JPH0517471A - Furan derivative - Google Patents

Abstract

PURPOSE:To obtain new furan derivatives useful as medicines for diseases caused by a central nervous system disorders such as constipation, diarrhea, abdominal distention, Altzheimer geriatric dementia or amnesia. CONSTITUTION:A compound expressed by formula I [X is H, R7CH2-(R7 is lower alkoxy, etc.), etc.; R1 is H, lower alkyl, (substituted)phenyl, (substituted) aralkyl, picolyl, etc.; R2 to R6 are H or lower alkyl; (n) is 0 or 1], e.g. {1-[2-[(5- dimethylaminomethyl-2-furanyl) methylthio] ethyl]-2-imidazolidylidene} propanedinitrile. The compound expressed by formula I is e.g. produced by reacting a compound expressed by formula II with an equimolar compound expressed by formula III to afford a compound expressed by formula IV, reacting the compound of formula IV with a 1-3 equivalent sulfonyl halide to give a compound expressed by formula V (L is eliminable group such as sulfonates and then reacting the compound expressed by formula V with a compound expressed by formula VI [Xa is R8R9NCH2 (R8 and R9 are H, lower alkyl, etc.)] in a solvent in the presence of a base at ambient temperature for 2-7 day.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a furan derivative having an acetylcholinesterase inhibitory action. Compounds having an acetylcholinesterase inhibitory action are used in various diseases (eg, constipation,
Diarrhea, bloating, etc.) and diseases caused by disorders of the central nervous system (eg Alzheimer-type senile dementia,
For example, amnesia) is expected to be a useful therapeutic drug.

[0002]

Furan derivatives related to the compound of the present invention and having a thioether bond include, for example, compounds of the formula (A):

[0003]

[Chemical 6]

[Wherein X is (CH ₃ ) ₂ NCH ₂ or

[0005]

[Chemical 7]

Represents Y, and Y is

[0007]

[Chemical 8]

A compound having a histamine H ₂ antagonistic action [Annu. Rep. Med. Chem. 22 , 191 (1
987); ibid. 25 , 159 (1989)] Formula (B):

[0009]

[Chemical 9]

A furan derivative having a gastric motility-promoting action represented by the formula (wherein p represents 1 or 2) (JP-A-1-31
3424), formula (C):

[0011]

[Chemical 10]

Ranitidine having a histamine H ₂ antagonistic activity (Japanese Patent Laid-Open No. 56-103171) and a ranitidine derivative having an acetylcholinesterase inhibitory activity [197th ACS National Meeting, Division of Me
dicinal Chemistry, Abstract, 50 (1989)] and the like are known.

[0013]

[Problems to be Solved by the Invention] Acetylcholinester
Histamine H while retaining the enzyme activity₂Antagonism
The furan derivative from which the
Excellent cure without side effects for a wide range of diseases caused by
Expected to have medical effects. The present invention is a strong acetylco
Has a phosphorus esterase inhibitory effect and histamine H ₂
To provide a novel furan derivative having no antagonistic action
With the goal.

[0014]

The present invention provides a compound of formula (I)

[0015]

[Chemical 11]

{Wherein X is hydrogen or R₇CH₂-(Expression
Medium, R₇Is lower alkoxy or R₈R ₉N- (in the formula, R
₈And R₉Are the same or different and are hydrogen or lower
Represents Rukiru or R₈And R₉Adjoined together
Formula (II) with the nitrogen atom

[0017]

[Chemical 12]

[Wherein

[0019]

[Chemical 13]

Is a single bond or a double bond,

[0021]

[Chemical 14]

When is a single bond, W is --CH _2- , --O-,
-S - or -NR ₁₀ - represents (wherein, R ₁₀ represents hydrogen or lower alkyl),

[0023]

[Chemical 15]

When is a double bond, W represents = CH-,
G₁And G₂Are the same or different and are hydrogen, lower
Represents kill, hydroxyl or lower alkoxy, m is
A group forming a heterocycle represented by
Means], and R ₁Is hydrogen, lower alk
Group, unsubstituted or substituted phenyl, unsubstituted or substituted
Aralkyl, lower alkynyl, lower alkenyl or phenyl
Represents Coryl, R₂~ R₆Are the same or different and
Or lower alkyl, and n represents 0 or 1. }so
Furan derivative represented or its pharmacologically acceptable
Regarding salt.

In some compounds (I), optically active isomers may exist, but all possible stereoisomers and their mixtures, including these optical isomers, are also included in the present invention. Here, in the definition of each group of the formula (I), as the alkyl moiety of lower alkyl and lower alkoxy, a linear or branched alkyl group having 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl, sec- Butyl, tert
-Butyl, pentyl, isopentyl and the like.

Examples of aralkyl include benzyl, phenethyl, benzhydryl and the like having 7 to 13 carbon atoms. Examples of the lower alkynyl include alkynyl having 2 to 5 carbon atoms, such as ethynyl and propynyl, and examples of the lower alkenyl include linear or branched C 2 to C 6
Alkenyl, such as vinyl, allyl, crotyl, prenyl and the like.

Substituents in the substituted phenyl and the substituted aralkyl include, for example, the same or different, lower alkyl having 1 to 3 substituents, lower alkoxy, halogen, nitro and the like. Here, the alkyl moiety in lower alkyl and lower alkoxy has the same definition as the above alkyl, and examples of halogen include fluorine, chlorine, bromine, iodine and the like.

The pharmacologically acceptable salt of compound (I) is a pharmacologically acceptable acid addition salt, for example, inorganic salts such as hydrochloride, sulfate and phosphate, and maleate. Examples thereof include organic acid salts such as fumarate and citrate. The compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.

Next, a method for producing the compound of the present invention will be described.

[0030]

[Chemical 16]

[In the formula, L represents a leaving group, and Xa represents formula (I)
R in the definition of X in₈R₉NCH₂(R ₈And R₉Is before
(Synonymous with) and R₂~ R₆And n are
Are synonymous. ] Here, the leaving group represented by L is tosile
And sulfonates such as mesylate or chlorine, odor
It means halogen such as elemental and iodine. First, the compound
(V) does not dissolve compound (III) and an equivalent amount of compound (IV)
In a medium, or tetrahydrofuran, dimethylform
Room temperature to solvent in an inert solvent such as amide or methylene chloride
It is obtained by reacting at the boiling point of. Reaction without solvent
When carrying out, it is desirable to carry out under reduced pressure.

