JP2003183270A - Himbacine analogue having aliphatic heterogeneous ring - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new hydronaphtho[2,3-c]furan derivative exhibiting a strong and selective antagonistic activity against muscarine M<SB>2</SB>receptors and a physiologically acceptable acid adduct salts thereof, to provide a method for producing the same, and to provide an Alzheimer's disease medicine containing the same as an active ingredient. <P>SOLUTION: This hydronaphtho [2,3-c]furan derivative having aliphatic heterogeneous ring represented by the general formula (1) (R<SB>1</SB>and R<SB>2</SB>are each identically or differently H or a lower alkyl; R<SB>3</SB>is H, a lower alkyl or a substituted or unsubstituted aralkyl; A is combined with R<SB>4</SB>to form a group represented by the general formula (2); R<SB>4</SB>is a 5 to 14-membered heteroaliphatic ring which may have one or more substituents and may contain one or more heterogeneous atoms such as O, N, and S; R<SB>5</SB>and R<SB>6</SB>together express an oxygen atom or the like, and an acid adduct salt thereof. <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.

[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.). Also,
Regarding the himbacine analog, the following patent by the Schering group, which uses the intramolecular Diels-Alder reaction as a key reaction, is disclosed (Chackalamannil et al., WO992694
3). However, in the patent, "Het" in the figure only claims a monocyclic, bicyclic or tricyclic heteroaromatic ring, and a himbacine analog having an aliphatic heterocycle as shown in the present invention has been heretofore known. Not known at all. 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 it is difficult to synthesize an analog which is important in improving activity and reducing side effects. There was a problem that was. On the other hand, if the intermolecular Diels-Alder reaction is used for the key reaction in the preparation of the production intermediate, the necessary structural units can be separately synthesized and reacted in any combination. Not only that, the synthesis of new analogs will be facilitated. 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, at present, the synthesis of the himbacine analogs having various aliphatic heterocycles using the production intermediate produced by using the 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 R4, the following general formula (2) (M and n are 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ has one or more substituents. Also represents a 5- to 14-membered ring O, N, represents an aliphatic heterocycle which may contain one or more heteroatoms such as S, 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)
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 “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. "One or more substituents in" an aliphatic heterocycle which may have one or more substituents, 5- to 14-membered ring O, N, S, etc. and may contain one or more heteroatoms "" Examples of the “” include a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, an amino group, a cyano group, and the like, and a “5- to 14-membered ring O, N, S Heteroatoms such as
Examples of the "aliphatic heterocycle which may include one or more" include pyrrolidyl, piperidyl, piperazyl, morpholyl and the like. 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. "Acid addition salt"
Examples of the pharmaceutically acceptable salt are 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 3-methyl-4- [2- (4-morpholyl) acetoxy] decahydronaphtho [2,3-c] furan-1 (3H) -one and 3-methyl-4. -[2-Morpholin-4-yl-2-oxoethoxy] decahydronaphtho [2,3-c]
Furan-1 (3H) -one, 3-methyl-4- [2-morpholin-4-yl
-1-Ethoxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, 3-methyl-4- [2-piperidin-4-yl-1-ethoxy] decahydronaphtho [2,3-c] furan -1 (3H) -one, 3-methyl-4
-[(3S) -1- (Phenylmethyl) -3-pyrrolidinyl] oxymethyldecahydronaphtho [2,3-c] furan-1 (3H) -one, 3-methyl-4-[(3S) -1 -Methyl-3-piperidinyloxymethyl]
Decahydronaphtho [2,3-c] furan-1 (3H) -one, 3-methyl
-4- [1-benzyl-4-piperidinyloxymethyl] decahydronaphtho [2,3-c] furan-1 (3H) -one, 4-[[(1-benzylpiperidin-4-yl) -methylamino ] -Methyl] -3-methyldecahydronaphtho [2,3-c] furan-1 (3H) -one and 4-[[(3R)-(1-benzylpiperidin-3-yl) -methylamino] Examples include -methyl] -3-methyldecahydronaphtho [2,3-c] furan-1 (3H) -one.

