WO2016165677A1 - New forms of ixazomib citrate - Google Patents
New forms of ixazomib citrate Download PDFInfo
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- WO2016165677A1 WO2016165677A1 PCT/CZ2016/000043 CZ2016000043W WO2016165677A1 WO 2016165677 A1 WO2016165677 A1 WO 2016165677A1 CZ 2016000043 W CZ2016000043 W CZ 2016000043W WO 2016165677 A1 WO2016165677 A1 WO 2016165677A1
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- ixazomib citrate
- formula
- solvate
- citrate
- ixazomib
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- the invention relates to novel polymorphic forms of Ixazomib citrate of formula I, with the chemical name (R)-2,2'-(2-(1-(2-(2,5-dichlorobenzamido)acetamido)-3- methylbuty!)-5-oxo-1 ,3,2-dioxaborolan-4,4-diyl)diacetic acid:
- Ixazomib is a novel member of the group of proteasome inhibitors with a structure belonging to the group of peptidic boronic acids.
- a well-known and already commercially available member of this group is bortezomib of formula A.
- Bortezomib is used for the treatment of multiple myelomas.
- Ixazomib citrate is envisaged for the treatment of the same disease but, due to stabilization of the boronic acid in the form of a mixed ester-anhydride with citric acid, it will be possible to administer the substance also in the oral form.
- Boronic acids are sometimes difficult to prepare in the pure form. In conditions that are favourable for dehydration, boronic acids form cyclic anhydrides and are often sensitive to light. Therefore, boronic acids are advantageously stabilized with a complexing agent, e.g.
- Ixazomib citrate whose novel forms and process for the preparation are provided by this invention, also belongs to such stabilized compounds.
- Ixazomib citrate and a process for the preparation were first described in the patent application WO 2009/154737.
- Boroxine of formula III is reacted with citric acid in a solvent at an elevated temperature; after cooling, the crystallized product is isolated by filtering. If after the reaction of boroxine of formula HI with citric acid in ethyl acetate at 74°C uncontrolled cooling of the reaction mixture is conducted, this may lead to formation of the 5-membered isomeric Form 1 (meiting point 198.8°C), while controlled cooling of the reaction mixture to the room temperature or to 40°C results in formation of the more stable isomeric Form 2 (melting point 219.9°C).
- Form 2 can also be prepared through a reaction of the compound of formula 111 with citric acid and crystallization from various solvents (tetrahydrofuran, acetonitrile, methyl /so-butyl ketone, 2- methyltetrahydrofuran, acetone), followed by addition of the acetic acid ethyl ester as an antisolvent.
- various solvents tetrahydrofuran, acetonitrile, methyl /so-butyl ketone, 2- methyltetrahydrofuran, acetone
- the invention provides novel polymorphic forms - crystalline C2- C4 alcoholic solvate of Ixazomib citrate of isomeric Form 1 of formula I:
- Ixazomib citrate as the first proteasome inhibitor that can also be administered orally places high demands on stability of the given form. For this reason, as many stable forms of the given pharmaceutical substance - in this case Ixazomib citrate - as possible should be available.
- Both the solvates have crystallized in the monoclinic system with two molecules of Ixazomib citrate and two molecules of the solvent in the asymmetrical part of the cell ( Figures 3 and 4, Tables 3 and 4).
- Ixazomib citrate isopropanol In the structure of the Ixazomib citrate isopropanol solvate both the molecules of the solvent in the asymmetrical part of the cell were disordered with the occupancies of 0.666 : 0.334 and 0.696 : 0.304.
- novel crystalline forms of Ixazomib citrate of formula I are referred to as the ethanol solvate and isopropanol solvate.
- the single crystal X-ray diffraction (shown in Figs. 3, 3a and 4, 4a) also clearly illustrates the arrangement of the citrate, which corresponds to isomeric Form 1 , i.e. forming a 5-membered cycle with boron.
- This invention also provides processes for the production of the above mentioned forms of Ixazomib citrate.
- Preparation of the alcohol solvates of Ixazomib citrate of formula I comprises dissolution of Ixazomib citrate in an alcohol and subsequent crystallization from the solution of the compound in the alcohol.
- ethanol As a suitable alcohol, ethanol, or isopropanol us used.
- the crystallization is conducted at a temperature of 20 to 85°C.
- the crystallization is conducted at a temperature of 20 to 25°C.
- an antisolvent is used for the crystallization.
- n-hexane or ethyl acetate is used as the antisolvent.
- the prepared alcohol solvates are characterized by a different powder diffraction pattern from those of the hitherto known Forms 1 and 2 disclosed in the application WO 2009/154737 and Form 3.
- the ethanol solvate of Ixazomib citrate of formula la exhibits the following characteristic reflections in an X-ray powder pattern measured with the use of CuKa radiation: 6.0; 12.1 ; 14.4; 18.2; 22.4 and 24.4 ⁇ 0.2° 2-theta and more reflections, presented in Table 1.
- the isopropanol solvate of Ixazomib citrate of formula lb exhibits the following characteristic reflections in an X-ray powder pattern measured with the use of CuKa radiation: 6.2; 10.0; 14.5; 17.1 and 21.0 ⁇ 0.2° 2-theta and more reflections, presented in Table 2.
- Another aspect of this invention is provided by an amorphous form of Ixazomib citrate that was prepared by lyophilization of a freeze-dried solution of Ixazomib citrate in a suitable solvent.
- a suitable solvent is an alcohol.
- fert-butanol is used as the alcohol for the preparation of the amorphous form of Ixazomib citrate of formula I.
- Fig. 3 X-ray diffraction on a single crystal of Ixazomib citrate I ethanol solvate; for clarity just one half of the asymmetrical part of the cell is shown with displayed thermal oscillations and atom descriptions
- Fig. 4 - X-ray diffraction on a single crystal of Ixazomib citrate I isopropyl alcohol solvate; asymmetrical part of the cell with displayed thermal oscillations
- Fig. 4A - X-ray diffraction on a single crystal of Ixazomib citrate I isopropyl alcohol solvate; for clarity just one half of the asymmetrical part of the cell without the disorder is shown, with displayed thermal oscillations and atom descriptions
- Fig. 5 Comparison of the crystal structures of Ixazomib citrate of formula I isopropyl alcohol solvate (at the top) and Ixazomib citrate of formula I ethanol solvate (at the bottom) and their calculated powder diffraction patterns.
- Fig. 6 X-ray powder diffraction pattern of the amorphous form of Ixazomib citrate
- Fig. 7 DSC record of the amorphous form of Ixazomib citrate
- a 10mm mask and a 1/4° fixed anti-dispersion slit were used.
- the irradiated area of the sample is 10 mm, programmable divergence slits were used.
- the measurement was carried out with a flat sample applied onto a Si plate.
- Ixazomib citrate (Form 3), 25 mg was dissolved in 1 ml of ethanol in a hot state. During 48 hours, in the presence of hexane vapours Ixazomib citrate crystallizes in the ethanol solvate form.
- Ixazomib citrate (Form 2), 25 mg was dissolved in a mixture of 10 ml of ethyl acetate and 2 ml of ethanol in a hot state. During 20 hours, crystals of Ixazomib citrate are formed by slow spontaneous evaporation in the ethanol solvate form.
- the X-ray pattern is equal to the pattern of Example 1.
- ixazomib citrate (Form 3), 20 mg was dissolved in 1.5 ml of isopropanol in a hot state. During 20 hours, in the presence of hexane vapours Ixazomib citrate crystallizes in the isopropanol solvate form.
- Ixazomib citrate (Form 3) was dissolved in 15 ml of fe/f-butanol. After freeze-drying of the solution (the bath consisting of an ethanol/dry ice mixture; -70°C and subsequent lyophilization (3.5 Pa; 24 h) Ixazomib citrate was obtained in an amorphous form.
- Fig. 6 The X-ray pattern of the amorphous form is shown in Fig. 6 and its DSC record is in Fig. 7.
Abstract
The present invention relates to new polymorphic forms - crystalline C2- C4 alcohol solvate of Ixazomib citrate of isomeric Form 1 of formula I and a method of their preparation. It especially relates to the crystalline structure of two novel forms of the ethanol and isopropanol solvate of Ixazomib citrate.
Description
New forms of Ixazomib citrate
Technical Field
The invention relates to novel polymorphic forms of Ixazomib citrate of formula I, with the chemical name (R)-2,2'-(2-(1-(2-(2,5-dichlorobenzamido)acetamido)-3- methylbuty!)-5-oxo-1 ,3,2-dioxaborolan-4,4-diyl)diacetic acid:
I (Form 1) as well as an amorphous form of Ixazomib citrate and a process for preparing these new forms.
Background Art
Ixazomib is a novel member of the group of proteasome inhibitors with a structure belonging to the group of peptidic boronic acids. A well-known and already commercially available member of this group is bortezomib of formula A.
Bortezomib is used for the treatment of multiple myelomas.
Ixazomib citrate is envisaged for the treatment of the same disease but, due to stabilization of the boronic acid in the form of a mixed ester-anhydride with citric acid, it will be possible to administer the substance also in the oral form.
Boronic acids are sometimes difficult to prepare in the pure form. In conditions that are favourable for dehydration, boronic acids form cyclic anhydrides and are often sensitive to light. Therefore, boronic acids are advantageously stabilized with a complexing agent, e.g. an a- or β-hydroxy acid (WO2009/154737), or by preparation of precursors with azanediylbis alcohols (WO 2012/177835, WO 2011/087822A1), which enhances their stability and makes it possible to prepare a dosage form suitable for oral administration.
Ixazomib citrate, whose novel forms and process for the preparation are provided by this invention, also belongs to such stabilized compounds.
Ixazomib citrate and a process for the preparation were first described in the patent application WO 2009/154737.
A process for preparing the citrate Form 1 or 2 of formula I or II from boroxine of formula III is described in the patent application WO 2009/154737 and is illustrated by Scheme 1.
1 (Form 2)
Boroxine of formula III, or its free boronic acid, is reacted with citric acid in a solvent at an elevated temperature; after cooling, the crystallized product is isolated by filtering.
If after the reaction of boroxine of formula HI with citric acid in ethyl acetate at 74°C uncontrolled cooling of the reaction mixture is conducted, this may lead to formation of the 5-membered isomeric Form 1 (meiting point 198.8°C), while controlled cooling of the reaction mixture to the room temperature or to 40°C results in formation of the more stable isomeric Form 2 (melting point 219.9°C). Form 2 can also be prepared through a reaction of the compound of formula 111 with citric acid and crystallization from various solvents (tetrahydrofuran, acetonitrile, methyl /so-butyl ketone, 2- methyltetrahydrofuran, acetone), followed by addition of the acetic acid ethyl ester as an antisolvent.
Disclosure of Invention
The invention provides novel polymorphic forms - crystalline C2- C4 alcoholic solvate of Ixazomib citrate of isomeric Form 1 of formula I:
Preparation of new forms of ixazomib citrate represents a very important part of pharmaceutical development as more pharmaceutically acceptable salts and forms of course significantly increase the chance of obtaining a stable, pharmaceutically acceptable substance, complying with the formulation demands.
The unique use of Ixazomib citrate as the first proteasome inhibitor that can also be administered orally places high demands on stability of the given form. For this reason, as many stable forms of the given pharmaceutical substance - in this case Ixazomib citrate - as possible should be available.
It has surprisingly been found out that the relatively instable isomeric Form 1 of Ixazomib citrate forms stabilized alcoholic solvates in the presence of alcohols.
The crystalline structure of the two new forms of Ixazomib citrate of formula I; the ethanol and isopropanol solvate, has also been studied on the single crystal and their structure has been confirmed with the use of X-ray crystallography.
Both the solvates (ethanol, isopropanol) have crystallized in the monoclinic system with two molecules of Ixazomib citrate and two molecules of the solvent in the asymmetrical part of the cell (Figures 3 and 4, Tables 3 and 4). In the structure of the Ixazomib citrate isopropanol solvate both the molecules of the solvent in the asymmetrical part of the cell were disordered with the occupancies of 0.666 : 0.334 and 0.696 : 0.304.
The crystal structures of the two solvates are very similar to each other, both as regards the lattice parameters (Tables 3 and 4), or the molecular packing (Fig. 5). This also results in similar X-ray powder diffraction patterns (Figs. 5, 1 and 2).
The novel crystalline forms of Ixazomib citrate of formula I, prepared according to this invention, are referred to as the ethanol solvate and isopropanol solvate.
The ethanol solvate of Ixazomib citrate of formula la
The isopropanol solvate of Ixazomib citrate of formula lb
The single crystal X-ray diffraction (shown in Figs. 3, 3a and 4, 4a) also clearly illustrates the arrangement of the citrate, which corresponds to isomeric Form 1 , i.e. forming a 5-membered cycle with boron.
What is interesting is a very strong interaction between boron and the carbonyl of the amidic group of the protected glycine, which can be represented by means of the resonance structures of formula IV and formula V in Scheme 2.
Scheme 2
In both the determined structures a solid state is observed that is rather represented by the resonance state V (Figs. 3A and 4A). The bond of the amide group to boron can be considered as a coordinate covalent one. In the determined crystalline structure the difference from the remaining two (covalent) B-0 bonds was observed in a different bond length. The average length of the covalent B-0 bonds was, in the structures of the solvates of Ixazomib citrate I, 1.47 A, and that of the coordinate bond 1.56 A. This also corresponds very well to similar crystal structures found in the Cambridge Structural Database, where the corresponding values were 1.44 A and 1.61 A, respectively.
Another aspect of this invention provides an amorphous form of Ixazomib citrate, which is characterized by the X-ray pattern shown in Fig. 6 and the glass transition temperature Tg=104.1 °C according to the DSC record presented in Fig. 7.
This invention also provides processes for the production of the above mentioned forms of Ixazomib citrate.
Preparation of the alcohol solvates of Ixazomib citrate of formula I comprises dissolution of Ixazomib citrate in an alcohol and subsequent crystallization from the solution of the compound in the alcohol.
As a suitable alcohol, ethanol, or isopropanol us used.
The crystallization is conducted at a temperature of 20 to 85°C.
Preferably, the crystallization is conducted at a temperature of 20 to 25°C.
In a preferred embodiment, an antisolvent is used for the crystallization.
In a preferred embodiment, n-hexane or ethyl acetate is used as the antisolvent.
The prepared alcohol solvates are characterized by a different powder diffraction pattern from those of the hitherto known Forms 1 and 2 disclosed in the application WO 2009/154737 and Form 3.
The ethanol solvate of Ixazomib citrate of formula la, prepared in the above mentioned manner, exhibits the following characteristic reflections in an X-ray powder pattern measured with the use of CuKa radiation: 6.0; 12.1 ; 14.4; 18.2; 22.4 and 24.4 ± 0.2° 2-theta and more reflections, presented in Table 1.
Table 1:
32 24.41 3.644 8.2
34 24.99 3.561 6.4
36 25.89 3.439 2.4
40 27.69 3.219 1.3
50 32.43 2.758 2.6
58 36.71 2.446 1.6
The isopropanol solvate of Ixazomib citrate of formula lb, prepared in the above mentioned manner, exhibits the following characteristic reflections in an X-ray powder pattern measured with the use of CuKa radiation: 6.2; 10.0; 14.5; 17.1 and 21.0 ± 0.2° 2-theta and more reflections, presented in Table 2.
Table 2:
44 36.88 2.435 3.0
Table 3
Basic crystallographic data of the structure of Ixazomib citrate I ethanol solvate
Table 4
Basic crystallographic data of the structure of Ixazomib citrate I isopropyi alcohol solvate
System Monoclinic
Symmetry Group P21
a (A) 10.9292(10)
b (A) 8.5476(10)
c (A) 29.3322(10)
β (°) 92.518(10)
Υ θ 90
Volume (A3) 2737.52
Z 4
D calc. (g/ml) 1.400
Number of reflections 9104
Number of reflections 8758
with 1 > 2 σ (1)
R {l > 2 a (l)) 0.0310
Another aspect of this invention is provided by an amorphous form of Ixazomib citrate that was prepared by lyophilization of a freeze-dried solution of Ixazomib citrate in a suitable solvent.
A suitable solvent is an alcohol.
In a preferred embodiment, fert-butanol is used as the alcohol for the preparation of the amorphous form of Ixazomib citrate of formula I.
The X-ray pattern of the amorphous form of Ixazomib citrate of formula I is shown in Fig. 6 and its DSC record is in Fig. 7.
Brief Description of Drawings
Fig. 1 - X-ray powder diffraction pattern of ixazomib citrate of formula I ethanol solvate
Fig. 2 - X-ray powder diffraction pattern of Ixazomib citrate of formula I isopropanol solvate
Fig. 3 - X-ray diffraction on a single crystal of Ixazomib citrate I ethanol solvate; asymmetrical part of the cell with displayed thermal oscillations
Fig. 3 - X-ray diffraction on a single crystal of Ixazomib citrate I ethanol solvate; for clarity just one half of the asymmetrical part of the cell is shown with displayed thermal oscillations and atom descriptions
Fig. 4 - X-ray diffraction on a single crystal of Ixazomib citrate I isopropyl alcohol solvate; asymmetrical part of the cell with displayed thermal oscillations
Fig. 4A - X-ray diffraction on a single crystal of Ixazomib citrate I isopropyl alcohol solvate; for clarity just one half of the asymmetrical part of the cell without the disorder is shown, with displayed thermal oscillations and atom descriptions
Fig. 5 - Comparison of the crystal structures of Ixazomib citrate of formula I isopropyl alcohol solvate (at the top) and Ixazomib citrate of formula I ethanol solvate (at the bottom) and their calculated powder diffraction patterns.
Fig. 6 - X-ray powder diffraction pattern of the amorphous form of Ixazomib citrate Fig. 7 - DSC record of the amorphous form of Ixazomib citrate
Examples
X-ray powder diffraction
The diffraction pattern was obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ = 0.1542 nm (1.542 A)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01 ° 2Θ at the reflection dwell time of 50 s. For the correction of the primary array 0.02 rad Soiler slits, a 10mm mask and a 1/4° fixed anti-dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soiler slits and a 5.0 anti-dispersion slit were used. The measurement was carried out with a flat sample applied onto a Si plate.
Single crystal X-ray diffraction
The analysis was conducted at the temperature of 120 K using the Xcalibur, Atlas, Gemini ultra diffractometer with a mirror monochromator and CCD detector, Cu KQ radiation with the wavelength of 1.5418 A. The data were collected and reduced by the CrysAlisPro program by Agilent Technologies, version 1.171.36.28. The absorption correction was done in the program Jana2006, version 03/1 1/2014. The structures were determined with the use of direct methods (SIR92 program) and specified in the CRYSTALS 14.40b program. All non-hydrogen atoms were specified with thermal oscillations.
Preparation of the ethanol solvate of ixazomib citrate of formula I
Example 1
Ixazomib citrate (Form 3), 25 mg was dissolved in 1 ml of ethanol in a hot state. During 48 hours, in the presence of hexane vapours Ixazomib citrate crystallizes in the ethanol solvate form.
The X-ray pattern of the ethanol solvate is shown in Fig. 1. Example 2
Ixazomib citrate (Form 2), 25 mg was dissolved in a mixture of 10 ml of ethyl acetate and 2 ml of ethanol in a hot state. During 20 hours, crystals of Ixazomib citrate are formed by slow spontaneous evaporation in the ethanol solvate form.
The X-ray pattern is equal to the pattern of Example 1.
Preparation of the isopropanol solvate of Ixazomib citrate I
Example 3
ixazomib citrate (Form 3), 20 mg was dissolved in 1.5 ml of isopropanol in a hot state. During 20 hours, in the presence of hexane vapours Ixazomib citrate crystallizes in the isopropanol solvate form.
The X-ray pattern of the isopropanol solvate is shown in Fig. 2.
Preparation of the amorphous form of Ixazomib citrate I
Example 4
300 mg of Ixazomib citrate (Form 3) was dissolved in 15 ml of fe/f-butanol. After freeze-drying of the solution (the bath consisting of an ethanol/dry ice mixture; -70°C and subsequent lyophilization (3.5 Pa; 24 h) Ixazomib citrate was obtained in an amorphous form.
The X-ray pattern of the amorphous form is shown in Fig. 6 and its DSC record is in Fig. 7.
Claims
1. A crystalline C2- C alcohol solvate of ixazomib citrate Form 1 of formula I:
2. The crystalline ethanol solvate of Ixazomib citrate of isomeric Form 1, of formula la, according to claim 1 :
3. The crystalline isopropanol solvate of Ixazomib citrate of isomeric Form 1 , of formula lb, according to claim 1:
4. A process for preparing the alcohol solvates defined in claims 2 and 3, characterized in that the crystallizing solvent is a C2 to C4 alcohol.
5. The process according to claim 4, characterized in that the crystallizing solvent is isopropanol or ethanol.
6. The process according to claims 4 and 5, characterized in that the antisolvent is n-hexane or ethyl acetate.
7. An amorphous form of Ixazomib citrate, which is characterized by the X-ray pattern shown in Fig. 6.
8. The amorphous form of Ixazomib citrate with the glass transition temperature Tg=104.1°C.
9. A process for preparing the amorphous form of Ixazomib citrate defined in claims 6 or 7, characterized in that the amorphous form is prepared by lyophilization of a freeze-dried solution of Ixazomib citrate.
10. The process for preparing the amorphous form of Ixazomib citrate according to claim 8, characterized in that the solvent is an alcohol.
11.The process for preparing the amorphous form of Ixazomib citrate according to claim 9, characterized in that the solvent is iert-butanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16721061.6A EP3283491A1 (en) | 2015-04-15 | 2016-04-14 | New forms of ixazomib citrate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ2015-253A CZ2015253A3 (en) | 2015-04-15 | 2015-04-15 | Novel forms of ixazomib citrate |
| CZPV2015-253 | 2015-04-15 |
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| EP (1) | EP3283491A1 (en) |
| CZ (1) | CZ2015253A3 (en) |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017046815A1 (en) * | 2015-09-16 | 2017-03-23 | Mylan Laboratories Limited | Polymorphs of ixazomib citrate and processes for the preparation thereof |
| WO2017163190A1 (en) * | 2016-03-23 | 2017-09-28 | Dr. Reddy’S Laboratories Limited | Amorphous ixazomib citrate and solid dispersion thereof |
| WO2017174046A1 (en) * | 2016-04-08 | 2017-10-12 | Zentiva, K.S. | A formulation of ixazomib citrate form 3 |
| WO2017222819A2 (en) | 2016-06-21 | 2017-12-28 | Teva Pharmaceuticals International Gmbh | Solid state forms of ixazomib citrate |
| WO2018158697A1 (en) | 2017-03-03 | 2018-09-07 | Fresenius Kabi Oncology Limited | A process for the preparation of ixazomib citrate |
| WO2023220655A1 (en) | 2022-05-11 | 2023-11-16 | Celgene Corporation | Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy |
| WO2023220641A2 (en) | 2022-05-11 | 2023-11-16 | Juno Therapeutics, Inc. | Methods and uses related to t cell therapy and production of same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009154737A1 (en) | 2008-06-17 | 2009-12-23 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
| WO2011087822A1 (en) | 2009-12-22 | 2011-07-21 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
| WO2012177835A1 (en) | 2011-06-22 | 2012-12-27 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
-
2015
- 2015-04-15 CZ CZ2015-253A patent/CZ2015253A3/en unknown
-
2016
- 2016-04-14 EP EP16721061.6A patent/EP3283491A1/en not_active Withdrawn
- 2016-04-14 WO PCT/CZ2016/000043 patent/WO2016165677A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009154737A1 (en) | 2008-06-17 | 2009-12-23 | Millennium Pharmaceuticals, Inc. | Boronate ester compounds and pharmaceutical compositions thereof |
| WO2011087822A1 (en) | 2009-12-22 | 2011-07-21 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
| WO2012177835A1 (en) | 2011-06-22 | 2012-12-27 | Cephalon, Inc. | Proteasome inhibitors and processes for their preparation, purification and use |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017046815A1 (en) * | 2015-09-16 | 2017-03-23 | Mylan Laboratories Limited | Polymorphs of ixazomib citrate and processes for the preparation thereof |
| WO2017163190A1 (en) * | 2016-03-23 | 2017-09-28 | Dr. Reddy’S Laboratories Limited | Amorphous ixazomib citrate and solid dispersion thereof |
| WO2017174046A1 (en) * | 2016-04-08 | 2017-10-12 | Zentiva, K.S. | A formulation of ixazomib citrate form 3 |
| WO2017222819A2 (en) | 2016-06-21 | 2017-12-28 | Teva Pharmaceuticals International Gmbh | Solid state forms of ixazomib citrate |
| US10604537B2 (en) | 2016-06-21 | 2020-03-31 | Teva Pharmaceuticals International Gmbh | Solid state forms of ixazomib citrate |
| EP3798224A1 (en) | 2016-06-21 | 2021-03-31 | Teva Pharmaceuticals International GmbH | Solid state forms of ixazomib citrate |
| US11053261B2 (en) | 2016-06-21 | 2021-07-06 | Teva Pharmaceuticals International Gmbh | Solid state forms of ixazomib citrate |
| WO2018158697A1 (en) | 2017-03-03 | 2018-09-07 | Fresenius Kabi Oncology Limited | A process for the preparation of ixazomib citrate |
| WO2023220655A1 (en) | 2022-05-11 | 2023-11-16 | Celgene Corporation | Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy |
| WO2023220641A2 (en) | 2022-05-11 | 2023-11-16 | Juno Therapeutics, Inc. | Methods and uses related to t cell therapy and production of same |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ2015253A3 (en) | 2016-10-26 |
| EP3283491A1 (en) | 2018-02-21 |
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