JPH09227523A - Anti-cck active compound derived from serine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new serine derivative compound, having strong and selective antagonistic and inhibiting activities for cholecystokinin receptors and effective against pancreatitis, pancreatic cancer, duodenal cancer, gastric cancer, peptic ulcer, colitis, cholecystic functional dystonia, etc. SOLUTION: This anti-cholecystokinin (anti-CCK) active compound is represented by formula I [R is phenyl, naphthyl, thiazolopyrimidinyl, pyrazolopyrimidinyl or a group which is a 5- or a 6-membered ring group having one to two O, S or N atoms as ring constituent hetero-atoms and may be condensed with a benzene ring (except indolyl group); (n) is 0 or 1] or its pharmacologically permissible salt, e.g. (R)-1-[3-(3-carboxy-2-pyridyl)thio-2-(N'-2- methylphenyl)ureido]propionyl-4-diphenylmethylpiperazine. The compound represented by formula I is obtained by reacting, e.g. a compound represented by formula II or its reactive derivative or a compound having a protecting group thereof with an isocyanate represented by the formula, RNCO or a carboxylic acid represented by the formula, RCOOH.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a serine derivative compound and a compound having potent and selective competitive inhibitory activity against cholecystokinin (CCK) receptor.

[0002]

2. Description of the Related Art CCK is a peptide gastrointestinal hormone released into the blood from the mucosal epithelium of the duodenum by degradation products of proteins and fats in food. It is known to exert physiological effects such as a stimulating effect. Subsequently, it was revealed that CCK also exists in the central nervous system such as the brain, and CCK has become known as a cerebral intestinal peptide hormone having both a function as a neurotransmitter and a function as a gastrointestinal hormone. As its effects, there are currently reported effects such as promotion of pancreatic exocrine secretion, promotion of gallbladder contraction, promotion of intestinal peristalsis, suppression of small intestinal absorption, and increase in gastric acid secretion. CCK is CCK58, CCK39,
Peptides such as CCK33 and CCK8 have been isolated from tissues, and their structures are common at the four C-terminal amino acid residues of the gastrointestinal hormone gastrin. recent years,
As a result of research on CCK and CCK receptor, CCK-A receptor as a peripheral receptor and CCK as a central receptor
-B receptor has been found to be present,
Various physiologically active effects have also been reported for antagonists against these. For example, CCK-A receptor antagonists are known to inhibit pancreatic exocrine secretion, inhibit gallbladder contraction, promote gastric emptying, inhibit intestinal motility, and CCK-B receptor antagonists are known to have antiulcer activity. I have. Therefore, it is speculated that the CCK receptor antagonist may be useful for treating diseases such as pancreatitis, pancreatic cancer, peptic ulcer, biliary dysfunction, and colitis (Japanese Patent Laid-Open No. 62-1812).
46, 63-201156, JP-A-2-1117.
No. 74, etc.). In particular, since it has important actions such as stimulation of pancreatic enzyme secretion on the pancreas, the onset of acute pancreatitis,
It is highly possible that CCK is mediated by the binding to the receptor as one of the factors of progress, and it is predicted that the CCK receptor antagonist will be useful for the treatment of pancreatitis. Against this background, many compounds that competitively and competitively inhibit the CCK receptor have been reported, and their clinical application is drawing attention. For example, glutamic acid derivative CR-1505 (roxyglumide, JP-A-62-181246), which is a CCK-A receptor antagonist, and benzodiazepine derivative FK-480 (JP-A-2-111774).
Japanese patent publication) etc. are regarded as promising as a remedy for pancreatitis.

[0003]

An object of the present invention is to provide a serine derivative having a strong inhibitory activity on CCK and a selective competitive inhibitory effect on CCK-A receptor. That is, the present invention is a CCK receptor antagonist which is useful for the prevention and treatment of pancreatitis, pancreatic cancer, duodenal ulcer, gastric ulcer, peptic ulcer, colitis, dysfunction of schizophrenia, etc. It is an object to provide an effective serine derivative.

[0004]

The compound of the present invention which achieves the above object relates to a compound represented by the following general formula (Formula 1) or a pharmaceutically acceptable salt thereof.

[0005]

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[In the formula, R represents a phenyl group, a naphthyl group, a thiazolopyrimidinyl group, a pyrazolopyrimidinyl group, one oxygen, nitrogen, or sulfur as a ring-constituting heteroatom, or a 5-membered ring having two of the same or different. Or a 6-membered ring group which may be condensed with a benzene ring (excluding indolyl group), and the same or different 1 in each of the above groups
Represents a group selected from the group consisting of groups having 1 or more substituents, and n represents 0 or 1.]

The compound represented by the general formula (Formula 1) is
Since it is a derivative from serine, the basic skeleton of the compound of the general formula (Formula 1) is represented by the following formula (Formula 2).

[0008]

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Since the compound of the present invention has an asymmetric carbon atom at the 2-position in the basic skeleton, it is obtained as a racemate or an enantiomer.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be specifically described below. Examples of the group R in the compound represented by the general formula (Formula 1) having one or two hetero atoms include a furyl group, a pyrazolyl group, a thiazolyl group, an isoxazolyl group, a pyridyl group, a benzofuryl group, A benzothienyl group,
Examples thereof include a quinolyl group, a benzopyranyl group, a benzodioxanyl group, and a thioxanthenyl group.

When R is a group having a substituent, examples of the substituent include a lower alkyl group such as a methyl group,
Lower alkoxy group such as methoxy group, lower alkylthio group such as methylthio group, halogen such as chlorine, hydroxyl group, trihalomethyl group such as trifluoromethyl group, nitro group, amino group, substituted amino group such as phenylamino group, benzoyl group , A substituted phenoxy group, for example, a dichlorophenoxy group, an oxo group and the like.

The salt of the compound represented by the general formula (Formula 1) of the present invention includes a salt derived from a free carboxyl group and an acid addition salt derived from a basic group.

Specific examples of the compound represented by the general formula (Formula 1) are shown in Tables 1 and 2 below. The compound numbers in the table are the same as the example numbers described below.

[0014]

Table 1 Compound number n R 1 1 2-Methylphenyl 2 1 3 -methoxyphenyl 3 0 4-oxo-4H-chromen-3-yl 4 0 2-naphthyl 5 0 2-quinolyl 6 0 benzo [b ] Thiophen-2-yl 7 0 benzo [b] furan-2-yl 8 0 2-methylthio-3-pyridyl 9 0 2-amino-4-chlorophenyl 10 0 4-oxo-4H-chromen-2-yl 110 9-oxo-10,10-dioxide-9H-thioxanthen-3-yl 120 0 2-amino-3-pyridyl 13 0 2-nitro-4-trifluoromethylphenyl 14 0 4-chloro-2-methoxyphenyl 15 0 2-phenylaminophenyl 16 0 2-benzoylphenyl 17 1 3,4-dichlorophenyl

[0015]

Table 2 Compound number n R 18 1 3-methylphenyl 19 1 3-chlorophenyl 20 0 2,3-dihydro-5-oxothiazolo [3,2-a] pyrimidin-6-yl 21 0 3,5- Dimethyl-4-isoxazolyl 22 0 6-chloro-2H-1-benzopyran-3-yl 23 0 4,7-dimethylpyrazolo [1,5-a] pyrimidin-3-yl 24 0 5- (3,5 -Dichlorophenoxy) -2-furyl 25 1 2,6-dichloro-4-pyridyl 26 0 3-chlorobenzo [b] thiophen-2-yl 27 0 3-quinolyl 28 0 1,5-dimethyl-1H-pyrazole- 3-yl 29 0 1,4-benzodioxan-2-yl 30 0 4,8-dihydroxy-2-quinolyl 31 0 2,4-dimethylthiazol-5-i

The compound of the present invention represented by the above general formula (Formula 1) is, for example, the following formula (Formula 3):

[0017]

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The compound represented by the formula (1), a reactive derivative thereof, or a compound having a protecting group thereof is added to the compound of formula RN
Isocyanate represented by CO, or carboxylic acid represented by the formula RCOOH [wherein R has the same meaning as in formula (1)], or a reactive derivative thereof is reacted with ureido or amide. It can be manufactured by

The compound represented by the above formula (Formula 3) has already been disclosed in, for example, Japanese Patent Application No. 6-286138, and its production method will be described below.

Basically, serine is acid amidated with diphenylmethylpiperazine (also known as benzhydrylpiperazine), and then reacted with 2-mercaptonicotinic acid,
The hydroxyl group of serine can be thioetherified to obtain a compound represented by the formula (Formula 3). Hereinafter, one example thereof will be specifically described.

First step: 3,4-dihydropyran is reacted with a compound in which the amino group of serine is protected by a t-butoxycarbonyl group to obtain a compound represented by the following formula (Formula 4).

[0022]

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(In the formula, Boc represents a t-butoxycarbonyl group and R ₁ represents a tetrahydropyranyl group). Pyridinium p-toluenesulfonate is used as a catalyst for this addition reaction. Examples of the solvent used include dichloromethane, chloroform, tetrahydrofuran and the like.

Second step: A compound represented by the following formula (formula 5) is obtained by subjecting the compound represented by the formula (formula 4) to condensation reaction with diphenylmethylpiperazine.

[0025]

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1-Ethyl-3-as the condensation reagent used
(3-Dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide is used. 1-hydroxybenztriazole (HOBT) is appropriately used as an auxiliary agent. Examples of the solvent used include tetrahydrofuran, ethyl acetate, acetonitrile, dimethoxyethane, dimethylformamide, dichloromethane and the like. The reaction temperature is -10 to 30 ° C, and the reaction time is 3
0 minutes to 20 hours is desirable, but is not limited thereto.

Third step: The compound represented by the formula (Formula 5) is hydrolyzed under acidic conditions to remove the protecting group of the --OH group to give a free alcohol. As the hydrolysis conditions, for example, a 1N hydrochloric acid aqueous solution in tetrahydrofuran is added and stirred to easily obtain the target product.

Fourth step: The target compound of the third step is reacted with methanesulfonyl chloride or p-toluenesulfonyl chloride to obtain a compound represented by the following formula (Formula 6).

[0029]

[Chemical 6]

(In the formula, R ₂ represents a mesyl group or a tosyl group). As the solvent used in this reaction, dichloromethane, chloroform, tetrahydrofuran, dioxane,
Ethyl acetate, dimethylformamito, etc., and mixtures thereof are used. The base used may be a tertiary amine such as triethylamine, pyridine, diisopropylethylamine, N, N-diethylaniline, or an inorganic base such as potassium carbonate. The reaction temperature is preferably -20 to 50 ° C.

