JPH06287167A - Aldehyde derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having a selective carpine activation- inhibiting action and a platelet-agglutination-inhibiting action and useful for the therapy of ischemic di seases. CONSTITUTION:A compound of formula I (R<1> is aromatic hydrocarbon, heterocycluc group, substituted alkyl or cycluc alkyl; R<2> is H, alkyl, aromatic hydrocarbon; R<3> is H, alkyl; R<4> is alkoxycarbonyl, acyl, carbamoyl, sulfonyl; X is O,-S(O)m-; m is 0-2; n is 1-5), e.g. L-N-benzyloxycarbonyl leucine-(25)-(1- formyl-2-benzyloxy)ethylamide. The compound of formula I is obtained by reacting an alcohol derivative of formula II with an oxidizing agent (e.g. dicyclohexylcarbodiimide) in a solvent (e.g. chloroform) at -20 to 30 deg.C. The compound of formula I can be administered not only orally but also intravenously, subcutaneously and intramuscularly.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has the general formula

[0002]

[Chemical 2]

(In the formula, 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 —, where m is 0, 1 or 2, and n is 1 to 5. ) Related to the aldehyde derivative. The aldehyde derivative represented by the general formula (1) is a compound that has calpain inhibitory activity and platelet aggregation inhibitory activity and can be used as a therapeutic agent for ischemic diseases.

[0004]

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

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

Conventionally, as therapeutic agents for this ischemic disease, calcium antagonists, β-blockers and the like, which have a vasodilating action, have been used. However, these drugs do not have the effect of treating or preventing the cell damage or necrosis that is seen in ischemic diseases.

Therefore, calpain inhibitors may be useful as therapeutic agents for these intractable diseases. As a compound having a calpain inhibitory activity, an epoxysuccinic acid derivative (J. Biochem., 87, 33) has already been used.
9 (1980), piperazine derivative (JP-A-57-16)
9478, JP-A-58-126879, JP-A-63.
No. 25575), an amino aldehyde derivative (Japanese Patent Laid-Open Publication No.
1-103897, JP-A-1-12157, JP-A-2-268145), aminoaldehyde and aminoketone derivatives (JP-A-2-256654) and the like are known.

[0008]

Among these compounds, piperazine derivatives have been reported to have a myocardial protective action and have potential as therapeutic agents for ischemic diseases. However, this derivative has a low calpain inhibitory activity and myocardial protection activity, and a sufficient therapeutic effect cannot be expected. In addition, compounds other than the piperazine derivative had calpain-inhibiting activity, but could not be used as therapeutic agents for ischemic diseases.

[0009]

[Means for Solving the Problems] Therefore, the present inventors have conducted research to find a useful calpain inhibitor for ischemic diseases, and as a result, in order to enhance the therapeutic effect of ischemic diseases, platelet aggregation inhibitory activity and calpain The present invention has been completed by finding an aldehyde derivative represented by the general formula (I) having a specific inhibitory activity against

In the aldehyde derivative represented by the general formula (I), R ¹ is an aromatic hydrocarbon group, a heterocyclic group,
It is a substituted alkyl group or a cyclic alkyl group. As the aromatic hydrocarbon group, for example, phenyl group, naphthyl group, anthranyl group, etc., as the heterocyclic group, for example, furyl group, cenyl group, pyrrolyl group, pyridyl group, quinolyl group, isoquinolyl group, indolyl group, etc., as substituted alkyl group. A linear or branched alkyl group having 1 to 10 carbon atoms, which has the aromatic hydrocarbon group or the heterocyclic group as a substituent, and is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group. , Hexyl group, 2-propyl group, sec
-Butyl group, t-butyl group and the like can be mentioned, and as the cyclic alkyl group, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like can be mentioned.

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

R ² is a hydrogen atom, a linear or branched alkyl group or an aromatic hydrocarbon group. The alkyl group represented by 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. Furthermore, 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, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a cinnamyloxycarbonyl group and a benzyloxycarbonyl group. As the acyl group, for example, acetyl group, propionyl group, butyryl group, valeryl group, benzoyl group, 1-naphthoyl group, 2-naphthoyl group, cyclohexanecarbonyl group,
Examples thereof include a toluyl group and a 1- (benzyloxycarbonyl) piperidine-4-carbonyl group. Examples of the carbamoyl group include an N-methylcarbamoyl group and
N-ethylcarbamoyl group, N-phenylcarbamoyl group, N- (2-chlorophenyl) carbamoyl group, N-
(1-naphthyl) carbamoyl group, N-benzylcarbamoyl group and the like can be mentioned. Further, examples of the substituted sulfonyl group include methanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, 4-methylbenzenesulfonyl group, isoquinoline- Examples thereof include 5-sulfonyl group and quinoline-8-sulfonyl group.

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

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

Formula I

[0018]

[Chemical 3]

(In the formula, 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.) [Step 1] This step comprises reacting the carboxylic acid derivative represented by the general formula (II) with the amine derivative represented by the general formula (III) in the presence of a condensing agent to form the ester derivative represented by the general formula (IV). Is manufactured.

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

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

The condensing agent used in this step is represented by the general formula (I
A carboxylic acid derivative represented by I) or the general formula (III)
1 to 3 equivalents relative to 1 mol of the amine derivative represented by the formula (1), and preferably 1.5 to 2 equivalents for good yield. The reaction is preferably 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 in combination. The reaction usually proceeds at −50 ° C. to the reflux temperature under normal pressure, but −30 ° C. to 3 ° C. for good yield.
It is preferably carried out at 0 ° C.

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

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

As the amine derivative represented by the general formula (III), which is the starting material for this step, a commercially available amino acid ester can be used, or in addition, for example, it is represented by the general formula (VII) according to the reaction formula shown in the following formula 2. It can be produced from amino acids.

Equation 2

[0027]

[Chemical 4]

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

Further, the amine derivative represented by the general formula (III) shown in the formula 2 is, if necessary, the general formula (VII).
It can also be produced after protecting the amino group of the amino acid represented by 4) with a protecting group for the amino group used in peptide synthesis.

Examples of the amine derivative represented by the general formula (III) used in this step include L-O- (benzyl) serine ethyl ester, L-S- (2-phenylethyl) cysteine methyl ester and 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, L-S- (1-naphthylmethyl) cysteine ethyl ester, L-S- (2-naphthylmethyl) cysteine ethyl ester, L-S- (2
-Chlorobenzyl) cysteine ethyl ester and the like can be mentioned.