Of the compounds represented by the general formula (7), R ₁ , R ₂ , R ₃ and R ₅ represent a hydrogen atom, R ₆ represents a methoxy group, and B represents m = 0. Where Q is a compound having a hydroxyl group, R ₁ , R ₂ , R ₃ and R ₅ represent a hydrogen atom, and R ₆
Represents a methoxy group, B is methylene of m = 1, Q is a hydroxyl group, and R ₁ , R ₂ , R ₃ and R ₅ represent a hydrogen atom, R ₆ represents a methoxy group, B Is a methylene of m = 1 and Q is a phenylsulfonyl group 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 carbons and may have a corresponding optical isomer,
These optical isomers and mixtures thereof are included in the present invention.

The compound represented by the general formula (1) of the present invention can be produced from the compound represented by the general formula (7) or a reactive derivative thereof, for example, according to the following production steps. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , n, A, B and Q are as described above, and R ₁₈ is a hydroxyl group, a reactive derivative of a hydroxyl group or a halogen atom. R ₁₉ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group.) In this step, the compound represented by the general formula (7) is
By reacting the compound represented by the general formula (8) or (9),
It is for producing a compound represented by the above general formula (1). 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-ether complex and lithium perchlorate. 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, 1,
An ether solvent such as 4-dioxane is preferably used.
The reaction proceeds smoothly at -110 ° C to 100 ° C. This step also includes a step of subjecting the compound represented by the general formula (1-2) to an oxidation reaction under acidic conditions to produce the compound represented by the general formula (1-1). 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 (1-2) in an acidic aqueous solution (R ₈ represents a lower alkoxy group, a substituted or unsubstituted aralkyloxy group or a lower acyloxy group)
To react with the compound represented by the general formula (1-2) (R ₈
Represents a hydroxyl group), and then reacts it under ordinary oxidation reaction conditions to produce the compound represented by the general formula (1-1). 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. Alternatively, when R ₁₈ is a hydroxyl group, it can also be produced under the above-mentioned reaction conditions by using a 3-substituted phosphine and an azo-based reagent such as diethyl azodicarboxylate under ordinary Mitsunobu reaction conditions. Alternatively, particularly in the case of producing the compound shown in claims 10 and 11, it can also be produced by the following reaction. (Wherein, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , Q and m are as described above, B is methylene, R ₂₀ represents a hydroxyl group, a reactive derivative of a hydroxyl group or a halogen atom. , R ₂₁ represents a carbon atom or a nitrogen atom)

In this reaction, the compound represented by the general formula (7) is reacted with the compound represented by the general formula (10) under appropriate reaction conditions to produce a compound represented by the general formula (11), Then, the amide carbonyl group is reduced to produce the compound represented by the general formula (4). "Reacting the compound (10) under appropriate reaction conditions" means generally suitable reaction agents, for example, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, n-butyllithium, lithium bis (trimethylsilyl) amide. , Alkali metal organic bases such as sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine,
Piperidine, 1,5-diazabicyclo [4.3.0] non-5-ene,
It can be carried out in the presence of a tertiary organic base such as 1,8-diazabicyclo [5.4.0] unde-7-sen or under Mitsunobu reaction conditions. 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,
Halogenated hydrocarbon solvents such as chloroform and carbon tetrachloride and ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane are preferably used. The reaction is
It goes smoothly from -110 ℃ to 100 ℃. "Reduction of amidocarbonyl group" means diisobutylaluminum hydride,
It is carried out using an aluminum hydride-based reactant such as lithium aluminum hydride. 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,
Halogenated hydrocarbon solvents such as 1,2-dichloroethane, chloroform and carbon tetrachloride, and ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane are used. The reaction proceeds smoothly at -100 ° C to 100 ° C.