Fifth step: A compound represented by the formula (Formula 6) is reacted with ethyl 2-mercaptonicotinate,
Obtain the corresponding thioether compound. As the reaction solvent, dimethylformamide, dimethylsulfoxide, N, N'-dimethylimidazolidinone, tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile and the like may be used, and if necessary, a base such as potassium carbonate and triethylamine may be used.

Sixth step: The protecting group Boc of the object of the fifth step is eliminated to obtain a compound represented by the following formula (Formula 7) corresponding to the compound of the formula (Formula 3).

[0033]

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The above Boc group (t-butoxycarbonyl group) can be easily eliminated by acid treatment with trifluoroacetic acid or hydrogen chloride / ethyl acetate,
A corresponding compound represented by the formula (Formula 7) is obtained.

Next, as described above, the compound represented by the formula (Formula 3) or a derivative thereof, for example, the compound represented by the formula (Formula 7) and the compound represented by the formula RCOOH or RNCO, Alternatively, the reaction conditions in the case of producing the compound represented by the general formula (Formula 1) by reacting with a reactive derivative thereof will be described. Hereinafter, as an example, the case of using the compound represented by the formula (Formula 7) will be described.

Amidation step: The reaction conditions in the case of using RCOOH or its reactive derivative may be the same as those in the above-mentioned second step. Ureidation step: Examples of the solvent used when RNCO or its reactive derivative is dichloromethane,
Tetrahydrofuran, acetonitrile, ethyl acetate, dimethylformamide and the like can be mentioned. The reaction condition may be a conventional condition for ureido formation by addition of isocyanate.

The amide or ureide obtained in the above step is hydrolyzed to obtain the compound of the present invention represented by the general formula (Formula 1). Examples of the reagent used include lithium hydroxide, potassium hydroxide, potassium carbonate and the like.
Further, examples of the solvent include tetrahydrofuran, ethanol, acetonitrile, water, and a mixture thereof.

Subsequent Steps The carboxyl group in the formula (Formula 1) can be converted into its salt, or when the compound itself is basic, it may be converted into its acid addition salt.

[0039]

EXAMPLES Examples of the compounds of the present invention will be shown below. The production examples of the raw material compounds used in the examples will be omitted by showing production examples of the raw material compounds used in the examples, but the present invention is not limited thereto.

Production Example 1 Ethyl 2-mercaptonicotinate (1) Ethyl 2-chloronicotinate 25.7 g of 2-chloronicotinic acid was dissolved in 350 ml of dimethylformamide, and 23.6 g of potassium carbonate and 15.8 ml of ethyl iodide were added. The mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and ethyl acetate (200 ml x
It was extracted in 3), washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 29.7 g of the title compound. Yield: 98% NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.1 Hz), 4.41 (2
H, q, J = 7.1Hz), 7.35 (1H, dd, J = 7.5Hz, 5.9Hz), 8.16 (1H, d
d, J = 7.5Hz, 1.7Hz), 8.52 (1H, dd, J = 5.9Hz, 1.7Hz)

(2) Ethyl 2-mercaptonicotinate 55.9 g of sodium sulfide nonahydrate, 59.7 g of sulfur powder
250 ml of ethanol was added to g, and the mixture was heated under reflux for 1.5 hours. 28.8 g of ethyl 2-chloronicotinate was added to this solution.
40 ml ethanol solution was added and the mixture was stirred at 70 ° C. for 4 hours. After allowing to cool to room temperature, the reaction solution was cooled with ice 2
It was added to 240 ml of N hydrochloric acid aqueous solution. The pH was adjusted to 6 with sodium hydrogen carbonate, and the insoluble matter was filtered off. About 250
The mixture was concentrated to ml, saturated with sodium chloride, and extracted with dichloromethane / ethanol = 9/1 (100 ml × 3). After washing with a saturated saline solution, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 22.4 g of the title compound. Yield: 79% NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1 Hz), 4.42 (2
H, q, J = 7.1Hz), 6.89 (1H, dd, J = 7.5Hz, 5.9Hz), 7.89 (1H, d
d, J = 5.9Hz, 1.7Hz), 7.96 (1H, dd, J = 7.5Hz, 1.7Hz)

Example 1 (1) Nt-butoxycarbonyl-O- (2-tetrahydropyranyl) -L-serine Nt-butoxycarbonyl-L-serine 7.65 g,
3.88 g of 3,4-dihydro-2H-pyran was dissolved in 60 ml of dichloromethane, 0.47 g of pyridinium p-toluenesulfonate was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with water and saturated brine, the solvent was evaporated under reduced pressure to give the title compound (1) as a colorless oily substance, 9.90 g.
Obtained. Yield: 92%

(2) (S) -4-diphenylmethyl-1
-(3-Hydroxy-2-t-butoxycarbonylamino) propionylpiperazine Nt-butoxycarbonyl-O- (2-tetrahydropyranyl) -L-serine 2.89 g, 1-diphenylmethylpiperazine 2.52 g, 1 -Hydroxybenzotriazole monohydrate (1.53 g) in dichloromethane (30 ml)
Was dissolved in the solution, 1.92 g of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.98 g of a residue. To this, 20 ml of tetrahydrofuran, 1N hydrochloric acid 30
After adding ml, the mixture was stirred at room temperature for 1 hour. The reaction solution was made alkaline with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate (50 ml × 3), and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 4.56 g of a residue. This was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1
/ 1) to give 2.31 g of the title compound (2) as colorless crystals. Yield: 53%

IR (KBr) cm ⁻¹ : 1690, 1640, 1450, 1360 NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.3 to 2.5 (4H,
m), 3.4 ~ 3.8 (7H, m), 4.24 (1H, s), 4.5 ~ 4.7 (1H, m), 5.
72 (1H, bd), 7.1-7.3 (6H, m), 7.3-7.5 (4H, m) TLC: _Rf = 0.26 [hexane / ethyl acetate = 1
/ 1)

(3) (S) -4-diphenylmethyl-1
-(3-Mesyloxy-2-t-butoxycarbonylamino) propionylpiperazine 2.20 g of the above compound (2), triethylamine 1.1.
15 g of dichloromethane was added to 1 g and dissolved, and methanesulfonyl chloride 1.15 g of dichloromethane 5 ml
The solution was added dropwise at −10 ° C. over 30 minutes and then stirred for 30 minutes. Add dichloromethane to the reaction solution,
After washing with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.53 g of the title compound (3) as a colorless amorphous substance. Yield: 98%

NMR (CDCl ₃ ) δ: 1.42 (9H, s),
2.3 ~ 2.5 (4H, m), 3.00 (3H, s), 3.5 ~ 3.7 (4H, m), 4.24 (1
H, s), 4.2 ~ 4.4 (2H, m), 4.8 ~ 5.0 (1H, m), 5.54 (1H, bd),
7.1 to 7.3 (6H, m), 7.3 to 7.5 (4H, m) TLC: R _f = 0.54 [hexane / ethyl acetate = 1
/ 1)

(4) (R) -4-diphenylmethyl-1
-[3- (3-Ethoxycarbonyl-2-pyridyl) thio-2-t-butoxycarbonylamino] propionylpiperazine Sodium hydride (60%) (76 mg) was added with dimethylformamide (5 ml) under an argon stream at -5 ° C. In 2
-330 mg of ethyl mercaptonicotinate was added with 5 ml of dimethylformamide. After stirring at -5 ° C for 30 minutes, 490 mg of the above compound (3) was added together with 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 5 hours. The reaction solution was added to 150 ml of water, and the precipitate was collected by filtration,
When dried under reduced pressure, 830 mg of a crude product was obtained. This was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give the title compound (4).
Was obtained as yellow crystals (516 mg). Yield: 90%

NMR (CDCl ₃ ) δ: 1.2 to 1.4 (3H,
m), 1.35 (9H, s), 2.2 ~ 2.5 (4H, m), 3.0 ~ 3.9 (6H, m), 4.
25 (1H, s), 4.35 (2H, q, J = 7.0Hz), 4.9 ~ 5.1 (1H, m), 5.4
~ 5.6 (1H, m), 6.9 ~ 7.1 (1H, m), 7.1 ~ 7.6 (10H, m), 8.6
~ 8.7 (1H, m), 8.3 ~ 8.4 (1H, m)

(5) (R) -4-diphenylmethyl-1
-[3- (3-Ethoxycarbonyl-2-pyridyl) thio-2- (N'-2-methylphenyl) ureido] propionylpiperazine The compound (4) 500 mg was added to dichloromethane 5 ml.
Add 1 ml of concentrated hydrochloric acid at room temperature to vigorously dissolve.
Stirred for a minute. The reaction mixture was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate solution, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 5 ml of dichloromethane was added and dissolved. 116 mg of o-tolyl isocyanate was added, and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off to obtain 536 mg of a crude product.
This was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to obtain 373 mg of the title compound (5) as colorless crystals. Yield: 7
2%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 6.
9Hz), 2.18 (3H, s), 2.1 ~ 2.6 (4H, m), 3.1 ~ 4.0 (6H, m),
4.32 (1H, s), 4.35 (2H, q, J = 6.9Hz), 5.1 to 5.3 (1H, m), 6.4
~ 6.6 (1H, m), 6.8 ~ 7.5 (16H, m), 8.1 ~ 8.2 (1H, m), 8.
2 to 8.3 (1H, m)

(6) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (N'-2-methylphenyl) ureido] propionyl-4-diphenylmethylpiperazine The above compound (5 ) 373 mg of tetrahydrofuran 2
95 ml of lithium hydroxide, 1 ml of water and 2 ml of methanol were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, neutralized with 10% aqueous citric acid solution, and extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6) as colorless crystals, 332 mg. Yield: 93%

IR (KBr) cm ⁻¹ : 1635, 1540, 1450, 1390 NMR (CDCl ₃ ) δ: 2.0 to 2.2 (3H, m), 2.2 to 2.6
(4H, m), 3.4 ~ 4.0 (6H, m), 4.32 (1H, s), 5.1 ~ 5.3 (1H, m),
6.9 ~ 7.5 (16H, m), 7.7 ~ 7.9 (1H, m), 8.0 ~ 8.1 (1H, m),
8.3 to 8.4 (1H, m) Specific rotation: [α] _D ²⁵ = + 3.6 ° (c = 1.1, DM
SO)

