JPS58216129A - Novel alkane and alkene derivative, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an alkane or alkene derivative or a pharmacologically acceptable salt or ester thereof, a method for producing the same, and a drug containing the same as an active ingredient.

More specifically, the present invention provides compounds of the formula (Io): (wherein R and R are the same or different, and H1OaS has 1 to 4 carbon atoms.
alkoxy group, benzyloxy group or methoxymethoxy group; A is the formula: (wherein, n is 0 or 1-4; R is H
, OH, hydrogen atom, alkoxy group having 1 to 4 carbon atoms,
benzyloxy group, methoxymethoxy group, 2,3-dihydroxypropoxy group or a group represented by the formula: is a group capable of forming a 6- to 6-membered ring containing a nitrogen atom; R is OH1,L , OI NB
iF in which r, engineering, formyloxy group, mesyloxy group, tosyloxy group, alkyloxy group having 1 to 4 carbon atoms or 10H2R' is substituted with OHO;
t is H or OH; or R and R5 together form a 10-bridge between adjacent carbon atoms; provided that a) if n is 0, R and R are simultaneously H or a methoxy group; (b) If n is 0, R3 is other than a herogen atom. (c) If n is 91 and R and R are both OH, or R4 and R5 are the same duck. When a 10-bridge is formed between adjacent carbon atoms, R, R and R3 do not become H at the same time, or.

(d) When n is 2 and R and R together form a 10-bridge between adjacent carbon atoms, RlR and R do not become H at the same time). and when A in the formula (1, O) is the formula:, the formula (Io) is the formula (I):3 or the formula (■): (wherein RXR, R, R, R and n (same as above) or a pharmacologically acceptable non-toxic salt or ester thereof, or a mixture thereof.

One of the characteristics of the compound of the present invention is the functional group attached to the end of the alkyl side chain of the triphenylethene or triphenylethane skeleton.

Among the compounds represented by formula (I) or (II) of the present invention, preferred are those in which at least one of R1, R2, or R3 has a group represented by OH, methoxy group, or ethoxy group. It is something that exists.

When R and R are taken together to form a 10-bridge between adjacent carbon atoms, preferred heterocyclic rings include a tetrahydro-heptarane ring and a tetrahydro-tetrabilane ring.

When R6 and/or R is an alkyl group having 1 to 4 carbon atoms, it is preferably a methyl group or ethyl group, such as an aziridinyl group, a pyrrolidinyl group, a piperidino group or a morpholino group. Further, the value of n is preferably 1 or 2.

Among the compounds of the present invention, preferred are 1-phenyl-1,2-bis(4-hydroxyphenyl)-1
-buten-4-ol, 4-bromo-1-7enyl-1
, 2-bis(4-hydroxyphenyl)-1-butene,
2-phenyl-2,3-bis(4-hydroxyphenyl)tetrahydrofuran, 1,2-diphenyl-1-(4
-hydroxyphenyl)-1-pentan-5-ol,
2.6-diphenyl-2-(4-hydroxyphenyl)
Tetrahytotetrabiran, 1,2-diphenyl-1-(4-
hydroxyphenyl)-1-penten-5-ol, 1
．． 2-diphenyl-1-(4-hydroxyphenyl)-
1-buten-4-ol, 2,6-diphenyl-2-(
4- and dorxiphenyl)tetrahydrofuran, 1.2
-diphenyl-1-(4-(2-(N,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol, 4-chloro-1,2-diphenyl-1-(4(2-(
N, N-dimethylamino)ethoxy]phenyl]-1
-butene, 4-chloro-1,2-diphenyl-1-(4
-(2-(1-aziridinyl)ethoxy]phenyl]-
1-Butene, 4-butetramo 1,2-diphenyl-1-(
4-(2-(1-pyrrolidinyl)ethoxy]phenyl)
-1-butene, 2. +-diphenyl-2-[4-(2-
(N, N-diethylamino)ethoxy]phenyl]tetrahydrofuran, 1-phenyl-1,2-bis(4-
hydroxyphenyl)butan-4-ol, 4-bromo-1-phenyl-1,2-bis(4-hydroxyphenyl)butane, 1,2-diphenyl-1-(4-hydroxyphenyl)butan-4-ol, 4-chloro-1,2
-diphenyl-1(4-(2-piperidinoethoxy)phenylcobutane, 1,2-diphenyl-1-(4-hydroxyphenyl)butane-1,4-diol, 1-phenyl-1,2-bis (4-hydroxyphenyl)butane-1,4-diol, 1,2-diphenyl-1-(4-
methoxyphenyl)-1-buten-4-ol, 4-bromo-1,2-diphenyl-1-[4(2-(N, N
-dimethylamino)ethoxy]phenyl]-1-butene, 4-chloro-1,2-diphenyl-1-(4-hydroxyphenyl)butane, 4-chloro0-1,2-diphenyl-1-'(4- hydroxyphenyl)-1-butene,
Examples include 1,2-diphenyl-1(4(2-(N, N-dimethylamino)ethoxy]phenyl]butane-1,4-diol).

The compounds of the present invention include not only their pure (RR,5S)-enantiomers and (R8,E[R)-enantiomers and mixtures thereof, but also their (2)-isomers and (E)-
It includes isomers and mixtures thereof.

The present invention provides an organic or inorganic acid of the amino-substituted compound of the compound of formula (Io) of the present invention, such as citric acid,
It relates to pharmacologically acceptable salts with hydrochloric acid. The present invention further provides quaternary ammonium salts, such as N-oxides made from amino-substituted compounds as well as mesoiodides (
It also includes salts such as methoiodid θ) and benzochloride. The present invention includes pharmacologically acceptable salts made by treating phenol derivatives with an inorganic base, such as sodium hydroxide. The invention further includes esters made by treating phenol derivatives with aliphatic carboxylic acids, aromatic carboxylic acids, such as acetic acid, benzoic acid.

The compounds of the present invention are estrogens (θstrogeni
o) action, antiestrogens
io) action or progestani
o) It is pharmacologically useful because it has an action. Therefore, among the compounds of the present invention, those with suspected estrogen, anti-estrogen O'f > or progestan activity are useful as medicines.

The compounds of the present invention are useful against hormone-dependent tumors, and are particularly useful in the treatment of breast cancer.

According to the present invention, a compound of formula (I) or formula (II) (wherein Rlag and R21L are R1 and R21L, respectively)
2 or a mixed acetal, e.g. (tetrahydropyran-2-yl)oxy group) or a derivative thereof of the formula: hal-(OH2),0H20R"
(IV) Protected haloalcohols represented by the formula (wherein haj is a halogen atom, n is the same as above, and OR'' is a mixed acetal, such as a (tetrahydropyran-2-yl)oxy group or a benzyloxy group) It can be produced by alkylating with formula (V): (wherein Rla, R2a, n and OR8 are the same as above) to obtain a protected diphenyloxoalkanol of formula (V) or of formula (
vl): (wherein haj is the same as above, R31 is the same as R3 or mixed acetal, for example (tetrahydropyran-
2-yl)oxy group) or its corresponding lithium compound by Grignard reaction, and the formula α@: (where nXR15, R2'', R3 & and R8 are the above-mentioned ) is a protected triphenyldiol.

The same protected triphenyl diol can be obtained by exchanging R2a of the intermediate of formula (1) and R3- of the reagent of formula (2) or (to). When OR is a mixed acetal, the protecting group R can be removed, for example, with a suitable acid catalyst in the presence of water. If there is a mixed acetal of protective groups on the phenyl ring, it can be removed in the same manner. As a result of such a protecting group removal reaction, the formula
:η3 The indicated triphenyl diol can be changed. Triphenyldiol of formula (1) is dehydrated, for example, in the presence of water or under dry conditions with a suitable acid catalyst. Depending on the reaction conditions and the value of n, triphenylcyclooxaalkane t[is] triphenyl represented by 2〇〇: 3 or the formula (XD: R3 (where nXR1, R2 and R3 are the same as above) Alkenols or mixtures thereof can be used. If the protecting group removal reaction and dehydration reaction are performed simultaneously, triphenylcyclo-oxa-alkane (3) or triphenylalkenol (3) or a mixture thereof can be obtained from protected triphenyldiol in one step. I can do it. Furthermore, by selecting appropriate reaction conditions, triphenylalkenol (I) can be obtained from triphenylcyclo-oxa-alkane (I).

When R8 is a benzyl group, the protecting group R8 can be removed by catalytic reduction of the protected triphenyldiol function.
It is preferable to remove. If appropriate conditions are selected, compounds similar to those obtained by removing the mixed acetal can be obtained. If a benzyl protecting group is present on the phenyl ring, it can be removed in the same manner.

The reaction of removing the protecting group from the protected triphenyldiol (a) and then dehydrating it can also be carried out in the reverse order as shown below. That is, first, for example, protected triphenyldiol size 0 is dehydrated using a mixture of an acid anhydride and an acid chloride to obtain a compound represented by the formula (2): (where n5R1aXR2a1R3aOyohiR8 is the same as above). The protected triphenylalkenol is then removed as before, and the protective group mixed acetal or ether is removed as before to give the triphenylalkenol.

The deoxybenzoin or its derivative (Ill) can also be alkylated with an alcohol from which the protecting group has been removed, in which R8 in (to) is H, and R8 in
can be a diphenyloxoalkanol from which the protecting group is removed, where is H. Furthermore, in the next reaction, the diphenyloxoalkanol from which the protecting group has been removed is reacted with the halogenated phenylmagnesium derivative (b) or the corresponding lithium compound (5) to form triphenyldiol (from which the protecting group has been removed) (formula Inside, R8 is H)
t-can be obtained. Even if R2 & of intermediate (1) and R3a of reagent (2) or (2) are exchanged, the same triphenyldiol from which the protecting group has been removed can be obtained.

Further, if there is a mixed acetal of protective groups on the phenyl ring, it can be removed by dehydration in the same manner as described above.

Another method for producing the compounds of the present invention includes formula (]I): (
In the formula, R is the same as above, n is 0 or 1 to 6, R9 is 10HO1 part, OH, -000H or the corresponding ester thereof), and a styrene derivative represented by an aluminum hydrate reducing agent, e.g. Hydroalumination with lithium aluminum hydrate yields At-
A complex reaction can be cited.

kl-:I complex (xIv) is expressed as formula (XV):
3 (wherein R and R are the same as above) to form triphenyldiol (t) in one step, and then, for example & (XVIゝ“
? [H-(OH2)n-C″120 (
The hydroxyl group is esterified in advance by reacting with a carboxylic acid anhydride represented by yyD (wherein n is the same as above) or the corresponding carboxylic acid, and the hydroxyl group is esterified in advance by formula (stand): 3 (wherein nXRXR and R3 are as above). It is also possible to obtain triphenyl diol esters shown in the same formula.

The ester is then dehydrated with, for example, a carboxylic acid chloride to obtain a triphenyl ester represented by the formula (W: (where n, R, R and R are the same as above), and the ester group is further hydrolyzed. triphenylalkenol (to)
It is possible to obtain triphenyldiol (3), triphenylcyclo-oxa-alkane (3) or protected or deprotected triphenyldiol α′@, where OR is a mixed acetal, benzyloxy group or OH ) is reacted with a suitable acid catalyst in a carboxylic acid having 1 to 4 carbon atoms to obtain triphenyl ester (
XI) can be obtained. Under more aggressive reaction conditions, any ether linkage is simultaneously braked to form the corresponding phenol. It can also be obtained by refluxing or warming triphenyl ester (triphenyl/L/furkanol) in a carboxylic acid having 1 to 4 carbon atoms.

As another method for producing the compound of the present invention (in the formula, n
, R1, R2 and R4 are the same as above, and R10 is an alkyl group or an aralkyl group) to obtain the formula (XX): 0■ (where n, R1, R2 and R4 is the same as above), and the corresponding phenol or 4-hydroxyphenyl-diphenylalkene is the same as above. If the other two phenyl groups have ether bonds, they can be removed in the same manner. Furthermore, if there are other ether bonds, they can be simultaneously decomposed to produce bisphenol or trisphenol.

Another method for producing the compounds of the present invention is to prepare 4-human tetraxyphenyl-diphenylalkene (XX) with the formula ('X
xi): R''-hal(XX[) (wherein haj is a halogen atom, R11 has 1 to 4 carbon atoms
Alkyl group, benzyl group, methoxymethyl group, 2.3
-dihydroxypropyl group or a group represented by the same surrogate) with a halogenated alkyl derivative represented by the formula (XX[); (where n, R, 'RX
(R and R11 are the same as above). At the same time, more than 11 phenolic OH groups can also be alkylated to give the mono-, bis- or tris-ether form G. 4-Hydroxyphenyl-dife = /
l/7 l)-n (XX) also has the formula (XXIll):
, hal(CH2)-0H2hal(XXIII) (wherein hal is the same or different) - rogene atom, m is the same as above). As a result, the formula (XXN): (where n, m,
1 (1, R2, R4 and haz are the same as above), and the compound is converted into a compound of the formula (XXV): 6 HN and R7 (wherein R6 and R7 are the same as above). By reacting with an amine represented by the formula (XXI/I): (where m', n, R1, R2, R4, R6 and R7 are the same as above), (4- aminoalkoxy)phenyl-diphenylalkene. The compound (true corresponding saturated phenol (II)) can also be obtained by alkylation, which is similar to the method for producing the corresponding unsaturated phenol (I) (formulas (XIX) to (XXVI: see)). I can do it.

