CN105732575A - Novel crystal form of novel antiandrogen drug for treating prostate cancer and preparation method thereof - Google Patents
Novel crystal form of novel antiandrogen drug for treating prostate cancer and preparation method thereof Download PDFInfo
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- CN105732575A CN105732575A CN201610076073.8A CN201610076073A CN105732575A CN 105732575 A CN105732575 A CN 105732575A CN 201610076073 A CN201610076073 A CN 201610076073A CN 105732575 A CN105732575 A CN 105732575A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
The invention relates to a novel crystal form of a novel antiandrogen drug for treating prostate cancer and a preparation method thereof.The crystal form has good stability, and dissolubility and hygroscopicity meet medicinal requirements.The preparation method of the crystal form is simple, cost is low, and the crystal form has important value on optimization and development of the novel antiandrogen drug in future.Please see the formula in the description.
Description
Technical field
The present invention relates to chemical medicine, particularly relate to a kind of novel crystal forms of antiandrogens (ARN-509) treating carcinoma of prostate and preparation method thereof.
Background technology
ARN-509, compound shown in formula (I), is second filial generation androgen receptor signal inhibitor.This medicine by Aragon drugmaker of the U.S. research and develop, after by Johnson & Johnson (JNJ) purchase.This medicine is used for treating castration-resistant prostate cancer, is currently under clinical development, if granted, will disclosure satisfy that the demand of patients with prostate cancer widely.
Polymorph in pharmaceuticals (drugpolymorphism) refers to that medicine has two or more different crystal forms state of matter.Polymorphism is widely present in medicine.The different crystal forms of same medicine has significant difference in dissolubility, fusing point, density, stability etc., thus affecting the stability of medicine, homogeneity, bioavailability, efficacy and saferry to some extent.Therefore, medicament research and development carries out comprehensive and systematic screening polymorph, select to be best suitable for the crystal formation of exploitation, be one of very important important research content.
Based on this, carry out polymorphic research and the screening of formula (I) compound, develop the crystal formation of good stability, dissolubility height, low in hygroscopicity, applicable industrialized production, Subsequent pharmacological exploitation is significant.
Summary of the invention
The present invention relates to two kinds of novel crystal forms of formula (I) compound, be respectively designated as crystal formation I and crystal form II.The stability of crystal form of the present invention is good, dissolubility, draws the moist medicinal requirements that meets, and preparation method is simple, and with low cost, optimization and exploitation to this medicine following have important value.
It is an object of the present invention to provide the crystal formation I of formula (I) compound.
The X-ray powder diffraction figure of crystal formation I provided by the invention is that 16.7 ° ± 0.2 °, 20.4 ° ± 0.2 °, 12.1 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, the X-ray powder diffraction figure of crystal formation I provided by the invention is that 23.7 ° ± 0.2 °, 8.2 ° ± 0.2 °, 16.0 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, the X-ray powder diffraction figure of crystal formation I provided by the invention is that 17.8 ° ± 0.2 °, 25.0 ° ± 0.2 °, 27.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
In a specific embodiment, the X-ray powder diffraction figure of crystal formation I provided by the invention is that 8.2 ° ± 0.2 °, 12.1 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.8 ° ± 0.2 °, 20.4 ° ± 0.2 °, 23.7 ° ± 0.2 °, 25.0 ° ± 0.2 °, 27.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
In another embodiment, the X-ray powder diffraction figure of crystal formation I provided by the invention is substantially as shown in Figure 1.
Further, crystal formation I provided by the invention starts endothermic peak occur when heating is to about 193 DEG C, and its differential scanning calorimetric thermogram is substantially as shown in Figure 2.
Further, crystal formation I provided by the invention has the loss in weight gradient of about 1.3% when heating is to 160 DEG C, and its thermogravimetric analysis figure is as shown in Figure 3.
The preparation method that it is a further object to provide crystal formation I, adds in crystallization solvent including by formula (I) compound, prepares by volatilizing or suspending to stir.
Further, described crystallization solvent is one or more mixing of alcohols, ketone, ethers, fat hydrocarbon, esters, aromatic hydrocarbon solvent, preferred methanol, acetone, 1, one or more mixing of 4-dioxane, hexamethylene, normal heptane, isopropyl acetate, ethyl acetate, toluene and dimethylbenzene, more preferably one or more mixing of hexamethylene, isopropyl acetate, toluene.
It is a further object to provide the crystal form II of formula (I) compound.