Example 2 (1) (R) -4-diphenylmethyl-1- [3- (3
-Ethoxycarbonyl-2-pyridyl) thio-2-
(N′-3-methoxyphenyl) ureido] propionylpiperazine (R) -4-diphenylmethyl-1- [3- (3-ethoxycarbonyl-2-pyridyl) thio-2-t-butoxycarbonylamino] propionylpiperazine [ Less than,
500 mg (abbreviated as (4) of Example 1) was dissolved by adding 5 ml of dichloromethane, 1 ml of concentrated hydrochloric acid was added at room temperature, and the mixture was vigorously stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate solution, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and 5 ml of dichloromethane was added and dissolved. 148 g of 3-methoxyphenyl isocyanate was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off to obtain 620 mg of a crude product. This was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1 /
Purified in 1) and the title compound (1) as colorless crystals 43
2 mg was obtained. Yield: 82%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.3Hz), 2.2 ~ 2.5 (4H, m), 3.2 ~ 3.4 (2H, m), 3.5 ~ 4.0 (4
H, m), 3.67 (3H, s), 4.32 (1H, s), 4.36 (2H, q, J = 7.3Hz),
5.2 ~ 5.4 (1H, m), 6.3 ~ 6.5 (1H, m), 6.7 ~ 7.0 (4H, m), 7.
0 ~ 7.4 (11H, m), 7.4 ~ 7.6 (1H, m), 8.1 ~ 8.2 (1H, m),
8.3 ~ 8.4 (1H, m)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (N'-3-methoxyphenyl) ureido] propionyl-4-diphenylmethylpiperazine The above compound (1 ) 414 mg and the title compound (2) as yellow crystals in the same manner as in (6) of Example 1 to give 376 mg.
mg. Yield: 95%

IR (KBr) cm ^-1 : 1605, 1550, 149
0, 1450, 1395 NMR (DMSO-d ₆ ) δ: 2.1 to 2.5 (4H, m), 3.0 to
4.0 (6H, m), 3.76 (3H, s), 4.32 (1H, s), 4.9 ~ 5.1 (1H, m),
6.4 ~ 6.5 (1H, m), 6.5 ~ 6.6 (1H, m), 6.7 ~ 6.8 (1H, m), 7.0
~ 7.5 (13H, m), 8.1 ~ 8.2 (1H, m), 8.4 ~ 8.5 (1H, m), 8.78
(1H, s) Specific rotation: [α] _D ²⁵ = + 7.4 ° (c = 1.1, DM
SO)

Example 3 (1) (R) -4-diphenylmethyl-1- [3- (3
-Ethoxycarbonyl-2-pyridyl) thio-2- (4
-Oxo-4H-chromen-3-yl) carbonylamino] propionylpiperazine 310 mg of (4) of Example 1 was added to 5 ml of dichloromethane.
Add 1 ml of concentrated hydrochloric acid at room temperature to vigorously dissolve.
Stirred for a minute. The reaction mixture was diluted with ethyl acetate, neutralized with saturated sodium hydrogen carbonate, washed with saturated brine solution, and dried over anhydrous sodium sulfate. Evaporate the solvent,
8 ml of dichloromethane was added and dissolved. Cromon-3-
Carboxylic acid 116 mg, 1-hydroxybenzotriazole monohydrate 110 g and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 156 mg
Was added and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine solution. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 410 mg of a crude product. This was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to obtain 276 mg of the title compound (1) as colorless crystals. Yield: 79%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.0Hz), 2.1 ~ 2.6 (4H, m), 3.1 ~ 4.0 (6H, m), 4.23 (1H,
s), 4.35 (2H, q, J = 7.0Hz), 5.4 ~ 5.7 (1H, m), 6.9 ~ 7.6 (1
3H, m), 7.6 ~ 7.8 (1H, m), 8.0 ~ 8.3 (2H, m), 8.3 ~ 8.5
(1H, m), 8.83 (1H, s), 8.9 ~ 9.1 (1H, m)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (4-oxo-4H-chromen-3-yl) carbonylamino] propionyl-
4-Diphenylmethylpiperazine Using 276 mg of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as off-white crystals in the same manner as in 2.
42 mg was obtained. Yield: 91%

IR (KBr) cm ^-1 : 1640, 1550, 144
5, 1390, 1230 NMR (DMSO-d ₆ ) δ: 2.1 to 2.4 (4H, m), 3.2 to
4.0 (6H, m), 4.32 (1H, s), 5.2 ~ 5.4 (1H, m), 7.0 ~ 7.5 (10
H, m), 7.6 ~ 7.7 (1H, m), 7.7 ~ 7.8 (1H, m), 8.0 ~ 8.3 (3
H, m), 8.4 ~ 8.5 (1H, m), 8.7 ~ 8.8 (1H, m), 9.2 ~ 9.3 (2H,
m) Specific rotation: [α] _D ²⁵ = -53.3 ° (c = 1.0, D
MSO)

Example 4 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2-naphthyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Naphthalene-2-carboxylic acid 0.68 g instead of chromone-3-carboxylic acid, (4) 2 of Example 1. Using 0.000 g of the title compound (1) in the same manner as in (3) of Example 3.
Was obtained as a colorless amorphous form to obtain 1.80 g. Yield: 83%

NMR (CDCl ₃ ) δ: 1.36 (3H, t, J =
7.0Hz), 2.3 ~ 2.6 (4H, m), 3.4 ~ 3.6 (1H, m), 3.6 ~ 3.8
(Total 3H, m, m), 3.8 to 4.0 (2H, m), 4.24 (1H, s), 4.35 (2H,
q, J = 7.0Hz), 5.5 to 5.7 (1H, m), 7.05 (1H, dd, J = 4.6Hz, 7.2H
z), 7.2 to 7.7 (13H, m), 7.7 to 7.9 (4H, m), 8.1 to 8.3 (2H,
m), 8.4 ~ 8.5 (1H, m)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (2-naphthyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Compound (1) 1. Using 50 g, (6) of Example 1
By a method similar to that of the above, 1.40 g of the title compound (2) was obtained as pale yellow crystals. Yield: 98%

IR (KBr) cm ⁻¹ : 1640, 1440, 1220, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 3.3 to
4.0 (6H, m), 4.32 (1H, s), 5.2 ~ 5.4 (1H, m), 7.1 ~ 7.5 (11
H, m), 7.5 ~ 7.7 (2H, m), 7.9 ~ 8.1 (4H, m), 8.23 (1H, d, J
= 7.6Hz), 8.5 to 8.7 (2H, m), 8.9 to 9.1 (1H, m) Specific optical rotation: [α] _D ²⁵ = -54.2 ° (c = 1.0, D)
MSO)

Example 5 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2-quinolyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid was replaced with 0.69 g of quinoline-2-carboxylic acid, (4) 2 of Example 1. Using 0.000 g of the title compound (1) in the same manner as in (3) of Example 3.
1.01 g was obtained as a colorless amorphous form. Yield: 46%

NMR (CDCl ₃ ) δ: 1.36 (3H, t, J =
7.0Hz), 2.3 ~ 2.5 (4H, m), 3.50 (1H, dd, J = 8.5Hz, 13.9H
z), 3.6 ~ 4.0 (5H, m), 4.22 (1H, s), 4.35 (2H, q, J = 7.0H
z), 5.5 ~ 5.7 (1H, m), 7.03 (1H, dd, J = 4.9Hz, 7.9Hz), 7.1
~ 7.5 (10H, m), 7.5 ~ 7.9 (3H, m), 8.1 ~ 8.3 (4H, m), 8.5
1 (1H, dd, J = 4.9Hz, 1.8Hz), 9.04 (1H, d, J = 9.2Hz)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (2-quinolyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Compound (1) 1. (6) of Example 1 using 00 g
By a method similar to the above, 0.94 g of the title compound (2) was obtained as pale yellow crystals. Yield: 98%

IR (KBr) cm ⁻¹ : 1640, 1500, 1450, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 3.5 to
3.7 (4H, m), 3.7 ~ 4.0 (2H, m), 4.33 (1H, s), 5.3 ~ 5.5 (1
H, m), 7.1 ~ 7.5 (11H, m), 7.6 ~ 7.8 (1H, m), 7.8 ~ 8.0 (1
H, m), 8.0 ~ 8.3 (4H, m), 8.5 ~ 8.7 (2H, m), 9.1 ~ 9.2 (1H,
m) Specific rotation: [α] _D ²⁵ = −39.3 ° (c = 1.0, D
MSO)

Example 6 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (benzo [b] thiophene-
2-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid was replaced by 0.71 g of benzo [b] thiophene-2-carboxylic acid, (4) of Example 1.
Using 2.00 g, and in the same manner as in (3) of Example 3, 1.78 g of the title compound (1) was obtained as a colorless amorphous form. Yield: 81%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.0Hz), 2.3 ~ 2.5 (4H, m), 3.44 (1H, dd, J = 8.9Hz, 13.9H
z), 3.5 ~ 3.8 (3H, m), 3.8 ~ 4.0 (2H, m), 4.24 (1H, s),
4.36 (2H, q, J = 7.0Hz), 5.4 ~ 5.6 (1H, m), 7.05 (1H, d
d, J = 4.6Hz, 7.8Hz), 7.1 ~ 7.6 (13H, m), 7.7 ~ 7.9 (3H,
m), 8.21 (1H, dd, J = 7.8Hz, 1.8Hz), 8.48 (1H, dd, J = 1.8
(Hz, 4.6Hz)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (benzo [b] thiophen-2-yl) carbonylamino] propionyl-4-
Diphenylmethylpiperazine Using 1.50 g of the above compound (1), (6) of Example 1 was used.
By a method similar to that of the above, 1.38 g of the title compound (2) was obtained as pale yellow crystals. Yield: 96%

IR (KBr) cm ⁻¹ : 1630, 1530, 1450, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 3.2 to
4.0 (6H, m), 4.31 (1H, s), 5.1 ~ 5.3 (1H, m), 7.1 ~ 7.6 (13
H, m), 7.9 ~ 8.1 (2H, m), 8.2 ~ 8.3 (2H, m), 8.5 ~ 8.6 (1
H, m), 9.1 to 9.3 (1H, m) Specific rotation: [α] _D ²⁵ = -63.9 ° (c = 1.1, D
MSO)

