JPH04279581A - Furan derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an enhancing agent for digestive tract peristatic motion, having excellent enhancing action on the peristatic motion. CONSTITUTION:A compound shown by formula I [R<1> is H, (substituted)phenyl, (substituted)aralkyl, lower alkyl, lower alkenyl or picolyl; R<2> to R<8> are H or lower alkyl; R<1> to R<8> are not H at the same time], such as (+ or -) {1-[2-[5- piperidinomethyl-2-furanyl)methylamino]ethyl]-5-methyl-2-imidazolidiny lidene} propanedinitrile. The compound shown by formula I is obtained by reacting a compound shown by formula II (R<2a> and R<3a> are as shown as R<2> and R<3>; L is eliminable group) with sodium azide in an inert solvent such as DMF, reducing the prepared compound in an inert solvent such as ethyl acetate in the presence of a catalyst such as palladium-carbon to give a compound shown by formula III, reacting this compound with an equivalent of a compound shown by formula IV in a lower alkyl such as methanol and then reacting the resulting compound with a reducing agent such as sodium borohydride at 0 deg.C to room temperature.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to furan derivatives. The furan derivative has an excellent gastrointestinal motility-promoting effect and is useful as a gastrointestinal motility-promoting agent.

0002

[Prior Art] Furan derivatives related to the compounds of the present invention include, for example, the formula (A)

0003

[Case 2]

Ranitidine, which has a histamine H2 antagonistic effect represented by
Formula (B)

[0005]

[Chemical formula 3]

(In the formula, T represents CH2, O or S)
A ranitidine derivative having an anti-ulcer effect represented by (Japanese Unexamined Patent Publication Nos. 53-18557 and 55-153761), formula (C)

[0007]

[C4]

[0008] A furan derivative having a gastric motility-enhancing action represented by the following formula (wherein p represents 1 or 2)
3424) is known. Also, formula (D)

[0009]

[C5]

An application has been filed for furan derivatives including the furan derivative represented by the formula (Japanese Patent Application No. 1-211920, filed August 17, 1999).

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a furan derivative having an excellent effect of promoting gastrointestinal motility.

0012

[Means for Solving the Problems] The present invention provides formula (I)

00
13]

[C6]

(wherein R1 represents hydrogen, unsubstituted or substituted phenyl, unsubstituted or substituted aralkyl, lower alkynyl, lower alkenyl or picolyl; R2
~R8 are the same or different and represent hydrogen or lower alkyl. However, R1 to R8 are not hydrogen at the same time) or a pharmacologically acceptable salt thereof.

Although some of the compounds (I) may have optically active forms, the present invention includes all possible stereoisomers and mixtures thereof, including these optical isomers. In the definition of R1, examples of aralkyl include benzyl, phenethyl, benzhydryl, phenylpyropenyl, etc. having 7 to 13 carbon atoms, and examples of lower alkynyl include alkynyl having 2 to 5 carbon atoms, such as ethynyl, propargyl, etc. Examples of the lower alkenyl include alkenyl having 2 to 6 carbon atoms, such as vinyl, allyl, crotyl, prenyl, and methylbutenyl.

Examples of substituents in substituted phenyl and substituted aralkyl include lower alkyl, lower alkoxy, halogen, nitro, and the like having 1 to 3 substitutions, which may be the same or different. Examples of the alkyl moiety in lower alkyl and lower alkoxy include linear or branched carbon atoms such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and isopentyl. It will be done. Examples of halogens include fluorine, chlorine, bromine, and iodine.

The pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, such as inorganic salts such as hydrochloride, sulfate, phosphate, and maleate; Examples include organic acid salts such as fumarate and citrate. Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

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

[0019]

[Chemical 7]

[0020]

[Chemical formula 8]

[In the formula, R2a and R3a represent hydrogen in the definition of R2 and R3 in formula (I), R12 represents a hydroxyl protecting group, L represents a leaving group, and Me represents a methyl group. , R4 to R8 have the same meanings as above. ] Here, the hydroxyl protecting group represented by R12 is t-butyldimethylsilyl, tetrahydropyranyl, benzyl,
4-methoxybenzyl, etc., and the leaving group represented by L means sulfonates such as tosylate and mesylate, or halogens such as chlorine, bromine, and iodine.

First, compound (IVa) is compound (II)
and an equivalent amount of compound (IIIa) in tetrahydrofuran,
In aprotic polar solvents such as dimethylformamide,
It can be obtained by reaction at room temperature in a halogenated hydrocarbon such as methylene chloride or chloroform or in the absence of a solvent. Compound (VIa) can be obtained by reacting compound (IVa) and an equivalent amount of compound (Va) at 50 to 100°C in the absence of a solvent. The reaction is preferably carried out under reduced pressure.

The conversion of compound (VIa) to (VIIa) is carried out according to conventional methods. For example, the compound (V
IIa) is a compound (VI
It is obtained by reacting a) 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. In addition, when L is a halogen, by reacting the compound (VIa) with a halogenating agent such as thionyl chloride, phosphorus pentachloride, or phosphorus tribromide, the above-mentioned sulfonates can be reacted with lithium chloride, lithium bromide, or the like. Obtained by reacting with lithium iodide etc.

Compound (VIIa) is compound (VIIIa
) in tetrahydrofuran, dimethylformamide, etc. in the presence of 1 to 3 equivalents of a strong base such as potassium t-butoxy, sodium hydride, diazabicycloundecene, etc.
It is obtained by reacting at 0°C to room temperature for 0.5 to 1 hour. Compound (VIIIa) can be converted to compound (IXa) according to a conventional method. For example, in compound (IXa), when R12 is a t-butyldimethylsilyl group or a tetrahydropyranyl group, compound (VIIIa) is dissolved in an alcohol such as methanol or ethanol, a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid, or p-
By reacting at 0°C to room temperature for 3 to 18 hours in the presence of an organic acid such as toluenesulfonic acid, or when R12 is a benzyl group, hydrogen is added in the presence of a catalytic amount of palladium-carbon in an alcohol such as ethanol. By adding, or when R12 is a 4-methoxybenzyl group, in the presence of a catalytic amount of water in methylene chloride, 2 to 3 equivalents of 2,3
It is obtained by reacting with an oxidizing agent such as -dichloro-5,6-dicyano-p-benzoquinone.

