U.S. patent application number 15/497896 was filed with the patent office on 2017-08-10 for crystalline forms of a bruton's tyrosine kinase inhibitor.
The applicant listed for this patent is Pharmacyclics LLC. Invention is credited to Erick Goldman, Norbert Purro, Mark Stephen Smyth, David D. Wirth.
Application Number | 20170226112 15/497896 |
Document ID | / |
Family ID | 49712527 |
Filed Date | 2017-08-10 |
United States Patent
Application |
20170226112 |
Kind Code |
A1 |
Purro; Norbert ; et
al. |
August 10, 2017 |
CRYSTALLINE FORMS OF A BRUTON'S TYROSINE KINASE INHIBITOR
Abstract
Described herein is the Bruton's tyrosine kinase (Btk) inhibitor
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, including crystalline forms, solvates
and pharmaceutically acceptable salts thereof. Also disclosed are
pharmaceutical compositions that include the Btk inhibitor, as well
as methods of using the Btk inhibitor, alone or in combination with
other therapeutic agents, for the treatment of autoimmune diseases
or conditions, heteroimmune diseases or conditions, cancer,
including lymphoma, and inflammatory diseases or conditions.
Inventors: |
Purro; Norbert; (Los Gatos,
CA) ; Smyth; Mark Stephen; (Foster City, CA) ;
Goldman; Erick; (Concord, CA) ; Wirth; David D.;
(Oak Ridge, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pharmacyclics LLC |
Sunnyvale |
CA |
US |
|
|
Family ID: |
49712527 |
Appl. No.: |
15/497896 |
Filed: |
April 26, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15386118 |
Dec 21, 2016 |
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15497896 |
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|
14405317 |
Dec 3, 2014 |
9540382 |
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PCT/US2013/043888 |
Jun 3, 2013 |
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15386118 |
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61655381 |
Jun 4, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61P 21/04 20180101; A61P 1/16 20180101; A61K 45/06 20130101; A61P
7/06 20180101; C07D 487/04 20130101; A61K 9/2054 20130101; A61P
9/00 20180101; A61K 31/519 20130101; A61P 37/02 20180101; A61P
17/00 20180101; A61P 19/02 20180101; A61P 29/00 20180101; A61P
43/00 20180101; A61P 11/06 20180101; B65D 75/36 20130101; A61P
35/00 20180101; A61K 9/4866 20130101; A61P 13/08 20180101; A61J
1/035 20130101; A61P 11/00 20180101; A61P 3/10 20180101; A61P 37/00
20180101; A61P 13/10 20180101; A61P 27/02 20180101; A61P 35/02
20180101; A61K 9/4825 20130101; A61P 17/06 20180101; A61P 13/12
20180101; A61P 37/06 20180101; A61P 15/02 20180101; A61P 39/00
20180101; A61K 9/4858 20130101; C07B 2200/13 20130101; A61K 9/2013
20130101; A61P 11/04 20180101; A61K 9/2018 20130101; A61P 1/02
20180101; A61P 7/02 20180101; A61P 15/00 20180101; A61P 1/00
20180101; A61P 11/02 20180101; A61P 19/08 20180101; A61K 31/519
20130101; A61K 2300/00 20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1. A crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one that has an X-ray powder diffraction
(XRPD) pattern comprising 2-Theta peaks at 5.7.+-.0.1.degree.,
18.9.+-.0.1.degree., and 21.3.+-.0.1.degree..
2. The crystalline form of claim 1, wherein the X-ray powder
diffraction (XRPD) pattern further comprises a 2-Theta peak at
16.1.+-.0.1.degree..
3. The crystalline form of claim 1, wherein the X-ray powder
diffraction (XRPD) pattern further comprises a 2-Theta peak at
13.6.+-.0.1.degree..
4. The crystalline form of claim 1, wherein the X-ray powder
diffraction (XRPD) pattern further comprises a 2-Theta peak at
21.6.+-.0.1.degree..
5. The crystalline form of claim 1, wherein the X-ray powder
diffraction (XRPD) pattern further comprises 2-Theta peaks at
13.6.+-.0.1.degree., 16.1.+-.0.1.degree., and
21.6.+-.0.1.degree..
6. The crystalline form of claim 1, wherein the X-ray powder
diffraction (XRPD) pattern further comprises 2-Theta peaks at
13.6.+-.0.1.degree. and 16.1.+-.0.1.degree..
7. The crystalline form of claim 1, wherein the X-ray powder
diffraction (XRPD) pattern further comprises 2-Theta peaks at
13.6.+-.0.1.degree. and 21.6.+-.0.1.degree..
8. The crystalline form of claim 1, wherein the X-ray powder
diffraction (XRPD) pattern further comprises 2-Theta peaks at
16.1.+-.0.1.degree. and 21.6.+-.0.1.degree..
9. The crystalline form of claim 1, wherein the crystalline form
has Infrared (IR) spectrum weak peaks at about 1584 cm.sup.-1,
about 1240 cm.sup.-1, about 1147 cm.sup.-1, about 1134 cm.sup.-1,
about 1099 cm.sup.-1, and about 1067 cm.sup.-1.
10. The crystalline form of claim 1, wherein the crystalline form
has a melting temperature of about 155-156.degree. C.
11. The crystalline form of claim 1, wherein the crystalline form
has a DSC thermogram with an endotherm having an onset at about
154.degree. C. and a peak at about 157.degree. C. and an exotherm
at about 159.degree. C.
12. The crystalline form of claim 1, wherein the crystalline form
is non-hygroscopic.
13. The crystalline form of claim 1, wherein the crystalline form
has an observed aqueous solubility of about 0.013 mg/mL at about pH
8.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/386,118, filed Dec. 21, 2016, which is a divisional of U.S.
patent application Ser. No. 14/405,317, filed Dec. 3, 2014, now
U.S. Pat. No. 9,540,382, which is the U.S. National Stage
application of PCT/US13/043888, filed Jun. 3, 2013, which claims
the benefit of U.S. provisional patent application No. 61/655,381
entitled "CRYSTALLINE FORMS OF A BRUTON'S TYROSINE KINASE
INHIBITOR" filed Jun. 4, 2012, each of which is herein incorporated
by reference in its entirety.
FIELD OF THE INVENTION
[0002] Described herein is the Bruton's tyrosine kinase (Btk)
inhibitor
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, including crystalline forms, solvates
and pharmaceutically acceptable salts thereof, as well as
pharmaceutical compositions that include the Btk inhibitor and
methods of using the Btk inhibitor in the treatment of diseases or
conditions that would benefit from inhibition of Btk activity.
BACKGROUND OF THE INVENTION
[0003] Bruton's tyrosine kinase (Btk), a member of the Tec family
of non-receptor tyrosine kinases, is a key signaling enzyme
expressed in all hematopoietic cells types except T lymphocytes and
natural killer cells. Btk plays an essential role in the B-cell
signaling pathway linking cell surface B-cell receptor (BCR)
stimulation to downstream intracellular responses.
[0004] Btk is a key regulator of B-cell development, activation,
signaling, and survival. In addition, Btk plays a role in a number
of other hematopoetic cell signaling pathways, e.g., Toll like
receptor (TLR) and cytokine receptor--mediated TNF-.alpha.
production in macrophages, IgE receptor (FcepsilonRI) signaling in
Mast cells, inhibition of Fas/APO-1 apoptotic signaling in
B-lineage lymphoid cells, and collagen-stimulated platelet
aggregation.
[0005]
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-
-yl)piperidin-1-yl)prop-2-en-1-one is also known by its IUPAC name
as
1-{(3R)-3[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]pi-
peridin-1-yl}prop-2-en-1-one or 2-Propen-1-one,
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]--
1-piperidinyl-, and has been given the USAN name, ibrutinib. The
various names given for ibrutinib are used interchangeably
herein.
SUMMARY OF THE INVENTION
[0006] Described herein is the Btk inhibitor
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, including pharmaceutically acceptable
solvates (including hydrates), polymorphs, and amorphous phases,
and methods of uses thereof. Also described are pharmaceutically
acceptable salts of the Btk inhibitor, including pharmaceutically
acceptable solvates (including hydrates), polymorphs, and amorphous
phases, and methods of uses thereof
1-((R)-3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, as well as the pharmaceutically
acceptable salts thereof, are used in the manufacture of
medicaments for the treatment of diseases or conditions that are
associated with Btk activity.
1-((R)-3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimid-
in-1-yl)piperidin-1-yl)prop-2-en-1-one is an irreversible Btk
inhibitor.
[0007] Also described herein are methods for preparing crystalline
forms of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl-
)piperidin-1-yl)prop-2-en-1-one. Further described are
pharmaceutical compositions that include the crystalline forms and
methods of using the Btk inhibitor in the treatment of diseases or
conditions (including diseases or conditions wherein irreversible
inhibition of Btk provides therapeutic benefit to a mammal having
the disease or condition).
[0008] In one embodiment is anhydrous
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one.
[0009] In another embodiment is crystalline anhydrous
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one.
[0010] In a further embodiment is amorphous anhydrous
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one.
[0011] In one aspect is a solvate of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one.
[0012] In one embodiment is a solvate, wherein
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is solvated with methyl isobutyl
ketone (MIBK), toluene or methanol. In one embodiment is a solvate,
wherein
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is solvated with methyl isobutyl
ketone (MIBK) or toluene. In one embodiment is a solvate, wherein
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-y1)prop-2-en-1-one is solvated with methanol.
[0013] In a further embodiment, the solvate is anhydrous.
[0014] In another embodiment the solvate is crystalline.
[0015] In yet another embodiment the solvate is amorphous.
[0016] In one aspect, described herein is a crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one that has at least one of the following
properties: [0017] (a) an X-Ray powder diffraction (XRPD) pattern
substantially the same as shown in FIG. 1; [0018] (b) an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
5.7.+-.0.1.degree. 2-Theta, 13.6.+-.0.1.degree. 2-Theta,
16.1.+-.0.1.degree. 2-Theta, 18.9.+-.0.1.degree. 2-Theta,
21.3.+-.0.1.degree. 2-Theta, and 21.6.+-.0.1.degree. 2-Theta;
[0019] (c) substantially the same X-ray powder diffraction (XRPD)
pattern post storage at 40.degree. C. and 75% RH for at least a
week; [0020] (d) substantially the same X-ray powder diffraction
(XRPD) pattern post storage at 25.degree. C. and 97% RH for at
least a week; [0021] (e) Infrared (IR) spectrum substantially
similar to the one set forth in FIG. 2; [0022] (f) Infrared (IR)
spectrum weak peaks at about 1584 cm.sup.-1, about 1240 cm.sup.-1,
about 1147 cm.sup.-1, about 1134 cm.sup.-1, about 1099 cm.sup.-1,
and about 1067cm.sup.-1; [0023] (g) a DSC thermogram substantially
similar to the one set forth in FIG. 3; [0024] (h) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 4; [0025] (i) a DSC thermogram with an
endotherm having an onset at about 154.degree. C. and a peak at
about 157.degree. C. and an exotherm at about 159.degree. C.;
[0026] (j) non-hygroscopicity; [0027] (k) an observed aqueous
solubility of about 0.013 mg/mL at about pH 8; [0028] or [0029] (l)
combinations thereof.
[0030] In some embodiments, the crystalline Form A has an X-Ray
powder diffraction (XRPD) pattern substantially the same as shown
in FIG. 1. In some embodiments, the crystalline Form A has an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
5.7.+-.0.1.degree. 2-Theta, 13.6.+-.0.1.degree. 2-Theta,
16.1.+-.0.1.degree. 2-Theta, 18.9.+-.0.1.degree. 2-Theta,
21.3.+-.0.1.degree. 2-Theta, and 21.6.+-.0.1.degree. 2-Theta. In
some embodiments, the crystalline Form A has substantially the same
X-ray powder diffraction (XRPD) pattern post storage at 40.degree.
C. and 75% RH for at least a week. In some embodiments, the
crystalline Form A has substantially the same X-ray powder
diffraction (XRPD) pattern post storage at 25.degree. C. and 97% RH
for at least a week. In some embodiments, the crystalline Form A
has an Infrared (IR) spectrum substantially similar to the one set
forth in FIG. 2. In some embodiments, the crystalline Form A has an
Infrared (IR) spectrum weak peaks at about 1584 cm.sup.-1, about
1240 cm.sup.-1, about 1147 cm.sup.-1, about 1134 cm.sup.-1, about
1099 cm.sup.-1, and about 1067cm.sup.-1. In some embodiments, the
crystalline Form A has a melting temperature of about
155-156.degree. C. In some embodiments, the crystalline Form A has
a DSC thermogram substantially similar to the one set forth in FIG.
3. In some embodiments, the crystalline Form A has a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 4. In some embodiments, the
crystalline Form A has a DSC thermogram with an endotherm having an
onset at about 154.degree. C. and a peak at about 157.degree. C.
and an exotherm at about 159.degree. C. In some embodiments, the
crystalline Form A is non-hygroscopic. In some embodiments, the
crystalline Form A has an observed aqueous solubility of about
0.013 mg/mL at about pH 8. In some embodiments, the crystalline
Form A that is characterized as having properties (a), (b), (c),
(d), (e), (f), (g), (h), (i), (j), and (k). In some embodiments,
the crystalline Form A was obtained from ethyl acetate, isopropyl
acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl
ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile,
dioxane, methyl tert-butyl ether (MTBE), anisole, acetone,
heptanes, a methanol/water mixture or an acetone/heptane mixture.
In some embodiments, the crystalline Form A was obtained from a
methanol/water mixture. In some embodiments, the crystalline Form A
is unsolvated. In some embodiments, the crystalline Form A is
anhydrous.
[0031] In one aspect, described herein is a crystalline Form B of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one that has at least one of the following
properties: [0032] (a) an X-Ray powder diffraction (XRPD) pattern
substantially the same as shown in FIG. 5; [0033] (b) an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
5.2.+-.0.1.degree. 2-Theta, 10.2.+-.0.1.degree. 2-Theta,
16.5.+-.0.1.degree. 2-Theta, 18.5.+-.0.1.degree. 2-Theta, and
20.8.+-.0.1.degree. 2-Theta; [0034] (c) substantially the same
X-ray powder diffraction (XRPD) pattern post storage at 40.degree.
C. and 75% RH for at least a week; [0035] (d) substantially the
same X-ray powder diffraction (XRPD) pattern post storage at
25.degree. C. and 97% RH for at least a week; [0036] (e) Infrared
(IR) spectrum substantially similar to the one set forth in FIG. 6;
[0037] (f) Infrared (IR) spectrum weak peaks at about about 1586
cm.sup.-1, about 1573 cm.sup.-1, about 1562 cm.sup.-1, about 1229
cm.sup.-1, about 1141 cm.sup.-1, about 1103 cm.sup.-1, about 1056
cm.sup.-1, and about 1033 cm.sup.-1; [0038] (g) a DSC thermogram
substantially similar to the one set forth in FIG. 7; [0039] (h) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 8; [0040] (i) a DSC thermogram with an
endotherm having an onset at about 99-106.degree. C. and a peak at
about 115-118.degree. C.; [0041] (j) an observed aqueous solubility
of about 0.0096 mg/mL at a pH of about 7.42; [0042] or [0043] (k)
combinations thereof.
[0044] In some embodiments, the crystalline Form B has an an X-Ray
powder diffraction (XRPD) pattern substantially the same as shown
in FIG. 5. In some embodiments, the crystalline Form B has an an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 5.2.+-.0.1.degree. 2-Theta, 10.2.+-.0.1.degree. 2-Theta,
16.5.+-.0.1.degree. 2-Theta, 18.5.+-.0.1.degree. 2-Theta, and
20.8.+-.0.1.degree. 2-Theta. In some embodiments, the crystalline
Form B has an substantially the same X-ray powder diffraction
(XRPD) pattern post storage at 40.degree. C. and 75% RH for at
least a week. In some embodiments, the crystalline Form B has an
substantially the same X-ray powder diffraction (XRPD) pattern post
storage at 25.degree. C. and 97% RH for at least a week. In some
embodiments, the crystalline Form B has an Infrared (IR) spectrum
substantially similar to the one set forth in FIG. 6. In some
embodiments, the crystalline Form B has an Infrared (IR) spectrum
weak peaks at about 1586 cm.sup.-1, about 1573 cm.sup.-1, about
1562 cm.sup.-1, about 1229 cm.sup.-1, about 1141 cm.sup.-1, about
1103 cm.sup.-1, about 1056 cm.sup.-1, and about 1033 cm.sup.-1. In
some embodiments, the crystalline Form B has a DSC thermogram
substantially similar to the one set forth in FIG. 7. In some
embodiments, the crystalline Form B has a thermo-gravimetric
analysis (TGA) thermogram substantially similar to the one set
forth in FIG. 8. In some embodiments, the crystalline Form B has a
DSC thermogram with an endotherm having an onset at about
99-106.degree. C. and a peak at about 115-118.degree. C. In some
embodiments, the crystalline Form B has an observed aqueous
solubility of about 0.0096 mg/mL at a pH of about 7.42. In some
embodiments, the crystalline Form B that is characterized as having
properties (a), (b), (c), (d), (e), (f), (g), (h), (i), and (j). In
some embodiments, the crystalline Form B was obtained from a
mixture of methanol and water. In some embodiments, the crystalline
Form B is unsolvated. In some embodiments, the crystalline Form B
is anhydrous.
[0045] In one aspect, described herein is a crystalline Form C of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one that has at least one of the following
properties: [0046] (a) an X-Ray powder diffraction (XRPD) pattern
substantially the same as shown in FIG. 9; [0047] (b) an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
7.0.+-.0.1.degree. 2-Theta, 14.0.+-.0.1.degree. 2-Theta,
15.7.+-.0.1.degree. 2-Theta, 18.2.+-.0.1.degree. 2-Theta,
19.1.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.3.+-.0.1.degree. 2-Theta, 22.1.+-.0.1.degree. 2-Theta, and
22.9.+-.0.1.degree. 2-Theta; [0048] (c) a DSC thermogram
substantially similar to the one set forth in FIG. 10; [0049] (d) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 11; [0050] (e) a DSC thermogram with
an endotherm having an onset at about 134-135.degree. C. and a peak
at about 137-139.degree. C.; [0051] or [0052] (f) combinations
thereof.
[0053] In some embodiments, the crystalline Form C has an X-Ray
powder diffraction (XRPD) pattern substantially the same as shown
in FIG. 9. In some embodiments, the crystalline Form C has an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
7.0.+-.0.1.degree. 2-Theta, 14.0.+-.0.1.degree. 2-Theta,
15.7.+-.0.1.degree. 2-Theta, 18.2.+-.0.1.degree. 2-Theta,
19.1.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.3.+-.0.1.degree. 2-Theta, 22.1.+-.0.1.degree. 2-Theta, and
22.9.+-.0.1.degree. 2-Theta. In some embodiments, the crystalline
Form C has a DSC thermogram substantially similar to the one set
forth in FIG. 10. In some embodiments, the crystalline Form C has a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 11. In some embodiments, the
crystalline Form C has a DSC thermogram with an endotherm having an
onset at about 134-135.degree. C. and a peak at about
137-139.degree. C. In some embodiments, the crystalline Form C that
is characterized as having properties (a), (b), (c), (d), and (e).
In some embodiments, the crystalline Form C was obtained from a
mixture of methanol and water. In some embodiments, the crystalline
Form C is unsolvated. In some embodiments, the crystalline Form C
is anhydrous.
[0054] In one aspect, described herein is a crystalline Form D of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one that has at least one of the following
properties: [0055] (a) an X-Ray powder diffraction (XRPD) pattern
substantially the same as shown in FIG. 12; [0056] (b) an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
7.2.+-.0.1.degree. 2-Theta, 8.0.+-.0.1.degree. 2-Theta,
9.2.+-.0.1.degree. 2-Theta, 14.5.+-.0.1.degree. 2-Theta,
18.5.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.7.+-.0.1.degree. 2-Theta, 21.0.+-.0.1.degree. 2-Theta,
21.9.+-.0.1.degree. 2-Theta, and 22.4.+-.0.1.degree. 2-Theta;
[0057] (c) a thermo-gravimetric analysis (TGA) thermogram
substantially similar to the one set forth in FIG. 13; [0058] or
[0059] (d) combinations thereof.
[0060] In some embodiments, the crystalline Form D has an X-Ray
powder diffraction (XRPD) pattern substantially the same as shown
in FIG. 12. In some embodiments, the crystalline Form D has an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 7.2.+-.0.1.degree. 2-Theta, 8.0.+-.0.1.degree. 2-Theta,
9.2.+-.0.1.degree. 2-Theta, 14.5.+-.0.1.degree. 2-Theta,
18.5.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.7.+-.0.1.degree. 2-Theta, 21.0.+-.0.1.degree. 2-Theta,
21.9.+-.0.1.degree. 2-Theta, and 22.4.+-.0.1.degree. 2-Theta. In
some embodiments, the crystalline Form D has a thermo-gravimetric
analysis (TGA) thermogram substantially similar to the one set
forth in FIG. 13. In some embodiments, the crystalline Form D that
is characterized as having properties (a), (b), and (c). In some
embodiments, the crystalline Form D was obtained from methyl
isobutyl ketone (MIBK). In some embodiments, the crystalline Form D
is solvated. In some embodiments, the crystalline Form D is
solvated with methyl isobutyl ketone (MIBK).
[0061] In one aspect, described herein is a crystalline Form E of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one that has at least one of the following
properties: [0062] (a) an X-Ray powder diffraction (XRPD) pattern
substantially the same as shown in FIG. 14; [0063] (b) an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
7.8.+-.0.1.degree. 2-Theta, 8.8.+-.0.1.degree. 2-Theta,
16.1.+-.0.1.degree. 2-Theta, 18.1.+-.0.1.degree. 2-Theta,
19.3.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.5.+-.0.1.degree. 2-Theta, 21.6.+-.0.1.degree. 2-Theta, and
25.2.+-.0.1.degree. 2-Theta; [0064] (c) a DSC thermogram
substantially similar to the one set forth in FIG. 15; [0065] (d) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 15; [0066] or [0067] (e) combinations
thereof.
[0068] In some embodiments, the crystalline Form E has an X-Ray
powder diffraction (XRPD) pattern substantially the same as shown
in FIG. 14. In some embodiments, the crystalline Form E has an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 7.8.+-.0.1.degree. 2-Theta, 8.8.+-.0.1.degree. 2-Theta,
16.1.+-.0.1.degree. 2-Theta, 18.1.+-.0.1.degree. 2-Theta,
19.3.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.5.+-.0.1.degree. 2-Theta, 21.6.+-.0.1.degree. 2-Theta, and
25.2.+-.0.1.degree. 2-Theta. In some embodiments, the crystalline
Form E has a DSC thermogram substantially similar to the one set
forth in FIG. 15. In some embodiments, the crystalline Form E has a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 15. In some embodiments, the
crystalline Form E that is characterized as having properties (a),
(b), (c), and (d). In some embodiments, the crystalline Form E was
obtained from toluene. In some embodiments, the crystalline Form E
is solvated. In some embodiments, the crystalline Form E is
solvated with toluene.
[0069] In one aspect, described herein is a crystalline Form F of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one that has at least one of the following
properties: [0070] (a) an X-Ray powder diffraction (XRPD) pattern
substantially the same as shown in FIG. 16; [0071] (b) an X-ray
powder diffraction (XRPD) pattern with characteristic peaks at
6.2.+-.0.1.degree. 2-Theta, 10.1.+-.0.1.degree. 2-Theta,
17.6.+-.0.1.degree. 2-Theta, 18.6.+-.0.1.degree. 2-Theta,
20.0.+-.0.1.degree. 2-Theta, 20.4.+-.0.1.degree. 2-Theta,
20.7.+-.0.1.degree. 2-Theta, 22.4.+-.0.1.degree. 2-Theta,
23.0.+-.0.1.degree. 2-Theta, 23.2.+-.0.1.degree. 2-Theta,
24.4.+-.0.1.degree. 2-Theta, 25.1.+-.0.1.degree. 2-Theta,
27.6.+-.0.1.degree. 2-Theta, 29.3.+-.0.1.degree. 2-Theta, and
29.7.+-.0.1.degree. 2-Theta; [0072] (c) unit cell parameters
substantially equal to the following at 100(2) K:
TABLE-US-00001 [0072] Crystal system Triclinic Space group P1 a
9.6332(3) .ANG. .alpha. 105.762(3).degree. b 9.7536(4) .ANG. .beta.
95.132(2).degree. c 15.0592(4) .ANG. .gamma. 111.332(3).degree. V
1240.15(7) .ANG..sup.3 Z 1 Density 1.308 Mg/m.sup.3 (calculated)
Absorption 0.726 mm.sup.-1 coefficient Wavelength 1.54178 .ANG.
F(000) 518
[0073] or [0074] (d) combinations thereof.
[0075] In some embodiments, crystalline Form F has an X-Ray powder
diffraction (XRPD) pattern substantially the same as shown in FIG.
