CN1321127C - Iodine (I)-23-hydroxyl betulinic acid, rpeparation method and application thereof - Google Patents
Iodine (I)-23-hydroxyl betulinic acid, rpeparation method and application thereof Download PDFInfo
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- CN1321127C CN1321127C CNB2005100387689A CN200510038768A CN1321127C CN 1321127 C CN1321127 C CN 1321127C CN B2005100387689 A CNB2005100387689 A CN B2005100387689A CN 200510038768 A CN200510038768 A CN 200510038768A CN 1321127 C CN1321127 C CN 1321127C
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Abstract
The present invention relates to iodine (I)-23-hydroxyl betulinic acid, a preparation method thereof and the application thereof, which relates to the technical field of nuclear medicine, oncology, pharmaceutical preparation, wherein I is disclosed in the specification. The compound iodine (I)-23-hydroxyl betulinic acid of the present invention is an iodine-labelled product of 23-hydroxyl betulinic acid which is a traditional Chinese medicine active ingredient with antitumor effect; the preparation method comprises structure reorganization of 23-hydroxyl betulinic acid; radionuclide iodine is introduced in the position of a double bond; the present invention also provides medicines or medicinal compositions containing iodine (I)-23-hydroxyl betulinic acid as an active ingredient and pharmaceutically acceptable carriers; the medicines or medicinal compositions can be used for the diagnosis and treatment of various tumours/cancers. The compound of the present invention is reported for the first time; the preparation technology is simple, and the purity is high; the present invention provides convenience for clinicians to obtain tumour diagnostic reagents at any time and provides atraumatic and timely SPECT or PET display for patients; the present invention integrates the advantages of radioactive and chemotherapeutic medicines so that the targeting property of medicines is enhanced, and the present invention is helpful to treat tumours / cancers.
Description
Technical field
The present invention relates to a kind of diagnosing tumor (single photon emission computed tomography/SPECT, Positron Emission Computed Tomography/PET), treatment reagent iodine (
*I)-23-hydroxyl radical white birck acid and medicine or pharmaceutical composition, preparation method and application.Relate to nuclear medicine, oncology, pharmaceutical formulations technical field.
Background technology
Tumour is one of disease of serious harm human health.Although the modern medical diagnosis level improves constantly, as The Application of Technology such as Medical Imaging inspection, tumor markers detection and molecular biology gene chips, but the five year survival rate of tumour patient and the raising of quality of life are still not ideal, and one of reason is exactly to lack the Detection Techniques and the effectively treatment that can obtain real infantile tumour histopathology physiology, biochemical metabolism change information.In recent years, along with the development of nuclear medicine image instrument and the development and the development and use of close tumour radiotherapy medicine, the radionuclide tumor imaging to the early diagnosis of tumour, good pernicious discriminating, by stages, classification and outcome prediction demonstrate its unique advantage, brought Gospel to tumour patient.For this reason, the radionuclide tumor diagnosis and treatment more and more is subjected to people and pays close attention to, and it has become an important individual branches subject-tumour nuclear medicine of nuclear medicine ambit.
In radiation nuclear species therapeutics (internal radionuclide therapy IRT) is the characteristic of tumour nuclear medicine, and its action principle is to utilize suitable radiopharmaceutical agent to be delivered to high radiation dose by the target diseased tissue and avoid healthy tissues.For the selectivity location, be used as the carrier of treatment for the narrow spectrum lewis' acid of diseased tissue tool with the radioactivity nuclear species, perhaps solubility and micropartical radiopharmaceutical agent are introduced regionally, take in or the radioactivity medicine is limited in health one chamber to improve.The radioactivity nuclear species that uses for medical use must can radiate the radioactive rays with high linear energy transfer, destroys the cell group of pernicious and other fast breedings.
131I is by the treatment radiopharmaceutical agent of widespread use, and for being used for the treatment of thyroid carcinoma and hyperthyroidism;
123I,
124I is respectively applied for SPECT and PET video picture.