The conversion of compound (IXa) to compound (Xa) is carried out by converting the aforementioned compound (VIa) into compound (VIIa).
This can be done in the same way as for. Compound (X
In Ia), compound (Xa) and 5 to 10 equivalents of sodium azide are mixed in an inert solvent such as dimethylformamide,
It is obtained by reacting at 50 to 80°C for 1 to 10 hours. Compound (XIIa) is prepared by reducing compound (XIa) using a suitable reduction method, for example, by adding 2 to 5 equivalents of triphenylphosphine in an inert solvent such as toluene or ethyl acetate.
By reacting an equivalent amount of water at 50° C. to the boiling point of the solvent for 3 to 7 hours, in a lower alcohol such as ethanol or an inert solvent such as ethyl acetate, in the presence of a catalyst such as palladium on carbon, It is obtained by reacting at room temperature to 50° C. for 6 to 12 hours in a hydrogen atmosphere at normal pressure. Compound (XIIa) can also be isolated as a salt with an organic acid such as fumaric acid, maleic acid, or oxalic acid.

Compound (Ia) is prepared by mixing Compound (XIIa) and 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. It is obtained by reacting for 24 hours and then reacting for 1 to 6 hours at 0°C to room temperature in the presence of a suitable reducing agent such as sodium borohydride.

[0027]

[Chemical formula 9]

[0028]

[Chemical formula 10]

[In the formula, one or both of R2b and R3b represents lower alkyl, R5a represents hydrogen in the definition of R5 in formula (I), Hal represents chlorine, bromine, or iodine, and R12 and R13 are different and each represents a hydroxyl protecting group as defined above, and R4 and R6 to R8 are defined as defined above. ] Compound (II)
and Compound (Vb) to obtain Compound (IVb) according to the method described in Method 1, and then convert it into Compound (I
Compound (VIb-1) by reacting with IIb)
get.

From compound (VIb-1) to compound (XV)
The conversion to is carried out according to conventional methods. For example, in compound (XV), when R13 is a t-butyldimethylsilyl group, compound (VIb-1) is replaced with tetrahydrofuran,
0.degree. C. to room temperature in the presence of 1 to 3 equivalents of t-butyldimethylchlorosilane and a suitable base such as imidazole in an inert solvent such as dimethylformamide.
It is obtained by reacting for 5 to 3 hours.

Compound (VIb-2) from compound (XV)
Conversion to is achieved by various methods depending on the types of R12 and R13. For example, R12 is a benzyl group, R
When 13 is a t-butyldimethylsilyl group, hydrogenation can be performed in the presence of a suitable catalyst such as palladium-carbon, or when R12 is a 4-methoxybenzyl group, R
When 13 is a t-butyldimethylsilyl group, it can be obtained by reacting with 2 to 3 equivalents of 2,3-dichloro-5,6-dicyano-p-benzoquinone in methylene chloride in the presence of a catalytic amount of water. Can be done. Furthermore, when R12 is a tetrahydropyranyl group and R13 is a t-butyldimethylsilyl group, treatment with an appropriate Lewis acid such as magnesium bromide or dimethylaluminum chloride in an inert solvent such as methylene chloride or diethyl ether is performed. It can be obtained by

Hereinafter, compound (VI-2) to compound (I
The conversion to b) can be carried out in the same manner as the method for obtaining compound (Ia) from compound (VIa) described in Method 1.

[0033]

[Chemical formula 11]

[In the formula, R1a is R1 in formula (I)]
represents unsubstituted or substituted aralkyl, lower alkynyl, lower alkenyl or picolyl, and R2 to
R8 and Hal have the same meanings as 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. Thereafter, compound (XVIII) is reacted according to the method for converting compound (XIa) to compound (Ia) described in Method 1 to obtain compound (Ic).

[0035]

[Chemical formula 12]

[0036]

[Chemical formula 13]

[In the formula, R1b is R1 in formula (I)]
represents unsubstituted or substituted phenyl, R4a
represents hydrogen in the definition of R4 in formula (I), H
al-a and Hal-b are the same or different and represent a halogen as defined above, and R2, R3, R5 to R
8 and L have the same meanings as above. ] Compound (XXI) is prepared by combining compound (II) and 1 to 2 equivalents of compound (XX) in an inert solvent such as dimethylformamide or tetrahydrofuran in the presence of a strong base such as t-butoxypotassium or diazabicycloundecene. ,60℃～
Obtained by heating at the boiling point of the solvent. Compound (X
Compound (XXIII) is obtained by reacting XI) with compound (XXII) according to the method for converting compound (IVa) to compound (VIa) described in Method 1. Then, compound (XXIII) was converted into compound (VIIa) according to the method described in Method 1 from compound (VIa) to compound (VIIa).
Compound (XXIV), further compound (XXIV),
Compound (XXV) is obtained in the same manner as the method for converting compound (VIIa) to compound (VIIIa). Next, compound (XXV) and compound (XXVI) were mixed in the presence of a base,
By reacting in an inert solvent, the compound (XXVII
). As the base, potassium hydroxide, sodium hydride, etc. are used, and as the inert solvent, tetrahydrofuran, dimethylformamide, etc. are used alone or in combination. The reaction is usually completed in 5 to 48 hours at a temperature ranging from 0°C to the boiling point of the solvent.

Compound (Id) is compound (XXVII)
from compound (Xa) described in Method 1 to compound (Ia
) can be obtained by processing in the same manner as for The intermediates and target compounds in the above-mentioned production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can be done. Further, the intermediate can also be subjected to the next reaction without being particularly purified.

When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, or if it is obtained in a free form, it can be purified by a conventional method. All you have to do is form salt. Specific examples of compound (I) are shown in Tables 1-1 and 1-2. In addition, compounds 1, 2,...
... corresponds to the compounds obtained in Examples 1, 2, ....

[0040]

[Table 1]

[0041]

[Table 2]

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

Test Example 1 Acute toxicity test Body weight 20±1g
A group of 3 DD male mice were used, and the test compound was administered orally (
po: 300 mg/kg). The state of death was observed 7 days after administration, and the minimum mortality dose (MLD) value was determined. The results are shown in Tables 2-1 and 2-2.

Test Example 2 Gastrointestinal hypermotility test Weight 25
The ileum of a male Hartley guinea pig weighing 0 to 400 g was
~3 cm was excised. A Tyrode liquid tank (capacity 30 m) at 37 ± 1°C supplied with a mixed gas of 95% oxygen and 5% carbon dioxide.
l), and the contraction movement in the longitudinal direction was recorded using an isotonic transducer. Transmural electrical stimulation had a duration of 1 ms, an interstimulus interval of 10 s, and a Supramaximal (
The test was carried out under the following conditions: supra maximal).

