SN-38 derivatives, nanoparticles containing said derivatives, medicines, and methods for producing said nanoparticles

Abstract

The problem to be solved by the present invention is to provide novel organic nano-particles and a novel compound for constituting the organic nano-particles. The present invention provides a compound represented by general formula (1) or a salt thereof. [In the formula, R1's may be the same as or different from each other and independently represent a hydrogen atom, a hydroxy group or a carbon-containing organic group; and R2's may be the same as or different from each other and independently represent an ethylene or trimethylene group which may have a substituent.]

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority based on the specification of Japanese Patent Application No. 2021-40799, filed on March 12, 2021, the entire disclosure of which is incorporated herein by reference. The present invention relates to an SN-38 derivative, a nanoparticle containing the derivative, a medicine, and a method for producing the nanoparticle. [Background technology]

[0002] In recent years, many carrier-free nanomedicines have been developed to avoid various problems caused by carriers. Several methods are known, such as the top-down method of crushing and disintegrating drug plasma and the bottom-up method of producing nanoparticles from molecules. Under these circumstances, the present inventors have developed a unique organic nanoparticle production method called the "reprecipitation method" and established a technology for producing nanoparticles with a particle size of 100 nm or less (Non-Patent Document 1, Patent Document 1). It has been revealed that the carrier-free nanomedicines obtained by these methods have high pharmacological effects.

[0003] However, there is still a demand for the development of new organic nanoparticles and new compounds for constituting the organic nanoparticles. For example, there is a strong demand for organic nanoparticles that can selectively release drugs in tumor tissues when used as antitumor agents. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent Publication No. 2019-094260 [Non-patent literature]

[0005] [Non-Patent Document 1] Jpn. J. Appl. Phys. 1992, 31, L1132-L1134 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide new organic nanoparticles and new compounds for constituting the organic nanoparticles. In a typical embodiment, an object of the present invention is to provide organic nanoparticles capable of selectively releasing a drug in tumor tissue. [Means for solving the problem]

[0007] Under these circumstances, the present inventors focused on glutathione (GSH), a compound present in high concentrations in cancer cells, which acts as an electron donor and reduces disulfide bonds to cysteine, and attempted to dimerize antitumor compounds through SS bonds. More specifically, first, from among a wide variety of compounds, we selected SN-38, represented by the following formula:

[0008] [ka]

[0009] The following compound was selected. The compound was then synthesized by linking the primary hydroxyl groups of SN-38 (hydroxyl groups indicated by * in the above formula) together via an S-S bond, and its performance was evaluated. However, it was found that rapid hydrolysis in the blood caused the drug to be released before it reached the affected area. Therefore, the following compound was then synthesized by linking the tertiary hydroxyl groups (hydroxyl groups indicated by ** in the above formula) together via an S-S bond, based on a derivative in which the primary hydroxyl groups of SN-38 were replaced with C6 acyloxy.

[0010] [ka]

[0011] We synthesized and prepared nanoparticles, and the prepared nano-prodrug showed good dispersion stability for more than 7 days. However, when dithiothreitol and glutathione (reduced type) were added to the nano-prodrug to confirm whether drug release triggered by the SS bond could be achieved, the cleavage of the SS bond proceeded to some extent, but the cleavage reaction stopped midway. Furthermore, the production of C6 acyloxy-substituted SH-38 derivatives was not confirmed, suggesting that the group -CC(=O)-CH generated by the cleavage of the SS bond is a toxic group. 2 -CH 2 -CH 2 It is believed that the reaction of -S-SH being eliminated and ring formation to form a C6 acyloxy-substituted SH-38 derivative and dihydrothiophene-2(3H)-one did not proceed. Based on these results, the present inventors further examined a wide variety of reaction systems and conducted intensive research, and found that when SH-38 or a derivative thereof is dimerized via an SS bond, dissociation of SH-38 or a derivative thereof proceeds smoothly by using a carbonate bond (-OC(=O)-O-) instead of an ester bond as in the above compound. The present invention is based on such new findings. Therefore, the present invention provides the following: Item 1. A compound represented by the following general formula (1) or a salt thereof:

[0012] [ka]

[0013] [In the formula, R 1 R may be the same or different and represents hydrogen, a hydroxyl group, or a carbon-containing organic group. 2 are the same or different and each represents an ethylene group or a trimethylene group which may have a substituent. Item 2. The compound or a salt thereof according to item 1, wherein ClogP is 5.0 to 14.0.

[0014] Section 3.R 1 is hydrogen, hydroxyl group, -OC(=O)-LR 3 (In the formula, L represents a single bond or a linker group. R 3represents an unsaturated hydrocarbon ring group or a heterocyclic group which may have a substituent) or -OC(=O)-(Y)nR 4 (In the formula, Y represents a nitrogen atom or an oxygen atom. n represents 0 or 1. R 4 represents a C2-C10 alkyl group, a C3-C10 cycloalkyl group, a C4-C10 cycloalkyl-alkyl group, or a C4-C10 alkyl-cycloalkyl group), or a salt thereof according to item 1 or 2.

[0015] Item 4. Nanoparticles comprising the compound or a salt thereof according to any one of items 1 to 3.

[0016] Item 5. A pharmaceutical composition comprising the compound or a salt thereof according to any one of items 1 to 3, or the nanoparticles according to item 4.

[0017] Item 6. The pharmaceutical agent according to Item 5 for use in the prevention or treatment of cancer.

[0018] Item 7. A method for producing nanoparticles, comprising the step of injecting a solution of the compound or a salt thereof according to any one of items 1 to 3 into water in a water-miscible organic solvent.

[0019] Item 8. A method for preventing or treating cancer, comprising administering an effective amount of the compound or salt thereof according to any one of items 1 to 3, or the nanoparticle according to item 4 to a subject in need thereof.

[0020] Item 9. Use of the compound or a salt thereof according to any one of Items 1 to 3, or the nanoparticles according to Item 4, for the production of an agent for the prevention or treatment of cancer.

[0021] Item 10. The compound or a salt thereof according to any one of items 1 to 3, or the nanoparticle according to item 4, for use in the prevention or treatment of cancer. Effect of the Invention

[0022] According to the present invention, it is possible to provide organic nanoparticles capable of selectively releasing a drug in tumor tissue. [Brief description of the drawings]

[0023] [Figure 1] 1 shows the results of the in vitro activity test in Test Example 1. [Diagram 2] 1 shows an SEM photograph of nanoparticles of compound B in Example 1. [Diagram 3] The results of selection of compounds used in carrying out Test Example 2 are shown below. [Figure 4] 1 shows SEM photographs of nanoparticles of SNC4DC in Example 9 and the results of changes in particle size over time. [Diagram 5] 1 shows the results of an in vivo antitumor activity test in Test Example 2. [Figure 6] The changes in body weight over time in each test group in Test Example 2 are shown in FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Compound or its salt The present invention provides a compound represented by the following general formula (1) or a salt thereof:

[0025] [ka]

[0026] [In the formula, R 1 R may be the same or different and represents hydrogen, a hydroxyl group, or a carbon-containing substituent. 2 are the same or different and each represents an ethylene group or a trimethylene group which may have a substituent. In the present invention, examples of the carbon-containing organic group include organic groups having 1 to 20, preferably 2 to 17 carbon atoms. The carbon-containing organic group may have at least one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. More specifically, examples of the carbon-containing organic group include an alkyl group, an alkoxy group, -OC(=O)-LR 3 (In the formula, L represents a single bond or a linker group. R 3 represents an unsaturated hydrocarbon ring group or a heterocyclic group which may have a substituent), -OC(=O)-(Y)nR 4(In the formula, Y represents a nitrogen atom or an oxygen atom. n represents 0 or 1. R 4 represents an alkyl group having from C2 to C10, a cycloalkyl group having from C3 to C10, a cycloalkyl-alkyl group having from C4 to C10, or an alkyl-cycloalkyl group having from C4 to C10. 3 Examples of the carbon-containing organic group represented by the formula include a 5-(1,2-dithiolane-3-yl)pentanoyloxy group. 4 Examples of the carbon-containing organic group represented by the formula (I) include an acyloxy group, a cycloalkylcarbonyloxy group, a cycloalkylalkylcarbonyloxy group, an alkylcycloalkylcarbonyloxy group, an alkylcarbamoyloxy group, and an alkoxycarbonyloxy group.

