JPH11292868A - Novel naphthofuranone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel compound having strong bonding inhibition activity against progesterone receptor and useful as a therapeutic agent of progesterone associated diseases for progesterone receptor-expressing organs such as pestle, uterus, ovary, etc. SOLUTION: A compound of formula I (R<1> is H or the like; R<2> is H or the like; R<3> is H or the like), e.g. (4a*,6R*)-6-acetoxy-3, 4a-dimethyl-4a,5,6,7- tetrahydronaphtho[2,3-b]furan-2(4H)-one. The compound of formula I is obtained by using, e.g. a compound of formula II as a starting raw material to synthesize a compound of formula III through the site-selective ketalization and the Rubottom reaction in order, and acylating the compound of formula III with 1-10 equivalent of a reagent such as acetyl chloride, etc., in the presence of an aprotic solvent such as mehtylene chloride, etc., preferably at 20-60 deg.C for 10 min.-2 hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel naphthofuranone derivative or a naphthofuranone derivative useful as a contraceptive based on a progesterone receptor binding inhibitory activity, or a progesterone-related disease therapeutic agent for a progesterone receptor-expressing organ such as the breast, uterus, ovary, bone, and center It relates to a pharmaceutically acceptable salt.

[0002]

2. Description of the Related Art In recent years, the number of patients with breast cancer has been increasing in Japan, and it is expected that breast cancer will become the first female malignant tumor in the 21st century. Surgical endocrine therapy for breast cancer began with ovariectomy and has been the mainstay of surgical endocrine therapy since adrenalectomy and hypophysectomy were reported to be useful as treatments for advanced breast cancer . These surgical endocrine therapies regress estrogen-dependent breast cancer by removing organs involved in estrogen secretion. However, as a result, not only estrogen but also steroid hormones and other hormones necessary for sustaining life are lacking, so that there have been many problems in terms of quality of life.

[0003] Nonsteroidal antiestrogens such as tamoxifen citrate, which appeared in the late 1970's, have revolutionized the history of breast cancer treatment and have replaced surgical endocrine therapy, which has been the mainstream until then. This is because tamoxifen citrate has a high response against breast cancer,
This is because the side effect is significantly lower than that of the conventional androgen therapy or estrogen therapy, and the concept of estrogen receptor (ER) has been introduced, so that ER measurement can be easily performed on a daily basis. For these reasons,
It has become the first-line drug for ER-positive breast cancer and has been widely applied to clinical practice.

[0004] Recently, medroxyprogesterone acetate which has a myeloprotective effect and an effect of reducing the side effects when used in combination with certain anticancer drugs (Clinic of breast cancer, Vol. 2, No. 1, 5-197, 1986) ), An aromatase inhibitor that exerts an effect by inhibiting aromatase, an enzyme that converts androgen to estrogen, which is present in tissues; luteinizing hormone-releasing hormone receptor in the pituitary gland to downregulate luteinizing hormone; follicle stimulation New mechanisms of action, such as luteinizing hormone-releasing hormone agonists (cancer and chemotherapy, 16, 2729, 1994), which are thought to lead to reduced secretion of hormones and consequently the same effects as surgical ovariectomy Has been developed, and endocrine therapy for breast cancer has been diversified. Came.

[0005] In recent years, treatment of breast cancer with an antiprogesterone agent focusing on the progesterone receptor has recently been actively attempted. For example, mifepristone (M
ifristone; RU38486) (Cancer Res., 49, 28).
51-2856, 1989), Onapristone (Ona)
prism; ZK98299) (Journal Steroid Biochemical Molecular Biology (J. Steroid Biochem. Molec.)).
Biol. ), 41, 339-348, 1992) are currently under development. These new types of drugs that target the inhibition of progesterone receptor binding are expected to be effective not only for the treatment of endometriosis, uterine fibroids, meningioma, etc., but also for breast cancer. In addition, endometrial cancer, thrombosis, side effects such as liver cancer due to weak estrogen-agonist action expressed from long-term administration of tamoxifen citrate, as well as tamoxifen citrate-resistant cancer have been reported as new problems, Antiprogestational agents have a different mechanism of action from tamoxifen citrate, and are expected to be new therapeutic agents that avoid these.

However, since these all have a steroid skeleton, a problem has been pointed out that they also have side effects unique to steroids. Therefore,
In order to avoid these problems, it is expected that a drug that does not have a steroid skeleton and selectively has a binding inhibitory effect on a progesterone receptor will appear.

The present inventors previously isolated from a culture of a strain belonging to the genus Penicillium a PF1092 substance (Japanese Patent Application Laid-Open No. 8-253467) having a non-steroidal skeleton but having a binding inhibitory effect on a progesterone receptor. , 2 or 3 position of elemophylan skeleton of this substance
It has been found that a derivative in which the hydroxyl group at the position is modified with an appropriate substituent has a strong binding inhibitory effect on the progesterone receptor (WO97 / 30040).
In addition, PR of a substance known in the literature having an eremofilan skeleton
Toxin [R. D. Wei, P .; E. FIG. Still,
E. FIG. B. Smally, H .; K. Schnoes a
nd F. M. Strong, Appl. Microb
iol. 25, 111, 1973; D. We
i, H .; K. Schnoes, P .; A. Hart an
d F. M. Strong, Tetrahedron,
31, 109, 1975] have also been found to have a strong binding inhibitory effect on the progesterone receptor (Japanese Patent Laid-Open No. 10-67710).

[0008]

SUMMARY OF THE INVENTION To date, P
There are reports that a substance containing an elemophyllane-type sesquiterpene (liglarenolide skeleton), which is a basic constituent nucleus of the F1092 substance, has a binding inhibitory effect on a progesterone receptor. No. 253467, JP-A-10-67710, WO
97/3040). Therefore, there has been an interest in the structure and activity of related compounds obtained by chemical transformation based on the constituent nuclei. The present invention provides a novel naphthofuranone derivative or a pharmaceutically acceptable salt having a progesterone receptor inhibitory activity.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted synthetic chemistry studies to meet the above-mentioned expectations, and have developed a novel naphthofuranone represented by the general formula (I) using commercially available Wiland-Mischer ketone as a starting material. We established a chemical synthesis method to supply derivatives and synthesized new compounds. As a result, they have found that certain compounds have a strong binding inhibitory effect on progesterone receptors, and have completed the present invention.

That is, the gist of the present invention is as follows.
The following general formula (I) as a novel compound

Embedded image [Wherein, R ¹ represents a hydrogen atom or an optionally substituted C ₂
-C alkylcarbonyl group _10, aromatic acyl group which may C ₇ -C ₁₅ optionally having a substituent, at least one or more nitrogen atoms optionally C ₂ -C ₁₅ which may have a substituent Alternatively, a heteroaromatic acyl group having an oxygen atom or a sulfur atom, R ² may have a hydrogen atom, a hydroxyl group, a C ₁ -C ₁₀ alkyloxy group which may have a substituent, or a substituent. A C ₂ -C ₁₀ alkylcarbonyloxy group, a C ₇ -C ₁₅ aromatic acyloxy group which may have a substituent, at least one or more C ₂ -C ₁₅ which may have a substituent A heteroaromatic acyloxy group having a nitrogen atom, an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group] or a pharmaceutically acceptable salt thereof. Permissible salts.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the general formula (I) according to the present invention can be prepared by the following reaction schemes 1-1 and 1 described below.
-2, Step 2, Step 3, Step 4-1 and Step 4-2.

First, a specific synthesis of the compound (I) of the formula (I) in which R is defined by claim 2 is as follows.

