JPH05222073A - Bone-selective estrogen - Google Patents

Abstract

PURPOSE:To provide the subject new estrogen compound selectively acting on the osseous tissue, low in side effect and useful as a medicine for preventing and improving osteoporosis. CONSTITUTION:A compound of formula I (E is estrogen residue; R<1> is a single bond or a lower alkylene; R<2> is a lower alkylene, a lower alkenyl, etc.; R<3> is H or a lower alkyl; R<4> is OH, a lower alkyl, etc.; Y<1> is a single bond, O, etc.; Z<1> is a single bond, O, etc.; Z<2> is H, a lower alkyl, etc.; provided that R<2> is a >=2C lower alkylene and Z<2> is H when Z<1>=O, S or NH.), its pharmaceutically permissible nontoxic salts and esters, e.g. 1-(2- phosphonomethylthioethyl)-2-(4-hydroxyphenyl)-3-methyl-6--hydroxyindole. The compound of formula I can be obtained, e.g. by reacting a compound of formula II (X<5> is Cl Br, etc.) with a compound of formula III (R<20> is a lower alkyl; R<21> is a lower alkyl or a lower alkoxy) in the presence of a base and hydrolyzing the resultant bisphosphonic acid ester of formula IV (Z<3> is H, a lower alkyl, etc.).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bone-selective estrogen useful for treating osteoporosis.

[0002]

2. Description of the Related Art Conventionally, estrogen has an excellent therapeutic effect on osteoporosis, particularly postmenopausal osteoporosis,
In addition, estrogen suppresses bone resorption, directly proliferates osteoblasts, and promotes bone formation,
It has been reported. However, it has been reported that estrogen therapy has a risk of developing genital bleeding, breast pain, endometrial cancer, breast cancer, etc. as a side effect. 2-phenylindoles, 2-phenylindenes, 1,2-
Diphenyl-3,4-dihydronaphthalene, hexestrols, diethylstilbestrols, triarylethylenes, coumarins, isoflavenes, isoflavones, 2-phenylbenzo [b] thiophenes, steroidal estrogens, etc. The estrogen is disclosed in the following documents, for example.

2-Phenylindoles: Journal of Medicinal Chemistry (J.Med.Che
m.) Volume 9, 527-536 (1966); Volume 26, 113-116 (198
3); Volume 27, 1439-1447 (1984); Volume 33, 2635-2640
(1990), Archief der Pharmacy (Arch.Phar
m. (Weinheim)) Volume 320, 407-417 (1987) and Chemical and Pharmaceutical Bulletin (Chem.Pharm.Bull.) Volume 31, 3168-3178 (1983) 2-Phenylindene Type: Journal of Medicinal Chemistry (J.Med.Chem.) Vol. 29, 75-
79 (1986); Volume 31, 1316-1326 (1988); Volume 32, 2163-
2171 (1989) and the Journal of American
Chemical Society (J. Amer. Chem. Soc.) Volume 65, 23
70-2375 (1943) * 1,2-diphenyl-3,4-dihydronaphthalene: Journal of Steroids Biochemistry (J.Steroid Biochem.) Vol. 23, 929 (1985)

-Hexestrols and diethylstilbestrols: Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 26, 1371-1144.
(1983); Volume 29, 1668-1674 (1986); Volume 30, 156-16
5 (1987); Volume 32, 1532 to 1547 (1989) ・ Triarylethylenes: Journal of Medicinal Chemistry (J.Med.Chem.) Volume 25, 1056
~ 1060 (1982); Volume 26, 683-699 (1983); Volume 28, 1491
〜1497 (1985) ・ Coumarins, isoflavenes and isoflavones: Journal of Medicinal Chemistry (J.Med.Chem.) Vol. 18, 982-985 (1975); Journal of Steroids Biochemistry And Molecular Biology (J.Steroid Biochem.Molec.
Biol.) Volume 38, 293-299 (1991) 2-Phenylbenzo [b] thiophenes: Journal of Medicinal Chemistry (J. Med. Chem.)
Volume 27, 1057-1066 (1989) ・ Steroid estrogens: Steroids
s) Volume 56, 375-387 (1991); Journal of Medicinal Chemistry (J. Med. Chem.) Volume 33, 3143-
3155 (1990); Volume 33, 3155-3160 (1990)

An ester of bisphosphonic acid which can be easily hydrolyzed in vivo is described in JP-A-3-106893. On the other hand, examples of compounds in which the drug is bound to an appropriate bone affinity agent in order to enhance the migration of the drug to bone tissue are disclosed in the following patent publications. Compounds in which carbonic anhydrase inhibitor is bound with tetracycline or bisphosphonic acid as an osteophilic agent:
JP-A-62-26256-Compound in which a polymalonic acid is used as an osteophilic agent and combined with a bone resorption inhibitor or an osteogenesis promoter: JP-A-2-
Japanese Patent No. 6145-Compound in which bisphosphonic acid is used as an osteophilic agent and combined with an anti-inflammatory agent or an anti-arthritic agent: JP-A-58-174393
JP-A No. 2-104593 discloses a compound in which a bisphosphonic acid is used as an osteophilic agent and is bound to a pharmaceutical compound having a carboxylic acid. There is no description about the compound to which is attached.

[0006]

An object of the present invention is to provide a prophylactic and therapeutic agent for osteoporosis, which contains a novel estrogen compound that selectively acts on bone tissue as an active ingredient, has a high therapeutic effect and has few side effects. Especially.

[0007]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have shown that by binding bisphosphonic acid, which is a bone affinity agent, to estrogen, the compound represented by the following general formula (1) is obtained. It was found that the above compound and a non-toxic salt or ester thereof are excellent therapeutic agents for osteoporosis that selectively act on bone tissue, and completed the present invention.

That is, the compound of the present invention has the general formula (1):

[Chemical 5](In the formula, E is a residue of estrogen, R¹Is a single bond or
Is lower alkylene, R ²Is lower alkylene, lower ar
Kenylene or lower alkynylene is replaced by R³Is a hydrogen atom
Or a lower alkyl group, R^FourIs hydroxyl group, lower alkyl
Group or a lower alkoxy group is represented by Y¹Is a single bond, -O
-, -S (O)_n-(Where n is 0, 1 or 2
You ), -NR^Five-(Where R^FiveIs a hydrogen atom or lower
Represents an alkyl group. ) Or ─ CONR⁶─ (here R
⁶Represents a hydrogen atom or a lower alkyl group. ), Z¹
Is a single bond, -O-, -S- or -NH-, Z²Is water
Elementary atom, lower alkyl group, lower alkylthio group, hydroxyl group
Alternatively, it represents an amino group. However, Z¹Is -O-, -S-
Or when it represents -NH-, R²Is C₂Or lower level
Rukiren, Z²Represents a hydrogen atom. ) Compound
And a pharmaceutically acceptable non-toxic salt thereof, and
Preventing osteoporosis containing ester as an active ingredient
And therapeutic agents.

Examples of the estrogen include non-steroidal estrogen and steroidal estrogen. Examples of the non-steroidal estrogen include hexestrols such as hexestrol, octestrol or the compounds described in the above references, diethylstilbestrols or diethylstilbestrols such as the compounds described in the above references, 1 -Ethyl-2- (4-hydroxyphenyl) -3-methyl-6-hydroxyindole, 1-ethyl-2- (4-hydroxyphenyl)
2-Phenylindoles such as 3-methyl-5-hydroxyindole or the compounds described in the above references, 2-phenylindenes such as indenstrol or the compounds described in the above references, 1,2-bis (4-hydroxy) 1,2-diphenyl-3,4-dihydronaphthalene such as phenyl) -6-hydroxy-3,4-dihydronaphthalene, triarylethylenes such as compounds described in the above documents, compounds described in the above documents, etc. Examples include coumarins, isoflavenes and isoflavones, and 2-phenylbenzo [b] thiophenes. Examples of the steroidal estrogen include estradiol, estrone, estriol, ethinyl estradiol, 16α-fluoroestradiol, 11β-methoxyestradiol, 11β-ethylestradiol, and their protected 3- or 17-position hydroxyl groups. Be done.

In particular, the general formula (2)

[Chemical 6] (In the formula, R ⁷ and R ⁸ may be the same or different and each may be a hydrogen atom, a lower alkyl group, a benzoyl group or a lower alkanoyl group, and R ⁹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a phenyl group or a substituted group. A phenyl group, X ¹ and X ² may be the same or different, a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a substituted lower alkyl group or a halogen atom, and Y ² is —S—, —NR ¹⁰ —. (Wherein R ¹⁰ represents a hydrogen atom or a lower alkyl group), —CH ₂ CH ₂ —, or —C.
HR ¹¹ — (wherein R ¹¹ represents a hydrogen atom or a lower alkyl group). ) Or a compound represented by the general formula (3)

[Chemical 7] (In the formula, R ¹² and R ¹³ are the same or different hydrogen atom, lower alkyl group, benzoyl group or lower alkanoyl group, and X ³ and X ⁴ are the same or different hydrogen atom, lower alkyl group, Lower alkoxy group, hydroxy group, substituted lower alkyl group or halogen atom, R ¹⁴ is lower alkyl group, phenyl group or substituted phenyl group, R ¹⁵ is hydrogen atom, lower alkyl group, substituted lower alkyl group, cyano group or lower A compound represented by an alkoxycarbonyl group represented by a broken line and a solid double line represents a single bond or a double bond, or a general formula (4).

[Chemical 8] (In the formula, R ¹⁶ and R ¹⁷ may be the same or different and may be a hydrogen atom, a lower alkyl group, a benzoyl group or a lower alkanoyl group, and R ¹⁸ is a hydrogen atom, a lower alkyl group,
A substituted lower alkyl group, a lower alkenyl group or a lower alkoxy group, and R ¹⁹ represents a hydrogen atom or a halogen atom. ). The estrogen residue in the present invention refers to an estrogen obtained by removing hydrogen. The binding position of the estrogen with the bisphosphonic acid may be any position, but for example, in the case of the compound represented by the general formula (2), the substituent represented by R ⁹ and the substitution represented by Y ² are preferable. The position where it is bonded to a hydrogen atom in the group or benzene ring is mentioned,
For example, in the case of the compound represented by the general formula (3), the substituent represented by R ¹⁴ , the substituent represented by R ¹⁵ , or the position bonded to a hydrogen atom in the benzene ring is preferable. , For example, in the case of the compound represented by the general formula (4),
Preferably, 2nd, 4th, 6th, 7th, 11th, 12th,
The 15-position, 16-position, 17-position, 18-position, or the position bonded to a hydrogen atom among the substituents represented by R ¹⁸ .

Examples of the lower alkylene include C ₁ -C ₆ straight chain or branched chain alkylene.
For example, methylene, ethylene, trimethylene, propylene, 2-methyltrimethylene, tetramethylene, 2,2
-Dimethyltrimethylene, hexamethylene, 3-ethyl-tetramethylene, 1,2-dimethyltrimethylene and the like can be mentioned. Examples of the lower alkenylene include C _{2 to} C ₆ linear or branched alkenylene, and specific examples thereof include vinylene, propenylene, 1-butenylene, 2-butenylene, 2-pentenylene, and 2-methyl-.
2-butenylene, 3-hexenylene, 1,2-dimethyl-1-pentenylene, 2-butenylene, 2,4-hexadienylene and the like can be mentioned. Examples of the lower alkynylene include C _{2 to} C ₆ linear or branched alkynylene, and specifically, for example, ethynylene, propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene, 2 -Methyl-2-butynylene,
3-hexynylene, 1,2-dimethyl-2-butynylene, 2,4-hexadiynylene and the like can be mentioned.

Examples of the lower alkyl group include a straight chain or branched chain alkyl group having ₆ or less carbon atoms, and specific examples thereof include methyl, ethyl, propyl, 1-methylethyl,
Butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 2-ethylpropyl, 1-methylbutyl, hexyl, 2-methylbutyl and the like can be mentioned. Examples of the lower alkenyl group include a straight chain or branched chain alkenyl group having ₆ or less, and specifically, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 3-butenyl,
2-Methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl, 4-methyl-3-butynyl, 1-hexenyl, 2-hexenyl, 2,4-dimethyl-1-butenyl and the like can be mentioned. Examples of the lower alkylthio group include linear or branched alkylthio groups having C ₆ or less, and specific examples thereof include methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, and 2 -Methylpropylthio, pentylthio, 2-ethylpropylthio, 1-methylbutylthio, hexylthio, 2-methylbutylthio and the like can be mentioned.

Examples of the lower alkoxy group include linear or branched C ₆ or lower alkoxy groups, specifically, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1,1-dimethyl. Ethoxy,
1-methylpropoxy, 2-methylpropoxy, pentyloxy, 2-ethylpropoxy, 1-methylbutoxy, hexyloxy, 2-methylbutoxy and the like can be mentioned. Examples of the lower alkoxycarbonyl group include C ₇ or lower linear or branched alkoxycarbonyl groups, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl, butoxycarbonyl, 1, 1-dimethylethoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl, pentyloxycarbonyl, 2-ethylpropoxycarbonyl, 1-methylbutoxycarbonyl, hexyloxycarbonyl,
2-Methylbutoxycarbonyl etc. are mentioned. Examples of the lower alkanoyl group include linear or branched alkanoyl groups having ₆ or less carbon atoms, and specific examples thereof include formyl, acetyl, propanoyl, butanoyl, pentanoyl, 2-methylbutanoyl, pivaloyl and 2-ethyl. Propanoyl, hexanoyl, 2,2-dimethylbutanoyl, 2-methylpentanoyl and the like can be mentioned.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The substituted phenyl group is 1 to 3 selected from a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group.
A phenyl group substituted with 4 substituents, and specific examples thereof include 4-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 3-methoxyphenyl and 4
-Methoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl and the like can be mentioned. Examples of the substituted lower alkyl group include a lower alkyl group substituted with 1 to 3 substituents selected from a halogen atom, a lower alkoxy group, a hydroxyl group, a phenyl group or a substituted phenyl group, and specifically, for example, , Chloromethyl, dichloromethyl, trifluoromethyl, 2-
Chloroethyl, 2,2,2-trichloroethyl, methoxymethyl, 2-methoxyethyl, benzyl, 2-phenylethyl, 4-chlorobenzyl, 3-methylbenzyl,
4-methoxybenzyl, 2-hydroxyethyl, 3-hydroxypropyl and the like can be mentioned.

The pharmaceutically acceptable non-toxic salts include, for example, inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, organic bases such as triethylammonium salt, pyridinium salt and diisopropylammonium salt. Examples thereof include basic salts. The ester means a mono-, di-, tri- or tetra-ester of bisphosphonic acid which can be easily hydrolyzed in vivo, and examples thereof include alkanoyloxymethyl ester containing C _{3 to} C _21, preferably C _{3 to} C _10. Can be mentioned. Specific examples of such ester include acetoxymethyl ester, propanoyloxymethyl ester, butanoyloxymethyl ester, pivaloyloxymethyl ester, 2,2-dimethylbutanoyloxymethyl ester, hexanoyloxymethyl ester, Examples thereof include decanoyloxymethyl ester, dodecanoyloxymethyl ester, tetradecanoyloxymethyl ester, hexadecanoyloxymethyl ester, octadecanoyloxymethyl ester and eicosanoyloxymethyl ester.

