen (100%).

3-5 mg/kg
Connection # Heterotropia action (% of estradiol). Introduction without estradiolOestrogen antagonism (% inhibition of estradiol). Introduction with estradiol
dose:10-50 mg/kg3-5 mg/kg10-50 mg/kg
142742631
344546538
1913371044
203362520
2048722639
2126391020
3543663532

(Table 3 continued)
Connection

No.
Heterotropia action (% of estradiol). Introduction without estradiolOestrogen antagonism (% inhibition of estradiol). Introduction with estradiol
dose:3-5 mg/kg10-50 mg/kg3-5 mg/kg10-50 mg/kg
36142905
387372012
399 195070
401394554
445575n42
4543623030
467710000
Tamoxifen44515158
Toremifene26444558
Raloxifene11139092

Table 3 (continued). The size of the uterus after the 4-week introduction of new compounds undergo oophorectomy rats (oral daily dose is given in mg/kg).

Falsely operated (simulated)treated with estradiol and treated with raloxifene subjected oophorectomy rats served as control.

GroupThe size of the uterus (g)
Simulated control0,497±0,103
Undergone oophorectomy0,099±0,016
No. 3 3.0 mg/kg0,140±0,006
No. 19 1.0 mg/kg0,192±0,029
No. 19 5.0 mg/kg0,221±0,023
No. 20 5.0 mg/kgof 0.133±0,032
Raloxifene 3.0 mg/kg0,141±0,021
FC-1271a 5.0 mg/kg0,411±0,042

Table 4. The effect of compounds No. 3, 19 and 20 on the cholesterol level in the serum of rats subjected oophorectomy (OVX) rats after 4-week dosed injection of the drug.

Estradiol give one group for comparison. The result shows that oophorectomy causes an increase in cholesterol. Estradiol, compounds No. 3, 19 and 20 can prevent this growth even at very low dose and lower the level specified below is false the operated level. The number of animals in each group was 8.

GroupThe level of serum cholesterol (mmol/l)
Falsely operated rat3,8±0,4
OVX-rat4,6±0,7
OVX-rat + estradiol 3 mg/kg4,0±0,4
OVX + # 3 of 3 mg/kg3,1±0,4
OVX + No. 19 0.3 mg/kg3,6±0,4
OVX + No. 19, 10 mg/kg3,9±0,6
OVX + No. 20 1 mg/kg3.3V±0,6
OVX + No. 20 5 mg/kg2,3±0,4

Table 5. Dei is a journey of compounds No. 3, 19 and 20 on the bones undergo oophorectomy rats after 4-week dosed injection of the drug.

Rats subjected oophorectomy (false controls operate). Connections give for 4 weeks in the dose (mg/kg) P.O., starting one week after oophorectomy. Tibial epiphysis and the neck of the femur dissect to assess the quality of bone.

Group dose (mg/kg)Ash weight (mg) tibial epiphysisMaximum load (N) on the neck of the femur
Stimulated control(n=10)34,0±2,986,7±10,4*
OVX(n=10)32,2±2,868,4±8,5
No. 3 3.0 mg/kg(n=22)36,0±3,4*of 92.5±11,1*
No. 19 1.0 mg/kg(n=10)34,8±1,3*81,6±7,9*
No. 19 5.0 mg/kg(n=10)34,9±1,9*85,7±17,0*
No. 20 3.0 mg/kg(n=20)35,0±3,281,7±15,2*
Raloxifene 3.0 mg/kg(n=10)34,9±3,584,2±18,4*
*indicates a statistically significant (p<0.05) difference from the values for otvergnutyj oophorectomy animals.

Table 6. Antitumor activity of compound No. 19 on DMBA-induced breast cancer in rats.

Connection # 19 given P.O. daily for 5 weeks in the dose. Tumors are classified into a growing, stable, regressing and disappearing. The number of tumors in each group is counted and expressed as a percentage of the total number of tumors. The number of animals in each group was 7. Compound No. 19 does not affect the body weight of animals compared to the controls.

GroupGrowingStableRegressingEndangered
Control82%18%0%0%
No. 19 3 mg/kg20%20%40%20%
No. 19, 15 mg/kg14%14%57%14%
Tamoxifen 3 mg/kg36%56%8%0%
Toremifene 3 mg/kg31%51%11%10%

Table 7. The effect of compound No. 19 on the weight of the prostate in intact and castrated male rats after 4 weeks of daily introduction dvokriselnyh doses.

Castration significantly reduces the weight of the prostate and estrogen, as is known, do the same thing. Connection # 19 has no estrogenic activity at the dose of 0.5 mg/kg and has weak estrogenic activity at the dose of 5.0 mg/kg Noted that the specified connection has significant antitumor activity in models of DMBA-induced breast cancer at a dose of 0.5 mg/kg (table 6).

GroupThe weight of the prostate gland (mg) mean and sd (Stockl.)
Control2,60±0,77
Castrated rats0,59±0,07
No. 19 0.5 mg/kg2,66±0,21
No. 19 5.0 mg/kg1,58±0,50
No. 19 0.5 mg/kg castrated rats0,59±0,07
No. 19 5.0 mg/kg castrated rats0,62±0,07

For the purpose in accordance with the present invention new Sarmy or their pharmaceutically acceptable salts can be introduced in various ways. Suitable forms of introduction include, for example, oral formulations, parenteral injection, including intravenous, intramuscular and subcutaneous injection; transdermal or rectal formulations. Suitable oral formulations include, for example, conventional tablets or tablets is key with a slow release and gelatin capsules.

The required dosage new Sermon varies depending on the specific condition requiring treatment, severity of disease, duration of treatment, route of administration and the specific compounds used. The usual daily dose for adults is 5 to 200 mg, preferably 20-100 mg Sarmy can be given in the form of tablets or other formulations, such as capsules, alone or in mixture with any clinically acceptable inactive ingredients used in pharmacy.

Examples

EXAMPLE 1.

a) O-alkylation of derivatives of 4-hydroxybenzophenone

Under conditions of phase transfer catalysis (PTC - IFC)

[4-(2-Dimethylaminoethoxy)phenyl]-(4-forfinal)metano

4-Hydroxybenzophenone (28,1 g, 0.13 mol) dissolved in toluene (140 ml). Add tetrabutylammonium (TBABr-Tbug) (2.1 g). Add aqueous 48% sodium hydroxide (140 ml) at 50-55°C. the Mixture is heated to 80°C and add small portions of the hydrochloride of 2-chloroethylamine (a total of 20.0 g, 0.14 mol)and the reaction mixture stirred at 97-100°C for 3 hours, the Layers separated and the organic layer washed with water, dried over sodium sulfate and evaporated to dryness. The output of 33.0 g, 88%. The product is used in the next stage without additional purification.

1H-NMR (CDCl3): a 2.36(s, 6N), 2,77(t, 2H), 4,15(t, 2H), 6,99(d, 2H), 7,15(t, 2H), 7,27-7,83(m, 4H)

Using this method, the following compounds are square:

(4-Chlorophenyl)-[4-(2-dimethylaminoethoxy)phenyl]metano

1H-NMR (CDCl3): a 2.36 (s, 6N), 2,77 (t, 2H), 4,15 (t, 2H), 6,98 (d, 2H), 7,45 (2N), 7,71 (d, 2H), 7,79 (d, 2H)

[4-(2-Benzyloxyethyl)phenyl]-(4-forfinal)metano

1H-NMR (CDCl3): a 3.87 (ICCAT, 2H), 4,24 (ICCAT, 2H)and 4.65 (s, 2H), 6,99 (d, 2H), 7,15 (t, 2H), 7,32-7,39 (m, 5H), 7,76-7,83 (m, 4H)

[4-(2-Benzyloxyethyl)phenyl]-(4-chlorophenyl)metano

1H-NMR (CDCl3): 3,86(t, 2H), 4,24(t, 2H)and 4.65(s, 2H), 6,99(d, 2H), 7.3 to 7.4(m, 5H), was 7.45(d, 2H), of 7.70(d, 2H), 7,78 (D, 2H)

By acid catalysis

(4-Chlorophenyl)-[4-(tetrahydropyranyloxy)phenyl]metano 4-Chloro-4’-hydroxybenzophenone (50 g, 0,215 mol) is dissolved in dichloromethane (400 ml). To the solution was added 3,4-dihydro-2H-Piran (21,7 g, 0,257 mol) and a catalytic amount of p-toluenesulfonic acid. The solution is stirred for 6 hours at room temperature and left to stand over night. To the reaction mixture add 1 N. aqueous sodium hydroxide solution (100 ml) and stirred for 15 minutes. The organic layer is separated and washed twice 1 N. aqueous sodium hydroxide solution and once with water. The dichloromethane solution is dried and evaporated to dryness. The output of 68.6,

1H-NMR (CDCl3): 1,52-of 2.20 (m, 6N), 3,60-to 3.67 (m, 1H), 3,8-of 3.94(m, 1H), and 5.5 to 5.6(m, 1H), 7,10(d, 2H), 7,45(d, 2H), 7,72 (d, 2H), 7,78(d, 2H)

Using this method, you receive the following connection:

Bis[4-(tetrahydropyranyloxy is)phenyl]metano

1H-NMR (CDCl3): 1,55-of 2.20(m, N), up 3.6-3.7(m, 2H), 3,8-4,0 (m, 2H), and 5.5 to 5.6(m, 2H), 7,11(d, 4H), 7,78(d, 4H)

NaH as the base

(4-Chlorophenyl)-[4-(2,2-dimethyl- [1, 3]dioxolane-4-ylethoxy) -phenyl]metano

Sodium hydride (3.4 g, 0,072 mol) in oil, washed with heptane and mixed with formamide (DMF - DMF) (120 ml). To the solution is added dropwise 4-chloro-4’-hydroxybenzophenone (12 g, 0,052 mol) in DMF and the reaction mixture is stirred for one hour at room temperature. Then 2,2-dimethyl-[1,3]dioxolane-4-ymetray ester toluene-4-sulfonic acids (17,7 g, 0,0618 mol, obtained from the S-1,2-O-isopropylpyrazine and p-toluensulfonate) in DMF is added dropwise to the solution within hours. The mixture is heated to 60°C. and stirred at the same temperature for two days. To the reaction mixture add 1 N. aqueous sodium hydroxide solution (200 ml) and the solution extracted three times with toluene (60 ml). Toluene layers are combined and washed twice with water (60 ml), dried and evaporated to dryness. The residue is crystallized from methanol. The yield of 13.7 g, 76.7 per cent.

1H-NMR (CDCl3): of 1.42(s, 3H), of 1.48(s, 3H), 3,90-4,24(m, 4H), to 4.52(quintet, 1H), 6,99(d, 2H), 7,46(d, 2H), 7,71(d, 2H), 7,79(d, 2H)

b) Reaction hydroalumination reactions benzophenone derivatives cinnamic aldehyde or methylcinnamic

1-[4-(2-N,N-dimethylaminoethoxy)phenyl]-1-(4-forfinal)-2-phenylbutane-1,4-diol

Socialogical (2.6 g, 0,068 mol) we use the t in dry tetrahydrofuran (120 ml) under nitrogen atmosphere. Cinnamic aldehyde (13.8 g, 0.1 mol) in dry tetrahydrofuran (30 ml) is added at 24-28°C. the Reaction mixture was stirred at ambient temperature for 1 h Add [4-(2-dimethylamino-ethoxy)phenyl]-(4-forfinal)methanon (29,6 g, 0,103 mol) in dry tetrahydrofuran (60 ml) at 50-55°C. the Reaction mixture was stirred at 60°C for 3 hours the Greater part of the tetrahydrofuran evaporated. Add toluene (300 ml), 48% aqueous sodium hydroxide (118 ml) and water (30 ml). The mixture is heated to boiling point under reflux for 10 min and the aqueous layer is separated, while it is still warm. Processing NaOH repeat. Toluene layer is washed twice with hot water. The product is crystallized from toluene in the form of a mixture of stereoisomers (26,4 g, 62%).

1H-NMR (CDCl3+Meon-d4): 1,95-2,12 (m, 2H), 2,30, and 2.37 (2s, together 6N), 2,68 and 2.77(2T, together 2H), 3,31-of 3.48 (m, 2H), under which a signalfrom another diastereoisomer, of 3.80 (DD,another diastereoisomer), 3,95 and 4,08(2T, together 2H), 6,62 and 6,91(2D, together 2H), 7.03, and 6,72 (2T, together 2H), 7,05-7,20(m, 7H), 7,51(m, 2H)

Using this method, you receive the following connections:

1-(4-Chlorophenyl)-1-[4-(2-N,N-dimethylaminoethoxy)phenyl]-2-phenylbutane-1,4-diol, mixture of stereoisomers.

1H-NMR (CDCl3+MeOH-d4): 1,85-2,10(m, 2H), 2,27, and of 2.33 (2s, together 6N), 2,66, and a 2.75(2T, together 2H), 3,25-3,50(who, 2H), 3,62, and of 3.84 (t and DD, together 1H), 3,93 and 4.04 (2T, together 2H), BY 6.6 AND 7.6(13H)

1-[4-(2-Benzyloxyethyl)phenyl]-1-(4-forfinal)-2-phenyl-butane-1,4-diol, mixture of stereoisomers.

1H-NMR (CDCl3): 1,92-of 2.15(m, 2H), 3,30-3,48 and 3,48-3,66 (2m, together 2H), 3,74, and 3,83(2 iskat, together 2H), 4.02 and 4,15(2 iskat, together 2H), under the last two groups of signals, 4,58 and 4.63(2 s, together 2H), 6,6-7,6(N)

1-[4-(2-Benzyloxyethyl)phenyl]-1,2-bis(4-chlorophenyl)butane-1,4-diol, mixture of stereoisomers.

Instead of cinnamic aldehyde using methyl ether 4-harkerite acid.

1H-NMR (CDCl3): 1,80-of 2.15(m, 2H), and 3.2 and 3.4 and 3.4-3.6(2m, together 2H), 3.75 to and 3,82(2T, together 2H), 3,95(ICCAT, 1H), 4.00 and 4,14(2T, together 2H), 4,59 and 4.63(2 s, together 2H), 6,80-7,55(17 H)

1,2-Bis(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]-butane-1,4-diol, mixture of stereoisomers

Instead of cinnamic aldehyde using methyl ether 4-harkerite acid.

