JPH07119217B2 - New benzodiazepine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention relates to pharmaceuticals, particularly to novel benzodiazepine derivatives having CCK-B receptor antagonistic activity and/or gastrin receptor antagonistic activity, and a method for producing the same.

BACKGROUND ART Conventionally, numerous synthetic studies have been conducted on benzodiazepine derivatives with the aim of developing central nervous system drugs (psychotropic drugs) that act on benzodiazepine receptors.

Recently, some benzodiazepine derivatives have been shown to inhibit CCK-A
(Cholecystokinin-A) receptor antagonism and CCK-B
It has been reported that it exhibits cholecystokinin-B receptor antagonism.
It has been reported that compounds with strong KB receptor antagonistic activity inhibit pentagastrin-stimulated gastric acid secretion (Eur. J. Pharmacol., 162, 273-280, 1989).

DISCLOSURE OF THE INVENTION In the synthesis research of benzodiazepine derivatives, the present inventors have found that they have low affinity for benzodiazepine receptors,
The present invention has been accomplished by discovering novel benzodiazepine derivatives which do not exhibit significant central nervous system effects based on benzodiazepine receptors and which have potent CCK-B receptor antagonistic activity and/or gastrin receptor antagonistic activity.

Although the derivatives disclosed in U.S. Patent Publication No. US 4,820,834 are known as benzodiazepine derivatives having CCK-B receptor antagonistic activity, the compounds of the present invention are novel compounds that are clearly different in chemical structure from benzodiazepines in the substituent at position 1, and that exhibit more potent and selective CCK-B receptor antagonistic activity and/or gastrin receptor antagonistic activity in pharmacological action (i.e., weaker benzodiazepine receptor and CCK-A receptor activity).

The present invention relates to novel benzodiazepine derivatives represented by general formula (I).

(The symbols in the formula have the following meanings:

R ¹ : An aryl group, a thienyl group, a pyridyl group or an indolyl group, which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom.

R ² : a lower alkyl group, a lower alkoxy group, or an aryl group which may be substituted with a halogen atom. The compounds of the present invention are further described below.

The "aryl group" in the above general formula (I) includes, for example, a phenyl group, an indenyl group, and a naphthyl group. These aryl groups and thienyl groups, pyridyl groups, and indolyl groups may have a substituent. Examples of the substituent include a lower alkyl group, a lower alkoxy group, and a halogen atom.

Here, the lower alkyl group is a straight or branched hydrocarbon chain having 1 to 6 carbon atoms, and representative examples include methyl, ethyl, propyl, n-butyl, n-pentyl, isopropyl, and sec-butyl groups. The lower alkoxy group is an alkoxy group having the above-mentioned lower alkyl group, such as methoxy, ethoxy, propoxy, isopropoxy, and n-
butoxy group.

Examples of halogen atoms include fluorine, chlorine, and bromine atoms.

The compounds of the present invention have asymmetric carbon atoms and therefore exist as isomers. Furthermore, the compounds of the present invention form salts with acids. Examples of such salts include salts with inorganic or organic acids, such as hydrochlorides, sulfates, and acetates.

The compounds of the present invention and their salts can be produced by various synthetic methods, taking advantage of the characteristics based on the basic skeleton or the type of substituents. Representative production methods are shown below.

(wherein ^R1 and ^R2 have the same meanings as above.) Compound (I) of the present invention can be obtained by reacting an amino compound represented by general formula (II) with an isocyanate compound represented by general formula (III). The isocyanate compound is usually used in an equimolar amount relative to the amino compound.

This reaction can be carried out in N,N-dimethylformamide, pyridine, benzene, toluene, dioxane, tetrahydrofuran,
This is usually carried out at room temperature in a reaction-inert solvent such as ether, chloroform, dichloromethane, dichloroethane, or n-hexane.

The reaction product can be isolated and purified by conventional procedures such as concentration, recrystallization, extraction, etc. The reaction product can be isolated as various salts by reacting with a chemically equivalent or excess amount of an acid for salt formation.

INDUSTRIAL APPLICABILITY The compounds of the present invention have potent and selective CCK-B receptor antagonistic activity and pentagastrin-stimulated gastric acid secretion inhibitory activity. These activities are shown below together with the methods for measuring them.

Binding activity to CCK-B receptor: Measurement method: Approximately 100 SD rats were decapitated under unanesthetized conditions, and the whole brain was quickly removed. The whole brain was homogenized with 10 volumes of 0.32 M sucrose solution using a Teflon glass homogenizer. The homogenate was centrifuged at 900 G for 10 minutes in a refrigerated centrifuge, and the supernatant was further centrifuged at 11,500 G for 15 minutes. The resulting sediment was diluted with 0.08% Triton X-100, 50 mM Tris-H
The suspension was left to stand for 30 minutes, then centrifuged again at 11,500 G for 15 minutes, and the pellet was washed twice with 5 mM and 50 mM Tris-HCl buffers.
The membrane preparation was suspended in a buffer solution and stored frozen at -80°C.

After thawing the membrane preparation at room temperature, it was diluted with 10 mM HEPES buffer (130 mM NaCl, 5 mM
The cells were diluted with _0.1 mM MgCl2, 1 mM EGTA, 0.25 mg/ml bacitracin, pH 6.5, and incubated in the presence of [ ^125I ]BH and CCK-8 at 25°C for 120 minutes, after which B/F separation was performed by aspiration. Nonspecific binding was determined in the presence of 1 μM CCK-8. The amount of labeled ligand bound to the receptor was measured using a γ-counter. The maximum binding amount of the labeled ligand to the receptor was set as 100%, and the Ki(CCK-B) value was calculated from the binding inhibition curve of the test drug.

The Ki values of the compounds of the present invention were 0.03 to 10 nM. Specific examples are shown below.

Measurement of the inhibitory effect of pentagastrin on gastric acid secretion: After inserting a cannula into the trachea of a rat anesthetized with urethane (1.25 g/kg intraperitoneally), the abdomen was opened to expose the stomach and duodenum. After ligating the cardia, a polyethylene cannula was placed in the forestomach. Furthermore, a small incision was made in the duodenum, and
A polyethylene cannula was inserted into the stomach through the incision, and the pylorus was ligated to fix the cannula in place.

Physiological saline (adjusted to pH 7.0) was perfused from the forestomach to the pylorus at a rate of 3 ml/min. Gastric acid secretion was measured by continuous titration of the perfusate using a pH-stat (Toa Denpa Kogyo, AUT-201). The endpoint of the continuous titration was pH 7.0.
This was done by dripping 25 mM sodium hydroxide solution. The results were obtained as gastric acid analysis (μEq/10 min) every 10 min. Pentagastrin (15 μg/kg/h) was administered intravenously. Acid secretion increased after pentagastrin injection, and after the injection
The maximum value was reached and stabilized in 60 minutes. After that, the test drug was administered intravenously and gastric acid secretion was measured. The maximum value after pentagastrin injection was set as 100%, and the gastric acid secretion after administration of the test drug was calculated as follows:
The dose required for 50% inhibition was calculated as the ED ₅₀ value. Two types of rats were used in this test: Wistar rats and SD rats. A specific example of SD rats is shown below.

CCK-B receptor selectivity assay by comparison with binding activity to rat CCK-A receptors: SD rat pancreas was soaked in 20 volumes of 50 mM Tris-HCl buffer (pH 7.
The homogenate was centrifuged at 50,000 G for 10 min using a Polytron homogenizer.
The resulting precipitate was centrifuged twice for 1 minute.
50mM Tris-HCl buffer (0.2% BSA, 5mM _MgCl2 , 0.1mg/ml
The membrane preparation was prepared by suspending the cells in a solution of 5 mM bacitracin, 5 mM DTT, pH 7.7, and storing the suspension frozen at -80°C.

After thawing the membrane preparation at room temperature, it was diluted 10 times with buffer and [ ^3H ]L-
After incubation at 37°C for 30 minutes in the presence of L-364,718, B/F separation was performed by aspiration filtration. Nonspecific binding was determined in the presence of 1 μM L-364,718. The amount of labeled ligand bound to the receptor was measured using a liquid scintillation counter. The maximum amount of labeled ligand bound to the receptor was defined as 100%.
The Ki(CCK-A) value was calculated from the binding inhibition curve of the test drug.