The compound of the present invention represented by the general formula (1) is
For example, it can be manufactured as follows. I) In the compound represented by the general formula (1), Z ¹ represents a single bond, and Z ² represents a hydrogen atom, a lower alkyl group or a lower alkylthio group.

[Chemical 9] (Wherein E, R ¹ , R ² , R ³ , R ⁴ and Y ¹ have the same meanings as described above, E ¹ is an estrogen residue or an estrogen residue in which a hydroxyl group is protected, X ⁵ and X ⁶ is a chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group or 4-toluenesulfonyloxy group which may be the same or different, R ²¹ is a lower alkyl group or a lower alkoxy group, R ²⁰ , R ²² and R ²³ is a lower alkyl group which may be the same or different, Z ³ is a hydrogen atom,
It represents a lower alkyl group or a lower alkylthio group. ) Examples of the hydroxyl-protecting group in the estrogen residue include ether-type protecting groups such as methyl, 1,1-dimethylethyl, allyl, benzyl and triphenylmethyl, and acetal-type protecting groups such as methoxymethyl and tetrahydropyranyl. ,
And silyl ether type protecting groups such as trimethylsilyl and (1,1-dimethylethyl) dimethylsilyl.

Introduction and deprotection of a protective group for a hydroxyl group can be carried out according to a general method, for example, Protective Groups in Organic Synthesis (Pro
tective Groups in Organic Synthesis, TWGreene, J
Ohn Wiley and Sons, Inc.) 10-50, 87-101 (1981). Journal of Organometal Chemistry (J.Organometal.Chem.) No. 13
Vol., 199-207 (1968), the compound (5) is reacted with the compound (6) in the presence of a base such as sodium hydride, and then Z is added to the compound (9). ^{When 3} is a lower alkyl group or a lower alkylthio group, the compound (8) can be obtained by further reacting the compound (7) in the same manner. When the hydroxyl group of the estrogen residue in the compound (8) is protected, it is deprotected, and then, if necessary, hydrolysis of the bisphosphonic acid ester is carried out. Method (Aldrichimica Actor
ica Acta) Vol. 14, 267-274 (1981)) or using hydrochloric acid (Journal of Medicinal Chemistry (J. Med. Chem.) Vol. 30, 1426-1433 (1987)). By doing so, the compound (9) can be obtained. When iodotrimethylsilane is used to hydrolyze the bisphosphonate, deprotection of the protective group for the hydroxyl group of the estrogen residue can be performed at the same time.

II) In the compound represented by the general formula (1), Z ¹ represents a single bond, Z ² represents a hydroxyl group, and R ⁴ represents a hydroxyl group or a lower alkoxy group.

[Chemical 10] (In the formula, E, E ¹ , R ¹ , R ² , R ³ and Y ¹ have the same meanings as described above, and R ²⁴ represents a lower alkyl group.) For carboxylic acid (10), for example, thionyl chloride (Survey of Organic Syntheses, CABuehle
r and DEPearson, Wiley-Interscience) 859 ~ 868 (19
70)) Carboxylic acid chloride (11), and the Journal of Medicinal Chemistry (J.Med.Chem.)
30, 1426 to 1433 (1987), by a method similar to that described, phosphite triester and phosphite diester are reacted, and then, if necessary, deprotection of the protective group for the hydroxyl group of the estrogen residue. Then, if necessary, the compound (12) can be obtained by hydrolyzing the bisphosphonate by the same method as described above. Further, in the compound (10), if the hydroxyl group of the estrogen residue is protected, it is deprotected, and then by a method similar to the method described in JP-A-51-77596 or JP-B-63-7526. A compound (12) in which R ³ represents a hydrogen atom can be obtained by reacting with phosphorus trichloride.

III) In the compound represented by the general formula (1), Z ¹ represents a single bond, Z ² represents an amino group, R ³ represents a hydrogen atom, and R ⁴ represents a hydroxyl group.

[Chemical 11] (In the formula, E, R ¹ , R ² and Y ¹ have the same meanings as described above.) Compound (13) is reacted with phosphorus tribromide by a method similar to that described in JP-B-59-25797. By doing so, the compound (14) can be obtained. IV) In the compounds represented by the general formula (1), Z ¹ is-
When S ² represents a hydrogen atom in S-.

[Chemical 12] (In the formula, E, E ¹ , R ¹ , R ² , R ³ , R ⁴ , Y ¹ , R
²⁰ and R ²¹ have the same meanings as described above, and X ⁷ represents a chlorine atom or a bromine atom. ) The compound (15) is oxidized with, for example, iodine, a cupric salt, a ferric salt, sulfuryl chloride, or air to give a disulfide, or is oxidized with chlorine or bromine to give sulfenyl. Halides (Organic Sulfur Chemistry-Reaction Mechanism Edition-Shigeru Ootsu) Chemistry Dojin 263-306 (198
2)), followed by reacting with compound (6) in the same manner as in the method for producing compound (9) described in I), and then deprotecting the hydroxyl-protecting group of the estrogen residue, if necessary. Further, the compound (17) can be obtained by further hydrolyzing the bisphosphonate, if necessary.

V) In the compound represented by the general formula (1), Z ¹ represents -O-, Z ² represents a hydrogen atom, and R ⁴ represents a hydroxyl group or a lower alkoxy group.

[Chemical 13] (Wherein E, E ¹ , R ¹ , R ² , R ³ , Y ¹ and R ²⁴
Represents the same meaning as described above. ) By reacting formic acid / acetic anhydride against alcohol (18) (Lucay de Travo Simique de Paiva
ec.Trav.Chim.Pay-Bas) Vol. 84, 1247-1252 (1965)) Formyl ester (19), followed by the action of phosphorus pentachloride (Lucay de Travo Simique de Pay-Bas (Rec.Trav.Chim.Pay-Bas) Volume 90, 556-561 (19
71)) Dichloromethyl ether (20) and further reacted with phosphite triester in the presence of Lewis acid (Japanese Patent Publication No. 61-503034) to give compound (21), and then, if necessary, The compound (22) can be obtained by deprotecting the hydroxyl-protecting group of the estrogen residue and further hydrolyzing the bisphosphonate, if necessary.

VI) In the compounds represented by the general formula (1), Z ¹ represents —NH— and Z ² represents a hydrogen atom.

[Chemical 14] (In the formula, E, E ¹ , R ¹ , R ² , R ³ , R ⁴ , R ²⁴ and Y ¹ have the same meanings as described above, and R ²⁵ represents a lower alkyl group or a lower alkoxy group.) Amine ( 23) by reacting an orthoformate ester and a phosphite diester (JP-A-1-308290,
Phosphorus, Sulfur and Silicon (Phos
phorus, Sulfur and Silicon) Vol. 51/52, 23-26 (1
990)), compound (24), and then, if necessary, deprotecting the hydroxyl-protecting group of the estrogen residue, and further,
The compound (25) can be obtained by hydrolyzing the bisphosphonate, if necessary. The compound (9), compound (12), compound (14), compound (17), compound (22) and compound (25) obtained above can be easily produced by another synthetic method. For example, among these compounds, Y ¹ is —O—, —S (O) _n — (where n represents the same meaning as described above), —NR ⁵ — (here R is).
⁵ has the same meaning as above. ) Or -CONR ^6-
(Wherein R ⁶ has the same meaning as described above),
It is also possible to synthesize this part by synthesizing it at the end, deprotecting the hydroxyl-protecting group if necessary, and further hydrolyzing the bisphosphonate ester if necessary. Further, these compounds can be further converted into a pharmaceutically acceptable non-toxic salt, or can be converted into an ester by the method described in the above-mentioned document (JP-A-3-106893).

The synthesis of compound (6) is described in US Pat.
No. 1,907 (Chem.Abst
r.) Volume 65, 3908d (1966)), Journal of Organometallic Chemistry (J. Organometal. Chem.)
Volume 13, 199-207 (1968), Synthetic Communications (Synth.Commun.) Volume 20, 1865-1867 (199)
0), and Tetrahedron, Volume 46, 6645.
~ 6658 (1990). Compound (5), compound (10), compound (13), compound (15),
The compounds (18) and (23) can be synthesized as follows.

[Chemical 15] (In the formula, E, E ¹ , R ¹ , R ² , Y ¹ and X ⁵ have the same meanings as described above.) The compound (5) can be synthesized by using, for example, thionyl chloride or trichloride. It can be carried out by reacting phosphorus, phosphorus tribromide, phosphorus pentachloride, triphenylphosphine / carbon tetrachloride, methanesulfonyl chloride, 4-toluenesulfonyl chloride, etc. (Survey of Organic Synthesis (Survey of Organic) Syntheses, CA
Buehler and DEPearson, Wiley-Interscience) 329〜
339 (1970)).

The synthesis of compound (15) is carried out by converting compound (5) into
For example, it can be carried out by reacting with thioacetic acid, thiourea, potassium xanthate or the like and hydrolyzing (organic sulfur chemistry-synthesis reaction edition-Daishige Shigeru chemistry doujin 32-33 (1982)). The compound (23) can be synthesized, for example, by reacting the compound (18) with phthalimide and allowing hydrazine to act (Synthesis 1-28 (19).
80)), or Gabriel reaction to compound (5) (Angew. Chem.) 80, 986-996 (1)
968)) or reduction of the corresponding nitriles (Surve of Organic Syntheses (Surve
y of Organic Syntheses, CABuehler and DEPearso
n, Wiley-Interscience) 419-421 (1970))
Can be implemented. Compound (10) can be synthesized, for example, by reacting compound (5) with sodium cyanide (survey.
Survey of Organic Syntheses
Syntheses, CABuehler and DEPearson, Wiley-Int
erscience) 329-339 (1970)), hydrolysis (Survey of Organic Syntheses)
ntheses, CABuehler and DEPearson, Wiley-Inters
cience) 752 to 753 (1970)) or oxidize the corresponding alcohol (Survey of Organic Syntheses, CABuehle
r and DEPearson, Wiley-Interscience) 761-764 (19
70)) can be implemented.

The synthesis of compound (13) is carried out by converting compound (5) into
For example, it can be carried out in the same manner as in the synthesis of compound (10) by reacting with sodium cyanide and, if necessary, deprotecting the hydroxyl-protecting group. The compound (18) is synthesized by the 2-phenylindoles described in the prior art,
2-phenylindenes, hexestrols, diethylstilbestrols, 1,2-diphenyl-3,4
-Dihydronaphthalene, triarylethylenes, coumarins, isoflavenes, isoflavones, steroidal estrogens and 2-phenylbenzo [b] thiophenes can be carried out by methods similar to the methods described in the literature and the like. .. In addition, compound (5), compound (10), compound (13), compound (15) and compound (2
3) can be directly synthesized not by the compound (18) but by a method similar to the method described in the above literature and the like. Preferred estrogen contained as a partial structure of the compound (1) of the present invention are nonsteroidal estrogens, hexestrols, diethylstilbestrols, 2
-Phenylindoles, 2-phenylbenzo [b] thiophenes, or 2-phenylindenes, and steroidal estrogen estradiol or ethinylestradiol.

Particularly preferred examples of the substituent represented by Z ² in the compound (1) of the present invention include a hydrogen atom and a hydroxyl group. Particularly preferred as the substituent represented by R ³ in the compound (1) of the present invention is a hydrogen atom. Particularly preferred as the substituent represented by R ⁴ in the compound (1) of the present invention is a hydroxyl group. The compound (1) of the present invention, or a pharmaceutically acceptable non-toxic salt or ester thereof, when used for the prevention and treatment of osteoporosis, particularly postmenopausal osteoporosis, is acceptable as it is or as a pharmaceutical. It is administered as a pharmaceutical composition containing, for example, 0.01 to 99% in a nontoxic and inert carrier.
As the carrier, a solid, semi-solid, or liquid diluent,
One or more fillers or other formulation aids are used.

The pharmaceutical composition of the present invention can be administered orally or parenterally (eg, intravenous or intramuscular injection, topical, rectal, transdermal, or nasal). Although the dose varies depending on the patient's condition such as age and body weight, symptoms, and administration route, it is usually a daily dose of 1 to 500 mg as an active ingredient amount of the present invention for adults and 1 to 1 day per day.
It is administered 3 times. Also, an intermittent administration method can be performed.

[0027]

INDUSTRIAL APPLICABILITY The compound (1) of the present invention, or a pharmaceutically acceptable non-toxic salt or ester thereof, is administered to the bone tissue more than other organs other than bone after administration. Since they are collected, they have a high therapeutic effect on osteoporosis, have far fewer side effects than estrogen, and are extremely useful as a persistent preventive or therapeutic agent. Exemplified examples of the compounds included in the present invention include the compounds shown below. However, these compounds are merely examples, and the present invention is not limited thereto.

1- (2-diphosphonomethylthioethyl) -2- (4-hydroxyphenyl) -3-methyl-
6-Hydroxyindole 1- (2-diphosphonomethylaminoethyl) -2-
(4-Hydroxyphenyl) -3-ethyl-6-hydroxyindole 1- (3-diphosphonomethoxypropyl) -2- (4
-Hydroxyphenyl) -3-ethyl-5-hydroxyindole N-methyl-N- (4,4-bis (dimethoxyphosphinyl) pentyl)-(2- (4-methoxyphenyl)
-3-Propyl-6-methoxy-1-indolyl) -acetamide. 1- (3,3-diphosphono-3-methylthiopropyl) -2- (4-hydroxyphenyl) -3-methyl-
6-Hydroxyindole 1- (3- (N-methyl-N- (3,3-diphosphono-3-hydroxypropyl) -amino) -propyl)-
2- (4-Hydroxyphenyl) -3-methyl-6-hydroxyindole 1- (4,4-diphosphono-2-butenyl) -2-
(4-Hydroxyphenyl) -3-methyl-6-hydroxyindole

.3- (2- (4-hydroxyphenyl))
-3-Methyl-6-hydroxy-1-indolyl) -1
-Ethyl-propylidene-1,1-bisphosphonic acid tri (pivaloyloxymethyl) ester 3- (2- (4-hydroxyphenyl) -3-ethyl-5-hydroxy-1-indolyl) -propylidene-
1,1-Bisphosphonic acid tetra (2,2-dimethylbutanoyloxymethyl) ester-1- (4,4-diphosphonopentyl) -2- (4-acetoxyphenyl) -3-ethyl-6-acetoxyindole * 1- (2- (3,3-bis (diethoxyphosphinyl) propylthio) -ethyl) -2- (4-methoxyphenyl) -3-trifluoromethyl-6-methoxyindole * 1- (3- (3-Diphosphonomethylthio-propoxy) -propyl) -2- (4-hydroxyphenyl)-
3-benzyl-6-hydroxyindole 1- (3,3-diphosphono-3-hydroxypropyl) -2- (4-hydroxyphenyl) -3-isopropyl-6-hydroxyindole 1- (5-amino-5 , 5-Diphosphono-2-methylpentyl) -2- (4-methoxyphenyl) -3-butyl-6-methoxyindole

1-ethyl-2- (4-hydroxyphenyl) -3- (3,3-diphosphonopropyl) -5-hydroxyindole 1-propyl-2- (3- (4,4-diphosphonobutyl) ) -4-Hydroxyphenyl) -3-ethyl-6-hydroxyindole 1-methyl-2- (4-methoxyphenyl) -3-phenyl-5- (4,4-diphosphono-4-methylthiobutyl) -6 -Methoxyindole 1- (3,3-bis (dimethoxyphosphinyl) propyl) -2- (4-methoxy-3-methylphenyl)-
3-methyl-5-chloro-6-methoxyindole

1- (3,3-diphosphonopropyl)-
2- (4-hydroxyphenyl) -3-methyl-5,6
-Dihydroxyindole 1- (3- (3-bis (diethoxyphosphinyl) methylamino-propylsulfinyl) -propyl) -2
-(4-Ethoxyphenyl) -3- (3-hydroxypropyl) -6-ethoxyindole-l- (3,3-bis (diisopropoxyphosphinyl) propyl) -2- (4-methoxy-3-) Bromophenyl) -3-methyl-5-trifluoromethyl-6-methoxyindole. 1- (4,4-bis (dimethoxyphosphinyl)-
2,2-Dimethylbutyl) -2- (4-methoxyphenyl) -3-ethyl-5- (3-phenylpropyl) -6
-Ethoxyindole

1- (4,4-bis (diisopropoxyphosphinyl) pentyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindene 1- (4,4-diphospho Nopentyl) -2- (4-hydroxyphenyl) -3-methyl-6-hydroxyindene 2- (4-methoxyphenyl) -3- (3,3-bis (diethoxyphosphinyl) propyl) -6 -Methoxybenzo [b] thiophene- (E) -3- (3- (4,4-diphosphonobutyl)-
4-hydroxyphenyl) -4- (4-hydroxyphenyl) -3-hexene. (E) -3- (3- (3-diphosphonomethylaminopropyl) -4-hydroxyphenyl) -4- (4- Hydroxyphenyl) -3-hexene- (E) -3- (3- (3-diphosphonomethoxypropyl) -4-hydroxyphenyl) -4- (4-hydroxyphenyl) -3-hexene- (E)- 3- (3- (3,3-diphosphono-3-hydroxypropyl) -4-hydroxyphenyl) -4-
(4-Hydroxyphenyl) -3-hexene. (E) -3- (3- (3,3-diphosphono-3-aminopropyl) -4-hydroxyphenyl) -4- (4-
Hydroxyphenyl) -3-hexene. (E) -3- (3- (3,3-diphosphonopropylthiomethyl) -4-hydroxyphenyl) -4- (4-hydroxyphenyl) -3-hexene

Erythro 3- (3- (3-diphosphonomethylaminopropyl) -4-hydroxyphenyl)-
4- (4-hydroxyphenyl) -hexane-erythro 3- (3- (3-diphosphonomethoxypropyl) -4-hydroxyphenyl) -4- (4-hydroxyphenyl) -hexane-erythro 3- (3- (3,3-Diphosphono-3-hydroxypropyl) -4-hydroxyphenyl) -4-
(4-Hydroxyphenyl) -hexane-erythro 3- (3- (3,3-diphosphono-3-aminopropyl) -4-hydroxyphenyl) -4- (4
-Hydroxyphenyl) -hexane-erythro 3- (3- (3,3-diphosphonopropylthiomethyl-4-hydroxyphenyl) -4- (4-hydroxyphenyl) -hexane-erythro 3- (3- (2 , 2-diphosphonoethyl)
-4-Hydroxyphenyl) -4- (4-hydroxyphenyl) -hexane-erythro 3- (3-diphosphonomethylaminomethyl-4-hydroxyphenyl) -4- (4-hydroxyphenyl) -hexane-erythro 2 , 3-bis (4-hydroxyphenyl)
-1- (3,3-Diphosphonopropoxy) -pentane * erythro 4- (3- (3,3-bis (diisopropoxyphosphinyl) propyl) -4-methoxyphenyl) -5- (4-methoxy- 3-Methylphenyl) -octane-erythro 3- (3- (3,3-bis (dimethoxyphosphinyl) propyl) -4-acetoxyphenyl)-
4- (4-acetoxyphenyl) -hexane

17α- (4,4-diphosphono-1-butynyl) -3,17-dihydroxy-estra-1,
3,5 (10) -triene.17α- (4-diphosphonomethylamino-1-butenyl) -3,17-dihydroxy-estra-1,3,5
(10) -triene.17α- (4,4-diphosphonopentyl) -3,17
-Dihydroxy-oestra-1,3,5 (10) -triene. 11- (2-diphosphonomethylthioethyl) -3,1
7β-Dihydroxy-oestra-1,3,5 (10)-
Triene 11- (3,3-diphosphonopropoxy) -3,17
β-dihydroxy-oestra-1,3,5 (10) -triene .7- (3,3-diphosphonopropyl) -3,17β-
Dihydroxy-oestra-1,3,5 (10) -triene .2- (4,4-diphosphonobutyl) -3,17β-dihydroxy-estra-1,3,5 (10) -triene .17α- (4-bis (Diethoxyphosphinyl) methoxy-1-butynyl) -3-benzoyloxy-17-
Hydroxy-oestra-1,3,5 (10) -triene .17α- (3- (3,3-diphosphonobutylthio)-
1-propenyl) -3-methoxy-17-hexanoyloxy-oestra-1,3,5 (10) -triene

(Z) -1- (4- (2-dimethylaminoethoxy) -phenyl) -1- (3-hydroxyphenyl) -2-phenyl-5,5-diphosphono-1-pentene.3,3 -Bis (4-hydroxyphenyl) -2-
(4- (4,4-Diphosphonobutyl) -phenyl) -acrylonitrile-2- (2,2-diphosphonoethyl) -3- (4-hydroxyphenyl) -4-ethyl-7-hydroxy-2H
-Chromene The above compounds can be used as such or as sodium salts,
Inorganic base salts such as potassium salt, calcium salt, magnesium salt and ammonium salt, and non-toxic salts such as organic base salts such as triethylammonium salt, pyridinium salt and diisopropylammonium salt may be used.

Test Example 6-week-old female Wistar rats were purchased and their ovaries were excised at 7-week old. After ovariectomy, the test compound dissolved in distilled water for injection and 17β-estradiol dissolved in a 5% ethanol / 95% MCT (medium chain fatty acid triglyceride) mixed solution were subcutaneously applied to the back at a volume of 0.5 ml / kg. Administration was performed once a day for 5 days a week for 3 weeks. Three days after the final administration, the rat was killed and the uterus and tibia were collected. Wet weight was measured for the uterus, and bone mineral content was measured for the tibia with an X-ray bone mineral content quantification device, and the average value ± standard deviation of the measured values of 5 rats in each group was calculated. Are shown in Tables 1 and 2 below. Further, in the same manner, the group in which the ovary was not removed (control group) and the group in which the ovary was removed (ovariectomized group) were also measured, assuming that the test compound was not administered.

[Table 1]

[Table 2]

[0037]

EXAMPLES The present invention will be described in more detail below with reference to Reference Examples and Examples, but the present invention is not limited to these. Reference Example 1 Tetraisopropyl 4-triphenylmethoxy-butyl
Liden-1,1-bisphosphonate

[Chemical 16] 27.8 g of 3-bromo-1-propanol under a nitrogen atmosphere,
55.8 g of triphenylchloromethane and 1.24 g of 4-dimethylaminopyridine were added to 200 ml of methylene chloride, and 50.2 ml of triethylamine was slowly added dropwise at room temperature. 1
After stirring for 0 hours, water was added, and the mixture was washed twice with saturated aqueous sodium hydrogen carbonate, and the solvent was evaporated to give 3-triphenylmethoxy-1-.
Bromo-propane was obtained. Under a nitrogen atmosphere, 9.64 g of 60% sodium hydride was added to 100 ml of toluene, 83 g of tetraisopropyl methylene bisphosphonate was slowly added, and at 110 ° C., 3-triphenylmethoxy-precursor was added.
Toluene (200 ml) solution of 1-bromo-propane was added and stirred for 2.5 hours. Water was added, the mixture was extracted twice with ethyl acetate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (containing 3% methanol / chloroform 0.2% triethylamine) to give tetraisopropyl 4-triphenylmethoxy-butylidene-. 95.6 g (yield 75%) of 1,1-bisphosphonate was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.25 to 1.45 (24H, m), 1.80 to 2.10
(4H, m), 2.15 (1H, tt, J = 25 and 6Hz), 3.0
6 (2H, t, J = 5.8Hz), 4.70-4.85 (4H, m),
7.20 ~ 7.50 (15H, m)

Reference Example 2 Tetraisopropyl 4-hydroxy-butylidene-
1,1-bisphosphonate

[Chemical 17] In a nitrogen atmosphere, 8.0 g of tetraisopropyl 4-triphenylmethoxy-butylidene-1,1-bisphosphonate obtained in Reference Example 1 was dissolved in 50 ml of methanol, 0.5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 40 ° C. for 30 minutes. By distilling off the solvent and purifying by silica gel column chromatography (5% methanol / chloroform), tetraisopropyl 4-hydroxy-butylidene-1,1-
4.3 g (yield 86%) of bisphosphonate was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.25 to 1.45 (24H, m), 1.75 to 2.15
(4H, m), 2.21 (1H, tt, J = 24 and 6Hz), 3.0
6 (1H, m), 3.50 to 3.80 (2H, m) 4.70 to
4.85 (4H, m)

Reference Example 3 4,4-bis (diisopropoxyphosphinyl) -1-
Pentanol

[Chemical 18] Under a nitrogen atmosphere, 12.2 g of tetraisopropyl 4-hydroxy-butylidene-1,1-bisphosphonate obtained in Reference Example 2 was dissolved in 90 ml of tetrahydrofuran, 8.5 ml of triethylamine was added, and chlorotrimethylsilane was added.
6.9 ml was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. Toluene was washed twice with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was evaporated to give tetraisopropyl 4-.
Trimethylsilyloxy-butylidene-1,1-bisphosphonate was obtained. Under a nitrogen atmosphere, 2.43 g of 60% sodium hydride was added to 48 ml of toluene, and the tetraisopropyl 4-trimethylsilyloxy-butylidene-1,1-bisphosphonate obtained above was added and the temperature was 20 to 30 ° C.
Then, 4.3 ml of dimethylsulfate was slowly added and stirred for 1 hour. Water was added, the mixture was extracted with ethyl acetate, the solvent was evaporated, 50 ml of methanol was added, about 0.5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give 12.9 g of 4,4-bis (diisopropoxyphosphinyl) -1-pentanol (yield 100
%) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.25 to 1.45 (27H, m), 1.75 to 2.00
(4H, m), 3.61 (2H, m), 4.70 to 4.85 (4H,
m)

Reference Example 4 4,4-bis (diisopropoxyphosphinyl) -1-
Iodine pentane

[Chemical 19] 4,4-bis (diisopropoxyphosphinyl) -1-pentanol obtained in Reference Example 3 under a nitrogen atmosphere 11.
2 g was dissolved in 50 ml of methylene chloride, 7.68 g of 4-toluenesulfonyl chloride, 4.36 ml of pyridine and 0.1 g of 4-dimethylaminopyridine were added, and the mixture was refluxed for 5 hours. After adding methanol and stirring, the solvent was distilled off, ethyl acetate was added, and the mixture was washed with water and the solvent was distilled off. The concentrated residue was dissolved in 100 ml of acetone, 6.74 g of sodium iodide was added, and the mixture was refluxed for 1 hour. Water was added, the solvent was evaporated, ethyl acetate was added, washed with water, the solvent was evaporated, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give 4,4-bis ( 10.01 g (71% yield) of diisopropoxyphosphinyl) -1-iodopentane was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.25 to 1.45 (27H, m), 1.75 to 1.95
(2H, m), 2.05 to 2.20 (2H, m), 3.17 (2H, m)
t, J = 6.8Hz), 4.70-4.90 (4H, m)

Reference Example 5 N- (4,4-bis (diisopropoxyphosphinyl))
Pentyl) -phthalimide

[Chemical 20] 4,4-bis (diisopropoxyphosphinyl) -1-iodopentane 2.0 obtained in Reference Example 4 under a nitrogen atmosphere.
g, phthalimide 1.12 g, potassium carbonate 1.05 g, N,
It was added to 10 ml of N-dimethylformamide and stirred at 60 ° C. for 1 hour. Water was added, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and purified by silica gel column chromatography (2% methanol / chloroform) to give N- (4,4-bis (diisopropoxyphosphinyl)). Pentyl) -phthalimide (1.9 g, yield 92%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.20 to 1.50 (27H, m), 1.70 to 2.10
(4H, m), 3.66 (2H, t, J = 6.9Hz), 4.65-4.
90 (4H, m), 7.65-7.76 (2H, m), 7.78
~ 7.90 (2H, m)

Reference Example 6 4,4-bis (diisopropoxyphosphinyl) -1-
Aminopentane

[Chemical 21] Under a nitrogen atmosphere, 1.9 g of N- (4,4-bis (diisopropoxyphosphinyl) pentyl) -phthalimide obtained in Reference Example 5 was dissolved in 10 ml of ethanol and 0.5 ml of water, and 0.34 ml of hydrazine hydrate was added. And stirred at 60 ° C. for 1 hour. 1.39 g of 4,4-bis (diisopropoxyphosphinyl) -1-aminopentane was made alkaline with sodium hydroxide and extracted twice with chloroform.
(Yield 100%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.25 to 1.40 (27H, m), 1.65 to 1.95
(4H, m), 2.66 (2H, t, J = 6.6Hz), 4.70-4.
90 (4H, m)

Reference Example 7 1- (2-hydroxyethyl) -2- (4-methoxyphenol)
Phenyl) -3-methyl-6-methoxyindole

[Chemical formula 22] At 0 ° C. under a nitrogen atmosphere, 822 mg of 60% sodium hydride was added to 40 ml of N, N-dimethylformamide,
5.0 g of (4-methoxyphenyl) -3-methyl-6-methoxyindole (J. Med. Chem., Vol. 27, 1439-1447 (1984))
N, N-dimethylformamide (20 ml) solution of was added dropwise and stirred for 20 minutes. A solution of 4.1 g of 1-bromo-2-tetrahydropyranoxyethane in N, N-dimethylformamide (20 ml) was added dropwise, and the mixture was stirred for 40 minutes. Water 20
0 ml was added, the mixture was extracted twice with 200 ml of ether, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, it was dissolved in 40 ml of methanol at room temperature, 10 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 3 hours. After neutralizing with saturated aqueous sodium hydrogen carbonate, methanol was distilled off, 100 ml of water was added, and the mixture was extracted with 100 ml of chloroform and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform) to give 1- (2-hydroxyethyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole.
1.97 g (yield 34%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.44 (1H, brs), 2.17 (3H, s), 3.71
(2H, q, J = 5.8Hz), 3.86 (3H, s), 3.88 (3H,
s), 4.13 (2H, t, J = 5.8Hz), 6.81 (1H, dd, J =
8.6 and 2.1Hz), 6.88 (1H, d, J = 2.1Hz), 6.9
4 (2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.6Hz), 7.4
4 (1H, d, J = 8.6Hz)

Reference Example 8 1- (2-Methanesulfonyloxyethyl) -2- (4
-Methoxyphenyl) -3-methyl-6-methoxyin
Doll

[Chemical formula 23] 1- (2-) obtained in Reference Example 7 at 0 ° C. under a nitrogen atmosphere.
Hydroxyethyl) -2- (4-methoxyphenyl)-
1.97 g of 3-methyl-6-methoxyindole was dissolved in 20 ml of methylene chloride, 1.0 g of triethylamine was added, 0.74 g of methanesulfonyl chloride was added dropwise, and the mixture was stirred for 30 minutes. After adding 20 ml of water and 0.5 ml of 29% ammonia water, stirring, separating the layers, washing once with water, drying with anhydrous magnesium sulfate, and distilling off the solvent, purification by silica gel column chromatography (chloroform) was performed. By doing so, 1- (2-methanesulfonyloxyethyl) -2-
1.39 g (yield 56%) of (4-methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 2.17 (3H, s), 2.56 (3H, s), 3.87 (3
H, s), 3.89 (3H, s), 4.23 (2H, t, J = 5.4Hz),
4.31 (2H, t, J = 5.4Hz), 6.82 (1H, dd, J = 8.6 and 2.3Hz), 6.88 (1H, d, J = 2.3Hz), 7.02 (2
H, d, J = 8.6Hz), 7.28 (2H, d, J = 8.6Hz), 7.43
(1H, d, J = 8.6Hz)

Reference Example 9 1- (3-Hydroxypropyl) -2- (4-methoxy)
Phenyl) -3-methyl-6-methoxyindole

[Chemical formula 24] In the same manner as in the method of Reference Example 7, 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole (6.9 g) and 1-bromo-3-tetrahydropyranoxypropane (5.99)
From g, 1- (3-hydroxypropyl) -2- (4-
7.44 g (yield 89%) of methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.22 (1H, brs), 1.75 (2H, qui, J = ∼6.4Hz),
2.19 (3H, s), 3.37 (2H, q, J = ~ 5.6Hz),
3.85 (3H, s), 3.87 (3H, s), 4.11 (2H,
t, J = 6.9Hz), 6.80 (1H, dd, J = 8.3 and 2.3Hz),
6.87 (1H, d, J = 2.3Hz), 6.99 (2H, d, J = 8.9H
z), 7.29 (2H, d, J = 8.9Hz), 7.44 (1H, d, J = 8.3)
Hz)

Reference Example 10 1- (3-Methanesulfonyloxypropyl) -2-
(4-Methoxyphenyl) -3-methyl-6-methoxy
Indole

[Chemical 25] In the same manner as in the method of Reference Example 8, 1-obtained in Reference Example 9
From (4-hydroxypropyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole (7.44 g) to 1- (3-methanesulfonyloxypropyl) -2
8.87 g (yield 96%) of-(4-methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.92 (2H, qui, J = ∼6.3Hz), 2.19 (3H, s),
2.76 (3H, s), 3.87 (3H, s), 3.89 (3H,
s), 3.94 (2H, t, J = 5.8Hz), 4.16 (2H, t, J =
6.9Hz), 6.80 (1H, dd, J = 8.6 and 2.3Hz),
6.83 (1H, d, J = 2.3Hz), 7.01 (2H, d, J = 8.9Hz),
7.28 (2H, d, J = 8.9Hz), 7.44 (1H, d, J = 8.6H)
z)

Reference Example 11 1- (4-chlorobutyl) -2- (4-methoxyphenyl)
) -3-Methyl-6-methoxyindole

[Chemical formula 26] In the same manner as in the method of Reference Example 7, from 4.0 g of 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole and 3.85 g of 4-chloro-1-bromobutane, 1-
(4-chlorobutyl) -2- (4-methoxyphenyl)
5.35 g of -3-methyl-6-methoxyindole (yield 1
00%). ¹ H-NMR (CDCl ₃ ) δ: ppm 1.54 (2H, qui, J = 7.0Hz), 1.74 (2H, qui, J = 7.4)
Hz), 2.19 (3H, s), 3.33 (2H, t, J = 6.4Hz),
3.88 (3H, s), 3.89 (3H, s), 4.00 (2H,
t, J = 7.3Hz), 6.81 (1H, dd, J = 9.2 and 2.3Hz),
6.82 (1H, d, J = 2.3Hz), 7.00 (2H, d, J = 8.9H
z), 7.28 (2H, d, J = 8.9Hz), 7.45 (1H, d, J = 9.2)
Hz)

Reference Example 12 1- (5-Bromopentyl) -2- (4-methoxyphen)
Nyl) -3-methyl-6-methoxyindole

[Chemical 27] In the same manner as in the method of Reference Example 7, from 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole 2.0 g and 1,5-dibromopentane 9.6 g, 1- (5-
Bromopentyl) -2- (4-methoxyphenyl) -3
2.56 g of -methyl-6-methoxyindole (yield 74
%) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.15 to 1.33 (2H, m), 1.48 to 1.74 (4
H, m), 2.19 (3H, s), 3.25 (2H, t, J = 6.8Hz),
3.88 (3H, s), 3.90 (3H, s), 3.97 (2
H, t, J = 7.5Hz), 6.79 (1H, d, J = 2.3Hz), 6.81
(1H, dd, J = 9.2 and 2.3Hz), 7.01 (2H, d, J = 8.6H
z), 7.28 (2H, d, J = 8.6Hz), 7.45 (1H, d, J = 9.2)
Hz)

Reference Example 13 1- (3-hydroxypropyl) -2- (4-methoxy)
Phenyl) -3-methyl-5-methoxyindole

[Chemical 28] In the same manner as in the method of Reference Example 7, 2- (4-methoxyphenyl) -3-methyl-5-methoxyindole (J. Med. Chem.
m.) 27, 1439-1447 (1984)) 3.37 g and 1-bromo-
From 3.90 g of 3-tetrahydropyranoxypropane, 1-
(3-Hydroxypropyl) -2- (4-methoxyphenyl) -3-methyl-5-methoxyindole 3.36 g
(Yield 85%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.97 (1H, t, J = ∼5.4Hz), 1.77 (2H, qui, J =
~ 6.3Hz), 2.20 (3H, s), 3.38 (2H, q, J = ~
5.8Hz), 3.88 (3H, s), 3.90 (3H, s), 4.
15 (2H, t, J = 6.8Hz), 6.88 (1H, dd, J = 8.6 and
2.3Hz), 7.02 (1H, d, J = 2.3Hz), 7.02 (2H,
d, J = 8.9Hz), 7.27 (1H, d, J = 8.6Hz), 7.31 (2H,
(d, J = 8.9Hz)

Reference Example 14 1- (3-Methanesulfonyloxypropyl) -2-
(4-methoxyphenyl) -3-methyl-5-methoxy
Indole

[Chemical 29] 1 obtained in Reference Example 13 in the same manner as in the method of Reference Example 8
-(3-Hydroxypropyl) -2- (4-methoxyphenyl) -3-methyl-5-methoxyindole 3.35 g
From 1- (3-methanesulfonyloxypropyl)-
3.74 g (yield 86%) of 2- (4-methoxyphenyl) -3-methyl-5-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.93 (2H, qui, J = ∼6.3Hz), 2.19 (3H, s),
2.77 (3H, s), 3.88 (3H, s), 3.89 (3H,
s), 3.94 (2H, q, J = 5.9Hz), 4.17 (2H, t, J =
6.8Hz), 6.89 (1H, dd, J = 8.6 and 2.3Hz),
7.02 (1H, d, J = 2.3Hz), 7.02 (2H, d, J = 8.6Hz),
7.24 (1H, d, J = 8.6Hz), 7.30 (2H, d, J = 8.6H)
z)

Reference Example 15 1- (3-Hydroxypropyl) -2,3-bis (4-)
Methoxyphenyl) -5-methoxyindole

[Chemical 30] Similar to the method of Reference Example 7, 2,3-bis (4-methoxyphenyl) -5-methoxyindole (Journal of Medicinal Chemistry, Vol. 9, 527-536 (J. Med. Chem.). 1961)) 4.0 g and 1-bromo-3-tetrahydropyranoxypropane 2.73 g, 1- (3-hydroxypropyl) -2,3-bis (4-methoxyphenyl) -5-methoxyindole 3.82 g 82%)
Got ¹ H-NMR (CDCl ₃ ) δ: ppm 1.12 (1H, t, J = to 5.5 Hz), 1.86 (2H, qui, J =
~ 6.4Hz), 3.43 (2H, q, J = ~ 5.4Hz), 3.79
(3H, s), 3.82 (3H, s), 3.83 (3H, s), 4.
21 (2H, q, J = 6.9Hz), 6.83 (2H, t, J = 8.6Hz),
6.90 (2H, d, J = 8.6Hz), 6.92 (1H, dd, J = 8.9 and 2.6Hz), 7.19 (2H, d, J = 8.9Hz), 7.19 (1
H, d, J = 2.6Hz), 7.23 (2H, d, J = 8.9Hz), 7.34
(1H, d, J = 8.9Hz)

Reference Example 16 1- (3-Methanesulfonyloxypropyl) -2,3
-Bis (4-methoxyphenyl) -5-methoxyindo
The

[Chemical 31] 1 obtained in Reference Example 15 in the same manner as in the method of Reference Example 8
-(3-Hydroxypropyl) -2,3-bis (4-methoxyphenyl) -5-methoxyindole 3.82 g to 1- (3-methanesulfonyloxypropyl)-
4.53 g (yield 100%) of 2,3-bis (4-methoxyphenyl) -5-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 2.00 (2H, qui, J = ∼6.3Hz), 2.80 (3H, s),
3.79 (3H, s), 3.83 (6H, s), 4.01 (2H,
t, J = 5.9Hz), 4.23 (2H, t, J = 6.9Hz), 6.83 (2
H, d, J = 8.9Hz), 6.91 (2H, d, J = 8.6Hz), 6.93
(1H, dd, J = 8.6 and 2.6Hz), 7.18 (1H, d, J = 2.6H
z), 7.19 (2H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.
9Hz), 7.30 (1H, d, J = 8.9Hz)

Reference Example 17 1-Cyanomethyl-2- (4-methoxyphenyl) -3
-Methyl-6-methoxyindole

[Chemical 32] In the same manner as in the method of Reference Example 7, 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole (5.0 g) and chloroacetonitrile (4.32 g) were used to prepare 1-cyanomethyl-2- (4-methoxyphenyl) -3. -Methyl-6-
3.15 g (yield 57%) of methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 2.21 (3H, s), 3.88 (3H, s), 3.91 (3H,
s), 4.75 (2H, s), 6.78 to 7.10 (2H, m),
7.04 (2H, d, J = 8.6Hz), 7.33 (2H, d, J = 8.6Hz),
7.47 (1H, d, J = 8.6Hz)

Reference Example 18 1- (2-aminoethyl) -2- (4-methoxyphenyl)
) -3-Methyl-6-methoxyindole

[Chemical 33] In a nitrogen atmosphere, 0.45 g of lithium aluminum hydride,
In addition to 30 ml of tetrahydrofuran, at room temperature, Reference Example 17
A solution of 3.15 g of 1-cyanomethyl-2- (4-methoxyphenyl) -3-methyl-6-methoxyindole obtained in 1. in tetrahydrofuran (20 ml) was added, and the mixture was refluxed for 2 hours. After cooling, add water, add 2N hydrochloric acid and stir, then add 2N
The mixture was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate three times. The solvent was distilled off, and the residue was purified by silica gel column chromatography (containing 10% methanol / chloroform, 4% aqueous ammonia) to give 1- (2-aminoethyl) -2- (4-methoxyphenyl) -3-. Methyl-
1.7 g of 6-methoxyindole (yield 51%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.32 (2H, brs), 2.18 (3H, s), 2.85 (2
H, t, J = 6.5Hz), 3.87 (3H, s), 3.89 (3H, s),
4.05 (2H, t, J = 6.5Hz), 6.81 (1H, dd, J = 8.6 and 2.0Hz), 6.85 (1H, d, J = 2.0Hz), 7.00
(2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.6Hz), 7.45
(1H, d, J = 8.6Hz)

Reference Example 19 1-Ethoxycarbonylmethyl-2- (4-methoxyphenol)
Phenyl) -3-methyl-6-methoxyindole

[Chemical 34] In the same manner as in the method of Reference Example 7, from 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole (1.95 g) and ethyl bromoacetate (2.4 g), 1-ethoxycarbonylmethyl-2- (4-methoxyphenyl) was obtained. ) -3-Methyl-6-methoxyindole (1.36 g, yield 53%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.23 (3H, t, J = 7.2Hz), 2.22 (3H, s), 3.8
59 (3H, s), 3.863 (3H, s), 4.18 (2H, q, J
= 7.2Hz), 4.60 (2H, s), 6.67 (1H, d, J = 2.3H
z), 6.83 (1H, dd, J = 8.6 and 2.3Hz), 6.9
8 (2H, d, J = 8.6Hz), 7.30 (2H, d, J = 8.6Hz), 7.4
6 (1H, d, J = 8.6Hz)

Reference Example 20 1-Carboxymethyl-2- (4-methoxyphenyl)
-3-Methyl-6-methoxyindole

[Chemical 35] Under a nitrogen atmosphere, 3.97 g of 1-ethoxycarbonylmethyl-2- (4-methoxyphenyl) -3-methyl-6-methoxyindole obtained in Reference Example 19 was added to methanol 3
It was dissolved in 0 ml, 30 ml of 10% aqueous potassium carbonate solution was added, and the mixture was refluxed for 1.5 hours. 1-Carboxymethyl-2- (4-
2.74 g (yield 75%) of methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: ppm 2.13 (3H, s), 3.78 (3H, s), 3.81 (3H,
s), 4.67 (2H, s), 6.72 (1H, dd, J = 8.6 and
2.3Hz), 6.92 (1H, d, J = 2.3Hz), 7.05 (2H, d, J
= 8.6Hz), 7.27 (2H, d, J = 8.6Hz), 7.38 (1H,
(d, J = 8.6Hz)

Reference Example 21 Erythro 3- (3-allyl-4-methoxyphenyl)
-4- (4-methoxyphenyl) -hexane

[Chemical 36] Erythro 3- (3-allyl-4-hydroxyphenyl) -4- (4-hydroxyphenyl) -under nitrogen atmosphere
Hexane (J.Med.Chem.) Vol. 24, 435-450 (1981) 5.70g
Is dissolved in 20 ml of ethanol, and at 60 ° C, 4.34 ml of dimethyl sulfate and 2.21 g of sodium hydroxide in water (3.5 ml).
The solution of was added little by little alternately and the mixture was refluxed for 1 hour. Ethanol was distilled off, ethyl acetate was added, and the mixture was washed with water. Erythro 3- (3-allyl-4-methoxyphenyl) -4- was obtained by distilling off the solvent and crystallizing from methanol.
5.14-g (4-methoxyphenyl) -hexane (yield 83
%) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.53 (6H, t, J = 7.3Hz), 1.15 to 1.50 (4H, 4H,
m), 2.46 (2H, brd, J = 6.3Hz), 3.38 (2H, d, J =
6.6Hz), 3.81 (3H, s), 3.82 (3H, s), 5.0
2 (1H, d, J = 15.5Hz), 5.03 (1H, d, J = 11.5Hz),
6.02 (1H, ddt, J = 15.5, 11.5 and 6.6Hz), 6.
75 to 7.00 (5H, m), 7.07 (2H, d, J = 8.6Hz)

Reference Example 22 Erythro 3- (3- (3-hydroxypropyl) -4
-Methoxyphenyl) -4- (4-methoxyphenyl)
-Hexane

[Chemical 37] Erythro 3-obtained in Reference Example 21 under nitrogen atmosphere
5.14 g of (3-allyl-4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane was dissolved in 50 ml of tetrahydrofuran, 0.29 g of sodium borohydride was added, and boron trifluoride diethyl ether complex was added at room temperature. 1.4
1 ml was added and stirred for 1 hour. 3.5g sodium hydroxide
Of water (17.3 ml) and 8% of 30% hydrogen peroxide solution were added, and the mixture was stirred at 50 ° C. for 30 minutes. After adding sodium sulfite and water and stirring, the mixture was extracted twice with ethyl acetate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give erythro-3.
-(3- (3-Hydroxypropyl) -4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane 4.
31 g (yield 80%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.54 (6H, t, J = 7.3Hz), 1.15 to 1.55 (4H, 4H,
m), 1.85 (2H, qui, J = ~ 6.6Hz), 1.99 (1H,
brs), 2.40 to 2.55 (2H, m), 2.72 (2H, t, J
= 7.3Hz), 3.59 (2H, brs), 3.80 (3H, s),
3.83 (3H, s), 6.75 to 7.00 (5H, m), 7.0
6 (2H, d, J = 8.6Hz)

Reference Example 23 Erythro 3- (3- (3-methanesulfonyloxyp
Ropyr) -4-methoxyphenyl) -4- (4-methoxy)
Cyphenyl) -hexane

[Chemical 38] Erythro 3- (3- (3-hydroxypropyl) -4- obtained in Reference Example 22 was treated in the same manner as in Reference Example 8.
Methoxyphenyl) -4- (4-methoxyphenyl)-
1.95 g of hexane to 2.38 g of erythro 3- (3- (3-methanesulfonyloxypropyl) -4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane
(Yield 100%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.526 (3H, t, J = 7.2Hz), 0.533 (3H, t, J = 7.2)
Hz), 1.15 to 1.50 (4H, m), 2.00 to 2.1
5 (2H, m), 2.35 to 2.55 (2H, m), 2.74
(2H, t, J = 7.3Hz), 3.00 (3H, s), 3.81 (3H,
s), 3.82 (3H, s), 4.24 (2H, t, J = 6.4Hz),
6.75 ~ 7.05 (3H, m), 6.85 (2H, d, J = 8.6H
z), 7.07 (2H, d, J = 8.6Hz)

Reference Example 24 Erythro 3- (3- (3-aminopropyl) -4-me
Toxyphenyl) -4- (4-methoxyphenyl) -f
Xanthane

[Chemical Formula 39] In the same manner as in the methods of Reference Examples 5 and 6, Reference Example 2
Erythro 3- (3- (3-methanesulfonyloxypropyl) -4-methoxyphenyl) -4-obtained in 3
From 1.09 g of (4-methoxyphenyl) -hexane, 0.61 g (yield 69%) of erythro 3- (3- (3-aminopropyl) -4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane. Obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.53 (6H, t, J = 7.4Hz), 1.15 to 1.50 (4H, 4H,
m), 1.61 (2H, brs), 1.74 (2H, qui, J = 7.2H
z), 2.35 to 2.55 (2H, m), 2.65 (2H, t, J =
7.5Hz), 2.71 (2H, t, J = 6.9Hz), 3.81 (3H,
s), 3.82 (3H, s), 6.77 (1H, d, J = 8.2Hz),
6.85 (2H, d, J = 8.6Hz), 6.89 (1H, s), 6.94
(1H, d, J = 8.2Hz), 7.06 (2H, d, J = 8.6Hz)

Reference Example 25 2,3-bis (4-methoxyphenyl) -1-pentene

[Chemical 40] Under a nitrogen atmosphere, 250 ml of tetrahydrofuran was added with 34.1 g of methyltriphenylphosphonium bromide to give 0-15
Add 6M butyllithium / hexane 59.6ml at ℃,
After stirring for 30 minutes at room temperature, 1,2-bis (4-methoxyphenyl) -1-butanone (Journal of Medicinal Chemistry, Vol. 23, 1002-1008).
(1980)) 10.5 g was added, and the mixture was further stirred for 2 hours. Toluene (300 ml) was added, washed with water (100 ml) twice, the solvent was distilled off, and the residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give 2,3-bis (4-methoxyphenyl)-. 10.9 g (yield 98%) of 1-pentene was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.89 (3H, t, J = 7.4Hz), 1.65 to 2.00 (2H, 2H,
m), 3.57 (1H, t, J = 7.4Hz), 3.75 (3H, s),
3.76 (3H, s), 5.10 (1H, d, J = 1.0Hz), 5.31
(1H, d, J = 1.0Hz), 6.76 (2H, d, J = 8.9Hz), 6.8
0 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.6Hz), 7.
19 (2H, d, J = 8.9Hz)

Reference Example 26 Erythro 2,3-bis (4-methoxyphenyl) -1
-Pentanol

[Chemical 41] 2,3-bis (4-methoxyphenyl) -1-pentene obtained in Reference Example 25 in the same manner as in Reference Example 22
By reacting 13.0 g and crystallizing from methylene chloride / hexane, 8.34 g (yield 61%) of erythro 2,3-bis (4-methoxyphenyl) -1-pentanol was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.55 (3H, t, J = 7.3Hz), 0.99 (1H, t, J = 6.3Hz),
1.20 to 1.50 (2H, m), 2.59 (1H, td, J = 10.
9 and 3.6 Hz), 2.82 to 2.96 (1H, m), 3.
47 (2H, m), 3.81 (3H, s), 3.82 (3H, s),
6.88 (2H, d, J = 8.6Hz), 6.92 (2H, d, J = 8.9Hz),
7.13 (2H, d, J = 8.9Hz), 7.21 (2H, d, J = 8.6Hz)

Reference Example 27 Erythro 2,3-bis (4-methoxyphenyl) -1
-Methanesulfonyloxypentane

[Chemical 42] Erythro 2,3-bis (4-methoxyphenyl) -1- obtained in Reference Example 26 in the same manner as in Reference Example 8.
From 1.0 g of pentanol, erythro 2,3-bis (4
1.26 g (yield 100%) of -methoxyphenyl) -1-methanesulfonyloxypentane was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.57 (3H, t, J = 7.4Hz), 1.15 to 1.55 (2H, 2H,
m), 2.51 (3H, s), 2.67 (1H, td, J = 10.9 and
3.6Hz), 3.00 to 3.15 (1H, m), 3.82 (6
H, s), 4.00 to 4.15 (2H, m), 6.89 (2H, d,
J = 8.6Hz), 6.90 (2H, d, J = 8.6Hz), 7.13 (2H,
d, J = 8.6Hz), 7.20 (2H, d, J = 8.6Hz)

Reference Example 28 Erythro 2,3-bis (4-methoxyphenyl) -1
-Acetylthiopentane

[Chemical 43] Erythro 2,3 obtained in Reference Example 27 under nitrogen atmosphere
1.26 g of -bis (4-methoxyphenyl) -1-methanesulfonyloxypentane was dissolved in 10 ml of tetrahydrofuran, 0.7 g of sodium carbonate and 0.48 ml of thioacetic acid.
Was added and the mixture was stirred at 70 ° C. for 1 hour. 20 ml of toluene was added, washed twice with water, and purified by silica gel column chromatography (15% ethyl acetate / hexane) to give erythro 2,3-bis (4-methoxyphenyl).
0.78 g (yield 66%) of -1-acetylthiopentane was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.56 (3H, t, J = 7.3Hz), 1.20 to 1.55 (2H, 2H,
m), 2.14 (3H, s), 2.60 (1H, td, J = 10.2 and
6.6Hz), 2.70 to 2.97 (2H, m), 3.09 (1
H, dd, J = 12.2 and 3.3Hz), 3.806 (3H, s),
3.814 (3H, s), 6.85 (2H, d, J = 8.9Hz), 6.8
8 (2H, d, J = 8.6Hz), 7.06 (2H, d, J = 8.6Hz), 7.
11 (2H, d, J = 8.9Hz)

Reference Example 29 Erythro 2,3-bis (4-methoxyphenyl) -pe
Tannic acid

[Chemical 44] 2.0 g of erythro 2,3-bis (4-methoxyphenyl) -1-pentanol obtained in Reference Example 26 was dissolved in 20 ml of acetone, about 5 ml of Jones reagent was added, and the mixture was stirred at room temperature for 1 hour. 2-propanol was added, water was added,
After the solvent was distilled off, the residue was extracted twice with ethyl acetate and crystallized from methylene chloride / hexane to give erythro 2,3
-Bis (4-methoxyphenyl) -1-pentanoic acid 1.5
0 g (yield 72%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.56 (3H, t, J = 7.4Hz), 1.15 to 1.50 (2H, 2H,
m), 3.03 (1H, td, J = 11.3 and 3.3Hz), 3.6
3 (1H, d, J = 11.3Hz), 3.77 (3H, s), 3.84
(3H, s), 6.80 (2H, d, J = 8.6Hz), 6.87 (2H, d,
J = 8.6Hz), 7.12 (2H, d, J = 8.6Hz), 7.31 (2H,
(d, J = 8.6Hz)

Reference Example 30 1,2-bis (4-methoxyphenyl) -6,6-bis
(Diisopropoxyphosphinyl) -1-heptanone

[Chemical 45] Under a nitrogen atmosphere, 80% of 60% sodium hydride was added to 10 ml of tetrahydrofuran to give 333 mg of deoxyanisoin.
Was added and stirred at room temperature for 30 minutes. Reference Example 4 at 40 ° C
526 mg of 4,4-bis (diisopropoxyphosphinyl) -1-iodopentane obtained in 4. was added and stirred for 1 hour. Water was added, extracted with ethyl acetate, and silica gel column chromatography (5% methanol / chloroform).
Was purified by to obtain 1,2-bis (4-methoxyphenyl) -6,6-bis (diisopropoxyphosphinyl) -1-heptanone (780 mg, yield 100%). ¹ H-NMR (CDCl ₃ ) δ: ppm 1.20 to 2.20 (33H, m), 3.74 (3H, s),
3.82 (3H, s), 4.44 (1H, t, J = 6.6Hz), 4.6
5 to 4.85 (4H, m), 6.80 (2H, d, J = 8.6Hz),
6.85 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz),
7.94 (2H, d, J = 8.6Hz)

Reference Example 31 3,4-bis (4-methoxyphenyl) -8,8-bis
(Diisopropoxyphosphinyl) -3-hydroxyno
naan

[Chemical 46] Under a nitrogen atmosphere, 49 mg of magnesium was added to 1 ml of ether, 0.16 ml of iodoethane was added, and the mixture was stirred at room temperature for 1 hour to prepare ethylmagnesium iodide. 1,2-bis (4-obtained in Reference Example 30 under a nitrogen atmosphere
800 mg of methoxyphenyl) -6,6-bis (diisopropoxyphosphinyl) -1-heptanone was dissolved in 20 ml of tetrahydrofuran, ethylmagnesium iodide obtained above was added, and the mixture was stirred at room temperature for 1 hour. Water and diluted hydrochloric acid were added, the mixture was extracted twice with ethyl acetate, and silica gel column chromatography (5% methanol / chloroform).
Was purified by to obtain 550 mg (yield 66%) of 3,4-bis (4-methoxyphenyl) -8,8-bis (diisopropoxyphosphinyl) -3-hydroxynonane. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.72 (3H, t, J = 7.3Hz), 1.10 to 1.95 (33H, 33H,
m), 2.84 (1H, brd, J = 8.9Hz), 3.74 (3H, s),
3.79 (3H, s), 4.55 to 4.85 (4H, m),
6.70 (2H, d, J = 8.9Hz), 6.79 (2H, d, J = 8.9Hz),
6.83 (2H, d, J = 8.9Hz), 7.09 (2H, d, J = 8.9H)
z)

Example 1 1- (4,4-bis (diisopropoxyphosphinyl))
Pentyl) -2- (4-methoxyphenyl) -3-methyl
Le-6-methoxyindole

[Chemical 47] In the same manner as in the method of Reference Example 7, 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole 1.34 g,
And from 4,3-bis (diisopropoxyphosphinyl) -1-iodopentane 2.63 g, 1- (4,4-
Bis (diisopropoxyphosphinyl) pentyl) -2
2.75 g (yield 83%) of-(4-methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.10 to 1.40 (27H, m), 1.55 (2H, m),
1.88 (2H, m), 2.17 (3H, s), 3.86 (3H,
s), 3.88 (3H, s), 3.93 (2H, m), 4.70
~ 4.90 (4H, m), 6.75 ~ 6.85 (2H, m),
6.99 (2H, d, J = 8.7Hz), 7.28 (1H, m), 7.4
2 (2H, d, J = 8.7Hz)

Example 2 1- (4,4-diphosphonopentyl) -2- (4-hydr)
Roxyphenyl) -3-methyl-6-hydroxyindo
Disodium salt

