JP2008106005A - Compound having amino acid residue or peptide residue and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having a structure bondable to various compounds and supporting carriers and having a side chain containing an amino acid or an oligopeptide and bonded to a main chain. <P>SOLUTION: The compound is expressed by general formula (1). In formula (1), n1 is an integer of 0-10; n2 is an integer of 1-50; n3 is an integer of 1-10; m1 is an integer of 0-100; m2 is an integer of 0-100; m3 is an integer of 0-100; m4 is an integer of 0 or 1; m5 is an integer of 0-100; m6 is an integer of 0-100; Y<SB>1</SB>is a hydroxyl group or an amino group; E is N or CH; R is an amino acid residue or a peptide residue composed of 2-100 amino acid residues; and L is an amino group to which a functional group (excluding an amino group) capable of forming a peptide bond, a disulfide bond or a biotin-avidin bond is bonded through a linker. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a compound having an amino acid residue or a peptide residue and capable of effectively expressing the functionality of the residue. Furthermore, this invention relates to the manufacturing method of the said compound.

  Various useful actions according to the type of amino acid or oligopeptide are known. For example, arginine and its oligopeptides are known to have an action of permeating the cell membrane, and are known to be useful as reagents for introducing a target substance into cells. In addition, it may be advantageous to use a compound in which a plurality of these amino acids are combined rather than using an amino acid or an oligopeptide alone in terms of enhancement of desired action and improvement of safety. I know.

  So far, the present inventors have found a compound in which a side chain having an amino acid or an oligopeptide is bonded to the main chain and a method for producing the same, and have filed patent applications for these compounds (International Application No. PCT / JP2006 / 308476). .

However, in the technical field that effectively utilizes the functions of amino acids and oligopeptides, development of further improved technologies is enormous, and compounds having amino acids and oligopeptides have new structures, new functions, new It is anxious to develop applications. In particular, development of compounds that can be easily bound to various compounds and holding carriers and that can effectively express the functions of amino acids and oligopeptides is desired.
Japanese National Patent Publication No. 10-502337

  An object of the present invention is to provide a novel compound having a structure in which a side chain having an amino acid or an oligopeptide is bound to a main chain, which can be bound to various compounds and holding carriers. In addition, the present invention provides a novel compound that can be bound to various compounds and holding carriers, in which a side chain having an amino acid or an oligopeptide is bound to a main chain, and a functional group is protected by a protecting group. For the purpose. Furthermore, this invention aims at providing the manufacturing method of the said compound.

The present invention provides compounds represented by the following general formulas (1) and (1a), and methods for producing them:
Item 1. Compound represented by the following general formula (1):

[In the formula (1), n1 represents an integer of 0 to 10, n2 represents an integer of 1 to 50, and n3 represents an integer of 1 to 10;
m1 is an integer from 0 to 100, m2 is an integer from 0 to 100, m3 is an integer from 0 to 100, m4 is an integer from 0 or 1, m5 is an integer from 0 to 100, and m6 is an integer from 0 to 100 ;
Y ₁ represents a hydroxyl group or an amino group;
E represents N or CH;
R represents an amino acid residue or a peptide residue consisting of 2 to 100 amino acid residues;
L represents an amino group to which a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding the amino group) is bonded via a linker;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and R in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ]
Item 2. Item 2. The compound according to Item 1, wherein L is an amino group to which a thiol group or a carboxyl group is bonded via a linker.
Item 3. In the formula (1), R is an amino acid residue selected from the group consisting of an arginine residue, a lysine residue, and a serine residue, or a peptide residue containing at least one of these amino acid residues. Item 3. The compound according to Item 1 or 2.
Item 4. Item 3. The compound according to Item 1 or 2, wherein, in the formula (1), R is a peptide residue composed of 2 to 5 arginine residues.
Item 5. Item 5. The compound according to any one of Items 1 to 4, wherein n1 is an integer of 0 to 2, n2 is an integer of 1 to 10, and n3 is an integer of 0 to 2.
Item 6. Item 6. The compound according to any one of Items 1 to 5, wherein in Formula (1), E is N, m2 is 2, m3 and m4 are 1, and m5 is 5.
Item 7. Compound represented by the following general formula (1a):

[N1-n3, m1-m6, E and R are the same as above,
Y ₂ represents a solid phase resin;
X is a protecting group X ₁ , a hydrogen atom, a group —CO—L (L is the same as described above), a group —CO—LX ₁ (L is the same as described above. LX ₁ is a functional group in L and a protecting group X ₁ Indicates that they are bound);
Z represents different protecting group Za, or a protecting group X ₁ and the same protective groups Zb is a protecting group X _1;
RZ means that a protective group Z is bonded to the functional group of the amino acid residue or peptide residue of R;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and RZ in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ]
Item 8. In formula (1a), R comprises an amino acid residue selected from the group consisting of an arginine residue, a lysine residue, and a serine residue, or at least one of these amino acid residues, and the total number of amino acid residues Item 8. The compound according to Item 7, wherein is 2 to 20 peptide residues.
Item 9. Item 9. The compound according to Item 7 or 8, which is a peptide residue composed of 2 to 5 arginine residues in the formula (1a).
Item 10. Item 10. The compound according to any one of Items 7 to 9, wherein in the formula (1a), n1 is an integer of 0 to 2, n2 is an integer of 1 to 10, and n3 is an integer of 0 to 2.
Item 11. Item 11. The compound according to any one of Items 7 to 10, wherein in formula (1a), E is N, m2 is 2, m3 and m4 are 1, and m5 is 5.
Item 12. A method for producing a compound represented by the following general formula (1), comprising the following steps 1-1 to 1-6:

[In the formula (1), n1 represents an integer of 0 to 10, n2 represents an integer of 1 to 50, and n3 represents an integer of 1 to 10;
m1 is an integer from 0 to 100, m2 is an integer from 0 to 100, m3 is an integer from 0 to 100, m4 is an integer from 0 or 1, m5 is an integer from 0 to 100, and m6 is an integer from 0 to 100 ;
Y ₁ represents a hydroxyl group or an amino group;
E represents N or CH;
R represents an amino acid residue or a peptide residue consisting of 2 to 100 amino acid residues;
L represents an amino group to which a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding the amino group) is bonded via a linker;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and R in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ]
Step 1-1: Compound represented by the following general formula (I)

[In formula (I), X ₁ represents a protecting group, and m6 is the same as defined above. ]
Is condensed to a solid phase resin or a solid phase compound, and then the elimination of the protecting group X ₁ of the compound condensed to the solid phase resin and the condensation polymerization of the compound represented by the general formula (I) are performed n3 −1 times. By carrying out, the compound represented by the following general formula (i)

Wherein (i), n3, m6, and X ₁ are as defined above. Y ₂ represents a solid phase resin. ]
Obtaining a step,
Step 1-2: Compound represented by the following general formula (II) with respect to the compound represented by the general formula (i)

Wherein (II), m2~m5, and X ₁ are as defined above, Za represents a protecting group different from X _1. ]
The compound represented by the following general formula (ii) by performing the condensation reaction of n2 times

Wherein (ii), n2, n3, m2~m6, X 1, Za and Y ₂ are as defined above. ]
Obtaining a step,
Step 1-3: A compound represented by the following general formula (III) with respect to the compound represented by the general formula (ii)

Wherein (III), m1 and X ₁ are as defined above. ]
The compound represented by the following general formula (iii) by performing the condensation reaction of n1 times

[In the formula (iii), n1 to n3, m1 to m6, X ₁ , Za and Y ₂ are the same as above. ]
Obtaining a step,
Step 1-4: After removing the protecting group X ₁ of the compound represented by the general formula (iii), the amino group from which the protecting group X was removed and the compound X ₁ L-COOH [X ₁ and L is the same as described above, and X ₁ L is a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding an amino group), and is a functional group protected with a protecting group X ₁ Represents an amino group bonded through a linker] to obtain a compound represented by the following general formula (iv),

[In the formula (iv), n1 to n3, m1 to m6, X ₁ L, Za and Y ₂ are the same as above. ]
Step 1-5: Condensation reaction of an amino acid in which a protecting group Za is bonded to a functional group other than a carboxyl group bonded to the α-position carbon atom for the compound represented by the general formula (iv) 1 to 100 times By carrying out, the compound represented by the following general formula (v)

[In the formula (iv), n1 to n3, m1 to m6, X ₁ L, RZa and Y ₂ are the same as above. ]
Steps 1-6: From the compound represented by the general formula (v), the solid phase resin is separated to form —COOH or —CONH ₂ at the terminal, and the protecting groups X ₁ and Za are eliminated. A step of obtaining a compound represented by the general formula (1).
Item 13. A method for producing a compound represented by the following general formula (1a), comprising the following steps 3-1 to 3-5:

[N1-n3, m1-m6, E and R are the same as above,
Y ₂ represents a solid phase resin;
X is a protecting group X ₁ , a hydrogen atom, a group —CO—L (L is the same as described above), a group —CO—LX ₁ (L is the same as described above. LX ₁ is a functional group in L and a protecting group X ₁ Indicates that they are bound);
Z represents different protecting group Za, or a protecting group X ₁ and the same protective groups Zb is a protecting group X _1;
RZ means that a protective group Z is bonded to the functional group of the amino acid residue or peptide residue of R;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and RZ in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ]
Step 3-1: Compound represented by the following general formula (I)

[In the formula (I), X ₁ and m6 are the same as above. ]
Is condensed to a solid phase resin having an amino group, and then the elimination of the protecting group X ₁ of the compound condensed to the solid phase resin and the condensation polymerization of the compound represented by the general formula (I) are performed as n3 −1. The compound represented by the following general formula (i)

Wherein (i), n3, m6, X 1 and Y ₂ are as defined above. ]
Obtaining a step,
Step 3-2: Compound represented by the following general formula (II) with respect to the compound represented by the general formula (i)

Wherein (II), m2~m5, X ₁ and Za are as defined above. ]
The compound represented by the following general formula (ii) by performing the condensation reaction of n2 times

Wherein (ii), n2, n3, m2~m6, X 1, Za and Y ₂ are as defined above. ]
Obtaining a step,
Step 3-3: Compound represented by the following general formula (III) with respect to the compound represented by the general formula (ii)

Wherein (III), m1 and X ₁ are as defined above. ]
The compound represented by the following general formula (iii) by performing the condensation reaction of n1 times

[In the formula (iii), n1 to n3, m1 to m6, X ₁ , Za and Y ₂ are the same as described above. ]
Obtaining a step,
Step 3-4: The protecting group X1 of the compound represented by the general formula (iii) is removed, and the compound X-OH [X is the same as described above]. ] To obtain a compound represented by the following general formula (iv-a),

Wherein (iv-a), n1~n3, m1~m6, X, Za and Y ₂ are as defined above. ]
Step 3-5: A compound represented by the general formula (iv-a) is subjected to a condensation reaction of an amino acid in which a protective group Z is bonded to an amino group 1 to 100 times, whereby the general formula (1a) A step of obtaining a compound represented by the formula:

  Hereinafter, in the present specification, “membrane permeability” refers to a property of permeating a cell membrane.

  The compounds represented by the general formulas (1) and (1a) of the present invention have amino acids or oligopeptides in their side chains and can more effectively exhibit useful activities based on these amino acids or oligopeptides. In particular, in the compound represented by the general formula (1), by providing an amino acid selected from the group consisting of arginine, lysine, and serine or an oligopeptide containing these amino acids, it effectively exhibits a membrane permeation function. Can do.