16. In some embodiments, crystalline Form F has an X-ray powder
diffraction (XRPD) pattern with characteristic peaks at
6.2.+-.0.1.degree. 2-Theta, 10.1.+-.0.1.degree. 2-Theta,
17.6.+-.0.1.degree. 2-Theta, 18.6.+-.0.1.degree. 2-Theta,
20.0.+-.0.1.degree. 2-Theta, 20.4.+-.0.1.degree. 2-Theta,
20.7.+-.0.1.degree. 2-Theta, 22.4.+-.0.1.degree. 2-Theta,
23.0.+-.0.1.degree. 2-Theta, 23.2.+-.0.1.degree. 2-Theta,
24.4.+-.0.1.degree. 2-Theta, 25.1.+-.0.1.degree. 2-Theta,
27.6.+-.0.1.degree. 2-Theta, 29.3.+-.0.1.degree. 2-Theta, and
29.7.+-.0.1.degree. 2-Theta.
[0076] In some embodiments, crystalline Form F has unit cell
parameters substantially equal to the following at 100(2) K:
TABLE-US-00002 Crystal system Triclinic Space group P1 a 9.6332(3)
.ANG. .alpha. 105.762(3).degree. b 9.7536(4) .ANG. .beta.
95.132(2).degree. c 15.0592(4) .ANG. .gamma. 111.332(3).degree. V
1240.15(7) .ANG..sup.3 Z 1 Density 1.308 Mg/m.sup.3 (calculated)
Absorption 0.726 mm.sup.-1 coefficient Wavelength 1.54178 .ANG.
F(000) 518
[0077] In some embodiments, crystalline Form F was obtained from
methanol.
[0078] In some embodiments, crystalline Form F is solvated. In some
embodiments, crystalline Form F is solvated with methanol.
[0079] In one aspect, described herein is a pharmaceutically
acceptable salt of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
-1-yl)piperidin-1-yl)prop-2-en-1-one, wherein the pharmaceutically
acceptable salt is an acid addition salt. In some embodiments, the
pharmaceutically acceptable salt is amorphous. In some embodiments,
the pharmaceutically acceptable salt is crystalline.
[0080] In a further aspect are provided pharmaceutical
compositions, which include
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-
-1-yl)piperidin-1-yl)prop-2-en-1-one as described herein, and at
least one additional ingredient selected from pharmaceutically
acceptable carriers, diluents and excipients. In some embodiments,
the pharmaceutical composition comprises Form A. In some
embodiments, the pharmaceutical composition comprises Form B. In
some embodiments, the pharmaceutical composition comprises Form C.
In some embodiments, the pharmaceutical composition comprises Form
D. In some embodiments, the pharmaceutical composition comprises
Form E. In some embodiments, the pharmaceutical composition
comprises Form F. In some embodiments, the pharmaceutical
composition is in a form suitable for oral administration to a
mammal. In some embodiments, the pharmaceutical composition is an
oral solid dosage form. In some embodiments, the pharmaceutical
composition comprises about 0.5 mg to about 1000 mg of crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one.
[0081] In another aspect, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0082] (a) about 40 mgs to about 200 mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0083] (b) about 40 wt % to about 50 wt % of a diluent;
[0084] (c) about 3 wt % to about 10 wt % of a disintegrating
agent;
[0085] (d) about 2 wt % to about 7 wt % of a surfactant; and
[0086] (e) about 0.2 wt % to about 1.0 wt % of a lubricant.
[0087] In some embodiments, the diluent is selected from the group
consisting of lactose, sucrose, dextrose, dextrates, maltodextrin,
mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate,
calcium sulfate, starches, modified starches, microcrystalline
cellulose, microcellulose, and talc. In some embodiments the
diluent is microcrystalline cellulose. In some embodiments, the
disintegrating agent is selected from the group consisting of
natural starch, a pregelatinized starch, a sodium starch,
methylcrystalline cellulose, methylcellulose, croscarmellose,
croscarmellose sodium, cross-linked sodium carboxymethylcellulose,
cross-linked carboxymethylcellulose, cross-linked croscarmellose,
cross-linked starch such as sodium starch glycolate, cross-linked
polymer such as crospovidone, cross-linked polyvinylpyrrolidone,
sodium alginate, a clay, or a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium. In some embodiments,
the surfactant is selected from the group consisting of sodium
lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan
monooleate, polysorbates, polaxomers, bile salts, glyceryl
monostearate, copolymers of ethylene oxide and propylene oxide. In
some embodiments, the surfactant is sodium lauryl sulfate. In some
embodiments, the lubricant is selected from the group consisting of
stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl
fumerate, stearic acid, sodium stearates, magnesium stearate, zinc
stearate, and waxes. In some embodiments, the lubricant is
magnesium stearate.
[0088] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0089] (a) about 40 mgs to about 200 mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0090] (b) about 40 wt % to about 50 wt % of microcrystalline
cellulose;
[0091] (c) about 3 wt % to about 10 wt % of croscarmellose
sodium;
[0092] (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate;
and
[0093] (e) about 0.2 wt % to about 1.0 wt % of magnesium
stearate.
[0094] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0095] (a) about 40 wt % to about 50 wt % of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0096] (b) about 40 wt % to about 50 wt % of microcrystalline
cellulose;
[0097] (c) about 3 wt % to about 10 wt % of croscarmellose
sodium;
[0098] (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate;
and
[0099] (e) about 0.2 wt % to about 1.0 wt % of magnesium
stearate.
[0100] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0101] (a) 140 mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)pi-
peridin-1-yl)prop-2-en-1-one;
[0102] (b) 45.9 wt % of microcrystalline cellulose;
[0103] (c) 7.0 wt % of croscarmellose sodium;
[0104] (d) 4.2 wt % of sodium lauryl sulfate; and
[0105] (e) 0.5 wt % of magnesium stearate.
[0106] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0107] (a) 140 mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)pi-
peridin-1-yl)prop-2-en-1-one;
[0108] (b) 151.4 mgs of microcrystalline cellulose;
[0109] (c) 23.0 mgs of croscarmellose sodium;
[0110] (d) 14.0 mgs of sodium lauryl sulfate; and
[0111] (e) 1.6 mgs of magnesium stearate.
[0112] In another aspect, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0113] (a) about 40 mgs to about 200 mgs of crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0114] (b) about 40 wt % to about 50 wt % of a diluent;
[0115] (c) about 3 wt % to about 10 wt % of a disintegrating
agent;
[0116] (d) about 2 wt % to about 7 wt % of a surfactant; and
[0117] (e) about 0.2 wt % to about 1.0 wt % of a lubricant.
[0118] In some embodiments, the diluent is selected from the group
consisting of lactose, sucrose, dextrose, dextrates, maltodextrin,
mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate,
calcium sulfate, starches, modified starches, microcrystalline
cellulose, microcellulose, and talc. In some embodiments the
diluent is microcrystalline cellulose. In some embodiments, the
disintegrating agent is selected from the group consisting of
natural starch, a pregelatinized starch, a sodium starch,
methylcrystalline cellulose, methylcellulose, croscarmellose,
croscarmellose sodium, cross-linked sodium carboxymethylcellulose,
cross-linked carboxymethylcellulose, cross-linked croscarmellose,
cross-linked starch such as sodium starch glycolate, cross-linked
polymer such as crospovidone, cross-linked polyvinylpyrrolidone,
sodium alginate, a clay, or a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium. In some embodiments,
the surfactant is selected from the group consisting of sodium
lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan
monooleate, polysorbates, polaxomers, bile salts, glyceryl
monostearate, copolymers of ethylene oxide and propylene oxide. In
some embodiments, the surfactant is sodium lauryl sulfate. In some
embodiments, the lubricant is selected from the group consisting of
stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl
fumerate, stearic acid, sodium stearates, magnesium stearate, zinc
stearate, and waxes. In some embodiments, the lubricant is
magnesium stearate.
[0119] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0120] (a) about 40 mgs to about 200 mgs of crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0121] (b) about 40 wt % to about 50 wt % of microcrystalline
cellulose;
[0122] (c) about 3 wt % to about 10 wt % of croscarmellose
sodium;
[0123] (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate;
and
[0124] (e) about 0.2 wt % to about 1.0 wt % of magnesium
stearate.
[0125] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0126] (a) about 40 wt % to about 50 wt % of crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0127] (b) about 40 wt % to about 50 wt % of microcrystalline
cellulose;
[0128] (c) about 3 wt % to about 10 wt % of croscarmellose
sodium;
[0129] (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate;
and
[0130] (e) about 0.2 wt % to about 1.0 wt % of magnesium
stearate.
[0131] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0132] (a) 140 mgs of crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0133] (b) 45.9 wt % of microcrystalline cellulose;
[0134] (c) 7.0 wt % of croscarmellose sodium;
[0135] (d) 4.2 wt % of sodium lauryl sulfate; and
[0136] (e) 0.5 wt % of magnesium stearate.
[0137] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0138] (a) 140 mgs of crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0139] (b) 151.4 mgs of microcrystalline cellulose;
[0140] (c) 23.0 mgs of croscarmellose sodium;
[0141] (d) 14.0 mgs of sodium lauryl sulfate; and
[0142] (e) 1.6 mgs of magnesium stearate.
[0143] In some embodiments of the aforementioned pharmaceutical
formulation embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)pi-
peridin-1-yl)prop-2-en-1-one is crystalline Form A. In some
embodiments of the aforementioned pharmaceutical formulation
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is crystalline Form B. In some
embodiments of the aforementioned pharmaceutical formulation
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is crystalline Form C. In some
embodiments of the aforementioned pharmaceutical formulation
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is crystalline Form D. In some
embodiments of the aforementioned pharmaceutical formulation
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is crystalline Form E. In some
embodiments of the aforementioned pharmaceutical formulation
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is crystalline Form F. In some
embodiments of the aforementioned pharmaceutical formulation
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is a mixture of two or more
crystalline forms selected from the group consisting of Form A,
Form B, Form C, Form D, Form E, and Form F. In another embodiment
of the aforementioned pharmaceutical formulation embodiments
provided herein, is a pharmaceutical formulation wherein the dosage
form is a hard gelatin capsule.
[0144] In another aspect, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0145] (a) about 40 mgs to about 200 mgs of crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0146] (b) about 40 wt % to about 50 wt % of a diluent;
[0147] (c) about 3 wt % to about 10 wt % of a disintegrating
agent;
[0148] (d) about 2 wt % to about 7 wt % of a surfactant; and
[0149] (e) about 0.2 wt % to about 1.0 wt % of a lubricant.
[0150] In some embodiments, the diluent is selected from the group
consisting of lactose, sucrose, dextrose, dextrates, maltodextrin,
mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate,
calcium sulfate, starches, modified starches, microcrystalline
cellulose, microcellulose, and talc. In some embodiments the
diluent is microcrystalline cellulose. In some embodiments, the
disintegrating agent is selected from the group consisting of
natural starch, a pregelatinized starch, a sodium starch,
methylcrystalline cellulose, methylcellulose, croscarmellose,
croscarmellose sodium, cross-linked sodium carboxymethylcellulose,
cross-linked carboxymethylcellulose, cross-linked croscarmellose,
cross-linked starch such as sodium starch glycolate, cross-linked
polymer such as crospovidone, cross-linked polyvinylpyrrolidone,
sodium alginate, a clay, or a gum. In some embodiments, the
disintegrating agent is croscarmellose sodium. In some embodiments,
the surfactant is selected from the group consisting of sodium
lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan
monooleate, polysorbates, polaxomers, bile salts, glyceryl
monostearate, copolymers of ethylene oxide and propylene oxide. In
some embodiments, the surfactant is sodium lauryl sulfate. In some
embodiments, the lubricant is selected from the group consisting of
stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl
fumerate, stearic acid, sodium stearates, magnesium stearate, zinc
stearate, and waxes. In some embodiments, the lubricant is
magnesium stearate.
[0151] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0152] (a) about 40 mgs to about 200 mgs of crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0153] (b) about 40 wt % to about 50 wt % of microcrystalline
cellulose;
[0154] (c) about 3 wt % to about 10 wt % of croscarmellose
sodium;
[0155] (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate;
and
[0156] (e) about 0.2 wt % to about 1.0 wt % of magnesium
stearate.
[0157] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0158] (a) about 40 wt % to about 50 wt % of crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0159] (b) about 40 wt % to about 50 wt % of microcrystalline
cellulose;
[0160] (c) about 3 wt % to about 10 wt % of croscarmellose
sodium;
[0161] (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate;
and
[0162] (e) about 0.2 wt % to about 1.0 wt % of magnesium
stearate.
[0163] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0164] (a) 140 mgs of crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0165] (b) 45.9 wt % of microcrystalline cellulose;
[0166] (c) 7.0 wt % of croscarmellose sodium;
[0167] (d) 4.2 wt % of sodium lauryl sulfate; and
[0168] (e) 0.5 wt % of magnesium stearate.
[0169] In some embodiments, provided herein is a pharmaceutical
formulation for oral administration comprising:
[0170] (a) 140 mgs of crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one;
[0171] (b) 151.4 mgs of microcrystalline cellulose;
[0172] (c) 23.0 mgs of croscarmellose sodium;
[0173] (d) 14.0 mgs of sodium lauryl sulfate; and [0174] (e) 1.6
mgs of magnesium stearate.
[0175] In another aspect provided herein, is a pharmaceutical
formulation comprising: a) about 40 mgs to about 200 mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one; b) about 40 wt % to about 50 wt % of
a diluent; c) about 3 wt % to about 10 wt % of a disintegrating
agent; d) about 2 wt % to about 7 wt % of a surfactant; and e)
about 0.2 wt % to about 1.0 wt % of a lubricant; wherein the
formulation is in a unit dosage form in a blister pack, and said
blister pack comprises metal or plastic foil. In some
embobodiments, is a pharmaceutical formulation comprising: a) 140
mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one; b) 45.9 wt % of microcrystalline
cellulose; c) 7.0 wt % of croscarmellose sodium; d) 4.2 wt % of
sodium lauryl sulfate; and e) 0.5 wt % of magnesium stearate
wherein the formulation is in a unit dosage form in a blister pack,
and said blister pack comprises metal or plastic foil.
[0176] In another embodiment is a package comprising one or more
discrete blister pockets, wherein each blister pocket comprises a
unit dosage form comprising: [0177] a) about 40 mgs to about 200
mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one; [0178] b) about 40 wt % to about 50
wt % of a diluent; c) about 3 wt % to about 10 wt % of a
disintegrating agent; d) about 2 wt % to about 7 wt % of a
surfactant; and [0179] e) about 0.2 wt % to about 1.0 wt % of a
lubricant; [0180] wherein each blister pocket comprises metal or
plastic foil.
[0181] In another aspect provided herein, is a pharmaceutical
formulation comprising: a) about 40 mgs to about 200 mgs of
crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one; b) about 40 wt % to about 50 wt % of
a diluent; c) about 3 wt % to about 10 wt % of a disintegrating
agent; d) about 2 wt % to about 7 wt % of a surfactant; and e)
about 0.2 wt % to about 1.0 wt % of a lubricant; wherein the
formulation is in a unit dosage form in a blister pack, and said
blister pack comprises metal or plastic foil. In some
embobodiments, is a pharmaceutical formulation comprising: a) 140
mgs of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one; b) 45.9 wt % of microcrystalline
cellulose; c) 7.0 wt % of croscarmellose sodium; d) 4.2 wt % of
sodium lauryl sulfate; and e) 0.5 wt % of magnesium stearate
wherein the formulation is in a unit dosage form in a blister pack,
and said blister pack comprises metal or plastic foil.
[0182] In another embodiment is a package comprising one or more
discrete blister pockets, wherein each blister pocket comprises a
unit dosage form comprising: [0183] a) about 40 mgs to about 200
mgs of crystalline Form A of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl-
)piperidin-1-yl)prop-2-en-1-one; [0184] b) about 40 wt % to about
50 wt % of a diluent; c) about 3 wt % to about 10 wt % of a
disintegrating agent; d) about 2 wt % to about 7 wt % of a
surfactant; and [0185] e) about 0.2 wt % to about 1.0 wt % of a
lubricant; [0186] wherein each blister pocket comprises metal or
plastic foil.
[0187] In one embodiment, a kit is provided which contains a
multiplicity of oral dosage forms, such as tablets or capsules,
packaging such as a jar containing the oral dosage forms, and
instructions for use to administer the oral dosage forms in
accordance with the method described herein. Unit dose packaging
such as blister packs provide a useful way of packaging the oral
dosage form of the formulations described herein, and in other
embodiments embody a kit when combined with instructions for use.
In other embodiments, detailed product information are included
with the instructions for use in the kit. Blister packaging is
particularly useful with solid oral dosage forms and are in further
embodiments useful for alternate day dosing schedules for example.
In one embodiment, solid unit dosage forms of the formulations
described herein included in a blister pack with instructions to
administer one or more tablets or capsules on a daily basis so that
the dosage of the formulations described herein are sufficiently
administered. In another embodiment, solid unit dosage forms are
included in a blister pack with instructions to administer one or
more tablets or capsules on an alternate day basis so that the
dosage per day is sufficiently administered.
[0188] In one aspect, provided herein are methods for treating a
patient by administering Compound 1. In some embodiments, provided
herein is a method of inhibiting the activity of tyrsoine
kinase(s), such as Btk, or of treating a disease, disorder, or
condition, which would benefit from inhibition of tyrosine
kinase(s), such as Btk, in a mammal, which includes administering
to the mammal a therapeutically effective amount of Compound 1, or
pharmaceutically acceptable salt, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate.
[0189] In another aspect, provided herein is the use of Compound 1
for inhibiting Bruton's tyrosine kinase (Btk) activity or for the
treatment of a disease, disorder, or condition, which would benefit
from inhibition of Bruton's tyrosine kinase (Btk) activity.
[0190] In some embodiments, crystalline Compound 1 is administered
to a human.
[0191] In some embodiments, crystalline Compound 1 is orally
administered.
[0192] In other embodiments, crystalline Compound 1 is used for the
formulation of a medicament for the inhibition of tyrosine kinase
activity. In some other embodiments, crystalline Compound 1 is used
for the formulation of a medicament for the inhibition of Bruton's
tyrosine kinase (Btk) activity.
[0193] In one aspect, provided herein is a method of treating
cancer in a mammal comprising administering to the mammal a
pharmaceutical composition described herein comprising Compound 1.
In some embodiments, the cancer is a B cell malignancy. In some
embodiments, the cancer is a B cell malignancy selected from
chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma
(SLL), mantle cell lymphoma (MCL), diffuse large B Cell lymphoma
(DLBCL), and multiple myeloma. In some embodiments, the cancer is a
lymphoma, leukemia or a solid tumor. In some embodiments, the
cancer is diffuse large B cell lymphoma, follicular lymphoma,
chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell
prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom
macroglobulinemia, splenic marginal zone lymphoma, plasma cell
myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma,
nodal marginal zone B cell lymphoma, mantle cell lymphoma,
mediastinal (thymic) large B cell lymphoma, intravascular large B
cell lymphoma, primary effusion lymphoma, burkitt
lymphoma/leukemia, or lymphomatoid granulomatosis. In some
embodiments, where the subject is suffering from a cancer, an
anti-cancer agent is administered to the subject in addition to one
of the above-mentioned compounds. In one embodiment, the
anti-cancer agent is an inhibitor of mitogen-activated protein
kinase signaling
[0194] In one aspect, provided herein is a method of treating an
inflammatory or an autoimmune disease in a mammal comprising
administering to the mammal a pharmaceutical composition described
herein comprising Compound 1. In some embodiments, the inflammatory
disease is asthma, appendicitis, blepharitis, bronchiolitis,
bronchitis, bursitis, cervicitis, cholangitis, cholecystitis,
colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis,
dermatomyositis, encephalitis, endocarditis, endometritis,
enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,
fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis
suppurativa, laryngitis, mastitis, meningitis, myelitis
myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,
otitis, pancreatitis, parotitis, pericarditis, peritonitis,
pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,
proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis,
sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis,
vaginitis, vasculitis, or vulvitis. In some embodiments, the
autoimmune disease is inflammatory bowel disease, arthritis, lupus,
rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's
disease, juvenile arthritis, diabetes, myasthenia gravis,
Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease
Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome,
acute disseminated encephalomyelitis, Addison's disease,
opsoclonus-myoclonus syndrome, ankylosing spondylitisis,
antiphospholipid antibody syndrome, aplastic anemia, autoimmune
hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic
thrombocytopenic purpura, optic neuritis, scleroderma, primary
biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,
temporal arteritis, warm autoimmune hemolytic anemia, Wegener's
granulomatosis, psoriasis, alopecia universalis, Behet's disease,
chronic fatigue, dysautonomia, endometriosis, interstitial
cystitis, neuromyotonia, scleroderma, or vulvodynia
[0195] Articles of manufacture including packaging material,
Compound 1 within the packaging material, and a label that
indicates that Compound 1 is used for inhibiting the activity of
tyrosine kinase(s), such as Btk, are provided.
[0196] In a further aspect, provided herein is a method of treating
an autoimmune disease in a mammal, comprising administering
Compound 1 to the mammal.
[0197] In a further aspect, provided herein is a method of treating
a heteroimmune disease or condition in a mammal, comprising
administering Compound 1 to the mammal.
[0198] In a further aspect, provided herein is a method of treating
an inflammatory disease in a mammal, comprising administering
Compound 1 to the mammal.
[0199] In a further aspect, provided herein is a method of treating
cancer in a mammal, comprising administering Compound 1 to the
mammal.
[0200] In a further aspect, provided herein is a method of treating
a thromboembolic disorder in a mammal, comprising administering
Compound 1 to the mammal. Thromboembolic disorders include, but are
not limited to, myocardial infarct, angina pectoris, reocclusion
after angioplasty, restenosis after angioplasty, reocclusion after
aortocoronary bypass, restenosis after aortocoronary bypass,
stroke, transitory ischemia, a peripheral arterial occlusive
disorder, pulmonary embolism, or deep venous thrombosis.
[0201] In another aspect are methods for modulating, including
irreversibly inhibiting the activity of Btk or other tyrosine
kinases, wherein the other tyrosine kinases share homology with Btk
by having a cysteine residue (including a Cys 481 residue) that can
form a covalent bond with Compound 1, in a mammal comprising
administering to the mammal at least once an effective amount of
Compound 1. In another aspect are methods for modulating, including
including irreversibly inhibiting, the activity of Btk in a mammal
comprising administering to the mammal at least once an effective
amount of Compound 1. In another aspect are methods for treating
Btk-dependent or Btk mediated conditions or diseases, comprising
administering to the mammal at least once an effective amount of
Compound 1.
[0202] In another aspect are methods for treating inflammation
comprising administering to the mammal at least once an effective
amount of Compound 1.
[0203] A further aspect are methods for the treatment of cancer
comprising administering to the mammal at least once an effective
amount of Compound 1. The type of cancer may include, but is not
limited to, pancreatic cancer and other solid or hematological
tumors.
[0204] In another aspect are methods for treating respiratory
diseases comprising administering to the mammal at least once an
effective amount of Compound 1. In a further embodiment of this
aspect, the respiratory disease is asthma. In a further embodiment
of this aspect, the respiratory disease includes, but is not
limited to, adult respiratory distress syndrome and allergic
(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe
asthma, chronic asthma, clinical asthma, nocturnal asthma,
allergen-induced asthma, aspirin-sensitive asthma, exercise-induced
asthma, isocapnic hyperventilation, child-onset asthma, adult-onset
asthma, cough-variant asthma, occupational asthma,
steroid-resistant asthma, seasonal asthma.
[0205] In another aspect are methods for preventing rheumatoid
arthritis and/or osteoarthritis comprising administering to the
mammal at least once an effective amount of Compound 1.
[0206] In another aspect are methods for treating inflammatory
responses of the skin comprising administering to the mammal at
least once an effective amount of Compound 1. Such inflammatory
responses of the skin include, by way of example, dermatitis,
contact dermatitis, eczema, urticaria, rosacea, and scarring. In
another aspect are methods for reducing psoriatic lesions in the
skin, joints, or other tissues or organs, comprising administering
to the mammal an effective amount of Compound 1.
[0207] In another aspect is the use of Compound 1 in the
manufacture of a medicament for treating an inflammatory disease or
condition in an animal in which the activity of Btk or other
tyrosine kinases, wherein the other tyrosine kinases share homology
with Btk by having a cysteine residue (including a Cys 481 residue)
that can form a covalent bond with at least one irreversible
inhibitor described herein, contributes to the pathology and/or
symptoms of the disease or condition. In one embodiment of this
aspect, the tyrosine kinase protein is Btk. In another or further
embodiment of this aspect, the inflammatory disease or conditions
are respiratory, cardiovascular, or proliferative diseases.
