KR101576231B1 - Peptidomimetic compounds comprising chemical formula I and pharmaceutical composition comprising the same for treating allergic disease - Google Patents

Abstract

The present invention relates to a novel peptidomimetic compound exhibiting a preventive or therapeutic activity against an allergic disease, and a pharmaceutical composition for preventing or treating an allergic disease comprising the same.

Description

TECHNICAL FIELD The present invention relates to a peptidomimetic compound having a structure represented by the formula (I) and a pharmaceutical composition for treating an allergic disease comprising the peptidomimetic compound,

The present invention relates to a novel peptidomimetic compound exhibiting a preventive or therapeutic activity against an allergic disease, and a pharmaceutical composition for preventing or treating an allergic disease comprising the same.

Mast cells and blood neutrophils are known to be endocrine cells that cause various allergic diseases such as allergic rhinitis, allergic atopic dermatitis, allergic conjunctivitis, allergic asthma, food allergy and anaphylactic shock . These cells have receptors for antibodies that induce allergens on the cell surface and, when stimulated, secrete substances that induce their various allergens outside the cells.

Various attempts have been made to treat allergies, but most of the allergic therapies are currently being directed towards alleviating symptoms rather than eliminating them. Typically, antagonists against histamine and leukotrienes secreted by allergens in mast cells are dominant. However, since these drugs show tolerance within a short period of time after administration, they often fail to improve their symptoms after a certain period of time or repeatedly. Therefore, there is a demand for the development of an allergy treatment agent free from side effects such as antihistamines.

In addition, there are therapeutic approaches such as blocking the binding of IgE to receptors of mast cells by other therapeutic methods, and treating the antibody against IL-4, an allergen-inducing cytokine, Are costly or have yet to be fully characterized.

There are many peptides involved in physiological activity in living body, and most physiologically active peptides are easily hydrolyzed by in vivo enzymes or acids, and the molecular weight is generally large, which makes it difficult to use as a drug. In order to overcome this problem, methods of using a peptide as a template for modifying a side chain or skeletal structure of a peptide or inducing a specific structure have been proposed. All of these substances are collectively referred to as a peptidomimetic compound. These compounds can be used for molecular diagnostics such as detection of harmful microorganisms and environmental hormones in addition to disease-inducing biomarkers, and can be used as a new drug design, a nanocomposite and a new drug delivery system.

However, studies on peptidomimetic compounds for the treatment of allergic diseases have not yet been conducted, and there is a strong demand for the development of therapeutic agents capable of treating allergies without side effects.

It is an object of the present invention to provide a peptidomimetic compound which is novel in preventing or treating an allergic disease.

It is another object of the present invention to provide a pharmaceutical composition for preventing or treating an allergic disease, which comprises the above compound.

As one embodiment for achieving the above object, the present invention relates to a novel peptidomimetic compound exhibiting a preventive or therapeutic activity against an allergic disease.

More specifically, the present invention relates to a peptide consisting of the amino acid sequence of SEQ ID NO: 1 (Trp-Tyr-Val-Tyr-Pro-Ser-Met) or a fragment thereof, wherein the first amino acid of the sequence number is tryptophan or the fourth amino acid is tyrosine Acyl group is introduced, and a novel peptidomimetic compound exhibiting a preventive or therapeutic activity against an allergic disease.

The peptide consisting of the amino acid sequence of SEQ ID NO: 1 is a heptamer also known as dTBP2 (dimerized translationally controlled tumor protein binding peptide 2). The peptides are known to bind with high affinity to dTCTP and inhibit the interaction between dTCTP and its receptor thereby inhibiting the transmission of allergy-related information due to their interaction. It is also known to be involved in alleviating the various allergic diseases that can be induced by inhibiting the secretion of cytokines and histamines, including interleukin (IL) -8, IL-5, and the like.

[Chemical structure of dTBP2]

Accordingly, the present inventors have conducted intensive studies on peptidomimetic compounds acylated with various acids at the NH ₂ end and peptidomimetic compounds varied in dTBP2 in order to inhibit the binding between dTCTP and its receptor And the biological activities of these compounds were measured to confirm their efficacy.

Prior to the synthesis of the peptidomimetic compounds, alanine scanning mutagenesis was performed by preparing mutants in which the amino acid residues of dTBP2 were substituted one by one with alanine and evaluating their activity (alanine scanning mutagenesis) to find out what essential residues of dTBP2 in dTTP-dTBP2 binding Respectively.

As can be seen from the results shown in Table 1, the first amino acid, tryptophan and the fourth amino acid, tyrosine, retained the same activity of dTBP2 even when substituted with alanine. Therefore, in the present invention, a peptidomimetic compound of dTBP2, which is modified with tryptophan or tyrosine and whose activity and bioavailability are further enhanced, was designed.

First, an acyl group was introduced into tryptophan, which is an amino acid at the N-terminus, and a compound exhibiting an effective effect was selected. These compounds have increased binding capacity to dTCTP. We have also found that tyrosine located at the 4th amino acid position which is found to be not the most essential from the alanine scanning mutagenesis is changed to a diamino-acid such as diaminopropionic acid (Dpr) ) (Fig. 1).

It was confirmed that the newly introduced functional groups can provide additional binding sites and significantly increase the binding force of dTCTP-dTBP2 by replacing loose binding residues such as internal tyrosine with tight binding (Experimental Examples 1 to 4 ).

Accordingly, an example of the novel peptidomimetic compound provided by the present invention is a peptide comprising the amino acid sequence of SEQ ID NO: 1 or a fragment thereof, wherein the peptidomimetic compound having an acyl group introduced into tryptophan, Lt; / RTI >

More preferably, it may be a peptidomimetic compound having a structure represented by the following formula (1).

[Chemical Formula 1]

,

,

또는

이고,R ₁ is

,

,

or

ego,

W is tryptophan (W)

Y is tyrosine (Y)

V is valine (V)

P is proline (P)

S is serine (S)

M is methionine (M).

The above formula (1) may specifically be represented by the following chemical structure:

More specifically, the compound is selected from the group consisting of 2-methylhexanoyl-tryptophan-tyrosine-valine-tyrosine-proline-serine-methionine, isonicotinyl-tryptophan-tyrosine-valine-tyrosine- Tyrosine-valine-tyrosine-proline-serine-methionine, or 5-nitro-3-pyrazolcarboxylyl-tryptophan-tyrosine-valine-tyrosine-proline-serine-methionine.

In another embodiment, the present invention provides a peptide comprising the amino acid sequence of SEQ ID NO: 1, wherein the acyl group is introduced at the tryptophan site, which is the first amino acid of the sequence number, and the tyrosine acyl group (acyl group) May be a peptidomimetic compound substituted by diaminopropionic acid (Dpr) and exhibiting a preventive or therapeutic activity against an allergic disease.

More preferably, the isotonitinyl group may be introduced at the tryptophan site, which is the first amino acid of the sequence number.

The Dpr may be a benzoyl group, a cinnamyl group, a carboxyl group, an acetyl group, a hexyloyl group, an aroyl group, a naphthoyl group, a nicotinyl group, a hexadienoyl group, a glyoxyl group, a furyl group, a hexanoyl group, An acyl group-containing substituent including at least one group selected from the group consisting of a hydroxyl group, a hydroxyl group, a hydroxyl group, a hydroxyl group, a hydroxyl group, a hydroxyl group, a hydroxyl group,

More preferably, it may be a peptidomimetic compound having a structure represented by the following formula (2).

(2)

Dpr is a diaminopropionic acid,

R ₂ is an unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms, unsubstituted or substituted alkoxy having 1 to 10 carbon atoms, unsubstituted or substituted aryl, or N, O or S, or is an unsubstituted or substituted heterocycle containing N, O or S,

W is tryptophan (W)

Y is tyrosine (Y)

V is valine (V)

P is proline (P)

S is serine (S)

M is methionine (M).

The above formula (2) can be represented specifically by the following chemical structure:

More specifically, the compound is selected from the group consisting of isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr -Dimethylbenzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamyl) Tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- (2-cyanophenylthio) benzoyl) -proline-3, < / RTI > Tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-tyrosine-valine-Dpr (phenoxyacetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr 2-hexenoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-hexynoyl) -proline-serine- methionine non- Tyrosine-valine-Dpr (aurothyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Dpr (4-benzyloxybenzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan - tyrosine-valine-Dpr (4-benzyloxybenzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-naphthoyl) -proline-serine-methionine oxidized form, Tyrin-tryptophan-tyrosine-valine-Dpr (2-naphthoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-pyrazinecarboxylyl) -proline-serine-methionine oxidized form , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-pyrazinecarboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine- - methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-chloronicotinyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Oil-proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2,4- Tyrosine-valine-Dpr (biphenyl-4-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine- Valine-Dpr (phenylglyoxyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (biphenyl-4-carboxylyl) -proline- - tryptophan-tyrosine-valine-Dpr (phenylglyoxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl) -proline-serine-methionine oxidized form , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (trans- - Methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (1-naphthoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Dpr (1-naphthoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro- Threonine-valine-Dpr (beta-naphthoxyacetyl) -prolyl-serine-methionine, tryptophan-tyrosine-valine-Dpr (5-nitro-2-furoyl) Tyrosine-valine-Dpr (3-phenoxybenzoyl) -proline-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (beta-naphthoxyacetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan- -Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-phenoxybenzoyl) -proline- Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-Dpr (7-methoxy-1-benzofuran- Tyrosine-valine-Dpr (2-methoxyhexanoyl) -proline-methionine non-oxidized form, valine-Dpr (7-methoxy- Tyrosine-valine-Dpr (2-methoxyhexanoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-chlorobenzo [b] thiophene-2-carbox yl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinadyl) -proline-serine-methionine oxidized form, Tyrosine-purine-Dpr (quinadyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-tyrosine-valine-Dpr Tyrosine-Dpr (isonicotinyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (tyglyle) -proline-serine-methionine -Prinoline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (iso-nicotinyl) Tyrosine-valine-Dpr (5-phenyl-2-furoyl) -nicotinic acid-tryptophan-tyrosine-valine-Dpr ) Proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-phenyl- Tyrosine-valine-Dpr (5-nitro-3-pyrazolecarboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine- Tyrosine-valine-Dpr ((R) - (+) - troloxyl) -proline-prorine-serine-methionine disulfide-type, isonicotinyl- Tyrosine-valine-Dpr ((R) - (+) - troloxyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (R) - (+) - 2-pyrrolidone-5-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Pyrrolidone-5-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano- 1- cyclopropanecarboxylyl) -proline-serine-methionine oxidation Isonicotinyl Tyrosine-valine-Dpr (rhodanine-3-acetyl) -prrine-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine- -Prinoline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr -Hydroxycoumarin-4-acetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (7- Tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Sulfonamido) acetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1- (1-acetylpiperidine-4-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Pyruvate-4-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Prr (1-phenyl-5- (trifluoromethyl) Tyrosine-valine-Dpr (1-phenyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylyl) -proline-serine- methionine- Dpr (2-thiopheneacetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr (benzotriazol-5-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (benzotriazol- (4-oxo-4H-chromene-3-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (4-methyl-2-oxo-4H-chromene-3-carboxylyl) -proline-serine-methionine disappeared, isotonicotinyl-tryptophan- Tyrosine-valine-Dpr (4-methyl-2-oxo-2H-chromen-7-yloxy) acetyl) -proline- serine- methionine oxidized form and isonicotinyl- Yloxy) acetyl) -proline-serine-methionine is of the non-oxidised form.

In another embodiment, the present invention provides a peptide fragment consisting of the amino acid sequence of SEQ ID NO: 1, wherein the fragment is a peptide fragment consisting of four amino acids and the C-terminal is methionine and the tyrosine residue corresponding to the fourth amino acid sequence of SEQ ID NO: May be a peptidomimetic compound which is substituted with diaminopropionic acid (Dpr) in which an acyl group is connected and exhibits a preventive or therapeutic activity against an allergic disease.

More preferably, the Dpr is an aryl group having at least one atom selected from the group consisting of a benzoyl group, a cinnamyl group, a carboxyl group, an acetyl group, an aroyl group, a quinadyl group, a tiglylamyl group, a trolyl group, a heteroalkyl and an arylheteroalkyl group. Group-containing substituent.

More preferably, the present invention can be a peptidomimetic compound having a structure represented by the following formula (3).

(3)

Dpr is a diaminopropionic acid,

R ₃ is an unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms, unsubstituted or substituted alkoxy having 1 to 10 carbon atoms, unsubstituted or substituted aryl, or N, O or S, or is an unsubstituted or substituted heterocycle containing N, O or S,

P is proline (P)

S is serine (S)

M is methionine (M).

The above formula (3) can be specifically represented by the following chemical structure:

The peptidomimetic compound having the structure of Formula 3 is preferably selected from the group consisting of Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -proline-serine-methionine oxidized form, Dpr [2.2.2] octane-1-carboxylyl) -proline-serine-methionine non-oxidized form, Dpr (tyglyle) -proline-serine-methionine oxidized form, Dpr (tyglyle) -proline-serine-methionine non- , Dpr (5-chloroindole-2-carboxylyl) -proline-serine-methionine oxidized form, Dpr (5-chloroindole- Proline-serine-methionine oxidized form, Dpr (2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine non-oxidized form, Dpr (quinadyl) -proline-serine-methionine Dpr (7-methoxy-1-benzofuran-2-carboxylic acid), Dpr (2-fluorophenylacetyl) -proline-serine-methionine, - Proline - Serine - Proline-serine-methionine, Dpr (1-cyano-1-cyclopropanecarboxylyl) -proline-serine-methionine, Dpr (alpha-cyano- Proline-serine-methionine, Dpr (2- (4-methylphenyl) -methanone, Dpr (3,5-dimethylbenzoyl) Sulfonamido) acetyl) -proline-serine-methionine and Dpr (5-nitro-3-pyrazolecarboxylyl) -proline-serine-methionine.

In another aspect, the present invention provides a peptide fragment comprising the amino acid sequence of SEQ ID NO: 1, wherein the fragment is a fragment consisting of four amino acids from the N-terminus of SEQ ID NO: 1, wherein the first amino acid of the SEQ ID NO: And a tyrosine acyl group corresponding to the fourth amino acid sequence of SEQ ID NO: 1 is linked to a diaminopropionic acid (Dpr), and a peptidomycin that has a prophylactic or therapeutic activity against an allergic disease Lt; / RTI >

More preferably, the isotonitinyl group may be introduced at the tryptophan site, which is the first amino acid of the sequence number.

The Dpr may further include an acyl group-containing substituent containing at least one group selected from the group consisting of a benzoyl group, a carboxyl group, an acetyl group, an aroyl group, a quinadyl group, a tiglylamyl group, a trolyl group, a heteroalkyl and an arylheteroalkyl, Can be connected.

More preferably, the present invention can be a peptidomimetic compound having a structure represented by the following formula (4).

[Chemical Formula 4]

Dpr is a diaminopropionic acid,

R ₄ is an unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms, unsubstituted or substituted alkoxy having 1 to 10 carbon atoms, unsubstituted or substituted aryl, or N, O or S, or is an unsubstituted or substituted heterocycle containing N, O or S,

W is tryptophan (W)

Y is tyrosine (Y)

V is Valine (V).

The formula (4) can be represented by the following chemical structure:

The peptidomimetic compounds having the structure of Formula 4 are preferably isonicotinyl-tryptophan-tyrosine-valine-Dpr (aurotyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) ) Benzoyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr ((R) - (+) - troloxyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano- Tyrosine-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl), isonicotinyl- - valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinadyl), isonicotinyl- Tyrosine-valine-Dpr (5-nitro-pyrrole), isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-chloroindole- Pyrazolecarboxyl) and isonicotinyl-tryptophan-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl).

In another aspect, the present invention provides a peptide fragment consisting of the amino acid sequence of SEQ ID NO: 1, wherein the fragment is a peptide fragment consisting of three or four amino acids and C-terminal serine, Tyrosine may be a peptidomimetic compound which is substituted by diaminopropionic acid (Dpr) linked with an acyl group and exhibits a preventive or therapeutic activity against an allergic disease.

More preferably, the Dpr may be linked to an acyl group-containing substituent comprising at least one group selected from the group consisting of a benzoyl group, a carboxyl group, an acetyl group, an aroyl group, a heteroalkyl and an arylheteroalkyl.

More preferably, it may be a peptidomimetic compound having a structure represented by the following formula (5) or (6).

 [Chemical Formula 5]

Dpr is a diaminopropionic acid,

R ₅ is an unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms, unsubstituted or substituted alkoxy having 1 to 10 carbon atoms, unsubstituted or substituted aryl, or N, O or S, or is an unsubstituted or substituted heterocycle containing N, O or S,

P is proline (P)

S is serine (S).

The above formula (5) can be specifically represented by the following chemical structure:

[Chemical Formula 6]

Dpr is a diaminopropionic acid,

R ₆ is at least one selected from the group consisting of a benzoyl group, a carboxyl group, an acetyl group, an aroyl group, a heteroalkyl and an arylheteroalkyl,

V is valine (V)

P is proline (P)

S is serine (S).

The formula (6) can be represented by the following chemical structure:

The peptidomimetic compound having the structure of Formula 5 or Formula 6 is preferably selected from the group consisting of valine-Dpr (ourotyl) -prolyl-serine, valine-Dpr (7-methoxy-1-benzofuran- Proline-serine, valine-Dpr (3,5-dimethylbenzoyl) -proline-serine, valine-Dpr (5-chloroindole- Proline-serine, Dpr (3,5-dimethylbenzoyl) -proline-serine, Dpr (7-methoxy-1-benzofuran- , Dpr (5-chloroindole-2-carboxylyl) -proline-serine, or Dpr (2-fluorophenylacetyl) -proline-serine.

In the definition of substituents of the compounds according to the invention, the term " alkyl " means an aliphatic hydrocarbon group. Alkyl may be a "saturated alkyl" that does not include an alkene or alkyne moiety, or may be an "unsaturated alkyl" moiety that includes at least one alkene or alkyne moiety. "Alkene" means a group comprising at least one carbon-carbon double bond, and "alkyne " means a group comprising at least one carbon-carbon triple bond. Alkyl, when used alone or in combination with alkoxy, may be branched or straight chain, respectively.

