JPH09301915A - Flavone and naphthalene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject derivative useful as an estrogenic agent for preventing and treating diseases such as menopausal disorders, prostatic cancer and prostatomegaly. SOLUTION: This new derivative is a flavone or naphthalene derivative shown by the formula (R<1> is OH or H; R<2> is a nonsubstituted 1-6C alkyl or nonsubstituted 2-6C alkenyl having one double bond; R<3> is H or a nonsubstituted 1-4C alkyl; R<4> and R<5> are each H or a nonsubstituted 1-4C alkyl; R<6> is OH, a halogen or nonsubstituted 1-4C alkyl; X is O or methylene; bond bearing ...mark is a single or double bond), e.g. 5,7-dihydroxy-2-(4-hydroxy-3- methoxyphenyl)-8-(3-methyl-2-butenyl)-4-chromanone.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a compound that exerts an estrogenic effect by specifically binding to an estrogen receptor. The present invention also relates to a medicament comprising these compounds, which is useful as an estrogen agonist, and a pharmaceutical composition containing the compound as an active ingredient.

[0002]

2. Description of the Related Art Estrogen is a kind of female hormone, and is a general term for hormones having an estrous effect and substances having a similar effect. As a naturally occurring estrogen, estradiol, which is a steroidal estrogen, is known as a major human estrogen. As steroid-based estrogen agonists, for example, estrone, estriol, equilin, homoestrone, ethinyl estradiol, etc. are also known.
Further, as nonsteroidal estrogen agonists, for example, diethylstilbestrol, hexestrol and the like are known.

Among these estrogen agonists, the steroidal estrogen agonists are, for example, pharmaceuticals indicated for amenorrhea, anovulatory cycle, functional uterine bleeding, uterine dysgenesis, etc. due to a decrease in estrogen. It is also used for the treatment of menopausal disorders and suppression of milk secretion. In addition, nonsteroidal estrogen agonists are mainly used as therapeutic agents for prostate cancer and benign prostatic hyperplasia.

All of the estrogen agonists currently used have a problem that they have side effects such as gastrointestinal disorders, thrombosis, uterine bleeding, and liver disorders.
It is known that endometrial cancer and breast cancer may develop. Therefore, an estrogen agonist with reduced side effects is desired.

[0005]

An object of the present invention is to provide a compound having an excellent estrogen-like action and useful as an active ingredient of an estrogen agent. Another object of the present invention is to have an excellent estrogenic effect, and
It is intended to provide a compound in which side effects of conventional estrogen agents are reduced. Yet another object of the present invention is to
The present invention provides a drug comprising a compound having the above characteristics as an active ingredient. In addition, by using the above drug, diseases caused by a decrease in estrogen (for example, amenorrhea, anovulatory cycle, functional Uterine bleeding, uterine growth failure, etc.)
Another object is to provide a method for treating menopausal disorders, osteoporosis, prostate cancer, benign prostatic hyperplasia, and the like.

[0006]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies to solve the above problems, and have found various compounds in order to find a substance that antagonizes the ligand estradiol in binding estradiol to the estrogen receptor. Synthesized. As a result, it was found that specific flavone and naphthalene derivatives have strong estrogen activity (agonist activity). The present invention has been completed based on the above findings.

That is, the present invention has the following general formula (I):

[0008]

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[Wherein R ₁ represents a hydrogen atom or a hydroxyl group, R ₂ represents an unsubstituted or aryl-substituted alkyl group or an unsubstituted or aryl-substituted alkenyl group, and R ₃ represents a hydrogen atom or Represents a lower alkyl group, R
₄ and R ₅ each independently represent a hydrogen atom or a lower alkyl group, R ₆ represents a hydroxyl group, a halogen atom, or a lower alkyl group, X represents an oxygen atom or a methylene group, and ---- represents The bond is a single bond or a double bond], and a salt thereof.

According to a preferred embodiment of the present invention, R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C 1 containing one double bond.
_2-6 alkenyl group, or a C _1-4 be C _1-4 alkyl group having an alkyl substituted or unsubstituted phenyl group as a substituent; R ₃ is hydrogen atom or an unsubstituted C _1-4 alkyl group;
R ₄ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₅
Is a hydrogen atom or an unsubstituted C _1-4 alkyl group; and R ₆ is a hydroxyl group, a halogen atom, or an unsubstituted C _1-4 alkyl group, and a salt thereof.

Furthermore, in the above preferred compounds and salts thereof, compounds wherein R ₁ is a hydroxyl group and X is an oxygen atom and salts thereof; R ₁ is a hydroxyl group, R ₆ is a hydroxyl group, and X is A compound which is a methylene group and the bond to which ---- is attached is a single bond and a salt thereof; a compound in which R ₁ is a hydrogen atom, R ₆ is a hydroxyl group, and X is an oxygen atom. And a salt thereof; and R ₁ is a hydrogen atom, R ₃ is a hydrogen atom, R ₄ is a hydrogen atom, and R
₆ is a hydroxyl group, X is a methylene group, and ----
Provided are compounds and salts thereof in which the bond marked with is a single bond.

According to another aspect of the present invention, a drug comprising the above compound or a pharmaceutically acceptable salt thereof, and a drug containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient. A composition for use is provided. As a preferred pharmaceutical composition, the above composition used as an estrogen agonist; the above composition used for the prevention and / or treatment of a disease selected from the group consisting of diseases caused by a decrease in estrogen, menopausal disorders, prostate cancer, and benign prostatic hyperplasia. A composition; and the above-mentioned composition used for suppressing lactation.
Further, according to another aspect of the present invention, there is also provided use of the above compound or a pharmaceutically acceptable salt thereof for the production of each of the above compositions.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I), R ₂
Represents an unsubstituted or aryl-substituted alkyl group, or an unsubstituted or aryl-substituted alkenyl group. The alkyl group represented by R ₂ may be linear or branched. As the alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl,
t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-
Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4- Dimethylpentyl,
Octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,
6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2- Ethyl heptyl, 6,6-
Dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,
8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13- Examples thereof include dimethyltetradecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl, and docosyl. Preferably, it is a straight chain or branched chain C _1-10 (having 3 to 10 carbon atoms).
C) alkyl groups, more preferably linear or branched C
_1-6 alkyl groups, particularly preferably linear or branched C _2-5
Alkyl groups can be used.

When R ₂ represents an aryl-substituted alkyl group, those exemplified above can be used as the alkyl group, preferably a linear or branched C _1-4 alkyl group, and more preferably a straight chain C _1-4 alkyl group. Chain C _1-4 alkyl groups can be used. The position of the aryl group (aromatic ring group), which is a substituent on the alkyl group, is not particularly limited, and it may be substituted at any position on the alkyl group. The number of aryl groups on the alkyl group is not particularly limited, and one or two or more, preferably one aryl group may be substituted on the alkyl group. As the aryl group, for example, a phenyl group, a naphthyl group, or a pyridyl group, preferably a phenyl group can be used, and these aryl groups have 1 or 2 or more, preferably 1 or more substituents on the aromatic ring. It may have a group. As such a substituent on the aromatic ring, for example, a linear or branched C _1-4 alkyl group, preferably a methyl group can be used. More specifically, examples of the aryl-substituted alkyl group include, for example, benzyl group, (2-methylphenyl) methyl group, (3-methylphenyl) methyl group, (4-methylphenyl) methyl group, (3
4-dimethylphenyl) methyl group, 2-naphthylmethyl group, 4-pyridylmethyl group, 2-phenylethyl group, 1-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 3-phenyl-2-propyl group, 2-phenylbutyl group, 3-phenylbutyl group, 3-phenyl-2-butyl group, 4-phenylbutyl group, 4-phenyl
Examples thereof include -2-butyl group, 4-phenyl-3-butyl group, and 3,3-diphenylpropyl group.

The alkenyl group represented by R ₂ may be linear or branched. The number of double bonds in the alkenyl group is not particularly limited, but it may have 1 to 3, more preferably 1 or 2, and particularly preferably 1 double bond. Each double bond present in the alkenyl group is
It may have either cis or trans configuration. Examples of the alkenyl group include 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl and 1-methyl-2.
-Butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3
-Butenyl, 3-methyl-2-butenyl (prenyl), 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl- 3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 9- Hexadecenyl, cis-9-octadecenyl, trans-11-octadecenyl, cis, cis-9,12-octadecadienyl, 9,12,15-octadecatrienyl, 6,
Straight or branched chain C ₂ such as 9,12-octadecatrienyl, 9,11,13-octadecatrienyl, 5,8,11,14-eicosatetraenyl, cis-15-tetracosenyl _-25 alkenyl groups can be used.

Of these alkenyl groups, preferably a straight-chain or branched-chain C _2-12 alkenyl group, more preferably a straight-chain or branched-chain C _2-8 alkenyl group having one double bond. Particularly preferably, a straight-chain or branched C _2-6 alkenyl group having one double bond can be used. For example, 2-propenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 4-hexenyl, and 9-hexadecenyl are particularly preferably used. When R ₂ represents an aryl-substituted alkenyl group, those exemplified above can be used as the alkenyl group, but preferably a straight chain or branched chain C
_{A 2-4} alkenyl group, more preferably a linear C _2-4 alkenyl group, can be used. The position of the aryl group which is a substituent on the alkenyl group is not particularly limited, and it may be substituted at any position. As the aryl group, the substituted or unsubstituted aryl groups exemplified above can be used, and the alkenyl group may be substituted with one or two or more, preferably one aryl group. For example, 3-phenyl-2-propenyl, 4- (4-methylphenyl) -3-butenyl and the like can be used.

The lower alkyl group for R ₃ , R ₄ , R ₅ and R ₆ may be linear or branched. Examples of the lower alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl,
2-methylbutyl, neopentyl, 1-ethylpropyl, n-
Hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, Use a linear or branched C _1-6 alkyl group such as 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, preferably a linear or branched C _1-4 alkyl group. be able to. As the halogen atom for R _{6, any} of a fluorine atom, a chlorine atom, a bromine atom or an iodine atom may be used. Among the bonds existing in the mother nucleus of the compound of the formula (I), the bond marked with ---- (the bond shown by the combination of the dotted line and the solid line) is either a single bond or a double bond.

The compound represented by the above general formula may be a salt, preferably a pharmacologically acceptable salt, if necessary. Examples of such salts include metal salts such as sodium salts, potassium salts, lithium salts and calcium salts, ammonium salts, and base addition salts such as organic amine compound salts such as monomethylamine and triethylamine. Further, the compound of the present invention is not limited to a particular isomer, and in addition to a cis or trans isomer based on the double bond present in the alkenyl group, one or more isomers that may be present in the molecule Any optical isomers based on asymmetric carbons, racemates, any diastereoisomers based on two or more asymmetric carbons, optical isomers and / or any mixture of diastereomers are all within the scope of the present invention. Included in. Furthermore, any solvates and hydrates of the compounds in free and salt form are also within the scope of the invention.

Preferred compounds of the present invention include, for example, (a) in the above formula (I), R ₁ is a hydroxyl group or a hydrogen atom; R ₂ is an unsubstituted C _1-6 alkyl group, a double bond An unsubstituted C _2-6 alkenyl group containing 1 or a C _1-4 alkyl-substituted phenyl group or a C substituted with an unsubstituted phenyl group
_1-4 alkyl group; R ₃ is a hydrogen atom or unsubstituted C _1-4
An alkyl group; R ₄ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₆ is a hydroxyl group, a halogen atom, or an unsubstituted group C
_1-4 alkyl group; X is an oxygen atom or a methylene group; and the bond with ---- is a single bond or a double bond.

More preferred compounds include, for example, (b) in the above general formula (I), R ₁ is a hydroxyl group;
₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted phenyl group or a C _1-4 substituted by an unsubstituted phenyl group An alkyl group; R ₃ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₄ is a hydrogen atom or an unsubstituted C _1-4 alkyl group;
R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₆
Is a hydroxyl group, a halogen atom, or an unsubstituted C _1-4 alkyl group; X is an oxygen atom; and the bond with ---- is a single bond or a double bond; (c) In the general formula (I), R ₁ is a hydroxyl group; R
₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted phenyl group or a C _1-4 alkyl substituted with an unsubstituted phenyl group R ₃ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₄ is a hydrogen atom or an unsubstituted C _1-4 alkyl group;
R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₆
Is a hydroxyl group; X is a methylene group; and the bond with ---- is a single bond; (d) In the general formula (I), R ₁ is a hydrogen atom;
R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted phenyl group or a C _1-4 substituted by an unsubstituted phenyl group An alkyl group; R ₃ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₄ is a hydrogen atom or an unsubstituted C _1-4 alkyl group;
R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₆
Is a hydroxyl group; X is an oxygen atom; and a bond having ---- is a single bond or a double bond; and (e) In the general formula (I), R ₁ is hydrogen. Is an atom;
R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted phenyl group or a C _1-4 substituted by an unsubstituted phenyl group An alkyl group; R ₃ is a hydrogen atom; R ₄ is a hydrogen atom; R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group;
R ₆ is a hydroxyl group; X is a methylene group; and
A compound in which the bond with --is a single bond can be mentioned.

Particularly preferred compounds include (f) R ₁ in the general formula (I) is a hydroxyl group;
₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted phenyl group or a C _1-4 alkyl substituted with an unsubstituted phenyl group R ₃ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₄ is a hydrogen atom or an unsubstituted C _1-4 alkyl group;
R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₆
Is a hydroxyl group; X is an oxygen atom; and the bond with ---- is a single bond or a double bond; (g) In the above general formula (I), R ₁ is a hydroxyl group. Yes; R
₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted phenyl group or a C _1-4 alkyl substituted with an unsubstituted phenyl group R ₃ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₄ is a hydrogen atom; R ₅ is a hydrogen atom or an unsubstituted group
A compound having a C _1-4 alkyl group; R _{6 a} hydroxyl group; X a methylene group; and a bond with ---- being a single bond; (h) the above general formula (I) In, R ₁ is a hydrogen atom;
R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted or unsubstituted benzyl group; R ₃ is a hydrogen atom And R
₄ is a hydrogen atom; R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₆ is a hydroxyl group; X is an oxygen atom; and the bond with ---- is A compound which is a single bond or a double bond; and (i) in the above general formula (I), R ₁ is a hydrogen atom;
R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted or unsubstituted benzyl group; R ₃ is a hydrogen atom And R
₄ is a hydrogen atom; R ₅ is a hydrogen atom or an unsubstituted C _1-4 alkyl group; R ₆ is a hydroxyl group; X is a methylene group; and the bond with ---- is Mention may be made of compounds which are single bonds.

Specific examples of preferred compounds of the compound of the present invention are shown in the following table. In the table, for example, Et to R ₂ column, Allyl,
The compounds described as Prenyl, Benzyl, and 3-Ph-2-Pro- are each represented by the formula (I) in which R ₂ is CH ₃ CH _2- , CH ₂ = C.
H-CH _2- , CH ₃ -CH (CH ₃ ) = CH-CH _2- , C ₆ H ₅ -CH _2- , and C ₆ H _5-
CH ₂ -CH (CH ₃ )-.

[0023]

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[0024]