Another method for producing the compound of the present invention is to prepare triphenylalkenol of formula (■) by various methods.
: 3 (in the formula, n (True: (in the formula, n5
An example is a method in which triphenyl sulfonate is used (R1, R2 and R3 are the same as above, and R12 is a methyl group or 4-tolyl group). Therefore, triphenyldiol ■ has the formula (XXIK)♂ 3 or the formula (XXx): 0 (where n% ha1% R1, R2, R3 and R1
2 can be converted into triphenylhydroxyparide or triphenylhydroxysulfonate (same as above). Triphenyl hydroxy halide (XXD
C), triphenylhuman tetraxysulfone) (XXX
) to the corresponding triphenyl halide ('XXy1) and triphenyl sulfonate (expletive), respectively.
I can be hatched. In addition, triphenyl halide (pus)
It is obtained by a one-step reaction not only from triphenylcyclo-oxa-alkane (3) but also from triphenyldiol (2). For example, if triphenyldiol (trademark) is treated with thionyl chloride, triphenyl tetralide (XX
I) can also be prepared from the corresponding sulfonate or other halide.

Deoxybenzoin or deoxybenzoin derivatives (
Ill) with the formula (XXXI) : haj (OH2)nO
By alkylating with a dihaloalkane represented by H2haj (XXXI) (wherein n and haj are the same as above), the formula (XXXI)
: (In the formula, n, Rla and R2a are the same as above.) Diphenyloxoparite is obtained. moreover,
Diphenyl oxopallide (triphenylhydroxyparite α-carbohydrate prepared by reacting the compound with a tetragenated phenylmagnesium derivative (b) or the corresponding lithium compound)′: (wherein, Rla, R"o, J-hiR3Jt (same as above) is produced. Also, by exchanging the intermediate R2a and the reagent R3a, diphenyl hydroxyparide can be obtained in the same way. A mixed acetal with a protecting group on the phenyl ring If there is, it can be replaced by removing it.If the removal of the protecting group and the dehydration reaction are performed simultaneously, triphenylhydroxyhalide (alpha order)' can be converted from triphenylhydroxyhalide in one step. Light (X
XVI) I can use it.

Another method for producing the compound of the present invention is the formula (X
XXI[l): (where n, haj, R1, R2 and R3 are the same as above) is converted into triphenyl halide of formula (XX
XIl[) '3 (where nXR1, R2 and ♂ are the same as above, X is M
ghaj or Li), respectively, to the corresponding Grignard complex or lithium salt. By reacting such complexes or salts with formaldehyde, ethylene oxide or trimethylene oxide, the triphenylalkeno (n) can be changed in any number from 1 to 4).

Triphenyl halide (XXVi) or triphenyl sulfonate (formula % by reacting W (where n is 0 or 1 to 3) with a cyano group): (wherein nl, R1, R2 and R3 are (same as ) can be changed to Further, by hydrolyzing the triphenylnitrile, a corresponding triphenylcarboxylic acid represented by the formula (XXXV): 3 (where nl, R1, R2 and R3 are the same as above) is obtained. Triphenylcarvone! ! CXXXV) is reduced in one step, for example via an ester intermediate, to give the corresponding tri7enyl alkenol (n=1-4).

According to another method, by reacting Grignard complexes or lithium salts (XXXIII) with carbon dioxide, tris of the formula: Phenylcarboxylic acid can be converted.The triphenylcarboxylic acid is reduced to tri-7enyl alkenol (
To) be changed.

Another method for producing the compounds of the present invention includes deoxybenzoin or deoxybenzoin derivatives (III
) with the formula (W(t): (wherein n and ha/ are the same as above, R13 and R1' are the same or different, for example, an ethyl group or R13 and R14 together are 1.3
- a group forming a propylene bridge of the dioxolane ring) or a mixed acetal-protected haloaldehyde. The resulting reaction mixture has the formula (2): (where n, Rla, R2a,
R13oJ: IJR" is a protected diphenyloxoaldehyde represented by the above-mentioned t'wjd. The diphenyloxoaldehyde is then reacted with a halogenated phenylmagnesium derivative (b) or a corresponding lithium compound (d). By letting the formula (XXXIX)
: (wherein nXR1,a, R2a, R3a, R13 and R14 are the same as above). Intermediate (R of m
By replacing 2a with R3a of reagent (b) or (to), the same triphenylhydroxyaldehyde (
plate) can be changed. Protecting groups can be removed, for example, by suitable acid catalysis in the presence of water. During the same step, any mixed acetals of binding groups attached to the phenyl ring are also removed. As a result, depending on the value of n, triphenylhydroxyaldehyde (XXXXa)
*or the corresponding cyclic hemiacetal (XXX
x'b), or a mixture thereof.

1:+3 (XXXXa) 3 H (XXXXb) The compound (XXXXa) or (twin), or a mixture thereof is represented by the formula (XXXXI): (wherein, n, R1, R2 and R3 are the same as above) becomes triphenylaldehyde. On the other hand, by dehydrating the protected triphenylhydroxyaldehyde (Dish), the formula
The protected triphenylaldehyde represented by iJ: iJ
)G) Curled. Furthermore, triphenylalganol () is oxidized or triphenylcarboxylic acid (
Reduction of Q also gives triphenylaldehyde (XXX)G 2 in one step or via intermediates.

Further, triphenylaldehyde (XXXXI) can be dealkylated or alkylated in the same manner as in the case of the alcohol (see formula (XIX) to) above.

Regarding the triphenylalkane compound of the present invention, the triphenylalkene derivative (I) of the present invention (where n, R
1, R2, R3 and R4 are the same as above, R5 is other than H) to prepare the corresponding formula (XX
A triphenylalkane derivative represented by XXl[l): 3 (where n, R1, R2, R3 and R4 are the same as above) is produced. The triphenylalkane derivative (XXXXl[) is subjected to a conversion reaction in the same manner as in the case of the corresponding triphenylalkene derivative described above. Such transformation reactions are, for example, phenyl ether dealkylation, phenol alkylation, halide and sulfonate production, side chain extension, reduction or oxidation reactions, and the like.

When the double bond of the triphenylalkene derivative is formed, a mixture of the (2)- and (K)-isomers is converted. In this case, by selecting appropriate reaction conditions, it is possible to obtain a mixture enriched in one of the isomers. Reaction conditions can also be chosen such that equal amounts of (Z) and (IIG)-isomers are formed.

For example, a protected diphenyloxoalkanol (
When V) is reacted with a halogenated phenylmagnesium derivative (b) by Grignard reaction, the pair of (RR,SS) or (R8XSR) -1 nanantiomers is changed by aesymmetric induction. By exchanging the starting material R2a and the reagent R3a, the opposite pair of enantiomers can be exchanged.

Aluminum complex (XIV) was converted into benzophenone derivative (
(RRXSS) and (R
3, SR) -) Riphenyldiol ■ is obtained.

From triphenyldiol (foundation) to triphenylcyclo-
When making oxa-alkane, (RR.

5S)-enantiomeric pair is converted into only (RRXSS)-enantiomeric pair, and (R8,5R)-enantiomeric pair is converted into a mixture of (R8,5R)-enantiomeric pair and (RR,5S)-pair.

When triphenylalkene derivative (I) or latriphenylalkane derivative (■) (in the formula, R'' is H) is produced by catalytic reduction, (RR, 5S
)-enantiomeric pair is changed, and (RS, 5R)-enantiomeric pair is changed from the (Ei)-isomer.

Although isomerization may occur depending on the reaction conditions, when phenol is alkylated, pure isomers or enantiomeric pairs are generally obtained from corresponding pure isomers or enantiomeric pairs. Also, mixtures thereof are corresponding mixtures.

When functional groups at the ends of alkane or alkene chains are transformed, in most cases pure isomers or enantiomeric pairs are obtained from their respective counterparts.

Also, their mixtures are corresponding mixtures.

Pure (RR,5S)- and (R8,%SR)-x
Not only nanthiomer bears (Z)- and (IIC)
- Isomers can also be fractionated from mixtures of isomers.
nal) Crystallization, fractional division 1
．． It may be isolated by chromatography or a combination thereof. (RR,88)- and (R8XSR)-enantiomeric pairs as well as (Z)- and (E
)-isomers can also be isolated from mixtures of isomers, whether the original compound is in the free base or in the form of a salt.

Therefore, isomers and enantiomers of phenol can be isolated whether the phenol is in the form of a free acid or a salt.

Amine salts are obtained by reacting amines with organic or inorganic acids, such as citric acid or hydrochloric acid.

Quaternary ammonium salts of the compounds of the invention are obtained by reacting an amine with an alkylating agent such as methyl iodide or benzyl chloride. N-oxides can also be obtained by reacting amines with suitable oxidizing agents, such as hydrogen peroxide.

Salts of phenol are obtained by reacting phenol with inorganic acids such as sodium hydroxide. Furthermore, esters of phenol are obtained by reacting phenol with aliphatic or aromatic carboxylic acids, the corresponding acid chlorides or acid anhydrides.

The compounds represented by formula (I) or (II>) of the present invention, non-toxic pharmacologically acceptable salts or esters thereof, have est4gen activity, anti-est4gen activity, progestene activity, and antitumor activity. It exhibits useful pharmacological effects such as

The isomers of the compounds of formula (I) or (n), their non-toxic pharmacologically acceptable salts or esters, or mixtures thereof, may be administered parenterally, orally or by intravenous injection. Generally, an effective amount of such derivatives is used in combination with a suitable pharmaceutical carrier. The term "effective amount" as used herein refers to an amount that has the desired pharmacological activity without causing undesirable M++ effects. The exact manner of administration in any individual case will depend on many factors, including the method of administration, the type of mammal to which it is administered, the conditions in which the derivative is administered, and, of course, the structure of the derivative to be administered. It also changes.

Pharmaceutical carriers commonly used with the derivatives of the invention may be solid or liquid and are usually selected with regard to the route of administration. Thus, for example, solid carriers include lactose, sucrose, gelatin, agar, and the like; liquid carriers include water, syrup, peanut oil, olive oil, and the like. In addition, suitable carriers known to those skilled in the art of bone division may also be used. The derivatives of the invention and carriers may be combined in a variety of acceptable forms, such as tablets, capsules, suppositories, solutions, emulsions, powders, and the like.

The affinity of the derivatives of the present invention for estrogen receptors was demonstrated in the rat uterus cytoskeleton (uteru Bcytoso).
The activity of the test compound to compete with 3H-labeled 17-β-estradiol in 1) was measured and investigated.

That is, after incubation, the ligands bound to the receptor and the ligands not bound to the receptor are separated using the known dextran-charcoal method (Kohrenman, Niss, C.: [Comparative binding affinity of estrogens and their relationship to estrogenic potency). ”, Steroids 16.16
6-177 (1969) (Korenynan,
S, G, : @Comparativebindin
gravity of estrogens
d its relation t.

estogenio potency ”', 5
teroids i 5.163-177 (1969)
) was separated.

The in vivo estogen-antiestrogen (progesterone) effect was investigated by the method shown below.

The test compound was suspended in sesame oil and subcutaneously administered to immature mice, 21 days after birth, for 3 consecutive days to examine the estrogenic effect of the test compound. The test animals were sacrificed 4 days after administration, and the weight of the uterus was measured.

Estradiol, used as a positive control, increased uterine weight, and uterine weight correlated with the estrogenic effects of the test compound.

The anti-estrogenic effects of the test compounds were investigated using immature mice in the same manner as for the estrogen effects described above.

In this case, an effect of inhibiting the increase in uterine weight caused by estrogen was also observed.

The progesterone effect of the test compound was investigated in the same manner as the estrogen effect described above. Metoxyprogesterone acetate, which has the effect of reducing uterine weight, was used as a comparative example.

The antitumor effect of the test compound was determined in vitro as shown below.
I considered it with tro.

MO? -7 cell line (MO'F-7cell 1ine)
(Human mammary gland known to be estrogen dependent11)
The growth of h) was investigated in the presence or absence of estradiol, methoxyprogesterone acetate or the test compound. In addition, combinations of the test compound and estradiol and combinations of the test compound and methoxyprogesterone acetate were similarly investigated. The number of surviving cells at 4, 24 and 48 hours after incubation was determined by bioluminescence method.
i? (ATP in cells)
(fixed position method).

The antitumor effects of the test compounds against DMBA-induced rat mammary adenocarcinoma, transplantable mammary adenocarcinoma and ovarian adenocarcinoma, and transplantable prostatic squamous cell carcinoma were investigated in vivo according to the method shown below.

Breastfeeding of female rats (65-40 days old) with DMBA)
It triggered a pig box. Test compounds were administered after the appearance of palpable tumors. Tumor size and number were measured once every two weeks. The tumor size between a control group administered with a vehicle and a group administered with a test compound was compared.

The effects on other tumors were investigated by administering the test compound to mice with implantable uterine sarcoma or rats with implantable prostate cancer via stomach tube. Administration is carried out daily or twice a week, and test animals weigh approximately 20. Female NMR mice and male Fiecher 644 rats weighing approximately 200 g were used. Also, estramustine phosphate (F! stramst)
ine osphate) was used as a positive control.

Transplantable rat mammary adenocarcinomas were generated by subcutaneous inoculation of DMBA-induced sarcoma strips into healthy adult female rats.

Among the tumors that developed, those that showed malignant growth were selected and used for the next transplant. Other transplantable tumors were inoculated subcutaneously as washed cell suspensions (10 cells/test animal).

As a result of examining the affinity of the test compound for the varnish a gene receptor by the dextran-charcoal method,
The compounds of the invention had excellent affinity for estrogen receptors. The results are shown in Table 1.

The affinity in Table 1 is the concentration of the test compound that causes 50% competition (inhibition) when 6H-labeled estradiol and the test compound compete for binding to estrogen-receptor. The meanings of the symbols shown are as follows.

+++ 1o-6M (inhibition) ~ 10-7M (weak affinity) + 10-5M (// ) ~ 1[1-6
M(II) 10-'M(tt)～
Formula (I) or (n) of the present invention, in which no obvious inhibition is observed even at 10-5M (tt) ± 10""M
The estrogenic effects of the compounds were always much inferior to that of estradiol, which was used as a positive control, as measured by their ability to increase uterine weight in immature mice.

