JP2003183278A - Himbacine analog containing aromatic heterocyclic ring - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new hydronaphtho[2,3-c]furan derivative having strong and selective antagonism on a muscarine M<SB>2</SB>receptor and a pharmacological acceptable acid addition salt, to provide a method for producing the same and to obtain a therapeutic agent for Alzheimer's disease comprising the derivative or the salt as active ingredient. <P>SOLUTION: This hydronaphtho [2,3-c]furan derivative containing aromatic heterocyclic ring is represented by general formula (1) and its acid addition salt. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel hydronaphtho [2,3-c] furan derivative showing a potent and selective antagonism to muscarinic M ₂ receptor and a pharmacologically acceptable acid addition salt thereof, The present invention relates to a production method and a therapeutic agent for Alzheimer's disease containing them as an active ingredient.

[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 reuptake inhibitor, (2) acetylcholinesterase inhibitor, (3) choline acetyltransferase synthesis activator, (4) muscarinic receptor agonist (muscarinic M ₁ agonist or M ₂ receptor antagonist) ). Among them, the M ₂ receptor is considered to have negative presynaptic regulation of acetylcholine release from nerve endings. In recent years, M ₂ receptor antagonists, which have a function of interfering with this control mechanism and increasing the amount of acetylcholine in the interstitial space to smooth signal transmission, have been particularly noted as new therapeutic agents for Alzheimer's disease. Recently, it was revealed that hinbasin strongly and selectively antagonizes this M ₂ receptor, and its potential as a therapeutic agent for Alzheimer's disease was found. Thus, himbacine has a strong activity and interesting chemical structure.
It is a compound that attracts worldwide attention from two points, and in recent years, several groups have reported total synthesis using intramolecular Diels-Alder reaction as a key reaction and derivative synthesis (Kozikowski et al., Total synthesis: a). J. Am. Chem. Soc. 199
5, 117, 9369-9370.b) J. Org. Chem. 1997, 62, 5023
-5033. Derivative synthesis: a) Bioorg. Med. Chem. Lett. 199
2, 2, 797-802.b) Bioorg. Med. Chem. Lett. 1993,
3, 1247-1252.c) Bioorg. Med. Chem. 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: Bioorg. Med. Chem. Let
t. 1999, 9, 901-906.). Regarding the himbacin analog, the following patents by the Schering group, which uses the intramolecular Diels-Alder reaction as a key reaction, are disclosed (Chackalamannil et al., WO9926943). Although the claims of the patent include compounds similar to the claims of the present invention, they are not actually manufactured. Further, the patent is disclosed as a compound having a thrombin receptor antagonistic action, and there is no mention of muscarinic M ₂ subtype receptor antagonistic action as shown in the present invention. it is conceivable that.

These methods using the intramolecular Diels-Alder reaction require complicated steps in synthesizing the skeleton, and are important for improving the activity and reducing side effects. There was a problem that it was difficult to manufacture. On the other hand, if the intermolecular Diels-Alder reaction is used as the key reaction in the preparation of the production intermediate, the necessary constitutional units can be produced separately and reacted in arbitrary combinations, so the total synthesis Not only that, it also facilitates the production of new analogs. From this perspective,
The total synthesis of himbacine using intermolecular Diels-Alder reaction as a key reaction was reported (Terashima et al., JP 2000-22996A).
1, Takadoi et al., Tetrahedron Lett. 1999, 40, 3399-340.
2.). However, the production of a himbacine analog having various aromatic heterocycles using a production intermediate produced by using an intermolecular Diels-Alder reaction as a key reaction has not yet been achieved.

[0005]

The object of the present invention is considered to be greater in diversity than the intramolecular Diels-Alder reaction in the production of a himbacin analog expected to be used as a therapeutic drug for Alzheimer's disease. The present invention provides a method for producing a novel himbacin analog and a production intermediate thereof, which utilizes the production intermediate obtained by using the intermolecular Diels-Alder reaction as a key reaction.

[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:
It has a muscarinic M ₂ receptor antagonistic action, and was found to be extremely useful as a production intermediate in the production thereof,
The present invention has been completed. That is, the present invention is represented by the following general formula (1) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and
Together with R ₄ is the following general formula (B) (N is 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ may have one or more substituents. , 5 ~ 14
A membered ring O, N, represents an aromatic heterocyclic ring which may contain one or more heteroatoms such as S, or A represents a general formula (C) together with R _4. Or R ₅ and R ₆ together represent an oxygen atom, or
Alternatively, R ₅ represents a hydrogen atom, R ₆ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group, and R ₈ represents a lower alkyl group or a substituted or unsubstituted aralkyl group) The present inventors have found that the hydronaphtho [2,3-c] furan derivative represented by and the acid addition salts thereof have a surprising muscarinic M ₂ subtype receptor antagonistic activity, and have completed the present invention.

[0007]

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. ~ 6 can be mentioned. As the substituent, a lower alkoxy group, a halogen atom, a cyano group,
Examples include nitro group. As an “aralkyl group”,
Examples thereof 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 and a nitro group. The "lower alkoxy group" is a linear or branched one having 1 to 6 carbon atoms such as methoxy group, ethoxy group, 1-methylethoxy group, 1,1-dimethylethoxy group, propoxy group, 2-methylpropoxy group. Can be given. "Aralkyloxy group"
Examples thereof 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. The "lower acyloxy group" is a formyl group,
Examples thereof include those having 1 to 5 carbon atoms such as acetoxy group, propionyloxy group and 2,2-dimethylpropionyloxy group. Examples of the “lower acyl group” include those having 1 to 4 carbon atoms such as acetyl and propionyl. Examples of the "amino group-protecting group" include lower acyl groups such as acetyl and propionyl, ethoxycarbonyl, lower alkoxycarbonyl groups such as t-butoxycarbonyl, and benzyl group. "R ₇ and R ₈ are The phrase “to form a protective group for an amino group together” includes, for example, a phthaloyl group. "1
May have one or more substituents, 5-14 membered ring O,
“One or more substituents” in the “aromatic heterocycle which may contain one or more hetero atoms such as N and S” means, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl. Group, nitro group,
Examples of the amino group, cyano group and the like, the "halogen atom" here is a fluorine atom, a chlorine atom, a bromine atom,
Iodine atom can be mentioned. “Aromatic heterocycle which may contain one or more heteroatoms such as 5- to 14-membered ring O, N and S” is
For example, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyratyl and the like can be mentioned, and they may be condensed with the benzene ring at any position. 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.