Regarding the production process of the above general formula (1), particularly when producing a compound represented by the following general formula (5),
It can also be manufactured by the following manufacturing process. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , B, Q, m and n are as described above, and R ₂₂ is a hydroxyl group, a reactive derivative of a hydroxyl group or a halogen atom. In this step, the compound represented by the general formula (7) is reacted with the compound represented by the general formula (12) to produce the ester compound represented by the general formula (5). The reaction is usually when R ₂₂ is a hydroxyl group (carboxylic acid),
Reacting with a suitable condensing agent in the presence of a suitable base, R
_{When 22} is a reactive derivative of a hydroxyl group or a halogen atom (acid halide), it can be obtained by reacting in the presence of a suitable base. In this case, "suitable condensing agent" means N, N'-
Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (ED
CI), N, N′-carbonyldiimidazole (CDI) and the like. 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, potassium bis (trimethylsilyl) amide. Alkali metal organic bases such as, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine,
Examples include tertiary organic bases such as 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene. Examples of the “hydroxyl group reactive derivative” include lower alkyl ester, active ester, acid anhydride, acid halide (particularly 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-hydroxy Examples thereof include quinoline ester, 2-hydroxyphenyl ester, 2-hydroxy4,5-dichlorophenyl ester, 2-hydroxypyridine ester and 2-pyridinethiol ester. Examples of the acid anhydride include symmetrical acid anhydrides and mixed acid anhydrides, and specific examples of the latter include ethyl chlorocarbonate, isobutyl chlorocarbonate, chlorocarbonic acid alkyl ester such as benzyl chlorocarbonate and chlorocarbonic acid aralkyl ester. And mixed acid anhydrides with chlorocarbonic acid aryl esters such as phenyl chlorocarbonate, isovaleric acid, mixed acid anhydrides with alkanoic acids such as pivalic acid, and the like. 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, 1,4-
Ether solvents such as 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. Reaction is from -110 ℃ to 100
At ℃, proceed smoothly.

[0014]

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

Example 1 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4- [2- (4-morpholyl) acetoxy] 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 N, N-dimethylformamide solution 3 mL
At room temperature, sodium hydride (60%, oily) (99.9 mg,
2.50 mmol) was added and stirred for 30 minutes. Then, chloroacetyl chloride (99.4 μL, 1.25 mmol) was added dropwise and stirred for 6 hours. 5 mL of cold water was added to the reaction mixture, which was extracted with ether (3 mL × 3). Wash the organic layer with saturated saline (5 mL).
, Dried over anhydrous magnesium sulfate, filtered and evaporated.
The residue was further purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 110.0 mg (1
S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4- (2-chloroacetoxy) -1-
Methoxy-3-methyldodecahydronaphtho [2,3-c] furan was obtained (yield 83%). To this, add 0.50 mL of morpholine and add 100
The mixture was heated and stirred at ℃ for 2 hours. After cooling, 10 mL of water was added and extracted with ether (3 mL x 3). Wash the organic layer with saturated saline (5 m
L), dried over anhydrous magnesium sulfate, filtered and evaporated to remove the residue, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give (1S, 3S, 3
45.7 mg of aR, 4R, 4aS, 8aR, 9aS) -1-methoxy-3-methyl-4- [2- (4-morpholyl) acetoxy] dodecahydronaphtho [2,3-c] furan was obtained (yield 36%). Of this, 15.2 mg was dissolved in 2 mL of acetone, 0.10 mL of Jones reagent was added, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent, dilute aqueous sodium hydroxide solution
10 mL was added and the mixture was extracted with ether (3 mL 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 subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 1 :).
Purified in 2), 8.00 mg of the title compound was obtained (yield 55
%). [α] _D ²⁵ + 41 ° (c0.76, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.82-1.40 (m, 7H), 1.42 (d, J = 5.9 Hz, 3
H), 1.57-1.81 (m, 4H), 1.89 (dd, J = 10.8, 6.4 Hz,
1H), 2.53-2.62 (m, 5H), 2.72-2.78 (m, 1H), 3.16
(d, J = 16.6 Hz, 1H), 3.25 (d, J = 16.6 Hz, 1H),
3.76 (t, J = 4.7 Hz, 4H), 4.74 (dq, J = 12.2, 5.9
Hz, 1H), 4.97 (dd, J = 11.3, 5.9 Hz, 1H). HRMS (E
I) for C ₁₉ H ₂₉ NO ₅ (M ⁺ ): calcd, 351.2046; found, 35
1.2045.

