JPH09227494A - N-((2-substituted-aminocarbonyl)phenyl)-n((n-methylanilino)carbonylmethyl)-2-(3-(3-methylphenyl) ureido)2-substituted acetamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel subject compound which has excellent antagonism against cholecystokinin-A, B and gastrin receptors and is useful as a preventive or therapeutic agent for diseases relating to these receptors in the nervous system and the digestive organ system, particularly the gall, pancreas, stomach and intestines. SOLUTION: This novel compound is represented by formula I [R<1> is H, a lower alkyl, benzyl; R<2> and R<3> are identical or different from each other and denotes H, a lower alkyl, phenyl or they may be incorporated to form a 4-6C alkylene], typically N-[2-(isopropylaminocarbonyl)phenyl]-N-[(N- methylanilino)carbonylmethyl]-2-[3-(3-methylphenyl)ureido]-acetamide. The compound of formula I is prepared by reaction of a compound of formula II with N-bromomethylcarbonyl-N-methylaniline, allowing hydrazine hydrate to act on the product, then treating the product with hydrochloric acid followed by reaction of the product with 3-methylphenylisocyanate.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel N-{(2-substituted aminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido. } More specifically, regarding the 2-substituted acetamide derivative, cholecystokinin (CCK)-
The present invention relates to compounds having an antagonistic effect on A, B and gastrin receptors.

[0002]

2. Description of the Related Art CCK, gastrin receptor antagonism and substances having these actions are described in Anals of the New York Academy of Science,
Volume 713, pp. 1-167 (1994) [Annals
of The New York Academy of Sciences, 713, 1-167 (19
94)]. That is, CCK is present in digestive organs, brain and peripheral nerve cells and nerve terminals, and is a peptide hormone involved in secretion of pancreatic enzymes such as amylase and insulin, gall bladder contraction and regulation of gastric emptying and intestinal motility in the peripheral system. , And in the central system, neurotransmitters involved in neuromodulation of gastrointestinal motility, regulation of oxytocin, vasopressin and dopamine release, regulation of pain and morphine analgesia, appetite regulation, induction of anxiety, memory promotion, etc. Is positioned as. on the other hand,
Gastrin is mainly synthesized by G cells distributed in the gastric pylorus, and is secreted by gastric expansion by food intake and stimulation by digested proteins, which stimulates gastric acid secretion, promotes histamine synthesis and release, It has a growth promoting effect on gastrointestinal mucosal cells, particularly enterochromaffin-like (ECL) cells. CCK receptor is CCK mainly distributed in the periphery
The -A receptor and the centrally distributed CCK-B receptor are known, and antagonists showing selectivity for each have been found. The former antagonist is expected to be useful as a therapeutic drug for digestive organs such as pancreatitis, and the latter antagonist is useful as an anorexic drug and anxiolytic drug. The gastrin receptor is mainly present on the fundus mucosa and parietal cells, and this antagonist is expected to be useful as an antiulcer drug and the like. To date, CCK and gastrin receptor antagonists include cyclic nucleotides, amino acid derivatives, peptides, benzodiazepine derivatives,
Peptoids and substances produced by microorganisms have been found. For example, N- having a structure similar to the compound of the present invention
The phenyl-2- (3-phenylureido) acetamide derivative is disclosed in JP-A-3-56453 and Japanese Patent Publication No.
It is disclosed in Japanese Patent Publication No. 504967. However, N having a benzamide structure and a 2- {3- (3-methylphenyl) ureido} -2-substituted acetamide structure in the compound
-{(2-substituted aminocarbonyl) phenyl} -N-
{(N-methylanilino) carbonylmethyl} -2-
No {3- (3-methylphenyl) ureido} -2-substituted acetamide derivative is known.

[0003]

Therefore, the present invention has more excellent CCK and gastrin receptor antagonism,
Nervous system and digestive system, especially C such as gallbladder, pancreas, gastrointestinal
Novel N-{(2-substituted aminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3) for prevention and treatment of CK and gastrin receptor related diseases An object is to provide a -methylphenyl) ureido} -2-substituted acetamide derivative.

[0004]

The present inventors have conducted extensive studies in view of the above situation, and as a result, N-{(2-
Substituted aminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -2-substituted acetamide derivatives are excellent CCK-A, B and gastrin receptors They found that they have an antagonistic effect, and completed the present invention.

That is, the present invention provides the following general formula (I)

[0006]

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[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a benzyl group. R ² and R ³ are the same or different and represent a hydrogen atom, a lower alkyl group or a phenyl group, or R ² and R ³ are taken together to form a C ₄ -C ₆ alkylene group. ] N-{(2-substituted aminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -2-substituted acetamide derivative represented by The present invention relates to a preventive and therapeutic drug for diseases associated with CCK and gastrin receptor, which contain these as active ingredients.

Next, specific examples of R ¹ , R ² and R ^{3 in} the above general formula (I) representing the compound of the present invention can be shown as follows.

R ¹ is a hydrogen atom, a methyl group, an ethyl group,
Propyl group, isopropyl group, 1-methylpropyl group,
Examples thereof include an isobutyl group and a benzyl group, but a hydrogen atom, a methyl group or a benzyl group is particularly preferable.

Examples of R ² and R ³ include a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a phenyl group, and an isopropyl group or a phenyl group is particularly preferable. Alternatively, R ² and R ³ may be taken together to form a tetramethylene group, a pentamethylene group, or a hexamethylene group, with a pentamethylene group being particularly preferred.

Some of the compounds (I) of the present invention contain at least one asymmetric center, and the optical isomers and stereoisomers due to the structures thereof are also included in the present invention. Further, the compound of the present invention can form a hydrate.

Furthermore, the following compounds can be mentioned as particularly preferred specific examples of the compound of the present invention.

N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} acetamide N-{(N- Methylanilino) carbonylmethyl}-
2- {3- (3-methylphenyl) ureido} -N-
{2- (piperidinocarbonyl) phenyl} acetamide-N- {2- (anilinocarbonyl) phenyl} -N-
{(N-methylanilino) carbonylmethyl} -2-
{3- (3-Methylphenyl) ureido} acetamide

(+)-N- {2- (isopropylaminocarbonyl) phenyl} -2-methyl-N-{(N-
Methylanilino) carbonylmethyl} -2- {3- (3
-Methylphenyl) ureido} acetamide-(-)-N- {2- (isopropylaminocarbonyl) phenyl} -2-methyl-N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methyl (Phenyl) ureido} acetamide-(+)-2-methyl-N-{(N-methylanilino)
Carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -N- {2- (piperidinocarbonyl)
Phenyl} acetamide-(-)-2-methyl-N-{(N-methylanilino)
Carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -N- {2- (piperidinocarbonyl)
Phenyl} acetamide

(+)-2-benzyl-N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N
-Methylanilino) carbonylmethyl} -2- {3-
(3-Methylphenyl) ureido} acetamide-(-)-2-benzyl-N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3 -Methylphenyl) ureido} acetamide-(+)-2-benzyl-N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -N- {2- (piperidi) Nocarbonyl) phenyl} acetamide

The compound (I) of the present invention can be produced by various methods. Typical methods are as follows.

[0017]

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[0018]

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[In the formula, R ¹ , R ² and R ³ have the same meanings as described above. ]

[Step A], [Step B], [Step C] and [Step D] will be sequentially described below.