If the CCK-A receptor antagonism is strong, side effects such as cholestasis and gallstones may occur.
Preferably, it is a B receptor antagonist.

The compounds of the present invention exhibited a Ki(CCK-A)/Ki(CCK)
The larger this value, the greater the CCK-
This means that the selectivity for CCK-B receptors is high, and the CCK-B activity is equal to or higher than that of the compound described in Example 281 of US Pat. No. 4,820,834.
B selectivity was observed.

For example, the compound CCK-B described in Example 281 of US Pat. No. 4,820,834
The receptor selectivity is 186-fold, while the compound in Example 2 is 173-fold.
The compound in Example 7 showed an extremely high CCK-
B receptor selectivity was demonstrated.

Binding to benzodiazepine receptors The binding activity of the compounds of the present invention to benzodiazepine receptors is extremely weak. For example, the _IC50 value of the compound described in Example 281 of US Pat. No. 4,820,834 is 1.2 μM (Eur. J. Pharmacol., 16
2 , 273-280, 1989), but the compound described in Example 16 was used at 10 μM
However, it showed no binding activity at all.

The compounds of the present invention also have low toxicity and are suitable for use as medicines. For example, in a test using SD rats, no serious side effects were observed even when orally administered at a dose of 100 mg/kg.

From the above experiments, it has been demonstrated that the compounds of the present invention have CCK-B receptor antagonistic activity and pentagastrin-stimulated gastric acid secretion inhibitory activity, and are therefore useful for the treatment and prevention of diseases involving CCK-B receptors and gastrin receptors.

Examples of such diseases include digestive system diseases such as gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, Zollinger-Billison syndrome, and gastrin-sensitive pancreas, as well as disorders of the appetite control system, pain, anxiety, and other central nervous system disorders.

The compound of the present invention or a salt thereof is prepared into tablets, powders, fine granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., and is administered orally (including sublingual administration) or parenterally.

The carriers and excipients for the formulations include solid or liquid non-toxic pharmaceutical substances, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used substances.

The clinical dose of the compound of the present invention is determined appropriately taking into consideration the symptoms, body weight, age, sex, etc. of the patient to be treated.
The usual oral dose for adults is 1 to 1000 mg per day, administered in one or several divided doses.

BEST MODE FOR CARRYING OUT THE INVENTION Next, examples of preparation of pharmaceutical preparations using the compounds of the present invention will be explained.

Preparation example (tablets) Preparation of 20 mg Tablets: 100 g of the compound of Example 16, 367 g of lactose, and 90 g of cornstarch were uniformly mixed using a fluidized bed granulation coating device (Okawahara Seisakusho). 200 g of 10% hydroxypropyl cellulose solution was sprayed onto the mixture to granulate. After drying, the mixture was passed through a 20-mesh sieve, and 20 g of carboxymethylcellulose calcium and 3 g of magnesium stearate were added. Tablets weighing 120 mg each were made using a 7 mm x 8.4 mm punch and pestle in a rotary tablet press (Hata Iron Works).

Preparation of 40 mg Tablets: 140 g of the compound of Example 16, 280 g of lactose, and 70 g of cornstarch were uniformly mixed using a fluidized bed granulation coating device (Okawahara Seisakusho). 175 g of 10% hydroxypropyl cellulose solution was sprayed onto the mixture to granulate. After drying, the mixture was passed through a 20-mesh sieve, and 14.7 g of carboxymethylcellulose calcium and 2.8 g of magnesium stearate were added. Tablets weighing 150 mg each were made using a 7.5 mm x 9R mortar and pestle in a rotary tablet press (Hata Iron Works).

EXAMPLES The present invention will now be described in more detail with reference to examples.
Among the raw material compounds used in the examples, the production methods for novel compounds are shown as reference examples.

Reference Example 1 (raw materials of Example 1) (a) 3.54 g of 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 10.45 g of phenacyl bromide, 0.15 ml of tricaprylmethylammonium chloride, and 60 ml of toluene were mixed with 9 g of sodium hydroxide and 20 g of water under ice cooling.
The reaction mixture was added with 15 ml of water and stirred at room temperature for 6 hours.
The mixture was extracted twice with 100 ml of toluene, and the extract was diluted with 100 ml of water.
The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate and n-hexane (1:2) to obtain 1,3-dihydro-1-phenacyl-5-phenyl-2H-1,4-benzodiazepine-
4.8 g of 2-one was obtained.

Physical and chemical properties Melting point: 131-133℃ Mass spectrometry value EI (m/z): 354 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.95 (1H, d), 4.88 (1H, d), 5.14 (1H, d), 5.41 (1
H,d), 7.1-8.1 (14H,m) (b) A mixture of 4.61 g of 1,3-dihydro-1-phenacyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 3.65 g of potassium tert-butoxide and 65 ml of toluene was
Under ice-methanol cooling, 2.1 ml of isoamyl nitrite was added and stirred for 2 hours. The reaction mixture was poured into a mixture of 130 ml of ice water, 6.5 ml of acetic acid, and 130 ml of ethyl acetate, stirred for 1 hour, and then separated. The aqueous layer was extracted with 130 ml of ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Toluene was added to the residue, and the mixture was azeotroped.
20 ml of toluene was added and the mixture was stirred under ice cooling for 1 hour, and the precipitated crystals were collected to give 2.74 g of 1,3-dihydro-3-oxyimido-1-phenacyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

Physical and chemical properties Melting point: 209-213℃ Mass spectrometry value EI (m/z): 383 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ + DMSO-d ₆ , TMS internal standard) δ: 5.25 (1H, d), 5.51 (1H, d), 7.0-8.1 (14H, m), 10.
6(1H,br) (c) 1,3-dihydro-3-oximido-1-phenacyl-5-phenyl-2H-1,4-benzodiazepine-2
A mixture of 0.84 g of ruthenium-ion, 0.21 g of 5% ruthenium-carbon powder, and 20 ml of methanol was subjected to hydrogen gas pressure (8 kg/cm ² ), 60
The reaction mixture was stirred at 50°C overnight. The catalyst was removed from the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of chloroform and methanol (30:1) to give 3-amino-1,3-dihydro-1-phenacyl-
0.76 g of 5-phenyl-2H-1,4-benzodiazepin-2-one was obtained.

Physical and chemical properties Mass spectrometry values EI (m/z): 369 (M ⁺ ) δ: 2.46 (2H, br), 4.65 (1H, s), 5.33 (2H, s), 7.0~8.
1 (14H,m) Reference Example 2 (raw material for Example 2) (a) To a mixture of 12.12 g of 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 16.40 g of 2-bromo-2'-methylacetophenone, 0.27 g of tricaprylmethylammonium chloride, and 180 ml of toluene, a mixture of 29.55 g of sodium hydroxide and 60 ml of water was added under ice cooling, and the mixture was stirred at room temperature.
The mixture was stirred for 1.5 hours, and the organic layer was separated.
The organic layers were combined, washed four times with 150 ml of water and then with saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated and the resulting residue was subjected to silica gel column chromatography.
1) The eluted fraction of the mixture was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 14.78 g of 1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one.

Physical and chemical properties Melting point: 119-121℃ Mass spectrometry value EI (m/z): 368 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.46 (3H, s), 3.93 (1H, d), 4.87 (1H, d), 5.14 (2
H,d), 7.05-7.75 (13H,m) (b) 1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepine-2
In a mixture of 14.70 g of ketone and 205 ml of toluene, potassium chloride was added at -20°C.
11.19 g of tert-butoxide was added and stirred for 20 minutes. 7.01 g of isoamyl nitrite was added dropwise over 10 minutes, and the mixture was stirred at -20 to -15°C for 1.5 minutes.
The reaction mixture was added to 410 g of ice water, 20 ml of acetic acid, and ethyl acetate.
The mixture was poured into 410 ml of a mixed solution, stirred for 1 hour, and then separated. The aqueous layer was extracted with 200 ml of ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was powdered with an ethyl acetate-n-hexane mixture to obtain 1,3-dihydro-1-
(2'-methylphenacyl)-3-oxyimido-5-
Phenyl-2H-1,4-benzodiazepin-2-one 12.
A portion of this was subjected to silica gel column chromatography, and the fraction eluted with a mixture of ethyl acetate and n-hexane (1:1) was recrystallized from a mixture of ethyl acetate and n-hexane to obtain a pure specimen.