  Furthermore, the compounds represented by the general formulas (1) and (1a) of the present invention include amino acids, PNA (peptide nucleic acid) oligomers, PNA monomers, artificial nucleic acids, peptides, lipids, fatty acids, carbohydrates, proteins, sugar chains, nucleic acids. It can be easily combined with target compounds such as enzymes, antibodies, fluorescent labeling compounds, physiologically active substances, pharmacologically active substances, or holding carriers such as microbeads, magnetic beads, and nanobeads. Therefore, the compound represented by the general formulas (1) and (1a) of the present invention binds to the target compound or the holding carrier, whereby an amino acid or an oligosaccharide having a membrane permeability or the like is formed with respect to the target compound or the holding carrier. Useful activity based on peptides can be conferred.

  Furthermore, in the compounds represented by the general formulas (1) and (1a) of the present invention, the side chain portion has a branched structure, so that it is difficult to undergo in vivo molecular recognition. Because of these advantages, (i) a long-lasting effect can be expected as a substrate that is difficult to undergo metabolism, (ii) even when the side chain moiety is used simply by linking it, even if it shows high toxicity, the present invention By adopting the structure of the compounds represented by the general formulas (1) and (1a), it is possible to enjoy the usefulness such that the effect of suppressing the toxicity can be expected while maintaining its function, It can be said that the range of biological applications is wide.

1. A compound represented by the following general formula (1) is provided as a compound having a structure in which a side chain having an amino acid or oligopeptide having the amino acid or oligopeptide is bonded to the main chain.

  In the formula (1), n1 represents the number of the repeating unit A, and represents an integer of 0 to 10, preferably an integer of 0 to 5, more preferably an integer of 0 to 2.

  In the repeating unit A, m1 represents an integer of 0 to 100, preferably an integer of 0 to 30, more preferably an integer of 0 to 11. When n1 is an integer of 2 or more, that is, when there are two or more repeating units A, m1 may be the same or different in each repeating unit A.

  In formula (1), n2 represents the number of repeating units B, and represents an integer of 1 to 50, preferably an integer of 1 to 20, and more preferably an integer of 1 to 10.

  In the repeating unit B, m2 represents an integer of 0 to 100, preferably an integer of 0 to 20, and more preferably an integer of 0 to 2. m3 represents an integer of 0 to 100, preferably an integer of 0 to 20, more preferably an integer of 0 to 2. m4 represents an integer of 0 or 1. m5 represents an integer of 0 to 100, preferably an integer of 0 to 30, more preferably an integer of 0 to 11.

  In the repeating unit B, E represents N or CH. In repeating unit B, when E is N, m2 is 0-2, preferably 2, m3 is 0-1, preferably 1, m4 is 1, m5 is 0-11, preferably The compound which is 5 is illustrated suitably. In the repeating unit B, when E is CH, m2 is 0 to 2, preferably 0; m3 is 0 to 1, preferably 0; m4 is 0; m5 is 0 to 11, The compound which is preferably 5 is preferably exemplified.

  In the repeating unit B, R represents an amino acid residue or a peptide residue composed of 2 to 100 amino acid residues. Of R, the amino acid residue may be either a natural amino acid residue or a non-natural amino acid residue, and is not particularly limited, but an α amino acid is preferred. From the viewpoint of imparting membrane permeability to the compound represented by the general formula (1), an arginine residue, a lysine residue, and a serine residue are preferable, and an arginine residue is more preferable.

  In addition, the type of constituent amino acid residues is not particularly limited as long as the peptide residues in R are composed of 2 to 100 amino acid residues. As an example of the peptide residue, at least one selected from the group consisting of an arginine residue, a lysine residue, and a serine residue from the viewpoint of providing the compound represented by the general formula (1) with membrane permeability. Peptide residues containing only the amino acid residues; preferably peptide residues having only arginine residues, lysine residues, and serine residues as constituent amino acid residues; particularly preferably only arginine residues and / or lysine residues. Peptide residues as constituent amino acid residues are exemplified.

  In addition, when the peptide residue includes a lysine residue as a constituent amino acid residue, either the α-position or the ε-position amino group of lysine, or both of the amino groups are adjacent to the carboxyl group of the adjacent amino acid. Peptide bonds can be constructed.

  The number of amino acid residues constituting the peptide residue is preferably 2 to 50, more preferably 2 to 20, more preferably 2 to 5, particularly preferably 2 to 3.

  An example of a preferred form of R is a peptide residue consisting of 2 to 5 arginine residues, and a particularly preferred example is a triarginine residue consisting of 3 arginine residues. By having such a peptide residue, the compound represented by the general formula (1) can be provided with more excellent membrane permeability.

  In repeating unit B, the amino acid residue or peptide residue is bonded in a form in which the carboxyl group of the constituent amino acid on the C-terminal side is dehydrated and condensed with the amino group of the side chain of the repeating unit. That is, the amino acid residue or peptide residue of R corresponds to a group in which the OH of the carboxyl group of the constituent amino acid on the C-terminal side of the amino acid or peptide is removed.

  In repeating unit B, when m2 is an integer of 2 or more, that is, when there are two or more repeating units B, m2 to m5 and R may be the same or different in each repeating unit B. May be.

  In the formula (1), n3 represents the number of repeating units C and represents an integer of 0 to 10, preferably an integer of 0 to 5, more preferably an integer of 0 to 2.

  In the repeating unit C, m6 represents an integer of 0 to 100, preferably an integer of 0 to 30, more preferably an integer of 0 to 11. When n3 is an integer of 2 or more, that is, when there are two or more repeating units C, m6 may be the same or different in each repeating unit C.

  As specific examples of n1 to n3 in the formula (1), n1 is an integer of 0 to 2, n2 is an integer of 1 to 10, and n3 is an integer of 0 to 2, particularly preferably, n1 is an integer of 1 or 2. Examples are n2 is an integer of 4 to 6, and n3 is an integer of 1 or 2.

In the formula (1), Y ₁ represents a hydroxyl group or an amino group.

  In the formula (1), L represents an amino group to which a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding the amino group) is bonded via a linker.

  Here, among the functional groups in L, specific examples of the functional group capable of forming a peptide bond include a carboxyl group, a maleimide group, an aldehyde group, a succinimide group, and a pentafluorophenyl group. Moreover, a thiol group is illustrated as a functional group which can form a disulfide bond. Examples of functional groups capable of forming a biotin-avidin bond include biotin residues and avidin residues. The functional group in L is preferably a carboxyl group and a thiol group, more preferably a thiol group.

  Further, in L, the linker that bonds the functional group and the amino group is not particularly limited, but examples of the linker shown in the following (a) and (b) are illustrated. Is done.

  i represents an integer of 1 to 20, preferably 1 to 8, and j represents an integer of 1 to 1000, preferably 1 to 21.

Further, when the functional group in L is a carboxyl group, L may be an amino acid residue, that is, a group in which one hydrogen atom has been removed from the amino group of the amino acid. In addition, when the functional group in L is a thiol group, the linker is bonded to an amino group via —CH ₂ CHNH ₂ CO— as a linker, that is, L is a group HS—CH ₂ CHNH ₂ CO—NH. -May be sufficient.

In the formula (1), preferable examples of L include a group HS— (CH ₂ ) _i —NH— and a group HOOC— (CH ₂ ) _i —NH— (j and i are as defined above).

  When the compound represented by the general formula (1) has the above L, it binds to another compound having a functional group capable of forming a peptide bond, a disulfide bond, or a biotin-avidin bond, a holding carrier, or the like to form a complex. Can be formed. For example, when the functional group in L is capable of forming a peptide bond, the compound of the general formula (1) is subjected to a condensation reaction with another compound having a functional group capable of forming a peptide bond or a holding carrier. , Can be combined. When the functional group in L is a thiol group, the compound of the general formula (1) can be bonded to another compound having a thiol group or a holding carrier by a disulfide bond. In addition, when the functional group in L is a biotin residue, the compound of the general formula (1) can be bound to another compound having an avidin residue or a holding carrier by a biotin-avidin bond. Further, when the functional group in L is an avidin residue, the compound of the general formula (1) can be bound to another compound having a biotin residue or a holding carrier by a biotin-avidin bond.

  The target compound and holding carrier to which the compound represented by the general formula (1) is to be bound differ depending on the type of L in the compound represented by the general formula (1) and cannot be defined uniformly. As amino acids, PNA (peptide nucleic acid) oligomers, PNA monomers, artificial nucleic acids, peptides, lipids, fatty acids, carbohydrates, sugar chains, proteins, nucleic acids, enzymes, antibodies, fluorescent labeling compounds, physiologically active substances, pharmacologically active substances, etc. Examples include a target carrier or a holding carrier such as a microbead, a magnetic bead, or a nanobead.

2. A compound represented by the following general formula (1a) is further provided as a compound having a structure in which a side chain having an amino acid or oligopeptide having the amino acid or oligopeptide is bonded to the main chain.

  In the formula (1a), n1 to n3, m1 to m6, E and R are the same as described above.

In the formula (1a), Y ₂ represents a solid phase resin. Here, as the solid phase resin, solid phase synthesis resins generally used in peptide solid phase synthesis can be widely used. Specific examples include solid phase resins having an amino group. More specifically, MBHA (methylbenzidylamine resin), PAL (peptide amide linker), Oxime (P-nitrobenzophenone oxime), PAM (4 -Hydroxymethylphenylacetamidomethyl resin), Wang (oxymethylphenoxymethyl resin), Merrifield resin and the like. Among these, MBHA and PAL are preferable.

In the compound represented by the general formula (1a), the amino group of the solid phase resin Y ₂ is bonded to the structural unit C.

In the formula (1a), X represents a protecting group X ₁ , a hydrogen atom, a group —CO—L (L is the same as above), a group —CO—LX ₁ (where L is the same as described above. LX ₁ is This indicates that the protective group X ₁ is bonded to the functional group.) Here, the protective group is a functional group in a specific region constituting the compound represented by the general formula (1a), A group that is protected from the effects of reactions such as oxidation, reduction, hydrolysis, condensation, etc. in other constituent regions of the compound, and can be eliminated and replaced with hydrogen atoms or hydroxyl groups under specified conditions. It refers to a basic group.

In the formula (1a), X is preferably a protecting group X ₁ .

In the formula (1a), the protecting group Z is a protecting group different from the protecting group X ₁ (denoted as protecting group Za) or the same protecting group as the protecting group X ₁ (denoted as protecting group Zb). Show.

In the formula (1a), specific examples of the protecting group include a tertiary butoxycarbonyl group (Boc group) or a 9-fluorenylmethoxycarbonyl group (Fmoc group). Also, the protecting groups shown below are exemplified. If X is a protecting group X _1, as the protecting group X _1, and preferably Boc group or Fmoc group. The protecting group Z is preferably a protecting group different from the protecting group X (protecting group Za).

In particular, when the protecting group X ₁ is a Boc group or an Fmoc group, the protecting group Z is preferably an Aloc group shown below.

  In the formula (1a), RZ indicates that a protecting group Z is bonded to the functional group of the amino acid residue or peptide residue of R. In the amino acid residue or peptide residue of R, when two or more functional groups are present, the protective groups Z bonded to the respective functional groups may be the same protective groups, There may be different types of protecting groups. Examples of functional groups of amino acid residues or peptide residues include amino groups, carboxyl groups, guanidyl groups, imidazole groups, and thiol groups.

  When n2 is an integer of 2 or more, that is, when there are two or more repeating units B, RZ may be the same or different in each repeating unit B.

By removing the solid phase resin Y ₂ of the compound represented by the general formula (1a) to liberate the carboxyl group, this is subjected to a condensation reaction with a target compound having amino group or hydroxyl group, a holding carrier, etc. Thus, the compound represented by the general formula (1a) from which the solid phase resin Y ₂ has been removed can be easily bound to a target compound, a holding carrier or the like. Here, in the compound represented by the general formula (1a), for the method of removing the solid phase resin Y _2, depending on the type of the solid phase resin can be employed generally adopted when the condition in the art . The condensation reaction between the compound represented by the general formula (1a) from which the solid phase resin Y ₂ has been removed and the target compound or holding carrier having an amino group or a hydroxyl group is generally used for peptide synthesis or DNA or RNA synthesis. There is an advantage in that it is not necessary to use a solid-phase synthesis method, and it can be carried out easily in a liquid phase.