[0013]

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[0014]

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[0015] A commercially available Wiland-Mischer ketone {compound (1)} was subjected to a regioselective ketalization reaction, followed by a Ruboton reaction to obtain compound (2). Compound (3) was obtained by reacting compound (2) with t-butyldimethylsilyl chloride. When the compound (3) was treated with lithium aluminum hydride in methanol, a compound (4) stereoselectively reduced to a β-configuration hydroxyl group was obtained. As a reducing agent used in the present reduction reaction, sodium borohydride, lithium borohydride, or the like may be used, but lithium aluminum hydride is preferable, and 1 to 4 equivalents may be used. As a reaction solvent to be used, an alcohol solvent is preferable, and methanol is preferable. The reaction is preferably performed under ice cooling, and the reaction time is several minutes to 30 minutes. Next, a compound (5) was obtained by a Barton reaction, and further deketalization was performed to obtain a compound (6).

After adding a base and, if necessary, a catalytic amount of zinc chloride to the compound (6), an aldol condensation reaction with methyl pyruvate was carried out to obtain a compound (7).
The base used in this reaction may be an organic base used in a usual aldol reaction, preferably lithium diisopropylamide, and 1 to 3 equivalents may be used. Also,
This reaction often gives good results in the yield when a catalytic amount of dry zinc chloride is added. The reaction solvent used at this time may be ether or the like in addition to THF.
0 minutes to 6 hours.

The tricyclic compound (8) was obtained by heating the compound (7) in the presence of an acid catalyst.
The acid catalyst used in the present ring closing reaction may be an organic acid such as paratoluenesulfonic acid, and is preferably used in an amount of 0.1 to 0.5 equivalent. The reaction solvent used at that time is benzene,
Xylene may be used, but toluene is preferred. The reaction temperature proceeds in the range of 80 ° C to 100 ° C, and the reaction time is
0 minutes to 1 hour. Then, t-
The butyldimethylsilyl group was removed to give compound (9). In this reaction, an excess amount of tetrabutylammonium fluoride, hydrogen fluoride pyridine or the like may be used in THF at room temperature.

The compound (9) was acylated to complete the synthesis of the compound (I) (excluding the compound in which R ¹ is represented by a hydrogen atom). As the reagent used in the acylation reaction, acetyl chloride, in addition to acyl halides such as propionyl chloride, acetic anhydride,
An acid anhydride such as propionic anhydride may be used, and 1 to 10 equivalents may be used. The solvent used in this reaction may be a combination of an aprotic solvent and an organic base used in an ordinary acylation reaction, in addition to pyridine which also functions as a base. The reaction proceeds at a high reaction temperature in the range of 20 ° C to 60 ° C, and the reaction time is 10 minutes to 2 hours.

Second, a specific synthesis of the compound (I) of the formula (I) in which R is defined by claim 3 is as follows.

[0020]

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The compound (4) was subjected to methylation of a hydroxyl group by reaction with trifluoromethanesulfonylmethyl in the presence of 2,6-di-t-butylpyridine to obtain a compound (10). The reaction is carried out in dichloromethane at room temperature for 1 day to 2 hours.
It is advisable to use both reagents in excess for days. Next, the ketal was deprotected by treatment with an acid such as p-toluenesulfonic acid in acetone, which led to compound (11). Compound (1
1) was subjected to aldol reaction with pyruvate methyl ester, ring closure reaction, and de-tert-butyldimethylsilylation reaction to give compound (14) in the same manner as described above.

The compound (14) is acylated,
The synthesis of the compound (I) shown in claim 3 (excluding the compound in which R ¹ is represented by a hydrogen atom) was completed. The reagent used in the acylation reaction may be an acyl halide such as acetyl chloride or propionyl chloride, or an acid anhydride such as acetic anhydride or propionic anhydride.
It is good to use equivalent. The solvent used in this reaction may be a combination of an aprotic solvent and an organic base used in an ordinary acylation reaction, in addition to pyridine which also functions as a base. Reaction temperature is 20 ° C to 60 ° C
The reaction time is 10 minutes to 2 hours.

Third, a specific synthesis of the compound (I) of the general formula (I) wherein R is as defined in claim 4 is as follows.

[0024]

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The t-butyldimethylsilyl group of compound (4) was removed to obtain compound (15). This reaction proceeds well by using 1 to 5 equivalents of tetrabutylammonium fluoride and hydrogen fluoride pyridine in THF at room temperature. By treating compound (15) with an acid such as paratoluenesulfonic acid in acetone, compound (16) in which deketalization and acetalization of two hydroxyl groups proceeded simultaneously was obtained.

Compound (16) was subjected to aldol reaction, ring closure reaction, and deacetalization reaction with pyruvate methyl ester in the same manner as described above to give compound (18).
The compound (18) was acylated to complete the synthesis of the compound (I) described in claim 4 (excluding the compound in which R ¹ is represented by a hydrogen atom). As the reagent used in the acylation reaction, in addition to acyl halides such as acetyl chloride and propionyl chloride, acid anhydrides such as acetic anhydride and propionic anhydride may be used, and 1 to 10 equivalents may be used. The solvent used in this reaction may be a combination of an aprotic solvent and an organic base used in an ordinary acylation reaction, in addition to pyridine which also functions as a base. The reaction proceeds at a high reaction temperature in the range of 20 ° C to 60 ° C, and the reaction time is 10 minutes to 2 hours.

Fourth, a specific synthesis of the compound (I) of the general formula (I) wherein R is as defined in claim 5 is as follows.

[0028]

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[0029]

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The compound (3) is subjected to an epoxidation reaction using trimethylsulfonium iodide and potassium hexamethyldisilazane in THF in compound (19).
And Next, the t-butyldimethylsilyl group was removed to obtain a compound (20). This reaction is carried out at room temperature in THF.
Medium progresses well by using 1 to 5 equivalents of tetrabutylammonium fluoride or hydrogen fluoride pyridine. The epoxide was reduced by reacting the compound (20) with lithium aluminum hydride to obtain a compound (21) having a β-configuration hydroxyl group. Compound (21)
Is treated in the same manner as for compound (15) to give compound (2)
2).

The compound (22) was subjected to an aldol reaction, a ring closure reaction, and a deacetalization reaction with pyruvate methyl ester in the same manner as described above to give a compound (24).
The compound (24) was acylated to complete the synthesis of the compound (I) shown in claim 5 (excluding the compound in which R ¹ is represented by a hydrogen atom). As the reagent used in the acylation reaction, in addition to acyl halides such as acetyl chloride and propionyl chloride, acid anhydrides such as acetic anhydride and propionic anhydride may be used, and 1 to 10 equivalents may be used. The solvent used in this reaction may be a combination of an aprotic solvent and an organic base used in an ordinary acylation reaction, in addition to pyridine which also functions as a base. The reaction proceeds at a high reaction temperature in the range of 20 ° C to 60 ° C, and the reaction time is 10 minutes to 2 hours.

The pharmaceutically acceptable salts of the compounds according to the invention include, for example, lithium, sodium, potassium, magnesium, calcium salts and salts with ammonia and suitable non-toxic amines, such as C1 to C6. Alkylamine (e.g., triethylamine) salt, C1-C6
Alkanolamine (eg, diethanolamine or triethanolamine) salt, procaine salt, cyclohexylamine (eg, dicyclohexylamine) salt, benzylamine (eg, N-methylbenzylamine, N-ethylbenzylamine, N-benzyl-β-phenethylamine, N, N-dibenzylethylenediamine or dibenzylamine) salts and heterocyclic amine (e.g., morpholine, N-ethylpyridine) salts, or hydrohalides such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid , Sulfate, nitrate, phosphate, perchlorate, carbonate and other inorganic acid salts, acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid , Butyric acid, maleic acid, propionic acid, formic acid, malic acid Carboxylate, alginic acid, aspartic acid, amino acid salts such as glutamate,
Organic acid salts such as methanesulfonic acid and p-toluenesulfonic acid are exemplified.