In recent years, natural drug is a novel tumor medicine hot of research and development.Clearing heat and detoxicating, the blood circulation invigorating efficacies of traditional Chinese medicine Root of Chinese Pulsatilla tool, tcm clinical practice are mainly used in the treatment of intestinal canal tumours such as colorectal carcinoma, the rectum cancer and cervical cancer, pituitary gland knurl, thyroid tumor, lung cancer.The 23-hydroxyl is the activeconstituents that extracts from the Root of Chinese Pulsatilla root from birch acid (23-HBA), belongs to the pentacyclic triterpene saponins, and its structural formula is:
Molecular formula is C
30H
48O
4, the off-white color meal, molecular weight is 472, is soluble in organic solvents such as chloroform, ethyl acetate, ethanol, and is water insoluble.It can obtain by taking " application of 23-hydroxyl radical white birck acid in preparation treatment or prophylaxis of tumours and AIDS-treating medicine " (Chinese patent application number is to have done detailed narration in 03152904.6 the application for a patent for invention file), but this is not unique method and the unique source that obtains the 23-hydroxyl radical white birck acid.
The 23-hydroxyl radical white birck acid has the activity that inducing tumor cell is expressed to normal cell differentiation, inhibition telomerase activation and downward modulation " cell longevity gene " bcl-2.23-hydroxyl radical white birck acid low toxicity, inside and outside melanoma effect is strong, and all there is restraining effect in kinds of tumor cells system as people's cancer of the stomach SGC-7901 clone, human ovarian cancer A0 clone, human leukemia HL-60 cell system, human leukemia K562 clone, human cervical carcinoma Hela cell system and mouse ascites knurl S180 clone etc.In addition, lung cancer, liver cancer, glioma brain tumour, intestinal canal tumour, virus of AIDS (Chinese patent application number be 03152904.6), carcinoma of gallbladder, new vessel (Chinese patent application number be 200510038469.5) etc. all there is treatment/prophylactic effect.
The inventor shows that to the pharmacokinetic studies of 23-hydroxyl radical white birck acid the 23-hydroxyl radical white birck acid is fat-soluble strong, and polarity is little; The solubleness of absorption and pharmaceutical preparation is closely related in the mouse body, the good then good absorption of dissolving; And the 23-hydroxyl radical white birck acid is dense poly-at digestive tube, gall-bladder especially, and this may be one of its anti-alimentary tract tumor mechanism; Tritium mark 23-hydroxyl radical white birck acid is solid tumor and control sides muscle picked-up ratio＞2 in lotus liver cancer HepA knurl mouse, and dense gathering of tumor mouse digestive tube is higher than normal mice, and is lasting dense especially poly-in the gall-bladder, eliminates slowly.
23-HBA belongs to the technological achievement of China's innovation, does not see external report.A lot of to its analog white birch acid research abroad, white birch acid belongs to the acid saponin(e of pentacyclic triterpene together with 23-HBA, and its structural formula is as follows:
Antitumor research is carried out to about 3000 kind of plant extracts in american cancer research centre (NCI), thinks that white birch acid is an effective anticancer agent.It has specificity (principle is a cell death inducing) to melanoma, neuroblastoma, to normal cell nontoxicity then, be better than now used chemotherapeutic such as taxol, camptothecine, Etoposide, vinealeucoblastine(VLB), vincristine(VCR) etc., the latter is all toxic to normal cell and cancer cells, and suppresses duplicating of they.White birch acid still is an effective antiphlogistic in addition, but the molecule mechanism of its effect is not still understood.
Summary of the invention
The purpose of this invention is to provide a kind of
*I-23-hydroxyl radical white birck acid and pharmaceutical composition thereof, preparation method and application.The present invention intends the 23-hydroxyl radical white birck acid 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 antitumor active ingredient of Chinese herbs is developed to radionuclide tumor diagnosis and treatment medicine, and organically that China is traditional Chinese materia medica combines with nuclear medicine, for exploitation radioactivity new drug provides new thinking; For tumour patient provides novel, the potent agent that does not have the wound video picture, help diagnosis morning, discovery morning, the early treatment of tumour; The close tumprigenicity of medicine self can be brought into play the target that antitumour drug is treated better in conjunction with the ray of nucleic simultaneously, reduces toxic side effect and the suffered injury of healthy tissues.
