JPH0234933B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 1,1,2-triphenyl-
The present invention relates to propane and -propene derivatives, processes for their production, and pharmaceutical compositions containing the same. As is well known, some triphenylalkene derivatives have estrous effects [J. Grun ^- dy: Chem.Rev. 57 , 281 (1957); PR Carter et al.: J.Chem.Soc. 1948 , 150;
NP boo. Buu-Hoi et al.: Chim.Ther.
1969, 327; WJ Middleton et al.
J.Med.Chem. 14 , 1193 (1971): U.S. Patent No.
Specification No. 3712929]. Similar derivatives having a basic substituent on the phenyl ring mainly have an estrus-suppressing effect [DJ Collins et al.: J.Med.Chem. 14 ,
952 (1971)]. The two most important of these compounds are
Two examples are 1-[4-(2-diethylaminoethoxy)-phenyl]-1,2-diphenyl-2-chloroethylene [Clomifen and (Z)-1-[4-(2-dimethyaminoethoxy) )−
phenyl]-1,2-diphenyl-1-butene [Tamoxi ^- fen] [FP
Palopoli et al.: J.Med.Chem. 10 , 84
(1966); GR Bedford et al.
See Nature 212 , 733 (1966)]. Both of these compounds exhibit antiestrus activity (estrogen-antagonist and weak estrogen agonist activity), but the former compound primarily because it induces ovulation [M. Murray et al.: J. Obstet. Gynaec.
Br.Commow. 78 , 1108 (1971)] and for the treatment of oligospermia [JF Potts: J.Am.Med.Ass.
231, 907 (1975)], and the main field of use of tamoxifen is the treatment of mammary tumors [MP Cole et al.: Brit. J. Cancer 1971 , 270].
However, both of these compounds can cause ocular damage with long-term treatment [H.J. Silverman; Am.J.Optom. 49 , 335 (1972); L.
M. Roch et al.: Arch. Ophtalm. 77 , 14
(1967); MJ Kaiser-
Kupfer et al.: Cancer Treatment Rep. 62 , 315
(1978)], liver damage [Martindale: The Extra Pharmacopoeia
, 1392 (1977); The Pharmaceutical
Press, London] and thrombosis [K. Nevasaari et al.: Lancet, 946 (1978)]. The present invention aims to provide new compounds that are more active, more specific and cause fewer undesirable side effects than known compounds. The novel compounds of the present invention have various effects on the endocrine system and significantly inhibit the growth of mammary tumors induced experimentally by 7,12-dimethyl-benzoanthracene (DMBA). The novel 1,1,2-triphenyl-propane and -propane derivatives according to the present invention correspond to the following general formula (). In the above formula (), A and B each represent hydrogen, or A and B
together form a valence bond, X and Y may be the same or different, and a phenyl group or a halogen, hydroxy,
Represents a phenyl group having a methoxymethoxy, C _1-6 alkoxy or benzyloxy substituent, R ₁ is a C _1-4 epoxyalkyl, azidoethyl or methoxymethyl group or the general formula () [In the above formula (), R ₂ and R ₃ each represent hydrogen, C _1-4 alkyl, hydroxyalkyl, or haloalkyl group, or R ₂ and
R ₃ together with the adjacent nitrogen atom is an 8-membered or less heterocyclic group, and a 5- or 6-membered heterocyclic group further has a nitrogen or oxygen atom (the heterocyclic group is a C _1-4
(substituted with an alkyl or hydroxyalkyl group or unsubstituted), forming an aminoguanidino group or a nitroguanidino group], provided that (i) A and B taken together have a valence of and when X and Y each represent phenyl, R ₁ is not dimethylaminoethyl, diethylaminoethyl, morpholinoethyl or piperidinoethyl; (ii) A and B together form a valence bond; and when X is phenyl and Y is p-methoxyphenyl, R ₁ is not pyrrolidinoethyl. Stereoisomers and isomeric mixtures as well as acid addition salts of the compounds are also included within the scope of the invention. The term "alkyl group", whether used alone or in combination (e.g. alkoxy, azidoalkyl, epoxyalkyl, hydroxyalkyl or haloalkyl), refers to 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
straight-chain or branched aliphatic saturated hydrocarbyl groups (e.g. methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, etc., preferably methyl or ethyl group).
