JP3029876B2 - Furan derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

This invention relates to furan derivatives.
The furan derivative has an excellent gastrointestinal motility enhancing action and is useful as a gastrointestinal motility enhancer.

[0002]

BACKGROUND OF THE INVENTION Furan derivatives related to the compounds of the present invention include, for example, compounds of the formula (A)

[0003]

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Ranitidine having histamine H ₂ antagonistic activity (JP-A-56-103171) represented by the formula (B)

[0005]

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(Wherein T represents CH ₂ , O or S), a ranitidine derivative having an anti-ulcer action (JP-A-53-18557 and JP-A-55-153761), and a compound represented by the formula (C) )

[0007]

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(Wherein p represents 1 or 2), a furan derivative having a gastric motility-enhancing effect (JP-A-1-31
No. 3424) is known. Equation (D)

[0009]

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[0010] A furan derivative containing a furan derivative represented by the following formula (1) has been filed (Japanese Patent Application No. 1-21920, filed on August 17, 1999).

[0011]

An object of the present invention is to provide a furan derivative having an excellent gastrointestinal motility-enhancing action.

[0012]

The present invention relates to a compound of the formula (I)

[0013]

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[0014] (In the formula, R ¹ is hydrogen, unsubstituted or substituted phenyl, unsubstituted or substituted aralkyl, lower alkynyl, lower alkenyl or picolyl R ² to R
⁸ is the same or different and represents hydrogen or lower alkyl. Provided that R ^{1 to} R ⁸ are not simultaneously hydrogen) or a pharmacologically acceptable salt thereof.

Although some of the compounds (I) may exist in the form of optically active isomers, all possible stereoisomers including these optical isomers and mixtures thereof are also included in the present invention. In the definition of R ¹ , aralkyl includes, for example, benzyl, phenethyl, benzhydryl, and phenylpyropenyl having 7 to 13 carbons, and lower alkynyl includes alkynyl having 2 to 5 carbons, such as ethynyl and propargyl. Examples of the lower alkenyl include alkenyl having 2 to 6 carbon atoms, for example, vinyl, allyl, crotyl, prenyl, methylbutenyl and the like.

Examples of the substituent in the substituted phenyl and the substituted aralkyl include the same or different and substituted or unsubstituted lower alkyl, lower alkoxy, halogen, nitro and the like. Here, examples of the alkyl moiety in lower alkyl and lower alkoxy include straight-chain or branched C1-C5 methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and the like. Can be Examples of the halogen include fluorine, chlorine, bromine, iodine and the like.

The pharmacologically acceptable salts of the compound (I) include pharmacologically acceptable acid addition salts, for example, inorganic salts such as hydrochloride, sulfate and phosphate, and maleate; Organic acid salts such as fumarate and citrate are exemplified. In addition, compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts 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.

[0019]

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[0020]

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Wherein R ^2a and R ^3a represent hydrogen in the definition of R ² and R ³ in formula (I), R ¹² represents a hydroxyl-protecting group, L represents a leaving group, and Me Represents a methyl group, and R ^{4 to} R ⁸ are as defined above. Here, the hydroxyl-protecting group represented by R ¹² means t-butyldimethylsilyl, tetrahydropyranyl, benzyl, 4-methoxybenzyl and the like, and the leaving group represented by L is tosylate; It means sulfonates such as mesylate or halogens such as chlorine, bromine and iodine.

First, compound (IVa) is prepared by combining compound (II) with an equivalent amount of compound (IIIa) in an aprotic polar solvent such as tetrahydrofuran or dimethylformamide, or in a halogenated hydrocarbon such as methylene chloride or chloroform. It is obtained by reacting at room temperature in a solvent. Compound (VIa) is obtained by mixing compound (IVa) with an equivalent amount of compound (Va) by 50.
It is obtained by reacting at 〜100 ° C. in the absence of a solvent. The reaction is desirably performed under reduced pressure.

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

Compound (VIIa) is prepared by reacting compound (VIIIa) in tetrahydrofuran, dimethylformamide or the like in the presence of 1 to 3 equivalents of a strong base such as potassium t-butoxide, sodium hydride or diazabicycloundecene. It is obtained by reacting at room temperature for 0.5 to 1 hour. Conversion of compound (VIIIa) to compound (IXa) can be carried out according to a usual method. For example, when R ¹² is t-butyldimethylsilyl group or tetrahydropyranyl group or the like, compound (IXa) is prepared by converting compound (VIIIa) into an alcohol such as methanol or ethanol in a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid; Or by reacting at 0 ° C. to room temperature for 3 to 18 hours in the presence of an organic acid such as p-toluenesulfonic acid,
Also when R ¹² is a benzyl group, palladium in the alcohol catalytic amounts such as ethanol - by hydrogenation in the presence of carbon, also in the case of R ¹² is 4-methoxybenzyl group water weight catalyst in methylene chloride By reacting with 2-3 equivalents of an oxidizing agent such as 2,3-dichloro-5,6-dicyano-p-benzoquinone.

Conversion of compound (IXa) to compound (Xa) can be carried out in the same manner as in the above-mentioned method of converting compound (VIa) to compound (VIIa). Compound (XIa) is prepared by reacting compound (Xa) with 5 to 10 equivalents of sodium azide in an inert solvent such as dimethylformamide at 50 to 80 ° C.
It is obtained by reacting for 10 hours. Compound (XII
a) is a method of reducing compound (XIa) by an appropriate reduction method, for example, by converting 2 to 5 equivalents of triphenylphosphine and 10 to 20 equivalents of water in an inert solvent such as toluene or ethyl acetate from 50 ° C. to a boiling point of the solvent of 3 to By reacting for 7 hours,
In an inert solvent such as lower alcohols such as ethanol or ethyl acetate, for example, in the presence of a catalyst such as palladium-carbon, a hydrogen atmosphere at room temperature to 50 ° C.
It is obtained by reacting for ~ 12 hours. Compound (XI
Ia) can also be isolated as a salt with an organic acid such as fumaric acid, maleic acid, and oxalic acid.

Compound (Ia) is prepared by reacting compound (XIIa) with an equivalent amount of compound (XIII) in a lower alcohol such as methanol or ethanol at room temperature to 60 ° C., if necessary, in the presence of a base such as triethylamine. Let react for 24 hours,
Then, it is obtained by reacting at 0 ° C. to room temperature for 1 to 6 hours in the presence of a suitable reducing agent such as sodium borohydride.

[0027]

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[0028]

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[Wherein, R^2bAnd R^3bIs one of them
Represents both lower alkyl, R^5aIn formula (I)
R^FiveIn the definition, represents hydrogen, Hal is chlorine, bromine, iodine
Represents the prime, R¹²And R¹³Are different and the same as above.
Represents a hydroxyl-protecting group, ^FourAnd R⁶~ R⁸Is before
Synonymous with Compound (II) and compound (Vb)
The compound (IVb) was prepared according to the method described in Method 1.
And then reacting it with compound (IIIb).
Compound (VIb-1) is obtained.

Conversion of compound (VIb-1) to compound (XV) is carried out according to a conventional method. For example, when R ¹³ is a t-butyldimethylsilyl group, compound (XV) is prepared by subjecting compound (VIb-1) to 1-3 equivalents of t-butyldimethylchlorosilane in an inert solvent such as tetrahydrofuran or dimethylformamide. It is obtained by reacting at 0 ° C. to room temperature for 0.5 to 3 hours in the presence of a base such as imidazole.