Technical scheme of the present invention comprises four contents: (1) is a kind of
*The I-23-hydroxyl radical white birck acid; (2) a kind of
*The preparation method of I-23-hydroxyl radical white birck acid; (3) with
*The I-23-hydroxyl radical white birck acid is the pharmaceutical composition of activeconstituents; (4)
*The application of I-23-hydroxyl radical white birck acid and pharmaceutical composition thereof.
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 imaging of nuclear medicine uniqueness.
Of the present invention
*The I-23-hydroxyl radical white birck acid 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, stablizer.
The * I-23-hydroxyl radical white birck acid that the present invention relates to prepares as follows:
(1) ethanolic soln of 23-hydroxyl radical white birck acid is mixed with oxygenant and an amount of NaI* under acidic conditions, place 10-30min down for 20-60 ℃;
(2) in (1), add reductive agent, termination reaction; Adding the pH regulator agent transfers pH to neutral;
(3) in (2), add organic extractant phase, get organic layer, dry up.
Acidic conditions can be selected a kind of in hydrochloric acid, acetic acid, the sulphuric acid soln for use in the above-mentioned steps (1).
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.
Reductive agent can be selected a kind of of Sodium Metabisulfite, Sulfothiorine for use in the step (2).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.
Organic phase can be selected a kind of in ethyl acetate, ethanol, ether, acetone, the acetonitrile for use in the step (3).
Optimum condition is as follows:
A:20 μ g23-hydroxyl radical white birck acid is dissolved in 20 μ L ethanol, adds 4mol/L hydrochloric acid soln 20 μ L, adds 3% hydrogen peroxide, 20 μ L, the 5 microcuries～10 millicuries (NaI of 5 μ Ci～10mCi)
*, 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 (5mL * 3 time), the collection organic phase, nitrogen dries up under 60 ℃ of water-baths, promptly.
* I-23-hydroxyl radical white birck acid of the present invention and pharmaceutical composition thereof are of value to kinds of tumors diagnosis, treatment, prevention.
The application of described medicine, for diagnosing, treat and/or prevent the medicine of cancer, described cancer is: mammary cancer, thyroid tumor, glioma brain tumour, intestinal canal tumour, liver cancer, lung cancer.Described medicine is the medicine that treats and/or prevents new vessel class disease.Described medicine is the medicine that treats and/or prevents acquired immune deficiency syndrome (AIDS).
Beneficial effect of the present invention: from above result, it is as follows to draw advantage of the present invention.
(1) the present invention has prepared new compound * I-23-hydroxyl radical white birck acid.
(2) * I-23-hydroxyl radical white birck acid safety non-toxic of the present invention, antitumor pharmacology effect is strong, is indicating good prospect in medicine.
(3) preparation technology of the present invention is simple, marker purity height, and good stability is convenient to the clinicist and is obtained diagnostic reagent at any time, is convenient to patient and obtains not have wound video picture and treatment at any time.
(4) * I-23-hydroxyl radical white birck acid of the present invention 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 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 white birch acid can adopt this method fully.
Embodiment 1:
*The preparation of I-23-hydroxyl radical white birck acid
A:20 μ g23-hydroxyl radical white birck acid is dissolved in 20 μ L ethanol, adds 4mol/L hydrochloric acid soln 20 μ L, adds 3% hydrogen peroxide, 20 μ L, 1mCiNaI
*, 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 (5mL * 3 time), the collection organic phase, nitrogen dries up under 60 ℃ of water-baths, promptly.
Embodiment 2:
*The evaluation of I-23-hydroxyl radical white birck acid
Adopt thin-layer chromatography and high-efficient liquid phase technique to measure.