The term "halogen" includes all four halogens: fluorine, chlorine, bromine and iodine. R ₂ and R ₃ together with adjacent nitrogen atoms,
When forming an alkyl- or hydroxyalkyl-substituted or unsubstituted heterocyclic group, this group is preferably a pyrrolidino, piperidino, heptamethyleneimino, morpholino, piperazino or N-methylpiperazino group. In a preferred subgroup of compounds having the general formula (), A and B together form a valence bond. A and B each represent hydrogen or A and B
together form a valence bond;
may be the same or different and are phenyl or p-hydroxyphenyl groups; R ₁ is
C _1-4 ethoxyalkyl group, C _1-4 azidoalkyl group or general formula () [wherein R ₂ and R ₃ each represent hydrogen, C _1-4 alkyl group or C _1-4 hydroxyalkyl group] or R ₂ and R ₃ taken together with adjacent nitrogen atoms to form piperazino, pyrrolidino, with or without a C _1-4 alkyl substituent;
Preference is also given to compounds of the general formula () which represent a group of 1 to form a piperidino or morpholino group. Particularly preferred examples of compounds of general formula () are the following derivatives: threo-1-[4-(2,3-epoxypropoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro -propane,
(E)-1,2-diphenyl-3,3,3-trifluoro-1-{4-[2-(4-methylpiperazino)
-ethoxy]-phenyl}-propene, 1-[4-
(2-dimethylaminoethoxy)-phenyl]-2
-phenyl-3,3,3-trifluoro-1-
(4-hydroxyphenyl)-propene, 1,2-
diphenyl-3,3,3-trifluoro-1-
{4-[2-(2-hydroxyethylamino)-ethoxy]-phenyl}-propene, (E)-1-[4-
(2-azidoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, 1-[4-(2-dimethylamino-ethoxy)
-phenyl]-3,3,3-trifluoro-1,
2-bis-(4-hydroxyphenyl)-propene and its pharmaceutically acceptable acid addition salts The basic compounds of general formula () include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, and lactic acid. ,
Forms acid addition salts with inorganic or organic acids such as methanesulfonic acid, p-toluenesulfonic acid, citric acid, and the like. Compounds of general formula () can exist in various stereoisomeric forms such as the (Z) isomer and the (E) isomer, the threo isomer and the erythro isomer. All stereoisomers of the compound of general formula () and mixtures thereof, processes for their preparation, and pharmaceutical compositions containing said isomers or said mixtures of isomers are included within the scope of the present invention. The present invention also provides a general formula () (wherein A, B,
1, 1, where X, Y and R ₁ are as described above)
Methods for producing 2-triphenyl-propane and -propene derivatives and their stereoisomers and isomer mixtures and acid addition salts are provided. These compounds are prepared according to the invention as follows: a General formula () [wherein A and B are as described above; phenyl, p-halophenyl or p
-(C _1-6 alkoxy)-represents a phenyl group;
When producing a compound of the general formula () in which R ₁ is an azidoethyl group or a group of the general formula () (in which R ₂ and R ₃ are as described above), the compound of the general formula () [In the above formula (), A and B are as described above; X and Y may be the same or different, and represent phenyl, p-halofenyl or p-(C _1-6 alkoxy)-phenyl group Z represents a halogen or a sulfonyloxy group] _{A phenoxyalkyl} halide or _{a phenoxyalkyl} sulfonate of or with an alkali metal azide, and if desired further reduce the azide derivative obtained, and if desired further convert the amino derivative obtained to the corresponding guanidino, aminoguanidino or nitroguanidino derivative. b general formula () {where A and B together form a valence bond; X and Y may be the same or different; Chloro, bromo, methoxymethoxy at para position,