[Table 1] X = O compound ─────────────────────────────── No. ---- R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ ─────────────────────────────── 1 Single bond OH Et H H H OH 2 Single Bonded OH Et H H H F 3 Single bond OH Et H H H Cl 4 Single bond OH Pr H H H OH 5 Single bond OH Pr H H H F 6 Single bond OH Pr H H Me OH 7 Single bond OH Pr H Me Me OH 8 single bond OH Pr Me Me Me OH 9 single bond OH Allyl H H H OH 10 single bond OH Allyl H H H F 11 single bond OH Allyl H H H Cl 12 single bond OH Allyl H H H Br 13 single bond OH Allyl H H Me OH 14 single bond OH Allyl H Me Me OH 15 single bond OH Allyl Me Me Me OH 16 single bond OH Bu H H H OH 17 single bond OH Bu H H Me OH 18 single bond OH Bu H Me Me OH 19 single bond OH Bu Bu Me Me Me OH 20 single bond OH 2-Butene H H H OH 21 single bond OH 2-Butene H H Me OH 22 single bond OH 2-Butene H Me Me OH 23 single bond OH 2-Butene Me Me Me OH 24 single bond OH 3-Butene H H H OH 25 single bond OH 1-Butene H H H OH 26 single bond OH Prenyl Me H H OH 27 single bond OH Prenyl H H H F 28 single bond OH Prenyl H H H Cl 29 single bond OH Prenyl H H H Br 30 single bond OH Prenyl H H H I 31 single bond OH Prenyl H H H Me 32 single bond OH Prenyl H H H Et 33 single bond OH Prenyl H H H Pr 34 single bond OH Prenyl H H Me OH 35 single bond OH Prenyl H Me Me OH 36 single bond OH Prenyl Me H Me OH 37 Bonded OH Prenyl H H Et OH 38 Single Bonded OH Prenyl H H Pr OH 39 Single Bonded OH Prenyl H H Bu OH 40 Single Bonded OH Prenyl H Me Et OH 41 Single Bonded OH Prenyl H Me Pr OH 42 Single Bonded OH Prenyl H Me Bu OH 43 single bond OH Prenyl H MetBu OH 44 single bond OH Prenyl H Et Et OH 45 single bond OH Prenyl H Et Pr OH 46 single bond OH Prenyl H Et Bu OH 47 single bond OH Prenyl H Et tBu OH 48 single bond OH Prenyl H Pr Pr OH 49 single bond OH Prenyl H Pr Bu OH 50 single bond OH Prenyl H Pr tBu OH 51 single bond OH Prenyl H Bu Bu OH 52 single bond OH Prenyl H But t Bu OH 53 single bond OH Prenyl H tBu Bu OH 54 single bond OH Prenyl Me H Me OH 55 single bond OH Prenyl Me H Et OH 56 single OH Prenyl Me H Pr OH 57 single bond OH Prenyl Me H Bu OH 58 single bond OH Prenyl Me Me Et OH 59 single bond OH Prenyl Me Me Pr OH 60 single bond OH Prenyl Me Me Me OH 61 M single bond OH Prenyl tBu OH 62 single bond OH Prenyl Me Et Et OH 63 single bond OH Prenyl Me Et Pr OH 64 single bond OH Prenyl Me Et Bu OH 65 single bond OH Prenyl Me Et Et tBu OH 66 single bond OH PrenylPr Pr Pr Me Pr OH Prenyl Me Pr But OH 68 Single Bond OH Prenyl Me Pr ButBu OH 69 Single Bond OH Prenyl Me But Bu OH 70 Single Bond OH Prenyl Me But But OH 71 Single Bond OH Prenyl Met But But Pr OH 72 Single Bond OH Prenyl Me But But OH 71 Single Bond OH Prenyl Me But But OH 71 Single Bond OH 73 Single bond OH Pentyl H H H OH 74 Single bond Combined OH Pentyl H H Me OH 75 Single bond OH Pentyl H Me Me OH 76 Single bond OH Pentyl Me Me Me OH 77 Single bond OH 1-Pentenyl H H H OH 78 Single bond OH 1-Pentenyl H H Me OH 79 Single bond OH 1-Pentenyl H Me Me OH 80 single bond OH 1-Pentenyl Me Me Me OH 81 single bond OH 2-Pentenyl H H H OH 82 single bond OH 2-Pentenyl H H Me OH 83 single bond OH 2-Pentenyl H Me MeOH 84 Single bond OH 2-Pentenyl Me Me Me OH 85 Single bond OH 3-Pentenyl H H H OH 86 Single bond OH 3-Pentenyl H H Me OH 87 Single bond OH 3-Pentenyl H Me Me OH 88 Single bond OH 3-Pentenyl Me Me Me OH 89 Single bond OH 4-Pentenyl H H H OH 90 Single bond OH 4-Pentenyl H H Me OH 91 Single bond OH 4-Pentenyl H Me Me OH 92 Single bond OH 4-Pentenyl Me e Me OH 93 single bond OH 3-MeBu H H H OH 94 single bond OH 3-MeBu H H Me OH 95 single bond OH 3-MeBu H Me Me OH 96 single bond OH 3-MeBu Me Me Me OH 97 single bond OH 2-MeBu H H H OH 98 Single bond OH 2-MeBu H H Me OH 99 Single bond OH 2-MeBu H Me Me OH 100 Single bond OH 2-MeBu Me Me Me OH 101 Single bond OH Benzyl H H H OH 102 single bond OH Benzyl H H H F 103 single bond OH Benzyl H H H Cl 104 single bond OH Benzyl H H H Br 105 single bond OH Benzyl H H H I 106 single bond OH Benzyl H H H Me 107 single bond OH Benzyl H H H Et 108 single bond OH Benzyl H H H Pr 109 single bond OH Benzyl H H Me OH 110 single bond OH Benzyl H Me Me OH 111 single bond OH Benzyl Me H Me OH 112 single bond OH Benzyl H H Et OH 113 Single bond OH Benzyl H H Pr OH 114 Single bond OH Benzyl H H Bu OH 115 Single bond OH Benzyl H Me Et OH 116 Single bond OH Benzyl H Me Pr OH 117 Single bond OH Benzyl H Me Bu OH 118 Single bond OH Benzyl H MetBu OH 119 Single bond OH Benzyl H Et Et OH 120 Single bond OH Benzyl H Et Pr OH 121 Single bond OH Benzyl H Et Bu OH 122 Single bond OH Benzyl H Et tBu OH 123 Single bond OH Benzr H Pr 124 Pr Single bond OH Benzyl H Pr But OH 125 Single bond OH Benzyl H Pr tBu OH 126 Single bond OH Benzyl H But Bu OH 127 Single bond OH Benzyl H But But OH 128 Single bond OH Benzyl H tBu tBu OH yl 129 yl H Me OH 130 Single bond OH Benzyl Me H Et OH 131 Single bond OH Benzyl Me H Pr OH 132 Single bond OH Benzyl Me H Bu OH 133 Single bond OH Benzyl Me Me Et OH 134 Single bond OH Benzyl Me Me Pr Pr OH 135 Single bond OH Benzyl Me Me Bu Bu OH 136 Single bond OH Meu Benz Methyl Ben Bonded OH Benzyl Me Et Et OH 138 Single Bonded OH Benzyl Me Et Pr OH 139 Single Bonded OH Benzyl Me Et Et OH 140 Single Bonded OH Benzyl Me Et Et BuBu OH 141 Single Bonded OH Benzyl Me Benz Pr Pr OH 142 Single Bonded OH Benzyl Me Benz Pr Pr OH 142 Bu OH 143 Single bond OH Benzyl Me PrtBu OH 144 Single bond OH Benzyl Me Bu Bu OH 145 Single bond OH Benzyl Me But But OH 146 Single bond OH Benzyl Me Bu Benz But OH Benz benzyl OH Benz benzyl OH 2-MeBzl H H H OH 149 Single bond H 2-MeBzl H H Me OH 150 single bond OH 2-MeBzl H Me Me OH 151 single bond OH 2-MeBzl Me Me Me OH 152 single bond OH 3-MeBzl H H H OH 153 single bond OH 3-MeBzl H H Me OH 154 Single bond OH 3-MeBzl H Me Me OH 155 Single bond OH 3-MeBzl Me Me Me OH 156 Single bond OH 4-MeBzl H H H OH 157 Single bond OH 4-MeBzl H H Me OH 158 Single bond OH 4-MeBzl H Me Me OH 159 Single bond OH 4-MeBzl Me Me Me OH 161 Single bond OH 2-PhEt H H Me OH 162 Single bond OH 2-PhEt H Me Me OH 163 Single bond OH 2-PhEt Me Me Me OH 164 Single bond OH 3-PhPr H H H OH 165 Single bond OH 3-PhPr H H Me OH 166 Single bond OH 3-PhPr H Me Me OH 167 Single bond OH 3-PhPr Me Me Me OH 168 Single bond OH 3 -Ph-2-Prp H H H OH 169 Single bond O 3-Ph-2-Prp H H Me OH 170 Single bond OH 3-Ph-2-Prp H Me Me OH 171 Single bond OH 3-Ph-2-Prp Me Me Me OH 172 Single bond OH 3-PhBu H H H OH 173 Single bond OH 3-PhBu H H Me OH 174 Single bond OH 3-PhBu H Me Me OH 175 Single bond OH 3-PhBu Me Me Me OH 176 Single bond OH 4-PhBu H H H OH 177 Single bond OH 4-PhBu H H Me OH 178 Single bond OH 4-PhBu H Me Me OH 179 Single bond OH 4-PhBu Me Me Me OH 180 Double bond OH Et H H H OH 181 Double bond OH Et H H H F 182 Double bond OH Et H H H Cl 183 Double bond OH Pr H H H OH 184 Double bond OH Pr H H H F 185 Double bond OH Pr H H Me OH 186 Double bond OH Pr H Me Me OH 187 Double bond OH Pr Me Me Me OH 188 Double bond OH Allyl H H H OH 189 Double bond OH Allyl H H H F 190 Double bond OH Allyl H H H Cl 191 Double bond OH Allyl H H H Br 192 Double bond OH Allyl H H Me OH 193 Double bond OH Allyl H Me Me OH 194 Double bond OH Allyl Me Me Me OH 195 Double bond OH Bu H H H OH 196 Double bond OH Bu H H Me OH 197 Double bond OH Bu H Me Me OH 198 Double bond OH Bu Me Me Me OH 199 Double bond OH 2-Butene H H H OH 200 Double bond OH 2-Butene H H Me OH 201 Double bond OH 2-Butene H Me Me OH 202 Double bond OH 2-Butene Me Me Me OH 203 Double bond OH 3-Butene H H H OH 204 Double bond OH 1-Butene H H H OH 205 Double bond OH Prenyl Me H H OH 206 Double bond OH Prenyl H H H F 207 Double bond Union OH Prenyl H H H Cl 208 double bond OH Prenyl H H H Br 209 double bond OH Prenyl H H H I 210 double bond OH Prenyl H H H Me 211 double bond OH Prenyl H H H Et 212 double bond OH Prenyl H H H Pr 213 double bond OH Prenyl H H Me OH 214 double bond OH Prenyl H Me Me OH 215 double bond OH Prenyl Me H Me OH 216 double bond OH Prenyl H H Et OH 217 double bond OH Prenyl H H Pr OH 218 Double bond OH Prenyl H H Bu OH 219 Double bond OH Prenyl H Me Et OH 220 Double bond OH Prenyl H Me Pr OH 221 Double bond OH Prenyl H Me Bu OH 222 Double bond OH Prenyl H MetBu OH 223 Double bond OH Prenyl H Et Et OH 224 Double bond OH Prenyl H Et Pr OH 225 Double bond OH Prenyl H Et Bu OH 2 26 Double bond OH Prenyl H Et tBu OH 227 Double bond OH Prenyl H Pr Pr OH 228 Double bond OH Prenyl H Pr Bu OH 229 Double bond OH Prenyl H Pr tBu OH 230 Double bond OH Prenyl H Bu Bu OH 231 Double bond OH Prenyl H But tBu OH 232 Double bond OH Prenyl H tBu tBu OH 233 Double bond OH Prenyl Me H Me OH 234 Double bond OH Prenyl Me H Et OH 235 Double bond OH Prenyl Me H Pr OH 236 Double bond OH Prenyl Me H Bu OH 237 Double bond OH Prenyl Me Me Et OH 238 Double bond OH Prenyl Me Me Pr OH 239 Double bond OH Prenyl Me Me Bu OH 240 Double bond OH Prenyl Me MetBu 241 Double bond OH Prenyl Me Et Et OH 242 Double bond OH Prenyl Me Et Pr OH 243 Double bond Combined OH Prenyl Me Et Bu OH 244 Double bond OH Prenyl Me Et tBu OH 245 Double bond OH Prenyl Me Pr Pr OH 246 Double bond OH Prenyl Me Pr Pr OH 247 Double bond OH Prenyl Me Pr 248Bu Bond OH Prenyl Me Bu Bu OH 249 Double bond OH Prenyl Me But But OH 250 Double bond OH Prenyl Me t But t Bu OH 251 Double bond OH Prenyl Me t But t Bu OH 252 Double bond OH Pentyl H H H OH 253 Bond OH Pentyl H H Me OH 254 Double Bond OH Pentyl H Me Me OH 255 Double Bond OH Pentyl Me Me Me OH 256 Double Bond OH 1-Pentenyl H H H OH 257 Double Bond OH 1-Pentenyl H H Me OH 258 Double bond OH 1-Pentenyl H Me Me OH 259 Double bond OH 1-Pentenyl Me Me Me OH 260 Bond OH 2-Pentenyl H H H OH 261 Double bond OH 2-Pentenyl H H Me OH 262 Double bond OH 2-Pentenyl H Me Me OH 263 Double bond OH 2-Pentenyl Me Me Me OH 264 Double bond OH 3-Pentenyl H H H OH 265 double bond OH 3-Pentenyl H H Me OH 266 double bond OH 3-Pentenyl H Me Me OH 267 double bond OH 3-Pentenyl Me Me OH 268 double bond OH 4- Pentenyl H H H OH 269 Double bond OH 4-Pentenyl H H Me OH 270 Double bond OH 4-Pentenyl H Me Me OH 271 Double bond OH 4-Pentenyl Me Me OH 272 Double bond OH 3-MeBu H H H OH 273 Double bond OH 3-MeBu H H Me OH 274 Double bond OH 3-MeBu H Me Me OH 275 Double bond OH 3-MeBu Me Me Me OH 276 Double bond OH 2-MeBu H H H OH 277 Double bond OH 2-MeBu H H Me OH 278 Double bond OH 2-MeBu H Me Me OH 279 Double bond OH 2-MeBu Me Me Me OH 280 Double bond OH Benzyl H H H OH 281 Double bond OH Benzyl H H H F 282 Double bond OH Benzyl H H H Cl 283 Double bond OH Benzyl H H H Br 284 Double bond OH Benzyl H H H I 285 Double bond OH Benzyl H H H Me 286 Double bond OH Benzyl H H H Et 287 Double bond OH Benzyl H H H Pr 288 Double bond OH Benzyl H H Me OH 289 Double bond OH Benzyl H Me Me OH 290 Double bond OH Benzyl Me H Me OH 291 Double bond OH Benzyl H H Et OH 292 Double bond OH Benzyl H H Pr OH 293 Double bond OH Benzyl H H Bu OH 294 Double bond OH Benzyl H Me Et OH 295 Double bond OH Benzyl H Me Pr OH 296 Double bond OH Benzyl H Me Bu OH 297 Double bond OH Benzyl H MetBu OH 298 Double bond OH Benzyl H Et Et OH 299 Double bond OH Benzyl H Et Pr OH 300 Double bond OH Benzyl H Et Bu OH 301 Double bond OH Benzyl H Et tBu OH 302 Double bond OH Benzyl H Pr Pr OH 303 Double bond OH Benzyl H Pr Bu OH 304 Double bond OH Benzyl H Pr tBu OH 305 Double bond OH Benzyl H Bu Bu OH 306 Double bond OH Benzyl H Bu tBu OH 307 Double bond OH Benzyl H tBu tBu OH 308 Double bond OH Benzyl Me H Me OH 309 Double bond OH Benzyl Me H Et OH 310 Double bond OH Benzyl Me H Pr OH 311 Double bond OH Benzyl Me H Bu OH 312 Double bond OH Benzyl Me Me Et OH 313 Double bond OH Benzyl Me Me Pr OH 314 N OH Benzyl Me Me Bu OH 315 Double Bond OH Benzyl Me MetBu OH 316 Double Bond OH Benzyl Me Et Et OH 317 Double Bond OH Benzyl Me Et Et Pr OH 318 Double Bond OH Benz Benz E Me Bond OH Benzyl Me Et tBu OH 320 Double bond OH Benzyl Me Pr Pr OH 321 Double bond OH Benzyl Me Pr Pr OH 322 Double bond OH Benzyl Me Pr PtBu OH 323 Double bond OH BenzuBu Mu bu BenzylBu Meu Bond OH Benzyl Me But But OH 325 Double Bond OH Benzyl Me But But t Bu OH 326 Double Bond OH Benzyl Met But tBu OH 327 Double Bond OH 2-MeBzl H H H OH 328 Double Bond OH 2-MeBzl H H OH 329 Double bond OH 2-MeBzl H Me Me OH 330 Double bond OH 2-MeBzl Me Me Me O H 331 Double bond OH 3-MeBzl H H H OH 332 Double bond OH 3-MeBzl H H Me OH 333 Double bond OH 3-MeBzl H Me Me OH 334 Double bond OH 3-MeBzl Me Me Me OH 335 Double bond OH 4-MeBzl H H H OH 336 Double bond OH 4-MeBzl H H Me OH 337 Double bond OH 4-MeBzl H Me Me OH 338 Double bond OH 4-MeBzl Me Me Me OH 339 Double Bond OH 2-PhEt H H H OH 340 Double bond OH 2-PhEt H H Me OH 341 Double bond OH 2-PhEt H Me Me OH 342 Double bond OH 2-PhEt Me Me Me OH 343 Double bond OH 3-PhPr H H H OH 344 double bond OH 3-PhPr H H Me OH 345 double bond OH 3-PhPr H Me Me OH 346 double bond OH 3-PhPr Me Me Me OH 347 double bond OH 3- Ph-2-Prp H H H OH 348 Double bond OH 3-Ph-2-Prp H H MeOH 349 Heavy bond OH 3-Ph2-Prp H Me Me OH 350 Double bond OH 3-Ph2-Prp Me Me Me OH 351 Double bond OH 3-PhBu H H H OH 352 Double bond OH 3-PhBu H H Me OH 353 Double bond OH 3-PhBu H Me Me OH 354 Double bond OH 3-PhBu Me Me Me OH 355 Double bond OH 4-PhBu H H H OH 356 Double bond OH 4-PhBu H H Me OH 357 II Heavy bond OH 4-PhBu H Me Me OH 358 Double bond OH 4-PhBu Me Me Me OH ───────────────────────────── ───

[0025]

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[0026]

[Table 2] X = CH ₂ compound ─────────────────────────────── No. ---- R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ ─────────────────────────────── 359 Single bond OH Et H H H OH 360 Single bond OH Et H H H F 361 Single bond OH Et H H H Cl 362 Single bond OH Pr H H H OH 363 Single bond OH Pr H H H F 364 Single bond OH Pr H H Me OH 365 Single bond OH Pr H Me Me OH 366 Single bond OH Pr Me Me Me OH 367 Single bond OH Allyl H H H OH 368 Single bond OH Allyl H H H F F 369 Single bond OH Allyl H H H Cl 370 Single bond OH Allyl H H H Br 371 Single bond Bonded OH Allyl H H Me OH 372 Single bond OH Allyl H Me Me OH 373 Single bond OH Allyl Me Me Me OH 37 4 Single bond OH Bu H H H OH 375 Single bond OH Bu H H Me OH 376 Single bond OH Bu H Me Me OH 377 Single bond OH Bu Me Me Me OH 378 Single bond OH 2-Butene H H H OH 379 Single bond OH 2-Butene H H Me OH 380 single bond OH 2-Butene H Me Me OH 381 single bond OH 2-Butene Me Me Me OH 382 single bond OH 3-Butene H H H OH 383 single bond OH 1-Butene H H H OH 384 Single bond OH Prenyl H H H OH 385 Single bond OH Prenyl H H H F 386 Single bond OH Prenyl H H H Cl 387 Single bond OH Prenyl H H H Br 388 Single bond OH Prenyl H H H I 389 Single bond OH Prenyl H H H Me 390 Single bond OH Prenyl H H H Et 391 Single bond OH Prenyl H H H Pr 392 Single bond OH Prenyl H H Me OH 393 Single bond OH Prenyl H Me Me OH 394 Single bond OH Prenyl Me H H OH 395 Single bond OH Prenyl H H Et OH 396 Single bond OH Prenyl H H Pr OH 397 Single bond OH Prenyl H H Bu OH 398 Single bond OH Prenyl H Me Et OH 399 Single bond OH Prenyl H Me Pr OH 400 Single bond OH Prenyl H Me Bu OH 401 Single bond OH Prenyl H MetBu OH 402 Single bond OH Prenyl H Et Et OH 403 Single bond OH Prenyl H Et Pr OH 404 Single bond OH Prenyl H Et Bu OH 405 OH Prenyl H Et tBu OH 406 Single bond OH Prenyl H Pr Pr OH 407 Single bond OH Prenyl H Pr Bu OH 408 Single bond OH Prenyl H Pr tBu OH 409 Single bond OH Prenyl H Bu Bu OH 410 Single bond OH Prenyl H Buenyl H 411 Single bond OH Prenyl H tBu tBu OH 412 Single bond OH Prenyl Me H Me O 413 Single bond OH Prenyl Me H Et OH 414 Single bond OH Prenyl Me H Pr OH 415 Single bond OH Prenyl Me H Bu OH 416 Single bond OH Prenyl Me Me Et OH 417 Single bond OH Prenyl Me Me Pr Pr OH 418 Me Me Bu OH 419 Single bond OH Prenyl Me MetBu OH 420 Single bond OH Prenyl Me Et Et OH 421 Single bond OH Prenyl Me Et Pr OH 422 Single bond OH Prenyl Me Et Bu But OH Pr Pr enyl Single bond OH Prenyl Me Et Et OH 421 Single bond OH Prenyl Single bond OH Prenyl Me Pr Pr OH 425 Single bond OH Prenyl Me Pr Pr OH 426 Single bond OH Prenyl Me Pr tBu OH 427 Single bond OH Prenyl Me But Bu OH 428 Single bond OH Prenyl Me Bu OH But 428 tBu tBu OH 430 Single bond OH Prenyl Me ButtBu OH 431 Single bond OH Pentyl H H H OH 432 Single bond OH Pentyl H H Me OH 433 Single bond OH Pentyl H Me Me OH 434 Single bond OH Pentyl Me Me Me OH 435 Single bond OH 1-Pentenyl H H H OH 436 Single bond OH 1-Pentenyl H H Me OH 437 Single bond OH 1-Pentenyl H Me Me OH 438 Single bond OH 1-Pentenyl Me Me Me OH 439 Single bond OH 2-Pentenyl H H H OH 440 Single bond OH 2- Pentenyl H H MeOH 441 Single bond OH 2-Pentenyl H Me Me OH 442 Single bond OH 2-Pentenyl Me Me Me OH 443 Single bond OH 3-Pentenyl H H H OH 444 Single bond OH 3-Pentenyl H H Me OH 445 Single bond OH 3-Pentenyl H Me Me OH 446 Single bond OH 3-Pentenyl Me Me Me OH 447 Single bond OH 4-Pentenyl H H H OH 448 Single bond OH 4-Pentenyl H H Me O 449 Single bond OH 4-Pentenyl H Me Me OH 450 Single bond OH 4-Pentenyl Me Me Me OH 451 Single bond OH 3-MeBu H H H OH 452 Single bond OH 3-MeBu H H Me OH 453 Single bond OH 3- MeBu H Me Me OH 454 Single bond OH 3-MeBu Me Me Me OH 455 Single bond OH 2-MeBu H H H OH 456 Single bond OH 2-MeBu H H Me OH 457 Single bond OH 2-MeBu H Me Me OH 458 Single bond OH 2-MeBu Me Me Me OH 459 Single bond OH Benzyl H H H OH 461 Single bond OH Benzyl H H H Cl 462 Single bond OH Benzyl H H H Br 463 Single bond OH Benzyl H H H I 464 Single bond OH Benzyl H H H Me 465 Single bond OH Benzyl H H H Et 466 Single bond OH Benzyl H H H Pr 467 Single bond OH Benzyl H H Me OH 468 Single bond OH Benzyl H Me Me OH 469 Single bond OH Benzyl Me H e OH 470 Single bond OH Benzyl H H Et OH 471 Single bond OH Benzyl H H Pr OH 472 Single bond OH Benzyl H H Bu OH 473 Single bond OH Benzyl H Me Et OH 474 Single bond OH Benzyl H Me Pr Pr 475 475 OH Benzyl H Me Bu OH 476 single bond OH Benzyl H MetBu OH 477 single bond OH Benzyl H Et Et OH 478 single bond OH Benzyl H Et Pr OH 479 single bond OH Benzyl H Et Bu OH Bt OH benzyl single bond OH 481 Single bond OH Benzyl H Pr Pr OH 482 Single bond OH Benzyl H Pr Bu OH 483 Single bond OH Benzyl H Pr tBu OH 484 Single bond OH Benzyl H Butu OH 485 485 Single bond OH Benzyl H OH But 486 Benzyl H tBu tBu OH 487 Single bond OH Benzyl Me H Me OH 488 Single bond OH Ben zyl Me H Et OH 489 single bond OH Benzyl Me H Pr OH 490 single bond OH Benzyl Me H Bu OH 491 single bond OH Benzyl Me Me Et OH 492 single bond OH Benzyl Me Me Pr Pr OH 493yl single bond 494 Single bond OH Benzyl Me MetBu OH 495 Single bond OH Benzyl Me Et Et OH 496 Single bond OH Benzyl Me Et Pr OH 497 Single bond OH Benzyl Meyl Et Bu Bu OH 498 Single bond Benz But OH Et Benzoyl Me Pr Pr OH 500 Single bond OH Benzyl Me Pr Pr OH 501 Single bond OH Benzyl Me Pr TtBu OH 502 Single bond OH Benzyl Me Bu Bu OH 503 505 Single bond OH Benzyl Me But But Bu But OH Benzyl Single bond OH Benzyl Me tBu tBu OH 5 06 Single bond OH 2-MeBzl H H OH 507 Single bond OH 2-MeBzl H H Me OH 508 Single bond OH 2-MeBzl H Me Me OH 509 Single bond OH 2-MeBzl Me Me Me OH 510 Single bond OH 3- MeBzl H H H OH 511 single bond OH 3-MeBzl H H Me OH 512 single bond OH 3-MeBzl H Me Me OH 513 single bond OH 3-MeBzl Me Me Me OH 514 single bond OH 4-MeBzl H H H OH 515 Single bond OH 4-MeBzl H H Me OH 516 Single bond OH 4-MeBzl H Me Me OH 517 Single bond OH 4-MeBzl Me Me Me OH 519 Single bond OH 2-PhEt H H Me OH 520 Single bond OH 2-PhEt H Me Me OH 521 Single bond OH 2-PhEt Me Me Me OH 522 Single bond OH 3-PhPr H H H OH 523 Single bond OH 3-PhPr H H Me OH 524 Single bond OH 3-PhPr H Me Me OH 525 Single Bonding OH 3-PhPr Me Me Me OH 526 Bonded OH 3-Ph-2-Prp H H H OH 527 Single bond OH 3-Ph-2-Prp H H Me OH 528 Single bond OH 3-Ph-2-Prp H Me Me OH 529 Single bond OH 3-Ph2 -Prp Me Me Me OH 530 Single bond OH 3-PhBu H H H OH 531 Single bond OH 3-PhBu H H Me OH 532 Single bond OH 3-PhBu H Me Me OH 533 Single bond OH 3-PhBu Me Me OH 534 Single bond OH 4-PhBu H H H OH 535 Single bond OH 4-PhBu H H Me OH 536 Single bond OH 4-PhBu H Me Me OH 537 Single bond OH 4-PhBu Me Me Me OH ───── ────────────────────────────

[0027]

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[0028]