Conversion of compound (V) to compound (VIa) is carried out according to a conventional method. For example, compound (VIa)
When L is a sulfonate, the compound (V) and 1 to 3
It can be obtained by reacting an equivalent amount of a corresponding sulfonyl halide in a basic solvent such as pyridine at 0 ° C. to room temperature for 1 to 6 hours. When L is halogen, the compound (V) is reacted with a halogenating agent such as thionyl chloride, phosphorus pentachloride or phosphorus tribromide to give the above sulfonate compound and lithium chloride or lithium bromide. It can be obtained by reacting with lithium iodide or the like.

The compound (Ia) is obtained by mixing the compound (VIa) and 1 to 2 equivalents of the compound (VIIa) in a polar solvent such as water, tetrahydrofuran or dimethylformamide in the presence of a base such as potassium carbonate at room temperature for 2 to 7 Obtained by reacting for a day.

[0034]

[Chemical 17]

[In the formula, X has the same meaning as described above. 〕Compound
Compound (VIIb) is obtained by heating (VIII) in the presence of a suitable reducing agent, preferably sodium borohydride, in an alcohol such as ethanol at room temperature to the boiling point of the solvent for 1 to 3 hours. Then, without isolating the compound (VIIb), the compound (VIa) is reacted at 50 ° C. to the boiling point of the solvent to obtain the compound (I).

In the compound (VIII), X is R ₈ R
Compound (VIIIa), which is ₉ NCH ₂ , can be prepared by the following steps (Mannich
Reaction).

[0037]

[Chemical 18]

(Wherein R ₈ and R ₉ have the same meanings as described above) Compound (VIIIa) comprises compound (VIIIb) and 3 to 10 equivalents of compound (IX) in an acidic solvent such as acetic acid. Room temperature to 100 ° C in the presence of 10 equivalents of paraformaldehyde
It can be obtained by reacting with.

[0039]

[Chemical 19]

[0040]

[Chemical 20]

[In the formula, R ₁₁ and R ₁₂ are different from each other and represent a protective group for a hydroxyl group, Hal represents chlorine, bromine or iodine, and R _{2 to} R ₆ , L and n have the same meanings as described above. ]
Here, the hydroxyl protecting group is a t-butyldimethylsilyl group,
It means a tetrahydropyranyl group, a benzyl group, a 4-methoxybenzyl group and the like. First, compound (III) and an equivalent amount of compound (X) are reacted at room temperature in an aprotic polar solvent such as tetrahydrofuran or dimethylformamide, or in the absence of solvent to obtain compound (XI).

Then, an equivalent amount of compound (XII) to compound (XI)
Compound (XIII) is obtained by reacting and at 50 to 100 ° C. in the absence of a solvent. It is desirable to carry out the reaction under reduced pressure. The conversion of compound (XIII) to compound (XV) can be carried out by a conventional method. For example, when R ₁₂ is a t-butyldimethylsilyl group, the compound (XIII) is added to 1 to 3 equivalents of t-butyldimethylchlorosilane in an inert solvent such as tetrahydrofuran or dimethylformamide,
In the presence of a suitable base such as imidazole, at 0 ° C.
To give a compound (XV) by reacting at room temperature for 0.5 to 3 hours.

Conversion of compound (XV) to compound (XVI) can be achieved by various methods depending on the kind of R ₁₁ and R ₁₂ . For example, in the compound (XV), when R ₁₁ is a 4-methoxybenzyl group and R ₁₂ is a t-butyldimethylsilyl group, 2-3 equivalents of 2,2 are added in methylene chloride in the presence of water.
Compound (XVI) can be obtained by reacting with 3-dichloro-5,6-dicyano-p-benzoquinone.

The conversion of compound (XVI) to compound (XVII) can be carried out according to the above-mentioned method for obtaining compound (VIa) from compound (V). Then, the compound (XVII) is treated in tetrahydrofuran, dimethylformamide or the like for 1 to 3 equivalents in the presence of a strong base such as potassium t-butoxy, sodium hydride or diazabicycloundecene at 0 ° C to room temperature for 0.5 to 1 hour. To give compound (XVIII)
To get

Conversion of compound (XVIII) to compound (V) is carried out according to a conventional method. For example, R ₁₂ is t-
In the case of a butyldimethylsilyl group, the compound (XVIII) is heated from 0 ° C in a lower alcohol such as methanol or ethanol in the presence of a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as p-toluenesulfonic acid. It can be obtained by treating at room temperature for 3 to 18 hours.

The conversion of compound (V) to compound (I) can be carried out in the same manner as the above-mentioned method.

[0047]

[Chemical 21]

[In the formula, R _1a represents a group other than hydrogen in the definition of R ₁ , and Hal, L, R _{2 to} R ₆ and n have the same meanings as described above. ] Compound (VIa) and 1 to 5 equivalents of compound (XIV)
Compound (VIb) is obtained by reacting and with dimethylformamide, tetrahydrofuran or a mixed solvent thereof in the presence of a suitable base such as sodium hydride. Then, the compound (VIb) is reacted with the compound (VIIa) or (VIIb) according to the method described in Method 1 or Method 2 to obtain the compound (I).

The intermediates and the target compounds in the above-mentioned production methods are purified by conventional purification methods in synthetic organic chemistry, for example,
It can be isolated and purified by subjecting it to filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. In addition, the intermediate can be subjected to the next reaction without further purification. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is. When it is obtained in a free form, a salt is formed by an ordinary method. You can do it.

Specific examples of the compound (I) are shown in Table 1. The compounds 1, 2, ..., 15 are the compounds of Examples 1, 2, ...
, Corresponding to the compound obtained in 15.

[0051]

[Table 1]

[0052]

[Table 2]

Next, the pharmacological action of compound (I) will be explained. Test Example 1. Acute toxicity test A test compound was orally administered (po: 300 mg / kg) using 3 male dd strain mice each having a body weight of 20 ± 1 g per group. The mortality situation 7 days after administration was observed, and the minimum mortality (MLD) value was calculated. The results are shown in Table 2. Test Example 2. Acetylcholinesterase Inhibition Test Using rat brain homogenate as a source of acetylcholinesterase, the method of Ellman et al. [Biochem. Pha
The esterase activity was measured according to rmacol., 7 , 88 (1961)]. Acetylthiocholine, a test substance and 5,5-dithiobis (2-nitrobenzoic acid) (DTNB) were added to a rat brain homogenate as a substrate, and after incubation, the produced thiocholine reacted with DTNB to produce a yellow product at 412 nm. The acetylcholinesterase activity was determined by measuring the change in the absorbance at. The acetylcholinesterase inhibitory activity of the sample was expressed as a 50% inhibitory concentration (IC ₅₀ ). The results are shown in Table 2.

