JPH11322786A - Depsipeptide containing non-natural amino acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new depsipeptide (salt) having an apolipoprotein E production-promoting action and useful for the treatments of dementia, hyperlipemia, etc. SOLUTION: The compound of formula I R<1> is a 5-20C alkyl or a 5-15C alkoxymethyl; R<2> is O-CO-CH(R<5> )-X-CH(R<6> )-NH (X is CH2 -CO, CH2 -CH2 or the like; R<5> and R<6> are each H or a 1-6C alkyl); R<3> is a group of formula II [Y is CH2 -CH2 , CH=CH or the like; R<9> and R<10> are each H or a 1-6C alkyl; R<11> is an amino-protecting group; (n) is 1-3]; R<4> is hydroxyl group, a 1-6C alkoxy, benzyloxy or the like], for example, a compound of formula III, is obtained, e.g., by reacting a compound of formula IV with a compound of formula V and subsequently reacting the obtained compound of formula VI with Fmoc-L-aspartic acid β-t-butyl ester.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel depsipeptide and a medicament containing the same as an active ingredient. The depsipeptide of the present invention has an apolipoprotein E production promoting effect, is useful as a therapeutic agent for nerve damage, particularly as a therapeutic agent for dementia, and is also useful as a therapeutic agent for hyperlipidemia.

[0002]

2. Description of the Related Art Drugs for improving cerebral circulation and metabolism are mainly used as therapeutic drugs for senile dementia, but these drugs are not suitable for the destruction of the central nervous system, which is considered to be the cause of senile dementia. No improvement effect is shown. As a result, it does not show any improvement effect on memory impairment or computational impairment, which is the core symptom of dementia. Therefore, a drug that promotes repair and growth of the nervous system and suppresses the breakdown of the central nervous system is required as a therapeutic agent for a new type of senile dementia. On the other hand,
Apolipoprotein E has been reported to be expressed at high levels in damaged and recovering nervous system sites (eg, MJ Igunalius et al., Pro. Natl. Acad. Sci. U.
SA, 83: 1125 (1986)), suggesting that it may play an important role in nervous system repair. More recently,
It has been reported that when apolipoprotein E is intravenously administered to WHHL rabbits, which are human model animals of familial hypercholesterolemia homozygous, a marked decrease in plasma cholesterol level is observed (Yamada, et. Al., Proceeding
ofNational Academy Science USA, Vol.86, pp665-66
9, 1989), and it has been reported that when apolipoprotein E gene is introduced into mouse liver in a large amount and apolipoprotein E is expressed in large amounts, plasma cholesterol and triglyceride are significantly reduced (Shimano, H. et al.). .
al., Journal of Clinical Investigation, Vol.90, pp
2084-2091, 1992).

[0003] As revealed by these reports, increasing plasma apolipoprotein E levels is associated with hyperlipidemia, especially familial hypercholesterolemia, which has been considered difficult to treat with conventional drugs. It is extremely effective as a treatment for homozygotes. The present inventors have previously proposed a possible method for increasing plasma apolipoprotein E concentration,
Various depsipeptide compounds have been found to be useful as orally administrable low-molecular-weight compounds, which have the effect of promoting the production of apolipoprotein E in the liver, which is a major organ for producing apolipoprotein E, and have been found to be useful in Japanese Patent Application Laid-Open No. H10-163,873. 8-1839
No. 60 and Japanese Patent Application No. 8-271321 were completed.

[0004]

Under such circumstances, the present inventors have conducted intensive studies to provide a drug which promotes the production of apolipoprotein E. Thus, the present invention was completed.

[0005]

According to the present invention, there is provided a compound represented by the general formula (1):

Embedded image [Wherein, R ¹ represents a linear or branched C ₅ -C ₂₀ alkyl group or a linear or branched C ₅ -C ₁₅ alkoxymethyl group, and R ² represents — ^{O-CO-CH (R 5} ) -X-CH (R 6) -NH- ( wherein, X ^{is, N (R 7) -CO,} N (R 8) -CH 2, CH 2
_{-CO, CH 2 -CH 2, CH} = CH, CH 2 -CH (O
H), CH (OH) -CH (OH), R ⁵ , R ⁶ , R ⁷ ,
R ⁸ is hydrogen or linear or branched C ₁ -C ₆
R ³ represents an alkyl group).

Embedded image(Where Y is N (R¹²) -CO, N (R¹³) -CH_Two, C
H_Two-CO, CH_Two-CH_Two, CH = CH, CH_Two-CH
(OH), CH (OH) -CH (OH), wherein n is 1 to 3
Represents an integer;⁹, R^Ten, R¹², R¹³Is hydrogen or direct
Chain or branched C₁~ C₆Represents an alkyl group;
¹¹Is commonly used in peptide chemistry as an amine protecting group.
R represents a protecting group).^FourIs a hydroxyl group, linear
Or branched C₁~ C₆Alkoxy group, benzyloxy
Group, A, AB, or -NH-CH (R¹⁴) -Z-CH (R^Fifteen) -COR¹⁶  (Where Z is CH_Two−N (R¹⁷), CO-CH_Two, CO-
N (R¹⁸), CH_Two-CH_Two, CH = CH, CH (OH) -C
H_Two, CH (OH) -CH (OH), R¹⁴Is hydrogen, C₁
~ C₆Alkyl group or-(CH_Two)_m-COR¹⁹Indicates that
R^Fifteen, R¹⁷, R¹⁸Is hydrogen or a linear or branched chain
C₁~ C₆Represents an alkyl group;¹⁶Is a hydroxyl group, straight chain
Or branched C₁~ C₆Alkoxy group or ben
Represents a zyloxy group;¹⁹Is a hydroxyl group, an amino group or C
₁~ C₆Represents an alkoxy group, and m represents an integer of 1 to 3)
A represents alanine, valine, leucine, isoleuc
Syn, phenylalanine, tyrosine, proline, Aspa
Laginic acid, asparagine, glutamic acid, glutamine,
Consists of serine, lysine and β-t-butylalanine
Amino acid residues or the N-methyl of these amino acid residues
Body, B is alanine, valine, leucine, isolo
Isine, serine, threonine, lysine, hydroxylysine
Arginine, cysteine, methionine, phenyla
Lanin, tyrosine, tryptophan, histidine, pro
Phosphorus, 4-hydroxyproline, aspartic acid, as
Paragine, glutamic acid, glutamine, piperidine-4
-Carboxylic acids, homoproline, octahydroindole
-2-carboxylic acid, norvaline, norleucine, α-t
-Butylglycine, cyclohexylglycine, azetidi
2-carboxylic acid, 3- (3-pyridyl) alanine,
(3-N-methyl) piperidylalanine, 3- (2-na)
Fthyl) alanine, β-cyclohexylalanine, β-
t-butylalanine, 9-anthracenylalanine, α
-Selected from methylalanine and 2-aminobutanoic acid
Amino acid residues or the N-methyl
A free amino group in A or B, free
Carboxyl group, free ω-carbamide group, free water
Acid groups, free mercapto groups and / or N-terminal
Mino groups are commonly used in peptide chemistry as their protecting groups
Each may be protected by a protecting group, and
The amino acid residue in the above A or B is lysine, hydro
Xylosine, glutamic acid or aspartic acid
In this case, an amino group that binds the peptide to the adjacent amino acid
Or the carboxyl group is in the α-position or ω
-Position. Where X is N (R⁷) -CO
And Y is N (R¹²) -CO and R^FourIs a hydroxyl group,
Chain or branched C₁~ C₆Alkoxy group, benzyl
Group, A, AB or -NH-CH (R¹⁴) -Z
-CH (R^Fifteen) -COR¹⁶｛Z is CO-N (R^{1 8})
Except when. ] Containing an unnatural amino acid
Depsipeptide or a pharmacologically acceptable salt thereof
About.

[0006] The present invention also relates to a medicament comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. The present invention specifically relates to an apolipoprotein E production enhancer comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a therapeutic agent for nerve damage, comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. More specifically, the present invention also relates to a therapeutic agent for dementia comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. The present invention further relates to a therapeutic agent for hyperlipidemia containing the above-mentioned unnatural amino acid-containing depsipeptide or a pharmaceutically acceptable salt thereof as an active ingredient.

In the general formula (1), preferably, X is CHＣＨCH or CH ₂ —CH ₂ and Y is N (R ¹² ) —
CO or N (R ¹³⁾ is -CH _2, R ⁴ is hydroxyl, A,
A-B or ^{-NH-CH (R 14) -Z} -CH (R 15) -C
OR ¹⁶ (Z is CH = CH). The general formula
Preferred compounds of (1) are those wherein X is CH = CH, Y is N (R ¹² ) -CO or N (R ¹³ ) -CH ₂ , and R ⁴ is hydroxyl, A, AB or -NH -CH (R ¹⁴⁾ -Z-CH
(R ¹⁵⁾ -COR ¹⁶ (Z is CH = is CH) and a depsipeptide or a pharmacologically acceptable salt thereof, and X is CH ₂ -CH _2, Y is N (R ¹²⁾ -CO And
A depsipeptide wherein R ⁴ is AB or a pharmacologically acceptable salt thereof. In the general formula (1), R ⁴
Is a hydroxyl group, or A is aspartic acid, asparagine, glutamic acid or glutamine, and B is alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, proline, aspartic acid, asparagine, glutamic acid, glutamine, β-t-butyl. A depsipeptide containing an unnatural amino acid that is alanine or a pharmaceutically acceptable salt thereof is preferred. In the general formula (1), R ¹⁶ is preferably a hydroxyl group.

[0008] The amino acid constituting the depsipeptide containing an unnatural amino acid having the general formula (1) of the present invention described above may be either an L-form or a D-form. In amino acids A and B, free amino groups, free carboxyl groups, free ω-carbamide groups, free hydroxyl groups, free mercapto groups and / or N-terminal amino groups are usually used as their protecting groups in peptide chemistry. Each of the amino acid residues of A and B may be protected with lysine,
In the case of hydroxylysine, glutamic acid or aspartic acid, the amino group or carboxyl group that binds to a peptide adjacent to an adjacent amino acid may be at the α-position or at the ω-position.

The protecting groups for the above free amino group include a t-butoxycarbonyl (hereinafter referred to as "Boc") group and a benzyloxycarbonyl (hereinafter referred to as "Cbz").
) Group, p-methoxybenzyloxycarbonyl group or 9-fluorenylmethoxycarbonyl (hereinafter, referred to as
And a protecting group for a free carboxyl group such as benzyloxy (hereinafter referred to as “OBz”).
l ") group, t-butoxy (hereinafter" OtBu ") group or phenacyloxy (hereinafter" OPac ") group
A protecting group for the ω-carbamide group of Gln or Asn, such as a 4,4′-dimethoxybenzhydryl (hereinafter, referred to as “Mbh”) group or a trityl (hereinafter, referred to as “Trt”) group; The protecting groups for free hydroxyl groups are OBzl group and OtBu group, and the protecting groups for free mercapto groups in amino acid residues are benzyl group and T
rt group, acetamide methyl group and the like. The protecting group for the N-terminal amino group of the depsipeptide may be Bo
Protecting groups usually used in peptide chemistry such as c group, Cbz group, p-methoxybenzyloxycarbonyl group and Fmoc group are used. Protecting groups for the C-terminal carboxyl group of the depsipeptide include OBzl group, Ot
A Bu group, an OPac group or the like is used.