(Example 2) (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-methyl-4- [2-morpholine-4
-Yl-2-oxoethoxy] decahydronaphtho [2,3-c] furan-1 (3H) -one (1S, 3S, 3aS, 4R, 4aS, 8aR, 9aS) -4-hydroxy-1-methoxy
-3-methyldodecahydronaphtho [2,3-c] furan (59.0 mg,
(0.25 mmol) in N, N-dimethylformamide solution (2 mL) was stirred at room temperature with sodium hydride (60%, oily) (49.1 mg, 1.2
(3 mmol) was added and stirred for 30 minutes. 2-chloro-1-to the reaction mixture
Morpholin-4-ylethanone (80.3 mg, 0.49 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Cold water (10 mL) was added to the reaction mixture, and the mixture was extracted with ether (3 mL × 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 (hexane: ethyl acetate = 1: 2) to give 76.0
The adduct of mg was obtained (yield 84%). This was dissolved in 2 mL of acetone, 0.20 mL of Jones reagent was added, and the mixture was stirred at room temperature for 10 hours. After distilling off the solvent, dilute with 10 mL of water and extract with ether (3
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 (hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain 25.9 mg of the title compound (yield 36 %). mp. 142-143 ℃ (Hexane: Ethyl acetate = 1: 1). ¹ H NM
R (400 MHz, CDCl ₃ ): δ0.83-1.35 (m, 7H), 1.51 (d,
J = 5.9 Hz, 3H), 1.66-1.87 (m, 4H), 2.09-2.17 (m,
1H), 2.65 (dt, J = 12.7, 6.4 Hz, 1H), 2.76 (dt, J
= 9.8, 6.4 Hz, 1H), 3.38 (dd, J = 10.8, 5.9 Hz, 1
H), 3.43-3.74 (m, 8H), 4.12 (d, J = 13.2 Hz, 1H),
4.24 (d, J = 13.2 Hz, 1H), 4.73 (dq, J = 12.2, 6.4
Hz, 1H) .Anal. For C ₁₉ H ₂₉ NO ₅ : calcd, C: 64.93, H:
8.32, N: 3.99; found, C: 64.66, H: 8.24, N: 4.03.

(Example 3) (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-methyl-4- [2-morpholine-4
-Yl-1-ethoxy] decahydronaphtho [2,3-c] furan-1 (3
H) -On (3S, 3aR, 4R, 4aS, 8aR, 9aS) -1-methoxy-3-methyl-4- [2-
To 4 mL of a tetrahydrofuran solution of morpholin-4-yl-2-oxoethoxy] decahydronaphtho [2,3-c] furan (55.8 mg, 0.15 mmol) was added lithium aluminum hydride (11.5 mg, 0.30 mmol) with stirring under ice cooling. The mixture was stirred at room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ether (3 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) to give 24.0 mg.
Was obtained (yield 45%). This was dissolved in 2 mL of acetone, 0.20 mL of Jones reagent was added, and the mixture was stirred at room temperature for 22 hours. After 10 mL of water was added and the solvent was distilled off, dilute aqueous sodium hydroxide solution was added to alkalize and extract with ether (5 mL x
3) I did. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, evaporated to remove the solvent, and further purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 0.60 mg of the title. A compound was obtained (yield 3%). Rf = 0.07 (ethyl acetate: hexane = 2: 1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 0.76-1.85 (m, 10H), 1.
51 (d, J = 6.4 Hz, 3H), 2.13-2.21 (m, 1H), 2.43-2.
66 (m, 8H), 3.18 (dd, J = 10.8, 5.7 Hz, 1H), 3.45
(dt, J = 10.3, 6.2 Hz, 1H), 3.64-3.78 (m, 6H), 4.6
7-4.74 (m, 1H).