[Step A] Intermediate (IV) is synthesized
309-310 (1977) [Synthesis, 309
-310 (1977)], the compound (I
It can be produced by reacting I) with 2-bromo-N-methyl-N-phenylacetamide (III) in a solvent, usually in the presence or absence of a base and a small amount of water. The solvent used in this reaction step is ethanol, isopropanol, butanol, chloroform, carbon tetrachloride, 1,2-
Organic solvents such as dichloroethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, acetone, methylethylketone, acetonitrile, pyridine, N, N-dimethylformamide and dimethylsulfoxide can be mentioned, but 1,2-dichloroethane is particularly preferable. Examples of the base used in this reaction step include organic bases such as triethylamine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Sodium is preferred. Further, the reaction temperature is in the range of room temperature to the boiling point of the solvent, and especially 70
C. to 120.degree. C. is preferable, and the reaction time is usually 10 hours to 48 hours.

[Step B] The intermediate (VI) is the intermediate (IV) obtained in the step A and Journal of American Chemical Society, Vol. 74, pages 3822-3825 (1952) [J., Am., Chem., Soc., 74, 3822-382
5 (1952)], the compound (V) synthesized according to the method described in
Can be usually produced by reacting in a solvent in the presence or absence of a base and a small amount of water. The solvent used in this reaction step is methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, acetone,
Methyl ethyl ketone, acetonitrile, pyridine, N,
Organic solvents such as N-dimethylformamide can be mentioned, and 1,2-dichloroethane is particularly preferable. The base used in this reaction step is an organic base such as triethylamine or 4-dimethylaminopyridine, or sodium hydrogen carbonate, sodium carbonate, potassium carbonate,
Although inorganic bases such as cesium carbonate can be mentioned, sodium hydrogen carbonate is particularly preferable. Furthermore, the reaction temperature is 0
The temperature is in the range of 0 ° C. to the boiling point of the solvent, particularly preferably about room temperature, and the reaction time is usually 1 hour to 48 hours.

[Step C] The intermediate (VII) can be produced by reacting the intermediate (VI) obtained in the step B with hydrazine hydrate in a solvent and then adding hydrochloric acid for treatment. The solvent used in this reaction step is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane,
Examples thereof include organic solvents such as N, N-dimethylformamide and mixed solvents of these organic solvents and water.
Particularly preferred is methanol. Furthermore, the reaction temperature when the hydrazine hydrate is allowed to act is in the range of 0 ° C. to the boiling point of the solvent, but it is preferably about room temperature, and the reaction time is usually 1 to 24 hours. The reaction temperature at the time of adding hydrochloric acid is in the range of 0 ° C to 60 ° C, preferably about room temperature, and the reaction time is usually 30 minutes to 6 hours.

[Step D] The compound (I) of the present invention is prepared by the step C
Usually, it can be produced by reacting the intermediate (VII) obtained in (3) with 3-methylphenylisocyanate (VIII) in a solvent. Examples of the solvent used in this reaction step include organic solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, acetonitrile and pyridine. Particularly preferred is tetrahydrofuran. The reaction temperature is in the range of room temperature to the boiling point of the solvent, preferably about room temperature, and the reaction time is usually 1 hour to 48 hours.

Since the compound (I) of the present invention obtained as described above has CCK-A, B and gastrin receptor antagonistic activity, it is particularly useful for human nervous system and digestive system, especially gallbladder, pancreas, It is useful as a drug that can be expected to be effective in the prevention and treatment of diseases associated with CCK and gastrin receptor such as gastrointestinal. Examples of general pharmaceutical preparation forms include tablets, powders, granules, capsules, syrups or solutions, and injections. The method of administration may be oral administration, or intravenous or intramuscular administration as an injection.

Excipients used in the production of solid oral preparations include, for example, lactose, corn starch, sucrose,
Glucose, sorbit, crystalline cellulose, silicon dioxide, etc. are used. As the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragand, gelatin, shellac, hydroxypropyl starch, polyvinyl pyrrolidone, etc. are used. Examples of lubricants include silica, talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, and examples of disintegrants include starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, citric acid. Calcium, dextrin, pectin and the like are used. Examples of the flavoring agent include cocoa powder, peppermint oil,
Dragon brain and cinnamon powder are used. These tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating may be applied. In addition, examples of the solvent or suspending agent used for producing an injection for parenteral administration include water, propylene glycol, polyethylene glycol, benzyl alcohol, lecithin and the like.

The clinical dose of the compound (I) of the present invention is about 5 to 1500 m per day depending on the symptoms and age of the patient.
g, preferably increased or decreased in the range of 20 to 800 mg,
It can be administered once to several times a day.

The present invention will be described in more detail below with reference to Examples, Formulation Examples and Test Examples, but the invention is not limited to these Examples, Formulation Examples and Test Examples.

[0029]

EXAMPLES The melting points (mp) stated are uncorrected. Specific rotation ([α]) is determined by the sodium lamp (589n) as the light source.
m). Low resolution fast atom bombardment mass spectrum (LR-FAB-MS) and high resolution fast atom bombardment mass spectrum (HR-FAB-MS) are positive ionization method by follow injection, methanol as mobile phase, glycerol as matrix reagent, high resolution. Standard reagent for polyethylene glycol-600, resolution is 5
00 or 3000 was used. The proton nuclear magnetic resonance spectrum ( ¹ H-NMR) was measured using tetramethylsilane as an internal standard substance. The chemical shift value (δ) is in ppm, the binding constant (J) is in Hz, and the multiplicity of each peak is s for singlet, d for doublet, t for triplet, and qua.
rtet is q, multiplet is m, and broad
The singlet is represented by bs.

Example 1 Synthesis of N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} acetamide [ Step A]: 2-Amino-N-isopropylbenzamide (5.34 g, 0.03 mol) was dissolved in 1,2-dichloroethane (50 ml), and sodium hydrogen carbonate (5
g) and 2-bromo-N-methyl-N-phenylacetamide (3.42 g, 0.015 mol) were added, and the mixture was heated under reflux for 48 hours with stirring. After 1,2-dichloroethane was distilled off under reduced pressure, ethyl acetate and water were added to the residue to dissolve it, the organic layer was separated, and the organic layer was mixed with 1N hydrochloric acid (20 ml x
3), washed with a saturated aqueous solution of sodium hydrogencarbonate and water successively. After drying over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of diethyl ether and diisopropyl ether to give m.
2- [2 of white prism crystals showing p119-121 ° C
-(Isopropylcarbamoyl) anilino] -N-methyl-N-phenylacetamide (4.3 g, 88%) was obtained. IR (nujol method) ν _max cm ^-1 : 3320 (N
H), 1660, 1640 (C = O). LR-FAB-MS m / z (%): 326 (M + 1).
⁺ (100). _{NMR (DMSO-d 6) δ} : 1.14 (6H, d, J
= 6.6 Hz), 3.06 and 3.23 (3H,
each bs), 3.60 and 3.75 (2
H, each bs), 4.08 (1H, m), 6.1
5 (1H, bs), 6.54 (1H, t, J = 7.4H
z), 7.1-7.6 (7H, m), 8.01 (1H,
d, J = 7.8 Hz), 8.09 (1H, bs). Elemental analysis (C ₁₉ H ₂₃ N ₃ O ₂ ) Theoretical value (%): C, 70.13; H, 7.12; N, 12.91 Measured value (%): C, 70.07; H, 7 .27; N, 12.45.