Among the novel derivatives thus obtained according to the present invention and the pharmaceutically acceptable salts thereof, the compounds having progesterone receptor binding inhibitory activity include progesterone such as breast, uterus, ovary, bone and central nervous system. Drugs for treating progesterone-related diseases against receptor-expressing organs (breast cancer, ovarian cancer, fibroids, endometriosis, meningioma,
It is useful as a drug for myeloma, osteoporosis, menopause, abortion drug, oral contraceptive, etc.).

[0034]

EXAMPLES Examples for obtaining the compounds of the present invention and the physicochemical properties of the compounds of the present invention are shown below. It should be noted that the present invention is not limited to the examples, and based on the properties of the compounds revealed by the present invention, as well as the modifying means of the examples, synthesis, production, extraction, Includes all methods of purification.

Example 1 A Wieland-Miescher under an argon atmosphere
Ketone {compound (1)} (56.2 mmol, 10 g)
Was dissolved in methylene chloride (100 ml) and cooled to -78 ° C. To this, trimethylsilyltrifluoromethanesulfonate (1.4 mmol, 0.262 ml) and 1,2-bis (trimethylsilyloxy) ethane (16
7.5 mmol, 19.4 ml) at −78 ° C.,
Stirred at -78 ° C for 4 days. Thereafter, pyridine (1 ml) was added at -78 ° C, and the reaction solution was brought to room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain 11.4 g (51.6 mmol, 92%) of the corresponding ketal compound.
%)Obtained. ¹ H NMR (CDCl ₃ ) δ 1.32 (3H, s),
1.63-1.84 (4H, complex), 2.0
3 (1H, m), 2.12 (1H, m), 2.27 (1
H, m), 2.38 (1H, m), 2.56 (1H, d
dt, J = 3.3, 7.7, 13.3 Hz), 2.64
(1H, ddd, J = 6.2, 12.7, 17.5H
z), 3.88-4.04H, complex),
5.41 (1H, s); m / z 223 (M + H) ⁺ .

In an argon atmosphere, the above ketal body (9 m
mol, 2 g) was dissolved in tetrahydrofuran (23 ml) and cooled to -15 ° C. To this was added 2.0M lithium diisopropylamine / tetrahydrofuran (13.5
mmol, 6.75 ml) at -15 ° C.
Stirred at 30 ° C. for 30 minutes. Thereafter, trimethylsilyl chloride (13.5 mmol, 1.67 ml) was added at −15 ° C., and the temperature was gradually raised to room temperature. After stirring at room temperature for 1 hour, the reaction solution was concentrated, and the residue was inactivated with distilled water using silica gel column chromatography (hexane / ethyl acetate = 4/1).
To give a silyl enol ether. Under an argon atmosphere, sodium hydrogen carbonate (36 mmol, 3.0
3 g) and 80% metachloroperbenzoic acid (12 mmol,
Hexane (20 ml) was added to 2.59 g) to suspend the mixture.
This was cooled to -15C. To this, a silyl enol ether (total amount) / hexane (5 ml) was added dropwise at -15 ° C, followed by stirring at -15 ° C for 8 hours. Thereafter, the temperature was adjusted to room temperature, and the reaction solution was filtered. After concentrating the filtrate, the residue was dissolved in tetrahydrofuran (30 ml), and 1.0 M tetrabutylammonium fluoride / tetrahydrofuran (5.0 mmol, 5.0 ml) was added dropwise at room temperature to give 20 ml.
Stirred for minutes. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2/2).
By purifying in 1), 1.74 g of compound (2) (7.
(30 mmol, 81%). At this stage, α-form and β-form could not be separated by silica gel column chromatography (α-form: β-form = 1: 7). ¹ H NMR (CDCl ₃ ) δ 1.31 (3H, s),
1.65 (1H, m), 1.76-1.89 (4H, c
oplex), 2.31-2.67 (3H, comp
lex), 3.45 (1H, br), 3.86-4.0.
3 (4H, complex), 4.25 (1H, dd,
J = 7.4, 12.3 Hz), 5.51 (1H, d, J
= 2.0 Hz); m / z 238 M ⁺ .

Example 2 Compound (2) (9 mmol, 2 g) under an argon atmosphere
Was dissolved in dimethylformamide (18 ml) and imidazole (22 mmol, 1.42 g) and t-chloride were added at room temperature.
-Butyltrimethylsilyl (11 mmol, 1.64
g) was added and stirred for 4 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give compound (3) 2.4.
6 g (6.98 mmol, 95%) were obtained. At this stage α
And β-form could not be separated by silica gel column chromatography (α-form: β-form = 1: 7). ¹ H NMR (CDCl ₃ ) δ 0.04 (3H, s),
0.08 (3H, s), 0.87 (9H, s), 1.3
5 (3H, s), 1.69-1.96 (6H, comp
lex), 2.22 (1H, m), 2.72 (1H,
m), 3.83-3.98 (4H, complex),
4.17 (1H, t, J = 7.3 Hz), 5.41 (1
H, s); m / z 353 (M + H) ⁺ .

Example 3 Compound (3) (1.11 mmol,
(390 mg) was dissolved in tetrahydrofuran (5 ml) and cooled to 0 ° C. To this, lithium aluminum hydride (1.66 mmol, 63 mg) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction solution was filtered at 0 ° C using silica gel, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 5).
313 mg of compound (4)
(0.884 mmol, 79%). ¹ H NMR (CDCl ₃ ) δ 0.09 (3H, s),
0.10 (3H, s), 0.92 (9H, s), 1.1
7 (3H, s), 1.54 (1H, m), 1.68-
1.88 (5H, complex), 2.13 (1H,
d, J = 11.4 Hz), 2.49 (1H, ddt, J)
= 2.5, 4.9, 14.4 Hz), 3.19 (1H,
dd, J = 3.3, 11.2 Hz), 3.97-4.0
0 (4H, complex), 4.05 (1H, d, J
= 2.9 Hz), 5.35 (1H, s); m / z 355
(M + H) ⁺ .

Example 4 Compound (4) (4.01 mmol,
1.42 g) in tetrahydrofuran (40 ml) and 55% sodium hydride (16 mmol,
697 mg). Thereafter, the mixture was refluxed for 3 hours. Carbon disulfide (27 mmol, 1.6 ml) was added to the reaction solution,
Reflux for 0 minutes, then methyl iodide (26 mmol,
(1.6 ml) and refluxed for 30 minutes. The reaction solution was brought to room temperature, concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 12/1) to give 1.2 g (2.70 mmol, 67%) of compound (5).
%)Obtained. ¹ H NMR (CDCl ₃ ) δ 0.00 (3H, s),
0.04 (3H, s), 0.90 (9H, s), 1.4
1 (3H, s), 1.58-1.69 (2H, comp
lex), 1.73-1.85 (4H, complete)
x), 1.92 (1H, br), 2.57 (3H,
s), 2.64 (1H, ddt, J = 2.8, 4.9,
10.9 Hz), 3.83-3.99 (4H, comp
lex), 4.40 (1H, q, J = 2.6 Hz),
5.33 (1H, d, J = 3.3 Hz), 5.39 (1
H, s); m / z 445 (M + H) ⁺ .