[Chemical 48] 1- (4,4-bis (diisopropoxyphosphinyl) pentyl) -2-obtained in Example 1 under nitrogen atmosphere
2.09 g of (4-methoxyphenyl) -3-methyl-6-methoxyindole was dissolved in 13 ml of acetonitrile,
Add 5.36 ml of iodotrimethylsilane, 80-85 ℃
It was stirred at. After distilling off the solvent, the operation of adding 2-propanol and distilling off 2-propanol was repeated twice. After adding 30 ml of methylene chloride and 30 ml of water, the pH was adjusted to about 7 with an aqueous sodium hydroxide solution, the layers were separated, the aqueous layer was concentrated, and the CHP20P gel column (manufactured by Mitsubishi Kasei Co .;
By purifying with 0-2% acetonitrile / water), 1
510 mg (yield 30%) of disodium salt of-(4,4-diphosphonopentyl) -2- (4-hydroxyphenyl) -3-methyl-6-hydroxyindole was obtained. ¹ H-NMR (CD ₃ OD: D ₂ O = 9: 1) δ: ppm 1.31 (3H, t, J = 15.5Hz), 1.70 to 1.90 (2
H, m), 1.90 to 2.10 (2H, m), 2.11 (3H,
s), 3.84 (2H, brs), 6.61 (1H, d, J = 8.6Hz),
6.92 (2H, d, J = 7.8Hz), 6.93 (1H, s), 7.
21 (2H, d, J = 7.8Hz), 7.28 (1H, d, J = 8.6Hz)

Example 3 1- (3,3-bis (diisopropoxyphosphinyl))
Propyl) -2- (4-methoxyphenyl) -3-methyl
Le-6-methoxyindole

[Chemical 49] 1- (2-Methanesulfonyloxyethyl) -obtained in Reference Example 8 in the same manner as in the alkylation method of Reference Example 1.
1.2 g of 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole and tetraisopropyl
From 3.17 g of methylene bisphosphonate, 1- (3,3-
Bis (diisopropoxyphosphinyl) propyl) -2
0.67 g (yield 35%) of-(4-methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.10 to 1.45 (24H, m), 1.90 to 2.25
(3H, m), 2.18 (3H, s), 3.86 (3H, s), 3.
91 (3H, s), 4.26 (2H, t, J = 7.8Hz), 4.55
4.85 (4H, m), 6.80 (1H, dd, J = 8.6 and 2.0H
z), 7.00 (2H, d, J = 8.6Hz), 7.13 (1H, d, J =
2.0Hz), 7.32 (2H, d, J = 8.6Hz), 7.42 (1H, d,
(J = 8.6Hz)

Example 4 1- (3,3-diphosphonopropyl) -2- (4-hydr
Roxyphenyl) -3-methyl-6-hydroxyindo
Disodium salt

[Chemical 50] In the same manner as in the method of Example 2, 1-obtained in Example 3
(3,3-bis (diisopropoxyphosphinyl) propyl) -2- (4-methoxyphenyl) -3-methyl-
From 0.67 g of 6-methoxyindole, 1- (3,3-
0.19 g (yield 37%) of diphosphonopropyl) -2- (4-hydroxyphenyl) -3-methyl-6-hydroxyindole disodium salt was obtained. ¹ H-NMR (CD ₃ OD: D ₂ O = 1: 1) δ: ppm 1.87 (1H, tt, J = 21.8 and 6.0 Hz), 2.12 (3
H, s), 2.05 to 2.30 (2H, m), 4.24 (2H, br
t, J = 8Hz), 6.74 (1H, d, J = 8.6Hz), 7.04 (2H,
d, J = 7.2Hz), 7.25 (1H, s), 7.31 (2H, d, J = 7.
2Hz), 7.42 (1H, brs)

Example 5 1- (3,3-diphosphonopropyl) -2- (4-meth)
Xyphenyl) -3-methyl-6-hydroxyindole
Rusodium salt

[Chemical 51] Similar to the method of Example 2, but with a reaction temperature of 65
1- (3,3-bis (diisopropoxyphosphinyl) propyl) -2- (4- obtained in Example 3
Methoxyphenyl) -3-methyl-6-methoxyindole (4.12 g) was reacted to give 1- (3,3-diphosphonopropyl) -2- (4-methoxyphenyl) -3-methyl-
0.92 g (yield 28%) of 6-hydroxyindole disodium salt was obtained. ¹ H-NMR (CD ₃ OD: D ₂ O = 1: 1) δ: ppm 1.90 (1H, tt, J = 16.5 and 6.9 Hz), 2.16 (3
H, s), 2.05 to 2.35 (2H, m), 3.93 (3H,
s), 4.15 to 4.35 (2H, m), 6.71 (1H, dd, J
= 8.6 and 2.3Hz), 7.15 (2H, d, J = 8.6Hz),
7.21 (1H, d, J = 2.3Hz), 7.41 (2H, d, J = 8.6Hz),
7.43 (1H, d, J = 8.3Hz)

Example 6 1- (3,3-diphosphonopropyl) -2- (4-meth)
Xyphenyl) -3-methyl-6-methoxyindole
Disodium salt

[Chemical 52] 1- (3,3-bis (diisopropoxyphosphinyl) propyl obtained in Example 3 as in Example 2 but using bromotrimethylsilane at a reaction temperature of 60 ° C. ) -2- (4-Methoxyphenyl)-
4.0 g of 3-methyl-6-methoxyindole was reacted to give 1- (3,3-diphosphonopropyl) -2- (4-
2.0 g (yield 61%) of disodium salt of methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (D ₂ O) δ: ppm 1.87 (1 H, tt, J = 16.5 and 6.9 Hz), 2.21 (3
H, s), 2.00-2.20 (2H, m), 3.96 (3H,
s), 4.00 (3H, s), 4.20-4.40 (2H, m),
6.92 (1H, dd, J = 8.6 and 2.3Hz), 7.22 (2
H, d, J = 8.9Hz), 7.35 (1H, d, J = 2.3Hz), 7.49
(2H, d, J = 8.9Hz), 7.60 (1H, d, J = 8.6Hz)

Example 7 1- (4,4-bis (diisopropoxyphosphinyl))
Butyl) -2- (4-methoxyphenyl) -3-methyl
-6-Methoxyindole

[Chemical 53] In the same manner as in the alkylation method of Reference Example 1, Reference Example 10
1- (3-Methanesulfonyloxypropyl) -2- (4-methoxyphenyl) -3-methyl-6 obtained in
-Methoxyindole 8.87 g and tetraisopropyl methylene bisphosphonate 15 g to give 1- (4
4-bis (diisopropoxyphosphinyl) butyl)-
11.3 g (yield 80%) of 2- (4-methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.10 to 1.45 (24H, m), 1.52 to 1.80
(2H, m), 1.80 to 2.00 (3H, m), 2.17 (3H,
s), 3.86 (3H, s), 3.89 (3H, s), 3.97
(2H, t, J = 7.1Hz), 4.55 to 4.90 (4H, m), 6.
77 (1H, d, J = 2.0Hz), 6.81 (1H, dd, J = 8.6 and
2.0Hz), 6.99 (2H, d, J = 8.6Hz), 7.29 (2H,
d, J = 8.6Hz), 7.42 (1H, d, J = 8.6Hz)

Example 8 1- (4,4-diphosphonobutyl) -2- (4-hydro)
Xyphenyl) -3-methyl-6-hydroxyindole
Rusodium salt

[Chemical 54] In the same manner as in the method of Example 2, 1-obtained in Example 7
(4,4-bis (diisopropoxyphosphinyl) butyl) -2- (4-methoxyphenyl) -3-methyl-6
-From 3.38 g of methoxyindole, 1- (4,4-diphosphonobutyl) -2- (4-hydroxyphenyl) -3
-Methyl-6-hydroxyindole disodium salt
1.26 g (yield 48%) was obtained. ¹ H-NMR (CD ₃ OD: D ₂ O = 2: 1) δ: ppm 1.70 to 2.20 (5H, m), 2.08 (3H, s), 3.
87 (2H, brs), 6.66 (1H, d, J = 8.3Hz), 6.92
(2H, d, J = 8.6Hz), 7.03 (1H, s), 7.15 (2H,
d, J = 8.6Hz), 7.30 (1H, d, J = 8.3Hz)

Example 9 1- (5,5-bis (diisopropoxyphosphinyl))
Pentyl) -2- (4-methoxyphenyl) -3-methyl
Le-6-methoxyindole

[Chemical 55] In the same manner as in the alkylation method of Reference Example 1, Reference Example 11
1- (4-chlorobutyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole obtained in
From 5.35 g and 10.3 g of tetraisopropyl methylene bisphosphonate, 1- (5,5-bis (diisopropoxyphosphinyl) pentyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole was obtained.
3.95 g (yield 40%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.15 to 1.35 (24H, m), 1.35 to 1.90
(6H, m), 2.02 (1H, tt, J = 24.3 and 5.8Hz),
2.18 (3H, s), 3.80 (3H, s), 3.89 (3H,
s), 3.95 (2H, t, J = 7.4Hz), 4.60 to 4.85
(4H, m), 6.79 (1H, d, J = 8.6Hz), 6.80 (1H,
s), 6.99 (2H, d, J = 8.9Hz), 7.28 (2H, d, J = 8.
9Hz), 7.43 (1H, d, J = 8.6Hz)

Example 10 1- (5,5-diphosphonopentyl) -2- (4-hydr
Roxyphenyl) -3-methyl-6-hydroxyindo
Disodium salt

[Chemical 56] In the same manner as in the method of Example 2, 1-obtained in Example 9
(5,5-bis (diisopropoxyphosphinyl) pentyl) -2- (4-methoxyphenyl) -3-methyl-
From 3.95 g of 6-methoxyindole, 1- (5,5-diphosphonopentyl) -2- (4-hydroxyphenyl)
1.09 g (yield 36%) of disodium salt of 3-methyl-6-hydroxyindole was obtained. ¹ H-NMR (D ₂ O) δ: ppm 1.20 to 1.50 (4H, m), 1.50 to 1.90 (3
H, m), 1.87 (3H, s), 3.74 (2H, brs), 6.
64 (1H, d, J = 8.6Hz), 6.85 (2H, d, J = 8.3Hz),
6.84 (1H, s), 7.01 (2H, d, J = 8.3Hz), 7.2
6 (1H, d, J = 8.6Hz)

Example 11 1- (6,6-bis (diisopropoxyphosphinyl)
Hexyl) -2- (4-methoxyphenyl) -3-methyl
Le-6-methoxyindole

[Chemical 57] In the same manner as in the alkylation method of Reference Example 1, Reference Example 12
From 1- (5-bromopentyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole (208 mg) obtained above and tetraisopropyl methylenebisphosphonate (516 mg), 1- (6,6-bis ( Diisopropoxyphosphinyl) hexyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole
156 mg (yield 46%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.10 to 1.90 (32H, m), 2.03 (1H, tt, J = 2)
4.5 and 5.9Hz), 2.18 (3H, s), 3.88 (3H,
s), 3.90 (3H, s), 3.93 (2H, t, J = 7.3Hz),
4.65-4.85 (4H, m), 6.80 (1H, dd, J = 9.2
And 2.3Hz), 6.79 (1H, d, J = 2.3Hz), 7.00 (2
H, d, J = 8.6Hz), 7.27 (2H, d, J = 8.6Hz), 7.44
(1H, d, J = 9.2Hz)

Example 12 1- (6,6-diphosphonohexyl) -2- (4-hydr
Roxyphenyl) -3-methyl-6-hydroxyindo
Disodium salt

[Chemical 58] In the same manner as in the method of Example 2, 1 obtained in Example 11
-(6,6-bis (diisopropoxyphosphinyl) hexyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole From 950 mg, 1- (6,6-
130 mg (yield 18%) of disodium salt of diphosphonohexyl) -2- (4-hydroxyphenyl) -3-methyl-6-hydroxyindole was obtained. ¹ H-NMR (CD ₃ OD: D ₂ O = 1: 1) δ: ppm 1.10 to 1.30 (2H, m), 1.50 to 1.90 (6
H, m), 2.15 (3H, s), 2.10 to 2.30 (1H,
m), 3.98 (2H, t, J = 7Hz), 6.71 (1H, d, J = 8.6H)
z), 6.98 (1H, s), 7.00 (2H, d, J = 8.6Hz),
7.27 (2H, d, J = 8.6Hz), 7.44 (1H, d, J = 8.6Hz)

Example 13 1- (4,4-bis (diisopropoxyphosphinyl))
Butyl) -2- (4-methoxyphenyl) -3-methyl
-5-methoxyindole

[Chemical 59] In the same manner as in the alkylation method of Reference Example 1, Reference Example 14
1- (3-Methanesulfonyloxypropyl) -2- (4-methoxyphenyl) -3-methyl-5 obtained in
-From 3.0 g of methoxyindole and 2.82 g of tetraisopropyl methylenebisphosphonate, 1-
(4,4-bis (diisopropoxyphosphinyl) butyl) -2- (4-methoxyphenyl) -3-methyl-5
1.2 g of methoxyindole (yield 26%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.15 to 1.30 (24H, m), 1.55 to 2.10
(5H, m), 2.19 (3H, s), 3.88 (3H, s), 3.
89 (3H, s), 3.98 (2H, t, J = 7.1Hz), 4.60〜
4.80 (4H, m), 6.87 (1H, dd, J = 8.9 and 2.6H
z), 7.00 (1H, d, J = 8.6Hz), 7.02 (2H, d, J =
2.6Hz), 7.27 (1H, d, J = 8.9Hz), 7.30 (2H, d,
(J = 8.6Hz)

Example 14 1- (4,4-diphosphonobutyl) -2- (4-hydro)
Xyphenyl) -3-methyl-5-hydroxyindole
Rusodium salt

[Chemical 60] In the same manner as in the method of Example 2, 1 obtained in Example 13
-(4,4-bis (diisopropoxyphosphinyl) butyl) -2- (4-methoxyphenyl) -3-methyl-
From 1.2 g of 5-methoxyindole, 1- (4,4-diphosphonobutyl) -2- (4-hydroxyphenyl)-
3-Methyl-5-hydroxyindole disodium salt
124 mg (yield 13%) was obtained. ¹ H-NMR (D ₂ O) δ: ppm 1.45 to 1.90 (5H, m), 2.18 (3H, s), 3.
99 (2H, t, J = 7.3Hz), 6.84 (1H, dd, J = 8.6 and 2.
6Hz), 7.00 (2H, d, J = 8.3Hz), 7.02 (1H, br
s), 7.30 (2H, d, J = 8.3Hz), 7.44 (1H, d, J = 8.
6Hz)

Example 15 1- (4,4-bis (diisopropoxyphosphinyl))
Butyl) -2,3-bis (4-methoxyphenyl) -5
-Methoxyindole

