CA1179359A - 1,1,2-triphenylpropane- and propene derivatives, a process for preparation thereof and pharmaceutical compositions containing the new compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention rotates to new 1,1,2-tri-phenylprepane and -propene derivatives of the gen-eral formual (I), (I) wherein A and B each stand for hydrogen or they fore to-gether a valence bond, X and Y are identical or different and stand for phenyl group or a phenyl group having a halogen, hydroxy, methoxymethoxy, C1-6 alkoxy or benzyloxy substituent in the para position, R1 is a C1-6 alkyl, epoxyalkyl, azidoalkyl, methoxy-methyl or benzyl group or a group of the general formual (II), (II) wherein R2 and R3 each represent hydrogen or a C1-6 alkyl, hydroxyalkyl or haloalkyl group, or R2 and R3 form together with the adjacent nitrogen atom an up in 8-mem-bered heterocyclic group, an up to 6-membered heterocyclic group optionally containing further hetero atom(s), which hetero-cyclic groups optionally have a lower alkyl or hydroxyalkyl sub-stitutent, a guanidino group, an ?inoguanidino group or a nitro-guanidino group, with the proviso that if A and B form together a valence bond and X and Y each stand for phenyl or X
is phenyl and Y is p-methoxyphenyl, R1 may not stand for a dimethylaminoethyl, diethylaminoethyl, pyrroli-dinoethyl, piperidinoethyl or morpholinoethyl group in the (Z) isomers, stereosiomers and isomeric mixtures thereof, further-more to acid additon salts of the basic compounds of the general formual (I).
The compounds of the general formula (I) can be prepared so that a) a compound of the general formula (III), (III) is reacted with an amino of the general formula H2R3NH or with an allkali metal azide, or b) a compound of the general formual (IV) (IV) is reacted with an alcohol derivative of the general formula R1OM, and, if desired, the methoxymethyl or benzyl protecting group is split off, or c) a compound of the general formula (V), (V) is reacted with an R1-halido or an R1-sulfonate in the presence of an acid binding agent, or d) a propane derivative of the general formula (I) in dehydrogenated.
In the above formulae A, B, X, Y and R1 are as defined above, Z is halogen or sulfonyloxy and M represents an alkali metal atom.
The new compounds of the general formual (I) act on the endoorine system. They exert oestrogenic or antioestrogenic effects of varying strength, further-more inhibit the growth of the mammary tumor induced by 7, 12-dimethyl-benz(a)anthracene.

Description

~7~33~
NEW L,L,2-TRIPE~NYLPROP~NE A~ -PROPENE ~ERIVATIVES, A PROCESS FOR Tl~ PRE`PARATION r~REOF AND PFfARMA-CE~TICAL COMPOSITIONS CONTAINING T~ NEW CO~POUNI~

The invention reLates to ne~ ~,1,2-t~i-pherlylpropane and -propene deri~ati~e~ a process for the preparation thereof and pharmace~ticaL conipositions which contain the ~ew compounds, It is l~nown that some triphen~LaLkane deri~a-tive~ posses~ oestrogenic properties ~JO Grundy: Chem, Rev, ~7~ 281 (L9~7); P.R, Ca~rter et aL.: J. Chem. Scc~
L ~ 0; N,P~ Buu-Hoi et aLO Chim, Thex~ L96~ 327;
W.J~ MiddLeton et aL,: J, Med~ Chem, L4, 1193 (L97L);
U,~, patent specification No~ 3,7L2,929~, AnaLogous L~ derirative~ with a ba~ic substit~ent on the phenyL
xing posse~s primaxiLy antioes-tro~enic e~fects ~D.J.
ColLins et aL,: J, Med, Chem. L4, 9~2 (L97L)], The two most impoxtant repxesentatives of these compounds are L-C4-(2-diethyLaminoetho~y)-phenyL~-L,2-dipher~

-2-chloroethyLene (Clomlfen) and (Z)-1-~4-(2-dimetb~L-amlnoethox~)-pherl~L~-L~2-dLphenyL-'L-~uterle (Tamo~i~en) - ~oe F,P, PaLopoli et ~L, J, Med, Chem, 'LO, 84 (L966);
G.R, ~od~ord et al.: Natw~o 272, ~33 (L966), ~lthough ~)oth oompounds show antioestrogenlo (oestro~en-anta-2~ ~onlzlng and sLL~ht oestrogen-agonlæin~) aotl~itLes, the ~ormor oompound is appLied prlmaril~ to Lncl~loe 0~7LatLon CM. Murray et aL,: ~, Obstet, ~ynaeoJ Br.

1~ 3~9 - La -,~ .
~ommon~. 78~ L108 (L97L)~ and in the treatment o~
oLigospel~y ~J~F. Potts: J. Am. Med. Ass, 23L~ 907 (L97~)~, whereas ~he main ~ield of use o~ Tamoxifen ls the tre-t=-nt o~ =a=mary tumors ~M.P. CaLe et al.:

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.~ ' ' , .

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Brit. J. Cancer 1971, 27 ~ . Both compounds have, however, the disadvantage that upon prolonged treatment undesired side effects~ such as eye damages LH.J. Silverman: Am. J. Optom. ~9, 335 (1972); L.M. Roch et al.: Arch.
Ophtalm. 77, 1~ (1967); M.J. Kaiser-Kupfer et al.: Cancer Treatment Rep. 62, 315 ~1978)7, liver damages LMartindale: The Extra Pharmacopoeia XXVII. 1392 (1977); The Pharmaceutical Press, LondonJ , and thrombosis LK. ~evassaari et al.: Lancet, 9~6 (1978~ appear.
The invention aims at providing new compounds which are superior in activity than the known ones, exert more specific effects and cause only 10minor undesired side effects.
The new compounds according to the invention exert various effects on the endocrinous system, and greatly inhibit the growth of mammary tumors induced experimentally by 7,12-dimethyl-benz~a)anthracene (DMBA).
The new 1,1,2-triphenylpropane and -propene derivatives according to the invention correspond to the general formula ~I), C~'3 - C - C - ~ - ORl ~I) X Y

wherein Emd n each stancl Eor hydrogen or they Eorm together a valcllcc bond, 20X ancl Y are idcntical or diEEcrent and stand for phenyl group or a phcnyl group having a halogen, hydroxy, methoxymethoxy~ Cl 6 alkoxy or benzyloxy substituent in the para position, w

3~17~3~9 Rl is a Cl_6 alkyl, Cl_6 epoxyalkyl; Cl 6 azidoalkyl, methoxymethyl or benzyl group or a group of the general formula (II), -cH2-cH2-N (II) wherein R2 and R3 each represent hydrogen or a Cl 6 alkyl, Cl 6 hydroxylalkyl or Cl 6 haloalkyl group, or R2 and R3 form together with the adjacent nitrogen atom an up to 8-membered heterocyclic group, an up to 6-membered heterocyclic group optionally containing further hetero atom(s), which heterocyclic groups optionally have a lower alkyl or hydroxyalkyl substituent, a guanidino groupJ an aminoguanidino group or a nitroguanidino group, with the proviso that A) if A and B form together a valence bond and X and Y each stand for phenyl or X is phenyl and Y is p-methoxyphenyl, Rl may not stand for a dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the (Z) isomers, B) if A and B form together a valence bond and X and Y each stand for phenyl, Rl may not stand for methyl or ethyl, C) if A ancl B orm together a valence bond and X and Y each stancl 2~ for phenyl, then in the case of the (Z) isomers Rl may not stand for dimethyl-c~minoethyl, diethylaminocthyl, morpholinoethyl or piperidinoethyl, .'~.

33~9 D) if A and B form together a valence bond, X stands for phenyl and Y stands for paramethoxyphenyl, Rl may not stand for methyl or pyrrolid-inoethyl, E) if A and B form together a valence bond, X stands for paramethoxy-phenyl, parafluorphenyl or paraethoxyphenyl, and Y stands for phenyl, Rl may not stand for methyl, F) if A and B form together a valence bond, X is phenyl and Y is parahydroxyphenyl, Rl may not stand for methyl, G) if A and B form together a valence bond, and X and Y each stand for paramethoxyphenyl, Rl may not stand for methyl, or stereoisomers or isomeric mixtures of the above compo~mds~ or pharmaceutically acceptable acid addition salts of the basic compounds having the general formula (I), when prepared by the process of the present invention which is described in detail hereina~ter.
The term "alkyl group"~ used either alone or in combinations (such as alkoxy, azidoalkyl, epoxylakyl, hydroxyalkyl or haloalkyl) refers to a straight-chained or branched saturated aliphatic hydrocarbyl group of 1 to 6, preferably 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl~ etc., preferably methyl or ethyl group). The term "halogen" embraces all the four halogens, i.e. fluorine, chlorine, bromine and iodine. When R2 and R3 form together with the adjacent nitrogen atom an optionally alkyl-substituted heterocyclic group, this group is preferably a pyrrol:idino, piperidino, hcptlmethyleneimono, morpholino, piperaz:ino or N-mcthylpiperazino group.
In a preEcrred subgroup oE the compounds having the gencral formula ~7~
~I) A and B form together a valence bond.
Those compounds of the general formula (I) are also preferred, in which A and B each stand for hydrogen or they form together a valence bond, X and Y are identical or different and stand for a phenyl or p-hydroxyphenyl group, and ~1 represents an epoxyalkyl wi~h up to 4 carbon atoms, an a~idoethyl group of a group of the general formula (II), wherein R2 and ~3 each stand for hydrogen, a Cl 4 alkyl group or a Cl 4 hydroxyalkyl group or they form, together with the adjacent nitrogen atom, a piperazino, pyrrolidino, peperidino or morpholino group having optionally a Cl 4 alkyl substituent with a proviso that, A) when A and B form together a valence bond and X and Y each stand for phenyl, Rl may not stand for a dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the case of the (Z) isomers, or stereoisomers or isomeric mixtures thereof, or a pharmaceutically acceptable acid addition salt o~ the basic compound having the general formula (I)-Particularly preferred representatives of the compounds of thegeneral formula (I) are the following derivatives:
threo-1-L4-(2,3-epoxypropoxy)-pheny ~ -1,2-diphenyl-3,3,3-trifluoro-propane, (E)-1,2-diphenyl-3,3,3-trifluoro-1 ~ -(2-/4-methylpiperazino/-ethoxy)-phenyl7 -propene, 1- /4-(2-dimethylaminoethoxy)-phenyl 7 -2-phenyl-3,3,3-tri:Eluoro-l-~-hydroxyphellyl)-propene, (~ 2-diphenyl-3,3,3-trifluoro-l- L4-(2-/2-hy(lroxyethylamino/-c-tlloxy~-phenyl 7 -propene, (E.)-:L- ~ -(2-azicloethoxy)-phcnyl 7 -1,2,-d.iphenyl-3,3,3-tri:eluoro-propene, 1- L4-(2-di.methylc~ino-ethoxy)-~17~35~

phenyl 7-3,3,3-trifluoro-1,2-bis-(~-hydroxyphenyl)-propene and pharmaceutical-ly acceptable acid addition salts thereof.

The basic compounds of the general formula (I) form pharmaceutically acceptable acid addition salts with mineral or organic acids, such as hydro-chloric, hydrobromic, sulfuric, phosphoric, maleic, fumaric, lactic, methane-sulfonic, p-toluenesulfonic, citric, etc. acids.
The compounds of the general formula (I) can be presented in the form of various stereoisomers, such as (Z) and (E) isomers, threo and erythro isomers. All of the stereolsomers and mixtures thereof are embraced by the scope of the invention.
The invention relates further to a process for the preparation of 1,1,2-triphenylpropane and -propene derivatives of the general formula (I), wherein A, B, X, Y and Rl are as defined above, stereoisomers and isomeric mixtures thereof, and pharmaceutically acceptable acid addition salts of the basic compounds having the general formula (I)~ These compounds are prepared according to the invention as follows:
a) to prepare a compound of the general formula (I) in which A and B are as defined above, X and Y are identical or different and represent a phenyl group, a p-halophenyl group or a p-(Cl 6 alkoxy)-phenyl group, Rl stands for azidoe~hyl group or a group of the general ormula (II), wherein R2 and R3 are as defined above, a phenoxyalkylhalide or sulfonate of the general formula (III), ~ y ~ - ~ C~12 ~ C~12 ~ Z (I[I) whercin A and B are as defilled above, Y and X are as deflned in point a) and Z stands eor halogen or a sulfonyloxy ~roup, - 5a -3~

is reacted with an amine of the general formula R2R3N~I, wherein R2 and R3 are as defined above, or with an aLkali metaL azide, and, if desired, the re-suLting azido deri~ative is reduced, and, if desixed, a resuLting amino deri~ative is con~erted into the respecti~e guanidino~ aminoguanidino or nitroguanidino deri~ati~e; or b) to prepare a compound of the generaL
foImuLa (I) i. which A and B foxm to~ether a ~aLence L0 bond, X and Y are identical or different and represent an unsubstituted phenyl. group or a phen~l gl'OUp ~hioh has a chLoro, bromo, metho~ymethoxy, CL 6 alko~ or benzyLo~y sl1bstituent in the para position, and Rl stands ~or.a group of the general fol~ula (II), wherein 1~ R2 arld R3 each repre~ent hydrogen or a Cl 6 aLk~L group, or R2 arlcl R3 form togethQr with the ad~acent ni$rogen atom an up to 8-membered he$erocycLic group or an up to 6-membered heterocycLic group optionally ~ontai~ing further hetero atom(s), whi.ch heterocrclic groups optLonaLly ha~e a lowar aLkyl or hydro~yalkrL substi-tuerlt, a oompound of the ~;eneral :rormuLa (IV), ~ :B

2~ X ~ ~ ~ F (IV) wherein A and B ~tand fox b.ydrogen ancl X and Y are as defined in point b) abo~e, is dehydro~enated and then raacted with an aLcohoL deri~ative of the gen-eral formuLa RLQM, wherein RL is as defi.ned in point b) and M stands for an alkali metal atom; or c) to prepare a compound of the ~eneral formula ~I) in which A and B are as defined abo~e, X and Y are identicaL or different and represent an unsub~tituted phenyL group or a phenyl group having a halo~en or CL 6 aLkoxy substit-uent in the para LO position and Rl stand~ for a Cl 6 aLkyl, apox~aLkyL, methoxymethyL or ben~yL group or represents a group of the g~neraL formuLa (II), wherein R2 and R3 each stand for a CL 6 alkyL group or they form togethar with the adjaoent nitrogen. atom an up to 8-me~bered 1~ heterocycLic group or an up to 6-membered heterocycLic group optionalLy containing further hetero atom(s), which heterocyoLic groups optionalL~ have a lower alkyl substituellt, a compound of the gen.eraL fonnula ('V~ , ! I ~ OI-~ (V) .~ Y

2~ wherein ~ and B are a~ defLned above and X and Y ar-e as defined ln polnt c), ls reacted wlth an RL-haLlde ~ 1 35~

- 7a -or an Rl-sulfonate, wherein Rl i~ as defined in point c) abo~e, in the pre3ence of an acid binding agent; or d) to prepare a compound of the general formuLa (I) in which A and B form tog~ether a ~aLence bond~ X and/or Y 3tands for a p-hydroxyphenyL ~roup and RL is a group of the general formuLa (II), where-ln R2 and R3 each rep.resent hydrogen or a Cl 6 aLkyL
group or they form together with the adjaoent nitrogen L0 atom an up to 8-membered heterocycLic group or an up to 6-membered heterocycLic group optionalLy contai.ning further hetero atom(s), which heterocycLic groups op-tionaLLy ha~e a Lower alkyl substituent, a compound of the genaral foxmula (IV), wherein A and B are as l~ defined in point d) and X and/or Y i9 a p-(meth.ox~-metho~y)-phenyL group or a benzyLoxyphenyL group, is reacted with an aLcohoL deri~ati~e of the general formuLa RLOM, wherein RL i~ as defîned in point d) and M is an aLkaLi metal atom, and then the methoxy-methoxy g.roup ox the benzyLo~y group 1s s~jected tonn ether spllttlne~ reactlon; or ~'7~35~

e~ to prepare a compound of the general formula ~I) in which A and B form together a valence bond, X and Y are identical or different and stand for an unsubstituted phenyl group or a phenyl group which has a halo, methoxy-methoxy, Cl 6 alkoxy or benzyloxy substituent in the para position and Rl represents a Cl 6 alkyl, epoxyalkyl, azidoethyl, methoxymethyl or benzyl group, a compound of the general formula (I), wherein A and B each stand or hydrogen and X, Y and Rl are as defined in point e), is dehydrogenated; or f~ to prepare a compound of the general formula ~I~ in which Rl represents a group of the general formula (II) and in this latter formula R2 and/or R3 stands for a Cl 6 haloalkyl group, a compound of the general formula (I), wherein Rl is a group of the general formula (II) and in this latter formula R2 and/or R3 represents a Cl 6 hydroxyalkyl group, is halogenated;
and, if desired, the individual stereoisomers are separated from a resulting isomeric mixture, and, if desired, a basic compound of the general formula (I) is converted into its pharmaceutically acceptable acid addition salt or liberated from its acid addition salt.
Process variant a) of the invention is performed preferably so that the starting substance of the general formula (III) is heated with an amine of the general formula R2R3~-1 in an inert solvent or diluent (such as alcohol, aqueous alcohol, acetone, etc.) in the presence of an acid binding agent (such as potassium carbonate or an excess of the amine reactant), or is reacted with an allcali metal azlde in dimethylEormamicle or preEerabLy in aqueous 2-methoxy-cthanol. lE desired, a resulting azido clerivative can hc reduced in a manner known per se e.g. with an alkali metal hydride or '~.'~' 3~
g with hydro~en in the presence of paLLadi.um-on-carbon cataLyst.
In the ~tarting~ substances of thc general formula (III) Z is preferably a haLogen atom (~luorine, chLorine, bromine or iodine), an alkyLsuLfonyloxy group (e g. methrlsuL`onylo~ group) or an aryLsuLfonyLoxy group (e.g an optionaLLy substituted phen~LsuL~onyL~
oxy group, such as phenyLsuLfonyLoxy, p-toLuene~ul~onyL-oxy or p-bromophenyLsuLfonylo~y group).
L0 Process variant b) o~ the in~ention -Ls par-formed preferably so that a compound o~ the general formuLa (IV), wherei.n A and B stand for hydrogen, is reacted wl.th L to 3 moLar equi~aLents of 2,3-dLchloro--~6-dicyano~1,4-ben%oqllinone in an inert sol~ent 1~ (e.~. ben~ene or dioxane) at the boilin~ point of the reaction rnixture, and the resuLting compound is reacted with an aLcohol deri~ative of the g~eneral foxmula RlOM in a bipoLar aprotic sol~ent (e g di.-methyl aoetamide~ hexamethy'lphosphoric triamide, etc.) ox pro~rab'L~ ln an excess o~ the aLcoho'L o~ the gen-eral :~oI~rlula RLOH. Thl~ Latter reaction Ls per`ormed pre:~erabLy at '100 lo '160 C.
.hooordln~ to proce~s varlant o) of the in~en-tLon a pheno'l deri~ative o` the genera'l ~ormuLa ~V) i~
2~ reacted with an R~~haLide or an RL-suL`onate in a sol-~ent or cliluent, such a~ benzene, aloohol, etc., in the ,i.~

~:17~3~

presence of an acid bindingP agent, such as an aLkali metaL hydroxide or an aLkaLî metaL carbonate. Accord-ing to a preferred method the process is performed with an aLkaLi metaL salt of the starting phenoL
deri~ati~e, which also qer~es as acid bindingP a~ent, Prooess ~axiant d) of the invention is per-foI~ed preferablr a~ described above for process variant b)~ The resulting methoxymethoxy or benzyl-oxy deri~ative is treated then with an acid or reduced 1~ to effect the spLittin~ of the ether group.
In process ~ariant e) of the invention a compound of the generaL formula (I), wherein A and B
each ~tand for hydrogen, is deh~drogenatedt Dehydroge-nation is performed preferabLy by reactingP the start~
L5 ingP 9ub9tance wi.th 2~3-dichloro-~6-dicyano-1~4-benzo-quinone in an inert ~oL~ent (e,gP. ben~ene or dioxane) at the boiLin~ point of the reaction mixture (see Org~ Synth, ColL, Vol, ~, 428-431).
According to proce~s variant f) of the in~en-tion a compound of the generaL f`ormuLa (.L), whereinR'L 1~ a ~roup of the gPene.raL f'orlnuLa (II) and l.n thi~
L~tter ~ormula R2 and/or I~3 stands f.`or hydroxyaLkyL, :Ls reaoted with a haLogPenatin~ a~ent to obtaLn the re~pectl~e deri~ati~e wh.e~rein R2 and/or E~3 i~ a halo-2~ aLkyL ~roup, ~a'LogPenatlon .Ls per~formecl in a mannerknown per ge, utLLi~ing con~entionaL halogenating agPents~ such as thionyL chLoricie, etc, .~1 35i~3:

The individual stereoisomers can be separated from their mi~tures by methods ~nown per~
se, such as fractionaL crystallization~
The basic compounds of thc ~eneral foxmula (I) oan be converted into their acid addition saLts by reacting them with the appropr-late acid in an inert soLvent Of the acid addition saLts those formed with pha~naceuticaLly acceptabLe acids are preferred The bases can be liberated from the re-L0 spec-tire acid addition salts by treatment with a strong base The startin~ substances of the ~eneral fo~nuLae (III), (I~) and (V) are, ~ith the exception of (Z)-L,2-diphenyL-3,3,3-trifLuoro-L-(4-fLuorophenyL)-1~ ~propene, tZ)-L,2-diphenyL-3,3~3-tri~Luoro-L-(4-hydroxy-phenrL)-propene and (E)-2-phenyL-3,3,3-tri~Luoro-L--(4-hydrox~phen~L)-L-(4-methoxyphenrL)-propene, new compound~. The preparation of the new startin~ substances i9 described in detail in the exampLes The endoorinolo~loal and tutllour-inhlb.Lto:ry c~*ects of the new compounds aoeordirl~ to the lnven-t;Lon aro clemon~trated by the ~olLowi.n~ tests J The oom-pound~ tc~ted are llsted below:
L = throo-L-~4-(2,3-epoxypropoxy)-phenyL~ 2-diphenyl-2~ -3,3,3-trl~Luoro-propane, 2 = 1-~4-(2,3-epoxypropoxy)-phenyL~-1,2-diphenyL-3~3,3-~;,. -trifluoro-propene, ~7~3~

3 = ~E)-L~2-diphenyl-3~3~3-trifLuoro-l-c4-(2-/bis-/2 -hydroxyethyL)-amino/-ethoxy)-phenyL~-propene,

4 = (E)-L,2-diphenyl-3,3,3-trifluoro-L-[4-(2-f4-methyl-piperazino/-ethoxy)-phenyL~-propene, .~ = L-C4-(2-dimethylaminoethoxy)-phenyL~-2-phenyl--373,3-txifLuoro-1-(4-methoxyphenyl)-propene1 6 = 1-C4-(2-dimethylaminoethoxy)-phenyl~-2-Phenyl--3,3,3-trifLuoro-1-(4-hydroxyphenyL)-propene, 7 = 1,2-diphenyl-3,3,3-trifLuoro-L-C4-(2-/2-hydrox~-LO ethylamino/-ethoxy)-phenyl~-propene, 8 = L-C4-~2-dimethylaminoethoxy)-phenyl~-l-phenyl--3,3,3-trifluoro-2-(4-hydro~yphenyL)-propene, 9 = (E)-L~2-diphenyl-3~3~3-trifluoro-2-[4-(2 pyrro-lidinoethoxy)-phenyLJ-propene, Lg 10 = (E~-1,2-di.phenyl-3,3,3-trifluoro-1-~4-(2-morpholino~
ethoxy)-phenyL~-pr~opene, 11 = (E)-l-C4-(2-diethyLaminoethoxy)-pheny7~ 2-di-phenyl-3,3,3-trifluoro-propene, 12 = (E)-l-C4-(2-azidoethoxy)-phenylJ-1,2-diphenyL--3,3,3-trifluoro~propene, 13 - (E)-1,2-dipherlyl-3,373-trlfluoro-L-C4-(2-/bi~--~2-ohloreth~L)-amLrlo/-ethoxy)-phenyl~-propene7 'lL~ = 'l-C4-(2 dlmethr'lamLnoethoxy)-phenyl~-3,3,3-tri-~luor-1,2-bl~-(4-hrdroxyphen~l)-propene hydro-2g ohlorlde~
Lg = L-phenyl-2-(4-tnethoxyphenyl)-L-C4-(2-c11methyl-amLnoethoxy)-phenyl~-3,3,3-trifluoro-propene, 7~S~
- L2a -L6 = (E)-L,2-diphenyl-3,3,3-trifLuoro-1-[4~(2-~nitro-~uanidino)-etho~y)-phenyL~-propens, The antioestrogenic effect was detex~ined by the method of M,J~K, Harper et aL, 1J~ Reprod, Fert, 13, lOl (1967)~. 24 days oLd infantiLe female rats were treat0d with daiLy dosages of ~ /ug/kg of oestradioL for 3 days~ The test compound was aLso ad-ministered once a day oraLLy for 3 da~s~ On the 4th day the animaLs were sacrificed~ and their utex~s was re~o~ed and weighed. The data characteristic of the antioestro~enic aotivity (inhibition of the utero-tropic effect of oestrac1ioL) of some compounds accorcl-ing to the in~ention are listed in Table l, The antioestrogenio acti~ity of some of the compounds Listed in Table l reaches the acti~ity of Clomifen or TamoxLfen, applied as reference substances, Compound No, l produces~ howe~er, onL~ a sLi~ht inhibi-tion when appLied Ln an oral dosage of 1 mg/kg, The degree of inhibition ~tilL remains Low (39 %) when the dosage is i~oreased to LO mg~

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The oestrogenic (uterotropic) effect was determined according to the method of R. J. Dorfman [Endocrinology 55, 65 (1954)]. 24 Days old female rats were treated with single daily oral dosages of the test compounds. On the 4th day the animals were sacrificed, and their uterus was removed and weighed. The data characteristic of the oestrogenic (uterotropic) effects of some of the compounds according to the invention are listed in Table 2. Ethynyloestradiol, a highly effective oestrogenic substance, and Clomifen and Tamoxifen, two known antioestrogenic agents, were also tested and their activity data are also pre-sented.
The compounds listed in Table 2 possess generally weak oestrogenic properties, or, in the dosage range of 0.1 to 1.0 mg/kg, their activity is somewhat lower than that of Tamoxifen.
The dosage-activity curve oE Compound No. 1 is, however, some-what steeper than those of the other compounds. Thus, in the lower dosage range (0.01 to 3.0 mg/kg) applied, the oestrogenic effect of Compound No. 1 is even weaker than the weak agonistic effects of the antioestrogenic agents, whereas the maximum increase in uterine weight attainable at higher dose ranges (10 mg/kg) wi.th Compound No. 1 is higher than that attalnable by -the antloestrogenic agents.

- o o o cl~
o ~ ~
C~t ,l r~
~ ;t CO ~1 CO "`
~ ~ ~ o ~ ~o oo ~ t-i +l +l +~ +l +l +~
~ +1 ~1 ~ O ~ C~ ~ O O
O C~
O ~C~ O
oc~ o r~
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c~ ~r~ r~
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a) ~ ~ o r~~o ~ oo~
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d .co .
o ~ ~ ~ o ~ ~ r~~ ~ r~ ~
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+l +l +l +l +l +l +l +l rl O
o~ ~1 o ~ l O~ 0~ 0 o c~ ,Q
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c~l ~ ~ ~ ~ r~ ~ ~o o ~ r~ o o _l ~ r~ o ` ` ~i .Q o ~ +l +l ~1 +1 +1 -~1 +1 +1 +1 _ ~ ~o c~ ~ oo co oo ~o o O ~
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r~ r~ o o r~ o ~ ~o ~ ~
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sl ~ ~ o ~t In +l +l +l +l +l ~1 +1 d o C~ In ~o ~ In o ~ . .
r~ r~ o ~ o~ a~
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c~l r~ t c~ t r~ r~
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In ~ t ~ ~ t a) a~
d + 1~ + 1 ~1 + 1 ~ 1 Q. ,d o o ~ +1 o c~l In ~o o~ a ~ ~~ ~ ~n ~ ,~ ~o~o ~ h ~
d ,~ In ~ oo ~o ~ r~ oo o .,1 ~O ~O ~O t~
,U~ do ~n ~ ~ n In ~ n ~1 +1 ~ 1 +1 ~ 1 ~ a c~ In ~n ~n c~ In ~ ~ c~
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~ ~ h t~ , ~1 o ~ s~
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~ ~q ~ ~g ~ o .1 o a) ~ a) ~ _l v ~ ¢l O 1~ v ~:~'7 The stimulating effect exerted on the secre-tion of Luteinizlng hormone (LH) was determined as foLLow3: 24 days oLd infantile female rats were treated subcutaneously with the compounds to be tested on two consecuti~e days, Two hours after the second treatment the animals were bled and the luteinizing hoxtnone (LE) Le~el of the plasma was determined b~ raclioimmune assay, When administared in subcutaneous dosages of L mg/kg, the oompounds tested pro~oke a considerabLe inorea~e in the LE 'le~0L of the pLasma. The re~ults are sutmmari~ed in Table 3, TabLe 3 LE-le~el increasing effect on infantLLe femaLe rats Compound testedPercentage change of the LE Level in relation to the controls __ Tamoxif 3 n LL7 3 L3L~
1~. 1.06 9 ~3 _ . _ _ . . . . . _ _ . ~ _ 2~ Remarks: The tests were per~o~ed on groups o~ 4 or anima'Ls, Dosage: 2xl mg ~ g s,c, ~. ~,t~ ,s~
- ~7 -The effects of the new compounds exerted on hormone-dependent twnours were tested b~ the method of P. GriswoLd et aL. CCancer Research 26, 2L69 (L966)~
on mammary cancer induced by 7,L2-dimethyl-benz(a)~
anthracene (DMBA). The treatment was s-tarted when the weight of the twnor reached about ~00 mg, and the animaLs were trea-ted for 3 months with oraL dosages o~` 20 m~/kg of the active a~ent, administered three times a ~eek. The size of the tumors was measured as L0 descrihed by the abo~e authors as well as accordin~
to the method of V.C. Jordan et aL. CEurcp, J. Cancer L2, 419 (L976)~, with 3 caLiper gauge. The ~olume of the twnor was determined 'by the method of ~.riswoLd~
The anirnaLs were kept under ob~ervation for 2 addi-L~ tionaL months af-ter the termination of the treatment period, and the tumors were measured in this latter period as weLl.
A relati~e effectivity index was lntroduced to characterize the activities of the compounds tested~
'rO oaLou~ate the relatLve effeotLvit~ index the nwnber o~ an;Ltnals showinr; a permarlent or transitory oure or relrl:L9~iorl o~ varLou~ d~lratLorl~ was determlnod and soored aooorclLn~ to the fo'Llowing ta'ble:
pornlF1,rlentLy oured L0 points 2~ temporariLy oured 8 poLnts dura'b'le rem-Ls~ion 6 points sho.rt remission or unohanged state 4 points - L7a -The ohanges in average tumor number appear-ing during the treatment period were evaLuated acoord-ing to the folLowing scale:
no increase in tumor count in any of the animaLs 8 points the a~erage number of tumors inoreases twofoLd 6 points higher inorease in the a~erage nurnber of tumors O points The soore numbers deterrnined for -the indi-~iduaL animaLs by the abo~e two scaLes were added 7 and the resuLt was expressed in percents reLated to the LO scOr~ number which oorresponds to the ma~imum ac-ti~ity (permanent cure). This percentage ~a'lue is the reLati~e effectivit~ index.
The resuLts of the test are listed in Table 47 where the figures in brackcts ha~e the folLowing L~ meanings:

., /

3~9 ~l) pormanently cured; ~2) temporarilg Cured; (3) durable remission; (4) shor~ remission; (5) unchanged sta~a~
Table 4 ~fect on tlle marr~ary cance $_Dc5g__~ogyg~g_gy_ Compound Activity Relative ~ested (l) (2) (33 (4) (5) index ~_ ~ ~
Untreated.
controls - - - 25/25 0 Tamoxi~en 2/5 1/5 - l/5 l/5 7 l 4/5 1~5 _ _ _ 96 3 l/5 l/5 - 3/5 - 65 4 _ _ 3/~ 1/4 -- 60 6- 2/5 1/5 l/5 - l/5 78 7 2/5 l/5 l/5 ~ l/5 78 l~ ~j5 ~ 5 9 11 l/5 - 3/5 - l/5 72 12 2/5 2/5 l/5 - - 85 13 l/5 l/5 l/5 2~5 ~ 67 2/5 - 2/5 - l/5 7 16 _ l/L~ 3/4 - - 73 The invention relake~ ~urkher ~o pharmaceutical composi-bion~ which conbain as actlve agent o~e or more compound90f bhe ~enaral ~ormula (I) in the form o~ single isomers or mi~tures o~ i30m~r~, or .acid addibion sal~ o~ the basic compou~d~ oP the general ~'orrnula (I) to~ether with con~entio~al inert~ solid or liqui.d phaxmaceu~ical carriers. q'hese phar-maceutic~l compo~itions can be applied both in the human therap,y and ~or veterina~,; purposes to in~luence bhe endocrine ~y~tem~ Some o~ the compound~ o~ ~he genaral :~'ormula (I) can 3~

aLso b0 applied in the treatment of t~nors, since the~
inhibit the growth of tumors induced experimentaLLy by DMBA to a great extent. The pharmaceuticaL compositions can be presented preferabLy in the form of oraLLy ad-minister-abLe preparations (such as tabLets~ capsuLes, powder mixtures, soLutions, suspensîons~ emulsions, elixirs, etc ) or as compositions for paren.texaL ad-ministration (e g. injectable solutions or suspensions) These compositions may con-tain con~entionaL inert, soLid or liquid carriers (such as starch, lactose, magnesium stearate, siLicon dio~ido, ma~nesiwrl carbon-ate, polyvinyLpyrroLidone, water, etc )~ The active a~ent contents of the compositions ~aries generaLLy between 0.0~ and 98 %. The pha~naceutical compositions L~ ma~ aLso contain con~entional pharmaceutical. additi~es or au~iLLar~ agents, such as emuLsifyin~, dispe.rsing, wetting, or disintegrating agents, b~fers, etc.
The pha~rlaceuticaL compositions can be pre-pared by methods commonLy applied in the pharmaceuticaL
inclu9t~y The claLLy dosage of the co1npouncls acco.rdi~Æ
to the l~ent1on depend~ on varLous faotors, such as the a~e and genexaL hea'lth oonclit~ons of the patient, se~erLty of the disorc1er, actLvity of the inclividua'L
2~ oompound~ eto. The daiLy oral do9ages va.ry gene.raLly withLn about O OL to L() mg/.kg 'body we~ght The abo~e clata are, howe~er, onLy of informative ix ~l'7~
- L9a -charaoter, sinoe hi~her or Lower dosa~es oan aLso be appLied, if neccssar~, ~:

:

:
:, :

~l~'7~3S~

The invention is elucidated in detail by the aid o~
the following non-limiti~g ~l~ample~J
~a~
~ _ o- and threo-1,2-d~p~,y3~,~ ,~

5 trifluoro~ L(?-mo:~linoethoxy~-phe~1 A mixture o~ 1.20 g (2~67 mmoles) o~ erythro~
(2-bromoethoxy)-phenyl7-1, 2~diphe~yl-3,3,3-tri~luoro-propane and 4~80 g of morpholine is hea~ed to boili~gl ~hen cooled, diluted with 50 ml of ether and washed with water u~bil neu~r~ he e~heral solution is dried, evaporate~ to dryn~ss~
~nd the residue i~ crystallized ~rom hexane. 1002 ~ (8~.6 o~ ery~hro-1,2-diphenyl~3,~,3-trifluoro~ 4-(2-morpholino-etho~y)-phen~_7-propane ar~ obtained~ m.p.: 112~115Ca ~aly~
calculated for C27H28~3N02:
C: 71.19 ~, ~: 6.20 %, ~: 12.51 %, ~: 3.08 %;
~ou~d: C: 71.07 %, ~: 6.37 %, ~: 12.71 %, ~: 2.97 %.
A mix~ure of 3.60 g (8 mmoles) of threo~ 2-bromo-ethoxy)-phen~-1,2-diphen~ 3,3-trifluoro-propana and 20 14 g of morpholine is heated to boili~g, and ~herea~t~r one proceed~ as described aboveO The resulti~g product is or;~tallized from he~ane ~o ob~ain 2085 g (78"3 %) o~ threo-1~2-dlph9nyl-3,3 ,3-~ri:eluoro~ (2-morpholinoethoxy)-phenyl7-propane; m ~.p.: 88-91C .
h~ly~ls:
aalcul~od :Eo~ a27H28F3N02:
a: 71019 %, H: 6.20 %, F: 12051 %, N: 3~08 %;
found: a: 71.24 ~/1 H: 6.44 %, F: 12.45 %, N: 3.03 ~0.
~he startin~ substenc~s, erythro and threo~ L(2-bromoe thoxy) -phen~l~r-1 ,2-diphenyl-3, 3,3-trifluoro-propane, are prepared a~ follow~
A solution of 456 g ( 1~17 moles) of benzyl-triphenyl-phospho~iumchloride ~.~ibtig: Chem. Ber. 87~ 1318 (1954~,7 in 1500 ml of dry ethanol is add~d to a solutio~ of 27 g (1.17 g.~atom~) of sodium i~. 500 ml of dry etha~ol at 0-~C.
~he re~ulting mixture i~ combined wibh 3 ~olution OI 204 g (1.17 moles) oî 2,2 ,2-tri~luoroacstophenon~ in 100 ml o~ dry ethanol 7 and the mixbura is allowed to ~and ovarnight~. ~he ~olutio~ i~ svapora~ad, the re~idue i~ admixed with 800 ml of petroleum ethar, filtered, and the îilter cake iY wa~hed.
~he Iiltr~be is evaporated~ and bhe residue i~ di3billed i~
D rc7p~
~, V'8CUO. 268 g (92.5 %) of 1,2-diphallyl-3,3,3-tri~luoro~
are obtained; bop~ 107-109C/0.2 mm Hg9 m.p.: 58-61Co Analy~is: .
calculated ~or C15HllF3:
C: 72.57 %, H: 4.47 ~0, F: 22.96 %7 found: C: 72.49 %~ H: 4.23 ~0, ~: 23.20 %.
268 g ( 1.08 mole ~) o~ tha above producb are ~ydro-genated at 20C for 6-8 hour~ in 4000 ml of acetic acid, i~
the pre~ence of 20 g of a lO~o palladium-on-carbo~ cataly~
The ~olution i~ evaporatad and the residue i~ distilled in v~cuoO 252 g (93.3 %) of 1,2-diphanyl-3,3,3-briPluoro-propana - are ob~ained; b.,p.: 94--96C/0.1 mm Hg, nD = 1.5100.
Analy~ ls:
¢~lcul~ted Por C15H13~3s C: 71.98 %, ~I: 5.26 %, ~: 22.75 %;
Pound: a: 72.12 %, H: 5,L~. %~ F: 22.50 %0 5 g (0.02 moles) of benzo~l peroxide are added to a solution of' 250 g (1 mole) of the sbove produc~ in 2500 ~il o~ carbon betrachlorid~, and then a solution of 176 g (1.1 3S~
_ 22 -mole~) oP bromi~e in 500 ml of carbo~ ~etrachloride i~ add~d to ths mi~ture at 50C within 30 mi~utes~ The re3ulti~g mi~-ture i~ boiled Yor 2 hours9 then cooled, washed with ~odium thio~ul~ate solution, sodium hydrocarbonata solution and then with water, dried and evapora~edO ~he residus i~
crystallized ~rom 1260 ml oP ethanol to obtai~ 140 g ~42.6 %~
o~ erythro-1-bromo-1~2-diphsnyl-3,3,3-trifluoro propane;
m.p.: 1~64-165OC
An~ly~
calcula~ed ~or al5H12Br~3:
C: 54.73 %~ ~: 3767 ~09 ~r: 24~28 %9F~ 17,32 %~
fou~d: C: 54.97 %, ~: 3.93 %~ Br: 230~8 ~17.36 %.
~he mother liquor is evaporated to about o~e~third of its origin~l volume~ 130 g (3905 %) of ~hreo-1-bromo-1,2-diphenyl-3,3~3-tri~luoro propane separate; m.p.: 91 94C.
Analysis:
calculated ~or C15H12Br~3:
a: 54.73 Y0, H: 3.67 ~09 Br: 24.28 %, F: 17.32 %;
îo~d: C: 54.86 %, H: 3082 %, BI~: 24.01 %, ~: 17.27 %.
~he N~R spectra of the compou~ds confirm th~
assigned ~tructure~.
270 g (0.82 moles) oî an erythro thr~o i~omeric mixbure obbained as described ~bove flre dissolv~d :Ln 2500 oiL
of anisole, 110 g (0.83 moles) oP anhydrous alumi~ium trl-~5 ohloride are addod to the stirred solution at 6C~ a~d the mixture ~s allowed to 3tand ab room temperature over~lghb.
~'he reaction mixture is poured onto a mixture of 4 kg of crushed ice and 600 ml of 36~o aqueous hydrochloric acid a~d extractod with 3 litres of chloroform. The organic solutio~
is wash~d with aqu~ous sodium hydrocarbonate solution and ~h~n with water, d:riad and evaporaked. The dry rs~idue i~
cry~tsllized ~rom 750 ml of isoprop~nol, and the rq~ulti~g crude product (~62 g3 55 ~o~, m.p.: 121-126C3 is cr~tallized ~g~in ïrom 1500 ml of i80prOpa~101. 109 g (37 ~0) oî bhreo 1,2-diphsn~1-3,3,3-brifluoro-1~ methoxyphe~yl)-propane are obtained; m.p.: 129-131C.
A~ si ~:
calculated ~or C22H19F30:
C: 74~14 ~, H: 5.37 %, F: 16~00 æ;
~ou~d: C: 74.08 %, ~ 5.47 %9 F: 15.75 %
Spqotr~l daba: ~ CH 35~ 30259 2995, 2950, 2925 2900, 2830 ~C=C 1~05~ 1580, 150~
~ Ar 8Q~ ~ 7~6, 758, 702 ~CH(Ar)2 ~ 4-60 (d) a L~
8CH(GF3) - 4-23 (m)~ lH
~O~H3 = 3~60 ~), lH
~Ar = 6.7-703 ~m), 14H
~hc ~obher liquor obtained in the fir~t cry~talliza~
20 tion ~ep i3 evaporated bo dryne~s, the residue i~ admixad wibh 300 ml oP hexane and ~ilbered. 'rhe.re~ulbi~@s crude l~roduct ~96 g, 27 S~o, m.p.: 89-101C) is cry~balïi~d a~;ain from 9~0 ml oî i~opropanol ~o obtai~ 4-1.4 g (14 %) o~ erg~ro-1,2 diph~yl-3,3,3-triPluoro~ matho~yph~ prop~no~
m.p. s 108-111C.
A~aly~is:
¢alculabed.~Or a22Hl9~l3o:
a: 74014 a/O~ H: 5.37 %1 F: 16.00 %;
fou~d: C: 74"23 %9 H: 5 ,18 //a~ F: 16.17 %.

