JP2003327582A - 4-epihimbacine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new useful analog for himbacine being an alkaloid, having strong and selective antagonism against a muscarine M<SB>2</SB>receptor. <P>SOLUTION: The 4-epihimbacine derivative is represented by general formula (1), its enantiomer and its acid addition salt. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel analog of himbacine, which has a potent and selective antagonism to muscarinic M ₂ receptor and is expected to be used as a therapeutic drug for Alzheimer's disease. The present invention relates to a mandrabine derivative and a method for producing the same.

[0002]

2. Description of the Related Art Himbacin is a piperidine alkaloid isolated and structurally determined from Galbulimima baccata, a kind of pine family in 1956, and its structural characteristic is that it has a thermodynamically stable transdecalin ring. A 5-membered ring lactone is condensed in a cis configuration, and it has 8 asymmetric centers containing 4 internuclear hydrogens. Furthermore, the tricyclic moiety and the piperidine ring are linked via a trans double bond. Points,
There are three points.

In recent years, senile dementia typified by Alzheimer's dementia has become a socially serious problem, and an essential remedy for it has been earnestly desired. As one of the approaches, the so-called “choline hypothesis” is derived from the phenomenon of hypofunction of central cholinergic nerves in patients with dementia.
The development of therapeutic agents based on is being actively conducted. They can be roughly divided into the following four. That is,
(1) Choline uptake inhibitor, (2) Acetylcholinesterase inhibitor, (3) Choline acetyltransferase synthesis activator, (4) Those acting on muscarinic receptor (muscarinic M ₁ agonist or M ₂ receptor antagonist), Is. Recently, it was revealed that himbacine has a strong and selective inhibitory effect on the M ₂ receptor, which is thought to have a function of suppressing the release of acetylcholine at nerve endings, and its potential as an anti-dementia drug. Was found.

[0004] As described above, himbacine is a compound that has attracted worldwide attention because of its strong activity and interesting chemical structure.
Total synthesis using Alder reaction as a key reaction and derivative synthesis have been reported (Kozikowski et al., Total Synthesis: a) J. A.
m. Chem. Soc. 1995, 117, 9369-9370.b) J. Org. Che
m. 1997, 62, 5023-5033. Derivative synthesis: a) Bioorg. Me
d. Chem. Lett. 1992, 2, 797-802. b) Bioorg. Med. C
hem. Lett. 1993, 3, 1247-1252.c) Bioorg. Med. Che
m. Lett. 1995, 5, 61-66., Chackalamannil et al., Total Synthesis: a) J. Am. Chem. Soc. 1996, 118, 9812-9813. b)
J. Org. Chem. 1999, 64, 1932-1940. Derivative synthesis: Bio
org. Med. Chem. Lett. 1999, 9, 901-906. Further, the present inventors have disclosed the total synthesis of himbacine using intermolecular Diels-Alder reaction as a key reaction (Terashima et al., JP 2000-229961, Takadoi et al., Tetrahedron.
Lett. 1999, 40, 3399-3402). The patent claims a manufacturing intermediate required for the synthesis of himbacine. This compound is different from the compound as shown in the present invention in that the stereochemistry at the 4-position of the tricyclic site has the same stereochemistry as that of himbacine. Therefore, the synthesis of a himbacin analog characterized in that only the 4-position of the natural type as shown in the present invention is epidermalized has not yet been reported, and its muscarinic M ₂ subtype receptor antagonism is also revealed. It has not been.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel himbacin analog which is expected to be used as a therapeutic drug for Alzheimer's disease and an intermediate for producing the same.

[0006]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in view of the above problems, the following compounds of the present invention were found to be:
The present invention was completed by finding that it has a strong and extremely subtype-selective muscarinic M ₂ receptor antagonistic action and that it is extremely useful as a production intermediate in the production thereof.