Further, in this step, the above-mentioned general formula (IV)
The ester derivative represented by the formula (II) is the same as the first step after the carboxyl group of the carboxylic acid derivative represented by the general formula (II) is converted to, for example, an active ester compound, a carboxylic acid halide compound, an acid anhydride or the like. It can be produced by reacting in a solvent in the presence of the amine derivative represented by the general formula (III).

[Second Step] This step is carried out according to the general formula (IV)
The ester derivative represented by the formula (1) is reduced to produce the alcohol derivative represented by the general formula (V).

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

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

[Third Step] This step is carried out according to the general formula (V)
The alcohol derivative represented by the formula (1) is oxidized 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, and dicyclohexylcarbodiimide, phosphorus pentoxide, pyridine-sulfur trioxide complex, oxalyl chloride, acetic anhydride, as an activator of DMSO and DMSO. Trifluoroacetic anhydride or the like can be used. The amount of the oxidizing agent used is 1 mol of the alcohol derivative represented by the general formula (V).
1 to 4 equivalents can be used.

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

[Fourth Step] This step is carried out 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 formula (4) 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 aminoalcohol derivative represented by the general formula (VI), which is the starting 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 formula 3.

Equation 3

[0041]

[Chemical 5]

(In the formula, R ¹ , X, and n are the same as above, and R ⁶ is a protecting group for amino group.) The aminoalcohol derivative represented by the general formula (VI) used in this step. Is, 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 the starting material in this step, is converted into, for example, an active ester compound, a carboxylic acid halide compound, an acid anhydride, etc., as in the first step. Then, it can also be produced as an alcohol derivative represented by the general formula (V).

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

[0045]

The aldehyde derivative represented by the general formula (I) of the present invention does not have an inhibitory effect on proteases such as trypsin and α-chymotrypsin as shown in the test examples, and all have an excellent specific calpain activity inhibitory effect. Furthermore, since it has an inhibitory effect on platelet aggregation, it is useful for the treatment of ischemic diseases. In addition to oral administration, these compounds may be administered intravenously, subcutaneously or intramuscularly. To that end, these compounds can be used in various dosage forms, such as tablets, capsules, liquids or suppositories.

[0046]

EXAMPLES 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, and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, 1.3 ml (17 mmol) of thionyl chloride was added to the ethanol solution of the obtained residue, and the mixture was stirred overnight at room temperature.
The reaction solution was evaporated under reduced pressure to remove the title compound (1) 2.01.
g (yield 91.6%) was obtained.

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 = 3.33Hz, 1H), 1.27 (t, J = 7.17Hz, 3H) (Reference Example 2) L-S- (2-phenylethyl) cysteine methyl ester hydrochloride (Compound (2)) Cysteine hydrochloride water Japanese product 4.85 g (29.28 mmol)
Was added to 200 ml of a methanol solution of 4.74 g of sodium methoxide under ice cooling, and the mixture was stirred 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, the obtained residue was dissolved in water and washed with diethyl ether, and 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 L-S-phenylethylcysteine. 5.3 g of the above compound obtained
A solution of (23.5 mmol) in methanol (200 ml) was added dropwise under ice cooling, and 8.6 ml of thionyl chloride was added dropwise. After the addition, the reaction solution was brought to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with diethyl ether and dried, and then the title compound (2) was used.
27 g (yield 96.3%) was 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 thionyl chloride (6.7 ml), 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)) L-N- (t-butoxycarbonyl) serine 3 g (1
(4.6 mmol) in anhydrous dimethylformamide solution under stirring with ice-cooling, 60% oily sodium hydride 1.28 g (32 mmo)
l) was added, the mixture was returned to room temperature and stirred for 2 hours, 3.18 g (16 mmol) of 3-bromopropylbenzene was added, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N-hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent under reduced pressure. The residue obtained by evaporation was dissolved in ethanol, concentrated hydrochloric acid was added, and the mixture was stirred overnight and thionyl chloride 4 was added.
ml was added and stirred overnight. The solvent was distilled off under reduced pressure, and the obtained crystals 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) L-O- (thiophen-3-ylmethyl)
Serine ethyl ester hydrochloride (compound (5)) According to Reference Example 4, L-Boc-Ser-OH 40 g (1
9.5 mmol) 60% oily sodium hydride 172 g (4
3 mmol), 4.44 g of 3-bromomethylthiophene (2
(5 mmol), concentrated hydrochloric acid (2.2 g) and thionyl chloride (2.3 ml) were used 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
= 7.11Hz, 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 and stirred at room temperature for 1 hour.
Trifluoroacetic acid was distilled off under reduced pressure, diethyl ether was added to the residue for crystallization, washed with water, ethanol and diethyl ether, and dried under reduced pressure to give 5.2 g (yield-100%) of L-S-diphenylmethylcysteine. Obtained. To the obtained methanol solution of the above compound (1.0 g, 3.5 mmol) was added dropwise thionyl chloride (1.0 ml) under ice-cooling, and the reaction solution was warmed to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with diethyl ether to give the title compound (6) 1.
11 g (yield-100%) was 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 by the method according to 2 by using cyclohexylmethyl bromide 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 According to the same manner as in Example 2, using cyclopentyl bromide instead of 2-bromoethylbenzene, the title compound (8) was obtained.

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 = 7.20Hz, 3H) (Reference Example 9) L-S- (thiophen-2-ylmethyl)
Cysteine methyl ester hydrochloride (Compound (9)) The title compound (9) was obtained by the method according to Reference Example 2 using 2-chloromethylthiophene 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) L-S- (thiophen-3-ylmethyl) cysteine ethyl ester hydrochloride (compound (1
0)) The title compound (10) was obtained by the method according to Reference Example 2 using 3-bromomethylthiophene 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 = 14.82Hz, J = 8.13Hz, 1H), 1.31 (t, J = 7.23Hz, 3H) (Reference Example 11) L-S- (1-naphthylmethyl) cysteine ethyl ester hydrochloride (compound (11 )) 1-naphthylmethyl bromide was used instead of 2-bromoethylbenzene by the method according to Reference Example 2 to obtain the title compound (11).

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 by the method according to Reference Example 2 using 2-naphthylmethyl bromide instead of 2-bromoethylbenzene.

