CN1211396C - Estrogen compound of bone tendency, preparing method and application thereof - Google Patents
Estrogen compound of bone tendency, preparing method and application thereof Download PDFInfo
- Publication number
- CN1211396C CN1211396C CN 02136890 CN02136890A CN1211396C CN 1211396 C CN1211396 C CN 1211396C CN 02136890 CN02136890 CN 02136890 CN 02136890 A CN02136890 A CN 02136890A CN 1211396 C CN1211396 C CN 1211396C
- Authority
- CN
- China
- Prior art keywords
- bone
- compound
- estradiol
- tendency
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention provides an oestrogen compound with bone affinity, a preparation method thereof, medicine compositions containing the compound and the application thereof.
Description
Technical field
The present invention relates to estrogen compound of bone tendency, its preparation method and application thereof.
Background technology
Osteoporosis is not only the harm the elderly, and especially the postmenopausal women is healthy and influence the medical problem of its quality of life, and become the serious social concern of current aging society, for this reason, great amount of manpower and material resources is all poured in countries in the world, in the hope of illustrating on the basis of its genesis mechanism, reasonable, potent control strategy is proposed.
Various senile fractures are one of serious consequences of causing of osteoporosis.The determinative that causes osteoporotic fracture is not losing of bone amount, and more close with the relation of bone structure integrity and mechanical characteristics change.Bone remodeling with mould in the cycle, the function " coupling connection " between " bone resorption " that is caused by osteoclast and " bone forming " that caused by scleroblast is a key link of keeping bone structure integrity and suitable bone strength.In the recent period, we experimental studies have found that to broken bone (precursor) cell transformation by scleroblast, marrow Monocytes to the patients with osteoporosis that directly has drawn from: the osteoporosis scleroblast exists the inoblast sample to become; The marrow Monocytes increases to broken bone (precursor) cell transformation rate.Point out, the scleroblast that the inside and outside environment is caused and the change of osteoclast biological property, and then the scleroblast that is caused and osteoclast produce the mistake of information and the defective or the variation of information answer each other, might be ground substance of bone composition deficiency in the osteoporosis generating process, ground substance of bone calcification not exclusively, scleroblast and the osteoclast function " is lost the coupling connection ", the bad main factor of bone remodeling.Therefore, preventing and treating osteoporosis then should be to regulate and to improve the function of osteoporosis scleroblast and osteoclast, and recovering therebetween, " coupling connection " pass is one of major objective.
The osteoporotic fact easily takes place based on the postmenopausal women, and the discovery of scleroblast estrogen receptor, three kinds of hormone (parathyroid hormones to the alcium and phosphor metabolization adjusting, thyrocalcitonin and 1.25 (OH) 2D3) with by bone or other tissue with from/various cytokines interactional further investigation in bone conversion and bone resorption-bone forming that the paracrine mode produces, the osteoporotic measure of many controls has been proposed, developed the high amount of drug that is intended to reduce bone loss, mainly comprise estrogens, the fluorochemical class, the vitamins D class, the thyrocalcitonin class, bisphosphate salt etc., and played certain effect (Gideon AR, T.John M.Therapeutic Approaches to BoneDiseases.Science, 2000:289:1508-1514).Wherein, the part medicine is realized by raising scleroblast activity, inhibition osteoclast activity osteoporotic therapeutic action.But the relative low feature with metabolism of volume of blood flow because of bone makes the distributive law of these medicines in osseous tissue lower, thereby is difficult to reach the ideal curative effect or is restricted in application.If be gathered in osseous tissue with will making the medicine high density, more effectively to regulate and to improve the function of osteoporosis scleroblast and osteoclast, reach the desirable purpose that increases the osteoporotic bone amount, improves the bone structure quality, must increase dosage and time, this can increase the airframe systems incidence rate of adverse reaction undoubtedly, and some untoward reaction is serious often and secular, thereby has limited the further widespread use of medicine.At this present situation, existing it concentrated in bone the oestrogenic hormon and the bone sequestrant splicing that becomes and reduce research report and patent achievement-oestrogenic hormon and tsiklomitsin mixture TE2 (Mark WO, Virender ML.Synthese of β-estradiol-3-benzoate-17 (succinyl-12a-tetracycline): apotential bone-seeking estrogen.Bioorganic ﹠amp the influence of reproductive organ; Medicinal Chemistry Letters, 1994:4:1375-80), oestrogenic hormon and bisphosphonic acid derivatives SM-16896 (Naomi T, Masashi Y, HideyukiH., et al.Tissue distribution and pharmacological potential of SM-16896, a noveloestrogen-bisphosphate hybrid compound.J.Pharm.Pharmacol., 2000:52:27-73).But the selected conduct tsiklomitsin of bone carrier that becomes previously, himself since to the detrimentally affect of bone and tooth by clinical forbidding; The bone though the bisphosphonic acid derivatives tool becomes is preferably easily lost estrogen activity.Therefore, the choose reasonable of sequestrant is the key in this research field and the design of this compounds, the development, is still constantly screening and is seeking in the process as the carrier compound of the bone that becomes.
Summary of the invention
Goal of the invention
One of the object of the invention is to provide a kind of estrogen compound of bone tendency.
The present invention also aims to provide a kind of method for preparing estrogen compound of bone tendency.
The present invention also aims to provide a kind of pharmaceutical composition that comprises compound of the present invention.
The present invention also aims to provide the purposes of described compound in preparation treatment medicine for treating osteoporosis.
Technical scheme
In order to realize above purpose, technical scheme of the present invention is to utilize the bone that becomes of bis-phenol propylhomoserin, the formation chemical bonds such as effective components of Chinese medicinal of bis-phenol propylhomoserin with the treatment osteoporosis that can promote and/or be maintained in bone cell function (as estrogens), inhibition osteoclast activity (as two phosphorus phosphoric acid salts) medicine and our screening combined, make bone sex camplex medicine.
Known, bis-phenol propylhomoserin (CBMIDA) is the many carboxylic acids chelating agents of polyamines that have bone, has following structural formula:
Toxicological experiment proves that it has no adverse effects to bone, and bone metabolism there is higher activity, can promotes formation (Fukuda S, the et al. of ground substance of bone, Toxicological study of DIPA as a drug.HokenButsuri, 1991:26:101-107).Therefore, the present invention considers it as the small molecules carrier, will the medicine tropism ground that osteoporosis has a therapeutic action be imported and concentrate in osseous tissue.
Specifically, the invention provides a kind of estrogen compound of bone tendency, it has following structural formula:
Wherein, R1 to R4 is selected from-CH
2COOH and estradiol-3-oxygen-carbonyl-methylene radical, condition are to have at least two to be-CH among the R1 to R4
2COOH, first estradiol-3-oxygen-carbonyl-methylene radical at least.
In the preferred embodiment for the present invention, above-described compound has following structural formula:
More than, also can consider to carry the estrogenic mode of a part by the bis-phenol propylhomoserin of a part for the bis-phenol propylhomoserin of a part carries the estrogenic mode of two molecules.
The present invention also provides a kind of method for preparing estrogen compound of bone tendency, comprising:
Wherein,
1) bis-phenol propylhomoserin and acid anhydrides carry out the anhydridization reaction in the presence of pyridine;
2) product of step 1 and beta estradiol are in anhydrous pyridine, and with 4-N, N-lutidine (DMAP) is a catalyzer, reaction.
Described bis-phenol propylhomoserin can be bought and obtain, also can prepare, for example with reference to Xu MZ., et al., Studieson uranium mobilization agents II:synthesis of polyaminopolycarboxilic acid amideswith catechol moieties.Acta Pharmaceutica Sinica, the described method of 1986:21:148-151 (seeing embodiment 1).Described acid anhydrides is such as but not limited to formic anhydride, diacetyl oxide, and propionic anhydride etc., embodiment of the present invention has adopted diacetyl oxide.
The present invention also provides a kind of pharmaceutical composition, wherein contains the The compounds of this invention and the pharmaceutical excipient for the treatment of significant quantity.
Described " treatment significant quantity " refers to that the content of The compounds of this invention should be enough to the bone disease treatment effect that provides required with regard to its lower limit, simultaneously, with regard to its upper limit, still be unlikely to cause serious adverse side effect, promptly within the extensive effect danger of approving, this area is than scope.This significant quantity depends on multiple factor, such as but not limited to: the indication of being controlled, severity, the treatment same period, the course of treatment and patient age, healthy state, known factor such as medical history.Based on selected osteopathy medicine is above-mentioned factor, and those skilled in the art are not difficult to determine or get described surely significant quantity by routine test.
The formulation of pharmaceutical composition of the present invention can be a solid formulation at least, as tablet; Or liquid agent, as injection, mainly be that whole body is systemic medication.For example, can be oral, injection, comprise intramuscular injection and intravenous administration.
Described pharmaceutical excipient is known in the art.According to activeconstituents, formulation, required preparation characteristic, under the prerequisite that does not influence the The compounds of this invention curative effect, those skilled in the art are not difficult directly or by routine test to make suitable selection.Described vehicle is such as but not limited to thinner, filling agent, disintegrating agent, tackiness agent, thickening material, correctives, biocide, antioxidant, lubricant etc.
The present invention also provides the purposes of The compounds of this invention in the medicine of preparation treatment osteoporosis and relative disease thereof.
Beneficial effect
According to embodiment hereinafter as can be seen, estrogen compound of bone tendency of the present invention can increase the concentration of medicine in osseous tissue specifically, improves the useful effect that it improves osteoporosis scleroblast and osteoclast function, keeps the cells characteristic phenotype.Simultaneously,, body is had no side effect because the bis-phenol propylhomoserin after osteoporotic medicine combines with control, does not influence the activity of medicine, thus the stability of osteopathy medicine complex chemical compound can be improved, and the systemic undesirable action of minimizing medicine.
Embodiment
Embodiment 1
2,3-dihydroxyl-N, N '-dicarboxyl-N, N '-diacetyl estradiol-1, the preparation of 4-benzene dimethylamine (ES1)
The fusing point of compound is measured with Fisher-John fusing point instrument.Nuclear magnetic resonance spectrum Bruker AM-400 type spectrophotometer.Infrared spectra Perkin-Elmer 983G determination of infrared spectroscopy, the KBr compressing tablet.Mass spectrum is measured with the VG-707E mass spectrograph.Ultimate analysis is measured with Carlo Erba 1106 type elemental analysers.
1. the preparation of bis-phenol propylhomoserin
Get pyrocatechol 11.0g (0.10mol), iminodiethanoic acid 26.6g (0.2mol) and be suspended in 40ml acetate and the 80ml water, drip 37% formaldehyde solution 20ml under the room temperature, 60 ℃ of stirring heating 1h, a large amount of white precipitates are separated out in cooling.Filter, water, washing with alcohol, dry 30.7g, mp240 ℃ (decomposition), productive rate is 75.0%.Ultimate analysis C
16H
20N
2O
100.5H
2O, theoretical value (%): C 46.95, and H 5.17, and N 6.84; Measured value (%): C 46.85, and H 5.13, and N 6.69.
2. 2,3-diacetoxy-1, the preparation of 4-benzene dimethylamine diethyl acid anhydrides
With 10g (25mmol) 2,3-dihydroxyl-1,4-benzene dimethylamine tetraacethyl, 30ml diacetyl oxide and 6ml pyridine place the 100ml round-bottomed flask, and 60 ℃ of stirring heating 4h make reactant all dissolve, and continue to stir the 1h postcooling, separate out a large amount of solids.The filter collection gets white solid 5.48g with the diacetyl oxide recrystallization, and mp167-169 ℃, productive rate is 49.8%.Ultimate analysis C
20H
20N
2O
10, theoretical value (%): C 53.57, and H 4.50, and N 6.25; Measured value (%): C 53.60, and H 4.47, and N 6.04.
1H-NMR(d-DMSO)δppm：2.26(s，6H，CH
3CO-)，3.39(s，4H，-CH
2-)，3.65(s，8H，-CH
2-)，7.33(s，2H，Ar-H)。
3. 2,3-dihydroxyl-N, N '-two carboxymethyls-N, N '-diacetyl estradiol-1, the preparation of 4-benzene dimethylamine (ES1)
Get 2,3-diethoxy-1,4-benzene dimethylamine diethyl acid anhydrides 5.0g (11mmol), beta estradiol 9.1g (33mmol) is dissolved in the 100ml anhydrous pyridine, adds catalyzer 4-N, N-lutidine (DMAP) 1.4g (11mmol), 55 ℃ of stirring heating 12h.The elimination small amount of impurities is separated out white solid in the mother liquor impouring 500ml cold water.The filter collection gets product 7.0g with acetate-water recrystallization behind water, the washing with acetone, and mp85-186 ℃, productive rate is 70.0%.Ultimate analysis C
52H
64N
2O
102H
2O, theoretical value (%): C 68.42, and H 7.46, and N 3.07; Measured value (%): C 68.31, and H 7.37, and N 3.38.
1H-NMR(d-DMSO)δppm：0.77(s，6H，Es：-CH
3)，1.15-1.48(m，16H，Es：-CH
2-)，1.54-1.58(m，2H，Es：-CH＜)，1.61-1.89(m，4H，Es：-CH＜)，2.01-2.09(m，2H，Es：-CK＜)，2.19-2.25(m，2H，Es：-CK＜)，2.65-2.79(m，4H，Es：-CH
2-)，3.35(s，4H，Ar-CH
2-)，3.52-3.55(m，2H，Es：-CH＜)，3.71-3.90(m，8H，-CH
2COO-)，4.55(s，2H，-OH)，6.42(s，2H，Es：Ar-H)，6.51-6.53(d，2H，Es：Ar-H)，6.98-7.05(d，2H，Es：Ar-H)，8.28(s，2H，Ar-H)，8.55(s，2H，Ar-OH)。MS(EI)m/z：439.6。313.6 (CH
2COOEs
+), 271.6 (Es
+) (annotate: Es refers to estradiol).IR(KBr)νcm
-1：3270.7，1739.5，1648.9，1209.2，1006.7，817.7。
Embodiment 2
The compd E S1 experiment that in the mouse body, distributes
In the ES1 radioiodination posterior vein injection mouse body,, understand compound characteristic distributions in each internal organs in animal body, to investigate its bone that becomes by radioassay.
1. compound
125The marking method of I-ES1
Iodine labeling has common methods such as chloramine-T oxidation style, iodine monochloride method, glucose oxidase method and Iodogen method.ES1 is an estrogen analogue, and molecular weight is lower and contain the group (aromatic nucleus) that is easy to mark, so we adopt gentle Iodogen method to carry out mark.
Get the plastics that glass stirring spillikin is housed and refer to the type pipe, have transfer pipet to move into the dichloromethane solution that 20ml contains 40 μ g chlorine glycolurils, feeding nitrogen and continuous rotation refer to that the type pipe is evenly coated on tube wall and the stirring spillikin solution.Add phosphoric acid buffer 20 μ l (pH=7.2) and the Na that wait to mark compound 2 μ g, 0.2M
125I solution 2-3mci, in ice-water bath the concussion half an hour after stopped reaction, carry out the HPLC separation and purification.Elutriant is the methanol aqueous solution (25%-100%) of different proportionings, and drip washing speed is the 0.5-1.0ml/ branch.Collect main iodine mark peak for experimentation on animals usefulness after removing free-iodine.Gross activity 200 μ ci, radioactive concentration 40 μ ci/ml are 20 μ ci/ μ g than degree.
2. experiment distributes in the mouse body
Animal is a Kunming mouse, is provided by the Shanghai Experimental Animal Center, and is female, body weight 19-21g.Instrument is COBRA γ-calculating instrument.Radioactivity stoste distilled water diluting is 30 μ ci/ml.
Mouse is pressed the 0.005ml/g body weight, the above-mentioned diluent of tail vein injection.Mouse is divided 12 groups after the administration, and every group 6 mouse put cage raising.After regularly eye socket is got blood, put to death and take off the row organ: skull bone, femur, vertebra, liver, ovary, uterus, muscle, Tiroidina, thymus gland, heart, spleen, claim weight in wet base, measure radioactive intensity in each organ (cpm).
The cpm/mg that records is converted into each internal organs dpm/mg (dpm=cpm/ instrument efficient * disintegration coefficient).Calculate each time point, the mean value of each internal organs and standard deviation the results are shown in following form.
Table 1:
125I-ES1 contains scale in the different tissues of mice internal organs
dpm/mg(x±SD)
| Internal organs | 1h | 2h | 4h | 8h | 24h |
| Skull bone | 46.5±18.4 | 26.2±6.3 | 15.9±5 | 12.1±7.4 | 0.8±0.4 |
| Femur | 41.3±8.6 | 23.5±2.0 | 17.5±11.3 | 15.5±6.5 | 2.3±0.5 |
| Vertebra | 37.4±14.1 | 22.7±3.9 | 16.9±6.6 | 19.1±10.4 | 3.0±0.3 |
| Ovary | 69.9±19.6 | 75.2±58 | 33.9±13.7 | 79.9±21.7 | 3.2±1.3 |
| The uterus | 76.9±29.3 | 77.3±6 | 66.6±42.2 | 11.8±3.5 | 4.8±0.5 |
| Liver | 808±138 | 543±96 | 386±82 | 318±108 | 65.8±10.9 |
| Kidney | 110±22 | 71.4±8.5 | 48.4±12.6 | 19.6±21.4 | 14.9±2.2 |
| Muscle | 25.4±4.2 | 14.4±5.6 | 12.2±2.7 | 24.1±8.5 | 1.6±0.1 |
| Tiroidina | 143±40 | 81.8±20 | 72.9±26.6 | 36.5±14.7 | 4.8±0.7 |
| Thymus gland | 52.2±17.9 | 29.5±8.1 | 18.2±7.9 | 26.8±24.1 | 3.9±2.7 |
| Heart | 51.5±13.9 | 28.8±6.1 | 18.4±5.6 | 24.1±11.3 | 3.6±0.5 |
| Spleen | 340±44 | 176±43 | 117±43 | 104±53 | 17.2±3.2 |
| Lungs | 155±37 | 90.4±18 | 56.1±15.7 | 44.9±16.7 | 11.6±3 |
| Whole blood (μ l) | 110±33 | 69.7±15 | 36.3±9.4 | 35.9±14.9 | 11±3.4 |
| Internal organs | 2d | 3d | 5d | 7d | 10d |
| Skull bone | 0.7±0.5 | 0.8±0.4 | 0.8±0 | 0.6±0.6 | 0.3±0 |
| Femur | 1.3±0.4 | 1.9±1.1 | 1.0±0.3 | 0.4±0.3 | 0.4±0.3 |
| Vertebra | 2.8±1.1 | 2.8±0.5 | 1.4±0.3 | 0.9±0.3 | 0.14±0.1 |
| Ovary | 1.7±1.5 | 3.5±1.2 | 1.0±0.7 | 0.6±0.4 | 1.0±0.3 |
| The uterus | 3.2±1.1 | 4.4±1.3 | 2.1±1.2 | 1.6±0.6 | 0.7±0.4 |
| Liver | 37.5±3.8 | 40.8±6.1 | 24.1±5.0 | 22.8±6.7 | 7.9±2.2 |
| Kidney | 11.8±3.1 | 7.6±1.8 | 7.6±0.8 | 3.4±1.0 | 2.6±0.6 |
| Muscle | 1.3±0.7 | 1.6±0.5 | 0.6±0.3 | 0.4±0.3 | 0.3±0.1 |
| Tiroidina | 5.0±2.8 | 4.8±1.9 | 2.1±0.3 | 1.9±0.6 | 1.2±0.7 |
| Thymus gland | 1.9±0.8 | 2.0±0.7 | 1.2±0.2 | 1.0±0.6 | 0.4±0.4 |
| Heart | 3.1±1.2 | 3.4±0.7 | 1.4±0.6 | 1.3±0.6 | 0.6±0.3 |
| Spleen | 12.4±4.6 | 15.9±4.8 | 10.2±2.2 | 16.7±8.4 | 15.0±2.6 |
| Lungs | 7.0±2.3 | 8.1±2.7 | 6.2±4.4 | 3.0±0.9 | 2.2±0.7 |
| Whole blood (μ l) | 10.8±3.5 | 9.0±2.4 | 3.9±1.4 | 2.9±0.6 | 1.9±0.4 |
Roughly suitable with in uterus, ovary of above data presentation, the content of The compounds of this invention ES1 in bone, but apparently higher than other organs and tissue.ES1 of the present invention in the uterus, entovarial enrichment may be because histoorgans such as uterus, ovary are rich in estrogen receptor, thereby make and carry that external source is estrogenic wherein a higher abundance, but this also shows that estradiol is after The compounds of this invention is modified simultaneously, and its biological nature does not have obvious change.Simultaneously, with other organs and tissue in the bone that obviously becomes that has relatively shown The compounds of this invention of content.
Claims (5)
1. estrogen compound of bone tendency, it has following structural formula:
Wherein, R1 to R4 is selected from-CH
2COOH and estradiol-3-oxygen-carbonyl-methylene radical, condition are to have at least two to be-CH among the R1 to R4
2COOH, first estradiol-3-oxygen-carbonyl-methylene radical at least.
2. compound according to claim 1 is characterized in that its structural formula is as follows
3. method for preparing the described estrogen compound of bone tendency of claim 1 comprises:
1) bis-phenol propylhomoserin and the acid anhydrides with following structural formula reacts in the presence of pyridine;
2) product of step 1 and beta estradiol are in anhydrous pyridine, and with 4-N, N-lutidine (DMAP) reacts for catalyzer.
4. a pharmaceutical composition wherein contains claim 1 or 2 described compound and pharmaceutical excipients.
5. the purposes of the described compound of claim 1 in the medicine of preparation treatment osteoporosis and relative disease thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02136890 CN1211396C (en) | 2002-09-09 | 2002-09-09 | Estrogen compound of bone tendency, preparing method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02136890 CN1211396C (en) | 2002-09-09 | 2002-09-09 | Estrogen compound of bone tendency, preparing method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1482135A CN1482135A (en) | 2004-03-17 |
| CN1211396C true CN1211396C (en) | 2005-07-20 |
Family
ID=34146728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02136890 Expired - Fee Related CN1211396C (en) | 2002-09-09 | 2002-09-09 | Estrogen compound of bone tendency, preparing method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1211396C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009123978A1 (en) | 2008-03-31 | 2009-10-08 | The Trustees Of Columbia University In The City Of New York | Methods of diagnosing, preventing and treating bone mass diseases |
-
2002
- 2002-09-09 CN CN 02136890 patent/CN1211396C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1482135A (en) | 2004-03-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP4469465A1 (en) | Trinucleotide cap analogs and methods of use thereof | |
| CN1211396C (en) | Estrogen compound of bone tendency, preparing method and application thereof | |
| KR100219965B1 (en) | Methods for treating and / or diagnosing soft tissue tumors | |
| CN107126432A (en) | Lian Bizhi Neulized inhalation pharmaceutical solutionses and preparation method thereof | |
| CN112876442A (en) | Anti-osteoporosis acacetin derivative and preparation method thereof | |
| EP1443918B1 (en) | Calcium l-threonate for treating bone facture | |
| CN1211395C (en) | Estrogen compound of bone tendency, preparing method and application thereof | |
| CN101028252A (en) | Injection acetylcysteine powdery medicinal composition and its making method | |
| CN113277989B (en) | A kind of68Ga-labeled molecular probe, preparation method and application thereof | |
| CN1184225C (en) | A kind of tetrofosmin quaternary phosphonium salt and its preparation method, two-step method tetrofosmin kit and its application | |
| CN108514645B (en) | A preparation combining bone imaging and bone metastases treatment and its preparation and application | |
| CN108570081B (en) | A kind of ligand compound for glucose imaging diagnosis and treatment and its preparation and application | |
| Li et al. | Biodistribution of fullerene derivative C60 (OH) x (O) y | |
| CN101074231A (en) | [18F] fluoraro-marked purine compound, its production and use | |
| CN108553437A (en) | One kind passing through mercaptopurine chewable tablets and preparation method thereof made from ion exchange technique | |
| CN108191603B (en) | A kind of 3-18F-fluorolactic acid analog and its preparation method and application | |
| CN113861254A (en) | A kind of tumor PET imaging agent 68Ga-NOTA-ADG and its preparation method and application | |
| CN113398117A (en) | Application of dimethylamine 4-O-acetyl baseline leaf inula lactone A and salt thereof in preparation of medicine for treating chronic renal failure | |
| CN116396358B (en) | Preparation and application of bone-targeted nano lipid particles | |
| CN1169579C (en) | Medicine C-AEDP using C as carrier for target therapy of osteopath and its usage | |
| CN1065769C (en) | Method for preparing radiopharmaceutical preparation | |
| CN116570736B (en) | Radioactive probe for targeting angiotensin receptor II based on SARS-CoV series virus S protein sequence | |
| CN111039873B (en) | Preparation method of fenbendazole sulfoxide | |
| CN1511840A (en) | Puerarin compound containing water soluble group and its preparation and use | |
| US20210101905A1 (en) | Development of Imaging and Therapeutic Glucose Analogues for Sodium Dependent Glucose Transporters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050720 Termination date: 20150909 |
|
| EXPY | Termination of patent right or utility model |