A preferred compound in the present invention is 3-methyl-4-[(1Z) -2-[(1-methyl-2-imidazolyl) -2-yl]
Ethenyl] decahydronaphtho [2,3-c] furan-1 (3H) -one, 3-methyl-4-[(1E) -2-[(1-methyl-2-imidazolyl)-
2-yl] ethenyl] decahydronaphtho [2,3-c] furan-1 (3
H) -one, 3-methyl-4-[(2-pyridylmethyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, 3-methyl-4-
[(3-Pyridylmethyl) oxy] decahydronaphtho [2,3-c]
Furan-1 (3H) -one, 3-methyl-4-[(4-pyridylmethyl)
Oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, 3
-Methyl-4-[(2-pyridylcarbamoyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, 3-methyl-4-[(3
-Pyridylcarbamoyl) oxy] decahydronaphtho [2,3
-c] furan-1 (3H) -one, 3-methyl-4-[(2-pyridylcarbamoyl) oxymethyl] decahydronaphtho [2,3-c] furan-1 (3H) -one, 3-methyl-4 -[(6-Methyl-2-pyridylcarbamoyl) oxymethyl] decahydronaphtho [2,3-c] furan-1 (3H) -one, 4-aminomethyl-1-methoxy-3-methyldodecahydronaphtho [2, 3-c] furan-1 (3H) -one, 3-methyl-4- (6-methyl-2-pyridinecarboxamido) methyldecahydronaphtho [2,3-c] furan-1 (3H) -one, and 3-
Methyl-4- (2-pyridinecarboxamido) methyldecahydronaphtho [2,3-c] furan-1 (3H) -one and the like can be mentioned.

The compound of the general formula (7) can be prepared by a known method (Terashima et al., JP 2000-229961, Takadoi et al., Tetrahedron).
Lett. 1999, 40, 3399-3402.). The compound of the present invention has a plurality of asymmetric carbon atoms and corresponding optical isomers may exist, and these optical isomers and mixtures thereof are included in the present invention.

Among the compounds represented by the above general formula (1) of the present invention, the compounds represented by the above general formula (2) include compounds represented by the above general formula (7). It can be manufactured according to the manufacturing process. (In the formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ and R ₈ are as described above, R ₁₄ represents an arylsulfonyl group, and n is 1.) 1-Substitution to the compound represented by (7) -2-
Imidazole carboxaldehyde in the presence of a suitable base
The compound represented by the general formula (2) is produced by subjecting to Julia coupling and then reduction treatment.

In the present reaction, the "suitable base" is, for example, an alkali metal alkoxide such as sodium methoxide or 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,
Examples include tertiary organic bases such as 1,8-diazabicyclo [5.4.0] unde-7-cene. 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 solvents such as xylene, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane are preferably used. . The reaction proceeds smoothly at -110 ° C to 100 ° C.
In the subsequent "reduction treatment", sodium amalgam, samarium iodide or the like can be usually used. 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 0 ° C to 100 ° C. Alternatively, in this step, R ₁₄ of the compound represented by the general formula (7) is changed to a 1-phenyl-1H-tetrazol-5-ylsulfonyl group, a benzothiazol-2-ylsulfonyl group, etc. The above general formula
The compound represented by (2-1) can be produced (Julia
Modified Lynn-Lythgoe Coupling Reaction: Blakemore, PR
Et al., Synlett. 1998, 26.). In this step, the compound represented by the above general formula (2-1) (R ₅ represents a hydrogen atom, R ₆ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group) Is subjected to an oxidation reaction under acidic conditions to produce the compound represented by the general formula (2-2). In this reaction, an oxidizing agent such as Jones reagent is usually used. As the solvent, any solvent may be used as long as it does not participate in the reaction, and for example, a halogenated hydrocarbon solvent such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like is used. The reaction proceeds smoothly at -100 ° C to 100 ° C. Alternatively, the compound represented by the general formula (2-1) (wherein R ₆ represents a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, or a lower acyloxy group) is reacted in an acidic aqueous solution to produce the compound represented by the general formula ( The compound represented by the general formula (2-2) may be produced by producing the compound represented by 2-1) (R ₆ represents a hydroxyl group) and then reacting it under a normal oxidation reaction condition. The "acidic aqueous solution" used in this reaction is an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid,
And an aqueous solution of an organic acid such as acetic acid, citric acid, succinic acid, fumaric acid, maleic acid, tartaric acid. Also, the oxidation reaction is chromic acid, chromium trioxide-pyridine mixed system,
It can be performed using a dimethylsulfoxide-oxalyl chloride-triethylamine mixed system, a ruthenium complex, a Dess-Martin reagent, or 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, among the compounds represented by the general formula (1) of the present invention, the compound represented by the general formula (3) is particularly prepared from the compound represented by the general formula (7), for example, by the following production. It can be manufactured according to the process. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as described above, R ₁₄ represents a hydroxyl group, R ₂₃ represents a hydroxyl group, a reactive derivative of a hydroxyl group or a halogen atom. , N = 0) In this step, the compound represented by the general formula (7) is reacted with the compound represented by the general formula (8) to produce the compound represented by the general formula (3). It is a thing. As used herein, the “reactive derivative of a hydroxyl group” includes, for example, lower alkylsulfonyloxy, substituted arylsulfonyloxy and the like.