Conversion of compound (XV) to compound (VIb-2) can be achieved by various methods depending on the type of R ¹² and R ¹³ . For example, when R ¹² is a benzyl group and R ¹³ is a t-butyldimethylsilyl group, hydrogenation is carried out in the presence of a suitable catalyst such as palladium-carbon,
When R ¹² is 4-methoxybenzyl group and R ¹³ is t-butyldimethylsilyl group, 2-3 equivalents of 2,3-dichloro-5,6-dicyano- in methylene chloride in the presence of a catalytic amount of water.
It can be obtained by reacting with p-benzoquinone. Further, R ¹² is a tetrahydropyranyl group, and R ¹³ is t
In the case of -butyldimethylsilyl group, a suitable Lewis acid in an inert solvent such as methylene chloride and diethyl ether,
For example, it can be obtained by treating with magnesium bromide, dimethyl aluminum chloride or the like.

The compounds (VI-2) to (Ib)
The conversion to compound (Ia) can be carried out in the same manner as in the method for obtaining compound (Ia) from compound (VIa) described in method 1.

[0033]

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[Wherein R ^1a represents unsubstituted or substituted aralkyl, lower alkynyl, lower alkenyl or picolyl in the definition of R ¹ in formula (I), and R ^{2 to} R ⁸
And Hal are as defined above. Compound (XVIII) can be obtained by reacting compound (XVI) with 1.5 to 5 equivalents of compound (XVII) in an inert solvent such as dimethylformamide or tetrahydrofuran in the presence of a suitable base such as sodium hydride. . afterwards,
Compound (Ic) is obtained by reacting compound (XVIII) according to the method for converting compound (XIa) to compound (Ia) described in Method 1.

[0035]

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[0036]

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[Wherein, R^1bIs R in formula (I)¹Constant
In the definition, represents an unsubstituted or substituted phenyl;^4aIs the expression
R in (I)^FourIn the definition of, represents hydrogen, Hal-a and
And Hal-b are the same or different and have the same meaning as defined above.
And R^Two, R^Three, R^Five~ R ⁸And L are the same as above
Righteous. Compound (XXI) is compound (II) and 1-2 equivalents of compound (X
X) and dimethylformamide, tetrahydrofuran
In any inert solvent, potassium t-butoxide, diazabi
In the presence of a strong base such as cloundecene, 60 ° C.
Obtained by heating at the boiling point. Compound (XXI):
From compound (IVa) to compound (VIa) described in Method 1
Reaction with compound (XXII) according to the method
Compound (XXIII) is obtained. Then, the compound (XXIII) is prepared by the method
Method for converting compound (VIa) to compound (VIIa) described in 1
According to the following formula, compound (XXIV) and further compound (XXIV)
In the same manner as in the method for converting compound (VIIa) to compound (VIIIa),
To give compound (XXV). Then, compound (XXV)
(XXVI) in an inert solvent in the presence of a base
Thereby, compound (XXVII) is obtained. Hydroxyl as base
Potassium chloride, sodium hydride, etc. are used and are inert
Solvents include tetrahydrofuran, dimethylforma
A mid or the like is used alone or as a mixture. The reaction is 0
The reaction is usually completed in 5 to 48 hours from the temperature of the solvent to the boiling point of the solvent.

Compound (Id) can be obtained by treating compound (XXVII) in the same manner as in the method for converting compound (Xa) to compound (Ia) described in Method 1. Intermediates and target compounds in the above-mentioned production method are isolated and purified by purification methods commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. Can be. In addition, the intermediate can be subjected to the next reaction without purification.

When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is, or if compound (I) is obtained in a free form, it may be purified by a conventional method. What is necessary is just to form a salt. Specific examples of the compound (I) are shown in Tables 1-1 and 1-2. .. Correspond to the compounds obtained in Examples 1, 2,.

[0040]

[Table 1]

[0041]

[Table 2]

Next, the pharmacological action of compound (I) will be described.

Test Example 1 Acute Toxicity Test A test compound was orally administered (po: 300 mg / kg) using three dd male mice weighing 20 ± 1 g per group. The state of death 7 days after administration was observed, and the minimum mortality (MLD) value was determined. The results are shown in Tables 2-1 and 2-2.

Test Example 2 Gastrointestinal Hypermotility Test The ileum of a male Hartley guinea pig weighing 250 to 400 g was excised 2-3 cm. The vessel was suspended in a Tyrode liquid tank (capacity: 30 ml) at 37 ± 1 ° C. supplied with a mixed gas of 95% oxygen and 5% carbon dioxide gas, and the contraction movement in the major axis direction was recorded using an isotonic transducer. Transmural electrical stimulation was performed under the conditions of a duration of 1 millisecond, a stimulation interval of 10 seconds, and supra maximal.

The test compound was dissolved or suspended in a physiological saline solution and administered to the tank. The effect on transmural stimulation was calculated from the contraction height (A) before administration of the test compound and the contraction height (B) after administration of the test compound according to the following formula. Amplification rate (%) = (BA) / A × 100 The results are shown in Tables 2-1 and 2-2.

[0046]

[Table 3]

[0047]

[Table 4]

As is clear from Table 2, the compounds of the present invention have an excellent gastrointestinal motility-enhancing effect. Further, the compound does not show histamine H ₂ antagonism and is excellent in separation from undesired effects such as suppression of gastric acid secretion. Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.

The route of administration is preferably the one that is most effective in the treatment, and may be oral or parenteral (for example, 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, for example, 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 the like, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. In addition, capsules, tablets, powders, granules and the like, lactose, glucose, sucrose, excipients such as mannitol, starch, disintegrants such as sodium alginate, magnesium stearate,
It can be produced using a lubricant such as talc, a binder such as polyvinyl alcohol, hydroxypropylcellulose, gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin.

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

Formulations for enteral administration are provided as suppositories with conventional carriers, such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids, and the like. Also in these parenteral preparations, diluents, fragrances, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for the oral preparations One or more auxiliary components selected from the following may also be added.

The effective dose and the number of administrations of the compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, age of the patient, body weight, nature or severity of the condition to be treated, and the like. Normal dosage is 0.01 to 1000 per day
mg / person, and the administration frequency is preferably once a day or divided.

[0054]

EXAMPLES Examples and reference examples are shown below.

Example 1 (±)-｛1- [2-[(5-piperidinomethyl-2-
Furanyl) methylamino] ethyl] -5-methyl-2-
Imidazolidinylidene propane dinitrile (compound 1) [bis (methylthio) methylene] propane dinitrile (compound II) 13.7 g (80.59 mmol) and [2- (2
-Tetrahydropyraniloxy)] ethylamine 11.68 g
(80.55 mmol) in 350 ml of chloroform,
Stir at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 5 v / v) to give a pale yellow oil, ｛(methylthio) -2- [2- (tetrahydro 18.41 g (yield: 80.6%) of pyraniloxy) ethylamino] methylene @ propanedinitrile (compound a) were obtained.

NMR (CDCl ₃ ) δ (ppm): 7.33 (1H, bs), 4.
46 (1H, m), 3.76 (6H, m), 2.63 (3H, s), 1.61 (6H, m)

18.41 g (68.95 mmol) of compound a and 1-
A mixture with 5.17 g (68.93 mmol) of amino-2-propanol is added at 80 ° C. with suction on a water aspirator.
Heated for 0.5 hour. The reaction mixture is subjected to silica gel column chromatography (chloroform: methanol = 30: 1 v
/ V), and recrystallizing the obtained crude crystals from a mixed solvent of ethyl acetate and 2-propyl ether,
{[2- (2-tetrahydropyraniloxy) ethylamino]-[(2-hydroxy) propylamino] methylene} propanedinitrile (compound b) 13.6 g (yield 67.3)
%) As white crystals.