The depsipeptide having the general formula (1) of the present invention has an action of promoting the production of apolipoprotein E by Hep G2 cells having various liver functions. Apolipoprotein E has a repair effect on nerve damage and also has an effect of lowering blood levels of cholesterol and triglyceride.Therefore, the depsipeptide of the present invention having an action of promoting production of apolipoprotein E is a therapeutic agent for nerve damage, particularly It is useful as a therapeutic drug for dementia and hyperlipidemia.

The depsipeptide containing an unnatural amino acid represented by the general formula (1) or a pharmacologically acceptable salt thereof of the present invention can be produced by a method usually used in peptide synthesis. For example, the condensing agent method, azide method, chloride method, acid anhydride method, mixed acid anhydride method, mixed acid anhydride method, active ester method, described in Nobuo Izumiya et al. An oxidation-reduction method, an enzymatic method, or the like can be used.

For example, the depsipeptide containing an unnatural amino acid of the present invention or a pharmaceutically acceptable salt thereof is represented by the general formula (2)

Embedded image(Where R¹Has the same meaning as described above)
The hydroxyl group of 3-hydroxycarboxylic acid or
After protecting or activating the carboxyl group,
N-terminal required for hydroxyl group of droxycarboxylic acid
End-protected aminocarboxylic acid, ie, P-HN-CH (R⁶) -X-CH (R^Five) -COOH (wherein P represents a protecting group for an amino group)
And the carboxy group of the 3-hydroxycarboxylic acid.
The required aminocarboxylic acid derivative, ie, H_TwoN-CH (R¹⁴) -Z-CH (R^Fifteen) -COR¹⁶  Are condensed according to a standard method, and the N-terminal and
Or after deprotection of the C-terminal protecting group, the amino group
And carboxyl groups in order according to the standard method of peptide synthesis.
Next, to produce by condensing with the desired amino acid
Can be.

Alternatively, the above-mentioned aminocarboxylic acid can be prepared by condensing the above-mentioned aminocarboxylic acid with a necessary amino acid in advance, and then bonding it to the hydroxyl group or carboxyl group of the above-mentioned 3-hydroxycarboxylic acid by an ester bond or an amide bond. can do.

The carboxyl group of the compound represented by the general formula (2) is protected by a methyl esterification reaction by reacting with diazomethane in a solvent such as ether or methanol under ice-cooling or at room temperature, or dimethylformamide (hereinafter referred to as "DMDM").
F ”), dimethyl sulfoxide (hereinafter“ DMS ”).
O ") in the presence of a basic substance such as triethylamine in the presence of a basic substance such as triethylamine in a solvent such as benzyl esterification.

Condensation of an aminocarboxylic acid with a hydroxyl group of a compound having a protected carboxyl group can be carried out by ether, acetone, chloroform, dichloromethane, ethyl acetate, DMF, tetrahydrofuran (hereinafter referred to as “THF”).
N, N'- as a condensing reagent in a solvent such as acetonitrile, DMSO or the like under ice-cooling or room temperature, preferably in the presence of an acylation catalyst such as dimethylaminopyridine (hereinafter referred to as "DMAP"). Dicyclohexylcarbodiimide (N, N'-Dicyclohexylcarbodiimide)
(Hereinafter referred to as “DCC”), 1-ethyl-3- (3 ′
-Dimethylaminopropyl) carbodiimide (1-Ethy
l-3- (3′-dimethylaminopropyl) carbodiimide) hydrochloride, that is, water-soluble carbodiimide (hereinafter “WSC”)
I ").

Specific examples of the 3-hydroxycarboxylic acid of the general formula (2) which is a starting material of the depsipeptide of the present invention include 3-hydroxycaprylic acid, 3-hydroxypelargonic acid, 3-hydroxy-capric acid, Hydroxylauric acid, 3-hydroxymyristic acid, 3-hydroxypalmitic acid, 3-hydroxymargaric acid, 3-hydroxystearic acid, 4-octyloxy-3-hydroxybutyric acid, 4-nonyloxy-3-hydroxybutyric acid,
4-decyloxy-3-hydroxybutyric acid, 4-undecyloxy-3-hydroxybutyric acid, 4-dodecyloxy-
3-hydroxybutyric acid or 4-tridecyloxy-3-
Hydroxybutyric acid and the like. These 3-hydroxycarboxylic acids of the general formula (2) may be an optically active substance and racemic R- form or S- body, C ₅ ~ of R ¹ is a linear or branched chain it is preferable to use R- body case to C ₂₀ alkyl radical, if R ¹ is a linear or branched chain C ₅ -C ₁₅ alkoxymethyl group S
-It is preferred to use the body.

In producing the depsipeptide having the general formula (1), when the condensing agent method is used, DCC,
WSCI, O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-yl-oxy-tris (dimethylamino) Phosphonium hexafluorophosphate (BOP) or O
-(7-azabenzotriazol-1-yl) -1,2,
3-Tetramethyluronium hexafluorophosphate (HATU) or the like can be used. Also, at the same time, additives usually used to suppress racemization,
For example, N-hydroxysuccinimide, 1-hydroxybenzotriazole (1-Hydroxybenzotriazole) (hereinafter, referred to as “HOBt”), N-hydroxy-5-norbonene-2,3-dicarbodiimide or 1-hydroxy-7-azabenzotriazole ( HOAt) is also preferable. The main condensing agent used in the azide method is diphenylphosphate azide (hereinafter referred to as “DP
PA "). Before performing the condensation reaction, it is preferable to protect the carboxyl group, amino group, hydroxyl group, mercapto group, ω-carbamide group and the like which are not involved in the condensation reaction by a generally known means. In this case, the above-mentioned various protecting groups can be used as the protecting group used for the protecting means.

The elimination reaction of the protecting group in the production process of the depsipeptide of the present invention needs to be capable of eliminating the protecting group without affecting the peptide bond, and may be appropriately selected depending on the kind of the protecting group to be used. I just need. Examples of the solvent used for the above-mentioned peptide synthesis include chloroform, dichloromethane, ethyl acetate, DMF, DMSO, pyridine,
Examples thereof include dioxane, THF, dimethoxyethane, and acetonitrile. If necessary, two or more solvents may be used in combination. In addition, this condensation reaction is carried out in the range of about -20 to 50 ° C. as in the usual case. Further, peptide synthesis can be produced by any of a liquid phase method and a solid phase method, and further, any of a column method and a batch method may be used.

When the depsipeptide of the present invention is a compound in the form of a salt, it is converted into a compound in a free form, and the thus prepared depsipeptide of the present invention is a compound in a free form. If desired, this can be converted into the compound in the form of its pharmacologically acceptable salts. And in the latter case, when the depsipeptide is an acidic compound due to the presence of a carboxyl group, a salt with an inorganic base, such as a sodium salt, a potassium salt, a calcium salt, an ammonium salt, or a salt with an organic base, and the peptide When the derivative is a basic compound due to the presence of an amino group, salts with inorganic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates, etc., or salts with organic acids, such as acetates, succinates Pharmaceutically acceptable salts such as acid, oxalate, malate and tartrate salts may be formed.

The depsipeptide of the present invention or a pharmaceutically acceptable salt thereof can be formulated into various dosage forms. That is, this preparation is orally administered as tablets, dragees,
It can be administered in the form of solid preparations such as hard capsules, soft capsules, granules and powders and liquid preparations such as solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of injections, suppositories and the like. In preparing these preparations, conventional additives for preparation such as excipients, stabilizers, preservatives, solubilizers, wetting agents, emulsifiers, lubricants, sweeteners, coloring agents, flavoring agents, and tonics are used. The preparation can be prepared by adding a preparation, buffer, antioxidant and the like.

Examples of additives include starch, sucrose,
Fructose, lactose, glucose, mannitol, sorbitol,
Precipitated calcium carbonate, crystalline cellulose, carboxymethylcellulose, dextrin, gelatin, gum arabic, magnesium stearate, talc, hydroxypropylmethylcellulose and the like can be mentioned.

When the depsipeptide of the present invention is used as a liquid preparation or an injection, the depsipeptide of the present invention can be dissolved or suspended in a conventional diluent. As a diluent, physiological saline, Ringer's solution, aqueous glucose solution,
Examples include alcohols, fatty acid esters, glycols, glycerin, fats and oils derived from animals and plants, paraffins, and the like. In addition, these preparations can be manufactured by a usual method.

The usual clinical dose is 0.5 to 2000 mg, preferably 1 to 1000 mg, and more preferably 5 to 50 mg per oral dose per adult.
Used in the range of 0 mg. In the case of parenteral administration per adult per day, the dose is 0.05 to 5000 mg.

Next, a specific example of the method for producing the depsipeptide of the present invention will be described as an example, a test on the apolipoprotein E-producing ability of the depsipeptide of the present invention will be described as a test example, and a preparation containing the depsipeptide of the present invention as an active ingredient will be described. Will be described as formulation examples.

The reaction steps in Example 1 are shown in Reaction Scheme 1, the reaction steps in Example 2 are shown in Reaction Scheme 2, and the reaction steps in Example 3 are shown in Reaction Scheme 3.
The reaction steps in Example 4 are shown in Reaction Scheme 4, the reaction steps in Example 5 are shown in Reaction Scheme 5, and the reaction steps in Example 6 are shown in Reaction Scheme 6. The compound numbers in each Example correspond to the compounds and their numbers shown in each reaction scheme.

[0026]

Embedded image

[0027]

Embedded image

[0028]

Embedded image

[0029]

Embedded image

[0030]

Embedded image

[0031]

Embedded image

[0032]

Embedded image

[0033]

EXAMPLES Example 1 1-i) To a mixed solution of 5-amino-3-pentenoic acid (1.00 g) in dioxane (17 mL), water (8.7 mL) and a 1M aqueous sodium carbonate solution (8.7 mL). Di-t-butyl dicarbonate (2.09 g) was added under ice cooling. After stirring the solution at room temperature for 5 hours, the solution was concentrated under reduced pressure to about 15 mL. This solution was adjusted to about pH 3 with a 10% aqueous citric acid solution under ice cooling. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was recrystallized from ethyl acetate-hexane to give 1.81 g of 5-Bocamino-3-pentenoic acid (intermediate compound 1). ¹ H-NMR (d ppm, CDCl ₃ ): 6.10 (1H, br s), 5.55-5.75
(2H, m), 4.66 (1H, br s), 3.65-3.80 (2H, m), 3.11
(2H, d, J = 6.4 Hz), 1.45 (9H, s).

1-ii) 3-hydroxymyristic acid 5.
Was dissolved in 50 mL of DMF, and triethylamine 2.
85 mL and 2.43 mL of benzyl bromide were added at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was distilled off, and ethyl acetate and water were added to the residue. The organic layer was separated, washed twice with water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the crude product was purified by silica gel column chromatography to obtain 3.69 g of benzyl 3-hydroxymyristate (intermediate compound 2). ¹ H-NMR (δ ppm, CDCl ₃ ) 7.33-7.40 (m, 5H), 5.16 (s, 2
H), 3.95-4.05 (m, 1H), 2.85 (d, J = 4.4Hz, 1H), 2.56 (d
d, J = 2.9, 17Hz, 1H), 2.46 (dd, J = 9.0, 17Hz, 1H), 1.2
0-1.60 (m, 20H), 0.88 (t, J = 6.8Hz, 3H)

1-iii) Intermediate compound 1 (1.00
g), intermediate compound 2 (1.55 g) and dimethylaminopyridine (40 mg) in dichloromethane (40 mL) were added with DCC (1.44 g) under ice-cooling.
Stirred for hours, then overnight at room temperature. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate and 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 2.29 g of intermediate compound 3. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.30-7.40 (5H, m), 5.50-5.
68 (2H, m), 5.20-5.25 (1H, m), 5.11 (2H, s), 4.59
(1H, br s), 3.71 (2H, br s), 2.96 (2H, d, J = 4.9 H
z), 2.57-2.66 (2H, m), 1.50-1.65 (2H, m), 1.44 (9
H, s), 1.20-1.35 (18H, m), 0.88 (3H, t, J = 6.8 Hz).