1H-NMR (CDCl3+ MeOH-d4): 1,85-of 2.20 (m, 2H), 2.35 and 2,37 (2s, together 6N), 2,77 and 2.82 (2T, together 2H), 3,20 is-3.45(m, together 2H), 3,81 and 3.85(2 iskat, together 1H), 4,10 and 4,21 (2T, together 2H), 6,9-7,8(m, 12 H)

1,1-Bis[4-(tetrahydropyranyloxy)phenyl]-2-phenylbutane-1,4-diol

1H-NMR (CDCl3): of 1.5-2.1(m, 14 H), 3,3-4,1(m, 7H), 5,25 is 5.28(m, 1H), 6,77(d, 2H), 7,00(d, 2H), 7,1-7,2(m, N), 7,47 (d, 2H)

1-(4-Chlorophenyl)-2-phenyl-1- [4- (tetrahydropyranyloxy) phenyl] -butane-1,4-diol

1H-NMR (CDCl3): 1,5-2,1(who, 8H), 3,2-4,0(m, 5H), 5,27(m, 1H), 6,79(d, 2 H), 6,9-7,32(m, N), 7.5(d, 2H)

1-(4-Chlorophenyl))-[4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy) -phenyl]-2-phenylbutane-1,4-diol

1H-NMR (CDCl3): to 1.37 and 1.40 and 1.42 are, and 1,46(4C, together 6N), 1,9-2,1(m, 2H), 3,2-4,5(m, 8H), 6,6-of 7.55(m, 13H)

1,2-Diphenyl-1-[3-(tetrahydropyranyloxy)phenyl]butane-1,4-diol receive, based on the phenyl-[3-(tetrahydropyranyloxy)phenyl]-methanone and cinnamic aldehyde. The connection used for the next reaction stage without further purification.

C) Dehydration derivatives 1,1,2-triarylmethane-1,4-diol

4-[4-(2-Dimethylaminoethoxy)phenyl]-4-(4-forfinal)-3-phenylbut-3-EN-1-ol

1-[4-(2-N,N-Dimethylaminoethoxy)phenyl]-1-(4-forfinal)-2-phenylbutane-1,4-diol (8,46 g, 0.02 mol) is heated to the boiling point under reflux in 80 ml of acetic anhydride for 3 hours the Mixture is cooled to 60°C and add acetylchloride (a 7.85 g, 0.1 mol). The mixture was stirred at 80-90°C for 4 h, the Solvents evaporated. Add a solution containing 5% sodium hydroxide in 80%aqueous methanol and the mixture is stirred for 2 h at RT (room temperature). The methanol evaporated. Add water and the product extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The residue (9.5 g) is a mixture of E - and Z-isomers of the product. Isomers share flash chromatography (eluent: toluene:triethylamine=9:1).

E-isomer, H-NMR (CDCl3): of 2.27 (s, 6N), of 2.64 (t, 2H), 2,74 (t, 2H), only 3.57(t, 2H), 3,92(t, 2H), to 6.57(d, 2H), 6.75 in(d, 2H), 7,03(t, 2H), 7,10-to 7.18(m, 5H), 7,27(DD, 2H)

Z-isomer,1H-NMR (CDCl3): of 2.34(s, 6N), is 2.74 (t, 2H), and 2.79 (t, 2H), 3,60(t, 2H), of 4.05(t, 2H), 6,69(t, 2H), 6,84(DD, 2H), 6,91(d, 2H), 7,09-7,17(m, 5H), 7,20(m, 2H)

Using this method, you receive the following connections:

4-(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-3-phenylbut-3-EN-1-ol

E-isomer,1H-NMR (CDCl3): of 2.27 (s, 6N), of 2.64 (t, 2H), by 2.73 (t, 2H), of 3.56(t, 2H), 3,91(t, 2H), 6,56(d, 2H), 6,74(d, 2H), 7,10-7,34(m, N)

4-[4-(2-Benzyloxyethyl)phenyl]-4-(4-forfinal)-3-phenylbut-3-EN-1-ol

E-isomer,1H-NMR (CDCl3): is 2.74 (t, 2H), only 3.57(m, 2H), 3,74 (ICCAT, 2H), 4,01(ICCAT, 2H), 4,58(s, 2H), to 6.57(d, 2H), 6.75 in(d, 2H), 7,00-7,40(m, 14N), which can be identified signal 7,03 (t, 2H).

Z-isomer,1H-NMR (CDCl3): and 2.79 (t, 2H), 3,60(m, 2H), 3,84 (ICCAT, 2H), 4,17(ICCAT, 2H)and 4.65(s, 2H), 6,69(t, 2H),

6,83(DD, 2H), 6,91(d, 2H), 1.00 and was 7.45 (m, 14N), which can be identified signal then 7.20 (d, 2H).

4-[4-(2-Benzyloxyethyl)phenyl]-3,4-bis(4-chlorophenyl)-but-3-EN-1-ol

E-isomer,1H-NMR (CDCl3): 2,70(t, 2H), 3,50-the 3.65(m, 2H), 3,75(ICCAT, 2H), 4,03(ICCAT, 2H), 4,59(s, 2H), 6,59(d, 2H), 6.73 x(d, 2H), 7,00-7,40(m, 13H)

3,4-Bis(4-chlorophenyl)-4-[4-(2-hydroxyethoxy)phenyl]but-3-EN-1-ol

get as a by-product by the reaction of dehydration of 1-[4-(2-benzyloxyethyl)phenyl]-1,2-bis(4-chlorophenyl)butane-1,4-diol.

E-isomer,1H-NMR (CDCl3): of 2.72(t, 2H), 3,50-3,6(m, 2H), 3,80-of 3.96(m, 4H), 6,59(d, 2H), 6.75 in(d, 2H), 7,00-7,40(m, 8H)

Z-isomer,1H-NMR (CDCl3+ MeOH-d4): of 2.75(t, 2H), of 3.56(t, 2H), 3,95(t, 2H), 4.09 to(t, 2H), 6,79(d, 2H), b,91(d, 2H), 7,01 (d, 2H), 7,05(d, 2H), 7,16(d, 2H), 7,19(d, 2H),

3,4-Bis(4-chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-but-3-EN-1-ol

E-isomer,1H-NMR (CDCl3): to 2.29 (s, 6N), to 2.66(t, 2H), rating of 2.72 (t, 2H), only 3.57(t, 2H), 3,94(t, 2H), 6,60(d, 2H), 6.73 x(d, 2H), 7,06(d, 2H), 7,15(d, 2H), 7.23 percent(d, 2H), 7,32(d, 2H)

Z-isomer, HCl-salt,1H-NMR (MeOH-d4):), 2,77(t, 2H), 3,03 (C, 6N), 3,53(t, 2H), the 3.65(t, 2H), 4,42(t, 2H), 6.89 in(d, 2N), was 7.08(d, 2H), 7,10(d, 2H), 7,16(d, 2H), 7.23 percent(d, 2H), 7,31(d, 2H)

4,4-Bis(4-hydroxyphenyl)-3-phenylbut-3-EN-1-ol

Protective tetrahydropyranyl (TNR-TBM) group can be removed by dehydration reaction.

1H-NMR (CDCl3): was 2.76 (t, 2H), 3,54(m, 2H), 6,46(d, 2H), 6,70(d, 2H), 6,80(d, 2H), 7,0-7,2(m, 7H)

4-(4-Chlorophenyl)-4-(4-hydroxyphenyl)-3-phenylbut-3-EN-1-ol

Protective Tgp-group is removed by reaction of dehydration.

E-isomer1H-NMR (CDCl3): to 2.65 (t, 2H), 3.45 points (t, 2H), 6,29 (d, 2H), of 6.49(d, 2H), 7,00-to 7.15(m, 5H), from 7.24(d, 2H), 7,33(d, 2N) Z-isomer1H-NMR (CDCl3): and 2.79 (t, 2H), to 3.58 (t, 2H), 6,80 (d, 2H), for 6.81(d, 2H), 6,97(d, 2H), 7,1-7,2(m, 7H)

4-(4-Chlorophenyl)-4-[4-(2,3-dihydroxypropyl)phenyl]-3-phenylbut-3-EN-1-ol

The reaction reveals the cycle 2,2-dimethyl[1,3]-dioxolane.

E-isomer1H-NMR (CDCl3): by 2.73 (t, 2H), 3,55 (t, 2H), 3,60 - of 3.77(m, 2H), a 3.87-of 4.05(m, 3H), 6,56(d, 2H), 6,76(d, 2H), 7,1-7,35(m, N)

3-(4-Hydroxy-1,2-diphenylbuta-1-enyl)phenol

Protective Tgp-GRU the PU is removed by dehydration reaction.

Z-isomer1H-NMR (CDCl3): by 2.73 (t, 2H), 3,55 (t, 2H), 6,4-7,4 (m, N)

d) Conversion of the hydroxy-group 3,3,4-trainbot-3-EN-1-tins to chlorine

Using thionyl chloride

(E)-(2-{4-[4-Chloro-1-(4-forfinal)-2-phenylbut-1-enyl]phenoxy}-ethyldimethylamine (No. 1)

(E)-4-[4-(2-Dimethylaminoethoxy)phenyl]-4-(4-forfinal)-3-phenylbut-3-EN-1-ol (0.8 g, 2 mmol) dissolved in toluene (30 ml) and added dropwise thionyl chloride (0.7 g, 6 mmol). The mixture is heated to boiling point under reflux for one hour. Toluene is partially evaporated. The formed crystals of the hydrochloric salt of the product is filtered and the precipitate washed with toluene. Yield 0.79 g, 86%.

1H-NMR (HCl-salt, MeOH-d4): 2,90(t, 2H), 2,92(C, 6N), 3,40 (t, 2H), 3,49(ICCAT, 2H), 4,21(ICCAT, 2H), 6,70(d, 2H), 6,85(d, 2H), 7,11(t, 2H), 7,12-7,22(m, 5H), 7,32(DD, 2H)

Using this method, you receive the following connections:

(Z)-(2-{4-[4-Chloro-1-(4-forfinal)-2-phenylbut-1-enyl]phenoxy}-ethyldimethylamine (No. 2)

1H-NMR (HCl-salt, MeOH-d4): of 2.93(t, 2H), 2,99 (C, 6N), of 3.42 (t, 2H), 3,61(ICCAT, 2H), 4,39(ICCAT, 2H), 6.73 x(t, 2H), to 6.88(DD, 2H), 7,07(d, 2H), 7,12-7,22(m, 5H), 7,29(d, 2H)

(E)-(2-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}-ethyl) - dimethylamine (No. 3)

1H-NMR (CDCl3): 2,30(C, 6N), to 2.66(t, 2H), 2.91 in(t, 2H), 3,40(t, 2H), 3,94(t, 2H), to 6.57(d, 2H), 6.75 in(d, 2N), and 7.1 to 7.4 (m, N) (2-{4-[4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethyl)-dimethylamine (No. 4 and 5)

E-isomer (No. 4), HCl-is ol, 1H-NMR (CDCl3): 2,90(C, 6N), to 2.94(t, 2H), 3,40(t, 4H), to 4.38(t, 2H), 6,59(d, 2H), 6,78(d, 2H), 7,06(d, 2H), 7,19(d, 2H), 7.23 percent(d, 2H), 7,35(d, 2H)

Z-isomer (No. 5), HCl-salt,1H-NMR (MeOH-d4):), 2,95(t, 2H), 3,41(C, 6N), to 3.41(t, 2H), 3,48-to 3.58(m, 2H) 4,56 with 4.65(m, 2H), 6,79(d, 2H), 6,92(d, 2H), 7,02(d, 2H), 7,05(d, 2H), 7,19 (d, 2H), 7,22(d, 2H)

(E)-1-[4-(2-Benzyloxyethyl)phenyl]-4-chloro-1- (4-forfinal) -2-phenylbut-1-ene

1H-NMR (CDCl3): of 2.92 (t, 2H), 3,41 (t, 2H), 3,74 (ICCAT, 2H), 4,01(ICCAT, 2H), 4,59(s, 2H), return of 6.58(d, 2H), 6,76(d, 2H), 7,06(t, 2H), 7,10-7,40(m, N)

(E)-1-[4-(2-Benzyloxyethyl)phenyl]-4-chloro-1,2-bis(4-chloro-phenyl)-buta-1-ene

1H-NMR (CDCl3): 2,90 (t, 2H), 3,39(t, 2H), 3,76(ICCAT, 2H), 4.04 the(ICCAT, 2H), 4,60(s, 2H), 6,60(d, 2H), 6,74(d, 2H), 7,06(d, 2H), 7,17(d, 2H), 7.23 percent(d, 2H) 7,25 to 7.4(m, 7H)

4-Chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)-but-1-ene (No. 6 and 7) is obtained from 3, 4-bis(4-chlorophenyl)-4-[4-(2-hydroxyethoxy)phenyl]-but-3-EN-1-ol.

E-isomer (No. 6),1H-NMR (CDCl3): 2,90 (t, 2H), 3,39(m, 2H), of 3.73(t, 2H), 4,10(t, 2H), 6,59(d, 2H), 6,76(d, 2H), 7,10(d, 2H), 7,17(d, 2H), 7.23 percent(d, 2H), 7,33(d, 2H)

Z-isomer (No. 7),1H-NMR (CDCl3): to 2.94 (t, 2H), 3,40 (t, 2H), 3,83(t, 2H), 4,25(t, 2H), 6,79(d, 2H), 6,92(d, 2H), 7,02 (d, 2H), 7,05(d, 2H), 7,18(d, 2H), 7,20(m, 2H)

Using triphenylphosphine-carbon tetrachloride

1-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)phenyl-4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-ene

Triphenylphosphine (0,19 g, 0.73 mmol) dissolved in acetonitrile (4 ml). To the solution was added carbon tetrachloride (0,237 g, 1.3 mmol) and tritium is n (0,043 g, 0.43 mmol) and the mixture is stirred for half an hour at ambient temperature. 4-(2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)-phenyl-4-(4-chlorophenyl)-3-phenyl-but-3-EN-1-ol (0.2 g, 0.43 mmol, obtained from 4-(4-chlorophenyl)-4-[4-(2,3-dihydroxypropane)-phenyl]-3-phenylbut-3-EN-1-ol using the acetonide group for the protection of the diol group) is dissolved in acetonitrile, is added to the reaction mixture and continue stirring for 2 hours. The solvent is then evaporated and the residue is dissolved in 20 ml methanol-water (8:2). The solution is extracted twice with petroleum ether (20 ml) at boiling point. Phase petroleum ether are combined and washed once again with a hot solution of methanol-water. The output of 0.07,

E-isomer1H-NMR (CDCl3): to 1.37 and 1.41 (2s, together 6N), only 2.91 (t, 2H), 3,40(t, 2H), 3,70-to 4.14(m, 4H), 4,39(quintet, 1H), 6,56(d, 2H), 6,76(d, 2H), 7,05 to 7.4(m, N)

e) removing the protective groups

(E)-2-{4-[4-Chloro-2-phenyl-1-(4-forfinal) buta-1-enyl] phenoxy}-ethanol (No. 8)

(E)-1-[4-(2-Benzyloxyethyl)phenyl]-4-chloro-1- (4-forfinal) -2-phenylbut-1-ene (400 mg, 0.8 mmol) dissolved in toluene. Zn (106 mg, 1.6 mmol) and acetylchloride (126 mg, 1.6 mmol) is added under nitrogen atmosphere. The mixture is stirred at room temperature for 6 hours the Mixture is filtered and the solvent evaporated. The residue is dissolved in 80% aqueous methanol containing 5% sodium hydroxide. The mixture is stirred at room temperature for 2 h and methane is l evaporated. Add some water and the product extracted with ethyl acetate. The mixture is dried and the solvent evaporated. The product was then purified flash chromatography (eluent toluene:methanol=9:1).