(Example 4) (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-methyl-4- [2-piperidine-4
-Yl-1-ethoxy] 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 (44.4 m
g, 0.18 mmol) N, N-dimethylformamide solution 2 mL
, Sodium hydride (60%, oily) under stirring at room temperature (36.9 m
g, 0.92 mmol) was added and stirred for 30 minutes. 2-Chloro-1-piperidin-4-ylethanone (59.7 mg, 0.37 mm) was added to the reaction mixture.
ol) was added and the mixture was stirred at room temperature for 14 hours. 10 mL of cold water in the reaction mixture
Was added and extracted with ether (3 mL x 3). The organic layer was washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate,
Filtration and evaporation of the solvent gave 67.5 mg of adduct (yield 100
%). This was dissolved in tetrahydrofuran (10 mL) and stirred under ice-cooling with lithium aluminum hydride (14.0 mg, 0.37 mmo).
l) was added and stirred for 1 hour. Water (10 mL) was added, the solvent was evaporated, and the residue was extracted with ether (5 mL x 3). The organic layer was washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 64.9 mg of a crude adduct (yield 100
%). Dissolve this in 4 mL of acetone and add 0.2 parts of Jones reagent.
0 mL was added and the mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, dilute aqueous sodium hydroxide solution was added to alkalize, and the mixture was extracted with ether (3 mL × 3). The organic layer was washed with saturated saline (3
(mL), dried over anhydrous magnesium sulfate, filtered, evaporated to remove the solvent, and further purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain 0.60 mg of the title compound (yield 1%). . Rf = 0.14 (ethyl acetate: methanol = 2: 1) ¹ H NMR (400 MHz, CDCl ₃ ): δ 0.77-1.86 (m, 17H), 1.
50 (d, J = 5.9 Hz, 3H), 2.11-2.19 (m, 1H), 2.41-2.
66 (m, 8H), 3.19 (dd, J = 10.3, 5.7 Hz, 1H), 3.47-
3.53 (m, 1H), 3.75-3.80 (m, 1H), 4.66-4.73 (m, 1
H).

Example 5 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(3S) -1- (phenylmethyl) -3-pyrrolidinyl] oxymethyldecahydronaphtho [ 2,3-c] Fran-1 (3H) -on (S) -1-Benzyl-3-pyrrolidinol (104.0 mg, 0.59 mm
ol) in N, N-dimethylformamide (2 mL), stirred at room temperature with sodium hydride (60%, oil, 39.1 mg, 0.98 m
mol) was added and stirred for 20 minutes. (1S, 3S, 3aR, 4R, 4aS, 8aR, 9a
O-mesyl derivative prepared from (S) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan (65.
0 mg, 0.20 mmol) was added, and the mixture was heated with stirring at 80 ° C. for 17 hours. After cooling, add water (10 mL) and extract with ether (3 mL × 3).
did. 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 (ethyl acetate), (1S, 3S, 3aR, 4R , 4aS, 8aR, 9aS) -1-Methoxy-3-methyl
-4-[(3S) -1- (phenylmethyl) -3-pyrrolidinyl] oxymethyldodecahydro [2,3-c] furan (12.4 mg, yield 8%)
Got Next, 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 3 hours. After the solvent was distilled off, a dilute aqueous solution of sodium hydroxide was added to alkalize, 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, evaporated to remove the solvent, and further purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1).
7.60 mg of the title compound was obtained (yield 64%). [α] _D ²⁴ + 36 ° (c0.76, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.79-1.29 (m, 8H), 1.42 (d, J = 5.9 Hz, 3
H), 1.62-1.88 (m, 6H), 2.01-2.10 (m, 1H), 2.40 (d
t, J = 10.8, 5.4 Hz, 1H), 2.47 (dd, J = 10.3, 3.9
Hz, 1H), 2.53-2.65 (m, 3H), 2.79 (dd, J = 10.3, 6.4
Hz, 1H), 3.26-3.38 (m, 2H), 3.62 (q, J = 12.7 Hz,
2H), 3.88-3.93 (m, 1H), 4.66 (dq, J = 10.3, 5.9 H
z, 1H), 7.23-7.35 (m, 5H). HRMS (EI) for C ₂₅ H ₃₅ NO ₃
(M ⁺ ): calcd, 397.2617; found, 397.2623.

