JP3409494B2 - Azapeptide derivatives - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel azapeptide derivative and a salt thereof which are antagonists of the neurokinin A (NKA) receptor which is a tahikinin family neuropeptide.

[0002]

2. Description of the Prior Art As a transmitter of primary sensory nerves, the peptide has a common C-terminal (-Phe-X-Gly-Leu-M).
et-NH ₂ ), a tahikinin group neuropeptide having an amino acid sequence is known, and among those derived from mammals, neurokinin A (NKA) and substance P shown below are shown.
(SP) and neurokinin B (NKB) are known [Kimura, S., et al,: Proc. Japan Acd., 59B, 10
1-104 (1983)].

NKA: His-Lys-Thr-Asp-Ser-Phe-Val-Gl
y-Leu-Met-NH ₂ NKB: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH
₂ SP: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Me
t-NH ₂

These peptides have excitatory effects in the central and peripheral nervous systems, and in non-neural tissues have similar physiological activities such as smooth muscle contraction (other than blood vessels), vasodilation, endocrine / excited line stimulation, plasma exudation, and immuno-inflammation. [Perow, B: Pharmaco
l. Rev., 35, 86 (1983), Yukio Takano, Hiroo Kamiya: Pharmaceutical Journal 108, 201 (1988), Maggio, JM: Ann. Rev. Neurosc
i. 11, 13 (1989)].

Of these, NKA is known to co-exist with SP and exhibit a strong inducing action on airway smooth muscle spasm, airway mucosal secretion enhancement, airway mucosal edema and the like in the pathological condition of asthma [Lundberg, JM, Arch. Int. Pharmacody
n. 303, 9 (1990), Barnes, PJ, Arch. Int. Pharmac
odyn. 303, 67 (1990)]. It is also known as a strong contractile active substance in tissues other than the trachea, for example, in the bladder and gastrointestinal tract. Therefore, NKA antagonists have potential as therapeutic agents for bronchial asthma, gastrointestinal hyperactivity and urinary incontinence.

So far, peptide I: [Tyr ⁵ , D-Trp ^6,8,9 , Arg ¹⁰ ] NKA (4-10) peptide II: [Tyr ⁵ , D-Trp ⁶ has been used as a compound having NKA antagonistic activity. ^{, 8,9} , Arg ¹⁰ ] NKA (3-10) peptide III: Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH _{2 and} other peptide derivatives with 6 or more amino acid residues have been reported [Br. J. Pharmacol., 100, 588-592 (1990), JP-A-3-17098].

[0007]

Generally, long-chain peptide derivatives are likely to undergo enzymatic decomposition and are expected to have poor absorbability and tissue transferability. Compounds that are resistant are desired.

An object of the present invention is to provide a novel azapeptide derivative having a potent NKA antagonism which is effective and lasting in vivo.

[0009]

Means for Solving the Problems In order to solve the above-mentioned problems, the present invention is represented by the general formula (I) containing an azaamino acid in which the carbon atom at the α-position of phenylalanine or tyrosine is replaced with a nitrogen atom. The present inventors have found that the azapeptide derivative having a strong NKA antagonism, which is effective and has a long-lasting effect in vivo, has completed the present invention.

The present invention has the general formula (I):

[Chemical 2]

[Wherein A represents a direct bond, an α-amino acid or a residue of a dipeptide; R ¹ represents a hydrogen atom or a protecting group of a terminal amino group; R ² represents an unsubstituted phenyl group or lower alkyl; R ³ represents a phenyl group substituted with 1 or 2 substituents selected from halogen, optionally protected hydroxyl, nitro, optionally protected amino and perhalo lower alkyl; R ³ is a hydroxyl group or a terminal carboxyl group Represents a group-protecting group] or a salt thereof.

In the above general formula (I), the α-amino acid of A includes natural α-amino acids and non-natural α-amino acids. The α-amino acid includes L-isomer, D-isomer or DL-racemate.

As the natural α-amino acid, glycine,
Alanine, valine, leucine, isoleucine, serine,
It is selected from methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, cystine, proline, 4-hydroxyproline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, citrulline, ornithine and lysine.

Examples of non-natural α-amino acids include norleucine, norvaline, alloisoleucine, homoarginine, thiaproline, methionine sulfoxide, methionine sulfone, dehydroproline, homoserine, cyclohexylglycine (Chg), α-amino-n-butyric acid (A).
ba), cyclohexylalanine (Cha), aminophenylbutyric acid (Pba), phenyl moiety of phenylalanine is substituted with one or two lower alkyl, lower alkoxy, halogen or nitro group, or methylenedioxy group is substituted. Phenylalanine, β- (2-
Or 3-thienyl) alanine, β- (2- or 3-furanyl) alanine, β- (2-, 3- or 4-pyridyl) alanine, β- (benzothiophen-2- or 3-yl) alanine, β -(1- or 2-naphthyl) alanine may be mentioned.

Preferred are natural α-amino acids, especially methionine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, citrulline or ornithine; non-natural α-amino acids are especially methionine sulfoxides; as dipeptides. Are dipeptides of these α-amino acids, particularly aspartic acid-glutamine and asparagine-glutamine.

The α-amino acids and dipeptides of A also include those having a substituent exemplified in the side chain thereof. a) As a substituent of an amino group, for example, a substituted or unsubstituted lower alkanoyl group such as formyl, acetyl, propionyl, trifluoroacetyl; a phthaloyl group;
Lower alkoxycarbonyl groups such as butoxycarbonyl and t-amyloxycarbonyl; substituted or unsubstituted aralkyloxycarbonyl groups such as benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; substituted or unsubstituted such as benzenesulfonyl and tosyl Arenesulfonyl group; 2-nitrophenylsulfenyl group; aralkyl groups such as trityl and benzyl; substituents of guanidino group include, for example, nitro, benzyloxycarbonyl, tosyl, 4-methoxybenzenesulfonyl, 4-methoxy- 2,3,6-trimethylbenzenesulfonyl, etc.

As the b) amidated carboxyl group, for example, a substituted or unsubstituted lower alkyl group such as methyl, ethyl, isobutyl, 2-hydroxyethyl, 2-methoxyethyl, 2-benzyloxyethyl, etc. can be used. Or a di-substituted lower alkyl-substituted amide; an aryl-substituted amide substituted with phenyl or the like; for example, benzyl, 4
An aralkyl-substituted amide substituted with a substituted or unsubstituted aralkyl group such as fluorobenzyl, phenethyl, 2,4-dimethoxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, xanthyl; and the like; for example, morpholino, thiomorpholino, pyrrolidine 1-yl, pyrazolidin-1-yl, piperazino, pyrrolin-1-yl and the like substituted with a heterocyclic imide-substituted carboxyl group,

C) an esterified carboxyl group, for example, a substituted or unsubstituted lower alkyl group such as methyl, ethyl, trichloroethyl, t-butyl;
For example, cycloalkyl groups such as cyclopentyl and cyclohexyl; carboxyl groups esterified with substituted or unsubstituted aralkyl groups such as benzyl, phenacyl, 4-nitrobenzyl, 4-methoxybenzyl and benzhydryl;

D) Substituents on the thiol group include, for example, substituted or unsubstituted lower alkyl groups such as methyl, ethyl, t-butyl and acetamidomethyl; substituted or unsubstituted such as benzyl, trityl and 4-methoxybenzyl. Aralkyl groups, etc.,

E) As a substituent of the hydroxyl group, for example, a lower alkyl group such as t-butyl; a cycloalkyl group such as cyclohexyl; a substituted or unsubstituted group such as benzyl, 2-nitrobenzyl, 3-bromobenzyl, etc. Aralkyl groups; acyl groups such as acetyl and benzoyl; t-butyloxycarbonyl; benzyloxycarbonyl and the like,

As the amino-terminal protecting group for R ¹ , an acyl group; a C ₁ -C ₈ preferably C ₁ -C ₆ alkoxycarbonyl group; an alkyl moiety having a C ₁ -C ₈ preferably C ₁ -C An aralkyloxycarbonyl group of ₆ ; an N-alkylcarbamoyl group and a cycloalkyl moiety are C ₃ -C
The N-cycloalkylcarbamoyl group of _{6 and} the like can be mentioned.

Examples of the acyl group include formyl,
C ₁ such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, isopentylcarbonyl, trifluoroacetyl, etc.
-C _8, preferably alkanoyl group of C ₁ -C _6; e.g. acryloyl, methacryloyl, C etc. crotonoyl
₃ -C _8, preferably C ₃ alkenoyl group -C _4; e.g. cyclopentylcarbonyl, cycloalkylcarbonyl group C ₄ -C ₇ such as cyclohexylcarbonyl; such as phenyl; such as benzoyl, toluoyl, naphthoyl, an aroyl group phthaloyl etc. acetyl, phenyl butyryl, aryl alkanoyl groups alkanoyl moiety, such as phenyl-hexanoyl is C ₂ -C _6; e.g. morpholinocarbonyl, furoyl, thenoyl, nicotinoyl, heteromonocyclic group such isonicotinoyl; for example quinolylcarbonyl, indolyl Fused heterocyclic carbonyl groups such as carbonyl; heteromonocyclic alkanoyl groups such as morpholinoacetyl, furylacetyl, thienylacetyl, thienylpropionyl; condensed rings such as indolylacetyl, acridinylacetyl Heterocyclic alkanoyl group and the like.

Examples of the alkoxycarbonyl group for R ¹ include methoxycarbonyl, ethoxycarbonyl,
Isopropoxycarbonyl, t-butoxycarbonyl (Boc), isopentyloxycarbonyl and the like; examples of the aralkyloxycarbonyl group include benzyloxycarbonyl, phenethyloxycarbonyl, 4-nitrobenzyloxycarbonyl and the like.

The N-alkylcarbamoyl group is, for example, _{one in which} an alkyl moiety such as N-methylcarbamoyl, N-ethylcarbamoyl, Nt-butylcarbamoyl, N-isopentylcarbamoyl is C ₁ -C ₅ ;
Examples of the N-cycloalkylcarbamoyl group include N
- cyclopentylcarbamoyl, N- cyclohexylene cycloalkyl moiety carbamoyl and the like are intended C ₃ -C _6, other N- N- arylcarbamoyl group such as phenylcarbamoyl; N- benzylidene N- aralkylcarbamoyl such as carbamoyl Groups can also be used.

Further, as the protective group for the terminal amino group of R ¹ , lower alkanesulfonyl groups such as methanesulfonyl and ethanesulfonyl; arenesulfonyl groups such as benzenesulfonyl, tosyl and mesitylsulfonyl can also be used.

A preferred protecting group for the terminal amino group of R ¹ is
A C ₁ -C ₈ preferably C ₁ -C ₆ alkanoyl group,
C ₄ -C ₈ , preferably C ₄ -C ₆ cycloalkanoyl group, aroyl group, alkoxy moiety is C ₁ -C ₈ , preferably C ₁ -C ₄ alkoxycarbonyl group, aralkyloxycarbonyl group, alkyl moiety is C ₁ -C _8, preferably C ₁ N-alkylcarbamoyl group or cycloalkyl moiety of the -C ₅ is C ₃ -C _8, preferably C ₃ -C
_{6 is} an N-cycloalkylcarbamoyl group.

A preferred group for R ² is an unsubstituted phenyl group or a phenyl group substituted with one or two substituents selected from lower alkyl, halogen, optionally protected hydroxyl and perhalo lower alkyl. Examples of the lower alkyl group include linear or branched alkyl groups such as methyl, ethyl, propyl, butyl, isobutyl, t-butyl, pentyl, and hexyl, and the halogen atom includes chlorine, bromine, iodine, Examples thereof include fluorine. As the protecting group for the hydroxyl group which may be protected, those exemplified as the substituent (e) in the case where the side chain of the amino acid of A is a hydroxyl group are used, and particularly a benzyl group. Examples of the perhalo lower alkyl group include a trifluoromethyl group.

As the protective group for the terminal carboxyl group of R ^3, the carboxyl group of the α-amino acid of A is (b) amidated, and (c) esterified.
Although those exemplified as the above are used, particularly when R ³ is the formula —O
R ⁴ or the formula —N (R ⁵ ) (R ⁶ ), and the protecting groups R ⁴ and R ⁵
And R ⁶ may be a substituted or unsubstituted lower alkyl group or an aralkyl group, or R ⁵ and R ⁶ may be combined with the nitrogen atom to which they are bonded to form a hetero-saturated monocycle.

Particularly preferred examples of R ⁴ are aralkyl groups such as benzyl. Particularly preferred examples of R ⁵ are methyl, ethyl, isobutyl, 2-hydroxyethyl, 2-
Unsubstituted, such as benzyloxyethyl, 2- (4-fluorobenzyloxy) ethyl, 2- (2-pyridylmethyloxy) ethyl, 2-benzhydryloxyethyl, 2- (2-naphthylmethyloxy) ethyl Or a lower alkyl group substituted with hydroxyl or aralkyloxy; an aralkyl group which is unsubstituted or substituted with halogen or lower alkoxy such as benzyl, 4-fluorobenzyl, 2,4-dimethoxybenzyl and phenethyl, and is particularly preferably R ⁶ . An example is the hydrogen atom. Also, R
³ is a group such as morpholino, pyrrolidin-1-yl, pyrazolidin-1-yl, piperidino, in which R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a heterosaturated monocycle. In the present specification, “lower” unless otherwise specified, has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Means individual.

Examples of the salt of the azapeptide derivative represented by the above general formula (I) include acid addition salts and basic salts. Such acid addition salts include inorganic acids (eg hydrochloric acid, sulfuric acid, phosphoric acid) or organic acids (eg acetic acid,
Propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid) and the like; basic salts include pharmacologically acceptable salts such as sodium salt, potassium salt, ammonium salt and amine salt. Can be mentioned.

The azapeptide derivative (I) of the present invention can be prepared by a method commonly used in peptide chemistry, for example, Schrod.
er and Libke "The Peptides" Volume 1 Academic Pres
S., New York, USA (1965), Nobuo Izumiya et al., "Basics and Experiments of Peptide Synthesis," Maruzen Co., Ltd. (1985). It can be produced by any of the phase methods. Protected azaphenylalanine as a starting material can be produced by a known method found in the following document, and a synthesis example will be described in Reference Example below.

Dutta, AS, et al .: J. Chem. Soc., P
erkin Trancs. 1 (1975) 712. Pinnen, F., et al .: JCS Perkin I (1993) 819-
824 (Boc-AzPhe-ONp)

As the condensation method for forming a peptide bond, azide method, acid chloride method, acid anhydride method, mixed acid anhydride method, carbodiimide method, carbodiimide additive method, active ester method, carbonyldiimidazole method, oxidation Examples include a reduction method and a method using Woodward reagent K.

Before carrying out the condensation reaction, the carboxyl group and amino group not involved in the reaction may be protected or the carboxyl group and amino group involved in the reaction may be activated by a means known per se.

Examples of activated carboxyl groups include corresponding acid anhydrides; azides; alcohols such as pentachlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, 4-nitrophenol, N-hydroxy-. 5-norbornene-2,3-dicarboximide, N-hydroxysuccinimide, 1-
Examples thereof include active esters with hydroxybenzotriazole. Examples of activated amino groups include corresponding phosphoric acid amides.

The reaction is usually carried out in a solvent such as chloroform, dichloromethane, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, pyridine,
It can be carried out in a solvent such as dioxane, tetrahydrofuran, water, methanol or a mixed solvent thereof. The reaction can generally be carried out in the range of about -30 ° C to about 50 ° C.

The elimination reaction of the protecting group of the peptide depends on the kind of the protecting group used, but it does not affect the peptide bond and it is necessary to remove the protecting group. Examples of the method for removing the protective group include acid treatment with hydrogen chloride, hydrogen bromide, anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture thereof. In addition, reduction with sodium in liquid ammonia, palladium carbon and the like can also be mentioned. In the deprotection reaction by the acid treatment, it is effective to add a cation trapping agent such as anisole, phenol or thioanisole.

After the completion of the reaction, the azapeptide derivative of the present invention produced in this manner can be obtained by peptide separation means known per se, such as extraction, partitioning, reprecipitation, recrystallization, column chromatography and the like. You can

The azapeptide derivative of the present invention can be converted into a pharmacologically acceptable salt thereof by a method known per se.

[0040]

INDUSTRIAL APPLICABILITY The azapeptide derivative of the present invention exhibits a strong antagonistic action in the NKA contraction inhibition test in the hamster trachea. It is also useful as a therapeutic agent for NKA-dependent pathology, particularly as a therapeutic agent for respiratory nervous system inflammation, asthma and bronchospasm.

The toxicity of the azapeptide derivative of the present invention was extremely low, and there were no deaths even at doses far exceeding the effective dose.

The effective dose of the azapeptide derivative of the present invention is 0.01 to 10 per 1 kg of mammal body weight per day.
It is 0 mg, preferably used in a daily dose of 0.1 to 50 mg.

When administered for therapeutic purposes, one of the azapeptide derivatives of the present invention or a salt thereof is used as an active ingredient, and this is used as a pharmaceutically acceptable carrier, for example, an organic compound suitable for oral, parenteral, external use or inhalation. It is used as a pharmaceutical composition mixed with an inorganic solid or liquid excipient. These pharmaceutical compositions can take the form of capsules, tablets, sugar-coated tablets, granules, solutions, suspensions, emulsions and the like. If necessary, auxiliary agents, stabilizers, wetting agents, emulsifiers, buffers or other conventional additives can be added to these preparations.

[0044]

[Examples] The following examples will further explain the synthetic examples of the azapeptide derivatives of the present invention.

In the present specification, amino acids, peptides,
The protecting groups, solvents and the like use the abbreviations commonly used in the art or the following abbreviations adopted by the IUPAC-IUB nomenclature committee. The abbreviation for α-aza amino acid is represented by prefixing “Az” to the corresponding amino acid, for example, AzPhe represents α-aza-phenylalanine.

AzPhe: α-aza-phenylalanine AzPhe (4-F): α-aza-4-fluoro-phenylalanine AzPhe (2-Me): α-aza-2-methyl-phenylalanine AzPhe (3-Me): α -Aza-3-methyl-phenylalanine AzPhe (4-Me): α-aza-4-methyl-phenylalanine AzPhe (4-i Pr): α-aza-4-isopropyl-phenylalanine AzPhe (2,4-diMe): α-aza-2,4-dimethyl-phenylalanine AzPhe (2,5-diMe): α-aza-2,5-dimethyl-phenylalanine AzPhe (2-F): α-aza-2-fluoro-phenylalanine AzPhe (2 -CF _3): alpha-aza-2- (trifluoromethyl) - phenylalanine AzTyr: α- aza Tyrosine Asn: asparagine acid Asp: Aspartic acid Arg: Arginine Cit: citrulline Gln: Glutamine Met: Methionine Met (O _2): methionine sulfone Orn: ornithine Trp: Tryptophan Ph: phenyl Boc: t-butoxycarbonyl Z: benzyloxycarbonyl Bz: Benzoyl t-Bu: t-butyl OBzl: benzyl ester OSu: N-hydroxysuccinimide ester Dmob: 2,4-dimethoxybenzyl ONp: 4-nitrophenyl ester ONo: 2-nitrophenyl ester DCC: N, N'- dicyclohexylcarbodiimide DCUrea: N, N'-dicyclohexylurea HOBt: 1-hydroxybenzotriazole Et ₃ N: triethylamine M: morpholino NMM: N-menu Rumoruhorin TFA: trifluoroacetic acid AcOEt: ethyl acetate CH ₂ Cl _2: methylene chloride DMF: N, N-dimethylformamide MeOH: methanol THF: tetrahydrofuran

In each example, the developing solvents for thin layer chromatography are as follows, and TLC manufactured by Merck & Co., Inc.
Plate silica gel 60 F ₂₅₄ was used.

Rf ₁ : chloroform-methanol-acetic acid-water (80: 20: 2.5: 5) lower layer Rf ₂ : chloroform-methanol (10: 1) Rf ₃ : chloroform-acetone (5: 1) Rf ₄ : Ethyl acetate-hexane (2: 1) Rf ₅ : Ethyl acetate-hexane (1: 1)

Reference Example 1 Synthesis of Boc-AzPhe-NHDmob 2,4-dimethoxybenzylamine hydrochloride 6.80 g
Was dissolved in 150 ml of acetonitrile, and Et ₃ N4.8 was added.
0 ml and Boc-AzPhe-ONp 13.00 g were added, and the mixture was heated under reflux for 31 hours. The solvent was evaporated, the residue was dissolved in AcOEt, washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was treated with AcOE.
Purify on a silica gel column with t-hexane to give the title compound. Yield: 9.44 g Rf ₃ : 0.52, Rf ₅ : 0.27 NMR (δ, DMSO-d ₆ , 55 ° C): 1.34 (9H, s), 3.74 (3H, s),
3.78 (3H, s), 4.17 (2H, d, J = 6Hz), 4.54 (2H, br s),
6.42-6.53 (3H, m), 7.10-7.32 (6H, m), 8.72 (1H, br)

Reference Example 2 Boc-AzPhe-NH (CH ₂ ) ₂ OCH ₂ Ph 2-benzyloxyethylamine hydrochloride 14.92 g,
16.60 ml Et ₃ N and Boc-AzPhe-ON
The title compound was obtained from 15.39 g of p in the same manner as in Reference Example 1. Yield: 13.60 g Rf ₃ : 0.42, Rf ₅ : 0.22 NMR (δ, DMSO-d ₆ , 55 ° C): 1.33 (9H, s), 3.28 (2H, td,
J = 6Hz, 6Hz), 3.47 (2H, t, J = 6Hz), 4.48 (2H, s), 4.5
3 (2H, br s), 6.32 (1H, br), 7.23-7.32 (10H, m), 8.69
(1H, br)

Reference Example 3 Boc-AzPhe-NHCH ₂ Ph (4-F) 4-fluorobenzylamine 0.60 ml, Et ₃ N
0.72 ml and Boc-AzPhe-ONp 2.00
The title compound was obtained from g in the same manner as in Reference Example 1. Yield: 1.47 g Rf ₃ : 0.45, Rf ₅ : 0.30 NMR (δ, CDCl ₃ , 55 ° C.): 1.41 (9H, s), 4.42 (2H, d, J =
6Hz), 4.74 (2H, br s), 5.67 (1H, br), 5.87 (1H, br
s), 6.96-7.15 (2H, m), 7.24-7.35 (7H, m)

Reference Example 4 Boc-AzPhe-NH (CH ₂ ) ₂ OCH ₂ Ph (4
-F) 2-(4-fluorobenzyloxy) ethylamine hydrochloride 2.47g, Et ₃ N 2.52ml and Boc-Az
The title compound was obtained from 2.33 g of Phe-ONp in the same manner as in Reference Example 1. _{Yield: 2.49g Rf 3: 0.38, Rf} 4: 0.30 NMR (δ, CDCl 3, 55 ℃): 1.42 (9H, s), 3.45-3.49 (2H,
m), 3.56 (2H, t, J = 5Hz), 4.47 (2H, s), 4.71 (2H, br
s), 5.70 (1H, br), 5.88 (1H, br s), 6.96-7.03 (2H,
m), 7.23-7.34 (7H, m)

Reference Example 5 Boc-AzPhe-NH (CH ₂ ) ₂ Ph β-phenethylamine 0.94 ml and Boc-AzPh
The title compound was obtained in the same manner as in Reference Example 1 from 1.50 g of e-ONp. Yield: 1.20 g Rf ₃ : 0.51, Rf ₅ : 0.32 NMR (δ, CDCl ₃ , 55 ° C.): 1.42 (9H, s), 2.83 (2H, t, J =
7Hz), 3.49-3.55 (2H, m), 4.71 (2H, br s), 5.38 (1H, b
r), 5.77 (1H, br s), 7.16-7.35 (10H, m)

Reference Example 6 Boc-AzPhe-M morpholine 0.68 ml, Et ₃ N 0.54 ml and Bo
The title compound was obtained from 1.50 g of c-AzPhe-ONp in the same manner as in Reference Example 1. Yield: 1.10 g Rf ₃ : 0.34, Rf ₅ : 0.15 NMR (δ, CDCl ₃ ): 1.44 (9H, s), 3.44 (4H, t, J = 5Hz),
3.68 (4H, t, J = 5Hz), 4.51 (2H, br), 6.27 (1H, br), 7.
28-7.38 (5H, m)

Reference Example 7 Boc-AzPhe-OBzl 12.16 g of t-butyl 3-benzylcarbazinate was added to T
Was dissolved in HF 100 ml, N-carbobenzoxy risk of THF succinimide 13.63g solution 50ml and Et ₃
7.62 ml of N was added and the mixture was heated under reflux for 18 hours. The solvent was evaporated, the residue was dissolved in AcOEt, and washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine,
It was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column using AcOEt-hexane to obtain the title compound. Yield: 12.81 g Rf ₃ : 0.62, Rf ₅ : 0.54 NMR (δ, CDCl ₃ , 55 ° C.): 1.39 (9H, s),
4.68 (2H, br s), 5.20 (2H,
s), 6.20 (1H, br), 7.23-
7.34 (10H, m)

Reference Example 8 Boc-AzPhe-NHCH ₂ Ph 3-tert-butyl benzylcarbazate (1.50 g) and benzyl isocyanate (0.83 ml) were added to acetonitrile 20.
It was dissolved in ml and heated under reflux for 20 hours. The following compound was obtained in the same manner as in Reference Example 7. Yield: 2.27 g Rf ₃ : 0.46, Rf ₅ : 0.33 NMR (δ, CDCl ₃ , 55 ° C.): 1.42 (9H, s), 4.46 (2H, d, J =
6Hz), 4.75 (2H, br s), 5.67 (1H, br), 5.86 (1H, br
s), 7.23-7.35 (10H, m)

Reference Example 9 Boc-AzPhe-NHCH ₃ methylamine hydrochloride 456 mg, Et ₃ N 0.94 ml and carbodiimidazole 1.09 g were added to acetonitrile 2
After being dissolved in 0 ml and heated under reflux for 20 hours, 1.50 g of t-butyl 3-benzylcarbazate and Et ₃ N 0.
94 ml was added and the mixture was heated under reflux for 96 hours. The following compound was obtained in the same manner as in Reference Example 7. Yield: 1.50 g Rf ₃ : 0.24, Rf ₅ : 0.10 NMR (δ, CDCl ₃ , 55 ° C.): 1.44 (9H, s), 2.83 (3H, s),
4.72 (2H, br s), 5.28 (1H, br), 5.86 (1H, br s), 7.25
-7.35 (5H, m)

Reference Example 10 Boc-AzPhe-NHCH ₂ CH (CH ₃ ) ₂ isobutylamine 0.67 ml, carbodiimidazole 1.10 g and t-butyl 3-benzylcarbazate 1.50 g were dissolved in acetonitrile 50 ml. And heated to reflux for 20 hours. The following compound was obtained in the same manner as in Reference Example 7. Yield: 1.64 g Rf ₃ : 0.48, Rf ₅ : 0.34 NMR (δ, CDCl ₃ , 55 ° C.): 0.91 (6H, d, J = 7Hz), 1.45 (9
H, s), 1.71-1.84 (1H, m), 3.09 (2H, t, J = 6Hz), 4.71 (2
H, br s), 5.41 (1H, br), 5.86 (1H, br s), 7.25-7.35
(5H, m)

Reference Example 11 Boc-AzPhe (4-F) -NH (CH ₂ ) ₂ OCH
₂ Ph (1) Boc-AzPhe (4-F) -ONp 4-nitrophenyl chloroformate 12.00 g THF 5
Dissolve in 0 ml and under ice cooling 3- (4-fluorobenzyl)
14.40 g of t-butyl carbazate and NMM 6.6
0 ml was added and the mixture was stirred at room temperature for 18 hours. Evaporate the solvent,
The residue was dissolved in AcOEt, washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column using AcOEt-hexane to obtain the title compound. Yield: 19.50 g Rf ₃ : 0.60, Rf ₅ : 0.52 NMR (δ, DMSO-d ₆ , 55 ° C.): 1.38 (9H, s), 4.64 (2H, br)
s), 7.14-7.43 (6H, m), 8.30 (2H, d, J = 9Hz), 9.54 (1H,
br)

(2) Boc-AzPhe (4-F) -N
H (CH ₂ ) ₂ OCH ₂ Ph 2-benzyloxyethylamine hydrochloride 627 mg and B
The title compound was obtained from 1.40 g of oc-AzPhe (4-F) -ONp in the same manner as in Reference Example 1. _{Yield: 940mg Rf 3: 0.38, Rf} 4: 0.33 NMR (δ, DMSO-d 6, 55 ℃): 1.31 (9H,
s), 3.25 (2H, td, J = 6Hz, 6
Hz), 3.45 (2H, t, J = 6Hz),
4.46 (2H, s), 4.49 (2H, br)
s), 6.31 (1H, br), 7.03-7.
30 (9H, m), 8.67 (1H, br)

Reference Example 12 Boc-AzTyr (CH ₂ Ph) -NHDmob (1) Boc-AzTyr-ONp 2.86 g of 4-nitrophenyl chloroformate, NMM1.
The title compound was obtained from 54 ml and 4.00 g of t-butyl 3- (4-hydroxybenzyl) carbazate in the same manner as in Reference Example 11 (1). Yield: 4.55 g Rf ₃ : 0.36, Rf ₅ : 0.34 NMR (δ, DMSO-d ₆ , 55 ° C): 1.38 (9H, s), 4.54 (2H, b
r), 6.74 (2H, d, J = 8Hz), 7.15 (2H, d, J = 8Hz), 7.37 (2
H, d, J = 9Hz), 8.29 (2H, d, J = 9Hz), 9.19 (1H, s), 9.44
(1H, br)

(2) Boc-AzTyr-NHDmob 2,4-dimethoxybenzylamine hydrochloride 2.20 g,
1.54 ml Et ₃ N and Boc-AzTyr-ONp
The title compound was obtained from 4.04 g in the same manner as in Reference Example 1. _{Yield: 3.63g Rf 3: 0.23, Rf} 4: 0.28 NMR (δ, CDCl 3, 55 ℃): 1.40 (9H, s), 3.77 (3H, s),
3.78 (3H, s), 4.36 (2H, s), 4.62 (2H, br), 5.83 (2H, b
r), 6.41-6.44 (2H, m), 6.74-6.78 (2H, m), 7.09-7.20
(3H, m)

(3) Boc-AzTyr (CH ₂ Ph)
-NHDmob Boc-AzTyr-NHDmob 3.16 g in DMF
The mixture was dissolved in 5 ml, potassium carbonate (2.00 g) and benzyl bromide (1.38 g) were added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated, the residue was dissolved in AcOEt, washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column using AcOEt-hexane to obtain the title compound. Yield: 3.00 g Rf ₃ : 0.53, Rf ₄ : 0.42 NMR (δ, CDCl ₃ , 55 ° C): 1.40 (9H, s), 3.78 (6H, s),
4.36 (2H, s), 4.64 (2H, br), 5.05 (2H, s), 5.82 (2H, b
r), 6.41-6.44 (2H, m), 6.90-7.41 (10H, m)

Reference Example 13 Peptide III: Ac-Leu-Asp-Gln-
The title compound was synthesized as a Trp-Phe-Gly-NH ₂ comparative compound.

Reference Example 14 Boc-Asp (OBzl) -Gln-Trp-Phe
The title compound was synthesized as a —NH ₂ comparison compound.

Reference Example 15 Boc-AzPhe (2-Me) -NH (CH ₂ ) ₂ OC
H ₂ Ph (1) PhCH ₂ O (CH ₂ ) ₂ NHCO ₂ Np 2-benzyloxyethylamine 4-toluenesulfonate 40.40 g was dissolved in THF 300 ml and cooled under ice-cooling E
T ₃ N (35.00 ml) and 4-nitrophenyl chloroformate (25.00 g) were added, and the mixture was stirred at room temperature for 1 hr, and the solvent was evaporated. The residue was dissolved in AcOEt, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column using AcOEt-hexane to obtain the title compound. Yield: 37.70 g NMR (δ, CDCl3): 3.51 (2H, td, J = 5Hz, 5Hz), 3.64 (2
H, t, J = 5Hz), 4.57 (2H, s), 5.52 (1H, br), 7.28-7.41
(7H, m), 8.21-8.27 (2H, m)

(2) Boc-AzPhe (2-Me)-
NH (CH ₂₎ a ₂ OCH ₂ Ph 3- (2- methylbenzyl) carbazate t- butyl 3. 200 g was dissolved in THF30ml, PhCH ₂ O (C
_{H 2) 2 NHCO 2 Np4.} 00g and Et ₃ N2. 00
ml was added, and the mixture was stirred at room temperature for 18 hours, and then the solvent was distilled off.
Thereafter, the title compound was obtained in the same manner as in Reference Example 7. _{Yield:. 4 62g Rf 3: 0} . 45, Rf ₅ : 0.21 NMR (δ, CDCl ₃ , 55 ° C.): 1.41 (9H, s), 2.31 (3H, s), 3.
45-3.50 (2H, m), 3.55-3.60 (2H, m), 4.51 (2H, s), 4.7
7 (2H, br), 5.75 (2H, br), 7.13-7.29 (9H, m)

Reference Example 16 Boc-AzPhe (3-Me) -NH (CH ₂ ) ₂ OC
The H ₂ Ph 3- (3- methylbenzyl) carbazate t- butyl 3. 200 g was dissolved in THF30ml, PhCH ₂ O (C
_{H 2) 2 NHCO 2 Np4.} 00g and Et ₃ N2. 00
ml was added, and the mixture was stirred at room temperature for 18 hours, and then the solvent was distilled off.
Thereafter, the title compound was obtained in the same manner as in Reference Example 7. _{Yield:. 5 15g Rf 3: 0} . 46, Rf ₅ : 0.22 NMR (δ, CDCl ₃ , 55 ° C.): 1.43 (9H, s), 2.33 (3H, s), 3.
47 (2H, td, J = 5Hz, 5Hz), 3.58 (2H, t, J = 5Hz), 4.51 (2
H, s), 4.68 (2H, br), 5.72 (1H, br), 5.84 (1H, br s),
7.03-7.09 (9H, m)

Reference Example 17 Boc-AzPhe (4-Me) -NH (CH ₂ ) ₂ OC
The H ₂ Ph 3- (4- methylbenzyl) carbazate t- butyl 3. 200 g was dissolved in THF30ml, PhCH ₂ O (C
_{H 2) 2 NHCO 2 Np4.} 00g and Et ₃ N2. 00
ml was added, and the mixture was stirred at room temperature for 18 hours, and then the solvent was distilled off.
Thereafter, the title compound was obtained in the same manner as in Reference Example 7. _{Yield:. 4 94g Rf 3: 0} . 46, Rf ₅ : 0.22 NMR (δ, CDCl ₃ , 55 ° C.): 1.43 (9H, s), 2.33 (3H, s), 3.
45-3.49 (2H, m), 3.55-3.59 (2H, m), 4.50 (2H, s), 4.6
7 (2H, br), 5.71 (1H, br), 5.82 (1H, br s), 7.13-7.29
(9H, m)

Reference Example 18 Boc-AzPhe (4-i Pr) -NH (CH ₂ ) ₂ O
3.34 g of t-butyl CH ₂ Ph 3- (4-isopropylbenzyl) carbazate was dissolved in 30 ml of THF, and PhCH ₂ O was added.
(CH ₂ ) ₂ NHCO ₂ Np 4.00 g and Et ₃ N2.
After adding 00 ml and stirring at room temperature for 18 hours, the solvent was distilled off. Thereafter, the title compound was obtained in the same manner as in Reference Example 7. _{Yield:. 5 61g Rf 3: 0} . 47, Rf ₅ : 0.23 NMR (δ, CDCl ₃ , 55 ° C.): 1.23 (3H, s), 1.25 (3H, s), 1.
42 (9H, s), 2.89 (1H, septet, J = 7Hz), 3.46 (2H, td, J =
5Hz, 5Hz), 3.57 (2H, t, J = 5Hz), 4.50 (2H, s), 4.67 (2
H, br), 5.70 (1H, br), 5.87 (1H, br s), 7.17-7.31 (9
H, m)

Reference Example 19 Boc-AzPhe (2,4-diMe) -NH (CH ₂ ).
₂ OCH ₂ Ph (1) PhCH ₂ O (CH ₂ ) ₂ NCO 3-benzyloxypropionic acid 8.70 g of AcOE
It was dissolved in 80 ml of t, added with 6.80 ml of Et ₃ N and 5.10 ml of ethyl chlorocarbonate at -10 ° C and stirred for 15 minutes, and then added with 16 ml of an aqueous solution of 4.78 g of sodium azide at -5 to 0 ° C for 30 minutes. It was stirred. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. AcOEt15 separately
ml of the acid azide in AcO
The Et solution was added dropwise over 20 minutes, and the mixture was heated under reflux for 10 minutes. After distilling off the solvent, the residue was distilled under reduced pressure (97
(° C / 4 mmHg) to give the title compound. Yield: 6.40 g NMR (δ, CDCl ₃ ): 3.43 (2H, t, J
= 5 Hz), 3.61 (2H, t, J = 5H)
z), 4.59 (2H, s), 7.26-7.3.
7 (5H, m)

(2) Boc-AzPhe (2,4-di
_{Me) -NH (CH 2) 2} OCH 2 Ph 3- (2, 4- dimethylbenzyl) carbazate t- butyl 2. 200 g and _{PhCH 2 O (CH 2) 2} NCO1.
40 g was dissolved in 20 ml of THF and stirred at room temperature for 18 hours. Thereafter, the title compound was obtained in the same manner as in Reference Example 7. _{Yield:. 3 00g Rf 3: 0} . 46, Rf ₅ : 0.23 NMR (δ, CDCl ₃ , 55 ° C.): 1.41 (9H, s), 2.27 (3H, s),
2.29 (3H, s), 3.47 (2H, td, J = 5Hz, 5Hz), 3.57 (2H, t,
J = 5Hz), 4.50 (2H, s), 4.73 (2H, br s), 5.70-5.74 (2
H, m), 6.93-7.02 (3H, m), 7.24-7.31 (5H, m)

Reference Example 20 Boc-AzPhe (2,5-diMe) -NH (CH ₂ ).
2.00 g of t-butyl ₂ OCH ₂ Ph 3- (2,5-dimethylbenzyl) carbazate and PhCH ₂ O (CH ₂ ) ₂ NCO 1.
40 g was dissolved in 20 ml of THF and stirred at room temperature for 18 hours. Thereafter, the title compound was obtained in the same manner as in Reference Example 7. _{Yield:. 3 07g Rf 3: 0} . 46, Rf ₅ : 0.23 NMR (δ, CDCl ₃ , 55 ° C.): 1.41 (9H, s), 2.26 (3H, s), 2.
28 (3H, s), 3.47 (2H, td, J = 5Hz, 5Hz), 3.58 (2H, t, J =
5Hz), 4.51 (2H, s), 4.73 (2H, br s), 5.71-5.77 (2H,
m), 6.94-7.06 (3H, m), 7.24-7.31 (5H, m)

Reference Example 21 Boc-Trp-NHNHCH ₂ Ph (2-F) 3.00 g of Boc-Trp-NHNH _{2 and} 1.23 g of 2-fluorobenzaldehyde were dissolved in 30 ml of MeOH and stirred at room temperature for 18 hours. The solvent was distilled off. The residue was redissolved in 30 ml of THF and stirred for 1 week in a stream of hydrogen in the presence of 1.00 g of 10% palladium carbon.
After the palladium carbon was filtered off, the solvent was distilled off and the residue A
Purification with a silica gel column using cOEt-hexane gave the title compound. Yield: 680mg Rf _3: 0. 15, Rf ₄ : 0.25 [α] _D : -9.07 (C = 1.19, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.29 (9H, s), 2.87 (1H, dd,
J = 14Hz, 8Hz), 2.99 (1H, dd, J = 14Hz, 5Hz), 3.81-3.92
(2H, m), 4.12-4.20 (1H, m), 5.11-5.17 (1H, m), 6.45
(1H, br), 6.93-7.56 (9H, m), 9.29 (1H, br), 10.65 (1
H, br s)

Reference Example 22 Boc-Trp-NHNHCH ₂ Ph (2-CF ₃ ) Boc-Trp-NHNH ₂ 3.00 g, 2- (trifluoromethyl) benzaldehyde 1.72 g in MeOH.
After dissolving in 30 ml and stirring at room temperature for 18 hours, the solvent was distilled off. The residue was redissolved in 30 ml of THF and stirred in the presence of 1.00 g of 10% palladium on carbon for one week in a hydrogen stream (3.50 kg / cm ² ). Then, the title compound was obtained in the same manner as in Reference Example 21. _{Yield:. 1 56g Rf 3: 0} . 20, Rf ₄ : 0.33 [α] _D : −8.39 (C = 1.04, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.28 (9H, s), 2.86 (1H, dd,
J = 14Hz, 8Hz), 2.98 (1H, dd, J = 14Hz, 5Hz), 4.01-4.04
(2H, m), 4.12-4.20 (1H, m), 5.22-5.28 (1H, m), 6.50
(1H, br), 6.93-7.73 (9H, m), 9.34 (1H, br), 10.65 (1
H, br s)

[Reference Example 23] 60.00 g of Boc-Trp-NHNHCH ₂ Ph Boc-Trp-NHNH _{2 and} 21.00 g of benzaldehyde were dissolved in 600 ml of MeOH to give 10
% Palladium carbon in the presence of 3.80 g, the mixture was stirred in a hydrogen stream for 18 hours. Then, the title compound was obtained in the same manner as in Reference Example 21. _{Yield:. 68 90g Rf 4: 0} . 25 [α] _D : -8.41 (C = 1.20, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.29 (9H, s), 2.88 (1H, dd,
J = 15Hz, 9Hz), 3.00 (1H, dd, J = 15Hz, 5Hz), 3.72-3.84
(2H, m), 4.13-4.20 (1H, m), 5.05-5.07 (1H, m), 6.47
(1H, br), 6.93-7.32 (9H, m), 9.24 (1H, br), 10.65 (1
H, br s)

Reference Example 24 Boc-AzPhe-NH (CH ₂ ) ₂ O- (2-naphthylmethyl) 2- (2-naphthylmethyl) oxyethylamine 2.7
4 g, Et ₃ N 1.90 ml and Boc-AzPhe-O
The title compound was obtained from 5.27 g of Np in the same manner as in Reference Example 1. Yield: 5.40g Rf _3: 0. 43, Rf ₅ : 0.18 NMR (δ, DMSO-d ₆ , 55 ° C.): 1.31 (9H, s), 3.31 (2H, td,
J = 6Hz, 6Hz), 3.53 (2H, t, J = 6Hz), 4.53 (2H, br s),
4.65 (2H, s), 6.35 (1H, br), 7.23-7.31 (5H, m), 7.46-
7.52 (3H, m), 7.83-7.90 (4H, m), 8.68 (1H, br)

Example 1 Boc-Asp (OBzl) -Gln-Trp-AzP
he-NH ₂ (1) and Z-Trp-AzPhe-NHDmob Boc -AzPhe-NHDmob 11.60g M
4. Dissolve in eOH and 4-toluenesulfonic acid monohydrate
31 g was added and the mixture was heated under reflux for 2 hours. The solvent was evaporated, the residue was dissolved in AcOEt, washed successively with 10% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. After drying the residue under reduced pressure, T
Dissolved in 50 ml of HF and separately prepared Z-Trp-OH mixed acid anhydride (9.07 g of Z-Trp-OH was added to THF80.
It was dissolved in 0.1 ml of NMM, added with 2.95 ml of NMM and 3.48 ml of isobutyl chloroformate-20 ml of THF solution under ice cooling, and stirred for 1 hour), and stirred at room temperature for 18 hours. The solvent was evaporated, the residue was dissolved in CH ₂ Cl ₂ , washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column using AcOEt-hexane to obtain the title compound. _{Yield: 10.34g Rf 3: 0.23, Rf} 4: 0.24 [α] _{D: -20.74 (C = 1.03,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 2.94 (1H, dd, J = 14Hz, 8H
z), 3.04 (1H, dd, J = 14Hz, 6Hz), 3.70 (2H, s), 3.74 (3
H, s), 4.12-4.24 (4H, m), 4.66 (1H, d, J = 14Hz), 4.76
(1H, d, J = 13Hz), 4.83 (1H, d, J = 13Hz), 6.39-6.49 (3
H, m), 6.92-7.54 (17H, m), 10.09 (1H, br s), 10.68 (1
H, br s)

(2) Boc-Gln-Trp-AzPh
e-NHDmob Z-Trp-AzPhe-NHDmob 8.53 g,
10% Palladium on carbon 0.85 in 150 ml MeOH
Stirred in a stream of hydrogen for 18 hours in the presence of g. After the palladium carbon was filtered off, the solvent was distilled off. The residue was dried under reduced pressure, dissolved in DMF (70 ml), and cooled under ice with Boc-G.
ln-ONp (4.93 g) and NMM (1.48 ml) were added, and the mixture was stirred at room temperature for 18 hours. DMF was distilled off, the residue was dissolved in CH ₂ Cl ₂ , washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue is treated with M
Purification by silica gel column using eOH-CH ₂ Cl _2, to give the title compound. Yield: 6.94 g Rf ₁ : 0.48, Rf ₂ : 0.14 [α] _D : -15.00 (C = 1.15, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.33 (9H, s), 1.58-1.82 (2
H, m), 2.04-2.10 (2H, m), 2.95-3.13 (2H, m), 3.73 (3H,
s), 3.76 (3H, s), 3.86-3.94 (1H, m), 4.09-4.15 (3H,
m), 4.34-4.42 (1H, m), 4.61 (1H, d, J = 14Hz), 6.41-6.
65 (5H, m), 6.93-7.53 (12H, m), 8.07 (1H, br s), 10.0
0 (1H, br s), 10.71 (1H, br s)

(3) Boc-Asp (OBzl) -Gl
_{n-Trp-AzPhe-NH 2} Boc-Gln-Trp-AzPhe-NHDmob
After 4.00 g was allowed to stand in a 48.00 ml TFA-ethanedithiol-dimethyl sulfide (10: 1: 1) solution under water temperature for 9 hours, TFA was distilled off. Ether was added to the residue and the precipitated crystals were collected by filtration and dried under reduced pressure.
Dissolve in 40 ml of DMF, 0.76 ml of Et ₃ N under ice cooling,
Boc-Asp (OBzl) -OSu 2.30 g and N
0.60 ml of MM was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off, and the residue was treated with 2-butanol-CH ₂ Cl.
_It was dissolved in ₂ (5: 1), washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was washed with MeOH.
Purification by silica gel column using -CH ₂ Cl _2, to give the title compound. Yield: 1.44 g Rf ₁ : 0.39, Rf ₂ : 0.11 [α] _D : −26.71 (C = 1.21, DMF) FAB mass spectrum (M + 1): 785 NMR (δ, DMSO- d ₆ , 55 ℃): 1.36 (9H, s), 1.69-1.91 (2
H, m), 2.09 (2H, t, J = 8Hz), 2.60 (1H, dd, J = 16Hz, 9H
z), 2.77 (1H, dd, J = 16Hz, 5Hz), 2.96 (1H, dd, J = 15Hz,
7Hz), 3.07 (1H, dd, J = 15Hz, 8Hz), 4.06 (1H, d, J = 15
Hz), 4.24-4.36 (3H, m), 4.59 (1H, d, J = 15Hz), 5.08 (2
H, s), 5.78 (2H, br s), 6.58 (1H, br), 6.93-7.53 (17H,
br), 7.75 (1H, d, J = 8Hz), 8.19 (1H, br s), 9.95 (1H,
br s), 10.68 (1H, br s)

Example 2 Boc-Asp (OBzl) -Gln-Trp-AzP
_{he-NH (CH 2) 2} OCH 2 Ph (1) Boc-Trp-AzPhe-NH (CH 2) 2 O
_{CH 2 Ph Boc-AzPhe-NH} (CH 2) 2 OCH 2 Ph 8
After leaving 15 mg in 5.00 ml of 4N HCl-AcOEt at room temperature for 1 hour, the solvent was distilled off. After drying the residue under reduced pressure, 5 ml of DMF and 0.28 ml of Et ₃ N were added,
Separately prepared Boc-Trp-OH mixed acid anhydride (Bo
C-Trp-OH (690 mg) was dissolved in THF (5 ml), and NMM (0.22 ml) and isobutyl chloroformate (0.2) under ice cooling.
7 ml was added and stirred for 1 hour), and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off, the residue was dissolved in AcOEt,
The extract was washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column using AcOEt-hexane to obtain the title compound. _{Yield: 650mg Rf 3: 0.17, Rf} 4: 0.21 [α] _{D: -8.31 (C = 1.01,} DMF) FAB mass spectrum (M + 1): 586 NMR (δ, DMSO-d 6 , 55 ℃): 1.32 (9H, s), 2.91 (1H, dd,
J = 14Hz, 8Hz), 2.99 (1H, dd, J = 14Hz, 7Hz), 3.20-3.3
1 (2H, m), 3.41 (2H, t, J = 6Hz), 4.08-4.15 (2H, m), 4.
45 (2H, s), 4.62 (1H, d, J = 15Hz), 6.18 (1H, br), 6.91
-7.52 (16H, m), 9.98 (1H, br s), 10.70 (1H, br s)

(2) Boc-Gln-Trp-AzPh
_{e-NH (CH 2) 2} OCH 2 Ph Boc-Trp-AzPhe-NH (CH 2) 2 OCH 2
After 750 mg of Ph was left in 3.20 ml of 4N HCl-AcOEt under ice cooling for 1 hour, the solvent was distilled off. The residue was dried under reduced pressure, dissolved in 5 ml of DMF, and cooled under ice-cooling to Bo.
470 mg of c-Gln-ONp, 0.18 ml of Et ₃ N and 0.14 ml of NMM were added, and the mixture was stirred at room temperature for 18 hours. DMF was distilled off, the residue was dissolved in CH ₂ Cl ₂ ,
The extract was washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column with MeOH-CH ₂ Cl _2, to give the title compound. Yield: 800 mg Rf ₁ : 0.46, Rf ₂ : 0.12 [α] _D : -19.19 (C = 1.38, DMF) FAB mass spectrum (M + 1): 714 NMR (δ, DMSO-d ₆ , 55 ℃): 1.34 (9H, s), 1.66-1.86 (2
H, m), 2.07-2.13 (2H, m), 2.95-3.14 (4H, m), 3.39 (2H,
t, J = 6Hz), 3.90-3.97 (1H, m), 4.11 (1H, d, J = 15Hz),
4.34-4.41 (1H, m), 4.46 (2H, s), 4.57 (1H, d, J = 15H
z), 6.10 (1H, br), 6.57-6.75 (2H, br), 6.94-7.53 (16
H, m), 8.08 (1H, br s), 9.97 (1H, br s), 10.74 (1H, br
s)

(3) Boc-Asp (OBzl) -Gl
n-Trp-AzPhe-NH ( CH 2) 2 OCH 2 Ph Boc-Gln-Trp-AzPhe-NH (CH 2) 2
OCH ₂ Ph 300 mg, 4N HCl-AcOEt
1.50 ml, Et ₃ N 0.06 ml, NMM 0.05
ml and Boc-Asp (OBzl) -OSu 177 mg
From above, the title compound was obtained in the same manner as in Example 2 (2). Yield: 230 mg Rf ₁ : 0.50, Rf ₂ : 0.25 [α] _D : -18.08 (C = 1.15, DMF) FAB mass spectrum (M + 1): 919 NMR (δ, DMSO-d ₆ , 55 ℃): 1.36 (9H, s), 1.71-1.91 (2
H, m), 2.10 (2H, t, J = 8Hz), 2.60 (1H, dd, J = 16Hz, 8H
z), 2.78 (1H, dd, J = 16Hz, 4Hz), 2.93-3.13 (4H, m),
3.38 (2H, t, J = 6Hz), 4.11 (1H, d, J = 14Hz), 4.25-4.36
(3H, m), 4.44 (2H, s), 4.54 (1H, d, J = 14Hz), 5.07 (2
H, s), 6.04 (1H, br), 6.59 (1H, br), 6.92-7.52 (22H,
m), 7.75 (1H, d, J = 7Hz), 8.21 (1H, br s), 9.95 (1H, b
rs), 10.71 (1H, br s)

Example 3 i-Pent-CO-Gln-Trp-AzPhe-N
_{H (CH 2) 2 OCH 2} Ph (i-Pent: isopentyl) Boc-Gln-Trp-AzPhe -NH (CH 2) 2
OCH ₂ Ph 2.00 g, 4N HCl-AcOEt
7.00 ml, Et ₃ N 0.37 ml, NMM 0.31
The title compound was obtained in the same manner as in Example 2 (2) from ml and 4-methyl valeric acid N-hydroxysuccinimide ester (0.60 g). Yield: 1.57 g Rf ₁ : 0.46, Rf ₂ : 0.09 [α] _D : -21.03 (C = 1.49, DMF) FAB mass spectrum (M + 1): 712 NMR (δ, DMSO- d ₆ , 55 ℃): 0.84 (6H, d, J = 6Hz), 1.33-
1.54 (3H, m), 1.68-1.92 (2H, m), 2.05-2.10 (4H, m),
2.94-3.10 (4H, m), 3.40 (2H, t, J = 6Hz), 4.11-4.25 (2
H, m), 4.30-4.40 (1H, m), 4.46 (2H, s), 4.57 (1H, d,
J = 14Hz), 6.10 (1H, br), 6.60 (1H, br), 6.95-7.52 (16
H, m), 7.77 (1H, d, J = 7Hz), 8.06 (1H, brs), 9.93 (1H,
br s), 10.73 (1H, br s)

Example 4 Bz-Gln-Trp-AzPhe-NH (CH ₂ ) ₂ O
_{CH 2 Ph Boc-Gln-Trp} -AzPhe-NH (CH 2) 2
OCH ₂ Ph 350 mg, 4N HCl-AcOEt
1.50 ml, Et ₃ N 0.07 ml, NMM 0.06
ml and benzoyl chloride 0.06 ml to give Example 2
The title compound was obtained in the same manner as in (2). Yield: 170 mg Rf ₁ : 0.48, Rf ₂ : 0.16 [α] _D : -13.35 (C = 1.06, DMF) FAB mass spectrum (M + 1): 718 NMR (δ, DMSO-d ₆ , 55 ℃): 1.93-2.06 (2H, m), 2.21 (2
H, t, J = 8Hz), 2.96-3.12 (4H, m), 3.38 (2H, t, J = 6H
z), 3.99-4.03 (1H, m), 4.14 (1H, d, J = 15Hz), 4.32-4.
39 (1H, m), 4.41 (2H, s), 4.59 (1H, d, J = 15Hz), 6.15
(1H, br), 6.71 (1H, br), 6.92-7.83 (16H, m), 8.21 (1H,
d, J = 6Hz), 8.52 (1H, d, J = 7Hz), 9.93 (1H, br s), 1
0.72 (1H, br s)

Example 5 cyPent-CO-Gln-Trp-AzPhe-N
_{H (CH 2) 2 OCH 2} Ph (cyPent: cyclopentyl) Boc-Gln-Trp-AzPhe -NH (CH 2) 2
OCH ₂ Ph 350 mg, 4N HCl-AcOEt
1.50 ml, Et ₃ N 0.07 ml and cyclopentanecarboxylic acid anhydride (cyclopentanecarboxylic acid 0.11
ml, prepared from 101 mg of DCC), Example 2
The title compound was obtained in the same manner as in (2). Yield: 230 mg Rf ₁ : 0.47, Rf ₂ : 0.14 [α] _D : −26.39 (C = 1.08, DMF) FAB mass spectrum (M + 1): 710 NMR (δ, DMSO-d ₆ , 55 ℃): 1.43-1.77 (8H, m), 1.79-1.
92 (2H, m), 2.12 (2H, t, J = 8Hz), 2.55-2.60 (1H, m), 2.
94-3.14 (4H, m), 3.14 (2H, t, J = 6Hz), 4.12-4.24 (2H,
m), 4.31-4.38 (1H, m), 4.46 (2H, s), 4.58 (1H, d, J = 1
5Hz), 6.13 (1H, br s), 6.62 (1H, br s), 6.93-7.53 (16
H, m), 7.71 (1H, d, J = 5Hz), 8.04 (1H, br s), 9.94 (1H,
br s), 10.74 (1H, br s)

Example 6 t-Bu-NHCO-Gln-Trp-AzPhe-N
_{H (CH 2) 2 OCH 2} Ph Boc-Gln-Trp-AzPhe-NH (CH 2) 2
OCH ₂ Ph 350 mg, 4N HCl-AcOEt
The title compound was obtained from 1.50 ml, 0.03 ml of Et ₃ N and 0.06 ml of t-butyl isocyanate in the same manner as in Example 2 (2). Yield: 270 mg Rf ₁ : 0.48, Rf ₂ : 0.11 [α] _D : -18.91 (C = 1.00, DMF) FAB mass spectrum (M + 1): 713 NMR (δ, DMSO-d ₆ , 55 ℃): 1.18 (9H,
s), 1.56-1.83 (2H, m), 2.0
7 (2H, t, J = 8Hz), 3.02-3.1
8 (4H, m), 3.40 (2H, t, J = 6
Hz), 4.01-4.08 (1H, m), 4.
14 (1H, d, J = 15 Hz), 4.31-
4.38 (1H, m), 4.46 (2H, s),
4.57 (1H, d, J = 15Hz), 5.8
2-5.86 (2H, m), 6.12 (1H, b
r), 6.57 (1H, br), 6.93-7.
53 (16H, m), 8.17 (1H, d, J
= 6 Hz), 9.95 (1H, br s), 1
0.72 (1H, br s)

Example 7 i-Pent-NHCO-Gln-Trp-AzPhe
_{-NH (CH 2) 2 OCH 2} Ph (i-Pent: isopentyl) Boc-Gln-Trp-AzPhe -NH (CH 2) 2
OCH ₂ Ph 300 mg, 4N HCl-AcOEt
1.50 ml, Et ₃ N 0.06 ml and isopentyl isocyanate (4-methylvaleric acid 0.05 ml were dissolved in toluene 5 ml, diphenylphosphoryl azide 0.09 ml
And Et ₃ N (0.06 ml) and the mixture was stirred at 80 ° C. for 2 hours) to give the title compound in the same manner as in Example 2 (2). Yield: 120 mg Rf ₁ : 0.49, Rf ₂ : 0.11 [α] _D : -18.89 (C = 1.15, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 0.85 (6H , d, J = 7Hz), 1.25
(2H, td, J = 7Hz, 7Hz), 1.49-1.85 (3H, m), 2.08 (2H, t,
J = 8Hz), 2.93-3.20 (6H, m), 3.40 (2H, t, J = 6Hz), 4.0
5-4.19 (2H, m), 4.30-4.37 (1H, m), 4.46 (2H, s), 4.58
(1H, d, J = 15Hz), 5.90-5.95 (2H, m), 6.12 (1H, br),
6.57 (1H, br), 6.93-7.52 (16H, m), 8.19 (1H, br s),
9.96 (1H, br s), 10.71 (1H, br s)

Example 8 cyPent-NHCO-Gln-Trp-AzPhe
_{-NH (CH 2) 2 OCH 2} Ph (cyPent: cyclopentyl) Boc-Gln-Trp-AzPhe -NH (CH 2) 2
OCH ₂ Ph 300 mg, 4N HCl-AcOEt
1.50 ml, Et ₃ N 0.06 ml and cyclopentyl isocyanate (cyclopentanecarboxylic acid 0.05 ml)
Was dissolved in 5 ml of toluene, 0.09 ml of diphenylphosphoryl azide and 0.06 ml of Et ₃ N were added, and the mixture was stirred at 80 ° C. for 2 hours) to give the title compound as in Example 2 (2). . Yield: 150 mg Rf ₁ : 0.46, Rf ₂ : 0.11 [α] _D : -18.46 (C = 1.00, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.22-1.32 (2H, m), 1.44-1.
82 (8H, m), 2.08 (2H, t, J = 8Hz), 2.96-3.15 (4H, m), 3.
40 (2H, t, J = 6Hz), 3.76-3.83 (1H, m), 4.04-4.18 (2H,
m), 4.30-4.36 (1H, m), 4.46 (2H, s), 4.57 (1H, d, J = 1
5Hz), 5.86 (1H, d, J = 7Hz), 5.98 (1H, br), 6.13 (1H, b
r), 6.59 (1H, br), 6.93-7.52 (16H, m), 8.21 (1H, br
s), 9.98 (1H, br s), 10.72 (1H, br s)

Example 9 Boc-Met (O ₂ ) -Trp-AzPhe-NH (C
_{H 2) 2 OCH 2 Ph Boc} -Trp-AzPhe-NH (CH 2) 2 OCH 2
After 520 mg of Ph was left in 2.50 ml of 4N HCl-AcOEt under ice cooling for 1 hour, the solvent was distilled off. The residue was dried under reduced pressure, dissolved in 10 ml of DMF, and cooled under ice-cooling E.
_{t 3 N 0.18ml, Boc-Met} (O 2) -OH 2
50 mg, DCC 190 mg, HOBt 160 mg and NM
M (0.14 ml) was added, and the mixture was stirred at room temperature for 18 hours. D
MF was distilled off, the residue was dissolved in CH ₂ Cl ₂ and DCU
The rea was filtered off, washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was treated with MeOH-C.
Purify on a silica gel column with H ₂ Cl ₂ to give the title compound. Yield: 370 mg Rf ₁ : 0.58, Rf ₂ : 0.38 [α] _D : −7.28 (C = 1.15, DMF) FAB mass spectrum (M + 1): 749 NMR (δ, DMSO-d ₆ , 55 ℃): 1.35 (9H, s), 1.93-2.04 (2
H, m), 2.90 (3H, s), 2.95-3.10 (6H, m), 3.40 (2H, t,
J = 6Hz), 4.06-4.15 (2H, m), 4.36-4.40 (1H, m), 4.46 (2
H, s), 4.58 (1H, d, J = 15Hz), 6.07 (1H, br), 6.84 (1H,
br), 6.94-7.53 (15H, m), 8.16 (1H, br s), 10.02 (1H,
br s), 10.75 (1H, br s)

Example 10 Boc-Asn-Trp-AzPhe-NH (CH ₂ ) _{2
OCH 2 Ph Boc-Trp-AzPhe} -NH (CH 2) 2 OCH 2
Ph 500 mg, 4N HCl-AcOEt 2.50 ml,
Et ₃ N 0.12 ml, NMM 0.09 ml and Boc
The title compound was obtained from 300 mg of -Asn-ONp in the same manner as in Example 2 (2). Yield: 290 mg Rf ₁ : 0.49, Rf ₂ : 0.24 [α] _D : -21.26 (C = 1.20, DMF) FAB mass spectrum (M + 1): 700 NMR (δ, DMSO-d ₆ , 55 ℃): 1.33 (9H, s), 2.30-2.44 (2
H, m), 2.96-3.11 (4H, m), 3.40 (2H, t, J = 6Hz), 4.21-
4.39 (3H, m), 4.46 (2H, s), 4.52 (1H, d, J = 15Hz), 6.0
8 (1H, br), 6.67 (1H, br), 6.74 (1H, br), 6.93-7.52 (1
6H, m), 8.02 (1H, br s), 9.91 (1H, br s), 10.71 (1H,
br s)

Example 11 Boc-Met-Trp-AzPhe-NH (CH ₂ ) _{2
OCH 2 Ph Boc-Trp-AzPhe} -NH (CH 2) 2 OCH 2
Ph 500 mg, 4N HCl-AcOEt 2.00 ml,
Et ₃ N 0.12 ml, NMM 0.09 ml and Boc
The title compound was obtained from 295 mg of -Met-OSu in the same manner as in Example 2 (2). Yield: 500 mg Rf ₁ : 0.73, Rf ₂ : 0.58 [α] _D : -12.85 (C = 1.04, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.35 (9H,
s), 1.73-1.83 (2H, m), 2.0
0 (3H, s), 2.40 (2H, t, J = 7)
Hz), 2.96-3.16 (4H, m), 3.
40 (2H, t, J = 6Hz), 4.00-4.
14 (2H, m), 4.35-4.42 (1H,
m), 4.47 (2H, s), 4.59 (1H,
d, J = 14 Hz), 6.10 (1H, b
r), 6.72 (1H, br), 6.96-7.
53 (15H, m), 8.07 (1H, br
s), 9.96 (1H, br s), 10.74
(1H, br s)

Example 12 Z-Asn-Trp-AzPhe-NH (CH ₂ ) _{2
OCH 2 Ph Boc-Trp-AzPhe} -NH (CH 2) 2 OCH 2
Ph 450 mg, 4N HCl-AcOEt 2.00 ml,
Et ₃ N 0.11 ml, NMM 0.09 ml and ZA
The title compound was obtained from 272 mg of sn-ONp in the same manner as in Example 2 (2). Yield: 290 mg Rf ₁ : 0.53, Rf ₂ : 0.21 [α] _D : -20.27 (C = 1.02, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 2.40 (1H , dd, J = 15Hz, 8H
z), 2.51 (1H, dd, J = 15Hz, 6Hz), 2.93-3.21 (4H, m),
3.40 (2H, t, J = 6Hz), 4.22-4.40 (3H, m), 4.45 (2H, s),
4.53 (1H, d, J = 15Hz), 4.95 (1H, d, J = 13Hz), 5.01 (1
H, d, J = 13Hz), 6.09 (1H, br), 6.75 (1H, br), 6.93-7.
52 (22H, m), 8.12 (1H, br s), 9.92 (1H, brs), 10.72 (1
H, br s)

Example 13 Boc-Orn-Trp-AzPhe-NH (CH ₂ ) ₂
OCH ₂ Ph (1) Boc-Orn (Z) -Trp-AzPhe-N
_{H (CH 2) 2 OCH 2} Ph Boc-Trp-AzPhe-NH (CH 2) 2 OCH 2
Ph 500 mg, 4N HCl-AcOEt 2.50 ml,
Et ₃ N 0.12 ml, NMM 0.09 ml and Boc
From Orn (Z) -OSu 395 mg, Example 2
The title compound was obtained in the same manner as in (2). Yield: 570 mg Rf ₁ : 0.72, Rf ₂ : 0.53 [α] _D : -14.17 (C = 1.08, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34-1.55 (13H, m), 2.95-
3.18 (6H, m), 3.38 (2H, t, J = 6Hz), 3.87-3.93 (1H, m),
4.12 (1H, d, J = 14Hz), 4.34-4.41 (1H, m), 4.45 (2H,
s), 4.56 (1H, d, J = 14Hz), 5.01 (2H, s), 6.06 (1H, b
r), 6.60 (1H, br), 6.93-7.53 (21H, m), 8.01 (1H, br
s), 9.93 (1H, br s), 10.72 (1H, br s)

(2) Boc-Orn-Trp-AzPh
_{e-NH (CH 2) 2} OCH 2 Ph Boc-Orn (Z) -Trp-AzPhe-NH (C
H ₂ ) ₂ OCH ₂ Ph 410 mg 1 in 1 ml MeOH
Stirred in a stream of hydrogen for 18 hours in the presence of 41% 0% palladium on carbon. After filtering off the palladium carbon, the solvent was evaporated, and the residue was purified by silica gel column with MeOH-CH ₂ Cl _2, to give the title compound. Yield: 170 mg Rf ₁ : 0.18, Rf ₂ : 0.01 [α] _D : -23.09 (C = 1.07, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.24-1.57 (13H, m), 2.89-
3.17 (8H, m), 3.39 (2H, t, J = 6Hz), 3.87-3.94 (1H, m),
4.11 (1H, d, J = 15Hz), 4.35-4.40 (1H, m), 4.46 (2H,
s), 4.58 (1H, d, J = 15Hz), 6.11 (1H, br), 6.62 (1H, b
r), 6.93-7.52 (16H, m), 8.08 (1H, br), 10.74 (1H, br
s)

Example 14 Boc-Cit-Trp-AzPhe-NH (CH ₂ ) _{2
OCH 2 Ph Boc-Trp-AzPhe} -NH (CH 2) 2 OCH 2
Ph 500 mg, 4N HCl-AcOEt 2.50 ml,
Et ₃ N 0.12 ml, NMM 0.09 ml, Boc-
Cit-OH 234 mg, DCC 176 mg and HOB
The title compound was obtained in the same manner as in Example 9 from t 115 mg. Yield: 410 mg Rf ₁ : 0.47, Rf ₂ : 0.11 [α] _D : -19.82 (C = 1.05, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.28-1.61 (13H, m), 2.89-
3.15 (6H, m), 3.39 (2H, t, J = 6Hz), 3.89-3.97 (1H, m),
4.11 (1H, d, J = 15Hz), 4.33-4.40 (1H, m), 4.46 (2H,
s), 4.57 (1H, d, J = 15Hz), 5.24 (2H, br s), 5.80 (1H,
br s), 6.10 (1H, br), 6.60 (1H, br), 6.93-7.53 (15H,
m), 8.04 (1H, br s), 9.94 (1H, br s), 10.72 (1H, br
s)

Example 15 Boc-Arg (NO ₂ ) -Trp-AzPhe-NH
_{(CH 2) 2 OCH 2 Ph} (NO 2 is substituted guanidino group) Boc-Trp-AzPhe-NH (CH 2) 2 OCH 2
Ph 500 mg, 4N HCl-AcOEt 2.50 ml,
_{Et 3 N 0.12ml, Boc-Arg} (NO 2) -OH
Mixed acid anhydride _{(Boc-Arg (NO 2)} -OH272mg
Was dissolved in 5 ml of THF, 0.09 ml of N-methylmorpholine and 0.11 ml of isobutyl chloroformate were added under ice cooling, and the mixture was stirred for 1 hour) to give the title compound in the same manner as in Example 2 (1). It was _{Yield: 340mg Rf 1: 0.51, Rf} 2: 0.18 [α] _{D: -17.44 (C = 1.04,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.35 (9H , s), 1.42-1.60 (4
H, m), 2.95-3.16 (6H, m), 3.39 (2H, t, J = 6Hz), 3.90-
3.98 (1H, m), 4.11 (1H, d, J = 14Hz), 4.35-4.42 (1H,
m), 4.46 (2H, s), 4.57 (1H, d, J = 14Hz), 6.09 (1H, b
r), 6.67 (1H, br), 6.94-7.53 (16H, m), 7.78 (2H, br
s), 8.06 (1H, br s), 9.95 (1H, br s), 10.72 (1H, br
s)

Example 16 Boc-Asp-Trp-AzPhe-NH (CH ₂ ) ₂
OCH ₂ Ph (1) Boc-Asp (OBzl) -Trp-AzPh
_{e-NH (CH 2) 2} OCH 2 Ph Boc-Trp-AzPhe-NH (CH 2) 2 OCH 2
Ph 500 mg, 4N HCl-AcOEt 2.50 ml,
Et ₃ N 0.12 ml, NMM 0.09 ml and Boc
The title compound was obtained from 385 mg of -Asp (OBzl) -OSu in the same manner as in Example 2 (2). Yield: 410 mg Rf ₁ : 0.76, Rf ₂ : 0.65 [α] _D : −28.67 (C = 1.02, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34 (9H , s), 2.57 (1H, dd,
J = 16Hz, 9Hz), 2.71 (1H, dd, J = 16Hz, 5Hz), 2.95-3.1
6 (4H, m), 3.38 (2H, t, J = 6Hz), 4.13-4.24 (1H, m), 4.
34-4.38 (2H, m), 4.44 (2H, s), 4.51-4.57 (1H, m), 5.0
7 (2H, s), 6.05 (1H, br), 6.93-7.52 (21H, m), 8.01 (1
H, br), 9.92 (1H, br s), 10.74 (1H, brs)

(2) Boc-Asp-Trp-AzPh
_{e-NH (CH 2) 2} OCH 2 Ph Boc-Asp (OBzl) -Trp-AzPhe-N
In the same manner as in the H (CH _{2) 2} OCH ₂ Ph 440 mg and implementation 10% palladium on carbon 44mg Example 13 (2) to give the title compound. Yield: 170 mg Rf ₁ : 0.48, Rf ₂ : 0.09 [α] _D : −28.42 (C = 1.09, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34 (9H , s), 2.44 (1H, dd,
J = 16Hz, 8Hz), 2.58 (1H, dd, J = 16Hz, 5Hz), 2.89-3.2
0 (4H, m), 3.40 (2H, t, J = 6Hz), 4.16-4.37 (3H, m), 4.
46 (2H, s), 4.55 (1H, d, J = 14Hz), 6.07 (1H, br), 6.82
-7.52 (17H, m), 7.98 (1H, br s), 9.93 (1H, br s), 10.7
3 (1H, br s)

Example 17 Boc-Asp (OBzl) -Gln-Trp-AzP
he-NHCH ₂ Ph (4-F) (CH ₂ Ph (4-
F): 4-fluorobenzyl group) (1) Boc-Trp-AzPhe-NHCH ₂ Ph
(4-F) Boc-AzPhe-NHCH ₂ Ph (4-F) 700
mg, 4N HCl-AcOEt4.50ml, Et 3 N
0.26 ml and Boc-Trp-OH mixed acid anhydride (B
oc-Trp-OH 636 mg was dissolved in THF 10 ml,
NMM (0.21 ml) and isobutyl chloroformate (0.24 ml) were added under ice cooling and the mixture was stirred for 1 hour.
The title compound was obtained in a similar manner to. _{Yield: 630mg Rf 3: 0.24, Rf} 4: 0.29 [α] _{D: -5.31 (C = 1.04,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.24 (9H , s), 2.89-3.04 (2
H, m), 4.04-4.25 (4H, m), 4.67 (1H, d, J = 15Hz), 6.72-
7.52 (16H, m), 10.06 (1H, br s), 10.71 (1H, br s)

(2) Boc-Gln-Trp-AzPh
e-NHCH ₂ Ph (4-F) Boc-Trp-AzPhe-NHCH ₂ Ph (4-
F) 500 mg, 4N HCl-AcOEt 2.50 ml, E
t ₃ N 0.13 ml, NMM 0.10 ml and Boc-
The title compound was obtained from 327 mg of Gln-ONp in the same manner as in Example 2 (2). Yield: 460 mg Rf ₁ : 0.49, Rf ₂ : 0.21 [α] _D : -13.59 (C = 1.15, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34 (9H , s), 1.61-1.85 (2
H, m), 2.05-2.12 (2H, m), 2.99 (1H, dd, J = 15Hz, 7Hz),
3.09 (1H, dd, J = 15Hz, 7Hz), 3.89-3.96 (1H, m), 4.00-
4.16 (3H, m), 4.33-4.39 (1H, m), 4.62 (1H, d, J = 15H
z), 6.65 (2H, br), 6.93-7.25 (16H, m), 8.13 (1H, br
s), 10.00 (1H, br s), 10.73 (1H, br s)

(3) Boc-Asp (OBzl) -Gl
_{n-Trp-AzPhe-NHCH 2} Ph (4-F) Boc-Gln-Trp-AzPhe-NHCH 2 Ph
(4-F) 160 mg, 4N HCl-AcOEt 0.5
From 0 ml, Et ₃ N 0.03 ml, NMM 0.03 ml and Boc-Asp (OBzl) -OSu 100 mg,
The title compound was obtained in the same manner as in Example 2 (2). Yield: 190 mg Rf ₁ : 0.52, Rf ₂ : 0.21 [α] _D : -14.97 (C = 0.98, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.34 (9H , s), 1.66-1.86 (2
H, m), 2.07-2.12 (2H, m), 2.59 (1H, dd, J = 16Hz, 9Hz),
2.77 (1H, dd, J = 16Hz, 5Hz), 2.95-3.15 (2H, m), 3.99-
4.15 (3H, m), 4.24-4.34 (3H, m), 4.59 (1H, d, J = 15H
z), 5.07 (2H, s), 6.65 (2H, br), 6.92-7.51 (21H, m),
7.71 (1H br s), 8.27 (1H, br s), 10.01 (1H, br s), 1
0.71 (1H, br s)

Example 18 Boc-Gln-Trp-AzPhe-NH (CH ₂ ) ₂
OCH ₂ Ph (4-F) (1) Boc-Trp-AzPhe-NH (CH ₂ ) ₂ O
_{CH 2 Ph (4-F)} Boc-AzPhe-NH (CH 2) 2 OCH 2 Ph (4
-F) 2.00 g, 4N HCl-AcOEt 6.00 m
1, Et ₃ N (0.67 ml) and Boc-Trp-OH mixed acid anhydride (Boc-Trp-OH 1.62 g, TH
After dissolving in F15 ml and adding NMM 0.52 ml and isobutyl chloroformate 0.62 ml under ice cooling and stirring for 1 hour), the title compound was obtained in the same manner as in Example 2 (1). _{Yield: 1.02g Rf 3: 0.20, Rf} 4: 0.23 [α] _{D: -7.06 (C = 1.38,} DMF) NMR (δ, CDCl 3, 55 ℃): 1.39 (9H , s), 3.14 (2H, d, J =
7Hz), 3.23-3.41 (2H, m), 3.52 (2H, t, J = 5Hz), 4.18-4.
25 (1H, m), 4.46-4.52 (3H, s), 4.68 (1H, d, J = 15Hz),
4.92 (1H, d, J = 6Hz), 5.41 (1H, br), 6.90-7.59 (15H,
m), 8.10 (1H, br)

(2) Boc-Gln-Trp-AzPh
_{e-NH (CH 2) 2} OCH 2 Ph (4-F) Boc-Trp-AzPhe-NH (CH 2) 2 OCH 2
Ph (4-F) 810 mg, 4N HCl-AcOEt 4.
Example 2 from 00 ml, Et ₃ N 0.19 ml, NMM 0.15 ml and Boc-Gln-ONp 493 mg.
The title compound was obtained in the same manner as in (2). Yield: 600 mg Rf ₁ : 0.50, Rf ₂ : 0.18 [α] _D : -20.28 (C = 1.08, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34 (9H , s), 1.64-1.88 (2
H, m), 1.98-2.16 (2H, m), 2.95-3.15 (4H, m), 3.38 (2H,
t, J = 6Hz), 3.90-3.96 (1H, m), 4.11 (1H, d, J = 15Hz),
4.34-4.41 (1H, m), 4.44 (2H, s), 4.57 (1H, d, J = 15H
z), 6.09 (1H, br), 6.62 (1H, br), 6.94-7.53 (15H, m),
8.07 (1H, br s), 9.96 (1H, br s), 10.73 (1H, br s)

Example 19 Boc-Asp (OBzl) -Gln-Trp-AzP
_{he-NH (CH 2) 2} Ph (1) Boc-Trp-AzPhe-NH (CH 2) 2 P
h Boc-AzPhe-NH (CH 2) 2 Ph 1.00
g, 4N HCl-AcOEt6.00ml, Et 3 N
0.38 ml and Boc-Trp-OH mixed acid anhydride (B
oc-Trp-OH (917 mg) was dissolved in THF (10 ml), NMM (0.30 ml) and isobutyl chloroformate (0.35 ml) were added under ice cooling, and the mixture was stirred for 1 hour).
The title compound was obtained in the same manner as in (1). _{Yield: 810mg Rf 3: 0.23, Rf} 4: 0.30 [α] _{D: +8.83 (C = 1.35,} DMF) NMR (δ, CDCl 3, 55 ℃): 1.40 (9H, s) , 2.71-2.78 (2H,
m), 3.11-3.14 (2H, m), 3.27-3.38 (2H, m), 4.13-4.20
(1H, m), 4.42 (1H, d, J = 15Hz), 4.73 (1H, d, J = 15Hz),
4.92 (1H, d, J = 6Hz), 5.45 (1H, br), 6.84-7.58 (16H,
m), 7.82 (1H, br)

(2) Boc-Gln-Trp-AzPh
_{e-NH (CH 2) 2} Ph Boc-Trp-AzPhe-NH (CH 2) 2 Ph 6
30 mg, 4N HCl-AcOEt 3.00 ml, Et ₃ N
0.16 ml, NMM 0.13 ml and Boc-Gln
The title compound was obtained from 415 mg of -ONp in the same manner as in Example 2 (2). Yield: 420 mg Rf ₁ : 0.48, Rf ₂ : 0.14 [α] _D : -10.00 (C = 1.12, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.31 (9H, s ), 1.85-1.91 (2H,
m), 2.17 (2H, t, J = 6Hz), 2.76 (2H, t, J = 7Hz), 3.18 (2
H, d, J = 7Hz), 3.35 (2H, t, J = 7Hz), 3.95-3.99 (1H,
m), 4.38-4.49 (2H, m), 4.70 (1H, d, J = 15Hz), 5.60 (3
H, br), 6.89-7.54 (17H, m), 7.96 (1H, br s), 8.21 (1
H, br)

(3) Boc-Asp (OBzl) -Gl
n-Trp-AzPhe-NH ( CH 2) 2 Ph Boc-Gln-Trp-AzPhe-NH (CH 2) 2
Ph 250 mg, 4N HCl-AcOEt 1.00 m
l, Et ₃ N 0.05 ml, NMM 0.04 ml and B
The title compound was obtained from 154 mg of oc-Asp (OBzl) -OSu in the same manner as in Example 2 (2). Yield: 200 mg Rf ₁ : 0.53, Rf ₂ : 0.24 [α] _D : -10.60 (C = 1.09, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.35 (9H , s), 1.70-1.98 (2
H, m), 2.13 (2H, t, J = 8Hz), 2.57-2.65 (3H, m), 2.79
(1H, dd, J = 16Hz, 5Hz), 2.95-3.15 (4H, m), 4.08 (1H,
br), 4.27-4.39 (3H, m), 4.56 (1H, d, J = 15Hz), 5.06 (5
H, s), 6.07 (1H, br), 6.61 (1H, br), 6.94-7.53 (22H,
m), 7.80 (1H, br s), 8.26 (1H, br s), 9.95 (1H, br
s), 10.75 (1H, br s)

Example 20 Boc-Asp (OBzl) -Gln-Trp-AzP
_{he-NHCH 2 Ph (1)} Boc-Trp-AzPhe-NHCH 2 Ph Boc-AzPhe-NHCH 2 Ph 1.50g, 4
-Toluenesulfonic acid monohydrate 803 mg and Boc-T
rp-OH mixed acid anhydride (Boc-Trp-OH 1.
43 g was dissolved in 20 ml of THF, and NMM 0.
Add 47 ml and 0.55 ml isobutyl chloroformate to 1
After stirring for an hour), the title compound was obtained in the same manner as in Example 1 (1). _{Yield: 600mg Rf 3: 0.23, Rf} 4: 0.29 [α] _{D: -5.13 (C = 0.55,} DMF) NMR (δ, CDCl 3, 55 ℃): 1.31 (9H, s ), 3.11-3.15 (2H,
m), 4.16-4.23 (1H, m), 4.29-4.35 (2H, m), 4.49 (1H,
d, J = 15Hz), 4.74 (1H, d, J = 15Hz), 4.91 (1H, d, J = 6H
z), 5.70 (1H, br), 6.82-7.56 (17H, m)

(2) Boc-Gln-Trp-AzPh
e-NHCH ₂ Ph Boc-Trp-AzPhe-NHCH ₂ Ph 470
mg, 4N HCl-AcOEt2.20ml, Et 3 N
0.12 ml, NMM 0.10 ml and Boc-Gln-
The title compound was obtained from 320 mg of ONp in the same manner as in Example 2 (2). Yield: 540 mg Rf ₁ : 0.47, Rf ₂ : 0.13 [α] _D : -14.45 (C = 0.70, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.30 (9H, s ), 1.37-1.80 (2H,
m), 2.10-2.15 (2H, m), 3.18 (2H, d, J = 7Hz), 3.89-3.9
5 (1H, m), 4.24-4.45 (4H, m), 4.81 (1H, d, J = 14Hz),
5.38 (1H, br), 6.86-7.53 (16H, m), 7.85 (2H, br)

(3) Boc-Asp (OBzl) -Gl
_{n-Trp-AzPhe-NHCH 2} Ph Boc-Gln-Trp-AzPhe-NHCH 2 Ph
470 mg, 4N HCl-AcOEt 2.00 ml, Et
₃ N 0.10 ml, NMM 0.08 ml and Boc-A
From 295 mg of sp (OBzl) -OSu, Example 2
The title compound was obtained in the same manner as in (2). Yield: 590 mg Rf ₁ : 0.52, Rf ₂ : 0.26 [α] _D : -17.21 (C = 1.13, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.43 (9H, s ), 1.75-1.83 (2H,
m), 1.98-2.04 (2H, m), 2.60 (1H, dd, J = 17Hz, 6Hz),
2.70 (1H, dd, J = 17Hz, 5Hz), 3.15 (1H, dd, J = 15Hz, 8H
z), 3.27 (1H, dd, J = 15Hz, 6Hz), 3.98-4.06 (1H, m),
4.13-4.19 (1H, m), 4.32 (1H, d, J = 15Hz), 4.44 (1H, d,
J = 15Hz), 4.45-4.52 (1H, m), 4.60-4.72 (2H, m), 5.02
(2H, s), 5.28-5.70 (3H, br m), 6.89-7.53 (22H, m),
7.92 (1H, brs), 8.13 (1H, br s), 8.20 (1H, br)

Example 21 i-Pent-CO-Asp (OBzl) -Gln-T
_{rp-AzPhe-NHCH 2 Ph (} i-Pent: isopentyl group) Boc-Asp (OBzl) -Gln -Trp-AzP
he-NHCH ₂ Ph 280 mg, 4N HCl-AcOE
t 1.00 ml, Et ₃ N 0.05 ml, NMM 0.
The title compound was obtained from 04 ml and 4-methyl valeric acid N-hydroxysuccinimide ester 68 mg in the same manner as in Example 2 (2). Yield: 170 mg Rf ₁ : 0.53, Rf ₂ : 0.22 [α] _D : -20.17 (C = 1.01, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 0.81 (6H , d, J = 6Hz), 1.32-
1.52 (3H, m), 1.65-1.86 (2H, m), 2.05-2.12 (4H, m),
2.60 (1H, dd, J = 16Hz, 9Hz), 2.79 (1H, dd, J = 16Hz, 6H
z), 2.95-3.15 (2H, m), 4.02-4.38 (5H, m), 4.55-4.65
(2H, m), 5.07 (2H, s), 6.65 (2H, br), 6.92-7.51 (21H,
m), 7.79 (1H, d, J = 7Hz), 8.02 (1H, br s), 8.18 (1H,
br s), 9.99 (1H, br s), 10.71 (1H, br s)

Example 22 Boc-Asp (OBzl) -Gln-Trp-AzP
he-NHDmob Boc-Gln-Trp-AzPhe of Example 1 (2).
-NHDmob 1.00 g, 4N HCl-AcOEt
4.00 ml, Et ₃ N 0.22 ml, NMM 0.17
ml and Boc-Asp (OBzl) -OSu 670 mg
From above, the title compound was obtained in the same manner as in Example 2 (2). Yield: 1.15 g Rf ₁ : 0.52, Rf ₂ : 0.22 [α] _D : -20.20 (C = 1.16, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.36 (9H, s), 1.69-1.90 (2
H, m), 2.08 (2H, t, J = 8Hz), 2.61 (1H, dd, J = 16Hz, 8H
z), 2.77 (1H, dd, J = 16Hz, 5Hz), 2.91-3.15 (2H, m),
3.71 (3H, s), 3.78 (3H, s), 3.81-3.98 (3H, m), 4.25-
4.37 (3H, m), 4.59 (1H, d, J = 15Hz), 5.07 (2H, s), 5.6
8 (2H, br s), 6.36-6.62 (3H, m), 6.75-7.47 (17H, m),
7.74 (1H, d, J = 7Hz), 8.20 (1H, br s), 9.82 (1H, br
s), 10.41 (1H, br s)

Example 23 Boc-Asp (OBzl) -Gln-Trp-AzP
he-NHCH ₃ (1) Boc-Trp-AzPhe-NHCH ₃ Boc-AzPhe-NHCH ₃ 460 mg, 4-toluenesulfonic acid monohydrate 330 mg and Boc-Trp-O
H mixed acid anhydride (Boc-Trp-OH 560 mg
It was dissolved in 5 ml of HF, 0.18 ml of NMM and 0.21 ml of isobutyl chloroformate were added under ice cooling, and the mixture was stirred for 1 hour) to give the title compound in the same manner as in Example 1 (1). _{Yield: 200mg Rf 3: 0.10, Rf} 4: 0.12 [α] _{D: -12.30 (C = 0.86,} DMF) NMR (δ, CDCl 3, 55 ℃): 1.41 (9H , S),
2.65 (3H, s), 3.07-3.22 (2
H, m), 4.13-4.21 (1H, m),
4.38 (1H, d, J = 15Hz), 4.75
(1H, d, J = 15Hz), 4.98 (1H,
d, J = 6 Hz), 5.40 (1H, br),
6.95-7.59 (11H, m), 8.03
(1H, br)

(2) Boc-Gln-Trp-AzPh
_{e-NHCH 3 Boc-Trp-} AzPhe-NHCH 3 530mg, 4
N HCl-AcOEt 3.00 ml, Et ₃ N 0.16
ml, NMM 0.13 ml and Boc-Gln-ONp
From 419 mg as in Example 2 (2),
The title compound was obtained. Yield: 590 mg Rf ₁ : 0.38, Rf ₂ : 0.06 [α] _D : −29.50 (C = 1.10, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.30 (9H, s ), 1.92 (2H, td, J
= 6Hz, 6Hz), 2.20 (2H, t, J = 6Hz), 2.65 (3H, s), 3.21 (2
H, d, J = 7Hz), 3.99-4.05 (1H, m), 4.42-4.49 (2H, m),
4.74 (1H, d, J = 15Hz), 5.65 (3H, br), 6.97-7.56 (12H,
m), 8.00 (1H, br s), 8.29 (1H, br s)

(3) Boc-Asp (OBzl) -Gl
_{n-Trp-AzPhe-NHCH 3} Boc-Gln-Trp-AzPhe-NHCH 3 50
0 mg, 4N HCl-AcOEt 2.00 ml, Et ₃ N
0.12 ml, NMM 0.09 ml and Boc-Asp
From (OBzl) -OSu 355 mg, Example 2 (2)
The title compound was obtained in a similar manner to. Yield: 550 mg Rf ₁ : 0.49, Rf ₂ : 0.14 [α] _D : -30.00 (C = 1.01, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.37 (9H,
s), 1.71-1.91 (2H, m), 2.1
0 (2H, t, J = 7Hz), 2.49 (3H,
s), 2.61 (1H, dd, J = 16Hz,
9Hz), 2.79 (1H, dd, J = 16H
z, 5 Hz), 2.98 (1H, dd, J = 15)
Hz, 7 Hz), 3.09 (1H, dd, J =
15Hz, 8Hz), 4.02-4.09 (1H,
m), 4.27-4.33 (3H, m), 4.4
8-4.58 (1H, m), 5.08 (2H,
s), 5.83 (1H, br), 6.60 (1
H, br), 6.94-7.52 (17H, m),
7.76 (1H, br s), 8.29 (1H, brs)
br s), 9, 90 (1H, br s), 1
0.75 (1H, br s)

Example 24 Boc-Asp (OBzl) -Gln-Trp-AzP
_{he-NH (CH 2) 2} OH (1) Boc-Gln-Trp-AzPhe-NH (C
_{H 2) 2 OH Boc-Gln} -Trp-AzPhe-NH (CH 2) 2
200 mg of OCH ₂ Ph was added to 10 ml of 10% of 80% acetic acid.
The mixture was stirred for 18 hours in a hydrogen stream in the presence of 100% palladium carbon. After the palladium carbon was filtered off, the solvent was distilled off and the residue was dried under reduced pressure. The residue is converted to MeOH-C
Purify on a silica gel column with H ₂ Cl ₂ to give the title compound. Yield: 143 mg Rf ₁ : 0.27, Rf ₂ : 0.07 [α] _D : -19.40 (C = 1.20, DMF) NMR (δ, CD ₃ OD, 55 ° C.): 1.40 (9H, s), 1.82-2.05 (2H,
m), 2.27 (2H, t, J = 8Hz), 3.13-3.25 (4H, m), 3.57 (2H,
t, J = 6Hz), 3.90 (1H, d, J = 15Hz), 4.06 (1H, t, J = 7H
z), 4.38 (1H, t, J = 8Hz), 4.76 (1H, d, J = 15Hz), 6.38
(1H, br), 6.86-7.58 (10H, m)

(2) Boc-Asp (OBzl) -Gl
n-Trp-AzPhe-NH ( CH 2) 2 OH Boc-Gln-Trp-AzPhe-NH (CH 2) 2
OH 110 mg, 4N HCl-AcOEt 0.50 m
l, Et ₃ N 0.03 ml, NMM 0.02 ml and B
The title compound was obtained from 74 mg of oc-Asp (OBzl) -OSu in the same manner as in Example 2 (2). Yield: 70 mg Rf ₁ : 0.43, Rf ₂ : 0.09 [α] _D : -21.30 (C = 0.90, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.37 (9H , s), 1.68-1.94 (2
H, m), 2.10 (2H, t, J = 6Hz), 2.60 (2H, dd, J = 16Hz, 9H
z), 2.79 (2H, dd, J = 16Hz, 5Hz), 2.93-3.11 (4H, m),
3.36 (2H, td, J = 6Hz, 6Hz), 4.08 (1H, d, J = 15Hz), 4.2
5-4.35 (3H, m), 4.56 (1H, d, J = 15Hz), 5.08 (2H, s),
6.03 (1H, br), 6.61 (1H, br), 6.91-7.52 (18H, m), 7.7
5 (1H, d, J = 8Hz), 8.24 (1H, br s), 9.93 (1H, br s), 1
0.70 (1H, brs)

Example 25 Boc-Asp (OBzl) -Gln-Trp-AzP
_{he-NHCH 2 CH (CH 3} ) 2 (1) Boc-Trp-AzPhe-NHCH 2 CH
_{(CH 3) 2 Boc-AzPhe} -NHCH 2 CH (CH 3) 2 1.1
3 g, 670 mg of 4-toluenesulfonic acid monohydrate and B
oc-Trp-OH mixed acid anhydride (Boc-Trp-O
Dissolve 1.19 g of H in 10 ml of THF and add N under ice cooling.
MM 0.39 ml and isobutyl chloroformate 0.46 ml
Was added and stirred for 1 hour), and in the same manner as in Example 1 (1), the title compound was obtained. _{Yield: 460mg Rf 3: 0.20, Rf} 4: 0.27 [α] _{D: -0.55 (C = 1.28,} DMF) NMR (δ, CDCl 3, 55 ℃): 0.85 (6H, d , J = 7Hz), 1.39 (9
H, s), 1.65-1.76 (1H, m), 2.96-3.24 (4H, m), 4.13-4.2
2 (1H, m), 4.37 (1H, d, J = 15Hz), 4.76 (1H, d, J = 15Hz),
4.91 (1H, d, J = 6Hz), 5.61 (1H, br), 6.95-7.59 (11H,
m), 7.94 (1H, br)

(2) Boc-Gln-Trp-AzPh
_{e-NHCH 2 CH (CH 3} ) 2 Boc-Trp-AzPhe-NHCH 2 CH (CH 3)
₂ 400 mg, 4N HCl-AcOEt 2.00 ml, Et
₃ N 0.11 ml, NMM 0.09 ml and Boc-G
The title compound was obtained from 290 mg of ln-ONp in the same manner as in Example 2 (2). Yield: 400 mg Rf ₁ : 0.44, Rf ₂ : 0.14 [α] _D : -22.60 (C = 0.99, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 0.87 (6H, d , J = 7Hz), 1.29 (9
H, s), 1.68-1.80 (1H, m), 1.91 (2H, td, J = 6Hz, 6Hz),
2.20 (2H, t, J = 6Hz), 2.98 (2H, t, J = 6Hz), 3.14-3.28
(2H, m), 3.95-4.01 (1H, m), 4.38-4.45 (1H, m), 4.51
(1H, d, J = 15Hz), 4.71 (1H, d, J = 15Hz), 5.40 (1H, br),
5.58 (1H, d, J = 5Hz), 5.74 (1H, br), 6.93-7.56 (12H,
m), 7.97 (1H, br s), 8.14 (1H, br s)

(3) Boc-Asp (OBzl) -Gl
_{n-Trp-AzPhe-NHCH 2} CH (CH 3) 2 Boc-Gln-Trp-AzPhe-NHCH 2 CH
_{(CH 3) 2 300mg, 4N} HCl-AcOEt 1.2
0ml, Et ₃ N 0.07ml, from NMM 0.05 ml and Boc-Asp (OBzl) -OSu 198mg ,
The title compound was obtained in the same manner as in Example 2 (2). _{Yield: 320mg Rf 1: 0.53, Rf} 2: 0.21 [α] _{D: -17.40 (C = 0.53,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 0.77 (6H , d, J = 7Hz), 1.37
(9H, s), 1.57-1.93 (3H, m), 2.08-2.14 (2H, m), 2.60
(1H, dd, J = 16Hz, 9Hz), 2.75-2.82 (3H, m), 2.97 (1H,
dd, J = 15Hz, 7Hz), 3.07 (1H, dd, J = 15Hz, 8Hz), 4.04
(1H, d, J = 14Hz), 4.25-4.38 (3H, m), 4.58 (1H, d, J = 14
Hz), 5.08 (2H, s), 5.97 (1H, br), 6.60 (1H, br), 6.93
-7.51 (17H, m), 7.70 (1H, d, J = 8Hz), 8.23 (1H, br s),
9.92 (1H, br s), 10.72 (1H, br s)

Example 26 Boc-Asp (OBzl) -Gln-Trp-AzP
he-M (1) Boc-Trp-AzPhe-M Boc-AzPhe-M 1.00 g, 4-toluenesulfonic acid monohydrate 567 mg, Boc-Trp-OH mixed acid anhydride (Boc-Trp-OH 1. 01 g in THF
The product was dissolved in 10 ml, NMM (0.33 ml) and isobutyl chloroformate (0.39 ml) were added under ice cooling, and the mixture was stirred for 1 hour) to give the title compound in the same manner as in Example 1 (1). _{Yield: 960mg Rf 3: 0.10, Rf} 4: 0.12 [α] _{D: -20.50 (C = 1.27,} DMF) NMR (δ, CDCl 3, 55 ℃): 1.38 (9H, s ), 3.18 (2H, d, J =
7Hz), 3.27 (4H, t, J = 5Hz), 3.54 (4H, t, J = 5Hz), 4.30
-4.46 (3H, m), 4.89 (1H, d, J = 7Hz), 6.96-7.63 (11H,
m), 8.00 (1H, br s)

(2) Boc-Gln-Trp-AzPh
e-M Boc-Trp-AzPhe-M 930 mg, 4N HC
l-AcOEt 4.50 ml, Et ₃ N 0.25 ml, N
MM 0.20 ml and Boc-Gln-ONp655 mg
From the above, the title compound was obtained in the same manner as in Example 2 (3). Yield: 700 mg Rf ₁ : 0.45, Rf ₂ : 0.09 [α] _D : −27.40 (C = 1.06, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.36 (9H, s) ), 1.80-1.95 (2H,
m), 2.11-2.17 (2H, m), 3.14-3.31 (4H, m), 3.56 (4H,
t, J = 5Hz), 3.96 (1H, br), 4.36 (1H, d, J = 15Hz), 4.42
(1H, d, J = 15Hz), 4.66-4.73 (1H, m), 5.46 (3H, br),
6.76-7.61 (11H, m), 8.08 (1H, br), 8.17 (1H, br s)

(3) Boc-Asp (OBzl) -Gl
n-Trp-AzPhe-M Boc-Gln-Trp-AzPhe-M 500 mg,
4N HCl-AcOEt 2.00 ml, Et ₃ N 0.1
1 ml, NMM 0.09 ml and Boc-Asp (OBz
1) From 324 mg of -OSu, the title compound was obtained in the same manner as in Example 2 (2). Yield: 500 mg Rf ₁ : 0.52, Rf ₂ : 0.18 [α] _D : -21.80 (C = 1.01, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.36 (9H , s), 1.66-1.93 (2
H, m), 2.08 (2H, t, J = 8Hz), 2.61 (1H, dd, J = 16Hz, 9H
z), 2.78 (1H, dd, J = 16Hz, 5Hz), 2.89 (1H, dd, J = 15Hz,
8Hz), 3.02 (1H, dd, J = 15Hz, 6Hz), 3.08-3.14 (4H,
m), 3.41 (4H, t, J = 5Hz), 4.20-4.53 (5H, m), 5.08 (2H,
s), 6.58 (1H, br), 6.93-7.54 (17H, m), 7.70 (1H, d, J =
8Hz), 8.12 (1H, br s), 10.10 (1H, br s), 10.67 (1H, b
rs)

Example 27 Boc-Asp (OBzl) -Gln-D-Trp-A
zPhe-NH ₂ (1) Z-D-Trp-AzPhe-NHDmob Boc-AzPhe-NHDmob 1.62 g, 4-
Toluenesulfonic acid monohydrate 742 mg, Boc-DT
rp-OH mixed acid anhydride (Boc-D-Trp-OH
Dissolve 1.30 g in 10 ml of THF and cool with NMM under ice cooling.
0.83 ml and 0.50 ml of isobutyl chloroformate were added and the mixture was stirred for 1 hour) to give the title compound in the same manner as in Example 1 (1). _{Yield: 1.00g Rf 3: 0.21, Rf} 4: 0.22 [α] _{D: +19.17 (C = 1.48,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 2.93 ( 1H, dd, J = 14Hz, 8H
z), 3.03 (1H, dd, J = 14Hz, 6Hz), 3.70 (3H, s), 3.74 (3
H, s), 4.12-4.21 (4H, m), 4.66 (1H, d, J = 14Hz), 4.76
(1H, d, J = 13Hz), 4.83 (1H, d, J = 13Hz), 6.39-6.49 (3
H, m), 6.92-7.54 (17H, m), 10.10 (1H, br s), 10.69 (1
H, br s)

(2) Boc-Gln-D-Trp-Az
Phe-NHDmob Z-D-Trp-AzPhe-NHDmob 950m
g, 10% Palladium on carbon 95 mg, NMM 0.16 ml
And Boc-Gln-ONp 549 mg from Example 1
The title compound was obtained in the same manner as in (2). Yield: 1.00 g Rf ₁ : 0.45, Rf ₂ : 0.19 [α] _D : -11.42 (C = 1.02, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.32 (9H, s), 1.59-1.77 (2
H, m), 1.99 (2H, t, J = 7Hz), 2.96-3.16 (2H, m), 3.73
(3H, s), 3.76 (3H, s), 3.86-3.92 (1H, m), 4.00-4.21
(3H, m), 4.31-4.40 (1H, m), 4.50 (1H, d, J = 14Hz), 6.
36-6.73 (5H, m), 6.93-7.53 (12H, m), 8.07 (1H, br),
9.90 (1H, br s), 10.71 (1H, br s)

(3) Boc-Asp (OBzl) -Gl
n-D-Trp-AzPhe- NH 2 Boc-Gln-D-Trp-AzPhe-NHDmo
b300mg, TFA- ethanedithiol - dimethylsulfide (10: 1: 1) 3.60ml , Et 3 N0.06
The title compound was obtained in the same manner as in Example 1 (3) from ml, Boc-Asp (OBzl) -OSu (172 mg) and NMM (0.05 ml). Yield: 186 mg Rf ₁ : 0.36, Rf ₂ : 0.07 [α] _D : +3.45 (C = 1.30, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.38 (9H, 9H, s), 1.68-1.88 (2
H, m), 2.01 (2H, t, J = 8Hz), 2.61 (1H, dd, J = 16Hz, 9H
z), 2.78 (1H, dd, J = 16Hz, 5Hz), 2.91-3.14 (2H, m),
4.13-4.23 (1H, m), 4.29-4.39 (2H, m), 4.48-4.56 (2H,
m), 5.09 (2H, s), 5.76 (2H, br s), 6.57 (1H, br), 6.91
-7.53 (17H, m), 7.90 (1H, br), 8.11 (1H, br), 9.90 (1H,
br s), 10.68 (1H, br s)

Example 28 Boc-Asp (OBzl) -Gln-Trp-AzP
he-OBzl (1) Boc-Trp-AzPhe-OBzl Boc-AzPhe-OBzl 1.02 g, 4N HC
1-AcOEt 7.00 ml, Et ₃ N 0.39 ml and Boc-Trp-OH mixed acid anhydride (Boc-Trp-
Dissolve 951 mg of OH in 10 ml of THF and add N under ice cooling.
MM 0.31 ml and isobutyl chloroformate 0.37 ml
Was added and stirred for 1 hour), and in the same manner as in Example 2 (1), the title compound was obtained. _{Yield: 1.43g Rf 3: 0.40, Rf} 4: 0.42 [α] _{D: -2.78 (C = 1.55,} DMF) NMR (δ, CDCl 3, 55 ℃): 1.34 (9H , s), 3.16 (2H, d, J =
6Hz), 4.37-4.43 (1H, m), 4.51 (1H, d, J = 15Hz), 4.70 (1
H, d, J = 15Hz), 4.91 (1H, d, J = 7Hz), 5.12 (1H, d, J = 1
2Hz), 5.17 (1H, d, J = 12Hz), 6.89-7.60 (16H, m), 7.81
(1H, br)

(2) Boc-Gln-Trp-AzPh
e-OBzl Boc-Trp-AzPhe-OBzl 550 mg, 4
N HCl-AcOEt 2.50 ml, Et ₃ N 0.14
ml, NMM 0.11 ml and Boc-Gln-ONp
From 371 mg, as in Example 2 (2),
The title compound was obtained. Yield: 500 mg Rf ₁ : 0.50, Rf ₂ : 0.19 [α] _D : −7.06 (C = 1.41, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.34 (9H, s ), 1.79-1.90 (2H,
m), 2.10 (2H, t, J = 6Hz), 3.19-3.23 (2H, m), 3.93-3.9
8 (1H, m), 4.46 (1H, d, J = 15Hz), 4.69-4.75 (2H, m),
5.12 (1H, d, J = 12Hz), 5.17 (1H, d, J = 12Hz), 6.95-7.5
7 (16H, m), 8.00 (1H, br), 8.35 (1H, br)

(3) Boc-Asp (OBzl) -Gl
n-Trp-AzPhe-OBzl Boc-Gln-Trp-AzPhe-OBzl 30
0 mg, 4N HCl-AcOEt 1.20 ml, Et ₃ N
0.06 ml, NMM 0.05 ml and Boc-Asp
From (OBzl) -OSu 188 mg, Example 2 (2)
The title compound was obtained in a similar manner to. Yield: 293 mg Rf ₁ : 0.59, Rf ₂ : 0.31 [α] _D -12.30 (C = 1.40, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.35 (9H , s), 1.64-1.92 (2
H, m), 2.07 (2H, t, J = 8Hz), 2.60 (1H, dd, J = 16Hz, 9H
z), 2.77 (1H, dd, J = 16Hz, 5Hz), 2.87 (1H, dd, J = 15Hz,
8Hz), 3.04 (1H, dd, J = 15Hz, 5Hz), 4.24-4.58 (5H,
m), 5.07 (2H, s), 5.09 (2H, s), 6.58 (1H, br), 6.91-7.
51 (22H, m), 7.67 (1H, d, J = 7Hz), 8.04 (1H, br s), 1
0.31 (1H, br s), 10.62 (1H, br s)

Example 29 Boc-Asp (OBzl) -Gln-Trp-AzP
he-NHPh (1) Boc-Trp-AzPhe-NHPh Boc-Trp-AzPhe-OBzl 559 mg, T
Stirred in a stream of hydrogen for 18 hours in the presence of 60 mg of 10% palladium on carbon in 10 ml of HF. After the palladium carbon was filtered off, the solvent was distilled off. The residue was dried under reduced pressure, dissolved in DMF (10 ml), phenylisocyanate (0.11 ml) was added, and the mixture was stirred at room temperature for 18 hr. DMF
Was distilled off, the residue was dissolved in AcOEt, washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column using AcOEt-hexane to obtain the title compound. _{Yield: 490mg Rf 3: 0.34, Rf} 4: 0.44 [α] _{D: -59.5 (C = 1.09,} DMF) NMR (δ, CDCl 3, 55 ℃): 1.38 (9H, s ), 3.11 (1H, dd, J
= 14Hz, 7Hz), 3.23 (1H, dd, J = 14Hz, 8Hz), 4.18-4.25
(1H, m), 4.41 (1H, d, J = 15Hz), 4.85 (1H, d, J = 15Hz),
4.95 (1H, d, J = 5Hz), 6.97-7.65 (17H, m), 7.93 (1H, b
rs)

(2) Boc-Gln-Trp-AzPh
e-NHPh Boc-Trp-AzPhe-NHPh 410 mg, 4
N HCl-AcOEt 2.00 ml, Et ₃ N 0.11
ml, NMM 0.09 ml and Boc-Gln-ONp
From 287 mg, as in Example 2 (2),
The title compound was obtained. Yield: 380 mg Rf ₁ : 0.48, Rf ₂ : 0.14 [α] _D : +9.44 (C = 1.05, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.27 (9H, s) , 1.83-1.90 (2H,
m), 2.10 (2H, t, J = 6Hz), 3.15-3.30 (2H, m), 3.98-4.2
0 (1H, m), 4.38-4.52 (2H, m), 4.80 (1H, d, J = 15Hz),
5.45 (2H, br), 5.61 (1H, br), 6.94-7.58 (16H, m), 7.8
5 (1H, br), 8.20 (1H, br s), 8.33 (1H, br s)

(3) Boc-Asp (OBzl) -Gl
n-Trp-AzPhe-NHPh Boc-Gln-Trp-AzPhe-NHPh 30
0 mg, 4N HCl-AcOEt 1.20 ml, Et ₃ N
0.06 ml, NMM 0.05 ml and Boc-Asp
From (OBzl) -OSu (193 mg) to Example 2 (2).
The title compound was obtained in a similar manner to. Yield: 370 mg Rf ₁ : 0.52, Rf ₂ : 0.27 [α] _D : +14.62 (C = 1.02, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.36 (9H, s), 1.71-1.96 (2
H, m), 2.09-2.16 (2H, m), 2.61 (1H, dd, J = 16Hz, 9Hz),
2.80 (1H, dd, J = 16Hz, 5Hz), 3.01-3.11 (2H, m), 3.79-
3.94 (1H, m), 4.34-4.41 (3H, m), 4.73 (1H, d, J = 14H
z), 5.08 (2H, s), 6.62 (1H, br), 6.89-7.59 (22H, m),
7.86 (1H, br s), 8.26 (1H, br s), 8.42 (1H, br s), 1
0.24 (1H, br s), 10.77 (1H, br s)

Example 30 Boc-Gln-Trp-AzPhe (4-F) -NH
_{(CH 2) 2 OCH 2 Ph} (1) Boc-Trp-AzPhe (4-F) -NH
_{(CH 2) 2 OCH 2 Ph} Boc-AzPhe (4-F) -NH (CH 2) 2 OCH
₂ Ph 800 mg, 4N HCl-AcOEt 5.00 m
1, Et ₃ N 0.27 ml and Boc-Trp-OH mixed acid anhydride (Boc-Trp-OH 580 mg in THF
It was dissolved in 10 ml, NMM (0.21 ml) and isobutyl chloroformate (0.26 ml) were added under ice cooling, and the mixture was stirred for 1 hour) to give the title compound as in Example 2 (1). _{Yield: 300mg Rf 3: 0.18, Rf} 4: 0.20 [α] _{D: -5.20 (C = 1.10,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.33 (9H , s), 2.89-3.04 (2
H, m), 3.15-3.29 (2H, m), 3.40 (2H, t, J = 6Hz), 4.00-
4.19 (2H, m), 4.45 (2H, s), 4.48-4.60 (1H, m), 6.21 (1
H, br), 6.94-7.52 (15H, m), 9.96 (1H, br s), 10.71 (1
H, br s)

(2) Boc-Gln-Trp-AzPh
e (4-F) -NH ( CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (4-F) -NH (CH 2)
₂ OCH ₂ Ph 250 mg, 4N HCl-AcOEt
1.00 ml, Et ₃ N 0.06 ml, NMM 0.05 ml
And Boc-Gln-ONp 152 mg from Example 2
The title compound was obtained in the same manner as in (2). Yield: 230 mg Rf ₁ : 0.45, Rf ₂ : 0.15 [α] _D : −14.00 (C = 0.58, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34 (9H , s), 1.13-1.89 (2
H, m), 2.07-2.14 (2H, m), 2.96-3.14 (4H, m), 3.39 (2H,
t, J = 6Hz), 3.90-4.06 (2H, m), 4.33-4.39 (1H, m), 4.
45 (2H, s), 4.50 (1H, d, J = 15Hz), 6.11 (1H, br), 6.63
(2H, br), 6.94-7.53 (15H, m), 8.10 (1H, br), 9.93 (1
H, br), 10.75 (1H, br)

Example 31 t-Bu-NHCO-Gln-Trp-AzPhe (4
_{-F) -NH (CH 2) 2} OCH 2 Ph (t-Bu: t-
Butyl group) Boc-Gln-Trp-AzPhe (4 of Example 30)
_{-F) -NH (CH 2) 2} OCH 2 Ph 140mg, 4N
HCl-AcOEt 0.50 ml, Et ₃ N 0.03 ml
Then, from 0.03 ml of t-butyl isocyanate, the title compound was obtained in the same manner as in Example 2 (2). Yield: 74 mg Rf ₁ : 0.40, Rf ₂ : 0.09 [α] _D : −14.27 (C = 0.92, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.18 (9H , s), 1.62-1.82 (2
H, m), 2.07 (2H, t, J = 8Hz), 2.96-3.15 (4H, m), 3.39
(2H, t, J = 6Hz), 4.02-4.09 (2H, m), 4.30-4.37 (1H,
m), 4.46 (2H, s), 4.52 (1H, d, J = 15Hz), 5.83 (2H, br
s), 6.12 (1H, br), 6.58 (1H, br), 6.96-7.53 (15H, m),
8.19 (1H, br), 9.93 (1H, br s), 10.74 (1H, br s)

Example 32 Boc-Gln-Trp-AzTyr (CH ₂ Ph)-
NHDmob (1) Boc-Trp- AzTyr (CH 2 Ph) -N
_{HDmob Boc-AzTyr (CH 2 Ph} ) -NHDmob2.
90 g, 4-toluenesulfonic acid monohydrate 1.05 g and Boc-Trp-OH mixed acid anhydride (Boc-Trp
1.70 g of —OH was dissolved in 20 ml of THF, and 0.61 ml of NMM and 0.44 of isobutyl chloroformate under ice cooling.
(ml) and the mixture was stirred for 1 hour) to give the title compound in the same manner as in Example 1 (1). Yield: 1.63 g Rf ₃ : 0.22, Rf ₄ : 0.22 [α] _D : +4.32 (C = 1.11, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.34 (9H, s), 3.14 (2H, d, J =
7Hz), 3.75 (3H, s), 3.78 (3H, s), 4.21-4.31 (3H, m),
4.42 (1H, d, J = 13Hz), 4.62 (1H, d, J = 13Hz), 4.92 (1H,
d, J = 7Hz), 5.00 (2H, s), 6.43-7.59 (19H, m), 7.75 (1
H, br)

(2) Boc-Gln-Trp-AzTy
_{r (CH 2 Ph) -NHDmob Boc} -Trp-AzTyr (CH 2 Ph) -NHDm
ob 1.50 g, 4N HCl-AcOEt 6.00 m
l, Et ₃ N 0.30 ml, NMM 0.23 ml and B
oc-Gln-ONp (780 mg) to Example 2 (2)
The title compound was obtained in a similar manner to. Yield: 557 mg Rf ₁ : 0.45, Rf ₂ : 0.15 [α] _D : −6.30 (C = 1.30, DMF) NMR (δ, CDCl ₃ , 55 ° C.): 1.34 (9H, s ), 1.86-1.92 (2H,
m), 2.14-2.20 (2H, m), 3.18 (1H, dd, J = 14Hz, 7Hz),
3.35 (1H, dd, J = 14Hz, 8Hz), 3.75 (3H, s), 3.82 (3H,
s), 3.89-4.05 (4H, m), 4.37-4.45 (1H, m), 4.67 (1H,
d, J = 15Hz), 4.96 (2H, s), 5.65 (2H, br), 6.39-7.48 (2
0H, m), 7.93 (1H, br), 8.06 (1H, br)

Example 33 t-Bu-NHCO-Gln-Trp-AzPhe (2
_{-Me) -NH (CH 2) 2} OCH 2 Ph (1) Boc-Trp-AzPhe (2-Me) -NH
_{(CH 2) 2 OCH 2 Ph} Boc-AzPhe (2-Me) -NH (CH 2) 2 OC
H ₂ Ph4.50g, 4- toluenesulfonic acid monohydrate 2.07g and Boc-Trp-OH mixed acid anhydride (B
oc-Trp-OH (3.30 g) was dissolved in THF (30 ml), and NMM (1.20 ml) and isobutyl chloroformate (1.42 ml) were added under ice cooling and the mixture was stirred for 1 hour).
The title compound was obtained in the same manner as in (1). _{Yield: 4.10g Rf 3: 0.21, Rf} 4: 0.22 [α] _{D: -16.88 (C = 1.22,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.31 (9H, s), 2.21 (3H, s),
2.86-2.91 (2H, m), 3.14-3.32 (2H, m), 3.41 (2H, t, J =
6Hz), 4.06-4.12 (1H, m), 4.30-4.38 (1H, m), 4.45 (2H,
s), 4.65 (1H, d, J = 16Hz), 6.15 (1H, br), 6.80-7.51 (1
5H, m), 9.98 (1H, br s), 10.66 (1H, br s)

(2) Boc-Gln-Trp-AzPh
e (2-Me) -NH ( CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (2-Me) -NH (CH
₂ ) ₂ OCH ₂ Ph 2.00 g, 4N HCl-AcOEt
8.30 ml, Et ₃ N 0.47 ml and Boc-Gln-
The title compound was obtained from 1.22 g of ONp in the same manner as in Example 2 (2). Yield: 1.56 g Rf ₁ : 0.54, Rf ₂ : 0.30 [α] _D : -27.62 (C = 1.24, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.33 (9H, s), 1.63-1.88 (2H,
m), 2.06-2.12 (2H, m), 2.19 (3H, s), 2.93 (1H, dd, J
= 15Hz, 8Hz), 3.02 (1H, dd, J = 15Hz, 6Hz), 3.13-3.20
(2H, m), 3.39 (2H, t, J = 6Hz), 3.88-3.95 (1H, m), 4.3
0-4.42 (2H, m), 4.46 (2H, s), 4.60 (1H, d, J = 15Hz), 6.
04 (1H, br), 6.62 (2H, br), 6.92-7.51 (15H, m), 8.01
(1H, br), 9.93 (1H, br s), 10.69 (1H, br s)

(3) t-Bu-NHCO-Gln-Tr
p-AzPhe (2-Me) -NH (CH 2) 2 OCH 2
Ph Boc-Gln-Trp-AzPhe (2-Me) -N
H (CH ₂ ) ₂ OCH ₂ Ph 500 mg, 4N HCl-Ac
The title compound was obtained in the same manner as in Example 2 (2) from 1.70 ml of OEt, 0.10 ml of Et ₃ N and 68 mg of t-butyl isocyanate. Yield: 456 mg Rf ₁ : 0.53, Rf ₂ : 0.16 [α] _D : −27.65 (C = 1.41, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.18 (9H , s), 1.57-1.83 (2H,
m), 2.06 (2H, t, J = 8Hz), 2.19 (3H, s), 2.95 (1H, dd,
J = 15Hz, 8Hz), 3.05 (1H, dd, J = 15Hz, 6Hz), 3.14-3.21
(2H, m), 3.40 (2H, t, J = 6Hz), 4.00-4.07 (1H, m), 4.3
1-4.39 (2H, m), 4.46 (2H, s), 4.62 (1H, d, J = 15Hz),
5.81-5.86 (2H, m), 6.09 (1H, br), 6.56 (1H, br), 6.92
-7.51 (15H, m), 8.12 (1H, br), 9.93 (1H, br s), 10.68
(1H, brs)

Example 34 t-Bu-NHCO-Gln-Trp-AzPhe (3
_{-Me) -NH (CH 2) 2} OCH 2 Ph (1) Boc-Trp-AzPhe (3-Me) -NH
_{(CH 2) 2 OCH 2 Ph} Boc-AzPhe (3-Me) -NH (CH 2) 2 OC
H ₂ Ph4.50g, 4- toluenesulfonic acid monohydrate 2.07g and Boc-Trp-OH mixed acid anhydride (B
oc-Trp-OH (3.30 g) was dissolved in THF (30 ml), and NMM (1.20 ml) and isobutyl chloroformate (1.42 ml) were added under ice cooling and the mixture was stirred for 1 hour).
The title compound was obtained in the same manner as in (1). _{Yield: 4.75g Rf 3: 0.20, Rf} 4: 0.20 [α] _{D: -7.40 (C = 1.21,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.32 (9H, s), 2.24 (3H, s),
2.86-3.01 (2H, m), 3.15-3.31 (2H, m), 3.40 (2H, t, J =
6Hz), 4.02-4.14 (2H, m), 4.45 (2H, s), 4.59 (1H, d, J
= 15Hz), 6.18 (1H, br), 6.85-7.53 (15H, m), 9.99 (1H,
br s), 10.70 (1H, br s)

(2) Boc-Gln-Trp-AzPh
e (3-Me) -NH ( CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (3-Me) -NH (CH
₂ ) ₂ OCH ₂ Ph 2.00 g, 4N HCl-AcOEt
8.30 ml, Et ₃ N 0.47 ml and Boc-Gln-
The title compound was obtained from 1.22 g of ONp in the same manner as in Example 2 (2). Yield: 1.55 g Rf ₁ : 0.54, Rf ₂ : 0.28 [α] _D : -20.49 (C = 1.29, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34 (9H, s), 1.74-1.89 (2H,
m), 2.07-2.13 (2H, m), 2.23 (3H, s), 2.98 (1H, dd, J
= 15Hz, 8Hz), 3.08 (1H, dd, J = 15Hz, 7Hz), 3.11-3.20
(2H, m), 3.40 (2H, t, J = 6Hz), 3.90-3.97 (1H, m), 4.0
5-4.14 (1H, m), 4.34-4.42 (1H, m), 4.46 (2H, s), 4.55
(1H, d, J = 15Hz), 6.08 (1H, br), 6.61 (2H, br), 6.83-
7.53 (15H, m), 8.04 (1H, br), 9.94 (1H, br s), 10.72
(1H, br s)

(3) t-Bu-NHCO-Gln-Tr
p-AzPhe (3-Me) -NH (CH 2) 2 OCH 2
Ph Boc-Gln-Trp-AzPhe (3-Me) -N
H (CH ₂ ) ₂ OCH ₂ Ph 500 mg, 4N HCl-Ac
The title compound was obtained in the same manner as in Example 2 (2) from 1.70 ml of OEt, 0.10 ml of Et ₃ N and 68 mg of t-butyl isocyanate. Yield: 440 mg Rf ₁ : 0.53, Rf ₂ : 0.16 [α] _D : -18.67 (C = 1.24, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.18 (9H , s), 1.58-1.82 (2H,
m), 2.07 (2H, t, J = 7Hz), 2.23 (3H, s), 2.97-3.20 (4
H, m), 3.40 (2H, t, J = 6Hz), 4.01-4.12 (2H, m), 4.31-
4.37 (1H, m), 4.46 (2H, s), 4.56 (1H, d, J = 15Hz), 5.8
2-5.86 (2H, m), 6.12 (1H, br), 6.57 (1H, br), 6.84-7.5
2 (15H, m), 8.17 (1H, br), 9.94 (1H, brs), 10.71 (1H,
br s)

Example 35 t-Bu-NHCO-Gln-Trp-AzPhe (4
_{-Me) -NH (CH 2) 2} OCH 2 Ph (1) Boc-Trp-AzPhe (4-Me) -NH
_{(CH 2) 2 OCH 2 Ph} Boc-AzPhe (4-Me) -NH (CH 2) 2 OC
H ₂ Ph4.50g, 4- toluenesulfonic acid monohydrate 2.07g and Boc-Trp-OH mixed acid anhydride (B
oc-Trp-OH (3.30 g) was dissolved in THF (30 ml), and NMM (1.20 ml) and isobutyl chloroformate (1.42 ml) were added under ice cooling and the mixture was stirred for 1 hour).
The title compound was obtained in the same manner as in (1). _{Yield: 4.56g Rf 3: 0.18, Rf} 4: 0.19 [α] _{D: -5.82 (C = 1.01,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.32 (9H, s), 2.24 (3H, s),
2.90 (1H, dd, J = 15Hz, 8Hz), 2.99 (1H, dd, J = 15Hz, 7H
z), 3.19-3.31 (2H, m), 3.40 (2H, t, J = 6Hz), 4.04-4.17
(2H, m), 4.45 (2H, s), 4.58 (1H, d, J = 15Hz), 6.15 (1
H, br), 6.89-7.52 (15H, m), 9.92 (1H, br s), 10.69 (1
H, br s)

(2) Boc-Gln-Trp-AzPh
e (4-Me) -NH ( CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (4-Me) -NH (CH
₂ ) ₂ OCH ₂ Ph 2.00 g, 4N HCl-AcOEt
8.30 ml, Et ₃ N 0.47 ml and Boc-Gln-
The title compound was obtained from 1.22 g of ONp in the same manner as in Example 2 (2). Yield: 1.72 g Rf ₁ : 0.54, Rf ₂ : 0.26 [α] _D : -16.88 (C = 1.26, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.34 (9H, s), 1.65-1.90 (2H,
m), 2.07-2.13 (2H, m), 2.24 (3H, s), 2.98 (1H, dd, J
= 15Hz, 7Hz), 3.08 (1H, dd, J = 15Hz, 7Hz), 3.12-3.20
(2H, m), 3.39 (2H, t, J = 7Hz), 3.90-3.97 (1H, m), 4.0
5-4.14 (1H, m), 4.35-4.41 (1H, m), 4.46 (2H, s), 4.52
(1H, d, J = 16Hz), 6.06 (1H, br), 6.64 (2H, br), 6.90-
7.53 (15H, m), 8.06 (1H, br), 9.90 (1H, br s), 10.73
(1H, br s)

(3) t-Bu-NHCO-Gln-Tr
p-AzPhe (4-Me) -NH (CH 2) 2 OCH 2
Ph Boc-Gln-Trp-AzPhe (4-Me) -N
H (CH ₂ ) ₂ OCH ₂ Ph 500 mg, 4N HCl-Ac
The title compound was obtained in the same manner as in Example 2 (2) from 1.70 ml of OEt, 0.10 ml of Et ₃ N and 68 mg of t-butyl isocyanate. Yield: 472 mg Rf ₁ : 0.53, Rf ₂ : 0.15 [α] _D : -15.34 (C = 1.44, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.19 (9H , s), 1.59-1.82 (2H,
m), 2.07 (2H, t, J = 8Hz), 2.24 (3H, s), 2.96-3.19 (4
H, m), 3.39 (2H, t, J = 6Hz), 4.02-4.12 (2H, m), 4.31-
4.38 (1H, m), 4.46 (2H, s), 4.52 (1H, d, J = 15Hz), 5.8
2-5.86 (2H, m), 6.08 (1H, br), 6.58 (1H, br), 6.94-7.5
2 (15H, m), 8.17 (1H, br), 9.90 (1H, brs), 10.72 (1H,
br s)

Example 36 t-Bu-NHCO-Gln-Trp-AzPhe (4
_{-I Pr) -NH (CH 2)} 2 OCH 2 Ph (1) Boc-Trp-AzPhe (4-i Pr) -N
_{H (CH 2) 2 OCH 2} Ph Boc-AzPhe (4-i Pr) -NH (CH 2) 2 O
CH ₂ Ph 4.80 g, 4-toluenesulfonic acid monohydrate 2.07 g and Boc-Trp-OH mixed acid anhydride (Boc-Trp-OH 3.30 g) were dissolved in THF 30 ml, and NMM 1.20 ml and ice-cooled. Example 1 was added from 1.42 ml of isobutyl chloroformate and stirred for 1 hour).
The title compound was obtained in the same manner as in (1). _{Yield: 4.11g Rf 3: 0.20, Rf} 4: 0.20 [α] _{D: -3.92 (C = 1.07,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.15 (3H, s), 1.17 (3H, s),
1.32 (9H, s), 2.78-3.03 (3H, m), 3.14-3.31 (2H, m),
3.40 (2H, t, J = 6Hz), 4.05-4.16 (2H, m), 4.45 (2H, s),
4.58 (1H, d, J = 15Hz), 6.14 (1H, br), 6.85-7.53 (15H,
m), 9.95 (1H, br s), 10.70 (1H, br s)

(2) Boc-Gln-Trp-AzPh
e (4-i Pr) -NH (CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (4-i Pr) -NH (C
_{H 2) 2 OCH 2 Ph2.00g,} 4N HCl-AcOE
t8.00 ml, Et ₃ N 0.46 ml and Boc-Gln
The title compound was obtained from 1.17 g of -ONp in the same manner as in Example 2 (2). Yield: 1.51 g Rf ₁ : 0.54, Rf ₂ : 0.27 [α] _D : -15.38 (C = 1.17, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.15 (3H, s), 1.17 (3H, s),
1.34 (9H, s), 1.64-1.90 (2H, m), 2.07-2.14 (2H, m),
2.82 (1H, septet, J = 7Hz), 2.98 (1H, dd, J = 15Hz, 7H
z), 3.08 (1H, dd, J = 15Hz, 7Hz), 3.12-3.19 (2H, m),
3.39 (2H, t, J = 6Hz), 3.90-3.97 (1H, m), 4.06-4.15 (1
H, m), 4.35-4.41 (1H, m), 4.46 (2H, s), 4.53 (1H, d,
J = 16Hz), 6.04 (1H, br), 6.63 (2H, br), 6.94-7.53 (15
H, m), 8.05 (1H, d, J = 5Hz), 9.94 (1H, br s), 10.73 (1
H, br s)

(3) t-Bu-NHCO-Gln-Tr
p-AzPhe (4-i Pr ) -NH (CH 2) 2 OCH
₂ Ph Boc-Gln-Trp-AzPhe (4-i Pr)-
NH (CH ₂ ) ₂ OCH ₂ Ph 500 mg, 4N HCl-A
The title compound was obtained in the same manner as in Example 2 (2) from 1.70 ml of cOEt, 0.10 ml of Et ₃ N and 66 mg of t-butyl isocyanate. Yield: 449 mg Rf ₁ : 0.53, Rf ₂ : 0.16 [α] _D : -14.14 (C = 1.11, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.15 (3H , s), 1.17 (3H, s),
1.18 (9H, s), 1.58-1.82 (2H, m), 2.07 (2H, t, J = 8Hz),
2.82 (1H, septet, J = 7Hz), 2.96-3.19 (4H, m), 3.39 (2
H, t, J = 6Hz), 4.03-4.12 (2H, m), 4.32-4.38 (1H, m),
4.46 (2H, s), 4.53 (1H, d, J = 16Hz), 5.82-5.86 (2H,
m), 6.08 (1H, br), 6.57 (1H, br), 6.93-7.53 (15H, m),
8.17 (1H, br), 9.94 (1H, br s), 10.73 (1H, br s)

Example 37 t-Bu-NHCO-Gln-Trp-AzPhe
(2, 4-diMe) -NH (CH 2) 2 OCH 2 Ph (1) Boc-Trp-AzPhe (2, 4-diMe)
_{-NH (CH 2) 2 OCH 2} Ph Boc-AzPhe (2, 4-diMe) -NH (CH
₂ ) ₂ OCH ₂ Ph 700 mg, 4N HCl-AcOEt
4.10 ml, Et ₃ N 0.23 ml and Boc-Trp-
OH mixed acid anhydride (Boc-Trp-OH 555 mg
It was dissolved in 5 ml of HF, 0.18 ml of NMM and 0.21 ml of isobutyl chloroformate were added under ice cooling, and the mixture was stirred for 1 hour) to give the title compound in the same manner as in Example 2 (1). _{Yield: 300mg Rf 3: 0.20, Rf} 4: 0.23 [α] _{D: -15.50 (C = 1.10,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.31 (9H , s), 2.18 (3H, s),
2.21 (3H, s), 2.84-2.92 (2H, m), 3.14-3.31 (2H, m),
3.40 (2H, t, J = 6Hz), 4.06-4.12 (1H, m), 4.30 (1H, d,
J = 15Hz), 4.45 (2H, s), 4.62 (1H, d, J = 15Hz), 6.12 (1
H, br), 6.82-7.50 (14H, m), 9.92 (1H, br s), 10.67 (1
H, br s)

(2) Boc-Gln-Trp-AzPh
e (2, 4-diMe) -NH (CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (2, 4-diMe) -NH
_{(CH 2) 2 OCH 2 Ph250mg} , 4N HCl-AcO
Et1.03ml, Et ₃ N0.06ml, NMM0.05
Example 2 from ml and Boc-Gln-ONp 151 mg.
The title compound was obtained in the same manner as in (2). Yield: 280 mg Rf ₁ : 0.54, Rf ₂ : 0.30 [α] _D : -25.04 (C = 1.19, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.33 (9H , s), 1.62-1.88 (2H,
m), 2.06-2.11 (2H, m), 2.15 (3H, s), 2.21 (3H, s),
2.92 (1H, dd, J = 14Hz, 8Hz), 3.01 (1H, dd, J = 14Hz, 6H
z), 3.13-3.19 (2H, m), 3.36-3.41 (2H, m), 3.89-3.95
(1H, m), 4.28-4.41 (2H, m), 4.45 (2H, s), 4.56 (1H,
d, J = 14Hz), 6.01 (1H, br), 6.57-6.69 (2H, br), 6.80-
7.50 (14H, m), 8.02 (1H, br s), 9.88 (1H, br s), 10.7
0 (1H, br s)

(3) t-Bu-NHCO-Gln-Tr
p-AzPhe (2, 4- diMe) -NH (CH 2) 2 O
CH ₂ Ph Boc-Gln-Trp-AzPhe (2,4-diM
_{e) -NH (CH 2) 2} OCH 2 Ph150mg, 4N HC
1-AcOEt 0.50 ml, Et ₃ N 0.03 ml and t
-From 0.03 ml of butyl isocyanate, Example 2
The title compound was obtained in the same manner as in (2). Yield: 120 mg Rf ₁ : 0.53, Rf ₂ : 0.17 [α] _D : -25.71 (C = 0.98, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.18 (9H , s), 1.55-1.82 (2H,
m), 2.06 (2H, t, J = 8Hz), 2.15 (3H, s), 2.20 (3H, s),
2.94 (1H, dd, J = 15Hz, 8Hz), 3.04 (1H, dd, J = 15Hz, 6
Hz), 3.11-3.19 (2H, m), 3.39 (2H, t, J = 6Hz), 4.03 (1
H, td, J = 7Hz, 7Hz), 4.27-4.37 (2H, m), 4.46 (2H, s),
4.58 (1H, d, J = 14Hz), 5.81-5.85 (2H, m), 6.06 (1H, b
r), 6.56 (1H, br), 6.80-7.50 (14H, m), 8.13 (1H, br
s), 9.88 (1H, br s), 10.70 (1H, br s)

Example 38 t-Bu-NHCO-Gln-Trp-AzPhe
(2, 5-diMe) -NH (CH 2) 2 OCH 2 Ph (1) Boc-Trp-AzPhe (2, 5-diMe)
_{-NH (CH 2) 2 OCH 2} Ph Boc-AzPhe (2, 5-diMe) -NH (CH
₂ ) ₂ OCH ₂ Ph 1.30 g, 4N HCl-AcOEt
7.60 ml, Et ₃ N 0.42 ml and Boc-Trp-
OH mixed acid anhydride (1.03 g of Boc-Trp-OH is dissolved in 10 ml of THF, 0.33 ml of NMM and 0.40 ml of isobutyl chloroformate are added under ice cooling, and the mixture is stirred for 1 hour)
From the above, the title compound was obtained in the same manner as in Example 2 (1). _{Yield: 500mg Rf 3: 0.22, Rf} 4: 0.23 [α] _{D: -16.27 (C = 1.01,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.31 (9H , s), 2.17 (6H, s),
2.84-2.87 (2H, m), 3.16-3.31 (2H, m), 3.41 (2H, t, J =
6Hz), 4.05-4.12 (1H, m), 4.35 (1H, br), 4.45 (2H, s),
4.62 (1H, d, J = 15Hz), 6.15 (1H, br), 6.85-7.51 (14H,
m), 9.99 (1H, br s), 10.67 (1H, br s)

(2) Boc-Gln-Trp-AzPh
e (2, 5-diMe) -NH (CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (2, 5-diMe) -NH
(CH ₂ ) ₂ OCH ₂ Ph 400 mg, 4N HCl-AcO
Et1.63ml, Et ₃ N0.09ml, NMM0.07
Example 2 from ml and Boc-Gln-ONp 240 mg.
The title compound was obtained in the same manner as in (2). Yield: 460 mg Rf ₁ : 0.54, Rf ₂ : 0.30 [α] _D : −27.24 (C = 1.27, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.33 (9H , s), 1.62-1.87 (2H,
m), 2.05-2.12 (2H, m), 2.14 (3H, s), 2.18 (3H, s),
2.89-3.02 (2H, m), 3.15-3.20 (2H, m), 3.37-3.41 (2H, m
m), 3.86-3.94 (1H, m), 4.30-4.42 (2H, m), 4.46 (2H,
s), 4.59 (1H, d, J = 14Hz), 6.05 (1H, br), 6.56-6.70 (2
H, br), 6.90-7.51 (14H, m), 8.00 (1H, brs), 9.95 (1H,
br s), 10.69 (1H, br s)

(3) t-Bu-NHCO-Gln-Tr
p-AzPhe (2, 5- diMe) -NH (CH 2) 2 O
CH ₂ Ph Boc-Gln-Trp-AzPhe (2,5-diM
_{e) -NH (CH 2) 2} OCH 2 Ph300mg, 4N HC
l-AcOEt 1.00 ml, Et ₃ N 0.06 ml and t
-From butyl isocyanate 0.05 ml, Example 2
The title compound was obtained in the same manner as in (2). Yield: 220 mg Rf ₁ : 0.53, Rf ₂ : 0.18 [α] _D : −29.72 (C = 1.11, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.18 (9H , s), 1.55-1.81 (2H,
m), 2.06 (2H, t, J = 8Hz), 2.15 (3H, s), 2.18 (3H, s),
2.89-3.05 (2H, m), 3.15-3.21 (2H, m), 3.41 (2H, t, J
= 6Hz), 4.03 (1H, td, J = 7Hz, 7Hz), 4.31-4.38 (2H, m),
4.47 (2H, s), 4.60 (1H, d, J = 14Hz), 5.81-5.84 (2H,
m), 6.09 (1H, br), 6.57 (1H, br), 6.90-7.50 (14H, m),
8.12 (1H, br s), 9.95 (1H, br s), 10.68 (1H, br s)

Example 39 t-Bu-NHCO-Gln-Trp-AzPhe (2
_{-F) -NH (CH 2) 2} OCH 2 Ph (1) Boc-Trp-AzPhe (2-F) -NH
_{(CH 2) 2 OCH 2 Ph} Boc-Trp-NHNHCH 2 Ph (2-F) 550
Dissolve mg in THF (7 ml) and add PhCH ₂ O (CH
₂ ) ₂ NCO (229 mg) was added, and the mixture was stirred at room temperature for 18 hours.
After the solvent was distilled off, the residue was dissolved in AcOEt, washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained crude product was recrystallized from AcOEt-hexane to obtain the title compound. _{Yield: 710mg Rf 3: 0.20, Rf} 4: 0.23 [α] _{D: -14.24 (C = 1.00,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.31 (9H , s), 2.86-3.02 (2H,
m), 3.15-3.32 (2H, m), 3.41 (2H, t, J = 6Hz), 4.09-4.
16 (1H, m), 4.33-4.42 (1H, m), 4.45 (2H, s), 4.68 (1H,
d, J = 15Hz), 6.22 (1H, br), 6.92-7.53 (15H, m), 10.10
(1H, br s), 10.68 (1H, br s)

(2) Boc-Gln-Trp-AzPh
e (2-F) -NH ( CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (2-F) -NH (CH
₂ ) ₂ OCH ₂ Ph 500 mg, 4N HCl-AcOEt
Example 2 from 2.10 ml, Et ₃ N 0.12 ml, NMM 0.09 ml and Boc-Gln-ONp 305 mg.
The title compound was obtained in the same manner as in (2). Yield: 550 mg Rf ₁ : 0.53, Rf ₂ : 0.27 [α] _D : -22.40 (C = 1.02, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.33 (9H , s), 1.63-1.89 (2H,
m), 2.06-2.12 (2H, m), 2.97 (1H, dd, J = 15Hz, 8Hz),
3.07 (1H, dd, J = 15Hz, 6Hz), 3.14-3.20 (2H, m), 3.40
(2H, t, J = 6Hz), 3.88-3.96 (1H, m), 4.33-4.42 (2H,
m), 4.46 (2H, s), 4.65 (1H, d, J = 15Hz), 6.11 (1H, br),
6.61 (1H, br), 6.68 (1H, br), 6.92-7.53 (15H, m), 8.
05 (1H, br), 10.04 (1H, br s), 10.70 (1H, br s)

(3) t-Bu-NHCO-Gln-Tr
p-AzPhe (2-F) -NH (CH 2) 2 OCH 2 P
h Boc-Gln-Trp-AzPhe (2-F) -NH
(CH ₂ ) ₂ OCH ₂ Ph 300 mg, 4N HCl-AcO
The title compound was obtained in the same manner as in Example 2 (2) from 1.03 ml of Et, 0.06 ml of Et ₃ N and 0.05 ml of t-butyl isocyanate. Yield: 270 mg Rf ₁ : 0.51, Rf ₂ : 0.16 [α] _D : −26.55 (C = 1.49, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.18 (9H , s), 1.58-1.82 (2H,
m), 2.06 (2H, t, J = 7Hz), 3.00 (1H, dd, J = 15Hz, 8H
z), 3.10 (1H, dd, J = 15Hz, 6Hz), 3.15-3.21 (2H, m), 3.
40 (2H, t, J = 6Hz), 4.02 (1H, td, J = 7Hz, 7Hz), 4.32-
4.39 (2H, m), 4.47 (2H, s), 4.67 (1H, d, J = 16Hz), 5.8
2-5.87 (2H, m), 6.15 (1H, br), 6.57 (1H, br), 6.92-7.5
2 (15H, m), 8.16 (1H, br), 10.04 (1H, br s), 10.70 (1
H, br s)

Example 40 t-Bu-NHCO-Gln-Trp-AzPhe (2
_{-CF 3) -NH (CH 2)} 2 OCH 2 Ph (1) Boc-Trp-AzPhe (2-CF 3) -N
_{H (CH 2) 2 OCH 2} Ph Boc-Trp-NHNHCH 2 Ph (2-CF 3)
The title compound was obtained from 1.03 g and 385 mg of PhCH ₂ O (CH ₂ ) ₂ NCO in the same manner as in Example 39 (1). _{Yield: 1.24g Rf 3: 0.24, Rf} 4: 0.30 [α] _{D: -10.67 (C = 1.03,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.30 (9H, s), 2.87-3.02 (2H,
m), 3.16-3.31 (2H, m), 3.42 (2H, t, J = 6Hz), 4.10-4.
17 (1H, m), 4.46 (2H, s), 4.53-4.62 (1H, m), 4.80 (1H,
d, J = 16Hz), 6.30 (1H, br), 6.88-7.66 (15H, m), 10.21
(1H, br s), 10.65 (1H, br s)

(2) Boc-Gln-Trp-AzPh
_{e (2-CF 3) -NH} (CH 2) 2 OCH 2 Ph Boc-Trp-AzPhe (2-CF 3) -NH (C
_{H 2) 2 OCH 2 Ph800mg,} 4N HCl-AcOEt
Example 2 from 3.10 ml, Et ₃ N 0.17 ml, NMM 0.13 ml and Boc-Gln-ONp 450 mg.
The title compound was obtained in the same manner as in (2). Yield: 800 mg Rf ₁ : 0.54, Rf ₂ : 0.32 [α] _D : -19.33 (C = 1.20, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.33 (9H, s),
1.62-1.88 (2H, m), 2.06-
2.12 (2H, m), 2.98 (1H, dd,
J = 15Hz, 8Hz), 3.07 (1H, d
d, J = 15 Hz, 7 Hz), 3.15-3.2
2 (2H, m), 3.42 (2H, t, J = 6
Hz), 3.87-3.95 (1H, m), 4.
36-4.43 (1H, m), 4.47 (2H,
s), 4.47-1.56 (1H, m), 4.80.
(1H, d, J = 15Hz), 6.24 (1H,
br), 6.61 (1H, br), 6.76
(1H, br), 6.88-7.66 (15H,
m), 8.09 (1H, br), 10.13 (1
H, br s), 10.66 (1H, brs)

(3) t-Bu-NHCO-Gln-Tr
_{p-AzPhe (2-CF 3} ) -NH (CH 2) 2 OC
_{H 2 Ph Boc-Gln-Trp} -AzPhe (2-CF 3) -
NH (CH ₂ ) ₂ OCH ₂ Ph 400 mg, 4N HCl-A
The title compound was obtained in the same manner as in Example 2 (2) from 1.28 ml of cOEt, 0.07 ml of Et ₃ N and 0.06 ml of t-butyl isocyanate. Yield: 360 mg Rf ₁ : 0.52, Rf ₂ : 0.19 [α] _D : −27.13 (C = 1.16, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.18 (9H , s), 1.56-1.81 (2H,
m), 2.06 (2H, t, J = 8Hz), 3.03 (1H, dd, J = 15Hz, 8H
z), 3.12 (1H, dd, J = 15Hz, 6Hz), 3.15-3.24 (2H, m), 3.
43 (2H, t, J = 6Hz), 3.98 (1H, td, J = 7Hz, 7Hz), 4.32-
4.39 (1H, m), 4.48 (2H, s), 4.54 (1H, d, J = 17Hz), 4.8
3 (1H, d, J = 17Hz), 5.84-5.90 (2H, m), 6.31 (1H, br),
6.57 (1H, br), 6.88-7.66 (15H, m), 8.17 (1H, br), 10.
13 (1H, brs), 10.66 (1H, br s)

Example 41 t-Bu-NHCO-Gln-Trp-AzPhe-N
_{H (CH 2) 2 O- (} 2- naphthylmethyl) (1) Boc-Trp- AzPhe-NH (CH 2) 2 O
- (2-naphthylmethyl) Boc-AzPhe-NH (CH 2) 2 O- (2- naphthylmethyl) 3.98g, 4N HCl-AcOEt22.
90ml, Et ₃ N1.28ml and Boc-Trp-OH
Mixed acid anhydride (Boc-Trp-OH 3.11 g TH
The product was dissolved in 30 ml of F, 1.01 ml of NMM and 1.19 ml of isobutyl chloroformate were added under ice cooling, and the mixture was stirred for 1 hour) to give the title compound as in Example 2 (1). _{Yield: 2.44g Rf 3: 0.17, Rf} 4: 0.19 [α] _{D: -8.03 (C = 1.17,} DMF) NMR (δ, DMSO-d 6, 55 ℃): 1.29 (9H, s), 2.91 (1H, dd,
J = 15Hz, 8Hz), 2.99 (1H, dd, J = 15Hz, 7Hz), 3.16-3.35
(2H, m), 3.46 (2H, t, J = 6Hz), 4.09-4.15 (2H, m), 4.60
-4.65 (1H, m), 4.63 (2H, s), 6.22 (1H, br), 6.92-7.88
(18H, m), 10.00 (1H, br s), 10.70 (1H, br s)

(2) Boc-Gln-Trp-AzPh
_{e-NH (CH 2) 2} O- (2- naphthylmethyl) Boc-Trp-AzPhe-NH (CH 2) 2 O- (2
-Naphthylmethyl) 1.08 g, 4N HCl-AcOE
t 4.35 ml, Et ₃ N 0.25 ml, NMM 0.19 ml
And Boc-Gln-ONp671 mg from Example 2
The title compound was obtained in the same manner as in (2). Yield: 1.09 g Rf ₁ : 0.54, Rf ₂ : 0.29 [α] _D : -15.10 (C = 1.16, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.33 (9H, s), 1.65-1.90 (2
H, m), 2.08-2.14 (2H, m), 2.99 (1H, dd, J = 14Hz, 7Hz),
3.09 (1H, dd, J = 14Hz, 7Hz), 3.14-3.23 (2H, m), 3.46
(2H, t, J = 6Hz), 3.91-3.99 (1H, m), 4.11-4.18 (1H,
m), 4.36-4.42 (1H, m), 4.58 (1H, d, J = 14Hz), 4.63 (2
H, s), 6.12 (1H, br), 6.56-6.72 (2H, br), 6.93-7.88
(18H, m), 8.07 (1H, br), 9.96 (1H, br s), 10.73 (1H,
br s)

(3) t-Bu-NHCO-Gln-Tr
_{p-AzPhe-NH (CH 2} ) 2 O- (2- naphthylmethyl) Boc-Gln-Trp-AzPhe -NH (CH 2) 2
O- (2-naphthylmethyl) 500 mg, 4N HCl-A
The title compound was obtained in the same manner as in Example 2 (2) from 1.68 ml of cOEt, 0.09 ml of Et ₃ N and 0.08 ml of t-butyl isocyanate. Yield: 350 mg Rf ₁ : 0.53, Rf ₂ : 0.18 [α] _D : -14.11 (C = 1.19, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.18 (9H , s), 1.61-1.82 (2
H, m), 2.08 (2H, t, J = 8Hz), 2.98-3.25 (4H, m), 3.47
(2H, t, J = 6Hz), 4.02-4.09 (1H, m), 4.16 (1H, d, J = 15H
z), 4.32-4.39 (1H, m), 4.57 (1H, d, J = 15Hz), 4.64 (2
H, s), 5.82-5.87 (2H, m), 6.15 (1H, br), 6.56 (1H, b
r), 6.93-7.87 (18H, m), 8.17 (1H, d, J = 5Hz), 9.96 (1
H, br s), 10.71 (1H, br s)

Example 42 t-Bu-NHCO-Gln-Trp-AzPhe-N
_{H (CH 2) 2 O- (} 3- pyridylmethyl) (1) Boc-Trp- AzPhe-NH (CH 2) 2 O
₁ .- (3-Pyridylmethyl) Boc-Trp-NHNHCH2Ph 1.50 g was dissolved in 10 ml of anhydrous DMF and separately prepared under ice cooling. 2- (3
-Pyridylmethoxy) ethyl isocyanate solution (3-
800 mg of (3-pyridylmethoxy) propionic acid was dissolved in 10 ml of anhydrous DMF, 0.80 ml of diphenylphosphoryl azide and 1.04 ml of Et ₃ N were added, and the mixture was stirred at 80 ° C. for 2 hours.
The mixture was stirred for 18 hours at room temperature. Then, the title compound was obtained in the same manner as in Example 2 (2). Yield: 1.73 g Rf ₁ : 0.61, Rf ₂ : 0.42 [α] _D : -9.92 (C = 1.31, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.32 (9H, s), 2.90 (1H, dd,
J = 15Hz, 8Hz), 2.99 (1H, dd, J = 15Hz, 7Hz), 3.07-3.32
(2H, m), 3.43 (2H, t, J = 6Hz), 4.07-4.15 (2H, m), 4.49
(2H, s), 4.62 (1H, d, J = 15Hz), 6.20 (1H, br), 6.93-
7.34 (11H, m), 7.51 (1H, d, J = 8Hz), 7.70 (1H, d, J = 8H
z), 8.46 (1H, d, J = 5Hz), 8.51 (1H, s), 9.99 (1H, br
s), 10.70 (1H, br s)

(2) Boc-Gln-Trp-AzPh
_{e-NH (CH 2) 2} O- (3- pyridylmethyl) Boc-Trp-AzPhe-NH (CH 2) 2 O- (3
-Pyridylmethyl) 1.00 g, 4N HCl-AcOE
t4.25 ml, Et ₃ N 0.48 ml, NMM 0.19 ml
And Boc-Gln-ONp 656 mg from Example 2
The title compound was obtained in the same manner as in (2). Yield: 1.16 g Rf ₁ : 0.44, Rf ₂ : 0.14 [α] _D : -22.53 (C = 1.04, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.34 (9H, s), 1.63-1.89 (2H,
m), 2.06-2.16 (2H, m), 2.98 (1H, dd, J = 15Hz, 7Hz),
3.08 (1H, dd, J = 15Hz, 7Hz), 3.12-3.21 (2H, m), 3.42
(2H, t, J = 6Hz), 3.90-3.97 (1H, m), 4.12 (1H, d, J = 15
Hz), 4.34-4.40 (1H, m), 4.50 (2H, s), 4.57 (1H, d, J =
15Hz), 6.11 (1H, br), 6.59 (1H, br), 6.70 (1H, br),
6.94-7.34 (11H, m), 7.51 (1H, d, J = 8Hz), 7.71 (1H, d,
J = 8Hz), 8.08 (1H, d, J = 5Hz), 8.46-8.53 (1H, m), 8.5
3 (1H, s), 9.96 (1H, br s), 10.73 (1H, br s)

(3) t-Bu-NHCO-Gln-Tr
_{p-AzPhe-NH (CH 2} ) 2 O- (3- pyridylmethyl) Boc-Gln-Trp-AzPhe -NH (CH 2) 2
O- (3-pyridylmethyl) 500 mg, 4N HCl-A
The title compound was obtained in the same manner as in Example 2 (2) from 1.75 ml of cOEt, 0.20 ml of Et ₃ N and 0.08 ml of t-butyl isocyanate. Yield: 440 mg Rf ₁ : 0.36, Rf ₂ : 0.07 [α] _D : -20.37 (C = 1.08, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.18 (9H , s), 1.59-1.82 (2H,
m), 2.07 (2H, t, J = 8Hz), 2.97-3.22 (4H, m), 3.43 (2
H, t, J = 6Hz), 4.02-4.15 (2H, m), 4.30-4.38 (1H, m),
4.50 (2H, s), 4.57 (1H, d, J = 16Hz), 5.82-5.86 (2H,
m), 6.14 (1H, br), 6.57 (1H, br), 6.94-7.34 (11H, m),
7.51 (1H, d, J = 8Hz), 7.72 (1H, d, J = 8Hz), 8.17 (1H, b
r), 8.47 (1H, d, J = 4Hz), 8.53 (1H, s), 9.95 (1H, br
s), 10.72 (1H, br s)

Example 43 Boc-Gln-Trp-AzPhe-NH (CH ₂ ) ₂
O-benzhydryl Boc-Gln-Trp-AzPhe-OBzl130
mg was stirred in 3 ml of MeOH in the presence of 13 mg of 10% palladium-carbon for 18 hours in a hydrogen stream, the palladium-carbon was filtered off, and then the solvent was distilled off. The residue was dried under reduced pressure, dissolved in 3 ml of anhydrous DMF, and prepared separately under ice cooling.
-Benzhydryloxyethyl isocyanate solution (3
-64 mg of benzhydryloxypropionic acid in anhydrous DM
After dissolving in ₃ ml of F, 68 mg of diphenylphosphoryl azide and 0.03 ml of Et ₃ N were added and stirred at 80 ° C. for 2 hours), and the mixture was stirred at room temperature for 18 hours. Hereinafter, Example 2 (2)
The title compound was obtained in the same manner as in. Yield: 55 mg Rf ₁ : 0.54, Rf ₂ : 0.32 [α] _D : -15.52 (C = 0.57, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.34 (9H , s), 1.62-1.83 (2H,
m), 2.05-2.11 (2H, m), 2.94-3.15 (4H, m), 3.33 (2H,
t, J = 6Hz), 3.87-3.95 (1H, m), 4.09-4.17 (1H, m), 4.33
-4.40 (1H, m), 4.50-4.57 (1H, m), 5.43 (1H, s), 6.09
(1H, br), 6.62 (2H, br), 6.93-7.52 (21H, m), 8.06 (1
H, br), 9.92 (1H, br), 10.72 (1H, br)

Example 44 t-Bu-NHCO-Gln-Trp-AzPhe-N
H (CH _{2) 2} O- benzhydryl (1) t-Bu-NHCO -Gln-Trp-AzPh
e-OBzl Boc-Gln-Trp-AzPhe-OBzl2.0
0 g, 4N HCl-AcOEt 7.45 ml, Et ₃ N
The title compound was obtained from 0.42 ml and 0.34 ml of t-butyl isocyanate in the same manner as in Example 2 (2). Yield: 1.88 g Rf ₁ : 0.52, Rf ₂ : 0.16 [α] _D : -5.36 (C = 1.23, DMF) NMR (δ, DMSO-d ₆ , 55 ° C.): 1.19 (9H, s), 1.58-1.85 (2
H, m), 2.05 (2H, t, J = 8Hz), 2.85-3.08 (2H, m), 4.04-
4.11 (1H, m), 4.43-4.60 (3H, m), 5.09 (2H, s), 5.80-
5.82 (2H, m), 6.55 (1H, br), 6.92-7.31 (15H, m), 7.51
(1H, d, J = 8Hz), 7.88 (1H, d, J = 8Hz), 10.30 (1H, br
s), 10.62 (1H, br s)

(2) t-Bu-NHCO-Gln-Tr
_{p-AzPhe-NH (CH 2} ) 2 O- benzhydryl t-Bu-NHCO-Gln- Trp-AzPhe-O
130 mg of Bzl was stirred in 3 ml of MeOH in the presence of 13 mg of 10% palladium-carbon for 18 hours in a hydrogen stream, the palladium-carbon was filtered off, and the solvent was distilled off. The residue was dried under reduced pressure, dissolved in 3 ml of anhydrous DMF, and separately prepared under ice-cooling 2-benzhydryloxyethylisocyanate solution (3-benzhydryloxypropionic acid 55 mg.
Was dissolved in ₃ ml of anhydrous DMF, 58 mg of diphenylphosphoryl azide and 0.03 ml of Et ₃ N were added, and the mixture was stirred at 80 ° C. for 2 hours) and stirred at room temperature for 18 hours. Then, the title compound was obtained in the same manner as in Example 2 (2). Yield: 75 mg Rf ₁ : 0.53, Rf ₂ : 0.20 [α] _D : -19.14 (C = 0.47, DMF) NMR (δ, DMSO-d ₆ , 55 ° C): 1.18 (9H , s), 1.55-1.80 (2H,
m), 2.05 (2H, t, J = 7Hz), 2.97-3.19 (4H, m), 3.35 (2
H, t, J = 6Hz), 3.87-3.92 (1H, m), 4.18 (1H, d, J = 14H
z), 4.31-4.38 (1H, m), 4.55 (1H, d, J = 14Hz), 5.44 (1
H, s), 5.82-5.86 (2H, m), 6.12 (1H, br), 6.57 (1H, b
r), 6.93-7.52 (21H, m), 8.13 (1H, br), 9.91 (1H, br
s), 10.71 (1H, br s)

[Test Example 1] The activity of the azapeptide derivative of the present invention acting on the NKA receptor was evaluated by the following method. (1) Action on contraction of hamster trachea by NKA The trachea was excised from a male Syrian golden hamster having a body weight of 100 to 180 g to prepare an annular sample having a width of 3 to 6 mm. This sample was kept warm at 37 ℃, 95% O ₂ -5% CO
₂ aerated Tyrode's solution (NaCl 137 mM, KCl
2.7 mM, CaCl ₂ 1.8 mM, MgCl ₂ 1.02 m
M, NaHCO ₃ 11.9 mM, NaH ₂ PO ₄ 0.42 m
In a reactor filled with 15 ml of M and glucose (5.5 mM), 0.5 g of static tension was loaded and suspended.

The test compound was added to the reaction vessel and held for 5 minutes, and 1 × 10 ⁻⁷ M NKA was added to record the tension generated. The potency of the evaluated test compound as an antagonist is expressed as the IC ₅₀ . The IC ₅₀ is expressed as the molar concentration of the antagonist that produces 50% inhibition on the tension generated by the addition of 1 × 10 ⁻⁷ M NKA when no antagonist is added. The obtained results are as shown in Table 1.

[0173]

[Table 1]

(2) Effect on NKA-induced contraction of guinea pig airways Male Hartley guinea pigs weighing 350 to 500 g were intraperitoneally injected with 1.5 g / kg of urethane to be anesthetized. Insert a polyethylene cannula into the jugular vein and trachea, 1 mg
Was administered from the carotid artery cannula to stop breathing, the tracheal cannula was connected to an artificial respirator, and artificial respiration was performed at an insufflation rate of 4 to 6 ml and an insufflation frequency of 70 times / min. The side branch of the tracheal cannula was introduced into a water tank, and a water pressure of 8 cmH ₂ O was applied to measure the amount of excess air discharged above this water pressure. Administer 2 nmol / kg of NKA from the carotid cannula, administer the test compound 15 minutes later, and administer 1, 1,
After 5, 30, 45 and 60 minutes, 2 nmol / kg N
KA was administered. The amount of increase in excess air after administration of each NKA was measured, and the percentage to the amount of increase in excess air when the airway was completely closed was calculated, and this was taken as the airway contraction rate. The amount of decrease in the airway contraction rate after administration of the test compound was expressed as a percentage with respect to the airway contraction rate before administration of the test compound, and this was defined as the inhibition rate, which was taken as the efficacy of the test compound as an antagonist. The obtained results are as shown in Table 2.

[0175]

[Table 2]

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Tetsuaki Yamaura               2-7-1, Nishi-Shinjuku, Shinjuku-ku, Tokyo Wealth               Shirebio Co., Ltd. (72) Inventor Hiroshi Ikawa               2-7-1, Nishi-Shinjuku, Shinjuku-ku, Tokyo Wealth               Shirebio Co., Ltd.                (56) Reference JP-A-3-17098 (JP, A)                 JP-A-57-212148 (JP, A)                 J. Med. Chemical. , V               ol. 35 (11), p. 2015-2025               (1992)

Claims (11)

(57) [Claims] 1. A compound represented by the general formula (I): [Wherein A represents a direct bond, an α-amino acid or a residue of a dipeptide; R ¹ represents a hydrogen atom or a terminal amino group-protecting group; R ² represents an unsubstituted phenyl group or lower alkyl;
R ³ represents a phenyl group substituted with 1 or 2 substituents selected from halogen, optionally protected hydroxyl, nitro, optionally protected amino and perhalo lower alkyl; R ³ is a hydroxyl group or a terminal carboxyl group Which represents a protecting group for a group) or a salt thereof. 2. The azapeptide derivative or a salt thereof according to claim 1, wherein the residue of the α-amino acid or dipeptide of A is a residue of a natural or unnatural α-amino acid or a dipeptide thereof. 3. A is glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, cystine, proline, 4-hydroxyproline, histidine, aspartic acid, asparagine, glutamic acid, The azapeptide derivative or a salt thereof according to claim 1, which is a residue of a natural α-amino acid selected from glutamine, arginine, citrulline, ornithine and lysine, or a dipeptide thereof. 4. A is methionine, aspartic acid, asparagine, glutamic acid, glutamine, arginine,
The azapeptide derivative or a salt thereof according to claim 3, which is a residue of citrulline or ornithine, or a dipeptide thereof. 5. The azapeptide derivative or a salt thereof according to claim 4, wherein the dipeptide is aspartic acid-glutamine or asparagine-glutamine. 6. A is norleucine, norvaline, alloisoleucine, homoarginine, thiaproline, methionine sulfoxide, methionine sulfone, dehydroproline, homoserine, cyclohexylglycine, α-amino-n-butyric acid, cyclohexylalanine, aminophenylbutyric acid, phenylalanine. Of the phenyl moiety of is substituted with lower alkyl, lower alkoxy, halogen or nitro, or is substituted with methylenedioxy, β- (2- or 3-thienyl) alanine, β- (2- or 3 -Furanyl) alanine, β-
(2-, 3- or 4-pyridyl) alanine, β-
The azapeptide derivative or a salt thereof according to claim 1, which is an unnatural α-amino acid selected from (benzothiophen-2- or 3-yl) alanine and β- (1- or 2-naphthyl) -alanine. 7. The R ¹ protecting group is an alkanoyl group having 1 to 8 carbon atoms, a cycloalkanoyl group having 4 to 8 carbon atoms, an aroyl group, an alkoxycarbonyl group having 1 to 8 carbon atoms, and an alkyl moiety having 1 carbon atoms. ~ 8 aralkyloxycarbonyl group, the alkyl moiety has 1 to 8 carbon atoms N-alkylcarbamoyl group, or the cycloalkyl moiety has 3 to 6 carbon atoms N-.
An azapeptide derivative or a salt thereof according to any one of claims 1 to 6, which is a cycloalkylcarbamoyl group. 8. R ² is an unsubstituted phenyl group or 1 or 2 selected from lower alkyl having 1 to 8 carbon atoms, halogen, optionally protected hydroxyl and perhaloalkyl having 1 to 4 carbon atoms. The azapeptide derivative or a salt thereof according to any one of claims 1 to 7, which is a phenyl group substituted with a substituent. 9. R ³ is the formula —OR ⁴ or the formula —N (R ⁵ ).
(R ⁶ ), R ⁴ , R ⁵ and R ⁶ each represent a hydrogen atom, a substituted or unsubstituted C 1-8 alkyl group or an aralkyl group, or R ⁵ and R ⁶ are bonded to each other. The azapeptide derivative or the salt thereof according to any one of claims 1 to 8, which may form a hetero-saturated monocyclic ring together with the nitrogen atom. 10. R ⁴ is an aralkyl group; or R ⁵ is an alkyl group having 1 to 8 carbon atoms which may be substituted with hydroxyl or aralkyloxy, or substituted with halogen or alkoxy having 1 to 8 carbon atoms. The azapeptide derivative or a salt thereof according to claim 9, which is an optionally substituted aralkyl group and R ⁶ is a hydrogen atom. 11. A therapeutic agent for respiratory nervous system inflammation, asthma and bronchospasm, which comprises the azapeptide derivative represented by the general formula (I) or a salt thereof as an active ingredient.