[0054]

[Table 3]

As is clear from Table 2, compound (I) or a pharmaceutically acceptable salt thereof obtained by the present invention has low toxicity and an excellent acetylcholinesterase inhibitory action. Further, the compound is histamine H ₂
It does not show an antagonistic effect and is excellent in separation from undesirable effects such as suppression of gastric acid secretion. Although compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, it is usually preferably provided as various pharmaceutical preparations. Further, those pharmaceutical preparations are used for animals and humans.

The administration route is preferably the one which is most effective for the treatment, and it may be oral or parenteral (eg, rectal, buccal, subcutaneous, intramuscular, intravenous, etc.). Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections and the like.

Liquid preparations suitable for oral administration, such as emulsions and syrups, include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil. And oils such as, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint, and the like. In addition, capsules, tablets, powders, granules, etc., include excipients such as lactose, glucose, sucrose, and mannitol, starch, disintegrating agents such as sodium alginate, magnesium stearate,
It can be produced by using a lubricant such as talc, a binder such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin.

Formulations suitable for parenteral administration preferably comprise sterile aqueous preparations containing the active compound isotonic with the blood of the recipient. For example, as an injection, a solution for injection is prepared by using a carrier such as a salt solution, a glucose solution or a mixture of salt water and a glucose solution. Topical formulations are prepared by dissolving or suspending the active compound in one or more media, such as mineral oil, petroleum, polyhydric alcohols or other bases used in topical pharmaceutical formulations.

Formulations for enteral administration may be presented as suppositories with conventional carriers such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids and the like. Also in these parenteral agents, diluents, fragrances, preservatives (including antioxidants), excipients, disintegrating agents, lubricants, binders, surfactants, plasticizers, etc. exemplified for oral agents It is also possible to add one or more auxiliary components selected from

The effective dose of Compound (I) or a pharmacologically acceptable salt thereof and the number of administrations will vary depending on the administration form, age of the patient, body weight, nature or severity of symptoms to be treated, etc. The usual dosage is 0.01 to 1000 per day
The dose is mg / person, and the administration frequency is preferably once a day or dividedly. Examples and reference examples are shown below.

[0061]

【Example】

Example 1. {1- [2-[(5-dimethylaminomethyl-2-furanyl) methylthio] ethyl] -2
-Imidazolidinylidene} propanedinitrile (Compound 1) N- (2-aminoethyl) ethanolamine 3.12 g (3
A mixture of 0 mmol) and [bis (methylthio) methylene] propanedinitrile (5.1 g, 30 mmol) was reacted at room temperature for 2 hours while sucking with an aspirator.
After adding 50 ml of ethanol to the reaction mixture and stirring for 30 minutes, the insoluble matter was collected by filtration to give [1- (2-
4.81 g (yield 91.8%) of hydroxyethyl) imidazolidinylidene] propanedinitrile (compound a) was obtained.

Melting point: 137-139 ° C. NMR (DMSO-d ₆ ) δ (ppm): 7.79 (1H, bs), 4.87 (1H, b
s), 3.1 ~ 3.9 (8H, m)

3.0 g (16.85 mmol) of compound a was dissolved in 20 ml of pyridine. 1.43 ml (18.54 mmol) of methanesulfonyl chloride was added dropwise to this under ice cooling, and then 1.
Stir for 5 hours. 5 ml of methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. Methylene chloride was added to the residue, the mixture was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and then with saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to give {1-[(2-mesyloxy) ethyl] imidazolidinylidene} propanedinitrile (compound b) (3.62 g, yield 84.0) as colorless crystals. %) Was obtained.

Melting point: 122-122.5 ° C. NMR (DMSO-d ₆ ) δ (ppm): 8.01 (1H, bs), 4.43 (2H, t,
J = 5.71Hz), 3.98 (2H, t, J = 5.71Hz), 3.67 (4H, m), 3.21
(3H, s)

2.32 g of the compound f obtained in Reference Example 1 (6.
82 mmol) was dissolved in 30 ml of ethanol. to this,
A solution of 570 mg (15.01 mmol) of sodium borohydride in 10 ml of ethanol was added dropwise, and the mixture was heated at 80 ° C for 1 hour. Then, to this was added 3.5 g of compound b (13.65 mmol).
Was added and the mixture was further heated at 80 ° C. for 4.5 hours. After adding 5 ml of acetone to the reaction mixture, the mixture was concentrated under reduced pressure, methylene chloride was added to the residue, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (acetone). The obtained crude crystals were washed with ethyl acetate: 2-propyl ether to give Compound 1 as white crystals.
1.32 g (yield 29.2%) was obtained. Compound 1 1.0 g (3.
(02 mmol) was dissolved by heating in 10 ml of ethanol, 351 mg (3.03 mmol) of fumaric acid was added, and the mixture was allowed to cool. Precipitated white crystals were collected by filtration and 1.21 g of 1-fumarate of Compound 1
(89.6%) was obtained.

Melting point of 1-fumarate: 105-108 ° C. Elemental analysis: 1 fumarate as C ₁₆ H ₂₁ N ₅ OS.C ₄ H
₄ O ₄ Calculated value (%); C 53.68, H 5.63, N 15.65 Measured value (%); C 53.71, H 5.78, N 15.66 MS (m / z): 331 (M ⁺ ) NMR (CDCl ₃ ) δ ( ppm): 6.15, 6.07 (each 1H, each d,
J = 3.11Hz), 6.11 (1H, bs), 3.75 (2H, s), 3.68 (6H, m),
3.41 (2H, s), 2.80 (2H, t, J = 6.1Hz), 2.23 (6H, s) IR (KBr; cm ^-1 ): 3075, 2200, 2175

Example 2. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -2-imidazolidinylidene} propanedinitrile (Compound 2) 6.17 g (24.1 mmol) of compound b and A mixture of 6.33 g (60.24 mmol) of lithium bromide monohydrate was heated in 60 ml of dimethylformamide at 80 ° C for 4 hours. After distilling off the solvent under reduced pressure, water was added to the residue and the precipitated crystals were collected by filtration to give 5.75 g of [1- (2-bromoethyl) imidazolidinylidene] propanedinitrile (compound c) as white crystals (yield 99.0% ) Got.

