CN103130814B - Two kinds of 9-nitrocamptothecin new crystal and preparation method thereof - Google Patents
Two kinds of 9-nitrocamptothecin new crystal and preparation method thereof Download PDFInfo
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- CN103130814B CN103130814B CN201110385245.7A CN201110385245A CN103130814B CN 103130814 B CN103130814 B CN 103130814B CN 201110385245 A CN201110385245 A CN 201110385245A CN 103130814 B CN103130814 B CN 103130814B
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Abstract
The invention provides a kind of 9-nitrocamptothecin new crystal I and preparation method thereof.This crystal formation I is better than existing 9-nitrocamptothecin crystal formation to heat and wet stability.Present invention also offers 9-nitrocamptothecin crystal form II and preparation method thereof, the solubleness of this crystal form II is greater than existing 9-nitrocamptothecin crystal formation.The crystal formation I of 9-nitrocamptothecin of the present invention and the preparation method of crystal form II simple to operation, applicable technique changes into product.
Description
Technical field
The present invention relates to two kinds of new crystal of 9-nitrocamptothecin (also known as rubitecan): crystal formation I and crystal form II, and preparation method thereof.
Background technology
9-nitrocamptothecin, chemical name: 4 (S)-ethyl-4 hydroxyl-10-nitro-1H-pyrans also [3 ', 4 ': 6,7] benzazole also [1,2-b] quinoline-3,14 (4H, 12H)-diketone, be a kind of novel semi-synthetic camptothecin derivative, belong to the topoisomerase enzyme inhibitor of new research and development in recent years.9-nitrocamptothecin is oral preparations, and the new drug researched and developed by SuperGen company is used for the treatment of carcinoma of the pancreas and other solid tumor, and great advantage can take in the non-while in hospital, and therefore patient can treat at home.
Clinical pharmacology experimental study proves that 9-nitrocamptothecin is less than other camptothecine toxic side effect now having dropped into Clinical practice, and the advantage of its uniqueness is effectively oral.9-nitrocamptothecin has very strong tumor-suppression activity to multiple cancer cells, and it is more in site distribution such as pancreas, ovary, prostate glands, the certain drug of carcinoma of the pancreas, ovarian cancer and prostate cancer may be become, especially special-effect is had to the treatment of carcinoma of the pancreas, american cancer research organization thinks that 9-nitrocamptothecin very likely becomes a line medication for the treatment of advanced pancreatic cancer, has very large clinical value.
The seven kinds of crystal formations at present having had the crystal formation of the 9-nitrocamptothecin of patent report to have to announce in WO03/072027.Solvent when this patent also discloses this seven kinds of crystal formations of recrystallization can be: acetone, methylene dichloride, tetrahydrofuran (THF) and acetonitrile etc., and muffin acetone, methylene dichloride, tetrahydrofuran (THF), acetonitrile crystal formation recrystallization in dry DMF and moisture DMF of obtaining obtains.A kind of crystal formation that cooling down obtains in methyl alcohol is disclosed in CN1611505.
Summary of the invention
Technical problem to be solved by this invention there are provided two kinds of novel 9-nitrocamptothecin crystal formations, crystal formation I and crystal form II.Crystal formation I of the present invention is better than existing 9-nitrocamptothecin crystal formation to heat and wet stability, and the solubleness of crystal form II is greater than existing 9-nitrocamptothecin crystal formation.The present invention also each provides the preparation method of 9-nitrocamptothecin crystal formation I and crystal form II.
The invention provides a kind of crystal formation I of 9-nitrocamptothecin, this crystal formation I is using in the powder x-ray diffraction spectrum that source of radiation is Cu-K α, in diffraction angle 2 θ=6.100, 8.392, 10.932, 12.197, 12.591, 13.381, 13.932, 15.055, 16.535, 16.873, 18.332, 18.885, 19.674, 21.292, 21.607, 21.964, 22.753, 23.958, 24.433, 25.041, 25.360, 25.674, 26.957, 27.962, 28.771, 29.719, 30.352, 31.596, 32.603, 35.937, 37.001, there is characteristic peak at 38.463 and 39.960 degree of places, 2 θ limit of error are ± 0.2.
Wherein, the fusing point of the crystal formation I of described 9-nitrocamptothecin is generally 263 ± 1 DEG C.
Present invention also offers the preparation method of the crystal formation I of described 9-nitrocamptothecin, it comprises the steps:, and 9-nitrocamptothecin is dissolved in organic solvent by (1); (2) adopt method of evaporation to remove solvent, obtain the crystal formation I of 9-nitrocamptothecin; Wherein said organic solvent is the single solvent being selected from following solvents or the mixed solvent be made up of following solvents: methyl alcohol, ethyl formate, ethyl acetate, isobutyl acetate, dithiocarbonic anhydride, tetrahydrofuran (THF), 2-butanone and n-propyl alcohol.
