KR101830838B1 - Pharmaceutical composition comprising peptidomimetic compounds for preventing and treating rheumatoid arthritis - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of rheumatoid arthritis, which comprises a specific peptidomimetic compound and a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating rheumatoid arthritis, Secretion inhibition and the like, and thus it has been confirmed through experiments that it is effective for the treatment and prevention of rheumatoid arthritis, and thus it can be used as a therapeutic agent for rheumatoid arthritis.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for preventing and treating rheumatoid arthritis containing peptidomimetic compounds,

The present invention relates to a pharmaceutical composition for preventing and treating rheumatoid arthritis, which comprises a peptidomimetic compound as an active ingredient.

The immune system is a very complex and sophisticated self-defense system involving lymphocytes and immune-mediating substances. However, in the recent decades, autoimmune diseases that attack by attacking normal cells that are not external antigens have been noticeably increased. There is a problem with the immune response system that only responds to external antigens and should not respond to the body. Rheumatoid arthritis is a typical disease related to this.

Rheumatoid arthritis is a chronic inflammatory systemic disease characterized by a persistent inflammatory reaction of the synovial membrane. The chronic inflammatory reaction of the synovial membrane is a major clinical feature that causes cartilage damage and bone erosion (damage to be thinned) of the joints, resulting in disruption of the joints resulting in functional impairment. It can occur at any age, but it is most common between the ages of 35 and 50, with a male to female ratio of about 1: 3, which is more common in women. The course of the disease ranges from mild minor arthritis to progressive multicenter involvement with severe functional impairment. Also, about 10 years after the disease, 50% of the patients have disabilities in daily life.

Rheumatoid arthritis is an autoimmune disease that is known to occur when lymphocytes attack the synovial membrane, which is part of our body. In general, when a lymphocyte functioning to protect our body from microorganisms invading from the outside mistakes a part of our body as a foreign object invading from the outside, various diseases arise and it is called autoimmune disease. Rheumatoid arthritis is classified as one of these autoimmune diseases.

When rheumatoid arthritis occurs, lymphocytes stimulate many cells in the synovial membrane and produce a number of cytokines that cause inflammation in the process. These cytokines include tumor necrosis factor and interleukin-1 (IL-1), which destroy joints and bones around the joints and cause systemic symptoms such as fatigue, fever, loss of appetite, and weight loss.

On the other hand, it is known that translationally controlled tumor protein (TCTP) associated with the release of basophils such as histamine may cause late allergic reactions (MacDonald et al ., Science , 269, 688-690, 1995) It has not been clear yet that IgE-dependent hintamine releasing factor (HRF) binds to specific cell membrane receptors, but the specific action of HRF has not yet been elucidated (Bheekha-Escura et al. , Blood, 96, 2191-2198, 2000).

Accordingly, the present inventors confirmed that the TCTP dimer was HRF, and confirmed that the extracellularly secreted HRF promoted the secretion of histamine and the like in the basophils. Based on the results of these studies, we have focused on the fact that peptides that bind HRF and peptidomimetic compounds that enhance its activity will be able to prevent or treat rheumatoid arthritis. Accordingly, while studying peptidomimetic compounds that enhanced the activity of the peptides bound to HRF, it was confirmed that the peptidomimetic compounds having a specific chemical structure excelled in the inhibitory rate of inflammatory cytokine and histamine secretion, and in the rheumatoid arthritis model The present inventors completed the present invention by confirming that there is a preventive and therapeutic effect on rheumatoid arthritis.

It is an object of the present invention to provide a peptidomimetic compound or peptidomimetic compound capable of producing a specific peptidomimetic compound that promotes activity from a peptide binding to an IgE-dependent histamine releasing factor (HRF) To provide a pharmaceutical composition containing a pharmaceutically acceptable salt thereof.

In order to achieve the above object, the present invention provides a peptide comprising the amino acid sequence of SEQ ID NO: 1, a fragment thereof, and an analogue thereof, wherein the first amino acid of SEQ ID NO: 1, (acyl group) is introduced, or the fourth amino acid of SEQ ID NO: 1 is replaced by a diaminopropionic acid to which an acyl group is connected, or an acyl group is introduced at the tryptophan site of the first amino acid of SEQ ID NO: 1 Wherein the fourth amino acid of SEQ ID NO: 1 is substituted by diaminopropionic acid to which an acyl group is connected, or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a pharmaceutical composition for preventing or treating rheumatoid arthritis comprising the peptidomimetic compound or a pharmaceutically acceptable salt thereof.

The peptidomimetic compound of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent prophylactic and therapeutic effects in an animal model of rheumatoid arthritis, such as suppressing the secretion of cytokines and histamines involved in autoimmune reactions, , It is possible to block various side effects by blocking the pathway leading to rheumatoid arthritis and thus it can be usefully used.

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.
FIG. 3 is a schematic diagram of dividing the compound prepared in Example 3 into two parts, a tetramer at the NH ₂ end and a tetramer at the COOH end, centering on the Dpr site.
FIG. 4 shows compounds selected from the compounds prepared through Example 3 that are more efficacious than dTBP2.
Fig. 5 shows the degree of inhibition of IL-8 secretion by the compound prepared in Example 2. Fig.
Fig. 6 shows the degree of inhibition of IL-8 secretion by the compound prepared in Example 3. Fig.
Figure 7 compares the relative activity between the compound prepared in Example 4 and the compound prepared in Example 5.
8 shows the degree of inhibition of interleukin-8 secretion by the compound prepared in Example 6. Fig.
FIG. 9 shows the results of in situ competition assay of the compound prepared in Example 2. FIG.
FIG. 10 shows the arthritis severity clinical score by administration of compound (122) of Example < 6-2 > in a rheumatoid arthritis mouse model.
FIG. 11 shows the arthritic severity clinical score by administration of the compound (123) of Example < 6-3 > in a rheumatoid arthritis mouse model.
Figure 12 shows the arthritis severity clinical score through administration of compound (129) of Example < 6-9 > in a rheumatoid arthritis mouse model.

Hereinafter, the present invention will be described in detail.

The present invention relates to a peptide comprising the amino acid sequence of SEQ ID NO: 1 (Trp-Tyr-Val-Tyr-Pro-Ser-Met), a fragment thereof and analogues thereof, The present invention relates to novel peptidomimetic compounds, their pharmaceutically acceptable salts and their use, wherein the first amino acid is tryptophan, the fourth amino acid tyrosine, or both are modified.

Specifically, the present invention provides a peptide comprising the amino acid sequence of SEQ ID NO: 1 (Trp-Tyr-Val-Tyr-Pro-Ser-Met), a fragment thereof, An acyl group is introduced into the tryptophan site of the first amino acid of SEQ ID NO: 1, or a fourth amino acid of the above SEQ ID NO: 1 is substituted by a diaminopropionic acid to which an acyl group is connected, Wherein the acyl group is introduced at the tryptophan site of the first amino acid of the amino acid sequence of SEQ ID NO: 1 and the fourth amino acid of SEQ ID NO: 1 is substituted by diaminopropionic acid to which an acyl group is connected, Or a pharmaceutically acceptable salt thereof.

The present invention also relates to a peptide comprising the amino acid sequence (Trp-Tyr-Val-Tyr-Pro-Ser-Met) of SEQ ID NO: 1, a fragment thereof and analogues thereof, 1, a tyrosine, a fourth amino acid, or a peptidomimetic compound in which both are modified, or a pharmaceutically acceptable salt thereof, for the prophylaxis or treatment of rheumatoid arthritis.

Specifically, the present invention relates to a peptide comprising an amino acid sequence of SEQ ID NO: 1, a fragment thereof, and an analog thereof, wherein the first amino acid of SEQ ID NO: 1 is an acyl group at the tryptophan site, Or the fourth amino acid of SEQ ID No. 1 is replaced by diaminopropionic acid to which the acyl group is connected or the acyl group is introduced into the first amino acid of the sequence of SEQ ID No. 1 and the amino acid sequence of SEQ ID No. 1 Wherein the fourth amino acid of the tyrosine is substituted with a diaminopropionic acid to which an acyl group is connected, or a pharmaceutically acceptable salt thereof, as an active ingredient, for the prophylaxis or treatment of rheumatoid arthritis.

The peptide comprising the amino acid sequence of SEQ ID NO: 1 is a heptamer produced by the present inventors (see Example 1) and named as dTBP2 [dTTP (dimerized translationally controlled tumor protein) binding peptide 2] Lt; / RTI &gt; In addition, dTCTP is involved in secretion of cytokines and histamines including interleukin (IL) -8 and IL-5, and dTBP2 is involved in relieving rheumatoid arthritis which can be induced by dTCTP. The chemical structure of dTBP2 is shown below.

[Chemical structure of dTBP2]

Accordingly, the present inventors synthesized peptidomimetic compounds that have undergone various changes in dTBP2 in order to inhibit the binding between dTTP and its receptor, and measured the biological activity of these compounds to confirm their efficacy.

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

(W is tryptophane, Y is tyrosine, V is valine, P is proline, S is serine, M is methionine, A is alanine)

As shown in Table 1, the first amino acid, tryptophan and 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 the tyrosine located at the 4th amino acid position, which is found to be not the most essential from the alanine scanning mutagenesis, has been converted to a diamino-acid (e.g., Diaminopropionic acid (Dpr) 1).

It was confirmed that the newly introduced functional group can provide an additional binding site and significantly increase the binding force of dTCTP-dTBP2 by changing loose binding residues such as tyrosine inside to a tight binding (Experimental Examples 1 to See Example 4).

Thus, one example of the novel peptidomimetic compounds provided by the present invention is a peptide comprising an amino acid sequence of SEQ ID NO: 1, fragments thereof, and analogs thereof, wherein the first Acyl group at the tryptophan site, which is an amino acid, or a peptidomimetic compound, or a pharmaceutically acceptable salt thereof, wherein the fourth amino acid, tyrosine, is replaced by Dpr or an acyl group-linked Dpr.