The test compound was dissolved or suspended in physiological saline and administered into the tank. The effect on transmural stimulation was calculated from the contraction height before administration of the test compound (A) and the contraction height after administration of the test compound (B) according to the following formula. Amplification rate (%) = (B-A)/A x 100 The result is the second
Shown in Tables -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 effect of promoting gastrointestinal motility. Furthermore, the compound does not exhibit histamine H2 antagonistic activity and is excellent in isolation from undesirable effects such as suppression of gastric acid secretion. Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as is, but it is usually preferable to provide it as various pharmaceutical preparations. Additionally, these pharmaceutical preparations are for use in animals and humans.

[0049] It is preferable to use the most effective administration route for treatment, and examples include oral or parenteral routes (eg, rectal, oral, subcutaneous, intramuscular, intravenous, etc.). Examples of dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, and injections.

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

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

Formulations for enteral administration are presented as suppositories with the usual carriers such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids, and the like. In addition, these parenteral preparations also include diluents, fragrances, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc., as exemplified for oral preparations. It is also possible to add one or more auxiliary ingredients selected from:

The effective dose and frequency of administration of Compound (I) or a pharmacologically acceptable salt thereof will vary depending on the dosage form, age and weight of the patient, the nature or severity of the symptoms to be treated, etc. The usual dosage is 0.01~ per day.
The dose is 1000 mg/person, and the administration frequency is preferably once a day or in divided doses.

[0054]

[Example] Examples and reference examples are shown below.

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

NMR (CDCl3) δ (ppm)
:7.33(1H, bs), 4.46(1H, m
), 3.76 (6H, m), 2.63 (3H,
s), 1.61 (6H, m)

Compound a
A mixture of 18.41 g (68.95 mmol) and 5.17 g (68.93 mmol) of 1-amino-2-propanol was added to the
Heated at 0°C for 0.5 hour. The reaction mixture was subjected to silica gel column chromatography (chloroform:methanol=
By 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%) was obtained as a white crystalline substance.

Melting point: 92.5-94.0°C NMR (CD
Cl3) 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)

Compound b
13.0 g (44.37 mmol) of pyridine 20
0 ml, 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 brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The residue was dissolved in 400 ml of tetrahydrofuran, and 7.42 g (48.81
A solution of 50 ml of tetrahydrofuran (mmol) 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 brine. The organic layer was dried with anhydrous magnesium sulfate,
The solvent was distilled off. Next, the residue was dissolved in 200 ml of methanol.
850 mg of p-toluenesulfonic acid monohydrate (
After adding 4.47 mmol), the mixture was stirred at room temperature for 15 hours. After neutralizing the reaction mixture, it was concentrated under reduced pressure, water was added to the residue, and the precipitated white crystals were collected by filtration.
1-[2-(2-hydroxyethyl)]-5-methyl-
6.82 g (yield 80.0% from compound b) of 2-imidazolidinylidene}propanedinitrile (compound c) was obtained.

Melting point: 124.5-125.0°CNM
R(DMSO-d6)δ(ppm): 7.80(1
H, bs), 3.59 (7H, m), 3.14
(1H, bs), 1.22 (3H, d, J=5
．． 8Hz)

Compound c 6.42g (33
．． 44 mmol) was dissolved in 60 ml of pyridine, and 5.18 ml of methanesulfonyl chloride (66 mmol) was dissolved under ice-cooling.
96 mmol) was added dropwise. After stirring the reaction solution for 1 hour, the solvent was distilled off under reduced pressure, and methylene chloride was added to the residue to give a 1N solution.
It was washed with hydrochloric acid, saturated aqueous sodium bicarbonate, and then saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. Dissolve the residue in 100 ml of dimethylformamide,
Sodium azide 6.52g (100.31 mmol)
was added and stirred at 80°C for 2 hours. After concentrating the reaction solution under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off,
By washing the obtained crude crystals with a mixed solvent of ethyl acetate and 2-propyl ether, (±)-{1-(2-azidoethyl)-5-methyl-2-imidazolidinylidene}propanedinitrile (compound d ) 6.34 g (yield 87.3% from compound c) was obtained as a white crystalline substance.

Melting point: 90.5-91.5°C NMR (CD
Cl3) δ (ppm): 6.02 (1H, b
s), 3.0-4.3 (7H, m), 1.35 (
3H, d, J=6.2Hz)

Compound d
6.23 g (28.71 mmol) of ethyl acetate
Triphenylphosphine 11.28 mL dissolved in 00 ml
g (43.06 mmol) was added, and the mixture was stirred at 60° C. for 10 minutes. Next, 5.16 ml (287.11 mmol) of water was added and the mixture was further stirred at 60° C. for 6 hours. After concentrating the reaction solution under reduced pressure and repeating toluene azeotropy twice, the residue was dissolved in 100 ml of ethanol and 1 ml of fumaric acid was added.
．． 99 g (17.23 mmol) were added. The precipitated white crystals were collected by filtration and 6.98 g (97.6%) of (±)-{
1-(2-aminoethyl)-5-methyl-2-imidazolidinylidene}propanedinitrile 1/2 fumarate (compound e) was obtained. Melting point: 157-159.5℃

5-Piperidinomethylfurfural 2.3
3 g (12.07 mmol) and 3.0 g (1
2.05 mmol) and triethylamine 3.4 ml (
24.44 mmol) and 150 m of ethanol
1 was added thereto, 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) was gradually added, and after the entire amount was added, the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, chloroform was added to the residue, and after washing with saturated brine, 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),
Pale yellow oily compound 1 3.43g (yield 77.4%)
I got it. 1.0 g (2.72 mmol) of Compound I was dissolved in 10 ml of ethanol, and 290 mg (2.72 mmol) of Compound I was dissolved in 10 ml of ethanol.
96 mmol) and stirred at room temperature. The precipitated white crystals were collected by filtration, and compound 1 monooxalate monohydrate 1.1
7 g (yield 89%) was obtained.