[0027] In the present invention, the term "alkyl group" refers to a linear or branched saturated hydrocarbon group, and examples thereof include C1-C10 alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, and n-decyl group, and preferably includes C1-C8 alkyl groups, more preferably includes C1-C6 alkyl groups, and more preferably includes C1-C3 alkyl groups.

[0028] In the present invention, the "alkoxy group" includes an alkoxy group whose alkyl portion is the above-mentioned alkyl group. More specifically, the alkoxy group includes, for example, a C1-C10 alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, an isopentyloxy group, an n-hexyloxy group, an n-heptyloxy group, an n-octyloxy group, an n-nonyloxy group, or an n-decyloxy group, and preferably includes a C1-C8 alkoxy group, more preferably includes a C1-C6 alkoxy group, and more preferably includes a C1-C3 alkoxy group. In the present invention, the acyloxy group is a straight-chain or branched branch It refers to a carbonyloxy group to which a chain-like (preferably linear) saturated hydrocarbon is bonded, and examples thereof include an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a pivaloyloxy group, a pentanoyloxy group, a hexanoyloxy group, a heptanoyloxy group, an octanoyloxy group, a nonanoyloxy group, a decanoyloxy group, an undecanoyloxy group, and a dodecanoyloxy group. In the present invention, a C2-C10 acyloxy group is preferred, a C4-C8 acyloxy group is more preferred, and a C4-C6 acyloxy group is even more preferred. In the present invention, the term "CX acyloxy group" refers to an acyloxy group having X carbon atoms, including the carbon atom constituting the carbonyl group. Thus, for example, an acetoxy group (-OC(=O)-CH 3 ) is a C2 acyloxy group, and the undecanoyloxy group (-OC(=O)-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ) is a C11 acyloxy group. In the present invention, the term "cycloalkyl group" refers to a cyclic hydrocarbon group, and examples thereof include C3-C10 alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, and cyclosyl group, preferably C3-C8 alkyl groups, more preferably C3-C6 alkyl groups, and more preferably C3-C4 alkyl groups. In the present invention, the term "cycloalkyl-alkyl group" refers to an alkyl group substituted with one cycloalkyl group. The term "cycloalkyl-alkyl group" includes cycloalkyl-alkyl groups in which the cycloalkyl moiety is the above-mentioned cycloalkyl group and the alkyl moiety is the above-mentioned alkyl group. In the present invention, a C4-C10 cycloalkyl-alkyl group is preferred, and a C4-C6 cycloalkyl-alkyl group is preferred. In the present invention, the term "C4-C10 cycloalkyl-alkyl group" refers to a cycloalkyl-alkyl group in which the total number of carbon atoms in the cycloalkyl moiety and the alkyl moiety is 4 to 10. More specifically, examples of the cycloalkyl-alkyl group include cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclononylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 6-cyclopropylhexyl, and the like, with cyclopropylmethyl and the like being preferred. In the present invention, the term "alkyl-cycloalkyl group" refers to a cycloalkyl group substituted with one alkyl group. The term "alkyl-cycloalkyl group" includes an alkyl-cycloalkyl group in which the alkyl portion is the above-mentioned alkyl group and the cycloalkyl portion is the above-mentioned cycloalkyl group. In the present invention, a C4-C10 alkyl-cycloalkyl group is preferred, and a C4-C6 alkyl-cycloalkyl group is preferred. In the present invention, the term "C4-C10 alkyl-cycloalkyl group" refers to an alkyl-cycloalkyl group in which the total number of carbon atoms in the alkyl portion and the cycloalkyl portion is 4 to 10. More specifically, examples of the alkyl-cycloalkyl group include 1-methylcyclopropyl, 2-methylcyclopropyl, 1-methylcyclobutyl, 2-methylcyclohexyl, 4-methylcyclohexyl, 5-methylcyclononyl, 2-ethylcyclopropyl, 2-propylcyclopropyl, and 2-hexylcyclopropyl, with 1-methylcyclopropyl and 2-methylcyclopropyl being preferred. In the general formula (1), R 1 may be the same or different, but is preferably the same.

[0029] In the general formula (1), R 2 The ethylene group or trimethylene group represented by the formula (I) may be unsubstituted or substituted. 2 When the ethylene group or trimethylene group represented by the formula (I) has a substituent, the substituent is not particularly limited, but examples thereof include an alkyl group (e.g., a C1-C10 alkyl group) and the like. 2 When the ethylene group or trimethylene group represented by the formula (I) has a substituent, the number of the substituents is not limited. For example, one R 2 It is preferred that each R has one or two substituents. 2 When there are two substituents per carbon atom, it is preferred that the two substituents are bonded to one carbon atom of the methylene group constituting the ethylene group or trimethylene group.

[0030] In the present invention, examples of the linker group include -OC(=O)-L 1 -L 2 -, -OC(=S)-L 1 -L 2 -, -OC(=O)-OL 1 -L 2 -, -OC(=O)-NH-L 1 -L 2 -, -OC(=S)-NH-L 1 -L 2 -(In the formula, L 1 represents a single bond or a divalent linear C1-6 (preferably C3-5) saturated hydrocarbon group. 2 In the above notation, the left bond of these linker groups is bonded to -OC(=O)- and the right bond is bonded to R 3 For example, the linker group is the group -OC(=O)-L 1 -L 2 In the case of -, the group -OC(=O)-L 1 -L 2 - is the bond on the oxygen side, and bonds to -OC(=O)-, and L 2 R on the side 3 Also, L 2 When -OC(=O)-, the bond on the -O- side is L 1and R 3 and combine.

[0031] In the present invention, the term "unsaturated hydrocarbon ring group" refers to a hydrocarbon ring group having at least one (preferably two or more) double bond, and includes an aryl group and a non-aromatic unsaturated hydrocarbon ring group, with a non-aromatic unsaturated hydrocarbon ring group being preferred. Examples of unsaturated hydrocarbon ring groups include those having 5 to 10 carbon atoms. The number of double bonds in the unsaturated hydrocarbon ring group is not limited, and examples include 1 to 5, preferably 2 to 4, etc.

[0032] In the present invention, the term "aryl group" refers to a monovalent group obtained by removing one hydrogen from an aromatic ring of an aromatic hydrocarbon, and examples thereof include monocyclic or bicyclic aryl groups having 6 to 10 carbon atoms, such as a naphthyl group.

[0033] In the present invention, the term "non-aromatic unsaturated hydrocarbon ring group" refers to an unsaturated hydrocarbon ring group other than an aryl group, and includes a monocyclic or bicyclic (preferably monocyclic) group having 5 to 10 carbon atoms (preferably 6 to 8 carbon atoms). The number of double bonds in the non-aromatic unsaturated hydrocarbon ring group is not limited, and may be, for example, 1 to 4, preferably 2 to 3, etc. More specifically, examples include a cyclopentenyl group, a cyclopenta-2,4-dienyl group, a cyclohexa-2,4-dienyl group, a cyclohepta-2,4,6-trienyl group, a 1H-indenyl group, a 1,2-dihydronaphthyl group, etc.

