JPH07304755A - Condensed diazepine derivative - Google Patents

Abstract

PURPOSE:To obtain a compound having a strong renin inhibitory effect and useful as a preventive and therapeutic agent for hypertension. CONSTITUTION:A compound of formula I [A ring is benzene ring or thiophene ring; R<1> is H, a lower alkyl or an aralkyl; R<2> is a lower alkyl, an aralkyl or phenyl; L<1> is a bond or an alkylene; X is a bond, CO or NHCO; R<3> and R<5> are an aralkyl or a lower alkyl; L<2> is (CHOH)n or CONHCHR<5>; (n) is 1 or 2; Y is Het, CH2Het, CH2SHet, etc.; Het is a heterocycle], e.g. (3R)-3-[3-[(1S)-1- cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl)thio]propyl]ureid o]-1- methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one. The compound of formula I can be synthesized by conducting a coupling reaction between a compound of formula II and a compound of the formula H2NCHR<3> L<2> Y in the presence of a compound of formula III (V and W are each an eliminable group such as a halogen or an imidazolyl).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fused diazepine derivative or a salt thereof which is useful as a drug, especially as a prophylactic / therapeutic agent for hypertension.

[0002]

BACKGROUND OF THE INVENTION Renin inhibitors inhibit the reaction between renin and a renin substrate (angiotensinogen), which is said to be the rate-determining step of the renin-angiotensin system, which is a pressor system in the living body, and inhibits the production of angiotensin I. By lowering it, it is intended to suppress the production of angiotensin II, which strongly acts on pressor such as vasoconstrictor action and aldosterone secretory action.

In recent studies on renin inhibitors, the specific amino acid statin contained in the natural renin inhibitor pepstatin is replaced by the renin substrate analogs Leu-Val and L.
Considering that it is a transition state of the eu-Leu site (hydrolysis site by renin), transition-state analogs in which a statin is introduced into a synthetic renin substrate analog are attracting attention. As the latest renin inhibitors to be noted, which are included in the category of this transition state analog, and are notable as JP-A-6-
4-19071, JP-A-4-279952, J. Med. Chem., 35 , 1735-1746 (19).
92) and the like.

[0004]

DISCLOSURE OF THE INVENTION In order to make a renin inhibitor clinically usable, (1) it has a strong inhibitory activity against human renin, and (2) the action time suitable for clinical treatment. There is a demand for a renin inhibitor that is persistent, (3) has excellent absorbability from the intestinal tract, and (4) has a high specificity of inhibitory activity against human renin.

[0005] The problem of enhancing inhibitory activity is due to the use of a statin-introduced transition state analog, and regarding the problem of prolonged action, the N-terminal and / or C of the peptide.
It can be said that by introducing a protecting group at the terminal and further by optimizing each side chain for the problem of specificity enhancement, good results have been produced, and a tentative solution direction has been given.

However, improvement of intestinal absorption is still unsolved. That is, in order to improve the intestinal absorbability, a lower molecular weight is being considered, and in the development research of transition state analogs, a lower molecular weight tripeptide or dipeptide is being transitioned. The peptides described above are typical compounds of these, but the compound of the present invention is a non-peptide renin inhibitor found for the purpose of further lowering the molecular weight. Further, JP-A-2-204491, JP-A-4-230380, and JP-A-5-239.
The compound described in 059 is also non-peptidic, but has a different chemical structure from the compound of the present invention.

[0007]

[Means for Solving the Problems] Under such a technical level,
The present inventors have earnestly studied for the purpose of providing a renin inhibitor that can meet the above-mentioned requirements (1) to (4), and as a result, by introducing a fused diazepine ring as a transition state analog, the above-mentioned objects are surprisingly achieved. The present invention has been completed by discovering that the achievement can be achieved. That is, the present invention relates to a fused diazepine derivative represented by the following general formula (I) or a salt thereof.

[0008]

[Chemical 2]

(However, the symbols in the formulas have the following meanings: A ring: optionally substituted benzene ring or thiophene ring, R ¹ : hydrogen atom, lower alkyl group or aralkyl group, R ² : lower An alkyl group, an aralkyl group or an optionally substituted phenyl group, L ¹ : a bond, an alkylene group optionally substituted with a lower alkyl group or an aralkyl group, X: a bond, a group represented by the formula —CO— or a formula -NHC
A group represented by O-, R ^3: aralkyl group or a cycloalkyl lower alkyl group which may be substituted with a group, L ^2:
A group represented by the formula- (CHOH) _n- or a formula-CONHC
Group represented by HR ⁵ —, n: 1 or 2, R ⁵ : lower alkyl group optionally substituted with aralkyl group or cycloalkyl group, Y: —Het, —CH ₂ —Het, —CH ₂ —
S-Het or -CO ₂ -R ^4, Het: may be substituted, and 3-6 membered heterocyclic ring containing 1 to 4 nitrogen atoms, R ^4: a hydrogen atom or a lower alkyl group. In the present invention, L ₂ is preferably a group represented by the formula — (CHOH) _n — and Het is a tetrazolyl group or a 2-oxo-oxazolidinyl group which may be substituted.

The compound (I) of the present invention will be described in detail below. When X is a group represented by formula -CO-, the compound of the present invention is an amide derivative (IIa). Also, X is the formula −
When it is a group represented by NHCO-, the compound of the present invention is
It is a urea derivative (IIb). Further, when X is a bond, the compound of the present invention is a secondary amine (IIc).

[0011]

[Chemical 3]

(Wherein A ring, R ¹ , R ² , R ³ , L ¹ and L ²
And Y have the meanings given above. ) Unless otherwise specified in the definition of the general formula in the present specification,
The term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. Accordingly, examples of the "lower alkyl group" include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s
ec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2
-Dimethylpropyl group, hexyl group, isohexyl group,
1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-
Dimethylbutyl group, 2,2-dimethylbutyl group, 1,3
-Dimethylbutyl group, 2,3-dimethylbutyl group, 3,
3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,
2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like can be mentioned. Of these groups, methyl group, ethyl group,
An alkyl group having 1 to 4 carbon atoms such as a propyl group, an isopropyl group and a butyl group is preferable, a methyl group and an ethyl group are more preferable, and a methyl group is still more preferable.

Examples of the "lower alkylene group" include alkylene groups having 1 to 6 carbon atoms, specifically, methylene group, ethylene group, methylmethylene group, trimethylene group, dimethylmethylene group, tetramethylene group. , Methyltrimethylene group, ethylethylene group, dimethylethylene group, ethylmethylmethylene group, pentamethylene group, methyltetramethylene group, dimethyltrimethylene group, trimethylethylene group, diethylmethylene group, hexamethylene group, methylpentamethylene group, Examples thereof include a dimethyltetramethylene group. Of these groups, an alkylene group having 1 to 3 carbon atoms such as a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, and a dimethylmethylene group is preferable, a methylene group and an ethylene group are more preferable, and a methylene group is still more preferable.

The "aralkyl group" means a group in which any hydrogen of the above "lower alkyl group" is substituted with an aryl group. The "aryl group" means an aromatic hydrocarbon group, but an aryl group having 6 to 14 carbon atoms is preferable. Specifically, it is a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an indenyl group, an anthryl group or a phenanthryl group, more preferably a phenyl group or a naphthyl group. The "cycloalkyl group" has 3 carbon atoms.
To 7 cyclic alkyl groups, and specific examples include cyclopropyl group, cyclobutyl group, cyclopentyl group,
Examples thereof include cyclohexyl group and cycloheptyl group.

The "3- to 6-membered heterocyclic ring containing 1 to 4 nitrogen atoms" may further contain an oxygen atom or a nitrogen atom. Specifically, for example, a pyrrolyl group, a pyrrolidinyl group, a pyridyl group, an imidazolyl group, a piperazinyl group, a pyrazolyl group, a pyrazinyl group, a pyrimidinyl group,
It may be a pyridazinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an imidazolidinyl group, a homopiperazinyl group, a pyrazolidinyl group, a triazinyl group or a tetrazolyl group. Examples of the heterocycle containing an oxygen atom also include an oxazolyl group, an oxazolidinyl group, and an isoxazolyl group. Further, as a heterocycle containing a sulfur atom, a thiazolyl group, a thiazolinyl group, an isothiazolinyl group, a 1,3,4-thiadiazolyl group, 1,2,
Examples thereof include a 5-thiadiazolyl group. This heterocycle is 5
It is preferably a ring having 6 to 6 members. Furthermore, the compound of the present invention may easily form a salt with an inorganic acid or an organic acid. Examples of the salt include inorganic acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid,
Propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
Examples thereof include organic acid salts such as methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid.

Since the compound (I) of the present invention has two or more asymmetric carbon atoms, optical isomers and diastereoisomers based on the asymmetric carbon atoms exist. The present invention includes isolated forms of these various isomers and mixtures of these isomers. Further, in some cases, various hydrates, various solvates, compatible isomers, crystalline polymorphisms, etc. also exist, but the compounds of the present invention include isolated compounds of these compounds and all compounds of their mixtures. included.

Manufacturing method First manufacturing method

[0018]

[Chemical 4]

(In the formula, V and W represent a leaving group such as a halogen atom and an imidazolyl group. A ring, R ¹ , R ² and R
³ , L ¹ , L ² and Y have the meanings given above. ) The compound (IIb) of the present invention is a primary amine compound (IV)
And a primary amine compound (V) are coupled in the presence of a compound (VI) such as a phosgene equivalent or the like. As the compound (VI), phosgene,
Examples include triphosgene and carbonyldiimidazole. For example, in Examples 1 to 9, 11 and 12, 20 to 26, the first manufacturing method is applied. Further, in order to promote the reaction, it may be preferable to carry out the reaction in the presence of an inorganic base such as sodium carbonate, sodium hydroxide or potassium hydroxide, or an organic base such as triethylamine or N, N-dimethylaniline.

The reaction solvent is an inert solvent such as N, N-dimethylformamide, chloroform, benzene, toluene, xylene, dioxane, ether, tetrahydrofuran, dichloromethane, dichloroethane, or a commonly used solvent such as an arbitrary mixed solvent thereof. Is used. This reaction is usually performed at room temperature or under heating with stirring. Second manufacturing method

[0021]

[Chemical 5]

(In the formula, Pc means a protective group for a carboxyl group. Ring A, R ¹ , R ² , R ³ , L ¹ , L ² and Y are
It has the above meaning. ) Carboxylic acid derivative (VII) and amine derivative (VII
The compound of the present invention (IIa) is obtained by condensing with I). For example, Examples 13 and 14 and Examples 17 to 1
In 9 and 27 to 29, the second production method is applied. The amino terminus of the amine derivative (VIII) may be protected with a protecting group (Pa). This protecting group (Pa) is deprotected by a catalytic hydrogenation reaction or the like before the condensation reaction.

Instead of the carboxylic acid derivative, an active ester may be used for condensation. An active ester obtained by reacting with a phenol-based compound such as p-nitrophenol, N-hydroxysuccinimide, N-hydroxylamine-based compound such as 1-hydroxybenzotriazole; a monoalkyl carbonate, or an organic acid The resulting mixed acid anhydride, diphenylphosphoryl chloride, or a phosphoric acid-based mixed acid anhydride obtained by reacting with N-methylmorpholine; acid azide obtained by reacting an ester with hydrazine or alkyl nitrite; acid chloride, acid It can be produced by applying a C-terminal activation method using an acid halide such as bromide; a symmetric acid anhydride and the like.

In the condensation reaction, it is preferable to use a condensing agent, and as the condensing agent, 1-ethyl-3- (3- (N,
N-dimethylamino) propyl) carbodiimide (WS
CD) can be preferably used. In addition, N, N
-For the formation of peptide bonds such as dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), isobutyl chloroformate, carbonyldiimidazole, benzotriazolyl-N-hydroxytrisdimethylaminophosphonium hexafluorophosphide salt (Bop reagent) Commonly used condensing agents can be used.

As an additive which may be used together with a condensing agent such as WSCD and DCC, there is HOBT, and N-
Examples thereof include hydroxysuccinimide (HONSu) and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt).

Further, depending on the method applied, it may be preferable to carry out the reaction in the presence of a base such as triethylamine, pyridine, N-methylmorpholine or the like, for the reaction to proceed smoothly. The reaction is usually performed in a solvent under cooling to room temperature. As the solvent used, a commonly used solvent such as chloroform, carbon tetrachloride, cycloloethane, tetrahydrofuran, dioxane, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, dimethylformamide, dimethyl sulfoxide, or any mixed solvent thereof is used. To be

Pa and Pc are preferably protective groups commonly used in the peptide field. Specific examples of the amino group-protecting group (Pa) include a benzyloxycarbonyl group,
p-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, 1,1-dimethylethoxycarbonyl group, isobornyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, 3, 5-dimethoxy-α, α-dimethylbenzyloxycarbonyl group, 9-
Examples thereof include a fluorenylmethyloxycarbonyl group and a methylsulfonylethoxycarbonyl group.