Melting point of monooxalate monohydrate: 157
-159.5℃ Elemental analysis: C20H28N6 O・(CO2 H)2
・Calculated value as H2O (%); C 55.45, H 6.77,
N 17.64 actual value (%); C 55.63,
H 6.87, N 17.84 MS (m/z): 3
68(M+) NMR(CDCl3) δ0pm): 6.21(
1H, bs), 6.06 (2H, s), 4.0
4 (2H, m), 3.74 (2H, s), 3.7
2 (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), 1.2
7 (3H, d, J = 5.9Hz) IR (KBr; c
m-1): 2200, 2160

Example 2 (±)-{1-[2-[(5-piperidinomethyl-2-
Furanyl)methylamino]propyl]-2-imidazolidinylidene}propanedinitrile (Compound 2) Example 1
According to the method of 20.76 g (122.
From 22.84 g (143.65 mmol) of [2-(2-tetrahydropyraniloxy)]propylamine) and [2-(2-tetrahydropyranyloxy)]propylamine, a pale yellow oily {[(methylthio)-2-(2
-tetrahydropyranyloxy)propylamino]methylene}propanedinitrile (compound f) 27.39 g (
A yield of 79.8%) was obtained. Then compound f 27.3
9 g (97.47 mmol) and ethanolamine 5.9
5g (97.54 mmol) of pale yellow oil {[2-
(2-tetrahydropyraniloxy)propylamino] [
(2-Hydroxy)ethylamino]methylene}propanedinitrile (compound g) 19.36g (67.6%)
I got it. Hereinafter, compound g is replaced with compound b in Example 1.
Compound 2 was obtained in the form of white crystals by treating in the same manner as for Compound 1.

Melting point: 129-130°C Elemental analysis: Calculated value (%) as C20H28N6O; C 65.19, H 7.66,
N 22.81 actual value (%); C 64.97,
H 7.60, N 23.08MS (m/z): 3
68 (M+) NMR (CDCl3) δ (ppm): 6.11
, 6.09 (each 1H, each d, J=3.12H
z), 5.89 (1H, bs), 3.81 (4H,
m), 3.49 (4H, m), 3.45 (2H
, s), 3.07 (1H, m), 2.39 (4
H, m), 1.59 (4H, m), 1.44 (
2H, m), 1.12 (3H, d, J=6.4
2Hz) IR (KBr; cm-1): 2200, 21
60

Example 3 (±)-{1-[[2-[(5-piperidinomethyl-2
-Furanyl)methylamino]-1-methyl]ethyl]-
2-Imidazolidinylidene}propanedinitrile (Compound 3) According to the method of Example 1, 21.74 g (1
27.88 mmol) and 20.33 g (1
{(methylthio)[1-methyl-[2-(2-tetrahydropyranyloxy)]ethylamino]methylene}propanedinitrile (
Compound h) 32.98 g (yield 91.8%) was obtained. Next, from 32.98 g (117.37 mmol) of compound h and 7.16 g (117.38 mmol) of ethanolamine, pale yellow oily {[[2-(2-tetrahydropyraniloxy)-1-methyl]ethylamino] was obtained. [(2-
22.0 g (yield: 64.0%) of hydroxy)ethylamino]methylene}propanedinitrile (compound i) was obtained. Thereafter, Compound i was treated in the same manner as in Example 1 from Compound b to Compound 1 to obtain Compound 3 as a pale yellow oil.

Melting point of monofumarate monohydrate: 89.0
-89.5℃ Elemental analysis: C20H28N6O・C4 H4 O4 ・
Calculated value as H2O (%); C 57.36, H 6.82,
N 16.72 Actual value (%); C 57.05,
H 7.04, N 16.89MS (m/z): 3
68 (M+) NMR (D2O; monofumarate monohydrate) δ (pp
m): 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, d
d, 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=6.78Hz)I
R (KBr; cm-1): 2200, 2160

00
70 Example 4 (±)-{1-[2-[(5-piperidinomethyl-2-
Furanyl)methylamino]ethyl]-4-methyl-2-
imidazolidinylidene}propanedinitrile (compound 4
) Compound II 316 mg (1.86 mmol) and [
336 mg (1.86 mmol) of 1-methyl-2-(4-methoxybenzyloxy)]ethylamine was dissolved in 10 ml of chloroform and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 v/v) to obtain a yellow oily {(methylthio)[1
-Methyl[2-(4-methoxybenzyloxy)]ethylamino]methylene}probandinitrile (compound j) 4
88 mg (yield 86.7%) was obtained.

NMR (CDCl3) 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)

[
Compound j 461 mg (1.52 mmol)
and 114 mg (1.52 mmol) of ethanolamine were heated at 80° C. for 1.5 hours while suctioning with a water aspirator. The reaction mixture was subjected to silica gel column chromatography (chloroform:methanol=30:1v/v
) to obtain 321 mg of {[1-methyl-[2-(4-methoxybenzyloxy)]ethylamino][(2-hydroxy)ethylamino]methylene}propanedinitrile (compound k). (63.9%)
I got it.

NMR (CDCl3) δ (ppm)
: 7.23, 6.84 (each 2H, each 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, d, J=6.41Hz)

314 mg (0.95 mmol) of compound k was dissolved in 3 ml of methylene chloride, and 1 ml of triethylamine was added.
60 mg (1.58 mmol) and 215 mg (1.43 mmol) of t-butyldimethylchlorosilane were added, and 1
Stirred for 6 hours. The reaction solution was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3 v/v) to give (±)-{[1-methyl-[2-(4-methoxybenzyloxy)]ethyl) as a colorless oil. Amino][(2-t-butyldimethylsiloxy)ethylamino]methylene}propanedinitrile (compound 1) 243 mg (yield 57.6%)
I got it.

NMR (CDCl3) 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)

240 mg (0.54 mmol) of Compound I was dissolved in a mixed solvent of 2 ml of methylene chloride and 0.1 ml of water, and 150 mg (0.5 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone was dissolved under ice cooling. .66 mmol) was added. After stirring the reaction solution at room temperature for 17 hours, insoluble matter was filtered off, and the filtrate was washed with saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform:methanol = 30:1).
(v/v), colorless crystals (±)-{
[1-methyl-(2-hydroxy)ethylamino] [(
2-t-butyldimethylsiloxy)ethylamino]methylene}propanedinitrile (compound m) 141 mg (
A yield of 80.6%) was obtained.

Melting point: 135.5-136°C NMR (
CDCl3) δ (ppm): 6.52 (1H,
bt, J=5.7Hz), 6.34(1H, b
t, 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)

Compound m9.
Dissolve 0 g (27.69 mmol) in 120 ml of pyridine, and add 4.3 m of methanesulfonyl chloride under ice cooling.
1 (55.58 mmol) was added dropwise. 1 of the reaction mixture
After stirring for an hour, the solvent was distilled off under reduced pressure. Methylene chloride was added to the residue, which was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in 100 ml of tetrahydrofuran, and diazabicycloundecene (DBU) 6.31
g (41.51 mmol) of tetrahydrofuran 20 m
1 solution 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 brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Then, the residue was dissolved in methanol.
Dissolve p-toluenesulfonic acid monohydrate 5 in 100 ml.
6. At room temperature after adding 26 mg (2.77 mmol).
Stirred for 5 hours. After neutralizing the reaction mixture, it 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]. Lyden] propane dinitrile (compound n) 4.78 g (yield from compound m 89.8
%) was obtained.