[Step B]: 2 obtained in the above [Step A]
-[2- (isopropylcarbamoyl) anilino] -N
-Methyl-N-phenylacetamide (4.1 g, 0.
0126 mol of 1,2-dichloroethane (50 m
l) and dissolved in sodium hydrogen carbonate (5 g) and 2-phthalimidoacetyl chloride (3.35 g, 0.015
mol) was added, and water (2 ml) was added with stirring at room temperature. After stirring overnight at room temperature, add water (50 ml) and
The mixture was heated and stirred for 0 minutes at about 60 ° C. After 1,2-dichloroethane was distilled off under reduced pressure, the released oily substance was dissolved in ethyl acetate (50 ml), the organic layer was separated, and the solution was sequentially washed with saturated aqueous sodium carbonate solution, 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. Washed. After drying over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and diethyl ether.
N- of a white prism crystal showing mp 144-146 ° C
{2- (isopropylaminocarbonyl) phenyl}-
N-{(N-methylanilino) carbonylmethyl} -2
-Phthalimidoacetamide (6.0 g, 93%) was obtained. IR (nujol method) ν _max cm ^-1 : 3270 (N
H), 1780, 1720, 1670, 1650 (C =
O). LR-FAB-MS m / z (%): 513 (M + 1).
⁺ (87). _{NMR (DMSO-d 6) δ} : 0.8-1.2 (6H,
m), 3.06, 3.15 and 3.25 (3H,
eachs), 3.5-4.5 (5H, m), 7.2
-8.0 (13H, m), 8.39 (1H, d, J =
6.7 Hz,). Elemental analysis (C ₂₉ H ₂₈ N ₄ O ₅ ) Theoretical value (%): C, 67.96; H, 5.51; N, 10.93 Measured value (%): C, 67.96; H, 5 .57; N, 10.57

[Step C]: N obtained in the above [Step B]
-{2- (isopropylaminocarbonyl) phenyl}
-N-{(N-methylanilino) carbonylmethyl}-
2-phthalimidoacetamide (5.12 g, 0.01
(mol) dissolved in methanol (100 ml) with heating,
0% hydrazine hydrate (0.75 g, 0.012 m
ol). After stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure to half volume, and 0.5N hydrochloric acid (70 ml) was added. After stirring at room temperature for 3 hours, the mixture was neutralized with a saturated aqueous sodium carbonate solution. After filtering the precipitated insoluble matter, methanol was distilled off under reduced pressure, and the pH was adjusted to 10 with a saturated sodium carbonate aqueous solution. The liberated oily substance was extracted with methylene chloride, the organic layer was washed with water and dried over anhydrous sodium sulfate, and then methylene chloride was distilled off under reduced pressure.
N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} acetamide was obtained.

[Step D]: 2 obtained in the above [Step C]
-Amino-N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} acetamide was added to tetrahydrofuran (20
ml), and 3-methylphenylisocyanate (1.33 g, 0.01 mol) was added. 2 at room temperature
After stirring for 4 hours, the tetrahydrofuran was distilled off under reduced pressure,
Methylene chloride was added to the residue to dissolve it, and the residue was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. After drying over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and diethyl ether to give N- {2- (white powdery crystals showing mp184-186 ° C. Isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} acetamide (4.0 g, 78%) was obtained. IR (nujol method) ν _max cm ⁻¹ : 3420, 337
0,3310 (NH), 1680,1670,165
0,1620 (C = O). LR-FAB-MS m / z (%): 516 (M + 1).
⁺ (66). HR-FAB-MS m / z (C 29 H 34 N 5 O 4) (M +
1) ⁺ : theoretical value: 516.2611; measured value: 516.260
3. _{NMR (DMSO-d 6) δ} : 0.85 and 0.
96 (6H, each, J = 6.0 and 6.3)
Hz), 2.22 (3H, s), 3.17 (3H,
s), 3.45-4.6 (5H, m), 6.32 (1)
H, t, J = 4.6 Hz), 6.7 (1H, m), 7.
0-7.2 (3H, m), 7.25-7.8 (9H,
m), 8.25 (1H, d, J = 7.9 Hz), 8.7
0 (1H, s). Elemental analysis (C ₂₉ H ₃₃ N ₅ O ₄ ) Theoretical value (%): C, 67.55; H, 6.45; N, 13.58 Actual value (%): C, 67.31; H, 6 .36; N, 13.44

Example 2 Synthesis of N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -N- {2- (piperidinocarbonyl) phenyl} acetamide Using 2- (piperidinocarbonyl) aniline as a raw material compound, [Example] 1 {[Step A], [Step B],
According to the same method as [Step C] and [Step D]}, m
N-{(N- of a white powder crystal showing p207-210 ° C.
Methylanilino) carbonylmethyl} -2- {3- (3
-Methylphenyl) ureido} -N- {2- (piperidinocarbonyl) phenyl} acetamide (3.9 g, 7
2%). IR (nujol method) ν _max cm ^-1 : 3380,334
0 (NH), 1700, 1670, 1610 (C =
O). LR-FAB-MS m / z (%): 542 (M + 1).
⁺ (56). HR-FAB-MS m / z (C 31 H 36 N 5 O 4) (M +
1) ⁺ : theoretical value: 542.2767; measured value: 542.277
0. _{NMR (DMSO-d 6) δ} : 1.0-1.6 (6H,
m), 2.22 (3H, s), 3.18 (3H, s),
3.20-4.6 (8H, m), 6.25 (1H, b
S), 6.7 (1H, m), 7.0-7.3 (3H,
m), 7.3-7.8 (9H, m), 8.69 (1H,
s). Elemental analysis (C ₃₁ H ₃₅ N ₅ O ₄ ) Theoretical value (%): C, 68.74; H, 6.51; N, 12.93 Measured value (%): C, 68.71; H, 6 .75; N, 12.65.

Example 3 N- {2- (anilinocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl)
Synthesis of ureido} acetamide Using 2-amino-N-phenylbenzamide as a starting compound, [Example] 1 {[Step A], [Step B],
According to the same method as [Step C] and [Step D]}, m
N- {2- of the white powder crystal which shows p127-129 degreeC.
(Anilinocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} acetamide (2.8 g, 6
8%). IR (nujol method) ν _max cm ⁻¹ :
3420, 3400, 3200 (NH), 1680, 1
660, 1650, 1620 (C = O). LR-FAB-MS m / z (%): 550 (M + 1)
⁺ (50). HR-FAB-MS m / z (C ₃₂ H ₃₂ N ₅ O ₄ ) (M +
1) ⁺ : theoretical value: 550.2454; measured value: 550.246
6. NMR (DMSO-d ₆ ) δ: 2.21 (3H, s),
3.18 (3H, s), 3.5-4.6 (4H, m),
6.31 (1H, t, J = 4.6Hz), 6.7 (1
H, m), 7.0-7.2 (4H, m), 7.2-7.
55 (9H, m), 7.55-7.75 (3H, m),
7.8 (1H, m), 8.68 (1H, bs), 10.
46 (1H, bs). Elemental analysis (C ₃₂ H ₃₁ N ₅ O ₄ ) Theoretical value (%): C, 69.93; H, 5.68; N, 12.74 Actual value (%): C, 69.66; H, 5 .77; N, 12.59.