Example 7 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (benzo [b] furan-2-
Yield) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of benzo [b] furan-2-carboxylic acid 0.64 g, (4) 2.0 of Example 1
Using 0 g, and in the same manner as in (3) of Example 3, 1.85 g of the title compound (1) was obtained as a colorless amorphous form. Yield: 8
6%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.0Hz), 2.3 ~ 2.6 (4H, m), 3.45 (1H, dd, J = 8.9Hz, 14.2H
z), 3.6 ~ 4.0 (5H, m), 4.24 (1H, s), 4.36 (2H, q, J = 7.0H
z), 5.5 ~ 5.7 (1H, m), 7.07 (1H, dd, J = 4.9Hz, 7.8Hz), 7.1
~ 7.5 (14H, m), 7.62 (1H, d, J = 7.3Hz), 7.80 (1H, d, J = 8.2H
z), 8.21 (1H, dd, J = 7.8Hz, 1.8Hz), 8.51 (1H, dd, J = 1.8Hz,
(4.9Hz)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (benzo [b] furan-
2-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 1.50 g of the above compound (1), (6) of Example 1 was used.
By a method similar to the above, 1.34 g of the title compound (2) was obtained as pale yellow crystals. Yield: 94%

IR (KBr) cm ⁻¹ : 1640, 1600, 1440, 750, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 3.3 to
4.0 (6H, m), 4.32 (1H, s), 5.1 ~ 5.3 (1H, m), 7.1 ~ 7.5 (13
H, m), 7.59 (1H, s), 7.68 (1H, d, J = 7.9Hz), 7.78 (1H, d, J =
7.6Hz), 8.22 (1H, d, J = 7.9Hz), 8.5〜8.6 (1H, m), 9.0〜9.
1 (1H, m) Specific rotation: [α] _D ²⁵ = -53.7 ° (c = 1.1, D
MSO)

Example 8 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2-methylthio-3-pyridyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid was replaced with 0.67 g of 2-methylthionicotinic acid, Example 1 ( 4) Using 2.00 g, the title compound (1) was prepared in the same manner as in (3) of Example 3.
Was obtained as a colorless amorphous form, and 1.33 g was obtained. Yield: 61%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.0Hz), 2.3 ~ 2.5 (4H, m), 2.51 (3H, s), 3.3 ~ 3.5 (1H, m),
3.6 to 4.0 (5H, m), 4.25 (1H, s), 4.36 (2H, q, J = 7.0Hz), 5.
5 to 5.7 (1H, m), 6.9 to 7.1 (2H, m), 7.1 to 7.5 (11H, m), 7.7
3 (1H, dd, J = 7.6Hz, 1.8Hz), 8.21 (1H, dd, J = 1.8Hz, 7.6Hz),
8.4 to 8.5 (2H, m)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (2-methylthio-3-)
Pyridyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 1.00 g of the above compound (1), (6) of Example 1 was used.
By a method similar to that of the above, 0.93 g of the title compound (2) was obtained as pale yellow crystals. Yield: 97%

IR (KBr) cm ⁻¹ : 1640, 1550, 1390, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 2.36
(3H, s), 3.1 ~ 3.9 (6H, m), 4.32 (1H, s), 5.0 ~ 5.3 (1H, m),
7.1 ~ 7.5 (12H, m), 7.80 (1H, d, J = 7.6Hz), 8.22 (1H, d, J =
7.6Hz), 8.5-8.7 (2H, m), 8.8-9.0 (1H, m) Specific rotation: [α] _D ²⁵ = -23.7 ° (c = 1.1, D
MSO)

Example 9 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2-amino-4-chlorophenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine 0.68 g of 4-chloroanthranilic acid instead of chromone-3-carboxylic acid, of Example 1 ( 4) Using 2.00 g, the title compound (1) was prepared in the same manner as in (3) of Example 3.
To give 1.59 g of a colorless amorphous form. Yield: 73%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.0Hz), 2.3 ~ 2.6 (4H, m), 3.40 (1H, dd, J = 8.9Hz, 13.9H
z), 3.6 ~ 4.0 (5H, m), 4.26 (1H, s), 4.37 (2H, q, J = 7.0H
z), 5.3 ~ 5.7 (3H, m, bs), 6.5 ~ 6.7 (2H, m), 7.05 (1H, d
d, J = 4.8Hz, 7.8Hz), 7.1 ~ 7.6 (12H, m), 8.21 (1H, dd,
J = 7.8Hz, 1.8Hz), 8.44 (1H, dd, J = 1.8Hz, 4.8Hz)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (2-amino-4-chlorophenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine The above compound ( 1) Using 1.50 g, (6) of Example 1
By a method similar to that of the above, 1.36 g of the title compound (2) was obtained as pale yellow crystals. Yield: 94%

IR (KBr) cm ⁻¹ : 1630, 1450, 1240, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 3.1 to
4.0 (6H, m), 4.33 (1H, s), 5.0 to 5.2 (1H, m), 6.5 to 6.7 (total 3H, m, bs), 6.75 (1H, d, J = 2.1Hz), 7.1 to 7.5 (11H, m),
7.60 (1H, d, J = 8.6Hz), 8.21 (1H, dd, J = 7.8Hz, 1.8Hz), 8.5
0 (1H, dd, J = 1.8Hz, 4.7Hz), 8.60 (1H, d, J = 7.6Hz) Specific rotation: [α] _D ²⁵ = -27.5 ° (c = 1.0, D)
MSO)

Example 10 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (4-oxo-4H-chromen-2-yl) carbonylamino] propionyl-4-
Diphenylmethylpiperazine Chromone-2-carboxylic acid 0.75 g was used instead of chromone-3-carboxylic acid, and 2.00 g of (4) of Example 1 was used, and the title compound ((1) of Example 3 was used. 1)
To give 1.90 g of a pale yellow amorphous form. Yield: 85%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.0Hz), 2.3 ~ 2.6 (4H, m), 3.2 ~ 3.4 (1H, m), 3.6 ~ 4.0 (5
H, m), 4.27 (1H, s), 4.36 (2H, q, J = 7.0Hz), 5.5 ~ 5.7 (1H,
m), 7.04 (1H, s), 7.10 (1H, dd, J = 4.7Hz, 7.8Hz), 7.2 ~ 7.
6 (12H, m), 7.6 ~ 7.8 (1H, m), 8.03 (1H, d, J = 8.6Hz), 8.1
~ 8.3 (2H, m), 8.48 (1H, dd, J = 1.5Hz, 4.7Hz)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (4-oxo-4H-chromen-2-yl) carbonylamino] propionyl-
4-Diphenylmethylpiperazine Using 1.50 g of the above compound (1), (6) of Example 1
The title compound (2) was obtained as yellow crystals in the same manner as in 1.
12 g were obtained. Yield: 78%

IR (KBr) cm ^-1 : 1700, 1640, 146
0, 1300, 760, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 3.2 to
3.8 (6H, m), 4.32 (1H, s), 4.9 ~ 5.2 (1H, m), 6.9 ~ 7.6 (14
H, m), 7.7 ~ 7.8 (1H, m), 7.8 ~ 8.0 (1H, m), 8.2 ~ 8.3 (1
H, m), 8.4 to 8.6 (2H, m) Specific rotation: [α] _D ²⁵ = -9.8 ° (c = 1.1, DM
SO)

Example 11 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (9-oxo-10,10-
Dioxide-9H-thioxanthen-3-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 9-oxo-9H-
Using the thioxanthene-3-carboxylic acid 10,10-dioxide (1.14 g) and the compound (4) of Example 1 (2.00 g), the title compound (1) was prepared in the same manner as in Example 3 (1). 2.01 g of a crystalline form was obtained. Yield: 78%

NMR (CDCl ₃ ) δ: 1.36 (3H, t, J =
7.0Hz), 2.3 ~ 2.6 (4H, m), 3.5 ~ 3.8 (4H, m), 3.8 ~ 4.0 (2
H, m), 4.28 (1H, s), 4.36 (2H, q, J = 7.0Hz), 5.4 ~ 5.6 (1H,
m), 7.12 (1H, dd, J = 4.9Hz, 7.9Hz), 7.2 ~ 7.4 (6H, m), 7.
4 to 7.5 (4H, m), 7.7 to 7.9 (2H, m), 8.0 to 8.2 (2H, m), 8.2
~ 8.4 (4H, m), 8.43 (1H, s), 8.55 (1H, dd, J = 1.8Hz, 4.9Hz)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (9-oxo-10,1
0-Dioxide-9H-thioxanthen-3-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 1.50 g of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as brown crystals in the same manner as in 1.
40 g was obtained. Yield: 97%

IR (KBr) cm ⁻¹ : 1670, 1640, 1310, 1150, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 3.2 to
4.0 (6H, m), 4.32 (1H, s), 5.2 ~ 5.4 (1H, m), 7.1 ~ 7.5 (11
H, m), 7.9 ~ 8.2 (2H, m), 8.2 ~ 8.6 (6H, m), 8.70 (1H, s),
9.5-9.7 (1H, m) Specific rotation: [α] _D ²⁵ = -46.2 ° (c = 1.1, D
MSO)

Example 12 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2-amino-3-pyridyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 2-aminonicotinic acid 152 mg, (4) of Example 1. Using 604 mg, 372 mg of the title compound (1) was obtained as a colorless oil in the same manner as in (3) of Example 3. Yield: 36%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.1Hz), 2.3 to 2.6 (4H, m), 3.40 (1H, dd, J = 13.9Hz, 9.5H
z), 3.5 to 4.0 (5H, m), 4.26 (1H, s), 4.36 (2H, q, J = 7.1H
z), 5.3 ~ 5.5 (1H, m), 6.31 (2H, bs), 6.50 (1H, dd, J = 7.5H
z, 4.9Hz), 7.06 (1H, dd, J = 7.8Hz, 4.7Hz), 7.1 ~ 7.3 (6H,
m), 7.3 ~ 7.5 (4H, m), 7.57 (1H, d, J = 8.0Hz), 7.65 (1H, dd,
J = 7.8Hz, 1.7Hz), 8.07 (1H, dd, J = 4.9Hz, 1.7Hz), 8.21 (1H,
dd, J = 7.8Hz, 1.9Hz), 8.44 (1H, dd, J = 4.6Hz, 1.7Hz)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (2-amino-3-pyridyl) carbonylamino] propionyl-4-diphenylmethylpiperazine The above compound ( 1) Using 248 mg, (6) of Example 1
The title compound (2) was obtained as colorless crystals in the same manner as
2 mg was obtained. Yield: 81%

IR (KBr) cm ⁻¹ : 1630, 1580, 1450, 1240 NMR (DMSO-d ₆ ) δ: 2.1 to 2.4 (4H, m), 3.1 to
3.9 (6H, m), 4.34 (1H, s), 5.0 ~ 5.2 (1H, m), 6.59 (1H, dd, J
= 7.6Hz, 4.9Hz), 6.96 (2H, bs), 7.1 ~ 7.5 (11H, m), 7.97
(1H, dd, J = 7.9Hz, 1.5Hz), 8.08 (1H, dd, J = 4.6Hz, 1.5Hz),
8.21 (1H, dd, J = 7.9Hz, 1.9Hz), 8.50 (1H, dd, J = 4.9Hz, 1.9H
z), 8.74 (1H, d, J = 7.9Hz) Specific optical rotation: [α] _D ²⁵ = -25.8 ° (c = 1.1, D)
MSO)