[0208] In any of the aforementioned aspects are further embodiments
in which Compound 1 is (a) systemically administered to the mammal;
(b) administered orally to the mammal; (c) intravenously
administered to the mammal; (d) administered by inhalation; (e)
administered by nasal administration; or (f) administered by
injection to the mammal; (g) administered topically (dermal) to the
mammal; (h) administered by ophthalmic administration; or (i)
administered rectally to the mammal.
[0209] In any of the aforementioned aspects are further embodiments
comprising single administration of Compound 1, including further
embodiments in which Compound lis administered (i) once; (ii)
multiple times over the span of one day; (iii) continually; or (iv)
continuously.
[0210] In any of the aforementioned aspects are further embodiments
comprising multiple administrations of Compound 1, including
further embodiments in which (i) Compound 1 is administered in a
single dose; (ii) the time between multiple administrations is
every 6 hours; (iii) Compound 1 is administered to the mammal every
8 hours. In further or alternative embodiments, the method
comprises a drug holiday, wherein the administration of Compound
lis temporarily suspended or the dose of Compound 1 being
administered is temporarily reduced; at the end of the drug
holiday, dosing of Compound 1 is resumed. The length of the drug
holiday can vary from 2 days to 1 year.
[0211] In some embodiments, in any of the embodiments disclosed
herein (including methods, uses, formulations, combination therapy,
etc.), Compound 1, or a pharmaceutically acceptable salt or solvate
thereof, is: optically pure (i.e. greater than 99% chiral purity by
HPLC). In some embodiments, in any of the embodiments disclosed
herein (including methods, uses, formulations, combination therapy,
etc.), Compound 1, or a pharmaceutically acceptable salt or solvate
thereof, is replaced with: a) Compound 1, or a pharmaceutically
acceptable salt or solvate thereof, of lower chiral purity; b)
1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt
or solvate thereof of any optical purity; or c) racemic
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-
din-1-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt or
solvate thereof.
[0212] In any of the embodiments disclosed herein (including
methods, uses, formulations, combination therapy, etc.), amorphous
Compound 1 is used. In any of the embodiments disclosed herein
(including methods, uses, formulations, combination therapy, etc.),
crystalline Compound 1 is used. In any of the embodiments disclosed
herein (including methods, uses, formulations, combination therapy,
etc.), crystalline Compound 1 (Form A) is used. In any of the
embodiments disclosed herein (including methods, uses,
formulations, combination therapy, etc.), crystalline Compound 1
(Form B) is used. In any of the embodiments disclosed herein
(including methods, uses, formulations, combination therapy, etc.),
crystalline Compound 1 (Form C) is used. In any of the embodiments
disclosed herein (including methods, uses, formulations,
combination therapy, etc.), crystalline Compound 1 (Form D) is
used. In any of the embodiments disclosed herein (including
methods, uses, formulations, combination therapy, etc.),
crystalline Compound 1 (Form E) is used. In any of the embodiments
disclosed herein (including methods, uses, formulations,
combination therapy, etc.), crystalline Compound 1 (Form F) is
used.
[0213] In some embodiments, in any of the embodiments disclosed
herein (including methods, uses, formulations, combination therapy,
etc.), Compound 1, or a pharmaceutically acceptable salt thereof,
is replaced with an active metabolite of Compound 1. In some
embodiments, the active metabolite is in a crystalline form. In
some embodiments, the active metabolite is in an amorphous phase.
In further embodiments the metabolite is isolated. In some
embodiments, in any of the embodiments disclosed herein (including
methods, uses, formulations, combination therapy, etc.), Compound
1, or a pharmaceutically acceptable salt thereof, is replaced with
a prodrug of Compound 1, or a deuterated analog of Compound 1, or a
pharmaceutically acceptable salt thereof.
[0214] Other objects, features and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the present disclosure will become apparent to those
skilled in the art from this detailed description. The section
headings used herein are for organizational purposes only and are
not to be construed as limiting the subject matter described. All
documents, or portions of documents, cited in the application
including, but not limited to, patents, patent applications,
articles, books, manuals, and treatises are hereby expressly
incorporated by reference in their entirety for any purpose.
Incorporation by Reference
[0215] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the extent
applicable and relevant.
BRIEF DESCRIPTION OF THE FIGURES
[0216] FIG. 1. Illustrates an X-Ray powder diffraction (XRPD)
pattern of Form A.
[0217] FIG. 2. Illustrates an an Infrared (IR) spectrum of Form
A.
[0218] FIG. 3. Illustrates DSC thermograms of Form A.
[0219] FIG. 4. Illustrates a thermo-gravimetric analysis (TGA)
thermogram of Form A.
[0220] FIG. 5. Illustrates an X-Ray powder diffraction (XRPD)
pattern of Form B.
[0221] FIG. 6. Illustrates an an Infrared (IR) spectrum of Form
B.
[0222] FIG. 7. Illustrates DSC thermograms of Form B.
[0223] FIG. 8. Illustrates a thermo-gravimetric analysis (TGA)
thermogram of Form B.
[0224] FIG. 9. Illustrates an X-Ray powder diffraction (XRPD)
pattern of Form C.
[0225] FIG. 10. Illustrates DSC thermograms of Form C.
[0226] FIG. 11. Illustrates a thermo-gravimetric analysis (TGA)
thermogram of Form C.
[0227] FIG. 12. Illustrates an X-Ray powder diffraction (XRPD)
pattern of Form D.
[0228] FIG. 13. Illustrates a thermo-gravimetric analysis (TGA)
thermogram of Form D.
[0229] FIG. 14. Illustrates an X-Ray powder diffraction (XRPD)
pattern of Form E.
[0230] FIG. 15. Illustrates a DSC thermogram and a
thermo-gravimetric analysis (TGA) thermogram of Form E.
[0231] FIG. 16. Illustrates a simulated X-Ray powder diffraction
(XRPD) pattern of Form F.
DETAILED DESCRIPTION OF THE INVENTION
[0232] The diverse roles played by Btk signaling in various
hematopoietic cell functions, e.g., B-cell receptor activation,
suggests that small molecule Btk inhibitors, such as Compound 1,
are useful for reducing the risk of or treating a variety of
diseases affected by or affecting many cell types of the
hematopoetic lineage including, e.g., autoimmune diseases,
heteroimmune conditions or diseases, inflammatory diseases, cancer
(e.g., B-cell proliferative disorders), and thromboembolic
disorders. Further, irreversible Btk inhibitor compounds, such as
Compound 1, can be used to inhibit a small subset of other tyrosine
kinases that share homology with Btk by having a cysteine residue
(including a Cys 481 residue) that can form a covalent bond with
the irreversible inhibitor.
[0233] In some embodiments, Compound 1 can be used in the treatment
of an autoimmune disease in a mammal, which includes, but is not
limited to, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's disease, juvenile arthritis, lupus,
diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's
thyroiditis, Graves' disease Sjogren's syndrome, multiple
sclerosis, Guillain-Barre syndrome, acute disseminated
encephalomyelitis, Addison's disease, opsoclonus-myoclonus
syndrome, ankylosing spondylitisis, antiphospholipid antibody
syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease,
Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic
neuritis, scleroderma, primary biliary cirrhosis, Reiter's
syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune
hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia
universalis, Behet's disease, chronic fatigue, dysautonomia,
endometriosis, interstitial cystitis, neuromyotonia, scleroderma,
and vulvodynia.
[0234] In some embodiments, Compound 1 can be used in the treatment
of a heteroimmune disease or condition in a mammal, which include,
but are not limited to graft versus host disease, transplantation,
transfusion, anaphylaxis, allergies (e.g., allergies to plant
pollens, latex, drugs, foods, insect poisons, animal hair, animal
dander, dust mites, or cockroach calyx), type I hypersensitivity,
allergic conjunctivitis, allergic rhinitis, and atopic
dermatitis.
[0235] In some embodiments, Compound 1 can be used in the treatment
of an inflammatory disease in a mammal, which includes, but is not
limited to asthma, inflammatory bowel disease, appendicitis,
blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
endocarditis, endometritis, enteritis, enterocolitis,
epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
mastitis, meningitis, myelitis myocarditis, myositis, nephritis,
oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,
rhinitis, salpingitis, sinusitis, stomatitis, synovitis,
tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and
vulvitis.
[0236] In yet other embodiments, the methods described herein can
be used to treat a cancer, e.g., B-cell proliferative disorders,
which include, but are not limited to diffuse large B cell
lymphoma, follicular lymphoma, chronic lymphocytic lymphoma,
chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,
lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic
marginal zone lymphoma, plasma cell myeloma, plasmacytoma,
extranodal marginal zone B cell lymphoma, nodal marginal zone B
cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B
cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid
granulomatosis.
[0237] In further embodiments, the methods described herein can be
used to treat thromboembolic disorders, which include, but are not
limited to myocardial infarct, angina pectoris (including unstable
angina), reocclusions or restenoses after angioplasty or
aortocoronary bypass, stroke, transitory ischemia, peripheral
arterial occlusive disorders, pulmonary embolisms, and deep venous
thromboses.
Hematological Malignancies
[0238] Disclosed herein, in certain embodiments, is a method for
treating a hematological malignancy in an individual in need
thereof, comprising: administering to the individual an amount of
Compound 1.
[0239] In some embodiments, the hematological malignancy is a
non-Hodgkin's lymphoma (NHL). In some embodiments, the
hematological malignancy is a chronic lymphocytic leukemia (CLL),
small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL
lymphoma. In some embodiments, the hematological malignancy is
follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL),
mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia,
multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma,
non-Burkitt high grade B cell lymphoma, or extranodal marginal zone
B cell lymphoma. In some embodiments, the hematological malignancy
is acute or chronic myelogenous (or myeloid) leukemia,
myelodysplastic syndrome, acute lymphoblastic leukemia, or
precursor B-cell acute lymphoblastic leukemia. In some embodiments,
the hematological malignancy is chronic lymphocytic leukemia (CLL).
In some embodiments, the hematological malignancy is mantle cell
lymphoma (MCL). In some embodiments, the hematological malignancy
is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the
hematological malignancy is diffuse large B-cell lymphoma (DLBCL),
ABC subtype. In some embodiments, the hematological malignancy is
diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some
embodiments, the hematological malignancy is Waldenstrom's
macroglobulinemia (WM). In some embodiments, the hematological
malignancy is multiple myeloma (MM). In some embodiments, the
hematological malignancy is Burkitt's lymphoma. In some
embodiments, the hematological malignancy is follicular lymphoma
(FL). In some embodiments, the hematological malignancy is
transformed follicular lymphoma. In some embodiments, the
hematological malignancy is marginal zone lymphoma.
[0240] In some embodiments, the hematological malignancy is
relapsed or refractory non-Hodgkin's lymphoma (NHL). In some
embodiments, the hematological malignancy is relapsed or refractory
diffuse large B-cell lymphoma (DLBCL), relapsed or refractory
mantle cell lymphoma (MCL), relapsed or refractory follicular
lymphoma (FL), relapsed or refractory CLL, relapsed or refractory
SLL, relapsed or refractory multiple myeloma, relapsed or
refractory Waldenstrom's macroglobulinemia, relapsed or refractory
multiple myeloma (MM), relapsed or refractory marginal zone
lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or
refractory non-Burkitt high grade B cell lymphoma, relapsed or
refractory extranodal marginal zone B cell lymphoma. In some
embodiments, the hematological malignancy is a relapsed or
refractory acute or chronic myelogenous (or myeloid) leukemia,
relapsed or refractory myelodysplastic syndrome, relapsed or
refractory acute lymphoblastic leukemia, or relapsed or refractory
precursor B-cell acute lymphoblastic leukemia. In some embodiments,
the hematological malignancy is relapsed or refractory chronic
lymphocytic leukemia (CLL). In some embodiments, the hematological
malignancy is relapsed or refractory mantle cell lymphoma (MCL). In
some embodiments, the hematological malignancy is relapsed or
refractory diffuse large B-cell lymphoma (DLBCL). In some
embodiments, the hematological malignancy is relapsed or refractory
diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some
embodiments, the hematological malignancy is relapsed or refractory
diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some
embodiments, the hematological malignancy is relapsed or refractory
Waldenstrom's macroglobulinemia (WM). In some embodiments, the
hematological malignancy is relapsed or refractory multiple myeloma
(MM). In some embodiments, the hematological malignancy is relapsed
or refractory Burkitt's lymphoma. In some embodiments, the
hematological malignancy is relapsed or refractory follicular
lymphoma (FL).
[0241] In some embodiments, the hematological malignancy is a
hematological malignancy that is classified as high-risk. In some
embodiments, the hematological malignancy is high risk CLL or high
risk SLL.
[0242] B-cell lymphoproliferative disorders (BCLDs) are neoplasms
of the blood and encompass, inter alia, non-Hodgkin lymphoma,
multiple myeloma, and leukemia. BCLDs can originate either in the
lymphatic tissues (as in the case of lymphoma) or in the bone
marrow (as in the case of leukemia and myeloma), and they all are
involved with the uncontrolled growth of lymphocytes or white blood
cells. There are many subtypes of BCLD, e.g., chronic lymphocytic
leukemia (CLL) and non-Hodgkin lymphoma (NHL). The disease course
and treatment of BCLD is dependent on the BCLD subtype; however,
even within each subtype the clinical presentation, morphologic
appearance, and response to therapy is heterogeneous.
[0243] Malignant lymphomas are neoplastic transformations of cells
that reside predominantly within lymphoid tissues. Two groups of
malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's
lymphoma (NHL). Both types of lymphomas infiltrate
reticuloendothelial tissues. However, they differ in the neoplastic
cell of origin, site of disease, presence of systemic symptoms, and
response to treatment (Freedman et al., "Non-Hodgkin's Lymphomas"
Chapter 134, Cancer Medicine, (an approved publication of the
American Cancer Society, B. C. Decker Inc., Hamilton, Ontario,
2003).
[0244] Non-Hodgkin's Lymphomas
[0245] Disclosed herein, in certain embodiments, is a method for
treating a non-Hodgkin's lymphoma in an individual in need thereof,
comprising: administering to the individual an amount of Compound
1.
[0246] Further disclosed herein, in certain embodiments, is a
method for treating relapsed or refractory non-Hodgkin's lymphoma
in an individual in need thereof, comprising: administering to the
individual a therapeutically-effective amount of Compound 1. In
some embodiments, the non-Hodgkin's lymphoma is relapsed or
refractory diffuse large B-cell lymphoma (DLBCL), relapsed or
refractory mantle cell lymphoma, relapsed or refractory follicular
lymphoma, or relapsed or refractory CLL.
[0247] Non-Hodgkin lymphomas (NHL) are a diverse group of
malignancies that are predominately of B-cell origin. NHL may
develop in any organs associated with lymphatic system such as
spleen, lymph nodes or tonsils and can occur at any age. NHL is
often marked by enlarged lymph nodes, fever, and weight loss. NHL
is classified as either B-cell or T-cell NHL. Lymphomas related to
lymphoproliferative disorders following bone marrow or stem cell
transplantation are usually B-cell NHL. In the Working Formulation
classification scheme, NHL has been divided into low-,
intermediate-, and high-grade categories by virtue of their natural
histories (see "The Non-Hodgkin's Lymphoma Pathologic
Classification Project," Cancer 49(1982):2112-2135). The low-grade
lymphomas are indolent, with a median survival of 5 to 10 years
(Horning and Rosenberg (1984) N. Engl. J. Med. 311:1471-1475).
Although chemotherapy can induce remissions in the majority of
indolent lymphomas, cures are rare and most patients eventually
relapse, requiring further therapy. The intermediate- and
high-grade lymphomas are more aggressive tumors, but they have a
greater chance for cure with chemotherapy. However, a significant
proportion of these patients will relapse and require further
treatment.
[0248] A non-limiting list of the B-cell NHL includes Burkitt's
lymphoma (e.g., Endemic Burkitt's Lymphoma and Sporadic Burkitt's
Lymphoma), Cutaneous B-Cell Lymphoma, Cutaneous Marginal Zone
Lymphoma (MZL), Diffuse Large Cell Lymphoma (DLBCL), Diffuse Mixed
Small and Large Cell Lympoma, Diffuse Small Cleaved Cell, Diffuse
Small Lymphocytic Lymphoma, Extranodal Marginal Zone B-cell
lymphoma, follicular lymphoma, Follicular Small Cleaved Cell (Grade
1), Follicular Mixed Small Cleaved and Large Cell (Grade 2),
Follicular Large Cell (Grade 3), Intravascular Large B-Cell
Lymphoma, Intravascular Lymphomatosis, Large Cell Immunoblastic
Lymphoma, Large Cell Lymphoma (LCL), Lymphoblastic Lymphoma, MALT
Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic large cell
lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma,
chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma
(SLL), extranodal marginal zone B-cell lymphoma-mucosa-associated
lymphoid tissue (MALT) lymphoma, Mediastinal Large B-Cell Lymphoma,
nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell
lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmocytic
lymphoma, hairy cell leukemia, Waldenstrom's Macroglobulinemia, and
primary central nervous system (CNS) lymphoma. Additional
non-Hodgkin's lymphomas are contemplated within the scope of the
present invention and apparent to those of ordinary skill in the
art.
[0249] DLBCL
[0250] Disclosed herein, in certain embodiments, is a method for
treating a DLCBL in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory DLCBL in an individual in need thereof,
comprising: administering to the individual a
therapeutically-effective amount of Compound 1.
[0251] As used herein, the term "Diffuse large B-cell lymphoma
(DLBCL)" refers to a neoplasm of the germinal center B lymphocytes
with a diffuse growth pattern and a high-intermediate proliferation
index. DLBCLs represent approximately 30% of all lymphomas and may
present with several morphological variants including the
centroblastic, immunoblastic, T-cell/histiocyte rich, anaplastic
and plasmoblastic subtypes. Genetic tests have shown that there are
different subtypes of DLBCL. These subtypes seem to have different
outlooks (prognoses) and responses to treatment. DLBCL can affect
any age group but occurs mostly in older people (the average age is
mid-60s).
[0252] Disclosed herein, in certain embodiments, is a method for
treating diffuse large B-cell lymphoma, activated B cell-like
subtype (ABC-DLBCL), in an individual in need thereof, comprising:
administering to the individual an irreversible Btk inhibitor in an
amount from 300 mg/day up to, and including, 1000 mg/day. The ABC
subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to
arise from post germinal center B cells that are arrested during
plasmatic differentiation. The ABC subtype of DLBCL (ABC-DLBCL)
accounts for approximately 30% total DLBCL diagnoses. It is
considered the least curable of the DLBCL molecular subtypes and,
as such, patients diagnosed with the ABC-DLBCL typically display
significantly reduced survival rates compared with individuals with
other types of DLCBL. ABC-DLBCL is most commonly associated with
chromosomal translocations deregulating the germinal center master
regulator BCL6 and with mutations inactivating the PRDM1 gene,
which encodes a transcriptional repressor required for plasma cell
differentiation.
[0253] A particularly relevant signaling pathway in the
pathogenesis of ABC-DLBCL is the one mediated by the nuclear factor
(NF)-.kappa.B transcription complex. The NF-.kappa.B family
comprises 5 members (p50, p52, p65, c-rel and RelB) that form homo-
and heterodimers and function as transcriptional factors to mediate
a variety of proliferation, apoptosis, inflammatory and immune
responses and are critical for normal B-cell development and
survival. NF-.kappa.B is widely used by eukaryotic cells as a
regulator of genes that control cell proliferation and cell
survival. As such, many different types of human tumors have
misregulated NF-.kappa.B: that is, NF-.kappa.B is constitutively
active. Active NF-.kappa.B turns on the expression of genes that
keep the cell proliferating and protect the cell from conditions
that would otherwise cause it to die via apoptosis.
[0254] The dependence of ABC DLBCLs on NF-kB depends on a signaling
pathway upstream of IkB kinase comprised of CARD11, BCL10 and MALT1
(the CBM complex). Interference with the CBM pathway extinguishes
NF-kB signaling in ABC DLBCL cells and induces apoptosis. The
molecular basis for constitutive activity of the NF-kB pathway is a
subject of current investigation but some somatic alterations to
the genome of ABC DLBCLs clearly invoke this pathway. For example,
somatic mutations of the coiled-coil domain of CARD11 in DLBCL
render this signaling scaffold protein able to spontaneously
nucleate protein-protein interaction with MALT1 and BCL10, causing
IKK activity and NF-kB activation. Constitutive activity of the B
cell receptor signaling pathway has been implicated in the
activation of NF-kB in ABC DLBCLs with wild type CARD11, and this
is associated with mutations within the cytoplasmic tails of the B
cell receptor subunits CD79A and CD79B. Oncogenic activating
mutations in the signaling adapter MYD88 activate NF-kB and
synergize with B cell receptor signaling in sustaining the survival
of ABC DLBCL cells. In addition, inactivating mutations in a
negative regulator of the NF-kB pathway, A20, occur almost
exclusively in ABC DLBCL.
[0255] Indeed, genetic alterations affecting multiple components of
the NF-.kappa.B signaling pathway have been recently identified in
more than 50% of ABC-DLBCL patients, where these lesions promote
constitutive NF-.kappa.B activation, thereby contributing to
lymphoma growth. These include mutations of CARD11 (.about.10% of
the cases), a lymphocyte-specific cytoplasmic scaffolding protein
that--together with MALT1 and BCL10--forms the BCR signalosome,
which relays signals from antigen receptors to the downstream
mediators of NF-.kappa.B activation. An even larger fraction of
cases (.about.30%) carry biallelic genetic lesions inactivating the
negative NF-.kappa.B regulator A20. Further, high levels of
expression of NF-.kappa.B target genes have been observed in
ABC-DLBCL tumor samples. See, e.g., U. Klein et al., (2008), Nature
Reviews Immunology 8:22-23; R. E. Davis et al., (2001), Journal of
Experimental Medicine 194:1861-1874; G. Lentz et al., (2008),
Science 319:1676-1679; M. Compagno et al., (2009), Nature
459:712-721; and L. Srinivasan et al., (2009), Cell
139:573-586).
[0256] DLBCL cells of the ABC subtype, such as OCI-Ly10, have
chronic active BCR signalling and are very sensitive to the Btk
inhibitor described herein. The irreversible Btk inhibitor
described herein potently and irreversibly inhibits the growth of
OCI-Ly10 (EC.sub.50 continuous exposure=10 nM, EC.sub.50 1 hour
pulse=50 nM). In addition, induction of apoptosis, as shown by
capsase activation, Annexin-V flow cytometry and increase in sub-G0
fraction is observed in OCILy10. Both sensitive and resistant cells
express Btk at similar levels, and the active site of Btk is fully
occupied by the inhibitor in both as shown using a fluorescently
labeled affinity probe. OCI-Ly10 cells are shown to have
chronically active BCR signalling to NF-kB which is dose
dependently inhibited by the Btk inhibitors described herein. The
activity of Btk inhibitors in the cell lines studied herein are
also characterized by comparing signal transduction profiles (Btk,
PLC.gamma., ERK, NF-kB, AKT), cytokine secretion profiles and mRNA
expression profiles, both with and without BCR stimulation, and
observed significant differences in these profiles that lead to
clinical biomarkers that identify the most sensitive patient
populations to Btk inhibitor treatment. See U.S. Pat. No. 7,711,492
and Staudt et al., Nature, Vol. 463, Jan. 7, 2010, pp. 88-92, the
contents of which are incorporated by reference in their
entirety.
[0257] Follicular Lymphoma
[0258] Disclosed herein, in certain embodiments, is a method for
treating a follicular lymphoma in an individual in need thereof,
comprising: administering to the individual an amount of Compound
1. Further disclosed herein, in certain embodiments, is a method
for treating relapsed or refractory follicular lymphoma in an
individual in need thereof, comprising: administering to the
individual a therapeutically-effective amount of Compound 1.
[0259] As used herein, the term "follicular lymphoma" refers to any
of several types of non-Hodgkin's lymphoma in which the
lymphomatous cells are clustered into nodules or follicles. The
term follicular is used because the cells tend to grow in a
circular, or nodular, pattern in lymph nodes. The average age for
people with this lymphoma is about 60.
[0260] CLL/SLL
[0261] Disclosed herein, in certain embodiments, is a method for
treating a CLL or SLL in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory CLL or SLL in an individual in need thereof,
comprising: administering to the individual a
therapeutically-effective amount of Compound 1.
[0262] Chronic lymphocytic leukemia and small lymphocytic lymphoma
(CLL/SLL) are commonly thought as the same disease with slightly
different manifestations. Where the cancerous cells gather
determines whether it is called CLL or SLL. When the cancer cells
are primarily found in the lymph nodes, lima bean shaped structures
of the lymphatic system (a system primarily of tiny vessels found
in the body), it is called SLL. SLL accounts for about 5% to 10% of
all lymphomas. When most of the cancer cells are in the bloodstream
and the bone marrow, it is called CLL.
[0263] Both CLL and SLL are slow-growing diseases, although CLL,
which is much more common, tends to grow slower. CLL and SLL are
treated the same way. They are usually not considered curable with
standard treatments, but depending on the stage and growth rate of
the disease, most patients live longer than 10 years. Occasionally
over time, these slow-growing lymphomas may transform into a more
aggressive type of lymphoma.