  The target compound to be bound to the compound represented by the general formula (1a) and the holding carrier are not particularly limited as long as they have an amino group or a hydroxyl group. Specific examples include amino acids, PNA (peptide nucleic acid) oligomers, Target compounds such as PNA monomers, artificial nucleic acids, peptides, lipids, fatty acids, sugars, sugar chains, proteins, nucleic acids, enzymes, enzymes, fluorescently labeled compounds, bioactive substances, pharmacologically active substances, or microbeads, magnetic beads, nanobeads And the like.

3. Production Method of Compound Represented by General Formula (1) As a first production method of the compound represented by general formula (1), there is a method of sequentially carrying out the following Step 1-1 to Step 1-6. It is done. Step 1-1 to Step 1-6 will be described in detail for each step.

In Step 1-1 Step 1-1, a compound represented by the following formula (I), using solid phase resin Y _2, to synthesize a compound represented by the general formula (i).

[In formula (I), X ₁ represents a protecting group, and m6 is the same as defined above. ]

Wherein (i), n3, m6, X 1 and Y ₂ are as defined above. ]
The compound represented by the general formula (I) is a known compound or a compound produced according to a known production method.

First, a compound represented by the general formula (I), to a solid phase resin Y ₂ and condensation reaction.

A compound represented by formula (I), a condensation reaction between a solid phase resin Y ₂ has the general formula 1 mol of the compound represented by (I), usually 0.01 to 100 mol of solid resin Y _2, preferably Is carried out by mixing 0.1 to 10 moles.

The condensation reaction between the compound represented by the general formula (I) and the solid phase resin Y ₂ is usually performed in an appropriate solvent. As the solvent, known solvents can be widely used as long as they do not inhibit the reaction. Examples of such a solvent include dimethylformamide (DMF), N-methylpyrrolidone (NMP), and the like.

The condensation reaction between the compound represented by the general formula (I) and the solid phase resin Y ₂ is preferably carried out using a condensing agent and a reaction accelerator. Examples of the condensing agent include O- (azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), O- (benzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide ( DCC). As the condensing agent, HATU is preferably used. Examples of the reaction accelerator include N, N-diisopropylethylamine (DIEA) and triethylamine (TEA). The reaction accelerator is preferably DIEA.

The amount of the condensing agent relative to the solid phase resin Y ₂ 1 mole, usually 0.01 to 100 mol condensing agent in a total amount, preferably from to 0.1 to 10 mol.

The amount of the reaction accelerator, relative to the solid phase resin Y ₂ 1 mole, usually 0.01 to 100 mol condensing agent in a total amount, preferably from to 0.1 to 10 mol.

The condensation reaction between the compound represented by the general formula (I) and the solid phase resin Y ₂ is usually 5 to 80 ° C., preferably 10 to 30 ° C., 0.1 to 48 hours, preferably 0.1 to 1 hour. It is carried out by stirring accordingly.

Thus, a compound having the following structure obtained by condensing one compound represented by the general formula (I) to the solid phase resin Y ₂ can be obtained. Hereinafter, a compound bonded to a solid phase resin is referred to as a solid phase binding compound.

The protecting group X ₁ of the solid phase binding compound thus obtained is eliminated. Removal of the protecting group X ₁ of the solid phase-bound compound is carried out employing appropriate method according to the type of the protecting group X _1. For example, when the protecting group X ₁ is a Boc group, a method of treating in a TFA (trifluoroacetic acid) solution (95% by volume TFA / 5% by volume m-cresol) at 10 to 30 ° C. for 0.1 to 1 hour is exemplified. The The protective group X ₁ be a Fmoc group, piperidine solution (20% by volume piperidine / 80 volume% DMF) method of processing 0.01-0.5 hours at 10 to 30 ° C. in may be exemplified. Further, when the protecting group X ₁ is Alloc, in a Pd (PPh3) 4 (tetrakis-triphenylphosphine palladium complex, 312 mg) solution (55 vol% chloroform / 30 vol% acetic acid / 15 vol% N-methylmorphorine) And a method of treating at 10 to 30 ° C. for 0.1 to 1 hour.

Next, a condensation reaction between the solid-phase-bound compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (I) is carried out. The conditions for the condensation reaction are the same as those in the above condensation reaction except that the solid phase resin and the solid phase binding compound are replaced.

Elimination reaction of the protecting group X ₁ of the solid phase-bound compounds described above, and the condensation reaction of the compound represented by the solid phase-bound compound of the protecting groups X ₁ eliminated and the formula (I), repeated n3 -1 times performed By doing so, the compound represented by the general formula (i) is obtained.

Step 1-2 In Step 1-2, using the compound represented by General Formula (i) obtained in Step 1-1 and the compound represented by General Formula (II) below, A compound represented by formula (ii) is synthesized.

Wherein (II), m2~m5, X ₁ and Za are as defined above. Further, the compound represented by the general formula (II) is a known compound or a compound produced according to a known production method.

Wherein (ii), n2, n3, m2~m6, X 1, Za and Y ₂ are as defined above.

In the second step, first, the elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first step 1-1.

Next, a condensation reaction between the solid-phase-bound compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (II) is carried out.

For the condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the following general formula (II), the same conditions as the condensation reaction in the above-mentioned step 1-1 can be employed. Specifically, in the condensation reaction conditions of Step 1-1 above, the solid phase resin is replaced with a solid phase binding compound, and the compound represented by general formula (I) is further replaced with a compound represented by general formula (II). As a result, the condensation reaction in Step 1-2 is carried out.

The elimination reaction of the protecting group X ₁ of the above-mentioned solid phase binding compound and the condensation reaction of the compound represented by the general formula (II) with the solid phase binding compound from which the protecting group X ₁ has been eliminated are performed a total of n2 times. Thus, a compound represented by the general formula (ii) is obtained.

Step 1-3 In Step 1-3, using the compound represented by General Formula (ii) obtained in Step 1-2 and the compound represented by General Formula (III) below, A compound represented by the formula (iii) is synthesized.

Wherein (III), m1 and X ₁ are as defined above. The compound represented by the general formula (III) is a known compound or a compound produced according to a known production method.

In the formula (iii), n1 to n3, m1 to m6, X ₁ , Za and Y ₂ are the same as described above.

In the 1-3 step, first, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first step.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (III) is carried out.

For the condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the following general formula (III), the same conditions as those for the condensation reaction in Step 1-1 above can be employed. Specifically, in the condensation reaction conditions of Step 1-1 above, the solid phase resin is replaced with a solid phase binding compound, and the compound represented by the general formula (I) is further replaced with a compound represented by the general formula (III). Thus, the condensation reaction in the first to third steps is performed.

Elimination reaction of the protecting group X ₁ of the solid phase-bound compounds described above, and that the protecting group X ₁ a condensation reaction of the compound represented by the desorbed solid phase-bound compound and a formula (III), carried out a total of n3 times Thus, a compound represented by the general formula (iii) is obtained.

Step 1-4 In Step 1-4, the compound represented by General Formula (iii) obtained in Step 1-3 and Compound X ₁ L-COOH [X ₁ and L are the same as described above, X ₁ L is a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding an amino group), and a functional group protected with a protecting group X ₁ is bonded via a linker. Is used to synthesize a compound represented by the following general formula (iv).

In formula (iv), n1 to n3, m1 to m6, X ₁ L, Za and Y ₂ are the same as described above.

Compound X ₁ L-COOH is a known compound or a compound produced according to a known production method.

In the first to fourth steps, first, the elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first step.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound X ₁ L-COOH is carried out.

For the condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound X ₁ L-COOH, the same conditions as those for the condensation reaction in the above step 1-1 can be employed. Specifically, in the condensation reaction conditions of Step 1-1 above, by replacing the solid phase resin with a solid phase binding compound, and further replacing the compound represented by the general formula (I) with the compound X ₁ L-COOH, The condensation reaction in the first to fourth steps is performed.

Step 1-5 In Step 1-5, the compound represented by the general formula (iv) obtained in Step 1-4 and a functional group other than a carboxyl group bonded to the carbon atom at the α-position are protected with a protective group Za. A compound represented by the following general formula (v) is synthesized using an amino acid to which is bound.

In formula (v), n1 to n3, m1 to m6, X ₁ L, RZa and Y ₂ are the same as described above.

  In the above amino acid used in this step, the protective group Za may be bonded to a functional group other than the carboxyl group bonded to the α-position carbon atom.

  For example, in the case of an amino acid having no functional group other than the carboxyl group and amino group bonded to the α-position carbon atom, the protective group Za may be bonded to the amino group bonded to the α-position carbon atom.

  In addition, in the case of an amino acid having a functional group other than the α-position carbon atom, such as lysine, arginine, serine, etc., all the functional groups other than the carboxyl group bonded to the α-position carbon atom are protected. It is sufficient that the group Za is bonded. In this case, the protecting group Za for the amino group bonded to the carbon atom at the α-position and the protecting group Za for the functional group bonded to a site other than the carbon atom at the α-position are preferably different types of protecting groups. Thus, when the amino acid has two or more protecting groups Zb, by adopting different types of them, only the protecting group Za bonded to the amino group used for the condensation reaction is selectively eliminated. The protecting group Za bonded to another functional group can be left in a remaining state.

  In the step 1-5, first, elimination reaction of the protecting group Za bonded to the amino group used for the condensation reaction in the solid phase binding compound is performed. The method for removing the protecting group Za can employ the same conditions as in the first step 1-1.

  Next, a condensation reaction of the amino acid and the solid phase binding compound from which the protecting group Za has been eliminated as described above is performed.

  For the condensation reaction between the solid-phase-bonded compound from which the protecting group Za has been removed and the amino acid, the same conditions as in the condensation reaction in Step 1-1 can be employed. Specifically, in the condensation reaction conditions of the above step 1-1, the solid phase resin is replaced with a solid phase binding compound, and the compound represented by the general formula (I) is further replaced with the above amino acid to A process condensation reaction is carried out.

  By repeating the elimination reaction of the protecting group Za of the solid phase binding compound and the condensation reaction of the amino acid with the solid phase binding compound from which the protecting group Za has been eliminated, the general formula (v) Is obtained. For example, when the elimination and condensation reaction of the protecting group Za is performed once, a compound in which R is an amino acid residue is synthesized. For example, when the elimination and condensation reaction of the protecting group Za is performed three times, R A peptide residue compound consisting of three amino acid residues is synthesized.

Step 1-6 Next, from the compound represented by the general formula (v) obtained in Step 1-5, the solid phase resin was separated to form —COOH or —CONH 2 at the terminal, and the protecting group X ₁ and Za is desorbed and replaced with a hydrogen atom. If necessary, a group having a lipid group, a group having a fatty acid residue, or a group having a fluorescent group is bonded to the terminal amino group of the repeating unit A of the compound represented by the general formula (1). . Thus, the compound represented by the general formula (1) is synthesized.

For example, when a Merrifield resin is used as the solid phase resin or solid phase compound, the compound represented by the general formula (1) in which Y ₁ is a hydroxyl group can be obtained by exposure to super strong acidic conditions. it can. Further, for example, when MBHA resin resin is used as the solid phase resin, the compound represented by the general formula (1) in which Y ₁ is an amino group can be obtained by exposing it to a super strong acidic condition. it can.