The alkyl group may have from 1 to 20 carbon atoms, unless otherwise defined. The alkyl group may be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group may be lower alkyl having 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl and the like. For example, C ₁ -C ₄ -alkyl has from 1 to 4 carbon atoms in the alkyl chain and is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t- Group.

The term " alkoxy " means alkyloxy having 1 to 10 carbon atoms unless otherwise specified.

The term " cycloalkyl " means a saturated aliphatic 3- to 10-membered ring unless otherwise defined. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term " aryl " includes at least one ring having a covalent pi electron system and includes, for example, a monocyclic or fused ring polycyclic (i.e., rings that divide adjacent pairs of carbon atoms) groups. That is, in the present specification, aryl means 4- to 10-membered, preferably 6- to 10-membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl and the like unless otherwise defined.

The term " heteroaryl ", unless otherwise defined, includes aromatic 3- to 10-membered rings containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S and fused with benzo or C ₃ -C ₈ cycloalkyl Preferably a 4- to 8-membered ring, more preferably a 5- to 6-membered ring. Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole Sol, pyridine, pyridazine, pyrimidine, pyrazine, and similar groups. Examples of bicyclic heteroaryls include indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine , Furopyridine, and similar groups.

The term " heterocycle ", unless otherwise defined, includes 1 to 3 heteroatoms selected from the group consisting of N, O and S, which may be fused with benzo or C ₃ -C ₈ cycloalkyl, Means a 3- to 10-membered ring containing two double bonds, preferably a 4- to 8-membered ring, more preferably a 5- to 6-membered ring. Examples of the heterocycle include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, However, the present invention is not limited to these.

Other terms and abbreviations used herein can be interpreted as commonly understood by a person skilled in the art to which the present invention belongs, unless otherwise defined.

In another embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating an allergic disease comprising the novel peptidomimetic compound.

The novel peptidomimetic compounds provided by the present invention exhibit biological activity of dTBP2 and are characterized by their activity and bioavailability. Therefore, the present invention provides a novel peptidomimetic compound which is useful for allergic diseases capable of alleviating, improving, preventing, inhibiting or treating dTBP2 It can be applied for medicinal purposes. For example, the peptidomimetic compounds of the present invention can be applied for medicinal use for allergic diseases capable of alleviating, improving, preventing, inhibiting or treating by inhibiting the interaction between dTCTP and its receptor. In another embodiment, the peptidomimetic compounds of the present invention are useful for all allergic diseases capable of alleviating, improving, preventing, inhibiting or treating cytokine and histamine, including IL-8, IL-5, Can be used for therapeutic purposes.

In particular, the allergic disease can be, but is not limited to, asthma, rhinitis, chlamydia, anaphylaxis, allergic bronchiectasis, allergic conjunctivitis, urticaria or atopic dermatitis, -8, < / RTI > IL-5, and the like, and all allergic diseases that can be induced by the secretion of histamine are included within the scope of the present invention.

In addition, the pharmaceutical composition of the present invention can be administered to children, adolescents, and adults, and both oral and parenteral administration routes are possible. Preferably parenterally.

The term "administering" in the present invention means introducing the pharmaceutical composition of the present invention into an individual in need of treatment of the disease by any appropriate method, and the administration route of the composition of the present invention is not limited Orally, parenterally, or parenterally.

The term "pharmaceutically effective amount " as used herein means the amount of the active ingredient from which the desired pharmaceutical effect can be obtained, and in some cases, the concentration of the active ingredient in the pharmaceutical composition for exerting the desired pharmaceutical effect May mean a dose.

For purposes of the present invention, the specific pharmaceutically effective amount for a particular patient will depend upon the nature and extent of the reaction to be achieved, the specific composition including whether or not other agents are used, the age, weight, general health status, sex And various factors including diet, time of administration, route of administration and minute of composition, duration of treatment, drugs used or co-used with the specific composition, and similar factors well known in the medical field.

In addition, for parenteral administration, injectable formulations include isotonic aqueous solutions or suspensions, etc., and may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. For example, each component can be formulated by injection in saline or buffer solution. In addition, formulations for oral administration include, but are not limited to, powders, granules, tablets, pills, emulsions, syrups and capsules.

In addition, the composition for preventing or treating allergic diseases of the present invention may further comprise a pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not significantly stimulate the organism and does not interfere with the biological activity and properties of the administered compound. Pharmaceutically acceptable carriers include, for example, carriers for oral administration such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like, and water for parenteral administration such as water, suitable oils, saline, aqueous glucose, Carrier and the like. Such a pharmaceutically acceptable carrier may be a mixture of one or more ingredients selected from the group consisting of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, Other excipients such as stabilizers, preservatives, antioxidants, buffers and bacteriostats may be added as excipients.

The peptidomimetic compounds of the present invention exhibit excellent antiallergic effects in allergic animal models such as inhibiting the secretion of cytokines and histamines including IL-8, IL-5 and the like, And thus can be used more effectively.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic diagram for synthesizing a peptidomimetic compound. FIG.
Figure 2 shows the selective removal of the Mtt protecting group as determined by HPLC.
3 shows a schematic diagram of dividing the compound prepared in Preparation Example 3 into two portions, a tetramer at the terminal of NH2 and a tetramer at the terminal of COOH, centering on the Dpr site.
FIG. 4 is a graph showing a total of 15 compounds that are more effective than dTBP2 among the compounds prepared through Preparation Example 3. FIG.
Fig. 5 shows the degree of inhibition of IL-8 secretion by the compound prepared in Preparation Example 2. Fig.
Fig. 6 shows the degree of inhibition of IL-8 secretion by the compound prepared in Preparation Example 3. Fig.
Fig. 7 compares the relative activity between the compound prepared in Preparation Example 4 and the compound prepared in Preparation Example 5. Fig.
Fig. 8 shows the degree of inhibition of IL-8 secretion by the compound prepared in Preparation Example 6. Fig.
FIG. 9 shows the results of in situ competition assay of the compound prepared in Preparation Example 2. FIG.
FIG. 10A shows that the symptom score decreased when dTBP2 was treated, and FIG. 10B shows changes in eosinophilia when treated with dTBP2.
FIG. 11 shows that the secretion of interleukin-5 is inhibited in the bronchoalveolar lavage fluid by treating compounds No. 122, 123, and 129.
FIG. 12 shows the treatment of compounds 122, 123 and 129 and staining with Periodic Acid-Schiff (PAS) reagent to observe the mucosal thickness of lung tissue.
Fig. 13 shows that the secretion of interleukin-5 was inhibited in the bronchoalveolar lavage fluid by treating compounds No. 97 and No. 121.
FIG. 14 shows the results of treatment of the compounds No. 97 and No. 121, and the change of staining of the mucous membrane of the lung tissue with Hematoxylin and eosin (H & E) reagent.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Manufacturing example  One. Trp - Tyr - Val - Tyr - Pro - Ser - Met  Sequence Peptides  ( dTBP2 ) Synthesis of

1-1. Wang resin Wang Resin ) In LL Fmoc - Met - OH  loading( loading )

Add Wang resin LL (100-200 mesh, 300 mg, 0.44 mmol / g, 0.13 mmol) to a 20 mL TORVIQ PP syringe equipped with a filter and add dimethylformamide (DMF) After swelling for 30 minutes, it was drained.

Fmoc (Fluorenylmethyloxycarbonyl chloride) -Met-OH (10.0 eq., 483.0 mg, 1.3 mmol) was placed in a 50 mL pear-type flask and replaced with argon gas. Anhydrous dichloromethane (CH ₂ Cl ₂ ) ) And anhydrous dimethylformamide (DMF, approximately 20 drops). DIC (5.0 eq, 0.1 mL, 0.65 mmol) was added to the mixture and stirred at 0 < 0 > C for 20 min. After distillation under reduced pressure at room temperature, the remaining suspension was dissolved in a minimum amount of anhydrous DMF (7.0 mL) and DMAP (0.1 eq., 1.6 mg, 0.013 mmol) was dissolved in anhydrous DMF (0.1 mL) The resin was mixed with an orbital shaker (130 rpm) at room temperature for 1 hour at room temperature, and the solvent was drained and then washed with anhydrous dimethylformamide (DMF), isopropyl alcohol (iPrOH) and anhydrous dichloromethane (CH ₂ Cl ₂ ) (10 mL> 1 min> 3 respectively). Standard Fmoc quantification was performed using UV spectrometry to determine loading (99.9%).

1-2. Fmoc - base solid phase peptide synthesis  ( SPPS )

To remove the Fmoc (Fluorenylmethyloxycarbonyl chloride) group, the resin (300 mg, 0.13 mmol) was swollen in anhydrous DMF for 30 minutes and then 20% piperidine / anhydrous DMF (6.0 mL, ) Was added and mixed with an orbital shaker (130 rpm) at room temperature for 10 minutes. The solvent was drained and washed with DMF, iPrOH and CH ₂ Cl ₂ (10 mL> 1 min> 3). After drying for 30 minutes using an aspirator, the reaction was completed using a Kaiser test. (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate) (8.0 eq., 394.5 mg, 1.04 mmol) was added to couple serine with methionine. (8.0 eq., 0.18 mL, 1.04 mmol), HOBt (Hydroxybenzotriazole) .H ₂ O (8.0 eq., 159.3 mg, 1.04 mmol), Fmoc-Ser (tBu) -OH (8.0 eq, 398.8 mg, 1.04 mmol) Was dissolved in anhydrous DMF (6.0 mL), stirred for 3 minutes, added to resin (300 mg, 0.13 mmol) which had been swollen in DMF for 30 minutes and then washed with an orbital shaker (130 rpm) Lt; / RTI > After 2 h, the solvent was drained and washed with DMF, iPrOH and CH ₂ Cl ₂ (10 mL> 1 min> 3, respectively). After drying for 30 minutes using an aspirator, the reaction was completed using the Kaiser test.

(TBu) -OH, and Fmoc-Trp (Boc) -OH in the order of the protecting group removal and coupling method in the order of Fmoc-Pro-OH, Fmoc-Tyr To synthesize dTBP2 and Trp-Tyr-Val-Tyr-Pro-Ser-Met. When the Fmoc group, which is a proline protecting group, was removed and when tyrosine was coupled to proline, it was confirmed that the reaction was completed with the Chloranil test.

1-3. cut( Cleavage )

The peptide (30 mg, 0.013 mmol) prepared in 1-2 above was placed in a 1 mL Micro Bio-Spin chromatography column, and the Fmoc group was removed using 20% piperidine / anhydrous DMF (0.6 mL) The reaction mixture was reacted at room temperature for 1 hour with addition of TFA (trifluoroacetic acid) cocktail (TFA: H ₂ O: EDT: TIS, 94%: 2.5%: 2.5%: 1%, 0.6 mL) The resin was again washed with TFA solution (0.3 mL> 2) to receive the filtrate. The above filtrates were combined, and the TFA was removed using an evaporator, followed by decantation three times using cold ether. In order to prevent the loss of the resulting compound, a centrifugal separator was used. After drying, the residue was purified by semi-preparative HPLC (solvent A: 0.1% TFA / H ₂ O, solvent B: 0.1% TFA / CH ₃ CN, -73% B over 30 min), followed by lyophilization and mass spectrometry (MS).

Trp - Tyr - Val - Tyr - Pro - Ser - Met  ( dTBP2 )

99.9% purity. R _t 19.9 min. MALDI m / z calculated for C ₄₇ H ₆₁ N ₈ O ₁₁ S ⁺ [M + H] ⁺ 945.42, found 945.58.

Manufacturing example  2. Acyl - Trp - Tyr - Val - Tyr - Pro - Ser - Met Synthesis of

In the binding site, NH ₂ terminus and by making acid libraries (acid library) to determine the tyrosine (tyrosine) around the space in the center, and then acylating the NH ₂ terminus were screened by in situ, synthesis method, solid phase protocol was used. HOOC-TentaGel resin and dTBP2 were synthesized by linking with SS linker. This method can be easily performed by SS linker with DTT-Tris (Dithiothreitol-Tris (2-carboxyethyl) phosphine HCl) buffer and screening without purification. It is a useful and effective method of experiment. Using this method, 88 NH ₂ terminated acylated peptidomimetic compounds were synthesized as follows in a 96-well filter plate.

The compounds prepared by the above synthesis had to be confirmed at the COOH end, since the SS bond was broken and NHCH ₂ CH ₂ SH was attached and mixed with the cleavage cocktail. Thus, based on the results of the competition assay, four compounds were selected and re-synthesized in a manner that no NHCH ₂ CH ₂ SH was attached, that is, individually subjected to the Fmoc-based solid phase peptide synthesis (SPPS) protocol Lt; / RTI >

As a solid support, Wang resin LL on polystyrene on polystyrene was selected and Fmoc-Met-OH was made into Fomc-methionine anhydride by using dichloromethane (DCC) After that, Fmoc-methionine was loaded into Wang resin by esterification with DMAP (4-dimethlyaminopyridin) as a catalyst.

Subsequently, the remaining amino acids of dTBP2 were sequentially adhered using 1H-Benzotriazolium 1- [bis (dimethylamino) methylene] -5chloro-, hexafluorophosphate (1 -) and 3-oxide (HCTU) The Fmoc protecting group was removed using DMF containing piperidine. The cleavage of the Fmoc protecting group and the progress of the amino acid coupling reaction were confirmed by the Kaiser test or the chloranil test at each step. Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) was used for the coupling reaction of 4 acids (isonicotinic acid, 2-methylhexanoic acid, α-cyano-4-hydroxy cinnamic acid, and 5-nitro-3-pyrazolecarboxylic acid) And 94% TFA containing 1,2-ethanedithiol and triisopropylsilane (TIS) was used to remove the side-chain protecting groups and Wang resin of the amino acid residues. Finally, after analysis and purification using HPLC, the material was identified by MALDI-TOF by lyophilization.

2-1. 2- Methyl hexanoyl - tryptophan - Tyrosine - Balin - Tyrosine - proline-serine-methionine (2- Methylhexanoyl - Trp - Tyr - Val - Tyr - Pro - Ser - Met ) Synthesis of

The peptide-resin (50 mg, 0.022 mmol) was dissolved in 30% piperidine / dry DMF (1.0 mL) in the same manner as dTBP2 of Preparation Example 1, (10.0 eq, 114.5 mg, 0.22 mmol), HOBt.H ₂ O (10.0 eq, 33.7 mg, 0.22 mmol), 2-Methylhexanoic acid (10.0 eq, 28.6 mg, 0.22 mmol) and NMM (20 eq, 48.4 uL, 0.44 mmol) and then by stirring for 3 minutes and then dissolved in anhydrous DMF (0.6 mL), added to the resin (500 mg, 0.22 mmol) was swelled for 30 min DMF orbital shaker ( 130 rpm) for 2 hours. After 2 hours, 2-Methylhexanoic acid was coupled. The resin (50 mg, 0.022 mmol) thus prepared was placed in a 3 mL TORVIQ PP syringe equipped with a filter and immersed in a degassed 94% TFA cocktail (TFA: H ₂ O: EDT: TIS, 94%: 2.5%: 2.5% , 1.0 mL) was added and reacted at room temperature for 1 hour, followed by filtration to obtain filtrate. Resin was again washed with TFA solution (0.5 m > 2) to receive the filtrate. The supernatants were combined and the TFA was removed using an evaporator, followed by decantation three times using cold ether. In order to prevent the loss of the resulting compound, a centrifugal separator was used. After drying, the residue was purified by semi-preparative HPLC (solvent A: 0.1% TFA / H ₂ O, solvent B: 0.1% TFA / CH ₃ CN, separation using a -100% B over 30 min) and freeze-dried was confirmed that the compound generated in the mass spectrometer (mass spectometry, MS) (84.1 % Purity. R t 20.5 min. MALDI m / z calcd for C 54 H ₇₂ N ₈ NaO ₁₂ S ⁺ [M + Na] < ⁺ > 1079.49, found 1079.50.).

2-2. Isonicotinyl - tryptophan - Tyrosine - Balin - Tyrosine - proline-serine-methionine ( Isonicotinyl - Trp - Tyr - Val - Tyr - Pro - Ser - Met ) Synthesis of

The compound was synthesized using the same method as in the above 2-1. Coupling was performed using isonicotinic acid as an acid, and a compound produced by mass spectrometry (MS) was identified after synthesis _{(94.3% Purity. R t 15.9} min. MALDI m / z calculated for C 53. H 63 N 9 NaO 12 S + [M + Na] + 1072.42, found 1072.41).

2-3. Alpha- Cyano -4- Hydroxycinnamate - tryptophan - Tyrosine - Balin - Tyrosine - proline-serine-methionine (a- Cyano -4- hidroxycinnamyl - Trp - Tyr - Val - Tyr - Pro - Ser - Met ) Synthesis of

Was synthesized using the same method as in 2-1 above and coupled using α-Cyano-4-hydroxycinnamic acid as an acid. After the synthesis, (mass spectrometry, MS) (99.2% Purity. R _t 19.3 min. MALDI m / z calculated for C ₅₇ H ₆₅ N ₉ NaO ₁₃ S ⁺ [M + Na] ⁺ 1138.43, found 1138.37. ).

2-4. 5-Nitro-3- Pyrazole carboxylate - tryptophan - Tyrosine - Balin - Tyrosine - proline-serine-methionine (5- Nitro -3- pyrazolecarboxylyl - Trp - Tyr - Val - Tyr - Pro - Ser - Met ) Synthesis of

Nitro-3-pyrazolecarboxylic acid was used as an acid, and the reaction was carried out using a mass spectrometer (mass spectrometer) (85.3% Purity. R _t 19.0 min. MALDI m / z calculated for C ₅₁ H ₆₁ N ₁₁ NaO ₁₄ S ⁺ [M + Na] ⁺ 1106.41, found 1106.40).