Example 4 (+)-N- {2- (isopropylaminocarbonyl) phenyl} -2-methyl-
N-{(N-methylanilino) carbonylmethyl} -2
Synthesis of-{3- (3-methylphenyl) ureido} acetamide [Step B]: 2- [2 obtained in [Step A] of [Example 1]]
-(Isopropylcarbamoyl) anilino] -N-methyl-N-phenylacetamide (3.3 g, 0.01 m
ol) was dissolved in 1,2-dichloroethane (50 ml), sodium hydrogen carbonate (5 g) and (2S) -2-phthalimidopropionyl chloride (2.9 g, 0.01
2 mol) was added, and water (1 ml) was added with stirring at room temperature. After stirring overnight at room temperature, add water (50 ml) and
The mixture was heated and stirred for 0 minutes at about 60 ° C. After 1,2-dichloroethane was distilled off under reduced pressure, the released oily substance was dissolved in ethyl acetate (50 ml), the organic layer was separated, and the solution was sequentially washed with saturated aqueous sodium carbonate solution, 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. Washed. After drying over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and diethyl ether.
N- of a white prism crystal showing mp115-117 ° C
{2- (isopropylaminocarbonyl) phenyl}-
2-Methyl-N-{(N-methylanilino) carbonylmethyl} -2-phthalimidoacetamide (4.7 g,
89%). IR (nujol method) ν _max cm ⁻¹ : 3320, 323
0 (NH), 1780, 1720, 1680, 166
0,1640 (C = O). LR-FAB-MS m / z (%): 527 (M + 1)
⁺ (100). NMR (DMSO-d ₆ ) δ: 0.8-1.4 (9H,
m), 3.06, 3.13 and 3.16 (3H,
eachs), 3.5-4.5 (3H, m), 4.9.
-5.1 (1H, m), 7.2-8.0 (13H,
m), 8.58 (1H, d, J = 6.7Hz,). Elemental analysis _{(C 30 H 30 N 4 O} 5) theory (%): C, 68.42; H, 5.74; N, 10.64 Found (%): C, 68.02; H, 6 .15; N, 10.18

[Step C]: N obtained in the above [Step B]
-{2- (isopropylaminocarbonyl) phenyl}
2-Methyl-N-{(N-methylanilino) carbonylmethyl} -2-phthalimidoacetamide (4.53
g, 0.0086 mol) was dissolved in methanol (70 ml) with heating to give 80% hydrazine hydrate (0.63
g, 0.01 mol) was added. After stirring at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure to half volume, and 0.5N hydrochloric acid (45 ml) was added. After stirring at room temperature for 3 hours, the mixture was neutralized with a saturated aqueous sodium carbonate solution. After filtering the precipitated insoluble matter, methanol was distilled off under reduced pressure, and the pH was adjusted to 10 with a saturated sodium carbonate aqueous solution. The liberated oily substance was extracted with methylene chloride, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the methylene chloride was distilled off under reduced pressure.
-Amino-N- {2- (isopropylaminocarbonyl) phenyl} -2-methyl-N-{(N-methylanilino) carbonylmethyl} acetamide was obtained.

[Step D]: 2 obtained in the above [Step C]
-Amino-N- {2- (isopropylaminocarbonyl) phenyl} -2-methyl-N-{(N-methylanilino) carbonylmethyl} acetamide was dissolved in tetrahydrofuran (20 ml) with heating to give 3-methylphenylisocyanate (1 .33 g, 0.01 mol) was added. After stirring at room temperature for 24 hours, tetrahydrofuran was distilled off under reduced pressure, methylene chloride was added to the residue to dissolve it, and the residue was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and then with water. After drying over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give (+)-N- {2- (isopropylamino) as white prism crystals showing mp201-203 ° C. Carbonyl) phenyl} -2-methyl-N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} acetamide (3.5 g, 77
%) Was obtained. [Α] _D ; +0.181 (25 ° C., c = 1.04, Me
OH). IR (nujol method) ν _max cm ^-1 : 3370,330
0,3240 (NH), 1680,1670,164
0, 1630 (C = O). LR-FAB-MS m / z (%): 530 (M + 1)
⁺ (25). HR-FAB-MS m / z (C 30 H 36 N 5 O 4) (M +
1) ⁺ : theoretical value: 530.2767; measured value: 530.280
2. NMR (DMSO-d ₆ ) δ: 0.70 to 1.30 (9
H, m), 2.20 and 2.24 (3H, each)
s), 3.14 and 3.17 (3H, each)
s), 3.4-4.6 (4H, m), 6.36 an
d6.54 (1H, each d), 6.71 (1H,
t), 7.0-7.2 (3H, m), 7.2-7.8.
(9H, m), 8.0 and 8.25 (1H, ea
ch d), 8.54 and 8.57 (1H, ea
ch s). Elemental analysis _{(C 30 H 35 N 5 O} 4) theory (%): C, 68.03; H, 6.66; N, 13.22 Found (%): C, 68.08; H, 6 .81; N, 13.21.

Example 5 (-)-N- {2- (isopropylaminocarbonyl) phenyl} -2-methyl-
N-{(N-methylanilino) carbonylmethyl} -2
Synthesis of-{3- (3-methylphenyl) ureido} acetamide (2R) -2-phthalimidopropionyl chloride as a starting compound and 2 obtained in [Step A] of [Example 1]
-[2- (isopropylcarbamoyl) anilino] -N
Using -methyl-N-phenylacetamide and following the same procedure as in [Example 4] {[Step B], [Step C] and [Step D]}, a white powder crystal (- ) -N- {2- (isopropylaminocarbonyl) phenyl} -2-methyl-N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} acetamide (3.5, 79
%) Was obtained. [Α] _D ; +0.181 (25 ° C., c = 1.02, Me
OH). IR (nujol method) ν _max cm ^-1 : 3380,329
0, 3230 (NH), 1680, 1660, 164
0, 1630 (C = O). LR-FAB-MS m / z (%): 530 (M + 1)
⁺ (24). HR-FAB-MS m / z (C 30 H 36 N 5 O 4) (M +
1) ⁺ : theoretical value: 530.2767; measured value: 530.274
0. NMR (DMSO-d ₆ ) δ: 0.70 to 1.30 (9
H, m), 2.20 and 2.24 (3H, each)
s), 3.15 and 3.17 (3H, each)
s), 3.4-4.6 (4H, m), 6.37 an
d6.54 (1H, each d), 6.69 (1H,
bs), 7.0-7.2 (3H, m), 7.2-7.8.
(9H, m), 8.04 and 8.27 (1H, e
achd), 8.55 and 8.58 (1H, ea
ch s). Elemental analysis _{(C 30 H 35 N 5 O} 4) theory (%): C, 68.03; H, 6.66; N, 13.22 Found (%): C, 68.05; H, 6 .80; N, 13.17.

Example 6 (+)-2-methyl-N-
{(N-methylanilino) carbonylmethyl} -2-
{3- (3-Methylphenyl) ureido} -N- {2-
Synthesis of (piperidinocarbonyl) phenyl} acetamide [Step A]: N- (2-aminobenzoyl) piperidine (20.4 g, 0.1 mol) was dissolved in 1,2-dichloroethane (150 ml), and sodium hydrogen carbonate was added. (1
6.8 g) and 2-bromo-N-methyl-N-phenylacetamide (11.4 g, 0.05 mol) were added and 2
The mixture was heated to reflux with stirring for 4 hours. After 1,2-dichloroethane was distilled off under reduced pressure, ethyl acetate and water were added to the residue to dissolve it, the organic layer was separated, and the organic layer was mixed with 1N hydrochloric acid (50 ml x
3), washed with a saturated aqueous solution of sodium hydrogencarbonate and water successively. After drying over anhydrous sodium sulfate, the ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of methylene chloride and diisopropyl ether to give mp1.
N-methyl- of white prism crystals showing 71-173 ° C
N-phenyl-2- [2- (piperidinocarbonyl) anilino] acetamide (16.9 g, 96%) was obtained. IR (nujol method) ν _max cm ^-1 : 3360 (N
H), 1670, 1620 (C = O). LR-FAB-MS m / z (%): 352 (M + 1).
⁺ (100). NMR (DMSO-d ₆ ) δ: 1.4-1.7 (6H,
m), 3.23 (3H, s), 3.3-3.5 (4H,
m), 3.5-3.7 (2H, m), 5.55 (1H,
bs), 6.21 (1H, bs), 6.61 (1H,
t, J = 7.4 Hz), 7.0 (1H, m), 7.13
(1H, m), 7.3-7.6 (5H, m). Elemental analysis (C ₂₁ H ₂₅ N ₃ O ₂ ) theoretical value (%): C, 71.77; H, 7.17; N, 1
1.96 Found (%): C, 71.70; H, 7.08; N, 1
2.03