Examples of the protective group (Pc) for the carboxyl group include, for example, benzyl group, p-nitrobenzyl group, p-methoxybenzyl group, diphenylmethyl group, substituted benzyl groups such as benzhydryl group, tert.
-Butyl group, methyl group, ethyl group, phenacyl group, trichloroethyl group and the like can be mentioned. Third method

[0029]

[Chemical 6]

(Wherein A ring, R ¹ , R ² , R ³ , L ¹ ,
L ² , R ⁵ , Y and Pc have the meanings given above. ) The condensed diazepine derivative (IX) is used as a starting material and condensed with the amine derivative (X) to obtain the compound (III) of the present invention. The reaction conditions are the same as in the second production method. As another production method, for a compound of the present invention in which a nitrogen atom of a heterocyclic group is substituted with a lower alkyl group, a conventional N-alkylation reaction is applied to the compound of the present invention in which a hydrogen atom is bonded to the nitrogen atom. Can be obtained by

In the above production method, it may be effective in terms of production technology to replace the carbonyl group of the intermediate compound or the compound of the present invention with an appropriate protecting group, that is, a functional group which can be easily converted into a carbonyl group. is there. Examples of such a protecting group include “Protective Gr” by Greene and Wuts.
oops in Organic Synthesi
s ", the protective groups described in the second edition can be mentioned, and these can be appropriately used depending on the reaction conditions. In addition, as a functional group that can be easily converted to a carbonyl group,
For example, a hydroxymethylene group (—CH (OH) —) can be mentioned, and such a functional group can also be used as an equivalent of a carbonyl group.

The compound according to the invention thus prepared is isolated and purified in free form or as a salt thereof. Isolation and purification are carried out by appropriately applying usual chemical operations such as extraction, crystallization, recrystallization and various kinds of chromatography. In addition, the racemic compound can be prepared by using an appropriate starting material compound or by a general racemic resolution method (for example, a method of leading to a diastereomeric salt with a general optically active acid (such as tartaric acid) and performing optical resolution). , Can lead to stereochemically pure isomers. The diastereomeric mixture can be separated by a conventional method, for example, fractional crystallization or chromatography.

[0033]

INDUSTRIAL APPLICABILITY The condensed diazepine compound of the present invention or a salt thereof has a specific and potent inhibitory activity against human renin, has a long duration of action suitable for clinical administration, and is absorbed from the intestinal tract. It has excellent properties. Therefore, the compound of the present invention is useful as a prophylactic / therapeutic agent for hypertension, particularly renin-angiotensin-dependent hypertension.

The specific and potent inhibitory activity of the compound of the present invention on human renin was confirmed by the test method shown below. Inhibitory activity against human plasma renin 250 μl of human plasma having angiotensin 1-producing activity of 0.5 / ng / ml / hr (37 ° C.) was added to an enzyme in a commercial renin activity measurement kit (Dextran charcoal powder method) (Midori Cross). 225 μl of an inhibitor (BAL, 8-hydroxysulfate, pH 4.6) solution (prepared by adding 10 ml of distilled water at the time of use) and 25 μl of a dimethylsulfoxide solution of a test compound were added and stirred, and part of the mixture was kept at 37 ° C. for 2 hours. Incubate, leave the rest at 4 ° C, sample 100 µl from each and subject to radioimmunoassay using a commercial renin activity assay kit (Dextran charcoal method) to determine the difference in the amount of angiotensin 1 produced at 37 ° C and 4 ° C. The 50% inhibitory concentration IC ₅₀ (M) was determined by measuring.

The preparation containing the condensed diazepine compound of the present invention or a salt thereof as an active ingredient is usually orally administered using a carrier, an excipient or other additives for oral administration such as tablets, pills and capsules. However, it may be a parenteral preparation such as an injection. The clinical dose of the compound of the present invention is appropriately determined in consideration of the symptoms, age, sex, etc. of the patient to whom it is applied, and is administered in 2 to 4 divided doses.

[0036]

EXAMPLES The compounds of the present invention and the method for producing the same have been described above. The following examples will further explain the details. In the examples, ¹ H-NMR means a proton nuclear magnetic resonance spectrum using tetramethylsilane as an internal standard, MS means a mass spectrum, and IR means an infrared absorption spectrum.

Example 1 (3R) -3- [3-[(1S) -1-Cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] ureido] -1- Methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3R) -3-amino-1-methyl-5-phenyl-
133 mg of 2,3-dihydro-1H-benzodiazepin-2-one was dissolved in 2 ml of methylene chloride, 0.15 ml of triethylamine and 122 mg of carbonyldiimidazole were added, and the mixture was stirred at room temperature for 1 hour. (1
S) -1-Cyclohexylmethyl-2-hydroxy-3
-[(1-Methyl-5-tetrazolyl) thio] propylamine hydrochloride 322 mg and triethylamine 0.31
A solution prepared by dissolving ml in 4 ml of methylene chloride was added, and the mixture was further stirred at room temperature for 2 hours. 20 ml of water was added to the reaction solution and extracted twice with 20 ml of methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate / n-hexane = 3/1),
152 mg of the target product was obtained.

¹ H-NMR (CDCl ₃ ): 0.81-1.80 (15H; m), 3.41-
3.44 (1H; m), 3.48 (3H; s), 3.90 (3H; s), 4.01 (1H; br),
4.35 (1H; br), 5.40 (1H; d, J = 8.8Hz), 5.44 (1H; d, J = 8.4H
z), 6.65 (1H; d, J = 8.4Hz), 7.21-7.63 (9H; m) MS (FAB, Pos.): 577 (M + 1) Example 2 (3S) -3- [3- [ (1S) -1-Cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] ureido] -1-methyl-5-phenyl-2,3-dihydro-1H-1, 4-Benzodiazepin-2-one By the same procedure as in Example 1, (3R) -3-amino-1
-Methyl-5-phenyl-2,3-dihydro-1H-benzodiazepin-2-one instead of (3S) -3-amino-1-methyl-5-phenyl-2,3-dihydro-
150 mg of the target product was obtained by using 133 mg of 1H-benzodiazepin-2-one.

¹ H-NMR (CDCl ₃ ): 0.79-1.83 (15H; m), 3.42-
3.53 (1H; m), 3.48 (3H; s), 3.91 (3H; s), 3.91-3.95 (1H;
m), 4.41 (1H; br), 5.47 (2H; d, J = 8.4Hz), 6.70 (1H; d, J =
8.4Hz), 7.20-7.60 (9H; m) MS (FAB, Pos.): 577 (M + 1) Example 3 (3R) -3- [3-[(1S, 2R) -1-cyclohexylmethyl- 2-((5S) -3-ethyl-2-oxo-5-oxazolidinyl) -2-hydroxyethyl]
Ureido] -2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 1, (1S) -1-cyclohexylmethyl-2-hydroxy-3. -[(1-methyl-5
-Tetrazolyl) thio] propylamine hydrochloride instead of (1S, 2R) -1-cyclohexylmethyl-2-
Using ((5S) -3-ethyl-2-oxo-5-oxazolidinyl) -2-hydroxyethylamine hydrochloride, the target product was obtained in a yield of 62%.

¹ H-NMR (CDCl ₃ ): 0.76-1.82 (13H; m), 1.14
(3H; t, J = 8.8Hz), 3.26-3.31 (2H; m), 3.49 (3H; s), 3.48-
3.56 (1H; m), 3.62-3.66 (2H; m), 4.44-4.48 (2H; m), 5.31
-5.48 (1H; m), 5.42 (1H; d, J = 8.4Hz), 5.88 (1H; d, J = 7.6H
z), 6.82 (1H; d, J = 8.4Hz), 7.22-7.69 (9H, m) MS (FAB, Pos.): 562 (M + 1) Example 4 (3R) -3- [3- [ (1S, 2R) -1-Cyclohexylmethyl-2-((5R) -3-ethyl-2-oxo-5-oxazolidinyl) -2-hydroxyethyl]
Ureido] -2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 1, (1S) -1-cyclohexylmethyl-2-hydroxy-3. -[(1-methyl-5
-Tetrazolyl) thio] propylamine hydrochloride instead of (1S, 2R) -1-cyclohexylmethyl-2-
Using ((5R) -3-ethyl-2-oxo-5-oxazolidinyl) -2-hydroxyethylamine hydrochloride, the desired product was obtained in a yield of 47%.

¹ H-NMR (CDCl ₃ ): 0.81-1.81 (13H; m), 1.09
(3H; t, J = 6.8Hz), 3.21-3.32 (2H; m), 3.48 (3H; s), 3.52-
3.57 (1H; m), 3.65-3.69 (1H; m), 3.93-3.99 (1H; m), 4.46
(2H; q, J = 7.2Hz), 5.32 (1H; d, J = 10.0Hz), 3.39 (1H; d, J = 1
0.0Hz), 6.59 (1H; d, J = 8.4Hz), 7.21-7.67 (9H, m) MS (FAB, Pos.): 562 (M + 1) Example 5 (3R) -3- [3- [(1S) -1-Cyclohexylmethyl-2-hydroxy-2-isopropyloxycarbonyl] ethylureido] -2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one By the same operation as in Example 1, (1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5
-Tetrazolyl) thio] propylamine hydrochloride instead of 3-amino- (3S) -3-cyclohexylmethyl-
The target product was obtained in 71% yield using 2-hydroxypropionic acid isopropyl ester hydrochloride.

¹ H-NMR (CDCl ₃ ): 0.78-1.84 (17H; m), 3.16
(2H; br), 3.46 (3H; s), 3.98 (1H; br), 4.11 (1H; br) 5.02
-5.24 (3H; m), 5.42 (1H; d, J = 8.1Hz), 6.43 (1H; d, J = 8.1H
z), 7.18-7.68 (9H; m) MS (FAB, Pos.): 535 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3398, 2992, 1740, 1680 Example 6 (3R) -3 -[3-[[(1S, 2R-1-Cyclohexylmethyl-2,3-dihydroxy-4- (morpholino)] butyl] ureido] -2,3-dihydro-1-
Methyl-5-phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 1, triethylamine and (1
S) -1-Cyclohexylmethyl-2-hydroxy-3
Diisopropylethylamine and (1S) -1-cyclohexylmethyl-2,3-dihydroxy-4- (4-morpholino) butylamine hydrochloride were used instead of-[(1-methyl-5-tetrazolyl) thio] propylamine hydrochloride. The desired product was obtained with a yield of 59%.

¹ H-NMR (CDCl ₃ ): δ: 0.89-1.70 (14H; m), 2.
56-2.86 (8H; m), 3.43-3.56 (2H; m), 3.52 (3H; s), 3.70-
3.72 (2H; m) 4.17-4.22 (1H; m), 5.13 (1H; br), 5.40 (1H;
d, J = 8.8Hz), 5.68 (1H; d, J = 9.2Hz), 6.90 (1H; d, J = 8.8H
z), 7.24-7.63 (9H; m) MS (FAB): 578 (M ⁺⁺ 1) Example 7 (3R) -N- (2,3-dihydro-1-methyl-5-
Phenyl-1H-1,4-benzodiazepin-2-on-3-yl) aminocarbonyl-L-leucyl-L-leucine methyl ester By the same operation as in Example 1, (1S) -1-cyclohexylmethyl-2-hydroxy was obtained. -3-[(1-methyl-5
The target compound was obtained in a yield of 44% by using L-leucyl-L-leucine methyl ester hydrochloride instead of -tetrazolyl) thio] propylamine hydrochloride.

¹ H-NMR (CDCl ₃ ): 0.84-0.97 (12H; m), 1.48-
1.82 (6H; m), 3.46 (3H; s), 3.69 (3H; s), 4.27-4.37 (1H;
m), 4.53-4.57 (1H; m), 5.41 (1H; d, J = 8.0Hz), 5.72 (1H;
d, J = 8.0Hz), 6.71 (2H; br), 7.20-7.61 (9H; m) MS (FAB, Pos.): 550 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3364, 2968 , 1750, 1648 Example 8 (3R) -N- (2,3-dihydro-1-methyl-5-
Phenyl-1H-1,4-benzodiazepin-2-on-3-yl) aminocarbonyl-L-phenylalanyl-L-phenylalanine methyl ester By the same procedure as in Example 1, (1S) -1-cyclohexylmethyl-2 -Hydroxy-3-[(1-methyl-5
The target product was obtained in 68% yield using L-phenylalanyl-L-phenylalanine methyl ester hydrochloride instead of -tetrazolyl) thio] propylamine hydrochloride.

¹ H-NMR (CDCl ₃ ): 2.92-3.16 (4H; m), 3.58 (3
H; s), 3.70 (3H; s), 4.11 (1H; q, J = 7.2Hz), 4.59 (1H; q, J =
7.2Hz), 4.89 (1H; dd, J = 6.8Hz), 5.40 (1H; d, J = 8Hz), 6.1
5 (1H; d, J = 8Hz), 6.75 (1H; d, 8Hz), 6.96-7.45 (16H; m),
7.54-7.62 (2H; m), 7.75 (1H; d, J = 8Hz) MS (FAB): 618 (M ⁺⁺ 1) Example 9 (3R) -N- (2,3-dihydro-1-methyl) -5
Phenyl-1H-1,4-benzodiazepin-2-on-3-yl) aminocarbonyl-L-leucyl-L-valine methyl ester By the same operation as in Example 1, (1S) -1-cyclohexylmethyl-2-hydroxy was obtained. -3-[(1-methyl-5
The target product was obtained in 82% yield using L-leucyl-L-valine methyl ester hydrochloride instead of -tetrazolyl) thio] propylamine hydrochloride.