[0264] Chronic lymphoid leukemia (CLL) is the most common type of
leukemia. It is estimated that 100,760 people in the United States
are living with or are in remission from CLL. Most (>75%) people
newly diagnosed with CLL are over the age of 50. Currently CLL
treatment focuses on controlling the disease and its symptoms
rather than on an outright cure. CLL is treated by chemotherapy,
radiation therapy, biological therapy, or bone marrow
transplantation. Symptoms are sometimes treated surgically
(splenectomy removal of enlarged spleen) or by radiation therapy
("de-bulking" swollen lymph nodes). Though CLL progresses slowly in
most cases, it is considered generally incurable. Certain CLLs are
classified as high-risk. As used herein, "high risk CLL" means CLL
characterized by at least one of the following 1) 17p13-; 2)
11q22-; 3) unmutated IgVH together with ZAP-70+ and/or CD38+; or 4)
trisomy 12.
[0265] CLL treatment is typically administered when the patient's
clinical symptoms or blood counts indicate that the disease has
progressed to a point where it may affect the patient's quality of
life.
[0266] Small lymphocytic leukemia (SLL) is very similar to CLL
described supra, and is also a cancer of B-cells. In SLL the
abnormal lymphocytes mainly affect the lymph nodes. However, in CLL
the abnormal cells mainly affect the blood and the bone marrow. The
spleen may be affected in both conditions. SLL accounts for about 1
in 25 of all cases of non-Hodgkin lymphoma. It can occur at any
time from young adulthood to old age, but is rare under the age of
50. SLL is considered an indolent lymphoma. This means that the
disease progresses very slowly, and patients tend to live many
years after diagnosis. However, most patients are diagnosed with
advanced disease, and although SLL responds well to a variety of
chemotherapy drugs, it is generally considered to be incurable.
Although some cancers tend to occur more often in one gender or the
other, cases and deaths due to SLL are evenly split between men and
women. The average age at the time of diagnosis is 60 years.
[0267] Although SLL is indolent, it is persistently progressive.
The usual pattern of this disease is one of high response rates to
radiation therapy and/or chemotherapy, with a period of disease
remission. This is followed months or years later by an inevitable
relapse. Re-treatment leads to a response again, but again the
disease will relapse. This means that although the short-term
prognosis of SLL is quite good, over time, many patients develop
fatal complications of recurrent disease. Considering the age of
the individuals typically diagnosed with CLL and SLL, there is a
need in the art for a simple and effective treatment of the disease
with minimum side-effects that do not impede on the patient's
quality of life. The instant invention fulfills this long standing
need in the art.
[0268] Mantle Cell Lymphoma
[0269] Disclosed herein, in certain embodiments, is a method for
treating a Mantle cell lymphoma in an individual in need thereof,
comprising: administering to the individual an amount of Compound
1. Further disclosed herein, in certain embodiments, is a method
for treating relapsed or refractory Mantle cell lymphoma in an
individual in need thereof, comprising: administering to the
individual a therapeutically-effective amount of Compound 1.
[0270] As used herein, the term, "Mantle cell lymphoma" refers to a
subtype of B-cell lymphoma, due to CD5 positive antigen-naive
pregerminal center B-cell within the mantle zone that surrounds
normal germinal center follicles. MCL cells generally over-express
cyclin D1 due to a t(11:14) chromosomal translocation in the DNA.
More specifically, the translocation is at t(11;14)(q13;q32). Only
about 5% of lymphomas are of this type. The cells are small to
medium in size. Men are affected most often. The average age of
patients is in the early 60s. The lymphoma is usually widespread
when it is diagnosed, involving lymph nodes, bone marrow, and, very
often, the spleen. Mantle cell lymphoma is not a very fast growing
lymphoma, but is difficult to treat.
[0271] Marginal Zone B-cell Lymphoma
[0272] Disclosed herein, in certain embodiments, is a method for
treating a marginal zone B-cell lymphoma in an individual in need
thereof, comprising: administering to the individual an amount of
Compound 1. Further disclosed herein, in certain embodiments, is a
method for treating relapsed or refractory marginal zone B-cell
lymphoma in an individual in need thereof, comprising:
administering to the individual a therapeutically-effective amount
of Compound 1.
[0273] As used herein, the term "marginal zone B-cell lymphoma"
refers to a group of related B-cell neoplasms that involve the
lymphoid tissues in the marginal zone, the patchy area outside the
follicular mantle zone. Marginal zone lymphomas account for about
5% to 10% of lymphomas. The cells in these lymphomas look small
under the microscope. There are 3 main types of marginal zone
lymphomas including extranodal marginal zone B-cell lymphomas,
nodal marginal zone B-cell lymphoma, and splenic marginal zone
lymphoma.
[0274] MALT
[0275] Disclosed herein, in certain embodiments, is a method for
treating a MALT in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory MALT in an individual in need thereof,
comprising: administering to the individual a
therapeutically-effective amount of Compound 1.
[0276] The term "mucosa-associated lymphoid tissue (MALT)
lymphoma", as used herein, refers to extranodal manifestations of
marginal-zone lymphomas. Most MALT lymphoma are a low grade,
although a minority either manifest initially as intermediate-grade
non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most
of the MALT lymphoma occur in the stomach, and roughly 70% of
gastric MALT lymphoma are associated with Helicobacter pylori
infection. Several cytogenetic abnormalities have been identified,
the most common being trisomy 3 or t(11;18). Many of these other
MALT lymphoma have also been linked to infections with bacteria or
viruses. The average age of patients with MALT lymphoma is about
60.
[0277] Nodal Marginal Zone B-Cell Lymphoma
[0278] Disclosed herein, in certain embodiments, is a method for
treating a nodal marginal zone B-cell lymphoma in an individual in
need thereof, comprising: administering to the individual an amount
of Compound 1. Further disclosed herein, in certain embodiments, is
a method for treating relapsed or refractory nodal marginal zone
B-cell lymphoma in an individual in need thereof, comprising:
administering to the individual a therapeutically-effective amount
of Compound 1.
[0279] The term "nodal marginal zone B-cell lymphoma" refers to an
indolent B-cell lymphoma that is found mostly in the lymph nodes.
The disease is rare and only accounts for 1% of all Non-Hodgkin's
Lymphomas (NHL). It is most commonly diagnosed in older patients,
with women more susceptible than men. The disease is classified as
a marginal zone lymphoma because the mutation occurs in the
marginal zone of the B-cells. Due to its confinement in the lymph
nodes, this disease is also classified as nodal.
[0280] Splenic Marginal Zone B-Cell Lymphoma
[0281] Disclosed herein, in certain embodiments, is a method for
treating a splenic marginal zone B-cell lymphoma in an individual
in need thereof, comprising: administering to the individual an
amount of Compound 1. Further disclosed herein, in certain
embodiments, is a method for treating relapsed or refractory
splenic marginal zone B-cell lymphoma in an individual in need
thereof, comprising: administering to the individual a
therapeutically-effective amount of Compound 1.
[0282] The term "splenic marginal zone B-cell lymphoma" refers to
specific low-grade small B-cell lymphoma that is incorporated in
the World Health Organization classification. Characteristic
features are splenomegaly, moderate lymphocytosis with villous
morphology, intrasinusoidal pattern of involvement of various
organs, especially bone marrow, and relative indolent course. Tumor
progression with increase of blastic forms and aggressive behavior
are observed in a minority of patients. Molecular and cytogenetic
studies have shown heterogeneous results probably because of the
lack of standardized diagnostic criteria.
[0283] Burkitt Lymphoma
[0284] Disclosed herein, in certain embodiments, is a method for
treating a Burkitt lymphoma in an individual in need thereof,
comprising: administering to the individual an amount of Compound
1. Further disclosed herein, in certain embodiments, is a method
for treating relapsed or refractory Burkitt lymphoma in an
individual in need thereof, comprising: administering to the
individual a therapeutically-effective amount of Compound 1.
[0285] The term "Burkitt lymphoma" refers to a type of Non-Hodgkin
Lymphoma (NHL) that commonly affects children. It is a highly
aggressive type of B-cell lymphoma that often starts and involves
body parts other than lymph nodes. In spite of its fast-growing
nature, Burkitt's lymphoma is often curable with modern intensive
therapies. There are two broad types of Burkitt's lymphoma--the
sporadic and the endemic varieties:
[0286] Endemic Burkitt's lymphoma: The disease involves children
much more than adults, and is related to Epstein Barr Virus (EBV)
infection in 95% cases. It occurs primarily is equatorial Africa,
where about half of all childhood cancers are Burkitt's lymphoma.
It characteristically has a high chance of involving the jawbone, a
rather distinctive feature that is rare in sporadic Burkitt's. It
also commonly involves the abdomen.
[0287] Sporadic Burkitt's lymphoma: The type of Burkitt's lymphoma
that affects the rest of the world, including Europe and the
Americas is the sporadic type. Here too, it's mainly a disease in
children. The link between Epstein Barr Virus (EBV) is not as
strong as with the endemic variety, though direct evidence of EBV
infection is present in one out of five patients. More than the
involvement of lymph nodes, it is the abdomen that is notably
affected in more than 90% of the children. Bone marrow involvement
is more common than in the sporadic variety.
[0288] Waldenstrom Macroglobulinemia
[0289] Disclosed herein, in certain embodiments, is a method for
treating a Waldenstrom macroglobulinemia in an individual in need
thereof, comprising: administering to the individual an amount of
Compound 1. Further disclosed herein, in certain embodiments, is a
method for treating relapsed or refractory Waldenstrom
macroglobulinemia in an individual in need thereof, comprising:
administering to the individual a therapeutically-effective amount
of Compound 1.
[0290] The term "Waldenstrom macroglobulinemia", also known as
lymphoplasmacytic lymphoma, is cancer involving a subtype of white
blood cells called lymphocytes. It is characterized by an
uncontrolled clonal proliferation of terminally differentiated B
lymphocytes. It is also characterized by the lymphoma cells making
an antibody called immunoglobulin M (IgM). The IgM antibodies
circulate in the blood in large amounts, and cause the liquid part
of the blood to thicken, like syrup. This can lead to decreased
blood flow to many organs, which can cause problems with vision
(because of poor circulation in blood vessels in the back of the
eyes) and neurological problems (such as headache, dizziness, and
confusion) caused by poor blood flow within the brain. Other
symptoms can include feeling tired and weak, and a tendency to
bleed easily. The underlying etiology is not fully understood but a
number of risk factors have been identified, including the locus
6p21.3 on chromosome 6. There is a 2- to 3-fold risk increase of
developing WM in people with a personal history of autoimmune
diseases with autoantibodies and particularly elevated risks
associated with hepatitis, human immunodeficiency virus, and
rickettsiosis.
[0291] Multiple Myeloma
[0292] Disclosed herein, in certain embodiments, is a method for
treating a myeloma in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory myeloma in an individual in need thereof,
comprising: administering to the individual a
therapeutically-effective amount of Compound 1.
[0293] Multiple myeloma, also known as MM, myeloma, plasma cell
myeloma, or as Kahler's disease (after Otto Kahler) is a cancer of
the white blood cells known as plasma cells. A type of B cell,
plasma cells are a crucial part of the immune system responsible
for the production of antibodies in humans and other vertebrates.
They are produced in the bone marrow and are transported through
the lymphatic system.
[0294] Leukemia
[0295] Disclosed herein, in certain embodiments, is a method for
treating a leukemia in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. Further
disclosed herein, in certain embodiments, is a method for treating
relapsed or refractory leukemia in an individual in need thereof,
comprising: administering to the individual a
therapeutically-effective amount of Compound 1.
[0296] Leukemia is a cancer of the blood or bone marrow
characterized by an abnormal increase of blood cells, usually
leukocytes (white blood cells). Leukemia is a broad term covering a
spectrum of diseases. The first division is between its acute and
chronic forms: (i) acute leukemia is characterized by the rapid
increase of immature blood cells. This crowding makes the bone
marrow unable to produce healthy blood cells. Immediate treatment
is required in acute leukemia due to the rapid progression and
accumulation of the malignant cells, which then spill over into the
bloodstream and spread to other organs of the body. Acute forms of
leukemia are the most common forms of leukemia in children; (ii)
chronic leukemia is distinguished by the excessive build up of
relatively mature, but still abnormal, white blood cells. Typically
taking months or years to progress, the cells are produced at a
much higher rate than normal cells, resulting in many abnormal
white blood cells in the blood. Chronic leukemia mostly occurs in
older people, but can theoretically occur in any age group.
Additionally, the diseases are subdivided according to which kind
of blood cell is affected. This split divides leukemias into
lymphoblastic or lymphocytic leukemias and myeloid or myelogenous
leukemias: (i) lymphoblastic or lymphocytic leukemias, the
cancerous change takes place in a type of marrow cell that normally
goes on to form lymphocytes, which are infection-fighting immune
system cells; (ii) myeloid or myelogenous leukemias, the cancerous
change takes place in a type of marrow cell that normally goes on
to form red blood cells, some other types of white cells, and
platelets.
[0297] Within these main categories, there are several
subcategories including, but not limited to, Acute lymphoblastic
leukemia (ALL), precursor B-cell acute lymphoblastic leukemia
(precursor B-ALL; also called precursor B-lymphoblastic leukemia),
Acute myelogenous leukemia (AML), Chronic myelogenous leukemia
(CML), and Hairy cell leukemia (HCL). Accordingly, disclosed
herein, in certain embodiments, is a method for treating Acute
lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic
leukemia (precursor B-ALL; also called precursor B-lymphoblastic
leukemia), Acute myelogenous leukemia (AML), Chronic myelogenous
leukemia (CML), or Hairy cell leukemia (HCL) in an individual in
need thereof, comprising: administering to the individual an amount
of Compound 1. In some embodiments, the leukemia is a relapsed or
refractory leukemia. In some embodiments, the leukemia is a
relapsed or refractory Acute lymphoblastic leukemia (ALL), relapsed
or refractory precursor B-cell acute lymphoblastic leukemia
(precursor B-ALL; also called precursor B-lymphoblastic leukemia),
relapsed or refractory Acute myelogenous leukemia (AML), relapsed
or refractory Chronic myelogenous leukemia (CML), or relapsed or
refractory Hairy cell leukemia (HCL).
[0298] Symptoms, diagnostic tests, and prognostic tests for each of
the above-mentioned conditions are known. See, e.g., Harrison's
Principles of Internal Medicine.COPYRGT.," 16th ed., 2004, The
McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24),
and the "Revised European American Lymphoma" (REAL) classification
system (see, e.g., the website maintained by the National Cancer
Institute).
[0299] A number of animal models of are useful for establishing a
range of therapeutically effective doses of irreversible Btk
inhibitor compounds, such as Compound 1, for treating any of the
foregoing diseases.
[0300] The therapeutic efficacy of Compound 1 for any one of the
foregoing diseases can be optimized during a course of treatment.
For example, a subject being treated can undergo a diagnostic
evaluation to correlate the relief of disease symptoms or
pathologies to inhibition of in vivo Btk activity achieved by
administering a given dose of Compound 1. Cellular assays known in
the art can be used to determine in vivo activity of Btk in the
presence or absence of an irreversible Btk inhibitor. For example,
since activated Btk is phosphorylated at tyrosine 223 (Y223) and
tyrosine 551 (Y551), phospho-specific immunocytochemical staining
of P-Y223 or P-Y551-positive cells can be used to detect or
quantify activation of Bkt in a population of cells (e.g., by FACS
analysis of stained vs unstained cells). See, e.g., Nisitani et al.
(1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus, the amount
of the Btk inhibitor inhibitor compound that is administered to a
subject can be increased or decreased as needed so as to maintain a
level of Btk inhibition optimal for treating the subject's disease
state.
[0301] Compound 1 can irreversibly inhibit Btk and may be used to
treat mammals suffering from Bruton's tyrosine kinase-dependent or
Bruton's tyrosine kinase mediated conditions or diseases,
including, but not limited to, cancer, autoimmune and other
inflammatory diseases. Compound 1 has shown efficacy is a wide
variety of diseases and conditions that are described herein.
[0302] In some embodiments, Compound 1 is used for the manufacture
of a medicament for treating any of the foregoing conditions (e.g.,
autoimmune diseases, inflammatory diseases, allergy disorders,
B-cell proliferative disorders, or thromboembolic disorders).
Compound 1, and Pharmaceutically Acceptable Salts Thereof
[0303] The Btk inhibitor compound described herein (i.e. Compound
1) is selective for Btk and kinases having a cysteine residue in an
amino acid sequence position of the tyrosine kinase that is
homologous to the amino acid sequence position of cysteine 481 in
Btk. The Btk inhibitor compound can form a covalent bond with Cys
481 of Btk (e.g., via a Michael reaction).
[0304] "Compound 1" or
"1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)p-
iperidin-1-yl)prop-2-en-1-one" or
"1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)
piperidin-1-yl}prop-2-en-1-one" or "2-Propen-1-one,
1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]1-
-piperidinyl-" or ibrutinib or any other suitable name refers to
the compound with the following structure:
##STR00001##
[0305] A wide variety of pharmaceutically acceptable salts is
formed from Compound 1 and includes:
[0306] acid addition salts formed by reacting Compound 1 with an
organic acid, which includes aliphatic mono- and dicarboxylic
acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic
acids, amino acids, etc. and include, for example, acetic acid,
trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,
oxalic acid, maleic acid, malonic acid, succinic acid, fumaric
acid, tartaric acid, critric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonica acid,
p-toluenesulfonic acid, salicylic acid, and the like;
[0307] acid addition salts formed by reacting Compound 1 with an
inorganic acid, which includes hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,
hydrofluoric acid, phosphorous acid, and the like.
[0308] The term "pharmaceutically acceptable salts" in reference to
Compound 1 refers to a salt of Compound 1, which does not cause
significant irritation to a mammal to which it is administered and
does not substantially abrogate the biological activity and
properties of the compound.
[0309] It should be understood that a reference to a
pharmaceutically acceptable salt includes the solvent addition
forms (solvates). Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent, and are formed during the
process of product formation or isolation with pharmaceutically
acceptable solvents such as water, ethanol, methanol, methyl
tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate,
isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone
(MIBK), methyl ethyl ketone (MEK), acetone, nitromethane,
tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes,
toluene, anisole, acetonitrile, and the like. In one aspect,
solvates are formed using, but not limited to, Class 3 solvent(s).
Categories of solvents are defined in, for example, the
International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH),
"Impurities: Guidelines for Residual Solvents, Q3C(R3), (November
2005). Hydrates are formed when the solvent is water, or
alcoholates are formed when the solvent is alcohol. In some
embodiments, solvates of Compound 1, or pharmaceutically acceptable
salts thereof, are conveniently prepared or formed during the
processes described herein. In some embodiments, solvates of
Compound 1 are anhydrous. In some embodiments, Compound 1, or
pharmaceutically acceptable salts thereof, exist in unsolvated
form. In some embodiments, Compound 1, or pharmaceutically
acceptable salts thereof, exist in unsolvated form and are
anhydrous.
[0310] In yet other embodiments, Compound 1, or a pharmaceutically
acceptable salt thereof, is prepared in various forms, including
but not limited to, amorphous phase, crystalline forms, milled
forms and nano-particulate forms. In some embodiments, Compound 1,
or a pharmaceutically acceptable salt thereof, is amorphous. In
some embodiments, Compound 1, or a pharmaceutically acceptable salt
thereof, is amorphous and anhydrous. In some embodiments, Compound
1, or a pharmaceutically acceptable salt thereof, is crystalline.
In some embodiments, Compound 1, or a pharmaceutically acceptable
salt thereof, is crystalline and anhydrous.
[0311] In some embodiments, Compound 1 is prepared as outlined in
U.S. Pat. no. 7,514,444.
Amorphous Compound 1
[0312] In some embodiments, Compound 1 is amorphous and anhydrous.
In some embodiments, Compound 1 is amorphous. In some embodiments,
amorphous Compound 1 has an X-Ray Powder Diffraction (XRPD) pattern
showing a lack of crystallinity.
Compound 1, Form A
[0313] In some embodiments, Compound 1 is crystalline. In some
embodiments, Compound 1 is crystalline Form A. Crystalline Form A
of Compound 1 is characterized as having at least one of the
following properties: [0314] (a) an X-Ray powder diffraction (XRPD)
pattern substantially the same as shown in FIG. 1; [0315] (b) an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 5.7.+-.0.1.degree. 2-Theta, 13.6.+-.0.1.degree. 2-Theta,
16.1.+-.0.1.degree. 2-Theta, 18.9.+-.0.1.degree. 2-Theta,
21.3.+-.0.1.degree. 2-Theta, and 21.6.+-.0.1.degree. 2-Theta;
[0316] (c) substantially the same X-ray powder diffraction (XRPD)
pattern post storage at 40.degree. C. and 75% RH for at least a
week; [0317] (d) substantially the same X-ray powder diffraction
(XRPD) pattern post storage at 25.degree. C. and 97% RH for at
least a week; [0318] (e) Infrared (IR) spectrum substantially
similar to the one set forth in FIG. 2; [0319] (f) Infrared (IR)
spectrum weak peaks at about 1584 cm.sup.-1, about 1240 cm.sup.-1,
about 1147 cm.sup.-1, about 1134 cm.sup.-1, about 1099 cm.sup.-1,
and about 1067cm.sup.-1; [0320] (g) a DSC thermogram substantially
similar to the one set forth in FIG. 3; [0321] (h) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 4; [0322] (i) a DSC thermogram with an
endotherm having an onset at about 154.degree. C. and a peak at
about 157.degree. C. and an exotherm at about 159.degree. C.;
[0323] (j) non-hygroscopicity; [0324] (k) an observed aqueous
solubility of about 0.013 mg/mL at about pH 8; [0325] or [0326] (l)
combinations thereof.
[0327] In some embodiments, Form A of Compound 1 is characterized
as having at least two of the properties selected from (a) to (k).
In some embodiments, Form A of Compound 1 is characterized as
having at least three of the properties selected from (a) to (k).
In some embodiments, Form A of Compound 1 is characterized as
having at least four of the properties selected from (a) to (k). In
some embodiments, Form A of Compound 1 is characterized as having
at least five of the properties selected from (a) to (k). In some
embodiments, Form A of Compound 1 is characterized as having at
least six of the properties selected from (a) to (k). In some
embodiments, Form A of Compound 1 is characterized as having at
least seven of the properties selected from (a) to (k). In some
embodiments, Form A of Compound 1 is characterized as having at
least eight of the properties selected from (a) to (k). In some
embodiments, Form A of Compound 1 is characterized as having at
least nine of the properties selected from (a) to (k). In some
embodiments, Form A of Compound 1 is characterized as having at
least ten of the properties selected from (a) to (k). In some
embodiments, Form A of Compound 1 is characterized as having
properties (a) to (k).
[0328] In some embodiments, Form A has an X-Ray powder diffraction
(XRPD) pattern substantially the same as shown in FIG. 1. In some
embodiments, Form A has an X-ray powder diffraction (XRPD) pattern
with characteristic peaks at 5.7.+-.0.1.degree. 2-Theta,
13.6.+-.0.1.degree. 2-Theta, 16.1.+-.0.1.degree. 2-Theta,
18.9.+-.0.1.degree. 2-Theta, 21.3.+-.0.1.degree. 2-Theta, and
21.6.+-.0.1.degree. 2-Theta. In some embodiments, Form A has
substantially the same X-ray powder diffraction (XRPD) pattern post
storage at 40.degree. C. and 75% RH for at least a week. In some
embodiments, Form A has substantially the same X-ray powder
diffraction (XRPD) pattern post storage at 25.degree. C. and 97% RH
for at least a week.
[0329] In some embodiments, Form A has an Infrared (IR) spectrum
substantially similar to the one set forth in FIG. 2. In some
embodiments, Form A has an Infrared (IR) spectrum weak peaks at
about 1584 cm.sup.-1, about 1240 cm.sup.-1, about 1147 cm.sup.-1,
about 1134 cm.sup.-1, about 1099 cm.sup.-1, and about
1067cm.sup.-1.
[0330] In some embodiments, Form A has a DSC thermogram
substantially similar to the one set forth in FIG. 3. In some
embodiments, Form A has a thermo-gravimetric analysis (TGA)
thermogram substantially similar to the one set forth in FIG. 4. In
some embodiments, Form A has a DSC thermogram with an endotherm
having an onset at about 154.degree. C. and a peak at about
157.degree. C. and an exotherm at about 159.degree. C.
[0331] In some embodiments, Form A has non-hygroscopicity.
[0332] In some embodiments, Form A has an observed aqueous
solubility of about 0.013 mg/mL at about pH 8.
[0333] In some embodiments, Form A was obtained from ethyl acetate,
isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK),
methyl ethyl ketone (MEK), nitromethane, methanol, ethanol,
acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole,
acetone, heptanes, a methanol/water mixture or an acetone/heptane
mixture. In some embodiments, Form A was obtained from ethyl
acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone
(MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol,
acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole,
acetone, heptanes, or an acetone/heptane mixture.
[0334] In some embodiments, Form A is unsolvated. In some
embodiments, Form A is anhydrous.
Compound 1, Form B
[0335] In some embodiments, Compound 1 is crystalline. In some
embodiments, Compound 1 is crystalline Form B. Crystalline Form B
of Compound 1 is characterized as having at least one of the
following properties: [0336] (a) an X-Ray powder diffraction (XRPD)
pattern substantially the same as shown in FIG. 5; [0337] (b) an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 5.2.+-.0.1.degree. 2-Theta, 10.2.+-.0.1.degree. 2-Theta,
16.5.+-.0.1.degree. 2-Theta, 18.5.+-.0.1.degree. 2-Theta, and
20.8.+-.0.1.degree. 2-Theta; [0338] (c) substantially the same
X-ray powder diffraction (XRPD) pattern post storage at 40.degree.
C. and 75% RH for at least a week; [0339] (d) substantially the
same X-ray powder diffraction (XRPD) pattern post storage at
25.degree. C. and 97% RH for at least a week; [0340] (e) Infrared
(IR) spectrum substantially similar to the one set forth in FIG. 6;
[0341] (f) Infrared (IR) spectrum weak peaks at about about 1586
cm.sup.-1, about 1573 cm.sup.-1, about 1562 cm.sup.-1, about 1229
cm.sup.-1, about 1141 cm.sup.-1, about 1103 cm.sup.-1, about 1056
cm.sup.-1, and about 1033 cm.sup.-1; [0342] (g) a DSC thermogram
substantially similar to the one set forth in FIG. 7; [0343] (h) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 8; [0344] (i) a DSC thermogram with an
endotherm having an onset at about 99-106.degree. C. and a peak at
about 115-118.degree. C.; [0345] (j) an observed aqueous solubility
of about 0.0096 mg/mL at a pH of about 7.42; [0346] or [0347] (k)
combinations thereof.
[0348] In some embodiments, Form B of Compound 1 is characterized
as having at least two of the properties selected from (a) to (j).
In some embodiments, Form B of Compound 1 is characterized as
having at least three of the properties selected from (a) to (j).
In some embodiments, Form B of Compound 1 is characterized as
having at least four of the properties selected from (a) to (j). In
some embodiments, Form B of Compound 1 is characterized as having
at least five of the properties selected from (a) to (j). In some
embodiments, Form B of Compound 1 is characterized as having at
least six of the properties selected from (a) to (j). In some
embodiments, Form B of Compound 1 is characterized as having at
least seven of the properties selected from (a) to (j). In some
embodiments, Form B of Compound 1 is characterized as having at
least eight of the properties selected from (a) to (j). In some
embodiments, Form B of Compound 1 is characterized as having at
least nine of the properties selected from (a) to (j). In some
embodiments, Form B of Compound 1 is characterized as having
properties (a) to (j).
[0349] In some embodiments, Form B has an X-Ray powder diffraction
(XRPD) pattern substantially the same as shown in FIG. 5. In some
embodiments, Form B has an X-ray powder diffraction (XRPD) pattern
with characteristic peaks at 5.2.+-.0.1.degree. 2-Theta,
10.2.+-.0.1.degree. 2-Theta, 16.5.+-.0.1.degree. 2-Theta,
18.5.+-.0.1.degree. 2-Theta, and 20.8.+-.0.1.degree. 2-Theta. In
some embodiments, Form B has substantially the same X-ray powder
diffraction (XRPD) pattern post storage at 40.degree. C. and 75% RH
for at least a week. In some embodiments, Form B has substantially
the same X-ray powder diffraction (XRPD) pattern post storage at
25.degree. C. and 97% RH for at least a week.
[0350] In some embodiments, Form B has an Infrared (IR) spectrum
substantially similar to the one set forth in FIG. 6. In some
embodiments, Form B has an Infrared (IR) spectrum weak peaks at
about about 1586 cm.sup.-1, about 1573 cm.sup.-1, about 1562
cm.sup.-1, about 1229 cm.sup.-1, about 1141 cm.sup.-1, about 1103
cm.sup.-1, about 1056 cm.sup.-1, and about 1033 cm.sup.-1.
[0351] In some embodiments, Form B has a DSC thermogram
substantially similar to the one set forth in FIG. 7. In some
embodiments, Form B has a thermo-gravimetric analysis (TGA)
thermogram substantially similar to the one set forth in FIG. 8. In
some embodiments, Form B has a DSC thermogram with an endotherm
having an onset at about 99-106.degree. C. and a peak at about
115-118.degree. C.
[0352] In some embodiments, Form B has an observed aqueous
solubility of about 0.0096 mg/mL at a pH of about 7.42.
[0353] In some embodiments, Form B was obtained from a mixture of
methanol and water.
[0354] In some embodiments, Form B is unsolvated. In some
embodiments, Form B is anhydrous.
Compound 1, Form C
[0355] In some embodiments, Compound 1 is crystalline. In some
embodiments, Compound 1 is crystalline Form C. Crystalline Form C
of Compound 1 is characterized as having at least one of the
following properties: [0356] (a) an X-Ray powder diffraction (XRPD)
pattern substantially the same as shown in FIG. 9; [0357] (b) an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 7.0.+-.0.1.degree. 2-Theta, 14.0.+-.0.1.degree. 2-Theta,
15.7.+-.0.1.degree. 2-Theta, 18.2.+-.0.1.degree. 2-Theta,
19.1.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.3.+-.0.1.degree. 2-Theta, 22.1.+-.0.1.degree. 2-Theta, and
22.9.+-.0.1.degree. 2-Theta; [0358] (c) a DSC thermogram
substantially similar to the one set forth in FIG. 10; [0359] (d) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 11; [0360] (e) a DSC thermogram with
an endotherm having an onset at about 134-135.degree. C. and a peak
at about 137-139.degree. C.; [0361] or [0362] (f) combinations
thereof.
[0363] In some embodiments, Form C of Compound 1 is characterized
as having at least two of the properties selected from (a) to (e).
In some embodiments, Form C of Compound 1 is characterized as
having at least three of the properties selected from (a) to (e).
In some embodiments, Form C of Compound 1 is characterized as
having at least four of the properties selected from (a) to (e). In
some embodiments, Form C of Compound 1 is characterized as having
properties (a) to (e).
[0364] In some embodiments, Form C has an X-Ray powder diffraction
(XRPD) pattern substantially the same as shown in FIG. 9. In some
embodiments, Form C has an X-ray powder diffraction (XRPD) pattern
with characteristic peaks at 7.0.+-.0.1.degree. 2-Theta,
14.0.+-.0.1.degree. 2-Theta, 15.7.+-.0.1.degree. 2-Theta,
18.2.+-.0.1.degree. 2-Theta, 19.1.+-.0.1.degree. 2-Theta,
19.5.+-.0.1.degree. 2-Theta, 20.3.+-.0.1.degree. 2-Theta,
22.1.+-.0.1.degree. 2-Theta, and 22.9.+-.0.1.degree. 2-Theta.
[0365] In some embodiments, Form C has a DSC thermogram
substantially similar to the one set forth in FIG. 10. In some
embodiments, Form C has a thermo-gravimetric analysis (TGA)
thermogram substantially similar to the one set forth in FIG. 11.
In some embodiments, Form C has a DSC thermogram with an endotherm
having an onset at about 134-135.degree. C. and a peak at about
137-139.degree. C.
[0366] In some embodiments, Form C was obtained from a mixture of
methanol and water. In some embodiments, Form C was obtained from
methanol.
[0367] In some embodiments, Form C is unsolvated. In some
embodiments, Form C is anhydrous.
Compound 1, Form D
[0368] In some embodiments, Compound 1 is crystalline. In some
embodiments, Compound 1 is crystalline Form D. Crystalline Form D
of Compound 1 is characterized as having at least one of the
following properties: [0369] (a) an X-Ray powder diffraction (XRPD)
pattern substantially the same as shown in FIG. 12; [0370] (b) an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 7.2.+-.0.1.degree. 2-Theta, 8.0.+-.0.1.degree. 2-Theta,
9.2.+-.0.1.degree. 2-Theta, 14.5.+-.0.1.degree. 2-Theta,
18.5.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.7.+-.0.1.degree. 2-Theta, 21.0.+-.0.1.degree. 2-Theta,
21.9.+-.0.1.degree. 2-Theta, and 22.4.+-.0.1.degree. 2-Theta;
[0371] (c) a thermo-gravimetric analysis (TGA) thermogram
substantially similar to the one set forth in FIG. 13; or [0372]
(d) combinations thereof.
[0373] In some embodiments, Form D of Compound 1 is characterized
as having at least two of the properties selected from (a) to (c).
In some embodiments, Form D of Compound 1 is characterized as
having properties (a), (b), and (c).
[0374] In some embodiments, Form D has an X-Ray powder diffraction
(XRPD) pattern substantially the same as shown in FIG. 12. In some
embodiments, Form D has an X-ray powder diffraction (XRPD) pattern
with characteristic peaks at 7.2.+-.0.1.degree. 2-Theta,
8.0.+-.0.1.degree. 2-Theta, 9.2.+-.0.1.degree. 2-Theta,
14.5.+-.0.1.degree. 2-Theta, 18.5.+-.0.1.degree. 2-Theta,
19.5.+-.0.1.degree. 2-Theta, 20.7.+-.0.1.degree. 2-Theta,
21.0.+-.0.1.degree. 2-Theta, 21.9.+-.0.1.degree. 2-Theta, and
22.4.+-.0.1.degree. 2-Theta.
[0375] In some embodiments, Form D has a thermo-gravimetric
analysis (TGA) thermogram substantially similar to the one set
forth in FIG. 13.
[0376] In some embodiments, Form D was obtained from methyl
isobutyl ketone (MIBK). In some embodiments, Form D is solvated. In
some embodiments, Form D is solvated with methyl isobutyl ketone
(MIBK).
Compound 1, Form E
[0377] In some embodiments, Compound 1 is crystalline. In some
embodiments, Compound 1 is crystalline Form E. Crystalline Form E
of Compound 1 is characterized as having at least one of the
following properties: [0378] (a) an X-Ray powder diffraction (XRPD)
pattern substantially the same as shown in FIG. 14; [0379] (b) an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 7.8.+-.0.1.degree. 2-Theta, 8.8.+-.0.1.degree. 2-Theta,
16.1.+-.0.1.degree. 2-Theta, 18.1.+-.0.1.degree. 2-Theta,
19.3.+-.0.1.degree. 2-Theta, 19.5.+-.0.1.degree. 2-Theta,
20.5.+-.0.1.degree. 2-Theta, 21.6.+-.0.1.degree. 2-Theta, and
25.2.+-.0.1.degree. 2-Theta; [0380] (c) a DSC thermogram
substantially similar to the one set forth in FIG. 15; [0381] (d) a
thermo-gravimetric analysis (TGA) thermogram substantially similar
to the one set forth in FIG. 15; [0382] or [0383] (e) combinations
thereof.
[0384] In some embodiments, Form E of Compound 1 is characterized
as having at least two of the properties selected from (a) to (d).
In some embodiments, Form E of Compound 1 is characterized as
having at least three of the properties selected from (a) to (d).
In some embodiments, Form E of Compound 1 is characterized as
having properties (a) to (d).
[0385] In some embodiments, Form E has an X-Ray powder diffraction
(XRPD) pattern substantially the same as shown in FIG. 14. In some
embodiments, Form E has an X-ray powder diffraction (XRPD) pattern
with characteristic peaks at 7.8.+-.0.1.degree. 2-Theta,
8.8.+-.0.1.degree. 2-Theta, 16.1.+-.0.1.degree. 2-Theta,
18.1.+-.0.1.degree. 2-Theta, 19.3.+-.0.1.degree. 2-Theta,
19.5.+-.0.1.degree. 2-Theta, 20.5.+-.0.1.degree. 2-Theta,
21.6.+-.0.1.degree. 2-Theta, and 25.2.+-.0.1.degree. 2-Theta.
[0386] In some embodiments, Form E has a DSC thermogram
substantially similar to the one set forth in FIG. 15. In some
embodiments, Form E has a thermo-gravimetric analysis (TGA)
thermogram substantially similar to the one set forth in FIG.
15.
[0387] In some embodiments, Form E was obtained from toluene.
[0388] In some embodiments, Form E is solvated. In some
embodiments, Form E is solvated with toluene.
Compound 1, Form F
[0389] In some embodiments, Compound 1 is crystalline. In some
embodiments, Compound 1 is crystalline Form F. Crystalline Form F
of Compound 1 is characterized as having at least one of the
following properties: [0390] (a) an X-Ray powder diffraction (XRPD)
pattern substantially the same as shown in FIG. 16; [0391] (b) an
X-ray powder diffraction (XRPD) pattern with characteristic peaks
at 6.2.+-.0.1.degree. 2-Theta, 10.1.+-.0.1.degree. 2-Theta,
17.6.+-.0.1.degree. 2-Theta, 18.6.+-.0.1.degree. 2-Theta,
20.0.+-.0.1.degree. 2-Theta, 20.4.+-.0.1.degree. 2-Theta,
20.7.+-.0.1.degree. 2-Theta, 22.4.+-.0.1.degree. 2-Theta,
23.0.+-.0.1.degree. 2-Theta, 23.2.+-.0.1.degree. 2-Theta,
24.4.+-.0.1.degree. 2-Theta, 25.1.+-.0.1.degree. 2-Theta,
27.6.+-.0.1.degree. 2-Theta, 29.3.+-.0.1.degree. 2-Theta, and
29.7.+-.0.1.degree. 2-Theta; [0392] (c) unit cell parameters
substantially equal to the following at 100(2) K:
TABLE-US-00003 [0392] Crystal system Triclinic Space group P1 a
9.6332(3) .ANG. .alpha. 105.762(3).degree. b 9.7536(4) .ANG. .beta.
95.132(2).degree. c 15.0592(4) .ANG. .gamma. 111.332(3).degree. V
1240.15(7) .ANG..sup.3 Z 1 Density 1.308 Mg/m.sup.3 (calculated)
Absorption 0.726 mm.sup.-1 coefficient Wavelength 1.54178 .ANG.
F(000) 518
[0393] or [0394] (d) combinations thereof.
[0395] In some embodiments, Form F of Compound 1 is characterized
as having at least two of the properties selected from (a) to (c).
In some embodiments, Form F of Compound 1 is characterized as
having properties (a), (a), and (c).
[0396] In some embodiments, Form F has an X-Ray powder diffraction
(XRPD) pattern substantially the same as shown in FIG. 16. In some
embodiments, Form F has an X-ray powder diffraction (XRPD) pattern
with characteristic peaks at 6.2.+-.0.1.degree. 2-Theta,
10.1.+-.0.1.degree. 2-Theta, 17.6.+-.0.1.degree. 2-Theta,
18.6.+-.0.1.degree. 2-Theta, 20.0.+-.0.1.degree. 2-Theta,
20.4.+-.0.1.degree. 2-Theta, 20.7.+-.0.1.degree. 2-Theta,
22.4.+-.0.1.degree. 2-Theta, 23.0.+-.0.1.degree. 2-Theta,
23.2.+-.0.1.degree. 2-Theta, 24.4.+-.0.1.degree. 2-Theta,
25.1.+-.0.1.degree. 2-Theta, 27.6.+-.0.1.degree. 2-Theta,
29.3.+-.0.1.degree. 2-Theta, and 29.7.+-.0.1.degree. 2-Theta.
[0397] In some embodiments, Form F has unit cell parameters
substantially equal to the following at 100(2) K:
TABLE-US-00004 Crystal system Triclinic Space group P1 a 9.6332(3)
.ANG. .alpha. 105.762(3).degree. b 9.7536(4) .ANG. .beta.
95.132(2).degree. c 15.0592(4) .ANG. .gamma. 111.332(3).degree. V
1240.15(7) .ANG..sup.3 Z 1 Density 1.308 Mg/m.sup.3 (calculated)
Absorption 0.726 mm.sup.-1 coefficient Wavelength 1.54178 .ANG.
F(000) 518
[0398] In some embodiments, Form F was obtained from methanol.
[0399] In some embodiments, Form F is solvated. In some
embodiments, Form F is solvated with methanol.
Preparation of Crytalline Forms
[0400] In some embodiments, crystalline forms of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one are prepared as outlined in the
Examples. It is noted that solvents, temperatures and other
reaction conditions presented herein may vary.
Suitable Solvents
[0401] Therapeutic agents that are administrable to mammals, such
as humans, must be prepared by following regulatory guidelines.
Such government regulated guidelines are referred to as Good
Manufacturing Practice (GMP). GMP guidelines outline acceptable
contamination levels of active therapeutic agents, such as, for
example, the amount of residual solvent in the final product.
Preferred solvents are those that are suitable for use in GMP
facilities and consistent with industrial safety concerns.
Categories of solvents are defined in, for example, the
International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH),
"Impurities: Guidelines for Residual Solvents, Q3C(R3), (November
2005).
[0402] Solvents are categorized into three classes. Class 1
solvents are toxic and are to be avoided. Class 2 solvents are
solvents to be limited in use during the manufacture of the
therapeutic agent. Class 3 solvents are solvents with low toxic
potential and of lower risk to human health. Data for Class 3
solvents indicate that they are less toxic in acute or short-term
studies and negative in genotoxicity studies.
[0403] Class 1 solvents, which are to be avoided, include: benzene;
carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and
1,1,1-trichloroethane.
[0404] Examples of Class 2 solvents are: acetonitrile,
chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene,
dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide,
N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol,
ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol,
methylbutyl ketone, methylcyclohexane, N-methylpyrrolidine,
nitromethane, pyridine, sulfolane, tetralin, toluene,
1,1,2-trichloroethene and xylene.
[0405] Class 3 solvents, which possess low toxicity, include:
acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate,
tert-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol,
ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane,
isobutyl acetate, isopropyl acetate, methyl acetate,
3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone,
2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol,
propyl acetate, and tetrahydrofuran.
[0406] Residual solvents in active pharmaceutical ingredients
(APIs) originate from the manufacture of API. In some cases, the
solvents are not completely removed by practical manufacturing
techniques. Appropriate selection of the solvent for the synthesis
of APIs may enhance the yield, or determine characteristics such as
crystal form, purity, and solubility. Therefore, the solvent is a
critical parameter in the synthetic process.
[0407] In some embodiments, compositions comprising Compound 1
comprise an organic solvent(s). In some embodiments, compositions
comprising Compound 1 comprise a residual amount of an organic
solvent(s). In some embodiments, compositions comprising Compound 1
comprise a residual amount of a Class 3 solvent. In some
embodiments, the organic solvent is a Class 3 solvent. In some
embodiments, the Class 3 solvent is selected from the group
consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol,
butyl acetate, tert-butylmethyl ether, cumene, dimethyl sulfoxide,
ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid,
heptane, isobutyl acetate, isopropyl acetate, methyl acetate,
3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone,
2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol,
propyl acetate, and tetrahydrofuran. In some embodiments, the Class
3 solvent is selected from ethyl acetate, isopropyl acetate,
tert-butylmethylether, heptane, isopropanol, and ethanol.
Certain Terminology
[0408] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the claimed subject matter belongs. It
is to be understood that the foregoing general description and the
following detailed description are exemplary and explanatory only
and are not restrictive of any subject matter claimed. In this
application, the use of the singular includes the plural unless
specifically stated otherwise. It must be noted that, as used in
the specification and the appended claims, the singular forms "a,"
"an" and "the" include plural referents unless the context clearly
dictates otherwise. In this application, the use of "or" means
"and/or" unless stated otherwise. Furthermore, use of the term
"including" as well as other forms, such as "include", "includes,"
and "included," is not limiting.
[0409] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, but not limited to, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
[0410] The term "acceptable" or "pharmaceutically acceptable", with
respect to a formulation, composition or ingredient, as used
herein, means having no persistent detrimental effect on the
general health of the subject being treated or does not abrogate
the biological activity or properties of the compound, and is
relatively nontoxic.
[0411] As used herein, the term "agonist" refers to a compound, the
presence of which results in a biological activity of a protein
that is the same as the biological activity resulting from the
presence of a naturally occurring ligand for the protein, such as,
for example, Btk.
[0412] As used herein, the term "partial agonist" refers to a
compound the presence of which results in a biological activity of
a protein that is of the same type as that resulting from the
presence of a naturally occurring ligand for the protein, but of a
lower magnitude.
[0413] As used herein, the term "antagonist" refers to a compound,
the presence of which results in a decrease in the magnitude of a
biological activity of a protein. In certain embodiments, the
presence of an antagonist results in complete inhibition of a
biological activity of a protein, such as, for example, Btk. In
certain embodiments, an antagonist is an inhibitor.
[0414] As used herein, "amelioration" of the symptoms of a
particular disease, disorder or condition by administration of a
particular compound or pharmaceutical composition refers to any
lessening of severity, delay in onset, slowing of progression, or
shortening of duration, whether permanent or temporary, lasting or
transient that can be attributed to or associated with
administration of the compound or composition.
[0415] "Bioavailability" refers to the percentage of Compound 1
dosed that is delivered into the general circulation of the animal
or human being studied. The total exposure (AUC.sub.(0-.infin.)) of
a drug when administered intravenously is usually defined as 100%
bioavailable (F%). "Oral bioavailability" refers to the extent to
which Compound 1 is absorbed into the general circulation when the
pharmaceutical composition is taken orally as compared to
intravenous injection.
[0416] "Blood plasma concentration" refers to the concentration of
Compound 1 in the plasma component of blood of a subject. It is
understood that the plasma concentration of Compound 1 may vary
significantly between subjects, due to variability with respect to
metabolism and/or possible interactions with other therapeutic
agents. In accordance with one embodiment disclosed herein, the
blood plasma concentration of Compound 1 may vary from subject to
subject. Likewise, values such as maximum plasma concentration
(C.sub.max) or time to reach maximum plasma concentration
(T.sub.max), or total area under the plasma concentration time
curve (AUC.sub.(0-.infin.)) may vary from subject to subject. Due
to this variability, the amount necessary to constitute "a
therapeutically effective amount" of Compound 1 may vary from
subject to subject.
[0417] The term "Bruton's tyrosine kinase," as used herein, refers
to Bruton's tyrosine kinase from Homo sapiens, as disclosed in,
e.g., U.S. Pat. No. 6,326,469 (GenBank Accession No. NP
000052).
[0418] The term "Bruton's tyrosine kinase homolog," as used herein,
refers to orthologs of Bruton's tyrosine kinase, e.g., the
orthologs from mouse (GenBank Acession No. AAB47246), dog (GenBank
Acession No. XP 549139.), rat (GenBank Acession No. NP_001007799),
chicken (GenBank Acession No. NP_989564), or zebra fish (GenBank
Acession No. XP_698117), and fusion proteins of any of the
foregoing that exhibit kinase activity towards one or more
substrates of Bruton's tyrosine kinase (e.g. a peptide substrate
having the amino acid sequence "AVLESEEELYSSARQ").
[0419] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0420] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result can be reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired
alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition
including a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms without undue
adverse side effects. An appropriate "effective amount" in any
individual case may be determined using techniques, such as a dose
escalation study. The term "therapeutically effective amount"
includes, for example, a prophylactically effective amount. An
"effective amount" of a compound disclosed herein is an amount
effective to achieve a desired pharmacologic effect or therapeutic
improvement without undue adverse side effects. It is understood
that "an effect amount" or "a therapeutically effective amount" can
vary from subject to subject, due to variation in metabolism of
Compound 1, age, weight, general condition of the subject, the
condition being treated, the severity of the condition being
treated, and the judgment of the prescribing physician. By way of
example only, therapeutically effective amounts may be determined
by routine experimentation, including but not limited to a dose
escalation clinical trial.
[0421] The terms "enhance" or "enhancing" means to increase or
prolong either in potency or duration a desired effect. By way of
example, "enhancing" the effect of therapeutic agents refers to the
ability to increase or prolong, either in potency or duration, the
effect of therapeutic agents on during treatment of a disease,
disorder or condition. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of a
therapeutic agent in the treatment of a disease, disorder or
condition. When used in a patient, amounts effective for this use
will depend on the severity and course of the disease, disorder or
condition, previous therapy, the patient's health status and
response to the drugs, and the judgment of the treating
physician.
[0422] The term "homologous cysteine," as used herein refers to a
cysteine residue found with in a sequence position that is
homologous to that of cysteine 481 of Bruton's tyrosine kinase, as
defined herein. For example, cysteine 482 is the homologous
cysteine of the rat ortholog of Bruton's tyrosine kinase; cysteine
479 is the homologous cysteine of the chicken ortholog; and
cysteine 481 is the homologous cysteine in the zebra fish ortholog.
In another example, the homologous cysteine of TXK, a Tec kinase
family member related to Bruton's tyrosine, is Cys 350. Other
examples of kinases having homologous cysteines are shown in FIG.
