CN1995020B - Radioactive iodine-17- allylamino-17-demethoxygeldanamycin and its preparation method - Google Patents
Radioactive iodine-17- allylamino-17-demethoxygeldanamycin and its preparation method Download PDFInfo
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- CN1995020B CN1995020B CN2006100983395A CN200610098339A CN1995020B CN 1995020 B CN1995020 B CN 1995020B CN 2006100983395 A CN2006100983395 A CN 2006100983395A CN 200610098339 A CN200610098339 A CN 200610098339A CN 1995020 B CN1995020 B CN 1995020B
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- propyl group
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- methoxy geldanamycin
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Abstract
The invention discloses a making method of radioactive iodine-17-allylamine-17-normethoxy geldanamycin in the nuclear medical, tumour and medical agent technical domain, which is characterized by the following: marking the product of 17-allylamine-17-normethoxy geldanamycin through iodine for HSP90; modifying the structure of 17-allylamine-17-normethoxy geldanamycin; guiding radioactive nuclear iodine on the end of double-bond; providing the medical acceptable drug or drug composition to treat tumor or cancer.
Description
Technical field
The present invention relates to a kind of oncotherapy reagent radioiodine (
*I)-17-propyl group amido-17-de-methoxy geldanamycin, diagnostic agent for tumor (single photon emission computed tomography/SPECT, Positron Emission Computed Tomography/PET) and medicine or preparation of pharmaceutical compositions method and application.Relate to nuclear medicine, oncology, the pharmaceutical preparation field that learns a skill.
Background technology
Malignant tumour is serious threat human survival and healthy disease, and the early diagnosis difficulty.In recent years, the sickness rate and the mortality ratio of tumour raise year by year, lose surgical engine can and recurrence after operation transfer be to cause tumour to be difficult to control and quicken the major cause of patient death.At present, tumor treatment is mainly relied on aggregate measures such as operative treatment, chemotherapy, radiotherapy and biotherapy.But though these conventional treatments are good to the prevention and the therapeutic action short-term effect of metastases, long-term effect is very poor.The early diagnosis and therapy that develops into tumour of tumour nuclear medicine provides new approaches, novel method.Use nucleic internal radiation therapy for treating noumenal tumour as one of general treatment measures, be subjected to people in recent years day by day and pay attention to.According to radiobiological theory, the therapeutic action of radionuclide has persistence; Cell is relevant with the functional state of cell to the susceptibility of nuclear ray, and the malignant cell rate of propagation is fast, and is comparatively responsive to the nuclear ray.So the nucleic internal-radiation therapy number of times course of treatment is few, and can obtain good, persistent effect.
The suitable radiopharmaceutical agent that the action principle of nucleic internal radiation therapy will have high liner energy transfer(LET) is delivered to diseased region or its periphery, the nuclear ray can make tumor tissues generation sex change, the necrosis in the effective range, has avoided the radiobiology damage of normal adjacent tissue beyond the range simultaneously reaching treatment tumour purpose.Radiopharmaceutical agent is to utilize the molecule of specific effect pathological tissues or the ion carrier as radionuclide, can make radionuclide after administration, mainly concentrate in tumor tissues, and the delay of long period is arranged in tumor tissues, and the accumulative radionuclide reduces as far as possible in the healthy tissues beyond the tumour, organ.Therefore, be fit to very much local heavy dose of ground tumour is carried out internal-radiation therapy, and can alleviate the infringement of radiation to greatest extent contiguous vital tissue organ.
The β ray is better than gamma-rays at aspects such as tissue dose decay and radio-protective, so become the focus of radiopharmaceutical agent research at present with the beta ray therapy tumour.The radionuclide that uses for medical use must can radiate the radioactive rays with high liner energy transfer(LET), to destroy the abnormality proliferation differentiated tissues.
131I use radiopharmaceutical agent by the video picture of widespread use and treatment, is used for thyroid function determination and video picture, treats thyroid carcinoma and hyperthyroidism;
123I,
124I is respectively applied for SPECT and PET video picture.
Along with deepening continuously on molecular level to the tumor invasion Mechanism Study, the investigator finds in vivo heat shock protein 90 (the Heat-Shock Proteins90 as molecular chaperones, HSP90) tumor development is played an important role, at present, be that the research of inhibitor of target spot is in the ascendant with HSP90.Protein kinase and transcription factor that HSP90 effect protein in vivo plays an important role in the body signal transduction pathway often comprise the protein that blood supply, nutritional support, token stimulus and substance metabolism that tyrosine kinase receptor (Her-2), vascular endothelial growth factor receptor (EGFR), cell cycle dependant kinase (CDK4), mutant p53 and hypoxic inducing factor-1 α (HIF-1 α) etc. shift tumor growth ovarian cancer, mammary cancer, prostate cancer, cancer of the stomach, retinoblastoma and kidney etc. play an important role.The HSP90 inhibitor can effectively suppress many cellular signal transduction pathways by suppressing HSP90, treatment mammary cancer, prostate cancer, melanoma, ovarian cancer, cervical cancer, liver cancer, lung cancer, thyroid carcinoma, leukemia etc.
17-propylene amido-17-de-methoxy geldanamycin (17-allylamino, 17-demethoxygeldanamycin, 17-AAG) be first HSP90 inhibitor that enters clinical experimental stage, the HSP90 in tumour cell source has high-affinity to 17-AAG, the avidity that the HSP90 that studies show that 17-AAG and tumour cell source is arranged be derive from healthy tissues HSP90 20-200 doubly, therefore, 17-AAG can be used as suitable carriers and carries radioactive nuleus and usually diagnose, treat tumour.17-AAG is a class purple meal, and molecular weight is 585.7, is soluble in organic solvents such as methyl alcohol, DMSO, chloroform, ethyl acetate, ethanol, and is water insoluble, is the lavender clarified liq after the dissolving.17-AAG derives from Sigma company.Its molecular formula is C
31H
43N
3O
8, its structural formula is:
17-AAG can suppress many cellular signal transduction pathways, make the effect protein of HSP90, comprise that the propagation fusion protein BCR-ABL of ERB-B2, HER2, estrogen receptor, androgen receptor, RAF, P13 kinase signal albumin A KT, chronic myelocytic leukemia (CML), CDK4, h-TERT etc. degrade by ubiquitin protein enzyme body approach; Influence many cell signaling paths simultaneously and realize the multiple spot attack, the whole signal path network that destroyed tumor is depended on for existence is suppressed apoptosis of tumor cells, growth.17-AAG can induce leukocyte recruitment, make tumour cell that G2 phase growth-inhibiting take place, increase the expression of E cadherin, change wild-type and mutant is female, androgen receptor, suppress its transcriptional activity, eliminate many cellular signal transduction pathways of hormone receptor activatory that promote ligand-dependent.Studies show that in a large number 17-AAG increases the susceptibility of tumour to chemotherapeutics, the reversing drug resistance tumour is to the susceptibility of medicine, increase tumour cell to the susceptibility of radioactive rays (as using earlier the 17-AAG inducing cancer cell, re-use ionizing rays, find that cancer cells is to the susceptibility increase of ionizing rays behind medication 6-48h).Therefore, 17-AAG can be used for treating mammary cancer, prostate cancer, melanoma, ovarian cancer, cervical cancer, CML, lung cancer, liver cancer, thyroid carcinoma etc.
Summary of the invention
Technical problem: the purpose of this invention is to provide a kind of radioiodine (
*I)-17-propyl group amido-17-de-methoxy geldanamycin and preparation method thereof.Preparation technology of the present invention is simple, marker purity height, and good stability is used for diagnosis when low dose of, be used for the treatment of tumour when heavy dose of, is convenient to patient and obtains not have wound video picture and treatment at any time.
Technical scheme: technical scheme of the present invention comprises two contents:
(1) a kind of
*The preparation method of I-17-propyl group amido-17-de-methoxy geldanamycin;
(2) with
*I-17-propyl group amido-17-de-methoxy geldanamycin is the pharmaceutical composition of activeconstituents.
Of the present invention
123The I compound can be used for SPECT (single photon emission computed tomography),
124The I compound can be used for PET (Positron Emission Computed Tomography), and this is no wound, live body, the dynamic display method of nuclear medicine uniqueness.
Of the present invention
*I-17-propyl group amido-17-de-methoxy geldanamycin can be used as activeconstituents and pharmaceutically acceptable excipient one is used from pharmaceutical compositions, this pharmaceutical composition can adopt the ordinary method of formulation art to be prepared into various formulations, as injection liquid, tablet, pulvis, granula, pill, capsule, tincture, oral liquid, paste, creme, emulsion or applicator etc.Difference according to formulation, the excipient that this pharmaceutical composition uses is also different, and excipient commonly used comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant, emulsifying agent, osmotic pressure regulator.
The present invention relates to
*I-17-propyl group amido-17-de-methoxy geldanamycin prepares as follows:
1.) with the ethanolic soln of 17-propylene amido-17-de-methoxy geldanamycin under acidic conditions with oxygenant and Na
*I mixes, and places 10-30min down for 20-60 ℃;
2.) add reductive agent in the mixture in step 1), termination reaction; Adding the pH regulator agent transfers pH to neutral;
3.) to step 2) product in add organic extractant phase, get organic layer, nitrogen dries up;
Above-mentioned steps 1) acidic conditions can be selected a kind of in hydrochloric acid, acetic acid, the sulphuric acid soln for use in.
The method of iodine labeling has a variety of, as chloramine-t method, and iodine chloride method (ICl), Iodogen method, peroxide oxidation method etc.The present invention selects the peroxide oxidation method for use, the mark rate height, and impurity is few.The oxygenant of selecting for use can be a kind of in hydrogen peroxide, the Peracetic Acid.
Above-mentioned steps 2) reductive agent can be selected a kind of of Sodium Metabisulfite, Sulfothiorine for use in.Transfer the reagent of pH will select a kind of in sodium hydroxide, phosphate buffered saline buffer, sodium carbonate/bicarbonate damping fluid, the ammoniacal liquor for use.
Above-mentioned steps 3) organic phase can be selected a kind of in ethyl acetate, ethanol, ether, acetone, the acetonitrile for use in.
Optimum condition is as follows:
A:20 μ g17-propylene amido-17-de-methoxy geldanamycin is dissolved in 100 μ L ethanol, adds 4mol/L hydrochloric acid soln 20 μ L, adds 7% hydrogen peroxide, 20 μ L, 37～370MBq (Na of 1～10mCi)
*I, vortex 1min mixes, and places 15min down for 40 ℃; Add 0.01mol/L Sodium Metabisulfite termination reaction.Transfer pH to 7 with ammoniacal liquor.
B: in A, add 2mL water, ethyl acetate extraction (3mL * 3 time), the collection organic phase, nitrogen dries up, promptly.
Of the present invention
*I-17-propyl group amido-17-de-methoxy geldanamycin and pharmaceutical composition thereof are of value to kinds of tumors treatment, diagnosis and prevention.
17-propyl group amido-17-de-methoxy geldanamycin is fat-soluble strong, and polarity is little.The present invention intends 17-propylene amido-17-de-methoxy geldanamycin is carried out structure of modification, introduces radioactive nuclide iodine at its pair key place, strengthens the polarity and the target of compound, is used for the diagnosis and the treatment of tumour better.The present invention feels free to try existing antitumour drug activeconstituents is developed to radionuclide tumor diagnosis and treatment medicine, organically the HSP90 inhibitor is combined with nucleic, make it when low dose level diagnosis applicable to tumour and metastasis thereof, when heavy dose of applicable to tumor treatment.The present invention provides new thinking for exploitation radioactivity new drug; The close tumprigenicity of medicine self can be brought into play the target that antitumour drug is treated better in conjunction with the radioactive radiation of nucleic, reduces toxic side effect and the suffered injury of healthy tissues; For tumour patient provides novel, the potent agent that does not have the wound video picture, help early diagnosis, the treatment of tumour simultaneously.
The present invention also is applicable to the compound of 17-AAG etc. and 17-AAG similar.
Beneficial effect: from above result, it is as follows to draw advantage of the present invention.
(1) the present invention has prepared new compound
*I-17-propyl group amido-17-de-methoxy geldanamycin.
(2) of the present invention
*I-17-propyl group amido-17-de-methoxy geldanamycin safety non-toxic has kept original biological characteristics of 17-AAG, and the targeting in tumour is strong and synergistic function is arranged, and is indicating good prospect in medicine.
(3) preparation technology of the present invention is simple, marker purity height, and good stability is used for diagnosing tumor when low dose of, be used for the treatment of tumour when heavy dose of, is convenient to patient and obtains not have wound video picture and treatment at any time.
(4) the present invention
*I-17-propyl group amido-17-de-methoxy geldanamycin can be used as activeconstituents and pharmaceutically acceptable excipient one is used from pharmaceutical compositions, and can be used for the diagnosis and treatment of kinds of tumors.
(5) the present invention has opened up a new Application Areas, can be used for oncotherapy, SPECT and PET video picture.
Embodiment
Various details embodiment, but content of the present invention is not limited to this fully.The iodo thing of geldanamycin can adopt this method fully.
Embodiment
(1):
*The preparation of I-17-propyl group amido-17-de-methoxy geldanamycin
A:20 μ g17-propylene amido-17-de-methoxy geldanamycin is dissolved in 100 μ L ethanol, adds 4mol/L hydrochloric acid soln 20 μ L, adds 7% hydrogen peroxide, 20 μ L, 37～370MBq (1～10mCi) Na
*I, vortex 1min mixes, and places 15min down for 40 ℃; Add 0.01mol/L Sodium Metabisulfite termination reaction.Transfer pH to 7 with ammoniacal liquor.
B: add 2mL water in A, ethyl acetate extraction (3mL * 3 time) is collected organic phase, and nitrogen dries up, promptly.
Na
*Iodine among the I (
*I) be nucleic iodine
123I,
124I,
125I,
127I,
131A kind of among the I; Oxygenant is a hydrogen peroxide, a kind of in the Peracetic Acid; Acidic conditions is a kind of in hydrochloric acid, acetic acid, the sulfuric acid; Reductive agent is a kind of in Sodium Metabisulfite, the Sulfothiorine; The pH regulator agent is a kind of in sodium hydroxide, ammoniacal liquor, sodium carbonate/bicarbonate damping fluid, the phosphate buffered saline buffer; The organic phase of extraction is a kind of in ethyl acetate, ether, ethanol, acetone, the acetonitrile.
(2):
*The evaluation of I-17-propyl group amido-17-de-methoxy geldanamycin
Adopt thin-layer chromatography and high-efficient liquid phase technique to measure.
A: thin-layer chromatography: thin layer gel GF 254 plate, polyamide layer or silica gel paper are upholder, and developping agent is methylene chloride=9/1, Rf=0.6～0.9.
Wait behind the point sample to launch to finish, the certification mark thing is faint yellow spot at Rf=0.6～0.9 place under ultraviolet; Chromatographic paper is cut into ten sections, and the γ calculating instrument is measured radiocounting rate value, and dense poly-in Rf=0.6～0.9 place's radioactivity, free-iodine is at Rf=0～0.1 place.