The X-ray powder diffraction figure of crystal form II provided by the invention is that 14.4 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.9 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, the X-ray powder diffraction figure of crystal form II provided by the invention is that 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, 15.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, the X-ray powder diffraction figure of crystal form II provided by the invention is that 25.4 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° ± 0.2 ° place has characteristic peak in 2theta value.
In a specific embodiment, the X-ray powder diffraction figure of crystal form II provided by the invention is that 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.5 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 25.4 ° ± 0.2 ° place has characteristic peak in 2theta value.
In another embodiment, the X-ray powder diffraction figure of crystal form II provided by the invention is substantially as shown in Figure 5.
Further, crystal form II provided by the invention starts endothermic peak occur when heating is to about 170 DEG C, and its differential scanning calorimetric thermogram is substantially as shown in Figure 6.
Further, crystal form II provided by the invention has the loss in weight gradient of about 1.6% when heating is to 170 DEG C, and its thermogravimetric analysis figure is as shown in Figure 7.
The preparation method that it is a further object to provide crystal form II, including by formula (I) compound dissolution in positive solvent, dropping anti-solvent to solid precipitate out obtain crystal form II.
Further, described positive solvent be esters, arene, ketones solvent one or more mixing, it is preferable that toluene, isopropyl acetate, 4-methyl-2 pentanone one or more mixing.
Further, described anti-solvent is fat hydrocarbon solvent, it is preferable that normal heptane.
It is a further object to provide the Pharmaceutical composition of a kind of crystal formation I of formula (I) compound, crystal form II or the mixing of both arbitrary proportions and pharmaceutic adjuvant comprising effective therapeutic dose.Be usually by the crystal formation I of formula (I) compound of therapeutically effective amount, crystal form II or both arbitrary proportions mixing with one or more pharmaceutic adjuvants be mixed and made into Pharmaceutical composition or preparation, this Pharmaceutical composition or preparation be know in pharmaceutical field in the way of be prepared.
Another purpose of the present invention is to provide the crystal formation I of formula (I) compound, crystal form II or its Pharmaceutical composition and is used for preparing treatment cancer drug, particularly the purposes in carcinoma of prostate medicine.
The invention have the benefit that
The present invention breaks through prior art, it is provided that the novel crystal forms of the multiple applicable drug development of formula (I) compound.
Crystal formation I and II provided by the invention has good stability.Medicine can be avoided well to store and development process occurs turn crystalline substance, thus avoiding the change of bioavailability and drug effect.
Crystal formation dissolubility provided by the invention is high, it is moist relatively low to draw, and meets bioavailability and drug effect requirement, and is susceptible to humidity impact, it is simple to long storage periods.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of formula (I) compound crystal form I；
Fig. 2 is the DSC figure of formula (I) compound crystal form I；
Fig. 3 is the TGA figure of formula (I) compound crystal form I；
Fig. 4 is the DVS figure of formula (I) compound crystal form I；
Fig. 5 is the XRPD figure of formula (I) compound crystal form II；
Fig. 6 is the DSC figure of formula (I) compound crystal form II；
Fig. 7 is the TGA figure of formula (I) compound crystal form II；
Fig. 8 is formula (I) the compound crystal form I 90 days stability test XRPD comparison diagrams (A: crystal formation I initial sample under different test conditions；B: crystal formation I places 90 days under 25 DEG C/60% relative humidity；C: crystal formation I places 90 days under 40 DEG C/75% relative humidity)；
Fig. 9 is formula (I) compound crystal form I and the DVS comparison diagram (test condition: 80% relative humidity repeating formula (I) compound solid that patented method prepares；A represents formula (I) compound solid that repetition patent CN101454002B method prepares, and B represents formula (I) compound crystal form I)；
Figure 10 is the PLM figure of formula (I) compound crystal form I；
Figure 11 is the PLM figure repeating formula (I) compound solid that patent CN101454002B method prepares.
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.Preparation method and use instrument can be made improvements by those skilled in the art in right, and these improvement also should be regarded as protection scope of the present invention.
In following example, for same crystal formation, the crystal XRPD data that different preparation methoies prepare are likely to incomplete same, but the record that those skilled in the art are according to description, can determine that according to its principal character peak and belong to same crystal formation.