Physical and chemical properties: Melting point: 222-227°C; Elemental analysis (as _{C24H19N3O3 ) :} (%) H (%) N (%) Theoretical value _: 72.53 4.82 10.57 Experimental value: 72.37 4.91 10.32; Mass analysis EI (m/z): 397 (M ⁺ ); Nuclear magnetic resonance spectrum (DMSO, TMS internal standard): δ: 2.33 (3H, s), 5.35 (2H, s), 7.10-7.90 (13H, m), 1
1.08 (1H,s) (c) A mixture of 20.98 g of 1,3-dihydro-1-(2'-methylphenacyl)-3-oximido-5-phenyl-2H-1,4-benzodiazepin-2-one, 4.20 g of 5% ruthenium-carbon powder, and 420 ml of methanol was stirred under hydrogen gas pressure (8 kg/ ^cm2 ) at 60°C for 23 hours. The catalyst was removed from the reaction solution, and the solvent was distilled off. The resulting residue (19.07 g) was mixed with 285 ml of acetonitrile, 10 ml of a solution of 7.57 g of (±)-mandelic acid in acetonitrile, and 10 ml of a solution of 7.57 g of (±)-mandelic acid in acetonitrile.
After stirring at room temperature for 1 hour, the precipitated crystals were collected and washed with 65 ml of acetonitrile to give 3-amino-1,3-dihydro-1-(2'-methylphenacyl)
16.36 g of 5-phenyl-2H-1,4-benzodiazepin-2-one mandelate was obtained.

Physical and chemical properties Melting point: 146-150℃ Mass spectrometry value FAB, Pos (m/z): 384 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO, TMS internal standard) δ: 2.33 (3H, s), 4.64 (1H, s), 4.86 (1H, s), 5.35 (2
The mandelate salt obtained above was dissolved in methylene chloride, 0.2
Treatment with 5N aqueous sodium hydroxide gave the free 3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one.

Physical and chemical properties Mass spectrometry values FAB, Pos (m/z): 384 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.10 (2H, br, s), 2.44 (3H, s), 4.62 (1H, s), 5.20
(2H, s), 7.10-7.69 (13H, m) In the same manner as in Reference Example 1 or 2, the following compounds of Reference Examples 3 to 10 were obtained.

Reference Example 3 (raw materials for Example 3) (a) Target compound: 1,3-dihydro-1-(4'-methoxyphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (b) Target compound: 1,3-dihydro-1-(4'-methoxyphenacyl)-3-oximido-5-phenyl-2H
-1,4-benzodiazepin-2-one Starting compound: 1,3-dihydro-1-(4'-methoxyphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (c) Target compound: 3-amino-1,3-dihydro-1-
(4'-methoxyphenacyl)-5-phenyl-2H-1,
4-Benzodiazepin-2-one starting compound: 1,3-dihydro-1-(4'-methoxyphenacyl)-3-oximido-5-phenyl-2H-1,4
-Benzodiazepine-2-one Physical and chemical properties Mass analysis value EI (m/z): 399 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.74 (3H, s), 5.15 (1H, d), 5.29 (1H, s), 5.40 (1
(H,d), 6.81 (2H,d), 7.0-7.7 (9H,m), 7.84 (2H,m) Reference Example 4 (raw material of Example 4) (a) 1,3-dihydro-1-nicotinoylmethyl-5-
Phenyl-2H-1,4-benzodiazepin-2-one Physical and chemical properties Melting point: 179-181°C Elemental analysis ( _{as C22H17N3O2} ) C (%) H (%) N (%) Theoretical value 74.35 4.82 _11.82 Experimental value 74.47 4.78 11.65 (b) Target compound: 1,3-dihydro-1-nicotinoylmethyl _- 3-oximido-5-phenyl-2H-1,4-benzodiazepin-2-one Starting compound: 1,3-dihydro-1-nicotinoylmethyl-
5-Phenyl-2H-1,4-benzodiazepin-2-one (c) Target compound: 3-amino-1,3-dihydro-1-nicotinoylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one Starting compound: 1,3-dihydro-1-nicotinoylmethyl-
3-Oxyimido-5-phenyl-2H-1,4-benzodiazepin-2-one Physical and chemical properties Mass analysis EI (m/z): 370 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.56 (2H, br), 4.67 (1H, s), 5.32 (2H, s), 7.0-7.
8 (10H, m), 8.19 (1H, bt), 8.73 (1H, dd), 9.14 (1H,
d) Reference Example 5 (raw materials for Example 5) (a) Target compound: 1,3-dihydro-1-(2'-methoxyphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (b) Target compound: 1,3-dihydro-1-(2'-methoxyphenacyl)-3-oximido-5-phenyl-2H
-1,4-benzodiazepine-2-one starting compound: 1,3-dihydro-1-(2'-methoxyphenal)-5-phenyl-2H-1,4-benzodiazepine
2-one (c) Target compound: 3-amino-1,3-dihydro-1-
(2'-methoxyphenacyl)-5-phenyl-2H-1,
4-Benzodiazepine-2-one starting compound: 1,3-dihydro-1-(2'-methylphenacyl)-3-oximido-5-phenyl-2H-1,4-
Benzodiazepine-2-one Physical and chemical properties Mass analysis EI (m/z): 399 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.90 (3H, s), 4.63 (1H, s), 5.11 (1H, d), 5.38 (1
H,d), 6.8-8.0 (13H,m) Reference Example 6 (raw material of Example 6) (a) Target compound: 1,3-dihydro-1-(3'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (b) Target compound: 1,3-dihydro-1-(3'-methylphenacyl)-3-oximido-5-phenyl-2H-
1,4-Benzodiazepine-2-one starting compound: 1,3-dihydro-1-(3'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepine
2-one (c) Target compound: 3-amino-1,3-dihydro-1-
(3'-methylphenacyl)-5-phenyl-2H-1,4
- Benzodiazepine-2-one raw material compound: 1,3-dihydro-1-(2'-methylphenacyl)-3-oximido-5-phenyl-2H-1,4-
Benzodiazepine-2-one Physical and chemical properties Mass analysis value FAB, Pos (m/z): 384 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.12 (2H, br, s), 2.31 (3H, s), 4.62 (1H, s), 5.30
(2H,s), 7.08-7.78 (13H,m) Reference Example 7 (raw material of Example 7) (a) Target compound: 1,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one. Physical and chemical properties. Mass analysis value: EI (m/z): 368 (M ⁺ ). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 2.33 (3H, s), 3.93 (1H, d), 4.88 (1H, d), 5.26 (2H, s).
H,d), 7.06-7.85 (13H,m) (b) Target compound: 1,3-dihydro-1-(4'-methylphenacyl)-3-oximido-5-phenyl-2H-
1,4-Benzodiazepine-2-one starting compound: 1,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepine
2-one Physical and chemical properties Melting point: 221-224°C Elemental analysis ( _{as C24H19N3O3} ) C ( _% ) H (%) N (%) Theoretical value _72.53 4.82 10.57 Experimental value 72.45 4.91 10.39 Mass analysis value EI (m/z): 397 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO, TMS internal standard) δ: 2.36 (3H, s), 5.52 (2H, d), 7.24-7.94 (13H, m), 1
1.07 (1H, s) (c) Target compound: 3-amino-1,3-dihydro-1-
(4'-methylphenacyl)-5-phenyl-2H-1,4
- Benzodiazepine-2-one raw material compound: 1,3-dihydro-1-(4'-methylphenacyl)-3-oximido-5-phenyl-2H-1,4-
Benzodiazepine-2-one Physical and chemical properties Mass analysis value FAB, Pos (m/z): 384 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.00 (2H, br, s), 2.34 (3H, s), 4.66 (1H, s), 5.34
(2H,s), 7.16-7.88 (13H,m) Mass spectrometry value FAB,Pos (m/z): 384 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.00 (2H,br,s), 2.34 (3H,s), 4.66 (1H,s), 5.34
(2H,s), 7.16-7.88 (13H,m) Reference Example 8 (raw material of Example 8) (a) Target compound: 1-(4'-chlorophenacyl)-1,
3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (b) Target compound: 1-(4'-chlorophenacyl)-1,
3-dihydro-3-oximido-5-phenyl-2H-
1,4-Benzodiazepine-2-one starting compound: 1-(4'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine
2-one (c) Target compound: 3-amino-1-(4'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one Starting compound: 1-(4'-chlorophenacyl)-1,3-dihydro-3-oximido-5-phenyl-2H-1,4-
Benzodiazepine-2-one Reference Example 9 (raw material for Example 9) (a) Target compound: 1-(2'-chlorophenacyl)-1,
3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (b) Target compound: 1-(2'-chlorophenacyl)-1,
3-dihydro-3-oximido-5-phenyl-2H-
1,4-Benzodiazepine-2-one starting compound: 1-(2'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine
2-one (c) Target compound: 3-amino-1-(2'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one Starting compound: 1-(2'-chlorophenacyl)-1,3-dihydro-3-oximido-5-phenyl-2H-1,4-
Benzodiazepine-2-one Physical and chemical properties Mass analysis EI (m/z): 403 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.33 (2H, br), 4.62 (1H, s), 5.09 (1H, d), 5.28 (1H)
H,d), 7.1-7.8 (13H,m) Reference Example 10 (raw material for Example 10) (a) Target compound: 1-(3'-chlorophenacyl)-1,
3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (b) Target compound: 1-(3'-chlorophenacyl)-1,
3-dihydro-3-oximido-5-phenyl-2H-
1,4-Benzodiazepine-2-one starting compound: 1-(3'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine
2-one (c) Target compound: 3-amino-1-(3'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one Starting compound: 1-(3'-chlorophenacyl)-1,3-dihydro-3-oximido-5-phenyl-2H-1,4-
Benzodiazepine-2-one Physical and chemical properties Mass analysis EI (m/z): 403 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.85 (2H, br), 4.70 (1H, s), 5.20 (1H, d), 5.43 (1H)
H,d), 7.0-8.1 (13H,m) Reference Example 11 (raw material for Example 11) (a) 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one 1.18 g, 2-bromoacetylthiophene 3.6 g, tricaprylmethylammonium chloride 0.0
To a mixture of 5 ml of toluene and 20 ml of toluene, 6 ml of 10N aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. 100 ml of water was added to the reaction mixture, which was then extracted with toluene. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and purified by chloroform-methanol (100:1)
The mixture was eluted with 1,3-dihydro-5-phenyl-1-
0.79 g of (2-thenoyl)methyl-2H-1,4-benzodiazepin-2-one was obtained.