[Step B]: N-methyl-N-phenyl-2- [2- (piperidinocarbonyl) anilino] acetamide (3.51 g, 0.01 m) obtained in the above step A
ol) was dissolved in 1,2-dichloroethane (50 ml), sodium hydrogen carbonate (5 g) and (2S) -2-phthalimidopropionyl chloride (2.9 g, 0.01
2 mol) was added, and water (2 ml) was added with stirring at room temperature. After stirring overnight at room temperature, add water (50 ml) and
The mixture was heated and stirred for 0 minutes at about 60 ° C. After 1,2-dichloroethane was distilled off under reduced pressure, the released oily substance was dissolved in ethyl acetate (50 ml), the organic layer was separated, and the solution was sequentially washed with saturated aqueous sodium carbonate solution, 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. Washed. After drying over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and diisopropyl ether to give 2-methyl-N- as white prism crystals showing mp 177-179 ° C. {(N-methylanilino) carbonylmethyl} -2-phthalimido-N- {2- (piperidinocarbonyl) phenyl} acetamide (5.3 g, 9
6%) was obtained. IR (nujol method) ν _max cm ^-1 : 1780,172
0, 1690, 1670, 1620 (C = O). LR-FAB-MS m / z (%): 553 (M + 1).
⁺ (100). NMR (DMSO-d ₆ ) δ: 0.8-1.8 (9H,
m), 2.7-3.7 (8H, m), 3.8-5.5.
(2H, m), 6.9-8.1 (13H, m). Elemental analysis (C ₃₂ H ₃₂ N ₄ O ₅ ) Theoretical value (%): C, 69.55; H, 5.84; N, 10.14 Actual value (%): C, 69.40; H, 5 .77; N, 10.22

[Step C]: 2 obtained in the above [Step B]
-Methyl-N-{(N-methylanilino) carbonylmethyl} -2-phthalimido-N- {2- (piperidinocarbonyl) phenyl} acetamide (4.8 g, 0.0
087 mol) was dissolved in methanol (100 ml) with heating, and 80% hydrazine hydrate (0.63 g, 0.03 g) was added.
1 mol) was added. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure to half volume, and 0.5N hydrochloric acid (50 m
l) was added. After stirring at room temperature for 3 hours, the mixture was neutralized with a saturated aqueous sodium carbonate solution. After filtering the precipitated insoluble matter, methanol was distilled off under reduced pressure, and the pH was adjusted to 10 with a saturated sodium carbonate aqueous solution. The liberated oily substance was extracted with methylene chloride, the organic layer was washed with water and dried over anhydrous sodium sulfate, and then methylene chloride was distilled off under reduced pressure to give 2-amino-2-methyl-N-{(N-methylanilino). ) Carbonylmethyl} -N- {2- (piperidinocarbonyl) phenyl} acetamide was obtained.

[Step D]: 2 obtained in the above [Step C]
-Amino-2-methyl-N-{(N-methylanilino)
Carbonylmethyl} -N- {2- (piperidinocarbonyl) phenyl} acetamide was added to tetrahydrofuran (2
It was dissolved in 0 ml) with heating, and 3-methylphenylisocyanate (1.16 g, 0.0087 mol) was added. After stirring at room temperature for 24 hours, tetrahydrofuran was distilled off under reduced pressure, methylene chloride was added to the residue to dissolve it, and diluted hydrochloric acid,
It was washed successively with saturated aqueous sodium hydrogen carbonate solution and water.
After drying over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of petroleum ether and diethyl ether to give mp111-113 ° C.
(+)-2-methyl-N-{(N
-Methylanilino) carbonylmethyl} -2- {3-
(3-Methylphenyl) ureido} -N- {2- (piperidinocarbonyl) phenyl} acetamide (4.0
g, 83%). [Α] _D ; +0.926 (25 ° C., c = 1.05, Me
OH). IR (nujol method) ν _max cm ^-1 : 3350,334
0 (NH), 1660, 1640, 1630, 1620
(C = O). LR-FAB-MS m / z (%): 556 (M + 1).
⁺ (50). HR-FAB-MS m / z (C ₃₂ H ₃₈ N ₈ O ₄ ) (M +
1) ⁺ : theoretical value: 556.2924; actual value: 556.294
7. NMR (DMSO-d ₆ ) δ: 0.6-1.9 (9H,
m), 2.20, 2.25 and 2.28 (3H,
eachs), 2.7-3.5 (7H, m), 3.
5 and 4.7 (3H, m), 6.3-6.9 (2
H, m), 7.0-8.0 (12H, m), 8.4-
8.7 (1H, m). Elemental analysis (C ₃₂ H ₃₇ N ₅ O ₄ ) Theoretical value (%): C, 69.17; H, 6.71; N, 12.60 Measured value (%): C, 69.03; H, 6 .79; N, 12.39.

Example 7 (-)-2-Methyl-N-
{(N-methylanilino) carbonylmethyl} -2-
{3- (3-Methylphenyl) ureido} -N- {2-
Synthesis of (piperidinocarbonyl) phenyl} acetamide (2R) -2-phthalimidopropionyl chloride as a starting compound and N obtained in [Step A] of [Example 6]
-Methyl-N-phenyl-2- [2- (piperidinocarbonyl) anilino] acetamide using the same method as in [Example 6] {[Step B], [Step C] and [Step D]} According to the method, (-)-2-methyl-N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -N- {2 of white powder crystal showing mp117-119 ° C. -(Piperidinocarbonyl) phenyl} acetamide (3.8 g, 77%) was obtained. [Α] _D ; −0.138 (25 ° C., c = 1.03, Me
OH). IR (nujol method) ν _max cm ^-1 : 3350,334
0 (NH), 1660, 1640, 1630, 1620
(C = O). LR-FAB-MS m / z (%): 556 (M + 1).
⁺ (52). HR-FAB-MS m / z (C ₃₂ H ₃₈ N ₅ O ₄ ) (M +
1) ⁺ : theoretical value: 556.2924; actual value: 556.294
4. NMR (DMSO-d ₆ ) δ: 0.6-1.9 (9H,
m), 2.20, 2.25 and 2.28 (3H,
eachs), 2.7-3.5 (7H, m), 3.5
-4.7 (3H, m), 6.3-6.9 (2H,
m), 7.0-8.0 (12H, m), 8.4-8.7.
(1H, m). Elemental analysis (C ₃₂ H ₃₇ N ₅ O ₄ ) Theoretical value (%): C, 69.17; H, 6.71; N, 12.60 Measured value (%): C, 68.76; H, 6 .79; N, 12.43.

