HK1163658A - Auto magnetic metal salen complex compound - Google Patents

Description

Self-magnetic metal salen complex

Technical Field

The invention relates to a self-metal salen complex compound with self-magnetism.

Background

Generally, a drug reaches an affected part after administration to a living body, and exerts a pharmacological effect at a local position of the affected part to produce a therapeutic effect, but if the drug reaches a tissue other than the affected part (i.e., a normal tissue), the drug does not become a treatment.

Therefore, it is important how to effectively guide the drug to the affected part. A technique for guiding a drug to an affected part is called drug delivery, and is a field in which research and development have been actively performed in recent years. Such drug delivery has at least two advantages. One advantage is that a sufficiently high drug concentration is obtained in the affected tissue. If the concentration of the drug in the affected part does not exceed a certain value, no pharmacological effect is produced, and the desired therapeutic effect cannot be obtained at a low concentration.

The second advantage is that the drug is guided only to the affected tissue, and side effects on normal tissues can be suppressed.

The drug delivery plays an optimal role in cancer treatment using anticancer agents. Since most anticancer agents are agents that inhibit the cell proliferation of cancer cells that are actively dividing, the proliferation of cells in tissues that are actively dividing, such as bone marrow, hair roots, and digestive tract mucosa, is also inhibited in normal tissues.

Therefore, side effects such as anemia, alopecia, and vomiting occur in cancer patients who receive administration of anticancer agents. These side effects are a heavy burden on patients, and therefore, the dose must be limited, and there is a problem that the pharmacological effect of the anticancer agent cannot be sufficiently obtained.

Among these anti-malignant tumor drugs, an alkylating agent is an anti-malignant tumor drug having an alkyl group (-CH)₂-CH₂-) ability to bind to nucleic acid proteins and the like. DNA replication is hindered by alkylating the DNA, resulting in cell death. This effect works independently of the cell cycle, for G₀The cells in the stage and the actively proliferating cells have strong actions, and thus easily cause damage to bone marrow, digestive tract mucosa, germ cells, hairy roots, and the like.

In addition, antimetabolite antineoplastic agents are compounds having a structure similar to that of metabolites in nucleic acid and protein synthesis processes, and act specifically on cells in the division phase by damaging the cells by inhibiting nucleic acid synthesis and the like.

In addition, antitumor antibiotics are chemical substances produced by microorganisms, and have the effects of inhibiting DNA synthesis, cleaving DNA strands, and the like, thereby exhibiting antitumor activity.

In addition, microtubule inhibitors exhibit an antitumor effect by forming spindles during cell division or by directly acting on microtubules that play an important role in maintaining normal functions of cells such as disposition of intracellular small organs and substance transport. Microtubule inhibitors act on actively dividing cells, nerve cells, and the like.

In addition, platinum agents block DNA synthesis by forming DNA strands or interchain bonds or DNA protein bonds. Cisplatin is a representative drug, but is highly damaging to the kidney, requiring a large amount of fluid replacement.

In addition, hormone-analogous anti-malignant tumor drugs are effective against hormone-dependent tumors. For male hormone-dependent prostate cancer, a female hormone is administered or an anti-male hormone agent is administered.

In addition, molecular targeted drugs are therapeutic methods that target molecules corresponding to specific molecular biological characteristics in various malignant tumors.

In addition, topoisomerase inhibitors are enzymes that alter the number of chain loops of a DNA strand by temporarily introducing a nick into the DNA. Topoisomerase I is an enzyme that introduces a nick on one strand of circular DNA and closes the nick after passing the other strand; topoisomerase inhibitor II is an enzyme that temporarily cleaves 2 strands of circular DNA, passes additional 2 strands of DNA therebetween, and reconnects the nicks.

In addition, non-specific immunopotentiators inhibit the proliferation of cancer cells by activating the immune system.

Since most anticancer agents inhibit the cell proliferation of cancer cells whose cell division is active, the cell proliferation of tissues whose cell division is active, such as bone marrow or hair roots, digestive tract mucosa, and the like, is also inhibited in normal tissues. Therefore, side effects such as anemia, alopecia, and vomiting occur in cancer patients who have received administration of anticancer agents.

These side effects are a heavy burden on patients, and therefore, the dose must be limited, and there is a problem that the pharmacological effect of the anticancer agent cannot be sufficiently obtained. Furthermore, in the worst case, the patient may die due to side effects.

Therefore, it is expected that anticancer agents are guided to cancer cells by drug delivery, concentrated in cancer cells, and exert pharmacological effects, thereby effectively treating cancer while suppressing side effects. The same problem exists with local anesthetics. The local anesthetic is used for treating local itching or pain of mucosa and skin caused by hemorrhoid, oral inflammation, periodontal disease, dental caries, tooth extraction or operation. Lidocaine (trade name: picrocaine) is known as a representative local anesthetic, but lidocaine has an antiarrhythmic effect although it is excellent in quick-acting properties.

In addition, in spinal anesthesia, if lidocaine, which is an anesthetic, is injected into spinal fluid, the lidocaine spreads in the spinal fluid, and there is a fear that a serious side effect such as respiratory function stoppage may be caused by reaching the spinal cord of the neck in the worst case.

Therefore, it is expected that anticancer agents are guided to cancer cells by drug delivery, concentrated in cancer cells, and exert pharmacological effects, thereby effectively treating cancer while suppressing side effects.

In addition, it is expected that diffusion of local anesthetic is prevented by drug delivery, and that duration of drug efficacy and reduction of side effects are achieved.

As a specific method of drug delivery, for example, there is a method using a carrier (carrier). The method is to load the drug on a carrier which is easily concentrated on the affected part and to transport the drug to the affected part.

As the carrier, a magnetic material is considered to be promising, and a method of attaching a carrier as a magnetic material to a drug and focusing the carrier on an affected part by a magnetic field has been proposed (for example, see japanese patent application laid-open No. 2001-10978).

However, when a magnetic body carrier is used as the carrier, it is known that: oral administration is difficult, and generally, the carrier molecule has a large size, and there are technical problems in the binding strength and affinity between the carrier and the drug molecule, which makes practical use difficult.

Therefore, the present inventors propose: a local therapeutic agent in which a side chain for imparting a positive or negative spin charge density is bonded to the basic skeleton of an organic compound, and which has overall adaptability to a magnetically common induced range with respect to an external magnetic field, and when applied to a human body or an animal, is maintained within a range in which a magnetic field is locally applied by an external magnetic field, so that the drug effect originally retained within the above range is exhibited (WO 2008/001851). The same publication describes an iron salen (salen) complex as such a drug.

