Patent Application: US-71225200-A

Abstract:
the invention provides novel selective estrogen receptor modulator compounds of the general formula : wherein r1 and r2 , which are the same or different are a ) h , halogen , och 3 , oh ; or where x is o , nh or s ; and n is an integer from 1 to 4 ; and r4 and r5 , which are the same or different , are a 1 to 4 carbon alkyl , h , — ch 2 c ≡ ch or — ch 2 ch 2 oh ; or r4 and r5 form an n - containing five - or six - membered ring or heteroaromatic ring ; or c ) — y — n ch 2 — o — r6 where y is o , nh or s and n is an integer from 1 to 4 ; and r6 is h , — ch 2 ch 2 oh , or — ch 2 ch 2 cl ; or d ) 2 , 3 - dihydroxypropoxy , 2 - methylsulfamylethoxy , 2 - chloroethoxy , 1 - ethyl - 2 - hydroxyethoxy , 2 , 2 - diethyl - 2 - hydroxyethoxy or carboxymethoxy ; and r3 is h , halogen , oh or — och 3 ; stereoisomers thereof and their non - toxic pharmaceutically acceptable salts and esters and mixtures thereof , which compounds exhibit valuable pharmacological properties .

Description:
this invention relates to the use of novel selective estrogen receptor modulators ( serms ) and their pharmaceutical preparations in men and women for the treatment of degenerative diseases and symptoms due to estrogen deficiency . typically serms act as estrogens in bone and cardiovascular system while they are antiestrogenic in breast tissue . serms may have agonistic and antagonistic effects in other tissues also . depending on their chemical structure and hormonal properties some compounds can be especially suited for elderly women for the prevention of osteoporosis whereas others ( which are not feminizing estrogens ) may also be used in men in the prevention of osteoporosis , cardiovascular diseases and alzheimer &# 39 ; s disease . some compounds are specifically suited for the treatment of climacteric symptoms in menopausal women . it is the common property of the described novel compounds that they are antiestrogenic in the mammary gland and inhibit the proliferation of breast cancer cells . they are also weak estrogens in the uterus and do not induce uterine cancers , the side effect of the well known serm , tamoxifen . the new serms of the present invention thus have tissue - specific estrogenic and / or antiestrogenic effects in vitro and in vivo and are useful in the prevention and treatment of osteoporosis , cardiovascular diseases and alzheimer &# 39 ; s disease in men and women , as well as in the treatment of climacteric symptoms and breast cancer in women . the compounds of formula ( i ) can be prepared by a process which comprises reaction of a compound of the formula where r7 is the same as r1 or r2 as defined before or is a protected such group , r 3 ′ is r3 as defined before or a protected oh , r8 is benzyl or tetrahydropyranyl , with an organometallic compound of the formula where r9 is h , r1 or r2 as defined before or is a protected such group and m is — mg - halogen or li , to give a compound of the formula where r 3 ′, r7 , r8 , and r9 are as defined above . r8 is tetrahydropyranyl when r7 or r9 is — x —( ch 2 ) n ch 2 — or6 where x and n are as defined in ( i ). the compound ( iv ) is dehydrated by an appropriate acid catalyst preferable with acetic anhydride / acetyl chloride to give a triphenylethylene derivative of the formula where r 8 ′ is h or benzyl , r 7 ′ and r 9 ′ are r1 and r2 or benzyl protected oh or benzyl protected — xch 2 ch 2 or6 . the possible protecting tetrahydropyranyl groups in r3 , r7 , r8 and r9 are removed in this process to give radicals r3 , r 7 ′, r 8 ′ and r 9 ′. the removal of the possible benzylic r 8 ′ can be carried out by treatment with zn and acetyl chloride in toluene to give the triphenylbutenol of the formula the hydroxy compound ( vi ) can be converted to a corresponding chloride by treatment with thionyl chloride or with triphenyl phosphine - carbon tetrachloride in organic solvent to give the compound of the formula the claimed compounds ( i ) are prepared from the compounds of the formula ( vii ) where r 7 ′ and / or r 9 ′ are benzyl protected — xch 2 ch 2 or6 by treatment with zn and acetyl chloride in organic solvent or by catalytic hydrogenation . another process to prepare compounds of the formula ( iv ) is the hydroalumination reaction of a “ styrene ” derivative of the formula where r10 is — cho , — ch 2 oh , — cooh or a corresponding ester and r3 is as defined before with a benzophenone derivative of the formula yet another process for the preparation of the compounds of the invention comprises o - alkylation of the compound of the formula ( v ) where r 7 ′, and / or r 9 ′ is oh with an alkyl halide derivative of the formula where m is an integer from 1 to 5 and r11 is halogen , where r 6 ′ is r6 or protected r6 , or — coor to give a compound of the formula the compound of the formula ( xi ) where r11 is halogen is reacted with an amine of the formula yet another process for the preparation of the compounds of the formula ( vii ) comprises the mcmurry reaction of an benzophenone derivative of the formula where r 7 ′ and r 9 ′ are as defined before , with an 3 - chloropropiophenone derivative of the formula the claimed compound of the formula ( i ) where r1 or r2 is 2 , 2 - diethyl - 2 - hydroxyethoxy can be prepared by reaction of the compound of the formula ( xi ), where m is 1 and r11 is — coor , with ethylmagnesium bromide . the claimed compound of the formula ( i ) where r1 or r2 is 1 - ethyl - 2 - hydroxyethoxy can be prepared by o - alkylation of the compound of the formula ( v ), where r 7 ′ or r 9 ′ is oh with ethyl α - bromobutyrate and by reduction of the formed ester by lithium aluminum hydride . compounds of formula ( i ) contain one or more asymmetric centers and may thus give rise to enantiomers , diastereomers and other stereoisomeric forms . the present invention is also meant to encompass racemic mixtures , resolved forms and mixtures thereof as well as the individual enantiomers that may be separated according to methods known to those of ordinary skill in the art . the invention disclosed herein is also meant to encompass non - toxic pharmaceutically acceptable salts and esters of compounds of formula ( i ) and their stereoisomers . the non - toxic pharmaceutically acceptable salts and esters can be prepared by methods well - known to those of ordinary skill in the art . the non - toxic pharmaceutically acceptable salts include , but are not limited to , chlorides , bromides , sulfates , nitrates , phosphates , sulfonates , formates , tartrates , maleates , citrates , benzoates , salicylates , ascorbates and the like . the non - toxic pharmaceutically esters include , but are not limited to , methyl esters , ethyl esters , propyl esters , butyl esters and the like . evaluation of estrogenic and antiestrogenic properties of compounds in mcf - 7 cell growth experiments in vitro estrogen - sensitive human breast cancer cells , mcf - 7 ( mcgrath clone ), were maintained in rpmi - 1640 medium supplemented with 10 % fetal calf serum , 2 mm l - glutamine , 10 μg / ml insulin and 10 μg / ml gentamicin . the cells were grown as monolayer cultures in 75 cm 2 plastic tissue culture flask ( nunc , roskilde , denmark ) in 25 ml medium at 37 ° c . in an atmosphere of 95 % air , 5 % co 2 and subcultured twice a week . for experiments involving hormone or anti - hormone treatment , the cells in exponential growth phase were precultivated in the absence of estradiol for one day . cells were plated at a density of 3 . 5 × 10 3 cells / well in 96 - well microtiter plates ( nunclon , roskilde , denmark ) and incubated for 24 hours at 37 ° c ., 95 % air , 5 % co 2 , rpmi - 1640 medium ( l - glutamine and gentamicin as above ) with 5 % stripped fetal calf serum ( stripped twice with dextran - coated charcoal to remove the steroids ) and without phenol red . after the incubation period the medium was removed . the exposure to study drugs was started immediately by adding fresh medium with 5 % stripped serum . half of the cells were grown with estradiol , half without estradiol . study compounds ( dissolved in ethanol in 0 . 01 m concentration and diluted with the growth medium as appropriate ) were added . the final concentrations of the compounds were 1 , 10 , and 100 nm , and 1 and 10 μm . the cells were incubated for four days . the amount of living cells was measured after 4 days by luminometer based on the amount of atp and luciferase reaction as described by kangas et al , 1984 . this method allows evaluation of estrogenicity based on the ability of the compounds to stimulate the growth of the estrogen - dependent cells in the absence of estradiol . estrogenicity was estimated by comparing the maximal growth stimulus ( at any concentration ) of study compound as per cent from growth stimulus by estradiol ( 100 % stimulus ). in the present studies antagonism was estimated at the concentration of 1 μmol / l as per cent of theoretical full ( 100 %) antagonism , which would mean complete inhibition of estradiol - stimulus . at high concentrations molecules may also show toxicity . toxicity was estimated as the fraction of dead cells ( i . e . 100 % means that all cells have died during the exposure ). the results are presented in table 2 . the classical method to evaluate estrogenic and antiestrogenic effect is immature mouse or rat uterus ( terenius , 1971 ). the animals were exposed for 3 days to the compounds to be investigated at the age of 18 days . on the fourth day the animals were asphyxicated with co 2 and body weight and uterine weight was recorded . estrogens increase the size and weight of the uterus ( uterotropic effect ) while antiestrogens inhibit this action . the compounds are therefore given alone and with estradiol in order to evaluate both agonistic and antagonistic effects . the results have been shown in table 3 both as per cent of estrogen stimulation ( 100 %), and as inhibition of estrogen action ( full inhibition is 100 %). the values are given at two dose levels , low i . e . 3 - 5 mg / kg and high i . e . 