In following embodiment, the condition of test method generally conventionally condition or manufacturer's suggestion is implemented, and wherein room temperature refers to 25 DEG C ± 2 DEG C.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
DVS: dynamic water is adsorbed
PLM: polarizing microscope
X-ray powder diffraction figure of the present invention gathers on PanalyticalEmpyreanX ray powder diffractometer.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α radiation
Kα11.540598；Kα21.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliamperes (mA)
Sweep limits: spend from 3.0 to 40.0
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TAQ5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Dynamic water of the present invention absorption (DVS) figure gathers on the Intrinsic dynamic water adsorption instrument produced by SMS company (SurfaceMeasurementSystemsLtd.).The method parameter of described dynamic water adsorption instrument is as follows:
Temperature: 25 DEG C
Carrier gas, flow velocity: N2, 200 ml/min
Unit interval mass change: 0.002%/minute
RH range: 0%RH-95%RH
In following example use formula (I) compound solid (that is, ARN509) be according to Chinese patent CN101454002B disclosed in method prepare.
Embodiment 1
The preparation method of formula (I) compound crystal form I:
Being added by 24.5mg formula (I) compound in 0.8mL isopropyl acetate/normal heptane (1:4, v/v) mixed solvent, room temperature condition low suspension stirs 24 hours, and centrifugation solid also both obtained at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal formation I that the present embodiment obtains are as shown in table 1, and its X-ray powder diffraction, DSC and TGA collection of illustrative plates are respectively as shown in Figures 1 to 3.
Table 1
Embodiment 2
The preparation method of formula (I) compound crystal form I:
5.5mg formula (I) compound is added in 0.5mL toluene, the heating of this suspension is obtained settled solution to 85 DEG C.This settled solution at room temperature having evaporated into solid precipitate out, centrifugation solid also both obtained at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal formation I that the present embodiment obtains are as shown in table 2.Measure through X-ray powder diffraction, confirm as formula (I) compound crystal form I.
Table 2
Embodiment 3
The preparation method of formula (I) compound crystal form I:
Being added in 0.8mL methanol by 50mg formula (I) compound, be placed in 50 DEG C of stirrings 24 hours that suspend, centrifugation solid also both obtained at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal formation I that the present embodiment obtains are as shown in table 3.Measure through X-ray powder diffraction, confirm as formula (I) compound crystal form I.
Table 3
Embodiment 4
The preparation method of formula (I) compound crystal form I:
Being added in 5.0mL ethyl acetate/normal heptane (1:5, v/v) mixed solvent by 304.9mg formula (I) compound, be placed in 50 DEG C of stirrings 24 hours that suspend, centrifugation solid also both obtained at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal formation I that the present embodiment obtains are as shown in table 4.Measure through X-ray powder diffraction, confirm as formula (I) compound crystal form I.
Table 4
Embodiment 5
The preparation method of formula (I) compound crystal form I:
5.2mg formula (I) compound is joined acquisition suspension in 0.5mL hexamethylene.The heating of this suspension to 85 DEG C and being placed 2 minutes at such a temperature, naturally cool to room temperature and stir 24 hours at ambient temperature, centrifugation solid also both obtains at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal formation I that the present embodiment obtains are as shown in table 5.Measure through X-ray powder diffraction, confirm as formula (I) compound crystal form I.
Table 5
Embodiment 6
The preparation method of formula (I) compound crystal form I:
Being added in 0.2mL1,4-dioxane/normal heptane (1:11, v/v) mixed solvent by 3.73mg formula (I) compound, be placed in 50 DEG C of stirrings 24 hours that suspend, centrifugation solid also both obtained at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal formation I that the present embodiment obtains are as shown in table 6.Measure through X-ray powder diffraction, confirm as formula (I) compound crystal form I.
Table 6
Embodiment 7
The preparation method of formula (I) compound crystal form II:
Being added dropwise over normal heptane by molten in 1.5mL toluene for 10.4mg formula (I) compound dissolution and precipitate out to solid clearly, centrifugation solid also both obtained at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal form II that the present embodiment obtains are as shown in table 7, and its X-ray powder diffraction, DSC and TGA collection of illustrative plates are respectively as shown in Figs. 5 to 7.
Table 7
Embodiment 8
The preparation method of formula (I) compound crystal form II:
Being added dropwise over normal heptane to there being solid to precipitate out clearly by molten in 0.2mL4-methyl-2 pentanone for 10.2mg formula (I) compound dissolution, centrifugation solid also both obtained at room temperature dry 2 hours.
The X-ray powder diffraction data of the crystal form II that the present embodiment obtains are as shown in table 8.Measure through X-ray powder diffraction, confirm as formula (I) compound crystal form II.