1-iv) Intermediate compound 3 (1.29 g) was treated with trifluoroacetic acid (hereinafter referred to as "TFA") (13 m
L) and the solution was stirred at room temperature for 30 minutes. After the TFA was distilled off, the residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, ethyl acetate was distilled off to obtain an amine compound.
The obtained amine compound and Fmoc-L-aspartic acid β-
t-butyl ester (Fmoc-Asp (OtBu)) (1.00 g)
To a solution of HOBt.monohydrate (0.41 g) in dichloromethane (30 mL) was added WSCI (0.51 g) under ice-cooling. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, the residue was dissolved in ethyl acetate, and a 10% aqueous citric acid solution, water and 5%
After washing with an aqueous sodium hydrogen carbonate solution and water in that order, it was dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 1.59 g of Compound 1. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz), 7.
58 (2H, d, 7.3 Hz), 7.40 (2H, t, 7.3 Hz), 7.27-7.35
(7H, m), 6.53 (1H, br s), 5.94 (1H, d, J = 7.8 Hz),
5.62-5.67 (1H, m), 5.45-5.55 (1H, m), 5.19-5.26
(1H, m), 5.10 (2H, s), 4.50 (1H, br s), 4.43 (2H,
d, J = 6.8 Hz), 4.22 (1H, t, J = 6.8 Hz), 3.80-3.85 (2
H, m), 2.94 (2H, d, J = 6.8 Hz), 2.89 (1H, br s), 2.
50-2.65 (3H, m), 1.50-1.65 (2H, m), 1.44 (9H, s),
1.20-1.35 (18H, m), 0.88 (3H, t, J = 6.8 Hz).

1-v) DMF of compound 1 (1.59 g)
(21 mL), diethylamine (2.1 mL) was added to the solution, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent, the obtained crude product was purified by silica gel column chromatography to obtain 0.92 g of an amine compound. The obtained amine compound (0.50)
g) and Cbz-L-valine (0.21 g) and HOB
t.monohydrate (0.14 g) in dichloromethane (30 m
L) WSCI (0.17 g) was added to the solution under ice cooling. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 0.63 g of Compound 2. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.35 (10H, m), 5.45-
5.70 (2H, m), 5.15-5.25 (1H, m), 5.05-5.15 (4H,
m), 4.60-4.70 (1H, m), 3.85-3.90 (2H, m), 3.65-3.7
5 (1H, m), 2.55-2.90 (6H, m), 2.00-2.10 (1H, m),
1.50-1.65 (2H, m), 1.43 (9H, s), 1.20-1.45 (18H,
m), 0.80-1.00 (9H, m).

1-vi) Ammonium formate (0.24 g) was added to a solution of compound 2 (0.53 g) in methanol (15 mL).
And 5% palladium on carbon (25 mg).
Stirred for hours. After filtering off palladium carbon and distilling off methanol, the obtained crude product was purified by silica gel column chromatography to obtain 0.28 g of compound 3. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.40 (5H, m), 5.50-5.
75 (2H, m), 5.15-5.30 (1H, m), 5.11, 5.10 (2H, 2
s), 4.60-4.70 (1H, m), 3.85-3.90 (1H, m), 3.70-3.8
0 (2H, m), 2.35-3.05 (6H, m), 2.00-2.15 (1H, m),
1.50-1.65 (2H, m), 1.43, 1.44 (9H, 2s), 1.20-1.40
(18H, m), 0.85-1.05 (9H, m).

1-vii) Compound 3 (0.14 g) and N-
γ-Mbh-L-glutamine ethyl ester (Gln (Mb
h) -OEt) (75 mg) and HOBt monohydrate (32 m
g) in dichloromethane (10 mL) solution under ice-cooling
I (40 mg) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 0.08 g of compound 4.
Obtained. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.40 (5H, m), 7.10-7.
15 (4H, m), 6.85 (4H, d, J = 8.8 Hz), 6.08 (1H, s),
5.45-5.70 (2H, m), 5.15-5.25 (1H, m), 5.09 (2H, s),
4.60-4.75 (1H, m), 4.30-4.40 (1H, m), 4.10-4.20
(2H, m), 3.88 (1H, d, J = 6.4 Hz), 3.76 (6H, s), 3.60
-3.80 (2H, m), 2.95-3.05 (2H, m), 2.25-2.85 (6H,
m), 1.90-2.20 (3H, m), 1.50-1.70 (2H, m), 1.42, 1.
43 (9H, 2s), 1.20-1.45 (21H, m), 0.85-1.00 (9H, m).

1-viii) TF of compound 4 (0.08 g)
The A (2 mL) solution was stirred at room temperature for 3.5 hours. After the TFA was distilled off, ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution were added to the residue. The separated aqueous layer was washed with ethyl acetate and adjusted to about pH 4 with concentrated hydrochloric acid. The resulting solid was collected by filtration and dried to obtain 0.02 g of Compound 5. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.40 (5H, m), 5.65-5.
75 (1H, m), 5.50-5.60 (1H, m), 5.15-5.30 (1H, m),
5.11 (2H, 2s), 4.65-4.75 (1H, m), 4.35-4.45 (1H,
m), 4.10-4.20 (2H, m), 3.90 (1H, d, J = 6.4 Hz), 3.6
0-3.80 (2H, m), 3.00-3.10 (2H, m), 2.00-3.00 (8H,
m), 1.85-2.00 (1H, m), 1.55-1.70 (2H, m), 1.20-1.40
(21H, m), 0.85-1.05 (9H, m).

1-ix) Gln (Mbh) -OEt used in the process of synthesizing compound 4 was synthesized as follows. Ethyl bromide was added to a suspension of N-α-Cbz-N-γ-Mbh-L-glutamine (Cbz-Gln (Mbh)) (5.00 g) and sodium bicarbonate (1.66 g) in DMF (50 mL). (7.52 mL) in DMF (50 mL) was added dropwise at room temperature. After stirring the reaction solution at room temperature overnight,
Water was added. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained crude product was recrystallized from ethyl acetate-hexane to give 4.62 g of Cbz-Gln (Mbh) -OEt. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.27-7.40 (5H, m), 7.14
(4H, dd, J = 6.1, 7.8 Hz), 6.84 (4H, dd, J = 0.92, 8.8
Hz), 6.45 (1H, d, J = 7.8 Hz), 6.14 (1H, d, J = 7.8 H
z), 5.60 (1H, d, J = 7.8 Hz), 5.09 (2H, s), 4.29-4.3
8 (1H, m), 4.11-4.22 (2H, m), 3.78 (6H, s), 2.19-
2.40 (3H, m), 1.90-2.02 (1H, m), 1.25 (3H, t, J = 7.1
Hz).

This Cbz-Gln (Mbh) -OEt
(2.62 g) was dissolved in methanol (50 mL), 5% palladium carbon (0.26 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After filtering off the palladium carbon and distilling off methanol, the obtained crude product was recrystallized with ethyl acetate-hexane to obtain 1.95 g of Gln (Mbh) -OEt. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.13 (4H, d, J = 8.8 Hz),
6.85 (4H, td, J = 2.6,8.8 Hz), 6.52 (1H, d, J = 7.8 H
z), 6.14 (1H, d, J = 7.8 Hz), 4.16 (2H, q, J = 7.2 H
z), 3.79 (6H, s), 3.40-3.47 (1H, m), 2.33-2.48 (2
H, m), 2.08-2.20 (1H, m), 1.78-1.89 (1H, m), 1.56
(2H, s), 1.26 (3H, t, J = 7.3 Hz).

Example 2 2-i) Compound 3 (120 mg) and Gln (Mbh) -Ot
To a solution of Bu (86 mg) and HOBt monohydrate (25 mg) in dichloromethane (10 mL) was added WSCI (3
1 mg) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 0.08 g of compound 6. ¹ H-NMR (δ ppm, CD ₃ OD): 7.28-7.41 (8H, m), 7.11-7.
18 (4H, m), 6.62-6.96 (6H, m), 6.16 (1H, d, J = 8.3
Hz), 5.53-5.78 (1H, m), 5.12-5.53 (2H, m), 5.05-5.12
(2H, m), 4.65-4.76 (1H, m), 4.39-4.49 (1H, m), 3.
96-4.05 (1H, m), 3.63-3.85 (8H, m), 2.78-3.04 (2H,
m), 2.52-2.67 (1H, m), 2.08-2.51 (7H, m), 1.73-1.96
(1H, m), 1.51-1.67 (2H, m), 1.33-1.50 (18H, m),
1.21-1.33 (18H, m), 0.85-1.00 (9H, m).

2-ii) TFA of compound 6 (0.08 g)
(2 mL) The solution was stirred at room temperature for 1 hour. After the TFA was distilled off, ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution were added to the residue. The separated aqueous layer was adjusted to about pH 4 with concentrated hydrochloric acid. The resulting solid was collected by filtration and dried to give Compound 7 in 0.01.
g was obtained. ¹ H-NMR (δ ppm, CD ₃ OD): 7.23-7.39 (5H, m), 5.65-5.
74 (1H, m), 5.50-5.59 (1H, m), 5.17-5.29 (1H, m),
5.11 (1H, s), 5.10 (1H, s), 4.64-4.74 (1H, m), 4.32
-4.40 (1H, m), 3.87-3.92 (1H, m), 3.68-3.79 (2H,
m), 3.01-3.07 (1H, m), 2.72-2.91 (2H, m), 2.45-2.56
(2H, m), 2.22-2.40 (3H, m), 2.04-2.19 (2H, m), 1.
89-1.99 (1H, m), 1.55-1.67 (2H, m), 1.21-1.37 (18
H, m), 0.86-1.07 (9H, m).

2-iii) Gln (Mbh) -OtBu used in the process of synthesizing compound 6 was synthesized as follows. That is, N-α-Cbz-N-γ-Mbh-L-
Glutamine (Cbz-Gln (Mbh)) (3.00 g), tert-butyl alcohol (0.62 mL) and dimethylaminopyridine (0.36 g) in DMF (20 mL) were added under ice-cooling to WS.
CI (1.25 g) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After distilling off DMF, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography and recrystallization from ethyl acetate-hexane to give N-α-Cbz-N-γ-Mbh-.
L-glutamine-t-butyl ester (Cbz-Gln (Mbh)
-OBu) 1.28 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.24-7.39 (5H, m), 7.04-
7.20 (4H, m), 6.76-6.88 (4H, m), 6.57 (1H, d, J = 7.
3 Hz), 6.13 (1H, d, J = 8.3 Hz), 5.52 (1H, d, J = 8.3 H
z), 5.08 (2H, s), 4.16-4.26 (1H, m), 3.78 (6H, s),
2.12-2.41 (3H, m), 1.84-2.06 (1H, m), 1.44 (9H,
s).

This Cbz-Gln (Mbh) -OBu
(0.11 g) was dissolved in methanol (5 mL), 5% palladium on carbon (10 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. Palladium carbon was removed by filtration, and methanol was distilled off to obtain Gln (Mbh) -OBu.