Melting point: 76.0-77.0°C NMR (DM
SO-d6) δ (ppm): 7.95 (1H,
bs), 4.89 (1H, m), 3.87 (2
H, m), 3.34 (4H, m), 3.29 (
1H, bt), 1.17 (3H, d, J=5.
82Hz)

Compound n was treated in the same manner as in Example 1 from compound b to compound 1 to obtain compound 4 as a pale yellow oil. Melting point of monooxalate 0.5 hydrate: 169.5-
173.0℃ Elemental analysis: C20H28N6 O・(C
O2 H)2 ・0.5 Calculated value as H2 O (%); C 56.52, H 6.68,
N 17.98 actual value (%); C 56.46,
H 6.71, N 18.26 MS (m/z): 3
68 (M+) NMR (D2O; monooxalate/0.5 hydrate) δ
(ppm): 6.75, 6.72 (each 1H, each d, 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=12.09H
z), 3.37 (3H, m), 2.96 (2H,
bt, J=11.91, 12.45Hz), 1
．． 85 (6H, m), 1.25 (3H, d, J
=6.23Hz) 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 as a pale yellow oil was obtained from Compound II and (+)-[1-methyl-2-(4-methoxybenzyloxy)]ethylamine.

1.5 Melting point of oxalate: 154-15
4.5℃ Elemental analysis: C20H28N6 O・1.5(
Calculated value (%) as CO2 H)2; C 54.8
6, H 6.21, N 16.69 Actual value (%
); C 54.92, H 6.39, N 17
．． 13MS (m/z): 368 (M+) IR (KBr; cm-1): 2200, 2160
Optical rotation: [α] D 20 = -4.5 (c = 0.5,
H2O)

Example 6 (+)-{1-[2-[(5-piperidinomethyl-2-
Furanyl)methylamino]ethyl]-4-methyl-2-
imidazolidinylidene}propanedinitrile (compound 6
) Compound II and (-)-[1-
Compound 6 as a pale yellow oil was obtained from methyl-2-(4-methoxybenzyloxy)]ethylamine. Melting point of 2 fumarate: 141-143 °C Elemental analysis:
Calculated value (%) as C20H28N6 O・2C4 H4 O4; C 55.99, H 6.04,
N 13.99 Actual value (%); C 56.06,
H 6.24, N 14.08MS (m/z): 3
68 (M+) IR (KBr; cm-1): 2200, 2160
Optical rotation: [α]D 20=+1.8 (c=0.5,
H2O)

Example 7 (±)-{1-[2-[[2-(5-piperidinomethyl-2-furanyl)ethyl]amino]ethyl]-2-imidazolidinylidene}propanedinitrile (compound 7) 5
-Piperidinomethylfurfural 3.2g (16.5
8 mmol) was dissolved in 65 ml of anhydrous tetrahydrofuran, the system was purged with nitrogen, and then cooled to -60°C. Methylmagnesium bromide diethyl ether solution (3M) 1
Add 0 ml (30.0 mmol) and heat to 0°C for 1 hour.
The temperature rose to . After adding a saturated aqueous ammonium chloride solution 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 sodium hydroxide solution. After extraction with ethyl acetate, 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 distilled under reduced pressure (150°C; 0.5 mmH
g) 1-(5-piperidinomethyl-2-furan)ethanol (compound o) as a colorless oil by 2.9
4 g (yield 84.7%) was obtained.

NMR (CDCl3) 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)

2.86 g (13.68 mmol) of compound o was dissolved in 100 ml of chloroform, and 44 g (5.5 g) of activated manganese dioxide was dissolved in 100 ml of chloroform.
05.75 mmol) was added and stirred vigorously for 2 days at room temperature. Insoluble matters were 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 obtain 5-piperidinomethyl-2-acetylfuran as a pale yellow oil. (Compound p) 2.48g (87.6%) was obtained.

NMR (CDCl3) δ (ppm)
: 7.13, 6.34 (1H each, d each, J=
3.15Hz), 3.62 (2H, s), 2.44
(3H, s), 2.42 (4H, m), 1.5
0 (6H, m)

Compound p 2.48g (
11.98 mmol) and [1-(2-aminoethyl)-
2-imidazolidinylidene]propanedinitrile 1/2
50 ml of ethanol was added to a mixture of 2.81 g (11.96 mmol) of fumarate and 3.5 ml (25.16 mmol) of triethylamine, 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) was gradually added, and after the entire amount was added, the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and after washing with saturated brine, 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 793 mg (yield 18.0%) of Compound 7 as a pale yellow oil.

Melting point of 1.5 oxalate/0.5 hydrate: 94.5-96.0°C Elemental analysis: C20H28N6 O/1.5 (CO2 H
)2 ・0.5 Calculated value (%) as H2O; 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 (CDCl3) 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=6.1Hz) IR (KBr; c
m-1) :2200, 2160

Example 8 (±)-{1-[2-[[5-(1-piperidinoethyl)-2-furanyl]methylamino]ethyl-2-imidazolidinylidene}propanedinitrile (Compound 8) Example 7, 2.48 g of compound p and [1-(2-
5-(1-piperidinoethyl)furfural 1.93 g (9.32 mmol) and [1 -(2-aminoethyl)-2-imidazolidinylidene]propanedinitrile 1/2 fumarate 2.
08g (8.85 mmol) and triethylamine 2.6
ml (18.7 mmol) was used in the same manner as in Example 7 to obtain 82.95 g of a pale yellow oily compound (yield 90.
5%).