This reaction is usually carried out using a suitable reagent such as sodium methoxide, an alkali metal alkoxide such as sodium ethoxide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis. Alkali metal organic bases such as (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-
Tertiary organic bases such as methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] unde-7-sen,
It can be carried out in the presence of a Lewis acid such as zinc chloride, zinc bromide, zinc iodide, boron trifluoride, aluminum chloride, tin tetrachloride, boron trifluoride-diethyl ether complex and lithium perchlorate. 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 solvents such as xylene, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane are preferably used. . The reaction proceeds smoothly at -110 ° C to 100 ° C.
Alternatively, when R ₂₃ is a hydroxyl group, it can also be produced under ordinary Mitsunobu reaction conditions using a 3-substituted phosphine and an azo-based reagent such as diethyl azodicarboxylate under the above reaction conditions. In addition, among the compounds represented by the general formula (1) of the present invention, particularly the compound represented by the general formula (4) is prepared from the compound represented by the general formula (7), for example, by the following production. It can be manufactured according to the process. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₁₀ are as described above, R ₁₄ represents a hydroxyl group, Y represents a carboxyl group,
Represents an amino group or an isocyanato group, n is 0, 1 or 2
Is)

In this reaction, the hydroxyl group of the compound represented by the general formula (7) is carbamoylated with the carboxylic acid, amine or isocyanate compound represented by the general formula (9). This reaction is shown below, for example.
It can be done in four ways. (1) After reacting thionyl chloride and sodium azide sequentially with the corresponding carboxylic acid, or after reacting diphenylphosphoryl azide (DPPA), the isocyanic acid ester generated in the system by the Curtius rearrangement reaction is generally used. It is reacted with the compound represented by the formula (9). (2) The corresponding amino compound is reacted with phosgene or its analogue (eg, trichloromethyl chloroformate, triphosgene, etc.) in the presence of the compound represented by the general formula (9). (3) Alternatively, the corresponding amino compound can be represented by the general formula (9)
In the presence of the compound represented by, the compound is reacted with a carbonyl group inserting agent such as N, N′-carbonyldiimidazole (CDI). (4) The corresponding isocyanate is reacted in the presence of the compound represented by the general formula (9). 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,
Ether-based solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2- An alcohol solvent such as propanol and a mixed solvent of these and water are preferably used, and the reaction is carried out even without a solvent. In some cases, the following reagents, namely, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis ( Alkali metal organic bases such as (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] The reaction may be performed in the presence of a tertiary organic base such as unde-7-sen. Reaction is -20 ℃ to 100 ℃
And it progresses well. Further, among the compounds represented by the general formula (1) of the present invention, a compound represented by the general formula (6-1) is particularly preferably a compound represented by the general formula (7), for example, It can be manufactured according to the manufacturing process. (In the formula, R ₁ , R ₂ , R ₃ , R ₅ and R ₆ are as described above, R ₁₄ is a hydroxyl group or a reactive derivative thereof, and n is
0, 1 or 2)

In this reaction, the compound represented by the general formula (7) (R ₁₄ represents a hydroxyl group) is aminated to obtain the compound represented by the general formula (6-1). As used herein, the “reactive derivative of a hydroxyl group” includes, for example, lower alkylsulfonyloxy, substituted arylsulfonyloxy and the like. This reaction is carried out by dehydration condensation of phthalimide or the like under ordinary Mitsunobu reaction conditions in the presence of an azo-based reagent such as 3-substituted phosphine and diethyl azodicarboxylate, and then under acidic conditions of hydrochloric acid or hydrazine water. It can be produced by decomposing the imide structure using a hydrate or the like. At this time, any solvent can be used as long as it does not participate in the reaction, but 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,
An alcohol solvent such as 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol is preferably used. The reaction proceeds well at -20 ° C to 100 ° C. Alternatively, when R ₁₄ is a reactive derivative of a hydroxyl group, it can also be produced by directly reacting with ammonia (aqueous solution or gas). A solvent is not particularly required, but 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 solvents such as carbon tetrachloride,
Ether-based solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2- An alcohol solvent such as propanol is preferably used. The reaction is
Good progress from -20 ℃ to 100 ℃. Further, among the compounds represented by the general formula (1) of the present invention, particularly the general formula (5)
The compound represented by can be produced from the compound represented by the general formula (7) via the general formula (6-1), for example, according to the following production steps. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ , R ₁₂ , R ₁₃ and n are as described above, R ₁₄ is a hydroxyl group, and Z is a carboxylic acid. Or represents a reactive derivative of carboxylic acid)

In this reaction, the compound represented by the general formula (6) is prepared by amination of the compound represented by the general formula (7) (R ₁₄ represents a hydroxyl group). The compound represented by the formula (5) is obtained by performing an amidation reaction with the compound represented. The reaction is usually Z
When is a carboxyl group, it is obtained by reacting with a suitable condensing agent in the presence of a suitable base, and when Z is a reactive derivative of carboxylic acid or a halide (acid halide), it is obtained by reacting with a suitable base. You can In this case, “suitable condensing agent” means N, N′-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), N, N′-carbonyldiene. Examples include imidazole (CDI). Also "suitable base"
Examples of alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal organic compounds such as n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide. 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- Examples include tertiary organic bases such as sen. Examples of the “reactive derivative of carboxylic acid” include lower alkyl ester, active ester, acid anhydride, acid halide (especially acid chloride) and the like. Specific examples of the active ester include
p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-
Hydroxyphthalimide ester, N-hydroxy-5-norbornene-2,3-dicarboximide ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-hydroxy4,5-dichlorophenyl ester, 2-hydroxypyridine ester, 2 -Pyridine thiol ester and the like can be mentioned. Examples of the acid anhydride include symmetrical acid anhydrides and mixed acid anhydrides, and specific examples of the latter include:
Mixed acid anhydride with chlorocarbonic acid alkyl ester or chlorocarbonic acid aralkyl ester such as ethyl chlorocarbonate, isobutyl chlorocarbonate, benzyl chlorocarbonate, mixed acid anhydride with chlorocarbonic acid aryl ester such as phenyl chlorocarbonate, isovaleric acid And mixed acid anhydrides with alkanoic acids such as pivalic acid. As the solvent, 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 solvents such as carbon tetrachloride, diethyl ether, tetrahydrofuran, ether solvents such as 1,4-dioxane, Methanol, ethanol, 1-propanol,
An alcohol solvent such as 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol and a mixed solvent of these and water are preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C.