Example 8 (+)-2-benzyl-N
-{2- (isopropylaminocarbonyl) phenyl}
-N-{(N-methylanilino) carbonylmethyl}-
Synthesis of 2- {3- (3-methylphenyl) ureido} acetamide [Step B]: 2- [2 obtained in [Step A] of [Example 1]]
-(Isopropylcarbamoyl) anilino] -N-methyl-N-phenylacetamide (3.3 g, 0.01 m
1) was dissolved in 1,2-dichloroethane (50 ml), sodium hydrogen carbonate (5 g) and (2S) -3-phenyl-2-phthalimidopropionyl chloride (3.
14 g, 0.01 mol) was added, and water (1 ml) was added with stirring at room temperature. After stirring at room temperature overnight, water (50
ml) was added, and the mixture was heated and stirred at about 60 ° C. for 30 minutes.
After 1,2-dichloroethane was distilled off under reduced pressure, the released oily substance was dissolved in ethyl acetate (50 ml), the organic layer was separated, and the solution was sequentially washed with saturated aqueous sodium carbonate solution, 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. Washed. After drying over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using a mixed solvent of ethyl acetate and diethyl ether (1: 1) as an eluting solvent (mobile phase). Mp95-97
2-benzyl-N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-
Methylanilino) carbonylmethyl} -2-phthalimidoacetamide (3.9 g, 65%) was obtained. IR (nujol method) ν _max cm ^-1 : 3240 (N
H), 1780, 1720, 1670 (C = O). LR-FAB-MS m / z (%): 603 (M + H)
⁺ (47). NMR (CDCl ₃ ) δ: 0.7-1.4 (6H, m),
3.10-4.7 (8H, m), 5.1-5.2 (1
H, m), 6.8-8.5 (19H, m). Elemental analysis (C ₃₆ H ₃₄ N ₄ O ₅ ) Theoretical value (%): C, 71.74; H, 5.69; N, 9.30 Measured value (%): C, 71.72; H, 5 .70; N, 9.10

[Step C]: 2 obtained in the above [Step B]
-Benzyl-N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2-phthalimidoacetamide (3.6
g, 0.006 mol) was dissolved in methanol (100 ml) with heating, and 80% hydrazine hydrate (0.5 g,
0.008 mol) was added. After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure to half volume, and 0.5N hydrochloric acid (40 ml) was added. After stirring at room temperature for 3 hours, the mixture was neutralized with a saturated aqueous sodium carbonate solution. After filtering the precipitated insoluble matter, methanol was distilled off under reduced pressure, and the pH was adjusted to 10 with a saturated sodium carbonate aqueous solution. The liberated oily substance was extracted with methylene chloride, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the methylene chloride was distilled off under reduced pressure.
-Amino-2-benzyl-N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} acetamide was obtained.

[Step D]: 2 obtained in the above [Step C]
-Amino-2-benzyl-N- {2- (isopropylaminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} acetamide was dissolved in tetrahydrofuran (20 ml) with heating, and 3-methylphenylisocyanate (0 0.8 g, 0.006 mol) was added. After stirring at room temperature for 24 hours, tetrahydrofuran was distilled off under reduced pressure, methylene chloride was added to the residue to dissolve it, and the residue was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. After drying over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of methylene chloride and ethyl acetate to give mp 152-154 ° C.
(+)-2-benzyl-N- {2 of white needle crystal showing
-(Isopropylaminocarbonyl) phenyl} -N-
{(N-methylanilino) carbonylmethyl} -2-
{3- (3-Methylphenyl) ureido} acetamide (3.2 g, 88%) was obtained. [Α] _D : +1.310 (25 ° C., c = 1.033, C
HCl ₃ ) IR (nujol method) ν _max cm ⁻¹ : 3410,334
0,3290 (NH), 1660,1650,1620
(C = O). LR-FAB-MS m / z (%): 606 (M + 1)
⁺ (8). HR-FAB-MS m / z (C 36 H 40 N 5 O 4) (M +
1) ⁺ : Theoretical value: 606.3080. Found: 606.308
3. NMR (DMSO-d ₆ ) δ: 0.70, 0.85 a
nd 1.03 (6H, eachch d, J = 5.7,
6.1 and 6.6 Hz), 2.17 and
2.23 (3H, each), 2.3-2.8 (1
H, m), 3.13 and 3.20 (3H, each)
s), 3.1-4.0 (3H, m), 4.3-4.
8 (2H, m), 6.30 and 6.57 (1H,
eachd, J = 9.0 and 8.3 Hz), 6.
65-6.85 (1H, m), 6.9-7.3 (8H,
m), 7.3-7.8 (9H, m), 7.8 and
8.3 (1H, each d, J = 6.3 and
7.8 Hz), 8.48 and 8.54 (1H, ea
ch s). Elemental analysis (C ₃₆ H ₃₉ N ₅ O ₄ ) Theoretical value (%): C, 71.38; H, 6.49; N, 11.57 Actual value (%): C, 71.28; H, 6 .61; N, 11.44.

Example 9 (-)-2-benzyl-N
-{2- (isopropylaminocarbonyl) phenyl}
-N-{(N-methylanilino) carbonylmethyl}-
Synthesis of 2- {3- (3-methylphenyl) ureido} acetamide (2R) -3-phenyl-2-phthalimidopropionyl chloride as a raw material compound and 2- [obtained in [Step A] of [Example 1]] 2- (isopropylcarbamoyl)
Using anilino] -N-methyl-N-phenylacetamide, following the same procedure as in [Example 8] {[Step B], [Step C] and [Step D]}, mp150-15
(-)-2-benzyl-N- of white powder crystals showing 2 ° C
{2- (isopropylaminocarbonyl) phenyl}-
N-{(N-methylanilino) carbonylmethyl} -2
-{3- (3-Methylphenyl) ureido} acetamide (2.7 g, 56%) was obtained. [Α] _D : −0.767 (25 ° C., c = 1.048, C
HCl ₃ ) IR (nujol method) ν _max cm ⁻¹ : 3410,334
0,3290 (NH), 1660,1650,1620
(C = O). LR-FAB-MS m / z (%): 606 (M + 1)
⁺ (16). HR-FAB-MS m / z (C 36 H 40 N 5 O 4) (M +
1) ⁺ : Theoretical value: 606.3080. Found: 606.308
0. _{NMR (DMSO-d 6):} 0.70,0.85 an
d 1.03 (6H, eachach d, J = 5.7,
6.1 and 6.6 Hz), 2.17 and2.
23 (3H, each), 2.3-2.8 (1H,
m), 3.13 and 3.20 (3H, each)
s), 3.1-4.0 (3H, m), 4.3-4.8.
(2H, m), 6.30 and 6.57 (1H, e
ach d, J = 9.0 and 8.3 Hz), 6.
65-6.85 (1H, m), 6.9-7.3 (8H,
m), 7.3-7.8 (9H, m), 7.8 and
8.3 (1H, each d, J = 6.3 and
7.8 Hz), 8.48 and 8.54 (1H, e
achs). Elemental analysis (C ₃₆ H ₃₉ N ₅ O ₄ ) Theoretical value (%): C, 71.38; H, 6.49; N, 11.57 Actual value (%): C, 71.34; H, 6 .62; N, 11.54