Example 13 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2-nitro-4-trifluoromethylphenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 2-nitro-4-trifluoromethylbenzoic acid Using 0.93 g and 2.00 g of (4) of Example 1, 2.11 g of the title compound (1) was obtained as a colorless amorphous form in the same manner as in (1) of Example 3. Yield: 88%

NMR (CDCl ₃ ) δ: 1.39 (3H, t, J =
7.0Hz), 2.3 ~ 2.5 (4H, m), 3.33 (1H, dd, J = 8.5Hz, 14.3H
z), 3.4 ~ 3.5 (2H, m), 3.70 (1H, dd, J = 14.3Hz, 8.5Hz),
3.8 to 3.9 (2H, m), 4.24 (1H, s), 4.38 (2H, q, J = 7.0Hz), 5.5
~ 5.7 (1H, m), 7.06 (1H, dd, J = 4.6Hz, 7.8Hz), 7.2 ~ 7.5 (1
0H, m), 7.61 (1H, d, J = 8.9Hz), 7.73 (1H, d, J = 7.6Hz), 7.8
6 (1H, d, J = 7.6Hz), 8.2〜8.4 (2H, m), 8.44 (1H, dd, J = 1.5H
(z, 4.6Hz)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (2-nitro-4-trifluoromethylphenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using (2.00) of the above compound (1), (6) of Example 1
By a method similar to that of the above, 1.63 g of the title compound (2) was obtained as pale yellow crystals. Yield: 85%

IR (KBr) cm ⁻¹ : 1640, 1540, 1320, 1140, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 3.2 to
3.9 (6H, m), 4.32 (1H, s), 5.1 ~ 5.3 (1H, m), 7.1 ~ 7.6 (11
H, m), 7.8 ~ 7.9 (1H, m), 8.1 ~ 8.3 (2H, m), 8.56 (1H, s),
8.5 to 8.6 (1H, m), 9.3 to 9.5 (1H, m) Specific rotation: [α] _D ²⁵ = -4.9 ° (c = 1.0, DM
SO)

Example 14 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (4-chloro-2-methoxyphenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine 4-chloro-2-methoxybenzoic acid 0.74 g instead of chromone-3-carboxylic acid, (4) 2.00 of Example 1
In the same manner as in Example 3, (1), 2.03 g of the title compound (1) was obtained as a colorless amorphous form. Yield: 91
%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.0Hz), 2.3 ~ 2.5 (4H, m), 3.2 ~ 3.4 (1H, m), 3.6 ~ 4.0 (5
H, m), 3.96 (3H, s), 4.23 (1H, s), 4.36 (2H, q, J = 7.0Hz),
5.5 ~ 5.7 (1H, m), 6.9 ~ 7.1 (3H, m), 7.2 ~ 7.5 (10H, m),
8.04 (1H, d, J = 8.6Hz), 8.2 ~ 8.3 (1H, m), 8.4 ~ 8.5 (1H,
m), 8.6〜8.7 (1H, m)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (4-chloro-2-methoxyphenyl) carbonylamino] propionyl-4-
Diphenylmethylpiperazine Using 2.00 g of the above compound (1), (6) of Example 1
In the same manner as in 1., 1.90 g of the title compound (2) was obtained as pale yellow crystals. Yield: 99%

IR (KBr) cm ⁻¹ : 1640, 1590, 1240, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 3.2 to
3.8 (6H, m), 3.88 (3H, s), 4.31 (1H, s), 5.2 ~ 5.4 (1H, m),
7.09 (1H, d, J = 8.2Hz), 7.2 ~ 7.6 (12H, m), 7.74 (1H, d, J =
8.2Hz), 8.20 (1H, d, J = 7.6Hz), 8.51 (1H, d, J = 4.6Hz), 8.64
(1H, d, J = 8.2Hz) Specific rotation: [α] _D ²⁵ = -19.5 ° (c = 1.2, D
MSO)

Example 15 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2-phenylaminophenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine N-phenylanthranilic acid 0.85 g instead of chromone-3-carboxylic acid, (4) of Example 1 Using 2.00 g, the title compound (1) was prepared in the same manner as in (3) of Example 3.
To give 1.87 g of a colorless amorphous form. Yield: 81%

NMR (CDCl ₃ ) δ: 1.34 (3H, t, J =
7.0Hz), 2.3 ~ 2.6 (4H, m), 3.44 (1H, dd, J = 5.5Hz, 11.6H
z), 3.6 ~ 3.8 (3H, m), 3.8 ~ 4.0 (2H, m), 4.23 (1H, s),
4.31 (2H, q, J = 7.0Hz), 5.3 ~ 5.5 (1H, m), 6.6 ~ 6.8 (1H,
m), 6.9 to 7.6 (20H, m), 8.20 (1H, d, J = 7.6Hz), 8.44 (1H,
d, J = 4.6Hz), 9.17 (1H, s)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (2-phenylaminophenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine The above compound (1) Using 1.50 g, (6) of Example 1
By a method similar to that of the above, 1.40 g of the title compound (2) was obtained as pale yellow crystals. Yield: 97%

IR (KBr) cm ^-1 : 1640, 1590, 151
0, 1440, 740, 700 NMR (DMSO-d ₆ ) δ: 2.1 to 2.5 (4H, m), 3.2 to
4.0 (6H, m), 4.29 (1H, s), 5.1 ~ 5.3 (1H, m), 6.8 ~ 7.1 (2H,
m), 7.1 ~ 7.6 (17H, m), 7.7 ~ 7.8 (1H, m), 8.2 ~ 8.3 (1H,
m), 8.5 to 8.6 (1H, m), 8.8 to 9.0 (1H, m), 9.39 (1H, s) Specific rotation: [α] _D ²⁵ = + 4.4 ° (c = 1.1, DM
SO)

Example 16 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (2-benzoylphenyl)
Carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid was replaced with 0.90 g of o-benzoylbenzoic acid and 2.00 g of (4) of Example 1,
By a method similar to (1) of Example 3, 1.09 g of the title compound (1) was obtained as a colorless amorphous form. Yield: 46%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.0Hz), 2.1 ~ 2.5 (4H, m), 3.2 ~ 4.0 (6H, m), 4.22 (1H,
s), 4.37 (2H, q, J = 7.0Hz), 4.8 ~ 5.0 (1H, m), 6.8 ~ 7.0 (4
H, m), 7.1 ~ 7.5 (16H, m), 7.8 ~ 7.9 (1H, m), 8.0 ~ 8.2
(2H, m)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (2-benzoylphenyl) carbonylamino] propionyl-4-diphenylmethylpiperazine The above compound (1) 1 Using 0.000 g, (6) of Example 1
By a method similar to that of the above, 0.89 g of the title compound (2) was obtained as pale yellow crystals. Yield: 93%

IR (KBr) cm ⁻¹ : 1700, 1610, 1450, 700 NMR (DMSO-d ₆ ) δ: 1.9 to 2.3 (4H, m), 3.0 to
3.9 (6H, m), 4.17 (1H, s), 4.8 ~ 5.0 (1H, m), 6.8 ~ 7.0 (1H,
m), 7.0 ~ 7.8 (20H, m), 8.1 ~ 8.2 (1H, m), 8.4 ~ 8.5 (1H,
m) Specific rotation: [α] _D ²⁵ = + 1.0 ° (c = 1.0, DM
SO)

Example 17 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (N′-3,4-dichlorophenyl) ureido] propionyl-4-diphenylmethylpiperazine o-tolyl isocyanate 164 mg of 3,4-dichlorophenyl isocyanate instead of o-tolyl isocyanate, (4 of Example 1 ) 5
By using 01 mg, and in the same manner as in (5) of Example 1, 521 mg of the title compound (1) was obtained as a colorless amorphous form. Yield: 91%

NMR (CDCl ₃ ) δ: 1.36 (3H, t, J =
7.2Hz), 2.41 (2H, bs), 2.51 (2H, bs), 3.45 (1H, dd, J = 13.8
Hz, 9.5Hz), 3.5 to 4.0 (5H, m), 4.27 (1H, s), 4.35 (2H, q, J =
7.2Hz), 5.2 ~ 5.4 (1H, m), 6.9 ~ 7.5 (15H, m), 7.97 (1H,
s), 8.12 (1H, dd, J = 7.6Hz, 1.8Hz), 8.40 (1H, dd, J = 4.6Hz,
1.8Hz)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (N'-3,4-dichlorophenyl) ureido] propionyl-4-diphenylmethylpiperazine The above compound ( 1) Using 376 mg, (6) of Example 1
The title compound (2) was obtained as pale yellow crystals in the same manner as in 2.
Obtained 99 mg. Yield: 83%

IR (KBr) cm ^-1 : 1700, 1630, 159
0, 1540, 1480 NMR (DMSO-d ₆ ) δ: 2.1 to 2.4 (4H, m), 3.0 to
4.0 (6H, m), 4.32 (1H, s), 4.9 ~ 5.1 (1H, m), 6.75 (1H, d, J =
8.8Hz), 7.0 ~ 7.5 (13H, m), 7.78 (1H, d, J = 2.4Hz), 8.20
(1H, dd, J = 7.1Hz, 1.5Hz), 8.51 (1H, d, J = 3.6Hz), 9.09 (1
H, s) Specific rotation: [α] _D ²⁵ = + 9.2 ° (c = 1.1, DM
SO)

Example 18 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (N′-3-methylphenyl) ureido] propionyl-4-diphenylmethylpiperazine o-tolyl isocyanate 80 mg, m-tolyl isocyanate 80 mg, (4) 344 mg of Example 1 Used,
In the same manner as in (5) of Example 1, 363 mg of the title compound (1) was obtained as a colorless amorphous form. Yield: 100%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.0Hz), 2.17 (3H, s), 2.2 ~ 2.5 (4H, m), 3.39 (1H, dd, J = 1
3.8Hz, 9.5Hz), 3.5 ~ 4.0 (5H, m), 4.21 (1H, s), 4.37 (2H,
q, J = 7.0Hz), 5.3 to 5.5 (1H, m), 6.6 to 6.8 (1H, m), 6.82 (1
H, d, J = 8.5Hz), 6.9 ~ 7.1 (4H, m), 7.1 ~ 7.5 (10H, m), 7.5
5 (1H, s), 8.15 (1H, dd, J = 7.6Hz, 1.8Hz), 8.41 (1H, dd, J =
4.6Hz, 1.8Hz)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (N'-3-methylphenyl) ureido] propionyl-4-diphenylmethylpiperazine The above compound (1 ) 281 mg was used and (6) of Example 1 was used.
The title compound (2) was obtained as yellow crystals in the same manner as
8 mg were obtained. Yield: 85%