[Chemical formula 61] In the same manner as in the alkylation method of Reference Example 1, Reference Example 16
From 1.77 g of 1- (3-methanesulfonyloxypropyl) -2,3-bis (4-methoxyphenyl) -5-methoxyindole obtained in 1. and 6.6 g of tetraisopropyl methylenebisphosphonate, 1- (4,4
-Bis (diisopropoxyphosphinyl) butyl)-
2.3 g (41% yield) of 2,3-bis (4-methoxyphenyl) -5-methoxyindole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.10 to 1.40 (24H, m), 1.55 to 2.10
(5H, m), 3.75 (3H, s), 3.79 (3H, s), 3.
83 (3H, s), 4.05 (2H, t, J = 7Hz), 4.55
4.85 (4H, m), 6.77 (2H, d, J = 8.9Hz), 6.8
2 (2H, d, J = 8.9Hz), 6.87 (1H, dd, J = 8.9 and 2.6H
z), 7.10-7.38 (6H, m)

Example 16 1- (4,4-diphosphonobutyl) -2,3-bis (4
-Hydroxyphenyl) -5-hydroxyindole
Disodium salt and 1- (4,4-diphosphonobu)
Chill) -2- (4-methoxyphenyl) -3- (4-hi)
Droxyphenyl) -5-hydroxyindole dina
Thorium salt

[Chemical formula 62] In the same manner as in the method of Example 2, 1 obtained in Example 15
-(4,4-bis (diisopropoxyphosphinyl) butyl) -2,3-bis (4-methoxyphenyl) -5-
From 2.3 g of methoxyindole, 1- (4,4-diphosphonobutyl) -2,3-bis (4-hydroxyphenyl) -5-hydroxyindole disodium salt 698
mg (yield 39%) and 1- (4,4-diphosphonobutyl) -2- (4-methoxyphenyl) -3- (4-
Hydroxyphenyl) -5-hydroxyindole disodium salt (269 mg, yield 15%) was obtained. ¹ H-NMR (D ₂ O: 1- (4,4-diphosphonobutyl) -2,3-bis (4-hydroxyphenyl) -5-
Hydroxyindole disodium salt) δ: ppm 1.50 to 1.92 (5H, m), 3.89 (2H, t, J = 7.4H)
z), 6.65 (2H, d, J = 8.6Hz), 6.79 (2H, d, J = 8.
6Hz), 6.85 (1H, dd, J = 8.6 and 2.0Hz), 6.93
(2H, d, J = 8.6Hz), 7.00 (2H, d, J = 8.6Hz), 7.0
3 (1H, d, J = 2.0Hz), 7.44 (1H, d, J = 8.6Hz) ¹ H-NMR (D ₂ O: 1- (4,4-diphosphonobutyl) -2- (4-methoxy) Phenyl) -3- (4-hydroxyphenyl) -5-hydroxyindole disodium salt) δ: ppm 1.50 to 1.90 (5H, m), 3.73 (3H, s), 3.
88 (2H, t, J = 7.4Hz), 6.64 (2H, d, J = 8.6Hz), 6.
80 (2H, d, J = 8.9Hz), 6.85 (1H, dd, J = 8.6 and
2.3Hz), 6.91 (2H, d, J = 8.6Hz), 7.01 (2H,
d, J = 8.9Hz), 7.05 (1H, d, J = 2.3Hz), 7.45 (1H,
(d, J = 8.6Hz)

Example 17 1- (2-bis (diethoxyphosphinyl) methylami
No-ethyl) -2- (4-methoxyphenyl) -3-me
Chill-6-methoxyindole

[Chemical 63] Under a nitrogen atmosphere, 1- (2-aminoethyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole (500 mg) obtained in Reference Example 18 was added to triethyl orthoformate (288 mg) and phosphorous acid. Add 894 mg of diethyl,
The mixture was stirred at 100 ° C for 2.5 hours. After distilling off low-boiling components under reduced pressure, silica gel column chromatography (1
% Methanol / chloroform)
There was obtained 344 mg (yield 36%) of-(2-bis (diethoxyphosphinyl) methylamino-ethyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.15 to 1.30 (12H, m), 2.17 (3H, s),
2.90 to 3.15 (3H, m), 3.87 (3H, s), 3.
89 (3H, s), 3.94 to 4.20 (10H, m), 6.79
(1H, dd, J = 8.6 and 2.3Hz), 6.85 (1H, d, J = 2.3H)
z), 7.00 (2H, d, J = 8.6Hz), 7.32 (2H, d, J = 8.6)
Hz), 7.42 (1H, d, J = 8.6Hz)

Example 18 1- (2-Diphosphonomethylamino-ethyl) -2-
(4-hydroxyphenyl) -3-methyl-6-hydro
Xindole disodium salt

[Chemical 64] In the same manner as in the method of Example 2, 1 obtained in Example 17
-(2-bis (diethoxyphosphinyl) methylamino-ethyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole From 344 mg, 1- (2-diphosphonomethylamino-ethyl) ) -2- (4-Hydroxyphenyl) -3-methyl-6-hydroxyindole disodium salt 3 mg (yield 1%) was obtained. ¹ H-NMR (D ₂ O) δ: ppm 2.10 (3H, s), 2.82 (1H, t, J = 17Hz), 3.2
2 to 3.40 (2H, m), 4.20 to 4.33 (2H, m),
6.73 (1H, d, J = 8.6Hz), 6.98 (2H, d, J = 8.6Hz),
7.07 (1H, s), 7.30 (2H, d, J = 8.6Hz), 7.
47 (1H, d, J = 8.6Hz)

Example 19 1- (2,2-diphosphono-2-hydroxyethyl)-
2- (4-methoxyphenyl) -3-methyl-6-meth
Xindole disodium salt

[Chemical 65] 1-Carboxymethyl-2- (4-methoxyphenyl) -3-methyl-6 obtained in Reference Example 20 under nitrogen atmosphere
-Methoxyindole 1.0g, chlorobenzene 21ml
And phosphoric acid 376mg were added, and under reflux, phosphorus trichloride 843mg
Was added and refluxed for 2 hours. After cooling, the chlorobenzene layer was removed, 20 ml of water was added, and the mixture was refluxed for 2 hours. Water was distilled off, and CHP20P gel column (manufactured by Mitsubishi Kasei; 0-2%)
1- (2, by purifying with acetonitrile / water)
2-diphosphono-2-hydroxyethyl) -2- (4-
5 mg (yield 0.3%) of disodium salt of methoxyphenyl) -3-methyl-6-methoxyindole was obtained. ¹ H-NMR (D ₂ O) δ: ppm 2.16 (3H, s), 3.05 (2H, t, J = 18Hz), 3.8
7 (3H, s), 3.90 (3H, s), 6.6 to 7.6 (7H, m)

Example 20 Erythro 3- (3- (4,4-bis (diisopropoxy)
Cyphosphinyl) butyl) -4-methoxyphenyl)-
4- (4-methoxyphenyl) -hexane

[Chemical 66] 2.38 g of erythro 3- (3- (3-methanesulfonyloxypropyl) -4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane obtained in Reference Example 23 in the same manner as in the method of Reference Example 1. From Erythro 3- (3
3.21 g (yield 86%) of-(4,4-bis (diisopropoxyphosphinyl) butyl) -4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.51 (6H, t, J = 7.1Hz), 1.10 to 1.50 (28H, 28H,
m), 1.60 to 2.35 (5H, m), 2.35 to 2.5
5 (2H, m), 2.61 (2H, t, J = 7.2Hz), 3.80 (3
H, s), 3.81 (3H, s), 4.70-4.90 (4H,
m), 6.76 (1H, d, J = 7.9Hz), 6.86 (2H, d, J = 8.
6Hz), 6.91 (1H, s), 6.92 (1H, d, J = 7.9Hz),
7.07 (2H, d, J = 8.6Hz)

Example 21 Erythro 3- (3- (4,4-diphosphonobutyl)-
4-hydroxyphenyl) -4- (4-hydroxyphen)
Nyl) -hexane disodium salt

[Chemical 67] Erythro 3- (3- (4,4-bis (diisopropoxyphosphinyl) butyl) -4-methoxyphenyl) -4 obtained in Example 20 in a similar manner to that of Example 2.
From 1.0 g of-(4-methoxyphenyl) -hexane, erythro 3- (3- (4,4-diphosphonobutyl) -4
-Hydroxyphenyl) -4- (4-hydroxyphenyl) -hexane disodium salt 440 mg (54% yield)
Got ¹ H-NMR (D ₂ O) δ: ppm 0.57 (6H, t, J = 7.4Hz), 1.20 to 1.50 (4H, 4H,
m), 1.70 to 2.05 (5H, m), 2.50 to 2.7
0 (4H, m), 6.87 (1H, d, J = 7.3Hz), 6.87 (2
H, d, J = 8.6Hz), 7.03 (1H, d, J = 7.3Hz), 7.10
(1H, s), 7.16 (2H, d, J = 8.6Hz)

Example 22 Erythro 3- (3- (3-bis (diethoxyphosphine
Nyl) methylamino-propyl) -4-methoxyphenyl
) -4- (4-Methoxyphenyl) -hexane

[Chemical 68] In the same manner as in the method of Example 17, from 1.19 g of erythro 3- (3- (3-aminopropyl) -4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane obtained in Reference Example 24, Erythro 3- (3- (3-bis (diethoxyphosphinyl) methylamino-propyl)
150 mg (yield 7%) of -4-methoxyphenyl) -4- (4-methoxyphenyl) -hexane was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.52 (6H, t, J = 7.3Hz), 1.15 to 1.50 (12H, 12H,
m), 1.50 to 1.85 (4H, m), 2.38 to 2.5
5 (2H, m), 2.55 to 2.95 (4H, m), 3.82
(6H, s), 4.05 to 4.35 (8H, m), 6.72 to
7.02 (5H, m), 7.02 to 7.12 (2H, m)

Example 23 Erythro 1- (4,4-bis (diisopropoxyphos)
Finyl) pentylthio) -2,3-bis (4-methoxy)
Cyphenyl) -pentane

[Chemical 69] Erythro 2,3 obtained in Reference Example 28 under nitrogen atmosphere
-Bis (4-methoxyphenyl) -1-acetylthiopentane (980 mg) was dissolved in tetrahydrofuran (5 ml), and 28% sodium methoxide (0.61 ml) was added at room temperature.
Stir for 0 minutes. Subsequently, 4,4 obtained in Reference Example 4
1.44 g of -bis (diisopropoxyphosphinyl) -1-iodopentane was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off, and silica gel column chromatography (3%
By purifying with methanol / chloroform, erythro 1- (4,4-bis (diisopropoxyphosphinyl) pentylthio) -2,3-bis (4-methoxyphenyl) -pentane 1.94 g (yield 99 %) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.54 (3H, t, J = 7.3Hz), 1.20 to 1.50 (27H, 27H,
m), 1.60 to 3.60 (12H, m), 3.80 (3H,
s), 3.81 (3H, s), 4.70 to 4.90 (4H, m),
6.86 (4H, d, J = 8.6Hz), 7.08 (2H, d, J = 8.6H)
z), 7.12 (2H, d, J = 8.6Hz)

Example 24 Erythro 1- (4,4-diphosphonopentylthio)-
2,3-bis (4-hydroxyphenyl) -pentane
Disodium salt

[Chemical 70] Erythro 1- (4,4-bis (diisopropoxyphosphinyl) pentylthio) -2,3-bis (4-methoxyphenyl) -pentane obtained in Example 23 in a similar manner to that of Example 2. From 1.0g, Erythro 1-
53 mg of (4,4-diphosphonopentylthio) -2,3-bis (4-hydroxyphenyl) -pentane disodium salt (yield 7%) was obtained. ¹ H-NMR (D ₂ O) δ: ppm 0.57 (3H, brs), 1.31 (3H, t, J = 15.2Hz),
1.20 to 1.55 (2H, m), 1.55 to 1.95 (4
H, m), 2.30-2.45 (2H, m), 2.55-2.
85 (3H, m), 2.85-3.10 (1H, m), 6.80
~ 7.05 (4H, m), 7.10-7.35 (4H, m)

Example 25 Erythro N- (4,4-bis (diisopropoxyphos)
Finyl) pentyl) -2,3-bis (4-methoxyphenyl)
) -Pentanamide

[Chemical 71] Erythro 2,3 obtained in Reference Example 29 under nitrogen atmosphere
-Bis (4-methoxyphenyl) -pentanoic acid 550 mg,
And 700 mg of 4,4-bis (diisopropoxyphosphinyl) -1-amino-pentane obtained in Reference Example 6
Was dissolved in 10 ml of chloroform, 430 mg of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 12 hours.
The solvent was distilled off, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give erythro N- (4,4-bis (diisopropoxyphosphinyl) pentyl) -2,3-bis (. 4-Methoxyphenyl) -pentanamide (980 mg, yield 80%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.58 (3H, t, J = 7.3Hz), 1.20 to 1.65 (29H, 29H,
m), 1.65 to 2.00 (4H, m), 2.70 to 3.0
0 (2H, m), 3.17 (1H, td, J = 10.9 and 3.3Hz),
3.27 (1H, d, J = 10.9Hz), 3.78 (3H, s), 3.
80 (3H, s), 4.65-4.90 (4H, m), 5.39
(1H, t, J = 5Hz), 6.82 (2H, d, J = 8.9Hz), 6.86
(2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.3
5 (2H, d, J = 8.9Hz)

Example 26 Erythro N- (4,4-diphosphonopentyl) -2,
3-bis (4-hydroxyphenyl) -pentanamide
Disodium salt

[Chemical 72] Erythro N- (4,4-bis (diisopropoxyphosphinyl) pentyl) -2,3-bis (4-methoxyphenyl) -pentane obtained in Example 25 in a similar manner to that of Example 2. From 1.15 g of amide, Erythro N-
(4,4-diphosphonopentyl) -2,3-bis (4-
Hydroxyphenyl) -pentanamide disodium salt
546 mg (yield 62%) was obtained. ¹ H-NMR (D ₂ O) δ: ppm 0.53 (3H, t, J = 7Hz), 1.15 (3H, t, J = 15.5Hz),
1.10 to 1.60 (6H, m), 2.60 to 2.85 (2
H, m), 3.05 (1H, t, J = ~ 12Hz), 3.63 (1H, d,
J = 11.9Hz), 6.85 (2H, d, J = 8.6Hz), 6.87 (2
H, d, J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz), 7.33 (2
(H, d, J = 8.6Hz)

Example 27 8,8-bis (diisopropoxyphosphinyl) -3,
4-bis (4-methoxyphenyl) -3-nonene

[Chemical formula 73] 3,4-bis (4 obtained in Reference Example 31 under a nitrogen atmosphere
1.18 g of -methoxyphenyl) -8,8-bis (diisopropoxyphosphinyl) -3-hydroxynonane was dissolved in 3.5 ml of chloroform, and phosphorus tribromide 0.3 g was added at 0 ° C.
3 ml was added, and the mixture was stirred at room temperature for 30 minutes. After adding methanol and water, the mixture was extracted twice with chloroform. After the solvent was distilled off, the product was purified by silica gel column chromatography (3% methanol / chloroform) to give 8,8-bis (diisopropoxyphosphinyl)-.
3,4-bis (4-methoxyphenyl) -3-nonene
1.0 g (yield 87%, E: Z = 2: 1) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.76 (3H, t, J = 7.2Hz) ¹⁾ , 0.94 (3H, t, J = 6.8)
Hz) ²⁾ , 1.10 to 1.90 (31H, m), 2.00
2.60 (4H, m), 3.70 to 3.90 (6H, m), 4.6
0 to 4.90 (4H, m), 6.55 to 7.20 (8H, m) (1) Peak of E form 2) Peak of Z form
)