The in vivo estrogenic effects of compounds 5.7.16 and 14 were observed only at higher concentrations, with the effect of compound 5 administered at 5 m,/% body weight (mp/% body weight, hereinafter the same) being greater than that of estradiol compared to compound 7. .1
In the case of 6.14, it was about 50%.

On the other hand, compounds 4 and 11, compounds 2.16 and 17
itself had no estrogenic effect even when administered up to 5 mg/kq.

Compounds 4.7.11.13.14 and 15 had antiestrogenic activity as measured by their ability to inhibit estradiol, which causes uterine weight increase in immature mice. and compounds 4 and 7 at 0.5 mg/kg
At 5 ms+/%, compound lLi3.14 suppressed the effects of estradiol in the mouse uterus by 12%, respectively.
, 27%, 61%, 25%, 25% and 20% inhibition.

The progesterone effect of the test compound was measured in the same manner as above. Metoxyprogesterone acetate, used as a positive control, increased uterine weight by 40% in immature mice.
It was even inhibited. The action of compound 2 is thought to be due to its progesterone action;
No anti-estrogenic or estrogenic effects were shown even when administered up to Administration at 0.05 m,/9 times reduced the uterine weight of mice by 50%, and no synergistic effect was observed when administered with metroxyprogesterone.

Compounds 4 or 11, when administered alone, reduced uterine weight in mice by 38% and 56%, respectively. This is thought to be due in part to the antiestrogenic effect of Compound 4 or 11. Compound 11 had a synergistic effect with methoxyprogesterone, whereas compound 4
caused only a slight inhibition and reduced uterine weight by about 17%. Compound 5 represented by formula (I[) did not have anti-estrogenic effects, but caused a 64% decrease in uterine weight when administered o, osmp/hp due to progesterone effects. On the other hand, no inhibitory effect of methoxyprogesterone was observed at 0.05mp/kp.

However, as the dose increased, a weaker estrogenic effect was seen, which exceeded that of methoxyprogesterone. A slight increase in uterine weight was also observed. Compound 7, which has antiestrogenic and estrogenic effects, was also found to have progestational effects, causing a slight inhibition of methoxyprogesterone at the lowest concentration found in the wound.

Table 2 summarizes the estrogen action/anti-estrogen action and progesterone action determined as described above. The percentage in the table indicates the rate of increase or decrease in the weight of the mouse uterus, and the hardware samples tested correspond to those in Table 1.

The antitumor effect of the compound of formula (1) or (II) of the present invention was tested in vitro using MOF-7 (human mammary adenocarcinoma cell line) and in rats induced by DMBA in 4n vi*'o. Breast gland station 1. It was tested and investigated using rat ovarian tumor, rat prostate cancer and mouse uterine sarcoma.

The in vitro test results are shown in Table 6. In Table 3, the antitumor effect is expressed as a50 (concentration of the test compound that inhibits cell growth by 50%), and the test compound is the same as in Table 1, and the symbol indicates The meaning is as follows.

+10+10-6. ~5X10 M1+'
5X10 ~10 M5 +10, ~5X10 M -5X10''M Table 6 ゛ □ As shown in Table 3, all test compounds were in v
It showed a very strong antitumor effect against MOF-7 in vitro, and cell death was observed with each compound as the compound concentration increased.

The in vivo antitumor effects of compounds 4 and 7 on DMBA-induced rat mammary □ adenocarcinoma were tested. Regarding Compound 4, the tumor growth rate was reduced to ⅛ compared to the control when administered at 10 m/cm.

Compound 7 showed an antitumor effect when administered from 1 to 30n+/. The highest dose used stopped tumor growth. The results are shown in Table 4. However, in Table 4, tumor size refers to the (width) of the tumor.
It is the value of x (height), and the growth rate is the difference between the tumor size on the 10th day after administration and the tumor size on the day of measurement.

Table 4 Regarding the antitumor effect on mammary adenocarcinoma induced by DMBA 't' in the same manner as above, compounds 2.12 and 13
Although it was inferior to Compound 7, an antitumor effect was also observed.

Compound 7 was examined for antitumor activity against rat ovarian cancer and mouse uterine sarcoma in the same manner as described above. Two weeks after administering 100 myAq of Compound 7, the size of mouse uterine sarcoma decreased by 60% compared to controls, and 10 days after administering 5 m/m, the size of rat ovarian cancer decreased by 2% compared to controls.
It decreased by 0%.

The antitumor effect of Compound 2 on transplantable prostate cancer was investigated in the same manner as described above. Twelve days after administering Compound 2 at 1 m/cm, the tumor size was reduced by 29% compared to the control.

The acute toxicity of the test compounds used in the various tests mentioned above is LDao value of 1000-62 when administered orally to mice.
It was from 00 to /. The appropriate daily dosage for adults is 10 to 200 mp.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. In addition, in the following examples, H-NMR spectra were measured using R24A manufactured by Perkin-Elmer or wp6o:as manufactured by Purker with TMS as an internal standard, and chemical shifts were expressed as δ values (ppm). Also, lowercase S
, a, t, and m represent singlet, doublet, triplet, and multiplet, respectively, and the number of hydrogen atoms is shown behind these. The mass spectrum is MSf30 RIP manufactured by Kratos.
using direct inlet, ionization voltage 70e
Measured at V.

Example 1 (47((tetrahydrobilan-2-yl)oxy)-
Preparation of 1,2-diphenylbutan-1-one) 48% of 19.69 deoxybenzoin, 20.99 tetrahydrobilan-2-yl ether protected with bromoethanol, 1.09 IBAO and 50mj
A mixture containing a +3% hydroxide solution was heated to 75°0
The mixture was stirred for 2 hours. Water was added and the product was extracted into toluene. The toluene solution was washed with water and dried over sodium sulfate. Finally the solvent was evaporated. Although the yield was quantitative, the oily product contained approximately 20% of the 0-alkylated product.
It contained %.

Example 2 (a) (Production of 4-((tetrahydrobilan-2-yl)oxy)-1゜1.2-triphenylbutan-1-ol) First, a Grignard complex was
6.69 m of magnesium dust in 50 m of dry tetrahydrofuran
was prepared under dry conditions by reacting with bromobenzene. Then 75 ml of the evaporation residue from Example 1 in dry tetrahydrofuran were added. The reaction mixture was refluxed for 2 hours.

After the reaction mixture thus obtained was cooled, it was added all at once to a saturated solution of ammonium chloride.

After shaking, the organic layer was separated. The extraction was repeated with ether. The organic layers thus obtained were combined and dried over sodium sulfate. Finally the solvent was evaporated.

(Production of bHl, 1.2-)diphenylbutane-1,4-diol) The evaporation residue obtained in step (a) above was
0+nl absolute ethanol, 10g concentrated sulfuric acid and 75
It was dissolved in a mixture containing ml of water. The mixture was stirred at room temperature for 2 hours. After neutralizing the solution thus obtained with 2M sodium hydroxide solution, the ethanol was evaporated. Water was added to the residue. The product thus obtained was then extracted into ethyl acetate. The ethyl acetate solution was dried with Q ram (sulfuric acid) and the solvent was evaporated. The product obtained was recrystallized from toluene. The yield is 16.59 (
52% yield from deoxybenzoin), melting point 185
It was ~187oO.

1H-NMR spectrum analysis (in cD3oD, δ value: p
pm): 2.06(2HXq)j, 63(2H,
t), 3.92 (IH, t), 4.76 (2m, s),
6.85-7.45 (13HXm), 7.68 (2H,
aa) (C) (2+2.3-) Production of liphenyltetrahydrofuran) First, 31.89 1,112-)
IJ 7elptan-1,4-diol 400m/
of absolute ethanol, 10 ml of concentrated sulfuric acid and 75 ml of water and the mixture was
Stirred at 5°C for 6 hours. The solution thus obtained is 2M
After neutralization with sodium hydroxide solution, the ethanol was evaporated. Water was added to the residue and the product was extracted into toluene. The toluene solution was dried over sodium sulfate and the solvent was evaporated. The yield of the product recrystallized from ethanol is 26.49 (88% yield), and the melting point is 112.
It was ~116%.

1H-NMR spectrum analysis (in 0DOI3, a value: p
pm): 1, 90-2.60 (2H, m), 6.
85-4.55 (AH, m), 6.90-7.45 (1
3H, m), 7.66 (2H, aa) Example 3 (a) (4-acetoxy-1,1,2-trif/1/-
1-Butene production) First, 30.09 2.2.3-)
After dissolving Riphenyltetrahydrofuran in 125yn4 acetic acid, add 25ml of acetic acid containing 40% hydrogen bromide.
added. The mixture was stirred at 7580 for 1 hour. The solvent was evaporated and an excess of 1M carbonate solution was added. The product was extracted into toluene. The toluene solution was dried over sodium sulfate and the solvent was evaporated.

The product was recrystallized from aqueous methanol solution.

Yield: 28.7p (yield: 84%), melting point: 81-860
There was ote.

1H-NMR spectrum analysis (ODO/3, δ value: p
pm) ~ 1-82 (6H, S), 2.78 (2a, t
), 4.02 (2a, t), 6.85 (5H.

B), 7.02 (5H, a), 7-21 (5H, a) M
S analysis (m/e): 342 (M”, 5), 282 (
64), 205(28), 191(1o(1), 167
(27), 91(70) (b) Production of N, 1,2-trifluor-1-buten-4-ol) 4-acetoxy-1,1,2-triphenyl-1-butene of 34.27 was
After dissolving in 0ffiJ of 94% ethanol, 20 m
1 part of water and 45 ml of 20% sodium hydroxide solution were added. The mixture was refluxed for 1 hour. After the solution thus obtained was neutralized with 2M hydrochloric acid, the ethanol was evaporated. Water was added to the residue. The product was extracted into ethyl acetate, the ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated. The product was recrystallized from aqueous methanol solution. Yield: 23.79 (79% yield), melting point: 117
~119°0.

IH-NMR spectrum analysis (in ODO!3, δ value: p
pm): 1.34 (IH, 8), 2.73 (2a, t)
, 6.05 (2HXt), 6.90 (5H.

8), 7.11 (5HX8), 7.25 (5H,s)
(o) Production of (4-)siloxy-1,1,2-triphenyl-1-butene) This reaction was carried out under dry conditions. First, a, 1 of 0g.
112-) Lifuniru-1-buten-4-ol to 10
The TCo was dissolved in 0 ml of dry pyridine, then the mixture was stirred on ice and, while cooling, 57.09 4-toluenesulfonic acid salts in 50 ml of dry pyridine was added dropwise to the mixture. Stirred at 0°C for 6 hours. Then 250m1 of ice water and 750m/2M
of cold hydrochloric acid was added. The precipitate was collected by p-filtration and washed with water. Finally the product was recrystallized from ethanol. Yield: 66.89<81% yield), melting point: 167-169°
It was C.

1m-NMR spectrum analysis ((!DOj, δ value:
ppm): 2, 52 (AH, g), 2.77 (2H,
t), 6. "92 (2u, t), 6-'86 (5H.

8), 6.98 (5H, s), 7.16 (2H, (1)
, 7.21 (5H,s), 7.60 (2HXd) Example 4 (4-, ((tetrahydrobilan-2-yl)oxy)
Preparation of -2-phenyl-1-(4-methoxyphenyl)-butan-1-one → Example from 4-methoxydeoxybenzoin 22.69 and bromoethanol protected with tetrahydrobilan-2-yl ether 20.99 1. The target compound was prepared according to the method described in Example 0 f! 15 (a) (,,47((tetrahydrobilan-2-yl)oxy)-1,2-diphenyl-1-(4-methoxyphenyl)butan-1-ol ((RR,SS) and (RsXSR)- Preparation of the enantiomer → (,RR,jl!S)-enantiomer of the target compound from the evaporation residue obtained in Example 1 and the 4-bromoanisole of 28.19 according to the method described in Example 2, (a) was manufactured.

The (R8,5R)-enantiomer of the target compound was prepared from the evaporation residue obtained in Example 4 and 23.69 bromobenzene in the same manner as in the case of the (RR,5S)-enantiomer.

From the evaporation residue of the (RR,SS,)-enantiomer obtained in step (a) above, according to the method described in Example 2(b)? The (RRSBS)-enantiomer of the target compound was produced. The product was recrystallized from toluene.

Yield: 13.9g (yield from deoxybenzoin: 40g)
%), and the melting point was 124-126°0.

1H-NMR spectrum analysis (in OD30D, a value:
ppm): 2,06 (2H,q), 3.32 (2a
, t), 6.77 (6 Otori 8), 6.84 (IH.

aa), 4.78 (2H, 8), 6, . 80-7, 2
5 (12H, m ), 7.56 (2H.

d) From the evaporation residue of the (,R8,SR)-enantiomer obtained in step (a) above, the target compound (IjSXSR) is obtained in the same manner as in the case of the (RR,88)-enantiomer.
- Enantiomers were produced. The product was recrystallized from toluene. The yield is 16. o (yield 46% from 4-methoxydeoxybenzoin), melting point 172-174'o
Met.

1H-NMR spectrum analysis (OD30D1δ value: p
pm) '2.06 (2H, q), 3.62 (2n, t
), 3.65 (6H, s), 5.86 (IH.

t), 4.75 (2H, a), 6.54 (2H,, 11
), 6.95-7.45 (lOH, m), 7.65 (2
HXaa) (c) (Production of 2,3-diphenyl-2-(4-methoxyphenyl)tetrahuman I:27 run ((RR,88) and (R8,5R)-enantiomer)) obtained in step (b) above The (RR,8B)-enantiomer of the target compound was produced from the evaporation residue of the (RR,88)-enantiomer according to the method described in Example 2(C). The product was recrystallized from isopropanol.