[Table 3] X = O compound ─────────────────────────────── No. ---- R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ ─────────────────────────────── 538 Single bond H Et H H H OH 539 Single Combined H Et H H H F 540 Single bond H Et H H H Cl 541 Single bond H Pr H H H OH 542 Single bond H Pr H H H F 543 Single bond H Pr H H Me OH 544 Single bond H Pr H Me Me OH 545 Single bond H Pr Me Me Me OH 546 Single bond H Allyl H H H OH 547 Single bond H Allyl H H H F 548 Single bond H Allyl H H H Cl 549 Single bond H Allyl H H H Br 550 Single bond H Allyl H H Me OH 551 Single bond H Allyl H Me Me OH 552 Single bond H Allyl Me Me Me OH 553 Single bond H Bu H H H OH 554 Single bond Bonded H Bu H H Me OH 555 Single bond H Bu H Me Me OH 556 Single bond H Bu Me Me Me OH 557 Single bond H 2-Butene H H H OH 558 Single bond H 2-Butene H H Me OH 559 Single bond H 2-Butene H Me Me OH 560 Single bond H 2-Butene Me Me Me OH 561 Single bond H 3-Butene H H H OH 562 Single bond H 1-Butene H H H OH 563 Single bond H Prenyl H H H OH 564 Single bond H Prenyl H H H F 565 Single bond H Prenyl H H H Cl 566 Single bond H Prenyl H H H Br 567 Single bond H Prenyl H H H I 568 Single bond H Prenyl H H H Me 569 Single bond H Prenyl H H H Et 570 Single bond H Prenyl H H H Pr 571 Single bond H Prenyl H H Me OH 572 Single bond H Prenyl H Me Me OH 573 Single bond H Prenyl Me H Me OH 574 Single bond H Prenyl H H Et OH 575 Single bond H Preny l H H Pr OH 576 single bond H Prenyl H H Bu OH 577 single bond H Prenyl H Me Et OH 578 single bond H Prenyl H Me Pr OH 579 single bond H Prenyl H Me Bu OH 580 single bond H Prenyl H MetBu OH 581 single bond H Prenyl H Et Et OH 582 single bond H Prenyl H Et Pr OH 583 single bond H Prenyl H Et Bu OH 584 single bond H Prenyl H Et tBu OH 585 single bond H Prenyl H Pr Pr OH 586 single bond H Prenyl HPrBu OH 587 Single bond H Prenyl H Prt Bu OH 588 Single bond H Prenyl H But Bu OH 589 Single bond H Prenyl H But Bu OH 590 Single bond H Prenyl H tBu tBu OH 591 Single bond H Prenyl Me H Me 592 Single bond H Prenyl Me H Et OH 593 Single bond H Prenyl Me H Pr OH 594 Single bond H Prenyl Me H Bu OH 595 Single bond H Prenyl Me Me Et OH 596 single bond H Prenyl Me Me Pr OH 597 single bond H Prenyl Me Me Bu OH 598 single bond H Prenyl Me MetBu OH 599 single bond H Prenyl Me Et Et OH 600M single bond H Prenyl OH 601 Single bond H Prenyl Me Et Bu OH 602 Single bond H Prenyl Me Et tBu OH 603 Single bond H Prenyl Me Pr Pr OH 604 Single bond H Prenyl Me Pr Pr OH 605 Single bond H Prenyl Me H Pr 606 Prenyl Me Bu But OH 607 single bond H Prenyl Me But But OH 608 single bond H Prenyl Me t But But Bu OH 609 single bond H Prenyl Me t But t Bu OH 610 single bond H Pentyl H H H OH 611 H single bond H Pentyl H 612 Single bond H Pentyl H Me Me OH 613 Single bond H Pentyl Me Me Me O 614 single bond H 1-Pentenyl H H H OH 615 single bond H 1-Pentenyl H H Me OH 616 single bond H 1-Pentenyl H Me Me OH 617 single bond H 1-Pentenyl Me Me Me OH 618 single bond H 2- Pentenyl H H H OH 619 Single bond H 2-Pentenyl H H Me OH 620 Single bond H 2-Pentenyl H Me Me OH 621 Single bond H 2-Pentenyl Me Me Me OH 622 Single bond H 3-Pentenyl H H H OH 623 Single bond H 3-Pentenyl H H MeOH 624 Single bond H 3-Pentenyl H Me Me OH 625 Single bond H 3-Pentenyl Me Me Me OH 626 Single bond H 4-Pentenyl H H H OH 627 Single bond H 4-Pentenyl H H MeOH 628 Single bond H 4-Pentenyl H Me Me OH 629 Single bond H 4-Pentenyl Me Me Me OH 630 Single bond H 3-MeBu H H H OH 631 Single bond H 3-MeBu H H Me OH 632 Single Bonded H 3-MeBu H Me Me OH 633 Single bond H 3-MeBu Me Me Me OH 634 Single bond H 2-MeBu H H H OH 635 Single bond H 2-MeBu H H Me OH 636 Single bond H 2-MeBu H Me Me OH 637 Single bond H 2-MeBu Me Me Me OH 638 Single bond H Benzyl H H H OH 639 Single bond H Benzyl H H HF F 640 Single bond H Benzyl H H H Cl 641 Single bond H Benzyl H H H Br 642 Single bond H Benzyl H H H I 643 Single bond H Benzyl H H H Me 644 single bond H Benzyl H H H Et 645 single bond H Benzyl H H H Pr 646 single bond H Benzyl H H Me OH 647 single bond H Benzyl H Me Me OH 648 single bond H Benzyl Me H MeOH 649 Single bond H Benzyl H H Et OH 650 Single bond H Benzyl H H Pr OH 651 Single bond H Benzyl H H Bu OH 652 Single bond H Benzyl H Me Et OH 653 Single bond H Benzyl H Me Pr OH 654 Single bond H Benzyl H Me Bu OH 655 Single bond H Benzyl H MetBu OH 656 Single bond H Benzyl H Et Et OH 657 Single bond H Benzyl H Et Pr OH 658 Single bond H Benzyl H Et Bu OH 659 Single bond H Benzyl H Et 660 Bu OH bond H Benzyl H Pr Pr OH 661 Single bond H Benzyl H Pr Bu OH 662 Single bond H Benzyl H Pr tBu OH 663 Single bond H Benzyl H Bu Bu OH 664 Single bond H Benzyl H But Bu OH 665 B u B H Benzyl OH 666 Single bond H Benzyl Me H Me OH 667 Single bond H Benzyl Me H Et OH 668 Single bond H Benzyl Me H Pr OH 669 Single bond H Benzyl Me H Bu OH 670 Single bond H Benzyl Me Me Me Et HOH 671 Benzyl Me Me Pr OH 672 Single bond H Benzyl Me Me Bu OH 673 Single bond H Benzyl Me MetBu OH 674 Single bond H Benzyl Me Et Et OH 675 Single bond H Benzyl Me Et Pr OH 676 Single bond H Benzyl Me Et Et Bu OH 677 Single bond H Benzyl Me Et Et Bu OH 678 Single bond H Benzyl Me Hyl Pr Pr 679 Pr Bu OH 680 single bond H Benzyl Me Pr tBu OH 681 single bond H Benzyl Me Bu Bu OH 682 single bond H Benzyl Me But But OH 683 single bond H Benzyl Me tBu tBu But HOH Benzyl 684 Bond H 2-MeBzl H H H OH 686 Single bond H 2-MeBzl H H Me OH 687 Single bond H 2-MeBzl H Me Me OH 688 Single bond H 2-MeBzl Me Me Me OH 689 Single bond H 3-MeBzl H H H OH 690 Single bond H 3-MeBzl H H Me OH 691 Single bond H 3-MeBzl H Me Me OH 692 Single bond H 3-MeBzl Me Me Me OH 693 Single bond H 4-MeBzl H H H OH 694 Single bond H 4-MeBzl H H Me OH 695 Single bond H 4-MeBzl H Me Me OH 696 Single bond H 4-MeBzl Me Me Me OH 697 Single bond H 2-PhEt H H H OH 698 Single bond H 2-PhEt H H Me OH 699 Single bond H 2-PhEt H Me Me OH 700 Single bond H 2-PhEt Me Me Me Me OH 701 Single bond H 3-PhPr H H H OH 702 Single Bonded H 3-PhPr H H MeOH 703 Single bond H 3-PhPr H Me Me OH 704 Single bond H 3-PhPr Me Me Me OH 706 Single bond H 3-Ph-2-Prp H H Me OH 707 Single bond H 3-Ph-2-Prp H Me Me OH 708 single bond H 3-Ph-2-Prp Me Me Me OH 709 single bond H 3-PhBu H H H OH 710 single bond H 3-PhBu H H Me OH 711 single bond Bonded H 3-PhBu H Me MeOH 712 Single bond H 3-PhBu Me Me Me OH 713 Single bond H 4-PhBu H H H OH 714 Single bond H 4-PhBu H H MeOH 715 single bond H 4-PhBu H Me Me OH 716 single bond H 4-PhBu Me Me Me OH 717 double bond H Et H H H OH 718 double bond H Et H H H F 719 Double bond H Et H H H Cl 720 Double bond H Pr H H H OH 721 Double bond H Pr H H H F 722 Double bond H Pr H H Me OH 723 Double bond H Pr H Me Me OH 724 Double bond H Pr Me Me Me OH 725 Double bond H Allyl H H H OH 726 Double bond H Allyl H H H F 727 Double bond H Allyl H H H Cl 728 Double bond H Allyl H H H Br 729 Double bond H Allyl H H Me OH 730 Double bond H Allyl H Me Me OH 731 Double bond H Allyl Me Me Me OH 732 Double bond H Bu H H H OH 733 Double bond H Bu H H Me OH 734 Double bond H Bu H Me Me OH 735 Double bond H Bu Me Me Me OH 736 Double bond H 2-Butene H H H OH 737 Double bond H 2-Butene H H Me OH 738 Double bond H 2-Butene H Me Me OH 739 Double Bond H 2-Butene Me Me Me OH 740 Double bond H 3-Butene H H H OH 741 Double bond H 1-Butene H H H OH 742 Double bond H Prenyl H H H OH 743 Double bond H Prenyl H H HF 744 Double bond H Prenyl H H H Cl 745 Double bond H Prenyl H H H Br 746 Double bond H Prenyl H H HI 747 Double bond H Prenyl H H H Me 748 Double bond H Prenyl H H H Et 749 double bond H Prenyl H H H Pr 750 double bond H Prenyl H H Me OH 751 double bond H Prenyl H Me Me OH 752 double bond H Prenyl Me H Me OH 753 double bond H Prenyl H H Et OH 754 Double bond H Prenyl H H Pr O 755 Double bond H Prenyl H H Bu OH 756 Double bond H Prenyl H Me Et OH 757 Double bond H Prenyl H Me Pr OH 758 Double bond H Prenyl H Me Bu OH 759 Double bond H Prenyl H MetBu OH 760 Double bond H Prenyl H Et Et OH 761 Double bond H Prenyl H Et Pr OH 762 Double bond H Prenyl H Et Bu OH 764 Double bond H Prenyl H Pr Pr OH 765 Double bond H Prenyl H Pr Bu OH 766 Double bond H Prenyl H Pr tBu OH 767 Double bond H Prenyl H But Bu OH 768 Double bond H Prenyl H But Bu OH 769 Double bond H Prenyl H tBu tBu OH 770 Double bond H Prenyl Me H Me OH 771 double bond H Prenyl Me H Et OH 772 double bond H Prenyl Me H Pr OH 773 double bond H Prenyl Me H Bu OH 774 double bond H Prenyl M Me Et OH 775 Double bond H Prenyl Me Me Pr OH 776 Double bond H Prenyl Me Me Bu OH 777 Double bond H Prenyl Me MetBu OH 778 Double bond H Prenyl Me Et Et OH 779 Double bond H Prenyl Me Et Pr OH 780 Double bond H Prenyl Me Et Bu OH 781 Double bond H Prenyl Me Et tBu OH 782 Double bond H Prenyl Me Pr Pr OH 783 Double bond H Prenyl Me Pr Pr Bu OH 784 Double bond H Prenyl Me PrtBu OH 785 Double bond H Prenyl Me Bu Bu OH 786 Double bond H Prenyl Me But But OH 787 Double bond H Prenyl Me ButBu OH 788 Double bond H Prenyl Me tBu Bu 789 H Double Pen Htylyl H H OH 790 Double bond H Pentyl H H Me OH 791 Double bond H Pentyl H Me Me OH 792 Double bond Pentyl Me Me Me OH 793 Double bond H 1-Pentenyl H H H OH 794 Double bond H 1-Pentenyl H H Me OH 795 Double bond H 1-Pentenyl H Me Me OH 796 Double bond H 1-Pentenyl Me Me Me OH 797 Double bond H 2-Pentenyl H H H OH 798 Double bond H 2-Pentenyl H H Me OH 799 Double bond H 2-Pentenyl H Me Me OH 800 Double bond H 2-Pentenyl Me Me Me OH 801 Double bond H 3-Pentenyl H H H OH 802 Double bond H 3-Pentenyl H H Me OH 803 Double bond H 3-Pentenyl H Me Me OH 804 Double bond H 3-Pentenyl Me Me Me OH 805 Double bond H 4-Pentenyl H H H OH 806 Double bond H 4-Pentenyl H H Me OH 807 Double bond H 4-Pentenyl H Me Me OH 808 Double bond H 4-Pentenyl Me Me Me OH 809 Double Bonded H 3-MeBu H H H OH 810 Double bond H 3-MeBu H H MeOH 811 double bond H 3-MeBu H Me Me OH 812 double bond H 3-MeBu Me Me Me OH 813 double bond H 2-MeBu H H H OH 814 double bond H 2-MeBu H H Me OH 815 double bond H 2-MeBu H Me Me OH 816 double bond H 2-MeBu Me Me Me OH 817 double bond H Benzyl H H H OH 818 double bond H Benzyl H H H F 819 double bond H Benzyl H H H Cl 820 Double bond H Benzyl H H H Br 821 Double bond H Benzyl H H H I 822 Double bond H Benzyl H H H Me 823 Double bond H Benzyl H H H Et 824 Double bond H Benzyl H H H Pr 825 double bond H Benzyl H H Me OH 826 double bond H Benzyl H Me Me OH 827 double bond H Benzyl Me H Me OH 828 double bond H Benzyl H H Et OH 829 double bond H Benzyl H H Pr OH 830 Double bond H Benzyl H H Bu OH 831 double bond H Benzyl H Me Et OH 832 double bond H Benzyl H Me Pr OH 833 double bond H Benzyl H Me Bu OH 834 double bond H Benzyl H MetBu OH 835 double bond H Benzyl H Et Et OH 836 double bond H Benzyl H Et Pr OH 837 double bond H Benzyl H Et Bu OH 838 double bond H Benzyl H Et tBu OH 839 double bond H Benzyl H Pr Pr OH 840 double bond H Benzyl H Pr Bu OH 841 Double bond H Benzyl H Pr tBu OH 842 Double bond H Benzyl H But Bu OH 843 Double bond H Benzyl H But But OH 844 Double bond H Benzyl H tBu tBu OH 845 Double bond H Benzyl Me H Me OH 846 Double bond H Benzyl Me H Et OH 847 Double bond H Benzyl Me H Pr OH 848 Double bond H Benzyl Me H Bu OH 849 Double bond H Benzyl Me Me Et OH 851 double bond H Benzyl Me Me Bu OH 852 double bond H Benzyl Me MetBu OH 853 double bond H Benzyl Me Et Et OH 854 double bond H Benzyl Me Et Et OH double bond H Benzyl Me Et Bu OH 856 Double bond H Benzyl Me Et tBu OH 857 Double bond H Benzyl Me Pr Pr OH 858 Double bond H Benzyl Me Pr Pr OH 859 Double bond H Benzyl Me Pr Pr OH Bu bond H Benzyl Me Bu But OH 861 Double bond H Benzyl Me But But OH 862 Double bond H Benzyl Me But But t Bu OH 863 Double bond H Benzyl Met But t Bu OH 864 Double bond H 2-MeBzl H 2 H H OH Heavy bond H 2-MeBzl H H MeOH 866 Double bond H 2-MeBzl H Me Me OH 867 Double bond H 2-MeBzl Me Me Me O H 868 double bond H 3-MeBzl H H H OH 869 double bond H 3-MeBzl H H MeOH 870 double bond H 3-MeBzl H Me MeOH 871 double bond H 3-MeBzl Me Me Me OH 872 Double bond H 4-MeBzl H H H OH 873 Double bond H 4-MeBzl H H Me OH 874 Double bond H 4-MeBzl H Me Me OH 875 Double bond H 4-MeBzl Me Me Me OH 876 Double Bond H 2-PhEt H H H OH 877 Double bond H 2-PhEt H H MeOH 878 Double bond H 2-PhEt H Me Me OH 880 Double bond H 3-PhPr H H H OH 881 Double bond H 3-PhPr H H Me OH 882 double bond H 3-PhPr H Me Me OH 883 double bond H 3-PhPr Me Me Me OH 884 double bond H 3-Ph-2-Prp H H H OH 885 double bond Bonded H 3-Ph-2-Prp H H MeOH 886 Double bond H 3-Ph-2-Prp H Me Me OH 887 Double bond H 3-Ph-2-Prp Me Me Me O 888 Double bond H 3-PhBu H H H OH 889 Double bond H 3-PhBu H H MeOH 890 Double bond H 3-PhBu H Me Me OH 891 Double bond H 3-PhBu Me Me Me OH 892 Two Heavy bond H 4-PhBu H H H OH 893 Double bond H 4-PhBu H H Me OH 894 Double bond H 4-PhBu H Me Me OH 895 Double bond H 4-PhBu Me Me OH ──── ────────────────────────────

[0029]

[Chemical 6]

[0030]

[Table 4] X = CH ₂ compounds ─────────────────────────────── No. ---- R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ ─────────────────────────────── 896 Single bond H Et H H H OH 897 Single bond H Et H H H F 898 Single bond H Et H H H Cl 899 Single bond H Pr H H H OH 900 Single bond H Pr H H H F 901 Single bond H Pr H H Me OH 902 Single bond H Pr H Me Me OH 903 Single bond H Pr Pr Me Me Me OH 904 Single bond H Allyl H H H OH 905 Single bond H Allyl H H H F 906 Single bond H Allyl H H H Cl 907 Single bond H Allyl H H H Br 908 Single bond Combined H Allyl H H Me OH 909 Single bond H Allyl H Me Me OH 910 Single bond H Allyl Me Me Me OH 911 Single bond H Bu H H H OH 912 Single bond H Bu H H Me OH 913 Single bond H Bu H Me Me OH 914 Single bond H Bu Me Me Me OH 915 Single bond H 2-Butene H H H OH 916 Single bond H 2-Butene H H Me OH 917 Single Bond H 2-Butene H Me Me OH 918 Single bond H 2-Butene Me Me Me OH 919 Single bond H 3-Butene H H H OH 920 Single bond H 1-Butene H H H OH 921 Single bond H Prenyl H H H OH 922 Single bond H Prenyl H H H F 923 Single bond H Prenyl H H H Cl 924 Single bond H Prenyl H H H Br 925 Single bond H Prenyl H H H I 926 Single bond H Prenyl H H H Me 927 Single bond H Prenyl H H H Et 928 single bond H Prenyl H H H Pr 929 single bond H Prenyl H H Me OH 930 single bond H Prenyl H Me Me OH 931 single bond H Prenyl Me H Me OH 932 single bond H Prenyl H H Et OH 933 Single bond HP renyl H H Pr OH 934 single bond H Prenyl H H Bu OH 935 single bond H Prenyl H Me Et OH 936 single bond H Prenyl H Me Pr OH 937 single bond H Prenyl H Me Bu OH 938 single bond H Prenyl H MetBu OH 939 Single bond H Prenyl H Et Et OH 940 Single bond H Prenyl H Et Pr OH 941 Single bond H Prenyl H Et Bu OH 942 Single bond H Prenyl H Et tBu OH 943 Single bond H Prenyl H Pr Pr OH 944 Single bond H Prenyl HPrBu OH 945 Single bond H Prenyl H PrtBu OH 946 Single bond H Prenyl H Butu OH 947 Single bond H Prenyl H ButtBu OH 948 Single bond H Prenyl H tBu tBu OH 949 Single bond H Prenyl Me H 950 Me Single bond H Prenyl Me H Et OH 952 Single bond H Prenyl Me H Bu OH 953 Single bond H Prenyl Me Me Et OH 954 Single bond H Prenyl Me Me Pr OH 955 Single bond H Prenyl Me Me Bu OH 956 Single bond H Prenyl Me MetBu OH 957 Single bond H Prenyl Me Et Et OH 958 Single bond H Prenyl Me Et Pr Pr OH 959 Et Bu OH 960 single bond H Prenyl Me Et PrBu OH 961 single bond H Prenyl Me Pr Pr OH 962 single bond H Prenyl Me Pr Pr OH 963 single bond H Prenyl Me Pr Pr Bu OH 964 single OH B Prenyl Me Bonded H Prenyl Me ButBu OH 966 Single bond H Prenyl MetBu tBu OH 967 Single bond H Prenyl MetBu tBu OH 968 Single bond H Pentyl H H H OH 969 Single bond H Pentyl H H Me Me OH 970 M Single bond H Pentyl H MeOH 971 Single bond H Pentyl Me Me Me OH 972 Single bond H 1-Pentenyl H H H O H 973 Single bond H 1-Pentenyl H H MeOH 974 Single bond H 1-Pentenyl H Me Me OH 975 Single bond H 1-Pentenyl Me Me Me OH 976 Single bond H 2-Pentenyl H H H OH 977 Single bond H 2 -Pentenyl H H Me OH 978 single bond H 2-Pentenyl H Me Me OH 979 single bond H 2-Pentenyl Me Me Me OH 981 single bond H 3-Pentenyl H H Me OH 982 single bond H 3-Pentenyl H Me Me OH 983 Single bond H 3-Pentenyl Me Me Me OH 984 Single bond H 4-Pentenyl H H H OH 985 Single bond H 4-Pentenyl H H Me OH 986 Single bond H 4-Pentenyl H Me Me OH 987 Single bond H 4- Pentenyl Me Me Me OH 988 Single bond H 3-MeBu H H H OH 989 Single bond H 3-MeBu H H Me OH 990 Single bond H 3-MeBu H Me Me OH 991 Single bond H 3-MeBu Me Me OH 992 Single bond H 2-MeBu H H H OH 993 Single bond H 2-MeBu H H MeOH 994 single bond H 2-MeBu H Me Me OH 995 single bond H 2-MeBu Me Me Me OH 996 single bond H Benzyl H H H OH 997 single bond H Benzyl H H H F 998 single bond Single bond H Benzyl H H H Cl 999 Single bond H Benzyl H H H Br 1000 Single bond H Benzyl H H H I 1001 Single bond H Benzyl H H H Me 1002 Single bond H Benzyl H H H Et 1003 Single bond H Benzyl H H H Pr 1004 single bond H Benzyl H H Me OH 1005 single bond H Benzyl H Me Me OH 1006 single bond H Benzyl Me H Me OH 1007 single bond H Benzyl H H Et OH 1008 single bond H Benzyl H H Pr OH 1009 single bond H Benzyl H H Bu OH 1010 Single bond H Benzyl H Me Et OH 1011 Single bond H Benzyl H Me Pr OH 1012 Single bond H Benzyl H Me Bu OH 1013 Single bond H Benzyl H MetBu OH 1014 Single bond H Benzyl H Et Et OH 1015 Single bond H Benzyl H Et Pr OH 1016 Single bond H Benzyl H Et Bu OH 1017 Single bond H Benzyl H Et tBu OH 1018 Single bond H Benzyl H Pr Pr Pr OH 1019 Single bond H Benzyl H OH 1020 single bond H Benzyl H Pr tBu OH 1021 single bond H Benzyl H But Bu OH 1022 single bond H Benzyl H But But OH 1023 single bond H Benzyl H tButBu OH 1024 single bond H Benzyl Me H 25 Me OH bond Benzyl Me H Et OH 1026 single bond H Benzyl Me H Pr OH 1027 single bond H Benzyl Me H Bu OH 1028 single bond H Benzyl Me Me Et OH 1029 single bond H Benzyl Me Me Pr OH 1030 M single bond H Benzyl 1031 Single bond H Benzyl Me MetBu OH 1032 Single bond H Benzyl Me Et Et OH 1033 Single bond Combined H Benzyl Me Et Pr OH 1034 single bond H Benzyl Me Et Et OH 1035 single bond H Benzyl Me Et Et Bu OH 1036 single bond H Benzyl Me Pr Pr OH 1037 single bond H Benzyl Me Pr Pr OH 1036 single bond H Benzyl Me Pr Pr OH 1036 single bond tBu OH 1039 single bond H Benzyl Me Bu Bu OH 1040 single bond H Benzyl Me But Bu OH 1041 single bond H Benzyl Me tBu bu 1042 single bond H Benzyl Me OH tBenz Bu H OH 1043 10H single bond Single bond H 2-MeBzl H H MeOH 1045 Single bond H 2-MeBzl H Me Me OH 1046 Single bond H 2-MeBzl Me Me Me OH 1047 Single bond H 3-MeBzl H H H OH 1048 Single bond H 3-MeBzl H H MeOH 1049 Single bond H 3-MeBzl H Me Me OH 1050 Single bond H 3-MeBzl Me Me Me OH 1051 Single bond H 4-MeBzl H H H OH 1052 single bond H 4-MeBzl H H MeOH 1053 single bond H 4-MeBzl H Me Me OH 1054 single bond H 4-MeBzl Me Me Me OH 1055 single bond H 2-PhEt H H H OH 1056 single bond H 2- PhEt H H MeOH 1057 single bond H 2-PhEt H Me Me OH 1058 single bond H 2-PhEt Me Me Me OH 1059 single bond H 3-PhPr H H H OH 1060 single bond H 3-PhPr H H Me OH 1061 Single bond H 3-PhPr H Me Me OH 1062 Single bond H 3-PhPr Me Me Me OH 1063 Single bond H 3-Ph-2-Prp H H H OH 1064 Single bond H 3-Ph-2-Prp H H Me OH 1065 Single bond H 3-Ph-2-Prp H Me Me OH 1066 Single bond H 3-Ph-2-Prp Me Me OH 1068 Single bond H 3-PhBu H H Me OH 1069 Single bond H 3-PhBu H Me Me OH 1070 Single bond H 3-PhBu Me Me Me OH 1071 Single bond H 4-PhBu H H H OH 1072 Single bond H 4-PhBu H H e OH 1073 Single bond H 4-PhBu H Me Me OH 1074 Single bond H 4-PhBu Me Me Me OH ──────────────────────────── ───── Specific compounds suitable for the present invention are No. 1 in the above table,
4, 6, 9, 13, 14, 15, 16, 17, 20, 2
1, 24, 25, 26, 27, 28, 29, 31, 3
2, 34, 35, 36, 37, 38, 39, 40, 4
4, 53, 54, 55, 56, 73, 74, 77, 8
1, 82, 85, 86, 89, 90, 93, 94, 9
7, 101, 109, 111, 112, 129, 14
8, 149, 152, 153, 156, 157, 16
0, 161, 164, 165, 168, 172, 17
3, 176, 180, 181, 185, 188, 19
2, 195, 196, 199, 200, 203, 20
4, 205, 206, 207, 210, 213, 21
6, 232, 233, 234, 252, 253, 25
6, 257, 260, 264, 265, 268, 26
9, 272, 273, 276, 277, 280, 28
8, 289, 307, 327, 328, 331, 33
2, 335, 336, 339, 340, 343, 34
7, 351, 355, 359, 364, 365, 36
7, 371, 374, 375, 378, 382, 38
3, 384, 392, 393, 402, 411, 41
2, 431, 432, 435, 436, 439, 44
0, 443, 444, 447, 448, 451, 45
2, 455, 456, 459, 467, 468, 48
7, 488, 506, 507, 510, 511, 51
4, 515, 518, 519, 522, 523, 52
6,527,530,531,534,535,53
8, 541, 543, 546, 550, 553, 55
7, 563, 571, 591, 592, 610, 61
4, 615, 618, 619, 622, 623, 62
6, 627, 630, 634, 638, 646, 68
5,689,690,693,697,701,70
5, 709, 713, 717, 725, 732, 73
6, 740, 741, 742, 750, 751, 78
9, 793, 797, 801, 805, 809, 81
0, 813, 817, 825, 864, 868, 87
2, 876, 896, 899, 904, 908, 91
1, 915, 919, 920, 921, 929, 96
8, 972, 976, 980, 984, 988, 99
2,996,1004,1043,1047,105
1 and 1055.

Further preferred compounds of the present invention are Nos. 9, 26, 34, 35, 36, 53, 73 and 8 in the above table.
1, 93, 94, 101, 109, 111, 112, 1
29, 148, 149, 152, 153, 156, 15
7, 160, 161, 188, 195, 199, 20
0, 205, 213, 232, 233, 252, 26
0, 272, 273, 280, 288, 327, 33
1, 335, 339, 367, 374, 378, 38
4,392,412,431,435,439,45
1, 459, 467, 506, 510, 514, 51
8, 546, 557, 563, 571, 618, 62
2,630,634,638,646,685,68
9, 693, 742, 750, 789, 797, 81
3, 817, 825, 868, 872, 915, 92
1, 929, 976, 992, 996, 1043, 10
47 and 1051. However, the scope of the present invention is not limited to the compounds exemplified in the above table and the above preferable compounds.