Example 3 3-i) Nt-butylcarbonyl-D-leucine-1
THF of hydrate (Boc-D-Leu-OH.H ₂ O) (2.5 g)
(12 mL), triethylamine (1.25 g) was added to the solution, and then ethyl chloroformate (1.09 g) was added under ice cooling. This solution was stirred for 30 minutes under ice cooling and filtered. A suspension of NaBH ₄ (946 mg) in water (12 mL) was gradually added to the filtrate under ice-cooling. The solution was stirred for 4 hours under ice cooling, and ether (100 mL) was added. The aqueous layer was chloroform (200
The mixture was extracted three times with an organic layer and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 1.35 g of intermediate compound 4. ¹ H-NMR (δ ppm, CDCl ₃ ): 4.55 (1H, br s), 3.64-3.72
(2H, m), 3.47-3.52 (1H, m), 2.43 (1H, br s), 1.61-
1.72 (1H, m), 1.24-1.36 (2H, m), 1.45 (9H, s), 0.9
2-0.95 (6H, m).

3-ii) Intermediate compound 4 (1.35 g) and triethylamine (1.9 g) in dichloromethane (4
Mesyl chloride (1.78 g) was added to the solution under ice-cooling. After stirring this solution for 1 hour under ice cooling, chloroform (100 mL) was added, and the mixture was washed twice with water (50 mL). The organic layer was dried with anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 1.76 g of intermediate compound 5. ¹ H-NMR (δ ppm, CDCl ₃ ): 4.50-4.56 (1H, m), 4.16 (1
H, br d, J = 4.0 Hz), 4.15 (1H, dd, J = 4.0, 10 Hz), 3.
92 (1H, br s), 3.03 (3H, s), 1.65-1.73 (1H, m), 1.
44 (9H, s), 1.28-1.45 (2H, m), 0.94 (3H, d, J = 3.2
Hz), 0.93 (3H, d, J = 3.2 Hz).

3-iii) Sodium methoxide (1.
03g) and thiophenol (2.17g) in THF (8m
L) and methanol (3 mL) in solution.
A solution of 6 g) in THF (7 mL) was added. Add this solution to 50
After stirring at 4 ° C for 4 hours, chloroform (50 mL) and 10 mL
A 15% aqueous solution of sodium hydroxide (15 mL) was added. After washing the organic layer with a 5% aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogen carbonate solution,
Dry over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 1.77 g of intermediate compound 6. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.37-7.40 (2H, m), 7.26-7.
29 (2H, m), 7.15-7.19 (1H, m), 4.50-4.57 (1H, m),
3.75-3.91 (1H, m), 2.93-3.10 (2H, m), 1.57-1.65 (1
H, m), 1.41 (9H, s), 1.38-1.48 (2H, m), 0.90 (3H,
d, J = 6.4 Hz), 0.87 (3H, d, J = 6.4 Hz).

3-iv) Alternatively, a solution of the intermediate compound 4 (1.20 g) obtained in 3-i) in THF (15 mL) was added with diphenyl disulfide (1.88 g) and tri-n- Butylphosphine (1.68 g) was added. The solution was stirred at room temperature for 16 hours. After distilling off the solvent,
Purification by silica gel column chromatography gave 1.70 g of intermediate compound 6.

3-v) Intermediate compound 6 obtained (1.7)
0g) in dichloromethane (45 mL) solution under ice cooling
BA (3.03 g) was added. After the solution was stirred for 1 hour under ice cooling, chloroform (50 mL), a 15% aqueous sodium hydroxide solution (15 mL) and sodium bisulfite (15 mL) were added. The aqueous layer is chloroform (20 mL)
, And the combined organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was crystallized from hexane-ethyl acetate to obtain 1.74 g of intermediate compound 7. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.91-7.94 (2H, m), 7.64 (1
H, m), 7.55-7.59 (2H, m), 4.82 (1H, br s), 3.94-4.
01 (1H, m), 3.41-3.44 (1H, m), 3.23-3.28 (1H, m),
1.50-1.72 (3H, m), 1.40 (9H, s), 0.87-0.90 (6H,
m).

3-vi) To a solution of methyl 1-methyl- (S) -2-hydroxypropionate (1.18 g) and dihydropyran (1.10 g) in dichloromethane (20 mL) at room temperature was added p-toluenesulfonic acid ( 50 mg) was added. After the solution was stirred at room temperature for 4 hours, chloroform (10
(0 mL) and water (80 mL). The aqueous layer was extracted with chloroform (20 mL), and the combined organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 2.03 g of intermediate compound 8.
Obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 4.60 and 4.62 (1H, t, J = 3.
2 Hz), 3.74-3.94 (2H, m), 3.70 (s, 3H), 3.42-3.62
(2H, m), 2.74 (1H, m), 1.52-1.80 (6H, m), 1.18 and
1.20 (3H, d, J = 6.8 Hz).

3-vii) To a solution of intermediate compound 7 (683 mg) in THF (24 mL) at -78 ° C was added methyllithium (1.03 M in diethyl ether) (4.27 mL). The solution was stirred at -78 C for 30 minutes (Solution A). To a solution of intermediate compound 8 (971 mg) in diethyl ether (14 mL) at −78 ° C. was added dropwise DIBAH (0.95 M in hexane) (5.5 mL). This solution is
Stirred at 78 ° C. for 30 minutes (solution B). Solution B to solution A
Was added using a cannula and stirred at -78 ° C for 30 minutes. To this solution, diethyl ether (100 mL) and water (8
0 mL) and a saturated aqueous solution of ammonium chloride (100 mL).
L) was added. After the aqueous layer was extracted twice with diethyl ether (100 mL), the combined organic layers were sequentially washed with a saturated aqueous solution of Rochelle salt, a saturated aqueous solution of ammonium chloride, water, and saturated saline, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained intermediate compound 9 was directly used in the next reaction.

3-viii) To a solution of the obtained intermediate compound 9 in methanol (40 mL) was added sodium phosphate (3.25).
g) and 5% sodium amalgam (12.5 g) were added under ice cooling. This solution was stirred for 4 hours under ice cooling, and then filtered. After the filtrate was concentrated under reduced pressure, diethyl ether (100 mL)
Was added and washed twice with water (50 mL). The organic layer was dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give intermediate compound 10
330 mg were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 5.51-5.59 (1H, m), 5.31-5.
41 (1H, m), 4.55-4.60 (1H, m), 4.25-4.41 (1H, m),
4.00-4.16 (1H, m), 3.81-3.88 (1H, m), 3.45-3.63 (2
H, m), 3.17-3.30 (1H, m), 2.41-2.49 (1H, m), 1.39
(9H, s), 1.23-1.87 (9H, m), 1.02 and 1.03 (3H, d,
J = 4.4 Hz), 0.92 (3H, d, 4.4 Hz), 0.90 (3H, d, J = 4.
4 Hz).

3-ix) Intermediate compound 10 (330 mg)
In acetone (50 mL) was added to Jones reagent (1.9).
2M) (1.6 mL) was added under ice cooling. The solution was stirred under ice cooling for 2 hours, and then water (100 mL) and diethyl ether (5 mL) were added.
0 mL) was added. After the aqueous layer was extracted twice with diethyl ether (50 mL), the combined organic layers were washed three times with a 5% aqueous sodium hydroxide solution (50 mL). 3N hydrochloric acid was added to the aqueous layer to adjust the pH to 3-4, and then diethyl ether (50 mL) was added.
The organic layer was extracted three times and dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting intermediate compound 11
Was used for the next reaction as it was.

3-x) T was added to the obtained intermediate compound 11.
FA (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the obtained intermediate compound 12 was directly used in the next reaction.

3-xi) 1 of the obtained intermediate compound 12
Fmoc-Cl in 0% aqueous sodium carbonate (6 mL)
(365 mg) in dioxane (6 mL) was added. After the solution was stirred at room temperature for 4 hours, isopropyl ether (20 mL) and water (10 mL) were added. After washing the aqueous layer with isopropyl ether, 3N aqueous hydrochloric acid was added to pH 3 and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 50 mg of an intermediate compound 13. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.73-7.75 (2H, m), 7.56-7.
58 (2H, m), 7.36-7.37 (2H, m), 7.27-7.31 (2H, m),
5.28-5.76 (2H, m), 4.63-4.75 (1H, m), 4.34-4.54 (2
H, m), 4.13-4.28 (2H, m), 2.96-3.22 (1H, m), 1.50-
1.67 (1H, m), 1.14-1.43 (5H, m), 0.69-0.99 (6H, m).

3-xii) Intermediate compound 13 (160 mg)
And intermediate compound 14 (369 mg) in dichloromethane (5
dimethylaminopyridine (10 mg) and DCC
(99 mg) was added under ice cooling. The solution was stirred at room temperature for 6 hours and then filtered through celite. After the solvent was distilled off from the filtrate, chloroform was added, and the mixture was washed successively with water, a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 310 mg of intermediate compound 15. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.71-7.81 (2H, m), 7.52-
7.69 (2H, m), 7.09-7.43 (8H, m), 6.48-6.89 (5H,
m), 6.07-6.28 (1H, m), 5.35-5.78 (1H, m), 5.05-5.2
8 (1H, m), 3.98-4.48 (7H, m), 3.76 and 3.78 (3H,
s), 3.75 and 3.76 (3H, s), 3.41-3.54 (1H, m), 1.41
and 1.42 (9H, s), 1.02-2.46 (3H, m), 0.67-0.96 (15
H, m).

3-xiii) Intermediate compound 15 (310 mg)
To a DMF (3 mL) solution of was added diethylamine (0.3 mL) at room temperature. After the solution was stirred at room temperature for 2.5 hours, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 200 mg of intermediate compound 16. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.60-7.69 (1H, m), 7.12-
7.25 (4H, m), 6.63-6.88 (5H, m), 6.15-6.23 (1H,
m), 5.59-5.76 (1H, m), 5.38-5.53 (1H, m), 5.13-5.2
2 (1H, m), 4.25-4.46 (2H, m), 3.78 and 3.79 (3H,
s), 3.76 and 3.78 (3H, s) ,, 3.29-3.41 (1H, m), 3.00
-3.16 (1H, m), 2.32-2.77 (4H, m), 1.40and 1.42 (9
H, s), 1.17-1.67 (31H, m), 0.82-0.94 (15H, m).

3-xiv) Intermediate compound 16 (200 mg)
And Hmoc-L-aspartic acid β-t-butyl ester (FmocAsp (OtBu)) (106 mg) in dichloromethane (5 mL) solution of HOBt monohydrate (35 mg)
And WSCI (50 mg) were added under ice cooling. After stirring this solution at room temperature for 66 hours, the solvent was distilled off, and the residue was dissolved in chloroform. This solution was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 220 mg of compound 8. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.72-7.79 (2H, m), 7.51-
7.62 (m, 2H), 7.27-7.43 (4H, m), 7.03-7.24 (5H,
m), 6.56-6.87 (6H, m), 6.07-6.48 (2H, m), 5.54-5.7
5 (1H, m), 5.35-5.49 (1H, m), 5.09-5.22 (1H, m),
4.17-4.73 (7H, m), 3.76 and 3.77 (3H, s), 3.76 (3H,
s), 1.88-3.08 (7H, m), 1.42 and 1.43 (9H, s), 1.4
1 and 1.42 (9H, s), 1.09-1.70 (31H, m), 0.71-0.92
(15H, m).