Physical and chemical properties Mass spectrometry values FAB, Pos (m/z): 361 (M ⁺ + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.94 (1H, d), 4.88 (1H, d) 5.11 (1H, d), 5.33 (1H,
d), 6.9-7.9 (12H,m) (b) 1,3-dihydro-5-phenyl-1-(2-thenoyl)methyl-2H-1,4-benzodiazepin-2-one
To a mixture of 0.78 g of nitrite, 0.61 g of potassium tert-butoxide, and 11 ml of toluene, 0.
The reaction mixture was diluted with 20 ml of ice water and 1 ml of acetic acid.
The aqueous layer was extracted with 20 ml of ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Toluene was added to the residue, and the mixture was washed. After that, 5 ml of toluene was added, and the crystals were collected by filtration.
0.43 g of oximido-5-phenyl-1-(2-thenoyl)methyl-2H-1,4-benzodiazepin-2-one was obtained.

Physical and chemical properties Mass spectrometry value EI (m/z): 389 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 5.27 (1H, d), 5.53 (1H, d), 7.0-8.3 (12H, m), 10.
9) (1H,br) (c) 1,3-dihydro-3-oximido-5-phenyl-1-(2-thenoyl)methyl-2H-1,4-benzodiazepin-2-one 0.4 g, 5% ruthenium-carbon powder
A mixture of 0.15g of ethanol and 15ml of methanol was pressurized with hydrogen gas (8kg/cm
² ) and stirred overnight at 60° C. The catalyst was removed from the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with a mixture of chloroform and methanol (40:1) to obtain 0.27 g of 3-amino-1,3-dihydro-5-phenyl-1-(2-thenoyl)methyl-2H-1,4-benzodiazepin-2-one.

Physical and chemical properties Mass spectrometry values FAB, Pos. (m/z): 376 (M ⁺ + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.0 (2H, br), 4.68 (1H, s), 5.25 (2H, s), 6.9 to 7.9
(12H,m) Reference Example 12 (raw material for Example 12) (a) 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 1.18 g, sodium hydride 0.21 g, N,
After stirring the mixture with 25 ml of N-dimethylformamide at room temperature for 30 minutes, 2.05 g of 1-benzyloxycarbonyl-3-bromoacetylindole was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 3
The reaction mixture was cooled with ice, 100 ml of water was added, and the mixture was extracted with a mixture of ethyl acetate and toluene (2:1). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and purified with ethyl acetate and n-hexane (1:2).
The mixture was eluted with a mixture of 1-[(1-benzyloxycarbonyl-3-indolylcarbonyl)methyl]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2
1.4 g of methyl-1-one was obtained.

Physical and chemical properties Mass spectrometry value EI (m/z): 527 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.95 (1H, d), 4.90 (1H, d), 5.16 (2H, s), 5.37 (2
(16H,s), 7.0-7.8 (16H,s), 8.0-8.4 (3H,m) (b) 1-[(1-benzyloxycarbonyl-3-indolylcarbonyl)methyl]-1,3-dihydro-5-
Phenyl-2H-1,4-benzodiazepin-2-one 1.58
To a mixture of 0.84 g of potassium tert-butoxide and 15 ml of toluene, 0.67 ml of isoamyl nitrite was added under ice-methanol cooling.
The reaction mixture was added with 30 ml of ice water, 1.5 ml of acetic acid,
The mixture was poured into a mixture of 30 ml of ethyl acetate, stirred for 1 hour, and then separated. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Toluene was added to the residue, and the mixture was azeotroped. 20 ml of toluene was added, and the precipitated crystals were collected by filtration to give 1.21 g of 1,3-dihydro-1-(3-indolylcarbonyl)methyl-3-oximido-5-phenyl-2H-1,4-benzodiazepin-2-one.

Physical and chemical properties Mass spectrometry value EI (m/z): 422 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO−d ₆ , TMS internal standard) δ: 5.27 (1H, d), 5.51 (1H, d), 7.0 to 8.3 (13H, m), 8.4
8 (1H,d), 11.03 (1H,s), 12.09 (1H,s) (c) 1,3-dihydro-1-(3-indolylcarbonyl)methyl-3-oximido-5-phenyl-2H-1,
4-benzodiazepine-2-one 1.18g, 5% ruthenium
A mixture of 0.3 g of carbon powder and 23 ml of methanol was stirred overnight at 60°C under hydrogen gas pressure (8 kg/ ^cm2 ). The catalyst was removed from the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and purified by chloroform-methanol (2
0:1) mixture, and 3-amino-1,3-dihydro-1
0.38 g of 3-(3-indolylcarbonyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one was obtained.

Physical and chemical properties Mass spectrometry values FAB, Pos (m/z): 409 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 3.23 (2H, br), 4.48 (1H, s), 5.17 (1H, d), 5.46 (1)
H,d),7.0~7.8(12H,m),8.0~8.3(1H,m),8.43(1H,
s), 12.0 (1H, br) The compound of Reference Example 13 was obtained by treating in the same manner as in Reference Example 1 or 2.

Reference Example 13 (raw materials for Example 13) (a) Target compound: 1,3-dihydro-1-(3-methyl-
2-thenoyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Physical and chemical properties Mass analysis EI (m/z): 374 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.59 (3H, s), 3.95 (1H, d), 4.80 (1H, d), 4.88 (1
(1H,d), 5.32 (1H,d), 6.97 (1H,d), 7.0-7.8 (10H,m) (b) Target compound: 1,3-dihydro-1-(3-methyl-
2-thenoyl)methyl-3-oximido-5-phenyl-2H-1,4-benzodiazepin-2-one Raw material compound: 1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Physical and chemical properties Mass analysis value EI (m/z): 403 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.49 (3H, s), 5.24 (2H, s), 7.0-8.0 (11H, m), 11.
03 (1H, s) 6.97 (1H, d), 7.0-7.8 (10H, m) (c) Target compound: 3-amino-1,3-dihydro-1-
(3-methyl-2-thenoyl)methyl-5-phenyl-
2H-1,4-Benzodiazepin-2-one starting compound: 1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-3-oximido-5-phenyl-2H
-1,4-benzodiazepine-2-one Physical and chemical properties Mass analysis value EI (m/z): 389 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.44 (2H, s), 2.57 (3H, s), 4.64 (1H, s), 4.89 (1
Reference Example 14 (raw material for Example 14) 3-amino-1,3-dihydro-1-(3-methyl-2-
(S)-mandelic acid 1.59 g, 3,
5-Dichlorosalicylaldehyde 63mg, acetonitrile 11
The resulting mixture was stirred at room temperature for 3 days. The precipitated crystals were collected and washed with 100 ml of acetonitrile to give (R)-3-amino-1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (S)-mandelate as white crystals.
5.13g was obtained.