  Furthermore, as a second production method of the compound represented by the general formula (1), there can be mentioned a method of sequentially carrying out the following Steps 2-1 to 2-6. Step 2-1 to Step 2-6 will be described in detail for each step.

Step 2-1 In Step 2-1, the compound represented by the general formula (i) is synthesized using the compound solid phase resin or solid phase compound represented by the general formula (I).

  First, the compound represented by the general formula (I) is condensed with a solid phase resin or a solid phase compound to obtain a solid phase binding compound, and then the protecting group X of the solid phase binding compound is eliminated. The elimination of the protecting group X is carried out under the same conditions as in Step 1-1 above.

  Next, the condensation reaction of the solid-phase bonded compound from which the protecting group X has been removed and the compound represented by the general formula (I) is repeatedly carried out n3-1 times. The condensation reaction is carried out under the same conditions as in Step 1-1 above. Thus, the compound represented by the general formula (i) can be obtained.

Step 2-2 Step 2-2 uses the compound represented by the general formula (II) and an amino acid in which a protective group Za is bonded to a functional group other than a carboxyl group bonded to a carbon atom at the α-position. Then, a compound represented by the following general formula (II ′) is synthesized.

Wherein (II '), m2~m5, E , X 1 and RZa are as defined above.

In Step 2-2, the carboxyl group of the compound represented by the general formula (II) is preferably protected with a protecting group different from X ₁ and Zb.

  First, the protecting group Za of the compound represented by the general formula (II) is eliminated. The removal of the protecting group Za is carried out under the same conditions as in Step 1-5 above.

  Next, a condensation reaction of the above amino acid with the compound represented by the general formula (II) from which the protecting group Za has been eliminated is carried out. The condensation reaction is carried out under the same conditions as in Steps 1-5 above.

  As described above, the elimination reaction of the protecting group Za bonded to the amino group used in the condensation reaction, and the condensation of the amino acid with the compound from which the protecting group Za bonded to the amino group used in the condensation reaction is eliminated. A compound represented by the general formula (II ′) is obtained by carrying out the reaction 1 to 100 times in total.

Step 2-3 In Step 2-3, the compound represented by Formula (i) obtained in Step 2-1 and the compound represented by Formula (II ′) obtained in Step 2-2 Is used to synthesize a compound represented by the following general formula (ii ′).

Wherein (ii '), n2, n3 , m2~m6, E, RZa, X 1 and Y ₂ are as defined above.

First, removal of the protecting group X ₁ of the solid phase-bound compound. The method for removing the protecting group X ₁ can employ the same conditions as in the first and second steps.

Next, a condensation reaction of the solid-phase-bound compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (II ′) is carried out. The condensation reaction is performed under the same conditions as in Step 1-2 above.

Elimination reaction of the protecting group X ₁ of solid phase-bound compounds described above, and the condensation reaction of the compound represented the protecting group X ₁ by solid desorbed phase bound compound of the general formula (II '), carried out a total of n2 times Thus, a compound represented by the general formula (ii ′) is obtained.

Step 2-4 In Step 2-4, using the compound represented by general formula (ii ′) and the compound represented by general formula (III) obtained in Step 2-3, the following general formula (iii) A compound represented by ') is synthesized.

Wherein (iii '), n1~n3, m1~m6 , E, RZa, X 1 and Y ₂ are as defined above.

First, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first to third steps.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (III) is carried out. The condensation reaction is carried out under the same conditions as in Step 1-3 above.

Elimination reaction of the protecting group X ₁ of the solid phase-bound compounds described above, and that the protecting group X ₁ a condensation reaction of the compound represented by the desorbed solid phase-bound compound and a formula (III), carried out a total of n1 times Thus, a compound represented by the general formula (iii ′) is obtained.

Step 2-5 In Step 2-5, using the compound represented by formula (iii ′) obtained in Step 2-4 and compound X ₁ L-COOH [X ₁ L is the same as above] Then, a compound represented by the following general formula (iv ′) is synthesized.

Wherein (iv '), n1~n3, m1~m6 , E, RZa, LX 1 and Y ₂ are as defined above.

First, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first to fourth steps.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound X ₁ L-COOH is carried out. The condensation reaction is performed under the same conditions as in Step 1-4 above.

Step 2-6 Next, from the compound represented by the general formula (iv ′) obtained in Step 2-5, the solid phase resin was cleaved to form —COOH or —CONH 2 at the terminal, and the protecting group X ₁ And Za is desorbed. Thus, the compound represented by the general formula (1) is synthesized. The second to sixth steps are performed by the same method as the first to sixth steps.

4). Production method of the compound represented by the general formula (1a) As a first production method of the compound represented by the general formula (1a), there is a method of sequentially performing the following steps 3-1 to 3-5. It is done. Hereinafter, Step 3-1 to Step 3-5 will be described in detail for each step.

Step 3-1 In Step 3-1, a compound represented by the general formula (i) is synthesized using a compound represented by the general formula (I) and a solid phase resin.

The solid phase resin used for the synthesis of the compound represented by the general formula (1a) is appropriately selected depending on the types of the protecting groups X ₁ and Z contained in the compound represented by the general formula (1a). For example, when one or both of the protecting groups X ₁ and Z contained in the compound represented by the general formula (1a) is a Boc group, it is desirable to employ Oxime resin or oxylbenzyl as the solid phase resin. In addition, when one or both of the protecting groups X ₁ and Z contained in the compound represented by the general formula (1a) is an Fmoc group, it is desirable to employ a PAM resin as the solid phase resin.

First, a compound represented by the general formula (I) is condensed with a solid phase resin to obtain a solid phase bound compound, and then the protecting group X ₁ of the solid phase bound compound is eliminated. The elimination of the protecting group X ₁ is carried out under the same conditions as in Step 1-1 above.

Next, the condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (I) is repeatedly carried out n3 −1 times. The condensation reaction is carried out under the same conditions as in Step 1-1 above. Thus, the compound represented by the general formula (i) can be obtained.

Step 3-2 In step 3-2, using the compound represented by general formula (i) obtained in step 3-1 and the compound represented by general formula (II), general formula (ii) Is synthesized.

First, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first and second steps.

Next, a condensation reaction between the solid-phase-bound compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (II) is carried out. The condensation reaction is performed under the same conditions as in Step 1-2 above.

By carrying out the elimination reaction of the protecting group X ₁ of the above-mentioned solid phase binding compound and the condensation reaction of the compound represented by the general formula (II) with the solid phase binding compound from which the protecting group X ₁ has been eliminated, a total of n2 times. Thus, a compound represented by the general formula (ii) is obtained.

Step 3-3 In Step 3-3, using the compound represented by general formula (ii) obtained in step 3-2 and the compound represented by general formula (III), general formula (iii) Is synthesized.

First, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first to third steps.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (III) is carried out. The condensation reaction is carried out under the same conditions as in Step 1-3 above.

Removal of the protecting group X ₁ of the solid phase-bound compounds described above, and the condensation reaction of the compound represented by the protection solid phase binding compound group X ₁ desorbed and formula (III), by performing a total of n1 times Thus, a compound represented by the general formula (iii) is obtained.

Step 3-4 Step 3-4 step uses the compound represented by general formula (iii) obtained in step 3-3 and compound X-OH [wherein X is the same as described above], A compound represented by (iv-a) is synthesized. In the formula (1a), when X is a protecting group X ₁ , this step is not necessary.

Wherein (iv-a), n1~n3, m1~m6, E, Za, X and Y ₂ are as defined above.

First, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first to fourth steps.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound X-OH is carried out. The condensation reaction is performed under the same conditions as in Step 1-4 above.

Step 3-5 In Step 3-5, the compound represented by the general formula (iv-a) obtained in Step 3-4 is protected with a functional group other than the carboxyl group bonded to the α-position carbon atom. A compound represented by the general formula (1a) is synthesized using an amino acid to which a group Za is bonded.

  The amino acids used in Step 3-5 are the same as the amino acids used in Step 1-5 above.

  First, the protecting group Za of the compound represented by the general formula (iv-a) is removed. The removal of the protecting group Za is carried out under the same conditions as in Step 1-5 above.

  Next, a condensation reaction of the above amino acid with the compound represented by the general formula (iv-a) from which the protecting group Za has been eliminated is carried out. The condensation reaction is carried out under the same conditions as in Steps 1-5 above.

  As described above, the elimination reaction of the protecting group Za bonded to the amino group used in the condensation reaction, and the condensation of the amino acid with the compound from which the protecting group Za bonded to the amino group used in the condensation reaction is eliminated. By carrying out the reaction 1 to 100 times in total, a compound represented by the general formula (1a) is obtained.

Za is bonded as a protecting group to the compound represented by the general formula (1a) obtained in this step. Therefore, if necessary, the protecting group Za is replaced with the same protecting group as the protecting group X ₁ (protecting group Zb) according to a known method.

  Furthermore, as a second production method of the compound represented by the general formula (1a), a method of carrying out the following Steps 4-1 to 4-5 can be mentioned. Hereinafter, Step 4-1 to Step 4-5 will be described in detail for each step.

Step 4-1 In Step 4-1, the compound represented by the general formula (i) is synthesized using the compound represented by the general formula (I) and a solid phase resin or solid phase compound. This 4-1 process is implemented on the same conditions as the said 3-1 process.

Step 4-2 Step 4-2 uses the compound represented by the general formula (II) and an amino acid in which a protective group Za is bonded to a functional group other than a carboxyl group bonded to a carbon atom at the α-position. Then, a compound represented by the general formula (II ′) is synthesized.

  The amino acids used in Step 1-2 are the same as those used in Step 3-4 above.

  First, the protecting group Za of the compound represented by the general formula (II) is eliminated. The removal of the protecting group Za is carried out under the same conditions as in Step 3-5 above.

  Next, a condensation reaction of the above amino acid with the compound represented by the general formula (II) from which the protecting group Za has been eliminated is carried out. The condensation reaction is carried out under the same conditions as in Step 3-5 above.

  As described above, the elimination reaction of the protective group Za bonded to the amino group used in the condensation reaction, and the compound obtained by eliminating the protective group Za bonded to the amino group used in the condensation reaction and the amino acid By performing the condensation reaction 1 to 100 times in total, the compound represented by the general formula (II ′) is obtained.

Step 4-3 In step 4-3, the compound represented by general formula (i) obtained in step 4-1 and the compound represented by general formula (II ′) obtained in step 4-2 Is used to synthesize a compound represented by the general formula (ii ′).

First, removal of the protecting group X ₁ of the solid phase-bound compound. The method for removing the protecting group X ₁ can employ the same conditions as in Step 3-2.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (III) is carried out. The condensation reaction is carried out under the same conditions as in Step 3-2 above.

The condensation reaction of elimination, and compounds represented by the solid phase-bound compound of the protecting group X ₁ desorbed and formula (II ') of the protecting group X ₁ of the solid phase-bound compounds described above, be carried out a total of n2 times Thus, a compound represented by the general formula (ii ′) is obtained.

Step 4-4 In Step 4-4, using the compound represented by General Formula (ii ′) and the compound represented by General Formula (III) obtained in Step 4-3, General Formula (iii ′ ) Is synthesized.

First, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in Step 3-3.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound represented by the general formula (III) is carried out. The condensation reaction is carried out under the same conditions as in Step 3-3 above.

Removal of the protecting group X ₁ of the solid phase-bound compounds described above, and the condensation reaction of the compound represented by the protection solid phase binding compound group X ₁ desorbed and formula (III), by performing a total of n1 times Thus, a compound represented by the general formula (iii ′) is obtained.

Step 4-5 Za is bonded as a protecting group to the compound represented by the general formula (iii ′) obtained in Step 4-4. Therefore, if necessary, the protecting group Za is replaced with the same protecting group as the protecting group X ₁ (protecting group Zb) according to a known method.