Melting point: 87-87.5 ° C. NMR (DMSO-d ₆ ) δ (ppm): 8.01 (1H, bs), 3.3-4.0 (8H,
m)

2.8 g (11.62 mmol) of compound c and 3.5 g (11.63 mmol) of compound g obtained in Reference Example 2 were dissolved in a mixed solvent of 60 ml of tetrahydrofuran and 40 ml of water, and nitrogen was sprinkled into the mixture. Anhydrous potassium carbonate 6.42 g (46.51 mmol) was added. The reaction mixture was stirred under a nitrogen stream at room temperature for 6 days. The solvent was distilled off under reduced pressure, and the residue was partitioned between methylene chloride and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1 v / v). The obtained crude crystals were recrystallized from ethyl acetate: 2-propyl ether to give 2.46 g of compound 2 as white crystals (yield: 57.1
%) Was obtained.

Melting point: 117-119 ° C. Elemental analysis: C ₁₉ H ₂₅ N ₅ OS Calculated value (%); C 61.43, H 6.78, N 18.85 Measured value (%); C 61.58, H 6.99, N 18.90 MS (m / z): 371 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.15, 6.06 (each 1H, each d,
J = 3.14Hz), 5.90 (1H, bs), 3.76 (2H, s), 3.71 (6H, m),
3.46 (2H, s), 2.81 (2H, t, J = 6.2Hz), 2.40 (4H, m),
1.51 (6H, m) IR (KBr; cm ^-1 ): 3120, 2200, 2175

Example 3 {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-benzyl-2-imidazolidinylidene} propanedinitrile (Compound 3) Compound a 8.79 g ( 49.38 mmol) pyridine 100
After dissolving in ml, 14.1 g (74.02 mmol) of p-toluenesulfonyl chloride was added under ice cooling. 4 at room temperature
After stirring for an hour, the solvent was distilled off under reduced pressure, and water was added to the residue.
The precipitated crystals were collected by filtration and washed with ethanol to give {1-[(2-tosyloxy) ethyl] imidazolidinylidene} propanedinitrile (compound d) 15.52 g (yield 94.7%) as white crystals. It was

Melting point: 174 ° -176 ° C. NMR (DMSO-d ₆ ) δ (ppm): 7.93 (1H, bs), 7.88, 7.45
(Each 2H, each d, J = 9.2Hz), 4.23 (2H, t), 3.2 to 3.9 (6
H, m), 2.44 (3H, s)

Compound d 8.0 g (24.1 mmol) was dissolved in 100 ml of dimethylformamide, and the mixture was cooled with ice to 60
% Sodium hydride 1.16 g (29 mmol) was added.
After stirring under ice cooling for 0.5 hours, α-bromotoluene 3.5 ml
(29.43 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr.
After adding water to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was partitioned between methylene chloride and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:
n-hexane = 3: 1 v / v) to give {1-[(2-tosyloxy) ethyl] -3 as white crystals.
7.24 g (yield 71.2%) of -benzyl-2-imidazolidinylidene} propanedinitrile (compound e) was obtained.

Melting point: 132-133 ° C. NMR (CDCl ₃ ) δ (ppm): 7.72 (2H, d, J = 9.2 Hz), 7.29
(7H, m), 4.73 (2H, s), 4.29, 3.84 (each 2H, each t, J =
6.60, 6.92Hz), 3.56 (4H, m), 2.45 (3H, s)

Compound e 6.3 g (14.93 mmol) and compound g 5.0 g (16.61 mmol) were reacted in the same manner as in Example 2 to obtain 1.43 g of Compound 3 as a pale yellow oily substance (yield 20.5%). Got

Melting point of 1 oxalate: 150.5 to 151.5 ° C. Elemental analysis: C ₂₆ H ₃₁ N ₅ OS. (CO ₂ H) ₂ calculated value (%); C 60.96, H 6.03, N 12.70 Measured value (%) C 60.70, H 6.17, N 12.56 MS (m / z): 461 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.37 (5H, m), 6.18, 6.11
(Each 1H, each d, J = 3.07Hz), 4.76 (2H, s), 3.78 (2H,
s), 3.62 (6H, m), 3.46 (2H, s), 2.85 (2H, t, J = 6.60,
6.92Hz), 2.40 (4H, m), 1.49 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 4. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-
(4-Fluorobenzyl) -2-imidazolidinylidene} propanedinitrile (Compound 4) Compound d 7.0 g (21.08 mmol) obtained in the same manner as in Example 3 and 4-fluoro-α-bromotoluene 3.1 ml (2)
4.88 mmol) was reacted in the same manner as in Example 3 to give {1
There was obtained 3.48 g (yield 37.5%) of-[(2-tosyloxy) ethyl] -3- (4-fluorobenzyl) -2-imidazolidinylidene} propanedinitrile. Then, 6.5 g (14.77 mmol) of this compound and 5.0 g (1
4.61 mmol) was reacted in the same manner as in Example 2 to give 44.31 g of compound as a pale yellow oil (yield: 60.9
%) Was obtained.

Melting point of 1 oxalate salt: 137 to 138 ° C. Elemental analysis: C ₂₆ H ₃₀ FN ₅ OS. (CO ₂ H) ₂ calculated value (%); C 59.04, H 5.66, N 12.29 measured value (%) C 59.05, H 5.79, N 12.36 MS (m / z): 479 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.11 (4H, m), 6.16, 6.03 (each 1H, each d, J = 3.05Hz), 4.74 (2H, s), 3.78 (2H, s),
3.61 (6H, m), 3.46 (2H, s), 2.86 (2H, t, J = 6.58, 6.88
Hz), 2.38 (4H, m), 1.47 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 5. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-
[4- (2-Methyl-2-butenyl)]-2-imidazolidinylidene} propanedinitrile (Compound 5) Compound d 8.0 g (24.1 mmol) obtained in the same manner as in Example 3 and 1-bromo-3 -Methyl-2-butene 3.4 ml (2
9.5 mmol) and reacted in the same manner as in Example 3 {1-
8.37 g (yield 86.8%) of [(2-tosyloxy) ethyl] -3- [4- (2-methyl-2-butenyl)]-2-imidazolidinylidene} propanedinitrile was obtained. Next, 5.32 g (13.3 mmol) of this compound and compound g
1.35 g of compound 5 was obtained as a pale yellow oil by reacting with 4.0 g (13.29 mmol) in the same manner as in Example 2.
(Yield 23.2%) was obtained.