Manufacturing example  3. Isonicotinyl - Trp - Tyr - Val - Dpr ( acyl ) - Pro - Ser - Met Synthesis of

After identifying additional binders at the NH ₂ end, the tyrosine moiety with weaker binding was altered as a result of alanine scanning mutagenesis. It was decided to introduce a linker at the position of tyrosine to increase the binding force and it was found that the amine of one of the diamines was protected by 4-methyltrityl (Mtt) group Diaminopropionic acid (Fmoc-Dpr (Mtt) -OH). The 4-methyltrityl (Mtt) group was dissolved in CH ₂ Cl ₂ containing 1% TFA Lt; RTI ID = 0.0 > acid < / RTI > conditions. In order to establish the removal conditions, the amount of Mtt-OH remaining in each filtrate was determined by HPLC (FIG. 2) while repeating the same deprotection procedure five times. At this time, butylated hydroxytoluene (BHT, 2,6-di- tert- butyl-4-methylphenol) was added as an internal standard. After 5 cuttings, it was confirmed that 61.7%, 28.6%, 8.5%, 1.1%, and 0.1% of Mtt-OH were removed, and the removal rate was measured as a ratio to an internal standard and an area of BHT (Table 2). As a result, it was confirmed that 98.8% of the Mtt group was selectively removed while 3-times treatment with 1% TFA retained the protecting groups of the amino acid residues. TIS (triisopropylsilane, Sigma-Aldrich) was added to the 1% TFA solution to stabilize the cation of the Mtt group.

After selective removal of the Mtt protecting group was established, it was synthesized by Fmoc-based SPPS method using Wang resin. In order to increase the productivity, some experimental conditions such as coupling reagents, their equivalents and reaction times were adjusted. Especially, HBTU was used in place of HCTU or PyBOP because it was confirmed on HPLC system that less byproducts were produced when HBTU was used.

8 residues of methionine, serine, proline, Fmoc-Dpr (Mtt) -OH, valine, tyrosine, tryptophan (Trp) and isonicotinic acid Were sequentially loaded onto Wang resin and the Mtt group of the Dpr residue was removed by treatment with CH ₂ Cl ₂ containing 1% TFA and 5% TIS and the protected amine was removed by treatment with 44 Acetic acid. Subsequently, all protecting groups of the peptide and the resin were removed by treatment with 94% TFA and the synthesized compounds were analyzed by HPLC. Two peaks were observed on HPLC and as a result of MALDI-TOF, the former peak was of the sulfur-oxidized compound of methionine and the latter peak was the unoxidized compound.

82 compounds were synthesized (6 to 87) in the same manner as above, and the compounds produced by mass spectrometry (MS) were identified, and some compounds were further confirmed by ¹ H NMR.

3-1. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (3,5- Dimethylbenzoyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (3,5- dimethylbenzoyl ) - Pro - Ser - Met (O)

In the same manner as in the synthesis of dTBP2 in Preparation Example 1, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) -proline-serine-methionine was synthesized in a solid phase and then the diaminopropionic acid- The resin (25 mg, 0.011 mmol) was added to a 1 mL Micro Bio-Spin chromatography column equipped with a filter, swelled in CH ₂ Cl ₂ for 30 minutes, and then CH ₂ Cl ₂ was removed using argon gas pressure. After the addition of the removed 1% TFA (TFA: TIS: DCM, 1: 5: 94, 0.66 mL), the mixture was mixed for 2 minutes using an orbital shaker (130 rpm) The% TFA solution was removed and the procedure was repeated three times. The resin was washed three times with CH ₂ Cl ₂ , once with anhydrous DMF, and then swelled with anhydrous DMF for 30 minutes.

HBTU (8.0 eq., 33.4 mg, 0.088 mmol) and HOBt (0.08 mmol) were added in order to couple 3,5-dimethylbenzoic acid to the amine from which the Mtt group of diaminopropionic acid was removed. .H ₂ O (8.0 equiv, 13.5 mg, 0.088 mmol), 3,5- dimethyl-benzoic acid (3,5-dimethylbenzoic acid) (8.0 equiv, 13.2 mg, 0.088mmol), DIPEA (8.0 equiv., 15.4μL, 0.088 mmol ) And anhydrous DMF (0.5 mL) according to the method of Preparation Example 1-2. To the resulting peptide (25 mg, 0.011 mmol) was added 94% TFA cocktail (0.5 mL), which had been degassed. The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was washed with TFA (0.3 mL> 2) I received the payment. The supernatant was collected, and TFA was removed using an evaporator, followed by decantation three times using cold ether. After drying under high pressure, the residue was purified by semi-preparative HPLC (binary solvent system, solvent A: 0.1% TFA / H ₂ O, solvent B: 0.1% TFA / CH ₃ CN, 5-100% B over 42 min), and lyophilized, followed by mass spectrometry (MS), and further confirmed by ¹ H NMR.

97.0% Purity. R _t 22.6 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ10.73 (d, 1H, J = 2.0), 9.10 (s, 1H), 8.78 (d, 1H, J = 8.4), 8.67 (dd, 2H, J = 4.4, J = 1.6) , 8.33 (t, 1H, J = 6.0), 8.21 (d, 2H, J = 8.0), 8.06 (dd, 1H, J = 7.6, J = 3.6), 8.00 (dd, 1H, J = 7.6, J = 3.2), 7.80 (d, 1H, J = 8.4), 7.65 (d, 1H, J = 8.0), 7.63 (dd, 2H, J = 4.4, J = 1.6), 7.45 ( s, 2H), 7.29 (d , 1H, J = 8.0), 7.14 (d, 1H, J = 2.0), 7.13 (s, 1H), 7.03 (t, 1H, J = 8.0), 7.01 (d, 2H , J = 8.4), 6.95 ( t, 1H, J = 8.0), 6.57 (d, 2H, J = 8.4), 4.75-4.67 (m, 2H), 4.52 (td, 1H, J = 8.4, J = 4.0 ), 4.42 (m, 1H), 4.31-4.25 (m, 2H), 4.21 (dd, 1H, J = 8.4, J = 7.2), 3.68-3.54 -3.23 (m, 2H), 3.15 (dd, 1H, J = 14.4, J = 4.0), 3.05 (dd, 1H, J = 14.4, J = 10.4), 2.91 (dd, 1H, J = 13.6, J = 2H), 0.84 (d, 3H, m), 2.80-2.57 (m, 3H) J = 6.8), 0.81 (d, 3H, J = 6.8). MALDI m / z calculated for C ₅₆ H ₆₈ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1143.46, found 1143.43.

3-2. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (3,5- Dimethylbenzoyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (3,5- dimethylbenzoyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in the above step 3-1, and the compound produced by mass spectrometry (MS) was identified and further confirmed by ¹ H NMR.

98.0% Purity. R _t 24.8 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ 12.70 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.10 (brs, 1H), 8.82 (d, 1H, J = 8.8), 8.70 (d, 2H, J = 5.6), 8.32 (t, 1H, J = 6.4), 8.22 (d, 1H, J = 8.0), 8.20 (d, 1H, J = 6.8), 8.08 (d, 1H, J = 8.0), 7.93 (d , 1H, J = 8.0), 7.79 (d, 1H, J = 8.4), 7.68 (dd, 2H, J = 5.6, J = 1.6), 7.66 (d, 1H, J = 8.0), 7.45 (s, 2H ), 7.29 (d, 1H, J = 8.0), 7.14 (d, 1H, J = 2.0), 7.13 (s, 1H), 7.03 (t, 1H, J = 8.0), 7.01 (d, 2H, J = 8.4), 6.95 (t, 1H, J = 8.0), 6.57 (d, 2H, J = 8.4), 4.73 (m, 1H), 4.66 (q, 1H, J = 6.8) , 4.52 (td, 1H, J = 8.8, J = 4.0), 4.43 (dd, 1H, J = 8.0, J = 4.0), 4.34-4.28 (m, 2H), 4.20 (dd, 1H, J = 8.4, J = 7.2), 3.63-3.43 (m , 7H), 3.16 (dd, 1H, J = 14.8, J = 4.0), 3.05 (dd, 1H, J = 14.8, J = 10.8), 2.91 (dd, 1H, J = 14.0, J = 4.0) , 2.72 (dd, 1H, J = 14.0, J = 9.6), 2.52-2.38 (m, 2H), 2.27 (s, 6H), 2.07-1.75 (m, 7H), 2.00 (s, 3H), 0.84 (d, 3H, J = 6.8), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C ₅₆ H ₆₈ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1127.46, found 1127.43.

3-3. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (Alpha- Cyano -4- Hydroxycin Nylon) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (? cyano  -4- hidroxycinnamyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as the above-mentioned 3-1, and α-cyano-4-hydroxycinnamic acid was used as an acid for coupling. The compound was identified by mass spectrometry (MS) and further confirmed by ¹ H NMR.

99.9% Purity. R _t 17.2 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ12.84 (brs, 1H), 10.73 (s, 1H), 10.59 (brs, 1H), 9.10 (brs, 1H), 8.80 (d, 1H, J = 8.4), 8.69 (dd, 2H, J = 4.4, J = 1.6), 8.28-8.22 (m, 2H), 8.19 (d, 1H, J = 6.8), 8.10 (s, 1H), 8.05-8.01 ( m, 2H), 7.86 (d , 2H, J = 8.8), 7.80 (d, 1H, J = 8.8), 7.67 (dd, 2H, J = 4.4, J = 1.6), 7.65 (d, 1H, J = 8.0), 7.29 (d, 1H , J = 8.0), 7.14 (d, 1H, J = 2.0), 7.04 (t, 1H, J = 8.0), 7.03 (d, 2H, J = 8.0), 6.95 (t , 1H, J = 8.0), 6.91 (d, 2H, J = 8.8), 6.56 (d, 2H, J = 8.0), 4.75-4.65 (m, 2H), 4.52 (td, 1H, J = 8.4, J = 4.0), 4.42-4.32 (m, 2H), 4.28-4.18 (m, 2H), 3.64-3.45 (m, 7H), 3.15 (dd, 1H, J = 14.4, J = 4.0), 3.05 (m, 1H), 2.93 (dd, 1H , J = 14.4, J = 4.0), 2.80-2.60 (m, 3H), 2.53 (s, 3H), 2.15-1.75 (m, 7H), 0.85 (d, 3H, J = 6.8), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C ₅₇ H ₆₅ N ₁₁ NaO ₁₄ S ⁺ [M + Na] ⁺ 1182.43, found 1182.32.

3-4. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (Alpha- Cyano -4- Hydroxycin Nylon) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (? cyano  -4- hidroxycinnamyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-3 above. Mass spectrometry (MS) was confirmed and further confirmed by ¹ H NMR.

99.9% Purity. R _t 19.3 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ12.73 (brs, 1H), 10.73 (s, 1H), 10.59 (brs, 1H), 9.10 (brs, 1H), 8.80 (d, 1H, J = 8.0), 8.69 (d, 2H, J = 4.4), 8.28-8.22 (m, 2H), 8.18 (d, 1H, J = 6.8), 8.10 (s, 1H), 8.04 (d, 1H, J = 7.6), 7.91 (d, 1H , J = 7.6), 7.86 (d, 2H, J = 8.8), 7.81 (d, 1H, J = 8.8), 7.67-7.65 (m, 3H), 7.29 (d, 1H , J = 8.0), 7.14 ( d, 1H, J = 2.0), 7.04 (t, 1H, J = 8.0), 7.01 (d, 2H, J = 8.4), 6.95 (t, 1H, J = 8.0), 1H, J = 8.0, J = 8.4), 6.91 (d, 2H, J = 8.8), 6.57 (d, 2H, J = 8.4), 4.75-4.67 3.6), 4.34 (m, 1H ), 4.27 (m, 1H), 4.20 (dd, 1H, J = 8.8, J = 6.8), 3.64-3.35 (m, 7H), 3.15 (dd, 1H, J = 15.2 , J = 3.6), 3.05 ( dd, 1H, J = 15.2, J = 10.4), 2.92 (dd, 1H, J = 14.0, J = 4.4), 2.73 (dd, 1H, J = 14.0, J = 10.4) 3H), 1.91-1.75 (m, 4H), 0.85 (d, 3H, J = 6.8), 0.82 (d, 2H), 2.53-2.38 3H, J = 6.8). MALDI m / z calculated for C ₅₇ H ₆₅ N ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1166.44, found 1166.38.

3-5. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (4- Pentyl bicyclo [2.2.2] octane -One- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (4-pentylbicyclo [2.2.2] octane -One- carboxylyl ) - Pro - Ser - Met (O)

Synthesis was carried out in the same manner as in 3-1 above except that 4-pentylbicyclo [2.2.2] octane-1-carboxylic acid (4-pentylbicyclo [2.2.2] -carboxylic acid) was used. The compound was identified by mass spectrometry (MS) and further confirmed by ¹ H NMR.

99.9% Purity. R _t 27.2 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ12.86 (brs, 1H), 10.73 (s, 1H), 9.09 (brs, 1H), 8.82 (d, 1H, J = 8.4), 8.70 (dd , 2H, J = 4.4, J = 1.6), 8.23 (d, 1H, J = 8.0), 8.08 (d, 1H, J = 6.4), 8.03 (d, 1H, J = 6.4), 7.92 (dd, 1H , J = 8.0, J = 4.0 ), 7.79 (d, 1H, J = 8.8), 7.68 (dd, 2H, J = 4.4, J = 1.6), 7.66 (d, 1H, J = 8.0), 7.29 (d , 1H, J = 8.0), 7.27 (t, 1H, J = 6.0). 7.14 (d, 1H, J = 2.4), 7.04 (t, 1H, J = 8.0), 7.03 (d, 2H, J = 8.4), 6.96 (t, 1H, J = 8.0), 6.57 (d, 2H, J = 8.4), 4.73 (m , 1H), 4.60-4.51 (m, 2H), 4.38-4.30 (m, 2H), 4.25 (m, 1H), 4.19 (dd, 1H, J = 8.8, J = 6.4 ), 3.62-3.37 (m, 7H) , 3.16 (dd, 1H, J = 14.4, J = 7.6), 3.05 (dd, 1H, J = 14.4, J = 10.4), 2.93 (dd, 1H, J = 13.6 , J = 4.0), 2.83-2.60 ( m, 3H), 2.52 (s, 3H), 2.12 (m, 1H), 2.02-1.80 (m, 6H), 1.60-1.56 (m, 6H), 1.29-1.20 (m, 8H), 1.18-1.06 ( m, 4H), 1.00-0.96 (m, 2H), 0.84 (d, 3H, J = 6.8), 0.83 (t, 3H, J = 6.8), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C ₆₁ H ₈₂ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1217.57, found 1217.38.

3-6. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (4- Pentyl bicyclo [2.2.2] octane -One- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (4-pentylbicyclo [2.2.2] octane -One- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as 3-5 above, and the compound produced by mass spectrometry (MS) was identified and further confirmed by ¹ H NMR.

99.9% Purity. R _t 29.9 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ12.76 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.10 (brs, 1H), 8.81 (d, 1H, J = 8.0) , 8.70 (dd, 2H, J = 4.4, J = 1.6), 8.23 (d, 1H, J = 8.0), 8.08 (d, 1H, J = 6.4), 7.94 (d, 2H, J = 8.0), 7.79 (d, 1H, J = 8.8 ), 7.68 (dd, 2H, J = 4.4, J = 1.6), 7.66 (d, 1H, J = 7.6), 7.29 (d, 1H, J = 7.6), 7.26 (t , 1H, J = 6.4), 7.14 (d, 1H, J = 2.0), 7.04 (t, 1H, J = 7.6), 7.03 (d, 2H, J = 8.8), 6.95 (t, 1H, J = 7.6 ), 6.58 (d, 2H, J = 8.8), 4.73 (m, 1H), 4.58-4.51 (m, 2H), 4.38-4.31 , J = 8.4, J = 6.4 ), 3.64-3.35 (m, 7H), 3.16 (dd, 1H, J = 14.8, J = 3.2), 3.05 (dd, 1H, J = 14.8, J = 10.4), 2.93 (dd, 1H, J = 14.4 , J = 3.6), 2.74 (dd, 1H, J = 14.4, J = 10.4), 2.52-2.40 (m, 2H), 2.02 (s, 3H), 2.00-1.78 (m , 7H), 1.61-1.57 (m, 6H), 1.29-1.22 (m, 8H), 1.19-1.05 (m, 4H), 1.01-0.97 (m, 2H), 0.84 (d, 3H, J = 6.8) , 0.83 (t, 3H, J = 7.2), 0.82 (d, 3H, J = 6.8). MALDI m / z calculated for C ₆₁ H ₈₂ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1201.57, found 1201.43.

3-7. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (2- (2- Cyanophenylthio ) Benzoyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- (2- cyanophenylthio ) benzoyl ) - Pro - Ser - Met (O)

2- (2-cyanophenylthio) benzoic acid was used as the acid for coupling, and was synthesized using the same method as the above-mentioned 3-1. The compound was identified by mass spectrometry (MS) and further confirmed by ¹ H NMR.

99.9% Purity. R _t 23.4 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ12.89 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.10 (brs, 1H), 8.83 (d, 1H, J = 8.0) , 8.70 (d, 2H, J = 6.0), 8.45 (t, 1H, J = 6.0), 8.25 (d, 2H, J = 8.0), 8.05 (d, 1H, J = 8.4), 7.98 (dd, 1H , J = 8.0, J = 2.0 ), 7.93 (dd, 1H, J = 8.0, J = 0.8), 7.81 (d, 1H, J = 8.8), 7.68 (dd, 2H, J = 6.0, J = 2.0) , 7.66-7.64 (m, 2H), 7.63 (d, 1H, J = 7.2), 7.53 (t, 1H, J = 8.0), 7.45 (dd, 1H, J = 8.0, J = 0.8), 7.39-7.32 (m, 2H), 7.29 ( d, 1H, J = 8.0), 7.14 (d, 1H, J = 2.0), 7.03 (t, 1H, J = 8.0), 7.02 (d, 2H, J = 8.4), 1H, J = 8.8, J = 4.0), 4.40 (m, IH), 6.97-6.93 (m, 2H), 6.58 (d, 2H, J = 8.4), 4.81-4.71 , 4.34 (m, 1H), 4.29-4.23 (m, 2H), 3.69-3.30 (m, 7H), 3.17 (dd, 1H, J = 14.8, J = 4.0), 3.06 (dd, 1H, J = 14.8 , J = 10.4), 2.93 ( dd, 1H, J = 14.4, J = 4.0), 2.82-2.59 (m, 3H), 2.51 (s, 3H), 2.11 (m, 1H), 2.03-1.93 (m, 3H), 1.91-1.77 (m, 3H), 0.85 (d, 3H, J = 6.8), 0.83 (d, 3H, J = 6.8). MALDI m / z calculated for C ₆₁ H ₆₇ N ₁₁ NaO ₁₃ S ²⁺ [M + Na] ⁺ 1248.43, found 1248.44.

3-8. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (2- (2- Cyanophenylthio ) Benzoyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- (2- cyanophenylthio ) benzoyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as the above 3-7, and the compound produced by mass spectrometry (MS) was identified and further confirmed by ¹ H NMR.

99.9% Purity. R _t 25.4 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ12.73 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.09 (brs, 1H), 8.82 (d, 1H, J = 8.4) , 8.70 (d, 2H, J = 6.0), 8.44 (t, 1H, J = 6.0), 8.30-8.22 (m, 2H), 8.00 (d, 1H, J = 8.0), 7.95 (d, 1H, J = 8.0), 7.93 (d, 1H, J = 8.0), 7.81 (d, 1H, J = 8.8), 7.67 (dd, 2H, J = 6.0, J = 1.6), 7.66-7.64 (m, 2H), 7.63 (td, 1H, J = 7.6, J = 1.6), 7.53 (td, 1H, J = 8.0, J = 1.2), 7.44 (d, 1H, J = 8.0), 7.37 (td, 1H, J = 7.6 , J = 1.6), 7.33 ( dd, 1H, J = 8.0, J = 1.2), 7.29 (d, 1H, J = 8.0), 7.14 (d, 1H, J = 2.0), 7.04 (t, 1H, J = 8.0), 7.03 (d, 2H, J = 8.0), 6.99-6.93 (m, 2H), 6.58 (d, 2H, J = 8.0), 4.80-4.71 (m, 2H), 4.53 (td, 1H, J = 8.8, J = 4.0) , 4.40 (dd, 1H, J = 8.4, J = 3.6), 4.33 (m, 1H), 4.29-4.23 (m, 2H), 3.68-3.63 (m, 2H), 3.62 -3.45 (m, 5H), 3.17 (dd, 1H, J = 14.8, J = 3.6), 3.06 (dd, 1H, J = 14.8, J = 10.4), 2.93 (dd, 1H, J = 14.4, J = 3.6), 2.73 (dd, 1H , J = 14.4, J = 10.0), 2.52-2.39 (m, 2H), 2.36-1.94 (m, 3H), 2.01 (s, 3H), 1.88-1.76 (m, 4H ), 0.85 (d, 3H, J = 6.8), 0 .83 (d, 3H, J = 6.8). MALDI m / z calculated for C ₆₁ H ₆₇ N ₁₁ NaO ₁₂ S ₂ ⁺ [M + Na] ⁺ 1232.43, found 1232.53.

3-9. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Phenoxyacetyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( 폴리oxyacetyl ) - Pro - Ser - Met (O)

Synthesis was carried out in the same manner as in 3-1 above, and phenoxyacetic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 15.8 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₅ H ₆₆ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1145.44, found 1145.03.

3-10. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Phenoxyacetyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( 폴리oxyacetyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as 3-9 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 17.7 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₅ H ₆₆ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1129.44, found 1129.08.

3-11. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Hexenoyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- hexynoyl ) - Pro - Ser - Met (O)

2-hexynoic acid was used as the acid for coupling. The reaction was carried out in the same manner as in 3-1 above except that 2-hexynoic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

97.4% Purity. R _t 15.5 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₃ H ₆₆ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1105.44, found 1105.15.

3-12. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Hexenoyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- hexynoyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-11 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 17.4 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₃ H ₆₆ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1089.45, found 1089.51.

3-13. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Orotile ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( orotyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as in the above 3-1, and orotic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

88.0% Purity. R _t 12.9 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₂ H ₆₂ N ₁₂ NaO ₁₅ S ⁺ [M + Na] ⁺ 1149.41, found 1149.37.

3-14. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Orotile ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( orotyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-13 above, and the compound produced by mass spectrometry (MS) was confirmed.

93.6% Purity. R _t 14.8 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₂ H ₆₂ N ₁₂ NaO ₁₄ S ⁺ [M + Na] ⁺ 1133.41, found 1133.39.

3-15. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (4- Benzyloxybenzoyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (4- benzyloxybenzoyl ) - Pro - Ser - Met (O)

4-benzyloxybenzoic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above, except that 4-benzyloxybenzoic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 17.9 min (5-100% B over 36 min). MALDI m / z calculated for C ₆₁ H ₇₀ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1221.47, found 1221.41.

3-16. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (4- Benzyloxybenzoyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (4- benzyloxybenzoyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-15 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 19.7 min (5-100% B over 36 min). MALDI m / z calculated for C ₆₁ H ₇₀ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1205.47, found 1205.42.

3-17. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Naphtoole ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- naphthoyl ) - Pro - Ser - Met (O)

2-naphthoic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above except that 2-naphthoic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 16.5 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1165.44, found 1165.42.

3-18. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Naphtoole ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- naphthoyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-17, and the compound was confirmed by mass spectrometry (MS).

99.9% Purity. R _t 18.3 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1149.45, found 1149.40.

3-19. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Pyrazine carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- pyrazine carboxylyl ) - Pro - Ser - Met (O)

2-pyrazine carboxylic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above, except that 2-pyrazine carboxylic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 13.7 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₂ H ₆₂ N ₁₂ NaO ₁₃ S ⁺ [M + Na] ⁺ 1117.42, found 1117.39.

3-20. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Pyrazine carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- pyrazine carboxylyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-19 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 15.5 min (5-100% B over 36 min). MALDI m / z calculated for C ₅₂ H ₆₂ N ₁₂ NaO ₁₂ S ⁺ [M + Na] ⁺ 1101.42, found 1101.39.

3-21. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Chloronicotinyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- kloronicotinyl ) - Pro - Ser - Met (O)

2-chloronicotinic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above except that 2-chloronicotinic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 16.1 min. MALDI m / z calculated for C ₅₃ H ₆₂ ClN ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1150.38, found 1150.24.

3-22. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Chloronicotinyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- kloronicotinyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-21 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 18.2 min. MALDI m / z calculated for C ₅₃ H ₆₂ ClN ₁₁ NaO ₁₂ S ⁺ [M + Na] ⁺ 1134.39, found 1134.28.

3-23. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2,4- Hexadiene oil ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2,4- hexadienoyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as the above-mentioned 3-1, and sorbic acid (2,4-hexadienoic acid) was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 17.5 min. MALDI m / z calculated for C ₅₃ H ₆₆ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1105.44, found 1105.40.

3-24. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2,4- Hexadiene oil ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2,4- hexadienoyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-23 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 19.6 min. MALDI m / z calculated for C ₅₃ H ₆₆ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1089.45, found 1089.43.

3-25. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Biphenyl -4- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( biphenyl -4- carboxylyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as the above-mentioned 3-1, and biphenyl-4-carboxylic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 24.8 min. MALDI m / z calculated for C ₆₀ H ₆₈ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1191.46, found 1191.46.

3-26. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Biphenyl -4- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( biphenyl  -4- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-25 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 27.0 min. MALDI m / z calculated for C ₆₀ H ₆₈ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1175.46, found 1175.46.

3-27. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Phenylglyoxyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( phenylglyoxylyl ) - Pro - Ser - Met (O)

The compound was synthesized using the same method as the above-mentioned 3-1, and phenylglyoxylic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 21.5 min. MALDI m / z calculated for C ₅₅ H ₆₄ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1143.42, found 1143.44.

3-28. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Phenylglyoxyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( phenylglyoxylyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-27 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 23.8 min. MALDI m / z calculated for C ₅₅ H ₆₄ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1127.43, found 1127.51.

3-29. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Fluorophenylacetyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- fluorophenylacetyl ) - Pro - Ser - Met (O)

2-fluorophenylacetic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above except that 2-fluorophenylacetic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 21.5 min. MALDI m / z calculated for C ₅₅ H ₆₅ FN ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1147.43, found 1147.51.

3-30. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Fluorophenylacetyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (2- fluorophenylacetyl ) - Pro - Ser - Met )

The compound was synthesized in the same manner as in 3-29, and mass spectrometry (MS) was used to identify the compound.

99.9% Purity. R _t 23.5 min. MALDI m / z calculated for C ₅₅ H ₆₅ FN ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1131.44, found 1131.53.

3-31. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (Trans- Thinner mill ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( trans - cinnamyl ) - Pro - Ser - Met (O)

It was synthesized using the same method as 3-1, with an acid (acid) for coupling trans- the cinnamic acid (trans -cinnamic acid) was used. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 22.2 min. MALDI m / z calculated for C ₅₆ H ₆₆ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1141.44, found 1141.51.

3-32. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (Trans- Thinner mill ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( trans - cinnamyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as that of 3-31 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 24.3 min. MALDI m / z calculated for C ₅₆ H ₆₆ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1125.45, found 1125.57.

3-33. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (One- Naphtoole ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (One- naphthoyl ) - Pro - Ser - Met (O)

1-naphthoic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above except that 1-naphthoic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 21.9 min. MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1165.44, found 1165.53.

3-34. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (One- Naphtoole ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (One- naphthoyl ) - Pro - Ser - Met )

Was synthesized in the same manner as 3-33 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 24.4 min. MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1149.45, found 1149.64.

3-35. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5-nitro-2- Fouroyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- nitro -2- furoyl ) - Pro - Ser - Met (O)

5-nitro-2-furoic acid was used as the acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

93.1% Purity. R _t 20.9 min. MALDI m / z calculated for C ₅₂ H ₆₁ N ₁₁ NaO ₁₆ S ⁺ [M + Na] ⁺ 1150.39, found 1150.17.

3-36. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5-nitro-2- Fouroyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- nitro -2- furoyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-35 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 22.9 min. MALDI m / z calculated for C ₅₂ H ₆₁ N ₁₁ NaO ₁₅ S ⁺ [M + Na] ⁺ 1134.40, found 1134.23.

3-37. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (beta- Naphthoxyacetyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (β- naphthoxyacetyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as described in 3-1, and β-naphthoxyacetic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 23.7 min. MALDI m / z calculated for C ₅₉ H ₆₈ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1195.45, found 1195.18.

3-38. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (beta- Naphthoxyacetyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (β- naphthoxyacetyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-37 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 25.7 min. MALDI m / z calculated for C ₅₉ H ₆₈ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1179.46, found 1179.32.

3-39. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (3- Phenoxybenzoyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (3- phenoxybenzoyl ) - Pro - Ser - Met (O)

3-Phenoxybenzoic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above except that 3-phenoxybenzoic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

97.3% Purity. R _t 24.3 min. MALDI m / z calculated for C ₆₀ H ₆₈ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1207.45, found 1207.24.

3-40. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (3- Phenoxybenzoyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (3- phenoxybenzoyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-39 above, and the compound produced by mass spectrometry (MS) was confirmed.

98.2% Purity. R _t 26.3 min. MALDI m / z calculated for C ₆₀ H ₆₈ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1191.46, found 1191.30.

3-41. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (7- 메틸oxy -One- benzofuran -2- carboxylyl ) - Pro - Ser - Met (O)

7-methoxy-1-benzofuran-2-carboxylic acid as an acid for coupling was synthesized using the same method as the above-mentioned 3-1. Respectively. A mass spectrometry (MS) was used to identify the resulting compound.

97.6% Purity. R _t 22.3 min. MALDI m / z calculated for C ₅₇ H ₆₆ N ₁₀ NaO ₁₅ S ⁺ [M + Na] ⁺ 1185.43, found 1185.34.

3-42. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (7- 메틸oxy -One- benzofuran -2- carboxylyl ) - Pro - Ser - Met )

Was synthesized in the same manner as in 3-41 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 24.4 min. MALDI m / z calculated for C ₅₇ H ₆₆ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1169.44, found 1169.40.

3-43. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Methoxyhexanoyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- methylhexanoyl ) - Pro - Ser - Met (O)

2-methoxyhexanoic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above, except that 2-methylhexanoic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

95.7% Purity. R _t 22.4 min. MALDI m / z calculated for C ₅₄ H ₇₂ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1123.49, found 1123.53.

3-44. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Methoxyhexanoyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- methylhexanoyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-43 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 24.8 min. MALDI m / z calculated for C ₅₄ H ₇₂ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1107.49, found 1107.53.

3-45. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (3- Chlorobenzo [b] thiophene Carboxylic < / RTI > yl) -proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (3- chlorobenzo [b] thiophene-2- carboxylyl ) - Pro - Ser - Met (O)

3-chlorobenzo [b] thiophene-2-carboxylic acid was used as the acid for coupling, and 3-chlorobenzo [b] thiophene- Respectively. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 23.1 min. MALDI m / z calculated for C ₅₆ H ₆₃ ClN ₁₀ NaO ₁₃ S ₂ ⁺ [M + Na] ⁺ 1205.36, found 1205.36.

3-46. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (3- Chlorobenzo [b] thiophene Carboxylic < / RTI > yl) -proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (3- chlorobenzo [b] thiophene-2- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as the above 3-45, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 25.1 min. MALDI m / z calculated for C ₅₆ H ₆₃ ClN ₁₀ NaO ₁₂ S ₂ ⁺ [M + Na] ⁺ 1189.36, found 1189.47.

3-47. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Quinadil ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( quinaldyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as in the above 3-1, and quinaldic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 22.3 min. MALDI m / z calculated for C ₅₇ H ₆₅ N ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1166.44, found 1166.47.

3-48. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Quinadil ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( quinaldyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-47 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 24.0 min. MALDI m / z calculated for C ₅₇ H ₆₅ N ₁₁ NaO ₁₂ S ⁺ [M + Na] ⁺ 1150.44, found 1150.47.

3-49. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Taiglail ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( tiglyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as in the above 3-1, and tiglic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.2% Purity. R _t 20.4 min. MALDI m / z calculated for C ₅₂ H ₆₇ N ₁₀ O ₁₃ S ⁺ [M + H] ⁺ 1071.46, found 1071.56.

3-50. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Taiglail ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( tiglyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-49 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 22.3 min. MALDI m / z calculated for C ₅₂ H ₆₆ N ₁₀ NaO ₁₂ S ⁺ [M + Na] ⁺ 1077.45, found 1077.51.

3-51. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Isonicotinyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( isonicotinyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as the above 3-1, and isonicotinic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 18.0 min. MALDI m / z calculated for C ₅₃ H ₆₃ N ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1116.42, found 1116.49.

3-52. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Isonicotinyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( isonicotinyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as that of 3-51 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 19.9 min. MALDI m / z calculated for C ₅₃ H ₆₃ N ₁₁ NaO ₁₂ S ⁺ [M + Na] ⁺ 1100.43, found 1100.48.

3-53. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5- Chloroindole -2- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (5- chloroindole -2- carboxylyl ) - Pro - Ser - Met (O)

3-54. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5- Chloroindole -2- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (5- chloroindole -2- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as the above 3-53, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 25.6 min. MALDI m / z calculated for C ₅₆ H ₆₄ ClN ₁₁ NaO ₁₂ S ⁺ [M + Na] ⁺ 1172.40, found 1172.47.

3-55. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5- Phenyl -2- Fouroyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- phenyl -2- furoyl ) - Pro - Ser - Met (O)

5-phenyl-2-furoic acid was used as the acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 23.0 min. MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1181.44, found 1181.44.

3-56. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5- Phenyl -2- Fouroyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- phenyl -2- furoyl ) - Pro - Ser - Met )

Was synthesized in the same manner as in 3-55 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 25.2 min. MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₃ S ⁺ [M + Na] ⁺ 1165.44, found 1165.48.

3-57. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (5-nitro-3- Pyrazole carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- nitro -3- pyrazolecarboxylyl ) - Pro - Ser - Met (O)

5-nitro-3-pyrazolecarboxylic acid was used as the acid for coupling. The reaction was carried out in the same manner as in 3-1 above. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 20.4 min. MALDI m / z calculated for C ₅₁ H ₆₁ N ₁₃ NaO ₁₅ S ⁺ [M + Na] ⁺ 1150.40, found 1150.54.

3-58. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (5-nitro-3- Pyrazole carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- nitro -3- pyrazolecarboxylyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-57, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 22.3 min. MALDI m / z calculated for C ₅₁ H ₆₁ N ₁₃ NaO ₁₄ S ⁺ [M + Na] ⁺ 1134.41, found 1134.51.

3-59. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ((R) - (+) - Trolloxil ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (( R ) - (+) - troloxyl ) - Pro - Ser - Met (O)

6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox) was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 22.6 min. MALDI m / z calculated for C ₆₁ H ₇₆ N ₁₀ NaO ₁₅ S ⁺ [M + Na] ⁺ 1243.51, found 1243.49.

3-60. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ((R) - (+) - Trolloxil ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (( R ) - (+) - troloxyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-59, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 24.7 min. MALDI m / z calculated for C ₆₁ H ₇₆ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1227.52, found 1227.51.

3-61. Isonicotinyl - tryptophan - Tyrosine - Balin-Dpr (( R ) - (+) - 2- Pyrrolidone -5- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (( R ) - (+) - 2- 피리로드로one -5- carboxylyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as 3-1, with an acid (acid) for the coupling (R) - (+) - 2- pyrrolidone-5-carboxylic acid ((R) - (+) - 2- pyrrolidone-5-carboxylic acid. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 18.4 min. MALDI m / z calculated for C ₅₂ H ₆₅ N ₁₁ NaO ₁₄ S ⁺ [M + Na] ⁺ 1122.43, found 1122.34.

3-62. Isonicotinyl - tryptophan - Tyrosine - Balin-Dpr (( R ) - (+) - 2- Pyrrolidone -5- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (( R ) - (+) - 2- 피리로드로one -5- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-61 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 20.5 min. MALDI m / z calculated for C ₅₂ H ₆₅ N ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1106.44, found 1106.45.

3-63. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (1- Cyano -One- Cyclopropane carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (One- cyano -One- cyclopropanecarboxylyl ) - Pro - Ser - Met (O)

1-cyano-1-cyclopropanecarboxylic acid was used as an acid for coupling. The reaction was carried out in the same manner as in the above-mentioned 3-1 except that 1-cyano-1-cyclopropanecarboxylic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 19.9 min. MALDI m / z calculated for C ₅₂ H ₆₃ N ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1104.42, found 1104.43.

3-64. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (1- Cyano -One- Cycloprop Incarboxylate) - Proline-Serine-Methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (One- cyano -One- cyclopropanecarboxylyl ) - Pro - Ser - Met

Was synthesized in the same manner as in 3-63 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 22.3 min. MALDI m / z calculated for C ₅₂ H ₆₃ N ₁₁ NaO ₁₂ S ⁺ [M + Na] ⁺ 1088.43, found 1088.47.

3-65. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Rhodanin Acetyl) -proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( rhodanine -3- acetyl ) - Pro - Ser - Met (O)

Was synthesized using the same method as in the above 3-1, and rhodanine-3-acetic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 20.6 min. MALDI m / z calculated for C ₅₂ H ₆₃ N ₁₁ NaO ₁₄ S ₃ ⁺ [M + Na] ⁺ 1184.36, found 1184.36.

3-66. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Rhodanin Acetyl) -proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( rhodanine -3- acetyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-65 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 23.1 min. MALDI m / z calculated for C ₅₂ H ₆₃ N ₁₁ NaO ₁₃ S ₃ ⁺ [M + Na] ⁺ 1168.37, found 1168.43.

3-67. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (7-hydroxycoumarin-4-acetyl) -proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (7- hydroxycoumarine -4- acetyl ) - Pro - Ser - Met (O)

7-hydroxycoumarine-4-acetic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above, except that 7-hydroxycoumarine-4-acetic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

98.0% Purity. R _t 20.0 min. MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₆ S ⁺ [M + Na] ⁺ 1213.43, found 1213.35.

3-68. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (7-hydroxycoumarin-4-acetyl) -proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (7- hydroxycoumarine -4- acetyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-67 above, and the compound produced by mass spectrometry (MS) was confirmed.

96.3% Purity. R _t 22.0 min. MALDI m / z calculated for C ₅₈ H ₆₆ N ₁₀ NaO ₁₅ S ⁺ [M + Na] ⁺ 1197.43, found 1197.43.

3-69. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- (4- Methylphenylsulfonamido ) ≪ / RTI > acetyl) -prolyl-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- (4- methylphenylsulfonamido ) acetyl ) - Pro - Ser - Met (O)

2- (4-methylphenylsulfonamido) acetic acid was used as the acid for coupling, and was synthesized using the same method as in the above 3-1. A mass spectrometry (MS) was used to identify the resulting compound.

96.7% Purity. R _t 21.9 min. MALDI m / z calculated for C ₅₆ H ₆₉ N ₁₁ NaO ₁₅ S ₂ ⁺ [M + Na] ⁺ 1222.43, found 1222.45.

3-70. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- (4- Methylphenylsulfonamido ) ≪ / RTI > acetyl) -prolyl-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- (4- methylphenylsulfonamido ) acetyl ) - Pro - Ser - Met )

3-71. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (1- Acetyl piperidine -4- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (One- acetylpiperidine -4- carboxylyl ) - Pro - Ser - Met (O)

1-acetylpiperidine-4-carboxylic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above except that 1-acetylpiperidine-4-carboxylic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

98.1% Purity. R _t 18.7 min. MALDI m / z calculated for C ₅₅ H ₇₁ N ₁₁ NaO ₁₄ S ⁺ [M + Na] ⁺ 1164.48, found 1164.57.

3-72. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (1- Acetyl piperidine -4- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  (One- acetylpiperidine -4- carboxylyl ) - Pro - Ser - Met )

Was synthesized in the same manner as in 3-71 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 20.7 min. MALDI m / z calculated for C ₅₅ H ₇₁ N ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1148.48, found 1148.57.

3-73. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (1- Phenyl -5- ( Trifluoromethyl )-One H - Pyrazole -4- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr  - Val - Dpr (One- phenyl -5- ( trifluoromethyl )-One H - pyrazole -4- carboxylyl ) - Pro - Ser - Met (O)

It was synthesized using the same method as 3-1, with an acid (acid) for the coupling 1-phenyl-5- (trifluoromethyl) -1 H - pyrazole-4-carboxylic acid (1-phenyl-5 - a (trifluoromethyl) -1 H -pyrazole-4 -carboxylic acid) was used. A mass spectrometry (MS) was used to identify the resulting compound.

94.9% Purity. R _t 23.0 min. MALDI m / z calculated for C ₅₈ H ₆₅ F ₃ N ₁₂ NaO ₁₃ S ⁺ [M + Na] ⁺ 1249.44, found 1249.50.

3-74. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (1- Phenyl -5- ( Trifluoromethyl )-One H - Pyrazole -4- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr  - Val - Dpr (One- phenyl -5- ( trifluoromethyl )-One H - pyrazole -4- carboxylyl ) - Pro - Ser - Met (O)

The compound was synthesized by the same method as that of 3-73 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 25.3 min. MALDI m / z calculated for C ₅₈ H ₆₅ F ₃ N ₁₂ NaO ₁₂ S ⁺ [M + Na] ⁺ 1233.44, found 1233.52.

3-75. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Thiophene acetyl ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- thiopheneacetyl ) - Pro - Ser - Met (O)

2-thiopheneacetic acid was used as an acid for coupling. The reaction was carried out in the same manner as in 3-1 above, except that 2-thiopheneacetic acid was used as an acid for coupling. A mass spectrometry (MS) was used to identify the resulting compound.

95.6% Purity. R _t 20.9 min. MALDI m / z calculated for C ₅₃ H ₆₄ N ₁₀ NaO ₁₃ S ₂ ⁺ [M + Na] ⁺ 1135.40, found 1135.40.

3-76. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Thiophene acetyl ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- thiopheneacetyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-75 above, and the compound produced by mass spectrometry (MS) was confirmed.

97.0% Purity. R _t 23.1 min. MALDI m / z calculated for C ₅₃ H ₆₄ N ₁₀ NaO ₁₂ S ₂ ⁺ [M + Na] ⁺ 1119.40, found 1119.41.

3-77. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Benzotriazole -5- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( benzotriazole -5- carboxylyl ) - Pro - Ser - Met (O)

Benzotriazole-5-carboxylic acid as an acid for coupling was synthesized using the same method as the above-mentioned 3-1. A mass spectrometry (MS) was used to identify the resulting compound.

97.4% Purity. R _t 19.0 min. MALDI m / z calculated for C ₅₄ H ₆₃ N ₁₃ NaO ₁₃ S ⁺ [M + Na] ⁺ 1156.43, found 1156.55.

3-78. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Benzotriazole -5- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr ( benzotriazole -5- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-77 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 21.2 min. MALDI m / z calculated for C ₅₄ H ₆₃ N ₁₃ NaO ₁₂ S ⁺ [M + Na] ⁺ 1140.43, found 1140.50.

3-79. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (4-oxo-4 H - Kromen -3- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (4- oxo -4 H - chromene -3- carboxylyl ) - Pro - Ser - Met (O)

It was synthesized using the same method as 3-1, with an acid (acid) for the coupling of 4-oxo -4 H - chromen-3-carboxylic acid (4-oxo-4 H -chromene -3-carboxylic acid) Were used. A mass spectrometry (MS) was used to identify the resulting compound.

98.4% Purity. R _t 21.4 min. MALDI m / z calculated for C ₅₇ H ₆₄ N ₁₀ NaO ₁₅ S ⁺ [M + Na] ⁺ 1183.42, found 1183.48.

3-80. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (4-oxo-4 H - Kromen -3- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr (4- oxo -4 H - chromene -3- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as 3-79 above, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 23.5 min. MALDI m / z calculated for C ₅₇ H ₆₄ N ₁₀ NaO ₁₄ S ⁺ [M + Na] ⁺ 1167.42, found 1167.57.

3-81. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (4- methyl -2-oxo-2 H - Kromen -7 days jade Yl) acetyl) - proline-serine-methionine Oxidized type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  ((4- methyl -2- oxo -2 H - chromen -7- yloxy ) acetyl ) - Pro - Ser - Met (O)

2-oxo- 2H -chromen-7-yloxy) acetic acid (4-methyl-2-oxo -2 H -chromen-7-yloxy) acetic acid) was used. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 21.0 min. MALDI m / z calculated for C ₅₉ H ₆₈ N ₁₀ NaO ₁₆ S ⁺ [M + Na] ⁺ 1227.44, found 1227.51.

3-82. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (4- methyl -2-oxo-2 H - Kromen -7 days jade Yl) acetyl) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl - Trp - Tyr - Val - Dpr  ((4- methyl -2- oxo -2 H - chromen -7- yloxy ) acetyl ) - Pro - Ser - Met )

Was synthesized in the same manner as in 3-81 above, and the compound produced by mass spectrometry (MS) was confirmed.

96.4% Purity. R _t 23.0 min. MALDI m / z calculated for C ₅₉ H ₆₈ N ₁₀ NaO ₁₅ S ⁺ [M + Na] ⁺ 1211.45, found 1211.54.

Manufacturing example  4. Dpr ( acyl ) - Pro - Ser - Met Synthesis of

Since the seven amino acid residues of the compounds prepared in Preparation Example 3 do not all contribute to the same binding strength or essentially to the peptide-dTCTP binding, loose binding residues (loose binding residues) binding residues of the present invention can be cut to minimize the size of the compound without affecting the activity. For this purpose, a tetramer of the NH ₂ terminus and a tetramer of the COOH terminus, And divided into two parts (Fig. 3).

Among the compounds prepared through Preparation Example 3, the compounds that were more effective than dTBP2 showed that four acid structures were common and the remaining 11 structures were effective on either side (FIG. 4). Thus, 15 acids were selected and the compounds of Preparation Examples 4 and 5 were synthesized.

A tetramer at the COOH terminal was synthesized by coupling 15 acids with Wang resin using Fmoc-based SPPS. However, 14 compounds except rhodanine-3-acetic acid and methionine residue Of sulfur compounds were made. The production rates of the oxidized and non - oxidized form ranged from 1: 2.3 to 1: 5.6. As a result, a total of 19 compounds were synthesized (88-106).

4-1. Dpr (4- Pentyl bicyclo [2.2.2] octane -One- Carboxylate ) - proline-serine-methionine oxidized form ( Dpr (4- pentylbicyclo [2.2.2] octane-l- carboxylyl ) - Pro - Ser - Met (O)

(4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -proline-serine-methionine was synthesized in the same manner as in Preparation Example 3, and then resin (25 mg, 0.011 mmol) , And the Fmoc group was removed using 20% piperidine / anhydrous DMF (0.5 mL). The degassed 94% TFA cocktail (0.5 mL) was added thereto, and the mixture was incubated at room temperature After mixing for 1 hour, the filtrate was filtered and again washed with TFA solution (0.3 mL> 2) to receive the filtrate. The supernatant was combined, the TFA was removed using an evaporator, and decantation was performed three times using cold ether. In order to prevent the loss of the resulting compound, a centrifugal separator was used. After drying, the residue was purified by semi-preparative HPLC (solvent A: 0.1% TFA / H ₂ O, solvent B: 0.1% TFA / CH ₃ CN, -100% B over 42 min), followed by lyophilization and mass spectrometry (MS).

99.9% Purity. R _t 24.8 min. MALDI m / z calculated for C ₃₀ H ₅₂ N ₅ O ₈ S ⁺ [M + H] < ⁺ > 642.35, found 642.38

4-2. Dpr (4- Pentyl bicyclo [2.2.2] octane -One- Carboxylate ) -Prolyine-serine-methionine non-oxidized ( Dpr (4- pentylbicyclo [2.2.2] octane-l- carboxylyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as in the above 4-1, and the compound produced by mass spectrometry (MS) was identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 27.4 min. ^{1 H NMR (400 MHz, D} 2 O): δ4.62-4.56 (m, 2H), 4.52-4.47 (m, 2H), 3.97-3.89 (m, 2H), 3.80-3.73 (m, 2H), 3H), 2.07-1.92 (m, 4H), 1.79 (m, 2H), 2.66 (m, 1.70 (m, 6H), 1.46-1.39 (m, 6H), 1.32-1.08 (m, 8H), 0.85 (t, 3H, J = 6.8). ^{13 C NMR (100 MHz, D} 2 O): δ182.2, 175.2, 173.2, 171.5, 167.0, 61.3, 60.8, 56.0, 52.1, 51.1, 48.3, 41.4, 40.0, 39,4, 33.0, 30.8, 30.6, 30.3, 29.9, 29.7, 28.6, 24.8, 23.5, 22.7, 14.8, 14.0. MALDI m / z calculated for C ₃₀ H ₅₂ N ₅ O ₇ S ⁺ [M + H] < ⁺ > 626.36, found 626.38.

4-3. Dpr ( Taiglail ) - proline-serine-methionine Oxidized type  ( Dpr ( tiglyl ) - Pro - Ser  - Met (O)

Proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1 and mass spectrometry (MS) was used to synthesize Dpr ≪ / RTI >

99.9% Purity. R _t 12.2 min. _{MALDI m / z calculated for C 21} H 36 N 5 O 8 S + [M + H] < ⁺ > 518.23, found 518.27.

4-4. Dpr ( Taiglail ) - proline-serine-methionine Non-oxidizing type  ( Dpr ( tiglyl ) - Pro - Ser  - Met )

The compound was synthesized by the same method as that of 4-3 above, and the compound produced by mass spectrometry (MS) was identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 16.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ6.57 (q, 1H, J = 7.2), 4.63-4.55 (m, 3H), 4.46 (t, 1H, J = 5.6), 3.97-3.88 (m 2H), 2.40 (s, 3H), 2.32 (m, 2H) 2.12-1.98 (m, 4H), 1.86 (s, 3H), 1.81 (d, 3H, J = 7.2). ^{13 C NMR (125 MHz, D} 2 O): δ175.7, 173.8, 173.7, 171.6, 166.6, 135.2, 130.0, 61.1, 60.8, 56.0, 52.3, 52.2, 48.2, 39.5, 30.4, 29.7, 29.5, 24.9, 14.3, 13.7, 11.6. _{MALDI m / z calculated for C 21} H 36 N 5 O 7 S + [M + H] < ⁺ > 502.23, found 502.30.

4-5. Dpr (5- Chloroindole -2- Carboxylate ) - proline-serine-methionine Oxidized type  (Dpr (5- chloroindole -2- carboxylyl ) - Pro - Ser - Met (O)

Proline-serine-methionine was synthesized in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1, and a mass spectrometer (mass spectrometer) was used to synthesize Dpr (5-chloroindole- spectometry, MS).

99.9% Purity. R _t 19.4 min. MALDI m / z calculated for C ₂₅ H ₃₄ ClN ₆ O ₈ S ⁺ [M + H] ⁺ 613.18, found 613.22.

4-6. Dpr (5- Chloroindole -2- Carboxylate ) - proline-serine-methionine Non-oxidizing type  (Dpr (5- chloroindole -2- carboxylyl ) - Pro - Ser - Met )

Synthesis was carried out in the same manner as in the above 4-5, and a compound produced by mass spectrometry (MS) was identified and further confirmed by ¹ H NMR and ¹³ C NMR.

97.3% Purity. R _t 22.5 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.74 (d, 1H, J = 2.0), 7.50 (dd, 1H, J = 8.8, J = 0.4), 7.33 (dd, 1H, J = 8.8, J = 2.0), 7.07 (s , 1H), 4.70-4.63 (m, 2H), 4.48-4.42 (m, 2H), 4.00 (td, 1H, J = 14.8, J = 5.6), 3.96 (td, 1H 1H, J = 14.8, J = 5.6), 3.91 (d, 2H, J = 5.6), 3.83 (m, 1H), 3.72 (m, 1H), 2.51-2.37 4H), 1.99 (s, 3H), 1.94 (m, 1 H). ^{13 C NMR (125 MHz, D} 2 O): δ175.7, 173.8, 171.5, 166.8, 164.3, 135.4, 130.8, 128.1, 125.8, 125.3, 121.4, 113.8, 104.6, 61.0, 60.9, 56.0, 52.4, 52.0, 48.4, 39.2, 30.3, 29.7, 29.5, 24.9, 14.2. MALDI m / z calculated for C ₂₅ H ₃₄ ClN ₆ O ₇ S ⁺ [M + H] ⁺ 597.19, found 597.26.

4-7. Dpr (2- (2- Cyanophenylthio ) Benzoyl ) - proline-serine-methionine Oxidized type  (Dpr (2- (2- cyanophenylthio ) benzoyl ) - Pro - Ser - Met (O)

(2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1, (mass spectometry, MS).

99.9% Purity. R _t 19.0 min. _{MALDI m / z calculated for C 30} H 37 N 6 O 8 S 2 + [M + H] + 673.21, found 673.31.

4-8. Dpr (2- (2- Cyanophenylthio ) Benzoyl ) - proline-serine-methionine Non-oxidizing type  (Dpr (2- (2- cyanophenylthio ) benzoyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as the above 4-7, and the compound produced by mass spectrometry (MS) was identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 22.1 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.85 (d, 1H, J = 8.0), 7.67-7.35 (m, 7H), 4.66 (t, 1H, J = 5.2), 4.60 (t, 1H J = 7.2), 4.47 (dd, IH, J = 8.8, J = 4.8), 4.38 (t, IH, J = 5.6), 3.92-3.71 (m, 6H), 2.59-2.34 2.15 (m, 1 H), 2.07 (s, 3 H), 2.06 - 1.93 (m, 3 H). ¹³ C NMR (125 MHz, D ₂ O): δ 175.4, 173.6, 172.1, 171.5, 166.5, 138.7, 136.1, 134.7, 134.4, 133.8, 133.2, 132.5, 132.1, 128.9, 128.8, 128.5, 117.9, 114.5, 61.1, 60.9, 55.9, 52.1, 52.0, 48.4, 39.6, 30.3, 29.6, 29.5, 24.9, 14.3. _{MALDI m / z calculated for C 30} H 37 N 6 O 7 S 2 + [M + H] + 657.22, found 657.33.

4-9. Dpr ( Quinadil ) - proline-serine-methionine Oxidized type  ( Dpr ( quinaldyl ) - Pro - Ser - Met (O)

Proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Preparation Example 4-1. Mass spectrometry (MS) Compound.

99.9% Purity. R _t 16.2 min. MALDI m / z calculated for C ₂₆ H ₃₅ N ₆ O ₈ S ⁺ [M + H] ⁺ 591.22, found 591.25.

4-10. Dpr ( Quinadil ) - proline-serine-methionine Non-oxidizing type  ( Dpr ( quinaldyl ) - Pro - Ser - Met )

The compound was synthesized by the same method as the above 4-9, and the compound produced by mass spectrometry (MS) was confirmed.

99.9% Purity. R _t 19.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ8.61 (d, 1H, J = 8.8), 8.15 (d, 1H, J = 8.4), 8.12 (d, 1H, J = 8.8), 8.09 (d , 1H, J = 8.4), 7.95 (t, 1H, J = 8.4), 7.79 (t, 1H, J = 8.4), 4.74 (t, 1H, J = 5.6), 4.63 (m, 1H), 4.44- (M, 2H), 4.39 (m, 2H), 4.08-4.06 (m, 2H), 3.87-3.83 (m, 4H), 2.49-2.33 1.90 (m, 1 H). ^{13 C NMR (125 MHz, D} 2 O): δ175.1, 173.6, 171.5, 167.8, 166.7, 148.3, 145.6, 140.0, 131.8, 129.7, 129.3, 128.5, 128.3, 118.8, 61.0, 55.9, 52.1, 51.8, 51.7, 48.4, 39.4, 30.1, 29.7, 29.4, 24.9, 14.2. MALDI m / z calculated for C ₂₆ H ₃₅ N ₆ O ₇ S ⁺ [M + H] ⁺ 575.23, found 575.28.

4-11. Dpr (2- Fluorophenylacetyl ) - proline-serine-methionine ( Dpr  (2- fluorophenylacetyl ) - Pro - Ser - Met )

(2-fluorophenylacetyl) -proline-serine-methionine was synthesized in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1. Mass spectrometry (MS ) Were identified and further confirmed using < ¹ > H NMR and < ¹³ > C NMR.

99.9% Purity. R_t 19.1 min.^One≪ 1 > H NMR (400 MHz, D₂(M, 2H), 4.61-4.54 (m, 3H), 4.46 (t, 1H,J = 5.6), 3.94-3.61 (m, 8H), 2.66-2.51 (m, 2H), 2.38 (m, ).¹³≪ 1 > C NMR (100 MHz, D₂O): [delta] 175.3, 173.7, 171.6, 166.6, 162.3, 159.9, 132.0 (d,J _{C -F} = 3.7), 129.9 (d,J _{C -F} = 8.8), 124.8 (d,J _{C -F} = 3.6), 121.5 (d,J _{C -F} = 16.1), 115.6 (d,J _{C -F} = 21.3), 61.1, 60.9, 55.9, 51.9, 48.3, 39.5, 35.7, 35.6, 30.1, 29.6, 29.5, 24.9, 14.2. MALDI m / z calculated for C₂₄H₃₅FN₅O₇S⁺[M + H] <⁺556.22, found 556.29.

4-12. Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) - proline-serine-methionine ( Dpr  (7- 메틸oxy -One- benzofuran -2- carboxylyl ) - Pro - Ser - Met )

(7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine-methionine was synthesized in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1 , Mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 20.5 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.57 (s, 1H), 7.39 (dd, 1H, J = 8.0, J = 0.8), 7.34 (t, 1H, J = 8.0), 7.14 (dd , 1H, J = 8.0, J = 0.8), 4.70 (dd, 1H, J = 6.0, J = 4.8), 4.62 (dd, 1H, J = 8.8, J = 5.6), 4.45 (d, 1H, J = 6.0), 4.44 (dd, 1H , J = 5.2, J = 2.0), 4.05 (s, 3H), 4.02-3.95 (m, 2H), 3.89 (d, 2H, J = 5.6), 3.86-3.77 (m , 2H), 2.52-2.37 (m, 3H), 2.15-2.05 (m, 4H), 2.02 (s, 3H), 1.91 (m, ^{13 C NMR (100 MHz, D} 2 O): δ174.9, 173.4, 171.2, 166.3, 161.8, 146.8, 144.9, 144.3, 128.5, 124.9, 115.2, 112.2, 109.6, 60.8, 60.7, 56.1, 55.6, 51.8, 51.6, 48.1, 38.8, 29.9, 29.3, 29.1, 24.6, 13.9. MALDI m / z calculated for C ₂₆ H ₃₆ N ₅ O ₉ S ⁺ [M + H] ⁺ 594.22, found 594.35.

4-13. Dpr ( Orotile ) - proline-serine-methionine ( Dpr ( orotyl ) - Pro - Ser - Met )

Proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1 except that Dpr (aurotyl) -prolyl-serine-methionine was synthesized by mass spectrometry The compound was identified and further confirmed using < ¹ > H NMR and < ¹³ > C NMR.

99.9% Purity. R _t 13.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ6.37 (s, 1H), 4.69 (dd, 1H, J = 6.0, J = 3.2), 4.62 (dd, 1H, J = 8.4, J = 6.4) , 4.59 (dd, 1H, J = 9.2, J = 4.4), 4.48 (dd, 1H, J = 6.4, J = 5.2), 4.11 (dd, 1H, J = 15.2, J = 4.4), 3.96-3.81 ( 2H), 2.11 (s, 3H), 2.10-1.95 (m, 2H), 2.41 (m, 3H). ^{13 C NMR (125 MHz, D} 2 O): δ175.5, 173.9, 171.6, 166.9, 166.0, 162.6, 152.3, 144.8, 101.6, 61.0, 60.8, 56.2, 52.2, 52.1, 48.2, 39.1, 30.4, 29.6, 29.5, 25.0, 14.2. MALDI m / z calculated for C ₂₁ H ₃₂ N ₇ NaO ₉ S ⁺ [M + Na] ⁺ 580.18, found 580.22.

4-14. Dpr (One- Cyano -One- Cyclopropanecarboxylic acid ) -Proline-serine-methionine (Dpr (1- cyano -One- cyclopropanecarboxylyl ) - Pro - Ser - Met )

Proline-serine-methionine was synthesized in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 4-1, except that Dpr (1-cyano-1-cyclopropanecarboxylyl) (mass spectometry, MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 15.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ4.63-4.56 (m, 3H), 4.51 (t, 1H, J = 6.0), 3.97 (dd, 1H, J = 14.8, J = 3.6), 3.93 (m, 1H), 3.90 ( dd, 1H, J = 11.6, J = 6.0), 3.83-3.72 (m, 2H), 3.67 (dd, 1H, J = 14.8, J = 7.2), 2.69-2.54 (m , 2H), 2.40 (ddd, 1H, J = 11.6, J = 8.0, J = 6.0), 2.23 (m, 1H), 2.13 (s, 3H), 2.12-1.95 (m, 4H), 1.79-1.69 ( m, 4H). ^{13 C NMR (100 MHz, D} 2 O): δ177.9, 176.0, 174.0, 172.2, 168.5, 122.5, 63.4, 63.0, 58.2, 54.5, 54.4, 50.5, 42.2, 32.6, 31.9, 31.8, 27.2, 20.9, 20.8, 16.5, 16.4. _{MALDI m / z calculated for C 21} H 33 N 6 O 7 S + [M + H] + 513.21, found 513.23.

4-15. Dpr (Alpha- Cyano -4- Hydroxycinnamate ) -Prochlor-serine-methionine (Dpr (a- cyano -4- hidroxycinnamyl ) - Pro - Ser - Met )

Proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1, except that Dpr (alpha-cyano-4-hydroxycinnamyl) (mass spectometry, MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

83.7% Purity. R _t 18.4 min. ^{1 H NMR (400 MHz, D} 2 O): δ8.12 (s, 1H), 7.94 (d, 2H, J = 8.8), 7.03 (d, 2H, J = 8.8), 4.80-4.60 (m, 2H ), 4.53-4.46 (m, 2H) , 3.99 (dd, 1H, J = 15.2, J = 4.4), 3.91-3.87 (m, 2H), 3.86-3.75 (m, 3H), 2.55-2.39 (m, 3H), 2.14-2. 07 (m, 2H), 2.06 (s, 3H), 2.04-1.96 (m, 3H). ^{13 C NMR (100 MHz, D} 2 O): δ173.6, 171.6, 166.5, 165.6, 161.1, 153.9, 134.0, 123.9, 117.1, 116.5, 116.1, 99.6, 61.0, 60.9, 55.9, 51.9, 51.8, 48.3, 39.8, 30.2, 29.6, 29.4, 24.9, 14.2. MALDI m / z calculated for C ₂₆ H ₃₅ N ₆ O ₈ S ⁺ [M + H] < ⁺ > 591.22, found 591.22.

4-16. Dpr (3,5- Dimethylbenzoyl ) - proline-serine-methionine ( Dpr  (3,5- dimethyl benzoyl ) - Pro - Ser - Met )

(3,5-dimethylbenzoyl) -proline-serine-methionine was synthesized in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1. Mass spectrometry (MS ). ≪ / RTI >

99.9% Purity. R _t 21.1 min. _{MALDI m / z calculated for C 25} H 38 N 5 O 7 S + [M + H] + 552.25, found 552.28.

4-17. Dpr ((R) - (+) - Trolloxil ) - proline-serine-methionine ( Dpr  ((R) - (+) - troloxyl) - Pro - Ser - Met )

Proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1 except that Dpr ((R) - (+) - mass spectometry, MS).

99.9% Purity. R _t 21.3 min. _{MALDI m / z calculated for C 30} H 46 N 5 O 9 S + [M + H] + 652.30, found 652.40.

4-18. Dpr (2- (4- Methylphenylsulfonamido ) Acetyl) -proline-serine-methionine (Dpr (2- (4- methylphenylsulfonamido ) acetyl ) - Pro - Ser - Met )

Proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1, except that Dpr (2- (4-methylphenylsulfonamido) (mass spectometry, MS).

99.9% Purity. R _t 20.0 min. MALDI m / z calculated for C ₂₅ H ₃₉ N ₆ O ₉ S ₂ ⁺ [M + H] ⁺ 631.22, found 631.34.

4-19. Dpr (5-nitro-3- Pyrazole carboxylate ) -Proline-serine-methionine (Dpr (5- nitro -3- pyrazolecarboxylyl ) - Pro - Ser - Met )

(5-nitro-3-pyrazolecarboxylyl) -proline-serine-methionine was synthesized as a solid in the same manner as in Preparation Example 3, and then synthesized in the same manner as in Production Example 4-1, mass spectometry, MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 17.2 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.56 (s, 1H), 4.71 (dd, 1H, J = 6.4, J = 4.0), 4.65 (dd, 1H, J = 8.8, J = 6.0) , 4.53 (dd, IH, J = 8.8, J = 4.4), 4.49 (t, IH, J = 5.6), 4.09 (dd, IH, J = 14.8, J = 4.0), 3.96-3.82 , 3.75 (m, 1H), 2.63-2.48 (m, 2H), 2.35 (m, 1H), 2.18 (m, 1H), 2.09 (s, 3H), 2.07-1. ^{13 C NMR (125 MHz, D} 2 O): δ175.9, 173.9, 171.4, 166.3, 160.5, 155.8, 138.6, 102.6, 61.1, 60.8, 56.1, 52.6, 52.1, 48.3, 38.9, 30.5, 29.7, 29.5, 25.0, 14.2. _{MALDI m / z calculated for C 20} H 31 N 8 O 9 S + [M + H] + 559.19, found 559.18.

Manufacturing example  5. Isonicotinic - Trp - Tyr - Val - Dpr ( acyl ) Synthesis of

Synthesis of isonicotinic-Trp-Tyr-Val-Dpr (acyl) was generally carried out under the conditions of Preparation Example 4, but the size of the Mtt protecting group was large. Thus, Fmoc-Dpr (Mtt) anhydride (85.8%) using HBTU as the coupling reagent rather than loading it into the resin (79.2%) was more efficient and loaded with the latter method.

Synthesis of Isonicotinic-Trp-Tyr-Val-Dpr (acyl) was also carried out by using Fmoc-based SPPS in Wang resin. Of the 15 acids, 14 acids except α-cyano-4-hydroxy cinnamic acid ) Coupled compound (107-120).

5-1. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Orotile ) ( Isonicotinyl - Trp - Tyr - Val -Dpr ( orotyl )

Wang resin LL (100-200 mesh, 500 mg, 0.44 mmol / g, 0.22 mmol) was added to a 20 mL TORVIQ PP syringe equipped with a filter and anhydrous DMF was added to swell for 30 minutes and then drained. (5.0 eq, 614.0 mg, 1.1 mmol), HBTU (5.0 eq, 417 mg, 1.1 mmol), HOBt.H ₂ O (5.0 eq, 169 mg, 1.1 mmol), DIPEA (10.0 0.38 mL, 2.2 mmol) was dissolved in anhydrous DMF (10.0 mL), and the mixture was stirred for 3 minutes to be added to the swollen resin. The mixture was stirred for 3 hours using an orbital shaker (130 rpm) After draining, it was washed with DMF, iPrOH and CH ₂ Cl ₂ (15 mL>1m> 3, respectively). As a result of Fmoc quantification using a UV spectrophotometer, the loading level was 71.7%. The reaction was repeated twice (85.8%) to increase the loading level.

The isonicotinyl-tryptophan-tyrosine-valine-Dpr (aurothyl) was synthesized as a solid in the same manner as in Preparation Example 3, assuming that the concentration of the resin was 0.4 mmol by calculating the loading level at 90% To the resin (35 mg, 0.0154 mmol) was added 94% TFA cocktail (0.7 mL), which had been degassed. After mixing for 1 hour at room temperature, the filtrate was filtered and washed again with TFA solution (0.4 mL> 2) I received the filtrate. The supernatant was combined, the TFA was removed using an evaporator, and decantation was performed three times using cold ether. In this case, we used a centrifugal separator in order to prevent loss of the resulting compound, and then high-pressure drying semi-preparative HPLC (binary solvent system , solvent A: 0.1% TFA / H 2 O, solvent B: 0.1% TFA / CH 3 CN, 5 -100% B over 42 min), and then lyophilized and identified by mass spectrometry and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 19.2 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ11.34 (brs, 1H), 10.75 (brs, 1H), 10.74 (brs, 1H), 8.81 (d, 1H, J = 8.4), 8.77 (t , 1H, J = 5.6), 8.71 (brs, 2H), 8.27 (d, 1H, J = 7.6), 8.24 (d, 1H, J = 8.4), 7.92 (d, 1H, J = 8.0), 7.69 ( d, 2H, J = 5.2) , 7.65 (d, 1H, J = 7.6), 7.29 (d, 1H, J = 7.6), 7.15 (d, 1H, J = 2.0), 7.05 (m, 1H), 7.03 (d, 2H, J = 8.4), 6.95 (t, IH, J = 7.6) (T, 1H, J = 7.6, J = 6.8), 4.18 (m, 1H), 6.57 (d, 2H, J = 8.4), 6.04 , 1H, J = 8.0), 3.65-3.55 (m, 2H, identified from HSQC), 3.17 (dd, 1H, J = 14.4, J = 3.6), 3.06 (dd, 1H, J = 14.4, J = 10.4) , 2.94 (dd, 1H, J = 14.0, J = 3.6), 2.73 (dd, 1H, J = 14.0, J = 8.4), 2.00 (m, 1H), 0.89 (d, 3H, J = 6.4), 0.86 (d, 3H, J = 6.4). ^{13 C NMR (100 MHz, DMSO-} d 6): δ171.4, 171.3, 171.2, 170.9, 164.4, 164.3, 160.5, 155.7, 150.8, 149.5, 145.0, 141.6, 136.0, 130.2, 127.8, 127.2, 123.6, 121.7 , 120.9, 118.5, 118.2, 114.8, 111.3, 110.3, 100.1, 57.8, 54.2, 54.1, 51.3, 40.3, 36.3, 30.6, 27.3, 19.1, 18.1. MALDI m / z calculated for C ₃₉ H ₄₁ N ₉ NaO ₁₀ ⁺ [M + Na] < ⁺ > 818.29, found 818.58.

5-2. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (3,5- Dimethylbenzoyl ) (Isonicotinyl-Trp-Tyr-Val-Dpr (3,5-dimethyl benzoyl ))

Isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) was synthesized as a solid in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 5-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 24.7 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ10.74 (d, 1H, J = 2.0), 8.87 (d, 1H, J = 8.0), 8.74 (brs, 2H), 8.40 (t, 1H, J = 5.6), 8.29 (d , 1H, J = 6.8), 8.21 (d, 1H, J = 8.0), 7.86 (d, 1H, J = 8.8), 7.72 (d, 2H, J = 5.6), 7.66 (d, 1H, J = 7.6 ), 7.41 (s, 2H), 7.29 (d, 1H, J = 7.6), 7.15 (d, 1H, J = 2.0), 7.13 (s, 1H), 7.04 (t, 1H, J = 7.6), 7.01 (d, 2H, J = 8.4), 7.00 (t, 1H, J = 7.6), 6.57 (d, 2H, J = 8.4), 4.75 , 1H), 4.43 (q, 1H, J = 6.8), 4.23 (dd, 1H, J = 8.8, J = 6.8), 3.64-3.57 (m, 2H), 3.17 (dd, 1H, J = 14.8, J = 4.0), 3.06 (dd, 1H, J = 14.8, J = 10.4), 2.93 (dd, 1H, J = 14.0, J = 4.0), 2.73 (dd, 1H, J = 14.0, J = 9.6), 2.29 (s, 6H), 2.00 ( m, 1H), 0.88 (d, 3H, J = 6.4), 0.85 (d, 3H, J = 6.4). ^{13 C NMR (100 MHz, DMSO-} d 6): δ171.7, 171.2, 171.0, 170.8, 167.1, 164.3, 155.7, 149.1, 141.9, 137.4, 136.0, 134.3, 132.6, 130.1, 127.8, 127.2, 125.0, 123.6 , 121.9, 120.9, 118.5, 118.2, 114.8, 111.3, 110.4, 57.4, 54.2 (2C, identified from HSQC), 52.2, 40.3 (identified from HSQC), 36.2, 30.9, 27.2, 20.8, 19.1, 18.0. MALDI m / z calculated for C ₄₃ H ₄₇ N ₇ NaO ₈ ⁺ [M + Na] ⁺ 812.34, found 812.67.