Next, in Step 4-5, using the compound represented by General Formula (iii ′) obtained in Step 4-4 and Compound X—OH [wherein X is the same as described above], General Formula (1a) Is synthesized. However, in the formula (1a), when X is a protecting group X _1, the present step is unnecessary.

First, elimination reaction of the protecting group X ₁ of the solid phase binding compound is performed. The method for removing the protecting group X ₁ can employ the same conditions as in the first to fourth steps.

Next, a condensation reaction between the solid-phase bonded compound from which the protecting group X ₁ has been removed and the compound X-OH is carried out. The condensation reaction is carried out under the same conditions as in Step 3-4 above.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, the present invention is not limited by these examples and test examples. In the following examples, the notation “amino acid name (protecting group name)” indicates a structure in which the functional group of the side chain portion of the amino acid is protected with a protecting group. For example, the notation “Lys (Fmoc)” indicates a structure in which the amino group of the side chain portion of lysine is protected with the Fmoc group. For example, the notation Arg (Boc) ₂ indicates a structure in which the side chain portion of alginic acid is protected by two Boc groups.

Example 1 Synthesis of Compound (1a-1) Compound (1a-1) represented by the following general formula was synthesized.

  Compound (1a-1) was synthesized according to the reaction steps shown below.

Detailed conditions of the synthesis method are as follows.
1. Fmoc-AEG constituting the synthetic backbone main chain (Alloc-C5) -AEG (Alloc -C5) -AEG (Alloc-C5) -AEG (Alloc-C5) -AEG (Alloc-C5) -C 5 H The synthesis of ₁₀ -CONH-C ₅ H ₁₀ -CONH-PAL [compound (1a-1-vi)] was performed using the standard solid phase Fmoc method. That is, using a DMF solution in which Fmoc-HN-C ₅ H ₁₀ -COOH and a compound represented by the following formula (11) (hereinafter referred to as compound (11)) are added to condensing agents HATU and DIEA. A sequential extension reaction was performed. This extension reaction is a repetition of three steps: deprotection of the protecting group (reaction step 1), condensation of various amino acids (reaction step 2), and capping reaction (reaction step 3).

Reaction Step 1 Synthesis of H ₂ N-PAL [Compound (1a-1-i)] (Extension reaction toward main chain 1: Deprotection of protecting group)
Fmoc-HN-PAL (5- (4′-Aminomethyl-3 ′, 5′-dimethoxyphenoxy) -valeric acid) resin (180 mg, 72 μmol) was stirred with 2 mL of 20% piperidine in DMF for 5 minutes. After removing the solution by filtration, the remaining resin was washed with DMF (N, N-dimethylformamide) and DCM (dichloromethane). A part of the sample was collected in a test tube and positive in the ninhydrin test, confirming the formation of compound (1a-1-i).

Reaction Step 2 Synthesis of Fmoc-HN-C ₅ H ₁₀ -CONH-PAL [Compound (1a-1-ii)] (Extension reaction 2 toward the main chain: condensation of various amino acids)
Compound (1a-1-i) (72 μmol scale), Fmoc-HN-C ₅ H ₁₀ -COOH (305 mg, 720 μmol), condensing agent HATU (274 mg, 720 μmol) and DIEA (126 μL) 2 mL of the DMF solution added was added, and the mixture was stirred for 30 minutes under a nitrogen stream at room temperature. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the production of compound (1a-1-ii) was confirmed by being negative in the ninhydrin test.

Reaction Step 3 Synthesis of Compound (1a-1-ii) (Extension Reaction 3: Main Capping Reaction)
The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature, and then the remaining resin was washed with DMF.

_{Then, Fmoc-HN-C 5 H} 10 -COOH with compounds using (11), and repeatedly performing the reaction steps 1-3, by performing sequential solid phase synthesis, the compound (1a-1-vi) Synthesized.

2. The synthesis of the side chain moiety compound (1a-1) was performed using the Alloc method. That is, a sequential extension reaction was performed using a DMF solution in which the amino acid derivatives Alloc-Arg (Boc) ₂ —OH and Boc-Arg (Boc) ₂ —OH were added to the condensing agents HATU and DIEA, respectively. This extension reaction is a repetition of three steps: (1) deprotection of the protecting group, (2) batch condensation of amino acids, and (3) capping reaction.

Reaction Step 4 Fmoc-AEG (H ₂ N-C5) -AEG (H ₂ N-C5) -AEG (H ₂ N-C5) -AEG (H ₂ N-C5) -AEG (H ₂ N-C5)- Synthesis of C ₅ H ₁₀ -CONH-C ₅ H ₁₀ -CONH-PAL [Compound (1a-1-v)] (Extension reaction in the side chain direction 1: Deprotection of Alloc group)
Compound (1a-1-vi) in Pd (PPh3) 4 (tetrakis (triphenylphosphine) palladium (0)) 312 mg CHCl ₃ / AcOH / N-methylmorphorine solution (2.8 mL, 1.5 mL, 0.75 mL in this order) The mixture was shaken and stirred at room temperature for 30 minutes. The reaction solution was removed by filtration, and the remaining resin was washed. This was carried out twice, and a part of the sample was taken into a test tube and positive in the ninhydrin test, confirming the production of compound (1a-1-v). did.

Reaction Step 5 Fmoc-AEG (Alloc-Arg (Boc) ₂ -HN-C5) -AEG (Alloc-Arg (Boc) ₂ -HN-C5) -AEG (Alloc-Arg (Boc) ₂ -NH-C5)- AEG (Alloc-Arg (Boc) ₂ -HN-C5) -AEG (Alloc-Arg (Boc) ₂ -HN-C5) -C ₅ H ₁₀ -CONH-C ₅ H ₁₀ -CONH -PAL [Compound (1a- 1-vi)] (elongation reaction in the side chain direction 2: batch condensation of amino acids)
Alloc-Arg (Boc) ₂ -OH (495 mg, 1080 μmol), condensing agent HATU (410 mg, 1080 μmol) and DIEA (188 μL) were dissolved in compound (1a-1-v) (72 μmol scale) 2 mL of DMF solution was added and stirred for 30 minutes under a nitrogen stream at room temperature. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken up in a test tube, and the result was negative in the ninhydrin test, confirming the formation of compound (1a-1-vi).

Reaction Step 6 Synthesis of Compound (1a-1-vi) (Extension Reaction in the Side Chain 3: Capping Reaction)
The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Subsequently, by repeating the above reaction steps 4 to 6 using Alloc-Arg (Boc) 2-OH and Boc-Arg (Boc) 2-OH, and sequentially performing solid phase synthesis, the target compound ( 1a-1) was synthesized. To confirm the synthesis, after deprotecting the Fmoc group after piperidine treatment, the TFA treatment (95% TFA / 5% m-cresol) was used to cleave the solid phase carrier PAL and deprotect the Arg protecting group Boc group. H ₂ N-AEG (Arg-Arg-Arg-HN-C5) -AEG (Arg-Arg-Arg-HN-C5) -AEG (Arg-Arg-Arg-HN-C5) -AEG (Arg- Arg-Arg-HN-C5) -AEG (Arg-Arg-Arg-HN-C5) -C 5 H 10 confirmed the presence of _{-CONH-C 5 H 10 -CONH 2} . MALDI-TOF MS: calcd. 3653.53 (M + H +), found 3654.57.
Example 2 Synthesis of Compound (1a-2) Compound (1a-2) represented by the following general formula was synthesized.

  Specifically, compound (1a-2) was synthesized according to the reaction steps shown below.

Detailed conditions of the synthesis method are as follows.
1. Low titer of resin
Reaction Step 7 Synthesis of Boc-HN-C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a-2-ii)]
MBHA (4-Methyl-benzhydrylamine) resin (200 mg, 120 μmol) was shaken and stirred for 15 minutes with 2 mL of 5% DIEA (N, N′-diisopropylamine) methylene chloride (DCM) solution. After washing with DCM, the solution was shaken and stirred again with 2 mL of 5% DIEA in DCM for 15 minutes, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

The resin thus obtained was mixed with Boc-HN-C ₁₀ H ₂₀ -COOH (25.6 mg, 85 μmol), PyBOP (Benzotriazole-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate) (41.6 mg, 80 μmol), DIEA ( 27.2 μL, 160 μmol) was dissolved in 1 mL of a DMF / DCM (1: 1) solution at room temperature under a nitrogen stream for 3 hours. Next, after removing the DMF / DCM solution by filtration, the remaining resin was washed with DMF and DCM, and then reacted at room temperature for 30 minutes with 2 mL of capping reagent (acetic anhydride / pyridine / DMF = 1/25/25). Then, the remaining resin was washed with DMF, and reacted again with 2 mL of capping reagent for 30 minutes. The remaining resin was washed with DMF and DCM to obtain compound (1a-2-ii). A portion of the remaining resin was dispensed into a test tube, confirmed to be negative by a ninhydrin test, and confirmed that compound (1a-2-ii) was produced.

2. _{Boc-HN-C 10 H 20} -Lys constituting the synthetic backbone main chain (Fmoc) -C5-Lys (Fmoc ) -C5-Lys (Fmoc) -C5-Lys (Fmoc) -C5-Lys (Fmoc ) -C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a-2-v)] was synthesized using standard solid phase Boc method. That is, for the compound (1a-2-ii) (80 μmol scale), the amino acids Boc-Lys (Fmoc) -OH (69.2 mg, 125 μmol), Boc-HN-C ₅ H ₁₀ -COOH (28.9 mg, 125 μmol) ), Boc-HN-C ₁₀ H ₂₀ -COOH (37.7 mg, 125 μmol) and DMF solutions with condensing agents HCTU (49.6 mg, 120 μmol) and DIEA (40.8 μL, 240 μmol), respectively. A sequential extension reaction was performed. This extension reaction is a repetition of three steps: deprotection of the protecting group (reaction step 8), condensation of various amino acids (reaction step 9), and capping reaction (reaction step 10).

Reaction Step 8 Synthesis of H ₂ NC ₁₀ H ₂₀ -CONH-MBHA [Compound (1a-2-iii)] (Extension Reaction in Main Chain Direction 1: Deprotection of Protecting Group)
The compound (1a-2-ii) was stirred with 2 mL of 5% m-cresol / TFA for 30 minutes. After removing the solution by filtration, the remaining resin was washed with DMF and DCM. A part of this was dispensed into a test tube, and the carrier and solution were positive in the ninhydrin test, so the production of compound (1a-2-iii) was confirmed.

Reaction Step 9 Synthesis of Boc-Lys (Fmoc) -C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a-2-iv)] (Extension Reaction 2: Main Chain Condensation of Amino Acids)
Boc-Lys (Fmoc) -OH (69.2 mg, 125 μmol), HCTU (62.4 mg, 120 μmol), DIEA (40.8 μL, 240 μmol) were dissolved in compound (1a-2-iii) (80 μmol scale) The mixture was stirred in 2 mL of DMF solution at room temperature under a nitrogen stream for 30 minutes. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the production of compound (1a-2-iv) was confirmed by being negative in the ninhydrin test.

Reaction Step 10 Synthesis of Compound (1a-2-iv) (Extension Reaction 3: Main Capping Reaction)
The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Subsequently, the above reaction steps 8 to 10 were repeated using Boc-HN-C ₅ H ₁₀ -COOH, Boc-Lys (Fmoc) -OH, and Boc-HN-C ₁₀ H ₂₀ -COOH, and solidified sequentially. Compound (1a-2-v) was synthesized by performing phase synthesis.