Physicochemical properties i) ▲[α] ^20D ▼=+ ₁₇₀ ° (c=1.0, MeOH) ii) Melting point 179-182°C iii) Elemental analysis values (as _C30H27N3O5S ) C ( _% ) H ( _% ) N ( _% ) S (%) Theoretical value 66.53 5.02 7.76 5.92 Experimental value 66.48 5.08 7.71 5.90 Reference Example 15 (Raw material for Example 15) The following compound was obtained in the same manner as in Reference Example 14.

(S)-3-amino-1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4-
Benzodiazepin-2-one (R)-mandelate starting compound: 3-amino-1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4
Physicochemical properties _of (R)-benzodiazepine and ( _{R)-mandelic acid i) ▲[α]20D} ^▼ =-171° (c=1.0, MeOH) ii) Melting point 178-181°C iii) Elemental analysis (as _C30H27N3O5S ) C ( _{% )} H (%) N (%) S (%) Theoretical value 66.53 5.02 7.76 5.92 Experimental value 66.42 5.03 7.69 5.94 Reference Example 16 (raw material for Examples 18 and 19) (a) 200 mg of 3-amino-1,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one, 1.5 mg of N,N-dimethylformamide
To a mixture of 116 mg of N-(t-butoxycarbonyl)-D-phenylalanine and 172 mg of diphenylphosphoryl azide and 63 mg of triethylamine was added under ice cooling, and the mixture was stirred for 1 hour under ice cooling and then overnight at room temperature. 20 ml of 10% aqueous citric acid was added to the reaction mixture, and 50 ml of ethyl acetate-toluene (2:1) was added.
The extract was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure.
The residue was crystallized from n-hexane, and the crystals were collected by filtration, washed with n-hexane, and then 1,1-dimethylethyl [(S)-2-
[[2,3-dihydro-1-(4'-methylphenacyl)
324 mg of 5-phenyl-2H-1,4-benzodiazepin-3-yl]amino]-2-oxo-1-(phenylmethyl)ethyl]carbamate was obtained.

Physical and chemical properties Mass spectrometry values FAB, Pos. (m/z): 631 (M ⁺ + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.40 (9H, s), 2.33 (3H, s), 3.00 to 3.30 (3H, m), 5.
20~5.40(2H,m),5.59~5.62(1H,m),7.10~7.83(20
H,m) (b) 1,1-dimethylethyl [(s)-2-[[2,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-3-yl]amino]
300 mg of [2-oxo-1-(phenylmethyl)ethyl]carbamate was added to 1.2 ml of 4N hydrochloric acid-ethyl acetate solution under ice cooling.
The reaction mixture was adjusted to pH 9 with 1N aqueous sodium hydroxide solution and extracted twice with 10 ml of ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with ethyl acetate to give 2(S)-amino-N-[2,3-dihydro-1-
(4'-methylphenacyl)-5-phenyl-2H-1,4
89 mg of diastereomer A of [benzodiazepin-3-yl]benzenepropanamide (hereinafter referred to as compound (b)-A) (Rf value 0.58) and diastereomer B (hereinafter referred to as
Compound (b)-B (53 mg, Rf value 0.45) was obtained.

Physical and chemical properties Compound (b)-A Mass spectrometry value FAB, Pos. (m/z): 531 (M ⁺ + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.32 (3H, s), 2.82 (1H, dd), 3.38 (1H, dd), 3.71
(1H, dd), 5.28, 5.35 (each 1H, each d), 5.70 (1H,
d), 7.10-7.90 (20H, m), 8.90 (1H, d) Rf value 0.58, developing solvent ethyl acetate Compound (b)-B Mass analysis value FAB, Pos. (m/z): 531 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.32 (3H, s), 3.70 (1H, dd), 3.37 (1H, dd), 3.75
(1H, dd), 5.26, 5.38 (each 1H, each d), 5.68 (1H,
d), 7.10-7.90 (20H,m), 8.98 (1H,d) Rf value 0.45, developing solvent ethyl acetate (c) Compound (b)-A obtained in the above step (b) 89 mg
A mixture of 25 mg of phenylisothiocyanate and 0.5 ml of dichloromethane was added dropwise to the mixture and stirred at room temperature for 15 hours. The solvent was removed from the reaction mixture, and n-hexane was added to the residue. The precipitated crystals were collected by filtration and then purified by 1-
[[1-[2,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepine-
As a result, 91 mg of [3-yl]amino-1-oxo-3-phenyl]prop-2(S)-yl]-3-phenylthiourea (referred to as compound (c)-A) was obtained.

On the other hand, 53 mg of compound (b)-B obtained in the above step (b)
In the same manner as above, 1-[[1-[2,3-dihydro-1-(4'-methylphenacyl-5-phenyl-2H
-1,4-benzodiazepin-3-yl]amino-1-oxo-3-phenyl]prop-2(S)-yl]-3-
60 mg of phenylthiourea (compound (c)-B) was obtained.

Physical and chemical properties Compound (c)-A Mass spectrometry value FAB, Pos. (m/z): 666 (M ⁺ + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.33 (3H, s), 3.34-3.45 (2H, m), 5.23, 5.34 (each
1H,each d),5.41(1H,m),5.603(1H,d),6.80~8.00
(26H,m) Compound (c)-B Mass spectrometry value FAB, Pos. (m/z): 666 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.33 (3H, s), 3.35-3.42 (2H, m), 5.20, 5.37 (each
1H,each d),5.37(1H,m),5.60(1H,d),6.80~7.95
(26H,m) (d) 83 mg of the above compound (c)-A was added to 0.1 mL of trifluoroacetic acid.
The reaction mixture was stirred at room temperature for 3 hours after adding 5 ml of the solvent. The solvent was distilled off from the reaction mixture, and the residue was subjected to silica gel column chromatography, eluting with dichloromethane:methanol = 20:1. The eluate was dissolved in dichloromethane, washed with 1N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give (+)-3-amino-1,3-
29 mg of dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (referred to as compound (d)-A) was obtained.

On the other hand, 60 mg of compound (c)-B obtained in the above step (c)
In the same manner as above, (-)-3-amino-1,3
Thus, 19 mg of 1-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (referred to as compound (d)-B) was obtained.

Physical and chemical properties Compound (d)-A Mass spectrometry value FAB, Pos. (m/z): 384 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.33 (3H, s), 4.63 (1H, s), 5.31 (2H, s), 7.14~7.
84 (13H,m), Compound (d)-B Mass spectrometry value FAB, Pos. (m/z): 384 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.33 (3H, s), 4.63 (1H, s), 5.31 (2H, s), 7.14~7.
84 (13H, m), (e) the above compound (d)-A 15 mg, R(-)-mandelic acid 1 mg
A suspension of 100 mg of benzophenone and 1.5 ml of water was heated to dissolve the compound, and then allowed to cool. The precipitated crystals were collected by filtration and identified as (+)-3-amino-1,3-dihydro-1-(4'-methylphenacyl)-
15 mg of 5-phenyl-2H-1,4-benzodiazepin-2-one 2[R(-)-mandelate] monohydrate (diastereomer A, starting material for Example 18) was obtained.

On the other hand, 9 mg of the compound (d)-B and 8 mg of S(+)-mandelic acid were treated in the same manner as above to obtain (-)-3-amino-1,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepine-2
8 mg of 2-one 2[S(+)-mandelate] monohydrate (diastereomer B, starting material for Example 19) was obtained.