In addition, the pharmaceutical composition for preventing or treating rheumatoid arthritis provided by the present invention may be any one selected from the group consisting of a peptide comprising the amino acid sequence of SEQ ID NO: 1, a fragment thereof, and analogs thereof, A peptidomimetic compound in which an acyl group is introduced at the tryptophan site of the first amino acid of SEQ ID NO: 1, or a fourth amino acid tyrosine is replaced with Dpr or an acyl group-linked Dpr, or a pharmaceutically acceptable salt thereof A pharmaceutical composition for preventing or treating rheumatoid arthritis.

The fragment may be,

Wherein the C-terminus is a peptide fragment consisting of four amino acids of the amino acid sequence of SEQ ID NO: 1 and the tyrosine corresponding to the fourth amino acid of SEQ ID NO: 1 is a peptidomic acid substituted with diaminopropionic acid to which an acyl group is connected compound;

Wherein the first amino acid of SEQ ID NO: 1 is an acyl group, and the fourth amino acid of SEQ ID NO: 1 is a fragment consisting of four amino acids from the N-terminus of SEQ ID NO: A peptidomimetic compound substituted with an onic acid; And

A peptide fragment consisting of three or four amino acids of the amino acid sequence of SEQ ID NO: 1 and having a C-terminal serine, wherein the tyrosine corresponding to the fourth amino acid sequence of SEQ ID NO: 1 is a peptidyl substituted with diaminopropionic acid But it is not limited to these compounds.

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 (1), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating rheumatoid arthritis containing the same as an active ingredient.

,

,

또는

이고, WYVYPSM은 서열번호 1의 아미노산 서열이다.Wherein R &lt; _{1 &}

,

,

or

And WYVYPSM is the amino acid sequence of SEQ ID NO: 1.

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

The peptidomimetic compound may have an isonitotinyl group introduced into the tryptophan site, which is the first amino acid of SEQ ID NO: 1.

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-proline- serine- methionine, alpha- 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 method for producing a peptide comprising an amino acid sequence of SEQ ID NO: 1, a fragment thereof and an analogue thereof, wherein an acyl group is introduced at the tryptophan site of the first amino acid of SEQ ID NO: 1 A peptidomimetic compound substituted by a diaminopropionic acid (Dpr) in which a tyrosine diacyl group (acyl group) is linked, which is a fourth amino acid of SEQ ID NO: 1, a pharmaceutically acceptable salt thereof, Lt; RTI ID = 0.0 &gt; rheumatoid arthritis. &Lt; / RTI &gt;

It is preferable that the peptidomimetic compound has an isonitotinyl group introduced into the tryptophan site, which is the first amino acid of SEQ ID NO: 1.

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), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating rheumatoid arthritis containing the same as an active ingredient:

(W is Tryptophan, Y is Tyrosine, V is Valine, P is Proline, S is Serine, M is Methionine, and Dpr Is diaminopropionic acid,

R ₂ is

Unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms;

Unsubstituted or substituted alkoxy of 1 to 10 carbon atoms;

Unsubstituted or substituted aryl;

Unsubstituted or substituted heteroaryl comprising N, O or S; And

Lt; / RTI &gt; is selected from the group consisting of unsubstituted or substituted heterocyclyl containing N, O or S).

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

.

.

More specifically, the peptidomimetic compounds are isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (Alpha-cyano-4-hydroxycinnamyl) proline-serine-methionine oxidized form, iso-nicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine- 2.2.2] octane-1-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] ) - proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzo Tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-tyrosine -Prinoline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (phenoxyacetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine - valine-Dpr (2-hexynoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-hexynoyl) -proline-serine-methionine non-oxidized form, isonicotinyl - tryptophan - tyrosine - valine - Dpr (aurotyl) - proline - serine - methionine oxidized form, isonicotinyl - tryptophan - tyrosine - valine - Dpr (aurothyl) - proline - serine - methionine disappeared, isonicotinyl - tryptophan - tyrosine-valine-Dpr (4-benzyloxybenzoyl) -proline-serine-methionine oxidized form, Tyrin-tryptophan-tyrosine-valine-Dpr (4-benzyloxybenzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-naphthoyl) -proline-serine-methionine oxidized form , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-pyrazinecarboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr (2-chloronitocinyl) - proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-chloronitrienyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr - hexadiene oil) - proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tie Tyrosine-valine-Dpr (biphenyl-4-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2,4-hexadiene oil) Tyrosine-valine-Dpr (biphenyl-4-carboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (phenylglyoxyl) - serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (phenylglyoxyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenyl Tyrosine-valine-Dpr (2-fluorophenylacetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (Trans-cinnamyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tie - valine-Dpr (trans-cinnamyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-naphthoyl) -proline-serine-methionine oxidized form, - tyrosine-valine-Dpr (1-naphthoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro-2-furoyl) -proline-serine-methionine oxidized form , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro-2-furoyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (beta-naphthoxyacetyl) Proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (beta-naphthoxyacetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Cyano-benzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-phenoxy Tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl - tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine-methionine disappeared, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-methoxyhexa Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-methoxyhexanoyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-chlorobenzo [b] thiophene-2-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (quinald) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine- Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinaldyl) -proline-serine-methionine oxidized form, isonicotinyl- Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (isonitinyl) -proline-serine-methionine oxidized form, isonicotinyl- Tyrosine-valine-Dpr (5-chloroindole-2-carboxylyl) -proline-serine-methionine oxidized form, tryptophan-tyrosine-valine-Dpr (isonicotinyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr (5-phenyl-2-carboxyil) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr -Furoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5 Thiophene-valine-Dpr (5-nitro-3-pyrazolecarboxylyl) -proline-serine-methionine oxidized form, iso-nicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr ((R) - (+) - nicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro-3-pyrazolcarboxylyl) -proline- -Protonine-serine-methionine oxidized form, isonicotinyl-tryptophan-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- - (+) - 2-pyrrolidone-5-carboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl) - proline-serine-methionine oxidized, Tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl) -purine-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (rhodanine-3-acetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Dpr (7-hydroxycoumarin-4-acetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr 4-methylphenylsulfonamido) acetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tiro (1-acetylpiperidine-4-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr - proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-phenyl-5- (trifluoromethyl) -1H- pyrazole- Oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-phenyl-5- (trifluoromethyl) -1H-pyrazole- - tryptophan-tyrosine-valine-Dpr (2-thiophenacetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-thiophenacetyl) -proline-serine-methionine non- , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (benzotriazol-5-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (4-oxo-4H-chromene-3-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr (4-oxo-4H-chromene-3-carboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Methyl-2-oxo-2H-chromen-7-yloxy) acetyl) -proline-serine-methionine oxidized form and isonicotinyl-tryptophan-tyrosine- valine- Chromene-7-yloxy) acetyl) -proline-serine-methionine dehydrogenation type, a pharmaceutically acceptable salt thereof or a rheumatoid arthritis containing the same Or a pharmaceutical composition for prophylaxis and treatment.

In another embodiment, the present invention provides a peptide fragment comprising 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 corresponding to the fourth amino acid of SEQ ID NO: A peptidomimetic compound substituted with diaminopropionic acid (Dpr) to which the acyl group is linked, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating rheumatoid arthritis containing the same as an active ingredient Composition.

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 the structure of the following formula (3), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating rheumatoid arthritis containing the same as an active ingredient:

(Dpr is diaminopropionic acid, P is proline, S is serine, M is methionine,

R ₃ is

Unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms;

Unsubstituted or substituted alkoxy of 1 to 10 carbon atoms;

Unsubstituted or substituted aryl;

Unsubstituted or substituted heteroaryl comprising N, O or S; And

Lt; / RTI &gt; is selected from the group consisting of unsubstituted or substituted heterocyclyl containing N, O or S).

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 (quinaldyl) -proline-serine-methionine (2-fluorophenylacetyl) -proline-serine-methionine, Dpr (7-methoxy-1-benzofuran-2-carboxylyl) - 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, A peptidomimetic compound substituted with diaminopropionic acid (Dpr) in which an acyl group is introduced and an acyl group is connected to a tyrosine acyl group corresponding to the fourth amino acid of SEQ ID NO: 1; Or a pharmaceutical composition for the prevention or treatment of rheumatoid arthritis containing them as an active ingredient.

More preferably, the isotonicotinyl group may be introduced at the tryptophan site, which is the first amino acid of SEQ ID NO: 1.

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 the structure of the following formula (4), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating rheumatoid arthritis containing the same as an active ingredient:

(W is tryptophan, Y is tyrosine, V is valine, Dpr is diaminopropionic acid,

R ₄ is

Unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms;

Unsubstituted or substituted alkoxy of 1 to 10 carbon atoms;

Unsubstituted or substituted aryl;

Unsubstituted or substituted heteroaryl comprising N, O or S; And

Lt; / RTI &gt; is selected from the group consisting of unsubstituted or substituted heterocyclyl containing N, O or S).

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 (quinald), isonicotinyl- Tyrosine-valine-Dpr (5-nitro-pyrrole), isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-chloroindole- Pyrazole carboxylate) and isonicotinyl-tryptophan-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl).

In another embodiment, the present invention provides a peptide fragment comprising the amino acid sequence of SEQ ID NO: 1 or an analogue thereof, wherein the fragment or analogue thereof is a peptide fragment consisting of three or four amino acids and C-terminal serine, Wherein the tyrosine corresponding to the fourth amino acid of the compound is substituted with a diaminopropionic acid to which an acyl group is linked, a pharmaceutically acceptable salt thereof or a prophylactic or therapeutic agent for rheumatoid arthritis containing the same as an active ingredient May be a pharmaceutical composition.