That is, the present invention has the following general formula (1) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, Represents a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₄ and R ₅ together represent an oxygen atom, or R ₄ represents a hydrogen atom,
R ₅ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, or a lower acyloxy group, and R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or a protective group for an amino group. , R ₇ represents a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group)
Epihimbacine derivatives, their enantiomers, their acid addition salts, and the following general formula (1-1) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or Represents an unsubstituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group) a 4-epihimbacine derivative,
Those enantiomers, their acid addition salts, and the following general formula (1-2) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or Represents an unsubstituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group. Group, which represents a group), an enantiomer thereof, and acid addition salts thereof. Further, the present invention has the following general formula (2) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or Represents an unsubstituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group. It represents a group, R ₁₀ represents a hydrogen atom, a lower acyl group, a lower alkylsulfonyl group or an arylsulfonyl group, Ar 1
Represents a benzene ring which may have one or more substituents)
The production intermediate represented by and the following general formula (3) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group, R ₁₁ represents a lower alkylsulfonyloxy group, arylsulfonyl (Representing an oxy group, an arylsulfenyl group and an arylsulfonyl group) is provided. Furthermore, the present invention provides the following general formula (3) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group, and R ₁₁ represents an arylsulfonyl group) Compound represented by the following general formula (4) (In the formula, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino group-protecting group,
R ₇ represents a lower alkyl group, or a substituted or unsubstituted aralkyl group, and R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group), or a compound thereof. The following general formula (2) that can be obtained by reacting combinations (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or Represents an unsubstituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group. It represents a group, R ₁₀ represents a hydrogen atom, a lower acyl group, a lower alkylsulfonyl group or an arylsulfonyl group, Ar 1
Represents a benzene ring which may have one or more substituents)
Wherein the production intermediate represented by the formula (1) is dearylsulfonylated. (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, Represents a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₄ and R ₅ together represent an oxygen atom, or R ₄ represents a hydrogen atom,
R ₅ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, or a lower acyloxy group, and R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or a protective group for an amino group. , R ₇ represents a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group)
Provided are methods for producing epihimbacine derivatives, their enantiomers, and their acid addition salts. Furthermore, the present invention provides the following general formula (1) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, Represents a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₄ and R ₅ together represent an oxygen atom, or R ₄ represents a hydrogen atom,
R ₅ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, or a lower acyloxy group, and R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or a protective group for an amino group. , R ₇ represents a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group)
Disclosed is a muscarinic M ₂ subtype receptor antagonist, which comprises one or more epihimbacine derivatives, their enantiomers, and their acid addition salts as active ingredients.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, "lower alkyl" means a straight or branched carbon number 1 such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl and 2-methylpropyl. There are 6 to 6 types, regardless of whether they are saturated or unsaturated. Examples of the "aralkyl group" include a benzyl group and a 1-phenylethyl group, and examples of the substituent include a lower alkyl group, a lower alkoxy group, a halogen atom, a cyano group, a nitro group and the like. As the "lower alkoxy group", a methoxy group, an ethoxy group, a 1-methylethoxy group, a 1,1-dimethylethoxy group, a propoxy group,
Number of linear or branched carbon atoms such as 2-methylpropoxy group
1 to 6 can be mentioned, which can be saturated or unsaturated. Examples of the “aralkyloxy group” include a benzyloxy group and a 1-phenylethoxy group, and examples of the substituent include a lower alkyl group, a lower alkoxy group, a halogen atom, a cyano group, a nitro group and the like. "Lower acyloxy group"
Is a formyl group, acetoxy group, propionyloxy group, 2,2-dimethylpropionyloxy group and the like having 1 to 5 carbon atoms.
I can give you one. Examples of the "lower acyl group" include acetyl, propionyl and the like. Examples of the “amino group-protecting group” include lower acyl groups such as acetyl and propionyl, lower alkoxycarbonyl groups such as ethoxycarbonyl and t-butoxycarbonyl, and benzyl group, and the introduction and removal thereof are described in the literature. Method can be appropriately adopted (Green, TW; Wuts, P.
GM “Protective Groups in Organic Synthesis”, 2
^nd Ed., Wiley Interscience Publication, John-Weile
y & Sons, New York, 1991, pp 14-118). Examples of the “arylacyl group” include benzoyl and the like.
Examples of the "lower alkylsulfonyl group" include a methanesulfonyl group and the like, and examples of the "arylsulfonyl group" include a benzenesulfonyl group, a p-toluenesulfonyl group and the like. The "one or more substituents" in the "benzene ring which may have one or more substituents" means, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, Examples thereof include a nitro group, an amino group, a cyano group, etc., and in this case, the “amino group” may be substituted with acyl, such as acetyl, etc., and may be substituted with 1 to 2 lower alkyl groups. . The "acid addition salt" is a pharmacologically acceptable salt such as inorganic acids such as hydrochloric acid, acetic acid and sulfuric acid, and organic acids such as citric acid, succinic acid, fumaric acid, maleic acid and tartaric acid.

Preferred compounds in the present invention include (2R,
6S) -tert-Butyl 2- [2- (E)-[(1S, 3S, 3aR, 4S, 4aS, 8aR, 9a
S) -Dodecahydro-1-methoxy-3-methylnaphtho [2,3-c] furan-4-yl] ethenyl] -6-methylpiperidine-1-carboxylate and its enantiomer, (2R, 6S) -tert- Butyl
2- [2- (E)-[(3S, 3aR, 4S, 4aS, 8aR, 9aS) -dodecahydro-3-
Methyl-1-oxonaphtho [2,3-c] furan-4-yl] ethenyl] -6-methylpiperidine-1-carboxylate and its enantiomers, (3S, 3aR, 4S, 4aS, 8aR, 9aS) -decahydro -3-
Methyl-4- [2- (E)-[(2R, 6S) -6-methylpiperidin-2-yl] ethenyl] naphtho [2,3-c] furan-1 (3H) -one and its enantiomers, (3S, 3aR, 4S, 4aS, 8aR, 9aS) -decahydro-4-
[2- (E)-[(2R, 6S) -1,6-Dimethylpiperidin-2-yl] ethenyl] -3-methylnaphtho [2,3-c] furan-1 (3H) -one and its enantiomers , (1S, 3S, 3aR, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy-4- (methanesulfonyloxy) methyl
-3-methylnaphtho [2,3-c] furan, and its enantiomers,
(1S, 3S, 3aS, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy
-3-methyl-4- (phenylsulfenyl) methylnaphtho
[2,3-c] Fran, and its enantiomer, (1S, 3S, 3aS, 4S, 4
aS, 8aR, 9aS) -Dodecahydro-1-methoxy-3-methyl-4-
(Phenylsulfonyl) methylnaphtho [2,3-c] furan,
And its enantiomer, (2R, 6S) -tert-butyl 2- [2-benzenesulfonyl-1-benzoyloxy-2-[(1S, 3S, 3aR, 4
S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy-3-methylnaphtho [2,3-c] furan-4-yl] ethyl] -6-methylpiperidine-1-carboxylate and its enantiomers, etc. can give.

The group of compounds represented by the general formula (1) of the present invention comprises the compound represented by the general formula (3) as a key intermediate,
For example, it can be manufactured according to the following manufacturing process.
The following general formula (3-1) is a known compound, for example (Ta
kadoi et al., Tetrahedron Lett. 1999, 40, 3399-3402.).