Example 5 Under an argon atmosphere, tributyltin hydride (3.0 mmol, 686 m) was added to toluene (10 ml) at room temperature.
g) and 2,2'-azabisisobutyronitrile (0.3
(67 mmol, 60 mg) and refluxed. Compound (5) (2.70 mmol, 1.20 g) / toluene (10 ml) was added dropwise thereto, and the mixture was refluxed overnight. The reaction was brought to room temperature, concentrated and the residue was dissolved in acetone (10 ml). This was added at room temperature with p-toluenesulfonic acid (0.52
(6 mmol, 100 mg) and stirred at room temperature for 10 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 260 mg (0.884 m) of compound (6).
mol, 33%). ¹ H NMR (CDCl ₃ ) δ 0.07 (3H, s),
0.08 (3H, s), 0.91 (9H, s), 1.4
4 (3H, s), 1.53-1.66 (2H, comp
lex), 1.74-1.89 (4H, complete
x), 2.08 (1H, br), 2.32 (1H,
m), 2.53 (1H, ddd, J = 7.2, 12.
6,16.9 Hz), 2.86 (1H, ddt, J =
2.9, 15.7, 13.0 Hz), 4.13 (1H,
br), 5.76 (1H, s); m / z 295 (M +
H) ⁺ .

Example 6 Compound (6) (0.146 mmol) was placed in an argon atmosphere.
1, 43 mg) was dissolved in tetrahydrofuran (1 ml) and cooled to -78 ° C. Add 2.0M lithium diisopropylamine / tetrahydrofuran (0.25m
mol, 0.25 ml) at -78 ° C.
For 1 hour. Thereafter, at −78 ° C., zinc chloride (I
I) (0.25 mmol, 34 mg) / tetrahydrofuran (0.50 ml) was added, and the mixture was stirred at -78 ° C for 10 minutes. To this, pyruvate methyl ester (0.292 m
mol, 25 μl) and stirred at −78 ° C. for 3 hours. The reaction solution was concentrated and purified by silica gel thin layer chromatography (hexane / ethyl acetate = 4/1) to obtain 52 mg (0.131 mmol, 89 mg) of compound (7).
%)Obtained. The NMR spectrum of this compound was very complicated because it contained isomers. Therefore, the following compound (8)
The generation of the compound (7) was confirmed by identifying the compound (8). m / z 397 (M + H) ⁺ .

Example 7 Compound (7) (0.477 mmol) was placed in an argon atmosphere.
1,189 mg) in toluene (10 ml),
At room temperature, paratoluenesulfonic acid monohydrate (0.143m
mol, 27 mg) and refluxed for 1 hour. The reaction solution was brought to room temperature, concentrated, and purified by silica gel thin layer chromatography (hexane / ethyl acetate = 5/1) to obtain 30 mg (0.09 mmol, 30%) of compound (8). ¹ H NMR (CDCl ₃ ) δ 0.04 (6H, s),
0.07 (9H, s), 1.23 (3H, s), 1.7
2 (1H, dd, J = 3.3, 13.7 Hz), 1.8
3 (1H, dd, J = 5.9, 13.6 Hz), 1.9
0 (3H, d, J = 1.8 Hz), 2.23 (1H, d
t, J = 19.1, 4.0 Hz), 2.39 (1H,
d, J = 16.7 Hz), 2.45 (1H, dt, J =
18.7, 4.8 Hz), 2.57 (1H, d, J = 1)
6.5 Hz), 4.10 (1H, m), 5.73 (1
H, t, J = 4.4 Hz), 5.99 (1H, s); m
/ Z 346 (M + H) ⁺ .

Example 8 Compound (8) (87 μmol, 30
mg) was dissolved in tetrahydrofuran (3 ml), and 1.0 M tetrabutylammonium fluoride /
Tetrahydrofuran (150 μmol, 150 μl) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 1/1) to give 17% of compound (9).
mg (56 μmol, 64%). ¹ H NMR (CDCl ₃ ) δ 1.42 (3H, s),
1.81-1.88 (2H, complex), 1.9
0 (3H, d, J = 1.9 Hz), 2.25 (1H,
m), 2.43 (1H, d, J = 16.8 Hz);
54 (1H, m), 2.60 (1H, d, J = 16.7)
Hz), 3.51 (1H, br), 4.17 (1H,
m), 5.77 (1H, t, J = 5.0 Hz), 6.0
2 (1H, s); m / z 232 (M + H) ⁺ .

Example 9 (4aR *, 6R *)-6-acetoxy-3,4a-di
Methyl-4a, 5,6,7-tetrahydronaphtho [2,
3-b] Furan-2 (4H) -one Under an argon atmosphere, compound (9) (14 μmol, 3 m
g) was dissolved in methylene chloride (0.75 ml) and dimethylaminopyridine (100 μmol, 12 m
g) and acetyl chloride (80 μmol, 6 mg)
Stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate =
2/1) to give 3.4 mg (1%) of the title compound.
2.4 μmol, 57%). ¹ H NMR (CDCl ₃ ) δ 1.21 (3H, s),
1.80 (1H, dd, J = 3.3, 14.3 Hz),
1.91 (3H, d, J = 1.5 Hz), 2.04 (3
H, s), 2.06 (1H, m), 2.38 (2H,
d, J = 18.0 Hz), 2.57 (1H, dt, J =
21.3, 4.8 Hz), 2.61 (1H, d, J = 1)
6.5 Hz), 5.21 (1H, m), 5.73 (1
H, t, J = 4.0 Hz), 6.00 (1H, s); m
/ Z 275 (M + H) ⁺ .

Example 10 (4aR *, 6R *)-3,4a-dimethyl-6-pro
Pionyloxy-4a, 5,6,7-tetrahydronaph
[2,3-b] furan-2 (4H) -one Under an argon atmosphere, compound (9) (14 μmol, 3 m
g) was dissolved in methylene chloride (0.75 ml) and dimethylaminopyridine (100 μmol, 12 m
g) and propionyl chloride (80 μmol, 7 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 2/1) to give the title compound (3.6 mg).
(12.5 μmol, 57%). ¹ H NMR (CDCl ₃ ) δ 1.14 (3H, t, J =
7.7 Hz), 1.21 (3H, s), 1.81 (1
H, dd, J = 3.3, 14.3 Hz), 1.91 (3
H, d, J = 1.8 Hz), 2.07 (1H, dd, J)
= 3.7, 14.3 Hz), 2.31 (2H, q, J =
7.3 Hz), 2.35-2.40 (2H, compl
ex), 2.57 (1H, dt, J = 14.5, 4.8)
Hz), 2.60 (1H, d, J = 16.1 Hz),
5.23 (1H, m), 5.74 (1H, t, J = 4.
4 Hz), 5.99 (1H, s); m / z 289 (M +
H) ⁺ .

Example 11 (4aR *, 6R *)-3,4a-dimethyl-6- (2
-Furancarbonyloxy) -4a, 5,6,7-tet
Lahydronaphtho [2,3-b] furan-2 (4H) -O
Under emission argon atmosphere, Compound (9) (14μmol, 3m
g) was dissolved in methylene chloride (0.75 ml) and dimethylaminopyridine (100 μmol, 12 m
g) and 2-fluorofuryl chloride (80 μmol, 10 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 2/1) to give the title compound (34.7).
mg (14.4 μmol, 66%). ¹ H NMR (CDCl ₃ ) δ 1.28 (3H, s),
1.90 (1H, dd, J = 3.3, 13.7 Hz),
1.92 (3H, d, J = 1.5 Hz), 2.20 (1
H, dd, J = 4.4, 13.9 Hz), 2.41 (1
H, d, J = 16.9 Hz), 2.53 (1H, d, J)
= 20.5 Hz), 2.61-2.70 (2H, com
plex), 4.47 (1H, m), 5.77 (1H,
t, J = 4.4 Hz), 6.02 (1H, s), 6.5
0 (1H, q, J = 1.8 Hz), 7.14 (1H, d
d, J = 1.1, 1.6 Hz), 7.58 (1H, d
d, J = 0.7, 1.6 Hz); m / z 327 (M +
H) ⁺ .