1H-NMR (CDCl3): of 2.92(t, 2H,), is 3.41(t, 2H), a 3.87-3,95(m, 4H), to 6.57(d, 2H), 6,78(d, 2H), 7,06(t, 2H), 7,10-7,31(m, 7H)

Using this method, you receive the following compound according to the invention is:

(E)-2-{4-[(z)-4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}-ethanol (No. 9)

1H-NMR (CDCl3): 2,90(t, 2H), 3,39(t, 2H), 3,85-of 4.05(m, 4H), of 6.61(d, 2H), 6,77(d, 2H), 7,07(d, 2H), 7,1-7,26(m, 4H), 7,35(d, 2H)

(E)-3-{4-[(Z)-4-Chloro-1-(4-chlorophenyl)-2-phenyl-but-1-enyl]-phenoxy}propane-1,2-diol (No. 10)

1-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)phenyl-4-chloro-1-(4-chlorophenyl)-2-phenyl-buta-1-ene (0.5 g, 1.0 mmol) is dissolved in ethanol and to the solution add 2 N. aqueous hydrogen chloride (5 ml). The mixture is heated to 40°C. and stirring is continued for one hour. The ethanol is then evaporated and the product is extracted with toluene, the extract washed with water, dried and evaporated to dryness. The output of 0.45,

1H-NMR (CDCl3): only 2.91(t, 2H), 3,41(t, 2H), 3,60-to 4.15(m, 5H), 6,56(d, 2H), 6,77(d, 2H), and 7.1 to 7.4(m, N)

EXAMPLE 2.

a) O-alkylation of derivatives of 4-(1,2-diaryl-4-hydroxy-but-1-enyl)phenol

4,4-Bis[4-(2-benzyloxyethyl)phenyl]-3-phenylbut-3-EN-1-ol is obtained from 4,4-bis(4-hydroxyphenyl)-3-phenylbut-3-EN-1-ol (example 1C) and benzyl-2-bromatologia broadcast on IFC reaction according to methods which, described in example 1A.

1H-NMR (CDCl3): 2,78 (t, 2H)and 3.59(q, 2H), 3,74, 3,84, 4.02 and 4,17(4 iskat, along 8H), 4,59(s, 2H)and 4.65 (s, 2H), 6,56(d, 2H), 6,76(d, 2H), 6,91(d, 2H), 7,09-7,40(m, 17H)

Using this method, you receive the following connections:

(E)-4-[4-(2-Benzyloxyethyl)phenyl]-4-(4-chlorophenyl)-3-phenylbut-3-EN-1-ol

1H-NMR (CDCl3): is 2.74(t, 2H), of 3.56(t, 2H), 3,71 is 3.76(m, 2H), 3,98-a 4.03 (m, 2H), 4,60 (s, 2H), to 6.57(d, 2H), 6.75 in(d, 2H), 7,10-7,40(m, 14N)

(Z)-4-[3-(2-Benzyloxyethyl)phenyl]-3,4-diphenylbuta-3-EN-1-ol

1H-NMR (CDCl3): of 2.75(t, 2H), to 3.58(t, 2H), 3,63-3,66(m, 2H), 3,81-of 3.85(m, 2H), 4,55(s, 2H), 6,47-7,40(m, N)

(Z)-4-[4-(2-Methylsulfonylmethane)phenyl]-3,4-diphenylbuta-3-EN-1-ol

Connection receive, using the method described in example 1A from 4-(4-hydroxyphenyl)-3,4-diphenyl-but-3-EN-1-ol (method of obtaining described in U.S. patent No. 4996225) and 2-chloroethylnitrosourea.

1H-NMR (CDCl3): of 2.16(s, 3H), of 2.75(t, 2H), and 2.79(t, 2H)and 3.59(q, 2H), was 4.02(t, 2H), 6,55(d, 2H), 6,79(d, 2H), 7,05-7,40 (m, 10H)

(Z)-4-[4-(3-Benzyloxypropionic)phenyl]-3,4-diphenylbuta-3-EN-1-ol get the same way, using as reagent benzyl-3-bromopropyl ether.

1H-NMR (CDCl3): 2,00(Quint., 2H), 2, 75(t, 2H)and 3.59(2 t, 4H), of 3.95(t, 2H), 4,48(s, 2H), is 6.54(d, 2H), 6,78(d, 2H), 7,11-7,40 (m, 15 NM)

(E)-4-(4-Chlorophenyl)-3-phenyl-4-(4-{2-[2-(tetrahydropyranyloxy)ethoxy]ethoxy}phenyl)but-3-EN-1-ol

NaH (0.09 g, 2,69 mmol) is mixed with dimethylformamide (DMF) (30 m is). (E)-4-(4-Chlorophenyl)-4-(4-hydroxyphenyl)-3-phenyl-but-3-EN-1-ol is dissolved in the solution and the mixture is heated to 60°C. and stirred for half an hour. To the solution was added 2-[(2-(tetrahydropyranyloxy)ethoxy]ethylchloride (0,83 g, a 4.03 mmol)dissolved in DMF (5 ml), and heating continued for 3 hours. To the cooled reaction mixture is added saturated aqueous solution of ammonium chloride (30 ml) and toluene (30 ml) and stirring is continued for 10 minutes. The layers are separated and the aqueous layer was extracted with toluene (30 ml). Toluene phases are combined and washed with 2 N. aqueous sodium hydroxide and three times with water. The organic phase is dried and evaporated to dryness. Output 1.4 g, 99%.

1H-NMR (CDCl3): 1,40-1,90(m, 6N), 2,70(t, 2H), 3,4-of 3.94 (m, 10H), 3.95 to of 4.05(m, 2H), 4,55(m, 1H), 6,56(d, 2H), 6,74(d, 2H), 7,05-7,35(m, N)

Using this method, you receive the following connections:

(Z)-3,4-Diphenyl-4-(4-{2-[(2-(tetrahydropyranyloxy)ethoxy]-ethoxy}phenyl)but-3-EN-1-ol get the same way as the previous connection, on the basis of 4-(4-hydroxyphenyl)-3,4-diphenylbuta-3-EN-1-ol (method of obtaining described in U.S. patent No. 4996225) and 2-[2-(tetrahydropyranyloxy)ethoxy]ethylchloride.

1H-NMR (CDCl3): 1,40 is 1.91(m, 6N), is 2.74(t, 2H), 3,4-4,0(m, N), br4.61(m, 1H), 6,55(d, 2H), 6,77(d, 2H), 7,05-to 7.35(m, 10H)

4-(4-Forfinal)-3-phenyl-4-(4-{2-[2-(tetrahydropyranyloxy)-ethoxy]ethoxy}phenyl)but-3-EN-1-ol

E-isomer1H-NMR (CDCl3 ): 1,38-1,90(m, 6N), a 2.75(t, 2H), 3,32-a 4.03(m, 10H), of 4.00(m, 2H), to 4.62(m, 1H), 6,56(d, 2H), 6.75 in (d, 2H),? 7.04 baby mortality(t, 2H), 7,00-7,20(m, 5H), 7,27(DD, 2H)

Z-isomer1H-NMR (CDCl3): 1,40-1, 90 (m, 6N), 2, 79 (t, 2H), 3,43-a 4.03(m, 10H), to 4.15(m, 2H)and 4.65(m, 1H), 6,69(t, 2H), 6,83 (DD, 2H), 6.90 to(d, 2H), 7,05-7,20(m, 5H), 7,19(d, 2H)

(Z)-4-[4-(2,2-Dimethyl-[1,3]-dioxolane-4-ylethoxy)phenyl]-3,4-diphenylbuta-3-EN-1-ol

1H-NMR (CDCl3): to 1.37 and 1.41 (2s, together 6N), a 2.75 (t, 2H), to 3.58(t, 2H), 3,70-4,10(m, 4H), 4,39(quintet, 1H), 6,56(d, 2H), 6,78(d, 2H), 7,10-7,40(m, 10H)

Ethyl ester {4-[1-(4-chlorophenyl)-4-hydroxy-2-phenylbut-1-enyl]phenoxy}acetic acid obtained from 4-(4-chlorophenyl)-4-(4-hydroxyphenyl)-3-phenylbut-3-EN-1-ol (example 1C) and ethylbromoacetate according to the method described in example 1A, using NaH as a base.

E-isomer1H-NMR (CDCl3): a 1.25 (t, 3H), 2,74 (t, 2H), only 3.57 (t, 2H), 4,22(kV, 2H), 4,48(s, 2H), 6,56(d, 2H), 6,77(d, 2H), 7,0-7,4(m, N)

Z-isomer1H-NMR (CDCl3): 1,31 (t, ZN), 2,78 (t, 2H), to 3.58 (t, 2H), 4,29(kV, 2H), 4,63(s, 2H), 6,79(d, 2H), 6.89 in(d, 2H), 6,98(d, 2H), 7,15-7,30(m, 7H)

b) Conversion of hydroxyl groups to chlorine

1,1-Bis[4- (2-benzyloxyethyl)phenyl]-4-chloro-2-phenylbut-1-ene

The conversion of hydroxyl groups to chlorine carried out using thionyl chloride as the reagent according to the method described in example 1d.

1H-NMR (CDCl3): to 2.94(t, 2H), 3,42(t, 2H), of 3.73 and a 3.83(2 iskat, together 4H), 4.00 and 4,16(2 iskat, together 4H), 4,58 (s, 2H)and 4.65(s, 2H), 6,56(d, 2H), 6,76(d, 2H), 6,92 (d, 2H), 7,10-7,40(m, 17H)

Using the criminal code of the above method, receive the following connections:

(E)-1-[4-(2-Benzyloxyethyl)phenyl]-4-chloro-1-(4-chlorophenyl)-2-phenyl-buta-1-ene

1H-NMR (CDCl3): only 2.91(t, 2H), 3,40(t, 2H), 3,71 is 3.76(m, 2H), 3,98-a 4.03(m, 2H), 4,60(s, 2H), to 6.57(d, 2H), 6.75 in(d, 2H), 7,10-7,40(m, 14N)

(Z)-4-Chloro-1-[4-(2-methylsulfonylmethane)phenyl]-1,2-diphenyl-but-1-ene (No. 11)

1H-NMR (CDCl3): of 2.16(s, 3H), and 2.79(t, 2H), 2,92(t, 2H), 3,42(t, 2H), 4,01(t, 2H), 6,55(d, 2H), 6,78(d, 2H), 7,05 was 7.45 (m, 10H)

(Z)-1-[3-(2-Benzyloxyethyl)phenyl]-4-chloro-1,2-diphenyl-but-1-ene

1H-NMR (CDCl3): of 2.92(t, 2H), 3,41(t, 2H), 3,63-to 3.67(m, 2H), 3,81-of 3.85(m, 2H), 4,55(s, 2H), 6,47-7,40(m, N)

(Z)-1-[4-(3-Benzyloxypropionic)phenyl]-4-chloro-1,2-diphenyl-but-1-ene

1H-NMR (CDCl3): 2.0(quintet, 2H), 2,92(t, 2H), 3,42(t, 2H)and 3.59(t, 2H), 3,94(t, 2H), 4,48(s, 2H), is 6.54(d, 2H), 6,78 (d, 2H), 7,11-7,40(m, 15 NM)

Ethyl ester {4-[4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}acetic acid and the corresponding acid (No. 12 and 13)

E-isomer, ethyl ester1H-NMR (CDCl3): a 1.25(t, 3H), 2.91 in (t, 2H), 3,41(t, 2H), is 4.21(q, 2H), 4,49(s, 2H), to 6.57(d, 2H), 6,77(d, 2H), 7,0-7,4(m, N)

Ester hydrolyzing the corresponding acid in 80% aqueous methanol containing 5% sodium hydroxide.

E-isomer, acid (No. 12)1H-NMR (CDCl3): only 2.91(t, 2H), 3,41(t, 2H), 4,47(s, 2H), return of 6.58(d, 2H), 6,78(d, 2H), 7,0-7,4 (m, N)

Z-isomer, ethyl ester1H-NMR (CDCl3): 1,31(t, ZN), 2,95 (t, 2H), 3,42(t, 2H), 4,30(kV, 2H)and 4.65(s, 2H), 6,79(d, 2H), 6,91(d, 2H), 6,98(d, 2H), 7,15-7,30(m, 7H)

Z-isomer, acid (No. 3) 1H-NMR (CDCl3): 2,95 (t, 2H), 3,41 (t, 2H)and 4.65(s, 2H), 6,79(d, 2H), 6,94 (d, 2H), 6,98 (d, 2H), 7,10-7,30(m, 7H)

(Z)-1,2-Diphenyl-4-chloro-4-(4-{2-[2-(tetrahydropyranyloxy) -ethoxy]ethoxy}phenyl)buta-1-ene

The conversion of hydroxyl groups to chlorine carried out using PH3R and CCL4as reagents, according to the method described in example 1d.