The compound of the present invention can be produced, for example, by the method described below. In each scheme shown below, R ₁ to R ₆ are the same as above, and R ₁ ′ and R ₆ ′ are the same as a methoxy group or R ₇ -O- when R ₁ and R ₆ are hydroxyl groups. (R ₇ represents a hydroxyl-protecting group). When R ₁ and R ₆ are groups other than a hydroxyl group,
Each represents the same substituent as R ₁ and R ₆ .

The protective group for the hydroxyl group represented by R ₇ is not particularly limited as long as it can be used in ordinary organic reactions.
For example, an alkanoyl group which may be substituted with a lower alkoxy group such as formyl, acetyl and methoxyacetyl; a halogen atom such as benzoyl, 4-chlorobenzoyl and 4-toluoyl or a lower alkyl group may be substituted Benzoyl group; tetrahydropyran-2-yl, 4-
Tetrahydropyranyl group or tetrahydrothiopyranyl group optionally substituted by a lower alkoxy group such as methoxytetrahydropyran-2-yl, tetrahydrothiopyran-2-yl; trimethylsilyl, triethylsilyl,
lower alkylsilyl group such as tert-butyldimethylsilyl; lower alkylsilyl group optionally substituted by 1 or 2 phenyl groups such as diphenylmethylsilyl and diphenylbutylsilyl; methoxymethyl, 1,1-dimethyl
-1-Lower alkoxy-substituted lower alkyl groups such as methoxymethyl, 2-methoxyethoxymethyl, ethoxymethyl, ethoxyethyl; such as benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-cyanobenzyl, triphenylmethyl Lower alkyl, lower alkoxy, halogen,
Alternatively, an aralkyl group in which a cyano group may be substituted on the benzene ring; a lower alkylthiomethyl group such as methylthiomethyl can be used. Preferably, it has a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl and the like; a substituent on the aromatic ring such as benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethyl, triphenylmethyl and the like. An aralkyl group which may be substituted; a tetrahydropyranyl group which may be substituted with a lower alkoxy group such as tetrahydropyran-2-yl and 4-methoxytetrahydropyran-2-yl; trimethylsilyl and t-butyldimethylsilyl Lower alkylsilyl groups such as; lower alkoxy-substituted lower alkyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, 2-methoxyethoxymethyl, ethoxymethyl, ethoxyethyl; trichloroethyl, 2,2, An alkyl group which may be substituted with a halogen atom such as 2-trichloroethyl;
An alkyl group which may be substituted with a lower alkylsilyl group such as trimethylsilylmethyl and trimethylsilylethyl may be used. Of these, a methoxymethyl group can be particularly preferably used.

[0034]

[Chemical 7]

[Step 1] In this step, a compound represented by R ₂ -L (L represents a leaving group) is reacted with compound 2 in the presence of an acid or a base to obtain compound 3. . The leaving group is not particularly limited as long as it can be used in a usual reaction, and examples thereof include halogen atoms such as chlorine, bromine and iodine; alkylcarbonyloxy groups such as acetoxy and propionyloxy; chloro. Halogenated alkylcarbonyloxy groups such as acetyloxy, dichloroacetyloxy, trichloroacetyloxy, trifluoroacetyloxy; lower alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy;
(E) -2-methyl-2-aliphatic acyloxy groups such as unsaturated alkylcarbonyloxy groups such as butenoyloxy; arylcarbonyloxy groups such as benzoyloxy;
Arylcarbonyloxy groups such as 2-bromobenzoyloxy and 4-chlorobenzoyloxy; 2,4,
Lower alkylated arylcarbonyloxy groups such as 6-trimethylbenzoyloxy, 4-toluoyloxy; 4-
Lower alkoxylated arylcarbonyloxy groups such as anisoyloxy; aromatic acyloxy groups such as nitrated arylcarbonyloxy groups such as 4-nitrobenzoyloxy and 2-nitrobenzoyloxy; trihalogenomethyl such as trichloromethyloxy Oxy group; lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy group; halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy group;
An arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy can be used. More preferably, a halogen atom, a lower alkanesulfonyloxy group, a halogeno lower alkanesulfonyloxy group, or an arylsulfonyloxy group can be used.

The acid is not particularly limited as long as it can be used as an acid catalyst in a usual reaction. For example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, Or Bronsted acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, or organic acid such as trifluoromethanesulfonic acid, or zinc chloride, tin tetrachloride,
Lewis acids such as boron trichloride, boron trifluoride, boron tribromide can be used. A strong organic acid or a Lewis acid can be preferably used, and a Lewis acid can be more preferably used.

The base is not particularly limited as long as it can be used as a base in a usual reaction. For example, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, hydrogen carbonate. Alkali metal hydrogen carbonates such as potassium and lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide Inorganic bases such as alkali metal hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; mercaptan alkali such as methyl mercaptan sodium, ethyl mercaptan sodium Metals; Triethylamine, tributylamine, diisopropylethylamine, N- methylmorpholine, pyridine, 4-(N, N- dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo
[2.2.2] Octane (DABCO), 1,8-diazabicyclo [5.4.
0] Organic bases such as undec-7-ene (DBU); or organometallic bases such as butyllithium and lithium diisopropylamide can be used. In order to carry out the reaction efficiently, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, dibenzo-18-crown-6 are used.
It is also possible to add such crown ethers. Suitably, an alkali metal carbonate can be used.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene, etc. Halogenated hydrocarbons;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol , Alcohols such as methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide Amides such as, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide S; dimethyl sulfoxide, can be mentioned sulfoxides such as sulfolane. Halogenated hydrocarbons, amides, or ethers can be preferably used.

The reaction temperature is -78 ° C to 100 ° C, preferably in the range of 20 ° C to the reflux temperature of the solvent used.
Although the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually about 1 hour to 50 hours, preferably 10 hours to
It is about 30 hours.

After completion of the reaction, the target compound 3 of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are appropriately removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and after washing with water, the organic layer containing the target compound is separated. It is then obtained by drying over anhydrous magnesium sulfate or the like and then distilling off the solvent. The desired compound thus obtained can be further purified, if necessary, by a conventional method (for example, recrystallization, reprecipitation or chromatography).

[Step 2] In this step, the hydroxyl group of compound 3 is protected to obtain compound 4. When the protecting group is an acyl group, it may be represented by the general formula R ₇ -L (L represents a leaving group) or R ₇ -O-
Method of reacting R ₇ with compound 3 in the presence or absence of a base (method 1), or method of reacting R ₇ —OH with various esterifying agents and compound 3 in the presence of a base (method 2) Can be done at.

The leaving group (L) in the compound R ₇ -L used in Method 1 is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue. For example, a halogen atom such as chlorine or bromine;
An acetoxy-like acyloxy group; or a cyano group can be used, and a halogen atom or an acyloxy group can be preferably used. The base is not particularly limited as long as it is used as a base in a normal reaction, for example, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) Pyridine, N,
N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo
[2.2.2] Octane (DABCO), 1,8-diazabicyclo [5.4.
0] Organic bases such as undec-7-ene (DBU) can be used. Incidentally, 4- (N, N-dimethylamino) pyridine, 4-pyrrolidinopyridine or the like can be used in a catalytic amount in combination with other bases, and in order to carry out the reaction efficiently, benzyltriethylammonium chloride,
It is also possible to add quaternary ammonium salts such as tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like. The reaction temperature is
Usually, it is carried out in the range of -20 ° C to the reflux temperature of the solvent used, but is preferably in the range of 0 ° C to the reflux temperature of the solvent used. The reaction time varies depending on conditions such as reaction temperature, starting compound, type of base used or solvent used, etc., but is usually about 10 minutes to 3 days, preferably about 1 hour to 6 hours. is there.

Specific examples of the compound represented by the general formula R ₇ -L include aliphatic acyl halides such as acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride and the like; methoxycarbonyl chloride. And lower alkoxycarbonyl halides such as ethoxycarbonyl chloride and propoxycarbonyl chloride; arylcarbonyl halides such as benzoyl chloride and naphthoyl chloride. Specific examples of the compound represented by the general formula R ₇ —O—R ₇ include, for example, mixed acid anhydrides formed between formic acid and acetic acid; acetic anhydride, propionic anhydride, valeric anhydride, and the like. Such aliphatic carboxylic acid anhydrides can be mentioned.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; acetonitrile, isobutyro Nitriles such as nitriles; formamide,
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane can be used.

Examples of the esterifying agent in Method 2 include condensing agents; halogenated formate esters such as methyl chloroformate and ethyl chloroformate; cyanophosphoric acid diesters such as ethyl cyanophosphate. Examples of the condensing agent include N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, N-hydroxysuccinimide derivative and carbodiimide such as dicyclohexylcarbodiimide. Combination of active disulfides such as 2,2'-dipyridyl disulfide and triarylphosphines such as triphenylphosphine; N, N'-disuccinimidyl carbonate and disucciminidyl carbonate derivatives; N, N'-bis (2 -Oxo-3-oxazolidinyl) phosphinic chloride compounds such as N, N'-disuccimidyl oxalate (D
SO), N, N'-diphthalimide oxalate (DPO), 1,
1'-bis (benzotriazolyl) oxalate (BBTO),
Oxalate derivatives such as 1,1'-bis (6-chlorobenzotriazolyl) oxalate (BCTO); azodicarboxylic acid derivatives such as diethyl azodicarboxylate and diisopropyl azodicarboxylate and triphenylphosphine and tributylphosphine Combination with aralkylphosphine; N-ethyl-5-phenylisoxazolium-
N-lower alkyl-5-phenylisoxazolium-3'-sulfonates such as 3'-sulfonate; carbodiimides such as N, N'-dicyclohexylcarbodiimide; 2-
Chlor-1-, such as methylpyridinium iodide 2-
Halo-1-lower alkylpyridinium halides; diarylphosphoryl azides such as diphenylphosphoryl azide can be mentioned, but halogenated formic acid esters can be preferably used.

As the base, the same one as in method 1 can be used. The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent,
Suitably, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, toluene,
Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate, etc. Esters; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone,
Ketones such as methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Amides such as; dimethyl sulfoxide, sulfoxides such as sulfolane, and the like can be used.

When the protecting group is a lower alkyloxy group, an aralkyloxy group, a lower alkylthio group, a methyl group substituted with 1 to 3 aryl groups, or an alkyl group, the compound R ₇ -L (L is a (Representing a leaving group) is reacted with Compound 3 in the presence of a base or an acid (Method 3), or R ₇
A protecting group can be introduced by a method (Method 4) in which OC = NHCY ₃ (Y represents a halogen atom) and an acid are allowed to act on Compound 3.

In Method 3, the leaving group (L) of the compound R ₇ -L is
Is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue, and examples thereof include lower alkyloxy groups such as methoxy and ethoxy; halogen atoms such as chlorine, bromine and iodine; methoxycarbonyloxy and ethoxycarbonyloxy. Lower alkoxycarbonyloxy groups such as; halogenated alkylcarbonyloxy groups such as chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy, trifluoroacetyloxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy Halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy; benzenesulfonyloxy, p-toluenesulfonyloxy,
An arylsulfonyloxy group such as p-nitrobenzenesulfonyloxy can be mentioned, and more preferably,
A halogen atom, a halogeno lower alkanesulfonyloxy group, an arylsulfonyloxy group and the like can be used.

The base is not particularly limited as long as it can be used as a base in a usual reaction. For example, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate and hydrogen carbonate. Alkali metal hydrogen carbonates such as potassium and lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide Inorganic bases such as alkali metal hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine , Pyridine 4- (N, N- dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,
5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo
[5.4.0] Organic bases such as undec-7-ene (DBU);
Alternatively, an organometallic base such as butyllithium or lithium diisopropylamide can be used, and preferably an alkali metal hydride (particularly sodium hydride) can be used.

The acid is not particularly limited as long as it can be used as an acid catalyst in a usual reaction, and examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, or Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, organic acids such as trifluoromethanesulfonic acid, or zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, Lewis acids such as boron tribromide can be used. Preferably organic acids, more preferably strong organic acids can be used.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide,
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane can be used.

In Method 4, a fluorine atom, a chlorine atom or the like can be used as the halogen atom (Y) of the compound represented by R ₇ OC = NHCY ₃ , and the acid used is such as trifluoroacetic acid. Examples thereof include halogeno lower alkanoic acids; organic sulfonic acids such as trifluoromethane sulfonic acid, p-toluene sulfonic acid, camphor sulfonic acid; and strong acid ion exchange resins. The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; benzene, toluene, xylene, etc. Aromatic hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile Formamide, dimethylformamide, dimethylacetamide, amides such as hexamethylphosphoric triamide; dimethylsulfoxide, can be used sulfoxides such as sulfolane.

Further, the protecting group is a tetrahydropyranyl group,
In the case of a tetrahydrotothiopyranyl group, a tetrahydrofuranyl group, or a tetrahydrothiofuranyl group, the corresponding dihydro compound such as dihydropyran is added to the compound 3 in the presence of an acid.
Compound 4 can be produced by reacting with (Method 5).

The acid is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, or acetic acid. Bronsted acids such as organic acids such as, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron trifluoride A Lewis acid such as bromide can be used, preferably an organic acid, more preferably an organic strong acid.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide,
Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane can be used.

Further, when the protecting group is a silyl group, the compound represented by the general formula R ₇ -L (L represents a leaving group) is reacted with the compound 3 in the presence or absence of a base. Thus, compound 4 can be produced (method 6).

The leaving group (L) of the compound represented by R ₇ -L is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue. For example, a halogen atom such as chlorine, bromine or iodine; Alkylcarbonyloxy groups such as acetoxy and propionyloxy; halogenated alkylcarbonyloxy groups such as chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy, trifluoroacetyloxy; lower alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy An aliphatic acyloxy group such as an unsaturated alkylcarbonyloxy group such as (E) -2-methyl-2-butenoyloxy; an arylcarbonyloxy group such as benzoyloxy; a 2-bromobenzoyloxy or 4-chlorobenzoyloxy group Aryl carbonyloxy groups such as 2,4, Lower alkylated arylcarbonyloxy groups such as 6-trimethylbenzoyloxy, 4-toluoyloxy; lower alkoxylated arylcarbonyloxy groups such as 4-anisoyloxy; 4-nitrobenzoyloxy, 2-nitrobenzoyloxy Aromatic acyloxy groups such as nitrated arylcarbonyloxy groups; trihalogenomethyloxy groups such as trichloromethyloxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy; trifluoromethanesulfonyloxy, pentafluoro A halogeno lower alkanesulfonyloxy group such as ethanesulfonyloxy; an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy can be used. Preferably, a halogen atom, a halogeno lower alkanesulfonyloxy group,
Alternatively, an arylsulfonyloxy group or the like can be used.

The base is not particularly limited as long as it can be used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate. , Alkali metal hydrogencarbonates such as potassium hydrogen carbonate, lithium hydrogen carbonate; lithium hydride, sodium hydride,
Alkali metal hydrides such as potassium hydride; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-
Diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene, 1,4-diazabicyclo [2.2.2] octane (DABCO)
, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
Or an organic metal base such as butyllithium or lithium diisopropylamide can be used. In addition, 4- (N, N'-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in a catalytic amount in combination with other bases, and benzyltriethylammonium chloride can be used in order to carry out the reaction efficiently. Fourth, such as tetrabutylammonium chloride
It is also possible to add quaternary ammonium salts, crown ethers such as dibenzo-18-crown-6, and the like.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane can be used.

[Step 3] In this step, compound 5 is obtained by condensing compound 4 with an aldehyde compound in the presence of a base. The base is not particularly limited as long as it is used as a base in a usual reaction, and examples thereof include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate and carbonic acid. Alkali metal hydrogencarbonates such as lithium hydrogen; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkalis such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide Inorganic bases such as metal hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; mercaptan alkali metals such as methyl mercaptan sodium and ethyl mercaptan sodium; Triethyl Min, tributylamine, diisopropylethylamine, N- methylmorpholine, pyridine, 4-
(N, N-Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.
0] Non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-
Organic bases such as ene (DBU); or butyllithium,
Organometallic bases such as lithium diisopropylamide can be used. Alkali metal hydrides can preferably be used. In order to carry out the reaction efficiently, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like can be added.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, Alcohols such as cyclohexanol and methyl cellosolve; Nitriles such as acetonitrile and isobutyronitrile; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; Dimethyl sulfoxide, sulfolane, etc. Different sulfoxides can be used, and amides can be preferably used.

The reaction temperature is -78 ° C to 30 ° C, preferably
-30 ℃ ~ 10 ℃ range. The reaction time varies depending on the type of compound and reaction temperature, but is usually about 1 hour to 20 hours, preferably about 2 hours to 5 hours. After the reaction is completed, water is poured into the concentrate obtained by distilling off the solvent, and the mixture is extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and the solvent is distilled off from the extract. To obtain compound 5,
This product can be used in the next step without further purification. However, if desired, it is possible to further purify by various techniques such as chromatography or recrystallization.

[Step 4] In this step, compound 6 is produced by treating compound 5 with a base to effect ring closure. The base is not particularly limited as long as it is used as a base in a normal reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate. , Alkali metal hydrogen carbonates such as lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide Inorganic bases such as alkali metal hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, Pyridine, 4- (N, N-dime Cylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo
[4.3.0] Non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec
-Organic bases such as 7-ene (DBU); or organometallic bases such as butyllithium and lithium diisopropylamide. Suitably, an alkali metal hydroxide can be used. In order to carry out the reaction efficiently, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like can be added.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, Alcohols such as cyclohexanol, methyl cellosolve; Acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, ketones such as cyclohexanone; Nitro compounds such as nitroethane, nitrobenzene; Acetonitrile, isobutyronitrile Nitriles; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide S; dimethyl sulfoxide, sulfoxides such as sulfolane may be employed. Alcohols can be preferably used.

The reaction temperature is in the range of -50 ° C to 50 ° C, preferably
It is in the range of 0 ° C to 30 ° C. The reaction time varies depending on the conditions such as the compound and the reaction temperature, but is usually about 1 to 20 hours, preferably about 3 to 10 hours. After completion of the reaction, the concentrate obtained by distilling off the solvent is poured into water, extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and the solvent is distilled off from the extract to obtain a compound. 6 can be obtained and this product can be used in the next step without further purification. However, if desired, it is possible to further purify by various techniques such as chromatography or recrystallization.

[Step 5] In this step, the protective group for the hydroxyl group of compound 6 is removed, and in the compound of the present invention represented by the general formula (I), X is an oxygen atom, and ---- is added. This is a step of obtaining a compound (Compound 7) in which the bond is a single bond. The removal of the hydroxyl-protecting group varies depending on the type, but is generally carried out as follows by a method well known in the art. When a silyl group is used as a hydroxyl-protecting group, it can usually be removed by treatment with a compound that produces a fluorine anion, such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable. Although the reaction temperature and the reaction time are not particularly limited, the reaction is usually performed at room temperature for about 10 to 18 hours. When the hydroxyl-protecting group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by bringing it into contact with a reducing agent in a solvent (preferably by catalytic reduction at room temperature under a catalyst), or Alternatively, it can be removed using an oxidizing agent. The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane. Aromatic hydrocarbons such as toluene, benzene and xylene; Aliphatic hydrocarbons such as hexane and cyclohexane, ethyl acetate,
Preference is given to esters such as propyl acetate; fatty acids such as acetic acid or a mixed solvent of these organic solvents and water. The catalyst is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium hydroxide, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, trioxide. Phenylphosphine-rhodium chloride and palladium-barium sulfate can be used. The pressure is not particularly limited, but is usually 1
It can be performed at about 10 atm. The reaction temperature and reaction time will differ depending on the conditions such as the starting material, solvent and type of catalyst, but they are usually carried out at 0 to 100 ° C. for 5 minutes to 24 hours. The solvent for removal by oxidation is not particularly limited as long as it does not participate in this reaction, but a water-containing organic solvent can be preferably used. Examples of such an organic solvent include ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; diethyl ether, tetrahydrofuran, dioxane, etc. Ethers; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; and sulfoxides such as dimethylsulfoxide can be used. The oxidizing agent is not particularly limited as long as it is a compound used in a usual oxidation reaction, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro
-5,6-Dicyano-p-benzoquinone (DDQ) can be used. The reaction temperature and reaction time will differ depending on the conditions such as starting material, solvent and type of catalyst, but are usually 0 to 150 ° C.
Will be carried out for 10 to 24 hours. It can also be removed by reacting alkali metal such as metallic lithium or metallic sodium at -78 ° C to -20 ° C in liquid ammonia or alcohol such as methanol or ethanol. .

Further, it can be removed by using aluminum chloride-sodium iodide or alkylsilyl halides such as trimethylsilyl iodide in a solvent. The solvent is not particularly limited as long as it does not participate in this reaction, but for example, nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform; or a mixed solvent thereof is used. You can The reaction temperature and reaction time will differ depending on the conditions such as the starting materials and the solvent, but usually they may be carried out at 0 to 50 ° C. for 5 minutes to 3 days. When the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group, or an alkoxycarbonyl group, it can be removed by treating with a base in a solvent. The base is not particularly limited as long as it does not affect other parts of the compound, and examples thereof include metal alkoxides such as sodium methoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate. Salts; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; or aqueous ammonia, ammonia such as concentrated ammonia-methanol are used. The solvent is not particularly limited as long as it can be used in a usual hydrolysis reaction, for example, water;
Preference is given to alcohols such as methanol, ethanol and n-propanol; organic solvents such as ethers such as tetrahydrofuran and dioxane, or mixed solvents of water and the above organic solvents. The reaction temperature and the reaction time are different depending on the conditions such as the starting material, the solvent and the base used, and are not particularly limited.
It may be carried out at a temperature in the range of 150 ° C. for about 1 to 10 hours.

The hydroxyl-protecting group is an alkoxymethyl group,
A tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group can be usually removed by treating with an acid in a solvent.
The acid is not particularly limited as long as it is usually used as a Bronsted acid, and it is preferable to use an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid or paratoluenesulfonic acid. However, a strongly acidic cation exchange resin such as Dowex 50W may be used. The solvent is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; or a mixed solvent of these organic solvents and water is preferable. Is. The reaction temperature and the reaction time vary depending on the conditions such as the starting material, the solvent and the kind of the acid used, but are usually 0 to 50.
It may be carried out at ℃ for 10 minutes to 18 hours.

When the hydroxyl-protecting group is an alkenyloxycarbonyl group, the removal reaction conditions are usually the same when the hydroxyl-protecting group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. Similarly, it is achieved by treating with a base. In the case of allyloxycarbonyl, the method of removing it by using palladium and triphenylphosphine or nickel tetracarbonyl is simple and has few side reactions, which is preferable.

[Step 6] The compound 7 is treated with an oxidizing agent to produce X in the compound of the present invention represented by the general formula (I).
Is an oxygen atom and the bond with ---- is a double bond (Compound 8). The oxidizing agent used in this step is not particularly limited as long as it is usually used in an oxidation reaction, and examples thereof include manganese oxides such as potassium permanganate and manganese dioxide; ruthenium tetraoxide. Ruthenium oxides; Zelenic compounds such as selene dioxide; Iron compounds such as iron chloride; Osmium compounds such as osmium tetroxide; Silver compounds such as silver oxide; Mercury compounds such as mercury acetate; Lead oxides, tetraoxides Lead oxide compounds such as lead acetate; inorganic metal oxidizers such as potassium chromate, chromic acid compounds such as chromic acid-sulfuric acid complex, chromic acid-pyridine complex, cerium compounds such as ammonium cerium nitrate (CAN); Chlorine molecule,
Halogen molecules such as bromine and iodine molecules; Periodic acids such as sodium periodate; Ozone; Hydrogen peroxide solution;
Nitrite compounds such as nitrous acid; Chlorite compounds such as potassium chlorite and sodium chlorite; Inorganic oxidizers such as potassium persulfate and persulfate compounds such as sodium persulfate; Used for DMSO oxidation Reagents such as dimethyl sulfoxide and dicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride or phosphorus pentoxide complex or pyridine-sulfuric anhydride complex; peroxides such as t-butyl hydroperoxide; triphenylmethyl cation Stable cations; succinimides such as N-bromosuccinimide; hypochlorite compounds such as t-butyl hypochlorite; azodicarboxylic acid compounds such as azodicarboxylic acid esters; dimethyl disulfide, Disulfides such as diphenyl disulfide, dipyridyl disulfide and trif Phenylphosphine; nitrites such as methyl nitrite; tetrahalogenated carbon such as methane tetrabromide; quinone compounds such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) The organic oxidizers mentioned above can be mentioned. A halogen molecule can be preferably used.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform and the like. Halogenated hydrocarbons; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide; methanol, ethanol, Alcohols such as n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol; dilute acids such as sulfuric acid; dilute bases such as sodium hydroxide; water; ketones such as acetone and methyl ethyl ketone. An organic base such as pyridine or a nitrile such as acetonitrile can be used. Pyridine can be preferably used. Reaction temperature is -50 ℃
The reaction time is usually about 30 minutes to 15 hours, although it varies depending on the conditions such as the reaction temperature, the starting compound or the type of solvent used. After completion of the reaction, the solvent is distilled off and the concentrated reaction solution is poured into water, extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and the solvent is distilled off from the extract. The product can be isolated. If desired, it can be purified by various means such as chromatography or recrystallization.