Physicochemical properties: Diastereomer A Specific rotation [α] _D = +47.96 (c = 1.03, MeOH) Elemental analysis (as _C24H21N3O2 · _2C8H8O3 · _H2O ): C ( _% ) _{H ( %} ) N ( _% ) Theoretical value: 68.07 5.57 5.95 Experimental value: 68.23 5.33 5.96 Diastereomer B Specific rotation [α] _D = -50.68 (c = 1.10, MeOH) Nuclear magnetic resonance spectrum (DMSO, TMS internal standard): δ: 2.34 (3H, s), 4.89 (1H, s), 5.08 (2H, s), 5.25-5.
40 (2H,m), 7.10-7.85 (18H,m) Reference Example 17 (raw material for Examples 18 and 19) A suspension of 2.16 g of 3-amino-1,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one, 1.71 g of R(-)-mandenic acid, 32 mg of 3,5-dichlorosalicylaldehyde, and 20 ml of aqueous benzene was heated to dissolve and then allowed to cool to room temperature.

A small amount of diastereomer A obtained in Reference Example 16(e) was added, and the mixture was stirred at room temperature for 3 days. The precipitated crystals were collected by filtration and (+)-3-amino-1,3-dihydro-1-
(4'-methylphenacyl)-5-phenyl-2H-1,4
The specific rotation and nuclear magnetic resonance spectrum of this compound were identical to those of diastereomer A of Reference Example 16.

Treat as above to obtain 200 mg of diastereomer B, S (+)
- (-)-3-amino-1,3-dihydro-1-mandenic acid (159 mg) and 3,5-dichlorosalicylaldehyde (3 mg) were used.
-(4-methylphenacyl)-5-phenyl-2H-1,4
The physicochemical properties of this product were completely identical to those of diastereomer B.

Reference Example 18 (raw materials for Examples 16 and 20-25) To a solution of 2.75 g of 3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one in 55 ml of acetonitrile (S)
Add 0.98 g of (+)-mandelic acid and stir at room temperature. After 30 minutes, add 41 mg of 3,5-dichlorosalicylaldehyde and stir for an additional 18 hours. The precipitated crystals are collected by filtration, washed with 15 ml of acetonitrile, and diluted with (R)-3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-
2.94 g of 2H-1,4-benzodiazepin-2-one (S)-mandelate was obtained.

Physicochemical properties ▲[α] ^20D _{▼ =+152.5° (c=1.00, MeOH) Melting point 157-160°C Elemental analysis values (as C24H21N3O2·C8H8O3 ) C ( % ) H} (%) N (%) Theoretical value 71.76 5.46 7.85 Experimental value 71.64 5.49 7.79 The compound of Reference Example 19 was obtained in the same manner as in Reference Example 18.

Reference Example 19 (raw material for Example 17) Name of the resulting compound: (S)-3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one (R)-mandelate. Raw material: 3-amino-1,3-dihydro-1-(2'-
(R)(-)-mandelic acid, (R)(-)-methylphenacyl-5-phenyl-2H-1,4-benzodiazepin-2-one,
3,5-Dichlorosalicylaldehyde Physicochemical properties ▲[α] ²⁰ _D ▼=151.2° (c=1.00, MeOH) Melting point 157-160°C Elemental analysis values (as _C14H21N3O2 · _C8H8O3 ) C ( _% ) H _{( %} ) N ( _% ) Theoretical value 71.76 5.46 7.85 Experimental value 71.74 5.56 7.86 _The following compound of Reference Example 20 was obtained in the same manner as Reference Example 1 or 2.

Reference Example 20 (raw material for Example 26) Target compound: 3-amino-1,3-dihydro-1-(2'-naphthoylmethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one. Starting compound: 1,3-dihydro-1-(2'-naphthoylmethyl)-3-oximido-5-phenyl-2H-1,4-
Benzodiazepine-2-one Physical and chemical properties Mass analysis values FAB, Pos. (m/z): 420 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.78 (2H, dr), 4.71 (1H, s), 5.37 (1H, d), 5.59 (1H)
H,d), 7.0-8.1 (15H,m), 8.42 (1H,s) Example 1. A mixture of 0.74 g of 3-amino-1,3-dihydro-1-phenacyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 5 ml of tetrahydrofuran was added to a mixture of 0.27 g of 3-tolylisocyanate and 3 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 4 hours. The solvent of the reaction mixture was distilled off, and the residue was recrystallized from toluene-n-hexane to obtain 1-[2,3-dihydro-2-oxo-1-phenacyl-5-phenyl-
1H-1,4-benzodiazepin-3-yl]-3-(3-
Tolyl)urea (0.78 g) was obtained.

Physicochemical properties _: Melting point 212-214°C; Elemental analysis (as _{C31H26N4O3 )} : C (%), H (%), N (%) Theoretical value _: 74.09, 5.21, 11.15; Experimental value: 74.21, 5.26, 11.08; Mass analysis value: FAB, Pos. (m/z): 503 (M ⁺ +1) Example 2. In a mixture of 5.75 g of 3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one and 60 ml of tetrahydrofuran,
A mixture of 2.24 g of tolyl isocyanate and 5 ml of tetrahydrofuran was added and stirred at room temperature for 1.5 hours. The solvent was distilled off from the reaction mixture, and the resulting residue was recrystallized from methylene chloride-ether to give 1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea.
7.01g was obtained.

Physicochemical properties _: Melting point 141-143°C; Elemental analysis (as _{C32H28N4O3 )} : C (%), H (%), N (%) Theoretical value _: 74.40, 5.46, 10.85; Experimental value: 74.43, 5.49, 10.83; Mass analysis FAB, Pos. (m/z): 517 (M ⁺ +1). The compounds of the following examples were prepared in the same manner as in Example 1 or 2.

Example 3 Product compound name: 1-[2,3-dihydro-1-(4'-methoxyphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Starting compound: 3-amino-1,3-dihydro-1-(4'-
Physicochemical properties: Melting point 175-178°C; Elemental analysis (as _C32H28N4O4 ): C (%) _, H (%), N (%); Theoretical value: 72.17, _5.30 , _10.52 ; Experimental value: 72.20, 5.60, 10.23; Mass analysis value: FAB, Pos. (m/z): 533 (M ⁺ +1); Example 4. Name of the compound produced: 1-[2,3-dihydro-1-nicotinoylmethyl-2-
Oxo-5-phenyl-1H-1,4-benzodiazepine
3-yl]-3-(3-tolyl)urea Starting compounds: 3-amino-1,3-dihydro-1-nicotinoylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-tolyl isocyanate Physicochemical properties: Melting point _{239-241 °} C Elemental analysis (as _{C30H25N5O3 )} : C (%) H (%) N (%) Theoretical value 71.56 5.00 13.91 Experimental value 71.57 5.20 13.80 Mass analysis value EI (m/z): 503 (M ⁺ ) Example 5. Product compound name: 1-[2,3-dihydro-1-(2'-methoxyphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Starting compound: 3-amino-1,3-dihydro-1-(2'-
Physicochemical properties: Melting point 160-163°C; Elemental analysis (as C32H28N4O4.0.5H2O): C (%), H (%), N (%); Theoretical value: _70.95 , _5.41 , _10.35 ; Experimental value: 70.74, _5.28 , 10.23; Mass analysis value _: FAB, Pos. (m/z): 533 (M ⁺ +1); Example 6. Product compound name: 1-[2,3-dihydro-1-(3'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Starting compound: 3-amino-1,3-dihydro-1-(3'-
Physicochemical properties _: Melting point 225-227°C; Elemental analysis (as C32H28N4O3): C (%), H (%), N (%); Theoretical value: _74.40 , _5.46 , _10.85 ; Experimental value: 74.38, 5.43, 10.72; Mass analysis value: FAB, Pos. (m/z): 517 (M ⁺ +1); Example 7. Product compound name: 1-[2,3-dihydro-1-(4'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Starting compound: 3-amino-1,3-dihydro-1-(4'-
Physicochemical properties: Melting point 193-196°C. Elemental analysis (as _C32H28N4O3 ): C (%) H (%) N (%) Theoretical value: 74.40 _{5.46 10.85} Experimental value: 74.56 5.50 _10.77 Mass analysis value: FAB, Pos. (m/z): 517 (M ⁺ +1). Example 8. Example 9. Product compound: 1-[1-(4'-chlorophenacyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea. Starting compounds: 3-amino-1-(4'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-tolyl isocyanate. Physicochemical properties: Melting point _: 214-216°C _. Elemental analysis (as _C31H25N4O3Cl ): C (%), H (%), N (%) _, Cl (%). Theoretical value: 69.34, 4.69, 10.43, 6.60. Experimental value: 69.14, 4.69, 10.38, 6.76. Mass analysis value: EI (m/z): 536 (M ⁺ -1). Name of the compound produced: 1-[1-(2'-chlorophenacyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea. Starting compounds: 3-amino-1-(2'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 3 _{- tolyl isocyanate. Physical and chemical properties: Melting point: 191-193°C. Elemental analysis (as C31H25N4O3Cl.0.3H2O ) :} C (%), H (%) _, N (%), Cl
(%) Theoretical value 68.63 4.77 10.33 6.54 Experimental value 68.87 4.76 10.13 6.48 Mass spectrometry value FAB, Pos. (m/z): 517 (M ⁺ ) Example 10. Name of product compound: 1-[1-(3'-chlorophenacyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Raw material compounds: 3-amino-1-(3'-chlorophenacyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-tolyl isocyanate Physical and chemical properties _: Melting point _{: 139-142°C (PhCH3-C2H5OH) Elemental analysis (as C31H25N4O3Cl ) : C ( %} ) H (%) N (%) Cl
(%) Theoretical value 69.34 4.69 10.43 6.60 Experimental value 69.24 4.70 10.39 6.58 Mass spectrometry value EI (m/z): 536 (M ⁺ −1) Example 11. 3-amino-1,3-dihydro-5-phenyl-1-(2
-thenoyl)methyl-2H-1,4-benzodiazepine-2
A mixture of 0.26 g of 3-tolyl isocyanate, 95 mg of 3-tolyl isocyanate, and 5 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was diluted with toluene-ether (1:
5 ml of the mixture of 1) was added, and the crystals were collected by filtration. 1-[2,3-dihydro-2-oxo-5-phenyl-1-(2-thenoyl)
Methyl-1H-1,4-benzodiazepin-3-yl]-3
0.2 g of 3-tolyl urea was obtained.