NMR (δ, CD ₃ OD): 7.81-7.88 (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 = 8.19Hz, J = 6.39Hz, 1H), 1.22 (t, J = 7.05Hz, 3H) (Reference Example 13) L-S- (2-chlorobenzyl) cysteine ethyl ester hydrochloride (compound (13 )) The title compound (13) was obtained by the method according to Reference Example 2 using 2-chlorobenzyl chloride 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
4.65Hz, J = 7.86Hz, 1H), 1.31 (t, J = 7.16Hz, 3H) (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 sodium metal and 700 ml of methanol, 30.4 g (1 of L-cysteine hydrochloride hydrate)
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. Methanol was distilled off under reduced pressure, the resulting residue was dissolved in water and washed twice with ether, concentrated hydrochloric acid was added (pH = 7), and the precipitated crystals were collected by filtration, washed with water, ethanol and then diethyl ether, and reduced in pressure. Dried under (2R)-
29.7 g (yield 74.8%) of 2-amino-3 (2-fluorobenzylthio) propionic acid was obtained. Chlorotrimethylsilane was added to a solution of 0.58 g (26.4 mmol) of lithium borohydride in anhydrous tetrahydrofuran.
7 ml (52.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes. 2.02 g (8.8) of (2R) -2-amino-3 (2-fluorobenzylthiopropionic acid) was added to the mixed solution.
mmol) was added and the mixture was stirred overnight at room temperature. Methanol was added to the reaction solution and the solvent was distilled off under reduced pressure. 1N-
It was dissolved in an 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 = 13.35Hz, J = 8.22Hz, 1H) (Reference Example 15) (2R) -2-amino-3 (3-chlorobenzylthio) propanol (Compound (15)) Reference Example 14 The title compound (15) was obtained by a method similar to that described above using 3-chlorobenzyl bromide instead of 2-fluorobenzyl chloride.

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
3.4Hz, 1H), 2.45 (dd, J = 8.08Hz, J = 13.45Hz, 1H) (Reference Example 16) (2R) -2-amino-3 (4-chlorobenzylthio) propanol (Compound (16)) The title compound (16) was obtained by the method according to Reference Example 14 using 4-chlorobenzyl chloride 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)) 2-fluorobenzyl chloride was prepared by the method according to Reference Example 14. 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
9Hz, 1H), 3.25 (br s, 1H), 2.62 (d, J = 7.05Hz, 2H) (Reference Example 18) (2R) -2-amino-3 (4-fluorobenzylthio) propanol (Compound (18 )) The title compound (18) was obtained by the method according to Reference Example 14 using 4-fluorobenzyl chloride instead of 2-fluorobenzyl chloride.

NMR (δ, CDCl ₃ ): 7.25-7.30
(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 = 10.25Hz, 3H), 2.36 (dd, J = 8.31Hz, 13.30Hz, 1H) (Reference Example 19) (2R) -2-amino-3 (2-methoxybenzylthio) propanol (Compound (19 )) The title compound (19) was obtained by the method according to Reference Example 14 using 2-methoxybenzyl chloride instead of 2-fluorobenzyl chloride.

NMR (δ, CDCl ₃ ): 7.21 to 7.26
(m, 2H), 6.86 ~ 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 = 13.57Hz, J = 8.31Hz, 1H), 2.08 (br s, 3H) (Reference Example 20) (2R) -2-amino-3 (3-methoxybenzylthio) propanol ( Compound (20)) The title compound (20) was obtained by the method according to Reference Example 14 using 3-methoxybenzyl chloride 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 ~ 3.00 (m, 1H), 2.56 (dd, J = 4.88Hz, J = 13.29Hz, 1
H), 2.36 (dd, J = 8.19Hz, J = 13.35Hz, 1H), 2.11 (br s, 3H) (Reference Example 21) (2R) -2-amino-3 (4-methoxybenzylthio) propanol ( Compound (21)) The title compound (21) was obtained by the method according to Reference Example 14 using 4-methoxybenzyl chloride 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)) 3-nitrobenzyl was used instead of 2-fluorobenzyl chloride by the method according to Reference Example 14. 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 (br s, 3H) (Reference Example 23) (2R) -2-amino-3 (4-nitrobenzylthio) propanol (Compound (23)) L-Cysteine hydrochloride hydrate 5 0.27 g (30 mmol) was added to a 1N-sodium hydroxide aqueous solution, then a solution of 4-nitrobenzyl chloride 5.15 g (30 mmol) in dioxane was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made weakly acidic with concentrated hydrochloric acid, and cooled. The crystals precipitated were filtered, washed with ethanol, then with diethyl ether, and dried under reduced pressure. L-2-amino-3
(4-nitrobenzylthio) propionic acid 3.
55 g (yield 45.9%) was obtained. The conversion reaction to the alcohol compound was carried out by the method according to Reference Example 14 to obtain the title compound (23).

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 = 8.13Hz, J = 13.18Hz, 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) L-N
320 g (2.94 mol) of ethyl bromide was added dropwise to a solution of 142 g (0.59 mol) of potassium salt of-(t-butoxycarbonyl) -homoserine in anhydrous dimethylformamide, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure,
The obtained residue was dissolved in water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 44.5 g (yield 31%) of L-N- (t-butoxycarbonyl) -homoserine ethyl ester. 6.18 g (25
mmol) and 3.04 g (30 mmol) of triethylamine were added to 3.44 g (30 mmol) of methanesulfonyl chloride under stirring with ice cooling, and the mixture was stirred for 1 hour. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8.12 g of methanesulfonate (yield-
100%) was obtained. 60% oily sodium hydride was added to a solution of 0.88 g of phenol in anhydrous dimethylformamide.
After adding 35 g and stirring for 1 hour, a dimethylformamide solution of 2.55 g (7.83 mmol) of the methanesulfonate compound obtained in the previous reaction was added dropwise and stirred overnight at room temperature. Saturated aqueous NH ₄ Cl was added to the reaction solution, which was extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and then with water. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain L-N- (t-
Butoxycarbonyl) -O-phenylhomoserine ethyl ester (2.13 g, yield 84%) 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 = 7.06Hz, 3H) Add 0.28 g of lithium borohydride to a tetrahydrofuran solution of 2.10 g (6.5 mmol) of the above compound, and then stir with cooling. Lower 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.
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 hydrogencarbonate 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 ethyl acetate and stirred for 1 hour. The solvent was distilled off under reduced pressure, and 0.64 g of the title compound (24) (yield 46
%) Was obtained.

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 in the same manner as in Reference Example 24.
S-phenyl homocysteine 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 by the method according to Reference Example 24.