[0073]

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[Step 7] In this step, compound 9 and compound 10 are condensed in the presence of an acid catalyst to give compound 11. The acid catalyst is not particularly limited as long as it can be used as an acid catalyst in a usual reaction, but it is preferable to use tri-lower alkylsilyltrifluoromethanesulfonates such as trimethylsilyltrifluoromethanesulfonate and tin tetrachloride. Tins; zinc such as zinc bromide; titanium such as titanium tetrachloride; silver such as silver perchlorate and silver borofluoride; or trimethylsilyl perchlorate, triphenylmethyl perchlorate Perchloric acids such as can be used. The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; benzene, toluene, xylene Such as aromatic hydrocarbons; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone,
Ketones such as methyl ethyl ketone, methyl isobutyl ketone, isophorone, and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Amides such as; dimethyl sulfoxide, sulfoxides such as sulfolane, and the like can be used.

The reaction temperature is usually in the range of -50 ° C to 60 ° C, preferably -10 ° C to 30 ° C. The reaction time varies depending on the conditions such as the compound and the reaction temperature, but is usually 1 hour to
It is 20 hours, preferably about 2 to 6 hours. After completion of the reaction, for example, the solvent is distilled off and the reaction solution is poured into water,
The desired product can be isolated by extracting with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and distilling off the solvent from the extract to obtain the following product without purification. It can be used in the process. If desired, it can be purified by a means such as various chromatography or recrystallization method.

[Step 8] In this step, the compound 12 is obtained by carrying out a Wittig reaction on the compound 11 in the presence or absence of a solvent. Examples of the Wittig reagent include ethyl phosphonoacetates such as ethyl diethylphosphonoacetate and dimethylphosphonoacetate; ethoxycarbonylphosphonium salts such as ethoxycarbonyltriphenylphosphonium iodide. The base is not particularly limited as long as it is used as a base in a usual reaction, and examples thereof include alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate and carbonic acid. Alkali metal hydrogencarbonates such as lithium hydrogen; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkalis such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide Inorganic bases such as metal hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N- dimethyl Lumino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo
[4.3.0] Non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec
It is possible to use organic bases such as 7-ene (DBU) or organic metal bases such as butyllithium and lithium diisopropylamide. In order to efficiently carry out the reaction, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like can be added. .

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Kinds; methanol, ethanol, n-propanol,
Isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethyl Amides such as acetamide and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane can be used.

The reaction temperature is usually in the range of 0 ° C to 300 ° C, preferably 50 ° C to 200 ° C. The reaction time varies depending on the conditions such as the compound and the reaction temperature, but it is usually 1 hour to
It is about 20 hours, preferably about 3 to 10 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and the solvent is distilled off from the extract to isolate the desired product. can do. This product can be used in the next step without further purification. If desired, it can be purified by a means such as various chromatography or recrystallization method.

[Step 9] In this step, α, β-
In this step, compound 13 is obtained by subjecting the double bond to catalytic hydrogenation reaction. Examples of the catalyst used include palladium carbon, platinum oxide, Raney-nickel and the like. Examples of the solvent include alcohols such as methanol and ethanol; tetrahydrofuran,
Ethers such as dioxane; fatty acids such as acetic acid;
Alternatively, a mixed solvent of these organic solvents and water can be used. The reaction temperature is usually in the range of 0 ° C to 100 ° C,
It is preferably 10 ° C to 50 ° C. Although the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually about 1 hour to 30 hours, preferably about 2 hours to 10 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and the solvent is distilled off from the extract to isolate the desired product. can do. This product can be used as it is in the next step. If desired, further purification can be carried out by means of various chromatography or recrystallization method.

[Step 10] In this step, compound 14 is subjected to ring closure under acid catalysis in the presence or absence of an inert solvent for simultaneous deprotection, or compound 14 is subjected to ring closure and then deprotection to give compound 14 It is a process of obtaining. The acid catalyst is not particularly limited as long as it can be used as an acid catalyst in a normal reaction, and for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
Inorganic acids such as perchloric acid, phosphoric acid, polyphosphoric acid, or Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and other organic acids; or Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide can be used. Polyphosphoric acid and Lewis acids can be preferably used.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene. Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone,
Ketones such as cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethyl phosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane.

The reaction temperature is usually -100 ° C to 200 ° C, preferably -78 ° C to 100 ° C. While the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually about 1 hour to 50 hours, preferably about 2 hours to 30 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc., and the solvent is distilled off from the extract to isolate the desired product. The product thus obtained can be used in the next step without further purification. If desired, it can be purified by a means such as various chromatography or recrystallization method.

[Step 11] In this step, the hydroxyl group of compound 14 is reacted with the compound represented by R ₂ -L (L represents a leaving group) in the presence of a base to give compound 15. . The leaving group (L) in the compound of R ₂ -L is not particularly limited as long as it is used in a usual reaction, but for example, a halogen atom such as chlorine, bromine or iodine; acetoxy, Alkylcarbonyloxy groups such as propionyloxy, chloroacetyloxy, dichloroacetyloxy,
Halogenated alkylcarbonyloxy group such as trichloroacetyloxy, trifluoroacetyloxy; Lower alkoxyalkylcarbonyloxy group such as methoxyacetyloxy; Unsaturated alkylcarbonyloxy such as (E) -2-methyl-2-butenoyloxy Groups such as aliphatic acyloxy groups; arylcarbonyloxy groups such as benzoyloxy; halogenated arylcarbonyloxy groups such as 2-bromobenzoyloxy and 4-chlorobenzoyloxy; 2,4,6-trimethyl Benzoyloxy,
Lower alkylated arylcarbonyloxy groups such as 4-toluoyloxy; lower alkoxylated arylcarbonyloxy groups such as 4-anisoyloxy; 4-nitrobenzoyloxy, 2-nitrobenzoyloxy Aromatic acyloxy groups such as nitrated arylcarbonyloxy groups; trihalogenomethyloxy groups such as trichloromethyloxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy;
A halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy can be used. More preferably, a halogen atom, a lower alkanesulfonyloxy group, a halogeno lower alkanesulfonyloxy group, an arylsulfonyloxy group or the like can be used.

The base is not particularly limited as long as it can be used as a base in a usual reaction. For example, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate and hydrogen carbonate. Alkali metal hydrogen carbonates such as potassium and lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide Inorganic bases such as alkali metal hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; mercaptan alkali such as methyl mercaptan sodium, ethyl mercaptan sodium Metals Triethylamine, tributylamine, diisopropylethylamine, N- methylmorpholine, pyridine, 4-(N, N- dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo
[2.2.2] Octane (DABCO), 1,8-diazabicyclo [5.4.
0] Organic bases such as undec-7-ene (DBU); or organometallic bases such as butyllithium and lithium diisopropylamide can be used, and alkali metal carbonates can be preferably used. . In order to carry out the reaction efficiently, a fourth compound such as benzyltriethylammonium chloride or tetrabutylammonium chloride is used.
It is also possible to add quaternary ammonium salts, crown ethers such as dibenzo-18-crown-6, and the like.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, it is an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether; benzene. Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol , T-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitroethane, nitro such as nitrobenzene Compounds; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; dimethylsulfoxide,
Sulfoxides such as sulfolane can be used.

The reaction temperature is usually 0 ° C to 150 ° C, preferably 20 ° C to 100 ° C. While the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually about 1 hour to 10 hours, preferably about 2 hours to 5 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc. It can be separated and the product thus obtained can be used in the next step without further purification. If desired, it is possible to purify by various means such as chromatography and recrystallization.

[Step 12] In this step, the compound 15 of the present invention represented by the general formula (I) is treated with an acid to undergo a rearrangement reaction. This is a step of obtaining a compound 16 having a single bond. The acid catalyst is not particularly limited as long as it is used as an acid catalyst in a normal reaction, for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
Inorganic acids such as perchloric acid and phosphoric acid, or Bronsted acids such as organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid; or zinc chloride, Tin tetrachloride, boron trichloride, boron trifluoride,
Lewis acids such as boron tribromide, gallium chloride, germanium chloride; acidic clays such as montmorillonite can be used. Lewis acids and acidic clays can be used preferably, and acidic clays can be used more preferably.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol , Alcohols such as methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide ; Can be used dimethyl sulfoxide, sulfoxides such as sulfolane.

The reaction temperature is usually -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C. Although the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually about 1 hour to 30 hours, preferably about 5 hours to 24 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, the mixture is extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc. Can be separated. If desired, it is possible to purify by various techniques such as chromatography or recrystallization.

[0090]

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[Step 13] This step is the first step of the method shown in the above scheme as an alternative method for producing compound 12, and compound 11 is treated with bromoacetic acid ester in the presence of a metal and a metal salt. This is the step of obtaining compound 17.
The metal and the metal salt are not particularly limited as long as they can be used in a usual condensation reaction, but are preferably magnesium, zinc, zinc-copper alloy, tin, tin dichloride, cerium, cerium chloride, samarium iodide and the like. Can be used.
The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, hexane, heptane, ligroin, an aliphatic hydrocarbon such as petroleum ether; benzene, toluene, Aromatic hydrocarbons such as xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether; Nitro compounds such as nitrobenzene; Nitriles such as acetonitrile and isobutyronitrile; Formamide, dimethylformamide,
Amides such as dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane can be used.

The reaction temperature is usually -100 ° C to 200 ° C, preferably 0 ° C to 100 ° C. While the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually about 1 to 20 hours, preferably about 3 to 10 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc. It can be separated and the product thus obtained can be used in the next step without further purification. If desired, it can be purified by various techniques such as chromatography or recrystallization.

[Step 14] In this step, compound 12 is obtained by dehydrating compound 17 in the presence or absence of a base. The dehydrating agent is not particularly limited as long as it is used as a dehydrating agent in a usual reaction, and for example, N-ethyl-5-phenylisoxazolium-3'-sulfonate such as N- Lower alkyl-5-arylisoxazolium-3'-sulfonates; N ', N'-dicycloalkylcarbodiimides such as N', N'-dicyclohexylcarbodiimide (DCC); di-2-pyridyl Diheteroaryl diselenides such as diselenide; 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; thionyl chloride; oxalyl chloride; phosphorus pentachloride Etc. can be used.

The base is not particularly limited as long as it can be used as a base in a usual reaction. For example, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, hydrogen carbonate. Alkali metal hydrogen carbonates such as potassium and lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide Inorganic bases such as alkali metal hydroxides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; mercaptan alkalis such as methyl mercaptan sodium and ethyl mercaptan sodium Metals; Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N,
N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo
[2.2.2] Octane (DABCO), 1,8-diazabicyclo [5.4.
0] Organic bases such as undec-7-ene (DBU); or organometallic bases such as butyllithium and lithium diisopropylamide can be used. In order to carry out the reaction efficiently, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6 and the like can be added.

The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
Ethyl formate, ethyl acetate, propyl acetate, butyl acetate,
Esters such as diethyl carbonate; diethyl ether,
Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; acetonitrile, isobutyro Nitriles such as nitriles; formamide,
Examples thereof include amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; and sulfoxides such as dimethylsulfoxide and sulfolane.

The reaction temperature is usually -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. While the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually 1 hour to 10 hours, preferably 2 hours to 5 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, the mixture is extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc. It can be separated and the product thus obtained can be used in the next step without further purification. If desired, purification can be carried out by a technique such as various chromatography or recrystallization method.

[0097]

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[Step 15] In this step, compound 18 and compound 19
Is another method for producing compound 13 by reacting and in the presence of a metal or a metal salt. The metal and the metal salt are not particularly limited as long as they are used in a usual condensation reaction, but are preferably lithium, sodium, potassium, magnesium, zinc, zinc copper alloy, tin, tin dichloride, cerium,
Cerium chloride, samarium iodide, or the like can be used. The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent, but preferably, hexane, heptane, ligroin, an aliphatic hydrocarbon such as petroleum ether; benzene, toluene, Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate, etc. Esters; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide A class can be used.

The reaction temperature is usually -50 ° C to 50 ° C, preferably -30 ° C to 20 ° C. While the reaction time varies depending on the conditions such as the compound and the reaction temperature, it is usually about 1 hour to 10 hours, preferably about 2 hours to 8 hours. After completion of the reaction, the solvent is distilled off, the reaction solution is poured into water, the mixture is extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc. It can be separated and the product thus obtained can be used in the next step without further purification. If desired, it can be purified by a technique such as various chromatographic techniques or a recrystallization method.

Although the method for producing the compound of the present invention has been described above in detail, the method for producing the compound of the present invention is not limited thereto. Further, since the examples of the present specification more specifically describe the method for producing the compound of the present invention, by referring to the above disclosure of the present specification and the disclosure of the examples, By adding appropriate alterations or modifications to these methods described in the specification, if necessary,
It will be easily understood by those skilled in the art that any of the compounds of the present invention included in the above general formula (I) can be prepared.

The compound of the present invention or a physiologically acceptable salt thereof can specifically bind to the estrogen receptor and exert an excellent estrogenic effect. Therefore, according to another aspect of the present invention, there is provided a medicine comprising the compound represented by the above general formula (I) and a physiologically acceptable salt thereof. The above-mentioned medicament of the present invention is useful as an estrogen agonist, and includes, for example, amenorrhea, anovulatory cycle, functional uterine bleeding, and uterine hypoplasia caused by decreased estrogen in mammals including humans, preferably humans. Disease, menopause, osteoporosis,
It can be used for prevention and / or treatment of prostate cancer, benign prostatic hyperplasia, etc., as well as suppression of milk secretion. According to yet another aspect of the present invention, there is provided a method for preventing and / or treating a disease caused by decreased estrogen, menopausal disorder, osteoporosis, prostate cancer, and benign prostatic hyperplasia, which comprises the above compound. And a method of suppressing lactation comprising administering an effective amount of the compound to a mammal, including a human. However, the application target when the compound of the present invention is used as a medicine is not limited to the above.

When the compound of the present invention is used as a medicine, it may be administered orally or parenterally, but one or more of the above compounds and other pharmaceutically acceptable additives may be added. It is preferably used in the form of a pharmaceutical composition containing the product. Thus, according to yet another aspect of the invention,
There is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable additive, as well as the use of a compound of the invention for the manufacture of said pharmaceutical composition. Such pharmaceutical compositions include, for example, oral compositions such as tablets, capsules, granules, powders, or syrups; or injections, infusions, suppositories, patches, external preparations, etc. Examples thereof include compositions for parenteral administration, but the pharmaceutical composition of the present invention is not limited thereto.

For the production of such a composition, for example, an excipient (eg lactose, mannitol, corn starch, crystalline cellulose etc.); a binder (eg cellulose derivative, gum arabic, gelatin etc.); disintegration Agents (eg, carboxymethyl cellulose calcium); lubricants (eg, talc, magnesium stearate etc.);
Stabilizers; flavoring agents; solvents for injections (for example, distilled water for injection, ethanol, glycerin, etc.) and the like can be used, and they can be formulated according to methods well known in the art. The dose should be appropriately determined in consideration of various factors such as the type of compound, symptoms, purpose of treatment or prevention, and age of the patient.For example, the lower limit of the dose per day for an adult is about 0.6 mg. , Preferably about 6 mg, and the upper limit is about 600 mg, preferably about 120 mg. Such a daily dose may be divided into several doses for administration.

[0104]

[0105]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples.

[0106]

Example 1 5,7-Dihydroxy-2- (4-hydroxy-3-methoxyphenyi
) -8- (3-Methyl-2-butenyl) -4-chromanone (1a) 2,4,6-trihydroxyacetophenone 13.4 g
(79.7 mmol) was dissolved in THF and isoprenyl chloride was added.
10.8 g (104 mmol) and potassium carbonate 14.3 g (104 mmol)
After heating and refluxing for 20 hours, the solvent was evaporated, the residue was dissolved in ethyl acetate and washed with water, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Methylene chloride: methanol = 2
It was purified by subjecting it to 0: 1) to obtain 9.79 g (52%) of crystals. TLC: Rf = 0.4 (methylene chloride: methanol = 10: 1, silica gel tlc MERCK, Kieselgel 60 F ₂₅₄ ) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 5.81 (s, 1H, aro- H), 5.
22 (dt, 1H, J = 1.32,5.27Hz, CH = C), 3.27 (d, 2H, J = 7.25Hz, CH
₂ ), 2.64 (s, 3H, Me), 1.78 (s, 3H, Me), 1.69 (s, 3H, Me) (1b) 3
-Isoprenyl-2,4,6-trihydroxyacetophenone
Dissolve 5.13 g (21.7 mmol) in 200 ml of THF, add 9.62 g (119.5 mmol) of methoxymethyl chloride and 16.82 g (130.4 mmol) of diisopropylethylamine under ice cooling and stir at room temperature for 8 hours, then evaporate the solvent. Then, ethyl acetate was added and the mixture was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate).
= 6: 1) for purification to give 3.85 g (52.7%) of an oil. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.81 (s, 1H, OH), 6.39 (s, 1
H, arom-H), 5.25 (s, 2H, -CH ₂ ), 3.51 (s, 3H, -OMe), 3.47 (s, 3
H, -OMe), 3.30 (d, 2H, J = 7.26Hz, -CH ₂ ), 2.66 (s, 3H, -CH ₃ ),
1.78 (s, 3H, -CH ₃ ), 1.66 (s, 3H, -Me) (1c) Zymom protected 3-isoprenyl-2,4,6-trihydroxyacetophenone 1 g (3 mmol) dissolved in 20 ml DMF Then, under ice-cooling, 285 mg (6 mmol) of sodium hydride was added and the mixture was stirred for 30 minutes, then 600 mg (11.9 mmol) of mom-protected 3-methoxy-4-hydroxybenzaldehyde was added and the mixture was stirred at room temperature for 3 minutes.
Stir for hours. The solvent was distilled off, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give 1 g. An oily product (64.4%) was obtained. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.83 (d,
1H, J = 15.8Hz, -CH = C), 7.73 (d, 1H, J = 15.8Hz, -CH = C), 7.26-
7.15 (m, 3H, arom-H), 6.37 (s, 1H, arom-H), 5.27 (s, 2H, -OCH
₂ ), 5.26 (s, 2H, -OCH ₂ ), 5.24 (s, 2H, -OCH ₂ ), 5.22 (m, 1H, -C
H), 3.92 (s, 3H, -OCH ₃ ), 3.52 (s, 3H, 3H, -OCH ₃ , -OCH ₃ ), 3.48
(s, 3H, -OCH ₃ ), 3.33 (d, 2H, J = 6.8Hz, -CH ₂ ), 1.79 (s, 3H, -CH
₃ ), 1.67 (s, 3H, -CH ₃ ) (1d) chalcone 500 mg (1.2 mmol) in methanol 30
The solution was dissolved in ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, then 15 ml of 2N-HCl was added and stirred with heating for 6 hours. The solvent was evaporated, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:
The desired compound 130 mg (1
7.0%) was obtained as crystals. TLC: Rf = 0.35 (ethyl acetate: hexane = 2: 1), mp 194
~ 196 ℃ ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.09 (s, 1H, -OH), 7.02-
6.92 (m, 3H, arom-H), 5.99 (s, 1H, arom-H), 5.57 (d, d, 1H, J =
1.32,5.28Hz, -CH), 5.22 (m, 1H, -CH = C), 3.92 (s, 3H, OMe),
3.24 (d, 2H, J = 6.6Hz, -CH ₂ ), 2.93 (d, d, d, 2H, J = 3.3,12.54,
17.15Hz, -CH ₂ ), 1.65 (s, 3H, Me), 1.65 (s, 3H, Me)

[0107]

Example 2 5,7-Dihydroxy-2- (3-hydroxy-3-methoxyphenyi
) -8- (3-Methyl-2-butenyl) -4-chromanone (2a) 3-isoprenyl-2,4,6-trihydroxyacetophenone 1 g (3 mmol) was dissolved in 20 ml DMF and cooled on ice. , 285 mg (6 mmol) of sodium hydride was added and stirred for 30 minutes,
Thereafter, mom-protected 3-hydroxy-4-methoxybenzaldehyde (600 mg, 11.9 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate).
= 2: 1) for purification to obtain 1.24 g (79.8%) of an oil.

TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 13.9 (s, 1H, -OH), 7.84 (d, 1)
H, J = 15.8Hz, -CH = C), 7.72 (d, 2H, J = 15.8Hz, -CH = C), 7.50-
6.88 (m, 3H, arom-H), 6.41 (s, 1H, arom-H), 5.28 (s, 2H, -OCH
₂ ), 5.26 (s, 2H, -OCH ₂ ), 5.24 (s, 2H, -OCH ₂ ), 5.20 (m, 1H, -C
H), 3.91 (s, 3H, -OCH ₃ ), 3.53 (s, 2H, -OCH ₃ ), 3.48 (s, 3H, -OC
H ₃ ), 3.33 (d, 2H, J = 7.26Hz, -CH), 1.78 (s, 3H, -CH ₃ ), 1.67
(s, 3H, -CH ₃ ) (2b) Chalcone 730 mg (1.5 mmol) was added to methanol 40
It was dissolved in ml, several drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 100 mg (18%) of the desired compound as crystals. TLC: Rf = 0.3 (ethyl acetate: hexane = 2: 1), mp 105 ℃ ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.10 (s, 1H, -OH), 7.01 (m,
3H, arom-H), 5.99 (s, 1H, arom-H), 5.45 (d, d, 2H, J = 3.3,12.
54Hz), 5.19 (m, 1H), 3.900 (s, 1H, -OMe), 3.23 (d, 2H, J = 7.26
Hz), 2.83 (d, d, d, 2H, J = 3.3,12.54,17.16Hz), 1.65 (s, 3H,-
Me), 1.64 (s, 3H, -Me)

[0109]

Example 3 5,7-Dihydroxy-2- (4-hydroxyphenyl) -8- (3-me
(Cytylbutyl ) -4-chromanone (3a) Dymom protected 3-Isoprenyl-2,4,6-trihydroxyacetophenone 370 mg is dissolved in ethanol 30 ml, 10% Pd-C 150 mg is added and contact hydrogen is added under hydrogen flow. The addition was made. After 4 hours, the mixture was filtered through Celite, the solvent was distilled off, and the residue was purified by column chromatography (hexane: ethyl acetate = 3: 1) to obtain 150 mg (40%) of an oily substance. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 6.38 (s, 1
H, arom-H), 5.25 (s, 2H, -OCH ₂ ), 5.22 (s, 2H, -OCH ₂ ), 3.51
(s, 3H, -OCH ₃ ), 3.48 (s, 3H, -OCH ₃ ), 2.65 (s, 3H, O = C-CH ₃ ),
2.62-2.56 (m, 2H, -CH ₂ ), 1.78-1.53 (m, 1H, -CH), 1.40-1.31
(m, 3H, -CH ₃ ), 0.95 (s, 3H, -CH ₃ ), 0.92 (s, 3H, -CH ₃ ) (3b) 3- (3-methylbutyl) -2,4,6-trihydroxy Acetophenone 150 mg (0.4 mmol) was dissolved in DMF 10 ml.
Add 44 mg (0.8 mmol) of sodium hydride under ice cooling.
After stirring for 30 minutes, 76 mg (0.4 mmol) of mom-protected p-hydroxybenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours.
The solvent was distilled off, ethyl acetate was added, and the organic layer was washed with water.
After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 150 mg (68.4%) of an oily substance. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.83 (d, 1
H, J = 15.8Hz, -CH = C), 7.75 (d, 1H, J = 15.8Hz, -CH = C), 7.54
(d, 2H, J = 8.58Hz, arom-H), 7.05 (d, 2H, J = 8.58Hz, arom-H),
6.38 (s, 1H, arom-H), 5.26 (s, 2H, -OCH ₂ ), 5.23 (s, 2H, -OC
H ₂ ), 5.20 (s, 2H, -OCH ₂ ), 3.52 (s, 3H, -OCH ₃ ), 3.49 (s, 3H, -O
CH ₃ ), 3.48 (s, 3H, -OCH ₃ ), 2.62 (m, 2H, -CH ₂ ), 1.60 (m, 1H, -C
H), 1.39 (m, 2H, -CH ₂ ), 0.96 (s, 3H, -CH ₃ ), 0.94 (s, 3H, -CH ₃ ) (3c) Chalcone 150 mg (0.456 mmol) in methanol 3
It was dissolved in 0 ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours. Then, 15 ml of 2N-HCl was added and the mixture was heated with stirring for 6 hours, and the solvent was distilled off. Add ethyl acetate and add saturated sodium bicarbonate water,
After washing with water and saturated saline, it was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 16 mg (11.4%) of the desired compound as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1) mp 196
~ 198 ℃ ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.11 (s, 1H, -OH), 7.30 (d,
2H, J = 8.58Hz, arom-H), 6.87 (d, 2H, J = 8.58Hz, arom-H), 5.9
7 (s, 1H, arom-H), 5.32 (d, d, 1H, J = 2.64,12.54Hz), 2.89 (d,
d, d, 2H, J = 3.0,12.54,17.16Hz), 2.52 (d, d, 2H, J = 7.92,10.
56Hz), 1.53 (m, 1H, CH = Me), 1.35 (d, d, 2H, J = 7.92,10.56H
z), 0.89 (s, 3H, Me), 0.86 (s, 3H, Me)

[0110]

Example 4 8-allyl-5,7-dihydroxy-2- (4-hydroxyphenyl)
) -4-Chromanone (4a) 2,4,6-trihydroxyacetophenone 4.76 g (2
8.3 mmol) in THF (300 ml) and allyl bromide 2.6
g (33.9 mmol) and potassium carbonate 9.3 g (56.6 mmol) were added, and the mixture was heated under reflux for 20 hours. The solvent was distilled off, and the residue was 420 m.
To 100 g of THF was added and dissolved, and 760 mg (0.95 mmol) of methoxymethyl chloride and 1.46 g (1.8 mmol) of diisopropylethylamine were added under ice cooling, and the mixture was stirred at room temperature for 8 hours. The solvent was distilled off, ethyl acetate was added, and the mixture was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain 140 mg (1.5%) of a yellow oily substance. TLC: Rf = 0.4 (methylene chloride: methanol = 10: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 13.8 (ns, 1H, -OH),
6.41 (s, 1H, arom-H), 6.01-5.86 (m, 1H, -CH = C), 5.26 (s, 2H,
-OCH ₂ ), 5.22 (s, 2H, -OCH ₂ ), 5.12-4.91 (m, 2H, -CH ₂ ), 3.51
(s, 3H, -OCH ₃ ), 3.46 (s, 3H, -OCH ₃ ), 3.35 (m, 2H, -CH ₂ ), 2.67
(s, 3H, -CH ₃ ) (4b) Zymom-protected 3-allyl-2,4,6-trihydroxyacetophenone 140 mg (6.47 mmol) was dissolved in DMF 10 ml. Sodium hydride (42 mg, 0.94 mmol) was added under ice-cooling and the mixture was stirred for 30 minutes, then mom-protected p-hydroxybenzaldehyde (78 mg, 0.47 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 160 mg ( An oil (71.2%) was obtained. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.84 (d, 1
H, J = 15.8Hz, -CH = C), 7.77 (d, 1H, J = 15.8Hz, -CH = C), 7.54
(d, 2H, J = 8.58Hz, arom-H), 7.06 (d, 2H, J = 8.58Hz, arom-H),
6.40 (s, 1H, arom-H), 6.01-5.89 (m, 1H, -CH), 5.28 (s, 2H, -O
CH ₂ ), 5.24 (s, 2H, -OCH ₂ ), 5.21 (s, 2H, -OCH ₂ ), 5.12-4.48
(m, 2H, -CH = CH-), 3.59 (s, 3H, -OCH ₃ ), 3.49 (s, 3H, -OCH ₃ ),
3.48 (s, 3H, -OCH ₃ ), 3.39 (m, 2H, -CH ₂ ) (4c) chalcone form 160 mg (0.3 mmol) in methanol 30
It was dissolved in ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours. After adding 15 ml of 2N-HCl and heating and stirring for 6 hours, the solvent was evaporated, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The extract was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 30 mg (20.2%) of the desired compound as crystals. . TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1), mp 193-19
5 ℃ ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.1 (s, 1H, -OH), 7.29 (d, 2
H, J = 8.58Hz, arom-H), 6.92 (d, 2H, J = 8.58Hz, arom-H), 6.00
(s, 1H, arom-H), 5.91 (m, 1H, CH = C), 5.33 (d, d, 1H, J = 3.3,1
3.2Hz, -CH), 4.95 (d, d, 1H, J = 3.3,9.3Hz, CH = C), 3.29 (d, 2
H, J = 5.94Hz), 2.90 (d, d, d, 2H, J = 2.64,12.54,17.16Hz)

[0111]

Example 5 5,7-Dihydroxy-2- (3,4-dihydroxyphenyl) -8- (3
-Methyl-2-butenyl) -4-chromanone (5a) 3-isoprenyl-2,4,6-trihydroxyacetophenone 299 mg (0.8 mmol) was dissolved in DMF 10 ml and sodium hydride 88 mg under ice cooling. (1.6 mmol) was added and stirred for 30 minutes. Then, 1.97 g (11.9 mmol) of zymom-protected 3,4-dihydroxybenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
After purification by 4: 1), 300 mg (85.8%) of an oily substance was obtained. TLC: Rf = 0.5 (hexane: ethyl acetate = 2: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.83 (d, 1
H, J = 15.8Hz, -CH = C), 7.73 (d, 1H, J = 15.8Hz, -CH = C), 7.50-
7.18 (m, 4H, arom-H), 6.41 (s, 1H, arom-H), 5.28 (s, 2H, -OC
H ₂ ), 5.24 (s, 2H, -OCH ₂ ), 5.22 (s, 2H, -OCH ₂ ), 3.52 (s, 3H, 3
H, -OCH ₃ , -OCH ₃ ), 3.48 (s, 3H, -OCH ₃ ), 3.32 (d, 2H, J = 7.26H
z, -CH ₂ ), 1.78 (s, 3H, -CH ₃ ), 1.67 (s, 3H, -CH ₃ ) (5b) Chalcone 300 mg (0.58 mmol) in methanol 3
After dissolving in 0 ml, a few drops of 1N-NaOH were added and the mixture was stirred at room temperature for 6 hours, then 2 ml of 2N-HCl was added and the mixture was heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 22 mg (9.6%) of the desired compound as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 1: 1), mp 168 ° C ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.11 (s, 1H, -OH), 7.30-6.80
(m, 3H, arom-H), 5.99 (s, 1H, arom-H), 5.40 (d, d, 2H, J = 3.3,
12.54Hz), 5.19 (m, 1H), 3.24 (d, 2H, J = 6.6Hz, -CH ₂ ), 2.93
(d, d, d, 2H, J = 3.3,12.54,17.15Hz, -CH ₂ ), 1.65 (s, 3H, -M
e), 1.65 (s, 3H, -CH ₂ )

[0112]

Example 6 5,7-Dihydroxy-2- (4-hydroxyphenyl) -3-methyl
-8- (3-Methyl-2-butenyl) -4-chromanone (6a) 2,4,6-trihydroxypropiophenone 5 g (2
7.4 mmol) was dissolved in 300 ml of THF and 2.87 g (27.4 mmol) of isoprenyl chloride and 7.58 g (5
4.8 mmol) was added and the mixture was heated under reflux for 20 hours. The solvent was evaporated, and 680 mg of the residue was added with 200 ml of THF to dissolve the residue. Under ice cooling, 1.09 g (13.5 mmol) of methoxymethyl chloride and 2.1 g (16.2 mmol) of diisopropylethylamine were added and stirred at room temperature for 8 hours. . The solvent was distilled off, ethyl acetate was added, and the mixture was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 330 mg (3.5%) of an oily substance. TLC: Rf = 0.4 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 13.8 (s, 1H, -OH), 6.
39 (s, 1H, arom-H), 5.24 (s, 2H, -OCH ₂ ), 5.22 (s, 2H, -OCH ₂ ),
5.20 (m, 1H, -CH), 3.50 (s, 3H, -OCH ₃ ), 3.47 (s, 3H, -OCH ₃ ),
3.30 (d, 2H, J = 8.26Hz, -CH ₂ ), 3.06 (q, 2H, J = 7.26Hz, -CH ₂ ),
1.77 (s, 3H, -CH ₃ ), 1.65 (s, 3H, -CH ₃ ), 1.17 (t, 3H, J = 7.26H
z, -CH ₃ ) (6b) Dimom protected 3-isoprenyl-2,4,6-trihydroxypropiophenone 330 mg (0.97 mmol) in DMF 10 m
Dissolve in 10 ml of sodium hydride under ice-cooling 106 mg (2.1 mmo
l) was added and stirred for 30 minutes, then 162 mg (0.97 mmol) of mom-protected 4-hydroxybenzaldehyde was added and the mixture was stirred at room temperature for 3 minutes.
Stir for hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 180 mg (44.1%) of an oily substance. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 11.4 (s, 1H, -OH), 7.34 (d, 2
H, J = 8.58Hz, arom-H), 7.04 (d, 2H, J = 8.58Hz, arom-H), 6.79
(m, 1H, -CH = C), 6.43 (s, 1H, arom-H), 5.27 (m, 1H, -CH), 5.23
(s, 2H, -OCH ₂ ), 5.18 (s, 2H, -OCH ₂ ), 5.03 (s, 2H, -OCH ₂ ), 3.4
7 (s, 3H, 3H, -OCH ₃ , -OCH ₃ ), 3.32 (s, 3H, -OCH ₃ ), 2.19 (m, 3H,
C = C-CH ₃ ), 1.79 (s, 3H, -CH ₃ ), 1.68 (s, 3H, -CH ₃ ) (6c) 180 mg (0.41 mmol) of chalcone compound in methanol 1
The solution was dissolved in 0 ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, then 15 ml of 2N-HCl was added and heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 1) to separate and purify the trans form and the cis form, and 40 mg of the trans form (36.
2%) and 11 mg (0.099%) of cis isomer were obtained as crystals. Trans form: TLC: Rf = 0.3 (hexane: ethyl acetate = 2: 1),
mp157-160 ℃ cis isomer: TLC: Rf = 0.25 (hexane: ethyl acetate = 2: 1),
mp 60-63 ℃ Trans form: ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.28 (s, 1H,
-OH), 7.27 (d, 2H, J = 8.58Hz, arom-H), 6.87 (d, 2H, J = 8.58H
z, arom-H), 5.98 (s, 1H, arom-H), 5.16 (m, 1H, -OH), 4.89 (d,
1H, J = 11.88Hz, -CH), 3.18 (d, 2H, J = 7.26Hz, -CH ₂ ), 2.96 (d,
q, 1H, J = 7.26,11.87Hz, -CH), 1.64 (s, 3H, -Me), 1.56 (s, 3H,
-Me), 1.01 (d, 3H, J = 7.26Hz, -Me) cis isomer: ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.16 (s, 1H,
-OH), 7.38-6.84 (m, 4H, arom-H), 6.00 (s, 1H, arom-H), 5.44
(d, 1H, J = 3.3Hz, -CH), 5.23 (m, 1H), 3.30 (d, 2H, J = 7.0Hz, -C
H ₂ ), 2.48 (d, q, 1H, J = 2.64,7.26Hz, -CH), 1.72 (s, 3H, -Me),
1.68 (s, 3H, -Me), 1.00 (d, 3H, J = 7.26Hz, -Me)

[0113]

Example 7 2- (4-chlorophenyl) -5,7-dihydroxy-8- (3-methyl
-2-butenyl) -4-chromanone (7a) Zymom protected 3-isoprenyl-2,4,6-trihydroxyacetophenone 500 mg (1.47 mmol) in DMF 30 ml
Dissolve in 142 mg (2.94 mm) of sodium hydride under ice cooling.
was added and stirred for 30 minutes, 200 mg (1.47 mmol) of p-chlorobenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 5: 1)
And purified to give 500 mg (73%) of an oil. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.7 (s, 1H, -OH), 7.87 (d, 1
H, J = 15.1Hz, -CH = C), 7.68 (d, 1H, J = 15.1Hz, -CH = C), 7.51
(d, 2H, J = 8.57Hz, arom-H), 7.36 (d, 2H, J = 8.57Hz, arom-H),
6.38 (s, 1H, arom-H), 5.26 (s, 2H, -OCH ₂ ), 5.24 (s, 2H, -OC
H ₂ ), 5.22 (m, 1H, -CH), 3.50 (s, 3H, -OCH ₃ ), 3.48 (s, 3H, -OCH
₃ ), 3.32 (d, 2H, J = 7.26Hz, -CH ₂ ), 1.79 (s, 3H, -CH ₃ ), 1.67
(s, 3H, -CH ₃ ) (7b) Chalcone 500 mg (1 mmol) in methanol 30 ml
The solution was dissolved in the above solution, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, then, 20 ml of 2N-HCl was added, and the mixture was heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to obtain 70 mg (18%) of the desired compound as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 3: 1), mp 162 ° C ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.0 (s, 1H, -OH), 7.
39 (m, 4H, arom-H) 5.99 (s, 1H, arom-H), 5.38 (dd, 1H, J = 3.
3,12.5Hz, -CH), 5.18 (m, 1H, -CH), 3.23 (d, 2H, J = 7.26Hz, -C
H ₂ ), 2.88 (ddd, 2H, J = 3.3,12.5,17.1Hz, -CH ₂ ), 1.66 (s, 3H,
-CH ₃ ), 1.63 (s, 3H, -CH ₃ )

[0114]

Example 8 2- (4-Bromophenyl) -5,7-dihydroxy-8- (3-methyl
-2-butenyl) -4-chromanone (8a) Zymom protected 3-isoprenyl-2,4,6-trihydroxyacetophenone 450 mg (1.33 mmol) in DMF 40 ml
Dissolved in 128 mg (2.66 mm) of sodium hydride under ice cooling.
ol) was added and the mixture was stirred for 30 minutes, 246 mg (1.33 mmol) of p-bromobenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 3: 1)
After purification by filtration, 590 mg (87.4%) of an oily substance was obtained. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.7 (bs, 1H, -OH), 7.88 (d,
1H, J = 15.8Hz, -CH = C), 7.67 (d, 1H, J = 15.8Hz, -CH = C), 7.52
(d, 2H, J = 8.58Hz, arom-H), 7.44 (d, 2H, J = 8.58Hz, arom-H),
6.38 (s, 1H, arom-H), 5.26 (s, 2H, -OCH ₂ ), 5.24 (s, 2H, -OC
H ₂ ), 5.21 (m, 1H, -CH), 3.50 (s, 3H, -OCH ₃ ), 3.48 (s, 3H, -OCH
₃ ), 3.33 (d, 2H, J = 7.26Hz, -CH ₂ ), 1.78 (s, 3H, -CH ₃ ), 1.67
(s, 3H, -CH ₃ ) (8b) Chalcone 590 mg (1.16 mmol) was added to methanol 4
After dissolving in 0 ml, a few drops of 1N-NaOH were added and stirred at room temperature for 6 hours, then 25 ml of 2N-HCl was added and stirred with heating for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to obtain 60 mg (15.1%) of the desired compound as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 3: 1), mp 164 ° C ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.0 (bs, 1H, -OH),
7.54 (d, 2H, J = 7.9Hz, arom-H), 7.34 (d, 2H, J = 7.9Hz, arom-
H), 5.99 (s, 1H, arom-H), 5.37 (dd, 1H, J = 3.3,12.5Hz, -CH),
5.18 (m, 1H, -CH), 3.24 (d, 2H, J = 7.2Hz, -CH ₂ ), 2.88 (ddd, 2
H, J = 3.3,12.5,17.1Hz, -CH ₂ ), 1.66 (s, 3H, -CH ₃ ), 1.63 (s, 3
H, -CH ₃ )

[0115]

Example 9 2- (4-Fluorophenyl) -5,7-dihydroxy-8- (3-methyl
Ru-2-butenyl) -4-chromanone (9a) Zymom protected 3-isoprenyl-2,4,6-trihydroxyacetophenone 400 mg (1.18 mmol) in DMF 40 ml
Sodium hydride (113 mg (2.36 mm)
ol) was added and the mixture was stirred for 30 minutes, 147 mg (1.18 mmol) of p-fluorobenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 5: 1)
And purified to give 450 mg (86%) of an oil. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.7 (s, 1H, -OH), 7.83 (d, 1
H, J = 15.8Hz, -CH = C), 7.71 (d.1H, J = 15.8Hz, -CH = C), 7.56-
7.14 (m, 4H, arom-H), 6.38 (s, 1H, arom-H), 5.27 (s, 2H, -OCH
₂ ), 5.24 (s, 2H, -OCH ₂ ), 5.22 (m, 1H, -CH), 3.51 (s, 3H, -OC
H ₃ ), 3.48 (s, 3H, -OCH ₃ ), 3.43 (d, 2H, J = 6.6Hz, -CH ₂ ), 1.79
(s, 3H, -CH ₃ ), 1.67 (s, 3H, -CH ₃ ) (9b) Chalcone 450 mg (1 mmol) in methanol 40 ml
The solution was dissolved in the above solution, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, then, 25 ml of 2N-HCl was added, and the mixture was heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 130 mg (17.0%) of the desired compound as crystals. TLC: Rf = 0.6 (ethyl acetate: hexane = 3: 1), mp 152-15
3 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.0 (s, 1H, -OH), 7.
46-7.08 (m, 4H, arom-H), 5.99 (s, 1H, arom-H), 5.39 (dd, 1H,
J = 3.3,12.5Hz, -CH), 5.18 (m, 1H, -CH), 3.24 (d, 2H, J = 7.26H
z, -CH ₂ ), 2.86 (ddd, 2H, J = 2.6,12.5,17.1Hz, -CH ₂ ), 1.66
(s, 3H, -CH ₃ ), 1.63 (s3H, -CH ₃ )

[0116]

Example 10 2- (4-acetaminophenyl) -5,7-dihydroxy-8- (3-
Methyl-2-butenyl) -4-chromanone (10a) Zymom protected 3-Isoprenyl-2,4,6-trihydroxyacetophenone 700 mg (2 mmol) was dissolved in DMF 40 ml and sodium hydride 200 mg under ice cooling. (4 mmol) was added and stirred for 30 minutes, then p-acetaminobenzaldehyde was added.
340 mg (2 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate).
Obtained mg (39.8%) of an oil. TLC: Rf = 0.6 (Ethyl acetate) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.84 (d, 1
H, J = 15.8Hz, -CH = C), 7.70 (d, 1H, J = 15.8Hz, -CH = C), 7.69
(d, 2H, J = 8.58Hz, arom-H), 7.51 (d, 2H, J = 8.58Hz, arom-H),
6.38 (s, 1H, arom-H), 5.28 (s, 2H, -OCH ₂ ), 5.24 (s, 2H, -OC
H ₂ ), 5.22 (m, 1H, -CH), 3.50 (s, 3H, -OCH ₃ ), 3.48 (s, 3H, -OCH
₃ ), 3.32 (d, 2H, J = 7.26Hz, -CH ₂ ), 2.18 (s, 3H, O = C-CH ₃ ), 1.7
8 (s, 3H, -CH ₃ ), 1.60 (s, 3H, -CH ₃ ) (10b) 400 mg (0.82 mmol) of chalcone compound in methanol 8
After dissolving in 0 ml, several drops of 1N-NaOH were added and the mixture was stirred at room temperature for 6 hours, 20 ml of 2N-HCl was added, and the mixture was heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 13.9 mg (4.1%) of the desired compound as crystals.

TLC: Rf = 0.4 (ethyl acetate: hexane = 1: 1),
mp 222-223 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 11.9 (s, 1H, -OH), 7.
56 (d, 2H, J = 8.58Hz, arom-H), 7.40 (d, 2H, J = 8.58Hz, arom-
H), 6.03 (s, 1H, arom-H), 5.37 (dd, 1H, J = 3.3,12.58Hz, -C
H), 5.20 (m, 1H, -CH), 3.28 (d, 2H, J = 7.26Hz, -CH ₂ ), 2.89 (dd
d, 2H, J = 3.0,12.5,17.1Hz, -CH ₂ ), 2.20 (s, 3H, O = C-CH ₃ ), 1.
68 (s, 3H, 3H, -CH ₃ , -CH ₃ )

[0118]

Example 11 5,7-Dihydroxy-8- (3-methyl-2-butenyl) -2- phenyl
Ru-4-chromanone (11a) Zymom protected 3-isoprenyl-2,4,6-trihydroxyacetophenone 400 mg (1.18 mmol) in DMF 40 ml
Dissolve in 62 mg of sodium hydride under ice cooling (2.36 mmo
l) was added and stirred for 30 minutes, then benzaldehyde 142 mg
(1.18 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 470 mg (89.8%) of an oily substance. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.87 (d, 1
H, J = 15.18Hz, -CH = C), 7.75 (d, 1H, J = 15.18Hz, -CH = C), 7.49
(d, 2H, J = 7.9Hz, arom-H), 7.20 (d, 2H, J = 7.9Hz, arom-H), 6.
39 (s, 2H), 5.26 (s, 2H, -OCH ₂ ), 5.20 (s, 2H, -OCH ₂ ), 5.17 (m,
1H, -CH), 3.57 (s, 3H, -OCH ₃ ), 3.48 (s, 3H, -OCH ₃ ), 3.32 (d, 2
H, J = 7.26Hz, -CH ₃ ), 2.37 (s, 3H, -CH ₃ ), 1.78 (s, 3H, -CH ₃ ),
1.67 (s, 3H, -CH ₃ ) (11b) chalcone 470 mg (1 mmol) in methanol 50 ml
The solution was dissolved in the above solution, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to obtain the desired compound 64 mg (17%) as crystals. TLC: Rf = 0.7 (ethyl acetate: hexane = 3: 1), mp 162-16
3 ° C. ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.1 (s, 1
H, -OH), 7.34 (d, 2H, J = 8.58H
z, arom-H), 7.22 (d, 2H, J = 8.5.
8Hz, arom-H), 5.98 (s, 1H, aro
m-H), 5.37 (dd, 1H, J = 3.3, 12.
5 Hz, -CH), 5.20 (m, 1H, -CH =
C), 3.24 (d, 2H, J = 6.6 Hz, -C)
H ₂ ), 2.79 (ddd, 2H, J = 2.6, 12.
_{5,17.1Hz, -CH 2), 2.31 (} s, 3H,
_{-CH 3), 1.66 (s,} 3H, -CH 3), 1.6
_{3 (s, 3H, -CH 3} )

[0119]

Example 12 5,7-Dihydroxy-2- (4-hydroxy-3-methylphene)
Nil) -8- (3-Methyl-2-butenyl) -4-chromanone (12a) dimom protected 3-isoprenyl-2,4,6-trihydroxyacetophenone 400 mg (1.18 mmol) in DMF 40 ml
Sodium hydride (113 mg (2.36 mm)
ol) and stirred for 30 minutes, and then mom-protected 3-methyl-4-
213 mg (1.18 mmol) of hydroxybenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give 480 mg. (80.8%)
Oil was obtained. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.81 (d, 1
H, J = 15.8Hz, -CH = C), 7.73 (d, 1H, J = 15.8Hz, -CH = C), 7.41-
7.04 (m, 3H, arom-H), 6.83 (s, 1H, arom-H), 5.26 (s, 2H, -C
H ₂ ), 5.24 (s, 2H, 2H, -CH ₂ , -CH ₂ ), 5.20 (m, 1H, -CH), 3.56 (s,
3H, -OCH ₃ ), 3.52 (s, 3H, -OCH ₃ ), 3.48 (s, 3H, -OCH ₃ ), 3.32
(d, 2H, J = 6.6Hz, -CH ₂ ), 2.26 (s, 3H, -CH ₃ ), 1.78 (s, 3H, -C
H ₃ ), 1.66 (s, 3H, -CH ₃ ) (12b) Chalcone 480 mg (0.95 mmol) was added to methanol 4
The solution was dissolved in 0 ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, then 25 ml of 2N-HCl was added, and the mixture was heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to obtain 20 mg (5.9%) of the desired compound as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1), mp 156-15
8 ° C. ¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ OD) δ: 7.32-6.78
(M, 3H, arom-H), 5.97 (s, 1H, a
rom-H), 5.29 (dd, 1H, J = 3.3, 1)
2.8 Hz, -CH, 5.19 (m, 1H, -C
H), 3.22 (d, 2H, J = 7.26 Hz, -CH
₂ ), 2.89 (ddd, 2H, J = 3.2, 12.
_{8,17.2Hz, -CH 2), 2.26 (} s, 3H,
_{-CH 3), 1.65 (s,} 3H, -CH 3), 1.6
_{3 (s, 3H, -CH 3} )

[0120]

Example 13 7-Hydroxy-2- (4-hydroxyphenyl) -8- (3-methyl
Ru-2-butenyl) -4-chromanone (13a) 2,4-dihydroxyacetophenone 7 g (46 mmol)
Is dissolved in 300 ml of THF, and isoprenyl chloride 4.78 is dissolved.
After adding g (46 mmol) and potassium carbonate 19.1 g (138 mmol) and heating and refluxing for 20 hours, the solvent was distilled off. Residue 2.6
THF (200 ml) was added to 9 g to dissolve, and methoxymethyl chloride (1.97 g, 24.4 mmol) and diisopropylethylamine (3.15 g, 24.4 mmol) were added under ice-cooling at room temperature.
Stir for hours. The solvent was distilled off, ethyl acetate was added, and the mixture was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give 1.63 g. An oil (61%) was obtained. TLC: Rf = 0.6 (methylene chloride: methanol = 10: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 12.8 (s, 1H, -OH), 7.61-6.6
4 (m, 2H, arom-H), 5.28 (s, 2H, -OCH ₂ ), 5.21 (m, 1H, -CH), 3.5
0 (s, 3H, -OCH ₃ ), 3.39 (d, 2H, J = 7.26Hz, -CH ₂ ), 2.58 (s, 3H, O
= C-CH ₃ ), 1.81 (s, 3H, -CH ₃ ), 1.69 (s, 3H, -CH ₃ ) (13b) Mom protected 3-isoprenyl-2,4-dihydroxyacetophenone 500 mg (1.89 mmol) It was dissolved in 10 ml of DMF, 173 mg (3.78 mmol) of sodium hydride was added under ice cooling and stirred for 30 minutes, then 314 mg (3.78 mmol) of mom-protected p-hydroxybenzaldehyde was added and stirred for 3 hours at room temperature. . The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate).
= 6: 1) and purified to give 660 mg (81.3%) of an oil.