1H-NMR (CDCl3): 1,30-1,90(m, 6N), of 2.92(t, 2H), 3,42(t,

2H), 3,4-4,0(m, 10H), 4,62 with 4.65(m, 1H), 6,55(d, 2H), 6,77(d, 2H), 7,05-to 7.35(m, 10H)

Using this method, you receive the following connections:

(Z)-4-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxymethyl]-2,2-dimethyl[1,3]dioxolane

1H-NMR (CDCl3): to 1.37 and 1.41(2s, together 6N), only 2.91(t, 2H), 3,41(t, 2H), 3.7 to 4.1(m, 4H), 4,39(quintet, 1H), 6,55(d, 2H), 6,77(d, 2H), 7,10-7,41(m, 10H)

(E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-chloro-phenyl)-2-phenylbut-1-ene (No. 14)

Tetrahydropyranyloxy also in the reaction is converted to chlorine.

1H-NMR (CDCl3): to 2.94(t, 2H), 3.43 points(t, 2H), 3,65(ICCAT, 2H), 3,8-of 3.85(m, 4H), 4,0-4,06(m, 2H), 6,60(d, 2H), 6,78(d, 2H), 7,10-7,40(m, N)

(E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-fluoro-phenyl)-2-phenylbut-1-ene (No. 15)

Tetrahydropyranyloxy also in the reaction is converted to chlorine.

1H-NMR (CDCl3): only 2.91(t, 2H), 3,41(t, 2H), 3,62(ICCAT, 2H), 3,74-of 3.85(m, 4H), 4,01(ICCAT, 2H), to 6.57(d, 2H), 6,76 (d, 2H), 7,06(t, 2H), 7,09-7,22(M, 5H), 7,27(DD, 2H)

(C) removing the protective groups

2-(4-{4-chlorine is-1-[4-(2-hydroxyethoxy)phenyl]-2-phenylbut-1-enyl}phenoxy)-1-ethanol (No. 16)

Benzyl groups are removed using Zn and l as reagents, according to the method described in example 1E.

1H-NMR (CDCl3): 2,95(t, 2H), 3,42(t, 2H), 3,80-4,20(m, 8H), 6,56(d, 2H), 6,78(d, 2H), 6,92(d, 2H), 7,10-7,26(m, 7H)

Using this method, you receive the following compounds according to the invention is:

(E)-2-{4-[4-Chloro-2-phenyl-1-(4-chlorophenyl)but-1-enyl]phenoxy}-ethanol (No. 17)

1H-NMR (CDCl3): of 2.92(t, 2H), 3,41(t, 2H), 3,80-4,00 (m, 4H), to 6.57(d, 2H), 6,77(d, 2H), 7,10-7,40(m, N)

(z)-2-[3-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethanol (No. 18)

1H-NMR (CDCl3): of 2.93(t, 2H), 3,41(t, 2H), 3,70-of 3.80(m, 4H), 6,40-7,40(m, 14N)

(z)-2-{2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethoxy}-ethanol (No. 19)

Tetrahydropyranyloxy ether decompose H+/EtOH, using the method described in example 1E.

1H-NMR (CDCl3): of 2.92 (t, 2H), 3,41 (t, 2H), 3,61, 3,68, of 3.77 (3 iskat, 6N), 4,00(ICCAT, 2H), 6,56(d, 2H), 6,78(d, 2H), 7,1-7, 4 (m, 10H)

Using this method, you receive the following compound according to the invention is:

(z)-3-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]propane-1,2-diol (No. 20)

1H-NMR (CDCl3): of 2.92(t, 2H), 3,41(t, 2H), to 3.58-4,10(m, 5H), 6,53(d, 2H), 6,78(d, 2H), 7,10-7,41 (m, 10H)

EXAMPLE 3.

a) (z)-4-[4-(2-Imidazol-1-yl-ethoxy)phenyl]-3,4-diphenylbuta-3-EN-1-ol

(z)-4-[4-(2-Bromoethoxy)phenyl]-3,4-diphenylbuta-3-EN-1-ol (method of obtaining described in U.S. patent No. 4996225) (equal to 4.97 g, to 0.0117 mol) is dissolved in methyl ethyl ketone (50 ml) and the solution is to relax the Ute potassium carbonate (4.8 g, 0.035 mol) and sodium salt of imidazole (2,11 g, 0,0234 mol). The mixture is stirred and heated to boiling point under reflux for five hours. Then the solution is filtered and the filtrate evaporated to dryness. The residue is dissolved in ethyl acetate, washed with 2 N. aqueous sodium hydroxide solution and water, dried and evaporated to dryness. The residue is recrystallized from a mixture of toluene and acetonitrile.

1H-NMR (CDCl3): of 2.75(t, 2H), 3,59(ICCAT, 2H), 4,07 (ICCAT, 2H), 4,23(ICCAT, 2H), 6,51(d, 2H), 6,79(d, 2H), 6,97(s, 1H), 7,03(s, 1H), 7,05-7,40(m, 10H), 7,51(s, 1H)

(Z)-4-[4-(2-Methylenedioxy)phenyl]-3,4-diphenylbuta-3-EN-1-ol

(Z)-4-[4-(2-Chloroethoxy)phenyl]-3,4-diphenylbuta-3-EN-1-ol (obtained as (Z)-4-[4-(2-bromoethoxy)phenyl]-3,4-diphenylbuta-3-EN-1-ol synthesis method described in U.S. patent No. 4996225) (2.0 g, 0,0052 mol) and methylamine in 40% aqueous solution (5 ml, 0,065 mol) is mixed with dimethylformamide (8 ml). The mixture is heated in a sealed ampoule at 60°C for 8 hours. To the mixture add 60 ml of water and extracted with ethyl acetate. An ethyl acetate phase was washed with water 2 N. a solution of hydrogen chloride. The aqueous phase is alkalinized 2 N. a sodium hydroxide solution and extracted with ethyl acetate. An ethyl acetate phase is washed with water, dried over magnesium sulfate and evaporated to dryness. Output of 1.5,

1H-NMR (CDCl3): 2,39(s, 3H), 2,70(t, 2H), 2,84(t, 2H),

of 3.48(t, 2H), 3,93(t, 2H), 6,59(d, 2H), 6,77(d, 2H), ,10-7,40 (m, 10H)

b) (z)-4-(4-{2-[(2-Benzyloxyethyl)methylamino]ethoxy}phenyl)-3,4-diphenylbuta-3-EN-1-ol get, using the same IFC-way as in example 1A, using benzyl-2-bromatology ether as a reactant.

1H-NMR (CDCl3): 2,35(s, 3H), 2,70, 2,75, 2,79(3 t, 6N), of 3.56(t, 2H), 3,60(t, 2H), 3,94(t, 2H), 4,50(s, 2H), is 6.54(d, 2H), 6,77(d, 2H), 7,10-7,20(m, 5H), 7,25-to 7.35(m, 10H)

c) (z)-1-{2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethyl}-1H-imidazole (No. 21)

prepared as in example 1d using as reagents triphenylphosphine and carbon tetrachloride. Purification of the product is carried out, pariva acetonitrile, dissolving the residue in a solution acidified methanol-water (8:2) and extragere triphenylphosphine toluene (three times at room temperature). A solution of methanol-water alkalinized and the product is extracted with toluene. Toluene phase is washed twice with water and evaporated to dryness. The product is crystallized from ethyl acetate as HCl-salt. Yield 46%.

1H-NMR (HCl-salt, MeOH-d4): 2,89(t, 2H), 3,39(t, 2H), 4,23 (t, 2H), 4,60(t, 2H), 6,60(d, 2H), 6,80(d, 2H), 7,10-7,40(m, 10H), 7,54(s, 1H), to 7.67(s, 1H), 8,98(s, 1H)

(Z)-(2-Benzyloxyethyl)-{2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)-phenoxyethyl}methylamine

prepared as in example 1d, using thionyl chloride as reagent.

1H-NMR (CDCl3): 2,35(s, 3H), 2,70, and 2.79(2 t, 4H), of 2.92(t, 2H), 3,42(t, 2H), of 3.56(t, 2H), 3,93(t, 2H), 4,51(s, 2H), is 6.54 (d, 2H), 6,77(d, 2H), 7,10-7,40(m, 15 NM)

d) (z)-2-({2-[-4-(4-Chloro-1,2-diphenylbuta-1-Yeni is)phenoxy]-ethyl}methylamino)ethanol (No. 22)

get a manner analogous to 1E, using Zn and acetylchloride as reagents.

1H-NMR (CDCl3): 2, 32(s, 3H), 2,60(t, 2H), 2,78(t, 2H), 2,92(t, 2H), 3,42(t, 2H), only 3.57(t, 2H), 3,91(t, 2H), is 6.54(d, 2H), 6,78(d, 2H), 7,05-7,40(m, 10H)

EXAMPLE 4.

a) 2-(4-Chlorophenyl)-1-(4-methoxyphenyl)alanon

The anisole (13,9 g, 0.13 mol) is added to a stirred solution of 4-chlorophenylalanine acid (20,0 g, 0.12 mol) in triperoxonane anhydride (16.5 ml, 0.12 mol). The mixture is stirred at room temperature for 24 hours, Add ice water and crystallizing the product is collected in the form of a sinter and washed with water. The product is recrystallized from ethanol. Yield 20.4 g, 67%.

1H-NMR (CDCl3): 3,86(s, 3H), 4,20(s, 2H), 6,93(d, 2H), 7,20(m, 2H), 7,28(d, 2H), 7,98(d, 2H)

Using this method, you receive the following connections:

2-(4-Forfinal)-1-(4-methoxyphenyl)alanon

1H-NMR (CDCl3): a 3.87(s, 3H), is 4.21(s, 2H), 6,94(d, 2H), 7,01(t, 2H), 7,22(DD, 2H), to 7.99(d, 2H)

1-(4-Methoxyphenyl)-2-phenylethanone

1H-NMR (CDCl3): of 3.84(s, 3H), 4,23(s, 2H), 6,92(d, 2H), 7,20-7,40(m, 5H), to 7.99(d, 2H)

b) 2-(4-Chlorophenyl)-1-(4-hydroxyphenyl)alanon

Aluminium chloride (29,8 g, 0,223 mol) is added in small portions to a stirred solution of 2-(4-chlorophenyl)-1-(4-methoxyphenyl)ethanone (19,4 g 0,074 mol) in toluene (300 ml). The mixture is heated to 60°C. and stirring is continued for 2 hours cooled To CME and add diluted hydrochloric acid. To dissolve the product add ethyl acetate. The layers are separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried and the solvents evaporated. The product is recrystallized from toluene. Output is 17 g, 93%.

1H-NMR (CDCl3+ MeOH-d4): 4,19(s, 2H), 6,85(d, 2H), 7,19 (d, 2H), 7,28(d, 2H), of 7.90(d, 2H)

Using this method, you receive the following connections:

2-(4-Forfinal)-1-(4-hydroxyphenyl)alanon

1H-NMR (CDCl3+ MeOH-d4): 4,20(s, 2H), 6,86(d, 2H), 7,00 (t, 2H), 7,22(DD, 2H), to $ 7.91(d, 2H)

1-(4-Hydroxyphenyl)-2-phenylethanone

1H-NMR (CDCl3+ MeOH-d4): 4,20(s, 2H), at 6.84(d, 2H), 7,2-7,4(m, 5H) of 7.90(d, 2H)

c) O-Alkylation of derivatives of 4-hydroxyethoxymethyl

In IFC-conditions

2-(4-Chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]alanon

10% Aqueous sodium hydroxide is added to a mixture containing

2- (4-chlorophenyl) -1-.(4-hydroxyphenyl) alanon (6.0 g, 0,024 mol), Tbag (0.9 g) in toluene (60 ml) at 60°C. the Mixture is stirred for 30 minutes Add the hydrochloride of N,N-dimethylamino-ethylchloride (3.6 g, 0,025 mol) and stirring is continued at 70-75°C for 3 hours, the Layers separated and the aqueous phase is extracted with toluene. The combined toluene phases are evaporated, receiving the product (1.85 g, 24%).

1H-NMR (CDCl3): of 2.34(s, 6N), a 2.75 (t, 2H), 4,12 (t, 2H), 4,20(s, 2H), 6,95(d, 2H), 7,19(d, 2H), 7,29(d, 2H), of 7.97(d, 2H)

Using the asany way get the following connection:

1-[4-(2-Dimethylaminoethoxy)phenyl]-2-(4-forfinal)alanon

1H-NMR (CDCl3): of 2.34 (s, 6N), a 2.75(t, 2H), 4,12(t, 2H), is 4.21(s, 2H), of 6.96(d, 2H), 7,01 (t, 2H), 7,22(DD, 2H), 7,98(d, 2H)

With K2CO3in 2-butanone

1-[4-(2-Benzyloxyethyl)phenyl]-2-phenylethanone

1-(4-Hydroxyphenyl)-2-phenylethanone (17 g, 0.08 mol) dissolved in 2-butanone (200 ml) and to the solution was added potassium carbonate (33.1 g, 0.24 mol) and 2-benzyloxyaniline (25,8 g, 0.12 mol). The mixture is stirred and heated to boiling point under reflux for three hours. Then the solution is filtered and the filtrate evaporated to dryness. The residue is dissolved in toluene, washed with 2 N. aqueous sodium hydroxide solution and water, dried and evaporated to dryness. The product is crystallized from ethanol. The output of 23.2 g, 84%.

1H-NMR (CDCl3): 3,80-3,86(m, 2H), 4,20-4,22 (m, 2H), 4,23 (s, 2H), 4,63(s, 2H), 6.90 to(d, 2H), 7,20-7,40(m, 10H), of 7.90(d, 2H)

Using this method, you receive the following connections:

1-[4-(2-Benzyloxyethyl)phenyl]-2-(4-chlorophenyl)alanon1H-NMR (CDCl3): 3,84(ICCAT, 2H), 4,20(ICCAT, 2H), 4,20 (s, 2H), 4,63(s, 2H), 6,95(d, 2H), 7,19(d, 2H), 7,29(d, 2H), 7,30 was 7.45(m, 5H), of 7.96(d, 2H)

2-(3-Methoxyphenyl)-1-[4-(2-piperidine-1-ylethoxy)phenyl]-alanon

As the source materials using 1-(4-hydroxyphenyl)-2-(3-methoxyphenyl)Etalon hydrochloride and 1-(2-chloroethyl)piperidine.

