WO2015125641A1 - Composition pharmaceutique contenant un dérivé de camptothécine polymérisé, et dérivé inhibiteur de hsp90 polymérisé - Google Patents

Composition pharmaceutique contenant un dérivé de camptothécine polymérisé, et dérivé inhibiteur de hsp90 polymérisé Download PDF

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WO2015125641A1
WO2015125641A1 PCT/JP2015/053481 JP2015053481W WO2015125641A1 WO 2015125641 A1 WO2015125641 A1 WO 2015125641A1 JP 2015053481 W JP2015053481 W JP 2015053481W WO 2015125641 A1 WO2015125641 A1 WO 2015125641A1
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group
derivative
polymerized
triazol
substituted
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麻奈美 岡▲崎▼
丸山　佐起子
亮 増田
啓一朗 山本
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日本化薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/40—Polyamides containing oxygen in the form of ether groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment

Definitions

  • 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.
  • 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.
  • 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 side effects of diarrhea are mild because 20-40% of the dose is renal excretion.
  • 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.
  • EHC 7-ethyl-10-hydroxycamptothecin
  • Exert a stronger anti-tumor effect.
  • 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.
  • 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.
  • 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).
  • 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. .
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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 tumor (GIST).
  • GIST gastrointestinal stromal tumor
  • Patent Documents 2 to 4 report 1,2,4-triazol-3-one substituted resorcin derivatives useful as HSP90 inhibitors.
  • Patent Document 5 discloses a polymerized 1,2,4-triazol-3-one substituted resorcin derivative and a polymerized 1,2 which is a polymerized HSP90 inhibitor aimed at the sustained release of the drug. 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.
  • 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.
  • a polymerized camptothecin derivative and a polymerized HSP90 inhibitor derivative that exhibit sustained release of an active ingredient.
  • An object of the present invention is to provide a cancer chemotherapeutic agent having a high antitumor effect.
  • 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.
  • an antitumor effect enhancer for further enhancing the effect of an antitumor agent using a camptothecin derivative.
  • 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, by using together a polymerized HSP90 inhibitor that gradually releases a polymerized camptothecin derivative and a 1,2,4-triazol-3-one-substituted resorcin derivative, the toxicity to normal cells is low, and the affected area is efficient. In addition, the drug efficacy can be improved by delivering and releasing the drug.
  • the gist of the present invention is the following configurations 1) to 9).
  • 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 to C4) alkyl group, t represents an integer of 45 to 450, and A represents an (C1 to 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%
  • 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 )
  • 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 to C5) alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment has a 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 polyg
  • 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 to C4) alkyl group, u represents an integer of 45 to 450, and Aa represents a (C1 to C6) alkylene group.
  • R 12 represents a hydrogen atom or a (C1-C4) acyl group
  • R 13 represents —N (R 15 ) CONH (R 16 )
  • 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
  • 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 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.
  • 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 an ester bond.
  • 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.
  • X 1 is an isopropyl group
  • 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.
  • R 11 represents a hydrogen atom or an optionally substituted (C1 to C4) alkyl group
  • u represents an integer of 45 to 450
  • 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%
  • 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 )
  • 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
  • R 14 represents 1,2,4-triazole-3- On-
  • 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.
  • 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 to C4) alkyl group, t represents an integer of 45 to 450, and A represents a (C1 to 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%
  • 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 )
  • 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
  • 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
  • the 1,2,4-triazol-3-one substituted resorcin derivative-binding residue is such that X 1 is an isopropyl group and X 2 is a 5- (N-methylindolyl) group or 4-((4-methyl The antitumor effect potentiator according to 5) or 6) above, which is piperazin-1-yl) methyl) phenyl group.
  • a block 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 containing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are connected
  • 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 to C4) alkyl group, u represents an integer of 45 to 450, and Aa represents a (C1 to C6) alkylene group.
  • R 12 represents a hydrogen atom or a (C1-C4) acyl group
  • R 13 represents —N (R 15 ) CONH (R 16 )
  • 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
  • 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
  • hydroxyl group of the resorcin derivative in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is an ester bond.
  • 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).
  • R 1 represents a hydrogen atom or an optionally substituted (C1 to C4) alkyl group
  • t represents an integer of 45 to 450
  • A represents an (C1 to 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 )
  • 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
  • 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 )
  • 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
  • R 12 represents a hydrogen atom or a (C1-C4) acyl group
  • R 13 represents —N (R 15 ) CONH (R 16 )
  • 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
  • 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
  • the hydroxyl group of the resorcin derivative in the 1,2,4-triazol-3-one substituted resorcin derivative binding residue is an ester bond.
  • the polymerized camptothecin derivative and the polymerized triazol-3-one substituted resorcin derivative are simultaneously and sequentially prepared.
  • 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 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.
  • 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.
  • the present invention relates to a polymerized camptothecin derivative linked to 7-ethyl-10-hydroxycamptothecin (EHC) and a polymerized conjugated to 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.