Example 12 ( 4aR *, 6R *)-6-benzoyloxy-3,4
a-dimethyl-4a, 5,6,7-tetrahydronaphtho
[2,3-b] furan-2 (4H) -one Under an argon atmosphere, compound (9) (14 μmol, 3 m
g) was dissolved in methylene chloride (0.75 ml) and dimethylaminopyridine (100 μmol, 12 m
g) and benzoyl chloride (80 μmol, 11 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 2/1) to give 3.0 mg of the title compound.
(8.9 μmol, 41%). ¹ H NMR (CDCl ₃ ) δ 1.25 (3H, s),
1.91 (3H, s), 1.92 (1H, dd, J =
3.3, 15.9 Hz), 2.24 (1H, dd, J =
4.8, 14.5 Hz), 2.43 (1H, d, J = 1)
6.9 Hz), 2.54 (1H, d, J = 19.8H)
z), 2.66 (1H, d, J = 16.5 Hz);
68 (1H, dt, J = 16.5, 4.4 Hz);
48 (1H, br), 5.79 (1H, t, J = 4.4)
Hz), 6.03 (1H, s), 7.42-7.60.
(3H, complex), 8.00-8.09 (2
H, complex); m / z 337 (M + H) ⁺ .

Example 13 Compound (4) (2.45 mmol,
867 mg) in methylene chloride (20 ml),
Cooled to -15 ° C. To this, 2,6-di-t-butylpyridine (20 mmol, 4.49 ml) and methyl trifluoromethanesulfonate (19 mmol, 2.15 m
l) was added at −15 ° C. and then stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The methylene chloride phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was concentrated to obtain a crude compound (10) quantitatively. Crude compound (1
0) was dissolved in acetone (10 ml), paratoluenesulfonic acid monohydrate (158 μmol, 30 mg) was added at room temperature, and the mixture was stirred for 10 minutes. The reaction solution was concentrated, and the residue was purified by thin-layer chromatography on silica gel (hexane / ethyl acetate = 4/1) to give 249 m of compound (11).
g (0.769 mmol, 31%). ¹ H NMR (CDCl ₃ ) δ 0.03 (6H, s),
0.92 (9H, s), 1.35 (3H, s), 1.5
0 (1H, m), 1.72 (1H, dt, J = 4.4,
15.4 Hz), 1.90 (1 H, m), 2.05 (1
H, m), 2.22 (1H, ddd, J = 2.9,5.
3, 13.2 Hz), 2.32 (1H, m), 2.48
(1H, ddd, J = 5.1, 14.7, 25.2H
z), 2.67 (1H, d, J = 2.9 Hz), 2.8
1 (1H, m), 3.39 (3H, s), 4.29 (1
H, m), 5.78 (1H, s); m / z 325 (M +
H) ⁺ .

Example 14 Compound (11) (0.762 mmol) was placed in an argon atmosphere.
1,247 mg) was dissolved in tetrahydrofuran (4 ml) and cooled to -78 ° C. To this was added 2.0M lithium diisopropylamine / tetrahydrofuran (1.30
mmol, 0.650 ml) at −78 ° C.
Stirred at 8 ° C for 1 hour. Thereafter, zinc (II) chloride (1.30 mmol, 172 mg) / tetrahydrofuran (1.50 ml) was added at −78 ° C., and the mixture was stirred at −78 ° C. for 10 minutes. Methyl pyruvate (1.5
2 mmol, 132 μl) and stirred at −78 ° C. for 3 hours. The reaction solution was concentrated and purified by silica gel thin layer chromatography (hexane / ethyl acetate = 2/1) to obtain 309 mg (0.725 mmol) of compound (12).
1, 95%). The spectrum of this compound was very complicated because it contained isomers. Therefore, the following compound (1)
The formation of compound (12) was confirmed by identifying compound (13) and leading to 3). m / z 427 (M + H)
⁺ .

Example 15 Compound (12) (0.725 mmol) under an argon atmosphere
1,309 mg) in toluene (20 ml),
At room temperature, paratoluenesulfonic acid monohydrate (0.405 m
mol, 77 mg) and refluxed for 40 minutes. The reaction solution was concentrated and purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 5/1) to give compound (1).
80 mg (0.213 mmol, 29%) of 3) was obtained. ¹ H NMR (CDCl ₃ ) δ 0.08 (3H, s),
0.09 (3H, s), 0.88 (9H, s), 1.2
4 (3H, s), 1.91 (3H, d, J = 1.8H
z), 2.21 (1H, d, J = 16.5 Hz);
41 (1H, dd, J = 4.8, 19.5 Hz);
50 (1H, dt, J = 19.5, 4.0 Hz);
04 (1H, d, J = 16.1 Hz), 3.05 (1
H, d, J = 2.9 Hz), 4.37 (1H, m),
5.48 (3H, s), 5.64 (1H, t, J = 4.
0 Hz), 5.96 (1H, s); m / z 377 (M +
H) ⁺ .

Example 16 Compound (13) (27 μmol, 1
0 mg) was dissolved in tetrahydrofuran (0.70 ml), HF pyridine (52 μl) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 days. The reaction solution was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 1/1) to give 8 mg (27 μmol, 100 mg) of compound (14).
%)Obtained. ¹ H NMR (CDCl ₃ ) δ 1.25 (3H, s),
1.92 (3H, d, J = 1.8 Hz), 2.13 (1
H, s), 2.27 (1H, d, J = 17.2 Hz),
2.55-2.62 (2H, complex), 3.0
4 (1H, d, J = 16.4 Hz), 3.18 (1H, d, J = 16.4 Hz)
d, J = 2.9 Hz), 3.52 (3H, s), 4.4
3 (1H, m), 5.68 (1H, t, J = 4.0H)
z), 5.97 (1H, s), m / z 262M ⁺ .

Example 17 (4aS *, 5R *, 6S *)-6-acetoxy-3,
4a-dimethyl-5-methoxy-4a, 5,6,7-te
Trahydronaphtho [2,3-b] furan-2 (4H)-
Under On an argon atmosphere, the compound (14) (15μmol, 4
mg) in methylene chloride (1.0 ml) and dimethylaminopyridine (200 μmol, 24 m
g) and acetyl chloride (80 μmol, 6 mg)
Stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was subjected to silica gel thin layer chromatography (hexane / ethyl acetate =
3/1) to give 3.5 mg (1%) of the title compound.
1.5 μmol, 75%). ¹ H NMR (CDCl ₃ ) δ 1.23 (3H, s),
1.93 (3H, d, J = 1.6 Hz), 2.08 (3
H, s), 2.26 (1H, d, J = 16.3 Hz),
2.49 (1H, ddd, J = 0.7, 3.3, 22.
2Hz), 2.63 (1H, dt, J = 21.8, 2.
5 Hz), 3.08 (1H, d, J = 16.6 Hz),
3.25 (1H, d, J = 2.8 Hz), 3.47 (3
H, s), 5.62-5.68 (2H, complete
x), 5.98 (1H, s); m / z 305 (M + H)
⁺ .

Example 18 (4aS *, 5R *, 6S *)-3,4a-dimethyl-
5-methoxy-6-propionyloxy-4a, 5,
6,7-tetrahydronaphtho [2,3-b] furan-2
Under a (4H) -on argon atmosphere, compound (14) (15 μmol,
mg) in methylene chloride (1.0 ml) and dimethylaminopyridine (200 μmol, 24 m
g) and propionyl chloride (80 μmol, 7 mg) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate = 3/1) to give 4.2 mg of the title compound.
(13.2 μmol, 86%). ¹ H NMR (CDCl ₃ ) δ 1.15 (3H, t, J =
7.9 Hz), 1.23 (3H, s), 1.93 (3
H, d, J = 1.5 Hz), 2.25 (1H, d, J =
16.2 Hz), 2.35 (2H, q, J = 7.7H)
z), 2.48 (1H, ddd, J = 1.3, 4.6,
21.2 Hz), 2.63 (1H, dt, J = 19.
2,4.2 Hz), 3.07 (1H, d, J = 16.8)
Hz), 3.26 (1H, d, J = 2.7 Hz), 3.26.
47 (3H, s), 5.12-5.18 (2H, com
plex), 5.97 (1H, s); m / z 319 (M
+ H) ⁺ .