3-xv) Compound 8 (220 mg) in DMF
(2 mL) To the solution was added diethylamine (0.2 mL) at room temperature. After the solution was stirred at room temperature for 2.5 hours, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain Compound 9 (160 mg). ¹ H-NMR (δ ppm, CDCl ₃ ): 7.27-7.58 (2H, m), 7.12-
7.25 (4H, m), 6.62-7.01 (6H, m), 6.19-6.25 (1H,
m), 5.55-5.77 (1H, m), 5.39-5.51 (1H, m), 5.12-5.2
5 (1H, m), 4.25-4.47 (3H, m), 3.79 and 3.79 (6H,
s), 3.58-3.70 (1H, m), 2.99-3.10 (1H, m), 2.78-2.87
(1H, m), 2.28-2.51 (5H, m), 1.45 (9H, 2s), 1.43 (9
H, s), 1.15-2.15 (31H, m), 0.82-0.93 (15H, m).

3-xvi) Compound 9 (160 mg) and Fmo
To a solution of c-L-valine (59 mg) in dichloromethane (3 mL) was added HOBt monohydrate (24 mg) and WSCI (33 mM).
g) was added under ice cooling. After stirring this solution at room temperature for 16 hours, the solvent was distilled off, and the residue was dissolved in chloroform. This solution was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain a crude target product. This was solidified with a chloroform-ethyl acetate-hexane system to obtain 200 mg of a compound 10. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.73-7.80 (2H, m), 7.27-
7.61 (8H, m), 7.09-7.23 (5H, m), 6.60-6.97 (6H,
m), 6.18-6.26 (1H, m), 5.31-5.73 (3H, m), 5.09-5.2
3 (1H, m), 4.75-4.96 (1H, m), 4.15-4.52 (6H, m),
3.96-4.11 (1H, m), 3.76 (3H, 2s), 3.74 and 3.76 (3
H, s), 2.17-3.04 (7H, m), 1.08-2.15 (32H, m), 0.75
-1.00 (21H, m).

3-xvii) Compound 10 (200 mg) was converted to T
Dissolved in FA (3 mL). After the solution was stirred at room temperature for 3 hours, the solvent was distilled off. The residue was solidified with a chloroform-methanol-diethyl ether system to give compound 11.
70 mg was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.79 (2H, d, J = 7.6 Hz),
7.41-7.75 (2H, m), 7.39 (2H, t, J = 7.6 Hz), 7.32 (2
H, t, J = 7.6 Hz), 5.54-5.70 (1H, m), 5.38-5.49 (1H,
m), 5.10-5.25 (1H, m), 4.65-4.80 (1H, m), 4.20-4.
50 (6H, m), 3.83-3.90 (1H, m), 2.71-3.04 (3H, m),
2.22-2.58 (4H, m), 1.85-2.14 (3H, m), 1.06-1.78 (29
H, m), 0.81-1.00 (21H, m).

Example 4 4-i) Dioxane (162 mL), water (83 mL), 1M
To a mixed solution of aqueous sodium carbonate (83 mL) was added 5-aminovaleric acid (10 g). Di-t-butyl-
Dicarbonate (19.9 g) was added under ice cooling. After stirring at room temperature overnight, the solution was concentrated under reduced pressure to about 100 mL. After adjusting the pH to 3 with 10% aqueous citric acid under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. After removing the solvent, recrystallization was performed with hexane-ethyl acetate to obtain 17 g of N-Boc-5-aminovaleric acid.
Obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 5.78 (1H, brs), 4.61 (1H,
br s), 3.05-3.20 (2H, m), 2.38 (2H, t, J = 7.3 Hz),
1.60-1.70 (2H, m), 1.44 (9H, s), 1.35-1.60 (2H, m).

4-ii) The obtained N-Boc-5-aminovaleric acid (3 g) and dimethylaminopyridine (0.15)
g) and WSCI (2.89 g) were added to a solution of benzyl alcohol (1.36 mL) in dichloromethane (50 mL) under ice-cooling. The solution was stirred for 2 hours under ice cooling, and then stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate and water were added to the residue. The separated ethyl acetate was washed twice with a 5% aqueous sodium hydrogen carbonate solution and twice with water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 4 g of benzyl N-Boc-5-aminovalerate. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.27-7.37 (5H, m), 5.11 (2
H, s), 4.53 (1H, brs), 3.05-3.15 (2H, m), 2.38 (2
H, t, J = 7.3 Hz), 1.55-1.70 (2H, m), 1.44 (9H, s),
1.35-1.60 (2H, m).

4-iii) TFA (50 mL) was added to the obtained benzyl N-Boc-5-aminovalerate (4 g), and the mixture was stirred at room temperature for 20 minutes. After the TFA was distilled off, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added. The separated ethyl acetate was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2.7 g of benzyl 5-aminovalerate. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.80 (2H, br s), 7.25-7.38
(5H, m), 5.07 (2H, s), 2.85-2.95 (2H, m), 2.35-2.4
5 (2H, m), 1.60-1.70 (4H, m).

4-iv) The obtained benzyl 5-aminovalerate (2.04 g), Fmoc-aspartic acid β-t-
To a solution of butyl ester (2.03 g) and HOBt monohydrate (0.83 g) in dichloromethane (30 mL) was added WSCI (1.04 g) under ice-cooling. The solution was stirred for 2 hours under ice cooling, and then stirred at room temperature overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with a 10% aqueous citric acid solution, water, a 5% aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 2.41 g of intermediate compound 17. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.8 Hz), 7.
58 (2H, d, J = 7.3 Hz), 7.23-7.46 (6H, m), 6.52 (1H,
br s), 5.94 (1H, d, J = 8.0 Hz), 5.09 (2H, s), 4.36-
4.55 (3H, m), 4.22 (1H, t, J = 6.8 Hz), 3.15-3.29 (2
H, m), 2.90 (1H, d, J = 17 Hz), 2.59 (1H, dd, J = 6.4,
17 Hz), 2.37 (2H, t, J = 7.3 Hz), 1.58-1.82 (2H,
m), 1.44 (9H, s), 1.35-1.58 (2H, m).

4-v) Intermediate compound 17 (Fmoc-
_{Asp (OtBu) -NH- (CH 2} ) 4 -CO 2 Bzl)
(0.69 g) and a suspension of 5% palladium on carbon (70 mg) in methanol (20 mL) were reacted under a hydrogen atmosphere (2 kg / cm ² ) at room temperature for 5 hours. After filtering off the palladium carbon and distilling off the methanol, the obtained crude product was purified by silica gel column chromatography and further solidified with a hexane-diethyl ether system to obtain 0.26 g of an intermediate compound 18. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz),
7.58 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.3 Hz), 7.
31 (2H, t, J = 7.6 Hz), 6.62 (1H, t, J = 5.9 Hz), 6.03
(1H, d, J = 8.8 Hz), 4.49 (1H, br s), 4.43 (2H, d,
J = 6.8 Hz), 4.21 (1H, t, J = 7.1 Hz), 3.26 (2H, q, J =
6.3 Hz), 2.89 (1H, dd, J = 3.9, 18 Hz), 2.61 (1H, dd,
(J = 6.8, 17 Hz), 2.35 (2H, t, J = 7.1 Hz), 1.60-1.70
(2H, m), 1.50-1.59 (2H, m), 1.44 (9H, s).

4-vi) DCC was added to a solution of Intermediate Compound 2 (benzyl 3-hydroxymyristate) (0.16 g), Intermediate Compound 18 (0.25 g) and dimethylaminopyridine (4 mg) in dichloromethane (5 mL). (0.
15g) was added under ice cooling. The solution was stirred for 2 hours under ice cooling and further for 4 days at room temperature. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The obtained organic layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain Compound 12 (0.3).
6 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz),
7.58 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.3 Hz), 7.
28-7.38 (7H, m), 6.53 (1H, br s), 5.95 (1H, d, J = 8.
3 Hz), 5.22 (1H, qui., J = 6.3Hz), 5.10 (2H, s), 4.4
7 (1H, br s), 4.43 (2H, d, J = 6.8 Hz), 4.22 (1H, t,
J = 7.1 Hz), 3.22 (2H, q, J = 6.5 Hz), 2.90 (1H, dd, J =
4.2, 16 Hz), 2.53-2.65 (3H, m), 2.21 (2H, dt, J = 2.
9, 7.3Hz), 1.44 (9H, s), 1.41-1.65 (4H, m), 1.04-
1.41 (20H, m), 0.88 (3H, t, J = 6.8 Hz).

4-vii) D of compound 12 (0.36 g)
Diethylamine (0.5 mL) was added to the MF (5 mL) solution at room temperature. The solution was stirred at room temperature for 2 hours and concentrated under reduced pressure. The obtained amine compound, Fmoc-L-valine (0.18 g) and HOBt monohydrate (0.08 g)
WSCI in a dichloromethane (10 mL) solution under ice-cooling
(0.10 g) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, chloroform and a 10% aqueous citric acid solution were added to the residue. The separated chloroform layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After chloroform was distilled off, the residue was purified by silica gel column chromatography to obtain 0.40 g of compound 13. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.77 (2H, d, J = 7.3 Hz),
7.60 (2H, dd, J = 3.7,6.8 Hz), 7.40 (2H, t, J = 7.1 H
z), 7.24-7.36 (8H, m), 6.74 (1H, br s), 5.30 (1H,
d, J = 7.3 Hz), 5.21 (1H, qui., J = 6.3 Hz), 5.10 (2H,
s), 4.66-4.74 (1H, m), 4.37-4.48 (2H, m), 4.23 (1
H, t, J = 6.8 Hz), 4.01 (1H, br s), 3.10-3.26 (2H,
m), 2.86-2.97 (1H, m), 2.51-2.65 (3H, m), 2.17 (2
H, dt, J = 3.1, 7.3 Hz), 2.14-2.20 (1H, m), 1.35-1.6
3 (4H, m), 1.41 (9H, s), 1.04-1.35 (20H, m), 0.98
(3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.3 Hz), 0.88 (3
(H, t, J = 6.8 Hz).

4-viii) Compound 13 (0.40 g) was dissolved in methanol (20 mL) and 5% palladium on carbon (40
mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. After filtering off palladium carbon and distilling off methanol, the obtained crude product was purified by silica gel column chromatography to obtain 0.34 g of compound 14. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz),
7.54-7.67 (3H, m), 7.40 (2H, d, J = 7.6 Hz), 7.31 (2
H, t, J = 7.6 Hz), 6.87-6.98 (1H, m), 5.73 (1H, br
s), 5.19-5.30 (1H, m), 4.71-4.80 (1H, m), 4.33-4.4
5 (2H, m), 4.19-4.25 (1H, m), 4.03-4.11 (1H, m),
3.06-3.34 (2H, m), 2.75-2.87 (1H, m), 2.49-2.72 (3
H, m), 2.10-2.37 (3H, m), 1.40-1.71 (4H, m), 1.40
(9H, s), 1.16-1.35 (20H, m), 0.98 (3H, d, J = 6.8 H
z), 0.94 (3H, d, J = 6.8 Hz), 0.88 (3H, t, J = 6.8 H
z).