Melting point of 1 oxalate: 134.5-136 ° C. Elemental analysis: C ₂₄ H ₃₃ N ₅ OS. (CO ₂ H) ₂ calculated value (%); C 58.96, H 6.66, N 13.22 Measured value (%) C 58.74, H 6.75, N 13.11 MS (m / z): 439 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.18, 6.10 (each 1H, each d,
J = 3.07Hz), 5.16 (1H, m), 4.12 (2H, bd, J = 6.13Hz), 3.
77 (2H, s), 3.56 (6H, m), 3.47 (2H, s), 2.82 (2H, t, J
= 6.81, 6.72Hz), 2.39 (4H, m), 1.74 (6H, bd, J = 5.91H
z), 1.48 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 6. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-methyl-2-imidazolidinylidene} propanedinitrile (Compound 6) Same as Example 3. The compound d 8.0 g (24.1 mmol) thus obtained was reacted with 1.8 g (27.54 mmol) of methyl iodide in the same manner as in Example 3 to obtain {1-[(2-tosyloxy) ethyl] -3-methyl-2-. 4.68 g (yield 56.1%) of imidazolidinylidene} propanedinitrile was obtained. Next, 4.5 g (13.01 mmol) of this compound and compound g
1.54 g of compound 6 was obtained as a pale yellow oil by reacting with 4.35 g (14.45 mmol) in the same manner as in Example 2.
(Yield 30.7%) was obtained.

Melting point of 1 oxalate salt: 133-134 ° C. Elemental analysis: C ₂₀ H ₂₇ N ₅ OS. (CO ₂ H) ₂ calculated value (%); C 55.56, H 6.15, N 14.73 Measured value (%) C 55.65, H 6.40, N 14.78 MS (m / z): 385 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.18, 6.07 (each 1H, each d,
J = 3.25Hz), 3.77 (2H, s), 3.64 (6H, m), 3.47 (2H, s),
3.18 (3H, s), 2.82 (2H, t, J = 6.70, 6.89Hz), 2.41 (4H,
m), 1.52 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 7. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-ethyl-2-imidazolidinylidene} propanedinitrile (Compound 7) As in Example 3. 7.46 g (22.4 g) of the compound d obtained in
7 mmol) and ethyl iodide 2.2 ml (27.08 mmol)
Was reacted in the same manner as in Example 3 to obtain {1-[(2-tosyloxy) ethyl] -3-ethyl-2-imidazolidinylidene} propanedinitrile (6.0 g, yield 74.2%). Next, 5.2 g (14.44 mmol) of this compound and 4.35 g (14.45 mmol) of compound g were reacted in the same manner as in Example 2 to give compound 7 as a pale yellow oil.
1.84 g (yield 31.9%) was obtained.

Melting point of 1 oxalate: 139.5 to 140 ° C. Elemental analysis: C ₂₁ H ₂₉ N ₅ OS. (CO ₂ H) ₂ calculated value (%); C 56.42, H 6.38, N 14.30 measured value (%) C 56.43, H 6.59, N 13.92 MS (m / z): 399 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.19, 6.09 (each 1H, each d,
J = 3.15Hz), 3.77 (2H, s), 3.64 (6H, m), 3.59 (2H, q),
3.47 (2H, s), 2.82 (2H, t, J = 6.62, 6.91Hz), 2.43 (4H,
m), 1.52 (6H, m), 1.26 (3H, t) IR (KBr; cm ^-1 ): 2200, 2160

Example 8. (±)-{1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl]
-4-Methyl-2-imidazolidinylidene} propanedinitrile (Compound 8) [bis (methylthio) methylene] propanedinitrile 3
16 mg (1.86 mmol) and (±)-[1-methyl-2-
(4-Methoxybenzyloxy)] ethylamine 336 mg
(1.86 mmol) and dissolved in 10 ml of chloroform,
Stir at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n
-Hexane = 1: 2 v / v) to give (±)-{(methylthio) [1-methyl- [2-
(4-Methoxybenzyloxy)] ethylamino] methylene} propanedinitrile (Compound i) 488 mg (yield 8
6.7%).

NMR (CDCl ₃ ) δ (ppm): 7.25, 6.89 (each 2H, each d, J = 8.68Hz), 6.35 (1H, bs), 4.48 (2H, s),
3.81 (3H, s), 3.63 (4H, m), 2.56 (3H, s)

461 mg (1.52 mmol) of compound i and 114 mg (1.52 mmol) of ethanolamine were heated at 80 ° C. for 1.5 hours while sucking with a water aspirator. The reaction mixture was purified by silica gel column chromatography (chloroform: methanol = 30: 1 v / v) to give (±)-{[1-methyl- [2-
(4-Methoxybenzyloxy)] ethylamino] [(2
321 mg (yield 63.9%) of -hydroxy) ethylamino] methylene} propanedinitrile (Compound j) was obtained.

NMR (CDCl ₃ ) δ (ppm): 7.23, 6.84 (each 2H, each d, J = 8.81Hz), 6.58 (1H, bs), 6.42 (1H, b
s), 4.45 (2H, s), 3.78 (3H, s), 3.51 (7H, m), 1.14 (3
(H, d, J = 6.41Hz)

314 mg (0.95 mmol) of compound j was dissolved in 3 ml of methylene chloride, and triethylamine 16 was added thereto.
0 mg (1.58 mmol) and 215 mg (1.43 mmol) t-butyldimethylchlorosilane were added and a catalytic amount of 4-
The mixture was stirred at room temperature for 16 hours in the presence of dimethylaminopyridine. The reaction solution was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: n
-Hexane = 1: 3 v / v) and colorless oily (±)-
243 mg (yield 57.6%) of {[1-methyl- [2- (4-methoxybenzyloxy)] ethylamino] [(2-t-butyldimethylsiloxy) ethylamino] methylene} propanedinitrile (compound k) Obtained.