B:HPLC:BIORAD HPLC, YWG C18 reversed-phase column, 50% acetonitrile add 25mM phosphoric acid salt (pH 3.00) and contain the 10mM triethylamine, flow velocity 1mL/min, use UV-detector (wavelength 334nm) and radioactive detector to detect simultaneously, the retention time of free-iodine is about 1.3min
*The retention time of I-17-propyl group amido-17-de-methoxy geldanamycin is about 12min.
(3):
*The stability of I-17-propyl group amido-17-de-methoxy geldanamycin
Getting embodiment (1) dries up down and to make
*I-17-propyl group amido-17-de-methoxy geldanamycin adds physiological saline solution, puts 4 ℃ of refrigerators.Place after 8 days, putting is pure still greater than 90%.Illustrate that marker is stable under 4 ℃ of conditions, can satisfy routine clinical service requirements.
Claims (4)
- A radioiodine ( *I)-and the preparation method of 17-propyl group amido-17-de-methoxy geldanamycin, it is characterized in that, adopt the peroxide oxidation method to carry out radioiodination 17-propylene amido-17-de-methoxy geldanamycin, comprise the steps:1.) with the ethanolic soln of 17-propylene amido-17-de-methoxy geldanamycin under acidic conditions with oxygenant and NaI *Mix, place 10-30min down for 20-60 ℃;2.) add reductive agent in the mixture in step 1), termination reaction; Adding the pH regulator agent transfers pH to neutral;3.) to step 2) product in add organic extractant phase, get organic layer, dry up.
- Radioiodine 2. according to claim 1 ( *I)-and the preparation method of 17-propyl group amido-17-de-methoxy geldanamycin, it is characterized in that the described oxygenant of step 1) is a kind of in hydrogen peroxide, the Peracetic Acid; Described acidic conditions is a kind of in hydrochloric acid, acetic acid, the sulfuric acid.
- Radioiodine 3. according to claim 1 ( *I)-preparation method of 17-propyl group amido-17-de-methoxy geldanamycin, it is characterized in that step 2) described reductive agent is a kind of in Sodium Metabisulfite, the Sulfothiorine; Described pH regulator agent is a kind of in sodium hydroxide, ammoniacal liquor, sodium carbonate/bicarbonate damping fluid, the phosphate buffered saline buffer.
- Radioiodine 4. according to claim 1 ( *I)-and the preparation method of 17-propyl group amido-17-de-methoxy geldanamycin, it is characterized in that the described organic phase of step 3) is a kind of in ethyl acetate, ether, ethanol, acetone, the acetonitrile.
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| CN2006100983395A CN1995020B (en) | 2006-12-12 | 2006-12-12 | Radioactive iodine-17- allylamino-17-demethoxygeldanamycin and its preparation method |
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| CN2006100983395A CN1995020B (en) | 2006-12-12 | 2006-12-12 | Radioactive iodine-17- allylamino-17-demethoxygeldanamycin and its preparation method |
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| KR101254636B1 (en) | 2011-02-14 | 2013-04-15 | 한국수력원자력 주식회사 | Method for synthesis of radioactive methyl iodine and device thereof |
| IL299892A (en) | 2017-06-20 | 2023-03-01 | Madrigal Pharmaceuticals Inc | Combination therapies comprising targeted therapeutics |
| EP3641647A4 (en) | 2017-06-20 | 2021-05-05 | Madrigal Pharmaceuticals, Inc. | Targeted therapeutics |
| CN112881575A (en) * | 2021-02-09 | 2021-06-01 | 江南大学 | Application of alpha-lipomycin as marker for detecting and diagnosing hypertension to prepare corresponding detection tool |
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| Title |
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| 山广志 李卓荣.格尔德霉素衍生物研究进展.国外医药抗生素分册25 6.2004,25(6),274-277. |
| 山广志 李卓荣.格尔德霉素衍生物研究进展.国外医药抗生素分册25 6.2004,25(6),274-277. * |
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