C _1-6 represents a phenyl group having an alkoxy or benzyloxy substituent; R ₁ is the general formula () [wherein R ₂ and R ₃ are each hydrogen or
C _1-6 alkyl group or R ₂ and R ₃
represents, taken together with adjacent nitrogen atoms, a heterocyclic group of up to 8 members, or a heterocyclic group of up to 6 members, which may or may not further contain one or more other heteroatoms; The group is substituted with a lower alkyl or hydroxyalkyl group or is unsubstituted). [In the general formula (), A and B represent _hydrogen ; Representing a phenyl group having a benzyloxy substituent] is dehydrogenated, and then a compound of the general formula R ₁ OM {wherein R ₁ is the general formula () [wherein R ₂ and R ₃ each represent hydrogen] is dehydrogenated. mosquito,
or R ₂ and R ₃ taken together with adjacent nitrogen atoms form a heterocyclic group of up to 8 members or a heterocyclic group of up to 6 members with or without one or more other heteroatoms; (the heterocyclic group is substituted with a lower alkyl or hydroxyalkyl group or unsubstituted)]; M represents an alkali metal atom}; or; General formula () {wherein A and B _are as described above; R ₁ represents a phenyl group having a C _1-6 alkyl, epoxyalkyl, methoxymethyl or benzyl group, or a general formula ( ) [R ₂ and R ₃ each represent a C _1-6 alkyl group, or R ₂ and R ₃ taken together with adjacent nitrogen atoms represents a heterocyclic group of up to 8 members or a heterocyclic group of up to 6 members, which may or may not further contain one or more other heteroatoms. cyclic groups are substituted with lower alkyl groups or unsubstituted)]
When producing a compound of the general formula (representing a group), [In the general formula (), A and B _are as described above; R ₁ -halide or R ₁ -sulfonate {where R ₁ is
C _1-6 alkyl, epoxyalkyl, methoxymethyl or benzyl group or general formula ()
[R ₂ and R ₃ each represent a C _1-6 alkyl group,
or R ₂ and R ₃ taken together with adjacent nitrogen atoms form a heterocyclic group of up to 8 members or a heterocyclic group of up to 6 members with or without one or more other heteroatoms; (the heterocyclic group is substituted with a lower alkyl group or unsubstituted)]; or; d with the general formula () {in which A and B are the same to form a valence bond; X and/or Y are p-hydroxyphenyl groups; R ₁ is of the general formula () [wherein R ₂ and R ₃ are each hydrogen or
C _1-6 alkyl group or R ₂ and R ₃
and together with adjacent nitrogen atoms form a heterocyclic group of up to 8 members or a heterocyclic group of up to 6 members with or without one or more other heteroatoms (the heterocycle When producing a compound of the general formula () [wherein A and B together represent an atom form a valence bond; X and/or Y are p
-(methoxymethoxy)-phenyl group or benzyloxyphenyl group] is a compound of the general formula R ₁ OM {wherein R ₁ is the general formula () [in the formula,
R ₂ and R ₃ each represent hydrogen or a C _1-6 alkyl group, or R ₂ and R ₃ together with adjacent nitrogen atoms represent a heterocyclic group of up to 8 members or one or more (the heterocyclic group is substituted with a lower alkyl group or is unsubstituted); an alkali metal atom}, and then carry out an ether cleavage reaction on the methoxymethoxy group or benzyloxy group, or; form _a valence bond; ; R ₁ represents C _1-6 alkyl, epoxyalkyl, azidoethyl, methoxymethyl or benzyl group], when producing a compound of the general formula () [wherein A and B each represent hydrogen; and Y may be the same or different and represent an unsubstituted phenyl group or halo at the para position,
methoxymethoxy, a phenyl group having a C _1-6 alkoxy or benzyloxy substituent; R ₁ is a C _1-6 alkyl, epoxyalkyl,
