Detailed book
Title of the Invention: Peptide Derivative and Uses Thereof
Technical field
[0001]
　The present invention relates to peptide derivatives and uses thereof.
Background technique
[0002]
　Multiple kinds of peptide derivatives having cytotoxicity are isolated from the sea turtle present in the ocean. Dolastatin 10 is known as a compound of these peptide derivatives and has extremely strong cytotoxicity (Patent Document 1 and Non-Patent Document 1).
[0003]
　It has been clarified that cytotoxicity of dolastatin 10 is exerted by tubulin polymerization inhibitory action, and its structure activity correlation has been reported so far (Patent Documents 2 and 3 and Non-Patent Document 2). In addition, there are other monomethyl auristatins (Patent Documents 4 and 5) as a peptide derivative having a similar tubulin polymerization inhibitory action, and this compound binds to a specific amino acid of the antibody through a specific structure called a linker It is known that it is used as an antibody drug complex.
[0004]
　A medicament that can be used for the antibody drug conjugate must have a specific substituent (eg, an amino group, a sulfhydryl group or a hydroxy group) capable of binding to a linker or an antibody. In addition, since the binding method greatly affects the efficacy of the complex, the use of plural kinds of substituents has been reported so far (Non-Patent Documents 3 to 5).
[0005]
　Heretofore, derivatives having a functional group usable for a complex with a tubulin inhibitor include monomethyl auristatin or PF-063801010 (Non-Patent Document 6) having an amino group at the N-terminal or a derivative Auristatin F derivatives having an amino group, a hydroxy group, a carboxylic acid, a hydroxylamine or an alkyne (Patent Document 6 and Non-Patent Documents 7 to 9) have been reported.
[0006]
　On the other hand, as a development from the C-terminal of dolastatin 10, derivatives having ethyl ester, ethyl amide or thiazole amide have been reported (Non-Patent Document 10).
Advanced technical literature
Patent literature
[0007]
Patent Document 1: Japanese Patent Application Laid-Open No. 2-167278
Patent Document 2: International Publication No. 1993/003054
Patent Document 3: International Publication No. 1995/009864
Patent Document 4: International Publication No. 2002/088172
Patent Document 5: International Publication No. 2004/010957
Patent Document 6: International Publication No. 2012/171020
Non-patent literature
[0008]
Non-patent document 1: Pettit et al., Journal of the American Chemical Society, 1987, 109, p. 6883-6885
Non-Patent Document 2: Miyazaki et al., Chemical and Pharmaceutical Bullentin, 1995, Vol. 43, p. 1706-1718
Non-patent document 3: Jain et al., Pharmaceutical Research, 2015, 32, p. 3526-3540
Non-Patent Document 4: Trais et al., Antibodies, 2013, Vol. 2, p. 113-129
Non-Patent Document 5: Kern et al., Journal of the American Chemical Society, 2016, Vol. 138, p. 1430-1445
Non-Patent Document 6: Maerna et al., Journal of Medicinal Chemical Society, 2014, 57, p. 10527-43
Non-Patent Document 7: Doronia et al., Bioconjugate Chemistry, 2008, Vol. 19, p. 1960-1963
Non-Patent Document 8: Axup et al., Proceedings of the National Acede of Sciences, 2012, 109, p. 16101-16106
Non-Patent Document 9: Van Brunt et al., Bioconjugate Chemistry, 2015, Vol. 26, p. 2249-2260
Non-patent literature 10: Miyazakiら, Peptide Chemistry, 1993, p. 85-88
Summary of the invention
Problem to be Solved by Invention
[0009]
　However, no dolastatin 10 derivative having a functional group usable for forming a complex at the C terminus has been reported so far.
[0010]
　Derivatives having different types of substituents based on the same skeleton are thought to be useful for verifying the effect of the creation of new complexes and the composition of the complex on cytotoxicity, Such derivatives have not been reported.
[0011]
　Therefore, it is an object of the present invention to provide a dolastatin 10 derivative having a functional group usable for forming a complex at the C-terminal.
Means for solving the problem
[0012]
　As a result of intensive studies to achieve the above object, the present inventors have found that a novel peptide derivative having a specific functional group at the C-terminus or a pharmacologically acceptable salt thereof is effective against a plurality of cancer cells Have high cytotoxicity, and have completed the present invention.
[0013]
　That is, the present invention provides a peptide derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
[Formula 1]

[wherein, X represents an oxygen atom or NR, Y is NH 2 , N (Me) H, SH, an OH or any one of a hydrogen atom NH 2 phenyl substituted with or OH Group, and R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. With the proviso that X is NH and Y is NH 2 and derivatives in which X is NH and Y is N (Me) H. ]
[0014]
　In the peptide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, X is preferably an oxygen atom.
[0015]
　In this case, high cytotoxicity can be expected.
[0016]
　In the peptide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, X is an oxygen atom and Y is NH 2 , N (Me) H, SH or OH Is more preferable.
[0017]
　In this case, higher cytotoxicity can be expected.
[0018]
　In the peptide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, X is preferably NR.
[0019]
　In this case, high cytotoxicity can be expected.
[0020]
　In the peptide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, X is NR, and R is more preferably an alkyl group having 1 to 3 carbon atoms.
[0021]
　In this case, higher cytotoxicity can be expected.
[0022]
　In the peptide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, X is NR, and R is more preferably a methyl group.
[0023]
　In this case, even higher cytotoxicity can be expected.
[0024]
　The present invention also provides a complex comprising the peptide derivative represented by the above general formula (I) and a targeting ligand or polymer, or a pharmacologically acceptable salt thereof.
[0025]
　The present invention also provides a pharmaceutical composition comprising a peptide derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, or a complex or a pharmacologically acceptable salt thereof as an active ingredient And a cytotoxic agent.
Effect of the invention
[0026]
　Since the peptide derivative of the present invention or a pharmacologically acceptable salt thereof has high cytotoxicity, it can be used as a cytotoxic agent.
[0027]
　Further, since the peptide derivative of the present invention has various functional groups at the C-terminus, it is possible to conjugate the peptide derivative or its prodrug and the targeting ligand or polymer, and the complex or its pharmacological Can be used as a cytotoxic agent.
MODE FOR CARRYING OUT THE INVENTION
[0028]
　The peptide derivative of the present invention is characterized by being represented by the following general formula (I).
[

Wherein X represents an oxygen atom or NR, Y represents NH 2 , N (Me) H, SH, OH or phenyl in which any one hydrogen atom is substituted with NH 2 or OH Group, and R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. With the proviso that X is NH and Y is NH 2 and derivatives in which X is NH and Y is N (Me) H. ]
[0029]
　The following terms used in the present specification are as defined below, unless otherwise specified.
[0030]
　" A phenyl group in which one arbitrary hydrogen atom is substituted with NH 2 or OH" refers to a phenyl group substituted with a group selected from the group consisting of a 2-aminophenyl group, a 3-aminophenyl group, a 4-aminophenyl group, a 2-hydroxyphenyl group, Phenyl group or 4-hydroxyphenyl group.
[0031]
　The "alkyl group having 1 to 3 carbon atoms" means a methyl group, an ethyl group, a propyl group or an isopropyl group.
[0032]
　Specific examples of preferable compounds of the peptide derivative represented by the above general formula (I) are shown in Table 1, but the present invention is not limited thereto.
[0033]
[Table 1]

[0034]
　The compounds listed in Table 1 also include their pharmacologically acceptable salts.
[0035]
　The peptide derivative represented by the above general formula (I) (hereinafter, the peptide derivative (I)) contains a conformer, rotamer, tautomer, optical isomer, diastereomer, epimer or the like , Either one of the isomers and the mixture is included in the peptide derivative (I). Furthermore, when the optical isomer is present in the peptide derivative (I), optical isomers separated from the racemate are also included in the peptide derivative (I).
[0036]
　The configuration of the peptide derivative (I) is preferably the following formula (II).
[Chemical formula 3]

[0037]
　The present invention also includes a prodrug of the peptide derivative (I) or a pharmacologically acceptable salt thereof. The prodrug of the peptide derivative (I) is a compound that is converted in vivo enzymatically or chemically to the peptide derivative (I). The active principle of the prodrug of the peptide derivative (I) is the peptide derivative (I), but the prodrug itself of the peptide derivative (I) may have activity.
[0038]
　As the prodrug of the peptide derivative (I), for example, a compound in which the hydroxy group of the peptide derivative (I) is esterified, carbonated, carbamated, alkylated, phosphorylated or borated can be mentioned. These compounds can be synthesized from the peptide derivative (I) or a synthetic intermediate thereof according to a known method.
[0039]
　As the prodrug of the peptide derivative (I), for example, a compound in which the amino group of the peptide derivative (I) is carbamated or amidated can be mentioned. These compounds can be synthesized from the peptide derivative (I) or a synthetic intermediate thereof according to a known method.
[0040]
　As a prodrug of the peptide derivative (I), for example, a compound in which the sulfhydryl group of the peptide derivative (I) forms a disulfide bond can be mentioned. These compounds can be synthesized from the peptide derivative (I) or a synthetic intermediate thereof according to a known method.
[0041]
　Specific examples of the prodrug of the above peptide derivative (I) are shown in Table 2, but the present invention is not limited thereto.
[0042]
[Table 2]