TLC: Rf = 0.5 (hexane: ethyl acetate = 4: 1) ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 12.8 (s, 1H, -OH), 7.88 (d, 1
H, 15.8Hz, -CH = C), 7.80-6.71 (m, 6H, arom-H), 7.51 (d, 1H, J
= 15.8Hz, -CH = C), 5.31 (s, 2H, -OCH ₂ ), 5.27 (m, 1H, -CH), 5.2
5 (s, 2H, -OCH ₂ ), 3.51 (s, 3H, 3H, -OCH ₃ , -OCH ₃ ), 3.44 (d, 2H,
J = 7.26Hz, -CH ₂ ), 1.82 (s, 3H, -CH ₃ ), 1.72 (s, 3H, -CH ₃ ) (13c) Chalcone 660 mg (1.59 mmol) in methanol 5
The solution was dissolved in 0 ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, then 25 ml of 2N-HCl was added, and the mixture was heated and stirred for 6 hours. After the solvent was distilled off, ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 86.7 mg (16.8%) of the desired compound as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1), mp 183 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.8 (s, 1H, -OH), 7.
67-6.51 (m, 6H, arom-H), 5.34 (dd, 1H, J = 3.3,12.5Hz, -CH),
5.21 (m, 1H, -CH), 3.32 (d, 2H, J = 7.2Hz, -CH ₂ ), 2.79 (ddd, 2
H, J = 3.3,12.5,17.1Hz, -CH ₂ ), 1.65 (s, 3H, -CH ₃ ), 1.64 (s, 3
H, -CH ₃ )

[0122]

Example 14 8-Cinnamyl-5,7-dihydroxy-2- (4-hydroxyphen)
Nyl) -4-chromanone (14a) 2,4,6-trihydroxyacetophenone 5 g (2
9.5 mmol) in THF (300 ml) and add cinnamyl bromide.
5.8 g (29.5 mmol) and potassium carbonate 12.2 g (88.4 mmo
l) was added and the mixture was heated under reflux for 20 hours, the solvent was evaporated, and the residue was dissolved in ethyl acetate. After washing with water, drying over magnesium sulfate and evaporation of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 2
The product was purified by subjecting it to 0: 1) to obtain 2.42 g (23.7%) of yellow crystals. TLC: Rf = 0.4 (methylene chloride: methanol = 10: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.33 -7.13 (m, 5H, a
rom-H), 6.49-6.29 (m , 2H, -CH 2), 5.84 (s, 1H, arom-H), 3.46
-3.45 (m, 2H, -CH ₂ ), 2.67 (s, 3H, -CH ₃ ) (14b) 3-cinnamyl-2,4,6-trihydroxyacetophenone 2 g (6.9 mmol) dissolved in THF 80 ml Then, under ice cooling, 2.8 g (34.8 mmol) of methoxymethyl chloride and 5.4 g (41.8 mmol) of diisopropylethylamine were added, and the mixture was stirred at room temperature for 8 hours. The solvent was distilled off, ethyl acetate was added, and the mixture was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain 800 mg (30.8%) of a yellow oily substance. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.31-7.1
0 (m, 5H, arom-H), 6.44-6.26 (m, 2H, -CH = CH), 6.40 (s, 1H, ar
om-H), 5.25 (s, 2H, -OCH ₂ ), 5.24 (s, 2H, -OCH ₂ ), 3.50 (s, 3H,
-OCH ₃ ), 3.45 (s, 3H, -OCH ₃ ), 2.66 (s, 3H, -CH ₃ ) (14c) Zymom protected 3-cinnamyl-2,4,6-trihydroxyacetophenone 740 mg (1.99 mmol) Was dissolved in 10 ml of DMF, and 100 mg (3.8 mmol) of sodium hydride under ice cooling.
Was added and stirred for 30 minutes, then 331 mg (1.99 mmol) of mom-protected p-hydroxybenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate).
= 4: 1) to give 310 mg (29.3%) of an oily substance.

TLC: Rf = 0.5 (hexane: ethyl acetate = 2: 1) ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 13.9 (s, 1H, -OH), 7.82 (d, 1)
H, J = 15.18Hz, -CH = C), 7.76 (d, 1H, J = 15.18Hz, -CH = C), 7.56
-7.04 (m, 9H, arom-H), 6.47-6.29 (m, 2H, -CH ₂ ), 5.28 (s, 2H,
-OCH ₂ ), 5.26 (s, 2H, -OCH ₂ ), 5.17 (s, 2H, -OCH ₂ ), 3.59 (s, 3
H, -OCH ₃ ), 3.49 (s, 3H, -OCH ₃ ), 3.47 (s, 3H, -OCH ₃ ) (14d) Chalcone 310 mg (0.58 mmol) in methanol 4
The solution was dissolved in 0 ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, then 15 ml of 2N-HCl was added and heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 40 mg (17.5%) of the desired compound as crystals. TLC: Rf = 0.35 (ethyl acetate: hexane = 2: 1), mp 90-9
2 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.1 (s, 1
H, -OH), 7.302-6.83 (m, 9H, ar
om-H), 6.39-6.21 (m, 2H, -CH =
CH), 6.01 (s, 1H, arom-H), 5.3.
2 (d, 1H, J = 2.64, 12.54Hz, -C
_{H), 3.42 (m, 2H} , -CH 2), 3.09-
_{2.73 (m, 2H, -CH 2} )

[0124]

Example 15 8-Benzyl-5,7-dihydroxy-2- (4-hydroxyphene)
Nyl) -4-chromanone (15a) 2,4,6-trihydroxyacetophenone 5 g (2
9.6 mmol) in THF (300 ml) and benzyl bromide 5
g (29.6 mmol) and potassium carbonate 12.2 g (88.8 mmol)
Was added and the mixture was heated under reflux for 20 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to obtain 510 mg (6.65%) of crystals. TLC: Rf = 0.4 (methylene chloride: methanol = 10: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.32-7.04 (m, 5H, ar
om-H), 5.82 (s, 1H, arom-H), 3.89 (s, 2H, -CH ₂ Ph), 2.63 (s, 3
H, -CH ₃ ) (15b) 3-Benzyl-2,4,6-trihydroxyacetophenone 510 mg (1.97 mmol) was dissolved in THF 70 ml, and methoxymethyl chloride 795 mg (9.85 mmol) and Diisopropylethylamine (1.53 g, 11.8 mmol) was added, and the mixture was stirred at room temperature for 8 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated brine, the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and 240 mg (3
An oily substance (4.8%) was obtained. TLC: Rf = 0.7 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.9 (s, 1H, -OH), 7.30-6.9
9 (m, 5H, arom-H), 6.39 (s, 1H, arom-H), 5.25 (s, 2H, -OCH ₂ ),
5.20 (s, 2H, -OCH ₂ ), 3.96 (s, 2H, CH ₂ Ph), 3.50 (s, 3H, -OC
H ₃ ), 3.35 (s, 3H, -OCH ₃ ), 2.65 (s, 3H, -CH ₃ ) (15c) Zymom protected 3-benzyl-2,4,6-trihydroxyacetophenone 240 g (0.69 mmol) in DMF Dissolve in 20 ml, add 67 mg (13.8 mmol) of sodium hydride under ice-cooling and stir for 30 minutes, then add benzaldehyde 115 mg (0.69
mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1).
0 mg (40.7%) of oil was obtained. TLC: Rf = 0.5 (hexane: ethyl acetate = 2: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.9 (s, 1H, -OH), 7.83 (d, 1
H, J = 15.0Hz, -CH = C), 7.75 (d, 1H, J = 15.0Hz, -CH = C), 7.75-
7.04 (m, 9H, arom-H), 6.40 (s, 1H, arom-H), 5.27 (s, 2H-OC
H ₂ ), 5.22 (s, 2H, -OCH ₂ ), 5.21 (s, 2H, -OCH ₂ ), 3.99 (bs, 2H,-
CH ₂ ), 3.52 (s, 3H, -CH ₃ ), 3.48 (s, 3H, -CH ₃ ), 3.36 (s, 3H, -CH
₃ ) (15d) 140 mg (0.28 mmol) of chalcone compound in methanol 1
After dissolving in 0 ml, a few drops of 1N-NaOH were added and the mixture was stirred at room temperature for 6 hours, then 10 ml of 2N-HCl was added and stirred with heating for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 10 mg (9.8%) of the desired compound as crystals. TLC: Rf = 0.35 (ethyl acetate: hexane = 2: 1), mp 218-
219 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.2 (s, 1H, -OH), 7.
29-6.91 (m, 9H, arom-H), 6.08 (s, 1H, arom-H), 5.41 (dd, 1H,
J = 3.0,12.5Hz, -CH), 3.85 (s, 2H, -CH ₂ Ph), 2.99 (m, 2H, -C
H ₂ )

[0125]

Example 16 5,7-Dihydroxy-2- (4-hydroxyphenyl) -8- (3-phenyl)
(Phenylpropyl ) -4-chromanone (16a) Zymom protected 3-cinnamyl-2,4,6-trihydroxyacetophenone 340 mg (1 mmol) in ethanol 80 ml
Dissolved in 10% Pd-C (200 mg), and catalytic hydrogenation was carried out at room temperature under a hydrogen stream. After 3 hours, the reaction solution was filtered through Celite, the solvent was distilled off from the filtrate, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain mg of an oily substance. TLC: Rf = 0.5 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 13.8 (s, 1H, -OH), 7.
27-7.11 (m, 5H, arom-H), 6.37 (s, 1H, arom-H), 5.23 (s, 2H,-
OCH ₂ ), 5.19 (s, 2H, -OCH ₂ ), 3.50 (s, 3H, -OCH ₃ ), 3.44 (s, 3H,
-OCH ₃ ), 2.69-2.65 (m, 4H, -CH ₂ , -CH ₂ ), 1.83 (m, 2H, -CH ₂ ) (16b) Zymom protected 3-phenylpropyl-2,4,6-trihydroxy Acetophenone 340 mg (0.91 mmol) in DMF 20
Dissolve in 83 ml of sodium hydride under ice-cooling 83 mg (1.82 m
mol) and stirred for 30 minutes, then added mom-protected p-hydroxybenzaldehyde (151 mg, 0.91 mmol) and allowed to stand at room temperature for 3 minutes.
Stir for hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 320 mg (71.3%) of a colorless oil. TLC: Rf = 0.6 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.83 (d, 1
H, J = 15.1Hz, -CH = C), 7.75 (d, 1H, J = 15.1Hz, -CH = C), 7.56-
7.04 (m, 9H, arom-H), 6.38 (s, 1H, arom-H), 5.26 (s, 2H, -OCH
₂ ), 5.21 (s, 2H, 2H, -OCH ₂ , -OCH ₂ ), 3.52 (s, 3H, -OCH ₃ ), 3.48
(s, 3H, -OCH ₃ ), 3.46 (s, 3H, -OCH ₃ ), 2.69 (m, 2H, 2H, -CH ₂ , -C
H ₂ ), 1.85 (m, 2H, -CH ₂ ) (16c) Chalcone 320 mg (0.85 mmol) was added to methanol 5
The solution was dissolved in 0 ml, 1N-NaOH was added dropwise and the mixture was stirred at room temperature for 6 hours, then 2N-HCl (14 ml) was added and the mixture was heated and stirred for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 80 mg (24%) of the desired compound as crystals. TLC: Rf = 0.35 (ethyl acetate: hexane = 1: 1), mp 161
-162 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.0 (s, 1H, -OH), 7.
26-6.85 (m, 9H, arom-H), 5.98 (s, 1H, arom-H), 5.38 (dd, 1H,
J = 2.6,12.5Hz, -CH), 2.88 (ddd, 2H, J = 2.6,12.5,17.1Hz, -C
H ₂ ), 2.64-2.56 (m, 2H, 2H, -CH ₂ , -CH ₂ ), 1.88-1.78 (m, 2H, -C
H ₂ )

[0126]

Example 17 5,7-Dihydroxy-2- (4-hydroxyphenyl) -8- (2-me
Cylbenzyl) -4-chromanone (17a) 2,4,6-trihydroxyacetophenone 6 g (3
2.2 mmol) in THF 400 ml, 2-methylbenzyl bromide 6 g (32.3 mmol) and potassium carbonate 13.4 g (96.9
mmol) was added and the mixture was heated under reflux for 20 hours. Evaporate the solvent,
THF (200 ml) was added to the residue (820 mg) to dissolve it, and methoxymethyl chloride (1.21 g (15 mmol)) and diisopropylethylamine (1.94 g (15 mmol)) were added under ice cooling, and the mixture was stirred at room temperature for 8 hours. The solvent was distilled off and ethyl acetate was added,
The organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 410 mg (3.53%) of an oil. TLC: Rf = 0.4 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 13.89 (s, 1H, -OH),
7.24 -6.89 (m, 4H, arom-H), 6.43 (s, 1H, arom-H), 5.28 (s, 2
H, -OCH ₂ ), 5.15 (s, 2H, -OCH ₂ ), 3.90 (s, 2H, -CH ₂ Ph), 3.53
(s, 3H, -OCH ₃ ), 3.28 (s, 3H, -OCH ₃ ), 2.97 (s, 3H, -CH ₃ ), 2.43
(s, 3H, -CH ₃ ) (17b) Dimom-protected 3- (2-methylbenzyl) -2,4,6-trihydroxyacetophenone 410 mg (1.13 mmol) in DMF 20
100 ml of sodium hydride (2.2 mg
mmol) and stirred for 30 minutes, 190 mg (1.13 mmol) of mom-protected p-hydroxybenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 430 mg (74%) of an oily substance. TLC: Rf = 0.5 (hexane: ethyl acetate = 2: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 13.9 (s, 1H, -OH), 7.85 (d, 1
H, J = 15.1Hz, -CH = C), 7.76 (d, 1H, J = 15.1Hz, -CH = C), 7.56-
6.89 (m, 8H, arom-H), 6.43 (s, 1H, -CH), 5.30 (s, 2H, -OCH ₂ ),
5.20 (s, 2H, -OCH ₂ ), 5.16 (s, 2H, -OCH ₂ ), 3.93 (s, 2H, -CH ₂ P
h), 3.54 (s, 2H, -OCH ₃ ), 3.48 (s, 3H, -OCH ₃ ), 3.28 (s, 3H, -OC
H ₃ ), 2.44 (s, 3H, -CH ₃ ) (17c) Chalcone 430 mg (0.8 mmol) in methanol 50
After dissolving in ml, several drops of 1N-NaOH were added and stirred at room temperature for 6 hours, then 20 ml of 2N-HCl was added and stirred with heating for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1),
50 mg (15.7%) of the desired compound was obtained as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1), mp 198 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.1 (s, 1H, -OH), 7.
11-6.77 (m, 8H, arom-H), 6.02 (s, 1H, arom-H), 5.26 (dd, 1H,
J = 3.3,12.5Hz, -CH), 3.83 (s, 2H, -CH ₂ Ph), 2.98 (ddd, 2H, J =
3.3,12.5,17.1Hz, -CH ₂ ), 2.29 (s, 3H, -CH ₃ )

[0127]

Example 18 5,7-Dihydroxy-2- (4-hydroxyphenyl) -8- (3-me
Cylbenzyl) -4-chromanone (18a) 2,4,6-trihydroxyacetophenone 6 g (3
2.4 mmol) in 300 ml of THF, 6 g (32.3 mmol) of 3-methylbenzyl bromide and 13.4 g (96.9 g of potassium carbonate).
mmol) was added and the mixture was heated under reflux for 20 hours. THF (200 ml) was added to the solvent-distilled residue (1.25 g) to dissolve it, and methoxymethyl chloride (1.85 g, 22.9 mmol) and diisopropylethylamine (3 g, 22.9 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 8 hours. The solvent was distilled off and ethyl acetate was added,
The organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain 660 mg (5.68%) of an oily substance. TLC: Rf = 0.4 (hexane: ethyl acetate = 3: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 13.89 (s, 1H, -OH),
7.19 -6.84 (m, 4H, arom-H), 6.43 (s, 1H, arom-H), 5.27 (s, 2
H, -OCH ₂ ), 5.13 (s, 2H, -OCH ₂ ), 3.91 (s, 2H, -CH ₂ Ph), 3.53
(s, 3H, -OCH ₃ ), 3.28 (s, 3H, -OCH ₃ ), 2.98 (s, 3H, -CH ₃ ), 2.38
(s, 3H, -CH ₃ ) (18b) Dimomu-protected 3- (3-methylbenzyl) -2,4,6-trihydroxyacetophenone 330 mg (0.9 mmol) in DMF 20 ml
80 mg of sodium hydride (1.8 mmo
l) was added and the mixture was stirred for 30 minutes, then 152 mg (0.9 mmol) of mom-protected p-hydroxybenzaldehyde was added, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, ethyl acetate was added, and the organic layer was washed with water. After washing with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate).
= 4: 1) for purification to obtain 270 mg (57.7%) of an oil.

TLC: Rf = 0.5 (hexane: ethyl acetate = 2: 1) ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 13.8 (s, 1H, -OH), 7.83 (d, 1)
H, J = 15.8Hz, -CH = C), 7.75 (d, 1H, J = 15.8Hz, -CH = C), 7.14-
6.93 (m, 8H, arom-H), 6.40 (s, 1H, arom-H), 5.27 (s, 2H, -OCH
₂ ), 5.23 (s, 2H, -OCH ₂ ), 5.21 (s, 2H, -OCH ₂ ), 3.96 (s, 2H, -CH
₂ ), 3.52 (s, 3H, -OCH ₃ ), 3.49 (s, 3H, -OCH ₃ ), 3.39 (s, 3H, -OC
H ₃ ), 2.28 (s, 3H, -CH ₃ ) (18c) chalcone 270 mg (0.52 mmol) in methanol 2
It was dissolved in 00 ml, a few drops of 1N-NaOH was added, and the mixture was stirred at room temperature for 6 hours, 10 ml of 2N-HCl was added, and the mixture was heated and stirred for 6 hours.
The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 20 mg (11.3%) of the desired compound as crystals. TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1), mp 215 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.1 (s, 1H, -OH), 7.
35-6.83 (m, 8H, arom-H), 5.98 (s, 1H, arom-H), 5.29 (dd, 1H,
J = 3.3,12.5Hz, -CH), 3.83 (s, 2H, -CH ₂ Ph), 2.88 (ddd, 2H, J =
3.3,12.5,17.1Hz, -CH ₂ ), 2.21 (s, 3H, -CH ₃ )

[0129]

Example 19 5,7-Dihydroxy-2- (4-hydroxy-3,5-dimethylphene
Nil) -8- (3-Methyl-2-butenyl) -4-chromanone (19a) Zymom protected 3-isoprenyl-2,4,6-trihydroxyacetophenone 300 mg (0.9 mmol) is dissolved in DMF 10 ml and iced. Sodium hydride under cold 81 mg (1.9 mmol)
Was added and stirred for 30 minutes, then benzaldehyde 180 mg
(0.8 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, the residue was dissolved in methanol (20 ml), several drops of 1N-NaOH were added, and the mixture was stirred at room temperature for 6 hours, then 2N-HCl (15 ml) was added and the mixture was heated with stirring for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
The product was purified by 2: 1) to give 61 mg (19.2%) of the desired compound as crystals. TLC: Rf = 0.58 (ethyl acetate: hexane = 2: 1), mp 139-
140 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.06 (s, 2H, arom-
H), 6.01 (s, 1H, arom-H), 5.31 -5.26 (m, 1H, -CH), 5.25-5.2
0 (m, 1H, -CH = C), 3.31 (d, 2H, J = 7.2Hz, -CH ₂ ), 3.11-2.79 (m,
2H, -CH ₂ ), 2.28 (s, 3H, 3H, -CH ₃ , -CH ₃ ), 1.57 (s, 3H, -CH ₃ )

[0130]

Example 20 2- (3,5-di-t-butyl-4-hydroxyphenyl) -5,7-di
Hydroxy-8- (3-methyl-2-butenyl) -4-chromanone Jimomu protected 3 isoprenyl-2,4,6-trihydroxy acetophenone 300 mg of (0.9 mmol) were dissolved in DMF 10 ml, under ice-cooling 81 mg (1.9 mmol) of sodium hydride was added and stirred for 30 minutes, and then benzaldehyde 257 mg (0.9 m
mol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, the residue was dissolved in methanol (20 ml), several drops of 1N-NaOH were added, and the mixture was stirred at room temperature for 6 hours, then 2N-HCl (15 ml) was added and the mixture was heated with stirring for 6 hours. The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 52 mg (12.7%) of the desired compound as crystals. TLC: Rf = 0.58 (ethyl acetate: hexane = 3: 1), mp 190-
195 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.26 (s, 2H, arom-
H), 6.01 (s, 1H, arom-H), 5.36-5.30 (m, 1H, -CH), 5.26-5.21
(m, 1H, -CH), 3.31 (m, 2H, -CH ₂ ), 3.15-2.77 (m, 2H, -CH ₂ ), 1.
71 (s, 6H, -CH ₃ , -CH ₃ ), 1.46 (s, 18H, t-Bu)

[0131]

