Targeted drug conjugate, medicine including the same, and compound

Abstract

Provided is a compound or a salt thereof, said compound including: two or more structural parts M that are selected from a biologically active substance part and a radioisotope-including part; and a structure that is represented by general formula (I). Also provided are a targeted drug conjugate and a medicine including the same.　However, said compound and salt do not have a fluorescent substance part, and have at least one type of group selected from a specific group Pi of hydrophilic groups.　In the formula, X1 to X3 each represent –O–, –S–, >NR1, or >CR2R3, R1 to R3 and R11 each represent a hydrogen atom or a substituent, n is an integer greater than or equal to 2, and * is a bonding site.

Description

Targeted drug conjugates and pharmaceuticals containing the same, and compounds

[0001] The present invention relates to a targeted drug conjugate and a medicament and a compound containing the same.

[0002] Targeted drug conjugates are drugs that combine a target-binding substance that specifically binds to specific disease-causing cells (e.g., tumor cells) with a physiologically active substance (drug). Targeted drug conjugates enable the drug to be delivered to the specific cells with pinpoint accuracy and act thereon. In other words, it is possible to treat disease-causing cells with the drug without damaging healthy cells. The use of targeted drug conjugates is said to enable enhanced therapeutic effects while suppressing side effects with a smaller drug dose than when the drug itself is administered orally or intravascularly. Antibody drug conjugates (ADCs) are targeted drug conjugates that use an antibody as the target-binding substance. To date, Mylotarg, Zevalin, Kadcyla, Adcetris, Besponsa, Enhertz, Acalux, Porivy, Padcev, and Elahere (all trade names) have been approved as ADCs and are currently in use in clinical practice. Unlike drugs used in conventional chemotherapy, such as oral or intravascular administration, ADCs allow drugs to act on target cells with pinpoint accuracy. However, because the amount of drug that can act on target cells is limited when using ADCs, ADCs conjugate highly physiologically active drugs with antibodies. Still, many people desire higher therapeutic effects, and one solution has been proposed: conjugating a larger amount of drug to an antibody. Furthermore, if a larger amount of drug can be conjugated to an antibody, even drugs with relatively low physiological activity that have been considered unsuitable for ADCs may be able to exert the desired therapeutic effect specifically on target cells. However, in ADCs approved by the U.S. Food and Drug Administration (FDA), the number of drugs linked to one antibody molecule (the number of molecules that exhibit the desired physiological activity) is limited to approximately 2 to 8. On the other hand, drugs are generally highly hydrophobic, and if a complex is formed by binding a large number of drugs to a highly hydrophilic antibody, there is a concern that the drugs may interact hydrophobically with each other, making the complex more susceptible to aggregation.

[0003] In relation to techniques for linking multiple drugs to one antibody molecule, for example, Patent Documents 1 to 3 describe polymer structures having phosphoalkyl groups or phosphoalkyl ether groups as repeating units in the main chain of the polymer structure, with a drug bound to the repeating units. Patent Document 4 describes a polymer structure having charged structural moieties such as ammonium salts as repeating units in the main chain of the polymer structure, with a drug bound to the repeating units. Furthermore, Patent Document 5 describes a polymer structure having a main chain in which repeating units of acyclic amino acids and alkylene glycol are linked, with a drug bound to the repeating units of acyclic amino acids.

[0004] Furthermore, although not an ADC, a technique for linking many fluorescent compounds to one antibody molecule is known. For example, Patent Document 6 describes a compound having two or more fluorescent moieties with equivalent light absorption properties, in which adjacent fluorescent moieties are linked via a proline-derived ring structure or the like, and a labeled biological substance using the compound. Patent Document 6 describes that the proline-derived ring structure or the like functions as a rigid linker, thereby effectively suppressing quenching due to inter- or intramolecular association of the fluorescent moieties, thereby obtaining a labeled biological substance that exhibits excellent fluorescence intensity.

[0005] Patent Publication No. 2020-536847 Patent Publication No. 2021-510700 Patent Publication No. 2022-526651 Patent Publication No. 2021-506788 International Publication No. 2021 / 240155 International Publication No. 2023 / 032995

[0006] An object of the present invention is to provide a targeted drug conjugate that can retain a larger amount of drug while suppressing aggregation, and a medicament containing the same. Another object of the present invention is to provide a compound suitable for obtaining the targeted drug conjugate or medicament.

[0007] That is, the above-mentioned object of the present invention has been achieved by the following means: [1] A compound or a salt thereof comprising two or more structural moieties M selected from a physiologically active substance moiety and a radioisotope-containing moiety, and a structure represented by the following general formula (I), provided that the compound and salt do not have a phosphor moiety and have at least one group selected from the following hydrophilic group group Pi. In the formula, X １ ~X ３ is -O-, -S-, >NR １ Or >CR ２ R ３ Indicates. １ ~R ３ and R １１ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an acyl group, -NR ８ R ９ , -OR １０ or represents a group selected from the following hydrophilic group Pi: ８ ~R １０ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aryl group, a heteroaryl group, or a group selected from the following hydrophilic group group Pi. n is an integer of 2 or more. * represents a bond. <Hydrophilic group group Pi> Anionic group, cationic group, betaine residue, polyol residue, sugar residue, polyamino acid residue, polyalkyleneoxy group. [2] The compound according to [1] or a salt thereof, which is represented by the following general formula (II): In the formula, R ４ and R ５ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxy group, an alkoxy group, a sulfanyl group, an aryl group, or a heteroaryl group. ６ and R ７ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７At least one of the groups is a group containing a carboxy group or a group containing a substituent capable of binding to a target-binding substance. Q represents a group selected from the hydrophilic group group Pi or a substituent capable of binding to a target-binding substance. １ , L ３ , L ４ , L ６ and L ７ represents a single bond or a linking group. ２ and L ５ represents a single bond or a physiologically cleavable linker. ２ When is a single bond, L １ and L ３ at least one of L is a physiologically cleavable linker; ５ When is a single bond, L ４ and L ６ at least one of the above is a physiologically cleavable linker. M represents the structural moiety M. Y represents a structure represented by the above general formula (I). m is an integer of 1 or more. [3] The compound according to [2], which is represented by the following general formula (III), or a salt thereof: In the formula, Y １ ~Y ５ , Z １ ~Z ３ and W １ ~W ３ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxy group, an alkoxy group, a sulfanyl group, an aryl group, a heteroaryl group, or a group selected from the hydrophilic group Pi. ６Ａ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６Ａ is a carboxy group or a substituent capable of binding to a target binding substance, and / or R ７ is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. ４ , R ５ , R ７ , R １１ , L ２ , L ５ , X１ ~X ３ , M, Q, m and n are the above R ４ , R ５ , R ７ , R １１ , L ２ , L ５ , X １ ~X ３ , M, Q, m and n. ８ represents a single bond or a linking group. s, t, and u represent an integer of 0 or 1 or more. q is an integer of 0 or 1. [4] The compound according to [1], which is represented by the following general formula (IV), or a salt thereof: In the formula, X ４ ~X ９ is -O-, -S-, >NR １ Or >CR ２ R ３ where X ４ ~X ６ At least one of the above is >N-L ９ -M or >C(R ２ )-L ９ -M and X ７ ~X ９ At least one of the above is >N-L １０ -M or >C(R ２ )-L １０ -M. -L ９ -M and -L １０ -R that is neither M １ ~R ３ is the above R １ ~R ３ It is synonymous with L. ９ and L １０ indicates a physiologically cleavable linker. ６ and R ７ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７At least one of the groups is a group containing a carboxy group or a group containing a substituent capable of binding to a target-binding substance. Q represents a group selected from the hydrophilic group group Pi or a substituent capable of binding to a target-binding substance. m is an integer of 1 or more, q is an integer of 0 or 1, and v is an integer of 0 or 1 or more. R １１ , X １ ~X ３ and M is the above R １１ , X １ ~X ３ and M. [5] The compound according to [4], which is represented by the following general formula (V), or a salt thereof: In the formula, X １ａ , X １ｂ , X １ｃ , X ２ａ , X ２ｂ , X ２ｃ , X ３ａ , X ３ｂ and X ３ｃ -O-, -S-, >NR １ Or >CR ２ R ３ Indicates. １１ represents a single bond or a linking group. ６Ａ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６Ａ is a carboxy group or a substituent capable of binding to a target binding substance, and / or R ７ is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. １ ~R ３ , R ７ , R １１ , X ４ ~X ９ , L ９ , L １０ , M, Q, m and q are the above R １ ~R ３ , R ７ , R １１ , X ４ ~X ９ , L ９ , L １０, M, Q, m, and q. na, nb, and nc are 0 or an integer of 1 or more. r is an integer of 1 or more. [6] The compound according to any one of [1] to [5], or a salt thereof, having 3 to 6 of the structural moieties M. [7] A targeted drug conjugate formed by binding the compound according to any one of [1] to [6], or a salt thereof, to a target-binding substance. [8] The targeted drug conjugate according to [7], wherein the target-binding substance is an antibody. [9] The targeted drug conjugate according to [7] or [8], wherein the number of the structural moieties M in one molecule of the targeted drug conjugate is 8 or more.

[10] A pharmaceutical comprising the targeted drug conjugate according to any one of [7] to [9].

[0008] The targeted drug conjugate of the present invention and a medicament containing the same can retain a larger amount of drug while suppressing aggregation. Furthermore, the compound of the present invention can be suitably used to obtain the above-mentioned targeted drug conjugate and a medicament containing the same.

[0009] In the present invention, when there are multiple substituents, linking groups, structural units, etc. (hereinafter referred to as substituents, etc.) represented by a specific symbol or formula, or when multiple substituents, etc. are specified simultaneously, unless otherwise specified, the respective substituents, etc. may be the same or different from each other. The same applies to the specification of the number of substituents, etc. Furthermore, when multiple substituents, etc. are adjacent (especially when they are adjacent), they may be linked to each other to form a ring unless otherwise specified. Furthermore, unless otherwise specified, rings, such as alicyclic rings, aromatic rings, and heterocyclic rings, may be further condensed to form a fused ring. In the notation of groups (atomic groups) in the present invention, notations that do not indicate substituted or unsubstituted include groups (atomic groups) that have a substituent as well as groups (atomic groups) that have no substituent. For example, an "alkyl group" includes not only alkyl groups that have no substituent (unsubstituted alkyl groups) but also alkyl groups that have a substituent (substituted alkyl groups). The same applies to divalent linking groups such as alkylene groups. Preferred examples of the optional substituent possessed by such a group (atomic group) having a substituent include substituents selected from the below-described substituent group T. In the present invention, when the number of carbon atoms of a certain group is specified, this number of carbon atoms means the number of carbon atoms of the entire group unless otherwise specified in the present invention or this specification. In other words, when this group further has a substituent, it means the total number of carbon atoms including the substituent.

[0010] In the present invention, a numerical range expressed using "to" means a range that includes the numerical values ​​written before and after "to" as the lower and upper limits. In addition, the chemical structural formula in the present invention may be expressed as a simplified structural formula in which hydrogen atoms are omitted.

[0011] In the present invention, the term "alkyl group" is used to encompass linear alkyl groups, branched alkyl groups, and cycloalkyl groups. This also applies to groups that can form other cyclic structures (e.g., alkenyl groups, alkynyl groups), and groups containing groups that can form other cyclic structures (e.g., alkyl groups, alkenyl groups, alkynyl groups). When a group can form a cyclic skeleton, the lower limit on the number of atoms in the group forming the cyclic skeleton is at least 3, preferably 4 or more, and more preferably 5 or more, regardless of the lower limit on the number of atoms specifically described below for groups that can form this structure. In the present invention, an "alkyl group" that does not have a cyclic structure preferably has 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms, even more preferably 1 to 8 carbon atoms, even more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 3 carbon atoms. In the present invention, the "cycloalkyl group" which is an alkyl group having a cyclic structure preferably has 3 to 20 carbon atoms, more preferably 3 to 12 carbon atoms, even more preferably 3 to 8 carbon atoms, even more preferably 3 to 6 carbon atoms, and particularly preferably 3 carbon atoms. In the present invention, the "alkenyl group" which does not have a cyclic structure preferably has 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, even more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. In the present invention, the "cycloalkenyl group" which is an alkenyl group having a cyclic structure preferably has 4 to 20 carbon atoms, more preferably 4 to 12 carbon atoms, even more preferably 4 to 8 carbon atoms, and even more preferably 4 to 6 carbon atoms. In addition, in the present invention, the "alkyl group" and the "alkenyl group" are preferably an "alkyl group" not having a cyclic structure and an "alkenyl group" not having a cyclic structure, respectively. In the present invention, the "alkynyl group" not having a cyclic structure preferably has 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, even more preferably 2 to 6 carbon atoms, and still more preferably 2 to 4 carbon atoms. In the present invention, the "aryl group" may be a monocyclic group or a fused ring group. In the case of a fused ring group, it is preferably a fused ring group of 2 to 6 rings.The ring constituting the fused ring is preferably a 6- or 8-membered ring, more preferably a 6-membered ring. The monocycle is preferably a 6-membered ring. The aryl group preferably has 6 to 40 carbon atoms, more preferably 6 to 30 carbon atoms, even more preferably 6 to 26 carbon atoms, and particularly preferably 6 to 10 carbon atoms. In the present invention, the term "heterocyclic group" includes "aliphatic heterocyclic group" and "heteroaryl group." The "heterocyclic group" may be a group having at least one nitrogen atom, oxygen atom, sulfur atom, phosphorus atom, silicon atom, or selenium atom as a ring-constituting atom, and may be a monocyclic group or a fused ring group. In the case of a fused ring group, it is preferably a fused ring group of 2 to 6 rings. The number of ring members in the ring of the monocyclic group and the ring constituting the fused ring group is preferably 5 to 7, more preferably 5 or 6. The number of carbon atoms in the heterocyclic group is preferably 2 to 40, more preferably 2 to 20. In the present invention, the "alkoxy group" preferably has 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms, even more preferably 1 to 8 carbon atoms, still more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 3 carbon atoms. In the present invention, the "amino group" includes an unsubstituted amino group (-NH. ２), and mono- or di-substituted amino groups substituted with a group selected from alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, aryl groups, and heterocyclic groups. The above-mentioned groups (alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, aryl groups, and heterocyclic groups) substituting the unsubstituted amino group are synonymous with the above-mentioned groups (alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, aryl groups, and heterocyclic groups). The amino group preferably has 0 to 20 carbon atoms, more preferably 0 to 12 carbon atoms, even more preferably 0 to 8 carbon atoms, even more preferably 0 to 6 carbon atoms, and particularly preferably 0 to 3 carbon atoms. In the present invention, "acyl groups" include -C(=O)H, alkylcarbonyl groups, cycloalkylcarbonyl groups, arylcarbonyl groups, and heterocyclic carbonyl groups. The above-mentioned groups (alkyl group, cycloalkyl group, aryl group, and heterocyclic group) substituting the carbonyl group have the same meanings as the above-mentioned groups (alkyl group, cycloalkyl group, aryl group, and heterocyclic group). The acyl group preferably has 1 to 20 carbon atoms, more preferably 2 to 15 carbon atoms.