[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 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(1Z) -2-[(1-Methyl-2-imidazolyl) -2-yl] Ethenyl] decahydronaphtho [2,3-c] furan-1 (3H) -one and (3S, 3aR, 4R, 4a
S, 8aR, 9aS) -3-Methyl-4-[(1E) -2-[(1-Methyl-2-imidazolyl) -2-yl] ethenyl] decahydronaphtho [2,3-c] furan-1 (3H )-on (1S, 3S, 3aS, 4R, 4aS, 8aR, 9aS) -1-Methoxy-3-methyl-4-
(Phenylsulfonyl) methyl-dodecahydronaphtho [2,
3-c] furan (100.0 mg, 0.26 mmol) in 2 mL of 1,2-dimethoxyethane solution was added to n-butyllithium (1.5
mol / L) 0.44 mL was added dropwise, and 5 minutes later, 1-methyl-2-imidazolecarboxaldehyde (72.7 mg, 0.66 mmol) in 1,2-
1 mL of dimethoxyethane solution was added dropwise. After stirring for 1 hour, the reaction mixture was added to 5 mL of water, the solvent was evaporated, and the mixture was extracted with ether (5 mL x 3). Wash the organic layer with saturated saline (3 mL)
, Dried over anhydrous magnesium sulfate, filtered and evaporated.
The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1) to obtain 80.0 mg of coupling product. This was dissolved in 5 mL of methanol, 2.00 g of sodium-amalgam (5%) and 0.70 g of disodium hydrogenphosphate were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the residue was washed with ethyl acetate (20 mL).
Then, the solvent was distilled off. Add 5 mL of water and extract with ether (3
mL x 3). The organic layer was washed with saturated brine (3 mL),
After drying over anhydrous magnesium sulfate, filtration, removal of the solvent by distillation, and purification of the residue by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 4) gave (1S, 3S, 3aR, 4R , 4aS, 8aR, 9aS) -1-Methoxy-3-methyl-4-[(1Z) -2-[(1-methyl-2-imidazolyl) -2-yl] ethenyl] dodecahydronaphtho [2,3- c] 10.7 mg of furan
(Yield 20%), (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -1-methoxy
-3-methyl-4-[(1E) -2-[(1-methyl-2-imidazolyl) -2-
Il] ethenyl] dodecahydronaphtho [2,3-c] furan 22.
8 mg was obtained (yield 42%). 0.20 mL of Jones reagent was added dropwise to 2 mL of the acetone solution of the former (13.9 mg, 42.1 μmol).
Stir at room temperature for hours. The mixture was neutralized with dilute aqueous sodium hydroxide solution and extracted with ether (5 mL x 3). The organic layer was washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, evaporated to remove the solvent, and further purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1).
mg (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-methyl-4-[(1Z) -2-
[(1-Methyl-2-imidazolyl) -2-yl] ethenyl] decahydronaphtho [2,3-c] furan-1 (3H) -one was obtained (yield 64
%). [α] _D ²⁷ + 100 ° (c0.17, CHCl ₃ ). ¹ H NMR (400 MHz, CD
Cl ₃ ): δ 0.77-0.87 (m, 1H), 0.94-1.28 (m, 5H), 1.41
(d, J = 5.9 Hz, 3H), 1.60-1.78 (m, 5H), 1.86-1.93
(m, 1H), 2.75-2.82 (m, 2H), 3.63 (s, 3H), 3.67 (t
d, J = 11.8, 4.9 Hz, 1H), 4.70 (dq, J = 10.3, 5.9
Hz, 1H), 5.57 (dd, J = 11.7, 10.3 Hz, 1H), 6.28 (d,
J = 11.7 Hz, 1H), 6.84 (d, J = 1.0 Hz, 1H), 7.07
(d, J = 1.0 Hz, 1H). HRMS (EI) for C ₁₉ H ₂₆ N ₂ O ₂ (M ⁺ ):
calcd, 314.1994; found, 314.1992. 2 mL of the latter solution (31.2 mg, 94.4 μmol) in acetone,
0.20 mL of Jones reagent was added dropwise and stirred at room temperature for 3 hours. Neutralize with dilute aqueous sodium hydroxide and extract with ether (5
mL x 3). The organic layer was washed with saturated brine (5 mL),
After drying over anhydrous magnesium sulfate, the mixture was filtered, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 4.00 mg of colorless powder (3S, 3aR, 4R, 4aS, 8aR,
9aS) -3-Methyl-4-[(1E) -2-[(1-methyl-2-imidazolyl)
-2-yl] ethenyl] decahydronaphtho [2,3-c] furan-1 (3
H) -one was obtained (yield 13%). [α] _D ²⁷ -26 ° (c0.40, CHCl ₃ ). mp. 171-172 ℃. ¹ HN
MR (400 MHz, CDCl ₃ ): δ 0.71-0.81 (m, 1H), 1.00-1.2
8 (m, 5H), 1.45 (d, J = 5.9 Hz, 3H), 1.60-1.75 (m,
4H), 1.76-1.85 (m, 1H), 1.99 (ddd, J = 13.7, 6.4,
2.0 Hz, 1H), 2.26-2.35 (m, 2H), 2.66 (dt, J = 12.
7, 6.4 Hz, 1H), 3.64 (s, 3H), 4.73 (dq, J = 9.8,
6.1 Hz, 1H), 6.28 (d, J = 15.7 Hz, 1H), 6.45 (dd,
J = 15.5, 10.1 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H),
7.01 (d, J = 1.0 Hz, 1H) .HRMS (EI) for C ₁₉ H ₂₆ N ₂ O ₂
(M ⁺ ): calcd, 314.1994; found, 314.1991.