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), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating rheumatoid arthritis containing the same as an active ingredient:

(P is proline, S is serine, Dpr is diaminopropionic acid,

R ₅ is

Unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms;

Unsubstituted or substituted alkoxy of 1 to 10 carbon atoms;

Unsubstituted or substituted aryl;

Unsubstituted or substituted heteroaryl comprising N, O or S; And

Lt; / RTI &gt; is selected from the group consisting of unsubstituted or substituted heterocyclyl containing N, O or S).

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

.

.

(V is valine, P is proline, S is serine, Dpr is diaminopropionic acid,

R ₆ is

Unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 20 carbon atoms;

Unsubstituted or substituted alkoxy of 1 to 10 carbon atoms;

Unsubstituted or substituted aryl;

Unsubstituted or substituted heteroaryl comprising N, O or S; And

Lt; / RTI &gt; is selected from the group consisting of unsubstituted or substituted heterocyclyl containing N, O or S).

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

.

.

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

In the substituents of the compounds according to the invention, the alkyl group may have from 1 to 20 carbon atoms. 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, but is not limited thereto.

The alkoxy may be alkyloxy having 1 to 10 carbon atoms, but is not limited thereto.

Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Aryl includes at least one ring having a covalent pi electron system, for example a group of monocyclic or fused ring polycyclic (i. E., Rings dividing adjacent pairs of carbon atoms) groups. That is, in the present specification, aryl means, unless otherwise defined, 4 to 10 membered, preferably 6 to 10 membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl and the like, but is not limited thereto.

Heteroaryl is an aromatic 3- to 10-membered ring which contains 1 to 3 heteroatoms selected from the group consisting of N, O and S and which may be fused with benzo or C ₃ -C ₈ cycloalkyl, preferably from 4 to 8 And more preferably 5 to 6 membered ring, but not limited thereto, examples of the monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, But are not limited to, sols, pyrazoles, triazoles, triazines, thiadiazoles, tetrazoles, oxadiazoles, pyridines, pyridazines, pyrimidines, pyrazines 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 heterocycle includes, unless otherwise defined, 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, saturated or one or two double Means a 3- to 10-membered ring, 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 rheumatoid arthritis, which comprises the novel peptidomimetic compound or a pharmaceutically acceptable salt thereof.

Since the peptidomimetic compounds provided by the present invention are characterized by exhibiting the biological activity of dTBP2 and enhancing its activity and bioavailability, the peptidomimetic compounds of the present invention can be used for the treatment of all diseases capable of alleviating, improving, preventing, inhibiting or treating dTBP2, including rheumatoid arthritis &Lt; / RTI &gt; For example, the peptidomimetic compounds of the present invention can be applied to pharmaceutical uses for all autoimmune diseases and allergic diseases capable of alleviating, improving, preventing, inhibiting or treating by inhibiting the action of dTCTP. In another embodiment, the peptidomimetic compounds of the present invention are useful as therapeutic agents for all diseases capable of alleviating, improving, preventing, inhibiting or treating by inhibiting the secretion of cytokines and histamines including IL-8, Can be used for the purpose.

Specifically, the autoimmune diseases include autoimmune atrophic gastritis associated with rheumatoid arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, malignant anemia, autoimmune encephalomyelitis, autoimmune testisitis, Goodpasture disease, autoimmune thrombocytopenia, Sjogren's syndrome, Reiter's syndrome, multiple myositis / myelodysplastic syndromes, acute myasthenia gravis, Graves disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, systemic lupus erythematosus, Sjogren's syndrome, Dermatomyositis, allergic conjunctivitis, allergic conjunctivitis, urticaria or atopic dermatitis, allergic conjunctivitis, allergic conjunctivitis, allergic conjunctivitis, allergic conjunctivitis, allergic conjunctivitis, But is not limited to, dTCTP and its Or all diseases which can be induced by the secretion of cytokines and histamines, including IL-8, IL-5 and the like, are included in the scope of the present invention.

In addition, the peptidomimetic compounds of the present invention, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them can be administered orally and parenterally, preferably parenterally.

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 peptidomimetic compound of the present invention, its pharmaceutically acceptable salt and a composition containing these as an active ingredient may further comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers refer to carriers or diluents that do not significantly stimulate the organism and do not interfere with the biological activity and properties of the administered compound.

In addition, the peptidomimetic compounds of the present invention, pharmaceutically acceptable salts thereof, and compositions containing these as active ingredients can be used in the form of general pharmaceutical preparations. In other words, the composition of the present invention can be administered in various formulations of oral and parenteral administration at the time of actual clinical administration. In the case of formulation, a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant and a surfactant, But are not limited thereto. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like. Such solid preparations can be prepared by mixing the pharmaceutical composition of the present invention with at least one excipient such as starch, calcium carbonate, sucrose, lactose And gelatin, but the present invention is not limited thereto. In addition to simple excipients, lubricants such as magnesium stearate talc may also be used, but are not limited thereto. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. Various excipients such as wetting agents, sweeteners, fragrances and preservatives may be included in addition to water and liquid paraffin, which are commonly used simple diluents. But are not limited thereto. Formulations for parenteral administration include, but are not limited to, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include, but are not limited to, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol and gelatin. The composition of the present invention may be administered orally or parenterally when administered parenterally such as intra-articular injection, intradermal injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intramuscular injection, intrauterine injection, intracerebral injection, , Intraspinal injection, intracardiac injection, intramuscular injection, intramedullary injection, nasal, rectal and bronchial administration, transdermal administration, eye drops and spray formulations, and the like.

The dosage unit may contain, for example, 1, 2, 3 or 4 times the individual dose or may contain 1/2, 1/3 or 1/4 times the dose. The individual dosages preferably contain amounts in which the active drug is administered in one go, which usually corresponds to the full, half, one-third or one-fourth of the daily dose. The effective dose of the composition of the present invention is 0.001 to 10,000 mg / kg, preferably 0.1 g to 5 g / kg, and can be administered 1 to 6 times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.

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

< Example  1 > Trp- Tyr -Val- Tyr -Pro- Ser -Met sequence The peptide (dTBP2) Synthesis of

<1-1> Wang Resin LL  In Fmoc -Met-OH 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 &lt; 0 &gt; C for 20 min. The suspension was distilled under reduced pressure and the remaining suspension was dissolved in a minimum amount of anhydrous DMF (7.0 mL). DMAP (0.1 equivalent, 1.6 mg, 0.013 mmol) was dissolved in anhydrous DMF (0.1 mL) and the two solutions were added to the swollen resin The mixture was stirred at room temperature for 1 hour using an orbital shaker (130 rpm), and the solvent was drained and washed with DMF, iPrOH and CH ₂ Cl ₂ (10 mL X 1 min X 3, respectively). Standard Fmoc quantification was performed using UV spectrometry to determine the loading level (99.9%).

<1-2> Fmoc -base SPPS

To remove the Fmoc (Fluorenylmethyloxycarbonyl chloride) group, the resin (300 mg, 0.13 mmol) was swelled in anhydrous DMF for 30 minutes and then 20% piperidine / anhydrous DMF (6.0 mL, 2 mL per 100 mg of resin) The mixture was mixed at room temperature with orbital shaker (130 rpm) for several 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 the Kaiser test. (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate) (8.0 eq., 394.5 mg, 1.04 mmol) and HOBt (Hydroxybenzotriazole) to couple serine with methionine. 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) and DIPEA (8.0 eq., 0.18 mL, 1.04 mmol) in anhydrous DMF (6.0 mL ), And the mixture was stirred for 3 minutes and then added to resin (300 mg, 0.13 mmol) swollen in DMF for 30 minutes, followed by mixing with an orbital shaker (130 rpm) for 2 hours. After 2 hours, 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 protecting group of proline, was removed and tyrosine was coupled to proline, it was confirmed that the reaction was completed by the Chloranil test.

<1-3> 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) and degassed 94% TFA The reaction mixture was reacted at room temperature for 1 hour by adding a cocktail (TFA: H ₂ O: EDT: TIS, 94%: 2.5%: 2.5%: 1%, 0.6 mL) Resin was again washed with TFA solution (0.3 mL x 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) and lyophilized, followed by mass spectrometry (MS).

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

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

< Example  2> Acyl -Trp- Tyr -Val- Tyr -Pro- Ser Synthesis of Met

In the binding site, an acid library was constructed to identify the space around the tyrosine at the NH ₂ terminus and at the center. The NH ₂ terminus was acylated and screened in situ using the solid phase protocol. HOOC-TentaGel resin and dTBP2 were synthesized by linking with SS linker. This method allows SS linker to be easily cleaved with DTT-Tris (Dithiothreitol-Tris (2-carboxyethyl) phosphine HCl) buffer and screening without purification This is a useful and effective experimental method. Using this method, 88 NH ₂ terminated acylated peptidomimetic compounds were synthesized as follows in a 96-well filter plate.

Since the COOH end of the compound prepared by the above synthesis was subjected to an assay in which the SS bond was cleaved and NHCH ₂ CH ₂ SH was attached and mixed with the cleavage cocktail, validation of the hit compound was required. Based on the results of the competition assay, four compounds were selected and re-synthesized according to the Fmoc-based solid phase peptide synthesis (SPPS) protocol in which NHCH ₂ CH ₂ SH was not attached (Scheme 2).

Wang resin LL on polystyrene was selected as a solid support, Fmoc-Meth-OH-OH was converted into Fomc-methionine anhydride using DCC, and Fmoc-methionine was loaded on Wang resin by DMAP-catalyzed esterification.