1H-NMR (CDCl3):1,37-of 1.52(m, 2H), 1,52 by 1.68(m, 4H), 2,50 (ushort, 4H), 2,78(t, 2H), of 3.77(s, 3H), 4,14(t, 2H), 4,19(s, 2H), 6.73 x-6,90(m, 3H), 6.90 to(d, 2H), 7,22(m, 1H), of 7.96(d, 2H)

2-(2-Methoxyphenyl)-1-[4-(2-piperidine-1-ylethoxy)phenyl]-alanon

As the source materials using 1-(4-hydroxyphenyl)-2-(2-methoxyphenyl)Etalon hydrochloride and 1-(2-chloroethyl)piperidine.

1H-NMR (CDCl3): 1,40-of 1.53(m, 2H), 1,53 is 1.70(m, 4H), of 2.51 (ushort, 4H), and 2.79(t, 2H), 3,79(s, 3H), of 4.16(t, 2H), 4,22(s, 2H), 6,84-7,00(m, together 4H), under which 6,92(d, 2H), 7,14-7,30(m, 2H), 8,00(d, 2H)

d) C-Alkylation derivative deoxybenzoin

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]butane-1-he

A mixture containing 2-(4-chlorophenyl)-1-[4-(2-dimethylamino-ethoxy)phenyl]alanon (6.3 g, at 0.020 mol) and Tbag (0.5 g) in toluene (70 ml), heated to 70°C. and added 48% aqueous sodium hydroxide (70 ml). The mixture is stirred for 30 min and added dropwise (2-bromaocetic)benzene (5.5 g, 0,025 mol) at 85-90°C. the Reaction mixture was stirred at 95-100°C for 3 hours, the Layers separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with water and the solvent evaporated. The residual product (9.0 g) used in the next reaction stage without further purification.

1H-NMR (CDCl3): 1,93-2,15 and 2,38-2,58(2m, together 2H), 2,32 (C, 6N), of 2.72(t, 2H), 3.25 to 3,55(m, 2H), 4,08(t, 2H), 4,42(s, 2H), 4,82(t, 1H), to 6.88(d, 2H), 7,15-7,40(m, N), 7,92(d, 2H)

Using this method, get with ewusie connection:

4-Benzyloxy-1-[4-(2-dimethylaminoethoxy)phenyl]-2-(4-fluoro-phenyl)butane-1-he

1H-NMR (CDCl3): 1,95-2,15 and 2,40-2,60(2m, together 2H), 2,31 (C, 6N), a 2.71(t, 2H), 3.25 to 3,55(m, 2H), 4,07(t, 2H), 4,42(s, 2H), a 4.83(t, 1H), to 6.88(d, 2H), 6,94(t, 2H), 7,10-7,40(m, 7H), to 7.93(d, 2H)

4-Benzyloxy-2-(4-chlorophenyl)-1-(4-methoxyphenyl)butane-1-he1H-NMR (CDCl3): 1,95-2,15 and 2,35-2,55(2m, together 2H), 3,30-3,55(m, 2H), 3,82(s, 3H), 4,42(s, 2H), 4,82(t, 1H), 6,85 (d, 2H), 7,10-7,40(m, N), to 7.93(d, 2H)

1-[4-(2-Benzyloxyethyl)phenyl]-2-phenyl-4-(tetrahydropyranyloxy)butane-1-he

1H-NMR (CDCl3): 1,4-1,9(m, 6N), of 2.0-2.2(m, 1H), from 2.4 to 2.65 (m, 1H), 3,2-of 4.05(m, 6N), 4,1-4,2(m, 2H), 4,45 to 4.5(m, 1H), 4,60(s, 2H), 4,80(t, 1H), to 6.88(d, 2H), and 7.1 to 7.4(m, 10H), of 7.96 (d, 2H)

1-[4-(2-Benzyloxyethyl)phenyl]-2-(4-chlorophenyl)-4-(tetrahydropyranyloxy)butane-1-he

1H-NMR (CDCl3): 1,30-1,90(m, 6N), 1,95-2,15 and 2,38-2,58 (2m, together 2H), 3,20-of 4.05(m, 6N), 4,16(ICCAT, 2H), 4.75 V-is 4.85(m, 1H), br4.61(s, 2H), 4,80(t, 1H), to 6.88(d, 2H), 7,13-7,40 (m, N), 7,94(d, 2H)

1,2-Bisphenyl-4-(tetrahydropyranyloxy)butane-1-he

1H-NMR (CDCl3): 1,4-1,9(m, 6N), of 2.0-2.2(m, 1H), from 2.4 to 2.65 (m, 1H), 3,2-a 3.9(m, 4H), 4,45 to 4.5(m, 1H), around 4.85(t, 1H), and 7.1-7.5 (m, 8H), of 8.00(d, 2H)

2-(3-Methoxyphenyl)-1-[4-(2-piperidine-1-ylethoxy)phenyl]-4-(tetrahydropyranyloxy)butane-1-he

1H-NMR (CDCl3): 1,40-1,90(m, 13H), 1,95-2,2(m, 1H), 2,48 (ushort, 4H), to 2.75(t, 2H), 3,20-3,90(m, 4H), under which 3,76 (s, 3H), 4,11(t, 2H), 4,49(m, 1H), 4,77(m, 1H), 6.73 x(DD, 2H), 6,80-to 6.95(m, 4H), 7,21(t, 1H), of 7.96(d, 2N)

2-(2-Methoxyphenyl)-1-[4-(2-piperidine-1-ylethoxy)phenyl]-4-(tetrahed is pyranyloxy)butane-1-he

1H-NMR (CDCl3): 1,30-1,90(m, 13H), 1,95-2,15(m, 1H), 2,48 (m, 4H), to 2.74 (t, 2H), 3,20-4,00(m, 4H), under which 3,88(s, 3H), 4.09 to(t, 2H), 4,45-4,55(m, 1H), 5,22(m, 1H), 6.73 x-6,90(m, 4H) 7,14-7,30(m, 2H), of 7.97(d, 2H)

e) Reaction of the Grignard derivative of deoxybenzoin

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]-1-phenylbutane-1-ol

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]butane-1-he (9.4 g, 0,021 mol) are added to the Grignard reagent derived from bromine benzol (13,1 g, 0,083 mol) and mg-turnings (2.0 g, 0,083 mol) in dry tetrahydrofuran. The mixture is heated to boiling point for 3 hours To the cooled reaction mixture is added a saturated solution of ammonium chloride, THF layer was separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with water and the solvents evaporated. The residual product (10.7 g) used in the next reaction stage without further purification.

Using this method, you receive the following connections:

4-Benzyloxy-1-[4-(2-dimethylaminoethoxy)phenyl]-2-(4-fluoro-phenyl)-1-phenylbutane-1-ol

used in the next reaction stage without further purification.

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]-1-(4-methoxyphenyl)butane-1-ol

used in the next reaction stage without further purification.

1-(3-Benzyloxyphenyl)-1-[4-(2-benzyloxyethyl)phenyl]-2-phenyl-4-tetrahydropyranyloxy)butane-1-ol

used in the next reaction stage without further purification.

1-[4-(Benzyloxyethyl)phenyl]-2-(4-chlorophenyl)-1-(4-methoxy-phenyl)-4-(tetrahydropyranyloxy)butane-1-ol

used in the next reaction stage without further purification.

2-(3-Methoxyphenyl)-1-phenyl-1-[4-(2-piperidine-1-ylethoxy)-phenyl]-4-(tetrahydropyranyloxy)butane-1-ol

used in the next reaction stage without further purification.

2-(2-Methoxyphenyl)-1-phenyl-1-[4-(2-piperidine-1-ylethoxy)-phenyl]-4-(tetrahydropyranyloxy)butane-1-ol

used in the next reaction stage without further purification.

1-[3-(2-Dimethylaminoethoxy)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy) butane-1-ol

used in the next reaction stage without further purification.

1-[4-(2-Benzyloxyethyl)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy)butane-1-ol

used in the next reaction stage without further purification.

1-[4-(2-Dimethylaminoethanol)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy)butane-1-ol

used in the next reaction stage without further purification.

f) Dehydration derivatives triarylmethyl

(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-phenylbut-1-enyl]-phenoxy}ethyl)dimethylamine

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]-1-phenylbutane-1-ol (10.7 g) was dissolved in IU is anole (70 ml) and add concentrated hydrochloric acid, making the solution acidic. The mixture is stirred for 4.5 h at room temperature and then at 50°C for 1 h, the Solvent evaporated and the product purified flash chromatography (eluent toluene:triethylamine=24:1). The output is 5.6 g, in the form of a mixture of E - and Z-isomers (1:2).

1H-NMR (mixture of Z - and E-isomers, CDCl3): 2,28 and 2,34(2C, 6N), 2,64, and 2,73(2T, 2H), 2,78, and 2,83(2T, 2H), 3.40 in and 3,42 (2T, 2H), 3,93 and 4,07(2T, 2H), 4,36 of 4.38 and(2s, 2H), 6,55-7,40 (m, N), which can be identified to 6.58 and 6.75 (2D, 4H).

Using this method, you receive the following connections:

(2-{4-[4-Benzyloxy-2-(4-forfinal)-1-phenylbut-1-enyl]-phenoxy}ethyl)dimethylamine

1H-NMR (mixture of Z - and E-isomers, CDCl3): 2,28 and 2,34(2C, 6N), 2.65 and 2,74(2T, 2H), 2,78, and 2,83(2T, 2H), 3,41 and 3,43 (2T, 2H), 3,93 and 4,07(2T, 2H), 4,37, and 4,39(2s, 2H), 6,50-7,40 (m, 18 H), which can be identified to 6.58 and 6.75 (2D, 4H).

(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-(4-methoxyphenyl)buta-1-enyl]phenoxy}ethyl)dimethylamine

1H-NMR (mixture of Z - and E-isomers, CDCl3): and 2,35 2,30(2C, 6N), 2,67, and was 2.76(2T, 2H), of 2.81(t, 2H), 3,41(t, 2H), 3,69, and 3,81(2s, 3H), of 4.38(s, 2H), 6,56 and 6,86(2D, 2H), 6,58 and 6,85 (2D, 2H), 6.75 in(d, 2H), 6,76(d, 2H), 7,0-7,4(m, 11N)

4-[4-(2-Benzyloxyethyl)phenyl]-3-(4-chlorophenyl)-4-(4-methoxyphenyl)but-3-EN-1-ol

get by the method of example 1C. Z - and E-isomers share flash chromatography, eluent toluene:methanol=99:1.

Z-isomer1H-NMR (CDCl3): was 2.76 (t, 2H), 3,57(ushort, 2H), 3,75(ICCAT, 2H), 3,1(s, MN), 4,03(ICCAT, 2H), 4,59(s, 2H), 6,59(d, 2H), 6,76(d, 2H), 6.87 in(d, 2H), 7,05(d, 2H), 7,13 (d, 2H), 7,19(d, 2H), 7,27-7,40(m, 5H)

E-isomer1H-NMR (CDCl3): was 2.76(t, 2H), to 3.58(ushort, 2H), 3,70(s, 3H), 3,84(ICCAT, 2H), 4,17(ICCAT, 2H)and 4.65(s, 2H), to 6.57(d, 2H), 6,77(d, 2H), 6.90 to(d, 2H), 7,06(d, 2H), 7,15 (d, 2H), 7,18(d, 2H), 7,27-7,40(m, 5H)

Using this method, you receive the following connections.

3-(3-Methoxyphenyl)-4-phenyl-4-[4-(2-piperidine-1-ylethoxy)-phenyl]but-3-EN-1-ol

Z-isomer:1H-NMR (CDCl3): 1,33-1,50(m, 2H), 1,50-of 1.65(m, 4H), 2,45(ushort, 4H), to 2.67(t, 2H), by 2.73(t, 2H,), to 3.58(t, 2H), 3,65(s, ZN), of 3.96(t, 2H), 6,55(d, 2H), 6,63-6,77(m, MN), 6,79 (d, 2H), 7,10(t, 1H), 7,20-7,40(m, 5H)

E-isomer:1H-NMR (CDCl3): 1,40-of 1.55(m, 2H), 1,55-1,70(m, 4H), of 2.51(ushort, 4H), 2,77(t, 2H), 2,80(t, 2H), 3,61(s, 3H), 3,62(t, 2H), 3,94(t, 2H), 6,6-7,25(m, 13H)

3-(2-Methoxyphenyl)-4-phenyl-4-[4-(2-piperidine-1-ylethoxy)-phenyl]but-3-EN-1-ol

Z-isomer:1H-NMR (CDCl3): of 1.33 to 1.48 (m, 2H), 1,48-of 1.65 (m, 4H), 2,43(ushort, 4H), 2,20-of 2.50(t, 2H), 2,65(t, 2H), 3.43 points-of 3.60(t, 2H), 3,62(s, 3H), 3,93(t, 2H), of 6.52(d, 2H), 6,70-of 6.90 (m, 2H), under which PC 6.82 (d, 2H), 7,05-the 7.43(m, 7H)

E-isomer:1H-NMR (CDCl3): 1,38-1, 52 (m, 2H), 1,52 is 1.70(m, 4H), of 2.51(ushort, 4H), 2,38-of 2.58(t, 2H), 2,77(t, 2H)and 3.59(s, 3H), 3.45 points-of 3.65(m, 2H), 4,10(t, 2H), 6,6-7,35(m, 13H)

(E)-4-(3-Benzyloxyphenyl)-4-[4-(2-benzyloxyethyl)phenyl]-3-phenylbut-3-EN-1-ol

1H-NMR (CDCl3): by 2.73(t, 2H), 3,5-3,6(m, 2H), 3,7 is 3.76(m, 2H), 4.0 to a 4.03(m, 2H), 4,60(s, 2H), of 5.05(s, 2H), 6,56(d, 2H), 6,78(d, 2H), 6,8-to 6.95(m, 2H), 7,05-7,35(m, 17H)

(z)-4-[4-(2-Benzyloxyethyl) phenyl] -3, 4-diphenylbuta-3-EN-1-ol

1H-NMR (CDCl3): of 2.75(t, 2H), to 3.02(t, 2H), of 3.56(t, 4H), 4,47(s, 2H), 6,78(d, 2H), of 6.96(d, 2H), and 7.1 to 7.4(m, 15 NM)

(Z)-4-[4-(2-Dimethylaminoethanol)phenyl]-3,4-diphenyl-but-3-EN-1-ol

MS: EI, m/e 403 (M+, 1%), 332 (1%), 72 (12%), 58 (100%)

g) removing the protective benzyl groups

3-(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-4-phenyl-but-3-EN-1-ol

(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-phenylbut-1-enyl]-phenoxy}ethyl)dimethylamine (1.1 g, 2.1 mmol) dissolved in toluene, added Zn powder (0.4 g, 6.1 mmol) and acetylchloride (0.6 g, 7.6 mmol) and the mixture was stirred at 40°C for 3 hours Add an additional amount of Zn (0.5 g) and acetylchloride (0.6 g) and stirring is continued for another 5 hours Add ethyl acetate and the precipitate is filtered off. The solvents are evaporated and the residue is dissolved in methanol.

