JP7223502B6 - pharmaceutical composition - Google Patents

Description

PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions. In particular, the present invention relates to a pharmaceutical composition for treating or preventing cancer resistant to anticancer drugs.

When treated with anticancer drugs, temporary disappearance of cancer can be confirmed, but it is difficult to eradicate all cancer cells with the anticancer drugs developed to date. It is known that cancer recurs and metastasizes when a small number of cancer cells that have acquired resistance to anticancer drugs survive.

For example, gefitinib is an anticancer drug that inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), and is used as a therapeutic agent for non-small cell lung cancer. Gefitinib is effective against non-small cell lung cancer that expresses EGFR with the L858R mutation, but when the T790M mutation occurs, the cancer becomes gefitinib-resistant. Osimertinib is effective against gefitinib-resistant cancers that express EGFR with the T790M mutation. However, when the C797S mutation occurs, the cancer becomes resistant to osimertinib as well. At present, no drug has been developed that is effective against cancers that express EGFR with three mutations: L858R, T790M, and C797S.

On the other hand, Staurosporine is a natural product isolated from actinomycetes of the genus Streptomyces (Non-Patent Document 1), and is known to have antitumor effects (for example, Patent Document 1). ). To date, staurosporine analogs such as K252a have been reported (eg, Patent Document 2).

Japanese Unexamined Patent Publication No. 62-220196 US Patent No. 8,673,347

Omura S, et al., A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J Antibiot (Tokyo). 1977 Apr;30(4):275-82.

As mentioned above, when cancer acquires anticancer resistance due to genetic mutations, there is a problem in that it becomes difficult to treat with existing anticancer drugs. Therefore, there is a need to develop drugs that are effective against cancers that are resistant to anticancer drugs. On the other hand, staurosporine and its analogs have been known to have antitumor activity, but their effectiveness against anticancer drug-resistant cancers has not been shown. Furthermore, since the safety margin is extremely narrow, effective administration methods for cancer treatment are required. Furthermore, staurosporine and its analogs are difficult to administer intravenously because they are poorly soluble.
The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a pharmaceutical composition that can be used for the treatment or prevention of cancer resistant to anticancer drugs.

The present invention includes the following aspects.
[1] Compound (S) represented by the following general formula (S), or a pharmaceutically acceptable salt thereof, or the compound (S) or its pharmaceutically acceptable salt in a pharmaceutically acceptable polymer. A pharmaceutical composition for treating or preventing anticancer drug-resistant cancer, comprising a drug complex bound to a salt.

［式中、
Ｘ及びＹは、それぞれ独立に、Ｈ、ＯＨ、Ｃｌ、プロポキシ、又はエチルチオメチルであり；
Ｒ₆は、Ｈ、Ｃ_1-3アルキル、－ＮＨ₂、ベンジル、

[In the formula,
X and Y are each independently H, OH, Cl, propoxy, or ethylthiomethyl;
R ₆ is H, C _1-3 alkyl, -NH ₂ , benzyl,

又は

or

であり；
Ｒ₇及びＲ₈は、それぞれ独立に、Ｈ、－ＯＨ、又はメトキシであるか、或いは一緒になってＯ＝を形成してもよく；
Ｒ₉及びＲ₁₀は、それぞれ独立に、Ｈ、メチル、β－Ｄ－グルコピラノシル、４－Ｏ－メチル－β－Ｄ－グルコピラノシル、シアノエチル、又は

And;
R ₇ and R ₈ are each independently H, -OH, or methoxy, or may be taken together to form O=;
R ₉ and R ₁₀ are each independently H, methyl, β-D-glucopyranosyl, 4-O-methyl-β-D-glucopyranosyl, cyanoethyl, or

であるか、或いは一緒になって、以下の：

or together with:

を形成してもよく、ここで
Ｒ₁₁は、メチルであり；
Ｒ₁₂は、Ｈであり；
Ｒ₁₃及びＲ₁₄は、それぞれ独立に、Ｈ、メトキシ、－ＯＨ、ヒドロキシメチル、メチルカルボキシレート、メチルアミノ、メチルアミノメチル、プロピルアミノメチル、ジメチルアミノメチル、メトキシカルボニル、

may form, where R ₁₁ is methyl;
R ₁₂ is H;
R ₁₃ and R ₁₄ are each independently H, methoxy, -OH, hydroxymethyl, methylcarboxylate, methylamino, methylaminomethyl, propylaminomethyl, dimethylaminomethyl, methoxycarbonyl,

又は

or

であり；
Ｒ₁₅及びＲ₁₆は、それぞれ独立に、Ｈ、ＯＨ、又は

And;
R ₁₅ and R ₁₆ are each independently H, OH, or

であり；
Ｒ₁₇及びＲ₁₈は、Ｈ、ＯＨ、メチルアミノ、ジメチルアミノ、オキシム、又は下記のいずれかの式で表される基

And;
R ₁₇ and R ₁₈ are H, OH, methylamino, dimethylamino, oxime, or a group represented by any of the following formulas.

であり、ここで、
Ｒ_１９は、メトキシ、ヒドロキシ、－ＮＨ－ＮＨ_２、又は活性エステルを含む基である。］
〔２〕前記抗がん剤が、ゲフィチニブ、アファチニブ、オシメルチニブ、ダサチニブ、エルロチニブ、ゲムシタビン、シスプラチン、ペメトレキセド、及びミドスタウリンからなる群より選択される少なくとも１種の抗がん剤である、〔１〕に記載の医薬組成物。
〔３〕前記抗がん剤が、キナーゼを標的とする分子標的薬である、〔１〕～〔３〕のいずれかに記載の医薬組成物。
〔４〕前記キナーゼが、ＥＧＦＲ、ＡＢＬ１、ＡＬＫ１、ＨＥＲ２、ｃ－Ｋｉｔ、ＦＧＦＲ１、ＦＧＦＲ２、ＦＧＦＲ３、ｃ－Ｓｒｃ、ＰＤＧＦＲａ、ＲＥＴ、ＤＤＲ２、ＴＲＫＡ、及びＦｌｔ－３からなる群より選択される少なくとも１種のキナーゼである、〔３〕に記載の医薬組成物。
〔５〕前記抗がん剤耐性のがんが、ゲートキーパー変異を有するキナーゼを発現するがんである、〔１〕～〔４〕のいずれかに記載の医薬組成物。
〔６〕前記キナーゼが、ｄ７４６－７５０、Ｔ７９０Ｍ、及びＣ７９７Ｓの変異を有するＥＧＦＲである、〔５〕に記載の医薬組成物。
〔７〕前記化合物（Ｓ）が、スタウロスポリン、７－ヒドロキシスタウトスポリン、ＫＴ５９２６、スタウロスポリン・アグリコン、ＳＦ２３７０、ＫＴ５８２３、４’－Ｎ－ベンゾイルスタウロスポリン、Ｇｏ６９７６、Ｎ，Ｎ－ジメチルスタウロスポリン、ＮＡ ０３５９、Ｎ－エトキシカルボニル－７－オキソスタウロスポリン、ＫＴ－６１２４、ＣＧＰ４２７００、４’－デメチルアミノ－４’，５’－ジヒドロキシスタウロスポリン、７－オキソスタウロスポリン、ＣＥＰ７５１、ＮＡ０３４６、ＮＡ０３５９、３’－デメトキシ－３’－ヒドロキシスタウロスポリン、ＫＴ ６００６、７－Ｏ－メチル－ＵＣＮ ０１、ＴＡＮ ９９９、ＮＡ ０３４６、ＮＡ ０３４５、ＮＡ ０３４４、ＣＧＰ ４４１７１Ａ、ＳＣＨ ４７１１２、Ｎ，Ｎ－ジメチルスタウロスポリン、ＴＡＮ １０３０Ａ、レスタウルチニブ、４’－デメチルアミノ－４’－ヒドロキシスタウロスポリン、ＡＦＮ９４１、エドテカリン、ベカテカリン、Ｋ２５２ａ、及びＫ２５２ａヒドラジドからなる群より選択される少なくとも１種の化合物である、〔１〕～〔６〕のいずれかに記載の医薬組成物。
〔８〕前記化合物（Ｓ）が、スタウロスポリン、Ｋ２５２ａ、及びＫ２５２ａヒドラジドからなる群より選択される少なくとも１種の化合物である、〔７〕に記載の医薬組成物。
〔９〕前記薬物複合体がミセルを形成している、〔１〕～〔８〕のいずれかに記載の医薬組成物。

and here,
R ₁₉ is a group containing methoxy, hydroxy, -NH-NH ₂ or an active ester. ]
[2] In [1], the anticancer drug is at least one anticancer drug selected from the group consisting of gefitinib, afatinib, osimertinib, dasatinib, erlotinib, gemcitabine, cisplatin, pemetrexed, and midostaurin. Pharmaceutical compositions as described.
[3] The pharmaceutical composition according to any one of [1] to [3], wherein the anticancer drug is a molecular targeting drug that targets a kinase.
[4] The kinase is at least one selected from the group consisting of EGFR, ABL1, ALK1, HER2, c-Kit, FGFR1, FGFR2, FGFR3, c-Src, PDGFRa, RET, DDR2, TRKA, and Flt-3. The pharmaceutical composition according to [3], which is a species of kinase.
[5] The pharmaceutical composition according to any one of [1] to [4], wherein the anticancer drug-resistant cancer is a cancer that expresses a kinase with a gatekeeper mutation.
[6] The pharmaceutical composition according to [5], wherein the kinase is EGFR having mutations of d746-750, T790M, and C797S.
[7] The compound (S) is staurosporine, 7-hydroxystaurosporine, KT5926, staurosporine aglycon, SF2370, KT5823, 4'-N-benzoylstaurosporine, Go6976, N,N-dimethyl Staurosporine, NA 0359, N-ethoxycarbonyl-7-oxostaurosporine, KT-6124, CGP42700, 4'-demethylamino-4',5'-dihydroxystaurosporine, 7-oxostaurosporine, CEP751, NA0346, NA0359, 3'-demethoxy-3'-hydroxystaurosporine, KT 6006, 7-O-methyl-UCN 01, TAN 999, NA 0346, NA 0345, NA 0344, CGP 44171A, SCH 47112, N,N - at least one compound selected from the group consisting of dimethylstaurosporin, TAN 1030A, lestaurtinib, 4'-demethylamino-4'-hydroxystaurosporin, AFN941, edotecarin, becatecarin, K252a, and K252a hydrazide, The pharmaceutical composition according to any one of [1] to [6].
[8] The pharmaceutical composition according to [7], wherein the compound (S) is at least one compound selected from the group consisting of staurosporine, K252a, and K252a hydrazide.
[9] The pharmaceutical composition according to any one of [1] to [8], wherein the drug complex forms micelles.

According to the present invention, a pharmaceutical composition that can be used for treating or preventing cancer resistant to anticancer drugs is provided.

FIG. 1 is a synthesis scheme of an aromatic aldehyde group-containing polymer and an aliphatic aldehyde group-containing polymer. FIG. 2 is a ¹ H-NMR spectrum of an acetal group-containing polymer that is an intermediate of an aromatic aldehyde group-containing polymer. FIG. 3 is a ¹ H-NMR spectrum of an aromatic aldehyde group-containing polymer. FIG. 4 is a ¹ H-NMR spectrum of an acetal group-containing polymer that is an intermediate of an aliphatic aldehyde group-containing polymer. FIG. 5 is a ¹ H-NMR spectrum of an aliphatic aldehyde group-containing polymer according to one embodiment of the present invention. FIG. 6 is a synthesis scheme of an aromatic ketone group-containing polymer and an aliphatic ketone group-containing polymer. FIG. 7 is a ¹ H-NMR spectrum of the aliphatic ketone group-containing polymer. FIG. 8 is a ¹ H-NMR spectrum of K252a and K252a hydrazide (K252a-H). FIG. 9 shows the HPLC analysis results of K252a and K252a-H. FIG. 10 is a ¹ H-NMR spectrum of an aliphatic ketone group-containing polymer according to one embodiment of the present invention. FIG. 11 is a ¹ H-NMR spectrum of an aromatic aldehyde group-containing polymer according to one embodiment of the present invention. FIG. 12A shows the analysis results of the micelle size and polydispersion index (PDI) of the drug complex (K252a-H bonded aromatic polymer micelle) according to one embodiment of the present invention. FIG. 12B shows the analysis results of the micelle size and polydispersion index (PDI) of the drug complex (K252a-H-bonded aliphatic polymer micelle) according to one embodiment of the present invention. FIG. 13 is an ultraviolet absorption spectrum of a drug complex according to one embodiment of the present invention. FIG. 14 is an HPLC analysis result of a sample of a drug conjugate according to an embodiment of the present invention treated with a pH 1 aqueous buffer. FIG. 15 is a graph showing the results of a cytotoxicity test on lung cancer cells of K252a, K252a-H, K252a-H bonded aliphatic polymer, and K252a-H bonded aromatic polymer (K252a class) according to one embodiment of the present invention. be. FIG. 16 is a graph showing the results of a cytotoxicity test on lung cancer cells of K252a according to one embodiment of the present invention. FIG. 17 is a graph showing the results of a cytotoxicity test on pancreatic cancer cells of K252a according to one embodiment of the present invention. FIG. 18 is a graph showing the results of a cytotoxicity test on head and neck cancer cells of K252a according to one embodiment of the present invention. FIG. 19 is a graph showing the results of a cytotoxicity test on malignant mesothelioma cells of K252a according to one embodiment of the present invention. FIG. 20 is a diagram showing first to third generation TKIs and their resistance mutations. FIG. 21 is a diagram showing first to third generation TKIs and their resistance mutations. FIG. 22 is a diagram showing the results of a kinase assay of K252a-H against EGFR mutations. FIG. 23A shows the results of kinase profiling. FIG. 23B shows the results of kinase profiling. FIG. 23C shows the results of kinase profiling. FIG. 24 is a diagram showing a list of mutant kinases whose kinase activity was suppressed to 30% or less by K252a-H. FIG. 25 is a diagram showing the results of kinase profiling. FIG. 26 is a diagram showing the results of kinase profiling. FIG. 27 is a diagram showing the results of kinase profiling. FIG. 28 is a diagram showing the results of kinase profiling. FIG. 29 is a diagram showing the results of kinase profiling. FIG. 30 is a diagram showing the results of kinase profiling. FIG. 31 is a diagram showing the results of kinase profiling. FIG. 32 is a diagram showing the results of kinase profiling. FIG. 33A shows the results of kinase profiling. FIG. 33B shows the results of kinase profiling. FIG. 33C shows the results of kinase profiling. FIG. 33D shows the results of kinase profiling. FIG. 34A shows the results of kinase profiling. FIG. 34B shows the results of kinase profiling. FIG. 34B shows the results of kinase profiling. FIG. 34D shows the results of kinase profiling. FIG. 35 is a diagram showing a list of kinases whose IC50 of staurosporin is 0.2 nm. The underlined kinases are important as therapeutic targets for cancer (particularly drug-resistant cancer). FIG. 36 is a graph showing the results of a cytotoxicity test for non-small cell lung cancer of staurosporine and K252a according to one embodiment of the present invention. FIG. 37 is a graph showing the results of a cytotoxicity test for pancreatic cancer of staurosporine and K252a according to one embodiment of the present invention. FIG. 38 is a graph showing the results of a cytotoxicity test for head and neck cancer of staurosporine and K252a according to one embodiment of the present invention. FIG. 39 is a graph showing the results of a cytotoxicity test for malignant mesothelioma of staurosporine and K252a according to one embodiment of the present invention. FIG. 40 is a graph showing the results of an in vivo antitumor test of K252a according to one embodiment of the present invention. FIG. 41 is a graph showing the results of an in vivo antitumor test of K252a according to one embodiment of the present invention. FIG. 42 is a graph showing the results of an in vivo antitumor test of K252a according to one embodiment of the present invention. FIG. 43 is a graph showing the results of a cytotoxicity test for spontaneous pancreatic cancer of staurosporine and K252a according to one embodiment of the present invention. FIG. 44 is a graph showing the results of an in vivo antitumor test of K252a according to one embodiment of the present invention. FIG. 45 is a graph showing the results of an in vivo antitumor test of K252a according to one embodiment of the present invention. FIG. 46 is a graph showing the results of a cytotoxicity test for K252a type lymphoma according to one embodiment of the present invention. FIG. 47 is a graph showing the results of an inhibitory activity test against MDR-1 of staurosporine and K252a according to one embodiment of the present invention. FIG. 48 is a graph showing the results of a test evaluating the influence of human α1-acid glycoprotein (hAGP) on the cytotoxicity of K252a according to one embodiment of the present invention. FIG. 49 is a diagram showing an example of a reaction for binding a linker reagent (L1) to staurosporine. FIG. 50 shows a ¹ H-NMR spectrum of staurosporin bound to a linker reagent (L1). FIG. 51 illustrates a scheme for preparing a drug conjugate of staurosporine and polymer via a linker derived from a linker reagent (L1).