Subsequently, the remaining amino acids of dTBP2 were sequentially sequenced using HCTU, and the Fmoc protecting group was removed using 30% piperidine in DMF before each coupling. The removal of Fmoc protecting group and the progress of amino acid coupling reaction were confirmed by Kaiser test or Chloranil test at every step. PyBOP was used for the coupling reaction of 4 hits acids (isonicotinic acid, 2-methylhexanoic acid, α-cyano-4-hydroxy cinnamic acid, and 5-nitro-3-pyrazolecarboxylic acid), and 1,2-ethanedithiol and triisopropylsilane The side-chain protecting groups of amino acid residues and Wang resin were removed using 94% TFA containing TIS. 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 Synthesis of proline-serine-methionine (2-Methylhexanoyl-Trp-Tyr-Val-Tyr-Pro-Ser-Met)

The peptide-resin (50 mg, 0.022 mmol) was dissolved in 30% piperidine / anhydrous DMF (1.0 mL) in the same manner as the dTBP2 of Example 1 except that Trp-Tyr- (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 was dissolved in DMF (0.6 mL) and stirred for 3 min. The mixture was added to resin (500 mg, 0.22 mmol) which had been swollen in DMF for 30 min and then washed with 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 mL x 2) to receive the filtrate. The supernatant was collected, and 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, (84.1% Purity.Rt 20.5 min.MALDI m / z calcd for C ₅₄ H ₇₂ ) was used to identify the compound produced by mass spectrometry (MS) after separation and freeze- N ₈ NaO ₁₂ S ⁺ [M + Na] &lt; ⁺ &gt; 1079.49, found 1079.50.).

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

The compound was synthesized using the same method as the above 2-1 and coupled with isonicotinic acid as an acid, and the compound was confirmed by mass spectrometry (MS) after synthesis (94.3% Purity. Rt 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 Synthesis of proline-serine-methionine (α-Cyano-4-hydroxycinnamyl-Trp-Tyr-Val-Tyr-Pro-Ser-Met)

The compound was synthesized using the same method as in the above 2-1. Coupling was carried out using α-Cyano-4-hydroxycinnamic acid as an acid, and a compound produced by mass spectrometry (MS) was identified after synthesis (99.2% Purity. Rt 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 Synthesis of proline-serine-methionine (5-Nitro-3-pyrazolecarboxylyl-Trp-Tyr-Val-Tyr-Pro-Ser-Met)

The compound was synthesized using the same method as the above 2-1 and coupled using 5-nitro-3-pyrazolecarboxylic acid as an acid. The compound was identified by mass spectrometry (MS) after synthesis (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.).

< Example  3> Isonicotinyl -Trp- Tyr -Val- Dpr ( acyl ) -Pro- Ser Synthesis of Met

After confirming the additional binder at the NH ₂ end, we altered the tyrosine moiety with weak binding ability as a result of alanine scanning mutagenesis. It was decided to introduce a linker at the tyrosine position to increase the binding force and it was found that one amine of the diamine was protected with 4-methyltrityl (Mtt) group Diaminopropionic acid (Fmoc-Dpr (Mtt) -OH). The 4-methyltrityl (Mtt) group can be easily removed under mild acid conditions such as 1% TFA in CH ₂ Cl ₂ . In order to establish the removal conditions, the amount of Mtt-OH remaining in each filtrate was determined by HPLC (FIG. 8) 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 and their equivalents and reaction time were adjusted. Especially, HBTU was used in place of HCTU or PyBOP because it was confirmed on HPLC system that less byproducts were generated when HBTU was used.

8 residues of Met, Ser, Pro, Fmoc-Dpr (Mtt) -OH, Val, Tyr, Trp and isonicotinic acid were sequentially loaded onto Wang resin , The Mtt group of the Dpr residue was removed by treatment with 1% TFA & 5% TIS in CH ₂ Cl _2, and the protected amine was acylated to 44 acids. All the protecting groups and the resin of the peptide were then 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 analysis, the former peak was a compound of sulfur-oxidized compound of Met and the latter peak was an 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 Example 1, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) -proline-serine-methionine was synthesized in a solid phase, The resin (25 mg, 0.011 mmol) was added to a 1 mL Micro Bio-Spin chromatography column equipped with a filter and swelled in CH ₂ Cl ₂ for 30 min. Then, CH ₂ Cl ₂ was removed using argon gas pressure, (TFA: TIS: DCM, 1: 5: 94, 0.66 mL) was added to the flask and mixed with orbital shaker (130 rpm) for 2 minutes. The 1% TFA solution was removed using argon gas pressure, This procedure was repeated three times. After the reaction was completed, 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), HOBt.H ₂ O (8.0 eq., 0.045 mmol) was added in order to couple 3,5-dimethylbenzoic acid to the amine from which the Mtt group of diaminopropionic acid was removed. Using a mixture of 3,5-dimethylbenzoic acid (8.0 eq, 13.2 mg, 0.088 mmol), DIPEA (8.0 eq., 15.4 μL, 0.088 mmol) and anhydrous DMF (0.5 mL) 2 &lt; / RTI &gt; method. The degassed 94% TFA cocktail (0.5 mL) was added to the peptide (25 mg, 0.011 mmol) thus prepared, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, washed with TFA (0.3 mL × 2) . The supernatant was collected, and TFA was removed using an evaporator, followed by decantation three times using cold ether. To prevent loss of this time, the resulting compound was used for the centrifuge, high vacuum dry after 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 the resulting compound was identified by mass spectrometry (MS) and further confirmed by ¹ H NMR.

97.0% Purity. Rt 22.6 min. ^{1 H NMR (400 MHz, DMSO} -d6): δ 10.73 (d, 1H, J = 2.0), 9.10 (s, 1H), 8.78 (d, 1H, J = 8.4), 8.67 (dd, 2H, J = 2H), 8.06 (dd, 1H, J = 7.6, J = 3.6), 8.00 (dd, 1H, J = J = 7.6, J = 3.2), 7.80 (d, 1H, J = 8.4), 7.65 2H), 7.29 (d, IH, J = 8.0), 7.14 (d, IH, J = 2.0), 7.13 2H), 4.52 (td, 1H, J = 8.4, J = 4.0), 6.57 (d, 2H, J = 8.4) (M, 2H), 4.21 (dd, 1H, J = 8.4, J = 7.2), 3.68-3.54 (m, 4H), 3.47 (m, 2H), 3.15 (dd, 1H, J = 14.4, J = 4.0), 3.05 (dd, 1H, J = 14.4, J = 10.4), 2.91 3H), 2.27 (s, 6H), 2.13-1.86 (m, 5H), 1.84-1.79 (m, 2H), 0.84 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. Rt 24.8 min. ^{1 H NMR (400 MHz, DMSO} -d6): 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 = 8.0), 7.93 (d, IH, J = 8.0), 7.79 (d, IH, J = 8.4), 7.68 (dd, 2H, J = 5.6, 1H), 7.45 (s, 2H), 7.29 (d, 1H, J = 8.0), 7.14 (d, 2H, J = 8.4), 6.95 (t, 1H, J = 8.0), 6.57 1H), 4.52 (td, 1H, J = 8.8, J = 4.0), 4.43 (dd, 1H, J = 8.0, J = 4.0), 4.34-4.28 (Dd, 1H, J = 4.0), 3.05 2H), 2.27 (s, 6H), 2.07-1.75 (m, 7H), 2.00 (d, 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 - Balin - Dpr (Alpha- Cyano -4- Hydroxycinnamate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (? cyano  -4-hydroxycinnamyl) -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. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR.

99.9% Purity. Rt 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] &lt; ⁺ &gt; 1182.43, found 1182.32.

<3-4> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (Alpha- Cyano -4- Hydroxy cinnamate Wheat) -prolyl-serine-methionine Non-oxidizing type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (? cyano  -4-hydroxycinnamyl) -Pro-Ser-Met)

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

99.9% Purity. Rt 19.3 min. ^{1 H NMR (400 MHz, DMSO} -d6): δ 12.73 (brs, 1H), 10.73 (s, 1H), 10.59 (brs, 1H), 9.10 (brs, 1H), 8.80 (d, 1H, J = 8.0 1H), 8.69 (d, 2H, J = 4.4), 8.28-8.22 (m, 2H), 8.18 , 7.91 (d, IH, J = 7.6), 7.86 (d, 2H, J = 8.8), 7.81 (d, IH, J = 8.8), 7.67-7.65 = 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 2H, J = 8.8), 6.57 (d, 2H, J = 8.4), 4.75-4.67 (m, 2H), 4.52 , 4.34 (m, IH), 4.27 (m, IH), 4.20 (dd, IH, J = 8.8, J = 6.8), 3.64-3.35 = 3.6), 3.05 (dd, 1H, J = 15.2, J = 10.4), 2.92 (dd, 1H, J = 14.0, J = 2H), 2.03 (s, 3H), 2.02-1.93 (m, 3H), 1.91-1.75 (m, 4H), 0.85 (d, 3H, J = 6.8), 0.82 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 - Balin - Dpr (4- Pentyl bicyclo [2.2.2] octane -1-carboxylyl) -proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr -Val- Dpr (4-pentylbicyclo [2.2.2] octane-1- 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. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR.

99.9% Purity. R _t 27.2 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ 12.86 (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 - Balin - Dpr (4- Pentyl bicyclo [2.2.2] octane -1-carboxylyl) -proline-serine-methionine Non-oxidizing type  ( Isonicotinyl -Trp- Tyr -Val- Dpr (4-pentylbicyclo [2.2.2] octane-1- 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. Rt 29.9 min. ^{1 H NMR (400 MHz, DMSO} -d6): δ 12.76 (brs, 1H), 10.73 (d, 1H, J = 2.0), 9.10 (brs, 1H), 8.81 (d, 1H, J = 8.0), 8.70 1H, J = 6.4), 7.94 (d, 2H, J = 8.0), 7.79 (d, 2H, J = 1H, J = 8.8), 7.68 (dd, 2H, J = 4.4, J = 1.6), 7.66 1H, J = 7.6), 7.03 (d, 2H, J = 8.8), 6.95 (t, 1H, J = 8.8), 4.73 (m, 1H), 4.58-4.51 (m, 2H), 4.38-4.31 (m, 2H), 4.26 J = 6.4), 3.64-3.35 (m, 7H), 3.16 (dd, 1H, J = 14.8, J = 3.2), 3.05 (dd, 1H, J = 2H), 2.02 (s, 3H), 2.00 - 1.78 (m, 7H, J = ), 1.61-1.57 (m, 6H), 1.29-1.22 (m, 8H), 1.19-1.05 (m, 4H), 1.01-0.97 (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 - Balin - 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. Compounds produced by mass spectrometry (MS) were identified and further confirmed by ¹ H NMR.