1. See also the sequence alignments of tyrosine kinases (TK)
published on the world wide web at
kinase.com/human/kinome/phylogeny.html.
[0423] The term "identical," as used herein, refers to two or more
sequences or subsequences which are the same. In addition, the term
"substantially identical," as used herein, refers to two or more
sequences which have a percentage of sequential units which are the
same when compared and aligned for maximum correspondence over a
comparison window, or designated region as measured using
comparison algorithms or by manual alignment and visual inspection.
By way of example only, two or more sequences may be "substantially
identical" if the sequential units are about 60% identical, about
65% identical, about 70% identical, about 75% identical, about 80%
identical, about 85% identical, about 90% identical, or about 95%
identical over a specified region. Such percentages to describe the
"percent identity" of two or more sequences. The identity of a
sequence can exist over a region that is at least about 75-100
sequential units in length, over a region that is about 50
sequential units in length, or, where not specified, across the
entire sequence. This definition also refers to the complement of a
test sequence. By way of example only, two or more polypeptide
sequences are identical when the amino acid residues are the same,
while two or more polypeptide sequences are "substantially
identical" if the amino acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 amino acids in length,
over a region that is about 50 amino acids in length, or, where not
specified, across the entire sequence of a polypeptide sequence. In
addition, by way of example only, two or more polynucleotide
sequences are identical when the nucleic acid residues are the
same, while two or more polynucleotide sequences are "substantially
identical" if the nucleic acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 nucleic acids in
length, over a region that is about 50 nucleic acids in length, or,
where not specified, across the entire sequence of a polynucleotide
sequence.
[0424] The terms "inhibits", "inhibiting", or "inhibitor" of a
kinase, as used herein, refer to inhibition of enzymatic
phosphotransferase activity.
[0425] The term "irreversible inhibitor," as used herein, refers to
a compound that, upon contact with a target protein (e.g., a
kinase) causes the formation of a new covalent bond with or within
the protein, whereby one or more of the target protein's biological
activities (e.g., phosphotransferase activity) is diminished or
abolished notwithstanding the subsequent presence or absence of the
irreversible inhibitor.
[0426] The term "irreversible Btk inhibitor," as used herein,
refers to an inhibitor of Btk that can form a covalent bond with an
amino acid residue of Btk. In one embodiment, the irreversible
inhibitor of Btk can form a covalent bond with a Cys residue of
Btk; in particular embodiments, the irreversible inhibitor can form
a covalent bond with a Cys 481 residue (or a homolog thereof) of
Btk or a cysteine residue in the homologous corresponding position
of another tyrosine kinase.
[0427] The term "isolated," as used herein, refers to separating
and removing a component of interest from components not of
interest. Isolated substances can be in either a dry or semi-dry
state, or in solution, including but not limited to an aqueous
solution. The isolated component can be in a homogeneous state or
the isolated component can be a part of a pharmaceutical
composition that comprises additional pharmaceutically acceptable
carriers and/or excipients. By way of example only, nucleic acids
or proteins are "isolated" when such nucleic acids or proteins are
free of at least some of the cellular components with which it is
associated in the natural state, or that the nucleic acid or
protein has been concentrated to a level greater than the
concentration of its in vivo or in vitro production. Also, by way
of example, a gene is isolated when separated from open reading
frames which flank the gene and encode a protein other than the
gene of interest.
[0428] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0429] As used herein, the term "modulator" refers to a compound
that alters an activity of a molecule. For example, a modulator can
cause an increase or decrease in the magnitude of a certain
activity of a molecule compared to the magnitude of the activity in
the absence of the modulator. In certain embodiments, a modulator
is an inhibitor, which decreases the magnitude of one or more
activities of a molecule. In certain embodiments, an inhibitor
completely prevents one or more activities of a molecule. In
certain embodiments, a modulator is an activator, which increases
the magnitude of at least one activity of a molecule. In certain
embodiments the presence of a modulator results in an activity that
does not occur in the absence of the modulator.
[0430] The term "prophylactically effective amount," as used
herein, refers that amount of a composition applied to a patient
which will relieve to some extent one or more of the symptoms of a
disease, condition or disorder being treated. In such prophylactic
applications, such amounts may depend on the patient's state of
health, weight, and the like. It is considered well within the
skill of the art for one to determine such prophylactically
effective amounts by routine experimentation, including, but not
limited to, a dose escalation clinical trial.
[0431] The term "subject" as used herein, refers to an animal which
is the object of treatment, observation or experiment. By way of
example only, a subject may be, but is not limited to, a mammal
including, but not limited to, a human.
[0432] As used herein, the term "target activity" refers to a
biological activity capable of being modulated by a selective
modulator. Certain exemplary target activities include, but are not
limited to, binding affinity, signal transduction, enzymatic
activity, tumor growth, inflammation or inflammation-related
processes, and amelioration of one or more symptoms associated with
a disease or condition.
[0433] As used herein, the term "target protein" refers to a
molecule or a portion of a protein capable of being bound by a
selective binding compound. In certain embodiments, a target
protein is Btk.
[0434] The terms "treat," "treating" or "treatment", as used
herein, include alleviating, abating or ameliorating a disease or
condition symptoms, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, inhibiting
the disease or condition, e.g., arresting the development of the
disease or condition, relieving the disease or condition, causing
regression of the disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the
disease or condition. The terms "treat," "treating" or "treatment",
include, but are not limited to, prophylactic and/or therapeutic
treatments.
[0435] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response, such as inhibition of Btk,
in an assay that measures such response.
[0436] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
Pharmaceutical Compositions/Formulations
[0437] Pharmaceutical compositions may be formulated in a
conventional manner using one or more physiologically acceptable
carriers including excipients and auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically. Proper formulation is dependent upon the
route of administration chosen. Any of the well-known techniques,
carriers, and excipients may be used as suitable and as understood
in the art. A summary of pharmaceutical compositions described
herein may be found, for example, in Remington: The Science and
Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing
Company, 1995); Hoover, John E., Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A.
and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker,
New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug
Delivery Systems, Seventh Ed. (Lippincott Williams &
Wilkins1999), herein incorporated by reference in their
entirety.
[0438] A pharmaceutical composition, as used herein, refers to a
mixture of Compound 1 with other chemical components, such as
carriers, stabilizers, diluents, dispersing agents, suspending
agents, thickening agents, and/or excipients. The pharmaceutical
composition facilitates administration of the compound to a mammal.
In practicing the methods of treatment or use provided herein,
therapeutically effective amounts of Compound 1 are administered in
a pharmaceutical composition to a mammal having a disease,
disorder, or condition to be treated. Preferably, the mammal is a
human. A therapeutically effective amount can vary widely depending
on the severity of the disease, the age and relative health of the
subject, the potency of the compound used and other factors. The
compounds can be used singly or in combination with one or more
therapeutic agents as components of mixtures.
[0439] The term "pharmaceutical combination" as used herein, means
a product that results from the mixing or combining of more than
one active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. Compound 1 and
a co-agent, are both administered to a patient simultaneously in
the form of a single entity or dosage. The term "non-fixed
combination" means that the active ingredients, e.g. Compound 1 and
a co-agent, are administered to a patient as separate entities
either simultaneously, concurrently or sequentially with no
specific intervening time limits, wherein such administration
provides effective levels of the two compounds in the body of the
patient. The latter also applies to cocktail therapy, e.g. the
administration of three or more active ingredients.
[0440] In some embodiments, crystalline Compound 1 is
incoporporqated into pharmaceutical compositions to provide solid
oral dosage forms. In other embodiments, crystalline Compound 1 is
used to prepare pharmaceutical compositions other than oral solide
dosage forms. The pharmaceutical formulations described herein can
be administered to a subject by multiple administration routes,
including but not limited to, oral, parenteral (e.g., intravenous,
subcutaneous, intramuscular), intranasal, buccal, topical, rectal,
or transdermal administration routes. The pharmaceutical
formulations described herein include, but are not limited to,
aqueous liquid dispersions, self-emulsifying dispersions, solid
solutions, liposomal dispersions, aerosols, solid dosage forms,
powders, immediate release formulations, controlled release
formulations, fast melt formulations, tablets, capsules, pills,
delayed release formulations, extended release formulations,
pulsatile release formulations, multiparticulate formulations, and
mixed immediate and controlled release formulations.
[0441] Pharmaceutical compositions including a compound described
herein may be manufactured in a conventional manner, such as, by
way of example only, by means of conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping or compression processes.
Dosage Forms
[0442] The pharmaceutical compositions described herein can be
formulated for administration to a mammal via any conventional
means including, but not limited to, oral, parenteral (e.g.,
intravenous, subcutaneous, or intramuscular), buccal, intranasal,
rectal or transdermal administration routes. As used herein, the
term "subject" is used to mean an animal, preferably a mammal,
including a human or non-human. The terms patient and subject may
be used interchangeably.
[0443] Moreover, the pharmaceutical compositions described herein,
which include Compound 1 can be formulated into any suitable dosage
form, including but not limited to, solid oral dosage forms,
controlled release formulations, fast melt formulations,
effervescent formulations, tablets, powders, pills, capsules,
delayed release formulations, extended release formulations,
pulsatile release formulations, multiparticulate formulations, and
mixed immediate release and controlled release formulations.
[0444] Pharmaceutical preparations for oral use can be obtained by
mixing one or more solid excipient with one or more of the
compounds described herein, optionally grinding the resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients include, for example, fillers such as
sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth,
methylcellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or
others such as: polyvinylpyrrolidone (PVP or povidone) or calcium
phosphate. If desired, disintegrating agents may be added, such as
the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar,
or alginic acid or a salt thereof such as sodium alginate.
[0445] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0446] In some embodiments, the solid dosage forms disclosed herein
may be in the form of a tablet, (including a suspension tablet, a
fast-melt tablet, a bite-disintegration tablet, a
rapid-disintegration tablet, an effervescent tablet, or a caplet),
a pill, a powder (including a sterile packaged powder, a
dispensable powder, or an effervescent powder) a capsule (including
both soft or hard capsules, e.g., capsules made from animal-derived
gelatin or plant-derived HPMC, or "sprinkle capsules"), solid
dispersion, solid solution, bioerodible dosage form, controlled
release formulations, pulsatile release dosage forms,
multiparticulate dosage forms, pellets, granules, or an aerosol. In
other embodiments, the pharmaceutical formulation is in the form of
a powder. In still other embodiments, the pharmaceutical
formulation is in the form of a tablet, including but not limited
to, a fast-melt tablet. Additionally, pharmaceutical formulations
described herein may be administered as a single capsule or in
multiple capsule dosage form. In some embodiments, the
pharmaceutical formulation is administered in two, or three, or
four, capsules or tablets.
[0447] In some embodiments, solid dosage forms, e.g., tablets,
effervescent tablets, and capsules, are prepared by mixing
particles of Compound 1 with one or more pharmaceutical excipients
to form a bulk blend composition. When referring to these bulk
blend compositions as homogeneous, it is meant that the particles
of Compound 1 are dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective unit dosage forms, such as tablets, pills, and capsules.
The individual unit dosages may also include film coatings, which
disintegrate upon oral ingestion or upon contact with diluent.
These formulations can be manufactured by conventional
pharmacological techniques.
[0448] Conventional pharmacological techniques include, e.g., one
or a combination of methods: (1) dry mixing, (2) direct
compression, (3) milling, (4) dry or non-aqueous granulation, (5)
wet granulation, or (6) fusion. See, e.g., Lachman et al., The
Theory and Practice of Industrial Pharmacy (1986). Other methods
include, e.g., spray drying, pan coating, melt granulation,
granulation, fluidized bed spray drying or coating (e.g., wurster
coating), tangential coating, top spraying, tableting, extruding
and the like.
[0449] The pharmaceutical solid dosage forms described herein can
include Compound 1 and one or more pharmaceutically acceptable
additives such as a compatible carrier, binder, filling agent,
suspending agent, flavoring agent, sweetening agent, disintegrating
agent, dispersing agent, surfactant, lubricant, colorant, diluent,
solubilizer, moistening agent, plasticizer, stabilizer, penetration
enhancer, wetting agent, anti-foaming agent, antioxidant,
preservative, or one or more combination thereof. In still other
aspects, using standard coating procedures, such as those described
in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film
coating is provided around the formulation of Compound 1. In one
embodiment, some or all of the particles of the Compound 1 are
coated. In another embodiment, some or all of the particles of the
Compound 1 are microencapsulated. In still another embodiment, the
particles of the Compound 1 are not microencapsulated and are
uncoated.
[0450] Suitable carriers for use in the solid dosage forms
described herein include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerine, magnesium silicate, sodium
caseinate, soy lecithin, sodium chloride, tricalcium phosphate,
dipotassium phosphate, sodium stearoyl lactylate, carrageenan,
monoglyceride, diglyceride, pregelatinized starch,
hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate
stearate, sucrose, microcrystalline cellulose, lactose, mannitol
and the like.
[0451] Suitable filling agents for use in the solid dosage forms
described herein include, but are not limited to, lactose, calcium
carbonate, calcium phosphate, dibasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, cellulose powder, dextrose,
dextrates, dextran, starches, pregelatinized starch,
hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose
phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS),
sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride,
polyethylene glycol, and the like.
[0452] In order to release the Compound 1 from a solid dosage form
matrix as efficiently as possible, disintegrants are often used in
the formulation, especially when the dosage forms are compressed
with binder. Disintegrants help rupturing the dosage form matrix by
swelling or capillary action when moisture is absorbed into the
dosage form. Suitable disintegrants for use in the solid dosage
forms described herein include, but are not limited to, natural
starch such as corn starch or potato starch, a pregelatinized
starch such as National 1551 or Amijel.RTM., or sodium starch
glycolate such as Promogel.RTM. or Explotab.RTM., a cellulose such
as a wood product, methylcrystalline cellulose, e.g., Avicel.RTM.,
Avicel.RTM. PH101, Avicel.RTM. PH102, Avicel.RTM. PH105,
Elcema.RTM. P100, Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and
Solka-Floc.RTM., methylcellulose, croscarmellose, or a cross-linked
cellulose, such as cross-linked sodium carboxymethylcellulose
(Ac-Di-Sol.RTM.), cross-linked carboxymethylcellulose, or
cross-linked croscarmellose, a cross-linked starch such as sodium
starch glycolate, a cross-linked polymer such as crospovidone, a
cross-linked polyvinylpyrrolidone, alginate such as alginic acid or
a salt of alginic acid such as sodium alginate, a clay such as
Veegum.RTM. HV (magnesium aluminum silicate), a gum such as agar,
guar, locust bean, Karaya, pectin, or tragacanth, sodium starch
glycolate, bentonite, a natural sponge, a surfactant, a resin such
as a cation-exchange resin, citrus pulp, sodium lauryl sulfate,
sodium lauryl sulfate in combination starch, and the like. In some
embodiments provided herein, the disintegrating agent is selected
from the group consisting of natural starch, a pregelatinized
starch, a sodium starch, methylcrystalline cellulose,
methylcellulose, croscarmellose, croscarmellose sodium,
cross-linked sodium carboxymethylcellulose, cross-linked
carboxymethylcellulose, cross-linked croscarmellose, cross-linked
starch such as sodium starch glycolate, cross-linked polymer such
as crospovidone, cross-linked polyvinylpyrrolidone, sodium
alginate, a clay, or a gum. In some embodiments provided herein,
the disintegrating agent is croscarmellose sodium.
[0453] Binders impart cohesiveness to solid oral dosage form
formulations: for powder filled capsule formulation, they aid in
plug formation that can be filled into soft or hard shell capsules
and for tablet formulation, they ensure the tablet remaining intact
after compression and help assure blend uniformity prior to a
compression or fill step. Materials suitable for use as binders in
the solid dosage forms described herein include, but are not
limited to, carboxymethylcellulose, methylcellulose (e.g.,
Methocel.RTM.), hydroxypropylmethylcellulose (e.g. Hypromellose USP
Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate
(Aqoate HS-LF and HS), hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.),
microcrystalline dextrose, amylose, magnesium aluminum silicate,
polysaccharide acids, bentonites, gelatin,
polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone,
povidone, starch, pregelatinized starch, tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.),
lactose, a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone
(e.g., Povidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10,
and Povidone.RTM. K-12), larch arabogalactan, Veegum.RTM.,
polyethylene glycol, waxes, sodium alginate, and the like.
[0454] In general, binder levels of 20-70% are used in
powder-filled gelatin capsule formulations. Binder usage level in
tablet formulations varies whether direct compression, wet
granulation, roller compaction, or usage of other excipients such
as fillers which itself can act as moderate binder. Formulators
skilled in art can determine the binder level for the formulations,
but binder usage level of up to 70% in tablet formulations is
common.
[0455] Suitable lubricants or glidants for use in the solid dosage
forms described herein include, but are not limited to, stearic
acid, calcium hydroxide, talc, corn starch, sodium stearyl
fumerate, alkali-metal and alkaline earth metal salts, such as
aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates,
magnesium stearate, zinc stearate, waxes, Stearowet.RTM., boric
acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol or a methoxypolyethylene glycol such as
CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium
oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl
benzoate, magnesium or sodium lauryl sulfate, and the like. In some
embodiments provided herein, the lubricant is selected from the
group consisting of stearic acid, calcium hydroxide, talc, corn
starch, sodium stearyl fumerate, stearic acid, sodium stearates,
magnesium stearate, zinc stearate, and waxes. In some embodiments
provided herein, the lubricant is magnesium stearate.
[0456] Suitable diluents for use in the solid dosage forms
described herein include, but are not limited to, sugars (including
lactose, sucrose, and dextrose), polysaccharides (including
dextrates and maltodextrin), polyols (including mannitol, xylitol,
and sorbitol), cyclodextrins and the like. In some embodiments
provided herein, the diluent is selected from the group consisting
of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol,
xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium
sulfate, starches, modified starches, microcrystalline cellulose,
microcellulose, and talc. In some embodiments provided herein, the
diluent is microcrystalline cellulose.
[0457] The term "non water-soluble diluent" represents compounds
typically used in the formulation of pharmaceuticals, such as
calcium phosphate, calcium sulfate, starches, modified starches and
microcrystalline cellulose, and microcellulose (e.g., having a
density of about 0.45 g/cm.sup.3, e.g. Avicel, powdered cellulose),
and talc.
[0458] Suitable wetting agents for use in the solid dosage forms
described herein include, for example, oleic acid, glyceryl
monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds
(e.g., Polyquat 10.RTM.), sodium oleate, sodium lauryl sulfate,
magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and
the like.
[0459] Suitable surfactants for use in the solid dosage forms
described herein include, for example, sodium lauryl sulfate,
sorbitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts, glyceryl monostearate,
copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic.RTM. (BASF), and the like. In some embodiments provided
herein, the surfactant is selected from the group consisting of
sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene
sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl
monostearate, copolymers of ethylene oxide and propylene oxide. In
some embodiments provided herein, the surfactant is sodium lauryl
sulfate.
[0460] Suitable suspending agents for use in the solid dosage forms
described here include, but are not limited to,
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, polyethylene glycol, e.g., the
polyethylene glycol can have a molecular weight of about 300 to
about 6000, or about 3350 to about 4000, or about 7000 to about
5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium
carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, polysorbate-80,
hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum
tragacanth and gum acacia, guar gum, xanthans, including xanthan
gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone and the like.
[0461] Suitable antioxidants for use in the solid dosage forms
described herein include, for example, e.g., butylated
hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
[0462] It should be appreciated that there is considerable overlap
between additives used in the solid dosage forms described herein.
Thus, the above-listed additives should be taken as merely
exemplary, and not limiting, of the types of additives that can be
included in solid dosage forms described herein. The amounts of
such additives can be readily determined by one skilled in the art,
according to the particular properties desired.
[0463] In other embodiments, one or more layers of the
pharmaceutical formulation are plasticized. Illustratively, a
plasticizer is generally a high boiling point solid or liquid.
Suitable plasticizers can be added from about 0.01% to about 50% by
weight (w/w) of the coating composition. Plasticizers include, but
are not limited to, diethyl phthalate, citrate esters, polyethylene
glycol, glycerol, acetylated glycerides, triacetin, polypropylene
glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate,
stearic acid, stearol, stearate, and castor oil.
[0464] Compressed tablets are solid dosage forms prepared by
compacting the bulk blend of the formulations described above. In
various embodiments, compressed tablets which are designed to
dissolve in the mouth will include one or more flavoring agents. In
other embodiments, the compressed tablets will include a film
surrounding the final compressed tablet. In some embodiments, the
film coating can provide a delayed release of Compound 1 from the
formulation. In other embodiments, the film coating aids in patient
compliance (e.g., Opadry.RTM. coatings or sugar coating). Film
coatings including Opadry.RTM. typically range from about 1% to
about 3% of the tablet weight. In other embodiments, the compressed
tablets include one or more excipients.
[0465] A capsule may be prepared, for example, by placing the bulk
blend of the formulation of Compound 1 inside of a capsule. In some
embodiments, the formulations (non-aqueous suspensions and
solutions) are placed in a soft gelatin capsule. In other
embodiments, the formulations are placed in standard gelatin
capsules or non-gelatin capsules such as capsules comprising HPMC.
In other embodiments, the formulation is placed in a sprinkle
capsule, wherein the capsule may be swallowed whole or the capsule
may be opened and the contents sprinkled on food prior to eating.
In some embodiments, the therapeutic dose is split into multiple
(e.g., two, three, or four) capsules. In some embodiments, the
entire dose of the formulation is delivered in a capsule form.
[0466] In various embodiments, the particles of Compound 1 and one
or more excipients are dry blended and compressed into a mass, such
as a tablet, having a hardness sufficient to provide a
pharmaceutical composition that substantially disintegrates within
less than about 30 minutes, less than about 35 minutes, less than
about 40 minutes, less than about 45 minutes, less than about 50
minutes, less than about 55 minutes, or less than about 60 minutes,
after oral administration, thereby releasing the formulation into
the gastrointestinal fluid.
[0467] In another aspect, dosage forms may include
microencapsulated formulations. In some embodiments, one or more
other compatible materials are present in the microencapsulation
material. Exemplary materials include, but are not limited to, pH
modifiers, erosion facilitators, anti-foaming agents, antioxidants,
flavoring agents, and carrier materials such as binders, suspending
agents, disintegration agents, filling agents, surfactants,
solubilizers, stabilizers, lubricants, wetting agents, and
diluents.
[0468] Materials useful for the microencapsulation described herein
include materials compatible with Compound 1 which sufficiently
isolate the Compound 1 from other non-compatible excipients.
Materials compatible with Compound 1 are those that delay the
release of the compounds of Compound 1 in vivo.
[0469] Exemplary microencapsulation materials useful for delaying
the release of the formulations including compounds described
herein, include, but are not limited to, hydroxypropyl cellulose
ethers (HPC) such as Klucel.RTM. or Nisso HPC, low-substituted
hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl
cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat.RTM.,
Metolose SR, Methocel.RTM.-E, Opadry YS, PrimaFlo, Benecel MP824,
and Benecel MP843, methylcellulose polymers such as
Methocel.RTM.-A, hydroxypropylmethylcellulose acetate stearate
Aqoat (HF-LS, HF-LG,HF-MS) and Metolose.RTM., Ethylcelluloses (EC)
and mixtures thereof such as E461, Ethocel.RTM., Aqualon.RTM.-EC,
Surelease.RTM., Polyvinyl alcohol (PVA) such as Opadry AMB,
hydroxyethylcelluloses such as Natrosol.RTM.,
carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC)
such as Aqualon.RTM.-CMC, polyvinyl alcohol and polyethylene glycol
co-polymers such as Kollicoat IR.RTM., monoglycerides (Myverol),
triglycerides (KLX), polyethylene glycols, modified food starch,
acrylic polymers and mixtures of acrylic polymers with cellulose
ethers such as Eudragit.RTM. EPO, Eudragit.RTM. L30D-55,
Eudragit.RTM. FS 30D Eudragit.RTM. L100-55, Eudragit.RTM. L100,
Eudragit.RTM. S100, Eudragit.RTM. RD100, Eudragit.RTM. E100,
Eudragit.RTM. L12.5, Eudragit.RTM. S12.5, Eudragit.RTM. NE30D, and
Eudragit.RTM. NE 40D, cellulose acetate phthalate, sepifilms such
as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures
of these materials.
[0470] In still other embodiments, plasticizers such as
polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450,
PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid,
and triacetin are incorporated into the microencapsulation
material. In other embodiments, the microencapsulating material
useful for delaying the release of the pharmaceutical compositions
is from the USP or the National Formulary (NF). In yet other
embodiments, the microencapsulation material is Klucel. In still
other embodiments, the microencapsulation material is methocel.