Melting point: 92.5-94.0 ° C. NMR (CDCl ₃ ) δ (ppm): 6.76 (1H, bs), 6.19 (1H, bs),
4.57 (1H, m), 3.55 (9H, m), 2.68 (1H, m), 1.59 (6H, m),
1.24 (3H, d, J = 6.2Hz)

13.0 g (44.37 mmol) of compound b was dissolved in 200 ml of pyridine, and 21 ml (271.44 mmol) of methanesulfonyl chloride was added dropwise under ice cooling. After stirring the reaction mixture for 3.5 hours, the solvent was distilled off under reduced pressure. Chloroform was added to the residue, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in 400 ml of tetrahydrofuran, and a solution of 7.42 g (48.81 mmol) of diazabicycloundecene (DBU) in 50 ml of tetrahydrofuran was added dropwise under ice cooling. After stirring the reaction solution for 4.5 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Next, the residue was dissolved in 200 ml of methanol, and 850 mg (4.47 mmol) of p-toluenesulfonic acid monohydrate was added.
Stirred at room temperature for 15 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- (2-hydroxyethyl)]-5-methyl-. 6.82 g (yield 80.0% from compound b) of 2-imidazolidinylidenepropanedinitrile (compound c) was obtained.

Melting point: 124.5-125.0 ° C. NMR (DMSO-d ₆ ) δ (ppm): 7.80 (1H, bs), 3.59 (7H,
m), 3.14 (1H, bs), 1.22 (3H, d, J = 5.8Hz)

6.42 g (33.44 mmol) of compound c was dissolved in 60 ml of pyridine, and 5.18 ml (66.96 mmol) of methanesulfonyl chloride was added dropwise under ice cooling. Reaction solution 1
After stirring for an hour, the solvent was distilled off under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was treated with dimethylformamide 10
The mixture was dissolved in 0 ml, and sodium azide (6.52 g, 100.31 mmol) was added, followed by stirring at 80 ° C. for 2 hours. After the reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained crude crystals were washed with a mixed solvent of ethyl acetate and 2-propyl ether to give (±)-｛1-
6.34 g (yield 87.3% from compound c) of (2-azidoethyl) -5-methyl-2-imidazolidinylidenepropanedinitrile (compound d) was obtained as white crystals.

Melting point: 90.5-91.5 ° C. NMR (CDCl ₃ ) δ (ppm): 6.02 (1H, bs), 3.0-4.3 (7H,
m), 1.35 (3H, d, J = 6.2Hz)

Compound (d) 6.23 g (28.71 mmol) was dissolved in ethyl acetate (100 ml), and triphenylphosphine 11.2 was dissolved.
After addition of 8 g (43.06 mmol), the mixture was stirred at 60 ° C. for 10 minutes. Then, after adding 5.16 ml (287.11 mmol) of water, 6
Stirred at 0 ° C. for a further 6 hours. The reaction was concentrated under reduced pressure,
Then, the toluene azeotrope was repeated twice, and the residue was dissolved in ethanol (100 ml) and fumaric acid (1.99 g, 17.23 mmol) was added.
Was added. The precipitated white crystals are collected by filtration and 6.98 g (97.6%)
(±)-｛1- (2-aminoethyl) -5-methyl-
2-imidazolidinylidene @ propandinitrile 1/2
A fumarate (compound e) was obtained. Melting point: 157-159.5 ° C

2.33 g of 5-piperidinomethylfurfural
150 ml of ethanol was added to a mixture of (12.07 mmol), 3.0 g (12.05 mmol) of compound e and 3.4 ml (24.44 mmol) of triethylamine, and the mixture was stirred at 60 ° C. for 2 hours.
The reaction solution was cooled on ice, and 550 mg of sodium borohydride (14.
(47 mmol), and the mixture was stirred for 2 hours after the total amount was added. The reaction solution was concentrated under reduced pressure, chloroform was added to the residue, and the mixture was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol: triethylamine = 100: 10: 1 v / v) to obtain 3.43 g (yield 77.4%) of Compound 1 as a pale yellow oil. . Compound l 1.0g
(2.72 mmol) was dissolved in 10 ml of ethanol, 290 mg (2.96 mmol) of oxalic acid was added, and the mixture was stirred at room temperature. The precipitated white crystals were collected by filtration to obtain 1.17 g (yield: 89%) of monooxalate monohydrate of Compound 1.

Melting point of monooxalate monohydrate: 157-15
9.5 ° C. Elemental analysis: Calculated value (%) as C ₂₀ H ₂₈ N ₆ O · (CO ₂ H) ₂ · H ₂ O; C 55.45, H 6.77, N 17.64 Actual value (%); C 55.63, H 6.87, N 17.84 MS (m / z): 368 (M ⁺ ) NMR (CDCl ₃ ) δ0 pm): 6.21 (1H, bs), 6.06 (2H, s),
4.04 (2H, m), 3.74 (2H, s), 3.72 (2H, m), 3.46 (2H, m),
3.42 (2H, s), 3.15 (1H, m), 2.85 (2H, t, J = 6.7Hz),
2.37 (4H, m), 1.43 (6H, m), 1.27 (3H, d, J = 5.9 Hz) IR (KBr; cm ^-1 ): 2200, 2160

Example 2 (±)-｛1- [2-[(5-piperidinomethyl-2-
Furanyl) methylamino] propyl] -2-imidazolidinylidenepropanedinitrile (Compound 2)
According to the method described above, 20.76 g (122.1 mmol) of compound II and 22.84 g (143.65 mmol) of [2- (2-tetrahydropyraniloxy)] propylamine were used as a pale yellow oil of {[(methylthio) -2- (2-tetrahydro 27.39 g (yield: 79.8%) of pyraniloxy) propylamino] methylene @ propanedinitrile (compound f) were obtained. Then
Compound f 27.39 g (97.47 mmol) and ethanolamine
5.95 g (97.54 mmol) of pale yellow oily [[2- (2
-Tetrahydropyranyloxy) propylamino] [(2
-Hydroxy) ethylamino] methylene @ propanedinitrile (compound g) (19.36 g, 67.6%) was obtained. Less than,
The compound g was treated in the same manner as in the conversion of the compound b to the compound 1 in Example 1 to obtain a white crystalline compound 2.

Melting point: 129 ° -130 ° C. Elemental analysis: Calculated value (%) as C ₂₀ H ₂₈ N ₆ O: C 65.19, H 7.66, N 22.81 Actual value (%); C 64.97, H 7.60, N 23.08 MS ( m / z): 368 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.11, 6.09 (1H each, d, J each)
= 3.12Hz), 5.89 (1H, bs), 3.81 (4H, m), 3.49 (4H,
m), 3.45 (2H, s), 3.07 (1H, m), 2.39 (4H, m), 1.59 (4
H, m), 1.44 (2H, m), 1.12 (3H, d, J = 6.42 Hz) IR (KBr; cm ^-1 ): 2200, 2160

Example 3 (±)-｛1-[[2-[(5-piperidinomethyl-2)
-Furanyl) methylamino] -1-methyl] ethyl]-
2-imidazolidinylidenpropanedinitrile (compound 3) According to the method of Example 1, 21.74 g (127.88 mmol) of compound II and 20.33 g (127.86 mmol) of 1-methyl-2- (2-tetrahydropyraniloxy) ethylamine Δ (methylthio) [1-methyl- [2- (2
-Tetrahydropyranyloxy)] ethylamino] methylene} propanedinitrile (compound h) 32.98 g (yield 9
1.8%). Then 32.98 g (117.37 mmol) of compound h and 7.16 g (117.38 mmol) of ethanolamine
22.0 g of {[[2- (2-tetrahydropyranyloxy) -1-methyl] ethylamino] [(2-hydroxy) ethylamino] methylene} propanedinitrile (compound i) as a pale yellow oil (64.0% yield) ) Got. Thereafter, Compound i was treated in the same manner as in Compound 1 to Compound 1 in Example 1 to obtain Compound 3 as a pale yellow oil.