Example 2 (3S, 3aS, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(2-pyridylmethyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H )-on (1S, 3S, 3aS, 4R, 4aS, 8aR, 9aS) -4-hydroxy-1-methoxy
-3-Methyldodecahydronaphtho [2,3-c] furan (50.0 m
g, 0.21 mmol) N, N-dimethylformamide solution 2 mL
At room temperature, sodium hydride (60%, oily) (33.3 m
g, 0.42 mmol) and then 30 minutes later 2- (chloromethyl)
Pyridine hydrochloride (19.8 mg, 0.12 mmol) was added and stirred for 6 hours. Cold water (5 mL) was added to the reaction mixture, and the mixture was extracted with ether (3 mL x 3). Wash the organic layer with saturated saline (3 mL)
, Dried over anhydrous magnesium sulfate, filtered and evaporated.
The residue was further purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 18.8
mg was obtained (yield 27%). Of this, 17.2 mg (51.9 μmo
l) was dissolved in 2 mL of acetone, 0.10 mL of Jones reagent was added dropwise, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, 10 mL of dilute aqueous sodium hydroxide solution was added, and the mixture was extracted with ether (3 m
L x 3). The organic layer was washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 6.00 mg of the title compound (yield: Rate 37%). [α] _D ²⁰ + 52 ° (c0.60, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.74-1.46 (m, 7H), 1.48 (d, J = 5.9 Hz, 3
H), 1.61-1.87 (m, 4H), 2.16-2.24 (m, 1H), 2.67 (d
t, J = 12.2, 6.9 Hz, 1H), 2.73 (dt, J = 10.3, 6.8
Hz, 1H), 3.44 (dd, J = 10.3, 5.7 Hz, 1H), 4.54 (d,
J = 12.7 Hz, 1H), 4.76 (dq, J = 9.8, 5.9 Hz, 1H),
4.79 (d, J = 12.7 Hz, 1H), 7.21 (dd, J = 7.8, 4.9
Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.69-7.74 (m, 1
H), 8.55 (d, J = 4.4 Hz, 1H). HRMS (EI) for C ₁₉ H ₂₅
NO ₃ (M ⁺ ): calcd, 315.1834; found, 315.1834.

Example 3 (3S, 3aS, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(3-pyridylmethyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H )-on In the same manner as in Example 2, (1S, 3S, 3aS, 4R, 4aS, 8aR, 9aS) -4-
Hydroxy-1-methoxy-3-methyldodecahydronaphtho
16.8 mg of the title compound was obtained from [2,3-c] furan (30.0 mg, 0.12 mmol) (yield of 2 steps: 50%). [α] _D ²⁵ + 91 ° (c1.07, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.73-1.35 (m, 7H), 1.49 (d, J = 6.4 Hz, 3
H), 1.67-1.87 (m, 4H), 2.14-2.22 (m, 1H), 2.63-2.7
3 (m, 2H), 3.36 (dd, J = 10.8, 5.9 Hz, 1H), 4.43
(d, J = 11.7 Hz, 1H), 4.69 (d, J = 11.7 Hz, 1H),
4.74 (dq, J = 9.8, 5.9 Hz, 1H), 7.32 (dd, J = 7.8,
4.9 Hz, 1H), 7.66-7.71 (m, 1H), 8.55-8.60 (m, 2H).
HRMS (EI) for C ₁₉ H ₂₅ NO ₃ (M ⁺ ): calcd, 315.1834; fo
und, 315.1839.

Example 4 (3S, 3aS, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(4-pyridylmethyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H )-on In the same manner as in Example 2, (1S, 3S, 3aS, 4R, 4aS, 8aR, 9aS) -4-
Hydroxy-1-methoxy-3-methyldodecahydronaphtho
2.60 mg of the title compound was obtained from [2,3-c] furan (50.0 mg, 0.21 mmol) (2 step yield 13%). [α] _D ²⁶ + 95 ° (c0.26, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.77-1.39 (m, 7H), 1.46 (d, J = 6.4 Hz, 3
H), 1.67-1.95 (m, 4H), 2.17-2.25 (m, 1H), 2.64-2.7
4 (m, 2H), 3.36 (dd, J = 10.8, 5.4 Hz, 1H), 4.44
(d, J = 12.7 Hz, 1H), 4.72 (d, J = 12.7 Hz, 1H),
4.76 (dq, J = 9.3, 5.9 Hz, 1H), 7.29 (d, J = 5.3 H
z, 2H), 8.60 (d, J = 4.4 Hz, 2H). HRMS (EI) for C
₁₉ H ₂₅ NO ₃ (M ⁺ ): calcd, 315.1834; found, 315.1841.

Example 5 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(2-pyridylcarbamoyl) oxy] decahydronaphtho [2,3-c] furan-1
(3H) -On (1S, 3S, 3aS, 4R, 4aS, 8aR, 9aS) -4-hydroxy-1-methoxy
-3-Methyldodecahydronaphtho [2,3-c] furan (100.0 m
g, 0.42 mmol) in toluene solution (3 mL), picolinic acid (25
6.1 mg, 2.08 mmol), diphenylphosphoryl azide (4
48.3 μL, 2.08 mmol), triethylamine (580.0 μL
L, 4.16 mmol) was added and the mixture was heated with stirring at 100 ° C. for 6 hours.
After cooling, the solvent was distilled off, 5 mL of water was added, and the mixture was extracted with ether (3 mL
× 3) Yes. The organic layer was washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the carbamate. Body 95.5 mg
Was obtained (yield 64%). This was dissolved in 2 mL of acetone, 0.10 mL of Jones reagent was added, and the mixture was stirred at room temperature for 7 hours. After distilling off the solvent, the mixture was alkalified by adding dilute aqueous sodium hydroxide solution and extracted with ether (3 mL × 3). The organic layer was washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered,
The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 11.9 mg of the title compound (yield 13%). [α] _D ²⁵ + 36 ° (c0.11, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.77-1.31 (m, 6H), 1.35-1.44 (m, 1H), 1.39
(d, J = 5.9 Hz, 3H), 1.64-1.98 (m, 5H), 2.71-2.81
(m, 2H), 4.73 (dq, J = 10.3, 6.1 Hz, 1H), 4.89 (d
d, J = 11.2, 5.9Hz, 1H), 6.98-7.06 (m, 1H), 7.70-
7.76 (m, 1H), 8.00 (d, J = 8.3 Hz, 1H), 8.26-8.28
(m, 1H), 8.74 (br, 1H). HRMS (EI) for C ₁₉ H ₂₄ N ₂ O ₄
(M ⁺ ): calcd, 344.1736; found, 344.1745.