A: thin-layer chromatography: silica gel paper is a upholder, and developping agent is methylene chloride=9/1, Rf=0.5-0.7.Wait behind the point sample to launch to finish, the certification mark thing is yellow spotting at the Rf=0.5-0.7 place under ultraviolet; Silica gel paper is cut into ten sections, and the γ calculating instrument is measured radiocounting, and dense poly-in Rf=0.5-0.7 place radioactivity, free-iodine is at the Rf=0-0.1 place.
B:HPLC:BIORAD HPLC, YWG C18 reversed-phase column, acetonitrile/water=6/4 (including 0.1% Glacial acetic acid), and flow velocity 1mL/min uses UV-detector (wavelength 254nm) and radioactive detector to detect simultaneously, and the retention time of free-iodine is about 1.3min,
*The retention time of I-23-hydroxyl radical white birck acid is about 5min.
Embodiment 3:
131The stability of I-23-hydroxyl radical white birck acid
Get to dry up under 1 of the embodiment and make
131The I-23-hydroxyl radical white birck acid adds physiological saline solution, puts 4 ℃ of refrigerators, 37 ℃ of placements.Place after 8 days, putting is pure still greater than 90%.Illustrate that marker is stable under 4 ℃, 37 ℃ conditions, can satisfy routine clinical service requirements.
Embodiment 4: human breast cancer cell MCF-7 different time, different concns to [
131I]-picked-up of 23-HBA
Human breast cancer cell MCF-7 30,60, during 120min to [
131I]-picked-up of 23-HBA is respectively 5.56 ± 2.81%ID, 5.60 ± 1.41%ID, 7.09 ± 1.22%ID; The marker (2,8,32 μ g/mL) that adds different concns, the picked-up of MCF-7 is more not obvious than changing, and is respectively 5.56 ± 2.81%ID, 5.60 ± 1.41%ID, 7.09 ± 1.22%ID 30,60, during 120min.By the result as can be known, human breast cancer cell MCF-7 is high and fast to the picked-up of marker, and picked-up mechanism may be passive diffusion.
Embodiment 5:
131The I-23-hydroxyl radical white birck acid is in the bio distribution of lotus liver cancer HepA knurl mouse
Lotus liver cancer HepA solid tumor mouse through tail vein injection [
131I]-23-HBA (0.111MBq/ only) back 1,2,4h, sacrificed by decapitation is got tissue of interest such as blood, the heart, liver, spleen, lung, kidney, stomach, small intestine, muscle, gall-bladder, solid tumor, claims weight in wet base, and the γ calculating instrument is surveyed radioactivity, calculates the ID%/g tissue.
The result shows: absorb the highest by (124.48 ± 20.25%ID/g) in the 1h tumor mouse gall-bladder of injection back, stomach takes second place (6.45 ± 1.37%ID/g), be then small intestine (3.60 ± 0.97%ID/g), liver (3.61 ± 0.31%ID/g) and kidney (3.26 ± 0.29%ID/g).Solid tumor/offside normal muscle ratio is after injection 1,2, and 4h is respectively 3.36,2.52 and 2.96.
By the result as can be known, [
131I]-23-HBA is dense poly-than the offside normal muscle at the tumor locus of lotus liver cancer HepA solid tumor mouse.This marker may be a good tumor developer.
Embodiment 6: undue toxicity
Regulation by " Chinese Pharmacopoeia (two appendix of version in 2000) " is carried out:
Get six of NIH small white mouses, body weight 18-20 gram, male, the tail vein injects the solution 0.4mL (people inject consumption 20%) of firm preparation respectively, the conventional raising after 48 hours, no abnormality seen is dissected in survival fully one by one.
The weight of mouse is by 20g, and people's body weight is by 50kg, then the iodine accepted of every kilogram of mouse [
131I]-amount of 23-hydroxyl radical white birck acid is that people's multiple is:
Injection consumption=0.4/0.02/ (1/50)=1000 of dosis tolerata/people of mouse times
Result's demonstration,
131I-23-hydroxyl radical white birck acid injection liquid safety non-toxic.