Ester product and acetic acid hydrolyzing, Podlachia a mixture of 48% aqueous sodium hydroxide and stirring the mixture at room temperature for 2 hours, the Methanol is evaporated, the residue is dissolved in toluene and washed with water. The toluene evaporated and the isomers of the product is shared by flash chromatography. The output of the Z-isomer is 0.25 g of E-isomer of 0.15,

Z-isomer:1H-NMR (CDCl3): 2,28(C, 6N), to 2.65(t, 2H), rating of 2.72 (t, 2H), only 3.57(t, 2H), 3,94(t, 2H), return of 6.58(d, 2H), 6,76(d, 2H), 7,07(d, 2H), 7,15(d, 2H), 7,20-7,40(m, 5H)

E-isomer:1H-NMR (CDCl3): of 2.34 (s, 6N), is 2.74 (t, 2H), 2,78 (t, 2H)and 3.59(t, 2H), 4,07(t, 2H), 6,80-7,30(m, 13H)

<> Using this method, you receive the following connections:

4-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-forfinal)-4-phenyl-but-3-EN-1-ol

Z-isomer:1H-NMR (CDCl3): of 2.27 (s, 6N), of 2.64 (t, 2H), rating of 2.72 (t, 2H), of 3.56(t, 2H), 3,93(t, 2H), 6,56(d, 2H), 6,76(d, 2H), 6,86(t, 2H), 7,00-7,40(m, 7H)

E-isomer:1H-NMR (E-isomer, CDCl3): 2,35(C, 6N), a 2.75(t, 2H), 2,78(t, 2H), 3,60(t, 2H), 4,08(t, 2H), 6.75 in-7,40(m, 13H)

3-(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-4-(4-methoxyphenyl)but-3-EN-1-ol

Z-isomer:1H-NMR (CDCl3): 2,28 (C, 6N), to 2.65 (t, 2H), 2,75 (t, 2H), only 3.57(t, 2H), 3,81(s, 3H), of 3.94(t, 2H), return of 6.58(d, 2H), 6.75 in(d, 2H), 6.87 in (d, 2H), 7,05(d, 2H), 7,13(d, 2H), 7,19(d, 2H)

E-isomer:1H-NMR (CDCl3): 2, 33 (C, 6N), 2, 74 (t, 2H), 2,75 (t, 2H), of 3.56(t, 2H), 3,69(s, 3H), 4,07(t, 2H), 6,56(d, 2H), 6,76(d, 2H), to 6.88(d, 2H), 7,06(d, 2H), 7,13(d, 2H), 7,17(d, 2H)

h) Conversion of hydroxyl groups to chlorine

(z)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl) - dimethylamine (No. 23)

(z)-3-(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-4-phenylbut-3-EN-1-ol (0,22 g, 0.5 mmol) dissolved in toluene. Add thionyl chloride (0.2 g, 1.7 mmol) and the mixture is heated to boiling point under reflux for 45 minutes, the Toluene is partially evaporated and precipitated hydrochloric salt of the product was filtered. The output is 0.2,

1H-NMR (HCl-salt, CDCl3): 2,88 and 2,90(with, together 6N), only 2.91 (t, 2H), 3,40(m, 4H), and 4.40(m, 2H), return of 6.58(d, 2H), for 6.81(d, 2H), 7,07(d, 2H), 7,19(d, 2H), 7,20 is 7.50(m, 5H)

Using the pic is b, receive the following connections:

(E)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl) - dimethylamine (No. 24)

1H-NMR (HCl-salt, CDCl3): 2,35-to 3.02(m, 2H), 2.95 and(C, 6N), 3,35-3,55(m, 4H), 4,46-4,60(m, 2H), 6.75 in-7,30(m, 13H)

(z)-(2-{4-[4-Chloro-2-(4-forfinal)-1-phenylbut-1-enyl]phenoxy}-ethyl) - dimethylamine (No. 25)

1H-NMR (HCl-salt, CDCl3): 2,88(C, 6N), to 2.94(t, 2H,), is 3.41 (m, 4H), 4,39(m, 2H), 6,56(d, 2H), 6,80(d, 2H), 6,91(t, 2H), 7,10(DD, 2H), 7,20-7,40(m, 5H)

2-{4-[4-Chloro-2-(4-chlorophenyl)-!-(4-methoxyphenyl)buta-1-enyl]-phenoxy}ethyl)dimethylamine (No. 26 and 27)

Z-isomer (No. 26):1H-NMR (HCl-salt, CDCl3+MeOH-d4): 2,89 (C, 6N), to 2.94(t, 2H), 3,41(m, 4H), of 3.84(s, MN), 4,34(m, 2H), 6,59(d, 2H), for 6.81(d, 2H), 6.90 to (d, 2H), 7,06(d, 2H), 7,18 (d, 2H), 7,19(d, 2H)

E-isomer (No. 27):1H-NMR (HCl-salt, CDCl3+ MeOH-d4): only 2.91(t, 2H), 2,98(C, 6N), to 3.41(t, N), of 3.54(m, 2H), 3,71(s, 3H), of 4.45(m, 2H), 6,59(d, 2H), 6,77(d, 2H), 6,94(d, 2H), 7,06 (d, 2H), 7,17-to 7.18(d, 2H), 7.23 percent(d, 2H)

1-(2-{4-[4-Chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)piperidine (#28 and 29)

Z-isomer (No. 28):1H-NMR (HCl-salt, MeOH-d4): 1,45-2,10(m, 6N), of 2.92(t, 2H), 3,06(dt, 2H), 3,44(t, 2H), 3,47-3,66(m, 4H), 3,68(s, 3H), 4,27(ICCAT, 2H), 6,70-6,85(m, 5H), 6,92 (d, 2H), 7,15(dt, 1H), 7,30-to 7.50(m, 5H)

E-isomer (No. 29):1H-NMR (HCl-salt, MeOH-d4): 1,45-of 2.15(m, 6N), 2,96(t, 2H), 3,12(dt, 2H), 3,47(t, 2H), to 3.58 of 3.75(m, 4H), 3,62(s, 3H), of 4.44(ICCAT, 2H, 6,65-6,83(m, 3H), 6.90 to-6,97(m, 2H), 7,01-to 7.18(m, 6N), 7,31(d, 2H)

1-(2-{4-[4-Chloro-2-(2-methoxyphenyl)-1-phenylbut-1-enyl]-phenoxy}ethyl)piperidine (No. 30 and 31)

Z-isomer (No. 30):1H-NMR of HCl salt, MeOH-d4): 1,50-2,05 (m, 6N), is 2.88(t, 2H), 3,05(dt, 2H), 3,41(t, 2H), 3.45 points-of 3.65(m, 4H), 3,86(s, 3H), 4,25(ICCAT, 2H), 6,65-6,79(m, 3H), 6,88-7,00(m, 4H), 7,20(dt, 1H), 7,30-to 7.50(m, 5H)

E-isomer (No. 31):1H-NMR (HCl-salt, MeOH-d4): 1,55-of 2.20 (m, 6N), of 2.92(t, 2H), 3,13(dt, 2H), 3.43 points(t, 2H), to 3.58 of 3.75(m, 4H), of 3.84(s, 3H), 4,45(ICCAT, 2H), 6.73 x(dt, 1H), 6.89 in-7,30 (m, 7H), was 7.08(d, 2H), 7,18(dt, 1H), 7,32(d, 2H)

(Z)-1-[4-(2-Benzyloxyethyl)phenyl]-1,2-diphenyl-4-harbut-1-ene

1H-NMR (CDCl3): of 2.92 (t, 2H), to 3.02 (t, 2H), 3,41 (t, 2H), of 3.56(t, 2H), 4,47(s, 2H), 6,78(d, 2H), of 6.96(d, 2H), 7,10-7,40 (m, 15 NM)

(Z)-1-[4-(2-Dimethylaminoethanol)phenyl]-1,2-diphenyl-4-harbut-1-ene (No. 32)

1H-NMR (CDCl3): 2,28(C, 6N), 2,46(ICCAT, 2H), 2,85-2,95 (m, 4H), 3,41(ICCAT, 2H), 6,79(d, 2H), of 6.96(d, 2H), 7,00-7,40(m, 10H)

1-[4-(2-Benzyloxyethyl)phenyl]-4-chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)buta-1-ene

Z-isomer,1H-NMR (CDCl3): of 2.93(t, 2H), 3,41(t, 2H), 3,83 (s, 2H), 3,76(ICCAT, 2H), 4.04 the(ICCAT, 2H), 4,59(s, 2H), 6,59(d, 2H), 6,77(d, 2H), 6.87 in(d, 2H), 7,05(d, 2H), 7,15(d, 2H), 7,19(d, 2H), 7,27-7,40(m, 5H)

E-isomer1H-NMR (CDCl3): of 2.93(t, 2H), 3,41(t, 2H), 3,70 (s, 3H), 3,85(ICCAT, 2H), 4,18(ICCAT, 2H)and 4.65(s, 2H), to 6.57(d, 2H), 6,79(d, 2H), 6,92(2N), 7,06(d, 2H), 7,16(d, 2H), 7,18(d, 2H), 7,27-7,40(m, 5H)

(E)-1-(3-Benzyloxyphenyl)-1-[4-(2-benzyloxyethyl)phenyl] -4-chloro-3-phenylbut-1-ene

Connection receive, using the method described in example 1d, using PH3R and CCL4as reagents.

1H-NMR (CDCl3): of 2.93(t, 2H), 3,40(t, 2H), 3,71 is 3.76(m, 2H), 3,98-of 4.05(m, 2H), 4,58(s, 2 is), of 5.06(s, 2H), 6,60(d, 2H), 6,78(d, 2H), 6,85 is 7.50(m, N)

(Z)-{2-[3-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethyl}-dimethylamine (No. 33)

1-[3-(2-Dimethylaminoethoxy)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy)butane-1-ol (0,93 g, 1.9 mmol) dissolved in toluene (10 ml). To the solution add triethylamine (1.9 mmol) and the mixture is cooled to -10°C. To the mixture is added thionyl chloride (5.8 mmol) at -10±0°C. the Mixture is stirred for 1 hour at 0-5°C, heated to 80°C and stirred at the same temperature for 3 hours. The solvent is evaporated, the residue is dissolved in toluene, washed with 2 N. NaOH and water. Z-Isomer of the product is crystallized from ethyl acetate as HCl-salt. The output of 0.15,

1H-NMR (HCl-salt, CDCl3): and 2.79(s, 6N), to 2.94(t, 2H), 3,20 to be 3.29(m, 2H), 3,42(t, 2H), 4,12-4,20(m, 2H), 6,40(s, 1H), 6,51-6,62(m, 2H), 6, 98 (t, 1H), 7,10-7, 45 (m, 10H)

i) removing the protective groups.

(E)-3-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenylbut-1-enyl}phenol (No. 34)

(E)-4-(3-Benzyloxyphenyl)-4-[4-(2-benzyloxyethyl)phenyl]-4-chloro-3-phenylbut-1-ene (1,95 g, 3,39 mmol) hydronaut in a mixture of ethanol-ethyl acetate (5 ml:20 ml)containing triethylamine (3.4 mmol) and 10% palladium on coal (of € 0.195 g) as catalyst. The catalyst is filtered off and the solvent evaporated. The product was then purified flash chromatography and crystallized from a mixture of toluene-methanol (9:1). The output of 0.23,

1H-NMR (CDCl3+ MeOH-d4): 2,95 (t, 2H), 3,42 (t, 2H), 3,8-4,0(m, 4H), 6,56(d, 2H), 6.75 in-PC 6.82(m, 4H), 7,1-7,25(m, 7H)

Using this method, you receive the following connection

according to the invention is:

(Z)-3-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]propane-1-ol (No. 35)

1H-NMR (CDCl3): a 1.96(Quint., 2H), 2,92(t, 2H), 3,42(t, 2H), 3,80 (kV, 2H), 3,98 (t, 2H), 6,55(d, 2H), 6,78(d, 2H), 7,11-7,40 (m, 10H)

(Z)-2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenylsulfanyl]-ethanol (No. 36)

get by the method of example 2 D.

1H-NMR (CDCl3): of 2.93(t, 2H), 3.00 for(t, 2H), 3,41(t, 2H), to 3.64(t, 2H), for 6.81(d, 2H), 7,01(d, 2H), 7,10-7,40(m, 10H)

Using this method, you receive the following compound according to the invention.

(Z)-2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)buta-1-enyl]phenoxy}ethanol (No. 37)

1H-NMR (CDCl3): to 2.94(t, 2H), 3,41(t, 2H), 3,83(s, 3H), 3,85-4,00(m, 4H), 6,59(d, 2H), 6,78(d, 2H), 6.90 to(d, 2H), 7,06 (d, 2H), 7,16(d, 2H), 7,19(d, 2H)

EXAMPLE 5.

a) 1-[4-(2-Chloroethoxy)phenyl]-2-(2-chlorophenyl)alanon

1-[4-(2-Chloroethoxy)phenyl]-2-(2-chlorophenyl)Etalon get in the way described in example 4A, using as starting materials 2-chlorotoxin and 2-chlorophenylalanine acid.

1H-NMR (CDCl3): of 3.85(t, 2H), 4,30(t, 2H), 4,39(s, 2H), 6,98(d, 2H), 7,22-7,26(m, 3H), 7,39-to 7.50(m, 1H), 8,04(d, 2H)

Using this method, you receive the following

connection:

1-[4-(2-Chloroethoxy)phenyl]-2-phenylethanone

1H-NMR (CDCl3): a 3.83(t, 2H), 4,24(s, 2H), 4,28(t, 2H), 6,94(d, 2H), 7,2-7,4(m, 5H), of 8.00(d, 2H)

b) 2-(2-Chlorophenyl)-1-[4-(2-piperidinyloxy)phenyl]this is non -

A mixture of 1-[4-(2-chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone (4 g, 13 mmol) and piperidine (5.8 g, 68 mmol) in 80% aqueous acetone (50 ml) is heated to the boiling temperature under reflux for 12 hours To the mixture three times with intervals of 4 h, additional portions of 0.3 g of piperidine. The solvents evaporated. Add diethyl ether and filtered off the precipitated piperidine hydrochloride. Diethyl ether is evaporated and the residual product was then purified flash chromatography (eluent toluene:triethylamine=9:1). The output is 4.1 g, 89%.