The yield was 16°29 (yield 49 from deoxybenzoin).
%), and the melting point was 116-118'-'o.

-1H-NMR spectrum analysis (ODQl, medium, δ value:
ppm): 1.9 (1-2.60 (2H, m), 6-7
7 (3H, a), 5.80-4.50 (m, m), 6
．． 85 (2H, a), 7.02 (10H, s ), 7.
52 (2H% a) MEI analysis (m/e):, g
6o (M”, 13), 212 (85), 135 (87)
, 118 (96), 117 (100), 100 (44)
,91(,42),77(50)34.89(R8,
5R)-1s2-diphenyl-1-(4-methoxyphenyl)butane-1,4-diol to the above (RR, BS
)-enantiomer, a mixture of (BS, sR> and (RR,5S)-enantiomers of the target compound was obtained, and the (R8,5R)-enantiomer was prepared. The evaporation residue was recycled from isopropanol. It crystallized.

The precipitate consisting of the (RR,88)-,c-nanthiomer was removed by p-filtration, the mother liquor was evaporated, and the evaporation residue was recrystallized from methanol.The yield of the product was 4.69 (yield 1
4%), the melting point was 74-76°0.

1H-NMR spectrum analysis (in ODQl3, δ value:
ppm) 71.95-2.60 (2H, m), 3.
64 (3H, s), 3.30-4.55 (1, m), 6
．． 54 (2u, a), 6.90-7.45 (10H, m
), 7.59 (2H.

aa) Example 6 (a) (1,2-diphenyl-1-(4-methoxyphenyl)-1-buten-4-ol ((2) and (Ii
Production of (Z)-isomer) The (Z)-isomer of the target compound was produced as follows. After dissolving (Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-1-puten-4-ol obtained in Example 16(a) in methanol, excess diazomethane was added. When the reaction was complete the solvent was evaporated. Recrystallization was carried out from petroleum ether. The yield was almost quantitative and the melting point of the product was 121-126°C.

1H-NMR spectrum analysis (in '0DO13, δ value:
ppm): 1.2a (1a, s), 2.73 (2
1L t ), 3.57 (2HXt ), 6.65 (3
H.

day), 6.56 (2H, a), 6.80 (2H, cl
), 7.15 (5H% #), 7.29 (5H% s
) MS analysis (Vθ): 530 (M”, 79), 299
(100), 221 (46), 191 (70), 121
(46), 91(60) The (]1C)-isomer of the title compound was obtained in Example 16 ((E)-1,2-diphenyl-1-(4-hydroxyphenyl)-1- It was prepared analogously to the preparation of the (Z)-isomer from buten-4-ol.

1H-NMR spectrum analysis (in ODO13, δ value: p
pm): 1.31 (IH, s), 2.80 (2H, t
), 6.6'1 (2H,t ), 6.81 (3H.

8), 6.80-7.65 (14 wind m) f of the target compound
A mixture of Z) and (E)-isomers was prepared as follows. This reaction was conducted under dry conditions. First 54.
89 of 1,2-diphenyl-1-(4-methoxyphenyl)butane-1,4-diol was dissolved in 200 ml of acetic anhydride. Then 30+M acetic chloride was added. The mixture was kept at 100°C for 2 hours and then the solvent was evaporated. The intermediate thus obtained is pure (zsi)
-4-acetoxy-1,2-diphenyl-1-(4-methoxyphenyl)-1-butene.

Then 200 mj of 94% ethanol, 20 ml of water and 45 ml of 20% sodium hydroxide solution were added to the evaporation residue. The mixture was refluxed for 1 hour.

After the solution thus obtained was neutralized with 2M hydrochloric acid, the ethanol was evaporated. Water was added to the residue and the product was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated. The yield of the 7;6 mixture of pure fZ) and On)-isomers thus obtained was quantitative and its melting point was 91-105 oo.

After recrystallizing the evaporation residue from a 95:5 mixture of hexane and ethanol, 14.5 g (44% yield) of (Z)
-obtained an isomer.

(b) (4-bromo-1,2-diphenyl-1-(4-
(Production of (2)-isomer of methoxyphenyl)-1-butane) First, 6!1.09 (Z)-1,2-diphenyl-
1-(4-methoxyphenyl)-1-buten-4-ol was dissolved in 0 ml of dry acetonitrile and then 69.69 grams of triphenylphosphine and 49.82 grams of carbon tetrabromide were added with stirring. Stirring was continued for 1 hour at room temperature. The solvent was evaporated and the evaporation residue was dissolved in hot petroleum ether. Insoluble material was removed by p-filtration. The mother liquor was evaporated and the evaporation residue was recrystallized from methanol. The yield of the product was 26.79 (yield 68%), the melting point was 116-11
It was August.

1H-NMRX hex)/I' analysis (in cDo13, δ value? ppm): 3.01 (2H, t), 5.28 (2aX
t), 6.67 (3 turtles 8), 6.54 (2H.

d), 6.80 (2H, (1), 7.17 (5H, Sun)
, 7.32 (5H, day) MS analysis (mle): 5
921594 (M”, 86), 299 (65), 221
(79), 191 (94), 121 (100), 91
(50) Example 7 (1g2-diphenyl-1-(4-benzyloxyphenyl)(1,0],) Butane-1,4-diol ((RR,8B) and (R
8, SR) - Preparation of - mixture of enantiomers) 16.29 cinnamaldehyde and 28.8p 4-
From benzyloxybenzophenone to (RR,8B) and (R
e, SR) - a mixture of enantiomers was prepared. Recrystallization was carried out from toluene. The yield was 62.59 (yield 77%), and the melting point was 109-115°C. The product contained both (RR,SS) and (RS-,SR)-enantiomers in a ratio of 1=1.

1H-NMR spectrum analysis (in OD30D, δ value: p
pm): 1.88~2-24(2H,m),~5.5(
2H, t), 3.85 (IHXt), 4.76 (2H
, 8), 4.91 (IHXs), 5-07 (IH,s)
, 6.62 (1H.

d), 6.86-7.49 (16H1m) 7.57 (I
H, (1), 7.65 (IHN (ld) Example 8 (a) (1,2-diphenyl-1-(4-benzyloxyphenyl)-1-buten-4-ol ((2) and ( Preparation of K)-isomer) 1,2-diphenyl-1-(
Purpose according to the method described in Example 6(a) from a 1:1 mixture of (RR,88) and (R8,5R)-enantiomers of 4-benzyloxyphenyl)butane-1,4-diol (Z) and (K) of the compound
- An isomer mixture was prepared.

The intermediate thus obtained is pure 4-acetoxy-1,
2-diphenyl-1-(4-benzyloxyphenyl)
It was a 7:6 mixture of the (Z) and (to)-isomers of -1-butene.

The (z)-% exoisomer of the target compound was separated as follows. A precipitate formed after hydrolyzing the intermediate and was collected by filtration. After recrystallizing the precipitate from toluene-petroleum ether (CI), 15.19 (67% yield) of the (Z)-isomer was obtained. Melting point is 141-1
01H-NMR spectrum analysis (O
In DOI3, a value: ppm): 1.60 (IH, s
), 2.75 (2H,t ), 6.57 (2H% t
), 4-90 (2H%S), 6.60 (211,d
), 6.81 (2HS(1), 7.15(5H,s),
7.60 (5 turtles 8), 7.51 (5H, a) MS analysis (mle): 406 (M'', 28), 9
The (X)-isomer of the 1(100) target compound was separated as follows. After passing the hydrolysis solution, another precipitate formed, which was also collected during the pass.

Recrystallization of the precipitate from toluene-petroleum ether (1:4) gave 2.09 (5% yield) of the (1)-isomer. The melting point was 96-9800.01H-NMR spectrum analysis (in ODOj3, δ value:
ppm): 1-60 (IH% s), 2.79 (
2H,t ), 6.59(2H,t ), 5.05(2
H.

8), 6.84-7.47 (191 (, m) MS analysis (
mle): 406 (M+, 5), 91 (100) (
b) (4-chloro-1,2-diphenyl-1-(4-benzyloxyphenyl)-1-butene ((Z) and (
11:) Production of -M external body) The (Z)-isomer of the target compound was produced as follows. First of all, 40.69 (
Z)-1,2-diphenyl-1-(4-benzyloxyphenyl)-1-buten-4-ol was dissolved in 40 [1 mz] of dry acetonitrile. Then 2.8q of A triphenylphosphine and 76.99 of carbon tetrachloride were added. The mixture was refluxed for 1 hour. The product was allowed to precipitate on cooling and was filtered. Recrystallization was performed from ethanol.

Yield: 39.59 (96% yield), melting point: 115-1
It was 16'o/128-129°0.

1H-NMR spectrum analysis (in aDc13, δ value: p
pm): (104) 2.91 (2H%t), 5.41 (2HXt), 4.9
1 (2H, s), 6.60 (2H.

d), 6-81 (2)I, a), 7-16 (5H,
e), 7.52 (1oH, s) MS analysis (ITL/s
): 424/426 (M", 7/4), 91 (10
0) The (I)-isomer of the target compound was produced in the same manner as for the (2)-isomer described above. The product thus obtained was recrystallized from methanol. The yield is 65.22 (
Yield 86%), melting point was 91-96°0 〇'H-NMR spectrum analysis (in aDoz3, δ value:
ppm): 2-97 (2H,t), 3.43 (2H
, t ), 5.06 (2H, s), 6.8S ~ 7.48
(19H, m) Example 9 (a) (1t2-diphenyl-1-(4-(2-(N,
N-dimethylamino)ethoxy]phenyl]butane-1
,4-diol ((”R%SS) and (BS% 5R
)-enantiomer)) This reaction was carried out under dry conditions. First, 2.19 liters of lithium aluminum hydride and 50 ml of dry tetrahydro7ran were placed in a flask. 15.29 cinnamic aldehyde in 50 ml of dry tetrahydro7 run was then stirred and the temperature was brought to 25-
3500 (105). Stirring was continued for an additional 60 minutes at room temperature. 26 in 70 ml of dry tetrahydro7 run.
．． 9 of 4(2-(NIN-dimethylamino)ethoxy)benzophenone was added with stirring. The humidity was maintained between 65 and 45 °C during the addition. After stirring for 2 hours at 40 °C, the reaction mixture was diluted with 150 ml of It was added all at once to a 25% ammonium chloride solution, and the precipitated aluminum hydroxide was passed through.The P solution was transferred to a separatory funnel and the organic layer was separated.The aqueous layer was extracted once again with 60 ml of ethyl acetate. The layers were combined and dried over sodium sulfate. The solvent was evaporated. The residue was recrystallized from toluene. Yield: 27.59
(yield 68%). The product thus obtained contained both (RR% S S ) and (R8,8R)-enantiomers, but the (RR,88)-enantiomer was predominant due to solubility differences.

By recrystallizing the product from a7ton, the (RR,8B)-enantiomer of the target compound = 15.89
(yield 64%). The melting point of the product recrystallized from toluene was 165-167°O.

lH-NMR spectrum analysis (cD3oD, J value: p
pm): 2.07 (2H, q), 2.35 (6H, e
), 2.76 (2HXt ), 3.54 (2H.

t), 5.86 (IHS (1(1), 4.10(2)1
．． t), 4.76 (2H,a), 6.80-7.25
(12HSffi), 7.58 (2H, (1')) The acetone mother liquor was evaporated and the residue was recrystallized twice from a7tone to obtain 5.3 g (R8XSR)-enantiomer of the target compound (yield 16%). ).The melting point of the product recrystallized from toluene was 169-141°0.

1H-NMR spectrum analysis (in OD 30 n, a value: ppm): 2.03 (2H%q), 2.27 (6H,
B), 2.64 (2t), 5.32 (2a.

t), L86 (IH, t), 3.95 (2H, t),
4.76 (2HSs), 6.56 (2HX(1), 6.
95-7.45 (10H, m), 7.66 (2H, a(
1)(b)(2,5-diphenyl-2-(4-(2-(
Preparation of N,N-dimethylamino)ethoxy]phenyl]tetrahydrofuran ((RR%5s)-enantiomer) 40.59 of (RR,8B)-1,2-diyx2'h
-1-(4-(2-(N,N-dimethylamino)ethoxy]phenyl]butane-1,4-diol is 6, IQm
The target compound was produced in the same manner as in the case of 2.2.3-)riphenyltetrahydrofuran in Example 2 fc) except that 15 tons of concentrated sulfuric acid was used in place of 1 of concentrated sulfuric acid. was performed from ethanol. The yield of product is 2
9.8g (yield 77%), melting point 83-85oc.

1H-NMR spectrum analysis (1δ value in ODO/3:
ppm): 1.90-2.50 (2H, m), 2.3
0(6■,B), 2.68(2HXt)a, o2(2H
%t), 6.85-4.50 (3H, 6.87 (
2H, a), 7.02 (IQH.

sk7.51 (2H, d) MS analysis (m/8): 387 (M”, 2%), 2
69 (5%), 117 (22), 91 (7), 72 (1
0), 58(100) Example 10 (a) (4-acetoxy-1,2-diphenyl-1-(
4-(2-(N,N-dimethylamino)ethoxy]phenyl)-1-butene ((2) and (to))-isomer)
Production) This reaction was carried out under dry conditions. First 1, 2-
(RR,Si9) or (R8,SR) of diphenyl-1-(4-(2-(N,N-dimethylamino)ethoxyn]phenyl]butane-1,4-diol,
40.59 of either enantiomer (108) and 150n+j of acetic anhydride were placed in a flask. 04-acetoxy-1,2-diphenyl-1-(04-acetoxy-1,2-diphenyl-1-(
4-(2-(N,N-dimethylami[])]ethoxy[buenyl]butan-1-ol is obtained as an intermediate,
The melting point of the (RR,8B)-enantiomer is 97-99°
It was 0.