MS (FAB): 536 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3340, 2972, 1748, 1648 Example 10 3-[[(1S) -1-cyclohexylmethyl-2-hydroxy-] 3-[(1-Methyl-5-tetrazolyl) thio] propyl] amino] -2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one 2,3-dihydro-3-hydroxy- 5-phenyl-1
1.00 g of H-1,4-benzodiazepin-2-one was dissolved in 10 ml of thionyl chloride, and the mixture was heated under reflux for 40 minutes.
After distilling off the solvent, the residue was dissolved in 10 ml of 1,4-dioxane, and (1S) -1-cyclohexylmethyl-2 was added thereto.
-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propylamine hydrochloride 2.20 g and triethylamine 3.31 ml and 1,4-dioxane 30 ml.
What was melt | dissolved in was added, and it stirred at room temperature overnight. The reaction solution was poured into 200 ml of water and extracted twice with 200 ml of ethyl acetate. The organic layer is saturated sodium hydrogen carbonate water 200m
After washing with 1, 200 ml of water and 200 ml of saturated saline, the mixture was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate / n-hexane = 1/1),
1.53 g of the desired product was obtained.

¹ H-NMR (CDCl ₃ ): 0.75-1.76 (12H; m), 1.90
(1H; d, J = 8.2Hz), 2.88-2.92 (1H; m), 3.19-3.78 (4H; m),
3.89 (1.3H; s), 3.93 (1.7H; s), 4.38 (0.4H; s), 4.44 (0.6
H; s), 4.68 (0.4H; br), 5.27 (0.6H; br), 7.19-7.58 (9H;
m), 9.20 (1H; s) MS (FAB, Pos.): 520 (M + 1) Example 11 3- [3-[(1S) -1-cyclohexylmethyl-2
-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] ureido] methyl] -2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one carbonyldiimidazole 122 mg and Dissolve 0.15 ml of triethylamine in 2 ml of methylene chloride,
Aminomethyl-2,3-dihydro-5-phenyl-1H
A solution of 133 mg of -1,4-benzodiazepin-2-one in 2 ml of methylene chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. (1S) -1-Cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propylamine hydrochloride (322 mg) and triethylamine (0.31 ml) dissolved in methylene chloride (4 ml) were added, and the mixture was further cooled to room temperature. It was stirred overnight at. Water 5 in the reaction solution
0 ml was added and the mixture was extracted twice with 50 ml of ethyl acetate. 200 ml of saturated sodium hydrogen carbonate water and 200 m of water
After washing with 1 and 200 ml of saturated saline, it was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate / n-hexane = 5 / 1-ethyl acetate) to obtain 130 mg of the desired product.

¹ H-NMR (CDCl ₃ ): 0.76-1.78 (13H; m), 3.36-
3.51 (2H; m), 3.82,3.90 (3H; s), 3.75-4.12 (5H; m), 4.23
(1H; br), 5.05,5.77 (1H; d, J = 5.4Hz), 5.97-6.01 (1H; m),
7.13-7.56 (9H; m), 9.16 (1H; s) MS (FAB, Pos.): 577 (M + 1) Example 12 3-[[3-[(1S) -1-cyclohexylmethyl-
2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] ureido] methyl] -1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one By the same operation as in Example 11, 3-aminomethyl-2,
3-aminomethyl-2 instead of 3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
3-dihydro-1-methyl-5-phenyl-1H-1,
Using 4-benzodiazepin-2-one, 36
Obtained in% yield.

¹ H-NMR (CDCl ₃ ): 0.77-1.73 (13H; m), 3.33-
3.45 (2H; m), 3.44 (3H; s), 3.75 (1H; dd, J = 6.4Hz, 14.4H
z), 3.83-3.93 (1H; m), 3.90 (3H; s), 3.99-4.04 (2H; q, J =
6.4Hz), 4.13-4.23 (2H; m), 5.31 (1H; br), 6.85 (1H; br),
7.08-7.69 (9H; m) MS (FAB, Pos.): 591 (M + 1) Example 13 3-[[N-[(1S) -1-cyclohexylmethyl-
2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] carbamoyl] methyl] -2,3
-Dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (1) Nt-butyloxycarbonyl-L-aspartic acid α-2-benzophenone amide β-benzyl ester 2-aminobenzophenone 2.77 g Was dissolved in 130 ml of dimethylformamide, and 2.10 g of 1-hydroxybenzotriazole, Nt-butoxycarbonyl-
L-aspartic acid β-benzyl ester 5.00 g
And N, N'-dicyclohexylcarbodiimide 3.2
6 g was added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered and the solvent was evaporated. Ethyl acetate was added to the obtained residue, the mixture was filtered again, and the solvent was evaporated. The residue obtained is ethyl acetate 2
Dissolved in 00 ml and saturated sodium hydrogen carbonate water 200 m
After washing with 1, 200 ml of water and 200 ml of saturated saline, the mixture was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate / n-hexane = 1/5 to 1/3) to obtain 1.88 g of the desired product.

¹ H-NMR (CDCl ₃ ): 1.48 (9H; s), 2.83 (1H; d, J
= 17.2Hz), 3.28 (1H; d, J = 16.8Hz), 4.72 (1H; br), 5.12 (2
H; dd, J = 25.6Hz, 12.8Hz), 5.79 (1H; br), 7.10 (1H; t, J = 7.
6Hz), 7.32 (5H; s), 7.47 (2H; t, J = 7.6Hz), 7.54-7.60 (3H;
m), 7.69 (2H; d, J = 6.8Hz), 8.62 (1H; d, J = 8.8Hz), 11.60
(1H; s) (2) L-Aspartic acid α-2-benzophenone amide β-benzyl ester Nt-butyloxycarbonyl-L-aspartic acid α-2-benzophenone amide β-benzyl ester 1.86 g is 4N. It was dissolved in 40 ml of hydrogen chloride dioxane and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution was dissolved in 200 ml of ethyl acetate and washed with 200 ml of saturated sodium hydrogen carbonate solution, 200 ml of water and 200 ml of saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 1.43 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.84-3.02 (2H; m), 3.86 (1
H; br), 5.14 (2H, s), 7.00-7.77 (8H; m), 7.30 (5H; s), 8.
61 (1H; d, J = 8.0Hz), 11.92 (1H, s) MS (FAB, Pos.): 403 (M + 1), 385 (M + 1-H2O) (3) benzyl 2-((3S ) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate L-aspartic acid α-2-benzophenone amide
1.43 g of β-benzyl ester was dissolved in 30 ml of acetic acid, 1.29 g of ammonium acetate was added, and the mixture was stirred at 50 ° C. for 2 hours and 45 minutes. The residue obtained by concentrating the reaction solution was dissolved in 50 ml of ethyl acetate and washed with 50 ml of saturated sodium hydrogen carbonate solution, 50 ml of water and 50 ml of saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was crystallized from ethyl acetate / n-hexane to obtain 0.47 g of the desired product.

¹ H-NMR (CDCl ₃ ): 3.38 (1H; dd, J = 54.0,10.8H
z), 3.42 (1H; dd, J = 54.0,10.8Hz), 4.22 (1H; t, J = 5.4Hz),
5.20 (2H; s), 7.14-7.56 (14H; m), 8.74 (1H, s) MS (EI, In Beam): 384 (M +) (4) Nt-butyloxycarbonyl-D-aspartic acid α 2-Benzophenone amide β-benzyl ester By the same operation as in Example 13 (1), Nt-butoxycarbonyl-D-aspartic acid β was obtained instead of Nt-butoxycarbonyl-L-aspartic acid β-benzyl ester. -Using benzyl ester to give 43
Obtained in% yield.

¹ H-NMR (CDCl ₃ ): 1.48 (9H; s), 2.83 (1H; dd,
J = 16.2Hz, 5.4Hz), 3.27 (1H; dd, J = 16.2,5.4Hz), 4.72-4.
76 (1H, m), 5.13 (2H; dd, J = 18.9,13.5Hz), 5.82 (1H; d, J = 1
0.8Hz), 7.11 (1H; t, J = 8.1Hz), 7.28-7.72 (12H; m), 8.64
(1H; d, J = 10.8Hz), 11.60 (1H; s) MS (FAB, Pos): 503 (M + 1) (5) D-aspartic acid α-2-benzophenone amide β-benzyl ester Example 13 By the same operation as in (2), N-t-butyloxycarbonyl-L-aspartic acid α-2-benzophenone amide β-benzyl ester was replaced with N-
t-Butyloxycarbonyl-D-aspartic acid α
The target compound was obtained in a yield of 96% using 2-benzophenone amide β-benzyl ester.

¹ H-NMR (CDCl ₃ ): 2.65-3.01 (2H; m), 3.84 (1
H; br), 5.12 (2H, s), 7.00-7.77 (8H; m), 7.30 (5H; s), 8.
62 (1H; d, J = 8.0Hz), 11.92 (1H; s) MS (FAB, Pos): 403 (M + 1) (6) benzyl 2-((3R) -2,3-dihydro-2- Oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate By the same procedure as in Example 13 (3), L-aspartic acid α-2-benzophenone amide β-benzyl ester was replaced by D-asparagine. The target compound was prepared by using acid α-2-benzophenone amide β-benzyl ester.
Obtained in a yield of 8%.

¹ H-NMR (CDCl ₃ ): 3.39 (2H; dd, J = 7.1,5.2H
z), 4.12 (1H; t, J = 7.1Hz), 5.19 (2H; s), 7.12-7.48 (9H;
m), 7.34 (5H; s), 9.40 (1H; s) MS (EI, In Beam): 384 (M +) (7) 2- (2,3-dihydro-2-oxo-5-phenyl-1H- 1,4-benzodiazepin-3-yl)
Benzyl acetate 2-((3S) -2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R)
-2,3-Dihydro-2-oxo-5-phenyl-1H
0.38 g of an equal mixture of -1,4-benzodiazepin-3-yl) acetate was dissolved in 30 ml of ethanol,
Approximately 30 mg of 10% palladium / carbon and 1.5 ml of formic acid
Was added and stirred at 50 ° C. for 3 hours. The reaction solution was filtered using talc and the solvent was distilled off. The obtained residue was crystallized from ether-n-hexane to give the desired product 0.20 g.
Got

¹ H-NMR (CDCl ₃ -CD3OD): 3.02 (1H; dd, J = 18.
9,8.1Hz), 3.26 (1H; dd, J = 21.6,10.8Hz), 3.97 (1H; t, J =
8.1Hz), 7.16-7.60 (9H; m), 10.60 (1H; s) MS (EI, In Beam): 294 (M +) (8) 3-[[N-[(1S) -1-cyclohexylmethyl- 2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] carbamoyl] methyl]
-2,3-Dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl Amine hydrochloride (240 mg) was dissolved in dimethylformamide (2 ml), and triethylamine (0.23 m) was dissolved therein.
1, 2- (2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetic acid (0.20 g) in dimethylformamide (2 ml) and diphenylphosphoric acid azide (0.18 ml) Were sequentially added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and extracted with 50 ml of ethyl acetate × 2. The organic layer was washed successively with 50 ml of water and 50 ml of saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2/1 to 3).
/ 1) to obtain 0.12 g of a high polarity compound and 0.16 g of a low polarity compound.

High polarity compound Rf value 0.10 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.79-0 / 96 (3H; m), 1.10-1.41 (5H; m),
1.54-1.61 (4H; m), 1.78 (1H; d, J = 12.4Hz), 3.06 (1H; dd, J
= 14.8,5.6Hz), 3.24 (1H; dd, J = 14.8,7.2Hz), 3.36-3.51
(2H; m), 3.80-3.85 (1H; m), 3.87 (3H; s), 4.11-4.24 (2H;
m), 4.34 (1H; d, J = 4.4Hz), 6.96 (1H; d, J = 9.6Hz), 7.13-
7.53 (9H; m), 9.01 (1H; s) MS (FAB, Pos.): 562 (M + 1) Low polarity compound Rf value 0.16 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.74-0.93 (3H; m), 1.07-1.41 (5H; m),
1.54-1.66 (4H; m), 1.78 (1H; d, J = 12.4Hz), 3.14 (1H; d, J =
6.0Hz), 3.34-3.49 (2H; m), 3.81 (3H; s), 3.87-3.94 (1H;
m), 4.06-4.15 (3H; m), 4.47 (1H; d, J = 4.4Hz), 7.15-7.54
(9H; m), 8.65 (1H; s) MS (FAB, Pos.): 562 (M + 1) Example 14 3-[[N-[(1S) -1-cyclohexylmethyl-
2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] carbamoyl] methyl] -2,3
-Dihydro-1-methyl-5-phenyl-1H-1,4
-Benzodiazepin-2-one (1) Benzyl 2- (2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate Sodium hydride (60% 48 mg) was suspended in 2 ml of dimethylformamide, and benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo An equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate.
38 g of dimethylformamide 4 ml solution was added, and the mixture was stirred at room temperature for 30 minutes. Methyl iodide 0.09m
1 was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into 100 ml of ice water and extracted with 100 ml of ethyl acetate × 2. The organic layer is a saturated aqueous sodium hydrogen carbonate solution 100 m
1, washed with 100 ml of water and 100 ml of saturated saline solution in that order, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate / benzene = 1/20 to 1/1
0) to obtain 0.39 g of the desired product.