Example 21 7-Hydroxy-2- (4-hydroxy-3,5-dimethylphenyi
Le) - 8- (3-methyl-2-butenyl) -4-chromanone Mom protected 3 isoprenyl-2,4-dihydroxy acetophenone 300 mg of (1.1 mmol) were dissolved in DMF 10 ml, hydrogenated under ice-cooling After adding sodium 100 mg (2.2 mmol) and stirring for 30 minutes, benzaldehyde 220 mg (1.1 mmol) was added and it stirred at room temperature for 3 hours. Distill off the solvent to remove methanol
The mixture was dissolved in 20 ml, 1N-NaOH was added in a few drops, and the mixture was stirred at room temperature for 6 hours, then, 2N-HCl (15 ml) was added, and the mixture was heated and stirred for 6 hours.
The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 68.4 mg (17%) of the desired compound as crystals. TLC: Rf = 0.25 (ethyl acetate: hexane = 3: 1), mp 174-
175 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.76 (d, 1H, J = 8.6H
z, arom-H), 7.08 (s, 2H, arom-H), 6.53 (d, 1H, J = 8.6Hz, arom
-H), 5.35 -5.34 (m, 1H, -CH), 5.30-5.29 (m, 1H, -CH = C), 3.4
2 (d, 2H, J = 6.83Hz, -CH ₂ ), 3.06-2.74 (m, 2H, -CH ₂ ), 2.29 (s,
3H, 3H, -CH ₃ , -CH ₃ ), 1.76 (s, 3H, 3H, -CH ₃ , -CH ₃ )

[0132]

Example 22 2- (3,5-di t-butyl-4-hydroxyphenyl) -7-hydr
Proxy-8- (3-methyl-2-butenyl) -4-chromanone Mom protected 3 isoprenyl-2,4-dihydroxy acetophenone 300 mg of (1.1 mmol) were dissolved in DMF 10 ml, sodium hydride under ice-cooling After 100 mg (2.2 mmol) was added and stirred for 30 minutes, benzaldehyde 315 mg (1.1 mmol) was added and stirred at room temperature for 3 hours. Distill off the solvent to remove methanol
The mixture was dissolved in 20 ml, 1N-NaOH was added in a few drops, and the mixture was stirred at room temperature for 6 hours, then, 2N-HCl (15 ml) was added and the mixture was heated and stirred for 6 hours.
The solvent was evaporated, ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 89.7 mg (18%) of the desired compound as crystals. TLC: Rf = 0.58 (ethyl acetate: hexane = 2: 1), mp 180-
184 ° C. ¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ OD) δ: 7.70-7.6
7 (m, 2H, arom-H), 6.54-6.51
(M, 2H, arom-H), 5.37 (dd, 1H,
J = 2.9, 13.2 Hz, -CH), 5.28 (m,
1H, -CH), 3.37 (m , 2H, -CH 2),
_{3.09-2.77 (m, 2H, -CH 2} ), 1.66
_{(S, 3H, 3H, -CH} 3, -CH 3), 1.46
(S, 18H, t-Bu)

[0133]

Example 23 7-Hydroxy-2- (4-hydroxyphenyl) -8- (3-methyl
Ru-2-butenyl) -4 (4H) -chromenone flavanone derivative 136 mg (0.42 mmol) was dissolved in 10 ml of pyridine, and after adding 107 mg (0.42 mmol) of iodine at room temperature,
The mixture was heated and stirred at 90 ° C for 5 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
Purification was performed by 1: 1) to obtain 66 mg (49%) of the desired compound as crystals. TLC: Rf = 0.10 (ethyl acetate: hexane = 1: 1), mp 152-
153 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.90-6.23 (m, 6H, a
rom-H), 6.66 (s, 1H, -CH), 5.31 (m, 1H, -CH), 3.67 (d, 2H, -C
H ₂ ), 1.84 (s, 3H, -CH ₃ ), 1.70 (s, 3H, -CH ₃ )

[0134]

Example 24 5,7-Dihydroxy-2- (4-hydroxy-3-methylphenyi
) -8- (3-Methyl-2-butenyl) -4 (4H) -chromenone flavanone derivative 48.8 mg (0.14 mmol) was dissolved in 10 ml of pyridine, and 35 mg (0.14 mmol) of iodine was added at room temperature. , 9
The mixture was heated and stirred at 0 ° C for 5 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
1: 1) and purified to obtain 11.6 mg (24%) of the desired compound as crystals. TLC: Rf = 0.31 (ethyl acetate: hexane = 1: 1), mp 145-
153 ° C. ¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ OD) δ: 7.69-6.
87 (m, 3H, arom-H), 6.53 (s, 1
H, arom-H), 6.30 (s, 1H, -CH),
5.28 (dd, 1H, -CH), 3.54 (d, 2)
_{H, J = 7.75Hz, -CH 2} ), 2.30 (s, 3
_{H, -CH 3), 1.84 (} s, 3H, -CH 3),
_{1.70 (s, 3H, -CH 3} )

[0135]

Example 25 2- (4-Bromophenyl) -5,7-dihydroxy-8- (3-
Methyl-2-butenyl) -4 (4H) -chromenone flavanone derivative 27 mg (0.07 mmol) was dissolved in 10 ml of pyridine, and iodine (17 mg, 0.07 mmol) was added at room temperature.
The mixture was heated and stirred at 5 ° C for 5 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 4:
After purification by subjecting to 1), 5 mg (19%) of the desired compound was obtained as crystals. TLC: Rf = 0.35 (ethyl acetate: hexane = 3: 1), mp 220-
224 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.76-7.65 (m, 4H, a
rom-H), 6.66 (s, 1H, -CH), 6.34 (s, 1H, arom-H), 5.29 (m, 1H-
U), 3.59 (d, 2H, J = 7.04Hz, -CH ₂ ), 1.86 (s, 3H, -CH ₃ ), 1.77
(s, 3H, -CH ₃ )

[0136]

Example 26 2- (4-chlorophenyl) -5,7-dihydroxy-8- (3-methyl
-2-Butenyl) -4 (4H) -chromenone flavanone derivative 45.8 mg (0.13 mmol) was dissolved in 10 ml of pyridine, and 32 mg (0.13 mmol) of iodine was added at room temperature.
The mixture was heated and stirred at 0 ° C for 5 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
2: 1) to obtain the desired compound (8.3 mg, 18%) as crystals. TLC: Rf = 0.34 (ethyl acetate: hexane = 4: 1), mp 198-
^{202 ℃ 1 H-NMR (270MHz} , CDCl 3 + CD 3 OD) δ: 7.88-7.
50 (m, 4H, arom-H), 6.64 (s, 1
H, -CH), 6.32 (s, 1H, arom-H),
5.25-5.19 (m, 1H, -CH), 3.55
_{(D, 2H, -CH 2)} , 1.82 (s, 3H, -CH
_{3), 1.70 (s, 3H} , -CH 3)

[0137]

Example 27 5,7-Dihydroxy-2- (4-hydroxy-3-methoxyphenol
Phenyl) -8- (3-methyl-2-butenyl) -4 (4H) -chromenone flavanone derivative 132.8 mg (0.36 mmol) in pyridine (15 ml)
Was dissolved in water, and 91 mg (0.36 mmol) of iodine was added at room temperature, followed by heating with stirring at 90 ° C for 5 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1), and the desired compound 49.7 mg (38%)
Was obtained as crystals. TLC: Rf = 0.26 (ethyl acetate: hexane = 3: 2), mp 200-
210 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.46-7.00 (m, 3H, a
rom-H), 6.55 (s, 1H, -CH), 6.30 (s, 1H, arom-H), 5.31 (m, 1H,
-CH), 3.97 (s, 3H, -OCH ₃ ), 3.54 (m, 2H, -CH ₂ ), 1.81 (s, 3H, -C
H ₃ ), 1.69 (s, 3H, -CH ₃ )

[0138]

Example 28 5,7-Dihydroxy-2- (3-hydroxy-4-methoxyphenyi
) -8- (3-Methyl-2-butenyl) -4 (4H) -chromenone flavanone derivative 74.6 mg (0.2 mmol) was dissolved in 10 ml of pyridine, and after adding 51 mg (0.2 mmol) of iodine at room temperature. , 9
The mixture was heated and stirred at 0 ° C for 5 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
2: 1) for purification to obtain 26.1 mg (35%) of the desired compound as crystals. TLC: Rf = 0.25 (ethyl acetate: hexane = 3: 2), mp 190-
198 ° C. ¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ OD) δ: 7.47-6.
96 (m, 3H, arom-H), 6.54 (s, 1
H, -CH), 6.30 (s, 1H, arom-H),
5.27 (m, 1H, -CH), 3.54 (m, 2H,
_{-CH 2), 1.83 (s,} 3H, -CH 3), 1.7
_{0 (s, 3H, -CH 3} )

[0139]

Example 29 5,7-Dihydroxy-2- (4-methylphenyl) -8- (3-me
Tyl-2-butenyl) -4 (4H) -chromenone flavanone derivative 48.9 mg (0.14 mmol) was dissolved in 10 ml of pyridine, and after adding 37 mg (0.14 mmol) of iodine at room temperature, 9
The mixture was heated and stirred at 0 ° C for 5 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
3: 1) to obtain the desired compound (8.3 mg, 17%) as crystals. TLC: Rf = 0.47 (ethyl acetate: hexane = 2: 1), mp 220-
222 ℃ ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 7.83-7.32 (m, 4H, a
rom-H), 6.63 (s, 1H, -CH,), 6.30 (s, 1H, arom-H), 5.28 (m, 1
H, -CH), 3.55 (d, 2H, J = 6.69Hz, -CH ₂ ), 2.45 (s, 3H, -CH ₃ )

[0140]

Example 30 6,8-Dihydroxy-3- (4-hydroxyphenyl) -5- (3-me
Cyl-2-butenyl) -3,4-dihydro-2H-naphthalene-1-o
Down (30a) dry THF 30 ml to is previously suspended lithium dispersion 200 mg of washed with hexane under nitrogen atmosphere 3,5-dimethoxybenzyl chloride 1 g (5.3 mmol) and p- methoxycinnamate methyl ester 1 g (5.3 mmol) at -20 ° C
And stirred for 4 hours. The reaction solution was diluted with THF, a saturated aqueous solution of ammonium chloride was added, the organic layer was extracted, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to give the desired compound.
Obtained 546 mg (27%). TLC: Rf = 0.5 (hexane: ethyl acetate = 4: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 7.06 (d, 2H, J = 8.58Hz, arom
-H), 6.80 (d, 2H, J = 8.58Hz, arom-H), 6.26 (m, 1H, arom-H),
6.18-6.17 (m, 2H, arom-H), 3.78 (s, 3H, OCH ₃ ), 3.70 (s, 3H, 3
H, OCH ₃ , OCH ₃ ), 3.52 (s, 3H, OCH ₃ ), 3.34 (m, 1H, -CH), 2.80
(m, 2H, -CH ₂ ), 2.63 (m, 2H, -CH ₂ ) (30b) Ester 300 mg (0.87 mmol) to polyphosphoric acid 5 g
Was added and the mixture was heated with stirring at 80 ° C. for 2 hours under a nitrogen stream. Water and ethyl acetate were added to extract the organic layer, saturated aqueous sodium hydrogen carbonate,
After washing with water and saturated saline, it was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Dissolve 260 mg of the residue in 70 ml of methylene chloride and add 5.2 ml of 1M boron tribromide solution.
The mixture was added at -78 ° C and stirred at room temperature for 8 hours. The extract was washed with methanol, ethyl acetate, water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
Purification by 1: 1) yielded 200 mg (87.5%) of the desired compound. TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.8 (s, 1H, -OH), 7.
11 (d, 2H, J = 8.58Hz, arom-H), 6.81 (d, 2H, J = 8.58Hz, arom-
H), 6.22-6.21 (m, 2H, arom-H), 3.37-3.24 (m, 2H, -CH), 3.01
-2.98 (m, 2H, -CH ₂ ), 2.81 -2.71 (m, 2H, -CH ₂ ) (30c) Triphenol derivative 200 mg (0.75 mmol) in DMF 20
Dissolve in 78 ml of isoprenyl chloride 78 mg (0.75 mmo
l) and 100 mg (0.75 mmol) of potassium carbonate, and add 80
The mixture was heated and stirred at ℃ for 3 hours. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 2:
After purification by subjecting to 1), 230 mg (90%) of the desired compound was obtained. TLC: Rf = 0.5 (ethyl acetate: hexane = 2: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 12.8 (s, 1H, -OH), 7.
12 (d, 2H, J = 8.58Hz, arom-H), 6.82 (d, 2H, arom-H), 6.30-6.
29 (m, 2H, arom-H), 5.48 -5.42 (m, 1H, -CH), 4.54-4.51 (m, 2
H, -CH ₂ ), 3.37-3.25 (m, 1H, -CH), 3.02-2.99 (m, 2H, -CH ₂ ),
2.88-2.71 (m, 2H, -CH ₂ ), 1.79 (s, 3H, -CH ₃ ), 1.73 (s, 3H, -CH
₃ ) (30d) Monoisoprenyl ether 230 mg (0.67 mmol)
Was dissolved in 10 ml of methylene chloride, 50 mg of montmorillonite KSF was suspended in a nitrogen stream, and the mixture was stirred for 24 hours. The reaction solution was filtered through Celite, ethyl acetate was added to the filtrate, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to obtain 20 mg (8.6%) of the desired compound. TLC: Rf = 0.4 (ethyl acetate: hexane = 2: 1) ¹ H-NMR (270MHz, CDCl ₃ + CD ₃ OD) δ: 13.7 (s, 1H, -OH), 7.
12 (d, 2H, J = 8.58Hz, arom-H), 6.82 (d, 2H, J = 8.58Hz, arom-
H), 6.23 (s, 1H, arom-H), 5.05-4.99 (m, 1H, -CH), 3.28-3.25
(m, 2H, -CH ₂ ), 3.23-3.13 (m, 2H, -CH ₂ ), 2.98 -2.71 (m, m, 2
H, 1H, -CH ₂ , -CH), 1.69 (s, 3H, -CH ₃ ), 1.66 (s, 3H, -CH ₃ ) (30e) 3,5-dimethoxyphenylacetic acid 3 g (15.4 mmol) It was suspended in 50 ml of benzene, 2 g (16.0 mmol) of oxalyl chloride and 2 drops of DMF were added under ice cooling, and the mixture was stirred for 3 hours. After the solvent was distilled off, 10 ml of anisole and 2.1 g (15.8 mmol) of aluminum chloride were added, and the mixture was stirred at room temperature for 3 hours.
Dilute hydrochloric acid and ethyl acetate were added for extraction, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to obtain 3.18 g (72.4%) of the desired compound. TLC: Rf = 0.7 (ethyl acetate: hexane = 2: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 7.99 (d, 2H, J = 8.6Hz, arom-
H), 6.92 (d, 2H, J = 8.6Hz, arom-H), 6.43-6.34 (m, 3H, arom-
H), 4.15 (s, 2H , -CH 2), 3.85 (s, 3H, -CH 3), 3.76 (s, 3H, 3H, -O
CH _3, sodium hydride 14 washing with -OCH ₃₎ (30f) in advance hexane
g (62.5 mmol) was added to triethylphosphonoacetate 14 g (62.5 mmol) under ice cooling and stirred for 30 minutes,
3.18 g (11.1 mmol) of (3,5-dimethoxybenzyl) (4′-methoxyphenyl) ketone was added, and the mixture was stirred at 120 ° C. for 3 hours. Ethyl acetate was added to the reaction solution, washed with water and saturated saline, and the solvent was evaporated. 3 g of residue is 100 m of ethanol
10% Pd-C (500 mg) was added to the solution, and the mixture was catalytically hydrogenated at room temperature for 3 hours under a hydrogen stream. The reaction solution was filtered through Celite, the solvent in the filtrate was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 6: 1) to obtain 2.38 g (60%) of the desired compound. It was TLC: Rf = 0.7 (ethyl acetate: hexane = 5: 1) ¹ H-NMR (270MHz, CDCl ₃ ) δ: 7.02 (d, 2H, J = 8.6Hz, arom-
H), 6.79 (d, 2H, J = 8.6Hz, arom-H), 6.28-6.26 (m, 1H, arom-
H), 6.20-6.19 (m, 2H, arom-H), 3.99 (q, 2H, J = 7.1Hz, -CH ₂ ),
3.76 (s, 3H, -OCH ₃ ), 3.71 (s, 3H, 3H, -OCH ₃ , -OCH ₃ ), 3.38-3.
32 (m, 1H, -CH), 2.83-2.79 (m, 2H, -CH ₂ ), 2.68-2.50 (m, 2H,-
CH ₂ ), 1.11 (t, 3H, J = 7.1Hz, -CH ₃ ) (30g) (3,5-dimethoxybenzyl) (4'-methoxyphenyl) ketone 7.47 g (26 mmol) was dissolved in THF 150 ml. ,
3.2 g of a zinc-copper alloy (about 91% zinc and 5% copper) and 3.5 ml of ethyl bromoacetate were added, and the mixture was refluxed for 6 hours under a nitrogen atmosphere. Dilute hydrochloric acid and ethyl acetate were added to the reaction solution for extraction, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue (7.61 g) was added 100 ml of benzene and p-toluenesulfonyl chloride.
100 mg (0.524 mmol) was added and the mixture was refluxed for 3 hours under a nitrogen stream. Water and ethyl acetate were added to the reaction solution for extraction,
The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Residue 7.18 g
Was dissolved in 100 ml of ethanol, 500 mg of 10% Pd-C was added, and catalytic hydrogenation was carried out at room temperature for 6 hours under a hydrogen stream. The reaction solution was filtered through Celite, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane).
= 6: 1) to give the desired compound 5.66 g (57%). The physicochemical properties of this compound were the same as those of the compound obtained in (30f) above.

[0141]

INDUSTRIAL APPLICABILITY Since the compound of the present invention specifically binds to the estrogen receptor, it is useful as a drug such as an estrogen agonist.

[0142]

[Test example]

[0143]

[Test Example 1] Affinity to estrogen receptor Affinity to estrogen receptor was determined by Thibodeau, SN
The measurement was carried out by partially modifying and using the above method (Clin. Chem., 27 , 678-691 (1981)). That is, the test was performed using an estrogen receptor (estrogen binding protein) in a cell-soluble fraction obtained by grinding a bovine uterus and ultracentrifuging at 100,000 G for 1 hour. Final concentration of 1 nM
[ ³ H] estradiol (13
(6 Ci / mmol) solution, 10 μl of the sample solution (or solvent only) and 200 μl of the cell-soluble fraction were mixed, and then stored overnight at 4 ° C. Free [ ³ H] estradiol in the reaction solution was converted to dextran (Dextran T70, manufactured by Pharmacia) -coated activated carbon (C
4386, manufactured by Sigma), and the amount of [ ³ H] estradiol bound to the estrogen receptor was measured with a liquid scintillation counter to determine the amount of [ ³ H] estradiol bound to the estrogen receptor. For non-specific binding measurement, a 500-fold excess of [ ³ H] estradiol was added to estradiol instead of the sample solution, and the same treatment was performed. The affinity of the sample for the estrogen receptor is
The inhibition rate of the binding of [ ³ H] estradiol to the estrogen receptor was determined by the following equation. Binding inhibition rate = 100- (a / b × 100) a: dpm of sample addition-dpm of non-specific binding b: dpm of sample non-addition-dpm of non-specific binding As a control compound showing an estradiol antagonism , Genistein was used.

[0144]

Embedded image

[0145]

[Test Example 2] Estrogen activity: effect on cultured cells Human breast cancer-derived cells T47D whose proliferation is promoted by estrogen (Reddel, RR & Sutherland, RL, Eur.
J. Clin. Oncol., 20 , 1419-1424 (1984))
The compounds of the invention were tested for estrogenic activity. That is,
3000 T47D cells were seeded in each well of a 96-well microtest plate, and after cells adhered, 200I
RPMI 1640 containing 10% fetal bovine serum with U / I insulin and endogenous estrogen removed with activated charcoal
The medium was replaced. A sample solution (or solvent alone) was added to the mixture, and the mixture was incubated at 37 ° C for 4 days.

In addition, for the estradiol cell proliferation effect,
To determine whether the compounds of the present invention antagonize,
0.1 nM estradiol solution and sample solution (or 0.1.
An experiment in which 1 nM estradiol solution only) was added at the same time was also performed. After culture, the degree of proliferation of T47D cells
rmichael, J. et al. (Cancer Res., 47 , 936-942 (19
87)), MTT [(3- (4,5-dimethyl-2-thiazoly
l) -2,5-diphenyl-2H-tetrazolium bromide)] and the absorbance at a wavelength of 550 nm was used as an index. The growth promotion rate was determined by the following equation. Growth promotion rate = a / b × 100 a: Absorbance when sample is added b: Absorbance when sample is not added The growth promotion rate of each sample at various concentrations is plotted, and the maximum effect of estradiol is the maximum effect of each sample. To the concentration (E _max ), the concentration giving a half effect of E _max (EC ₅₀ ) and the effect of 0.1 nM estradiol on 5
The 0% antagonistic concentration (IC ₅₀ (T47D)) was determined. In addition, genistein was used as a control compound.

The compound of the present invention has a cell growth promoting effect (from the result of EC ₅₀ ) but is not a full agonist like genistein but a partial agonist (from the result of E _max ) and is not present in genistein, Since it has an estrogen antagonist activity (from the result of IC ₅₀ ), it is a preventive or therapeutic agent for osteoporosis that does not cause the growth of uterine cancer or breast cancer.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/35 AEK A61K 31/35 AEK C07D 311/30 C07D 311/30 311/32 311/32 ( 72) Inventor Yuji Iwano 1-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Yasuki Iijima 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Motohiko Taki 1-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Masahiro Kitaoka 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company

Claims (16)

[Claims] 1. The following formula: [In the formula, R ₁ represents a hydroxyl group or a hydrogen atom, R ₂ represents an unsubstituted or aryl-substituted alkyl group or an unsubstituted or aryl-substituted alkenyl group, and R ₃ represents a hydrogen atom or a lower alkyl group. , R ₄ and R ₅ each independently represent a hydrogen atom or a lower alkyl group, R ₆ represents a hydroxyl group, a halogen atom, or a lower alkyl group, X represents an oxygen atom or a methylene group, and ---- The bond indicated by means that the bond is a single bond or a double bond] and a salt thereof. 2. R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted or unsubstituted phenyl group. Have as
C _1-4 alkyl group, R ₃ is hydrogen atom or unsubstituted C _1-4 alkyl group, R ₄ is hydrogen atom or unsubstituted C _1-4 alkyl group, R ₅ is hydrogen The compound or a salt thereof according to claim 1, which is an atom or an unsubstituted C _1-4 alkyl group, and R ₆ is a hydroxyl group, a halogen atom, or an unsubstituted C _1-4 alkyl group. 3. The compound and salt thereof according to claim 2, wherein R ₁ is a hydroxyl group and X is an oxygen atom. 4. The compound or a salt thereof according to claim 3, wherein R ₆ is a hydroxyl group. 5. The compound according to claim 2, wherein R ₁ is a hydroxyl group, R ₆ is a hydroxyl group, X is a methylene group, and the bond with ---- is a single bond. Its salt. 6. The compound and salt thereof according to claim 5, wherein R ₄ is a hydrogen atom. 7. The compound and salt thereof according to claim 2, wherein R ₁ is a hydrogen atom, R ₆ is a hydroxyl group, and X is an oxygen atom. 8. R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted or unsubstituted benzyl group, The compound and salt thereof according to claim 7, wherein R ₃ is a hydrogen atom and R ₄ is a hydrogen atom. 9. R ₁ is a hydrogen atom, R ₃ is a hydrogen atom, R ₄ is a hydrogen atom, R ₆ is a hydroxyl group, X
Is a methylene group, and the bond marked with ---- is a single bond. 10. R ₂ is an unsubstituted C _1-6 alkyl group, an unsubstituted C _2-6 alkenyl group containing one double bond, or a C _1-4 alkyl-substituted or unsubstituted benzyl group. Item 9. A compound or a salt thereof according to item 9. 11. A medicine comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient. 13. The pharmaceutical composition according to claim 12, which is used as an estrogen agonist. 14. Use for prevention and / or treatment of a disease selected from the group consisting of a disease caused by a decrease in estrogen, menopausal disorder, prostate cancer, and benign prostatic hyperplasia.
The pharmaceutical composition according to 3. 15. The pharmaceutical composition according to claim 13, which is used for suppressing milk secretion. 16. Use of a compound according to any one of claims 1 to 10 for the manufacture of a pharmaceutical composition according to any one of claims 12 to 15.