WO2011096374A1 - Nouveau composé d'iodobenzyl-bléomycine - Google Patents

Nouveau composé d'iodobenzyl-bléomycine Download PDF

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WO2011096374A1
WO2011096374A1 PCT/JP2011/051974 JP2011051974W WO2011096374A1 WO 2011096374 A1 WO2011096374 A1 WO 2011096374A1 JP 2011051974 W JP2011051974 W JP 2011051974W WO 2011096374 A1 WO2011096374 A1 WO 2011096374A1
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iodobenzyl
bleomycin
blm
compound
cobalt
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PCT/JP2011/051974
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Japanese (ja)
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醇 安東
逸子 安東
昌宏 黒田
右 金澤
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国立大学法人 岡山大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present invention relates to a novel iodobenzyl-bleomycin compound.
  • the present invention also relates to a metal complex of an iodobenzyl-bleomycin compound and various metal atoms, for example, a novel iodobenzyl-cobalt-bleomycin compound (hereinafter sometimes referred to as “iodobenzyl-Co-bleomycin compound”).
  • iodobenzyl-Co-bleomycin compound a novel iodobenzyl-Co-bleomycin compound.
  • Diagnostic imaging is a device that uses X-rays, ultrasound, electromagnetic waves (including electromagnetic waves emitted from radioisotopes), etc., and images and observes lesions throughout the body including the head, chest, and abdomen. An inspection to be performed.
  • diagnostic agents for malignant tumors for SPECT include gallium citrate ( 67 Ga) and thallium chloride ( 201 Tl).
  • diagnostic imaging agents for inflammatory lesions include gallium citrate ( 67 Ga) and indium ( 111 In) labeled leukocytes.
  • sodium iodide As the radiopharmaceutical for treating thyroid cancer and its metastases, sodium iodide (131 I) is, as the for the treatment of low-grade non-Hodgkin's lymphoma and mantle cell lymphoma, ibritumomab Ma Booch tiuxetan - 90 Y And radiopharmaceuticals that treat a limited number of malignant tumors. However, there are still no radiopharmaceuticals to treat common malignant tumors.
  • Non-patent Document 1 As image diagnostic agents that may be a radiopharmaceutical of diagnosing general malignancies, bleomycin (non-patent document 1) is an anticancer agent, 57 Co- bleomycin conjugated with radioactive cobalt (57 Co) is synthesized The possibility of a positive drawing agent for malignant tumor tissue was reported (Non-patent Documents 2-4).
  • 67 Ga gallium citrate
  • 67 Ga has three types of gamma rays, 296 keV, 184 keV, and 93 keV, and measurement for image creation was not easy, but the point 123 I (one type of 160 keV gamma rays) is easy to measure and good quality Images can be created.
  • 67 Ga has a long physical half-life of 78 hours, which increases patient exposure, while 123 I has a physical half-life of 13 hours, which reduces patient exposure and is beneficial to the patient.
  • thallium chloride ( 201 Tl) When thallium chloride ( 201 Tl) is used, it is difficult to draw a malignant tumor lesion because many normal organs accumulate more than the accumulation in the malignant tumor lesion. In addition, thallium chloride ( 201 Tl) measures 69-80 keV mercury KX rays, so the energy is weak and the image becomes unclear when drawing with SPECT.
  • the physical half-life of 201 Tl is as long as 74 hours, but 123 I can produce high-quality images as described above, and the physical half-life is short, which reduces patient exposure and is beneficial to patients. is there.
  • 57 Co- bleomycin bleomycin is an anticancer agent to bind the radioactive cobalt (57 Co), compared to normal organs (except kidney), it was reported in conjunction that a large amount accumulate in malignant tissue (Non-Patent Documents 2-4). Therefore, it was experimentally used as a positive drawing agent for malignant tumor tissue, but because of the long physical half-life of 57 Co, which is 270 days, it was radioactively released by the Ministry of Health at that time in terms of radioactive contamination of the environment and human exposure. Not allowed as a medicine.
  • gallium citrate When conventional gallium citrate ( 67 Ga) is used, it accumulates in the liver, kidneys, bones and the like in addition to inflamed tissues, which hinders detection of inflamed tissues. As described above, 67 Ga is more difficult to measure for image drawing than 123 I, and at the same time has the disadvantage of increasing patient exposure.
  • indium (111 an In) labeled leukocytes indium leukocytes obtained from the patient (111 In) - labeled with oxine is intended to be administered to the patient, used in complex is very limited.
  • bleomycin bound to cobalt has a strong ability to accumulate malignant tumors.
  • 57- Co has a long physical half-life of 270 days, so it does not change the biological properties of Co-bleomycin on malignant tumor accumulation, and does not change the radioisotope (RI) to Co-bleomycin.
  • RI radioisotope
  • the following two methods can be considered as a method for labeling Co-bleomycin with RI.
  • the first method is a method of synthesizing RI-labeled bleomycin in which RI (or a reagent thereof) is bound to bleomycin, and then binding cobalt to synthesize RI-labeled Co-bleomycin.
  • Co-bleomycin is synthesized in advance, and then RI (or its reagent) is bound to synthesize RI-labeled Co-bleomycin.
  • the Co- bleomycin produced by the conventional method was tried labeling the above three RI, 131 I - In can not be labeled, 125 I- Bolton Hunter reagent, the 125 I-PIB reagent Co-bleomycin can be labeled with low yield.
  • Co-bleomycin labeled with 125 I-Bolton Hunter reagent obtained in a small amount was examined for malignant tumor accumulation in Erlich cancer subcutaneously transplanted mice, but strong malignant tumor accumulation was not observed.
  • An object of the present invention is to provide a novel iodobenzyl-bleomycin compound.
  • the present invention is capable of accumulating in a malignant tumor having a biological property related to malignant tumor accumulation of a metal complex of an iodobenzyl-bleomycin compound and various metal atoms, for example, an iodobenzyl-Co-bleomycin compound.
  • Another object of the present invention is to provide a method for synthesizing a metal complex of the iodobenzyl-bleomycin compound and of the iodobenzyl-bleomycin compound and various metal atoms.
  • It is another object of the present invention to provide a test agent and test method for malignant tumors or inflamed tissues, and a malignant tumor therapeutic agent, characterized by using the novel iodobenzyl-Co-bleomycin compound.
  • the inventors of the present invention added iodobenzyl iodide synthesized from iodobenzyl alcohol and iodine as starting materials to the terminal amino group of bleomycin, whereby iodobenzyl-Co having malignant tumor accumulation ability.
  • the present invention was completed by successfully synthesizing a novel iodobenzyl-bleomycin compound for producing metal complexes such as bleomycin.
  • this invention consists of the following. 1. An iodobenzyl-bleomycin compound characterized by comprising a benzyl group substituted with an iodine atom in R of bleomycin represented by the general formula (I). 2. 2. The iodobenzyl-bleomycin compound according to item 1, wherein R in the general formula (I) has a structure represented by the formula (II). 3. 3. The iodobenzyl-bleomycin compound according to item 2, wherein the iodine atom of the benzyl group represented by formula (II) is located at the meta position. 4). 4.
  • the method for synthesizing the iodobenzyl-Co-bleomycin compound according to item 6, comprising the following steps: 1) a step of synthesizing iodobenzyl iodide; 2) adding cobalt to bleomycin to synthesize Co-bleomycin; 3) A step of adding iodobenzyl-Co-bleomycin compound by adding Co-bleomycin dissolved in methanol to the iodobenzyl iodide prepared above. 8).
  • the method for synthesizing the iodobenzyl-Co-bleomycin compound according to item 6, comprising the following steps: 1) step of synthesizing 'iodobenzyl iodide; 2) 'adding bleomycin dissolved in methanol to the iodobenzyl iodide prepared above to synthesize an iodobenzyl-bleomycin compound; 3) 'A step of adding cobalt to the iodobenzyl-bleomycin compound prepared above to synthesize an iodobenzyl-Co-bleomycin compound.
  • a test for malignant tumors or inflamed tissues comprising the iodobenzyl-Co-bleomycin compound according to item 5 above.
  • a malignant tumor therapeutic agent comprising the iodobenzyl-Co-bleomycin compound according to item 5 as an active ingredient.
  • 12 6. A method for examining a malignant tumor or an inflamed tissue, comprising using the iodobenzyl-Co-bleomycin compound according to item 5 above.
  • the iodobenzyl-Co-bleomycin compound of the present invention can be easily synthesized.
  • the iodobenzyl-bleomycin compound of the present invention can form complexes with various metal atoms, and these complexes may be used for medical purposes.
  • Possible metal atoms that can form useful complexes include cobalt, iron, rhodium, ruthenium, tin, manganese, nickel, palladium, chromium, antimony, vanadium, and the like.
  • the novel iodobenzyl-Co-bleomycin compound of the present invention has the ability to accumulate malignant tumors by conventional Co-bleomycin, and if labeled with 123 I or 124 I, can be drawn clearly with the labeled iodine. Also, 123 I has a physical half-life of 13 hours and 124 I has a physical half-life of 4.2 days, compared to 57 Co-bleomycin where the physical half-life of radioactive cobalt ( 57 Co) was 270 days.
  • the novel iodobenzyl-Co-bleomycin compound of the present invention can reduce patient exposure and reduce radioactive contamination of the environment.
  • the physical half-life length of 124 I is 4.2 days, so it can be synthesized before the date of use and transported over a long distance. There are medical economic advantages.
  • the iodobenzyl-Co-bleomycin compound labeled with 131 I that emits beta rays is accumulated in the malignant tumor tissue and the malignant tumor cells are irradiated with the beta rays, a therapeutic effect on the malignant tumor is expected.
  • FIG. 3 shows a synthetic scheme for adding iodobenzyl iodide to the terminal amino group site of bleomycin demethyl A 2 or cobalt-bleomycin demethyl A 2 .
  • Example 1 Is a diagram illustrating a 3- 125 I- Akuchiguramu of iodobenzyl iodide and Co- thin layer chromatography after reaction bleomycin demethyl A 2.
  • Example 1 Is a diagram illustrating a 3- 125 I- autoradiogram and Akuchiguramu of iodobenzyl -Co- bleomycin 3A thin layer chromatography.
  • Example 1 3- 125 I- iodobenzyl - shows the autoradiogram and Akuchiguramu tlc bleomycin. (Example 2)
  • the present invention relates to a novel iodobenzyl-bleomycin compound.
  • the present invention also relates to metal complexes of iodobenzyl-bleomycin compounds such as iodobenzyl-Co-bleomycin compounds with various metal atoms.
  • Bleomycin has a structure represented by the following general formula (I).
  • various bleomycins are specified by the structure of R shown in Table 1.
  • the case where the structure of R shown in Table 1 is modified, for example, by binding an iodo compound, is referred to as “bleomycin compound”, and is simply distinguished from the case of “bleomycin”.
  • the iodobenzyl-bleomycin compound of the present invention is characterized by containing a benzyl group substituted with an iodine atom in R (terminal amino group) of bleomycin represented by the general formula (I).
  • the iodobenzyl-bleomycin compound has a structure in which R in the general formula (I) is represented by the formula (II).
  • the position of the iodine atom is not particularly limited and may be any of the meta position, the para position, and the ortho position, but is most preferably located at the meta position.
  • the substituted iodine atom may be radioactive or non-radioactive.
  • radioactive iodine atom it may be any one selected from 123 I, 124 I, 125 I or 131 I, 123 I and 124 I are suitable for diagnostic imaging, and malignant tumor treatment. 131 I is preferred, and 125 I is preferred for basic research.
  • the present invention provides a metal with any of the above-mentioned iodobenzyl-bleomycin compounds and any metal atom selected from cobalt, copper, iron, rhodium, ruthenium, tin, manganese, nickel, palladium, chromium, antimony, vanadium, etc. It extends to complexes.
  • the iodobenzyl- (metal atom) -bleomycin compound of the present invention is synthesized by binding a metal atom, such as cobalt, to the iodobenzyl-bleomycin compound synthesized as described above according to the conventional method of synthesizing (metal atom) -bleomycin.
  • the iodobenzyl- (metal atom) -bleomycin compound of the present invention is synthesized by adding iodobenzyl iodide to the terminal amino group of (metal atom) -bleomycin synthesized by a method known per se and reacting. You can also.
  • the metal complex of the iodobenzyl-bleomycin compound of the present invention and a metal atom is most preferably an iodobenzyl-Co-bleomycin compound.
  • the iodobenzyl-Co-bleomycin compound can also be synthesized by binding cobalt to the iodobenzyl-bleomycin compound synthesized as described above according to the conventional method for synthesizing Co-bleomycin.
  • the iodobenzyl-Co-bleomycin compound of the present invention can also be synthesized by adding iodobenzyl iodide to the terminal amino group of Co-bleomycin synthesized by a method known per se and reacting it.
  • the iodobenzyl-Co-bleomycin compound of the present invention can be synthesized by a method including a step of adding iodobenzyl iodide to the terminal amino group of bleomycin or Co-bleomycin.
  • a method for synthesize iodobenzyl -Co- bleomycin compounds of the present invention have the general formula (I) and among the various bleomycin shown in Table 1, it is particularly preferable to use bleomycin demethyl A 2.
  • iodobenzyl iodide to bleomycin demethyl A 2 or Co-bleomycin demethyl A 2 .
  • cobalt may be bonded to bleomycin in advance or may not be bonded.
  • the iodobenzyl-Co-bleomycin compound of the present invention can be synthesized by a method including the following steps 1) to 3). In the following, either step 1) or 2) may be performed first. 1) A step of synthesizing iodobenzyl iodide. 2) A step of adding cobalt to bleomycin to synthesize Co-bleomycin. 3) A step of adding an iodobenzyl-Co-bleomycin compound by adding Co-bleomycin dissolved in methanol to the synthesized iodobenzyl iodide.
  • the iodobenzyl-Co-bleomycin compound of the present invention can also be produced by a synthesis method including the following steps 1) ′ to 3) ′.
  • Iodobenzyl iodide can be synthesized using iodobenzyl alcohol and iodine ions as starting materials based on the synthesis scheme of FIG.
  • 125 I ⁇ is illustrated as an iodine ion added to iodobenzyl alcohol.
  • 123 I ⁇ , 124 I ⁇ , or 131 I ⁇ may be a radioactive iodine ion, or non-radioactive.
  • the iodine ion may be used.
  • the iodine atom of the benzene ring of the synthesized iodobenzyl iodide is located at the meta position in FIG.
  • iodobenzyl iodide was synthesized in, for example, a iodobenzyl iodide 125 I is located in the meta position 3 125 I- iodobenzyl iodide (3- 125 I-iodobenzyliodide: hereinafter "3-125 I-BZI ”) and it can be shown, those located in the ortho position 2- 125 I-BzI, those located at the para position can be shown as 4- 125 I-BzI.
  • the method of adding iodobenzyl iodide to the above 3) Co-bleomycin or the above 2) ′ bleomycin that is, the step of adding iodobenzyl iodide to the terminal amino group of Co-bleomycin or bleomycin is shown in FIG. It can be based on the synthesis scheme shown in FIG.
  • the method of adding cobalt to the bleomycin of the above 2) or the iodobenzyl bleomycin compound of the above 3) ′ for example, can be a method known per se. Specifically, for example, it can be based on the description of Non-Patent Document 2-4.
  • the novel iodobenzyl-Co-bleomycin compound of the present invention retains the malignant tumor accumulation property of conventional Co-bleomycin and can be drawn clearly with labeled iodine.
  • 123 I has a physical half-life of 13 hours and 124 I has a physical half-life of 4.2 days, so that the physical half-life of radioactive cobalt ( 57 Co) is 270 days.
  • the novel iodobenzyl-Co-bleomycin compound of the present invention can reduce patient dose and ambient radioactive contamination.
  • the iodobenzyl-Co-bleomycin compound labeled with 131 I that emits beta rays is accumulated in malignant tumor tissue and irradiated with malignant tumor cells with beta rays, a therapeutic effect on the malignant tumor is expected.
  • This compound is the first to discover a compound labeled with a nuclide that emits beta rays and accumulates in large amounts in general malignant tumors.
  • the present invention relates to a method for producing an iodobenzyl-Co-bleomycin compound, a diagnostic agent for a malignant tumor or inflammatory tissue containing the iodobenzyl-Co-bleomycin compound, a therapeutic agent for a malignant tumor containing the compound as an active ingredient, It extends to a method for examining malignant tumors or inflamed tissues using a compound.
  • the dosage is not particularly limited.
  • a therapeutic agent for malignant tumor containing the compound as an active ingredient is used in combination with a therapeutic agent known per se, or when the therapeutic agent for malignant tumor of the present invention is administered without using a therapeutic agent known per se, etc.
  • the appropriate dose can be easily selected.
  • the dose is appropriately set depending on the disease, weight, age, sex, etc. of the patient.
  • the active ingredient can be used in the range of about 0.01 to 1000 mg per adult day.
  • a malignant tumor therapeutic agent and a malignant tumor or inflamed tissue test agent containing the iodobenzyl-Co-bleomycin compound of the present invention as an active ingredient the compound and a pharmacologically and pharmaceutically acceptable carrier Or it can be used with an additive.
  • carriers or additives include appropriate buffers such as phosphate buffer, isotonic agents such as physiological saline, etc., for example, solubilizers or solubilizers, isotonic agents, pH adjusters, Examples of the stabilizer include ascorbic acid, and examples of the pH adjuster include hydrochloric acid and sodium hydroxide.
  • Malignant tumors or inflamed tissues can be examined by using a test drug containing the iodobenzyl-Co-bleomycin compound of the present invention as an image diagnostic drug. Since the compound has the property of being specifically taken up by malignant tumors, it is possible to image malignant tumors by detecting the radiation emitted from the compound using nuclear medicine inspection techniques such as PET and SPECT. .
  • the malignant tumor that can be examined with the compound of the present invention is not particularly limited as long as the compound can specifically accumulate, and for example, esophagus, stomach, pancreas, large intestine, lung, brain, ovary, breast, skin, Examples include malignant tumors existing in the uterus.
  • an image diagnosis can also be performed for the inflamed tissue.
  • 3-iodobenzyl alcohol (3-iodobenzyl alcohol) and radioactive iodine ion 125 I - 3 125 produced as a starting material I- iodobenzyl iodide and (3- 125 I-BzI) was added, was synthesized 3- 125 I- iodobenzyl -Co- bleomycin compound (3- 125 I-Bz-Co -BLM).
  • R of general formula (I) the following is shown in formula (III) 3- 125 I-Bz -Co-BLM is proposed structure.
  • the 3- 125 I-BzI (3.3 ⁇ M / starting 20 ⁇ l of 3-iodobenzyl alcohol) and was produced by the reaction of Co-BLM-dA 2 3- 125 I-Bz-Co-BLM, silica gel thin layer chromatography Separated (Rf 0.34 to 0.41).
  • the autoradiogram and actigram of thin-layer chromatography of this isolate are shown in FIG.
  • a fluoro image analyzer TM FLA-7000 manufactured by Fuji Photo Film Co., Ltd. was used for producing these autoradiograms and actigrams.
  • 3-iodobenzyl alcohol starting material is reduced to 0.33MyuM, the ratio at which radioactivity was the reaction product of the combined 3-125 I-BZI and Co-BLM-dA 2 further detail observed to increase, in FIG. 4 the resulting 3- 125 I-Bz-Co- BLM as shown in, 3A (Rf 0.39 ⁇ 0.48) , it was found that divides into two as 3B (Rf 0.35 ⁇ 0.43). Therefore 3A, 3B was separated by silica gel thin layer chromatography separately, to obtain a single 3- 125 I-Bz-Co- BLM 3A and 3- 125 I-Bz-Co- BLM 3B.
  • Figure 5 shows an example of the actigram and autoradiogram of the separated 3A silica gel thin layer chromatography.
  • Co-BLM-dA 2 About 3 times the amount of CoCl 2 is added to the aqueous solution of BLM-dA 2 to prepare three types of pH 6.0, 6.5 and 7.0, followed by freeze-drying. did.
  • 3-iodobenzyl alcohol 0.33MyuM, others above the conducted just as to obtain a high specific radioactivity 3- 125 I-BzI.
  • 3-iodobenzyl alcohol likewise performed using 2-iodobenzyl alcohol and 4-iodobenzyl alcohol to give the respective 2-125 I-BZI and 4- 125 I-BzI.
  • 3A having a radiochemical purity of 98% or more was obtained as shown in FIG.
  • 3B having a purity of 98% or more was obtained.
  • Tumor-bearing mice Male scid mice (8 weeks old) purchased from Clea Japan Co., Ltd. were transplanted with Ehrlich ascites tumor cells (approximately 4 ⁇ 10 7 cells) subcutaneously in the thigh. It used for experiment when it became the magnitude
  • Uptake rate of each 3- 125 I-Bz-Co- BLM of each tissue was expressed in uptake rate for each tissue 1 g in the case where the injection amount is 100% (% / g). Since there was variation in the body weight of the mice, in order to make the results easier to compare, the body weight was standardized to 100 g in the calculation (uptake rate (% / g) ⁇ mouse body weight (g) ⁇ 100 was calculated).
  • Table 3 shows the malignant tumor tissue / organ tissue-uptake ratio per unit weight. At 1 hour after administration, the organs of 1.0 or less (more concentrated than malignant tumor tissue) were blood, liver, and kidney, but after 3 hours, they became two organs, liver and kidney.
  • Tables 4 and 5 The results of the biodistribution of 3- 125 I-Bz-Co- BLM 3A and 3B in tumor-bearing mice are shown in Tables 4 and 5.
  • Table 4 shows the uptake rate per 1 g of each tissue (when weight is unified to 100 g) 1 hour and 3 hours after administration.