Melting point of dioxalate/0.5 hydrate:
133.5-134℃ Elemental analysis: C20H28N6 O・2(CO2 H)2
・Calculated value (%) as 0.5 H2O; C 51.70, H 5.97
, N 15.07 Actual value (%); C 51.55
, H 6.12, N 14.95MS (m/z):
368 (M+) NMR (CDCl3) δ (ppm): 6.35
(1H, bs), 6.12, 6.03 (1H each
, respectively d, J=3.08Hz), 3.78(2H
, s), 3.66 (7H, m), 2.91 (2
H, t, J=6.04, 6.26Hz), 2.
37 (4H, m), 1.97 (1H, bs), 1
．． 52 (6H, m), 1.38 (3H, d, J
=7.03Hz) IR (KBr; cm-1): 22
00, 2160

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

Melting point: 172.5-174°C NMR (
DMSO-d6) δ (ppm): 10.46 (
1H, bs), 7.25 (5H, m), 2.4
A mixture of 4.0 g (18.6 mmol) of 8(3H, s) compound q and 1.13 g (18.52 mmol) of ethanolamine was heated at 80° C. for 1.5 hours while being suctioned with a water aspirator. The reaction mixture was subjected to silica gel column chromatography (chloroform:methanol=20:1 v/
v), 1.58 g (yield 37.4%) of {(phenylamino)[(2-hydroxy)ethylamino]methylene}propanedinitrile (compound r) was obtained as a pale yellow oil.

NMR (DMSO-d6) δ (ppm
): 9.32 (1H, bs), 7.71 (1H
, bt), 7.18 (5H, m), 5.07 (
1H, bt), 3.52 (2H, m), 3.3
1 (2H, m)

Compound r 1.5g (6
．． 58 mmol) was dissolved in 15 ml of pyridine, and under ice-cooling, 1.0 ml of methanesulfonyl chloride (12.93 mmol) was dissolved in 15 ml of pyridine.
After dropping 1 mmol), the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and methylene chloride was added to the residue, which was then washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was dissolved in 10 ml of tetrahydrofuran, and 1.1 g of DBU (7.24
mmol) and stirred for 0.5 h. The reaction solution was concentrated under reduced pressure, and methylene chloride was added to the residue, which was then washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting crude crystals were washed with 2-propyl ether (1-phenyl-2
-imidazolidinylidene) propane dinitrile (compound s) (1.19 g (yield 86.2% from compound r)) was obtained as a pale yellow crystalline substance.

Melting point: 205-206°C NMR (CD
Cl3 + DMSO-d6) 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 the mixture was cooled with ice.
270 mg (6.75 mmol) of 60% sodium hydride was added. After adding the entire amount, stir at room temperature for 0.5 hour, and add 4.4 ml (52.8 ml) of 1-bromo-2-chloroethane.
3 mmol) and 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. Methylene chloride was added to the residue, 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 (chloroform:methanol = 50:1 v/v) [
1-(2-chloroethyl)-3-phenyl-2-imidazolidinylidene]propanedinitrile (compound t)1.
12 g (78.3%) was obtained as a white crystalline product.

Melting point: 168.5-170°C NMR (
CDCl3) 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 at 80° C. for 7 hours in 10 ml of dimethylformamide. The solvent was distilled off under reduced pressure, and methylene chloride was added to the residue, which was washed with saturated 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 obtain [1-(2-azidoethyl)-3-phenyl-2-imidazolidinylidene]propanedinitrile (compound u) 1.06g (yield 93.
8%) was obtained as a white crystalline substance.

Melting point: 113.5-115°C NMR (
CDCl3) δ (ppm): 7.29 (5H,
m), 3.91 (4H, m), 3.79 (4H
, m)

[0101] Compound 9 as a pale yellow oil was obtained in the same manner as in Example 1 from Compound d to Compound I. 1.5 Melting point of oxalate: 104-106 °C Elemental analysis: C25H30N6 O. 1.5 (CO2 H)
Calculated value (%) as 2; C 59.46, H
5.88, N 14.86 Actual value (%); C 5
9.25, H 6.01, N 14.75MS (
m/z): 430 (M+) NMR (CDCl3) δ (ppm): 7.29
(5H, m), 6.11 (2H, s), 3.8
6 (4H, m), 3.79 (2H, s), 3.
73 (2H, t, J=6.2Hz), 3.48(
2H, s), 2.98 (2H, t, J=6.2
Hz), 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 (41.12 mmol) and Compound II 7.0 g (4
1.18 mmol), 2.2 g (18.2%;
Step 6) was obtained as white crystals. Next, this product was reacted in accordance with the method from 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 ℃ Elemental analysis: C26H32N6 O・ 1.5 (CO2
H) Calculated value (%) as 2 ・0.5 H2 O; C 56.86, H 5.89
, N 13.26 Actual value (%); C 56.59
, H 5.94, N 13.16 MS (m/z):
444 (M+) NMR (CDCl3) δ (ppm): 7.18
(4H, m), 6.12 (2H, s), 3.8
4 (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):2
200, 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 3.1
5 g (29.44 mmol) and 5.0 g of compound II
(29.41 mmol), 0.8 g (9.3%;
Step 6) was obtained as a white crystalline substance. Next, this product was reacted in accordance with the method from compound d to compound 1 described in Example 1 to obtain compound 11 as a pale yellow oil.

1.5 Melting point of oxalate: 132-1
34℃ elemental analysis: C26H32N6 O・1.5(
Calculated value (%) as CO2 H)2; C 60.0
9, H 6.09, N 14.50 actual value (%
); C 59.94, H 6.37, N 14
．． 29MS (m/z): 444 (M+) NMR (D2O; 1.5 oxalate) δ(p
pm): 7.29 (4H, m), 6.75 (2
H, s), 4.42 (2H, s), 4.35 (2
H, s), 4.03 (4H, m), 3.87 (
2H, m), 3.47 (4H, m), 2.97
(2H, m), 2.36 (3H, s), 1.8
5(6H, m)IR (KBr; cm-1): 22
00, 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, p-anisidine 5.1
g (41.46 mmol) and Compound II 7.0 g (4
1.18 mmol), [1-(2-azidoethyl)
-3-(4-methoxyphenyl)-2-imidazolidinylidene]propanedinitrile 3.73 g (29.3%
; Step 6) was obtained as a white crystalline substance. Next, this product was reacted in accordance with the method from 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: C26H32N6 O2 1.5 (CO
2 H)2 ・0.5 Calculated value (%) as H2 O; C 57.61, H 6.00
, N 13.90 Actual value (%); C 57.76
, H 6.14, N 14.03 MS (m/z):
460 (M+) NMR (CDCl3) δ (ppm): 7.15
, 6.86 (2H each, d each, J=8.89H
z), 6.08 (2H, s), 3.77 (3H,
s), 3.76 (4H, m), 3.75 (2H
, s), 3.71 (2H, t, J=5.91H
z), 3.45 (2H, s), 2.96 (2H,
t, J=5.92Hz), 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-anidine 3.62
g (29.43 mmol) and Compound II 5.0 g (
29.41 mmol), 1.28 g (14.1 mmol) of [1-(2-azidoethyl)-3-(3-methoxyphenyl)-2-imidazolidinylidene]propanedinitrile
%; 6 steps) was obtained as a light brown crystalline substance. Next, this product was reacted according to the method from compound d to compound l described in Example 1 to obtain compound 1 as a pale yellow oil.
I got 3.

