CA2915107A1 - Novel crystalline form of a proteasome inhibitor - Google Patents
Novel crystalline form of a proteasome inhibitor Download PDFInfo
- Publication number
- CA2915107A1 CA2915107A1 CA2915107A CA2915107A CA2915107A1 CA 2915107 A1 CA2915107 A1 CA 2915107A1 CA 2915107 A CA2915107 A CA 2915107A CA 2915107 A CA2915107 A CA 2915107A CA 2915107 A1 CA2915107 A1 CA 2915107A1
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- Canada
- Prior art keywords
- cancer
- crystalline form
- lymphoma
- multiple myeloma
- crystalline
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a novel crystalline form of a proteasome inhibitor, and to the processes for the preparation thereof. The novel crystalline form according to the invention may be used in the preparation of pharmaceutical compositions for the treatment of cancer.
Description
NOVEL CRYSTALLINE FORM OF A PROTEASOME INHIBITOR
FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of a proteasome inhibitor, and to the processes for the preparation thereof. The novel crystalline form according to the invention may be used in the preparation of pharmaceutical compositions for the treatment of cancer.
BACKGROUND OF THE INVENTION
Boronic acid and its derivatives display a variety of pharmaceutically useful biological activities. Shenvi etal., U.S. Pat. No. 4,499,082 (1985) discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes. Kettner and Shenvi, U.S. Pat.
No. 5,187,157 (1993), U.S. Pat. No. 5,242,904 (1993), and U.S. Pat. No. 5,250,720 (1993), describe a class of peptide boronic acids that inhibit trypsin-like proteases. Kleeman et al., U.S. Pat. No.
5,169,841(1992), discloses N-terminally modified peptide boronic acids that inhibit the action of renin. Kinder etal., U.S. Pat. No. 5,106,948 (1992), discloses that certain boronic acid compounds inhibit the growth of cancer cells. Boehm/chin etal., WO
07/0005991, discloses peptide boronic acid compounds that inhibit fibroblast activating protein.
Boronic acid and ester compounds hold particular promise as inhibitors of the proteasome, a multicatalytic protease responsible for the majority of intracellular protein turnover. Adams etal., U.S. Patent No. 5,780,454 (1998), describes peptide boronic ester and acid compounds useful as proteasome inhibitors. The reference also describes the use of boronic ester and acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF-KB in a cell, to reduce the rate of degradation of p53 protein in a cell, to inhibit cyclin degradation in a cell, to inhibit the growth of a cancer cell, and to inhibit NF-KB
dependent cell adhesion. Furet et al., WO 02/096933, Chatterjee etal., WO
05/016859, and Bernadini et al, WO 05/021558 and WO 06/08660, disclose additional boronic ester and acid compounds that are reported to have proteasome inhibitory activity.
[(1 R) - 1 -( [(2,5-DichlorobenzoyDamino] acetyllamino)-3 -methylbutyl]boronic acid, also known as ixazomib, is a proteasome inhibitor in the peptide boronic acid class. Ixazomib selectively inhibits the proteasome. Ixazomib preferentially binds the 05 site of the 20S
proteasome with a concentration producing 50% inhibition (IC50) of 3.4 nM. At higher concentrations, it also inhibits the activity of the 131 and 132 sites.
Ixazomib is selective for the proteasome when tested against a panel of proteases (IC50 values between 20 and 100 M), kinases (IC50 values > 10 M), and receptors (IC50 values > 10 M). Ixazomib citrate has been evaluated at clinical studies that have included patients with advanced solid tumors, lymphoma, relapsed/refractory multiple myeloma (RRMM), and amyloidosis or relapsed or refractory light-chain (AL) amyloidosis and demonstrated signs of activity.
Ongoing studies continue to investigate both single-agent ixazomib citrate and ixazomib citrate in combination with standard treatments. Additional clinic studies are evaluating ixazomib citrate in combination with lenalidomide and dexamethasone (LenDex) versus placebo/LenDex.
Under dehydrating conditions, [(1 R) - 1 -( [(2,5-DichlorobenzoyDamino]acetyllamino)-3-methylbutyl]boronic acid readily forms anhydrides by combination of two or more molecules of a boronic acid compound, with loss of one or more water molecules. When mixed with water, the boronic acid anhydrides are hydrated to release the free boronic acid compounds. Boronic acids and their derivatives are often air-sensitive. For example, Korcek et al., J. Chem. Soc., Perkin Trans. 2 242 (1972), teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid. There is thus a continuing need for an additional stable form of [(1 R) - 1 -( [(2,5-DichlorobenzoyDamino]acetyl}amino)-3-methylbutyl]boronic acid or anhydrides thereof.
SUMMARY OF THE INVENTION
The present invention provides crystalline Pattern B comprising N,N,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)J]tris(2,5-dichlorobenzamide).
Crystalline Pattern B of this invention has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 5.79, 10.63, 16.06, and 23.58.
FIELD OF THE INVENTION
The present invention relates to a novel crystalline form of a proteasome inhibitor, and to the processes for the preparation thereof. The novel crystalline form according to the invention may be used in the preparation of pharmaceutical compositions for the treatment of cancer.
BACKGROUND OF THE INVENTION
Boronic acid and its derivatives display a variety of pharmaceutically useful biological activities. Shenvi etal., U.S. Pat. No. 4,499,082 (1985) discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes. Kettner and Shenvi, U.S. Pat.
No. 5,187,157 (1993), U.S. Pat. No. 5,242,904 (1993), and U.S. Pat. No. 5,250,720 (1993), describe a class of peptide boronic acids that inhibit trypsin-like proteases. Kleeman et al., U.S. Pat. No.
5,169,841(1992), discloses N-terminally modified peptide boronic acids that inhibit the action of renin. Kinder etal., U.S. Pat. No. 5,106,948 (1992), discloses that certain boronic acid compounds inhibit the growth of cancer cells. Boehm/chin etal., WO
07/0005991, discloses peptide boronic acid compounds that inhibit fibroblast activating protein.
Boronic acid and ester compounds hold particular promise as inhibitors of the proteasome, a multicatalytic protease responsible for the majority of intracellular protein turnover. Adams etal., U.S. Patent No. 5,780,454 (1998), describes peptide boronic ester and acid compounds useful as proteasome inhibitors. The reference also describes the use of boronic ester and acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF-KB in a cell, to reduce the rate of degradation of p53 protein in a cell, to inhibit cyclin degradation in a cell, to inhibit the growth of a cancer cell, and to inhibit NF-KB
dependent cell adhesion. Furet et al., WO 02/096933, Chatterjee etal., WO
05/016859, and Bernadini et al, WO 05/021558 and WO 06/08660, disclose additional boronic ester and acid compounds that are reported to have proteasome inhibitory activity.
[(1 R) - 1 -( [(2,5-DichlorobenzoyDamino] acetyllamino)-3 -methylbutyl]boronic acid, also known as ixazomib, is a proteasome inhibitor in the peptide boronic acid class. Ixazomib selectively inhibits the proteasome. Ixazomib preferentially binds the 05 site of the 20S
proteasome with a concentration producing 50% inhibition (IC50) of 3.4 nM. At higher concentrations, it also inhibits the activity of the 131 and 132 sites.