[0012] In the present invention, the "alkylene group, alkenylene group, alkynylene group, arylene group and heteroarylene group" which can constitute the "linking group" have the same meaning as the group obtained by removing one more hydrogen atom from the above-mentioned "alkyl group, alkenyl group, alkynyl group, aryl group and heteroaryl group", respectively, and the preferred meanings are also the same. In the present invention, the "physiologically cleavable linker" may be any molecular bond which can be cleaved or separated in a specified manner to give two or more individual molecules while existing in an in vivo or in vitro environment of an organism or cell system, and may be, for example, an amide bond, an ester bond, a disulfide bond, a thioester bond, a thioamide bond, a urea bond, a urethane bond or a thiourea bond, or a hydrazone, an imine, an acetal, an aminal, a phosphotriester, a diester, a β-glucuronide, a vinyl ether, a dialkyl or Preferred examples include linkers containing a divalent linking group (hereinafter referred to as a divalent linking group LL) obtained from a diaryldialkoxysilane, β-thiopropionate, glycine-glycine-phenylalanine, glycine-glycine-phenylalanine-glycine, valine-citrulline, p-aminobenzyl alcohol, or p-hydroxybenzyl alcohol structure, or linkers containing a linking group formed by combining two or more of these divalent linking groups LL (which may be directly bonded to each other or may be linked via a structure other than the linking group LL). There are no particular limitations on the structure other than the divalent linking group LL contained in the linker, and examples include linking groups such as alkylene groups.

[0013] In the present invention, the "anionic group" may be any group having an anion. Examples of such anionic groups include a carboxy group, a phosphono group (phosphonic acid group, -PO(OH) ２ ), phosphonooxy group (phosphate group, -OPO(OH) ２) and a sulfo group, among which a phosphono group, a phosphonooxy group or a sulfo group is preferred, and a phosphonooxy group or a sulfo group is more preferred. The anionic group may have an ionic structure formed by dissociation of a hydrogen ion, or may have a salt structure. For salts in which the anionic group has a salt structure, the description of salts in the section on pharmaceutically acceptable salts described below can be preferably applied. In the present invention, the "cationic group" may be any group having a cation. Examples of such cationic groups include a group having a quaternary ammonium ion (ammonio group), a group having a tertiary sulfonium ion (sulfonio group) and a group having a quaternary phosphonium ion (phosphonio group), among which a group having a quaternary ammonium ion is preferred. Note that, in the group having a quaternary ammonium ion, N ＋ the substituents in the group having a tertiary sulfonium ion, ＋ P in the substituent group and the group having a quaternary phosphonium ion ＋ Preferred examples of the substituents of N include alkyl groups and aryl groups. ＋ , S ＋ and P ＋ It is more preferable that all the substituents of are alkyl groups. The cationic group may have a salt structure in addition to an ionic structure. When the cationic group has a salt structure, examples of the monovalent or polyvalent anion include F － , Cl － Halide ions such as BF ４ － , P.F. ６ －Examples of suitable anions include monovalent or polyvalent organic anions such as bis(trifluoromethylsulfonyl)imide ion and bis(trifluoromethylsulfonyl)imide ion. In the present invention, the term "betaine residue" refers to a group obtained by removing one hydrogen atom from a compound having a betaine structure. A compound having a betaine structure may be any compound containing an anionic group and a cationic group in the same molecule, and is preferably a compound containing at least one anionic group selected from a carboxy group, a phosphono group, a phosphonooxy group, and a sulfo group, and at least one cationic group selected from an ammonio group, a sulfonio group, and a phosphonio group in the same molecule. Note that a group obtained by removing one hydrogen atom from a compound that does not contain an anionic group and a cationic group in the same molecule does not fall under the category of a betaine residue, but is classified as an anionic group having a salt structure or a cationic group having a salt structure, as described above. In the present invention, the term "polyol residue" refers to a group obtained by removing one hydrogen atom from a polyol compound having two or more hydroxy groups in the molecule, and does not fall under either the sugar residue or polyalkyleneoxy group described below. The polyol residue may be a chain-like group or a group having a cyclic structure, and examples thereof include cyclodextrin residues. In the present invention, the term "sugar residue" refers to a group obtained by removing one hydrogen atom from a sugar compound. The sugar compound may be any of monosaccharides, polysaccharides in which two or more sugars are bonded, sugar alcohols, and chemically modified sugars in which epichlorohydrin or the like is copolymerized with a sugar. Among polyol residues, those that fall under the category of sugar residues are classified as sugar residues.Examples of sugar residues include glucose, sucrose, maltose, lactose, trehalose, ribitol, sorbitol, mannitol, maltitol, lactitol, xylitol, fructose, 1-kestose, nystose trihydrate, fucose, dulcitol, galactooligosaccharide, 4'-galactosyllactose, isomaltooligosaccharide, lactulose, palatinite, palatinose monohydrate, raffinose pentahydrate, arabinose, dihydroxyacetone dimer, galactose, glyceraldehyde dimer, mannose, ribose, xylose, and lactositol. Examples of such a group include a group obtained by removing one hydrogen atom from a sugar compound such as dulfructoside, erythritol, dulcoside A, isosteviol, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside F, rubusoside, stevioside, 1-deoxynojirimycin, fucoidan, rhamnose, threose, arabinose, lyxose, allose, altrose, gulose, idose, talose, 1,3-dihydroxyacetone, erythrose, xylulose, ribulose, psicose, sorbose, tagatose, polysucrose, or fructooligosaccharide. In the present invention, the term "polyamino acid residue" refers to a group obtained by removing one hydrogen atom from an amino acid compound or a polyamino acid compound formed by the bonding of two or more amino acids. In the present invention, the term "polyalkyleneoxy group" refers to -(O-L). ｇ R Ｅ or -(L-O) ｇ R ＥIt is sufficient if it is a group represented by the formula: In addition, among polyol residues, those corresponding to polyalkyleneoxy groups are classified as polyalkyleneoxy groups. The above L represents the above alkylene group, preferably having 2 to 4 carbon atoms, more preferably 2 or 3, and even more preferably 2, and the number of carbon atoms contained in the shortest chain connecting the two carbon atoms that are the bonding hands of the alkylene group is preferably 0 to 2, more preferably 0 or 1, and even more preferably 0. In other words, L is most preferably an ethylene group. The above g represents the average repeat number (also simply referred to as the repeat number), and is preferably 1 to 24, more preferably 1 to 12, and even more preferably 4 to 12. Even when the repeat number is small, such as when g is 1, it is possible to exhibit moderate hydrophilicity and a moderate excluded volume effect. The above R Ｅ represents a hydrogen atom or an alkyl group. Ｅ The alkyl groups that can be used as R are preferably those described above for the alkyl groups, and among these, alkyl groups having 1 to 3 carbon atoms are preferred. Ｅ The alkyl group which can be taken as may have a substituent.

[0014] In the present invention, the structure represented by the general formula (I) below means that n (n is an integer of 2 or more) structures represented by the following general formula (i) are connected together. In this case, the n structures represented by the general formula (i) may be the same or different from each other. In addition, X in the following general formula (i) １ ~X ３ and R １１ represents X in general formula (I) described below. １ ~X ３ and R １１ This is the same as ( ) ｍ Structures enclosed in ( ) ｎａ Structures enclosed in ( ) ｎｂ Structures enclosed in ( ) ｎｃ Structures enclosed in ( ) ｒ Structures enclosed in ( ) ｓ Structures enclosed in ( ) ｔ Structures enclosed in ( ) ｕ Structures enclosed in ( ) and ｖThe same applies to structures bracketed by, where m structures may be the same or different from each other, na structures may be the same or different from each other, nb structures may be the same or different from each other, nc structures may be the same or different from each other, r structures may be the same or different from each other, s structures may be the same or different from each other, t structures may be the same or different from each other, u structures may be the same or different from each other, and v structures may be the same or different from each other.

[0015]

[0016] Salts of the compounds of the present invention include commonly known salts of basic groups such as amino groups, and salts of acidic groups such as hydroxy groups, carboxy groups, phosphono groups, phosphonooxy groups, sulfo groups, etc. Salts of basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid; and salts with phosphoric acid. Examples of salts of acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. That is, in the present invention, the term "acidic group" is used to include salt-type groups. Among the above salts, preferred salts include pharmaceutically acceptable salts or pharmacologically acceptable salts. When the compound of the present invention has a salt structure, the type of salt may be one type or two or more types may be present in combination. The compound may contain a mixture of salt-type and free acid-type groups, or may contain a mixture of salt-type and free acid-type compounds. When the compound of the present invention or a salt thereof has stereoisomers such as optical isomers, geometric isomers or rotational isomers, or tautomers, the present invention encompasses these isomers, as well as anhydrates, solvates, hydrates, and various forms of crystals.

[0017] The compounds of the present invention include those in which the structure has been partially modified as long as the effects of the present invention are not impaired.

[0018] The compound of the present invention or a salt thereof (hereinafter, all of these will be collectively referred to as the compound of the present invention) is a compound or a salt thereof comprising two or more structural moieties M selected from a physiologically active substance moiety and a radioisotope-containing moiety, and a structure represented by the general formula (I) described below. The details of why the compound of the present invention can obtain a targeted drug conjugate capable of retaining a larger number of drugs while suppressing aggregation, with the structural moiety M selected from a physiologically active substance moiety and a radioisotope-containing moiety, are not clear, but it is thought to be as follows. The compound of the present invention is a compound comprising two or more structural moieties M selected from a physiologically active substance moiety and a radioisotope-containing moiety, and a structure represented by the general formula (I) described below, and has at least one group selected from the hydrophilic group Pi described below. Therefore, even when two or more hydrophobic structural moieties M are linked, the resulting targeted drug conjugate or medicament is thought to be able to retain a larger number of drugs while suppressing aggregation and stably deliver them to the desired target cells. For this reason, the compound of the present invention is expected to be applicable to a variety of therapeutic methods, such as the use of drugs with low physiological activity in ADCs, which have not previously been possible to use in ADCs. Furthermore, the compound of the present invention contains, as a structure represented by general formula (I), a very stable structure that is inhibited from being decomposed by enzymes contained in the blood, consisting of a repeating unit (the number of repeats n is an integer of 2 or more) containing a nitrogen-containing saturated five-membered ring such as a ring structure derived from proline, which is one of the amino acids that constitute proteins. Therefore, it is possible to suppress the problem of the resulting targeted drug conjugate being decomposed by enzymes in the blood, and the target drug conjugate is decomposed and cleaved before reaching the desired target cells, releasing the drug from the structural moiety M, reducing the possibility of normal tissues being exposed to the drug and enabling it to be transported more stably in the blood (it also has excellent stability in the blood).

[0019] The compounds of the present invention will be described in detail below.

[0020] <Compound of the Present Invention> The compound of the present invention is a compound comprising two or more structural moieties M selected from a physiologically active substance moiety and a radioisotope-containing moiety, and a structure represented by the following general formula (I). However, the compound of the present invention does not have a fluorescent substance moiety and has at least one group selected from the hydrophilic group group Pi described below. The compound of the present invention may be a compound classified as a polymer or an oligomer.

[0021] The structural moiety M may be contained in the compound of the present invention as a structure separate from the structure represented by the following general formula (I), in a state where the structural moiety M is bonded to the bond * in the following general formula (I) directly or via a linking group, and the compound of the present invention may contain X in the structure represented by the following general formula (I): １ ~X ３ The structural moiety M may be contained in a state of being bonded via a linking group to any of the positions of the structural moiety M in the general formula (I). Examples of the form in which the structural moiety M is bonded to the bond * in the general formula (I) directly or via a linking group include compounds represented by the general formula (II) or (III) described below. In addition, when the structural moiety M is bonded to the X in the structure represented by the general formula (I), １ ~X ３Examples of the form in which the structural moiety M is bonded to any of the positions of the structural moiety M via a linking group include compounds represented by general formula (IV) or (V) described below. In addition, in the compounds represented by general formula (IV) or (V) described below, when v in general formula (IV) is an integer of 2 or more, and when the combination of na + nb + nc and r in general formula (V) is a combination in which one is an integer of 1 or more and the other is an integer of 2 or more, the structural moiety M can also be bonded to the bond * in general formula (I) via a linking group. As the compound of the present invention, it is preferable that adjacent structural moieties M are linked via a structure represented by general formula (I) below, that is, two structures having the structural moiety M as a substituent are linked via a group containing a structure represented by general formula (I) below, and it is more preferable that the adjacent structural moieties M are bonded to the bond * in general formula (I) via a linking group. In the compound in which adjacent structural portions M are bonded to the bond * in general formula (I) via a linking group, X in general formula (I) １ ~X ３ and R １１ is not a group containing the structural moiety M.