l793~9 ~p~ctral d~ta: ~)C:~[ 399 3060, 3025~ 3010, 2960 29L~0, 2915, 28L~O
')C=C 1658, ~612 9 1590, 1513 7 ~500 t Ar 808 9 790, 762, 708, 702 CH ( Ar) 2 CH~C1?3) = 4-23 (m) ~ 1~
~OCH3 - ~ .60 ( 8~, 3H
C Ar - 6 44-~7 " 6 ( m), l~H
100 g (0~,28 mOle9) of t~reo-1,2~-diph~nyl-3"3 j3-~ri-10 ~luoro~ m~ho~yphe~ propana are heated with ~00 g o~
pyridina h~drochloride for 3 hour~ at ~!00-220~Co ~he mixtur0 i~ cooledl, diluted with 700 ~nl of chloroîorm, w~shed with w~ter ur~til n~utral, dried and evaporat~d4 ~he rs~idue i3 cry~tallized ~rom a 1:2 mi~ture of Ghloroform a~d hexane to obt~in 85.7 g (90 %) o~ bhreo~ ?-diphenyl-3?3~3-tri~luoro-hydroxyphenyl)-propane; m.p.: 1?3- 125C.
Ana l;y ~
calculatsd ~or C2~ ?P30:
G: 73~67 ~o~ H: 5.01 ~0, F: 16.65 ~;
found: a: 73.56 %, H: 4.92 ~0, F: 16.?8 ~,~0~
40 g (0.11 mole 8) o~ erythro-1,2-diphenyl-3,3,3~tri;
Pluoro~ mothoxyphenyl)-propane are reac~ed with 120 g o~ pyxidi~e hydrochloride ~8 d~cribed aboveO ~he ra,sul~ing erythxo-1,2-diphenyl-3,3,3-~rifluoro~ 4-hydroxyph~Dyl)w ~5 prop~ne i~ ory~talliz~d ~rom a 1:2 mixtur~ oP chloro~orm and hex~ne to obt~n 32~,5 g ( 84, 5 ~0) o~ the product; m.p.s 114-117C,,.
A~ lya~ 5:
calculated ~or C211I17~;3:
C: 73.67 ~0, H: 5.01 %, E`: 16.65 %;
~ou~d: C: 73.52 'Y0, H: 4.97 %, ~`: 16.71 ,0.
~ a~l~

- ~5 --A mixture of 85.6 g (0.25 mole~) o~ thr~o-1,2-di-ph~nyl-3,3,3-trifluoro-1-(4-hydro~yphenyl)-propane, 400 ml of 1,2-dibromoethane and 18.5 g (0.33 mole~) o~ powdered potas~ium hydroxid~ is boiled undar ~tirring. ~he reac~io~
mixture is dilut~d with 1.5 litres of dichloromethane9 washed with 10% aqueou~ hydrochloric acid and wabar, dried, and the solvent and the excess o~ 1,2-dibromoethane are di~tilled off i~ vacuo. The re~idue i~ crystallized ~rom be~zene to obbain 97.7 g (87 %) OI bhreo-l-L4~ bromoeth oxy)-pheny ~ -1,2-diph0nyl-3,3~3-trifluoro-propana; m.p.:
144 lsla.
Analysi3:
calculabed îor c23~I20Br~l3,o:
C: 61.48 %9 H: 4049 %, Br: 17.,78 %, ~: lZ.68 ~0;
15found: C: 61.55 u~O, ~: 4.57 %, Br: 17063 %, ~: 12~71 %0 30 g (8706 mmoles) o~ er~hro-1~2-diph~yl-~3~3-tri-~luoro-1-(4-hydroxyphenyl)~propan~ are reacted wlth 1,2-dl-bromoethane a~ described above. Th~ resulting ~rythro-l-~(2-bromoethQxy)-phe~y~-1 92-diphenyl-3 ,3,3-tri~luoro- -propane is crysballlz~d from benzene bo obtai~ 2709 g (71 %) of ~hG product; m.p.: 130-133C.
~na l~
calculabcd for C23~20Br~30:
C: 61.48 %, ~I: 4~49 %, ~r: 17078 %, F: 12.68 %;
~5 ~ou~d: C: 61.60 %1 H~ 4~63 %, Br: 17060 %, ~: 12.77 %l ~a~ .
Prepar~tion o~ threo~ di~h~nlh=~ L~L____-A mix~ure of 6074 g (15 mmoles) of threo-1-/4-~2-bromoethox~)~ph~nyl7-1,2~dipheny1-3,3,3-tri~luoxo-propane, 35~3 prepared as da~cribed in ~`xample 19 9015 g ( 150 mmole~ o~
2-aminoethanol and 15 ml o:~ 2 m~ thoxyebhanol i~ boiled for 005 hour~. The reac~ion mixbure i5 coolad9 dilutad wi~h ,200 ml of chloroform) wa~hsd wibh water, dri~d and evapora~ed~
5 The residua i9 cry~tallized from a 1:1 mixture o~ b~nzena and hexane to obtairl ~.32 g (67 %~ o~ khe aimed compoundg, m.p.: 120-122C.
Ana lysis;
c~l c ula t ed î or C25H26~ ~;N2 10C: 69.go %, H: 6.10 ~ F: 1~.27 ç~0, N: 3.26 %;
found: C: 69.71 Yo9 H: 6015 ~13.17 %~ N: 3035 %0 ~2a~
~ ~ ~ri~luoro-~~ ~
~ ~
8.98 g (20 mmoles) of erybh~o 1~ 2-bromos~hoxy)-pheny ~-1,2-diphen~1-3, ~,3-tri~luoro-propa~e, prepaxed a~
described in :Example 1, are dis~olved in 42 g (400 mmoles) of diethanolamin~, a~d ~he so~ution 19 hea~d at lOV-120C
20 ~or 0.5 hour~0 ~he reacbion mixture is proces~sd a~
de~¢ribed i~ ~xample 2, alld bhe re~idue i~ cry~tallized :erom a 1:2 mixtur~ oï ~n i~opropanol ~olu~ion o~ hydrochloric aoid and ~bh~r. 5~,98 g (58~7 %) oî bho almed compou~d ara obbained; map.: l90-1g5c~
25An~ly~is i c~c~llated ~~ a27H31Cl?3N~S , C: 63.59 %, ~: 6013 %, Ols 6.95 %, F: 11.18 %, N: 2~75 %;
~ou~d: C: 63,~1 4~o~ H: 6029 ~%~ Cl: 7008 %, F: 10.98 %;
N: 2"80~.

9~3 Ex~ e 4 _ Preparation of erythro-L,2-diphenyL-393,3-~trifLuoro-l-C4-(2-/bi~;(2-chloroethyL)--amino/-ethoxy)-phenyl~-propane hydxo-_ ~ _ _ _ _ ~ chLoride _ A mixture of 2.o4 ~ (4 ~moLes) o~ cxythro--L,2-diphenyl-3,3,3-trifLuoro-L-~4-(2-/bis(2-hydroxy-ethyl)-amLno/-ethoxy)-phenyL~-propane-hydr-ochloxide, prepared as described in Example 3, 10 ml of chloro~
L0 form and 3 ml (40 mmoLes) o~ thionyL chloride 1s boiLed for 2 ho~lrs. The e~ce~s of thionyL chloride is e~ap-orated in ~aouo, and the residue 1s cxy~talli~ed from a L:2 mixture of methanol and ether~ l.16 g (~3 ~0) o~ th~ aimed compound are obtained; m p.: L40-l43 C.
L~ AnaLys i9:
calculated~for C27~I29c L3F3N
C: 59 30%~ 34%, Cl: L9.4~%, F: Lo.42%, N: 2.~6~o;
found: C ~9~ L6%~ 3%, Cl 19 32%~ F: 10. 60%~ N: 2 . 62%.

PreparatLon o~ ex~thx-o~l . ~
-phenyL~-'1,2-clLphony'L-3,3,3-trl~luoro~pxop _ A solutlon o~ 3.2S ~ (~0 t;mloles) o~ sodium a~lde Ln Ll InL of water 1~ addecl to a ~oLution of '1l.2 2S (2.S mtnole~) o:~ erythro-'L~ ~(2-bromoethoxy)~phenyL~-1,2--dLphenyl-3,3,3-tri~Luox-o-pxopane, prepared as descrL~ed Ln Examp'1e L~ Ln l'L2 ml of 2-methoxyetb.atloL, and the 33S~

mixture is boil.ecl ~'or one hour. The reaction mi~ture ls e~aporated to dryness, 30 ml of toluene is added to the residue, and the rrlixture is evaporated again to remove the Last traces of 2-metho~ethanoL The soLid resjdue is triturated w-lth ~ate-, fiLtered of~
and washed with ~ater, The crude product is recrys-taLLi~Ged twice from ethanoL. 7~83 g (76 %) of the aimed compound are o'btained; m. pO 144-L48 C
AnaLysis:
L0 calcuLated for C23~2oF3N30 C: 67~L4%~ H: 4.90'~, F: L3.8~ %~ N: L0.21 %;
~'ound: C 67.3~o~ H ~ %? F: 13.94 %, N: Lo.o6 %.

L~ ~
-phor~l]-1~2-dLpllenyL-3,3L3-____Luoro-propane ~.L~ g (12.~ mtnoLe~) o.~ erythro-L-C4-~2--a~ldoetho~y)-phenylJ 1,2-diphenyl-3,3,3-trifluoro--propane, prepared as described :Ln 'E~a~pLe ~, are hydrogenated ~`o.r cLbout one hou.r in a rrli.xture of L00 ml of rnethlnol and l~o ml o:~ te~.r~ahyclrofuran, ln the pre-sono~ o~ 0, 6 ~ of a ~~0 pa'llad~ n-on-ca~ibon oatal~t~
The solutlon L9 e~aporated and tho re~Lclu-3 is oryq taL'LLæed :~.rom hoxane. 3 86 ~ (80.2 ~0) o:~ the desirecl 2~ oompouncl ax-e o'btal.ned; m.p~: L2~-L27 C.

~:~'7~3~
- 29 _ Analysis:
calculated for C23H22F3NO:
C: 7L 67 ~0, E: ~ 7~ %, F: 14~80 ~0, N: 3 63 %;
found: C: 7L.87 %, H: ~.7L ~0, F: L4.80 ~0, N: 3.~4 ~0.

Example 7 _eparation of _ -L-~4-(2-~zidoethoxy)--phenyl~-L,2-diph0nyL-3,3,3-trifLuoro---propene ._ _ LO 9.83 g (22 mmoLes) of ~E)-L-C4-~2-bromoethoxy~
phenyL~-L,2-diphenyL-3,3,3-tri~Luoro-propene are dis-soLved in 100 ml of 2~ethoxyethanoL, a soLution of 2D86 g ~44 mmoLes) of sodium azide in LQ ml of water i9 added, and the mixture is boiled for one hour~ The L~ reaction mixture i~ processed as described in Example ~, and the product i~ recrystaLLized twice from ethanoL. 7 40 g (82 ~o) of the aimed compound a~e obtained, rn.p : 73 -7~ C.
AnaLysis:
0 caLouLated for a23El8F3N30:
a 67 47 %~ ~: 4 43 ~%, F: L3.92 ~u, 'N: 10~27 %
~ound: a 67,61 %, :EI: L~ %, F: L3.77 ~o~ N: LO.LL %
The startLng ~ub3tance, ('E)~ 4-(2-bromo-ethoxy)-p~enyl~-L,2-d-LphenyL-3,3,3-tri~'luoro-p.ropene, ~ l~ prepared a9 fol'lows:

4~ 4 g (0.2 moLes) of 2,3-dichLoro-~,6-di-cyano-1,4-'benzoql1Lnone CD. 'WaLl~r et alA: ~. Org Chem.

1 ~';'~3S~

30, 3240 (L96~)~ axe added to a soLution of 44 7 g (0~1 moles) of threo-1-~4-(2-bromoethox~)-phenyl~-1,2--diphenyl-3,3,3~trifluoro-propane, pxepared as descxibed in ExampLe L, in 22~ mL of dxy benzene~ and the mix-ture is cooLed and the separated 2,3-dichloro-~6--dicyano-1,4-hydr-oquinone are fiLtexed off~. The fil-txate is evaporated to dryness, the residue is ad-mixed with 100 ml of chloroform, and the separated 2,3-d:Lchloro-~,6-dicyano-1~4~benzoquinone i9 fi~tered L0 o~f Tho filtrate is diLuted with 400 ml of chloro-fo~m, ~ashed with a L0 % aqueous sodium hydrocarbon-ate solution and then w.ith water, dried and e~apor-ated. The residue is crystaLLiæed from 220 mL of ethanol to obtain 34 4 ~ (77 %) of a crude product L~ melting at lL0-lL8 C This crude product, which is a 4:1 mi~ture of the E and Z isomers, is rocrystaLliæe~
from 200 ~1 of ethanol~ 29.~ g (66 %) of the E isomer are obtained; m, p,: 118-120 C
AnaLysis:
oa'lcuLatecl *or C23H~8BrF30:
C: 61.67 %~ H: 4~o6 %7 BX': 'L7,87 %~ F: L2 74 %;
Founcl: ~: 61,80 %, El: 4~L~ %~ Br: 17.~9 (70, F: 12~90 %.
Spoot.ra'L data: ~C~I 3060, 3020~ 2920~ 2900, 28~0 ~C=a 1~90~ 'L49 2~ ~r 81~, 822, 7~8, 70 ~OCH2 = 4 08 (t)y 2H
dBXa~I2= 3.46 (t)s 2H

Ar - 6 4-7 4 ~m), L4H

35~

The mother liquor obtained abo~e is evap-orated, and th0 residue is recrystaLlized se~eraL
times from ethanoL, 2,L4 g (4,8 ~) of (Z)-L-~4-(2--bromoethoxy)-phenyL~-L,2-diphenyl-3,3~3-trifLuoro--propene are obtained; m.p.: L3~-'138 C, SpectraL data: ~CII 3080~ 3060, 303~, 293~ 2870 ~C C L6Lo, L5L0 ~Al~ 832~ 770, 760, 7L~
~OCH2 4,28 (t), 2H
~BrC~I2 = 3~9 (t), 2H
3Ar = 6,8-7~4 (tn), 14H

~e~ ~
Preparation of (E)~ 4-(2-aminoetho~y)-L~ _phenyl~-1,2-cliphen~L-3,3,3-trifluoro--propene 7~40 g (18 mmoLes) of (E)-L-~4-(2-azido-ethoxy)-phenyl~-L,2-cdiphenyL-3,3,3-trifLuoro-propane, preparod ~ d~sori'bed in Examp1e 7~ are cllssolvod in 'L00 ml o~ mothano'L, 0,70 g o~ a ~% pa'Llacliulll-or1-oar'bon oata'lyst are adcl~cl, ,ancl the tllixture Ls hydrogenatecd ~or about one hour, Tho oataL~st is fiLterecl off, the soLut,Lon 1~ e~aporated, and the resicl1le L~ or~staLLLzed from hexane~ 3,63 g (~2,3 %) o~ the aimed compound are 2~ obtalned; m,p~: 7L -76 C, 3~

Analysis:
calcuLated ~or C23H20F3N0:
C: 72 0~ %, E: ~26 %, F: L4 87 %, N: 3.6~ ~;
found: C; 72.36 ~0, ~: ~.30 %, F: 14.88 %, N: 3.~2 ~/0.

ExampLe 9 _ Preparation of (E)-1,2-diphonyL-3,3,3-tri-~luoro-L-C4-(2-morpholinoethoxy)-phenyL~--prop0ne A mixture of 3.34 g (7 ~ mmoles) of (E)--L-[4-(2-bromoethoxy)-phenyLJ-L,2-diphenyl-3,3,3--tri~luoro-propene, p.repared as described in ExampLe 7, and L3 ~ of morp~oline is boiled for one hour The reaction mixture is proce~sed as described in ExampLe 1~ 1, and the crude product is cr~staLlized from hexane.
2 80 g (82 4 %) of the aimed compound are obtained;
m.p. 84-89 C.
AnaLysis:
oalculated for C27E26F3N02:
C: 71 ~L %, :E.[: ~ 78 %, F: 12.~7 %1 N: 3~09 ~0;
founcl: C: 71.80 %~ :EI: ~.98 'lo~ F: 12.70 %, N: 3.28 ~0.

~X~

-PreparatLon of (E)-1,2-dlphen~1-3,3~3-trl-. . , . _ _ 2~ :~L~oro-L C4-(2 /4-.lTIethylpLperazlno/-ethox~)-L~;o g of :N~meth~lpiperaæine are added to a : '.

sol~tion of 4.47 g (lO mmoLes) of (E)-L-~4-(2-bromo-ethoxy)-phenyL]-L,2-dlphenrL-3,3,3-trifLuoro-propene, prepared as described in ExampLe 7, in 80 mL of dry ethanoL, and -the mixture is boiLed for 6 hours, The 5 reaction mixture is evaporated to dryness, and then one proceeds as described in ExampLe L. The product is crystaLLlzed from hexane, 3,45 g (7~ %) oP the aimed compound are obtained; m.p.: 94-97 C, AnaLysis:
10 calcuLated Por C28H29F3N 0:
C: 72,08 yO, EI: 6.27 %, F: L2.22 ~0, N: 6,oo a~O;
found: C: 72.27 %, H: 6,32 %, F: L2,28 ~0, N: 5,77 %.

ExampLe lL
L~ Preparation of (E)-L72-diphenyL-3,3?3--piperazino/-ethoxy)-phenyL~-propene 1~ mixture of L,79 ~ (4 mmoles) of (E)-l--~4-(2-bromoethoxy)-phenyl~-L72-diphenyL-3,3,3-tri 20 Pluoro-propene, preparecl as de~cribed in ExampLe 7, and Lo.4 ~ of L~(2-hrdroxyHthy'1)-plpera~slt~e ;ls heated for ol~o hour. Th(3 mixture L~ proce~secl EIS deqcribed ln Example 'I, and the product i4 crystclllLæed Prom hexlne~ l.3~ (68 %) of the al~ned compour~cl ar~e ob-2~ taLned; rn~p,: 79-8L C.

i.~

7~33S9 3~

AnaLysis:
calcuLated for C29H3LF3N202:
C: 70.L~ %, H: 6.29 %, F: 11,48 %, N: ~,6Lf %;
found: C: 70.L~ %, H: ~.6~ ~0, F: LL,36 %, N: ~,48 %.

ExampLe L2 Preparation of (E)-L,2 diphenyl-3,3,3-tr~i~
fLuoro~ 4-(2-/2-hydroxyethylamino/-ethoxy)-

6,71 g (1~ mmoles) of (E)-L-C4-(2-bromo-etho~y)-phenyL~-1,2-diphonyl-393,3-trifluoro-propene, prepared as described in E:~ampLe 7, are dls~oL~ed in a mixture of ).1~ g of 2-amino-athanol and 1~ ml of 2-me-thoxyetharloL. The solution is boiLed ~or 30 1~ minutes~ and then the mixture is process~d as described in Example 2, The product is crystalliæecl from a l:L
mi~ture o:f e-thyl acetate and hexane, ~29 g (83 %) of the aimed compound are obtained9 m,p,: 96-98 C, Analys i9:
20 oaLculated f`or C2~1~I24F3N02:
a: 70.24 %~ ,66 %~ F: 13,33 %~ N: 3~28 ~o;
:found: (~: 70,1~2 %, ~it: ~.80 %, F: L3.39 ~o, N: 3,23 ~o, Ex:ulp'L~ L3 _.
2~ æh~ 3,3~3--tri:~Luoro-L- r 4 f 2-/bLs~2-hydroxye-thyL)-yl~~propen~

!~;.