Melting point of fumarate monohydrate: 89.0-8
9.5 ° C. Elemental _{analysis: C 20 H 28 N 6 O} · C 4 H 4 O 4 · H 2 O Calculated (%); C 57.36, H 6.82, N 16.72 Found (%); C 57.05, H 7.04, N 16.89 MS (m / z): 368 (M ⁺ ) NMR (D ₂ O; monofumarate monohydrate) δ (ppm):
6.76, 6.73 (1H each, d each, J = 3.48Hz), 6.53 (2H, s),
4.73 (1H, m), 4.37 (2H, s), 4.35 (2H, s), 3.65 (4H,
m), 3.48 (2H, m), 3.38 (1H, dd, J = 9.16, 13.56Hz),
3.19 (1H, dd, J = 5.13, 13.56Hz), 2.97 (2H, m), 1.73
(6H, m), 1.32 (3H, d, J = 6.78 Hz) IR (KBr; cm ^-1 ): 2200, 2160

Example 4 (±)-｛1- [2-[(5-Piperidinomethyl-2-
Furanyl) methylamino] ethyl] -4-methyl-2-
Imidazolidinylidene-propanedinitrile (Compound 4) 316 mg (1.86 mmol) of compound II and [1-methyl-2
-(4-methoxybenzyloxy)] ethylamine 336
mg (1.86 mmol) was dissolved in 10 ml of chloroform and stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (ethyl acetate: n-ethyl acetate).
Purification with hexane = 1: 2 v / v) yielded 488 mg of {(methylthio) [1-methyl [2- (4-methoxybenzyloxy)] ethylamino] methylene} propandinitrile (compound j) as a yellow oil. (86.7% yield).

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 j 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 a pale yellow oil of {[1-methyl- [2- (4-methoxybenzyloxy)] ethylamino] [( 321 mg (63.9%) of 2-hydroxy) ethylamino] methylene} propanedinitrile (compound k) were obtained.

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

314 mg (0.95 mmol) of compound k were dissolved in 3 ml of methylene chloride, 160 mg (1.58 mmol) of triethylamine and 215 mg (1.43 mmol) of t-butyldimethylchlorosilane were added, and a catalytic amount of 4-dimethylaminopyridine was added. Stirred at room temperature for 16 hours. The reaction solution was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 3 v /
v) and purified as a colorless oil (±)-｛[1-methyl- [2
-(4-methoxybenzyloxy)] ethylamino]
[(2-t-butyldimethylsiloxy) ethylamino]
243 mg (yield 57.6%) of methylene dipropane dinitrile (compound 1) was 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 = 5.92 Hz), 0.87 (9H, s), 0.06 (6H,
s)

Compound 1 (240 mg, 0.54 mmol) was dissolved in a mixed solvent of methylene chloride (2 ml) and water (0.1 ml).
3-dichloro-5,6-dicyano-p-benzoquinone 150 m
g (0.66 mmol) was added. After stirring the reaction solution at room temperature for 17 hours, insolubles were removed by filtration, and the filtrate was washed with saturated saline.
The organic layer is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (chloroform: methanol = 30: 1 v).
/ V) to give (±)-｛[1
-Methyl- (2-hydroxy) ethylamino] [(2-
t-butyldimethylsiloxy) ethylamino] methylene @ propanedinitrile (compound m) 141 mg (80.6 yield)
%).

Melting point: 135.5-136 ° C. NMR (CDCl ₃ ) δ (ppm): 6.52 (1H, bt, J = 5.7 Hz), 6.
34 (1H, bt, J = 5.1Hz), 3.91 (1H, m), 3.62 (2H, m), 3.3
0 (4H, m), 3.12 (1H, bs), 1.07 (3H, d, J = 6.39Hz), 0.
79 (9H, s), 0.12 (6H, s)

9.0 g (27.69 mmol) of the compound m was dissolved in 120 ml of pyridine, and 4.3 ml (55.58 mmol) of methanesulfonyl chloride was added dropwise under ice cooling. 1 reaction mixture
After stirring for an hour, the solvent was distilled off under reduced pressure. Methylene chloride was added to the residue, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate 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 6.31 g of diazabicycloundecene (DBU) (41.51 g) was added.
(Mmol) was added dropwise under ice-cooling. After stirring the reaction solution for 1 hour, the solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Next, the residue was dissolved in 100 ml of methanol and p-
After adding 526 mg (2.77 mmol) of toluenesulfonic acid monohydrate, the mixture was stirred at room temperature for 6.5 hours. After neutralizing the reaction mixture, the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the precipitated white crystals were collected by filtration to give (±)-[1- (2-hydroxyethyl) -4-methyl-2-imidazolidini. 4.98 g (yield 89.8% from compound m) of propidinitrile (compound n) was obtained.

Melting point: 76.0-77.0 ° 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 (3
(H, d, J = 5.82Hz)

The compound n was treated in the same manner as in the conversion of the compound b to the compound 1 in Example 1 to obtain a pale yellow oily compound 4. Melting point of monooxalate · 0.5 hydrate: 169.5-173.0 ° C. Elemental analysis: C ₂₀ H ₂₈ N ₆ O · (CO ₂ H) ₂ · 0.5 H ₂
Calculated value (%) as O; C 56.52, H 6.68, N 17.98 Actual value (%); C 56.46, H 6.71, N 18.26 MS (m / z): 368 (M ⁺ ) NMR (D ₂ O; Acid salt / hemihydrate) δ (ppm)
: 6.75, 6.72 (1H each, d each, J = 3.29Hz), 4.38 (2H,
s), 4.35 (2H, s), 4.07 (1H, m), 3.94 (2H, m), 3.89 (1H,
m), 3.48 (2H, bd, J = 12.09 Hz), 3.37 (3H, m), 2.96
(2H, bt, J = 11.91, 12.45Hz), 1.85 (6H, m), 1.25 (3
H, d, J = 6.23 Hz) IR (KBr; cm ^-1 ): 2200, 2160

Example 5 (-)-{1- [2-[(5-piperidinomethyl-2-)
Furanyl) methylamino] ethyl] -4-methyl-2-
Imidazolidinylidene propanedinitrile (Compound 5) According to the method of Example 4, Compound 5 was obtained as a pale yellow oil from Compound II and (+)-[1-methyl-2- (4-methoxybenzyloxy)] ethylamine. Obtained.

Melting point of 1.5 oxalate: 154-154.5 ° C. Elemental analysis: Calculated value (%) as C ₂₀ H ₂₈ N ₆ O.1.5 (CO ₂ H) ₂ ; C 54.86, H 6.21, N 16.69 Actual value ( %); C 54.92, H 6.39, N 17.13 MS (m / z): 368 (M ⁺ ) IR (KBr; cm ^-1 ): 2200, 2160 Optical rotation: [α] D ²⁰ = -4.5 (c = 0.5 , H ₂ O)

Example 6 (+)-{1- [2-[(5-Piperidinomethyl-2-)
Furanyl) methylamino] ethyl] -4-methyl-2-
Imidazolidinylidene propanedinitrile (Compound 6) According to the method of Example 4, Compound 6 is a pale yellow oil from Compound II and (-)-[1-methyl-2- (4-methoxybenzyloxy)] ethylamine. I got 2 fumarate mp: 141-143 ° C. Elemental _{analysis: C 20 H 28 N 6 O} · 2C 4 Calculated as _{H 4 O 4 (%);} C 55.99, H 6.04, N 13.99 Found (%); C 56.06, H 6.24, N 14.08 MS (m / z): 368 (M ⁺ ) IR (KBr; cm ^-1 ): 2200, 2160 Optical rotation: [α] D ²⁰ = + 1.8 (c = 0.5, H ₂ O)