Table 8
Embodiment 9
The stability test of formula I compound crystal form I:
Formula (I) the compound crystal form I sample present invention prepared is respectively placed in when 25 DEG C/60% relative humidity and 40 DEG C/75% relative humidity 90 days, tests in sampling in the 90th day.Test result shows that the crystal formation I of the present invention has good stability, and as shown in Figure 8, wherein A represents crystal formation I initial sample to its XRPD comparison diagram；B represents placement 90 days under 25 DEG C/60% relative humidity；C represents placement 90 days under 40 DEG C/75% relative humidity.
Embodiment 10
Formula I compound crystal form I draws moist test:
Take formula (I) compound crystal form I and the 10mg of 10mg present invention formula (I) compound solid prepared by patented method respectively and carry out dynamic water absorption (DVS) test.Test result shows, formula (I) the compound crystal form I of the present invention increases weight 0.1676% after balancing under 80% relative humidity, draws moist relatively low；And formula (I) compound solid that patented method prepares increases weight 3.148% after balancing under 80% relative humidity, draws moist of a relatively high.Test result is as shown in Figure 9.
About draw moist feature description with draw moist weightening finish define (Chinese Pharmacopoeia version annex XIXJ medicine in 2010 draws moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity):
Deliquescence: absorb the fractal one-tenth liquid of enough water；
Great draw moist: draw wet weightening finish and be not less than 15%；
Have draw moist: drawing wet weightening finish and less than 15% but being not less than 2%；
Slightly draw moist: draw wet weightening finish and less than 2% but be not less than 0.2%；
Nothing or moist almost without drawing: drawing wet weightening finish less than 0.2%.
Embodiment 11
The PLM test of formula I compound crystal form I:
The formula I compound crystal form I of the present invention and formula (I) compound solid that patented method is prepared is observed under polarizing microscope (PLM).Observed result is as follows:
Formula (I) compound crystal form I is the flat crystal of comparatively rule, and good fluidity possesses the advantageous properties such as easy filtration in explained hereafter, and therefore the brilliant of formula (I) compound crystal form I is practised well, and its PLM schemes as shown in Figure 10；And formula (I) compound solid that patented method prepares is reunited serious and granule is uneven, poor fluidity, its PLM schemes as shown in figure 11.
Claims (17)
1. a crystal formation I for formula (I) compound,
It is characterized in that, its X-ray powder diffraction figure is that 16.7 ° ± 0.2 °, 20.4 ° ± 0.2 °, 12.1 ° ± 0.2 ° place has characteristic peak in 2theta value.
2. crystal formation I according to claim 1, it is characterised in that its X-ray powder diffraction figure is that 23.7 ° ± 0.2 °, 8.2 ° ± 0.2 °, 16.0 ° ± 0.2 ° place has characteristic peak in 2theta value.
3. crystal formation I according to claim 1, it is characterised in that its X-ray powder diffraction figure is that 17.8 ° ± 0.2 °, 25.0 ° ± 0.2 °, 27.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
4. the crystal formation I according to any one of claim 1-3, it is characterized in that, its X-ray powder diffraction figure is that 8.2 ° ± 0.2 °, 12.1 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.7 ° ± 0.2 °, 17.8 ° ± 0.2 °, 20.4 ° ± 0.2 °, 23.7 ° ± 0.2 °, 25.0 ° ± 0.2 °, 27.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
5. the preparation method of formula (I) compound crystal form I, it is characterised in that added in crystallization solvent by formula (I) compound, by volatilizing or suspension stirring prepares crystal formation I.
6. preparation method according to claim 5, it is characterised in that described crystallization solvent is one or more mixing of alcohols, ketone, ethers, fat hydrocarbon, esters, aromatic hydrocarbon solvent.
7. preparation method according to claim 6, it is characterised in that described crystallization solvent is one or more mixing of methanol, acetone, Isosorbide-5-Nitrae-dioxane, hexamethylene, normal heptane, isopropyl acetate, toluene.
8. preparation method according to claim 7, it is characterised in that described crystallization solvent is one or more mixing of hexamethylene, isopropyl acetate, toluene.
9. the crystal form II of formula (I) compound, it is characterised in that its X-ray powder diffraction figure is that 14.4 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.9 ° ± 0.2 ° place has characteristic peak in 2theta value.
10. crystal form II according to claim 9, it is characterised in that its X-ray powder diffraction figure is that 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, 15.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
11. crystal form II according to claim 9, it is characterised in that its X-ray powder diffraction figure is that 25.4 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° ± 0.2 ° place has characteristic peak in 2theta value.