3S~
-- 3~ --A soLution of 7,L~ ~ (L6 mmoLes) of (E)--l-C4-(2-bromoethoxy)-phenyl]-1,2-cliphenyL-3,3,3-tri-fLuoro-propene, prepared as de~cribed in ExampLe 7, in L6.8 ~ of diethanoLamine is heated at L20-L40 C
for 0.~ hours, and then one proceods as described in Example 2, The pxoduct is crysta.Llized from a L:l mixture of ethyl acetate and hexane, ~,66 g (7~ %) of the desired compound are obtained; m.p~: LL3,5-LL6 C~
Analysis:
L0 caLcuLated for C27H28F3N03:
C: 68.78 ~0, H: ~,~9 %, F: L2,09 %;
found: C; 68,7~ %, H: ~,78 %, F: L2.L3 ~.

.ExampLe L4 L~
fLuoro-L-C4-(2-/bis (2-chLoroethyL)-amino/--ethoxy)-pheny'L~-propene 3,6 mL (~0 mmoLes) of thionyl chloride are added to a solutlon of 2,36 g (~ mmoles) of (E)-1,2--diphen-yL-3,3,3-trLfluoro-l-C4-(2-/bis~2-hydro~yethyL)--am:Lno/-ethoxy)-pheny'l~ properle, prepared as desorLbed lt.~ E~alrlp'le 13, ln 12 mL o~ ohLox~ofo~sl, anq the mL~ture 1~ boLled for 2 hour~.. The exoess of thLonyl chLoride ls e~aporated Ln vaouo 7 and the req-Ldue is crystaLLized 2~ :~.r~om hexane. L,90 g (74~7 %) of the desi.red oompound are obtained; m,p~ 74-76 ~, "

63~S~

AnaLysis:
caLcuLated for C27H2~C12F3NO:
C: 63~.79%, H: ~,L~%, CL: L3,9~%, F: LL,2L~oJ N: 2,7~o;
found: C: 64,o3%, H: ~.03~0, CL: 14.00~o~ F 10.93%, N: 2,7~olo, Preparation of L-C4-(2-az-idoethoxy)-phenyL~--L-phenyl-3,3,3-trifLuoro-2-(4-fLuorophenyL)-_ opene lL.63 g (2~ mmoles) of L-~4-(2-bromoethoxy~--phenyl~-L-phenyL-3 t 3,3-trifluoro-2-( 4-f luorophenyl)--propene are con~erted in-to the a~ido deri~ati~e as describ~d in E~ample ~. The product is cryqtaLL-.ized ~roln ethanoL -to obtain 8,~4 g (80 %) of the aimed com-L~ pound; m.p,: 62-64 C.
AnaLysis:
caLculated for C23HL~F4N3:
~ : 64.63 %, H: 4,oL %, F: L7,78 %, N: 9.83 %;
found: C: 64,71 %~ H: 4.13 ~ F: L7..74 %, N: 9.63 %, 2() L-C4-(2-Bromoethox-y)-pherlyL~-:L-pheny:L-3,3,3--tx~l~'Luoro-2-(4-~'Luorophenyl)-propene, appLLecl a~
~tlrtln~5 gub9tanoe~ i3 preparod by the method of Examp'les '1 and 7 as ~oLLow~:
L~ ~-Fl~lo.ro-2, 2, 2-trlfLuoroacetophQnone ~F,E.
2~ Elerkes et aL.: J, O.rg, Chelll, 32~ L31L-18 (1967)~ is reaoted with benzyl-triphenyL-phosphoniuln ohloride in the presence o~ arl ethanol soLution of ~odium ethoxide, L-PhenyL-3,3,3-tri~luor~o-2-(4-fLuorophen~L)-propene is ~1 ` !

~ ~7~33~9 obtained with a yield of 9L %; b.p~ L10-LL4 C/0.2 mm H~, m.p,: 43-4~ C.
Analysis:
caLcuLated for CL~HloF4:
C: 67J67 %, E: 3.79 %, F: 28,~4 %;
found: C: 67~83 %, H: 3.90 %, F: 28.33 ~0.
This compound is h~drogenated in the pre-sence of a paLladium-on-oarbon cataL~st to obtain L--phenyL-3,3,3-trifLuoro-2-(4-fLuorophenyl)-propane L0 with a yieLd of' 9L.7 %; b~p~: 100-L04 C/0.2 mm H~;
nD = 1~4980A
Analysis:
calculated fo~ Cl~H12~4 0: 67.16 %, H: 4.~L %, F: 28.33 %;
1~ found: C: 67.30 %, ~: 4.68 ~0, F: 28.L8 %.
The above product is brominated in caxbon tetraohlor-Lde, and the brominated compound Ls crys-tal-Lized from ethanoL, l-Bromo-l-phenyl-3,3,3-trif`Luoro--2-(4-fluorophenyL)-propene i~ obtained wlth a ~ieLd f` 48.2 %; m,p,: L44-146 C, ~ naLy~Ls:
oa'lou'lat~d ~or a ~ BrFI:

~ : ~1.90 %~ FL: 3.19 %~ Br: 23.02 %, F: 21.89 ~0;
~o~mcl: a: ~L.70 ~, ~: 3JL8 %~ Br: 23,0(; ~0, F: 22.03 %.
2~ The br~omlnated compound is reaoted wLth anl301e ln the pre3ence of aLumLnium trlohloride. The resu'Ltln~
'L-phenyl-3~3~3-trLfLuc)ro-2-(4-fLuorophenyl)-l-(4-methox-sr 1~7~35~

phenyl)-propane (mixture of isomers) is crystaLLized from isopropanoL Yield: 79.8 /0, m. p.: 1~2-167 C~
Analysis-caLcuLated for C22HL8F40:
C: 70~8 ~0, H: 4.8~ ~0, F: 20.30 %;
found: C: 70.80 %, E: 4.78 alO, F: 20.40 %.
The above compound is heated with p~ridine hydrochloride, and the resulting l-phenyl-3,3,3-tri-Pluoro-2-(4-fluorophenyl)~ 4-h~droxyphe~yL)-prOpane is reacted directly, without puri~ication, with L,2--dibromoethane in the presence oP potassi~m hydroxide under heating. The resulting L-~4-~-bromoethoxy)--phanyL~-L-phenyL-3,3,3-trifluoro-2-(4-fluorophenyl)-propane is crystaLLi~ed .~rom isopropanoL; L~ to 20 ml 1~ of isopropanol are applied Por 1 g of the crude product.
The Pirst Praction, which is a mixture oP isomers, melts at 'L70-175 C.
Analysis:
caLculated ~or C23HLgBrF40:
a: ~9.LL %, H: 4.Lo %, Br: 17 10 %~ F: L6 26 ~0;
-~ound: C: ~8.88 alO~ .a: 4.21 %, Br: 16 96 %, F: L6.~o %0.
The mother lLquor is evapo.rated to clryness~

and tho solld Ls reorystaLlLzed Prom benzene ~ Inl oP

'ben~ene are appLied for 1 g oP the solid. The result-2~ in~ qecond Praotion, whioh Ls a mixture of Lsomers, me'l-ts at 100-110 C.

. ~

.

7~3 Analysis:
calcuLated for C23HlgBrF40 C: ~9~LL ~0, II: 4.Lo %, Br: L7.L0 %, F: L6026 ~0;
found: C: ~8.96 %, H 4.07 %9 Br- L7.0~ %, F: L6~32 %.
The abo~e two fractions are combined and hoiled with 2,3-dichlo~o-~,6 dicyano-L,4-benzoquinone for 2~ hours as described in ExampLe 7~ The product is crrystaLLized from ethanoL. l-C4-(2-Bromoethoxy)--phen-yL~-l-phenyl-3~3~3-t~ifLuoro-2 (4-fLuorophenyl)-L0 -pxopene is obtained with a yieLd of 66.~ %; m.p.:
Ll~-lL8 C.
AnaLysis:
caLcuLated for C23~IL7BrrF40 C: ~9.37 %, H: 3J68 %, Br: L7.L7 %, F: L6,33 ~0;
L~ found: C ~9.48 %, H: 3.87 %, Br: L7.L9 %, F: L6.~L %.

E ~
Prepar~ation of L-C4-(2-aminoethoxy)-phenyL~--L-phenyL-3,3,3-tri~'luoro-2-(4-fLuorophenyL)=

-prope~e ~ soLutlt~n of 8.~l~ B (20 nmlo'Los) o* L-~
-(2-azlcloetho~ phonyL ¦-L-pheny'L-3~3~3-tri:l~luoro-2-(L~--fLuorophenyL)-propent-~9 prepart-~cl a~ desorLbed in Example L~, Ln 170 ml o* methano'L i~ hydro~enated ~or a`bout one 2~ hour in the preserloe of 0.9 g o* a ~ % palladi~ orl--oarhorl oatalyst~ The solution is e~aporatecl and the product L3 orys~aLLiæed ~rom hexane. 4~51 g (~6~4 %) .~

~:~'7~
39a -of the title compound are obtainecl; m.p,: 83-89 C.
Ana ly9 is:
calculated for C23HLgF4N0:
C: 68.82 %, H: 4.77 ~0, F: L8.93 %, N: 3.49 %;
found: C: 68.93 ~0, H: 4.g9 %, F: L8.83 ~, N: 3.33 %.

~1~ .
Preparation o~ L~phenyl-3,3,3-tri~L-uoro-2--(4-fLuorophenyL)-L ~4-(2-morpholinoethoxy)-L0 -phenyL~-propene 3.2~ g (7 mmoles) of 1-[4-(2-br~moethoxy)--phenyl~-L-phenyl-3,3,3-trifLuoro-2-(4-fluorophenyl)--propene~ prepared as described in Example 1~, are reacted ~ith morphoLine as described in Example 1.
L5 The product i9 crystaLli~ed frotn hexane~ 2.~ ~ (75~7 ~0) of th~ aimcd compound are obtained; m~p~: 67-69 C.
Analysis:
calculated for C27E2~F4N02:
C: 68~78 %, H: ~3~ %, F: L6~L2 %, N: 2,97 ~0;
~ound: C: 68.62 %, EI: ~.94 %, F: L6.40 %, N: 3.L4 %~

'~.~
Prcparatlon o~ 2-phenyL-3,3,3-trL~lu~ro--L-(4-~LuorophenyL)-l-C4-(2-tnorphoLlnoethoxy)-2~ -phe~yl]-propene ..,_ 3.2~ g (7 mmoLe3) of L-C4-(2-bl~omoethoxy)--phenyL ¦-2-phenyl.-3,3,3-trifLI:loro-L-(4-:ELuorophenyl)-i,~;' ~7~35~

- 39b --propene are reacted with morphoLine as descxibed in Example L The product is crystallized from hexane.
3.03 g (92 %) of the aimed compound are obtained;
m~p : 9~-96 C.
AnaLrsis:
caLcuLated for C27~I2~F4N02 C: 68.78 %, H: ~3~ a~o~ F: 16.L2 ~0, N: 2~97 %;
found: C: 68,96 %~ H: ~ 83 alO~ F: L~.98 alO~ N: 3~00 %.
L-C4-(2-Bromoethoxr)-phenyL~-2-phenrL-3, 3 ~ 3--trifluoro-1-(4-fluoxophenrl)-propene, applLed as startin~ substance~ is prepared accordin~ to the method of E~ample 1 as foLLows:
2~2~2-1`ri.Eluoroacetophenone is reacted ~ith -triphenyl-(4-fLuoroben~rl)-phosphonium chLoride CR.A~
1~ Jon0s: Australian J. Chern. 18, 903-6 (196~)~ in ethanol in the p.res~nce oE sodium ethoxicle. 2-Phenyl-3~3~3--trifluoro 1-(4-fLuorophenyL)-propene is obtained with a yield o~ 90 %; b,p.: 10~-L07 C/0.2 mm Hg, m~p, 3~-41 C.
~na'l.~sLs:
oa:Lou'lateCl for CL~HL0Fl~:
C~: 67,67 a~O~ :Ll: 3.79 %~ F: 28,~4 %;
:Eou~.d: ~: 67~8 a~O~ ~: 3.9~ %~ F: 28.~0 ~o, The abo~e procluct Ls h~drog--~natecl ~-Lth a 2~ paLLacl;il:lm-on-carb~n oataLyst to obtain 2-phenyL-3~3~3--trLfL-uoro-L-(L~-fLuorophen~L)-p.ropene with a yieLd o:E

9~ %; b~p,: 9~-100 a/o. 3 mm Hg, ,~./.. .' 3S~
-- 39c --AnaLysis:
calcuLatod for CL,,~EL2F4:
C: 67~L6 %, EI: 4.~L %, F: 28.33 %;
found: C: 67~22 %, H: 4J73 %, F: 28.40 %, ,,~ The obta1ned product is brominated in carbon tetrachLoride, and the resuLtin~ L-hrorno-2-phen~1-3~3,3-trif1uoro~ (L~-~luorophenyL) propane is cry-staLLized from ethanoL. 3.,~ rnL of ethanoL is appLiecl for one ~ of the soLid. The obtained first fractiorl, L0 which is a mixture o~ isomers, rneLts at L43-L4~ C.
AnaL~sis:
caLcuLated for CL,~ILlBrFL~:
C: ~L,90 %, H: 3,L9 ~o, Br: 23.02 %, F: 2L~89 ~0;
fol:lnd: C: ~L.9L %, E: 3.L3 %7 Br: 22"92 ~0~ F: 22.o6 %0 L~ The mother Liquor is e~aporated to a'bowt one--third of' its originaL ~oLuma, The obtained seconcl frac~
tion, a mixture of -Lsomer~s, meLts at 69-76 C.
AnaL~rsis:
oaLo~lated for CL~E1LBr~F4 20C: ,~'L.90 %~ 'fC: 3.1~) %, Br: 23.02 %~ F: 2L,89 %;
~o~-Lnd: C: ~L.74 %, EC: 3.33 %7 Br: 23108 %7 F: 22.02 j~.
The tota'L rie'Ld amoLlnts to 76 %.
The above fraotLons are oom'binecl ancl reaotecl hr;Ltt,l arl:LsoLe Ln the presence of a1LLm;LrlLLlrn txich'Loricle, 2~ '[`he restlLt-,Lng 2-pheny'1-3~3~3-trif'luoro-L-(4-:~Luoro-phenyL) L-(LI-rnethoxyphenyl)-propane is crrstaLLized frorn ethanoL. 4 mg o~ ethanoL are appLLecl for L g of 35i~
- 39d -the solid, The ~irst fraction, a mi~ture of isomers~
meLts at L20-L27 C, Ana Ly9 is:
calcuLated for C22~IL8F40:
C: 70,S8 %, H: 4,8~ %, F: 20,30 %;
fo-und: C: 70,81 %, H: S,OL %, F: 20.3~ %.
The mother liquor is concentrated to about one-si~th of its originaL ~oL~e, The resuLting second ~raction, a mixture o~ isomers, meLts at 84-9~ C.
AnaL~sis:
calculated for C22HL8F40:
C: 70,~8 %~ H 4,8~ %, F: 20.30 %;
found: C: 70~72 %, H: 4,92 %, F: 20,L8 ~, The totaL yieLd amounts to 78.8 %, LS The above fractions (mi~tures of isomers) are combined and heated with p~ridine hydrochLoride, The rasuLting crude ~-phen~L-3,3,3-tri~Luoro-1-(4~
-fLuorophenyL)-L-(4-hydroxy-'`,`"''`~

~7~3 phenyl)-propane i~ reacted directlyg withQut puri~ication~
with 1,2-dibromoethane in the presence of potassium hydro~lde.
~he resulti~g 1- ~ (2-bromoethoxy)-phe~y~-2-phe~yl-393t3-~ri-~luoro~ fluorophenyl)-propane is cry~allized ~rom etharLol.
5 4 ml of e~ha~ol are applied for 1 g o~ tha ~olid,. ~he ~ir~'G
~r~ction,, a mixture o~ isomers, mel~s at 119-123C~, ~ nal~sis ~
c~lculated for C23HlgBrF40:
C: 59~11 %9 H: 4010 æ, Br: 17010 %, F: 16.26 %;
~ourld: C: 59~30 %, H: 4016 y~, :Br: 17.03 ~9 F: 16.26 5~.
~ he mo~her liquor i~ evaporated to aboll~ one-hal~
o~ its origi~l volume. The obtained second ~rac~ion~ a mi~-~ure o~ i~omer~, melts at 7~74C.
~ alysi~:
15 calcul~ted for C23HlgBrF~,~:
C: 59.11 %, H: 4.10 %, Br: 17010 %, F: 16,.26 %;
~ou~d: C: 59D27 ~ H~ 4.,30 %~ Br: 17.13 %, F~ 16.3~ ~.
~ he above ~ractions (mixtures of isom~rs) are com-blned and reacted with 2,3-dichloro-5,6 dicyano-1,4-bsnzo;-20 quinorLe in be~e~e under bolli~g, as de~cribed in E~ample 7.The reaction ~i~ture is proca~ed as de~cribad in ~ample 79 ~d th~ product i~ cry~tallizod ~rom i~opropanol~ (2-bromoetho~y3~phan~ ~-2 phonyl-3,3,3-briPluoro-1-(4-fluoro-phenyl)-prop~ne 1~ ob~ained wibh a yi~l~ o~ 58.4 %9 m.p.:
1~2~14~~.
A~ly~is:
c~lcul~ d ~~ a23~17Br~4 c: 59037 ~/o~ H: 3.68 %, Br: 17u17 '~0, F: 16~33 %;
founds ~: 59.20 %, ~: 3.90 Y~" Br: 17.36 %, F: 16.20 %D

.. eJ~, ~

'7~S~

Pr~parabion~o.f~
=~b~3yL=~hlb~= ~ ro~
-39 g ~t~7 g~-atanS) ~ sodium are dis301ved i~
7.12 g (35 mmole~) of 2-dimethylamino~ethanol~ 3015 ~ ~805 mmole~) of 1 pheDyI 3j3,3 brifluoro-].-(4~1uorophe~yl3-2~
me~ho~yphe~ propen~ are added to th.e solution9 and the mix-.
tur~ i8 heated at 150~155C ~or one hour. The rea¢bio~ mixture i~ cooled, diluted with 200 ml o~ ~bher) wa9hed wibh wa~er until n~utral, dried and e~aporat~d~, The resi~ue is di~olYed in 30 ml oî ho:~:a~e3 bhs solution i9 ~iltered~ and bhe filtrate i3 evaporated. 3039 g (90 70) of l~ dimebhyl~mino-ebhoxy~
phe~ phenyl-3,3,3-tri~luoro-2~ methoxyphe~yl)-propene ara obb~ d as ~ resinou~ ~ub~bance; bhe produ¢t i~ ~ 3:4 mixture oî bhe (~) and (E3 i~omer~
~naly~
calculaSed for C26H2 ~ 3~0~:
C: 70073 ~0, H: 5.94 %, F: 12091 %, ~: 3017 %;
~o~d~ C: 70~65 %, H: 6.07 %, F: 13.05 %, N: 3.26 %.
l~Pho~yl-3,3,3-triPluoro-1~(4-~luorophe~J.)-2~(L~
methoxyph0nyl)-propa~e~ applied a~ sbarti~g substan~e, i~ prs-p~red a¢cordinæ ~o the method of ~xampl~ 1 a~ ~ollow~:
4~-Mebhoxy-2~2,2-bri~luoro~cebophenone ~ ~, ~uch~s J. Or~. Chom. 22~ 99~_99L~ ~195'7L7 i9 rea¢t~d wibh triph0nyl-25 (4~fluorob~nz~ pho~phonium chloride (~e~ ampl~ :L8) in~abha~ol in th~ pr~nce o~ ~odlum othoxida. 3,3,3-~ri~luoro-~ luorophenyl)-2-~4-methox~p~en~ prop~n~ i~ ob~flined wlbh a yl~ld o~ 87 ~0; b~p,: 138-142C/005 mm ~gO
An~ly~
calcLllat~d Por ~16~