5-3. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) ( Isonicotinyl - Trp - Tyr - Val - Dpr (7- 메틸oxy -One- benzofuran -2- carboxylyl ))

In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) . Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 24.3 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ10.73 (s, 1H), 8.85 (d, 1H, J = 8.0), 8.73 (brs, 2H), 8.66 (t, 1H, J = 5.6) , 8.35 (d, 1H, J = 7.2), 8.21 (d, 1H, J = 8.0), 7.86 (d, 1H, J = 8.4), 7.71 (d, 2H, J = 4.0), 7.66 (d, 1H , J = 7.6), 7.50 ( s, 1H), 7.29 (d, 2H, J = 7.6), 7.23 (t, 1H, J = 7.6), 7.14 (d, 1H, J = 1.6), 7.06-7.01 ( m, 2H), 6.99 (d , 2H, J = 8.8), 6.95 (t, 1H, J = 7.6), 6.56 (d, 2H, J = 8.8), 4.74 (m, 1H), 4.54 (m, 1H ), 4.45 (q, IH, J = 7.2), 4.23 (dd, IH, J = 8.4, J = 6.8), 3.94 (s, 3H), 3.70-3.60 (m, 2H, identified from HSQC) dd, 1H, J = 14.8, J = 3.6), 3.06 (dd, 1H, J = 14.8, J = 9.8), 2.93 (dd, 1H, J = 13.6, J = 4.0), 2.72 (dd, 1H, J = 13.6, J = 9.2), 2.00 (m, 1H), 0.87 (d, 3H, J = 6.8), 0.84 (d, 3H, J = 6.8). ^{13 C NMR (100 MHz, DMSO-} d 6): δ171.6, 171.2, 170.9, 170.8, 164.3, 158.3, 155.7, 149.2, 148.9, 145.2, 143.6, 141.8, 136.0, 130.1, 128.6, 127.8, 127.2, 124.6 Identified from HSQC), 36.3, 30.9, 27.2 (2C), 123.6, 121.8, 120.9, 118.5, 118.2, 114.8, 114.5, 111.3, 110.4, 110.2, 108.8, 57.4, 55.7, , 19.1, 18.0. MALDI m / z calculated for C ₄₄ H ₄₅ N ₇ NaO ₁₀ ⁺ [M + Na] ⁺ 854.31, found 854.67.

5-4. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (2- (2- Cyanophenylthio ) Benzoyl ) ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- (2- Cyanophenylthio ) benzoyl ))

Tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) was synthesized in the same manner as in Preparation Example 3 and used in the same manner as in Production Example 5-1 Were synthesized. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 25.5 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ12.70 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.10 (brs, 1H), 8.83 (d, 1H, J = 8.4) , 8.70 (brs, 2H), 8.53 (t, 1H, J = 5.6), 8.28 (d, 1H, J = 7.6), 8.22 (d, 1H, J = 7.6), 7.92 (dd, 1H, J = 8.0 , J = 1.2), 7.85 ( d, 1H, J = 8.8), 7.68-7.64 (m, 4H), 7.56-7.51 (m, 2H), 7.44 (d, 1H, J = 8.0), 7.40-7.33 ( m, 2H), 7.29 (d , 1H, J = 7.6), 7.15 (d, 1H, J = 2.0), 7.05-6.99 (m, 2H), 7.02 (d, 2H, J = 8.0), 6.96 (t , 1H, J = 7.6), 6.57 (d, 2H, J = 8.0), 4.74 (m, 1H), 4.55 (m, 1H), 4.46 (q, 1H, J = 7.2), 4.25 (dd, 1H, J = 8.8, J = 6.8) , 3.62-3.56 (m, 2H), 3.17 (dd, 1H, J = 14.8, J = 4.0), 3.07 (dd, 1H, J = 14.8, J = 10.4), 2.94 ( dd, 1H, J = 14.4, J = 4.0), 2.74 (dd, 1H, J = 14.4, J = 9.6), 2.02 (m, 1H), 0.89 (d, 3H, J = 6.8), 0.86 (d, 3H, J = 6.8). ^{13 C NMR (100 MHz, DMSO-} d 6): δ171.6, 171.3, 171.0, 170.8, 167.4, 164.5, 155.7, 149.7, 141.3, 138.7, 136.8, 136.0, 134.4, 134.1, 133.8, 133.5, 131.0, 130.5 Identified from HSQC, 51.9, 40.0 (identified from Table 1), 130.1, 128.8, 128.5, 127.9, 127.2, 127.1, 123.6, 121.6, 120.9, 118.5, 118.2, 117.0, 115.0, 114.8, 111.3, HSQC), 36.3, 30.9, 27.2, 19.2, 18.0. MALDI m / z calculated for C ₄₈ H ₄₆ N ₈ NaO ₈ S ⁺ [M + Na] ⁺ 917.31, found 917.72.

5-5. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ((R) - (+) - Trolloxil ) ( Isonicotinyl - Trp - Tyr - Val - Dpr ((R) - (+) - troloxyl ))

(R) - (+) - Troloxyl) was synthesized in the same manner as in Preparation Example 3, except that isonicotinyl-tryptophan-tyrosine-valine- Respectively. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

91.3% Purity. R _t 25.0 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ10.73 (d, 1H, J = 2.4), 8.87 (d, 1H, J = 8.0), 8.74 (brs, 2H), 8.31 (d, 1H, J = 7.2), 8.25 (d , 1H, J = 8.0), 7.83 (d, 1H, J = 8.8), 7.73 (d, 2H, J = 6.0), 7.66 (d, 1H, J = 8.0), 7.53 (dd, 1H, J = 6.8 , J = 5.6), 7.29 (d, 1H, J = 8.0), 7.15 (d, 1H, J = 2.4), 7.03 (m, 1H), 7.02 (d, 2H, J = 8.4), 6.96 (t, 1H, J = 8.0), 6.57 (d, 2H, J = 8.4), 4.75 (m, 1H), 4.55 (m, 1H), 4.27 (q, 1H, J = 7.2) , 4.20 (dd, 1H, J = 8.8, J = 6.4), 3.55 (m, 1H), 3.34 (m, 1H), 3.17 (dd, 1H, J = 14.4, J = 4.0), 3.06 (dd, 1H , J = 14.4, J = 9.6 ), 2.94 (dd, 1H, J = 14.4, J = 4.0), 2.73 (dd, 1H, J = 14.4, J = 9.6), 2.54-2.41 (m, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 1.96 d, 3H, J = 6.8), 0.84 (d, 3H, J = 6.8). ^{13 C NMR (100 MHz, DMSO-} d 6): δ173.9, 171.6, 171.2, 170.9, 170.8, 164.2, 155.7, 149.0, 145.9, 143.7, 142.1, 136.0, 130.1, 127.8, 127.2, 123.6, 122.7, 121.9 , Identified by HSQC, 52.3, 39.5 (identified from HSQC), 36.3, 31.1, 29.3, 27.2, 23.3 , 19.9, 19.0, 18.0, 12.8, 12.0, 11.8. MALDI m / z calculated for C ₄₈ H ₅₅ N ₇ NaO ₁₀ ⁺ [M + Na] ⁺ 912.39, found 912.74.

5-6. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (1- Cyano -One- Cyclopropanecarboxylic acid ) ( Isonicotinyl - Trp - Tyr - Val - Dpr (One- cyano -One- cyclopropanecarboxylyl ))

In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl) was synthesized in the form of a solid, Were synthesized. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 21.4 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ10.74 (d, 1H, J = 1.2), 8.87 (d, 1H, J = 8.4), 8.74 (brs, 2H), 8.24 (d, 2H, J = 7.2), 8.13 (t , 1H, J = 6.0), 7.85 (d, 1H, J = 8.8), 7.73 (d, 2H, J = 4.4), 7.67 (d, 1H, J = 7.6), 7.29 (d, 1H, J = 7.6 ), 7.15 (d, 1H, J = 1.2), 7.04 (m, 1H), 7.03 (d, 2H, J = 8.0), 6.96 (t, 1H, J = 7.6), 6.57 (d, 2H, J = 8.0), 4.75 (m, 1H), 4.56 (m, 1H), 4.34 (q, 1H, J = 7.2), 4.20 (dd, 1H, J = 8.8, J = 6.8) , 3.51-3.40 (m, 2H), 3.17 (dd, 1H, J = 14.8, J = 4.0), 3.07 (dd, 1H, J = 14.8, J = 10.4), 2.96 (dd, 1H, J = 14.0, J = 4.4), 2.76 (dd , 1H, J = 14.0, J = 9.6), 2.00 (m, 1H), 1.57-1.51 (m, 2H), 1.50-1.44 (m, 2H), 0.89 (d, 3H , J = 6.4), 0.85 (d, 3H, J = 6.4). ^{13 C NMR (100 MHz, DMSO-} d 6): δ171.5, 171.2, 170.9, 170.8, 165.6, 164.3, 155.7, 149.1, 142.0, 136.0, 130.1, 127.8, 127.2, 123.6, 121.9, 120.9, 119.9, 118.5 , 118.2, 114.8, 111.3, 110.4, 57.4, 54.2 (2C, identified from HSQC), 51.7, 40.5, 36.3, 30.9, 27.2, 19.1, 18.0, 16.8, 16.7, 13.6. MALDI m / z calculated for C ₃₉ H ₄₂ N ₈ NaO ₈ ⁺ [M + Na] ⁺ 773.30, found 773.57.

5-7. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Rhodanin -3-acetyl) ( Isonicotinyl - Trp - Tyr - Val - Dpr ( rhodanine -3- acetyl ))

Isonikotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl) was synthesized as a solid in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 5-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 22.3 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ10.73 (d, 1H, J = 1.6), 8.84 (d, 1H, J = 8.4), 8.72 (brs, 2H), 8.28 (t, 1H, J = 6.0), 8.24 (d , 1H, J = 8.0), 8.20 (d, 1H, J = 7.6), 7.83 (d, 1H, J = 8.0), 7.69 (d, 2H, J = 4.0), 7.66 (d, 1H, J = 7.6 ), 7.29 (d, 1H, J = 7.6), 7.14 (d, 1H, J = 1.6), 7.04 (m, 1H), 7.03 (d, 2H, J = 8.4), 6.96 (t, 1 H, J = 7.6), 6.57 (d, 2H, J = 8.4), 4.74 (m, 1H), 4.55 (m, 1H), 4.49 (s, 2H), 4.31 (s, 2H), 4.29 (m, 1H), 4.20 (dd, 1H, J = 8.0, J = 6.8), 3.44-3.33 (m, 2H, identified from HSQC), 3.16 (dd, 1H, J = 14.8, J = 3.6), 3.06 (dd, 1H, J = 14.8, J = 10.4), 2.97 (dd, 1H, J = 14.0, J = 3.6), 2.76 (dd, 1H, J = 14.0, J = 9.6), 2.00 (m, 1H), 0.88 (d, 3H, J = 6.8 ), 0.85 (d, 3H, J = 6.8). ^{13 C NMR (100 MHz, DMSO-} d 6): δ202.8, 173.9, 171.5, 171.3, 171.1, 170.8, 165.2, 164.5, 155.7, 149.5, 141.6, 136.1, 130.1, 127.9, 127.2, 123.6, 121.7, 120.9 , 118.5, 118.2, 114.9, 111.3, 110.4, 57.5, 54.2, 54.1, 51.9, 45.9, 39.5, 36.2, 36.0, 30.9, 27.3, 19.2, 18.0. MALDI m / z calculated for C ₃₉ H ₄₂ N ₈ NaO ₉ S ₂ ⁺ [M + Na] < ⁺ > 853.24, found 853.52.

5-8. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- Fluorophenylacetyl ) ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- fluorophenylacetyl ))

Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl) was synthesized as a solid in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 5-1. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 23.3 min. MALDI m / z calculated for C ₄₂ H ₄₄ FN ₇ NaO ₈ ⁺ [M + Na] ⁺ 816.31, found 816.63.

5-10. Isonicotinyl - tryptophan - Tyrosine - Valine-Dpr (4- Pentyl bicyclo [2.2.2] octane -One- Carboxylate ) ( Isonicotinyl - Trp - Tyr - Val - Dpr (4- pentylbicyclo [2.2.2] octane-1- carboxylyl ))

In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) And synthesized using the same method. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 31.1 min. MALDI m / z calculated for C ₄₈ H ₆₁ N ₇ NaO ₈ ⁺ [M + Na] ⁺ 886.45, found 886.80.

5-11. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Quinadil ) ( Isonicotinyl - Trp - Tyr - Val - Dpr ( quinaldyl ))

Isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinadil) was synthesized as a solid in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 5-1. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 24.4 min. MALDI m / z calculated for C ₄₄ H ₄₄ N ₈ NaO ₈ ⁺ [M + Na] ⁺ 835.32, found 835.66

5-12. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Taiglail ) ( Isonicotinyl  - Trp - Tyr - Val - Dpr ( tiglyl ))

Isonicotinyl-tryptophan-tyrosine-valine-Dpr (tyglyle) was synthesized as a solid in the same manner as in Preparation Example 3 and synthesized in the same manner as in Production Example 5-1. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 22.1 min. MALDI m / z calculated for C ₃₉ H ₄₅ N ₇ NaO ₈ ⁺ [M + Na] ⁺ 762.32, found 762.72.

5-13. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5- Chloroindole -2- Carboxylate ) ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- chloroindole -2- carboxylyl ))

In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-PrP (5-chloroindole-2-carboxylyl) was synthesized as a solid and synthesized in the same manner as in Production Example 5-1 . A mass spectrometry (MS) was used to identify the resulting compound.

96.2% Purity. R _t 25.7 min. MALDI m / z calculated for C ₄₃ H ₄₃ ClN ₈ NaO ₈ ⁺ [M + Na] ⁺ 857.28, found 857.62.

5-14. Isonicotinyl - tryptophan - Tyrosine -Valine-Dpr (5-nitro-3- Pyrazole carboxylate ) ( Isonicotinyl - Trp - Tyr - Val - Dpr (5- nitro -3- pyrazolecarboxylyl ))

In the same manner as in Preparation Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro-3-pyrazolcarboxylyl) was solid-phase synthesized and synthesized in the same manner as in Production Example 5-1 Respectively. A mass spectrometry (MS) was used to identify the resulting compound.

87.7% Purity. R _t 21.5 min. MALDI m / z calculated for C ₃₈ H ₄₀ N ₁₀ NaO ₁₀ ⁺ [M + Na] ⁺ 819.28, found 819.68

5-15. Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- (4- Methylphenylsulfonamido ) Acetyl) ( Isonicotinyl - Trp - Tyr - Val - Dpr (2- (4- methylphenylsulfonamido ) acetyl ))

Tyrosine-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) was synthesized as a solid in the same manner as in Preparation Example 3, Were synthesized. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 23.7 min. MALDI m / z calculated for C ₄₃ H ₄₈ N ₈ NaO ₁₀ S ⁺ [M + Na] ⁺ 891.31, found 891.59.

Manufacturing example  6. Val - Dpr ( acyl ) - Pro - Ser  / Dpr ( acyl ) - Pro - Ser Synthesis of

Since the biological activity of the truncated peptidomimetic compounds has been shown to be good, it has been shown that another truncated peptidomimetic compound, a compound consisting of a trimer and a tetramer in which the COOH terminus is serine Synthesis was designed.

As shown in FIG. 7, since most of the compounds synthesized in Preparation Examples 4 and 5 were more effective than dTBP2, it was confirmed that the five acids (2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid 2-carboxylic acid and 2-fluorophenylacetic acid were selected as the starting materials and the synthesis method of the above-mentioned Production Example 3 (121-130). ≪ / RTI >

6-1. Valin - Dpr ( Orotile ) - proline-serine ( Val - Dpr ( orotyl ) - Pro - Ser )

Wang resin LL (100-200 mesh, 320 mg, 0.44 mmol / g, 0.141 mmol) was added to a 20 mL TORVIQ PP syringe equipped with a filter, and anhydrous DMF was added to swell for 30 minutes and then drained. Fmoc-Ser (tBu) -OH (10.0 equiv., 541 mg, 1.41 mmol) was placed in a 50 mL pear shape flask and replaced with argon gas and dissolved in anhydrous CH ₂ Cl ₂ (4 mL). DIC (5.0 eq, 0.11 mL, 0.705 mmol) was added to the mixture and stirred at 0 < 0 > C for 20 min (white solid formation). After distillation under reduced pressure at room temperature, the remaining suspension was dissolved in a minimum amount of anhydrous DMF (4.5 mL) and DMAP (0.1 eq., 1.7 mg, 0.014 mmol) was dissolved in anhydrous DMF (0.1 mL) The resin was mixed with an orbital shaker (130 rpm) at room temperature for 1 hour at room temperature, and the solvent was drained and washed with DMF, iPrOH and CH ₂ Cl ₂ (10 mL> 1 min> 3 ). As a result of Fmoc quantification using a UV spectrometry, the loading level was 97.0%.

The resin (200 mg, 0.088 mmol) was swelled in anhydrous DMF for 30 minutes to remove the Fmoc group, then 20% piperidine / anhydrous DMF (4.0 mL) was added and the mixture was stirred for 10 minutes at room temperature with a rotary shaker , 130 rpm) and the solvent was drained and washed with DMF, iPrOH and CH ₂ Cl ₂ (10 mL> 1 min> 3). After vacuum drying for 30 minutes using an aspirator, the reaction was completed using the Kaiser test.

The resin (40 mg, 0.018 mmol) was added to a 3 mL TORVIQ PP syringe equipped with a filter, and 20% piperidine / water was added to the solution in the same manner as in Preparation Example 3, The Fmoc group was deprotected using anhydrous DMF (0.8 mL), and the degassed 94% TFA cocktail (0.8 mL) was added. After mixing for 1 hour at room temperature, the filtrate was filtered, 2) and received the filtrate. The supernatant was combined, and the TFA was removed using an evaporator, followed by decantation three times using cold ether. After drying under high pressure, a semi-preparative HPLC (solvent A: 0.1% TFA / H ₂ O, solvent B: 0.1% TFA / MeOH, 90% B over 31 min) and then mass spectrometry (MS) was confirmed and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 13.7 min. ^{1 H NMR (400 MHz, D} 2 O): δ6.23 (s, 1H), 5.08 (dd, 1H, J = 7.2, J = 5.2), 4.59-4.54 (m, 2H), 4.02 (dd, 1H , J = 12.0, J = 4.4 ), 3.94-3.84 (m, 4H), 3.78 (m, 1H), 3.68 (dd, 1H, J = 14.0, J = 7.6), 2.36 (m, 1H), 2.24 ( m, 1H), 2.11-1.98 (m, 3H), 1.03 (d, 3H, J = 6.8), 1.02 (d, 3H, J = 6.8). ^{13 C NMR (100 MHz, D} 2 O): δ174.0, 173.4, 169.4, 169.0, 166.9, 162.2, 152.3, 145.2, 101.3, 61.2, 60.7, 58.5, 55.0, 51.2, 48.4, 40.5, 30.1, 29.6, 24.8, 17.7, 16.9. _{MALDI m / z calculated for C 21} H 32 N 7 O 9 + [M + H] + 526.23, found 526.34.