In step (1), described 9-nitrocamptothecin can be various forms of 9-nitrocamptothecin crystal formation or unformed 9-nitrocamptothecin in this area.
In step (1), the consumption of described organic solvent does not have particular requirement, as long as can dissolve 9-nitrocamptothecin completely.
In step (1), when described organic solvent is mixed solvent, this mixed solvent is preferably by 2 kinds of solvent compositions, and the volume ratio of two kinds of solvents is preferably 5: 1-7: 1.
In step (1), described single solvent is preferably tetrahydrofuran (THF), n-propyl alcohol or 2-butanone.Described mixed solvent is preferably ethyl acetate and methyl alcohol, isobutyl acetate and methyl alcohol, ethyl formate and methyl alcohol, or dithiocarbonic anhydride and methyl alcohol, wherein the volume ratio of ethyl acetate, isobutyl acetate, ethyl formate or dithiocarbonic anhydride and methyl alcohol is preferably 5: 1-7: 1.
In step (2), the vaporization temperature of described method of evaporation is preferably 25 ~ 60 DEG C, is more preferably 25 ~ 40 DEG C.
In step (2), the evaporating pressure of described method of evaporation is preferably 0.05 ~ 0.1MP.
In step (2), after removing solvent by method of evaporation, preferably carry out vacuum-drying, described vacuum drying pressure is preferably 65 ~ 165mBar.
Present invention also offers a kind of crystal form II of 9-nitrocamptothecin, this crystal form II is using in the powder x-ray diffraction spectrum that source of radiation is Cu-K α, in diffraction angle 2 θ=7.834, there is characteristic peak at 8.863,12.058,14.248,14.623,16.025,18.035,19.755,21.156,22.004,23.524,25.773,26.565,27.054,28.911 and 32.700 degree of places, and 2 θ limit of error are ± 0.2.
Wherein, the fusing point of the crystal form II of described 9-nitrocamptothecin is 156 ± 1 DEG C.
Present invention also offers the preparation method of the crystal form II of described 9-nitrocamptothecin, it comprises the steps:, and 9-nitrocamptothecin mixes with organic solvent by (1), and intensification stirring makes 9-nitrocamptothecin dissolve completely; (2) cooling down, obtains the crystal form II of 9-nitrocamptothecin; Wherein said organic solvent is selected from acetone or 2-butanone etc.
In step (1), described 9-nitrocamptothecin can be various forms of 9-nitrocamptothecin crystal formation or unformed 9-nitrocamptothecin in this area.
In step (1), the consumption of described organic solvent does not have particular requirement, as long as 9-nitrocamptothecin can be dissolved completely.
In step (1), the terminal temperature of described intensification is preferably 45 ~ 55 DEG C.
In step (1), described temperature-rise period preferably carries out under agitation.
In step (2), the temperature of described cooling is preferably less than 28 DEG C.
In step (2), after described cooling down, preferably adopt the method for this area routine to carry out solid-liquid separation, then carry out drying.Described solid-liquid separation adopts conventional solid-liquid separating method, such as evaporating solvent or filtration at normal temperatures and pressures.Described filtration can adopt the filter method of the various routine in this area, as vacuum filtration.
In the present invention, above-mentioned optimum condition can arbitrary combination on the basis meeting this area general knowledge, obtains each preferred embodiment of the present invention.
Raw material of the present invention and reagent are all commercially.
Positive progressive effect of the present invention is:
1, the invention provides a kind of crystal formation I of 9-nitrocamptothecin, this crystal formation I is better than existing 9-nitrocamptothecin crystal formation to heat and wet stability.
2, present invention also offers a kind of crystal form II of 9-nitrocamptothecin, the solubleness of this crystal form II is greater than existing 9-nitrocamptothecin crystal formation.
3, the crystal formation I of 9-nitrocamptothecin of the present invention and the preparation method of crystal form II simple to operation, applicable technique changes into product.
Accompanying drawing explanation
Fig. 1 is the DSC-TGA analysis chart of the crystal formation I of 9-nitrocamptothecin.
Fig. 2 is the Powder XRD pattern of the crystal formation I of 9-nitrocamptothecin.
Fig. 3 is the DSC-TGA analysis chart of the crystal form II of 9-nitrocamptothecin.
Fig. 4 is the Powder XRD pattern of the crystal form II of 9-nitrocamptothecin.
Fig. 5 is the humidity stability figure of the crystal formation I of 9-nitrocamptothecin, crystal form II and bulk drug.
Above-mentioned explanation and the following examples are only exemplary and illustrative, and its protection should be not limited to this.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but the present invention is not limited to this.
The preparation of embodiment 1-169-nitro campotothecin crystal form I
Embodiment 1
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add THF200ml, stir and make it dissolve, under normal temperature and pressure, evaporating solvent obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 2
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add ethyl acetate 700ml and 100ml methyl alcohol, stir and make it dissolve, under normal temperature and pressure, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 3
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add isobutyl acetate 700ml and 100ml methyl alcohol, stir and make it dissolve, under normal temperature and pressure, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 4
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add ethyl formate 700ml and 100ml methyl alcohol, stir and make it dissolve, under normal temperature and pressure, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 5
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add dithiocarbonic anhydride 700ml and 100ml methyl alcohol, stir and make it dissolve, under normal temperature and pressure, evaporating solvent obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 6
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add n-propyl alcohol 700ml, after stirring 8h, under normal temperature and pressure, evaporating solvent obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 7
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add 2-butanone 500ml, stir and make it dissolve, under normal temperature and pressure, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 8
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add THF200ml, stir and make it dissolve, at normal pressure 40 DEG C, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 9
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add ethyl acetate 700ml and 100ml methyl alcohol, stir and make it dissolve, at normal pressure 40 DEG C, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 10
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add isobutyl acetate 700ml and 100ml methyl alcohol, stir and make it dissolve, at normal pressure 40 DEG C, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 11
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add ethyl formate 700ml and 100ml methyl alcohol, stir and make it dissolve, at normal pressure 40 DEG C, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 12
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add dithiocarbonic anhydride 700ml and 100ml methyl alcohol, stir and make it dissolve, at normal pressure 40 DEG C, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 13
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add n-propyl alcohol 700ml, at normal pressure 60 DEG C, does evaporating solvent crystallization (carry out recrystallization with which kind of solvent after stirring 8h?) obtain crystal formation I, preserve after the crystal vacuum-drying obtained.
Embodiment 14
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add 2-butanone 500ml, stir and make it dissolve, at normal pressure 40 DEG C, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 15
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, stir at adding 700ml methyl alcohol 60 DEG C and make it dissolve, after keeping 60 DEG C to stir 3h, at cooling to 40 DEG C, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
Embodiment 16
In 1 liter of reaction flask, drop into 9-nitrocamptothecin 1g, add the stirring of 800ml ethyl acetate and make it dissolve, under normal temperature condition, evaporating solvent crystallization obtains crystal formation I, preserves after the crystal vacuum-drying obtained.
The preparation of the crystal form II of embodiment 17-199-nitrocamptothecin
Embodiment 17
Claim 9-nitrocamptothecin 0.5g to put in 1000ml crystallizer, add 250ml acetone, heat up 55 DEG C and stir 3h, under being slow cooling to room temperature condition, under normal temperature and pressure, after evaporating solvent, obtain crystal form II, preserve after the crystal vacuum-drying obtained.
Embodiment 18
Claim 9-nitrocamptothecin to claim 0.5mg to put in 1000ml crystallization, add 350ml butanone, heat up 45 DEG C and stir 3h, stop stirring static 0.5h under being slow cooling to 5 DEG C of conditions long brilliant, filter, drain, normal-temperature vacuum oven for drying 48h obtains crystal form II.
Embodiment 19
Claim 9-nitrocamptothecin 0.5g to put in 1000ml crystallization, add 300ml acetone, heat up 55 DEG C and stir 3h, under being slow cooling to 5 DEG C of conditions, under normal temperature and pressure, after evaporating solvent, obtain crystal form II.
The crystal formation I of effect example 19-nitrocamptothecin
Carry out powder x-ray diffraction to the crystal formation I of the 9-nitrocamptothecin that embodiment 1-16 obtains, source of radiation is Cu-K α, and spectrogram is shown in Fig. 2, and the specific features peak value of crystal formation I is in table 1.
The PXRD characteristic peak of the crystal formation I of table 19-nitrocamptothecin
The crystal form II of effect example 29-nitrocamptothecin
Carry out powder x-ray diffraction to the crystal form II of the 9-nitrocamptothecin that embodiment 17-19 obtains, source of radiation is Cu-K α, and spectrogram is shown in Fig. 4, and the specific features peak value of crystal form II is in table 2.
The PXRD characteristic peak of the crystal form II of table 29-nitrocamptothecin
Effect example 3
Detect with the crystal formation I of differential scanning calorimetric (DSC) method to the 9-nitrocamptothecin of embodiment 1, from 20 DEG C of beginnings, with the ramp to 350 DEG C of 10 DEG C/min, it has endotherm(ic)peak at 263 ± 1 DEG C of places, specifically sees Fig. 1.The TGA figure of this crystal formation I is shown in Fig. 1 equally.DSC and the TGA figure of other embodiments is with this embodiment.
Detect with the crystal form II of differential scanning calorimetric (DSC) method to the 9-nitrocamptothecin in embodiment 17, from 20 DEG C of beginnings, with the ramp to 350 DEG C of 10 DEG C/min, it has endotherm(ic)peak at 156 ± 1 DEG C of places, specifically sees Fig. 3.The TGA figure of this crystal form II is shown in Fig. 3 equally.DSC and the TGA figure of other crystal form II embodiments is with this embodiment.
Effect example 4
1, solubleness
What the test of solubleness adopted is application HPLC method, and measure by external standard method, the condition of HPLC is as follows:
Pillar model: Synergi4 μ hydro-RP80A250mm*4.60mm
Moving phase: methyl alcohol: water=0.6: 0.4
Column temperature: 30 DEG C
Wavelength: 287nm
Detected result is as follows:
| Sample ID | Crystal formation I | Crystal form II | Bulk drug |
| Solubleness μ g/ml | 0.946 | 2.329 | 1.234 |
2, humidity stability
Crystal formation I of the present invention is the most stable crystal formation through detecting, and finds that bulk drug and newfound crystal form II have the tendency being converted into crystal formation I, and crystal formation I does not then transform under experimental conditions.Experiment condition: get appropriate crystal formation I, crystal form II and bulk drug under 97% humidity condition, timing sampling detects respectively.
Claims (4)
1. the preparation method of the crystal formation I of a 9-nitrocamptothecin, it is characterized in that: described crystal formation I is using in the powder x-ray diffraction spectrum that source of radiation is Cu-K α, in diffraction angle 2 θ=6.100, 8.392, 10.932, 12.197, 12.591, 13.381, 13.932, 15.055, 16.535, 16.873, 18.332, 18.885, 19.674, 21.292, 21.607, 21.964, 22.753, 23.958, 24.433, 25.041, 25.360, 25.674, 26.957, 27.962, 28.771, 29.719, 30.352, 31.596, 32.603, 35.937, 37.001, there is characteristic peak at 38.463 and 39.960 degree of places, 2 θ limit of error are ± 0.2,
Described preparation method comprises the steps: that 9-nitrocamptothecin is dissolved in organic solvent by (1); (2) adopt method of evaporation to remove solvent, obtain the crystal formation I of 9-nitrocamptothecin;
Wherein, in step (1), described organic solvent is single solvent or mixed solvent: described single solvent is tetrahydrofuran (THF), n-propyl alcohol or 2-butanone; Described mixed solvent is ethyl acetate and methyl alcohol, isobutyl acetate and methyl alcohol, ethyl formate and methyl alcohol, or dithiocarbonic anhydride and methyl alcohol, and wherein the volume ratio of ethyl acetate, isobutyl acetate, ethyl formate or dithiocarbonic anhydride and methyl alcohol is 5:1-7:1;
In step (2), the vaporization temperature of described method of evaporation is 25 ~ 60 DEG C; The evaporating pressure of described method of evaporation is 0.05 ~ 0.1MP.
2. preparation method as claimed in claim 1, is characterized in that: the fusing point of described crystal formation I is 263 ± 1 DEG C.
3. preparation method as claimed in claim 1 or 2, is characterized in that: in step (2), and after removing solvent by method of evaporation, carry out vacuum-drying, described vacuum drying pressure is 65 ~ 165mBar.
4. preparation method as claimed in claim 1, it is characterized in that: in step (2), the vaporization temperature of described method of evaporation is 25 ~ 40 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110385245.7A CN103130814B (en) | 2011-11-25 | 2011-11-25 | Two kinds of 9-nitrocamptothecin new crystal and preparation method thereof |
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| CN201110385245.7A CN103130814B (en) | 2011-11-25 | 2011-11-25 | Two kinds of 9-nitrocamptothecin new crystal and preparation method thereof |
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| CN103130814B true CN103130814B (en) | 2016-03-09 |
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Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6482830B1 (en) * | 2002-02-21 | 2002-11-19 | Supergen, Inc. | Compositions and formulations of 9-nitrocamptothecin polymorphs and methods of use therefor |
| CN1324032C (en) * | 2004-01-07 | 2007-07-04 | 重庆医药工业研究院有限责任公司 | Novel 9-nitro campotothecin crystal form and medicinal composition |
| CN100334089C (en) * | 2004-07-21 | 2007-08-29 | 王洋 | Production method of 9-nitro camptothecin |
| CN1781923A (en) * | 2004-11-29 | 2006-06-07 | 中国科学院成都有机化学有限公司 | Method for preparing 9-nitro-20(s)-camptothecine |
| CN1312155C (en) * | 2005-01-21 | 2007-04-25 | 华东理工大学 | Method for separating and purifying 9-nitro camptothecin |
| CN102229615B (en) * | 2011-07-27 | 2013-08-21 | 河南东泰制药有限公司 | Method for synthesizing 9-nitrocamptothecin |
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