10 - 50 mg / kg . estrogenic activity can be estimated also after a 4 weeks &# 39 ; treatment of ovariectomized rats based on the uterine size . this assay was carried out in selected molecules as shown in table 4 . compounds were given p . o . to female rats for 4 or 5 weeks daily . at the end a blood sample was taken . serum was separated by centrifugation and frozen until analyzed for total amount of cholesterol . bone samples were taken from vertebra and tibia . physical strength of the bones was studied as described by peng et al , 1994 . the assessments of the bone included : epiphyses of one tibia was carefully prepared and burned . samples were burned to remove water and organic material . ash weight relates to the mineral content of the bone . in addition , bone samples were taken to study the histomorphometry . in some cases the bone formation was studied by injecting tetracycline ( 50 mg / kg i . p . 10 days before autopsy ) and calcein ( 20 mg / kg i . p . 3 days before autopsy ). the method is based on permanent binding of tetracycline into growing bone and its detection by fluorescence ( peng et al , 1994 ). the mechanical testing of bones was carried out by materials testing machine , constructed in - house at oulu university ( technical services department of the medical faculty ). the testing machine is based on lever arm principle . one end of a steel lever is fixed . the pressing rod and the driving motor are connected to the lever arm with a moment ratio of 12 . 5 cm / 50 cm = ¼ . as a driving motor a linear actuator ( sey 10 magnetic elektromotoren ag , switzerland ) is used to obtain constant vertical movement ( 0 . 62 cm / s ). the interchangeable compression head is mounted on the pressing rod for different tests transmitting compressive force to the specimen , and moving at a constant speed of 0 . 155 mm / s up to a maximal load capacity of 1200 n . the pressing rod is guided via an axial ball bearing to keep the movement vertical . compressive force is measured by a temperature - compensated force sensor , which is attached to the stationary part of the compression stage . the measuring electronics include sensor calibration and adjustments . the maximal load on the femoral neck was measured by the cantilever bending test . the supporter for the bone was a thick polymethyl methacrylate plate in which several holes of different sizes were drilled . on one side of each hole a groove was engraved for the third trochanter of the femur . the femur was cut exactly between the middle and lower third of the shaft . the bone was inserted perpendicularly and tightly into a suitable hole on the supporter . the lesser trochanter of each bone touched the surface of the plate . this procedure allowed rapid and stable fixation of the bone without using any additional embedding materials . the concave compressing head , 2 . 5 mm in diameter , was made of aluminum . the femoral head - neck complex was tested until failure by loading the head with a force parallel to the shaft . antitumor activity was estimated by using dmba ( dimethylbenz [ a ] anthracene ) model . one single peroral dose of dmba ( 12 mg ) initiates mammary gland carcinogenesis . new compounds were administered for 5 weeks when palpable tumors appeared . size of the tumors and number of new tumors were carefully estimated once a week until termination . the model has been described in detail by kangas et al , 1986 . the growth of the tumors was measured once a week . all tumors were classified according to their growth properties to progressing , stable and regressing ones . disappeared tumors were separately calculated . the tumors were considered to be progressing , if the tumor volume grew more than 8 - fold during the 5 weeks dosing period , and regressing if the tumor volume decreased to one fourth or less from the volume in the beginning . if tumor volume changed less or remained unchanged , the tumors were considered to be stable . altogether 46 compounds were evaluated by the methods described above which are included in the list of example compounds numbered and listed in table 1 . the estrogenic and antiestrogenic as well as cytotoxic effects of several compounds in vitro are presented in table 2 . it can be seen that the spectrum of hormonal activity of the compounds varies and thus gives the possibility to use the compounds in different clinical conditions . compounds with weak hormonal activity , which kill mcf - 7 cells ( human breast cancer cells ) effectively at the highest investigated concentration ( 10 μm ) could be used preferably in the treatment of breast cancer . such compounds are among others compounds no . 1 , 3 , 16 , 19 , 26 , 27 , 39 and 40 ( table 2 ). these compounds and several others are less effective estrogens and antiestrogens than the well known breast cancer drugs tamoxifen and toremifene ( table 3 ). especially compound no . 19 is of interest , because it is a more effective anticancer drug in vivo in the dmba - induced rat mammary tumor model even at very low doses than clinically used tamoxifen and toremifene ( table 6 ). compounds with weak estrogenic and no antiestrogenic action could be especially suitable for the prevention and treatment of osteoporosis and climacteric symptoms . such compounds are ( among others ) compounds no . 3 , 10 , 11 , 18 , 19 , 20 , 25 , 32 , 36 and 44 ( tables 2 , 3 and 4 ). compounds , which decrease cholesterol could be useful as cardiovascular drugs . for women some estrogenicity for such compounds can be allowed , but compounds which are not estrogens or are very weak estrogens and decrease cholesterol , could be used also in men for the prevention and treatment of cardiovascular diseases . such compounds include ( among others ) compounds no . 3 , 19 , 20 ( also for men ) and 33 ( for women ) ( table 4 ). the same compounds are expected to be useful also in the treatment or prevention of alzheimer &# 39 ; s disease . in the latter case the cytotoxic action of the compounds should be weak , like e . g . with compound no . 33 ( table 2 ). it should be noted that compound no . 19 does not show any estrogenic action on the weight of the prostate gland at doses which are active in dmba - induced mammary tumor model ( tables 6 and 7 ). therefore it could be of special benefit in men and could be of benefit in addition to the above mentioned conditions in the treatment of prostate cancer . the hormonal profile of the compounds may be in some cases different in vitro and in vivo , e . g . compound no . 1 has no estrogenic action in vitro ( table 2 ), but is a weak estrogen in vivo ( table 3 ). therefore the examples above should be understood as examples of the usefulness in different conditions . they should not be understood as limitations for their possible use in different clinical indications . for the purpose of this invention , the novel serms , their stereoisomers or pharmaceutically acceptable salts thereof can be administered by various routes . the suitable administration forms include , for example , oral formulations , parenteral injections including intravenous , intramuscular , intradermal and subcutaneous injections ; and transdermal or rectal formulations . suitable oral formulations include e . g . conventional or slow - release tablets and gelatin capsules . the required dosing of the novel serms will vary with the particular condition being treated , the severity of the condition , the duration of the treatment , administration route and specific compounds being employed . typically the daily dose for an adult person is 5 - 200 mg , preferably 20 - 100 mg . serms can be given as tablets or other formulations like gelatin capsules alone or mixed in any clinically acceptable non - active ingredients which are used in the pharmaceutical industry . 4 - hydroxybenzophenone ( 28 . 1 g , 0 . 13 mol ) is dissolved in toluene ( 140 ml ). tetrabutylammonium bromide ( tbabr ) ( 2 . 1 g ) is added . aqueous 48 % sodium hydroxide ( 140 ml ) is added at 50 - 55 ° c . the mixture is heated to 80 ° c . and 2 - chloroethyldimethylamine hydrochloride ( total 20 . 0 g , 0 . 14 mol ) is added in small portions and the reaction mixture is stirred at 97 - 100 ° c . for 3 h . the layers are separated and the organic layer is washed with water , dried over sodium sulfate and evaporated to dryness . yield 33 . 0 g , 88 %. the product is used for the next step without further purification . 1 h nmr ( cdcl 3 ): 2 . 36 ( s , 6h ), 2 . 77 ( t , 2h ), 4 . 15 ( t , 2h ), 6 . 99 ( d , 2h ), 7 . 15 ( t , 2h ), 7 . 27 - 7 . 83 ( m , 4h ). 1 h nmr ( cdcl 3 ): 2 . 36 ( s , 6h ), 2 . 77 ( t , 2h ), 4 . 15 ( t , 2h ), 6 . 98 ( d , 2h ), 7 . 45 ( 2h ), 7 . 71 ( d , 2h ), 7 . 79 ( d , 2h ). 1 h nmr ( cdcl 3 ): 3 . 87 ( dist . t , 2h ), 4 . 24 ( dist . t , 2h ), 4 . 65 ( s , 2h ), 6 . 99 ( d , 2h ), 7 . 15 ( t , 2h ), 7 . 32 - 7 . 39 ( m , 5h ), 7 . 76 - 7 . 83 ( m , 4h ). 1 h nmr ( cdcl 3 ): 3 . 86 ( t , 2h ), 4 . 24 ( t , 2h ), 4 . 65 ( s , 2h ), 6 . 99 ( d , 2h ), 7 . 3 - 7 . 4 ( m , 5h ), 7 . 45 ( d , 2h ), 7 . 70 ( d , 2h ), 7 . 78 ( d , 2h ). 4 - chloro - 4 ′- hydroxybenzophenone ( 50 g , 0 . 215 mol ) is dissolved in dichloromethane ( 400 ml ). 3 , 4 - dihydro - 2h - pyran ( 21 . 7 g , 0 . 257 mol ) and a catalytic amount of p - toluenesulfonic acid are added to the solution . the solution is stirred for 6 hours at room temperature and then allowed to stand over night . 1 n aqueous sodium hydroxide solution ( 100 ml ) is added to the reaction mixture and stirred for 15 minutes . organic layer is separated and washed twice with 1 n aqueous sodium hydroxide solution and once with water . dichloromethane solution is dried and evaporated to dryness . yield 68 . 6 g . 1 h nmr ( cdcl 3 ): 1 . 52 - 2 . 20 ( m , 6h ), 3 . 60 - 3 . 67 ( m , 1h ), 3 . 8 - 3 . 94 ( m , 1h ), 5 . 5 - 5 . 6 ( m , 1h ), 7 . 10 ( d , 2h ), 7 . 45 ( d , 2h ), 7 . 72 ( d , 2h ), 7 . 78 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 55 - 2 . 20 ( m , 12h ), 3 . 6 - 3 . 7 ( m , 2h ), 3 . 8 - 4 . 0 ( m , 2h ), 5 . 5 - 6 . 6 ( m , 2h ), 7 . 11 ( d , 4h ), 7 . 78 ( d , 4h ). sodium hydride ( 3 . 4 g , 0 . 072 mol ) in oil is washed with heptane and mixed with dimethyl formamide ( dmf ) ( 120 ml ). 4 - chloro - 4 ′- hydroxybenzophenone ( 12 g , 0 . 052 mol ) in dmf is added dropwise to the solution and the reaction mixture is stirred for an hour at room temperature . then toluene - 4 - sulfonic acid 2 , 2 - dimethyl -[ 1 , 3 ] dioxolan - 4 - yl methyl ester ( 17 . 7 g , 0 . 0618 mol , prepared from s - 1 , 2 - o - isopropyl glycerol and p - toluenesulfonyl chloride ) in dmf is added dropwise to the solution during an hour . the mixture is heated to 60 ° c . and stirred at that temperature for two days . 