¹ H-NMR (CDCl ₃ ): 3.10-3.50 (2H; m), 3.40 (3
H; s), 4.15 (1H; t, J = 7.2Hz), 5.12 (2H; s), 7.11-7.56 (14
H; m) MS (EI, In Beam): 398 (M +) (2) 2- (2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3- Il) acetic acid By the same procedure as in Example 13 (7), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo Benzyl 2- (2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1 instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate , 4-benzodiazepin-3-yl) acetate
Obtained in% yield.

¹ H-NMR (DMSO-d ₆ ): 2.79-3.26 (2H; m), 3.35
(3H; s), 3.94 (1H; t, J = 6.9Hz), 7.21-7.72 (9H; m) MS (EI, In Beam): 308 (M +) (3) 3-[[N-[(1S ) -1-Cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] carbamoyl] methyl]
-2,3-Dihydro-1-methyl-5-phenyl-1H
-1,4-benzodiazepin-2-one 2- (2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) was prepared by the same procedure as in Example 13 (8). 2- (2, instead of acetic acid
Using 3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetic acid, the target product was obtained in a yield of 64% (highly polar compound 0.
13 g and low polar compounds 0.14 g).

High polarity compound Rf value 0.11 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.78-0.96 (3H; m), 1.10-1.41 (5H; m),
1.60-1.68 (4H; m), 1.79 (1H; d, J = 12.8Hz), 3.09 (1H; dd, J
= 21.2,14.4Hz), 3.11 (1H; dd, J = 21.6,14.8Hz), 3.42 (3H;
s), 3.38-3.50 (2H; m), 3.91 (3H; s), 4.09-4.16 (3H; m),
6.99 (1H; d, J = 9.6Hz), 7.20-7.61 (9H; m) MS (FAB, Pos.): 576 (M + 1) Low polarity compound Rf value 0.20 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.79-0.93 (3H; m), 1.12-1.42 (5H; m),
1.62-1.65 (4H; m), 1.77 (1H; d, J = 20.4Hz), 3.09 (1H; dd, J
= 14.4,31.2Hz), 3.10 (1H; dd, J = 14.4,28.8Hz), 3.51 (3H;
s), 3.30-3.56 (1H; m), 3.76 (3H; s), 3.86-3.91 (1H; m),
4.05-4.10 (2H; m), 4.32 (1H; d, J = 6.4Hz), 7.17-7.61 (10H;
m) MS (FAB, Pos.): 576 (M + 1) Example 15 3- [N-[(1S) -1-cyclohexylmethyl-2.
-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] carbamoyl] -2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-
2-one (1) 3-ethoxycarbonyl-2,3-dihydro-
2-oxo-5-phenyl-1H-benzodiazepine 2-aminobenzophenone 22.0 g was added to pyridine 100
Dissolve in ml, diethylaminomalonate hydrochloride 2
5.0 g was added and the mixture was heated under reflux for 7.5 hours. The solvent was evaporated, the obtained residue was dissolved in 300 ml of ethyl acetate, and washed with 300 ml of water three times. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was recrystallized from acetonitrile to obtain 4.73 g of the desired product.

¹ H-NMR (CDCl ₃ ): 1.30 (3H; t, J = 8.4Hz), 4.3
5 (2H; q, J = 8.4Hz), 4.60 (1H; s), 7.06-7.63 (9H; m), 9.60
(1H; s) (2) 2,3-dihydro-2-oxo-5-phenyl-1H-benzodiazepin-3-ylcarbonylhydrazide 3-ethoxycarbonyl-2,3-dihydro-2-oxo-5-phenyl- 1H-benzodiazepine 1.00g
Is dissolved in 10 ml of ethanol to give hydrazine monohydrate 1
ml and ethanol 10 ml were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the obtained residue was washed with ethanol and ethyl acetate to give the desired product (0.57 g).

(3) 3- [N-[(1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] carbamoyl] -2,3-dihydro- 5-phenyl-1H-1,4
-Benzodiazepin-2-one 2,3-dihydro-2-oxo-5-phenyl-1H-
Benzodiazepin-3-ylcarbonylhydrazide 0.
Dissolve 50 g in 5 ml of dimethylformamide-40
Cooled to ° C. 4N hydrogen chloride / dioxane 1.
Add 7 ml and 0.23 ml isoamyl nitrite, -4
The mixture was stirred at 0 ° C for 40 minutes. The reaction mixture was cooled to −78 ° C., 0.95 ml of triethylamine was added, and (1
S) -1-Cyclohexylmethyl-2-hydroxy-3
-[(1-Methyl-5-tetrazolyl) thio] propylamine hydrochloride 534 mg and triethylamine 0.28
Add 7 ml of dimethylformamide in 4 ml,
Stirred overnight at ° C. The solvent of the reaction mixture was distilled off, and the obtained residue was dissolved in 50 ml of ethyl acetate. This in water 5
0 ml, saturated aqueous sodium hydrogen carbonate solution 50 ml, water 5
It was washed successively with 0 ml and 50 ml of saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2/1) to obtain the desired product in a yield of 76% (0.41 g of high polarity compound and 0.30 g of low polarity compound). ).

High polarity compound Rf value 0.13 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.87-1.88 (13H; m), 3.48 (1H; dd, J = 14.
0,6.8Hz), 3.54 (1H; d, J = 5.6Hz), 3.68 (1H; dd, J = 34.8,1
4.4Hz), 3.69 (1H; dd, J = 34.8,14.4Hz), 3.90,3.92 (3H;
s), 4.02 (1H; bs), 4.20-4.28, 4.42-4.49 (1H; m), 4.34 (1
H; s), 7.13-7.91 (9H; m), 9.55,9.56 (1H; s) MS (FAB, Pos.): 548 (M + 1) low polarity compound Rf value 0.21 (ethyl acetate / n- Hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.87-1.97 (13H; m), 3.48 (1H; dd, J = 14.
0,6.8Hz), 3.54 (1H; d, J = 6.0Hz), 3.68 (1H; dd, J = 35.6,1
4.4Hz), 3.69 (1H; dd, J = 35.6,14.4Hz), 3.90,3.92 (3H;
s), 4.02,4.09 (1H; bs), 4.20-4.27,4.42-4.49 (1H; m),
4.33 (1H; s), 7.10-7.58 (8H; m), 7.90,8.27 (1H; d, J = 9.6H
z), 9.63, 9.66 (1H; s) MS (FAB, Pos.): 548 (M + 1) Example 16 N-[(1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1- Methyl-5-tetrazolyl) thio] propyl] -2,3-dihydro-1-methyl-2-
Oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxamide (1) 3-ethoxycarbonyl-2,3-dihydro-
1-Methyl-2-oxo-5-phenyl-1H-benzodiazepine By the same procedure as in Example 14 (1), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo 3-Ethoxycarbonyl-2,3-dihydro-2 instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate
Using -oxo-5-phenyl-1H-benzodiazepine, the target product was obtained in a yield of 60%.

¹ H-NMR (CDCl ₃ ): 1.37 (3H; t, J = 8.1Hz), 3.4
5 (3H; s), 4.43 (2H; q, J = 8 / 1Hz), 4.53 (1H; s), 7.16-7.70
(9H; m) MS (FAB, Pos.): 323 (M + 1) (2) 2,3-dihydro-1-methyl-2-oxo-
5-Phenyl-1H-benzodiazepin-3-ylcarbonylhydrazide By the same procedure as in Example 15 (2), 3-ethoxycarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-benzodiazepine was replaced with 3 -Ethoxycarbonyl-2,3-dihydro-1-methyl-2-oxo-
The target product was obtained with 5-phenyl-1H-benzodiazepine in a yield of 53%.

¹ H-NMR (DMSO-d ₆ ): 1.06 (3H; t, J = 7.0Hz),
3.33 (3H; s), 4.20 (1H; s), 4.32 (2H; q, J = 7.0Hz), 4.49 (2
H; bs), 7.29-7.80 (9H; m), 9.38 (1H; bs) MS (FAB, Pos.): 309 (M + 1) (3) N-[(1S) -1-cyclohexylmethyl-
2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxamide By the same operation as in Example 15 (2), 2,3-dihydro-2-oxo-5-phenyl-1H-benzodiazepin-3-ylcarbonylhydrazide was replaced by 2,3-dihydro-1-methyl-2-oxo. -5-phenyl-1H
-Benzodiazepin-3-ylcarbonyl hydrazide was used to obtain the desired product in a yield of 61% (highly polar compound 0.
22 g and low polar compounds 0.13 g).

High polarity compound Rf value 0.16 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.88-1.88 (13H; m), 3.42 (3H; s), 3.48
(1H; q, J = 6.8Hz), 3.64-3.78 (2H; m), 3.93 (3H; s), 3.94-
4.07 (2H; m), 4.11-4.18, 4.42-4.47 (1H; m), 4.35 (1H;
s), 7.22-7.65 (8H; m), 8.83 (1H; d, J = 10.0Hz) MS (FAB, Pos.): 562 (M + 1) low polarity compound Rf value 0.19 (ethyl acetate / n -Hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.88-1.03 (3H; m), 1.16-1.36 (5H; m),
1.52-1.55 (2H; m), 1.6-1.74 (3H; m), 1.88-1.96 (2H; m),
3.45 (3H; s), 3.48 (1H; q, J = 7.2Hz), 3.54-3.56 (2H; m),
3.93 (3H; s), 4.14-4.15 (2H; m), 4.32 (1H; s), 4.90 (1H;
d, J = 6.4Hz), 7.21-7.65 (8H; m), 8.22 (1H; d, J = 8.8Hz) MS (FAB, Pos.): 562 (M + 1) Example 17 N-[(1S ) -1-Cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -2-((3S) -2,3-dihydro-
1-methyl-2-oxo-5-phenyl-1H-1,4
-Benzodiazepin-3-yl) propionamide (1) benzyl 2-((3S) -2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,
4-Benzodiazepin-3-yl) acetate By the same procedure as in Example 14 (1), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo Benzyl 2-((3S) -2,3-dihydro-instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate
2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate was used to give 94% of the desired product.
It was obtained in a yield of.

(2) benzyl 2-((3S) -2,
3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) propionate 0.22 ml of diisopropylamine was dissolved in 2 ml of tetrahydrofuran and cooled to -78 ° C. 5Mn-
Butyl lithium / n-hexane (0.68 ml) was added,
The mixture was stirred at 78 ° C for 15 minutes. Benzyl 2-
((3S) -2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-
A solution of 0.42 g of 3-yl) acetate in 4 ml of tetrahydrofuran was added, and the mixture was stirred at -78 ° C for 15 minutes. Methyl iodide (0.10 ml) was added to this, and the mixture was stirred at -78 ° C for 3 times.
Stir for 0 minutes. The reaction mixture was added with 0.1N aqueous hydrochloric acid solution 1
Pour into 100 ml and extract with 100 ml x 2 ethyl acetate,
The organic layer was washed successively with 100 ml of water, 100 ml of saturated aqueous sodium hydrogen carbonate solution, 100 ml of water, and 100 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2).
0) to obtain 0.21 g of the desired product.

¹ H-NMR (CDCl ₃ ): 1.42 (3H; d, J = 7.1Hz), 3/4
0 (3H; s), 3.60-3.93 (2H; m), 5.16 (2H; dd, J = 23.0,10.6H
z), 7.17-7.65 (14H; m) MS (EI, In Beam): 412 (M +) (3) 2-((3S) -2,3-dihydro-1-methyl-2-oxo-5-phenyl -1H-1,4-benzodiazepin-3-yl) propionic acid By the same procedure as in Example 13 (7), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo Benzyl 2-((3S) -2,3-dihydro-instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate
1-methyl-2-oxo-5-phenyl-1H-1,4
The target product was obtained using -benzodiazepin-3-yl) propionate.

(4) N-[(1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5)
-Tetrazolyl) thio] propyl] -2-((3S)-
2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) propionamide By the same procedure as in Example 13 (8), 2- (2,3- Instead of dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetic acid, 2-((3
S) -2,3-Dihydro-1-methyl-2-oxo-5
-Phenyl-1H-1,4-benzodiazepin-3-yl) propionic acid was used to obtain the desired product in a yield of 77% (0.07 g of high polarity compound and 0.15 of low polarity compound).
g).

High polarity compound Rf value 0.05 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.80-1.01 (3H; m), 1.05-1.43 (5H; m),
1.34 (3H; d, J = 7.2Hz), 1.52-1.79 (6H; m), 3.08-3.18 (1H;
m), 3.39 (3H; m), 3.41-3.55 (2H; m), 3.70 (1H; d, J = 4.4H
z), 3.78-3.80 (1H; m), 3.89 (3H; s), 4.04 (1H; d, J = 6.8H
z), 4.09-4.14 (1H; m), 7.21-7.64 (8H; m), 7.98 (1H; d, J =
8.4Hz) MS (FAB, Pos.): 590 (M + 1) low polarity compound Rf value 0.18 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.80-0.99 (3H; m), 1.09-1.42 (5H; m),
1.36 (3H; d, J = 7.4Hz), 1.51-1.69 (5H; m), 1.78 (1H; d, J = 1
2.4Hz), 3.31 (1H; dd, J = 9.2,7.2Hz), 3.38 (3H; s), 3.44-
3.55 (2H; m), 3.83 (1H; d, J = 9.2Hz), 3.88-3.97 (1H; m),
3.93 (3H; s), 6.47 (1H; d, J = 8.8Hz), 7.19-7.63 (9H; m) MS (FAB, Pos.): 590 (M + 1) Example 18 N-[(1S) -1-Cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -2-((3S) -2,3-dihydro-
1-methyl-2-oxo-5-phenyl-1H-1,4
-Benzodiazepin-3-yl) valeramide (1) benzyl 2-((3S) -2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,
4-Benzodiazepin-3-yl) -4-pentenoate By the same procedure as in Example 17 (2), allyl bromide was used in place of methyl iodide to obtain the desired product in a yield of 50%.

