JP2697495B2 - Aldehyde derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula

[0002]

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Wherein R ¹ is an aromatic hydrocarbon group, a heterocyclic group, a substituted alkyl group or a cyclic alkyl group, R ² is a hydrogen atom, an alkyl group or an aromatic hydrocarbon group, and R ³ is a hydrogen atom Or an alkyl group, R ⁴ is an alkoxycarbonyl group, an acyl group, a carbamoyl group or a sulfonyl group, X
Is an oxygen atom or a group represented by —S (O) _m —, wherein m is 0, 1 or 2, and n is 1 to 5. )). The aldehyde derivative represented by the general formula (1) is a compound having a calpain inhibitory activity and a platelet aggregation inhibitory activity and can be used as a therapeutic agent for ischemic disease.

[0004]

2. Description of the Related Art Calpain is a proteolytic enzyme (cysteine protease) that exists widely in cells of tissue in a living body and is activated by calcium. Calpain is known to have physiological activities such as tissue breakdown using muscle proteins, enzyme proteins, receptor proteins or cytoskeletal proteins as substrates, activation of inactive zymogen, and intracellular processing (protein nucleic acid). Enzyme, No. 33
Vol. 12, No. 2, 2175 (1988)).

[0005] The abnormal calpain activity caused by the increased calpain activity is involved in many intractable diseases. For example, involvement in ischemic disease, inflammation, muscular dystrophy, cataract, immune disease, essential hypertension and the like has been reported. Particularly in ischemic diseases, it is thought that calpain is activated by an increase in intracellular calcium during ischemia, causing cell damage and necrosis.

[0006] Conventionally, as a therapeutic agent for this ischemic disease, a calcium antagonist, a β-blocker or the like, which has a blood vessel expanding effect, has been used. However, these drugs did not have the effect of treating or preventing the cell damage or necrosis seen in ischemic diseases.

Therefore, calpain inhibitors may be useful as therapeutic agents for these intractable diseases. Compounds having calpain inhibitory activity include epoxy succinic acid derivatives (J. Biochem., 87, 33).
9 (1980), piperazine derivatives (JP-A-57-16)
9478, JP-A-58-126879, JP-A-63
No. 25575), an aminoaldehyde derivative (Japanese Unexamined Patent Publication No.
Nos. 1-103897, JP-A-1-12157 and JP-A-2-268145), aminoaldehydes and aminoketone derivatives (JP-A-2-256654) are known.

[0008]

Among these compounds, piperazine derivatives are reported to have a cardioprotective effect, and have potential as therapeutic agents for ischemic diseases. However, this derivative also had a low inhibitory activity on calpain and a protective effect on myocardium, and could not be expected to have a sufficient therapeutic effect. Compounds other than the piperazine derivative have calpain inhibitory activity but could not be used as a therapeutic agent for ischemic disease.

[0009]

The present inventors have conducted research to find a calpain inhibitor useful for ischemic disease. An aldehyde derivative represented by the above general formula (I) having specific inhibitory activity on aldehydes has been found, and the present invention has been completed.

In the aldehyde derivative represented by the general formula (I), R ¹ represents an aromatic hydrocarbon group, a heterocyclic group,
It is a substituted alkyl group or a cyclic alkyl group. As this aromatic hydrocarbon group, for example, a phenyl group, a naphthyl group, an anthranyl group, etc. A linear or branched alkyl group having 1 to 10 carbon atoms having the aromatic hydrocarbon group or the heterocyclic group as a substituent, such as a methyl group, an ethyl group, a propyl group, a butyl group, or a pentyl group; , Hexyl group, 2-propyl group, sec
-Butyl group, t-butyl group and the like. Examples of the cyclic alkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.

Further, the aromatic hydrocarbon or heterocyclic group represented by R ^{1 and} the aromatic hydrocarbon or heterocyclic group which is a substituent of the substituted alkyl group may have a substituent. As an example, a methyl group, an ethyl group, a propyl group, an alkyl group having 1 to 10 carbon atoms such as a butyl group,
Methoxy, ethoxy, propoxy, butoxy,
An alkoxy group having 1 to 10 carbon atoms such as a benzyloxy group,
Examples include a halogen group such as fluorine, chlorine, bromine and iodine, an amino group such as an amino group, a dimethylamino group and a diethylamino group, a hydroxyl group and a nitro group.

R ² is a hydrogen atom, a linear or branched alkyl group or an aromatic hydrocarbon group. The alkyl group of R ^{2 is} a linear or branched alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, Examples thereof include an isobutyl group, a t-butyl group, a pentyl group, a neopentyl group, and a hexyl group. Examples of the aromatic hydrocarbon group include the same groups as the aromatic hydrocarbon group represented by R ^1. it can. Further, the alkyl group of R ² may have a substituent, and examples of the substituent include the aromatic hydrocarbon group and the heterocyclic group represented by R ¹ .

R ³ is a hydrogen atom or an alkyl group;
Examples of the alkyl group include the same alkyl groups as those described above for R ² .

R ⁴ is an alkoxycarbonyl group, an acyl group, a carbamoyl group or a sulfonyl group. The alkoxycarbonyl group is an alkoxycarbonyl group having an alkoxy group having 1 to 10 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a cinnamyloxycarbonyl group, and a benzyloxycarbonyl group. As the acyl group, for example, acetyl, propionyl, butyryl, valeryl, benzoyl, 1-naphthoyl, 2-naphthoyl, cyclohexanecarbonyl,
Examples thereof include a toluyl group and a 1- (benzyloxycarbonyl) piperidine-4-carbonyl group. Examples of the carbamoyl group include an N-methylcarbamoyl group,
N-ethylcarbamoyl group, N-phenylcarbamoyl group, N- (2-chlorophenyl) carbamoyl group, N-
(1-Naphthyl) carbamoyl group, N-benzylcarbamoyl group, and the like. Examples of the substituted sulfonyl group include, for example, methanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, 4-methylbenzenesulfonyl group, and isoquinoline Examples thereof include a 5-sulfonyl group and a quinoline-8-sulfonyl group.

X is an oxygen atom or a group represented by -S (O) _m- , wherein m is 0, 1 or 2. n is 1
~ 5.

The aldehyde derivative represented by the general formula (I) can be produced, for example, according to the production method shown in the following formula I.

Formula I

[0018]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , X, and n are the same as above, and R ⁵ is an alkyl group having 1 to 15 carbon atoms.) [First step] In this step, the carboxylic acid derivative represented by the general formula (II) is reacted with the amine derivative represented by the general formula (III) in the presence of a condensing agent, whereby the ester derivative represented by the general formula (IV) is reacted. Is to manufacture.

In the amine derivative represented by the general formula (III), R ⁵ is an alkyl group having 1 to 15 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, a diphenylmethyl group and the like. It is.

This step can be carried out in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC.HCl).
And the like.

The condensing agent used in this step is represented by the general formula (I)
A carboxylic acid derivative represented by the formula (I) or the above-mentioned general formula (III)
) Is preferably used in an amount of 1 to 3 equivalents to 1 mol of the amine derivative represented by the formula (1), and 1.5 to 2 equivalents in order to obtain a good yield. The reaction is desirably carried out in an inert solvent. For example, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, dimethoxyethane, tetrahydrofuran (TH
F), ethers such as dioxane, amides such as dimethylformamide (DMF), dimethyl sulfoxide (D
MSO), acetonitrile and the like can be used alone or as a mixture. The reaction usually proceeds at −50 ° C. to reflux temperature under normal pressure.
It is preferably performed at 0 ° C.

The carboxylic acid derivative represented by the general formula (II), which is a starting material in this step, is obtained by converting a commercially available amino acid derivative or an amino group of a commercially available amino acid into a group represented by R ³ and R ^4. It was manufactured.
(See Reference Example below).

The carboxylic acid derivative represented by the general formula (II) used in the present invention includes, for example, LN-
[1- (benzyloxycarbonyl) piperidine-4-
Carbonyl] leucine, LN- (N-phenylcarbamoyl) leucine, LN- (4-methylbenzenesulfonyl) leucine, LN-methyl-N- (benzyloxycarbonyl) leucine, LN- (cinnamoyl )
Leucine, LN- (2-naphthoyl) leucine, L-
N- (benzyloxycarbonyl) valine, LN-
(Benzyloxycarbonyl) phenylalanine and the like.

As the amine derivative represented by the general formula (III) as a starting material in this step, a commercially available amino acid ester can be used. In addition, for example, the amine derivative represented by the general formula (VII) can be used according to the following reaction formula (2). Can be produced from the amino acid.

Equation 2

[0027]

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(Wherein R ¹ , R ⁵ , X and n are the same groups as above, and X ¹ is a halogen atom).

Further, the amine derivative represented by the general formula (III) shown in the formula (2) can be optionally substituted by the general formula (VII)
)) Can be produced after protecting the amino group of the amino acid with the amino group protecting group used in peptide synthesis.

Examples of the amine derivative represented by the general formula (III) used in this step include, for example, L-O- (benzyl) serine ethyl ester, L-S- (2-phenylethyl) cysteine methyl ester, L-S -(3-phenylpropyl) cysteine methyl ester, L-O-
(3-phenylpropyl) serine ethyl ester, L-
O- (3-thienylmethyl) serine ethyl ester, L
-S- (diphenylmethyl) cysteine methyl ester, LS- (cyclohexylmethyl) cysteine ethyl ester, LS- (cyclopentyl) cysteine ethyl ester, LS- (2-thienylmethyl) cysteine methyl ester, L- S- (3-thienylmethyl)
Cysteine ethyl ester, LS- (1-naphthylmethyl) cysteine ethyl ester, LS- (2-naphthylmethyl) cysteine ethyl ester, LS- (2
-Chlorobenzyl) cysteine ethyl ester and the like.

In this step, the compound represented by the general formula (IV)
Is obtained by converting the carboxyl group of the carboxylic acid derivative represented by the general formula (II) into, for example, an active ester compound, a carboxylic acid halide compound, an acid anhydride, and the like. It can be produced by reacting in a solvent in the presence of the amine derivative represented by the above general formula (III).

[Second Step] This step is carried out according to the general formula (IV)
Is reduced to produce an alcohol derivative represented by the general formula (V).

As the reducing agent for carrying out this step,
Examples thereof include boron compounds such as sodium borohydride and lithium borohydride.

The reducing agent is used in an amount of 1 to 4 equivalents per 1 mol of the ester derivative represented by the above general formula (IV). The reaction is preferably carried out in an inert solvent, for example, water, alcohols such as methanol and ethanol, ethers such as ether, THF, dimethoxyethane and dioxane, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and benzene. And aromatic hydrocarbons such as toluene and xylene can be used alone or in combination. The reaction can be carried out at -20C to 50C.

[Third Step] This step is performed according to the general formula (V)
Oxidizes the alcohol derivative represented by the general formula (I) to produce the aldehyde derivative represented by the general formula (I). The oxidation method for carrying out this step is an active dimethyl sulfoxide (DMSO) oxidation method, in which dicyclohexylcarbodiimide, phosphorus pentoxide, pyridine-sulfur trioxide complex, oxalyl chloride, acetic anhydride, Trifluoroacetic anhydride or the like can be used. The amount of the oxidizing agent used is based on 1 mol of the alcohol derivative represented by the general formula (V).
1-4 equivalents can be used.

The reaction is preferably carried out in an inert solvent. For example, halogenated hydrocarbons such as dichloromenthane, dichloroethane and chloroform, DMSO and the like can be used. The reaction can be carried out at -20C to 30C.

[Fourth Step] This step is performed according to the general formula (II)
The alcohol derivative represented by the general formula (V) is produced by reacting the carboxylic acid derivative represented by the general formula (VI) with the amino alcohol derivative represented by the general formula (VI) in the presence of a condensing agent.

This step can be carried out using the same condensing agent, reaction conditions and reaction solvent as in the first step.

The amino alcohol derivative represented by the general formula (VI), which is a raw material in this step, can be produced, for example, from the amino acid represented by the general formula (VII) according to the reaction formula shown in the formula 3.

Equation 3

[0041]

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(Wherein R ¹ , X and n are the same as described above, and R ⁶ is a protecting group for an amino group.) The amino alcohol derivative represented by the above general formula (VI) used in this step For example, (2R) -2-amino-3- (2
-Fluorobenzylthio) propanol, (2R) -2
-Amino-3- (3-chlorobenzylthio) propanol, (2R) -2-amino-3- (4-chlorobenzylthio) propanol, (2R) -2-amino-3- (3
-Fluorobenzylthio) propanol, (2R) -2
-Amino-3- (2-methoxybenzylthio) propanol, (2R) -2-amino-3- (3-fluorobenzylthio) propanol, (2R) -2-amino-3-
(3-methoxybenzylthio) propanol, (2R)
-2-amino-3- (4-methoxybenzylthio) propanol, (2R) -2-amino-3- (3-nitrobenzylthio) propanol, (2R) -2-amino-3
-(4-nitrobenzylthio) propanol, (2S)
-2-amino-4-phenoxybutanol, (2S)-
2-amino-4- (phenylthio) butanol, (2
S) -2-Amino-3- (2-chlorobenzyloxy)
Propanol, (2S) -2-amino-4- (2-fluorophenoxy) butanol, (2S) -2-amino-
4- (3-fluorophenoxy) butanol, L-2-
Amino-4- (2-chlorophenoxy) butanol,
(2S) -2-amino-4- (3-chlorophenoxy)
Butanol, (2S) -2-amino-4-benzylthiobutanol, (2S) -2-amino-4- (2-fluorobenzylthio) butanol, (2S) -2-amino-
4- (2-chlorobenzylthio) butanol, (2S)
-2-amino-4- (2-fluorophenylthio) butanol, (2S) -2-amino-4- (2-chlorophenylthio) butanol, (2S) -2-amino-4-
(4-chlorophenylthio) butanol, (2S) -2
-Amino-4- (2-chlorobenzyloxy) butanol, (2S) -2-amino-4- (2-fluorobenzyloxy) butanol, (2S) -2-amino-4-
(3-Nitrobenzyloxy) butanol and the like can be mentioned.