4-ix) Compound 14 (0.34 g) and Gl
n (Mbh) -Leu-OtBu (0.22 g) and HO
To a solution of Bt monohydrate (0.06 g) in DMF (10 mL) was added WSCI (0.08 g) under ice-cooling. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. D
After the MF was distilled off, chloroform and a 10% aqueous citric acid solution were added to the residue. The separated chloroform layer was washed with water, 5
% Aqueous sodium hydrogen carbonate solution and water,
Dry over anhydrous sodium sulfate. After chloroform was distilled off, the residue was purified by silica gel column chromatography to obtain 0.47 g of compound 15. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.8 Hz), 7.
59 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.6 Hz), 7.30
(2H, dt, J = 1.1, 7.6 Hz), 7.28-7.47 (3H, m), 7.14
(2H, dd, J = 2.4, 8.8 Hz), 7.16 (2H, t, J = 7.6 Hz),
7.05-7.21 (1H, m), 6.85-7.04 (2H, m), 6.82 (4H, dd,
J = 2.0, 8.8 Hz), 6.20 (1H, d, J = 7.8Hz), 5.52, 5.47
(1H, 2d, J = 8.3 Hz), 5.12-5.22 (1H, m), 4.66-4.77
(1H, m), 4.30-4.49 (4H, m), 4.21 (1H, dt, J = 2.9,
6.8 Hz), 3.95-4.05 (1H, m), 3.76 (6H, 2s), 3.06-3.
27 (2H, m), 2.72-2.83 (1H, m), 2.51-2.65 (1H, m),
2.32-2.48 (4H, m), 1.99-2.27 (4H, m), 1.43 (9H,
s), 1.39 (9H, s), 1.35-1.66 (7H, m), 1.17-1.34 (20
H, m), 0.80-0.99 (15H, m).

4-x) Compound 15 (0.47 g) was converted to TF
A (5 mL). The solution was stirred at room temperature for 2 hours and concentrated under reduced pressure. After adding chloroform to the residue,
A saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to about 7. The obtained solid was collected by filtration, washed with chloroform, and dried to obtain 0.29 g of compound 16. ¹ H-NMR (δ ppm, DMSO-d6): 8.10-8.30 (1H, m), 7.97
-8.07 (1H, m), 7.86 (2H, d, J = 7.8 Hz), 7.68-7.89 (3
H, m), 7.40 (2H, t, J = 7.3 Hz), 7.31 (2H, t, J = 7.3 H
z), 7.28-7.43 (1H, m), 7.15-7.24 (1H, m), 6.78-6.8
4 (1H, m), 6.62 (1H, br s), 5.04-5.12 (1H, m), 4.4
8-4.56 (1H, m), 4.11-4.34 (5H, m), 3.82-3.88 (1H,
m), 3.66-3.75 (1H, m), 2.95-2.98 (2H, m), 2.31-2.6
8 (4H, m), 2.15-2.23 (2H, m), 1.83-2.12 (4H, m), 1.
59-1.76 (2H, m), 1.33-1.57 (7H, m), 1.16-1.30 (20H,
m), 0.79-0.92 (15H, m).

Example 5 5-i) Intermediate compound 2 (3.18 g), Fmoc-L
DCC (3.14 g) was added to a solution of isoleucine (3.70 g) and dimethylaminopyridine (0.10 g) in dichloromethane (250 mL) under ice-cooling.
Stirred for hours, then overnight at room temperature. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate (30 mL) was added to the residue, and the insolubles were removed by filtration. The residue was purified by silica gel column chromatography to obtain 7.14 g of intermediate compound 19. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.29-7.77 (13H, m), 5.27-5.
33 (2H, m), 5.11 (2H, s), 4.29-4.34 (3H, m), 4.23
(1H, t, J = 6.8 Hz), 2.57-2.72 (2H, m), 1.07-1.90 (2
3H, m), 0.86-0.95 (9H, m).

5-ii) Intermediate compound 19 (7.14 g)
Was dissolved in DMF (70 mL) and diethylamine (7 mL)
Was added and stirred at room temperature for 5 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 4.33 g of intermediate compound 20. ¹ H-NMR (δppm, CDCl ₃ ) 7.33-7.36 (5H, m), 5.24-5.31
(1H, m), 5.11 (2H, s), 3.19 (1H, d, J = 4.9 Hz), 2.5
7-2.66 (2H, m), 1.05-1.75 (25H, m), 0.86-0.94 (9H,
m).

5-iii) Fmoc-L-aspartic acid t-butyl ester (9.05 g), D-leucine benzyl ester (4.43 g) and HOBt monohydrate (3.37 g) in dichloromethane (80 mL) In solution, W
SCI (4.22 g) was added under ice cooling, and the mixture was stirred at this temperature for 2 hours and further at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate was added, and a 10% aqueous citric acid solution, water,
After washing with a 5% aqueous sodium hydrogen carbonate solution and water, the resultant was dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained crude product was crystallized from hexane-ethyl acetate and purified to obtain 8.36 g of an intermediate compound 21. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.77 (2H, d, J = 7.3 Hz), 7.59
(2H, d, J = 7.8Hz), 7.40 (2H, t, J = 7.3Hz), 7.28-7.37
(7H, m), 6.94 (1H, d, J = 7.8Hz), 5.96 (1H, d, J = 7.8H
z), 5.17 (1H, d, J = 12Hz), 5.13 (1H, d, J = 12Hz), 4.53
-4.67 (2H, m), 4.39 (2H, d, J = 6.8Hz), 4.23 (1H, t, J =
7.1Hz), 2.89 (1H, dd, J = 3.2, 17Hz), 2.62 (1H, dd, J =
6.8, 17Hz), 1.51-1.70 (3H, m), 1.44 (9H, s), 0.90 (3
H, d, J = 2.4Hz), 0.88 (3H, d, J = 2.4Hz).

5-iv) Intermediate compound 21 (6.15 g)
Was dissolved in DMF (100 mL) and diethylamine (10 mL) was added.
mL) and stirred at room temperature for 3 hours. The solvent was distilled off to obtain 3.93 g of an intermediate compound 22. ¹ H-NMR (δ ppm, d ₆ -DMSO) 7.86 (1H, d, J = 7.8 Hz), 7.6
8-7.75 (3H, m), 7.49 (1H, d, J = 8.3Hz), 7.38-7.42 (2H,
m), 7.29-7.33 (2H, m), 4.18-4.41 (5H, m), 2.64-2.69
(1H, m), 2.43-2.49 (1H, m), 1.69-1.73 (1H, m), 1.42-
1.48 (1H, m), 1.37 (9H, s), 0.86 (9H, s).

5-v) Intermediate compound 22 (3.93)
g), Fmoc-L-valine (3.39 g) and HO
To a solution of Bt monohydrate (1.53 g) in DMF (70 mL) was added WSCI (1.92 g) under ice-cooling, and the mixture was stirred at this temperature for 2 hours and further at room temperature overnight. After distilling off DMF, chloroform was added and a 10% aqueous citric acid solution, water,
After washing with a 5% aqueous sodium hydrogen carbonate solution and water, the resultant was dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained crude product was solidified from chloroform-diethyl ether to obtain 6.19 g of an intermediate compound 23. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.77 (2H, d, J = 7.3 Hz), 7.60
(2H, d, J = 8.3Hz), 7.40 (2H, dt, J = 3.4, 7.3Hz), 7.27
-7.37 (7H, m), 7.22 (1H, d, J = 7.8Hz), 7.08 (1H, d, J =
7.3Hz), 5.29 (1H, d, J = 6.8Hz), 5.09 (2H, s), 4.79-4.
86 (1H, m), 4.56-4.63 (1H, m), 4.41 (2H, d, J = 7.3Hz),
4.23 (1H, t, J = 6.8Hz), 4.01 (1H, t, J = 6.3Hz), 2.90
(1H, dd, J = 4.4, 17Hz), 2.58 (1H, dd, J = 6.5, 17Hz),
2.10-2.20 (1H, m), 1.56-1.68 (3H, m), 1.42 (9H, s),
0.98 (3H, d, J = 6.8Hz), 0.93 (3H, d, J = 6.8Hz), 0.85-0.
91 (6H, m).

5-vi) A solution of 5-amino-3-pentenoic acid (0.57 g) in dioxane (20 mL) was added under ice-cooling.
A solution of concentrated sulfuric acid (0.6 mL) and a solution of isobutylene (1.5 mL) in dichloromethane (2.5 mL) were sequentially added, and the mixture was sealed and stirred at room temperature for 14 hours. The reaction vessel was cooled with ice and opened, and a water (30 mL) solution containing sodium hydroxide (1.7 g) was added to the reaction solution, followed by extraction with diethyl ether and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off, and the intermediate compound 25 was dissolved in 0.1%.
14 g were obtained. ¹ H-NMR (δ pm, CDCl ₃ ) 5.68-5.66 (2H, m), 3.32 (2H, b
rs), 2.97-2.99 (2H, m), 1.87 (2H, br s), 1.45 (9H,
s).

5-vii) Intermediate compound 23 (5.12)
g) was dissolved in DMF (15 mL), and methanol (250
mL). To this solution was added 10% palladium on carbon (0.96 g) and the resulting suspension was stirred under a hydrogen atmosphere (1 atm) at room temperature for 2 hours. The palladium carbon was removed by filtration, and methanol in the filtrate was distilled off to obtain an intermediate compound 2
4.87 g of 4 was obtained. 3.84 g of this was added to DMF (1
0 mL) and diluted with dichloromethane (20 mL). To this solution was added intermediate compound 20 (2.68 g), HOBt
・ After adding monohydrate (1.04 g) at room temperature, the mixture was cooled on ice,
WSCI (1.77 g) was added, and the mixture was stirred under ice cooling for 2 hours, and then at room temperature overnight. The reaction solution was chloroform (50m
L), washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 4.88 g of compound 17. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.27-7.76 (13H, m), 6.99 (1H,
br), 6.91 (2H, br), 6.83 (1H, br), 5.57 (1H, br), 5.1
9-5.24 (1H, m), 5.02-5.10 (2H, m), 3.95-4.85 (7H, m),
2.46-2.86 (4H, m), 1.08-2.11 (36H, m), 0.85-0.95 (21
H, m).

5-viii) Compound 17 (4.88 g) was dissolved in methanol (350 mL), 10% palladium on carbon (0.98 g) was added, and the resulting suspension was placed under a hydrogen atmosphere at room temperature for 2 hours. Stirred. After filtering off the palladium carbon and evaporating the methanol from the filtrate, the residue was purified by silica gel column chromatography to obtain 3.58 g of compound 18. ¹ H-NMR (δ ppm, d ₆ -DMSO) 12.25 (1H, br), 7.28-8.27
(12H, m), 5.04-5.09 (1H, m), 4.56-4.58 (1H, m), 4.14
-4.31 (5H, m), 3.81-3.84 (1H, m), 2.38-2.70 (4H, m),
1.87-2.01 (1H, m), 1.74-1.78 (1H, m), 1.09-1.53 (34H,
m), 0.78-0.87 (21H, m).

5-ix) Intermediate compound 25 (0.19
g), compound 18 (0.52 g) and HOBt monohydrate (0.19 g) in dichloromethane (20 mL) were added with WSCI (0.32 g) at room temperature and stirred for 22 hours. After the dichloromethane was distilled off, the residue was purified by silica gel column chromatography to give compound 19 (0.56).
g was obtained. ¹ H-NMR (δ ppm, d ₆ -DMSO) 7.76 (2H, d, J = 7.3Hz), 7.5
9-7.64 (3H, m), 6.90-7.42 (8H, m), 6.20-6.27 (1H, m),
5.64-5.72 (1H, m), 5.50-5.54 (1H, m), 5.14-5.21 (1H, m
m), 4.81-4.88 (1H, m), 4.21-4.51 (6H, m), 3.71-3.98
(4H, m), 2.73-2.99 (2H, m), 2.15-2.51 (2H, m), 1.08-
1.92 (45H, m), 0.86-0.99 (21H, m).