In this specification and claims, some structures represented by chemical formulas may have asymmetric carbon atoms, and enantiomers or diastereomers may exist; In this case, one formula is used to represent the isomers. These isomers may be used alone or as a mixture.
[First aspect]
<Pharmaceutical composition>
In one embodiment, the present invention provides a compound (S) represented by the following general formula (S), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable polymer containing the compound (S) or its Provided is a pharmaceutical composition for treating or preventing anticancer drug-resistant cancer, which includes a drug complex bound to a pharmaceutically acceptable salt.

(Compound (S))
The pharmaceutical composition of the present embodiment includes a compound (S) represented by the following general formula (S), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable polymer containing the compound (S) or its pharmaceutically acceptable salt. Includes drug conjugates with attached pharmaceutically acceptable salts.

［式中、
Ｘ及びＹは、それぞれ独立に、Ｈ、ＯＨ、Ｃｌ、プロポキシ、又はエチルチオメチルであり；
Ｒ₆は、Ｈ、Ｃ_1-3アルキル、－ＮＨ₂、ベンジル、

[In the formula,
X and Y are each independently H, OH, Cl, propoxy, or ethylthiomethyl;
R ₆ is H, C _1-3 alkyl, -NH ₂ , benzyl,

又は

or

であり；
Ｒ₇及びＲ₈は、それぞれ独立に、Ｈ、－ＯＨ、又はメトキシであるか、或いは一緒になってＯ＝を形成してもよく；
Ｒ₉及びＲ₁₀は、それぞれ独立に、Ｈ、メチル、β－Ｄ－グルコピラノシル、４－Ｏ－メチル－β－Ｄ－グルコピラノシル、シアノエチル、又は

And;
R ₇ and R ₈ are each independently H, -OH, or methoxy, or may be taken together to form O=;
R ₉ and R ₁₀ are each independently H, methyl, β-D-glucopyranosyl, 4-O-methyl-β-D-glucopyranosyl, cyanoethyl, or

であるか、或いは一緒になって、以下の：

or together with:

又は

or

を形成してもよく、ここで
Ｒ₁₁は、メチルであり；
Ｒ₁₂は、Ｈであり；
Ｒ₁₃及びＲ₁₄は、それぞれ独立に、Ｈ、メトキシ、－ＯＨ、ヒドロキシメチル、メチルカルボキシレート、メチルアミノ、メチルアミノメチル、プロピルアミノメチル、ジメチルアミノメチル、メトキシカルボニル、

may form, where R ₁₁ is methyl;
R ₁₂ is H;
R ₁₃ and R ₁₄ are each independently H, methoxy, -OH, hydroxymethyl, methylcarboxylate, methylamino, methylaminomethyl, propylaminomethyl, dimethylaminomethyl, methoxycarbonyl,

又は

or

であり；
Ｒ₁₅及びＲ₁₆は、それぞれ独立に、Ｈ、ＯＨ、又は

And;
R ₁₅ and R ₁₆ are each independently H, OH, or

であり；
Ｒ₁₇及びＲ₁₈は、それぞれ独立に、Ｈ、ＯＨ、メチルアミノ、ジメチルアミノ、オキシム、又は下記のいずれかの式で表される基

And;
R ₁₇ and R ₁₈ are each independently H, OH, methylamino, dimethylamino, oxime, or a group represented by any of the following formulas.

であり、ここで、
Ｒ_１９は、メトキシ、ヒドロキシ、－ＮＨ－ＮＨ_２、又は活性エステルを含む基である。］

and here,
R ₁₉ is a group containing methoxy, hydroxy, -NH-NH ₂ or an active ester. ]

Preferred examples of the above compound (S) include compounds (S-1) and compounds (S-2) represented by the following general formulas (S-1) and (S-2), respectively.

［式中、Ｘ、Ｙ、Ｒ₆～Ｒ₈、Ｒ₁₁～Ｒ₁₈は上記で定義するとおりである。］

[In the formula, X, Y, R ₆ to R ₈ and R ₁₁ to R ₁₈ are as defined above. ]

In the general formula (S-1) or (S-2), X, Y, and R ₆ are preferably H.

In the above general formula (S-1) or (S-2), R ₁₃ and R ₁₄ are each independently represented by H, methoxy, -OH, hydroxymethyl, methoxycarbonyl, or the following formula (h1) It is preferable that it is a group.

It is more preferable that R ₁₃ and R ₁₄ in the above (S-1) are each independently H, methoxycarbonyl, or a group represented by the above formula (h1). It is more preferable that R ₁₃ and R ₁₄ in the above (S-2) are each independently H or methoxy.

In the above general formula (S-1) or (S-2), R ₁₅ and R ₁₆ are each independently preferably H or OH.

In the above general formula (S-2), R ₁₇ and R ₁₈ are preferably H, OH, methylamino, dimethylamino, oxime, or a group represented by the following formula (11), and H, methylamino Or, it is more preferable that it is a group represented by formula (l1).

［Ｒ_１９は、メトキシ、ヒドロキシ、－ＮＨ－ＮＨ_２、又は活性エステルを含む基である。］

[R ₁₉ is a group containing methoxy, hydroxy, -NH-NH ₂ , or an active ester. ]

The group containing an active ester in the above formula (l1) is an active esterifying agent (N-hydroxysuccinimide (NHS), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt)). , pentafluorophenol, p-nitrophenol, etc.).

As the above compound (S-1), a compound (S-1-1) represented by the following general formula (S-1-1) is preferably exemplified. Further, as the above compound (S-2), a compound (S-2-1) represented by the following general formula (S-2-1) is preferably exemplified.

［式中、
Ｒ₇はＨ又はＯＨであり、
Ｒ₁₃及びＲ₁₄は、それぞれ独立に、Ｈ、メトキシ、－ＯＨ、ヒドロキシメチル、メトキシカルボニル、又は下記式で表される基である。］

[In the formula,
_R7 is H or OH,
R ₁₃ and R ₁₄ are each independently H, methoxy, -OH, hydroxymethyl, methoxycarbonyl, or a group represented by the following formula. ]

Examples of the above compound (S) include the following compounds: staurosporine, 7-hydroxystaurosporine, KT5926, staurosporine aglycone, SF2370, KT5823, 4'-N-benzoylstaurosporine, PKC412 , Go6976, N,N-dimethylstaurosporine, NA0359, N-ethoxycarbonyl-7-oxostaurosporin, KT-6124, CGP42700, 4'-demethylamino-4',5'-dihydroxystaurosporine, 7- Oxostaurosporin, CEP751, NA0346, NA0359, 3'-demethoxy-3'-hydroxystaurosporin, KT6006, 7-O-methyl-UCN01, TAN999, NA0346, NA0345, NA0344, CGP44171A, SCH47112, N,N- Compounds selected from the group consisting of dimethylstaurosporine, TAN1030A, lestaurtinib, 4'-demethylamino-4'-hydroxystaurosporine, AFN941, edotecarin, becatecarin, K252a, and K252a hydrazide are included.

Specific examples of the above compound (S-1-1) include K252a and K252a hydrazide (hereinafter also referred to as "K252a-H"). A specific example of the above compound (S-2-1) is staurosporine.

Compound (S) may be in the form of a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" means a salt that does not inhibit the pharmacological action (anticancer activity, kinase inhibitory activity, etc.) of compound (S). It is preferable that the pharmaceutically acceptable salt causes no side effects when administered to a living body. Pharmaceutically acceptable salts are not particularly limited, and include, for example, salts with alkali metals (sodium, potassium, etc.); salts with alkaline earth metals (magnesium, calcium, etc.); organic bases (pyridine, triethylamine, etc.) salts with amines, salts with organic acids (acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, etc.) and salts with inorganic acids (hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, nitric acid, etc.).

Further, compound (S) may be compound (K) or a pharmaceutically acceptable salt of compound (K) described in [Second Aspect] described below.

One type of compound (S) may be used alone, or two or more types may be used in combination.

(drug complex)
The pharmaceutical composition of this embodiment may contain a drug complex in which the compound (S) is bound to a pharmaceutically acceptable polymer. Note that the term "drug complex" refers to a compound in which a molecule (drug) having a pharmacological effect is bound to another molecule (eg, a polymer). "Pharmaceutically acceptable polymer" means a polymer that does not inhibit the pharmacological effects (anticancer activity, kinase inhibitory activity, etc.) of compound (S) when forming a drug complex with compound (S). . Preferably, the pharmaceutically acceptable polymer does not cause any side effects when administered to a living body.
By forming a drug complex with a polymer, the safety margin of compound (S) can be widened. Moreover, the solubility of the compound (S) is increased, and intravenous injection becomes possible.

The polymer that forms the drug complex with compound (S) is not particularly limited as long as it does not inhibit the pharmacological action of compound (S). The polymer may be a hydrophilic polymer, a hydrophobic polymer, or a copolymer containing a hydrophilic polymer segment and a hydrophobic polymer segment.

Specific examples of the hydrophilic polymer segment include polyalkylene glycol, poly(2-oxazoline), polysaccharide, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polymethacrylamide, polyacrylic ester, polymethacrylic ester, and polysaccharide. (2-methacroyloxyethylphosphorylcholine), poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA), and derivatives thereof. Among these, polyalkylene glycol, poly(2-oxazoline), etc. are preferred, and polyalkylene glycol is more preferred. Examples of the polyalkylene glycol include polyethylene glycol, polypropylene glycol, polyethylene glycol/polypropylene glycol copolymers, and polyethylene glycol is particularly preferred.

Specific examples of hydrophobic polymer segments include, for example, polymers having repeating units derived from amino acids and/or derivatives thereof. More specifically, polyamino acids or derivatives thereof can be mentioned. Examples of polyamino acids and derivatives thereof include polyaspartic acid, polyglutamic acid, polylysine, poly(benzylaspartic acid), poly(benzylglutamic acid), and the like.
The hydrophobic polymer segment may also include repeating units derived from amino acids having, for example, alkyl or aralkyl side chains. Amino acids having an alkyl group side chain include alanine, valine, leucine, and isoleucine. Furthermore, examples of amino acids having an aralkyl group side chain include phenylalanine. When having repeating units derived from two or more alkyl group side chain amino acids and/or aralkyl group side chain amino acids, those side chains may be the same or different. The ratio of repeating units derived from alkyl group side chain amino acids or aralkyl group side chain amino acids to all repeating units of the hydrophobic polymer segment is not particularly limited, and is, for example, 20% or more, 35% or more, 40% or more, 50% or more. % or more, 80% or more, 95% or more, 99% or more, or 100%.

Preferred examples of the polymer that forms a drug complex with compound (S) include the following polymers (P).

≪Polymer (P)≫
The polymer (P) is a polymer having a repeating unit (I) represented by the following general formula (I) and a repeating unit (II) represented by the following general formula (II).

［式中、ｍは１又は２を表す。Ｌは２価の芳香族炭化水素基又は２価の脂肪族炭化水素基を表す。Ｒ^１は水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。ＸはＯＲ^ｘ、ＳＲ^ｘ又はＮＲ^ｘ１Ｒ^ｘ２を表す。Ｒ^ｘは水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。Ｒ^ｘ１及びＲ^ｘ２はそれぞれ独立に水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。］

[In the formula, m represents 1 or 2. L represents a divalent aromatic hydrocarbon group or a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. X represents OR ^x , SR ^x or NR ^x1 R ^x2 . R ^x represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. R ^x1 and R ^x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. ]

In the general formulas (I) and (II), m is 1 or 2, preferably 1.
In the general formula (I), L represents a divalent aromatic hydrocarbon group or a divalent aliphatic hydrocarbon group.
Examples of the divalent aromatic hydrocarbon group for L include a phenylene group and a benzylene group.
The divalent aromatic hydrocarbon group of L may have a substituent. Examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a nitro group, and a halide.
Examples of the divalent aliphatic hydrocarbon group for L include ethylene group, propylene group, butylene group, and pentylene group. The divalent aliphatic hydrocarbon group of L may have a substituent.
Examples of the substituent include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, and halides.
Among these, L is preferably a methylene group, an ethylene group, a propylene group, or a benzylene group, and more preferably a methylene group, an ethylene group, or a benzylene group. From the viewpoint of antitumor activity, L is preferably a divalent aliphatic hydrocarbon group, more preferably a methylene group, an ethylene group, or a propylene group, and more preferably a methylene group or an ethylene group.

In the general formula (I), R ¹ represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group.
Examples of the aliphatic hydrocarbon group for R ¹ include ethyl group, propyl group, butyl group, and pentyl group. The aliphatic hydrocarbon group of R ¹ may have a substituent. Examples of the substituent include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, cyclohexyl group, trihalomethyl group, etc. .
Examples of the aromatic hydrocarbon group for ^R1 include phenyl group, benzyl group, pyridyl group, naphthyl group, hydroxyphenyl group, methoxyphenyl group, ethoxyphenyl group, xylyl group, methylphenyl group, nitrophenyl group, chlorophenyl group, and chlorophenyl group. Examples include an orophenyl group, an iodophenyl group, a bromophenyl group, and the like.
Among these, R ¹ is preferably a hydrogen atom or an aliphatic hydrocarbon group, more preferably a hydrogen atom or a methyl group, and even more preferably a methyl group.

In the general formula (II), X represents OR ^x , SR ^x or NR ^x1 R ^x2 .
R ^x represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. Examples of the aliphatic hydrocarbon group for R ^x include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, cyclohexyl group, trifluoro Examples include methyl group.
Aromatic hydrocarbon groups for R ^x include phenyl, benzyl, pyridyl, naphthyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, xylyl, methylphenyl, nitrophenyl, chlorophenyl, Examples include an orophenyl group, an iodophenyl group, a bromophenyl group, and the like.
R ^x1 and R ^x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group.
The aliphatic hydrocarbon groups for R ^x1 and R ^x2 include methyl group, ethyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, cyclohexyl group, trihalomethyl Groups can be mentioned.
The aromatic hydrocarbon groups for R ^x1 and R ^x2 include phenyl group, benzyl group, pyridyl group, naphthyl group, hydroxyphenyl group, methoxyphenyl group, ethoxyphenyl group, xylyl group, methylphenyl group, hydrophenyl group, chlorophenyl group. group, fluorophenyl group, iodophenyl group, bromophenyl group, etc.
Among these, as X, OR ^x is preferable, and OH (hydroxy group) is more preferable.

The polymer (P) may have other repeating units (hereinafter sometimes referred to as "repeat units (III)") other than the repeating units (I) and (II).
The repeating unit (III) is preferably a hydrophilic repeating unit, such as a repeating unit derived from polyethylene glycol, a repeating unit derived from poly(ethyl ethylene phosphate), a repeating unit derived from polyvinyl alcohol, or a repeating unit derived from polyvinyl alcohol. Examples include repeating units derived from pyrrolidone, repeating units derived from poly(oxazoline), repeating units derived from poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA), and the like. Among these, repeating units (III) are preferably repeating units derived from polyethylene glycol.

In the polymer (P), the content of repeating units (I) to (III) is not particularly limited.
The content of the repeating unit (I) is preferably 5 to 100 mol%, more preferably 10 to 80 mol%, and 20 to 50 mol%, based on the total (100 mol%) of all repeating units constituting the polymer (P). More preferred is mole %.
The content of the repeating unit (II) is preferably 0 to 80 mol%, more preferably 10 to 60 mol%, and 20 to 40 mol%, based on the total (100 mol%) of all repeating units constituting the polymer (P). More preferred is mole %.
The content of the repeating unit (III) is preferably 0 to 95 mol%, more preferably 20 to 90 mol%, and 50 to 80 mol%, based on the total (100 mol%) of all repeating units constituting the polymer (P). More preferred is mole %.

The molecular weight of the polymer (P) is preferably 2,000 to 1,000,000D, more preferably 5,000 to 100,000D, and even more preferably 10,000 to 40,000D.

[Method for producing polymer (P) (1)]
The method for producing polymer (P) (hereinafter sometimes referred to as "manufacturing method (1)") is a method for producing polymer (P1) having a repeating unit (II') represented by the following general formula (II') and the following general formula. Step (1) of obtaining a polymer (P2) having a repeating unit represented by the following general formula (I') and the repeating unit (II') by reacting the compound (1a) represented by the formula (1a). ), and the polymer (P2) is hydrolyzed under weakly acidic conditions to produce repeating units (I) represented by the following general formula (I) and repeating units (I) represented by the following general formula (II-1) ( Step (2) of obtaining a polymer (P) having II-1).

［式中、ｍは１又は２を表す。Ｒ^２は水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。Ｌは２価の芳香族炭化水素基又は２価の脂肪族炭化水素基を表す。Ｒ^１は水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。Ｒａ^１１及びＲａ^１２はそれぞれ独立にメチル基若しくはエチル基を表す、又はＲａ^１１及びＲａ^１２は相互に結合してエチレン基若しくはプロピレン基を表す。Ｒ^ｘは水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。］

[In the formula, m represents 1 or 2. R ² represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group. L represents a divalent aromatic hydrocarbon group or a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. Ra ¹¹ and Ra ¹² each independently represent a methyl group or an ethyl group, or Ra ¹¹ and Ra ¹² combine with each other to represent an ethylene group or a propylene group. R ^x represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. ]

In the general formulas (I'), (II'), (I) and (II-1), m, L, R ¹ and R ^x are m, L in the general formulas (I) and (II). , R ¹ and R ^x .
In the general formulas (1a) and (I'), Ra ¹¹ and Ra ¹² each independently represent a methyl group or an ethyl group, or Ra ¹¹ and Ra ¹² combine with each other to represent an ethylene group or a propylene group. When Ra ¹¹ and Ra ¹² are bonded to each other to represent an ethylene group or a propylene group, the compound (1a) becomes a cyclic acetal or a cyclic ketal.
In the general formula (1a), n1 and n2 are each independently 0 or 1, and 1 is preferable.

・Process (1)
Step (1) of production method (1) is an aminolysis reaction between polymer (P1) and compound (1a). In step (1), the acetal structure or ketal structure of compound (1a) is introduced into the side chain of polymer (P1).
The reaction temperature in step (1) is not particularly limited as long as the acetal structure or ketal structure of compound (1a) is introduced into the side chain of polymer (P1), but it is usually 4°C to 100°C, and room temperature ~40°C is preferred.
The reaction time of step (1) is not particularly limited as long as the acetal structure or ketal structure of compound (1a) is introduced into the side chain of polymer (P1), and depends on the reaction time, the type of compound (1a), and the like. It can be selected depending on the amount, but it is usually 4 hours to 5 days.

・Process (2)
In step (2) of production method (1), polymer (P2) is hydrolyzed under neutral conditions or weakly acidic conditions to convert the acetal structure of repeating unit (I') of polymer (P2) into aldehyde or ketal. Convert structure to ketone.
Hydrolysis is not particularly limited as long as it can convert the acetal structure of the repeating unit (I') of the polymer (P2) into an aldehyde or the ketal structure into a ketone. For example, (i) a method of treatment with 0.1N hydrochloric acid for about 30 minutes, (ii) a method of treatment in the presence of acetone and indium (III) trifluoromethanesulfonate (catalyst), (iii) a method of treatment in water at 30°C in a catalytic amount. (iv) using 1-5 mol% Er(OTf) ₃ in wet nitromethane at room temperature; (v) using nearly neutral sodium tetrakis(3,5-trifluoromethylphenyl)borate; Known methods include methods using catalytic amounts of cerium (III) triflate in wet nitromethane at room temperature under pH conditions.

[Method for producing polymer (P) (2)]
The method for producing polymer (P) (hereinafter sometimes referred to as "manufacturing method (2)") is a method for producing polymer (P1) having a repeating unit (II') represented by the following general formula (II') and the following general formula (II'). Step (1) of reacting with a compound (1a) represented by formula (1a) to obtain a polymer (P2) having a repeating unit represented by the following general formula (I') and the repeating unit (II') )and,
The polymer (P2) is subjected to at least one treatment selected from the group consisting of hydrolysis under alkaline conditions, transesterification, aminolysis, hydrolysis under alkaline conditions and amide coupling, and the polymer (P2) is then subjected to at least one treatment selected from the group consisting of hydrolysis under alkaline conditions, transesterification, aminolysis, hydrolysis under alkaline conditions and amide coupling. Step (2a) of obtaining a polymer (P3) having a repeating unit (I') represented by ') and a repeating unit (II') represented by the following general formula (II');
The polymer (P3) is hydrolyzed under neutral conditions or weakly acidic conditions to obtain repeating units (I) represented by the following general formula (I) and repeating units (I) represented by the following general formula (II) ( Step (2b) of obtaining a polymer (P) having II);
including.

［式中、ｍは１又は２を表す。Ｒ^２は水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。Ｌは２価の芳香族炭化水素基又は２価の脂肪族炭化水素基を表す。Ｒ^１は水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。Ｒａ^１１及びＲａ^１２はそれぞれ独立にメチル基若しくはエチル基を表す、又はＲａ^１１及びＲａ^１２は相互に結合してエチレン基若しくはプロピレン基を表す。ＸはＯＲ^ｘ、ＳＲ^ｘ又はＮＲ^ｘ１Ｒ^ｘ２を表す。Ｒ^ｘは水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。Ｒ^ｘ１及びＲ^ｘ２はそれぞれ独立に水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。］

[In the formula, m represents 1 or 2. R ² represents a hydrogen atom, an aliphatic hydrocarbon group or an aromatic hydrocarbon group. L represents a divalent aromatic hydrocarbon group or a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. Ra ¹¹ and Ra ¹² each independently represent a methyl group or an ethyl group, or Ra ¹¹ and Ra ¹² combine with each other to represent an ethylene group or a propylene group. X represents OR ^x , SR ^x or NR ^x1 R ^x2 . R ^x represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. R ^x1 and R ^x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. ]

In the general formulas (I'), (II'), (I) and (II), m, L, X, R ^x , R ^x1 and R ^x2 are Same as m, L, X, R ^x , R ^x1 and R ^x2 .
In the general formulas (1a) and (I'), R ¹ , Ra ¹¹ and Ra ¹² are as defined above.

・Process (1)
Step (1) of manufacturing method (2) is the same as step (1) of manufacturing method (1).

・Process (2a)
In step (2a) of production method (2), the polymer (P2) is subjected to a predetermined treatment so that the side chain of the repeating unit (II') is protected with the repeating unit (I') protected by an acetal structure. A desired functional group can be introduced into.
Hydrolysis under alkaline conditions can be carried out, for example, by treatment in a mixture of 0.5N NaOH solution and DMSO (volume ratio: 50/50) at room temperature for 30 minutes, or with triethylamine in DMSO at room temperature for 1 hour. The method includes a method of treating with diisopropylethylamine in DMSO at room temperature for 1 hour. The carboxylic acid residues obtained by hydrolysis under alkaline conditions attract protons in the core of the micelles described below, facilitate hydrolysis of hydrazone bonds, and enable release of biomaterials under low pH conditions.
Aminolysis can, for example, cleave the ester with ethylenediamine or diaminopropane to introduce an amino functionality. By introducing an amino group, it can be bonded to a fluorescent dye. Further, it can also be subjected to known amino coupling with other diagnostic imaging agents having carboxylic acid groups. Since the acetal structure and ketal structure are stable under such amino group introduction conditions, they can be used in the design of multifunctional nanocarriers in polymers.
For hydrolysis and amide coupling under alkaline conditions, for example, after treating the ester residue by hydrolysis under alkaline conditions, the resulting carboxylic acid is subjected to transesterification or amide coupling using a known coupling agent. be able to. Appropriate structural motifs with hydroxy/amine functionality can provide the desired hydrophilic/hydrophobic balance of the polymer, contributing to self-assembly in polar or non-polar solvents.

・Process (2b)
In step (2b) of production method (2), the polymer (P3) is hydrolyzed under weakly acidic conditions to convert the acetal structure of the repeating unit (I') of the polymer (P3) into an aldehyde. The conditions for hydrolysis are the same as in step (2) of manufacturing method (1).

<<Drug complex of polymer (P) and compound (S)>>
The bond between the polymer (P) and the compound (S) is such that the compound (S) contains a nitrogen atom-containing group that can form a Schiff base with an aldehyde group or a ketone group (hereinafter sometimes referred to as a "Schiff base forming group"). In some cases, this can be carried out by reacting the Schiff base-forming group with an aldehyde group or ketone group contained in the repeating unit (I) of the polymer (P). Examples of such Schiff bases include amino groups, imino groups, hydrazide groups, and the like. Also. When compound (S) does not have a Schiff base-forming group, a Schiff base-forming group may be introduced into compound (S). The Schiff base-forming group can be introduced by a known method.

For example, since K252a does not have a Schiff base-forming group, it can be bonded to the polymer (P) by introducing a hydrazide group to form K252a-H, as shown in Examples below. Examples of the drug complex of polymer (P) and K252a include polymers having repeating units (ka-1) and repeating units (II) described in [Second Aspect] described below.

The drug complex of polymer (P) and compound (S) has a repeating unit (Ia) represented by the following general formula (Ia) and a repeating unit (II) represented by the following general formula (II). Preferably it is a polymer.

［式中、ｍは１又は２を表す。Ｌは２価の芳香族炭化水素基又は２価の脂肪族炭化水素基を表す。Ｒ^１は水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。ＢＭは化合物（Ｓ）から誘導される基を表す。ＸはＯＲ^ｘ、ＳＲ^ｘ又はＮＲ^ｘ１Ｒ^ｘ２を表す。Ｒ^ｘは水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。Ｒ^ｘ１及びＲ^ｘ２はそれぞれ独立に水素原子、脂肪族炭化水素基又は芳香族炭化水素基を表す。］

[In the formula, m represents 1 or 2. L represents a divalent aromatic hydrocarbon group or a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. BM represents a group derived from compound (S). X represents OR ^x , SR ^x or NR ^x1 R ^x2 . R ^x represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. R ^x1 and R ^x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. ]

In the general formulas (Ia) and (II), m, L, R ¹ , X, R ^x , R ^x1 and R ^x2 are m, L, R ¹ in the general formulas (I) and (II), Same as X, R ^x , R ^x1 and R ^x2 .
In the general formula (Ia), BM represents a group derived from compound (S). A suitable example of the group derived from compound (S) is a group derived from K252a-H.

In the polymer (P), the amount of aldehyde or ketone groups introduced can be controlled, and the amount of drug bonded to the aldehyde or ketone groups can also be controlled. Therefore, the dosage of compound (S) can be appropriately controlled.
Further, in the polymer (P), the aldehyde group or ketone group to be introduced can be selected from aromatic aldehyde groups, aliphatic aldehyde groups, aromatic ketone groups, and aliphatic ketone groups.
Since the Schiff base of an aromatic aldehyde group or an aromatic ketone group is more stable than that of an aliphatic aldehyde group or an aliphatic ketone group, when an aromatic aldehyde group is introduced, compound (S) becomes more stable. Maintained stably. Therefore, by selecting the type of aldehyde group or ketone group to be introduced depending on the disease state and the type of drug, the sustained release properties of the drug can be controlled. Furthermore, in a drug complex of polymer (P) and compound (S), while compound (S) is retained in polymer (P), compound (S) is maintained stably and toxicity is alleviated. , can reduce side effects and enhance therapeutic effects.
In the drug complex of polymer (P) and compound (S), it is preferable to introduce an aliphatic ketone group from the viewpoint of antitumor effect when administered in vivo. That is, in the above general formula (Ia), L is preferably a divalent aliphatic hydrocarbon group (preferably a methylene group or an ethylene group), and R ¹ is an aliphatic hydrocarbon group (preferably a methyl group). It is preferable that there be.

Further, the compound (S) and the polymer (P) may be bonded using a known linker reagent. When the linker reagent contains a Schiff base-forming group, the compound (S) can be bonded to the polymer (P) using the Schiff base-forming group.

On the other hand, when the linker reagent does not have a Schiff base-forming group, the Schiff base-forming group may be introduced into a compound obtained by bonding a linker to compound (S). Usable linker reagents are not particularly limited, but for example, a glutathione (GSH)/glutathione-S-transferase (GST)-sensitive linker reagent represented by the following formula (L1) (linker reagent (L1); International Publication No. 2012/039499, Huang CH et al., ChemMedChem. 2017 Jan 5;12(1):19-22.; Zhang J et al., J Am Chem Soc. 2011 Sep 7;133(35):14109-19 ).

For example, a compound (SL1) represented by the following general formula (SL1) is a compound obtained by reacting the compound (S-2-1) with the linker reagent (L1). The following compound (SL1-H) containing a Schiff base-forming group can be obtained by refluxing the following compound (SL1) without a solvent in the presence of anhydrous hydrazine or hydrazine hydrate. Alternatively, compound (SL1-H) can be used, for example, to convert compound (SL1) into methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF). ), it can also be produced by dissolving it in a solvent such as dioxane, acetonitrile, toluene, etc., adding it to anhydrous hydrazine, and reacting it. The reaction temperature and reaction time are not particularly limited, but are exemplified by, for example, room temperature to 50°C for 30 minutes to 15 hours.

［式中、Ｒ_７、Ｒ_１３、及びＲ_１４は、前記一般式（Ｓ－２－１）におけるＲ_７、Ｒ_１３、及びＲ_１４と同様である。］

[In the formula, R ₇ , R ₁₃ , and R ₁₄ are the same as R ₇ , R ₁₃ , and R ₁₄ in the general formula (S-2-1). ]

A drug complex in which the above compound (SL1-H) is bound to a polymer (P) has a repeating unit (Ia-S) represented by the following general formula (Ia-S) and a repeating unit (Ia-S) represented by the following general formula (II). repeating unit (II).

［式中、ｍ、Ｌ、Ｒ^１及びＸは、前記一般式（Ｉａ）及び（ＩＩ）におけるｍ、Ｌ及びＲ^１及びＸと同様である。Ｒ_７、Ｒ_１３、及びＲ_１４は、前記一般式（Ｓ－２－１）におけるＲ_７、Ｒ_１３、及びＲ_１４と同様である。］

[In the formula, m, L, R ¹ and X are the same as m, L, R ¹ and X in the general formulas (Ia) and (II). R ₇ , R ₁₃ , and R ₁₄ are the same as R ₇ , R ₁₃ , and R ₁₄ in the general formula (S-2-1). ]

The drug conjugate includes a pH-sensitive bond (I) and a GSH/GST-sensitive bond (II). Therefore, when the above drug complex is administered in vivo, the bond (I) is first cleaved around the tumor tissue in a low pH environment, and the compound (SL1-H) is released. Furthermore, compound (SL1-H) is taken up into tumor cells, and bond (II) is cleaved by the action of GSH/GST, and compound (S-2-1) is released. Therefore, the release of compound (S) from polymer (P) in vivo can be controlled in two stages.

≪Drug complex with other polymers≫
Compound (S) may be a drug complex with a polymer other than the polymer (P). In that case, the bonding between the compound (S) and the polymer can be performed using a known method depending on the functional groups contained in the compound (S) and the polymer. For example, the compound (S) may be directly bonded to a polymer, or a functional group capable of bonding to a polymer may be introduced into the compound (S), and the compound (S) may be bonded to the polymer via the functional group. Also, known linker reagents may be used. The linker reagent is not particularly limited, but includes, for example, the linker reagent (L1) described above. Alternatively, after introducing a linker into the compound (S), an active ester may be introduced using an active esterifying agent and bonded to a polymer having a hydroxy group or an amino group. Conversely, an active ester may be introduced into the polymer.

For example, after bonding the linker reagent (L1) to the compound (S) to obtain the above compound (SL1), the compound (SL1) is demethylated and the active esterifying agent (N-hydroxysuccinimide (NHS) , 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), pentafluorophenol, p-nitrophenol, etc.) to form an active ester represented by the following formula (SL2). A compound containing (SL2) may be obtained.

［式中、Ｒ^７、Ｒ^１３、Ｒ^１４は、上記で定義するとおりである。Ｅは、活性エステル化剤からヒドロキシ基を除いた基を表す。］

[In the formula, R ⁷ , R ¹³ and R ¹⁴ are as defined above. E represents a group obtained by removing the hydroxy group from the active esterifying agent. ]

By reacting the active ester-containing compound (SL2) with any polymer having an amino group or hydroxy group, a drug complex of the compound (S-2-1) and the polymer can be obtained.

［上記反応式中、Ｒ^７、Ｒ^１３、Ｒ^１４、Ｅは、上記で定義するとおりである。Ｐｘは任意のポリマーを表し、Ｅｘはヒドロキシ基又はアミノ基を表す。Ｅｘ’はエステル結合又はアミド結合を表す。］

[In the above reaction formula, R ⁷ , R ¹³ , R ¹⁴ and E are as defined above. Px represents any polymer, and Ex represents a hydroxy group or an amino group. Ex' represents an ester bond or an amide bond. ]

≪Drug complex micelles≫
The drug complex of the compound (S) and the polymer contained in the pharmaceutical composition of this embodiment may form micelles. When the drug complex forms a micelle, the polymer included in the drug complex preferably has a hydrophilic polymer segment and a hydrophobic polymer segment. A micelle of a drug complex of compound (S) and a polymer can be prepared by a known method. For example, micelles of a drug conjugate are prepared by dissolving or suspending the drug conjugate in a lipophilic or hydrophilic solvent, and dropping the solution or suspension into the hydrophilic or lipophilic solvent and stirring. can do.

(optional ingredient)
The pharmaceutical composition of this embodiment may contain other components in addition to compound (S). Other ingredients include, for example, pharmaceutically acceptable carriers. "Pharmaceutically acceptable carrier" means a carrier that does not inhibit the physiological activity of the active ingredient and does not exhibit substantial toxicity to the subject to which it is administered. "Substantially non-toxic" means that the component exhibits no toxicity to the recipient at doses commonly used. As the pharmaceutically acceptable carrier, those commonly used in the pharmaceutical field can be used without particular restriction, such as water, physiological saline, phosphate buffer, DMSO, dimethylacetamide, ethanol, glycerol, minerals, etc. Oil etc. can be mentioned.
Other ingredients include solvents, solubilizers, suspending agents, tonicity agents, buffers, pH adjusters, excipients, stabilizers, antioxidants, osmotic pressure adjusters, preservatives, Coloring agents, fragrances, etc. may be mentioned.
Furthermore, the pharmaceutical composition of the present embodiment may contain an anticancer agent other than compound (S) or an active ingredient other than the anticancer agent. Active ingredients other than anticancer agents include, but are not limited to, anti-inflammatory agents, analgesics, antipyretics, anti-inflammatory agents, blood circulation promoters, irritation relievers, antibiotics, and herbal medicines.

Compound (S) may be encapsulated or supported in known drug delivery particles such as liposomes and micelles. Encapsulation and support in particles for drug delivery can be performed by known methods. The pharmaceutical composition of this embodiment may also contain such drug delivery particles as an optional component.

(Cancer resistant to anticancer drugs)
The pharmaceutical composition of this embodiment can be used to treat or prevent cancer resistant to anticancer drugs. "Cancer resistant to anticancer drugs" refers to cancer that exhibits resistance to one or more anticancer drugs. The anticancer drug to which cancer is resistant is preferably an anticancer drug developed for the treatment of the cancer. More preferably, the anti-cancer agent is an anti-cancer agent approved for the treatment of the cancer in question. For example, it is an anticancer drug used in standard treatment for the cancer.
Cancers that have acquired resistance to such anticancer drugs used in standard treatments cannot be treated with effective drug therapy and are intractable. However, as shown in the Examples below, compound (S) exhibits high antitumor activity against anticancer drug-resistant cancers. Therefore, the pharmaceutical composition of this embodiment can be effectively used to treat or prevent cancer resistant to anticancer drugs.

Whether cancer is resistant to anticancer drugs or not depends on whether, for example, the growth of cancer cells in the presence of anticancer drugs is suppressed compared to the growth of cancer cells in the absence of anticancer drugs. This can be determined based on whether or not the Compared to the cancer cell proliferation rate in the absence of the anticancer drug, the growth inhibition rate of cancer cells in the presence of the anticancer drug is, for example, 50% or less, preferably 30% or less, more preferably 20%. Hereinafter, the cancer can be determined to be resistant to the anticancer drug when the resistance is more preferably 10% or less.
Alternatively, whether or not cancer is resistant to anticancer drugs may be evaluated, for example, by IC50 of the anticancer drug. For example, when the IC50 of the anticancer drug to cancer cells is, for example, 10 nM or more, preferably 10 nM or more, more preferably 30 nM or more, and even more preferably 50 nM or more, the cancer cells It can be determined that it is resistant to.

The type of cancer to which the pharmaceutical composition of this embodiment is applied is not particularly limited as long as it is resistant to anticancer drugs. Examples of cancer include lung cancer, pancreatic cancer, head and neck cancer, mesothelioma, neuroblastoma, liver cancer, malignant melanoma, uterine cancer, bladder cancer, biliary tract cancer, esophageal cancer, osteosarcoma, testicular cancer, and thyroid cancer. Examples include cancer, acute myeloid leukemia, brain tumor, prostate cancer, head and neck squamous cell carcinoma, colon cancer, renal cancer, ovarian cancer, and breast cancer. For example, preferred examples include lung cancer, pancreatic cancer, head and neck cancer, and mesothelioma.

Specific examples of anticancer drugs to which cancers exhibit resistance to which the pharmaceutical composition of the present embodiment can be applied include gefitinib, afatinib, osimertinib, dasatinib, erlotinib, gemcitabine, cisplatin, pemetrexed, and midostaurin. .

Specific examples of cancers resistant to anticancer drugs to which the pharmaceutical composition of this embodiment can be applied are illustrated below.
(1) Cancer showing resistance to at least one anticancer drug selected from the group consisting of gefitinib, afatinib, osimertinib, dasatinib, erlotinib, gemcitabine, cisplatin, pemetrexed, and midostaurin.
(2) Lung cancer (especially non-small cell lung cancer) showing resistance to at least one anticancer drug selected from the group consisting of gefitinib, afitinib, osimertinib, and dasatinib. Among these, lung cancer (especially non-small cell lung cancer) that is resistant to osimertinib.
(3) Pancreatic cancer (especially non-small cell lung cancer) showing resistance to at least one anticancer drug selected from the group consisting of gemcitabine and erlotinib.
(4) Head and neck cancer showing resistance to at least one anticancer drug selected from the group consisting of cisplatin, erlotinib, gefitinib, and midostaurin.
(5) Cancer showing resistance to at least one anticancer drug selected from the group consisting of cisplatin, pemetrexed, and midostaurin.
(6) Cancer that is resistant to molecular targeted drugs that target kinases. Examples of the molecular target drugs include gefitinib, afatinib, osimertinib, dasatinib, erlotinib, and midostaurin.
(7) at least one kinase selected from the group consisting of EGFR, ABL1, ALK1, HER2, c-Kit, FGFR1, FGFR2, FGFR3, c-Src, PDGFRa, RET, DDR2, TRKA, and Flt-3; Cancer that is resistant to molecularly targeted drugs.
(8) Cancers expressing kinases with gatekeeper mutations. "Gatekeeper mutation" refers to a mutation in the gatekeeper site. "Gatekeeper site" refers to the site of amino acid residues located at the innermost part of the ATP-binding pocket of a kinase.
(9) Cancer expressing EGFR having at least one mutation selected from the group consisting of d746-750, T790M, C797S, and L858R. Among them, EGFR with mutations of d746-750 and T790M; EGFR with mutations of d746-750, T790M, and C797S; EGFR with mutations of T790M and L858R; or EGFR with mutations of T790M, C797S, and L858R. Cancer that develops.
(10) Cancer expressing ABL1 having at least one mutation selected from the group consisting of T315I and G1269A.
(11) Cancer expressing ALK1 having at least one mutation selected from the group consisting of L1196M and G1269A.
(12) Cancer expressing Her2 with the P780_Y781insGSP mutation.
(13) Cancer expressing at least one type of c-Kit selected from the group consisting of D816E, D816F, D816H, D816I, D816V, D816Y, T670I, and V559D. Among them, cancer expressing at least one type of c-Kit selected from the group consisting of T670I and V559D.
(14) Cancer expressing FGFR1 with the V561M mutation.
(15) Cancer expressing FGFR2 with the V564F mutation.
(16) Cancer expressing FGFR3 with the V565M mutation.
(17) Cancer expressing c-Src with T341M mutation.
(18) Cancer expressing PDGFRa with T674I mutation.
(19) Cancer expressing RET with the V804L mutation.
(20) Cancer expressing DDR2 with T654M mutation.
(21) Cancer expressing TRKA with the G667C mutation.
(22) Cancer expressing Flt-3 with the D835Y mutation.
(23) Cancer expressing a kinase having at least one mutation shown in FIG.
(24) A cancer that expresses at least one of the kinases listed in Table 3 below. Among them, the group consisting of AuroraA, AuroraB, CAMK2a, CAMK2d, CyclinC, CyclinA, CyclinA1, CHK1, DDR1, DYRK3, AK3, MEK3, MEK5, PDK1, PIM3, PKCmu, PKC nu, TRKB, and TRKC. at least one selected from Cancers that express species kinases.
(25) Cancer expressing at least one kind of kinase shown in FIG. 35.

Preferably, the anticancer drug-resistant cancer has at least one characteristic selected from the group consisting of (1) to (25) above, and from the group consisting of (1) to (25) above. More preferably, it has a plurality of selected characteristics.

The dosage form of the pharmaceutical composition of this embodiment is not particularly limited, and known formulation methods can be applied. Examples of the dosage form of the pharmaceutical composition of this embodiment include emulsions, emulsions, liquids, gels, capsules, ointments, patches, poultices, granules, and tablets. Not limited.

The administration route of the pharmaceutical composition of this embodiment is not particularly limited, and it can be administered orally or parenterally. The parenteral route includes all administration routes other than oral administration, such as intravenous, intramuscular, subcutaneous, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, and intraperitoneal administration. Furthermore, administration may be local or systemic.
The pharmaceutical composition of the present embodiment can be administered once or multiple times, and the administration period and interval depend on the type and condition of the disease, the route of administration, the age, body weight, sex, etc. of the subject. can be selected as appropriate. Examples of the administration interval include, but are not limited to, 1 to 3 times a day, once every 2 to 3 days, 1 to 3 times a week, and once every 10 days.
The dosage, period and interval of administration of the pharmaceutical composition of the present embodiment can be appropriately selected depending on the type of drug, the type and condition of the disease, the route of administration, the age, body weight, sex, etc. of the subject to be administered. . The dosage of the pharmaceutical composition of this embodiment can be a therapeutically effective amount of compound (S). "Therapeutically effective amount" means an amount of compound (S) effective for the treatment or prevention of anticancer drug-resistant cancer. For example, the dose of compound (S) per administration can be about 0.01 to 1000 mg, about 0.1 to 100 mg, about 0.5 to 50 mg, or about 1 to 10 mg per kg of body weight.

[Second aspect]
<Compound>
In another aspect, the present invention provides a compound represented by the following general formula (k1).

［式中、Ｒｋ^１及びＲｋ^２は同じまたは異なる残基であり、
（ａ）水素、ハロゲン、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、ヒドロキシ、低級アルコキシ、カルボキシ、低級アルコキシカルボニル、アシル、ニトロ、カルバモイル、低級アルキルアミノカルボニル、－ＮＲ^５Ｒ^６［ここで、Ｒ^５およびＲ^６は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアラルキル、置換もしくは非置換の低級アルキルアミノカルボニル、置換もしくは非置換の低級アリールアミノカルボニル、アルコキシカルボニル、カルバモイル、アシルからそれぞれ独立に選択されるか、またはＲ^５およびＲ^６は、ヘテロ環式基由来の窒素原子と結合している]、
（ｂ）－ＣＯ（ＣＨ_２）_ｊＲ^４［ここで、ｊは１から６であり、Ｒ^４は、
（ｉ）水素、ハロゲン、－Ｎ_３、
（ｉｉ）－ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は上記に定義されたとおりである）、
（ｉｉｉ）－ＳＲ^７（ここで、Ｒ^７は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアラルキル、－（ＣＨ_２）_ａＣＯ_２Ｒ^１０（ここで、ａは、１または２であり、Ｒ^１０は、水素および置換もしくは非置換の低級アルキルからなる群から選択される）および－（ＣＨ_２）_ａＣＯ_２ＮＲ^５Ｒ^６、
（ｉｖ）－ＯＲ^８、－ＯＣＯＲ^８（ここで、Ｒ^８は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールから選択される）
からなる群から選択される］、
（ｃ）－ＣＨ（ＯＨ）（ＣＨ_２）_ｊＲ^４（ここで、ｊおよびＲ^４は、上記に定義したとおりである）；
（ｄ）－（ＣＨ_２）_ｄＣＨＲ^１１ＣＯ_２Ｒ^１２または－（ＣＨ_２）_ｄＣＨＲ^１１ＣＯＮＲ^５Ｒ^６（ここで、ｄは、０から５であり、Ｒ^１１は、水素、－ＣＯＮＲ^５Ｒ^６、または－ＣＯ_２Ｒ^１３であり、Ｒ^１３は、水素または置換もしくは非置換の低級アルキルであり、Ｒ^１２は、水素または置換もしくは非置換の低級アルキルである）；
（ｅ）－（ＣＨ_２）_ｋＲ^１４［ここで、ｋは２から６であり、Ｒ^１４は、ハロゲン、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、－ＣＯＯＲ^１５、－ＯＲ^１５（ここで、Ｒ^１５は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリールまたはアシルである）、－ＳＲ^７（ここで、Ｒ^７は、上記に定義したとおりである）、－ＣＯＮＲ^５Ｒ^６、－ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は、上記に定義したとおりである）または－Ｎ_３である］；
（ｆ）－ＣＨ＝ＣＨ（ＣＨ_２）_ｍ1Ｒ^１６［ここで、ｍ１は、０から４であり、Ｒ^１６は、水素、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、－ＣＯＯＲ^１５、－ＯＲ^１５（ここで、Ｒ^１５は上記に定義したとおりである）、－ＣＯＮＲ^５Ｒ^６または－ＮＲ^５Ｒ^６（ここで、Ｒ^５およびＲ^６は上記に定義したとおりである）］；
（ｇ）－ＣＨ＝Ｃ（ＣＯ_２Ｒ^１２）_２（ここで、Ｒ^１２は、上記に定義したとおりである）；
（ｈ）－Ｃ≡Ｃ（ＣＨ_２）_ｎＲ^１６（ここで、ｎは０から４であり、Ｒ^１６は、上記に定義したとおりである）；
（ｉ）－ＣＨ_２ＯＲ^２２（ここで、Ｒ^２２は、３個の低級アルキル基が同じかもしくは異なっているトリ－低級アルキルシリルであるか、またはＲ^２２は、Ｒ^８と同じ意味を有する）；
（ｊ）－ＣＨ（ＳＲ^２３）_２および－ＣＨ_２－ＳＲ^７（ここで、Ｒ^２３は、低級アルキル、低級アルケニルまたは低級アルキニルであり、Ｒ^７は、上記に定義したとおりである）
からなる群から、それぞれ独立して、選択され；
Ｒｋ^３は、水素、ハロゲン、アシル、カルバモイル、置換もしくは非置換の低級アルキル、置換もしくは非置換のアルケニル、置換もしくは非置換の低級アルキニルまたはアミノであり;
Ｗｋ^１およびＷｋ^２は、独立して、水素、ヒドロキシであるか、またはＷｋ^１およびＷｋ^２は一緒に酸素を表す。］

[wherein Rk ¹ and Rk ² are the same or different residues,
(a) Hydrogen, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, nitro, carbamoyl, lower alkyl Aminocarbonyl, -NR ⁵ R ⁶ [where R ⁵ and R ⁶ are hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted each independently selected from aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkylaminocarbonyl, substituted or unsubstituted lower arylaminocarbonyl, alkoxycarbonyl, carbamoyl, acyl; or R ⁵ and R ⁶ are bonded to the nitrogen atom from the heterocyclic group],
(b) -CO(CH ₂ ) _j R ⁴ [where j is 1 to 6 and R ⁴ is
(i) Hydrogen, halogen, -N ₃ ,
(ii) -NR ⁵ R ⁶ where R ⁵ and R ⁶ are as defined above;
(iii) -SR ⁷ (where R ⁷ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted aralkyl, -(CH ₂ ) _a CO ₂ R ¹⁰ (where a is 1 or 2 and R ¹⁰ consists of hydrogen and substituted or unsubstituted lower alkyl) ) and -(CH ₂ ) _a CO ₂ NR ⁵ R ⁶ ,
(iv) -OR ⁸ , -OCOR ⁸ (where R ⁸ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl) , substituted or unsubstituted heteroaryl)
[selected from the group consisting of ],
(c) -CH(OH) ⁽ _CH2 ) _jR4 , where j and ^R4 are as defined above;
(d) -(CH ₂ ) _d CHR ¹¹ CO ₂ R ¹² or -(CH ₂ ) _d CHR ¹¹ CONR ⁵ R ⁶ (where d is 0 to 5, R ¹¹ is hydrogen, -CONR ⁵ R ⁶ or -CO ₂ R ¹³ , R ¹³ is hydrogen or substituted or unsubstituted lower alkyl, and R ¹² is hydrogen or substituted or unsubstituted lower alkyl);
(e) -(CH ₂ ) _k R ¹⁴ [where k is 2 to 6, R ¹⁴ is halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COOR ¹⁵ , -OR ¹⁵ (Here, R ¹⁵ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or acyl), -SR ⁷ (where R ⁷ is as defined above), -CONR ⁵ R ⁶ , -NR ⁵ R ⁶ (where R ⁵ and R ⁶ are as defined above) ) or -N ₃ ];
(f) -CH=CH(CH ₂ ) _m1 R ¹⁶ [where m1 is 0 to 4, and R ¹⁶ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COOR ¹⁵ , -OR ¹⁵ (wherein R ¹⁵ is as defined above), -CONR ⁵ R ⁶ or -NR ⁵ R ⁶ (where R ⁵ and R ⁶ are as defined above)];
(g) -CH=C(CO ₂ R ¹² ) ₂ (where R ¹² is as defined above);
(h) -C≡C(CH ₂ ) _n R ¹⁶ (where n is 0 to 4 and R ¹⁶ is as defined above);
(i) -CH ₂ OR ²² (wherein R ²² is tri-lower alkylsilyl in which the three lower alkyl groups are the same or different, or R ²² has the same meaning as R ⁸ );
(j) -CH(SR ²³ ) ₂ and -CH ₂ -SR ⁷ (where R ²³ is lower alkyl, lower alkenyl or lower alkynyl and R ⁷ is as defined above)
each independently selected from the group consisting of;
Rk ³ is hydrogen, halogen, acyl, carbamoyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkynyl or amino;
Wk ¹ and Wk ² are independently hydrogen, hydroxy or Wk ¹ and Wk ² together represent oxygen. ]

The term "lower alkyl", when used alone or in conjunction with other groups, refers to carbon atoms having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, more preferably 1 to 4 carbon atoms, particularly preferably 1 means a straight or branched lower alkyl group containing ~3 or 1 to 2 carbon atoms. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, amyl, isoamyl, neopentyl, 1-ethylpropyl, hexyl, and the like, among others. The lower alkyl portion of "lower alkoxy", "lower alkoxycarbonyl", "lower alkylaminocarbonyl", "lower hydroxyalkyl" and "tri-lower alkylsilyl" has the same meaning as "lower alkyl" defined above. .

A "lower alkenyl" group is defined as a C ₂ -C ₆ alkenyl group which may be straight chain or branched and may be of the Z or E configuration. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2 -pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, such as 1,3- or 2,4-pentadienyl. More preferred C2-C6-alkenyl groups are C2 _{- C5-} , _C2 - _C4 -alkenyl groups, even more preferred _C2 - _C3 -alkenyl groups.

The term “lower alkynyl” group means a C ₂ -C ₆ -alkynyl group which may be straight chain or branched and includes ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -Methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, etc. More preferred C ₂ -C ₆ -alkynyl groups are C ₂ -C ₅ -, C ₂ -C ₄ -alkynyl groups, even more preferably C ₂ -C ₃ -alkynyl groups.

The term "aryl" group means a C ₆ -C ₁₄ -aryl group containing from 6 to 14 ring carbon atoms. These groups may be monocyclic, bicyclic, or tricyclic and are fused rings. Preferred aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. The aryl portion of the "arylcarbonyl" and "arylaminocarbonyl" groups has the same meaning as defined above.

The term “heteroaryl” group may contain 1 to 3 heteroatoms independently selected from nitrogen, sulfur or oxygen and refers to a C ₃ -C ₁₃ -heteroaryl group. These groups may be monocyclic, bicyclic or tricyclic. C ₃ -C ₁₃ heteroaryl groups of the present invention include heteroaromatics and saturated and partially saturated heterocyclic groups. These heterocycles may be monocyclic, bicyclic, or tricyclic. Preferred 5- or 6-membered heterocyclic groups are thienyl, furyl, pyrrolyl, pyridyl, pyranyl, monophorinyl, pyrazinyl, methylpyrrolyl, and pyridazinyl. C ₃ -C ₁₃ -heteroaryl may be a bicyclic heterocyclic group. Preferred bicyclic heterocyclic groups are benzofuryl, benzothienyl, indolyl, imidazolyl, and pyrimidinyl. The most preferred C ₃ -C ₁₃ -heteroaryls are furyl and pyridyl.

The term "lower alkoxy" includes an alkoxy group containing 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, more preferably 1 to 4 carbon atoms, particularly preferably 1 to 3 or 1 to 2 carbon atoms. may be linear or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isopropoxy, tert-butoxy, pentoxy, hexoxy, and the like.

The term "acyl" includes lower alkanoyl containing 1 to 6 carbon atoms, preferably 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms, straight chain or It may be a branch. These groups preferably include formyl, acetyl, propionyl, butyryl, isobutyryl, tert-butyryl, pentanoyl and hexanoyl. The acyl portion of the "acyloxy" group has the same meaning as defined above.

The term "halogen" includes fluoro, chloro, bromo, iodo, and the like.

The term "aralkyl" group refers to C ₇ -C ₁₅ -aralkyl in which the alkyl group is substituted by aryl. The alkyl and aryl groups can be selected from the C ₁ -C ₆ -alkyl and C ₆ -C ₁₄ -aryl groups defined above, where the total number of carbon atoms is from 7 to 15. Preferred C ₇ -C ₁₅ -aralkyl groups are benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl. The aralkyl portion of the "aralkyloxy" group has the same meaning as defined above.

Substituted lower alkyl, substituted lower alkenyl, and substituted lower alkynyl groups include lower alkyl, hydroxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, nitro, halogen, amino, mono- or di-lower alkylamino, dioxolane, dioxane, dithiolane, and 1 to 3 independently selected substituents such as dithione. Lower alkyl substituents of substituted lower alkyl groups, substituted lower alkenyl groups and substituted lower alkynyl groups, and lower alkoxy substituents, lower alkoxycarbonyl substituents, mono or di The lower alkyl portion of the lower alkylamino substituent has the same meaning as "lower alkyl" as defined above.

The substituted aryl, heteroaryl and aralkyl groups are each independently selected, such as lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, and halogen. It has 1 to 3 substituents.

Heterocyclic groups formed by R ⁵ and R ⁶ bonded to a nitrogen atom include pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, N-methylpiperazinyl, indolyl, and isoindolyl.

α-amino acid groups include glycine, alanine, proline, glutamic acid and lysine, and may be in the L-form, D-form or racemic form.

Preferably, Rk ¹ and Rk ² are hydrogen, halogen, nitro, -CH ₂ OH, -(CH ₂ ) _k R ¹⁴ , -CH=CH(CH ₂ ) _m R ¹⁶ , -C≡C(CH ₂ ) _n R ¹⁵ , -CO(CH ₂ ) _j R ⁴ (wherein R ⁴ is -SR ⁷ ), CH ₂ O- (substituted or unsubstituted) lower alkyl (wherein substituted lower alkyl is preferably is independently selected from the group consisting of methoxymethyl, methoxyethyl or ethoxymethyl), -NR ⁵ R ⁶ . More preferably Rk ¹ and Rk ² are hydrogen.

In the above preferred meanings of Rk ¹ and Rk ² , the residue R ¹⁴ is preferably phenyl, pyridyl, imidazolyl, thiazolyl, tetrazolyl, -COOR ¹⁵ , -OR ¹⁵ (wherein R ¹⁵ is preferably hydrogen, methyl, ethyl, phenyl or acyl), -SR ⁷ (wherein R ⁷ is preferably selected from substituted or unsubstituted lower alkyl, 2-thiazoline and pyridyl) and -NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are preferably selected from hydrogen, methyl, ethyl, phenyl, carbamoyl and lower alkylaminocarbonyl. Furthermore, the residues R ¹⁶ are preferably hydrogen, methyl, ethyl, phenyl, imidazole, thiazole, tetrazole, -COOR ¹⁵ , -OR ¹⁵ and -NR ⁵ R ⁶ , where the residues R ¹⁵ , R ⁵ and R ⁶ has the preferred meanings given above). In the above preferred meanings of Rk ¹ and Rk ² , the residue R ⁷ is preferably selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, thiazole and tetrazole. Furthermore, k is preferably 2, 3 or 4, j is preferably 1 or 2, and m1 and n are independently preferably 0 or 1.

Preferably Rk ³ is hydrogen or acetyl, most preferably hydrogen.

Preferably each Wk ¹ and Wk ² is hydrogen.

The compound (K) is preferably represented by the following formula (k1-1).

<Method for producing compound (K)>
Compound (K) can be produced, for example, by refluxing a compound represented by the following general formula (k0) without a solvent in the presence of anhydrous hydrazine or hydrazine hydrate. For example, a compound represented by the following general formula (k0) may be used as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or tetrahydrofuran (THF). It can be produced by dissolving it in a solvent such as dioxane, acetonitrile, toluene, etc., adding it to anhydrous hydrazine, and reacting it. Although the reaction temperature and reaction time are not particularly limited, the reaction can be carried out, for example, at room temperature to 50°C for 30 minutes to 15 hours.

<Drug complex>
A second aspect of the present invention is a drug complex containing a polymer having a repeating unit (ka) represented by the following general formula (ka) and a repeating unit (II) represented by the following general formula (II). (hereinafter sometimes referred to as "drug complex (K)").

［式（ｋａ）中、ｍ、Ｌ及びＲ^１は、前記一般式（Ｉ）中のｍ、Ｌ及びＲ^１と同様である。Ｒｋ^１、Ｒｋ^２、Ｒｋ^３、Ｗｋ^１及びＷｋ^２は、前記一般式（ｋ１）中のＲｋ^１、Ｒｋ^２、Ｒｋ^３、Ｗｋ^１及びＷｋ^２と同様である。式（ＩＩ）中、Ｘ及びｍは、前記一般式（ＩＩ）のＸ及びｍと同様である。］

[In formula (ka), m, L and R ¹ are the same as m, L and R ¹ in the general formula (I). Rk ¹ , Rk ² , Rk ³ , Wk ¹ and Wk ² are the same as Rk ¹ , Rk ² , Rk ³ , Wk ¹ and Wk ² in the general formula (k1). In formula (II), X and m are the same as X and m in general formula (II) above. ]

In the general formula (ka), m is preferably 1.
In the general formula (ka), L is preferably a methylene group, an ethylene group, a propylene group, or a benzylene group, and more preferably a methylene group, an ethylene group, or a benzylene group.
In the general formula (ka), R ¹ is preferably a hydrogen atom or an aliphatic hydrocarbon group, and more preferably a hydrogen atom or a methyl group.
In the general formula (ka), Rk ¹ and Rk ² each independently represent hydrogen, halogen, nitro, -CH ₂ OH, -(CH ₂ ) _k R ¹⁴ , -CH=CH(CH ₂ ) _m R ¹⁶ , -C≡C(CH ₂ ) _n R ¹⁵ , -CO(CH ₂ ) _j R ⁴ (wherein R ⁴ is -SR ⁷ ), CH ₂ O- (substituted or unsubstituted) lower alkyl (wherein The substituted lower alkyl is preferably methoxymethyl, methoxyethyl or ethoxymethyl) or -NR ⁵ R ⁶ , more preferably hydrogen.
In the general formula (ka), Rk ³ is preferably hydrogen or acetyl, more preferably hydrogen.
In the general formula (ka), Wk ¹ and Wk ² are preferably hydrogen.
In the general formula (II), m is preferably 1.
In the general formula (II), X is preferably OR ^x , and more preferably OH (hydroxy group).

The drug complex (K) contains a polymer having a repeating unit (ka-1) represented by the following general formula (ka-1) and a repeating unit (II) represented by the following general formula (II). It is preferable to do so.

［式（ｋａ－１）中、ｍ、Ｌ及びＲ^１は、前記一般式（Ｉ）中のｍ、Ｌ及びＲ^１と同様である。式（ＩＩ）中、Ｘ及びｍは、前記一般式（ＩＩ）のＸ及びｍと同様である。］

[In formula (ka-1), m, L and R ¹ are the same as m, L and R ¹ in the general formula (I). In formula (II), X and m are the same as X and m in general formula (II) above. ]

In the general formula (ka-1), m is preferably 1.
In the general formula (ka-1), L is preferably a methylene group, an ethylene group, a propylene group, or a benzylene group, and more preferably a methylene group, an ethylene group, or a benzylene group.
In the general formula (ka-1), R ¹ is preferably a hydrogen atom or an aliphatic hydrocarbon group, more preferably a hydrogen atom or a methyl group.

In the general formula (II), X is preferably OR ^x , and more preferably OH (hydroxy group).

Compound (K) or drug complex (K) exhibits efficacy against malignant cancers and metastatic cancers for which existing cancer therapeutics are ineffective. Therefore, compound (K) and drug complex (K) are useful as therapeutic agents for cancers that are resistant to existing cancer therapeutic agents.

By forming compound (K) into a drug complex (K), the sustained release properties of compound (K) can be controlled similarly to the drug complex of the first embodiment. While compound (K) is retained in the polymer, compound (K) is maintained stably and toxicity is alleviated, so side effects can be reduced and therapeutic effects can be enhanced.
Furthermore, by preparing micelles containing the drug complex (K), similarly to the micelles of the first embodiment, the compound (K) from the drug complex (K) can be release can be controlled. The micelles containing the drug complex (K) can be prepared by a known method, similar to the drug complex micelles of the first embodiment. For example, the drug complex (K) can be dissolved or suspended in a lipophilic or hydrophilic solvent, and the solution or suspension is added dropwise to the hydrophilic or lipophilic solvent and stirred. Micelles containing K) can be prepared.
Note that the drug complex (K) is an embodiment in which the drug is compound (K) in the drug complex of the first embodiment, and is included in the drug complex of the first embodiment. Moreover, the drug complex (K) can also be said to be an embodiment in which BM is compound (K) in the general formula (Ia) in the first embodiment.

Compound (K) and drug complex (K) can be used as compound (S) and drug complex thereof in the pharmaceutical composition of the first embodiment, respectively.

[Other aspects]
In another embodiment, the present invention provides compound (S) or a pharmaceutically acceptable polymer in which the compound (S) is used in the production of a pharmaceutical composition for treating or preventing anticancer drug-resistant cancer. Uses of bound drug conjugates are provided.
In another aspect, the present invention targets compound (S) or a drug conjugate in which said compound (S) is bound to a pharmaceutically acceptable polymer (for example, for patients suffering from cancer resistant to anticancer drugs). ), a method for treating or preventing anticancer drug-resistant cancer is provided.
In another aspect, the present invention provides a compound (S) or a drug complex in which the compound (S) is bound to a pharmaceutically acceptable polymer for use in the treatment or prevention of anticancer drug-resistant cancer. ,I will provide a.
In another aspect, the present invention provides the use of compound (S) or a drug complex in which said compound (S) is bound to a pharmaceutically acceptable polymer for treating or preventing cancer resistant to anticancer drugs. ,I will provide a.

The present invention will be explained based on examples. However, the embodiments of the present invention are not limited to the description of these Examples.

<Polymer synthesis>
[Polymer Synthesis Example 1] Synthesis of methoxy-poly(ethylene glycol)-b-poly(β-benzyl-aspartamide) Initiated by the terminal primary amino group of α-methoxy-ω-amino poly(ethylene glycol), By ring-opening polymerization of β-benzylaspartic acid N-carboxaldehyde, methoxy-poly(ethylene glycol)-b-poly(β-benzyl-aspartamide) (MeO-PEG-PBLA; PEG molecular weight = 12 kDa; polymerization degree of PBLA = 40) A copolymer was synthesized. The ω-amine group was blocked by acetylation.

[Polymer synthesis example 2] Synthesis of aromatic acetal group-introduced polymer PEG-PBLA polymer (220 mg, 0.011 mmol) was dissolved in DMF (2 mL), and {[4-(dimethoxymethyl)phenyl]methanamine} (100 μL, 0 .58 mmol) was added thereto, the temperature was gradually raised, and the mixture was stirred at 40° C. for 4 days. For characterization, a portion of the reaction mixture was ether precipitated to recover the aromatic acetal group-introduced polymer.
The reaction scheme is shown in Figure 1. Furthermore, the results of ¹ H-NMR analysis of the obtained aromatic acetal group-introduced polymer are shown in FIG.
¹ H-NMR analysis confirmed the substitution of 25 benzyl ester units with amide. The remaining benzyl ester (40-25=15) was probably hydrolyzed during the ether precipitation operation.

[Polymer synthesis example 3] Synthesis of aromatic aldehyde group-containing polymer After the aminolysis reaction, the reaction mixture was acidified (0.1N HCl, 100 μL, 30 minutes), then dialyzed against water, and the polymer was freeze-dried. The aldehyde group-introduced polymer was recovered from the dialysis bag. The reaction scheme is shown in Figure 1. Furthermore, the results of ¹ H-NMR analysis of the obtained aromatic aldehyde group-containing polymer are shown in FIG. 27 aldehyde units were confirmed in the ¹ H-NMR spectrum.

[Polymer Synthesis Example 4] Synthesis of polymer containing aliphatic aldehyde group In the synthesis of polymer containing aliphatic aldehyde group, 1-amino-3,3-diethoxy was used instead of {[4-(dimethoxymethyl)phenyl]methanamine}. The synthesis was carried out in the same manner as for the synthesis of aromatic aldehyde group-containing polymers, except that propane was used. The reaction scheme is shown in Figure 1. Furthermore, the results of ¹ H-NMR analysis of the intermediate aliphatic acetal group-containing polymer are shown in FIG. Furthermore, the results of ¹ H-NMR analysis of the obtained aromatic aldehyde group-containing polymer are shown in FIG. 23 aldehyde units were confirmed in the ¹ H-NMR spectrum.

[Polymer Synthesis Example 5] Synthesis of aliphatic ketone group-containing polymer PEG-PBLA polymer (318 mg, 0.016 mmol) was dissolved in DMF (3 mL), and 3,3-dimethoxybutane (200 μL) was added to the resulting solution. did. The reaction solution was stirred at 40° C. for 72 hours, then HCl solution (100 μL, 0.1N) was added and stirred for 1 hour. A polymer with an aliphatic ketone introduced into the side chain was recovered by dialysis against water and lyophilization of the polymer.
The reaction scheme is shown in FIG. Furthermore, the results of ¹ H-NMR analysis of the obtained aliphatic ketone group-containing polymer are shown in FIG. It was confirmed that 35 aliphatic ketone units were introduced into the polymer.

[Example 1] Synthesis of K252a-hydrazide (K252a-H) K252a was purchased from BOC Science (US). K252a (20 mg) was dissolved in anhydrous methanol (200 μL) and added to anhydrous hydrazine (300 μL). The reaction mixture was stirred at 40°C for 15 hours. The reaction mixture was evaporated to obtain a dry product. In the evaporation, toluene was used as a co-evaporation solvent. The obtained product was used for the preparation of drug conjugates and micelles without further purification. The results of ¹ H-NMR analysis of the obtained product are shown in FIG. In the obtained product, the methyl group of K252a disappeared and a peak of hydrazide group proton was observed, which confirmed that K252a-H was obtained. Additionally, K252a-H was analyzed by HPLC. The analysis results are shown in FIG. Since K252a-H and K252a have different retention times, it was confirmed that they have different structures. Note that the conditions for HPLC analysis are as follows.
TSK-GEL ODS-100V column 4.6 x 150mm, particle size 5μm (Tosoh Corporation)
Column pressure: 10.7MPa
Column temperature: constant temperature around 40°C Mobile phase: methanol/formic acid buffer (pH 3.0) mixture (3:2)
Flow rate: 1.2 mL/min, 20-30 minutes UV detection: Wavelength 290 nm
The synthesis scheme of K252a-H from K252a is shown below.

[Example 2] Preparation of drug complex of K252a-H and polymer Aromatic aldehyde group-containing polymer or aliphatic ketone group-containing polymer and K252a-H were mixed at a mass ratio of 2:1 and dissolved in DMSO. (15 mg drug/polymer mixture dissolved per mL DMSO). The bonding reaction between the aromatic aldehyde group-containing polymer and K252a-H was carried out by stirring the reaction mixture at 40° C. overnight. The binding reaction between the aliphatic ketone group-containing polymer and K252a-H was carried out by stirring the reaction mixture for 96 hours. The reaction was monitored by ¹ H-NMR to confirm that K252a-H was completely bound to the polymer. FIG. 10 shows the results of ¹ H-NMR analysis that confirmed the bond between the aliphatic ketone group-containing polymer and K252a-H. FIG. 11 shows the results of ¹ H-NMR analysis that confirmed the bond between the aliphatic aldehyde group-containing polymer and K252a-H.

[Example 3] Preparation of K252a-H bonded polymer micelles (preparation of micelles)
The reaction mixture in DMSO was dialyzed against dimethylacetamide (DMAc) and a solvent exchange was performed from DMSO to DMAc (dialysis for 4 hours, dialysis solvent changed once). Furthermore, free K252a-H was removed by dialysis. A DMAc solution of the drug complex of polymer and K252a-H obtained as above was used for preparing micelles. The DMAc solution was added dropwise to water at a volume ratio of 1:10 to water and vortexed to prepare micelles. This solution was dialyzed against water for 24 hours using a dialysis bag with a molecular weight cutoff (MWCO) of 3500 Da. Dialysis media was changed five times during dialysis. The solution in the dialysis bag was filtered (0.22 μm) and concentrated by ultrafiltration using a 100 kDa MWCO filter membrane (Amicon). Note that the micelles of the drug complex of K252a-H and the above polymer are sometimes referred to as "K252a-H-binding polymer micelles."

(Measurement of micelle size and PDI)
Micelle size and polydispersity index (PDI) were determined by dynamic light scattering (DLS) technique. Measurements were carried out using a Zetasizer nano ZS (Malvern instruments, UK) at a temperature condition of 25° C. with a green laser (532 nm) as the input beam and a detection angle of 173°. The results are shown in FIGS. 12A and 12B. FIG. 12A shows a micelle of a drug complex of an aromatic aldehyde group-containing polymer and K252a-H (hereinafter referred to as "K252a-H bonded aromatic polymer micelle"), and FIG. 12B shows an aliphatic ketone group-containing polymer. and K252a-H (hereinafter referred to as "K252a-H bonded aliphatic polymer micelle"). It was confirmed that the K252a-H-bonded aliphatic ketone group-containing polymer micelle has a smaller micelle size compared to the K252a-H-bonded aromatic aldehyde group-containing polymer micelle. Therefore, K252a-H-bonded aliphatic ketone group-containing polymer micelles are expected to have a higher ability to accumulate in cancer than K252a-H-bonded aromatic aldehyde group-containing polymer micelles.

[Example 4] Solubilization test of K252a-H and drug complex micelles in water K252a-H powder was dissolved in distilled water or methanol at 1 mg/mL and mixed well. Thereafter, it was filtered through a filter with a pore size of 22 μm. The ultraviolet absorption spectrum of the filtrate prepared as described above was measured using a spectrophotometer (Jusco V670). The results are shown in FIG. 27. From the results in FIG. 13, it was confirmed that K252a-H dissolves in water at only 1 μg/mL or less.
On the other hand, when K252a-H bonded aromatic polymer micelles and K252a-H bonded aliphatic polymer micelles were dissolved in water and the concentration of K252a-H was measured by HPLC, it was found that the solubility in water was 2 mg/mL or more. (not shown). The above results showed that even for a compound that is poorly soluble in water, such as K252a-H, its solubility in water can be increased by forming micelles.

[Example 5] Release of K252a-H from K252a-H-conjugated polymeric micelles K252a-H-conjugated aliphatic polymeric micelles were treated in an aqueous pH 1 buffer (methanol:formate buffer (pH 3) = 3:2). Incubate for 1 hour at 37°C. After that, HPLC analysis was performed. HPLC conditions are the same as in Example 1. The results are shown in FIG. The same peak as K252a-H was observed in the sample treated with pH 1 aqueous buffer, indicating that K252a-H is released from K252a-H bonded aliphatic polymer micelles under acidic conditions. .

[Example 6] Cytotoxicity test for K252a type lung cancer cells Using the lung cancer cell lines shown in Table 1, K252a, K252a-H, K252a-H bonded aromatic polymer micelles and K252a-H bonded aliphatic polymer micelles (hereinafter referred to as (sometimes collectively referred to as "K252a class") were tested for cytotoxicity.
In the following examples, the cell line used was American type. It was purchased from the American Type Culture Collection (ATCC) or JCRB (National Institute of Biomedical Innovation) cell bank. PC14 PE6 was kindly provided by Professor Hosho (Tottori University). DMEM, RPMI, or E-MEM was used as the medium unless otherwise specified. Gefetinib, Afatinib, Erlotinib, Cisplatin, Pemetrexed, and Gemicitabine were purchased from Funakoshi Co., Ltd. Osimertinib was purchased from Selleck Chemicals.

A cell solution of 2000 cells/50 μL was prepared in an appropriate amount, and 50 μL each was seeded in rows 2 to 2 of a 96-well plate. Only medium (DMEM medium with 10% FBS) was added to row 1. After seeding, it was incubated for 24 hours.
300 μL of medium was added to each of the 10 wells of a 24-well plate. 100 μL of the drug solution was added to well 1A of a 24-well plate and stirred by pipetting (approximately 10 times), and then 100 μL was transferred to well 2B and stirred in the same manner. The same operation was repeated 10 times to prepare drug solutions with 10 different concentrations.
50 μL of the drug solution prepared above was added to columns 3 to 12 of the 96-well plate in which cancer cells were seeded, in descending order of micelle concentration. To rows 1 and 2, 50 μL of medium alone was added. Thereafter, it was incubated for 48 hours.
After 48 hours, 10 μL of cell-counting kit-8 solution (DOJINDO) was added to each well. The cells were incubated again, and absorbance at 450 nm was measured 30 minutes, 1 hour, and 2 hours later.

The results are shown in FIG. Gefenitib, Afatinib, and Osimetinib are currently FDA-approved molecular targeted treatments for lung cancer. The results in Figure 15 indicate that K252a (particularly K252a, K252a-H, and K252a-H-bonded aliphatic polymer micelles) exhibit high cytotoxic activity against lung cancer that is resistant to existing lung cancer therapeutics. It was done.

FIG. 16 shows an extraction of the PC14 strain and the PC14/PE6 strain in FIG. 15. The PC14/PE6 strain is a cancer cell line obtained by administering the PC14 strain into the tail vein of mice and establishing cancer cells that have metastasized into the thoracic cavity six times (Yano et al., Oncology Research 9:573- 579 (1997)). Therefore, the PC14/PE6 line is a cancer cell line that has extremely high metastatic potential and has become malignant. As shown in FIGS. 15 and 16, Gefenitib, Afatinib, and Osimetinib exhibited high cytotoxic activity against the PC14 strain. However, the cytotoxic activity of these existing molecular target drugs was significantly reduced against the malignant PC14/PE6 strain. On the other hand, K252a (particularly K252a-H and K252a-H-bonded aliphatic polymer micelles) had higher cytotoxic activity against the PC14/PE6 strain. These results indicate that K252a is more effective against malignant metastatic cancer. Note that between the K252a-H-bonded aromatic polymer micelles and the K252a-H-bonded aliphatic polymer micelles, the K252a-H-bonded aliphatic polymer micelles tended to have higher cytotoxic activity against cancer cells.

[Example 7] Cytotoxicity test of K252a type against pancreatic cancer cells Cytotoxicity test of K252a type was conducted in the same manner as above using various pancreatic cancer cell lines. The results are shown in FIG. The BXPC3-F3 strain is a metastatic strain that was orthotopically transplanted into mice and then established as a cancer cell line that metastasized to the liver three times, resulting in malignant transformation. In addition, KP-3L is a metastatic cell line that was established after human liver metastatic pancreatic cancer was transplanted into the spleen of a nude mouse (National Institute of Biomedical Innovation, Health and Nutrition, JCRB Cell Bank) (obtained from ). Additionally, Gemcitabine and Erlotinib are currently approved pancreatic cancer therapeutics.
As shown in FIG. 17, K252a was confirmed to be effective against K-ras mutant strains and malignant metastasis strains for which Gemcitabine and Erlotinib are less effective. Note that between the K252a-H-bonded aromatic polymer micelles and the K252a-H-bonded aliphatic polymer micelles, the K252a-H-bonded aliphatic polymer micelles tended to have higher cytotoxic activity against cancer cells.

[Example 8] Cytotoxicity test of K252a type against head and neck cancer cells Cytotoxicity test of K252a type was conducted in the same manner as above using various head and neck cancer cell lines. The results are shown in FIG. Note that CDDP indicates cisplatin, which is a standard therapeutic drug for head and neck cancer. The SAS strain, FaDu strain, and HSC2 strain are all cisplatin-resistant cell lines.
As shown in FIG. 18, K252a showed higher cytotoxic activity than cisplatin and Erlotinib against all head and neck cancer cell lines. In particular, in the FaDu strain, the cytotoxic activity of the K252a-H-linked aliphatic polymer micelles was high. This result shows that K252a is effective against cisplatin-resistant strains.

[Example 9] Cytotoxicity test for K252a type mesothelioma cells Cytotoxicity test for K252a type was conducted in the same manner as above using mesothelioma cell line MSTO-211H. The results are shown in FIG. Note that CDDP stands for cisplatin, which is a standard treatment drug for mesothelioma. Pemetrexed is also a standard treatment for mesothelioma.
As shown in FIG. 19, K252a showed higher cytotoxic activity than cisplatin, Pemetrexed, and Midostaurin.

[Example 10] Hotspot Kinase Profiling of K252a-H Kinase profiling of K252a-H was carried out outsourced to Rection Biology using the Monthly 202 mutant kinase panel. The conditions for the kinase assay are as follows. K252a was dissolved in DMSO and assayed at 100 nM.
Buffer conditions: 20mM HEPES, pH 7.5, 10mM _MgCl2 , 1mM EGTA, ( _2mM MnCl2 if applicable)
ATP concentration: 10μM
Reaction time: 2 hours

For reference, first-generation, second-generation, and third-generation tyrosine kinase inhibitors (TKIs) and their resistance mutations are shown in FIGS. 20 and 21. As shown in FIGS. 20 and 21, the first to third generation TKIs are not effective against the C797S mutation, so a TKI that is effective against the C797S mutation is being sought.

The results of the K252a-H kinase assay against EGFR mutations are shown in FIG. As shown in Figure 22, K252a-H is specific for gatekeeper mutations (d746-750/T790M, d746-750/T790M/C797S, L858R, T790M, etc.) for which many TKIs do not show efficacy. showed high activity.
Figures 23A-C show the results of kinase profiling of K252a-H. FIG. 24 shows a list of mutant kinases whose kinase activity was suppressed to 30% or less as a result of kinase profiling for K252a-H. K252a-H was confirmed to be a potent inhibitor of the oncogene c-kit/Flt3/RET.

[Example 11] Kinase profiling of K252a-H and staurosporine Kinase profiling of K252a-H and staurosporine was commissioned to Rection Biology. The concentrations of K252a or staurosporine in the kinase assay were as specified. Monthly wild type Kinase panel or Monthly Mutant Kinase panel was used for the kinase panel. Assays were performed in duplicate at each concentration. Kinase activity and IC50 data for each drug concentration tested were obtained, and the average value was determined by performing the test three times in duplicate with N=6. The kinase activity at each drug concentration was converted into activity inhibition rate (%), analyzed using Prism7, and graphed.

Kinase profiling results using the Monthly Mutant Kinase Panel are shown in Figures 25-34. In Figures 25 to 32, the kinases surrounded by solid lines have mutations associated with drug resistance and exhibit high inhibitory activity against the tested drugs. These mutations are summarized in Table 2. Staurosporine and K252a were shown to have high inhibitory activity against kinases having the mutations listed in Table 2. It was also shown to have a high inhibitory effect on osimertinib-resistant triple mutations (d746-750/T790M/C797S, L858R/T790M/C797S) in EGFR. In addition, although a kinase with the HER2 gatekeeper mutation (T798I) was not included in the kinase panel used in the assay, since HER2 is a homolog of EGFR, it was inhibited by staurosporine and K252a as well as the EGFR gatekeeper mutation. It is expected to be highly effective. Figure 33 shows the results of kinase profiling with 500 nM K252a-H. Figure 34 shows the results of kinase profiling with 20 nM staurosporine.

From the results of kinase profiling using the monthly wild type kinase panel, the IC50 of K252a-H for each wild type kinase was determined. As a result, Table 3 shows the kinases for which the IC50 of K252a-H was 5 nM or less. In Table 3, the underlined kinases are kinases that are thought to be involved in drug resistance.

From the results of kinase profiling using the monthly wild type kinase panel, the IC50 of staurosporine for each wild type kinase was determined. As a result, the kinases for which the IC50 of staurosporin was 0.2 nM or less are shown in FIG. In FIG. 35, the underlined kinases are important as therapeutic targets for cancer (particularly drug-resistant cancer). Staurosporine exhibited a particularly high inhibitory effect on CaMK2a, CaMK2b, JAK3, ROS1, RSK4, STK22, and TRKB with an IC50 of 0.1 nM or less. These results indicate that low concentrations of staurosporine are highly specific for cancers that express these kinases.

[Example 12] Cytotoxicity of K252a-H and staurosporine to cancer cells (cell line)
PC14, A549, H358, H2228, PancI, Mia-Paca2, SAS, FaDU, and HSC2 were purchased from ATCC. H460, NCI-1650, H1975, H520, BxPC3, KP3L, and AsPC-1 were purchased from JCRB cell bank.
PC14-PE6 is a malignant cell line with extremely high metastatic potential (Yano et al, Oncology Research 9:573 -579 (1997)) was used. PC14-PE6 was further transduced with Cignal Lenti positive control (Luc) (Qiagen) and cloned to produce PC14-PE6-Luc.
BxPC3 F3 is a malignant liver metastasis strain of BxPC3. BxPC3 F3 was produced by orthotopically transplanting BxPC3 into the pancreas of a mouse, treating cells that had metastasized to the liver with trypsin to establish a cell line, and repeating this process (cell line establishment) three times.

(anticancer drug)
Anticancer drugs (Gefetinib, Afetinib, Osimertinib, Gemicitabine, Cisplatin, Erlotinib, Pemetrexed, Midostaurin) were purchased from Funakoshi.

(Method for measuring cytotoxicity)
The cytotoxicity of the test drug was measured by the following method using cell counting kit 8 (DOJINDO, JAPAN). Cancer cell lines were seeded at 1 to 3×10 ³ cells/well. The next day, the medium was replaced and 50 μL of medium was added. Additionally, a dilution series of the test drug was made and 50 μL was added to the wells and stirred. After 72 hours, 10 μL of cell counting kit 8 was added, and after 1 hour, absorbance at 450 nm was measured using a microplate reader (TECAN). Based on the measured absorbance, the cell survival rate at each dilution rate was calculated for each test drug using the following formula (1). Based on the cell survival rate calculated above, the IC50 of the test drug was calculated.

(Non-small cell lung cancer)
The results of the cytotoxicity test on non-small cell lung cancer cell lines are shown in FIG. 36. The characteristics of each cell line are as shown in Table 1 above. Known lung cancer therapeutics (Gefetinib, Afatinib, Osimertinib, Dasatinib) showed high cytotoxicity against PC14, but Gefetinib, Afatinib, and Osimertinib showed high cytotoxicity against PC14 PE6, a malignant metastatic strain of PC14. Cytotoxicity was low.
On the other hand, staurosporine, K252a, and K252a-H showed higher effects on PC14 PE6 than on PC14.
PC14 is a known lung cancer treatment drug (Gefetinib, Afatinib, Osimertinib, Dasatinib) PC14 PE6, A549, H358, NCI1650, and H520 were resistant to all known lung cancer therapeutics. On the other hand, staurosporine, K252a, and K252a-H showed high cytotoxicity even against these lung cancer drug-resistant strains.

(pancreatic cancer)
The results of the cytotoxicity test on pancreatic cancer cell lines are shown in FIG. 37. In FIG. 37, BxPC3 F3 is a malignant liver metastasis strain of BxPC3. KP-3L is a metastatic strain that metastasized to the liver of a mouse after transplanting human pancreatic cancer that metastasized to the liver into the spleen of a nude mouse. Standard therapeutic drugs for pancreatic cancer (Gemicitabine, Erlotinib) showed high cytotoxicity against BxPC3, but low cytotoxicity against BxPC3 F3 and KP3L.
On the other hand, staurosporine, K252a, and K252a-H showed high cytotoxicity even against strains resistant to these therapeutic drugs for pancreatic cancer.

(head and neck cancer)
The results of the cytotoxicity test on pancreatic cancer cell lines are shown in FIG. 38. In FIG. 38, "CDDP" represents cisplatin. In all cell lines, staurosporine, K252a, and K252a-H exhibited higher cytotoxicity than known head and neck cancer therapeutics (Midostaurin, Cisplatin, Erlotinib, Gefetinib). In particular, staurosporine, K252a, and K252a-H showed high cytotoxicity even against SAS, which is a midostaurin-resistant strain.

(malignant mesothelioma)
The results of the cytotoxicity test on malignant mesothelioma cell lines are shown in FIG. 39. In FIG. 39, "CDDP" represents cisplatin. Staurosporine, K252a, and K252a-H exhibited higher cytotoxicity than known malignant mesothelioma therapeutics (Midostaurin, Cisplatin, Pemetrexed).

[Example 13] In vivo antitumor activity of K252a-H (non-small cell lung cancer)
A Balb/c nude mouse was anesthetized with isoflurane, and 5x10 ⁵ cells/50 μL of 20% Matrigel non-small cell lung cancer cell line (PC14 PE6-luc: a cell in which a luciferase gene was introduced into PC14 PE6) was directly injected into the lungs of the mouse. injected into. Make a mark 5 mm from the tip of the injection needle, insert the injection needle from the 3rd to 4th rib position toward the lower lobe of the lung to the mark, and insert a 20% matrigel suspension of non-small cell lung cancer cell line. Cells were injected with 50 μL of the solution directly into the lungs. In this way, a mouse model for orthotopic transplantation of human non-small cell lung cancer was created.
Starting 5 days after the cancer cell injection, the drug was injected into the human non-small cell lung cancer orthotopically transplanted model mouse at a dose of 1 mg/kg body weight twice a week by tail vein injection. Tumor growth was monitored twice a week under isoflurane anesthesia using IVIS spectroscopy (Xwnogen Corporation) to evaluate the antitumor effect of the drug. Statistical processing of tumor size and survival days was performed using Prism7. K252a-H and K252a-H-bonded aliphatic polymer micelles (prepared in Example 3) were used as test agents. PBS was used as a negative control.

The results are shown in FIGS. 40 and 41. Figure 40 shows tumor growth, and Figure 41 shows Kaplan-Meier survival curves for mice. When K252a-H-conjugated aliphatic polymer micelles were administered, tumor growth was significantly inhibited and survival period was significantly prolonged compared to when PBS was administered. There was a tendency for survival time to be prolonged when K252a-H was administered compared to when PBS was administered. These results confirmed that K252a (particularly K252a-H-bonded aliphatic polymer micelles) exhibits antitumor effects against osimertinib-resistant lung cancer in vivo.

(Pancreatic cancer: test using orthotopic transplant model mouse)
Same method as described in "(Non-small cell lung cancer)" above, except that BxPC3 F3-luc (a cell in which a luciferase gene has been introduced into BxPC3 F3) was used as the cancer cell line, and the cancer cell line was injected into the pancreas in a controlled manner. A mouse model for orthotopic transplantation of human pancreatic cancer was created using the method described above.
The drug was administered to the human pancreatic cancer orthotopically transplanted mouse model prepared as above in the same manner as described in "(Non-small cell lung cancer)" above, except for the type of drug and the dose. Ta. As drugs, K252a-H, K252a-H-linked aliphatic polymer micelles, K252a-H-linked aromatic polymer micelles (prepared in Example 3), and gemcitabine were used. PBS was used as a negative control. The single dose of each drug is 3 mg/kg body weight for K252a-H, K252a-H-linked aliphatic polymer micelles, and K252a-H-linked aromatic polymer micelles, and 5 mg/kg body weight for gemcitabine. And so.

The results are shown in FIG. When gemcitabine was administered, tumors grew similarly to when PBS was administered. On the other hand, when K252a (K252a-H, K252a-H-bonded aliphatic polymer micelles, K252a-H-bonded aromatic polymer micelles) was administered, tumor growth was suppressed compared to when PBS was administered. Ta. In particular, tumor growth was significantly inhibited when K252a-H-conjugated aliphatic polymer micelles were administered. These results confirmed that K252a (particularly K252a-H-linked aliphatic polymer micelles) exhibits antitumor effects against gemcitabine-resistant pancreatic cancer in vivo as well.

(Pancreatic cancer: Test using mice with spontaneous pancreatic cancer)
Transgenic mice that spontaneously develop pancreatic cancer (Capiler corp) were purchased, and pancreatic cancer spontaneous model mice (EL-1-luc/TAg) were created (Proc Natl Acad Sci US A. 2013 Jul 9; 110(28): 11397-11402.). Administration of the drug was started from 13 to 15 weeks of age, when pancreatic cancer develops. The drug administration method was the same as that described in "(Non-small cell lung cancer)." K252a-H bonded aliphatic polymer micelles and K252a-H bonded aromatic polymer micelles were used as drugs. PBS was used as a negative control. The dose of each drug was 1 mg/kg body weight.

Figure 43 shows the IC50 of staurosporine and K252a for spontaneous pancreatic cancer EL1-luc/TAg cells taken from mouse pancreas and made into a cell line. IC50 was calculated using a method similar to that described in Example 12. As shown in Figure 43, EL-1/TAg is resistant to gemcitabine and erlotinib. On the other hand, EL-1/TAg was sensitive to staurosporine and K252a.

FIG. 44 and FIG. 45 are diagrams showing the results of an antitumor effect evaluation test using spontaneous pancreatic cancer model mice. Figure 44 shows tumor growth, and Figure 45 shows Kaplan-Meier survival curves for mice. Tumor growth was significantly inhibited when both K252a-H-bonded aliphatic polymer micelles and K252a-H-bonded aliphatic polymer micelles were administered, compared to when PBS was administered. When K252a-H-conjugated aliphatic polymer micelles were administered, survival time was significantly prolonged compared to when PBS was administered. Administration of K252a-H-linked aromatic polymer micelles also tended to extend survival time compared to administration of PBS. These results confirmed that K252a (particularly K252a-H-linked aliphatic polymer micelles) exhibits antitumor effects against gemcitabine- and erlotinib-resistant pancreatic cancer in vivo.

[Example 14] Cytotoxicity of K252a against lymphomas The IC50 of K252a against lymphoma cell lines was calculated in the same manner as described in Example 12.
The results are shown in FIG. K252a (particularly K252a, K252a-H, and K252a-H-conjugated aliphatic polymer micelles) also showed high cytotoxicity against lymphoma cell lines.

[Example 15] Drug efflux inhibitory effect of ABC transporter (MDR-1) The human renal cancer cell line 780-0 is a cell line that highly expresses MDR-1 (ABCB-1, p-gp). (data not shown). Therefore, using 780-0, the influence of staurosporine and K252a on the drug efflux activity of MDR-1 was evaluated.
Evaluation of drug efflux activity was performed using eFluxx-ID ^™ Green Multidrug Resistance Assay kit (Enzo Life Science). After culturing 780-0 cells in a well plate, a trypsin/EDTA solution was added and incubated, and the cells were detached from the wells. After collecting the detached cells and washing them with a medium, the cells were suspended in the medium at a concentration of 1×10 ⁶ cells/mL to obtain a cell suspension. The cell suspension was prewarmed at 37° C. for 10 minutes or more, and a diluted drug was added to 250 μL of the cell suspension (2.5×10 ⁵ cells).
Staurosporine, K252a, K252a-H, and sunitinib were used as drugs. Verapamil (final concentration 30 μM), an MDR-1 inhibitor, was used as a positive control.
After drug addition, eFluxx-ID ^TM Green detection reagent was added, incubated at 37°C for 30 minutes, DAPI at a final concentration of 0.5 μg/mL was added, and the cells were analyzed using a flow cytometer (BD, Cell Analyzer LSRFortessa X-20). Analyzed. From the flow cytometer analysis results, LD50 was calculated as the drug concentration at which the amount of eFluxx-GFP excreted was halved.

The results are shown in FIG. It was confirmed that staurosporine, K252a, and K252a-H have a lower LD50 than verapamil, the most commonly used MDR-1 inhibitor, and have a higher MDR-1 inhibitory effect.

[Example 16] Effect of human α1-AGP In order to evaluate the effect of human α1-AGP (acid glycoprotein), which is a human serum protein, in the presence of human α1-AGP (hereinafter also referred to as “hAGP”). , evaluated the cellular attributes of K252a-H and K252a-H-conjugated aliphatic polymer micelles.
Cytotoxicity was evaluated using cell counting kit 8 (DOJINDO, JAPAN). H460, a lung cancer cell line, was seeded in the wells at 1 to 3×10 ³ cells/well and cultured. The next day, the medium was replaced, and hAGP was added to a final concentration of 0.5 mg/mL. As a control, 50 μL of a medium containing no hAGP was also prepared. Next, a drug (K252a-H or K252a-H-bonded aliphatic polymer micelle) was added at a concentration of 1 μM. After 48 hours, 10 μL of cell counting kit 8 was added. After 1 hour, absorbance at 450 nm was measured using a microplate reader (TECAN). Based on the measured absorbance, cell survival rate was calculated using the above formula (1).

The results are shown in FIG. In K252a-H-conjugated aliphatic polymer micelles, cell viability was maintained at a low level even in the presence of hAGP. These results confirmed that K252a-H-bonded aliphatic polymer micelles have lower affinity for hAGP than K252a, avoid inactivation by hAGP, and maintain cytotoxicity against cancer cells. .

[Example 17] Preparation of staurosporine-containing micelles To prepare staurosporine-containing micelles, a linker reagent (L1) represented by the following formula (L1) was bound to staurosporine. A scheme of the linker binding reaction is shown in Figure 49. In FIG. 49, "DIC" represents diisopropylcarbodiimide. Activated esters in Figure 49 include N-hydroxysuccinimide (NHS), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), pentafluorophenol, p-nitrophenol. Examples include active esters derived from.

The above bonding reaction was carried out in N,N-dimethylformamide (DMF), and after the reaction was completed, the water-soluble components were removed by liquid separation. Thin layer chromatography confirmed complete consumption of staurosporine and generation of a new fraction. FIG. 50 shows the results of 1H NMR analysis of the organic phase components. The increase in aromatic content and the appearance of ester content (~4.0 ppm) suggested that a linker was attached to staurosporine.

Staurosporine with an active ester linker attached can be attached to a polymer such as polyethylene glycol (PEG) to form a drug conjugate with the polymer. The upper diagram of FIG. 51 shows a reaction in which polyethylene glycol is bonded to staurosporine via a linker. The lower diagram in FIG. 51 shows a reaction in which a PEG-polyamino acid block copolymer is bonded to staurosporine via a linker. (Figure 51 bottom view).

The polymer-linker-staurosporine complex reacts with glutathione (GSH) by glutathione transferase (GST) within the cell and staurosporine is released. The reaction in which staurosporine is released from the PEG-linker-staurosporine complex by glutathione transferase (GST) is shown below.

A compound (S'L1) obtained by reacting staurosporine with a linker reagent (L1) is introduced with a hydrazide group by reacting with anhydrous hydrazine in an anhydrous methanol solvent in the same manner as in Example 1. (Compound (S'L1-H)). The scheme is shown below.

Furthermore, as in Example 2, the compound (S'L1-H) can be bonded to the polymers synthesized in Polymer Synthesis Examples 1 to 5. A drug complex in which the compound (S'L1-H) is bound to an aromatic aldehyde group-containing polymer is exemplified below. In the following formula, the bond (I) and pH represent a pH-sensitive bond. Bond (II) represents a GSH-sensitive bond that reacts with GSH in the presence of GST.

A drug complex in which the compound (S'L1-H) is bound to an aliphatic ketone group-containing polymer is exemplified below.

When a drug complex containing the bond (I) and bond (II) is administered to a living body, the bond (I) is first cleaved in the low pH environment around the tumor tissue, and the compound (S'L1-H) is released. Next, the compound (S'L1-H) is taken up into tumor cells, reacts with GSH by GST, and bond (II) is cleaved to produce staurosporine. The staurosporine kills tumor cells.

Claims (11)

Comprising a drug complex in which a compound (S) represented by the following general formula (S) or a pharmaceutically acceptable salt thereof is bound to a pharmaceutically acceptable polymer,
The drug complex contains a polymer having a repeating unit (Ia) represented by the following general formula (Ia) and a repeating unit (II) represented by the following general formula (II),
A pharmaceutical composition for treating or preventing cancer resistant to anticancer drugs.

[In the formula, m represents 1 or 2. L represents a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group . BM represents a group derived by bonding compound (S) with a hydrazide group in R ₁₃ or R ₁₈ in the following general formula (S) . X represents OR ^x , SR ^x or NR ^x1 R ^x2 . R ^x represents a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. R ^x1 and R ^x2 each independently represent a hydrogen atom, an aliphatic hydrocarbon group, or an aromatic hydrocarbon group. ]

[In the formula,
X and Y are each independently H, OH, Cl, propoxy, or ethylthiomethyl;
R ₆ is H, C _1-3 alkyl , NH ₂ , benzyl,

or

And;
R ₇ and R ₈ are each independently H 2 , O 2 H, or methoxy, or may be taken together to form O=;
R ₉ and R ₁₀ together form a group represented by the following general formula (a) or (b) :

here,
In the general formula (a),
R ₁₁ is methyl;
R ₁₂ is H;
_R13 is

And;
R ₁₄ is H , methoxy, -OH, hydroxymethyl, methylcarboxylate, methylamino, methylaminomethyl, propylaminomethyl, dimethylaminomethyl, methoxycarbonyl, or

And ;
R ₁₅ and R ₁₆ are each independently H, OH, or

And;
In the general formula (b),
R ₁₁ is methyl;
R ₁₂ is H;
R ₁₃ and R ₁₄ are each independently H, methoxy, -OH, hydroxymethyl, methylcarboxylate, methylamino, methylaminomethyl, propylaminomethyl, dimethylaminomethyl, methoxycarbonyl, or

And;
R ₁₅ and R ₁₆ are each independently H, OH, or

And;
R ₁₇ is H, OH, methylamino, dimethylamino, or oxime ;
R ₁₈ is a group represented by the following formula

and here,
R ₁₉ is NH- NH ₂ . ] The medicament according to claim 1, wherein the anticancer drug is at least one anticancer drug selected from the group consisting of gefitinib, afatinib, osimertinib, dasatinib, erlotinib, gemcitabine, cisplatin, pemetrexed, and midostaurin. Composition. The pharmaceutical composition according to claim 1 or 2, wherein the anticancer drug is a molecular targeting drug that targets a kinase. The kinase is at least one kinase selected from the group consisting of EGFR, ABL1, ALK1, HER2, c-Kit, FGFR1, FGFR2, FGFR3, c-Src, PDGFRa, RET, DDR2, TRKA, and Flt-3. The pharmaceutical composition according to claim 3, which is The pharmaceutical composition according to any one of claims 1 to 4, wherein the anticancer drug-resistant cancer is a cancer that expresses a kinase with a gatekeeper mutation. The pharmaceutical composition according to claim 5, wherein the kinase is EGFR with mutations d746-750, T790M, and C797S. Pharmaceutical composition according to any one of claims 1 to 6, wherein the compound (S) is K 252a hydrazide . The pharmaceutical composition according to any one of claims 1 to 5 , wherein the repeating unit (Ia) is a repeating unit represented by the following general formula.

[In the formula, m represents 1 or 2. L represents a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group . ] The pharmaceutical composition according to any one of claims 1 to 6, wherein the repeating unit (Ia) is a repeating unit represented by the following general formula (ka).

[In the formula, m represents 1 or 2. L represents a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group .
Rk ¹ and Rk ² are each independently H, OH, Cl, propoxy, or ethylthiomethyl;
Rk ³ is H, C _1-3 alkyl , NH ₂ , benzyl,

or

And;
Wk ¹ and Wk ² are each independently H 2 , O 2 H, or methoxy, or may be taken together to form O=. ] The pharmaceutical composition according to claim 9, wherein the repeating unit (Ia) is a repeating unit represented by the following general formula (ka-1).

[In the formula, m represents 1 or 2. L represents a divalent aliphatic hydrocarbon group. R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group . ] The pharmaceutical composition according to any one of claims 1 to 10, wherein the drug complex forms micelles.

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