IR (KBr) cm ⁻¹ : 1700, 1610, 1560, 1450 NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 2.2 to 2.5
(4H, m), 3.1 ~ 3.9 (6H, m), 4.31 (1H, s), 4.9 ~ 5.1 (1H, m),
6.60 (1H, d, J = 7.8Hz), 6.6 ~ 6.8 (1H, m), 7.0 ~ 7.5 (14
H, m), 8.21 (1H, d, J = 7.6Hz), 8.5 to 8.6 (1H, m), 8.61 (1H,
s) Specific rotation: [α] _D ²⁵ = + 8.5 ° (c = 1.0, DM
SO)

Example 19 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (N′-3-chlorophenyl) ureido] propionyl-4-diphenylmethylpiperazine o-tolyl isocyanate 94 mg instead of o-tolyl isocyanate, (4) 351 mg of Example 1
Was used in the same manner as in (5) of Example 1 to obtain 363 mg of the title compound (1) in a colorless amorphous form. Yield: 95
%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.1Hz), 2.41 (2H, bs), 2.49 (2H, bs), 3.45 (1H, dd, J = 14.3
Hz, 7.7Hz), 3.5 to 4.0 (5H, m), 4.26 (1H, s), 4.37 (2H, q, J =
7.1Hz), 5.2 to 5.4 (1H, m), 6.8 to 7.5 (16H, m), 7.77 (1H,
s), 8.12 (1H, dd, J = 7.6Hz, 1.8Hz), 8.41 (1H, dd, J = 4.8Hz,
1.8Hz)

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (N'-3-chlorophenyl) ureido] propionyl-4-diphenylmethylpiperazine The above compound (1) Using 298 mg, (6) of Example 1
The title compound (2) was obtained as light brown crystals in the same manner as in 2.
62 mg was obtained. Yield: 92%

IR (KBr) cm ^-1 : 1690, 1620, 159
0, 1540, 1480 NMR (DMSO-d ₆ ) δ: 2.1 to 2.4 (4H, m), 3.0 to
3.9 (6H, m), 4.31 (1H, s), 4.9 ~ 5.1 (1H, m), 6.6 ~ 6.8 (1H,
m), 6.8 ~ 7.0 (1H, m), 7.0 ~ 7.5 (13H, m), 7.60 (1H, s),
8.1 to 8.3 (1H, m), 8.4 to 8.6 (1H, m), 8.94 (1H, s) Specific rotation: [α] _D ²⁵ = + 10.0 ° (c = 1.0, D)
MSO)

Example 20 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2,3-dihydro-5-oxothiazolo [3,2-a] pyrimidin-6-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 2,3-dihydro-
Using 236 mg of 5-oxothiazolo [3,2-a] pyrimidine-6-carboxylic acid and 600 mg of (4) of Example 1, the title compound (1) was prepared in the same manner as in (1) of Example 3.
Was obtained as a yellow amorphous form to give 458 mg. Yield: 67%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.0Hz), 2.2 ~ 2.6 (4H, m), 3.23 (1H, dd, J = 13.9Hz, 8.8H
z), 3.51 (2H, t, J = 8.1Hz), 3.72 (1H, dd, J = 13.9Hz, 4.9H
z), 3.4 ~ 4.0 (4H, m), 4.22 (1H, s), 4.36 (2H, q, J = 7.0H
z), 4.53 (2H, t, J = 8.1Hz), 5.5 ~ 5.6 (1H, m), 7.02 (1H, d
d, J = 8.0Hz, 4.8Hz), 7.1 to 7.5 (10H, m), 8.20 (1H, dd, J = 8.
0Hz, 1.8Hz), 8.43 (1H, dd, J = 4.8Hz, 1.8Hz), 8.64 (1H, s),
9.57 (1H, brd, J = 4.3Hz) HPLC: ethyl acetate: methanol = 10: 1 R _f =
0.40

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (2,3-dihydro-5)
-Oxothiazolo [3,2-a] pyrimidin-6-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 458 mg of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as colorless crystals in the same manner as
1 mg was obtained. Yield: 79%

IR (KBr) cm ^-1 : 3450, 1720, 167
0, 1620, 1530, 1440 NMR (DMSO-d ₆ ) δ: 2.1 to 2.5 (4H, m), 2.9 to
3.9 (8H, m), 4.31 (1H, s), 4.86 (2H, s), 5.0 ~ 5.2 (1H, m),
6.8 ~ 6.9 (1H, m), 7.1 ~ 7.6 (12H, m), 8.2 ~ 8.4 (1H, m),
8.51 (1H, s), 8.6 to 8.8 (1H, m) Specific rotation: [α] _D ²⁵ = -13.3 ° (c = 1.1, D
MSO)

Example 21 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (3,5-dimethyl-4-isoxazolyl) carbonylamino] propionyl-4
-Diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 3,5-dimethylisoxazole-4-carboxylic acid 182 mg, Example 1
650 mg of (4) of (4) were prepared in the same manner as in (1) of Example 3 to give 616 mg of the title compound (1) as a yellow amorphous form.
Obtained. Yield: 91%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.1Hz), 2.41 (3H, s), 2.3 ~ 2.6 (4H, m), 2.58 (3H, s), 3.2
6 (1H, dd, J = 13.8Hz, 8.5Hz), 3.5 ~ 4.1 (5H, m), 4.29 (1H,
s), 4.37 (2H, q, J = 7.1Hz), 5.4 ~ 5.5 (1H, m), 6.81 (1H, br
d, J = 8.1Hz), 7.06 (1H, dd, J = 7.8Hz, 4.6Hz), 7.2 ~ 7.5 (10
H, m), 8.22 (1H, dd, J = 7.8Hz, 2.0Hz), 8.42 (1H, dd, J = 4.6H
z, 2.0Hz) TLC: hexane: ethyl acetate = 1: 2 R _f = 0.4
1

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (3,5-dimethyl-4)
-Isoxazolyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 616 mg of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as colorless crystals in the same manner as
2 mg was obtained. Yield: 73%

IR (KBr) cm ^-1 : 3440, 1630, 145
0, 1390, 1240, 1150, 700 NMR (CDCl ₃ ) δ: 2.39 (3H, s), 2.4 to 2.6 (4H,
m), 2.56 (3H, s), 3.31 (1H, dd, J = 14.7Hz, 9.0Hz), 3.6 ~
3.8 (4H, m), 3.9 ~ 4.1 (1H, m), 4.33 (1H, s), 5.4 ~ 5.6 (1
H, m), 7.05 (1H, dd, J = 7.8Hz, 4.9Hz), 7.2 ~ 7.5 (11H,
m), 8.19 (1H, dd, J = 7.8Hz, 2.0Hz), 8.41 (1H, dd, J = 4.9H
z, 2.0Hz) Specific rotation: [α] _D ²⁵ = -0.4 ° (c = 1.1, DM
SO)

Example 22 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (6-chloro-2H-1-benzopyran-3-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 6-chloro-2H-
Using 238 mg of benzopyran-3-carboxylic acid and 620 mg of (4) of Example 1, 595 mg of the title compound (1) was obtained as a colorless amorphous form in the same manner as in (1) of Example 3. Yield: 83%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.1Hz), 2.3 to 2.6 (4H, m), 3.35 (1H, dd, J = 14.3Hz, 9.1H
z), 3.6 ~ 3.7 (3H, m), 3.8 ~ 4.0 (2H, m), 4.25 (1H, s),
4.38 (2H, q, J = 7.1Hz), 4.84 and 4.90 (1H, ABq, J = 14.5H
z), 4.84 and 4.91 (1H, ABq, J = 14.5Hz), 5.3 to 5.5 (1H,
m), 6.70 and 6.74 (total 1H, each s), 6.88 (1H, s), 7.0
4 and 7.06 (total 1H, each s), 7.1 to 7.5 (13H, m), 8.23
(1H, dd, J = 7.8 Hz, 1.8Hz), 8.45 (1H, dd, J = 4.6Hz, 1.8Hz) TLC: hexane: ethyl acetate = 1: 1 R _f = 0.4
6

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (6-chloro-2H-1)
-Benzopyran-3-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 590 mg of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as colorless crystals in the same manner as.
1 mg was obtained. Yield: 85%

IR (KBr) cm ^-1 : 3420, 1640, 148
0, 1450, 1240, 700 NMR (DMSO-d ₆ ) δ: 2.1 to 2.4 (4H, m), 3.1 to
3.9 (6H, m), 4.31 (1H, s), 4.86 (2H, s), 5.1 ~ 5.2 (1H, m),
6.87 (1H, d, J = 8.4Hz), 7.2 ~ 7.6 (14H, m), 8.21 (1H, d, J =
8.1Hz), 8.51 (1H, d, J = 4.0Hz), 8.6 to 8.7 (1H, m) Specific rotation: [α] _D ²⁵ = -48.8 ° (c = 1.1, D)
MSO)

Example 23 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (4,7-dimethylpyrazolo [1,5-a] pyrimidin-3-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 4, 7-Dimethylpyrazolo [1,5-a] pyrimidine-3-carboxylic acid 17
Example 3 using 5 mg and 552 mg of (4) of Example 1
In the same manner as in (1) of Example 1, 606 mg of the title compound (1) was obtained as a yellow amorphous form. Yield: 98%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.1Hz), 2.3 to 2.7 (4H, m), 2.51 (3H, s), 2.91 (3H, s), 3.2
9 (1H, dd, J = 14.2Hz, 9.8Hz), 3.5 ~ 4.0 (4H, m), 3.71 (1H, d
d, J = 14.2Hz, 4.2Hz), 4.27 (1H, s), 4.37 (2H, q, J = 7.1Hz),
5.4 ~ 5.6 (1H, m), 6.47 (1H, s), 7.08 (1H, dd, J = 7.8Hz, 4.
7Hz), 7.1 ~ 7.5 (11H, m), 8.23 (1H, dd, J = 7.8Hz, 1.7Hz),
8.43 (1H, s), 8.44 (1H, dd, J = 4.7Hz, 1.7Hz) TLC: Ethyl acetate only R _f = 0.41

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (4,7-dimethylpyrazolo [1,5-a] pyrimidin-3-yl) carbonyl Amino] propionyl-4-diphenylmethylpiperazine Using 600 mg of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as colorless crystals in the same manner as in 46.
3 mg was obtained. Yield: 81%