Example 7 (±)-{1- [2-[[2- (5-Piperidinomethyl-2-furanyl) ethyl] amino] ethyl] -2-imidazolidinylidene} propanedinitrile (Compound 7) 5 3.2 g (16.58 mmol) of -piperidinomethylfurfural was dissolved in 65 ml of anhydrous tetrahydrofuran, and the system was replaced with nitrogen and cooled to -60 ° C. Methyl magnesium bromide diethyl ether solution (3M) 10 ml (30.0
Mmol) and the temperature was raised to 0 ° C. over 1 hour. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, tetrahydrofuran was distilled off under reduced pressure, water was added to the residue, and the pH was adjusted to 13 with a 10N aqueous solution of sodium hydroxide. After extraction with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure (150 ° C; 0.5 mmHg) to give 2.94 g (yield 84.7%) of 1- (5-piperidinomethyl-2-furan) ethanol (compound o) as a colorless oil. I got

NMR (CDCl ₃ ) δ (ppm): 6.07 (2H, s), 4.
85 (1H, q), 3.45 (2H, s), 2.67 (1H, bs), 2.42 (4H, m),
1.54 (6H, m), 1.51 (3H, d)

Compound 2.86 g (13.68 mmol) of compound o was dissolved in 100 ml of chloroform, and 44 g of active manganese dioxide was dissolved.
(505.75 mmol) was added and stirred vigorously at room temperature for 2 days. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 v / v) to give 5-piperidinomethyl-2-acetylfuran as a pale yellow oil. 2.48 g (87.6%) of (compound p) were obtained.

NMR (CDCl ₃ ) δ (ppm): 7.13, 6.34 (each 1 H, each d, J = 3.15 Hz), 3.62 (2H, s), 2.44 (3H, s),
2.42 (4H, m), 1.50 (6H, m)

The compound p (2.48 g, 11.98 mmol) and [1-
(2-Aminoethyl) -2-imidazolidinylidene] Propandinitrile 1/2 fumarate (2.81 g, 11.96 mmol) and triethylamine (3.5 mL, 25.16 mmol) were mixed with 50 mL of ethanol, and the mixture was heated under reflux for 48 hours.
The reaction solution was cooled on ice and 910 mg of sodium borohydride (23.95
Mmol), and the mixture was stirred for 1 hour after the total amount was added.
The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (acetone) to obtain 7793 mg of a pale yellow oily compound (18.0% yield).

Melting point of 1.5 oxalate 0.5 hydrate: 94.5
-96.0 ° C. Elemental _{analysis: C 20 H 28 N 6 O} · 1.5 (CO 2 H) 2 · 0.5 H
Calculated value (%) as ₂ O; C 53.90, H 6.29, N 16.40 Actual value (%); C 53.81, H 6.11, N 16.57 MS (m / z): 368 (M ⁺ ) NMR (CDCl ₃ ) δ ( ppm): 6.08 (2H, s), 5.93 (1H, bs),
3.71 (7H, m), 3.52 (2H, s), 2.87 (2H, t, J = 6.1Hz),
2.44 (4H, m), 1.54 (6H, m), 1.41 (3H, d, J = 6.1 Hz) IR (KBr; cm ^-1 ): 2200, 2160

Example 8 (±)-{1- [2-[[5- (1-Piperidinoethyl) -2-furanyl] methylamino] ethyl-2-imidazolidinylidene} propanedinitrile (Compound 8) 7, 2.48 g of compound p, 2.81 g of [1- (2-aminomethyl) -2-imidazolidinylidene] propanedinitrile 1/2 fumarate and triethylamine
Instead of 3.5 ml, 1.93 g (9.32 mmol) of 5- (1-piperidinoethyl) furfural and 2.08 g (8.85 mmol) of [1- (2-aminoethyl) -2-imidazolidinylidene] propanedinitrile 1/2 fumarate Example 7 except that) and 2.6 ml (18.7 mmol) of triethylamine were used.
82.95 g (yield 90.5) of a pale yellow oily compound
%).

Melting point of dioxalate / hemihydrate: 133.5
-134 ° C. Elemental _{analysis: C 20 H 28 N 6 O} · 2 (CO 2 H) 2 · 0.5 H 2
Calculated value (%) as O; C 51.70, H 5.97, N 15.07 Actual value (%); C 51.55, H 6.12, N 14.95 MS (m / z): 368 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm) ): 6.35 (1H, bs), 6.12, 6.03 (1H each, d each, J = 3.08 Hz), 3.78 (2H, s), 3.66 (7H, m),
2.91 (2H, t, J = 6.04, 6.26 Hz), 2.37 (4H, m), 1.97 (1
H, bs), 1.52 (6H, m), 1.38 (3H, d, J = 7.03 Hz) IR (KBr; cm- ¹ ): 2200, 2160

Example 9 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3-phenyl-2-imidazolidinylidene} propanedinitrile (Compound 9) Compound II 5.2 g ( 30.59 mmol) and 3.0 g of aniline (32.26
Mmol) and 7.0 g of diazabicycloundecene (DBU)
(46.06 mmol) was dissolved in 60 ml of tetrahydrofuran and heated to reflux for 3 hours. The reaction solution was poured into 50 ml of ice water, extracted with methylene chloride, and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethanol to give [(methylthio) (phenylamino) methylene] propanedinitrile (compound q).
3.85 g (58.5% yield) were obtained as reddish brown needles.

Melting point: 172.5-174 ° C. NMR (DMSO-d ₆ ) δ (ppm): 10.46 (1H, bs), 7.25 (5H,
m), 2.48 (3H, s) Compound q 4.0 g (18.6 mmol) and ethanolamine 1.
13 g (18.52 mmol) of the mixture were heated at 80 ° C. for 1.5 hours with suction on a water aspirator. The reaction mixture is subjected to silica gel column chromatography (chloroform:
Purification with (methanol = 20: 1 v / v) yielded a pale yellow oil of {(phenylamino) [(2-hydroxy)
1.58 g (yield 37.4%) of ethylamino] methylene @ propanedinitrile (Compound r) was obtained.

NMR (DMSO-d ₆ ) δ (ppm): 9.32 (1H, b
s), 7.71 (1H, bt), 7.18 (5H, m), 5.07 (1H, bt), 3.52
(2H, m), 3.31 (2H, m)

Compound 1.5 g (6.58 mmol) of compound r was added to pyridine
Dissolve in 15 ml, and cool on ice with methanesulfonyl chloride 1.
After dropwise addition of 0 ml (12.93 mmol), the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was dissolved in 10 ml of tetrahydrofuran, and 1.1 g (7.24 mmol) of DBU was added under ice cooling, followed by stirring for 0.5 hour. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crude crystals were washed with 2-propyl ether to give (1-phenyl-2-imidazolidinylidene) propanedinitrile (compound s).
1.19 g (yield 86.2% from compound r) was obtained as pale yellow crystals.

Melting point: 205-206 ° C. NMR (CDCl ₃ + DMSO-d ₆ ) δ (ppm): 7.68 (1H, bs),
7.34 (5H, m), 4.02 (2H, m), 3.71 (2H, m)

1.1 g (5.24 mmol) of compound s was dissolved in 50 ml of dimethylformamide, and 270 mg (6.75 mmol) of 60% sodium hydride was added under ice-cooling. After the whole amount was added, the mixture was stirred at room temperature for 0.5 hour, 1-bromo-2-chloroethane (4.4 ml, 52.83 mmol) was added, and the mixture was heated at 80 ° C for 20 hours. 5 ml of ice water was added to the reaction solution, and the solvent was distilled off under reduced pressure. After adding methylene chloride to the residue and washing with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 v / v) to obtain [1- (2-chloroethyl) -3-phenyl-2.
-Imidazolidinylidene] propanedinitrile (compound t) 1.12 g (78.3%) was obtained as white crystals.