1H-NMR (CDCl3): 1,38-of 1.56(m, 2H), 1.56 to its 1.68(m, 4H), 2,45-2,62(m, 4H), and 2.79(t, 2H), 4,17(t, 2H), to 4.38(s, 2H), of 6.96(d, 2H), 7,19-7.25 and 3,37-7,44(2m, together 4H), 8,01(d, 2H)

1-[4-(2-Imidazol-1-ylethoxy)phenyl]-2-phenylethanol obtained from 1-[4-(2-chloroethoxy)phenyl]-2-phenylethanone and imidazole in DMF using sodium hydride as the base, according to the method described in example 1A.

1H-NMR (CDCl3): 4,22(s, 2H), 4,20-4,37(m, 4H), to 6.88(d, 2H), 7,03(s, 1H), 7,07(s, 1H), 7,20-7,37(m, 5H), 7,60(s, 1H), of 7.97(d, 2H)

c) 2-(2-Chlorophenyl-1-[4-(2-piperidinyloxy)phenyl]-4-(tetrahydropyranyloxy)butane-1-he 2-(2-Chlorophenyl-1-[4-(2-piperidinyloxy)phenyl]-4-(tetrahydropyranyloxy)butane-1-he receives IFC reaction according to the method described in example 4d, using 2-(2-chlorophenyl)-1-[4-(2-piperidinyloxy)phenyl]alanon (1.5 g, 4.2 mmol) and 2-tetrahydropyranyloxy-1-iodata (1.3 g, 5.1 mmol) as shoddybattle. The product (1.6 g) used in the next reaction stage without further purification.

1H-NMR (CDCl3): complex spectrum can be identified 2,40-2,60(m, 4H), to 2.75(t, 2H), 4,12(t, 2H), 4,50-to 4.62(m, 1H), 5,24 and 5.36(m, 1H), 6.87 in(d, 2H), 7,10-7.25 and 3,37-7,44(2m, together 4H), 7,98(d, 2H)

Using this method, you receive the following connection.

1-[4-(2-Imidazol-1-ylethoxy)phenyl]-2-phenyl-4-(tetrahydropyranyloxy)butane-1-he

1H-NMR (CDCl3): 1,4-1,9(m, 6N), 1,95-2,2(m, 1H), 2,4-2,60 (m, 1H), 3,2-a 3.9(m, 4H), 4,2-4,37(m, 4H), 4,45-4,55(m, 1H), 4,79(dt, 1H), 6,80(DD, 2H), 6,99(s, 1H), 7,05(s, 1H), 7,15-to 7.3 (m, 5H), 7,55(s, 1H), of 7.95(d, 2H)

d) 2-(2-Chlorophenyl-1-phenyl-1-[4-(2-piperidinyloxy)phenyl]-4-(tetrahydropyranyloxy)butane-1-ol

receive the procedure described in example 4E. The product is used in the next reaction stage without further purification.

Using this method, you receive the following connections:

1-[4-(2-Imidazol-1-yl-ethoxy)phenyl]-2-phenyl-4-(tetrahydropyranyloxy)-1-[3-(tetrahydropyranyloxy)phenyl]-butane-1-ol

The connection used for the next reaction stage without further purification.

e) 3-(2-Chlorophenyl) -4-phenyl-4-[4- (2-piperidine-1-yl-ethoxy)phenyl]but-Z-ene-1-ol

2-(2-Chlorophenyl-1-phenyl-1-[4-(2-piperidinyloxy)phenyl]-4-(tetrahydropyranyloxy)butane-1-ol dehydration according to the method described in example 1C. Z-Isomer of the product was then purified flash chromatography (eluent of tolua the-triethylamine=13:1)

Z-isomer:1H-NMR (CDCl3): of 1.35 to 1.48(m, 2H), 1,48 by 1.68(m, 4H), 2,38-2,48(m, 4H), to 2.66(t, 2H), 2,58-2,87(m, 2H), 3,47-to 3.67(m, 2H), 3,94(t, 2H), is 6.54 (d, 2H), at 6.84(d, 2H), 7,07-7,41 (m, N)

Using this method, you receive the following connection.

3-{4-Hydroxy-1-[4-(2-imidazol-1-ylethoxy)phenyl]-2-phenyl-but-1-enyl}phenol

E-isomer:1H-NMR (CDCl3+MeOH-d4): and 2.83(t, 2H), 3,60(t, 2H), 4,11(ICCAT, 2H), 4,20(t, 2H), 6.48 in(d, 2H), 6,76(d, 2H), 6,66-6,9(m, 4H), 6,92(s, 1H), 6,98(s, 1H), 7,08-to 7.32(m, 5H), was 7.36(s, 1H)

Z-isomer:1H-NMR (CDCl3+MeOH-d4): by 2.73(t, 2H), 3,54(t, 2H), 4,23-4,4(m, 4H), 6,35-of 7.23(m, 15 NM), at 7.55(s, 1H)

f) (Z)-1-(2-{4-[4-Chloro-2- (2-chlorophenyl) -1-phenylbut-1-enyl] -phenoxy}ethyl)piperidine (No. 38)

receive the procedure described in example 1d.

1H-NMR (CDCl3): 1,33-1,49(m, 2H), 1,49 by 1.68(m, 4H), 2.40 a-

of 2.50(m, 4H), to 2.67(t, 2H), 2,80-to 3.50(m, 2H), 3.25 to to 3.56(m, 2H), 3,95(t, 2H), is 6.54(d, 2H), 6,85(d, 2H), 7,06-the 7.43(m, N)

Using this method, you receive the following compound according to the invention.

3-{4-Chloro-1-[4-(2-imidazol-1-ylethoxy)phenyl]-2-phenylbut-1-enyl}phenol (No. 39 and 40)

E-isomer (No. 39):1H-NMR (CDCl3): to 2.94 (t, 2H), 3,41 (t, 2H), 4,07(ICCAT, 2H), 4,25(t, 2H), 6,50(d, 2H), 6,79(d, 2H), 6,70-for 6.81(m, 2H), 6,98(s, 2H), 7,10-7,24(m, 7H), 7,51(s, 1H)

Z-isomer (No. 40):1H-NMR (CDCl3+MeOH-d4HCl-salt): 2,90 (ICCAT, 2H), 3,40(ICCAT, 2H), 4,33(ICCAT, 2H)and 4.65 (ICCAT, 2H), 6,35-7,25(m, 13H), 7,38(s, 1H), of 7.48(s, 1H), 9,20(s, 1H)

EXAMPLE 6.

a) (4-AMINOPHENYL)phenylmethane

4-Nitrobenzophenone (5.0 g, of 0.022 mol) restauraut mixture of ethanol-dichloromethane (40 ml:30 ml) and hydronaut at room temperature with 10% palladium on coal (0.5 g) as catalyst. The catalyst is filtered off and the filtrate evaporated to dryness. The product is used in the next reaction stage without further purification. The output of 5.2,

1H-NMR (CDCl3): to 6.67(d, 2H), 7,4-7,6(m, 3H), 7,7-to 7.6(m, 4H)

b) reaction of the Mac-Marri

4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenylamine

Zinc (10.0 g, 0,154 mol) and tetrahydrofuran (THF) (120 ml) contribute to the reaction vessel and cooled to -10°C. To the mixture is added dropwise a titanium tetrachloride (14.4 g, 0,076 mol) at a temperature of about -10°C. After complete addition, the mixture is heated to boiling point under reflux for two hours. Then cooled to 40°and (4-AMINOPHENYL)phenylmethane (5,1 g, 0,0258 mol) and 3-chloro-propiophenone (4,36 g, 0,0258 mol) is dissolved in THF (50 ml) and added dropwise to the mixture. Boiling under reflux continued for another 3.5 hours. The cooled reaction mixture was poured into an aqueous solution of sodium carbonate (14 g2CO3+ 140 ml of water) and leave to stand over night. The mixture is filtered and the precipitate three times washed with THF. The filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and washed three times with water. The output of 9.6 G. of Z-Isomer is the only isomer.

Z-isomer:1H-NMR (CDCl3): 2,90 (t, 2H), 3,41 (t, 2H), 6,32 (d, 2H), only 6.64(d, 2H), 7,0-7,4(m, 10H)

Using this method, you receive the following compound according to the invention

N-[4-(4-Chloro-1,2-shall openiboot-1-enyl)phenyl]-N’,N’-dimethylated-1,2-diamine (No. 47),

on the basis of [4-(2-diethylaminoethylamine)phenyl]phenylmethanone

(method of obtaining described in U.S. patent No. 5693674) and 3-chloropropiophenone.

Z-isomer:1H-NMR (as HCl-salt, MeOH-d4): 2,95(c, 6H), to 2.99(t, 2H), 3,44(t, 2H), 3,47(t, 2H), 3,68(t, 2H), 6.90 to-7,10 (m, 4H), 7,15-7,40(m, 10H)

(C) Ethyl ester of (Z)-[4-(4-chloro-1,2-diphenylbuta-1-enyl)-phenylamino]acetic acid

(z)-4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenylamine (2.0 g, of 5.99 mmol), ethanol (30 ml), ethylbromoacetate (2.5 g, 15 mmol) and sodium acetate (2.4 g, to 17.9 mmol) contribute to the reaction vessel and heated to the boiling temperature under reflux for three hours. The solvent is then evaporated and the residue is dissolved in water and ethyl acetate. An ethyl acetate phase is dried and evaporated to dryness. The output of 2.9,

1H-NMR (CDCl3): of 1.26(t, 3H), 2,90(t, 2H), 3,41(t, 2H), 4,20(kV, 2H), and 6.25(d, 2H), of 6.68 (d, 2H), 7,10-7,40(m, 10H)

d) (Z)-2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenylamino]-ethanol (No. 41)

Ethyl ester of (z)-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenylamino]acetic acid (2.9 g, 6,9 mmol) is dissolved in tetrahydrofuran and socialogical (0.34 g, 8,97 mmol) added in small portions within fifteen minutes. The mixture is stirred at room temperature for two hours. The solvent is then evaporated to dryness and the residue is dissolved in ethyl acetate and washed with water. An ethyl acetate phase is evaporated to dryness and the product purified flash chromatography using a solution of t is luol:methanol:triethylamine (10:0,3:0,3) as eluent. The output of 0.47,

1H-NMR (CDCl3): 2,89(t, 2H), 3,17(t, 2H), 3,41(t, 2H), of 3.73(t, 2H), 6,29(d, 2H), to 6.67 (d, 2H), 7,10-7,40(m, 10H)

EXAMPLE 7.

a) 4-{2-[4-(2-Benzyloxyethyl)phenyl]-1-(2-chloroethyl)-2-phenylphenyl}phenol

receive by way of example 6b using [(4-benzyloxy-ethoxy)phenyl]phenylmethanone and 3-chloro-1-(4-hydroxyphenyl)propane-1-source materials. The product is a mixture of Z - and E-isomers.

1H-NMR (CDCl3): is 2.88 and 2.93(2T, 2H), 3.42 points and 3,43(2T, 2H), 3,74, and 3,84(2 iskat, 2H), 4,01 and 4,16(2 iskat, 2H), 4,58 and 4,65(2s, 2H), 6,55-7,40(m, N)

b) 4-{1-(2-Chloroethyl)-2-[4-(2-hydroxyethoxy)phenyl]-2-phenylphenyl}phenol (No. 42 and 43)

receive by way of example 1E. Isomers purified flash chromatography (eluent dichloromethane-methanol-triethylamine 98:2:1).

Z-isomer (No. 42):1H-NMR (CDCl3): 2,87 (t, 2H), 3.43 points(t, 2H), 3,83-3,90(m, 2H), 3,90-of 3.97(m, 2H), 6,56(d, 2H), 6,66(d, 2H), 6,80(d, 2H), of 6.96(d, 2H), 7,20-7,40(m, 5H)

E-isomer (No. 43):1H-NMR (CDCl3): of 2.92 (t, 2H), 3,38 (t, 2H), 3,90-was 4.02(m, 2H), 4,03-to 4.14(m, 2H), 6,63(d, 2H), 6.89 in(d, 2N), to 6.95(d, 2H), 7,20(m, 2H), 6,85-7,17(m, 5H)

EXAMPLE 8.

{2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethyl} (methyl-prop-2-ynylamine (No. 44)

prepared as in example 1, on the basis of Z-4-chloro-1,2-diphenyl-1[4-[2-(N-methylamino)ethoxy]phenyl]-1-butene (the method of obtaining described in U.S. patent No. 5491173) and propylbromide.

1H-NMR (outrata salt, MeOH-d4): is 2.74(s, 3H), 2,82 and 2.86 (2s, 4H), of 2.93(t, 2H), 3,06(t, 1H), 3,29 (ICCAT, 2H), 3,44 (t, 2H), 3,85(d, 2H), 4,16(Skagit, 2N), of 6.68(d, 2H), 6,86(d, 2H), 7,15-7,47 (m, 10H)

EXAMPLE 9.

a) Ethyl ester of (z)-[4-(4-hydroxy-1,2-diphenylbuta-1-enyl)phenyloxy]acetic acid is obtained from (Z)-(4-hydroxy-1,2-diphenylbuta-1-enyl)phenol (method of obtaining described in U.S. patent No. 4996225) and ethylbromoacetate in example 1A, using NaH as a base.

1H-NMR (CDCl3): a 1.25 (t, 3H), 2,74(t, 2H), only 3.57(t, 2H), 4,23(kV, 2H), 4,47(s, 2H), 6,56(d, 2H), 6,79(d, 2H), 7,10 was 7.45 (m, 10H)

Ethyl ester of (Z)-2-[4-(4-hydroxy-1,2-diphenylbuta-1-enyl)phenoxy]butyric acid

get in the same way, using ethyl-2-bromobutyrate as alkylating reagent.

