CN107540638A - Anticancer compound CX1409 novel crystal forms and preparation method and application - Google Patents
Anticancer compound CX1409 novel crystal forms and preparation method and application Download PDFInfo
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Abstract
The present invention relates to compound field, more particularly to anticancer compound CX1409 two kinds of novel crystal forms, wherein, anticancer compound CX1409 crystal formation A is determined with powder x-ray diffraction determination method, and characteristic diffraction peak is shown at 4.3 °, 8.7 °, 11.0 °, 12.5 °, 13.0 °, 14.1 °, 15.4 °, 17.4 °, 18.4 °, 19.6 °, 20.1 °, 20.8 °, 21.7 °, 27.0 °, 29.0 °, 30.6 ° and 31.4 ° with the X-ray powder diffraction pattern that the 2 θ ± 0.3 ° angles of diffraction represent.Anticancer compound CX1409 crystal formation B is determined with powder x-ray diffraction determination method, and characteristic diffraction peak is shown at 4.9 °, 5.4 °, 5.8 °, 6.4 °, 8.0 °, 9.4 ° and 12.9 ° with the X-ray powder diffraction pattern that the 2 θ ± 0.3 ° angles of diffraction represent.Above two crystal formation has no report, its sharp outline, can perfect reproduction, and possess the characteristics of good stability, high income, high purity, can be used as the purposes in antineoplastic, have broad application prospects.
Description
Technical field
The present invention relates to compound crystal, and in particular to anticancer compound CX1409 two kinds of novel crystal forms and preparation method thereof
With application.
Background technology
Since U.S. FDA approval taxol in 1993 is used to treat oophoroma, taxol and its derivative are extensive so far
For breast cancer, non-small cell lung cancer, head and neck neoplasm, stomach cancer, prostate cancer.In current cancer therapy drug, taxanes
Medicine is that therapeutic action is most wide, and toxicity is minimum, curative effect highest one kind cancer therapy drug.
At present, the taxanes medicine for worldwide ratifying to use has 3, and they are taxol, Docetaxel
And Cabazitaxel.
Anticancer compound CX1409 involved in the present invention, No. CAS is 125354-16-7, molecular formula C45H55NO15, molecule
Amount：849.92, methanol is soluble in, its chemical structural formula is as follows：
Above-mentioned anticancer compound CX1409 becomes known for anticancer, but so far, has no the correlative study on crystal formation.
The content of the invention
The first object of the present invention is two kinds of novel crystal forms for providing anticancer compound CX1409, above two crystal form
Report is had no, and there is more preferably stability and purity on the basis for the treatment of cancer activity is ensured, is had wide
Application prospect.
To achieve the above object, the present invention adopts the following technical scheme that：
Anticancer compound CX1409 crystal formation A, the crystal formation is determined with powder x-ray diffraction determination method, with 2 θ ± 0.3 °
The angle of diffraction represent X-ray powder diffraction pattern 4.3 °, 8.7 °, 11.0 °, 12.5 °, 13.0 °, 14.1 °, 15.4 °, 17.4 °,
Characteristic diffraction peak is shown at 18.4 °, 19.6 °, 20.1 °, 20.8 °, 21.7 °, 27.0 °, 29.0 °, 30.6 ° and 31.4 °.
Specifically, anticancer compound CX1409 of the present invention crystal formation A has powder x-ray diffraction as shown in Figure 3
Figure.
Anticancer compound CX1409 of the present invention crystal formation A fusing point is 170 to 185 DEG C.
The second object of the present invention is the preparation method for providing above-mentioned anticancer compound CX1409 crystal formation A, the system
Preparation Method comprises the following steps：
(1) CX1409 crude products are put into ethanol solution, being heated to 50-60 DEG C makes to be dissolved to clear, holding 30-60min；
(2) settled solution obtained by step (1) is slowly dropped into 50-60 DEG C of water, stirring at low speed, slow cooling to 25-
40 DEG C, constant temperature growing the grain 40-80min, the rear slow cooling that continues is to 15-25 DEG C, growing the grain 90-150min；Above-mentioned temperature-fall period twice
In, the temperature difference is not less than 10 DEG C；
(3) step (2) resulting solution system is filtered, is dried to obtain CX1409 crystal formation A.
Preferably, in step (2) first with 0.5 DEG C/min cooling rate by solution slow cooling to 25-40 DEG C, after with
0.3 DEG C/min cooling rate is by solution slow cooling to 15-25 DEG C.By the control of above-mentioned rate of temperature fall, contribute to crystal
Slow precipitation and ensure epigranular.