(Example 6) (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-methyl-4-[(3S) -1-methyl-
3-Piperidinyloxymethyl] decahydronaphtho [2,3-
c] Fran-1 (3H) -on Similarly to Example 5, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho
O-mesyl derivative prepared from [2,3-c] furan (65.0 mg, 0.20
2.30 mg of the title compound was obtained from (mmol) (3 step yield 4
%). [α] _D ²⁴ + 13 ° (c0.23, CHCl ₃ ). ¹ H NMR (400 MHz, CDC
l ₃ ): δ 0.83-1.35 (m, 10H), 1.45 (d, J = 5.9 Hz, 3
H), 1.56-2.04 (m, 9H), 2.29 (s, 3H), 2.38-2.43 (m,
1H), 2.57 (dt, J = 12.7, 6.4 Hz, 1H), 2.63-2.71
(m, 1H), 2.87-2.96 (m, 1H), 3.30-3.35 (m, 1H), 3.4
5 (dd, J = 8.6, 8.6 Hz, 1H), 3.52 (dd, J = 9.3, 3.2
Hz, 1H), 4.68 (dq, J = 10.3, 6.4 Hz, 1H). HRMS (E
I) for C ₂₀ H ₃₃ NO ₃ (M ⁺ ): calcd, 335.2460; found, 33
5.2492.

Example 7 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4-[(3R) -1-Methyl-
3-Piperidinyloxymethyl] decahydronaphtho [2,3-
c] Fran-1 (3H) -on Similarly to Example 5, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho
O-mesyl derivative prepared from [2,3-c] furan (58.0 mg, 0.17
From 3.0 mmol, 3.06 mg of the title compound was obtained (3 step yield 5
%). Rf = 0.11 (ethyl acetate: methanol = 2: 1). ¹ H NMR
(400 MHz, CDCl ₃ ): δ 0.79-1.93 (m, 19H), 1.46 (d,
J = 5.9 Hz, 3H), 2.29 (s, 3H), 2.42 (dt, J = 10.3,
5.5 Hz, 1H), 2.57 (dt, J = 13.2, 6.7 Hz, 1H), 2.63
-2.70 (m, 1H), 2.88-2.96 (m, 1H), 3.29-3.36 (m, 1
H), 3.41 (apparent t, J = 8.8 Hz, 1H), 3.56 (dd, J
= 9.3, 3.2 Hz, 1H), 4.67 (dq, J = 11.7, 5.9 Hz, 1
H).

Example 8 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -3-Methyl-4- [1-benzyl-4-
Piperidinyloxymethyl] decahydronaphtho [2,3-c]
Fran-1 (3H) -on Similarly to Example 5, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho
O-mesyl derivative prepared from [2,3-c] furan (50.0 mg, 0.15
mmol) gave 1.20 mg of the title compound (2 step yield 2
%). Rf = 0.07 (hexane: ethyl acetate = 1: 1). ¹ H NMR (40
0 MHz, CDCl ₃ ): δ 0.77-1.30 (m, 8H), 1.44 (d, J =
5.9 Hz, 3H), 1.54-1.90 (m, 9H), 2.08-2.18 (m, 2H),
2.35-2.41 (m, 1H), 2.57 (dt, J = 12.7, 6.4 Hz, 1
H), 2.66-2.75 (m, 2H), 3.17-3.25 (m, 1H), 3.39-3.50
(m, 4H), 4.69 (dq, J = 9.8, 6.1 Hz, 1H), 7.28-7.3
4 (m, 5H).