Example 10 (+)-2-benzyl-
N-{(N-methylanilino) carbonylmethyl} -2
-{3- (3-methylphenyl) ureido} -N- {2
Synthesis of-(piperidinocarbonyl) phenyl} acetamide [Step B]: N-methyl-N-phenyl-2- [2- (piperidinocarbonyl) anilino obtained in [Step A] of [Example 6]] ] Acetamide (3.51 g, 0.01 m
Ol) was dissolved in 1,2-dichloroethane (50 ml), sodium hydrogen carbonate (5 g) and (2R) -3-phenyl-2-phthalimidopropionyl chloride (3.
6 g, 0.0115 mol) was added, and water (2 ml) was added with stirring at room temperature. After stirring at room temperature overnight, water (50
ml) was added, and the mixture was heated and stirred at about 60 ° C. for 30 minutes.
After 1,2-dichloroethane was distilled off under reduced pressure, the released oily substance was dissolved in ethyl acetate (50 ml), the organic layer was separated, and the solution was sequentially washed with saturated aqueous sodium carbonate solution, 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. Washed. After drying over anhydrous sodium sulfate, the ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using a mixed solvent of ethyl acetate and diethyl ether (1: 1) as an eluting solvent (mobile phase). , 2-benzyl-N-{(N-methylanilino) carbonylmethyl} -2-phthalimido-N- of white crystals showing mp 97-99 ° C.
{2- (piperidinocarbonyl) phenyl} acetamide (5.3 g, 84%) was obtained. IR (nujol method) ν _max cm ^-1 : 1780,172
0, 1680, 1640 (C = O). LR-FAB-MS m / z (%): 629 (M + 1)
⁺ (71). NMR (DMSO-d ₆ ) δ: 0.8-1.8 (6H,
m), 2.7-3.7 (10H, m), 4.3-5.8.
(2H, m), 6.7-8.1 (18H, m). Elemental analysis (C ₃₈ H ₃₆ N ₄ O ₅ ) Theoretical value (%): C, 72.59; H, 5.77; N, 8.91 Actual measurement value (%): C, 72.63; H, 5 .84; N, 9.06

[Step C]: 2 obtained in the above [Step B]
-Benzyl-N-{(N-methylanilino) carbonylmethyl} -2-phthalimido-N- {2- (piperidinocarbonyl) phenyl} acetamide (5.1 g, 0.
8012 mol) was dissolved in methanol (100 ml) with heating, and 80% hydrazine hydrate (0.613 g,
0.0098 mol) was added. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure to half volume, and 0.5N hydrochloric acid (50 ml) was added. After stirring at room temperature for 3 hours, the mixture was neutralized with a saturated aqueous sodium carbonate solution. After filtering the precipitated insoluble matter, methanol was distilled off under reduced pressure, and the pH was adjusted to 10 with a saturated sodium carbonate aqueous solution. The liberated oily substance was extracted with methylene chloride, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the methylene chloride was distilled off under reduced pressure.
-Amino-2-benzyl-N-{(N-methylanilino) carbonylmethyl} -N- {2- (piperidinocarbonyl) phenyl} acetamide was obtained.

[Step D]: 2 obtained in the above [Step C]
-Amino-2-benzyl-N-{(N-methylanilino) carbonylmethyl} -N- {2- (piperidinocarbonyl) phenyl} acetamide was dissolved in tetrahydrofuran (20 ml) with heating to give 3-methylphenylisocyanate ( 1.08 g, 0.00812 mol) was added. After stirring at room temperature for 24 hours, tetrahydrofuran was distilled off under reduced pressure, methylene chloride was added to the residue to dissolve it, and the residue was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water. After drying over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of petroleum ether and diethyl ether to give mp 92-94 ° C.
(+)-2-benzyl-N- of white powder crystals showing
{(N-methylanilino) carbonylmethyl} -2-
{3- (3-Methylphenyl) ureido} -N- {2-
(Piperidinocarbonyl) phenyl} acetamide (4.0 g, 78%) was obtained. [Α] _D ; +9.16 (25 ° C., c = 1.023, Me
OH). IR (nujol method) ν _max cm ^-1 : 3370,335
0 (NH), 1670, 1660, 1640, 1620
(C = O). LR-FAB-MS m / z (%): 632 (M + 1)
⁺ (14). HR-FAB-MS m / z (C 38 H 42 N 5 O 4) (M +
1) ⁺ : theoretical value: 632.3237; measured value: 632.326
2. NMR (DMSO-d ₆ ) δ: 0.8-1.7 (9H,
m), 2.22, 2.27 and 2.31 (3H,
each), 2.7-5.0 (9H, m), 6.5.
-8.7 (20H, m). Elemental analysis (C ₃₈ H ₄₁ N ₅ O ₄ ) Theoretical value (%): C, 72.24; H, 6.54; N, 11.09 Actual value (%): C, 71.97; H, 6 .91; N, 10.65.

[Formulation Example 1] The compound of Example 7 and lactose are mixed and ground, and lactose, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate, carboxymethyl cellulose calcium, and talc are added to the mixture, and the mixture is further homogenized. 20 and containing 50 mg of the active ingredient by pressure molding using a tableting machine.
0 mg / tablet tablets were produced. Compound of Example 7 50 mg Lactose 60 mg Corn starch 40 mg Microcrystalline cellulose 30 mg Hydroxypropyl cellulose 8 mg Magnesium stearate 1 mg Carboxymethyl cellulose calcium 10 mg Talc 1 mg Total 200 mg

[Formulation Example 2] The following components are mixed and pressure-molded using a tableting machine to contain 100 mg of the active ingredient 22.
Tablets of 5 mg / tablet were produced. Compound of Example 7 100 mg Microcrystalline cellulose 55 mg Lactose 49 mg Magnesium stearate 2 mg Hydroxypropyl cellulose 2 mg Carboxymethyl cellulose sodium 15 mg Talc 2 mg Total 225 mg

Formulation Example 3 The compound of Example 7 and lactose are mixed and ground, and the mixture is further homogenized by adding lactose, corn starch, magnesium stearate, calcium carboxymethyl cellulose, hydroxypropyl cellulose and light anhydrous silicic acid. Mixed. No. 3 gelatin hard capsules were filled with this at a ratio of 200 mg per capsule to produce capsules. Compound of Example 7 50 mg Lactose 115 mg Corn starch 20 mg Magnesium stearate 1 mg Carboxymethyl cellulose calcium 10 mg Hydroxypropyl cellulose 2 mg Light anhydrous silicic acid 2 mg Total 200 mg

Formulation Example 4 After thoroughly mixing the following compounds, a wetting liquid (30% ethanol) was added and kneaded, granulated by an extrusion granulator, immediately sized by a marumerizer, and then dried, It was sieved to produce 12-42 mesh columnar granules. Composition in columnar granules 200 mg Compound of Example 7 50 mg Lactose 59 mg Corn starch 40 mg Microcrystalline cellulose 39 mg Hydroxypropyl cellulose 2 mg Carboxymethyl cellulose 10 mg

Formulation Example 5 An injection containing the following components containing 1 mg of the compound of Example 7 per 1 ml was prepared by a conventional method. Compound of Example 7 10 mg Polyethylene glycol 400 for injection 2 ml Sodium chloride 1 mg Distilled water for injection is added to make a total volume of 10 ml.