5-x) Compound 19 (0.56 g) was converted to TF
A (3 mL) and the solution was stirred at room temperature for 90 minutes.
Diluted with chloroform (30 mL) and washed with water. The organic layer was separated and the solvent was distilled off. Diethyl ether and hexane were added to the residue (0.33 g), and the deposited precipitate was collected by filtration and dried under reduced pressure to obtain 0.33 g of compound 20. ¹ H-NMR (δ ppm, d ₆ -DMSO) 12.18 (1H, br), 8.27 (1H, b
r), 7.68-8.00 (7H, m), 7.29-7.42 (6H, m), 5.44-5.65
(2H, m), 5.08-5.15 (1H, m), 4.54-4.56 (1H, m), 4.12-
4.31 (5H, m), 3.83-3.89 (1H, m), 3.57-3.69 (2H, m),
2.96 (2H, d, J = 6.6Hz), 2.28-2.67 (4H, m), 1.01-2.00
(27H, m), 0.82-0.87 (21H, m).

Example 6 6-i) DMSO (0.70 mL) was added to a dichloromethane (5 mL) solution containing oxalyl chloride (0.40 mL).
A solution of Fmoc-L-valinol (1.00 g) in dichloromethane (15 mL) was added dropwise over 15 minutes, and a solution of Fmoc-L-valinol (1.00 g) was added dropwise over 15 minutes. Stirred for minutes. Diisopropylethylamine (2.6 mL) was added to the reaction solution,
After stirring at room temperature for 30 minutes, saturated saline was added. The dichloromethane layer was separated and dried over anhydrous sodium sulfate. After the dichloromethane was distilled off, the residue was purified by silica gel column chromatography to obtain an intermediate compound 26 of 1.2.
5 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 9.66 (1H, s), 7.76 (2H, d, J =
7.3Hz), 7.60 (2H, d, J = 7.3Hz), 7.41 (2H, t, J = 7.3Hz),
7.30-7.34 (2H, m), 5.36 (1H, d, J = 7.8Hz), 4.17-4.62
(4H, m), 2.30-2.35 (1H, m), 1.04 (3H, d, J = 6.8Hz),
0.96 (3H, d, J = 7.3Hz).

6-ii) Intermediate compound 26 (1.25
g), L-aspartic acid α-benzyl β-t-butyl ester (0.86 g) was converted to 1,2-dichloroethane (1
5 mL), sodium triacetoxyborohydride (0.89 g) was added with stirring at room temperature, and the mixture was stirred for 13 hours. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the separated organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After 1,2-dichloroethane was distilled off, the residue was purified by silica gel column chromatography.
1.55 g of intermediate compound 27 were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.75 (2H, d, J = 7.3 Hz), 7.59-
7.62 (2H, m), 7.27-7.52 (10H, m), 5.17 (1H, d, J = 12H
z), 5.13 (1H, d, J = 12Hz), 4.84 (1H, d, J = 7.8Hz), 4.3
5-4.45 (2H, m), 4.22 (1H, t, J = 6.8Hz), 3.65 (1H, br),
3.46 (1H, br), 2.51-2.76 (3H, m), 1.87 (1H, br), 1.40
(9H, s), 0.84-0.88 (6H, m).

6-iii) Intermediate compound 27 (0.81
g) was dissolved in methanol (50 mL), 5% palladium on carbon (0.20 g) was added, and the resulting suspension was stirred under a hydrogen atmosphere at room temperature for 30 minutes. The palladium carbon was removed by filtration, and methanol was distilled off.
9 g were obtained. ¹ H-NMR (δ ppm, d ₆ -DMSO) 7.86 (2H, d, J = 7.3 Hz), 7.6
7-7.71 (2H, m), 7.30-7.42 (4H, m), 7.05 (1H, d, J = 8.3
Hz), 4.21-4.36 (3H, m), 3.44 (2H, brs), 2.44-2.78 (4
H, m), 1.78 (1H, br), 1.39 (9H, s), 0.80-0.84 (6H,
m).

6-iv) Phenacyl bromide (2.0) was added to a solution of (R) -3-hydroxymyristic acid (2.50 g) and triethylamine (1.43 mL) in DMF (25 mL).
4g) at room temperature and stirred overnight. After removing the solvent, ethyl acetate was added and the mixture was washed three times with water. After drying over anhydrous sodium sulfate, the ethyl acetate was distilled off and the residue was purified by silica gel column chromatography to obtain an intermediate compound 29 of 3.5.
3 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.92 (2H, d, J = 6.8Hz), 7.63
(1H, d, J = 7.3Hz), 7.50 (2H, d, J = 7.6Hz), 5.48 (1
(H, d, J = 17Hz), 5.37 (1H, d, J = 17Hz), 4.09-4.18
(1H, m), 3.41 (1H, br s), 2.70 (1H, dd, J = 2.9, 15
Hz), 2.57 (1H, dd, J = 9.3, 15Hz), 1.19-1.67 (20H,
m), 0.88 (3H, t, J = 6.8Hz).

6-v) 5-amino-3-pentenoic acid (1.00 g) in 10% aqueous sodium carbonate solution (20 m
L) and dioxane (10 mL) solution under ice-cooling, Fmoc
A solution of -Cl (2.20 g) in dioxane (10 mL) was added and stirred overnight. The reaction was diluted with ethyl acetate and
The mixture was extracted three times with a 10% aqueous sodium carbonate solution. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off to give the intermediate compound 30 as 2.
44 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.75-7.76 (2H, m), 7.57-7.5
9 (2H, m), 7.37-7.41 (2H, m), 7.28-7.32 (2H, m), 5.
50-5.70 (2H, m), 4.88 (1H, m), 4.40-4.43 (2H, m),
4.20-4.30 (1H, m), 3.60-3.82 (2H, m), 3.00-3.12 (2
H, m).

6-vi) Intermediate compound 29 (0.86
g), intermediate compound 30 (0.93 g) and DMAP
(61 mg) in dichloromethane (30 mL) solution under ice-cooling,
DCC (0.77 g) was added, and the mixture was stirred under ice cooling for 2 hours, and then at room temperature overnight. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate (30 mL) was added to the residue, and the mixture was washed with a 10% aqueous citric acid solution, water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained crude product was purified by silica gel column chromatography to obtain 1.54 g of an intermediate compound 31. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.88 (2H, d, J = 6.8Hz), 7.75
(2H, d, J = 7.8Hz), 7.58 (2H, d, J = 7.3Hz), 7.58 (1H,
t, J = 7.6Hz), 7.45 (2H, t, J = 7.6Hz), 7.39 (2H, t,
J = 7.6Hz), 7.30 (2H, t, J = 7.3Hz), 5.69-5.80 (1H,
m), 5.57-5.68 (1H, m), 5.27-38 (3H, m), 4.99 (1H, b
rs), 4.36 (2H, d, J = 6.8 Hz), 4.19 (1H, t, J = 6.6 H
z), 3.81 (2H, br s), 3.05-3.17 (2H, m), 2.77 (1H,
(dd, J = 3.4Hz), 2.75 (1H, d, J = 1.5Hz), 1.53-1.76 (2
H, m), 1.18-1.41 (18H, m), 0.88 (3H, t, J = 6.8Hz).

6-vii) Intermediate compound 31 (0.33
g) was dissolved in DMF (5 mL) and diethylamine (0.5 mL) was added.
4 mL) and stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure to obtain an intermediate compound 32. DMF (30 mL) was added to and dissolved in the obtained intermediate compound 32 (0.31 g).
g), HOBt monohydrate (90 mg) was added. This solution was ice-cooled, WSCI (0.14 g) was added, and the mixture was stirred at room temperature overnight. After filtering off the insoluble matter and evaporating the solvent of the filtrate,
Purification by silica gel column chromatography gave 0.10 g of compound 21. ^{1 H-NMR (δppm, CDCl} 3) 7.87 (2H, d, J = 7.3Hz), 7.75 (2
H, d, J = 7.3Hz), 7.28-7.61 (11H, m), 5.66-5.74 (1H,
m), 5.52-5.59 (1H, m), 5.25-5.31 (3H, m), 4.86 (1H,
d, J = 9.8Hz), 4.47-4.51 (1H, m), 4.33-4.37 (1H, m),
4.19-4.22 (1H, m), 3.76-3.88 (2H, m), 3.57 (1H, br),
3.34-3.37 (1H, m), 3.00-3.11 (2H, m), 2.46-2.77 (5H,
m), 1.74-1.79 (1H, m), 1.65 (2H, br s), 1.41 (9H, s),
1.24-1.28 (18H, m), 0.86-0.92 (9H, m).

6-viii) Compound 21 (77 mg) was dissolved in acetic acid (3 mL), and zinc powder (150 mg) was added.
Stirred at C for 4 hours. The insoluble material was separated by filtration, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography to obtain 41 mg of compound 22. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.75 (2H, d, J = 7.3 Hz), 7.54-
7.61 (2H, m), 7.29-7.41 (5H, m), 6.46 (1H, d, J = 8.8H
z), 5.53-5.67 (2H, m), 5.09-5.20 (2H, m), 4.32-4.55
(3H, m), 3.81 (2H, br s), 3.51-3.60 (2H, m), 2.31-3.
02 (7H, m), 1.03-1.81 (30H, m), 0.78-0.94 (9H, m).

6-ix) Compound 22 (41 mg) was converted to TFA
(1 mL) and the solution was stirred at room temperature for 1 hour. TF
After evaporating A, the residue was purified by silica gel column chromatography to obtain 31 mg of compound 23. ¹ H-NMR (δ ppm, CD ₃ OD) 7.78 (2H, d, J = 7.3 Hz), 7.64-
7.67 (2H, m), 7.28-7.40 (4H, m), 5.55 (2H, br s), 5.3
6 (1H, br s), 4.50-4.54 (1H, m), 4.20-4.34 (2H, m),
3.90-3.95 (1H, m), 3.56 (1H, br s), 3.42 (1H, br s),
2.92-3.05 (2H, m), 2.39-2.67 (7H, m), 1.71 (1H, br
s), 1.26-1.29 (20H, m), 0.87-0.94 (9H, m).

[0093]

[Test Example] Next, the depsipeptide of the present invention is Hep G2
The effects on apolipoprotein E-producing ability and apolipoprotein B-producing ability of cells are described together with test methods. First, 1 × 10 ⁵ Hep G2 cells / ml (Dulbecco's modified Eagle's medium (manufactured by Nissui Pharmaceutical Co., Ltd .; hereinafter, “D-
MEM medium) and 10% fetal bovine serum added thereto), and inject 1 ml each into a 24-well tissue culture plate at 37 ° C. in a mixed gas atmosphere of 5% carbon dioxide and 95% air. And cultured. Three days later, the medium was removed with a pipettor, and 1 ml of D-MEM medium was newly added.
10 μl of a MeOH solution of the depsipeptide of the present invention, Compound 5, Compound 7, Compound 11, Compound 16, Compound 20, and Compound 23, was added at the concentration shown in FIG. 18
After a lapse of time, the medium was replaced again (D-MEM medium), 10 μl of this methanol solution of pedepsi peptide was added, and the mixture was further cultured at 37 ° C. for 8 hours, and the supernatant was used as a sample solution. Apolipoprotein E and apolipoprotein B produced in the medium were quantified by the enzyme immunoassay shown below. The composition of the buffer used in the enzyme immunoassay is shown below. In addition,
PBS is phosphate buffer, PBS-T is Tween
20 was added to the phosphate buffer, and the blocking solution was a milk protein-derived immunization blocking agent “Bl
5 shows a phosphate buffer containing "ock Ace".