99.9% Purity. Rt 23.4 min. ^{1 H NMR (400 MHz, DMSO} -d6): δ 12.89 (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 = 8.0, J = 2.0), 7.93 (dd, 1H, J = 8.0, J = 0.8), 7.81 (D, 1H, J = 8.0, J = 0.8), 7.39-7.32 (m, 2H), 7.63 2H), 7.29 (d, IH, J = 8.0), 7.14 (d, IH, J = 2.0), 7.03 1H, J = 8.8, J = 4.0), 4.40 (m, 1H), 4.34 (d, 2H, J = (m, 2H), 3.69-3.30 (m, 7H), 3.17 (dd, 1H, J = 14.8, J = 4.0), 3.06 (dd, (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 S2 + [M + Na] + 1248.43, found 1248.44.

<3-8> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- (2- Cyanophenylthio ) Benzo Yl) -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): δ 12.73 (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. , 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 form (Isonicotinyl-Trp-Tyr-Val-Dpr (phenoxyacetyl) -Pro-Ser-Met

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 form (Isonicotinyl-Trp-Tyr-Val-Dpr (2-hexynoyl)

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 (2-hexynoyl) -Pro-Ser-Met) -Proproin-Serine-Methionine-Depleted (Isonicotinyl-Trp-Tyr-

The compound was synthesized in the same manner as in 3-11, 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 form (Isonicotinyl-Trp-Tyr-Val-Dpr (orotyl) -Pro-Ser-Met

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 ) -Prolyine-serine-methionine-depleted (Isonicotinyl-Trp-Tyr-Val-Dpr (orotyl) -Pro-

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 the 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)

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 (2-naphthoyl) -Pro-Ser-Met (O)) - proline-serine-methionine oxidized form (Isonicotinyl-Trp-Tyr-

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 (2-naphthoyl) -Pro-Ser-Met) -pro- enine-serine-methionine dehydrogenase (Isonicotinyl-Trp-Tyr-

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

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 was confirmed by mass spectrometry (MS).

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 by the same method 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 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 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 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 (1-naphthoyl) -Pro-Ser-Met) -prodrin-serine-methionine-depleted (Isonicotinyl-Trp-Tyr-

The compound was synthesized by the same method 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)

Was synthesized in the same manner as 3-35 above, and a 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)

Was synthesized in the same manner 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)

Was synthesized in the same manner as 3-39 above, and a 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 - Balin - Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (7- 메틸oxy -1-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 - Balin - Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (7-methoxy-1-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 the 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)

Was synthesized in the same manner 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 - Balin - Dpr (3- Chlorobenzo [b] thiophene Carboxylic &lt; / RTI &gt; 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 - Balin - Dpr (3- Chlorobenzo [b] thiophene Carboxylic &lt; / RTI &gt; 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 ( Quiland ) - 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 ( Quiland ) - proline-serine-methionine depleted form (Isonicotinyl-Trp-Tyr-Val-Dpr (quinaldyl) -Pro-

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)

Was synthesized in the same manner as in 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)

5-Chloroindole-2-carboxylic acid was used as an acid for coupling in the same manner as in 3-1 above. A mass spectrometry (MS) was used to identify the resulting compound.

89.3% Purity. R _t 23.3 min. MALDI m / z calculated for C ₅₆ H ₆₄ ClN ₁₁ NaO ₁₃ S ⁺ [M + Na] ⁺ 1188.40, found 1188.44.

<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 that of 3-53 above, 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)

The compound was synthesized by the same method as 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 - Balin - 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 - Balin - 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-pyrrolidone-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-pyrrolidone-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 - Balin - Dpr (One- Cyano -One- Cycloprop Gt; &lt; RTI ID = 0.0 &gt; carboxyyl) -proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (1-cyano-1-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 - Balin - Dpr (One- Cyano -One- Cyclopropane carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (1-cyano-1-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)

Was synthesized in the same manner as in 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 ) &Lt; / RTI &gt; 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 ) &Lt; / RTI &gt; acetyl) -prolyl-serine-methionine Non-oxidizing type  ( Isonicotinyl -Trp- Tyr -Val- Dpr (2- (4-methylphenylsulfonamido) acetyl) -Pro-Ser-Met)

The compound was synthesized by the same method as 3-69 above, and the compound produced by mass spectrometry (MS) was confirmed.

97.5% Purity. R _t 24.3 min. MALDI m / z calculated for C ₅₆ H ₆₉ N ₁₁ NaO ₁₄ S ₂ ⁺ [M + Na] ⁺ 1206.44, found 1206.49.

<3-71> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (One- Acetyl piperidine -4- Carboxylate ) - proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (1-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 - Balin - Dpr (One- Acetyl piperidine -4- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  (1-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 - Balin - Dpr (1-phenyl-5- ( Trifluoromethyl )-One H -Pyrazole-4-carboxylyl) -proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr  -Val-Dpr (1-phenyl-5- (trifluoromethyl) -1 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 - Balin - Dpr (1-phenyl-5- ( Trifluoromethyl )-One H -Pyrazole-4-carboxylyl) -proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr  -Val-Dpr (1-phenyl-5- (trifluoromethyl) -1 H -pyrazole-4-carboxylyl) -Pro-Ser-Met (O))

Was synthesized in the same manner as in 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)

Was synthesized in the same manner as in 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)

Was synthesized in the same manner as in 3-77 above, and a 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 - Balin - Dpr (4-oxo-4 H - Kromen -3- Carbop Actin) -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 - Balin - 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)

Was synthesized in the same manner 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 - Balin - Dpr (4- methyl -2-oxo-2 H - Kromen -7-yloxy) acetyl) -proline-serine-methionine Oxidized type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  ((4-methyl-2-oxo-2 H -chromene-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 - Balin - Dpr (4- methyl -2-oxo-2 H - Kromen -7-yloxy) acetyl) -proline-serine-methionine Non-oxidizing type  ( Isonicotinyl -Trp- Tyr -Val- Dpr  ((4-methyl-2-oxo-2 H -chromene-7-yloxy) acetyl) -Pro-Ser-Met)

The compound was synthesized by the same method as 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.

< Example  4> Dpr ( acyl ) -Pro- Ser Synthesis of Met

Since the seven amino acid residues of the compounds prepared in Example 3 do not all contribute to the same binding strength or essential peptide-dTCTP binding, if the tight binding residues are left and the loose binding residues are cleaved, For this purpose, the Dpr site was divided into two parts, a tetramer at the NH ₂ terminus and a tetramer at the COOH terminus (Fig. 3).

Among the compounds prepared through Example 3, the four acid structures were common, and the remaining 11 structures were effective on either side, as compared to dTBP2 (Figure 4). Thus, the compounds of Examples 4 and 5 were synthesized by selecting 15 acids.

Fung-based SPPS was used to synthesize a tetramer of 15 COOH-terminated acid in Wang resin. However, 14 compounds except rhodanine-3-acetic acid and 5 compounds Was created. 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 type  ( Dpr (4- pentylbicyclo [2.2.2] octane -One- carboxylyl ) -Pro- Ser -Met (O)

(4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -proline-serine-methionine was obtained as a solid in the same manner as in Example 3, and resin (25 mg, 0.011 mmol) (1 mL), remove the Fmoc group with 20% piperidine / anhydrous DMF (0.5 mL), add degassed 94% TFA cocktail (0.5 mL), mix at room temperature for 1 hour After filtration, the filtrate was collected and washed again with TFA solution (0.3 mL X 2) to receive the filtrate. The supernatant was collected, and 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, -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] &lt; ⁺ &gt; 642.35, found 642.38

<4-2> Dpr (4- Pentyl bicyclo [2.2.2] octane -One- Carboxylate ) - proline-serine-methionine Non-oxidizing type  ( Dpr (4- pentylbicyclo [2.2.2] octane -One- 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): δ 4.62-4.56 (m, 2H), 4.52-4.47 (m, 2H), 3.97-3.89 (m, 2H), 3.80-3.73 (m, 2H), 3.67 2H), 2.66-2.52 (m, 2H), 2.40 (m, 1H), 2.21 (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): δ 182.2, 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] &lt; ⁺ &gt; 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 in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1, and mass spectrometry (MS) was used to synthesize Dpr &Lt; / RTI &gt;

99.9% Purity. R _t 12.2 min. _{MALDI m / z calculated for C 21} H 36 N 5 O 8 S + [M + H] &lt; ⁺ &gt; 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): δ 6.57 (q, 1H, J = 7.2), 4.63-4.55 (m, 3H), 4.46 (t, 1H, J = 5.6), 3.97-3.88 (m, 3H), 2.13 (s, 3H), 2.12 (m, 2H), 2.40 -1.98 (m, 4H), 1.86 (s, 3H), 1.81 (d, 3H, J = 7.2). ¹³ C NMR (125 MHz, D ₂ O): 隆 175.7, 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] &lt; ⁺ &gt; 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)

(5-chloroindole-2-carboxylyl) -proline-serine-methionine was synthesized as a solid in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1. Mass spectrometry spectrometry, 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)

The compound was synthesized by the same method as that of 4-5 above, and the 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): δ 7.74 (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, 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 (m, 3H), 2.12-2.01 (m, 4H ), 1.99 (s, 3H), 1.94 (m, IH). ¹³ C NMR (125 MHz, D ₂ O): δ 175.7, 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, , 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-cyanophenylthio) benzoyl) -proline-serine-methionine was synthesized in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1, except that a mass spectrometer (mass spectrometry, 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 in the same manner as in 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): δ 7.85 (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, 1H, J = 8.8, J = 4.8), 4.38 (t, 1H, J = 5.6), 3.92-3.71 (m, 6H), 2.59-2.34 - 1.93 (m, 5 H), 2.07 (s, 3 H). ¹³ C NMR (125 MHz, D ₂ O):? 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, , 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 ( Quiland ) - 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 Example 3, and then synthesized in the same manner as in 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 ( Quiland ) - 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): δ 8.61 (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), 4.44-4.39 (m, 4H), 1.98 (s, 3H), 1.90 (m, 2H), 4.08-4.06 (m, 2H), 3.87-3.83 (m, 1H). ^{13 C NMR (125 MHz, D} 2 O): δ 175.1, 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)

Proline-serine-methionine was synthesized as a solid in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1. Mass spectrometry (MS) was used to synthesize Dpr (2-fluorophenylacetyl) ) Were identified and further confirmed using &lt; ¹ &gt; H NMR and &lt; ¹³ &gt; C NMR.