Test Example 1 CCK in vitro
-A, CCK-B and test on gastrin receptor antagonism (1) CCK-A and CCK-B receptor antagonism Preparation of CCK receptor preparation: ddY male mice were decapitated and then pancreas (CCK-A ) And cerebral cortex (CCK-B)
Was promptly removed. Preparation of Receptor Specimen (Coarse Membrane Fraction): Mice were killed by decapitation,
Immediately, the pancreas and the cerebrum were taken out and washed with a pre-cooled PBS solution to separate the cerebral cortex. The pancreas and cerebral cortex were washed again with 50 mM Tris buffer (pH 7.4, cooled). The pancreas was weighed at 0.5 to 1.0 g / vial and stored at −80 ° C. until use. Add 10 times amount of 50 mM Tris buffer, homogenize (7 strokes) with a Teflon-glass homogenizer,
Furthermore, it homogenized for 20 seconds with a Polytron homogenizer. The pellet was obtained by centrifugation at 40,000 xg for 15 minutes. A 10-fold amount of 50 mM Tris buffer was added, the mixture was homogenized with a Polytron homogenizer for 20 seconds, and similarly centrifuged to obtain a pellet (repeated twice to measure the protein amount). 10 volumes of incubation buffer (10 mM HEPES, 130 mM N
_{aCl, 4.7mM KCl, 5mM MgCl 2} · 6H
₂ O, 1 mM EGTA, 5 mg / ml BSA and 0.
25 mg / ml bacitrosin) was added and homogenized for 20 seconds with a Polytron homogenizer, and finally the cerebral cortex was 200 times and the pancreas was 100 times with the same buffer.
It was diluted twice and used as CCK-B and CCK-A receptor specimens, respectively. Binding assay: Preparation of test drug solution: Weigh test compound in glass test tube,
It was dissolved in a DMSO solution to prepare a 10 mM concentration. Then
Dilute 2 times with distilled water and 2 times with 50% DMSO solution to obtain 2.5
mM (final concentration 0.1 mM) was prepared. Furthermore,
Each 1/10 concentration was diluted to 2.5 nM (final concentration 0.1 nM). 20 μl of the above test drug solution in a tube,
10 μl of [ ³ H] CCK-8 (50 nM) and 470 μl of receptor preparation were added. After incubation at 25 ° C for 30 minutes, suction filtration (Whatman gla
ss microfilter, GF / C), and washed 3 times with cold 50 mM Tris buffer. 5 ml
Add Instagel Cocktail of, and leave it for several hours after shaking,
Radioactivity was measured by liquid scintillation counter. The binding number was measured by 50% DMS instead of the test drug solution.
Solution O was used, and cerulein (1 μM) was used to measure the number of non-specific bindings. The specific binding number [total binding number (dpm) -non-specific binding number (dpm)] of the test drug solution was calculated and the competitive inhibition rate was determined. The results are shown in Table 1 as IC ₅₀ values.

(2) Gastrin Receptor Antagonistic Action Preparation of Gastrin Receptor Specimen: After slaughtering a Hartley male guinea pig by decapitation, the stomach was rapidly removed and Berglin and Obrink, Actor Physiologica Scandinavian, Vol. 96, Pages 150-159 (1976
Year) [Berglingh and Obrink, Acta Physiologica Scan
dinavica, 96, 150-159 (1976)] and Priceman et al. J. Receptor Research, Volume 3, 647-
Page 665 (1983) [Praissman et al., CJ
Receptor Res., 3, 647-665 (1983)]
Gastric mucosal glands were prepared. Preparation of receptor specimen (free gastric gland): A guinea pig was killed by decapitation, the stomach was immediately removed, the greater curvature was incised, and the contents were washed in cold water. The gastric mucosa was peeled off, thoroughly washed, and then chopped with sharp scissors in a standard buffer solution containing the following ingredients: 1
28 mM NaCl, 4.8 mM KCl, 5 mM N
aHCO ₃ , 1.2 mM KH ₂ PO ₄ , 1.2 mM Mg
SO _4, 2mM CaCl _2, 10mM glucose and 4 mM L-glutamine, 12.5 mM of pH7.4
HEPES with 0.025% trypsin inhibitor, M
Add EM vitamin solution and MEM amino acid solution. After washing the minced tissue, 0.1% collagenase and 0.
Incubated for 40 minutes in a 37 ° C. shaking bath with buffer containing 1% BSA. The tissue was passed through a 20 ml plastic syringe four times to release the gastric glands and then filtered through a 200 mesh filter. The filtered gastric glands were centrifuged at 270 xg for 2 minutes and washed twice by resuspension and centrifugation to obtain gastrin receptor specimens. Binding assay: Preparation of test drug solution: Weigh test compound in glass test tube,
It was dissolved in DMSO solution to prepare 10 mM (final concentration 0.1 mM). Furthermore, each 1/10 concentration was diluted to 10 nM (final concentration 0.1 nM). The prepared washed guinea pig gastric glands were resuspended in 40 ml of standard buffer containing 0.25 mg / ml bacitracin. Siliconized 1.5
Add 230 μl of gastric gland to a ml plastic tube and
After incubation for 5 minutes, 10 μl of buffer (for total binding) or gastrin (final concentration 1 μM, for non-specific binding) and 2.5 μl of DMSO or the test drug solution and 10 μl of ¹²⁵ I-gastrin (NEW, 2200).
Ci / mmol, final 100 pM) was added. After incubation for 15 minutes at 25 ° C., 1 ml of chilled buffer was added and centrifuged at 9000 × g for 1 minute.
After washing with 0.5 ml of a buffer solution, the radioactivity of the free gastric glands collected by cutting the tip of the plastic tube in which the free gastric glands were precipitated was measured by a gamma counter. Specific binding number of test drug solution [total binding number (dp
m) -the number of non-specific bindings (dpm)] was calculated and the competitive inhibition rate was determined. The results are shown in Table 1 as IC ₅₀ values.

[0059]

[Table 1]

[Test Results] From the above results, it was revealed that the compound of the present invention has CCK-A, B and gastrin receptor antagonistic activity.

Test Example 3 Acute Toxicity Test In a ddY male mouse (5 weeks old, 5 mice per group), the compound of the present invention (500 mg / kg) was suspended in a 0.5% sodium carboxymethylcellulose solution and fasted for 24 hours. ,
Oral administration and observation for 7 days after administration revealed no death in any case.

[0062]

As described above, N-{(2-substituted aminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido of the present invention is obtained. Since the 2-substituted acetamide derivative has CCK-A, B and gastrin receptor antagonistic activity, it is effective in treating diseases related to CCK and gastrin receptor such as nervous system and digestive system, especially gallbladder, pancreas, gastrointestinal system. It is useful as a preventive and therapeutic drug.

 ─────────────────────────────────────────────────── --Continued front page (54) [Title of the Invention] N-{(2-substituted aminocarbonyl) phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methyl) Phenyl) ureido} -2-substituted acetamide derivative

Claims (5)

[Claims] 1. A compound represented by the following general formula (I): [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group or a benzyl group. R ² and R ³ are the same or different and each is a hydrogen atom,
Or a lower alkyl group or a phenyl group, or R ^2, R ³ together form a C ₄ -C ₆ alkylene group. ] N-{(2-substituted aminocarbonyl) represented by
Phenyl} -N-{(N-methylanilino) carbonylmethyl} -2- {3- (3-methylphenyl) ureido} -2-substituted acetamide derivative. 2. R ¹ , R ² are hydrogen atoms, R ³ is an isopropyl group or a phenyl group, or R ² , R ³
The compound of claim 1, wherein are taken together as a pentamethylene group. 3. R ¹ is a methyl group, R ² is a hydrogen atom, R ³ is an isopropyl group or a phenyl group,
Alternatively, the compound according to claim 1, wherein R ² and R ³ together are a pentamethylene group. 4. R ¹ is a benzyl group, R ² is a hydrogen atom, R ³ is an isopropyl group or a phenyl group, or R ⁴ and R ³ together are a pentamethylene group. The compound according to item 1. 5. A preventive and / or therapeutic agent for a disease associated with CCK and gastrin receptor, which comprises the compound according to any one of claims 1 to 4 as an active ingredient.