The carboxylic acid derivative represented by the general formula (II), which is a starting material in this step, is converted into, for example, an active ester compound, a carboxylic acid halide compound, an acid anhydride and the like in the first step. After that, it can also be produced as an alcohol derivative represented by the general formula (V).

The above general formula (V) produced by this step
The aldehyde derivative represented by the general formula (I) can be produced from the alcohol derivative represented by the formula (I) according to the third step.

[0045]

As shown in the test examples, the aldehyde derivatives of the present invention represented by the above general formula (I) have no specific inhibitory activity against proteases such as trypsin and α-chymotrypsin, and all have excellent specific calpain activity inhibitory activity. In addition, since it has a platelet aggregation inhibitory action, it is useful for treating ischemic diseases. In addition to oral administration, these compounds can be administered intravenously, subcutaneously or intramuscularly. For this purpose, these compounds can be used in various dosage forms such as tablets, capsules, liquids or suppositories.

[0046]

The present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples.

Reference Example 1 L-O- (benzyl) serine ethyl ester hydrochloride (compound (1)) 25 g (8.5 mmol) of L-N- (t-butoxycarbonyl) -O- (benzyl) serine 1 ml of concentrated hydrochloric acid was added to the ethanol solution, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure of the reaction solution, and 1.3 ml (17 mmol) of thionyl chloride was added to an ethanol solution of the obtained residue, followed by stirring at room temperature overnight.
The solvent was distilled off from the reaction solution under reduced pressure to give the title compound (1) (2.01).
g (91.6% yield).

NMR (δ, CD ₃ OD): 7.30-7.36 (m,
5H), 4.59 (dd, J = 31.74Hz, J = 12.15Hz, 2H), 4.24-4.31 (m, 3
H), 3.93 (dd, J = 10.53Hz, J = 4.29Hz, 1H), 3.82 (dd, J = 10.65H
z, J = 3.33 Hz, 1H), 1.27 (t, J = 7.17 Hz, 3H) (Reference Example 2) L-S- (2-phenylethyl) cysteine methyl ester hydrochloride (compound (2)) Cysteine hydrochloride aqueous solution 4.85 g (29.28 mmol) of Japanese product
Was added to 200 ml of a methanol solution of 4.74 g of sodium methoxide under ice cooling, followed by stirring at room temperature for 1 hour. A methanol solution of 5.55 g (30 mmol) of 2-bromoethylbenzene was added dropwise to the reaction solution, and the mixture was stirred for 1 hour under ice cooling. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in water and washed with diethyl ether. The aqueous layer was neutralized with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, ethanol and diethyl ether, and dried to obtain 5.37 g (yield: 85.9%) of LS-phenylethylcysteine. 5.3 g of the above compound obtained
(23.5 mmol) in methanol (200 ml) was added dropwise 8.6 ml of thionyl chloride under ice-cooling, and the reaction solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with diethyl ether, dried and dried to give the title compound (2) 6.
27 g (96.3% yield) were obtained.

NMR (δ, CD ₃ OD): 7.20-7.31 (m,
5H), 4.25 (dd, J = 7.26Hz, J = 4.23Hz, 1H), 3.83 (s, 3H), 3.12
(dd, J = 14.49Hz, J = 4.23Hz, 1H), 3.00 (dd, J = 14.54Hz, J = 7.2
7Hz, 1H), 2.82-2.94 (m, 4H) (Reference Example 3) L-S- (3-phenylpropyl) cysteine methyl ester hydrochloride (Compound (3)) Cysteine hydrochloride hydrate according to Reference Example 2 4.85g
(29.28 mmol) sodium methoxide 4.75 g
(87.84 mmol), 3-bromopropylbenzene 5.
Using 97 g (30 mmol) and 6.7 ml of thionyl chloride, 5.196 g of the title compound (3) was obtained.

NMR (δ, CD ₃ OD): 7.16-7.30 (m,
5H), 4.27 (dd, J = 6.57Hz, J = 4.18Hz, 1H), 3.82 (s, 3H), 3.15
(dd, J = 14.54Hz, J = 4.18Hz, 1H), 3.03 (dd, J = 14.49Hz, J = 7.5
4Hz, 1H), 2.73 (t, J = 7.33Hz, 2H), 2.58 (t, J = 7.54Hz, 2H), 1.
86-1.97 (m, 2H) (Reference Example 4) L-O- (3-phenylpropyl) serine ethyl ester hydrochloride (compound (4)) LN- (t-butoxycarbonyl) serine 3 g (1
1.28 g (32 mmol) of 60% oily sodium hydride was added to an anhydrous dimethylformamide solution (4.6 mmol) under ice-cooling and stirring.
l) was added, and the mixture was returned to room temperature and stirred for 2 hours. Then, 3.18 g (16 mmol) of 3-bromopropylbenzene was added, and the mixture was stirred overnight. The reaction solution is concentrated under reduced pressure, the residue is dissolved in water, washed with diethyl ether, the aqueous layer is acidified with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, the organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue obtained by evaporation was dissolved in ethanol, concentrated hydrochloric acid was added, and the mixture was stirred overnight, and then thionyl chloride was added.
ml and stirred overnight. The crystals obtained by evaporating the solvent under reduced pressure were washed with diethyl ether and dried, and then the title compound (4) 1.
13 g were obtained.

NMR (δ, CD ₃ OD): 7.15-7.28 (m,
5H), 4.32 (q, J = 6.52Hz, 2H), 4.25 (t, J = 1.68Hz, 1H), 3.92 (d
d, J = 10.91Hz, J = 4.40Hz, 1H), 3.82 (dd, J = 10.04Hz, J = 2.82H
z, 1H), 3.44-3.59 (m, 2H), 2.67 (t, J = 7.32,2H), 1.85-1.95
(m, 2H), 1.32 (t, J = 7.49,3H) (Reference Example 5) LO- (thiophen-3-ylmethyl)
Serine ethyl ester hydrochloride (compound (5)) 40 g of L-Boc-Ser-OH (1
9.5 mmol) 172 g of 60% oily sodium hydride (4
3 mmol), 4.44 g of 3-bromomethylthiophene (2
5 mmol), 2.2 g of concentrated hydrochloric acid and 2.3 ml of thionyl chloride to obtain 1.25 g of the title compound (5).

NMR (δ, CD ₃ OD): 7.36-7.42 (m,
2H), 7.08-7.10 (m, 1H), 4.60 (q, J = 12.21Hz, 2H), 4.27 (q, J =
7.11Hz, 1H), 4.21 (t, J = 3.18Hz, 1H), 3.90 (dd, J = 4.32Hz, J =
9.87Hz, 1H), 3.81 (dd, J = 3.27Hz, J = 10.47Hz, 1H), 1.27 (t, J
(7.11 Hz, 3H) (Reference Example 6) L-S- (diphenylmethyl) cysteine methyl ester hydrochloride (compound (6)) L-cysteine hydrochloride hydrate 3.0 g (17.1 mmol)
And 3.15 g (17.1 mmol) of diphenylmethanol were added to 40 ml of trifluoroacetic acid, followed by stirring at room temperature for 1 hour.
The trifluoroacetic acid was distilled off under reduced pressure, and diethyl ether was added to the residue for crystallization. Obtained. Thionyl chloride (1.0 ml) was added dropwise to a methanol solution of the obtained compound (1.0 g, 3.5 mmol) under ice-cooling. After the dropwise addition, the reaction solution was raised to room temperature and stirred overnight. The crystals obtained by evaporating the solvent under reduced pressure were washed with diethyl ether to give the title compound (6) 1.
11 g (yield ~ 100%) were obtained.

NMR (δ, CDCl ₃ ): 7.41-7.44 (m,
4H), 7.15-7.29 (m, 6H), 5.42 (s, 1H), 4.22-4.32 (m, 1H), 3.6
1 (s, 3H), 2.98-3.03 (m, 2H), 2.78-2.89 (m, 2H) (Reference Example 7) L-S- (cyclohexylmethyl) cysteine ethyl ester hydrochloride (Compound (7)) Reference Example The title compound (7) was obtained in the same manner as in Example 2, except that cyclohexylmethyl bromide was used instead of 2-bromoethylbenzene.

NMR (δ, CDCl ₃ ): 4.35-4.39 (m,
1H), 4.30 (q, J = 7.17Hz, 2H), 3.24 (d, J = 5.22Hz, 2H), 2.50 (d
d, J = 6.90Hz, J = 3.18,2H), 2.20-2.65 (m, 2H), 1.38-1.88 (m,
5H), 1.33 (t, J = 14.28, J = 7.17, 3H), 0.87-1.28 (m, 6H) (Reference Example 8) L-S- (cyclopentyl) cysteine ethyl ester hydrochloride (Compound (8)) Reference The title compound (8) was obtained according to Example 2 using cyclopentyl bromide instead of 2-bromoethylbenzene.

NMR (δ, CD ₃ OD): 4.44 (t, J = 5.1
9Hz, 1H), 4.32 (t, J = 6.99Hz, 2H), 4.27-4.29 (m, 1H), 3.31-
3.46 (m, 4H), 3.17 (dd, J = 17.19, J = 4.77,1H), 3.07 (dd, J = 1
3.91, J = 6.99,1H), 2.00-2.11 (m, 1H), 1.72-1.81 (m, 1H), 1.
46-1.68 (m, 2H), 1.35 (t, J = 7.20 Hz, 3H) (Reference Example 9) L-S- (thiophen-2-ylmethyl)
Cysteine methyl ester hydrochloride (compound (9)) The title compound (9) was obtained in the same manner as in Reference Example 2 except that 2-chloromethylthiophene was used instead of 2-bromoethylbenzene.

NMR (δ, CD ₃ OD): 7.34 (dd, J = 5.
26Hz, J = 1.36Hz, 1H), 7.04 (d, J = 4.56Hz, 1H), 6.95 (dd, J = 5.
04Hz, J = 1.62Hz, 1H), 4.22 (dd, J = 7.92Hz, J = 4.5Hz, 1H), 4.0
6 (d, J = 3.31Hz, 2H), 3.84 (s, 3H), 3.10 (dd, J = 14.81Hz, J = 4.
56Hz, 1H), 2.96 (dd, J = 14.92Hz, J = 8.03Hz, 1H) (Reference Example 10) LS- (thiophen-3-ylmethyl) cysteine ethyl ester hydrochloride (compound (1
0)) The title compound (10) was obtained in the same manner as in Reference Example 2 except that 3-bromomethylthiophene was used instead of 2-bromoethylbenzene.

NMR (δ, CD ₃ OD): 7.41 (dd, J = 4.
95Hz, J = 2.01Hz, 1H), 7.32 (br, s, 1H), 7.12 (d, J = 4.89Hz, 1
H), 4.29 (q, J = 7.26Hz, 2H), 4.14 (dd, J = 8.04Hz, J = 3.57Hz, 1
H), 3.87 (s, 2H), 3.03 (dd, J = 14.76Hz, J = 4.5Hz, 1H), 2.90 (d
d, J = 14.82 Hz, J = 8.13 Hz, 1H), 1.31 (t, J = 7.23 Hz, 3H) (Reference Example 11) L-S- (1-naphthylmethyl) cysteine ethyl ester hydrochloride (compound (11 )) The title compound (11) was obtained in the same manner as in Reference Example 2, except that 1-naphthylmethyl bromide was used instead of 2-bromoethylbenzene.

NMR (δ, CD ₃ OD): 8.18 (d, J = 8.3
7Hz, 1H), 7.80-7.90 (m, 2H), 7.35-7.58 (m, 4H), 4.33 (s, 2
H), 4.17-4.29 (m, 3H), 3.04 (dd, J = 4.44Hz, J = 9.72,1H), 2.9
5 (dd, J = 7.80Hz, J = 14.64Hz, 1H), 1.25 (t, J = 7.02Hz, 3H) (Reference Example 12) L-S- (2-naphthylmethyl) cysteine ethyl ester hydrochloride (compound (12)) The title compound (12) was obtained in the same manner as in Reference Example 2 except that 2-naphthylmethyl bromide was used instead of 2-bromoethylbenzene.

NMR (δ, CD ₃ OD): 7.81 to 7.88 (m,
4H), 7.47-7.55 (m, 3H), 4.21-4.25 (m, 2H), 4.13-4.20 (m, 1
H), 4.00 (s, 2H), 3.01 (dd, J = 9.78Hz, J = 4.38Hz, 1H), 2.89 (d
d, J = 8.19 Hz, J = 6.39 Hz, 1 H), 1.22 (t, J = 7.05 Hz, 3 H) (Reference Example 13) LS- (2-chlorobenzyl) cysteine ethyl ester hydrochloride (compound (13 )) The title compound (13) was obtained in the same manner as in Reference Example 2 except that 2-chlorobenzyl chloride was used instead of 2-bromoethylbenzene.