Reference Example 26 (2R) -2-amino-3
-(2-chlorobenzyloxy) -propanol hydrochloride (Compound (26)) LN- (t-butoxycarbonyl) serine 7.0 g
60% in anhydrous dimethylformamide solution (34 mmol)
3.0 g of oily sodium hydride was added, and the mixture was stirred at room temperature for 3 hours. Then 2-chlorobenzyl chloride 6.0 g (3
(7 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the obtained residue 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 the solvent was evaporated to give LN- (t- Butoxycarbonyl) -O- (2-chlorobenzyl) -serine (4.3 g, yield 38%) was obtained. 0.93 g of ethyl chlorocarbonate was added dropwise to a tetrahydrofuran solution of 2.15 g (6.5 mmol) of the obtained compound and triethylamine while cooling with salt-ice, and the mixture was stirred for 2 hours. The precipitated crystals were removed by filtration, and sodium borohydride and then methanol were added dropwise to the filtrate while stirring with ice cooling, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, a 1N-hydrochloric acid aqueous solution was added to the obtained residue aqueous solution, 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, the solvent was distilled off, and the residue was 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 and stirred at room temperature for 30 minutes.
55 g (yield 19%) was 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)) L-N- (t-butoxycarbonyl) -O- (2-fluorophenyl) -homoserine ethyl ester was obtained by using 2-fluorophenol instead of phenol by the method according to Reference Example 24.

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 = 7.16Hz, 3H) Furthermore, the title compound (27) was obtained by the method according to Reference Example 24.

Reference Example 28 (2S) -2-amino-4
(3-Fluorophenyloxy) butanol hydrochloride (Compound (28)) L-N- (t-butoxycarbonyl) -O- (3 was obtained by the method according to Reference Example 24 using 3-fluorophenol instead of phenol. -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 = 7.11Hz, 3H) The title compound (28) was obtained by the method according to Reference Example 24.

(Reference Example 29) (2S) -2-amino-4
(2-Chlorophenyloxy) butanol hydrochloride (Compound (29)) By the method according to Reference Example 24, benzyl bromide was used instead of ethyl bromide, and 2-chlorophenol was used instead of phenol to produce LN- (t. -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) Furthermore, the title compound (29) was obtained by the method according to Reference Example 24.

(Reference Example 30) (2S) -2-amino-4
(3-Chlorophenyloxy) butanol hydrochloride (Compound (30)) By the method according to Reference Example 24, benzyl bromide was used in place of ethyl bromide, and 3-chlorophenol was used in place of phenol. LN- (t -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 = 5.96Hz, 2H), 2.25-2.37 (m, 2H), 1.43 (s, 9H) Furthermore, the title compound (30) was obtained by the method according to Reference Example 24.

Reference Example 31 L-2-Amino-4-benzylthiobutanol (Compound (31)) Metallic sodium 1 was added to liquid ammonia cooled to −78 ° C.
g, and stirred for 30 minutes, and then homocysteine in the reaction solution.2.
0 g (7.45 mmol) was added and stirred for 30 minutes. Ammonium chloride was added to the reaction solution until the blue color of the reaction solution disappeared, and then 0.69 g (30 mmol) of benzyl bromide was added and liquid ammonia was evaporated at room temperature. The obtained residue was dissolved in water, washed with diethyl ether, weakly acidified by adding concentrated hydrochloric acid to precipitate crystals 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 (yield 86%) of (2S) -2-amino-4-benzylthiobutanoic acid.

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

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 Then, 2-fluorobenzyl bromide was used instead of benzyl bromide to give the title compound (3
2) was obtained.

NMR (δ, CDCl ₃ ): 7.31-7.36 (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)) 2-Chlorobenzyl chloride was used in place of benzyl bromide according to the method of Reference Example 31 to obtain the title compound (33).
Got

NMR (δ, CDCl ₃ ): 7.33-7.39 (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)) According to Reference Example 24. By the method, benzyl bromide was used instead of ethyl bromide, and 2-fluorothiophenol was used instead of phenol to obtain L-N- (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) Furthermore, the title compound (34) was obtained by the method according to Reference Example 24.

(Reference Example 35) (2S) -2-amino-4
(2-Chlorophenylthio) butanol hydrochloride (Compound (35)) By the method according to Reference Example 24, benzyl bromide was used in place of ethyl bromide, and 2-chlorothiophenol was used in place of phenol. LN- (t -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 the method according to Reference Example 24.

(Reference Example 36) (2S) -2-amino-4
(4-Chlorophenylthio) butanol hydrochloride (Compound (36)) By the method according to Reference Example 24, benzyl bromide was used in place of ethyl bromide, and 4-chlorothiophenol was used in place of phenol. 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 by the method according to 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)
2.5 g (25.5 mmol) of triethylamine, 6.7 g (25.5 mmol) of N- (benzyloxycarbonyl) -piperidine-4-carboxylic acid and 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 hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give L-N- [1- (benzyloxycarbonyl) -piperidine-4-carbonyl. ] 10.1 g (yield 98%) of leucine ethyl ester was obtained.

1.02 g of sodium hydroxide was added to a methanol solution of 10.1 g of the obtained ester compound while stirring with ice cooling.
An aqueous solution (10 ml) of (25.5 mmol) was added and the mixture was kept as it was.
Stir for hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in water, and washed twice with ether. The aqueous layer was acidified (pH = 1) by adding concentrated hydrochloric acid, extracted twice with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (37) 9.3.
g (yield 96%) was obtained as an oily substance.

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)
(16 mmol) in chloroform solution (200 ml) was added with triethylamine (5.16 g, 51 mmol) under ice-cooling stirring, and then 2.76 ml (25.5 mm) of isocyanic acid phenyl ester.
ol) in chloroform was added dropwise. After stirring overnight, the reaction solution was washed successively with 1N-hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (L) -N- (N-phenylcarbamoyl). Leucine ethyl ester (5.85 g, yield 82%) was obtained.