[0043]
　Compounds listed in Table 2 also include salts thereof.
[0044]
　In Table 2, Q is a known method (for example, Ellen M. Sletten et al., Angewante Chimie International Edition, 2009, Vol. 48, p.6974-6998, Greg T. Hermanson., "Bioconjugate Technique", Elsevier , Xi Chem et al., Organic & Biomolecular Chemistry, 2016, Vol. 14, p. 5417-5439) or functional groups compatible with them (for example, maleimide group, carboxyl group, activated carboxyl group, carbonyl group, an aminooxy group, a hydrazide group, a diazo group, alkyne group or hydroxy group), J represents a non-existent or spacer, a 1 , a 2及 A 3 represents an amino acid, Z is a hydrogen atom or a methyl group, and the other symbols are the same as defined above.
[0045]
　"Spacer" refers to a structure linking Q with a prodrug of the peptide derivative (I) or peptide derivative (I), and includes, for example, a linear or branched alkyl group having 1 to 12 carbon atoms, -C (═O) A structure composed of N (Z) - or -N (Z) C (═O) -, PEG, a disulfide bond or a combination thereof, and a structure composed of these combinations is preferable.
[0046]
　"A linear or branched alkyl group having 1 to 12 carbon atoms" means, for example, - (CH 2 ) n -, - CH (Me) -, - C (Me) 2 -, - (CH 2 ) o CH (Me) -, - CH (Me) (CH 2 ) o -, - (CH 2 ) p C (Me) 2 - or -C (Me) 2 (CH 2 ) p -. n represents an integer of 1 to 12, o represents an integer of 1 to 10, and p represents an integer of 1 to 9.
[0047]
　"PEG" represents a linear polyethylene glycol having a number average molecular weight of 200 to 2,000 represented by a repeating structure of - (CH 2 CH 2 O) m -, and m represents an integer of 5 to 45.
[0048]
　In the present specification, when an amino acid or the like is indicated by an abbreviation, it is based on the abbreviation by IUPAC-IUB Commission on Biochemical Nomenclature or a common abbreviation in the relevant field, examples of which are described below. In the case where there are optical isomers with respect to amino acids, unless otherwise specified, unless otherwise specified, the L form is shown (for example, "Lys" is the L form of Lys). Also, when it is denoted as "D-", it indicates the D form (for example, "D-Lys" means L form of D form); when it is indicated as "DL-", it indicates the racemic form of D form and L form (For example, "DL-Lys" is a racemic form of Lys of D form and Lys of L form).
[0049]
　"Amino acid" refers to the amino acid sequence of DL-Ala, DL-Arg, DL-Asn, DL-Asp, DL-Cit, DL-Cys, DL-Gln, DL-Glu, DL-Gly, DL-His, DL- -Leu, DL-Lys, DL- Met, DL-Phe, DL-Pro, DL-Ser, DL-Thr, DL-Trp, although any one of DL-Tyr or DL-Val is selected, A 1 is , Lys, A 2 and A 3 are absent, A 1 is Cit or Lys, A 2 is Val or Phe, A 3 is absent or A 1 is Asp It is preferable that A 2 and A 3 are Ala.
[0050]
　A 1 described in Table 2 is bonded at the carbonyl terminal to NH of the phenyl group, and A 1 , A 2 and A 3 are bonded to each other at the main chain via an amide bond.
[0051]
　The preferred structure of the prodrug of the peptide derivative (I) described in the number 6 in Table 2 is shown in Table 3, but the present invention is not limited thereto.
[0052]
[table 3]

[0053]
　The compounds listed in Table 3 also include their salts.
[0054]
　In Table 3, Alk 1 and Alk 2 each independently represents a linear or branched alkyl group having 1 to 12 carbon atoms, and E represents an absent or -C (═O) N (Z) - or -N (Z) C (═O) -, and the other symbols are as defined above.
[0055]
More preferably, 　Alk 1 is - (CH 2 ) 2 -, X is NR, Alk 1 is - (CH 2 ) 2 -, E is -N (Z) C (═O) -, PEG is - (CH 2 CH 2 O) 12 -, and Q is a maleimide group, But the present invention is not limited thereto.
[0056]
　A prodrug of the peptide derivative (I) according to the number 8 in Table 2 is a compound wherein J is -Alk 1 -E-Alk 2 - or -Alk 1 -E-PEG- (CH 2 ) 2 -E-Alk 2 -, it is preferred that J is - (CH 2 ) 2 --N (Z) C (═O) - Alk 2 - or - (CH 2 ) 2 --N (Z) C (═O) - (CH 2 CH 2 O) 12 - (CH 2 ) 2 --N (Z) C (═O) - Alk 2 -, and Q is a maleimide group, but the present invention is limited to these is not.
[0057]
　Table prodrug peptide derivative according to the numbers 9-11 in 2 (I) may, J is, -C (= O) -Alk 1 -, - C (= O) -PEG- (CH 2 ) 2 - E-Alk 1 - or -C (═O) -Alk 1 -E-PEG- (CH 2 ) 2 -E-Alk 1 -, and J is preferably -C (═O) - (CH 2 ) n -, - C (= O) -PEG- (CH 2 ) 2 -E- (CH 2 ) n - or -C (= O) - (CH 2 ) n -E-PEG-(CH 2 ) 2 -E- (CH 2 ) N-, A 1 is Cit or Lys, A 2 is Val or Phe, A 3 is absent, and Q is a maleimide group or an aminooxy group, more preferably the present invention Are not limited to these.
[0058]
　Prodrugs of the peptide derivative (I) can also be prepared according to known literatures ("Development of pharmaceuticals", Hirokawa Shoten, 1990, Vol. 7, pp. 163-198 and Progress in Medicine, Volume 5, 1985, p. 2157 to 2161), it may be changed to a peptide derivative (I) under physiological conditions.
[0059]
　The peptide derivative (I) may be labeled with an isotope and examples of a labeled isotope include 2 H, 3 H, 13 C, 14 C, 15 N, 15 O, 17 O, 18 O And / or 125 I.
[0060]
　As the "pharmacologically acceptable salt" of the peptide derivative (I), for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate or Oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, Ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate or Organic acid salts such as cinnamate and the like, with hydrochloride, sulfate, hydrobromide, maleate, benzoate or methanesulfonate being preferred.
[0061]
　The peptide derivative (I) or a pharmacologically acceptable salt thereof may be an anhydride or a solvate such as a hydrate. Here, as a solvate, a pharmacologically acceptable solvate is preferable. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferred. Examples of the solvent constituting the solvate include alcoholic solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide, dimethylsulfoxide or water.
[0062]
　The peptide derivative (I) can be produced by an appropriate method based on features derived from its basic skeleton and type of substituent. The starting materials and reagents used in the preparation of these compounds can generally be purchased or can be produced by a known method or a method analogous thereto.
[0063]
　Peptide derivatives (I) and intermediates and starting materials used for their preparation can be isolated and purified by known means. Examples of known means for isolation and purification include solvent extraction, recrystallization or chromatography.
[0064]
　When the peptide derivative (I) contains optical isomers or stereoisomers, each isomer can be obtained as a single compound by a known method. Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.
[0065]
　In each reaction of the production method described below, when the starting compound has a hydroxy group, an amino group, a sulfhydryl group or a carboxyl group, a protective group may be introduced into these groups, and if necessary after protection The desired compound can be obtained by deprotecting the group.
[0066]
　Examples of the hydroxy-protecting group include a trityl group, a tetrahydropyranyl group, an aralkyl group having 7 to 10 carbon atoms (eg, a benzyl group), or a substituted silyl group (eg, trimethylsilyl group, triethylsilyl group or tert-butyldimethyl Silyl group).
[0067]
　Examples of the amino-protecting group include an alkylcarbonyl group having 2 to 6 carbon atoms (eg, acetyl group), a benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy A carbonyl group), an aralkyl group having 7 to 10 carbon atoms (eg, a benzyl group), or a phthaloyl group.
[0068]
　Examples of the sulfhydryl group protecting group include a trityl group, a 2-mercaptopyridyl group, and a 2-mercapto-5-nitropyridyl group.
[0069]
　Examples of the protecting group for the carboxyl group include an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group or tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group).
[0070]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0071]
　The peptide derivative (I) can be obtained by deprotection reaction of the protected peptide derivative (III), for example, as shown in Scheme 1.
[Formula 4]