1 n aqueous sodium hydroxide solution ( 200 ml ) is added to reaction mixture and the solution is 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 . yield 13 . 7 g , 76 . 7 %. 1 h nmr ( cdcl 3 ): 1 . 42 ( s , 3h ), 1 . 48 ( s , 3h ), 3 . 90 - 4 . 24 ( m , 4h ), 4 . 52 ( quintet , 1h ), 6 . 99 ( d , 2h ), 7 . 46 ( d , 2h ), 7 . 71 ( d , 2h ), 7 . 79 ( d , 2h ). b ) hydroalumination reaction of benzophenone derivatives with cinnamaldehyde or a methyl cinnamate lithium aluminum hydride ( 2 . 6 g , 0 . 068 mol ) is added into dry tetrahydrofuran ( 120 ml ) under nitrogen atmosphere . cinnamaldehyde ( 13 . 8 g , 0 . 1 mol ) in dry tetrahydrofuran ( 30 ml ) is added at 24 - 28 ° c . the reaction mixture is stirred at ambient temperature for 1 h . [ 4 -( 2 - dimethylaminoethoxy ) phenyl ]-( 4 - fluorophenyl ) methanone ( 29 . 6 g , 0 . 103 mol ) in dry tetrahydrofuran ( 60 ml ) is added at 50 - 55 ° c . the reaction mixture is stirred at 60 ° c . for 3 h . most of tetrahydrofuran is evaporated . toluene ( 300 ml ), 48 % aqueous sodium hydroxide ( 118 ml ) and water ( 30 ml ) are added . the mixture is refluxed for 10 min and the aqueous layer is separated while warm . the naoh treatment is repeated . the toluene layer is washed twice with hot water . the product is crystallized from toluene as a mixture of stereoisomers ( 26 . 4 g , 62 %). 1 h nmr ( cdcl 3 + meoh - d 4 ): 1 . 95 - 2 . 12 ( m , 2h ), 2 . 30 and 2 . 37 ( 2s , together 6h ), 2 . 68 and 2 . 77 ( 2t , together 2h ), 3 . 31 - 3 . 48 ( m , 2h ) under which the signal of ch ch 2 of the other diastereoisomer , 3 . 80 ( dd , ch ch 2 the other 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 ). 1 h nmr ( cdcl 3 + meoh - d 4 ): 1 . 85 - 2 . 10 ( m , 2h ), 2 . 27 and 2 . 33 ( 2s , together 6h ), 2 . 66 and 2 . 75 ( 2t , together 2h ), 3 . 25 - 3 . 50 ( m , 2h ), 3 . 62 and 3 . 84 ( t and dd , together 1h ), 3 . 93 and 4 . 04 ( 2t , together 2h ), 6 . 6 - 7 . 6 ( 13h ). 1 h nmr ( cdcl 3 ): 1 . 92 - 2 . 15 ( m , 2h ), 3 . 30 - 3 . 48 and 3 . 48 - 3 . 66 ( 2m , together 2h ), 3 . 74 and 3 . 83 ( 2 dist . t , together 2h ), 4 . 02 and 4 . 15 ( 2 dist . t , together 2h ), under the two last signal groups ch ch 2 , 4 . 58 and 4 . 63 ( 2s , together 2h ), 6 . 6 - 7 . 6 ( 18h ). 1 h nmr ( cdcl 3 ): 1 . 80 - 2 . 15 ( m , 2h ), 3 . 2 - 3 . 4 and 3 . 4 - 3 . 6 ( 2m , together 2h ), 3 . 75 and 3 . 82 ( 2 t , together 2h ), 3 . 95 ( dist . t , 1h ), 4 . 00 and 4 . 14 ( 2 t , together 2h ), 4 . 59 and 4 . 63 ( 2s , together 2h ), 6 . 80 - 7 . 55 ( 17h ). 1 h nmr ( cdcl 3 + meoh - d 4 ): 1 . 85 - 2 . 20 ( m , 2h ), 2 . 35 and 2 . 37 ( 2s , together 6h ), 2 . 77 and 2 . 82 ( 2t , together 2h ), 3 . 20 - 3 . 45 ( m , together 2h ), 3 . 81 and 3 . 85 ( 2 dist . t , together 1h ), 4 . 10 and 4 . 21 ( 2 t , together 2h ), 6 . 9 - 7 . 8 ( m , 12h ). 1 h nmr ( cdcl 3 ): 1 . 5 - 2 . 1 ( m , 14h ), 3 . 3 - 4 . 1 ( m , 7h ), 5 . 25 - 5 . 28 ( m , 1h ), 6 . 77 ( d , 2h ), 7 . 00 ( d , 2h ), 7 . 1 - 7 . 2 ( m , 9h ), 7 . 47 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 5 - 2 . 1 ( m , 8h ), 3 . 2 - 4 . 0 ( m , 5h ), 5 . 27 ( m , 1h ), 6 . 79 ( d , 2h ), 6 . 9 - 7 . 32 ( m , 9h ), 7 . 5 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 37 and 1 . 40 and 1 . 42 and 1 . 46 ( 4s , together 6h ), 1 . 9 - 2 . 1 ( m , 2h ), 3 . 2 - 4 . 5 ( m , 8h ), 6 . 6 - 7 . 55 ( m , 13h ). is prepared starting from phenyl -[ 3 -( tetrahydropyranyloxy ) phenyl ] methanone and cinnamaldehyde . the compound is used in the next reaction step without further purification . 1 -[ 4 -( 2 - n , n - dimethylaminoethoxy ) phenyl ]- 1 -( 4 - fluorophenyl )- 2 - phenylbutane - 1 , 4 - diol ( 8 . 46 g , 0 . 02 mol ) is refluxed in 80 ml of acetic anhydride for 3 h . the mixture is cooled to 60 ° c . and acetyl chloride ( 7 . 85 g , 0 . 1 mol ) is added . the mixture is stirred at 80 - 90 ° c . for 4 h . the solvents are evaporated . solution containing 5 % of sodium hydroxide in 80 % aqueous methanol is added and the mixture is stirred for 2 h at rt . methanol is evaporated . water is added and the product is extracted into ethyl acetate . the organic layer is washed with water , dried and evaporated . the residue ( 9 . 5 g ) is mixture of e - and z - isomers of the product . the isomers are separated by flash chromatography ( eluent : toluene : triethylamine 9 : 1 ). e - isomer , 1 h nmr ( cdcl 3 ): 2 . 27 ( s , 6h ), 2 . 64 ( t , 2h ), 2 . 74 ( t , 2h ), 3 . 57 ( t , 2h ), 3 . 92 ( t , 2h ), 6 . 57 ( d , 2h ), 6 . 75 ( d , 2h ), 7 . 03 ( t , 2h ), 7 . 10 - 7 . 18 ( m , 5h ), 7 . 27 ( dd , 2h ); z - isomer , 1 h nmr ( cdcl 3 ): 2 . 34 ( s , 6h ), 2 . 74 ( t , 2h ), 2 , 79 ( t , 2h ), 3 . 60 ( t , 2h ), 4 . 05 ( t , 2h ), 6 . 69 ( t , 2h ), 6 . 84 ( dd , 2h ), 6 . 91 ( d , 2h ), 7 . 09 - 7 . 17 ( m , 5h ), 7 . 20 ( d , 2h ). e - isomer , 1 h nmr ( cdcl 3 ): 2 . 27 ( s , 6h ), 2 . 64 ( t , 2h ), 2 . 73 ( t , 2h ), 3 . 56 ( t , 2h ), 3 . 91 ( t , 2h ), 6 . 56 ( d , 2h ), 6 . 74 ( d , 2h ), 7 . 10 - 7 . 34 ( m , 9h ). e - isomer , 1 h nmr ( cdcl 3 ): 2 . 74 ( t , 2h ), 3 . 57 ( m , 2h ), 3 . 74 ( dist . t , 2h ), 4 . 01 ( dist . t , 2h ), 4 . 58 ( s , 2h ), 6 . 57 ( d , 2h ), 6 . 75 ( d , 2h ), 7 . 00 - 7 . 40 ( m , 14h ) from which the signal 7 . 03 ( t , 2h ) can be identified . z - isomer , 1 h nmr ( cdcl 3 ): 2 . 79 ( t , 2h ), 3 . 60 ( m , 2h ), 3 . 84 ( dist . t , 2h ), 4 . 17 ( dist . t , 2h ), 4 . 65 ( s , 2h ), 6 . 69 ( t , 2h ), 6 . 83 ( dd , 2h ), 6 . 91 ( d , 2h ), 7 . 00 - 7 . 45 ( m , 14h ) from which the signal 7 . 20 ( d , 2h ) can be identified . e - isomer , 1 h nmr ( cdcl 3 ): 2 . 70 ( t , 2h ), 3 . 50 - 3 . 65 ( m , 2h ), 3 . 75 ( dist . t , 2h ), 4 . 03 ( dist . t , 2h ), 4 . 59 ( s , 2h ), 6 . 59 ( d , 2h ), 6 . 73 ( d , 2h ), 7 . 00 - 7 . 40 ( m , 13h ). is produced as a side product in the dehydration reaction of 1 -[ 4 -( 2 - benzyloxyethoxy ) phenyl ]- 1 , 2 - bis ( 4 - chlorophenyl ) butane - 1 , 4 - diol . e - isomer , 1 h nmr ( cdcl 3 ): 2 . 72 ( t , 2h ), 3 . 50 - 3 . 65 ( m , 2h ), 3 . 80 - 3 . 96 ( m , 4h ), 6 . 59 ( d , 2h ), 6 . 75 ( d , 2h ), 7 . 00 - 7 . 40 ( m , 8h ); z - isomer , 1 h nmr ( cdcl 3 + meoh - d 4 ): 2 . 75 ( t , 2h ), 3 . 56 ( t , 2h ), 3 . 95 ( t , 2h ), 4 . 09 ( t , 2h ), 6 . 79 ( d , 2h ), 6 . 91 ( d , 2h ), 7 . 01 ( d , 2h ), 7 . 05 ( d , 2h ), 7 . 16 ( d . 2h ), 7 . 19 ( d , 2h ). e - isomer , 1 h nmr ( cdcl 3 ): 2 . 29 ( s , 6h ), 2 . 66 ( t , 2h ), 2 . 72 ( t , 2h ), 3 . 57 ( t , 2h ), 3 . 94 ( t , 2h ), 6 . 60 ( d , 2h ), 6 . 73 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 15 ( d , 2h ), 7 . 23 ( d , 2h ), 7 . 32 ( d , 2h ); z - isomer , hcl - salt , 1 h nmr ( meoh - d 4 ): 2 . 77 ( t , 2h ), 3 . 03 ( s , 6h ), 3 . 53 ( t , 2h ), 3 . 65 ( t , 2h ), 4 . 42 ( t , 2h ), 6 . 89 ( d , 2h ), 7 . 08 ( d , 2h ), 7 . 10 ( d , 2h ), 7 . 16 ( d , 2h ), 7 . 23 ( d , 2h ), 7 . 31 ( d , 2h ). the protecting tetrahydropyranyl ( thp ) groups are removed in the dehydration reaction . 1 h nmr ( cdcl 3 ): 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 ). e - isomer 1 h nmr ( cdcl 3 ): 2 . 65 ( t , 2h ), 3 . 45 ( t , 2h ), 6 . 29 ( d , 2h ), 6 . 49 ( d , 2h ), 7 . 00 - 7 . 15 ( m , 5h ), 7 . 24 ( d , 2h ), 7 . 33 ( d , 2h ); z - isomer 1 h nmr ( cdcl 3 ): 2 . 79 ( t , 2h ), 3 . 58 ( t , 2h ), 6 . 80 ( d , 2h ), 6 . 81 ( d , 2h ), 6 . 97 ( d , 2h ), 7 . 1 - 7 . 2 ( m , 7h ). e - isomer 1 h nmr ( cdcl 3 ): 2 . 73 ( t , 2h ), 3 . 55 ( t , 2h ), 3 . 60 - 3 . 77 ( m , 2h ), 3 . 87 - 4 . 05 ( m , 3h ), 6 . 56 ( d , 2h ), 6 . 76 ( d , 2h ), 7 . 1 - 7 . 35 ( m , 9h ). z - isomer 1 h nmr ( cdcl 3 ): 2 . 73 ( t , 2h ), 3 . 55 ( t , 2h ), 6 . 4 - 7 . 4 ( m , 12h ). ( e )- 4 -[ 4 -( 2 - dimethylaminoethoxy ) phenyl ]- 4 -( 4 - fluorophenyl )- 3 - phenylbut - 3 - en - 1 - ol ( 0 . 8 g , 2 mmol ) is dissolved in toluene ( 30 ml ) and thionyl chloride ( 0 . 7 g , 6 mmol ) is added . the mixture is refluxed for an hour . toluene is partly evaporated . the crystallized hydrochloride salt of the product is filtered off and the precipitate is washed with toluene . the yield is 0 . 79 g , 86 %. 1 h nmr ( hcl salt , meoh - d 4 ): 2 . 90 ( t , 2h ), 2 . 92 ( s , 6h ), 3 . 40 ( t , 2h ), 3 . 49 ( dist . t , 2h ), 4 . 21 ( dist . t , 2h ), 6 . 70 ( d , 2h ), 6 . 85 ( d , 2h ), 7 . 11 ( t , 2h ), 7 . 12 - 7 . 22 ( m , 5h ), 7 . 32 ( dd , 2h ). 1 h nmr ( hcl salt , meoh - d 4 ): 2 . 93 ( t , 2h ), 2 . 99 ( s , 6h ), 3 . 42 ( t , 2h ), 3 . 61 ( dist . t , 2h ), 4 . 39 ( dist . t , 2h ), 6 . 73 ( t , 2h ), 6 . 88 ( dd , 2h ), 7 . 07 ( d , 2h ), 7 . 12 - 7 . 22 ( m , 5h ), 7 . 29 ( d , 2h ). 1 h nmr ( cdcl 3 ): 2 . 30 ( s , 6h ), 2 . 66 ( t , 2h ), 2 . 91 ( t , 2h ), 3 . 40 ( t , 2h ), 3 . 94 ( t , 2h ), 6 . 57 ( d , 2h ), 6 . 75 ( d , 2h ), 7 . 1 - 7 . 4 ( m , 9h ). e - isomer ( no . 4 ), hcl - salt 1 h nmr ( cdcl 3 ): 2 . 90 ( s , 6h ), 2 . 94 ( t , 2h ), 3 . 40 ( t , 4h ), 4 . 38 ( t , 2h ), 6 . 59 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 19 ( d , 2h ), 7 . 23 ( d , 2h ), 7 . 35 ( d , 2h ); z - isomer ( no . 5 ) hcl - salt , 1 h nmr ( meoh - d 4 ):), 2 . 95 ( t , 2h ), 3 . 41 ( s , 6h ), 3 . 41 ( t , 2h ), 3 . 48 - 3 . 58 ( m , 2h ) 4 . 56 - 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 ). 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 74 ( dist . t , 2h ), 4 . 01 ( dist . t , 2h ), 4 . 59 ( s , 2h ), 6 . 58 ( d , 2h ), 6 . 76 ( d , 2h ), 7 . 06 ( t , 2h ), 7 . 10 - 7 . 40 ( m , 12h ). 1 h nmr ( cdcl 3 ): 2 . 90 ( t , 2h ), 3 . 39 ( t , 2h ), 3 . 76 ( dist . t , 2h ), 4 . 04 ( dist . t , 2h ), 4 . 60 ( s , 2h ), 6 . 60 ( d , 2h ), 6 . 74 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 17 ( d , 2h ), 7 . 23 ( d , 2h ) 7 . 25 - 7 . 4 ( m , 7h ). e - isomer ( no . 6 ), 1 h nmr ( cdcl 3 ): 2 . 90 ( t , 2h ), 3 . 39 ( m , 2h ), 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 ( d , 2h ), 7 . 33 ( d , 2h ); z - isomer ( no . 7 ), 1 h nmr ( cdcl 3 ): 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 ( d , 2h ). triphenyl phosphine ( 0 . 19 g , 0 . 73 mmol ) is dissolved in acetonitrile ( 4 ml ). carbon tetrachloride ( 0 . 237 g , 1 . 3 mmol ) and triethylamine ( 0 . 043 g , 0 . 43 mmol ) is added to the solution and the mixture is stirred for half an hour at ambient temperature . 4 -( 2 , 2 - dimethyl -[ 1 , 3 ] dioxolan - 4 - ylmethoxy ) phenyl - 4 -( 4 - chlorophenyl )- 3 - phenyl - but - 3 - en - 1 - ol ( 0 . 2 g , 0 . 