IR (KBr) cm ^-1 : 3430, 1630, 160
0, 1520, 1450, 1390, 1250, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.6 (4H, m), 2.47
(3H, s), 2.78 (3H, s), 3.0 to 4.1 (6H, m), 4.35 (1H, s), 5.
2 to 5.4 (1H, m), 6.60 (1H, s), 7.1 to 7.6 (11H, m), 8.22 (1H,
d, J = 7.2Hz), 8.41 (1H, s), 8.54 (1H, s), 9.03 (1H, d, J = 7.
7Hz) Specific rotation: [α] _D ²⁵ = -44.3 ° (c = 1.0, D
MSO)

Example 24 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- {5- (3,5-dichlorophenoxy) -2-furyl} carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 5- (3,5- Dichlorophenoxy) furan-2-carboxylic acid 325 mg,
Using (4) 600 mg of Example 1, (1) of Example 3
The title compound (1) was converted into a colorless amorphous form in the same manner as in 6
38 mg was obtained. Yield: 85%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.1Hz), 2.3 ~ 2.6 (4H, m), 3.3 ~ 3.9 (6H, m), 4.24 (1H,
s), 4.36 (2H, q, J = 7.1Hz), 5.4 ~ 5.6 (1H, m), 5.70 (1H, d,
J = 3.4Hz), 6.9 ~ 7.1 (3H, m), 7.00 (1H, d, J = 3.4Hz), 7.1 ~
7.5 (12H, m), 8.19 (1H, dd, J = 7.6Hz, 2.0Hz), 8.23 (1H, dd,
J = 4.9Hz, 2.0Hz) TLC: hexane: ethyl acetate = 1: 1 R _f = 0.5
6

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- {5- (3,5-dichlorophenoxy) -2-furyl} carbonylamino] propionyl-4 -Diphenylmethylpiperazine 638 mg of the above compound (1) was used, and (6) of Example 1 was used.
The title compound (2) was obtained as colorless crystals in the same manner as.
3 mg was obtained. Yield: 72%

IR (KBr) cm ^-1 : 3420, 1650, 158
0, 1540, 1430, 1260 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 3.2 to
3.3 (1H, m), 3.4 ~ 3.9 (5H, m), 4.32 (1H, s), 5.6 ~ 5.7 (1
H, m), 6.05 (1H, d, J = 3.4Hz), 7.1 ~ 7.5 (15H, m), 8.20 (1
H, dd, J = 7.6Hz, 1.7Hz), 8.49 (1H, dd, J = 4.4Hz, 1.7Hz), 8.6
6 (1H, d, J = 8.1Hz) Specific rotation: [α] _D ²⁵ = -31.2 ° (c = 1.1, D
MSO)

Example 25 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (N'-2,6-dichloro-
4-pyridyl) ureido] propionyl-4-diphenylmethylpiperazine o-tolyl isocyanate instead of 2,6-dichloro-
Using 206 mg of pyridyl-4-isocyanate and 600 mg of (4) of Example 1, 653 mg of the title compound (1) was obtained as a colorless amorphous form in the same manner as in (5) of Example 1. Yield: 95%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.1Hz), 2.3 ~ 2.8 (4H, m), 3.5 ~ 4.0 (6H, m), 4.2 ~ 4.5 (3
H, m), 5.4 ~ 5.6 (1H, m), 6.93 (2H, s), 7.00 (1H, dd, J = 7.8
Hz, 4.9Hz), 7.07 (1H, d, J = 7.8Hz), 7.1 to 7.5 (10H, m),
8.02 (1H, d, J = 2.0Hz), 8.40 (1H, dd, J = 4.9Hz, 2.0Hz), 8.4
5 (1H, s) TLC: hexane: ethyl acetate = 1: 2 R _f = 0.3
5

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (N'-2,6-dichloro-4-pyridyl) ureido] propionyl-4-diphenylmethyl Piperazine Using the above compound (1) 650 mg, (6) of Example 1
The title compound (2) was obtained as colorless crystals in the same manner as in 47.
4 mg were obtained. Yield: 76%

IR (KBr) cm ^-1 : 3420, 1620, 157
0, 1520, 1370, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.4 (4H, m), 3.18
(1H, dd, J = 13.9Hz, 8.4Hz), 3.3 ~ 3.9 (5H, m), 4.35 (1H, s),
5.4 ~ 5.6 (1H, m), 7.1 ~ 7.5 (15H, m), 8.22 (1H, dd, J = 7.6H
z, 1.8Hz), 8.51 (1H, dd, J = 4.9Hz, 1.8Hz), 9.80 (1H, s) Specific rotation: [α] _D ²⁵ = + 9.7 ° (c = 1.1, DM
SO)

Example 26 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (3-chlorobenzo [b] thiophen-2-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 3-chlorobenzo [b] thiophen-2- Using 253 mg of carboxylic acid and 600 mg of (4) of Example 1, the title compound (1) was converted into a colorless amorphous form in the same manner as in (1) of Example 3 to obtain 643 m.
g was obtained. Yield: 93%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.1Hz), 2.3 to 2.6 (4H, m), 3.39 (1H, dd, J = 14.0Hz, 8.2H
z), 3.6 ~ 4.0 (5H, m), 4.26 (1H, s), 4.37 (2H, q, J = 7.1H
z), 5.4 ~ 5.6 (1H, m), 7.03 (1H, dd, J = 7.8Hz, 4.6Hz), 7.1
~ 7.5 (12H, m), 7.8 ~ 7.9 (2H, m), 8.17 (1H, m), 8.21 (1
H, dd, J = 7.8Hz, 1.7Hz), 8.44 (1H, dd, J = 4.6Hz, 1.7Hz) TLC: hexane: ethyl acetate = 1: 1 R _f = 0.3
0

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (3-chlorobenzo [b] thiophen-2-yl) carbonylamino] propionyl-4-diphenylmethyl Piperazine (6) of Example 1 was prepared using 640 mg of the above compound (1).
The title compound (2) was obtained as colorless crystals in the same manner as
6 mg was obtained. Yield: 71%

IR (KBr) cm ⁻¹ : 3450, 1630, 1520, 1460, 700 NMR (DMSO-d ₆ ) δ: 2.2 to 2.6 (4H, m), 3.2 to
3.9 (6H, m), 4.2 ~ 4.5 (1H, m), 5.2 ~ 5.4 (1H, m), 7.1 ~ 7.
7 (13H, m), 7.8 ~ 8.0 (1H, m), 8.1 ~ 8.2 (1H, m), 8.22 (1
H, d, J = 7.6Hz), 8.56 (1H, br), 8.68 (1H, d, J = 7.3Hz) Specific rotation: [α] _D ²⁵ = -27.5 ° (c = 1.1, D
MSO)

Example 27 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (3-quinolyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid was replaced with 179 mg of quinoline-3-carboxylic acid and 509 mg of (4) of Example 1. The title compound (1) was prepared in the same manner as in (3) of Example 3.
389 mg was obtained as off-white crystals. Yield: 68%

NMR (CDCl ₃ ) δ: 1.36 (3H, t, J =
7.2Hz), 2.1 ~ 2.7 (4H, m), 3.2 ~ 4.0 (6H, m), 4.23 (1H,
s), 4.37 (2H, q, J = 7.2Hz), 5.5 ~ 5.7 (1H, m), 6.9 ~ 7.1 (1
H, m), 7.1 ~ 7.6 (13H, m), 7.6 ~ 7.7 (1H, m), 8.1 ~ 8.4
(2H, m), 8.4 ~ 8.6 (1H, m), 8.7 ~ 8.8 (1H, m), 8.9 ~ 9.1 (1
H, m)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (3-quinolyl) carbonylamino] propionyl-4-diphenylmethylpiperazine 155 mg of the above compound (1) Use (6) of Example 1
The title compound (2) was obtained as off-white crystals in the same manner as in 1.
Obtained 35 mg. Yield: 91%

IR (KBr) cm ⁻¹ : 1670, 1610, 1460, 1305 NMR (DMSO-d ₆ ) δ: 2.0 to 2.6 (4H, m), 3.1 to
4.0 (6H, m), 4.32 (1H, s), 5.3 ~ 5.5 (1H, m), 7.0 ~ 7.5 (12
H, m), 7.5 ~ 7.6 (1H, m), 7.6 ~ 7.7 (1H, m), 7.8 ~ 7.9 (1
H, m), 8.1 ~ 8.3 (2H, m), 8.4 ~ 8.6 (1H, m), 9.00 (1H, s),
9.6 to 9.8 (1H, m), 13.1 to 13.7 (1H, bs) Specific optical rotation: [α] _D ²⁵ = -22.6 ° (c = 1.1, D
MSO)

Example 28 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (1,5-dimethyl-1H-
Pyrazol-3-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 1,5-dimethyl-
Using 145 mg of 1H-pyrazole-3-carboxylic acid and 509 mg of (4) of Example 1, the title compound (1) was obtained as off-white crystals in the same manner as in (1) of Example 3 (404 m).
g was obtained. Yield: 75%

NMR (CDCl ₃ ) δ: 1.37 (3H, t, J =
7.0Hz), 2.22 (3H, s), 2.2 ~ 2.5 (4H, m), 3.3 ~ 3.9 (6H, m),
3.72 (3H, s), 4.21 (1H, s), 4.37 (2H, q, J = 7.0Hz), 5.4 ~
5.6 (1H, m), 6.43 (1H, s), 6.9 ~ 7.1 (1H, m), 7.1 ~ 7.5 (1
0H, m), 7.7 ~ 7.8 (1H, m), 8.1 ~ 8.3 (1H, m), 8.3 ~ 8.4 (1
H, m)

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (1,5-dimethyl-1)
H-pyrazol-3-yl) carbonylamino] propionyl-4-diphenylmethylpiperazine Using 404 mg of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as pale green crystals in the same manner as in 3.
Obtained 59 mg. Yield: 93.0%

IR (KBr) cm ⁻¹ : 1645, 1530, 1450, 1235 NMR (CDCl ₃ ) δ: 2.1 to 2.6 (4H, m), 2.24 (3H,
s), 3.2 ~ 4.0 (6H, m), 3.76 (3H, s), 4.32 (1H, s), 5.1 ~
5.3 (1H, m), 6.4 (1H, s), 7.1 ~ 7.6 (11H, m), 8.0 ~ 8.3
(2H, m), 8.5 to 8.7 (1H, m) Specific rotation: [α] _D ²⁵ = -9.7 ° (c = 1.1, DM
SO)