99.9% Purity. R _t 19.1 min. ^{1 H NMR (400 MHz, D} 2 O): δ 7.43-7.33 (m, 2H), 7.24-7.17 (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, 1H), 2.21 (m, 1H), 2.09 (s, 3H), 2.07-1. ^{13 C NMR (100 MHz, D} 2 O): δ 175.4, 175.1, 173.4, 171.3, 166.3, 160.9 (d, J C -F = 242.2), 131.9 (d, J C -F = 3.8), 129.6 (d, J C -F = 7.7), 124.5 (d, J _{C -F} = 3.9), 121.2 (d, J _{C -F} = 16.2), 115.3 (d, J _{C -F} = 20.9), 60.9, 60.6, 55.6, 51.7, 48.0, 39.2, 35.5, 35.4, 30.0, 29.4, 29.3, 24.6, 13.9. MALDI m / z calculated for C ₂₄ H ₃₅ FN ₅ O ₇ S ⁺ [M + H] ⁺ 556.22, found 556.29.

<4-12> Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) - proline-serine-methionine ( Dpr  (7-methoxy-1-benzofuran-2-carboxylyl) -Pro-Ser-Met)

(7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine-methionine was synthesized as a solid in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1 , Mass spectrometry (MS), 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): δ 7.57 (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): δ 174.9, 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, , 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 Example 3, and then synthesized in the same manner as in Example 4-1, except that Dpr (aurotyl) -prolylene-serine-methionine synthesized by mass spectrometry The compound was identified and further confirmed using &lt; ¹ &gt; H NMR and &lt; ¹³ &gt; C NMR.

99.9% Purity. R _t 13.8 min. ^{1 H NMR (400 MHz, D} 2 O): δ 6.37 (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 (m 2H), 2.10 (s, 3H), 2.10-1.95 (m, 3H), 3.74 (m, ). ^{13 C NMR (125 MHz, D} 2 O): δ 175.5, 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-1-cyclopropanecarboxylyl) -Pro-Ser-Met)

Proline-serine-methionine was synthesized as a solid in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1, except that Dpr (1-cyano-1-cyclopropanecarboxylyl) (mass spectrometry, 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): δ 4.63-4.56 (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 , 4H). ¹³ C NMR (100 MHz, D ₂ O): δ 177.9, 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 ) - proline-serine-methionine ( Dpr (? -cyano-4-hydroxycinnamyl) -Pro-Ser-Met)

Was synthesized in the same manner as in Example 3, except that Dpr (alpha-cyano-4-hydroxycinnamyl) -proline-serine-methionine was synthesized in the solid phase and then synthesized in the same manner as in Example 4-1, (mass spectrometry, 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): δ 8.12 (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): δ 173.6, 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, , 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] &lt; ⁺ &gt; 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 Example 3, and then synthesized in the same manner as in Example 4-1. Mass spectrometry (MS ). &Lt; / RTI &gt;

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 Example 3, and then synthesized in the same manner as in Example 4-1, except that Dpr ((R) - (+) - mass spectrometry, 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 ) &Lt; / RTI &gt; acetyl) -prolyl-serine-methionine ( Dpr (2- (4-methylphenylsulfonamido) acetyl) -Pro-Ser-Met)

(2- (4-methylphenylsulfonamido) acetyl) -proline-serine-methionine was synthesized in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1, (mass spectrometry, 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 in the same manner as in Example 3, and then synthesized in the same manner as in Example 4-1, and a mass spectrometer mass spectrometry, 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): δ 7.56 (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, 1H, J = 8.8, J = 4.4), 4.49 (t, 1H, J = 5.6), 4.09 (dd, 1H, J = 14.8, J = 4.0), 3.96-3.82 (m, 4H), 2H), 2.35 (m, 1H), 2.18 (m, 1H), 2.09 (s, 3H), 2.07-1.97 (m, 4H). ^{13 C NMR (125 MHz, D} 2 O): δ 175.9, 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.

< Example  5> Isonicotinic -Trp- Tyr -Val- Of Dpr (acyl)  synthesis

In general, the synthesis of isonicotinic-Trp-Tyr-Val-Dpr (acyl) was performed under the conditions of Example 4 above. However, since the size of the Mtt protecting group was large, Fmoc-Dpr (Mtt) anhydride was prepared using DMAP / DIC (85.8%) using HBTU as a coupling reagent rather than loading resin (79.2%) was more effective than loading two times.

Synthesis of isonicotinic-Trp-Tyr-Val-Dpr (acyl) was also carried out using Fmoc-based SPPS in Wang resin (Scheme 5), except for α-cyano-4-hydroxy cinnamic acid (107-120). &Lt; / RTI &gt;

<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 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 (0.30 mL, 2.2 mmol) was dissolved in anhydrous DMF (10.0 mL), added to the swollen resin for 3 minutes, mixed with orbital shaker (130 rpm) for 3 hours, and the solvent was drained. DMF, washed with iPrOH and CH ₂ Cl ₂ (15 mL x 1 m x 3, respectively). As a result of Fmoc quantification using UV Spectroptometry, the loading level was 71.7%. The reaction was repeated twice (85.8%) to increase the loading level.

The isonitrile-tryptophan-tyrosine-valine-Dpr (aurothyl) was synthesized as a solid in the same manner as in Example 3, assuming that the concentration of the resin was 0.4 mmol by calculating the loading level at 90% degassed 94% TFA cocktail (0.7 mL) was added to the resin (35 mg, 0.0154 mmol), and the mixture was stirred at room temperature for 1 hour. After filtration, the filtrate was washed with TFA solution (0.4 mL X 2) received. The supernatant was collected, and TFA was removed using an evaporator, followed by decantation three times using cold ether. In this case, we used a centrifugal separator in order to prevent loss of the resulting compound, high vacuum dry after 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). After lyophilization, it was confirmed 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): δ 11.34 (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, 1H, 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): δ 171.4, 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] &lt; ⁺ &gt; 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 Example 3, and synthesized in the same manner as in 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): δ 10.74 (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 (m, 1H), 4.55 (m, 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): δ 171.7, 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, Identified HSQC), 36.2, 30.9, 27.2, 20.8, 19.1, 18.0, &lt; RTI ID = 0.0 &gt; 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 - Balin - Dpr (7- Methoxy -One- Benzofuran -2- Car Isonicotinyl-Trp-Tyr-Val-Dpr (7-methoxy-1-benzofuran-2-carboxylyl)

In the same manner as in Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) was synthesized as a solid. . 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): δ 10.73 (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, , 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) , 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): δ 171.6, 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 HSQC), 36.3, 30.9, 27.2, 32.3, 35.8, 37.9, 37.5, 55.7, 54.2, 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 - Balin - Dpr (2- (2- Cyanophenylthio ) Benzo (Isonicotinyl-Trp-Tyr-Val-Dpr (2- (2-Cyanophenylthio) benzoyl)

Tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) was synthesized as a solid in the same manner as in Example 3, and the same procedure as in Example 5-1 was used to prepare isonicotinyl- 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): δ 12.70 (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): δ 171.6, 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 HSQC), 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, ), 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) - (+) - trolyloxy) was synthesized in the same manner as in 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): δ 10.73 (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 (m, , 3H, J = 6.8), 0.84 (d, 3H, J = 6.8). ^{13 C NMR (100 MHz, DMSO-} d 6): δ 173.9, 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 from HSQC), 36.3, 31.1, 29.3, 27.2, 23.3, &lt; RTI ID = 0.0 &gt; 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 - Balin - Dpr (One- Cyano -One- Cyclopropanecarboxylic acid ) ( Isonicotinyl -Trp- Tyr -Val- Dpr (One- cyano -One- cyclopropanecarboxylyl ))

In the same manner as in Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl) was synthesized in the form of a solid. Using the same method as in 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 21.4 min. ^{1 H NMR (400 MHz, DMSO-} d 6): δ 10.74 (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): δ 171.5, 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 (Isonicotinyl-Trp-Tyr-Val-Dpr (rhodanine-3-acetyl)

Isonikotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl) was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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): δ 10.73 (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): δ 202.8, 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] &lt; ⁺ &gt; 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 Example 3, and synthesized in the same manner as in 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.

<5-9> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (4- Pentyl bicyclo [2.2.2] octane -1-carboxylyl) ( Isonicotinyl -Trp- Tyr -Val- Dpr (4- pentylbicyclo [2.2.2] octane  -1-carboxylyl))

Tyrosine-valine-Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) was synthesized as a solid in the same manner as in Example 3, 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.

<5-10> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Quiland ) ( Isonicotinyl - Trp-Tyr-Val-Dpr (quinaldyl))

Isonikotinyl-tryptophan-tyrosine-valine-Dpr (quinadil) was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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

<5-11> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr ( Taiglail ) ( Isonicotinyl  -Trp-Tyr-Val-Dpr (tiglyl))

Isonitriyl-tryptophan-tyrosine-valine-Dpr (tyglyle) was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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.

<5-12> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5- Chloroindole -2- Carboxylate ) (Isonicotinyl-Trp-Tyr-Val-Dpr (5-chloroindole-2-carboxylyl)

In the same manner as in Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-chloroindole-2-carboxylyl) was synthesized in the form of a solid and synthesized in the same manner as in 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.