50 ml of acetic acid in 50 m/l of acetic anhydride while stirring the reaction mixture at 90°C! Added ride. Stirring was continued at that temperature for 2 hours. The solvent was evaporated.

Then, after adding an excess of 1M sodium carbonate solution,
The product was extracted into toluene. sulfuric acid solution)
It was dried with a Q ram and the solvent was evaporated. The yield of a 2:1 mixture of pure (Z) and (1)-isomers was quantitative. The (Z)-isomer of the target compound, prepared by refluxing the corresponding (Z)-isomer of the alcohol in acetic acid, had a melting point of 67-69°0.

(bHl, 2-diphenyl-1-(4-(2-(N,N
-Production of dimethyl(109)amino)ethoxy[phenyl]-1-buten-4-ol ((2) and (to)-isomers)) (Production route 1) 4-acetoxy-1,2-diphenyl- 1-(4-(2
-(”+N-dimethylamino)ethoxy]phenyl]
-(Z) and (to)-isomers of -1-butene are 2:1
from the mixture 44.7G+ of Example 6(b) 1,1s2
-) The target compound was prepared in the same manner as in the case of rifunyl-1-buten-4-ol.
The yield of a 2:1 mixture of ) and (E)-isomers was quantitative, with a melting point of 96-100°0.

(Production route 2) 1,2-diphenyl-1-(4-(2-(
N.

N-dimethylamino])eth,oxy]phenyl]butane-1,4-diol or 38.79 2,6-diphenyl-2-(4-(2-(N,N-dimethylamino)ethoxy]phenyl]tetrahydro 7 runs (in either case (RRX8B) or (R8,S
R)-either enantiomer) was dissolved in 250 ml of dry ethanol containing excess hydrochloric acid gas. The mixture was refluxed for 1 hour, then the solvent was evaporated.

A mixture of (Z) and fE)-isomers of the target compound was obtained as its hydrochloride. The product was liberated from the salt form, for example.

After suspending the evaporation residue in 1M IJ carbonate solution, the product was extracted as free base into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated. (Z) and (1))-isomers in 2:1
The concentration of the mixture is stationary and the power of the mixture is about 5%.
It contained 2,6-diphenyl-2-(4-(2-(N,N-dimethylamino)ethoxy]phenyl]tetrahydrofuran as an impurity.

(Production route 3) 1,2-diphenyl-1-(4-(2,(
IJ, N-dimethylamino)ethoxy]phenyl]butane-1,4-diol or 6B, 79, 2,6-di7enyl-2-(4-(2-(N,N-dimethylamino)ethoxy) [phenyl]tetrahydro7rane (in either case (RnXsS) or (Rs, 5
R)-enantiomer) in 250ml
of hot concentrated hydrochloric acid. The mixture was heated to 90-1000C.
The mixture was stirred for 15 minutes. After the mixture was cooled and neutralized with 48% sodium hydroxide solution, the product was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and one solvent was evaporated. Although the aggregation of the 1;2 mixture of (2) and (g)-isomers was quantitative, the mixture contained approximately 5% 2°6-diphenyl-2-(4-(2-(
It contained N,N-dimethylamino)ethoxy]phenyl]tetrahydro7rane as an impurity.

After recrystallizing the 2:1 mixture of (2) and (E)-isomers obtained in the above (production route 1) from toluene, 1
5.99 (41% yield) of the (2)-isomer of the target compound was isolated as the free amine. Melting point is 110-112°
It was C.

IH-NMR spectrum analysis COD, in O13, δ value:
ppm): 2.23 (6H, s), 2.60. (
2H,t), 2.71(2HXt), 6.5”)(2
H.

t), 3.89 (2a, t), 6.53 (2H, a
), 6.78 (2HXa), 7.12 (112) (5HXB), 7.28 (5HN 8) of the target compound (
Z) -Q exobody was isolated as a hydrochloride salt as follows.

The 2=1 mixture of (Z) and (E)-isomers obtained in the above (Production route 1) was dissolved in ethanol, and 1 excess of concentrated hydrochloric acid was added. After evaporating the solvent, the residue was recrystallized twice from ethanol to obtain 12.59 (29% yield) of the (Z)-isomer of the target compound as the hydrochloride. The melting point of the wax crystallized from acetone was 166-168°C.

The salt #R of the (Z)-isomer could also be prepared from the base of the (Z)-isomer, for example, as follows.

The (2)-isomer was dissolved in ethanol, hydrochloric acid gas was passed through the solution and finally the solvent was evaporated.

The (E)-isomer of the target compound was isolated as follows.

The mother liquor obtained in the isolation of the hydrochloride of the isomer (2) above was
The solvent was evaporated. After recrystallizing the evaporation residue from acetone 1, 9.7p (yield 26%) of the (E)-isomer was obtained as a hydrochloride. The melting point was 265(113) to 267°G. The (m)-isomer obtained could be liberated in the form of its salt in the same manner as in the case of the isomer mixture described above. (E) as free amine (from toluene)
- The melting point of the isomer was 129-161°C.

lH-NMR spectrum analysis (in CDCl2, δ value'
ppm): 2.61 (6 wind S), 2.71 (2a, t
), 2.78 (21 (, t), 6.57 (2 turtle t), 4
．． 05 (2H, t ), 6.87 (2H, a), 6, .
94 (5H,,s), 7.10 (5HS8), 7.
21(2H,d)(Q)(4-chloro-1,2-diphenyl-1-(4-(2-(N.

Preparation of N-dimethylamino)ethoxy]phenyl]-1-butene ((Z) and (E)-isomers) The +2)-isomer of the target compound was produced as follows.

This reaction was conducted under dry conditions. First 42.49(')
(Z) -1+ 2- Schiff x Nil-1-(4-
(2-' (N +' ``dimethylamine)ethoxy]
Phenyl]-1-buten-4-ol was dissolved in 250 mj of tetraroform. Then 23.89 g of thionyl chloride was added dropwise. The mixture was refluxed for 3 hours.

After evaporation of the solvent, the product was recrystallized from ethyl acetate. The yield of the hydrochloride thus obtained was 36.79 (86% yield), and the melting point was 194-196. The product could be liberated from its hydrochloride form with 1M II carbonate solution, after which the product was extracted into toluene. The toluene solution was dried and the solvent was evaporated. (
The melting point (from acetone) was 108-110° CI.

1H-NMR spectrum analysis (in CDC13, δ value: p
pm): 2.27 (6H, B), 2.65 (2H, t)
, 2.91 (2f(,t ), 6.41(2H.

t), 3.92 (2HXt), 6.54 (2H,a)
, 6.79 (i, a), 7.15 (5H 1 day), 7.3
1 (5H,s) MS analysis (rJe): 405
/407 (M”, 7/6), 72 (20), 58 (10
0) The citrate salt of the compound could be prepared as follows. First, the (Z)-isomer 40.69 as the free base was converted into 1
To 75 rnl of warm acetone, add 1 part of 24.59 citric acid.
Each was dissolved in 0.0 m of warm acetone.

The solutions were then combined and the mixture was allowed to cool. The final citrate was collected by filtration. The melting point was 160-162°0.

The (m)-isomer of the target compound was produced as follows.

(E)-1,'2-diphenyl-1-(4-(2-(N
, N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol in the same manner as in the case of the corresponding (Z)-isomer. The obtained hydrochloride was recrystallized from toluene. Yield is 5
5.89 (yield 81%), melting point was 186-185°0. The product could be liberated from its salt form in a manner similar to that of the corresponding (Z)-isomer. Melting point (from hexane) was 69-710a.

IH-NMR spectrum analysis (in oDaz3, δ value;
pp'm): 2.64 (6H, s), 2.74 (Sl
, t), 2.97 (2u, t, ), 6.45 (2H.

t), 4. oa(2a, t>, 6.80~7.50 (
14H, m) MS analysis (m/e): 405/40
7 (M'', 7/6), 72 (19), 58 (100) Example 11 (a) (Production of 4-benzyloxy-1,2-diphenylbutan-1-o(116)) Deoxybenzoin Example 1 from 19.69 and benzyl ether protected bromoethanol 21.52
The target compound was produced according to the method described in .

Example 12 (a) (4-benzyloxy-1,2-diphenyl-1
-(4-[(tetrahydropyran-2-yl)oxy]
Preparation of phenyl]butan-1-ol ((RR,58)-enantiomer) Example 2 from the evaporation residue obtained in Example 11 and 68.6 p of 4-bromophenol protected with tetrahydrobilan-2-yl ether (a
) The target compound was produced according to the method described in tc.

(b) (4-benzyloxy-1,2-diphenyl-1
-(4-hydroxyphenyl)butan-1-ol ((
Example 2 (preparation of RRNSS)-enantiomer) from the evaporation residue obtained in step fa) above
The target compound was produced according to the method described in b).

(cHl, Production of 2-diphenyl-1-(4-hydroxyphenyl)p(117) tan-1,4-diol ((RRSSS)-enantiomer)) The evaporation residue obtained in step (b) above was heated at 300 rn
1 of 94% ethanol. Then 2 g of 5% palladium on charcoal was added and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen until one equivalent of hydrogen was consumed. The catalyst was distributed door to door. After evaporating the solvent, the product obtained was recrystallized from toluene. The yield is 12.7g (
68% yield from deoxybenzoin), melting point 192
01H-NMR spectrum analysis (OD30D, δ value: ~194°C)
ppm): 2.08 (2H, +1), 6.54 (2H
Nt) 5.83 (IH, dd), 4.76 (AH.

8), 6.76 (2H, (1), 6.85-7.25 (
10H,m), 7.47(2H,a)(a)(2,S-
Preparation of dipheny*-2-(4-hydroxyphenyl)tetrahydrofuran ((in,ss) and (R8XSR)-enantiomers) '6''), 49's (RR,SS)-1,2-diphenyl-1-( 4-hydroxyphel)butane-1,4-
The (RRNSS)-enantiomer was prepared from the diol according to the method described in 1HRJ2(C). The extraction procedure used ethyl acetate as the solvent. The resulting product was recrystallized from isopropanol. Yield after drying: is 2
8.19 (89% yield), melting point was 167-140'c.

1H-NMR spectrum analysis (in oD3oD, ati
: ppm) :1-85~2.60(2H,m), 5
．． 80-4-45 (6H, m), 4.79 (IH.

m), 6.75 (2H, a), 7.01 (IOH, s)
, 7.44 (2H, a) MS analysis: (m/s):
616 (M”, 6), 121 (25), 11B (10
0), 117(52) (R8,5R)-enantiomer was prepared as follows. The isopropanol mother liquor solvent was evaporated. After recrystallizing the evaporation residue from toluene, CRszs
The a>-enantiomer was obtained in low yield. Melting point is 119~
It was 162qO.

1H-NMR spectrum analysis (in OD30D, δ value:
ppm): 1.85 to 2-50 (2H, m), 3.7
5-4.45 (3H, m), 4.75 (IH.

8), 6.41 (2a, a), 6.80-7.45 (1
0H, m), 7.62 (12H.

aa) Example 16 (a) (1,2-diphenyl-1-(4-hydroxyphenyl)-1-buten-4-ol ((2) and (E
)-isomer) (Production route 1) First, 61.69 of 2,6-diphenyl-2-(4-hydroxyphenyl)tetrahydrofuran was dissolved in 125 m+/ of acetic acid, and then a solution containing 4o% of hydrogen bromide was dissolved. acetic acid 2
Added 5m4. The mixture was stirred at 75°C for 1 hour. The solvent was evaporated (the intermediate was a 4-acetoxy-1-butene derivative) and the evaporation residue was 94% of 200 m
The solution was dissolved in a mixture containing ethanol, 20 mj of water and 60 mj of 20% sodium hydroxide solution and the mixture was then refluxed for 1 hour. The seedling liquid thus obtained was neutralized with 2M hydrochloric acid, and then the ethanol was evaporated.

Water was added to the residue and the product was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated. The evaporation residue was treated with charcoal in methanol.

The methanol was evaporated and the product was recrystallized from toluene. The yield of a 1:1 mixture of pure (Z) and (K)-isomers was 22.89 (72% yield), with a melting point of (120
) It was 164-167°C.

(Production Route 2) First, 55.09 of 2,6-diphenyl-2-(4-methoxyphenyl)tetrahydro7rane was dissolved in 100mj of acetic acid, and then acetic acid 501 containing 40% hydrogen bromide was dissolved.
! added. The mixture was refluxed for Tt2 hours. Then 50 ml of acetic acid containing 40% hydrogen bromide were added and reflux was continued for a further 2 hours. The 0 ester from which the solvent was evaporated (the intermediate was a 4-acetoxy-1-butene derivative) was hydrolyzed and purified according to the method described above (Production Route 1). The yield of a 1=1 mixture of pure (2) and (E)-isomers was 11.7 g (37% yield).

Isolation of the isomers: First 20.0 g of the isomer mixture was dissolved in methylene chloride and then an excess of 2M hydroxide was added. After mixing or shaking, the mixture was filtered. The precipitate, primarily the (IIG)-isomer as the sodium salt, was suspended in 2M hydrochloric acid.

Reif (K)-isomer with free phenol (1
21) Extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated.

Finally, convert the isomer into water-methanol (50:50 >
It was recrystallized from The yield was 7.29 (66% for several options), and the melting point was 165-167°C.

1H-NMR spectrum) # analysis (in CD3COcD3, δ
Value: ppm) 2.78 (2H1t), 3.54 (2
H, t), 6.83 (2a, a), 6.90-7-35
(12H, m), 8.32 (IH, B ) MS analysis (m
l'@): 316 (M", 64), 285 (I
DO), 207(87), 191(58), 107(5
5), 91 (94) Its sodium salt could be prepared as described above. Another method consists of dissolving the pure (E)-isomer in ethanol, adding an equivalent amount of sodium hydroxide to the ethanol and evaporating the solvent.

Finally, the sodium salt was washed with acetone.

The melting point was 216-226°C.

Isolation of (Z)-isomer: The sodium hydroxide-methylene chloride mother liquor was transferred to a separatory funnel. The methylene chloride layer was removed. After neutralizing the aqueous layer with concentrated hydrochloric acid, extraction with ethyl acetate was performed. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated.

Finally (Z) ~ isomer is mixed with water-methanol (50:50)
It was recrystallized from The yield was 6.2 g (yield 61%), and the melting point was 169-171°0.

1H-NMR spectrum analysis (in OD3000D3, δ
Value: ppm): 2.70 (2uXt), 6.52 (
2H,t), 6.48(2H,d), 6.74(2H
.

d), 7-15(F)HN s ), 7.32 (in 5,
, s), 8.08 (1 turtle s) MS analysis (m/e)
: 316 (M, 35), 285 (38), 20
7 (54), 191 (37), 107 (50), 91
(100')(2)-isomer sodium salt (g))
-Produced in the same manner as for the isomers. Melting point is 205
It was the 217th season.

(b) (4-chloro-1,2-diphenyl-1-(4-
Hydroxyphenyl)-1-butene ((2) and (m
) -isomer)) (Z)-isomer: First, 42.59 (Z)-'4-chloro1,2-diphenyl-1-(4-benzyloxyphenyl)-1-butene was dissolved in ethyl acetate. and a 1:1 mixture of ethanol 8
Dissolved in 00d. Then 4g of 5% palladium charcoal was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere until one equivalent of hydrogen was consumed.
Separated. After evaporating the solvent, the product obtained was washed with petroleum ether. The yield was quantitative and the melting point (from methanol) was 85-87°a.

1H-NMR spectrum analysis (in CD3OD, δ value:
ppm): 2-87 (2H, t), 6.38 (2H,
t), 4.76 (IH, 8), 6.42 (2H.

d), 6.70 (2H, d), 7.15 (5HXs)
, 7.30 (5 melons 8) MS analysis (m/6): 33
4/3B6 (M”, 94/32), 285 (71), 2
07 (78), 191 (56), 185 (100), 1
07(56), 91(86)(g)-isomer: The (E)-isomer was produced in the same manner as the above (2)-isomer. The product was washed with petroleum ether.

Yield is almost quantitative, melting point 109-112°
It was 0.

1H-NMR spectrum analysis (in CD3OD, δ value i
ppm): 2.96 (2H, t), 5.42 (21 (
, t), 4.79 (1) I, a), 6.79 (2nd d)
, 6.96 (5H, 8), 7.12 (2H, d), 7.
12(5H,5)(124) Example 14 (4-chloro-1,2-diphenyl-1-(4-hydroxyphenyl)butane ((RuXss3 and (R8%
5R)-enantiomer) (RR,88)-isomer at 42.59 (Z)-4-
from c+o-1,2-diphenyl-1-(4-benzyloxyphenyl)-1-butene, the method described in Example 1x(b), but using 10% palladium on charcoal and 800 ml of ethanol as solvent. Manufactured according to. The reaction was stopped when 2 equivalents of hydrogen were consumed. After evaporation of the solvent, the product was washed with petroleum ether and recrystallized from methanol. Melting point is 118-12
It was 0'O.

LH-NMR spectrum analysis (in 0DO1z, δ value: p
pm) +1.62 to 2.57 (2H% m), 2-
94-3.43 C2HXm), l 66 (1H.

ta), 4-08 (1 & d)% 4-64 (1
& a), 6.77 (2 & a), 7.05 (5H,
a), Otsu 12 (5H, a), Otsu 2B (2H, (
1) ys analysis (rrv/e) ' 556733B (
M” 1.1/rJ, 4), 185 (100), 1
65 (15), 91 (14) (RR% 8B) - the benzoate from the isomer as follows (
125'). First, the TBAI of 0.49 (5
ml of water. Then 3 ml of 20% sodium hydroxide solution and 3.49 of the (RR,88)-enantiomer were added. The mixture was stirred at room temperature for 10 minutes. Then 1.72 ml of benzoyl chloride in 30 ml of chloroform was added ◇The mixture was stirred at room temperature for 2 hours. Methylene chloride was added. After shaking, the aqueous layer was removed, the organic layer was washed with water, the solution was washed with sulfuric acid, and the solvent was evaporated. The evaporation residue was washed with methanol. Yield is quantitative, melting point is 202-205
It was °0.

The (R8,5R)-enantiomer was prepared from the corresponding (co-isomer) in a similar manner as for the (RRXS8)-enantiomer above. The product was recrystallized from petroleum ether. The yield was 62%, mp. It was 82-84°0.

LH-NMR spectrum analysis (in ODO/3, δ value:
ppm): 1,78-2.21 (2H,m),
2.94-3.44 (2H,'m), 3.69 (
iH.

td), 4.08 (IH% d), 4.48 (IH
, br s), 6.48 (2H, (1), 6, 96
(2H, d), Otsu 14 (5H, s), Otsu 53 (
5H% br s) The benzoate was prepared from the (R3,SR)-enantiomer and recrystallized from methanol. Yield was 88%, melting point 128-131°0.

Example 15 C4-C(tetrahydropyran-2-yl)oxyph-
Production of 1,2-bis((4-(tetrahytotetrabilan-2-yl)oxy]phenyl]butan-1-one) 4.4
-bis[(tetrahydropyran-2-yl)oxyfudeoxybenzoin 39.69 and tetrahydropyran-2-yl ether protected bromoethanol 20
．． The target compound was prepared from No. 99 according to the method described in Example 1.

Example 16 (a) (4-((tetrahydrobyran-2-yl)oxy-1-phenyl-1,2-bis(ni(4-(tetrahydropyran-2-yl)oxy]phenyl)butan-1-ol( Preparation of (R8,SR)-enantiomer) The target compound was prepared from the evaporation residue obtained in Example 15 and 23.69 bromobenzene according to the method described in Example 2.(a).

(b) (1-phenyl-1,2-bis(4-hydroxyphenyl)butane-1,4-diol ((R8,5R)
- production of enantiomer)) From the evaporation residue obtained in step (a) above, Example 2 (
The target compound was produced according to the method described in b). The product was recrystallized from toluene. The yield is 8.49 (4,
4-bis[(tetrahydrobilan-2-yl)oxyfudeoxybenzoin yield 24%), melting point 213
~215°C.

(Q) (Production of 2-phenyl-2,3-bis(4-hydroxyphenyl)tetrahydrofuran ((RR,5S)-enantiomer)) From the evaporation residue obtained in step (a) above, acetic acid was added in place of toluene. Example 2 (C) except that extraction with ethyl
The target compound was produced in the same manner as in the case of 2.2.3-triphenyltetrahydrofuran. The product was recrystallized from toluene. Yield is 14.91. (4, 4'-
Bis[45% yield from (tetrahydrotetrapyran-2-yl)oxyfudeoxybenzoin], melting point 194-1
〇(128) 1H-NMR spectrum analysis (in OD30D, δ value:
ppm): 1, 90-2.45 (2HSm), 3
．． 80-4.45 (3H, m), 4.75 (2H.

8), 6.48 (2H, d), 6.72 (2H, d),
6.85 (2H, d), 6.80-7.15 (5H,
→, 7.41 (2H, (1) MS analysis (m/e):
332 (M”, 4), 134 (100) Example 17, (5-hydroxy-1,2-diphenylpentane-1
-one preparation) Method 1: 19.69 deoxybenzoin, 13.99 3-prof-propan-1-ol, 1 g TBAH, 40
A mixture containing 48% sodium hydroxide solution of mj+ and 60 ml of toluene was stirred at 45°0 for 24 hours.

Water was added and the product was extracted into toluene. The toluene solution was washed with water and dried over sodium sulfate. Finally the solvent was evaporated. The yield was almost quantitative; the converted product contained approximately 10-15% of 0-alkylated product. The melting point of a sample purified by chromatography is 4
5-48°0 (129) 1H-NMR spectrum analysis (δ value + ppm in 0D300D3); 1.30-2.49 (4H% m),
2-82 (I R18), 3-55 (2H% t
), 4, 82 (IH, t), 7.03-7.64 (
8H, m), 8.04 (2H, da) Method 2: Deoxybency of 19.69 was prepared according to the method described in Example 1, except that the reaction was first carried out at room temperature.
By alkylation with 3-bromo-1-chloropropane. Isolation yielded 2,6-diphenyl-4,5-dihydro-6H-pyran as an intermediate in quantitative yield;
The resulting product contains about 10 acyclic O-alkylated products.
It contained %.

The melting point of a sample purified by p-madography and recrystallized from methanol was 119-122°0.

1H-NMR spectrum analysis (in CJDO13, δ value:
ppm): 1, 87-2.17 (2H, m), 2.
48 (2■, t), 4.16 (2H, ad), 7
, 02-7.55 (10 H, m) The crude intermediate was then first dissolved in 900 ml of ethanol. Then 100ml of water and 5ml of concentrated sulfur were added. The mixture was stirred at room temperature for 3 days. The cyclic intermediate was hydrolyzed to 5-hydroxy-12-diphenylpentan-1-one. After neutralizing the reaction mixture with 2M sodium hydroxide solution, the solvent was evaporated.

The obtained product was dissolved in toluene. The toluene solution was washed with water and dried over sulfuric acid. The solvent was then evaporated. The evaporation residue is converted into hot oil
Treatment dissolved the acyclic O-alkylation product. After cooling, the solvent was decanted leaving the pure product as an oil. The yield was 20.19 (yield 7
9%).

Example 18 (Preparation of 1,1,2-triphenylpentane-1,5-diol) 69 mag* in 42 ml dry tetrahydrofuran
Shira A ff4, B4. 39.3 g of bromobenzene in ml of dry tetrahydrofuran and 25.49 of 5-hydroxy-1,2-diphenylpentan-1-oncara in 75 ml of dry tetrahydrofuran Example 2
The target compound was produced according to the method described in (a). The product was recrystallized from toluene. The yield was 14.99 (45% yield), and the melting point was 120-122°C.

1H-NMR spectrum analysis (in OD3OD, δ value:
ppm): 1.12-1.52 (2H1m),
1.75-2.12 (2Hs m), 3.40 (2
H%t>, 3.71 (IH,t), 4.78 (2H
, s), 6.90-7.44 (13H, m), 7, 6
5 (2H, dd) Example 19 (a) (Production of 5-acetoxy-1,1,'2-triphenyl-1-pentene) 1.1.2- of 33, 29) diphenylpentane-1
, 5-diol according to the method described in Example 10(a). The product was recrystallized from methanol. Yield: 22.19 (62% yield), melting point: 8
It was 0 to 81°0.

LH-NMR spectrum analysis (in oDat3, δ value:
ppm): 1.49-1.89 (2H% m),
1.94 (3H1s), 2.44~2.62 (2H
.

m), 3.96 (2&t), 6.95 (5HXbr 8
), 7.12 (5H, 8), 7, 27 (5HXbr
a) (b) (1,1,2-)rifuniru 1-pentene-
Production of 5-ol) The target compound was produced from 5-acetoxy-1,1,2-triphenyl-1-pentene of (132) 35,69 according to the method described in Example 3(b). The product was recrystallized from toluene-petroleum ether. The yield was 12.69 (yield 40%)
), the melting point was 128-130°0.

LH-NMR spectrum analysis (in oDa13, δ value:
ppm): L30 (IHLs), 1.44~
1.79 (2HXm), 2.44-2.63 (21(
.

! 11), 3.51 (2H,t), 6.9;6 (s
HXbr s), 7.13 (5H, 8), 7-50
(5H% br s) MS analysis (mle): 314 (M'', 34)
, 26B (13), 205 (25), 191 (
60), 167 (42), 105 (21), 91
(100) Example 20 (5-((tetrahydrobilan-2-yl)oxyfuran-
Production of 1,2-diphenylpentan-1-one)19.
69 deoxybenzoin and tetrahydrobilane-
The target compound was prepared from 2-yl ether-protected 3-bromopropatol 22.39 according to the method described in Example 1.

Example 21 (a) (5-((tetrahydrobilan-2-yl)ogi(133)cy)-1,2-diphenyl-1-(:(4-(tetrahydrobilan-2-yl)oxy)phenyl) Preparation of pentan-1-ol ((RR,88)-enantiomer) Example 2 (a The target compound was produced according to the method described in ).

(b) (1,2-diphenyl-1-(4-hydroxyphenyl)pentane-1,5-dio-/l, ((RR,
88) - Preparation of enantiomer)) From the evaporation residue obtained in step (a) above, Example 2 (
The target compound was produced in the same manner as in the case of 1.1.2-triphenylbutane-1,4-diol in b). The product was recrystallized from toluene.

The yield was 1 g of N (32% yield from deoxybenzoin).
), the melting point was 182-184°0.

LH-NMR spectrum analysis (in OD30D, δ value: p
pm): 1.10-1.6rJ (2HXI11),
1.65-2.15 (2H% m), 3-58 (
2H%t), 3.61 (IHsdd), 4.80 (3H
ss), 6.72 (2H, d), 6.80-7.25
(10H,%m), Otsu39 (2H,d)(c)(2
, 3-diphenyl-2-(4-hydroxyphenyl)tetrahydropyran ((RR,SS)-enantiomer) Example 2 from the evaporation residue obtained in step (a) above
The target compound was produced in the same manner as in the case of 2.2.3-triphenyltetrahydro7rane (0). Ethyl acetate was used for extraction. The evaporation residue was recrystallized from isopropanol to give the tetrahydropyran derivative. The yield was 7.3 g (22% yield from deoxybenzoin), and the melting point was 194-196°a.