12. according to the crystal form II described in any one of claim 9-11, it is characterized in that, its X-ray powder diffraction figure is that 7.6 ° ± 0.2 °, 8.9 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.3 ° ± 0.2 °, 14.4 ° ± 0.2 °, 15.5 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.9 ° ± 0.2 °, 25.4 ° ± 0.2 ° place has characteristic peak in 2theta value.
13. the preparation method of formula (I) compound crystal form II, it is characterised in that added by formula (I) compound in positive solvent, dropping anti-solvent precipitates out to solid and obtains crystal form II.
14. preparation method according to claim 13, it is characterised in that described positive solvent esters, arene, ketones solvent one or more mixing, described anti-solvent fat hydrocarbon solvent.
15. preparation method according to claim 14, it is characterised in that described positive solvent is one or more mixing of toluene, isopropyl acetate, 4-methyl-2 pentanone, and described anti-solvent is normal heptane.
16. a Pharmaceutical composition, described Pharmaceutical composition comprises the crystal formation I described in Claims 1-4 any one of effective therapeutic dose or the crystal form II described in claim 9 to 12 any one or the mixing of both arbitrary proportions and pharmaceutically acceptable excipient.
17. the crystal formation I according to Claims 1-4 any one or the crystal form II described in claim 9 to 12 any one or both arbitrary proportions mix or the Pharmaceutical composition according to claim 16 purposes in preparation treatment carcinoma of prostate medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590740A (en) * | 2019-09-20 | 2019-12-20 | 武汉大学 | Apaglus amine compound and pharmaceutical preparation thereof |
| WO2019242439A1 (en) * | 2018-06-20 | 2019-12-26 | 苏州科睿思制药有限公司 | Crystal form of arn-509, preparation method therefor and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11149017B2 (en) | 2016-12-13 | 2021-10-19 | Watson Laboratories Inc. | Solid state forms of apalutamide |
| WO2019135254A1 (en) | 2018-01-02 | 2019-07-11 | Mylan Laboratories Limited | Apalutamide polymorphs and their preparation thereof |
| WO2020049598A2 (en) | 2018-09-08 | 2020-03-12 | Cipla Limited | Apalutamide polymorphs |
| IT201900003839A1 (en) | 2019-03-15 | 2020-09-15 | Olon Spa | STABLE AMORPHOUS APALUTAMIDE SYNTHESIS |
| WO2020234817A1 (en) * | 2019-05-21 | 2020-11-26 | Laurus Labs Limited | Polymorphic forms of apalutamide and its preparation thereof |
| IT201900010593A1 (en) | 2019-07-01 | 2021-01-01 | Dipharma Francis Srl | CRYSTALLINE FORM OF AN ANDROGEN RECEPTOR INHIBITOR |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2593379T3 (en) * | 2006-03-27 | 2016-12-09 | The Regents Of The University Of California | Androgen receptor modulator for the treatment of prostate cancer and diseases associated with the androgen receptor |
| WO2008119015A2 (en) * | 2007-03-27 | 2008-10-02 | Sloan-Kettering Institute For Cancer Research | Synthesis of thiohydantoins |
| US9108944B2 (en) * | 2010-02-16 | 2015-08-18 | Aragon Pharmaceuticals, Inc. | Androgen receptor modulators and uses thereof |
| CA2908326C (en) * | 2013-05-29 | 2017-09-12 | Hinova Pharmaceuticals Inc. | Imidazolidinedione compounds and their uses |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019242439A1 (en) * | 2018-06-20 | 2019-12-26 | 苏州科睿思制药有限公司 | Crystal form of arn-509, preparation method therefor and use thereof |
| CN111344283A (en) * | 2018-06-20 | 2020-06-26 | 苏州科睿思制药有限公司 | ARN-509 crystal form and preparation method and application thereof |
| US11066384B2 (en) | 2018-06-20 | 2021-07-20 | Crystal Pharmaceutical (Suzhou) Co., Ltd. | Crystalline forms of ARN-509, preparation method and use thereof |
| CN111344283B (en) * | 2018-06-20 | 2022-08-12 | 苏州科睿思制药有限公司 | ARN-509 crystal form and preparation method and application thereof |
| CN110590740A (en) * | 2019-09-20 | 2019-12-20 | 武汉大学 | Apaglus amine compound and pharmaceutical preparation thereof |
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| WO2016124149A1 (en) | 2016-08-11 |
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Application publication date: 20160706 |