Example 19 (4aS *, 5R *, 6S *)-3,4a-dimethyl-
6- (2-furancarbonyloxy) -5-methoxy-
4a, 5,6,7-tetrahydronaphtho [2,3-b]
Furan-2 (4H) -one Under an argon atmosphere, compound (14) (15 μmol,
mg) in methylene chloride (1.0 ml) and dimethylaminopyridine (100 μmol, 12 m
g) and 2-fluorofuryl chloride (80 μmol, 10 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate = 2/1) to give the title compound (3.0 m).
g (8.4 μmol, 55%). ¹ H NMR (CDCl ₃ ) δ 1.32 (3H, s),
1.94 (3H, d, J = 1.8 Hz), 2.20 (1
H, d, J = 16.3 Hz), 2.61 (1H, dd)
d, J = 1.9, 5.3, 20.6 Hz), 2.73
(1H, dt, J = 19.4, 5.1 Hz), 3.11
(1H, d, J = 16.5 Hz), 3.34 (1H,
d, J = 2.6 Hz), 3.51 (3H, s), 5.6
8 (1H, t, J = 4.0 Hz), 5.83 (1H,
m), 6.00 (1H, s), 6.50 (1H, dd,
J = 1.8, 3.5 Hz), 7.13 (1H, dd, J
= 0.7, 3.3 Hz), 7.58 (1H, dd, J =
1.1, 1.6 Hz); m / z 357 (M + H) ⁺ .

Example 20 (4aS *, 5R *, 6S *)-6-benzoyloxy
-3,4a-dimethyl-5-methoxy-4a, 5,6
7-tetrahydronaphtho [2,3-b] furan-2 (4
H) -On Under an argon atmosphere, compound (14) (15 μmol, 4
mg) in methylene chloride (1.0 ml) and dimethylaminopyridine (100 μmol, 12 m
g) and benzoyl chloride (80 μmol, 11 mg) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the residue was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 2/1) to give the title compound (4.8 mg).
(13.1 μmol, 86%). ¹ H NMR (CDCl ₃ ) δ 1.36 (3H, s),
1.94 (3H, d, J = 1.7 Hz), 2.32 (1
H, d, J = 16.7 Hz), 2.65 (1H, dd)
d, J = 1.8, 4.8, 20.7 Hz), 2.78
(1H, dt, J = 21.4, 3.9 Hz), 3.10
(1H, d, J = 16.6 Hz), 3.39 (1H, d, J = 16.6 Hz)
d, J = 3.0 Hz), 3.51 (3H, s), 5.6
9 (1H, t, J = 3.8 Hz), 5.90 (1H,
m), 6.01 (1H, s), 7.41-7.68 (3
H, complex), 7.99-8.05 (2H, c
oplex); m / z 367 (M + H) ⁺ .

Example 21 Compound (4) (2.56 mmol,
907 mg) was dissolved in tetrahydrofuran (10 ml), and 1.0M tetrabutylammonium fluoride / tetrahydrofuran (3.93 mmol, 3.
93 ml) was added dropwise and stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by silica gel thin layer chromatography (hexane / ethyl acetate = 1/1) to obtain 463 mg (1.93 mol, 75%) of compound (15). ¹ H NMR (CDCl ₃ ) δ 1.23 (3H, s),
1.59 (1H, ddt, J = 2.5, 4.1, 14.
2Hz), 1.65-1.74 (2H, complete
x), 1.78-1.93 (3H, complex),
1.97 (1H, m), 2.18 (1H, s), 2.2
3 (1H, d, J = 7.9 Hz), 2.55 (1H, d
dt, J = 2.4, 4.9, 14.4 Hz), 3.31
(1H, m), 3.58-4.02 (4H, compl
ex), 4.06 (1H, br), 5.38 (1H,
s); m / z 240 M ⁺ .

Example 22 Compound (15) (1.93 mmol, 463 mg) was dissolved in acetone (10 ml), paratoluenesulfonic acid monohydrate (1.05 mmol, 200 mg) was added at room temperature, and the mixture was added at room temperature for 3 hours. Stirred. The reaction solution was concentrated, and the residue was purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 2/1) to give compound (16).
3 mg (860 μmol, 46%) were obtained. ¹ H NMR (CDCl ₃ ) δ 1.30 (3H, s),
1.39 (3H, s), 1.54 (3H, s), 1.8
9 (1H, dt, J = 5.5, 13.3 Hz), 1.9
7-2.19 (3H, complex), 2.28-
2.44 (2H, complex), 2.54 (1H,
ddd, J = 5.5, 13.3, 16.4 Hz), 2.
64 (1H, ddt, J = 1.5, 16.6, 5.5H
z), 3.89 (1H, d, J = 7.3 Hz), 4.4
5 (1H, q, J = 7.7 Hz), 5.87 (1H,
s); m / z 236M ⁺ .

Example 23 Compound (16) (860 μmol,
203 mg) was dissolved in tetrahydrofuran (5 ml) and cooled to -78 ° C. Add 2.0M lithium diisopropylamine / tetrahydrofuran (1.4mmo
1, 0.70 ml) was added dropwise at -78 ° C, and 1
Stirred for hours. Then, at -78 ° C zinc chloride (II)
(1.4 mmol, 186 mg) / tetrahydrofuran (2.5 ml) was added, and the mixture was stirred at -78 ° C for 10 minutes.
Methyl pyruvate (2.5 mmol, 2
11 μl), and the mixture was stirred at −78 ° C. for 3 hours and at room temperature overnight. The reaction solution was concentrated and purified by silica gel thin layer chromatography (hexane / ethyl acetate = 1/1) to quantitatively obtain compound (17). The NMR spectrum of this compound was very complicated because it contained isomers. For this reason, the production of compound (17) was confirmed by leading to the compound of Example 25 and identifying the compound of Example 25. m / z 339 (M + H) ⁺ .

Example 24 Compound (17) (0.799 mmol) was placed in an argon atmosphere.
1,270 mg) in toluene (40 ml),
At room temperature, paratoluenesulfonic acid monohydrate (0.21 mm
ol, 40 mg) and refluxed for 30 minutes. The reaction solution was brought to room temperature, concentrated, and roughly purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 1/1) to obtain 17 mg of compound (18) (including by-products). Since it was difficult to separate this compound from by-products, the production of the compound (18) was confirmed by leading to the compound of Example 25 and identifying the compound of Example 25. m / z 249 (M + H) ⁺ .

Example 25 (4aS *, 5R *, 6S *)-3,4a-dimethyl-
5,6-dipropionyloxy-4a, 5,6,7-te
Trahydronaphtho [2,3-b] furan-2 (4H)-
Compound (18) (including by-products) in an on- argon atmosphere
(4 mg) was dissolved in methylene chloride (0.75 ml), and dimethylaminopyridine (160 μmol,
20 mg) and propionyl chloride (80 μmol, 7 m
g) was added and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction,
The residue was subjected to silica gel thin layer chromatography (hexane /
Ethyl acetate = 1/1 + chloroform / methanol = 30
/ 1) to give 2.4 mg of the title compound (6.
7 μmol, 7%, two steps). ¹ H NMR (CDCl ₃ ) δ 1.15 (3H, t, J =
7.7 Hz), 1.19 (3H, t, J = 7.7H)
z), 1.30 (3H, s), 1.91 (3H, d, J
= 1.8 Hz), 2.34 (2H, q, J = 7.3H)
z), 2.36 (1H, overlapped wit
other peak), 2.41 (2H, q, J
= 7.3 Hz), 2.43 (1H, ddd, J = 2.
0, 5.8, 20.8 Hz), 2.72 (1H, d, J
= 16.5 Hz), 2.74 (1H, m), 5.07
(1H, d, J = 3.3 Hz), 5.49 (1H,
m), 5.71 (1H, t, J = 4.0 Hz), 6.0
1 (1H, s); m / z 361 (M + H) ⁺ .

Example 26 (4aS *, 5R *, 6S *)-5,6-di (2-furan
Carbonyloxy) -3,4a-dimethyl-4a,
5,6,7-tetrahydronaphtho [2,3-b] furan
Compound (18) (including by-products) under -2 (4H) -one argon atmosphere
(4 mg) was dissolved in methylene chloride (0.75 ml), and dimethylaminopyridine (160 μmol,
20 mg) and 2-fluorofuryl chloride (80 μmol, 10 m
g) was added and the mixture was stirred at room temperature for 2 hours. Concentrate the reaction,
The residue was subjected to silica gel thin layer chromatography (hexane /
Ethyl acetate = 1/1 + chloroform / methanol = 30
2.8 mg (6./1) of the title compound.
4 μmol, 7%). ¹ H NMR (CDCl ₃ ) δ 1.48 (3H, s),
1.89 (3H, d, J = 1.5 Hz), 2.44 (1
H, d, J = 16.9 Hz), 2.67 (1H, dd,
J = 3.7, 20.0 Hz), 2.81 (1H, d, J
= 16.5 Hz), 2.89 (1H, dt, J = 21.
3,3.8 Hz), 5.38 (1H, d, J = 2.9H)
z), 5.72-5.79 (2H, complex),
6.05 (1H, s), 6.53 (2H, t, J = 1.
8 Hz), 7.16 (2H, d, J = 3.3 Hz),
7.61 (2H, dd, J = 0.7, 1.8 Hz); m
/ Z437 (M + H) ⁺ .

Example 27 In an argon atmosphere, trimethylsulfonium iodide (1
0 mmol, 2.04 g) in tetrahydrofuran (20
ml) and cooled to 0 ° C. 0.5M potassium hexamethyldisilazane / toluene (9.0 mmol)
1, 18 ml) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. Thereafter, at 0 ° C., the compound (3) (4.8 mmol,
1.69 g) / tetrahydrofuran (5 ml) was slowly added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to obtain 1.43 g (53.9 mmol, 81) of compound (19).
%)Obtained. ¹ H NMR (CDCl ₃ ) δ 0.02 (3H, s),
0.09 (3H, s), 0.89 (9H, s), 1.3
8 (3H, s), 1.53-1.73 (3H, comp
lex), 1.76-1.84 (3H, complete
x), 1.98 (1H, m), 2.43 (1H, d, J
= 4.4 Hz), 2.76 (1H, m), 3.01 (1
H, d, J = 4.7 Hz), 3.46 (1H, t, J =
3.3Hz), 3.87-3.98 (4H, compl
ex), 5.35 (1H, s); m / z 367 (M +
H) ⁺ .

Example 28 Compound (19) (2.54 mmol) under an argon atmosphere
l, 930 mg) in tetrahydrofuran (7.0 ml)
And at room temperature 1.0M tetrabutylammonium fluoride / tetrahydrofuran (5.1 mmol,
5.1 ml) and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 50/1) to give 620 mg (2.46 mmol,
97%). ¹ H NMR (CDCl ₃ ) δ 1.35 (3H, s),
1.76-1.87 (4H, complex), 1.9
3-2.08 (3H, complex), 2.64 (1
H, d, J = 4.4 Hz), 2.72 (1H, m),
3.05 (1H, d, J = 3.7 Hz), 3.56 (1
H, t, J = 4.4 Hz), 3.88-4.02 (4
H, complex), 5.38 (1H, s); m / z
253 (M + H) ⁺ .

Example 29 Compound (20) (0.48 mmol
1, 121 mg) was dissolved in tetrahydrofuran (5 ml), lithium aluminum hydride (1.8 mmol, 70 mg) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered using silica gel, and the filtrate was concentrated to obtain 120 mg of a residue. Compound (21) was used for the next reaction without purification. ¹ H NMR (CDCl ₃ ) δ 1.17 (3H, s),
1.34 (3H, s), 1.48-1.88 (5H, c
omplex), 1.92 (1H, ddd, J = 4.
2, 7.2, 16.7 Hz), 2.06 (1H, dt,
J = 5.4, 13.5 Hz), 2.18 (1H, b
r), 2.27 (1H, br), 2.59 (1H, dd)
t, J = 2.2, 5.3, 16.5 Hz), 3.80
(1H, t, J = 2.9 Hz), 3.86-4.02
(4H, complex), 5.37 (1H, s); m
/ Z254M ⁺ .

Example 30 Compound (21) (120 mg) was added to acetone (10 ml).
And paratoluenesulfonic acid monohydrate (0.42 mmol, 80 mg) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel thin layer chromatography (chloroform / methanol = 40 /
By purifying in 1), 97 mg (38) of compound (22) was obtained.
8 μmol, 81%, two steps). ¹ H NMR (CDCl ₃ ) δ 1.32 (3H, s),
1.41 (3H, s), 1.44 (3H, s), 1.5
0 (3H, s), 1.85 (1H, dq, J = 12.
8, 2.6 Hz), 1.97 (1H, m), 2.18
(1H, dt, J = 9.2, 14.4 Hz), 2.28
(1H, m), 2.34-2.47 (2H, compl
ex), 2.52-2.68 (2H, complete
x), 4.25 (1H, t, J = 8.4 Hz), 5.8
3 (1H, s); m / z 250 M ⁺ .

Example 31 Under an argon atmosphere, compound (22) (388 μmol,
97 mg) was dissolved in tetrahydrofuran (3.9 ml) and cooled to -78 ° C. To this, 2.0 M lithium diisopropylamine / tetrahydrofuran (660 μm
mol, 330 μl) was added dropwise at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Then, at -78 ° C zinc chloride (II)
(660 μmmol, 88 mg) / tetrahydrofuran (1.0 ml) was added, and the mixture was stirred at −78 ° C. for 10 minutes.
To this, pyruvate methyl ester (1.0 mmol, 8
5 μl) and stirred at −78 ° C. for 3 hours and at room temperature overnight. The reaction solution was concentrated and purified by silica gel thin layer chromatography (hexane / ethyl acetate = 1/1) to obtain 133 mg (378 μmol, 97 mg) of compound (23).
%)Obtained. The NMR spectrum of this compound was very complicated because it contained isomers. Therefore, the following compound (2)
The production of compound (23) was confirmed by identifying compound (24) and leading to 4). m / z 352M ⁺ .

Example 32 Compound (23) (0.893 mmol) was placed in an argon atmosphere.
1, 300 mg) in toluene (44 ml),
At room temperature, paratoluenesulfonic acid monohydrate (0.23 mm
ol, 44 mg) and refluxed for 30 minutes. The reaction solution was brought to room temperature, concentrated, and purified by silica gel thin-layer chromatography (hexane / ethyl acetate = 1/1 + chloroform / methanol = 30/1) to obtain 15 mg of compound (24) (57 μmol, 6.4%). Obtained. ¹ H NMR (CDCl ₃ ) δ 1.22 (3H, s),
1.35 (3H, s), 1.93 (3H, d, J = 1.
8Hz), 2.12 (1H, d, J = 4.8Hz),
2.38 (1H, s), 2.50 (1H, ddd, J =
1.9, 6.0, 19.5 Hz), 2.59-2.69
(2H, complex), 2.73 (1H, d, J =
16.5 Hz), 3.91 (1H, m), 5.67 (1
H, t, J = 4.2 Hz), 5.98 (1H, s); m
/ Z262M ⁺ .

