WO2015125640A1 - Composé polymère auquel sont liés un dérivé de camptothécine et un inhibiteur de hsp90, et son utilisation - Google Patents

Composé polymère auquel sont liés un dérivé de camptothécine et un inhibiteur de hsp90, et son utilisation Download PDF

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WO2015125640A1
WO2015125640A1 PCT/JP2015/053479 JP2015053479W WO2015125640A1 WO 2015125640 A1 WO2015125640 A1 WO 2015125640A1 JP 2015053479 W JP2015053479 W JP 2015053479W WO 2015125640 A1 WO2015125640 A1 WO 2015125640A1
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hsp90 inhibitor
polymer compound
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compound
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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
    • C08G69/40—Polyamides containing oxygen in the form of ether groups
    • 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
    • C08G69/02—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
    • 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 polymer compound in which a camptothecin derivative and an HSP90 inhibitor are bound to the same molecule.
  • the polymer compound of the present invention relates to a drug delivery system for simultaneously delivering a camptothecin derivative and an HSP90 inhibitor to an affected area, and also relates to a pharmaceutical compound exhibiting excellent antitumor activity.
  • 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 anticancer drug in the 1960s. However, clinical trials were canceled due to myelosuppression and hemorrhagic cystitis as strong toxicity.
  • topotecan and irinotecan were developed as derivatives that are more soluble in water than camptothecin and have stronger antitumor activity but 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, it is metabolized in vivo by carboxylesterase to the active metabolite 7-ethyl-10-hydroxycamptothecin (hereinafter sometimes referred to as EHC) and is stronger. Demonstrate antitumor effect.
  • irinotecan and EHC are characterized by being present in plasma as a lactone type that is more biologically active than topotecan and having a longer half-life.
  • 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 to exhibit a high distribution in the tumor tissue, thereby selectively exerting a medicinal effect on the tumor tissue and causing side effects. It is described that there are few antitumor agents.
  • 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.
  • Patent Document 7 and Non-Patent Document 2 report a polymer compound retaining doxorubicin and another anticancer agent. However, there are no reports on drug delivery compounds that take into account optimal drug delivery of two drugs in combination therapy of camptothecin derivatives and HSP90 inhibitors.
  • a drug delivery system DDS
  • the present inventors have created a polymer compound in which a camptothecin derivative and an HSP90 inhibitor, particularly a 1,2,4-triazol-3-one substituted resorcin derivative having HSP90 inhibitory activity, are bound to the same molecule,
  • the present inventors have found that a compound can provide a satisfactory therapeutic effect as a chemotherapeutic agent, and have reached the present invention. That is, the gist of the present invention is the following configurations 1) to 8).
  • D + e + f + g + h represents an integer of 6 to 60
  • the ratio of d to d + e + f + g + h is 5 to 50%
  • the ratio of e is 5 to 90%
  • the ratio of f is 0 to 90%
  • the ratio of g is 0 to 90%
  • h the ratio is 0 ⁇ 90%
  • R 2 represents a hydrogen atom or a (C1 ⁇ C4) acyl group
  • R 3 represents aspartic acid residue bound binding residue or HSP90 inhibitors of HSP90 inhibitors
  • R 4 represents an aspartic acid residue or an aspartic imide residue
  • R 5 represents —N (R 6 ) CONH (R 7 )
  • R 6 and R 7 may be the same or different and may be branched or Annular (C3-C6) Al A branched or straight-chain (C1-C5) alkyl group optionally substituted with a thio group or a tertiary amino group, wherein the poly
  • R 3 is a binding residue of an HSP90 inhibitor, and the HSP90 inhibitor is represented by the general formula (2) [Wherein, X 1 represents a linear or branched (C1 to C6) alkyl group or —CONR 11 R 12 , wherein R 11 and R 12 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 polymer compound according to 1) above which is a 1,2,4-triazol-3-one-substituted resorcin derivative represented by formula (I), wherein the hydroxyl group of the resorcin moiety is a binding residue of an HSP90 inhibitor having an ester bond.
  • R 3 is an aspartic acid residue to which an HSP90 inhibitor is bound, and the aspartic acid residue is represented by the general formula (3) or (4) [Wherein R 8 and R 9 each independently represent a hydrogen atom or a (C1-C6) alkyl group, R 10 represents a hydrogen atom, a (C1-C40) alkyl group, a (C1-C40) aralkyl group, an aromatic group, One or more substituents selected from the group consisting of amino acid residues in which a group group and a carboxy group are protected, CX-CY represents CH—CH or C ⁇ C (double bond), and D represents HSP90. The binding residues of the inhibitor are indicated. ] The polymer compound according to 1) above.
  • the HSP90 inhibitor of the binding residue of the HSP90 inhibitor of D is represented by the general formula (2) [Wherein, X 1 represents a linear or branched (C1 to C6) alkyl group or —CONR 11 R 12 , and R 11 and R 12 may be the same or different, and may be linear, branched or A cyclic (C1 to C6) alkyl group, and X 2 represents an aryl group which may have a substituent.
  • the polymer compound according to 3) above which is a 1,2,4-triazol-3-one-substituted resorcin derivative represented by formula (II), wherein the hydroxyl group of the resorcin moiety is a binding residue of an HSP90 inhibitor having an ester bond.
  • An antitumor agent comprising the polymer compound according to any one of 1) to 6) as an active ingredient. 8) The antitumor agent according to 7) above, which is prescribed for a malignant tumor treated with an anticancer treatment with a camptothecin derivative in the previous treatment.
  • a camptothecin derivative which is a key drug in cancer chemotherapy
  • an HSP90 inhibitor particularly a 1,2,4-triazol-3-one substituted resorcin derivative having HSP90 inhibitory activity.
  • the drug delivery system of the present invention can deliver two drugs to the affected area at the same time, and can act on the drug at an ideal drug concentration and drug sensitization time, thus producing a synergistic effect of the two drugs. Enables theoretical combination therapy and can achieve enhanced antitumor effects and reduced side effects. Thus, efficient and safe cancer chemotherapy can be achieved.
  • the ratio of the released amount of EHC and compound 5 to the total amount of bound drug at 37 ° C. in PBS solution of compound 1 (phosphate buffered saline; pH 7.1) is shown.
  • the ratio of the released amount of EHC and Compound 5 to the total amount of bound drug at 37 ° C. in PBS solution of Compound 2 (phosphate buffered saline; pH 7.1) is shown.
  • the ratio of the released amounts of EHC and compound 5 to the total amount of bound drug at 37 ° C. in PBS solution of compound 3 (phosphate buffered saline; pH 7.1) is shown.
  • mouth is shown.
  • the present invention is a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment in which a camptothecin derivative and an HSP90 inhibitor are bonded to the same molecule are linked, and 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 + f + g + h represents an integer of 6 to 60
  • the ratio of d to d + e + f + g + h is 5 to 50%
  • the ratio of e is 5 to 90%
  • the ratio of f is 0 to 90%
  • the ratio of g is 0 to 90%
  • h the ratio is 0 ⁇ 90%
  • R 2 represents a hydrogen atom or a (C1 ⁇ C4) acyl group
  • R 3 represents aspartic acid residue bound binding residue or HSP90 inhibitors of HSP90 inhibitors
  • R 4 represents an aspartic acid residue or an aspartic imide residue
  • R 5 represents —N (R 6 ) CONH (R 7 )
  • R 6 and R 7 may be the same or different, (C3 To C6) branched or cyclic alkyl Or a (C1-C5) branched or straight chain alkyl group optionally substituted with a tertiary amino group, wherein the polyglutamic acid segment
  • R 1 is a terminal modification group of the polyethylene glycol segment, and is a hydrogen atom or an optionally substituted (C1-C4) alkyl group.
  • the (C1-C4) alkyl group which may have a substituent for R 1 is a linear or branched (C1-C4) alkyl group. 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, and a carboxyl group.
  • R 1 is preferably a methyl group or an ethyl group, and particularly preferably a methyl group.
  • t in the general formula (1) indicating the number of unit repeating structures of an ethyleneoxy group; (OCH 2 CH 2 ) group is 45 to 450, preferably 90 to 340. is there. That is, the molecular weight of the polyethylene glycol moiety is preferably 2,000 to 20,000, and more preferably 4,000 to 15,000.
  • a in the general formula (1) is a linking group that connects a polyethylene glycol segment and a polyglutamic acid segment.
  • a in the general formula (1) is an alkylene group of (C1 to C6), and examples thereof include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, and 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 polymer compound of the present invention represented by the general formula (1) is 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 (number of polyglutamic acid polymerizations) in the general formula (1) is represented by d + e + f + g + h and is 6 to 60.
  • d + e + f + g + h 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 to 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 5 in the general formula (1) is a urea structure substituent represented by —N (R 6 ) CONH (R 7 ), and R 6 and R 7 may be the same or different, and may be branched or cyclic (C3 To C6) a branched or straight chain (C1 to C5) alkyl group optionally substituted with an alkyl group or a tertiary amino group.
  • Examples of the branched or cyclic (C3 to C6) alkyl group include isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-methylbutyl group, 2-methylbutyl group, neopentyl group, cyclohexyl group and the like.
  • isopropyl group and cyclohexyl group More preferred are isopropyl group and cyclohexyl group.
  • examples of the branched or straight chain (C1 to C5) alkyl group optionally substituted with the tertiary amino group include an ethyl group and a dimethylaminopropyl group.
  • R 6 and R 7 it is preferable that R 6 and R 7 are both an isopropyl group or a cyclohexyl group, or R 6 and R 7 are a combination of an ethyl group and a dimethylaminopropyl group.
  • a substituent in which R 6 and R 7 are both an isopropyl group or a cyclohexyl group is particularly preferable.
  • EHC 7-ethyl-10-hydroxycamptothecin
  • R 3 in the general formula (1) is a binding residue of the HSP90 inhibitor or an aspartic acid residue to which the HSP90 inhibitor is bound.
  • the HSP90 inhibitor is a drug that inhibits the binding of HSP90 to the client protein by binding to the ATP binding site of HSP90, and finally suppresses cell proliferation, such as a geldanamycin derivative.
  • substituted resorcin derivatives Particularly preferred is a substituted resorcin derivative having a hydroxyl group that can be bonded to the polyglutamic acid segment by an ester bond.
  • Examples of the substituted resorcin derivative include those represented by the general formula (2) [Wherein, X 1 represents a linear or branched (C1 to C6) alkyl group or —CONR 11 R 12 , and R 11 and R 12 may be the same or different and may be linear, branched or A cyclic (C1 to C6) 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 (2) represents a linear or branched (C1 to C6) alkyl group or —CONR 11 R 12 , and the R 11 and R 12 may be the same or different linear, A branched or cyclic (C1-C6) alkyl group.
  • Examples of the linear or branched (C1-C6) alkyl group 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.
  • Examples of the linear, branched or cyclic (C1-C6) alkyl group which may be the same or different in R 11 and R 12 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and n-butyl.
  • X 1 is an isopropyl group, sec-butyl group, isobutyl group, tert-butyl group or —CONR 11 R 12 , preferably R 11 is a methyl group and R 12 is 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 linear, branched, or cyclic (C1 to C30) alkyl group is substituted.
  • Preferred is a phenyl group substituted by a linear or branched (C1-C8) alkyl group.
  • 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 primary, secondary, or tertiary (C1-C10) 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 a carbocyclic aryl group provided.
  • examples of the non-cyclic primary amino group include a linear, branched or cyclic (C1-C10) alkyl group, or an amino group substituted with an aryl group.
  • acyclic secondary amino group which may be the same or different, is a linear, branched or cyclic (C1-C10) 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, 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 non-cyclic primary amino group include a linear, branched or cyclic (C1-C10) alkyl group, or an amino group substituted with an aryl group.
  • acyclic secondary amino group which may be the same or different, is a linear, branched or cyclic (C1-C10) 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 which may have a substituent for X 2 includes a pyridyl group which may have a substituent, a pyrimidinyl group which 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 A pyrrolyl group, an indolyl group which may have a substituent, an imidazolyl group which may have a substituent, a pyrazolyl group which may have a substituent, an oxazolyl group which may have a substituent , An isoxazolyl group which may have a substituent, a triazolyl group which may have a substituent, and the like.
  • 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
  • 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 indolyl group which may have a substituent.
  • a pyridyl group a pyridyl group having an alkyl group as a substituent, and a pyridyl 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 a 2-methylpyrimidin-4-yl group and a 2-methylpyrimidin-3-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 11 R 12 , R 11 is a methyl group, and R 12 is n-butyl. It is a group.
  • 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-isopropyl, wherein X 1 is an isopropyl group and X 2 is a 1-methylindol-5-yl group Phenyl) -4- (1-methyl-1H-indol-5-yl) -2,4-dihydro- [1,2,4] triazol-3-one (the following general formula (5); compound 5); X 5- (2,4-dihydroxy-5- (N-methyl), wherein 1 is —CONR 11 R 12 , R 11 is a methyl group, R 12 is an n-butyl group, and X 2 is a 2-methylphenyl group -N-butylamido))-4- (2-methylphenyl) -2,4-dihydro- [1,2,4] triazol-3-one (general formula (6) below; compound 6); or X 1 There is an isopropyl group, X 2 is 4-
  • 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.
  • the compound 5 represented by the general formula (5) is a known compound, and can be produced, for example, according to the description in International Publication No. 2007/139552.
  • the compound 6 represented by the general formula (6) is a known compound, and can be produced, for example, according to the description in International Publication No. 2008/086857.
  • Compound 7 represented by the general formula (7) is a known compound, and can be produced, for example, according to the description in International Publication No. 2006/095783.
  • the polymer compound in the present invention has a structure in which an HSP90 inhibitor is bound to a polyglutamic acid segment. That is, the HSP90 inhibitor is bound using the carboxylic acid side chain of the polyglutamic acid segment.
  • the binding mode is not particularly limited, and the carboxylic acid side chain of the polyglutamic acid segment and the substituent of the HSP90 inhibitor may be chemically bonded in an appropriate binding mode.
  • the polyglutamic acid segment and the HSP90 inhibitor are preferably bonded via an ester bond.
  • the HSP90 inhibitor has a phenolic hydroxyl group in the molecule
  • the phenolic hydroxyl group and the side chain carboxy group of the polyglutamic acid segment may be bound by an ester bond.
  • the ester bond is gradually cleaved non-enzymatically. That is, the release of the HSP90 inhibitor from the polymer compound of the present invention can be controlled to cause sustained release. Since the 1,2,4-triazol-3-one-substituted resorcin derivative preferable as the HSP90 inhibitor has a phenolic hydroxyl group in the resorcin moiety, the resorcin hydroxyl group and the side chain carboxy group of the polyglutamic acid segment are ester-bonded. A mode of bonding by the above can be used.
  • the polyglutamic acid segment is bound to the HSP90 inhibitor according to another embodiment.
  • an aspartic acid derivative is used as a linker between the HSP90 inhibitor and the side chain carboxy group of the polyglutamic acid segment.
  • a method of bonding can be mentioned. That is, the aspartic acid derivative serving as a linker is a derivative in which one carboxy group is amidated, and the amino group of the aspartic acid derivative and the side chain carboxy group of the polyglutamic acid segment of the block copolymer are bonded by an amide bond. A bonded group.
  • the HSP90 inhibitor can be bound to the polyglutamic acid segment by ester-linking the remaining carboxy group of this aspartic acid derivative and the alcoholic hydroxyl group of the HSP90 inhibitor.
  • the HSP90 inhibitor conjugate using the aspartic acid derivative as a linker is administered in vivo, the HSP90 inhibitor dissociates non-enzymatically, and the drug can be released slowly.
  • examples of the aspartic acid residue include the following general formula (3) or general formula (4).
  • R 8 and R 9 each independently represent a hydrogen atom or a (C1 to C6) alkyl group
  • R 10 represents a hydrogen atom, a (C1 to C40) alkyl group, a (C1 to C40) aralkyl group, an aromatic group
  • One or more substituents selected from the group consisting of amino acid residues in which a group group and a carboxy group are protected CX-CY represents CH—CH or C ⁇ C (double bond)
  • D represents HSP90.
  • the binding residues of the inhibitor are indicated.
  • the aspartic acid derivative used as a linker in the present invention is preferably a group represented by the general formula (3) or the general formula (4).
  • CX-CY is C ⁇ C (double bond)
  • the E configuration is preferable.
  • D is a binding residue of the HSP90 inhibitor, and the terminal carboxyl group of the aspartic acid derivative and the HSP90 inhibitor are bonded by an ester bond.
  • Examples of the (C1 to C6) alkyl group in R 8 and R 9 include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, n-pentyl group, n -Hexyl group and the like.
  • R 8 and R 9 are preferably hydrogen atoms.
  • the (C1 to C40) alkyl group in R 10 is a (C1 to C40) alkyl group which may have a substituent, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group.
  • the substituent include a phenyl group, a naphthyl group, a methoxy group, an ethoxy group, and a dimethylamino group.
  • the (C1-C40) aralkyl group is an optionally substituted (C1-C40) aralkyl group, and examples thereof include a benzyl group, a naphthylmethyl group, a phenethyl group, and a 4-phenylbutyl group.
  • substituent include a methyl group, an ethyl group, a nitro group, a chlorine atom, a bromine atom, and a dimethylamino group.
  • the aromatic group is an aromatic group which may have a substituent, and examples thereof include a phenyl group, a 4-nitrophenyl group, a 4-chlorophenyl group, a naphthyl group, and a fluorenyl group.
  • the substitution position of the substituent in each group of R 8 , R 9 , and R 10 is not particularly limited as long as substitution is possible, and the number of substituents is not particularly limited.
  • amino acid of the amino acid residue in which the carboxy group in R 10 is protected includes an amino acid in which the carboxy group used in normal peptide synthesis is protected, and the carboxy group of the amino acid is protected by an ester or an amide. Are preferred.
  • the amino acid protected with an ester is, for example, a (C1-C12) alkyl ester optionally having an amino acid substituent, such as a (C1-C12) alkyl ester of alanine, an ⁇ of aspartic acid or ⁇ - (C1-C12) alkyl ester, ⁇ - or ⁇ - (C1-C12) alkyl ester of glutamic acid, (C1-C12) alkyl ester of phenylalanine, (C1-C12) alkyl ester of cysteine, (C1-C12 of glycine) ) Alkyl esters, (C1-C12) alkyl esters of leucine, (C1-C12) alkyl esters of isoleucine, (C1-C12) alkyl esters of histidine, (C1-C12) alkyl esters of proline, (C1-C12) of serine ) Alkyl esters, (C
  • phenylalanine methyl ester Particularly preferred are phenylalanine methyl ester, glycine methyl ester, glycine (4-phenyl-1-butanol) ester, leucine methyl ester, phenylalanine benzyl ester, phenylalanine (4-phenyl-1-butanol) ester and the like.
  • the amino acid may be D-form, L-form or a mixture thereof.
  • R 10 is particularly preferably an n-butyl group, a 4-phenylbutyl group, etc. Among them, a phenylbutyl group is particularly preferable. Further, CX-CY is preferably CH—CH.
  • D is a binding residue of the HSP90 inhibitor.
  • the embodiment in which the HSP90 inhibitor is bonded to the terminal carboxyl group of the aspartic acid derivative by an ester bond is preferable.
  • the HSP90 inhibitor include several developed compounds such as geldanamycin derivatives and substituted resorcin derivatives.
  • a substituted resorcin derivative having a hydroxyl group that can be bonded to the polyglutamic acid segment by an ester bond is particularly preferable.
  • Examples of the substituted resorcin derivative include those represented by the general formula (2) [Wherein, X 1 represents a linear or branched (C1 to C6) alkyl group or —CONR 11 R 12 , and R 11 and R 12 may be the same or different and may be linear, branched or A cyclic (C1 to C6) alkyl group, and X 2 represents an aryl group which may have a substituent]], 1,2,4-triazol-3-one substituted resorcin derivatives it can.
  • the definition of the substituent in X ⁇ 1 >, X ⁇ 2 >, R ⁇ 11> , R ⁇ 12 > in General formula (2) is synonymous with the above-mentioned.
  • R 4 in the general formula (1) is an aspartic acid residue represented by the following general formula (8) or general formula (9) and / or an aspartic imide residue represented by the following general formula (10).
  • R 8 , R 9 , R 10 and CX-CY are the same as the substituent groups defined in the general formulas (3) and (4).
  • a substituent selected from the group of groups is preferred. When these substituents are present in the polymer compound, these groups may be mixed.
  • R 8, R 9, R 10 , CX-CY is the same as R 8, R 9, R 10 , CX-CY in the R 3, it is the same preferable groups.
  • a glutamic acid moiety to which any of EHC, R 3 , R 4 and R 5 is not bonded may be present.
  • a glutamic acid residue having a free acid type carboxy group is shown, but the carboxy group may be an alkali metal salt or an alkaline earth metal salt, and a glutamic acid moiety containing such a carboxyl group is included.
  • the polymer compound of the general formula (1) having the formula is also included in the present invention.
  • the alkali metal salt or alkaline earth metal salt include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt and the like.
  • it when it is provided parenterally as an anticancer agent, it is prepared as a solution in a solution, but it may be a glutamate based on a salt of the pH buffer of the solution with a cation.
  • a glutamic acid unit (containing d is the number of glutamic acid units) in which EHC is bonded to the side chain carboxy group, and a glutamic acid unit (including the number of units containing the R 3 is bonded to the side chain carboxy group).
  • the side chain carboxy group has a glutamic acid unit (containing unit is h) which is a free carboxy group or a salt thereof.
  • the glutamic acid unit to which EHC is bound and the glutamic acid unit to which R 3 which is a binding residue of the HSP90 inhibitor is bound are essential constituent units.
  • the glutamic acid unit to which R 4 is bonded, the glutamic acid unit to which R 5 is bonded, and the glutamic acid unit which is a free carboxy group or a salt thereof are arbitrary constituent units. Each of these glutamic acid units is independently and randomly arranged.
  • the total number of glutamic acid units in the polyglutamic acid segment of the general formula (1) is represented by d + e + f + g + h.
  • the ratio of d is 5 to 50%, preferably 5 to 40%
  • the ratio of e is 5 to 90%, preferably 5 to 80%
  • the ratio of f is 0 to 90%, preferably 0 to 60%.
  • the proportion is 0 to 90%, preferably 5 to 40%
  • the proportion of h is 0 to 90%, preferably 0 to 30%.
  • the ratio of the drug content of EHC, which is a camptothecin derivative, and an HSP90 inhibitor is not particularly limited, and can be arbitrarily set at a mixture ratio that provides a synergistic effect enhancing action by the combined use of EHC and HSP90 inhibitor. can do.
  • the mixing ratio of EHC and HSP90 inhibitor is indicated by the amount of each drug bound in the polyglutamic acid segment, and is set by the d value and e value representing the ratio of each unit of the polyglutamic acid segment.
  • EHC and HSP90 inhibitor are released from the block copolymer and have a medicinal effect.
  • the binding amount of each drug should be set to a combined concentration ratio that exhibits a synergistic effect enhancing action in consideration of the dissociation rate of the drug from the block copolymer.
  • a 1,2,4-triazol-3-one substituted resorcin derivative represented by the general formula (2) is used as an HSP90 inhibitor, a mixture of EHC and 1,2,4-triazol-3-one substituted resorcin derivative
  • the polymer compound represented by the general formula (1) of the present invention may form a micelle having a polyethylene glycol segment as an outer shell and a polyglutamic acid segment to which a drug or the like is bound as an inner shell in water. That is, the polymer compound of the present invention is an antitumor agent using a block copolymer in which polyethylene glycol and polyglutamic acid are linked as a carrier, but becomes a polymer having a higher molecular weight due to the formation of a self-aggregate.
  • 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 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 the Example and reference example of a postscript.
  • the method for constructing the main chain of the block copolymer having a polyethylene glycol segment and a polyglutamic acid segment which is a polymer compound of the present invention represented by the general formula (1), is a method of binding a polyethylene glycol segment and a polyglutamic acid segment, Any method of sequentially polymerizing glutamic acid structural units to polyethylene glycol segments may be used.
  • N -A method of constructing a polyglutamic acid segment by sequentially reacting carbonyl glutamic anhydride in accordance with the method described in International Publication No. 2006/120914 pamphlet or the like, for example, polyethylene glycol modified with a modifying group such as a methyl group at one end and an aminopropyl group at the other end, N -A method of constructing a polyglutamic acid segment by sequentially reacting carbonyl glutamic anhydride.
  • the N-carbonylglutamic acid anhydride may be a derivative of EHC, in which the carboxy group of the glutamic acid side chain may be modified with an appropriate carboxylic acid protecting group, and is a derivative having a predetermined carboxy group substituent in advance.
  • Conjugates conjugates of HSP90 inhibitors according to R 3 of general formula (1), conjugates of R 4 of general formula (1), conjugates of R 5 of general formula (1), free carboxylic acids, etc. There may be.
  • 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 protecting group is preferable.
  • the N-carbonylglutamic acid anhydride modified with an appropriate carboxylic acid protecting group is used for 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 to which EHC, an HSP90 inhibitor corresponding to R 3 according to the general formula (1), and a general formula (1
  • the terminal amino group of the polyglutamic acid segment of the block copolymer may be acylated.
  • 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.
  • a reaction in which EHC, an HSP90 inhibitor, an aspartic acid derivative to which an HSP90 inhibitor is bound, or the like is bound to the block copolymer in which the polyethylene glycol segment and the polyglutamic acid segment are linked is performed.
  • the binding method is not particularly limited, and the ESP is bound first, and then the HSP90 inhibitor or the aspartic acid derivative to which the HSP90 inhibitor is bound may be bound simultaneously or in the reverse order. Also good.
  • a block copolymer in which a polyethylene glycol segment and a polyglutamic acid segment are linked to an aspartic acid derivative to which an EHC and HSP90 inhibitor or an HSP90 inhibitor is bonded is subjected to a dehydration condensation reaction in the presence of a carbodiimide dehydration condensation agent.
  • a —N (R 6 ) CONH (R 7 ) group corresponding to R 4 can be introduced into the block copolymer simultaneously with EHC and HSP90 inhibitors and the like.
  • the carbodiimide dehydrating condensing agent dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and the like can be used.
  • a reaction aid such as N, N-dimethylaminopyridine (DMAP) may be used.
  • DMAP N, N-dimethylaminopyridine
  • the binding amount of EHC and HSP90 inhibitor can be adjusted by appropriately increasing or decreasing the amount of each drug charged in the dehydration condensation reaction.
  • R 6 and R 7 of —N (R 6 ) CONH (R 7 ) are cyclohexyl groups.
  • DIPCI diisopropylcarbodiimide
  • R 6 and R 7 are isopropyl groups.
  • R 6 and R 7 of —N (R 6 ) CONH (R 7 ) are an ethyl group and 3-dimethylaminopropyl It becomes a mixed substitution product.
  • the polymer compound of the present invention can be produced via an optional purification step.
  • the polymer compound of the present invention gradually dissociates and releases EHC and HSP90 inhibitors, which are antitumor active ingredients, in a phosphate buffered saline (PBS) solution. This indicates that even when administered in vivo, it has physical properties to release the EHC and HSP90 inhibitors gradually.
  • PBS phosphate buffered saline
  • high molecular weight compounds and low molecular weight compounds have greatly different pharmacokinetic behaviors in the body and their distribution in the body. From this, the high molecular compound of the present invention is different in drug expression characteristics and side effect expression characteristics from low molecular weight drugs, and can provide a new therapeutic method using a camptothecin derivative and an HSP90 inhibitor.
  • the polymer compound of the present invention can be used as an anticancer agent, and the use of the anticancer agent is also included in the present invention.
  • the anticancer agent can be used in commonly used preparations such as injections, drops, tablets, capsules, powders and the like.
  • commonly used pharmaceutically acceptable carriers and additives such as binders, lubricants, disintegrants, solvents, excipients, solubilizers, dispersants, stabilizers, suspensions Agents, preservatives, soothing agents, pigments, fragrances and the like can be used. Among them, it is preferably used as an injection or a drip infusion.
  • Water physiological saline, 5% glucose or mannitol solution, water-soluble organic solvent (for example, glycerol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, polyethylene glycol, cremophor, etc. And a mixture thereof, and a mixture of water and the water-soluble organic solvent are preferred.
  • water-soluble organic solvent for example, glycerol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, polyethylene glycol, cremophor, etc. And a mixture thereof, and a mixture of water and the water-soluble organic solvent are preferred.
  • the dose of the polymer compound represented by the general formula (1) is appropriately set in consideration of the patient's sex, age, physique, physiological condition, disease state, therapeutic effect and the like.
  • the dose per body surface area of a patient is 0.01 to 500 mg / m 2 , preferably 1 to 200 mg / m 2 parenterally, in terms of EHC, which is an active ingredient, per day for an adult.
  • the dose per body surface area of the patient is 0.01 to 500 mg / m 2 , preferably 1 to 200 mg / m 2 .
  • the polymer compound 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 polymer compound of the present invention is used for the treatment of malignant tumor diseases.
  • the malignant tumor applied to the treatment with the polymer compound of 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 carcinoma, Prostate cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, soft tissue sarcoma, Kaposi sarcoma, carcinoid carcinoma, head and neck cancer, melanoma, ovarian cancer, bile duct cancer, mesothelioma, and multiple myeloma, etc. widely It can be applied to general cancer treatment.
  • breast cancer non-small cell lung cancer, small cell lung cancer, colorectal cancer, non-Hodgkin lymphoma (NHL), renal cell carcinoma, Prostate cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, soft tissue sarcoma, Kaposi sarcoma,
  • 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 present invention will be further described below with reference to examples. However, the present invention is not limited to these examples.
  • the present invention products Gaussian distribution analysis showing the size of the particles constituting in aqueous solution (particle size) were performed at Zeta Potential / Particlesizer NICOMP TM 380ZLS ( Particle Sizing Systems , Inc.).
  • the methoxypolyethylene glycol-polyglutamic acid block copolymer (with a molecular weight of 12,000 at one end is a methyl group and the other end is at aminopropyl) by a method according to the method described in the pamphlet of International Publication No.
  • EHC 7-ethyl-10-hydroxycamptothecin
  • DIPCI diisopropylcarbodiimide
  • DMAP N, N-dimethylaminopyridine
  • the contents of EHC and compound 5 bound to compound 1 were analyzed by HPLC (high performance liquid chromatography) after adding 1N sodium hydroxide aqueous solution to compound 1 and stirring at 37 ° C. for 1 hour. And calculated from the amount obtained from the calibration curve obtained with EHC and Compound 5. As a result, the contents of bound EHC and compound 5 were 3.4% (w / w) and 15.4% (w / w), respectively. Further, according to 1 H-NMR method, the bond content of —N (R 6 ) CONH (R 7 ) (R 6 and R 7 are isopropyl groups) corresponding to R 5 according to the general formula (1) is 3.0 % (W / w).
  • 2006/120914 pamphlet It consists of a polyethylene glycol segment and a polyglutamic acid segment (terminal N acetyl group) having a polymerization number of 23, and the binding group is A block copolymer which is a rimethylene group) was prepared.
  • the methoxypolyethylene glycol-polyglutamic acid block copolymer (389 mg), EHC (70 mg) and Compound 5 (70 mg) obtained in Synthesis Example 1 were dissolved in DMF (7.0 mL), stirred at 35 ° C. for 30 minutes, and then stirred at 20 ° C. for 2 hours. did. To this was added 167 ⁇ L of DIPCI and 6.9 mg of DMAP, and the mixture was stirred at 20 ° C. for 21 hours.
  • the content of EHC and compound 5 bound to compound 2 was determined by adding 1N sodium hydroxide aqueous solution to compound 1 and stirring at 37 ° C. for 1 hour, and then measuring the content of free EHC and compound 5 by HPLC (high performance liquid chromatography). And calculated from the amount obtained from the calibration curve obtained with EHC and Compound 5. As a result, the contents of bound EHC and compound 5 were 10.9% (w / w) and 9.0% (w / w), respectively.
  • the bond content of —N (R 6 ) CONH (R 7 ) (R 6 and R 7 are isopropyl groups) corresponding to R 5 according to the general formula (1) was 2.9% by 1 H-NMR method. (W / w).
  • a block copolymer comprising a glycol segment and a polyglutamic acid segment (terminal acetyl group) having a polymerization number of 10 .
  • the methoxypolyethylene glycol-polyglutamic acid block copolymer 473 mg, EHC 32 mg, and Compound 5 150 mg obtained in Synthesis Example 1 were dissolved in DMF 10 mL, stirred at 35 ° C. for 25 minutes, and then stirred at 25 ° C. for 2 hours. Then, 235 ⁇ L of DIPCI and 9 mg of DMAP were added and stirred at 25 ° C. for 20 hours. Thereafter, 118 ⁇ L of DIPCI was added, and the mixture was further stirred for 5 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 2 hours.
  • the precipitate was collected by filtration and washed with ethyl acetate.
  • the obtained precipitate was dissolved in 11.0 mL of acetonitrile and 2.0 mL of water, an ion exchange resin (Dow Chemical Dowex 50 (H + ), 5.0 mL) was added, and the mixture was stirred and filtered.
  • the obtained filtrate 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 freeze-dried to obtain Compound 3 (500 mg).
  • the content of EHC and compound 5 bound to compound 3 was determined by adding 1N sodium hydroxide aqueous solution to compound 1 and stirring at 37 ° C. for 1 hour, and then determining the content of free EHC and compound 5 by HPLC (high performance liquid chromatography). And calculated from the amount obtained from the calibration curve obtained with EHC and Compound 5. As a result, the contents of bound EHC and compound 5 were 3.6% (w / w) and 16.6% (w / w), respectively.
  • the bond content of —N (R 6 ) CONH (R 7 ) (where R 6 and R 7 are isopropyl groups) corresponding to R 5 according to the general formula (1) is 3.4% by 1 H-NMR method. (W / w).
  • control drug 1 was hydrolyzed at room temperature for 10 minutes with a 1N-sodium hydroxide aqueous solution, and then the liberated EHC was quantitatively analyzed by the HPLC method to obtain an EHC content of 21% (w / w )Met.
  • the bond content of —N (R 6 ) CONH (R 7 ) (where R 6 and R 7 are isopropyl groups) corresponding to R 5 according to the general formula (1) was 5.6% by 1 H-NMR method. (W / w).
  • DIPCI diisopropylcarbodiimide
  • DMAP N, N-dimethylaminopyridine
  • the bond content of the group —N (R 6 ) CONH (R 7 ) (where R 6 and R 7 are isopropyl groups) corresponding to R 5 according to the general formula (1) by 1 H-NMR method is 3 0.0% (w / w).
  • the high molecular compounds of the present invention release and release both EHC and compound 5 slowly in a PBS solution without hydrolase. I was able to.
  • the drug release rates of EHC and Compound 5 varied depending on the composition of the block copolymer in which polyethylene glycol and polyglutamic acid were linked and the amount of each drug bound. It has been shown that the release rate of EHC and compound 5 can be controlled.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Polymers & Plastics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)

Abstract

L'invention concerne un composé polymère pour amener efficacement deux médicaments sur une zone affectée, réduire les effets secondaires et augmenter l'efficacité du médicament; et un médicament antitumoral comprenant ledit composé polymère en tant que principe actif. Ce composé polymère est obtenu par liaison ester d'un dérivé de camptothécine et d'un inhibiteur de HSP90 à un groupe carboxyle d'une chaîne latérale d'un polymère à blocs obtenu par réunion d'un segment polyéthylèneglycol et d'un segment poly(acide glutamique).
PCT/JP2015/053479 2014-02-19 2015-02-09 Composé polymère auquel sont liés un dérivé de camptothécine et un inhibiteur de hsp90, et son utilisation WO2015125640A1 (fr)

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WO2018025657A1 (fr) * 2016-07-30 2018-02-08 日本化薬株式会社 Nouveaux dérivés polymères, et nouvelle sonde d'imagerie dérivée de polymères utilisant lesdits nouveaux dérivés polymères
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

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WO2008041610A1 (fr) * 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Mélange d'un dérivé de résorcinol avec un polymère
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WO2008041610A1 (fr) * 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Mélange d'un dérivé de résorcinol avec un polymère
JP2010519305A (ja) * 2007-02-26 2010-06-03 ウィスコンシン・アルムニ・リサーチ・ファウンデーション 併用薬物送達のためのポリマー性ミセル
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Publication number Priority date Publication date Assignee Title
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
WO2018025657A1 (fr) * 2016-07-30 2018-02-08 日本化薬株式会社 Nouveaux dérivés polymères, et nouvelle sonde d'imagerie dérivée de polymères utilisant lesdits nouveaux dérivés polymères
JPWO2018025657A1 (ja) * 2016-07-30 2019-06-27 日本化薬株式会社 新規な高分子誘導体、及びそれらを用いた新規な高分子誘導体イメージングプローブ
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