  • 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.
  • the polyglutamic acid segment is a segment in which glutamic acid is polymerized to have a plurality of ⁇ -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.
  • 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 to C4) alkyl group, t represents an integer of 45 to 450, and A represents an (C1 to 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 )
  • 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
  • R 1 is a terminal modifying group of the polyethylene glycol segment, and is a hydrogen atom or an optionally substituted (C1-C4) alkyl group.
  • R 1 is preferably a (C1-C4) alkyl group which may have a substituent. Specific examples are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • substituent of the (C1-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 1 a methyl group or an ethyl group is preferable, and a methyl group is particularly preferable.
  • 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).
  • a methylene group, ethylene group, trimethylene group, tetramethylene group, hexamethylene group, and the like can be given.
  • 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 ⁇ -amide bond type, but may include a structure bonded with a ⁇ -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 (the number of polyglutamic acid polymerizations) in the general formula (1) is represented by d + e + f and is 6 to 60.
  • d + e + f is 8 to 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, for example, a formyl group, an acetyl group, a propionyl group, etc. 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 ), and R 4 and R 5 may be the same or different, a branched or cyclic alkyl group of (C3 to C6), or A branched or straight chain alkyl group of (C1 to C5) 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.
  • an isopropyl group and a cyclohexyl group are mentioned.
  • Examples of the (C1 to C5) branched or straight chain alkyl group optionally substituted with the tertiary amino group include an ethyl group and a dimethylaminopropyl group.
  • 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.
  • 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.
  • 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.
  • 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.
  • the alkali metal salt or alkaline earth metal salt include lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt.
  • 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.
  • 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.
  • 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.
  • the amount of the free glutamic acid unit represented by f in the general formula (1) is 0 to 60% in the glutamic acid segment.
  • Preferred ranges of d, e, and f for each glutamic acid unit with respect to the entire glutamic acid segment are 20 to 70% for d, 1 to 40% for e, and 1 to 40% for f.
  • 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 preferred method for synthesizing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked is the following: N- A method of sequentially reacting carbonylglutamic acid anhydride to construct a polyglutamic acid segment can be mentioned.
  • 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 or a carboxylic acid protecting group conjugate is used. be able to.
  • N-carbonylglutamic acid anhydride it is preferable to use N-carbonylglutamic acid anhydride in which the side chain carboxy group is modified with a suitable 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 in which the 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.
  • a polyethylene glycol compound modified with a methoxy group at one end and an amino group at the other end and a ⁇ -benzyl-N-carbonylglutamic anhydride are reacted sequentially, 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.
  • 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.
  • 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.
  • carbodiimide condensing agent examples include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCI), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC).
  • a reaction aid such as N, N-dimethylaminopyridine (DMAP) may be used.
  • DCC dicyclohexylcarbodiimide
  • DMAP N-dimethylaminopyridine
  • R 4 and R 5 of —N (R 4 ) CONH (R 5 ) are cyclohexyl groups.
  • R 4 and R 5 are isopropyl groups.
  • DIPCI diisopropylcarbodiimide
  • R 4 and R 5 are isopropyl groups.
  • 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 bound 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.
  • 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.
  • 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 effect and side effect, 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.
  • pharmaceutically acceptable carriers such as binders, lubricants, disintegrants, solvents, excipients, solubilizers, dispersants, stabilizers, suspending agents, Preservatives, soothing agents, pigments and fragrances can be used.
  • water 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.
  • water-soluble organic solvent eg glycerol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, polyethylene glycol
  • polymerized triazol-3-one substituted resorcin derivative of the present invention is a polymer-bonded drug in which a carboxy group in the side chain 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.
  • the polymerized triazol-3-one substituted resorcin derivative will be described in detail below.
  • the polymerized triazol-3-one-substituted resorcin derivative of the present invention has 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 It has a structure in which a hydroxyl group of a triazol-3-one substituted resorcin derivative is ester-bonded.
  • 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 )
  • 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
  • R 14 represents 1,2,4-triazole-3- On-substituted resorcin derivative binding residue
  • 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
  • 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.
  • 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 an ester bond. 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 an optionally substituted (C1-C4) alkyl group.
  • R 11 is preferably a (C1 to 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-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.
  • Examples of Aa in the general formula (2) which 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 ⁇ -amide bond type, but may include a structure bonded with a ⁇ -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.
  • 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 a (C1 to C4) acyl group.
  • R 12 is preferably a (C1 to C4) acyl group, for example, a formyl group, an acetyl group, a propionyl group, etc. 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 ), and R 15 and R 16 may be the same or different, a branched or cyclic alkyl group of (C3 to C6), or A branched or straight chain alkyl group of (C1 to C5) 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.
  • an isopropyl group and a cyclohexyl group are mentioned.
  • Examples of the (C1 to C5) branched or straight chain alkyl group optionally substituted with the tertiary amino group include an ethyl group and a dimethylaminopropyl group.
  • 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.
  • 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 derivatives include those represented by 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 1,2,4-triazol-3-one substituted resorcin derivatives.
  • X 1 in the general formula (3) represents a linear or branched alkyl group of (C1 to C6) or —CONR 17 R 18 , and R 17 and R 18 may be the same or different (C1 to C6).
  • the (C1 to C6) linear or branched alkyl group in X 1 includes 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.
  • R 17 and R 18 examples 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 an isopropyl group, sec-butyl group, isobutyl group, tert-butyl group or —CONR 17 R 18 , wherein R 17 is a methyl group and R 18 is preferably an n-butyl group.
  • the X 2 group in the general formula (2) is an aryl group which may have a substituent.
  • 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.
  • 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.
  • 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.
  • Preferred is a phenyl group substituted by a linear or branched alkyl group of (C1 to C8).
  • 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 to C10) primary, secondary or tertiary alkoxy group.
  • Examples thereof include a 4-methoxyphenyl group, a 3-methoxyphenyl group, a 3,4-dimethoxyphenyl group, and a 3,4-methylenedioxyphenyl group. 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.
  • examples of the non-cyclic primary amino group include (C1-C10) linear, branched or cyclic alkyl groups, or amino groups substituted with aryl groups.
  • 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 include dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group, N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group and the like.
  • 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, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, and an 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.
  • 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 any substitution product at the 2-6 position may be used. A substituted amino group at the 3-position or 4-position is preferred.
  • 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.
  • 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 to C8) alkyl group having as a substituent.
  • Examples of the acyclic primary amino group include (C1 to C10) linear, branched or cyclic alkyl groups, or amino groups substituted with aryl groups.
  • 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 include dimethylamino group, diisopropylamino group, N-methyl-N-cyclohexylamino group, N-methyl-N-phenylamino group, N-methyl-N-pyridylamino group, diphenylamino group and the like.
  • 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, an isopropylamino group, a neopentylamino group, an n-hexylamino group, a cyclohexylamino group, and an 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.
  • Examples of the (C1 to C8) alkyl group having an 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 any substitution product at the 2-6 position may be used.
  • a substituted amino group at the 3-position or 4-position is preferred.
  • a preferred embodiment is that a cyclic aliphatic secondary amino group is substituted at the terminal position of the (C1 to C5) alkyl group, and the other terminal group is a phenyl group. In which the 4-position is substituted.
  • 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 ,
  • 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.
  • 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 a 2-methylpyrimidin-4-yl group and a 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, 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.
  • 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.
  • 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-butylamido))-4- (2-methylphenyl) -2,4-dihydro- [1,2,4] triazol-3-one (general formula (5) below; compound 5); or X 1 There is an isopropyl group, X 1
  • 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.
  • 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.
  • 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.
  • alkali metal salt or alkaline earth metal salt examples include lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt.
  • 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 defined as that of the solution.
  • 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.
  • the amount of 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.
  • the abundance of the R 13 -bonded glutamic acid unit is represented by h in the general formula (2), and occupies 0 to 60% of the glutamic acid segment.
  • the free glutamic acid unit is represented by i in the general formula (2), and occupies 0 to 60% of the glutamic acid segment.
  • the preferred ranges of g, h, and i for each glutamic acid unit for the entire glutamic acid segment are 20 to 70% for g, 1 to 40% for h, and 1 to 40% for i.
  • a method for producing a polymerized triazol-3-one substituted resorcin derivative in the present invention will be described.
  • a method for constructing a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked is a method of bonding a polyethylene glycol segment and a polyglutamic acid segment, 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.
  • the carboxy group of the glutamic acid side chain is a conjugate of R 14 according to general formula (2), a conjugate of R 13 according to general formula (2), a free carboxylic acid or A carboxylic acid protecting group conjugate or the like can be used.
  • 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 is preferably an ester bond protecting group. That is, for the side chain carboxy group, an N-carbonylglutamic acid anhydride modified with an appropriate carboxylic acid protecting group is used, 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 this 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).
  • a polyethylene glycol compound modified with a methoxy group at one end and an amino group at the other end is sequentially reacted with ⁇ -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.
  • 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.
  • a triazol-3-one-substituted resorcin derivative and -N (R 15 ) CONH (R 16 as R 13 in the general formula (2) ) Group can be coupled to each other to prepare a polymerized triazol-3-one-substituted resorcin derivative according to the present invention.
  • 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.
  • the —N (R 15 ) CONH (R 16 ) group may be subjected to a binding reaction, the reverse process thereof, or a bonding reaction at the same time.
  • 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 to the block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked is the block copolymer.
  • carbodiimide condensing agent examples include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCI), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC).
  • a reaction aid such as N, N-dimethylaminopyridine (DMAP) may be used.
  • DCC dicyclohexylcarbodiimide
  • DMAP N-dimethylaminopyridine
  • R 15 and R 16 of —N (R 15 ) CONH (R 16 ) become a cyclohexyl group.
  • R 15 and R 16 are isopropyl groups.
  • DIPCI diisopropylcarbodiimide
  • R 15 and R 16 are isopropyl groups.
  • 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.
  • a triazol-3-one substituted resorcin derivative 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 triazol-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.
  • PBS phosphate buffered saline
  • the polymerized triazol-3-one-substituted resorcin derivative has physical properties that release the triazol-3-one-substituted resorcin derivative gradually upon biological administration.
  • 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.
  • 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.
  • 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.
  • this polymerized triazol-3-one substituted resorcin derivative is pharmacologically different from the low molecular weight triazol-3-one substituted resorcin preparation in terms of pharmacological effects and side effect expression characteristics.
  • This is an antitumor preparation that can provide a new clinical treatment method for 3-one-substituted resorcin derivatives.
  • 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.
  • pharmaceutically acceptable carriers such as binders, lubricants, disintegrants, solvents, excipients, solubilizers, dispersants, stabilizers, suspending agents, Preservatives, soothing agents, pigments and fragrances can be used.
  • water 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.
  • water-soluble organic solvent eg glycerol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, polyethylene glycol
  • 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
  • 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.
  • the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative are prepared as separate formulations, 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. Alternatively, the polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative may be in the form of a mixture containing the same preparation.
  • 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. Further, 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 polymerized camptothecin derivative and the polymerized triazol-3-one-substituted resorcin derivative are administered at intervals after the administration of one polymerizing drug. Represents administration of a molecular drug.
  • 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.
  • the interval may be arbitrarily set, but may be an interval of several hours to several days after administration of one polymerizing drug.
  • 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.
  • 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 kinds of polymerized drugs.
  • the administration timing and the administration order are not particularly limited and are included 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 as long as it has a sufficient antitumor effect.
  • 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.
  • the dosage per body surface area of a patient in terms of EHC, which is an active ingredient is 0.01 to 500 mg / m 2 , preferably 1 to 100 mg / m 2 parenterally per day for an adult.
  • the dose of the polymerized triazol-3-one-substituted resorcin derivative is appropriately determined in consideration of the patient's sex, age, physique, physiological condition, disease state, therapeutic effect, and the like.
  • the dosage per body surface area of a patient in terms of a 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.
  • camptothecin derivative-binding residue triazol-3-one-substituted resorcin derivative-binding residue It is preferably used in the range of 1: 1 to 20. More preferably, it is desired to use a dose ratio or a mixture ratio of 1: 1 to 10.
  • 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.
  • 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, mel
  • 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).
  • 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
  • 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.
  • the effect enhancer for improving the therapeutic effect by a camptothecin derivative is calculated
  • 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.
  • a polymerized camptothecin derivative represented by the general formula (1) is preferable.
  • the polymerized camptothecin derivative represented by the general formula (1) 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 sustained release of ethyl-10-hydroxycamptothecin (EHC).
  • EHC ethyl-10-hydroxycamptothecin
  • 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.
  • R 12 represents a hydrogen atom or a (C1-C4) acyl group
  • R 13 represents —N (R 15 ) CONH (R 16 )
  • R 15 and R 16 may be the same or different ( A branched or linear (C1 to C5) alkyl group optionally substituted with a branched or cyclic alkyl group or a tertiary amino group of C3 to C6), wherein R 14 is 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
  • 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.
  • 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 an ester bond.
  • R 11 to R 18 , Aa, X 1 and X 2 , u, g, h, i are as defined above.
  • the present invention also provides a new use of the polymeric camptothecin in combination therapy with the polymeric 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.
  • 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.).
  • WO2006 / 120914 (methoxypolyethylene having a molecular weight of 12,000 at 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.
  • DIPCI diisopropylcarbodiimide
  • DMAP N, N-dimethylaminopyridine
  • the content of compound 4 bound to compound 1 was determined by adding 1N-aqueous sodium hydroxide 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).
  • the bond content of a group represented by —N (R 15 ) CONH (R 16 ) (where 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).
  • 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 determined by adding 1N aqueous sodium hydroxide to Compound 1 and stirring at 37 ° C. for 1 hour, and then analyzing the content of Compound 4 released 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 18.9% (w / w).
  • the bond content of a group represented by —N (R 15 ) CONH (R 16 ) (where 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).
  • 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 Co., Ltd. (H + )). The obtained compound 3 was hydrolyzed in a 1N-sodium hydroxide aqueous 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. Further, 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).
  • 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. Table 1 shows the dose in each administration group. Each test compound was used after being dissolved in a 5% glucose solution or physiological saline.
  • 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.
  • 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.

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Abstract

[Problème] Fournir un médicament pour chimiothérapie du cancer, présentant un fort effet antitumoral. Plus précisément, fournir un médicament pour chimiothérapie du cancer présentant un effet antitumoral plus fort, au moyen d'un dérivé de camptothécine polymérisé, qui est un dérivé de camptothécine fonctionnant comme médicament clé en chimiothérapie du cancer. [Solution] Composition pharmaceutique antitumorale qui combine un dérivé de camptothécine polymérisé et un dérivé polymérisé d'un dérivé du résorcinol à substitution 1,2,4-triazol-3-one, ayant une activité inhibitrice de HSP90, et qui doit être administrée de façon à apporter les deux dérivés simultanément, successivement, ou avec un intervalle de temps entre eux. Ces deux dérivés médicamenteux polymérisés rendent possible une amélioration de l'efficacité du médicament, une réduction de la toxicité vis-à-vis des cellules normales, et l'apport sélectif d'une activité pharmacologique au site d'une tumeur, par administration efficace du médicament et libération du médicament dans la zone affectée.
PCT/JP2015/053481 2014-02-19 2015-02-09 Composition pharmaceutique contenant un dérivé de camptothécine polymérisé, et dérivé inhibiteur de hsp90 polymérisé WO2015125641A1 (fr)

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CN108697806A (zh) * 2016-03-01 2018-10-23 日本化药株式会社 含有喜树碱类高分子衍生物的药物制剂
EP3345654A4 (fr) * 2015-09-03 2019-05-08 Nippon Kayaku Kabushiki Kaisha Composition pharmaceutique à teneur en dérivé de polymère de camptothécine

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CN112279863A (zh) * 2019-07-25 2021-01-29 华东师范大学 Hsp90抑制剂与喜树碱衍生物的偶联物及其制备方法与应用

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WO2004039869A1 (fr) * 2002-10-31 2004-05-13 Nippon Kayaku Kabushiki Kaisha Derives de haut poids moleculaire de camptothecine
WO2008041610A1 (fr) * 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Mélange d'un dérivé de résorcinol avec un polymère
WO2013067162A1 (fr) * 2011-11-02 2013-05-10 Synta Pharmaceuticals Corp. Thérapie anticancéreuse utilisant une combinaison d'inhibiteurs de hsp 90 et d'inhibiteurs de topoisomérase i

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WO2004039869A1 (fr) * 2002-10-31 2004-05-13 Nippon Kayaku Kabushiki Kaisha Derives de haut poids moleculaire de camptothecine
WO2008041610A1 (fr) * 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Mélange d'un dérivé de résorcinol avec un polymère
WO2013067162A1 (fr) * 2011-11-02 2013-05-10 Synta Pharmaceuticals Corp. Thérapie anticancéreuse utilisant une combinaison d'inhibiteurs de hsp 90 et d'inhibiteurs de topoisomérase i

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3345654A4 (fr) * 2015-09-03 2019-05-08 Nippon Kayaku Kabushiki Kaisha Composition pharmaceutique à teneur en dérivé de polymère de camptothécine
US10543281B2 (en) 2015-09-03 2020-01-28 Nippon Kayaku Kabushiki Kaisha Pharmaceutical composition containing camptothecin polymer derivative
CN108697806A (zh) * 2016-03-01 2018-10-23 日本化药株式会社 含有喜树碱类高分子衍生物的药物制剂
EP3424513A4 (fr) * 2016-03-01 2019-10-23 Nippon Kayaku Kabushiki Kaisha Préparation pharmaceutique contenant un dérivé polymère à base de camptothécine

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