NMR (CDCl ₃ ) δ (ppm): 7.17, 6.83 (each 2H, each d, J = 8.63Hz), 6.31 (2H, m), 4.44 (2H, s),
3.88 (1H, m), 3.76 (3H, s), 3.49 (4H, m), 3.24 (2H,
m), 1.09 (3H, d, J = 5.92Hz), 0.87 (9H, s), 0.06 (6H,
s)

Compound k (240 mg, 0.54 mmol) was dissolved in a mixed solvent of methylene chloride (2 ml) and water (0.1 ml), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (150 mg, 0.66) was added thereto under ice cooling. Mmol) was added. The reaction solution was stirred at room temperature for 17 hours, the insoluble material was filtered off, and the filtrate was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1 v / v) to give colorless crystals of (±)-{[1-methyl- 141 mg (yield 80.6%) of (2-hydroxy) ethylamino] [(2-t-butyldimethylsiloxy) ethylamino] methylene} propanedinitrile (Compound 1) was obtained.

Melting point: 135.5-136 ° C NMR (CDCl ₃ ) δ (ppm): 6.52 (1H, bt, J = 5.7Hz), 6.34
(1H, bt, J = 5.1Hz), 3.91 (1H, m), 3.62 (2H, m), 3.30
(4H, m), 3.12 (1H, bs), 1.07 (3H, d, J = 6.39Hz), 0.79
(9H, s), 0.12 (6H, s)

After 9.0 g (27.69 mmol) of compound 1 was dissolved in 120 ml of pyridine, 4.3 ml (55.58 mmol) of methanesulfonyl chloride was added dropwise under ice cooling. After stirring the reaction mixture for 1 hour, the solvent was evaporated under reduced pressure. Methylene chloride was added to the residue, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The residue was dissolved in 100 ml of tetrahydrofuran, and a solution of 6.31 g (41.51 mmol) of diazabicycloundecene in 20 ml of tetrahydrofuran was added dropwise under ice cooling. After stirring the reaction solution for 1 hour, the solvent was evaporated under reduced pressure, the residue was dissolved in methylene chloride, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was dissolved in 100 ml of methanol, 526 mg (2.77 mmol) of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was stirred at room temperature for 6.5 hours. After neutralizing the reaction mixture, the mixture was concentrated under reduced pressure, water was added to the residue, and the precipitated white crystals were collected by filtration to obtain (±)-[1- (2-hydroxyethyl) -4-methyl-2-imidazolidini. Ridene] propanedinitrile (compound m) (4.78 g, yield from compound l: 89.8%) was obtained.

Melting point: 76.0 to 77.0 ° C NMR (DMSO-d ₆ ) δ (ppm): 7.95 (1H, bs), 4.89 (1H, m),
3.87 (2H, m), 3.34 (4H, m), 3.29 (1H, bt), 1.17 (3H,
d, J = 5.82Hz)

Thereafter, the compound m was treated with (±)-{1- in the same manner as in the method from the compound a to the compound d in Example 3.
[(2-tosyloxy) ethyl] -4-methyl-2-imidazolidinylidene} propanedinitrile (compound n) is obtained, and then compound n is obtained from compound c in Example 2 and compound g Similarly, compound g
Compound 8 was obtained as a light brown oil by reacting with.

Melting point of 1 oxalate: 152.5 to 155 ° C. Elemental analysis: C ₂₀ H ₂₇ N ₅ OS. (CO ₂ H) ₂ calculated value (%); C 55.56, H 6.15, N 14.73 Measured value (%) C 55.62, H 6.36, N 14.46 MS (m / z): 385 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.17, 6.09 (each 1H, each d,
J = 3.14Hz), 5.98 (1H, bs), 3.95 (2H, m), 3.73 (2H, s),
3.67 (2H, m), 3.45 (2H, s), 3.38 (1H, m), 2.81 (2H,
t, J = 6.50, 6.85Hz), 2.41 (4H, m), 1.51 (6H, m), 1.33
(3H, d, J = 5.91Hz) IR (KBr; cm ^-1 ): 2200, 2160

Example 9. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl-3- (3,
4-dimethoxybenzyl) -2-imidazolidinylidene} propanedinitrile (Compound 9) To a solution of 3.2 g (19.05 mmol) of 3,4-dimethoxybenzyl alcohol in 30 ml of methylene chloride, under ice-cooling, 2.1 ml of thionyl chloride (28.78 mmol). ) Was added dropwise, and the mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Thus obtained
By reacting 3,4-dimethoxybenzyl chloride with 4.5 g (13.55 mmol) of compound d in place of α-bromotoluene in Example 3 without purification, {1-[(2-tosyloxy) ethyl]- 3- (3,4
-Dimethoxybenzyl) -2-imidazolidinylidene}
5.81 g (89%) of propanedinitrile was obtained. Next, 5.68 g (11.78 mmol) of this compound and Reference Example 3 were used.
By reacting 2.0 g (4.76 mmol) of the compound h obtained in 1. in the same manner as in the method of obtaining the compound 1 from the compound b and the compound f in Example 1, 4.54 g of the compound 9 as a pale yellow oily substance (yield 91.5%).

Melting point of 1 oxalate: 150.5 to 151.5 ° C. Elemental analysis: 1 oxalate C ₂₈ H ₃₅ N ₅ O ₃ S. (CO
₂ H) ₂ Calculated value (%); C 58.90, H 6.10, N 11.45 Measured value (%); C 58.61, H 6.25, N 11.23 MS (m / z): 521 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.85 (3H, m), 6.19, 6.09 (each 1H, each d, J = 3.30Hz), 4.68 (2H, s), 3.87 (6H, s),
3.78 (2H, s), 3.64 (6H, m), 3.45 (2H, s), 2.83 (2H, t,
J = 6.59, 6.91Hz), 2.39 (4H, m), 1.47 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 10. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-
Cinnamyl-2-imidazolidinylidene} propanedinitrile (Compound 10) Compound d 8.0 g (24.10 mmol) obtained in the same manner as in Example 3 and 5.7 g (28.93 mmol) of cinnamyl bromide were treated in the same manner as in Example 3. The reaction was conducted to obtain 8.82 g (81.7%) of {1-[(2-tosyloxy) ethyl] -3-cinnamyl-2-imidazolidinylidene} propanedinitrile. Then 5.48 g (12.23 mmol) of this compound
And 2.57 g (6.12 mmol) of the compound h obtained in Reference Example 3 were reacted in the same manner as in Example 1 to obtain 102.9 g of compound 10 (yield 48.7%) as a pale yellow oil.