  • the uptake rates of malignant tumor tissues were 0.319% / g, 0.280% / g, 3 hours after 3A, and 0.331% / g, 0.259% / g after 1 hour, 3 hours, respectively. there were. Accumulation in the kidney was very large, and accumulation in the liver was also large. There was no significant difference between 3A and 3B, but all organs were smaller after 3 hours than after 1 hour.
  • Table 5 shows the malignant tumor tissue / organ tissue-uptake ratio per unit weight.
  • the organs of 1.0 or less were blood, liver, kidney, and lung 1 hour after administration, but after 3 hours, they became 2 types of organs, liver and kidney. It was. From these results, it was found that 3 hours after administration, 3A and 3B were accumulated in malignant tumor tissue more than normal organ tissue except kidney and liver.
  • Example 1-2 Inflammatory Tissue Accumulation of Various 125 I-Bz-Co-BLM
  • confirmation of the inflamed tissue accumulation of various 125 I-Bz-Co-BLM was performed using inflammation-initiating substances.
  • Inflamed mice 0.2 ml of turpentine oil was injected subcutaneously into the back of male ddY mice (5 weeks old) purchased from Japan SLC Co., and used for experiments 5 days later.
  • 3- 125 I-Bz- BLM injection solutions and 3- 125 I-Bz-Co- BLM was obtained by injection solutions and bearing mice
  • 3- 125 I-Bz-BLM and 3- 125 I-Bz -Co-BLM was dissolved in physiological saline to prepare the following two types of physiological saline solutions for injection.
  • 3- 125 I-Bz-BLM saline solution content 20 [mu] g ⁇ 30 [mu] g in 0.3 ml, approximately 10KBq
  • 3- 125 I-Bz-Co- BLM saline solution content 20 [mu] g ⁇ 30 [mu] g in 0.3 ml, approximately 10KBq
  • Tumor-bearing mice Male scid mice (8 weeks old) purchased from Clea Japan Co., Ltd. were transplanted with Ehrlich ascites tumor cells (approximately 4 ⁇ 10 7 cells) subcutaneously in the thigh. It used for experiment when it became the magnitude
  • novel iodobenzyl-bleomycin compound of the present invention complexes with various metal atoms can be formed, and these complexes may be used for medical purposes.
  • Possible metal atoms that can form useful complexes include cobalt, iron, rhodium, ruthenium, tin, manganese, nickel, palladium, chromium, antimony, vanadium, and the like.
  • the novel iodobenzyl-Co-bleomycin compound of the present invention has the ability to accumulate malignant tumors by conventional Co-bleomycin, and if labeled with 123 I or 124 I, can be drawn clearly with the labeled iodine.
  • 123 I has a physical half-life of 13 hours and 124 I has a physical half-life of 4.2 days, compared to 57 Co-bleomycin where the physical half-life of radioactive cobalt ( 57 Co) was 270 days.
  • the novel iodobenzyl-Co-bleomycin compound of the present invention can reduce patient exposure and reduce radioactive contamination of the environment.
  • the present invention 124 In the case of a novel iodobenzyl-Co-bleomycin compound labeled with I, it can be manufactured before the date of use due to its long physical half-life and can be transported over a long distance, which is advantageous in terms of medical economy.
  • the iodobenzyl-Co-bleomycin compound labeled with 131 I that emits beta rays is accumulated in malignant tumor tissue and irradiated with malignant tumor cells with beta rays, a therapeutic effect on the malignant tumor is expected.

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Abstract

La présente invention concerne un nouveau composé d'iodobenzyl-bléomycine. La présente invention concerne en outre des complexes de métal qui sont constitués du composé d'iodobenzyl-bléomycine et de différents atomes de métal, tels qu'un composé d'iodobenzyl-Co-bléomycine, qui peuvent s'accumuler sur des tumeurs malignes, et qui ont des caractéristiques biologiques améliorées en termes de capacité d'accumulation sur des tumeurs malignes par rapport à des composés conventionnels. La présente invention concerne en outre des procédés pour synthétiser le composé d'iodobenzyl-bléomycine et les complexes de métal du composé d'iodobenzyl-bléomycine et de différents atomes de métal. Le nouveau composé d'iodobenzyl-bléomycine est synthétisé par ajout, à un groupe amino terminal de bléomycine, d'iodure d'iodobenzyle synthétisé en utilisant de l'alcool iodobenzylique et de l'iode en tant que matériaux de départ.
PCT/JP2011/051974 2010-02-05 2011-02-01 Nouveau composé d'iodobenzyl-bléomycine WO2011096374A1 (fr)

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