Melting point: 168.5-170 ° C. NMR (CDCl ₃ ) δ (ppm): 7.32 (5H, m), 3.94 (8H, m)

A mixture of 1.1 g (4.04 mmol) of compound t and 1.3 g (20.0 mmol) of sodium azide was heated in 10 ml of dimethylformamide at 80 ° C. for 7 hours. The solvent was distilled off under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with ethyl acetate / 2-propyl ether to give [1- (2-azidoethyl) -3-phenyl-2-imidazolidinylidene] propanedinitrile (compound u) 1.06 g (93.8% yield) was obtained as white crystals.

Melting point: 113.5-115 ° C. NMR (CDCl ₃ ) δ (ppm): 7.29 (5H, m), 3.91 (4H, m),
3.79 (4H, m)

Then, a pale yellow oily compound 9 was obtained according to the method of converting the compound d to the compound 1 in Example 1. 1.5 Melting point of oxalate: 104-106 ° C Elemental analysis: Calculated value (%) as C ₂₅ H ₃₀ N ₆ O · 1.5 (CO ₂ H) ₂ ; C 59.46, H 5.88, N 14.86 Actual value (%); C 59.25, H 6.01, N 14.75 MS (m / z): 430 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.29 (5H, m), 6.11 (2H, s),
3.86 (4H, m), 3.79 (2H, s), 3.73 (2H, t, J = 6.2Hz),
3.48 (2H, s), 2.98 (2H, t, J = 6.2Hz), 2.43 (4H, m), 1.
54 (6H, m) IR (KBr; cm ^-1 ): 2200, 2155

Example 10 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (4-methylphenyl) -2-imidazolidinylidene} propanedinitrile (Compound 10) According to the method described in Example 9, p-toluidine 4.4 g (4
[1- (2-azidoethyl) -3- (4-methylphenyl) -2-imidazolidinylidene] propanedinitrile 2.2 g (18.2%; 6 steps) from 1.12 mmol) and 7.0 g (41.18 mmol) of compound II Was obtained as white crystals. Then, this was reacted according to the method for converting compound d to compound 1 described in Example 1 to obtain compound 10 as a pale yellow oil.

Melting point of dioxalate · 0.5 hydrate: 151-
152.5 ° C. Elemental _{analysis: C 26 H 32 N 6 O} · 1.5 (CO 2 H) 2 · 0.5
Calculated for H ₂ O (%); C 56.86, H 5.89, N 13.26 Actual (%); C 56.59, H 5.94, N 13.16 MS (m / z): 444 (M ⁺ ) NMR (CDCl ₃ ) δ. (ppm): 7.18 (4H, m), 6.12 (2H, s),
3.84 (4H, m), 3.80 (2H, s), 3.73 (2H, t, J = 6.04Hz),
3.47 (2H, s), 2.98 (2H, t, J = 6.04Hz), 2.39 (4H, m),
2.36 (3H, s), 1.88 (1H, bs), 1.50 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 11 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (3-methylphenyl) -2-imidazolidinylidene} propanedinitrile (Compound 11) According to the method described in Example 9, m-toluidine 3.15 g
(29.44 mmol) and 5.0 g (29.41 mmol) of compound II
From this, 0.8 g (9.3%; 6 steps) of [1- (2-azidoethyl) -3- (3-methylphenyl) -2-imidazolidinylidene] propanedinitrile was obtained as white crystals.
Then, this was reacted according to the method for converting compound d to compound 1 described in Example 1 to obtain compound 11 as a pale yellow oil.

1.5 Melting point of oxalate: 132-134 ° C. Elemental analysis: C ₂₆ H ₃₂ N ₆ O · 1.5 (CO ₂ H) ₂ Calculated value (%); C 60.09, H 6.09, N 14.50 Actual value ( %); C 59.94, H 6.37, N 14.29 MS (m / z): 444 (M ⁺ ) NMR (D ₂ O; 1.5 oxalate) δ (ppm): 7.29 (4H, m),
6.75 (2H, s), 4.42 (2H, s), 4.35 (2H, s), 4.03 (4H,
m), 3.87 (2H, m), 3.47 (4H, m), 2.97 (2H, m), 2.36 (3
H, s), 1.85 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 12 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (4-methoxyphenyl) -2-imidazolidinylidene} propanedinitrile (Compound 12) According to the method described in Example 9, 5.1 g of p-anisidine (4 g
[1- (2-azidoethyl) -3- (4-methoxyphenyl) -2-imidazolidinylidene] propanedinitrile 3.73 g (29.3%; 6 steps) from 1.46 mmol) and 7.0 g (41.18 mmol) of compound II Was obtained as white crystals. Then, this was reacted according to the method for converting compound d to compound 1 described in Example 1 to obtain compound 12 as a pale yellow oil.

Melting point of 1.5 oxalate 0.5 hydrate: 128
- 129 ° C. Elemental _{analysis: C 26 H 32 N 6 O} 2 · 1.5 (CO 2 H) 2 · 0.
Calculated for 5 H ₂ O (%); C 57.61, H 6.00, N 13.90 Found (%); C 57.76, H 6.14, N 14.03 MS (m / z): 460 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.15, 6.86 (2H each, d, J each)
= 8.89Hz), 6.08 (2H, s), 3.77 (3H, s), 3.76 (4H, m),
3.75 (2H, s), 3.71 (2H, t, J = 5.91Hz), 3.45 (2H, s),
2.96 (2H, t, J = 5.92 Hz), 2.36 (4H, m), 1.50 (6H, m) IR (KBr; cm- ¹ ): 2200, 2160

Example 13 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (3-methoxyphenyl) -2-imidazolidinylidene} propanedinitrile (Compound 13) According to the method described in Example 9, m-anidin 3.62 g (2
From 9.43 mmol) and 5.0 g (29.41 mmol) of compound II, 1.28 g (14.1%; 6 steps) of [1- (2-azidoethyl) -3- (3-methoxyphenyl) -2-imidazolidinylidene] propanedinitrile Was obtained as pale brown crystals. Then, this was reacted according to the method for converting compound d to compound 1 described in Example 1 to obtain compound 13 as a pale yellow oil.

1.5 Melting point of oxalate: 127.5-129 ° C. Elemental analysis: C ₂₆ H ₃₂ N ₆ O ₂ .1.5 (CO ₂ H) ₂ Calculated value (%); C 58.48, H 5.92, N 14.11 Actual value (%); C 58.23, H 6.24, N 14.15 MS (m / z): 460 (M ⁺ ) NMR (D ₂ O; 1.5 oxalate) δ (ppm): 7.43 (1H, t,
J = 8.24, 7.88Hz), 7.01 (3H, m), 6.75 (2H, s), 4.42
(2H, s), 4.35 (2H, s), 4.03 (4H, m), 3.88 (2H, m), 3.8
5 (3H, s), 3.48 (2H, m), 3.46 (2H, t, J = 6.78Hz), 2.9
7 (2H, m), 1.86 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 14 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (2-methoxyphenyl) -2-imidazolidinylidene} propanedinitrile (Compound 14) According to the method described in Example 9, 7.24 g of o-anisidine
(58.86 mmol) and 10.0 g (58.82 mmol) of compound II
Thus, 3.04 g (16.7%; 6 steps) of [1- (2-azidoethyl) -3- (2-methoxyphenyl) -2-imidazolidinylidene] propanedinitrile was obtained as white crystals. Then, this was reacted according to the method for converting compound d to compound 1 described in Example 1 to obtain compound 14 as a pale yellow oil.