43 mmol , prepared from 4 -( 4 - chlorophenyl )- 4 -[ 4 -( 2 , 3 - di - hydroxypropyloxy ) phenyl ]- 3 - phenyl - but - 3 - n - 1 - ol by protecting the diol group as acetonide ) is dissolved in acetonitrile , added to the reaction mixture and stirring is continued for additional 2 hours . then the solvent is evaporated and the residue is dissolved in 20 ml of methanol - water - solution ( 8 : 2 ). solution is extracted twice with petroleum ether ( 20 ml ) at boiling point . petroleum ether phases are combined and washed once again with hot methanol - water solution . yield 0 . 07 g . e - isomer 1 h nmr ( cdcl 3 ): 1 . 37 and 1 . 41 ( 2s , together 6h ), 2 . 91 ( t , 2h ), 3 . 40 ( t , 2h ), 3 . 70 - 4 . 14 ( m , 4h ), 4 . 39 ( quintet , 1h ), 6 . 56 ( d , 2h ), 6 . 76 ( d , 2h ), 7 . 05 - 7 . 4 ( m , 9h ). ( e )- 1 -[ 4 -( 2 - benzyloxyethoxy ) phenyl ]- 4 - chloro - 1 -( 4 - fluorophenyl )- 2 - phenyl - but - 1 - ene ( 400 mg , 0 . 8 mmol ) is dissolved in toluene . zn ( 106 mg , 1 . 6 mmol ) and acetyl chloride ( 126 mg , 1 . 6 mmol ) are added under nitrogen atmosphere . the mixture is stirred at room temperature for 6 h . the mixture is filtered and the solvent evaporated . the residue is dissolved in 80 % aqueous methanol containing 5 % of sodium hydroxide . the mixture is stirred at room temperature for 2 h and methanol is evaporated . some water is added and the product is extracted into ethyl acetate . the mixture is dried and the solvent is evaporated . the product is purified by flash chromatography ( eluent toluene : methanol 9 : 1 ). 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 87 - 3 . 95 ( m , 4h ), 6 . 57 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 06 ( t , 2h ), 7 . 10 - 7 . 31 ( m , 7h ). using the same method the following compound included in the invention is prepared : 1 h nmr ( cdcl 3 ): 2 . 90 ( t , 2h ), 3 . 39 ( t , 2h ), 3 . 85 - 4 . 05 ( m , 4h ), 6 . 61 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 07 ( d , 2h ), 7 . 1 - 7 . 26 ( m , 4h ), 7 . 35 ( d , 2h ). 1 -( 2 , 2 - dimethyl -[ 1 , 3 ] dioxolan - 4 - ylmethoxy ) phenyl - 4 - chloro - 1 -( 4 - chlorophenyl )- 2 - phenyl - but - 1 - ene ( 0 . 5 g , 1 . 0 mmol ) is dissolved in ethanol and 2 n aqueous hydrogen chloride ( 5 ml ) is added to the solution . the mixture is heated to 40 ° c . and stirring is continued for an hour . then ethanol is evaporated and the product is extracted in toluene , which is washed with water , dried and evaporated to dryness . yield 0 . 45 g . 1 h nmr ( cdcl 3 ): 2 . 91 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 60 - 4 . 15 ( m , 5h ), 6 . 56 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 1 - 7 . 4 ( m , 9h ). is prepared from 4 , 4 - bis ( 4 - hydroxyphenyl )- 3 - phenylbut - 3 - en - 1 - ol ( example 1c ) and benzyl 2 - bromoethyl ether by ptc reaction according to the method described in the example 1a . 1 h nmr ( cdcl 3 ): 2 . 78 ( t , 2h ), 3 . 59 ( q , 2h ), 3 . 74 , 3 . 84 , 4 . 02 and 4 . 17 ( 4 dist . t , together 8h ), 4 . 59 ( s , 2h ), 4 . 65 ( s , 2h ), 6 . 56 ( d , 2h ), 6 . 76 ( d , 2h ), 6 . 91 ( d , 2h ), 7 . 09 - 7 . 40 ( m , 17h ). 1 h nmr ( cdcl 3 ): 2 . 74 ( t , 2h ), 3 . 56 ( t , 2h ), 3 . 71 - 3 . 76 ( m , 2h ), 3 . 98 - 4 . 03 ( m , 2h ), 4 . 60 ( s , 2h ), 6 . 57 ( d , 2h ), 6 . 75 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 14h ). 1 h nmr ( cdcl 3 ): 2 . 75 ( t , 2h ), 3 . 58 ( t , 2h ), 3 . 63 - 3 . 66 ( m , 2h ), 3 . 81 - 3 . 85 ( m , 2h ), 4 . 55 ( s , 2h ), 6 . 47 - 7 . 40 ( m , 19h ). the compound is prepared by using the method described in the example 1a starting from 4 -( 4 - hydroxyphenyl )- 3 , 4 - diphenyl - but - 3 - en - 1 - ol ( preparation described in u . s . pat . no . 4 , 996 , 225 ) and 2 - chloroethyl methyl sulfide . 1 h nmr ( cdcl 3 ): 2 . 16 ( s , 3h ), 2 . 75 ( t , 2h ), 2 . 79 ( t , 2h ), 3 . 59 ( q , 2h ), 4 . 02 ( t , 2h ), 6 . 55 ( d , 2h ), 6 . 79 ( d , 2h ), 7 . 05 - 7 . 40 ( m , 10h ). is prepared by the same method using benzyl 3 - bromopropyl ether as a reagent . 1 h nmr ( cdcl 3 ): 2 . 00 ( quint ., 2h ), 2 . 75 ( t , 2h ), 3 . 59 ( 2 × t , 4h ), 3 . 95 ( t , 2h ), 4 . 48 ( s , 2h ), 6 . 54 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 11 - 7 . 40 ( m , 15h ). nah ( 0 . 09 g , 2 . 69 mmol ) is mixed with dimethylformamide ( dmf ) ( 30 ml ). ( e )- 4 -( 4 - chlorophenyl )- 4 -( 4 - hydroxyphenyl )- 3 - phenylbut - 3 - en - 1 - ol is dissolved in the solution and the mixture is heated to 60 ° c . and stirred for half an hour . 2 -[( 2 -( tetrahydropyranyloxy ) ethoxy ] ethyl chloride ( 0 . 83 g , 4 . 03 mmol ) dissolved in dmf ( 5 ml ) is added to the solution and heating is continued for 3 hours . saturated aqueous ammonium chloride solution ( 30 ml ) and toluene ( 30 ml ) is added to the cooled reaction mixture and stirring is continued for 10 minutes . layers are separated and aqueous layer is extracted with toluene ( 30 ml ). toluene phases are combined and washed with 2 n aqueous sodium hydroxide and three times with water . organic phase is dried and evaporated to dryness . yield 1 . 4 g , 99 %. 1 h nmr ( cdcl 3 ): 1 . 40 - 1 . 90 ( m , 6h ), 2 . 70 ( t , 2h ), 3 . 4 - 3 . 94 ( m , 10h ), 3 . 95 - 4 . 05 ( m , 2h ), 4 . 55 ( m , 1h ), 6 . 56 ( d , 2h ), 6 . 74 ( d , 2h ), 7 . 05 - 7 . 35 ( m , 9h ). is prepared by the same method as previous compound starting from 4 -( 4 - hydroxyphenyl )- 3 , 4 - diphenyl - but - 3 - en - 1 - ol ( preparation described in u . s . pat . no . 4 , 996 , 225 ) and 2 -[ 2 -( tetrahydropyranyloxy ) ethoxy ] ethyl chloride 1 h nmr ( cdcl 3 ): 1 . 40 - 1 . 91 ( m , 6h ), 2 . 74 ( t , 2h ), 3 . 4 - 4 . 0 ( m , 12h ), 4 . 61 ( m , 1h ), 6 . 55 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 05 - 7 . 35 ( m , 10h ). e - isomer 1 h nmr ( cdcl 3 ): 1 . 38 - 1 . 90 ( m , 6h ), 2 . 75 ( t , 2h ), 3 . 32 - 4 . 03 ( m , 10h ), 4 . 00 ( m , 2h ), 4 . 62 ( m , 1h ), 6 . 56 ( d , 2h ), 6 . 75 ( d , 2h ), 7 . 04 ( t , 2h ), 7 . 00 - 7 . 20 ( m , 5h ), 7 . 27 ( dd , 2h ); z - isomer 1 h nmr ( cdcl 3 ): 1 . 40 - 1 . 90 ( m , 6h ), 2 . 79 ( t , 2h ), 3 . 43 - 4 . 03 ( m , 10h ), 4 . 15 ( m , 2h ), 4 . 65 ( m , 1h ), 6 . 69 ( t , 2h ), 6 . 83 ( dd , 2h ), 6 . 90 ( d , 2h ), 7 . 05 - 7 . 20 ( m , 5h ), 7 . 19 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 37 and 1 . 41 ( 2s , together 6h ), 2 . 75 ( t , 2h ), 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 ). is prepared from 4 -( 4 - chlorophenyl )- 4 -( 4 - hydroxyphenyl )- 3 - phenylbut - 3 - en - 1 - ol ( example 1c .) and ethyl bromoacetate according to the procedure described in the example 1a using nah as a base . e - isomer 1 h nmr ( cdcl 3 ): 1 . 25 ( t , 3h ), 2 . 74 ( t , 2h ), 3 . 57 ( t , 2h ), 4 . 22 ( q , 2h ), 4 . 48 ( s , 2h ), 6 . 56 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 0 - 7 . 4 ( m , 9h ); z - isomer 1 h nmr ( cdcl 3 ): 1 . 31 ( t , 3h ), 2 . 78 ( t , 2h ), 3 . 58 ( t , 2h ), 4 . 29 ( q , 2h ), 4 . 63 ( s , 2h ), 6 . 79 ( d , 2h ), 6 . 89 ( d , 2h ), 6 . 98 ( d , 2h ), 7 . 15 - 7 . 30 ( m , 7h ). conversion of the hydroxy group to chlorine is carried out using thionyl chloride as a reagent according to the procedure described in the example 1d . 1 h nmr ( cdcl 3 ): 2 . 94 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 73 and 3 . 83 ( 2 dist . t ., together 4h ), 4 . 00 and 4 . 16 ( 2 dist . t ., together 4h ), 4 . 58 ( s , 2h ), 4 . 65 ( s , 2h ), 6 . 56 ( d , 2h ), 6 . 76 ( d , 2h ), 6 . 92 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 17h ). 1 h nmr ( cdcl 3 ): 2 . 91 ( t , 2h ), 3 . 40 ( t , 2h ), 3 . 71 - 3 . 76 ( m , 2h ), 3 . 98 - 4 . 03 ( m , 2h ), 4 . 60 ( s , 2h ), 6 . 57 ( d , 2h ), 6 . 75 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 14h ). 1 h nmr ( cdcl 3 ): 2 . 16 ( s , 3h ), 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 - 7 . 45 ( m , 10h ). 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 63 - 3 . 67 ( m , 2h ), 3 . 81 - 3 . 85 ( m , 2h ), 4 . 55 ( s , 2h ), 6 . 47 - 7 . 40 ( m , 19h ). 1 h nmr ( cdcl 3 ): 2 . 0 ( quintet , 2h ), 2 . 92 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 59 ( t , 2h ), 3 . 94 ( t , 2h ), 4 . 48 ( s , 2h ), 6 . 54 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 11 - 7 . 40 ( m , 15h ). e - isomer , ethyl ester 1 h nmr ( cdcl 3 ): 1 . 25 ( t , 3h ), 2 . 91 ( t , 2h ), 3 . 41 ( t , 2h ), 4 . 21 ( q , 2h ), 4 . 49 ( s , 2h ), 6 . 57 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 0 - 7 . 4 ( m , 9h ). the ester is hydrolyzed to the corresponding acid in 80 % aqueous methanol containing 5 % of sodium hydroxide . e - isomer , acid ( no . 12 ) 1 h nmr ( cdcl 3 ): 2 . 91 ( t , 2h ), 3 . 41 ( t , 2h ), 4 . 47 ( s , 2h ), 6 . 58 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 0 - 7 . 4 ( m , 9h ); z - isomer ethyl ester 1 h nmr ( cdcl 3 ): 1 . 31 ( t , 3h ), 2 . 95 ( t , 2h ), 3 . 42 ( t , 2h ), 4 . 30 ( q , 2h ), 4 . 65 ( s , 2h ), 6 . 79 ( d , 2h ), 6 . 91 ( d , 2h ), 6 . 98 ( d , 2h ), 7 . 15 - 7 . 30 ( m , 2h ); z - isomer , acid ( no . 13 ) 1 h nmr ( cdcl 3 ): 2 . 95 ( t , 2h ), 3 . 41 ( t , 2h ), 4 . 65 ( s , 2h ), 6 . 79 ( d , 2h ), 6 . 94 ( d , 2h ), 6 . 98 ( d , 2h ), 7 . 10 - 7 . 30 ( m , 7h ). conversion of hydroxy group to chlorine is carried out using ph 3 p and ccl 4 as reagents according to the procedure described in the example 1d . 1 h nmr ( cdcl 3 ): 1 . 30 - 1 . 90 ( m , 6h ), 2 . 92 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 4 - 4 . 0 ( m , 10h ), 4 . 62 - 4 . 65 ( m , 1h ), 6 . 55 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 05 - 7 . 35 ( m , 10h ). 1 h nmr ( cdcl 3 ): 1 . 37 and 1 . 41 ( 2s , together 6h ), 2 . 91 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 7 - 4 . 1 ( m , 4h ), 4 . 39 ( quintet , 1h ), 6 . 55 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 10 - 7 . 41 ( m , 10h ). the tetrahydropyranyloxy group is also converted to chlorine in the reaction . 1 h nmr ( cdcl 3 ): 2 . 94 ( t , 2h ), 3 . 43 ( t , 2h ), 3 . 65 ( dist . t , 2h ), 3 . 8 - 3 . 85 ( m , 4h ), 4 . 0 - 4 . 06 ( m , 2h ), 6 . 60 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 9h ). the tetrahydropyranyloxy group is also converted to chlorine in the reaction . 1 h nmr ( cdcl 3 ): 2 . 91 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 62 ( dist . t , 2h ), 3 . 74 - 3 . 85 ( m , 4h ), 4 . 01 ( dist . t , 2h ), 6 . 57 ( d , 2h ), 6 . 76 ( d , 2h ), 7 . 06 ( t , 2h ), 7 . 09 - 7 . 22 ( m , 5h ), 7 . 27 ( dd , 2h ) the benzyl groups are removed using zn and accl as reagents according to the method described in the example 1e . 