¹ H-NMR (CDCl ₃ ): 2.55-2.84 (2H; m), 3.40 (3
H; s), 3.64-4.00 (2H; m), 4.69-5.35 (2H; m), 5.21 (2H;
s), 5.45-6.00 (1H; m), 7.10-7.68 (14H; m) MS (FAB, Pos.): 439 (M + 1) (2) 2-((3S) -2,3-dihydro- 1-Methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) pentanoic acid By the same procedure as in Example 13 (7), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo Benzyl 2-((3S) -2,3-dihydro-instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate
1-methyl-2-oxo-5-phenyl-1H-1,4
-Benzodiazepin-3-yl) -4-pentenoate was used to obtain the desired product in a yield of 85%.

MS (FAB, Pos.): 351 (M + 1) (3) N-[(1S) -1-cyclohexylmethyl-
2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -2-((3S) -2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-
1,4-benzodiazepin-3-yl) valeramide 2- (2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl was prepared by the same procedure as in Example 13 (8). ) 2-((3
S) -2,3-Dihydro-1-methyl-2-oxo-5
The target compound was obtained with 31% yield using -phenyl-1H-1,4-benzodiazepin-3-yl) pentanoic acid.

¹ H-NMR (CDCl ₃ ): 0.84-1.90 (20H; m), 3.11-
3.31 (2H; m), 3.39,3.50 (3H; s), 3.74-3.85 (1H; m), 3.9
2,3.95 (3H; s), 4.22-4.39 (1H; m), 4.55-4.77 (1H; m), 4.
86 (1H; d, J = 8.1Hz), 6.22 (1H; d, J = 10.8Hz), 7.21-7.64 (8
H; m), 8.10 (1H; d, J = 10.8Hz) MS (FAB, Pos.): 618 (M + 1) Example 19 (1) 2- (benzoylanilino) -N- (t-butoxy) Carbonyl) -L-aspartic acid β-benzyl ester In 150 ml of dimethylformamide, 4.46 g of hydroxybenzotriazonyl, 7.43 g of dicyclohexylcarbodiimide and N- (t-butoxycarbonyl)-
L-aspartic acid β-benzyl ester 10.67
g sequentially, and then 2-aminobenzophenone 5.9
2 g was added and the mixture was stirred overnight at room temperature. Saturated sodium hydrogen carbonate aqueous solution 10 was added to the filtrate obtained by suction filtration of the suspension solution.
0 ml was poured and the mixture was extracted with 100 ml of ethyl acetate. The obtained organic layer was washed successively with purified water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate / n-hexane = 1/3) to obtain 9.02 g of the desired product.

¹ H-NMR (CDCl ₃ ): 1.47 (9H; s), 3.10 (2H; b
r), 4.70 (1H; br), 5.11 (2H; s), 5.85 (1H; br), 6.95-7.6
3 (13H; m), 8.62 (1H; br), 11.60 (1H; br) MS (FAB): 503 (M ⁺ +1) (2) (3R) -3-[(benzyloxycarbonyl)
Methyl] -2,3-dihydro-5-phenyl-1H-
1,4-benzodiazepin-2-one 2- (benzoylanilino) -N- (t-butoxycarbonyl) -L-aspartic acid β-benzyl ester 9.0 g was added to 160 ml of 4N hydrochloric acid-dioxane solution for 1 hour. After stirring at room temperature, the solvent was distilled off and to the resulting residue was added saturated aqueous sodium hydrogencarbonate solution (150 ml) and the mixture was extracted with ethyl acetate (250 ml). The organic layer was washed successively with purified water and saturated brine, and dried over anhydrous magnesium sulfate. 150m of benzene was added to the oily substance produced by distilling off the solvent.
1 was poured and the mixture was heated under reflux for 4 hours. After pouring an appropriate amount of purified water into the reaction solution and washing with water, the organic layer was dried and concentrated, and the resulting residue was crystallized with a small amount of diisopropyl ether and collected by filtration to obtain 3.54 g of the desired product.

¹ H-NMR (CDCl ₃ ): 3.32-3.45 (2H; m), 4.20 (1
H; t, J = 7.2Hz), 5.19 (2H; s), 7.16-7.53 (14H; m), 8.64 (1
H; br) MS (FAB): 385 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 1746, 1688, 1612, 1174 (3) (3R) -3-[(benzyloxycarbonyl)
Methyl] -2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 25 (3), 2,3-dihydro-7-ethyl- 5-phenyl-1H-thieno [2,3
Instead of -e] [1,4] diazepin-2-one (3
R) -3-[(benzyloxycarbonyl) methyl]-
Using 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one, the target product was obtained in a yield of 87%.

¹ H-NMR (CDCl ₃ ): 3.28-3.48 (2H; m), 3.42 (3
H; s), 4.16 (1H; t, J = 8.0Hz), 5.15 (2H; d, J = 2.0Hz), 7.14
-7.66 (14H; m) MS (EI, In Beam): 398 (4) 2-[(3S) -2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- Benzodiazepin-3-yl] -3-phenylpropionic acid benzyl ester Diisopropylamine 0.34 ml, butyllithium-hexane solution at -78 ° C under an argon gas stream.
10 ml of tetrahydrofuran (THF) containing 42 ml
0.8 g of (3R) -3-[(benzyloxycarbonyl) methyl] -2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one
3 ml of THF containing was added dropwise and stirred for 15 minutes.
Subsequently, 2.38 ml of benzyl bromide was added dropwise, the mixture was stirred at room temperature for 1 hour, poured into a solution of 100 ml of 0.1N hydrochloric acid and 100 ml of ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was subjected to silica gel column chromatography (eluent: benzene /
Purification with ethyl acetate = 50/1) gave 0.35 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.85-3.15 (2H; m), 3.38 (3
H; s), 3.80-4.02 (2H; m), 5.00 (2H; qJ = 12.6Hz), 6.98-
7.53 (19H; m) MS (EI, In Beam): 489 (5) 2-[(3S) -2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine -3-yl] -3-phenylpropionic acid 2-[(3S) -2,3-dihydro-1-methyl-2-
Oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-phenylpropionic acid benzyl ester (0.3 g) was added to a solution of ethanol (15 ml) in a catalytic amount of 10% palladium carbon at 50 ° C. Heated overnight. After the reaction, the catalyst was filtered off with ceride, and the obtained filtrate was concentrated to obtain 0.24 g of the desired product.

¹ H-NMR (CDCl ₃ ): 3.20-3.84 (4H; m), 3.44 (3
H; s), 5.10 (1H; br), 7.26-7.66 (14H; m) MS (FAB): 399 (M ⁺ +1) (6) N-[(1S) -1-cyclohexylmethyl-2
-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -2-[(3S) -2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-
1,4-benzodiazepin-3-yl] -3-phenylpropionamide 2-[(3S) -2,3-dihydro-1-methyl-2-
Oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-phenylpropionic acid 0.2 g and (1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5) -Tetrazolyl) thio] propylamine hydrochloride (0.33 g) was dissolved in dimethylformamide (5 ml), and diphenylphosphoric acid azide (0.2) was added under ice cooling.
13 ml and 0.08 ml triethylamine are added,
Stir overnight at room temperature. 50 ml of a saturated aqueous solution of sodium hydrogen carbonate was poured into the reaction solution, extracted with 50 ml of ethyl acetate, and then washed with 50 ml of purified water and 50 ml of saturated saline. After drying the organic layer with anhydrous magnesium sulfate,
The residue produced by evaporation of the solvent was subjected to silica gel column chromatography (eluent; ethyl acetate / hexane = 1/1).
And purified to obtain 0.03 g of the desired product.

MS (FAB): 666 (M ⁺ +1) Example 20 (1) 2,3-dihydro-1-ethyl-5-phenyl-
1H-1,4-benzodiazepin-2-one A catalytic amount of All in 40 ml of toluene cooled to 0 ° C.
iquat336, 1.2 ml of ethyl iodide, 15 ml of 50% sodium hydroxide aqueous solution, 2,3-dihydro-5
2.36 g of -phenyl-1H-1,4-benzodiazepin-2-one was sequentially added, and the mixture was stirred at room temperature for 4 hours. After the reaction, 50 ml of purified water and 50 ml of ethyl acetate were poured to separate the layers, and the obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue generated by distilling off the solvent was purified by silica gel column chromatography (eluent: chloroform) to obtain 1.27 g of the desired product.

¹ H-NMR (CDCl ₃ ): 1.13 (3H; t, J = 6.0Hz), 4.2
7 (2H; q, J = 6.0Hz), 3.64-4.45 (2H; m), 7.12-7.68 (9H; m) MS (GC): 264 (M ⁺ ) IR νmax (KBr) cm ^-1 : 2966, 2952, 1674, 1610 (2) 2,3-Dihydro-1-ethyl-3-oximid-5-phenyl-1H-1,4-benzodiazepine-2
-One 1.83 g of 2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one was added to 30 ml of toluene under an argon stream, and t-butoxypotassium was added at -20 ° C. 2.0 g was added and stirred for 10 minutes. Subsequently, 1.1 ml of amyl nitrite was added dropwise and stirred for 1 hour, and then a cooled mixed liquid (60 ml of purified water, 4 ml of acetic acid and 60 ml of ethyl acetate) was poured. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.79 g of the desired product.

¹ H-NMR (CDCl ₃ ): 1.13 (3H; t, J = 10.8Hz), 4.
08 (2H; br), 7.10-7.86 (9H; m), 8.12 (1H; m) MS (EI, In Beam): 293 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3300, 1684, 1610, 698 (3) 3-Amino-2,3-dihydro-1-ethyl-5
-Phenyl-1H-1,4-benzodiazepin-2-one 2,3-dihydro-1-ethyl-3-oximid-5-
1.73 g of phenyl-1H-1,4-benzodiazepin-2-one was dissolved in 20 ml of methanol, 0.43 g of 5% ruthenium carbon was added, and then, in the presence of hydrogen gas,
The mixture was stirred overnight at 70 ° C. under a pressure of 4.2 atm. The catalyst was filtered off and the resulting filtrate was concentrated and the resulting residue was subjected to silica gel column chromatography (eluent; chloroform).
Purification was carried out to obtain 0.83 g of the desired product.

¹ H-NMR (CDCl ₃ ): 1.66-1.26 (3H; m), 3.67-
4.43 (3H; m), 7.10-7.67 (9H; m) MS (EI, In Beam): 279 (M ⁺ ) (4) (3R) -3- [3-[(1S) -1-cyclohexylmethyl- 2-Hydroxy-2-isopropyloxycarbonyl] ethylureido] -1,3-dihydro-
1-Ethyl-5-phenyl-2H-1,4-benzodiazepin-2-one By the same procedure as in Example 1, (3R) -3-amino-
2,3-dihydro-1-methyl-5-phenyl-1H-
1,4-benzodiazepin-2-one and (1S) -1
-Cyclohexylmethyl-2-hydroxy-3-[(1
-Methyl-5-tetrazolyl) thio] propylamine hydrochloride instead of 3-amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one and 3-amino- Using (3S) -3-cyclohexylmethyl-2-hydroxypropionic acid isopropyl ester hydrochloride, the target product was obtained in a yield of 51%.

MS (FAB): 549 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3412, 2940, 1738, 1680, 1106 Example 21 (1) 1-allyl-2,3-dihydro-5 -Phenyl-1H-
1,4-Benzodiazepin-2-one By the same operation as in Example 20 (2), the target compound was obtained in a yield of 94% by using allyl bromide instead of ethyl iodide.

¹ H-NMR (CDCl ₃ ): 4.36 (2H; q, J = 10.8Hz), 4.58
(2H; q, J = 16.2Hz), 5.08-5.24 (2H; m), 5.76-5.96 (1H; m), 7.
12-7.68 (9H; m) MS (GC): 276 (M ⁺ ) IR νmax (KBr) cm ^-1 : 1682, 1612, 786 Example 21 (2) 1-allyl-2,3-dihydro-3- Oximido-5
Phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 20 (2), 2,3-dividro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one was obtained. Instead, 1-allyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one was used to obtain the desired product in a yield of 25%.