1.5 Melting point of oxalate: 127.5
-129℃ Elemental analysis: C26H32N6 O2 ・1
．． Calculated value (%) as 5(CO2 H)2; C 5
8.48, H 5.92, N 14.11 Actual value (%); C 58.23, H 6.24, N
14.15 MS (m/z): 4 60 (M+) NMR (D2O; 1.5 oxalate) δ(p
pm): 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), 3.85 (3H, s),
3.48 (2H, m), 3.46 (2H, t,
J=6.78Hz), 2.97(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, o-anisidine 7.2
4 g (58.86 mmol) and Compound II 10.0
g (58.82 mmol), 3.04 g (16.
7%; 6 steps) was obtained as a white crystalline substance. Next, this product was reacted according to the method from compound d to compound l described in Example 1 to obtain compound 1 as a pale yellow oil.
I got 4.

1.5 Melting point of oxalate monohydrate:
132-136 °C Elemental analysis: C26H32N6 O2 ・1.5 (CO2
H) Calculated value (%) as 2 ・H2 O; C 56.76, H 6.08
, N 13.70 Actual value (%); C 57.00
, H 6.03, N 13.51 MS (m/z):
4 60 (M+) NMR (CDCl3) δ (ppm): 7.24
(2H, m), 6.96 (2H, m), 6.0
8 (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) in 40 ml of dimethylformamide, and 946 mg (23 mmol) of 60% sodium hydride was dissolved under ice-cooling.
．． 65 mmol) was added. After adding the entire amount, it was stirred for 0.5 hours, and then 2.46 ml of α-bromotoluene (
20.69 mmol) was added dropwise. The reaction mixture was reduced to 0.
After stirring for 5 hours, the solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed with saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. [1-(
4.47 g of 2-azidoethyl)-3-benzyl-2-imidazolidinylidene]propanedinitrile (compound w)
(77.5%) was obtained as a white crystalline product.

Melting point: 75.5-76°C NMR (CDCl3) δ (ppm): 7.28
(5H, m), 4.75 (2H, s), 3.6
9 (4H, s), 3.56 (4H, m)

011
4] Dissolve 2.0 g (6.83 mmol) of compound w in 200 ml of ethanol, add 10% palladium-carbon 1
00 mg (5 w/w%) was added and stirred for 1 hour at room temperature under a hydrogen atmosphere. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to obtain 1.78 g (97.8 g) of [1-(2-aminoethyl)-3-benzyl-2-imidazolidinylidene]propanedinitrile (compound %) was obtained.

0.5 Melting point of fumarate: 169-1
70°C NMR (CDCl3) 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)

0
116] Compound x 1.94g (5.96 mmol)
and 1.16 g of 5-piperidinomethylfurfural (6.
0 mmol), a pale yellow oily compound 15 was obtained in the same manner as in Example 1 from compound e to compound 1.
1.85g (69.8%) was obtained.

1.5 Melting point of oxalate: 143.5
-145℃ Elemental analysis: C26H32N6 O・1.5
Calculated value (%) as (CO2 H)2; C 60.
09, H 6.09, N 14.50 Actual value (
%); C 59.78, H 6.15, N 1
4.69MS (m/z): 444(M+) NMR (DMSO-d6; 1.5 oxalate) δ(
ppm): 7.29 (5H, m), 6.54 (
2H, s), 4.73 (2H, s), 4.14
(2H, s), 4.07 (2H, s), 3.6
6 (8H, m), 3.07 (4H, m), 1.
67 (6H, m)IR (KBr; cm-1): 22
00, 2160

Example 16 {1-[2-[(5-piperidinomethyl-2-furanyl)methylamino]ethyl]-3-[4-(2-methyl-
2-Butenyl)]-2-imidazolidinylidene}propanedinitrile (Compound 16) Compound v 2.03 according to the method described in Example 15
g (10 mmol) and 1-bromo-3-methyl-2
-By reacting 2.24 g (15.03 mmol) of butene, {1-[2-azidoethyl]-3-[
4-(2-Methyl-2-butenyl)]-2-imidazolidinylidene}propanedinitrile as a white crystalline substance 2
．． 35g (86.6%) was obtained. Next, this product was treated in the same manner as in Example 15 to obtain Compound 15 from Compound w to obtain Compound 16 as a pale yellow oil.

Melting point of 2-oxalate: 159.5-16
1℃ Elemental analysis: C24H35N6 O・2 (CO2
H) Calculated value (%) as 2; C 55.71,
H 6.51, N 13.92 Actual value (%); C
55.68, H 6.54, N 13.91M
S (m/z): 4 23 (M+) NMR (DMSO-d6; 2 oxalate) δ (ppm
): 6.56 (2H, s), 5.24 (1H,
m), 4.10 (6H, m), 3.67 (8H
, m), 3.10 (4H, m), 1.79 (3
H, 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} Propanedinitrile (Compound 17) Compound v 2.3 according to the method described in Example 15
By reacting 2 g (11.42 mmol) with 3.37 g (17.1 mmol) of 3-bromo-1-phenyl-1-propene, {1-[2-azidoethyl]-3-[3-( 1-phenyl-1-propenyl)]
3.34 g (91.5%) of 2-imidazolidinylidene}propanedinitrile was obtained as a pale yellow oil. Next, this product was treated in the same manner as in Example 15 to prepare Compound 15 from Compound w to obtain Compound 17 as a pale yellow oil.
I got it.

Melting point of monooxalate monohydrate: 147.
5-148℃ Elemental analysis: C28H34N6 O・(CO2 H) 2
・Calculated value as H2O (%); C 62.27, H 6.62
, N 14.52 Actual value (%); C 62.12, H 6.51
, N 14.24 MS (m/z): 470 (M+) NMR (CDCl3) δ (ppm): 7.33
(5H, m), 6.34 (2H, m), 6.1
0(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 1
8 {1-[2-[(5-piperidinomethyl-2-furanyl)methylamino]ethyl]-3-(3,4-dimethoxybenzyl)-2-imidazolidinylidene}propanedinitrile (Compound 18) Example 15 Compound v 2.0 according to the method described in
[1-(2-azidoethyl)- 3.11 g (88.1%) of 3-(3,4-dimethoxybenzyl)-2-imidazolidinylidene]propanedinitrile was obtained as a white crystalline substance. Next, this product was treated in the same manner as in Example 15 to prepare Compound 15 from Compound w to obtain Compound 1 as a pale yellow oil.
I got 8.