1 h nmr ( cdcl 3 ): 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 the same method the following compounds included in the invention are prepared : 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 80 - 4 . 00 ( m , 4h ), 6 . 57 ( d , 2h ), 20 6 . 77 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 9h ). 1 h nmr ( cdcl 3 ): 2 . 93 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 70 - 3 . 80 ( m , 4h ), 6 . 40 - 7 . 40 ( m , 14h ). the tetrahydropyranyl ether is cleaved with h + / etoh using the method described in the example 1e . 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 61 , 3 . 68 , 3 . 77 ( 3 dist . t , 6h ), 4 . 00 ( dist . t , 2h ), 6 . 56 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 1 - 7 . 4 ( m , 10h ). using the same method the following compound included in the invention is prepared : 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 58 - 4 . 10 ( m , 5h ), 6 . 53 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 10 - 7 . 41 ( m , 10h ). ( z )- 4 -[ 4 -( 2 - bromoethoxy ) phenyl ]- 3 , 4 - diphenylbut - 3 - en - 1 - ol ( preparation described in u . s . pat . no . 4 , 996 , 225 ) ( 4 . 97 g , 0 . 0117 mol ) is dissolved in methyl ethyl ketone ( 50 ml ) and potassium carbonate ( 4 . 8 g , 0 . 035 mol ) and imidazole sodium salt ( 2 . 1 1 g , 0 . 0234 mol ) is added to the solution . mixture is stirred and refluxed for five hours . then the solution is filtered and the filtrate is evaporated to dryness . the residue is dissolved in ethyl acetate , washed with 2 n aqueous sodium hydroxide solution and with water , dried and evaporated to dryness . the residue is recrystallized from the mixture of toluene and acetonitrile . 1 h nmr ( cdcl 3 ): 2 . 75 ( t , 2h ), 3 . 59 ( dist . t , 2h ), 4 . 07 ( dist . t , 2h ), 4 . 23 ( dist . t , 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 - chloroethoxy ) phenyl ]- 3 , 4 - diphenylbut - 3 - en - 1 - ol ( prepared as ( z )- 4 -[ 4 -( 2 - bromoethoxy ) phenyl ]- 3 , 4 - diphenylbut - 3 - en - 1 - ol preparation of which is described in u . s . pat . no . 4 , 996 , 225 ) ( 2 . 0 g , 0 . 0052 mol ) and methyl amine in 40 % aqueous solution ( 5 ml , 0 . 065 mol ) is mixed with dimethylformamide ( 8 ml ). mixture is heated in a sealed tube at 60 ° c . for 8 hours . to the mixture is added 60 ml of water and extracted with ethyl acetate . ethyl acetate phase is washed with aqueous 2 n hydrogen chloride solution . water phase is made alkaline with 2 n sodium hydroxide solution and extracted with ethyl acetate . ethyl acetate phase is washed with water , dried with magnesium sulfate and evaporated to dryness . yield 1 . 5 g . 1 h nmr ( cdcl 3 ): 2 . 39 ( s , 3h ), 2 . 70 ( t , 2h ), 2 . 84 ( t , 2h ), 3 . 48 ( t , 2h ), 3 . 93 ( t , 2h ), 6 . 59 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 10h ). prepared by using the same ptc method as in the example 1a using benzyl 2 - bromoethyl ether as a reagent . 1 h nmr ( cdcl 3 ): 2 . 35 ( s , 3h ), 2 . 70 , 2 . 75 , 2 , 79 ( 3 t , 6h ), 3 . 56 ( t , 2h ), 3 . 60 ( t , 2h ), 3 . 94 ( t , 2h ), 4 . 50 ( s , 2h ), 6 . 54 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 10 - 7 . 20 ( m , 5h ), 7 . 27 - 7 . 35 ( m , 10h ). is prepared according to the example 1d using triphenylphosphine and carbon tetrachloride as reagents . purification of product is made by evaporating acetonitrile and dissolving the residue to acidic methanol - water ( 8 : 2 ) solution and extracting triphenylphosphine with toluene ( three times , at room temperature ). methanol - water - solution was made alkaline and the product was extracted with toluene . toluene phase was washed twice with water and evaporated to dryness . the product was crystallized from ethyl acetate as hcl - salt . yield 46 %. 1 h nmr ( hcl - salt , meoh - d 4 ): 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 ), 7 . 67 ( s , 1h ), 8 . 98 ( s , 1h ). ( z )-( 2 - benzyloxyethyl )-{ 2 -[ 4 -( 4 - chloro - 1 , 2 - diphenyl - but - 1 - enyl ) phenoxy - ethyl ] methylamine is prepared according to example 1d using thionyl chloride as a reagent . 1 h nmr ( cdcl 3 ): 2 . 35 ( s , 3h ), 2 . 70 , 2 . 79 ( 2 t , 4h ), 2 . 92 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 56 ( t , 2h ), 3 . 93 ( t , 2h ), 4 . 51 ( s , 2h ), 6 . 54 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 15h ). is prepared by the same method as 1e using zn and acetyl chloride as reagents . 1 h nmr ( cdcl 3 ): 2 . 32 ( s , 3h ), 2 . 60 ( t , 2h ), 2 . 78 ( t , 2h ), 2 . 92 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 57 ( t , 2h ), 3 . 91 ( t , 2h ), 6 . 54 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 05 - 7 . 40 ( m , 10h ). anisole ( 13 . 9 g , 0 . 13 mol ) is added to a stirred solution of 4 - chlorophenylacetic acid ( 20 . 0 g , 0 . 12 mol ) in trifluoroacetic anhydride ( 16 . 5 ml , 0 . 12 mol ). the mixture is stirred in room temperature for 24 h . ice water is added and the crystallized product is collected on a sinter and washed with water . the product is recrystallized from ethanol . the yield is 20 . 4 g , 67 %. 1 h nmr ( cdcl 3 ): 3 . 86 ( s , 3h ), 4 . 20 ( s , 2h ), 6 . 93 ( d , 2h ), 7 . 20 ( d , 2h ); 7 . 28 ( d , 2h ), 7 . 98 ( d , 2h ). 1 h nmr ( cdcl 3 ): 3 . 87 ( s , 3h ), 4 . 21 ( s , 2h ), 6 . 94 ( d , 2h ), 7 . 01 ( t , 2h ), 7 . 22 ( dd , 2h ), 7 . 99 ( d , 2h ). 1 h nmr ( cdcl 3 ): 3 . 84 ( s , 3h ), 4 . 23 ( s , 2h ), 6 . 92 ( d , 2h ), 7 . 20 - 7 . 40 ( m , 5h ), 7 . 99 ( d , 2h ). aluminum 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 h . dilute hydrochloric acid is added to the cooled mixture . ethyl acetate is added to dissolve the product . the layers are separated and the aqueous phase is extracted with ethyl acetate . the combined organic phases are dried and the solvents are evaporated . the product is recrystallized from toluene . the yield is 17 g , 93 %. 1 h nmr ( cdcl 3 + meoh - d 4 ): 4 . 19 ( s , 2h ), 6 . 85 ( d , 2h ), 7 . 19 ( d , 2h ), 7 . 28 ( d , 2h ), 7 . 90 ( d , 2h ). 1 h nmr ( cdcl 3 + meoh - d 4 ): 4 . 20 ( s , 2h ), 6 . 86 ( d , 2h ), 7 . 00 ( t , 2h ), 7 . 22 ( dd , 2h ), 7 . 91 ( d , 2h ). 1 h nmr ( cdcl 3 + meoh - d 4 ): 4 . 20 ( s , 2h ), 6 . 84 ( d , 2h ), 7 . 2 - 7 . 4 ( m , 5h ) 7 . 90 ( d , 2h ). 10 % aqueous sodium hydroxide is added to the mixture containing 2 -( 4 - chlorophenyl )- 1 -( 4 - hydroxyphenyl ) ethanone ( 6 . 0 g , 0 . 024 mol ), tbabr ( 0 . 9 g ) in toluene ( 60 ml ) at 60 ° c . the mixture is stirred for 30 min . n , n - dimethylaminoethyl chloride hydrochloride ( 3 . 6 g , 0 . 025 mol ) is added and stirring is continued at 70 - 75 ° c . for 3 h . the layers are separated and the aqueous phase is extracted with toluene . the combined toluene phases are evaporated to give the product ( 1 . 85 g , 24 %). 1 h nmr ( cdcl 3 ): 2 . 34 ( s , 6h ), 2 . 75 ( t , 2h ), 4 . 12 ( t , 2h ), 4 . 20 ( s , 2h ), 6 . 95 ( d , 2h ), 7 . 19 ( d , 2h ), 7 . 29 ( d , 2h ), 7 . 97 ( d , 2h ). 1 h nmr ( cdcl 3 ): 2 . 34 ( s , 6h ), 2 . 75 ( t , 2h ), 4 . 12 ( t , 2h ), 4 . 21 ( s , 2h ), 6 . 96 ( d , 2h ), 7 . 01 ( t , 2h ), 7 . 22 ( dd , 2h ), 7 . 98 ( d , 2h ). 1 -[ 4 -( 2 - benzyloxyethoxy ) phenyl ]- 2 - phenylethanone 1 -( 4 - hydroxyphenyl )- 2 - phenylethanone ( 17 g , 0 . 08 mol ) is dissolved in 2 - butanone ( 200 ml ) and potassium carbonate ( 33 . 1 g , 0 . 24 mol ) and 2 - benzyloxyethyl bromide ( 25 . 8 g , 0 . 12 mol ) is added to the solution . mixture is stirred and refluxed for three hours . then the solution is filtered and the filtrate is evaporated to dryness . the residue is dissolved in toluene , washed with 2 n aqueous sodium hydroxide solution and with water , dried and evaporated to dryness . the product is crystallized from ethanol . yield 23 . 2 g , 84 %. 1 h nmr ( cdcl 3 ): 3 . 80 - 3 . 86 ( m , 2h ), 4 . 2054 . 22 ( m , 2h ), 4 . 23 ( s , 2h ), 4 . 63 ( s , 2h ), 6 . 90 ( d , 2h ), 7 . 20 - 7 . 40 ( m , 10h ), 7 . 90 ( d , 2h ). 1 h nmr ( cdcl 3 ): 3 . 84 ( dist . t ., 2h ), 4 . 20 ( dist . t ., 22 ), 4 . 20 ( s , 2h )), 4 . 63 ( s , 2h ), 6 . 95 ( d , 2h ), 7 . 19 ( d , 2 ), 7 . 29 ( d , 2h ), 7 . 30 - 7 . 45 ( m , 5 ) 7 . 96 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 37 - 1 . 52 ( m , 2h ), 1 . 52 - 1 . 68 ( m , 4h ), 2 . 50 ( br . t , 4h ), 2 . 78 ( t , 2h ), 3 . 77 ( s , 3h ), 4 . 14 ( t , 2h ), 4 . 19 ( s , 2h ), 6 . 73 - 6 . 90 ( m , 311 ), 6 . 90 ( d , 2h ), 7 . 22 ( t , 1h ), 7 . 96 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 40 - 1 . 53 ( m , 2h ), 1 . 53 - 1 . 70 ( t , 4h ), 2 . 51 ( br . t , 4h ), 2 . 79 ( t , 2h ), 3 . 79 ( s , 3h ), 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 ). the mixture containing 2 -( 4 - chlorophenyl )- 1 -[ 4 -( 2 - dimethylaminoethoxy ) phenyl ] ethanone ( 6 . 3 g , 0 . 020 mol ) and tbabr ( 0 . 5 g ) in toluene ( 70 ml ) is heated to 70 ° c . and 48 % aqueous sodium hydroxide ( 70 ml ) is added . the mixture is stirred for 30 min . and ( 2 - bromoethoxymethyl ) benzene ( 5 . 5 g , 0 . 025 mol ) is added dropwise at 85 - 90 ° c . the reaction mixture is stirred at 95 - 100 ° c . for 3 h . the layers are separated and the aqueous phase is extracted with toluene . the combined organic phases are washed with water and the solvent is evaporated . the residual product ( 9 . 0 g ) is used in the next reaction step without further purification . 1 h nmr ( cdcl 3 ): 1 . 93 - 2 . 15 and 2 . 38 - 2 . 58 ( 2m , together 2h ), 2 . 32 ( s , 6h ), 2 . 72 ( t , 2h ), 3 . 25 - 3 . 55 ( m , 2h ), 4 . 08 ( t , 2h ), 4 . 42 ( s , 2h ), 4 . 82 ( t , 1h ), 6 . 88 ( d , 2h ), 7 . 15 - 7 . 40 ( m , 9h ), 7 . 92 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 95 - 2 . 15 and 2 . 40 - 2 . 60 ( 2m , together 2h ), 2 . 31 ( s , 6h ), 2 . 71 ( t , 2h ), 3 . 25 - 3 . 55 ( m , 2h ), 4 . 07 ( t , 2h ), 4 . 42 ( s , 2h ), 4 . 83 ( t , 1h ), 6 . 88 ( d , 2h ), 6 . 94 ( t , 2h ), 7 . 10 - 7 . 40 ( m , 7h ), 7 . 93 ( d , 2h ). 1 h nmr ( cdcl 3 ): 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 , 9h ), 7 . 93 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 4 - 1 . 9 ( m , 6h ), 2 . 0 - 2 . 2 ( m , 1h ), 2 . 4 - 2 . 65 ( m , 1h ), 3 . 2 - 4 . 05 ( m , 6h ), 4 . 1 - 4 . 2 ( m , 2h ), 4 . 45 - 4 . 5 ( m , 1h ), 4 . 60 ( s , 2h ), 4 . 80 ( t , 1h ), 6 . 88 ( d , 2h ), 7 . 1 - 7 . 4 ( m , 10h ), 7 . 96 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 30 - 1 . 90 ( m , 6h ), 1 . 95 - 2 . 15 and 2 . 38 - 2 . 58 ( 2m , together 2h ), 3 . 20 - 4 . 05 ( m , 6h ), 4 . 