[0034] In the present invention, examples of the "heterocyclic group" include monocyclic or bicyclic (preferably monocyclic) saturated or unsaturated (preferably saturated) heterocycles having 1 to 9 carbon atoms (preferably 1 to 7, more preferably 2 to 5, and even more preferably 2 to 4) and at least one heteroatom (preferably 1 to 3, and more preferably 2) selected from the group consisting of oxygen, sulfur, and nitrogen. The heteroatom contained in the heterocycle is preferably sulfur. The heterocycle is preferably, for example, a 4- to 10-membered ring, and more preferably a 4- to 6-membered ring. More specifically, examples of the heterocycle include a dithietanyl group, a dithiolanyl group, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, a tetrazolidinyl group, a pyrrolidinyl group, a morpholinyl group, a pyridinyl group, a piperidinyl group, a dithianyl group, a furanyl group, a thiophenyl group, and a quinolinyl group.

[0035] In the present invention, the unsaturated hydrocarbon ring group and / or heterocyclic group may have a substituent. Examples of the substituent include an alkyl group, an oxo group, a hydroxy group, an alkoxy group, an amino group, an amine group, a halogen group, etc., and an alkyl group, an oxo group, etc. are preferred. In such an embodiment, when the unsaturated hydrocarbon ring group or the heterocyclic group has a plurality of substituents, the substituents may be the same or different. When the unsaturated hydrocarbon ring group and / or the heterocyclic group has a substituent, the number of the substituents is not limited, and examples thereof include at least 1, 1 to 3, 1 to 2, etc.

[0036] Of the present invention, R 1 In an embodiment where is an unsaturated hydrocarbon ring group which may have a substituent, the "unsaturated hydrocarbon ring group which may have a substituent" preferably exhibits aromaticity (electrons are delocalized as in a resonance structure). Thus, in this embodiment, preferred examples of the "unsaturated hydrocarbon ring group which may have a substituent" include aryl groups; aryl groups which have a substituent and exhibit aromaticity, etc. In addition, preferred examples of the "unsaturated hydrocarbon ring group which may have a substituent" include groups in which one or more hydrogen atoms of a non-aromatic unsaturated hydrocarbon ring group are substituted with the above-mentioned substituents and which have come to exhibit aromaticity. Preferred examples of the substituted unsaturated hydrocarbon ring group include a 5-isopropyl-7-oxocyclohepta-1,3,5-trienyl group.

[0037] In the present invention, the "amine group" refers to an amino group having one or two substituents such as an alkyl group, an aryl group, etc. When the amine group has two of the above-mentioned substituents, the two substituents may be the same or different.

[0038] In the present specification, the compound represented by the general formula (1) or a salt thereof may be simply referred to as compound (1). In a typical embodiment of the present invention, compound (1) is used as an antitumor agent, more specifically, as a prodrug of an antitumor agent. Therefore, in the present invention, it is preferable that compound (1) is inhibited from hydrolyzing in blood (release of an active ingredient from a prodrug molecule by cleavage of a carbonate moiety) and is hydrolyzed in tumor cells to generate the active ingredient SN-38 or a derivative thereof. In the present invention, from the viewpoints of hydrolysis resistance in blood, dispersion stability required for nanoparticle preparation, selective drug release in cancer cells, etc., compound (1) is preferably one having a ClogP of 5.0 to 14.0, more preferably one having a ClogP of 7.0 to 12.0. ClogP is the octanol / water partition coefficient LogP calculated from the structural formula of the target compound using the "CLogP" program of ChemDraw Professional 16.0.

[0039] The CLogP values ​​for some representative compounds of the present invention are shown in Table 1 below.

[0040] [Table 1]

[0041] In the above table, "SN-38 dimer (SS, carbonate)" refers to the compound represented by R 1 are both hydroxy groups, and R 2In the above table, "SN-38xC a "dimer (SS, carbonate)" refers to the group represented by R 1 are both acyloxy groups having a carbon number of a, and R 2 For example, SN-38xC 2 Dimer (SS, carbonate) is R 1 are both acetoxy groups, and R 2 and R 1 and R 2 are both ethylene groups.

[0042] Specific examples of compound (1) include dimers of the following groups: [ka] [ka] [ka]

[0043] In the present invention, the term "salt" refers to a pharma- ceutically acceptable salt. The salt of compound (1) includes an acid addition salt and a base salt. Specific examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate, organic acid salts such as oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate, and acidic amino acid salts such as glutamate and aspartate. Specific examples of the salt with a base include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt, or calcium salt, salts with organic bases such as pyridine salt and triethylamine salt, and salts with basic amino acids such as lysine and arginine.

[0044] Since compound (1) or a salt thereof may exist in the form of a hydrate or solvate, these hydrates and solvates are also included in the compound that is the active ingredient of the present invention. In addition, when the compound of the present invention has isomers such as geometric isomers, stereoisomers, and optical isomers, these isomers are included in the compound of the present invention unless otherwise specified.

[0045] Examples of solvents that form solvates include water, alcohols such as ethanol and propanol, organic acids such as acetic acid, esters such as ethyl acetate, ethers such as tetrahydrofuran and diethyl ether, ketones such as acetone, DMSO, and the like.

[0046] Compound (1) can be produced by various methods, for example, the method shown in the following reaction scheme. [Reaction scheme-1]

[0047] [ka]

[0048] [In the formula, R 1 as mentioned above] In reaction formula-1, first, compound 2 can be obtained by reacting compound 1 with triphosgene. The ratio of compound 1 to triphosgene is not particularly limited, but for example, 0.3 to 0.4 moles of the latter can be used per mole of the former. The reaction can be carried out in the presence of a base such as 4-dimethylaminopyridine (DMAP), triethylamine (TEA), pyridine, etc. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature, under cooling or heating. Preferably, the reaction temperature is 0 to 25°C, etc. The reaction time of the reaction is not particularly limited, but the reaction can be carried out for, for example, 5 to 1 hour.

[0049] Next, compound (1') can be obtained by reacting compound 2 with 2,2'-disulfanediylbis(ethan-1-ol). The ratio of compound 2 to 2,2'-disulfanediylbis(ethan-1-ol) is not particularly limited, but for example, the latter can be used in a range of 0.4 to 0.5 moles per mole of the former. The reaction temperature of the above reaction is not particularly limited, and the reaction is usually carried out at room temperature, under cooling or heating. Preferably, the reaction temperature is 0 to 25°C. The reaction time of the above reaction is not particularly limited, but for example, the reaction can be carried out for 60 minutes to 24 hours. [Reaction scheme-2]

[0050] [ka]

[0051] In reaction scheme 2, the compound 1 Compound (1'') can be obtained by reacting the above compound 1 with 2,2'-disulfanediylbis(propan-1-ol). The ratio of the above compound 1 and 2,2'-disulfanediylbis(propan-1-ol) is not particularly limited, but for example, the latter can be used in a range of 0.4 to 0.5 moles per mole of the former. The reaction temperature of the above reaction is not particularly limited, and the reaction is usually carried out at room temperature, or under cooling or heating. Preferably, the reaction temperature is 0 to 25°C. The reaction time of the above reaction is not particularly limited, but the reaction can be carried out for, for example, 60 minutes to 24 hours. These reactions are usually carried out in a conventional solvent which does not adversely influence the reaction, such as dichloromethane, triethylamine, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, diethyl ether diglyme, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof.

[0052] Nanoparticles The present invention provides nanoparticles containing compound (1) or a salt thereof. In the present invention, nanoparticles refer to particles having an average particle size of less than 1 μm. In a typical embodiment, the nanoparticles of the present invention are approximately spherical. In the present invention, the average particle size can be measured by a scanning electron microscope (SEM) or dynamic light scattering (DLS). The average particle size of the nanoparticles of the present invention is preferably 10 to 500 nm, more preferably 10 to 100 nm. The nanoparticles of the present invention can typically be prepared by injecting a solution of compound (1) or a salt thereof in a water-miscible organic solvent into water and dispersing it by the method described below. Therefore, in a typical embodiment, the nanoparticles of the present invention are organic nanocrystals of compound (1) or a salt thereof, and therefore are substantially composed of only compound (1) or a salt thereof. However, within the range in which the effects of the present invention can be obtained, the nanoparticles of the present invention may contain components other than compound (1) or a salt thereof (for example, additives to the water-miscible organic solvent used in the nanoparticle production method, etc.). For example, the content of compound (1) or a salt thereof in the nanoparticles of the present invention is preferably 95% by mass or more, more preferably 99% by mass or more, and even more preferably 99.9% by mass or more.

[0053] The nanoparticles of the present invention can be produced by a method including a step of injecting a water-miscible organic solvent solution of compound (1) or a salt thereof into water. In the method of the present invention, first, a water-miscible organic solvent solution of compound (1) or a salt thereof is injected into water using a syringe. The water-miscible organic solvent is not particularly limited as long as it is a good solvent for compound (1) or a salt thereof, and examples thereof include tetrahydrofuran, acetone, dioxane, acetonitrile, methanol, ethanol, propanol, N-methylpyrrolidone, dimethyl sulfoxide, etc., and from the viewpoint of solubility and safety, acetone, tetrahydrofuran, ethanol, dimethyl sulfoxide, etc. are preferred. These solvents can be used alone or in combination. The content of compound (1) or a salt thereof in the water-miscible organic solvent solution of compound (1) or a salt thereof is not particularly limited, and can be appropriately set within the range of, for example, 0.1 to 15% by mass, preferably 0.1 to 10% by mass. In addition to compound (1) or a salt thereof, polysorbate 80 (PS80), polyvinylpyrrolidone (PVP), etc. may be added to the water-miscible organic solvent solution. The amount of the water-miscible organic solvent solution of compound (1) or a salt thereof to be injected into water is not particularly limited, but for example, 0.1 to 1 ml, preferably 0.1 to 0.2 ml of the water-miscible organic solvent solution can be added to 10 ml of water. The injection time is not particularly limited, but for example, it is preferable to inject for 0.1 to 1 seconds, and more preferably to inject for 0.1 to 0.2 seconds. The temperature of the reaction system in this step is also not particularly limited, but can be appropriately set, for example, in the range of 0 to 30°C, preferably 10 to 20°C. In one embodiment of the present invention, it is preferable to stir the water-miscible organic solvent solution after injecting it into water. The stirring speed is not particularly limited, but can be appropriately set, for example, in the range of 1000 to 1500 rpm, preferably 1200 to 1500 rpm. The temperature in the stirring step is the same as that in the injection step. The stirring time is not particularly limited, and can be set appropriately within the range of, for example, 1 to 10 seconds, preferably 1 to 3 seconds. By injecting the water-miscible organic solvent solution into water and optionally stirring, compound (1) or a salt thereof is crystallized or granulated, and as a result, an aqueous dispersion of nanoparticles of compound (1) or a salt thereof can be obtained.In one embodiment of the present invention, the obtained nanoparticles can be used as a dispersion in a state where they are dispersed in water. When used as a dispersion, it is preferable to remove the water-miscible organic solvent used for dissolving the compound (1) or a salt thereof and adding it to water before use from the viewpoint of safety. The method for removing the organic solvent is not particularly limited, and a known method can be used, for example, it can be removed by distillation under reduced pressure (or normal pressure), dialysis, etc. In another embodiment of the present invention, the obtained nanoparticles can be used by isolating them as fine powder by subjecting the dispersion to a solid-liquid separation operation such as filtration. When using the above-mentioned production method, for example, the description of Patent Document 1 can be referred to, except that the compound (1) or a salt thereof is used as a raw material. The compound or a salt thereof of the present invention is preferable because a high-concentration dispersion (for example, a dispersion of 0.1 to 10 mM, preferably 1 to 10 mM) can be obtained when nanoparticles are formed as described above.

[0054] Pharmaceuticals The present invention provides a medicament comprising compound (1) or a salt thereof. The present invention also provides a medicament comprising the nanoparticles of the present invention described above.

[0055] In the present invention, compound (1) or a salt thereof may be used as a medicine by itself, or may be used as a pharmaceutical composition in combination with various pharma- ceutically acceptable carriers (e.g., isotonicity agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, solubilizing agents, thickening agents, etc.).

[0056] The medicament of the present invention can be used for the prevention or treatment of cancer. In this embodiment, the cancer to be prevented or treated is not particularly limited, but preferably includes solid tumors, specifically esophageal cancer, gastric cancer, colon cancer, large intestine cancer, rectal cancer, pancreatic cancer, liver cancer, laryngeal cancer, lung cancer, prostate cancer, bladder cancer, breast cancer, uterine cancer, or ovarian cancer. The target site is tumor cells, tissues, organs, or organs and their interiors, etc.

[0057] Examples of isotonicity agents include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol, and sorbitol; polyhydric alcohols such as glycerin, polyethylene glycol, and propylene glycol; and inorganic salts such as sodium chloride, potassium chloride, and calcium chloride.

[0058] Examples of chelating agents include edetate salts such as disodium edetate, calcium disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate; ethylenediaminetetraacetate; nitrilotriacetic acid or a salt thereof; sodium hexametaphosphate; and citric acid.

[0059] An example of the stabilizer is sodium hydrogen sulfite.

[0060] Examples of pH adjusters include acids such as hydrochloric acid, carbonic acid, acetic acid, and citric acid, as well as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as trometamol.

[0061] Examples of preservatives include sorbic acid, potassium sorbate, paraoxybenzoic acid esters such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate, chlorhexidine gluconate, quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine.

[0062] Antioxidants include, for example, sodium bisulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherols, and the like.

[0063] Examples of solubilizing agents include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol, etc. Examples of thickening agents include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol.

[0064] The pharmaceutical composition may further contain, in addition to compound (1) or a salt thereof, a compound known to have an antitumor effect, such as chemotherapeutic agents including podophyllotoxin (PPT), doxorubicin (DOX), and fluorouracil (5-FU).

[0065] In an embodiment of the pharmaceutical composition, the content of compound (1) or a salt thereof in the composition is not particularly limited and can be appropriately set based on conditions, such as, for example, 90% by mass or more, 70% by mass or more, 50% by mass or more, 30% by mass or more, 10% by mass or more, 5% by mass or more, or 1% by mass or more, calculated as the content of compound (1).

[0066] The formulation form is not particularly limited, and examples thereof include oral administration agents such as tablets, pills, capsules, powders, granules, syrups, and sublingual agents; parenteral administration agents such as injections (intravenous injections, intramuscular injections, local injections, etc.), mouthwashes, drip infusions, external preparations (ointments, creams, patches, inhalants), and suppositories. Among the above-mentioned formulation forms, preferred ones include injections (intravenous injections), drip infusions, etc. In a preferred embodiment of the present invention, compound (1) or a salt thereof is useful because it exhibits an antitumor effect even when administered by direct injection into a tumor.

[0067] The content of compound (1) of the present invention in the formulation varies depending on the administration route, age, weight, symptoms, etc. of the patient and cannot be generally specified, but it is sufficient that the daily dose of compound (1) is usually about 10 to 5000 mg, more preferably about 100 to 1000 mg. When administered once a day, this amount may be contained in one formulation, and when administered three times a day, one third of this amount may be contained in one formulation.

[0068] The pharmaceutical agent of the present invention is administered to patients such as mammals. Examples of mammals include humans, monkeys, mice, rats, rabbits, cats, dogs, pigs, cows, horses, sheep, etc. EXAMPLES

[0069] The present invention will be described in more detail and specifically below with reference to examples and comparative examples, but the examples should not be construed as limiting the scope of the present invention.

[0070] Comparative Example 1

[0071] [ka]

[0072] SN-38×C6 (106.2 mg, 0.216 mmol), 4,4'-disulfanediyldibutyric acid (27.9 mg, 0.117 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (175.1 mg, 0.913 mmol), and 4-dimethylaminopyridine (9.1 mg, 0.0745 mmol) were placed in a recovery flask equipped with a stirrer bar and dissolved in 2.2 mL of dichloromethane. After stirring overnight at room temperature, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform → chloroform / methanol = 50:1) to obtain compound A (87.1 mg, 68%) as a pale yellow solid.

[0073] 1 H-NMR (CDCl 3, 400 MHz): δ= 0.956 (6H, t, J = 7 Hz), 1.41 (7H, m), 1.77-1.88 (4H, m), 2.1 (1H, sext, J= 7.2 Hz), 2.24 (1H, sext, J = 7.2 Hz), 2.51 (2H, m), 2.63 (4H, m), 3.13 (2H, q, J = 7.7 Hz), 5.23 (2H, s), 5.37 (1H, d, J = 17 Hz), 5.7 (1H, d, J = 17 Hz), 7.12 (1H, s), 7.55 (1H, dd, 9.2, 2.4)

[0074] Example 1

[0075] [ka]

[0076] SN-38×C6 (50 mg, 0.1 mmol), triphosgene (12 mg, 0.04 mmol), and 4-dimethylaminopyridine (61 mg, 0.5 mmol) were placed in a recovery flask equipped with a stirrer bar and dissolved in 2 mL of dichloromethane. After stirring at room temperature for 15 minutes, 2,2-dithiodiethanol dissolved in 1 mL of dichloromethane was added dropwise. After stirring overnight at room temperature, the mixture was diluted with chloroform and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate=3:1→ethyl acetate) to obtain compound B (22 mg, 46%) as a pale yellow solid. In this specification, compound B may be referred to as compound SNC6DC. 1 H-NMR (CDCl 3, 400 MHz): δ= 0.956 (6H, t, J = 7 Hz), 1.38-1.44 (7H, m), 1.82 (2H, quin, J = 5.6 Hz), 2.05-2.11 (1H, m), 2.17-2.22 (1H, m), 2.66 (2H, t, J = 7.4 Hz), 2.78 (2H, t, J = 6.2 Hz),3.15 (2H, q, J = 7.7Hz), 3.88-4.00 (2H, m), 5.26-5.32 (2H, m), 5.35 (1H, d, J = 17 Hz), 5.8 (1H, d, J = 17 Hz), 7.21 (1H, s), 7.55 (1H, dd, J = 9.2, 2.4 Hz), 7.82 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 9.2 Hz).

[0077] Example 2 Method for Producing Nanoparticles of Compounds A to B of the Present Invention 100μL of a 10mM THF solution of compounds A-B was injected into 10mL of water at room temperature using a syringe and stirred at 1500rpm for 2 seconds to obtain an aqueous dispersion of nanoparticles. The final concentration of the aqueous dispersion was 0.1mM. SEM and DLS revealed that the particle size was about 100nm. Figure 2 shows an SEM of the nanoparticles of compound B obtained above.

[0078] Test Example 1 In vitro activity assay Human hepatoma cell line HePG2 or human breast cancer cell line KPL-4 were cultured in a 96-well plate at 2 × 10 4 The next day, irinotecan, SN-38 derivative (compound A (SN-38xC 6 dimer (SS, ester)), Compound B (SN-38xC 6A dispersion of dimer (SS, carbonate)) nanoparticles was added to HepG2 cell culture medium at a concentration of 0.04 to 10 μM. After 48 hours of culture, the cell viability was measured by colorimetry using Cell Counting Kit-8 (DOJINDO) and a microplate reader.

[0079] The results are shown in Figure 1. As shown in Figure 1, compound A did not exhibit good pharmacological activity, but compound B exhibited good pharmacological activity due to the drug derived from the cleavage of -SS- bond.

[0080] Example 3 Method for producing the compound SNBocDC of the present invention

[0081] [ka]

[0082] Boc-SN-38 (1476 mg, 3.00 mmol), triphosgene (356 mg, 1.20 mmol), 4-dimethylaminopyridine (1830 mg, 15.0 mmol), and 2-hydroxyethyl disulfide (193 mg, 1.25 mmol) were placed in a recovery flask equipped with a stirrer bar and dissolved in 50 mL of dichloromethane at 0 ° C. After stirring at 0 ° C for 1 hour, triphosgene (178 mg, 0.600 mmol) and 2-hydroxyethyl disulfide (193 mg, 1.25 mmol) were added. After stirring at room temperature for 2 hours, the mixture was diluted with chloroform and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue obtained by distilling off the solvent under reduced pressure was recrystallized using methanol and filtered to obtain compound SNBocDC (1269 mg, 71%) as a pale yellow solid. 1 H-NMR (CDCl 3, 400 MHz): δ= 0.949 (3H, t, J = 7.4 Hz), 1.39 (3H, t, J = 7.8 Hz), 1.60 (9H, s), 2.03-2.23 (2H, m), 2.77 (2H, t, J = 6.2 Hz), 3.15 (q, J = 7.7 Hz), 3.85-4.00 (2H, m), 5.25 (2H, d, J = 5.6 Hz), 5.34 (1H, d, J = 17.2 Hz), 5.80 (1H, d, J = 17.2 Hz), 7.20 (1H, s), 7.65 (1H, dd, J = 9.2, 2.4 Hz), 7.89 (1H, d, J = 2.4 Hz), 8.16 (1H, d, J = 9.2 Hz).

[0083] Example 4 Method for producing the compound SNCODC of the present invention

[0084] [ka]

[0085] SNBocDC (723 mg, 0.607 mmol) was placed in a recovery flask equipped with a stirrer bar and dissolved in 22 mL of dichloromethane. 2.2 mL of trifluoroacetic acid was added and stirred at room temperature for 3.5 hours, after which the solvent was distilled off under reduced pressure to obtain a residue, which was recrystallized using chloroform and filtered to obtain the compound SNC0DC (596 mg, 99%) as a pale yellow solid. 1 H-NMR (DMSO, 400 MHz): δ= 0.881 (3H, t, J =7.4 Hz), 1.26 (3H, t, J = 7.6 Hz), 2.08-2.15 (2H, m), 2.90-2.99 (2H, m), 3.04 (2H, q, J = 7.5 Hz), 5.23 (2H,s). 5.5 (2H, d, J = 3.2 Hz), 6.91 (1H, s). 7.36-7.38 (2H, m), 7.96 (1H, d, J = 10 Hz), 10.3 (1H, br).

[0086] Example 5 Method for producing the compound SNC2DC of the present invention

[0087] [ka]

[0088] SNC0DC (200 mg, 0.202 mmol), triethylamine (101 mg, 0.998 mmol), and 4-dimethylaminopyridine (5 mg, 0.0409 mmol) were placed in a recovery flask equipped with a stirrer bar and dissolved in 2.8 mL of dichloromethane at 0 ° C. 36 μL of acetyl chloride was added and stirred overnight at room temperature, after which the residue obtained by distilling off the solvent under reduced pressure was diluted with chloroform and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform → chloroform / acetone = 9:1) to obtain compound SNC2DC (80.8 mg, 37%) as a pale yellow solid. 1 H-NMR (CDCl 3 , 400 MHz): δ= 0.953 (3H, t, J = 7.4 Hz), 1.37 (3H, t, J = 7.6 Hz), 2.03-2.25 (2H, m), 2.40 (3H, s), 2.78 (2H, t, J = 6.2 Hz), 3.14 (2H, q, J = 7.7 Hz), 3.87-4.02 (2H, m), 5.25 (2H, d, J = 5.2 Hz), 5.34 (1H, d, J = 17.2 Hz), 5.78 (1H, d, J = 16.8 Hz), 7.20 (1H, s), 7.55 (1H, dd, J = 9.2, 2.8 Hz), 7.82 (1H, d, J = 2.4 Hz), 8.16 (1H, d, J = 9.2 Hz).

[0089] Example 6 Methods for producing the compounds SNC3DC, SNC4DC, SNC8DC, SNC10DC, and SNC5DC-(A), (B), (C), (D), (E), (F), (G), (H), and (I) of the present invention

[0090] [ka]

[0091] First, the manufacturing method will be described using SNC3DC as an example. SN0DC (200 mg, 0.202 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.502 mmol), and 4-dimethylaminopyridine (5 mg, 0.0409 mmol) were placed in a recovery flask equipped with a stirrer bar and dissolved in 8.0 mL of dichloromethane. Propionic acid (37 mg, 0.499 mmol) was added and stirred at room temperature for 3 hours, then diluted with chloroform and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform → chloroform / acetone = 5:1) to obtain compound SNC3DC (91.4 mg, 41%) as a pale yellow solid. 1 H-NMR (CDCl 3, 400 MHz): δ= 0.945 (3H, t, J = 7.6 Hz), (3H, t, J = 7.6 Hz), 1.39 (3H, t, J = 7.6 Hz), 2.03-2.12 (1H, m), 2.16-2.25 (1H, m), 2.69 (2H, q, J = 7.5 Hz), 2.78 (2H, t, J = 6.2 Hz), 3.14 (2H, q, J = 7.7 Hz), 3.87-4.02 (2H, m), 5.25 (2H, d, J = 4.8 Hz), 5.33 (1H, d, J = 17.2 Hz), 5.78 (1H, d, J = 17.2 Hz), 7.20 (1H, s), 7.54 (1H, dd, J = 9.0, 2.4 Hz), 7.82 (1H, d, J = 2.4 Hz), 8.16 (1H, d, J = 8.8 Hz).

[0092] SNC4DC The title compound was obtained in a yield of 62% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (500 mg, 0.504 mmol) and butyric acid (110 mg, 1.25 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.958 (3H, t, J = 7.4 Hz), 1.10 (3H, t, J = 7.4 Hz), 1.40 (3H, t, J = 7.4 Hz), 1.81-1.90 (2H, m), 2.05-2.12 (1H, m), 2.17-2.24 (1H, m), 2.65 (2H, t, J = 7.4 Hz), 2.78 (2H, t, J = 6.2 Hz), 3.15 (2H, q, J = 7.6 Hz), 3.87-3.93 (1H, m), 3.96-4.02 (1H, m), 5.27 (2H, d, J = 4.8 Hz), 5.30 (1H, d, J = 17.2 Hz), 5.80 (1H, d, J = 17.2 Hz), 7.21 (1H, s), 7.55 (1H, dd, J = 9.2, 2.4 Hz), 7.56 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 9.2 Hz).

[0093] SNC8DC The title compound was obtained in a yield of 50% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (100 mg, 0.101 mmol) and octanoic acid (58 mg, 0.402 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.905 (3H, t, J = 6.8 Hz), 0.957 (3H, t, J = 7.4 Hz), 1.31-1.42 (11H, m), 1.77-1.83 (2H, m), 2.05-2.24 (2H, m), 2.66 (2H, t, J = 7.6 Hz), 2.78 (2H, t, J = 6.2 Hz), 3.15 (2H, q, J = 7.7 Hz), 3.88-4.00 (2H, m), 5.26 (2H, d, J = 5.2 Hz), 5.35 (1H, d, J = 17.2 Hz), 5.80 (1H, d, J = 17.2 Hz), 7.21 (1H, s), 7.55 (1H, dd, J = 9.2, 2.4 Hz), 7.82 (1H, d, J = 2.8 Hz), 8.17 (1H, d, J = 9.2 Hz).

[0094] SNC10DC The title compound was obtained in a yield of 59% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (103.2 mg, 0.104 mmol) and capric acid (52.1 mg, 0.302 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.873 (3H, t, J = 7.0 Hz), 0.944 (3H, t, J = 7.6 Hz), 1.27-1.5 (15H, m), 1.76-1.82 (2H, m), 2.03-2.09 (1H, m), 2.17-2.23 (1H, m), 2.65 (2H, t, J = 7.6 Hz), 2.76 (2H, t, J = 6.2 Hz), 3.14 (2H, q, J = 7.7 Hz), 3.85-3.90 (1H, m), 3.93-3.98 (1H, m), 5.24 (2H, d, J = 5.2 Hz), 5.33 (1H, d, J = 17.2 Hz), 5.79 (1H, d, J = 17.2 Hz), 7.19 (1H, s), 7.53 (1H, dd, J = 9.2, 2.4 Hz), 7.80 (1H, d, J = 2.4 Hz), 8.15 (1H, d, J = 9.2 Hz).

[0095] SNC5DC-(A) The title compound was obtained in the same manner as in the above-mentioned production method of SNC3DC, except that SNC0DC (200 mg, 0.202 mmol) and 1-methylcyclopropanecarboxylic acid (50 mg, 0.499 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). Yield: 65%. 1 H-NMR (CDCl 3, 400 MHz): δ= 0.941-0.960 (5H, m), 1.38 (3H, t, J = 7.7 Hz), 1.48-1.51 (5H, m), 2.02-2.24 (2H, m), 2.77 (2H, t, J = 6.2 Hz), 3.13 (2H, q, J = 7.6 Hz), 3.86-4.01 (2H, m), 5.24 (2H, d, J = 4.4 Hz), 5.33 (1H, d, J = 17.2 Hz), 5.77 (1H, d, J = 17.2 Hz), 7.19 (1H, s), 7.51 (1H, dd, J = 9.2, 2.4 Hz), 7.78 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 9.2 Hz).

[0096] SNC5DC-(B) SN0DC (200mg, 0.202mmol) and びプロピオン acid (37mg, 0.499mmol) SNC0DC (200mg, 0.202mmol) and び2-methylcyclopropane-1-carboxylic In addition to using acid (50 mg, 0.499 mmol), the manufacturing method of SNC3DC mentioned above is the same as that of the labeled compound. The yield is 71%. 1 H-NMR (CDCl 3 , 400 MHz): δ= 0.914-0.961 (4H, m), 1.23 (3H, d, J = 5.6 Hz), 1.31-1.41 (5H, m), 1.62-1.65 (1H, m), 2.04-2.23 (2H, m), 2.77 (2H, t, J = 6.2 Hz), 3.13 (2H, q, J = 7.6 Hz), 3.88-3.99 (2H, m), 5.23 (2H, d, J = 4.4 Hz), 5.33 (1H, d, J = 17.1 Hz), 5.77 (1H, d, J = 17.1 Hz), 7.19 (1H, s), 7.54 (1H, dd, J = 9.2, 2.4 Hz), 7.81 (1H, d, J = 2.4 Hz), 8.14 (1H, d, J = 9.2 Hz).

[0097] SNC5DC-(C) The title compound was obtained in a yield of 71% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (200 mg, 0.202 mmol) and (R)-2-methylbutanoic acid (51 mg, 0.499 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3 , 400 MHz): δ= 0.943 (3H, t, J = 7.4 Hz), 1.07 (3H, t, J = 7.4 Hz), 1.34-1.40 (6H, m), 1.67-1.72 (1H, m), 1.86-1.91 (1H, m), 2.06-2.21 (2H, m), 2.17-2.78 (3H, m), 3.14 (2H, q, J = 7.7 Hz), 3.86-3.96 (2H, m), 5.24 (2H, d, J = 5.2 Hz), 5.33 (1H, d, J = 17.1 Hz), 5.77 (1H, d, J = 17.1 Hz), 7.19 (1H, s), 7.52 (1H, dd, J = 9.2, 2.4 Hz), 7.79 (1H, d, J = 2.4 Hz), 8.15 (1H, d, J = 9.2 Hz).

[0098] SNC5DC-(D) The title compound was obtained in a yield of 58% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (200 mg, 0.202 mmol) and (S)-2-methylbutanoic acid (51 mg, 0.499 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.944 (3H, t, J = 7.5 Hz), 1.07 (3H, t, J = 7.4 Hz), 1.34-1.40 (6H, m), 1.67-1.72 (1H, m), 1.86-1. 93 (1H, m), 2.06-2.21 (2H, m), 2.17-2.78 (3H, m), 3.14 (2H, q, J = 7.7 Hz), 3.87-3.99 (2H, m), 5.24 (2H, d, J = 5.2 Hz), 5.33 (1H, d, J = 17.2 Hz), 5.77 (1H, d, J = 17.2 Hz), 7.19 (1H, s), 7.53 (1H, dd, J = 9.2, 2.4 Hz), 7.79 (1H, d, J = 2.4 Hz), 8.15 (1H, d, J = 9.2 Hz).

[0099] SNC5DC-(E) The title compound was obtained in a yield of 58% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (200 mg, 0.202 mmol) and pentacyclic acid (51 mg, 0.499 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.929-1.01 (6H, m), 1.38 (3H, t, J = 7.7 Hz), 1.46-1.51 (2H, m), 1.75-1.83 (2H, m), 2.06-2.21 (2H, m), 2.65 (2H, t, J = 7.4 Hz), 2.77 (2H, t, J = 6.2 Hz), 3.14 (2H, q, J = 7.7 Hz), 3.87-3.99 (2H, m), 5.24 (2H, d, J = 5.2 Hz), 5.33 (1H, d, J = 17.1 Hz), 5.78 (1H, d, J = 17.1 Hz), 7.19 (1H, s), 7.53 (1H, dd, J = 9.2, 2.4 Hz), 7.80 (1H, d, J = 2.4 Hz), 8.15 (1H, d, J = 8.8 Hz).

[0100] SNC5DC-(F) The title compound was obtained in a yield of 56% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (200 mg, 0.202 mmol) and 3-methylbutanoic acid (51 mg, 0.499 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.945 (3H, t, J = 7.5 Hz), 1.10 (6H, d, J = 6.7 Hz), 1.38 (3H, t, J = 7.7 Hz), 2.04-2.33 (3H, m), 2.53 (2H, d, J = 7.1 Hz), 2.77 (2H, t, J = 6.2 Hz), 3.13 (2H, q, J = 7.7 Hz), 3.85-4.01 (2H, m), 5.24 (2H, d, J = 5.2 Hz), 5.33 (1H, d, J = 17.2 Hz), 5.78 (1H, d, J = 17.2 Hz), 7.19 (1H, s), 7.53 (1H, dd, J = 9.2, 2.4 Hz), 7.79 (1H, d, J = 2.4 Hz), 8.15 (1H, d, J = 9.2 Hz).

[0101] SNC5DC-(G) SN0DC (200mg, 0.202mmol) and びプロピオン acid (37mg, 0.499mmol) SNC0DC (200mg, 0.202mmol) and びPivalic In addition to using acid (51 mg, 0.499 mmol), the manufacturing method of SNC3DC described above is the same as that of the labeled compound. The yield is 26%. 1 H-NMR (CDCl 3 , 400 MHz): δ= 0.960 (3H, t, J = 7.5 Hz), 1.40 (3H, t, J = 7.7 Hz), 1.44 (9H, s), 2.08-2.19 (2H, m), 2.78 (2H, t, J = 6.3 Hz), 3.16 (2H, q, J = 7.7 Hz), 3.90-4.01 (2H, m), 5.26 (2H, d, J = 5.0 Hz), 5.34 (1H, d, J = 17.2 Hz), 5.78 (1H, d, J = 17.2 Hz), 7.21 (1H, s), 7.51 (1H, dd, J = 9.2, 2.4 Hz), 7.79 (1H, d, J = 2.4 Hz), 8.17 (1H, d, J = 9.2 Hz).

[0102] SNC5DC-(H) The title compound was obtained in a yield of 48% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (200 mg, 0.202 mmol) and 2-cyclopropylacetic acid (50 mg, 0.499 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3 , 400 MHz): δ= 0.330 (2H, q, J = 5.1 Hz), 0.690 (2H, q, J = 5.1 Hz), 0.980 (3H, t, VJ = 6.8 Hz), 1.21-1.25 (1H, m), 1.40 (3H, t, J = 7.7 Hz), 2.05-2.25 (2H, m), 2.57 (2H, d, J = 7.1 Hz), 2.79 (2H, t, J = 6.2 Hz), 3.16 (2H, q, J = 7.7 Hz), 3.89-4.01 (2H, m), 5.27 (2H, d, J = 5.4 Hz), 5.35 (1H, d, J = 17.2 Hz), 5.79 (1H, d, J = 17.2 Hz), 7.21 (1H, s), 7.57 (1H, dd, J = 9.2, 2.4 Hz), 7.85 (1H, d, J = 2.4 Hz), 8.18 (1H, d, J = 9.2 Hz).

[0103] SNC5DC-(I) The title compound was obtained in a yield of 65% in the same manner as in the above-mentioned production method for SNC3DC, except that SNC0DC (200 mg, 0.202 mmol) and cyclobutanecarboxylic acid (50 mg, 0.499 mmol) were used instead of SNC0DC (200 mg, 0.202 mmol) and propionic acid (37 mg, 0.499 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.945 (3H, t, J = 7.5 Hz), 1.38 (3H, t, J = 7.7 Hz), 2.04-2.19 (4H, m), 2.37-2.52 (4H, m), 2.77 (2H, t, J = 6.2 Hz), 3.13 (2H, q, J = 7.6 Hz), 3.45-3.49 (1H, m), 3.91-3.97 (2H, m), 5.23 (2H, d, J = 4.6 Hz), 5.33 (1H, d, J = 17.2 Hz), 5.77 (1H, d, J = 17.2 Hz), 7.19 (1H, s), 7.53 (1H, dd, J = 9.2, 2.4 Hz), 7.81 (1H, d, J =2.4 Hz), 8.15 (1H, d, J = 9.2 Hz).

[0104] Example 7 Method for producing the compounds SNC3NDC and SNC4NDC of the present invention

[0105] [ka]

[0106] First, the manufacturing method will be described using SNC3NDC as an example. SN0DC (263.9 mg, 0.266 mmol), 1-isocyanatopropane (64.3 mg, 0.756 mmol), and triethylamine (127.5 mg, 1.26 mmol) were placed in a recovery flask equipped with a stirrer bar and dissolved in 5.0 mL of dichloromethane. After stirring at room temperature for 4 hours, the mixture was diluted with chloroform and washed with water, a saturated aqueous ammonium chloride solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform → chloroform / acetone = 5:1) to obtain compound SNC3NDC (92.8 mg, 30%) as a pale yellow solid. 1 H-NMR (CDCl 3, 400 MHz): δ= 0.951-1.03 (6H, m), 1.37 (3H, t, J = 7.6 Hz), 1.63-1.68 (2H, m), 2.79 (2H, t, J = 6.2 Hz), 3.11 (2H, q, J = 6.8 Hz), 3.29 (2H, q, J = 6.8 Hz), 3.94-3.97 (1H, m), 4.01-4.06 (1H, m), 5.22 (2H, d, J = 1.6 Hz), 5.32-5.37 (2H, m), 5.77 (1H, d, J = 17.2 Hz), 7.20 (1H, s), 7.56 (1H, dd, J = 9.2, 2.4 Hz), 7.84 (1H, d, J = 2.4 Hz), 8.12 (1H, d, J = 9.2 Hz).

[0107] SNC4NDC The title compound was obtained in a yield of 19% in the same manner as in the above-mentioned production method for SNC3NDC, except that SNC0DC (255.4 mg, 0.258 mmol) and 1-isocyanatobutane (75 mg, 0.757 mmol) were used instead of SNC0DC (263.9 mg, 0.266 mmol) and 1-isocyanatopropane (64.3 mg, 0.756 mmol). 1 H-NMR (CDCl 3, 400 MHz): δ= 0.934-0.990 (6H, m), 1.34-1.46 (5H, m), 1.57-1.64 (2H, m), 2.05-2.10 (1H, m), 2.17-2.24 (1H, m), 2.79 (2H, t, J = 7.0 Hz), 3.07-3.13 (2H, m), 3.29-3.34 (2H, q, J = 6.6 Hz), 3.94-4.05 (2H, m), 5.21 (2H, d, J = 1.6 Hz), 5.32-5.36 (2H, m), 5.76 (1H, d, J = 17.2 Hz), 7.20 (1H, s), 7.55 (1H, dd, J = 9.2, 2.4 Hz), 7.83 (1H, d, J = 2.4 Hz), 8.11 (1H, d, J = 9.2 Hz).

[0108] Example 8 Preparation of SNCnDC (n = 0, 2, 4, 6, 8, 10) nanoparticles 100μL of a DMSO or THF solution of the compound prepared at 10mM was injected into 10mL of water at room temperature using a syringe and stirred at 1500rpm for 2 seconds to obtain an aqueous dispersion of nanoparticles. The final concentration of the aqueous dispersion was 0.1mM. SEM and DLS revealed that the nanoparticles immediately aggregated when n=0, 2. The particle size was found to be approximately 100nm when n=4, 6, 8, 10. SEM of the nanoparticles of the compound obtained above is shown in Figure 3.

[0109] Example 9 How to prepare highly concentrated nanoparticles 750μL of a THF solution of compound SNC4DC, prepared at 46.7mM, was injected into 4.25mL of water using a syringe at room temperature to obtain an aqueous dispersion of nanoparticles. The final concentration of the aqueous dispersion was 7mM. When preparing the THF solution, the same amount of polysorbate 80 as the compound was added. After removing the THF, the solution was again measured to make 5mL, and mixed with a 9% sodium chloride aqueous solution in a ratio of 9:1 to prepare the dispersion. The photographs in the upper right of Figure 4 show the SEM images of the nanoparticles immediately after preparation of the high-concentration dispersion and two months later. The graph in the lower right of Figure 4 shows the results of the change over time in the particle size distribution of the nanoparticles.

[0110] Test Example 2 In vitro activity assay As in Test Example 1, human colon adenocarcinoma cell line HCT-116 was cultured in a 96-well plate at 2 × 10 4 The cells were seeded at 1000 cells / well. The next day, SN-38 and each SN-38 derivative nanoparticle dispersion were added to the cell culture medium at a concentration of 0.04 to 10 μM. After 48 hours of culture, the cell viability was measured by colorimetry using Cell Counting Kit-8 (DOJINDO) and a microplate reader. The results are shown in Table 2 below. [Table 2] As shown in Table 2 above, each compound of the present invention exhibited different IC50 values ​​depending on the substituent. Based on the above results, the following Test Example 3 and Test Example 4 were carried out using SNC4DC, which has the highest pharmacological activity among the nanoparticles produced in FIG.

[0111] Test Example 3 In vivo antitumor activity test Under the conditions shown in Table 3 below, 100 μL of the solution was administered every two days for a total of five times to mice (n=5) bearing human colon adenocarcinoma-derived HCT116 cells. tail The drug was administered intravenously.

[0112] [Table 3]

[0113] In the table, SNC4DC NPDs refers to the nanoparticles of SNC4DC obtained in Example 9. The size of the tumor was measured using a vernier caliper. The results of the in vivo antitumor activity test are shown in Figure 5. As shown in Figure 5, SNC4DC NPDs exhibited higher antitumor activity than Irinotecan. Figure 6 shows the change in body weight over time in each test group. As shown in Figure 6, no significant weight loss was observed due to administration of SNC4DC NPDs. Therefore, no serious toxicity was confirmed due to administration of SNC4DC NPDs.

[0114] Test Example 4 In vitro activity assay As in Test Example 1, human colon adenocarcinoma cell line HCT-116 or human mammary epithelial cell line HMEC were cultured in a 96-well plate at 2 × 10 4 The cells were seeded at 1000 cells / well. The next day, SN-38 and SN-38 derivative (SNC4DC) nanoparticle dispersions were added to the cell culture medium at 0.04-10 μM. The cells were then cultured for 48 hours, and the cell viability was measured by colorimetry using Cell Counting Kit-8 (DOJINDO) and a microplate reader. The cell viability IC50 results are shown in Table 4 below. [Table 4] As shown in Table 4, SN-38 exhibited high toxicity to normal cells, whereas SNC4DC exhibited low toxicity to normal cells.

Claims

1. A compound represented by the following general formula (1) or a salt thereof: 【Chemistry 1】 [In the formula, R 1 are the same or different and represent a hydroxy group, a C2 to C10 acyloxy group, a C3 to C10 cycloalkylcarbonyloxy group, a C4 to C10 cycloalkylalkylcarbonyloxy group, a C4 to C10 alkylcycloalkylcarbonyloxy group, a C1 to C10 alkylcarbamoyloxy group, or a C1 to C10 alkoxycarbonyloxy group. R 2 are the same or different and each represents an ethylene group or a trimethylene group which may have a substituent.

2. R 1 is a hydroxy group or a C2 to C10 acyloxy group, or a salt thereof.

3. The compound according to claim 1, which is a dimer of a group selected from the group consisting of SNC0DC, SNC2DC, SNC3DC, SNC4DC, SNC6DC, SNC8DC, SNC10DC, SNC3NDC, SNC4NDC, SNBocDC, SNC5DC-(A), SNC5DC-(B), SNC0DC-(C), SNC0DC-(D), SNC0DC-(E), SNC0DC-(F), SNC0DC-(G), SNC0DC-(H) and SNC0DC-(I), represented by the following chemical structural formula, or a salt thereof. 【Chemistry 2】

4. 4. Nanoparticles comprising 95% by mass or more of the compound or salt thereof according to claim 1, wherein the compound has a ClogP value in the range of 5.0 to 14, an average particle size of less than 1 μm, and a substantially spherical shape.

5. A medicament comprising the compound or a salt thereof according to any one of claims 1 to 3 or the nanoparticles according to claim 4.

6. The pharmaceutical composition according to claim 5 for the prevention or treatment of cancer.

7. A method for producing nanoparticles, comprising the step of injecting a solution of the compound or salt thereof according to any one of claims 1 to 3 in a water-miscible organic solvent into water.

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