<5-13> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (5-nitro-3- Pyrazole carboxylate ) ( Isonicotinyl -Trp- Tyr -Val- Dpr (5-nitro-3- pyrazolecarboxylyl ))

In the same manner as in Example 3, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-nitro-3-pyrazolcarboxylyl) was synthesized in the form of a solid and synthesized in the same manner as in 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

<5-14> Isonicotinyl - tryptophan - Tyrosine - Balin - Dpr (2- (4- Methylphenylsulfonamido ) Acetyl) ( Isonicotinyl -Trp- Tyr -Val- Dpr (2- (4- methylphenylsulfonamido ) acetyl))

Tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) was synthesized in the same manner as in Example 3, and the same method as in Example 5-1 was used to synthesize isonicotinyl- 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.

< Example  6> Val- Dpr ( acyl ) -Pro- Ser  / Dpr ( acyl ) -Pro- Ser's  synthesis

Since the biological activity of the truncated peptidomimetic compounds has been shown to be good, the synthesis of another truncated peptidomimetic compound, a compound consisting of trimer and tetramer, the COOH terminus is designed.

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

<6-1> Balin - 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 &lt; 0 &gt; C for 20 min (white solid formation). Dissolve the remaining suspension in a small amount of anhydrous DMF (4.5 mL), dissolve DMAP (0.1 eq, 1.7 mg, 0.014 mmol) in anhydrous DMF (0.1 mL) and add the two solutions to the resin After mixing for 1 hour at room temperature using an orbital shaker (130 rpm), the solvent was drained and washed with DMF, iPrOH and CH ₂ Cl ₂ (10 mL X 1 min X 3, respectively). As a result of Fmoc quantification using UV spectrometry, the loading level was 97.0%.

The resin (200 mg, 0.088 mmol) was swelled in anhydrous DMF for 30 minutes to deprotect the Fmoc group and then an orbital shaker (130 rpm) was added at room temperature for 10 minutes with 20% piperidine / anhydrous DMF After mixing, the solvent was drained and washed with DMF, iPrOH and CH ₂ Cl ₂ (10 mL X 1 min X 3). After vacuum drying with an aspirator for 30 minutes, the Kaiser test was used to confirm that the reaction was complete.

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 Example 3, The Fmoc group was deprotected using anhydrous DMF (0.8 mL), and degassed 94% TFA cocktail (0.8 mL) was added. After mixing for 1 hour at room temperature, the filtrate was filtered, and again with TFA (0.4 mL X 2) Washed and received the filtrate. The supernatant was collected, and TFA was removed using an evaporator, followed by decantation three times using cold ether. After high vacuum drying, the reaction mixture was subjected to semi-preparative HPLC (solvent A: 0.1% TFA / H ₂ O, solvent B: 0.1% TFA / MeOH, 90% B over 31 min), and the resulting compound was identified by mass spectrometry (MS) 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): δ 6.23 (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): δ 174.0, 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> Balin - Dpr (7- Methoxy -One- Benzofuran -2- Carboxylate ) -Proline-serine (Val- Dpr  (7-methoxy-1-benzofuran-2-carboxylyl) -Pro-Ser)

Valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine was synthesized in the same manner as in Example 3 and synthesized in the same manner as in 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): δ 7.56 (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): δ 173.8, 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] &lt; ⁺ &gt; 562.25, found 562.32.

<6-3> Balin - Dpr (3,5- Dimethylbenzoyl ) -Proline-serine (Val- Dpr (3,5-dimethylbenzoyl) -Pro-Ser)

Valine-Dpr (3,5-dimethylbenzoyl) -proline-serine was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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): δ 7.44 (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 (m, 1H), 2.37 (m, 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): δ 173.9, 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, , 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> Balin - Dpr (5- Chloroindole -2- Carboxylate ) -Proline-serine (Val- Dpr  (5-chloroindole-2-carboxylyl) -Pro-Ser)

Valine-Dpr (5-chloroindole-2-carboxylyl) -proline-serine was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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): δ 7.61 (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, 1H, J = 6.8), 4.60-4.56 (m, 2H), 4.01 (dd, 1H, J = 11.6, J = 4.8), 3.93-3.73 (m, 5H) , 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 , 6H, J = 7.2). ¹³ C NMR (100 MHz, D ₂ O): δ 173.7, 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, , 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> Valine - Dpr (2- Fluorophenylacetyl ) -Proline-serine (Val- Dpr (2-fluorophenyl acetyl) -Pro- Ser )

Valine-Dpr (2-fluorophenylacetyl) -proline-serine was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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 )

Dupor (aurothyl) -proline-serine was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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): δ 6.29 (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  -1-benzofuran-2-carboxylyl) -Pro-Ser)

Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine was synthesized in the same manner as in Example 3, and synthesized in the same manner as in 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 Example 3, and synthesized in the same manner as in 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): δ 7.46 (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. 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 Example 3, and synthesized in the same manner as in 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): δ 7.73 (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 , &Lt; / RTI &gt; J = 6.0), 2.12-1.99 (m, 3H). ^{13 C NMR (100 MHz, D} 2 O): δ 173.7, 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 Example 3, and synthesized in the same manner as in 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)

By confirming that the peptidomimetic compounds obtained through the above Examples suppress the secretion of interleukin-8, it was confirmed that the peptidomimetic compounds can be used for the prevention and treatment of rheumatoid arthritis or allergic diseases.

<1-1> Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Example 2

The degree of inhibition of interleukin-8 secretion of dTBP2 of Example 1 and the compounds prepared in 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 &lt; ⁰ &gt; 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> Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Example 3

The degree of inhibition of interleukin-8 secretion of dTBP2 of Example 1 and the compounds prepared in Example 3 was measured and the same method as in 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 &gt; interleukin-8 &lt; / RTI &gt; secretion inhibitory activity.

<1-3> Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Example 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 the 14 compounds prepared in Example 4 except for the non-oxidation type. The measurement results are shown in Table 3 below.

<1-4> Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Example 5

As a result of measuring the degree of interleukin-8 secretion inhibition against 14 compounds prepared in Example 5, 10 out of 4 compounds were found to be more effective than dTBP2 (Table 4).

In order to compare the relative activity between the compound prepared in Example 4 and the compound prepared in Example 5, which were composed of truncated peptidomimetic compounds, bioassay was carried out in the same medium (Fig. 7 ). From these results, it was found that 24 of the compounds prepared in Example 4 and the compounds prepared in Example 5 showed stronger activity than dTBP2. Also, looking at the top four compounds prepared in Examples 4 and 5, it can be seen that the three compounds of acids 93, 99, 103, 100 of Example 4 and 107, 109, 108 and 114 of 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> Confirmation of the degree of inhibition of interleukin-8 secretion of the compound prepared in Example 6

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

< Experimental Example  2> Biological activity test using competition assay

The peptidomimetic compounds were designed and synthesized in 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 conducted for all of the peptidomimetic compounds synthesized in Examples 2 to 6, and the following 32 compounds of the top 32 compounds Respectively. FIG. 9 shows the results of in situ competition assay of the compound prepared in Example 2. FIG. From the results shown in FIG. 9, one compound was found to be acylated with isonicotinic acid.

< Experimental Example  3> IC for interleukin-8 secretion inhibitory activity 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 values were measured. Of these 22 compounds, IC ₅₀ values were found to be lower than dTBP 2 (IC ₅₀ = 960 nM), and 110 was found to have the lowest IC ₅₀ values (Table 7).

< Experimental Example  4> Peptidomic  Inhibition of histamine release by compounds

A PCR-cloned rat IgE-dependent histamine releasing factor (HRF) full-length sequence (Chitpatima et al., 1988) was cloned into the pRSET-A vector and overexpressed in E. coli . The expressed recombinant protein was purified using His-bound Ni column (Novagen) and used to stimulate RBL-2H3 cells. RBL-2H3 was grown in 24-wells with 1 x ¹⁰⁶ cells, followed by sensitization with rat IgE antibody (0.2 [mu] g / ml, Serotec) for 45-60 min and treated with 20 [mu] g / ml recombinant HRF protein ). The cells prepared as described above were treated with the peptidomimetic compound in a dose-dependent manner.

The sample obtained above was prepared as an acylated histamine using RIA-assay kit (Immunotech, France) and then competitively bound to ¹²⁵ I-acylated histamine and monoclonal antibody. This sample was again measured in a gamma-counter. As a result, it was confirmed that when the peptidomimetic compound was added to RBL-2H3 cells, the secretion of histamine by HRF was suppressed from 0.01 μg / ml.

< Experimental Example  5> Rheumatism  Arthritis in animal models Peptidomic  Identification of Rheumatoid Arthritis Therapeutic Effect of Compounds

The present inventors confirmed that the peptidomimetic compound of the present invention inhibits the activity of HRF or affects HRF or its receptor in the <Experimental Example 4>, thereby confirming that it has a preventive effect against rheumatoid arthritis. A variety of animal models have been used to study rheumatoid arthritis, the most widespread of which is the collagen-induced arthritis (CIA) mouse model. The inventors of the present invention found that the peptidomimetic compounds prepared in the above Examples had the same effect as that of the valine-Dpr (7-methoxy-1-benzofuran-2-ene) of Examples <6-2>, <6-3> (Val-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -Pro-Ser) "," valine-Dpr (3,5-dimethylbenzoyl) -proline-serine 5-chloroindole-2-carboxylyl-Pro-Ser) "and" Dpr (5-chloroindole-2-carboxylyl) In order to confirm the effect of the compound for preventing arthritis in collagen-induced arthritis mice, the following experiment was conducted.