PBS (pH 7.2) KH ₂ PO ₄ 0.2 g Na ₂ HPO ₄ .12H ₂ O 2.9 g NaCl 8.0 g KCl 0.2 g Distilled water qs 1000 ml

[0095] _{PBS-T (pH7.2) KH 2} PO 4 0.2g Na 2 HPO 4 · 12H 2 O 2.9g NaCl 8.0g KCl 0.2g Tween 20 0.5g Distilled water qs Total 1000ml

[0096] Blocking solution _{(pH7.2) Block Ace 250ml KH 2} PO 4 0.2g Na 2 HPO 4 · 12H 2 O 2.9g NaCl 8.0g KCl 0.2g Distilled water qs Total 1000ml

1) Measurement of Apolipoprotein E A mouse anti-human apolipoprotein E monoclonal antibody (manufactured by BYOSIS, SA, France) was dissolved in a 0.05 M aqueous sodium hydrogen carbonate solution (pH 9.5) at a concentration of 5 μg / ml. This 50 μl was dispensed into a Nunc immunoplate, and
The mixture was allowed to stand at 16 ° C. for 16 hours. After washing three times with 300 μl of PBS, 300 μl of blocking solution was added, and the mixture was allowed to stand at 37 ° C. for 2 hours and then at 4 ° C. for 16 hours. Again PBS
After washing three times with 300 μl, 50 μl of sample solution (He
pG2 cell culture medium) and allowed to stand at room temperature for 2 hours.
After washing three times with 300 μl of PBS-T, goat anti-apolipoprotein E polyclonal antibody (manufactured by Chemicon, USA)
3000 times dilution (10% Block Ace aqueous solution) 50μ
was added and left at room temperature for 2 hours. PBS-T 300
Washed three times with μl and peroxidase-labeled anti-goat IgG
Polyclonal antibody (manufactured by UK Binding Site)
And a 5000-fold diluted solution (10% aqueous solution of Block Ace) was added, and the mixture was allowed to stand at room temperature for 2 hours. After washing 5 times with 300 μl of PBS-T, a color developing solution (composition: 0.1 M potassium citrate p
H4.5 (1 ml), 30% hydrogen peroxide (0.4 μl, orthophenylenediamine (1 mg), 100 μl) were added and
Let stand for minutes. 100 μl of 2N sulfuric acid was added to stop the reaction,
The absorbance at 490 nm was measured using 650 nm as a control. Commercially available apolipoprotein E (manufactured by Chemicon, USA)
Was used to determine the amount of apolipoprotein E of the depsipeptide of the present invention from a calibration curve.

In this test example, apolipoprotein E was prepared in the same manner as in this test example except that methanol was simply added instead of the methanol solution of the depsipeptide of the present invention.
The amount was measured and used as a control. The relative amount of apolipoprotein E of the depsipeptide of the present invention was expressed as a relative value (%) when the control was taken as 100. As shown in Table 1, the depsipeptide of the present invention contained 1 to 5 μm.
It was found that the concentration of M strongly promotes the production of apolipoprotein E.

[0099]

[Table 1]

[0100]

[Preparation Examples] Next, preparation examples of preparations containing the depsipeptide of the present invention as an active ingredient are shown. Compound 20, magnesium silicate and lactose are mixed, kneaded with an alcohol solution in which hydroxypropylcellulose is dissolved, then granulated to an appropriate particle size, dried and sized, and then magnesium stearate and vegetable hydrogenated oil are further added. Add and mix to make uniform granules. Next, tablets having a diameter of 7.0 mm, a weight of 150 mg and a hardness of 6 kg were prepared by a rotary tableting machine.

[0101] The raw materials except for hydroxypropylcellulose in the above formulation examples were uniformly mixed, and an alcoholic solution in which hydroxypropylcellulose was dissolved was added and kneaded, followed by granulation by an extrusion granulator and drying to obtain granules. Was. The granules were sized, passed through a 12-mesh sieve, and remained on the 48-mesh sieve as granules.

[0102] Sucrose, D-sorbitol, ethyl paraoxybenzoate,
Dissolve propyl paraoxybenzoate and Compound 20 in 60 g of purified water (warm water). After cooling, a solution of glycerin and ethanol in which the flavor is dissolved is added. The mixture is then made up to 100 ml with purified water.

[0103] Sodium bicarbonate, sodium chloride and this compound 2
0 sodium salt was added to distilled water and dissolved, and the total amount was 1
Make up to 0.0 ml.

[0104] Glycerin is added to compound 20 and dissolved. Macrogol 4000 is added thereto, heated and dissolved, and then poured into a suppository mold, cooled and solidified to produce suppositories of 1.5 g per piece.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 237/12 C07K 5/06 C07K 5/06 A61K 37/02 (72) Inventor Tsuneji Kawamura Tsuruga Oimachi, Iruma-gun, Saitama 5-3-1 Oka, Nisshin Flour Milling Co., Ltd. Drug Discovery Research Laboratory (72) Inventor Shigeru Hiramoto 5-3-1, Tsurugaoka, Oi-machi, Iruma-gun, Saitama Prefecture Nisshin Flour Milling Co., Ltd. Drug Discovery Research Laboratory (72 ) Inventor Orie Yasuda 5-3-1 Tsurugaoka, Oi-machi, Iruma-gun, Saitama Prefecture Inside the drug discovery laboratory of Nisshin Flour Milling Co., Ltd. No. 1 Inside the Drug Discovery Research Laboratory of Nisshin Flour Milling Co., Ltd. (72) Inventor Akiko Makai 5-3-1, Tsurugaoka, Oimachi, Iruma-gun, Saitama Prefecture Inside the Drug Discovery Research Laboratory of Nisshin Flour Milling Co., Ltd. Tsuru, Oimachi, Iruma-gun, Prefecture Oka 5-chome third No. 1 Nisshin Flour Milling Co., Ltd. drug discovery within the Institute

Claims (14)

[Claims] 1. A compound of the general formula (1)[Wherein, R¹Is a linear or branched C_Five~ C₂₀A
Alkyl group or linear or branched C_Five~ C_FifteenA
A alkoxymethyl group;^TwoIs -O-CO-CH (R^Five) -X-CH (R⁶) -NH- (where X is N (R⁷) -CO, N (R⁸) -CH_Two, C
H_Two-CO, CH_Two-CH_Two, CH = CH, CH_Two-CH
(OH), CH (OH) -CH (OH), R^Five, R⁶, R
⁷, R⁸Is hydrogen or a linear or branched C₁~
C₆R represents an alkyl group);^ThreeIs(Where Y is N (R¹²) -CO, N (R¹³) -CH_Two, C
H_Two-CO, CH_Two-CH_Two, CH = CH, CH_Two-CH
(OH), CH (OH) -CH (OH), wherein n is 1 to 3
Represents an integer;⁹, R^Ten, R¹², R¹³Is hydrogen or direct
Chain or branched C₁~ C₆Represents an alkyl group;
¹¹Is commonly used in peptide chemistry as an amine protecting group.
R represents a protecting group).^FourIs a hydroxyl group, a linear or branched C₁~ C₆A
Alkoxy group, benzyloxy group, A, AB, or -NH-CH (R¹⁴) -Z-CH (R^Fifteen) -COR¹⁶  (Where Z is CH_Two−N (R¹⁷), CO-CH_Two, CO-
N (R¹⁸), CH_Two-CH_Two, CH = CH, CH (OH) -C
H_Two, CH (OH) -CH (OH), R¹⁴Is hydrogen, C₁
~ C₆Alkyl group or-(CH_Two)_m-COR¹⁹Indicates that
R^Fifteen, R¹⁷, R¹⁸Is hydrogen or a linear or branched chain
C₁~ C₆Represents an alkyl group;¹⁶Is a hydroxyl group, straight chain
Or branched C₁~ C₆Alkoxy group or ben
Represents a zyloxy group;¹⁹Is a hydroxyl group, an amino group or C
₁~ C₆Represents an alkoxy group, and m represents an integer of 1 to 3)
A represents alanine, valine, leucine, isoleucine,
Enylalanine, tyrosine, proline, asparagine
Acid, asparagine, glutamic acid, glutamine, seri
Amino-, lysine and β-t-butylalanine
No acid residues or N-methyl forms of these amino acid residues
B represents alanine, valine, leucine, isoleucine,
Phosphorus, threonine, lysine, hydroxylysine, argi
Nin, cysteine, methionine, phenylalanine, thi
Rosin, tryptophan, histidine, proline, 4-
Hydroxyproline, aspartic acid, asparagine,
Glutamic acid, glutamine, piperidine-4-carboxyl
Acid, homoproline, octahydroindole-2-cal
Boric acid, norvaline, norleucine, α-t-butyl group
Lysine, cyclohexylglycine, azetidine-2-ca
Rubonic acid, 3- (3-pyridyl) alanine, (3-N-
Methyl) piperidylalanine, 3- (2-naphthyl) a
Lanine, β-cyclohexylalanine, β-t-butyl
Alanine, 9-anthracenylalanine, α-methyla
Amino acids selected from lanine and 2-aminobutanoic acid
Residues or the N-methyl form of these amino acid residues
A free amino group in A or B, a free carboxy
Group, free ω-carbamide group, free hydroxyl group, free
The mercapto group and / or the N-terminal amino group
Protecting groups commonly used in peptide chemistry
And each may be protected by A or
The amino acid residue in B is lysine, hydroxylysine,
Adjacent if glutamic or aspartic acid
Amino groups or carbohydrates that bind to amino acids
The xyl group may be in the α-position or in the ω-position
May be. Where X is N (R⁷) -CO and Y is
N (R¹²) -CO and R^FourIs a hydroxyl group, linear or
Branched C₁~ C₆Alkoxy group, benzyloxy group,
A, AB or -NH-CH (R¹⁴) -Z-CH (R^Fifteen)
-COR¹⁶｛Z is CO-N (R^{1 8}) Is｝
except. ] Containing the unnatural amino acid represented by
Peptide or a pharmacologically acceptable salt thereof. 2. The depsipeptide according to claim 1, wherein X is CH ＝ CH, or a pharmaceutically acceptable salt thereof. 3. X is CH = CH and Y is N (R ¹² )-
CO or N (R ¹³⁾ depsipeptide or a pharmacologically acceptable salt thereof according to claim 2, wherein a -CH _2. 4. X is CH = CH and Y is N (R ¹² )-
CO or N (R ¹³⁾ is -CH _2, R ⁴ is hydroxyl, A,
A-B or ^{-NH-CH (R 14) -Z} -CH (R 15) -C
The depsipeptide according to claim 3, which is OR ¹⁶ (Z is CH = CH), or a pharmacologically acceptable salt thereof. 5. X is CH = CH and Y is N (R ¹² )-
^4. The depsipeptide or a pharmaceutically acceptable salt thereof according to claim 3, which is CO and R ⁴ is a hydroxyl group, A or AB. 6. X is CH = CH and Y is N (R ¹³ )-
The depsipeptide according to claim 3, which is CH ₂ and R ⁴ is a hydroxyl group, or a pharmaceutically acceptable salt thereof. 7. The depsipeptide according to claim 1, wherein X is CH ₂ —CH ₂ or a pharmaceutically acceptable salt thereof. 8. X is CH ₂ —CH ₂ and Y is N (R ¹² )
The depsipeptide according to claim 7, which is -CO, or a pharmacologically acceptable salt thereof. 9. X is CH ₂ —CH ₂ and Y is N (R ¹² )
8. The depsipeptide or a pharmaceutically acceptable salt thereof according to claim 7, wherein the compound is -CO and R ⁴ is AB. 10. A medicament comprising the depsipeptide containing the unnatural amino acid according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 11. A medicament according to claim 10, which is an apolipoprotein E production enhancer. 12. A drug according to claim 10, which is a drug for treating nerve damage. 13. A medicament according to claim 10, which is a therapeutic drug for dementia. 14. A medicament according to claim 10, which is a therapeutic drug for hyperlipidemia.