[0022] (Structural Moiety M) The compound of the present invention contains two or more structural moieties M selected from a physiologically active substance moiety and a radioisotope-containing moiety. The two or more structural moieties M selected from a physiologically active substance moiety and a radioisotope-containing moiety may be the same or different. The physiologically active substance moiety that can be employed as the structural moiety M is not particularly limited, as long as it is a structural moiety consisting of a drug (physiologically active substance) or a prodrug moiety as described below. Examples of the physiologically active substance moiety include antitumor agents, enediyne antitumor antibiotics, maytansinoids, topoisomerase inhibitors, NSAIDs (non-steroidal anti-inflammatory drugs), kinase inhibitors, anthracyclines, EGFR (epidermal growth factor receptor) inhibitors, alkylating agents, anticancer drugs, antibiotics, antifungals, anthelmintics, antivirals, etc. More specifically, the antitumor agents described in paragraphs

[0105] to

[0117] of JP-A No. 2022-526651 are mentioned. Examples of such biologically active moieties include those of antitumor agents, enediyne antitumor antibiotics, maytansinoids, topoisomerase inhibitors, NSAIDs (nonsteroidal anti-inflammatory drugs), kinase inhibitors, anthracyclines, EGFR (epidermal growth factor receptor) inhibitors, alkylating agents, and anticancer drugs, as well as those of antibiotics, antifungals, anthelmintics, antivirals, and the like described in paragraphs

[0185] to

[0207] of JP-A No. 2022-526651. In addition to the above, physiologically active substances include, for example, vitamins, coenzymes, hormones, antibiotics, neurotransmitters, cytokines, etc. More specifically, as described in paragraph

[0095] of JP 2021-020956 A, calicheamicin, doxorubicin, daunorubicin, mitomycin C, bleomycin, cyclocytidine, vincristine, vinblastine, methotrexate, cisplatin or a derivative thereof, auristatin or a derivative thereof, maytansine or a derivative thereof, taxol or a derivative thereof, camptothecin or a derivative thereof, etc., and the descriptions in paragraphs

[0095] to

[0099] of JP 2021-020956 A can be applied. The prodrug portion can be used without particular limitation as long as it is a structural portion consisting of a compound that is metabolized in the body and converted into a drug (biologically active substance).As the prodrug portion, for example, the description in paragraph

[0003] of JP-A-2020-105187 (prodrug form of 2-pyrrolinodoxorubicin) can be applied.

[0023] The radioisotope-containing moiety that can be used as the structural moiety M includes a radioisotope (metal ion or metal complex) that can be used in the medical field, and can be used without any particular limitation as long as it is a structural moiety that can be used for treatment or diagnosis. Examples of radioisotopes include nuclides that emit gamma rays, positrons, alpha rays, or beta rays, such as: ６７ Ga, ６８ Examples of suitable radioisotopes include, but are not limited to, Ga, iodine-131, indium-111, yttrium-90, lutetium-177, and copper-64. The descriptions in paragraphs

[0080] to

[0086] of International Publication No. 2016 / 153054 and paragraph

[0225] of Japanese Patent Application Laid-Open No. 2021-011483 can be applied. Examples of structural moieties containing radioisotopes include structural moieties in which the radioisotopes are bonded or coordinated to an amino group or a nitrogen atom of a tertiary amine, a sulfanyl group, an aryl group, a heteroaryl group, or the like. Examples of the structural moiety in which a nitrogen atom of a tertiary amine is coordinated to the radioisotope include a structural moiety in which DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or the like is coordinated to the radioisotope to form a complex, and examples of the structural moiety in which a sulfanyl group is coordinated to the radioisotope include a structural moiety made of a complex of diacetylbis(N(4)-methylthiosemicarbazone)copper(II) or the like.

[0024] In the compound of the present invention, the number of the structural moiety M is 2 or more, preferably 2 to 8, and more preferably 3 to 6.

[0025] (Structure represented by general formula (I))

[0026] In the formula, X １ ~X ３ is -O-, -S-, >NR １ Or >CR ２ R ３ Indicates. １ ~R ３ and R １１represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an acyl group, -NR ８ R ９ , -OR １０ or represents a group selected from the following hydrophilic group Pi: ８ ~R １０ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aryl group, a heteroaryl group, or a group selected from the following hydrophilic group group Pi. n is an integer of 2 or more. * represents a bond. <Hydrophilic group group Pi> Anionic group, cationic group, betaine residue, polyol residue, sugar residue, polyamino acid residue, polyalkyleneoxy group.

[0027] In the present invention, the structure represented by the above general formula (I) is preferably a structure represented by either of the following general formulas (IA) or (IB), taking into consideration stereoisomers. １ ~X ３ , R １１ and n is X in the above general formula (I). １ ~X ３ , R １１ and n.

[0028]

[0029] X １ ~X ３ is -O-, -S-, >NR １ Or >CR ２ R ３ indicates R １ ~R ３ and R １１ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an acyl group, -NR ８ R ９ , -OR １０ or represents a group selected from the hydrophilic group Pi. １ ~R ３ and R １１The preferred ranges of alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups and acyl groups that can be taken as R, and the preferred ranges of anionic groups, cationic groups, betaine residues, polyol residues, sugar residues, polyamino acid residues and polyalkyleneoxy groups in the hydrophilic group group Pi are as described above. １ ~R ３ and R １１ The alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group and acyl group that can be taken as R, and the betaine residue, polyol residue, sugar residue, polyamino acid residue and polyalkyleneoxy group in the hydrophilic group group Pi may be unsubstituted or may have a substituent. １ ~R ３ and R １１ In the above, the alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group and acyl group, as well as the betaine residue, polyol residue, sugar residue, polyamino acid residue and polyalkyleneoxy group in the above hydrophilic group group Pi, may have a substituent, such as a substituent in the below-described substituent group T, and for example, a halogen atom or a group selected from the above hydrophilic group group Pi. １ ~X ３ Any part of the above is >NR １ Or >CR ２ R ３ And this R １ ~R ３ may be a substituent containing the structural portion M, and examples of such compounds include compounds represented by the general formula (IV) or (V) described below.

[0030] R １ ~R ３ and R １１ Can be taken as -NR ８ R ９ and -OR １０ In this case, R ８ ~R １０ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an acyl group, or a group selected from the hydrophilic group Pi. ８ ~R １０The preferred ranges of alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups and acyl groups that can be taken as R, and the preferred ranges of anionic groups, cationic groups, betaine residues, polyol residues, sugar residues, polyamino acid residues and polyalkyleneoxy groups in the hydrophilic group group Pi are as described above. ８ ~R １０ The alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group and acyl group that can be taken as R, and the anionic group, cationic group, betaine residue, polyol residue, sugar residue, polyamino acid residue and polyalkyleneoxy group in the hydrophilic group group Pi may be unsubstituted or may have a substituent. ８ ~R １０ Examples of the substituent that may be possessed by the alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group and acyl group in the above hydrophilic group group Pi, and the anionic group, cationic group, betaine residue, polyol residue, sugar residue, polyamino acid residue and polyalkyleneoxy group in the above hydrophilic group group Pi include the substituents in the below-mentioned substituent group T, and for example, a halogen atom, a carbamoyl group, an acylamino group, an alkoxy group (preferably an alkoxy group having a group selected from the above hydrophilic group group Pi), a heteroaryl group or a group selected from the above hydrophilic group group Pi is preferred, and a carbamoyl group, an acylamino group, an alkoxy group (preferably an alkoxy group having a group selected from the above hydrophilic group group Pi), a heteroaryl group or a group selected from the above hydrophilic group group Pi is more preferred.

[0031] R １ Examples of the group include a hydrogen atom, an alkyl group, and —NR ８ R ９ , -OR １０ or a group selected from the hydrophilic group Pi. ２ and R ３ Examples of the group include a hydrogen atom and —NR ８ R ９ , -OR １０ or a group selected from the hydrophilic group Pi, ２ is a hydrogen atom, -NR ８ R ９ , -OR １０or a group selected from the hydrophilic group Pi, ３ It is more preferable that R is a hydrogen atom. １１ Examples of the group include a hydrogen atom, an alkyl group, and —NR ８ R ９ , -OR １０ Alternatively, a group selected from the hydrophilic group Pi is preferred, and a hydrogen atom is more preferred. ８ ~R １０ is preferably a hydrogen atom, an alkyl group, or an acyl group. The alkyl group may be an alkyl group having at least one group selected from the hydrophilic group group Pi, and the acyl group may be an acyl group containing at least one group selected from the hydrophilic group group Pi. The acyl group containing at least one group selected from the hydrophilic group group Pi is preferably an acyl group having at least one group selected from the hydrophilic group group Pi, or an acyl group substituted with an alkoxy group or a heteroaryl group having at least one group selected from the hydrophilic group group Pi. The alkyl group and acyl group may have a substituent other than a group selected from the hydrophilic group group Pi. Examples of the substituent that may be possessed include the substituents in the substituent group T described below, and for example, a carbamoyl group or an acylamino group are preferred. In addition, the aforementioned -(O-L) which is a polyalkyleneoxy group ｇ R Ｅ and -(L-O) ｇ R Ｅ is R Ｅ -(O-L) is included as a divalent group obtained by removing one hydrogen atom from a hydrogen atom or a substituent that can be taken as the formula (I), and may further be bonded to a carboxy group, a sulfo group, a phosphono group, a betaine residue, a polyol residue, a sugar residue, or a polyamino acid residue. ｇ R Ｅ or -(L-O) ｇ R Ｅ From R Ｅ Examples of the divalent group obtained by removing one hydrogen atom from a hydrogen atom or a substituent include -(OL) ｇ -, - (OL) ｇ -NHCO-, -(OL)ｇ -CONH-, -(OL) ｇ -CONH alkylene-, -(O-L) ｇ -NHCO alkylene-, -(L-O) ｇ -, -(L-O) ｇ -NHCO-, -(L-O) ｇ -CONH-, -(L-O) ｇ -CONH alkylene-, -(L-O) ｇ -NHCO alkylene- is an example of the above X １ ~X ３ At least one of them is >CR ２ R ３ Preferably, at least two are >CR ２ R ３ and the remaining one is —O—, —S— or >CR ２ R ３ It is more preferable that:

[0032] As described above, when a targeted drug conjugate is formed by binding a large number of drugs to a target-binding substance such as an antibody exhibiting high hydrophilicity, there is a concern that drugs exhibiting high hydrophobicity generally interact hydrophobically with each other, making the conjugate more likely to aggregate. From the viewpoint of eliminating this concern, the structure represented by the above general formula (I) is １ ~X ３ But >CR ２ R ３ It is preferable that the structure represented by general formula (I) contains a structure represented by X １ ~X ３ But >CR ２ R ３ The phrase "including a structure in which X is at least one of the n structures represented by the general formula (i)" means that X is at least one of the n structures represented by the general formula (i) １ ~X ３ All of them are >CR ２ R ３ In the structure represented by general formula (I), the above X １ ~X ３ But >CR ２ R ３The proportion of the number of structures represented by the general formula (I) is preferably 30% or more, more preferably 60% or more, and even more preferably 80% or more. There is no particular limitation on the upper limit, and it can be 100% or less. In addition, all of the structures represented by the general formula (I) are the above X １ ~X ３ But >CR ２ R ３ It is also preferable that the above X １ ~X ３ But >CR ２ R ３ At least one R in the structure ２ In order to dispel the concern that the above-mentioned complex may easily aggregate, -NR ８ R ９ , -OR １０ or a group selected from the hydrophilic group Pi, and from the viewpoint of imparting sufficient hydrophilicity to the targeted drug complex and further suppressing aggregation of the complex, -NR ８ R ９ , -OR １０ or a group selected from the hydrophilic group Pi, and R ８ ~R １０ It is more preferable that at least one of the above is a group containing at least one kind of group selected from the hydrophilic group group Pi. １ ~X ３ But >CR ２ R ３ At least one R in the structure ２ But, -NR ８ R ９ , -OR １０ or a group selected from the hydrophilic group Pi, and R ８ ~R １０ is a group containing at least one kind of group selected from the hydrophilic group group Pi" means that R ２ Ga-NR ８ R ９ If ８ and R ９ at least one of the groups is a group containing at least one selected from the hydrophilic group Pi; ２ Ga-OR １０If １０ is a group containing at least one group selected from the hydrophilic group Pi. １０ is a group containing at least one group selected from the hydrophilic group group Pi, １０ is a group selected from the hydrophilic group group Pi or a group having at least one group selected from the hydrophilic group group Pi as a substituent. ８ and R ９ The same applies to the case where at least one of the groups is a group containing at least one kind of group selected from the hydrophilic group Pi.

[0033] The structure represented by the general formula (I) above is X １ ~X ３ But >CR ２ R ３ and X １ ~X ３ But >CR ２ R ３ At least one R in the structure ２ But, -NR ８ R ９ , -OR １０ Alternatively, in the case where the group is a group selected from the hydrophilic group group Pi, the structure represented by the general formula (I) preferably contains a group selected from the hydrophilic group group Pi, and more preferably, the group selected from the hydrophilic group group Pi is specifically one of the following groups: In one embodiment, it is preferable that at least one of the groups selected from the hydrophilic group group Pi contained in the structure represented by the general formula (I) is a carboxy group, a sulfo group, or a phosphono group, and it is more preferable that the structure represented by the general formula (I) contains two or more groups selected from a carboxy group, a sulfo group, and a phosphono group.

[0034] In another embodiment, it is preferable that at least one of the groups selected from the hydrophilic group group Pi possessed by the structure represented by the general formula (I) above is a betaine residue, a polyol residue, a sugar residue, a polyamino acid residue, or a polyalkyleneoxy group. In one of these embodiments, it is preferable that at least one of the groups selected from the hydrophilic group group Pi possessed by the structure represented by the general formula (I) above is a polyol residue, a sugar residue, a polyamino acid residue, or a polyalkyleneoxy group. In this case, it is more preferable that the polyalkyleneoxy group further has, as a substituent, a group containing at least one group selected from a polyol residue, a sugar residue, and a polyamino acid residue. In another of these embodiments, it is also preferable that at least one of the groups selected from the hydrophilic group group Pi possessed by the structure represented by the general formula (I) above is a betaine residue.