Melting point of 1 oxalate: 143 to 147.5 ° C. Elemental analysis: 1 oxalate C ₂₈ H ₃₃ N ₅ OS. (CO ₂ H)
₂ Calculated value (%); C 62.37, H 6.11, N 12.12 Measured value (%); C 62.24, H 6.21, N 12.06 MS (m / z): 487 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm) : 7.29 (5H, m), 6.50 (1H, d, J
= 15.2Hz), 6.0-6.4 (3H, m), 4.28 (2H, d, J = 6.1H
z), 3.76 (2H, s), 3.66 (6H, m), 3.44 (2H, s), 2.85 (2
H, t, J ＝ 6.64, 6.75Hz), 2.43 (4H, m), 1.54 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 11. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-
(2-Propyl) -2-imidazolidinylidene} propanedinitrile (Compound 11) 7.0 g (21.08 mmol) of compound d obtained in the same manner as in Example 3 and 2.6 ml (27.69 mmol) of 2-propyl bromide were carried out. The reaction was conducted in the same manner as in Example 3, and 2.27 g (28.8 g of 1-[(2-tosyloxy) ethyl] -3- (2-propyl) -2-imidazolidinylidene} propanedinitrile
%) Was obtained. Then, 2.1 g (5.61 mmol) of this compound and 1.2 g (2.86 mmol) of the compound h obtained in Reference Example 3 were reacted in the same manner as in Example 1 to give 1.39 g of Compound 11 as a pale yellow oil (yield: Rate 59.7%).

Melting point of 1 oxalate: 142.5 to 143.5 ° C. Elemental analysis: 1 oxalate C ₂₂ H ₃₁ N ₅ OS. (CO ₂ H)
₂ Calculated value (%); C 57.24, H 6.60, N 13.91 Measured value (%); C 57.19, H 6.58, N 13.62 MS (m / z): 415 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm) : 6.18, 6.10 (each 1H, each d,
J = 3.07Hz), 4.60 (1H, m), 3.77 (2H, s), 3.59 (6H, m),
3.47 (2H, s), 2.82 (2H, t, J = 6.81, 6.71Hz), 2.36 (4H,
m), 1.48 (6H, m), 1.24 (6H, d, J = 6.59Hz) IR (KBr; cm ^-1 ): 2200, 2165

Example 12. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-
(2-Methyl-1-propyl) -2-imidazolidinylidene} propanedinitrile (Compound 12) Compound d 7.0 g (21.08 mmol) obtained in the same manner as in Example 3 and 1-bromo-2-methylpropane 3.0 ml (2
7.59 mmol) was reacted in the same manner as in Example 3 to give {1
-[(2-Tosyloxy) ethyl] -3- (2-methyl-
1.28 g (15.6%) of 1-propyl) -2-imidazolidinylidene} propanedinitrile was obtained. Then, 1.1 g (2.84 mmol) of this compound and 0.6 g (1.43 mmol) of the compound h obtained in Reference Example 3 were reacted in the same manner as in Example 1 to give compound 12 1.07 as a pale yellow oil.
g (yield 87.7%) was obtained.

Melting point of 1 oxalate: 124-125 ° C. Elemental analysis: 1 oxalate C ₂₃ H ₃₃ N ₅ OS. (CO ₂ H)
₂ Calculated value (%); C 58.01, H 6.82, N 13.53 Measured value (%); C 57.73, H 6.84, N 13.35 MS (m / z): 388 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm) : 6.18, 6.10 (each 1H, each d,
J = 3.18Hz), 3.77 (2H, s), 3.63 (6H, m), 3.47 (2H, s),
3.35 (2H, d, J = 7.47Hz), 2.83 (2H, t, J = 6.59, 7.04H
z), 2.44 (4H, m), 2.05 (1H, m), 1.51 (6H, m), 0.97 (6
H, d, J = 6.59Hz) IR (KBr; cm ^-1 ): 2200, 2160

Example 13. {1- [2-[(5-piperidinomethyl-2-furanyl) methylthio] ethyl] -3-
Cyclohexylmethyl-2-imidazolidinylidene} propanedinitrile (Compound 13) 8.0 g (24.10 mmol) of compound d obtained in the same manner as in Example 3 and 3.8 ml (30.93) of cyclohexylmethyl bromide.
(1 mmol) in the same manner as in Example 3 to give {1-
[(2-Tosyloxy) ethyl] -3-cyclohexylmethyl-2-imidazolidinylidene} propanedinitrile
4.07 g (45.9%) was obtained. Then 3.1 g of this compound
(8.49 mmol) and the compound h 1.78 obtained in Reference Example 3.
2.4 g of the compound 13 as a pale yellow oil (yield) was obtained by reacting g (4.24 mmol) with that of Example 1.
61.5%).

Melting point of 1 oxalate: 125.5 to 128 ° C. Elemental analysis: 1 oxalate C ₂₆ H ₃₇ N ₅ OS. (CO ₂ H)
₂ Calculated value (%); C 60.30, H 7.05, N 12.56 Actual value (%); C 60.40, H 7.01, N 12.49 MS (m / z): 467 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm) : 6.19, 6.10 (each 1H, each d,
J = 2.86Hz), 3.77 (2H, s), 3.63 (6H, m), 3.47 (2H, s),
3.35 (2H, d, J = 7.26Hz), 2.83 (2H, t, J = 6.65, 6.89H
z), 2.42 (4H, m), 1.0 −2.0 (17H, m) IR (KBr; cm ⁻¹ ): 2200, 2160

Example 14. (-)-{1- [2-[(5-
Piperidinomethyl-2-furanyl) methylthio] ethyl] -4-methyl-2-imidazolidinylidene} propanedinitrile (Compound 14) In Example 8, (±)-[1-methyl-2- (4-
Methoxybenzyloxy)] ethylamine instead of S
Compound 14 was obtained as a pale yellow oily substance in the same manner as in Example 8 except that-(+)-[1-methyl-2- (4-methoxybenzyloxy)] ethylamine was used.