[wherein, PG represents a protecting group, when X is NR, Y is NH 2 represents or SH, Y 'represents NH, or S. When X is an oxygen atom, Y represents NH 2 , SH, OH or a phenyl group in which any one hydrogen atom is substituted with NH 2 or OH, Y 'represents NH, S, O or an arbitrary one A phenyl group in which a hydrogen atom is substituted with NH or O. ]
[0072]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0073]
　The protected peptide derivative (III) can be obtained, for example, by a condensation reaction between the carboxylic acid derivative (IV) and the nucleophilic agent (V) as shown in Scheme 2.
Wherein

each symbol is as defined above. ]
[0074]
　The amount of the nucleophilic agent (V) used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the carboxylic acid derivative (IV).
[0075]
　Examples of the condensing agent used in the condensation reaction include ethyl chloroformate, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (7-aza-1H- benzotriazole- 1 - yl) -1,1,3,3-tetramethyluronium, O- (benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium hexafluorophosphate, 1 H-benzo Triazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but ethyl chloroformate, 2- (7-aza- 1 H-benzotriazole hexafluorophosphate -1-yl) -1,1,3,3-tetramethyluronium or 2-methyl-6-nito Benzoic anhydride is preferred.
[0076]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (IV).
[0077]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0078]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0079]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (IV).
[0080]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0081]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0082]
　The concentration of the carboxylic acid derivative (IV) used in the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0083]
　The nucleophilic agent (V) can be purchased or can be synthesized by a known method or a method analogous thereto.
[0084]
　The peptide derivative (I) can also be obtained by a condensation reaction of a carboxylic acid derivative (IV) and a nucleophilic agent (VI), for example, as shown in Scheme 3.
In the

formula, X represents NR, Y represents OH or a phenyl group in which any one hydrogen atom is substituted with NH 2 or OH, the other symbols are the same as defined above is there. ]
[0085]
　The amount of the nucleophilic agent (VI) used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the carboxylic acid derivative (IV).
[0086]
　Examples of the condensing agent used in the condensation reaction include ethyl chloroformate, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (7-aza-1H- benzotriazole- 1 - yl) -1,1,3,3-tetramethyluronium, O- (benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium hexafluorophosphate or 1 H-benzo Triazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, but ethyl chloroformate or hexafluorophosphate 2- (7-aza-1 H-benzotriazol-1-yl) -1, 1, 3, 3-Tetramethyluronium is preferred.
[0087]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (IV).
[0088]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0089]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0090]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (IV).
[0091]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0092]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0093]
　The concentration of the carboxylic acid derivative (IV) used in the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0094]
　The nucleophilic agent (VI) can be purchased or synthesized by a known method or a method analogous thereto.
[0095]
　The carboxylic acid derivative (IV) can be obtained, for example, by deprotection reaction of the ester derivative (VII) as shown in Scheme 4.
Wherein

each symbol is as defined above. ]
[0096]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0097]
　The ester derivative (VII) can be synthesized by a known method or a method analogous thereto.
[0098]
　As shown in, for example, Scheme 5, the protected phenoxy carbamate derivative (IX) can be obtained by a condensation reaction of a phenol derivative (Ia) with an electrophilic agent (VIII-a) or (VIII-b) it can.
Wherein

each symbol is as defined above. ]
[0099]
　The amount of the electrophilic agent (VIII-a) or (VIII-b) used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the phenol derivative (Ia).
[0100]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone, pyridine or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate , A chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane, a nitrile solvent such as acetonitrile or propionitrile, or a mixed solvent thereof, but a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane Is N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone, aprotic polar solvents such as pyridine or dimethyl sulfoxide preferred.
[0101]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or mixtures thereof, but organic bases such as triethylamine, diisopropylethylamine or pyridine A base is preferred.
[0102]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the phenol derivative (Ia).
[0103]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0104]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0105]
　The concentration at the start of the reaction of the phenol derivative (Ia) used for the condensation reaction is preferably 1 mmol / L to 1 mol / L.
[0106]
　The electrophiles (VIII-a) or (VIII-b) can be generated from known amine derivatives or carboxylic acid derivatives in a synthesis or reaction system by a known method or a method analogous thereto.
[0107]
　The protected polyethylene glycol derivative (XI) can be prepared, for example, as shown in Scheme 6 by deprotection of the protected phenoxy carbamate derivative (IX) followed by deprotection reaction of the carboxylic acid derivative (X) (In the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom) under sexual conditions.
In the

formula, G represents a hydrogen atom, a succinimidyl group or a p-nitrophenyl group, and the other symbols are the same as defined above. ]
[0108]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0109]
　The amount of the carboxylic acid derivative (X) used in the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the protected phenoxy carbamate derivative (IX).
[0110]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0111]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the protected phenoxy carbamate derivative (IX).
[0112]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0113]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0114]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0115]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0116]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0117]
　The concentration of the carboxylic acid derivative (X) used in the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0118]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0119]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (X).
[0120]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0121]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0122]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (X).
[0123]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0124]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0125]
　The concentration of the carboxylic acid derivative (X) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0126]
　The carboxylic acid derivative (X) can be purchased or synthesized by a known method or a method analogous thereto.
[0127]
　The prodrug (XIII) of the peptide derivative (I) can be prepared, for example, by deprotection reaction of the protected phenoxy carbamate derivative (IX) followed by deprotection reaction of the carboxylic acid derivative (XII) Can be obtained from a coupling reaction under neutral conditions (in the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom).
Wherein

each symbol is as defined above. ]
[0128]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0129]
　The amount of the carboxylic acid derivative (XII) used for the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the protected phenoxy carbamate derivative (IX).
[0130]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0131]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the protected phenoxy carbamate derivative (IX).
[0132]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0133]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0134]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0135]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0136]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0137]
　The concentration of the carboxylic acid derivative (XII) used in the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0138]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0139]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (XII).
[0140]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0141]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0142]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XII).
[0143]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0144]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0145]
　The concentration of the carboxylic acid derivative (XII) used in the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0146]
　The carboxylic acid derivative (XII) can be purchased or synthesized by a known method or a method analogous thereto.
[0147]
　The prodrug (XIII) of the peptide derivative (I) can be prepared, for example, by deprotection reaction of the protected polyethylene glycol derivative (XI) followed by deprotection reaction of the carboxylic acid derivative (XIV) Can be obtained from a coupling reaction under neutral conditions (in the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom).
Wherein

each symbol is as defined above. ]
[0148]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0149]
　The amount of the carboxylic acid derivative (XIV) used in the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the protected polyethylene glycol derivative (XI).
[0150]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0151]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the protected polyethylene glycol derivative (XI).
[0152]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0153]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0154]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0155]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0156]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0157]
　The concentration of the carboxylic acid derivative (XIV) used for the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0158]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0159]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (XIV).
[0160]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0161]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0162]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XIV).
[0163]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0164]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0165]
　The concentration of the carboxylic acid derivative (XIV) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0166]
　The carboxylic acid derivative (XIV) can be purchased or synthesized by a known method or a method analogous thereto.
[0167]
　The prodrug (XV) of the peptide derivative (I) can be prepared, for example, by deprotection reaction of the protected phenoxy carbamate derivative (IX) followed by deprotection reaction of the carboxylic acid derivative (XIV) Can be obtained from a coupling reaction under neutral conditions (in the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom).
Wherein

each symbol is as defined above. ]
[0168]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0169]
　The amount of the carboxylic acid derivative (XIV) used in the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the protected phenoxy carbamate derivative (IX).
[0170]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0171]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the protected phenoxy carbamate derivative (IX).
[0172]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0173]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0174]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0175]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0176]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0177]
　The concentration of the carboxylic acid derivative (XIV) used for the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0178]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0179]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (XIV).
[0180]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0181]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0182]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XIV).
[0183]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0184]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0185]
　The concentration of the carboxylic acid derivative (XIV) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0186]
　The disulfide derivative (XVII) can be obtained, for example, by a condensation reaction of a carboxylic acid derivative (IV) and a nucleophilic agent (XVI) as shown in Scheme 10.
In the

formula, W represents a 2-mercaptopyridyl group, a 2-mercapto-5-nitropyridyl group or -Alk 1 -N (Z) (PG), and the other symbols are as defined above . ]
[0187]
　The amount of the nucleophilic agent (XVI) used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the carboxylic acid derivative (IV).
[0188]
　Examples of the condensing agent used in the condensation reaction include ethyl chloroformate, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (7-aza-1H- benzotriazole- 1 - yl) -1,1,3,3-tetramethyluronium, O- (benzotriazol-1-yl) -N, N, N'N'-tetramethyluronium hexafluorophosphate, 1 H-benzo Triazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but ethyl chloroformate, 2- (7-aza- 1 H-benzotriazole hexafluorophosphate -1-yl) -1,1,3,3-tetramethyluronium, 1H-benzotriazole 1-yl oxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic acid anhydride are preferred.
[0189]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (IV).
[0190]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0191]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0192]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (IV).
[0193]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0194]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0195]
　The concentration of the carboxylic acid derivative (IV) used in the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0196]
　The nucleophilic agent (XVI) can be purchased or can be synthesized by a known method or a method analogous thereto.
[0197]
　The protected polyethylene glycol derivative (XVIII) can be prepared, for example, as shown in Scheme 11 by deprotection reaction of the disulfide derivative (XVII-a) followed by the carboxylic acid derivative (X) under basic to neutral conditions (In the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom).
Wherein

each symbol is as defined above. ]
[0198]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0199]
　The amount of the carboxylic acid derivative (X) used in the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the disulfide derivative (XVII-a).
[0200]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0201]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the disulfide derivative (XVII-a).
[0202]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0203]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0204]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0205]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0206]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0207]
　The concentration of the carboxylic acid derivative (X) used in the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0208]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0209]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (X).
[0210]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0211]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0212]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (X).
[0213]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0214]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0215]
　The concentration of the carboxylic acid derivative (X) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0216]
　The prodrug (XIX) of the peptide derivative (I) can be prepared, for example, as shown in Scheme 12 by the deprotection reaction of the disulfide derivative (XVII-a) followed by the deprotection reaction of the carboxylic acid derivative (XII) (In the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom) under sexual conditions.
Wherein

each symbol is as defined above. ]
[0217]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0218]
　The amount of the carboxylic acid derivative (XII) used in the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the disulfide derivative (XVII-a).
[0219]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0220]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the disulfide derivative (XVII-a).
[0221]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0222]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0223]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0224]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0225]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0226]
　The concentration of the carboxylic acid derivative (XII) used in the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0227]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0228]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (XII).
[0229]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0230]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0231]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XII).
[0232]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0233]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0234]
　The concentration of the carboxylic acid derivative (XII) used in the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0235]
　Prodrug (XIX) of peptide derivative (I) can be prepared, for example, by deprotection reaction of protected polyethylene glycol derivative (XVIII) followed by deprotection reaction of carboxylic acid derivative (XIV) Can be obtained from a coupling reaction under neutral conditions (in the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom).
Wherein

each symbol is as defined above. ]
[0236]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0237]
　The amount of the carboxylic acid derivative (XIV) used in the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the protected polyethylene glycol derivative (XVIII).
[0238]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0239]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the protected polyethylene glycol derivative (XVII).
[0240]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0241]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0242]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0243]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0244]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0245]
　The concentration of the carboxylic acid derivative (XIV) used for the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0246]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0247]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (XIV).
[0248]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0249]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0250]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XIV).
[0251]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0252]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0253]
　The concentration of the carboxylic acid derivative (XIV) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0254]
　The prodrug (XX) of the peptide derivative (I) can be prepared, for example, as shown in Scheme 14, from the deprotection reaction of the disulfide derivative (XVII-a) followed by the carboxylic acid derivative (XIV) (In the case where G is a succinimidyl group or a p-nitrophenyl group) or a condensation reaction (in the case where G is a hydrogen atom) under sexual conditions.
Wherein

each symbol is as defined above. ]
[0255]
　The deprotection of the protecting group varies depending on the kind of the protecting group, but deprotection is carried out according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto be able to.
[0256]
　The amount of the carboxylic acid derivative (XIV) used for the coupling reaction or the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 0.5 to 4 equivalents, relative to the disulfide derivative (XVII-a).
[0257]
　The pH of the coupling reaction can be adjusted with bases. As the base to be used, for example, an organic base such as triethylamine or diisopropylethylamine, an inorganic base such as sodium hydrogen carbonate or potassium carbonate, a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride, a methyl lithium or butyl lithium , Lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, but inorganic bases such as sodium hydrogencarbonate or potassium carbonate or organic bases such as triethylamine or diisopropylethylamine are preferred.
[0258]
　The amount of the base used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.001 to 4 equivalents, relative to the disulfide derivative (XVII-a).
[0259]
　The pH of the coupling reaction can also be adjusted by buffer. As the buffer solution to be used, for example, a phosphate buffer solution, a citrate buffer solution, a citrate phosphate buffer solution, a boric acid buffer solution, a tartaric acid buffer solution or a Tris buffer solution can be mentioned, but a pH of 7.0 to 8.0 Buffers are preferred.
[0260]
　The concentration of the buffer solution used for the coupling reaction is preferably 10 mmol / L to 1 mol / L.
[0261]
　The reaction solvent to be used for the coupling reaction is appropriately selected depending on the kind of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethyl An aprotic polar solvent such as acetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, Chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, water or a mixed solvent thereof, but chlorine type solvents such as dichloromethane, chloroform or 1,2-dichloroethane Melting , Acetonitrile or nitriles such as propionitrile, water or a mixed solvent thereof preferred.
[0262]
　The reaction temperature of the coupling reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0263]
　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0264]
　The concentration of the carboxylic acid derivative (XIV) used for the coupling reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0265]
　Examples of the condensing agent used in the condensation reaction include carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ethyl chloroformate, oxalyl chloride, hexafluorophosphoric acid 2- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Uronium hexafluorophosphate, 1 H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate or 2-methyl-6-nitrobenzoic anhydride, but dicyclohexylcarbodiimide, diisopropylcarbodiimide young Carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazole- 1 -yl) -1, 1, 3,3- tetramethyl hexafluorophosphate Uronium is preferred.
[0266]
　The amount of the condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, relative to the carboxylic acid derivative (XIV).
[0267]
　The reaction solvent to be used for the condensation reaction is appropriately selected depending on the type of the reagent to be used, but it is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide , An aprotic polar solvent such as N-methyl-2-pyrrolidone or dimethyl sulfoxide, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a dichloromethane , Chlorine-based solvents such as chloroform or 1,2-dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or a mixed solvent thereof, but chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or N , N Dimethylformamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.
[0268]
　For the condensation reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogencarbonate or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine, or mixtures thereof, but triethylamine, diisopropyl Ethylamine, 4-dimethylaminopyridine or pyridine, or a mixture thereof is preferable.
[0269]
　The amount of the base used in the condensation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the carboxylic acid derivative (XIV).
[0270]
　The reaction temperature of the condensation reaction is preferably from -40 ° C. to 200 ° C., more preferably from -20 ° C. to 150 ° C.
[0271]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.
[0272]
　The concentration of the carboxylic acid derivative (XIV) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
[0273]
　In addition, the complex of the present invention is characterized by containing a peptide derivative (I) and a targeting ligand or a polymer.
[0274]
　"Targeting ligand" is a substance for transporting a physiologically active compound containing a peptide derivative (I) to a specific cell, and examples thereof include an antigen binding protein, a cytokine or a low molecular weight ligand.
[0275]
　"Antigen binding protein" refers to a protein having the property of binding to a specific protein present on the cell surface and includes, for example, immunoglobulin molecule, single chain antibody, scFv, Fab fragment, F (ab ') fragment , Diabody, Tribody, Affibody, Affilin, Anticalins, Atrimer, Avimer, Bicyclie peptide, Cys-knot, DARPin, FN3, Fynomer, Kunitz domain or OBody.
[0276]
　"Cytokine" refers to interleukin, chemokine, interferon, cell growth factor, cytotoxic factor or a modified protein thereof such as interleukin-2, interleukin-2 fusion protein, interleukin-3, Interleukin-4, interleukin-6, interleukin-8, interleukin-12, interleukin-17, CCL 1 to 28, CXCL 1 to 17, XCL 1, XCL 2, CX 3 CL 1 interferon α, interferon β, interferon γ, interferon ω, Interferon τ, consensus interferon, granular colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GMCSF), CD-40 ligand, luteinizing hormone releasing h (LHRH), insulin-like growth factor (IGF), macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), platelet-derived growth factor, tissue growth factor, transforming growth factor- 1, vascular endothelial cell proliferation But are not limited to, factors, leukemia inhibitory factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), monocyte chemoattractant protein-1 or endothelial cell growth factor is not.
[0277]
　"Low molecular weight ligand" refers to an organic compound or peptide derivative having a molecular weight of less than 1,000 and capable of binding to a specific protein present on the cell surface, such as biotin, folic acid, integrin inhibitor, cRGD, RGD , PSMA inhibitors or VEGF inhibitors, but are not limited thereto.
[0278]
　"Polymer" refers to a macromolecular organic compound having a constant repeating structure and having a number average molecular weight of 1,000 to 1,000,000, for example, polyethylene glycol, polyglutamic acid, polyamino acid or polysaccharide, and polyethylene glycol Or polyglutamic acid, more preferably polyethylene glycol having a number average molecular weight of 20,000 to 100,000 or polyglutamic acid having a number average molecular weight of 20,000 to 100,000.
[0279]
　The above antigen binding proteins, cytokines and peptide derivatives can be used, for example, for their chemical synthesis, their recombinants, their natural products, their glycosylated or non-glycosylated forms, Forms in which amino acids are introduced, forms in which functional groups (eg, aldehyde group or sulfhydryl group) are introduced by chemical reaction such as oxidation or reduction or enzymatic reaction, and biologically active fragments thereof are also included.
[0280]
　"Unnatural amino acid" refers to an amino acid which is naturally occurring and not included in the amino acids (natural amino acids) constituting the protein and which is either naturally occurring or produced by chemical synthesis, ie, An amino acid that does not constitute a protein, an amino acid that does not constitute a protein, an amino acid that is chemically modified with a natural amino acid, or an amino acid that is not included in a natural amino acid, and that is produced by chemical synthesis. Specific examples include (S) -2-amino-3- ((S) -2-amino-3- 3-methyl-3H-diazirin-3-yl) propanoic acid, also called photo-L- leucine, (S) -2-amino-4- (S) -3- (4-acetylphenyl) -2- (3-methyl-3H-diazirin-3-yl) butanoic acid, also called photo- Aminopropanoic acid ((S) -3- (4-acetylphenyl) -2-aminopropanoic acid, 4-acetyl- (S) -2-amino-3- (4-azidophenyl) propanoic acid, 4-azido-L-phenylalanine However, it is not limited to these.
[0281]
　The above-described low molecular weight ligand suitably includes an analogue thereof, a derivative thereof, an agonist thereof, an antagonist thereof, an inhibitor thereof, an isomer thereof, and the like.
[0282]
　"Complex" refers to a substance comprising a peptide derivative (I) or a prodrug thereof or a prodrug thereof and the targeting ligand, a substance including the peptide derivative (I) or a prodrug thereof and the polymer, or a substance containing the peptide derivative (Hereinafter collectively referred to as "peptide derivative (I)") comprising the above-mentioned targeting ligand and the above-mentioned polymer (I) or its prodrug and the above targeting ligand and the aforementioned polymer, (Hereinafter referred to as a linker).
[0283]
　As the complex containing the peptide derivative (I), for example, an antibody drug conjugate in which the peptide derivative (I) or a prodrug thereof is directly bonded to the immunoglobulin molecule or indirectly bonded via a linker Can be mentioned.
[0284]
　In addition, as a complex containing the peptide derivative (I), for example, a conjugate comprising a peptide derivative (I) or a prodrug thereof or a low molecular weight ligand directly bound thereto or indirectly bonded via a linker Drug complexes.
[0285]
　Further, as a complex containing the peptide derivative (I), for example, a polymer drug composite (I) in which the peptide derivative (I) or a prodrug thereof is directly bonded to the polymer or indirectly bonded via a linker Body can be cited.
[0286]
　As a complex containing the peptide derivative (I), for example, each of the polymer and the targeting ligand is directly bonded to the peptide derivative (I) or a prodrug thereof, either directly or via a linker And indirectly binds to the substance.
[0287]
　In addition, as a complex containing the peptide derivative (I), for example, each of the above-mentioned polymers directly or indirectly bonds the peptide derivative (I) or a prodrug thereof and the targeting ligand directly or via a linker And indirectly binds to the substance.
[0288]
　In addition, as a complex containing the peptide derivative (I), for example, each of the peptide derivative (I) or a prodrug thereof is directly bonded to the targeting ligand directly or via the linker And indirectly binds to the substance.
[0289]
　"Containing a peptide derivative (I)" means that the peptide derivative (I) or a prodrug thereof is synthesized by a known method (for example, Ellen M. Sletten et al., Angewante Chimie International Edition, 2009, 48, 6974 -6998, Greg T. Hermanson., "Bioconjugate Technique", Elsevier, Xi Chem et al., Organic & Biomolecular Chemistry, 2016, 14, 5417-5439) Or is directly bonded by a covalent bond to the polymer or indirectly bonded via a linker. Specific examples of the covalent bond include a bond by addition of a sulfhydryl group to a maleimide group, a disulfide bond, a bond by condensation of an amino group or a hydroxy group with a carboxyl group, a bond by an click reaction between an alkyne group and an azide group, A bond by condensation of an aminooxy group with a carbonyl group or a bond by a phenolic group ene type reaction can be mentioned, and bonds by adding a sulfhydryl group to a maleimide group, disulfide bonds, bonds between an amino group or a hydroxy group and a carboxyl group The bond by condensation or the bond by condensation of an aminooxy group and a carbonyl group is preferable, but the invention is not limited thereto.
[0290]
　"Linker" refers to a peptide derivative (I) or a prodrug thereof, a targeting ligand and a polymer having a functional group (eg, a maleimide group, a carboxyl group, an activated carboxyl group, a carbonyl group, an aminooxy group, a hydrazide group , A diazo group, an alkyne group or a hydroxyl group). Examples of the compounds having these functional groups include N-succinimidyl 4- (maleimidomethyl) cyclohexane carboxylate (SMCC), sulfosuccinimidyl-4- (N-maleimidomethyl) -cyclohexane-1-carboxylate ( Sulfo-SMCC), N-succinimidyl-4- (N-maleimidomethyl) -cyclohexane-1-carboxy- (6-amidocaproate) (LC-SMCC), κ-maleimidoundecanoic acid N-succinimidyl ester (KMUA Maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), N- Succinimidyl 4- (p-maleimidophenyl) -butyrate (SMPB), and N- (p-maleimide (S-methyl maleimidophenyl) -butyrate (AMAS), succinimidyl- Phenyl) isocyanate (PMPI), N-succinimidyl 4 (2-pyridylthio) pentanoate (SPP), N-succinimidyl (4-iodoacetyl) aminobenzoic acid ester (SIAB), 6-maleimidocaproyl (MC), maleimidoprop But are not limited to, noil (MP), p-aminobenzyloxycarbonyl yl (PAB) and N-succinimidyl 4 (2-pyridylthio) butanoate (SPDB). In addition, the above-mentioned linkers may be used in combination as appropriate.
[0291]
　"Specific protein present on the cell surface" refers to a protein whose expression on the cell surface is increased in cancer, autoimmune disease or infectious disease, such as CD19, CD22, CD30, CD33, CD37, STEP-1, MUC 16, NaPi 2 b, GCC, EGFR viii, FGF-1, FGF-1, Fc, Fc, 5T4, TROP-2, LIV-1, SLITRK 6, Tissue Factor, Guanylyl Cyclase C, CEACAM 5, integrin receptor, interleukin receptor, PSMA, chemokine receptor, interface Emissions receptor, although cell growth factor receptors or cytotoxic factor receptors include, but are not limited thereto.
[0292]
　Examples of the pharmacologically acceptable salt of the complex containing the peptide derivative (I) include salts similar to the pharmacologically acceptable salts of the above peptide derivative (I).
[0293]
　The complex containing the peptide derivative (I) or a pharmacologically acceptable salt thereof may be an anhydrate or a solvate such as a hydrate. Here, as a solvate, a pharmacologically acceptable solvate is preferable. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferred. Examples of the solvent constituting the solvate include alcoholic solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide, dimethylsulfoxide or water.
[0294]
　Specific examples of the complex containing the peptide derivative (I) are shown in Table 4, but the present invention is not limited thereto.

The scope of the claims
[Request 1]
　A peptide derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
[Formula 1]

[wherein, X represents an oxygen atom or NR, Y is NH 2 , N (Me) H, SH, an OH or any one of a hydrogen atom NH 2 phenyl substituted with or OH Group, and R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. With the proviso that X is NH and Y is NH 2 and derivatives in which X is NH and Y is N (Me) H. ]
[Request 2]
　The peptide derivative according to claim 1 or a pharmacologically acceptable salt thereof according to claim 1, wherein X is an oxygen atom.
[Request 3]
3. The peptide derivative or a pharmaceutically acceptable salt thereof according to claim 2 , wherein 　Y is NH 2 , N (Me) H, SH or OH.
[Request Item 4]
　The peptide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is NR.
[Request 5]
　5. The peptide derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein R is an alkyl group having 1 to 3 carbon atoms.
[Request 6]
　6. The peptide derivative according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R is a methyl group.
[Request 7]
　A complex comprising a peptide derivative according to any one of claims 1 to 6 and a targeting ligand or a polymer or a pharmacologically acceptable salt thereof.
[Request 8]
　Containing the peptide derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof, or the complex according to claim 7 or a pharmacologically acceptable salt thereof as an active ingredient To, cytotoxic agent.