azidoethyl _, methoxymethyl or benzyl _{group ]} or _{; -6} haloalkyl group)], the compound of the general formula () [wherein R ₁ is the general formula () (wherein R ₂ and/or R ₃ are C _{1 -6} hydroxyalkyl group)] and; if desired, further separating the individual stereoisomers from the resulting isomer mixture; The basic compound of () is converted into an acid addition salt or the compound is liberated from its acid addition salt. Step a of the process of the invention is preferably carried out as follows: the starting material of general formula () is introduced into an acid binder (e.g. carbonic acid or reacted with an alkali metal azide in dimethylformamide or preferably aqueous _{2 -} methoxyethanol. If desired, the azide derivative obtained can be reduced according to methods known per se, for example with an alkali metal hydride or with hydrogen in the presence of a palladium-supported carbon catalyst. In the starting materials of general formula (), Z is preferably a halogen atom (fluorine, chlorine, bromine or iodine), an alkylsulfonyloxy group (e.g. methylsulfonyloxy group) or an arylsulfonyloxy group (e.g. phenylsulfonyloxy group). , p-toluenesulfonyloxy or p-bromophenylsulfonyloxy groups). b) of the process of the invention is preferably carried out as follows: a compound of the general formula () in which A and B represent hydrogen and 1 to 3 molar equivalents of 2,
3-dichloro-5,6-dicyano-1,4-benzoquinone in an inert solvent (e.g. benzene or dioxane) at the boiling point of the reaction mixture.
and the resulting compound is reacted in a dipolar neutral solvent (e.g. dimethylacetamide, hexamethylene triamide, etc.) or preferably in an excess amount of an alcohol of general formula R ₁ OH.
React with alcohol derivative of R ₁ OM. The latter reaction is preferably carried out at 100-160°C. According to c) of the process of the invention, a phenol derivative of the general formula () and R ₁ -halide or R ₁ -sulfonate are combined in an alkali metal hydroxide or an alkali solution in a solvent or diluent such as benzene, alcohol, etc. The reaction is carried out in the presence of an acid binder such as a metal carbonate. Preferably, the process is carried out using an alkali metal salt of the starting phenol derivative which also acts as an acid binding agent. Preferably, step d) of the method of the invention is carried out in the same manner as b) above. The resulting methoxymethoxy or benzyloxy derivative is then treated with acid or reduced to effect cleavage of the ether group. In e) of the method of the present invention, the general formula ()
The compound [wherein A and B are each hydrogen] is dehydrogenated. Dehydrogenation is carried out by combining the starting materials with 2,3-dichloro-5,
It is preferably carried out by reaction with 6-dicyano-1,4-benzoquinone (Org.
Synth.Coll.Vol. 5 , 428-431). According to f) of the method of the invention, the general formula () [wherein R ₁ is the general formula () (wherein R ₂ and/or R ₃
represents a hydroxyalkyl group]
By reacting the compound with a halogenating agent, the corresponding derivatives in which R ₂ and/or R ₃ are haloalkyl groups are obtained. The halogenation is carried out using customary halogenating agents such as thionyl chloride and the like according to methods known per se. Individual isomers can be separated from their mixtures according to methods known per se, such as fractional crystallization. Basic compounds of general formula () can be converted into their acid addition salts by reacting with a suitable acid in an inert solvent. Among acid addition salts, those formed with pharmaceutically acceptable acids are preferred. The corresponding base can be liberated from the acid addition salt by treating the acid addition salt with a strong base. The starting materials for the general formulas (), () and () are:
(Z)-1,2-diphenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-propene, (Z)-1,2-diphenyl-3,3,3-trifluoro- 1-(4-hydroxyphenyl)-propene and (E)-2-phenyl-3,3,3-
Trifluoro-1-(4-hydroxyphenyl)-
All compounds other than 1-(4-methoxyphenyl)-propene are new. The preparation of new starting materials is described in detail in the Examples. The endocrine effect and tumor suppressive effect of the novel compound according to the present invention will be demonstrated by the tests described below. The test compound is described below: 1 = threo-1-[4-(2,3-epoxypropoxy)-phenyl]-1,2-diphenyl-3,
3,3-trifluoro-propane; 2=(E)-1-[4-(2,3-epoxypropoxy)-phenyl]-1,2-diphenyl-3,
3,3-trifluoro-propene; 3=(E)-1,2-diphenyl-3,3,3-
Trifluoro-1-{4-[2-(bis-(2-hydroxyethyl)-amino)-ethoxy]-phenyl}
-propene; 4=(E)-1,2-diphenyl-3,3,3-
Trifluoro-1-{4-[2-(4-methylpiperazino)-ethoxy]-phenyl}-propene; 5=1-[4-(2-dimethylaminoethoxy)
-Phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)-propene; 6=1-[4-(2-dimethylaminoethoxy)
-Phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-propene; 7=(E)-1,2-diphenyl-3,3,3-
Trifluoro-1-{4-[2-(2-hydroxyethylamino)-ethoxy]-phenyl}-propene; 8=1-[4-(2-dimethylaminoethoxy)
-Phenyl]-1-phenyl-3,3,3-trifluoro-2-(4-hydroxyphenyl)-propene; 9=(E)-1,2-diphenyl-3,3,3-
Trifluoro-2-[4-(2-pyrrolidinoethoxy)-phenyl]-propene; 10=(E)-1,2-diphenyl-3,3,3-
Trifluoro-1-[4-(2-morpholinoethoxy)-phenyl]-propene; 11=(E)-1-[4-(2-diethylaminoethoxy)-phenyl]-1,2-diphenyl-3,
3,3-trifluoro-propene; 12=(E)-1-[4-(2-azidoethoxy)-
phenyl]-1,2-diphenyl-3,3,3-
Trifluoro-propene; 13=(E)-1,2-diphenyl-3,3,3-
Trifluoro-1-{4-[2-(bis-(2-chloroethyl)-amino)-ethoxy]-phenyl}-propene; 14 = 1-[4-(2-dimethylaminoethoxy)
-phenyl]-3,3,3-trifluoro-1,
2-bis-(4-hydroxyphenyl)-propene hydrochloride; 15=1-phenyl-2-(4-methoxyphenyl)-1-[4-(2-dimethylaminoethoxy)-
phenyl]-3,3,3-trifluoro-propene; 16=(E)-1,2-diphenyl-3,3,3-
Trifluoro-1-{4-[2-(nitroguanidino)-ethoxy]-phenyl}-propene. Estrus suppression effect was measured by the method of MJK Harper et al. [J. Report. Fert. 13 , 101 (1967)]. 24-day-old female rats were given estradiol at a daily dose of 5 μg/Kg for 3 days. Test compounds were also administered orally once daily for 3 days. On the fourth day, the animals were sacrificed and the uterus was removed and weighed. Table 1 shows data specific to the antiestrus effect (inhibition of the uterine stimulating effect of estradiol) of some compounds according to the present invention. The antiestrus activity of some of the compounds listed in Table 1 reaches that of clomifene or tamoxifen used as reference substances, but compound number 1 has negligible activity when applied at an oral dose of 1 mg/Kg. This will only result in severe restraint. Even when the dose was increased to 10 mg/Kg, the degree of inhibition was still low (39%). [Table] Estrus effect (uterine stimulation effect) is measured by RJ Dorfman's method [Endorinology 55 , 65
(1954)]. A daily dose of the test compound was orally administered once a day to 24-day-old female rats. 4
On day 1, the animals were sacrificed and the uterus was removed and weighed. Data specific to the estrous effect (uterine stimulatory effect) of some compounds according to the invention are shown in Table 2. We also tested ethinyl estradiol, a highly effective estrus stimulant, as well as two known estrus suppressants, clomiphene and tamoxifen.
Their activities are also listed in Table 2. The compounds listed in Table 2 generally have a weak estrous effect, or at doses ranging from 0.1 to 1.0 mg/Kg.
It is somewhat less active than tamoxifen in the range of . However, the dose-response curve for Compound No. 1 is somewhat steeper than for the other compounds. Therefore, low doses (0.01 to 3.0 mg/Kg)
When applied in greater than the maximum increase in uterine weight caused by oestrus drugs. [Table] [Table] The stimulatory effect on the secretion of luteinizing hormone (LH) was determined as follows: The test compound was administered subcutaneously to 24-year-old infant female rats for 2 consecutive days. Two hours after the second administration, blood was collected and luteinizing hormone (LH) levels in plasma were measured by radioimmunoassay. When administered subcutaneously at a dose of 1 mg/Kg, the test compound
Significantly increased LH levels. The results obtained are summarized in Table 3. [Table] The effects of new compounds on hormone-dependent tumors were determined according to the method of P. Griswold et al. [Cancer Research 26 , 2169 (1966)].
Breast adenocarcinoma induced by 7,12-dimethyl-benzoanthracene (DMBA) was tested. Treatment began when tumor weight reached approximately 500 mg. The animals were administered the active drug orally at a dose of 20 mg/Kg three times a week for three months.
The method of Griswold et al. and the method of VC Jordan et al. [Europ.J.Cancer 12 ,
419 (1976)], tumor dimensions were measured with a caliper gauge. Tumor volume was measured by Griswold's method. After completion of treatment, animals continued to be observed for an additional 2 months, during which time tumor size and volume were also measured. A relative efficacy index was determined to confirm the activity of the test compound. To calculate the relative efficacy index, the number of animals exhibiting curative or temporary cure or remission of disease of various durations was determined and scored according to the table below. Curative 10 points Temporary cure 8 points Permanent sedation 6 points Short-term sedation or unchanged state 4 points The change in the average number of tumors that occurred during the treatment period was evaluated according to the following scale. No change in the total number of tumors in any animal 8 points Average tumor number increased by 2 times 6 points Average tumor number increased by more than 2 times 0 points Measured for individual animals according to the two scales mentioned above The scores were added and the results were expressed as a percentage of the score corresponding to maximum activity (cure).
This percentage value is the relative effectiveness index. The test results obtained are shown in Table 4. In the table, numbers in parentheses have the following meanings: (1) permanent cure; (2) temporary cure; (3) permanent sedation; (4) short-term sedation; (5) unchanged state. [Table] The following table shows the acute toxicity test results for several compounds obtained in the Examples of the present invention and a comparative compound (tamoxifen). [Table] [Table] Mouse Rat Example number po. ip. po. ip.

Claims (1)

[Claims] 1 1,1,2-triphenyl- of the general formula ()
Propane and -propene derivatives and their stereoisomers and isomeric mixtures and acid addition salts: {In the above formula (), A and B each represent hydrogen, or A and B together form a valence bond, X and Y may be the same or different, and a phenyl group or halogen, hydroxy, at para position
Represents a phenyl group having a methoxymethoxy, C _1-6 alkoxy or benzyloxy substituent, R ₁ is C _1-4 epoxyalkyl, azidoethyl,
or methoxymethyl group or general formula () [In the above formula (), R ₂ and R ₃ each represent hydrogen, C _1-4 alkyl, hydroxyalkyl, or haloalkyl group, or R ₂ and R ₃
and together with the adjacent nitrogen atom are 8-membered or less heterocyclic groups, and 5- or 6-membered heterocyclic groups having nitrogen or oxygen atoms (the heterocyclic group is C _1-4 alkyl or (substituted with a hydroxyalkyl group or unsubstituted), forming an aminoguanidino group or a nitroguanidino group], provided that (i) A and B together form a valence bond; and when X and Y each represent phenyl, R ₁ is not dimethylaminoethyl, diethylaminoethyl, morpholinoethyl or piperidinoethyl; (ii) A and B together form a valence bond; and when X is phenyl and Y is p-methoxyphenyl, R ₁ is not pyrrolidinoethyl}. 2. The compound according to claim 1, wherein A and B together form a valence bond. 3 A and B together form a valence bond or A and B are each hydrogen;
may be the same or different and represent phenyl or p-hydroxyphenyl, and; R ₁ is
C _1-4 epoxyalkyl group, C _1-4 azidoalkyl group or general formula () [wherein R ₂ and R ₃ each represent hydrogen, C _1-4 alkyl group or C _1-4 hydroxyalkyl group] or R ₂ and R ₃ together with adjacent nitrogen atoms form a C _1-4 alkyl substituent-bearing or unsubstituted piperazino, pyrrolidino, piperidino or morpholino group. A compound according to item 1. 4 threo-1-[4-(2,3-epoxypropoxy)-phenyl]-1,2-diphenyl-3,
A compound according to claim 1 which is 3,3-trifluoro-propane. 5 (E)-1,2-diphenyl-3,3,3-
The compound according to claim 1, which is trifluoro-1-{4-[2-(4-methylpiperazino)-ethoxy]-phenyl}-propene. 6 (E)-1,2-diphenyl-3,3,3-
The compound according to claim 1, which is trifluoro-1-[4-(2-heptamethyleneimino-ethoxy)-phenyl]-propene. 7 (E)-1,2-diphenyl-3,3,3-
The compound according to claim 1, which is trifluoro-1-[4-(2-nitroguanidino-ethoxy)-phenyl]-propene. 8 1-[4-(2-dimethylaminoethoxy)-
[phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-propene. 9 1-[4-(2-dimethylamino-ethoxy)
-Phenyl]-1-phenyl-3,3,3-trifluoro-2-(4-methoxyphenyl)-propene. 10 1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)-propene Claim 1 Compounds described in Section. 11 (E)-1,2-diphenyl-3,3,3
The compound according to claim 1, which is -trifluoro-1-{4-[2-(2-hydroxyethylamino)-ethoxy]-phenyl}-propene. 12 (E)-1-[4-(2-azidoethoxy)-
phenyl]-1,2-diphenyl-3,3,3-
A compound according to claim 1 which is trifluoro-propene. 13 1-[4-(2-dimethylaminoethoxy)
-phenyl]-3,3,3-trifluoro-1,
The compound according to claim 1, which is 2-bis-(4-hydroxyphenyl)-propene. 14 1-[4-(2-dimethylaminoethoxy)
-phenyl]-3,3,3-trifluoro-1,
The compound according to claim 1, which is 2-bis-(4-hydroxyphenyl)-propene hydrochloride. 15 At least one general formula () {In the above formula (), A and B each represent hydrogen, or A and B together form a valence bond, X and Y may be the same or different, and a phenyl group or halogen, hydroxy, at para position
Represents a phenyl group having a methoxymethoxy, C _1-6 alkoxy or benzyloxy substituent, R ₁ is a C _1-6 alkyl, epoxyalkyl, azidoalkyl, methoxymethyl or benzyl group or the general formula () [In the above formula (), R ₂ and R ₃ each represent hydrogen, C _1-6 alkyl, hydroxyalkyl, or haloalkyl group, or R ₂ and R ₃
together with the adjacent nitrogen atom, a heterocyclic group of up to 8 members, a heterocyclic group of up to 6 members, which may or may not further contain one or more other heteroatoms (the heterocyclic group is substituted with a lower alkyl or hydroxyalkyl group or is unsubstituted), forming a guanidino group, an aminoguanidino group or a nitroguanidino group], provided that (i) A and B together form a valence bond and X and Y each represent phenyl, R ₁ is not dimethylaminoethyl, diethylaminoethyl, morpholinoethyl or piperidinoethyl; (ii) A and B taken together and when X is phenyl and Y is p-methoxyphenyl, R ₁ is not pyrrolidinoethyl. Hormone-dependent mammalian tumor suppressing effect and estrus suppressing effect, which contains a stereoisomer or a mixture of isomers or a pharmaceutically acceptable acid addition salt of the active ingredient, and is compounded with a commonly used inert solid or liquid pharmaceutical carrier. Pharmaceutical composition for use.