(First Step) This step is carried out according to the general formula (3-
1) a 4-hydroxymethyl-dodecahydronaphtho [2,3-c] furan derivative (R ₁₇ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group) By introducing a lower acyl group, a substituted or unsubstituted arylacyl group or a leaving group into the primary hydroxyl group, dodecahydronaphtho represented by the above general formula (3-2) [2,3-
c] Furan derivative (R ₁₈ is a lower alkyl group, a substituted or unsubstituted aralkyl group, a lower acyl group, an arylacyl group which may have one or more substituents, or an oxygen atom together with elimination. Which represents a group).
Examples of the reaction agent that can be used in this reaction include benzoyl chloride, 4-bromobenzoyl chloride,
Examples include methanesulfonyl chloride and p-toluenesulfonyl chloride. Any solvent can be used as long as it does not participate in the reaction, for example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvent such as carbon, diethyl ether,
Tetrahydrofuran, ether solvent such as 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-
Alcoholic solvents such as propanol and 2-methyl-2-propanol, and mixed solvents thereof are used. Examples of the base used include alkali metal alkoxides such as sodium methoxide and sodium ethoxide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and the like. Alkali metal organic base, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0]
It can be carried out in the presence or absence of a tertiary organic base such as unde-7-sen and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. The reaction proceeds smoothly at -110 ° C to 200 ° C.

(Second Step) This step is elimination of the 4-position in the dodecahydronaphtho [2,3-c] furan derivative represented by the general formula (3-2) obtained in the first step. The hydroxymethyl group substituted with a group is reacted with a sulfur-containing nucleophilic reactive agent such as thiophenol, and the compound represented by the general formula (3-3a) is represented by 4-
Arylsulfenylmethyl-dodecahydronaphtho [2,3
-c] A method for producing a furan derivative. Examples of the reaction agent that can be used in this reaction include the above-mentioned thiophenol and p-toluenethiol. Any solvent can be used as long as it does not participate in the reaction, for example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, diethyl ether, tetrahydrofuran, ether solvents such as 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl- An alcohol solvent such as 1-propanol or 2-methyl-2-propanol, or a mixed solvent thereof is used. Examples of the base used include alkali metal alkoxides such as sodium methoxide and sodium ethoxide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and the like. Alkali metal organic base, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine,
In the presence of tertiary organic bases such as 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene, and inorganic bases such as potassium carbonate and sodium hydrogen carbonate Alternatively, it can be performed in the absence. Reaction is from -110 ℃ to 200
At ℃, proceed smoothly.

(Third Step) This step is a 4-arylsulfenylmethyl-dodecahydronaphtho [2,3-c] furan derivative represented by the general formula (3-3a) obtained in the second step. The sulfenyl group therein is subjected to an oxidation reaction to produce a 4-arylsulfonylmethyl-dodecahydronaphtho [2,3-c] furan derivative represented by the general formula (3-3b). As the reaction agent used in this step, for example, hydrogen peroxide solution, m-chloroperbenzoic acid, peracetic acid, etc. are used. Any solvent can be used as long as it does not participate in the reaction, for example, pentane, hexane,
Cyclohexane, benzene, toluene, hydrocarbon solvents such as xylene, dichloromethane, 1,2-dichloroethane,
Chloroform, halogenated hydrocarbon solvent such as carbon tetrachloride, diethyl ether, tetrahydrofuran, ether solvent such as 1,4-dioxane, methanol, ethanol,
Alcohol solvents such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol and 2-methyl-2-propanol, and mixed solvents of these and water are preferably used. Examples of the base include alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal alkoxides such as n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide. Organic base, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] unde-7 -It can be carried out in the presence or absence of a tertiary organic base such as sen and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. The reaction is from -110 ℃
It proceeds smoothly at 200 ℃.

(Fourth Step) This step converts the 4-arylsulfonylmethyl-dodecahydronaphtho [2,3-c] furan derivative represented by the general formula (3-3b) obtained in the third step into By coupling the piperidine derivative represented by the general formula (4) and treating the resulting compound represented by the general formula (2-1) reductively.
It is intended to produce a dodecahydronaphtho [2,3-c] furan derivative represented by a). Any solvent can be used as long as it does not participate in the reaction, for example,
Hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane,
1,2-dichloroethane, chloroform, halogenated hydrocarbon solvents such as carbon tetrachloride, diethyl ether, tetrahydrofuran, ether solvents such as 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1- Alcohol solvents such as butanol, 2-butanol, 2-methyl-1-propanol and 2-methyl-2-propanol, and mixed solvents of these and water are preferably used. Examples of the base include alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal alkoxides such as n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide. Organic base, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.
3.0] Nona-5-ene, 1,8-diazabicyclo [5.4.0] unde-7
-It can be carried out in the presence or absence of a tertiary organic base such as sen and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. The reaction proceeds smoothly at -110 ° C to 200 ° C. In the subsequent reductive treatment, sodium amalgam or samarium iodide is mainly used. Alternatively, β-hydroxysulfone may be once converted to acetoxylation or benzoylation, and this can be removed by β-elimination using a base to reductively remove the sulfonyl group. Any solvent can be used as long as it does not participate in the reaction, for example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, diethyl ether, tetrahydrofuran, ether solvents such as 1,4-dioxane, methanol, ethanol, 1-propanol, 2-
Propanol, 1-butanol, 2-butanol, 2-methyl
An alcohol solvent such as -1-propanol or 2-methyl-2-propanol and a mixed solvent of these and water are preferably used. Examples of the base include sodium methoxide,
Alkali metal alkoxides such as sodium ethoxide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, alkali metal organic bases such as potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0]
It can be carried out in the presence or absence of a tertiary organic base such as unde-7-sen and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. The reaction proceeds smoothly at -110 ° C to 200 ° C.

(Fifth Step) In this step, the 1-position protecting group in the dodecahydronaphtho [2,3-c] furan derivative represented by the general formula (1-2a) obtained in the fourth step is removed. It is oxidatively removed to produce a 1-oxodecahydronaphtho [2,3-c] furan derivative represented by the general formula (1-1a).
As the reactant used in this step, an oxidizing agent such as Jones reagent is usually used. Any solvent can be used as long as it does not participate in the reaction, for example,
Dichloromethane, 1,2-dichloroethane, chloroform,
A halogenated hydrocarbon solvent such as carbon tetrachloride is used. The reaction proceeds smoothly at -100 ° C to 100 ° C. Alternatively, in an acidic aqueous solution, the compound represented by the general formula (1-2a) (wherein R ₉ is a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower alkoxy group representing a lower acyl group, a substituted or unsubstituted aralkyl group). An oxy group or a lower acyloxy group) is reacted with the above-mentioned general formula (1-
The compound represented by the above formula (1-1a) may be produced by producing the compound represented by 2a) (R ₉ represents a hydrogen atom) and then reacting it under a normal oxidation reaction condition. However, R ₉
When is a hydrogen atom, it has a hemiacetal structure and its stereochemistry cannot be specified. Examples of the "acidic aqueous solution" used in this reaction include aqueous solutions of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, citric acid, succinic acid, fumaric acid, maleic acid and tartaric acid. . The oxidation reaction can be carried out using chromic acid, chromium trioxide-pyridine mixed system, dimethylsulfoxide-oxalyl chloride-triethylamine mixed system, ruthenium complex, Dess-Martin reagent and the like. It is desirable to carry out this step usually in a solvent, and for example, a halogenated hydrocarbon solvent such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or the like is used. The reaction proceeds smoothly at -100 ° C to 100 ° C. Further, in the case of the 1-oxodecahydronaphtho [2,3-c] furan derivative represented by the general formula (1-1a) (R ₆ represents a protecting group for an amino group), the protecting group is removed, The 1-oxodecahydronaphtho [2,3-c] furan derivative represented by the general formula (1-1a) (R ₆ represents a hydrogen atom), or further this compound is reductively alkylated, 1-oxodecahydronaphtho represented by the formula (1-1a) [2,3-
c] A furan derivative (R ₆ represents a lower alkyl group or a substituted or unsubstituted aralkyl group) can be produced. The method of removing the amino-protecting group can be carried out by appropriately adopting the method described in the literature (Green, TW; Wuts,
PGM “Protective Groups in Organic Synthesis”,
^{2 nd Ed., Wiley Interscience Publication} , John-Wei
ley & Sons, New York, 1991, pp 14-118). Any solvent can be used as long as it does not participate in the reaction, for example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, diethyl ether, tetrahydrofuran, ether solvents such as 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,
An alcohol solvent such as 2-methyl-1-propanol or 2-methyl-2-propanol and a mixed solvent of these and water are preferably used. The reaction proceeds smoothly at -110 ° C to 200 ° C. The subsequent reductive alkylation can be carried out by reacting a reducing agent such as sodium cyanoborohydride or sodium borohydride in the presence of the corresponding alkyl aldehyde. Any solvent can be used as long as it does not participate in the reaction, and examples thereof include pentane, hexane, cyclohexane, benzene, toluene,
Hydroxyl solvent such as xylene, dichloromethane, 1,2-dichloroethane, chloroform, halogenated hydrocarbon solvent such as carbon tetrachloride, diethyl ether, tetrahydrofuran, ether solvent such as 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-
Alcohol solvents such as butanol, 2-butanol, 2-methyl-1-propanol and 2-methyl-2-propanol, and mixed solvents of these and water are preferably used. The reaction is
It goes smoothly from -110 ℃ to 200 ℃.

[0016]

EXAMPLES The present invention will be described in detail below with reference to Examples and Reference Examples, but it goes without saying that the present invention is not limited to these.

(Example 1) (1S, 3S, 3aR, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy
-4- (methanesulfonyloxy) methyl-3-methylnaphtho
[2,3-c] Franc (1S, 3S, 3aR, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy
-3-Methylnaphtho [2,3-c] furan-4-methanol 71.8 mg
Triethylamine (196.7 μL, 1.41 mmol) was added to methylene chloride solution (0.28 mmol) in 10 mL, and methanesulfonyl chloride (65.5 μL, 0.85 mmol) was added dropwise under an ice-cooled argon atmosphere. . The solvent was evaporated under reduced pressure, 10 mL of water was added to the residue, and the mixture was extracted with ether (3 mL
3), and the combined organic layer was washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain 76.9 mg of the title compound (yield 82%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.83-0.95 (m, 2H), 1.1
3-1.40 (m, 5H), 1.30 (d, J = 6.4 Hz, 3H), 1.51-1.6
2 (m, 2H), 1.63-1.72 (m, 2H), 1.77-1.81 (m, 1H), 1.
82-1.88 (m, 1H), 2.18-2.28 (m, 2H), 3.02 (s, 3H),
3.32 (s, 3H), 4.13 (dq, J = 9.3, 5.9 Hz, 1H), 4.16
(dd, J = 9.8, 8.3 Hz, 1H), 4.41 (dd, J = 9.8, 4.4
Hz, 1H), 4.54 (s, 1H). MS (FAB) (m / z): 438 [(M ⁺ + d
iethanolamine) + H]. HRMS (FAB) (m / z): Calcd. for C
₂₀ H ₄₀ NO ₇ S [(M ⁺ + diethanolamine) + H]: 438.2525. Foun
d, 438.2506.

(Example 2) (1S, 3S, 3aS, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy
-3-Methyl-4- (phenylsulfenyl) methylnaphtho [2,3
-c] franc To 2 mL of a dehydrated dimethyl sulfoxide solution containing 38.9 mg (0.35 mmol) of potassium-t-butoxide, 35.6 μL (0.35 mmol) of thiophenol was added dropwise under stirring at room temperature, and the mixture was stirred for 10 minutes.
This was added to 5 mL of a dehydrated dimethylsulfoxide solution containing 76.9 mg (0.23 mmol) of the compound of Example 1 and stirred at room temperature for about 12 hours. The reaction mixture was poured into 30 mL of cold water and extracted with ether (5
mL x 3). Wash the combined organic layers with saturated saline solution (5 m
L), dried over anhydrous magnesium sulfate, filtered, and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1, then 10: 1) to obtain 61.8 mg of the title compound. (Yield 77%). [α] _D ²⁵ -18 ° (c0.10, CHCl ₃ ). ¹ H-NMR (400 MHz, CD
Cl ₃ ): δ 0.82-0.94 (m, 2H), 1.12-1.43 (m, 5H), 1.22
(d, J = 5.9 Hz, 3H), 1.54-1.82 (m, 6H), 2.19 (dt,
J = 12.7, 6.4 Hz, 1H), 2.54 (dd, J = 9.8, 5.9 Hz,
1H), 2.60 (dd, J = 12.7, 10.8 Hz, 1H), 3.30 (dd, J
= 13.2, 2.9 Hz, 1H), 3.32 (s, 3H), 4.06 (dq, J =
9.3, 6.2 Hz, 1H), 4.52 (s, 1H), 7.14-7.19 (m, 1H),
7.24-7.30 (m, 2H), 7.32-7.36 (m, 2H). ¹³ C-NMR (1
00 MHz, CDCl ₃ ): δ 21.8, 26.3, 26.9, 30.3, 33.4, 3
3.9, 34.7, 34.7, 36.9, 40.8, 41.9, 46.0, 54.1, 76.
9,109.3, 126.0, 128.8, 128.8, 129.7, 129.7, 136.6.
IR (KBr): 2930, 1580,1480, 1090, 1050 cm ^-1 .MS
(FAB) m / z: 452 [(M ⁺ + diethanolamine) + H]. HRMS (FA
B) (m / z): Calcd. For C ₂₅ H ₄₂ NO ₄ S [(M ⁺ + diethanolamin
e) + H]: 452.2835.Found, 452.2806.

(Example 3) (1S, 3S, 3aS, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy
-3-Methyl-4- (phenylsulfonyl) methylnaphtho [2,3-
c] franc M-Chloroperbenzoic acid (65%) was added to a solution of the compound of Example 2 (58.8 mg, 0.17 mmol) in methylene chloride (10 mL) with stirring under ice cooling.
112.6 mg (0.42 mmol) and sodium bicarbonate 71.3 mg
(0.85 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was filtered through Celite, and the residue was washed with methylene chloride (30 m
L) Yes. After the solvent was distilled off under reduced pressure, it was diluted with ether (20 mL),
Saturated aqueous sodium hydrogen carbonate solution (5 mL x 3), then washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2). : 1) to obtain 51.4 mg of the title compound (yield 76%). [α] _D ²⁶ + 11 ° (c0.39, CHCl ₃ ), Mp. 159-160 ℃ (colorless powdery crystal). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.79-1.3
3 (m, 6H), 1.21 (d, J = 6.4 Hz, 3H), 1.51-1.75 (m,
6H), 2.02-2.07 (m, 1H), 2.12 (dt, J = 12.4, 6.0 H
z, 1H), 2.77 (dt, J = 8.8, 5.5 Hz, 1H), 2.99 (dd, J
= 14.7, 9.5 Hz, 1H), 3.27 (dd, J = 12.7, 6.4 Hz,
1H), 2.25-2.31 (m, 1H), 2.94 (dd, J = 14.7, 8.3 H
z, 1H), 3.28 (s, 3H), 3.28-3.32 (m, 1H), 4.07 (dq,
J = 9.8, 6.1 Hz, 1H), 4.49 (s, 1H), 7.55-7.62 (m,
2H), 7.64-7.69 (m, 1H), 7.89-7.95 (m, 2H). ¹³ CN
MR (100 MHz, CDCl ₃ ): δ 21.7, 26.0, 26.3, 29.7, 3
2.4, 32.9, 34.1, 34.2, 39.8, 42.0, 48.4, 54.0, 56.
7, 76.5, 108.8, 128.2, 128.2, 129.3, 129.3, 133.7,
139.5.IR (KBr): 2920, 1450, 1370, 1310, 1150, 10
90 cm ^-1 .MS (FAB) m / z: 484 [(M ⁺ + diethanolamine) +
H]. HRMS (FAB) (m / z): Calcd. For C ₂₅ H ₄₂ NO ₆ S [(M ⁺ + d
iethanolamine) + H]: 484.2733. Found, 484.2697.

(Example 4) (2R, 6S) -tert-butyl 2- [2-benzenesulfonyl-1-benzoyloxy-2-[(1S, 3S, 3aR, 4S, 4aS, 8aR, 9aS) -dodecahydro -1-Methoxy-3-methylnaphtho [2,3-c] furan-4-yl] ethyl] -6-methylpiperidine-1-carboxylate 94.8 μL of n-butyllithium-n-hexane solution (1.5 mol / L) was added to 2 mL of a dehydrated dimethoxyethane solution containing 34.8 mg (91.9 μmol) of the compound of Example 3 under an argon atmosphere at −78 ° C.
(0.14 mmol) was added dropwise. After stirring for 10 minutes, (2R, 6S) -tert-
0.50 mL of a dehydrated dimethoxyethane solution of 31.3 mg (0.14 mmol) of butyl 2-formyl-6-methyl-1-piperidinecarboxylate was added dropwise. While gradually raising the temperature to 0 ° C
After stirring for 2.5 hours, benzoyl chloride 32.0 μ at -78 ℃
L (0.28 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr. 34.7 μL of 3- (dimethylamino) propylamine (0.
28 mmol) was added and diluted with 10 mL of water. The aqueous layer was extracted with ether (5 mL x 3), washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 4: 1 and then 2: 1)
7.5 mg (yield 79%) and 12.6 mg of the title compound as yellow oil were obtained as a mixture of diastereomers (yield 19%, 92% in consideration of raw material recovery). HRMS (FAB) (m / z): Calcd. For C ₄₄ H ₆₇ N
₂ O ₁₀ S [(M ⁺ + diethanolamine) + H]: 815.4516. Found, 81
5.4505.

(Example 5) (2R, 6S) -tert-butyl 2- [2- (E)-[(1S, 3S, 3aR, 4S, 4aS, 8a
R, 9aS) -dodecahydro-1-methoxy-3-methylnaphtho [2,3-
c] Fran-4-yl] ethenyl] -6-methylpiperidine-1-carboxylate To a solution of the compound of Example 4 (12.6 mg, 17.7 μmol) in methanol (5 mL) was added sodium amalgam (5%) 0.10 while stirring at room temperature.
g and 0.50 g of disodium hydrogen phosphate were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered through Celite, the residue was washed with ethyl acetate (20 mL), and the organic layer was evaporated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with ether (3 mL × 3). The organic layer was washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
Purified in 1) to obtain 2.60 mg of the title compound as a colorless oil.
(Yield 33%). [α] _D ²² + 34 ° (c0.17, CHCl ₃ ). ¹ H-NMR (400 MHz, CD
Cl ₃ ): δ 0.80-0.94 (m, 4H), 1.07-1.83 (m, 12H), 1.2
4 (d, J = 6.9 Hz, 3H), 1.28 (d, J = 5.9 Hz, 3H), 1.
46 (s, 9H), 1.88-2.01 (m, 3H), 2.06-2.14 (m, 1H),
2.24 (dt, J = 12.7, 6.4 Hz, 1H), 3.30 (s, 3H), 3.98
-4.05 (m, 1H), 4.13 (dq, J = 10.3,6.1 Hz, 1H), 4.3
8-4.44 (m, 1H), 4.51 (s, 1H), 5.44 (dd, J = 15.7,
4.2 Hz, 1H), 5.54 (ddd, J = 15.7, 9.3, 1.5 Hz, 1
H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 13.7, 20.8, 22.0,
25.2, 26.3, 26.8, 28.6, 28.6, 28.6, 31.2, 33.3, 3
4.4, 34.5, 40.5, 41.7, 42.6, 47.1, 49.1, 52.1, 54.
0, 77.2, 78.9, 109.3, 130.1, 132.8, 155.2. One ca
rbon was not observed.IR (neat): 2930, 1690, 145
0, 1390, 1180 cm ^-1 .MS (FAB) m / z: 553 [(M ⁺ + dietha
nolamine) + H]. HRMS (FAB) (m / z): Calcd. for C ₃₁ H ₅₇
N ₂ O ₆ [(M ⁺ + diethanolamine) + H]: 553.4217.Found, 553.
4251.

(Example 6) (2R, 6S) -tert-butyl 2- [2- (E)-[(3S, 3aR, 4S, 4aS, 8aR, 9
aS) -Dodecahydro-3-methyl-1-oxonaphtho [2,3-c] furan-4-yl] ethenyl] -6-methylpiperidine-1-carboxylate Acetone solution of 2.60 mg (5.81 μmol) of the compound of Example 5
To 1 mL, 0.10 mL of Jones reagent was added with stirring at room temperature.
After stirring at room temperature for 0.5 hour, the solvent was evaporated, 5 mL of water was added to the residue, and the mixture was extracted with ether (3 mL x 3). The organic layer was washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, evaporated to remove the solvent, further purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and colorless. 2.00 mg of the title compound was obtained as an oil (yield 80%). [α] _D ²² -4.5 ° (c0.27, CHCl ₃ ). ¹ H-NMR (400 MHz, C
DCl ₃ ): δ 0.82-0.96 (m, 2H), 1.06-1.27 (m, 5H), 1.
24 (d, J = 6.9 Hz, 3H), 1.29-1.79 (m, 8H), 1.41
(d, J = 5.9 Hz, 3H), 1.46 (s, 9H), 1.82-2.06 (m, 4
H), 2.17-2.21 (m, 1H), 2.68 (dt, J = 13.2, 6.7 Hz,
1H), 3.99-4.07 (m, 1H), 4.40-4.44 (m, 1H), 4.58 (d
q, J = 10.8, 6.2 Hz, 1H), 5.45-5.54 (m, 2H). ¹³ C-
NMR (100 MHz, CDCl ₃ ): δ 13.6, 19.1, 20.8, 25.5, 2
6.1, 26.3, 26.5, 28.6, 28.6, 28.6, 31.0, 31.9, 33.
8, 34.1, 39.0, 40.6, 40.7, 47.1, 49.8, 52.0, 77.2,
79.0, 128.6, 134.0, 155.1, 178.6. IR (neat): 293
0, 1770, 1680, 1460 cm ^-1 .MS (FAB) m / z: 432 (M ⁺ + H).
HRMS (FAB) (m / z): Calcd. For C ₂₆ H ₄₂ NO ₄ (M ⁺ + H): 4
32.3114.Found, 432.3109.

Example 7 (3S, 3aR, 4S, 4aS, 8aR, 9aS) -decahydro-3-methyl-4- [2-
(E)-[(2R, 6S) -6-Methylpiperidin-2-yl] ethenyl] naphtho [2,3-c] furan-1 (3H) -one 0.10 mL of trifluoroacetic acid was added to a methylene chloride solution (1 mL) of the compound of Example 6 (4.70 mg, 10.9 μmol), and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent, 10 mL of cold dilute aqueous sodium hydroxide solution was added to the residue to make it alkaline, and extracted with ether (3 mL × 3). Wash the organic layer with saturated saline solution (3 m
L), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain 3.60 mg of the title compound as a pale yellow oil (yield 1
00%). [α] _D ²² -35 ° (c0.36, CHCl ₃ ). ¹ H-NMR (400 MHz, CD
Cl ₃ ): δ 0.81-0.98 (m, 2H), 1.06-1.38 (m, 7H), 1.13
(d, J = 6.9 Hz, 3H), 1.41 (d, J = 5.9 Hz, 3H), 1.4
8-1.79 (m, 8H), 1.91 (ddd, J = 13.7, 6.9, 2.7 Hz,
1H), 2.03 (br, 1H), 2.05-2.11 (m, 1H), 2.14-2.20
(m, 1H), 2.70 (dt, J = 13.2, 6.7 Hz, 1H), 3.08-3.16
(m, 1H), 3.56-3.62 (m, 1H), 4.58 (dq, J = 9.8, 6.
4 Hz, 1H), 5.58 (dd, J = 15.2, 8.8 Hz, 1H), 5.64
(dd, J = 15.2, 5.4 Hz, 1H). ¹³ C-NMR (100 MHz, CDC
l ₃ ): δ 19.1, 19.5, 21.1, 26.2, 26.6, 30.8, 31.1,
32.0, 32.5, 33.8, 34.1, 38.9, 40.5, 40.9, 46.4, 4
9.6, 52.9, 77.2, 130.4, 133.8, 178.6. IR (neat):
2920, 1770, 1450, 1200 cm ^-1 .MS (FAB) m / z: 332 (M ⁺
+ H). HRMS (FAB) (m / z): Calcd. For C ₂₁ H ₃₄ NO ₂ (M ⁺ +
H): 332.2590.Found, 332.2617.

(Example 8) (3S, 3aR, 4S, 4aS, 8aR, 9aS) -decahydro-4- [2- (E)-[(2R, 6
S) -1,6-Dimethylpiperidin-2-yl] ethenyl] -3-methylnaphtho [2,3-c] furan-1 (3H) -one A solution of 3.60 mg (10.9 μmol) of the compound of Example 7 in acetonitrile (1 mL) was added to 37% formaldehyde water under stirring at room temperature.
0.10 mL, then sodium cyanoborohydride 1.50 mg
(23.9 μmol) was added, and the mixture was stirred at room temperature for 1 hr. Acetic acid was added to the reaction mixture to make it neutral, and after stirring for 0.5 hour, 10 mL of cold dilute aqueous sodium hydroxide solution was added to make the mixture alkaline, and the solvent was evaporated under reduced pressure. Extract the residue with ether (3 mL x 3)
did. The organic layer was washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, the solvent was evaporated, and the residue was purified by column chromatography (silica gel NH, hexane: ethyl acetate = 3: 1). The colorless oily title compound 2.4
0 mg was obtained (yield 64%). [α] _D ²² -7.7 ° (c0.12, CHCl ₃ ). ¹ H-NMR (400 MHz, C
DCl ₃ ): δ 0.80-0.93 (m, 4H), 1.03 (d, J = 6.4 Hz,
3H), 1.11-1.32 (m, 4H), 1.33-1.72 (m, 10H), 1.42
(d, J = 5.9 Hz, 3H), 1.88-1.94 (m, 1H), 2.02-2.11
(m, 1H), 2.17-2.27 (m, 1H), 2.23 (s, 3H), 2.70 (d
t, J = 13.2, 6.6 Hz, 1H), 2.81-2.90 (m, 1H), 3.03-
3.10 (m, 1H), 4.58 (dq, J = 10.8, 5.9 Hz, 1H), 5.5
5 (dd, J = 14.7, 8.3 Hz, 1H), 5.62 (dd, J = 15.7,
8.3 Hz, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ): δ 14.1, 1
9.1, 22.7, 26.2, 26.6, 29.4, 30.0, 30.3, 31.0, 31.
9, 33.8, 34.1, 39.0, 40.5, 40.7, 49.9, 55.9, 67.8,
77.2, 125.5, 125.5, 178.3.IR (neat): 2930, 1770,
1450, 1200 cm ^-1 .MS (FAB) m / z: 346 (M ⁺ + H). HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₆ NO ₂ (M ⁺ + H): 346.274
6. Found, 346.2720.

[0025]

The binding to muscarinic M ₁ receptor was evaluated by the specific binding amount of ³ H-pirenzepine using the cerebral cortex as a sample. The binding to muscarinic M ₂ receptor was evaluated by the specific binding amount of ³ H-quinuclidinyl benzilate using brainstem and heart as samples. Nonspecific binding is 1 μmol /
Determined using L-atropine. The concentration of the radioligand, ³ H- pirenzepine 1 nmol / L, ³ H- quinuclidinyl benzilate was 0.5 nmol / L. Take the membrane preparation and radioligand in a test tube, and add 50 mL / L phosphate buffer to the total volume of 1 mL.
And When determining the amount of non-specific binding, 1 μmol / L atropine was added, and when performing the substitution experiment, the test compound was added. Each drug was diluted with 50 mmol / L phosphate buffer. After thoroughly stirring the assay sample, it was incubated on a constant temperature shaker and subjected to B / F separation using a cell harvester. GF / B was used as the filter. This B
To perform / F separation, the filter was washed 3 times with 5 mL of ice-cold phosphate buffer. The radioactivity collected on the filter was measured with a scintillation counter using 10 mL ACS-II. As a result, the compound of the present invention showed significant binding to the M2 receptor, and is expected to be used as a therapeutic drug for Alzheimer's disease.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) // C07M 7:00 C07M 7:00 F term (reference) 4C037 TA03 4C063 AA01 BB03 BB04 CC76 DD10 EE01 4C086 BC21 GA02 GA07 ZA15 ZC42

Claims (15)

[Claims] 1. The following general formula (1) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, Represents a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₄ and R ₅ together represent an oxygen atom, or R ₄ represents a hydrogen atom,
R ₅ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, or a lower acyloxy group, and R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or a protective group for an amino group. , R ₇ represents a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group)
Epihimbacine derivatives, their enantiomers, and their acid addition salts. 2. The following general formula (1-1) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or A non-substituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group), and the 4-epihimbacine derivative, an enantiomer thereof, or a derivative thereof. Acid addition salts. 3. The following general formula (1-2) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or Represents an unsubstituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group. Which represents a group), the 4-epihimvacine derivative according to claim 1, their enantiomers, and their acid addition salts. 4. The following general formula (2) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or Represents an unsubstituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group. It represents a group, R ₁₀ represents a hydrogen atom, a lower acyl group, a lower alkylsulfonyl group or an arylsulfonyl group, Ar 1
Represents a benzene ring which may have one or more substituents)
The intermediate for producing the 4-epihimvacine derivative according to claim 1, which is represented by 5. The following general formula (3) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group, R ₁₁ represents a lower alkylsulfonyloxy group, arylsulfonyl (Representing an oxy group, an arylsulfenyl group, and an arylsulfonyl group). 6. The following general formula (3) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group, and R ₁₁ represents an arylsulfonyl group) Compound represented by the following general formula (4) (In the formula, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino group-protecting group,
R ₇ represents a lower alkyl group, or a substituted or unsubstituted aralkyl group, and R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group), or a compound thereof. The following general formula (2) obtained by reacting combinations (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, A lower alkyl group or a substituted or unsubstituted aralkyl group, R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or an amino-protecting group, and R ₇ represents a lower alkyl group, or a substituted or Represents an unsubstituted aralkyl group, R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a lower acyl group. It represents a group, R ₁₀ represents a hydrogen atom, a lower acyl group, a lower alkylsulfonyl group or an arylsulfonyl group, Ar 1
Represents a benzene ring which may have one or more substituents)
The method for producing the compound according to claim 1, wherein the production intermediate represented by is dearylsulfonylated. 7. (2R, 6S) -tert-butyl 2- [2-benzenesulfonyl-1-hydroxy-2-[(1S, 3S, 3aS, 4S, 4aS, 8aR, 9a
The compound according to claim 1, which is S) -dodecahydro-1-methoxy-3-methylnaphtho [2,3-c] furan-4-yl] ethyl] -6-methylpiperidine-1-carboxylate and its enantiomers. . 8. (2R, 6S) -tert-butyl 2- [2- (E)-[(1S, 3
S, 3aR, 4S, 4aS, 8aR, 9aS) -Dodecahydro-1-methoxy-3-methylnaphtho [2,3-c] furan-4-yl] ethenyl] -6-methylpiperidine-1-carboxylate and its mirror image The compound of claim 1, which is the body. 9. (2R, 6S) -tert-butyl 2- [2- (E)-[(3S, 3a
R, 4S, 4aS, 8aR, 9aS) -Dodecahydro-3-methyl-1-oxonaphthof [2,3-c] furan-4-yl] ethenyl] -6-methylpiperidine-1-carboxylate and its enantiomers The compound of claim 1, wherein 10. (3S, 3aR, 4S, 4aS, 8aR, 9aS) -decahydro
-3-methyl-4- [2- (E)-[(2R, 6S) -6-methylpiperidine-2-
The compound according to claim 1, which is il] ethenyl] naphtho [2,3-c] furan-1 (3H) -one and its enantiomers. 11. (3S, 3aR, 4S, 4aS, 8aR, 9aS) -decahydro
-4- [2- (E)-[(2R, 6S) -1,6-Dimethylpiperidin-2-yl]
The compound according to claim 1, which is ethenyl] -3-methylnaphtho [2,3-c] furan-1 (3H) -one and its enantiomer. 12. (1S, 3S, 3aR, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy-4- (methanesulfonyloxy) methyl-3-methylnaphtho [2,3-c] furan, and its The compound according to claim 5, which is an enantiomer. 13. (1S, 3S, 3aS, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy-3-methyl-4- (phenylsulfenyl) methylnaphtho [2,3-c] furan, and its The compound according to claim 5, which is an enantiomer. 14. (1S, 3S, 3aS, 4S, 4aS, 8aR, 9aS) -dodecahydro-1-methoxy-3-methyl-4- (phenylsulfonyl) methylnaphtho [2,3-c] furan and its mirror image The compound of claim 5, which is the body. 15. The following general formula (1) (In the formula, R ₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₃ represents a hydrogen atom, Represents a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₄ and R ₅ together represent an oxygen atom, or R ₄ represents a hydrogen atom,
R ₅ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, or a lower acyloxy group, and R ₆ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or a protective group for an amino group. , R ₇ represents a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₈ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group)
A muscarinic M ₂ subtype receptor antagonist comprising one or more epihimbacine derivatives, their enantiomers, and their acid addition salts as active ingredients.