Ixazomib is selective for the proteasome when tested against a panel of proteases (IC50 values between 20 and 100 M), kinases (IC50 values > 10 M), and receptors (IC50 values > 10 M). Ixazomib citrate has been evaluated at clinical studies that have included patients with advanced solid tumors, lymphoma, relapsed/refractory multiple myeloma (RRMM), and amyloidosis or relapsed or refractory light-chain (AL) amyloidosis and demonstrated signs of activity.
Ongoing studies continue to investigate both single-agent ixazomib citrate and ixazomib citrate in combination with standard treatments. Additional clinic studies are evaluating ixazomib citrate in combination with lenalidomide and dexamethasone (LenDex) versus placebo/LenDex.
Under dehydrating conditions, [(1 R) - 1 -( [(2,5-DichlorobenzoyDamino]acetyllamino)-3-methylbutyl]boronic acid readily forms anhydrides by combination of two or more molecules of a boronic acid compound, with loss of one or more water molecules. When mixed with water, the boronic acid anhydrides are hydrated to release the free boronic acid compounds. Boronic acids and their derivatives are often air-sensitive. For example, Korcek et al., J. Chem. Soc., Perkin Trans. 2 242 (1972), teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid. There is thus a continuing need for an additional stable form of [(1 R) - 1 -( [(2,5-DichlorobenzoyDamino]acetyl}amino)-3-methylbutyl]boronic acid or anhydrides thereof.
SUMMARY OF THE INVENTION
The present invention provides crystalline Pattern B comprising N,N,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)J]tris(2,5-dichlorobenzamide).
Crystalline Pattern B of this invention has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 5.79, 10.63, 16.06, and 23.58.
2 Crystalline Pattern B of this invention has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 5.79, 10.63, 16.06, 17.12, 17.93, 19.69, 23.58 and 24.17.
The present invention further provides methods for the preparation of the crystalline Pattern B and pharmaceutical compositions comprising crystalline Pattern B;
and a pharmaceutically acceptable carrier.
The present invention further provides a method of treating cancer, comprising administering to a patient in need thereof crystalline Pattern B, wherein the cancer includes multiple myeloma, refractory or recurrence multiple myeloma, or lymphoma. A
use of crystalline Pattern B in treating cancer in a patient in need thereof is also provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an indexing solution an X-ray powder diffraction pattern (XRPD) of crystalline Pattern B.
FIG. 2 shows a XRPD pattern with labeled peaks of crystalline Pattern B.
FIG. 3 shows a XRPD pattern of crystalline Pattern B.
FIG. 4 shows HI NMR spectrum of crystalline Pattern B.
FIG. 5 shows solid state carbon-13 nuclear magnetic resonance spectrum of crystalline Pattern B.
FIG. 6 shows IR spectrum of crystalline Pattern B.
FIG. 7 shows thermal gravimetric analysis (TGA) profile of crystalline Form Pattern B.
FIG. 8 shows differential scanning calorimetry (DSC) profile of crystalline Pattern B.
FIG. 9 shows dynamic vapor sorption (DVS) analysis (weight % vs relative humidity).
FIG. 10 shows three XRPDs of crystalline Pattern B. The XRPD of crystalline Pattern B isolated from Example 7 is at the top. The XRPD of crystalline Pattern B
isolated from Example 6 is at the middle. The XRPD of crystalline Pattern B isolated from Example 1 is at the bottom.
The present invention further provides methods for the preparation of the crystalline Pattern B and pharmaceutical compositions comprising crystalline Pattern B;
and a pharmaceutically acceptable carrier.
The present invention further provides a method of treating cancer, comprising administering to a patient in need thereof crystalline Pattern B, wherein the cancer includes multiple myeloma, refractory or recurrence multiple myeloma, or lymphoma. A
use of crystalline Pattern B in treating cancer in a patient in need thereof is also provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an indexing solution an X-ray powder diffraction pattern (XRPD) of crystalline Pattern B.
FIG. 2 shows a XRPD pattern with labeled peaks of crystalline Pattern B.
FIG. 3 shows a XRPD pattern of crystalline Pattern B.
FIG. 4 shows HI NMR spectrum of crystalline Pattern B.
FIG. 5 shows solid state carbon-13 nuclear magnetic resonance spectrum of crystalline Pattern B.
FIG. 6 shows IR spectrum of crystalline Pattern B.
FIG. 7 shows thermal gravimetric analysis (TGA) profile of crystalline Form Pattern B.
FIG. 8 shows differential scanning calorimetry (DSC) profile of crystalline Pattern B.
FIG. 9 shows dynamic vapor sorption (DVS) analysis (weight % vs relative humidity).
FIG. 10 shows three XRPDs of crystalline Pattern B. The XRPD of crystalline Pattern B isolated from Example 7 is at the top. The XRPD of crystalline Pattern B
isolated from Example 6 is at the middle. The XRPD of crystalline Pattern B isolated from Example 1 is at the bottom.
3 DETAILED DESCRIPTION OF THE INVENTION
[(1 R) - 1 -( {[(2 , 5 -D chl orobenzoyl) amino ] acetyllamino)-3-methylbutyl]boronic acid has the following Formula (Ia):
ci 0 H OH
1\16'0H
CI
Formula (Ia).
Under dehydrating conditions, this compound forms anhydrides by combination of two or more molecules, with loss of one or more water molecules. In various embodiments, the boronic acid anhydride can comprise two, three, four, or more boronic acid units, and can have a cyclic or linear configuration. In some embodiments, [(1R)-1-({[(2,5-DichlorobenzoyDaminoF acetyllamino)-3-methylbutyl]boronic acid form a cyclic trimer (boroxine). In one embodiment, a cyclic timer is N,AP,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) of Formula (Ib):
CI
CI
CI 0 ICY B,0 0 CI
HH I I
BõB
c, c, Formula (Ib).
Chemical synthesis of Formula (Ia) or Formula (lb) are described in WO
2009/02448, US 7,442,830, WO 2009/154737 and US 8,859,504, which are incorporated herein by reference in their entirety.
In some embodiments, the compound of Formula (lb) may be depicted in one or more alternate resonance forms. A resonance form is another way of drawing a Lewis dot structure
[(1 R) - 1 -( {[(2 , 5 -D chl orobenzoyl) amino ] acetyllamino)-3-methylbutyl]boronic acid has the following Formula (Ia):
ci 0 H OH
1\16'0H
CI
Formula (Ia).
Under dehydrating conditions, this compound forms anhydrides by combination of two or more molecules, with loss of one or more water molecules. In various embodiments, the boronic acid anhydride can comprise two, three, four, or more boronic acid units, and can have a cyclic or linear configuration. In some embodiments, [(1R)-1-({[(2,5-DichlorobenzoyDaminoF acetyllamino)-3-methylbutyl]boronic acid form a cyclic trimer (boroxine). In one embodiment, a cyclic timer is N,AP,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) of Formula (Ib):
CI
CI
CI 0 ICY B,0 0 CI
HH I I
BõB
c, c, Formula (Ib).
Chemical synthesis of Formula (Ia) or Formula (lb) are described in WO
2009/02448, US 7,442,830, WO 2009/154737 and US 8,859,504, which are incorporated herein by reference in their entirety.
In some embodiments, the compound of Formula (lb) may be depicted in one or more alternate resonance forms. A resonance form is another way of drawing a Lewis dot structure
4 for a given compound. Equivalent Lewis structures are called resonance forms.
They are used when there is more than one way to place double bonds and lone pairs on atoms.
In some embodiments, the present invention includes a novel crystalline Pattern B
comprising 1V,AP,N"- [2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide).
In one embodiment, crystalline Pattern B comprises at least 98.0% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 98.5% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.0% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.5% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.8% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.9% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises 100% of the compound of Formula (Ib).
In some embodiments, crystalline Pattern B is prepared in a method comprising the steps of:
(a) dissolving or suspending a non-crystalline solid comprising a compound of Formula (lb) in a solvent;
(b) adding a second agent to the suspension or solution at a predetermined temperature;
(c) stirring the above mixture for a sufficient amount of time to form crystalline Pattern B;
and optionally (d) isolating crystalline Pattern B.
In some embodiments, the non-crystalline solid in the method may include a small amount of the boronic acid of Formula (Ia). For example, the non-crystalline solid may include 10%, 5%, 2%, 1%, 0.5%, 0.3%, 0.2%. 0.1, or 0.01% of the boronic acid of Formula (Ia).
In some embodiments, the non-crystalline solid in the method comprises at least 80%, 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of the cyclic trimer of Formula (lb).
In some embodiments, the non-crystalline solid comprises 100% of the cyclic trimer of Formula (lb).
In some embodiments, the solvent is selected from ethyl acetate.
In some embodiments, the second agent is selected from anethole, methyl benzoate, methyl cinnamate, triacetin, triethyl citrate, or caffeine.
In some embodiments, the predetermined temperature is between about 15 C to about 35 C. In other embodiments, the temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the predetermined temperature is room temperature, from about 15 C to about 35 C.
In some embodiments, room temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the isolation may be achieved by filtration, optionally followed by drying under reduced pressure.
In some embodiments, the amount of time sufficient to generate crystalline Pattern B
is from 4 hours to 24 hours. In other embodiments, the sufficient amount of time is about 6, 8, 10, 12, 14, or 16 hours.
In some embodiments, the present invention provides a process for producing large amounts of crystalline Pattern B. The process comprises the steps of:
(a) adding crystalline Pattern B as seeding material to a solution of non-crystalline solid comprising the compound of Formula (lb);
(b) stirring the solution at a predetermined temperature for a sufficient amount of time; and optionally (c) collecting crystalline Pattern B.
In some embodiments, the non-crystalline solid in the process may include a small amount of the boronic acid of Formula (Ia). For example, the non-crystalline solid may include 10%, 5%, 2%, 1%, 0.5%, 0.2%. 0.1, or 0.01% of the boronic acid of Formula (Ia).
In one embodiment, the non-crystalline solid in the process comprises at least 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of the cyclic trimer of formula (lb). In some embodiments, the non-crystalline solid comprises 100% of the cyclic trimer of formula (Ib).
In some embodiments, the solution is ethyl acetate solution.
In some embodiments, the amount of crystalline Pattern B as seeding material in the process is about from 0.1% to about 5% by weight of the non-crystalline solid.
In some embodiments, the amount of crystalline Pattern B as seeding material is from about 5% to about 10% by weight of the non-crystalline solid. In some embodiments, the amount of crystalline Pattern B as seeding material is about from 10% to about 20% by weight of the non-crystalline solid. In some embodiments, the amount of crystalline Pattern B as seeding material is about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%,
They are used when there is more than one way to place double bonds and lone pairs on atoms.
In some embodiments, the present invention includes a novel crystalline Pattern B
comprising 1V,AP,N"- [2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide).
In one embodiment, crystalline Pattern B comprises at least 98.0% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 98.5% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.0% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.5% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.8% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises at least 99.9% of the compound of Formula (Ib).
In another embodiment, crystalline Pattern B comprises 100% of the compound of Formula (Ib).
In some embodiments, crystalline Pattern B is prepared in a method comprising the steps of:
(a) dissolving or suspending a non-crystalline solid comprising a compound of Formula (lb) in a solvent;
(b) adding a second agent to the suspension or solution at a predetermined temperature;
(c) stirring the above mixture for a sufficient amount of time to form crystalline Pattern B;
and optionally (d) isolating crystalline Pattern B.
In some embodiments, the non-crystalline solid in the method may include a small amount of the boronic acid of Formula (Ia). For example, the non-crystalline solid may include 10%, 5%, 2%, 1%, 0.5%, 0.3%, 0.2%. 0.1, or 0.01% of the boronic acid of Formula (Ia).
In some embodiments, the non-crystalline solid in the method comprises at least 80%, 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of the cyclic trimer of Formula (lb).
In some embodiments, the non-crystalline solid comprises 100% of the cyclic trimer of Formula (lb).
In some embodiments, the solvent is selected from ethyl acetate.
In some embodiments, the second agent is selected from anethole, methyl benzoate, methyl cinnamate, triacetin, triethyl citrate, or caffeine.
In some embodiments, the predetermined temperature is between about 15 C to about 35 C. In other embodiments, the temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the predetermined temperature is room temperature, from about 15 C to about 35 C.
In some embodiments, room temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the isolation may be achieved by filtration, optionally followed by drying under reduced pressure.
In some embodiments, the amount of time sufficient to generate crystalline Pattern B
is from 4 hours to 24 hours. In other embodiments, the sufficient amount of time is about 6, 8, 10, 12, 14, or 16 hours.
In some embodiments, the present invention provides a process for producing large amounts of crystalline Pattern B. The process comprises the steps of:
(a) adding crystalline Pattern B as seeding material to a solution of non-crystalline solid comprising the compound of Formula (lb);
(b) stirring the solution at a predetermined temperature for a sufficient amount of time; and optionally (c) collecting crystalline Pattern B.
In some embodiments, the non-crystalline solid in the process may include a small amount of the boronic acid of Formula (Ia). For example, the non-crystalline solid may include 10%, 5%, 2%, 1%, 0.5%, 0.2%. 0.1, or 0.01% of the boronic acid of Formula (Ia).
In one embodiment, the non-crystalline solid in the process comprises at least 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of the cyclic trimer of formula (lb). In some embodiments, the non-crystalline solid comprises 100% of the cyclic trimer of formula (Ib).
In some embodiments, the solution is ethyl acetate solution.
In some embodiments, the amount of crystalline Pattern B as seeding material in the process is about from 0.1% to about 5% by weight of the non-crystalline solid.
In some embodiments, the amount of crystalline Pattern B as seeding material is from about 5% to about 10% by weight of the non-crystalline solid. In some embodiments, the amount of crystalline Pattern B as seeding material is about from 10% to about 20% by weight of the non-crystalline solid. In some embodiments, the amount of crystalline Pattern B as seeding material is about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%,
5.5%, 6%,
6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or 20%
by weight of the non-crystalline solid.
In some embodiments, the temperature in the process is between about 15 C to about 40 C. In other embodiments, the temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the predetermined temperature is room temperature, from about 15 C to about 35 C.
In some embodiments, room temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the collecting step of the process may be achieved by filtration, optionally followed by drying under reduced pressure.
In some embodiments, the sufficient amount of time for the process is from 4 hours to 24 hours. In other embodiments, the sufficient amount of time is about 6, 8, 10, 12, 14, or 16 hours.
In one embodiment, crystal Pattern B can be characterized as having an X-ray diffraction pattern having characteristic peaks (20) as shown in Table 1. A
discussion of the theory of X-ray powder diffraction patterns can be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, MacMillan Co., New York, N.Y. (1968), which is incorporated by reference in its entirety. The X-ray Powder Diffraction (XRPD) patterns were
by weight of the non-crystalline solid.
In some embodiments, the temperature in the process is between about 15 C to about 40 C. In other embodiments, the temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the predetermined temperature is room temperature, from about 15 C to about 35 C.
In some embodiments, room temperature is about 15 C, 20 C, 25 C, 30 C, or 35 C.
In some embodiments, the collecting step of the process may be achieved by filtration, optionally followed by drying under reduced pressure.
In some embodiments, the sufficient amount of time for the process is from 4 hours to 24 hours. In other embodiments, the sufficient amount of time is about 6, 8, 10, 12, 14, or 16 hours.
In one embodiment, crystal Pattern B can be characterized as having an X-ray diffraction pattern having characteristic peaks (20) as shown in Table 1. A
discussion of the theory of X-ray powder diffraction patterns can be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, MacMillan Co., New York, N.Y. (1968), which is incorporated by reference in its entirety. The X-ray Powder Diffraction (XRPD) patterns were
7 acquired using Cu - Ka radiation. Unless stated otherwise, all XRPD values described herein are measured on a 2-Theta (20) scale.
List of XRPD Peaks (+0.2 degrees) Angles ( 20) Intensity (%) 5.79 100 6.98 18 9.46 13 9.89 33 10.63 70 11.40 16 12.41 13 13.96 32 14.13 29 14.38 16 16.06 75 16.73 27 17.12 68 17.53 23 17.93 61 18.58 28 19.26 20 19.69 68 20.05 25 20.65 18 21.37 24 21.99 33 22.59 11 23.58 80 24.17 67 24.33 32 24.93 39 25.26 15 26.11 12 26.54 13 26.92 11 28.12 11 28.46 11 29.36 11 29.59 10
List of XRPD Peaks (+0.2 degrees) Angles ( 20) Intensity (%) 5.79 100 6.98 18 9.46 13 9.89 33 10.63 70 11.40 16 12.41 13 13.96 32 14.13 29 14.38 16 16.06 75 16.73 27 17.12 68 17.53 23 17.93 61 18.58 28 19.26 20 19.69 68 20.05 25 20.65 18 21.37 24 21.99 33 22.59 11 23.58 80 24.17 67 24.33 32 24.93 39 25.26 15 26.11 12 26.54 13 26.92 11 28.12 11 28.46 11 29.36 11 29.59 10
8 In one embodiment, the indexing solution from the XRPD pattern for crystalline Pattern B exhibits a primitive monoclinic unit cell having chiral contents, a P21 (4) space group, a volume of 2,605.5 A3, the extinction symbol P 1 21 1, and the following dimensions:
a 15.521A
11.032A
15.917A
a 90 107.06 In some embodiments, thermal gravimetric analysis (TGA) was performed using a TA
Instruments 2050 thermogravimetric analyzer. Crystalline Pattern B prepared by Example 7 exhibits a TGA profile as depicted in Figure 7. The profile graphs about 1.9%
weight loss up to 150 C at a temperature rate of 10 C per minute, and decomposition at about 272 C.
These temperatures have a variation of 5 C depending on the measuring condition.
In one embodiment, differential scanning calorimetry (DSC) was performed using a TA Instruments Q2000 differential scanning calorimeter. Crystalline Pattern B
prepared by Example 7 shows a DSC profile as depicted in Figure 8. These temperatures have a variation of 5 C depending on the measuring condition.
In one embodiment, crystalline Pattern B exhibits an endothermic transition from about 118 C to about 128 C. In a further embodiment, crystalline Pattern B
exhibits an endothermic transition from about 120 C to about 125 'C. In still a further embodiment, crystalline Pattern B exhibits an endothermic transition of about 123.4 C.
In some embodiments, the present invention includes a composition comprising crystalline Pattern B which comprises N,K,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide), and a pharmaceutically acceptable carrier.
In some embodiments, the present invention includes a composition comprising crystalline Pattern B which comprises /V,NR"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide), or a
a 15.521A
11.032A
15.917A
a 90 107.06 In some embodiments, thermal gravimetric analysis (TGA) was performed using a TA
Instruments 2050 thermogravimetric analyzer. Crystalline Pattern B prepared by Example 7 exhibits a TGA profile as depicted in Figure 7. The profile graphs about 1.9%
weight loss up to 150 C at a temperature rate of 10 C per minute, and decomposition at about 272 C.
These temperatures have a variation of 5 C depending on the measuring condition.
In one embodiment, differential scanning calorimetry (DSC) was performed using a TA Instruments Q2000 differential scanning calorimeter. Crystalline Pattern B
prepared by Example 7 shows a DSC profile as depicted in Figure 8. These temperatures have a variation of 5 C depending on the measuring condition.
In one embodiment, crystalline Pattern B exhibits an endothermic transition from about 118 C to about 128 C. In a further embodiment, crystalline Pattern B
exhibits an endothermic transition from about 120 C to about 125 'C. In still a further embodiment, crystalline Pattern B exhibits an endothermic transition of about 123.4 C.
In some embodiments, the present invention includes a composition comprising crystalline Pattern B which comprises N,K,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide), and a pharmaceutically acceptable carrier.
In some embodiments, the present invention includes a composition comprising crystalline Pattern B which comprises /V,NR"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide), or a
9 pharmaceutically acceptable salt thereof, and a therapeutically acceptable carrier (Formula (1b)).=
In some embodiments, the composition comprises at least 80%, 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of Formula (Ib). In some embodiments, the composition comprises 100% of Formula (Ib).
In some embodiments, the present invention includes a composition comprising a mixture of /V,NR"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)fitris(2,5-dichlorobenzamide), and [(1 R)-1-({ [(2,5-DichlorobenzoyDamino]acetyllamino)-3-methylbutyl]boronic acid.
In some embodiments, the present invention includes a composition comprising a mixture of N,AP,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide), or a pharmaceutically acceptable salt thereof, and R1R)-1-({[(2,5-DichlorobenzoyDamino]acetylfamino)-3-methylbutyl]boronic acid, or a pharmaceutically acceptable salt thereof, and a therapeutically acceptable carrier.
In some embodiments, the mixture of the compositions comprise at least 80%, 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of Formula (lb). In some embodiments, the mixture of the composition comprises 100% of Formula (lb).
Crystalline Pattern B may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.
For oral administration, the pharmaceutical compositions may take the form of capsules or tablets formulated with pharmaceutically acceptable excipients such as filler, lubricant, flow-aid, binder, buffer or bulking agent.
In some embodiments, the filler is selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low-moisture microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, or mixtures thereof. In other embodiments, the filler is selected from microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, or mixtures thereof. In one embodiment, the filler is microcrystalline cellulose.
In some embodiments, the lubricant is selected from magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, talc, zinc stearate, calcium stearate, sucrose stearate, sodium stearyl fumarate, or mixtures thereof In one embodiment, the lubricant is magnesium stearate.
In some embodiments, the flow-aid is talc. In some embodiments, the buffer is sodium citrate or citric acid. In some embodiments, the bulking agent is glycine.
In some embodiments, the pharmaceutically acceptable excipients are selected from microcrystalline cellulose, magnesium stearate, or talc.
The compound of Formula (Ia) and the cyclic trimer Formula (Ib) are selective proteasome inhibitors. As such, crystalline Pattern B and pharmaceutically acceptable compositions thereof may be useful for treating a patient having, or at risk of developing or experiencing a recurrence of, a proteasome-mediated disorder.
As used herein, the term "proteasome-mediated disorder" includes any disorder, disease or condition which is caused or characterized by an increase in proteasome expression or activity. The term "proteasome-mediated disorder" also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial.
For example, crystalline Pattern B or its pharmaceutical compositions may be useful for treating disorders mediated via proteins (e.g., NFKB, p271(iP, p21WAF/CIP1, p53) which are regulated by proteasome activity. Relevant disorders include inflammatory disorders (e.g., rheumatoid arthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, dermatosis (e.g., atopic dermatitis, psoriasis)), vascular proliferative disorders (e.g., atherosclerosis, restenosis), proliferative ocular disorders (e.g., diabetic retinopathy), benign proliferative disorders (e.g., hemangiomas), autoimmune diseases (e.g., multiple sclerosis, tissue and organ rejection), as well as inflammation associated with infection (e.g., immune responses), antibody-mediated disease, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, motor neurone disease, neuropathic pain, triplet repeat disorders, astrocytoma, and neurodegeneration as result of alcoholic liver disease), ischemic injury (e.g., stroke), and cachexia including accelerated muscle protein breakdown that accompanies various physiological and pathological states (e.g., nerve injury, fasting, fever, acidosis, HIV
infection, cancer affliction, and certain endocrinopathies), or useful for desensitization therapy.
Non-limiting examples of autoimmune diseases and antibody-mediated diseases include systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, ulcerative colitis, Crohn's disease, type 1 diabetes, myasthenia gravis, idiopathic pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, scleroderrna sclerosis, systemic sclerosis, antibody-mediated rejection, antibody-mediated rejection in organ transplantation, antibody-mediated rejection in kidney transplantation, antibody-mediated rejection in lung transplantation, antibody-mediated rejection in heart transplantation, antibody-mediated rejection in liver transplantation, antibody-mediated rejection in pancreas transplantation, or graft versus host disease.
Crystalline Pattern B or its pharmaceutical compositions may be particularly useful for the treatment of cancer. As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dis-regulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies. The term "cancer" encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "cancer" further encompasses primary and metastatic cancers.
Non-limiting examples of solid tumors that may be treated with the disclosed proteasome inhibitors or pharmaceutical compositions include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer;
prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma;
neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforrne, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma.
Non-limiting examples of hematologic malignancies that may be treated with the disclosed proteasome inhibitors or pharmaceutical compositions include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML
and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); lymphoma; non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia;
myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions thereof are useful in treatment of amyloidosis.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions thereof are used to treat a patient having or at risk of developing or experiencing a recurrence (relapse) in a cancer selected from multiple myeloma and mantle cell lymphoma.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions are used to treat a patient with refractory mantle cell lymphoma.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions are used to treat a patient with refractory multiple myeloma.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions are administered with one or more therapeutic agents. The other therapeutic agents may also inhibit the proteasome, or may operate by a different mechanism. In some embodiments, the other therapeutic agents are those that are normally administered to patients with the disease or condition being treated. crystalline Pattern B may be administered with the other therapeutic agent(s) in a single dosage form or as a separate dosage form.
When administered as a separate dosage form, the other therapeutic agent(s) may be administered prior to, at the same time as, or following administration of crystalline Pattern B.
In some embodiments, crystalline Pattern B or the pharmaceutical compositions thereof are administered with one or more anticancer agent(s). As used herein, the term "anticancer agents" refers to any agent that is administered to a patient with cancer for purposes of treating the cancer.
In some embodiments, the other therapeutic agent includes DNA damaging chemotherapeutic agents such as topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin);
topoisomerase II
inhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA
intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).
In some embodiments, the other therapeutic agent includes chemotherapeutic agents that disrupt cell replication such as: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide, lenalidomide, and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib);
proteasome inhibitors (e.g., bortezomib); NF-KB inhibitors, including inhibitors of IKB kinase;
antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which down-regulates cell replication.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with lenalidomide.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with melphalan.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with cyclophosphamide.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with dexamethasone.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with cyclophosphamide and dexamethasone.
The following Examples illustrate the preparation of crystalline Pattern B of the present invention but it is not limited to the details thereof.
To a solution comprising N,N,AP-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of methyl cinnamate was added (1:1). The mixture was stirred at room temperature overnight.
White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
The indexed Powder x-ray diffraction patterns (XRPD) for crystalline Pattern B
was collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640d) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A
specimen of the sample was sandwiched between 3- m-thick films and analyzed in transmission geometry. A
beam-stop, short antiscatter extension, and an antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b.
FIG. 1 shows an indexing solution of XRPD pattern for crystalline Pattern B
collected from Example 1.
To a solution comprising N,1V' [2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of methyl benzoate was added (1:1). The mixture was stirred at room temperature overnight.
White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising N,NVV"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of anethole was added (1:1). The mixture was stirred at room temperature overnight. White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising NAVV"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)fltris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of triacetin was added (1:1). The mixture was stirred at room temperature overnight. White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising N,N,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of triethyl lcitrate was added (1:1). The mixture was stirred at room temperature overnight.
White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline form of Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising 80 mg of N,N,N"-{2,4,6-boroxintriyltris[R1R)-3-methylbutylidenelimino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in 1 mL of ethyl acetate (80mg/mL), 6 mg of crystalline Pattern B resulting from EXAMPLE 1 was added at room temperature. The solution was stirred overnight. White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing approximately 50 mg of crystalline Pattern B.
FIG. 10 shows three XRPDs of crystalline Pattern B. The XRPD of crystalline Pattern B isolated from Example 7 is at the top. The XRPD of crystalline Pattern B
isolated from Example 6 is at the middle. The XRPD of crystalline Pattern B isolated from Example 1 is at the bottom.
Six milliliters (6 mL) of ethyl acetate was added in a vial containing 479.9 mg non-crystalline solid comprising the compound of Formula (Ib) under nitrogen flow.
The vial was capped and a sample was sonicated in a water bath, resulting in a clear solution. The solution was transferred into a vial containing 9.8 mg of crystalline Pattern B under nitrogen flow. The resulting turbid solution was stirred overnight in the closed vial, resulting in a white suspension. White solids were isolated under nitrogen protection with a yield of 374.8 mg of crystalline Pattern B (76.6%).
FIG. 2 shows the XRPD pattern with labeled peaks of crystalline Pattern B
collected from Example 7. Prominent XRPD peaks for crystalline Pattern B are shown below:
020 d space (A) Intensity (%) 5.79 0.20 15.247 0.526 100 6.98 0.20 12.647 0.362 18 9.46 0.20 9.345 0.197 13 9.89 0.20 8.936 0.180 33
In some embodiments, the composition comprises at least 80%, 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of Formula (Ib). In some embodiments, the composition comprises 100% of Formula (Ib).
In some embodiments, the present invention includes a composition comprising a mixture of /V,NR"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)fitris(2,5-dichlorobenzamide), and [(1 R)-1-({ [(2,5-DichlorobenzoyDamino]acetyllamino)-3-methylbutyl]boronic acid.
In some embodiments, the present invention includes a composition comprising a mixture of N,AP,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide), or a pharmaceutically acceptable salt thereof, and R1R)-1-({[(2,5-DichlorobenzoyDamino]acetylfamino)-3-methylbutyl]boronic acid, or a pharmaceutically acceptable salt thereof, and a therapeutically acceptable carrier.
In some embodiments, the mixture of the compositions comprise at least 80%, 90%, 95%, 98%, 99%, 99.50%, 99.80%, 99.90 or 99.99% of Formula (lb). In some embodiments, the mixture of the composition comprises 100% of Formula (lb).
Crystalline Pattern B may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.
For oral administration, the pharmaceutical compositions may take the form of capsules or tablets formulated with pharmaceutically acceptable excipients such as filler, lubricant, flow-aid, binder, buffer or bulking agent.
In some embodiments, the filler is selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low-moisture microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, or mixtures thereof. In other embodiments, the filler is selected from microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, or mixtures thereof. In one embodiment, the filler is microcrystalline cellulose.
In some embodiments, the lubricant is selected from magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, talc, zinc stearate, calcium stearate, sucrose stearate, sodium stearyl fumarate, or mixtures thereof In one embodiment, the lubricant is magnesium stearate.
In some embodiments, the flow-aid is talc. In some embodiments, the buffer is sodium citrate or citric acid. In some embodiments, the bulking agent is glycine.
In some embodiments, the pharmaceutically acceptable excipients are selected from microcrystalline cellulose, magnesium stearate, or talc.
The compound of Formula (Ia) and the cyclic trimer Formula (Ib) are selective proteasome inhibitors. As such, crystalline Pattern B and pharmaceutically acceptable compositions thereof may be useful for treating a patient having, or at risk of developing or experiencing a recurrence of, a proteasome-mediated disorder.
As used herein, the term "proteasome-mediated disorder" includes any disorder, disease or condition which is caused or characterized by an increase in proteasome expression or activity. The term "proteasome-mediated disorder" also includes any disorder, disease or condition in which inhibition of proteasome activity is beneficial.
For example, crystalline Pattern B or its pharmaceutical compositions may be useful for treating disorders mediated via proteins (e.g., NFKB, p271(iP, p21WAF/CIP1, p53) which are regulated by proteasome activity. Relevant disorders include inflammatory disorders (e.g., rheumatoid arthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, dermatosis (e.g., atopic dermatitis, psoriasis)), vascular proliferative disorders (e.g., atherosclerosis, restenosis), proliferative ocular disorders (e.g., diabetic retinopathy), benign proliferative disorders (e.g., hemangiomas), autoimmune diseases (e.g., multiple sclerosis, tissue and organ rejection), as well as inflammation associated with infection (e.g., immune responses), antibody-mediated disease, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, motor neurone disease, neuropathic pain, triplet repeat disorders, astrocytoma, and neurodegeneration as result of alcoholic liver disease), ischemic injury (e.g., stroke), and cachexia including accelerated muscle protein breakdown that accompanies various physiological and pathological states (e.g., nerve injury, fasting, fever, acidosis, HIV
infection, cancer affliction, and certain endocrinopathies), or useful for desensitization therapy.
Non-limiting examples of autoimmune diseases and antibody-mediated diseases include systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, ulcerative colitis, Crohn's disease, type 1 diabetes, myasthenia gravis, idiopathic pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, scleroderrna sclerosis, systemic sclerosis, antibody-mediated rejection, antibody-mediated rejection in organ transplantation, antibody-mediated rejection in kidney transplantation, antibody-mediated rejection in lung transplantation, antibody-mediated rejection in heart transplantation, antibody-mediated rejection in liver transplantation, antibody-mediated rejection in pancreas transplantation, or graft versus host disease.
Crystalline Pattern B or its pharmaceutical compositions may be particularly useful for the treatment of cancer. As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dis-regulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies. The term "cancer" encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "cancer" further encompasses primary and metastatic cancers.
Non-limiting examples of solid tumors that may be treated with the disclosed proteasome inhibitors or pharmaceutical compositions include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer;
prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma;
neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforrne, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma.
Non-limiting examples of hematologic malignancies that may be treated with the disclosed proteasome inhibitors or pharmaceutical compositions include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML
and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); lymphoma; non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia;
myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), (refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions thereof are useful in treatment of amyloidosis.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions thereof are used to treat a patient having or at risk of developing or experiencing a recurrence (relapse) in a cancer selected from multiple myeloma and mantle cell lymphoma.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions are used to treat a patient with refractory mantle cell lymphoma.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions are used to treat a patient with refractory multiple myeloma.
In some embodiments, crystalline Pattern B or its pharmaceutical compositions are administered with one or more therapeutic agents. The other therapeutic agents may also inhibit the proteasome, or may operate by a different mechanism. In some embodiments, the other therapeutic agents are those that are normally administered to patients with the disease or condition being treated. crystalline Pattern B may be administered with the other therapeutic agent(s) in a single dosage form or as a separate dosage form.
When administered as a separate dosage form, the other therapeutic agent(s) may be administered prior to, at the same time as, or following administration of crystalline Pattern B.
In some embodiments, crystalline Pattern B or the pharmaceutical compositions thereof are administered with one or more anticancer agent(s). As used herein, the term "anticancer agents" refers to any agent that is administered to a patient with cancer for purposes of treating the cancer.
In some embodiments, the other therapeutic agent includes DNA damaging chemotherapeutic agents such as topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin);
topoisomerase II
inhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA
intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).
In some embodiments, the other therapeutic agent includes chemotherapeutic agents that disrupt cell replication such as: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide, lenalidomide, and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib);
proteasome inhibitors (e.g., bortezomib); NF-KB inhibitors, including inhibitors of IKB kinase;
antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which down-regulates cell replication.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with lenalidomide.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with melphalan.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with cyclophosphamide.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with dexamethasone.
In some embodiments, crystalline Pattern B or its pharmaceutical composition is administered with cyclophosphamide and dexamethasone.
The following Examples illustrate the preparation of crystalline Pattern B of the present invention but it is not limited to the details thereof.
To a solution comprising N,N,AP-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of methyl cinnamate was added (1:1). The mixture was stirred at room temperature overnight.
White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
The indexed Powder x-ray diffraction patterns (XRPD) for crystalline Pattern B
was collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640d) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A
specimen of the sample was sandwiched between 3- m-thick films and analyzed in transmission geometry. A
beam-stop, short antiscatter extension, and an antiscatter knife edge were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 2.2b.
FIG. 1 shows an indexing solution of XRPD pattern for crystalline Pattern B
collected from Example 1.
To a solution comprising N,1V' [2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of methyl benzoate was added (1:1). The mixture was stirred at room temperature overnight.
White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising N,NVV"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of anethole was added (1:1). The mixture was stirred at room temperature overnight. White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising NAVV"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)fltris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of triacetin was added (1:1). The mixture was stirred at room temperature overnight. White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising N,N,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]
imino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in ethyl acetate, an equivalent mole of triethyl lcitrate was added (1:1). The mixture was stirred at room temperature overnight.
White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing crystalline form of Pattern B.
X-ray powder diffraction pattern is consistent with FIG. 1.
To a solution comprising 80 mg of N,N,N"-{2,4,6-boroxintriyltris[R1R)-3-methylbutylidenelimino(2-oxo-2,1-ethanediy1)]]tris(2,5-dichlorobenzamide) in 1 mL of ethyl acetate (80mg/mL), 6 mg of crystalline Pattern B resulting from EXAMPLE 1 was added at room temperature. The solution was stirred overnight. White solids were collected by filtration, washed with suitable solvent and dried in vacuo providing approximately 50 mg of crystalline Pattern B.
FIG. 10 shows three XRPDs of crystalline Pattern B. The XRPD of crystalline Pattern B isolated from Example 7 is at the top. The XRPD of crystalline Pattern B
isolated from Example 6 is at the middle. The XRPD of crystalline Pattern B isolated from Example 1 is at the bottom.
Six milliliters (6 mL) of ethyl acetate was added in a vial containing 479.9 mg non-crystalline solid comprising the compound of Formula (Ib) under nitrogen flow.
The vial was capped and a sample was sonicated in a water bath, resulting in a clear solution. The solution was transferred into a vial containing 9.8 mg of crystalline Pattern B under nitrogen flow. The resulting turbid solution was stirred overnight in the closed vial, resulting in a white suspension. White solids were isolated under nitrogen protection with a yield of 374.8 mg of crystalline Pattern B (76.6%).
FIG. 2 shows the XRPD pattern with labeled peaks of crystalline Pattern B
collected from Example 7. Prominent XRPD peaks for crystalline Pattern B are shown below:
020 d space (A) Intensity (%) 5.79 0.20 15.247 0.526 100 6.98 0.20 12.647 0.362 18 9.46 0.20 9.345 0.197 13 9.89 0.20 8.936 0.180 33
10.63 0.20 8.316 0.156 70
11.40 0.20 7.758 0.136 16
12.41 0.20 7.129 0.114 13
13.96 0.20 6.341 0.090 32
14.13 0.20 6.262 0.088 29 14.38 0.20 6.155 0.085 16 16.06 0.20 5.514 0.068 75 16.73 0.20 5.294 0.063 27 17.12 0.20 5.175 0.060 68 17.53 0.20 5.055 0.057 23 17.93 0.20 4.944 0.055 61 18.58 0.20 4.773 0.051 28 19.26 0.20 4.605 0.047 20 19.69 0.20 4.505 0.045 68 20.05 0.20 4.426 0.044 25 20.65 0.20 4.299 0.041 18 21.37 0.20 4.154 0.038 24 21.99 0.20 4.040 0.036 33 22.59 0.20 3.933 0.034 11 23.58 0.20 3.770 0.032 80 24.17 0.20 3.680 0.030 67 24.33 0.20 3.655 0.030 32 24.93 0.20 3.569 0.028 39 25.26 0.20 3.523 0.027 15 26.11 0.20 3.410 0.026 12 26.54 0.20 3.356 0.025 13 26.92 0.20 3.309 0.024 11 28.12 0.20 3.171 0.022 11 28.46 0.20 3.134 0.022 11 29.36 0.20 3.040 0.020 11 29.59 0.20 3.016 0.020 10 FIG. 3 shows the XRPD pattern without label of crystalline Pattern B collected from Example 7.
FIG. 4 shows H1 NMR spectrum of crystalline Pattern B collected from Example 7.
FIG. 5 shows solid state carbon-13 nuclear magnetic resonance spectrum of crystalline Pattern B collected from Example 7.
FIG. 6 shows IR spectrum of crystalline Pattern B collected from Example 7.
FIG. 7 shows thermal gravimetric analysis (TGA) profile of crystalline Form Pattern B
collected from Example 7.
Thermogravimetric analysis was performed using a TA Instruments 2050 thermogravimetric analyzer. Temperature calibration was performed using nickel and AIumelTM. The sample was placed in a platinum pan and inserted into the TG
furnace. The furnace was heated under a nitrogen purge. The sample was heated from 25 C to 350 C, at C/min (abbreviated "00-350-10").
FIG. 8 shows differential scanning calorimetry (DSC) profile of crystalline Pattern B
collected from Example 7.
Differential scanning calorimetry was performed using a TA Instruments Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum DSC pan, covered with a lid, and the weight was accurately recorded. (A Tzero crimped pan with a manual pinhole, abbreviated "TOCMP" was used.) A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The sample was heated from ¨30 C to 250 C, at 10 C/min. (abbreviated "(-30)-250-10").
FIG. 9 shows dynamic vapor sorption (DVS) analysis (weight % vs relative humidity) collected from Example 7.
Dynamic vapor sorption/ desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. NaCl and PVP were used as calibration standards. The sample was not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in five minutes with a maximum equilibration time of three hours. Data were not corrected for the initial moisture content of the samples.
FIG. 4 shows H1 NMR spectrum of crystalline Pattern B collected from Example 7.
FIG. 5 shows solid state carbon-13 nuclear magnetic resonance spectrum of crystalline Pattern B collected from Example 7.
FIG. 6 shows IR spectrum of crystalline Pattern B collected from Example 7.
FIG. 7 shows thermal gravimetric analysis (TGA) profile of crystalline Form Pattern B
collected from Example 7.
Thermogravimetric analysis was performed using a TA Instruments 2050 thermogravimetric analyzer. Temperature calibration was performed using nickel and AIumelTM. The sample was placed in a platinum pan and inserted into the TG
furnace. The furnace was heated under a nitrogen purge. The sample was heated from 25 C to 350 C, at C/min (abbreviated "00-350-10").
FIG. 8 shows differential scanning calorimetry (DSC) profile of crystalline Pattern B
collected from Example 7.
Differential scanning calorimetry was performed using a TA Instruments Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed into an aluminum DSC pan, covered with a lid, and the weight was accurately recorded. (A Tzero crimped pan with a manual pinhole, abbreviated "TOCMP" was used.) A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The sample was heated from ¨30 C to 250 C, at 10 C/min. (abbreviated "(-30)-250-10").
FIG. 9 shows dynamic vapor sorption (DVS) analysis (weight % vs relative humidity) collected from Example 7.
Dynamic vapor sorption/ desorption data were collected on a VTI SGA-100 Vapor Sorption Analyzer. NaCl and PVP were used as calibration standards. The sample was not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in five minutes with a maximum equilibration time of three hours. Data were not corrected for the initial moisture content of the samples.
Claims (41)
1. A crystalline form comprising N,N,N"-[2,4,6-boroxintriyltris[[(1R)-3-methylbutylidene]imino(2-oxo-2,1-ethanediyl)]]tris(2,5-dichlorobenzamide) haying the structure of Formula (1b):
2. The crystalline form according to claim 1, comprising an X-ray powder diffraction pattern haying characteristic peaks expressed in degrees two-theta at approximately 5.79, 10.63, 16.06, and 23.58.
3. The crystalline form according to claim 1, comprising an X-ray powder diffraction pattern haying characteristic peaks expressed in degrees two-theta at approximately 5.79, 10.63, 16.06, 17.12, 17.93, 19.69, 23.58 and 24.17.
4. The crystalline form according to claim 1, comprising an X-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately:
5. The crystalline form according to any one of claims 1 to 4, having a DSC profile characterized by an endothermic transition at about 123.4 °C.
6. The crystalline form according to any one of claims 1 to 4, having a DSC
profile characterized by an endothermic transition at about 120 °C to about 125 °C.
profile characterized by an endothermic transition at about 120 °C to about 125 °C.
7. The crystalline form according to claim 6, having a DSC profile characterized by an endothermic transition of about 123.0 °C.
8. The crystalline form according to any one of claims 1 to 7, having a TGA
profile losing about 1.9% weight up to 150 °C at a temperature rate of 10 °C per minute, and decomposition at about 272 5 °C.
profile losing about 1.9% weight up to 150 °C at a temperature rate of 10 °C per minute, and decomposition at about 272 5 °C.
9. A method for the preparation of the crystalline form according to claim 1 comprising:
(a) dissolving or suspending a non-crystalline solid comprising a compound of Formula (lb) in a solvent Formula (Ib);
(b) adding a second agent to the suspension or solution at a predetermined temperature;
(c) stirring the above mixture for a sufficient amount of time to form crystalline Pattern B; and optionally (d) isolating the resulting crystalline form.
(a) dissolving or suspending a non-crystalline solid comprising a compound of Formula (lb) in a solvent Formula (Ib);
(b) adding a second agent to the suspension or solution at a predetermined temperature;
(c) stirring the above mixture for a sufficient amount of time to form crystalline Pattern B; and optionally (d) isolating the resulting crystalline form.
10. The method according to claim 9, wherein the solvent is selected from ethyl acetate.
11. The method according to claim 9 or 10, wherein the second agent is selected from anethole, methyl benzoate, methyl cinnamate, triacetin, triethyl citrate, or caffeine.
12. The method of according to any one of claims 9to 11, wherein the temperature is between about 15 °C to about 35 °C.
13. A process for producing the crystalline form according to claim 1 comprising:
(a) adding the crystalline form of claim 1 as seeding material to a solution of non-crystalline solid comprising the compound of Formula (Ib) Formula (Ib);
(b) stirring the solution at a predetermined temperature for a sufficient amount of time; and optionally (c) collecting the resulting crystalline form of claim 1.
(a) adding the crystalline form of claim 1 as seeding material to a solution of non-crystalline solid comprising the compound of Formula (Ib) Formula (Ib);
(b) stirring the solution at a predetermined temperature for a sufficient amount of time; and optionally (c) collecting the resulting crystalline form of claim 1.
14. The process according to claim 13, wherein the seeding material is about 0.1% to about 5%, or about 5% to about 10%, or about 10% to about 20% by weight of the amount of non-crystalline solid of Formula (lb).
15. The process of claim 13 or 14, wherein the solution is ethyl acetate solution.
16. The process of any one of claims 13 to 15, wherein the temperature is between about 15 °C to about 40 °C.
17. The process of any one of claims 13 to 16, wherein the amount of time is from 4 hours to 24 hours.
18. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 4; and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
20. A method of treating cancer, comprising administering to a patient in need thereof the crystalline form according to any one of claims 1 to 4.
21. The method of claim 20, wherein the cancer is multiple myeloma, lymphoma, refractory multiple myeloma or lymphoma, or recurrence of multiple myeloma or lymphoma.
22. The method of claim 21, wherein the cancer is multiple myeloma.
23. The method of claim 21, wherein the cancer is lymphoma.
24. The method of claim 21, wherein the cancer is refractory multiple myeloma.
25. The method of claim 21, wherein the cancer is refractory lymphoma.
26. The method of claim 21, wherein the cancer is recurrence of multiple myeloma
27. The method of claim 21, wherein the cancer is recurrence of lymphoma.
28. The use of any one of claims 20 to 27, wherein the crystalline form is administered with one or more therapeutic agents.
29. The method of claim 28, wherein the therapeutic agent is melphalan or lenalidomide.
30. The method of claim 28, wherein the therapeutic agents are cyclophosphamide and dexamethasone.
31. Use of the crystalline form according to any one of claims 1 to 4 for treating cancer in a patient in need thereof.
32. The use of claim 31, wherein the cancer is multiple myeloma, lymphoma, refractory multiple myeloma or lymphoma, or recurrence of multiple myeloma or lymphoma.
33. The use of claim 32, wherein the cancer is multiple myeloma.
34. The use of claim 32, wherein the cancer is lymphoma.
35. The use of claim 32, wherein the cancer is refractory multiple myeloma.
36. The use of claim 32, wherein the cancer is refractory lymphoma.
37. The use of claim 32, wherein the cancer is recurrence of multiple myeloma
38. The use of claim 32, wherein the cancer is recurrence of lymphoma.
39. The use of any one of claims 31 to 38, wherein the crystalline form is administered with one or more therapeutic agents.
40. The use of claim 39, wherein the therapeutic agent is melphalan or lenalidomide.
41. The use of claim 39, wherein the therapeutic agents are cyclophosphamide and dexamethasone.
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