A solution of the above-obtained compound (5.85 g) in methanol (200 ml) was added with sodium hydroxide (1.
An aqueous solution (10 ml) of 848 g (46 mmol) was added and the mixture was stirred as it was for 3 hours. The reaction solution was concentrated under reduced pressure, 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 to give 3.55 g of the title compound (38) (yield 6. 7%)
Got

Melting point (° C.): 143.8 to 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 =
3.2Hz, 3H), 0.97 (d, J = 3.0Hz, 3H) (Reference Example 39) (L) -N- (4-methylbenzenesulfonyl) leucine (Compound (39)) Isocyanate was prepared according to Reference Example 39. 4-methylbenzenesulfonyl chloride instead of acid phenyl ester 4.
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), 3.86-3.99 (m, 1
H), 2.41 (s, 3H), 1.70 ~ 1.85 (m, 1H), 1.45 ~ 1.60 (m, 2H),
0.89 (d, J = 6.6Hz, 3H), 0.82 (d, J = 6.5Hz, 3H) (Reference Example 40) (L) -N-methyl-N- (benzyloxycarbonyl) leucine (Compound (40)) Commercially available L-N-methylleucine (1 g, 6.88 mmol) in 1N-sodium hydroxide aqueous solution (10 ml) was stirred under ice-cooling while stirring with benzyloxycarbonyl chloride (0.982 ml) (6.
88 mmol) of benzene solution (10 ml) and 1N-sodium hydroxide aqueous solution (10 ml) were added dropwise at the same time. After returning to room temperature and stirring overnight, the reaction solution was washed twice with ether. Concentrated hydrochloric acid was added to the aqueous layer to make it acidic (pH = 1), and then 2 times with ethyl acetate.
Extracted twice. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (40) 0.46 g.

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) L-N-benzyloxycarbonyl leucine- (2S)-(1-formyl-2-benzyloxy)
Ethylamide (Compound (41)) 2.01 g (7.8 mm) of the compound (1) synthesized in Reference Example 1
ol) in a chloroform suspension (200 ml) with stirring under ice-cooling with triethylamine (784 mg, 7.8 mmol), L-Cbz-
23 ml (8.5 mmol) of Len-OH / toluene solution and 1.18 g (7.
8 mmol) was sequentially added, and a chloroform solution (50 ml) of 1.76 g (8.525 mmol) of dicyclohexylcarbodiimide was added dropwise. After stirring overnight at room temperature, the insoluble matter was filtered off, the filtrate was washed with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a residue. The product was purified by silica gel column chromatography to obtain L-
N- (benzyloxycarbonyl) -leucyl-L-
(O-benzyl) -serine ethyl ester was obtained (2.
74, 75%). 1.58 g (3.
4 mmol) of anhydrous tetrahydrofuran (50 ml) under ice cooling with stirring, and 182 mg (8.4 mmo) of lithium borohydride.
l) was added and then 3 ml of methanol was 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 the step 1), it was extracted twice with methylene chloride. The organic layer was washed with saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated, and the obtained residue was recrystallized from benzene-ethyl acetate to give the corresponding alcohol (0.1%).
965 g (yield 67%) was obtained. 900 mg (2.1 mmol) of the obtained alcohol and triethylamine 850
mg (8.4 mmol) of anhydrous dimethyl sulfoxide solution (1
A solution of 1.33 g (8.4 mmol) of sulfur trioxide pyridine complex in anhydrous dimethyl sulfoxide (10 ml) was added dropwise to 0 ml) 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 layers were washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, 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 oily substance.

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) L-N-benzyloxycarbonyl leucine- (2R)-(1-formyl-2-benzylthio) ethylamide (Compound (42)) Synthesized in Reference Example 1 by a method similar to that in Example 1. 2.2 g of commercially available L-S-benzyl-cysteine ethyl ester hydrochloride was used in place of the compound (1) described above to give the title compound (4
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 =
5.86Hz, 2H), 1.48-1.75 (m, 3H), 0.95 (d, J = 5.97Hz, 6H) Rf value: 0.35 (developing solvent A): 0.25 (developing solvent B) (Example 3) ) L-N-benzyloxycarbonyl leucine- (2R)-[1-formyl-2- (2-phenylethylthio)] ethylamide (Compound (43)) A 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)
0.57 g of the title compound (43) was obtained as an oily substance.

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)) The compound (1) synthesized in Reference Example 1 by a method similar to that in Example 1. Compound (3) 3.4 synthesized in Reference Example 3 instead of
Using 0.7 g, 0.79 g of the title compound (44) was obtained as an oily substance.

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 = 6.73Hz, 6H) Rf value: 0.31 (developing solvent A): 0.26 (developing solvent B) (Example 5) L-N-benzyloxycarbonylleucine- (2R)-[ 1-Formyl-2- (3-phenylpropyloxy)] ethylamide (Compound (45)) Instead of the compound (1) synthesized in Reference Example 1 by the method according to Example 1, a compound (4 synthesized in Reference Example 4). ) 1.1
Using 3 g, 0.315 g of the title compound (45) was obtained as an oily substance.

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) L-N-benzyl Oxycarbonyl leucine- (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 the method according to Example 1
Using 0 g, 0.33 g of the title compound (46) was obtained as an oily substance.

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 = 4.45Hz, 6H) Rf value: 0.21 (developing solvent A): 0.24 (developing solvent B) Example 7) L-N-benzyloxycarbonylleucine- (2R)-(1-formyl-2-diphenylmethylthio) ethylamide (Compound (47)) The compound (1) synthesized in Reference Example 1 by a method similar to that in Example 1. In place of the compound (6) 1.1 synthesized in Reference Example 6
Using 3 g, 0.17 g of the title compound (47) was obtained as an oily substance.

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) L-N-benzyloxycarbonyl leucine -(2R)-(1-formyl-2-cyclohexylmethylthio) ethylamide (compound (48)) Instead of the compound (1) synthesized by the method according to Example 1, the compound (7) synthesized in Reference Example 7.2. Using 53 g, 0.74 g of the title compound (48) was obtained as an oily substance.

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 = 6.02Hz, 6H) Rf value: 0.38 (developing solvent A): 0.28 (developing solvent B) (Example 9) L-N-benzyloxycarbonyl leucine -(2R)-(1-formyl-2-cyclopentylthio) ethylamide (Compound (49)) Instead of the compound (1) synthesized in Reference Example 1 by the method according to Example 1, a compound synthesized in Reference Example 8 ( 8) 2.0
Using 0.2 g, 0.29 g of the title compound (49) was obtained as an oily substance.

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) L-N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- ( Thiophene-
2-ylmethyl) thio] ethylamide (compound (5
0)) Instead of the compound (1) synthesized in Reference Example 1 by the method according to Example 1, the compound (9) 0.9 synthesized in Reference Example 9 was used.
Using 6 g, 0.22 g of the title compound (50) was obtained as an oily substance.

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 = 6.08Hz, 6H) Rf value: 0.28 (developing solvent A): 0.18 (developing solvent B) (Example 11) L-N-benzyl Oxycarbonyl leucine- (2R)-[1-formyl-2- (thiophene-
3-ylmethyl) thio] ethylamide (compound (5
1)) A compound (10) synthesized in Reference Example 10 instead of the compound (1) synthesized in Reference Example 1 by the method according to Example 1.
Using 2.5 g, 1.49 g of the title compound (51) was obtained as an oily substance.