¹ H-NMR (CDCl ₃ ): 1.67 (1H; br), 4.62 (2H; b
r), 5.13-5.30 (2H; m), 5.78-6.00 (1H; m), 7.14-8.90 (9H; m) MS (EI, In Beam): 305 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3300, 1684, 1644, 1610, 696 Example 21 (3) 3-amino-2,3-dihydro-5-phenyl-1-propyl-1H-1,4-benzodiazepin-2-one Example 20 (3 ), 2,3-dividro-1-ethyl-3-oximid-5-phenyl-1H-
1-allyl-2,3-dihydro-3-oximido-5-phenyl-1H-1,4-benzodiazepin-2-one was used in place of 1,4-benzodiazepin-2-one to obtain 57% of the desired product. Obtained in yield.

¹ H-NMR (CDCl ₃ ): 0.96 (3H; t, J = 10.8Hz), 1.3
5-1.69 (2H; m), 2.42 (2H; br), 3.56-3.74 (1H; m), 4.16-4.44
(1H; m), 4.50 (1H; br), 7.16-7.70 (9H; m) MS (EI, In Beam): 293 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3408, 2980, 1680, 1606 Example 21 (4) (3R) -3- [3-[(1S) -1-cyclohexylmethyl-2-hydroxy-2- (isopropyloxycarbonyl)] ethylureido] -2,3-dihydro-5
-Phenyl-1-propyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 1, (3R) -3-amino-
2,3-dihydro-1-methyl-5-phenyl-1H-
Benzodiazepin-2-one and (1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propylamine hydrochloride instead of 3-amino-2,3-dihydro- 5-phenyl-
1-Propyl-1H-benzodiazepin-2-one and 3-amino- (3S) -3-cyclohexylmethyl-2
The target product was obtained in a yield of 24% using isopropyl hydroxypropionate hydrochloride.

MS (FAB): FAB 563 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3412, 2984, 1734, 1674 Example 22 (1) 2,3-dihydro-1-isopropyl-5- Phenyl-
1H-1,4-benzodiazepin-2-one By the same operation as in Example 20 (1), isopropyl iodide was used instead of ethyl iodide to obtain the target product in a yield of 39%.

¹ H-NMR (CDCl ₃ ): 1.24 (3H; d, J = 7.2Hz), 3.69
(1H; d, J = 10.4Hz), 4.48-4.78 (3H, m), 7.20-7.69 (9H; m) MS (GC): 278 (M ⁺ ) IR νmax (KBr) cm ^-1 : 2988, 1674 706 Example 22 (2) 2,3-dihydro-1-isopropyl-3-oximid-5-phenyl-1H-1,4-benzodiazepine-2
-One By the same procedure as in Example 20 (2), 2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one was replaced by 2,3-dihydro-1-.
Using isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the target product was obtained in a yield of 79%.

¹ H-NMR (CDCl ₃ ): 1.33 (3H; d, J = 7.9Hz), 1.57
(3H; d, J = 7.6Hz), 4.49 (1H: h, J = 7.6Hz), 7.23-7.86 (9H; m),
10.68 (1H, s) MS (EI, In Beam): 307 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3272, 3072, 1654, 1610, 698 Example 22 (3) 3-amino-2,3 -Dihydro-1-isopropyl-5
-Phenyl-1H-1,4-benzodiazepin-2-one By the same operation as in Example 20 (3), 2,3-dihydro-1-ethyl-3-oximido-5-phenyl-1H-.
2,3 instead of 1,4-benzodiazepin-2-one
-Dihydro-1-isopropyl-3-oximid-5-
Using phenyl-1H-1,4-benzodiazepin-2-one, the desired product was obtained in a yield of 28%.

¹ H-NMR (CDCl ₃ ): 1.25 (3H; d, J = 7.6Hz), 1.50
(3H; d, J = 7.6Hz), 2.56 (2H; br), 4.44 (1H; s), 4.59 (1H; h, J =
7.6 Hz), 7.15-7.69 (9H; m) MS (EI, In Beam): 293 (M ⁺ ) Example 22 (4) (3R) -3- [3-[(1S) -1-cyclohexylmethyl- 2-Hydroxy-2- (isopropyloxycarbonyl)] ethylureido] -2,3-dihydro-1
-Isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 1, (3R) -3-amino-
2,3-dihydro-1-methyl-5-phenyl-1H-
1,4-benzodiazepin-2-one and (1S) -1
-Cyclohexylmethyl-2-hydroxy-3-[(1
-Methyl-5-tetrazolyl) thio] propylamine hydrochloride instead of 3-amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one and 3-amino- Using (3S) -3-cyclohexylmethyl-2-hydroxypropionic acid isopropyl ester hydrochloride, the target product was obtained in a yield of 10%.

MS (m / z): FAB 563 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3416, 2992, 1736, 1676 Example 23 (1) 1-benzyl-2,3-dihydro- 5-phenyl-1H
-1,4-Benzodiazepin-2-one By the same operation as in Example 20 (2), benzyl bromide was used instead of ethyl iodide to obtain the target product in a yield of 94%.

¹ H-NMR (CDCl ₃ ): 4.37 (2H; q, J = 10Hz), 5.22
(2H; q, J = 16Hz), 6.92-7.52 (14H; m) MS (EI, In Beam): 326 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3456, 1674, 754, 702 Example 23 (2) 1-benzyl-2,3-dihydro-3-oximid-5
-Phenyl-1H-1,4-benzodiazepin-2-one By the same operation as in Example 20 (2), 2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one. 1-benzyl-2,3-instead of
The target product was obtained in 75% yield using dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one.

¹ H-NMR (CDCl ₃ ): 4.96 (1H; br), 5.58 (1H; b
r), 5.48-5.76 (1H; m), 6.94-7.31 (14H; m), 8.04 (1H; br) MS (EI, In Beam): 355 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3328 , 1682, 1608, 698 Example 23 (3) 3-Amino-1-benzyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one Similar to Example 20 (3). By operation 2,3-dihydro-1-ethyl-3-oximid-5-phenyl-1H-
Instead of 1,4-benzodiazepin-2-one, 1-benzyl-2,3-dihydro-3-oximid-5-phenyl-1H-1,4-benzodiazepin-2-one was used to give 36% of the desired product. Obtained in yield.

¹ H-NMR (CDCl ₃ ): 2.32 (2H; br), 4.61 (1H; b
r), 5.26 (2H; q, J = 16.2Hz), 6.95-7.54 (15H; m) MS (FAB): 342 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3412, 1672, 1608, 700 Example 23 (4) (3R) -3- [3-[(1S) -1-cyclohexylmethyl-2-hydroxy-2- (isopropyloxycarbonyl)] ethylureido] -1-benzyl-2,3
-Dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 1, (3R) -3-amino-
2,3-dihydro-1-methyl-5-phenyl-1H-
1,4-benzodiazepin-2-one and (1S) -1
-Cyclohexylmethyl-2-hydroxy-3-[(1
-Methyl-5-tetrazolyl) thio] propylamine hydrochloride instead of 3-amino-1-benzyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one and 3-amino- (3S) -3-Cyclohexylmethyl-2-hydroxypropionic acid isopropyl ester hydrochloride was used to obtain the desired product in a yield of 23%.

MS (m / z): 611 (M ⁺ +1) IR νmax (KBr) cm ^-1 : 3412, 2936, 1736, 1666, 698 Example 24 (1) 2-[(2-bromoacetyl) Amino] -5-chlorobenzophenone 4.63 g of 2-amino-5-chlorobenzophenone was added to a mixed solution of 20 ml of dichloromethane and 2 ml of purified water, and -1
8 ml of a dichloromethane solution containing 2 ml of promoacetyl bromide was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 8 hours.
The organic layer obtained by washing with 40 ml of purified water was dried over anhydrous magnesium sulfate, and the residue produced by distilling off the solvent was cooled and crystallized with hexane to obtain 6.04 g of the desired product.

¹ H-NMR (CDCl ₃ ): 4.02 (2H; s), 7.41-7.80 (7
H; m), 8.52-8.63 (1H; m) MS (EI, In Beam): 352 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3240, 1688, 1636 Example 24 (2) 7-chloro- 2,3-dihydro-5-phenyl-1H-
5.92 g of 1,4-benzazepin-2-one 2-[(2-bromoacetyl) amino] -5-chlorobenzophenone was dissolved in 100 ml of methanol, and the mixture was stirred while blowing ammonia gas under cooling at -10 ° C. . After 2 hours, return the reaction solution to room temperature, and
Heated to reflux for hours. Cooled purified water was added to the residue obtained by distilling off the solvent, and the resulting crystals were collected by filtration to obtain 3.15 g of the desired product.

¹ H-NMR (DMSO-d ₆ ): 4.17 (2H; br,), 7.20-7.7
1 (8H; m), 10.65 (1H; br) MS (EI, In Beam): 270 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3200, 2968, 1686 Example 24 (3) 7-chloro- 2,3-Dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one By the same procedure as in Example 20 (1), 2,3-dihydro-5-phenyl-1H-1, 4-benzodiazepine-2
7-chloro-2,3 instead of -one and ethyl iodide
Using dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one and methyl iodide,
Obtained in a yield of 0%.

¹ H-NMR (CDCl ₃ ): 3.40 (3H; s), 3.78 (1H; d, J =
10.8Hz), 4.85 (1H; d, J = 10.8Hz), 7.25-7.64 (8H; m) MS (EI, In Beam): 284 (M ⁺ ) IR νmax (KBr) cm ^-1 : 1684, 1614, 1486, 700 Example 24 (4) 7-Chloro-2,3-dihydro-1-methyl-3-oximid-5-phenyl-1H-1,4-benzodiazepin-2-one Similar to Example 20 (2). In place of 2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one by the operation of 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H The target compound was obtained in a yield of 98% using -1,4-benzodiazepin-2-one.

¹ H-NMR (CDCl ₃ ): 3.44 (3H; s), 7.22-7.88 (9
H; m) MS (EI, In Beam): 313 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3340,2972,1682,1614,698 Example 24 (5) 3-amino-7-chloro-2 , 3-Dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-
2-one 2,3-dihydro-1-ethyl-3-oximido-5-phenyl-1H- was prepared in the same manner as in Example 20 (3).
7-chloro-2,3-dihydro-1-methyl-3-oximid-5-phenyl-1H-1,4-benzodiazepine-2 instead of 1,4-benzodiazepin-2-one
The target compound was obtained in a yield of 41% using -one.

¹ H-NMR (CDCl ₃ ): 3.44 (3H; s), 4.25 (1H; br),
7.27-7.65 (8H; m) MS (GC): 299 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3400, 1686, 1600, 700 Example 24 (6) (3R) -3- [3- [ (1S) -1-Cyclohexylmethyl-2-hydroxy-2- (isopropyloxycarbonyl)] ethylureido] -7-chloro-2,3-
Dihydro-1-methyl-5-phenyl-1H-1,4-
Benzodiazepin-2-one By the same procedure as in Example 1, (3R) -3-amino-
2,3-dihydro-1-methyl-5-phenyl-1H-
1,4-benzodiazepin-2-one and (1S) -1
-Cyclohexylmethyl-2-hydroxy-3-[(1
3-Amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one and 3 in place of -methyl-5-tetrazolyl) thio] furopyramine hydrochloride -Amino- (3S) -3
-Cyclohexylmethyl-2-hydroxypropionic acid isopropyl hydrochloride was used to obtain the desired product in a yield of 54%.

MS (FAB): 569 (M ⁺ +1) IR νmax (KBr) cm ⁻¹ : 3410, 2936, 2856, 1740, 1680 Example 25 (1) 3-benzoyl-2-[(2-bromo Acetyl) amino] -5-ethylthiophene 2-amino-5- by the same operation as in Example 24 (1).
2-Amino-3-benzoyl-5-ethylthiophene was used in place of chlorobenzophenone to prepare the target compound.
Obtained in% yield.

¹ H-NMR (CDCl ₃ ): 1.29 (3H; t, J = 7,2Hz), 2.76
(2H; q, J = 7,2Hz), 4.11 (2H; s), 6.80-6.83 (1H; m), 7.41-7.8
0 (5H; m), 12.71 (1H; br) MS (EI, In Beam): 352 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3200,1680,1618,1534 Example 25 (2) 2, 3-dihydro-7-ethyl-5-phenyl-1H-
Thieno [2,3-e] [1,4] diazepin-2-one In place of 2-[(2-bromoacetyl) amino] -5-chlorobenzophenone according to the production method of Example 24 (2), 3- Ammonia gas was blown into benzoyl-5-ethylthiophene at a low temperature (-10 ° C) for 2 hours, and the mixture was stirred overnight and post-treated in the same manner to give a target product in a yield of 15%. Got with.

¹ H-NMR (CDCl ₃ ): 1.20 (3H; t, J = 7.2Hz), 2.74
(2H; q, J = 7.2Hz), 4.21 (2H; s), 6.52-6.54 (1H; m), 7.36-7.6
5 (5H; m), 11.16 (1H; br) MS (EI, In Beam): 270 (M ⁺ ) IR νmax (KBr) cm ^-1 : 3080,2848,1690,1496 Example 25 (3) 2, 3-Dihydro-7-ethyl-1-methyl-5-phenyl-1H-thieno [2,3-e] [1,4] diazepin-2-one 60% sodium hydride 0.24 g was added with dimethylformamide 15 ml. , After suspension under ice cooling, 2,3-
Dihydro-7-ethyl-5-phenyl-1H-thieno [2,3-e] [1,4] diazepin-2-one 1.3
5 g was added and stirred for 15 minutes. Subsequently, 0.37 ml of methyl iodide was added dropwise, the mixture was stirred at room temperature for 4 hours, 200 ml of purified water was poured, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1) to obtain the desired product. 0.93 g was obtained.