Example 29 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2-{(2R, S) -1,4-benzodioxan-2-yl} carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 1,4-benzo 179 mg of dioxane-2-carboxylic acid, (4) of Example 1
Using 500 mg, and in the same manner as in (3) of Example 3, 524 mg of the title compound (1) was obtained as a colorless amorphous form. Yield: 95%

NMR (CDCl ₃ ) δ: 1.39 and 1.40
(Total 3H, t, J = 7.1Hz, J = 7.1Hz), 2.3 to 2.6 (4H, m),
3.1 to 3.4 (1H, m), 3.5 to 4.1 (6H, m), 4.23 and 4.24 (1H each, s), 4.4 to 4.7 (2H, m), 4.37 and 4.39 (2 total)
H, q, J = 7.1Hz, J = 7.1Hz), 5.3〜5.6 (1H, m), 6.7〜
7.5 (15H, m), 7.5 ~ 7.7 (1H, m), 8.1 ~ 8.3 (1H, m), 8.4 ~
8.5 (1H, m) TLC: hexane: ethyl acetate = 1: 1 R _f = 0.4
6

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2-{(2R, S) -1,4
-Benzodioxan-2-yl} carbonylamino] propionyl-4-diphenylmethylpiperazine Using 560 mg of the above compound (1), (6) of Example 1 was used.
The title compound (2) was obtained as pale yellow crystals in the same manner as in 3.
91 mg were obtained. Yield: 73%

IR (KBr) cm ^-1 : 3410, 1700, 165
0, 1490, 1260, 750, 710 NMR (DMSO-d ₆ ) δ: 2.2 to 2.5 (4H, m), 3.0 to
3.9 (7H, m), 4.0 ~ 4.1 (1H, m), 4.2 ~ 4.4 (1H, m), 4.7 ~ 4.
8 (1H, brs), 5.0 ~ 5.2 (1H, m), 6.8 ~ 7.0 (4H, m), 7.2 ~ 7.
8 (11H, m), 8.1 to 8.3 (1H, m), 8.4 to 8.7 (2H, m) Specific rotation: [α] _D ²⁵ = −2.3 ° (c = 1.0, DM
SO)

Example 30 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-pyridyl) thio-2- (4,8-dihydroxy-2
-Quinolyl) carbonylamino] propionyl-4-diphenylmethylpiperazine Chromone-3-carboxylic acid was replaced with 244 mg of 4,8-dihydroxyquinoline-2-carboxylic acid and 600 mg of (4) of Example 1, using the compound of Example 3. By the same method as in (1), 287 mg of the title compound (1) was obtained as a colorless amorphous form. Yield: 42%

NMR (CDCl ₃ ) δ: 1.26 (3H, t, J =
7.3Hz), 2.2 to 2.6 (4H, m), 3.4 to 4.0 (6H, m), 4.1 to 4.4 (3
H, m), 5.4 ~ 5.7 (1H, m), 6.68 (1H, brs), 6.9 ~ 7.4 (14H,
m), 7.5 ~ 7.7 (1H, m), 7.9 ~ 8.2 (1H, m), 8.3 ~ 8.6 (1H,
m), 9.2 to 9.5 (2H, m) TLC: ethyl acetate only R _f = 0.38

(2) (R) -1- [3- (3-carboxy-2-pyridyl) thio-2- (4,8-dihydroxy-2-quinolyl) carbonylamino] propionyl-4
-Diphenylmethylpiperazine Using the above compound (1) (570 mg), (6) of Example 1
The title compound (2) was obtained as colorless crystals in the same manner as in 49.
3 mg was obtained. Yield: 90%

IR (KBr) cm ^-1 : 3410, 1630, 152
0, 1460, 1280, 1230, 700 NMR (DMSO-d ₆ ) δ: 2.1 to 2.6 (4H, m), 3.1 to
4.0 (7H, m), 5.2 ~ 5.4 (1H, m), 7.0 ~ 7.6 (15H, m), 8.1 ~
8.3 (1H, m), 8.6 ~ 8.7 (1H, m), 9.7 ~ 9.9 (2H, m), 10.10
(1H, brs), 11.78 (1H, brs) Specific rotation: [α] _D ²⁵ = −73.7 ° (c = 1.0, D
MSO)

Example 31 (1) (R) -1- [3- (3-ethoxycarbonyl-
2-Pyridyl) thio-2- (2,4-dimethyl-thiazol-5-yl) carbonylamino] propionyl-4
-Diphenylmethylpiperazine Chromone-3-carboxylic acid instead of 2,4-dimethyl-
Using 187 mg of thiazole-5-carboxylic acid and 600 mg of (4) of Example 1, 588 mg of the title compound (1) was obtained as a brown amorphous form in the same manner as in (3) of Example 3. Yield: 92%

NMR (CDCl ₃ ) δ: 1.38 (3H, t, J =
7.1Hz), 2.3 to 2.7 (4H, m), 2.60 (3H, s), 2.62 (3H, s), 3.3
3 (1H, dd, J = 14.4Hz, 9.0Hz), 3.5 ~ 4.0 (5H, m), 4.26 (1H,
s), 4.37 (2H, q, J = 7.1Hz), 5.3 ~ 5.5 (1H, m), 7.0 ~ 7.1 (1
H, m), 7.06 (1H, dd, J = 8.0Hz, 4.7Hz), 7.1 ~ 7.5 (11H, m),
8.21 (1H, dd, J = 8.0Hz, 1.9Hz), 8.44 (1H, dd, J = 4.7Hz, 1.9
Hz) TLC: Only ethyl acetate R _f = 0.54

(2) (R) -1- [3- (3-Carboxy-2-pyridyl) thio-2- (2,4-dimethyl-thiazol-5-yl) carbonylamino] propionyl-4-diphenylmethyl Piperazine Using the above compound (1) (580 mg), (6) of Example 1
The title compound (2) was obtained as colorless crystals in the same manner as
0 mg was obtained. Yield: 66%

IR (KBr) cm ^-1 : 3450, 1640, 163
0, 1560, 1540, 1460, 700 NMR (DMSO-d ₆ ) δ: 2.1 to 2.8 (4H, m), 2.46
(3H, s), 2.61 (3H, s), 3.1 ~ 4.1 (6H, m), 4.1 ~ 4.4 (1H,
m), 5.0 ~ 5.2 (1H, m), 7.1 ~ 7.9 (12H, m), 8.21 (1H, d, J =
7.7Hz), 8.4-8.6 (2H, m) Specific optical rotation: [α] _D ²⁵ = -17.2 ° (c = 1.1, D
MSO)

The results of the anti-CCK action experiment of the compound of the present invention are shown below. Anti-cholecystokinin (CC) in guinea pig isolated ileum
K) Action A male guinea pig (250 to 400 g) was bled to death and exsanguinated, and the excised ileum piece was subjected to Tyrode's solution (NaCl 136.9) at 37 ° with aeration with 5% CO ₂ mixed O ₂ gas.
mM, KCl 2.68 mM, CaCl ₂ 1.8 m
M, MgCl ₂ 1.05 mM, NaH ₂ PO ₄ 0.4
2 mM, NaHCO ₃ 11.9 mM, glucose 5.
A Magnus tube containing 30 ml of 55 mM) was suspended by applying 0.5 g of tension. The change in shrinkage was recorded isotonic via soot on smoke paper. The ileum piece was allowed to stand for 30 minutes, and 1 × 10 ⁻⁸ M CCK-8 was added to cause contraction. After washing, this was repeated several times to stabilize the contraction of CCK-8, and after 5 minutes after addition of the test compound, 1 × 10 ⁻⁸ M CCK was added.
The shrinkage was measured by adding -8. The contraction by CCK-8 and the contraction by CCK-8 in the presence of different concentrations of the test compound were compared, and the IC ₅₀ value [the concentration of the test compound that inhibits the contraction of CCK-8 by 50%] is shown in Table 3. . The compound numbers in Table 3 indicate the target compounds according to the example numbers.

[0174]

[Table 3] Table 3 Compound No. IC ₅₀ (M) 9 3.0 × 10 ⁻⁷ 22 2.2 × 10 ⁻⁷ 27 1.0 × 10 ⁻⁸ 29 29 2.6 × 10 ⁻⁷ 30 1.2 × 10 ^-8

[0175]

INDUSTRIAL APPLICABILITY The compound of the present invention is in vitro
^Shows a strong anti-CCK activity of 10 ⁻⁸ M. That is, the IC ₅₀ value of the compound of the present invention for the isolated guinea pig ileum (in vitro) in Table 3 is as shown in the experimental example of Table 3,
It was 1.0 x 10 ^-8 M (Compound 27). Therefore, the compound of the present invention is useful as a preventive and therapeutic agent for pancreatic cancer, gastric ulcer, duodenal ulcer, peptic ulcer, colitis, biliary dysfunction, especially acute pancreatitis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 401/12 213 C07D 401/12 213 231 231 405/12 213 405/12 213 409/12 213 409 / 12 213 413/12 213 413/12 213 417/12 12 213 417/12 213 487/04 142 487/04 142 513/04 355 513/04 355 // (C07D 401/12 213: 80 215: 48) ( (C07D 401/12 213: 80 231: 14) (C07D 405/12 213: 80 311: 20) (C07D 405/12 213: 80 311: 58) (C07D 405/12 213: 80 307: 84) (C07D 405 / 12 213: 80 307: 68) (C07D 405/12 213: 80 319: 16) (C07D 409/12 213: 80 333: 68) (C07D 413/12 213: 80 261: 08) (C07D 417/12 213: 80 277: 68) (72) Inventor Hideaki Suzuki 2-15-1, Honcho, Higashimurayama, Tokyo No. (72) Inventor Shinpei Jinsho 6-27-16 Shirota, Setagaya-ku, Tokyo

Claims (2)

[Claims] 1. A compound represented by the following general formula (1): [In the formula, R represents a phenyl group, a naphthyl group, a thiazolopyrimidinyl group, a pyrazolopyrimidinyl group, a ring-forming heteroatom having one oxygen, nitrogen, one sulfur, or the same or different two members, or a six-membered ring. A group selected from the group consisting of a cyclic group which may be condensed with a benzene ring (excluding indolyl group), and a group having at least one substituent which is the same or different in each group. Shows,
n represents 0 or 1] or a pharmaceutically acceptable salt thereof. 2. The substituent is a lower alkyl group, lower alkoxy group, lower alkylthio group, halogen, hydroxyl group, trihalomethyl group, nitro group, amino group, substituted amino group,
The compound according to claim 1, which is selected from the group consisting of a benzoyl group, a substituted phenoxy group and an oxo group, or a pharmaceutically acceptable salt thereof.