And/or being slowly dropped into described in step (2) refers to settled solution obtained by step (1) by 30-45 drops/min's
Speed is instilled in water.Using above-mentioned rate of addition, be advantageous to separate out the stable uniform of crystal and avoid the incorporation of impurity.
And/or the specific speed of the stirring at low speed described in step (2) is 100 turns/min~200 turn/min.It is low at this
Under speed stirring, the narrow particle size distribution of crystal.
Preparation method of the present invention, provide compound CX1409 crude products with limited company of Beijing Konruns Pharmaceutical Co., Ltd. and make
It is as follows for raw material, the preparation course of the CX1409 crude products：
As a kind of specific embodiment, the above method comprises the following steps：
(1) CX1409-01 (15g) is dissolved in DMF (45mL), adds imidazoles (5.22g), temperature control is at 20~25 DEG C
Under the stirring of left and right, TESCl (6.74g) is slowly added dropwise, drop finishes, 20~25 DEG C of stirring 0.5h.Reaction finishes, and adds purified water
(105mL) and DCM (150mL), liquid separation.Organic phase is washed with water (105mL), saturation NaCl (75mL) washings.Liquid separation, it has been evaporated
Machine mutually obtains crude product.N-hexane (150mL) and EA (15mL) are added in crude product, 1h is stirred at room temperature, is filtered, a small amount of n-hexane washing filter
Cake, 40 DEG C of vacuum drying 2h obtain 16.7g products CX1409-05.
(2) under nitrogen protection, temperature control is at -30 DEG C, to equipped with CX1409-05's (15.5g) and CX1409-08 (11.1g)
In anhydrous THF (250mL) solution, NaHMDS (1.0M in THF, 33.2mL) is added.The mixture insulated and stirred 1h, Ran Houjia
Enter saturation NH4The Cl aqueous solution (150mL), it is extracted twice with ethyl acetate (200mL).Merge organic phase, wash, after solvent evaporated
Column chromatography purifying (ethyl acetate/n-hexane=1/5) obtains 21.8g CX1409-09.
(3) CX1409-09 (20g) is dissolved in absolute ethyl alcohol (250mL), adds 0.5N aqueous hydrochloric acid solution
(125mL), is stirred overnight at room temperature.Reaction finishes, and is extracted twice with ethyl acetate (500mL), merges to obtain organic phase saturation
Na2CO3The aqueous solution is washed to pH=7, washing.Solvent evaporated rear pillar chromatographic purifying (ethyl acetate/n-hexane=1/1) obtains 14.7g
CX1409 crude products (verified, the compound is consistent with document report).
Anticancer compound CX1409 crystal formation A x-ray diffractogram of powder is as shown in Figure 3 obtained by the above method.
Anticancer compound CX1409 of the present invention crystal formation A fusing point is 170 to 185 DEG C.
Compound CX1409 crude products of the present invention are detected under identical testing conditions, gained X-ray powder
Diffraction pattern is shown in Fig. 1, by its X-ray diffractogram (i.e. Fig. 3) with claimed anticancer compound CX1409 crystal formation A
Contrast understands that the present invention has obtained a kind of brand-new crystal formation by specific recrystallization method, and by the anticancer compound
CX1409 crystal formation A makees pharmacodynamics test with compound CX1409 crude products, and drug effect is suitable each other, no significant difference.
Invention also provides another anticancer compound CX1409 novel crystal forms, i.e. anticancer compound CX1409's
Crystal formation B, the anticancer compound CX1409 crystal formation B are determined with powder x-ray diffraction determination method, with 2 θ ± 0.3 ° angle of diffraction tables
The X-ray powder diffraction pattern shown shows feature diffraction at 4.9 °, 5.4 °, 5.8 °, 6.4 °, 8.0 °, 9.4 ° and 12.9 °
Peak.
Specifically, anticancer compound CX1409 of the present invention crystal formation B has powder x-ray diffraction as shown in Figure 4
Figure.
Anticancer compound CX1409 of the present invention crystal formation B fusing point is 170 to 185 DEG C.
Present invention simultaneously provides above-mentioned anticancer compound CX1409 crystal formation B preparation method, the preparation method includes
Following steps：
(1) CX1409 crude products are put into ethanol solution, being heated to 50-60 DEG C makes to be dissolved to clear, holding 30-60min；
(2) by the settled solution slow cooling to 15-25 DEG C, constant temperature growing the grain 1.5-2.5h, rear continuation slow cooling to 5~
10 DEG C, growing the grain 2-3h；
(3) filter, be dried to obtain CX1409 crystal formation B.