16 ( dist . t ., 2h ), 4 . 75 - 4 . 85 ( m , 1h ), 4 . 61 ( s , 2h ), 4 . 80 ( t , 1h ), 6 . 88 ( d , 2h ), 7 . 13 - 7 . 40 ( m , 9h ), 7 . 94 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 4 - 1 . 9 ( m , 6h ), 2 . 0 - 2 . 2 ( m , 1h ), 2 . 4 - 2 . 65 ( m , 1h ), 3 . 2 - 3 . 9 ( m , 4h ), 4 . 45 - 4 . 5 ( m , 1h ), 4 . 85 ( t , 1h ), 7 . 1 - 7 . 5 ( m , 8h ), 8 . 00 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 40 - 1 . 90 ( m , 13h ), 1 . 95 - 2 . 2 ( m , 1h ), 2 . 48 ( br . t , 4h ), 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 ( dd , 2h ), 6 . 80 - 6 . 95 ( m , 4h ), 7 . 21 ( t , 1h ), 7 . 96 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 30 - 1 . 90 ( m , 13h ), 1 . 95 - 2 . 15 ( m , 1h ), 2 . 48 ( m , 4h ), 2 . 74 ( t , 2h ), 3 . 20 - 4 . 00 ( m , 4h ) under which 3 . 88 ( s , 3h ), 4 . 09 ( t , 2h ), 4 . 45 - 4 . 55 ( m , 1h ), 5 . 22 ( m , 1h ), 6 . 73 - 6 . 90 ( m , 4h ) 7 . 14 - 7 . 30 ( m , 2h ), 7 . 97 ( d , 2h ). 4 - benzyloxy - 2 -( 4 - chlorophenyl )- 1 -[ 4 -( 2 - dimethylaminoethoxy ) phenyl ] butan - 1 - one ( 9 . 4 g , 0 . 021 mol ) is added to grignard reagent prepared from bromobenzene ( 13 . 1 g , 0 . 083 mol ) and mg turnings ( 2 . 0 g , 0 . 083 mol ) in dry tetrahydrofuran . the mixture is refluxed for 3 h . saturated ammonium chloride solution is added to the cooled reaction mixture , the thf layer is separated and the aqueous phase is extracted with toluene . the combined organic phases are washed with water and the solvents are evaporated . the residual product ( 10 . 7 g ) is used in the next reaction step without further purification . is used in the next reaction step without further purification . 4 - benzyloxy - 2 -( 4 - chlorophenyl )- 1 -[ 4 -( 2 - dimethylaminoethoxy ) phenyl ]- 1 -( 4 - methoxyphenyl ) butan - 1 - ol 4 - benzyloxy - 2 -( 4 - chlorophenyl )- 1 -[ 4 -( 2 - dimethylaminoethoxy ) phenyl ]- 1 - phenylbutan - 1 - ol ( 10 . 7 g ) is dissolved in methanol ( 70 ml ) and concentrated hydrochloric acid is added to make the solution acidic . the mixture is stirred for 4 . 5 h at room temperature and then at 50 ° c . for 1 h . the solvent is evaporated and the product is purified by flash chromatography ( eluent toluene : triethylamine 24 : 1 ). the yield is 5 . 6 g as a mixture of e - and z - isomers ( 1 : 2 ). 1 h nmr ( mixture of z - and e - isomers , cdcl 3 ): 2 . 28 and 2 . 34 ( 2s , 6h ), 2 . 64 and 2 . 73 ( 2t , 2h ), 2 . 78 and 2 . 83 ( 2t , 2h ), 3 . 40 and 3 . 42 ( 2t , 2h ), 3 . 93 and 4 . 07 ( 2t , 2h ), 4 . 36 and 4 . 38 ( 2s , 2h ), 6 . 55 - 7 . 40 ( m , 18h ) from which can be identified 6 . 58 and 6 . 75 ( 2d , 4h ). 1 h nmr ( mixture of z - and e - isomers , cdcl 3 ): 2 . 28 and 2 . 34 ( 2s , 6h ), 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 , 18h ) from which can be identified 6 . 58 and 6 . 75 ( 2d , 4h ). 1 h nmr ( mixture of z - and e - isomers , cdcl 3 ): 2 . 30 and 2 . 35 ( 2s , 6h ), 2 . 67 and 2 . 76 ( 2t , 2h ), 2 . 81 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 69 and 3 . 81 ( 2s , 3h ), 4 . 38 ( s , 2h ), 6 . 56 and 6 . 86 ( 2d , 2h ), 6 . 58 and 6 . 85 ( 2d , 2h ), 6 . 75 ( d , 2h ), 6 . 76 ( d , 2h ), 7 . 0 - 7 . 4 ( m , 11h ). is prepared according to the procedure of the example 1c . the z - and e - isomers are separated by flash chromatography , eluent toluene : metanol 99 : 1 . z - isomer 1 h nmr ( cdcl 3 ): 2 . 76 ( t , 2h ), 3 . 57 ( br . t , 2h ), 3 . 75 ( dist . t , 2h ), 3 . 81 ( s , 3h ), 4 . 03 ( dist . t , 2h ), 4 . 59 ( s , 2h ), 6 . 59 ( d , 2h ), 6 . 76 ( d , 2h ), 6 . 87 ( d , 2h , 7 . 05 ( d , 2h ), 7 . 13 ( d , 2h ), 7 . 19 ( d , 2h ), 7 . 27 - 7 . 40 ( m , 5h ); e - isomer 1 h nmr ( cdcl 3 ): 2 . 76 ( t , 2h ), 3 . 58 ( br . t , 2h ), 3 . 70 ( s , 3h ), 3 . 84 ( dist . t , 2h ), 4 . 17 ( dist . t , 2h ), 4 . 65 ( s , 2h ), 6 . 57 ( d , 2h ), 6 . 77 ( d , 2h ), 6 . 90 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 15 ( d , 2h ), 7 . 18 ( d , 2h ), 7 . 27 - 7 . 40 ( m , 5h ). z - isomer : 1 h nmr ( cdcl 3 ): 1 . 33 - 1 . 50 ( m , 2h ), 1 . 50 - 1 . 65 ( m , 4h ), 2 . 45 ( br . t ., 4h ), 2 . 67 ( t , 2h ), 2 . 73 ( t , 2h ), 3 . 58 ( t , 2h ), 3 . 65 ( s , 3h ), 3 . 96 ( t , 2h ), 6 . 55 ( d , 2h ), 6 . 63 - 6 . 77 ( m , 3h ), 6 . 79 ( d , 2h ), 7 . 10 ( t , 1h ), 7 . 20 - 7 . 40 ( m , 5h ); e - isomer : 1 h nmr ( cdcl 3 ): 1 . 40 - 1 . 55 ( m , 2h ), 1 . 55 - 1 . 70 ( m , 4h ), 2 . 51 ( br . t ., 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 ). z - isomer : 1 h nmr ( cdcl 3 ): 1 . 33 - 1 . 48 ( m , 2h ), 1 . 48 - 1 . 65 ( m , 4h ), 2 . 43 ( br . t ., 4h ), 2 . 20 - 2 . 50 ( t , 2h ), 2 . 65 ( t , 2h ), 3 . 43 - 3 . 60 ( t , 2h ), 3 . 62 ( s , 3h ), 3 . 93 ( t , 2h ), 6 . 52 ( d , 2h ), 6 . 70 - 6 . 90 ( m , 2h ) under which 6 . 82 ( d , 2h ), 7 . 05 - 7 . 43 ( m , 7h ); e - isomer : 1 h nmr ( cdcl 3 ): 1 . 38 - 1 . 52 ( m , 2h ), 1 . 52 - 1 . 70 ( m , 4h ), 2 . 51 ( br . t ., 4h ), 2 . 38 - 2 . 58 ( t , 2h ), 2 . 77 ( t , 2h ), 3 . 59 ( s , 3h ), 3 . 45 - 3 . 65 ( m , 2h ), 4 . 10 ( t , 2h ), 6 . 6 - 7 . 35 ( m , 13h ). 1 h nmr ( cdcl 3 ): 2 . 73 ( t , 2h ), 3 . 5 - 3 . 6 ( m , 2h ), 3 . 7 - 3 . 76 ( m , 2h ), 4 . 0 - 4 . 03 ( m , 2h ), 4 . 60 ( s , 2h ), 5 . 05 ( s , 2h ), 6 . 56 ( d , 2h ), 6 . 78 ( d , 2h ), 6 . 8 - 6 . 95 ( m , 2h ), 7 . 05 - 7 . 35 ( m , 17h ). 1 h nmr ( cdcl 3 ): 2 . 75 ( t , 2h ), 3 . 02 ( t , 2h ), 3 . 56 ( t , 4h ), 4 . 47 ( s , 2h ), 6 . 78 ( d , 2h ), 6 . 96 ( d , 2h ), 7 . 1 - 7 . 4 ( m , 15h ). ms : ei , m / e 403 ( m + , 1 %), 332 ( 1 %), 72 ( 12 %), 58 ( 100 %). ( 2 -{ 4 -[ 4 - benzyloxy - 2 -( 4 - chlorophenyl )- 1 - phenylbut - 1 - enyl ] phenoxy } ethyl ) dimethylamine ( 1 . 1 g , 2 . 1 mmol ) is dissolved in toluene , zn powder ( 0 . 4 g , 6 . 1 mmol ) and acetyl chloride ( 0 . 6 g , 7 . 6 mmol ) are added and the mixture is stirred at 40 ° c . for 3 h . additional zn ( 0 . 5 g ) and acetyl chloride ( 0 . 6 g ) are added and stirring is continued for another 5 h . ethyl acetate is added and the precipitate is filtered off . the solvents are evaporated and the residue is dissolved in methanol . the acetate ester of the product is hydrolyzed by making the mixture alkaline with 48 % aqueous sodium hydroxide and stirring the mixture at room temperature for 2 h . methanol is evaporated , the residue is dissolved in toluene and washed with water . toluene is evaporated and the isomers of the product are separated by flash chromatography . the yield of the z - isomer is 0 . 25 g and of the e - isomer 0 . 15 g . z - isomer : 1 h nmr ( cdcl 3 ): 2 . 28 ( s , 6h ), 2 . 65 ( t , 2h ), 2 . 72 ( t , 2h ), 3 . 57 ( t , 2h ), 3 . 94 ( t , 2h ), 6 . 58 ( d , 2h ), 6 . 76 ( d , 2h ), 7 . 07 ( d , 2h ), 7 . 15 ( d , 2h ), 7 . 20 - 7 . 40 ( m , 5h ); e - isomer : 1 h nmr ( cdcl 3 ): 2 . 34 ( s , 6h ), 2 . 74 ( t , 2h ), 2 . 78 ( t , 2h ), 3 . 59 ( t , 2h ), 4 . 07 ( t , 2h ), 6 . 80 - 7 . 30 ( m , 13h ). z - isomer : 1 h nmr ( cdcl 3 ): 2 . 27 ( s , 6h ), 2 . 64 ( t , 2h ), 2 . 72 ( t , 2h ), 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 : 1 h nmr ( e - isomer , cdcl 3 ): 2 . 35 ( s , 6h ), 2 . 75 ( t , 2h ), 2 . 78 ( t , 2h ), 3 . 60 ( t , 2h ), 4 . 08 ( t , 2h ), 6 . 75 - 7 . 40 ( m , 13h ). z - isomer : 1 h nmr ( cdcl 3 ): 2 . 28 ( s , 6h ), 2 . 65 ( t , 2h ), 2 . 75 ( t , 2h ), 3 . 57 ( t , 2h ), 3 . 81 ( s , 3h ), 3 . 94 ( t , 2h ), 6 . 58 ( d , 2h ), 6 . 75 ( d , 2h ), 6 . 87 ( d , 2h ), 7 . 05 ( d , 2h ), 7 . 13 ( d , 2h ), 7 . 19 ( d , 2h ); e - isomer : 1 h nmr ( cdcl 3 ): 2 . 33 ( s , 6h ), 2 . 74 ( t , 2h ), 2 . 75 ( t , 2h ), 3 . 56 ( t , 2h ), 3 . 69 ( s , 3h ), 4 . 07 ( t , 2h ), 6 . 56 ( d , 2h ), 6 . 76 ( d , 2h ), 6 . 88 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 17 ( d , 2h ). ( z )- 3 -( 4 - chlorophenyl )- 4 -[ 4 -( 2 - dimethylaminoethoxy ) phenyl ]- 4 - phenylbut - 3 - en - 1 - ol ( 0 . 22 g , 0 . 5 mmol ) is dissolved in toluene . thionyl chloride ( 0 . 2 g , 1 . 7 mmol ) is added and the mixture is refluxed for 45 min . toluene is partly evaporated and the precipitated hydrochloride salt of the product is filtered . the yield is 0 . 2 g . 1 h nmr ( hcl salt , cdcl 3 ): 2 . 88 and 2 . 90 ( s , together 6h ), 2 . 91 ( t , 2h ), 3 . 40 ( m , 4h ), 4 . 40 ( m , 2h ), 6 . 58 ( d , 2h ), 6 . 81 ( d , 2h ), 7 . 07 ( d , 2h ), 7 . 19 ( d , 2h ), 7 . 20 - 7 . 50 ( m , 5h ). 1 h nmr ( hcl salt , cdcl 3 ): 2 . 35 - 3 . 02 ( m , 2h ), 2 . 95 ( s , 6h ), 3 . 35 - 3 . 55 ( m , 4h ), 4 . 46 - 4 . 60 ( m , 2h ), 6 . 75 - 7 . 30 ( m , 13h ). 1 h nmr ( hcl salt , cdcl 3 ): 2 . 88 ( s , 6h ), 2 . 94 ( t , 2h ), 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 ). z - isomer ( no . 26 ): 1 h nmr ( hcl salt , cdcl 3 + meoh - d 4 ): 2 . 89 ( s , 6h ), 2 . 94 ( t , 2h ), 3 . 41 ( m , 4h ), 3 . 84 ( s , 3h ), 4 . 34 ( m , 2h ), 6 . 59 ( d , 2h ), 6 . 81 ( d , 2h ), 6 . 90 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 18 ( d , 2h ), 7 . 19 ( d , 2h ); e - isomer ( no . 27 ): 1 h nmr ( hcl salt , cdcl 3 + meoh - d 4 ): 2 . 91 ( t , 2h ), 2 . 98 ( s , 6h ), 3 . 41 ( t , h ), 3 . 54 ( m , 2h ), 3 . 71 ( s , 3h ), 4 . 45 ( m , 2h ), 6 . 59 ( d , 2h ), 6 . 77 ( d , 2h ), 6 . 94 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 17 - 7 . 18 ( d , 2h ), 7 . 23 ( d , 2h ). z - isomer ( no . 28 ): 1 h nmr ( hcl salt , meoh - d 4 ): 1 . 45 - 2 . 10 ( m , 6h ), 2 . 92 ( t , 2h ), 3 . 06 ( dt , 2h ), 3 . 44 ( t , 2h ), 3 . 47 - 3 . 66 ( m , 4h ), 3 . 68 ( s , 3h ), 4 . 27 ( dist . t ., 2h ), 6 . 70 - 6 . 85 ( m , 5h ), 6 . 92 ( d , 2h ), 7 . 15 ( dt , 1h ), 7 . 30 - 7 . 50 ( m , 5h ); e - isomer ( no . 29 ): 1 h nmr ( hcl salt , meoh - d 4 ): 1 . 45 - 2 . 15 ( m , 6h ), 2 . 96 ( t , 2h ), 3 . 12 ( dt , 2h ), 3 . 47 ( t , 2h ), 3 . 58 - 3 . 75 ( m , 4h ), 3 . 62 ( s , 3h ), 4 . 44 ( dist . t ., 2h ), 6 . 65 - 6 . 83 ( m , 3h ), 6 . 90 - 6 . 97 ( m , 2h ), 7 . 01 - 7 . 18 ( m , 6h ), 7 . 31 ( d , 2h ). z - isomer ( no . 30 ): 1 h nmr ( hcl salt , meoh - d 4 ): 1 . 50 - 2 . 05 ( m , 6h ), 2 . 88 ( t , 2h ), 3 . 05 ( dt , 2h ), 3 . 41 ( t , 2h ), 3 . 45 - 3 . 65 ( m , 4h ), 3 . 86 ( s , 3h ), 4 . 25 ( dist . t ., 2h ), 6 . 65 - 6 . 79 ( m , 3h ), 6 . 88 - 7 . 00 ( m , 4h ), 7 . 20 ( dt , 1h ), 7 . 30 - 7 . 50 ( m , 5h ); e - isomer ( no . 31 ): 1 h nmr ( hcl salt , meoh - d 4 ): 1 . 55 - 2 . 20 ( m , 6h ), 2 . 92 ( t , 2h ), 3 . 13 ( dt , 2h ), 3 . 43 ( t , 2h ), 3 . 58 - 3 . 75 ( m , 4h ), 3 . 84 ( s , 3h ), 4 . 45 ( dist . t ., 2h ), 6 . 73 ( dt , 1h ), 6 . 89 - 7 . 30 ( m , 7h ), 7 . 08 ( d , 2h ), 7 . 