Specifically, to induce CIA, a 7-week-old male DBA1 / j mouse was purchased and the mice were administrated for 1 week or more. Then, the mice were treated with complete Freund's (Sigma) supplemented with bovine type 2 collagen (Type 2 collagen 2 mg / ml, Chondrex) Adjuvant (CFA containing 2 mg / ml M. tuberculosis, Chondrex) was mixed 1: 1 and 150 μl was slowly injected through the subcutaneous 2 cm below the base of the tail (0 day difference). After 3 weeks, a second injection was performed. Incomplete Freund's adjuvant (IFA) and bovine type II collagen solution were also mixed at a ratio of 1: 1 instead of CFA, and 100 μL of the mixed solution was slowly injected through the base of the tail of the tail ). Thereafter, the mice were divided into a control group (vehicle-only group) and a group to which 25 mg / kg of the peptidomimetic compound of the present invention was administered (n = 6). After arthritis induction (after the second immunization) 3 times a week. The peptidomimetic compounds of Examples <6-2>, <6-3> and <6-9> were dissolved and administered by 1.5 mg per 1 ml of PBS. Clinical scores were evaluated by grossly observing the development and progression of arthritis over a period of about 35-45 days after administration. The gross evaluation method of specific arthritis was evaluated in the following 0 to 4 steps (score) for each leg through the score of severity of arthritis, and the score of arthritis was as follows:

0, no swelling or swelling;

1, with mild edema and flare limited to the toe or ankle joint;

2, with moderate edema and redness from the ankle joint to the toes;

3, with severe swelling and redness throughout the toes from the ankle;

4: An ankle to the whole toe with severe edema and flare or joint stiffness.

The arthritic score was 0 to 4 points per knot in each of four feet, and arthritis score was assigned in the range of 0 to 16 points in each knot. The average value and standard error of arthritis score Respectively.

As a result, as shown in Figs. 10 to 12, the group to which 25 mg / kg of the peptidomimetic compound of Examples <6-2>, <6-3> and <6-9> One group showed improvement of clinical symptoms and treatment of rheumatoid arthritis. As the time elapsed, it was found that the administration of 25 mg / kg of the peptidomimetic compound inhibited the incidence than the control group (vehicle only). It was confirmed that the peptidomimetic compound of the present invention has an effect of treating rheumatoid arthritis.

<110> Ewha University - Industry Collaboration Foundation <120> Pharmaceutical composition comprising peptidomimetic compounds          for prevention and treating rheumatoid arthritis <130> 2016P-06-066 <150> KR 10-2015-0094598 <151> 2015-07-02 <160> 1 <170> Kopatentin 2.0 <210> 1 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> dTBP2 protein <400> 1 Trp Tyr Val Tyr Pro Ser Met   1 5

Claims (14)

delete delete A pharmaceutical composition for the prevention or treatment of rheumatoid arthritis, comprising a peptidomimetic compound of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

(R ₁ is in the formula (1)

,

,

or

And WYVYPSM is the amino acid sequence of SEQ ID NO: 1).
delete delete A pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising a peptidomimetic compound or a pharmaceutically acceptable salt thereof as an active ingredient:
The peptidomimetic compound may be selected from isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl) -proline-serine- methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Dimethyl-benzoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamyl) -proline-serine-methionine oxidized form, isonicotinyl- Tyrosine-valine-Dpr (alpha-cyano-4-hydroxycinnamyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine- (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine disulfide, isonicotinyl-tryptophan-tyrosine-valine-Dpr Thionine-valine-Dpr (2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine non-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- (2-naphthoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-naphthoyl) -purine-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 (biphenyl-4-carboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (phenylglyoxyl) -proline- Serine-methionine oxidized form, tryptophan-tyrosine-valine-Dpr (phenylglyoxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl) Tyrosine-valine-Dpr (2-fluorophenylacetyl) -prolyine-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (trans- Methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (trans- Tyrosine-valine-Dpr (1-naphthoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (5-nitro-2-furoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan- Tyrosine-valine-Dpr (5-nitro-2-furoyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (beta-naphthoxyacetyl) -proline-serine-methionine oxidized form , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-phenoxybenzoyl) -proline-serine - methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-phenoxybenzoyl) -proline-three Methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine- methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine -Drpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-methoxyhexanoyl) - methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-methoxyhexanoyl) -proline-serine- methionine disappeared, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3- chlorobenzo [ thiophene-2-carboxyyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (3-chlorobenzo [ - methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinadyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine -Prinoline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (quinadyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine- Tyrosine-valine-Dpr (isonicotinyl) proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine- Serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-PrP (5-chloroindole-2-carboxylyl) -proline-serine-methionine oxidized form, Tyrin-tryptophan-tyrosine-valine-Dpr (5-phenyl-2-furoyl) -pyridine- - proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (5-phenyl-2-furoyl) Tyrosine-valine-Dpr (5-nitro-3-pyrazolecarboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine- Dpr (5-nitro-3-pyrazolecarboxylyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr ((R) - (+) - Methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr ((R) - (+) - troloxyl) -proline-serine- methionine depleted form, isonicotinyl-tryptophan-tyrosine-valine-Dpr ) - (+) - 2-pyrrolidone-5-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Threonine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan- Isonicotinylate Tyrosine-valine-Dpr (rhodanine-3-acetyl) - pyruvate-tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl) -proline-serine- methionine disappeared, isonicotinyl- Proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (rhodanine-3-acetyl) (7-hydroxycoumarin-4-acetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrin-tryptophan-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl) -proline-serine-methionine oxidized form, isonicotinyl- Amido) acetyl) -proline-serine-methionine non-oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-acetylpiperidine-4-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr , Isonicotinyl-tryptophan-tyrosine-valine-Dpr (1-phenyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylyl) -proline-serine- methionine oxidized form, isonicotinyl- - tyrosine-valine-Dpr (1-phenyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylyl) -proline-serine-methionine disappeared, isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-thiopheneacetyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr - valine-Dpr (benzotriazol-5-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan-tyrosine-valine-Dpr (benzotriazole- Tyrosine-valine-Dpr (4-oxo-4H-chromene-3-carboxylyl) -proline-serine-methionine oxidized form, isonicotinyl-tryptophan- Tyrosine-valine-Dpr (4-methyl-2-oxo-4-oxo-4H-chromene-3-carboxylyl) -proline-serine- methionine disappeared, isonicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr (4-methyl-2-oxo-2H-chromen-7-yloxy) -2-oxo- Cyano) acetyl) -prolyine-serine-methionine non-oxidation type.
delete A pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising a peptidomimetic compound or a pharmaceutically acceptable salt thereof as an active ingredient:
The peptidomimetic compound may be selected from the group consisting of Dpr (4-pentylbicyclo [2.2.2] octane-1-carboxylyl) -proline-serine-methionine oxidized form, Dpr (4-pentylbicyclo [2.2.2] Dpr (5-chloroindole-methionine oxidized form, Dpr (tyglyle) -proline-serine-methionine non-oxidized form, Dpr Dpr (5-chloroindole-2-carboxylyl) -proline-serine-methionine oxidized form, Dpr (2- (2-cyanophenylthio) benzoyl) - Proline-serine-methionine oxidized form, Dpr (2- (2-cyanophenylthio) benzoyl) -proline-serine-methionine non-oxidized form, Dpr (quinadyl) Dpr (7-methoxy-1-benzofuran-2-carboxylyl) -proline-serine-methionine, Dpr (2-fluorophenylacetyl) (Orotile) - Proline - Serine - Methy Dpr (1-cyano-1-cyclopropanecarboxylyl) -proline-serine-methionine, Dpr (alpha-cyano-4-hydroxycinnamyl) -proline-serine- methionine, Dpr Proline-serine-methionine, Dpr ((R) - (+) - troloxyl) -proline-serine-methionine, Dpr (2- (4-methylphenylsulfonamido) acetyl) And Dpr (5-nitro-3-pyrazolecarboxylyl) -proline-serine-methionine.
delete A pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising a peptidomimetic compound or a pharmaceutically acceptable salt thereof as an active ingredient:
The peptidomimetic compounds may be selected from isonicotinyl-tryptophan-tyrosine-valine-Dpr (aurotyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (3,5-dimethylbenzoyl), isonicotinyl-tryptophan-tyrosine - valine-Dpr (2- (2-cyanophenylthio) benzoyl), isonicotinyl-tryptophan-tyrosine-valine- Tyrosine-valine-Dpr (1-cyano-1-cyclopropanecarboxylyl), isonicotinyl-tryptophan-tryptophan-tyrosine-valine-Dpr ((R) - Tyrosine-valine-Dpr (rhodanine-3-acetyl), isonicotinyl-tryptophan-tyrosine-valine-Dpr (2-fluorophenylacetyl), isonicotinyl- (Isoquinoline), isonicotinyl-tryptophan-tyrosine-valine-Dpr (tyglyle), isonicotinyl-tryptophan-tyrosine-valine-Dpr Tyrosine-valine-Dpr (5-nitro-3-pyrazolecarboxylyl) and isonicotinyl-tryptophan-tyrosine-valine- Tryptophan-tyrosine-valine-Dpr (2- (4-methylphenylsulfonamido) acetyl).
delete A pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising a peptidomimetic compound or a pharmaceutically acceptable salt thereof as an active ingredient:
The peptidomimetic compound may be selected from the group consisting of Dpr (aurotyl) -pro- rine-serine, Dpr (7-methoxy-1-benzofuran-2-carboxyyl) -proline-serine, Dpr (3,5-dimethylbenzoyl) Serine, Dpr (5-chloroindole-2-carboxylyl) -proline-serine and Dpr (2-fluorophenylacetyl) -proline-serine.
delete A pharmaceutical composition for preventing or treating rheumatoid arthritis, comprising a peptidomimetic compound or a pharmaceutically acceptable salt thereof as an active ingredient:
The peptidomimetic compounds may be selected from the group consisting of valine-Dpr (aurotyl) -prolyl-serine, valine-Dpr (7-methoxy-1-benzofuran- -Drpr (5-chloroindole-2-carboxylyl) -proline-serine and valine-Dpr (2-fluorophenylacetyl) -proline-serine It is either.

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