Melting point of 1.5-oxalate/0.5-hydrate:
149-150℃ Elemental analysis: C28H36N6 O3 ・1.5 (CO2
H) Calculated value as 2 ・H2 O (%); C 57.40, H 6.22
, N 12.96 Actual value (%); C 57.56, H 6.00
, N 12.94 MS (m/z): 504 (M+) NMR (CDCl3) δ (ppm): 6.85
(3H, m), 6.10 (2H, s), 4.6
8 (2H, s), 3.88 (6H, s), 3.
77 (2H, s), 3.61 (6H, m), 3
．． 46 (2H, s), 2.94 (2H, t, J
=6.2Hz), 2.41(4H, m), 1.6
1 (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) Compound v 2.0 according to the method described in Example 15
By reacting 3 g (10 mmol) with 2.83 g (15 mmol) of 4-fluorobenzyl bromide, [1-(2-azidoethyl)-3-(4-
2.90 g (93.9 g) of white crystalline fluorobenzyl-2-imidazolidinylidene propane dinitrile.
2%) obtained. Next, this product was treated in the same manner as in Example 15 to obtain Compound 15 from Compound w to obtain Compound 19 as a pale yellow oil.

1.5 Melting point of oxalate: 139-140
．． 5℃ Elemental analysis: C26H31N6 OF・1.5 (CO2
H) Calculated value (%) as 2; C 58.28, H 5.73
, N 14.06 Actual value (%); C 58.28, H 5.72
, N 14.01 MS (m/z): 462 (M+) NMR (CDCl3) δ (ppm): 7.11
(4H, m), 6.11 (2H, s), 4.7
3 (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}propanedinitrile (Compound 20) Compound v 2.6 according to the method described in Example 15
(12.79 mmol) and 2.5 g (19.6 mmol) of 3-picolyl chloride (synthesized from 3-picolyl chloride hydrochloride and potassium carbonate) to form [1-(2-azidoethyl )-3-(3-
1.34g (35.5%) of (picolyl)-2-imidazolidinylidene]propanedinitrile as pale yellow oil
Obtained. Next, this product was treated in the same manner as the method described in Example 15 for preparing compound 15 from compound w to obtain compound 20 as a pale yellow oil.

Melting point of 2-oxalate: 154.5-155
°C elemental analysis: C25H31N7 O・2 (CO2 H)
Calculated value (%) as 2; C 55.67, H
5.64, N 15.67 Actual value (%); C 55.75, H 5.88
, N 15.67 MS (m/z): 445 (M+) NMR (CDCl3) δ (ppm): 8.59
(2H, m), 7.71 (1H, m), 7.3
4 (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) Compound v 2.1 according to the method described in Example 15
By reacting 6 g (10.64 mmol) with 3.1 g (15.86 mmol) of 3,4-dichlorobenzyl chloride,
1. 3-(3,4-dichlorobenzyl)-2-imidazolidinylidene]propanedinitrile as a white oil.
22g (31.7%) was obtained. Next, this product was treated in the same manner as in Example 15 to obtain Compound 15 from Compound w to obtain Compound 21 as a pale yellow oil.

Melting point of 1.5-oxalate/0.5-hydrate:
135.5-137℃ Elemental analysis: C26H30N6 OCl2 ・1.5(C
Calculated value (%) as O2 H) 2 ・0.5H2 O; C 52.97, H 5.21
, N 12.78 Actual value (%); C 53.11, H 5.31
, N 12.82 MS (m/z): 513 (M+) NMR (CDCl3) δ (ppm): 7.32
(3H, m), 6.11 (2H, s), 4.7
2 (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 2
2) Compound v 2.0 according to the method described in Example 15
By reacting 3 g (10 mmol) with 3.7 g (15 mmol) of bromodiphenylmethane, [1-(2-azidoethyl)-3-benzohydryl-
1.76 g (47.7%) of 2-imidazolidinylidene]propanedinitrile was obtained as a pale yellow crystal. Next, this product was treated in the same manner as in Example 15 for preparing Compound 15 from Compound w to obtain Compound 22 as a pale yellow oil.

Melting point of dioxalate 0.5 hydrate: 11
5.5-116.5℃ Elemental analysis: C32H36N6 O・2 (CO2 H)
Calculated value (%) as 2.0.5H2O; C 60.92, H 5.82
, N 11.84 Actual value (%); C 60.72, H 6.05
, N 12.11 MS (m/z): 520 (M+) NMR (CDCl3) 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
．． 19Hz), 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}propanedinitrile (Compound 23) Compound v 2.0 according to the method described in Example 15
3 g (10 mmol) and 3-chloropropyne 1.
By reacting 12 g (15.03 mmol) of .8%) obtained. This was then converted into the compound w described in Example 15.
Compound 23 as a pale yellow oil was obtained in the same manner as in the method for Compound 15.

Melting point of 1.5 oxalate monohydrate: Unmeasurable due to amorphous Elemental analysis: C22H28N6 O・1.5 (CO2 H
) 2 ・Calculated value as H2 O (%); C 55.04, H 6.10
, N 15.40 Actual value (%); C 55.11, H 6.02
, N 15.51 MS (m/z): 392 (M+) NMR (CDCl3) 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, 21
60

Reference Example 1 Tablets 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 color
slight
amount

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

01
36] Reference Example 3 Syrup A powder having the following composition is prepared by a conventional method. Compound 14
50mg refined white sugar
40gp-ethyl benzoate 40mg propyl p-hydroxybenzoate 10mg strawberry flavor 0.1c
c Add water to make a total volume of 100 cc.

[0137]

[Effects of the Invention] Compound (I) is a compound that has an excellent effect of promoting gastrointestinal motility.

Claims (1)

[Claims] Claim 1: Formula (I) [Formula 1] (wherein R1 is hydrogen, unsubstituted or substituted phenyl,
It represents unsubstituted or substituted aralkyl, lower alkynyl, lower alkenyl or picolyl, and R2 to R8 are the same or different and represent hydrogen or lower alkyl. provided that R1 to R8 are not hydrogen at the same time) or a pharmacologically acceptable salt thereof.