WO2013094581A1 - Novel camptothecin derivative - Google Patents

Abstract

Provided is a compound in which a plurality of substructures that can be anticipated to have different anticancer activity mechanisms are included in the same molecule, the compound also exhibiting low toxicity as well as high antitumor activity. A camptothecin derivative having a platinum complex structure represented by general formula (1) or (2) (where A and B independently represent a nonexistent, substituted, or non-substituted alkylene group, alkylene carbonyl group, or non-cyclic or cyclic aminoalkylene aminocarbonyl group).

Description

New camptothecin derivatives

The present invention relates to a novel camptothecin derivative useful for the treatment of various cancers.

Camptothecin (CPT) is a compound that was isolated and structurally determined from Camptotheca cumacuminate in 1966 by Wall et al. (See Non-Patent Document 1). CPT has received a lot of attention because of its remarkable antitumor activity against mouse leukemia L1210. In the early 1970s, the National Cancer Institute conducted clinical trials using water-soluble sodium salts in which the E-ring lactone part of CPT was opened with an alkali. However, anti-tumor activity as expected was not obtained, and serious side effects such as myelosuppression and hemorrhagic cystitis occurred, and development as a therapeutic drug was abandoned (see Non-Patent Document 2, Non-Patent Document). Reference 3).

Since then, various camptothecin derivatives have been studied at research institutions around the world with the aim of improving both efficacy and safety. For example, irinotecan hydrochloride (7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxy CPT) (see Patent Document 1 and Non-Patent Document 4) and topotecan (9-dimethylaminomethyl-10) -Hydroxy CPT) has clinically useful activity. Irinotecan hydrochloride is a prodrug in which the piperidinopiperidine side chain is cleaved by an enzyme in vivo to release the active main body 7-ethyl-10-hydroxy CPT (SN-38). The mechanism of action of CPT derivatives such as CPT and SN-38 inhibits type I topoisomerase necessary for cell replication, stops DNA biosynthesis, and causes cell death (see Non-Patent Document 5).

Oxaliplatin is an organic platinum compound having a DACH (1,2-diaminocyclohexane) group (see Patent Document 2), and exhibits particularly strong activity against colorectal cancer cell lines. Oxaliplatin does not have cross-resistance to cisplatin-resistant cancer, and is therefore classified as an anticancer platinum derivative that is completely different from cisplatin and carboplatin. The mechanism of action of oxaliplatin is not well understood, but is presumed to be similar to that of cisplatin. That is, after the bond between the leaving group and platinum is cleaved by biotransformation that does not involve the enzyme, it is converted to active species by adding water and chlorine atoms to platinum (see Non-Patent Document 6). This active species reacts with DNA to form a platinum-DNA adduct, thereby inhibiting DNA replication and causing cell death (see Non-Patent Document 7).

Patent No. 1660064 Japanese Patent Application No. 07-209149

In cancer chemotherapy, in general, in order to enhance the action of anticancer drugs, multi-drug combination therapy in which several types of anticancer drugs with different effects and properties on cancer cells are administered in combination is performed. Is called. In multi-drug combination therapy, since a plurality of drugs having different effects are administered simultaneously, different therapeutic effects of each drug can be expected. However, due to the inherent toxicity of each drug, it is impossible to administer an amount exceeding its maximum tolerated dose, and the resulting antitumor effect is naturally limited. Moreover, the problem that the frequency | count of administration increases by use of a several chemical | medical agent often arises.
An object of the present invention is to provide a compound containing a plurality of partial structures that can be expected to have different anticancer action mechanisms in the same molecule and exhibiting high antitumor activity in addition to low toxicity. There is.

The inventors have studied the creation of a novel clinically useful CPT derivative having an anticancer active structure in the same molecule with different mechanisms of action in anticipation of enhancing the anticancer effect and reducing the number of administrations. As a result, the toxicity of a novel CPT derivative having a DACH platinum complex structure obtained by reacting a CPT derivative having a dicarboxyl group with a diaquo DACH platinum complex via a spacer is remarkably remarkable. The present invention was completed by finding that it can be administered in an amount lower than the amount of active substances (DACH platinum and SN-38) in the maximum tolerated dose of oxaliplatin and irinotecan hydrochloride and exhibits excellent antitumor activity. did.

The present invention has the following general formula (1) or (2):

(In the formula, A and B each independently represent a substituted or unsubstituted alkylene group, an alkylenecarbonyl group, an acyclic or cyclic aminoalkyleneaminocarbonyl group)
The camptothecin derivative which has a platinum complex structure represented by these is provided.

The present invention also provides a medicament or anticancer agent comprising the camptothecin derivative as an active ingredient.
The present invention also provides a pharmaceutical composition and an anticancer composition characterized by containing the camptothecin derivative in a form encapsulated in micelles.
The present invention also provides a method for treating cancer, which comprises administering an effective amount of the camptothecin derivative.
The present invention also provides use of the camptothecin derivative for producing a medicament.
The present invention also provides use of the camptothecin derivative for producing an anticancer agent.

The CPT derivative of the present invention has an anticancer active structure showing different mechanisms of action in the same molecule, has a significantly low toxicity, and is active in the maximum tolerated dose of oxaliplatin and irinotecan hydrochloride (DACH platinum and SN -38) It can be administered in an amount exceeding the amount and exhibits excellent antitumor activity, and is extremely promising as an anticancer agent.
In addition, since the CPT derivative of the present invention is a single compound, it can be administered with a smaller number of administrations compared to multi-drug combination therapy.

The CPT derivative of the present invention has a platinum complex structure and is represented by the general formula (1) or (2).
In the formula, A and B each independently represent a substituted or unsubstituted alkylene group, an alkylenecarbonyl group, an acyclic or cyclic aminoalkyleneaminocarbonyl group.
In the formula, A and B each independently represent a substituted or unsubstituted alkylene group, an alkylenecarbonyl group, an acyclic or a cyclic aminoalkyleneaminocarbonyl group containing a nitrogen atom. More preferred.
More specifically, a substituted or unsubstituted linear alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted linear alkylene carbonyl group having 1 to 18 carbon atoms, and 1 to 3 unsaturated bonds. Optionally having a substituted or unsubstituted linear alkylenecarbonyl group having 3 to 18 carbon atoms, 1 or more —CONR ¹ — (R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms) An interrupted alkylene carbonyl group having 2 to 18 carbon atoms, a linear aminoalkylene (2 to 4 carbon atoms) aminocarbonyl group, a cyclic diaminocarbonyl group having 2 to 6 carbon atoms and the like are preferable.

In particular, in the general formula (1) or (2), A is independently absent, a substituted or unsubstituted linear alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted carbon number of 1 to 18 linear alkylenecarbonyl groups, substituted or unsubstituted C3-C18 linear alkylenecarbonyl groups having 1 to 3 unsaturated bonds, or one or more —CONR ¹ — (R ¹ Represents a hydrogen atom or an alkylenecarbonyl group having 2 to 18 carbon atoms optionally interrupted by a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and B independently represents a non-existing or linear aminoalkylene group Those having a (C2-4) aminocarbonyl group or a cyclic diaminocarbonyl group having 2-6 carbon atoms are particularly preferred.

Various CPT derivatives represented by the general formula (1) or (2) can be produced by a condensation reaction between the spacer portion and SN-38, followed by a complexation reaction with a diaquo DACH platinum complex.
Diaqua DACH platinum complex can be prepared, for example, according to the method described in JP-A-9-40685.

The following compounds are preferred as the CPT derivative of the present invention.

Each of these CPT derivatives can be produced by the following method.

(1) Synthesis of SN38Pt-1:
Diethanolamine's amino group is converted to benzyloxycarbonyl (Cbz), then the hydroxy group is converted to mesyl (Ms), and then the dimesyl compound and di-tert-butyl malonate are reacted using NaH as the base to give 1-benzyl 4,4-di- tert-butyl piperidine-1,4,4-tricarboxylate (Cbz form) is obtained. Deprotect Cbz with 20% Pd (OH) ₂ , treat with triphosgene to lead to chlorocarbonyl, react with 7-ethyl-10-hydroxycamptothecin (SN-38), and then react with tFA with tFA. Is deprotected to give SN-38 dicarboxylic acid derivative (SN38Pt-SM1). SN38Pt-SM1 and diaquo DACH platin are reacted in ethanol and water at 40-70 ° C using NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-1.

(2) Synthesis of SN38Pt-2:
tert-Butyl piperazine-1-carboxylate is treated with triphosgene and then reacted with SN-38 to obtain 10- (4- (tert-butoxycarbonyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (Boc form). The Boc form is treated with TFA, and the Boc group is deprotected to obtain 7-ethyl-10-[(piperazin-1-yl) -carbonyloxy] camptothecin trifluoroacetate (PPC-SN38 · TFA). Reaction of PPC-SN38 ・ TFA with di-tert-butyl 1- (chlorocarbonyl) piperidine-4,4-dicarboxylate, followed by deprotection of t-Bu group with TFA, SN-38 dicarboxylic acid derivative (SN38Pt- Get SM2). SN38Pt-SM2 and diaquo DACH platin are reacted in ethanol and water at 40-70 ° C using NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-2.

(3) Synthesis of SN38Pt-3:
Di-tert-butyl piperidine-4,4-dicarboxylate is acylated with 2-bromoacetyl chloride and then reacted with PPC-SN38 · TFA to obtain a di-tert-butyl ester form. Subsequently, the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM3). SN38Pt-SM3 and diaquo DACH platin are reacted in ethanol and water at 40-70 ° C using NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-3.

(4) Synthesis of SN38Pt-4:
Di-tert-butyl piperidine-4,4-dicarboxylate and monoethyl dodecanedioate as condensing agents, O- (1H-6-chlorobenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TCTU) Reaction, followed by deprotection of the ester. The obtained carboxylic acid and PPC-SN38 · TFA are condensed using TCTU, and the t-Bu group is subsequently deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM4). SN38Pt-SM4 and diaquo DACH platin are reacted in ethanol and water at 40-70 ° C using NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-4.

(5) Synthesis of SN38Pt-5:
Di-tert-butyl piperidine-4,4-dicarboxylate and monomethyl succinate are reacted using TCTU as a condensing agent, and then the ester is deprotected. The obtained carboxylic acid and PPC-SN38 · TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM5). SN38Pt-SM5 and diaquo DACH platin are reacted in ethanol and water at 40-70 ° C using NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-5.

(6) Synthesis of SN38Pt-6:
Di-tert-butyl piperidine-4,4-dicarboxylate and monomethyl suberate are reacted with TCTU as a condensing agent, and then the ester is deprotected. The obtained carboxylic acid and PPC-SN38 · TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM6). SN38Pt-SM6 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-6.

(7) Synthesis of SN38Pt-7:
Isocyanate was prepared from Boc-β-Ala by Crutius rearrangement, reacted with SN-38, and the Boc group was further deprotected to give 10- (2-Aminoethyl) carbamoyloxy-7-ethylcamptothecin trifluoroacetate (AEC-SN38 TFA). Also, di-tert-butyl piperidine-4,4-dicarboxylate and dodecanedioic acid monoethyl ester are reacted using TCTU as a condensing agent, and then the ester is deprotected. The resulting carboxylic acid and AEC-SN38 · TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM7). SN38Pt-SM7 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-7.

(8) Synthesis of SN38Pt-8:
Only one ester of Eicosanedioic acid dimethyl ester is deprotected, and the resulting monocarboxylic acid and di-tert-butyl piperidine-4,4-dicarboxylate are reacted using TCTU as a condensing agent. The resulting ester is deprotected and condensed with PPC-SN38 · TFA and TCTU, followed by deprotection of the t-Bu group with TFA to give the SN-38 dicarboxylic acid derivative (SN38Pt-SM8). SN38Pt-SM8 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-8.

(9) Synthesis of SN38Pt-9:
Di-tert-butyl piperidine-4,4-dicarboxylate and monoethyl adipate are reacted using TCTU as a condensing agent, and then the ester is deprotected to obtain a carboxylic acid. Also, PPC-SN38 • TFA and 5- (tert-butoxycarbonylamino) valeric acid are condensed, followed by deprotection of the Boc group to give 10- [4- (5-Aminopentanoyl) piperazine-1-yl] carbonyloxy-7 -Ethylcamptothecin trifluoroacetate (APC-SN38 / TFA) is obtained. APC-SN38 · TFA and the previously synthesized carboxylic acid are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM9). SN38Pt-SM9 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-9.

(10) Synthesis of SN38Pt-10:
Monomethyl sebacate carboxylic acid sites are reduced and then oxidized to aldehydes, and unsaturated carboxylic acids are obtained by Horner-Wadsworth-Emmons reaction with (diethylphosphinoyl) acetic acid. The resulting carboxylic acid is reacted with di-tert-butyl piperidine-4,4-dicarboxylate using TCTU as a condensing agent, and then the ester is deprotected. The obtained carboxylic acid and PPC-SN38 · TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 dicarboxylic acid derivative (SN38Pt-SM10). SN38Pt-SM10 and diaquo DACH platin are reacted at 40-70 ° C using ethanol as the base and NaOH as the base. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-10.

(11) Synthesis of SN38Pt-11:
The carboxylic acid moiety of Dodecanedioic acid monoethyl ester is protected with a t-Bu group, and then the ethyl ester is deprotected. The obtained monocarboxylic acid and PPC-SN38 · TFA are condensed using TCTU, and then the t-Bu group is deprotected with TFA to obtain an SN-38 carboxylic acid derivative (SN38Pt-SM11). SN38Pt-SM11 and diaquo DACH platin are reacted at 50 ° C. using NaOH as a base under the two-phase conditions of chloroform and water. The resulting crude product is purified by reverse phase HPLC to yield SN38Pt-11.

The CPT derivative of the present invention is remarkably low in toxicity, can be administered in an amount exceeding the amount of active substances (DACH platinum and SN-38) in the maximum tolerated dose of oxaliplatin and irinotecan hydrochloride, and has antitumor activity. Since it is excellent, it is extremely useful as a pharmaceutical or anticancer agent comprising this as an active ingredient.
The dose of the CPT derivative of the present invention may be appropriately adjusted according to the administration method, patient's symptoms, etc. As the camptothecin derivative having a platinum complex structure represented by the general formula (1) or (2), It is preferable to administer 0.05 mg / kg to 0.2 g / kg, further 1.67 mg / kg to 0.2 g / kg, especially 8.33 mg / kg to 0.2 g / kg per day for an adult.

In addition, since the CPT derivative of the present invention has remarkably low toxicity, L-OHP and CPT-11 contained as active ingredients are each converted into an active substance (DACH platinum and SN-) converted from the maximum tolerated dose when administered alone. 38) Since administration exceeding the amount is possible and a dose-dependent antitumor effect is obtained, it is extremely useful as a pharmaceutical or anticancer agent comprising this as an active ingredient.
For example, the maximum tolerated dose of L-OHP (20 mg / kg) (Anticancer Drugs 1997 Oct; 8 (9): 876-85) and the maximum tolerated dose of CPT-11 (270 mg / kg) (Oncology Reports 27: 189-197, 2012) )), The amount of active substance is 16 mg / kg of DACH platinum and 156 mg / kg of SN-38. As shown in Example 12 described later, the CPT derivative (SN38Pt-4) of the present invention has almost no toxicity at 600 mg / kg, but the converted amount of the active substance at this dose is 157 mg / kg of DACH platinum. And SN-38 200 mg / kg, it is possible to administer an amount of the active substance far exceeding the maximum tolerated dose of L-OHP and CPT-11, and a dose-dependent antitumor effect is obtained.

When the CPT derivative of the present invention is used as a medicine or an anticancer agent, its dosage form is not particularly limited and can be prepared using commonly used additives.

The CPT derivative of the present invention can be produced by a condensation reaction between the spacer portion and SN-38 (anticancer agent A), followed by a complexation reaction with diaquo DACH platinum (anticancer agent B). Derivatives obtained by substituting the SN-38 and / or diaquo DACH platinum with other anticancer agents can also be suitably used. The anticancer agent A is not particularly limited, and for example, cyclophosphamide, melphalan, nimustine, ranimustine, methotrexate, pemetrexed, fluorouracil, doxyfluridine, capecitabine, cytarabine, enocytabine, gemcitabine, 6-mercaptopurine, fludarabine , Pentostatin, cladribine, hydroxyurea, doxorubicin, epirubicin, daunorubicin, idarubicin, pirarubicin, amrubicin, actinomycin D, bleomycin, pepleomycin, mitomycin C, aclarubicin, dinostatin, vincristine, vindesine, vinblastine, vinrelcerx, paclitaxel, paclitaxel, paclitaxel Irinotecan, Irinotecan active metabolite (SN-38), Nogitecan, D Examples include poside, prednisolone, dexamethasone, imatinib, gefitinib, sunitinib, sorafenib, dasatinib, tretinoin or a salt thereof, or an active metabolite thereof, and the anticancer agent B is not particularly limited. Examples thereof include platin, cisplatin, carboplatin, nedaplatin, or active metabolites thereof.
Among these, as the anticancer agent A, a plant alkaloid-based anticancer agent is preferable, and irinotecan, SN-38 or a salt thereof is particularly preferable. Moreover, as the anticancer agent B, a platinum complex anticancer agent is preferable, and oxaliplatin, cisplatin, or an active metabolite thereof is particularly preferable.

The CPT derivative of the present invention can be administered as it is, but it is mixed with a carrier such as a dispersion aid, excipient, etc., which is usually used for formulation, within a range that does not reduce the effect. , Capsules, suspensions, emulsions, syrups, elixirs, granules, pills, tablets, troches, limonades, and other oral forms or injections.
Examples of such carriers include water-soluble monosaccharides or oligosaccharides or polysaccharides such as mannitol, lactose, and dextran; for example, gel-forming or water-soluble celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose. For example, water-absorbing and poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, and derivatives thereof; for example, hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, Water-absorbing and poorly water-soluble polysaccharides such as pectin and derivatives thereof; for example, water-absorbing and poorly water-soluble gums such as gum arabic, tragacanth gum, glycomannan and derivatives thereof; Cross-linked vinyl polymers such as redone, cross-linked polyacrylic acid and salts thereof, cross-linked polyvinyl alcohol, polyhydroxyethyl methacrylate and derivatives thereof; lipids that form molecular aggregates such as liposomes such as phospholipids and cholesterol Can do.

When the solubility of the CPT derivative of the present invention is low, a solubilization treatment can be performed. As a solubilization treatment, a method that can be generally applied to a medicine, for example, a method of adding a surfactant such as polyoxyethylene alcohol ethers, polyoxyethylene acyl esters, sorbitan acyl esters, polyoxyethylene sorbitan acyl esters, Examples thereof include a method using a water-soluble polymer such as polyethylene glycol, a method of encapsulating in micelles, and the like. Further, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, and the like can be used.
In particular, it is preferable to apply the CPT derivative as a pharmaceutical composition or anticancer composition containing the micelle in an encapsulated form.
The method for preparing the micelle is not particularly limited, and examples thereof include an emulsion using a high-pressure homogenizer, a block polymer using a synthetic polymer, a gelling agent, and the like.
Examples of reagents used in preparing micelles include fats and oils such as SL-11 (manufactured by NOF Corporation), lecithin, polyethylene glycol, polylactic acid, polyglutamic acid, hydrophobic polysaccharides, emulsifiers and synthetic polymers. .
The particle diameter when micelles are formed is preferably 5 to 200 nm, and more preferably 5 to 100 nm.

Next, the present invention will be described in more detail with reference to examples. However, this is merely an example and does not limit the present invention.

Example 1 (Synthesis of SN38Pt-1)
(1) Synthesis of Benzyl bis- (2-hydroxyethyl) carbamate:

2- (2-Hydroxyethylamino) ethanol (Diethanolamine) (50.0 g, 0.476 mol) is dissolved in a mixture of 1,4-dioxane (500 mL) -water (500 mL) and stirred with ice-cooling sodium bicarbonate ( 120.0 g, 1.43 mol) was added, and then benzyl carbonochloridate (75 mL, 0.500 mol) was added dropwise over about 30 minutes. After completion of dropping, the mixture was stirred at room temperature for about 7 hours. A white solid was removed from the reaction mixture by filtration, and the filtrate was concentrated under reduced pressure and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, concentrated to dryness under reduced pressure, and dried to give 105.3 g (92.6%) of the title compound as a colorless viscous liquid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 3.46 (4H, br-s), 3.73 (2H, br-s), 3.79 (2H, br-s), 5.11 (2H, s), 7.22-7.42 (5H, m).
ESI-MS m / z 240 ([M + H] ⁺ ).

(2) Synthesis of (((Benzyloxy) carbonyl) azanediyl) bis (ethane-2,1-diyl) dimethanesulfonate:

Dissolve Benzyl bis- (2-hydroxyethyl) carbamate (30.1 g, 0.126 mol) in dehydrated dichloromethane (600 mL), add triethylamine (37.1 g, 0.367 mol) and stir under ice cooling while stirring with methanesulfonyl chloride (34.6 g, 0.302 mol). mol) was added dropwise over about 1 hour. After completion of dropping, the mixture was further stirred for 1 hour, and then stirred at room temperature for 15 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate and washed with 5% hydrochloric acid, water and then saturated brine in this order. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, filtered off sodium sulfate, concentrated to dryness and dried under reduced pressure to give 46.8 g (94.1%) of the title compound as an orange viscous oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 2.92 (3H, s), 2.98 (3H, s), 3.68 (4H, t, J = 5.4Hz), 4.29 (2H, t, J = 5.4Hz), 4.39 (2H, t, J = 5.4Hz), 5.16 (2H, s), 7.27-7.46 (5H, m).

(3) Synthesis of Benzyl bis (2-bromoethyl) carbamate:

Under an argon gas atmosphere, benzyl bis (2-hydroxyethyl) carbamate (5.0 g, 20.9 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0 ° C. Carbon tetrabromide (16.6 g, 50.2 mmol) was added to it, and then triphenylphosphine   A dichloromethane solution (20 mL) of (16.4 g, 62.7 mmol) was added dropwise, stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 2 hours. The reaction mixture was concentrated, ethyl acetate was added, and the resulting precipitate was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 4.51 g (59%) of the title compound as a colorless oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.56-3.61 (4H, m), 3.64-3.70 (4H, m), 5.11 (2H, s), 7.30-7.41 (5H, m ).
ESI-MS m / z 364 ([M + H] ⁺ ).

(4) Synthesis of 1-Benzyl 4,4-di-tert-butyl piperidine-1,4,4-tricarboxylate:

Method A:
Dissolve (((Benzyloxy) carbonyl) azanediyl) bis (ethane-2,1-diyl) dimethanesulfonate (46.83 g, 0.118 mol) in a mixture of dehydrated tetrahydrofuran (2180 mL)-dehydrated N, N-dimethylformamide (180 mL) Then, di-tert-butyl malonate (26.50 g, 0.123 mol) was added, and sodium hydride and oily (11.86 g, 0.296 mol) were added little by little over about 1 hour with stirring at room temperature. After adding sodium hydride, the mixture was stirred with heating at 70 ° C. for 14 hours. The reaction mixture was concentrated to dryness under reduced pressure, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted twice with ethyl acetate. The ethyl acetate layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered off sodium sulfate, and concentrated to dryness under reduced pressure to give the crude title compound. The crude title compound obtained by reaction and post-treatment in the same manner using 57.89 g of the starting mesyl compound was combined and purified by silica gel column chromatography (n-hexane: ethyl acetate 7: 1) to give a yellow viscous oil I got a thing. The yellow viscous oil was recrystallized from petroleum ether to give 25.22 g (22.7%) of the title compound as colorless needle-prism crystals.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.45 (18H, s), 1.89-2.09 (4H, br), 3.46-3.56 (4H, m), 5.12 (2H, s), 7.26- 7.40 (5H, m).
ESI-MS m / z 420 ([M + H] ⁺ ).

Method B:
Under an argon gas atmosphere, sodium hydride, oily (1.18 g, 29.5 mmol) was suspended in N, N-dimethylformamide (25 mL) and cooled to 0 ° C. A di-tert-butyl malonate (3.29 mL, 14.8 mmol) in N, N-dimethylformamide solution (25 mL) was added dropwise thereto, and the mixture was stirred at 0 ° C. for 30 minutes. Subsequently, an N, N-dimethylformamide solution (25 mL) of benzyl bis (2-bromoethyl) carbamate (4.51 g, 12.3 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes and then at 50 ° C. for 3 hours. The reaction mixture was concentrated, and the resulting residue was redissolved in ethyl acetate and washed with a saturated aqueous ammonium chloride solution and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 3.58 g (69%) of the title compound as a colorless solid.

(5) Synthesis of Di-tert-butyl piperidine-4,4-dicarboxylate:

1-Benzyl 4,4-di-tert-butyl piperidine-1,4,4-tricarboxylate (12.2 g, 0.029 mol) is dissolved in methanol (120 mL), and 20% palladium hydroxide (0.92 g) is added. The mixture was vigorously stirred at room temperature for about 15 hours under a hydrogen gas atmosphere. The disappearance of the raw materials was confirmed by thin layer chromatography (n-hexane: ethyl acetate 3: 1), palladium hydroxide was filtered off using a celite pad, and then concentrated to dryness under reduced pressure. The residue was reduced at room temperature. Drying down afforded 8.30 g (quantitative) of the title compound as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.45 (18H, s), 1.98 (4H, t, J = 5.6Hz), 2.46 (1H, br-s), 2.88 (4H, t, J = 5.6Hz).
ESI-MS m / z 286 ([M + H] ⁺ ).

(6) Synthesis of 10- (4,4- (Di-tert-butoxycarbonyl) piperidin-1-yl) carbonyloxy-7-ethylcamptothecin:

Di-tert-butyl piperidine-4,4-dicarboxylate (6.0 g, 0.021 mol) is dissolved in dry toluene (120 mL), dry pyridine (4.3 ml) is added, and triphosgene (3.32 g, 0.011 mol) was added and stirred for 30 minutes. It was then stirred overnight at room temperature. Dichloromethane was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order. The dichloromethane layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain crude di-tert-butyl 1- (chlorocarbonyl) piperidine-4,4-dicarboxylate as a yellow solution. Add 7-ethyl-10-hydroxycamptothecin (SN-38) to crude di-tert-butyl 1- (chlorocarbonyl) piperidine-4,4-dicarboxylate by adding dry pyridine (250 mL) and dry dichloromethane (430 mL). (8.62 g, 0.021 mol) was added and stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (chloroform containing 3% methanol), fractions containing the desired product were collected and concentrated to dryness, and the residue was chloroform-n- Crystallization from hexanes afforded 13.32 g (90.1%) of the title compound as a pale yellowish white powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.89 (3H, t, J = 7.6Hz), 1.29 (3H, t, J = 7.6Hz), 1.45 (18H, s), 1.79 -1.95 (2H, m), 1.95-2.10 (4H, br), 3.18 (2H, q, J = 7.6Hz), 3.43-3.58 (2H, br), 3.62-3.77 (2H, br), 5.32 (2H , s), 5.44 (2H, s), 6.52 (1H, s), 7.32 (1H, s), 7.67 (1H, dd, J = 2.4, 9.0Hz), 7.99 (1H, d, J = 2.4Hz) , 8.16 (1H, d, J = 9.0Hz).

(7) Synthesis of 10- (4,4- (Biscarboxyl) piperidin-1-yl) carbonyloxy-7-ethylcamptothecin (SN38Pt-SM1):

Trifluoroacetic acid (50 mL) is added to 10- (4,4- (Di-tert-butoxycarbonyl) piperidin-1-yl) carbonyloxy-7-ethylcamptothecin (5.0 g, 7.10 mmol), and the mixture is stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure to give a yellow viscous oily residue. Ethanol (20 mL) was added to the residue and dissolved by irradiation with ultrasonic waves (a yellow solid precipitated immediately after dissolution). Petroleum ether (40 mL) was added to the solution and stirred under ice cooling. The precipitated yellow solid was collected by filtration, washed with petroleum ether, and dried (70 ° C., reduced pressure) to give 4.13 g (98.2%) of the title compound as a yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.89 (3H, t, J = 7.6Hz), 1.29 (3H, t, J = 7.6Hz), 1.78-1.96 (2H, m) , 1.97-2.16 (4H, br), 3.19 (2H, q, J = 7.6Hz), 3.43-3.59 (2H, br), 3.61-3.78 (2H, br), 5.33 (2H, s), 5.44 (2H , s), 6.30-6.75 (1H, br), 7.32 (1H, s), 7.68 (1H, dd, J = 2.4, 9.0Hz), 8.00 (1H, d, J = 2.4Hz), 8.17 (1H, d, J = 9.0Hz), 12.75-13.35 (2H, br).
MS (ESI) m / z: 592 ([M + H] ⁺ ).

(8) Synthesis of SN38Pt-1:

SN38Pt-SM1 (592 mg, 1.00 mmol) was dissolved in ethanol (250 mL) with heating, then diaquo DACH platinum complex (469 mg, 1.00 mmol) (prepared by the method described in JP-A-9-40685), distilled Water (40 mL) was added followed by 0.2 N aqueous sodium hydroxide (10 mL, 2.00 mmol). After stirring at 60-70 ° C. for 21 hours, insoluble matters were removed by filtration under reduced pressure (glass filter). Distilled water (300 mL) was added to the residue obtained by distilling off the solvent to form a suspension (sonication). The suspension was heated with hot water and filtered under reduced pressure (filter paper). The obtained powder was dissolved by heating (60-70 ° C.) in a methanol / water (85/15) mixed solvent (about 200 mL), and insoluble matters were removed by filtration under reduced pressure (glass filter). The residue obtained by distilling off the solvent and vacuum drying was subjected to reverse phase HPLC (SHISEIDO CAPCELL PAK C18 (20 mmID X 250 mm), Solvent: methanol / water = 85/15, Flow rate: 4 mL / min, UV 254 nm) to give 140 mg (16%) of the title compound as a slightly yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3Hz), 0.94-1.10 (2H, br-m), 1.15-1.30 (2H, br), 1.30 (3H, t, J = 7.6Hz), 1.39-1.51 (2H, br), 1.75-2.15 (6H, m), 3.20 (2H, q, J = 7.6Hz), 3.43-3.79 (4H, br- m), 5.27-5.43 (2H, br), 5.34 (2H, s), 5.44 (2H, s), 6.02 (2H, d, J = 6.8Hz), 6.53 (1H, s), 7.33 (1H, s ), 7.67 (1H, dd, J = 2.0, 9.2Hz), 8.00 (1H, d, J = 2.0Hz), 8.17 (1H, d, J = 9.2Hz).
MS (ESI) m / z: 899 ([M + H] ⁺ ).

Example 2 (Synthesis of SN38Pt-2)
(1) Synthesis of 10- (4- (tert-butoxycarbonyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

Method A:
Dissolve tert-Butyl piperazine-1-carboxylate (5.0 g, 26.85 mmol) in dry toluene (150 mL), add dry pyridine (5.5 mL), and add triphosgene (4.24 g, 14.29 mmol) with stirring under ice cooling. The mixture was further stirred for 1 hour. It was then stirred overnight at room temperature. Dichloromethane was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain crude tert-butyl 4- (chlorocarbonyl) piperazine-1-carboxylate as a yellow solution. Dissolve crude tert-butyl 4- (chlorocarbonyl) piperazine-1-carboxylate by adding dry pyridine (400 mL) and dry dichloromethane (400 mL), add SN-38 (11.02 g, 26.85 mmol), and mix at room temperature. Stir overnight. The reaction mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography (chloroform containing 2% methanol), fractions containing the desired product were collected and concentrated to dryness, and the residue was chloroform-n- Crystallized from hexane. The crystals were collected by filtration, washed with n-hexane and dried (60 ° C., reduced pressure) to give 15.17 g (93.5%) of the title compound as a pale yellowish white powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.89 (3H, t, J = 7.3Hz), 1.29 (3H, t, J = 7.8Hz), 1.45 (9H, s), 1.78 -1.95 (2H, m), 3.17 (2H, q, J = 7.8Hz), 3.41-3.54 (6H, br), 3.62-3.71 (2H, br), 5.31 (2H, s), 5.44 (2H, s ), 6.53 (1H, s), 7.31 (1H, s), 7.67 (1H, dd, J = 2.4, 9.3Hz), 7.99 (1H, d, J = 2.4Hz), 8.16 (1H, d, J = (9.3Hz).
ESI-MS m / z 605 ([M + H] ⁺ ).

Method B:
Under an argon gas atmosphere, tert-Butyl piperazine-1-carboxylate (2.00 g, 10.7 mmol) was dissolved in dichloromethane (20 mL) and cooled to −10 ° C. Triethylamine (3.64 mL, 26.8 mmol) was added thereto, and then a solution of triphosgene (2.23 g, 7.49 mmol) in dichloromethane (5 mL) was added dropwise, followed by stirring at −10 ° C. for 1 hour. The reaction mixture was diluted with chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum. The obtained residue was dissolved in pyridine (40 mL), SN-38 (2.04 g, 5.20 mmol) was added, and the mixture was stirred at room temperature overnight. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 3.01 g (99%) of the title compound as a pale yellow solid.

(2) Synthesis of 7-Ethyl-10-((piperazine-1-yl) carbonyloxy) camptothecin trifluoroacetate:

Trifluoroacetic acid (25 mL) was added to 10- (4- (tert-Butoxycarbony) lpiperazine-1-yl) carbonyloxy-7-ethylcamptothecin (10.0 g, 16.54 mmol) and dissolved by irradiation with ultrasonic waves. The solution was stirred at room temperature for 2.5 hours and the reaction mixture was concentrated to dryness under reduced pressure to give a greenish yellow viscous oily residue. Ethanol (100 mL) was added to the residue and dissolved. While stirring the solution under ice-cooling (crystal precipitation), petroleum ether (200 mL) was added, and the precipitated crystals were collected by filtration, washed with petroleum ether, dried (55 ° C., reduced pressure), and yellow powder As a result, 10.23 g (quantitative) of the title compound was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.89 (3H, t, J = 7.6Hz), 1.30 (3H, t, J = 7.6Hz), 1.78-1.97 (2H, m) , 3.10-3.39 (6H, br-m), 3.61-3.80 (2H, br), 3.82-3.99 (2H, br), 5.33 (2H, s), 5.44 (2H, s), 6.20-6.93 (1H, br), 7.32 (1H, s), 7.70 (1H, dd, J = 2.4, 9.0Hz), 8.01 (1H, d, J = 2.4Hz), 8.20 (1H, d, J = 9.0Hz), 9.09 ( 2H, br-s).
ESI-MS m / z 505 ([M + H] ⁺ ).

(3) Synthesis of 10- (Piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

10- (Piperazine-1-yl) carbonyloxy-7-ethylcamptothecin trifluoroacetate (2.05 g, 3.31 mmol) was dissolved in chloroform and neutralized by adding a saturated aqueous sodium hydrogen carbonate solution. The chloroform solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a pale yellow viscous oily residue. The residue was crystallized from n-hexane-chloroform, collected by filtration, washed with n-hexane, and dried (70 ° C., reduced pressure) to give 1.43 g (85.7%) of the title compound as a pale yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.89 (3H, t, J = 7.3Hz), 1.29 (3H, t, J = 7.6Hz), 1.78-1.97 (2H, m) , 2.73-2.90 (4H, br), 3.18 (2H, q, J = 7.6Hz), 3.35-3.48 (2H, br), 3.55-3.69 (2H, br), 5.32 (2H, s), 5.44 (2H , s), 6.54 (1H, s), 7.32 (1H, s), 7.66 (1H, dd, J = 2.4, 9.0Hz), 7.98 (1H, d, J = 2.4Hz), 8.16 (1H, d, J = 9.0Hz).

(4) Synthesis of 10- (4-(((4,4-Di-tert-butoxycarbonyl) piperidin-1-yl) carbonyl) piperazine-1-yl) carbonyl oxy-7-ethylcamptothecin:

From Di-tert-butyl piperidine-4,4-dicarboxylate (0.75 g, 2.63 mmol), dry toluene (15 mL), dry pyridine (0.54 ml) and triphosgene (415 mg, 1.40 mmol), Example 1 (6) According to the method, crude Di-tert-butyl 1- (chlorocarbonyl) piperidine-4,4-dicarboxylate was obtained. To the crude Di-tert-butyl 1- (chlorocarbonyl) piperidine-4,4-dicarboxylate, add dry pyridine (50 mL) and dry dichloromethane (100 mL) and dissolve to dissolve 10- (piperazine-1-yl) carbonyloxy-7- Ethylcamptothecin (1.26 g, 2.50 mmol) was added and stirred at room temperature for 5 days. The suspension was removed by filtration, washed with chloroform, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and washed with 1N hydrochloric acid and then with water. The chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was crystallized from n-hexane-chloroform, filtered, washed with n-hexane and dried (50 ° C., reduced pressure) to give 1.66 g (81.6%) of the title compound as a pale yellowish white powder. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.04 (3H, t, J = 7.3Hz), 1.41 (3H, t, J = 7.8Hz), 1.47 (18H, s), 1.83-1.96 (2H, m), 2.02-2.08 (4H, br-m), 3.17 (2H, q, J = 7.8Hz), 3.26-3.42 (8H, br-m), 3.56-3.86 (5H, br-m) , 5.27 (2H, s), 5.31 (1H, d, J = 16.1Hz), 5.76 (1H, d, J = 16.1Hz), 7.61 (1H, dd, J = 2.4, 9.3Hz), 7.70 (1H, s), 7.86 (1H, d, J = 2.4Hz), 8.27 (1H, d, J = 9.3Hz).

(5) Synthesis of 10- (4-((4,4- (Biscarboxyl) piperidin-1-yl) carbonyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (SN38Pt-SM2):

10- (4-(((4,4-Di-tert-butoxycarbonyl) piperidin-1-yl) carbonyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (1.0 g, 1.23 mmol) to trifluoroacetic acid (10 mL) and dissolved, and stirred at room temperature for 8 hours. The reaction mixture was concentrated to dryness under reduced pressure to give a yellow viscous oily residue. Ethanol (10 mL) and petroleum ether (20 mL) were added to the residue for crystallization. The crystals were recrystallized from chloroform-n-hexane containing 10% methanol. The crystals were collected by filtration, washed with n-hexane, and dried (60 ° C., reduced pressure) to give the title compound (786 mg, 90.0%) as a yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3Hz), 1.30 (3H, t, J = 7.6Hz), 1.78-2.02 (6H, br- m), 3.10-3.39 (10H, br-m), 3.42-3.55 (2H, br), 3.62-3.78 (2H, br), 5.34 (2H, s), 5.44 (2H, s), 6.53 (1H, s), 7.32 (1H, s), 7.69 (1H, dd, J = 2.4, 9.3Hz), 8.02 (1H, d, J = 2.4Hz), 8.18 (1H, d, J = 9.3Hz), 12.99 ( 2H, br-s).
MS (ESI) m / z: 704 ([M + H] ⁺ ).

(6) Synthesis of SN38Pt-2:

SN38Pt-SM2 (155 mg, 0.22 mmol) was dissolved in ethanol (175 mL) with heating, then diaquo DACH platinum complex (103 mg, 0.22 mmol), distilled water (25 mL), followed by 0.2 N aqueous sodium hydroxide ( 2.2 mL, 0.441 mmol) was added. After stirring at 60-70 ° C. for 24 hours, the solvent was distilled off. To the resulting residue, a methanol / water (85/15) mixed solvent (90 mL) was added to make a suspension (sonication). The suspension was heated with hot water, and then insoluble matters were removed by filtration (glass filter). The filtrate was concentrated and dried in vacuo to give the crude title compound. Using the raw material SN38Pt-SM2 352 mg in the same manner, the crude title compound obtained by post-treatment was combined and reversed-phase HPLC (SHISEIDO CAPCELL PAK C18 (20 mmID X 250 mm), solvent: methanol / water = 80 / (20, Flow rate: 4 mL / min, UV 254 nm) to give 122 mg (17%) of the title compound as a pale yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3Hz), 0.93-1.06 (2H, br-m), 1.06-1.30 (2H, br), 1.29 (3H, t, J = 7.6Hz), 1.37-1.52 (2H, br), 1.75-1.95 (4H, m), 1.98-2.12 (2H, br), 2.37-2.53 (2H, br), 3.10- 3.33 (12H, m), 3.43-3.56 (2H, br), 3.63-3.76 (2H, br), 5.22-5.38 (2H, br), 5.33 (2H, s), 5.43 (2H, s), 5.96 ( 2H, br-d, J = 7.6Hz), 6.53 (1H, s), 7.33 (1H, s), 7.68 (1H, dd, J = 2.4, 9.3Hz), 8.01 (1H, d, J = 2.4Hz ), 8.18 (1H, d, J = 9.3Hz).
MS (ESI) m / z: 1011 ([M + H] ⁺ ).

Example 3 (Synthesis of SN38Pt-3)
(1) Synthesis of Di-tert-butyl 1- (2-bromoacetyl) piperidine-4,4-dicarboxylate:

2-Bromoacetyl chloride (1.21 g, 7.71 mmol) was dissolved in dry dichloromethane (20 mL) and stirred under ice cooling with di-tert-butyl piperidine-4,4-dicarboxylate (2.00 g, 7.01 mmol) and triethylamine ( A dry dichloromethane solution (20 mL) in which 780 mg, 7.71 mmol) was dissolved was added dropwise over 30 minutes. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was washed with 0.1 N hydrochloric acid and saturated brine, and the dichloromethane layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4: 1), and fractions containing the desired product were collected and concentrated to dryness to give 2.51 g (88.2%) of the title compound as a waxy solid. Got.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.46 (18H, s), 1.97-2.14 (4H, m), 3.50-3.68 (4H, m), 4.06 (2H, s).

(2) Synthesis of 10- (4-(((4,4-Di-tert-butoxycarbonyl) piperidin-1-yl) carbonylmethyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

Di-tert-butyl 1- (2-bromoacetyl) piperidine-4,4-dicarboxylate (658 mg, 1.62 mmol) and 10- (piperazine-1-yl) carbonyloxy-7-ethylcamptothecin trifluoroacetate (1.00 g, 1.62 mmol) Dissolved in dry N, N-dimethylformamide (10 mL), diisopropylethylamine (419 mg, 3.24 mmol) was added and stirred overnight with stirring under ice cooling. Chloroform was added to the reaction mixture, and the mixture was washed with water, 1N hydrochloric acid and then saturated brine. The chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure (about 20 mL). N-Hexane was added to the concentrate with stirring under ice-cooling, and the mixture was stirred overnight. The precipitated crystals were collected by filtration, washed with n-hexane, and dried (50 ° C., reduced pressure) to give 1.06 g (78.9%) of the title compound as a white powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3Hz), 1.29 (3H, t, J = 7.3Hz), 1.43 (18H, s), 1.75 -2.07 (6H, m), 2.43-2.80 (4H, br), 3.19 (2H, q, J = 7.3Hz), 3.38-3.89 (10H, br), 5.33 (2H, s), 5.44 (2H, s ), 6.53 (1H, s), 7.32 (1H, s), 7.68 (1H, dd, J = 2.4, 9.3Hz), 8.00 (1H, d, J = 2.4Hz), 8.18 (1H, d, J = (9.3Hz).

(3) Synthesis of 10- (4-((4,4-Biscarboxyl) piperidin-1-yl) carbonylmethyl) piperazine-1-yl) carbonyloxy-7-ethylcamptotecin trifluoroacetate (SN38Pt-SM3):

10- (4-(((4,4-Di-tert-butoxycarbonyl) piperidin-1-yl) carbonylmethyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (900 mg, 1.08 mmol) to trifluoroacetic acid (9 mL) was added and dissolved by irradiation with ultrasonic waves. The solution was stirred at room temperature for 4 hours and the reaction mixture was concentrated to dryness under reduced pressure to give a yellow viscous oily residue. Ethanol was added to the residue, and petroleum ether was added with stirring under ice-cooling and stirred overnight. The precipitated crystals were collected by filtration, washed with petroleum ether, and dried (40 ° C., reduced pressure) to give 900 mg (quantitative) of the title compound as a yellow powder.
MS (ESI) m / z: 718 ([M + H] ⁺ ).

(4) Synthesis of SN38Pt-3:

SN38Pt-SM3 (457 mg, 0.55 mmol) was dissolved in ethanol (165 mL) and distilled water (11 mL) with heating, and then 0.2 N aqueous sodium hydroxide solution (2.75 mL, 0.55 mmol) was added at 60-70 ° C. Stir for about 5 minutes. Then, diaquo DACH platinum complex (258 mg, 0.55 mmol), distilled water (22 mL), and then 0.2 N aqueous sodium hydroxide solution (5.5 mL, 1.1 mmol) were added. After stirring at 60-70 ° C. for 24 hours, the solvent was distilled off and vacuum-dried. By purifying the obtained residue using reverse phase HPLC (SHISEIDO CAPCELL PAK C18 (20 mmID X 250 mm), solvent: methanol / water = 85/15, Flow rate: 4 mL / min, UV 254 nm) The title compound 116 mg (21%) was obtained as a slightly yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3Hz), 0.93-1.08 (2H, br-m), 1.08-1.30 (2H, br), 1.29 (3H, t, J = 7.6Hz), 1.38-1.52 (2H, br), 1.75-1.95 (4H, m), 1.99-2.11 (2H, br), 2.30-2.62 (8H, br-m), 3.10-3.28 (4H, m), 3.41-3.75 (8H, br-m), 5.26-5.40 (2H, br), 5.34 (2H, s), 5.44 (2H, s), 6.00 (2H, br-d , J = 8.8Hz), 6.54 (1H, s), 7.32 (1H, s), 7.68 (1H, dd, J = 2.4, 9.3Hz), 8.01 (1H, d, J = 2.4Hz), 8.18 (1H , d, J = 9.3Hz).
MS (ESI) m / z: 1025 ([M + H] ⁺ ).

Example 4 (Synthesis of SN38Pt-4)
(1) Synthesis of Di-tert-butyl 1- (12-ethoxy-12-oxododecanoyl) piperidine-4,4-dicarboxylate:

Method A:
Dodecanedioic acid monoethyl ester (2.58 g, 10.0 mmol) was dissolved in dry dichloromethane (50 mL) and stirred under ice cooling with dicyclohexylcarbodiimide (2.48 g, 12.0 mmol) and di-tert-butyl piperidine-4,4-dicarboxylate. (3.00 g, 10.5 mmol) was added and stirred for 30 minutes. Subsequently, the mixture was stirred at room temperature for 2 hours, the precipitate was filtered off, and the dichloromethane layer was washed with 1 N hydrochloric acid and water. The dichloromethane layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain a colorless viscous oily residue. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 3: 1), and fractions containing the desired product were collected, concentrated to dryness under reduced pressure, dried (room temperature, reduced pressure), and colorless. The title compound 5.19 g (98.9%) was obtained as a viscous oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.20-1.37 (15H, m), 1.46 (18H, s), 1.55-1.67 (4H, m), 1.92-2.04 (4H, br), 2.22-2.38 (4H, m), 3.41-3.66 (4H, br-m), 4.12 (2H, q, J = 7.1Hz).

Method B:
Dodecanedioic acid monoethyl ester (1.54 g, 5.97 mmol) was dissolved in dry N, N-dimethylformamide (20 mL) and stirred under ice-cooling to give O- (1H-6-chlorobenzotriazil-1-yl) -N, N , N ', N'-tetramethyluronium tetrafluoroborate (TCTU) (2.12 g, 5.97 mmol), diisopropylethylamine (1.85 g, 14.33 mmol) and di-tert-butyl piperidine-4,4-dicarboxylate (1.42 g, 4.98 mmol) ) Was added and stirred for 30 minutes. Subsequently, the mixture was stirred overnight at room temperature, diluted with chloroform by adding chloroform to the reaction mixture, and washed with 1 N hydrochloric acid, water, 1 N aqueous sodium hydroxide solution, and then saturated brine. The chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a pale brown viscous oily residue. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate 3: 1). Fractions containing the desired product were collected, concentrated to dryness under reduced pressure, dried (room temperature, reduced pressure), and slightly yellow As a viscous oil, 2.61 g (99.9%) of the title compound was obtained.

(2) Synthesis of 12- (4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl) -12-oxododecanoic acid:

Di-tert-butyl 1- (12-ethoxy-12-oxododecanoyl) piperidine-4,4-dicarboxylate (5.19 g, 9.87 mmol) is dissolved in methanol (50 mL) and stirred with ice cooling to 1 N hydroxide A sodium aqueous solution (12 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 1 day (white crystals were precipitated). The reaction solution was concentrated under reduced pressure (methanol was distilled off), and acidified by adding 1 N hydrochloric acid to the alkaline aqueous solution containing the crystals while stirring under ice-cooling. The precipitated crystals were collected by filtration, washed with water, and dried (75 ° C., reduced pressure) to give 4.74 g (96.4%) of the title compound as a white powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.18-1.30 (12H, br-s), 1.37-1.90 (22H, m), 2.14-2.32 (4H, m), 3.20-3.50 (8H , m).

(3) Synthesis of 10- (4- (12- (4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl) -12-oxododecanoyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

12- (4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl) -12-oxododecanoic acid (3.93 g, 7.90 mmol) was dissolved in dry N, N-dimethylformamide (150 mL) and cooled with ice. While stirring, add TCTU (2.81 g, 7.90 mmol), diisopropylethylamine (3.61 g, 27.96 mmol) and 10- (piperazine-1-yl) carbonyloxy-7-ethylcamptothecin trifluoroacetate (4.64 g, 7.50 mmol), and stir for 30 minutes. did. Subsequently, the mixture was stirred at room temperature for 4 hours and concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and washed with saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid and then saturated brine. The chloroform layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform containing 1% methanol), the fractions containing the target compound were collected, concentrated to dryness under reduced pressure, dried (room temperature, reduced pressure), and the title compound as a yellow amorphous powder. 5.87 g (79.5%) were obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.04 (3H, t, J = 7.3Hz), 1.23-1.38 (12H, br), 1.40-1.49 (21H, m), 1.53- 1.71 (4H, m), 1.78-2.05 (6H, m), 2.27-2.43 (4H, m), 3.21 (2H, q, J = 7.8Hz), 3.40-3.85 (12H, br-m), 5.30 ( 1H, d, J = 16.6Hz), 6.31 (2H, s), 5.73 (1H, d, J = 16.6Hz), 7.56 (1H, dd, J = 2.4, 9.3Hz), 7.87-7.95 (2H, m ), 8.42 (1H, d, J = 9.3Hz).
MS (ESI) m / z: 984 ([M + H] ⁺ ).

(4) Synthesis of 10- (4- (12- (4,4-Biscarboxyl) piperidin-1-yl) -12-oxododecanoyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (SN38Pt-SM4):

10- (4- (12- (4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl) -12-oxododecanoyl) piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (5.86 g, 5.95 mmol) Fluoroacetic acid (30 mL) was added and dissolved by irradiation with ultrasonic waves. The solution was stirred at room temperature for 24 hours and the reaction mixture was concentrated to dryness under reduced pressure to give a yellow-orange viscous oily residue. Ethanol (3 mL) was added to the residue for dissolution, and ether was added to powder by stirring at room temperature. The powder was collected by filtration, washed with ether, and dried (room temperature, then 60 ° C., reduced pressure) to give 4.81 g (92.6%) of the title compound as a yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3Hz), 1.19-1.37 (15H, m), 1.40-1.58 (4H, m), 1.78- 1.98 (6H, m), 2.22-2.41 (4H, m), 3.19 (2H, q, J = 7.3Hz), 3.34-3.77 (12H, m), 5.34 (2H, s), 5.44 (2H, s) , 6.54 (1H, br-s), 7.32 (1H, s), 7.69 (1H, dd, J = 2.4, 9.3Hz), 8.02 (1H, d, J = 2.4Hz), 8.18 (1H, d, J = 9.3Hz), 13.00 (2H, br-s).
MS (ESI) m / z: 872 ([M + H] ⁺ ).

(5) Synthesis of SN38Pt-4:

SN38Pt-SM4 (654 mg, 0.75 mmol) was dissolved in ethanol (185 mL) with heating, then diaquo DACH platinum complex (352 mg, 0.75 mmol), distilled water (30 mL), followed by 0.2 N aqueous sodium hydroxide ( 7.5 mL, 1.5 mmol) was added. After stirring at 50-60 ° C. for 22 hours, the solution was concentrated under reduced pressure. The residue obtained after vacuum drying was subjected to reverse phase HPLC (SHISEIDO CAPCELL PAK C18 (20 mmID X 250 mm), solvent: methanol / water = 85/15, Flow rate: 4 mL / min, UV 254 nm) To give 423 mg (48%) of the title compound as a slightly yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3Hz), 0.94-1.05 (2H, br-m), 1.13-1.35 (14H, br-m ), 1.38-1.57 (6H, br-m), 1.74-1.95 (4H, m), 1.98-2.11 (2H, br), 2.18-2.44 (6H, m), 3.19 (2H, q, J = 7.6Hz ), 3.37-3.75 (12H, br-m), 5.21-5.37 (2H, br), 5.34 (2H, s), 5.44 (2H, s), 5.97 (2H, br-d, J = 8.5Hz), 6.52 (1H, s), 7.33 (1H, s), 7.69 (1H, dd, J = 2.4, 9.3Hz), 8.02 (1H, d, J = 2.4Hz), 8.18 (1H, d, J = 9.3Hz ).
MS (ESI) m / z: 1180 ([M + H] ⁺ ).

Example 5 (Synthesis of SN38Pt-5)
(1) Synthesis of Di-tert-butyl 1- (4-methoxy-4-oxobutanoyl) piperidine-4,4-dicarboxylate:

Under an argon gas atmosphere, monomethyl succinate (259 mg, 1.96 mmol) was dissolved in N, N-dimethylformamide (5 mL) and cooled to 0 ° C. TCTU (697 mg, 1.96 mmol) and N, N-diisopropylethylamine (1.00 mL, 5.88 mmol) were added thereto. Furthermore, di-tert-butyl piperidine-4,4-dicarboxylate (400 mg, 1.40 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 540 mg (97%) of the title compound as a colorless oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.41 (18H, s), 1.80 (2H, t, J = 5.5 Hz), 1.89 (2H, t, J = 5.4 Hz), 2.47 (2H, dd, J = 7.6, 5.4 Hz), 2.47-2.50 (2H, m), 3.41-3.64 (4H, m), 3.57 (3H, s).
ESI-MS m / z 400 ([M + H] ⁺ ).

(2) Synthesis of 4- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -4-oxobutanoic acid:

Di-tert-butyl 1- (4-methoxy-4-oxobutanoyl) piperidine-4,4-dicarboxylate (540 mg, 1.35 mmol) was dissolved in methanol (6 mL) and cooled to 0 ° C. 1 N sodium hydroxide aqueous solution (3 mL) was added there, and it returned to room temperature, and stirred for 2 hours. The reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was vacuum-dried to obtain 518 mg (99%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.41 (9H, s), 1.41 (9H, s), 1.79 (2H, t, J = 5.4 Hz), 1.89 (2H, t, J = 5.1 Hz), 2.40 (2H, t, J = 6.3 Hz), 2.52 (2H, t, J = 6.1 Hz), 3.41-3.46 (4H, m), 12.0 (1H, s).
ESI-MS m / z 386 ([M + H] ⁺ ).

(3) Synthesis of 10- (4- [4- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -4-oxobutanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

4- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -4-oxobutanoic acid (518 mg, 1.34 mmol) was dissolved in N, N-dimethylformamide (4 mL) under an argon gas atmosphere. And cooled to 0 ° C. TCTU (476 mg, 1.34 mmol), N, N-diisopropylethylamine (684 μL, 4.03 mmol) was added thereto. 7-ethyl-10-[(piperazine-1-yl) carbonyloxy] camptothecin trifluoroacetate (594 mg, 0.96 mmol), N, N-diisopropylethylamine (163 μL, 0.96 mmol) in N, N-dimethylformamide (3 mL) The solution was added and stirred at 0 ° C. for 10 minutes and then at room temperature for 4 hours. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 734 mg (88%) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.89 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.4 Hz), 1.42 (18H, s), 1.80 -1.93 (6H, m), 2.59 (4H, br.s), 3.16-3.22 (2H, m), 3.41-3.51 (6H, m), 3.55-3.73 (6H, m), 5.33 (2H, s) , 5.44 (2H, s), 6.53 (1H, s), 7.32 (1H, s), 7.69 (1H, dd, J = 9.3, 2.0 Hz), 8.02 (1H, d, J = 2.0 Hz), 8.18 ( (1H, d, J = 9.3 Hz).
ESI-MS m / z 872 ([M + H] ⁺ ).

(4) Synthesis of 10- [4- [4- (4,4-Biscarboxylpiperidin-1-yl) -4-oxobutanoyl] piperazine-1-yl] carbonyloxy-7-ethylcamptothecin (SN38Pt-SM5):

Under argon gas atmosphere, 10- (4- [4- [4,4-bis (tert-butoxycarbonyl) -piperidin-1-yl] -4-oxobutanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (734 mg , 0.842 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the resulting residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 542 mg (85%) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.82-1.93 (4H, m) , 1.96-1.98 (2H, m), 2.59 (4H, br.s), 3.17-3.22 (2H, m), 3.43-3.51 (6H, m), 3.56-3.79 (6H, m), 5.34 (2H, s), 5.44 (2H, s), 7.33 (1H, s), 7.70 (1H, dd, J = 9.3, 2.4 Hz), 8.03 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz), 13.0 (2H, br.s).
ESI-MS m / z 760 ([M + H] ⁺ ).

(5) Synthesis of SN38Pt-5:

Under an argon gas atmosphere, SN38Pt-SM5 (150 mg, 0.197 mmol) was dissolved in ethanol (50 mL). Diaqua DACH platinum complex (93 mg, 0.197 mmol) and water (5.91 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (3.94 mL, 0.394 mmol) was added, and it stirred at 50 degreeC for 22 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min). The resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 μm (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-5 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 63 mg (29%) of the title compound as a white powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 0.98-1.03 (2H, m), 1.18-1.23 (2H, m), 1.30 ( 3H, t, J = 7.6 Hz), 1.45 (2H, d, J = 9.3 Hz), 1.80-1.93 (4H, m), 2.02-2.08 (2H, m), 2.31-2.36 (2H, m), 2.46 -2.55 (2H, m), 2.58 (4H, s), 3.16-3.23 (2H, m), 3.44-3.74 (12H, m), 5.31 (2H, d, J = 9.3 Hz), 5.35 (2H, s ), 5.44 (2H, s), 6.01 (2H, d, J = 8.5 Hz), 6.55 (1H, s), 7.33 (1H, s), 7.71 (1H, dd, J = 9.0, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 534 ([M + 2H] ²⁺ ), 1067 ([M + H] ⁺ ).

Example 6 (Synthesis of SN38Pt-6)
(1) Synthesis of Di-tert-butyl 1- (8-methoxy-8-oxooctanoyl) piperidine-4,4-dicarboxylate:

Under an argon gas atmosphere, monomethyl suberate (345 μL, 1.96 mmol) was dissolved in N, N-dimethylformamide (5 mL) and cooled to 0 ° C. TCTU (697 mg, 1.96 mmol) and N, N-diisopropylethylamine (1.00 mL, 5.88 mmol) were added thereto. Further, di-tert-butyl piperidine-4,4-dicarboxylate (400 mg, 1.40 mmol) was added, stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 588 mg (92%) of the title compound as a transparent oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.23-1.27 (4H, m), 1.40 (18H, s), 1.43-1.54 (4H, m), 1.78-1.81 (2H, m ), 1.85-1.88 (2H, m), 2.25-2.30 (4H, m), 3.41-3.44 (4H, m), 3.58 (3H, s).
ESI-MS m / z 456 ([M + H] ⁺ ).

(2) Synthesis of 8- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -8-oxooctanoic acid:

Di-tert-butyl 1- (8-methoxy-8-oxooctanoyl) piperidine-4,4-dicarboxylate (588 mg, 1.29 mmol) was dissolved in methanol (6 mL) and cooled to 0 ° C. 1 N sodium hydroxide aqueous solution (3 mL) was added there, and it returned to room temperature, and stirred for 5 hours. The reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was vacuum-dried to obtain 737 mg (quantitative) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24-1.27 (4H, m), 1.40 (18H, s), 1.43-1.51 (4H, m), 1.79 (2H, t, J = 5.6 Hz), 1.87 (2H, t, J = 5.4 Hz), 2.18 (2H, t, J = 7.3 Hz), 2.28 (2H, t, J = 7.4 Hz), 3.42 (4H, t, J = 5.6 Hz), 12.0 (1H, s).
ESI-MS m / z 442 ([M + H] ⁺ ).

(3) Synthesis of 10- (4- [8- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -8-oxooctanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

Under argon gas atmosphere, 8- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -8-oxooctanoic acid (737 mg, 1.29 mmol) was dissolved in N, N-dimethylformamide (4 mL). And cooled to 0 ° C. TCTU (498 mg, 1.29 mmol) and N, N-diisopropylethylamine (714 μL, 3.87 mmol) were added thereto. Furthermore, 7-ethyl-10-[(piperazine-1-yl) carbonyloxy] camptothecin trifluoroacetate (570 mg, 0.921 mmol), N, N-diisopropylethylamine (170 μL, 0.921 mmol) in N, N-dimethylformamide (3 mL ) The solution was added and stirred at 0 ° C. for 10 minutes and then at room temperature for 4 hours. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 898 mg (quantitative) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.26-1.32 (7H, m), 1.41 (18H, s), 1.45-1.56 ( 4H, m), 1.78-1.81 (2H, m), 1.84-1.91 (4H, m), 2.30 (2H, t, J = 7.4 Hz), 2.36 (2H, t, J = 7.4 Hz), 3.16-3.22 (2H, m), 3.42-3.46 (6H, m), 3.52-3.70 (6H, m), 5.34 (2H, s), 5.44 (2H, s), 6.54 (1H, s), 7.32 (1H, s ), 7.69 (1H, dd, J = 9.0, 2.2 Hz), 8.02 (1H, d, J = 2.2 Hz), 8.18 (1H, d, J = 9.0 Hz).
ESI-MS m / z 928 ([M + H] ⁺ ).

(4) Synthesis of 10- [4- [8- (4,4-Biscarboxylpiperidin-1-yl) -8-oxooctanoyl] piperazine-1-yl] carbonyloxy-7-ethylcamptothecin (SN38Pt-SM6):

Under an argon gas atmosphere, 10- (4- [8- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -8-oxooctanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (898 mg, 0.921 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred overnight at room temperature. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the resulting residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give the title compound 581 mg (77%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.28-1.33 (7H, m), 1.46-1.54 (4H, m), 1.83- 1.89 (4H, m), 1.91-1.95 (2H, m), 2.30 (2H, t, J = 7.4 Hz), 2.36 (2H, t, J = 7.4 Hz), 3.17-3.22 (2H, m), 3.41 -3.47 (6H, m), 3.57-3.70 (6H, m), 5.34 (2H, s), 5.44 (2H, s), 7.33 (1H, s), 7.69 (1H, dd, J = 9.0, 2.4 Hz ), 8.02 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.0 Hz), 13.0 (2H, br.s).
ESI-MS m / z 816 ([M + H] ⁺ ).

(5) Synthesis of SN38Pt-6:

Under argon gas atmosphere, SN38Pt-SM6 (200 mg, 0.245 mmol) was dissolved in ethanol (60 mL). Diaqua DACH platinum complex (115 mg, 0.245 mmol) and water (7.35 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (4.90 mL, 0.490 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min). The resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 μm (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-6 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 82 mg (30%) of the title compound as a white powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 0.97-1.01 (2H, m), 1.16-1.23 (2H, m), 1.30 ( 3H, t, J = 7.6 Hz), 1.28-1.33 (4H, m), 1.43-1.54 (6H, m), 1.79-1.93 (4H, m), 2.02-2.07 (2H, m), 2.24-2.30 ( 4H, m), 2.36 (2H, t, J = 7.2 Hz), 2.50-2.60 (2H, m), 3.16-3.22 (2H, m), 3.42-3.71 (12H, m), 5.31 (2H, br. s), 5.34 (2H, s), 5.44 (2H, s), 5.99 (2H, br.s), 6.54 (1H, s), 7.33 (1H, s), 7.70 (1H, dd, J = 9.1, 2.3 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 562 ([M + 2H] ²⁺ ), 1123 ([M + H] ⁺ ).

Example 7 (Synthesis of SN38Pt-7)
(1) Synthesis of Di-tert-butyl 1- (12-ethoxy-12-oxododecanoyl) piperidine-4,4-dicarboxylate:

Under an argon gas atmosphere, dodecanedioic acid monoethyl ester (380 mg, 1.47 mmol) was dissolved in N, N-dimethylformamide (5 mL) and cooled to 0 ° C. TCTU (523 mg, 1.47 mmol) and N, N-diisopropylethylamine (750 μL, 4.41 mmol) were added thereto. Further, di-tert-butyl piperidine-4,4-dicarboxylate (300 mg, 1.05 mmol) was added, stirred at 0 ° C. for 10 minutes, and then stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 568 mg (quantitative) of the title compound as a colorless oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.17 (3H, t, J = 7.2 Hz), 1.24 (12H, br.s), 1.40 (18H, s), 1.40-1.56 ( 4H, m), 1.79 (2H, t, J = 5.6 Hz), 1.87 (2H, t, J = 4.8 Hz), 2.24-2.29 (4H, m), 3.42 (4H, t, J = 5.6 Hz), 4.04 (2H, q, J = 7.2 Hz).
ESI-MS m / z 526 ([M + H] ⁺ ).

(2) Synthesis of 12- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -12-oxododecanoic acid:

Di-tert-butyl 1- (12-ethoxy-12-oxododecanoyl) piperidine-4,4-dicarboxylate (568 mg, 1.05 mmol) was dissolved in ethanol (5 mL) and cooled to 0 ° C. 1 N sodium hydroxide aqueous solution (2.5 mL) was added there, and it returned to room temperature, and stirred for 4 hours. The reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was vacuum-dried to obtain 569 mg (quantitative) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24 (12H, br.s), 1.40 (18H, s), 1.40-1.49 (4H, m), 1.79 (2H, t, J = 5.2 Hz), 1.87 (2H, t, J = 5.5 Hz), 2.18 (2H, t, J = 7.4 Hz), 2.27 (2H, t, J = 7.4 Hz), 3.42 (4H, t, J = 5.6 Hz), 12.0 (1H, br.s).
ESI-MS m / z 498 ([M + H] ⁺ ).

(3) Synthesis of 10- [2-[(tert-Butoxycarbonyl) amino] ethyl] carbamoyloxy-7-ethylcamptothecin:

Under an argon gas atmosphere, Boc-β-Ala (946 mg, 5.00 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to −20 ° C. N-methylmorpholine (605 μL, 5.50 mmol) and chloroformic acid ethyl ester (524 μL, 5.50 mmol) were added thereto, and the mixture was stirred at −20 ° C. for 20 minutes. The reaction mixture was heated to 0 ° C., an aqueous solution (2.5 mL) of sodium azide (813 mg, 12.5 mmol) was added, and the mixture was stirred at 0 ° C. for 5 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried under vacuum to obtain 1.07 g (quantitative) of tert-butyl (3-azido-3-oxopropyl) carbamate as a pale yellow oily substance. This was used in the next step without purification.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.37 (9H, s), 2.48-2.51 (2H, m), 3.17 (2H, q, J = 6.3 Hz), 6.93 (1H, br.s).

Under an argon gas atmosphere, tert-butyl (3-azido-3-oxopropyl) carbamate (1.07 g, 5.00 mmol) was dissolved in toluene (10 mL), and stirred at 65 ° C. for 30 minutes until no bubbles were generated. The reaction mixture was cooled, and added to SN-38 (981 mg, 2.50 mmol) and triethylamine (681 μL, 5.00 mmol) in N, N-dimethylformamide (125 mL) under ice-cooling, and stirred at 0 ° C for 10 min. Thereafter, the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 325 mg (22%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.82-1.93 (2H, m) , 1.40 (9H, s), 3.08-3.21 (6H, m), 5.34 (2H, s), 5.44 (2H, s), 6.54 (1H, s), 6.94 (1H, t, J = 5.2 Hz), 7.32 (1H, s), 7.65 (1H, dd, J = 9.0, 2.4 Hz), 7.95 (2H, d, J = 2.4 Hz), 7.97 (1H, s), 8.18 (1H, d, J = 9.0 Hz) ).
ESI-MS m / z 579 ([M + H] ⁺ ).

(4) Synthesis of 10- (2-Aminoethyl) carbamoyloxy-7-ethylcamptothecin trifluoroacetate:

Under an argon gas atmosphere, 10- [2-[(tert-butoxycarbonyl) amino] ethyl] carbamoyloxy-7-ethylcamptothecin (307 mg, 0.531 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the resulting residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 283 mg (93%) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.82-1.93 (2H, m) , 2.97-3.02 (2H, m), 3.16-3.21 (2H, m), 3.36-3.41 (2H, m), 5.35 (2H, s), 5.45 (2H, s), 6.54 (1H, br.s) , 7.33 (1H, s), 7.70 (1H, dd, J = 9.0, 2.4 Hz), 7.89 (3H, br.s), 7.98 (1H, d, J = 2.4 Hz), 8.10 (1H, t, J = 5.5 Hz), 8.20 (1H, d, J = 9.3 Hz).
ESI-MS m / z 479 ([M + H] ⁺ ).

(5) Synthesis of 10- (2- [12- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -12-oxododecanamido] ethyl) carbamoyloxy-7-ethylcamptothecin:

In an argon gas atmosphere, 12- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -12-oxododecanoic acid (303 mg, 0.608 mmol) was dissolved in N, N-dimethylformamide (2 mL). And cooled to 0 ° C. TCTU (216 mg, 0.608 mmol) and N, N-diisopropylethylamine (310 μL, 1.82 mmol) were added thereto. Add 10- (2-aminoethyl) carbamoyloxy-7-ethylcamptothecin trifluoroacetate (250 mg, 0.434 mmol), N, N-diisopropylethylamine (74 μL, 0.434 mmol) in N, N-dimethylformamide (2 mL), The mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 90 minutes. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 142 mg (34%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.11-1.24 (12H, m), 1.30 (3H, t, J = 7.6 Hz) , 1.40 (18H, s), 1.37-1.43 (2H, m), 1.48-1.52 (2H, m), 1.76-1.79 (2H, m), 1.82-1.93 (4H, m), 2.07 (2H, t, J = 7.4 Hz), 2.24 (2H, t, J = 7.4 Hz), 3.13-3.24 (6H, m), 3.40 (4H, br.s), 5.34 (2H, s), 5.44 (2H, s), 6.53 (1H, s), 7.32 (1H, s), 7.65 (1H, dd, J = 9.3, 2.4 Hz), 7.96-7.90 (3H, m), 8.17 (1H, d, J = 9.3 Hz).
ESI-MS m / z 958 ([M + H] ⁺ ).

(6) Synthesis of 10- [2- [12- (4,4-Biscarboxylpiperidin-1-yl) -12-oxododecanamido] ethyl] carbamoyloxy-7-ethylcamptothecin (SN38Pt-SM7):

10- (2- [12- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -12-oxododecanamido] ethyl) carbamoyloxy-7-ethylcamptothecin (132 mg, 0.531 mmol) in an argon gas atmosphere Dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the resulting residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 105 mg (90%) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.18-1.25 (12H, m), 1.30 (3H, t, J = 7.6 Hz) , 1.38-1.43 (2H, m), 1.47-1.53 (2H, m), 1.81-1.93 (6H, m), 2.08 (2H, t, J = 7.4 Hz), 2.24 (2H, t, J = 7.4 Hz ), 3.13-3.24 (6H, m), 3.39-3.45 (4H, m), 5.34 (2H, s), 5.44 (2H, s), 7.32 (1H, s), 7.65 (1H, dd, J = 9.0 , 2.4 Hz), 7.90-7.96 (3H, m), 8.18 (1H, d, J = 9.0 Hz), 13.0 (2H, br.s).
ESI-MS m / z 846 ([M + H] ⁺ ).

(7) Synthesis of SN38Pt-7:

Under an argon gas atmosphere, SN38Pt-SM7 (80 mg, 0.0946 mmol) was dissolved in ethanol (23 mL). Diaqua DACH platinum complex (44 mg, 0.0946 mmol) and water (2.84 mL) were added thereto. Subsequently, 0.1 N sodium hydroxide aqueous solution (1.89 mL, 0.189 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min). The resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 μm (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-7 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 18 mg (17%) of the title compound as a white powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.2 Hz), 0.97-1.02 (2H, m), 1.21 (14H, s), 1.30 (3H, t, J = 7.6 Hz), 1.39-1.52 (6H, m), 1.80 (2H, d, J = 12.4 Hz), 1.84-1.93 (2H, m), 2.02-2.10 (4H, m), 2.23 (4H , t, J = 6.6 Hz), 2.50-2.57 (2H, m), 3.15-3.22 (6H, m), 3.40-3.46 (4H, m), 5.31 (2H, d, J = 7.3 Hz), 5.34 ( 2H, s), 5.44 (2H, s), 5.98 (2H, d, J = 8.3 Hz), 6.53 (1H, s), 7.33 (1H, s), 7.65 (1H, dd, J = 9.0, 2.4 Hz ), 7.90-7.96 (3H, m), 8.18 (1H, d, J = 9.3 Hz).
ESI-MS m / z 577 ([M + 2H] ²⁺ ), 1153 ([M + H] ⁺ ).

Example 8 (Synthesis of SN38Pt-8)
(1) Synthesis of Eicosanedioic acid monomethyl ester:

Under an argon gas atmosphere, methanol (40 mL) was added to eicosanedioic acid dimethyl ester (1.00 g, 2.70 mmol) and dissolved by heating at 50 ° C. The methanol solution (25 mL) of barium hydroxide anhydrous (231 mg, 1.35 mmol) was dripped there, and it stirred at 50 degreeC for 17 hours. The reaction solution was cooled to room temperature, and the precipitated solid was collected by filtration and washed with methanol. Ether and 1 N hydrochloric acid were added to the obtained white solid, and the mixture was shaken with a separatory funnel to separate the ether layer. The aqueous layer was further extracted with ether, combined with the previous ether layer, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 146 mg (15%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.23 (28H, s), 1.46-1.52 (4H, m), 2.18 (2H, t, J = 7.3 Hz), 2.28 (2H, t, J = 7.4 Hz), 3.57 (3H, s), 12.0 (1H, br.s).

(2) Synthesis of Di-tert-butyl 1- (20-methoxy-20-oxoicosanoyl) piperidine-4,4-dicarboxylate:

Under an argon gas atmosphere, eicosanedioic acid monomethyl ester (138 mg, 0.387 mmol) was dissolved in N, N-dimethylformamide (6 mL) and cooled to 0 ° C. TCTU (138 mg, 0.387 mmol) and N, N-diisopropylethylamine (197 μL, 1.16 mmol) were added thereto. Further, di-tert-butyl piperidine-4,4-dicarboxylate (92 mg, 0.323 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 171 mg (85%) of the title compound as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.25-1.31 (28H, s), 1.46 (18H, s), 1.58-1.63 (4H, m), 1.98 (4H, br.s), 2.28-2.32 (4H, m), 3.47 (2H, br.s), 3.61 (2H, br.s), 3.67 (3H, s).

(3) Synthesis of 20- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -20-oxoicosanoic acid:

Di-tert-butyl 1- (20-methoxy-20-oxoicosanoyl) piperidine-4,4-dicarboxylate (171 mg, 0.274 mmol) is dissolved in tetrahydrofuran (10 mL) and water (1 mL) and cooled to 0 ° C. did. Lithium hydroxide monohydrate (16 mg, 0.384 mmol) was added thereto, the mixture was returned to room temperature and stirred for 12 hours, lithium hydroxide monohydrate (16 mg, 0.384 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Furthermore, lithium hydroxide monohydrate (8 mg, 0.192 mmol) was added and stirred for 24 hours. The reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was vacuum-dried to obtain 148 mg (89%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24-1.35 (28H, m), 1.46 (18H, s), 1.56-1.67 (4H, m), 1.99 (4H, t, J = 5.5 Hz), 2.30-2.36 (4H, m), 3.49-3.62 (4H, m).

(4) Synthesis of 10- (4- [20- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -20-oxoicosanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

Dissolve 20- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -20-oxoicosanoic acid (148 mg, 0.242 mmol) in N, N-dimethylformamide (3 mL) under an argon gas atmosphere. And cooled to 0 ° C. TCTU (86 mg, 0.242 mmol) and N, N-diisopropylethylamine (123 μL, 0.242 mmol) were added thereto. 7-ethyl-10-[(piperazine-1-yl) carbonyloxy] camptothecin trifluoroacetate (150 mg, 0.242 mmol), N, N-diisopropylethylamine (41 μL, 0.242 mmol) in N, N-dimethylformamide (3 mL ) The solution was added and stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 194 mg (73%) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.23-1.32 (28H, m) , 1.40 (18H, s), 1.43-1.56 (4H, m), 1.77-1.80 (2H, m), 1.84-1.93 (4H, m), 2.25-2.30 (2H, m), 2.36 (2H, t, J = 7.4 Hz), 3.16-3.22 (2H, m), 3.42 (4H, t, J = 5.6 Hz), 3.45-3.70 (8H, m), 5.34 (2H, s), 5.44 (2H, s), 6.53 (1H, s), 7.33 (1H, s), 7.69 (1H, dd, J = 9.1, 2.6 Hz), 8.02 (1H, d, J = 2.7 Hz), 8.19 (1H, d, J = 9.3 Hz ).
ESI-MS m / z 1096 ([M + H] ⁺ ).

(5) Synthesis of 10- [4- [20- (4,4-Biscarboxylpiperidin-1-yl) -20-oxoicosanoyl] piperazine-1-yl] carbonyloxy-7-ethylcamptothecin (SN38Pt-SM8):

Under an argon gas atmosphere, 10- (4- [20- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -20-oxo-icosanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (183 mg, 0.167 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the resulting residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 98 mg (60%) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.9 Hz), 1.23-1.28 (28H, m), 1.30 (3H, t, J = 7.6 Hz) , 1.45 (2H, t, J = 6.5 Hz), 1.51 (2H, t, J = 6.6 Hz), 1.84 (2H, t, J = 7.0 Hz), 1.91 (2H, t, J = 6.7 Hz), 1.82 -1.93 (2H, m), 2.27 (2H, t, J = 7.4 Hz), 2.36 (2H, t, J = 7.4 Hz), 3.17-3.22 (2H, m), 3.38-3.70 (12H, m), 5.34 (2H, s), 5.44 (2H, s), 6.53 (1H, br.s), 7.33 (1H, s), 7.69 (1H, dd, J = 9.3, 2.4 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz), 13.0 (2H, br.s).
ESI-MS m / z 984 ([M + H] ⁺ ).

(6) Synthesis of SN38Pt-8:

Under an argon gas atmosphere, SN38Pt-SM8 (80 mg, 0.0813 mmol) was dissolved in ethanol (20 mL). Diaqua DACH platinum complex (38 mg, 0.0813 mmol) and water (2.44 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (1.63 mL, 0.163 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min). The obtained supernatant was subjected to reverse phase HPLC (SunFire OBD, C18, 5 μm (30 mmID X 150 mm), solvent: methanol / water = 9/1, Flow rate: 20 mL / min, UV 254 nm) After purification, a peak containing SN38Pt-8 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 37 mg (35%) of the title compound as a slightly yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.2 Hz), 0.96-1.02 (2H, m), 1.24 (30H, br.s), 1.30 ( 3H, t, J = 7.7 Hz), 1.42-1.47 (4H, m), 1.50-1.53 (2H, m), 1.80 (2H, d, J = 12.4 Hz), 1.84-1.93 (2H, m), 2.04 (2H, s), 2.25 (4H, t, J = 7.2 Hz), 2.36 (2H, t, J = 7.3 Hz), 2.47-2.58 (2H, m), 3.17-3.22 (2H, m), 3.40- 3.48 (4H, m), 3.51-3.70 (8H, m), 5.31 (2H, d, J = 8.5 Hz), 5.34 (2H, s), 5.44 (2H, s), 5.98 (2H, d, J = 8.3 Hz), 6.53 (1H, s), 7.33 (1H, s), 7.69 (1H, dd, J = 9.0, 2.4 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 646 ([M + 2H] ²⁺ ), 1291 ([M + H] ⁺ ).

Example 9 (Synthesis of SN38Pt-9)
(1) Synthesis of Di-tert-butyl 1- (6-ethoxy-6-oxohexanoyl) piperidine-4,4-dicarboxylate:

Under an argon gas atmosphere, monoethyl adipate (341 mg, 1.96 mmol) was dissolved in N, N-dimethylformamide (5 mL) and cooled to 0 ° C. TCTU (697 mg, 1.96 mmol) and N, N-diisopropylethylamine (1.00 mL, 5.88 mmol) were added thereto. Further, di-tert-butyl piperidine-4,4-dicarboxylate (400 mg, 1.40 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 622 mg (quantitative) of the title compound as a yellow oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.17 (3H, t, J = 7.2 Hz), 1.40 (18H, s), 1.44-1.56 (4H, m), 1.79 (2H, t, J = 5.5 Hz), 1.87 (2H, t, J = 4.5 Hz), 2.27-2.32 (4H, m), 3.42 (4H, t, J = 5.5 Hz), 4.04 (2H, q, J = 7.1 Hz).
ESI-MS m / z 442 ([M + H] ⁺ ).

(2) Synthesis of 6- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -6-oxohexanoic acid:

Di-tert-butyl 1- (6-ethoxy-6-oxohexanoyl) piperidine-4,4-dicarboxylate (568 mg, 1.05 mmol) was dissolved in ethanol (6 mL) and cooled to 0 ° C. 1 N sodium hydroxide aqueous solution (3 mL) was added there, and it returned to room temperature, and stirred for 4 hours. The reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was vacuum-dried to obtain 631 mg (quantitative) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.41 (18H, s), 1.51-1.45 (4H, m), 1.79 (2H, t, J = 5.4 Hz), 1.87 (2H, t, J = 5.2 Hz), 2.21 (2H, t, J = 6.7 Hz), 2.30 (2H, t, J = 6.3 Hz), 3.42 (4H, t, J = 5.6 Hz), 12.0 (1H, s) .
ESI-MS m / z 414 ([M + H] ⁺ ).

(3) Synthesis of 10- (4- [5-[(tert-Butoxycarbonyl) amino] pentanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin:

Under an argon gas atmosphere, 5- (tert-butoxycarbonylamino) valeric acid (426 mg, 1.96 mmol) was dissolved in N, N-dimethylformamide (4 mL) and cooled to 0 ° C. TCTU (697 mg, 1.96 mmol) and N, N-diisopropylethylamine (1.00 mL, 5.98 mmol) were added thereto. 7-ethyl-10-[(piperazine-1-yl) carbonyloxy] camptothecin trifluoroacetate (866 mg, 1.40 mmol), N, N-diisopropylethylamine (238 μL, 1.40 mmol) in N, N-dimethylformamide (3 mL ) The solution was added and stirred at 0 ° C. for 10 minutes and then at room temperature for 4 hours. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 969 mg (98%) of the title compound as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.89 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.38 (9H, s), 1.38 -1.44 (2H, m), 1.47-1.54 (2H, m), 1.82-1.93 (2H, m), 2.37 (2H, t, J = 7.2 Hz), 2.91-2.96 (2H, m), 3.16-3.22 (2H, m), 3.47-3.71 (8H, m), 5.33 (2H, s), 5.44 (2H, s), 6.54 (1H, s), 6.82 (1H, t, J = 5.5 Hz), 7.32 ( 1H, s), 7.69 (1H, dd, J = 9.4, 2.3 Hz), 8.01 (1H, d, J = 2.0 Hz), 8.18 (1H, d, J = 9.3 Hz).
ESI-MS m / z 704 ([M + H] ⁺ ).

(4) Synthesis of 10- [4- (5-Aminopentanoyl) piperazine-1-yl] carbonyloxy-7-ethylcamptothecin trifluoroacetate:

10- (4- [5-[(tert-butoxycarbonyl) amino] pentanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (969 mg, 1.38 mmol) in trifluoroacetic acid (5 mL) under argon gas atmosphere Dissolved and stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the resulting residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 851 mg (86%) of the title compound as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.4 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.57-1.60 (4H, m) , 1.82-1.93 (2H, m), 2.41-2.45 (2H, m), 2.79-2.85 (2H, m), 3.17-3.22 (2H, m), 3.47-3.72 (8H, m), 5.34 (2H, s), 5.45 (2H, s), 6.53 (1H, br.s), 7.33 (1H, s), 7.69 (2H, dd, J = 9.0, 2.4 Hz), 7.67-7.73 (2H, m), 8.01 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 604 ([M + H] ⁺ ).

(5) 10- [4- (5- [6- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -6-oxohexanamido] pentanoyl) piperazine-1-yl] carbonyloxy-7-ethylcamptothecin Synthesis:

6- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -6-oxohexanoic acid (631 mg, 1.40 mmol) was dissolved in N, N-dimethylformamide (4 mL) under an argon gas atmosphere. And cooled to 0 ° C. TCTU (498 mg, 1.40 mmol) and N, N-diisopropylethylamine (714 μL, 1.40 mmol) were added thereto. Furthermore, 10- [4- (5-aminopentanoyl) piperazine-1-yl] carbonyloxy-7-ethylcamptothecin trifluoroacetate (718 mg, 1.00 mmol), N, N-diisopropylethylamine (170 μL, 1.00 mmol) N, N-dimethyl A formamide (3 mL) solution was added, and the mixture was stirred at 0 ° C. for 10 min and then at room temperature for 4 hr. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 927 mg (93%) of the title compound as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.40 (18H, s), 1.40 -1.55 (8H, m), 1.77-1.80 (2H, m), 1.82-1.93 (4H, m), 2.06 (2H, t, J = 6.8 Hz), 2.29 (2H, t, J = 7.0 Hz), 2.38 (2H, t, J = 7.3 Hz), 3.03-3.07 (2H, m), 3.17-3.22 (2H, m), 3.40-3.44 (4H, m), 3.52-3.70 (8H, m), 5.34 ( 2H, s), 5.44 (2H, s), 6.55 (1H, s), 7.33 (1H, s), 7.69 (1H, dd, J = 9.3, 2.4 Hz), 7.80 (1H, t, J = 5.5 Hz ), 8.02 (1H, d, J = 2.2 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 999 ([M + H] ⁺ ).

(6) Synthesis of 10- (4- [5- [6- (4,4-Biscarboxylpiperidin-1-yl) -6-oxohexanamido] pentanoyl] piperazine-1-yl) carbonyloxy-7-ethylcamptothecin (SN38Pt-SM9) :

Under an argon gas atmosphere, 10- [4- (5- [6- [4,4-bis (tert-butoxycarbonyl) piperidin-1-yl] -6-oxohexanamido] pentanoyl) piperazine-1-yl] carbonyloxy-7- Ethylcamptothecin (927 mg, 0.927 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred overnight at room temperature. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the resulting residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give the title compound (646 mg, 79%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.6 Hz), 1.40-1.53 (8H, m) , 1.82-1.93 (6H, m), 2.06 (2H, t, J = 7.0 Hz), 2.29 (2H, t, J = 7.0 Hz), 2.38 (2H, t, J = 7.3 Hz), 3.03-3.07 ( 2H, m), 3.17-3.22 (2H, m), 3.41-3.47 (4H, m), 3.52-3.71 (8H, m), 5.35 (2H, s), 5.44 (2H, s), 7.33 (1H, s), 7.70 (1H, dd, J = 9.1, 2.3 Hz), 7.79 (1H, t, J = 5.5 Hz), 8.03 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz), 13.0 (2H, br.s).
ESI-MS m / z 887 ([M + H] ⁺ ).

(7) Synthesis of SN38Pt-9:

Under an argon gas atmosphere, SN38Pt-SM9 (200 mg, 0.225 mmol) was dissolved in ethanol (56 mL). Diaqua DACH platinum complex (106 mg, 0.225 mmol) and water (6.75 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (4.51 mL, 0.451 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min). The resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 μm (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-9 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 157 mg (58%) of the title compound as a yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 0.97-1.04 (2H, m), 1.17-1.23 (2H, m), 1.30 ( 3H, t, J = 7.6 Hz), 1.41-1.54 (10H, m), 1.80 (2H, d, J = 12.0 Hz), 1.84-1.93 (2H, m), 2.06 (4H, t, J = 6.8 Hz ), 2.23-2.29 (4H, m), 2.38 (2H, t, J = 6.8 Hz), 2.47-2.56 (2H, m), 3.03-3.07 (2H, m), 3.16-3.22 (2H, m), 3.42-3.71 (12H, m), 5.30 (2H, d, J = 8.5 Hz), 5.35 (2H, s), 5.44 (2H, s), 5.99 (2H, d, J = 7.6 Hz), 6.54 (1H , s), 7.33 (1H, s), 7.70 (1H, dd, J = 9.1, 2.1 Hz), 7.80 (1H, t, J = 5.5 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 598 ([M + 2H] ²⁺ ), 1194 ([M + H] ⁺ ).

Example 10 (Synthesis of SN38Pt-10)
(1) Synthesis of Methyl 10-hydroxydecanoate:

Under an argon gas atmosphere, monomethyl sebacate (1.00 g, 4.62 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -20 ° C. Borane hydrate complex (1M in tetrahydrofuran, 4.62 mL, 4.62 mmol) was added dropwise thereto, and the mixture was stirred for 4 hours while gradually warming to room temperature. Water (8 mL) was added to the reaction solution for quenching, and potassium carbonate (977 mg) was further added, followed by extraction with ether. The ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 896 mg (96%) of the title compound as a pale yellow oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24 (10H, br.s), 1.39 (1H, t, J = 6.6 Hz), 1.51 (2H, t, J = 7.1 Hz) , 2.28 (2H, t, J = 7.4 Hz), 3.34-3.39 (2H, m), 3.58 (3H, s), 4.32 (1H, t, J = 5.2 Hz).
ESI-MS m / z 203 ([M + H] ⁺ ).

(2) Synthesis of Methyl 10-oxodecanoate:

Under an argon gas atmosphere, oxalyl chloride (456 μL, 5.32 mmol) was dissolved in dichloromethane (6 mL) and cooled to −78 ° C. A dichloromethane solution (7 mL) of dimethyl sulfoxide (346 μL, 4.87 mmol) was added dropwise thereto, and the mixture was stirred at −78 ° C. for 5 minutes. Further, a dichloromethane solution (5 mL) of methyl 10-hydroxydecanoate (896 mg, 4.43 mmol) was added dropwise, and the mixture was stirred at −78 ° C. for 15 minutes. Triethylamine (3.02 mL) was added to the reaction mixture all at once, and the mixture was stirred at −78 ° C. for 10 minutes, and then stirred for 4 hours while gradually warming to room temperature. The reaction solution was diluted with chloroform and washed with a saturated aqueous ammonium chloride solution and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to give the title compound (569 mg, 64%) as a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24 (8H, br.s), 1.47-1.54 (4H, m), 2.28 (2H, t, J = 7.3 Hz), 2.41 ( 2H, td, J = 7.3, 2.6 Hz), 3.57 (3H, s), 9.66 (1H, t, J = 1.7 Hz).

(3) Synthesis of (E) -12-Methoxy-12-oxododec-2-enoic acid:

Under an argon gas atmosphere, (diethylphosphinoyl) acetic acid (613 mg, 3.12 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -78 ° C. N-BuLi (1.6 M in n-hexane, 3.90 mL, 6.86 mmol) was added dropwise thereto. Further, a tetrahydrofuran solution (5 mL) of methyl 10-oxodecanoate (569 mg, 2.84 mmol) was added dropwise, stirred at −78 ° C. for 2 hours, and then stirred for 16 hours while gradually warming to room temperature. Water (5 mL) was added to the reaction solution to quench it, and tetrahydrofuran was distilled off. The obtained aqueous layer was cooled to 0 ° C., adjusted to pH 1 with hydrochloric acid, and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 366 mg (53%) of the title compound as a reddish brown oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.25 (10H, br.s), 1.37-1.41 (2H, m), 2.14-2.20 (2H, m), 2.28 (2H, t , J = 7.2 Hz), 3.58 (3H, s), 5.75 (1H, d, J = 15.6 Hz), 6.81 (1H, dd, J = 15.6, 7.0 Hz), 12.1 (1H, br.s).
ESI-MS m / z 243 ([M + H] ⁺ ).

(4) Synthesis of (E) -Di-tert-butyl 1- (12-methoxy-12-oxododec-2-enoyl) piperidine-4,4-dicarboxylate:

Under an argon gas atmosphere, (E) -12-methoxy-12-oxododec-2-enoic acid (366 mg, 1.51 mmol) was dissolved in N, N-dimethylformamide (6 mL) and cooled to 0 ° C. TCTU (537 mg, 1.51 mmol) and N, N-diisopropylethylamine (770 mL, 4.53 mmol) were added thereto. Further, di-tert-butyl piperidine-4,4-dicarboxylate (359 mg, 1.26 mmol) was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 492 mg (77%) of the title compound as a yellow oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.25 (10H, br.s), 1.41 (18H, s), 1.48-1.53 (2H, m), 1.79-1.87 (4H, m ), 2.13-2.17 (2H, m), 2.25-2.30 (2H, m), 3.48-3.54 (4H, m), 3.57 (3H, s), 6.44 (1H, d, J = 14.6 Hz), 6.60- 6.67 (1H, m).
ESI-MS m / z 510 ([M + H] ⁺ ).

(5) Synthesis of (E) -12- (4,4-Bis (tert-butoxycarbonyl) piperidine-1-yl) -12-oxododec-10-enoic acid:

Dissolve (E) -Di-tert-butyl 1- (12-methoxy-12-oxododec-2-enoyl) piperidine-4,4-dicarboxylate (492 mg, 0.965 mmol) in ethanol (4 mL) at 0 ° C Cooled to. 1 N sodium hydroxide aqueous solution (2 mL) was added there, and it returned to room temperature, and stirred for 14 hours. The reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was vacuum-dried to obtain 562 mg (quantitative) of the title compound as a yellow oily substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24-1.26 (10H, m), 1.41 (18H, s), 1.46-1.49 (2H, m), 1.78-1.88 (4H, m ), 2.13-2.20 (4H, m), 3.41-3.52 (4H, m), 6.44 (1H, d, J = 15.1 Hz), 6.60-6.68 (1H, m), 12.0 (1H, br.s).
ESI-MS m / z 496 ([M + H] ⁺ ).

(6) 10-((E) -4- [12- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -12-oxododec-10-enoyl] piperazine-1-yl) carbonyloxy-7 Synthesis of -ethylcamptothecin:

Under an argon gas atmosphere, (E) -12- (4,4-Bis (tert-butoxycarbonyl) piperidine-1-yl) -12-oxododec-10-enoic acid (582 mg, 0.965 mmol) was replaced with N, N-dimethyl Dissolved in formamide (3 mL) and cooled to 0 ° C. TCTU (343 mg, 0.965 mmol) and N, N-diisopropylethylamine (492 μL, 2.90 mmol) were added thereto. Furthermore, 7-ethyl-10-[(piperazine-1-yl) carbonyloxy] camptothecin trifluoroacetate (497 mg, 0.804 mmol), N, N-diisopropylethylamine (137 μL, 0.804 mmol) in N, N-dimethylformamide (3 mL ) The solution was added and stirred at 0 ° C. for 10 minutes and then at room temperature for 1 hour. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 772 mg (98%) of the title compound as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.31-1.24 (13H, m), 1.40 (18H, s), 1.46-1.56 ( 2H, m), 1.78-1.93 (6H, m), 2.14-2.19 (2H, m), 2.36 (2H, t, J = 7.4 Hz), 3.16-3.22 (2H, m), 3.42-3.70 (12H, m), 5.34 (2H, s), 5.44 (2H, s), 6.45 (1H, d, J = 15.1 Hz), 6.54 (1H, s), 6.62-6.69 (1H, m), 7.32 (1H, s ), 7.69 (1H, dd, J = 9.4, 2.1 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.0 Hz).
ESI-MS m / z 982 ([M + H] ⁺ ).

(7) 10-[(E) -4- [12- (4,4-Biscarboxylpiperidin-1-yl) -12-oxododec-10-enoyl] piperazine-1-yl] carbonyloxy-7-ethylcamptothecin (SN38Pt-SM10 ) Synthesis:

10-((E) -4- [12- [4,4-Bis (tert-butoxycarbonyl) piperidin-1-yl] -12-oxododec-10-enoyl] piperazine-1-yl) carbonyloxy under argon gas atmosphere -7-ethylcamptothecin (772 mg, 0.786 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 2 hours. Concentrate the reaction mixture, add dimethyl sulfoxide to the residue, reverse phase HPLC (SunFire OBD, C18, 5 μm (30 mmID x 150 mm), solvent: 0.1% trifluoroacetic acid in water / 0.1% trifluoroacetic acid in acetonitrile gradient , Flow rate: 20 mL / min, UV 254 nm), and a peak containing SN38Pt-SM10 was collected. The fractions collected were collected and acetonitrile was distilled off. The resulting aqueous solution was lyophilized to give 156 mg (24%) of the title compound as a yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.27-1.32 (11H, m), 1.40-1.43 (2H, m), 1.50- 1.54 (2H, m), 1.82-1.93 (6H, m), 2.15-2.20 (2H, m), 2.32-2.38 (2H, m), 3.17-3.22 (2H, m), 3.45-3.70 (12H, m ), 5.34 (2H, s), 5.44 (2H, s), 6.45 (1H, d, J = 15.1 Hz), 6.62-6.69 (1H, m), 7.33 (1H, s), 7.70 (1H, dd, J = 9.0, 2.4 Hz), 8.02 (1H, d, J = 2.7 Hz), 8.19 (1H, d, J = 9.0 Hz).
ESI-MS m / z 870 ([M + H] ⁺ ).

(8) Synthesis of SN38Pt-10:

Under an argon gas atmosphere, SN38Pt-SM10 (80 mg, 0.0920 mmol) was dissolved in ethanol (23 mL). The diaquo DACH platinum complex (43 mg, 0.0920 mmol) and water (2.76 mL) were added there. Subsequently, 0.1 N sodium hydroxide aqueous solution (1.84 mL, 0.184 mmol) was added, and it stirred at 50 degreeC for 23 hours. The reaction mixture was concentrated to dryness, N, N-dimethylacetamide was added to the residue, and the mixture was centrifuged (8,000 rpm, 5 min). The resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 μm (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-10 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 32 mg (30%) of the title compound as a yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 0.97-1.02 (2H, m), 1.18-1.23 (2H, m), 1.27- 1.31 (11H, m), 1.39-1.45 (4H, m), 1.50-1.54 (2H, m), 1.80 (2H, d, J = 12.0 Hz), 1.84-1.93 (2H, m), 2.04 (2H, br.s), 2.15-2.25 (4H, m), 2.36 (2H, t, J = 7.4 Hz), 2.58-2.55 (2H, m), 3.17-3.22 (2H, m), 3.42-3.70 (12H, br.s), 5.31 (2H, br.s), 5.34 (2H, s), 5.44 (2H, s), 6.00 (2H, br.s), 6.46 (1H, d, J = 14.9 Hz), 6.55 (1H, br.s), 6.59-6.66 (1H, m), 7.33 (1H, s), 7.70 (1H, dd, J = 9.1, 2.6 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 589 ([M + 2H] ²⁺ ), 1177 ([M + H] ⁺ ).

Example 11 (Synthesis of SN38Pt-11)
(1) Synthesis of 1-tert-Butyl 12-ethyl dodecanedioate:

Under an argon gas atmosphere, dodecanedioic acid monoethyl ester (1.50 g, 5.81 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0 ° C. A solution of t-butanol (1.29 g, 17.4 mmol) in dichloromethane (5 mL) and dimethylaminopyridine (568 mg, 4.65 mmol) were added thereto. Further, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (1.23 g, 6.39 mmol) was added little by little, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 22 hours. The reaction mixture was concentrated, the residue was redissolved in ether, and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The ether layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate / n-hexane stepwise) to obtain 924 mg (51%) of the title compound as a colorless oily substance.
¹ H-NMR (400 MHz, CDCl ₃ ) δ [ppm]: 1.25 (3H, t, J = 7.1 Hz), 1.32-1.25 (12H, m), 1.44 (9H, s), 1.53-1.65 (4H, m), 2.20 (2H, t, J = 7.6 Hz), 2.28 (2H, t, J = 7.6 Hz), 4.12 (2H, q, J = 7.2 Hz).
ESI-MS m / z 315 ([M + H] ⁺ ).

(2) Synthesis of 12- (tert-Butoxy) -12-oxododecanoic acid:

1-tert-Butyl 12-ethyl dodecanedioate (924 mg, 2.94 mmol) was dissolved in ethanol (12 mL) and cooled to 0 ° C. 1 N sodium hydroxide aqueous solution (6 mL) was added there, and it returned to room temperature, and stirred for 19 hours. The reaction mixture was cooled to 0 ° C., 1N hydrochloric acid was added to adjust the pH to around 3, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was vacuum-dried to obtain the title compound (777 mg, 92%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24 (12H, s), 1.39 (9H, s), 1.44-1.50 (4H, m), 2.17 (4H, q, J = 7.6 Hz), 12.0 (1H, s).
ESI-MS m / z 287 ([M + H] ⁺ ).

(3) Synthesis of 10- [4- [12- (tert-Butoxy) -12-oxododecanoyl] piperazine-1-yl] carbonyloxy-7-ethylcamptothecin:

Under an argon gas atmosphere, 12- (tert-butoxy) -12-oxododecanoic acid (777 mg, 2.71 mmol) was dissolved in N, N-dimethylformamide (8 mL) and cooled to 0 ° C. TCTU (963 mg, 2.71 mmol) and N, N-diisopropylethylamine (1.38 mL, 8.13 mmol) were added thereto. Furthermore, 7-ethyl-10-[(piperazine-1-yl) carbonyloxy] camptothecin trifluoroacetate (1.20 mg, 1.94 mmol), N, N-diisopropylethylamine (330 μL, 1.94 mmol) in N, N-dimethylformamide solution ( 8 mL) was added, and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2 hours. Chloroform was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (methanol / chloroform stepwise) to obtain 1.30 g (87%) of the title compound as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.8 Hz), 1.30 (3H, t, J = 7.7 Hz), 1.26-1.32 (12H, m) , 1.39 (9H, s), 1.45-1.55 (4H, m), 1.82-1.93 (2H, m), 2.17 (2H, t, J = 7.3 Hz), 2.36 (2H, t, J = 7.4 Hz), 3.17-3.22 (2H, m), 3.46-3.70 (8H, m), 5.34 (2H, s), 5.44 (2H, s), 6.54 (1H, s), 7.33 (1H, s), 7.70 (1H, dd, J = 9.0, 2.0 Hz), 8.02 (1H, d, J = 2.2 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 773 ([M + H] ⁺ ).

(4) Synthesis of 10- [4- (11-Carboxyundecanoyl) piperazine-1-yl] carbonyloxy-7-ethylcamptothecin (SN38Pt-SM11):

10- [4- [12- (tert-butoxy) -12-oxododecanoyl] piperazine-1-yl] carbonyloxy-7-ethylcamptothecin (1.30 g, 1.68 mmol) in trifluoroacetic acid (10 mL) under an argon gas atmosphere Dissolved and stirred at room temperature for 14 hours. The reaction mixture was concentrated to dryness, ethanol / n-hexane was added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give the title compound (657 mg, 55%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (3H, t, J = 7.3 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.26-1.31 (12H, m) , 1.51 (4H, m), 1.82-1.93 (2H, m), 2.19 (2H, t, J = 7.3 Hz), 2.36 (2H, t, J = 7.2 Hz), 3.17-3.24 (2H, m), 3.43-3.70 (8H, m), 5.34 (2H, s), 5.45 (2H, s), 6.56 (1H, br.s), 7.32 (1H, s), 7.70 (1H, dd, J = 9.1, 2.3 Hz), 8.02 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.3 Hz).
ESI-MS m / z 717 ([M + H] ⁺ ).

(5) Synthesis of SN38Pt-11:

Under an argon gas atmosphere, diaquo DACH platinum complex (27 mg, 0.058 mmol) was suspended in chloroform (2.5 mL) and water (2.5 mL), and heated to 50 ° C. SN38Pt-SM11 (76 mg, 0.106 mmol) was added there, then 0.1 N sodium hydroxide aqueous solution (1.06 mL, 0.106 mmol) was added, and it stirred at 50 degreeC for 23 hours. The chloroform layer was separated and the aqueous layer was extracted with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. N, N-dimethylacetamide was added to the resulting residue and centrifuged (8,000 rpm, 5 min). The resulting supernatant was purified using reverse-phase HPLC (SunFire OBD, C18, 5 μm (30 mmID X 150 mm), solvent: methanol / water gradient, Flow rate: 20 mL / min, UV 254 nm), A peak containing SN38Pt-11 was collected. The fractions collected were collected and methanol was distilled off. The resulting aqueous solution was lyophilized to give 21 mg (21%) of the title compound as a yellow powder.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.88 (6H, t, J = 7.2 Hz), 0.94-0.99 (2H, m), 1.24-1.31 (29H, m), 1.39- 1.53 (10H, m), 1.81-1.92 (4H, m), 2.00-2.09 (4H, m), 2.12-2.18 (2H, m), 2.33-2.37 (4H, m), 2.47-2.53 (2H, m ), 3.14-3.20 (4H, m), 3.45-3.69 (16H, m), 5.04-5.08 (2H, m), 5.30 (4H, s), 5.43 (4H, s), 5.99 (2H, d, J = 9.5 Hz), 6.53 (2H, s), 7.30 (2H, s), 7.67 (2H, dd, J = 9.3, 2.2 Hz), 7.98 (2H, d, J = 1.7 Hz), 8.15 (2H, d , J = 9.3 Hz).
ESI-MS m / z 1741 ([M + H] ⁺ ).

Example 12 (Anti-tumor effect of SN38Pt-4)
The antitumor effect of SN38Pt-4 (Example 4) was examined using a tumor growth inhibition rate (IR%) as an index in a human colon cancer cell (HT-29) xenograft tumor model transplanted into nude mice. Table 1 shows the results of the antitumor effect test.
In addition, for each administration group shown in the table, the amount of active ingredient contained in the total dose (mg / kg) of the administered test substance is the SN-38 amount (mg / kg) or DACH-Pt amount (mg / kg). ) In the same table.

(experimental method)
1. Animals:
As animals, 5-week-old male nude mice (BALB / c Slc-nu) were purchased from Japan SLC Co., Ltd. and used as 5 animals per group.
2. Tumor cells:
Human colorectal cancer cells (HT-29) were purchased from the American Type Culture Collection (ATCC) and Dulbecco's Modified Eagle's Medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin and 100 μg / mL streptomycin. (DMEM medium) (10% FBS / DMEM) was used for subculture under conditions of 5% CO ₂ and 37 ° C.

3. Implementation of anti-tumor effect test:
2 × 10 ⁶ cells / 0.1 mL / mouse HT-29 cells were transplanted subcutaneously into the left groin of nude mice using a syringe and a needle. The average tumor volume of each group was made uniform as Day 1 when the average estimated tumor volume obtained from 1 / 2ab ² (a is the major axis of the tumor, b is the minor axis) reached approximately 155 mm ³ After grouping, the test substance was dissolved in dimethylacetamide a total of 3 times on Days 1, 8, and 15, and suspended uniformly in 10% Tween 80/5% glucose solution and administered intraperitoneally. Similarly, on days 1, 8, and 15, oxaliplatin (L-OHP) (6.7 mg / kg) or irinotecan hydrochloride (CPT-11) (71 mg / kg) was totaled 3 times (total 20, 213 mg / kg) Dissolved in physiological saline and administered intraperitoneally. The control group received the solvent on a similar schedule. After removing the tumor on Day 22 and measuring the weight, the tumor growth inhibition rate IR (%) was determined by the following formula.

Tumor growth inhibition rate IR (%)
= (1-average tumor weight in treated group / average tumor weight in control group) x 100

4. Dosage:
The dosage of SN38Pt-4 was set to the maximum dosage (MD = 200 mg / kg / day) at which no death occurred when administered intraperitoneally to mice on Days 1 and 8, The total dose was 600 mg / kg, and the dose was reduced by 2 (total dose 300 mg / kg, 150 mg / kg). The dose of CPT-11 is within the range that does not exceed the maximum tolerated dose (270 mg / kg) and is expected to have a sufficient antitumor effect. The total dose is 213 mg / kg (71 mg / kg / 1 Times). L-OHP was the maximum tolerated dose of 20 mg / kg (6.7 mg / kg / dose).

From the results of Table 1, SN38Pt-4 showed a significant (p <0.001) lower tumor weight in the HT-29 tumor model than the control group, confirming an excellent antitumor effect. SN38Pt-4 showed an antitumor effect in a dose-dependent manner, with a significantly higher antitumor effect (IR 81.8%) in the 600 mg / kg group than in the L-OHP + CPT-11 combination group (IR 50.5%) Indicated.
For L-OHP, the maximum tolerated total dose of 20 mg / kg was administered, and deaths were observed when the dose was increased more than that. However, SN38Pt-4 had a higher dose (DACH-Pt In the equivalent amount), no death cases are observed, and an excellent antitumor effect can be obtained in a dose-dependent manner. More specifically, when considering the maximum tolerated dose of L-OHP (including 16 mg / kg as DACH-Pt amount), in this study, SN38Pt-4 is 600 mg / kg (DACH-Pt amount is about 10 times the amount) (157 mg / kg), almost no toxicity was observed (Mortality: 1/5), and a dose-dependent antitumor effect was obtained.
Similarly, when considering the maximum tolerated dose of CPT-11 (including 156 mg / kg as the SN-38 amount), SN38Pt-4 can be used at higher doses (200 mg / kg as the SN-38 amount). Almost no toxicity was observed (Mortality: 1/5), and a dose-dependent antitumor effect was obtained.

Example 13 (Preparation of SN38Pt-4 micelles)
SN38Pt-4 (14.29 mg) was suspended in ethanol (0.3 mL), and SL-11 (392 μL) (manufactured by NOF) that had been heated to 90 ° C. was added and dissolved by heating. Ethanol was distilled off using a centrifugal evaporator, and dissolved again by warming.Add 5% glucose solution (1608 μL) that had been heated to 90 ° C, and stirred to prepare micelles (SN38Pt per unit of micelles) -4 amount: 7 mg / mL).

Claims (11)

1. The following general formula (1) or (2):
   

   

   (In the formula, A and B each independently represent a substituted or unsubstituted alkylene group, an alkylenecarbonyl group, an acyclic or cyclic aminoalkyleneaminocarbonyl group)
   A camptothecin derivative having a platinum complex structure represented by:
2. In general formula (1) or (2), A and B are each independently absent or a substituted or unsubstituted alkylene group, alkylenecarbonyl group, acyclic or a cyclic aminoalkyleneamino containing a nitrogen atom. The camptothecin derivative having a platinum complex structure according to claim 1, which represents a carbonyl group.
3. In general formula (1) or (2), A is independently absent, a substituted or unsubstituted linear alkylene group having 1 to 6 carbon atoms, a substituted or unsubstituted carbon group having 1 to 18 carbon atoms. A linear alkylenecarbonyl group, a substituted or unsubstituted C3-C18 linear alkylenecarbonyl group having 1 to 3 unsaturated bonds, or one or more of —CONR ¹ — (R ¹ is B represents an alkylenecarbonyl group having 2 to 18 carbon atoms optionally interrupted by a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and B is independently absent or linear aminoalkylene (carbon The camptothecin derivative having a platinum complex structure according to claim 1 or 2, which represents an aminocarbonyl group or a cyclic diaminocarbonyl group having 2 to 6 carbon atoms.
4. The following compounds:
   

   

   

   

   The camptothecin derivative having a platinum complex structure according to any one of claims 1 to 3, which is selected from the group consisting of:
5. A pharmaceutical comprising the camptothecin derivative having a platinum complex structure according to any one of claims 1 to 4 as an active ingredient.
6. An anticancer agent comprising the camptothecin derivative having a platinum complex structure according to any one of claims 1 to 4 as an active ingredient.
7. A pharmaceutical composition comprising the camptothecin derivative having a platinum complex structure according to any one of claims 1 to 4 in a form encapsulated in micelles.
8. An anticancer composition comprising the camptothecin derivative having a platinum complex structure according to any one of claims 1 to 4 in a form encapsulated in micelles.
9. A method for treating cancer, comprising administering an effective amount of a camptothecin derivative having a platinum complex structure according to any one of claims 1 to 4.
10. Use of a camptothecin derivative having a platinum complex structure according to any one of claims 1 to 4 for producing a medicament.
11. Use of the camptothecin derivative having a platinum complex structure according to any one of claims 1 to 4 for producing an anticancer agent.