[0471] Microencapsulated Compound 1 may be formulated by methods
known by one of ordinary skill in the art. Such known methods
include, e.g., spray drying processes, spinning disk-solvent
processes, hot melt processes, spray chilling methods, fluidized
bed, electrostatic deposition, centrifugal extrusion, rotational
suspension separation, polymerization at liquid-gas or solid-gas
interface, pressure extrusion, or spraying solvent extraction bath.
In addition to these, several chemical techniques, e.g., complex
coacervation, solvent evaporation, polymer-polymer incompatibility,
interfacial polymerization in liquid media, in situ polymerization,
in-liquid drying, and desolvation in liquid media could also be
used. Furthermore, other methods such as roller compaction,
extrusion/spheronization, coacervation, or nanoparticle coating may
also be used.
[0472] In one embodiment, the particles of Compound 1 are
microencapsulated prior to being formulated into one of the above
forms. In still another embodiment, some or most of the particles
are coated prior to being further formulated by using standard
coating procedures, such as those described in Remington's
Pharmaceutical Sciences, 20th Edition (2000).
[0473] In other embodiments, the solid dosage formulations of the
Compound 1 are plasticized (coated) with one or more layers.
Illustratively, a plasticizer is generally a high boiling point
solid or liquid. Suitable plasticizers can be added from about
0.01% to about 50% by weight (w/w) of the coating composition.
Plasticizers include, but are not limited to, diethyl phthalate,
citrate esters, polyethylene glycol, glycerol, acetylated
glycerides, triacetin, polypropylene glycol, polyethylene glycol,
triethyl citrate, dibutyl sebacate, stearic acid, stearol,
stearate, and castor oil.
[0474] In other embodiments, a powder including the formulations
with Compound 1 may be formulated to include one or more
pharmaceutical excipients and flavors. Such a powder may be
prepared, for example, by mixing the formulation and optional
pharmaceutical excipients to form a bulk blend composition.
Additional embodiments also include a suspending agent and/or a
wetting agent. This bulk blend is uniformly subdivided into unit
dosage packaging or multi-dosage packaging units.
[0475] In still other embodiments, effervescent powders are also
prepared in accordance with the present disclosure. Effervescent
salts have been used to disperse medicines in water for oral
administration. Effervescent salts are granules or coarse powders
containing a medicinal agent in a dry mixture, usually composed of
sodium bicarbonate, citric acid and/or tartaric acid. When salts of
the compositions described herein are added to water, the acids and
the base react to liberate carbon dioxide gas, thereby causing
"effervescence." Examples of effervescent salts include, e.g., the
following ingredients: sodium bicarbonate or a mixture of sodium
bicarbonate and sodium carbonate, citric acid and/or tartaric acid.
Any acid-base combination that results in the liberation of carbon
dioxide can be used in place of the combination of sodium
bicarbonate and citric and tartaric acids, as long as the
ingredients were suitable for pharmaceutical use and result in a pH
of about 6.0 or higher.
[0476] In some embodiments, the solid dosage forms described herein
can be formulated as enteric coated delayed release oral dosage
forms, i.e., as an oral dosage form of a pharmaceutical composition
as described herein which utilizes an enteric coating to affect
release in the small intestine of the gastrointestinal tract. The
enteric coated dosage form may be a compressed or molded or
extruded tablet/mold (coated or uncoated) containing granules,
powder, pellets, beads or particles of the active ingredient and/or
other composition components, which are themselves coated or
uncoated. The enteric coated oral dosage form may also be a capsule
(coated or uncoated) containing pellets, beads or granules of the
solid carrier or the composition, which are themselves coated or
uncoated.
[0477] The term "delayed release" as used herein refers to the
delivery so that the release can be accomplished at some generally
predictable location in the intestinal tract more distal to that
which would have been accomplished if there had been no delayed
release alterations. In some embodiments the method for delay of
release is coating. Any coatings should be applied to a sufficient
thickness such that the entire coating does not dissolve in the
gastrointestinal fluids at pH below about 5, but does dissolve at
pH about 5 and above. It is expected that any anionic polymer
exhibiting a pH-dependent solubility profile can be used as an
enteric coating in the methods and compositions described herein to
achieve delivery to the lower gastrointestinal tract. In some
embodiments the polymers described herein are anionic carboxylic
polymers. In other embodiments, the polymers and compatible
mixtures thereof, and some of their properties, include, but are
not limited to:
[0478] Shellac, also called purified lac, a refined product
obtained from the resinous secretion of an insect. This coating
dissolves in media of pH >7;
[0479] Acrylic polymers. The performance of acrylic polymers
(primarily their solubility in biological fluids) can vary based on
the degree and type of substitution. Examples of suitable acrylic
polymers include methacrylic acid copolymers and ammonium
methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE
(Rohm Pharma) are available as solubilized in organic solvent,
aqueous dispersion, or dry powders. The Eudragit series RL, NE, and
RS are insoluble in the gastrointestinal tract but are permeable
and are used primarily for colonic targeting. The Eudragit series E
dissolve in the stomach. The Eudragit series L, L-30D and S are
insoluble in stomach and dissolve in the intestine;
[0480] Cellulose Derivatives. Examples of suitable cellulose
derivatives are: ethyl cellulose; reaction mixtures of partial
acetate esters of cellulose with phthalic anhydride. The
performance can vary based on the degree and type of substitution.
Cellulose acetate phthalate (CAP) dissolves in pH >6. Aquateric
(FMC) is an aqueous based system and is a spray dried CAP
psuedolatex with particles<1 .mu.m. Other components in
Aquateric can include pluronics, Tweens, and acetylated
monoglycerides. Other suitable cellulose derivatives include:
cellulose acetate trimellitate (Eastman); methylcellulose
(Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate
(HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and
hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin
Etsu)). The performance can vary based on the degree and type of
substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S,
HP-55F grades are suitable. The performance can vary based on the
degree and type of substitution. For example, suitable grades of
hydroxypropylmethylcellulose acetate succinate include, but are not
limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which
dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
These polymers are offered as granules, or as fine powders for
aqueous dispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP
dissolves in pH>5, and it is much less permeable to water vapor
and gastric fluids.
[0481] In some embodiments, the coating can, and usually does,
contain a plasticizer and possibly other coating excipients such as
colorants, talc, and/or magnesium stearate, which are well known in
the art. Suitable plasticizers include triethyl citrate (Citroflex
2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl
phthalate, tributyl citrate, acetylated monoglycerides, glycerol,
fatty acid esters, propylene glycol, and dibutyl phthalate. In
particular, anionic carboxylic acrylic polymers usually will
contain 10-25% by weight of a plasticizer, especially dibutyl
phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are
employed to apply coatings. The coating thickness must be
sufficient to ensure that the oral dosage form remains intact until
the desired site of topical delivery in the intestinal tract is
reached.
[0482] Colorants, detackifiers, surfactants, antifoaming agents,
lubricants (e.g., carnuba wax or PEG) may be added to the coatings
besides plasticizers to solubilize or disperse the coating
material, and to improve coating performance and the coated
product.
[0483] In other embodiments, the formulations described herein,
which include Compound 1 are delivered using a pulsatile dosage
form. A pulsatile dosage form is capable of providing one or more
immediate release pulses at predetermined time points after a
controlled lag time or at specific sites. Many other types of
controlled release systems known to those of ordinary skill in the
art and are suitable for use with the formulations described
herein. Examples of such delivery systems include, e.g.,
polymer-based systems, such as polylactic and polyglycolic acid,
plyanhydrides and polycaprolactone; porous matrices,
nonpolymer-based systems that are lipids, including sterols, such
as cholesterol, cholesterol esters and fatty acids, or neutral
fats, such as mono-, di- and triglycerides; hydrogel release
systems; silastic systems; peptide-based systems; wax coatings,
bioerodible dosage forms, compressed tablets using conventional
binders and the like. See, e.g., Liberman et al., Pharmaceutical
Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al.,
Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753
(2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140,
5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175,
6,465,014 and 6,932,983, each of which is specifically incorporated
by reference.
[0484] In some embodiments, pharmaceutical formulations are
provided that include particles of Compound lat least one
dispersing agent or suspending agent for oral administration to a
subject. The formulations may be a powder and/or granules for
suspension, and upon admixture with water, a substantially uniform
suspension is obtained.
[0485] It is to be appreciated that there is overlap between the
above-listed additives used in the aqueous dispersions or
suspensions described herein, since a given additive is often
classified differently by different practitioners in the field, or
is commonly used for any of several different functions. Thus, the
above-listed additives should be taken as merely exemplary, and not
limiting, of the types of additives that can be included in
formulations described herein. The amounts of such additives can be
readily determined by one skilled in the art, according to the
particular properties desired.
Dosing and Treatment Regimens
[0486] In some embodiments, the amount of Compound 1 that is
administered to a mammal is from 300 mg/day up to, and including,
1000 mg/day. In some embodiments, the amount of Compound 1 that is
administered to a mammal is from 420 mg/day up to, and including,
840 mg/day. In some embodiments, the amount of Compound 1 that is
administered to a mammal is about 420 mg/day, about 560 mg/day, or
about 840 mg/day. In some embodiments, the amount of Compound 1
that is administered to a mammal is about 420 mg/day. In some
embodiments, the amount of Compound 1 that is administered to a
mammal is about 560 mg/day. In some embodiments, the AUC.sub.0-24
of Compound 1 is between about 150 and about 3500 ng*h/mL. In some
embodiments, the AUC.sub.0-24 of Compound 1 is between about 500
and about 1100 ng*h/mL. In some embodiments, Compound 1 is
administered orally. In some embodiments, Compound 1 is
administered once per day, twice per day, or three times per day.
In some embodiments, Compound 1 is administered daily. In some
embodiments, Compound 1 is administered once daily. In some
embodiments, Compound 1 is administered every other day. In some
embodiments, the Compound 1 is a maintenance therapy.
[0487] Compound 1 can be used in the preparation of medicaments for
the inhibition of Btk or a homolog thereof, or for the treatment of
diseases or conditions that would benefit, at least in part, from
inhibition of Btk or a homolog thereof, including a subject
diagnosed with a hematological malignancy. In addition, a method
for treating any of the diseases or conditions described herein in
a subject in need of such treatment, involves administration of
pharmaceutical compositions containing Compound 1, or a
pharmaceutically acceptable salt, pharmaceutically acceptable
N-oxide, pharmaceutically active metabolite, pharmaceutically
acceptable prodrug, or pharmaceutically acceptable solvate thereof,
in therapeutically effective amounts to said subject.
[0488] The compositions containing Compound 1 can be administered
for prophylactic, therapeutic, or maintenance treatment. In some
embodiments, compositions containing Compound 1 are administered
for therapeutic applications (e.g., administered to a subject
diagnosed with a hematological malignancy). In some embodiments,
compositions containing Compound 1 are administered for therapeutic
applications (e.g., administered to a subject susceptible to or
otherwise at risk of developing a hematological malignancy). In
some embodiments, compositions containing Compound 1 are
administered to a patient who is in remission as a maintenance
therapy.
[0489] Amounts of Compound 1 will depend on the use (e.g.,
therapeutic, prophylactic, or maintnenace). Amounts of Compound 1
will depend on severity and course of the disease or condition,
previous therapy, the patient's health status, weight, and response
to the drugs, and the judgment of the treating physician. It is
considered well within the skill of the art for one to determine
such therapeutically effective amounts by routine experimentation
(including, but not limited to, a dose escalation clinical trial).
In some embodiments, the amount of Compound 1 is from 300 mg/day up
to, and including, 1000 mg/day. In some embodiments, the amount of
Compound 1 is from 420 mg/day up to, and including, 840 mg/day. In
some embodiments, the amount of Compound 1 is from 400 mg/day up
to, and including, 860 mg/day. In some embodiments, the amount of
Compound 1 is about 360 mg/day. In some embodiments, the amount of
Compound 1 is about 420 mg/day. In some embodiments, the amount of
Compound 1 is about 560 mg/day. In some embodiments, the amount of
Compound 1 is about 840 mg/day. In some embodiments, the amount of
Compound 1 is from 2 mg/kg/day up to, and including, 13 mg/kg/day.
In some embodiments, the amount of Compound 1 is from 2.5 mg/kg/day
up to, and including, 8 mg/kg/day. In some embodiments, the amount
of Compound 1 is from 2.5 mg/kg/day up to, and including, 6
mg/kg/day. In some embodiments, the amount of Compound 1 is from
2.5 mg/kg/day up to, and including, 4 mg/kg/day. In some
embodiments, the amount of Compound 1 is about 2.5 mg/kg/day. In
some embodiments, the amount of Compound 1 is about 8
mg/kg/day.
[0490] In some embodiments, pharmaceutical compositions decribed
herein include about 140 mg of Compound 1. In some embodiments, a
capsule formulation is prepared that includes about 140 mg of
Compound 1. In some embodiments, 2, 3, 4, or 5 of the capsule
formulations are administered daily. In some embodiments, 3 or 4 of
the capsules are administered daily. In some embodiments, 3 of the
140 mg capsules are administered once daily. In some embodiments, 4
of the 140 mg capsules are administered once daily. In some
embodiments, the capsules are administered once daily. In other
embodiments, the capsules are administered multiple times a
day.
[0491] In some embodiments, Compound 1 is administered daily. In
some embodiments, Compound 1 is administered every other day.
[0492] In some embodiments, Compound 1 is administered once per
day. In some embodiments, Compound 1 is administered twice per day.
In some embodiments, Compound 1 is administered three times per
day. In some embodiments, Compound 1 is administered four times per
per day.
[0493] In some embodiments, Compound 1 is administered until
disease progression, unacceptable toxicity, or individual choice.
In some embodiments, Compound 1 is administered daily until disease
progression, unacceptable toxicity, or individual choice. In some
embodiments, Compound 1 is administered every other day until
disease progression, unacceptable toxicity, or individual
choice.
[0494] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the compounds may be
given continuously; alternatively, the dose of drug being
administered may be temporarily reduced or temporarily suspended
for a certain length of time (i.e., a "drug holiday"). The length
of the drug holiday can vary between 2 days and 1 year, including
by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7
days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50
days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days,
250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The
dose reduction during a drug holiday may be from 10%-100%,
including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or
100%.
[0495] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disease, disorder or condition is retained. Patients can, however,
require intermittent treatment on a long-term basis upon any
recurrence of symptoms.
[0496] The amount of a given agent that will correspond to such an
amount will vary depending upon factors such as the particular
compound, the severity of the disease, the identity (e.g., weight)
of the subject or host in need of treatment, but can nevertheless
be routinely determined in a manner known in the art according to
the particular circumstances surrounding the case, including, e.g.,
the specific agent being administered, the route of administration,
and the subject or host being treated. In general, however, doses
employed for adult human treatment will typically be in the range
of 0.02-5000 mg per day, or from about 1-1500 mg per day. The
desired dose may conveniently be presented in a single dose or as
divided doses administered simultaneously (or over a short period
of time) or at appropriate intervals, for example as two, three,
four or more sub-doses per day.
[0497] The pharmaceutical composition described herein may be in
unit dosage forms suitable for single administration of precise
dosages. In unit dosage form, the formulation is divided into unit
doses containing appropriate quantities of one or more compound.
The unit dosage may be in the form of a package containing discrete
quantities of the formulation. Non-limiting examples are packaged
tablets or capsules, and powders in vials or ampoules. Aqueous
suspension compositions can be packaged in single-dose
non-reclosable containers. Alternatively, multiple-dose reclosable
containers can be used, in which case it is typical to include a
preservative in the composition. By way of example only,
formulations for parenteral injection may be presented in unit
dosage form, which include, but are not limited to ampoules, or in
multi-dose containers, with an added preservative. In some
embodiments, each unit dosage form comprises 140 mg of Compound 1.
In some embodiments, an individual is administerd 1 unit dosage
form per day. In some embodiments, an individual is administerd 2
unit dosage forms per day. In some embodiments, an individual is
administerd 3 unit dosage forms per day. In some embodiments, an
individual is administerd 4 unit dosage forms per day.
[0498] The foregoing ranges are merely suggestive, as the number of
variables in regard to an individual treatment regime is large, and
considerable excursions from these recommended values are not
uncommon. Such dosages may be altered depending on a number of
variables, not limited to the activity of the compound used, the
disease or condition to be treated, the mode of administration, the
requirements of the individual subject, the severity of the disease
or condition being treated, and the judgment of the
practitioner.
[0499] Toxicity and therapeutic efficacy of such therapeutic
regimens can be determined by standard pharmaceutical procedures in
cell cultures or experimental animals, including, but not limited
to, the determination of the LD.sub.50 (the dose lethal to 50% of
the population) and the ED.sub.50 (the dose therapeutically
effective in 50% of the population). The dose ratio between the
toxic and therapeutic effects is the therapeutic index and it can
be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds exhibiting high therapeutic indices are preferred. The
data obtained from cell culture assays and animal studies can be
used in formulating a range of dosage for use in human. The dosage
of such compounds lies preferably within a range of circulating
concentrations that include the ED.sub.50 with minimal toxicity.
The dosage may vary within this range depending upon the dosage
form employed and the route of administration utilized.
Combination Therapy
[0500] In certain instances, it is appropriate to administer
Compound 1 in combination with another therapeutic agent.
[0501] In one embodiment, the compositions and methods described
herein are also used in conjunction with other therapeutic reagents
that are selected for their particular usefulness against the
condition that is being treated. In general, the compositions
described herein and, in embodiments where combinational therapy is
employed, other agents do not have to be administered in the same
pharmaceutical composition, and are, because of different physical
and chemical characteristics, administered by different routes. In
one embodiment, the initial administration is made according to
established protocols, and then, based upon the observed effects,
the dosage, modes of administration and times of administration,
further modified.
[0502] In various embodiments, the compounds are administered
concurrently (e.g., simultaneously, essentially simultaneously or
within the same treatment protocol) or sequentially, depending upon
the nature of the disease, the condition of the patient, and the
actual choice of compounds used. In certain embodiments, the
determination of the order of administration, and the number of
repetitions of administration of each therapeutic agent during a
treatment protocol, is based upon evaluation of the disease being
treated and the condition of the patient.
[0503] For combination therapies described herein, dosages of the
co-administered compounds vary depending on the type of co-drug
employed, on the specific drug employed, on the disease or
condition being treated and so forth.
[0504] The individual compounds of such combinations are
administered either sequentially or simultaneously in separate or
combined pharmaceutical formulations. In one embodiment, the
individual compounds will be administered simultaneously in a
combined pharmaceutical formulation. Appropriate doses of known
therapeutic agents will be appreciated by those skilled in the
art.
[0505] The combinations referred to herein are conveniently
presented for use in the form of a pharmaceutical compositions
together with a pharmaceutically acceptable diluent(s) or
carrier(s).
[0506] Disclosed herein, in certain embodiments, is a method for
treating a cancer in an individual in need thereof, comprising:
administering to the individual an amount of Compound 1. In some
embodiments, the method further comprises administering a second
cancer treatment regimen.
[0507] In some embodiments, administering a Btk inhibitor before a
second cancer treatment regimen reduces immune-mediated reactions
to the second cancer treatment regimen. In some embodiments,
administering Compound lbefore ofatumumab reduces immune-mediated
reactions to ofatumumab.
[0508] In some embodiments, the second cancer treatment regimen
comprises a chemotherapeutic agent, a steroid, an immunotherapeutic
agent, a targeted therapy, or a combination thereof. In some
embodiments, the second cancer treatment regimen comprises a B cell
receptor pathway inhibitor. In some embodiments, the B cell
receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor,
a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K
inhibitor, a Blnk inhibitor, a PLC.gamma. inhibitor, a PKC.beta.
inhibitor, or a combination thereof. In some embodiments, the
second cancer treatment regimen comprises an antibody, B cell
receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor,
an mTOR inhibitor, a radioimmunotherapeutic, a DNA damaging agent,
a proteosome inhibitor, a Cyp3A4 inhibitor, a histone deacetylase
inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an
Hsp90 inhibitor, a telomerase inhibitor, a Jak1/2 inhibitor, a
protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a
combination thereof.
[0509] In some embodiments, the second cancer treatment regimen
comprises chlorambucil, ifosphamide, doxorubicin, mesalazine,
thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine,
fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab,
dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab,
bortezomib, pentostatin, endostatin, or a combination thereof.
[0510] In some embodiments, the second cancer treatment regimen
comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and
prednisone, and optionally, rituximab.
[0511] In some embodiments, the second cancer treatment regimen
comprises bendamustine, and rituximab.
[0512] In some embodiments, the second cancer treatment regimen
comprises fludarabine, cyclophosphamide, and rituximab.
[0513] In some embodiments, the second cancer treatment regimen
comprises cyclophosphamide, vincristine, and prednisone, and
optionally, rituximab.
[0514] In some embodiments, the second cancer treatment regimen
comprises etoposide, doxorubicin, vinristine, cyclophosphamide,
prednisolone, and optionally, rituximab.
[0515] In some embodiments, the second cancer treatment regimen
comprises dexamethasone and lenalidomide.
[0516] In some embodiments, the second cancer treatment comprises a
proteasome inhibitor. In some embodiments, the second treatment
comprises bortezomib. In some embodiments, the second cancer
treatment comprises an epoxyketone. In some embodiments, the second
cancer treatment comprises epoxomicin. In some embodiments, the
second cancer treatment comprises a tetrapeptide epoxyketone In
some embodiments, the second cancer treatment comprises
carfilzomib. In some embodiments, the second cancer treatment
comprises disulfram, epigallocatechin-3-gallate, salinosporamide A,
ONX 0912m CEP-18770, MLN9708, or MG132.
[0517] In some embodiments, the second cancer treatment comprises a
Cyp3A4 inhibitor. In some embodiments, the second cancer treatment
comprises indinavir, nelfinavir, ritonavir, clarithromycin,
itraconazole, ketoconazole, nefazodone. In some embodiments, the
second cancer treatment comprises ketoconazole.
[0518] In some embodiments, the second cancer treatment comprises a
Janus Kinase (JAK) inhibitor. In some embodiments, the second
treatment comprises Lestaurtinib, Tofacitinib, Ruxolitinib, CYT387,
Baricitinib or Pacritinib.
[0519] In some embodiments, the second cancer treatment comprises a
histone deacetylase inhibitor (HDAC inhibitor, HDI). In some
embodiments, the second cancer treatment comprises a hydroxamic
acid (or hydroxamate), such as trichostatin A, vorinostat (SAHA),
belinostat (PXD101), LAQ824, and panobinostat (LBH589), a cyclic
tetrapeptide, such as trapoxin B, a depsipeptide, a benzamide, such
as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), an
electrophilic ketone, or an aliphatic acid compound, such as
phenylbutyrate and valproic acid,
[0520] Additional cancer treatment regimens include Nitrogen
Mustards such as for example, bendamustine, chlorambucil,
chlormethine, cyclophosphamide, ifosfamide, melphalan,
prednimustine, trofosfamide; Alkyl Sulfonates like busulfan,
mannosulfan, treosulfan; Ethylene Imines like carboquone, thiotepa,
triaziquone; Nitrosoureas like carmustine, fotemustine, lomustine,
nimustine, ranimustine, semustine, streptozocin; Epoxides such as
for example, etoglucid; Other Alkylating Agents such as for example
dacarbazine, mitobronitol, pipobroman, temozolomide; Folic Acid
Analogues such as for example methotrexate, permetrexed,
pralatrexate, raltitrexed; Purine Analogs such as for example
cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine,
tioguanine; Pyrimidine Analogs such as for example azacitidine,
capecitabine, carmofur, cytarabine, decitabine, fluorouracil,
gemcitabine, tegafur; Vinca Alkaloids such as for example
vinblastine, vincristine, vindesine, vinflunine, vinorelbine;
Podophyllotoxin Derivatives such as for example etoposide,
teniposide; Colchicine derivatives such as for example demecolcine;
Taxanes such as for example docetaxel, paclitaxel, paclitaxel
poliglumex; Other Plant Alkaloids and Natural Products such as for
example trabectedin; Actinomycines such as for example
dactinomycin; Antracyclines such as for example aclarubicin,
daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone,
pirarubicin, valrubicin, zorubincin; Other Cytotoxic Antibiotics
such as for example bleomycin, ixabepilone, mitomycin, plicamycin;
Platinum Compounds such as for example carboplatin, cisplatin,
oxaliplatin, satraplatin; Methylhydrazines such as for example
procarbazine; Sensitizers such as for example aminolevulinic acid,
efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfin;
Protein Kinase Inhibitors such as for example dasatinib, erlotinib,
everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib,
sorafenib, sunitinib, temsirolimus; Other Antineoplastic Agents
such as for example alitretinoin, altretamine, amzacrine,
anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib,
celecoxib, denileukin diftitox, estramustine, hydroxycarbamide,
irinotecan, lonidamine, masoprocol, miltefosein, mitoguazone,
mitotane, oblimersen, pegaspargase, pentostatin, romidepsin,
sitimagene ceradenovec, tiazofurine, topotecan, tretinoin,
vorinostat; Estrogens such as for example diethylstilbenol,
ethinylestradiol, fosfestrol, polyestradiol phosphate; Progestogens
such as for example gestonorone, medroxyprogesterone, megestrol;
Gonadotropin Releasing Hormone Analogs such as for example
buserelin, goserelin, leuprorelin, triptorelin; Anti-Estrogens such
as for example fulvestrant, tamoxifen, toremifene; Anti-Androgens
such as for example bicalutamide, flutamide, nilutamide, Enzyme
Inhibitors, aminoglutethimide, anastrozole, exemestane, formestane,
letrozole, vorozole; Other Hormone Antagonists such as for example
abarelix, degarelix; Immunostimulants such as for example histamine
dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex,
thymopentin; Immunosuppressants such as for example everolimus,
gusperimus, leflunomide, mycophenolic acid, sirolimus; Calcineurin
Inhibitors such as for example ciclosporin, tacrolimus; Other
Immunosuppressants such as for example azathioprine, lenalidomide,
methotrexate, thalidomide; and Radiopharmaceuticals such as for
example, iobenguane.