¹ H-NMR (CDCl ₃ ): 1.29 (3H; t, J = 7.6Hz), 2.79
(2H; q, J = 7.6Hz), 3.45 (3H; s), 4.41 (1H; br), 6.49-6.52 (1
H; m), 7.35-7.73 (5H, m) MS (FAB): 285 (M ⁺ ) Example 25 (4) 2,3-dihydro-7-ethyl-1-methyl-3-oximido-5-phenyl -1H-thieno [2,3-e]
[1,4] Diazepin-2-one By the same operation as in Example 20 (2), 2 instead of 2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one was used. , 3-dihydro-7-
Using ethyl-1-methyl-5-phenyl-1H-thieno [2,3-e] [1,4] diazepin-2-one, the target product was obtained in a yield of 51%.

¹ H-NMR (CDCl ₃ ): 1.29
(3H; t, J = 7.2 Hz), 2.77 (2H; q,
J = 7.2 Hz), 3.54 (3H; s), 6.53−
6.55 (1H; m), 7.38-7.91 (5H;
m) MS (EI, In Beam): 313 (M ^<+> ) Example 25 (5) 3-amino-2,3-dihydro-7-ethyl-1-methyl-5-phenyl-1H-thieno [2,3. -E] [1,
4] diazepin-2-one By the same operation as in Example 20 (3), 2,3-dihydro-1-ethyl-3-oximido-5-phenyl-1H-.
2,3 instead of 1,4-benzodiazepin-2-one
-Dihydro-7-ethyl-1-methyl-3-oximido-5-phenyl-1H-thieno [2,3-e] [1,
4] The target compound was obtained with a yield of 56% using diazepin-2-one.

¹ H-NMR (CDCl ₃ ): 1.30
(3H; t, J = 7.6 Hz), 2.40 (2H; b
r), 2.80 (2H; q, J = 7.6 Hz), 3.5
0 (3H; s), 4.12 (1H; q, J = 7.2H
z), 6.53 (1H; br), 7.39-7.74.
(5H; m) MS (EI, In Beam): 299 (M ⁺ ) Example 25 (6) (3R) -3- [3-[(1S) -1-cyclohexylmethyl-2-hydroxy-2- ( Isopropyloxycarbonyl)] ethylureido] -2,3-dihydro-7
-Ethyl-1-methyl-5-phenyl-1H-1,4-
Thieno [2,3-e] diazepin-2-one By the same procedure as in Example 1, (3R) -3-amino-
2,3-dihydro-1-methyl-5-phenyl-1H-
1,4-benzodiazepin-2-one and (1S) -1
-Cyclohexylmethyl-2-hydroxy-3-[(1
-Methyl-5-tetrazolyl) thio] furopyramine hydrochloride instead of 3-amino-1,3-dihydro-7-ethyl-1-methyl-5-phenyl-1H-thieno [2,2]
Using 3-e] [1,4] diazepin-2-one and 3-amino- (3S) -3-cyclohexylmethyl-2-hydroxypropionic acid isopropyl ester hydrochloride, the desired product was obtained in a yield of 42%. It was

MS (FAB): 569 (M ⁺ ) IR νmax (KBr) cm ⁻¹ : 3416,2940,1688,1550 Example 26 1-[(1S) -1-cyclohexylmethyl-2-hydroxy-3- [(1-Methyl-5-tetrazolyl) thio] propyl] -3- [2,3-dihydro-1-methyl-2-oxo-5- (p-tolyl) -1H-1,4-benzodiazepine-3- Il] urea (1) 2- (2-Bromoacetyl) amino-4'-methylbenzophenone 2-amino-4'-methylbenzophenone 21.1 g was dissolved in 130 ml of methylene chloride and 10 ml of water to obtain -10
Cooled to ° C. 2-bromoacetyl bromide 1
Add 0 ml of methylene chloride in 30 ml and add 5 ml at room temperature.
Stir for hours. 200 ml of water was added to the reaction mixture, and the mixture was extracted with 100 ml of methylene chloride × 2. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was washed with 100 ml of n-hexane to obtain 30.6 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.46 (3H; s), 4.03 (2H; s),
7.16 (1H; t, J = 8.1Hz), 7.31 (2H; d, J = 8.1Hz), 7.58-7.65
(2H; m), 7.66 (2H; d, J = 8.1Hz), 8.59 (1H; d, J = 8.1Hz) MS (EI, In Beam): 333, 331 (2) 2,3-dihydro-5 -(4-Methylphenyl) -2-oxo-1 (H) -benzodiazepine 2- (2-bromoacetyl) amino-4'-methylbenzophenone 3.50 g was suspended in 60 ml of methanol-
Cooled to 10 ° C. Ammonia gas was blown into this until the insoluble matter was dissolved, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was heated under reflux for 2 hours and then concentrated. The obtained residue was heated to 40 ° C., 10 ml of water was added, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration and washed with methanol / water = 1/1 to obtain 2.54 g of the desired product.

¹ H-NMR (DMSO-d ₆ ): 2.38 (3H; s), 4.14 (2H;
s), 7.02-7.59 (8H; m), 10.42 (1H; s) MS (EI, In Beam): 249 (M-1) (3) 2,3-dihydro-1-methyl-5- (4- Methylphenyl) -2-oxo-1 (H) -benzodiazepine Toluene 18 ml was cooled to 0 ° C. and aliquat 336 1 ml, methyl iodide 0.66 ml, 2,3-
Dihydro-5- (4-methylphenyl) -2-oxo-
1 (H) -benzodiazepine 2.42 g toluene 30
ml solution and 18% of 50% sodium hydroxide aqueous solution were sequentially added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with 50 ml of toluene x 2 and the obtained organic layer was 50 ml of water.
Washed with. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was crystallized from ether / n-hexane to obtain 2.05 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.39 (3H; s), 3.41 (3H; s),
3.76 (1H; d, J = 9.9Hz), 4.79 (1H; d, J = 10.8Hz), 7.15-7.5
6 (8H; m) MS (GC): 263 (M-1) (4) 2,3-dihydro-1-methyl-5- (4-methylphenyl) -3-oximido-2-oxo-1
(H) -Benzodiazepine 2,3-dihydro-1-methyl-5- (4-methylphenyl) -2-oxo-1 (H) -benzodiazepine 2.
00g was melt | dissolved in 40 ml of toluene, and it cooled at -20 degreeC. 2.24 g of potassium t-butoxide was added to this,
After stirring at -20 ° C for 15 minutes, 1.26 ml of isoamyl nitrite was added, and the mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was mixed with ice water 80 ml-acetic acid 4 ml-ethyl acetate 80 m.
The mixture was poured into 1 and extracted with 2 × 80 ml of ethyl acetate. The residue obtained by drying the organic layer over anhydrous sodium sulfate and distilling off the solvent was crystallized from toluene / n-hexane to obtain 1.59 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.42 (3H; s), 3.46 (3H; s),
7.19-7.76 (8H; m) MS (EI, In Beam): 293 (M +) (5) 3-amino-2,3-dihydro-1-methyl-
5- (4-methylphenyl) -2-oxo-1 (H)-
Benzodiazepine 2,3-dihydro-1-methyl-5- (4-methylphenyl) -3-oximido-2-oxo-1 (H) -benzodiazepine 0.59 g was dissolved in methanol 10 ml to give ruthenium / carbon 0.15 g. And hydrogen (40p
si) under 70 ° C. overnight. The reaction mixture was filtered through Celite, and the solvent was evaporated to obtain 0.57 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.39 (3H; s), 3.46 (3H; s),
7.15-7.57 (8H; m) MS (EI, In Beam): 279 (M +) (6) 1-[(1S) -1-cyclohexylmethyl-
2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -3- [2,3-dihydro-1-
Methyl-2-oxo-5- (p-tolyl) -1H-1,
4-Benzodiazepin-3-yl] urea By the same procedure as in Example 11, 3-aminomethyl-2,
3-Amino-2,3-dihydro-1-methyl-5- (4-methylphenyl) -2 instead of 3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one
Using -oxo-1 (H) -benzodiazepine, the target product was obtained in a yield of 81% (0.48 g of a high polarity compound and 0.47 g of a low polarity compound).

Highly polar compound Rf value 0.13 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.78-0.90 (3H; m), 1.08-1.34 (5H; m),
1.43-1.49 (1H; m), 1.58-1.69 (3H; m), 1.75 (1H; d, J = 12.8
Hz), 2.37 (3H; s), 3.40-3.51 (2H; m), 3.47 (3H; s), 3.88
(3H; s), 3.89-3.93 (1H; m), 3.96-4.00 (1H; m), 4.47 (1h;
s), 5.44 (1H; d, J = 8.4Hz), 5.58 (1H; d, J = 9.2Hz), 6.81 (1
H; d, J = 8.4Hz), 7.17-7.23 (2H; m), 7.34-7.40 (2H; m), 7.
50 (2H; d, J = 8.4Hz), 7.54-7.59 (1H; m) MS (FAB, Pos.): 591 (M + 1) Low polarity compound Rf value 0.26 (ethyl acetate / n-hexane = 2 /
1) ¹ H-NMR (CDCl ₃ ): 0.77-0.90 (3H; m), 1.06-1.42 (5H; m),
1.46-1.73 (5H; m), 2.37 (3H; s), 3.38-3.52 (2H; m), 3.47
(3H; s), 3.51-3.79 (1H; m), 3.88-3.93 (1H; m), 3.91 (3H;
s), 4.52-4.56 (1H; m), 5.46 (1H; d, J = 8.8Hz), 5.62 (1H;
d, J = 8.8Hz), 6.81 (1H; d, J = 8.4Hz), 7.16 (1H; d, J = 8.0H
z), 7.23 (1H; t, J = 7.6Hz), 7.34-7.39 (2H; m), 7.48 (2H;
d, J = 8.0Hz), 7.55-7.59 (1H; m) MS (FAB, Pos.): 591 (M + 1) Example 27 N-[(1S) -1-cyclohexylmethyl-2-hydroxy-3. -[(1-Methyl-5-tetrazolyl) thio] propyl] -2-((3S) -2,3-dihydro-
1,5-Dimethyl-2-oxo-1H-1,4-benzodiazepin-3-yl) acetamide (1) Nt-butyloxycarbonyl-L-aspartic acid α-2-benzophenone amide β-benzyl ester Example By the same operation as in 13 (1), 2-aminoacetophenone was used instead of 2-aminobenzophenone to obtain the desired product in a yield of 65%.

¹ H-NMR (CDCl ₃ ): 1.52 (9H; s), 2.63 (3H; s),
2.96, (2H; dd, J = 42.8,4.6Hz), 3.16 (1H; dd, J = 43.1,4.6)
Hz), 4.67 (1H; t, J = 4.6Hz), 4.77 (1H; t, J = 4.6Hz), 5.11,
5.13 (2H; s), 5.74,5.84 (1H; bs), 7.16,7.17 (1H; q, J = 7.7
Hz), 7.31 (5H; s), 7.54,7.56 (1H; t, J = 8.8Hz), 7.87,7.8
9 (1H; d, J = 7.9Hz), 8.72,8.73 (1H; d, J = 8.4Hz), 12.42 (1
H; s) MS (FAB, Pos.): 440 (M + 1) (2) benzyl 2- (2,3-dihydro-5-methyl-2-oxo-1 (H) -benzodiazepin-3-yl) Acetate Nt-butyloxycarbonyl-L-aspartic acid [alpha] -2-benzophenone amide [beta] -benzyl ester (4.40 g) was dissolved in 4N hydrogen chloride / dioxane (100 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, 100 ml of a saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with 100 ml of ethyl acetate × 2. The organic layer is 100m of water
1, washed with 100 ml of a saturated saline solution successively, dried over anhydrous sodium sulfate, and the solvent was distilled off.

The obtained residue was dissolved in 30 ml of benzene, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 4 hours. 100 ml of saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with 100 ml of ethyl acetate × 2. The organic layer was washed successively with 100 ml of water and 100 ml of saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 2.92 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.40, 2.43 (3H; s), 3.20,
3.27 (2H; q, J = 16.0Hz), 4.02 (1H; t, J = 18.0Hz), 5.13 (2H;
s), 6.99-7.58 (4H; m), 7.31 (5H; s), 9.07 (1H; s) MS (GC): 322 (M +) (3) benzyl 2- (2,3-dihydro-1,5 −
Dimethyl-2-oxo-1 (H) -benzodiazepine-
3-yl) acetate By the same procedure as in Example 14 (1), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo Benzyl 2- (2,3-dihydro-5-methyl-2-oxo-1 (H) -benzodiazepine-instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate The target product was obtained with a yield of 68% using 3-yl) acetate.