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 = 5.96Hz, 6H) Rf value: 0.33 (developing solvent A): 0.22 (developing solvent B) (Example 12) L-N- [1- (Benzyloxycarbonyl) -piperidine-4-carbonyl] leucine- (2
R)-[1-formyl-2-benzylthio) ethylamide (compound (52)) A compound (3) synthesized in Reference Example 37 in place of N- (benzyloxycarbonyl) leucine by the method according to Example 1
8) and the compound (1) synthesized in Reference Example 1 were replaced with 0.98 g of commercially available L-S-benzyl-cysteine ethyl ester hydrochloride to obtain 0.39 g of the title compound (52) as an oily substance.

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 = 5.58Hz, 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 the compound (11) synthesized in Reference Example 11 (3.
98 mmol) and L-N- (benzyloxycarbonyl) leucine N-hydroxysuccinimide ester 1.4
0.81 g (3.98 mmol) of triethylamine was added dropwise to 5 g (3.98 mmol) of a chloroform solution while stirring with ice cooling, and the mixture was further stirred overnight. The reaction solution was washed with a 1N-hydrochloric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and water, 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 give L as an ester. -N- (benzyloxycarbonyl)-
Leucyl- (L) -S- (naphthalen-1-yl-methyl) cysteine ethyl ester 0.9 g (42%) was obtained. A solution of 0.9 g (1.68 mmol) of the obtained ester compound in anhydrous tetrahydrofuran was added with lithium borohydride (0.1%).
073 g (3.35 mmol) was added, methanol was added dropwise under ice cooling, water was added dropwise to the reaction solution which was stirred for 3 hours, and the solvent was evaporated 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. The obtained residue was purified by silica gel column chromatography to give an alcohol compound. 0.577 g was obtained (yield 69%).

0.55 g (1.11 mmol) of alcohol
And 0.45 g (4.44 mmol) of triethylamine in anhydrous dimethylsulfoxide solution were stirred at room temperature under stirring with sulfur trioxide-pyridine complex (0.708 g, 4.44 mmo).
l) Dimethylsulfoxide solution was added dropwise and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted three times with ethyl acetate, washed successively with 10% aqueous citric acid solution, saturated saline solution, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Then, 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 to 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) L-N-benzyloxycarbonyl leucine- (2R)-[1-formyl-2 (naphthalene-2
-Ylmethyl) thio] ethylamide (Compound (54)) By a method similar to that in Example 13, the compound (1) synthesized in Reference Example 12 instead of the compound (11) synthesized in Reference Example 11 was obtained.
2) Using 1.26 g, 0.1 g of the title compound (54) was obtained as an oily substance.

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 = 6.36Hz, 6H) Rf value: 0.29 (developing solvent A): 0.22 (developing solvent B) (Example 15) L-N-benzyloxycarbonyl leucine- (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)
0.57 g of the title compound (55) was obtained using 1.24 g.

Melting point (° C): 128.6 to 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 = 4.29Hz, 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 (3.2) of the compound (40) synthesized in Reference Example 40
2 mmol), 0.326 g (3.22 mm) of triethylamine
ol) 1-hydroxybenztriazole 0.443 g
(3.22 mmol) and 0.748 g (3.22 mmol) of the compound (17) synthesized in Reference Example 16 in chloroform solution (100 ml) of 0.664 g (3.22 mmol) of dicyclohexylcarbodiimide with cooling and stirring in a salt-ice bath. The chloroform solution was added dropwise. It was further stirred overnight. The insoluble material was filtered off, the filtrate was washed successively with 1N-hydrochloric acid, saturated NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was 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.

0.89 g (1.8 mm) of the above compound obtained
ol) and 0.13 g of triethylamine (7.22 mmo
l) in anhydrous dimethylsulfoxide solution (10 ml) under stirring at room temperature, sulfur trioxide-pyridine complex 1.14
An anhydrous dimethyl sulfoxide solution (10 ml) of g (7.22 mmol) 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 layers were washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, 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 oily substance.

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) L-N- (N-phenylcarbamoyl)
Leucine- (2R)-[1-formyl-2- (4-chlorobenzylthio)] ethylamide (Compound (57)) A reference example was used instead of the compound (40) synthesized in Reference Example 40 by the method according to Example 16. Compound synthesized in 38 (38)
Using 1 g, 0.34 g of the title compound (57) was obtained as an amorphous substance.

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 ~ 4.40 (m, 1H), 3.60 ~ 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)) A compound (39) synthesized in Reference Example 39 instead of the compound (40) synthesized in Reference Example 40 by the method according to Example 16
Using 1 g, 0.54 g of the title compound (58) was obtained as an amorphous substance.

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) L-N- (benzyloxycarbonyl)
Phenylalanine- (2R)-[1-formyl-2-
(4-Chlorobenzylthio)] ethylamide (Compound (59)) 1 g of commercially available (L) -N- (benzyloxycarbonyl) phenylalanine instead of the compound (40) synthesized in Reference Example 40 by the method according to 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 ~ 4.51 (m, 2H), 3.35 ~ 3.45 (m, 2H), 3.00 ~ 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)) 1 g of commercially available LN- (benzyloxycarbonyl) valine was used in place of the compound (40) synthesized in Reference Example 40 by the method according to Example 16 to give the title compound (60) 0.1.
4 g was obtained.

Melting point (° C.): 126.2-128.7 NMR (δ, CDCl ₃ ): 9.52 (s, 1H), 7.20-7.45
(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 ~ 2.90 (m, 2H), 2.10 ~ 2.25 (m, 1H), 0.90 ~ 1.05 (m, 6
H) Rf value: 0.36 (developing solvent A): 0.21 (developing solvent B) (Example 21) L-N- (benzyloxycarbonyl)
Leucine- (2R)-[1-formyl-2- (4-chlorobenzyl) thio] ethylamide (Compound (61)) 4 g (17.26) of the compound (17) synthesized in Reference Example 16
mmol) and 1.74 g (17.26 g) of triethylamine.
L) in chloroform solution (200 ml) under ice cooling with stirring.
-N- (benzyloxycarbonyl) leucine N-hydroxysuccinimide ester 6.25 g (17.2)
(6 mmol) was added little by little, and the mixture was returned to room temperature and stirred overnight. The reaction solution was washed successively with 1N-hydrochloric acid, saturated sodium hydrogen carbonate solution (three times) and saturated brine, 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 was obtained.
7.8 g (16.28 mmol) of the obtained alcohol compound
And a solution of triethylamine (6.57 g, 65 mmol) in anhydrous dimethyl sulfoxide (100 ml) with stirring at room temperature, sulfur trioxide pyridine complex 10.34 g (65
Anhydrous dimethylsulfoxide solution (30 ml) of (mmol) 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 solution, saturated sodium hydrogen carbonate solution and saturated brine, 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 = 4.88Hz, 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) L-N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3-chlorobenzyl) thio] ethylamide (Compound (62)) A compound synthesized in Reference Example 16 by a method similar to that in Example 21. Instead of (16), the compound (1
5) Using 3.0 g, 0.68 g of the title compound (62) was obtained.