Example 6 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(3-pyridylcarbamoyl) oxy] decahydronaphtho [2,3-c] furan-1
(3H) -On In the same manner as in Example 5 (1S, 3S, 3aS, 4R, 4aS, 8aR, 9aS) -4-hydroxy-1-methoxy-3-methyldodecahydronaphtho [2,3
-c] Furan (15.2 mg, 63.2 μmol) gave 2.53 mg of the title compound (2 step yield 30%). Rf = 0.39 (ethyl acetate). ¹ H NMR (400 MHz, CDCl ₃ ):
δ 0.83-1.97 (m, 15H), 2.72-2.81 (m, 2H), 4.72-4.79
(m, 1H), 4.88 (dd, J = 10.8, 5.7 Hz, 1H), 6.69 (b
r, 1H), 7.29 (dd, J = 8.3, 4.9 Hz, 1H), 7.99 (br,
1H), 8.35 (dd, J = 4.4, 1.5 Hz, 1H), 8.50 (d, J =
2.4 Hz, 1H).

Example 7 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(2-pyridylcarbamoyl) oxymethyl] decahydronaphtho [2,3-c] furan-1 ( 3H) -ON In the same manner as in Example 5, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-
21.8 mg of the title compound was obtained from hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan (30.0 mg, 0.12 mmol) (yield of 2 steps: 52%). [α] _D ²⁴ + 22 ° (c0.10, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.84-1.31 (m, 7H), 1.44 (d, J = 5.9 Hz, 3
H), 1.63-1.94 (m, 6H), 2.42-2.47 (m, 1H), 2.64 (d
t, J = 13.2, 6.7 Hz, 1H), 4.09-4.15 (m, 1H), 4.33
(dd, J = 11.2, 3.9Hz, 1H), 4.67 (dq, J = 9.8, 6.1
Hz, 1H), 7.00-7.04 (m, 1H), 7.61 (br, 1H), 7.69-7.
73 (m, 1H), 7.94 (d, J = 8.3 Hz, 1H), 8.25-8.27
(m, 1H). HRMS (EI) for C ₂₀ H ₂₆ N ₂ O ₄ (M ⁺ ): calcd, 358.
1893; found, 358.1870.

Example 8 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(6-methyl-2-pyridylcarbamoyl) oxymethyl] decahydronaphtho
[2,3-c] Fran-1 (3H) -on In the same manner as in Example 5, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-
8.50 mg of the title compound was obtained from hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan (12.4 mg, 48.7 μmol) (2 step yield 47%). Rf = 0.36 (hexane: ethyl acetate = 1: 1). ¹ H NMR (40
0 MHz, CDCl ₃ ): δ 0.88-1.30 (m, 7H), 1.42 (d, J =
5.9 Hz, 3H), 1.66-1.93 (m, 5H), 2.40 (dt, J = 10.8,
5.4 Hz, 1H), 2.45 (s, 3H), 2.59-2.66 (m, 1H), 4.1
0 (d, J = 6.8 Hz, 1H), 4.14 (d, J = 7.3 Hz, 1H),
4.30 (dd, J = 11.3, 4.0 Hz, 1H), 4.65 (dq, J = 12.
2, 6.1 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 7.52 (b
r, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.74 (d, J = 8.3
Hz, 1H).

(Example 9) (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-aminomethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan-1 ( 3H)-
on (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan (10
0.0 mg, 0.39 mmol) in 3 mL of tetrahydrofuran solution,
Add phthalimide (63.6 mg, 0.43 mmol) and triphenylphosphine (113.4 mg, 0.43 mmol), and stir with ice.
Diethyl azodicarboxylate at 9 ° C (92.9 μL, 0.59 mm
ol) was added dropwise and the mixture was stirred at room temperature for 7 hours. After distilling off the solvent, 5 mL of dilute aqueous citric acid solution was added, 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, and the solvent was evaporated, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
(1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -1-methoxy-3-methyl-4-phthalimidomethyldodecahydronaphtho [2,3-c] furan (150.0 mg, yield 99%) was obtained. Then dissolve it in 5 mL of ethanol and add hydrazine hydrate.
(0.20 mL) was added and the mixture was stirred at room temperature for 4 hours. Water after distilling off the solvent
(10 mL) was added and extracted with ether (3 mL x 3). The organic layer was washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to give the crude title compound (51.2 mg, yield 52%). [α] _D ²⁵ + 85 ° (c0.25, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.79-1.04 (m, 6H), 1.15-1.90 (m, 9H), 1.39
(d, J = 6.4 Hz, 3H), 2.11-2.20 (m, 1H), 2.39-2.48
(m, 2H), 2.97 (dd, J = 13.2, 3.9 Hz, 1H), 3.33 (s,
3H), 4.16 (dq, J = 9.3, 6.1 Hz, 1H), 4.48 (s, 1H).
HRMS (FAB) for C ₁₅ H ₂₈ NO ₂ (MH ⁺ ): calcd, 254.2120;
found, 254.2104.