Patent document 1: japanese laid-open patent application No. 2001-10978

Patent document 2: WO2008/001851 publication

Disclosure of Invention

Problems to be solved by the invention

The present invention has been made in view of whether or not a metal salen other than iron has ferromagnetic properties, and further, whether or not a metal salen other than iron has a useful pharmacological action as in the case of an iron salen complex, and also provides a magnetic material which is obtained by chemically binding a desired drug to an iron salen complex and a metal salen complex other than iron, and which has magnetism in the molecular structure of one magnetic material compound in which a drug molecule and a metal salen complex including iron are chemically bound, whereby when the molecular structure is administered to an animal, the drug molecule is guided to a target affected part and locally exists in the affected part by suppressing a magnetic field, thereby exerting a therapeutic effect.

Means for solving the problems

The present invention has the following features to achieve the above object.

A self-magnetic metal salen complex represented by the following formula (I) or (II).

M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd, and each of a to f and Y is hydrogen (except the case where all of a to f and Y are hydrogen when M is Fe) or any of the following (A) to (G).

(A)-CO₂Me

(B)-CO(OCH₂CH₂)₂OCH₃

(C)

(R₂Formed by combining a plurality of nucleic acids containing adenine, guanine, thymine, cytosine or uracil)

(E)-NHCOH、-NH₂、NHR₁or-NR₁R₂(R₁R₂The same or an alkyl or alkane having 1 to 6 carbon atoms

(F)-NHR₃-、-NHCOR₃or-R₃(R₃Is a substituent combined after a sensitive group such as hydrogen or hydroxyl is separated)

(G) Halogen atoms, e.g. chlorine, bromine, fluorine

R₃Preferably, the charge moves less than 0.5 electrons (e).

In addition, R₃The compound is composed of any one of the following formulas (1) to (27).

(1): pekectofen and phenylpropionic acid series analgesic and anti-inflammatory agent

(2): mefenamic acid and anthranilic acid series antipyretic antiphlogistic analgesic

(3): therapeutic agent for hyperlipemia

(4): antibacterial agent

(5): fluorescent pigment (rhodamine)

(6): hormone (Estrogen)

(7): hormone (Estrogen)

(8): taxol (paclitaxel)

(9): amino acid (Glycine)

(10): amino acid (alanine)

(11): amino acid (arginine)

(12): amino acid (asparagine)

(13): amino acid (aspartic acid)

(14): amino acid (cysteine)

(15): amino acid (glutamic acid)

(16): amino acid (histidine)

(17): amino acid (isoleucine)

(18): amino acid (leucine)

(19): amino acid (lysine)

(20): amino acid (methionine)

(21): amino acid (phenylalanine)

(22): amino acid (proline)

(23): amino acid (serine)

(24): amino acid (threonine)

(25): amino acid (Tryptophan)

(26): amino acid (tyrosine)

(27): amino acid (valine)

In addition, the present invention is a local anesthetic having a self-magnetic metal salen complex, R₃Is any of the substituents of the following formulae (28) to (38) after dehydrogenation from a compound having a methyl group and a charge transfer of less than 0.5 electron (e),

(28) the common name is: lidocaine

(29) The common name is: aminobenzoic acid ethyl ester

(30) The common name is: oxybuprocaine hydrochloride

(31) The common name is: oxicaine

(32) The common name is: dibucaine

(33) The common name is: piperidinyl acetamidobenzoic acid ethyl ester

(34) The common name is: procaine

(35) The common name is: mepivacaine

(36) The common name is: hydrochloric acid p-butylaminobenzoic acid diethylaminoethyl ester

(37) The common name is: bupivacaine hydrochloride

(38) The common name is: ropivacaine hydrochloride

In addition, the invention provides an anti-malignant tumor drug with a self-magnetic metal salen complex, R₃The compound represented by any one of the following formulae (39) to (103) is bonded to the main skeleton of the compound represented by the above formula I or II via a bonding group moiety obtained by dehydrogenation (wherein, in the compound represented by formula (83), a cyano group (-CN) is a bonding group).

Formula 3

(39) The common name is: ifosfamide and alkylating agent series anti-malignant tumor medicine

Formula 4

(40) The common name is: cyclophosphamide and alkylating agent series antineoplastic medicine

Formula 5

(41) The common name is: dacarbazine and alkylating agent series anti-malignant tumor medicine

Formula 6

(42) The common name is: busulfan and alkylating agent series anti-malignant tumor medicine

Formula 7

(43) The common name is: melphalan and alkylating agent series anti-malignant tumor medicine

Formula 8

(44) The common name is: ramomustine and alkylating agent series anti-malignant tumor medicine

Formula 9

(45) The common name is: estramustine sodium phosphate and alkylating agent series anti-malignant tumor medicine

Formula 10

(46) The common name is: nimustine hydrochloride and alkylating agent series anti-malignant tumor medicine

Formula 11

(47) The common name is: enocitabine, antimetabolite antineoplastic agent

Formula 12

(48) The common name is: capecitabine, antimetabolite and anti-malignant tumor drug

Formula 13

(49) The common name is: carmofur, antimetabolite antineoplastic

Formula 14

(50) The common name is: gimeracil, antimetabolite and anti-malignant tumor medicine

Formula 15

(51) The common name is: potassium oxonate, antimetabolite antineoplastic agent

Formula 16

(52) The common name is: cytarabine, antimetabolite antineoplastic agent

Formula 17

(53) The common name is: cytarabine octadecyl phosphate, antimetabolite antineoplastic agent

Formula 18

(54) The common name is: furfurin, antimetabolite antineoplastic

Formula 19

(55) The common name is: doxifluridine, antimetabolite antineoplastic agent

Formula 20

(56) The common name is: hydroxyurea, antimetabolite, and anti-malignant tumor agent

Formula 21

(57) The common name is: fluorouracil, antimetabolite antineoplastic agent

Formula 22

(58) The common name is: mercaptopurine hydrate, antimetabolite antineoplastic agent

Formula 23

(59) The common name is: fludarabine phosphate, antimetabolite and anti-malignant tumor medicine

Formula 24

(60) The common name is: gemcitabine hydrochloride, antimetabolite antineoplastic

Formula 25

MeGly ═ N-methylglycine

MeVal ═ N-methylvaline

(61) The common name is: actinomycin D, antitumor antibiotic

Formula 26

(62) The common name is: aclacinomycin hydrochloride and antitumor antibiotic

Formula 27

(63) The common name is: idarubicin hydrochloride, antitumor antibiotic

Formula 28

(64) The common name is: epirubicin hydrochloride, antitumor antibiotic

Formula 29

R¹And R²Are different from each other and respectively represent

R’¹And R'²As well as the same thing as that of the above,

A¹h or NH₄，

A²、A³H or NH₄Or C₄H₉(A²、A³Do not simultaneously represent C₄H₉)，

m + n: on average, the average of the average is about 5.5,

(65) the common name is: net-stastatin and antitumor antibiotic

Formula 30

(66) The common name is: daunorubicin hydrochloride and antitumor antibiotic

Formula 31

(67) The common name is: adriamycin hydrochloride, antitumor antibiotic

Formula 32

Formula 33

(69) The common name is: peramicin sulfate, antitumor antibiotic

Formula 34

(70) The common name is: mitomycin C, antitumor antibiotic

Formula 35

(71) The common name is: amrubicin hydrochloride, antitumor antibiotic

Formula 36

(72) The common name is: doxycycline hydrochloride, antitumor antibiotic

Formula 37

(73) The common name is: pirarubicin hydrochloride, antitumor antibiotic

Formula 38

(74) The common name is: docetaxel hydrate, microtubule inhibitors

Formula 39

(75) The common name is: vincristine sulfate, microtubule inhibitor

Formula 40

(76) The common name is: vinca sulfate, microtubule inhibitor

Formula 41

(77) The common name is: vinorelbine tartrate, microtubule inhibitors

Formula 42

(78) The common name is: vinblastine sulfate, microtubule inhibitor

Formula 43

(79) The common name is: oxaliplatin and platinum preparation

Formula 44

(80) The common name is: carboplatin, platinum preparation

Formula 45

(81) The common name is: cisplatin and platinum preparation

Formula 46

(82) The common name is: nedaplatin and platinum preparation

Formula 47

(83) The common name is: anastrozole, hormone analog

Formula 48

(84) The common name is: fadrozole and hormone-like drugs

Formula 49

(85) The common name is: exemestane and hormone analogue medicine

Formula 50

(86) The common name is: tamoxifen citrate, hormone analogs

Formula 51

(87) The common name is: toremifene citrate, hormone analogs

Formula 52

(88) The common name is: bicalutamide, hormone analogs

Formula 53

(89) The common name is: flutamide and hormone analogs

Formula 54

(90) The common name is: cyclopenta epithioandrostane, hormone analogue

Formula 55

(91) The common name is: estramustine sodium phosphate and hormone analogue medicine

Formula 56

(92) The common name is: medroxyprogesterone acetate and hormone analogue medicine

Formula 57

(93) The common name is: tamibarotene (tamibarotene) molecular targeted therapeutic agent

Formula 58

(94) The common name is: gefitinib, molecular targeted therapeutic drug

Formula 59

(95) The common name is: retinoic acid, molecular targeted therapeutic agent

Formula 60

(96) The common name is: imatinib mesylate, and molecular targeted therapeutic agent

Formula 61

(97) The common name is: etoposide, topoisomerase inhibitors

Formula 62

(98) The common name is: sobuconazole, topoisomerase inhibitors

Formula 63

(99) The common name is: irinotecan hydrochloride, topoisomerase inhibitors

Formula 64

(100) The common name is: topotecan hydrochloride, topoisomerase inhibitors

Formula 65

(101) The common name is: ubenimex, non-specific immunopotentiator

Formula 66

(102) The common name is: schizophyllan, nonspecific immunity enhancer

Formula 67

(103) The common name is: lentinan, non-specific immunopotentiator

In addition, the invention is a self-magnetic metalAn anti-malignant tumor agent of salen complex, wherein R₃The compound is represented by any one of the following formulae (104) to (109).

(104) (trade name: lipperan, common name: leuprorelin acetate, anticancer agent)

(105) (trade name: maytansine, common name: methotrexate, anticancer agent)

(106) (trade name: Noxiaolin, common name: mitoxantrone hydrochloride, anticancer agent)

(107) (trade name: PHOTOFRIN, common name: porfimer sodium, anticancer agent)

(108) (trade name: PHOTOFRIN, common name: porfimer sodium, anticancer agent)

(109) (trade name: Myostat, common name: gemtuzumab ozogamicin, anticancer agent)

In addition, the present invention is a self-magnetism-imparting metal salen complex molecule in which at least one of the 1 to 8 positions of the following compound III is bonded to another compound to impart magnetism to the other compound.

M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

In addition, the present invention is a self-magnetism-imparting metal salen complex molecule, wherein at least one of the 1-8 positions and at least one of the 9-16 positions of the following compound IV are bonded to another compound to impart magnetism to the other compound.

M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

The present invention also provides an intermediate for producing a magnetic metal complex, which comprises the following compounds.

R₁And R₂Each is hydrogen, or one is hydrogen and the other is-COX (X is-OH or a halogen atom).

The present invention also provides a method for producing a magnetic body, wherein a drug molecule is bound to the 2-and/or 5-position of the following compound III via an amide group.

M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

The present invention also provides a method for producing a magnetic body, which comprises binding a drug molecule to the 5-and 10-positions, or the 2-and 13-positions, or the 2-, 5-, 10-, and 13-positions of the following compound IV via an amide group.

M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

The present invention also provides a method for producing a self-magnetic compound by mixing a drug component containing the drug molecular structure (X) with the self-magnetic compoundReact to produceFurther reacting ethylenediamine to produceFurther reacting a metal halide to obtain

The present invention also provides a method for producing a self-magnetic compound by reacting ethylenediamine with the compoundReact to formThen reacting a drug component containing the drug molecular structure (X) therewith, followed by reacting a metal halide therewith to obtain

In addition, a method for producing a self-magnetic compound by allowing a drug to have a molecular structure (X)React to produceAnd reacting ethylenediamine therewith to formAnd reacting the metal halide therewith to obtain

Effects of the invention

According to the present invention, it has been confirmed that a magnetic property exists in a metal salen other than iron, and further that a desired drug is chemically bound to the metal salen other than iron, and a magnetic substance having a magnetic property itself of one magnetic substance compound in which a drug molecule and an iron-containing metal salen complex are chemically bound is provided, and thus, when the molecular structure is administered to an animal, a magnetic field is controlled, and the drug molecule is guided to a target affected part and locally exists in the affected part, thereby providing a therapeutic effect.

Drawings

FIG. 1 shows the magnetic field-magnetization curve at 37 deg.C (310K) for Mn-salen complex.

FIG. 2 shows the magnetic field-magnetization curve at 37 deg.C (310K) for Cr-salen complex.

FIG. 3 shows the magnetic field-magnetization curve at 37 deg.C (310K) for Co-salen complex.

FIG. 4 shows the magnetic field-magnetization curves at 37 deg.C (310K) for iron-salen complex, manganese-salen complex, chromium-salen complex, and cobalt-salen complex.

FIG. 5 is a schematic side view showing a state in which a square flask containing a culture medium of rat L6 cells was brought into contact with a magnet bar.

FIG. 6 is a characteristic diagram showing the results of imaging from one end to the other end of the bottom surface of the square flask after 48 hours and calculating the number of cells.

Fig. 7 is a schematic perspective view of the magnetic induction device.

Fig. 8 is a graph showing the MRI measurement result (T1-emphasized signal) of the kidney of the mouse.

Fig. 9 is a photograph showing the effect of the salen complex on the growth of melanoma in mice.

Fig. 10 is a graph showing the effect of melanoma growth.

FIG. 11 shows the results of histological tests.

FIG. 12 is a graph showing the temperature rise when an alternating magnetic field is applied to a drug.

FIG. 13 is a graph showing peaks in NMR of Mn salen.

FIG. 14 is a diagram showing peaks in NMR of Cr salen.

Fig. 15 is a graph showing the NMR peak of iron salen.

FIG. 16 is a graph showing peaks of salen ligands.

Fig. 17 is a graph showing the measurement result of NMR of the compound in which paclitaxel (taxol) is bound to iron salen.

Fig. 18 shows the results of mass analysis of this compound.

Fig. 19 is a graph showing the results of NMR measurement of a compound obtained by binding a hyperlipemia agent (Gemfibrozil) to a dimer iron salen complex.

Fig. 20 shows the results of mass analysis of this compound.

Detailed Description

Next, embodiments of the present invention will be explained. The following embodiments are illustrative of the present invention, and the present invention is not limited to these embodiments. The present invention can be implemented in various ways without departing from the gist thereof.

The magnetic metal complex of the present invention has a pharmacological effect (e.g., anticancer effect) by itself or a property of chemically binding to other drugs to impart magnetism to the other drugs.

(example 1)

The metal salen complex of the present invention was produced as follows.

Step 1：

A mixture of 4-nitrophenol (25g, 0.18mol), hexamethylenetetramine (25g, 0.18mol) and polyphosphoric acid (200ml) was stirred at 100 deg.CFor 1 hour. The mixture is then poured into 500ml of ethyl acetate and 1L of water and stirred until complete dissolution. Adding 400ml of ethyl acetate into the solution until the solution separates into 2 phases, removing the water phase, washing the residual compound with alkaline solvent for 2 times, and adding anhydrous MgSO₄Drying was carried out, and 17g (yield: 57%) of Compound 2 was finally synthesized.

Step 2：

Compound 2(17g, 0.10mol), acetic anhydride (200ml), H₂SO₄(small amount) stirred at room temperature for 1 hour. The resulting solution was mixed with ice water (2L) for 0.5 hour to hydrolyze. The obtained solution was passed through a filter and dried in the air to obtain a white powdery substance. After recrystallization of the powder from a solution containing ethyl acetate, 24g of compound 3 (yield 76%) was obtained as white crystals.

Step 3：

A mixture of carbon (2.4g) supporting 10% palladium was reduced in compound 3(24g, 77mmol) and methanol (500ml) overnight under a hydrogen reducing atmosphere of 1.5 atm. After completion, compound 4(21g) was finally synthesized as a brown oil by filtration using a filter.

Step 4，5：

Compound 4(21g, 75mmol), di-tert-butyl dicarbonate (18g, 82mmol) was added to anhydrous Dichloromethane (DCM) (200ml) and stirred overnight under a nitrogen atmosphere. The resulting solution was evaporated in vacuo and dissolved in methanol (100 ml). Thereafter, sodium hydroxide (15g, 374mmol) and water (50ml) were added and refluxed for 5 hours.

After cooling, the mixture was filtered through a filter, washed with water, and dried in vacuo to obtain a brown compound. The obtained compound was subjected to flash chromatography using silica gel 2 times to obtain 10g of compound 6 (yield 58%).

Step 6：

Compound 6(10g, 42mmol) was added to 400ml of absolute ethanol, heated and refluxed, and several drops of ethylenediamine (1.3g, 21mmol) were added to 20ml of absolute ethanol and stirred for 0.5 hour. Then, the mixed solution was added to an ice container to be cooled and stirred for 15 minutes.

Thereafter, the reaction mixture was washed with 200ml of ethanol, passed through a filter, and dried under vacuum, whereby 8.5g of Compound 7 (yield: 82%) was finally synthesized.

Step 7：

Compound 7(8.2g, 16mmol), triethylamine (22ml, 160mmol) and in the case of Fe salen in 10ml methanol were added to N, N-Dimethylformamide (DMF) (50ml), FeCl was added₃(·4H₂O) (2.7g, 16mmol) and Mn salen were added with MnCl₃·4H₂Adding CrCl in the case of O (2.7g, 16mmol) and Cr salen₃·4H₂O (2.7g, 16mmol) and mixed under a nitrogen atmosphereThe resulting solutions were combined.

The mixture was mixed at 40 ℃ for 30 minutes under nitrogen at room temperature to give a brown compound. Thereafter, drying was performed in vacuo. The resulting compound was diluted with 400ml of dichloromethane, washed 2 times with an alkaline solution, and Na₂SO₄Drying is carried out, and the metal salen complex can be obtained after drying in vacuum.

The obtained compound was recrystallized from a solution of diethyl ether and paraffin, and the purity of the resulting product was measured by high performance liquid chromatography to obtain a Mn salen complex (5.7g, yield 62%), a Cr salen complex (5.0g, yield 54%), and an iron salen complex (5.7g, yield 62%) with a purity of 95% or more. On the other hand, compound 7(8.2g, 16mmol), triethylamine (22ml, 160mmol) were added to anhydrous methanol (50ml), and FeCl was added in the case of Fe salen in 10ml of methanol₃(·4H₂O) (2.7g, 16mmol), Mn salen with MnCl₃·4H₂Adding CrCl in the case of O (2.7g, 16mmol) and Cr salen₃·4H₂O (2.7g, 16mmol), and the resulting solution was mixed under a nitrogen atmosphere.

The mixture was mixed at room temperature under nitrogen for 1 hour to give a brown compound. Thereafter, drying was performed in vacuo. The resulting compound was diluted with 400ml of dichloromethane, washed 2 times with an alkaline solution, and washed with Na₂SO₄Drying is carried out, and the dimer metal salen complex can be obtained after drying in vacuum.

The obtained compound was recrystallized from a solution of diethyl ether and paraffin, and a dimer metal salen complex having a purity of 95% or more was obtained by measuring the compound by high performance liquid chromatography. Measurement by mass analysis, results: mn salen is M/z (ESI-MS) M +322.4(error +1.17mu) C₁₆H₁₄MnN₂O₂requires M/z 321.23, Cr salen M/z (ESI-MS) M +318.4(error +0.11mu) C₁₆H₁₄CrN₂O₂requires m/z 318.29. However, Co salen complex was chemically purchased from tokyo (TCI commercial code:s0318, CAS number: 14167-18-1).

(example 2)

The Mn-salen complex was measured for a 37 deg.C (310K) magnetic field-magnetization curve using MPMS 7 from Quantum Design, Inc., and the result was paramagnetic. The results are shown in FIG. 1.

(example 3)

The 37 deg.C (310K) magnetic field-magnetization curve of Cr-salen complex was measured using MPMS 7 from Quantum Design corporation, and the result was paramagnetic. The results are shown in FIG. 2.

(example 4)

The Co-salen complex was measured for a 37 ℃ (310K) magnetic field-magnetization curve using a quantity Design company MPMS 7, and the result was paramagnetic. The results are shown in FIG. 3.

(example 5)

The results of the magnetic field-magnetization curves at 37 ℃ (310K) for iron salen complex, manganese salen complex, chromium salen complex, and cobalt salen complex are shown in FIG. 4.

Co-salen magnetizes more at magnetic fields above 100000e (1T (Tesla)) than Fe-salen. Mn-salen magnetizes more at a magnetic field of 300000e (3T (Tesla)) or more than Fe-salen.

Therefore, Fe-salen has the largest magnetization at a magnetic field of 100000e (1T (tesla)) or less, and is suitable for a magnetic field-induced drug delivery system using a neodymium permanent magnet or the like. In addition, the magnetization of Co-salen and Mn-salen complexes is maximized at a magnetic field of 100000e (1T (Tesla)), and is most suitable for a magnetic field-induced drug delivery system using a superconducting magnet.

(example 6)

When rat L6 cells were in a 30% confluent state, powders of metal salen complexes were scattered on the medium in such amounts that the iron salen complex, manganese salen complex, chromium salen complex, and cobalt salen complex obtained by the above-described methods were visually attracted to a magnet, and the state of the medium was photographed after 48 hours.

FIG. 5 shows a state in which rat L6 cells were placed in a square flask in a medium with the cells in contact with a magnet bar. Then, 48 hours later, the number of cells was counted by taking an image from one end of the bottom surface of the square flask to the other end, and the results are shown in FIG. 6.

In fig. 6, the position close to the magnet indicates the projected area of the magnet end face on the bottom surface of the square flask, and the position far from the magnet indicates the range on the opposite side of the magnet end face on the bottom surface of the square flask. As shown in fig. 6, the Mn salen complex is attracted to the magnet at a position close to the magnet, the concentration of the iron complex increases, and the number of cells is extremely low compared to the far position due to the NDA inhibitory effect of the iron complex. The result is: according to the present invention, a system including a magnetic drug and a magnetic force generating device can concentrate and store the drug in a target affected part and tissue of an individual.

Next, an example of induction using the induction device will be described. In the case of this induction device, as shown in fig. 7, a pair of magnets 230, 232 opposed to each other in the gravity direction are supported by a frame plate 234 and a clamp 235 with a metal plate 236 interposed therebetween. By providing a metal plate, particularly an iron plate, between the pair of magnets, a magnetic field of the same strength can be locally realized. The induction device may use electromagnets instead of magnets to variably generate magnetism. In addition, the pair of magnetic force generating devices can be moved in XYZ directions, so that the magnetic force generating devices can be moved to a target position of the solid on the table.

By placing solid tissue within this magnetic field range, the drug can be concentrated in the tissue. After intravenous injection of the metal complex (drug concentration 5mg/ml (15mM)) into a mouse weighing about 30 g, laparotomy was performed, and the mouse was placed on an iron plate so that the right kidney was positioned between the pair of magnets.

The magnet used was a magnet manufactured by shin-Etsu chemical industries, Inc., trade number: n50 (neodymium permanent magnet), residual flux density: 1.39-1.44T. At this point, the magnetic field applied to the right kidney is about 0.3(T), while the magnetic field applied to the left kidney is about 1/10.

The magnetic field was applied to the right kidney of the mouse, and the SNR was measured by MRI in T1 mode and T2 mode 10 minutes later together with the left kidney and the kidney without the magnetic field (control).

As a result, as shown in fig. 8, it was confirmed that: the drug may be retained in the tissue in the right kidney (RT) with the magnetic field applied compared to the left kidney (LT) and control.

FIG. 9 shows the effect of salen complex on melanoma growth in mice. Melanoma is developed in vivo in the mouse tail tendon by local transplantation of cultured melanoma cells (clonally propagated M3 melanoma cells).

Salen complex was administered intravenously (50mg/kg) from the vein of the caudal tendon, and a magnetic field was applied locally using a commercially available magnetic rod (630mT, cylindrical neodymium magnet, 150mm in length, 20mm in diameter). The magnetic rod was used by stable contact at the melanoma site for 3 hours immediately 10-14 days after injection of the salen complex.

The magnetic rod was used during the growth period of 2 weeks for rat tail tendons of 150mm or less to maximize the intensity of the magnetic field at the site where melanoma is expected to grow. The growth of melanoma was assessed 12 days after the first injection of salen complex by assessing the sites stained by melanoma.

As shown in fig. 10, the melanoma growth was maximal (100 ± 17.2%) in the saline group (saline) injected with saline instead of salen complex.

On the other hand, in the SC group injected with salen complex without using a magnetic field, the melanoma growth decreased slowly (63.68 ± 16.3%). On the other hand, in the SC + Mag group into which salen complex was injected while using a magnetic field (n ═ 7 to 10), almost all melanomas disappeared (9.05 ± 3.42%).

As shown in fig. 11, histological tests were performed by hematoxylin-eosin staining and immunohistological staining using anti-Ki-67 antibody and anti-Cyclin D1 antibody as tumor proliferation markers at tissue sites. As a result, it was found that the tumor growth of melanoma was reduced in the case of injection of the Salen Complex (SC), and almost all of the melanoma disappeared in the case of combined use of a magnetic field with the salen complex.

Further, after an alternating magnetic field having a magnetic field intensity of 200Oe (oersted) and a frequency of 50kHz to 200kHz was applied to the drug, the temperature of the drug was increased from 2 ℃ to 10 ℃ (fig. 12). The results were equivalent to from 39 ℃ to 47 ℃ in terms of the temperature at the time of in vivo administration, and were confirmed to be in a temperature range capable of killing cancer cells.

(example 7)

FIG. 13 shows an NMR peak of Mn salen, FIG. 14 shows an NMR peak of Cr salen, FIG. 15 shows an NMR peak of iron salen, and FIG. 16 shows a peak of salen ligand. Since Mn salen, Cr salen, and iron salen are magnetic bodies, a signal of nuclear spin detected by NMR resonates with a signal of electron spin appearing due to the magnetic bodies, and peaks become wide.

For example, it can be confirmed that: mn salen as a magnetic material had peaks at 3.442ppm, 3.039ppm and 2.405ppm, Cr salen at 2.716ppm and 3.149ppm, and Fe salen at 2.502ppm and 3.347ppm, respectively, of 2ppm or more. On the other hand, no peak having a width of 2ppm or more was present in the salen conjugate of a nonmagnetic material.

(example 8)

(1) Synthesis of iron salen + paclitaxel (Taxol)

The synthesis is outlined below.

Step 1

Mixing compound 1, acetic anhydride (acetic anhydride), and H₂SO₄Mix at room temperature for 1 hour. The reaction in the mixture was confirmed by Thin Layer Chromatography (TLC). In detail, compound 2 was obtained after recrystallization from ethyl acetate (EtOAc)/phosphatidylethanolamine (P.E.). The molecular weight was determined by mass analysis and confirmed to be compound 2.

Step 2

Compound 2 and carbon containing 10% palladium were added to methanol (MeOH), and hydrogenation treatment was performed for 2 hours in a hydrogen atmosphere. The obtained compound was filtered to obtain compound 3. The molecular weight was determined by mass analysis and confirmed to be compound 3.

Step 3，4

Compound 3 and di-tert-butyl dicarbonate (di (tert-butyl) dicarbanate) were dissolved in Dichloromethane (DCM) and stirred overnight. After the solvent was vaporized and reacted in vacuo, the adhering oil was reduced with methanol, an aqueous NaOH solution was added, and the resulting solution was refluxed for 5 hours. After confirmation in detail, the starting material was purified by flash chromatography using silica gel to obtain compound 5.

Step 5

A solution of compound 5 was prepared in EtOH, refluxed, added with several drops of ethylenediamine (ethylenediamine), and placed in a hot water bath. After addition of ethylenediamine, the mixture was refluxed for 0.5 hour and mixed. After filtration, Compound 6 was obtained as a pale yellow needle-like ligand having Shiff group.

Step 6

To make a solution of compound 6 with Dichloromethane (DCM), a solution of hydrochloric acid in ether was added. The solution was stirred at room temperature for 5 hours, filtered using DCM and ether and washed to give compound 7. By passing¹HNMR confirmed compound 7.

Step 7

4-Nitrophenyl chloroformate dissolved in DCM was added in a few drops to Paclitaxel (Paclitaxel) dissolved in DCM. The solution was stirred at-50 ℃ for 3 hours. After the reaction, the solvent was evaporated. The obtained solid material was purified by flash chromatography using silica gel, and compound C was obtained at a yield of 68%. This compound was confirmed by mass analysis.

Step 8，9

Adding Compound 8 and K to DMF (N, N-dimethylformamide: N, N-dimethylformamide)₂CO₃Compound 7 was added to the solution of (1). The mixed solution was stirred at-20 ℃ for 3 hours, and then the reacted solution was filtered and concentrated. The resulting raw material was dissolved in methanol and FeCl was added₃。FeCl₃After the addition, the resulting mixed solution was stirred for another 30 minutes.

The resulting solvent was evaporated in vacuo to give a solid starting material. The obtained solid material was recrystallized from a mixed solution of methanol and diethyl ether to obtain a brown solid material. The compound of interest was confirmed as a result of measurement by mass analysis. Fig. 17 shows the results of NMR measurement. The mass analysis results are shown in fig. 18.

(example 9)

Synthesis of Compound comprising a dimer iron-salen Complex and a hyperlipemia agent (Gemfibrozil)

Steps 1 to 4 in the synthesis procedure were the same as in example 8, followed by the reaction of Step 6 described below.

Step 6

Compound 110-5 was dissolved in ethanol (EtOH), heated and refluxed, and several drops of a solution of ethylenediamine were added to the reflux. After the addition, the mixture was refluxed for a further 0.5 hours and stirred. Then, the precipitate was filtered through a filter and collected to obtain a pale yellow compound 110-6 as a Schiff (Shiff) -based ligand, which was formed into an acicular crystal.

Step 7

FeCl dissolved in Triethylamine (TEA) was added to the product (110-6) dissolved in methanol₃. After the addition, the resulting mixture was further stirred for 30 minutes. The solvent was evaporated in vacuo to give the product. The product thus obtained was recrystallized from methanol and diethyl ether to obtain 1g of the objective compound in a brown color. The molecular weight was 1649 by mass analysis (LC-MS), confirming that it is the target compound. Fig. 19 shows the results.

(example 10)

Synthesis of a Compound comprising an iron salen Complex and a hyperlipemia agent (Gemfibrozil) bonded thereto.

Steps 1 to 6 were the same as in example 8, followed by Step 8 described below.

Step 8

FeCl was added to the product (110-6)₂·4H₂And O. After the addition, the resulting mixture was further stirred for 30 minutes. The solvent was evaporated in vacuo to give the desired product. The product thus obtained was recrystallized from methanol and diethyl ether to obtain 1g of the objective compound in a brown color. The molecular weight was 816 by mass analysis (LC-MS), confirming that the compound was the target compound. The results are shown in FIG. 20.

(example 10)

The pharmaceutical effect of the compound having taxol bonded to iron salen

When rat L6 cells were in a 30% confluent state, the compound having taxol bound to iron salen of chemical formula (I) was sprinkled on the medium in such an amount that it could be visually observed to attract to 4.7 tesla (T) superconducting magnet (compact solenoid magnet) manufactured by the nauclear process, and the state of the medium was photographed after 48 hours.

The state in which the magnet was brought into contact with a square flask containing a culture medium of rat L6 cells is shown. Then, 48 hours later, an image was taken from one end of the bottom surface of the square flask to the other end, and the number of cells was calculated. It is found that a compound having taxol bonded to iron salen at a position close to the magnet is attracted, the concentration of the compound is increased, and the number of cells is extremely low compared to the number at a position far away from the magnet due to the DNA inhibitory action. The result is: according to the present invention, a system including a magnetic drug and a magnetic force generating device can concentrate and store the drug in a target affected part and tissue of an individual.

(example 11)

Pharmaceutical efficacy of a compound obtained by binding a hyperlipemia (Gemfibrozil) to iron salen

Gemfibrozil (Gemfibrozil, a therapeutic agent for hyperlipoproteinemia which lowers the level of triglycerides in the blood, a drug for lowering cholesterol in the blood)

When rat L6 cells were in a 30% confluent state, a compound of formula (I) in which a hyperlipemia agent (Gemfibrozil) was bound to iron salen was sprinkled on the culture medium in such an amount that the attraction thereof to a 4.7 tesla (T) superconducting magnet (dense solenoid magnet) manufactured by the nauclea process could be visually observed, and the state of the culture medium was photographed after 48 hours.

The state in which the magnet was brought into contact with a square flask containing a culture medium of rat L6 cells is shown. Then, 48 hours later, an image was taken from one end of the bottom surface of the square flask to the other end, and the number of cells was calculated. It was found that a compound obtained by binding a hyperlipemia (Gemfibrozil) to iron salen was attracted to a position close to the magnet, the concentration of the compound was increased, and the number of cells was extremely low compared to the number at the far position due to the DNA inhibitory effect.

The result is: according to the present invention, a system including a magnetic drug and a magnetic force generating device can concentrate and store the drug in a target affected part and tissue of an individual.

(example 12)

Medicinal effect of compound obtained by binding hyperlipemia (Gemfibrozil) to dimer iron salen

Gemfibrozil (Gemfibrozil, a therapeutic agent for hyperlipoproteinemia which lowers the level of triglycerides in the blood, a drug for lowering cholesterol in the blood)

When rat L6 cells were in a 30% confluent state, a compound obtained by binding a hyperlipemia agent (Gemfibrozil) to dimer iron salen of chemical formula (I) was sprinkled on the medium in such an amount that the attraction thereof to 4.7 tesla (T) superconducting magnet (dense solenoid magnet) manufactured by the nauclea process could be visually observed, and the state of the medium was photographed after 48 hours.

The state in which the magnet was brought into contact with a square flask containing a culture medium of rat L6 cells is shown. Then, 48 hours later, an image was taken from one end of the bottom surface of the square flask to the other end, and the number of cells was calculated. It is found that a compound in which a hyperlipemia agent (Gemfibrozil) is bound to dimer iron salen at a position close to the magnet is attracted, the concentration of the compound is increased, and the number of cells is extremely low as compared with the number at a far position due to the DNA inhibitory action. The result is: according to the present invention, a system including a magnetic drug and a magnetic force generating device can concentrate and store the drug in a target affected part and tissue of an individual.

(example 13)

The electron transfer of the compound bound to the metal salen complex can be calculated according to the first principle.

The system for performing the computer simulation is a system having known hardware resources as a computer, that is, a system including: a memory, an arithmetic device having an arithmetic circuit such as a CPU, and a display device for outputting an arithmetic result.

The memory is provided with: data defining existing organic compounds or 3-dimensional structures, and software and programs for performing computer simulations.

This software can add, modify, and delete side chains of each compound, crosslink between predetermined side chains, calculate the range in which the spin charge density is high, and determine the spin charge density of the entire structure. As this program, for example, commercially available products (Dmo13, Accelrys Co., Ltd.) can be used.

In the compound, the user selects and inputs a position to add a side chain, a change of a side chain, or a deletion, and further specifies a site to be crosslinked to the arithmetic unit by using a support program of the memory. The arithmetic device receives the input value, calculates the spin charge density, and outputs the result to the display screen. In addition, the user can obtain the spin charge density for a known compound by adding structural data of the existing compound to the computer system.

If the obtained upward and downward spin charge densities are integrated in a three-dimensional space, the charge transfer of a substance in which another compound is bonded to the metal salen complex can be obtained. The results of calculation of the charge transfer on e, b of formula (I), e, b, k, h of formula II, or e, h are shown in the tables below. A negative number indicates an increase in electrons. A positive number indicates a decrease in electrons.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

Watch 10

Claims (17)

1. A self-magnetic metal salen complex represented by the following formula (I) or (II),

wherein M is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd, a to f and Y are each hydrogen or any of the following (A) to (G), and when M is Fe, a to f and Y are not all hydrogen,

(A)-CO₂Me，

(B)-CO(OCH₂CH₂)₂OCH₃，

(C)

R₂is formed by combining a plurality of nucleic acids containing adenine, guanine, thymine, cytosine or uracil,

(E)-NHCOH、-NH₂、-NHR₁or-NR₁R₂Wherein R is₁R₂The same or an alkyl or alkane having 1 to 6 carbon atoms,

(F)-NHR₃-、-NHCOR₃or-R₃Wherein R is₃Is a substituent combined after sensitive groups such as hydrogen or hydroxyl are separated,

(G) halogen atoms such as chlorine, bromine and fluorine.

2. The self-magnetic metal salen complex of claim 1, R₃Less than 0.5 electrons (e).

3. The self-magnetic metal salen complex of claim 1 or 2, R₃Comprising a compound represented by any one of the following formulae (1) to (27),

(1): pekectofen and phenylpropionic acid series analgesic and anti-inflammatory agent

(2): mefenamic acid and anthranilic acid series antipyretic antiphlogistic analgesic

(3): therapeutic agent for hyperlipemia

(4): antibacterial agent

(5): fluorescent pigment (rhodamine)

(6): hormone (Estrogen)

(7): hormone (Estrogen)

(8): taxol (paclitaxel)

(9): amino acid (Glycine)

(10): amino acid (alanine)

(11): amino acid (arginine)

(12): amino acid (asparagine)

(13): amino acid (aspartic acid)

(14): amino acid (cysteine)

(15): amino acid (glutamic acid)

(16): amino acid (histidine)

(17): amino acid (isoleucine)

(18): amino acid (leucine)

(19): amino acid (lysine)

(20): amino acid (methionine)

(21): amino acid (phenylalanine)

(22): amino acid (proline)

(23): amino acid (serine)

(24): amino acid (threonine)

(25): amino acid (Tryptophan)

(26): amino acid (tyrosine)

(27): amino acid (valine).

4. A local anesthetic having the self-magnetic metal salen complex of claim 1 or 2, consisting of R₃Is composed of a compound having a methyl group and having any one of substituents represented by the following formulae (28) to (38) after dehydrogenation of a compound having a charge transfer of less than 0.5 electron (e),

(28) the common name is: lidocaine

(29) The common name is: aminobenzoic acid ethyl ester

(30) The common name is: oxybuprocaine hydrochloride

(31) The common name is: oxicaine

(32) The common name is: dibucaine

(33) The common name is: piperidinyl acetamidobenzoic acid ethyl ester

(34) The common name is: procaine

(35) The common name is: mepivacaine

(36) The common name is: hydrochloric acid p-butylaminobenzoic acid diethylaminoethyl ester

(37) The common name is: bupivacaine hydrochloride

(38) The common name is: ropivacaine hydrochloride hydrate.

5. A kind ofAn anti-malignant drug having the self-magnetic metal salen complex compound of claim 1 or 2, R₃A compound represented by any one of the following formulae (39) to (103), wherein a bonding group moiety obtained by dehydrogenation is bonded to the main skeleton of the compound represented by the above formula I or II, wherein in the compound represented by formula (83), a cyano group (-CN) is a bonding group,

(39) the common name is: ifosfamide and alkylating agent series anti-malignant tumor medicine

(40) The common name is: cyclophosphamide and alkylating agent series antineoplastic medicine

(41) The common name is: dacarbazine and alkylating agent series anti-malignant tumor medicine

(42) The common name is: busulfan and alkylating agent series anti-malignant tumor medicine

(43) The common name is: melphalan and alkylating agent series anti-malignant tumor medicine

(44) The common name is: ramomustine and alkylating agent series anti-malignant tumor medicine

(45) The common name is: estramustine sodium phosphate and alkylating agent series anti-malignant tumor medicine

(46) The common name is: nimustine hydrochloride and alkylating agent series anti-malignant tumor medicine

(47) The common name is: enocitabine, antimetabolite antineoplastic agent

(48) The common name is: capecitabine, antimetabolite and anti-malignant tumor drug

(49) The common name is: carmofur, antimetabolite antineoplastic

(50) The common name is: gimeracil, antimetabolite and anti-malignant tumor medicine

(51) The common name is: potassium oxonate, antimetabolite antineoplastic agent

(52) The common name is: cytarabine, antimetabolite antineoplastic agent

(53) The common name is: cytarabine octadecyl phosphate, antimetabolite antineoplastic agent

(54) The common name is: furfurin, antimetabolite antineoplastic

(55) The common name is: doxifluridine, antimetabolite antineoplastic agent

(56) The common name is: hydroxyurea, antimetabolite, and anti-malignant tumor agent

(57) The common name is: fluorouracil, antimetabolite antineoplastic agent

(58) The common name is: mercaptopurine hydrate, antimetabolite antineoplastic agent

(59) The common name is: fludarabine phosphate, antimetabolite and anti-malignant tumor medicine

(60) The common name is: gemcitabine hydrochloride, antimetabolite antineoplastic

MeGly ═ N-methylglycine

MeVal ═ N-methylvaline

(61) The common name is: actinomycin D, antitumor antibiotic

(62) The common name is: aclacinomycin hydrochloride and antitumor antibiotic

(63) The common name is: idarubicin hydrochloride, antitumor antibiotic

(64) The common name is: epirubicin hydrochloride, antitumor antibiotic

R¹And R²Are different from each other and respectively represent

R’¹And R'²As well as the same thing as that of the above,

A¹h or NH₄，

A²、A³H or NH₄Or C₄H₉，A²、A³Do not simultaneously represent C₄H₉，

m + n: on average, the average of the average is about 5.5,

(65) the common name is: net-stastatin and antitumor antibiotic

(66) The common name is: daunorubicin hydrochloride and antitumor antibiotic

(67) The common name is: adriamycin hydrochloride, antitumor antibiotic

(68) The common name is: bleomycin hydrochloride and antitumor antibiotic

(69) The common name is: peramicin sulfate, antitumor antibiotic

(70) The common name is: mitomycin C, antitumor antibiotic

(71) The common name is: amrubicin hydrochloride, antitumor antibiotic

(72) The common name is: doxycycline hydrochloride, antitumor antibiotic

(73) The common name is: pirarubicin hydrochloride, antitumor antibiotic

(74) The common name is: docetaxel hydrate, microtubule inhibitors

(75) The common name is: vincristine sulfate, microtubule inhibitor

(76) The common name is: vinca sulfate, microtubule inhibitor

(77) The common name is: vinorelbine tartrate, microtubule inhibitors

(78) The common name is: vinblastine sulfate, microtubule inhibitor

(79) The common name is: oxaliplatin and platinum preparation

(80) The common name is: carboplatin, platinum preparation

(81) The common name is: cisplatin and platinum preparation

(82) The common name is: nedaplatin and platinum preparation

(83) The common name is: anastrozole, hormone analog

(84) The common name is: fadrozole and hormone-like drugs

(85) The common name is: exemestane and hormone analogue medicine

(86) The common name is: tamoxifen citrate, hormone analogs

(87) The common name is: toremifene citrate, hormone analogs

(88) The common name is: bicalutamide, hormone analogs

(89) The common name is: flutamide and hormone analogs

(90) The common name is: cyclopenta epithioandrostane, hormone analogue

(91) The common name is: estramustine sodium phosphate and hormone analogue medicine

(92) The common name is: medroxyprogesterone acetate and hormone analogue medicine

(93) The common name is: tamibarotene and molecular targeted therapeutic agent

(94) The common name is: gefitinib, molecular targeted therapeutic drug

(95) The common name is: retinoic acid, molecular targeted therapeutic agent

(96) The common name is: imatinib mesylate, and molecular targeted therapeutic agent

(97) The common name is: etoposide, topoisomerase inhibitors

(98) The common name is: sobuconazole, topoisomerase inhibitors

(99) The common name is: irinotecan hydrochloride, topoisomerase inhibitors

(100) The common name is: topotecan hydrochloride, topoisomerase inhibitors

(101) The common name is: ubenimex, non-specific immunopotentiator

(102) The common name is: schizophyllan, nonspecific immunity enhancer

(103) The common name is: lentinan, and nonspecific immunopotentiator.

6. An anti-malignant tumor drug comprising the self-magnetic metal salen complex of claim 1 or 2, wherein R is₃Comprising a compound represented by any one of the following formulae (104) to (109),

(104) (trade name: lipperan, common name: leuprorelin acetate, anticancer agent)

(105) (trade name: maytansine, common name: methotrexate, anticancer agent)

(106) (trade name: Noxiaolin, common name: mitoxantrone hydrochloride, anticancer agent)

(107) (trade name: PHOTOFRIN, common name: porfimer sodium, anticancer agent)

(108) (trade name: PHOTOFRIN, common name: porfimer sodium, anticancer agent)

(109) (trade name: Myostat, common name: gemtuzumab ozogamicin, anticancer agent)

7. A self-magnetism-imparting metal salen complex molecule, wherein at least one of the 1-8 positions of the following compound III is bonded to another compound to impart magnetism to the other compound,

m is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

8. A self-magnetism-imparting metal salen complex molecule, wherein at least one of the 1-8 positions and at least one of the 9-16 positions of the following compound IV are bonded to another compound to impart magnetism to the other compound,

m is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

9. An intermediate for producing a magnetic metal complex, which is composed of,

R₁and R₂Each is hydrogen, or one is hydrogen and the other is-COX, and X is-OH or a halogen atom.

10. A method for producing a magnetic body, which comprises binding a drug molecule to the 2-and/or 5-position of the following compound III via an amide group,

m is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

11. A method for producing a magnetic body, which comprises binding a drug molecule to the 5-and 10-positions, or 2-and 13-positions, or 2, 5, 10, and 13-positions of the following compound IV via an amide group,

m is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu or Gd.

12. A process for producing a self-magnetic compound, which comprises reacting a drug component containing a drug molecular structure (X) with a compound having a self-magnetic propertyReact to produceFurther reacting ethylenediamine to produceFurther reacting a metal halide to obtain

13. The method of claim 12, wherein X-c (o) -Z is reacted withReact to produceZ in X-C (O) -Z is a halogen atom.

14. A process for producing a self-magnetic compound, which comprises reacting ethylenediamine with an organic solventReact to formThen reacting a drug component containing a drug molecular structure (X) therewith, followed by reacting a metal halide therewith, thereby obtaining

15. The method of claim 14, wherein X-O-c (O) -Y is reacted withReacting, wherein Y in X-O-C (O) -Y is p-nitrobenzene.

16. A process for preparing a self-magnetic compound by reacting a compound of formula (X) with a compound of formula (I)React to produceAnd reacting ethylenediamine therewith to formAnd reacting the metal halide therewith to obtain

17. The method of claim 16, wherein X-O-c (O) -Y is reacted withReact to obtainY in X-O-C (O) -Y is p-nitrobenzene.