NMR (δ, CD ₃ OD): 7.41-7.48 (m,
2H), 7.28-7.31 (m, 2H), 4.30 (q, J = 7.33Hz, 2H), 4.25-4.29
(m, 1H), 3.12 (dd, J = 14.71Hz, J = 4.45Hz, 1H), 2.97 (dd, J = 1
4.65 Hz, J = 7.86 Hz, 1 H), 1.31 (t, J = 7.16 Hz, 3 H) (Reference Example 14) (2R) -2-amino-3 (2-fluorobenzylthio) propanol (compound (14)) To a methanol solution of sodium methoxide prepared from 12.0 g (519 mmol) of metallic sodium and 700 ml of methanol, 30.4 g of L-cysteine hydrochloride hydrate (1
73 mmol) was added. Then, 25.0 g (173 mmol) of 2-fluorobenzyl chloride was added dropwise, and the mixture was further stirred at room temperature overnight. The residue obtained by distilling off methanol under reduced pressure was dissolved in water, washed twice with ether, concentrated hydrochloric acid was added (pH = 7), and the precipitated crystals were collected by filtration, washed with water, ethanol and diethyl ether, and then reduced in pressure. Dry under (2R)-
29.7 g (yield 74.8%) of 2-amino-3 (2-fluorobenzylthio) propionic acid was obtained. 5. To a solution of 0.58 g (26.4 mmol) of lithium borohydride in anhydrous tetrahydrofuran was added chlorotrimethylsilane.
7 ml (52.8 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 2.02 g (8.8 g) of (2R) -2-amino-3 (2-fluorobenzylthiopropionic acidide was added to the mixed solution.
mmol) and stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue obtained is 1N-
It was dissolved in aqueous sodium hydroxide solution and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.69 g (yield: 89.4%) of the title compound (14).

NMR (δ, CDCl ₃ ): 7.19-7.36 (m,
2H), 7.00-7.12 (m, 2H), 3.75 (s, 2H), 3.65 (dd, J = 10.86Hz, J
= 3.78Hz, 1H), 3.42 (dd, J = 10.74Hz, J = 6.45Hz, 1H), 3.00-3.
10 (m, 1H), 2.80 (br, s, 3H), 2.62 (dd, J = 13.56Hz, J = 4.92Hz,
1H), 2.45 (dd, J = 13.35 Hz, J = 8.22 Hz, 1H) (Reference Example 15) (2R) -2-amino-3 (3-chlorobenzylthio) propanol (Compound (15)) Reference Example 14 The title compound (15) was obtained using 3-chlorobenzyl bromide instead of 2-fluorobenzyl chloride according to a method similar to that described above.

NMR (δ, CDCl ₃ ): 7.15-7.35 (m,
4H), 3.68 (s, 2H), 3.64 (d, J = 3.52Hz, 1H), 3.44 (dd, J = 6.45H
z, J = 10.85Hz, 1H), 2.98 (br s, 4H), 2.60 (dd, J = 5.21Hz, J = 1
(3.4 Hz, 1H), 2.45 (dd, J = 8.08 Hz, J = 13.45 Hz, 1H) (Reference Example 16) (2R) -2-amino-3 (4-chlorobenzylthio) propanol (compound (16)) The title compound (16) was obtained in the same manner as in Reference Example 14 except that 4-chlorobenzyl chloride was used instead of 2-fluorobenzyl chloride.

NMR (δ, CDCl ₃ ): 7.26 (q, J = 8.5
2,4H), 3.68 (s, 2H), 3.60 (dd, J = 4.02Hz, J = 10.75Hz, 1H), 3.
38 (dd, J = 6.46Hz, J = 10.8Hz, 1H), 2.96 (br s, 1H), 2.54 (dd,
J = 4.77Hz, J = 13.18Hz, 1H), 2.36 (dd, J = 8.25Hz, J = 13.35Hz,
1H), 2.24 (br s, 3H) (Reference Example 17) L-2-amino-3 (3-fluorobenzylthio) propanol (compound (17)) Instead, 3-fluorobenzyl chloride was used to obtain the title compound (17).

NMR (δ, CDCl ₃ ): 7.21 to 7.28
(m, 1H), 6.89-7.10 (m, 3H), 4.76 (s, 3H), 3.76 (dd, J = 3.42
Hz, J = 11.5Hz, 1H), 3.72 (s, 2H), 3.57 (dd, J = 7.82Hz, J = 12.5
9 Hz, 1H), 3.25 (brs, 1H), 2.62 (d, J = 7.05 Hz, 2H) (Reference Example 18) (2R) -2-amino-3 (4-fluorobenzylthio) propanol (compound (18 )) The title compound (18) was obtained in the same manner as in Reference Example 14 except that 4-fluorobenzyl chloride was used instead of 2-fluorobenzyl chloride.

NMR (δ, CDCl ₃ ): 7.25 to 7.30
(m, 2H), 6.97 〜7.03 (m, 2H), 3.69 (s, 2H), 3.60 (dd, J = 4.23
Hz, J = 10.74Hz, 1H), 3.37 (dd, J = 6.57Hz, J = 10.74Hz, 1H), 2.
95 (brs, 1H), 2.55 (dd, J = 4.93Hz, J = 13.29Hz, 1H), 2.01 (br
d, J = 10.25 Hz, 3H), 2.36 (dd, J = 8.31 Hz, 13.30 Hz, 1H) (Reference Example 19) (2R) -2-amino-3 (2-methoxybenzylthio) propanol (compound (19 )) The title compound (19) was obtained in the same manner as in Reference Example 14 except that 2-methoxybenzyl chloride was used instead of 2-fluorobenzyl chloride.

NMR (δ, CDCl ₃ ): 7.21 to 7.26
(m, 2H), 6.86 to 6.94 (m, 2H), 3.85 (s, 3H), 3.74 (s, 2H), 3.6
2 (dd, J = 10.74Hz, J = 4.13Hz, 1H), 3.37 (dd, J = 10.74Hz, J = 6.
73,1H), 2.97-3.05 (m, 1H), 2.62 (dd, J = 13.51Hz, J = 4.83Hz,
1H), 2.40 (dd, J = 13.57 Hz, J = 8.31 Hz, 1H), 2.08 (brs, 3H) (Reference Example 20) (2R) -2-amino-3 (3-methoxybenzylthio) propanol ( Compound (20)) The title compound (20) was obtained in the same manner as in Reference Example 14 except that 3-methoxybenzyl chloride was used instead of 2-fluorobenzyl chloride.

NMR (δ, CDCl ₃ ): 7.22 (t, J = 8.2
5,1H), 6.88 (d, J = 6.68Hz, 1H), 6.86 (s, 1H), 6.79 (dd, J = 2.0
6Hz, J = 7.48Hz, 1H), 3.80 (s, 3H), 3.68 (s, 2H), 3.58 (dd, J =
4.18Hz, J = 10.8Hz, 1H), 3.36 (dd, J = 6.62Hz, J = 10.75Hz, 1
H), 2.90 to 3.00 (m, 1H), 2.56 (dd, J = 4.88 Hz, J = 13.29 Hz, 1
H), 2.36 (dd, J = 8.19 Hz, J = 13.35 Hz, 1H), 2.11 (brs, 3H) (Reference Example 21) (2R) -2-amino-3 (4-methoxybenzylthio) propanol ( Compound (21)) The title compound (21) was obtained in the same manner as in Reference Example 14 except that 4-methoxybenzyl chloride was used instead of 2-fluorobenzyl chloride.

NMR (δ, CDCl ₃ ): 7.22 (d, J = 8.6
3Hz, 2H), 6.85 (d, J = 8.63Hz, 2H), 3.80 (s, 3H), 3.67 (s, 2H),
3.59 (dd, J = 4.13Hz, J = 10.74Hz, 1H), 3.36 (dd, J = 6.62Hz, J =
10.75Hz, 1H), 2.90-2.98 (m, 1H), 2.55 (dd, J = 4.88Hz, J = 1
3.29Hz, 1H), 2.36 (dd, J = 8.24Hz, J = 13.29Hz, 1H), 1.99 (s, 3
H) (Reference Example 22) (2R) -2-Amino-3 (3-nitrobenzylthio) propanol (compound (22)) In the same manner as in Reference Example 14, 3-nitrobenzyl was used instead of 2-fluorobenzyl chloride. The title compound (22) was obtained using chloride.

NMR (δ, CDCl ₃ ): 8.20 (s, 1H),
8.13 (d, J = 8.24Hz, 1H), 7.67 (d, J = 7.75Hz, 1H), 7.51 (t, J =
7.87Hz, 1H), 3.81 (s, 2H), 3.62 (dd, J = 10.75Hz, J = 4.24Hz, 1
H), 3.42 (dd, J = 10.75Hz, J = 6.35Hz, 1H), 3.00-3.08 (m, 1H),
2.58 (dd, J = 13.18Hz, J = 4.94Hz, 1H), 2.41 (dd, J = 13.23Hz, J
= 8.13Hz, 1H), 2.05 (brs, 3H) (Reference Example 23) (2R) -2-amino-3 (4-nitrobenzylthio) propanol (compound (23)) L-cysteine hydrochloride hydrate 5 .27 g (30 mmol) were added to a 1N aqueous solution of sodium hydroxide, and then a solution of 5.15 g (30 mmol) of 4-nitrobenzyl chloride in dioxane was added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made weakly acidic with concentrated hydrochloric acid, and cooled. Crystals precipitated were filtered, washed with ethanol and then with diethyl ether, dried under reduced pressure, and dried under reduced pressure.
(4-nitrobenzylthio) propionic acid3.
55 g (45.9% yield) were obtained. The title compound (23) was obtained by a method similar to that in Reference Example 14 for the conversion reaction to the alcohol compound.

NMR (δ, CDCl ₃ ): 8.19 (d, J = 8.6
3Hz, 2H), 7.50 (d, J = 8.69Hz, 2H), 3.80 (s, 2H), 3.60 (dd, J =
4.18Hz, J = 10.74Hz, 1H), 3.40 (dd, J = 6.35Hz, J = 10.74Hz, 1
H), 2.92-3.02 (m, 1H), 2.57 (dd, J = 4.94Hz, J = 13.19Hz, 1H),
2.39 (dd, J = 8.13 Hz, J = 13.18 Hz, 1H), 2.01 (s, 3H) (Reference Example 24) (2S) -2-amino-4-phenyloxybutanol hydrochloride (compound (24)) ( Tetrahedron Letters, Volume 20,
2243, synthesized according to the method of 1978) LN
To a solution of potassium salt of-(t-butoxycarbonyl) -homoserine 142 g (0.59 mol) in anhydrous dimethylformamide, 320 g (2.94 mol) of ethyl bromide was added dropwise, and the mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure,
The obtained residue was dissolved in water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 44.5 g (yield: 31%) of LN- (t-butoxycarbonyl) -homoserine ethyl ester. 6.18 g of the compound obtained above (25
3.44 g (30 mmol) of triethylamine and 3.04 g (30 mmol) of triethylamine were added with 3.44 g (30 mmol) of methanesulfonyl chloride under ice-cooling with stirring. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.12 g of a methanesulfonate compound (yield to
100%). To a solution of 0.88 g of phenol in anhydrous dimethylformamide was added 60% oily sodium hydride.
After adding 35 g and stirring for 1 hour, a dimethylformamide solution of 2.55 g (7.83 mmol) of the methanesulfonate obtained in the previous reaction was added dropwise, and the mixture was stirred at room temperature overnight. Saturated aqueous NH ₄ Cl was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution and then with water. After drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue obtained is purified by silica gel column chromatography to obtain LN- (t-
2.13 g (yield 84%) of (butoxycarbonyl) -O-phenylhomoserine ethyl ester was obtained.

NMR (δ, CDCl ₃ ): 7.20-7.30 (m,
2H), 6.83-6.97 (m, 3H), 5.34-5.42 (m, 1H), 4.45-4.52 (m, 1
H), 4.18 (q, J = 7.22Hz, 2H), 4.04 (t, J = 6.08Hz, 2H), 2.20-2.
37 (m, 2H), 1.44 (s, 9H), 1.25 (t, J = 7.06 Hz, 3H) To a solution of 2.10 g (6.5 mmol) of the above compound in tetrahydrofuran was added 0.28 g of lithium borohydride, followed by cooling and stirring. Under methanol was added dropwise and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the solvent was distilled off under reduced pressure.
An aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 4N-ethyl acetate hydrochloride and stirred for 1 hour. The solvent was distilled off under reduced pressure, and 0.64 g of the title compound (24) was obtained (yield: 46).
%).

Reference Example 25 (2S) -2-Amino-4
-(Phenylthio) butanol hydrochloride (compound (2
5)) LN- (t-butoxycarbonyl)-using benzyl bromide instead of ethyl bromide and thiophenol instead of phenol according to the method of Reference Example 24.
S-phenylhomocysteine benzyl ester was obtained.

NMR (δ, CDCl ₃ ): 7.16-7.37 (m,
10H), 5.15 (d, J = 3.31Hz, 2H), 5.09-5.20 (m, 1H), 4.47-4.53
(m, 1H), 2.90 (dt, J = 6.3Hz, J = 2.11,2H), 2.10-2.20 (m, 1H),
1.89-2.00 (m, 1H), 1.43 (s, 9H) Further, the title compound (25) was obtained in the same manner as in Reference Example 24.