~:~'7 - ~2 -C: 64.86 %~ ~: 4.08 ~0, ~: 25~65 %9 found: C: 65~03 ~0, H: 4.27 %, ~: 25.40 %.
~ho above compound is hydr~ge~ated i~ the prese~ce o~ a palladium-on-carbo~ cataly~t to obtain 373,3-tri~luoro~
1-(4~1uorophe~yl3-2-~4-m~bhoxyphen~ propa~e wlth a yiald of 93 ~0; b.p.: 134~136C/0.4 mm Hg, ~ - 1.5070.
A~aly~is:
calculated ~or C16~14F40:
Cs 64.43 %, H: 4073 ~/0, F: 25048 ,~;
found: C: 54~60 %, H: 4085 %, F: 25.~5 %0 ~he ~bove compound i~ bromin~bed in carbo~ tatra-chloride, and th~ producb i~ cry~tallized from h~xane. l-Bromo-3,3,3~tri~1uoro-1~(4~Pluorophenyl)-2-(4-me~hoxyphe~yl)-propan3 (mixture o~ i~omers) i~ obtain~d with a yiald o~ 49 %;
mOp- 7~-94a.
Anal~si~:
calculatod Por C16Hl~BrF40:
C: 50~95 ~ .L~7 %~ Br: 21.19 Y0, F: 20~15 %;
found: C: 50.82 %, H: 3060 %~ Br: 21.11 %9 F: 20030 ~.
~he ~bove aompound is reacted w~th b~n~ene in ~he pre~e~ce o~ alumi~ium trichloride~ a~d the re~ul~ing l-ph~nyl-3,3,3-~bri~luoro-1-(4-Pluorophe~yl)-2~(4-mebhoxyphe~yl)-propane 1~ cry~tallized Prom i~oprop~olO 5 ml oP isopropanol are applied Por 1 g of the solid~ ~he Pir~t .~raat~t a mixture oP i~omers, melt~ ab 126--145C.
Anal~si~:
~lculat~d ~or ~22H18~4 C: 70.58 %, H: 4~85 ~0, F: 20.~0 70;
~ound: C~ 70~77 %, H: 4.67 %~ F: 20.45 ~70.
~h~ mother liquor i~ evaporated to one-Pifth oP it5 3~

original volume. Th~ re~ultin~ s~3cond f`raction~ a mi~ture of isomer~, m~lts a ~ 102-110C .
Analysis:
calculated for C22~Ilg~40:
C: 70.5~ Yo7 H: 4.85 570~ ~: 20330 %;
îound: C: 70.65 ~07 H: 4080 ~0~ F: 20~51 %.
~ he abov~ two fra ctions are combined and r~aoted wikh 2,3-dichloro-5,6-dicyano~ benzoqulnona as de~cribed in Example 7 ~or 120 hours under boili:ng. ~he product i~
10 crg~tallized from i~opropa~olO l-Phe~ ,3,3-triîluoro~
~luorophe~l)~2-(4-methoxyph~ prope~s is obtailled with a yield o~ 62 %; m.p.: 113-120CD
~n~l~si~:
~alcula~ed for C22~ LO
C: 70c,96 ,~0, fI: 4033 5'0, F: 20041 %~
fou~d: G~ .17 %, H: 4~48 %, F: 20.70 %,, ample 2Q

0046 g (OrO2 g.-a~oms) o~ sodium are di~olved 405 g ~50 mmoles) of 2-dimethylamino-ethanol,, ~o72 g (10 mmole~
o~ ~phe~1-~,3,~-trifluoro-1-(4-~luoroph~ 4-metho~y-phonyl)~prope~e are added to ~he ~olubio~, bh~ mlxture ia hoat-~d a~ 150-155C ~or one hour, and the~ p;roce~ed a~ de~cribed 1~ ~xample 19. 3.95 g ~890~ %) o~ (2 di~th;ylamino-ebh-ox~ ph~n;y~ pherurl-3, ~93-tri~luoro~1~ metho~rphengl) -propene ~xe obtai~ed ~ a re~i~ou~ ~u~s~ e; ~ha produc~ i.B
a 9:1 mixSure o~ the (Z) a~d (æ) i~omer90 An~ l~si~:
~0 ¢alculabed ~or C26H26F3N0 C: 70.73 ~, H: 5094 %, F: 12.91 %, N: ~.17 %;
found: C: 70.50 %, H: 6~11 %~ ~: 12.73 %, N: 2.91 %.
2-Phenyl 3,373-triîluoro-l-(~fluorophenyl~ bh-o~yphen~ propane, applied as starting sub~tance, i8 preparsd 5 as ~ollows:
2-Phe~ 3,393-tri~luoro 1~ fluorophsnyl)~ meth-oxyphe~yl)-propane, prepared a~ described in EXample 18, i~
reac~d wi~h 273-dichloro-5~6-dicyano~1,4-benzoquinona under boiling for 8 hour~ as described in EXample 7. ~he reacbion mixture i~ proce~sed, and the product i~ crysballizad from ethanolO 2 Phenyl 3,3, 3-tri~l uoro-l- ( 4-~luorophenyl ) -1~ ( 4~m~ th~
oxyphenyl~-propene ls ob~ained with ~ ~ield of 51 %; m.p.:
52-56C.
~aly~
calculated ~or C22H16F40:
C: 70096 ~0, H: 4.33 ~, F: 20.41 %;
îound: a: 71.22 ~0, H: 4~51 %, F: 20~54 %0 E:~
Prepara ~orl of 1-/~ ( 2-dime thYlamino-e~ho~y]=~Z
20 l-~he~yl 3, 3, 3-~ri~luoro-2~ b;sTdro~h~nyl~-pr~opene h;ydro-chl 0076 g ~1062 mmoles) of 1~ (2-dimeth~lamlno-etho~
phe~ ph~ 3, ~, 3-triîluoro -2-~r~ ( me thoxy-m3 ~ho:l~y) -phen~
prope~e ~re di~olved in 8 ml of a 1i'o metiha~ollo hydrochloric 25 ac~d. ~h~ ~olubio~ i~ hea~0d for 0c5 hour, ~he~ evapora~ed, a~d the product i~ cry~t~llized from i~opropanol" 0.56 ~; (7~ %) o~ thfl aimed compound i9 obtained; m.p~: 196-220C,.
Anal~si3:
calcula ted ~or a2s~25clF3~o2:
C: fi4~7~i~o~ H: 5.~%9 Cl: 7~64%, F: 12.29%,, N: 3.02%;

~'7~359 -- 1~5 --fou~d: C: 64.51%, H: 5.31%, Cl: 7.4~0, ~: 12.51~ N: 2.~4%~
~ 2- ~athylamino-ethoxy)-pheny ~ -1 phe~yl-3,393-tri~luoro-2-~,~ ( me thoxy-ms thoxy) -pheny~7-propene, applied starting substance, is preparsd as follows:
~ mixture of 18072 g (50 mmoles) of l-phanyl~393,3~
tri~luoro-l (4-fluorophenyl)-2~(4-methoxyphenyl)-propa~e5 pre-pared as described in ~'xample 19, a~d 56 g of pyridine hydro chlorid~, ls h~ated at 200a for 3 hours, and then processed as describsd in Exampla 1. ~he resulting crude l~pheDyl- .
3,3,~-tri~luoro-1-(4-fluorophe~yl)-2-(4-hydroxyphenyl)-propa~e then i9 dissolv~d in 70 ml o~ benzene,/6.44 g ~80 mm~le~) o~
ch}orom~th~Tlether and 6 g (300 mmoles) oî powd~ered sodium hydroxide are addsd, and the mixture i~ boiled ~ar one hour~
~he :reaction mixture i8 diluted with 100 ml o~ benzene, washcd 1$ until nsutral with a 20% aqueou~ ammo~ium chloride solution, dried and aYaporatad~ The rssidue is cry~tallized ~rom iso-propanol. 12.54 g (62 %) o~ 1-phen~ 3,3-trifluoro-1-(4-~luorophe~yl)-2- ~ (methoxy-methoxy)-phen~ ~ -propa~e are ob-tained; m.p.: 96.5-99C~
Analg~is:
calculated for C23H20FLI.02 C: 68.31 %, ~,.99 %, ~: 18.79 ~0; .
~ou~d: C: 68.45 %, EI:5.07 %, ~: 18.73 %.
12~13 ~ (30 mmole~3 of the abovo compound are boilad wlth 13.62 ~ l60 mmole~) of 2, 3-dichloro--5,6 dicya~o-1,4--benzoquinone in be~ze~e fox 120 hour~ ~he reaction mixture i8 proce~ed ~ de~cribed in ~'xample 7, and the producb i~
~ tallized ~rom isopropanol. 3.38 ~ (28 %) of l-phenyl 3,3,3~trifluoro~} (4-~luorophenyl)--2-~4-(methoxy-metho~y)-~ p~n~
3~ ph~ny ~ -~r~p~ are obtained; m.p.: 85~88C.

11 7~35;9 - ~6 -Analysi~:oalcul~ted ~or C23H18~42 C: 68.65 %, H: 4.51 c~O, ~: 18~89 %;
~ound: a: 68,78 ~ 4.65 %~ ~: 18.81 %0 0.09 g (0~004g_a~s)0~ sodium are di~solved i~ 0089 g (10 mmoles) o~ 2-dimeth~lamino-ethanol. 0.80 g (2 mmole~) o~
the above compou~d are added~ and the mixture is rea¢ted a~
des¢ribed in Example 19. 0.76 g (80.6 %) of 1-~(2-dimebh~
ami~o-stho~y)-phe~y ~ _l-phs~l 3,3,3-trifluoro 2~ tmebho~;
msbhoxy)-phsny ~ ~propene i9 obtai~d a~ a rssinou~ sub-~ance, whiah ca~ be utilized in the subsequan~ s~sp withou~
puriî~ cation.
xamPle 22 2.06 g (4.56 mm91a~ of 1~ benæ~lox~phen;yl)~
( 2-dima th;srla mino-e thoxy) -pheny~7-2-phe~1-3, 3 9 3-~riIl uoro-propene are di~olvad in 45 ml oP acetic acid an~ hydroge~at-ea i~ the px~senc0 of 0~,5 g o~ a lO~o palladium-on~-carbon 20 cataly~ he ~olution i~ evapora~ed and the residue i~
c~y~tallizsd ~rom e~her. 0~77 g (39,5 ~) o~ ~he al~ed com-pound is obtained; m.p.: 149-155C~, A~lysi~:
c~lcul~b~d for C25~24~3~ 2 25a: 70024 %, H: 5.66 ~0, F: 13.33 æ, N: ~.28 %;
~ounds a: 69.92 %, H: 6.1Z o~O~ ~: 13,.28 V/o, N: 3~38 yO~
1- ~ 4-B~z~loxy-phe nyl) ~ ( 2-di ms bhylflmino-~ tho~;sr) -E~hen~;~7 2-phsrl;yl-3,3,3-~ri~luoro-propen~, appli~d as starti~s ~ub~tanoe, is prepar~d es follows:
2-I'henyl-~,3,3-tri~luoro~ 4~1uorophenyl)-1-(4-mebh-~ t7 - ~7 -oxyph~nyl)-propa~e, prepaxed as described in ~ample 189 i~
reacted with pyridine h~ydrochioride as describeà i~ ~a~npla 1~
and th~ r~sulting 2~ phenyl-3~3~ rifluoro-1-(L~fluorophen;srl)-1-~4~hydroxyphenyl)-propane is reacted wlth benzyl chlorida in ethanol solu~io~:L, in the presence of sodium hydrvxide.
The product i9 cx~Tst~llized from ethanol. 1~ e~zyloxy-phenyl)-2-phenyl-373,3-tri~luoro-1-(4-fluorophenyl)-propa~e i~ obtained with z yield. o~ 64 ',~; m.p.: 104-125C.
An~ly~is:
calcula~ed for C28H~2F40:
C: 74.65 %, H: 4~92 ~" F~ 16,87 ~;
found: C: 74~,82 %, H: 4.68 5~, F: 16.92 ~. .
~his compound is rsacted with 2~3-dichloro~5,6-di-cyano~l,4 benzoqui~one ~or 6 hours a~ described i~ ~xample 7~
The obtained product is cry~allized from athanol. 1-(4-Be~z~l-~rop~
1~ oxypheDyl)-2-phenyl-333,~-trifluoro-l-t4--fluorophenyl)~e i~ obt~ined wi~h a yield o~ 24.5 %; m.pO~ 114C.
Analy~
c~lculated for C28H20F40:
C: 74O99 %, H: 4.50 %, F: 16.94 %;
~ound: C: 75.17 %, H: 4.81 %, F: 16.91 %.
Th~ oompound is reacted wi~h a ~olu~ion o~ 2-di-~th~l~mL~o~eth~ol snd sodium e~ describ~d in ~:ample 19.
q~he re~ulti~ ~bonzyloxyphe~rl) l~ (2-dimqthylamir~o-ethox~)_phe~y ~ ~2~phenyl-3,3,3-brifluoro- ~ c~n be appliod in the subsequ~n~ stop without purificationO
~` m~
Pr~paret;ion e~ threo-1,2-diEh~n~ luoro-~ (methox~-m~th ~
2 g (50 mmole~) of sodium h;ydroxide and 4 g (50 mmolea) ~'7~3S9 of chlorome~yl ether are added to a ~olutio~ o~ 10~26 g ~0 mmole~) of ~hreo-192-diphenyl-3"3"3-triIluoro~ ydro~-phenyl)~propane, prepared as de3cribed in ~ample 1~ in 40 ml o~ benzene, and the mixtur~ i~ boiled ~or one hour. The reac~
5 tion mixture i~ diluted wi~h 100 ml o~ benzene9 ws~hsd wi~h a 20~o squeou~ ammo~ium chloride solution, dried alld ev~porat~
ed. ~he residue iq crystallized from isoprop~ol., 7~.45 g (64.2 ,%JI of the almed compound are o~ai~ed; m.pO: 100-103C.
A~ly~
calcul~ted for C23H21~32 C~ 71049 %;, H: 5.43 ~0, F: 14.75 ~;
~oulld: C: 71.72 ~0, H: 5~71 ~ 14691 %
:~;xample 24 0"48 g ( 12 mmole ~) oî sod~um hydroxide and 9 .2 g ( 100 mmole~) o~ 1 ,2-epoxy-3~ohloropropane are added ~o a solut~o~ o~ 3.42 ~ (10 mmole~) of threo-1,2-diphsn~ 3,3,3~
tr~luoro-1-(4--hydroxyphe~ propar:le 7 prepared a~ d~scribed 20 in Bxample ls in 40 ml o~ ethanol, ~nd the mi~ture i~ boiled ~or o~e hour. ~h~ reactlon mixtAr~ is evaporated, ~-bubanol ~ gain i~ uddad to the residue, and th~ mix~ura i~/~vaporated.
'rhe re~idue i~ dilul;ad wibh 30 ml of dichlorom~thane, w~hed wl'Gh wab~r, dri~d und 25 e~porab~d. 'r'he re~idue ~ ¢ry~tallized ~rom metha~ol, 2~85 g ~71.6 %) o~ the aim~d compound are obt~i~ed; m.p.: 113-116C.
Analy~
c~lculabad ~or C2L~H21~302 a: 72~5 %, ~I: 5~31 "~o~ 14~31 ~o;
~0 fou~d: a: 72.26 %, H: 5014 %, ~ 1LI~.LI.7 0~O.

ExampLe 2~
__ Prep~ration o~ erythro~ 4-(2,3-epoxy-propoxy)-phenyL~ 1,2-diphenyL-3,3,3-trif1uoro--propane 4.28 ~ (12~ mmoles) of e.r~thro-1,2-diphen~L-3,3,3 trifLuoro-1-(4-hydroxyphenyL)-propane~ prepared as described in E~ampLe L, are reacted with 'L,2-epoxy--3-chLoropropane in the presence of sodiwm h~droxide a~ described in E~ampLe 240 The product is recrysta1-Lized twice from methanoL. 2~18 ~ (44 ~) of the aimed compound ar0 obtained; m~p : lL5-118 C.
Analysis:
caLculated for C24H2LF302:
C: 72.35 ~0, lI: 5.31 %, F: 14~31 %;
L5 found: C: 72.L8 %7 H: ~r46 ~, F: L4.37 %.

E~ample 26 Preparati.on of (E~-l.-r4-(2,3-epo:~ypr~'l::
-phen~'LJ -L 7 2~diphenyl-3,3,3-tri~Luoro propen~
0.29 g (L2 mmoles) of sodiwm hyclr-Lde are addecl to a soLut10n of 3~40 ~ (:L0 mmo:Les) o~ (.E)--1,2-d:iphen~'L-3,3~3-trl.~:Luoro-L-(L~-hydro~yphen~L)--propene in 30 m'L o:~ cl.ry 'benzene, ancl t'he mLxt-u.re i~

~1;1.rrecl fo.r 0.5 hour-s. Theroa:~ter '1.39 ~ ('1.~ nmloLes) 2~ of 'L,2-epoxy-3-oh'Loropropano a.r0 1ntroduc0d~ ancl the Illi~ ture ,i9 heatecl:~or ~ hours. The .reaotLon mLxtu.re 1.~ cli'Luted with 70 mL of benzene, washed with water, d~led, e~aporated~ ancl the resldue is crystaLLized - 49a -~om ~ethanoL. 2.46 ~ (62 %) of -the airned compound are obtained; m~.p~: 73 a ~~70 c AnaL~sis:
caLculated for C2L~HLgF30 C: 72.72 %~ H: 4~83 %~ F: L4938 found: C: 72.89 ~0, ~: 4.88 %, F: L4~6L %~

~L7~3~3 t~)-1,2 Dipheny~ 3~3-trifluoro-l-(4-hydroxyphenyl~-pxopene, applied as startin~ sub~tance9 i8 prepared a~ follows:
2~2 g (55 mmoles) of sodium hydro~ide and 6c9 g (55 mmole~) o~ b~nzyl chloride are added ~o a ~olutiorl o~ 15.4 g (45 mmole~) of 1 92-diphenyl-393,3-~xifluoro~ ydroxyphenyl)-proparle, prepared as described in :Example 1~ 75 ml of e~hanol~
snd ~he re~ulting mixture i~ boiled for one hour. The reaction mixture i~ diluted with 300 ml OI wa~er, neutralized with ~n 1 n aqueous solu~ion o~ hydrochloric acid, and extracted with 200 ml of chloroform. The or~;anic phase is wa~hed with w~ter, dried and evaporatad. ~he residue i~ crystelliæed ~rom ethanol.
17 g (86.6 ~) oî ~he produc~ are obtained; m,p.: 94-118C.
Analysi~:
calcul~ted ~or a28H23F30:
C: 77.76 G~o~ H: 5.~6 %, ~: 13.18 %;
~ou~d~ C: 77.95 %, H: 5.44 %, ~: 13.42 ~0 ~ mixturs of 16.42 g (38 mmole~) o~ the above produot~
17.25 g ~76 mmole~) o~ 2,~-dichloro-5~6-dicya~o-1,4~benzoquino and 80 ml of be~ze~e i8 boiled ~or 2 hour~ and th~n it i8 prcces~ea ~9 de~cribed in ~xample 70 ~ho p~oduct i~ cry~ ed ~rom ethanol. 6.21 g (38 %) o~ (E3~ 4-benzyloxyphenyl)-1,2-di-phcnyl-3,3,3-tri~luoro-prop~ ar~ obtai~ed; m.p.: 128-129C~
Analy~
~lc~l~b~d ~or C2~H21~3: .
~5 ~: 78013 %, H: ~o92 ~, ~?: 13.24 %;
~ound: C: 78.34 %, H: 5~10 C~o~ F: 13.2~ %.
~ h~ NMR 3pectrum of the product co~firms the structurev 6.02 g (14 mmoles) of` the above product ~re hydrogenat-ed in a 1:1 m ~ure o~ methanol and tetrahydrofuran in the pre~ence o~ e 57v p~lladium-on~c~l~bon c~t~lyst. The solution i3 ~:~'7~s~a e~aporated and the residue is crystaLLized from a L:2 mixture of chLoroform and hexane~ 3,~0 g (73.~ 3~0) o~ (E) L,2-diphenyL-3,3,3~trifLuoro-L-(4-hydrox~rphenyL)--propene are o'btained ; m, p,: LL3-L20 C~
Ana Lys i s:
caLcula-ted for C2lHL~;F30:
C: ~L~,Ll 9~o~ EI: 4,1~4 %, F: 16,7~ alO;
found: C: 74, L7 %~ EI: 4. 8~ ~0~ F: 16. ~3 ~.