1H-NMR (MeOH-d4): and 0.98 (t, 3H), of 1.17 (t, 3H), of 1.86(m, 2H), 2,70(t, 2H), 3,47(t, 2H), 4,12(m, 2H), 4,50(DD, 1H), 6,50(d, 2H), 6,76(d, 2H), 7,0-7,4(m, 10H)

b) Ethyl ester of (z)-[4-(4-chloro-1,2-diphenylbuta-1-enyl]-phenoxy)acetic acid prepared as in the method described in example 1d, using PH3R and CCL4as reagents.

1H-NMR (CDCl3): a 1.25(t, 3H), of 2.92(t, 2H), 3,41(t, 2H), 4,23(kV, 2H), 4,50(s, 2H), 6,55(d, 2H), 6,80(d, 2H), 7,10 was 7.45 (m, 10H)

Using this method, you receive the following connection

Ethyl ester of (z)-2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]-butyric acid

1H-NMR (MeOH-d4): a 1.01 (t, 3H), of 1.16 (t, 3H), 1,89(m, 2H), 2.91 in(t, 2H), 3,40(t, 2H), 4,15(m, 2H), and 4.40(DD, 1H), of 6.52(d, 2H), 6,76(d, 2H), 7,0-7,4 (m, 10H)

(C) (Z)-3-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxymethyl]-pentane-3-ol (No. 45)

The reagent is of Ringera obtained from MD-chips (0.29 grams, 12 mmol) and brometane (1,25 g, 12 mmol) in tetrahydrofuran (4 ml). Add at room temperature ethyl ester (Z)-[4-(4-chloro-1,2-diphenylbuta-1-enyl]phenoxy)acetic acid (1.0 g, 23 mmol, from example 9b) in tetrahydrofuran (11 ml) and the reaction mixture is heated to boiling point under reflux for 2 hours Add saturated ammonium chloride and tetrahydrofuran evaporated. The product is extracted with ethyl acetate. The organic layer is dried and evaporated to dryness. The output is 1.0,

1H-NMR (CDCl3): of 0.87(t, 6N), 1,58(kV, 4H), of 2.92(t, 2H), 3,42(t, 2H), 3,68(s, 2H), 6,56(d, 2H), 6,78(d, 2H), 7,10 was 7.45 (m, 10H)

EXAMPLE 10.

(Z)-2-[4-(4-Chloro-1,2-diphenylbuta-1-enyl)phenoxy]butane-1-ol (No. 46)

Ethyl ester of Z-2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]-butyric acid (0,98 g, 2.2 mmol) restore lydialydia level (0.041 g, 1.1 mmol) in tetrahydrofuran. Add a mixture of ice-water and the tetrahydrofuran evaporated. The product is extracted with ethyl acetate, dried and the solvent evaporated. The output of 0.55,

1H-NMR (CDCl3): 0, 89 (t, 3H), 1,54-1, 70 (m, 2H), 2, 91 (t, 2H), to 3.58 is 3.76(m, 2H), 4,10-4,20(m, 1H), to 6.57(d, 2H), 6,77(d, 2H), 7,10-7,40(m, 10H)

EXAMPLE 11.

E-3-(4-Chloro-1-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}-2-phenylbut-1-enyl)phenol

a) 1-{4-[2-(2-Benzyloxyethyl)ethoxy]phenyl}-2-phenylethanol prepared as in example 4C, on the basis of 1-(4-hydroxyphenyl)-2-phenylethanone (obtained according to examples 4 (a-b) (10.0 g, or 47.1 mmol) of the 2-(2-benzyloxyethyl)ethylchloride (11,0 g, to 51.8 mmol). Product three times ground to powder with warm heptane to remove by-products. The output of 9.6 g, 52%.

1H-NMR (CDCl3): 3,60-with 3.79(m, 4H), 3,85 (ICCAT, 2H), 4,16 (ICCAT, 2H), 4,20(s, 2H), 4,56(s, 2H), 6,92(d, 2H), 7,20-7,41(m, 10H), of 7.96(d, 2H)

b) 1-{4-[2-(2-Benzyloxyethyl)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)butane-1-he

receive, using the method described in example 4d, on the basis of 1-{4-[2-(2-benzyloxyethyl)ethoxy]phenyl}-2-phenylethanone (8,4 g, 21.5 mmol) and 2-(tetrahydropyran-2-yloxy)ethyliodide (6.6 g, from 25.8 mmol). Product (11.7 g) used in the next reaction stage without further purification.

1H-NMR (CDCl3): 1,40-of 1.95(m, 6N), from 2.00-2.20 2,40-2,60 (2m, together 2H), 3,60-of 3.80(m, 8H), 3,83(ICCAT, 2H), 4,13 (ICCAT, 2H), 4,45-4,55(m, 1H), 4,55(s, 2H), 4,80(t, 1H), 6,86(d, 2H), 7,14-7,39(m, 10H), of 7.96(d, 2H)

c) 1-{4-[2-(2-Benzyloxyethyl)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)-1-[3-(tetrahydropyran-2-yl-oxy)phenyl]butane-1-ol gain, using the method described in example 4E, on the basis of 1-{4-[2-(2-benzyloxyethyl)ethoxy]phenyl}-2-phenyl-4-(tetrahydro-Piran-2-yloxy)butane-1-it (10 g, 19.2 mmol) and 3-(tetrahydro-Piran-2-yloxy)panelbased (9,8 g, 38 mmol). The product was then purified flash chromatography using toluene-methanol (50:1) as eluent. Yield 5.7 g, 43%.

1H-NMR (CDCl3): 1,40-of 2.20 (m, 10H), 3,5-4,1(m, 14N), 4,30-4,50(2m, 1H), to 4.52(s, 1H), 4.53-in(s, 1H), 6,60(d, 2H), 6.90 to-7,40 (m, N).

d) Z,E-3-(1-{4-[2-(2-Be is siloxides)ethoxy]phenyl}-4-hydroxy-2-phenylbut-1-enyl)phenol

obtained from 1-{4-[2-(2-benzyloxyethyl)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)-1-[3-(tetrahydropyran-2-yloxy) phenyl] -butane-1-ol (5.7 g, 8.2 mmol)using the method described in example 1C, except that toluene is used instead of acetic anhydride (30 ml)and add triethylamine (0,91 g, 0.9 mmol). The product (3.8 g) used in the next reaction stage without further purification.

1H-NMR (CDCl3): 2,78 (t, 2H), 3,55-4,20 (m, 10H), 4,55 and 4,58(2s, 2H), 6,56(d, 2H), 6.73 x-6,93(m, 3H), and 7.1 to 7.4(m, 13H)

e) Z,E-3-(1-{4-[2-(2-Benzyloxyethyl)ethoxy]phenyl}-4-chloro-2-phenylbut-1-enyl)phenol

get out of the Z,E-3-(1-{4-[2-(2-benzyloxyethyl)ethoxy]phenyl}-4-hydroxy-2-phenylbut-1-enyl)phenol (3.8 g, 7.4 mmol)using the method described in example 4h, except that the reaction mixture is added triethylamine (1.64 g, 16.2 mmol). The product was then purified flash chromatography. Output of 2.5,

1H-NMR (CDCl3): of 2.92(t, 2H), 3,40 (t, 2H), to 3.58-4,17(m, 8H) 4,53 and 4.57(2s, 2H), 6,53(d, 2H), of 6.71-6,9(m, 6N), and 7.1 to 7.4 (m, 10H).

f) E-3-(4-Chloro-1-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}-2-phenylbut-1-enyl)phenol

Z,E-3-(1-{4-[2-(2-Benzyloxyethyl)ethoxy]phenyl}-4-chloro-2-phenylbut-1-enyl)phenol (2.0 g, of 3.78 mmol) was dissolved in ethyl acetate (30 ml). Zn (0,062 g, 0.95 mmol) and acetylchloride (0.74 g, 9.5 mmol) is added under nitrogen atmosphere. The mixture is stirred at 50°C for 3 hours the Mixture is filtered and the solvent evaporated. The rest of rest the accelerate in 80% aqueous methanol, containing 3% sodium hydroxide. The mixture is stirred at room temperature for 2 h and the methanol evaporated. Add water (5 ml) and the product extracted with ethyl acetate (10 ml). The mixture is dried and the solvent evaporated. The product is distilled first flash chromatography (eluent toluene:methanol=9:1) and then crystallized from toluene and recrystallized from a mixture of toluene-acetone. The output of 0.15,

1H-NMR (CDCl3): to 2.94(t, 2H), 3,41(t, 2H), 3,59-3,63(m, 2H), 3,67-and 3.72(m, 2H), 3,78(ICCAT, 2H), 4,01(ICCAT, 2H), 6,56(d, 2H), 6,78(d, 2H), 6,70-of 6.90(m, 3H), 7,1-7,3(m, 6N).

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Henderson VW: Estrogen, cognition, and a woman's risk of Alzheimer's disease. Am.J.Med., 103 ():11S-18S, 1997.

Kangas L,, Nieminen A-L; Bioluminescence of cellular ATP: A new method for evaluating cytotoxic agents in vitro. Medical Biol., 65: 338-343, 1984.

Kangas L, Nieminen A-L, Blanco G,, Kallio S, Karjalainen A,,, Toivola R: A new triphenylethylene compound, Fc-1157a. II. Antitumor effect. Cancer Chemother Pharmacol., 17: 109-113, 1986.

Khovidhunkit W, Shoback DM: Clinical effects of raloxifene hydrochloride in women. Ann.Intern.Med., 130(5):431-439, 1999.

Lobo RA: Benefits and risks of estrogen replacement therapy. Am.J.Obstet.Gynecol., 173:982-990, 1995.

Macgregor JI, Jordan VC: Basic guide to the mechanism of antiestrogen action. Pharmacol.Rev., 50:151-196, 1998.

Peng Z, Tuukkanen J, Zhang H,,The mechanical strength of bone in different rat models of experimental osteoporosis. Bone, 15: 523-532, 1994.

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1. The compound of the formula

where R1 denotes H, halogen, co3HE; and

R2 means

a)

where (i) X is NH or S; a n means an integer from 1 to 4;

R4 and R5, which are identical or different, denote alkyl with 1-4 carbon atoms, N, -CH2With≡CH or-CH2CH2IT;

or

R4 and R5 form a N-containing five - or six-membered cycle or heteroaromatic cycle; or

where (ii) X is O; and n means an integer from 1 to 4; and

one of R4 and R5 denotes-CH2With≡CH or-CH2CH2HE and the other represents N or C1-C4alkyl; or R4 and R5 together form a cycle of imidazole, N-containing six-membered cycle or heteroaromatic cycle; or

R2 means

b) -Y-(CH2)nCH2-O-R6,

where (i) Y means O, and n means an integer from 1 to 4; and

R6 denotes-CH2CH2HE or-CH2CH2CL; or

where (ii) Y represents NH or S, and n means an integer from 1 to 4; and

R6 denotes H, -CH2CH2HE or-CH2CH2CL; or

R2 means

c) 2,3-dihydroxypropane is, 2 methylsulfonylmethane, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy or 2,2-diethyl-2-hydroxy-ethoxy; and

R3 denotes H, halogen, HE or-och3;

or its stereoisomers, non-toxic, pharmaceutically acceptable salts or esters, or mixtures thereof.

2. Triphenylethylene according to claim 1, where R2 means

and X, n, R4 and R5 have the meanings indicated in claim 1.

3. Triphenylethylene according to claim 2, where X is O.

4. Triphenylethylene according to claim 3, where n is 1, one of R4 and R5 denotes-CH2With≡CH or-CH2CH2HE and the other represents N or C1-C4alkyl; or R4 and R5 together form a cycle of piperidine or cycle imidazole.

5. Triphenylethylene according to claim 2, where X is S.

6. Triphenylethylene according to claim 2 where X is NH.

7. The compound according to claim 4, which is chosen from the group including

1-{2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethyl}-1H-imidazole,

{2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethyl} (methyl-prop-2-ynylamine,

2-({2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethyl}methyl-amino)ethanol,

3-{4-chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenylbut-1-enyl}phenol,

1-(2-{4-[4-chloro-2-(2-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl) - piperidine,

1-(2-{4-[4-chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)piperidine and

1-(2-{4-[4-chloro-2-(2-methoxyphenyl)-1-phenylbut-1-enyl]-phenoxy}et the l)piperidine.

8. The compound according to claim 5, representing 1-[4-(2-dimethylaminoethanol)phenyl]-1,2-diphenyl-4-harbut-1-ene.

9. The connection according to claim 6, representing the N-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenyl]-N',N'-dimethylated-1,2-diamine.

10. Triphenylethylene according to claim 1, where R2 means-Y-(CH2)nCH2-O-R6and Y, n and R6 have the meanings indicated in claim 1.

11. Triphenylethylene of claim 10, where Y represents O.

12. Triphenylethylene of claim 10, where Y represents S.

13. Triphenylethylene of claim 10, where Y represents NH.

14. The connection 11, which is selected from the group including

2-{2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]ethoxy}-ethanol,

1-(4-{2-[2-chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-ene and

1-(4-{2-[2-chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-forfinal)-2-phenylbut-1-ene.

15. The connection section 12, which represents a 2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenylsulfanyl]ethanol.

16. The connection 13, which represents a 2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenylamino]ethanol.

17. The compound according to claim 1, which is selected from the group including

3-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxymethyl]pentane-3-ol,

2-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]butane-1-ol,

3-[4-(4-chloro-1,2-diphenylbuta-1-enyl)phenoxy]propane-1,2-diol,

3-{4-[4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}-propane-1,2-diol,

4-chloro-1-[4-(2-methylsulfonylmethane)phenyl]-12-diphenylbuta-1-ene and

4-chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)but-1-ene.

18. Pharmaceutical composition comprising effective to obtain tissue-specific estrogenic and/or antiestrogenic effect the specified number of new selective modulator of estrogen receptors, the compounds according to claim 1, or its non-toxic pharmaceutically acceptable salts and pharmaceutically acceptable compatible media.

19. Method of production of tissue-specific estrogenic and/or antiestrogenic effect in a patient for which the specified action is desirable, including the introduction of a specified patient of this new selective modulator of estrogen receptors, the compounds according to claim 1 or its non-toxic pharmaceutically acceptable salt in a quantity sufficient to create the desired actions.



 

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< / BR>
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Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
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R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

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"n" represents 2, 3 or 4,

and their physiologically acceptable salts

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

The invention relates to medicine and can be used to treat estrogenzawisimy malignant tumors
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