This compound has the following physicochemical properties:

i) Melting point: 189-192°C ii) _Elemental analysis (as _{C29H24N4O3 )} S (%) Theoretical value: 6.30 Experimental value _: 6.25 iii) Mass analysis FAB, Pos. (m/z): 509 (M ⁺ +1) The following compound was synthesized in the same manner as in Example 11.

Example 12 1-[2,3-Dihydro-1-(3-indolylcarbonyl)methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Starting compound: 3-amino-1,3-dihydro-1-(3-indolylcarbonyl)methyl-5-phenyl-2H-1,4
- Benzodiazepine-2-one and 3-tolylisocyanate This compound has the following physicochemical properties:

i) Melting point: 232-237° _C ii) _Elemental analysis values (as _{C33H27N5O3.0.1H2O} ) C (%) H (%) N (%) Theoretical value 72.91 5.38 12.88 Experimental value 72.76 5.17 12.71 iii) Mass analysis value FAB, _Pos . ₍ m/z): 542 (M ⁺ +1) Example 13. The following compound was obtained in the same manner as in Example 11.

1-[2,3-Dihydro-1-(3-methyl-2-thenoyl)methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Raw material compound: 3-amino-1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4
- Benzodiazepine-2-one and 3-tolylisocyanate Physical and chemical properties i) Melting point: 150-153°C ii) Mass analysis value FAB, Pos. (m/z): 523 (M ⁺ +1) iii) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.25 (3H, s), 2.53 (3H, s), 5.32 (2H, s), 5.42 (1
H,d),6.78(1H,d),7.0～7.8(14H,m),7.94(1H,d),
9.01 (1H,s) Example 14. (R)-3-amino-1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4-
Benzodiazepin-2-one (S)-mandelate 5.
A mixture of 1 g, 18 ml of 1 N aqueous sodium hydroxide, 50 ml of water, and 20 ml of dichloromethane was stirred for 30 minutes under ice cooling. The reaction mixture was extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.7 g of free amine.

A mixture of the free amine obtained above, 1.26 g of 3-tolylisocyanate, and 27 ml of tetrahydrofuran was stirred at room temperature for 5 hours.
The solvent was removed from the reaction mixture by evaporation under reduced pressure, and 50 ml of acetonitrile was added to the residue.
The precipitated crystals were collected and mixed with (R)-1-[2,3-
Dihydro-1-(3-methyl-2-thenoyl)methyl-
4.5 g of 2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea was obtained as white crystals.

Physicochemical properties i) ▲[α] ^20D _▼ =-158° (c= _1.0 , _CH2Cl2 ) ii) Melting point: 203-206°C iii) Elemental analysis values (as _C30H26N4O3S ) C (%) H _{( %} ) N ( _% ) S (%) Theoretical value 68.95 5.01 10.72 6.14 Experimental value 69.11 5.19 10.71 6.04 Example 15. The following compound was obtained in the same manner as in Example 14.

(S)-1-[2,3-dihydro-1-(3-methyl-2
-thenoyl)methyl-2-oxo-5-phenyl-1H-
1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Raw material compound: (S)-3-amino-1,3-dihydro-1
Example 16. Physicochemical properties _{of -(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (R)-mandelate and 3-tolylisocyanate i) ▲[α]20D ▼=-158° (c=1.0, CH2Cl2) ii) Melting point: 204-206°C iii) Elemental analysis (as C30H26N4O3S} ⁾ _{C ( % ) H} (%) N (%) S (%) Theoretical value 68.95 5.01 10.72 6.14 Experimental value 69.01 5.03 10.66 6.07 2.87 g of (R)-3-amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one·(S)-mandelate hydrochloride was dissolved in 60 ml of dichloromethane, 40 ml of 0.25N aqueous sodium hydroxide solution was added, and the mixture was stirred for 10 minutes. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting free amine and 0.75 g of 3-tolyl isocyanate were used to prepare (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-2-one hydrochloride] in the same manner as in Example 1 or 2.
-benzodiazepin-3-yl]-3-(3-tolyl)
2.39 g of urea was obtained.

Physicochemical properties ▲[α] ^20D _▼ =+138.1° (c= _0.99 , _CH2Cl2 ) Melting point: 197-199°C Elemental analysis values (as _{C32H26N4O3 )} C (%) H ( _% ) N (%) Theoretical value 74.40 _5.46 10.85 Experimental value 74.45 5.53 10.88 Mass analysis value FAB, Pos. (m/z): 517 (M ⁺ +1) The following compounds of Examples 17 to 25 were obtained in the same manner as in Example 16.