Preferably, in step (2) first with 0.5 DEG C/min cooling rate by solution slow cooling to 15-25 DEG C, after with
0.3 DEG C/min cooling rate is by solution slow cooling to 5~10 DEG C.By the control of above-mentioned rate of temperature fall, help to obtain
Even-grained crystal.
Preparation method of the present invention, the CX1409 crude products equally provided with limited company of Beijing Konruns Pharmaceutical Co., Ltd. are made
For raw material.
Anticancer compound CX1409 crystal formation B x-ray diffractogram of powder is as shown in Figure 3 obtained by the above method.
Anticancer compound CX1409 of the present invention crystal formation B fusing point is 160 to 170 DEG C.
By anticancer compound CX1409 of the present invention crystal formation B X-ray diffractogram (i.e. Fig. 4) and the X ray of crude product
Diffraction pattern (Fig. 1) contrast understands that the present invention has obtained a kind of brand-new crystal formation by specific recrystallization method, and by the anticancer
Compound CX1409 crystal formation B makees pharmacodynamics test with compound CX1409 crude products, and drug effect is suitable each other, no significance difference
It is different.
In addition, present invention also offers the crystal formation A containing above-mentioned anticancer compound CX1409 and/or anticancer compound
CX1409 crystal formation B pharmaceutical composition.
Specifically, pharmaceutical composition of the present invention includes but is not limited to various liquid preparations, preferably parenteral solution.
The liquid preparation medicine of the present invention can be prepared by conventional manner step.For example, take the CX1409 of recipe quantity
Crystal formation A, add in ethanol in proper amount solution, make its dissolving.The Tween 80 and citric acid of recipe quantity are added, makes its dissolving, mistake
0.22 micron membrane filter, it is last filling, thus prepare parenteral solution.
In addition, the present invention also further requirement protects above-mentioned anticancer compound CX1409 crystal formation A and/or anticancer compound
Applications of the CX1409 crystal formation B in treating cancer medicine is prepared, preferably described cancer include breast cancer, non-small cell lung cancer,
Head and neck neoplasm, stomach cancer and prostate cancer.
Anticancer compound CX1409 of the present invention crystal formation A and/or anticancer compound CX1409 crystal formation B are in pharmacodynamics
The activity of significant treating cancer is shown in experiment, can be widely used in the medicine preparation for treating above-mentioned cancer.
Using above-mentioned technical proposal, the present invention has the advantages that：
1st, crystal formation A and crystal formation B of the present invention have stability more more preferable than CX1409 crude product, and yield is good, and purity is high (general
CX1409 purity is only 97.5%~98.5%)；
2nd, preparation method of the present invention is simple and easy, can stablize and mass production, be advantageous to popularization and application；
3rd, in addition, crystal formation A is also relatively stable under illumination, high temperature, oxidizing condition, be advantageous to store and transport, beneficial to work
Industry metaplasia is produced.
Brief description of the drawings
Fig. 1：The X-ray powder diffraction figure of CX1409 crude product.The ordinate shows the intensity of X-ray, with Kcps
Represent；Abscissa is shown as 2 θ (°).
Fig. 2：The proton nmr spectra spectrogram of CX1409 crude product.
Fig. 3：CX1409 crystal formation A X-ray powder diffraction figure.The ordinate shows the intensity of X-ray, with Kcps
Represent；Abscissa is shown as 2 θ (°).
Fig. 4：CX1409 crystal formation B X-ray powder diffraction figure.The ordinate shows the intensity of X-ray, with Kcps
Represent；Abscissa is shown as 2 θ (°).
Embodiment
The present invention is described further with reference to the accompanying drawings and examples.
Embodiment 1：The preparation of CX1409 crude products
The preparation of CX1409 crude products specifically comprises the following steps：
(1) CX1409-01 (15g) is dissolved in DMF (45mL), adds imidazoles (5.22g), temperature control is at 20~25 DEG C
Under the stirring of left and right, TESCl (6.74g) is slowly added dropwise, drop finishes, 20~25 DEG C of stirring 0.5h.Reaction finishes, and adds purified water
(105mL) and DCM (150mL), liquid separation.Organic phase is washed with water (105mL), saturation NaCl (75mL) washings.Liquid separation, it has been evaporated
Machine mutually obtains crude product.N-hexane (150mL) and EA (15mL) are added in crude product, 1h is stirred at room temperature, is filtered, a small amount of n-hexane washing filter
Cake, 40 DEG C of vacuum drying 2h obtain 16.7g products CX1409-05.