Melting point (° C.): 97.6-103.3 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. Instead of the compound (14) synthesized in Reference Example 14
Using 8.7 g, 2.75 g of the title compound (63) was obtained.

Melting point (° C.): 110.1-118.3 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) L-N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3- Fluorobenzyl) thio] ethylamide (Compound (64)) Instead of the compound (16) synthesized in Reference Example 16 by the method according to Example 21, the compound (17) synthesized in Reference Example 17
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), 7.24-7.34 (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 = 5.37Hz, 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) L-N-benzyloxycarbonylleucine- (2R)-[1-formyl -2- (4-Fluorobenzyl) thio] ethylamide (Compound (65)) A compound (18) synthesized in Reference Example 18 instead of the compound (16) synthesized in Reference Example 16 by the method according to Example 21.
0.86 g of the title compound (65) was obtained using 6.46 g.

Melting point (° C.): 71.2 to 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) L-N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- ( 2-Methoxybenzyl) thio] ethylamide (Compound (66)) Instead of the compound (17) synthesized in Reference Example 17 by the method according to Example 21, the compound (19) synthesized in Reference Example 19
0.88 g of the title compound (66) was obtained using 5.0 g.

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 = 5.86Hz, 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) Example 27) L-N-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)
0.71 g of the title compound (67) was obtained using 3.41 g.

Melting point (° C.): 113.8 to 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 = 5.97Hz, 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)) A reference example instead of the compound (16) synthesized in Reference Example 16 according to the method of Example 21. Compound (21) synthesized in 21
Using 4.54 g, 0.13 g of the title compound (68) was obtained as an oily substance.

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 = 5.86Hz, 6H) Rf value: 0.19 (developing solvent A): 0.26 (developing solvent B) Example 29) L-N-benzyloxycarbonylleucine- (2R)-[1-formyl-2-3-nitrobenzyl) thio] ethylamide (Compound (69)) A 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)
0.37 g of the title compound (69) was obtained using 4.18 g.

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 = 5.68Hz, 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. Instead of the compound (23) synthesized in Reference Example 23
Using 2.17 g, 0.1 g of the title compound (70) was obtained as an oily substance.

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) L-N-benzyloxycarbonylleucine- ( 2S)-[1-Formyl-3-phenyloxy) propylamide (Compound (71)) The compound (24) synthesized in Reference Example 25 instead of the compound (16) synthesized in Reference Example 16 by the method according to Example 21. )
Using 0.52 g, 0.52 g of the title compound (71) was obtained as an oily substance.

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 = 6.24Hz, 6H) Rf value: 0.26 (developing solvent A): 0.19 (developing solvent B) Example 32) L-N-benzyloxycarbonylleucine- (2S)-[1-formyl-3-phenylthio)
Propylamide (Compound (72)) A compound (25) synthesized in Reference Example 25 instead of the compound (16) synthesized in Reference Example 16 by the method according to Example 21.
Using 0.87 g, 0.42 g of the title compound (72) was obtained as an oily substance.

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. Instead of the compound (26) synthesized in Reference Example 26.
Using 0.55 g, 0.50 g of the title compound (73) was obtained as an oily substance.

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) L-N-benzyloxycarbonylleucine- (2S)-[1-formyl-3- (2-fluorophenyl) oxy] propylamide (Compound (74)) A 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)
Using 0.69 g, 0.66 g of the title compound (74) was obtained as an oily substance.

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) L-N-benzyloxycarbonylleucine- (2S )-[1-Formyl-3- (3-fluorophenyl) oxy] propylamide (Compound (75)) Synthesized in Reference Example 28 instead of the compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (28)
Using 0.27 g, 0.06 g of the title compound (75) was obtained as an oily substance.

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) L-N-benzyl Oxycarbonylleucine- (2S)-[1-formyl-3- (2-chlorophenyl) oxy] propylamide (Compound (76)) Instead of the compound (16) synthesized in Reference Example 16 according to the method of 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), 7.33-7.39 (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) L-N-benzyloxycarbonylleucine- ( 2S)-[1-Formyl-3- (3-chlorophenyl) oxy] propylamide (Compound (77)) Synthesized in Reference Example 30 instead of the compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (30)
Using 1.07 g, 0.42 g of the title compound (77) was obtained as an oily substance.

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) ) L-N-benzyloxycarbonyl leucine- (2S)-[1-formyl-3-benzylthio)
Propylamide (Compound (78)) The compound (31) synthesized in Reference Example 31 instead of the compound (16) synthesized in Reference Example 16 by the method according to Example 21.
0.8 g of the title compound (78) was obtained using 1.9 g.

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) L-N-benzyloxycarbonyl leucine -(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 similar to that of 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), 7.19-7.37 (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 = 6.24Hz, 6H) Rf value: 0.51 (developing solvent A): 0.24 (developing solvent B) (Example 40) L-N-benzyloxycarbonyl leucine -(2S)-[1-Formyl-3 (2-chlorobenzyl) thio] propylamide (Compound (80)) Reference Example 33 instead of the compound (16) synthesized in Reference Example 16 by a method similar to that of Example 21. Compound synthesized in (33)
Using 1.2 g, 0.72 g of the title compound (80) was obtained as an oily substance.

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), 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) L-N-benzyloxycarbonylleucine- (2S)-[1-formyl-3 (2-Fluorophenyl) thio] propylamide (Compound (81)) Instead of the compound (16) synthesized in Reference Example 16 by the method according to Example 21, the compound (34) synthesized in Reference Example 34.
Using 1.35 g, 0.96 g of the title compound (81) was obtained as an oily substance.

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) L-N-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 the compound (16)
Using 1.25 g, 0.58 g of the title compound (82) was obtained.