1.5 Melting point of oxalate monohydrate: 132-
136 ° C. Elemental analysis: C ₂₆ H ₃₂ N ₆ O ₂ .1.5 (CO ₂ H) ₂ .H ₂
Calculated as O (%); C 56.76, H 6.08, N 13.70 Found (%); C 57.00, H 6.03, N 13.51 MS (m / z): 460 (M ⁺ ) NMR (CDCl ₃ ) δ ( ppm): 7.24 (2H, m), 6.96 (2H, m),
6.08 (2H, s), 3.87 (3H, s), 3.81 (2H, s), 3.75 (6H,
m), 3.44 (2H, s), 2.97 (2H, t, J = 5.99Hz), 2.39 (4H,
m), 1.52 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 15 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3-benzyl-2-imidazolidinylidene} propanedinitrile (compound 15) [1- (2 -Azidoethyl) -2-imidazolidinylidene] propanedinitrile (compound v) (4.0 g, 19.7 mmol) was dissolved in dimethylformamide (40 ml), and 946 mg (23.65 mmol) of 60% sodium hydride was added under ice-cooling. After adding the whole amount, the mixture was stirred for 0.5 hour, and then 2.46 ml (20.69 mmol) of α-bromotoluene was added dropwise. After stirring the reaction mixture for 0.5 hour, the solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 v / v), and the obtained crude crystals were washed with 2-propyl ether to give [1-
(2-azidoethyl) -3-benzyl-2-imidazolidinylidene] propanedinitrile (compound w) 4.47 g (7
7.5%) as white crystals.

Melting point: 75.5-76 ° C. NMR (CDCl ₃ ) δ (ppm): 7.28 (5H, m), 4.75 (2H, s),
3.69 (4H, s), 3.56 (4H, m)

2.0 g (6.83 mmol) of compound w was dissolved in 200 ml of ethanol, and 100 mg of 10% palladium-carbon (5 w / w) was dissolved.
%) And stirred at room temperature for 1 hour under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and [1- (2-aminoethyl) -3-benzyl-2-imidazolidinylidene] propanedinitrile (compound x) was obtained as a colorless oil.
78 g (97.8%) were obtained.

0.5 Melting point of fumarate: 169-170 ° C. NMR (CDCl ₃ ) δ (ppm): 7.27 (5H, m), 4.73 (2H, s),
3.56 (6H, m), 3.01 (2H, t, J = 6.2Hz), 1.35 (2H, bs)

From 1.94 g (5.96 mmol) of compound x and 1.16 g (6.0 mmol) of 5-piperidinomethylfurfural, compound 15 was obtained as a pale yellow oil in the same manner as in the conversion of compound e to compound 1 in Example 1. 1.85 g (69.8%) were obtained.

1.5 Melting point of oxalate: 143.5-145 ° C. Elemental analysis: Calculated value (%) as C ₂₆ H ₃₂ N ₆ O · 1.5 (CO ₂ H) ₂ : C 60.09, H 6.09, N 14.50 Actual value ( %); C 59.78, H 6.15, N 14.69 MS (m / z): 444 (M ⁺ ) NMR (DMSO-d ₆ ; 1.5 oxalate) δ (ppm): 7.29 (5H,
m), 6.54 (2H, s), 4.73 (2H, s), 4.14 (2H, s), 4.07 (2
H, s), 3.66 (8H, m), 3.07 (4H, m), 1.67 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 16 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- [4- (2-methyl-2-butenyl)]-2-imidazolidinylidene} Propandinitrile (Compound 16) According to the method described in Example 15, compound v 2.03 g (10 mmol) and 1-bromo-3-methyl-2-butene 2.24
g (15.03 mmol) to give
[2-azidoethyl] -3- [4- (2-methyl-2-
Butenyl)]-2-imidazolidinylidene-propanedinitrile was obtained as white crystals (2.35 g, 86.6%). Then, the compound 16 was obtained as a pale yellow oil in the same manner as in the method for converting the compound w to the compound 15 described in Example 15.

Melting point of oxalate: 159.5-161 ° C. Elemental analysis: Calculated value (%) as C ₂₄ H ₃₅ N ₆ O.2 (CO ₂ H) ₂ : C 55.71, H 6.51, N 13.92 Actual value ( %); C 55.68, H 6.54, N 13.91 MS (m / z): 423 (M ⁺ ) NMR (DMSO-d ₆ ; 2-oxalate) δ (ppm): 6.56 (2H,
s), 5.24 (1H, m), 4.10 (6H, m), 3.67 (8H, m), 3.10 (4
H, m), 1.79 (3H, s), 1.73 (3H, s), 2.89 (4H, m), 1.62
(6H, m) IR (KBr; cm ^-1 ): 2200, 2155

Example 17 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- [3- (1-phenyl-1-propenyl)]-2-imidazolidinylidene}
Propandinitrile (Compound 17) According to the method described in Example 15, compound v 2.32 g (1
1.42 mmol) and 3.37 g (17.1 mmol) of 3-bromo-1-phenyl-1-propene to give {1- [2-azidoethyl] -3- [3- (1-phenyl-1-propenyl). 3.34 g of 2-imidazolidinylidene @ propanedinitrile as a pale yellow oil.
1.5%). Next, Compound 17 was obtained in the same manner as in the conversion of Compound w to Compound 15 described in Example 15 as a pale yellow oil.

Melting point of oxalate monohydrate: 147.5
-148 ° C. Elemental _{analysis: C 28 H 34 N 6 O} · (CO 2 H) 2 · H 2 O Calculated (%); C 62.27, H 6.62, N 1
4.52 actual value (%); C 62.12, H 6.51, N 1
4.24 MS (m / z): 470 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.33 (5H, m), 6.34 (2H, m),
6.10 (2H, s), 4.32 (2H, d, J = 6.1Hz), 3.76 (2H, s),
3.62 (6H, m), 3.47 (2H, s), 2.94 (2H, t, J = 6.2Hz),
2.45 (4H, m), 1.63 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 18 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (3,4-dimethoxybenzyl) -2-imidazolidinylidene} propanedinitrile (compound 18) According to the method described in Example 15, compound v 2.03 g
(10 mmol) and 2.8 g (15 mmol) of 3,4-dimethoxybenzyl chloride (synthesized from 3,4-dimethoxybenzyl alcohol and thionyl chloride) to give [1- (2-azidoethyl) -3. -(3,4-Dimethoxybenzyl) -2-imidazolidinylidene] 3.11 g (88.1%) of propanedinitrile was obtained as white crystals.
Next, the compound 18 was obtained as a pale yellow oil in the same manner as in the method for converting the compound w to the compound 15 described in Example 15.

Melting point of 1.5 oxalate 0.5 hydrate: 14
9-150 ° C Elemental analysis: C ₂₈ H ₃₆ N ₆ O ₃ 1.5 (CO ₂ H) ₂ H
Calculated value (%) as ₂ O; C 57.40, H 6.22, N 1
2.96 actual value (%); C 57.56, H 6.00, N 1
2.94 MS (m / z): 504 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.85 (3H, m), 6.10 (2H, s),
4.68 (2H, s), 3.88 (6H, s), 3.77 (2H, s), 3.61 (6H, s)
m), 3.46 (2H, s), 2.94 (2H, t, J = 6.2Hz), 2.41 (4H,
m), 1.61 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 19 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (4-fluorobenzyl) -2-imidazolidinylidene} propanedinitrile (Compound 19) According to the method described in Example 15, compound v 2.03 g
(10 mmol) and 4-fluorobenzyl bromide 2.8
By reacting 3 g (15 mmol), [1-
(2-azidoethyl) -3- (4-fluorobenzyl)
-2-imidazolidinylidene] propanedinitrile was obtained as white crystals (2.90 g, 93.2%). Then, this was obtained in the same manner as in the method for converting compound w to compound 15 described in Example 15 to obtain compound 19 as a pale yellow oil.