10ExampLe 27 Preparatio7l of 1-~4-(2~3-cpoxypropo~)-~=~
- ( 4-chLorophenyL ) -propane 0.8 ,g (20 mmoles) of sodiurn h~rdro~ide and L~ 14~.8 ~ (160 mmoLe~) of 1,2-epoxy-3-chLoropropane are added to a soLu-tion of` 6,o3 ~ (L6 mmoLes) of l-phenyl--3 ~ 3, 3 -t rif luoro -1- ( 4 -hydroxyphenyL ) -2 - ( 4-chLorophenyl ) --propane in 60 ml o~ me thanoL. The mi~ture is 'boiled for 2 hours and then processed as descri~ed in Example 2a 2~, The product ,is cr~rstaLlL~;ed froln metharlol. 4.44 g (6l! %) o~ tho a,imed compound are obta,LrLecl j m~ p.:

LL~ 'Ll.~l~ (`~
Ana Lys ,Ls:
ocllou'Lat(3d l~or C2L~H20ClF302:
2~ C: 66,~i9 '~ E: 4,,66 %7 CL: 8.'L9 %~ F: 13.17 %
fol;lnd: C: 66,71 %~ EI: ~,0~ %, Cl: 8.3~ %, F: 13~29 %, l-Phen~ 'L-3 ~ 3 1 3 -t r~Lf luoro ~ L- ( 4-h~droYyphenyL ) -1~ 7~35~3i - ~La --2-(4-chlorophenyL)-propane, appLied as startin~ su~-stanee~ is prepared by the method of ExampLe L as follows:
4'-ChLoro~2~2~2-trifluoroacetophenone CR.
~uohs~ J. Or~. Chem. 22, 993-994 (L9~7)~ is reacted wlth bonzyL-trlphenyL-phosphonium chlorid~ in th~
presenee of an ethanoLie soLuticn of sodium etho~ide~
The produot is crystaLLized from hcxane~ L-Phen~L--3,3,3-trifLuoro-2-(4-ehLorophen~L)-propene is ob-10 tain0d .

:

, . ~ . . . .
' s~
~ ~2 with ~ yield o~ 68 %; mOpO 63-66C.
Ana ly~i s:
calcula~ed for C15HloClF3:
CJ 63~73 %9 ~Ia 3.57 ~v~ Cl: 12a54 %9 F: ~Oal6 %~
found: C: 63.91 %, H: 3081 %~ Cl: 12~37 %9 ~: 20~0~ ~
~ he above product is hydrogenated in acetie acid ~n ~he pre~ance oP a l~o palladium-on-carbon ca~alysb bo obtain l-phonyl~3,3,3~tri~1uoro-2-~4-chlorophenyl~-propane wlth a yield o~ 86 %; b~p.: 118-120C/0.4 mm Hg~ ~ - 1.5230.
Analysi~:
~alculabed for al5H12al~3:
C: 63.2~ ~o~ H: 4025 %~ Cl: 12~45 v~O, ~: 20~02 %~
~ou~d: C: 6~51 %~ H: 4.40 %t Cl: 12~38 ~o~ ~ 19~93 %~
The above product i9 bromi~ated in carbon ~etrachlorid~
~nd the bromine d~i~abive is cry~tallized from hexane~ l-Bromo-l-phonyl 3,3,3-~rifluoro~2-t~-chlorophenyl)-propana i9 obbainod wibh a yi~ld o~ 45~3 %; m.p.: 143-146a.
Analysis:
calculated ~or C15~1 ~rClF3:
C: 49.55~0, H: 3.05V~9 Br: 21~98%~ Cl: 9~75%~ F: 1506a~o~
Pound: C: 49~68%~ ~: 7015~o~ Br: 22.0~%, Cl: 9.71%, ~: 15.53%.
~h~ ~bove product i~ reacted with ani~ole in the pro~nc~ of aluminium brichloridc~ and ~he re~ultlng l-phanyl-713,~bri~1uoro-2-(4-chloroph~nyl)-1-(4-methoxyphenyl)~-propa~e i~ crys~lllzed Prom isopropanol. Yiold: 66 ~O; m.p.: 164-171C.
Ana~y~
c~lculated ~or C2~H18Clli~0~
a~ ~7.61 %, ~ .64 ~0, al; 9.07 %~ F: 14~58 %;
~ound: ~: 67075 %~ H: L~70 %9 Cl: 9.01 ~0, ~ 4~45 %.
,30 The abovo produc~ i9 reacted with pyridi~ hydxochlor-'79;~559 ide to obtain 1 phell~yl-3,3~3-trifluoro-1-(4-h~Tdro}~yphenyl)-2-(4-chlorophanyl)-propane~ which is utilized in the ~ubsequont step without purific~tion.
Exam~l~ 28 Preparstion of thr~o- ~Q=~3~-P~h~ 7-l ~2~d~phe nyl~3,3,~-trifluoro-~ropane h~drochloride A mixture o~ 6.84 g (20 mmoles) of threo-1,2-diph~
3,3,3-trifluoro-1-(~hydroxyphenyl)-propane, prepar~d a~
d~scribed in Example 1, 0.6 g (24 mmoles) of ~odium hydride and 60 ml of dry xylene is stirred for 0.5 hours, 7,2 ml o~ a 4.16 molar xylen~ ~olution of 2-dimethylaminoethyl chloride (= 30 mmol~s) are i~troduced, and the reaction mi~ture is heabed for 2 hoursO ~rhe mixture is evapora~ed, the re~iduo is admixod with 10 ml oî a 9.36% methanolic hydrochloric acid, and tho 15 solve~lt i9 evaporated. The residue is crystalli~ed îrom iso-proPanol. 5076 g (64 ~0) of the ai~ed compound are obtai~ed;
mOp- 229~231C.
Ana ly9i S:
calcula ~d fol C~25H27ClF3~0:
C: 66.74%, H: 6~05%, Cl: 7~88%~ F: 12.677~" N: 3.11%;
found: C: 66~47~o~ H: 6~03~/ot Cl: 7.96~ F: 12.86Yo, ~: 3.00~h.

~2~morpholinoethox;~ ~phe~yl7-pro~an~
301~2 ~ ~10 mmoles) o~ threo-1,2-dipheng1-3,3,3wtri-fluoro~l~(4-hgdroxyphorlyl)-propane, prepared as d~cribed in Ex~mple 19 ere reacted in xylene with ~odium hydride a~d then wit;h 2-chloroethyl-morpholine as de~cribed in ~xamplo 28. The product is cr~stalliYod f`rom hoxan~ 12 g (6~.5 ~0) o~ the de-sired compoun~ ar~ obt;ained; m.p.: 87-89C.
~53~

3~3 _ 51~ _ Analysi~:
calculat~d ~or C27H28~ ~ 2 C: 71019 %, H: 6.20 %, F: 12.51 %, N: 3.08 %, foundo C: 71.41 %, H: 6.48 %, Fo 12035 ~0~ N: 3.01 %.
~E~
Pr~aratio~ o~
e 2v72 g (8 mmoles) o~ 1,2-diphe~ 3,3~-tri~luorQ-1-(4-hydrox~phenyl)-propen0, prepared as describ~d i~ Ex~mple 26D are reacted in xylene with ~odium hydride and ~h~ wlth 2-chloroe~hyl-pyrrolidine as described in Example 26. The produ~t is cr~ballized ~rom haxane. 2015 g (61,4 %j o~ the de-sired compound aro obtai~ed, mOp. 84.5-86C9 A~aly~
cal~ul~ted Por ~27H26~3~-C: 74012 %, H: 5.99 ~, F: 13.03 ~0, ~: 3020 ~
~ou~d: C~o 74.40 %, E: 6.11 %~ F: 13.15 %, N: 3.15 %.
xa~le PreParation of 1~ 2-dim~th 20 .~ L~ 9~c~
0.46 ~; (0,02 g_a~m~ of sodium axe dis~olved 1~ 3.56 ~;
(40 mmoloa) of 2-dimethylamino-etha~ol, 4.02 g (10 mmola~) of 1~(4-~luoroph~ 3,3,~-trifluoro~1,2-bi~-~4 methox;~rpho~
prop~ re add~d~ and th~ mixture is hesbed at 170C ~or o~e hour. ~he roacbio~ mi~ture i~ coolod, diluted wibh 200 ml o~
~bh~r, wash~d with water until neutral~ dried and then ev~p_ orat~d. Th~ re~idu~ i~ recry~alliz~d from 45 ml of hexa~
3.43 ~ ~ 73 %) of the aimed compound ar~ obtained; m OpO:
77 79C.

~L793~i~
Analysis:
calculated ~or C27H28F3N~: .
C: 68.92 %, EI: 5078 %, F- 12~11 %, N: 2098 %9 found: C: 68~97 %~ H: 5085 ~o~ F: 12.10 ~v, ~: 2~99 %.
1-(4-Fluoropherlyl)-3,3,3~ tri~luoro-1,2-bis (4--m~thox~-phenyl)-prop~n~, applied as ~tarting substa~ce, i9 prepared as follows:
20 g (0.15 moles) of anhydrous aluminium trichloriae are 2dded ~o a solution of 56.6 g (0.15 mol~s) of l-bromo~
3,3,3-trifluoro-1-(4-~luorophenyl)-2-(4-methoxyphenyl)-propan~, prepared as described in f~xample 19, i~ 570 ml OI anisol at 6C under stirxing~ The reaG~ion mi~ture i~ allowed to s~a~d a~ room tempera~ure ov~r~ight, ~hen it is pour~d into a mi~ture o~ 600 g of crush~d ic~ and 100 ml o~ a 36~ aqueous hydro_ chloric acid, and the r~sulting mixturo is extracbsd with 500 ml o~ chloro~orm. ~he organic solutio~ is washed with aqueous ~odium hydrocarbon~te solu~ion and w~ter, dried~ and the solvant is evapora~ed. ~he dry residua i~ crystalliz~d Prom 2~0 ml of isopropanol to obtain 34.6 g (57 C~o) 0~ 1-(4-fluoro-ph~nyl)-3 9 3,3-trifluoro-1,2-bis (4-methoxyphenyl)-propans;
m.p.: 132-135C.
~na ly~
calculab~d ~or C23H20F~02.
C: 6a.31 %, II: 4099 %, h`: 18~79 %, 25fou~d: ~: 68045 ~0, EI: 5.14 ~0, F: 18.63 ~.
13.62 g (60 mmol~) of 2,3~dichloro-5,6-dlcyano-1,4-benzoquinor~e ar~ ~dded ~o a ~oluliion of 12013 g (30 mmol~) O.r the ~bove product in 60 ml o~ dry benzene, and the mixture is ~irr~d ~nd boiled for 16 hours. ~`her~after one proceeds ~s 3~ d~scrib~d in ~3xaLnpl~ 7. 'rhe crude produc t is c~ystallized - 56 ~

~rom 40 ml o~ isopropa~ol to ob~ai~ B~75 g ~72.5 %) o~ 1-(4-fluorophenyl)-3,~13-tri~luoro 1,2-bi (4-methoxyphanyl~-prop~e~
.p.: 75-77C.
A~alysi~:
calculated for C23~18F4o2-a: 68.65 ~o~ H~ 4.51 %9. F: 18~89 %~
found: a: 69.07 %, H: 4~57 %5 F: 19~03 %.
xample 32 ~ tr~luoro-1,2-bis (~ droxy~h~ propen~
10 ml o~ a 970 m~tha~olic hydrochloric acid ~rs adaad ~o a solu~ion o~ 4~0 g (7~47 mmole3) o~ (2-dime~hylamino-athoxy)-pheny_7~3,3,3-trifluoro-}~2-bisOt4-methoxym~thoxy-phenyl3-propa~e i~ 40 ml o~ matha~o~, ~nd the mixture is boiled for ona hour. ~h~ solu~io~ is evapo~a~ed to dr~nasj, a~d the ra idus is crystallized from ethanol. 2.67 g (74.4 %) o~ th~ de-~red.compound are obtalned; m.pu: 256-262C.
Analysis:
calculated Xor C25H25C1~ ~ 3 C: 6Z,57%~ H: 5.25~o~ Cl: 7.39%7 F~ 885o~ N: 2.,92%~
found: C: 62.61~, H: 5.52%, Cl: 7.62%, ~: 11.69~ 2.81%.
~ (2-Dimethylamlno-ethoxy)-phenyl7-3,3,3-trifluoro-1,2-bi~ methoxyme~hoxy-ph~nyl)-propene, applied ~ ~tarting ~ub~ta~ce~ i3 prepared a~ ~ollow~:
A mixture o~ 18.72 ~ ~46 mmole~) o.f 1-~4~Pluoroph~yl)-3,3,3-trlfluoro-1,2-bis-(4-methoxyphanyl)_propane, prepared d~eribed in Example ~1, and '76 ~ of pyridine hydrochloride i~
h~at~d fl~ 200-210C ~or 3 hour~. 'rhe mixture i9 cooled, dilu~ed with 200 ml of chloro~orm and washed with water until neutralO
'~ ~rhe ~ nn ia dried and evaporated. ~h~ resulting 17~7 g ~tjJ~335~

-- ~7 --of 1-(4-fLuorophenyL)-3,3,3-trifLuoxo-L,2-bis-(4--h~droxyphen~L)-pxopane are dissol~ed as ~uch, withou-t purif~cation, in 200 mL of benzeneq LL.L
(L38 mmoLes) of chLorometh~l ether and 10 ~ (27~
mmoLes) of powdered sodium hydroxide are added to the soLution, and the mlæture is boiled for one hour, The mixture is diluted with LQ0 ~L of benzene, washed with a 20 % aqueous ammonium chLoride soLution untiL neutraL, dried and evaporated, The xesidue is crystalLized from isopropanoL, L~,63 g (73 ~0~ o~
1-(4-fluorophenyL)-3,3,3-tr~ifluoro-1,2-bis-(4-tnethox~-metho~y-pheny1)-propane are obtained: m,p,: 106~107 C~
AnaLysis:
caLcuLat~d ~or C2~EI24~4o4:
L~ C: 64,6~ %~ EI: ~,21 %0, F: L6~36 %;
found: C: 64.60 %, H: ~,~2 %~ F: 16,47 %, ~ ,86 ~ (26 mmoLes) of 2~3-dlchLoro-~,6-di-cyano-1~4-benzoquinone al~ added to a soLution of 6~o g (L2,9 ~mnoles) o~ 1-(4-~luoropherlyl)-3,3,3-tri-~Luoro-L~2-bis-(4-metho~ymethoxy-p~1enyl)-propane ln 30 m'L o~ clx~ bonzone~ The mLxture Ls bo;LLecl ~or 28 ho~lr~ and then proce~secl as closcriberl ;Ln ExampLe 7 The produot ls cxystaLLLz~cl frorn LsopropanoL~ 4ll~2 g~

(71~ %) 0:~ th~ aLmecl compouncl ax~ obtaLnecl~
2~ rn,p,: 73-74 a , .~

AnaLysis:
caLcuLated for C2~I22F404:
C: 64,93 %, H: 4~0 %, F: L6,43 ~;
found: C: 64.67 %, ~I: 4.98 %, F: L6.49 %.
3~0 g (6,~ mmoLes) o~ -the abo~e product are addecl to a soLution of 0,3~ g (O.OL~ atoms) oP sod-Lum in 2,67 g (30 mmoles) of dimethyLamino~
-ethanol. and the mixtuxe is treated as dcscribed in Example 19~ 3.97 g (LOO ~) of 1-C4-(2-dimethy1amino-LO -ethoxy)-pherlyl~-37373~trifLuoro-L~2-bîs~4-moth ~ethoxy)-phenyL propene ax^e ohtained as a resinous substance, This product is utili~ed in the subsequent step without purification.

1~ Example 33 Preparation of 2-pher~1-3,3,3-trit`Luoro-1-. _ . . . _ -(4-hydroxy-phenyL)-L-C4-(2-morpho1inoethoxy)-~phsnyL~-propene '10 mL ot' 9 % methano'Llc hydroohLorLc ac,Lcl are aclded to a soLutLon o~ 3~08 ~ rmnoLes) o~ 2-~pheny'1-,'3~3,3-trl:fLuoro-L-~4-~2-moxphoLLnoethoxy)--ph~n~L~-L-(L~ ethox~rtletho~y-phonyl~-properle .~rl L~o ml o~ rrlethanoL~ ancl tho mLxtuxe Ls boLLed ~ox one hour, The soLution is renclerecl aLkaLine with L,~ mL o~ a 2~ LO n ~odi~n hydroxide soLution and then evaporated~

The reslduo L9 dLssoLved in 400 mL of ether~ -the soL-utLon is washed with water untiL neutral, dried and ~.~'7~33~

,~9 e~aporated. The residue is cr-ystalLized from acetone.
2.23 g (73.6 %) of the airned compound are obtained;
m.p.~ 7 C
Analysis calcuLated for C27H26F3N03:
C: 69.o7 %, H: S.~8 %, F: L2~14 %, N: 2.98 ~;
Eound: C: 69.37 %, H: ~ 82 %~ F: l2.04 %, N: 2~87 %~
2-Phenyl-3~3~3-trifLuoro-L-(4-methoxy-me-thoxy-phenyL)-L-~4-(2-morphoLinoetho~cy)-pher~yl~-LO -pxopene, appLied as starting substance, is pre-pared as fo7Lows:
9.6 g (L20 mmoles) of chLoromethyL ether and 8.4 g ~210 mmoLes) of powdered sodium h-ydroxide are added to a so'Lution of 27 7 ~ (76 mmoles) of 2-1~ -phenyL-3~3~3-trifLuoro-L-(4-fluorophenyl)-L-~4--h~droxyphenyL)-propane ln LOQ ml of benzene pre-pared as described in ExampLe 22, and the mixture is boiLed for one hour. The reaotion mixture is di7uted with L~O rnL of benzene, washed with a 20 % aclueous 20 amrnonlum ohloride soLution ~mtiL ne-utraL, dried and evaporated. The resLdue i9 d LssoL~ed in benser/le and pa~secl th:rou~h a ohromato~raphlc coLwTnn ~l'l'lecl with 6~o ~g of sLLLca ge'l~ The first eLuate fractions are oorrlbirlecl and e~aporatecl to o'btain 20.66 ~ (66 6 ~) 2~ oE 2-phony'L-3,3,3-trL~Luoro-'1-(4-~Luoropher~
-mothoxyrnethoxy-phenyL)-propane 9 which is appLied ln the subsequent step without purification.

3~9 _ 60 --22.7 g (100 mmoLes) o~ 2,3-dichLoro-~,6--clicyano-1.~4-benzocluinone are adcled to a solution of L9.70 ~ (48.7 mmoLes) o:E the abo~e product in LOO rnL
o:~ dry benzene~ The mixture is boiled :~or 17 hours and then processed as described in Example 7 The produot is crystaLLized :~rom isopropanol. 7120 ~ (36.7 %) of 2-phen~L-3~3~3-trifLuoro-L-~4-fLIlorophenyl)-l--(4~methoxymethoxy-phenyL)-propene are obtained;
m~p.: 66~68 C.
LO AnaLysis:
caLcuLated :~or C23~IL8F4Q2 C: 68.6~ %, H: L~ ~L ~0, F: L8.89 q'o;
found: C: 68..~0 ~90, ~ .73 ~, F: L9.OL %.
0,28 g (Q.012 ~.-atoms) o:E sodlum are L~ dissol~ed in 4,72 g (36 mrnoles) o:E (2-hydroxyethyL)--morphoLine, 2,40 ~ (6 rnmcLes) o:~ the abo~e product are adcled, and -the mi:2cture is heated at L~O C for one hour The mixture is cooled, diLutecl with LOO mL
OI ethor, wa~hed wi-th water untiL neutral and driedO
20 3,08 g (100 %) o:f 2-phenyL-3~3~3-trL:~Luoro~L-(4 rne-thoxy-~nethoxy-p~lerly'l)-'l.-Cl~-(2-tnorpho'lLnoethoxy)-phenyL~--propone a.re obtained as a resinou.s substanoe Thls produot i9 utlLlz;od Ln the subsequent step wlthout pur-l:f`lcat1on.
2~

7~3S~

ExampLe 34 Preparation of 2-phenyL-3,3,3-trifluor~--ethoxy?-phenyL~-propene hydroohLoride L.~ ml of 9 % methanoLic hydrochLoric aGid are added -to a soLution of L ~0 g (3.28 mmoLes) of 2-phenyL-3,3~3--trifLuoro-L-CL~-(2-methyLaminoethoxsr) -phenyl~-L-(4-metho~Lymethoxy-phen-yL)-propene in L~
mL of methanoL, and the mixture is boiLed for one L0 hour~. The soLution is e~aporated to dr~ness, and the residue is crystaLlized from isopropanoL L. o6 g (7L.5 %) of tke aimed compound are obtained; m.p 213-2L8 C.
AnaLysis:
L~ calcuLated for C24EI23CLF3N02:
C: 64 07%~ H: ~ 1~%, CL: 7.88%, F: L2.67%, N: 3.LL%;
found: C: 64.74%, H: ~.~3%, CL: 8.0L%, F: L2.4~%~ N: 3.03~0.
2-Phen~1-3~3,3-trifluoro-L~C4-(2 methylamino-ethox~)-phenyL~-L-(4-met;hoxymethoxy-phenyl)-propene~
20 appLLed as startLng~ substanoe, is preparod as foLlows:
0.28 g (0.012 g~-atoms) of soclL~ml are clLs-soLvod ln 2.70 g~ (36 mrnoLes) of N-methyLamLrlo-ethanol, 2~36 g (~.86 mmoles) of 2-phenyL-3~3~3-tri~`Luoro-1-(4--fl.uorophen~r'l)-L-(4-rnetho~c$rmetho~-phens~'l.)-ps~opene9 2~ preparecl as descrLbed in E~annpLe 33, are aclded~ ancl the mixtuxe Ls heated at L50 C for one hourO The mLxture i~ oooLed9 dLLuted with L00 mL of ether, `'~'~ ' 5~

~ 62 _ washecl with water untiL neutraL, dried and e~aporated The residue is crystaLLi~ed fro~ hexane L.94 ~ (72~4 %) of 2-phenyL-3,3,3-txifLuoro-L~4~(2-me-thyLa~inoethox~)--phenyl]-L-(4-methoxymethoxy-phenyL)-propene are ob-tained; m.p : 87-90 C.
Analysis:
calculated for C26E26F3N0 :
C: 69.2~ %, H: ~ 73 %, F: L2.46 %, N: 3 o6 %;
found: C: 70.08 %, H: ~.6~ %, F: L2066 %~ ~: 3.L6 %.