Example 9 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-[[(1-benzylpiperidine-
4-yl) -methylamino] -methyl] -3-methyldecahydronaphtho [2,3-c] furan-1 (3H) -one (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho [2,3-c] furan O-mesyl derivative prepared from furan (19.0 mg, 57.1 μmol), (1-benzylpiperidin-4-yl) methylamine (58.4 mg, 0.2
(9 mmol) was added and the mixture was heated with stirring at 80 ° C. for 10 hours. The reaction mixture was alkalified with 5 mL of a dilute aqueous sodium hydroxide solution and then 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 distilled off.The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) and added. 20.1 mg of the body was obtained. Then add this to 2 m of acetone
It melt | dissolved in L, Jones reagent 0.10 mL was dripped, and it stirred at room temperature for 24 hours. The solvent was distilled off, a dilute aqueous sodium hydroxide solution was added to alkalize, 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 to give the title compound.
(8.80 mg, 2 step yield 36%). Rf = 0.05 (hexane: ethyl acetate = 1: 1). ¹ H NMR (40
0 MHz, CDCl ₃ ): δ 0.76-2.04 (m, 20H), 1.42 (d, J =
6.4 Hz, 3H), 2.07 (s, 3H), 2.09-2.31 (m, 1H), 2.4
3-2.57 (m, 2H), 2.68-2.77 (m, 1H), 2.92-2.99 (m, 2
H), 3.50 (s, 2H), 4.58-4.72 (m, 1H), 7.27-7.36 (m,
5H).

Example 10 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-[[(3R)-(1-benzylpiperidin-3-yl) -methylamino] -methyl] -3- Methyldecahydronaphtho [2,3-c] furan-1 (3H) -one Similarly to Example 9, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho
O-mesyl derivative prepared from [2,3-c] furan (37.1 mg, 0.11
2.30 mg of the title compound was obtained from (mmol) (2 step yield 5%). Rf = 0.11 (hexane: ethyl acetate = 1: 1). ¹ H NMR (40
0 MHz, CDCl ₃ ): δ 0.66-1.87 (m, 19H), 1.35 (d, J =
5.9 Hz, 3H), 2.07 (s, 3H), 2.43-2.58 (m, 4H), 2.7
1 (dd, J = 12.2, 4.9 Hz, 1H), 2.78-2.86 (m, 2H), 3.
44 (d, J = 13.2Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H),
4.55-4.62 (m, 1H), 7.24-7.37 (m, 5H).

Example 11 (3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-[[(3S)-(1-benzylpiperidin-3-yl) -methylamino] methyl] -3-methyl Decahydronaphtho [2,3-c] furan-1 (3H) -one Similarly to Example 9, (1S, 3S, 3aR, 4R, 4aS, 8aR, 9aS) -4-hydroxymethyl-1-methoxy-3-methyldodecahydronaphtho
O-mesyl derivative prepared from [2,3-c] furan (61.8 mg, 0.19
4.83 mg of the title compound was obtained from (mmol) (2 step yield 6%). Rf = 0.11 (hexane: ethyl acetate = 1: 1). ¹ H NMR (40
0 MHz, CDCl ₃ ): δ 0.73-2.07 (m, 19H), 1.41 (d, J =
5.9 Hz, 3H), 2.10 (s, 3H), 2.46-2.62 (m, 4H), 2.7
3-2.81 (m, 2H), 2.90-2.96 (m, 1H), 3.42 (d, J = 1
3.2 Hz, 1H), 3.60 (d, J = 13.2 Hz, 1H), 4.61 (dq, J
= 9.8, 6.2 Hz, 1H), 7.24-7.42 (m, 5H).

[0026]

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.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 111 A61P 43/00 111 C07D 405/12 C07D 405/12 F term (reference) 4C037 TA04 4C063 AA01 BB08 BB09 CC76 DD03 DD10 EE01 4C086 AA01 AA02 AA03 AA04 BC07 BC21 BC73 GA02 GA09 GA12 MA01 MA04 NA14 ZA16 ZC42

Claims (18)