Example 28 8,8-Diphosphono-3,4-bis (4-hydroxyphenyl)
Phenyl) -3-nonene disodium salt

[Chemical 74] In the same manner as in the method of Example 2, 8, obtained in Example 3,
8-bis (diisopropoxyphosphinyl) -3,4-
From 500 mg of bis (4-methoxyphenyl) -3-nonene, 590 mg (yield 100%) of 8,8-diphosphono-3,4-bis (4-hydroxyphenyl) -3-nonene disodium salt was obtained. ¹ H-NMR (D ₂ O) δ: ppm 0.70 (3H, brs) ¹⁾ , 0.87 (3H, brs) ²⁾ , 1.0
0 to 2.60 (11H, m), 6.55 to 7.35 (8H, m) (1) Peak of E form 2) Peak of Z form
)

Example 29 17α- (6,6-bis (diisopropoxyphosphini
) -1-Heptinyl) -3,17-dihydroxy-e
Stra-1,3,5 (10) -triene

[Chemical 75] Under a nitrogen atmosphere, 17α-ethynyl-3,17-bis (tetrahydropyranyloxy) -estra-1,3,5
(10) -Trien (Journal of Medicinal Chemistry, Vol. 25, 1488-1492 (198)
2)) 1.19 g was dissolved in 20 ml of tetrahydrofuran and 0
1.92 ml of 1.6 M butyllithium / hexane was added at ℃, and stirred at room temperature for 30 minutes. 4,4-bis (diisopropoxyphosphinyl) -1-obtained in Reference Example 4
1.60 g of iodopentane was added, and the mixture was stirred at room temperature for 12 hours. The pH was adjusted to ~ 1 with dilute hydrochloric acid, the solvent was distilled off after stirring, and silica gel column chromatography (4% methanol /
By purification with chloroform, 17α- (6,6
-Bis (diisopropoxyphosphinyl) -1-heptinyl) -3,17-dihydroxy-estra-1,3
1.7 g (yield 96%) of 5 (10) -triene was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.85 (3H, s), 1.20 to 2.45 (52H, m),
2.70 to 2.90 (2H, m), 4.65 to 4.95 (4
H, m), 6.63 (1H, d, J = 2.4Hz), 6.69 (1H, dd, J
= 8.3 and 2.4Hz), 7.10 (1H, d, J = 8.3Hz),
7.79 (1H, s)

Example 30 17α- (6,6-diphosphono-1-heptinyl)-
3,17-dihydroxy-estra-1,3,5 (1
0) -triene disodium salt

[Chemical 76] Example 29 was carried out in the same manner as in Example 2 except that bromotrimethylsilane was used and the reaction temperature was 60 ° C.
17α- (6,6-bis (diisopropoxyphosphinyl) -1-heptynyl) -3,17-dihydroxy-estra-1,3,5 (10) -triene 1.7 obtained in
From g, 17α- (6,6-diphosphono-1-heptinyl) -3,17-dihydroxy-estra-1,3,5
104 mg of (10) -triene disodium salt (yield 7
%) Was obtained. ¹ H-NMR (CD ₃ OD: D ₂ O = 1: 1) δ: ppm 0.86 (3H, s), 1.36 (3H, t, J = 15.2Hz), 1.
20-2.90 (22H, m), 6.20 (1H, s), 6.6
2 (1H, s), 6.67 (1H, d, J = 8.2Hz), 7.19 (1
(H, d, J = 8.2Hz)

Example 31 1- (4,4-bis (diisopropoxyphosphinyl)
Hexyl) -2- (4-methoxyphenyl) -3-methyl
Le-6-methoxyindole

[Chemical 77] 1- (4,4-bis (diisopropoxyphosphinyl) butyl) -2- (4-methoxyphenyl) -3 obtained in Example 7 in the same manner as in the alkylation method of Reference Example 1.
From 3.75 g of methyl-6-methoxyindole and 1.5 g of ethyl iodide, 1- (4,4-bis (diisopropoxyphosphinyl) hexyl) -2- (4-methoxyphenyl) -3-methyl was obtained. -6-Methoxyindole
3.6 g (yield 92%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 0.89 (3H, t, J = 7.4Hz), 1.15 to 1.45 (24H,
m), 1.50 to 2.10 (6H, m), 2.18 (3H, s),
3.86 (3H, s), 3.88 (3H, s), 3.93 (2
H, t, J = 7.4Hz), 4.60 to 4.85 (4H, m), 6.7
4 to 6.86 (2H, m), 6.99 (2H, d, J = 8.6Hz),
7.30 (2H, d, J = 8.6Hz), 7.42 (1H, d, J = 8.6Hz)

Example 32 1- (4,4-diphosphonohexyl) -2- (4-hydr
Roxyphenyl) -3-methyl-6-hydroxyindo
Disodium salt

[Chemical 78] In the same manner as in the method of Example 2, 1 obtained in Example 31
-(4,4-bis (diisopropoxyphosphinyl) hexyl) -2- (4-methoxyphenyl) -3-methyl-6-methoxyindole 3.6 g to 1- (4,4-
0.66 g (yield 24%) of disodium salt of diphosphonohexyl) -2- (4-hydroxyphenyl) -3-methyl-6-hydroxyindole was obtained. ¹ H-NMR (D ₂ O) δ: ppm 0.82 (3H, t, J = 7.2Hz), 1.35 to 1.90 (6H, 6H,
m), 2.08 (3H, s), 3.91 (2H, t, J = 7.2Hz),
6.69 (1H, dd, J = 8.6 and 2.0Hz), 6.95 (2
H, d, J = 8.6Hz), 6.99 (1H, d, J = 2.0Hz), 7.26
(2H, d, J = 8.6Hz) 7.43 (1H, d, J = 8.6Hz)

Reference Example 32 3-Ethoxycarbonylmethyl-2- (4-methoxyphenol)
Phenyl) -5-methoxyindole

[Chemical 79] Under a nitrogen atmosphere, 4- (4-methoxyphenyl) -4-oxobutanoic acid (Organic Reactions (Org.Re
actions) Vol. 5, 262 (1949)) 7.0 g, 4-methoxyphenylhydrazine 4.7 g and acetic acid 0.35 ml were added to toluene 50 ml and refluxed for 1 hour while removing water. Toluene was distilled off, 50 ml of ethanol and 2 ml of concentrated sulfuric acid were added, and the mixture was refluxed for 1 hour. Ethanol was distilled off and 100 ml of water was added.
, Neutralize, extract twice with methylene chloride, wash with water,
Purification by silica gel column chromatography (20% ethyl acetate / hexane) gave 1.84 g (yield 16%) of 3-ethoxycarbonylmethyl-2- (4-methoxyphenyl) -5-methoxyindole. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.27 (3H, t, J = 7.1Hz), 3.76 (2H, s), 3.8
5 (3H, s), 3.87 (3H, s), 4.18 (2H, q, J = 7.1H
z), 6.84 (1H, dd, J = 8.9 and 2.3Hz), 6.99
(2H, d, J = 8.9Hz), 7.11 (1H, d, J = 2.3Hz), 7.2
2 (1H, d, J = 8.9Hz), 7.58 (2H, d, J = 8.9Hz), 8.
00 (1H, brs)

Reference Example 33 1-Ethyl-3-ethoxycarbonylmethyl-2- (4
-Methoxyphenyl) -5-methoxyindole

[Chemical 80] 3 obtained in Reference Example 32 in the same manner as in the method of Reference Example 7
From 4.47 g of -ethoxycarbonylmethyl-2- (4-methoxyphenyl) -5-methoxyindole and 3.1 g of ethyl iodide, 1-ethyl-3-ethoxycarbonylmethyl-2- (4-methoxyphenyl) -5-methoxy 4.95 g (yield 100%) of indole was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.22 (3H, t, J = 7.3Hz), 1.24 (3H, t, J = 7.3H)
z), 3.57 (2H, s), 3.877 (3H, s), 3.8
81 (3H, s), 4.01 (2H, q, J = 7.3Hz), 4.12 (2
H, q, J = 7.3Hz), 6.89 (1H, dd, J = 8.9 and 2.3H
z), 7.01 (2H, d, J = 8.9Hz), 7.11 (1H, d, J = 2.
3Hz), 7.25 (1H, d, J = 8.9Hz), 7.38 (2H, d, J = 8.
9Hz)

Reference Example 34 1-Ethyl-3- (2-chloroethyl) -2- (4-me
Toxyphenyl) -5-methoxyindole

[Chemical 81] In a nitrogen atmosphere, 0.17 g of lithium aluminum hydride,
In addition to 20 ml of tetrahydrofuran, at room temperature, Reference Example 33
A solution of 1.66 g of 1-ethyl-3-ethoxycarbonylmethyl-2- (4-methoxyphenyl) -5-methoxyindole obtained in 1. in tetrahydrofuran (20 ml) was added, and the mixture was refluxed for 1 hour. After cooling, water was added, 2N hydrochloric acid was added, and the mixture was stirred, neutralized with 2N aqueous sodium hydroxide solution, extracted three times with ethyl acetate, and the solvent was evaporated. Under a nitrogen atmosphere,
It was dissolved in 20 ml of methylene chloride, 0.71 g of triethylamine and 0.52 g of methanesulfonyl chloride were added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. By washing twice with water and purifying with silica gel column chromatography (methylene chloride), 1-ethyl-3- (2-chloroethyl) -2- (4
-Methoxyphenyl) -5-methoxyindole 0.25g
(Yield 16%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.19 (3H, t, J = 7.3Hz), 3.03 to 3.15 (2H, 2H,
m), 3.53 to 3.64 (2H, m), 3.889 (3H,
s), 3.893 (3H, s), 3.97 (2H, q, J = 7.3Hz),
6.90 (1H, dd, J = 8.9 and 2.3Hz), 7.01
(2H, d, J = 8.9Hz), 7.05 (1H, d, J = 2.3Hz), 7.2
5 (1H, d, J = 8.9Hz), 7.28 (2H, d, J = 8.9Hz)

Example 33 1-Ethyl-3- (3,3-bis (diisopropoxyfo
Sphinyl) propyl) -2- (4-methoxypheny
) -5-Methoxyindole

[Chemical formula 82] 1 obtained in Reference Example 34 in the same manner as in the method of Reference Example 1
-Ethyl-3- (2-chloroethyl) -2- (4-methoxyphenyl) -5-methoxyindole 0.25g and tetraisopropyl methylenebisphosphonate 0.5g
From 1-ethyl-3- (3,3-bis (diisopropoxyphosphinyl) propyl) -2- (4-methoxyphenyl) -5-methoxyindole 58 mg (yield 12
%) Was obtained. ¹ H-NMR (CDCl ₃ ) δ: ppm 1.18 (3H, t, J = 7.2Hz), 1.15 to 1.40 (24H,
m), 1.98 to 2.32 (3H, m), 2.82 to 2.9
5 (2H, m), 3.87 (3H, s), 3.90 (3H, s),
3.96 (2H, q, J = 7.2Hz), 4.60 to 4.85 (4H,
m), 6.88 (1H, dd, J = 8.6 and 2.5Hz), 6.9
9 (2H, d, J = 8.9Hz), 7.23 (1H, d, J = 8.6Hz), 7.
25 (1H, d, J = 2.5Hz), 7.31 (2H, d, J = 8.6Hz)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07F 9/40 E 7106-4H 9/572 A 7106-4H 9/6553 7106-4H // A61K 31 / 66 AEK 8314-4C

Claims (2)

[Claims] 1. A compound represented by the general formula (1): (In the formula, E is an estrogen residue, R ¹ is a single bond or lower alkylene, R ² is lower alkylene, lower alkenylene or lower alkynylene, R ³ is hydrogen atom or lower alkyl group, and R ⁴ is hydroxyl group. , A lower alkyl group or a lower alkoxy group, Y ¹ is a single bond, —O
_{-, - S (O) n} - ( wherein n represents 0, 1 or ^{2.), - NR 5 -} (. Wherein R ⁵ represents a hydrogen atom or a lower alkyl group) or ─CONR ⁶ ─ ( Where R
⁶ represents a hydrogen atom or a lower alkyl group. ) To Z ¹
Is a single bond, -O -, - S- or -NH-, Z ² represents a hydrogen atom, a lower alkyl group, a lower alkylthio group, a hydroxyl group or an amino group. However, Z ¹ is -O-, -S-
Or representing a -NH-, R ² is a C ₂ or more lower alkylene, Z ² represents a hydrogen atom. And a pharmaceutically acceptable non-toxic salt thereof, and
ester. 2. An estrogen residue is represented by the general formula (2): (In the formula, R ⁷ and R ⁸ may be the same or different and each may be a hydrogen atom, a lower alkyl group, a benzoyl group or a lower alkanoyl group, and R ⁹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a phenyl group or a substituted group. A phenyl group, X ¹ and X ² may be the same or different, a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a substituted lower alkyl group or a halogen atom, and Y ² is —S—, —NR ¹⁰ —. (Wherein R ¹⁰ represents a hydrogen atom or a lower alkyl group), —CH ₂ CH ₂ —, or —C.
HR ¹¹ — (wherein R ¹¹ represents a hydrogen atom or a lower alkyl group). ) Or a compound represented by the general formula (3): (In the formula, R ¹² and R ¹³ are the same or different hydrogen atom, lower alkyl group, benzoyl group or lower alkanoyl group, and X ³ and X ⁴ are the same or different hydrogen atom, lower alkyl group, Lower alkoxy group, hydroxy group, substituted lower alkyl group or halogen atom, R ¹⁴ is lower alkyl group, phenyl group or substituted phenyl group, R ¹⁵ is hydrogen atom, lower alkyl group, substituted lower alkyl group, cyano group or lower A compound represented by an alkoxycarbonyl group represented by a double-dashed line and a double-line represents a single bond or a double bond, or a compound represented by the general formula (4): (In the formula, R ¹⁶ and R ¹⁷ may be the same or different and may be a hydrogen atom, a lower alkyl group, a benzoyl group or a lower alkanoyl group, and R ¹⁸ is a hydrogen atom, a lower alkyl group,
A substituted lower alkyl group, a lower alkenyl group or a lower alkoxy group, and R ¹⁹ represents a hydrogen atom or a halogen atom. The compound of Claim 1 which represents the residue of the compound represented by these, and its non-toxic salt and a pharmaceutically acceptable salt.