Claims (9)
1, a kind of iodine (* I)-23-hydroxyl radical white birck acid is characterized in that having the compound of following general structure:
Iodine in the formula (* I) expression nucleic iodine
123I,
124I,
125I,
127I,
131A kind of among the I.
2, the preparation method of iodine as claimed in claim 1 (* I)-23-hydroxyl radical white birck acid is characterized in that, adopts the peroxide oxidation method to carry out iodine labeling the 23-hydroxyl radical white birck acid, and step is as follows:
(1) ethanolic soln of 23-hydroxyl radical white birck acid is mixed with oxygenant and an amount of NaI* under acidic conditions, place 10-30min down for 20-60 ℃;
(2) in (1), add reductive agent, termination reaction; Adding the pH regulator agent transfers pH to neutral;
(3) in (2), add organic extractant phase, get organic layer, dry up;
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;
The described reductive agent of step (2) 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;
The described organic phase of step (3) is a kind of in ethyl acetate, ether, ethanol, acetone, the acetonitrile.
3, application of compound according to claim 1 is characterized in that the application as preparation lesion/cancer disease drug.
4, application according to claim 3, it is characterized in that: add one or more pharmaceutically receptible carriers in the medicine of this lesion/cancer disease of preparation, examples of such carriers is: the thinner of pharmaceutical field routine, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant, emulsifying agent, osmotic pressure regulator, stablizer.
5, application according to claim 3 is characterized in that: described medicine can be made injection liquid, tablet, pulvis, granula, pill, capsule, tincture, oral liquid, paste, creme, emulsion or applicator.
6, application according to claim 3 is characterized in that: described medicine is single photon emission computed tomography and/or Positron Emission Computed Tomography reagent.
7, application according to claim 3 is characterized in that: described medicine is for diagnosing, treat and/or prevent the medicine of cancer, and described cancer is: mammary cancer, thyroid tumor, glioma brain tumour, intestinal canal tumour, liver cancer, lung cancer.
8, application according to claim 3 is characterized in that: described medicine is the medicine that treats and/or prevents new vessel class disease.
9, application according to claim 3 is characterized in that: described medicine is the medicine that treats and/or prevents acquired immune deficiency syndrome (AIDS).
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| KR101254636B1 (en) | 2011-02-14 | 2013-04-15 | 한국수력원자력 주식회사 | Method for synthesis of radioactive methyl iodine and device thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4541957A (en) * | 1983-09-07 | 1985-09-17 | The George Washington University | Process for preparing iodovinyl-estradiol |
| US5096694A (en) * | 1987-04-17 | 1992-03-17 | Ire-Celltarg S.A. | Compounds which are useful, in particular, for radiotherapy or imaging of cancer |
| WO1994005152A1 (en) * | 1992-09-10 | 1994-03-17 | Glycomed Incorporated | Derivatives of triterpenoid acids as inhibitors of cell-adhesion molecules elam-1 (e-selectin) and lecam-1 (l-selectin) |
| WO1995004526A1 (en) * | 1993-08-09 | 1995-02-16 | Glycomed Incorporated | Lupane triterpenoid derivatives |
-
2005
- 2005-04-06 CN CNB2005100387689A patent/CN1321127C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4541957A (en) * | 1983-09-07 | 1985-09-17 | The George Washington University | Process for preparing iodovinyl-estradiol |
| US5096694A (en) * | 1987-04-17 | 1992-03-17 | Ire-Celltarg S.A. | Compounds which are useful, in particular, for radiotherapy or imaging of cancer |
| WO1994005152A1 (en) * | 1992-09-10 | 1994-03-17 | Glycomed Incorporated | Derivatives of triterpenoid acids as inhibitors of cell-adhesion molecules elam-1 (e-selectin) and lecam-1 (l-selectin) |
| WO1995004526A1 (en) * | 1993-08-09 | 1995-02-16 | Glycomed Incorporated | Lupane triterpenoid derivatives |
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