Reference Example 26 (2R) -2-amino-3
-(2-chlorobenzyloxy) -propanol hydrochloride (compound (26)) 7.0 g of LN- (t-butoxycarbonyl) serine
(34 mmol) in 60% anhydrous dimethylformamide solution
3.0 g of oily sodium hydride was added, and the mixture was stirred at room temperature for 3 hours. Then, 6.0 g of 2-chlorobenzyl chloride (3
7 mmol), and the mixture was stirred at room temperature overnight. The residue obtained after evaporating the solvent under reduced pressure was dissolved in a mixed solvent of ethyl acetate-1N-hydrochloric acid, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to remove L-N- (t- 4.3 g of butoxycarbonyl) -O- (2-chlorobenzyl) -serine were obtained (yield 38%). 0.93 g of ethyl chlorocarbonate was added dropwise to a solution of 2.15 g (6.5 mmol) of the above compound and triethylamine in tetrahydrofuran while cooling with salt-ice, and the mixture was stirred for 2 hours. Precipitated crystals were removed by filtration, and sodium borohydride and then methanol were added dropwise to the filtrate under ice-cooling and stirring, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, a 1N aqueous hydrochloric acid solution was added to an aqueous solution of the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate, evaporated, and purified by silica gel column chromatography to obtain 0.81 g of an alcohol. 0.8 g of the obtained alcohol compound was dissolved in 4N-ethyl acetate hydrochloride, stirred at room temperature for 30 minutes, and the solvent was distilled off.
55 g (19% yield) were obtained.

NMR (δ, CD ₃ OD): 7.53-7.56 (m,
1H), 7.39-7.42 (m, 1H), 7.30-7.35 (m, 2H), 4.70 (s, 2H), 3.6
7-3.82 (m, 4H), 3.42-3.49 (m, 1H) (Reference Example 27) (2S) -2-amino-4- (2-fluorophenyloxy) butanol hydrochloride (compound (2
7)) LN- (t-butoxycarbonyl) -O- (2-fluorophenyl) -homoserine ethyl ester was obtained in the same manner as in Reference Example 24 except that 2-fluorophenol was used instead of phenol.

NMR (δ, CDCl ₃ ): 6.85-7.10 (m,
4H), 5.40-5.46 (m, 1H), 4.42-4.51 (m, 1H), 4.22 (q, J = 7.0H
z, 2H), 4.12 (q, J = 5.48Hz, 2H), 2.23-2.41 (m, 2H), 1.44 (s, 9
H), 1.26 (t, J = 7.16 Hz, 3H) Further, the title compound (27) was obtained in the same manner as in Reference Example 24.

Reference Example 28 (2S) -2-Amino-4
(3-Fluorophenyloxy) butanol hydrochloride (compound (28)) L-N- (t-butoxycarbonyl) -O- (3 -Fluorophenyl) -homoserine ethyl ester was obtained.

NMR (δ, CDCl ₃ ): 7.11-7.24 (m,
1H), 6.55-6.69 (m, 3H), 5.31-5.38 (m, 1H), 4.45-4.51 (m, 1
H), 4.20 (q, J = 7.16Hz, 2H), 4.03 (t, J = 6.02Hz, 2H), 2.20-2.
38 (m, 2H), 1.44 (s, 9H), 1.26 (t, J = 7.11 Hz, 3H) The title compound (28) was obtained in the same manner as in Reference Example 24.

Reference Example 29 (2S) -2-Amino-4
(2-Chlorophenyloxy) butanol hydrochloride (compound (29)) LN- (t) using benzyl bromide instead of ethyl bromide and 2-chlorophenol instead of phenol according to the method of Reference Example 24. -Butoxycarbonyl) -O- (2-chlorophenyl) -homoserine benzyl ester was obtained.

NMR (δ, CDCl ₃ ): 7.30-7.36 (m,
6H), 7.18 (dt, J = 6.67Hz, J = 1.6,1H), 6.90 (dt, J = 6.3Hz, J =
1.35Hz, 1H), 6.80 (d, J = 8.24Hz, 1H), 5.80-5.83 (m, 1H), 5.1
8 (d, J = 2.17Hz, 2H), 4.55-4.62 (m, 1H), 4.07-4.14 (m, 1H),
3.95-4.00 (m, 1H), 2.40-2.50 (m, 2H), 1.43 (s, 9H) Further, the title compound (29) was obtained in the same manner as in Reference Example 24.

Reference Example 30 (2S) -2-amino-4
(3-Chlorophenyloxy) butanol hydrochloride (compound (30)) LN- (t) using benzyl bromide instead of ethyl bromide and 3-chlorophenol instead of phenol according to the method of Reference Example 24. -Butoxycarbonyl) -O- (3-chlorophenyl) -homoserine benzyl ester was obtained.

NMR (δ, CDCl ₃ ): 7.34 (s, 5H),
7.16 (t, J = 8.14Hz, 1H), 6.92 (dd, J = 5.53Hz, J = 1.96Hz, 1H),
6.80 (s, 1H), 6.69 (dd, J = 6.35Hz, J = 2.01,1H), 5.25-5.30
(m, 1H), 5.18 (d, J = 2.23Hz, 2H), 4.50-4.57 (m, 1H), 3.98 (t,
J = 5.96 Hz, 2H), 2.25-2.37 (m, 2H), 1.43 (s, 9H) Further, the title compound (30) was obtained in the same manner as in Reference Example 24.

Reference Example 31 L-2-Amino-4-benzylthiobutanol (compound (31)) Metallic sodium was added to liquid ammonia cooled to -78 ° C.
g, and after stirring for 30 minutes, homocysteine was added to the reaction solution.
0 g (7.45 mmol) was added and stirred for 30 minutes. Ammonium chloride is added to the reaction solution until blue color of the reaction solution disappears, then 0.69 g (30 mmol) of benzyl bromide is added, and liquid ammonia is evaporated at room temperature. The obtained residue was dissolved in water, washed with diethyl ether, made weakly acidic by adding concentrated hydrochloric acid, and precipitated in a cold place. The obtained crystals were washed successively with water, ethanol and ether, and dried under reduced pressure to obtain 2.8 g (86% yield) of (2S) -2-amino-4-benzylthiobutanoic acid acid.

0.49 g of lithium borohydride (22 mm
ol) in anhydrous tetrahydrofuran, 5.6 ml (44 mmol) of trimethylsilyloxycyclolide was added, and the mixture was stirred at room temperature for 30 minutes. (2S) -2-amino-4- was added to the mixed solution.
2.5 g (11 mmol) of benzylthiobutanoic acid
Was added and stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a 1N aqueous solution of sodium hydroxide and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.0 g (yield: 85.5%) of the title compound (31).

NMR (δ, CDCl ₃ ): 7.22-7.32 (m,
5H), 3.72 (s, 2H), 3.51-3.56 (m, 1H), 3.26-3.30 (m, 1H), 2.9
0-3.00 (m, 1H), 2.42-2.58 (m, 2H), 2.00-2.12 (m, 1H), 1.62-
1.73 (m, 1H), 1.48-1.58 (m, 1H) (Reference Example 32) (2S) -2-amino-4 (2-fluorobenzylthio) butanol (Compound (32)) Method according to Reference Example 31 Using 2-fluorobenzyl bromide instead of benzyl bromide in the title compound (3
2) was obtained.

NMR (δ, CDCl ₃ ): 7.31 to 7.36 (m,
1H), 7.19-7.27 (m, 1H), 7.00-7.12 (m, 2H), 3.75 (s, 2H), 3.5
5 (dd, J = 10.68Hz, J = 3.96Hz, 1H), 3.28 (dd, J = 13.59Hz, J = 7.
49Hz, 1H), 2.89-2.97 (m, 1H), 2.47-2.62 (m, 2H), 1.98 (br
(s, 3H), 1.65-1.76 (m, 1H), 1.49-1.59 (m, 1H) (Reference Example 33) (2S) -2-amino-4 (2-chlorobenzylthio) butanol (Compound (33)) The title compound (33) using 2-chlorobenzyl chloride instead of benzyl bromide according to the method of Reference Example 31
I got

NMR (δ, CDCl ₃ ): 7.33 to 7.39 (m,
2H), 7.19-7.26 (m, 2H), 3.84 (s, 2H), 3.57 (dd, J = 10.69Hz, J
= 4.01Hz, 1H), 3.29 (dd, J = 10.69Hz, J = 7.49Hz, 1H), 2.93-3.
01 (m, 1H), 2.50-2.66 (m, 2H), 2.04 (br s, 3H), 1.66-1.78
(m, 1H), 1.50-1.62 (m, 1H) (Reference Example 34) (2S) -2-amino-4 (2-fluorophenylthio) butanol hydrochloride (Compound (34)) Using the method, benzyl bromide was used instead of ethyl bromide, and 2-fluorothiophenol was used instead of phenol to obtain LN- (t-butoxycarbonyl) -S- (2-fluorophenyl) homocysteine benzyl ester. .

NMR (δ, CDCl ₃ ): 7.18-7.42 (m,
6H), 7.01-7.07 (m, 2H), 5.16 (d, J = 2.66Hz, 2H), 5.09-5.14
(m, 1H), 4.45-4.53 (m, 1H), 2.90 (t, J = 7.49Hz, 2H), 2.06-2.
18 (m, 1H), 1.86-1.98 (m, 1H), 1.43 (s, 9H) Further, the title compound (34) was obtained in the same manner as in Reference Example 24.

Reference Example 35 (2S) -2-amino-4
(2-Chlorophenylthio) butanol hydrochloride (compound (35)) LN- (t) using benzyl bromide instead of ethyl bromide and 2-chlorothiophenol instead of phenol according to the method of Reference Example 24 -Butoxycarbonyl) -S- (2-chlorophenyl) homocysteine benzyl ester was obtained.

NMR (δ, CDCl ₃ ): 7.34 (s, 6H),
7.08-7.23 (m, 3H), 5.17 (d, J = 3.31Hz, 3H), 4.40-4.51 (m, 1
H), 2.90-2.96 (m, 2H), 2.17-2.25 (m, 1H), 1.95-2.05 (m, 1
H), 1.44 (s, 9H) Further, the title compound (35) was obtained by a method similar to that of Reference Example 24.

Reference Example 36 (2S) -2-Amino-4
(4-Chlorophenylthio) butanol hydrochloride (compound (36)) LN- (4-chlorothiophenol) was used in place of ethyl bromide, and 4-chlorothiophenol was used instead of phenol, according to the method of Reference Example 24. (t-butoxycarbonyl) -S- (4-chlorophenyl) homocysteine benzyl ester was obtained.

NMR (δ, CDCl ₃ ): 7.29-7.37 (m,
4H), 7.21 (s, 5H), 5.15 (d, J = 7.16Hz, 2H), 5.10-5.15 (m, 1
H), 4.12-4.19 (m, 1H), 2.84-2.90 (m, 2H), 2.05-2.18 (m, 1
H), 1.86-1.97 (m, 1H), 1.43 (s, 9H) Further, the title compound (36) was obtained in the same manner as in Reference Example 24.

Reference Example 37 (L) -N- [1- (benzyloxycarbonyl) -piperidine-4-carbonyl] leucine (compound (37)) L-leucine ethyl ester hydrochloride 5 g (25.5 mm)
ol) in a chloroform solution (100 ml) under ice-cooling and stirring, 2.58 g (25.5 mmol) of triethylamine, 6.7 g (25.5 mmol) of N- (benzyloxycarbonyl) -piperidine-4-carboxylic acid, 1-ethyl- 3 (3-dimethylaminopropyl) carbodiimide hydrochloride 4.88
g (25.5 mmol) were sequentially added, and the mixture was returned to room temperature and stirred overnight. The reaction solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and treated with LN- [1- (benzyloxycarbonyl) -piperidine-4-carbonyl. 10.1 g (yield 98%) of leucine ethyl ester was obtained.

To a methanol solution of 10.1 g of the ester obtained above was added 1.02 g of sodium hydroxide while stirring with ice cooling.
(25.5 mmol) in water (10 ml) and 3
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in water and washed twice with ether. The aqueous layer was made acidic (pH = 1) by adding concentrated hydrochloric acid, extracted twice with ethyl acetate, and washed with saturated saline. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the title compound (37) 9.3 was obtained.
g (96% yield) was obtained as an oil.

NMR (δ, CDCl ₃ ): 8.80-9.00 (m,
1H), 7.32-7.38 (m, 5H), 6.05-6.15 (m, 1H), 5.14 (s, 2H), 4.5
8-4.68 (m, 1H), 4.16-4.26 (m, 2H), 2.82-2.95 (m, 2H), 2.37-
2.48 (m, 1H), 1.82-1.92 (m, 2H), 1.56-1.75 (m, 5H), 0.95-0.
97 (m, 6H) (Reference Example 38) (L) -N- (N-phenylcarbamoyl) leucine (compound (38)) (L) -leucine ethyl ester hydrochloride 5 g (25.5)
5.16 g (51 mmol) of triethylamine was added to a chloroform solution (200 ml) of ice-cold solution with stirring under ice-cooling, and then 2.76 ml (25.5 mm) of phenyl isocyanate.
ol) in chloroform. After stirring overnight, the reaction solution is washed with 1N-hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated saline solution in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (L) -N- (N-phenylcarbamoyl). 5.85 g (82% yield) of leucine ethyl ester was obtained.