Example 3~
Preparation of (E)-L,2-diphen~1-3,3,3-tri-fLuoro-L-~4-(2-heptamethyLenei~ino-ethoxy)-.. .. .. _ _ . _ _ ,, , , _ -phenyl~ propene _ 2 32 ~ (20 mmoLes) of heptamethyleneimine are added to a solution of 4 47 ~ (L0 mmoLes) of (E~ 4-(2-bromoe-thoxy)-phenyl~-L,2-dLphenyl-3,3,3--trifluoxo-propene, preparecl as clescxibed in E~ampLe 7~ in 30 ml of ethanoL, ancl the ~ixture ls boiLed for ~ hours. The reaotion mixture ls e~aporatecl-to dry-ncss rhoxeaPtex one proceecls as desoribed in ExanlpLe L~ ancl orystalLizes tho procluct from he~ane. 3~22 (67 ~,) o~ tho closirecl oompo~lncl are obtaLned~

m.~.: 73-77 C~
AnaLysis:
calcuLated for C30~I32F3N0:
a: 7~L3 ~0, H: 6~73 %, F: LL 88 %, N: 2 92 %
found: C: 7~.1L %~ H: 6~7~ %~ F: LL.88 ~ N: 2 98 %

3~

I?xampLe 36 P~eparation of (E)-L-~4-(2-diethylaminoethox~)--phenrl~-L,2-diphenyl-3,3,3-trifluoxo -propene picrate 5,37 g (12 mmoles) of (E)-L-~4-(2-bromoethoxy)-~phenyL~-1,2-diphenyl-3,3,3-trifLuoro-propene, pre-pared as described in Example 7, are boiled with 8.8 g of diethyLa7nine for ~ hours,. The reaction mi~ture is diluted with ~Q ml of benzene, washed with water 10 untiL ne-utxaL, dried and e~aporated, The residue is dissolved in 20 mL of 95 % e-thanol, and a soLution of 3,22 ~ (14 mmoles) of picric acid in 32 mL of 9~ %
ethanol is added, The sepaxated crystals are fiLtered off, washed with ethanol and ether. 6,46 g (80.4 %) L~ of the aimed compound are obtained; ttl.p9: L3L-13~ C, Ana LrS is:
caLcuLated for C33H3LF3N48 C ~9,28 %, H: 4~ 67 %~ F: 8,~2 %, N: 8,40 ~;
folmd: C: ~9,~ %~ ~I: 4,78 %, F: 8,73 %, N: 8,3 XO
~E~
Prepar?tLon o~ ~-L-~4-(~ditnethyLamitlo-thox~ ph_nyLLL,2-diphen~ tx,Lfltloro--prop~3ne suLfate 2~ Q,03 mL (0.~ mtnoLes) o 98 % sulfuric acid axe addecl to a soLution of 0,20~ g (0.~ mmoLes) of (E)-'L-~4-(2-dimeth~latninoethox~)-phenyL~-1,2-diphen~l-~;

~17~g3~9 -3~3~3-trifluoro-propene in 1 J ~ ml of isopropanoL
The iseparatecl crystals are fiLtered of`f~ washed with ether, and the cr~de product is recrystaLLized ~rom isopropanol. 0.22 g (84.6 %) of the aimed com-pound are obtained; m.p.: L~0-1~3 C.
Analysis:
calcuLa-ted for C2~I26F3No~S
C: ~8~93%, ~ .14%, F: ll.l9~o~ N: 2 7~%~ S: ~29 ~'Q
found: C: ~9.07%~ H: 5 30%~ F: 11l29%, N: 2.70%~ S: 6.46 %
L0 (E)-L-C4-(2-DimethyLaminoethoxy)-phenyL~--L,2-diphenyl-3,3,3-trifluoro-propene, appLied as starting substanc0 Ls prepared as follows:
10 mL o~ a 40 % aqueous solution of climethyl_ atnine are added to a solution of ~.37 ~ (12 mmoles) 1~ of` (E)-L-C4-(2~bromoethoxy)-phenyl~-1,2-dlphenyl-3,3,3--tri~luoro-propene~ prepared as described in ExampLe 7~ in L0 ml o~ ethanol. The mixture is a'Llowed to s-tand ~or 3-4 days 7 then evaporated, the residue is di'Lut~cl with ~0 ml of benzene, the resulting so'Lution 20 ls washQd with wator until neutraL, driecl ancl e~apor-atecl, 'rho ro~ld~le Ls ory~ta'llized ~rotn hexane. 4. 26 g (86.2 %) o~ (E)-'l-~LI-(2-climethy'Latninoethoxy)~phenyL~--'L,2-dLpheny'1-3,3,3-trLf`lLloro-propeno are obtaLned;

In p-: 90-9L C
Ana'Ly~is:
oalouLated for C2~Ft24F3~0 C: 72.98 %~ H: ~.88 qO, F: 13.8~ %~ N: 3 40 %;

!;~. found: C: 72.80 ~, H: ~.~1 %, F: 14.0L qO, N: 3~3 %.

3~;~

Example 38 Preparation of (E)-1,2-dipheny~1-3,3,3-tri-.. ~
fLuoro-l-C4-~2-/4-(2-h~d~o~eth~L)-piperazino/--ethoxy)-phen~L3-propene mes~Late ~ _ A solution of 0 2 g (2 mmoles) of rne-thane-suLfonic acld in 2 ml of isopxopanol is added to a solution of Or ~SO g (L rrlmole) of (E)-L,2-diphenyl--3,3~3-trifluoro-1-C4-(2-/4-(2-h~rdroxye-th~rL)-pipera~ino/--etho}~y)-phenyl~-propene, prepared as desclibed in L0 ExampLe lL, in L mL of isopropanoL. The separated crystals are I iltered off and washed with ether .

0 ~8 g (96.7 %0) of the a-imed compound are obtained;

m.p.: 203-209 C.

AnaLysis:

1~ calculated for C31H39F3N208S2 c: ~4~o6%, H: ~.7L~o~ F: 8.28%, N: 4.07%, S: 9.31%;
found: a: ~3.71%, H: ~.90%, F: 8.42%, N: 3 81%, S: 9.03%.

ExatrlpLe 39 ProparatLon o~ -(2-aminoethoxy)--phe~yl~-1,2-dlphen~rL-3~3~3-trifLIloro-propene tosyl.ate . .,_ .. _. _ .
1~ ~oltttLon ol~ 0~20 g (L rnrnole) o~ p~toLuene~
suL~orlLo acid -ln 1 ml of Lsopx-opanoL Ls added to a sol-2~ utlon of 0.30 ~ (0~8 mr~oLes) of (E)-1-~4-(2-arninoethox$r)-~pherlyL J -L,2-dLphenyL-3,3,3-txlfluoro-propene, prepaxed as desorLb~d in ExarnpLe 8, in 0.~ rnL of Lsopxopanol. The , .

3~

separated crystaLs are filtered off and ~ashed with et;her. 0.37 ~ (84 ~0) o:f the aimecl compound are ob-tained; m.p : L62-L63 C.
Analysis:
calculated for C30~I28F3N4S
C: 64.8~ 7~0~ :H: $.08~ F: Lo.26~o7 N: 2.$2~o~ S: S.77%;
found: C: 64 98 %, H: S.3%, F: 10.S3%, N: 2 23%, S: S g3%-ExampLe 40 ___ L0 Preparation of (E)-L,2-diphenyl-3,3~3-tri-__ fLuoro-L-~4-(2-/2-hydroxyethylamino/-ethoxy)--phenyl~-propene citrate _ A solution of 0.13 ~ (o.6 mmoles) o:f` citric acid hydrate in 0.8 ml of acetone is added to a so~-1~ ution of 0.2L ~ (O.S mmoLes) of (E)-1~2-diphenyL--3,3,3-trlfLuoro-l-C4-(2-/2-hydroxyethyLamino/-ethoxy)--phenyL~-propene, prepared as descrlbed in ExampLe L2 in 0.2 mL of acetone The mixture is cooled, the separ-ated crystals are fiLterecl off ancl washecl wLth 2() aoetone~ 0~18 6 (S8 '~o) of the aimod colnpourld is ob-~tQirl~cl ; In~ p~: 127-129 C.
~n~LYsls oaloulated for C3~E32F3 N09:

C: 60.09 'J~o~ ~:[: S,21 %~ F: 9.20 ~o~ N: 2.26 %
2~ fOund: C 60.L8 %9 H S.13 ~o~ F 9~24 %9 N: 2,37 %

EæampLe 4L
.. . ... ....
Preparation of (E)-1,2-diphenyL-3,3,3-tri-fluoro-L-~ (2-hex~lamino-ethox~)-phenyL~--propene tosyLate .
2 23 g (~ mmoLes) of (E)-L-C4-(2-bromoethoxy)--phenyl~-L,2-diphen-yL-3,3,3-trifLuoro-propene, prepared as described in ExampLe 7, are clissoL~ed in a mixture of ~.0 g (~0 mmoLes) of n-he~yLamine and LO mL of 2--methoxyethanoL. The mixture is boiLed for 30 minut~s, LO then e~aporated~ and the residue is passed through a chromatographic coLumn fiLled with ~0 g of siLica geL. The coLumn is eLuted with ben~ene The fraotions which are chromatographicaLLy uniform are combined and e~aporated, the residue is dissoL~ed in ~ mL of L~ isopropanoL, and a soLution of L.20 g (6 mmoLes) of p-toLuenesuLfonic acid in 6 mL of isopropanoL is added, The separated crystaLs are fiLtered off and washed wi-th e-ther. 2~L4 g (9L.8 %) ~ the aimed compound are obtained; m p.: L~l-L~3 a , AnaL-y~ls:
oa'lc~l'latod ~or a36Etl F3NOIS:
C: 67.58%, EI: 6.30'~o, F: 8.9L%, N': 2.L9%, S ~.OL%;
fo-und: C: 67.6L%~ H: 6.~ oS F: 9.08%~ N: 2 39alu, S: ~.L~%.

2~ ExampLe 42 .
Pre~aration of ~I~-L,2-dipheny'L-3~3~3-tri-fLuoro-L-C4-(2-/3-hyclroxy-propylalnino~-et'hox~ -pheny ~ ropene :.

'7~S9 - 67a -2,23 g (5 mmoLes) of (E)~ 4-(2-bromoethoxy)--phen~lJ-L,2-diphen~rL-3,3,3~trifLuoro-propene~ prepared as descri'bed in ExampLe 7, are dissol~ed in a mix-ture of 3.80 g of 1-amino-3-propanol and 10 mL of 2-methoxy-ethanoL, The rnixtu~e is boiLed for 30 minutes anc3 then processed as descri'bed in Example 2. The mixture is cr5tstallized frotrl a 1:1 mixture of ethyL acetate and hexane, 1,77 g (80.'5 %~ of the aimed compound are ob-tained, m~p.: 97-99 C, L0 Anal~sis:
ca,lculated for C26H26F3N02:
C 70.73 %, H: ~.94 %, F: 12.91 %, N: 3.17 %;
~ound: C: 70.7L %, H. ~,94 %, F: L2.83 ~0, N: 3,.23 %.

L~ Example 43 Preparation oE (E)-1,2~diphenyL-3,3~3-tri-fLuoro-1-~4-(2-nitroguarlidino-ethoxy)-phenyL~--propene A soLutLon o~ 3,83 g (L0 mmoLes) o~ (E)-l-20 _r.L~ (2-amLnoethoxy)-phen~L~-'1,2-diphen~L-3,3,3-trL-r Luoxo-propcn~ pxcparocl as cle~;cxLbecl Ln Examp'Le 8~
ancl 'L.22 ~ (9 mmolcs) o~ 2-methy'l-1-nitro-2-Lsothiourea ~L,. Fish'b~ln et al.: J, Arn. (~hom. Soc. 76, 1877 ('19~4)~
in 2~ rnl o:~ ethanol is 'boLLocl ~or one hour. The xeactLon 25 mLxture is evaporated ancl the residue is crystalLlzed ~rom methanoL, 2.78 g (66 ~) o:~ the aimed compound aro o'btained; m.p.: 112-'LL6 C (decomposition).

~'79~35 - 67~ -Analysis:
caLcuLatod ~or C2~ 2 LF3N43 C: 6L.27 %, 'H: 4,~0 '~0, F: 12.L2 ~0, N: LL.9L %;
found: C: 6L.2L %, H: 4,80 %, F: L2.27 %, N: LL.62 %.

Example 44 Prep_ration of ~Z)-L,2-dLpheny_3,3,3-t~i-fLuoro-L-~4-(2-/2-hydroxyethyLamino/-0thoxy)--phen-yl~-propene fumarat,e L0 0.~9 ~ (L.L7 mrnoLes) of (Z)-L-C4-(2-bromo~
etho~ phenyL ~-L, 2-diphen~L-3 ~ 3 ~ 3 -t~i:~Luoro-propetle, propared as described in ExampLe 7, are dissoLved in a mixture of L.34 g o~ 2-arninoethanoL and L~ mL of 2-metho~yethanoL, The soLution is bo,LLed for 30 minutes L~ and then processed as described in ExampLe 2, The crude product is crystaL1ized from a 1:3 mi~turre o~
ethyL acetate and hexane, 013~ ~ (70 %) of the base ~orm of the -ti-tLe compound are o~tained, m~p,: 8L-83 C,, Thc ~rec 'base ;is dLssoL~ecl in L.~ rlll of ethcLrloL~ ~nd 20 an othanoL soLutlon o~ O,L2 g ('L mmoLe) o~ ~um,arLc aolcl ls adcled,, The ~cparatecl crystaLs are ~lLtored o~E
ancl washecl w1th ethe~, 0,28 g~ (62,2 '~0) o~ the clesLrccl oompollnd ar~-3 o'btalnecl; Itl, p.: L68-L72 C.

AnaLys1s:
2~ caLcul.~Lted ~o.~ C29ll28F3No6:

~ : 6l~,o8 %; II: ~, L9 %, F: 'LO,1~9 %, N: 2.~8 %;
fownd: C 6l~140 '~0~ H: ~,32 ~0, F: Lo,6~ %~ N: 2,8~ %, .~

35~
- 67c -ExampLe 4 Pr~parati ~

0.8Q g (20 mmoLes) of powdered sodium hydroxid'e and 6.8 g (40 mmoLes) of n~propyl iodide are added to soLution of 3t42 g (L0 mmoles) cf threo-1,2-diphen-yL--3~3~3-trifLuoro--1-(4-hydrox-yphen-yL)-propane~ prepared as described in ExampLe L~ in 3~ mL of d~y benzene, and the mixture is boiLed for 4 hours. The mi~ture is L0 diLuted with ~0 mL of benzene~ washed with water untiL
neutraL, dried a.d e~aporated The residue i.s ory~taL-lizecl ~rom isopropanoL~ 3 32 g (8~ 0) o~ the aimed compound are obtained; m.p.: 77-80 C
AnaLysis:
1~ caLcuLated ~o~ C24~I23F30 C 74,98 %, H: 6.o3 %, F: '14.83 ~0, ~ownd: C: 7~,0L ~o, H: 6~20 ~0~ F: L4.9~ ~o.

Exam~Le 46 Pre~ar.atlon o:~ threo-1-~4-(/(31L~-e ~ ~
~y-phenyL]-L,2 -cllphony'L-3 ? 373~
-trL~`luoro-propane A mlxture O:r 3~1~2 g~ ( L0 InrnoLes) o:f threo-- 1 7 2-cllphe~yL-3,3,3-trLfLuoro-'L-(4-hydroxypheny'L)-2~ -propane, prepared as de~orl'bed ln ~x~mpLe 1, and L7 mL o~ M,-cllepoxybutane ls heate d at LQ0 C ~o.r 0,~
hours. The reaction mixture is e~aporated~ t~e .resi.due ls d.iLuted with 300 mL o~ ethe.r, washed wi.th water, ~. .

~ ~'7~

- 67d -dried and e~aporated, The residue is crystalLized from isopropanol. The obtained subst~nce, ~eighing 3~22 g (7~2 %; m.p.: L2L~L26 C)~ is subjected to ch~omato~
graph~ in a 3:2 mlxtur0 of hexane and acetone, and the chromatographicaLly uniform produot is cr~staLLized from isopropanoL. L.90 g (44.4 ~o) of the desired com-pound are obtalned; m.p.: 130-L33 C, '~``'', 33S~39 Analysis:
calculated for C25H23F303:
C: 70.08 %, H: 5.41 %, F: 13.30 ~;
found: C: 70.30 %, H: 5.74 %, F: 13.09 %.
Example 47 Preparation of Pharmaceuti.cal compositions a) Tablets Tablets for oral administration, each containing lO mg of the active agent, are prepared in a manner known per se.. The composition of one tablet is as follows:
(E)-1,2-Diphenyl-3,3,3-trifluoro-1-~4-(2-/2-hydroxyethylamino/-ethoxy)-phenyl] -propene (calculated as free base) lO.0 mg Maize starch 4g.6 mg I,actose lO9.0 mg Polyvinylpyrrolidone 5.4 mg Magnesium stearate l.0 mg Colloidal silicon dioxide 5.0 mg Average weight: 180.0 mg b) CapsuIes Hard gelatine capsules, each containing lO mg of the active agent, a:re prepared in a ~manner known per se. The composition of one capsule is as follows:
threo-1-~4-(2~3-Epoxypropoxy)-pheny~ -1,2-diphenyl~3,3,3-trifluoro~
propane lO.0 mg Maize starch 84.0 mg Magnesium stearate l.0 mg Colloidal si:Licon dioxide 5.0 mg