3. The synthesis of the side chain moiety compound (1a-2) was performed using the standard solid phase Fmoc method. That is, a sequential extension reaction was performed using a DMF solution in which the amino acid Fmoc-Arg (Mts) -OH (340.4 mg, 500 μmol) and the condensing agent HCTU (198.6 mg, 480 μmol) and DIEA (163.3 μL, 960 μmol) were dissolved. went. This extension reaction is a repetition of three steps: deprotection of the protecting group (reaction step 11), batch condensation of amino acids (reaction step 12), and capping reaction (reaction step 13).

Reaction Step 11 Boc-HN-C ₁₀ H ₂₀ -Lys (NH ₂ ) -C ₅ H ₁₀ -Lys (NH ₂ ) -C ₅ H ₁₀ -Lys (NH ₂ ) -C ₅ H ₁₀ -Lys (NH ₂ ) Synthesis of -C ₅ H ₁₀ -Lys (NH ₂ ) -C ₁₀ H ₂₀ -CONH-MBHA [compound (1a-2-vi)] (extension reaction in the side chain direction 1: deprotection of protecting group)
The compound (1a-2-v) was shaken and stirred in 2 ml of a 20% piperidine DMF solution at room temperature for 5 minutes. Subsequently, the reaction solution was removed by filtration, and the remaining resin was washed with DMF and DCM. A part of this was dispensed into a test tube, and the carrier and solution were positive in the ninhydrin test, so the production of compound (1a-2-vi) was confirmed.

Reaction Step 12 Boc-HN-C ₁₀ H ₂₀ -Lys (Fmoc-Arg (Mts))-C ₅ H ₁₀ -Lys (Fmoc-Arg (Mts))-C ₅ H ₁₀ -Lys (Fmoc-Arg (Mts) ) -C ₅ H ₁₀ -Lys (Fmoc-Arg (Mts))-C ₅ H ₁₀ -Lys (Fmoc-Arg (Mts))-C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a-2-vii)] Synthesis (extension reaction in the direction of the side chain 2: batch condensation of amino acids)
Fmoc-Arg (Mts) -OH (340.4 mg, 500 μmol), HCTU (198.6 mg, 480 μmol), DIEA (163.3 μL, 960 μmol) were dissolved in compound (1a-2-vi) (80 μmol scale) The mixture was stirred in 2 mL of DMF solution at room temperature under a nitrogen stream for 30 minutes. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken into a test tube, and the production of compound (1a-2-vii) was confirmed by being negative in the ninhydrin test.

Reaction Step 13 Synthesis of Compound (1a-2-vii) (Elongation Reaction in Side Chain 3: Capping Reaction)
The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Subsequently, the above reaction steps 11 to 13 were repeatedly performed using Fmoc-Arg (Mts) -OH, and the target compound (1a-2) was synthesized by sequentially performing solid phase synthesis. Confirmation of the synthesis of the compound (1a-2) was carried out by deprotecting the Fmoc group by piperidine treatment and then by TFMSA treatment (TFA / TFMSA / p-cresol / thioanisol = 60/25/10/10). And the Arg protecting group Mts group is deprotected, and H ₂ NC ₁₀ H ₂₀ -Lys (Arg-Arg-Arg) -C ₅ H ₁₀ -Lys (Arg-Arg-Arg) -C ₅ H Confirm the presence of ₁₀ -Lys (Arg-Arg-Arg) -C ₅ H ₁₀ -Lys (Arg-Arg-Arg) -C ₅ H ₁₀ -Lys (Arg-Arg-Arg) -C ₁₀ H ₂₀ -NH ₂ It was done by doing. MALDI-TOF MS: calcd. 3820.96 (M + H +), found 3820.38.

Example 3 Synthesis of Compound (1a-3) Compound (1a-3) represented by the following general formula was synthesized.

  Specifically, using the compound (1a-2-v) shown in Example 2 above, compound (1a-3) was synthesized according to the reaction steps shown below.

Detailed conditions of the synthesis method are as follows.
Reaction Step 14 Boc-HN-C ₁₀ H ₂₀ -Lys (Fmoc-Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Fmoc-Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Fmoc-Arg ( Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Fmoc-Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Fmoc-Arg (Cbz) ₂ ) -C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a- 3-i)] (elongation reaction in the side chain direction)
The compound (1a-2-v) was shaken and stirred in 2 ml of a 20% piperidine DMF solution at room temperature for 5 minutes. Subsequently, the reaction solution was removed by filtration, and the remaining resin was washed with DMF and DCM. A part of the solution was taken into a test tube, and ninhydrin test confirmed that the carrier and the solution were positive. To the remaining resin, add 2 mL of DMF solution containing Fmoc-Arg (Cbz) ₂ -OH (340.4 mg, 500 μmol), HCTU (198.6 mg, 480 μmol), and DIEA (163.3 μL, 960 μmol) at room temperature. The mixture was stirred for 30 minutes under a nitrogen stream. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken into a test tube, and the production of compound (1a-3-i) was confirmed by being negative in the ninhydrin test. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction Step 15 Boc-HN-C ₁₀ H ₂₀ -Lys (Fmoc-Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Fmoc-Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Fmoc-Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Fmoc-Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H _10- Synthesis of Lys (Fmoc-Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₁₀ H ₂₀ -CONH-MBHA [compound (1a-3-ii)] (extension reaction in the side chain direction)
The compound (1a-3-i) was shaken and stirred in 2 ml of 20% piperidine DMF solution at room temperature for 5 minutes. Subsequently, the reaction solution was removed by filtration, and the remaining resin was washed with DMF and DCM. A part of the solution was taken into a test tube, and ninhydrin test confirmed that the carrier and the solution were positive. To the remaining resin, add 2 mL of DMF solution in which Fmoc-Arg (Cbz) ₂ -OH (340.4 mg, 500 μmol), HCTU (198.6 mg, 480 μmol) and DIEA (163.3 μL, 960 μmol) are dissolved. The mixture was stirred for 30 minutes under a nitrogen stream at room temperature. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the production of compound (1a-3-ii) was confirmed by being negative in the ninhydrin test. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction Step 16 Boc-HN-C ₁₀ H ₂₀ -Lys (Cbz-Arg (Cbz) ₂ -Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Cbz-Arg (Cbz) _2- Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Cbz-Arg (Cbz) ₂ -Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Cbz- Arg (Cbz) ₂ -Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₅ H ₁₀ -Lys (Cbz-Arg (Cbz) ₂ -Arg (Cbz) ₂ -Arg (Cbz) ₂ ) -C ₁₀ H ₂₀ Synthesis of -CONH-MBHA [Compound (1a-3-iii)] (Extension reaction toward the side chain)
The compound (1a-3-ii) was shaken and stirred in 2 ml of a 20% piperidine DMF solution at room temperature for 5 minutes. Subsequently, the reaction solution was removed by filtration, and the remaining resin was washed with DMF and DCM. A part of the solution was taken into a test tube, and ninhydrin test confirmed that the carrier and the solution were positive. At room temperature nitrogen in 2 mL of DMF solution in which Cbz-Arg (Cbz) ₂ -OH (340.4 mg, 500 μmol), HCTU (198.6 mg, 480 μmol), DIEA (163.3 μL, 960 μmol) were dissolved in the remaining resin The mixture was stirred for 30 minutes under an air stream. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the production of compound (1a-3-iii) was confirmed by being negative in the ninhydrin test. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction Step 17 Synthesis of Compound (1a-3) Compound (1a-3-iii) was stirred with 2 mL of 5% m-cresol / TFA for 30 minutes. After removing the solution by filtration, the remaining resin was washed with DMF and DCM. A part of the solution was taken into a test tube, and ninhydrin test confirmed that the carrier and the solution were positive.

  The mixture was stirred in 2 mL of a DMF solution in which Fmoc-Osu (69.2 mg, 125 μmol) and TEA (40.8 μL, 240 μmol) were dissolved in a nitrogen stream at room temperature for 30 minutes. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken up into a test tube, which was negative in the ninhydrin test, confirming the production of 16. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Confirmation of the synthesis of compound (1a-3) was carried out by deprotecting the Fmoc group by piperidine treatment, followed by TFMSA treatment (TFA / TFMSA / p-cresol / thioanisole = 60/25/10/10). And deprotection of the Arg protecting group Cbz, H ₂ N- C ₁₀ H ₂₀ -Lys (Arg-Arg-Arg) -C ₅ H ₁₀ -Lys (Arg-Arg-Arg) -C ₅ H ₁₀ -Lys (Arg-Arg-Arg) -C ₅ H ₁₀ -Lys (Arg-Arg-Arg) -C ₅ H ₁₀ -Lys (Arg-Arg-Arg) -C ₁₀ H ₂₀ -NH ₂ present It was done by confirming. MALDI-TOF MS: calcd. 3820.96 (M + H +), found 3820.38.

Example 4 Synthesis of Compound (1a-4) Compound (1a-4) represented by the following general formula was synthesized.

  Specifically, using the compound (1a-3-iii) shown in Example 3 above, compound (1a-4) was synthesized according to the reaction steps shown below.

Detailed conditions of the synthesis method are as follows.
Reaction Step 18 Synthesis of Compound (1a-4) Compound (1a-3-iii) was stirred with 2 mL of 5% m-cresol / TFA for 30 minutes. After removing the solution by filtration, the remaining resin was washed with DMF and DCM. A part of the solution was taken into a test tube, and ninhydrin test confirmed that the carrier and the solution were positive.

  The mixture was stirred in 2 mL of a pyridine solution in which glutaric anhydride (69.2 mg, 125 μmol) was dissolved under a nitrogen stream at room temperature for 30 minutes. Subsequently, the pyridine solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken up into a test tube, and the result was negative in the ninhydrin test, confirming the formation of compound (1a-4).

Example 5 Synthesis of Compound (1a-5) and Compound (1-1) Compound (1a-5) and compound (1-1) represented by the following general formula were synthesized.

  Specifically, compound (1a-5) and compound (1-1) were synthesized using compound (1a-2) shown in Example 3 according to the reaction steps shown below.

Detailed conditions of the synthesis method are as follows.
Reaction Step 19 Synthesis of Compound (1a-5) Compound (1a-2) was stirred with 2 mL of 5% m-cresol / TFA for 30 minutes. After removing the solution by filtration, the remaining resin was washed with DMF and DCM. A part of this was dispensed into a test tube and confirmed to be positive by a ninhydrin test. Using the DMF solution in which the condensing agent HCTU (31.2 mg, 60 μmol) and DIEA (20.4 μL, 120 μmol) were dissolved in AcS-C ₅ H ₁₀ -COOH (25.8 mg, 61 μmol) in the remaining resin, The mixture was stirred for 30 minutes under a nitrogen stream at room temperature. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken into a test tube, and the production of compound (1a-5) was confirmed by being negative in the ninhydrin test. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction Step 20 Synthesis of Compound (1-1) After the synthesis of the compound (1a-5) was completed, first, final deprotection of the side chain Fmoc group was performed. That is, the compound (1a-5) was shaken and stirred in 2 ml of 20% piperidine DMF solution at room temperature for 5 minutes. After the reaction solution was removed by filtration, the remaining solid phase resin was washed with DMF and methylene chloride. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken up in a test tube, and the final deprotection of the side chain Fmoc group was confirmed by being negative in the ninhydrin test. Next, 1 ml of TFMSA solution (TFA / TFMSA / p-cresol / thioanisol = 60/25/10/10) was added to the remaining resin, and the mixture was treated for 2 hours at room temperature, and the TFMSA solution was collected by filtration. The remaining resin was washed with 1 ml of TFA and mixed with the previous filtrate. The filtrate was added dropwise to cold diethyl ether (40 ml), and the precipitate was collected by centrifugation. The residual ether was removed, and after drying, a crude sample of compound (1-1) was obtained. This crude sample was purified by high performance liquid chromatography using an ODS column. MALDI-TOF MS: calcd. 3924.07 (M + H +), found 3925.14.