6-2. Valin - Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) - proline-serine ( Val - Dpr  (7- 메틸oxy -One- benzofuran -2- carboxylyl ) - Pro - Ser )

Valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine was synthesized in the same manner as in Preparation Example 3 and synthesized in the same manner as in Production Example 6-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 25.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.56 (s, 1H), 7.38 (dd, 1H, J = 8.0, J = 1.2), 7.33 (t, 1H, J = 8.0), 7.13 (dd , 1H, J = 8.0, J = 1.2), 5.09 (dd, 1H, J = 7.2, J = 5.6), 4.57 (dd, 1H, J = 8.8, J = 6.4), 4.55 (t, 1H, J = 4.4), 4.03 (s, 3H ), 4.10-3.77 (m, 7H), 2.37 (m, 1H), 2.23 (m, 1H), 2.11-1.99 (m, 3H), 1.03 (d, 6H, J = 7.2). ^{13 C NMR (100 MHz, D} 2 O): δ173.8, 173.5, 169.4, 169.3, 161.5, 147.2, 145.1, 144.4, 128.7, 125.0, 115.2, 112.0, 109.5, 61.3, 60.8, 58.6, 56.2, 55.1, 51.6, 48.4, 39.9, 30.1, 29.5, 24.8, 17.7, 17.0. MALDI m / z calculated for C ₂₆ H ₃₆ N ₅ O ₉ ⁺ [M + H] < ⁺ > 562.25, found 562.32.

6-3. Valin - Dpr (3,5- Dimethylbenzoyl ) - proline-serine ( Val -Drpr (3,5- dimethylbenzoyl ) - Pro - Ser )

Valine-Dpr (3,5-dimethylbenzoyl) -proline-serine was synthesized in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 6-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 26.9 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.44 (s, 2H), 7.34 (s, 1H), 5.05 (t, 1H, J = 6.4), 4.57 (dd, 1H, J = 8.4, J = 5.6), 4.49 (t, 1H, J = 4.4), 3.96 (dd, 1H, J = 11.6, J = 4.8), 3.90-3.80 (m, 5H), 3.72 1H), 2.36 (s, 6H), 2.24 (m, 1H), 2.06-1.95 (m, 3H), 1.04 (d, 3H, J = 6.8), 1.03 (d, 3H, J = 6.8). ^{13 C NMR (100 MHz, D} 2 O): δ173.9, 173.3, 171.7, 169.6, 169.3, 139.3, 134.1, 133.0, 124.9, 61.2, 60.7, 58.5, 55.1, 51.7, 48.4, 40.3, 30.1, 29.5, 24.8, 20.4, 17.6, 17.0. _{MALDI m / z calculated for C 25} H 38 N 5 O 7 + [M + H] + 520.28, found 520.38.

6-4. Valin - Dpr (5- Chloroindole -2- Carboxylate ) - proline-serine ( Val - Dpr  (5- chloroindole -2- carboxylyl ) - Pro - Ser )

Pyrrole (5-chloroindole-2-carboxylyl) -proline-serine was synthesized in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 6-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 28.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.61 (d, 1H, J = 2.0), 7.42 (d, 1H, J = 8.8), 7.26 (dd, 1H, J = 8.8, J = 2.0) , 6.97 (s, 1H), 5.00 (t, IH, J = 6.8), 4.60-4.56 (m, 2H), 4.01 (dd, 1H, J = 11.6, J = 4.8), 3.93-3.73 ), 3.67 (m, 1H), 2.36 (dd, 1H, J = 15.2, J = 6.8), 2.24 (td, 1H, J = 13.6, J = 6.8), 2.02-1.94 d, 6H, J = 7.2). ^{13 C NMR (100 MHz, D} 2 O): δ173.7, 173.3, 169.3, 169.1, 163.6, 134.9, 130.7, 127.7, 125.4, 124.8, 120.9, 113.4, 104.0, 61.0, 60.5, 58.3, 55.0, 51.4, 48.2, 39.7, 29.9, 29.3, 24.6, 17.4, 16.7. MALDI m / z calculated for C ₂₅ H ₃₃ ClN ₆ NaO ₇ ⁺ [M + Na] ⁺ 587.20, found 587.31.

6-5 Balin- Dpr (2- Fluorophenylacetyl ) - proline-serine ( Val -Drpr (2- fluorophenyl acetyl ) - Pro - Ser )

Valine-Dpr (2-fluorophenylacetyl) -proline-serine was synthesized in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 6-1. A mass spectrometry (MS) was used to identify the resulting compound.

96.3% Purity. R _t 22.2 min. MALDI m / z calculated for C ₂₄ H ₃₄ FN ₅ NaO ₇ ⁺ [M + Na] ⁺ 546.23, found 546.32.

6-6. Dpr ( Orotile ) - proline-serine ( Dpr ( orotyl ) - Pro - Ser )

Synthesis of Dpr (aurothyl) -proline-serine was carried out in the same manner as in Preparation Example 3 and synthesized in the same manner as in Production Example 6-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

93.9% Purity. R _t 10.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ6.29 (s, 1H), 4.69 (dd, 1H, J = 6.4, J = 3.2), 4.63 (dd, 1H, J = 8.0, J = 5.6) , 4.57 (t, 1H, J = 4.4), 4.08-4.00 (m, 2H), 3.94-3.75 (m, 4H), 2.41 (m, 1H), 2.16-2.00 (m, 3H). ¹³ C NMR (100 MHz, D ₂ O): δ 173.6, 173.5, 166.6, 165.8, 162.5, 152.1, 144.5, 101.4, 61.1, 60.7, 55.3, 51.9, 48.0, 39.0, 29.2, 24.7. _{MALDI m / z calculated for C 16} H 23 N 6 O 8 + [M + H] + 427.16, found 427.27.

6-7. Dpr (7- Metropolitan City -One- Benzofuran -2- Carboxylate ) -Proline-serine (Dpr (7- 메틸oxy  -One- benzofuran -2- carboxylyl ) - Pro - Ser )

Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine was synthesized in the same manner as in Preparation Example 3 and synthesized in the same manner as in Production Example 6-1. A mass spectrometry (MS) was used to identify the resulting compound.

99.9% Purity. R _t 24.7 min. _{MALDI m / z calculated for C 21} H 27 N 4 O 8 + [M + H] + 463.18, found 463.28.

6-8. Dpr (3,5- Dimethylbenzoyl ) - proline-serine ( Dpr (3,5- dimethylbenzoyl ) - Pro - Ser )

Dpr (3,5-dimethylbenzoyl) -proline-serine was synthesized in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 6-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 25.9 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.46 (s, 2H), 7.36 (s, 1H), 4.70 (dd, 1H, J = 6.0, J = 4.0), 4.63 (m, 1H), 4.40 (t, 1H, J = 4.0), 4.04 (dd, 1H, J = 15.2, J = 4.0), 3.93 (dd, 1H, J = 15.2, J = 4.8), 3.90 (dd, 1H, J = 15.2 , J = 6.0), 3.84 ( m, 1H), 3.77-3.70 (m, 2H), 2.41 (m, 1H), 2.38 (s, 6H), 2.09-1.99 (m, 3H). ¹³ C NMR (125 MHz, D ₂ O): δ 173.5, 173.2, 172.0, 166.2, 139.1, 134.0, 132.4, 124.8, 60.9, 60.6, 54.9, 52.1, 48.0, 39.3, 29.2, 24.7, 20.2. _{MALDI m / z calculated for C 20} H 29 N 4 O 6 + [M + H] + 421.21, found 421.30.

6-9. Dpr (5- Chloroindole -2- Carboxylate ) -Proline-serine (Dpr (5- chloroindole -2- carboxylyl ) - Pro - Ser )

Synthesis of Dpr (5-chloroindole-2-carboxylyl) -proline-serine was performed in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 6-1. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR and ¹³ C NMR.

99.9% Purity. R _t 28.3 min. ^{1 H NMR (400 MHz, D} 2 O): δ7.73 (d, 1H, J = 2.0), 7.50 (d, 1H, J = 8.8), 7.33 (dd, 1H, J = 8.8, J = 2.0) , 7.09 (s, 1H), 4.68 (dd, 1H, J = 6.0, J = 4.0), 4.64 (dd, 1H, J = 8.4, J = 6.0), 4.46 (dd, 1H, J = 4.8, J = 4.0), 4.04 (dd, 1H , J = 15.2, J = 4.0), 3.93 (dd, 1H, J = 15.2, J = 4.8), 3.92-3.71 (m, 4H), 2.42 (dd, 1H, J = 8.4, J = 6.0), 2.12-1.99 (m, 3H). ^{13 C NMR (100 MHz, D} 2 O): δ173.7, 173.6, 166.4, 164.3, 135.3, 130.7, 128.0, 125.7, 125.2, 121.2, 113.8, 104.6, 61.2, 60.9, 55.5, 52.3, 48.3, 39.1, 29.5, 24.9. _{MALDI m / z calculated for C 20} H 25 ClN 5 O 6 + [M + H] + 466.15, found 466.23.

6-10. Dpr (2- Fluorophenylacetyl ) - proline-serine ( Dpr (2- fluorophenylacetyl ) - Pro - Ser )

Drip (2-fluorophenylacetyl) -proline-serine was synthesized in the same manner as in Preparation Example 3, and synthesized in the same manner as in Production Example 6-1. A mass spectrometry (MS) was used to identify the resulting compound.

91.0% Purity. R _t 21.4 min. _{MALDI m / z calculated for C 19} H 26 FN 4 O 6 + [M + H] + 425.18, found 425.24.

Experimental Example  1. Interleukin-8 secretion inhibition assay ( IL -8 release inhibition assay )

1-1. Manufacturing example  Confirmation of inhibition of IL-8 secretion by the compound prepared in 2

The degree of inhibition of interleukin-8 secretion of dTBP2 of Production Example 1 and the compounds prepared in Production Example 2 was measured. Specifically, dTBP2 and the compounds were treated with 75 nM concentration for 15 minutes in BEAS-2B cells (human bronchial epithelial cells) and supernatant was taken after 18 hours after adding 75 nM of dTCTP. The supernatant was centrifuged at 4O < ⁰ > C to 10,000 xg and IL-8 assay was performed with the separated supernatant. In the IL-8 assay, IL-8 secretion inhibition was confirmed by PIERCE's IL-8 ELISA kit according to the manufacturer's protocol.

As a result, it was confirmed that 2-methylhexanoyl-tryptophan-tyrosine-valine-tyrosine-proline-serine-methionine (2) as well as isonicotinyl-tryptophan-tyrosine-valine-tyrosine- Tyrosine-valine-tyrosine-proline-serine-methionine (4), and 5-nitro-3-pyrazolcarboxylyl- All of the three serine-methionine (5) compounds were found to be more effective than dTBP2 (Figure 5).

1-2. Manufacturing example  Confirmation of inhibition of interleukin-8 secretion by the compound prepared in 3

The degree of inhibition of interleukin-8 secretion by dTBP2 of Preparation Example 1 and the compounds prepared by Preparation Example 3 was measured and the same method as that of Experimental Example 1-1 was used for measurement. As a result of the measurement, 9 out of 41 non-oxidizing compounds and 10 out of 41 oxidizing compounds, 29 compounds in total, showed stronger activities than dTBP2 (FIG. 6). This is because the isonicotinyl group (isonicotinyl group) is introduced as an extra binding residue and the loose binding residue tyrosine is replaced with a tight binding residue, whereby dTBP2-dTCTP binding Lt; RTI ID = 0.0 > interleukin-8 < / RTI > secretion inhibitory activity.

1-3. Manufacturing example  Confirmation of inhibition of interleukin-8 secretion by the compound prepared in 4

As a result of measuring the degree of inhibition of interleukin-8 secretion, 14 compounds were found to be more effective than dTBP2 in 14 compounds except for the non-oxidation type among the 19 compounds prepared in Production Example 4. [ The measurement results are shown in Table 3 below.

1-4. Manufacturing example  Confirmation of inhibition of interleukin-8 secretion by the compound prepared in 5

Fourteen compounds were found to be more effective than dTBP2 (Table 4) as measured by the inhibition of interleukin-8 secretion from the 14 compounds prepared in Preparation Example 5.

In order to compare the relative activity between the compound prepared in Preparation Example 4 and the compound prepared in Preparation Example 5 which were composed of truncated peptidomimetic compounds, bioassay was performed in the same medium (Fig. 7 ). From these results, it was found that 24 of the compounds prepared in Preparation Example 4 and the compounds prepared in Preparation Example 5 showed stronger activity than dTBP2. The top four compounds prepared in Preparations 4 and 5 were also found to have the same composition as the compounds of Preparations 93, 99, 103 and 100 of Production Example 4 and of three of the acids 107, 109, 108 and 114 of Production Example 5 (7-methoxy-1-benzofuran-2-carboxylic acid, 3,5-dimethylbenzoic acid and 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid) It was found to be effective in both Examples 4 and 5 (99/109, 103/108, 100/107).

1-5. Manufacturing example  Confirmation of inhibition of interleukin-8 secretion by the compound prepared in 6

The results of the biological activity assay (IL-8 Release Inhibition Assay) revealed that 8 out of 10 compounds were more effective than dTBP2 (Table 5, FIG. 8).

Experimental Example  2. Competition measurement method ( competition assay Biological activity test using

The peptidomimetic compounds were designed and synthesized through Production Examples 2 to 6 based on dTBP2. It was judged that these compounds had an excellent interleukin-8 secretion inhibitory activity in Experimental Example 1 due to the binding with dTCTP. Therefore, in order to confirm the above, a competition assay was performed on all the peptidomimetic compounds synthesized in Production Examples 2 to 6, Lt; RTI ID = 0.0 > 32 < / RTI > FIG. 9 shows the results of in situ competition assay of the compound prepared in Preparation Example 2. FIG. From the results shown in FIG. 9, one compound was found to be acylated with isonicotinic acid.

Experimental Example  3. Interleukin-8 secretion inhibitory activity IC ₅₀  Measure value

Based on the results of Experimental Examples 1 and 2, in order to determine which compound is more active, the top 66 compounds were selected and IC ₅₀ Respectively. Of these 22 compounds, IC ₅₀ Values were found to be lower than dTBP2 (IC ₅₀ = 960 nM), particularly 110 being the lowest IC ₅₀ (Table 7).

Experimental Example  4. In allergic animal models Peptidomic  Biological activity test of compound

4-1. dTBP2 Biological activity test

The biological activity of dTBP2 was measured in a mouse model (5 weeks old, Female Balb / c (orientbio), 5-6 animals per group) that induced allergic disease states with ovalbumin (OVA). Mice in each group (6 rats / group) were sensitized with albumin and treated with 2.5 mg / kg or 5 mg / kg of dTBP2 and challenged with albumin. When dTBP2 was treated, the symptom score decreased and eosinophil infiltration was dependent on the concentration (FIG. 10).

4-2. The New Peptidomic  Biological activity test of compound

A mouse model (5-week old, Female Balb / c (orientbio), 5-6 per group) that induced allergic airway inflammation with ovalbumin (OVA) On the basis of the results of Experimental Examples 1 to 3, three compounds (122, 123 and 129) were selected and treated for biological activity. The following three structures illustrate the structure of the compounds used in animal experiments.

Specifically, mice were sensitized with albumin and challenged with ovalbumin after administering 5 mg / kg of peptidomimetic compounds. Interleukin-5 was identified in bronchoalveolar lavage fluid using a mouse IL-5 ELISA kit (PIERCE), and the hyperplasia of the lung mucosa was determined using a Periodic Acid-Schiff (PAS) reagent (Sigma-Aldrich ).

The compounds significantly reduced the secretion of interleukin-5 in the bronchoalveolar lavage fluid (Fig. 11) and significantly reduced the thickness of the mucosal layer of the lung tissue (Fig. 12) The effect was the best.

Further, two compounds (97 and 121) were additionally selected, and further animal experiments were conducted on the allergic mouse model using the same experimental method. The following two structures illustrate the structure of the two additional compounds used.

The two compounds also effectively inhibited the secretion of interleukin-5 in the bronchoalveolar lavage fluid (FIG. 13). In addition, the mucous membrane of the lung tissue was stained with hematoxylin and eosin (H & E) reagent, and the change was observed, indicating that the mucosal hypertrophy was reduced (FIG. 14).

<110> Ewha University - Industry Collaboration Foundation <120> Peptidomimetic compounds comprising chemical formula I and          treating the same for treating same          allergic disease <130> DPP20136871 <160> 1 <170> Kopatentin 1.71 <210> 1 <211> 7 <212> PRT <213> dTBP2 protein <400> 1 Trp Tyr Val Tyr Pro Ser Met   1 5

Claims (5)

In a peptide consisting of the amino acid sequence of SEQ ID NO: 1, an acyl group is introduced at the tryptophan site, which is the first amino acid of the above sequence number, to form a peptidomimetic compound having a structure of the following general formula 1 and exhibiting a preventive or therapeutic activity against an allergic disease :
[Chemical Formula 1]

R ₁ is

,

,

or

ego,
W is tryptophan (W)
Y is tyrosine (Y)
V is valine (V)
P is proline (P)
S is serine (S)
M is methionine (M).
delete The peptidomimetic compound according to claim 1, wherein the allergic disease is asthma, rhinitis, chlamydia, anaphylaxis, allergic bronchiectasis, allergic conjunctivitis, urticaria or atopic dermatitis.
A pharmaceutical composition for the prevention or treatment of an allergic disease, comprising the compound of claim 1.
5. The pharmaceutical composition according to claim 4, wherein the allergic disease is asthma, rhinitis, chlamydia, anaphylaxis, allergic bronchiectasis, allergic conjunctivitis, urticaria or atopic dermatitis.

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