Claims (20)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a 1,1,2-triphenylpropane or -propene derivative of the general formula (I), (I) wherein A and B each stand for hydrogen or they form together a valence bond, X and Y are identical or different and stand for a phenyl group or a phenyl group having a halogen, hydroxy, methoxy-methoxy, C1-6 alkoxy or benzyloxy substituent in the para position, R1 is a C1-6 alkyl, a C1-6 epoxyalkyl, a C1-6 azidoalkyl, methoxy-methyl or benzyl group or a group of the general formula (II), (II) wherein R2 and R3 each stand for hydrogen or a C1-6 alkyl, a C1-6 hydroxyalkyl or a C1-6 haloalkyl group, or R2 and R3 form together with the adjacent nitrogen atom an up to 8-membered heterocyclic group, an up to 6-membered hetero-cyclic group optionally containing further hetero atom(s), which heterocyclic groups optionally have a lower alkyl or hydroxyalkyl substituent, a guanidino group, an amino-guanidino group or a nitroguanidino group, with the proviso that, A) when A and B form together a valence hond and X and Y each stand for phenyl or X is phenyl and Y is p-methoxyphenyl, R1 may not stand for a dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the case of the (Z) isomers, B) when A and B form together a valence bond and X and Y each stand for phenyl, R1 may not stand for methyl or ethyl, C) when A and B form together a valence bond and X and Y each stand for phenyl, then in the case of the (Z) isomers R1 may not stand for dimethylaminoethyl, diethylaminoethyl, morpholinoethyl or piper-idinoethyl, D) when A and B form together a valence bond, X stands for phenyl and Y stands for p-methoxyphenyl, R1 may not stand for methyl or pyrrolidinoethyl, E) when A and B form together a valence bond, X stands for p-methoxyphenyl, p-fluorophenyl or p-ethoxyphenyl, and Y stands for phenyl, R1 may not stand for methyl, F) when A and B form together a valence bond, X is phenyl and Y is p-hydroxyphenyl, R1 may not stand for methyl, G) when A and B form together a valence bond, and X and Y
each stand for p-methoxyphenyl, R1 may not stand for methyl, or stereoisomers or isomeric mixtures thereof, or a pharmaceutically acceptable acid addition salt of the basic compound having the general formula (I), which process comprises:
a) for preparing a compound of the general formula (I) in which A and B are as defined above, X and Y are identical or different and represent a phenyl group, a p-halophenyl group or a p-(C1-6 alkoxy)-phenyl group, R1 stands for azidoethyl group or a group of the general formula (II), wherein R2 and R3 are as defined above, reacting a phenoxyalkylhalide or -sulfonate of the general formula (III), (III) wherein A and B are as defined above, X and Y are as defined in point a) and Z stands for halogen or a sulfonyloxy group, with an amine of the general formula R2R3NH, wherein R2 and R3 are as defined above, or with an alkali metal azide, and, if desired, reducing the resulting azido derivative, and, if desired, a resulting amino derivative is converted into the respective guanidino, aminoguanidino or nitro-guanidino derivative; or b) for preparing a compound of the general formula (I) in which A and B form together a valence bond, X and Y are identical or different and represent an unsubstituted phenyl group or a phenyl group which has a chloro, bromo, methoxymethoxy, C1-6 alkoxy or benzyloxy substitutent in the para position, and R1 stands for a group of the general formula (II), wherein R2 and R3 form together with the adjacent nitrogen atom an up to 8-membered heterocyclic group or an up to 6-membered heterocyclic group optionally contain-ing further hetero atom(s), which heterocyclic groups optionally have a lower alkyl or hydroxyalkyl substituent, dehydrogenating a compound of the general formula (IV), (IV) wherein A and B stand for hydrogen and X and Y are as defined in point b) above, and then reacting the dehydrogenated product with an alcohol derivative of the general formula R1OM, wherein R1 is as defined in point b) and M stands for an alkali metal atom; or c) for preparing a compound of the general formula (I) in which A and B are as defined above, X and Y are identical or different and represent an unsubstituted phenyl group or a phenyl group having a halogen or C1-6 alkoxy substituent in the para position and R1 stands for a C1-6 alkyl, epoxyalkyl, methoxymethyl or benzyl group or represents a group of the general formula (II), wherein R2 and R3 each stand for a C1-6 alkyl group or they form together with the adjacent nitrogen atom an up to 8-membered heterocyclic group or an up to 6-membered heterocyclic group optionally containing further hetero atom(s), which heterocyclic groups optionally have a lower alkyl substituent, reacting a compound of the general formula (V), (V) wherein A and B are as defined above and X and Y are as defined in point c), with an R1-halide or an R1-sulfonate, wherein R1 is as defined in point c) above, in the presence of an acid binding agent;
or d) for preparing a compound of the general formula (I) in which A and B form together a valence bond, X and/or Y stands for a p-hydroxyphenyl group and R1 is a group of the general formula (II), wherein R2 and R3 each represent hydrogen or a C1-6 alkyl group or they form together with the adjacent nitrogen atom an up to 8-membered heterocyclic group or an up to 6-membered heterocyclic group optionally containing further hetero atom(s), which hetero-cyclic groups optionally have a lower alkyl substituent, reacting a compound of the general formula (IV), wherein A and B are as defined in point d) and X and/or Y is a p-(methoxymethoxy)-phenyl group or a benzyloxyphenyl group, with an alcohol derivative of the general formula R1OM, wherein R1 is as defined in point d) and M is an alkali metal atom, and then subjecting the methoxymethoxy group or the benzyloxy group to an ether splitting reaction; or e) for preparing a compound of the general formula (I) in which A and B form together a valence bond, X and Y are identical or different and stand for an unsubstituted pheny1 group or a pheny1 group which has a halo, methoxymethoxy, C1-6 alkoxy or benzyloxy substituent in the para position and R1 represents a C1-6 alkyl, epoxyalkyl, azidoethyl, methoxymethyl or benzyl group, dehydrogen-ating a compound of the general formula (I), wherein A and B each stand for hydrogen and X, Y and R1 are as defined in point e); or f) for preparing a compound of the general formula (I) in which R1 represents a group of the general formula (II) and in this latter formula R2 and/or R3 stands for a C1-6 haloalkyl group, halogenating a compound of the general formula (I), wherein R1 is a group of the general formula (II) and in this latter formula R2 and/or R3 represents a C1-6 hydroxyalkyl group;
and, if desired, separating the individual stereoisomers from a resulting isomeric mixture, and, if desired, converting a basic compound of the general formula (I) into its pharmaceutically acceptable acid addition salt or liberating a basic compound from its acid addition salt.

2. A process for the preparation of a 1,1,2-triphenylpropane or -propene derivative of the general formula (I), (I) wherein A and B each stand for hydrogen or they form together a valence bond, X and Y are identical or different and stand for a phenyl group or p-hydroxyphenyl group, R1 is an epoxyalkyl group with up to four carbon atoms, an azidoethyl group or a group of the general formula (II), (II) wherein R2 and R3 each stand for hydrogen, a C1-4 alkyl group or a C1-4 hydroxyalkyl group or they form together with the adjacent nitrogen atom, a piperazino, pyrrolidino, piperidino or morpholino group each optionally having a C1-4 alkyl substituent, with the proviso that, A) when A and B form togther a valence bond and X and Y each stand for phenyl, R1 may not stand for a dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl, piperidinoethyl or morpholino-ethyl group in the case of the (Z) isomers, or stereoisomers or isomeric mixtures thereof, or a pharmaceutically acceptable acid addition salt of the basic compound having the general formula (I), which process comprises:
a) for preparing a compound of the general formula (I) in which A and B are as defined above, X and Y are a phenyl group, R1 stands for azidoethyl group or a group of the formula (II), reacting a phenoxyalkylhalide or -sulfonate of the general formula (III), (III) wherein A and B are as defined above, X and Y are as defined in point a) and Z stands for halogen or a sulfonyloxy group, with an amine of the general formula R2R3NH, wherein R2 and R3 are as defined above, or with an alkali metal azide, and, if desired, reducing the resulting azido derivative, b) for preparing a compound of the general formula (I) in which A and B form together a valence bond, X and Y are a phenyl group and R1 stands for a group of the general formula (II) wherein R2 and R3 form together with the adjacent nitrogen atom a piper-azino, pyrrolidino, piperidino or morpholino group each optionally having a C1-4 alkyl substituent, dehydrogenating a compound of the general formula (IV), (IV) wherein A and B stand for hydrogen and X and Y are as defined in point b) above, and then reacting the dehydrogenated product with an alcohol derivative of the general formula R1OM, wherein R1 is as defined in point b) and M stands for an alkali metal atom; or c) for preparing a compound of the general formula (I) in which A and B are as defined above, X and Y are a phenyl group, R1 stands for an epoxyalkyl with up to 4 carbon atoms or represents a group of the general formula (II), wherein R2 and R3 each stand for a C1-6 alkyl group or they form together with the adjacent nitrogen atom, a piperazino, pyrrolidino, piperidino or morpholino group each optionally having a C1-4 alkyl substitutent, reacting a compound of the general formula (V), (V) wherein A and B are as defined above and X and Y are as defined in point c) with an R1-halide or an R1-sulfonate, wherein R1 is as defined in point c) above, in the presence of an acid binding agent;
or d) for preparing a compound of the general formula (I) in which A and B form together a valence bond, X and/or Y stands for a p-hydroxyphenyl group and R1 is a group of the general formula (II) wherein R2 and R3 are as defined above, reacting a compound of the general formula (IV), wherein A and B are as defined in point d) and X and/or Y is a p-(methoxy-methoxy) phenyl group or a benzyloxyphenyl group, with an alcohol derivative of the general formula R1OM, wherein R1 is as defined in point d) and M is an alkali metal atom, and then subjecting the methoxymethoxy group or the benzyloxy group to an ether splitting reaction; or e) for preparing a compound of the general formula (I) in which A and B form together a valence bond, X and Y are a phenyl group and R1 represents an epoxyalkyl of up to 4 carbon atoms or an azidoethyl group, dehydrogenating a compound of the general formula (I), wherein A and B each stand for hydrogen and X, Y and R1 are as defined in point e);
and, if desired, separating the individual isomers from a resulting isomeric mixture, and, if desired, converting a basic compound of the general formula (I) into its pharmaceutically acceptable acid addition salt or liberating a basic compound from its acid addition salt.

3. A process according to claim 1, wherein process variant a), b), c), d) or f) is carried out employing starting materials in which A and B form together a valence bond, or process variant e) is carried out, whereby a compound of the general formula (I) in which A and B form together a valence bond is prepared.

4. A process for the preparation of threo-1-[4-(2,3-epoxy-propoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propane, which process comprises; reacting threo-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-propane with 1,2-epoxy-3-chloropropane in the presence of an acid binding agent.

5. A process for the preparation of (E)-1,2-diphenyl-3,3,3-trifluoro-1-[4-(2-/4-methylpiperazino/-ethoxy)-phenyl]-propene or a pharmaceutically acceptable acid addition salt thereof, which process comprises; reacting (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene with N-methylpiperazine, and, if desired, converting the basic product into a pharmaceutically acceptable acid addition salt thereof.

6. A process for the preparation of 1 [4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-propene, or a pharmaceutically acceptable acid addition salt thereof, which process comprises; splitting off the benzyl group of 1-(4-benzyloxyphenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]-2-phenyl-3,3,3-trifluoropropene or the methoxymethyl group of 1-(4-methoxymethoxyphenyl)-1-[4-(2-dimethylaminoethoxy)-phenyl]-2-phenyl 3,3,3-trifluoropropene, and, if desired, converting the basic product into a pharmaceutically acceptable acid addition salt thereof.

7. A process for the preparation of (E)-1,2-diphenyl-3,3,3-trifluoro-1-[4-(2-/2-hydroxyethylamino/-ethoxy)-phenyl]-propene or a pharmaceutically acceptable acid addition salt thereof, which process comprises; reacting (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoropropene with 2-aminoethanol, and, if desired, converting the basic product into a pharmaceutically acceptable acid addition salt thereof.

8. A process for the preparation of (E)-1-[4-(2-azidoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, which process comprises; reacting (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl -3,3,3-trifluoropropene with an alkali metal azide.

9. A process for the preparation of 1-[4-(2-dimethylaminoethoxy)-phenyl]-3,3,3-trifluoro-1,2-bis (4-hydroxyphenyl)-propene or a pharmaceutical-ly acceptable acid addition salt thereof, which process comprises; splitting off the methoxymethyl group of 1-[4-(2-dimethylaminoethoxy)-phenyl]-3,3,3-trifluoro-1,2-bis(4-methoxymethoxyphenyl)-propene or the benzyl group of 1-[4-(2-dimethylaminoethyl)-phenyl]-3,3,3-trifluoro-1,2-bis(4-benzyloxyphenyl)-propene, and, if desired, coverting the basic product into a pharmaceutically acceptable acid addition salt thereof.

10. A 1,1,2-triphenylpropane and -propene derivative of the general formula (I) (I) wherein A and B each stand for hydrogen or they form together a valence bond, X and Y are identical or different and stand for phenyl group or a phenyl group having a halogen, hydroxy, methoxymethoxy, C1-6 alkoxy or benzyloxy substituent in the para position, R1 is a C1-6 alkyl, Cl-C6 cpoxyalkyl, C1-C6 azidoalkyl, methoxymethyl or benzyl group or a group of the general formual (II), (II) wherein R2 and R3 each represent hydrogen or a C1-6 alkyl, C1-C6 hydroxy-alkyl or C1-C6 haloalkyl group, or R2 and R3 form together with the adjacent nitrogen atom an up to 8-membered hetero-cyclic group, an up to 6-membered heterocyclic group optionally containing further hetero atom(s), which heterocyclic groups optionally have a lower alkyl or hydroxyalkyl substituent, a guanidino group, an amino-guanidino group or a nitroguanidino group, with the proviso that A) when A and B form together a valence bond and X and Y
each stand for phenyl or X is phenyl and Y is p-methoxyphenyl, R1 may not stand for a dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the case of the (Z) isomers, B) when A and B form together a valence bond and X and Y
each stand for phenyl, R1 may not stand for methyl or ethyl, C) when A and B form together a valence bond and X and Y
each stand for phenyl, then in the case of the (Z) isomers R1 may not stand for dimethylaminoethyl, diethylaminoethyl, morpholino-ethyl or piperidinoethyl, D) when A and B form together a valence bond, X stands for phenyl and Y stands for paramethoxyphenyl, R1 may not stand for methyl or pyrrolidinoethyl, E) when A and B form together a valence bond, X stands for paramethoxyphenyl, parafluorophenyl or paraethoxyphenyl, and Y
stands for phenyl, R1 may not stand for methyl, F) when A and B form together a valence bond, X is phenyl and Y is parahydroxyphenyl, R1 may not stand for methyl, G) when A and B form together a valence bond, and X and Y
each stand for paramethoxyphenyl, R1 may not stand for methyl, or stereoisomers of isomeric mixtures thereof, or a pharmaceutically acceptable acid addition salt of the basic compound having the, general formula (I), whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.

11. A compound of formula (I) as claimed in claim 10 in which A and B
form together a valence bond, whenever prepared or produced by the process of claim 3 or by an obvious chemical equivalent thereof.

12. A compound of formula (I) as claimed in claim 10 in which A and B
form together a valence bond or each of them represents hydrogen, X and Y
are identical or different and stand for phenyl or p-hydroxyphenyl and R1 is an epoxylakyl with up to four carbon atoms, an azidoethyl group or a group of the general formula (II), (II) wherin R2 and R3 each stand for hydrogen, a C1-4 alkyl group or a C1-4 hydroxyalkyl group or they form together with the adjacent nitrogen atom a piperazino, pyrrolidino, piperidino or morpholino group each optionally having a C1-4 alkyl substituent, with the proviso that, A) when A and B form together a valence bond and X and Y each stand for phenyl, R1 may not stand for a dimethylaminoethyl, diethylamino-ethyl, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the case of the (Z) isomers, or stereoisomers or isomeric mixtures thereof, or a pharmaceutically acceptable acid addition salt of the basic compound having the general formula (I), whenever prepared or produced by the process of claim 2 or by an obvious chemical equivalent thereof.

13. Threo-1-[4-(2,3-epoxypropoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propane, whenever prepared or produced by the process of claim 4 or by an obvious chemical equivalent therof.

14. (E)-1,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-/4-methyl-piperazino/-ethoxy)-phenyl]-propene or a pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process of claim 5 or by an obvious chemical equivalent thereof.

15. 1-[4-(2-Dimethylaminoethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-propene, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 6 or by an obvious chemical equivalent thereof.

16. (E)-1,2-Diphenyl-3,3,3-trifluoro-1-[4-(2-/2-hydroxy-ethylamino/-ethoxy)-phenyl] -propene, or a pharmaceutically accept-able acid addition salt thereof, whenever prepared or produced by the process of claim 7 or by an obvious chemical equivalent thereof.

17. (E)-1-[4-(2-Azidoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, whenever prepared or produced by the process of claim 8 or by an obvious chemical equivalent thereof.

18. 1-[4-(2-Dimethylaminoethoxy)-phenyl]-3,3,3-trifluoro-1,2-bis-(4-hydroxyphenyl)-propene or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 9 or by an obvious chemical equivalent thereof.

19. A process for the preparation of a 1,1,2-triphenylpropane derivative of the formula (I-i), (I-i) wherein X and Y are identical or different and stand for a phenyl group or a phenyl group having a fluorine atom, a chlorine atom, hydroxy or methoxy substituent in the para position, R1 is an epoxyalkyl with up to four carbon atoms, an azidoethyl, or a group of the formula (II-i) (II-i) wherein R2 and R3 each stand for hydrogen, a C1-6 alkyl group or a C2-4 hydroxyalkyl, or R2 and R3 form together with the adjacent nitrogen atom a heterocyclic group selected from heptamethyleneimino, piperazino, pyrrolidino, piperidino or morpholino group, each heterocyclic group optionally having methyl or hydroxyethyl substituent, or a stereoisomer or an isomeric mixture thereof, or a pharmaceuti-cally acceptable acid addition salt thereof, which process comprises:
a) for preparing a compound of the general formula (I-i) in which X and Y are identical or different and stand for a phenyl group or a phenyl group having a fluorine atom, a chlorine atom or methoxy substituent in the para position, R1 stands for azidoethyl group or a group of the general formula (II-i), reacting a phenoxyethylbromide of the general formula (III-i), (III-i) wherein X and Y are as defined in point a), with an amine of the general formula R2R3NH, wherein R2 and R3 are as defined above, or with an alkali metal azide, and, if desired, reducing the resulting azido derivative, and, if desired, converting a resulting amino derivative into the respective guanidino, aminoguanidino or nitro-guanidino derivative; or c) for preparing a compound of the general formula (I-i) in which X and Y are identical or different and represent an unsub-stituted phenyl group or a phenyl group having a fluorine, chlorine or methoxy substituent in the para position and R1 stands for an epoxyalkyl with up to 4 carbon atoms or a group of the formula (II-i), wherein R2 and R3 each stand for a C1-6 alkyl group or they form together with the adjacent nitrogen atom the heterocyclic group as defined above, reacting a compound of the formula (V-i), (V- i) wherein X and Y are as defined in point c), with. an R1-halide wherein R1 is as defined in point c) above in the presence of an acid binding agent;
and if desired, separating the individual isomers from a resulting isomeric mixture, and, if desired, liberating a basic compound from its acid addition salt and, if desired, converting a basic resulting compound into a pharmaceutically acceptable acid addition salt.

20. A process for the preparation of a 1,1,2-triphenylpropene derivative of the formula (I-ii), (I-ii) wherein X and Y are identical or different and stand for a phenyl group unsubstituted or substituted by p-fluoro, p-chloro-p-hydroxy or p-methoxy substituent, R1 is an epoxyalkyl with up to four carbon atoms, an azidoethyl or a group of the formula (II-ii), (II-ii) wherein R2 and R3 each stand for hydrogen, a C1-6 alkyl group or a C2-4 hydroxyalkyl, or R2 and R3 form together with the adjacent nitrogen atom a heterocyclic group selected from heptamethyleneimino, piperazino, pyrrolidino, piperidino or morpholino group, each heterocyclic group optionally having methyl or hydroxyethyl substitutent, with the proviso that, A) when X and Y each stand for phenyl or X is phenyl and Y is p- methoxyphenyl, R1 may not stand for a dimethylaminoethyl, diethyl-amino, pyrrolidinoethyl, piperidinoethyl or morpholinoethyl group in the case of (Z) isomers , D) when X stands for phenyl and Y stand for p-methoxyphenyl R1 may not stand for pyrrolidinoethyl, or a stereoisomer or an isomeric mixture thereof, or a pharmaceuti-cally acceptable acid addition salt thereof, which process comprises:
a) for preparing a compound of the general formula (I-ii) in which X and Y are identical or different and stand for a phenyl group unsubstituted or substituted by p-fluoro, p-chloro or p-methoxy substitutent, R1 stands for azidoethyl group or a group of the general formula (II-ii), reacting a phenoxyethylbromide of the general formula (III-ii), (III-ii) wherein X and Y are as defined in point a) with an amine of the formula R2R3NH, wherein R2 and R3 are as defined above, or with an alkali metal azide, and, if desired, reducing the resulting azido derivative, and if desired, converting a resulting amino derivative into the respective guanidino, aminoguanidino or nitro-guanidino derivative; or b) for preparing a compound of the general formula (I-ii) in which X and Y are identical or different and represent a phenyl group unsubstituted or substituted by p-chloro or p-methoxy sub-stituent and R1 stands for the general formula (II-ii), wherein R2 and R3 form together with the adjacent nitrogen atom the hetero-cyclic group as defined above, reacting a compound o e the general formula (IV-ii), (IV-ii) wherein X and Y are as defined in point b) above, with an alcohol derivative of the general formula R1OM, wherein R1 is as defined in point h) and M stands for an alkali metal atom;
c) for preparing a compound of the general formula (I-ii) in which X and Y are identical or different and represent a phenyl group unsubstituted or substituted with p-fluoro, p-chloro or p-methoxy substitutent and R1 stands for an epoxyalkyl with up to four carbon atoms or a group of the formula (II-ii), wherein R2 and R3 each stand for a C1-6 alkyl or they form together with the adjacent nitrogen atom the heterocyclic groups as defined above, reacting a compound of the general formula (V-ii), (V-ii) wherein X and Y are as defined in point c) with an R1-halide wherein R1 is as defined in point c) above in the presence of an acid binding agent; or d) for preparing a compound of the general formula (I-ii) in which X and Y stand for a p-hydroxyphenyl group and R1 is a group of the general formula (II-ii), wherein R2 and R3 each represent hydrogen or a C1-6 alkyl group or they form together with the adjacent nitrogen atom the heterocyclic group as defined above, reacting a compound of the general formula (IV-ii) wherein X and/or Y is a p-(methoxymethoxy)-phenyl group or a benzyloxyphenyl group with an alcohol derivative of the general formula R1OM wherein R1 is as defined in point d) and M is an alkali metal atom, and then splitting off the methoxy group or the benzyloxy group of the condensation product; or e) for preparing a compound of the general formula (I-ii) in which X and Y are identical or different and stand for a phenyl group unsubstituted or substituted with p-fluoro, p-chloro or p-methoxy substitutent and R1 represents an epoxyalkyl with up to four carbon atoms or azidoethyl, dehydrogenating a compound of the formula wherein X, Y and R1 are as defined in point e);
and, if desired, separating the individual isomers from a resulting isomeric mixture, and, if desired, liberating a basic compound from its acid addition salt, and, if desired, converting a basic compound to its pharmaceutically acceptable acid addition salt.