Example 6 Synthesis of Compound (1a-6) and Compound (1-2) Compound (1a-6) and compound (1-2) represented by the following general formula were synthesized.

  Specifically, using compound (1a-2-ii) shown in Example 2 above, compound (1a-6) and compound (1-2) were synthesized according to the reaction steps shown below.

1. Synthesis of main chain part
AcS-C ₅ H ₁₀ -CONH-C ₁₀ H ₂₀ -Lys (Fmoc) -C ₅ H ₁₀ -Lys (Fmoc) -C ₅ H ₁₀ -Lys (Fmoc) -C ₅ H ₁₀ -Lys (Fmoc)-C The synthesis of ₅ H ₁₀ -Lys (Fmoc) -C ₁₀ H ₂₀ -CONH-MBHA [compound (1-2-iii)] was performed using the standard solid phase Boc method. That is, amino acids Boc-Lys (Fmoc) -OH (25.8 mg, 61 μmol), Boc-HN-C ₅ H ₁₀ -COOH (25.8 mg, 61 μmol), Boc-HN-C ₁₀ H ₂₀ -COOH (25.8 mg , 61 μmol), AcS-C ₅ H ₁₀ -OH (25.8 mg, 61 μmol) and DMF solutions with condensing agents HCTU (31.2 mg, 60 μmol) and DIEA (20.4 μL, 120 μmol), respectively. The extension reaction was performed sequentially. This extension reaction is a repetition of three steps: deprotection of the protecting group (reaction step 21), condensation of various amino acids (reaction step 22), and capping reaction (reaction step 23).

Reaction Step 21 Synthesis of H ₂ NC ₁₀ H ₂₀ -CONH-MBHA [Compound (1-2-i)] (Extension Reaction in Main Chain Direction 1: Deprotection of Protecting Group)
The compound (1a-2-ii) was stirred with 2 mL of 5% m-cresol / TFA for 30 minutes. After removing the solution by filtration, the remaining resin was washed with DMF and DCM. A part of the sample was collected in a test tube, and it was confirmed by the ninhydrin test that the compound (1a-6-i) was produced because the carrier and the solution were positive.

Reaction Step 22 Synthesis of Boc-Lys (Fmoc) -C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a-6-ii)] (Extension Reaction 2: Main Chain Condensation of Amino Acids)
Boc-Lys (Fmoc) -OH (69.2 mg, 125 μmol), HCTU (62.4 mg, 120 μmol), DIEA (40.8 μL, 240 μmol) were dissolved in compound (1-2-i) (80 μmol scale) The mixture was stirred in 2 mL of DMF solution at room temperature under a nitrogen stream for 30 minutes. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the negative ninhydrin test confirmed the production of compound (1a-6-ii).

Reaction Step 23 Synthesis of Compound (1a-6-ii) (Elongation Reaction 3: Main Capping Reaction)
The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Then, using the Boc-HN-C ₅ H ₁₀ -COOH, Boc-Lys (Fmoc) -OH, Boc-HN-C ₁₀ H ₂₀ -COOH, and AcS-C ₅ H ₁₀ -COOH, the above reaction step 21 The compound (1a-6-iii) was synthesized by repeating the steps ˜23 and sequentially performing solid phase synthesis.

2. Synthesis of the side chain moiety
Reaction Step 24 AcS-C ₅ H ₁₀ -CONH-C ₁₀ H ₂₀ -Lys (Boc-Lys (Fmoc))-C ₅ H ₁₀ -Lys (Boc-Lys (Fmoc))-C ₅ H ₁₀ -Lys (Boc -Lys (Fmoc))-C ₅ H ₁₀ -Lys (Boc-Lys (Fmoc))-C ₅ H ₁₀ -Lys (Boc-Lys (Fmoc))-C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a- 6-iv)] synthesis (extension reaction toward the side chain)
Compound (1a-6-iii) (80 μmol scale) was shaken and stirred in 2 ml of 20% piperidine DMF solution at room temperature for 5 minutes. The reaction solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, a part of the solvent was taken up in a test tube, and the side chain Fmoc group was deprotected by being negative in the ninhydrin test. To the remaining resin, add 2 mL of DMF solution in which Boc-Lys (Fmoc) -OH (234.3 mg, 500 μmol), HCTU (198.6 mg, 480 μmol), and DIEA (163.3 μL, 960 μmol) are dissolved. The mixture was stirred for 30 minutes under a nitrogen stream. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the production of compound (1a-6-iv) was confirmed by being negative in the ninhydrin test. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction step 25 AcS-C ₅ H ₁₀ -CONH-C ₁₀ H ₂₀ -Lys (Fmoc-Lys (Fmoc) -Lys (Fmoc))-C ₅ H ₁₀ -Lys (Fmoc-Lys (Fmoc) -Lys (Fmoc) ) -C ₅ H ₁₀ -Lys (Fmoc-Lys (Fmoc) -Lys (Fmoc))-C ₅ H ₁₀ -Lys (Fmoc-Lys (Fmoc) -Lys (Fmoc))-C ₅ H ₁₀ -Lys (Fmoc -Lys (Fmoc) -Lys (Fmoc))-C ₁₀ H ₂₀ -CONH-MBHA [Compound (1a-6-v)] (Elongation reaction in the side chain direction)
Compound (1a-6-iv) (80 μmol scale) was stirred with 2 mL of 5% m-cresol / TFA for 30 minutes. After removing the solution by filtration, the remaining resin was washed with DMF and DCM. A part of the sample was collected in a test tube, and since the carrier and the solution were positive in the ninhydrin test, the deprotection of the Boc group was confirmed. To the remaining resin, add 2 mL of DMF solution containing Fmoc-Lys (Fmoc) -OH (295.3 mg, 500 μmol), HCTU (198.6 mg, 480 μmol), DIEA (163.3 μL, 960 μmol), and add nitrogen at room temperature. The mixture was stirred for 30 minutes under an air stream. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, a part of the solvent was taken into a test tube, and the production of the compound (1a-6-v) was confirmed by being negative in the ninhydrin test. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction Step 26 Synthesis of Compound (1a-6) Compound (1a-6-v) was shaken and stirred in 2 ml of 20% piperidine DMF solution at room temperature for 5 minutes. The reaction solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, a part of the solvent was taken up in a test tube, and the side chain Fmoc group was deprotected by being negative in the ninhydrin test. To the remaining resin, add 2 mL of DMF solution containing Me ₂ NC ₃ H ₆ -COOH (223.0 mg, 1330 μmol), HCTU (529.5 mg, 1280 μmol), DIEA (435.5 μL, 2560 μmol), and add nitrogen at room temperature. The mixture was stirred for 30 minutes under an air stream. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the production of compound (1a-6) was confirmed by being negative in the ninhydrin test. The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction Step 27 Synthesis of Compound (1-2) Add 1.0 ml of TFMSA solution (TFMSA / TFA / thioanisol = 10/90/1) to the dried compound (1a-6), treat at room temperature for 2 hours and filter. To recover the TFMSA solution. The remaining resin was washed with 1.0 ml of TFA and mixed with the previous filtrate. The filtrate was added dropwise to cold diethyl ether (40 ml), and the precipitate was collected by centrifugation. The residual ether was removed, and after drying, a crude sample of compound (1-2) was obtained. This crude sample was purified by high performance liquid chromatography using an ODS column. MALDI-TOF MS: calcd. 4587.47 (M + H +), found 4587.37.

Example 7 Synthesis of Compound (1a-7) Compound (1a-7) represented by the following general formula was synthesized.

  Specifically, using the compound (1a-1-iii) shown in Example 1 above, compound (1a-7) was synthesized according to the reaction steps shown below.

  Detailed conditions of the synthesis method are as follows.

  Compound (1a-7) was synthesized from compound (1a-1-iii) shown in Example 1 using the Alloc method. That is, a sequential extension reaction was performed using a DMF solution in which the amino acid derivatives Alloc-Lys (Boc) -OH and Boc-Lys (Boc) -OH were added to the condensing agents HATU and DIEA, respectively. This extension reaction is a repetition of three steps: deprotection of the protecting group (reaction step 28), batch condensation of amino acids (reaction step 29), and capping reaction (reaction step 30).

Reaction step 28 Fmoc-AEG (H ₂ N-C5) -AEG (H ₂ N-C5) -AEG (H ₂ N-C5) -AEG (H ₂ N-C5) -AEG (H ₂ N-C5)- _{C 5 H 10 -CONH-C 5} H 10 - CONH -PAL [ compound (1a-7-i)] ( elongation reaction to the side chain direction 1: deprotection of Alloc group)
Compound (1a-1-iii) in Pd (PPh3) 4 (tetrakis (triphenylphosphine) palladium (0)) 312 mg CHCl3 / AcOH / N-methylmorphorine solution (2.8 mL, 1.5 mL, 0.75 mL in this order) The mixture was stirred for 30 minutes at room temperature. The reaction solution was removed by filtration, and the remaining resin was washed. This was carried out twice, and a part of the sample was taken into a test tube and positive in the ninhydrin test, confirming the formation of compound (1a-1-iii).

Reaction Step 29 Fmoc-AEG (Alloc-Lys (Boc) -C5) -AEG (Alloc-Lys (Boc) -C5) -AEG (Alloc-Lys (Boc) -C5) -AEG (Alloc-Lys (Boc)- Synthesis of C5) -AEG (Alloc-Lys (Boc) -C5) -C ₅ H ₁₀ -CONH-C ₅ H ₁₀ -CONH-PAL [Compound (1a-7-ii)] (extension reaction in the side chain direction) 2: Batch condensation of amino acids)
Alloc-Lys (Boc) -OH (733 mg, 1080 μmol), condensing agent HATU (410 mg, 1080 μmol) and DIEA (188 μL) were dissolved in compound (1a-7-i) (72 μmol scale) 2 mL of DMF solution was added and stirred for 30 minutes under a nitrogen stream at room temperature. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken up in a test tube, and the result was negative in the ninhydrin test, confirming the formation of compound (1a-7-ii).

Reaction Step 30 Synthesis of Compound (1a-7-ii) (Extension Reaction in Side Chain 3: Capping Reaction)
The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Next, the above reaction steps 28 to 30 are repeatedly performed using Alloc-Lys (Boc) -OH and Boc-Lys (Boc) -OH, and the target compound (1a- 7) was synthesized. The synthesis of compound (1a-7) was confirmed by deprotecting the Fmoc group by piperidine treatment, followed by TFA treatment (95% TFA / 5% m-cresol) and cleaving from the solid support PAL and protecting Lys. The Boc group is deprotected, and H ₂ N-AEG (Lys-Lys-Lys-C5) -AEG (Lys-Lys-Lys-C5) -AEG (Lys-Lys-Lys-C5) -AEG (Lys- Lys-Lys-C5) -AEG (Lys-Lys-Lys-C5) -C ₅ H ₁₀ -CONH-C ₅ H ₁₀ -NH ₂ MALDI-TOF MS: calcd. 3233.32 (M + H ⁺ ), found 3233.60.
Example 8 Synthesis of Compound (1a-8) Compound (1a-8) represented by the following general formula was synthesized.

  Specifically, using the compound (1a-7-ii) shown in Example 7 above, compound (1a-8) was synthesized according to the reaction steps shown below.