[0035] (Group Selected from Hydrophilic Group Group Pi) The compound of the present invention does not have a fluorescent body portion and has at least one group selected from the aforementioned hydrophilic group group Pi. The type and number of groups selected from the aforementioned hydrophilic group group Pi possessed by the compound of the present invention are not particularly limited as long as they can impart sufficient hydrophilicity to the targeted drug complex and suppress aggregation of the complex. For example, with regard to the type of group selected from the hydrophilic group group Pi possessed by the compound of the present invention, it is preferable to have at least one of anionic groups, cationic groups, betaine residues, and polyalkyleneoxy groups, more preferably at least one of anionic groups, even more preferably at least one of phosphono groups, phosphonooxy groups, and sulfo groups, particularly preferably at least one of phosphonooxy groups and sulfo groups, and most preferably at least a sulfo group. Furthermore, the number of groups selected from the aforementioned hydrophilic group group Pi possessed by the compound of the present invention is preferably 2 to 30, more preferably 2 to 20, even more preferably 2 to 16, and particularly preferably 2 to 12. In the above description of each preferred range of the number of groups selected from the hydrophilic group group Pi that the compound of the present invention has, the lower limit is preferably 3 or more, more preferably 4 or more, and even more preferably 5 or more.

[0036] n is an integer of 2 or greater. When n is an integer of 2 or greater, the compound of the present invention can impart excellent stability in blood to the resulting targeted drug conjugate. In the present invention, from the viewpoint of achieving better stability in blood, the lower limit of n is preferably an integer of 3 or greater, more preferably an integer of 6 or greater, even more preferably an integer of 9 or greater, and particularly preferably an integer of 12 or greater. There is no particular limitation on the upper limit, and n can be, for example, an integer of 72 or less, preferably an integer of 36 or less, more preferably an integer of 24 or less, and even more preferably an integer of 21 or less. That is, n is preferably an integer of 3 to 72, more preferably an integer of 6 to 36, even more preferably an integer of 9 to 24, and particularly preferably an integer of 12 to 21. The above preferred values ​​of n can also be applied to n in compounds represented by general formula (II) or (III) described below. For compounds represented by general formula (IV) described below, the above-mentioned preferred value of n can be applied as the value of (v+1)×m+1, and for compounds represented by general formula (V) described below, the above-mentioned preferred value of n can be applied as the value of (((na+nb+nc)×r)+1)×m+1.

[0037] <Compound Represented by General Formula (II)> Among the compounds of the present invention, a compound in which the linking group connecting adjacent structural moieties M is a group containing the structure represented by the above general formula (I) is preferably represented by the following general formula (II).

[0038]

[0039] In the formula, R ４ and R ５ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxy group, an alkoxy group, a sulfanyl group, an aryl group, or a heteroaryl group. ６ and R ７ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７At least one of the groups is a group containing a carboxy group or a group containing a substituent capable of binding to a target-binding substance. Q represents a group selected from the hydrophilic group group Pi or a substituent capable of binding to a target-binding substance. １ , L ３ , L ４ , L ６ and L ７ represents a single bond or a linking group. ２ and L ５ represents a single bond or a physiologically cleavable linker. ２ When is a single bond, L １ and L ３ at least one of L is a physiologically cleavable linker; ５ When is a single bond, L ４ and L ６ At least one of the above is a physiologically cleavable linker. M represents the structural moiety M described above. Y represents the structure represented by general formula (I) described above. m is an integer of 1 or more.

[0040] R ４ and R ５ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxy group, an alkoxy group, a sulfanyl group, an aryl group, or a heteroaryl group. ４ or R ５ The preferred ranges of the alkyl group, alkenyl group, alkynyl group, acyl group, amino group, alkoxy group, aryl group, and heteroaryl group that can be taken as R are as described above. ４ or R ５ The alkyl group, alkenyl group, alkynyl group, acyl group, amino group, alkoxy group, aryl group and heteroaryl group that can be taken as R may be unsubstituted or may have a substituent, and examples of the substituent that may be had include the substituents in the substituent group T described below, and for example, a halogen atom is preferred. ４ and R ５ From the viewpoint of ease of synthesis, a hydrogen atom is preferred as R ４ and R ５Although R is often a hydrogen atom, the targeted drug conjugate obtained from the compound of the present invention retains a larger amount of drug while suppressing aggregation and exhibits excellent stability in blood. ４ and R ５ Since the substituents in R ４ and R ５ may be a substituent other than a hydrogen atom (an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxy group, an alkoxy group, a sulfanyl group, an aryl group, or a heteroaryl group).

[0041] R ６ and R ７ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７ At least one of R is a group containing a carboxy group or a group containing a substituent capable of binding to a target-binding substance. ６ or R ７ The preferred ranges of the alkyl group, alkenyl group, alkynyl group, aryl group, alkoxy group, amino group, acyl group and heteroaryl group that can be taken as R are as described above. ６ or R ７ The alkyl group, alkenyl group, alkynyl group, aryl group, alkoxy group, amino group, acyl group and heteroaryl group that can be taken as R may be unsubstituted or may have a substituent. ６ or R ７ In the above, the substituents that may be possessed by the alkyl group, alkenyl group, alkynyl group, aryl group, alkoxy group, amino group, acyl group and heteroaryl group include the substituents in the substituent group T described below, and preferred are alkyl group, acyl group, alkoxy group, amino group or Q, or a substituent in combination of two or more of these, and more preferred are alkyl group, acyl group, alkoxy group, amino group, -(O-L) ｇ R Ｅ , -(L-O) ｇ R Ｅ, a substituent capable of binding to a carboxy group or a target-binding substance, or a substituent that is a combination of two or more of these substituents, is more preferred.

[0042] R ６ or R ７ Q represents a group selected from the hydrophilic group Pi above or a substituent capable of binding to a target-binding substance. The substituent capable of binding to a target-binding substance described below can be applied to the substituent capable of binding to a target-binding substance. Q is preferably a carboxy group or a substituent capable of binding to a target-binding substance, and more preferably a substituent capable of binding to a target-binding substance.

[0043] R ６ As for -L, which will be described later, ８ R ６Ａ The description of the substituent represented by the following formula is preferably exemplified. Specifically, -L ８ R ６Ａ The description of the substituent represented by L ８ The groups that can be taken as R ６Ａ R means a substituent obtained by combining groups that can be taken as ７ As the linking group, a group in which the following substituents are substituted on the following linking group is preferred. That is, as the linking group, an alkylene group, —O—, >C═O, and >NR Ａ The linking group is preferably one or a combination of two or more of the following: an alkylene group, —O—, >C═O, >NR Ａ , -NR Ａ -alkylene, -[NR Ａ -NR to the right of a repeating unit represented by the formula (the number of repeating units is preferably 1 to 20) Ａ -alkylene group, -[NR Ａ -NR to the right of a repeating unit represented by the formula (the number of repeating units is preferably 1 to 20) Ａ -(L-O) ｇ -alkylene-linked group, -NR Ａ -(L-O) ｇ -Alkylene or -C(=O)-(L-O) ｇThe substituent is preferably an alkyl group, a sulfanyl group, an acylamino group, a carbamoyl group, an aryl group, a heteroaryl group, or Q, and more preferably an alkyl group, an acylamino group, a carbamoyl group, or Q. Ａ is the R described below. Ａ and represents a hydrogen atom or a substituent. L and g are the same as L and g described above. R ７ is also preferably a group containing a group selected from the hydrophilic group Pi. In this case, R ７ is preferably an alkylene group containing at least one group selected from the hydrophilic group group Pi, and more preferably an alkylene group having at least one group selected from the hydrophilic group group Pi as a substituent, or an alkylene group substituted with an aryl group having at least one group selected from the hydrophilic group group Pi as a substituent.

[0044] L ３ , L ４ and L ７ represents a single bond or a linking group, and is a single bond, an alkylene group, an alkenylene group, an alkynylene group, an arylene group, a heteroarylene group, —O—, —S—, >C═O, or >NR Ａ , >S=O, >S(=O) ２ and >P(=O)OR Ｂ Preferably, the linking group is one or a combination of two or more of the following: Ａ and R Ｂ is the R described below. Ａ and R Ｂ and represents a hydrogen atom or a substituent. １ and L ６ represents a single bond or a linking group, and is a single bond, an alkylene group, an alkenylene group, an alkynylene group, an arylene group, a heteroarylene group, —O—, —S—, >C═O, >NR Ａ , >S=O, >S(=O) ２ or >P(=O)OR Ｂ It is preferable that R Ａ and R Ｂ is the R described below. Ａ and RＢ and represents a hydrogen atom or a substituent. １ , L ３ , L ４ , L ６ and L ７ The preferred ranges of the alkylene group, alkenylene group, alkynylene group, arylene group and heteroarylene group that can constitute L are as described above. １ , L ３ , L ４ , L ６ and L ７ The alkylene group, alkenylene group, alkynylene group, arylene group and heteroarylene group that can constitute L may be an unsubstituted group or a group having a substituent. １ , L ３ , L ４ , L ６ and L ７ The substituents that may be contained in the alkylene group, alkenylene group, alkynylene group, arylene group and heteroarylene group that can constitute L are not particularly limited, and are preferably selected from the substituent group T described below, more preferably a halogen atom, an alkyl group, an acylamino group, a carbamoyl group, an aryl group or a group selected from the hydrophilic group Pi. １ , L ３ , L ４ , L ６ and L ７ The substituents that may be possessed by the alkylene group, alkenylene group, alkynylene group, arylene group and heteroarylene group that can constitute L may be further substituted with a substituent selected from the substituent group T described below, and for example, are preferably substituted with an amino group or a group selected from the hydrophilic group group Pi. １ , L ３ , L ４ , L ６ and L ７The number of substituents that the alkylene group, alkenylene group, alkynylene group, arylene group, and heteroarylene group that can constitute the above may have is not particularly limited as long as it can be adopted as a structure, and can be at least one or more. The upper limit is not particularly limited, and for example, all of the hydrogen atoms in the alkylene group, alkenylene group, alkynylene group, arylene group, and heteroarylene group may be replaced with substituents.

[0045] L １ , L ３ , L ４ , L ６ and L ７ can be constructed >NR Ａ R in Ａ and >P(=O)OR Ｂ R in Ｂ The substituents that can be adopted as R are not particularly limited, and are preferably selected from the substituent group T described below. Ａ R is preferably a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, or a group selected from the hydrophilic group Pi, more preferably a hydrogen atom or an alkyl group, and even more preferably a hydrogen atom. Ｂ is preferably a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or a heteroaryl group, more preferably a hydrogen atom or an alkyl group, and even more preferably a hydrogen atom. Ａ and R Ｂ The alkyl group, alkenyl group, alkynyl group, aryl group and heteroaryl group which can be taken as above may be either an unsubstituted group or a group having a substituent.

[0046] L ３ , L ４ and L ７ an alkylene group, an alkenylene group, an alkynylene group, an arylene group, a heteroarylene group, —O—, —S—, >C═O, >NR Ａ , >S=O, >S(=O) ２ and >P(=O)OR ＢIn the linking group formed by combining two or more of the above, the types of the groups to be combined are not particularly limited as long as a suitable chemical structure is obtained, but for example, 2 to 6 types are preferred, and 2 to 4 types are more preferred. Ａ , >S=O, >S(=O) ２ and >P(=O)OR Ｂ Each counts as one type, making a maximum of 12 types. ３ , L ４ and L ７ an alkylene group, an alkenylene group, an alkynylene group, an arylene group, a heteroarylene group, —O—, —S—, >C═O, >NR Ａ , >S=O, >S(=O) ２ and >P(=O)OR Ｂ In the linking group obtained by combining two or more of the above, the number of groups to be combined is not particularly limited, but is preferably 2 to 10, more preferably 2 to 6, and even more preferably 2 to 4, for example.

[0047] (i) L １ , L ６ L １ and L ６ represents a single bond, >C=O, >NR Ａ , an arylene group, an alkylene group, —O— or —S— is more preferred, and a single bond, >C═O, >NR Ａ , an arylene group or an alkylene group is more preferred, a single bond, >C=O or >NR Ａ is particularly preferred. ３ , L ４ , L ７ L ３ , L ４ and L ７ represents a single bond, >C=O, >NR Ａ , an alkylene group, an alkenylene group, an alkynylene group, an arylene group, or a heteroarylene group, or at least one of an alkylene group, an alkenylene group, an alkynylene group, an arylene group, a heteroarylene group, —O—, and —S—, and >C═O and >NR Ａ and a single bond, >C═O, >NRＡ , an alkylene group, an alkenylene group, an alkynylene group, an arylene group, or a heteroarylene group, or —C(═O)NR Ａ Between - and >C=O, or -NR Ａ C(=O)- and >NR Ａ and are more preferably linked by at least one of an alkylene group, an alkenylene group, an alkynylene group, an arylene group, a heteroarylene group, —O—, and —S—.

[0048] L ２ and L ５ represents a single bond or a physiologically cleavable linker. ２ When is a single bond, L １ and L ３ at least one of L is a physiologically cleavable linker; ５ When is a single bond, L ４ and L ６ At least one of L is a physiologically cleavable linker. ２ and L ５ The physiologically cleavable linker that can be used as the linker is as described above. The physiologically cleavable linker may be introduced by synthesis using a conventional method, or a commercially available physiologically cleavable linker may be used.

[0049] m is an integer of 1 or more. There is no particular upper limit, and for example, m can be an integer of 30 or less, preferably an integer of 20 or less, more preferably an integer of 10 or less, even more preferably an integer of 5 or less, and particularly preferably an integer of 3 or less. That is, m can be an integer of 1 to 30, preferably an integer of 1 to 20, more preferably an integer of 1 to 15, and even more preferably an integer of 1 to 10.

[0050] <Compound Represented by General Formula (III)> The compound represented by the general formula (II) above is preferably represented by the following general formula (III).

[0051]

[0052] In the formula, Y １ ~Y ５ , Z １ ~Z３ and W １ ~W ３ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxy group, an alkoxy group, a sulfanyl group, an aryl group, a heteroaryl group, or a group selected from the hydrophilic group Pi described above. ６Ａ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６Ａ is a carboxy group or a substituent capable of binding to a target binding substance, and / or R ７ is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. ４ , R ５ , R ７ , R １１ , L ２ , L ５ , X １ ~X ３ , M, Q, m and n are the above-mentioned R ４ , R ５ , R ７ , R １１ , L ２ , L ５ , X １ ~X ３ , M, Q, m and n. ８ represents a single bond or a linking group. s, t, and u represent an integer of 0 or 1 or more. q is an integer of 0 or 1.