(2) under nitrogen protection, temperature control is at -30 DEG C, to equipped with CX1409-05's (15.5g) and CX1409-08 (11.1g)
In anhydrous THF (250mL) solution, NaHMDS (1.0M in THF, 33.2mL) is added.The mixture insulated and stirred 1h, Ran Houjia
Enter saturation NH4The Cl aqueous solution (150mL), it is extracted twice with ethyl acetate (200mL).Merge organic phase, wash, after solvent evaporated
Column chromatography purifying (ethyl acetate/n-hexane=1/5) obtains 21.8g CX1409-09.
(3) CX1409-09 (20g) is dissolved in absolute ethyl alcohol (250mL), adds 0.5N aqueous hydrochloric acid solution
(125mL), is stirred overnight at room temperature.Reaction finishes, and is extracted twice with ethyl acetate (500mL), merges to obtain organic phase saturation
Na2CO3The aqueous solution is washed to pH=7, washing.Solvent evaporated rear pillar chromatographic purifying (ethyl acetate/n-hexane=1/1) obtains 14.7g
CX1409 crude products (purity 98.45%), its x-ray diffractogram of powder are shown in Fig. 1.
Resulting information：
MS:(ESI) m/z=872.3 (M+Na)+.
1H-NMR(δ,CDCL3,400MHz):8.11 (d, J=7.2Hz, 2H), 7.62 (t, J=7.2Hz, 1H), 7.50
(t, J=7.6Hz, 2H), 7.36-7.42 (m, 4H), 7.32 (t, J=6.8Hz, 1H), 6.29 (s, 1H), 6.25 (t, J=
8.4Hz, 1H), 5.67 (d, J=7.2Hz, 1H), 5.41 (d, J=9.2Hz, 1H), 5.26 (d, J=7.2Hz, 1H), 4.95 (d,
J=8.0Hz, 1H), 4.62 (s, 1H), 4.41 (q, J=6.8Hz, 1H), 4.30 (d, J=8.4Hz, 1H), 4.17 (d, J=
8.4Hz, 1H), 3.80 (d, J=7.2Hz, 1H), 2.51-2.59 (m, 1H), 2.38 (s, 3H), 2.25-2.31 (m, 5H),
1.87-1.91(m,1H),1.85(s,3H),1.68(s,3H),1.34(s,9H),1.27(s,3H),1.15(s,3H).Crude product
Proton nmr spectra spectrogram is shown in Fig. 2.
Embodiment 2：Prepare CX1409 crystal formations A
The CX1409 crude products (embodiment 1 is prepared) for weighing 1.0g are added in 5mL ethanol, stir 10min, then add
Enter 6mL ethanol, being heated to 55 DEG C makes to be dissolved to clear, holding 45min；The settled solution is slowly dropped into 55 DEG C of 9mL
In water, stirring at low speed, slow cooling to 30 DEG C (rate of temperature fall is 0.5 DEG C/min), constant temperature growing the grain 60min, the rear slow drop of continuation
Temperature is to 20 DEG C (rate of temperature fall is 0.3 DEG C/min), growing the grain 120min；Gained crystal is collected by filtration, and under vacuum
16h is dried at 40 DEG C, 684mg crystal formation A (purity 99.63%) is made, its x-ray diffractogram of powder is shown in Fig. 3.
Embodiment 3：Prepare CX1409 crystal formations A
The CX1409 crude products (embodiment 1 is prepared) for weighing 1.0g are added in 10mL ethanol, and being heated to 50 DEG C makes
It is dissolved to clear, holding 30min；The settled solution is slowly dropped into 9mL 50 DEG C of water, stirring at low speed, slow cooling is extremely
25 DEG C (rate of temperature fall is 0.5 DEG C/min), constant temperature growing the grain 40min, it is rear continue slow cooling to 15 DEG C (rate of temperature fall is 0.3 DEG C/
Min), growing the grain 90min；Gained crystal is collected by filtration, and dries 16h at 40 DEG C under vacuum, is made 696mg's
Crystal formation A (purity 99.87%), its x-ray diffractogram of powder are shown in Fig. 3.
Embodiment 4：Prepare CX1409 crystal formations A
The CX1409 crude products (embodiment 1 is prepared) for weighing 1.0g are added in 10mL ethanol, and being heated to 60 DEG C makes
It is dissolved to clear, holding 60min；The settled solution is slowly dropped into 9mL 60 DEG C of water, stirring at low speed, slow cooling is extremely
40 DEG C (rate of temperature fall is 0.5 DEG C/min), constant temperature growing the grain 80min, the rear slow cooling that continues is to 25 DEG C of (rate of temperature fall 0.3
DEG C/min), growing the grain 150min；Gained crystal is collected by filtration, and dries 16h at 40 DEG C under vacuum, is made
565mg crystal formation A (purity 99.75%), its x-ray diffractogram of powder are shown in Fig. 3.
Embodiment 5：Prepare CX1409 crystal formations B
The CX1409 crude products for weighing 1.0g are added in 10mL ethanol, and being heated to 55 DEG C makes to be dissolved to clear, holding 30-
60min；The settled solution slow cooling to 20 DEG C (rate of temperature fall is 0.5 DEG C/min), constant temperature growing the grain 2h is rear to continue slowly drop
To 5 DEG C (rate of temperature fall is 0.3 DEG C/min), crystal obtained by growing the grain 2.5h is collected by filtration temperature, and under vacuum 40
16h is dried at DEG C, 497mg crystal formation B (purity 99.23%) is made, its x-ray diffractogram of powder is shown in Fig. 4.
Embodiment 6：Prepare CX1409 crystal formations B
The CX1409 crude products for weighing 1.0g are added in 10mL ethanol, and being heated to 50 DEG C makes to be dissolved to clear, holding
30min；The settled solution slow cooling to 15 DEG C (rate of temperature fall is 0.5 DEG C/min), constant temperature growing the grain 1.5h is rear to continue slowly
It is cooled to 10 DEG C (rate of temperature fall is 0.3 DEG C/min), crystal obtained by growing the grain 2h is collected by filtration, and under vacuum 40
16h is dried at DEG C, 458mg crystal formation B (purity 99.48%) is made, its x-ray diffractogram of powder is shown in Fig. 4.
Embodiment 7：Prepare CX1409 crystal formations B
The CX1409 crude products for weighing 1.0g are added in 10mL ethanol, and being heated to 60 DEG C makes to be dissolved to clear, holding
60min；The settled solution slow cooling to 25 DEG C (rate of temperature fall is 0.5 DEG C/min), constant temperature growing the grain 2.5h is rear to continue slowly
It is cooled to 5 DEG C (rate of temperature fall is 0.3 DEG C/min), crystal obtained by growing the grain 3h is collected by filtration, and under vacuum 40
16h is dried at DEG C, 409mg crystal formation B (purity 99.12%) is made, its x-ray diffractogram of powder is shown in Fig. 4.
Test example 1
Stability test
This test example have detected CX1409 crystal formations A provided by the present invention, (result of the test is with each for crystal formation B stability
Test group CX1409 weight calculates).
Experimental subjects：
Experimental group 1 is that CX1409 crystal formations A is made in the embodiment of the present invention 2；
Experimental group 2 is the gained CX1409 crystal formations B of the embodiment of the present invention 3；
Control group 1 is CX1409 crude products (gained of the embodiment of the present invention 1)
Test method：
Accelerated test：Sample is packed with bottle, is put into the closed container (drier) that relative humidity is 75% ± 5%
In, drier is put into incubator, placed 6 months in 40 DEG C ± 2 DEG C, respectively at 0,1,2,3, respectively takes June a packaging to carry out
Detection.
Long term test：Sample is packed with bottle, is stored in 25 DEG C ± 2 DEG C of temperature, the condition of relative humidity 60% ± 10%
Under, in 0,3,6,9, respectively take December a packaging to be detected.
The accelerated test result of table 1
The long-term test results of table 2
Above-mentioned result of the test shows：Gained CX1409 crystal formations A and crystal formation B of the invention has bright compared with the stability of CX1409 crude products
It is aobvious to improve.The crystal formation A is easily reached on prepared by amplification, and method is simple, easier than crystal formation B a lot, itself is also
Thermodynamics most stable crystal form.Therefore, for industrial production process and quality, the crystalline substance is preferred in the liquid preparation medicine
Type A.
Embodiment in above-described embodiment can be further combined or replace, and embodiment is only to the present invention's
Preferred embodiment is described, and not the spirit and scope of the present invention are defined, and is not departing from design philosophy of the present invention
Under the premise of, various changes and modifications that professional and technical personnel in the art make to technical scheme belong to this hair
Bright protection domain.
Claims (10)
1. anticancer compound CX1409 crystal formation A, it is characterised in that the crystal formation A of the anticancer compound CX1409 is penetrated with powder X-ray
Line diffractometry determine, with the X-ray powder diffraction pattern that the 2 θ ± 0.3 ° angles of diffraction represent 4.3 °, 8.7 °, 11.0 °,
12.5°、13.0°、14.1°、15.4°、17.4°、18.4°、19.6°、20.1°、20.8°、21.7°、27.0°、29.0°、30.6°
With 31.4 ° at show characteristic diffraction peak.
2. anticancer compound CX1409 according to claim 1 crystal formation A, it is characterised in that：The anticancer compound
The fusing point of CX1409 novel crystal forms is 170 to 185 DEG C.
3. the anticancer compound CX1409 of claim 1 or 2 crystal formation A preparation method, it is characterised in that：Including following step
Suddenly：
(1) CX1409 crude products are put into ethanol solution, being heated to 50-60 DEG C makes to be dissolved to clear, holding 30-60min；
(2) settled solution obtained by step (1) is slowly dropped into 50-60 DEG C of water, stirring at low speed, slow cooling to 25-40 DEG C,
Constant temperature growing the grain 40-80min, the rear slow cooling that continues is to 15-25 DEG C, growing the grain 90-150min；In above-mentioned temperature-fall period twice, temperature
Difference is not less than 10 DEG C；
(3) step (2) resulting solution system is filtered, is dried to obtain CX1409 crystal formation A.
4. preparation method according to claim 3, it is characterised in that：First with 0.5 DEG C/min cooling rate in step (2)
By solution slow cooling to 25-40 DEG C, after with 0.3 DEG C/min cooling rate by solution slow cooling to 15-25 DEG C；
And/or being slowly dropped into described in step (2) refers to the speed by settled solution obtained by step (1) by 30-45 drops/min
Instill in water；
And/or the specific speed of the stirring at low speed described in step (2) is 100 turns/min~200 turn/min.
5. anticancer compound CX1409 crystal formation B, it is characterised in that the crystal formation B of the anticancer compound CX1409 is penetrated with powder X-ray
Line diffractometry determine, with the X-ray powder diffraction pattern that the 2 θ ± 0.3 ° angles of diffraction represent 4.9 °, 5.4 °, 5.8 °,
Characteristic diffraction peak is shown at 6.4 °, 8.0 °, 9.4 ° and 12.9 °.
6. anticancer compound CX1409 according to claim 5 crystal formation B, it is characterised in that：The anticancer compound
CX1409 crystal formation B fusing point is 160 to 170 DEG C.
7. the anticancer compound CX1409 of claim 5 or 6 crystal formation B preparation method, it is characterised in that：Including following step
Suddenly：
(1) CX1409 crude products are put into ethanol, being heated to 50-60 DEG C makes to be dissolved to clear, holding 30-60min；
(2) by the settled solution slow cooling to 15-25 DEG C, constant temperature growing the grain 1.5-2.5h, the rear slow cooling that continues is to 5~10
DEG C, growing the grain 2-3h；
(3) filter, be dried to obtain CX1409 crystal formation B.
8. the crystal formation B of anticancer compound CX1409 described in claim 7 preparation method, it is characterised in that：In step (2) first with
0.5 DEG C/min cooling rate by solution slow cooling to 15-25 DEG C, after it is with 0.3 DEG C/min cooling rate that solution is slow
It is cooled to 5~10 DEG C.
9. crystal formation A and/or the anticancer compound of claim 5 or 6 containing the anticancer compound CX1409 of claim 1 or 2
CX1409 crystal formation B pharmaceutical composition；It is preferred that described pharmaceutical composition is parenteral solution.
10. the anticancer compound CX1409 of claim 1 or 2 crystal formation A and/or the anticancer compound of claim 5 or 6
Applications of the CX1409 crystal formation B and/or claim 9 described pharmaceutical composition in treating cancer medicine is prepared, it is preferably described
Cancer includes breast cancer, non-small cell lung cancer, head and neck neoplasm, stomach cancer and prostate cancer.
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2016
- 2016-06-29 CN CN201610498032.8A patent/CN107540638A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| DANIELLE M. NEVAREZ等: ""An N-Aroyltransferase of the BAHD Superfamily Has Broad Aroyl CoA Specificity in Vitro with Analogues of N-Dearoylpaclitaxel"", 《J. AM. CHEM. SOC.》 * |
| KELLY, ROBERT C.等: ""12,13-Isobaccatin III. Taxane Enol Esters (12,13-Isotaxanes)"", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
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