LH-NMR spectrum analysis (in 0D30D, δ value: p
pm): 0, 95-1.55 (IH, m), i,
55-2.60 (5HXml), 3.55-4, 3
0 (3H, m), 4.80 (IH, a), 6.65
~7.55 (14H, m) MS analysis (m/e):
350 Qi! ”, 15), 198 (3B), 1
21 (57), 104 (100) Example 22 (&)(1,2-diphenyl-1-(4-hydroxyphenyl)-1-penten-5-ol ((2) and (
Et)-isomerism The mother liquor of isopropanol obtained in Example 21 (Q) was evaporated. The evaporation residue was recrystallized from toluene. Mixture of bentenol derivatives ((Z): (K
) = 171) Changed. Yield: 5.69 (17% yield from deoxybenzoin), melting point: 157-16
It was 3°0.

The resulting isomers were separated into their congeners as described in Example 13(a).

The (K)-isomer was recrystallized from water-methanol (2:3). The melting point was 167-169°0.

LH-NMR spectrum analysis (in OD30D, δ value:
ppm): 1.35-1.74 (2HXm),
2.44-2.67 (2H, m), 3.42 (2
H.

t), 4.75 (2HXs), 6.76 (2H, d),
6.91 (5H,br s), 7,05 (2H,a
), Otsu05' (5H,s) Ms analysis (m/e)
:33o(u+,10n),285(39),2
07 (75), 183 (89), 107 (57),
91 (90)(Z)-isomer in water-methanol (1:
2). The melting point was 164-167°0.

LH-NMR spectrum analysis (in OD30D, δ value: p
pm): (136) 1, 55-1.72 (2H, m), 2.37-2.
57 (2HXn9.5.59 (2H.

t), 4.74 (2H,%8), 6.40 (2H
, d), 6.68 (2H, cl), Otsu 12 (5H, a
), 7.26 (5HXbr s) MS analysis (m/
6): 330 (M”, I Do), 285
(19), 207 (7), 183 (97), 115
(76), 91 (81) (b) (5-acetoxy-
1,2-diphenyl-1-(4-hydroxyphenyl)
-Production of 1-pentene ((Z) and (1)) Isomer mixture of target compound ((z):(E)=1:1)
A mixture of alcohols corresponding to ((z):(E)=1=
1) by transesterification reaction with ethyl acetate using concentrated hydrochloric acid as a catalyst.

LH-NMR spectrum analysis (in 0D30D, δ value: p
pm): 1.34-i. 69 (2&m), 1.79
(1,5H1s), 1.83 (i, 5HX8), 2
, 29-2.56. (2H, m), 3.79 (IH
, t), 3.83 (IH, t), 4.57 (IH, s
), 5.30 (IH, cl), 5.59 (IH, d),
6.57 (IH.

(L), 6.94 (IH, d), 6°81-7.
24 (10H, m) Example 23 (Preparation of 5-chloro-1,2-diphenylpentan-1-one) (137) Example 17 except that the reaction time was only 15 minutes at room temperature.
The target compound was prepared from 19.69 deoxybenzoin alkylated with 15.89 3-bromo-1-chloropropane according to the method described in Method 1 of . The product was recrystallized from methanation. The yield was 16.6 g (61% yield, melting point 72-74°0).

LH-NMR spectrum analysis (in ODO1S, δ value:
ppm): 1, 54-2.56 (4H, m), 3.
50 (2HXt), 4.56 (IH,t), 7, 2
1~7.50 (8HXm), Otsu94 (2H, dd
) Example 24 (a) (5-ppm 1,2-diphenyl-1-(C4
- Preparation of (tetrahydropyran-2-yl)oxy]phenyl]pentan-1-ol ((RR,88)-enantiomer)) First, the Grignard complex was prepared by mixing 3.6 g of magnesium scraps in 50 ml of dry tetrahydrofuran with 75 ml of dry 4-bromophenol protected with tetrahydrofuran-2-yl ether in tetrahydrofuran58.69
It was produced under dry conditions by reacting with

Then two-thirds of the complex solution is boiled 27.3
g of 5-chloro-1,2-diphenylpentan-1-one and 100 ml of dry tetrahydrofuran. The remainder of the complex solution was then added in portions until all or nearly all starting material had reacted based on thin layer chromatography.

The reaction mixture was refluxed for 1 hour. Isolation was carried out in the same manner as in Example 2(a).

(b) (5-chloro-1,2-diphenyl-1-(4-
hydroxyphenyl)pentan-1-ol ((R&
ss) - production of enantiomer)) From the evaporation residue obtained in the above step product), only 5 g
The target compound was prepared according to the method described in Example 2(b) except that concentrated sulfuric acid of

Purified by recrystallizing a small sample from toluene-petroleum ether.

IH-NMR spectrum analysis (in OD30D, δ value:
ppm): L 30-1.77 (2HXm), 1
．． 85-2.15 (2H, m), 3.37 (2H, t
), 3.64 (IH, dd), 4.60 (2H, s),
6.78 (2H, d), (140) 6, 88~7.22 (IQH, m), 7.45 (
2H,a) Example 25 (Production of 5-chloro-1,2-diphenyl-1-(4-hydroxyphenyl)-1-pentene ((z)-Jift, body)) Example 24(b) 30% of the evaporated residue
After dissolving in 0+nl of ethanol, 10ml of concentrated hydrochloric acid was added and the mixture was refluxed for 30 minutes. The solution was treated with charcoal. After p-filtration, the solvent was evaporated to give a mixture of (2) and (lli)-M exobodies. The isomer mixture thus obtained was recrystallized from petroleum ether to give 7 g (22% yield of 5-chloro-1°2-diphenylpentane-1-onkara) of (Z)-
Obtained an isomer. The melting point was 116-118°O.

IH-NMR spectrum analysis (in 0D30D, δ value:
ppm): 1, 56-1.94 (2HXm), 2.
47-2.66 (2H, m), 3.35 (2H.

t), 4.74 (I H,s), 6-41 (2H
% d), 6.69 (2HN d), Otsu 13 (5
H,s), 7.22-7.41 (5) IS→Example 26 (4,4-jethoxy-1,2-diphenylbutane-1
(141) Production of one ion) The target compound was produced according to the method of Example 1 from 19.6 g of deoxybenzoin and 19.7 g of diethyl acetal of bromoacetaldehyde.

However, the reaction was carried out at 90°O, and TBAH was used as a catalyst instead of T]1iBAO.

Example 27 (a) (4,4-jethoxy-1,2-diphenyl-1
-[Production of 4-(2-morpholineethoxy)phenylcobutan-1-ol] Distillation residue obtained in Example 26 and 42.99 1-
The target compound was prepared from bromo-4-(2-morpholine ethoxy)benzene according to the method described in Example 2(b).

(b) (5-hydroxy-2,3-diphenyl-2-(
Preparation of 4-(2-morpholineethoxy)phenylcotetrahydrofuran) The evaporation residue obtained in step (a) above was dissolved in a mixture containing 19.59 m sulfur'H, 150 ml of water and 400 ml of tetrahydrofuran. . The mixture was stirred at room temperature for 3 hours. The resulting solution was neutralized with 2M IJ hydroxide solution and the solvent was evaporated. The product was extracted into toluene containing ethyl acetate. The solution was dried over sodium sulfate. The solvent was evaporated. Finally, the product was recrystallized from toluene with a yield of 12.0 g (
27% yield from deoxybenzoin), melting point 150
~153°0.

LH-NMR spectrum analysis (in ODO13, δ value: p
pm): 2, 20-2.55 (2H1m), 2.6
5 (4H1t), 2.86 (2H,t), 3, 7
8 (4H, t), 4.14 (2H, t), 4.5
4 (IHXdd), 5.85-6, 05 (IH, m
), 6.80-7.30 (12HXn+), 7.53
(2H, d) Priority claim 9 June 25, 1982■
United Kingdom (GB) ■8218414 0 Inventor Aldo Johannes Karjalainen Republic of Finland Nisev-90650 Oulu 65 Miyurjojancie 13 Ho 37 0 Inventor Kauko Oiva Antero Kurkela Republic of Finland Nisev- 90560 Oulu 56 Keulachie 4 @ Inventor Marjalisa Söderberg Republic of Finland Nisev-90560 Oulu 56 Annantie 9-13 Safe 0 Inventor Lauri Beikko Matsutsi Kangas Republic of Finland Nisev- 20100 Turku 1o Lihiperontier 16 Asunto 16 @ Inventor Guillermo Luis Blanco Nissev, Republic of Finland - 90250 Oulu 25 Suohaukancie 2A @ Inventor Hannu Kalervo Sundquist Nissev, Republic of Finland - 20780 Karlina Solonche 1be

Claims (1)

[Claims] 1 Formula (Io): 110A (yR2(IO) (wherein R1 and R2 are the same or different) HloH
, alkoxy group, benzyloxy group or methoxymethoxy group of carbon t1-4: A is the formula: (wherein... is 0 or 1-4; R3 is HlOH, halogen atom, carbon number 1-4
alkoxy group, benzyloxy group, methoxymethoxy group, 2,5-dihydroxydibrypoxy group or formula: R6 and R7 are the same or different, H or carbon number 1
~4 alkyl group or a group capable of forming a ring); R4 is OH, IF%Q1%Br
R
5 is H or OH; or k4 and R5 together form a 10-bridge between adjacent carbon atoms;
However, a) When n is 0, R2 and R3 cannot be H or methoxy groups at the same time. (b) When n is 0, R3 is other than a halogen atom. co) When n is 1, R4 and R5 are both OH or R4 and R5 together form a -0- bridge between adjacent carbon atoms: al, R2 and R
3 cannot become H at the same time, or (+1) If n is 2 and R4 and R5 together form a 10-bridge between adjacent carbon atoms, R1, R2 and R3 can become H at the same time. is a compound represented by the formula (Io): 3 or (n): (in which, R1, R2, R3, R4, R5 and n are the same as above) or a pharmacologically acceptable non-toxic salt or ester thereof, or a mixture thereof. 2 Claims in which n is 1 or 2 3. The compound according to claim 1 or 2, wherein at least one of R1, R2 and R3 is other than H. 4R1,R" and (y) At least one of R3 is The compound according to claim 1, 2 or 3, wherein R3 is a hydroxyl group, methoxy group or ethoxy group. 5 R3 is of the formula: (wherein m, R6 and R7 are the same as above) The compound according to claim 1, 2 or 6. 6 The compound according to claim 5, wherein m is 1 and R6 and R7 are a methyl group or an ethyl group. 7 R4 and R5 together form a 10-bridge between adjacent carbon atoms, according to claim 1, 2, 6, 4, 5, or 6. formula(
A compound represented by II). A compound represented by formula (1) according to claim 1, 2, 3, 4, 5 or 6, wherein B R4 is a halogen atom. 9 R1 and R2 are H, and R3 is -0OH20
9. The compound according to claim 8, which is H2N-+ 0H3)2. 10 The compound according to claim 1, which is 1,2-diphenyl-1-(4-hydroxyphenyl)butane-1,4-diol. 11 2.3-Diphenyl-2-(4-hydroxyphenyl)tetrahydrofuran Claim 1
Compounds described in Section. 12. The compound according to claim 1, which is 1,2-diphenyl-1-(4-methoxyphenyl)-1-buten-4-ol. 13 1.2-diphenyl-1-(4-(2-(N,N
-dimethylamino)ethoxycuphenyl)-1-buten-4-ol. 14. The compound according to claim 1, which is 2.5-diphenyl-2-(4-hydroxyphenyl)tetrahydrobilane. 15 1.2-Diphenyl-1-(4-hydroxyphenyl)-1-penten-5-ol Patent M sought (
7) Compounds described in Range 1. 164-ri p-1,2-diphenyl-1-(4-(2
-(N,N-dimethylamino)-ethoxy]phenyl]
The compound according to claim 1, which is -1-butene. 17 The compound according to claim 1, which is 1-phenyl-1,2-bis(4-hydroxyphenyl)butane-1,4-diol. 18 2-722-2,6-bis(4-hydroxyphenyl)tetrahydrofuran Claim 1
Compounds described in Section. 19 The compound according to claim 1, which is 1,2-diphenyl-1-(4-hydroxyphenyl)-1-buten-4-ol. 204-Bromo-1,2-diphenyl-1-(4-(2
The compound according to claim 1, which is -(N,N-dimethylamino)ethoxy]-phenyl]-1-butene. The compound according to claim 1, which is 214-chloro-1,2-diphenyl-1-(4-hydroxyphenyl)butane. The compound according to claim 1, which is 224-chloro-1,2-diphenyl-1-(4-hydroxyphenyl)-1-butene. 23 2.5-diphenyl-2-(4-(2-(N,N
The compound according to claim 1, which is -dimethylamino)ethoxy]-phenyl]-teFrahydro7rane. 24 1.2-diphenyl-1-(4-(2-(M,N
-dimethylamino)ethoxy)-phenyl]-butane-
The compound according to claim 1, which is a 1,4-diol. 25 Formula (10): (wherein R1 and R2 are the same or different, H, O
H, alkoxy group having 1 to 4 carbon atoms, benzyloxy group or methoxymethoxy group; A is the formula: (wherein, n is 0 or 1 to 4; R3 is H, OH. Ha) f atom, number of carbon atoms 1 to 4 alkoxy groups, benzyloxy groups, methoxymethoxy groups, 2,3-dihydroxypropoxy groups or l R6 and R7 are the same or different H or carbon number 1
~4 alkyl group or a group capable of forming a sequential ring); R4 is OH, ? , 01%Br
, a formyloxy group, a mesyloxy group, a tosyloxy group, an alkylcarbonyloxy group having 1 to 4 carbon atoms, or -0H2R' is substituted with OHO; R5
is H or OH; or R4 and R5 together form a 10-bridge between adjacent carbon atoms, provided that a) if n is 0, R2 and R3 are simultaneously H or methoxy; (b) When n is 0, R3 is other than a halogen atom; fc) When n is 1, R4 and R5 are both OH, or R4 and R5 together are adjacent carbon atoms; When a 10-bridge is formed between atoms, R1, R2 and R3
cannot be H at the same time, or (d) n is 2 and R4
and R5 together form a 10-bridge between adjacent carbon atoms, R1, R2 and R3 do not become H at the same time),
In the case where the person of formula (10) has the formula: , the formula (Io) is the formula (■): 3 or the formula (■): (wherein R1, R2, R3, R4, R5 and n are An antitumor agent for hormone-dependent tumors that contains a compound represented by (same as ) or a pharmacologically acceptable non-toxic salt or ester thereof as an active ingredient. 26 Anti-tumor tag according to claim 25, comprising a pharmacologically acceptable carrier 27 Formula: (wherein R11L and R2a are the same or different H
,O)1. It is an alkoxy group, benzyloxy group or methoxymethoxy group having 1 to 4 carbon atoms, or a mixed acetal group; n is 0 or 1 to 4: OR8 is a mixed acetal group, benzyloxy group or human tetraxy group ) is subjected to a reaction with the formula: or formula; R3a+Li (wherein, ha"
Lt H%OH, halogen atom, alkoxy group having 1 to 4 carbon atoms, □benzyloxy group, methoxymethoxy group, 2.5-dihydrokidibreboxy group or formula: R
6 and R7 are the same or different, H or a group forming a carbocyclic ring, or a mixed acetal group), and reacted with a halogenated phenylmagnesium derivative or a corresponding lithium compound represented by the formula: (
In the formula, the protected or unprotected triphenyldiol represented by n%R1a%R'', R3aOyoUR8(same as above), and the M retaining group 28 above ul
28. The manufacturing method according to claim 27, wherein a and/or u2a are (tetrahytotetrabilan-2-yl)oxy groups. 29 Claim 27 or 28, wherein E13a is a (tetrahydropyran-2-yl)oxy group
Manufacturing method described in section. 60 Formula: (In the formula, n, Rla, R3a and OR" are the same as described in claim 27) A compound represented by the formula: or formula: R2a +L1 (wherein R2a is the same as described in claim 27) or the corresponding lithiated derivative (in the formula, n%R'', R2a,
R3a, R8 are triphenyldiol shown in the above 1:, ), and then the protecting group R8 and the protecting group, if any, are removed from the 7-el ring to form the formula (■)
: 3 (wherein n, R1, R2, and R3 are the same as above, and R4 and R5 are OH). 61 The above formula (■) (wherein R4 and R5 are both O
A method for producing a compound represented by the above formula (■) (in the formula, R4 and R5 together form a 10-bridge between adjacent carbon atoms) by dehydrating the compound represented by H). . 62 The above formula (■) (wherein R4 and R5 are both O
A method for producing a compound represented by formula CI) (wherein R4 is OH), which is obtained by dehydrating a compound represented by H). 33 Formula: (where n, Rla, H2a, H3a and oH8
is the same as described in claim 27), by removing the protecting group R8 (however, R8 is not H) and/or the protecting group, if any, on the phenyl ring,
The above formula (II) obtained by dehydration (R' and R5 together form a 10-bridge between adjacent carbon atoms)
A method for producing the compound shown in Formula 64: (wherein n, Rla, R2a, R3a and oH8
is the same as described in claim 27), and a protecting group R8 (wherein R8 is not H) is used for producing a compound. 65 The above formula (■) (in the formula, R4 and R5 together form a 10-bridge between adjacent carbon atoms)
A method for producing a compound represented by formula (I) (wherein R4 is OH or a hydrogen atom) by cleaving the ring of the compound represented by formula (I). 36 An aluminum complex represented by the formula: (wherein n and R1 are the same as described in claim 1) and the formula: % formula % (wherein R2 and R3 are the same as described in claim 1) The above formula (■) (in the formula, both R4 and R5 are O
A method for producing the compound represented by H). 67 Formula (I) or (■) (wherein R4 is oH
) Formula (■) or (■) is obtained by esterifying a compound represented by the above formula (■) or (■) with a carboxylic acid having 1 to 5 carbon atoms or a corresponding carboxylic acid derivative (wherein R4 is a formyloxy group or a carboxylic acid derivative having 1 to 4 carbon atoms). A method for producing a compound represented by an alkylcarbonyloxy group. 38 A method for producing a compound represented by the above formula (I), which comprises dehydrating the compound represented by the above formula (R) (wherein R5 is OH). 69 The above formula (■) obtained by hydrolyzing the compound represented by the above formula (■) (wherein R4 is a formyloxy group t or an alkylcarbonyloxy group having 1 to 4 carbon atoms) (wherein R4 is A method for producing a compound represented by OH). 40 The above formula (■) (wherein, R4 and R5 are both O
The above-mentioned compound is obtained by reacting a compound represented by H or R4 and t together to form a -0-bridge between adjacent carbon atoms with a suitable acid catalyst in a carboxylic acid having 1 to 5 carbon atoms. A method for producing a compound represented by formula (■) (wherein R4 is a formyloxy group or an alkylcarbonyloxy group having 1 to 4 carbon atoms). 41 Formula: (wherein, n, Rla, R2a, R3a): U
:a8C (same as described in claim 27) of formula (I) (in the formula, R4 is a formyloxy group or an alkylcarbonyloxy group having 1 to 4 carbon atoms). 42 Formula (1) or (■) (in the formula, at least one of R1, R2 and R3 is an alkoxy or aralkoxy group) obtained by dealkylation of a compound represented by formula (I) or (1) (in the formula, at least one of R1, R2 and R3 is an alkoxy or aralkoxy group) A method for producing a compound in which at least one of R1, R2 and R3 is OH). 46 Formula (I) or (■) (wherein, R1, R2
and at least one of R3 is OH) with an appropriate alkylating agent, such as an alkyl halide. Carbon number 1
-4 alkoxy group, benzyloxy group or methoxymethoxy group). 44 The compound represented by formula (1) or (■) (in the formula, R3 is OH) is treated with a suitable alkylating agent, such as R''-
Halogen represented by hal (in the formula, ul is a group represented by alkyl having 1 to 4 carbon atoms (in the formula, R6, R7 and m are the same as described in claim 1), and ml is a halogen atom) Formula C obtained by alkylation with an alkyl derivative
I) or (I+) (wherein R3 is a carbon@1-4 alkoxy group, benzyloxy group, methoxymethoxy group, 2
．． A method for producing a compound represented by a 6-hydroxybroboxy group or the same as above. 45 The compound represented by the above formula (I) (wherein R3 is OH) is represented by the formula: hal-(OH3)rnOH2-hal
(wherein m is 0 or 1 to 6, hal is the same or different halogen atom), and alkylated with a dihydralkane represented by the formula: (wherein R1, R2, R4 and n are Reaction with an amine represented by 4-(haloalkoxy)-phene (wherein R6 and R7 are the same as described in claim 1) The above formula (■) (wherein, R
3 is a method for producing a compound represented by the aminoalkoxy group described in claim s.i. 46 The compound represented by the above formula (■) (wherein R3 is OH) is
l (wherein m is 0 or 1 to 6, hal is the same or different halogen atom) and alkylated with a dihaloalkane represented by the formula: 4-(haloalkoxy)-phenyldiphenylalkane (same range as described in item 1, m and hal are the same as above), and react with an amine represented by the following range (same as described in item 1) The formula (■) (in the formula,
R3 is an aminoalkoxy group according to claim 1). 47 Formula (I) or (■) (wherein, R4 is OH
) The corresponding formula (I) or (■) obtained by substituting the hydroxyl group of the compound shown with a halogen atom (in the formula, R
4 is a method for producing a compound represented by a halogen atom). 48 Formula (I) or (■) (wherein, R4 is OH
) corresponding formula (I) or (■) obtained by reacting a compound represented by methanesulfonic acid chloride t or toluenesulfonic acid chloride (in the formula, R4 is a mesyloxy group when methanesulfonic acid chloride is used, A method for producing a compound represented by a tosyloxy group when toluenesulfonic acid chloride is used. 49 A compound represented by the above formula (I) (wherein R4 is a halogen atom) obtained by dehydrating and substituting the hydroxyl group of the compound represented by the above formula (■) (wherein R4 and R5 are both OH) Method of manufacturing compounds. 50 A method for producing a compound represented by formula (I) (wherein R4 is og) by treating the compound represented by formula (■) (in which R4 and R5 are both OH) with cyclized thionyl. 51 Formula (1) obtained by substituting a compound represented by the above formula (I) or (■) (in the formula, R4 is a mesyloxy group, a tosyloxy group, or a halogen atom) with a halogen atom.
) or (■) (wherein R4 is a halogen atom). 52 Formula: (wherein Rla and R2a are as defined in claim 2 above)
The same compound as described in claim 7, where n is 0 or 1 to 4 and hal is a halogen atom) is reacted with the phenylmagnesium halide derivative described in claim 27 or its corresponding lithium compound by Grignard reaction. A compound represented by the formula: (wherein s halSHla and R21L are the same as above, and R3a is the same as described in claim 27), and if there is a protective group on the phenyl ring, it is removed. The above formula (n) (wherein R4 is a halogen atom and R5 is a hydroxyl group) The above formula (■) consisting of the same reaction as described in item 52 (wherein R4 is a halogen atom and R5 is a hydroxyl group) 54 Hydrolyzing the compound represented by the above symbol (in the formula, R5 is OHS'R'' is the same as described in claim 27), and adding protection to the phenyl ring of the compound. Formula (I) obtained by removing any groups (wherein R3 is O
A method for producing a compound represented by (H, R' are) 10 gene atoms. 55 Formula: (wherein R1, R2, R3 and n are the same as above, X is a halogen atom, 2 is H, Y is H or OH, or 2 and Y are bonded together) to the corresponding Grignard complex or lithium salt, where X is Mghal or Ll, respectively.
) and reacting the complex or salt with formaldehyde, ethylene oxide or trimethylene oxide.
is OH%n is 1 to 4). 56 A compound represented by the above formula (I) or (■) (in the formula, n is 0 or 1 to 3, R' halogen atom, mesyloxy group or tosyloxy group) is reacted with a cyano group to form a compound of the formula: (in the formula , R1, R2 and R3 are the same as described in claim 1, and 2 and Y are as described in claim 5.
Same as described in Section 5, where n is a compound represented by 0 or 1 to 6), the compound is hydrolyzed to the corresponding triphenylcarboxylic acid, and then the carboxylic acid is reduced in one step or through an intermediate. The above formula (I) or (11)
A method for producing a compound represented by the formula (wherein R4 is a side and n is 1 to 4). 57 The above-mentioned compound obtained by reacting the compound according to claim 55 (wherein X is Mghal or Li) with carbon dioxide to form the corresponding triphenylcarboxylic acid, and then reducing it in one step or through an intermediate. A method for producing a compound represented by formula (I) or (II> (wherein R4 is 0H1n is 1 to 4). 58 Formula: (wherein RlFL and R2a are the same as described in claim 27) , n is 0 or 1-4, R13 and R14 are the same or different, ethyl group, or R13
and R14 together form the 1,6-dioxolane ring.
A protected diphenyloxaldehyde represented by the formula: (forming a 6-propylene group) is represented by the formula: By reacting with a compound of the formula: (wherein Rla, R"a, R3a, n, R13
EJ: The above formula (■) obtained by using the protected triphenylhydroxyaldehyde represented by R14C (same as above), and finally removing any protective groups on the phenyl ring.
(In the formula, 0H2R' is substituted with OHO, and R5 is OH). 59 Starting material according to claim 58 Said formula (■) consisting of the same reaction as described in claim 58 (wherein 0HER' is substituted with OHO, R5 is OH ) The method for producing the compound shown in 60 Formula: or Formula: 3 OH (wherein R1, R2, R3 and n are the same as described in claim 1) or a mixture thereof is dehydrated to obtain the formula (I'> (In the formula, 0H2R' is replaced with OHO.) 61 Formula: (In the formula, Rla, R2a, R3&, 111, R13
The protected triphenylaldehyde represented by the formula: (wherein, Rla, R21L, H3a, n, R13)
and R14 are the same as above), and then the protecting group is removed to form the compound of formula (I) (wherein 0)i
2R' is substituted with OHO). 62 The above formula (1) or (■) (wherein, R' is OH
) A method for producing a compound represented by formula (1) or (It) (wherein 0H2R4 is substituted with OHO). 66 The above formula (1) or (■) (wherein, R4 is 0O
The above formula (I) or (■) obtained by reducing the compound represented by OH) in one step or through an intermediate (in the formula, 0H2
R' is replaced with OHO). 64 Compounds represented by the above formula rI) or the above formula (
II) A method for producing a compound represented by formula (n) (wherein R5 is H), which is obtained by hydrogenating a compound represented by formula (n) (wherein R5 is other than H). 65 Formula: % formula % (wherein Bla and H2a are
(same as described in Section 7) is a compound represented by the formula: % formula % (wherein, hal is a halogen atom, n is 0 or 1 to 4,
Q is a mixed acetal group, benzyloxy group, hydroxyl group, halogen atom, or OR14 where 10H2Q is struck
(In the formula, R13 and U R14 are substituted with the same as described in claim 58); A method for producing an intermediate represented by the above!: Ibid. 66 The above H2& is 13a (12m and H 13a
G! 67. Method for manufacturing an inner cylinder body according to claim 65, which is the same as described in claim 27). The pure (RR,8B)-enantiomeric bear of the compound of formula (n) and (R8
,5R)-enantiomeric bears from their corresponding mixtures, and likewise the pure (2)- and (]l[i)-isomers of compounds of formula (I) from their mixtures. Method.