18 ( dt , 1h ), 7 . 32 ( d , 2h ). 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 02 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 56 ( t , 2h ), 4 . 47 ( s , 2h ), 6 . 78 ( d , 2h ), 6 . 96 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 15h ). 1 h nmr ( cdcl 3 ): 2 . 28 ( s , 6h ), 2 . 46 ( dist . t , 2h ), 2 . 85 - 2 . 95 ( m , 4h ), 3 . 41 ( dist . t , 2h ), 6 . 79 ( d , 2h ), 6 . 96 ( d , 2h ), 7 . 00 - 7 . 40 ( m , 10h ). z - isomer , 1 h nmr ( cdcl 3 ): 2 . 93 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 83 ( s , 2h ), 3 . 76 ( dist . t , h ), 4 . 04 ( dist . t , 2h ), 4 . 59 ( s , 2h ), 6 . 59 ( d , 2h ), 6 . 77 ( d , 2h ), 6 . 87 ( d , 2h ), 7 . 05 ( d , 2h ), 7 . 15 ( d , 2h ), 7 . 19 ( d , 2h ), 7 . 27 - 7 . 40 ( m , 5h ); e - isomer 1 h nmr ( cdcl 3 ): 2 . 93 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 70 ( s , 3h ), 3 . 85 ( dist . t , 2h ), 4 . 18 ( dist . t , 2h ), 4 . 65 ( s , 2h ), 6 . 57 ( d , 2h ), 6 . 79 ( d , 2h ), 6 . 92 ( 2h ), 7 . 06 ( d , 2h ), 7 . 16 ( d , 2h ), 7 . 18 ( d , 2h ), 7 . 27 - 7 . 40 ( m , 5h ). the compound is prepared by using the method described in the examples 1d using ph 3 p and ccl 4 as reagents . 1 h nmr ( cdcl 3 ): 2 . 93 ( t , 2h ), 3 . 40 ( t , 2h ), 3 . 71 - 3 . 76 ( m , 2h ), 3 . 98 - 4 . 05 ( m , 2h ), 4 . 58 ( s , 2h ), 5 . 06 ( s , 2h ), 6 . 60 ( d , 2h ), 6 . 78 ( d , 2h ), 6 . 85 - 7 . 50 ( m , 19h ). 1 -[ 3 -( 2 - dimethylaminoethoxy ) phenyl ]- 1 , 2 - diphenyl - 4 -( tetrahydropyranyloxy ) butan - 1 - ol ( 0 . 93 g , 1 , 9 mmol ) is dissolved in toluene ( 10 ml ). triethylamine ( 1 . 9 mmol ) is added to the solution and the mixture is cooled to − 10 ° c . thionyl chloride ( 5 . 8 mmol ) is added to the mixture at − 10 -± 0 ° c . the mixture was stirred for 1 hour at 0 - 5 ° c ., warmed up to 80 ° c . and stirred at this temperature for 3 hours . solvent was evaporated , the residue was dissolved to toluene , washed with 2 n naoh and with water . the z - isomer of the product was crystallized from ethyl acetate as hcl salt . yield 0 . 15 g 1 h nmr ( hcl salt , cdcl 3 ): 2 . 79 ( s , 6h ), 2 . 94 ( t , 2h ), 3 . 20 - 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 ). ( e )- 4 -( 3 - benzyloxyphenyl )- 4 -[ 4 -( 2 - benzyloxyethoxy ) phenyl ]- 4 - chloro - 3 - phenyl - but - 1 - ene ( 1 . 95 g , 3 . 39 mmol ) is hydrogenated in ethanol - ethyl acetate ( 5 ml : 20 ml ) containing triethylamine ( 3 . 4 mmol ) and 10 % palladium on carbon ( 0 . 195 g ) as a catalyst . the catalyst is filtered off and the solvent is evaporated . the product is purified with flash chromatography and crystallized from toluene - methanol ( 9 : 1 ). yield 0 . 23 g . 1 h nmr ( cdcl 3 + meoh - d 4 ): 2 . 95 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 8 - 4 . 0 ( m , 4h ), 6 . 56 ( d , 2h ), 6 . 75 - 6 . 82 ( m , 4h ), 7 . 10 - 7 . 25 ( m , 7h ). using the same method the following compound included in the invention is prepared : 1 h nmr ( cdcl 3 ): 1 . 96 ( quint ., 2h ), 2 . 92 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 80 ( q , 2h ), 3 . 98 ( t , 2h ), 6 . 55 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 11 - 7 . 40 ( m , 10h ). 1 h nmr ( cdcl 3 ): 2 . 93 ( t , 2h ), 3 . 00 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 64 ( t , 2h ), 6 . 81 ( d , 2h ), 7 . 01 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 10h ). using the same method the following compound included in the invention is prepared . 1 h nmr ( cdcl 3 ): 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 ( d , 2h ), 7 . 06 ( d , 2h ), 7 . 16 ( d , 2h ), 7 . 19 ( d , 2h ). 1 -[ 4 -( 2 - chloroethoxy ) phenyl ]- 2 -( 2 - chlorophenyl ) ethanone is prepared according to the method described in the example 4a using 2 - chloroethoxybenzene and 2 - chlorophenylacetic acid as starting materials . 1 h nmr ( cdcl 3 ): 3 . 85 ( t , 2h ), 4 . 30 ( t , 2h ), 4 . 39 ( s , 2h ), 6 . 98 ( d , 2h ), 7 . 22 - 7 . 26 ( m , 3h ), 7 . 39 - 7 . 50 ( m , 1h ), 8 . 04 ( d , 2h ). 1 h nmr ( cdcl 3 ): 3 . 83 ( t , 214 ), 4 . 24 ( s , 214 ), 4 . 28 ( t , 214 ), 6 . 94 ( d , 214 ), 7 . 2 - 7 . 4 ( m , 5h ), 8 . 00 ( d , 2 ). the 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 refluxed for 12 h . additional portions of 0 . 3 g of piperidine are added three times in 4 h intervals to the mixture . the solvents are evaporated . diethyl ether is added and the precipitated piperidine hydrochloride is filtered off . diethyl ether is evaporated and the residual product is purified by flash chromatography ( eluent toluenetriethylamine 9 : 1 ). the yield is 4 . 1 g , 89 %. 1 h nmr ( cdcl 3 ): 1 . 38 - 1 . 56 ( m , 2h ), 1 . 56 - 1 . 68 ( m , 4h ), 2 . 45 - 2 . 62 ( m , 4h ), 2 . 79 ( t , 2h ), 4 . 17 ( t , 2h ), 4 . 38 ( s , 2h ), 6 . 96 ( d , 2h ), 7 . 19 - 7 . 25 and 3 . 37 - 7 . 44 ( 2m , together 4h ), 8 . 01 ( d , 2h ). is prepared from 1 -[ 4 -( 2 - chloroethoxy ) phenyl ]- 2 - phenylethanone and imidazole in dmf using sodium hydride as a base according to the procedure described in the example 1a . 1 h nmr ( cdcl 3 ): 4 . 22 ( s , 2h ), 4 . 20 - 4 . 37 ( m , 4h ), 6 . 88 ( d , 2h ), 7 . 03 ( s , 1h ), 7 . 07 ( s , 1h ), 7 . 20 - 7 . 37 ( m , 5h ), 7 . 60 ( s , 1h ), 7 . 97 ( d , 2h ). 2 -( 2 - chlorophenyl - 1 -[ 4 -( 2 - piperidinylethoxy ) phenyl ]- 4 -( tetrahydropyranyloxy ) butan - 1 - one is prepared by ptc reaction according to the method described in the example 4d using 2 -( 2 - chlorophenyl )- 1 -[ 4 -( 2 - piperidinylethoxy ) phenyl ] ethanone ( 1 . 5 g , 4 . 2 mmol ) and 2 - tetrahydropyranyloxy - 1 - iodoethane ( 1 . 3 g , 5 . 1 mmol ) as the starting materials . the product ( 1 . 6 g ) is used for the following reaction step without further purification . 1 h nmr ( cdcl 3 ): from the complex spectrum can be identified 2 . 40 - 2 . 60 ( m , 4h ), 2 . 75 ( t , 2h ), 4 . 12 ( t , 2h ), 4 . 50 - 4 . 62 ( m , 1h ), 5 . 24 - 5 . 36 ( m , 1h ), 6 . 87 ( d , 2h ), 7 . 10 - 7 . 25 and 3 . 37 - 7 . 44 ( 2m , together 4h ), 7 . 98 ( d , 2h ). 1 h nmr ( cdcl 3 ): 1 . 4 - 1 . 9 ( m , 6h ), 1 . 95 - 2 . 2 ( m , 1h ), 2 . 4 - 2 . 60 ( m , 1h ), 3 . 2 - 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 - 7 . 3 ( m , 5h ), 7 . 55 ( s , 1h ), 7 . 95 ( d , 2h ). is prepared according to the procedure described in the example 4e . the product is used in the following reaction step without further purification . the compound is used in the next reaction step without further purification . 2 -( 2 - chlorophenyl - 1 - phenyl - 1 -[ 4 -( 2 - piperidinylethoxy ) phenyl ]- 4 -( tetrahydro - pyranyloxy ) butan - 1 - ol is dehydrated according to the procedure described in the example 1c . the z - isomer of the product is purified by flash chromatography ( eluent toluene - triethylamine 13 : 1 ) z - isomer : 1 h nmr ( cdcl 3 ): 1 . 35 - 1 . 48 ( m , 2h ), 1 . 48 - 1 . 68 ( m , 4h ), 2 . 38 - 2 . 48 ( m , 4h ), 2 . 66 ( t , 2h ), 2 . 58 - 2 . 87 ( m , 2h ), 3 . 47 - 3 . 67 ( m , 2h ), 3 . 94 ( t , 2h ), 6 . 54 ( d , 2h ), 6 . 84 ( d , 2h ), 7 . 07 - 7 . 41 ( m , 9h ). e - isomer : 1 h nmr ( cdcl 3 + meoh - d 4 ): 2 . 83 ( t , 2h ), 3 . 60 ( t , 2h ), 4 . 11 ( dist . t , 2h ), 4 . 20 ( t , 2h ), 6 . 48 ( d , 2h ), 6 . 76 ( d , 2h ), 6 . 66 - 6 . 9 ( m , 4h ), 6 . 92 ( s , 1h ), 698 ( s , 1h ), 7 . 08 - 7 . 32 ( m , 5h ), 7 . 36 ( s , 1h ); z - isomer : 1 h nmr ( cdcl 3 + meoh - d 4 ): 2 . 73 ( t , 2h ), 3 . 54 ( t , 2h ), 4 . 23 - 4 . 4 ( m , 4h ), 6 . 35 - 7 . 23 ( m , 15h ), 7 . 55 ( s , 1h ). 1 h nmr ( cdcl 3 ): 1 . 33 - 1 . 49 ( m , 2h ), 1 . 49 - 1 . 68 ( m , 4h ), 2 . 40 - 2 . 50 ( m , 4h ), 2 . 67 ( t , 2h ), 2 . 80 - 3 . 50 ( m , 2h ), 3 . 25 - 3 . 56 ( m , 2h ), 3 . 95 ( t , 2h ), 6 . 54 ( d , 2h ), 6 . 85 ( d , 2h ), 7 . 06 - 7 . 43 ( m , 9h ). using the same method the following compound included in the invention is prepared . e - isomer ( no . 39 ): 1 h nmr ( cdcl 3 ): 2 . 94 ( t , 2h ), 3 . 41 ( t , 2h ), 4 . 07 ( dist . t , 2h ), 4 . 25 ( t , 2h ), 6 . 50 ( d , 2h ), 6 . 79 ( d , 2h ), 6 . 70 - 6 . 81 ( m , 2h ), 6 . 98 ( s , 2h ), 7 . 10 - 7 . 24 ( m , 7h ), 7 . 51 ( s , 1h ); z - isomer ( no . 40 ): 1 h nmr ( cdcl 3 + meoh - d 4 , hcl - salt ): 2 . 90 ( dist . t , 2h ), 3 . 40 ( dist . t , 2h ), 4 . 33 ( dist . t , 2h ), 4 . 65 ( dist . t , 2h ), 6 . 35 - 7 . 25 ( m , 13h ), 7 . 38 ( s , 1h ), 7 . 48 ( s , 1h ), 9 . 20 ( s , 1h ). 4 - nitrobenzophenone ( 5 . 0 g , 0 . 022 mol ) is dissolved in ethanol - dichloromethane ( 40 ml : 30 ml ) and hydrogenated at room temperature with 10 % palladium on carbon ( 0 . 5 g ) as a catalyst . the catalyst is filtered off and the filtrate is evaporated to dryness . the product is used in the next reaction step without further purification . yield 5 . 2 g . 1 h nmr ( cdcl 3 ): 6 . 67 ( d , 2h ), 7 . 4 - 7 . 6 ( m , 3h ), 7 . 7 - 7 . 6 ( m , 4h ). zinc ( 10 . 0 g , 0 . 154 mol ) and tetrahydrofuran ( thf ) ( 120 ml ) is added to the reaction vessel and cooled to − 10 ° c . to the mixture is added dropwise titan tetrachloride ( 14 . 4 g , 0 . 076 mol ) at about − 10 ° c . after the addition is completed the mixture is refluxed for two hours . then it is cooled to 40 ° c . and ( 4 - aminophenyl ) phenyl - methanone ( 5 . 1 g , 0 . 0258 mol ) and 3 - chloropropiophenone ( 4 . 36 g , 0 . 0258 mol ) are dissolved in thf ( 50 ml ) and added to the mixture . refluxing is continued for additional 3 . 5 hours . the cooled reaction mixture is poured in aqueous potassium carbonate solution ( 14 g k 2 co 3 + 140 ml water ) and allowed to stand over night . the mixture is filtered and the precipitate is washed three times with thf . the filtrate is evaporated to dryness . the residue is dissolved in ethyl acetate and washed with water . yield 9 . 6 g z - isomer being the only isomer . z - isomer : 1 h nmr ( cdcl 3 ): 2 . 90 ( t , 2h ), 3 . 41 ( t , 2h ), 6 . 32 ( d , 2h ), 6 . 64 ( d , 2h ), 7 . 0 - 7 . 4 ( m , 10h ). using the same method the following compound included in the invention is prepared . starting from [ 4 -( 2 - dimethylaminoethylamino ) phenyl ] phenyl methanone ( preparation described in u . s . pat . no . 5 , 693 , 674 ) and 3 - chloropropiophenone . z - isomer : 1 h nmr ( as hcl - salt , meoh - d 4 ): 2 . 95 ( s , 6h ), 2 . 99 ( t , 2h ), 3 . 44 ( t , 2h ), 3 . 47 ( t , 2h ), 3 . 68 ( t , 2h ), 6 . 90 - 7 . 10 ( m , 4h ), 7 . 15 - 7 . 40 ( m , 10h ). ( z )- 4 -( 4 - chloro - 1 , 2 - diphenyl - but - 1 - enyl ) phenylamine ( 2 . 0 g , 5 . 99 mmol ), ethanol ( 30 ml ), ethyl bromoacetate ( 2 . 5 g , 15 mmol ) and sodium acetate ( 2 . 4 g , 17 . 9 mmol ) are added to the reaction vessel and refluxed for three hours . then the solvent is evaporated and the residue is dissolved in water and ethyl acetate . ethyl acetate phase is dried and evaporated to dryness . yield 2 . 9 g . 1 h nmr ( cdcl 3 ): 1 . 26 ( t , 3h ), 2 . 90 ( t , 2h ), 3 . 41 ( t , 2h ), 4 . 20 ( q , 2h ), 6 . 25 ( d , 2h ), 6 . 68 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 10h ). ( z )-[ 4 -( 4 - chloro - 1 , 2 - diphenyl - but - 1 - enyl ) phenylamino ] acetic acid ethyl ester ( 2 . 9 g , 6 . 9 mmol ) is dissolved in tetrahydrofuran and lithium aluminum hydride ( 0 . 34 g , 8 . 97 mmol ) is added in small portions during fifteen minutes . the mixture is stirred at room temperature for two hours . then the solvent is evaporated to dryness and the residue is dissolved in ethyl acetate and washed with water . ethyl acetate phase is evaporated to dryness and the product is purified by flash chromatography with toluene : methanol : triethylamine solution ( 10 : 0 . 3 : 0 . 3 ) as an eluent . yield 0 . 47 g . 1 h nmr ( cdcl 3 ): 2 . 89 ( t , 2h ), 3 . 17 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 73 ( t , 2h ), 6 . 29 ( d , 2h ), 6 . 67 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 10h ). is prepared according to the method of example 6b using [( 4 - benzyloxyethoxy ) phenyl ] phenylmethanone and 3 - chloro - 1 -( 4 - hydroxyphenyl ) propan - 1 - one as starting materials . the product is mixture of z - and e - isomers . 1 h nmr ( cdcl 3 ): 2 . 88 and 2 . 93 ( 2t , 2h ), 3 . 42 and 3 . 43 ( 2t , 2h ), 3 . 74 and 3 . 84 ( 2dist . t , 2h ), 4 . 01 and 4 . 16 ( 2dist . t , 2h ), 4 . 58 and 4 . 65 ( 2s , 2h ), 6 . 55 - 7 . 40 ( m , 18h ). is prepared according to the procedure of the example 1e . the isomers are purified by flash chromatography ( eluent dichloromethane - methanol - triethylamine 98 : 2 : 1 ) z - isomer ( no . 42 ): 1 h nmr ( cdcl 3 ): 2 . 87 ( t , 2h ), 3 . 43 ( t , 2h ), 3 . 83 - 3 . 90 ( m , 2h ), 3 . 90 - 3 . 97 ( m , 2h ), 6 . 56 ( d , 2h ), 6 . 66 ( d , 2h ), 6 . 80 ( d , 2h ), 6 . 96 ( d , 2h ), 7 . 20 - 7 . 40 ( m , 5h ); e - isomer ( no . 43 ): 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 38 ( t , 2h ), 3 . 90 - 4 . 02 ( m , 2h ), 4 . 03 - 4 . 14 ( m , 2h ), 6 . 63 ( d , 2h ), 6 . 89 ( d , 2h ), 6 . 95 ( d , 2h ), 7 . 20 ( d , 2h ), 6 . 85 - 7 . 17 ( m , 5h ). { 2 -[ 4 -( 4 - chloro - 1 , 2 - diphenylbut - 1 - enyl ) phenoxy ] ethyl } methylprop - 2 - ynylamine ( no . 44 ) is prepared according to example 1a starting from z - 4 - chloro - 1 , 2 - diphenyl - 1 [ 4 -[ 2 -( n - methylamino ) ethoxy ]- phenyl ]- 1 - butene ( preparation described in u . s . pat . no . 5 , 491173 ) and propargyl bromide . 1 h nmr ( citrate salt , meoh - d 4 ): 2 . 74 ( s , 3h ), 2 . 82 and 2 . 86 ( 2s , 4h ), 2 . 93 ( t , 2h ), 3 . 06 ( t , 1h ), 3 . 29 ( dist . t , 2h ), 3 . 44 ( t , 2h ), 3 . 85 ( d , 2h ), 4 . 16 ( dist . t , 2h ), 6 . 68 ( d , 2h ), 6 . 86 ( d , 2h ), 7 . 15 - 7 . 47 ( m , 10h ). is prepared from ( z )-( 4 - hydroxy - 1 , 2 - diphenylbut - 1 - enyl ) phenol ( preparation described in u . s . pat . no . 4 . 996 . 225 ) and ethyl bromoacetate according to the procedure described in the example 1a using nah as a base . 1 h nmr ( cdcl 3 ): 1 . 25 ( t , 3h ), 2 . 74 ( t , 2h ), 3 . 57 ( t , 2h ), 4 . 23 ( q , 2h ), 4 . 47 ( s , 2h ), 6 . 56 ( d , 2h ), 6 . 79 ( d , 2h ), 7 . 10 - 7 . 45 ( m , 10h ). is prepared according to the same procedure using ethyl 2 - bromobutyrate as a alkylating reagent . 1 h nmr ( meoh - d 4 ): 0 . 98 ( t , 3h ), 1 . 17 ( t , 3h ), 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 ). is prepared according to procedure described in the example 1d using ph 3 p and ccl 4 as reagents . 1 h nmr ( cdcl 3 ): 1 . 25 ( t , 3h ), 2 . 92 ( t , 2h ), 3 . 41 ( t , 2h ), 4 . 23 ( q , 2h ), 4 . 50 ( s , 2h ), 6 . 55 . ( d , 2h ), 6 . 80 ( d , 2h ), 7 . 10 - 7 . 45 ( m , 10h ). 1 h nmr ( meoh - d 4 ): 1 . 01 ( t , 3h ), 1 . 16 ( t , 3h ), 1 . 89 ( m , 2h ), 2 . 91 ( t , 2h ), 3 . 40 ( t , 2h ), 4 . 15 ( m , 2h ), 4 . 40 ( dd , 1h ), 6 . 52 ( d , 2h ), 6 . 76 ( d , 2h ), 7 . 0 - 7 . 4 ( m , 10h ). grignard reagent is prepared from mg turnings ( 0 . 29 g , 12 mmol ) and bromoethane ( 1 . 25 g , 12 mmol ) in tetrahydrofuran ( 4 ml ). ( z )-[ 4 -( 4 - chloro - 1 , 2 - diphenyl - but - 1 - enyl ] phenoxy ) acetic acid ethyl ester ( 1 . 0 g , 23 mmol , from example 9b ) in tetrahydrofuran ( 11 ml ) is added in room temperature and the reaction mixture is refluxed for 2 h . saturated ammonium chloride is added and tetrahydrofuran is evaporated . the product is extracted into ethyl acetate . the organic layer is dried and evaporated to dryness . the yield is 1 . 0 g . 1 h nmr ( cdcl 3 ): 0 . 87 ( t , 6h ), 1 . 58 ( q , 414 ), 2 . 92 ( t , 2h ), 3 . 42 ( t , 2h ), 3 . 68 ( s , 2h ), 6 . 56 ( d , 2h ), 6 . 78 ( d , 2h ), 7 . 10 - 7 . 45 ( m , 10h ). z - 2 -[ 4 -( 4 - chloro - 1 , 2 - diphenylbut - 1 - enyl ) phenoxy ] butyric acid ethyl ester ( 0 . 98 g , 2 . 2 mmol ) is reduced by lithium aluminum hydride ( 0 . 041 g , 1 . 1 mmol ) in tetrahydrofuran . ice - water is added and tetrahydrofuran is evaporated . the product is extracted into ethyl acetate , dried and the solvent is evaporated . yield 0 . 55 g . 1 h nmr ( cdcl 3 ): 0 . 89 ( t , 3h ), 1 . 54 - 1 . 70 ( m , 2h ), 2 . 91 ( t , 2h ), 3 . 58 - 3 . 76 ( m , 2h ), 4 . 10 - 4 . 20 ( m , 1h ), 6 . 57 ( d , 2h ), 6 . 77 ( d , 2h ), 7 . 10 - 7 . 40 ( m , 10h ). is prepared according to example 4c starting from 1 -( 4 - hydroxyphenyl )- 2 - phenyl ethanone ( prepared according examples 4a - b ) ( 10 . 0 g , 47 . 1 mmol ) and 2 -( 2 - benzyloxyethoxy ) ethyl chloride ( 11 . 0 g , 51 . 8 mmol ). the product was triturated three times with warm heptane to remove byproducts . yield 9 . 6 g , 52 %. 1 h nmr ( cdcl 3 ): 3 . 60 - 3 . 79 ( m , 4h ), 3 . 85 ( dist . t , 2h ), 4 . 16 ( dist . t , 2h ), 4 . 20 ( s , 2h ), 4 . 56 ( s , 2h ), 6 . 92 ( d , 2h ), 7 . 20 - 7 . 41 ( m , 10h ), 7 . 96 ( d , 2h ). is prepared by using the method described in the example 4d starting from 1 -{ 4 -[ 2 -( 2 - benzyloxyethoxy ) ethoxy ] phenyl }- 2 - phenylethanone ( 8 . 4g , 21 . 5 mmol ) and 2 -( tetrahydropyran - 2 - yloxy ) ethyl iodide ( 6 . 6 g , 25 . 8 mmol ). the product ( 11 . 7 g ) is used in the next reaction step without further purification . 1 h nmr ( cdcl 3 ): 1 . 401 . 95 ( m , 6h ), 2 . 00 - 2 . 20 and 2 . 40 - 2 . 60 ( 2m , together 2h ), 3 . 60 - 3 . 80 ( m , 8h ), 3 . 83 ( dist . t , 2h ), 4 . 13 ( dist . t , 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 ), 7 . 96 ( d , 2h ). is prepared by using the method described in the example 4e starting from 1 -{ 4 -[ 2 -( 2 - benzyloxyethoxy ) ethoxy ] phenyl }- 2 - phenyl - 4 -( tetrahydropyran - 2 - yloxy ) butan - 1 - one ( 10 g , 19 . 2 mmol ) and 3 -( tetrahydropyran - 2 - yloxy ) phenyl bromide ( 9 . 8 g , 38 mmol ). the product is purified by flash chromatography with toluene - methanol ( 50 : 1 ) as eluent . yield 5 . 7 g , 43 %. 1 nmr ( cdcl 3 ): 1 . 40 - 2 . 20 ( m , 10h ), 3 . 5 - 4 . 1 ( m , 14h ), 4 . 30 - 4 . 50 ( 2m , 1h ), 4 . 52 ( s , 1h ), 4 . 53 ( s , 1h ), 6 . 60 ( d , 2h ), 6 . 90 - 7 . 40 ( m , 16h ). is prepared from 1 -{ 4 -[ 2 -( 2 - benzyloxyethoxy ) ethoxy ] phenyl }- 2 - phenyl - 4 -( tetrahydropyran - 2 - yloxy )- 1 -[ 3 -( tetrahydropyran - 2 - yloxy ) phenyl ] butan - 1 - ol ( 5 . 7 g , 8 . 2 mmol ) by using the method described in the example 1c except that toluene is used instead of acetic anhydride ( 30 ml ) and triethylamine ( 0 . 91 g , 0 . 9 mmol ) is added . the product ( 3 . 8 g ) is used in the next reaction step without further purification . 1 h nmr ( cdcl 3 ): 2 . 78 ( t , 2h ), 3 . 55 - 4 . 20 ( m , 10h ), 4 . 55 and 4 . 58 ( 2s , 2h ), 6 . 56 ( d , 2h ), 6 . 73 - 6 . 93 ( m , 3h ), 7 . 1 - 7 . 4 ( m , 13h ). is prepared from z , e - 3 -( 1 -{ 4 -[ 2 -( 2 - benzyloxyethoxy ) ethoxy ] phenyl }- 4 - hydroxy - 2 - phenylbut - 1 - enyl ) phenol ( 3 . 8 g , 7 . 4 mmol ) by using the method described in example 4h except that triethylamine ( 1 . 64 g , 16 . 2 mmol ) is added to the reaction mixture . the product is purified by flash chromatography . yield 2 . 5 g . 1 h nmr ( cdcl 3 ): 2 . 92 ( t , 2h ), 3 . 40 ( t , 2h ), 3 . 58 - 4 . 17 ( m , 8h ) 4 . 53 and 4 . 57 ( 2s , 2h ), 6 . 53 ( d , 2h ), 6 . 71 - 6 . 9 ( m , 6h ), 7 . 1 - 7 . 4 ( m , 10h ). z , e - 3 -( 1 -{ 4 -[ 2 -( 2 - benzyloxyethoxy ) ethoxy ] phenyl }- 4 - chloro - 2 - phenylbut - 1 - enyl ) phenol ( 2 . 0 g , 3 . 78 mmol ) is dissolved in ethyl acetate ( 30 ml ). zn ( 0 . 062 g , 0 . 95 mmol ) and acetyl chloride ( 0 . 74 g , 9 . 5 mmol ) are added under nitrogen atmosphere . the mixture is stirred at 50 ° c . for 3 h . the mixture is filtered and the solvent is evaporated . the residue is dissolved in 80 % aqueous methanol containing 3 % of sodium hydroxide . the mixture is stirred at room temperature for 2 h and methanol is evaporated . water ( 5 ml ) is added and the product is extracted into ethyl acetate ( 10 ml ). the mixture is dried and the solvent is evaporated . the product is purified first by flash chromatography ( eluent toluene : methanol 9 : 1 ) and then crystallized from toluene and recrystallized from toluene - acetone . yield 0 . 15 g . 1 h nmr ( cdcl 3 ): 2 . 94 ( t , 2h ), 3 . 41 ( t , 2h ), 3 . 59 - 3 . 63 ( m , 2h ), 3 . 67 - 3 . 72 ( m , 2h ), 3 . 78 ( dist . t , 2h ), 4 . 01 ( dist . t , 2h ), 6 . 56 ( d , 2h ), 6 . 78 ( d , 2h ), 6 . 70 - 6 . 90 ( m , 3h ), 7 . 1 - 7 . 3 ( m , 6h ). those skilled in the art will recognize that while specific embodiments have been illustrated and described , various modifications and changes may be made without departing from the spirit and scope of the invention . other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein . it is intended that the specification and examples be considered as exemplary only , with a true scope and spirit of the invention being indicated by the following claims . all publications , patent applications and patents cited herein are fully incorporated by reference . grodstein f , stampfer m j : estrogen for women at varying risk of coronary disease . maturitas 30 : 19 - 26 , 1998 . henderson v w : estrogen , cognition , and a woman &# 39 ; s risk of alzheimer &# 39 ; s disease . am j med 103 ( 3a ): 11s - 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