Example 17. (S)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea Raw material compound: (S)-3-amino-1,3-dihydro-1
-(2'-methylphenacyl)-5-phenyl-2H-1,
4-Benzodiazepine-2 _{-one (R)-mandelate and 3-tolylisocyanate Physicochemical properties ▲[α]20D} ^▼ =-136.9° (C= _1.01 , _CH2Cl2 ) Melting point: 194-198°C Elemental analysis (as _C32H28N4O3 ) C (%) H (%) N (%) Theoretical value 74.40 5.46 10.85 Experimental value 74.29 5.58 10.72 Mass analysis value FAB, Pos. (m/z ₎ : 517 (M ₊ ⁺¹ ) Example ₁₈ . Product compound name: (+)-1-[2,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-1H-1,4-benzodiazepin-2-one-3-yl]-3-(3-methylphenyl)urea Raw material compound: (+)-3-amino-1,3-dihydro-1
-(4'-methylphenacyl)-5-phenyl-2H-1,
4-Benzodiazepine-2-one 2[R(-)-mandelate] monohydrate and 3-tolylisocyanate Physical and chemical properties [α] _D = +88.3° (C = 1.00, MeOH) Melting point: 130-133°C _Elemental analysis (as _{C32H28N4O3 )} C ( _% ) H (%) N (%) Theoretical value 74.40 5.46 10.85 Experimental value 74.52 5.61 10.70 Mass analysis value FAB, Pos. (m/z): 517 (M ⁺ +1) Example 19. Name of the product compound: (-)-1-[2,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-1H-1,4-benzodiazepin-2-one-3-yl]-3-(3-methylphenyl)urea Starting compound: (-)-3-amino-1,3-dihydro-1
-(4'-methylphenacyl)-5-phenyl-2H-1,
4-Benzodiazepine-2-one 2[S(+)-mandelate] monohydrate and 3-tolyl isocyanate Physical and chemical properties [α] _D = -86.3° (c = 1.02, MeOH) Melting point: 143-145°C _Elemental analysis (as _{C32H28N4O3 )} C ( _% ) H (%) N (%) Theoretical value 74.40 5.46 10.85 Experimental value 74.11 5.58 10.69 Mass analysis value FAB, Pos. (m/z): 517 (M ⁺ +1) Example 20. Name of the product compound: (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-1H-1,4-benzodiazepin-2-one-3-yl]-3-phenylurea Starting compound: (R)-3-amino-2,3-dihydro-1
-(2'-methylphenacyl)-5-phenyl-2H-1,
4-Benzodiazepine-2-one S(+)-mandelate and phenyl isocyanate Physicochemical properties [α] _D = +128.7° (c = 1.00, CHCl ₃ ) Melting point: 229-231°C Elemental analysis (as C ₃₁ H ₂₆ N ₄ O ₃ ) C (%) H (%) N (%) Theoretical value 74.09 5.21 11.15 Experimental value 74.07 5.33 11.00 Mass analysis value FAB, Pos. (m/z): 503 (M ⁺ +1) Example 21. Name of the product compound: (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(2-tolyl)urea Starting compound: (R)-3-amino-1,3-dihydro-1
-(2'-methylphenacyl)-5-phenyl-2H-1,
4-Benzodiazepine-2 _{-one (S)-mandelate and 2-tolylisocyanate Physicochemical properties ▲[α]20D} ^▼ =+151.8° (c= _1.03 , _CH2Cl2 ) Melting point: 178-181°C Elemental analysis ( _{as C32H28N4O3} ) C ( _% ) H (%) N (%) Theoretical value 74.40 5.46 10.85 Experimental value 74.34 5.45 10.84 Mass analysis value FAB, Pos. (m/z ₎ : 517 (M ⁺ +1) Example 22. Name of the product compound: (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodizepin-3-yl]-3-(4-tolyl)urea Starting compound: (R)-3-amino-1,3-dihydro-1
-(2'-methylphenacyl)-5-phenyl-2H-1,
4-Benzodiazepine-2-one (S)-mandelate and 4-tolylisocyanate Physicochemical properties ▲[ _α]20D ^▼ =+149.6° (c=0.39, DMF) Melting point: 256-295°C _Elemental analysis ( _{as C32H28N4O3} ) C ( _% ) H (%) N (%) Theoretical value 74.40 5.46 10.85 Experimental value 74.33 5.60 10.68 Mass analysis value FAB, Pos. (m/z): 517 (M ⁺ +1) Example 23. Name of the product compound: (R)-1-(3-chlorophenyl)-3-[2,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-1,4-benzodiazepin-2-one-3-yl]urea Starting compound: (R)-3-amino-2,3-dihydro-1
-(2'-methylphenacyl)-5-phenyl-2H-1,
4-Benzodiazepin-2-one S(+)-mandelate and 3-chlorophenyl isocyanate Physical and chemical properties [α] _D = +115.8° (C = 1.00, CHCl ₃ ) Melting point: 132-133°C Elemental analysis (as C ₃₁ H ₂₅ N ₄ O ₃ Cl·0.2H ₂ O) C (%) H (%) N (%) Cl (%) Theoretical value 68.87 4.74 10.36 6.56 Experimental value 68.73 4.75 10.39 6.74 Mass analysis value FAB, Pos. (m/z): 537 (M ⁺ +1) Example 24. Name of the product compound: (R)-1-(4-chlorophenyl)-3-[2,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-1H-1,4-benzodiazepin-2-one-3-yl]urea Starting compound: (R)-3-amino-2,3-dihydro-1
-(2'-methylphenacyl)-5-phenyl-2H-1,
_{4-Benzodiazepin-2-one S(+) mandelate and 4-chlorophenyl isocyanate Physical and chemical properties [α] D = +134.9° (C = 1.00, DMF) Melting point: 244-246°C Elemental analysis (as C31H25N4O3Cl ) C ( %} ) H (%) N (%) Cl (%) Theoretical value 69.34 4.69 10.43 6.60 Experimental value 69.16 4.75 10.37 6.59 Mass analysis value FAB, Pos. (m/z): 537 (M ⁺ +1) Example 25. Name of the product compound: (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methoxyphenyl)urea Starting compound: (R)-3-amino-1,3-dihydro-1
-(2'-methylphenacyl)-2-oxo-5-phenyl-2H-1,4-benzodiazepin-2-one (S)
-Mandelate and 3 _{-methoxyphenyl isocyanate Physicochemical properties ▲[α]20D} ^▼ = ₊ 151.5° (c=0.31, _CH2Cl2 ) Melting point: 192-195°C Elemental analysis values (as _C32H28N4O4 ) C (% ₎ H ( _% ) N ( _% ) Theoretical value 72.17 5.30 10.52 Experimental value 72.11 5.32 10.51 Mass analysis value FAB, Pos. (m/z): 533 (M ⁺ +1) The following compound of Example 26 was obtained in the same manner as in Example 1 or 2.

Example 26. Name of the compound produced: 1-[2,3-dihydro-1-(2-naphthoylmethyl)]
10.08 重量％） 重量％（ ...水） 重量％ _（重量％） 重量％（重量％） 重量％（水） 重量％（重量％） 重量％（水） 重量％（重量％） 重量％（水） 重量％（水） 重量_％ （水_）重量％ _（重量_％ ）_{重量 ％} δ:2.25(3H,s),5.42(1H,d),5.69(1H,d),5.78(1
H,d),6.76(1H,d),7.0~7.8(15H,m),7.9~8.2(4H,
m),8.80(1H,s),9.00(1H,s)

Claims (11)

[Claims] [Claim 1] General formula (The symbols in the formula have the following meanings. R ¹ : an aryl group, a thienyl group, a pyridyl group, or an indolyl group, which may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom. R ² : a lower alkyl group, a lower alkoxy group, or an aryl group which may be substituted with a halogen atom.) or a pharmaceutically acceptable salt thereof. 2. A benzodiazepine derivative or a pharmaceutically acceptable salt thereof in which R ¹ in claim 1 is a lower alkyl group, a lower alkoxy group, or an aryl group which may be substituted with a halogen atom. 3. A benzodiazepine derivative or a pharmaceutically acceptable salt thereof in which R ¹ in claim 1 is a thienyl group optionally substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom. 4. 1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4
-benzodiazepin-3-yl]-3-(3-tolyl)
Urea or a pharmaceutically acceptable salt thereof. Claim 5: (R)-1-[2,3-dihydro-1-
(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-
(3-Tolyl)urea or a pharmaceutically acceptable salt thereof. 6. 1-[2,3-dihydro-1-(3-methyl-2-thenoyl)methyl-2-oxo-5-phenyl-
1H-1,4-benzodiazepin-3-yl]-3-(3-
tolyl)urea or a pharmaceutically acceptable salt thereof. Claim 7: (R)-1-[2,3-dihydro-1-(3
-methyl-2-thenoyl)methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3
-(3-tolyl)urea or a pharmaceutically acceptable salt thereof. 8. 1-[2,3-dihydro-1-(4'-methylphenacyl)-5-phenyl-1H-1,4-benzodiazepin-2-one-3-yl]-3-(3-methylphenyl)urea or a pharmaceutically acceptable salt thereof. Claim 9: (+)-1-[2,3-dihydro-1-
(4'-methylphenacyl)-5-phenyl-1H-1,4
-benzodiazepin-2-one-3-yl]-3-(3
-methylphenyl)urea or a pharmaceutically acceptable salt thereof. 10. A CCK-B receptor antagonist or gastrin receptor antagonist comprising the novel benzodiazepine derivative or salt thereof according to claim 1. [Claim 11] The pharmaceutical composition of claim 10, which is a therapeutic agent for diseases caused by physiological dysfunction controlled by gastrin, particularly gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, and Zollinger-Ellison syndrome, without inducing side effects related to CCK-A receptors.