¹ H-NMR (CDCl ₃ ): 2.43,2.45 (3H; s), 3.21,
3.28 (2H; dd, J = 33.2,17.0Hz), 3.38 (3H; s), 3.96 (1H; d, J
= 7.6Hz), 5.12 (2H; s), 7.15-7.59 (4H; m), 7.32 (5H; s) MS (GC): 336 (M +) (4) 2- (2,3-dihydro-1, 5-dimethyl-
2-oxo-1 (H) -benzodiazepin-3-yl)
0.34 g of benzyl 2- (2,3-dihydro-1,5-dimethyl-2-oxo-1 (H) -benzodiazepin-3-yl) acetate acetate was dissolved in 10 ml of methanol, and a catalytic amount of palladium / carbon was added. In addition, the mixture was stirred at room temperature under normal pressure hydrogen for 1.5 hours. The reaction mixture was filtered through Celite and the solvent was distilled off to obtain 0.26 g of the desired product.

¹ H-NMR (CDCl ₃ ): 2.49,2.51 (3H; s), 3.11 (2
H; dd, J = 16.6,14.0Hz), 3.40 (3H; s), 3.91 (1H; t, J = 5.6H
z), 7.19-7.63 (4H; m) (5) N-[(1S) -1-cyclohexylmethyl-
2-Hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -2-((3S) -2,3-dihydro-1,5-dimethyl-2-oxo-1H-1,4-
Benzodiazepin-3-yl) acetamide By the same procedure as in Example 13 (8), 2- (2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetic acid was replaced. 2- (2,
3-dihydro-1,5-dimethyl-2-oxo-1
Using (H) -benzodiazepin-3-yl) acetic acid, the target product was obtained in a yield of 51%.

¹ H-NMR (CDCl ₃ ): 0.81-0.97 (3H; m), 1.12-
1.28 (5H; m), 1.37-1.44 (1H; m), 1.61-1.67 (3H; m), 1.80
(1H; d, J = 19.6Hz), 2.48,2.49 (3H; s), 2.92-3.04 (2H; m),
3.34 (3H; s), 3.37-3.47 (1H; m), 3.93 (3H; s), 3.99 (1H;
bs), 4.15 (1H; bs), 4.56 (1H; bs), 6.93 (1H; d, J = 9.6Hz),
7.23-7.30 (2H; m), 7.497.54 (2H; m) MS (FAB, Pos.): 514 (M-H + D + 1) Example 28 2-((3S) -5-benzyl-2 , 3-dihydro-1
-Methyl-2-oxo-1H-1,4-benzodiazepin-3-yl) -N-[(1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] Propyl] acetamide (1) N-t-butyloxycarbonyl-L-aspartic acid α-2- (1-oxophenethyl) anilamide β-benzyl ester By the same procedure as in Example 27 (1), 2-aminobenzophenone was replaced. 2- (1-oxophenethyl) aniline was used as the solvent to obtain the desired product in a yield of 25%.

¹ H-NMR (CDCl ₃ ): 1.40 (9H; s), 2.79 (1H; dd,
J = 16.2,5.4Hz), 3.30 (1H; dd, J = 13.5,5.4Hz), 4.31 (2H;
s), 4.69-4.73 (1H; m), 5.10 (2H; q, J = 10.8Hz), 5.78 (1H;
d, J = 10.8Hz), 7.12 (1H; t, J = 10.8Hz), 7.20-7.36 (5H; m),
7.30 (5H; s), 7.52 (11H; t, J = 10.8Hz), 8.01 (1H; d, J = 10.
8Hz), 8.76 (1H; d, J = 10.8Hz), 12.46 (1H; bs) MS (FAB, Pos.): 517 (M + 1) (2) benzyl 2- (5-benzyl-2,3- Dihydro-2-oxo-1 (H) -benzodiazepine-3-
Yl) Acetate By the same operation as in Example 27 (2), Nt was replaced with Nt-butyloxycarbonyl-L-aspartic acid α-2-benzophenone amide β-benzyl ester.
-Butyloxycarbonyl-L-aspartic acid α-
The target product was obtained in 100% yield using 2- (1-oxophenethyl) anilamide β-benzyl ester.

¹ H-NMR (CDCl ₃ ): 3.02-3.58 (2H; m), 3.91-
4.31 (2H; m), 4.11-4.34 (1H; m), 5.16 (2H; s), 6.90-7.61
(4H; m), 7.15 (5H; s), 7.33 (5H; s), 7.98 (1H; s) MS (EI, In Beam): 397 (M-1) (3) benzyl 2- (5-benzyl -2,3-Dihydro-1-methyl-2-oxo-1 (H) -benzodiazepin-3-yl) acetate By the same procedure as in Example 14 (1), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo Benzyl 2- (5-benzyl-2,3-dihydro-2-oxo-1 (H) -benzodiazepine-instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate The target compound was obtained with a yield of 40% using 3-yl) acetate.

¹ H-NMR (CDCl ₃ ): 3.29 (1H; dd, J = 72.9,16.2H
z), 3.32 (1H; dd, J = 72.9,16.2Hz), 3.97-4.16 (3H; m), 5.
12 (2H; s), 7.06-7.52 (9H; m), 7.32 (5H; s) MS (EI, In Beam): 412 (M +) (4) 2- (5-benzyl-2,3-dihydro- 1-
Methyl-2-oxo-1 (H) -benzodiazepine-3
-Yl) acetic acid By the same procedure as in Example 27 (4), benzyl 2-
(2,3-dihydro-1,5-dimethyl-2-oxo-
Instead of 1 (H) -benzodiazepin-3-yl) acetate, benzyl 2- (5-benzyl-2,3-dihydro-1-methyl-2-oxo-1 (H) -benzodiazepin-3-yl) acetate was used. 88% target product
It was obtained in a yield of.

¹ H-NMR (CDCl ₃ ): 3.11 (1H; d, J = 8.1Hz), 3.2
9 (3H; s), 3.96 (1H; t, J = 5.4Hz), 4.06-4.20 (1H; m), 4.11
(2H; d, J = 5.4Hz), 7.09 (1H; d, J = 5.4Hz), 7.16-7.27 (6H;
m), 7.49 (1H; t, J = 8.1Hz), 7.59 (1H; d, J = 5.4Hz) MS (EI, In Beam): 322 (M +) (5) 2-((3S) -5 Benzyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl) -N-[(1S) -1-cyclohexylmethyl-2-hydroxy-3-[(1 -Methyl-5-tetrazolyl) thio] propyl] acetamide 2- (2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3- by the same operation as in Example 13 (8). 2- (5-) instead of (yl) acetic acid
The target product was obtained in a yield of 57% using benzyl-2,3-dihydro-1-methyl-2-oxo-1 (H) -benzodiazepin-3-yl) acetic acid.

¹ H-NMR (CDCl ₃ ): 0.80-0.98 (3H; m), 1.13-
1.26 (4H; m), 1.36-1.42 (1H; m), 1.54-1.66 (4H; m), 1.77
(1H; d, J = 12.0Hz), 2.99 (1H; dd, J = 35.2,6.8Hz), 3.03 (1
H; dd, J = 35.2,6.8Hz), 3.23 (3H; s), 3.89-4.11 (2H; m),
3.92 (3H; s), 4.01 (1H; t, J = 6.0Hz), 4.11 (2H; dd, J = 41.2,
14.4Hz), 4.39 (1H; s), 6.92 (1H; d, J = 9.2Hz), 7.09 (2H;
d, J = 7.2Hz), 7.14-7.22 (4H; m), 7.43 (1H; t, J = 8.0Hz),
7.55 (1H; d, J = 8.0Hz) MS (FAB, Pos.): 590 (M + 1) Example 29 N-[(1S) -cyclohexylmethyl-2-hydroxy-3-[(1-methyl- 5-Tetrazolyl) thio] propyl] -2-((3S) -2,3-dihydro-1-methyl-2-oxo-5-phenethyl-1H-1,4-benzodiazepin-3-yl) acetamide (1) Nt-butyloxycarbonyl-L-aspartic acid α-2- (1-oxo-3-phenylpropyl) anilamido β-benzyl ester By the same procedure as in Example 27 (1), 2 instead of 2-aminobenzophenone was used. The target product was obtained with 44% yield using-(1-oxo-3-phenylpropyl) aniline.

¹ H-NMR (CDCl ₃ ): 1.46,1.55 (9H; s), 2.75-
2.87 (1H; m), 2.99-3.13 (2H; m), 3.30-3.37 (2H; m), 4.64
-4.76 (1H; m), 5.06-5.24 (2H; m), 5.84 (1H; d, J = 10.8Hz),
7.09 (1H; t, J = 8.1Hz), 7.22-7.33 (4H; m), 7.31 (5H; s),
7.46-7.61 (2H; m), 7.87 (1H; d, J = 5.4Hz), 8.73 (1H; d, J =
5.4Hz), 12.48 (1H; bs) MS (EI, In Beam): 530 (M +) (2) benzyl 2- (2,3-dihydro-2-oxo-5-phenethyl-1 (H) -benzodiazepine- Three
-Yl) Acetate By the same operation as in Example 27 (2), N-t-butyloxycarbonyl-L-aspartic acid α-2-benzophenone amide β-benzyl ester was replaced with N-.
t-Butyloxycarbonyl-L-aspartic acid α
Using 2- (1-oxo-3-phenylpropyl) anilamide β-benzyl ester, the target product was obtained in a yield of 100%.

(3) Benzyl 2- (2,3-dihydro-1-methyl-2-oxo-5-phenethyl-1)
(H) -Benzodiazepin-3-yl) acetate By the same procedure as in Example 14 (1), benzyl 2-
((3S) -2,3-Dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate and benzyl 2-((3R) -2,3-dihydro-2-oxo Benzyl 2- (2,3-dihydro-2-oxo-5-phenethyl-1 (H) -benzodiazepine-instead of an equal mixture of -5-phenyl-1H-1,4-benzodiazepin-3-yl) acetate 3-
The target compound was obtained with a yield of 56% using (yl) acetate.

¹ H-NMR (CDCl ₃ ): 2.85 (2H; t, J = 8.1Hz), 3.0
5 (2H; d, J = 8.1Hz), 3.10 (1H; dd, J = 16.2,8.1Hz), 3.28 (3
H; s), 3.40 (1H; dd, J = 16.2,8.1Hz), 4.00 (1H; t, J = 8.1H
z), 5.11 (2H; dd, J = 10.8,16.2Hz), 7.06-7.50 (9H; m), 7.
32 (5H; s) MS (EI, In Beam): 426 (M +) (4) 2- (2,3-dihydro-1-methyl-2-oxo-5-phenethyl-1 (H) -benzodiazepine-
3-yl) acetic acid By the same procedure as in Example 27 (4), benzyl 2-
(2,3-dihydro-1,5-dimethyl-2-oxo-
Instead of 1 (H) -benzodiazepin-3-yl) acetate, benzyl 2- (2,3-dihydro-1-methyl-2-oxo-5-phenethyl-1 (H) -benzodiazepin-3-yl) acetate was used. Use 10 objects
Obtained in a yield of 0%.

(5) N-[(1S) -cyclohexylmethyl-2-hydroxy-3-[(1-methyl-5-tetrazolyl) thio] propyl] -2-((3S) -2,
3-Dihydro-1-methyl-2-oxo-5-phenethyl-1H-1,4-benzodiazepin-3-yl) acetamide 2- (2,3-dihydro-2) was prepared by the same procedure as in Example 13 (8). Instead of -oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) acetic acid, 2- (2,2
Using 3-dihydro-1-methyl-2-oxo-5-phenethyl-1 (H) -benzodiazepin-3-yl) acetic acid, the target product was obtained in a yield of 50%.

¹ H-NMR (CDCl ₃ ): 0.89-1.92 (13H; m), 2.94-
3.15 (6H; m), 3.17-3.26 (2H; m), 3.36 (3H; s), 3.54-3.60
(2H; m), 3.97-4.12 (1H; m), 4.03 (3H; s), 4.26 (1H; bs),
7.08-7.37 (7H; m), 7.56-7.62 (2H; m) MS (FAB, Pos.): 604 (M + 1)

[0130]

[Chemical 7]

[0131]

[Table 1]

[0132]

[Table 2]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area C07D 403/12 243 413/12 243 495/04 116

Claims (2)

[Claims] 1. A condensed diazepine derivative represented by the following general formula (I) or a salt thereof. [Chemical 1] (However, the symbols in the formulas have the following meanings: A ring: an optionally substituted benzene ring or thiophene ring, R ¹ : hydrogen atom, lower alkyl group or aralkyl group, R ² : lower alkyl group, Aralkyl group or optionally substituted phenyl group, L ¹ : bond, alkylene group optionally substituted with lower alkyl group or aralkyl group, X: bond, group represented by formula -CO- or formula -NHC
A group represented by O-, R ^3: aralkyl group or a cycloalkyl lower alkyl group which may be substituted with a group, L ^2:
A group represented by the formula- (CHOH) _n- or a formula-CONHC
Group represented by HR ⁵ —, n: 1 or 2, R ⁵ : lower alkyl group optionally substituted with aralkyl group or cycloalkyl group, Y: —Het, —CH ₂ —Het, —CH ₂ —
S-Het or -CO ₂ -R ^4, Het: may be substituted, and 3-6 membered heterocyclic ring containing 1 to 4 nitrogen atoms, R ^4: a hydrogen atom or a lower alkyl group. ) 2. The condensation according to claim 1, wherein L ₂ is a group represented by the formula — (CHOH) _n —, and Het is an optionally substituted tetrazolyl group or 2-oxo-oxazolidinyl group. A diazepine derivative or a salt thereof.