Melting point of 1 oxalate: 137.5 to 139 ° C. Elemental analysis: 1 oxalate C ₂₀ H ₂₇ N ₅ OS. (CO ₂ H)
₂ Calculated value (%); C 55.56, H 6.15, N 14.73 Measured value (%); C 55.44, H 6.02, N 14.67 MS (m / z): 385 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm) : 6.18, 6.10 (each 1H, each d,
J = 3.18Hz), 5.99 (1H, bs), 3.93 (2H, m), 3.77 (2H, s),
3.70 (2H, m), 3.47 (2H, s), 3.31 (1H, m), 2.81 (2H,
t, J = 6.48, 6.81Hz), 2.41 (4H, m), 1.58 (6H, m), 1.
29 (3H, d, J = 5.82Hz) IR (KBr; cm ^-1 ): 2200, 2215 Optical rotation: [α] _D = −4.23 (c = 1.0 / DMF / 20 ℃)

Example 15. (+)-{1- [2-[(5-
Piperidinomethyl-2-furanyl) methylthio] ethyl] -4-methyl-2-imidazolidinylidene} propanedinitrile (Compound 15) In Example 8, (±)-[1-methyl-2- (4-
Methoxybenzyloxy)] ethylamine instead of R
Compound 15 was obtained as a pale yellow oily substance in the same manner as in Example 8 except that-(-)-[1-methyl-2- (4-methoxybenzyloxy)] ethylamine was used.

Melting point of 1 oxalate: 138.5 to 139.5 ° C. Elemental analysis: 1 oxalate C ₂₀ H ₂₇ N ₅ OS. (CO ₂ H)
₂ Calculated value (%); C 55.56, H 6.15, N 14.73 Measured value (%); C 55.56, H 6.22, N 14.69 MS (m / z): 385 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm) : 6.17, 6.10 (each 1H, each d.
J = 3.16Hz), 5.97 (1H, bs), 3.93 (2H, m), 3.75 (2H, s),
3.71 (2H, m), 3.47 (2H, s), 3.32 (1H, m), 2.83 (2H,
t, J = 6.44, 6.83Hz), 2.40 (4H, m), 1.55 (6H, m), 1.
25 (3H, d, J = 5.77Hz) IR (KBr; cm ^-1 ): 2200, 2160 Optical rotation: [α] _D = + 5.87 (c = 1.0 / DMF / 20 ℃)

Reference Example 1. [5,5'-bis (dimethylaminomethyl)] furfuryl disulfide (Compound f) Furfuryl disulfide 5.0 g (22.09 mmol), dimethylamine hydrochloride 5.76 g (70.7 mmol) and paraformaldehyde 2.95 g (88.37 mmol) of acetic acid 5
After suspending in 0 ml, the mixture was heated at 80 ° C. for 1 hour. The reaction mixture was ice-cooled and adjusted to pH with 10N aqueous sodium hydroxide solution.
After setting to 12.5, it was extracted twice with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (chloroform: methanol = 10: 1 v / v)
The compound f 5.12 g (yield 68.2%) was obtained as a light brown oily substance.

NMR (CDCl ₃ ) δ (ppm): 6.15, 6.07 (each 2H, each d, J = 3.11Hz), 3.70 (4 H, s), 3.42 (4H, s),
2.22 (12H, s)

Reference Example 2.5- (piperidinomethyl) -2-
Furan methanethiol oxalic hydrochloric acid (compound g)
Compound g was obtained in the same manner as described in JP-A-103171.

NMR (DMSO-d ₆ ) δ (ppm): 6.68 (2H, bs),
6.48, 6.25 (each 1H, each d, J = 3.24Hz), 4.12 (2H, s),
3.76 (2H, s), 2.95 (4H, m), 1.69 (6H, m)

Reference Example 3. [5,5′-bis (piperidinomethyl)] furfuryl disulfide (Compound h) In the same manner as in Reference Example 1 except that piperidine hydrochloride was used in place of dimethylamine hydrochloride in Reference Example 1. Compound h was obtained. NMR (CDCl ₃ ) δ (ppm): 6.12, 6.04 (each 2H, each d,
J = 3.12Hz), 3.68 (4H, s), 3.44 (4H, s), 2.37 (8H, m),
1.51 (12H, m)

Reference Example 4. Tablets Tablets having the following composition are produced by a conventional method. Compound 2 100 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Small amount

Reference Example 5. Powder A powder having the following composition is produced by a conventional method. Compound 1 150mg Lactose 280mg

Reference Example 6. Syrup Agent A syrup agent having the following composition is produced by a conventional method. Compound 4 100 mg Purified sucrose 40 g Ethyl p-hydroxybenzoate 40 mg Propyl p-hydroxybenzoate 10 mg Strawberry flavor 0.1 cc Add water to make a total amount of 100 cc.

[0120]

The compound (I) has an excellent acetylcholinesterase inhibitory action.

Continuation of front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/54 7252-4C (72) Inventor Rika Yoshizaki 24-1 Mitsugaoka, Mishima City, Shizuoka Prefecture S-2 401 (72 ) Inventor Akio Ishii 1501-17 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture

Claims (1)

[Claims] 1. Formula (I) [Chemical 1] {In the formula, X is hydrogen or R₇CH₂-(In the formula, R₇Is low
Alkoxy or R₈R ₉N- (in the formula, R₈And R₉Is
The same or different, representing hydrogen or lower alkyl
Or R₈And R₉And adjacent nitrogen atoms together
With formula (II) [Chemical 2] [In the formula, [Chemical 3] Represents a single bond or a double bond, [Chemical 4] Is a single bond, W is -CH₂−, −O −, −S − or
-NR_Ten− (Where R_TenRepresents hydrogen or lower alkyl
), [Chemical 5] Is a double bond, W represents = CH-, G₁And G₂
Are the same or different and are hydrogen, lower alkyl, hydroxy
Represents sil or lower alkoxy, m is an integer of 1 to 3
Represents a group forming a heterocycle represented by]
], And R₁Is hydrogen, lower alkyl, unsubstituted or
Is substituted phenyl, unsubstituted or substituted aralkyl, lower
Represents alkynyl, lower alkenyl or picolyl, R
₂~ R₆Are the same or different and are hydrogen or lower alkyl
And n represents 0 or 1. } Franc invitation
Conductor or its pharmacologically acceptable salt.