Example 10 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4- (6-methyl-2-pyridinecarboxamide) methyldecahydronaphtho [2,3-c]
Fran-1 (3H) -on (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-Aminomethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan-1 (3H)-
3 mL of methylene chloride solution of on (46.2 mg, 0.18 mmol)
At room temperature, 6-methylpicolinic acid (75.0 mg, 0.55 mmol)
Further, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (104.9 mg, 0.55 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After distilling off the solvent, dilute aqueous sodium hydroxide solution (5 mL) was added, 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, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1).
Purified by (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -1-methoxy-
3-Methyl-4- (2-pyridinecarboxamide) methyldodecahydronaphtho [2,3-c] furan (54.1 mg, yield 80%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): δ 0.91-1.10 (m, 5H), 1.1
7-1.30 (m, 3H), 1.40 (d, J = 5.9 Hz, 3H), 1.53-1.7
3 (m, 2H), 1.76-1.87 (m, 2H), 1.98-2.05 (m, 1H), 2.
19 (dt, J = 12.2, 6.2 Hz, 1H), 2.46 (dt, J = 9.8,
4.9 Hz, 1H), 2.58 (s, 3H), 3.09 (ddd, J = 13.7, 9.
8, 5.7 Hz, 1H), 3.32 (s, 3H), 3.86 (ddd, J = 13.7,
5.9, 4.4 Hz, 1H), 4.24 (dq, J = 9.3, 6.1 Hz, 1H),
4.49 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.72 (t, J
= 7.8 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 8.20 (b
r, 1H). HRMS (EI) for C ₂₂ H ₃₂ N ₂ O ₃ (M ⁺ ): calcd, 372.
2413; found, 372.2452. Then, dissolve this in 2 mL of acetone and use Jones reagent.
0.10 mL was added dropwise and the mixture was stirred at room temperature for 3 hours. Evaporate the solvent,
Diluted aqueous sodium hydroxide solution was added, and the mixture was alkalified and extracted with ether (3 mL × 3). Wash the organic layer with saturated saline (3
(mL), dried over anhydrous magnesium sulfate, filtered and evaporated to remove the residue.
Purification with (hexane: ethyl acetate = 1: 1) gave the title compound (18.0 mg, yield 35%). mp. 137-139 ℃. [α] _D ²⁴ + 30 ° (c0.13, CHCl ₃ ). ¹ HN
MR (400 MHz, CDCl ₃ ): δ 0.97-1.33 (m, 7H), 1.55 (d,
J = 5.9 Hz, 3H), 1.67-1.96 (m, 5H), 1.99-2.06 (m,
1H), 2.47-2.52 (m, 1H), 2.58 (s, 3H), 2.64 (dt, J
= 12.7, 6.4 Hz, 1H), 3.12 (ddd, J = 14.2, 10.3,
5.9 Hz, 1H), 3.90 (dt, J = 12.7, 5.6Hz, 1H), 4.72
(dq, J = 10.3, 5.9 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1
H), 7.74 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 8.7 Hz,
1H), 8.24 (br, 1H). HRMS (EI) for C ₂₁ H ₂₈ N ₂ O ₃ (M ⁺ ):
calcd, 356.2100; found, 356.2079.

Example 11 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4- (2-pyridinecarboxamide) methyldecahydronaphtho [2,3-c] furan-1 (3
H) -On In the same manner as in Example 10, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4
0.85 mg of the title compound was obtained from -aminomethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan-1 (3H) -one (11.8 mg, 46.6 μmol) (2 step yield 11%). Rf = 0.07 (ethyl acetate). ¹ H NMR (400 MHz, CDCl ₃ ):
δ 0.80-1.97 (m, 12H), 1.51 (d, J = 5.9 Hz, 3H), 2.
27-2.38 (m, 1H), 2.43-2.49 (m, 1H), 2.65 (dt, J =
13.2, 6.7 Hz, 1H), 3.29 (ddd, J = 14.2, 8.8, 5.7 H
z, 1H), 3.76 (dt, J = 13.2, 5.2 Hz, 1H), 4.69 (dq,
J = 9.8, 6.2 Hz, 1H), 6.08 (br, 1H), 7.56 (d, J =
5.9 Hz, 2H), 8.77 (d, J = 5.9 Hz, 2H).

[0028]

EFFECT OF THE INVENTION (Receptor Binding Test) 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 was determined using 1 μmol / L atropine. The radioligand concentration was 1 n mol / L for ³ H-pirenzepine,
³ H-quinuclidinyl benzilate was 0.5 n mol / L.
The membrane preparation and radioligand were placed in a test tube, and the total volume was adjusted to 1 mL with 50 mMol / L phosphate buffer. 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. 50 mm for each drug
Diluted with ol / L phosphate buffer. After stirring the assay sample well, incubate it on a constant temperature shaker,
B / F separation was performed using a cell harvester. GF / B was used as the filter. To perform this B / 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 M ₂ receptor. The compound of the present invention 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) A61P 43/00 111 A61P 43/00 111 C07D 307/92 C07D 307/92 405/12 405/12 // C07M 7:00 C07M 7:00 F term (reference) 4C037 TA03 4C063 BB07 CC76 DD12 DD25 EE01 4C086 AA01 AA02 AA03 BA05 BC17 BC38 GA02 GA07 GA08 MA01 MA04 NA14 ZA16 ZC42

Claims (21)