1.5 Melting point of oxalate: 139-140.5
℃ Elemental _{analysis: C 26 H 31 N 6 OF} · 1.5 (CO 2 H) calcd _{2 (%); C 58.28,} H 5.73, N 1
4.06 actual value (%); C 58.28, H 5.72, N 1
4.01 MS (m / z): 462 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.11 (4H, m), 6.11 (2H, s),
4.73 (2H, s), 3.78 (2H, s), 3.75 (6H, m), 3.47 (2H,
s), 2.94 (2H, t, J = 6.2Hz), 2.39 (4H, m), 1.55 (6H,
m) IR (KBr; cm ^-1 ): 2200, 2160

Example 20 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (3-picolyl)-
2-imidazolidinylidene @ propandinitrile (compound 20) According to the method described in Example 15, compound v 2.6 g (1
2.79 mmol) and 2.5 g of 3-picolyl chloride (synthesized from 3-picolyl chloride hydrochloride and potassium carbonate)
(19.6 mmol) to give [1- (2
-Azidoethyl) -3- (3-picolyl) -2-imidazolidinylidene] propanedinitrile was obtained as a pale yellow oil (1.34 g, 35.5%). Then, this was used in Example 15
Compound 20 as pale yellow oil was obtained in the same manner as in the method for converting compound w to compound 15 described in (1).

Melting point of oxalate: 154.5-155 ° C. Elemental analysis: Calculated (%) as C ₂₅ H ₃₁ N ₇ O · 2 (CO ₂ H) ₂ : C 55.67, H 5.64 , N 1
5.67 found (%); C 55.75, H 5.88, N 1
5.67 MS (m / z): 445 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 8.59 (2H, m), 7.71 (1H, m),
7.34 (1H, m), 6.14 (2H, s), 4.80 (2H, s), 3.78 (2H,
s), 3.62 (6H, m), 3.52 (2H, s), 2.91 (2H, m), 2.44 (4H,
m), 1.53 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 21 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (3,4-dichlorobenzyl) -2-imidazolidinylidene} propanedinitrile (compound 21) According to the method described in Example 15, compound v 2.16 g (1
0.64 mmol) and 3,4-dichlorobenzyl chloride
By reacting 3.1 g (15.86 mmol) [1
-(2-azidoethyl) -3- (3,4-dichlorobenzyl) -2-imidazolidinylidene] propanedinitrile was obtained as a white oil (1.22 g, 31.7%). Next, Compound 21 was obtained in the same manner as in the conversion of Compound w to Compound 15 described in Example 15 to give pale yellow oily Compound 21.

Melting point of 1.5 oxalate 0.5 hydrate: 13
5.5-137 ° C. Elemental _{analysis: C 26 H 30 N 6 OCl} 2 · 1.5 (CO 2 H) 2
・ Calculated value (%) as 0.5H ₂ O; C 52.97, H 5.21, N 1
2.78 Found (%); C 53.11, H 5.31, N 1
2.82 MS (m / z): 513 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.32 (3H, m), 6.11 (2H, s),
4.72 (2H, s), 3.78 (2H, s), 3.61 (6H, m), 3.45 (2H,
s), 2.95 (2H, t, J = 6.2Hz), 2.37 (4H, m), 1.48 (6H,
m) IR (KBr; cm ^-1 ): 2200, 2155

Example 22 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3-benzohydryl-2
-Imidazolidinylidene @ propanedinitrile (compound 22) According to the method described in Example 15, compound v 2.03 g
(10 mmol) and 3.7 g of bromodiphenylmethane (15
) To give [1- (2-azidoethyl) -3-benzohydryl-2-imidazolidinylidene] propanedinitrile as pale yellow crystals, 1.76.
g (47.7%). Next, Compound 22 was obtained in the same manner as in the conversion of Compound w to Compound 15 described in Example 15 to give Compound 22 as a pale yellow oil.

Melting point of dioxalate 0.5 hydrate: 115.
5-116.5 ° C. Elemental _{analysis: C 32 H 36 N 6 O} · 2 (CO 2 H) 2 · 0.5H
Calculated value (%) as ₂ O; C 60.92, H 5.82, N 1
1.84 actual value (%); C 60.72, H 6.05, N 1
2.11 MS (m / z): 520 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 7.29 (10H, m), 6.10 (2H, s),
3.77 (2H, s), 3.60 (7H, m), 3.44 (2H, s), 2.95 (2H, t,
J = 6.19 Hz), 2.26 (4H, m), 1.44 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Example 23 {1- [2-[(5-Piperidinomethyl-2-furanyl) methylamino] ethyl] -3- (3-propargyl)
-2-imidazolidinylidene @ propandinitrile (Compound 23) Compound v 2.03 g according to the method described in Example 15.
(10 mmol) and 1.12 g (15.03 mmol) of 3-chloropropyne to give [1- (2-azidoethyl) -3- (3-propargyl) -2-imidazolidinylidene] propanedinitrile. As a light brown oil
1.73 g (71.8%) was obtained. Next, this was obtained in the same manner as in the method for converting compound w to compound 15 described in Example 15 to obtain pale yellow oily compound 23.

Melting point of 1.5 oxalate monohydrate: unmeasurable due to amorphous Elemental analysis: C ₂₂ H ₂₈ N ₆ O 1.5 (CO ₂ H) ₂ .H ₂
Calculated value (%) as O; C 55.04, H 6.10, N 1
5.40 Found (%); C 55.11, H 6.02, N 1
5.51 MS (m / z): 392 (M ⁺ ) NMR (CDCl ₃ ) δ (ppm): 6.11 (2H, s), 4.37 (2H, d, J)
= 2.4Hz), 3.71 (9H, m), 3.47 (2H, s), 2.95 (2H, t, J
= 6.2Hz), 2.45 (4H, m), 1.55 (6H, m) IR (KBr; cm ^-1 ): 2200, 2160

Reference Example 1 Tablet A tablet having the following composition is prepared by a conventional method. Compound 4 50mg Lactose 60mg Potato starch 30mg Polyvinyl alcohol 2mg Magnesium stearate 1mg Tar pigment Fine amount

Reference Example 2 Powder A powder having the following composition was prepared by a conventional method. Compound 8 100 mg Lactose 280 mg

Reference Example 3 Syrup A powder having the following composition was prepared by a conventional method. Compound 14 50 mg Purified sucrose 40 g Ethyl p-hydroxybenzoate 40 mg P-hydroxyhydroxybenzoate 10 mg Strawberry flavor 0.1 cc Add water to make a total volume of 100 cc.

[0137]

The compound (I) is a compound having an excellent gastrointestinal motility-enhancing action.

Continuing from the front page Examiner Tamotsu Tominaga (56) Reference European Patent Application Publication 413343 (EP, A2) (58) Field searched (Int. Cl. ⁷ , DB name) C07D 405/12 CA (STN) REGISTRY ( STN)

Claims (4)

(57) [Claims] 1. A compound of the formula (I) Wherein R ¹ represents unsubstituted or substituted phenyl, unsubstituted or substituted aralkyl, lower alkynyl, lower alkenyl or picolyl, and R ^{2 to} R ⁸ are the same or different and represent hydrogen or lower alkyl. Furan derivatives or pharmacologically acceptable salts thereof. 2. R ¹ Is unsubstituted or substituted phenyl, unsubstituted
Substituted or substituted aralkyl, lower alkenyl or pico
The furan derivative according to claim 1, which is ril, or its pharmacology.
A biologically acceptable salt. 3. R ¹ Is a substituted or unsubstituted aralkyl
The furan derivative according to claim 1 or a pharmacologically acceptable derivative thereof.
Salt to be carried. 4. R ^Two ~ R ⁸ Is hydrogen.
Or a pharmacologically acceptable salt thereof.