[0053] Y １ ~Y ５ , Z １ ~Z ３ and W １ ~W ３ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxy group, an alkoxy group, a sulfanyl group, an aryl group, a heteroaryl group, or a group selected from the hydrophilic group Pi described above. １ ~Y ５ , Z １ ~Z ３ Or W １ ~W ３The preferred ranges of the alkyl group, alkenyl group, alkynyl group, acyl group, amino group, alkoxy group, aryl group and heteroaryl group that can be taken as Y are as described above. １ ~Y ５ , Z １ ~Z ３ Or W １ ~W ３ The alkyl group, alkenyl group, alkynyl group, acyl group, amino group, alkoxy group, aryl group and heteroaryl group which can be taken as Y may be unsubstituted or may have a substituent, and examples of the substituent that may be had include the substituents in the substituent group T described below, and for example, an aryl group, a halogen atom or a group selected from the hydrophilic group group Pi described above are preferred. １ ~Y ５ , Z １ ~Z ３ Or W １ ~W ３ The substituents which the alkyl group, alkenyl group, alkynyl group, acyl group, amino group, alkoxy group, aryl group and heteroaryl group which can constitute the above may have may be further substituted with a substituent selected from the substituent group T described later, and for example, are preferably substituted with a group selected from the hydrophilic group group Pi described above.

[0054] Y １ ~Y ３ is preferably a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group, more preferably a hydrogen atom or an alkyl group. ４ and Y ５ is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom. １ ~W ３ is preferably a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group, more preferably a hydrogen atom. １ ~Z ３ is preferably an alkyl group, an aryl group or a heteroaryl group, more preferably an alkyl group.

[0055] In the compound represented by general formula (III), Z １ ~Z ３It is preferable that at least one of the groups is a group containing at least one of the groups selected from the hydrophilic group group Pi, and it is more preferable that at least one of the groups is an alkyl group containing at least one of the groups selected from the hydrophilic group group Pi. As the alkyl group containing at least one of the groups selected from the hydrophilic group group Pi, an alkyl group having at least one of the groups selected from the hydrophilic group group Pi as a substituent, or an alkyl group substituted with an aryl group having at least one of the groups selected from the hydrophilic group group Pi as a substituent, is preferable. １ ~Z ３ is a group containing at least one group selected from the hydrophilic group group Pi" means that at least one of the following conditions (Z1) to (Z3) is satisfied. Condition (Z1): The above s is an integer of 1 or more, and the above Z １ is a group containing at least one group selected from the hydrophilic group Pi. Condition (Z2): the t is an integer of 1 or more, and the Z ２ is a group containing at least one group selected from the hydrophilic group Pi. Condition (Z3): The u is an integer of 1 or more, and the Z ３ is a group containing at least one group selected from the hydrophilic group Pi. １ ~Z ３ is an alkyl group containing at least one kind of group selected from the hydrophilic group group Pi" means that at least one of the above conditions (Z1) to (Z3) is satisfied after reading "a group containing at least one kind of group selected from the hydrophilic group group Pi" in the above conditions (Z1) to (Z3) as "an alkyl group containing at least one kind of group selected from the hydrophilic group group Pi." １ ~Z ３ Each group of may contain two or more groups selected from the hydrophilic group Pi, from the viewpoint of suppressing aggregation of the resulting targeted drug complex.

[0056] R ６Ａ and L ８ is R ６Ａ is an unsubstituted group, and L８ is determined so that it is the longest group. ８ R ６Ａ When the group represented by the formula (I) has Q, the most terminal side (-L ８ R ６Ａ R in ６Ａ Q located on the R ６Ａ The value is determined so that:

[0057] R ６Ａ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６Ａ is a carboxy group or a substituent capable of binding to a target binding substance, and / or R ７ is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. ６Ａ The preferred ranges of alkyl groups, alkenyl groups, alkynyl groups, aryl groups, alkoxy groups, amino groups, acyl groups, and heteroaryl groups that can be taken as R are as described above. However, all of these are unsubstituted groups. ６Ａ The possible Q has the same meaning as the above-mentioned Q, and the preferred range is also the same.

[0058] R ６Ａ is preferably an alkyl group, a sulfanyl group, an aryl group, a heteroaryl group or Q, more preferably an alkyl group or Q, and even more preferably an alkyl group, a carboxy group or a substituent capable of binding to a target-binding substance.

[0059] L ８ represents a single bond or a linking group. ８ Examples of the linking group that can be taken as Ａ Preferably, the linking group is one or a combination of two or more of the following: Ａ represents a hydrogen atom or a substituent. ８ alkylene groups, alkenylene groups, alkynylene groups, arylene groups, heteroarylene groups, and >NR Ａ is the aforementioned L１ , L ３ , L ４ , L ６ and L ７ alkylene groups, alkenylene groups, alkynylene groups, arylene groups, heteroarylene groups, and >NR Ａ The description of the above can be preferably applied. ８ The substituents that may be contained in the alkylene group, alkenylene group, alkynylene group, arylene group and heteroarylene group that can constitute L are not particularly limited, and are preferably selected from the substituent group T described below, more preferably a halogen atom, an aryl group or an alkyl group. ８ The substituents that may be possessed by the alkylene group, alkenylene group, alkynylene group, arylene group and heteroarylene group that can constitute L may be further substituted with a substituent selected from the substituent group T described below, and are preferably substituted with, for example, a group selected from the hydrophilic group group Pi described above. ８ The number of substituents that the alkylene group, alkenylene group, alkynylene group, arylene group, and heteroarylene group that can constitute the above may have is not particularly limited as long as it can be adopted as a structure, and can be at least one or more. The upper limit is not particularly limited, and for example, all of the hydrogen atoms in the alkylene group, alkenylene group, alkynylene group, arylene group, and heteroarylene group may be replaced with substituents.

[0060] However, R ６Ａ is a carboxy group or a substituent capable of binding to a target-binding substance, ８ Is >NY ４ and R ６Ａ The linking group preferably has a minimum number of atoms connecting the linking group L to the group of 3 or more. ８ About ">NY ４ and R ６Ａ The shortest number of atoms connecting the two is ４ and R ６Ａ It means the number of atoms that make up the shortest chain connecting the ４ What is L ８ Directly bonded to NY ４ means.

[0061] L ８ represents a single bond, an alkylene group, —O—, >C═O, and >NR Ａ More preferably, the linking group is one or a combination of two or more of the following: a single bond, an alkylene group, —O—, >C═O, >NR Ａ , -[NR Ａ -NR to the right of a repeating unit represented by the formula (the number of repeating units is preferably 1 to 20) Ａ - an alkylene group bonded thereto, -NR Ａ -(L-O) ｇ -Alkylene or -C(=O)-(L-O) ｇ L and g have the same meanings as those defined above.

[0062] s, t, and u are integers of 0 or 1 or more. There is no particular limitation on the upper limit of s, t, and u, and they can be, for example, 20 or less, preferably 10 or less, and more preferably 5 or less. That is, s, t, and u are preferably integers of 0 to 20, more preferably integers of 0 to 10, and even more preferably integers of 0 to 5. In particular, s, t, and u are preferably integers of 0 or 1. Note that when a structure can be classified into both a structure grouped by t and a structure grouped by u, it is classified preferentially into a structure grouped by u.

[0063] q is an integer of 0 or 1, with 0 being preferred.

[0064] <Compounds represented by general formula (IV)> Among the compounds of the present invention, X in the structure represented by general formula (I) １ ~X ３ The compound having a structure in which the structural moiety M is bonded to any of the above directly or via a linking group is preferably represented by the following general formula (IV).

[0065]

[0066] In the formula, X ４ ~X ９ is -O-, -S-, >NR １ Or >CR ２ R ３ where X ４~X ６ At least one of the above is >N-L ９ -M or >C(R ２ )-L ９ -M and X ７ ~X ９ At least one of the above is >N-L １０ -M or >C(R ２ )-L １０ -M. -L ９ -M and -L １０ -R that is neither M １ ~R ３ represents R in the above general formula (I). １ ~R ３ It is synonymous with L. ９ and L １０ indicates a physiologically cleavable linker. ６ and R ７ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７ At least one of the groups is a group containing a carboxy group or a group containing a substituent capable of binding to a target-binding substance. Q represents a group selected from the hydrophilic group group Pi described above or a substituent capable of binding to a target-binding substance. m is an integer of 1 or more, q is an integer of 0 or 1, and v is an integer of 0 or 1 or more. R １１ , X １ ~X ３ and M is the aforementioned R １１ , X １ ~X ３ and M.

[0067] X ４ ~X ９ As for X ４ ~X ６ At least one of the following is >N-L ９ -M or >C(R ２ )-L ９ -M and X ７ ~X ９ At least one of the following is >N-L １０ -M or >C(R ２ )-L１０ Unless otherwise specified, X in the above general formula (I) is -M. １ ~X ３ The description of X can be applied. ４ and X ７ As for the aforementioned X １ The description of X ５ and X ８ As for the aforementioned X ２ The description of X ６ and X ９ As for the aforementioned X ３ The descriptions of -L can be applied, respectively. ９ -M and -L １０ -R that is neither M １ , R ２ and R ３ As the group, R in the above general formula (I) １ , R ２ and R ３ The descriptions of the above can be applied to each of the above.

[0068] X ４ ~X ９ Among them, -L ９ -M and -L １０ -None of M>NR １ and >CR ２ R ３ In this case, R １ is preferably an alkyl group, and R ２ and R ３ is preferably a hydrogen atom. ４ ~X ６ Among them, the above-mentioned -L ９ At least one of the two groups not having -M is >CR ２ R ３ and at least one of them is >CR ２ R ３ and the remaining one is —O—, —S— or >CR ２ R ３ It is more preferable that both are >CR ２ R ３ It is more preferable that X ７ ~X ９ Among them, the above-mentioned -L １０At least one of the two groups not having -M is >CR ２ R ３ and at least one of them is >CR ２ R ３ and the remaining one is —O—, —S— or >CR ２ R ３ It is more preferable that both are >CR ２ R ３ It is more preferable that:

[0069] X ４ ~X ６ Among them, >N-L ９ -M or >C(R ２ )-L ９ -M is >C(R ２ )-L ９ -M is preferred, and >CH-L ９ -M is more preferred. ７ ~X ９ Among them, >N-L １０ -M or >C(R ２ )-L １０ -M is >C(R ２ )-L １０ -M is preferred, and >CH-L １０ -M is more preferred. ４ ~X ６ Among them, -L ９ The group having -M is not particularly limited, but X ５ It is preferable that X ７ ~X ９ Among them, -L １０ The group having -M is not particularly limited, but X ８ It is preferable that:

[0070] L ９ and L １０ indicates a physiologically cleavable linker. ９ and L １０ The physiologically cleavable linker described above can be applied to the physiologically cleavable linker.

[0071] R ６ and R ７represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７ At least one of R is a group containing a carboxy group or a group containing a substituent capable of binding to a target-binding substance. ６ and R ７ represents R in the above general formula (II). ６ and R ７ The description of R ６ or R ７ The above description of Q in the general formula (II) can be applied to Q that can be taken as the above.

[0072] m is an integer of 1 or more, and the description of m in the above general formula (II) can be applied. q is an integer of 0 or 1, preferably 0. v is an integer of 0 or 1 or more, preferably an integer of 1 to 36, more preferably an integer of 2 to 24, still more preferably an integer of 3 to 36, particularly preferably an integer of 4 to 24, and of these, an integer of 5 to 18 is preferred.

[0073] <Compound Represented by General Formula (V)> The compound represented by the general formula (IV) above is preferably represented by the following general formula (V).

[0074]

[0075] In the formula, X １ａ , X １ｂ , X １ｃ , X ２ａ , X ２ｂ , X ２ｃ , X ３ａ , X ３ｂ and X ３ｃ -O-, -S-, >NR １ Or >CR ２ R ３ Indicates. １１ represents a single bond or a linking group. ６Ａ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q.６Ａ is a carboxy group or a substituent capable of binding to a target binding substance, and / or R ７ is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. １ ~R ３ , R ７ , R １１ , X ４ ~X ９ , L ９ , L １０ , M, Q, m and q are the above-mentioned R １ ~R ３ , R ７ , R １１ , X ４ ~X ９ , L ９ , L １０ , M, Q, m, and q. na, nb, and nc are 0 or an integer of 1 or more. r is an integer of 1 or more.

[0076] X １ａ , X １ｂ and X １ｃ represents X in the above general formula (I). １ The description of X can be applied. ２ａ , X ２ｂ and X ２ｃ represents X in the above general formula (I). ２ The description of X can be applied. ３ａ , X ３ｂ and X ３ｃ represents X in the above general formula (I). ３ The description of X can be applied. １ａ , X １ｂ and X １ｃ and X ３ａ , X ３ｂ and X ３ｃ is >NH or >CH ２ It is preferred that ２ It is more preferable that X ２ａ , X ２ｂ and X ２ｃ At least one of X is preferably a group containing a group selected from the hydrophilic group Pi described above, ２ｂ is a group containing a group selected from the hydrophilic group Pi described above, ２ａ and X２ｃ >NH or >CH ２ More preferably, X ２ｂ is a group containing a group selected from the hydrophilic group Pi described above, ２ａ and X ２ｃ Ga>CH ２ It is more preferable that X ２ａ , X ２ｂ and X ２ｃ Examples of the group containing a group selected from the above-mentioned hydrophilic group group Pi include >NR １ , >CR ２ H or a group selected from the hydrophilic group Pi, １ and R ２ is preferably an alkyl group, an arylacylamino group, or an arylaminocarbonyl group containing one or more groups selected from the above-mentioned hydrophilic group group Pi, and >NR １ Or >CR ２ A group represented by H, １ and R ３ is more preferably an aryl acylamino group or an aryl aminocarbonyl group containing one or more groups selected from the hydrophilic group group Pi described above, １ Or >CR ２ A group represented by H, １ and R ３ is more preferably an aryl acylamino group or an aryl aminocarbonyl group containing two or more groups selected from the above-mentioned hydrophilic group group Pi, １ Or >CR ２ A group represented by H, １ and R ３ However, a group which is an arylacylamino group or an arylaminocarbonyl group having two or more alkoxy groups each containing a group selected from the above-mentioned hydrophilic group group Pi is particularly preferred.