[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
Is integrated with R ₄ and the following general formula (2) (M and n are 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ has one or more substituents. Also represents a 5- to 14-membered ring O, N, represents an aliphatic heterocycle which may contain one or more heteroatoms such as S, 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 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
Is integrated with R ₄ and the following general formula (2) (M and n are 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ has one or more substituents. Represents a 5 to 14-membered ring O, N, S, etc., which may contain one or more heteroatoms such as O), hydronaphtho [2,3-c] furan according to claim 1. Derivatives, as well as their acid addition salts. 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
Is integrated with R ₄ and the following general formula (2) (M and n are 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ has one or more substituents. Also, a 5- to 14-membered ring O, N, represents an aliphatic heterocycle which may contain one or more heteroatoms such as S, R ₈ is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or The hydronaphtho [2,3-c] furan derivative according to claim 1, which is represented by a lower acyl group), and acid addition salts thereof. 4. 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, S represents an aliphatic heterocycle which may contain one or more heteroatoms, 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 m and n represent 0, 1 or 2), the hydronaphtho [2,3-c ] Furan derivatives and their acid addition salts. 5. 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, S represents an aliphatic heterocycle which may contain one or more heteroatoms, 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 m and n represent 0, 1 or 2), the hydronaphtho [2,3-c ] Furan derivatives and their acid addition salts. 6. 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, S represents an aliphatic heterocycle which may contain one or more heteroatoms, 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 m and n represent 0, 1 or 2), the hydronaphtho [2,3-c ] Furan derivatives and their acid addition salts. 7. The following general formula (6) (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, S represents an aliphatic heterocycle which may contain one or more heteroatoms, 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 ₉ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, and m and n are 0, 1 or Which represents 2), the hydronaphtho [2,3-c] furan derivative according to claim 1, and acid addition salts thereof. 8. The compound according to claim 1, which is 3-methyl-4- [2- (4-morpholyl) acetoxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and its acid addition. salts. 9. 3-Methyl-4- [2-morpholin-4-yl-2-oxoethoxy] decahydronaphtho [2,3-c] furan-1 (3H)-
The compound according to claim 1, which is on, and acid addition salts thereof. 10. 3-Methyl-4- [2-morpholin-4-yl-1-
2. The compound according to claim 1, which is ethoxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. 11. 3-Methyl-4- [2-piperidin-4-yl-1-
The compound according to claim 1, which is ethoxy] decahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. 12. 3-Methyl-4-[(3S) -1- (phenylmethyl) -3-pyrrolidinyl] oxymethyldecahydronaphtho [2,
The compound according to claim 1, which is 3-c] furan-1 (3H) -one, and acid addition salts thereof. 13. 3-Methyl-4-[(3S) -1-methyl-3-piperidinyloxymethyl] decahydronaphtho [2,3-c] furan-
The compound according to claim 1, which is 1 (3H) -one, or an acid addition salt thereof. 14. 3-Methyl-4- [1-benzyl-4-piperidinyloxymethyl] decahydronaphtho [2,3-c] furan-1 (3
The compound according to claim 1, which is H) -one, and acid addition salts thereof. 15. 4-[[(1-Benzylpiperidin-4-yl)-
Methylamino] -methyl] -3-methyldecahydronaphtho [2,3
The compound according to claim 1, which is -c] furan-1 (3H) -one, and acid addition salts thereof. 16. 4-[[(3R)-(1-benzylpiperidine-3-
2. The compound according to claim 1, which is yl) -methylamino] -methyl] -3-methyldecahydronaphtho [2,3-c] furan-1 (3H) -one, and acid addition salts thereof. 17. The following general formula (7) (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, B together with Q represents the following general formula (2-
1) (M is 0, 1 or 2 and R₇Is a hydrogen atom, lower alkyl
A group or a substituted or unsubstituted aralkyl group)
Yes, Q represents a hydroxyl group or a halogen atom, but R ₁, R₂
And R₃Represents a hydrogen atom, R_FiveAnd R₆Together
Represents an oxygen atom, except for compounds where m = 1)
The hydronaphtho according to claim 1 to claim [2,3-
c] Intermediate for the production of furan derivatives. 18. 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
Is integrated with R ₄ and the following general formula (2) (M and n are 0, 1 or 2, R ₇ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group), and R ₄ has one or more substituents. Also represents a 5- to 14-membered ring O, N, represents an aliphatic heterocycle which may contain one or more heteroatoms such as S, 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 one or more of acid addition salts thereof as an active ingredient. A muscarinic M ₂ subtype receptor antagonist characterized by comprising: