JP2018135297A - Metal complex and anticancer agent containing the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel complex that has excellent anticancer activity and can be orally administered, and an anticancer agent containing the same as an active ingredient.SOLUTION: An anticancer agent contains a metal complex represented by the following formula [2] or a salt thereof as an active ingredient.SELECTED DRAWING: Figure 17

Description

  The present invention relates to a metal complex and an anticancer agent containing the same as an active ingredient.

  Currently, there are platinum (II) complexes with a platinum-diamine skeleton, such as cisplatin and oxaliplatin, as platinum preparations currently used in clinical practice, and their spread is widespread, including research in combination with molecular target drugs. .

  On the other hand, cisplatin has serious side effects such as nephrotoxicity and oxaliplatin has peripheral neuropathy. The patient is forced to instill and rest for a long time, and the degree of side effects affects the continuation of treatment. There is also a case. In addition, these preparations require intravenous infusion, but when oxaliplatin is administered from a peripheral vein, vascular pain occurs, which is somewhat difficult to use. In order to improve the patient's QOL, it is desired to develop an oral preparation capable of obtaining the same effect as an existing platinum preparation.

  As a platinum anticancer agent after cisplatin, (Patent Document 1) discloses a drug whose fat solubility and stability are improved by Pt (IV) complexation. However, although this platinum (IV) complex was evaluated as a platinum preparation that can be administered orally, it was less effective and had side effects such as nausea.

International Publication No. 2016/208481

  Therefore, an object of the present invention is to provide a novel complex that is excellent in anticancer activity and can be administered orally, and an anticancer agent containing the complex.

  As a result of diligent research to solve the above problems, the present inventors synthesized 9-anthracenyldiamine in which an anthracene ring is bonded to a diamine having a specific structure, and this is combined with cisplatin and oxaliplatin. As a result, they were confirmed to have increased uptake into tumor cells and enhanced anticancer activity, and were found to be capable of oral administration without being decomposed by acid, thereby completing the invention. That is, the gist of the present invention is as follows.

（式中、Ｍは、Ｐｔ又はＰｄであり、
Ｒ_１及びＲ_２は、それぞれ独立して、水素原子又は炭素数１〜３の直鎖状もしくは分枝状アルキル基であるか、又はＲ_１及びＲ_２は一緒になって、炭素数５もしくは６の環状の飽和炭化水素を形成し、
Ｒ_３〜Ｒ_１１は、それぞれ独立して、水素原子、炭素数１〜３０のアルキル基、炭素数３〜３０のシクロアルキル基、炭素数２〜３０のアルケニル基、炭素数３〜３０のシクロアルケニル基、炭素数２〜３０のアルキニル基、炭素数７〜３０のアラルキル基、炭素数７〜３０のアラルケニル基、炭素数７〜３０のアラルキニル基、炭素数６〜３０のアリール基、ハロゲン原子、炭素数１〜３０のハロアルキル基、炭素数２〜３０のハロアルケニル基、炭素数２〜３０のハロアルキニル基、炭素数６〜３０のハロアリール基、炭素数１〜３０のアルコキシ基、炭素数６〜３０のアリールオキシ基、ヒドロキシ基、アミノ基、炭素数１〜３０のアルキルアミノ基、炭素数６〜３０のアリールアミノ基、シアノ基又はニトロ基である。）
で表される金属錯体又はその塩。
（２）Ｍが、Ｐｔである上記（１）に記載の金属錯体又はその塩。
（３）Ｒ_３〜Ｒ_１１が、水素原子である上記（１）又は（２）に記載の金属錯体又はその塩。
（４）下記式［２］

で表される金属錯体又はその塩。
（５）下記式［３］

で表される金属錯体又はその塩。
（６）上記（１）〜（５）のいずれかに記載の金属錯体又はその塩を有効成分として含有する抗がん剤。
（７）経口投与用である上記（６）に記載の抗がん剤。 (1) The following formula [1]

(Wherein M is Pt or Pd,
R ₁ and R ₂ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, or R ₁ and R ₂ together represent 5 or 6 cyclic saturated hydrocarbons are formed,
R _{3 to} R ₁₁ are each independently a hydrogen atom, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or a cyclohexane having 3 to 30 carbon atoms. Alkenyl group, C2-C30 alkynyl group, C7-C30 aralkyl group, C7-C30 aralkenyl group, C7-C30 aralkynyl group, C6-C30 aryl group, halogen atom Haloalkyl group having 1 to 30 carbon atoms, haloalkenyl group having 2 to 30 carbon atoms, haloalkynyl group having 2 to 30 carbon atoms, haloaryl group having 6 to 30 carbon atoms, alkoxy group having 1 to 30 carbon atoms, carbon number A 6-30 aryloxy group, a hydroxy group, an amino group, a C1-C30 alkylamino group, a C6-C30 arylamino group, a cyano group, or a nitro group. )
Or a salt thereof.
(2) The metal complex or the salt thereof according to (1), wherein M is Pt.
(3) The metal complex or the salt thereof according to (1) or (2), wherein R _{3 to} R ₁₁ are hydrogen atoms.
(4) The following formula [2]

Or a salt thereof.
(5) The following formula [3]

Or a salt thereof.
(6) The anticancer agent which contains the metal complex in any one of said (1)-(5), or its salt as an active ingredient.
(7) The anticancer agent according to (6), which is for oral administration.

  The metal complex of the present invention or a salt thereof is easily taken up into cells and has excellent anticancer activity. In addition, since it is stable even under strong acid conditions, it can be used as a prodrug for oral administration in the hope that it will reach the intestinal tract without being decomposed by gastric acid and be absorbed.

ATC2 · _HCl, shows the fluorescence spectrum of _{Pt (NH 3) 2 (AtC2} ) Cl 2, and Pt (dach) (AtC2) Cl 2. AtC3 · _HCl, shows the fluorescence spectrum of _{Pt (NH 3) 2 (AtC3} ) Cl 2, and Pt (dach) (AtC3) Cl 2. It is a diagram showing the ¹ H-NMR spectrum of _{Pt (NH 3) 2 (AtC2} ) Cl 2 in 24 hours after the strong acid under. It is a diagram showing the ¹ H-NMR spectrum of _{Pt (NH 3) 2 (AtC2} ) Cl 2 after 7 days in a strong acid under. It is a diagram showing the ¹ H-NMR spectrum of _{Pt (NH 3) 2 (AtC3} ) Cl 2 in 24 hours after the strong acid under. It is a diagram showing the ¹ H-NMR spectrum of _{Pt (NH 3) 2 (AtC3} ) Cl 2 after 7 days in a strong acid under. It is a diagram showing ¹ H-NMR spectrum of the Pt (dach) (AtC2) of Cl ₂ 24 hours later in the strong acid under. Is a diagram showing ¹ H-NMR spectrum of the Pt (dach) (AtC2) of Cl ₂ 7 days in a strong acid under. It is a diagram showing ¹ H-NMR spectrum of the Pt (dach) (AtC3) of Cl ₂ 24 hours later in the strong acid under. Is a diagram showing ¹ H-NMR spectrum of the Pt (dach) (AtC3) of Cl ₂ 7 days in a strong acid under. It is a graph which shows the amount of Pt taken up into the cell after 2 hours and 24 hours after exposure to oxaliplatin and Pt (dach) (AtC3). It is the fluorescence-microscope image (20 time) of 24 hours passage of the human colon adenocarcinoma cell LS180 exposed to the Pt (dach) (AtC3) containing medium. The left side is an excitation light exposure image, and the right side is an image obtained by superimposing a bright field image and an excitation light exposure image. It is a fluorescence-microscope image (100 time) after exposing human colon adenocarcinoma cell LS180 to Pt (dach) (AtC3) containing medium for 24 hours, and performing nuclear staining. The left side is an image in which a bright field image and a blue excitation light exposure image are superimposed, and the right side is an image in which a bright field image and a red excitation light exposure image are superimposed. It is a graph which shows the distribution in each organ of 2, 5, 24, and 48 hours after intravenous administration of Pt (dach) (AtC3). It is a graph which shows the distribution in each organ of 2, 5, 24, and 48 hours after intravenous administration of oxaliplatin. It is a graph which shows distribution in each organ of 3, 5, 24, and 48 hours after oral administration of Pt (dach) (AtC3). It is a graph which shows the change of the tumor size when Pt (dach) (AtC3) is orally administered to a cancer transplant mouse | mouth. It is a graph which shows the change of a body weight when Pt (dach) (AtC3) is orally administered to a cancer transplant mouse | mouth.

Hereinafter, the present invention will be described in detail based on embodiments.
The metal complex according to the present embodiment is represented by the following formula [1].

  In the formula [1], M is Pt or Pd. The metal complex (or salt thereof) of the present embodiment exhibits an excellent anticancer effect by containing platinum (Pt) or palladium (Pd) which is a noble metal. M is preferably Pt from the viewpoint of being less susceptible to substitution reaction with biological substances such as proteins in the body and having less side effects.

R ₁ and R ₂ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, or R ₁ and R ₂ together represent 5 or 6 cyclic saturated hydrocarbons are formed.

  Examples of the linear or branched alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

R _{3 to} R ₁₁ are each independently a hydrogen atom, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or 3 to 30 carbon atoms. A cycloalkenyl group having 2 to 30 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aralkenyl group having 7 to 30 carbon atoms, an aralkynyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, A halogen atom, a haloalkyl group having 1 to 30 carbon atoms, a haloalkenyl group having 2 to 30 carbon atoms, a haloalkynyl group having 2 to 30 carbon atoms, a haloaryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, An aryloxy group having 6 to 30 carbon atoms, a hydroxy group, an amino group, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, a cyano group, or a nitro group.

  Examples of the alkyl group having 1 to 30 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, Isopentyl group, neopentyl group, 1,2-dimethylpropyl group, n-hexyl group, 1,3-dimethylbutyl group, 1-isopropylpropyl group, 1,2-dimethylbutyl group, n-heptyl group, 1,4- Dimethylpentyl group, 2-methyl-1-isopropylpropyl group, 1-ethyl-3-methylbutyl group, n-octyl group, 2-ethylhexyl group, 3-methyl-1-isopropylbutyl group, 2-methyl-1-isopropyl Group, 1-t-butyl-2-methylpropyl group, n-nonyl group, 3,5,5-trimethylhexyl group and the like.

  Examples of the cycloalkyl group having 3 to 30 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

  Examples of the alkenyl group having 2 to 30 carbon atoms include vinyl group, allyl group, propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 2-methylallyl group, and 2-butenyl group.

  Examples of the C3-C30 cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a 2-cyclopenten-1-yl group, a 2-cyclohexen-1-yl group, and a 3-cyclohexen-1-yl group. It is done.

  Examples of the alkynyl group having 2 to 30 carbon atoms include an ethynyl group, a 2-propynyl group, and a 2-butynyl group.

  Examples of the aralkyl group having 7 to 30 carbon atoms include benzyl group, phenethyl group, diphenylmethyl group and the like.

  Examples of the aralkenyl group having 7 to 30 carbon atoms include styryl group, 2-phenyl-1-propenyl group, 3-phenyl-2-butenyl group, 2-naphthylethenyl group and the like.

  Examples of the aralkynyl group having 7 to 30 carbon atoms include 2-phenylethynyl group and 2-naphthylethynyl group.

  Examples of the aryl group having 6 to 30 carbon atoms include phenyl group, tolyl group, xylyl group, ethylphenyl group, naphthyl group, and anthranyl group.

  The halogen atom is fluorine, chlorine, bromine or iodine.

  Examples of the haloalkyl group having 1 to 30 carbon atoms include trifluoromethyl group, difluoromethyl group, trichloromethyl group, dichloromethyl group, fluoromethyl group, chloromethyl group, iodomethyl group, bromomethyl group, pentafluoroethyl group, penta A chloroethyl group etc. are mentioned.

  Examples of the haloalkenyl group having 2 to 30 carbon atoms include 2,2-difluoroethenyl group, 2,2-dichloroethenyl group, 3-chloro-2-allyl group, and 3,3-dichloro-2-allyl group 2,3-dibromo-2-allyl group and the like.

  Examples of the haloalkynyl group having 2 to 30 carbon atoms include a 3-chloro-2-propynyl group, a 1,3-dichloro-2-propynyl group, and a 1,3-dibromo-2-propynyl group.

  Examples of the haloaryl group having 6 to 30 carbon atoms include chlorophenyl group (for example, 4-chlorophenyl group), bromophenyl group, fluorophenyl group and the like.

  Examples of the alkoxy group having 1 to 30 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a hexyloxy group, an octyloxy group, and a 2-ethylhexyloxy group.

  Examples of the aryloxy group having 6 to 30 carbon atoms include a phenyloxy group, a naphthyloxy group, and a biphenyloxy group.

  Examples of the alkylamino group having 1 to 30 carbon atoms include a methylamino group, an ethylamino group, a hexylamino group, and a dodecylamino group.

  Examples of the arylamino group having 6 to 30 carbon atoms include a phenylamino group, a naphthylamino group, a benzylamino group, an indanylamino group, and an indenylamino group.

Preferably, the anthracene ring is unsubstituted, ie R _{3 to} R ₁₁ are hydrogen atoms. Preferably, R ₁ and R ₂ are hydrogen atoms, or R ₁ and R ₂ together form a C 6 cyclic saturated hydrocarbon. That is, a preferred specific example of the metal complex of the present embodiment is represented by the following formula [2] or formula [3]. The metal complexes of the formula [2] and the formula [3] correspond to compounds obtained by converting cisplatin and oxaliplatin into prodrugs, respectively.

  In the metal complex represented by the formula [1] described above, geometric isomers may exist depending on the coordination direction of the ligand with respect to the central metal M. This is the reason why some of the coordination bonds in the formula [1] are expressed by wavy lines (˜˜˜).

  When preparing metal complexes where geometric isomers may be present, the product is usually obtained as an equivalent mixture of two geometric isomers, unless selectively prepared. In this case, examples of means for purifying only one of the obtained mixture of geometric isomers include a crystallization method and a chromatography method. In the present invention, both the form of a mixture not subjected to such a purification treatment and the form of only one isomer after the purification treatment are claimed. It is intended to be included in the technical scope of the described invention.

  The metal complex according to the present embodiment may be in the form of a salt. The type of counter anion in the case where the metal complex is in the form of a salt is not particularly limited. Examples of such counter anions include chloride ions, fluoride ions, bromide ions, iodide ions and other halide ions, nitrate ions, sulfate ions, phosphate ions, acetate ions, carbonate ions, perchlorate ions. Etc.

  There is no restriction | limiting in particular about the manufacturing method of the metal complex of this invention, or its salt, It can manufacture by taking into consideration the technical common sense at the time of the application of this application.

As an example of the method for producing a metal complex according to the present embodiment, platinum or palladium such as cisplatin is used as a raw material from a noble metal complex such as chloroplatinate or chloropalladate such as potassium tetrachloride platinate K ₂ PtCl ₄ . Examples of the method of forming a complex and then reacting the obtained complex with a diamine derivative having an anthracene ring represented by the following “AtC3” to obtain a target metal complex. Here, AtC3 can be obtained by reacting a substituted or unsubstituted 9-anthracenecarboxaldehyde with diaminopropane.

During the reaction, be suitably selected according to the kind of AtC3 the substituents R ₃ to R _11, it is possible to produce a metal complex having a desired substituent. Moreover, a desired noble metal atom can be introduce | transduced with respect to the metal complex obtained by selecting the noble metal atom (Pt or Pd) which the noble metal complex to use has. In the above method, the noble metal complex as a raw material has a chlorine atom as a ligand. However, the present invention is not limited to this form, and is not particularly limited as long as it is a ligand that can be substituted with AtC3 in a subsequent reaction. Can be used.

  The obtained metal complex can be appropriately purified by a conventionally known purification means. The same applies to other compounds described later.

  There is no restriction | limiting in particular also about reaction conditions, It can set suitably. As an example, the temperature at which the platinum or palladium complex such as cisplatin is reacted with AtC3 is usually room temperature to 80 ° C, preferably room temperature to 60 ° C. The reaction time is usually 2 hours to 1 week, preferably several hours to several days.

  Since the metal complex according to the present embodiment or a salt thereof has high anticancer activity as described later, it can be used as an anticancer agent. That is, the anticancer agent which uses the metal complex mentioned above or its salt as an active ingredient is provided.

  The type of cancer to which the anticancer agent of the present embodiment is applied is not particularly limited. For example, leukemia, malignant melanoma, malignant lymphoma, digestive organ cancer, lung cancer, esophageal cancer, stomach cancer, colon cancer. , Rectal cancer, colon cancer, ureteral tumor, gallbladder cancer, bile duct cancer, biliary tract cancer, breast cancer, liver cancer, pancreatic cancer, testicular tumor, maxillary cancer, tongue cancer, lip cancer, Oral cancer, pharyngeal cancer, laryngeal cancer, ovarian cancer, uterine cancer, prostate cancer, thyroid cancer, brain tumor, Kaposi sarcoma, hemangioma, polycythemia vera, neuroblastoma, retinoblastoma, bone marrow Tumor, cystoma, sarcoma, osteosarcoma, myoma, skin cancer, basal cell cancer, skin appendage cancer, skin metastasis cancer, skin melanoma and the like. Moreover, it can be applied not only to malignant tumors but also to benign tumors. Moreover, the anticancer agent according to the present embodiment can be used to suppress cancer metastasis, and is particularly useful as a postoperative cancer metastasis inhibitor.

  In using the anticancer agent according to the present embodiment, it can be administered to humans or animals (particularly preferably humans) in various forms. The administration form may be oral administration or parenteral administration such as intravenous, intramuscular, subcutaneous or intradermal injection, rectal administration, transmucosal administration and the like. Examples of the dosage form suitable for oral administration include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, syrups and the like. Examples of the pharmaceutical composition suitable for parenteral administration include solid preparations for external use such as injections, drops, nasal drops, sprays, inhalants, suppositories, or ointments, creams, powder coatings, Examples thereof include transdermal absorbents such as liquid coating agents and patches. Furthermore, examples of the dosage form of the anticancer agent according to the present embodiment include an embedding pellet and a sustained-release preparation prepared by a known technique.

  A preferable administration form, preparation form, and the like are appropriately selected by a doctor according to the age, sex, constitution, symptom, treatment time, etc. of the patient.

  In particular, the anticancer drug according to the present embodiment is a prodrug that reaches the intestinal tract without being decomposed by gastric acid, is absorbed, is taken up into tumor cells, and is decomposed intracellularly to exhibit anticancer activity. Can function as. Therefore, it is useful as an anticancer agent for oral administration.

  When the anticancer agent is a solid preparation such as a tablet, pill, powder, powder, granule, or the like, these solid preparations contain the metal complex according to the present embodiment or a salt thereof as an appropriate additive according to a conventional method. For example, lactose, sucrose, D-mannitol, corn starch, synthetic or natural gum, excipients such as crystalline cellulose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, gelatin, binders such as polyvinylpyrrolidone, Disintegrants such as carboxymethylcellulose calcium, sodium carboxymethylcellulose, starch, corn starch, sodium alginate, lubricants such as talc, magnesium stearate, sodium stearate, calcium stearate, calcium carbonate, sodium carbonate, calcium phosphate It can be prepared by mixing as appropriate with fillers or diluents such as sodium phosphate. Tablets and the like may be subjected to sugar coating, gelatin, enteric coating, film coating, and the like, if necessary, using a coating agent such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, and titanium oxide.

  When the anticancer agent is a liquid preparation such as an injection, eye drops, nasal drop, inhalant, spray, lotion, syrup, liquid, suspension, emulsion, etc., these liquid preparations are Examples of the metal complex or salt thereof according to the embodiment include purified water, an appropriate buffer solution such as a phosphate buffer solution, physiological saline solution such as physiological saline, Ringer's solution, and lock solution, cocoa butter, sesame oil, olive oil, and the like. Dissolve in organic solvents such as vegetable oil, mineral oil, higher alcohol, higher fatty acid, ethanol, etc., if necessary, emulsifiers such as cholesterol, suspension agents such as gum arabic, dispersion aids, wetting agents, polyoxyethylene hydrogenated castor Oil-based, polyethylene glycol-based surfactants, solubilizing agents such as sodium phosphate, stabilizers such as sugar, sugar alcohol, albumin, preservatives such as parabens, sodium chloride, glucose, glycerin By adding a tonicity agent such as phosphorus, a buffering agent, a soothing agent, an adsorption inhibitor, a moisturizer, an antioxidant, a colorant, a sweetener, a flavor, an aromatic substance, etc. It can be prepared as an aqueous solution, suspension, liposome or emulsion. In this case, the injection preferably has a physiological pH, and particularly preferably has a pH within the range of 6-8.

  When the anticancer agent is a semi-solid preparation such as a lotion, cream or ointment, these semi-solid preparations contain the metal complex according to the present embodiment or a salt thereof as fat, fatty oil, lanolin, petrolatum, paraffin, It can be produced by appropriately mixing with wax, plasters, resins, plastics, glycols, higher alcohols, glycerin, water, emulsifiers, suspending agents and the like.

  The content of the metal complex according to the present embodiment or a salt thereof in the anticancer agent can vary depending on the dosage form, severity, desired dosage, etc., but generally the anticancer agent The total mass is 0.001 to 80 mass%, preferably 0.1 to 50 mass%.

  The dosage of the anticancer agent can be appropriately determined by a doctor according to conditions such as the age, sex, weight, symptoms, and administration route of the patient. Generally, the amount of the active ingredient per day for an adult is in the range of about 1 μg / kg to 1,000 mg / kg, and preferably in the range of about 10 μg / kg to 10 mg / kg. Such a dose of anticancer agent may be administered once a day, or may be administered divided into several times a day (for example, about 2 to 4 times).

  When using an anticancer agent, it may be used in combination with known chemotherapy, surgical treatment, radiation therapy, hyperthermia, immunotherapy and the like.

  The anticancer agent according to the present embodiment exhibits extremely high anticancer activity. In addition, the side effects are significantly reduced as compared with conventional platinum preparations in which serious side effects (nephrotoxicity, nausea, etc.) are problematic. Therefore, it has the potential to replace existing platinum preparations and can be a very promising new drug.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example and a comparative example, this invention is not limited to these Examples.

1. Synthesis The metal complex was synthesized by the following method. The synthesized compound was identified by ¹ H-NMR and elemental analysis.
(1) Synthesis of cis-Pt (NH ₃ ) ₂ I ₂ 2.0 g (4.8 mmol) of K ₂ PtCl ₄ was dissolved in 20 ml of H ₂ O, and 3.3 g (19.8 mmol) of KI was added thereto at 50 ° C. For 5 minutes. This solution was added to 1 mL (52.9 mmol) of 28% aqueous ammonia and stirred for 2 minutes. After standing for 3 hours, yellow powder was collected by filtration. After washing with hot water, ethanol, and diethyl ether in that order, they were vacuum dried.
Yield: 2.11g
Yield: 91.1%
Elemental analysis: H ₆ N ₂ I ₂ Pt ₁ (M = 482.88)

(2) Synthesis of cis-Pt (NH ₃ ) ₂ Cl ₂ 0.68 g (4.0 mmol) of AgNO ₃ was dissolved in 80 ml of H ₂ O, and 0.96 g of cis-Pt (NH ₃ ) ₂ I ₂ (2. 0 mmol) was dissolved in 10 ml of dimethylacetamide solution, and the mixture was stirred overnight under light shielding. The solution was filtered to remove AgI, 2 mL of 1M NaCl was added and stirred at 60 ° C. overnight. The produced yellow powder was collected by filtration and washed with a large amount of cold water.
Yield: 0.374g
Yield: 61.7%
Elemental analysis: H ₆ N ₂ PtCl ₂ (M = 300.08)
calcd. C: 0.00% H: 2.00% N: 9.33%
obsd.C: 0.00% H: 1.84% N: 9.44%

(3) Synthesis of Pt (dach) Cl ₂ 2.0 g (4.8 mmol) of K ₂ PtCl ₄ was added to 20 ml of H ₂ O, and 0.57 g (5.0 mmol) of 1R, 2R-cyclohexanediamine (dach) was added to H _2. Dissolved in 20 ml of O. This was heated and stirred at 60 ° C. for 5 hours. The produced yellow powder was collected by filtration, washed with H ₂ O and dried.
Yield: 1.31 g
Yield: 71.8%
Elemental analysis: C ₆ H ₁₄ N ₂ PtCl ₂ (M = 380.08)
calcd.C: 18.95% H: 3.68% N: 7.37%
obsd. C: 18.64% H: 3.60% N: 7.12%

(4) Synthesis of AtC2 5 ml (74.9 mmol) of ethylenediamine and 2.06 g (10 mmol) of 9-anthracenecarboxaldehyde were added to a solution obtained by mixing 40 mL of CHCl ₃ and 10 mL of MeOH, and stirred overnight. Thereafter, 1.13 g (30 mmol) of NaBH _{4 was} added little by little and stirred overnight. The solvent was removed by evaporation and acidified with 35% HCl to make it alkaline with 10N NaOH.
After extraction with 50 ml of CHCl _{3 and} washing 3 times with 50 ml of 1% Na ₂ CO ₃ , the organic layer was separated.
After dehydration with anhydrous MgSO ₄ , evaporation was performed, and the residue was dissolved in 20 ml of EtOH, stirred overnight, and 35% HCl was added and stirred to obtain the compound.
Yield: 1.49g
Yield: 46.1%
Elemental analysis: C ₁₇ H ₁₈ N ₂ · 2HCl (0H ₂ OM = 252 2HCl M '= 323)
calcd.C: 63.16% H: 6.19% N: 8.67%
obsd.C: 63.28% H: 6.16% N: 8.74%
NMR (D ₂ O, TSP standard)
δ1 (s): 8.662 δ2 (d): 8.271 δ3 (d): 8.154 δ4 (dd): 7.737 δ5 (dd): 7.635 C2 δ1 (s): 5.267 δ2 (dd): 3.136 δ3 (dd): 3.397

(5) Synthesis of AtC3 To a solution obtained by mixing 40 mL of CHCl ₃ and 10 mL of MeOH, 5 mL (59.9 mmol) of 1,3-diaminopropane and 2.06 g (10 mmol) of 9-anthracenecarboxaldehyde were added and stirred overnight. Thereafter, 1.13 g (30 mmol) of NaBH _{4 was} added little by little and stirred overnight. The solvent was evaporated by evaporation, and 35% HCl was added to make it acidic, and 10N NaOH was added to make it alkaline.
After extraction with 50 ml of CHCl _{3 and} washing 3 times with 50 ml of 1% Na ₂ CO ₃ , the organic layer was separated.
After dehydration with anhydrous MgSO ₄ , evaporation was performed, and the residue was dissolved in 20 ml of EtOH, stirred overnight, and 35% HCl was added and stirred to obtain the compound.
Yield: 1.81g
Yield: 53.7%
Elemental analysis: C ₁₈ H ₂ 0N ₂ · 2HCl (0H ₂ OM = 266 2HCl M '= 337)
calcd.C: 64.09% H: 6.52% N: 8.31%
obsd.C: 63.90% H: 6.89% N: 7.98%
NMR (D ₂ O, TSP standard)
δ1 (d): 8.630 δ2 (dd): 8.232 δ3 (dd): 8.140 δ4 (t): 7.732 δ5 (t): 7.634 C2 δ1 (s): 5.875 δ2 (t): 3.361 δ3 (t): 3.092 δ4 (m): 2.182, 2.102

_{(6) Pt} a (NH 3) 2 (AtC2) Synthesis of _{Cl 2 AtC2 · 2HCl 0.42g (1.3mmol} ) was dissolved in _H 2 O 10 ml, was added NaOH 0.20g (5mmol). AtC3 was extracted by adding 20 mL of CHCl ₃ , evaporated and dissolved in 10 mL of EtOH. To this was added a solution of 0.15 g (0.5 mmol) of Pt (NH ₃ ) ₂ Cl ₂ in 5 ml of H ₂ O, stirred at 60 ° C. for 24 hours, evaporated until the filtrate was 1 to ₂ ml, and re-reacted with acetone. A yellow powder was collected by suction filtration, washed and dried.
Yield: 0.212g
Yield: 71.3%
Elemental analysis: C ₁₇ H ₂₄ N ₄ PtCl ₂ .2.5H ₂ O (0H ₂ OM = 550.08 2.5H ₂ O M '= 595.08)
calcd.C: 34.28% H: 4.87% N: 9.41%
obsd.C: 34.05% H: 4.82% N: 9.64%
NMR (D ₂ O, TSP standard)
Anthracene ring δ1 (d): 8.740 δ2 (d): 8.206 δ3 (t): 7.801 δ4 (t): 7.667 C2 δ1 (d): 5.218 δ2 (m): 3.400, 3.325 δ3 (m): 3.173, 3.074 δ4 (m): 2.959.2.921

_{(7) Pt} a (NH 3) 2 (AtC3) Synthesis of _{Cl 2 AtC3 · 2HCl 0.44g (1.3mmol} ) was dissolved in _H 2 O 10 ml, was added NaOH 0.20g (5mmol). AtC3 was extracted by adding 20 mL of CHCl ₃ , evaporated and dissolved in 10 mL of EtOH. To this was added a solution of 0.15 g (0.5 mmol) of Pt (NH ₃ ) ₂ Cl ₂ in 5 ml of H ₂ O, stirred at 60 ° C. for 24 hours, evaporated until the filtrate was 1 to ₂ ml, and re-reacted with acetone. Precipitation occurred, the orange powder was collected by suction filtration, washed and dried.
Yield: 0.109g
Yield: 35.9%
Elemental analysis: C ₁₈ H ₂₆ N ₄ PtCl ₂ /3.5H ₂ O (0H ₂ OM = 564.08 3.5H ₂ O M '= 627.08)
calcd.C: 34.45% H: 5.26% N: 8.93%
obsd.C: 34.65% H: 5.37% N: 8.63%
NMR (D ₂ O, TSP standard)
Anthracene ring δ1 (d): 8.740 δ2 (d): 8.140 δ3 (m): 8.000,7.858 δ4 (s): 7.637 C3 δ1 (br): 5.12 δ2 (br): 4.52 δ3 (m): 3.51 δ4 (m ): 3.27 δ5 (m): 3.11 δ6 (m): 2.25 δ7 (m): 1.93

(8) Pt a (dach) (AtC2) Synthesis of _{Cl 2 AtC2 · 2HCl 0.42g (1.3mmol} ) was dissolved in _H 2 O 10 ml, was added NaOH 0.20g (5mmol). AtC2 was extracted by adding 20 mL of CHCl ₃ , evaporated and dissolved in 10 mL of EtOH. To this was added 5 ml H ₂ O solution of 0.15 g (0.5 mmol) of Pt (dach) Cl ₂ , stirred at 80 ° C. for 3 hours, evaporated until the filtrate became 1 to ₂ ml, and reprecipitated with acetone. The yellow powder was collected by suction filtration, washed and dried.
Yield: 0.570g
Yield: 86.4%
Elemental analysis: C ₂₃ H ₃₂ N ₄ PtCl ₂ · 2H ₂ O (0H ₂ OM = 630.08 2H ₂ O M '= 666.08)
calcd.C: 41.44% H: 5.41% N: 8.41%
obsd. C: 41.15% H: 5.55% N: 8.19%
NMR (D ₂ O, TSP standard)
Anthracene ring δ1 (br): 8.72 δ2 (br): 8.17 δ3 (br): 7.80 δ4 (br): 7.67 dach, C2 δ1 (br): 5.06 δ2 (m): 3.13 δ3 (m): 1.83 δ4 (m ): 1.71 δ5 (m): 1.34 δ6 (m): 0.87 δ7 (m): 0.55 δ8 (m): 0.11

(9) Pt a (dach) (AtC3) Synthesis of _{Cl 2 AtC3 · 2HCl 0.44g (1.3mmol} ) was dissolved in _H 2 O 10 ml, was added NaOH 0.20g (5mmol). AtC3 was extracted by adding 20 mL of CHCl ₃ , evaporated and dissolved in 10 mL of EtOH. To this was added 5 ml H ₂ O solution of 0.15 g (0.5 mmol) of Pt (dach) Cl ₂ , stirred at 80 ° C. for 3 hours, evaporated until the filtrate became 1 to ₂ ml, and reprecipitated with acetone. The orange powder was collected by suction filtration, washed and dried.
Yield: 0.329g
Yield: 45.3%
Elemental analysis: C ₂₄ H ₃₄ N ₄ PtCl ₂ .3.5H ₂ O (0H ₂ OM = 644.08 3.5H ₂ O M '= 707.08)
calcd.C: 40.74% H: 5.80% N: 7.92%
obsd.C: 40.36% H: 5.44% N: 7.86%
NMR (D ₂ O, TSP standard)
Anthracene ring δ1 (s): 8.66 δ2 (d): 8.153 δ3 (br): 7.84 δ4 (s): 7.669 dach, C3 δ1 (m): 2.24 δ2 (m): 1.90 δ3 (m): 1.76 δ4 (br ): 1.39 δ5 (br): 1.31 δ6 (m): 1.21 δ7 (m): 0.76

2. Stability Test Next, the stability of the synthesized polyamine-containing platinum (II) complex was examined.
First, in order to determine the concentration necessary for the experiment for confirming the stability in water, UV measurement was performed, and based on the result, a comparison experiment of the fluorescence intensity between the ligand and the complex was performed.
Furthermore, whether or not the complex is decomposed under strong acidic conditions in the stomach, which is the first barrier in oral administration, was examined by comparing ¹ H-NMR spectra.

(1) Measurement of fluorescence intensity The anthracene ring has the property of emitting fluorescence when irradiated with excitation light. However, since the anthracene ring in the Pt complex is deprived of excitation light energy by Pt, almost no fluorescence is detected. Based on this, the fluorescence intensity was compared between the complex and its ligands AtC2 and AtC3, and the stability of the complex was examined.

(Experiment)
AtC2 and AtC3 and a polyamine-containing platinum (II) complex are dissolved in water at a concentration of 1 μM, and after 24 hours, using a fluorescence spectrometer (FP-6500 JASCO), the excitation wavelength is 367 nm, which shows the maximum absorbance of both the ligand and the complex. Was fixed and the fluorescence spectrum was measured.
Comparison of fluorescence spectra between the complex and the ligand is shown in FIGS.

(result)
As shown in FIGS. 1 and 2, it was found that when the fluorescence intensity was compared between the ligand alone and the complex, the fluorescence of the complex was much weaker than that of the ligand and was hardly decomposed. Therefore, these complexes were considered stable in water.

(2) Stability comparison under acid conditions In the case of oral administration, the role as a prodrug is lost if it is easily degraded under strong acidity in the stomach. Expected to act as a prodrug with anticancer activity, the complex must be absorbed without being decomposed under acidic conditions similar to those in the stomach. Therefore, the spectrum of the ligand and the spectrum of the complex under strong acidity were compared to examine whether decomposition occurred.

(Experiment)
The 35% HCl and diluted with _{D 2} O, to prepare a 0.02M HCl / _{D 2} O, synthesized complex sample preparation after 24 hours of addition, result of ¹ H-NMR measured after 7 days. The results are shown in FIGS.

(result)
If the complex is decomposed, peaks of ligands such as AtC2 and AtC3 should be seen, but as shown in FIGS. It became clear that it was difficult to decompose under gastric acid conditions.

3. In Vitro Cell Growth Inhibition Evaluation by MTT Assay To compare the cytotoxicity of the synthesized Pt complex and the raw material, an MTT assay was performed using human colon adenocarcinoma LS180.

(Experiment)
-Production of medium 9.6 g of Eagle's minimum essential medium was added to 840 ml of MilliQ and stirred. Thereto, 100 ml of NaHCO ₃ and 100 ml of FBS were added and stirred, and MilliQ was added so that the total amount became 1000 ml. Then, it was sterilized and filtered into a medium bottle that had been autoclaved in a clean bench and used as a medium for the following culture experiment (hereinafter referred to as “MEM”).

-Cell culture and subculture LS180 cryopreserved in a sample container was rapidly dissolved at 37 ° C and transferred to a dish containing 20 ml of medium in a clean bench.
Two days later, the medium was removed, and after washing with 5 ml of PBS, 5 ml of a 0.5% -trypsin / 5.3 mM-EDTA solution diluted 5-fold was added and incubated at 37 ° C. for 10 minutes. After confirming that all the cells were detached, 5 ml of medium was added and subcultured. This passage experiment was performed three times.

-Preparation of drug | medical agent Each chemical | medical agent shown in Table 1 was made into 10 mM aqueous solution, and it diluted with MEM to 100 micromol. This was serially diluted and adjusted to 1000, 500, 100, 10, 1, 0.5, 0.25, 0.1, 0.05, 0.01 and 0.001 μM.

-MTT assay MEM was added to LS180 that had been cultured and the number of cells was counted so as to be 5.0 × 10 ³ cells / 100 μL, and 100 μL of each well was seeded in a 96-well and incubated at 37 ° C. overnight. The medium was sucked, washed once with PBS, each concentration of drug-containing medium was added (each concentration n = 3), and incubated for 24 hours. After sucking the medium and washing twice with PBS, 100 μL of medium containing 0.5 mg / mL MTT was added and incubated for 3 hours. The medium was sucked in, 100 μL of DMSO was added, and the absorbance at 570 nm was measured. The change in IC ₅₀ at 24 and 72 hours after drug exposure was compared. The results are shown in Table 1.

(result)
Pt (NH ₃ ) ₂ (AtC2) and Pt (dach) (AtC2) show almost no change in IC ₅₀ at 72 hours after exposure to 24 hours, whereas Pt (NH ₃ ) ₂ (AtC3), Pt (dach) ) (AtC3) decreased the IC ₅₀ at 72 hours compared to 24 hours after exposure. In particular, Pt (dach) (AtC3) was found to have an IC ₅₀ of about 1/100 and increased toxicity. From this result, Pt (NH ₃ ) ₂ (AtC3) and Pt (dach) (AtC3) are less toxic while they exist as complexes, and become more toxic as they enter the cell and are degraded. It became clear.

Pt (dach) (AtC3) had a higher IC ₅₀ compared to oxaliplatin, but considering the decrease in IC ₅₀ from 24 to 72 hours after exposure to Pt (dach) (AtC3), The possibility that it can be used as a drug was suggested.

4). Cell uptake experiment In order to compare the amount of Pt (dach) (AtC3) incorporated into cells with oxaliplatin, the following experiment was conducted.

(Experiment)
1.6 × 10 ⁶ cells were seeded in a sterile shallow petri dish (90φ × 15 mm) and incubated for 24 hours. It was exposed to Pt (dach) (AtC3) -containing medium (20 μM) and washed with PBS after 2 hours and 24 hours (n = 4). After aspirating PBS well, 1 mL of 60% nitric acid was added and heated at 60 ° C. for 24 hours to completely lyse the cells. Further, 5 mL of distilled water was added to obtain a sample solution, and the Pt concentration was quantified by ICP-AES, and the amount of Pt contained in the cells in the dish was calculated. The same experiment was performed using oxaliplatin-containing medium. The results are shown in FIG.

(result)
In the Pt (dach) (AtC3) -containing medium-exposed group, the Pt uptake amount was high after 2 hours and after 24 hours, compared with the oxaliplatin-exposed group. It was shown that the amount of uptake into cells was improved by binding the anthracene-polyamine structure.

5. Observation by fluorescence microscope In order to examine the behavior of the complex in the cells, cells exposed to the medium containing Pt (dach) (AtC3) were observed over time using an HS all-in-one fluorescence microscope (KEYENCE, BZ-9000). . In addition, in order to examine the intracellular localization after degradation of Pt (dach) (AtC3), nuclear staining of cells exposed to the drug was performed.

(1) Fluorescence microscope observation (experiment)
Human colon adenocarcinoma cells LS180 were plated on glass-based dishes and incubated overnight. After 24 hours of exposure to Pt (dach) (AtC3) -containing medium (10 μM), observation and imaging were performed with a fluorescence microscope. FIG. 12 shows an image taken at 20 times after 24 hours of exposure. The excitation light exposure image is shown on the left side, and the bright field image and the excitation light exposure image superimposed on the right side.

(result)
After 24 hours of exposure, the majority of cells fluoresced, suggesting that Pt (dach) (AtC3) degradation occurred in most cells.

(2) Fluorescence microscope observation after nuclear staining (experiment)
Nuclear staining was performed according to the following procedure.
After exposure to Pt (dach) (AtC3) -containing medium (10 μM) for 24 hours, it was confirmed that blue fluorescence was clearly seen with a fluorescence microscope. This was washed with PBS, exposed to RNase 16 μg / mL (/ MEM) for 30 minutes in a CO ₂ incubator, and then exposed to propidium iodide (PI) 15 μM (/ MEM) for 30 minutes in a refrigerator.
FIG. 13 shows an image obtained by imaging at a magnification of 100 times and superimposed with a bright field image and blue excitation light exposure image on the left side, and an image on which the bright field image and red excitation light exposure image are superimposed on the right side.

(result)
It was found that red fluorescence and blue fluorescence coexist in the nucleus. Since red fluorescence and blue fluorescence were confirmed at the same site in one cell, it was suggested that AtC3 produced after complex decomposition was present in the nucleus.

6). Distribution experiment In order to confirm the accumulation of Pt (dach) (AtC3) in organs and the accumulation in specific organs, distribution to each organ using ddY male mice (7 weeks old) Examined.

(Experiment)
・ Dose and administration method The experiment was conducted for each of intravenous administration and oral administration. For intravenous administration, Pt (dach) (AtC3) and oxaliplatin were dissolved in distilled water, administered at 8.25 μmol / kg from the tail vein, then killed and dissected after 2, 5, 24 and 48 hours to obtain each organ. . The distribution of Pt (dach) (AtC3) by intravenous administration is shown in FIG. 14, and the distribution of oxaliplatin is shown in FIG. For oral administration, Pt (dach) (AtC3) was dissolved in distilled water, administered at 165 μmol / kg, and killed and dissected after 3, 5, 24 and 48 hours to obtain each organ. The distribution of Pt (dach) (AtC3) by oral administration is shown in FIG.

-Preparation of measurement sample and measurement of Pt concentration 500 μL of 25% tetraammonium hydroxide (TMAH) was added to 100 mg of organ (60% HNO ₃ was added instead of TMAH to the bone), and overnight at 60 ° C. Heated to dissolve the organ. Next, 5 mL of 0.1M HNO ₃ containing Triton X-100 per 500 μL of the organ lysate was added to acidify the solution, and then filtered through a syringe filter (nylon: pore diameter 0.45 μm, diameter 32 mm). A calibration curve was created with a platinum solution of known concentration, and the platinum concentration of the prepared organ lysate was measured by ICP-AES.

(result)
As shown in FIG. 14, it was found that most of Pt (dach) (AtC3) gathered in the liver 2 hours after intravenous administration, and quickly moved to the liver after entering the blood. Pt (dach) (AtC3) is thought to undergo hepatic metabolism, whereas oxaliplatin is renal excretion. It disappeared with the passage of time, and there was almost no retention in the organ. It is considered that organ damage is low because of its low accumulation in organs.

  On the other hand, as shown in FIG. 15, oxaliplatin disappeared rapidly from the body within 2 hours after administration. Oxaliplatin has a blood half-life of 10 to 25 minutes, and is thought to disappear rapidly after distribution to organs. Comparison with FIG. 14 suggests that retention of Pt (dach) (AtC3) in the body was increased by AtC3.

  Furthermore, as shown in FIG. 16, it was confirmed that the complex was absorbed by oral administration. Three hours after administration, the Pt concentration in the stomach and small intestine is high, and the complex is considered to be in the absorption process. Since the Pt concentration in the digestive tract decreased and the blood concentration increased 5 hours after administration, it was suggested that the complex was slowly absorbed from the intestinal tract over 3 to 5 hours. Since the Pt concentration reached the peak in the kidney / liver, the absorbed complex quickly migrated to the kidney / liver, but it was suggested that it might be saturated in about 5 hours.

7). In vivo anticancer experiment using cancer-transplanted mice The in vivo anticancer activity effect of Pt (dach) (AtC3) was examined using BALB / c Slc.

(Experiment)
-Passage experiment of mouse colon cancer cell Colon26 Culture of Colon26 to produce tumor-bearing mice using mouse colon cancer cell Colon26 and to evaluate the anticancer activity of Pt (dach) (AtC3) in vivo The experiment was conducted. The operation procedure of the passage experiment is shown below.

The · CO ₂ incubator ready CO ₂ bomb incubator - connect to 5% was adjusted to 37 ° C.. A vat containing sterilized water was placed inside the incubator.

・ Preparation of clean bench The sterilization lamp of the clean bench was turned off, 70% ethanol was sprayed onto the hand, and the inside of the clean bench was wiped with a Kim wipe soaked with ethanol and sterilized.

-Production of medium A penicillin-streptomycin mixed solution was added to 500 mL RPMI-1640 so as to be penicillin 100 units / mL and streptomycin 100 mg / μL. In addition, 50 ml of FBS was added.

-Preparation of PBS 9.6 g of Dulbecco's phosphate-buffered physiological saline was added to 1000 ml of MilliQ, stirred, dissolved, and then sterilized by autoclaving at 121 ° C for 20 minutes.

-Cell culture and subculture Mouse colon cancer cell Colon26 which had been cryopreserved in a deep freezer was rapidly lysed at 37 ° C and transferred to a dish containing 20 ml of medium in a clean bench. One day later, the medium was removed, washed with 5 ml of PBS, 5 ml of a 5-fold diluted 0.5% -trypsin / 5.3 mM-EDTA solution was added, and the mixture was incubated at 37 ° C. for 5 minutes. After confirming that all the cells were detached, 5 ml of medium was added and subcultured. The same operation was performed for 3 days.

-Counting the number of cells A cell suspension stained with pan blue was placed on a counting plate and covered with a cover glass from above. The number of cells present in a total of eight counter parts of the counting plate was counted with an optical microscope, the average number of cells present in one place was calculated, and the number of cells in the cell suspension before dilution was calculated.

-Preparation and injection of cell suspension A cell suspension was prepared so that the number of cells was 1 × 10 ⁶ per 100 μl of medium. The adjusted cell suspension was injected subcutaneously in the vicinity of both shoulders of the mouse at 100 μl × 2 per mouse.

-Sample administration and measurement of tumor diameter The day when the tumor was injected into the mouse was defined as day 0, and Pt (dach) (AtC3) was added to 200 μmol / kg (1.41 mg) every 24 hours for 14 days in the treatment group (n = 5). /0.1 mL H ₂ O / 10 g). The control group was not treated with 0.1 mL H ₂ O / 10 g. The body weight and tumor diameter were measured on the 7th, 14th and 21st days. Tumor size was calculated as (length x width ² x 0.52) and indicated by relative evaluation. Each group had n = 5. The measured tumor size and body weight are shown in FIGS. 17 and 18, respectively.

(result)
As shown in FIG. 17, Pt (dach) (AtC3) suppressed tumor growth at a dose of 200 μmol / kg. Moreover, as shown in FIG. 18, weight loss was observed immediately after administration, which was thought to have caused a decrease in appetite. However, as the body weight recovered with the passage of days, the decrease in appetite was thought to have subsided gradually. During daily oral administration, no abnormal stools such as nausea and diarrhea were observed, and no abnormalities were observed in the appearance of the mice. it was thought.

Claims (7)

Following formula [1]

(Wherein M is Pt or Pd,
R ₁ and R ₂ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, or R ₁ and R ₂ together represent 5 or 6 cyclic saturated hydrocarbons are formed,
R _{3 to} R ₁₁ are each independently a hydrogen atom, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or a cyclohexane having 3 to 30 carbon atoms. Alkenyl group, C2-C30 alkynyl group, C7-C30 aralkyl group, C7-C30 aralkenyl group, C7-C30 aralkynyl group, C6-C30 aryl group, halogen atom Haloalkyl group having 1 to 30 carbon atoms, haloalkenyl group having 2 to 30 carbon atoms, haloalkynyl group having 2 to 30 carbon atoms, haloaryl group having 6 to 30 carbon atoms, alkoxy group having 1 to 30 carbon atoms, carbon number A 6-30 aryloxy group, a hydroxy group, an amino group, a C1-C30 alkylamino group, a C6-C30 arylamino group, a cyano group, or a nitro group. )
Or a salt thereof.   The metal complex or a salt thereof according to claim 1, wherein M is Pt. R < ₃ > -R < ₁₁ > is a hydrogen atom, The metal complex or its salt of Claim 1 or 2. Following formula [2]

Or a salt thereof. Following formula [3]

Or a salt thereof.   The anticancer agent which contains the metal complex of any one of Claims 1-5, or its salt as an active ingredient.   The anticancer agent according to claim 6, which is for oral administration.

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