Detailed conditions of the synthesis method are as follows.
Reaction step 31 Fmoc-AEG (Alloc-Arg (Boc) ₂ -Lys (Boc) -C5) -AEG (Alloc-Arg (Boc) ₂ -Lys (Boc) -C5) -AEG (Alloc-Arg (Boc) ₂ -Lys (Boc) -C5) -AEG (Alloc-Arg (Boc) ₂ -Lys (Boc) -C5) -AEG (Alloc-Arg (Boc) ₂ -Lys (Boc) -C5) -C ₅ H _10- Synthesis of CONH-C ₅ H ₁₀ -CONH-PAL [Compound (1a-8-i)] Compound (1a-7-ii) was converted to Pd (PPh3) 4 (tetrakis (triphenylphosphine) palladium (0)) 312 mg The mixture was shaken and stirred in a CHCl3 / AcOH / N-methylmorphorine solution (2.8 mL, 1.5 mL, and 0.75 mL in this order) at room temperature for 30 minutes. The reaction solution was removed by filtration, and the remaining resin was washed. This was carried out twice, and a part of the sample was taken into a test tube, and the ninhydrin test was positive. Therefore, the deprotection of the Alloc group was confirmed. To the remaining resin, add 2 mL of DMF solution containing Alloc-Arg (Boc) ₂ -OH (495 mg, 1080 μmol), condensing agent HATU (410 mg, 1080 μmol) and DIEA (188 μL), and add nitrogen at room temperature. The mixture was stirred for 30 minutes under an air stream. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Further, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was taken up into a test tube, and the result was negative in the ninhydrin test. Thus, production of compound (1a-8-i) was confirmed.

  The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

Reaction Step 32 Synthesis of Compound (1a-8) Compound (1a-8-i) (72 μmol scale) was added to Pd (PPh3) 4 (tetrakis (triphenylphosphine) palladium (0)) 312 mg CHCl3 / AcOH / N- The mixture was shaken and stirred in a methylmorphorine solution (2.8 mL, 1.5 mL, and 0.75 mL in this order) at room temperature for 30 minutes. The reaction solution was removed by filtration, and the remaining resin was washed. This was carried out twice, and a part of the sample was taken into a test tube, and the ninhydrin test was positive. Therefore, the deprotection of the Alloc group was confirmed.

  Add 2 mL of DMF solution in which Boc-Ser (tBu) -OH (733 mg, 1080 μmol), condensing agent HATU (410 mg, 1080 μmol) and DIEA (188 μL) are dissolved. Stir. Next, the DMF solution was removed by filtration, and the remaining resin was washed with DMF and DCM. Furthermore, excess solvent was removed by feeding dry nitrogen, and a part of the solvent was collected in a test tube, and the result was negative in the ninhydrin test, confirming the formation of compound (1a-8). The remaining resin was reacted with 2 mL of a capping reagent (acetic anhydride / pyridine / DMF = 1/25/25) for 5 minutes at room temperature. Next, the solution was removed by filtration, and the remaining resin was washed with DMF and DCM.

The synthesis of compound (1a-8) was confirmed by removing the Fmoc group by piperidine treatment, then cutting it out from solid phase resin PAL and protecting Lys by TFA treatment (95% TFA / 5% m-cresol). Deprotection of the Boc group, H ₂ N-AEG (Ser-Arg-Lys-C5) -AEG (Ser-Arg-Lys-C5) -AEG (Ser-Arg-Lys-C5) -AEG (Ser- Arg-Lys-C5) -AEG (Ser-Arg-Lys-C5) -C ₅ H ₁₀ -CONH-C ₅ H ₁₀ -NH ₂ MALDI-TOF MS: calcd. 3167.92 (M + H ⁺ ), found 3166.89.

Claims (13)

Compound represented by the following general formula (1):

[In the formula (1), n1 represents an integer of 0 to 10, n2 represents an integer of 1 to 50, and n3 represents an integer of 1 to 10;
m1 is an integer from 0 to 100, m2 is an integer from 0 to 100, m3 is an integer from 0 to 100, m4 is an integer from 0 or 1, m5 is an integer from 0 to 100, and m6 is an integer from 0 to 100 ;
Y ₁ represents a hydroxyl group or an amino group;
E represents N or CH;
R represents an amino acid residue or a peptide residue consisting of 2 to 100 amino acid residues;
L represents an amino group to which a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding the amino group) is bonded via a linker;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and R in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ] The compound according to claim 1, wherein L is an amino group to which a thiol group or a carboxyl group is bonded via a linker. In the formula (1), R is an amino acid residue selected from the group consisting of an arginine residue, a lysine residue, and a serine residue, or a peptide residue containing at least one of these amino acid residues. The compound according to claim 1 or 2. The compound according to claim 1 or 2, wherein in formula (1), R is a peptide residue composed of 2 to 5 arginine residues. In formula (1), n1 is an integer of 0-2, n2 is an integer of 1-10, n3 is an integer of 0-2, The compound in any one of Claims 1 thru | or 4. The compound according to any one of claims 1 to 5, wherein in the formula (1), E is N, m2 is 2, m3 and m4 are 1, and m5 is 5. Compound represented by the following general formula (1a):

[N1-n3, m1-m6, E and R are the same as above,
Y ₂ represents a solid phase resin;
X is a protecting group X ₁ , a hydrogen atom, a group —CO—L (L is the same as described above), a group —CO—LX ₁ (L is the same as described above. LX ₁ is a functional group in L and a protecting group X ₁ Indicates that they are bound);
Z represents different protecting group Za, or a protecting group X ₁ and the same protective groups Zb is a protecting group X _1;
RZ means that a protective group Z is bonded to the functional group of the amino acid residue or peptide residue of R;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and RZ in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ] In formula (1a), R comprises an amino acid residue selected from the group consisting of an arginine residue, a lysine residue, and a serine residue, or at least one of these amino acid residues, and the total number of amino acid residues 8. The compound of claim 7, wherein is a 2-20 peptide residue. The compound according to claim 7 or 8, which is a peptide residue composed of 2 to 5 arginine residues in the formula (1a). The compound according to any one of claims 7 to 9, wherein n1 is an integer of 0 to 2, n2 is an integer of 1 to 10, and n3 is an integer of 0 to 2 in formula (1a). The compound according to any one of claims 7 to 10, wherein in formula (1a), E is N, m2 is 2, m3 and m4 are 1, and m5 is 5. A method for producing a compound represented by the following general formula (1), comprising the following steps 1-1 to 1-6:

[In the formula (1), n1 represents an integer of 0 to 10, n2 represents an integer of 1 to 50, and n3 represents an integer of 1 to 10;
m1 is an integer from 0 to 100, m2 is an integer from 0 to 100, m3 is an integer from 0 to 100, m4 is an integer from 0 or 1, m5 is an integer from 0 to 100, and m6 is an integer from 0 to 100 ;
Y ₁ represents a hydroxyl group or an amino group;
E represents N or CH;
R represents an amino acid residue or a peptide residue consisting of 2 to 100 amino acid residues;
L represents an amino group to which a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding the amino group) is bonded via a linker;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and R in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ]
Step 1-1: Compound represented by the following general formula (I)

[In formula (I), X ₁ represents a protecting group, and m6 is the same as defined above. ]
Is condensed to a solid phase resin or a solid phase compound, and then the elimination of the protecting group X ₁ of the compound condensed to the solid phase resin and the condensation polymerization of the compound represented by the general formula (I) are performed n3 −1 times. By carrying out, the compound represented by the following general formula (i)

Wherein (i), n3, m6, and X ₁ are as defined above. Y ₂ represents a solid phase resin. ]
Obtaining a step,
Step 1-2: Compound represented by the following general formula (II) with respect to the compound represented by the general formula (i)

Wherein (II), m2~m5, and X ₁ are as defined above, Za represents a protecting group different from X _1. ]
The compound represented by the following general formula (ii) by performing the condensation reaction of n2 times

Wherein (ii), n2, n3, m2~m6, X 1, Za and Y ₂ are as defined above. ]
Obtaining a step,
Step 1-3: A compound represented by the following general formula (III) with respect to the compound represented by the general formula (ii)

Wherein (III), m1 and X ₁ are as defined above. ]
The compound represented by the following general formula (iii) by performing the condensation reaction of n1 times

[In the formula (iii), n1 to n3, m1 to m6, X ₁ , Za and Y ₂ are the same as above. ]
Obtaining a step,
Step 1-4: After removing the protecting group X ₁ of the compound represented by the general formula (iii), the amino group from which the protecting group X was removed and the compound X ₁ L-COOH [X ₁ and L is the same as described above, and X ₁ L is a functional group capable of forming a peptide bond, disulfide bond or biotin-avidin bond (excluding an amino group), and is a functional group protected with a protecting group X ₁ Represents an amino group bonded through a linker] to obtain a compound represented by the following general formula (iv),

[In the formula (iv), n1 to n3, m1 to m6, X ₁ L, Za and Y ₂ are the same as above. ]
Step 1-5: Condensation reaction of an amino acid in which a protecting group Za is bonded to a functional group other than a carboxyl group bonded to the α-position carbon atom for the compound represented by the general formula (iv) 1 to 100 times By carrying out, the compound represented by the following general formula (v)

[In the formula (iv), n1 to n3, m1 to m6, X ₁ L, RZa and Y ₂ are the same as above. ]
Steps 1-6: From the compound represented by the general formula (v), the solid phase resin is separated to form —COOH or —CONH ₂ at the terminal, and the protecting groups X ₁ and Za are eliminated. A step of obtaining a compound represented by the general formula (1). A method for producing a compound represented by the following general formula (1a), comprising the following steps 3-1 to 3-5:

[N1-n3, m1-m6, E and R are the same as above,
Y ₂ represents a solid phase resin;
X is a protecting group X ₁ , a hydrogen atom, a group —CO—L (L is the same as described above), a group —CO—LX ₁ (L is the same as described above. LX ₁ is a functional group in L and a protecting group X ₁ Indicates that they are bound);
Z represents different protecting group Za, or a protecting group X ₁ and the same protective groups Zb is a protecting group X _1;
RZ means that a protective group Z is bonded to the functional group of the amino acid residue or peptide residue of R;
when n1 is 2 or more, m1 in the repeating unit A may be the same or different in each repeating unit A;
When n2 is 2 or more, m2 to m5 and RZ in the repeating unit B may be the same or different in each repeating unit B;
When n3 is 2 or more, m6 in the repeating unit C may be the same or different in each repeating unit C. ]
Step 3-1: Compound represented by the following general formula (I)

[In the formula (I), X ₁ and m6 are the same as above. ]
Is condensed to a solid phase resin having an amino group, and then the elimination of the protecting group X ₁ of the compound condensed to the solid phase resin and the condensation polymerization of the compound represented by the general formula (I) are performed as n3 −1. The compound represented by the following general formula (i)

Wherein (i), n3, m6, X 1 and Y ₂ are as defined above. ]
Obtaining a step,
Step 3-2: Compound represented by the following general formula (II) with respect to the compound represented by the general formula (i)

Wherein (II), m2~m5, X ₁ and Za are as defined above. ]
The compound represented by the following general formula (ii) by performing the condensation reaction of n2 times

Wherein (ii), n2, n3, m2~m6, X 1, Za and Y ₂ are as defined above. ]
Obtaining a step,
Step 3-3: Compound represented by the following general formula (III) with respect to the compound represented by the general formula (ii)

Wherein (III), m1 and X ₁ are as defined above. ]
The compound represented by the following general formula (iii) by performing the condensation reaction of n1 times

[In the formula (iii), n1 to n3, m1 to m6, X ₁ , Za and Y ₂ are the same as above. ]
Obtaining a step,
Step 3-4: The protecting group X1 of the compound represented by the general formula (iii) is removed, and the compound X-OH [X is the same as described above]. ] To obtain a compound represented by the following general formula (iv-a),

Wherein (iv-a), n1~n3, m1~m6, X, Za and Y ₂ are as defined above. ]
Step 3-5: A compound represented by the general formula (iv-a) is subjected to a condensation reaction of an amino acid in which a protective group Z is bonded to an amino group 1 to 100 times, whereby the general formula (1a) A step of obtaining a compound represented by the formula: