JP6461088B2 - Pharmaceutical composition comprising a polymeric camptothecin derivative and a polymeric HSP90 inhibitor derivative - Google Patents

Description

  The present invention relates to a pharmaceutical composition for treating a malignant tumor administered by combining a polymerized camptothecin derivative and a polymerized HSP90 inhibitor derivative. In particular, the present invention relates to an antitumor pharmaceutical composition in which a polymerized HSP90 inhibitor derivative containing a 1,2,4-triazol-3-one-substituted resorcin derivative and a polymerized camptothecin derivative are used in combination as an HSP90 inhibitor.

Camptothecin is a plant alkaloid extracted from the Chinese plant “Yuki” and is a type I topoisomerase inhibitor. This selectively binds to type I topoisomerase complexed with DNA and stabilizes its structure. As a result, the cleaved DNA cannot be recombined, and is a drug that induces cell death by stopping DNA synthesis.
Camptothecin showed a high antitumor effect and was developed as an antitumor agent in the 1960s. However, clinical trials were discontinued due to myelosuppression and hemorrhagic cystitis as strong toxicity.

  Later, topotecan and irinotecan were developed as derivatives that are more soluble in water than camptothecin, have stronger antitumor activity and lower toxicity. Topotecan exerts an antitumor effect without undergoing metabolism, and diarrhea with side effects is mild because 20-40% of the dose is renal excretion. On the other hand, irinotecan itself has an antitumor effect and is metabolized in vivo to 7-ethyl-10-hydroxycamptothecin (hereinafter sometimes referred to as EHC) as an active metabolite by carboxylesterase. , Exert a stronger anti-tumor effect. In addition, irinotecan and EHC are characterized by having a higher half-life than topotecan in the presence of a biologically active lactone form in plasma as compared to topotecan.

  In clinical practice, camptothecin derivatives are used in many cancer types. Topotecan has been approved for use in small cell lung cancer and ovarian cancer that has been pre-treated with cancer chemotherapeutic agents. On the other hand, irinotecan is small cell lung cancer, non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer (inoperable or recurrent), colorectal cancer (inoperable or recurrent), breast cancer (inoperable or recurrent), spiny cells. Approved with broad indications for cancer and malignant lymphoma (non-Hodgkin lymphoma).

  In order to efficiently extract the pharmacological activity of an antitumor agent, a technique using a polymer carrier is known, and a polymer-camptothecin derivative conjugate using a camptothecin derivative has been reported. Patent Document 1 describes a polymerized camptothecin derivative prepared by esterifying a camptothecin derivative having a phenolic hydroxyl group with a copolymer in which polyethylene glycols and a polymer having a carboxy group in the side chain are linked. . In this polymerized derivative, it is described that a camptothecin derivative is bound by a phenyl ester bond that is easily chemically cleaved, and a camptothecin derivative having pharmacological activity is slowly released after administration in vivo. . Furthermore, the polymerized camptothecin derivative has a self-association property, and forms a micelle-like aggregate and exhibits a high distribution in the tumor tissue, thereby selectively exhibiting a medicinal effect on the tumor tissue and has few side effects. It is described as an antitumor agent. This high molecular weight camptothecin derivative is considered to have an advantage that the release of EHC, which is a medicinal component, does not depend on the enzyme, and thus is hardly affected by individual differences in the therapeutic effect.

Heat shock protein (HSP) is a molecular chaperone present in cells, and is a functional molecule classified into several families such as HSP90, HSP70, HSP60, HSP40, and small HSPs depending on the molecular weight. Molecular chaperone is a general term for proteins that temporarily form a complex with a target protein in order to promote the formation of a functional higher-order structure of the protein. That is, molecular chaperones have the activity of helping protein folding and association and inhibiting aggregation.
HSP is known to interact with various proteins involved in intracellular signal transduction systems. Molecules to which HSP binds are called client proteins, and about 200 molecules of HSP90 client proteins have been reported. That is, HSP90 is often necessary for the functional expression of various proteins, and the mechanism of action is that HSP90 specifically recognizes a client protein in an unstable folded state and binds to it to form a complex. Based on biochemical properties that form. Various proteins (steroid receptors, Raf serine kinases, tyrosine kinases) involved in cancer-related signal transduction depend on the structure of HSP90, and HSP90 regulates the cell cycle, canceration / proliferation / survival of cells It is clear that it is deeply involved in the signal.
Human tumors are abnormal in the regulation of many signal molecules, and HSP90 is required to maintain the function of these signal molecules. In recent years, it has been reported that a compound that acts on HSP90 and inhibits its function causes degradation of various client proteins involved in cancer-related signal transduction and can suppress the growth of cancer cells. That is, the HSP90 inhibitor has an action of changing the configuration of a chaperone complex containing a client protein and HSP90. Thereafter, the client protein released from the complex is decomposed mainly in the ubiquitin / proteasome system. As a result, the amount of HSP90 client protein decreases, and accordingly, downstream signal transduction is blocked and cancer cell growth is suppressed, thereby providing an antitumor effect. Cancer cells are expected to be more sensitive to HSP90 inhibitors than normal cells. Therefore, exploratory studies of HSP90 inhibitors targeting HSP90 as well as verification of their antitumor effects have been made.

Clinical applications of HSP90 inhibitors have been performed previously with geldanamycin derivatives. The geldanamycin derivative 17-AAG has been clinically tested for hematopoietic tumors, breast cancer, melanoma and gastrointestinal stromal tumors (GIST). There was a problem of developing. Accordingly, the search for a novel low-molecular HSP90 inhibitor and a structure optimization study that can overcome the problems of the geldanamycin derivative were advanced, and as a result, several heterocyclic HSP90 inhibitors were found.
For example, Patent Documents 2 to 4 report 1,2,4-triazol-3-one substituted resorcin derivatives useful as HSP90 inhibitors. Patent Document 5 discloses polymerized 1,2 which is a polymerized HSP90 inhibitor aimed at improving the pharmacokinetics of 1,2,4-triazol-3-one-substituted resorcin derivatives and the sustained release of drugs. 1,4-triazol-3-one substituted resorcin derivatives have been described. In the polymerized HSP90 inhibitor, a 1,2,4-triazol-3-one substituted resorcin derivative, which is an HSP90 inhibitor, was bound to a block copolymer having a polyethylene glycol segment and a polymer segment having a carboxy group. It is a polymerized drug-binding compound. This is an antitumor agent that has self-association properties, shows micelle-like aggregates, and shows high distribution in the tumor tissue, so that the drug is selectively acted on the tumor tissue and has a medicinal effect, and has few side effects It is described that. That is, when the polymerized HSP90 inhibitor is administered to a living body, the 1,2,4-triazol-3-one substituted resorcin derivative having a high concentration in the tumor tissue and having HSP90 inhibitory activity is gradually released to produce an antitumor agent. It is described as an antitumor agent that exerts an effect.

In addition, the HSP90 inhibitor is expected to enhance the antitumor effect when combined with a cell-killing antitumor agent, and the development of cancer treatment using a combination of the HSP90 inhibitor and another antitumor agent is promoted. ing.
Patent Document 6 describes the combined use of a 1,2,4-triazol-3-one-substituted resorcin derivative that is an HSP90 inhibitor and camptothecin that is a type I topoisomerase inhibitor. Non-Patent Document 1 reports a phase I clinical trial using a combination of 17-AAG, which is an HSP90 inhibitor, and irinotecan. However, there is no known report on the combined use of a polymerized camptothecin derivative and a polymerized HSP90 inhibitor derivative that exhibit sustained release of an active ingredient.

International Publication WO2004 / 039869 Pamphlet International Publication WO2006 / 055760 Pamphlet International Publication WO2006 / 087077 Pamphlet International Publication WO2006 / 095783 Pamphlet International Publication WO2008 / 041610 Pamphlet International Publication WO2013 / 067162 Pamphlet

Tse A. N. et al. , Clinical Cancer Research 2008 14:20 6704-6711.

  An object of the present invention is to provide a cancer chemotherapeutic agent having a high antitumor effect. In particular, an object of the present invention is to provide an antitumor pharmaceutical composition using a camptothecin derivative that is a key drug in cancer chemotherapy and enhancing its antitumor effect. It is another object of the present invention to provide an antitumor effect enhancer for further enhancing the effect of an antitumor agent using a camptothecin derivative. It is another object of the present invention to provide a treatment method using an camptothecin derivative with enhanced antitumor effect.

  The present inventors are characterized by combining a polymerized camptothecin derivative and a polymerized HSP90 inhibitor to which a 1,2,4-triazol-3-one substituted resorcin derivative that is an HSP90 inhibitor is bound. It was found that the antitumor pharmaceutical composition exerts a remarkably high therapeutic effect as a chemotherapeutic agent, leading to the present invention. That is, the combined use of a polymerized HSP90 inhibitor that slowly releases a polymerized camptothecin derivative and a 1,2,4-triazol-3-one-substituted resorcin derivative results in low toxicity to normal cells and efficiency in affected areas. In addition, the drug efficacy can be improved by delivering and releasing the drug.

［式中、Ｒ_１は水素原子または置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｔは４５〜４５０の整数を示し、Ａは（Ｃ１〜Ｃ６）アルキレン基であり、ｄ、ｅ及びｆはそれぞれ整数であり、ｄ＋ｅ＋ｆは６〜６０の整数を示し、ｄ＋ｅ＋ｆに対するｄの割合が１〜１００％、ｅの割合が０〜６０％、ｆの割合が０〜６０％であり、Ｒ_２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_３は−Ｎ（Ｒ_４）ＣＯＮＨ（Ｒ_５）を示し、Ｒ_４及びＲ_５は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐若しくは環状アルキル基または三級アミノ基で置換されていてもよい分岐若しくは直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基に７−エチル−１０−ヒドロキシカンプトテシンが結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される高分子化カンプトテシン誘導体であり、
前記高分子化トリアゾール−３−オン置換レゾルシン誘導体は一般式（２）

［式中、Ｒ_１１は水素原子又は置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｕは４５〜４５０の整数を示し、Ａａは（Ｃ１〜Ｃ６）アルキレン基であり、ｇ、ｈ及びｉはそれぞれ整数であり、ｇ＋ｈ＋ｉは６〜６０の整数を示し、ｇ＋ｈ＋ｉに対するｇの割合が１〜１００％、ｈの割合が０〜６０％、ｉの割合が０〜６０％であり、Ｒ_１２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_１３は−Ｎ（Ｒ_１５）ＣＯＮＨ（Ｒ_１６）を示し、Ｒ_１５及びＲ_１６は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐または環状アルキル基もしくは三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、Ｒ_１４が１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基であり、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基にＲ_１４が結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_１３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される高分子化トリアゾール−３−オン置換レゾルシン誘導体であり、
前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基における１，２，４−トリアゾール−３−オン置換レゾルシン誘導体が下記一般式（３）

［式中、Ｘ_１は（Ｃ１〜Ｃ６）の直鎖若しくは分岐のアルキル基または−ＣＯＮＲ_１７Ｒ_１８を示し、前記Ｒ_１７及びＲ_１８は同一でも異なっていてもよい（Ｃ１〜Ｃ６）の直鎖状、分岐状または環状アルキル基であり、Ｘ_２は置換基を有していてもよいアリール基を示す。］であり、前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基が、該レゾルシン誘導体の水酸基がエステル結合した該残基である高分子化トリアゾール−３−オン置換レゾルシン誘導体であり、前記高分子化カンプトテシン誘導体と前記高分子化トリアゾール−３−オン置換レゾルシン誘導体とを同時に、順次に又は間隔をおいて投与する、抗腫瘍性医薬組成物。
２） 前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基が、Ｘ_１がイソプロピル基であり、Ｘ_２が５−（Ｎ−メチルインドリル）基または４−（（４−メチルピペラジン−１−イル）メチル）フェニル基である、前記１）に記載の抗腫瘍性医薬組成物。
３） 前記高分子化カンプトテシン誘導体におけるカンプトテシン誘導体残基の含有モル当量と前記高分子化トリアゾール−３−オン置換レゾルシン誘導体における１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基の含有モル当量の比が、１：０．１〜２０である、前記１）または２）に記載の抗腫瘍性医薬組成物。
４） カンプトテシン誘導体に対する感受性が低下した悪性腫瘍の治療に用いる、前記１）〜３）のいずれか一項に記載の抗腫瘍性医薬組成物。That is, the gist of the present invention is the following configurations 1) to 9).
1) Polymerized camptothecin derivative containing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked, and a polymerized triazol-3-one substituted containing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked An antitumor pharmaceutical composition comprising a resorcin derivative,
The polymerized camptothecin derivative has the general formula (1)

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60%. R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment is 7- Ethyl-10-hydroxycan And glutamic acid units Toteshin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ] Is a polymerized camptothecin derivative represented by
The polymerized triazol-3-one substituted resorcin derivative has the general formula (2)

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to a side chain carboxy group, a glutamic acid unit in which an R ₁₃ group is bonded to a side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group, Each is independently a polyglutamic acid structure arranged at random. A polymerized triazol-3-one-substituted resorcin derivative represented by
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue is a polymerized triazol-3-one-substituted resorcin derivative in which the hydroxyl group of the resorcin derivative is ester-bonded Yes, an antitumor pharmaceutical composition, wherein the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative are administered simultaneously, sequentially or at intervals.
2) In the 1,2,4-triazol-3-one-substituted resorcin derivative binding residue, X ₁ is an isopropyl group, and X ₂ is a 5- (N-methylindolyl) group or 4-((4- The antitumor pharmaceutical composition according to 1) above, which is methylpiperazin-1-yl) methyl) phenyl group.
3) Containing molar equivalent of camptothecin derivative residue in the polymerized camptothecin derivative and inclusion of 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the polymerized triazol-3-one substituted resorcin derivative The antitumor pharmaceutical composition according to 1) or 2) above, wherein the molar equivalent ratio is from 1: 0.1 to 20.
4) The antitumor pharmaceutical composition according to any one of 1) to 3) above, which is used for the treatment of a malignant tumor having reduced sensitivity to a camptothecin derivative.

［式中、Ｒ_１１は水素原子又は置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｕは４５〜４５０の整数を示し、Ａａは（Ｃ１〜Ｃ６）アルキレン基であり、ｇ、ｈ及びｉはそれぞれ整数であり、ｇ＋ｈ＋ｉは６〜６０の整数を示し、ｇ＋ｈ＋ｉに対するｇの割合が１〜１００％、ｈの割合が０〜６０％、ｉの割合が０〜６０％であり、Ｒ_１２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_１３は−Ｎ（Ｒ_１５）ＣＯＮＨ（Ｒ_１６）を示し、Ｒ_１５及びＲ_１６は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐または環状アルキル基もしくは三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、Ｒ_１４が１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基であり、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基にＲ_１４が結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_１３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される高分子化トリアゾール−３−オン置換レゾルシン誘導体を含むカンプトテシン誘導体の抗腫瘍効果増強剤であって、
前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基における１，２，４−トリアゾール−３−オン置換レゾルシン誘導体が下記一般式（３）

［式中、Ｘ_１は（Ｃ１〜Ｃ６）の直鎖若しくは分岐のアルキル基または−ＣＯＮＲ_１７Ｒ_１８を示し、前記Ｒ_１７及びＲ_１８は同一でも異なっていてもよい（Ｃ１〜Ｃ６）の直鎖状、分岐状または環状アルキル基であり、Ｘ_２は置換基を有していてもよいアリール基を示す。］であり、前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基が、該レゾルシン誘導体の水酸基がエステル結合した該残基である、抗腫瘍効果増強剤。
６） 前記カンプトテシン誘導体が、ポリエチレングリコールセグメントとポリグルタミン酸セグメントが連結したブロック共重合体を含む高分子化カンプトテシン誘導体であって、該高分子化カンプトテシン誘導体が一般式（１）

［式中、Ｒ_１は水素原子又は置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｔは４５〜４５０の整数を示し、Ａは（Ｃ１〜Ｃ６）アルキレン基であり、ｄ、ｅ及びｆはそれぞれ整数であり、ｄ＋ｅ＋ｆは６〜６０の整数を示し、ｄ＋ｅ＋ｆに対するｄの割合が１〜１００％、ｅの割合が０〜６０％、ｆの割合が０〜６０％であり、Ｒ_２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_３は−Ｎ（Ｒ_４）ＣＯＮＨ（Ｒ_５）を示し、Ｒ_４及びＲ_５は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐若しくは環状アルキル基または三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基に７−エチル−１０−ヒドロキシカンプトテシンが結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される、前記５）に記載の抗腫瘍効果増強剤。
７） １，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基が、Ｘ_１がイソプロピル基であり、Ｘ_２が５−（Ｎ−メチルインドリル）基または４−（（４−メチルピペラジン−１−イル）メチル）フェニル基である、前記５）または６）に記載の抗腫瘍効果増強剤。5) General formula (2)

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to a side chain carboxy group, a glutamic acid unit in which an R ₁₃ group is bonded to a side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group, Each is independently a polyglutamic acid structure arranged at random. An antitumor effect enhancer of a camptothecin derivative including a polymerized triazol-3-one-substituted resorcin derivative represented by the formula:
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the 1,2,4-triazol-3-one-substituted resorcin derivative-binding residue is the residue obtained by ester-bonding the hydroxyl group of the resorcin derivative.
6) The camptothecin derivative is a polymerized camptothecin derivative containing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked, and the polymerized camptothecin derivative is represented by the general formula (1)

[Wherein R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60%. R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 7- Ethyl-10-hydroxycampto And glutamic acid units Singh bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ] The antitumor effect potentiator described in 5) above.
7) In the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue, X ₁ is an isopropyl group, and X ₂ is a 5- (N-methylindolyl) group or 4-((4-methyl The antitumor effect enhancer according to 5) or 6) above, which is piperazin-1-yl) methyl) phenyl group.

［式中、Ｒ_１１は水素原子又は置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｕは４５〜４５０の整数を示し、Ａａは（Ｃ１〜Ｃ６）アルキレン基であり、ｇ、ｈ及びｉはそれぞれ整数であり、ｇ＋ｈ＋ｉは６〜６０の整数を示し、ｇ＋ｈ＋ｉに対するｇの割合が１〜１００％、ｈの割合が０〜６０％、ｉの割合が０〜６０％であり、Ｒ_１２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_１３は−Ｎ（Ｒ_１５）ＣＯＮＨ（Ｒ_１６）を示し、Ｒ_１５及びＲ_１６は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐または環状アルキル基もしくは三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、Ｒ_１４が１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基であり、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基にＲ_１４が結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_１３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造であり、
前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基における１，２，４−トリアゾール−３−オン置換レゾルシン誘導体が下記一般式（３）

［式中、Ｘ_１は（Ｃ１〜Ｃ６）の直鎖若しくは分岐のアルキル基または−ＣＯＮＲ_１７Ｒ_１８を示し、前記Ｒ_１７及びＲ_１８は同一でも異なっていてもよい（Ｃ１〜Ｃ６）の直鎖状、分岐状または環状アルキル基であり、Ｘ_２は置換基を有していてもよいアリール基を示す。］であり、前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基におけるレゾルシン誘導体の水酸基がエステル結合した該残基である。］で表される高分子化トリアゾール−３−オン置換レゾルシン誘導体、と組み合わせて用いることを特徴とし、
前記ポリエチレングリコールセグメントとポリグルタミン酸セグメントが連結したブロック共重合体を含む高分子化カンプトテシン誘導体が、一般式（１）

［式中、Ｒ_１は水素原子または置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｔは４５〜４５０の整数を示し、Ａは（Ｃ１〜Ｃ６）アルキレン基であり、ｄ、ｅ及びｆはそれぞれ整数であり、ｄ＋ｅ＋ｆは６〜６０の整数を示し、ｄ＋ｅ＋ｆに対するｄの割合が１〜１００％、ｅの割合が０〜６０％、ｆの割合が０〜６０％であり、Ｒ_２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_３は−Ｎ（Ｒ_４）ＣＯＮＨ（Ｒ_５）を示し、Ｒ_４及びＲ_５は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐若しくは環状アルキル基または三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基に７−エチル−１０−ヒドロキシカンプトテシンが結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される、前記抗腫瘍剤。
９）一般式（１）

［式中、Ｒ_１は水素原子または置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｔは４５〜４５０の整数を示し、Ａは（Ｃ１〜Ｃ６）アルキレン基であり、ｄ、ｅ及びｆはそれぞれ整数であり、ｄ＋ｅ＋ｆは６〜６０の整数を示し、ｄ＋ｅ＋ｆに対するｄの割合が１〜１００％、ｅの割合が０〜６０％、ｆの割合が０〜６０％であり、Ｒ_２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_３は−Ｎ（Ｒ_４）ＣＯＮＨ（Ｒ_５）を示し、Ｒ_４及びＲ_５は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐若しくは環状アルキル基または三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基に７−エチル−１０−ヒドロキシカンプトテシンが結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］
で表される高分子化カンプトテシン誘導体と、一般式（２）

［式中、Ｒ_１１は水素原子又は置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｕは４５〜４５０の整数を示し、Ａａは（Ｃ１〜Ｃ６）アルキレン基であり、ｇ、ｈ及びｉはそれぞれ整数であり、ｇ＋ｈ＋ｉは６〜６０の整数を示し、ｇ＋ｈ＋ｉに対するｇの割合が１〜１００％、ｈの割合が０〜６０％、ｉの割合が０〜６０％であり、Ｒ_１２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_１３は−Ｎ（Ｒ_１５）ＣＯＮＨ（Ｒ_１６）を示し、Ｒ_１５及びＲ_１６は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐または環状アルキル基もしくは三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、Ｒ_１４が１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基であり、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基にＲ_１４が結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_１３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造であり、
前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基における１，２，４−トリアゾール−３−オン置換レゾルシン誘導体が下記一般式（３）

［式中、Ｘ_１は（Ｃ１〜Ｃ６）の直鎖若しくは分岐のアルキル基または−ＣＯＮＲ_１７Ｒ_１８を示し、前記Ｒ_１７及びＲ_１８は同一でも異なっていてもよい（Ｃ１〜Ｃ６）の直鎖状、分岐状または環状アルキル基であり、Ｘ_２は置換基を有していてもよいアリール基を示す。］であり、前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基におけるレゾルシン誘導体の水酸基がエステル結合した該残基である。］
で表される高分子化トリアゾール−３−オン置換レゾルシン誘導体の組合せを含む医薬キットであって、前記高分子化カンプトテシン誘導体と前記高分子化トリアゾール−３−オン置換レゾルシン誘導体を、同時に、順次に又は間隔をおいて投与する、腫瘍の治療のための医薬キット。8) A block in which a polyethylene glycol segment and a polyglutamic acid segment are linked, which is used in combination with a polymerized triazol-3-one substituted resorcin derivative containing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked. An antitumor agent comprising a polymerized camptothecin derivative containing a copolymer, wherein the polymerized triazol-3-one-substituted resorcin derivative is represented by the general formula (2)

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to the side chain carboxy group, a glutamic acid unit in which the R ₁₃ group is bonded to the side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group, Each independently and randomly arranged polyglutamic acid structure,
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the hydroxyl group of the resorcin derivative in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is an ester-bonded residue. And a polymerized triazol-3-one substituted resorcin derivative represented by the formula:
The polymerized camptothecin derivative containing a block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked is represented by the general formula (1).

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60% R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 7- Ethyl-10-hydroxycamp And glutamic acid units Taesin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ] The said antitumor agent represented by this.
9) General formula (1)

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60% R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 7- Ethyl-10-hydroxycamp And glutamic acid units Taesin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ]
A polymerized camptothecin derivative represented by the general formula (2):

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to the side chain carboxy group, a glutamic acid unit in which the R ₁₃ group is bonded to the side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group, Each independently and randomly arranged polyglutamic acid structure,
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the hydroxyl group of the resorcin derivative in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is an ester-bonded residue. ]
Wherein the polymerized camptothecin derivative and the polymerized triazol-3-one substituted resorcin derivative are simultaneously and sequentially Alternatively, a pharmaceutical kit for tumor treatment, administered at intervals.

  The antitumor pharmaceutical composition of the present invention comprises a polymerized camptothecin derivative that binds 7-ethyl-10-hydroxycamptothecin (EHC) and releases the EHC, and 1,2,4-triazole having HSP90 inhibitory activity. An antitumor pharmaceutical composition comprising a combination of a polymerized 1,2,4-triazol-3-one substituted resorcin derivative that binds to a 3-one substituted resorcin derivative and releases the resorcin derivative . The pharmaceutical composition can improve the antitumor effect and reduce side effects, and can achieve efficient and safe cancer chemotherapy. Further, the polymerized 1,2,4-triazol-3-one substituted resorcin derivative has an effect of enhancing the antitumor effect of the camptothecin derivative, and the camptothecin derivative and the polymerized camptothecin which are key drugs in cancer chemotherapy It can be used as an antitumor effect enhancer of a derivative. Therefore, it is possible to provide an antitumor agent against a tumor exhibiting resistance to a camptothecin derivative.

In the PBS solution of Compound 1 (phosphate buffered saline; pH 7.1), the ratio of the released amount of Compound 4 as an active ingredient at 37 ° C. to the total amount of bound drug is shown. The ratio of the released amount of compound 4 as an active ingredient at 37 ° C. in the PBS solution of compound 2 (phosphate buffered saline; pH 7.1) to the total amount of bound drug is shown. Combined administration of a polymerized 1,2,4-triazol-3-one substituted resorcin derivative (compound 1) and a polymerized camptothecin derivative (compound 3), compound 1 alone and compound to mice transplanted with mouse colon cancer Colon 38 3 is administered alone, and the change in relative tumor volume in each administration group is shown.

  The present invention relates to a polymerized conjugated camptothecin derivative linked with 7-ethyl-10-hydroxycamptothecin (EHC) and a 1,2,4-triazol-3-one substituted resorcin derivative having HSP90 inhibitory activity. The present invention relates to an antitumor pharmaceutical composition for treating tumors comprising a combination of 1,2,4-triazol-3-one substituted resorcin derivatives. Details of the present invention will be described below.

［式中、Ｒ_１は水素原子または置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｔは４５〜４５０の整数を示し、Ａは（Ｃ１〜Ｃ６）アルキレン基であり、ｄ、ｅ及びｆはそれぞれ整数であり、ｄ＋ｅ＋ｆは６〜６０の整数を示し、ｄ＋ｅ＋ｆに対するｄの割合が１〜１００％、ｅの割合が０〜６０％、ｆの割合が０〜６０％であり、Ｒ_２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_３は−Ｎ（Ｒ_４）ＣＯＮＨ（Ｒ_５）を示し、Ｒ_４及びＲ_５は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐若しくは環状アルキル基または三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基に７−エチル−１０−ヒドロキシカンプトテシンが結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される高分子化カンプトテシン誘導体である。In the polymerized camptothecin derivative of the present invention, in the block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked, the carboxy group of the side chain of the polyglutamic acid segment and the 10-position hydroxyl group of EHC which is a camptothecin derivative are ester-bonded. It is a polymer-drug-binding antitumor agent.
The polyethylene glycol segment is a polymer having a unit structure of an ethyleneoxy group; (—OCH ₂ CH ₂ ) group, and is a segment having a terminal group chemically modified. On the other hand, the polyglutamic acid segment is a segment in which glutamic acid is polymerized to have a plurality of γ-carboxy groups as side chains and the terminal groups are modified. The polymerized camptothecin derivative of the present invention is a side chain carboxylic acid and a camptothecin derivative having a polyvalent carboxylic acid-containing block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked by an appropriate bonding group as a main chain. It has a structure in which the hydroxyl group of EHC is bonded by an ester bond. That is, the polymerized camptothecin derivative of the present invention has the following general formula (1):

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60% R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 7- Ethyl-10-hydroxycamp And glutamic acid units Taesin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ] The high molecularization camptothecin derivative | guide_body represented by this.

In the general formula (1), R ₁ is a terminal modification group of the polyethylene glycol segment, and is a hydrogen atom or a (C1-C4) alkyl group which may have a substituent. The R ₁ is preferably a (C1-C4) alkyl group which may have a substituent. Specific examples are methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group or tert-butyl group. Examples of the substituent of the (C1 to C4) alkyl group which may have a substituent include an amino group, a dialkylamino group, an alkyloxy group, a formyl group, and a carboxy group. As R ₁ , a methyl group or an ethyl group is preferable, and a methyl group is particularly preferable.

In the general formula (1), it is preferable to use a polyethylene glycol segment having a molecular weight of 2,000 to 20,000, more preferably 4,000 to 15,000. That is, t, which is the number of unit repeating structures of an ethyleneoxy group; (—OCH ₂ CH ₂ ) group, is 45 to 450, preferably 90 to 340.

  A in the general formula (1) is a linking group that connects the polyethylene glycol segment and the polyglutamic acid segment, and is an alkylene group of (C1 to C6). For example, a methylene group, ethylene group, trimethylene group, tetramethylene group, hexamethylene group, and the like can be given. Among them, an ethylene group or a trimethylene group is preferable, and a trimethylene group is particularly preferable.

  The polyglutamic acid segment of the polymerized camptothecin derivative of the present invention represented by the general formula (1) has a structure in which glutamic acid units are amide-bonded. The amide bond is mainly a structure bonded with an α-amide bond type, but may include a structure bonded with a γ-amide bond type. The glutamic acid of each glutamic acid unit may be L-type or D-type. The total number of glutamic acid units in the general formula (1) (polyglutamic acid polymerization number) is represented by d + e + f and is 6 to 60. Preferably d + e + f is 8-40. Therefore, the average molecular weight of the polyglutamic acid segment is about 600 to 15,000, preferably about 800 to 10,000.

R ₂ in the general formula (1) includes a hydrogen atom or a (C1-C4) acyl group. R ₂ is preferably a (C1 to C4) acyl group, and examples thereof include a formyl group, an acetyl group, and a propionyl group. Among them, an acetyl group or a propionyl group is preferable, and an acetyl group is particularly preferable.

R ₃ in the general formula (1) is —N (R ₄ ) CONH (R ₅ ), R ₄ and R ₅ may be the same or different, and a branched or cyclic alkyl group of (C3 to C6), or (C1-C5) branched or straight chain alkyl group optionally substituted with a tertiary amino group.
Examples of the branched or cyclic alkyl group of (C3 to C6) include isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-methylbutyl group, 2-methylbutyl group, neopentyl group, cyclohexyl group and the like. More preferably, an isopropyl group and a cyclohexyl group are mentioned.
Examples of the (C1-C5) branched or straight chain alkyl group optionally substituted with the tertiary amino group include an ethyl group and a dimethylaminopropyl group.
As R ₄ and R _5, it is preferable that R ₄ and R ₅ are both isopropyl group or cyclohexyl group, or R ₄ and R ₅ are a combination of ethyl group and dimethylaminopropyl group. A group in which R ₄ and R ₅ are both an isopropyl group or a cyclohexyl group is particularly preferable.

  As shown in the general formula (1), the polyglutamic acid segment of the polymer compound of the present invention is a structure in which EHC, which is a camptothecin derivative, is ester-bonded with a hydroxyl group at the 10-position and a side chain carboxy group of polyglutamic acid. .

The polyglutamic acid segment may have a glutamic acid unit to which neither EHC nor R ₃ is bound. In the general formula (1), the side chain carboxylic acid in the glutamic acid unit to which EHC and R ₃ are not bonded is shown as a glutamic acid residue having a free acid type carboxy group. However, the carboxy group may be in the form of an alkali metal or alkaline earth metal salt, and the polymerized camptothecin derivative of the general formula (1) having a glutamic acid moiety containing such a carboxy group is also included in the present invention. It is. Examples of the alkali metal salt or alkaline earth metal salt include lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt. In addition, when the polymerized camptothecin derivative is provided for parenteral administration, the solution is prepared in a pharmaceutically acceptable solution, and the form of the free carboxylic acid side chain is determined by the pH of the solution, the buffer solution Depending on the salt, it may take the form of glutamate.

In the polyglutamic acid segment of the present invention, in each glutamic acid unit, a glutamic acid unit in which EHC is bonded to a side chain carboxy group, a glutamic acid unit in which the R ₃ is bonded to the side chain carboxy group, or a side chain carboxy group is free. A glutamic acid unit which is a carboxy group or a salt thereof is independently present in a random sequence.
In the polyglutamic acid segment, the abundance of the EHC-bound glutamic acid unit is represented by d in the general formula (1), and occupies 1 to 100% of the glutamic acid segment. The R ₃ -bonded glutamic acid unit is represented by e in the general formula (1), and occupies 0 to 60% of the glutamic acid segment. On the other hand, the abundance of the free glutamic acid unit is represented by f in the general formula (1) and occupies 0 to 60% in the glutamic acid segment. The preferable ranges of d, e, and f for each glutamic acid unit with respect to all glutamic acid segments are 20 to 70% for d, 1 to 40% for e, and 1 to 40% for f.

  Next, the manufacturing method of the polymeric camptothecin derivative in this invention is demonstrated. The polymerized camptothecin derivative of the present invention is summarized as disclosed in International Publication No. WO2004 / 039869, and includes the disclosed content. Preferable examples include a method in which a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked is used, and a side chain carboxy group and EHC are subjected to a condensation reaction.

  The method for constructing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked in the present invention is either a method of binding a polyethylene glycol segment and a polyglutamic acid segment, or a method of sequentially polymerizing polyglutamic acid to a polyethylene glycol segment. This method may be used.

A suitable method for synthesizing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked is as follows: a polyethylene glycol compound having a modified group such as a methoxy group at one end and an amino group modified at the other end; A method of sequentially reacting carbonylglutamic acid anhydride to construct a polyglutamic acid segment can be mentioned. In this case, in the N-carbonylglutamic acid anhydride, as the carboxy group of the glutamic acid side chain, an EHC conjugate, a conjugate of R _{3 according} to the general formula (1), a free carboxylic acid conjugate, a carboxylic acid protecting group conjugate, or the like is used. be able to. As the N-carbonylglutamic acid anhydride, it is preferable to use an N-carbonylglutamic acid anhydride in which the side chain carboxy group is modified with an appropriate carboxylic acid protecting group. The carboxylic acid protecting group is not particularly limited, but an ester bond type protecting group is preferable. That is, by using an N-carbonylglutamic acid anhydride whose side chain carboxy group is modified with an appropriate carboxylic acid protecting group and reacting with a polyethylene glycol compound having an amino group modified at one end, the N-carbonylglutamic acid anhydride is reacted. Is a method in which a block copolymer in which polyethylene glycol and a polyglutamic acid derivative are linked is constructed by sequential polymerization of EHC and optionally a substituent represented by R _{3 according} to the general formula (1) is introduced. It is preferable to use it.

  More specifically, a polyethylene glycol compound modified with a methoxy group at one end and an amino group at the other end and γ-benzyl-N-carbonylglutamic anhydride are sequentially reacted, and then by subsequent polymerization, polyethylene glycol and poly (ethylene glycol) are reacted. A block copolymer linked with glutamic acid benzyl ester is prepared. Thereafter, by deprotecting the benzyl group of polyglutamic acid by a suitable method, a block copolymer in which the polyethylene glycol and polyglutamic acid are linked can be prepared. Examples of the deprotection reaction of the benzyl group include a hydrolysis reaction and a hydrogenation reduction reaction under alkaline conditions.

Next, a synthesis method of the polymerized camptothecin derivative represented by the general formula (1) in the present invention will be described. EHC and —N (R ₄ ) CONH (R ₅ ) group which is R ₃ of the general formula (1) are allowed to bind to the glutamic acid side chain of the block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked. Thus, the polymerized camptothecin derivative according to the present invention can be prepared. The bonding reaction method of the EHC and the —N (R ₄ ) CONH (R ₅ ) group is not particularly limited, and the EHC is bonded first, and then the —N (R ₄ ) CONH (R ₅ ) The group may be subjected to a binding reaction, the reverse process thereof, or a simultaneous binding reaction.
Preferably, the polyethylene glycol segment and polyglutamate segment block copolymer linked, a method of condensation reaction in the presence of a carbodiimide condensing agent EHC is the block copolymer in the EHC and -N (R ₄₎ CONH This is an advantageous reaction because the (R ₅ ) groups can be attached simultaneously. Examples of the carbodiimide condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCI), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC). In the condensation reaction, a reaction aid such as N, N-dimethylaminopyridine (DMAP) may be used. In addition, when dicyclohexyl carbodiimide (DCC) is used as a carbodiimide condensing agent, R ₄ and R ₅ of —N (R ₄ ) CONH (R ₅ ) become a cyclohexyl group. When the condensation reaction is performed using diisopropylcarbodiimide (DIPCI), R ₄ and R ₅ are isopropyl groups. When 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) is used, R ₄ and R ₅ of —N (R ₄ ) CONH (R ₅ ) are an ethyl group and 3-dimethylamino It becomes a mixed substitution product of propyl.

EHC and —N (R ₄ ) CONH (R ₅ ) group as R _{3 in the} general formula (1) are bonded to the glutamic acid side chain of the block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked by the above reaction. Then, the polymerized camptothecin derivative of the present invention can be synthesized optionally through a purification step.

  The polymerized camptothecin derivative has the ability to gradually dissociate and continue to release EHC, which is an antitumor active ingredient, in a phosphate buffered saline (PBS) solution. That is, in living body administration, the polymerized camptothecin derivative has physical properties that release EHC in a sustained manner. A low molecular drug generally used in clinical practice shows the maximum blood concentration of a drug immediately after administration, and is then discharged from the body relatively quickly. On the other hand, the polymerized camptothecin derivative is a drug in the body in which EHC is released slowly from a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked, and the transition of EHC in blood is continuously maintained. It is a preparation characterized by kinetic transition. In addition, the polymer carrier conjugate is said to have a greatly different distribution in the body after administration than a low-molecular-weight drug, and exhibits a completely different pharmacokinetic behavior in the body from conventional drugs. From this, it is considered that this high molecular weight camptothecin derivative is completely different from low molecular weight camptothecin preparations such as topotecan and irinotecan in terms of pharmacological effects and side effects, and a new clinical treatment method for camptothecin derivatives. It is an antitumor preparation capable of providing

  The polymerized camptothecin derivative of the present invention is used as an antitumor agent. The polymerized camptothecin derivative is used in commonly used dosage forms such as injections, drops, tablets, capsules, powders and the like. In formulating, pharmaceutically acceptable carriers that are commonly used, such as binders, lubricants, disintegrants, solvents, excipients, solubilizers, dispersants, stabilizers, suspending agents, Preservatives, soothing agents, pigments and fragrances can be used. Preferably, it is desired to be used as an injection or drip, and usually water, physiological saline, 5% glucose or mannitol solution, water-soluble organic solvent (eg glycerol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, polyethylene glycol) , Cremophor and the like, and a mixture thereof) and a mixture of water and the water-soluble organic solvent.

  Next, the polymerized triazol-3-one substituted resorcin derivative of the present invention will be described. This is a polymer-bonded drug in which a side chain carboxy group of a polyglutamic acid segment and a hydroxyl group of a triazol-3-one substituted resorcin derivative are ester-bonded in a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked. is there. Hereinafter, the polymerized triazol-3-one substituted resorcin derivative will be described in detail.

［式中、Ｒ_１１は水素原子または置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｕは４５〜４５０の整数を示し、Ａａは（Ｃ１〜Ｃ６）アルキレン基であり、ｇ、ｈ及びｉはそれぞれ整数であり、ｇ＋ｈ＋ｉは６〜６０の整数を示し、ｇ＋ｈ＋ｉに対するｇの割合が１〜１００％、ｈの割合が０〜６０％、ｉの割合が０〜６０％であり、Ｒ_１２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_１３は−Ｎ（Ｒ_１５）ＣＯＮＨ（Ｒ_１６）を示し、Ｒ_１５及びＲ_１６は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐または環状アルキル基もしくは三級アミノ基で置換されていてもよい分岐または直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、Ｒ_１４が１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基であり、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基にＲ_１４が結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_１３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される高分子化トリアゾール−３−オン置換レゾルシン誘導体であり、
前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基における１，２，４−トリアゾール−３−オン置換レゾルシン誘導体が下記一般式（３）

［式中、Ｘ_１は（Ｃ１〜Ｃ６）の直鎖若しくは分岐のアルキル基または−ＣＯＮＲ_１７Ｒ_１８を示し、前記Ｒ_１７及びＲ_１８は同一でも異なっていてもよい（Ｃ１〜Ｃ６）の直鎖状、分岐状または環状アルキル基であり、Ｘ_２は置換基を有していてもよいアリール基を示す。］であり、前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基が、該レゾルシン誘導体の水酸基がエステル結合した該残基である高分子化トリアゾール−３−オン置換レゾルシン誘導体である。The polymerized triazol-3-one substituted resorcin derivative of the present invention comprises a polyvalent carboxylic acid-containing block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked by an appropriate bonding group as a main chain, and a side chain carboxylic acid and It has a structure in which a hydroxyl group of a triazol-3-one substituted resorcin derivative is ester-bonded. That is, the polymerized triazol-3-one substituted resorcin derivative has the following general formula (2)

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1 to C4) alkyl group, u represents an integer of 45 to 450, and Aa represents a (C1 to C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue And the polyglutamic acid segment comprises a glutamic acid unit in which R ₁₄ is bonded to a side chain carboxy group, a glutamic acid unit in which an R ₁₃ group is bonded to a side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group. These are each independently a randomly arranged polyglutamic acid structure. A polymerized triazol-3-one-substituted resorcin derivative represented by
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue is a polymerized triazol-3-one-substituted resorcin derivative in which the hydroxyl group of the resorcin derivative is ester-bonded is there.

R ₁₁ in the general formula (2) is a terminal modification group of the polyethylene glycol segment, and is a hydrogen atom or a (C1 to C4) alkyl group which may have a substituent. R ₁₁ is preferably a (C1-C4) alkyl group which may have a substituent. Specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group. Examples of the substituent of the (C1 to C4) alkyl group which may have a substituent include an amino group, a dialkylamino group, an alkyloxy group, a formyl group, and a carboxy group. R ₁₁ is preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

In general formula (2), it is preferable to use a polyethylene glycol segment having a molecular weight of 2,000 to 20,000, more preferably 4,000 to 15,000. That is, u, which is the number of unit repeating structures of an ethyleneoxy group; (—OCH ₂ CH ₂ ) group, is 45 to 450, preferably 90 to 340.

  Examples of Aa in the general formula (2) that is a linking group that connects a polyethylene glycol segment and a polyglutamic acid segment include (C1 to C6) alkylene groups such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, Examples include a hexamethylene group. Among them, an ethylene group or a trimethylene group is preferable, and a trimethylene group is particularly preferable.

  The polyglutamic acid segment of the polymerized triazol-3-one substituted resorcin derivative of the present invention represented by the general formula (2) is a segment structure in which a plurality of glutamic acid units are amide-bonded. The form of the amide bond is a structure bonded with an α-amide bond type, but may include a structure bonded with a γ-amide bond type. Each glutamic acid unit may be L-type or D-type. The total number of glutamic acid units in the general formula (2) is represented by g + h + i and is 6 to 60. Preferably g + h + i is 8-40. Therefore, the average molecular weight of the polyglutamic acid segment is about 600 to 15,000, preferably about 800 to 10,000.

R ₁₂ in the general formula (2) includes a hydrogen atom or (C1-C4) acyl group. R ₁₂ is preferably a (C1 to C4) acyl group, and examples thereof include a formyl group, an acetyl group, and a propionyl group. Among them, an acetyl group or a propionyl group is preferable, and an acetyl group is particularly preferable.

R ₁₃ in the general formula (2) is —N (R ₁₅ ) CONH (R ₁₆ ), R ₁₅ and R ₁₆ may be the same or different, and a branched or cyclic alkyl group of (C3 to C6), or (C1-C5) branched or straight chain alkyl group optionally substituted with a tertiary amino group.
Examples of the branched or cyclic alkyl group of (C3 to C6) include isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-methylbutyl group, 2-methylbutyl group, neopentyl group, cyclohexyl group and the like. More preferably, an isopropyl group and a cyclohexyl group are mentioned.
Examples of the (C1-C5) branched or straight chain alkyl group optionally substituted with the tertiary amino group include an ethyl group and a dimethylaminopropyl group.
As R ₁₅ and R _16, it is preferable that R ₁₅ and R ₁₆ are both an isopropyl group or a cyclohexyl group, or R ₁₅ and R ₁₆ are a combination of an ethyl group and a dimethylaminopropyl group. A group in which R ₁₅ and R ₁₆ are both an isopropyl group or a cyclohexyl group is particularly preferable.

［式中、Ｘ_１は（Ｃ１〜Ｃ６）の直鎖若しくは分岐のアルキル基または−ＣＯＮＲ_１７Ｒ_１８を示し、前記Ｒ_１７及びＲ_１８は同一でも異なっていてもよい（Ｃ１〜Ｃ６）の直鎖状、分岐状または環状アルキル基であり、Ｘ_２は置換基を有していてもよいアリール基を示す。］で示される１，２，４−トリアゾール−３−オン置換レゾルシン誘導体を挙げることができる。R ₁₄ in the general formula (2) is a binding residue of a triazol-3-one-substituted resorcin derivative that is an HSP90 inhibitor, and a bond in which the hydroxyl group of the resorcin moiety is ester-bonded to the side chain carboxy group of the polyglutamic acid segment Residue. The triazol-3-one-substituted resorcin derivative has the general formula (3)

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And a 1,2,4-triazol-3-one substituted resorcin derivative represented by the formula:

X ₁ in the general formula (3) represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , and the R ₁₇ and R ₁₈ may be the same or different (C1 to C6). ) Linear, branched or cyclic alkyl group.
Examples of the linear or branched alkyl group of (C1 to C6) in X ₁ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. Group, 1-pentyl group, 1-ethyl-propyl group, 1-hexyl group and the like.
Examples of the linear, branched or cyclic alkyl group (C1-C6) which may be the same or different in R ₁₇ and R ₁₈ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group. , Sec-butyl group, isobutyl group, tert-butyl group, 1-pentyl group, 1-ethyl-propyl group, 1-hexyl group, cyclohexyl group and the like.
X ₁ is preferably an isopropyl group, a sec-butyl group, an isobutyl group, a tert-butyl group or —CONR ₁₇ R ₁₈ , wherein R ₁₇ is a methyl group and R ₁₈ is an n-butyl group.

The X ₂ group in the general formula (2) is an aryl group which may have a substituent. Examples of the aryl group which may have a substituent include a carbocyclic aryl group which may have a substituent and a heterocyclic aryl group which may have a substituent.

In the carbocyclic aryl group which may have a substituent for X _2, examples of the carbocyclic aryl group include a phenyl group and a naphthyl group. The carbocyclic aryl group which may have a substituent includes a carbocyclic aryl group having an alkyl group as a substituent, a carbocyclic aryl group having a halogen atom as a substituent, and a carbocyclic aryl having an alkoxy group as a substituent. And a carbocyclic aryl group having an amino group as a substituent, or a carbocyclic aryl group having an aminoalkyl group as a substituent.

The carbocyclic aryl group having an alkyl group as the substituent is a carbocyclic aryl group in which at least one or more of (C1 to C30) linear, branched or cyclic alkyl groups are substituted. Preferably, it is a phenyl group substituted by a linear or branched alkyl group of (C1 to C8). For example, 2-methylphenyl group, 4-methylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, n-hexylphenyl group, n-octylphenyl group, 1-ethylpropylphenyl group, 2-methylpropylphenyl Groups and the like.
The carbocyclic aryl group having a halogen atom as the substituent is a carbocyclic aryl group in which at least one halogen atom is substituted. A monohalogen-substituted phenyl group or a dihalogen-substituted phenyl group is preferable. Examples include 2-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 2-bromophenyl group, 4-bromophenyl group, 2,4-dibromophenyl group, and the like.
The carbocyclic aryl group having an alkoxy group as the substituent is a carbocyclic aryl group having at least one (C1-C10) primary, secondary or tertiary alkoxy group. For example, 4-methoxyphenyl group, 3-methoxyphenyl group, 3,4-dimethoxyphenyl group, 3,4-methylenedioxyphenyl group can be mentioned. Of these, a 4-methoxyphenyl group is preferable.

The carbocyclic aryl group having an amino group as a substituent in X ₂ includes, as the amino group, an unsubstituted amino group, an acyclic primary or secondary amino group, or a cyclic secondary amino group as a substituent. And carbocyclic aryl groups.
In the amino group provided as a substituent, examples of the non-cyclic primary amino group include (C1-C10) linear, branched or cyclic alkyl groups, or amino groups substituted by aryl groups. For example, methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, n-octylamino group, phenylamino group and the like can be mentioned.
The acyclic secondary amino group, which may be the same or different, is a (C1-C10) linear, branched or cyclic alkyl group, or an amino group in which an aryl group is N, N-disubstituted. It is a group. Examples thereof include a dimethylamino group, a diisopropylamino group, an N-methyl-N-cyclohexylamino group, an N-methyl-N-phenylamino group, an N-methyl-N-pyridylamino group, and a diphenylamino group.
Examples of the cyclic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.

The amino group of the substituent is preferably an acyclic aliphatic primary or acyclic secondary amino group or a cyclic aliphatic secondary amino group. That is, preferred examples of the acyclic aliphatic primary amino group include a methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, and n-octylamino group. . Preferred examples of the acyclic aliphatic secondary amino group include a dimethylamino group, a diisopropylamino group, and an N-methyl-N-cyclohexylamino group. Preferred examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group. Can do.
Examples of the carbocyclic aryl group in the carbocyclic aryl group having an amino group as a substituent include a phenyl group and a naphthyl group. The carbocyclic aryl group is preferably a phenyl group. The substitution position of the amino group on the phenyl group is not particularly limited, and may be any substitution product at the 2-6 position. A substituted amino group at the 3-position or 4-position is preferred.
In the carbocyclic aryl group having an amino group as a substituent, a preferred embodiment is a phenyl group in which an acyclic aliphatic secondary amino group is substituted at the 4-position, or a cyclic aliphatic secondary amino group at the 4-position. Examples include substituted phenyl groups. In particular, 4-dimethylaminophenyl group, 4- (morpholino) phenyl group, or 4- (4-methylpiperazin-1-yl) phenyl group is preferable.

The carbocyclic aryl group having an aminoalkyl group as a substituent for X ₂ includes, as the amino group, an unsubstituted amino group, an acyclic primary or acyclic secondary amino group, or a cyclic secondary amino group And a carbocyclic aryl group substituted with a (C1-C8) alkyl group having a substituent.
Examples of the non-cyclic primary amino group include (C1-C10) linear, branched or cyclic alkyl groups, or amino groups substituted by aryl groups. For example, methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, n-octylamino group, phenylamino group and the like can be mentioned.
The acyclic secondary amino group may be the same or different, and is a (C1-C10) linear, branched or cyclic alkyl group, or an amino group in which an aryl group is N, N-disubstituted. It is a group. Examples thereof include a dimethylamino group, a diisopropylamino group, an N-methyl-N-cyclohexylamino group, an N-methyl-N-phenylamino group, an N-methyl-N-pyridylamino group, and a diphenylamino group.
Examples of the cyclic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group.

The amino group of the substituent is preferably an acyclic aliphatic primary or acyclic secondary amino group or a cyclic aliphatic secondary amino group. That is, preferred examples of the acyclic aliphatic primary amino group include a methylamino group, isopropylamino group, neopentylamino group, n-hexylamino group, cyclohexylamino group, and n-octylamino group. .
Preferred examples of the acyclic aliphatic secondary amino group include a dimethylamino group, a diisopropylamino group, and an N-methyl-N-cyclohexylamino group.
Preferred examples of the cyclic aliphatic secondary amino group include a morpholino group, a piperazin-1-yl group, a 4-methylpiperazin-1-yl group, a piperidin-1-yl group, and a pyrrolidin-1-yl group. Can do.
Examples of the (C1-C8) alkyl group having the amino group as a substituent include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and an octyl group.
Examples of the carbocyclic aryl group having an aminoalkyl group as a substituent include a phenyl group and a naphthyl group. The carbocyclic aryl group is preferably a phenyl group. The substitution position of the aminoalkyl group on the phenyl group is not particularly limited, and may be any substitution product at the 2-6 position. A substituted amino group at the 3-position or 4-position is preferred.
In the carbocyclic aryl group having an aminoalkyl group as a substituent, as a preferred embodiment, a cyclic aliphatic secondary amino group is substituted at the terminal position of the (C1-C5) alkyl group, and the other terminal group is a phenyl group. In which the 4-position is substituted.
In particular, 4- (morpholinomethyl) phenyl group, 4- (4-methylpiperazin-1-ylmethyl) phenyl group, 4- (2-morpholinoethyl) phenyl group, 4- [2- (4-methylpiperazine- A 1-yl) ethyl] phenyl group, a 4- (4-morpholinobutyl) phenyl group, and a 4- [5- (4-methylpiperazin-1-yl) pentyl] phenyl group are preferred. A more preferred embodiment is 4- (morpholinomethyl) phenyl group or 4- (4-methylpiperazin-1-ylmethyl) phenyl group.

The heterocyclic aryl group that may have a substituent in X ₂ includes a pyridyl group that may have a substituent, a pyrimidinyl group that may have a substituent, and a substituent. May have a quinolyl group, a quinazolinyl group which may have a substituent, a naphthyridinyl group which may have a substituent, a furyl group which may have a substituent, or a substituent. Pyrrolyl group, optionally substituted indolyl group, optionally substituted imidazolyl group, optionally substituted pyrazolyl group, optionally substituted oxazolyl group , An isoxazolyl group which may have a substituent, a triazolyl group which may have a substituent, and the like.
Preferably, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, an indolyl group which may have a substituent, an imidazolyl group which may have a substituent Can be mentioned. Particularly preferred are a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, and an indolyl group which may have a substituent.

Preferred embodiments of the heterocyclic aryl group which may have a substituent for X ₂ include a pyridyl group, a pyridyl group having an alkyl group as a substituent, a pyridyl group having an amino group as a substituent, and an alkyl group as a substituent. A pyrimidinyl group having an amino group, a pyrimidinyl group having an amino group as a substituent, an indolyl group having an alkyl group as a substituent, and an indolyl group having an amino group as a substituent.
Examples of the pyridyl group having an alkyl group as a substituent include a 6-methylpyridin-3-yl group and a 5-methylpyridin-2-yl group.
Examples of the pyridyl group having an amino group as a substituent include a 5-dimethylaminopyridin-2-yl group.
Examples of the pyrimidinyl group having an alkyl group as a substituent include 2-methylpyrimidin-4-yl group and 2-methylpyrimidin-5-yl group.
Examples of the pyrimidinyl group having an amino group as a substituent include 2-dimethylaminopyrimidin-5-yl group, 2-morpholinopyrimidin-5-yl group, and 2- (4-methylpiperazin-1-yl) pyrimidine-5 Yl group and the like.
Examples of the indolyl group having an alkyl group as a substituent include a 1-methylindol-5-yl group and a 1-ethylindol-5-yl group.

In a 1,2,4-triazol-3-one substituted resorcin derivative preferable as an HSP90 inhibitor in the present invention, X ₁ is an isopropyl group or —CONR ₁₇ R ₁₈ , R ₁₇ is a methyl group, and R ₁₈ is an n-butyl group. It is. X ₂ is selected from the group consisting of 2-methylphenyl group, 4- (morpholinomethyl) phenyl group, 4- (4-methylpiperazin-1-ylmethyl) phenyl group, and 1-methylindol-5-yl group. The substituent compounds are preferred.
As an HSP inhibitor that binds to the block copolymer, preferably 5- (2,4-dihydroxy-5-isopropylphenyl), wherein X ₁ is an isopropyl group and X ₂ is a 1-methylindol-5-yl group. ) -4- (1-Methyl-1H-indol-5-yl) -2,4-dihydro- [1,2,4] triazol-3-one (the following general formula (4); compound 4); X ₁ Is —CONR ₁₇ R ₁₈ , R ₁₇ is a methyl group, R ₁₈ is an n-butyl group, and X ₂ is a 2-methylphenyl group, 5- (2,4-dihydroxy-5- (N-methyl) -N-butyramide))-4- (2-methylphenyl) -2,4-dihydro- [1,2,4] triazol-3-one (the following general formula (5); compound 5); or X ₁ There is an isopropyl group, _{X 2} is 4 5- (2,4-dihydroxy-5-isopropylphenyl) -4- [4- (4-methylpiperazin-1-ylmethyl) phenyl] -2, which is a (4-methylpiperazin-1-ylmethyl) phenyl group 4-dihydro- [1,2,4] triazol-3-one dihydrochloride (the following general formula (6); compound 6) can be exemplified.

In the 1,2,4-triazol-3-one-substituted resorcin derivative represented by the general formula (3), each compound of the combination of the X ₁ group and the X ₂ group is synthesized based on known literature. be able to. The following documents can be cited as known documents for the synthesis of the 1,2,4-triazol-3-one substituted resorcin derivatives.
Compound 4 is a known compound and can be produced, for example, according to the description in International Publication WO2007 / 13952.
Compound 5 is a known compound and can be produced, for example, according to the description in International Publication WO2008 / 086857 Pamphlet.
Compound 6 is a known compound and can be produced, for example, according to the description in International Publication WO 2006/095783.

The compound serving as a substituent for R ₁₄ is a 1,2,4-triazol-3-one substituted resorcin derivative according to formula (3) within the same polymer or between polymers of the compound represented by formula (2) As long as it is a single type or a plurality of types, a single type is preferable.

The polyglutamic acid segment according to the general formula (2) may contain an HSP90 inhibitor corresponding to the R ₁₄ group and a glutamic acid unit to which neither of R ₁₃ is bound. In the general formula (2), the HSP90 inhibitor corresponding to R ₁₄ and the side chain carboxylic acid in the glutamic acid unit to which the R ₁₃ group is not bonded are shown as a glutamic acid residue having a free acid type carboxy group. However, the carboxy group may be in the form of an alkali metal or alkaline earth metal salt, and the polymerized triazol-3-one of general formula (2) having a glutamic acid moiety containing such a carboxyl group Substituted resorcin derivatives are also included in the present invention. Examples of the alkali metal salt or alkaline earth metal salt include lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt. In addition, when the polymerized triazol-3-one substituted resorcin derivative is provided for parenteral administration, it is prepared as a solution in a pharmaceutically acceptable solution. The form of the free carboxy group is the same as that of the solution. Depending on the pH, the salt of the buffer solution, it can take the form of glutamate.

The polyglutamic acid segment in the present invention is, in each glutamic acid unit, a glutamic acid unit in which an HSP90 inhibitor corresponding to R ₁₄ is bound to a side chain carboxy group, a glutamic acid unit in which the R ₁₃ is bound to a side chain carboxy group, Alternatively, glutamic acid units whose side chain carboxy group is a free carboxy group or a salt thereof are each independently present in a random arrangement.

In the polyglutamic acid segment, the HSP90 inhibitor-bound glutamic acid unit corresponding to R ₁₄ is represented by g in the general formula (2), and occupies 1 to 100% of the glutamic acid segment. Further, the abundance of the R ₁₃ -bonded glutamic acid unit is represented by h in the general formula (2), and occupies 0 to 60% in the glutamic acid segment. On the other hand, the amount of the free glutamic acid unit represented by i in the general formula (2) is 0 to 60% in the glutamic acid segment. The preferable ranges of g, h, and i for each glutamic acid unit with respect to all glutamic acid segments are 20 to 70% for g, 1 to 40% for h, and 1 to 40% for i.

Next, the manufacturing method of the polymeric triazol-3-one substituted resorcin derivative in this invention is demonstrated.
The method for constructing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked in the present invention is a method of binding a polyethylene glycol segment and a polyglutamic acid segment, and a method of sequentially polymerizing polyglutamic acid to a polyethylene glycol segment. Either method may be used.

A suitable method for synthesizing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked to each other is a N-terminal polyethylene glycol compound having a modifying group such as a methoxy group at one end and an amino group modified at the other end. A method of sequentially reacting carbonylglutamic acid anhydride to construct a polyglutamic acid segment can be mentioned. In this case, in the N-carbonylglutamic acid anhydride, the carboxyl group of the glutamic acid side chain is a conjugate of R _{14 according to} the general formula (2), a conjugate of R _{13 according} to the general formula (2), a free carboxylic acid or A carboxylic acid protecting group conjugate or the like can be used. As the N-carbonylglutamic acid anhydride, it is preferable to use an N-carbonylglutamic acid anhydride whose side chain carboxy group is modified with an appropriate carboxylic acid protecting group. The carboxylic acid protecting group is not particularly limited, but is preferably an ester bond protecting group. That is, the N-carbonylglutamic acid anhydride modified with an appropriate carboxylic acid protecting group is used as the side chain carboxy group, and the N-carbonylglutamic acid anhydride is reacted with a polyethylene glycol compound modified with an amino group at one end. A block copolymer in which polyethylene glycol and a polyglutamic acid derivative are linked is constructed by sequential polymerization, and is substituted with 1,2,4-triazol-3-one substituted represented by R _{14 according} to the general formula (2). It is preferable to use a method of introducing a resorcin derivative and optionally a substituent represented by R _{13 according} to the general formula (2).

  More specifically, a polyethylene glycol compound modified with a methoxy group at one end and an amino group at the other end is sequentially reacted with γ-benzyl-N-carbonylglutamic acid anhydride, and subsequently polymerized with polyethylene glycol. A block copolymer to which polyglutamic acid benzyl ester is linked is prepared. Thereafter, by deprotecting the benzyl group of polyglutamic acid by a suitable method, a block copolymer in which the polyethylene glycol and polyglutamic acid are linked can be prepared. Examples of the deprotection reaction of the benzyl group include a hydrolysis reaction and a hydrogenation reduction reaction under alkaline conditions.

Next, a method for synthesizing the polymerized triazol-3-one substituted resorcin derivative represented by the general formula (2) in the present invention will be described. In addition, the manufacturing method of the high molecular compound of this invention is not limited to the manufacturing method described here, and the method as described in an Example and a reference example of a postscript.
With respect to the glutamic acid side chain of the block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked, a triazole-3-one-substituted resorcin derivative and -N (R ₁₅ ) CONH (R ₁₆ as R _{13 in the} general formula (2) ) Group is allowed to undergo a coupling reaction, whereby the polymerized triazol-3-one substituted resorcin derivative according to the present invention can be prepared. The coupling reaction method of the triazol-3-one substituted resorcin derivative and the -N (R ₁₅ ) CONH (R ₁₆ ) group is not particularly limited, and the triazol-3-one substituted resorcin derivative is coupled first. After that, the —N (R ₁₅ ) CONH (R ₁₆ ) group may be subjected to a binding reaction, may be the reverse process thereof, or may be subjected to a binding reaction simultaneously.

Preferably, a method in which the triazol-3-one-substituted resorcin derivative is subjected to a condensation reaction in the presence of a carbodiimide condensing agent is added to the block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked. This is an advantageous reaction because the triazol-3-one substituted resorcin derivative and the —N (R ₁₅ ) CONH (R ₁₆ ) group can be bound simultaneously. Examples of the carbodiimide condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCI), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC). In the condensation reaction, a reaction aid such as N, N-dimethylaminopyridine (DMAP) may be used. In addition, when dicyclohexyl carbodiimide (DCC) is used as a carbodiimide condensing agent, R ₁₅ and R ₁₆ of —N (R ₁₅ ) CONH (R ₁₆ ) are cyclohexyl groups. When a condensation reaction is carried out using diisopropylcarbodiimide (DIPCI), R ₁₅ and R ₁₆ are isopropyl groups. When 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) is used, R ₁₅ and R ₁₆ of —N (R ₁₅ ) CONH (R ₁₆ ) are an ethyl group and 3-dimethylaminopropyl. It becomes a mixed substitution product.

With respect to the glutamic acid side chain of the block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked by the above reaction, a triazole-3-one-substituted resorcin derivative, and —N (R ₁₅ ) CONH as R _{13 in the} general formula (2) After bonding the (R ₁₆ ) group, the polymerized triazol-3-one substituted resorcin derivative of the present invention can be synthesized optionally through a purification step.

  The polymerized triazol-3-one substituted resorcin derivative has the ability to gradually dissociate and continue to release the triazol-3-one substituted resorcin derivative, which is a medicinal component, in a phosphate buffered saline (PBS) solution. Have. That is, in biological administration, the polymerized triazol-3-one substituted resorcin derivative has physical properties that release the triazol-3-one substituted resorcin derivative gradually. A low molecular drug generally used in clinical practice shows the maximum blood concentration of a drug immediately after administration, and is then discharged from the body relatively quickly. In contrast, the polymerized triazol-3-one substituted resorcin derivative has a continuous blood concentration transition of the triazol-3-one substituted resorcin derivative released from the block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked. It is a preparation characterized by taking various pharmacokinetic changes. In addition, the polymer carrier conjugate is said to have a significantly different distribution in the body after administration than a low-molecular-weight drug, and exhibits a completely different pharmacokinetic behavior in the body from conventional drugs. From this, it is considered that this polymerized triazol-3-one substituted resorcin derivative has pharmacological effects and side effect expression characteristics completely different from those of low molecular weight triazol-3-one substituted resorcin preparations. This is an antitumor preparation that can provide a new clinical method for treating a 3-one-substituted resorcin derivative.

  The polymerized triazol-3-one substituted resorcin derivative of the present invention is used as an antitumor agent. The polymer conjugate is used in commonly used dosage forms such as injections, drops, tablets, capsules, powders and the like. In formulating, pharmaceutically acceptable carriers that are commonly used, such as binders, lubricants, disintegrants, solvents, excipients, solubilizers, dispersants, stabilizers, suspending agents, Preservatives, soothing agents, pigments and fragrances can be used. Preferably, it is desired to be used as an injection or drip, and usually water, physiological saline, 5% glucose or mannitol solution, water-soluble organic solvent (eg glycerol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, polyethylene glycol) , Cremophor and the like, and a mixture thereof) and a mixture of water and the water-soluble organic solvent.

The polymer camptothecin derivative represented by the general formula (1) and the polymerized triazol-3-one-substituted resorcin derivative represented by the general formula (2) of the present invention have a polyethylene glycol segment as an outer shell in water to bind a drug or the like. A micelle having an inner polyglutamic acid segment as an inner shell may be formed. That is, the two polymerized antitumor agents of the present invention are antitumor agents using a block copolymer in which polyethylene glycol and polyglutamic acid are linked as a carrier, but a polymer having a higher molecular weight due to self-association formation. It becomes. The self-aggregate is preferably a high molecular weight body having a molecular weight of about 10 ^{6, and} has a pharmacokinetics depending on the molecular weight. That is, the drug is expected to have desirable pharmacokinetic properties for improving the efficacy of antitumor agents such as an increase in half-life, improved permeability to tumor tissues, and accumulation in tumor tissues.

The present invention relates to an antitumor pharmaceutical composition comprising a combination of a polymerized camptothecin derivative represented by the general formula (1) and a polymerized triazol-3-one substituted resorcin derivative represented by the general formula (2). And relates to an antitumor pharmaceutical composition in which these are administered simultaneously, sequentially or at intervals. That is, the antitumor pharmaceutical composition of the present invention can be used as a combination therapy of the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative. In the present invention, the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative are prepared as separate preparations, which are administered simultaneously, sequentially or at intervals. Good. Moreover, the aspect of the kit which uses these two high molecular weight pharmaceutical preparations in the same package and combines these may be sufficient. Moreover, the aspect of the mixture which contains this polymeric camptothecin derivative and this polymeric triazole-3-one substituted resorcin derivative in the same formulation may be sufficient.
The simultaneous administration of the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative is a mode in which the administration of the two polymerized drugs is performed in duplicate. It means that the other polymerizing agent is administered during the administration of the polymerizing agent. In addition, the mode in which the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative are sequentially administered is different from that in which the other polymerized camptothecin derivative and the other polymerized camptothecin derivative are administered at intervals after the administration of one polymerized drug. Represents administration of a molecular drug. In another embodiment, the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative are administered at intervals after administration of one polymerizing agent. It represents administration of the other polymerizing drug. Here, the interval may be arbitrarily set, but may be an interval of several hours to several days after administration of one polymerizing drug. In addition, when administered sequentially or at intervals, either the polymerized camptothecin derivative or the polymerized triazol-3-one-substituted resorcin derivative may be administered first, and the administration order is arbitrary. It may be set.
That is, the present invention relates to a combination therapy of the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative, and has an enhanced antimicrobial activity based on the interaction of these two types of polymerized drugs. As long as it is a combined administration regimen that exerts a tumor effect, the administration timing and the administration order are not particularly limited and are included in the present invention.

In the present invention, the dose of the polymerized camptothecin derivative represented by the general formula (1) and the polymerized triazol-3-one-substituted resorcin derivative represented by the general formula (2) is arbitrary so that sufficient antitumor effects can be exerted. Can be set at a dose of The dose of the polymerized camptothecin derivative is appropriately determined in consideration of the patient's sex, age, physique, physiological condition, disease state, therapeutic effect, and the like. For example, per day per adult, parenterally, 0.01 to 500 / ^{m 2} as the dose per body surface area of a patient in EHC terms which is the active ingredient, preferably from 1 to 100 mg / ^{m 2.} On the other hand, the dose of the polymerized triazol-3-one-substituted resorcin derivative is appropriately set in consideration of the patient's sex, age, physique, physiological condition, disease state, therapeutic effect, and the like. For example, the dose per patient body surface area in terms of triazol-3-one-substituted resorcin derivative, which is an active ingredient, parenterally per day for an adult is 0.01 to 500 mg / m ² , preferably 1 to 200 mg / m ² . a m ^2.
The dose ratio or mixing ratio in the combined use of the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative is the molar equivalent of the camptothecin derivative-binding residue of the polymerized camptothecin derivative. According to the content molar equivalent of the triazole-3-one substituted resorcin derivative binding residue of the polymerized triazol-3-one substituted resorcin derivative, camptothecin derivative binding residue: triazol-3-one substituted resorcin derivative binding residue , Preferably in the range of 1: 1-20. More preferably, it is desired to use at a dose ratio of 1: 1 to 10 or a mixing ratio.

  The antitumor pharmaceutical composition of the present invention is used for the treatment of malignant tumor diseases. The malignant tumor applied to the treatment according to the present invention is not particularly limited, and breast cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, non-Hodgkin lymphoma (NHL), renal cell cancer, prostate cancer, liver Cellular cancer, gastric cancer, pancreatic cancer, soft tissue sarcoma, Kaposi sarcoma, carcinoid carcinoma, head and neck cancer, melanoma, ovarian cancer, cholangiocarcinoma, mesothelioma, and multiple myeloma Can be applied to. In particular, non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer (inoperable or recurrent), colorectal cancer (inoperable or recurrent), breast cancer (inoperable or recurrent) for which camptothecin derivatives are being treated Suitable for the treatment of squamous cell carcinoma, malignant lymphoma (non-Hodgkin lymphoma). In particular, high therapeutic effects can be expected in chemotherapy for various cancers that have undergone pretreatment with a camptothecin derivative and have decreased sensitivity to the camptothecin derivative in the pretreatment.

  The antitumor pharmaceutical composition of the present invention can be used in combination with other antitumor agents. Other antitumor agents are not particularly limited, and pharmaceuticals approved as antitumor agents and malignant tumor therapeutic agents can be used. That is, alkylating agents such as cyclophosphamide, ifosfamide and mitomycin C, platinum complexes such as cisplatin, carboplatin and oxaliplatin, anthracycline antitumor agents such as doxorubicin, epirubicin, pirarubicin and amrubicin, etoposide, etoposide phosphate, teniposide Etoposides, paclitaxel, docetaxel and other taxanes, vincristine, vinblastine, vindesine, vinca albinoids such as vinorelbine, 5-fluorouracil, tegafur, tegafur / uracil combination (UFT), tegafur / gimeracil / oteracil calcium (TS-1), nucleic acid antimetabolites such as flutulon, capecitabine, gemcitabine, cytosine arabinoside, methotrexate, pemetrexed Antifolate antifolates, steroids such as prednisolone and dexamethasone, anti-EGFR antibodies such as trastuzumab and cetuximab, EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib and lapatinib, VEGFR tyrosine kinases such as sorafenib and sunitinib, everolimus and temsirolimus An anti-VEGF antibody such as an mTOR inhibitor or bevacizumab can be used.

The present invention also provides a new use of the polymerized triazol-3-one substituted resorcin derivative as an antitumor enhancer of a camptothecin derivative. Camptothecin derivatives such as irinotecan and topotecan are compounds that exhibit a strong antitumor effect and are used clinically as therapeutic agents for a wide range of malignant tumors. However, there are various tumors in the clinic, and there are tumors with low responsiveness to camptothecin derivatives and tumors with reduced sensitivity to chemotherapy. For this reason, the effect enhancer for improving the therapeutic effect by a camptothecin derivative is calculated | required.
The polymerized triazol-3-one-substituted resorcin derivative represented by the general formula (2) of the present invention can be used in combination with a camptothecin derivative even for a tumor that does not exhibit a tumor growth inhibitory effect when used alone. As compared with monotherapy of a camptothecin derivative, a remarkable antitumor effect can be exerted.
As the camptothecin derivative whose effect is enhanced by the polymerized triazol-3-one substituted resorcin derivative of the present invention, a polymerized camptothecin derivative represented by the general formula (1) is preferable. When administered to a living body, the polymerized camptothecin derivative represented by the general formula (1) is distributed at a high concentration in a tumor tissue in accordance with the pharmacokinetic properties associated with the polymerization, and has an antitumor effect at the tumor tissue site. -A new antitumor preparation that exhibits sustained tumor growth inhibitory effect by releasing ethyl-10-hydroxycamptothecin (EHC). By using the polymerized triazol-3-one-substituted resorcin derivative represented by the general formula (2) of the present invention in combination with the polymerized camptothecin derivative represented by the general formula (1), Compared with camptothecin derivative monotherapy, a remarkable antitumor effect can be exerted.

［式中、Ｒ_１１は水素原子又は置換基を有していてもよい（Ｃ１〜Ｃ４）アルキル基を示し、ｕは４５〜４５０の整数を示し、Ａａは（Ｃ１〜Ｃ６）アルキレン基であり、ｇ、ｈ及びｉはそれぞれ整数であり、ｇ＋ｈ＋ｉは６〜６０の整数を示し、ｇ＋ｈ＋ｉに対するｇの割合が１〜１００％、ｈの割合が０〜６０％、ｉの割合が０〜６０％であり、Ｒ_１２は水素原子または（Ｃ１〜Ｃ４）アシル基を示し、Ｒ_１３は−Ｎ（Ｒ_１５）ＣＯＮＨ（Ｒ_１６）を示し、Ｒ_１５及びＲ_１６は同一でも異なっていてもよい（Ｃ３〜Ｃ６）の分岐または環状アルキル基もしくは三級アミノ基で置換されていてもよい分岐又は直鎖の（Ｃ１〜Ｃ５）アルキル基を示し、Ｒ_１４が１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基であり、前記ポリグルタミン酸セグメントは、側鎖カルボキシ基にＲ_１４が結合したグルタミン酸単位と、側鎖カルボキシ基にＲ_１３基が結合したグルタミン酸単位及び側鎖カルボキシ基が遊離カルボキシ基であるグルタミン酸単位が、それぞれ独立して、ランダムに配列したポリグルタミン酸構造である。］で表される高分子化トリアゾール−３−オン置換レゾルシン誘導体であり、
前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基における１，２，４−トリアゾール−３−オン置換レゾルシン誘導体が下記一般式（３）

［式中、Ｘ_１は（Ｃ１〜Ｃ６）の直鎖若しくは分岐のアルキル基または−ＣＯＮＲ_１７Ｒ_１８を示し、前記Ｒ_１７及びＲ_１８は同一でも異なっていてもよい（Ｃ１〜Ｃ６）の直鎖状、分岐状または環状アルキル基であり、Ｘ_２は置換基を有していてもよいアリール基を示す。］であり、前記１，２，４−トリアゾール−３−オン置換レゾルシン誘導体結合残基が、該レゾルシン誘導体の水酸基がエステル結合した該残基である高分子化トリアゾール−３−オン置換レゾルシン誘導体である。ここで一般式（２）において、Ｒ_１１〜Ｒ_１８、Ａａ、Ｘ_１及びＸ_２、ｕ、ｇ、ｈ、ｉは前述と同義である。As the polymerized triazol-3-one-substituted resorcin derivative as an antitumor effect enhancer of the polymerized camptothecin derivative, the general formula (2):

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- Is an on-substituted resorcin derivative-binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to a side chain carboxy group, a glutamic acid unit in which an R ₁₃ group is bonded to a side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group. Each is independently a polyglutamic acid structure arranged at random. A polymerized triazol-3-one-substituted resorcin derivative represented by
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue is a polymerized triazol-3-one-substituted resorcin derivative in which the hydroxyl group of the resorcin derivative is ester-bonded is there. Here, in the general formula (2), R _{11 to} R ₁₈ , Aa, X ₁ and X ₂ , u, g, h, i are as defined above.

The polymerized camptothecin derivative represented by the general formula (1) has a remarkable antitumor effect when used in combination with the polymerized triazol-3-one substituted resorcin derivative represented by the general formula (2). To be enhanced. Accordingly, the present invention also provides a new use of the polymer camptothecin in combination therapy with the polymerized triazol-3-one substituted resorcin derivative.
The combination of the polymerized camptothecin derivative represented by the general formula (1) and the polymerized triazol-3-one substituted resorcin derivative represented by the general formula (2) of the present invention enhances the therapeutic effect of the camptothecin derivative. It can be applied to breast cancer, ovarian cancer, lung cancer, thyroid cancer, myeloid leukemia, hepatoblastoma, colon cancer, gallbladder cancer and the like. In particular, a high therapeutic effect can be expected in chemotherapy of various cancers pretreated with a camptothecin derivative.

The present invention will be further described below with reference to examples. However, the present invention is not limited to these examples. Note that Gaussian distribution analysis showing the size (particle diameter) of the particles present invention article is composed of an aqueous solution was measured by ^{Zeta Potential / Particlesizer NICOMP TM 380ZLS (} Particle Sizing Systems , Inc.).

[Synthesis Example 1]
5- (2,4-dihydroxy-5-isopropylphenyl) -4- (1-methyl-1H-indol-5-yl) -2,4-dihydro- [1,2,4] triazol-3-one ( Synthesis Example of Compound 4 (General Formula (4))) Synthesis was performed based on the description of International Publication WO2007 / 13952. ¹ H-NMR data of the obtained compound 4 are shown.
¹ H-NMR (400 MHz, DMSO-d ₆ , ppm): 11.841 (s, 1H), 9.507 (s, 1H), 9.407 (s, 1H), 7.417-7.366 ( m, 3H), 6.921 (dd, 1H), 6.761 (s, 1H), 6.406 (dd, 1H), 6.205 (s, 1H), 3.777 (s, 3H), 2.911 (hept, 1H), 0.866 (d, 6H)

[Synthesis Example 2]
Polymerized triazol-3-one substituted resorcin derivative represented by general formula (2) (polymer compound to which compound 4 is bonded; compound 1: R ₁₁ = methyl group, R ₁₂ = acetyl group in general formula (2) Aa = trimethylene group, R ₁₅ = R ₁₆ = isopropyl group, g + h + i = 23, u = 273, the ratio of g to 40%, the ratio of h to 20%, and the ratio of i to 40%)
A methoxypolyethylene glycol-polyglutamic acid block copolymer prepared in accordance with the method described in the pamphlet of International Publication WO2006 / 120914 (methoxypolyethylene having a molecular weight of 12,000 on one end with a methyl group and the other end with an aminopropyl group) 519 mg of a glycol segment and a polyglutamic acid segment (terminal N acetyl group) having a polymerization number of 23 and a linking group being a trimethylene group) 519 mg, compound 4 obtained by Synthesis Example 1 (represented by the formula (4)) 150 mg) was dissolved in 10 mL of DMF, stirred at 35 ° C. for 15 minutes, and then stirred at 25 ° C. for 1 hour. Thereafter, 234 μL of diisopropylcarbodiimide (DIPCI) and 13.7 mg of N, N-dimethylaminopyridine (DMAP) were added and stirred at 25 ° C. for 16 hours. To this, 117 μL of DIPCI was added, and the mixture was further stirred for 4 hours. The reaction solution was slowly added dropwise to a mixed solution of 20 mL of ethanol and 80 mL of diisopropyl ether, stirred at room temperature for 1 hour, and the precipitate was collected by filtration and washed with diisopropyl ether. The resulting precipitate was dissolved in 5.0 mL of acetonitrile and 5.0 mL of water, and then an ion exchange resin (Dow Chemical Dowex 50 (H ⁺ ), 2.0 mL) was added and stirred and filtered. Acetonitrile in the obtained filtrate was distilled off under reduced pressure, and then lyophilized to obtain Compound 1 (525 mg).

The content of Compound 4 bound to Compound 1 was determined by adding 1N-aqueous sodium hydroxide solution to Compound 1 and stirring at 37 ° C. for 1 hour, and then analyzing the content of released Compound 4 by HPLC (High Performance Liquid Chromatography) The amount calculated from the calibration curve obtained with Compound 4 was used. As a result, the content of bound compound 4 was 17.2% (w / w). Moreover, the bond content of the group which is —N (R ₁₅ ) CONH (R ₁₆ ) (R ₁₅ and R ₁₆ are isopropyl groups) corresponding to R ₁₃ according to the general formula (2) by ¹ H-NMR method is 3 0.0% (w / w).

  When Gaussian distribution analysis was performed using an aqueous solution of Compound 1 (1 mg / mL), the obtained value was 33 nm (volume weighting). Therefore, it was considered that Compound 1 self-associates in water to form a micelle-like aggregate.

[Synthesis Example 3]
Polymerized triazol-3-one-substituted resorcin derivative represented by general formula (2) (polymer compound to which compound 4 is bonded; compound 2: R ₁₁ = methyl group, R ₁₂ = acetyl group in general formula (2) Aa = trimethylene group, R ₁₅ = R ₁₆ = isopropyl group, g + h + i = 10, u = 114, the ratio of g to g + h + i is 40%, the ratio of h is 20%, and the ratio of i is 40%)
A methoxypolyethylene glycol-polyglutamic acid block copolymer prepared in accordance with the method described in the pamphlet of International Publication No. 2006/120914 (polyethylene glycol having a molecular weight of 5,000, one end having a methyl group and the other end having an aminopropyl group) 473 mg of a block copolymer consisting of a segment and a polyglutamic acid segment (terminal acetyl group) having a polymerization number of 10 (473 mg) and 150 mg of compound 4 (compound represented by formula (4)) obtained in Synthesis Example 1 were dissolved in 10 mL of DMF. The mixture was stirred at 35 ° C. for 15 minutes and then stirred at 25 ° C. for 1 hour. Thereafter, 234 μL of DIPCI and 13.7 mg of DMAP were added, and the mixture was stirred at 25 ° C. for 22 hours. 117 μL of DIPCI was added, and the mixture was further stirred for 2 hours. The reaction solution was slowly added dropwise to a mixed solution of 30 mL of ethyl acetate and 120 mL of diisopropyl ether and stirred at room temperature for 21 hours, and then the precipitate was collected by filtration and washed with diisopropyl ether. The resulting precipitate was dissolved in 8.0 mL of acetonitrile and 2.0 mL of water, added with an ion exchange resin (Dow Chemical Dowex 50 (H ⁺ ), 2.0 mL), stirred and filtered. Acetonitrile in the obtained filtrate was distilled off under reduced pressure, and then freeze-dried. The obtained lyophilized product was dissolved in 20 mL of acetonitrile and 20 mL of water, and then the solution was transferred to a dialysis membrane and dialyzed overnight at 5 ° C., and then the solution in the dialysis membrane was recovered. Acetonitrile in the obtained solution was distilled off under reduced pressure, and then lyophilized to obtain Compound 2 (460 mg).

The content of compound 4 bound to compound 2 was analyzed by HPLC (high performance liquid chromatography) after adding 1N sodium hydroxide aqueous solution to compound 1 and stirring for 1 hour at 37 ° C. The amount calculated from the calibration curve obtained with Compound 4 was used. As a result, the content of bound compound 4 was 18.9% (w / w). Moreover, the bond content of the group which is —N (R ₁₅ ) CONH (R ₁₆ ) (R ₁₅ and R ₁₆ are isopropyl groups) corresponding to R ₁₃ according to the general formula (2) by ¹ H-NMR method is 3 0.0% (w / w).

  When Gaussian distribution analysis was performed using an aqueous solution of Compound 2 (1 mg / mL), the obtained numerical value was 22 nm (volume weighting). Therefore, it was considered that Compound 2 self-associates in water to form a micelle-like aggregate.

[Synthesis Example 4]
Polymerized camptothecin derivative represented by general formula (1) (compound 3: in general formula (1) R ₁ = methyl group, R ₂ = acetyl group, A = trimethylene group, R ₄ = R ₅ = isopropyl group, d + e + f = 23, u = 273, the ratio of d to d + e + f is 50%, the ratio of e is 40%, and the ratio of f is 10%)
Based on the description of International Publication WO2004 / 39869, a methoxypolyethylene glycol-polyglutamic acid block copolymer (a methoxypolyethylene glycol segment having a molecular weight of 12,000 at one end and a methyl group at the other end and an aminopropyl group at the other end and an N-terminus) 7-ethyl-10-hydroxycamptothecin (EHC) was added to diisopropylcarbodiimide (DIPCI) and N, to a block copolymer having a polyglutamic acid segment having a polymerization number of 23 modified with an acetyl group and a linking group being a trimethylene group. Compound 3 was obtained by reacting with N-dimethylaminopyridine (DMAP) and then treating with an ion exchange resin (Dow Chemical 50 manufactured by Dow Chemical (H ⁺ )).
The obtained compound 3 was hydrolyzed in a 1N-aqueous sodium hydroxide solution at room temperature for 10 minutes, and then liberated EHC was quantitatively analyzed by the HPLC method to obtain an EHC content of 21% (w / w). Met. In addition, the bond content of —N (R ₄ ) CONH (R ₅ ) (group in which R ₄ and R ₅ are isopropyl groups) corresponding to R ₃ according to the general formula (1) was measured by ¹ H-NMR method. However, the binding content was 5.6% (w / w).

[Test Example 1] Drug release test from compound 1 and compound 2 in the absence of enzyme Compound 1 and compound 2 were each dissolved in PBS (phosphate buffered saline; pH 7.1) at a concentration of 1 mg / mL, Incubated at 37 ° C. Compound 4 released from compounds 1 and 2 into the PBS solution was analyzed over time by HPLC and quantified using a standard curve. The ratio of the released compound 4 to the total drug amount determined from the drug contents of compounds 1 and 2 was measured over time, and the results are shown in FIG. 1 and FIG.

  As is apparent from FIGS. 1 and 2, Compound 1 and Compound 2 released Compound 4 even in the absence of hydrolase. It is recognized that the release rate of compound 4 varies depending on the composition of the block copolymer. When a carrier having a large molecular weight and a large number of polymerized polyethylene glycol segments and polyglutamic acid segments is used, the release rate of compound 4 is suppressed. It was a tendency to. Therefore, it was shown that the drug release rate can be controlled by the carrier molecular weight.

[Example 1] Antitumor effect test of polymerized antitumor agent Mouse colon cancer Colon 38, which has been passaged subcutaneously in mice, is made into a block of about 2 mm square, and the dorsal skin of hairy mice is subcutaneously used using a trocar. Transplanted. On the 16th day after the tumor transplantation, Compound 1 and Compound 3 were administered intravenously in a single combination administration, Compound 1 alone, and Compound 3 alone. The dose in each administration group is shown in Table 1. Each test compound was used after being dissolved in a 5% glucose solution or physiological saline.

[Table 1]

The tumor volume after the administration start date and after the administration start was measured with a caliper over time for the major axis (L (mm)) and minor axis (W (mm)) of the tumor, and (L × W ² ) / 2 The tumor volume was calculated, and the change in the relative tumor volume with respect to the tumor volume on the administration start date in each administration group is shown in FIG.

As a result of the antitumor activity test, a group in which Compound 1 which is a polymerized 1,2,4-triazol-3-one-substituted resorcin derivative according to the present invention and Compound 3 which is a polymerized camptothecin derivative were used in combination (Examples) Group) in the single administration group of compound 3 which is a polymerized camptothecin derivative and the single administration group of compound 1 which is a polymerized 1,2,4-triazol-3-one substituted resorcin derivative Showed a stronger antitumor effect. In particular, Compound 1, which is a polymerized 1,2,4-triazol-3-one substituted resorcin derivative, showed no antitumor effect when administered alone. Therefore, the combined use of Compound 1 and Compound 3 according to the present invention is not an additive effect of the therapeutic effect of each compound, but a strong tumor growth inhibitory activity in which the pharmacological actions of Compound 1 and Compound 3 are related to each other. It is thought that it exerted a synergistic effect.
In addition, Compound 1, which is a polymerized 1,2,4-triazol-3-one-substituted resorcin derivative, does not exhibit an antitumor effect by itself, but the antitumor effect of Compound 3 which is a polymerized camptothecin derivative is remarkable. From these results, it was shown that the camptothecin derivative functions as an antitumor effect enhancer.

Claims (7)

Polymerized camptothecin derivative using a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked, and a polymerized triazol-3-one substitution using a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked the resorcinol derivatives a including a pharmaceutical composition,
The polymerized camptothecin derivative has the general formula (1)

[Wherein R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60% R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment is 7- Ethyl-10-hydroxycamp And glutamic acid units Taesin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ] Is a polymerized camptothecin derivative represented by
The polymerized triazol-3-one substituted resorcin derivative has the general formula (2)

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to a side chain carboxy group, a glutamic acid unit in which an R ₁₃ group is bonded to a side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group, Each is independently a polyglutamic acid structure arranged at random. A polymerized triazol-3-one-substituted resorcin derivative represented by
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue is a polymerized triazol-3-one-substituted resorcin derivative in which the hydroxyl group of the resorcin derivative is ester-bonded Yes, the molar equivalent of the camptothecin derivative residue in the polymerized camptothecin derivative and the inclusion of the 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the polymerized triazol-3-one substituted resorcin derivative the ratio of molar equivalents, 1: 1-20, the polymer of camptothecin derivatives and the polymerization triazol-3-one substituted resorcinol derivative and at the same time, to administered at sequential or interval, a pharmaceutical composition Antitumor agents including In the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue, X ₁ is an isopropyl group, and X ₂ is a 5- (N-methylindolyl) group or 4-((4-methylpiperazine The antitumor agent according to claim 1, which is a -1-yl) methyl) phenyl group. The antitumor agent according to claim 1 or 2 , which is used for the treatment of a malignant tumor having reduced sensitivity to a camptothecin derivative. General formula (2)

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to a side chain carboxy group, a glutamic acid unit in which an R ₁₃ group is bonded to a side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group, Each is independently a polyglutamic acid structure arranged at random. An antitumor effect enhancer of a camptothecin derivative, comprising a polymerized triazol-3-one substituted resorcin derivative represented by
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. A], the 1,2,4-triazole-3-one substituted resorcinol derivative binding residue, Ri the residues der which a hydroxyl group is ester-bonded to the resorcinol derivatives,
The camptothecin derivative is a polymerized camptothecin derivative using a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked, and the polymerized camptothecin derivative is represented by the general formula (1)

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60% R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 7- Ethyl-10-hydroxycamp And glutamic acid units Taesin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . A camptothecin derivative represented by:
The molar equivalent of the camptothecin derivative residue in the polymerized camptothecin derivative and the molar equivalent of the 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the polymerized triazol-3-one substituted resorcin derivative ratio is 1: 1 to 20 der Ru, antitumor effect enhancer. In the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue, X ₁ is an isopropyl group, and X ₂ is a 5- (N-methylindolyl) group or 4-((4-methylpiperazine- The antitumor effect potentiator according to claim 4 , which is 1-yl) methyl) phenyl group. A block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are connected, which is used in combination with a polymerized triazol-3-one substituted resorcin derivative using a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are connected. An antitumor agent comprising a polymerized camptothecin derivative using a polymer, wherein the polymerized triazol-3-one-substituted resorcin derivative is represented by the general formula (2)

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1 to C4) alkyl group, u represents an integer of 45 to 450, and Aa represents a (C1 to C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue And the polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to a side chain carboxy group, a glutamic acid unit in which an R ₁₃ group is bonded to the side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group. Each independently and randomly arranged polyglutamic acid structure,
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the hydroxyl group of the resorcin derivative in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is an ester-bonded residue. A polymerized triazol-3-one substituted resorcin derivative represented by:
A polymerized camptothecin derivative using a block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked is represented by the general formula (1).

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60% R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 7- Ethyl-10-hydroxycamp And glutamic acid units Taesin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ] ,
The molar equivalent of the camptothecin derivative residue in the polymerized camptothecin derivative and the molar equivalent of the 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the polymerized triazol-3-one substituted resorcin derivative ratio is 1: 1 to 20 der Ru, said anti-tumor agent. General formula (1)

[Wherein, R ₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, t represents an integer of 45-450, and A represents a (C1-C6) alkylene group. , D, e and f are each an integer, d + e + f represents an integer of 6 to 60, the ratio of d to d + e + f is 1 to 100%, the ratio of e is 0 to 60%, and the ratio of f is 0 to 60% R ₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₃ represents —N (R ₄ ) CONH (R ₅ ), and R ₄ and R ₅ may be the same or different ( C3-C6) branched or cyclic alkyl group or a branched or straight chain (C1-C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 7- Ethyl-10-hydroxycamp And glutamic acid units Taesin bound, glutamic units glutamate units and side chain carboxy group R ₃ group is attached to a side chain carboxyl group is a free carboxy group is, independently, are polyglutamic acid structures randomly arranged . ]
A polymerized camptothecin derivative represented by the general formula (2):

[Wherein R ₁₁ represents a hydrogen atom or an optionally substituted (C1-C4) alkyl group, u represents an integer of 45-450, and Aa represents a (C1-C6) alkylene group. , G, h and i are each an integer, g + h + i represents an integer of 6 to 60, the ratio of g to g + h + i is 1 to 100%, the ratio of h is 0 to 60%, and the ratio of i is 0 to 60% R ₁₂ represents a hydrogen atom or a (C1-C4) acyl group, R ₁₃ represents —N (R ₁₅ ) CONH (R ₁₆ ), and R ₁₅ and R ₁₆ may be the same or different ( C3-C6) represents a branched or linear (C1-C5) alkyl group which may be substituted with a branched or cyclic alkyl group or a tertiary amino group, and R ₁₄ represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue The polyglutamic acid segment includes a glutamic acid unit in which R ₁₄ is bonded to the side chain carboxy group, a glutamic acid unit in which the R ₁₃ group is bonded to the side chain carboxy group, and a glutamic acid unit in which the side chain carboxy group is a free carboxy group, Each independently and randomly arranged polyglutamic acid structure,
The 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is represented by the following general formula (3):

[Wherein, X ₁ represents a linear or branched alkyl group of (C1 to C6) or —CONR ₁₇ R ₁₈ , wherein R ₁₇ and R ₁₈ may be the same or different (C1 to C6) It is a chain, branched or cyclic alkyl group, and X ₂ represents an aryl group which may have a substituent. And the hydroxyl group of the resorcin derivative in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is an ester-bonded residue. ]
A pharmaceutical kit comprising a combination of polymerized triazol-3-one substituted resorcin derivatives represented by
The molar equivalent of the camptothecin derivative residue in the polymerized camptothecin derivative and the molar equivalent of the 1,2,4-triazol-3-one substituted resorcin derivative binding residue in the polymerized triazol-3-one substituted resorcin derivative For the treatment of tumor , wherein the ratio of 1: 1 to 20 and the polymerized camptothecin derivative and the polymerized triazol-3-one substituted resorcin derivative are administered simultaneously, sequentially or at intervals Pharmaceutical kit.

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