[0077] R ６Ａ and L １１ is R ６Ａ is an unsubstituted group, and L １１ is determined so that it is the longest group. １１ R ６Ａ When the group represented by the formula (I) has Q, the most terminal side (-L１１ R ６Ａ R in ６Ａ Q located on the R ６Ａ The value is determined so that:

[0078] R ６Ａ is R in the above general formula (III). ６Ａ The above description can be applied.

[0079] L １１ represents a single bond or a linking group. １１ Examples of the linking group that can be used as the linking group include L in the above-mentioned general formula (III). ８ The description of the linking group that can be taken as the above can be applied.

[0080] L １１ represents a single bond, an alkylene group, —O—, >C═O, and >NR Ａ More preferably, the linking group is one or a combination of two or more of the following: a single bond, an alkylene group, >NR Ａ , >C=O, or an alkylene group and >C=O or >NR Ａ and a single bond, an alkylene group, >NR Ａ Or >C=O is particularly preferred.

[0081] Each of na, nb, and nc is an integer of 0 or greater than 1. r is an integer of greater than 1. Each of na, nb, and nc is preferably an integer of 1 to 10, more preferably an integer of 1 to 5, and even more preferably an integer of 1 to 3. r is preferably an integer of 1 to 5.

[0082] When the compound of the present invention represented by any one of general formulas (II) to (V) is obtained by peptide synthesis, the C-terminal structure is usually on the right side of the paper and the N-terminal structure is on the left side of the paper.

[0083] The compound of the present invention preferably contains at least one carboxy group or a substituent capable of binding to a target-binding substance in the substituent represented by Q. The compound of the present invention can bind to a target-binding substance via the carboxy group or the substituent capable of binding to a target-binding substance described below, thereby obtaining the desired targeted drug conjugate. It should be noted that a substituent capable of binding to a target-binding substance can be easily derived from the carboxy group by a conventional method. In the present invention, for convenience, the substituent capable of binding to a target-binding substance does not include a carboxy group, and the "substituent capable of binding to a target-binding substance" includes a substituent derived from a carboxy group capable of binding to a target-binding substance. However, as described above, it is also possible to bind to a target-binding substance via a carboxy group. In the compound of the present invention, there are no particular restrictions on the position of the carboxy group or the substituent capable of binding to a target-binding substance, but it is preferable that it be located in a structure other than the structure represented by general formula (I) and the structural portion M, and in compounds represented by general formula (II) or (IV), R ６ and R ７ In the compound represented by general formula (III) or (V), R ６Ａ and R ７ The number of the carboxy group or the substituent capable of binding to a target-binding substance in the compound of the present invention may be at least one in total, and from the viewpoint of quantifying the substance to be detected, the number is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0084] Furthermore, the compound of the present invention is a compound having at least one group selected from the above-mentioned hydrophilic group group Pi. From the viewpoint of imparting sufficient hydrophilicity to the resulting targeted drug conjugate and suppressing aggregation, it is preferable that the compound has a total of 1 to 20 groups selected from the above-mentioned hydrophilic group group Pi at positions other than the structural moiety M, more preferably 1 to 16 groups, and even more preferably 1 to 12 groups. The positions of the groups selected from the above-mentioned hydrophilic group group Pi are not particularly limited unless otherwise specified, and for example, X in general formula (I), (III) or (IV) １ ~X ３ or R １１, X in Y in general formula (II) １ ~X ３ or R １１ , X in general formula (V) １ａ , X １ｂ , X １ｃ , X ２ａ , X ２ｂ , X ２ｃ , X ３ａ , X ３ｂ , X ３ｃ or R １１ The compound of the present invention is preferably a compound that does not have a phosphor moiety (a structural part made of an organic compound that exhibits fluorescence). That is, the compound of the present invention is a compound that does not have a phosphor moiety that can be used as M described in paragraph

[0045] of WO 2023 / 032995.

[0085] Specific examples of the compound of the present invention are shown below, but the present invention is not limited to these compounds.

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] The compounds of the present invention can be bound to target-binding substances such as proteins (including peptides), amino acids, nucleic acids, nucleotides, enzymes, sugar chains, lipids, antibodies, antibody fragments, cell surface receptor antagonists, and cell surface receptor agonists via at least one substituent possessed by the compound that can bind to the target-binding substance, and can be used as targeted drug conjugates.

[0092] The substituent capable of binding to a target-binding substance can be any group capable of acting on (including attaching to) or binding to a target-binding substance, and examples thereof include the substituents described in WO 2002 / 026891. Specifically, the electrophilic groups and nucleophilic groups described in Table 2 of WO 2002 / 026891, as well as the reactive group Rx described on page 18, line 16 to page 19, line 13 of WO 2002 / 026891, can be applied to the present invention. Specific examples of "substituents capable of binding to a target-binding substance" include the following structures. In the following structures, X represents a halogen atom such as an iodine atom or a bromine atom. * represents a bond.

[0093]

[0094] In addition to the above, peptide structures (polyamino acid structures), long-chain alkyl groups, etc. can also be used as the "substituent capable of binding to a target-binding substance." Among these, preferred examples include an NHS ester structure (N-hydroxysuccinimide ester structure), a succinimide structure, a maleimide structure, an azide group, an acetylene group, a peptide structure (polyamino acid structure), a long-chain alkyl group (preferably having 12 to 30 carbon atoms), and a quaternary ammonium group.

[0095] Specific examples of the compounds of the present invention having at least one substituent capable of binding to a target-binding substance include, for example, the above-mentioned exemplary compounds of the present invention in which the carboxy group is appropriately replaced with the above-mentioned substituent capable of binding to a target-binding substance, but the present invention is not limited to these compounds.

[0096] The compounds of the present invention can be synthesized by conventional methods. For example, they can be synthesized based on peptide synthesis such as solid-phase peptide synthesis, and the method using the automated peptide synthesizer described in WO 2018 / 174078 can also be preferably applied. The physiologically active substance portion and the radioisotope-containing portion can also be synthesized based on conventional methods and introduced into the compounds of the present invention. For example, the description of the synthesis of antibody-drug conjugates described in WO 2015 / 115091 can be referenced. Compounds having a substituent capable of binding to a target-binding substance can also be synthesized by conventional methods. For example, Bioconjugate Techniques (Third Edition, by Greg T. Hermanson) can be referenced.

[0097] <Targeted Drug Conjugate> The targeted drug conjugate of the present invention is a substance in which the compound of the present invention is bound to a target-binding substance. The compound of the present invention can retain a larger amount of drug while suppressing aggregation, and can provide a targeted drug conjugate with excellent stability in blood. The bond between the compound of the present invention and the target-binding substance may be in the form of a direct bond between the compound of the present invention and the target-binding substance, or may be in the form of a bond via a linking group.

[0098] The targeted drug conjugate of the present invention is a substance in which a compound of the present invention is conjugated to a target-binding substance, and is preferably an antibody-drug conjugate (ADC) in which the compound of the present invention is conjugated to an antibody, which is the target-binding substance. The term "target-binding substance" refers to a substance that has the property of selectively binding to or associating with a specific target substance, such as a tumor cell antigen. Furthermore, "selectively" binding or associating means that the target-binding substance preferentially associates with or binds to a desired target over other targets. The target-binding substance possessing these properties enables the targeted drug conjugate of the present invention to deliver a drug obtained from the structural moiety M described above to a target cell or its interior.

[0099] The number of the structural moieties M in one molecule of the targeted drug conjugate of the present invention is at least two or more when one or more molecules of the compound of the present invention are bound to one molecule of the target-binding substance. In the targeted drug conjugate of the present invention, the number of the structural moieties M linked to one molecule of the target-binding substance can be increased by binding two or more molecules of the compound of the present invention to one molecule of the target-binding substance. In this case, the number of the structural moieties M in one molecule of the targeted drug conjugate of the present invention (corresponding to the number of the structural moieties M per molecule of the target-binding substance in the targeted drug conjugate of the present invention) is four or more, preferably six or more, and more preferably eight or more. That is, the number of the structural moieties M in one molecule of the targeted drug conjugate of the present invention is 4 to 20, preferably six to 20, more preferably eight to 20, even more preferably 10 to 20, and particularly preferably 12 to 20. Furthermore, the number of groups selected from the aforementioned hydrophilic group Pi in one molecule of the targeted drug complex of the present invention is preferably 2 to 30, more preferably 6 to 30, and even more preferably 8 to 20.

[0100] Preferred examples of the target-binding substance include proteins (including peptides), amino acids, nucleic acids, nucleotides, enzymes, sugar chains, lipids, antibodies, antibody fragments, antigens, cell surface receptor antagonists, and cell surface receptor agonists. Preferred examples of lipids include phospholipids, fatty acids, and sterols, with phospholipids being more preferred. Of these, antibodies are preferred as the target-binding substance. More specific examples of the target-binding substance include those described in paragraphs

[0079] to

[0084] of JP-A No. 2022-526651, including antibodies, antibody fragments, cell surface receptor antagonists, cell surface receptor agonists, and targeting moieties of proteins, etc.

[0101] In the targeted drug conjugate of the present invention, anticancer drugs, anti-infective drugs, neuroprotective drugs, antihyperlipidemic drugs, nucleic acid drugs, etc. can be used as drugs, and targets to which the target-binding substance in the targeted drug conjugate of the present invention using these drugs binds include tumors, infected cells, nerve cells, immune cells, lipids, etc. Examples of substances targeted by the targeted drug conjugate of the present invention include cell surface receptors such as tumor cell antigens, and more specific examples include the description of antigens in paragraph

[0104] of JP-A No. 2022-526651.

[0102] Specific examples of the bond formed by interaction between the compound of the present invention and the target-binding substance include the following: i) a non-covalent bond (e.g., hydrogen bond, ionic bond including chelate formation) or covalent bond between a peptide in the compound of the present invention and a peptide in the target-binding substance, ii) van der Waals forces between a long-chain alkyl group in the compound of the present invention and a lipid bilayer membrane, lipids, etc. in the target-binding substance, iii) an amide bond formed by a reaction between an NHS ester (N-hydroxysuccinimide ester) in the compound of the present invention and an amino group in the target-binding substance, iv) a thioether bond formed by a reaction between a maleimide structure in the compound of the present invention and a sulfanyl group (—SH) in the target-binding substance, and v) formation of a triazole ring by a Click reaction between an azide group in the compound of the present invention and an acetylene group in the target-binding substance, or a Click reaction between an acetylene group in the compound of the present invention and an azide group in the target-binding substance. However, in the above embodiment i), the peptide in the compound of the present invention is not particularly limited as long as it is a peptide that can form a non-covalent or covalent bond with the peptide in the target-binding substance. Examples of the position having such a peptide include, for example, R ６ or R ７In addition to the above forms i) to v), binding can also be carried out in the form described in, for example, Lucas C. D. de Rezende and Flavio da Silva Emery, "A Review of the Synthetic Strategies for the Development of BODIPY Dyes for Conjugation with Proteins," Orbital: The Electronic Journal of Chemistry, 2013, Vol. 5, No. 1, pp. 62-83. Furthermore, in preparing the targeted drug conjugate of the present invention, the methods described in the same document can also be appropriately referenced.

[0103] <Medicine Comprising Targeted Drug Conjugate> In a pharmaceutical comprising the targeted drug conjugate of the present invention, the form of the targeted drug conjugate of the present invention can be appropriately selected depending on the intended use, etc., without particular limitation, and can be in the form of a solution dissolved in an aqueous medium such as physiological saline or phosphate buffer, or in the form of a solid such as a fine particle powder or a freeze-dried powder. For example, when the targeted drug conjugate of the present invention is used as an ADC pharmaceutical, it can also be used as a pharmaceutical comprising the targeted drug conjugate in any of the above forms.

[0104] [Medical Uses] The targeted drug conjugate of the present invention can be used for pharmaceutical purposes. In this case, the present invention also provides a pharmaceutical comprising the targeted drug conjugate, as well as a suitable targeted drug conjugate. The pharmaceutical may contain other additives. The present invention further provides: (A) use of the targeted drug conjugate for the manufacture of a pharmaceutical; (B) the targeted drug conjugate for use in treating a subject; (C) a treatment method comprising administering an effective dose of the targeted drug conjugate to a subject; and (D) a method of administering a pharmaceutical to a subject, wherein the pharmaceutical comprises the targeted drug conjugate. According to the treatment methods, by using the targeted drug conjugate or pharmaceutical of the present invention, a larger amount of drug can be retained while suppressing aggregation, and the subject can be treated while exhibiting excellent stability in the blood.

[0105] Here, "subject" refers to a mammal such as a human, mouse, monkey, or livestock animal in need of prevention or treatment, preferably a human in need of prevention or treatment. "Treatment" refers to the prevention or treatment of various diseases. "Prevention" refers to inhibition of onset, reduction of the risk of onset, or delay of onset. "Treatment" refers to improvement or suppression (maintenance or delay) of the progression of the target disease or condition. A "targeted drug conjugate" and a "targeted drug conjugate contained in a pharmaceutical" are preferably targeted drug conjugates in which two or more molecules of the compound of the present invention are bound to one molecule of a target-binding substance, and more preferably antibody-drug conjugates (ADCs) in which the "target-binding substance" is an antibody. The above descriptions of the target-binding substance, antibody, targeted drug conjugate, and antibody-drug conjugate (ADC) can be applied to the target-binding substance, antibody, targeted drug conjugate, and antibody-drug conjugate (ADC), respectively. The above "disease" refers to a disease suffered by the substance targeted by the targeted drug conjugate of the present invention, and the pharmaceutical of the present invention is used to treat this disease. Examples of diseases for which the medicament of the present invention is used include cancer, tumor, autoimmune disease, infectious disease, neurodegenerative disease, etc. More specific examples of cancer include those described in paragraphs

[0176] to

[0179] of JP-A No. 2022-526651.

[0106] The above-mentioned pharmaceuticals can be prepared according to conventional methods without any particular limitations. Regarding the above-mentioned methods (C) and (D), conditions such as commonly used techniques can be appropriately selected, except that the targeted drug conjugate or pharmaceutical of the present invention is used.

[0107] - Substituent Group T - In the present invention, when a group is simply described as a substituent, the description of the corresponding substituent in Substituent Group T can be referenced and applied in addition to the description of each substituent at the beginning of this specification. For example, when an "alkyl group" is simply described, the description of the "alkyl group" in Substituent Group T can be referenced and applied in addition to the description of the alkyl group defined at the beginning of this specification. This also applies to substituents other than "alkyl groups." Furthermore, in the present invention, examples of substituents that a certain substituent such as an "alkyl group" may have include substituents selected from Substituent Group T below. Furthermore, when a certain substituent such as an "alkyl group" has a substituent and further has a substituent, examples of the substituent that a certain substituent such as an "alkyl group" has include substituents formed by combining two or more substituents selected from Substituent Group T below. Furthermore, in the present invention, when an alkyl group is described separately from a cyclic (cyclo)alkyl group, the term "alkyl group" is used to encompass both linear and branched alkyl groups. On the other hand, when an alkyl group is not described separately from a cyclic alkyl group, or unless otherwise specified, the term "alkyl group" is used to encompass both linear and branched alkyl groups, and cycloalkyl groups. This also applies to groups (alkoxy groups, alkylthio groups, alkenyloxy groups, etc.) containing groups capable of adopting a cyclic structure (alkyl groups, alkenyl groups, alkynyl groups, etc.) and compounds containing groups capable of adopting a cyclic structure. When a group can form a cyclic skeleton, the lower limit of the number of atoms in the group forming the cyclic skeleton is 3 or more, preferably 4 or more, and more preferably 5 or more, regardless of the lower limit of the number of atoms specifically described below for groups capable of adopting this structure. In the description of the substituent group T below, for example, groups having a linear or branched structure and groups having a cyclic structure are sometimes described separately, such as alkyl groups and cycloalkyl groups, in order to clarify these.

[0108] Groups contained in the substituent group T include the following groups: an alkyl group (preferably having 1 to 20 carbon atoms, more preferably having 1 to 12 carbon atoms, even more preferably having 1 to 8 carbon atoms, still more preferably having 1 to 6 carbon atoms, and particularly preferably having 1 to 3 carbon atoms), an alkenyl group (preferably having 2 to 20 carbon atoms, more preferably having 2 to 12 carbon atoms, even more preferably having 2 to 6 carbon atoms, and even more preferably having 2 to 4 carbon atoms), an alkynyl group (preferably having 2 to 20 carbon atoms, more preferably having 2 to 12 carbon atoms, even more preferably having 2 to 6 carbon atoms, and even more preferably having 2 to 4 carbon atoms), a cycloalkyl group (preferably having 3 to 20 ... Alkenyl groups (preferably having 4 to 20 carbon atoms), aryl groups (which may be monocyclic groups or fused ring groups (preferably having 2 to 6 fused ring groups). In the case of a fused ring group, it is preferably a 6- or 8-membered ring, and more preferably a 6-membered ring. The monocyclic ring is preferably a 6-membered ring. The aryl group preferably has 6 to 40 carbon atoms, more preferably 6 to 30 carbon atoms, still more preferably 6 to 26 carbon atoms, and particularly preferably 6 to 10 carbon atoms), heterocyclic groups (which have at least one nitrogen atom, oxygen atom, sulfur atom, phosphorus atom, silicon atom, or the like as a ring-constituting atom) The heterocyclic group may be a group having a nitrogen atom or a selenium atom, and may be a monocyclic group or a fused ring group (preferably a fused ring group of 2 to 6 rings). The number of ring members in the ring of the monocyclic group and the ring constituting the fused ring group is preferably 5 to 7, more preferably 5 or 6. The number of carbon atoms in the heterocyclic group is preferably 2 to 40, more preferably 2 to 20. Heterocyclic groups include aromatic heterocyclic groups (heteroaryl groups) and aliphatic heterocyclic groups (aliphatic heterocyclic groups). ), alkoxy groups (preferably having 1 to 20 carbon atoms, more preferably having 1 to 12 carbon atoms, more preferably having 1 to 8 carbon atoms, even more preferably having 1 to 6 carbon atoms, particularly preferably having 1 to 3 carbon atoms), alkenyloxy group (preferably having 2 to 20 carbon atoms, more preferably having 2 to 12 carbon atoms), alkynyloxy group (preferably having 2 to 20 carbon atoms, more preferably having 2 to 12 carbon atoms), cycloalkyloxy group (preferably having 3 to 20 carbon atoms), aryloxy group (preferably having 6 to 40 carbon atoms, more preferably having 6 to 26 carbon atoms, even more preferably having 6 to 14 carbon atoms), heterocyclic oxy group (preferably having 2 to 20 carbon atoms), polyalkyleneoxy group,

[0109] Alkoxycarbonyl groups (preferably having 2 to 20 carbon atoms), cycloalkoxycarbonyl groups (preferably having 4 to 20 carbon atoms), aryloxycarbonyl groups (preferably having 6 to 20 carbon atoms), amino groups (preferably having 0 to 20 carbon atoms, more preferably having 0 to 12 carbon atoms, even more preferably having 0 to 8 carbon atoms, still more preferably having 0 to 6 carbon atoms, and particularly preferably having 0 to 3 carbon atoms), unsubstituted amino groups (-NH ２ ), as well as mono- and di-substituted amino groups substituted with a group selected from an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, and a heterocycle. Each of the above groups substituting the unsubstituted amino group has the same meaning as the corresponding group in Substituent Group T.), a sulfamoyl group (preferably having 0 to 20 carbon atoms, and an alkyl, cycloalkyl, or aryl sulfamoyl group is preferred), an acyl group (preferably having 1 to 20 carbon atoms, more preferably having 2 to 15 carbon atoms, and including —C(═O)H, an alkylcarbonyl group, a cycloalkylcarbonyl group, an arylcarbonyl group, or a heterocyclecarbonyl group), an acyloxy group (preferably having 1 to 20 carbon atoms), a carbamoyl group (preferably having 1 to 20 carbon atoms, and an alkyl, cycloalkyl, or aryl carbamoyl group is preferred),

[0110] an acylamino group (preferably having 1 to 20 carbon atoms), a sulfonamido group (preferably having 0 to 20 carbon atoms, and an alkyl, cycloalkyl, or aryl sulfonamido group is preferred), an alkylthio group (preferably having 1 to 20 carbon atoms, more preferably having 1 to 12 carbon atoms), a cycloalkylthio group (preferably having 3 to 20 carbon atoms), an arylthio group (preferably having 6 to 40 carbon atoms, more preferably having 6 to 26 carbon atoms, and even more preferably having 6 to 14 carbon atoms), a heterocyclic thio group (preferably having 2 to 20 carbon atoms), an alkyl, cycloalkyl, or arylsulfonyl group (preferably having 1 to 20 carbon atoms),

[0111] Silyl group (preferably a silyl group having 1 to 30 carbon atoms, more preferably a silyl group having 1 to 20 carbon atoms and substituted with alkyl, aryl, alkoxy or aryloxy), silyloxy group (preferably a silyloxy group having 1 to 20 carbon atoms and substituted with alkyl, aryl, alkoxy or aryloxy), hydroxy group, cyano group, nitro group, halogen atom (for example, fluorine atom, chlorine atom, bromine atom or iodine atom), oxygen atom (specifically, a >CH ２ is replaced with >C=O), anionic groups (carboxy groups (-CO ２ H), phosphono group [—PO(OH) ２ ], a phosphonooxy group [—O—PO(OH) ２ ], sulfo group (—SO ３ H)), boric acid group [—B(OH) ２ ], cationic groups (also called "onio groups"; including ammonio groups including cyclic ammonio groups, sulfonio groups, and phosphonio groups, preferably having 0 to 30 carbon atoms, more preferably having 1 to 20 carbon atoms), sulfanyl groups (—SH), guanidino groups (—NHC(═NH)NH ２ ), betaine residue, polyol residue, sugar residue, or polyamino acid residue. The preferred ranges of the anionic group, cationic group, betaine residue, polyol residue, sugar residue, polyamino acid residue, and polyalkyleneoxy group are as described above.

[0112] Examples of the group formed by combining a plurality of substituents selected from the substituent group T include an anionic group, a cationic group, a betaine residue, a polyol residue, a sugar residue, a polyamino acid residue, -(O-L) ｇ R Ｅ and -(L-O) ｇ R Ｅ

[0049] Examples of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkyloxy group, aryloxy group, heterocyclic oxy group, alkoxycarbonyl group, cycloalkoxycarbonyl group, aryloxycarbonyl group, amino group, sulfamoyl group, acyl group, acyloxy group, carbamoyl group, acylamino group, sulfonamide group, alkylthio group, cycloalkylthio group, arylthio group, heterocyclic thio group, alkyl, cycloalkyl or arylsulfonyl group, each of which has as a substituent at least one selected from the group consisting of

[0113] The substituent selected from the substituent group T is more preferably an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, a heterocyclic group, an alkoxy group, a cycloalkoxy group, an aryloxy group, an acyl group, an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an amino group, an acylamino group, a carbamoyl group, a cyano group, a halogen atom, an anionic group, a cationic group, a betaine residue, a polyol residue, a sugar residue, a polyamino acid residue, -(O-L) ｇ R Ｅ or -(L-O) ｇ R Ｅ and more preferably an alkyl group, an alkenyl group, an aryl group, a heterocyclic group, an alkoxy group, an acyl group, an alkoxycarbonyl group, an amino group, an acylamino group, a carbamoyl group, a cyano group, an anionic group, a cationic group, a betaine residue, a polyol residue, a sugar residue, a polyamino acid residue, -(O-L) ｇ R Ｅ or -(L-O) ｇ R Ｅ is.

[0114] The substituents selected from the substituent group T include not only groups formed by combining a plurality of substituents selected from the above-mentioned substituent group T, but also groups formed by combining a plurality of the above groups, unless otherwise specified. For example, when a compound or a substituent contains an alkyl group, an alkenyl group, or the like, it may be substituted or unsubstituted. Furthermore, when it contains an aryl group, a heterocyclic group, or the like, it may be a monocyclic or fused ring, and may be substituted or unsubstituted.

[0115] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Note that room temperature means 25°C.

[0116] The synthesis methods for each compound are explained in detail below, but the starting materials, intermediates and synthesis routes are not limited to these.

[0117] The abbreviations used in the synthesis of each compound shown below are as follows: SPPS: solid phase peptide synthesis, DBU: 1,8-diazabicyclo[5.4.0]-7-undecene, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, NAC: N-acetylcysteine, PBS: phosphate-buffered saline, NMP: N-methyl-2-pyrrolidone, DMSO: dimethyl sulfoxide, DIPEA: N,N-diisopropylethylamine, DODT: 3,6-dioxa-1,8-octanedithiol, TFA: trifluoroacetic acid, TIPS: triisopropylsilane, Me: methyl group, Fmoc: 9-fluorenylmethyloxycarbonyl group, Pro: proline

[0118] Additionally, % v / v means percent by volume, and % w / v means percent by mass by volume.

[0119] Unless otherwise specified, the carrier used in reverse-phase column chromatography was SNAP Ultra C18 (trade name, manufactured by Biotage) or Sfar C18 (trade name, manufactured by Biotage), and the carrier used in normal-phase column chromatography was Hi-Flash Column (trade name, manufactured by Yamazen). The mixing ratio of the eluents used in reverse-phase column chromatography or normal-phase column chromatography is a volume ratio. For example, "acetonitrile:water = 0:100 to 20:80" means that the eluent "acetonitrile:water = 0:100" was changed to the eluent "acetonitrile:water = 20:80".

[0120] Purification by liquid chromatography was carried out under the following conditions: Column: Waters XSelect CSH Prep C18 Column, particle size 5 μm, OBD preparative column (inner diameter 19 mm × length 250 mm) Column temperature: 40°C Flow rate: 20 mL / min Detection wavelength: 220 nm, 254 nm Solvent: Solution A: 0.1% formic acid - water Solution B: 0.1% formic acid - acetonitrile

[0121] Mass spectra (MS) were measured using an ACQUITY SQD LC / MS System (Waters Corporation, ionization method: ESI (ElectroSpray Ionization)). Retention times (RT) were measured using an ACQUITY SQD LC / MS System (Waters Corporation) and are shown in minutes (min). Column: Waters ACQUITY UPLC BEH C18 (particle size 1.7 μm, inner diameter 2.1 mm × length 30 mm) Solvent: Solution A: 0.1% formic acid - water Solution B: 0.1% formic acid - acetonitrile Gradient cycle: 0.00 min (Solution A / Solution B = 95 / 5), 2.00 min (Solution A / Solution B = 5 / 95), 3.00 min (Solution A / Solution B = 95 / 5) Flow rate: 0.5 mL / min Column temperature: Room temperature Detection wavelength: 254 nm

[0122] (Synthesis of Compound (1): (2S,4S)-1-((9H-fluoren-9-ylmethoxy)carbonyl)-4-(3,5-bis(3-sulfopropoxy)benzamido)pyrrolidine-2-carboxylic acid)

[0123] Compound (9-8) (i.e., ((5-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-1,3-phenylene)bis(oxy))bis(propane-1-sulfonic acid) (English name: ((5-(((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-1,3-phenylene)bis(oxy))bis(propane-1-sulfonic acid) ... 2.00 g of (2S,4S)-4-amino-1-{[(9H-fluoren-9-yl)methoxy]carbonyl}pyrrolidine-2-carboxylic acid (English name: (2S,4S)-4-amino-1-{[(9H-fluoren-9-yl)methoxy]carbonyl}pyrrolidine-2-carboxylic acid) (Enamine) were added to a reaction mixture, and the mixture was stirred at 50°C for 3 hours. After completion of the reaction, the mixture was purified by reverse phase column chromatography and lyophilized to obtain 1.25 g of compound (1).

[0124] (Synthesis of compound (2): (2S,4S)-1-((9H-fluoren-9-ylmethoxy)carbonyl)-4-(4-(tert-butoxy)-4-oxobutanamido)pyrrolidine-2-carboxylic acid)

[0125] In a 50 mL recovery flask, 1.00 g of 1-(9H-fluoren-9-ylmethyl)-2-methyl-(2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate hydrochloride, synthesized based on <Preparation 5, Step 1> described in WO 2018 / 020358, dichloromethane 15 mL, 562 mg of mono-tert-butyl succinate (Tokyo Chemical Industry Co., Ltd.), N,N-diisopropylethylamine (Tokyo Chemical Industry Co., Ltd.) 546 μL, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (Dojindo Chemical Industries Co., Ltd.) 600 mg was placed and stirred at room temperature for 18 hours. After completion of the reaction, water and chloroform were added, and the organic layer was separated. The organic layer was dried over sodium sulfate, filtered, and then the solvent was evaporated under vacuum to obtain 1.26 g of 1-((9H-fluoren-9-yl)methyl)-2-methyl-(2S,4S)-4-(4-(tert-butoxy)-4-oxobutanamido)pyrrolidine-1,2-dicarboxylate (English name: 1-((9H-fluoren-9-yl)methyl)-2-methyl-(2S,4S)-4-(4-(tert-butoxy)-4-oxobutanamido)pyrrolidine-1,2-dicarboxylate) (hereinafter referred to as "Compound A"). Next, 1.26 g of Compound A was dissolved in 15 mL of methanol, and the solution was immersed in an ice bath. 7.2 mL of 1 M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 7.2 mL of 1 M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under vacuum. The residue was purified by silica gel chromatography (chloroform:methanol = 10:1) to obtain 924 mg of compound (2).

[0126] (Solid Phase Synthesis: Synthesis of Pro Linker)

[0127] Solid-phase peptide synthesis was performed using an automated peptide synthesizer (Biotage, trade name: Syro I). The synthesis of the peptide chain was performed in accordance with the general method of the solid-phase peptide method described in WO 2018 / 174078. The synthesis apparatus was loaded with a solid-phase synthesis resin (H-Rink Amide ChemMatrix resin (trade name, manufactured by Sigma-Aldrich)), an N-methyl-2-pyrrolidone (NMP) solution of Fmoc amino acids (0.5 M), an NMP solution of cyano-hydroxyimino-acetic acid ethyl ester (1 M) and N,N-diisopropylethylamine (0.1 M), an NMP solution of diisopropylcarbodiimide (1 M), an NMP solution of piperidine (20% v / v), and an NMP solution of acetic anhydride (20% v / v), and synthesis was performed according to the manual. The peptide chain was elongated by repeating one cycle consisting of Fmoc deprotection (20 minutes), washing with NMP, Fmoc amino acid condensation (1 hour), and washing with NMP. After peptide chain elongation, the Fmoc group was deprotected, and 6-maleimidohexanoic acid was condensed in the same manner as for amino acids. Next, to cleave the linear peptide from the resin, a solution of trifluoroacetic acid: 3,6-dioxa-1,8-octanedithiol: triisopropylsilane: water = 92.5:2.5:2.5:2.5 equivalent to a 5-fold increase in the resin volume was added to the resin and shaken at room temperature for 2 hours. The reaction solution was collected by filtration. The reaction was further repeated once using a solution of trifluoroacetic acid: 3,6-dioxa-1,8-octanedithiol: triisopropylsilane: water = 92.5:2.5:2.5:2.5, and the reaction solution was collected by filtration. All the collected reaction solutions were combined, the solvent was evaporated under reduced pressure, and the mixture was thoroughly dried to obtain a crude linear peptide. The crude product was purified by liquid chromatography. The target fractions were collected, and the solvent was evaporated under vacuum to obtain the target Pro linker as a lyophilized powder, as shown in the scheme above. m / z (z = 2): [M (target Pro linker) + 2H ＋ ] ２＋ / 2 = 1833

[0128] The Fmoc-amino acids used were obtained from Watanabe Chemical Industry Co., Ltd. N-methyl-2-pyrrolidone, N,N-diisopropylethylamine, diisopropylcarbodiimide, piperidine, and acetic anhydride were obtained from Fujifilm Wako Pure Chemical Industries, Ltd. Cyano-hydroxyimino-acetic acid ethyl ester and 6-maleimidohexanoic acid were obtained from Tokyo Chemical Industry Co., Ltd.

[0129] (Payload-Degradable Linker Synthesis)

[0130] In a 10 mL recovery flask, 267 mg of monomethyl auristatin E (MMAE, Selleck Biotech) and 300 mg of Fmoc-Val-Cit-PAB-PNP (Tokyo Chemical Industry Co., Ltd., a dipeptide linker suitable for ADC) were dissolved in 3 mL of dimethylformamide and stirred at room temperature for 18 hours. Next, the reaction solution was poured into 50 mL of water to obtain a precipitate. The precipitate was collected by filtration, washed with water, and air-dried overnight at room temperature to obtain a white solid. Next, the obtained white solid was dissolved in 3 mL of dimethylformamide, and 59 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added and stirred at room temperature for 1 hour. The reaction solution was purified by liquid chromatography. The target fractions were collected, the solvent was removed under vacuum, and the desired payload-degradable linker described in the above scheme was obtained as a lyophilized powder. m / z (z=1): [M (target payload-degradable linker) + H ＋ ] ＋ =1124

[0131] (Synthesis of Drug Linkers)

[0132] 100 mg of the Pro linker synthesized above and 92 mg of the payload-degradable linker were placed in a 10 mL recovery flask and dissolved in 1 mL of dimethylformamide. 17 g (3.3 equivalents) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (Dojindo Laboratories) was added and stirred at room temperature for 18 hours. The solution after the reaction was purified by liquid chromatography. The target fractions were collected and the solvent was removed by vacuum distillation to obtain the target drug linker described in the above scheme as a lyophilized powder. m / z (z = 4): [M (target drug linker) + 4H ＋ ] ４＋ / 4 = 1746

[0133] (Synthesis of ADC) An antibody-drug conjugate (ADC) was synthesized as follows, with reference to the synthesis of antibody-drug conjugates described in WO 2015 / 115091. (1) Reduction of Antibody A 1.5 mL polypropylene tube was charged with 10 mg of a PBS solution of trastuzumab (molecular weight approximately 148,000) (concentration 20 mg / mL, manufactured by Biosynth, a PBS solution of an antibody that specifically binds to the "HER2 protein" present on the surface of cancer cells) and diluted with 0.5 mL of D-PBS (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (concentration 10 mg / mL). 11 μL (1.65 equivalents per antibody molecule) of tris(2-carboxyethyl)phosphine hydrochloride (TCEP, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) adjusted to a concentration of 10 mM was added thereto, and the pH of the prepared aqueous solution was confirmed to be within 7.4±0.1. Next, the disulfide bonds within the antibody were reduced by incubating at 37°C for 1 hour. (2) Synthesis of antibody-drug conjugate linker conjugate: The polypropylene tube containing the above solution was immersed in a 25°C water bath and left to stand for 10 minutes, after which 20 μL (3 equivalents per antibody molecule) of 10 mM drug linker dissolved in DMSO was added, and the tube was incubated for 4 hours while immersed in the 25°C water bath to bind the drug linker to the antibody. Next, 81 μL (12 equivalents per antibody molecule) of an aqueous solution of N-acetylcysteine ​​(NAC, Fujifilm Wako Pure Chemical Industries, Ltd.) adjusted to a concentration of 10 mM was added, and the mixture was further incubated at 25°C for 20 minutes to terminate the drug linker reaction, yielding a reaction solution of antibody-drug conjugate. (3) Purification: This was performed with reference to the description regarding the purification of antibody-drug conjugates in paragraph

[0110] of WO 2015 / 115091. 1.5 mL of the antibody-drug conjugate reaction solution was loaded onto a NAP-25 column (Cat. No. 17-0852-02, GE Healthcare Japan) using Sephadex G-25 carrier equilibrated with D-PBS (Fujifilm Wako Pure Chemical Industries, Ltd.), and elution was carried out according to the procedure attached to the NAP-25 to recover the target fraction. This fraction was purified by repeating the NAP-25 purification process three times to obtain the target antibody-drug conjugate (ADC).The target antibody-drug conjugate (ADC) obtained as described above mainly has a structure in which six highly hydrophobic drugs (payload, MMAE, manufactured by Selleck Biotech) are bound to one highly hydrophilic antibody molecule. Furthermore, a solution of this antibody-drug conjugate (ADC) at a concentration of 0.5% by mass in D-PBS (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) existed as a homogeneous solution without any aggregation, confirming that aggregation of the antibody-drug conjugate (ADC) was suppressed. Since the above antibody-drug conjugate (ADC) has a structure in which six drugs are bound to one antibody molecule and no aggregation occurs, it can be seen that aggregation of the antibody-drug conjugate (ADC) of the present invention can be sufficiently suppressed even when a structure in which more drugs (e.g., eight or more) are bound to one antibody molecule is used.

[0134] This application claims priority based on Japanese Patent Application No. 2023-141861, filed in Japan on August 31, 2023, the contents of which are incorporated herein by reference as part of the present specification.

Claims

1. A compound or a salt thereof comprising two or more structural moieties M selected from a biologically active substance moiety and a radioisotope-containing moiety, and a structure represented by the following general formula (I), provided that the above compound and salt do not have a phosphor moiety and have at least one group selected from the following hydrophilic group Pi. In the formula, X １ ~X ３ is -O-, -S-, >NR １ Or >CR ２ R ３ Indicates the following. １ ~R ３ and R １１ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an acyl group, -NR ８ R ９ , -OR １０ or a group selected from the following hydrophilic group Pi: ８ ~R １０ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aryl group, a heteroaryl group, or a group selected from the following hydrophilic group group Pi. n is an integer of 2 or more. * represents a bond. <Hydrophilic group group Pi> Anionic group, cationic group, betaine residue, polyol residue, sugar residue, polyamino acid residue, polyalkyleneoxy group.

2. The compound according to claim 1 or a salt thereof, which is represented by the following general formula (II): In the formula, R ４ and R ５ R represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxyl group, an alkoxy group, a sulfanyl group, an aryl group, or a heteroaryl group. ６ and R ７ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７ At least one of the groups is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. Q represents a group selected from the hydrophilic group group Pi or a substituent capable of binding to a target binding substance. １ , L ３ , L ４ , L ６ and L ７ represents a single bond or a linking group. ２ and L ５ represents a single bond or a physiologically cleavable linker. ２ When is a single bond, L １ and L ３ At least one of L is a physiologically cleavable linker, ５ When is a single bond, L ４ and L ６ At least one of the above is a physiologically cleavable linker. M represents the structural portion M. Y represents a structure represented by general formula (I). m is an integer of 1 or more.

3. The compound according to claim 2, which is represented by the following general formula (III) or a salt thereof: In the formula, Y １ ~Y ５ , Z １ ~Z ３ and W １ ~W ３ R represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an amino group, a hydroxyl group, an alkoxy group, a sulfanyl group, an aryl group, a heteroaryl group, or a group selected from the hydrophilic group Pi. ６Ａ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６Ａ is a carboxy group or a substituent capable of binding to a target binding substance, and / or R ７ is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. ４ , R ５ , R ７ , R １１ , L ２ , L ５ , X １ ~X ３ , M, Q, m and n are the same as R ４ , R ５ , R ７ , R １１ , L ２ , L ５ , X １ ~X ３ , M, Q, m and n are synonymous. ８ represents a single bond or a linking group. s, t and u each represent an integer of 0 or 1 or more. q is an integer of 0 or 1.

4. The compound according to claim 1 or a salt thereof, which is represented by the following general formula (IV): In the formula, X ４ ~X ９ is -O-, -S-, >NR １ Or >CR ２ R ３ Here, X ４ ~X ６ At least one of the following is >N-L ９ -M or >C(R ２ ) -L ９ -M and X ７ ~X ９ At least one of the following is >N-L １０ -M or >C(R ２ ) -L １０ -M. -L ９ -M and -L １０ -R not M １ ~R ３ is the above-mentioned R １ ~R ３ It is synonymous with. ９ and L １０ R represents a physiologically cleavable linker. ６ and R ７ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６ and R ７ At least one of the groups is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. Q represents a group selected from the hydrophilic group group Pi or a substituent capable of binding to a target binding substance. m is an integer of 1 or more, q is an integer of 0 or 1, and v is an integer of 0 or 1 or more. R １１ , X １ ~X ３ and M is the above-mentioned R １１ , X １ ~X ３ and M.

5. The compound according to claim 4, which is represented by the following general formula (V) or a salt thereof: In the formula, X １ａ , X １ｂ , X １ｃ , X ２ａ , X ２ｂ , X ２ｃ , X ３ａ , X ３ｂ and X ３ｃ -O-, -S-, >NR １ Or >CR ２ R ３ Indicates. １１ R represents a single bond or a linking group. ６Ａ represents a hydrogen atom, a hydroxy group, a sulfanyl group, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an alkoxy group, an amino group, an acyl group, a heteroaryl group, or Q. ６Ａ is a carboxy group or a substituent capable of binding to a target binding substance, and / or R ７ is a group containing a carboxy group or a group containing a substituent capable of binding to a target binding substance. １ ~R ３ , R ７ , R １１ , X ４ ~X ９ , L ９ , L １０ , M, Q, m and q are the same as R １ ~R ３ , R ７ , R １１ , X ４ ~X ９ , L ９ , L １０ Each of na, nb, and nc is an integer of 0 or 1 or more. r is an integer of 1 or more.

6. The compound or salt thereof according to claim 1, having 3 to 6 structural moieties M.

7. A targeted drug complex comprising the compound or salt thereof according to claim 1 bound to a target-binding substance.

8. The targeted drug conjugate of claim 7, wherein the target binding agent is an antibody.

9. The targeted drug complex described in claim 8, wherein the number of the structural portion M in one molecule of the targeted drug complex is 8 or more.

10. A pharmaceutical comprising the targeted drug complex of claim 7.

Images