Melting point (° C.): 109.5-149.0 (decomposition) NMR (δ, CDCl ₃ ): 9.54 (s, 1H), 7.12-7.40 (m, 9)
H), 6.62-6.85 (m, 1H), 5.09-5.15 (m, 3H), 4.54-4.60 (m, 1
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) L-N-benzyloxycarbonyl leucine- (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 the compound (16)
Using 1.58 g, 0.71 g of the title compound (83) was obtained as an oily substance.

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 extracted from Japanese white rabbit skeletal muscle by Tsuj.
i and Imahori (J. Biochem. 90, 23
3-240 (1981)), partially purified,
Used in the experiment.

Anticalpain activity was measured by Yoshimu
ra (J. Biol. Chem. 258, 8883-8.
889 (1983)) and the like. That is,
4% casein solution 0.05 ml, 50 mM cysteine solution 0.05 ml, calpain solution 0.05 ml, purified water 0.0
A mixed solution containing 0.025 ml of a 25 ml test drug solution (10% dimethyl sulfoxide solution) and 0.25 ml of a 200 mM imidazole hydrochloric acid buffer (pH 7.5) was heated at 30 ° C. for 3 minutes. Then, a 50 mM calcium chloride solution of 0.
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 trichloroacetic acid-soluble fraction of casein hydrolyzed by calpain was measured by Ross and Sc.
hatz (Anal. Biochem. 54, 304-
306 (1973)) to determine the absorbance (a). At the same time, a blind absorbance (b) was measured using only a 10% dimethyl sulfoxide solution instead of the test drug solution. The calpain inhibition rate is calculated by the following formula [(b-
a) / b] × 100, and the amount required for 50% inhibition [IC ₅₀ ] was calculated by the probit method. The compound produced in each Example is used as a test drug, and the measurement results are shown in Table 1.

[0146]

[Table 1]

Test Example 2 Measurement of Platelet Aggregation Inhibitory Action The preparation of rabbit platelet-rich plasma and the measurement of platelet aggregation were carried out according to B
orn and Cross (J. Phystol. 168, 1)
78-195 (1963)). That is, 3.8% from the Japanese white rabbit carotid artery without anesthesia
9 volumes of blood were collected for 1 volume of the sodium citrate solution. Immediately, centrifugation was carried out at 200 × g at 20 ° C. for 15 minutes to obtain a supernatant platelet-rich plasma (hereinafter abbreviated as PRP). P
RP is an automatic blood cell counter (Nihon Kohden: MEK-415
The number of platelets was measured in 0) and 55 × 10 ⁴ or more were used per 1 μl.

The platelet aggregation inhibitory action is 200 μl of PRP.
To the test drug solution, 10 μl of the test drug solution was added, and after heating at 37 ° C. for 5 minutes, 10 μl of 22 μg / ml collagen was added to induce agglutination reaction of platelets by an aglycometer (NKK, PAT-4).
It was measured using A). At the same time, a maximum aggregation rate of 10 was obtained 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 required for 50% inhibition [IC ₅₀ ] 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 prepared so that the final concentration was 1% or less. The compounds produced in each example are used as test drugs, and the measurement results are shown in Table 2.

[0150]

[Table 2]

Test Example 3 Measurement of Protease Inhibiting Activity Other than Calpain Measurement of Antitrypsin Activity The measurement of antitrypsin activity was carried out by Aoyagi (J. Ant).
ibiotics, 22, 558-568 (1969)
The method was partially improved.

0.5 ml of 2% casein solution, 0.05 ml of 50 mM calcium chloride, 0.05 ml of test drug solution (containing 10% dimethyl sulfoxide), 0.1 ml of purified water and 7
A mixture containing 0.25 ml of 0 mM borate buffer (pH 7.4) was heated at 37 ° C. for 3 minutes. Then, 0.1 mg / ml trypsin solution was added to start the reaction. After reacting at 37 ° C for 30 minutes, 1N of 1.7N perchloric acid was added to stop the reaction. After left at room temperature for 60 minutes, 3000 rpm, 1
Absorbance of supernatant at 280 nm (a) after centrifugation for 0 minutes
Was measured. At the same time, blind absorbance using only 10% dimethyl sulfoxide solution instead of the test drug solution (b)
Was measured. The trypsin inhibition rate is 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 inhibitory activity at a concentration of 10 ^-5 M.

Measurement of Anti-α-Chymotrypsin Activity The measurement of anti-α-chymotrypsin activity was carried out by Errange.
r, B. F. (Ach. Biochem. Biophy
s. 115, 206-210 (1966), etc. were partially improved. That is, 0.05 ml of 10 mM glutaryl-L-phenylalanine-p-nitroanilide solution (containing 10% dimethyl sulfoxide-10% polyoxyethylene 60 hydrogenated castor oil), 0.1 ml of 50 mM calcium chloride solution, 0.25 ml of purified water, Test drug solution (10%
Dimethyl sulfoxide-10% polyoxyethylene 6
A mixed solution containing 0.05 ml of 0 hydrogenated castor oil) and 0.5 ml of 100 mM Tris-HCl buffer (pH 7.8) at 25 ° C.
And warmed for 3 minutes. Then, 2 mg / ml α-chymotrypsin (Type-II) was added to start the reaction, and immediately 25 ° C.
The increase in absorbance at 405 nm was measured with time to obtain the rate of change (a) in absorbance per minute. At the same time, 10% dimethyl sulfoxide-10% instead of the test drug solution
The rate of change (b) in absorbance per minute in a blind test using only polyoxyethylene 60 hydrogenated castor oil solution was measured.
The α-chymotrypsin inhibition rate is calculated by the following formula [(b−a) / b] ×
Calculated by 100, the amount required for 50% inhibition [IC ₅₀ ]
Was calculated by the probit method. For comparison, Japanese Patent Laid-Open No. 1-1
Compound SUAM-14541 manufactured by 21257
Was used for the measurement. The results are shown in Table 3.

[0156]

[Table 3]

[0157]

INDUSTRIAL APPLICABILITY 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 the treatment of ischemic diseases caused by abnormal activity of calpain.

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[Procedure amendment]

[Submission date] February 16, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0156

[Correction method] Change

[Correction content]

[0156]

[Table 3]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yasuo Sekine 2-7-1, Nishi-Shinjuku, Shinjuku-ku, Tokyo Fuji Rebio Co., Ltd.

Claims (1)

[Claims] 1. A 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 —, and m is 0.1 Or 2, and n is 1 to 5).