[Claims] 1. The following general formula (1) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and
Together with R ₄ is the following general formula (B) (N is 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ may have one or more substituents. , 5 ~ 14
A membered ring O, N, represents an aromatic heterocyclic ring which may contain one or more heteroatoms such as S, or A represents a general formula (C) together with R _4. Or R ₅ and R ₆ together represent an oxygen atom, or
Alternatively, R ₅ represents a hydrogen atom, R ₆ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group, and R ₈ represents a lower alkyl group or a substituted or unsubstituted aralkyl group) And a hydronaphtho [2,3-c] furan derivative represented by and an acid addition salt thereof. 2. The following general formula (1-1) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and
Together with R ₄ is the following general formula (B) (N is 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ may have one or more substituents. , 5 ~ 14
A membered ring O, N, represents an aromatic heterocyclic ring which may contain one or more heteroatoms such as S, or A represents a general formula (C) together with R _4. And R ₈ represents a lower alkyl group or a substituted or unsubstituted aralkyl group), the hydronaphtho [2,3-c] furan derivative according to claim 1, and acid addition salts thereof. 3. The following general formula (1-2) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and
Together with R ₄ is the following general formula (B) (N is 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ may have one or more substituents. , 5 ~ 14
A membered ring O, N, represents an aromatic heterocyclic ring which may contain one or more heteroatoms such as S, or A represents a general formula (C) together with R _4. Wherein R ₈ represents a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₉ represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or a lower acyl group). 1. The hydronaphtho [2,3-c] furan derivative according to 1, and acid addition salts thereof. 4. The following general formula (2) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₅
And R ₆ together represent an oxygen atom, or R ₅
Represents a hydrogen atom, R ₆ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group, and R ₈ represents a lower alkyl group or a substituted or unsubstituted aralkyl group). , Claims
1. The hydronaphtho [2,3-c] furan derivative according to 1, and acid addition salts thereof. 5. The following general formula (3) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₄
Is a 5- to 14-membered ring which may have one or more substituents.
O, N, represents an aromatic heterocycle which may contain one or more heteroatoms such as S, R ₅ and R ₆ together represent an oxygen atom, or R ₅ represents a hydrogen atom, R ₆ Represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group).
1. The hydronaphtho [2,3-c] furan derivative according to 1, and acid addition salts thereof. 6. The following general formula (4) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₄
Is a 5- to 14-membered ring which may have one or more substituents.
O, N, represents an aromatic heterocycle which may contain one or more heteroatoms such as S, R ₅ and R ₆ together represent an oxygen atom, or R ₅ represents a hydrogen atom, R ₆ Represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group, R ₁₀ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and n is 0, 1 or 2. Claim 1
Hydronaphtho [2,3-c] furan derivatives described, and acid addition salts thereof. 7. The following general formula (5) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₄
Is a 5- to 14-membered ring which may have one or more substituents.
O, N, represents an aromatic heterocycle which may contain one or more heteroatoms such as S, R ₅ and R ₆ together represent an oxygen atom, or R ₅ represents a hydrogen atom, R ₆ Represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group, and R ₁₁ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group). Hydronaphtho [2,3
-c] Furan derivatives and their acid addition salts. 8. The following general formula (6) (In the formula, R₁And R₂Are the same or different
Represents a lower alkyl group, R₃Is a hydrogen atom, lower alkyl
Represents a group or a substituted or unsubstituted aralkyl group, R_Five
And R₆Together represent an oxygen atom, or R_Five
Represents a hydrogen atom, R₆Is a hydroxyl group, a lower alkoxy group,
A substituted or unsubstituted aralkyloxy group or a lower acyl group
Represents a ruoxy group, R₁₂Is a hydrogen atom or lower alkyl
Represents a group, R ₁₃Represents a hydrogen atom or amino-protecting group.
Or R₁₂And R₁₃Together to protect the amino group
May be formed and n is 0, 1 or 2)
The hydronaphtho [2,3-c] furan derivative according to claim 1,
Body, and their acid addition salts. 9. 3-Methyl-4-[(1Z) -2-[(1-methyl-2-imidazolyl) -2-yl] ethenyl] decahydronaphtho [2,3-c]
Furan-1 (3H) -one and 3-methyl-4-[(1E) -2-[(1-methyl-2-imidazolyl) -2-yl] ethenyl] decahydronaphtho [2,3-c] furan-1 2. The compound according to claim 1, which is (3H) -one, and acid addition salts thereof. 10. The compound according to claim 1, which is 3-methyl-4-[(2-pyridylmethyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. . 11. The compound according to claim 1, which is 3-methyl-4-[(3-pyridylmethyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. . 12. The compound according to claim 1, which is 3-methyl-4-[(4-pyridylmethyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. . 13. The compound according to claim 1, which is 3-methyl-4-[(2-pyridylcarbamoyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. . 14. The compound according to claim 1, which is 3-methyl-4-[(3-pyridylcarbamoyl) oxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. . 15. 3-Methyl-4-[(2-pyridylcarbamoyl) oxymethyl] decahydronaphtho [2,3-c] furan-1 (3
The compound according to claim 1, which is H) -one, and acid addition salts thereof. 16. The compound according to claim 1, which is 3-methyl-4-[(6-methyl-2-pyridylcarbamoyl) oxymethyl] decahydronaphtho [2,3-c] furan-1 (3H) -one. And acid addition salts thereof. 17. A 4-aminomethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan-1 (3H) -one,
2. The compound according to claim 1 and acid addition salts thereof. 18. 3-Methyl-4- (6-methyl-2-pyridinecarboxamido) methyldecahydronaphtho [2,3-c] furan-1
2. The compound according to claim 1, which is (3H) -one, and acid addition salts thereof. 19. The compound according to claim 1, which is 3-methyl-4- (2-pyridinecarboxamido) methyldecahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. . 20. The following general formula (7): (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and R ₅
And R ₆ together represent an oxygen atom, or R ₅
Represents a hydrogen atom, R ₆ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group, R ₁₄ represents a hydroxyl group or an arylsulfonyl group, and n is 0, 1 or 2. , R ₁ and R ₂ represent a hydrogen atom, R ₃ represents a hydrogen atom, R ₅ and R ₆ together represent an oxygen atom, R ₁₄ is a hydroxyl group, n = 1
Hydronaphtho [2,3-
c] The method for producing the compound according to claim 1, wherein the furan derivative is used as a production intermediate. 21. The following general formula (1) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a lower alkyl group, R ₃ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and
Together with R ₄ is the following general formula (B) (N is 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ may have one or more substituents. , 5 ~ 14
A membered ring O, N, represents an aromatic heterocyclic ring which may contain one or more heteroatoms such as S, or A represents a general formula (C) together with R _4. Or R ₅ and R ₆ together represent an oxygen atom, or
Alternatively, R ₅ represents a hydrogen atom, R ₆ represents a hydroxyl group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group, and R ₈ represents a lower alkyl group or a substituted or unsubstituted aralkyl group) A muscarinic M ₂ subtype receptor antagonist comprising the hydronaphtho [2,3-c] furan derivative represented by and one or more of acid addition salts thereof as an active ingredient.