Example 33 (4aS *, 5R *, 6S *)-5-hydroxy-6-
Propionyloxy-3,4a, 5-trimethyl-4
a, 5,6,7-tetrahydronaphtho [2,3-b] f
Run-2 (4H) -one Compound (24) (11.5 μmo) under an argon atmosphere
1, 3 mg) in methylene chloride (0.50 ml) and dimethylaminopyridine (160 μmol,
20 mg) and propionyl chloride (80 μmol, 7 m
g) was added and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction,
The residue was subjected to silica gel thin layer chromatography (hexane /
Ethyl acetate = 1/1 + chloroform / methanol = 30
/ 1) to give 2.2 mg of the title compound (6.
9 μmol, 60%). ¹ H NMR (CDCl ₃ ) δ 1.16 (3H, t, J =
7.3 Hz), 1.31 (3H, s), 1.58 (3
H, s), 1.93 (3H, d, J = 1.5 Hz),
2.39 (2H, q, J = 7.3 Hz), 2.46 (1
H, s), 2.48 (1H, dd, J = 4.8, 19.
8Hz), 2.61-2.73 (2H, complete)
x), 2.75 (1H, d, J = 16.1 Hz), 5.
01 (1H, d, J = 4.8 Hz), 5.63 (1H,
d, J = 4.0 Hz), 5.96 (1H, s); m / z
319 (M + H) ⁺ .

Example 34 (4aS *, 5R *, 6S *)-6- (2-furancal
Bonyloxy) -5-hydroxy-3,4a, 5-tri
Methyl-4a, 5,6,7-tetrahydronaphtho [2,
3-b] Furan-2 (4H) -one Compound (24) (11.5 μmo) under an argon atmosphere
1, 3 mg) in methylene chloride (0.50 ml) and dimethylaminopyridine (160 μmol,
20 mg) and 2-fluorofuryl chloride (80 μmol, 10 m
g) was added and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction,
The residue was subjected to silica gel thin layer chromatography (hexane /
Ethyl acetate = 1/1 + chloroform / methanol = 30
/ 1) to give 2.4 mg of the title compound (8.
4 μmol, 73%). ¹ H NMR (CDCl ₃ ) δ 1.36 (3H, s),
1.41 (3H, s), 1.94 (3H, d, J = 1.
5Hz), 2.49 (1H, s), 2.62 (1H, d
d, J = 3.7, 21.2 Hz), 2.69 (1H,
d, J = 16.5 Hz), 2.76 (1H, dt, J =
20.8, 4.2 Hz), 2.78 (1H, d, J = 1)
6.7 Hz), 5.23 (1H, d, J = 4.4H)
z), 5.66 (1H, t, J = 3.7 Hz), 5.9
9 (1H, s), 6.53 (1H, dd, J = 1.8,
3.5 Hz), 7.18 (1H, dd, J = 0.7,
3.7 Hz), 7.60 (1H, s); m / z 357
(M + H) ⁺ .

Test Example The progesterone receptor binding activity of the compound of the present invention was determined by H. K
ondo et al. [J. Antibiotics, 43, 15
33-1542, 1990]. That is, after porcine uterine cells were crushed with a polytron homogenizer in 5 mM phosphate buffer,
The supernatant was separated by centrifugation (100,000 × g, 30 minutes) to prepare a cytoplasmic fraction containing a progesterone receptor. This cytoplasmic fraction (2-3 mg protein / m
l) [ ³ H] -progesterone solution (3.84 TBq / mmol, 18.5 KBq /
ml) 40 μl of 10 μl of a test drug solution or mifepristone (RU38486) solution at an arbitrary concentration,
The reaction was performed at 4 ° C. for 60 minutes in a test tube. 0.5% in the reaction solution
100 μl of activated carbon solution was added, and the mixture was allowed to stand for 10 minutes, followed by centrifugation (2,000 × g, 10 minutes), and the radioactivity of the obtained supernatant was measured by a liquid scintillation counter. Further, under the above conditions, the radioactivity when the test drug was not added and the radioactivity when 10 μl of medroxyprogesterone acetate (MPA) (10 μg / ml) were added instead of the test drug were measured, and the radioactivity was measured for each cytoplasmic fraction.
³ H] - and the total binding amount and the nonspecific binding of progesterone. From these measured values, calculate the inhibition rate by the following formula,
The binding inhibitory activity (IC ₅₀ ) was determined.

[0071]

(Equation 1)

Embodiments 9, 10, 11, 12, 17, 1
The progesterone receptor binding inhibitory activities of the compounds of 8, 19, 20, 25, 26, 33, 34 and mifepristone (RU38486) were as shown in Table 1.

[0073]

[Table 1]

[0074]

EFFECTS OF THE INVENTION The derivatives obtained according to the present invention have a strong binding inhibitory activity against progesterone receptors, and their compounds or pharmaceutically acceptable salts thereof are based on the progesterone receptor binding inhibitory activity. Progesterone-related disease drugs for organs that express progesterone receptor such as uterus, ovary, bone, central nervous system (breast cancer, ovarian cancer, uterine fibroids, endometriosis, meningioma,
It is useful as a drug for myeloma, osteoporosis, menopause, abortion drug, oral contraceptive, etc.).

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/365 AED A61K 31/365 AED (72) Inventor Tsuneo Konokogi 760, Okaokacho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Meiji Seika Co., Ltd. Pharmaceutical Research Institute

Claims (5)

[Claims] 1. The following general formula (I): [Wherein, R ¹ represents a hydrogen atom or an optionally substituted C ₂
-C alkylcarbonyl group _10, aromatic acyl group which may C ₇ -C ₁₅ optionally having a substituent, at least one or more nitrogen atoms optionally C ₂ -C ₁₅ which may have a substituent Alternatively, a heteroaromatic acyl group having an oxygen atom or a sulfur atom, R ² may have a hydrogen atom, a hydroxyl group, a C ₁ -C ₁₀ alkyloxy group which may have a substituent, or a substituent. A C ₂ -C ₁₀ alkylcarbonyloxy group, a C ₇ -C ₁₅ aromatic acyloxy group which may have a substituent, at least one or more C ₂ -C ₁₅ which may have a substituent A heteroaromatic acyloxy group having a nitrogen atom, an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, a C ₁ -C ₁₀ alkyl group which may have a substituent], or a pharmaceutical thereof. Acceptable salts. 2. A formula according to claim ¹ (I), R 1 is a hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, represented by any of the organic groups of 2-furoyl group, R ²
Is a hydrogen atom and R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 3. A formula according to claim ¹ (I), R 1 is a hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, represented by any of the organic groups of 2-furoyl group, R ²
Is a methoxy group, and R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 4. In the general formula (I) of claim 1, R ¹ is a hydrogen atom, a propionyl group or a 2-furoyl group, and R ² is a hydroxyl group, a propionyloxy group or a 2-fluoroyl group. A compound represented by a furoyloxy group, wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 5. In the general formula (I) of claim 1, R ¹ is represented by a hydrogen atom, a propionyl group or a 2-furoyl group, R ² is represented by a hydroxyl group, and R ³ is represented by a hydroxyl group. A compound represented by methyl or a pharmaceutically acceptable salt thereof.