A solution of 5.85 g of the above compound in methanol (200 ml) was stirred under ice-cooling with sodium hydroxide 1.
An aqueous solution (10 ml) of 848 g (46 mmol) was added and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in water and washed twice with ether. Concentrated hydrochloric acid was added to the aqueous layer to make it acidic (pH = 1), and the precipitated crystals were collected by filtration, washed successively with water, cold ethanol and ether, and dried, yielding 3.55 g of the title compound (38) (yield 6.5). 7%)
I got

Melting point (° C.): 143.8-145.8 NMR (δ, CD ₃ OD): 7.33 (dd, J = 8.5 Hz, 0.96 Hz, 2
H), 7.25 (t, J = 5.1Hz, 2H), 6.96 (td, J = 8.5Hz, 1.2Hz, 1H), 4.
37 (dd, J = 9.3Hz, 5.1Hz, 1H), 1.51 ~ 1.89 (m, 3H), 0.99 (d, J =
(3.2 Hz, 3H), 0.97 (d, J = 3.0 Hz, 3H) (Reference Example 39) (L) -N- (4-methylbenzenesulfonyl) leucine (compound (39)) 3. 4-methylbenzenesulfonyl chloride instead of acid phenyl ester
Using 86 g, 6.2 g of the title compound (39) was obtained.

Melting point (° C.): 117.2 to 120 NMR (δ, CDCl ₃ ): 7.73 (d, J = 8.3 Hz, 2H), 7.28
(d, J = 8.3Hz, 2H), 5.07 (d, J = 9.7Hz, 1H), 3.86 to 3.99 (m, 1
H), 2.41 (s, 3H), 1.70 ~ 1.85 (m, 1H), 1.45 ~ 1.60 (m, 2H),
0.89 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H) (Reference Example 40) (L) -N-methyl-N- (benzyloxycarbonyl) leucine (compound (40)) 0.92 ml of benzyloxycarbonyl chloride was added to 1 g (6.88 mmol) of a commercially available LN-methylleucine aqueous solution (10 ml) of 1N sodium hydroxide under ice-cooling and stirring.
A benzene solution (88 ml) and a 1N aqueous solution of sodium hydroxide (10 ml) were simultaneously added dropwise. After returning to room temperature and stirring overnight, the reaction solution was washed twice with ether. The aqueous layer was made acidic (pH = 1) by adding concentrated hydrochloric acid and then extracted with ethyl acetate.
Extracted times. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, 0.46 g of the title compound (40) was obtained.

NMR (δ, CDCl ₃ ): 7.30-7.40 (m,
5H), 5.10-5.23 (m, 2H), 4.92 (t, J = 8.3Hz, 2 / 3H), 4.77 (dd, J
= 10.5Hz, 4.5Hz, 1 / 3H), 2.88 (s, 3H), 1.45-1.82 (m, 3H),
0.86 to 1.05 (m, 6H) (Example 1) LN-benzyloxycarbonylleucine- (2S)-(1-formyl-2-benzyloxy)
Ethylamide (compound (41)) 2.01 g (7.8 mm) of compound (1) synthesized in Reference Example 1
ol) in chloroform suspension (200 ml) under ice cooling and stirring, with 784 mg (7.8 mmol) of triethylamine, L-Cbz-
23 ml (8.5 mmol) of a Len-OH-toluene solution and 1.18 g of 1-hydroxybenztriazole (7.
Then, a solution of 1.76 g (8.525 mmol) of dicyclohexylcarbodiimide in chloroform (50 ml) was added dropwise. After stirring overnight at room temperature, the insolubles were removed by filtration, and the filtrate was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in that order. The product is purified by silica gel column chromatography to give L-
N- (benzyloxycarbonyl) -leucyl-L-
(O-benzyl) -serine ethyl ester was obtained (2.
74, 75%). 1.58 g of the obtained ester compound (3.
4 mmol) in anhydrous tetrahydrofuran (50 ml) was stirred under ice-cooling with lithium borohydride (182 mg, 8.4 mmol).
l) was added and then 3 ml of methanol were added dropwise. After further stirring for 1 hour, 10 ml of water was added dropwise to the reaction solution, and the mixture was concentrated under reduced pressure. 1N-hydrochloric acid was added to the obtained residue to make it acidic (pH =
After 1), the mixture was extracted twice with methylene chloride. The organic layer was washed with a saturated sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate and concentrated, and the residue obtained was recrystallized from benzene-ethyl acetate to give the corresponding alcohol.
965 g (67% yield) were obtained. The obtained alcohol compound 900 mg (2.1 mmol) and triethylamine 850
mg (8.4 mmol) of anhydrous dimethyl sulfoxide solution (1
(0 ml) was added dropwise a solution of 1.33 g (8.4 mmol) of sulfur trioxide pyridine complex (10 ml) in anhydrous dimethyl sulfoxide with stirring at room temperature. After stirring for 30 minutes, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic layer was washed successively with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.425 g (yield 47%) of the title compound (41) as an oil.

NMR (δ, CDCl ₃ ): 9.56 (s, 1H),
7.25-7.36 (m, 10H), 6.75-6.95 (m, 1H), 5.20-5.22 (m, 1H),
5.11 (s, 2H), 4.55-4.59 (m, 1H), 4.43-4.50 (m, 2H), 4.25-4.
35 (m, 1H), 3.99-4.03 (m, 1H), 3.66-3.70 (m, 1H), 1.49-1.73
(m, 3H), 0.92-0.95 (m, 6H) Rf value: 0.19 (developing solvent A, hexane: ethyl acetate = 1: 1): 0.14 (developing solvent B, methylene chloride: acetone = 1)
0: 1) (Example 2) LN-benzyloxycarbonylleucine- (2R)-(1-formyl-2-benzylthio) ethylamide (compound (42)) Synthesized in Reference Example 1 by a method similar to that in Example 1. The title compound (4) was obtained using 2.2 g of commercially available L-S-benzyl-cysteine ethyl ester hydrochloride instead of the compound (1).
2) 0.14 g was obtained.

Melting point (° C.): 116.8-122.1 NMR (δ, CDCl ₃ ): 9.49 (s, 1H), 7.28-7.34 (m, 1
0H), 6.72-6.79 (m, 1H), 5.11 (s, 2H), 5.17-5.20 (m, 2H), 4.4
8-4.57 (m, 1H), 4.20-4.28 (m, 1H), 3.71 (s, 2H), 2.88 (d, J =
5.86 Hz, 2H), 1.48-1.75 (m, 3H), 0.95 (d, J = 5.97 Hz, 6H) Rf value: 0.35 (developing solvent A): 0.25 (developing solvent B) (Example 3) ) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (2-phenylethylthio)] ethylamide (compound (43)) Compound synthesized in Reference Example 1 by a method similar to that in Example 1. Compound (2) 3.3 synthesized in Reference Example 2 instead of (1)
Using 0.5 g of the title compound (43), 0.57 g of the title compound (43) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.57 (s, 1H),
7.18-7.36 (m, 10H), 6.90-7.00 (m, 1H), 5.15-5.20 (m, 1H),
5.10 (s, 2H), 4.48-4.55 (m, 1H), 4.24-4.27 (m, 1H), 2.77-2.
96 (m, 6H), 1.49-1.71 (m, 3H), 0.92-0.95 (m, 6H) Rf value: 0.30 (developing solvent A): 0.23 (developing solvent B) (Example 4) L -N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3-phenylpropylthio)] ethylamide (compound (44)) Compound (1) synthesized in Reference Example 1 by a method similar to that in Example 1. Instead of compound (3) 3.4 synthesized in Reference Example 3
0.79 g of the title compound (44) was obtained as an oil using 7 g.

NMR (δ, CDCl ₃ ): 9.59 (br s, 1
H), 7.28-7.36 (m, 8H), 7.15-7.21 (m, 2H), 6.90-7.00 (m, 1
H), 5.11 (s, 2H), 5.10-5.20 (m, 1H), 4.50-4.58 (m, 1H), 4.22
-4.30 (m, 1H), 2.95 (br s, 2H), 2.69 (t, J = 7.33Hz, 2H), 2.53
(t, J = 7.32Hz, 2H), 1.84-1.94 (m, 2H), 1.48-1.70 (m, 3H), 0.
94 (d, J = 6.73 Hz, 6H) Rf value: 0.31 (developing solvent A): 0.26 (developing solvent B) (Example 5) LN-benzyloxycarbonylleucine- (2R)-[ 1-formyl-2- (3-phenylpropyloxy)] ethylamide (compound (45)) The compound (4) synthesized in Reference Example 4 in place of the compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1. ) 1.1
Using 3 g, 0.315 g of the title compound (45) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.57 (s, 1H),
7.25-7.36 (m, 8H), 7.14-7.21 (m, 2H), 6.77-6.93 (m, 1H), 5.
20-5.26 (m, 1H), 5.05-5.14 (m, 2H), 4.54-4.59 (m, 1H), 4.27
-4.32 (m, 1H), 3.94-3.98 (m, 1H), 3.61-3.65 (m, 1H), 3.41
(t, J = 6.35Hz, 2H), 2.62 (t, J = 7.92Hz, 2H), 1.79-1.90 (m, 2
H), 1.51-1.79 (m, 3H), 0.93-0.96 (m, 6H) Rf value: 0.18 (developing solvent A): 0.16 (developing solvent B) (Example 6) LN-benzyl Oxycarbonylleucine- (2S)-[1-formyl-2- (thiophene-3
-Ylmethyl) oxy] ethylamide (compound (4
6)) Compound (5) 1.2 synthesized in Reference Example 5 instead of compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1.
Using 0 g, 0.33 g of the title compound (46) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.55 (s, 1H),
7.26-7.34 (m, 6H), 7.18 (s, 1H), 6.97-7.05 (m, 1H), 6.70-6.
93 (m, 1H), 5.12 (s, 2H), 5.10-5.20 (m, 1H), 4.53-4.60 (m, 1
H), 4.49 (s, 2H), 4.22-4.31 (m, 1H), 3.97-4.05 (m, 1H), 3.65
-3.72 (m, 1H), 1.50-1.75 (m, 3H), 0.95 (t, J = 4.45 Hz, 6H) Rf value: 0.21 (developing solvent A): 0.24 (developing solvent B) (implementation Example 7) LN-benzyloxycarbonylleucine- (2R)-(1-formyl-2-diphenylmethylthio) ethylamide (compound (47)) Compound (1) synthesized in Reference Example 1 by a method similar to that in Example 1. Compound (6) 1.1 synthesized in Reference Example 6 instead of
Using 3 g, 0.17 g of the title compound (47) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.44 (s, 1H),
7.21-7.41 (m, 15H), 6.72-6.85 (m, 1H), 5.08-5.18 (m, 4H),
4.46-4.51 (m, 1H), 4.20-4.30 (m, 1H), 2.75-2.92 (m, 2H), 1.
47-1.71 (m, 3H), 0.93-0.95 (m, 6H) Rf value: 0.32 (developing solvent A): 0.25 (developing solvent B) (Example 8) LN-benzyloxycarbonylleucine -(2R)-(1-Formyl-2-cyclohexylmethylthio) ethylamide (Compound (48)) The compound (7) synthesized in Reference Example 7 instead of the compound (1) synthesized in the same manner as in Example 1. 0.74 g of the title compound (48) was obtained as an oil using 53 g.

NMR (δ, CDCl ₃ ): 9.61 (s, 1H),
7.35 (s, 5H), 6.89-6.93 (m, 1H), 5.12 (s, 2H), 5.10-5.20 (s,
1H), 4.51-4.57 (m, 1H), 4.22-4.30 (m, 1H), 2.92-2.96 (m, 2
H), 2.42 (d, J = 6.84Hz, 2H), 1.28-1.82 (m, 10H), 1.11-1.26
(m, 4H), 0.95 (d, J = 6.02 Hz, 6H) Rf value: 0.38 (developing solvent A): 0.28 (developing solvent B) (Example 9) LN-benzyloxycarbonyl leucine -(2R)-(1-Formyl-2-cyclopentylthio) ethylamide (Compound (49)) The compound synthesized in Reference Example 8 in place of the compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1 ( 8) 2.0
Using g, 0.29 g of the title compound (49) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.62 (s, 1H),
7.35 (s, 5H), 6.89-6.92 (m, 1H), 5.12 (s, 2H), 5.10-5.20 (m,
1H), 4.55-4.60 (m, 1H), 4.32-4.41 (m, 1H), 2.90-3.12 (m, 3
H), 1.95-2.05 (m, 3H), 1.46-1.72 (m, 8H), 0.95 (d, J = 5.26H
(z, 6H) Rf value: 0.37 (developing solvent A): 0.32 (developing solvent B) (Example 10) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- ( Thiophene-
2-ylmethyl) thio] ethylamide (compound (5
0)) Compound (9) 0.9 synthesized in Reference Example 9 instead of Compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1.
Using 6 g, 0.22 g of the title compound (50) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.50 (s, 1H),
7.34 (s, 5H), 7.21-7.23 (m, 1H), 6.89-6.96 (m, 2H), 6.79-6.
83 (m, 1H), 5.12 (s, 2H), 5.11-5.17 (m, 1H), 4.48-4.53 (m, 1
H), 4.21-4.30 (m, 1H), 3.92 (s, 2H), 2.94 (d, J = 5.76,2H), 1.
49-1.72 (m, 3H), 0.95 (d, J = 6.08 Hz, 6H) Rf value: 0.28 (developing solvent A): 0.18 (developing solvent B) (Example 11) L-N-benzyl Oxycarbonylleucine- (2R)-[1-formyl-2- (thiophene-
3-ylmethyl) thio] ethylamide (compound (5
1)) Compound (10) synthesized in Reference Example 10 in place of compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1.
Using 2.5 g, 1.49 g of the title compound (51) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.49 (s, 1H),
7.26-7.34 (m, 6H), 7.16 (s, 1H), 7.05 (d, J = 4.93,1H), 6.79-
6.91 (m, 1H), 5.14-5.18 (m, 1H), 5.12 (s, 2H), 4.48-4.52 (m,
1H), 4.20-4.30 (m, 1H), 3.73 (s, 2H), 2.86 (br s, 2H), 1.49-
1.71 (m, 3H), 0.95 (d, J = 5.96 Hz, 6H) Rf value: 0.33 (developing solvent A): 0.22 (developing solvent B) (Example 12) LN- [1- (Benzyloxycarbonyl) -piperidine-4-carbonyl] leucine- (2
R)-[1-Formyl-2-benzylthio) ethylamide (Compound (52)) Compound (3) synthesized in Reference Example 37 in place of N- (benzyloxycarbonyl) leucine according to the method of Example 1.
0.39 g of the title compound (52) was obtained as an oil using 0.98 g of commercially available LS-benzyl-cysteine ethyl ester hydrochloride instead of the compound (1) synthesized in 8) and Reference Example 1.

NMR (δ, CDCl ₃ ): 9.46 (s, 1H),
7.24-7.36 (m, 10H), 6.25-6.40 (m, 1H), 5.11 (s, 2H), 4.56-
4.59 (m, 1H), 4.42-4.47 (m, 1H), 4.10-4.25 (m, 2H), 3.70 (d,
J = 3.27Hz, 2H), 2.74-2.91 (m, 4H), 2.25-2.33 (m, 1H), 1.52-
1.82 (m, 8H), 0.93 (t, J = 5.58 Hz, 6H) Rf value: 0.04 (developing solvent A): 0.05 (developing solvent B) (Example 13) LN- (benzyloxy) Carbonyl)
Leucine- (2R)-[1-formyl-2- (naphthalen-1-ylmethylthio)] ethylamide (compound (5
3)) 1.25 g of compound (11) synthesized in Reference Example 11 (3.
98 mmol) and LN- (benzyloxycarbonyl) leucine N-hydroxysuccinimide ester 1.4
To a chloroform solution of 5 g (3.98 mmol), 0.81 g (3.98 mmol) of triethylamine was added dropwise with stirring under ice-cooling, and the mixture was further stirred overnight. The reaction solution was washed with a 1N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the ester L. -N- (benzyloxycarbonyl)-
0.9 g (42%) of leucyl- (L) -S- (naphthalen-1-yl-methyl) cysteine ethyl ester was obtained. To a solution of 0.9 g (1.68 mmol) of the obtained ester in anhydrous tetrahydrofuran was added lithium borohydride (0.5%).
073 g (3.35 mmol) was added, methanol was added dropwise under ice cooling, water was added dropwise to the reaction solution stirred for 3 hours, and the solvent was distilled off under reduced pressure. The aqueous solution of the obtained residue was acidified with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 0.577 g was obtained (69% yield).

Alcohol 0.55 g (1.11 mmol)
To a solution of 0.45 g (4.44 mmol) of triethylamine and anhydrous dimethyl sulfoxide, 0.708 g (4.44 mmol) of a sulfur trioxide-pyridine complex was stirred at room temperature.
l) A dimethyl sulfoxide solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted three times with ethyl acetate, washed sequentially with a 10% aqueous citric acid solution, a saturated saline solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography to obtain 0.26 g (yield 47%) of the title compound (53).

Melting point (° C.): 115.0-126.1 (decomposition) NMR (δ, CDCl ₃ ): 9.46 (s, 1H), 8.06 (d, J = 7.92)
Hz, 1H), 7.86 (d, J = 9.23,1H), 7.76-7.80 (m, 2H), 7.31-7.58
(m, 8H), 6.75-6.90 (m, 1H), 5.08 (d, J = 3.78Hz, 2H), 4.98-5.
05 (m, 1H), 4.48-4.58 (m, 1H), 4.17-4.27 (m, 1H), 4.17 (s, 2
H), 2.90-2.93 (m, 2H), 1.35-1.72 (m, 3H), 0.91-0.93 (m, 6H) Rf value: 0.28 (developing solvent A): 0.22 (developing solvent B) ( Example 14) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2 (naphthalene-2
-Ylmethyl) thio] ethylamide (compound (54)) The compound (1) synthesized in Reference Example 12 in place of the compound (11) synthesized in Reference Example 11 by a method similar to that of Example 13.
2) Using 1.26 g, 0.1 g of the title compound (54) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.48 (d, J = 5.1
0Hz, 1H), 7.71-7.83 (m, 3H), 7.32-7.49 (m, 9H), 6.80-6.82
(m, 1H), 5.11 (d, J = 3.36Hz, 2H), 5.07-5.18 (m, 1H), 5.50-5.
57 (m, 1H), 4.22-4.30 (m, 1H), 3.87 (s, 2H), 2.87 (d, J = 5.01H
(z, 2H), 1.45-1.80 (m, 3H), 0.93 (d, J = 6.36 Hz, 6H) Rf value: 0.29 (developing solvent A): 0.22 (developing solvent B) (Example 15) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (2-chlorobenzyl) thio] ethylamide (compound (55)) The compound synthesized in Reference Example 11 by a method similar to that in Example 13 ( Compound (13) synthesized in Reference Example 13 instead of 11)
Using 1.24 g, 0.57 g of the title compound (55) was obtained.

Melting point (° C.): 128.6-131.9 NMR (δ, CDCl ₃ ): 9.55 (s, 1H), 7.20-7.40 (m, 9
H), 6.83-6.91 (m, 1H), 5.10-5.20 (br s, 3H), 4.52-4.60 (m,
1H), 4.20-4.30 (m, 1H), 3.84 (s, 2H), 2.93 (br s, 2H), 1.49-
1.73 (m, 4H), 0.95 (d, J = 4.29 Hz, 6H) Rf value: 0.31 (developing solvent A): 0.24 (developing solvent B) (Example 16) L-N-methyl-N -(Benzyloxycarbonyl) leucine- (2R)-[1-formyl-2
-(4-chlorobenzylthio)] ethylamide (compound (56)) 0.9 g of compound (40) synthesized in Reference Example 40 (3.2)
2 mmol), 0.326 g of triethylamine (3.22 mm
ol) 1-hydroxybenztriazole 0.443 g
To a chloroform solution (100 ml) of (3.22 mmol) and 0.748 g (3.22 mmol) of the compound (17) synthesized in Reference Example 16, 0.664 g (3.22 mmol) of dicyclohexylcarbodiimide was stirred while cooling with a salt-ice bath. A chloroform solution was added dropwise. The mixture was further stirred overnight. The insoluble material was removed by filtration, and the filtrate was washed successively with 1N hydrochloric acid, a saturated NaHCO ₃ solution, and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give L-N-methyl-N- (benzyloxycarbonyl) leucine-
1.2 g (yield 75%) of (2R)-[1-hydroxymethyl-2- (4-chlorophenyl)] ethylamide was obtained.

The above compound (0.89 g, 1.8 mm) was obtained.
ol) and 0.13 g (7.22 mmol) of triethylamine.
l) An anhydrous dimethyl sulfoxide solution (10 ml) was added to a sulfur trioxide-pyridine complex 1.14 while stirring at room temperature.
g (7.22 mmol) in anhydrous dimethyl sulfoxide (10 ml) was added dropwise, and the mixture was further stirred for 30 minutes. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic layer was washed successively with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.52 g of the title compound (56) as an oil.

NMR (δ, CDCl ₃ ): 9.50 (s, 1H),
7.15-7.40 (m, 9H), 6.80-6.95 (m, 1H), 5.10-5.30 (m, 2H), 4.
60-4.90 (m, 1H), 4.40-4.55 (m, 1H), 3.60-3.71 (m, 2H), 2.85
(s, 3H), 2.60-2.85 (m, 2H), 1.60-1.80 (m, 2H), 1.42-1.60
(m, 1H), 0.80-1.05 (m, 6H) Rf value: 0.42 (developing solvent A): 0.30 (developing solvent B) (Example 17) LN- (N-phenylcarbamoyl)
Leucine- (2R)-[1-formyl-2- (4-chlorobenzylthio)] ethylamide (Compound (57)) Reference example instead of compound (40) synthesized in Reference example 40 by the method according to Example 16. Compound (38) synthesized in 38
Using 1 g, 0.34 g of the title compound (57) was obtained as amorphous.

NMR (δ, CDCl ₃ ): 9.40 (s, 1H),
7.97 (bs, 1H), 7.05-7.45 (m, 9H), 6.63 (bs, 1H), 4.50-
4.60 (m, 1H), 4.30 to 4.40 (m, 1H), 3.60 to 3.75 (m, 2H), 3.1
0 to 3.30 (m, 2H), 1.45 to 1.85 (m, 3H), 0.85 to 1.10 (m, 6H) Rf value: 0.20 (developing solvent A): 0.10 (developing solvent B) (Example 18) ) LN- (4-methylbenzenesulfonyl) leucine- (2R)-[1-formyl-2- (4-
Chlorobenzylthio)] ethylamide (compound (5
8)) Compound (39) synthesized in Reference Example 39 instead of compound (40) synthesized in Reference Example 40 by a method similar to that in Example 16.
Using 1 g, 0.54 g of the title compound (58) was obtained as amorphous.

NMR (δ, CDCl ₃ ): 9.37 (s, 1H),
7.73 (d, J = 8.2Hz, 2H), 7.20-7.35 (m, 6H), 6.61 (d, J = 8.4Hz,
1H), 4.99 (d, J = 5.8Hz, 1H), 4.29-4.45 (m, 2H), 3.63 (s, 2H),
2.70-2.90 (m, 2H), 2.40 (s, 3H), 1.40-1.70 (m, 3H), 0.90
-1.10 (m, 6H) Rf value: 0.33 (developing solvent A): 0.25 (developing solvent B) (Example 19) LN- (benzyloxycarbonyl)
Phenylalanine- (2R)-[1-formyl-2-
(4-chlorobenzylthio)] ethylamide (Compound (59)) 1 g of commercially available (L) -N- (benzyloxycarbonyl) phenylalanine instead of compound (40) synthesized in Reference Example 40 by a method similar to that in Example 16. Was used to obtain 0.4 g of the title compound (59).

Melting point (° C.): 129.4 to 133.4 NMR (δ, CDCl ₃ ): 9.38 (s, 1H), 7.10 to 7.41
(m, 14H), 6.30-6.40 (m, 1H), 5.20-5.30 (m, 1H), 5.09 (s,
2H), 4.35 to 4.51 (m, 2H), 3.35 to 3.45 (m, 2H), 3.00 to 3.20
(m, 2H), 2.70 to 2.80 (m, 2H) Rf value: 0.36 (developing solvent A): 0.24 (developing solvent B) (Example 20) (L) -N- (benzyloxycarbonyl) -Valine- (2R)-[1-formyl-2- (4-
Chlorobenzylthio)] ethylamide (compound (6
0)) The title compound (60) 0.1 was obtained using 1 g of commercially available LN- (benzyloxycarbonyl) valine in place of the compound (40) synthesized in Reference Example 40 by a method similar to that in Example 16.
4 g were obtained.

Melting point (° C.): 126.2-128.7 NMR (δ, CDCl ₃ ): 9.52 (s, 1H), 7.20 to 7.45
(m, 9H), 6.60-6.75 (m, 1H), 5.25-5.35 (m, 1H), 5.11 (s,
2H), 4.50-4.61 (m, 1H), 4.00-4.15 (m, 1H), 3.68 (s, 2H),
2.75 to 2.90 (m, 2H), 2.10 to 2.25 (m, 1H), 0.90 to 1.05 (m, 6
H) Rf value: 0.36 (developing solvent A): 0.21 (developing solvent B) (Example 21) LN- (benzyloxycarbonyl)
Leucine- (2R)-[1-formyl-2- (4-chlorobenzyl) thio] ethylamide (compound (61)) 4 g of compound (17) synthesized in Reference Example 16 (17.26
mmol) and 1.74 g of triethylamine (17.26
mmol) in chloroform solution (200 ml) under ice-cooling and stirring.
6.25 g of -N- (benzyloxycarbonyl) leucine N-hydroxysuccinimide ester (17.2
6 mmol) was added little by little, and after returning to room temperature, the mixture was stirred overnight. The reaction solution was washed successively with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution (three times) and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an alcohol (L)
-N- (benzyloxycarbonyl) leucine- (2
7.8 g (94%) of R)-[1-hydroxymethyl-2- (4-chlorobenzylthio)] ethylamide were obtained.
7.8 g (16.28 mmol) of the alcohol obtained above
To a solution of 6.57 g (65 mmol) of triethylamine and anhydrous dimethyl sulfoxide (100 ml) were added 10.34 g (65 ml) of sulfur trioxide pyridine complex under stirring at room temperature.
mmol) in anhydrous dimethylsulfoxide (30 ml) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic layers were washed successively with 10% aqueous citric acid, aqueous saturated sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.4 g of the title compound (61).

Melting point (° C.): 116.0 to 130.7 (decomposition) NMR (δ, CDCl ₃ ): 9.52 (d, J = 4.88 Hz, 1H), 7.22
-7.33 (m, 10H), 6.83-6.91 (m, 1H), 5.11 (d, J = 2.33Hz, 3H),
4.50-4.59 (m, 1H), 4.23-4.30 (m, 1H), 3.67 (s, 2H), 2.85 (d,
J = 4.99Hz, 2H), 1.49-1.72 (m, 3H), 0.94-0.96 (m, 6H) Rf value: 0.25 (developing solvent A): 0.19 (developing solvent B) (Example 22) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3-chlorobenzyl) thio] ethylamide (compound (62)) The compound synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (1) synthesized in Reference Example 15 instead of (16)
5) Using 3.0 g, 0.68 g of the title compound (62) was obtained.

Melting point (° C.): 97.6 to 103.3 NMR (δ, CDCl ₃ ): 9.53 (s, 1H), 7.16-7.34 (m, 9
H), 6.84-6.90 (m, 1H), 5.11 (s, 2H), 5.10-5.17 (m, 1H), 4.50
-4.60 (m, 1H), 4.20-4.30 (m, 1H), 3.68 (s, 2H), 2.80-2.93
(m, 2H), 1.48-1.76 (m, 3H), 0.94-0.97 (m, 6H) Rf value: 0.25 (developing solvent A): 0.18 (developing solvent B) (Example 23) L- N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (2-fluorobenzyl) thio] ethylamide (compound (63)) Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (14) synthesized in Reference Example 14 instead of
Using 8.7 g, 2.75 g of the title compound (63) was obtained.

Melting point (° C.): 110.1 to 118.3 NMR (δ, CDCl ₃ ): 9.54 (s, 1H), 7.08-7.34 (m, 7
H), 7.02-7.12 (m, 2H), 6.83 (br s, 1H), 5.11 (s, 3H), 4.50-
4.60 (m, 1H), 4.20-4.30 (m, 1H), 3.75 (d, J = 2.93Hz, 2H), 2.9
3 (d, J = 5.48Hz, 2H), 1.50-1.75 (m, 3H), 0.95 (d, J = 6.18Hz, 6
H) Rf value: 0.30 (developing solvent A): 0.22 (developing solvent B) (Example 24) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3- (Fluorobenzyl) thio] ethylamide (Compound (64)) Compound (17) synthesized in Reference Example 17 instead of Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 6.5 g, 0.37 g of the title compound (64) was obtained.

Melting point (° C.): 111.8 to 116.6 NMR (δ, CDCl ₃ ): 9.53 (s, 1H), 7.24 to 7.34 (m, 6
H), 7.06 (t, J = 8.19Hz, 1H), 6.95 (t, J = 8.96Hz, 1H), 6.81-6.
87 (m, 1H), 5.11 (s, 3H), 4.50-4.59 (m, 1H), 4.21-4.30 (m, 1
H), 3.70 (s, 7H), 2.87 (d, J = 5.37 Hz, 2H), 1.45-1.73 (m, 3H),
0.94-0.97 (m, 6H) Rf value: 0.23 (developing solvent A): 0.19 (developing solvent B) (Example 25) LN-benzyloxycarbonylleucine- (2R)-[1-formyl -2- (4-Fluorobenzyl) thio] ethylamide (compound (65)) Compound (18) synthesized in Reference Example 18 instead of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 6.46 g, 0.8 g of the title compound (65) was obtained.

Melting point (° C.): 71.2-76.3 NMR (δ, CDCl ₃ ): 9.52 (d, J = 5.37 Hz, 1H), 7.25
-7.34 (m, 7H), 6.95-7.07 (m, 2H), 6.82-6.90 (m, 1H), 5.11-
5.20 (m, 3H), 4.50-4.60 (m, 1H), 4.20-4.30 (m, 1H), 3.69 (s,
2H), 2.80-2.90 (m, 2H), 1.49-1.73 (m, 3H), 0.95 (d, J = 4.12H
(z, 6H) Rf value: 0.25 (developing solvent A): 0.20 (developing solvent B) (Example 26) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- ( 2-methoxybenzyl) thio] ethylamide (compound (66)) Compound (19) synthesized in Reference Example 19 instead of compound (17) synthesized in Reference Example 17 by a method similar to that in Example 21.
Using 5.0 g, 0.88 g of the title compound (66) was obtained.

Melting point (° C.): 110.8-120.2 NMR (δ, CDCl ₃ ): 9.51 (s, 1H), 7.22-7.34 (m, 7
H), 6.86-6.97 (m, 2H), 6.80-6.85 (m, 1H), 5.15-5.25 (m, 1
H), 5.11 (s, 2H), 4.51-4.59 (m, 1H), 4.22-4.28 (m, 1H), 3.83
(s, 3H), 3.85 (d, J = 5.42Hz, 1H), 3.74 (d, J = 5.7Hz, 1H), 2.91
(d, J = 5.86 Hz, 2H), 1.42-1.74 (m, 3H), 0.93-0.96 (m, 6H) Rf value: 0.27 (developing solvent A): 0.20 (developing solvent B) (implementation Example 27) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3-methoxybenzyl) thio] ethylamide (compound (67)) Synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (20) synthesized in Reference Example 20 instead of compound (16)
Using 3.41 g, 0.71 g of the title compound (67) was obtained.

Melting point (° C.): 113.8-117.8 NMR (δ, CDCl ₃ ): 9.50 (s, 1H), 7.20-7.34 (m, 6
H), 6.76-6.90 (m, 4H), 4.49-4.53 (m, 1H), 4.23-4.30 (m, 1
H), 3.80 (s, 3H), 3.68 (s, 2H), 2.88 (d, J = 5.75Hz, 2H), 1.50-
1.75 (m, 3H), 0.95 (d, J = 5.97 Hz, 6H) Rf value: 0.25 (developing solvent A): 0.19 (developing solvent B) (Example 28) L-N-benzyloxycarbonyl Leucine- (2R)-[1-formyl-2- (4-methoxybenzyl) thio] ethylamide (Compound (68)) Reference example instead of compound (16) synthesized in Reference example 16 by a method similar to Example 21. Compound (21) synthesized in 21
Using 4.54 g, 0.13 g of the title compound (68) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.45 (br s, 1
H), 7.30-7.35 (m, 5H), 7.22 (d, J = 8.57Hz, 2H), 6.85 (d, J = 7.
54Hz, 2H), 6.76-6.89 (m, 1H), 5.11 (s, 2H), 5.08-5.18 (m, 1
H), 4.45-4.52 (m, 1H), 4.20-4.30 (m, 1H), 3.79 (s, 3H), 2.78
-2.89 (m, 2H), 1.46-1.85 (m, 3H), 0.94 (d, J = 5.86 Hz, 6H) Rf value: 0.19 (developing solvent A): 0.26 (developing solvent B) (implementation Example 29) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2-nitrobenzyl) thio] ethylamide (Compound (69)) The compound was synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (22) synthesized in Reference Example 22 instead of compound (16)
Using 4.18 g, 0.37 g of the title compound (69) was obtained.

Melting point (° C.): 72.9 to 104.9 (decomposition) NMR (δ, CDCl ₃ ): 9.56 (d, J = 6.95 Hz, 1H), 8.21
(s, 1H), 8.13 (dd, J = 2.44Hz, 7.22Hz, 1H), 7.65 (d, J = 7.43H
z), 7.45-7.52 (m, 1H), 7.33 (d, J = 4.1Hz, 5H), 6.91-7.07 (m,
1H), 5.20 (d, J = 7.70Hz, 1H), 5.11 (d, J = 5.48Hz, 2H), 4.53-
4.59 (m, 1H), 4.20-4.35 (m, 1H), 3.80 (s, 2H), 2.80-2.95 (m,
2H), 1.51-1.80 (m, 3H), 0.95 (d, J = 5.68 Hz, 6H) Rf value: 0.17 (developing solvent A): 0.17 (developing solvent B) (Example 30) L- N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (4-nitrobenzyl) thio] ethylamide (compound (70)) Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (23) synthesized in Reference Example 23 instead of
Using 2.17 g, 0.1 g of the title compound (70) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.56 (s, 1H),
8.15-8.20 (m, 2H), 7.47-7.51 (m, 2H), 7.30-7.34 (m, 5H), 6.
84-7.00 (m, 1H), 5.05-5.15 (m, 3H), 4.53-4.60 (m, 1H), 4.20
-4.30 (m, 1H), 3.79 (s, 2H), 2.87 (d, J = 5.26Hz, 2H), 1.49-1.
75 (m, 3H), 0.94-0.97 (m, 6H) Rf value: 0.15 (developing solvent A): 0.15 (developing solvent B) (Example 31) LN-benzyloxycarbonylleucine- ( 2S)-[1-Formyl-3-phenyloxy) propylamide (Compound (71)) Compound (24) synthesized in Reference Example 25 instead of Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. )
0.52 g of the title compound (71) was obtained as an oil using 0.52 g.

NMR (δ, CDCl ₃ ): 9.64 (s, 1H),
7.24-7.33 (m, 8H), 6.82-6.98 (m, 3H), 4.95-5.15 (m, 3H), 4.
55-4.59 (m, 1H), 4.20-4.30 (m, 1H), 3.95-4.10 (m, 2H), 2.27
-2.53 (m, 2H), 1.45-1.72 (m, 3H), 0.92 (t, J = 6.24 Hz, 6H) Rf value: 0.26 (developing solvent A): 0.19 (developing solvent B) (implementation Example 32) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3-phenylthio)
Propylamide (Compound (72)) Compound (25) synthesized in Reference Example 25 instead of Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 0.87 g, 0.42 g of the title compound (72) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.52 (d, J = 6.2
4Hz, 1H), 7.12-7.38 (m, 10H), 6.71-6.86 (m, 1H), 5.14-5.16
(d, J = 6.95Hz, 1H), 5.10 (s, 2H), 4.51-4.59 (m, 1H), 4.20-4.
25 (m, 1H), 2.91-2.96 (m, 2H), 2.25-2.35 (m, 1H), 1.85-2.00
(m, 1H), 1.48-1.72 (m, 3H), 0.92-0.96 (m, 6H) Rf value: 0.31 (developing solvent A): 0.24 (developing solvent B) (Example 33) L- N-benzyloxycarbonylleucine- (2S)-[1-formyl-2- (2-chlorobenzyl) oxy] ethylamide (compound (73)) Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (26) synthesized in Reference Example 26 instead of
0.50 g of the title compound (73) was obtained as an oil using 0.55 g.

NMR (δ, CDCl ₃ ): 9.61 (s, 1H),
7.23-7.36 (m, 9H), 6.80-6.93 (m, 1H), 5.09-5.17 (m, 3H), 4.
55-4.63 (m, 3H), 4.25-4.35 (m, 1H), 4.08-4.16 (m, 1H), 3.75
-3.79 (m, 1H), 1.49-1.71 (m, 3H), 0.92-0.96 (m, 6H) Rf value: 0.31 (developing solvent A): 0.24 (developing solvent B) (Example 34) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3- (2-fluorophenyl) oxy] propylamide (compound (74)) Compound synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (27) synthesized in Reference Example 27 instead of (16)
0.66 g of the title compound (74) was obtained as an oil using 0.69 g.

NMR (δ, CDCl ₃ ): 9.65 (s, 1H),
7.28-7.37 (m, 5H), 7.02-7.10 (m, 3H), 6.88-6.95 (m, 2H), 5.
10-5.22 (m, 1H), 5.06 (s, 2H), 4.57-4.61 (m, 1H), 4.22-4.30
(m, 1H), 4.05-4.13 (m, 2H), 2.32-2.50 (m, 2H), 1.50-1.72
(m, 3H), 0.91-0.95 (m, 6H) Rf value: 0.26 (developing solvent A): 0.19 (developing solvent B) (Example 35) LN-benzyloxycarbonylleucine- (2S )-[1-Formyl-3- (3-fluorophenyl) oxy] propylamide (Compound (75)) In the same manner as in Example 21, synthesized in Reference Example 28 instead of compound (16) synthesized in Reference Example 16. Compound (28)
Using 0.27 g, 0.06 g of the title compound (75) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.64 (s, 1H),
7.30-7.35 (m, 5H), 7.20 (q, J = 8.25Hz, 1H), 6.81-6.88 (m, 1
H), 6.54-6.70 (m, 3H), 5.05-5.12 (m, 3H), 4.56-4.63 (m, 1
H), 4.17-4.27 (m, 1H), 3.96-4.04 (m, 2H), 2.27-2.54 (m, 2
H), 1.45-1.75 (m, 3H), 0.88-0.95 (m, 6H) Rf value: 0.25 (developing solvent A): 0.19 (developing solvent B) (Example 36) LN-benzyl Oxycarbonylleucine- (2S)-[1-formyl-3- (2-chlorophenyl) oxy] propylamide (Compound (76)) Instead of the compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (29) synthesized in Reference Example 29
Using 1.05 g, 0.41 g of the title compound (76) was obtained.

Melting point (° C.): 107.1 to 111.3 NMR (δ, CDCl ₃ ): 9.70 (s, 1H), 7.33 to 7.39 (m, 5
H), 7.18-7.23 (m, 2H), 7.06-7.09 (m, 1H), 6.85-6.94 (m, 2
H), 5.17-5.19 (m, 1H), 5.07 (s, 2H), 4.60-4.64 (m, 1H), 4.26
-4.29 (m, 1H), 4.06-4.10 (m, 2H), 2.42-2.46 (m, 2H), 1.45-
1.75 (m, 3H), 0.90-0.98 (m, 6H) Rf value: 0.27 (developing solvent A): 0.20 (developing solvent B) (Example 37) LN-benzyloxycarbonylleucine- ( 2S)-[1-Formyl-3- (3-chlorophenyl) oxy] propylamide (compound (77)) In the same manner as in Example 21, synthesized in Reference Example 30 instead of compound (16) synthesized in Reference Example 16. Compound (30)
Using 1.07 g, 0.42 g of the title compound (77) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.63 (s, 1H),
7.28-7.35 (m, 6H), 7.17 (t, J = 8.19Hz, 1H), 6.92-6.95 (m, 1
H), 6.85 (s, 1H), 6.72 (d, J = 8.31Hz, 1H), 5.03-5.18 (m, 3H),
4.56-4.59 (m, 1H), 4.16-4.22 (m, 1H), 3.93-4.03 (m, 2H), 2.
25-2.53 (m, 2H), 1.47-1.70 (m, 3H), 0.91-0.95 (m, 6H) Rf value: 0.28 (developing solvent A): 0.27 (developing solvent B) (Example 38) ) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3-benzylthio)
Propylamide (compound (78)) Compound (31) synthesized in Reference Example 31 instead of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 1.9 g, 0.8 g of the title compound (78) was obtained.

Melting point (° C.): 72.8-81.8 NMR (δ, CDCl ₃ ): 9.49 (d, J = 5.76 Hz, 1H), 7.24
-7.33 (m, 10H), 6.67-6.69 (m, 1H), 5.14-5.18 (m, 1H), 5.10
(s, 2H), 4.55-4.64 (m, 1H), 4.15-4.21 (m, 1H), 3.66 (s, 2H),
2.39-2.43 (m, 2H), 2.11-2.20 (m, 1H), 1.82-1.90 (m, 1H), 1.
47-1.69 (m, 3H), 0.92-0.95 (m, 6H) Rf value: 0.52 (developing solvent A): 0.25 (developing solvent B) (Example 39) LN-benzyloxycarbonylleucine -(2S)-[1-Formyl-3- (2-fluorobenzyl) thio] propylamide (Compound (79)) A reference example instead of the compound (16) synthesized in Reference example 16 by a method according to Example 21. Compound (32) synthesized in 32
Using 1.6 g, 1.3 g of the title compound (79) was obtained.

Melting point (° C.): 99.6 to 101.0 NMR (δ, CDCl ₃ ): 9.54 (s, 1H), 7.19 to 7.37 (m, 7
H), 6.67-6.69 (m, 1H), 5.11 (s, 2H), 5.10-5.15 (m, 1H), 4.50
-4.54 (m, 1H), 4.18-4.23 (m, 1H), 3.70 (s, 2H), 2.45-2.48
(m, 2H), 2.18-2.30 (m, 2H), 1.86-1.97 (m, 2H), 1.48-1.72
(m, 3H), 0.95 (d, J = 6.24 Hz, 6H) Rf value: 0.51 (developing solvent A): 0.24 (developing solvent B) (Example 40) L-N-benzyloxycarbonylleucine -(2S)-[1-Formyl-3 (2-chlorobenzyl) thio] propylamide (Compound (80)) Reference Example 33 was used in place of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (33) synthesized by
0.72 g of the title compound (80) was obtained as an oil using 1.2 g.

NMR (δ, CDCl ₃ ): 9.53 (d, J = 6.4)
6Hz, 1H), 7.30-7.38 (m, 7H), 7.16-7.25 (m, 2H), 6.73-6.75
(m, 1H), 5.20 (d, J = 7.81Hz, 1H), 5.10 (s, 2H), 4.47-4.53 (m, 1H
1H), 4.18-4.24 (m, 1H), 3.80 (s, 2H), 2.47-2.52 (m, 2H), 2.1
6-2.24 (m, 1H), 1.88-1.94 (m, 1H), 1.48-1.68 (m, 3H), 0.92-
0.94 (m, 6H) Rf value: 0.29 (developing solvent A): 0.26 (developing solvent B) (Example 41) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3 (2-Fluorophenyl) thio] propylamide (Compound (81)) Compound (34) synthesized in Reference Example 34 in place of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 1.35 g, 0.96 g of the title compound (81) was obtained as an oil.

NMR (δ, CDCl ₃ ): 9.54 (d, J = 6.7)
3,1H), 7.31-7.40 (m, 5H), 7.22-7.29 (m, 2H), 7.03-7.12 (m,
1H), 5.17 (d, J = 7.81Hz, 1H), 5.11 (s, 1H), 4.55-4.60 (m, 1
H), 4.20-4.30 (m, 1H), 2.89-2.94 (m, 2H), 2.10-2.20 (m, 1
H), 1.84-1.95 (m, 1H), 1.49-1.73 (m, 3H), 0.93-0.96 (m, 6H) Rf value: 0.42 (developing solvent A): 0.40 (developing solvent B) ( Example 42) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3 (2-chlorophenyl) thio] propylamide (compound (82)) Synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (35) synthesized in Reference Example 35 instead of compound (16)
Using 1.25 g, 0.58 g of the title compound (82) was obtained.

Melting point (° C.): 109.5 to 149.0 (decomposition) NMR (δ, CDCl ₃ ): 9.54 (s, 1H), 7.12 to 7.40 (m, 9
H), 6.62-6.85 (m, 1H), 5.09-5.15 (m, 3H), 4.54-4.60 (m, 1H
H), 4.21-4.25 (m, 1H), 2.94-3.00 (m, 2H), 2.27-3.40 (m, 1
H), 1.90-2.02 (m, 1H), 1.49-1.71 (m, 3H), 0.93-0.95 (m, 6H) Rf value: 0.27 (developing solvent A): 0.27 (developing solvent B) ( Example 43) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3 (4-chlorophenyl) thio] propylamide (compound (83)) Synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (36) synthesized in Reference Example 36 instead of compound (16)
0.71 g of the title compound (83) was obtained as an oil using 1.58 g.

NMR (δ, CDCl ₃ ): 9.52 (d, J = 7.2)
1Hz, 1H), 7.32 (s, 5H), 7.25 (s, 4H), 6.72-6.90 (m, 1H), 5.14
-5.17 (m, 1H), 5.10 (d, J = 4.88Hz, 2H), 4.53-4.60 (m, 1H), 4.
15-4.25 (m, 1H), 2.88-2.93 (m, 2H), 2.20-2.35 (m, 1H), 1.82
-1.98 (m, 1H), 1.49-1.68 (m, 3H), 0.93-0.98 (m, 6H) Rf value: 0.30 (developing solvent A): 0.30 (developing solvent B) (Test Example 1) Measurement of Calpain Inhibitory Activity Calpain was obtained from Japanese white rabbit skeletal muscle by Tsuj
i and Imahori (J. Biochem. 90, 23)
3-240 (1981)).
Used for experiments.

The measurement of anti-calpain activity was carried out by Yoshimu.
ra (J. Biol. Chem. 258, 8883-8)
889 (1983)). That is,
4% casein solution 0.05ml, 50mM cysteine solution 0.05ml, calpain solution 0.05ml, purified water 0.0
A mixture containing 0.025 ml of a 25 ml test drug solution (10% dimethyl sulfoxide solution) and 0.25 ml of a 200 mM imidazole hydrochloride buffer (pH 7.5) was heated at 30 ° C. for 3 minutes. Then, a 50 mM calcium chloride solution was added.
The reaction was started by adding 05 ml. After reacting at 30 ° C. for 30 minutes, 0.5 ml of 5% trichloroacetic acid was added to stop the reaction. The amount of protein in the fraction soluble in trichloroacetic acid of casein hydrolyzed by calpain was determined by Ross and Sc.
hatz (Anal. Biochem. 54, 304-
306 (1973)), and the absorbance (a) was determined. At the same time, the absorbance (b) of a blind test using only a 10% dimethyl sulfoxide solution instead of the test drug solution was measured. The calpain inhibition rate was calculated by the following formula [(b-
a) / b] × 100, and the amount [IC ₅₀ ] required for 50% inhibition was calculated by the probit method. The compounds produced in each Example were used as test drugs, and the measurement results are shown in Table 1.

[0146]

[Table 1]

Test Example 2 Measurement of Platelet Aggregation Inhibitory Effect The preparation of rabbit platelet-rich plasma and the measurement of platelet aggregation
orn and Cross (J. Physol. 168, 1)
78-195 (1963)). That is, 3.8% from the carotid artery of a Japanese white rabbit under no anesthesia
9 volumes of blood were collected per 1 volume of the sodium citrate solution. Immediately, the mixture was centrifuged at 200 × g at 20 ° C. for 15 minutes to obtain supernatant platelet-rich plasma (hereinafter abbreviated as PRP). P
RP is an automatic blood cell counter (Nihon Kohden: MEK-415)
In 0), the number of platelets was measured, and those having 55 × 10 ⁴ or more per μl were used.

The platelet aggregation-inhibiting effect was confirmed by PRP 200 μl
To the platelet, heated at 37 ° C. for 5 minutes, and added 10 μl of 22 μg / ml collagen to determine the agglutination of platelets by an aggregometer (NKK, PAT-4).
It measured using A). At the same time, the maximum agglutination rate was 10 when only the solvent for dissolving the test drug was used instead of the test drug solution.
The inhibition rate of the test drug group was determined as 0%, and the amount [IC ₅₀ ] required for 50% inhibition was calculated by the probit method.

However, the test drug was dissolved in dimethyl sulfoxide and polyoxyethylene 60 hydrogenated castor oil / ethanol solution (1: 1) and diluted with physiological saline before use. In addition, dimethyl sulfoxide and polyoxyethylene 60 hydrogenated castor oil were each prepared so that the final concentration was 1% or less. The compounds produced in each Example were used as test drugs, and the measurement results are shown in Table 2.

[0150]

[Table 2]

(Test Example 3) Measurement of protease inhibitory activity other than calpain Measurement of anti-trypsin activity The measurement of anti-trypsin activity was performed using Aoyagi (J. Ant)
ibiotics, 22, 558-568 (1969).
Were carried out with some improvements.

0.5 ml of a 2% casein solution, 0.05 ml of 50 mM calcium chloride, 0.05 ml of a test drug solution (containing 10% dimethyl sulfoxide), 0.1 ml of purified water and 7 ml
A mixture containing 0.25 ml of 0 mM borate buffer (pH 7.4) was heated at 37 ° C. for 3 minutes. Thereafter, a 0.1 mg / ml trypsin solution was added to start the reaction. After reacting at 37 ° C. for 30 minutes, 1 ml of 1.7N perchloric acid was added to stop the reaction. After standing at room temperature for 60 minutes, 3,000 rpm, 1
After centrifugation for 0 minutes, the absorbance of the supernatant at 280 nm (a)
Was measured. Simultaneously, a blind absorbance using only a 10% dimethyl sulfoxide solution instead of the test drug solution (b)
Was measured. The trypsin inhibition rate was calculated by the following formula [(ba) /
b] × 100.

Compounds (61) and (6) produced in Examples
3), (76) and (83) were used as test drugs.

None of the compounds showed any inhibitory activity at a concentration of 10 ^-5 M.

Measurement of anti-α-chymotrypsin activity The measurement of anti-α-chymotrypsin activity was determined according to Erlange.
r, B. F. (Ach. Biochem. Biophy
s. 115, 206-210 (1966) and the like. That is, 0.05 ml of a 10 mM glutaryl-L-phenylalanine-p-nitroanilide solution (containing 10% dimethyl sulfoxide-10% polyoxyethylene 60 hydrogenated castor oil), 0.1 ml of a 50 mM calcium chloride solution, 0.25 ml of purified water, Test drug solution (10%
Dimethyl sulfoxide-10% polyoxyethylene 6
A mixture containing 0.05 ml of 0 hydrogenated castor oil) and 0.5 ml of 100 mM Tris-HCl buffer (pH 7.8) was heated at 25 ° C.
For 3 minutes. Thereafter, 2 mg / ml α-chymotrypsin (Type-II) was added to start the reaction, and immediately
The change in absorbance per minute (a) was determined by measuring the increase in absorbance at 405 nm over time. At the same time, instead of the test drug solution, 10% dimethyl sulfoxide-10%
The rate of change in absorbance per minute (b) in a blind test using only polyoxyethylene 60 hydrogenated castor oil solution was measured.
The α-chymotrypsin inhibition rate was calculated by the following formula [(ba) / b] ×
The amount required for 50% inhibition [IC ₅₀ ] calculated by 100
Was calculated by the probit method. For comparison, see JP-A-1-1
Compound SUAM-14541 prepared in No. 21257
Was used for the measurement. Table 3 shows the results.

[0156]

[Table 3]

[0157]

The aldehyde derivative represented by the general formula (I) of the present invention exhibits a selective calpain activity inhibitory action and a platelet aggregation inhibitory action. Therefore, it can be expected to be used for treatment of ischemic diseases caused by abnormal activity of calpain.

Claims (1)

(57) [Claims] 1. A compound of the general formula Wherein R ¹ is an aromatic hydrocarbon group, a heterocyclic group, a substituted alkyl group or a cyclic alkyl group, R ² is a hydrogen atom, an alkyl group or an aromatic hydrocarbon group, and R ³ is , A hydrogen atom or an alkyl group, R ⁴ is an alkoxycarbonyl group, an acyl group, a carbamoyl group, a sulfonyl group, X is an oxygen atom or a group represented by —S (O) _m —, wherein m is 0,1 Or 2, and n is 1 to 5.)