[0521] Additional cancer treatment regimens include interferons,
interleukins, Tumor Necrosis Factors, Growth Factors, or the
like.
[0522] Additional cancer treatment regimens include
Immunostimulants such as for example ancestim, filgrastim,
lenograstim, molgramostim, pegfilgrastim, sargramostim; Interferons
such as for example interferon alfa natural, interferon alfa-2a,
interferon alfa-2b, interferon alfacon-1, interferon alfa-nl,
interferon beta natural, interferon beta-1a, interferon beta-lb,
interferon gamma, peginterferon alfa-2a, peginterferon alfa-2b;
Interleukins such as for example aldesleukin, oprelvekin; Other
Immunostimulants such as for example BCG vaccine, glatiramer
acetate, histamine dihydrochloride, immunocyanin, lentinan,
melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor,
poly I:C, poly ICLC, roquinimex, tasonermin, thymopentin;
Immunosuppressants such as for example abatacept, abetimus,
alefacept, antilymphocyte immunoglobulin (horse), antithymocyte
immunoglobulin (rabbit), eculizumab, efalizumab, everolimus,
gusperimus, leflunomide, muromab-CD3, mycophenolic acid,
natalizumab, sirolimus; TNF alpha Inhibitors such as for example
adalimumab, afelimomab, certolizumab pegol, etanercept, golimumab,
infliximab; Interleukin Inhibitors such as for example anakinra,
basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept,
tocilizumab, ustekinumab; Calcineurin Inhibitors such as for
example ciclosporin, tacrolimus; Other Immunosuppressants such as
for example azathioprine, lenalidomide, methotrexate,
thalidomide.
[0523] Additional cancer treatment regimens include Adalimumab,
Alemtuzumab, Basiliximab, Bevacizumab, Cetuximab, Certolizumab
pegol, Daclizumab, Eculizumab, Efalizumab, Gemtuzumab, Ibritumomab
tiuxetan, Infliximab, Muromonab-CD3, Natalizumab, Panitumumab,
Ranibizumab, Rituximab, Tositumomab, Trastuzumab, or the like, or a
combination thereof.
[0524] Additional cancer treatment regimens include Monoclonal
Antibodies such as for example alemtuzumab, bevacizumab,
catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab,
panitumumab, rituximab, trastuzumab, Immunosuppressants,
eculizumab, efalizumab, muromab-CD3, natalizumab; TNF alpha
Inhibitors such as for example adalimumab, afelimomab, certolizumab
pegol, golimumab, infliximab, Interleukin Inhibitors, basiliximab,
canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab,
Radiopharmaceuticals, ibritumomab tiuxetan, tositumomab; Others
Monoclonal Antibodies such as for example abagovomab, adecatumumab,
alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET
monoclonal antibody MetMab, apolizumab, apomab, arcitumomab,
basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab
vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab,
dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab,
ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab,
ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab,
inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab,
lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab,
monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab,
oregovomab, pertuzumab, ramacurimab, ranibizumab, siplizumab,
sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab,
tucotuzumab celmoleukin, veltuzumab, visilizumab, volociximab,
zalutumumab.
[0525] Additional cancer treatment regimens include agents that
affect the tumor micro-enviroment such as cellular signaling
network (e.g. phosphatidylinositol 3-kinase (PI3K) signaling
pathway, signaling from the B-cell receptor and the IgE receptor).
In some embodiments, the second agent is a PI3K signaling inhibitor
or a syc kinase inhibitor. In one embodiment, the syk inhibitor is
R788. In another embodiment is a PKCy inhibitor such as by way of
example only, enzastaurin.
[0526] Examples of agents that affect the tumor micro-environment
include PI3K signaling inhibitor, syc kinase inhibitor, Protein
Kinase Inhibitors such as for example dasatinib, erlotinib,
everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib,
sorafenib, sunitinib, temsirolimus; Other Angiogenesis Inhibitors
such as for example GT-111, JI-101, R1530; Other Kinase Inhibitors
such as for example AC220, AC480, ACE-041, AMG 900, AP24534,
Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762,
AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, BI
811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607,
BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036,
dinaciclib, dovitinib lactate, E7050, EMD 1214063, ENMD-2076,
fostamatinib disodium, GSK2256098, GSK690693, INCB18424, INNO-406,
JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265,
MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937,
ON 01919.Na, OSI-027, OSI-930, Btk inhibitor, PF-00562271,
PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502,
PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763,
ramucirumab, regorafenib, RO5185426, SAR103168, SCH 727965,
SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232,
TTP607, XL147, XL228, XL281RO5126766, XL418, XL765.
[0527] Further examples of anti-cancer agents for use in
combination with a Btk inhibitor compound include inhibitors of
mitogen-activated protein kinase signaling, e.g., U0126, PD98059,
PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,
wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and
antibodies (e.g., rituxan).
[0528] Other anti-cancer agents that can be employed in combination
with a Btk inhibitor compound include Adriamycin, Dactinomycin,
Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole
hydrochloride; acronine; adozelesin; aldesleukin; altretamine;
ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;
anastrozole; anthramycin; asparaginase; asperlin; azacitidine;
azetepa; azotomycin; batimastat; benzodepa; bicalutamide;
bisantrene hydrochloride; bisnafide dimesylate; bizelesin;
bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
cactinomycin; calusterone; caracemide; carbetimer; carboplatin;
carmustine; carubicin hydrochloride; carzelesin; cedefingol;
chlorambucil; cirolemycin; cladribine; crisnatol mesylate;
cyclophosphamide; cytarabine; dacarbazine; daunorubicin
hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine
mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;
iimofosine; interleukin Il (including recombinant interleukin II,
or rlL2), interferon alfa-2a; interferon alfa-2b; interferon
alfa-nl; interferon alfa-n3; interferon beta-1 a; interferon
gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide
acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; my cophenolic acid; nocodazoie; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin
hydrochloride.
[0529] Other anti-cancer agents that can be employed in combination
with a Btk inhibitor compound include: 20-epi-1, 25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunorunicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-such as for example growth factor-1 receptor inhibitor;
interferon agonists; interferons; interleukins; iobenguane;
iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylerie conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain
antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate;
sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0530] Yet other anticancer agents that can be employed in
combination with a Btk inhibitor compound include alkylating
agents, antimetabolites, natural products, or hormones, e.g.,
nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,
chlorambucil, etc.), alkyl sulfonates (e.g., busulfan),
nitrosoureas (e.g., carmustine, lomusitne, ete.), or triazenes
(decarbazine, etc.). Examples of antimetabolites include but are
not limited to folic acid analog (e.g., methotrexate), or
pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,
mercaptopurine, thioguanine, pentostatin).
[0531] Examples of alkylating agents that can be employed in
combination a Btk inhibitor compound include, but are not limited
to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,
chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines
(e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g.,
busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine,
streptozocin, etc.), or triazenes (decarbazine, ete.). Examples of
antimetabolites include, but are not limited to folic acid analog
(e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,
floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,
thioguanine, pentostatin.
[0532] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilized microtubules and which can be
used in combination with a Btk inhibitor compound include without
limitation the following marketed drugs and drugs in development:
Erbulozole (also known as R-55104), Dolastatin 10 (also known as
DLS-10 and NSC-376128), Mivobulin isethionate (also known as
CI-980), Vincristine, NSC-639829, Discodermolide (also known as
NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins
(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as
Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,
Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and
Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793
and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,
Epothilone C (also known as desoxyepothilone A or dEpoA),
Epothilone D (also referred to as KOS-862, dEpoB, and
desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B
N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,
21-aminoepothilone B (also known as BMS-310705),
21-hydroxyepothilone D (also known as Desoxyepothilone F and
dEpoF), 26-fluoroepothilone), Auristatin PE (also known as
NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P
(Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known
as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877
(Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198
(Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,
also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also
known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known
as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A),
Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as
NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and
TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261
and WHI-261), H10 (Kansas State University), H16 (Kansas State
University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313
(Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also
known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of
Medicine, also known as MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
also known as MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (also
known as NSC-698666), 3-lAABE (Cytoskeleton/Mt. Sinai School of
Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as
T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and
Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131
(Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620
(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis),
A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),
Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099
(Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes), and SSR-250411
(Sanofi).
[0533] Where the individual is suffering from or at risk of
suffering from an autoimmune disease, an inflammatory disease, or
an allergy disease, Compound 1 can be used in with one or more of
the following therapeutic agents in any combination:
immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin,
methotrexate, cyclophosphamide, azathioprine, mercaptopurine,
mycophenolate, or FTY720), glucocorticoids (e.g., prednisone,
cortisone acetate, prednisolone, methylprednisolone, dexamethasone,
betamethasone, triamcinolone, beclometasone, fludrocortisone
acetate, deoxycorticosterone acetate, aldosterone), non-steroidal
anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,
2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or
sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,
celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold
thiomalate, aurofin, sulfasalazine, hydroxychloroquinine,
minocycline, TNF-.alpha. binding proteins (e.g., infliximab,
etanercept, or adalimumab), abatacept, anakinra, interferon-.beta.,
interferon-.gamma., interleukin-2, allergy vaccines,
antihistamines, antileukotrienes, beta-agonists, theophylline, or
anticholinergics.
Kits/Articles of Manufacture
[0534] For use in the therapeutic methods of use described herein,
kits and articles of manufacture are also described herein. Such
kits include a carrier, package, or container that is
compartmentalized to receive one or more containers such as vials,
tubes, and the like, each of the container(s) comprising one of the
separate elements to be used in a method described herein. Suitable
containers include, for example, bottles, vials, syringes, and test
tubes. In one embodiment, the containers are formed from a variety
of materials such as glass or plastic.
[0535] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products include, e.g., U.S. Pat. No. 5,323,907.
Examples of pharmaceutical packaging materials include, but are not
limited to, blister packs, bottles, tubes, bags, containers,
bottles, and any packaging material suitable for a selected
formulation and intended mode of administration and treatment.
[0536] In some embodiments, the compounds or compositions described
herein, are presented in a package or dispenser device which may
contain one or more unit dosage forms containing the active
ingredient. The compound or composition described herein is
packaged alone, or packaged with another compound or another
ingredient or additive. In some embodiements, the package contains
one or more containers filled with one or more of the ingredients
of the pharmaceutical compositions. In some embodiments, the
package comprises metal or plastic foil, such as a blister pack. In
some embodiments, the package or dispenser device is accompanied by
instructions for administration, such as instructions for
administering the compounds or compositions for treating a
neoplastic disease. In some embodiments, the package or dispenser
is accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. In some embodiments, such notice, for
example, is the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. In some embodiments, compositions include a compound
described herein formulated in a compatible pharmaceutical carrier
are prepared, placed in an appropriate container, and labeled for
treatment of an indicated condition.
[0537] For example, the container(s) include Compound 1, optionally
in a composition or in combination with another agent as disclosed
herein. Such kits optionally include an identifying description or
label or instructions relating to its use in the methods described
herein.
[0538] A kit typically includes labels listing contents and/or
instructions for use, and package inserts with instructions for
use. A set of instructions will also typically be included.
[0539] In one embodiment, a label is on or associated with the
container. In one embodiment, a label is on a container when
letters, numbers or other characters forming the label are
attached, molded or etched into the container itself; a label is
associated with a container when it is present within a receptacle
or carrier that also holds the container, e.g., as a package
insert. In one embodiment, a label is used to indicate that the
contents are to be used for a specific therapeutic application. The
label also indicates directions for use of the contents, such as in
the methods described herein.
[0540] In certain embodiments, the pharmaceutical compositions are
presented in a pack or dispenser device which contains one or more
unit dosage forms containing a compound provided herein. The pack,
for example, contains metal or plastic foil, such as a blister
pack. In one embodiment, the pack or dispenser device is
accompanied by instructions for administration. In one embodiment,
the pack or dispenser is also accompanied with a notice associated
with the container in form prescribed by a governmental agency
regulating the manufacture, use, or sale of pharmaceuticals, which
notice is reflective of approval by the agency of the form of the
drug for human or veterinary administration. Such notice, for
example, is the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. In one embodiment, compositions containing a compound
provided herein formulated in a compatible pharmaceutical carrier
are also prepared, placed in an appropriate container, and labeled
for treatment of an indicated condition.
EXAMPLES
[0541] The following ingredients, formulations, processes and
procedures for practicing the methods disclosed herein correspond
to that described above.
Example 1
Preparation of Crystalline Forms of
14(R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pip-
eridin-1-yl)prop-2-en-1-one (Compound 1)
[0542] Form A--Route 1:
[0543] Amorphous Compound 1 (ca. 15 mg) was measured into a vial.
Ten volumes (150 .mu.l) of solvent [methyl tert-butyl ether (MTBE),
diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate,
isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl
ketone (MEK), acetone, methanol, nitromethane, 10% aqueous acetone,
or 10% aqueous isopropyl alcohol] were added to the vial. The vial
was sealed and placed in a shaker at 50.degree. C. for one hour. If
a slurry was obtained, an additional thirty volumes (total of 600
.mu.l) of solvent was added, then the slurry was returned to
50.degree. C. for another hour. If the sample remained as a slurry
at this point, no further solvent was added. The solution/slurry
was stirred at 50.degree. C. for one hour, then cooled to 0.degree.
C. at 0.1.degree. C./min, then held at 0.degree. C. overnight. If a
slurry was obtained, the solids were filtered under vacuum to
provide Compound 1, Form A; the solution was returned to ambient
temperature for slow evaporation through a pin-hole to furnish
Compound 1, Form A.
[0544] Form A--Route 2:
[0545] Amorphous Compound 1 (20 mg) was added to a vial, followed
by solvent [heptanes (10 volumes), dioxane (1 volume), toluene (10
volumes), MTBE (10 volumes), DIPE (10 volumes), anisole (1 volume),
ethyl acetate (10 volumes), isopropyl acetate (10 volumes),
tetrahydrofuran (1 volume), DCM (1 volume), MIBK (10 volumes), MEK
(10 volumes), acetone (10 volumes), methanol (10 volumes), ethanol
(10 volumes), acetonitrile (10 volumes), nitromethane (1 volume),
water (10 volumes), or 10% aqueous isopropyl alcohol (1 volume)].
The sealed vial was placed in a maturation chamber (cycling between
50.degree. C. and ambient for four hours each) for five days before
the solids were filtered under vacuum to provide Compound 1, Form
A.
[0546] In some embodiments, amorphous Compound 1 is prepared by
dissolving Compound 1, Form A (ca. 500 mg) in 10 ml dichloromethane
(DCM). The solvent was removed by rotary evaporation, occurring
rapidly enough to prevent crystallization to provide amorphous
Compound 1.
[0547] Form A--Route 3:
[0548] In a clean round bottom flask, 12.0 grams of Compound 1 were
dissolved in 120 ml of methanol by heating to 45.degree. C. with
magnetic stirring. To the warm solution of dissolved Compound 1 was
added 72 ml of water over 45 min, maintaining the internal
temperature at 45.degree. C. The solution slowly became a slurry
and was stirred for 3 hours at the elevated temperature. A sample
of the slurry was drawn, filtered and dried. The slurry was allowed
to cool to room temperature and stirred for at least 16 hours.
Another sample of the slurry was drawn, filtered and dried. The
solids were filtered, washed with 50 ml of a 3:2 mixture of
methanol: water, and dried on the filter for 40 hours. Yield 9.6
grams of Form A (melting points: 1.sup.st sample .about.152.degree.
C., 2.sup.nd sample .about.154.degree. C., main lot
.about.154.degree. C.).
[0549] Form A was also attained in an analogous manner using
aqueous acetone, ethanol, and n-propanol.
[0550] Form B--Route 1:
[0551] Compound 1, Form A (ca. 100 mg) was weighed into a vessel
and dissolved in methanol (2 ml). The solution was heated to
50.degree. C. to ensure full dissolution, then cooled to 5.degree.
C. Water was added to the solution at 5.degree. C. (200 .mu.l at a
time until sample became cloudy, totalling 1000 .mu.l ). Seeds of
Compound 1, Form C were added immediately upon appearance of
cloudiness. The slurry was stirred at 5.degree. C. for one day. An
aliquot was removed by pipette for analysis by XRPD, keeping the
bulk of the sample in the same conditions. The XRPD analysis
highlighted the low crystallinity of the material, so the sample
was held at 5.degree. C. for an additional three days. After this
time, re-analysis of an aliquot of the sample showed the material
to have converted to Compound 1, Form B. The sample was isolated by
filtration under vacuum to provide Compound 1, Form B.
[0552] Form B--Route 2:
[0553] Compound 1, Form A (ca. 500 mg) was weighed into a vessel
and dissolved in methanol (4 ml) at 50.degree. C. The solution was
cooled to 25.degree. C., remaining in solution. Water was added
(500 .mu.l of water added at a time, 2 ml in total) until the
solution became cloudy. The slurry was stirred for ten minutes. An
aliquot was removed by pipette to assess the material by XRPD while
the sample stirred at 25.degree. C. for an hour; however, the
material was of very low crystallinity. After the hour stirring at
25.degree. C., the sample was placed at 5.degree. C. for three
days. After this time, another aliquot was removed by pipette for
XRPD analysis. The remainder of the slurry was filtered under
vacuum and dried at 25.degree. C. under vacuum overnight to provide
Compound 1, Form B.
[0554] Form C:
[0555] In a clean round bottom flask, 2.0 grams of Compound 1 were
suspended in 25 ml of methanol and heated to 50.degree. C. The warm
solution of dissolved Compound 1 was filtered into a clean round
bottom flask. The polished solution was allowed to cool to room
temperature with magnetic stirring. The solution slowly became a
slurry and was stirred for over 14 hours. The solids were filtered,
washed with 5 mL of methanol, and dried on the filter for 20 hours,
then at 50.degree. C. in a vacuum-oven for 8 hours. Yield 1.4 grams
of Form C (melting point=.about.132.degree. C.).
[0556] Form D:
[0557] A dry mixture (ca. 5 mg of each component) was prepared
using two of Form A, Form B, or Form C of Compound 1. A slurry made
from amorphous Compound 1 in MIBK was filtered to obtain a
saturated solution. Ten volumes (100 .mu.l) of the saturated
solution were added to the dry mixture to prepare a new slurry. The
slurry was stored at 5.degree. C. for three days before filtration
under vacuum to provide Compound 1, Form D.
[0558] Form E:
[0559] Amorphous compound 1 (20 mg) was added to a vial, followed
by seeds of Compound 1, Form C (ca. 5 mg). Ten volumes of toluene
(200 .mu.l) were added to the vial to prepare a slurry. The vial
was sealed and matured (cycling between 50.degree. C. and ambient
temperature for four hours each) for one day. An aliquot was
removed by pipette for analysis by XRPD, TGA, and DSC; data were
consistent with Compound 1, Form E. However, this compound was
found to have converted to Compound 1, Form A after standing at
ambient temperature overnight and drying at 40.degree. C. in vacuo
for one day.
[0560] Form F:
[0561] In a clean 20 ml scintillation vial, 200 mgs of Compound 1
and 50 mgs of activated charcoal were suspended in 4 ml of methanol
and heated to 50.degree. C. The resulting mixture was stirred at
50.degree. C. for 2.5 hours. The warm solution of dissolved
Compound 1 was filtered though a syringe filter into a new, clean
20 ml vial, removing the charcoal. The polished solution was
allowed to cool to room temperature. Without stirring, the solution
was aged for over a week when some crystals were observed to have
formed. After 6 more weeks the bottom of the vial was covered with
large crystals. The crystals were maintained under the
supersaturated methanol solution for analysis.
Example 2
X-Ray Powder Diffraction (XRPD)
[0562] X-Ray powder diffraction patterns were collected on a Bruker
AXS C2 GADDS or Bruker AXS D8 diffractometer.
[0563] Bruker AXS C2 GADDS
[0564] X-Ray Powder Diffraction patterns were collected on a Bruker
AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA),
automated XYZ stage, laser video microscope for auto-sample
positioning and a HiStar 2-dimensional area detector. X-ray optics
consists of a single Gobel multilayer mirror coupled with a pinhole
collimator of 0.3 mm. A weekly performance check is carried out
using a certified standard NIST 1976 Corundum (flat plate). The
beam divergence, i.e. the effective size of the X-ray beam on the
sample, was approximately 4 mm. A .theta.-.theta. continuous scan
mode was employed with a sample-detector distance of 20 cm which
gives an effective 2.theta. range of 3.2.degree.-29.7.degree..
Typically the sample would be exposed to the X-ray beam for 120
seconds. The software used for data collection was GADDS for WNT
4.1.16 and the data were analysed and presented using Diffrac Plus
EVA v11.0.0.2 or v13.0.0.2.
[0565] Ambient Conditions
[0566] Samples run under ambient conditions were prepared as flat
plate specimens using powder as received without grinding.
Approximately 1-2 mg of the sample was lightly pressed on a glass
slide to obtain a flat surface.
Non-Ambient Conditions
[0567] Samples run under non-ambient conditions were mounted on a
silicon wafer with heatconducting compound. The sample was then
heated to the appropriate temperature at 10.degree. C./min (unless
otherwise stated) and subsequently held isothermally for 1 minute
before data collection was initiated.
[0568] Bruker AXS D8 Advance
[0569] X-Ray Powder Diffraction patterns were collected on a Bruker
D8 diffractometer using Cu Ka radiation (40 kV, 40 mA),
.theta.-2.theta. goniometer, and divergence of V4 and receiving
slits, a Ge monochromator and a Lynxeye detector. The instrument is
performance checked using a certified Corundum standard (NIST
1976). The software used for data collection was Diffrac Plus XRD
Commander v2.5.0 and the data were analysed and presented using
Diffrac Plus EVA v11.0.0.2 or v13.0.0.2. Samples were run under
ambient conditions as flat plate specimens using powder as
received. The sample was gently packed into a cavity cut into
polished, zero-background (510) silicon wafer. The sample was
rotated in its own plane during analysis. The details of the data
collection are: [0570] Angular range: 2 to 42.degree. 2.theta.
[0571] Step size: 0.05.degree. 2.theta. [0572] Collection time: 0.5
s/step
[0573] XRPD on Form A
[0574] The X-Ray powder diffraction for Form A is displayed in FIG.
1. Characteristic peaks include 5.7.+-.0.1.degree. 2-Theta,
13.6.+-.0.1.degree. 2-Theta, 16.1.+-.0.1.degree. 2-Theta,
18.9.+-.0.1.degree. 2-Theta, 21.3.+-.0.1.degree. 2-Theta, and
21.6.+-.0.1.degree. 2-Theta.
[0575] Crystallinity was unaffected after one week storage at
40.degree. C./75% RH or after one week storage at 25.degree. C./97%
RH.
[0576] XRPD on Form B
[0577] The X-Ray powder diffraction for Form B is displayed in FIG.
5. Characteristic peaks include 5.2.+-.0.1.degree. 2-Theta,
10.2.+-.0.1.degree. 2-Theta, 16.5.+-.0.1.degree. 2-Theta,
18.5.+-.0.1.degree. 2-Theta, and 20.8.+-.0.1.degree. 2-Theta.
[0578] Crystallinity was unaffected after one week storage at
40.degree. C./75% RH or after one week storage at 25.degree. C./97%
RH.
[0579] XRPD on Form C
[0580] The X-Ray powder diffraction for Form C is displayed in FIG.
9. Characteristic peaks include 7.0.+-.0.1.degree. 2-Theta,
14.0.+-.0.1.degree. 2-Theta, 15.7.+-.0.1.degree. 2-Theta,
18.2.+-.0.1.degree. 2-Theta, 19.1.+-.0.1.degree. 2-Theta,
19.5.+-.0.1.degree. 2-Theta, 20.3.+-.0.1.degree. 2-Theta,
22.1.+-.0.1.degree. 2-Theta, and 22.9.+-.0.1.degree. 2-Theta.
[0581] Crystallinity was unaffected after one week storage at
40.degree. C./75% RH or after one week storage at 25.degree. C./97%
RH.
[0582] XRPD on Form D
[0583] The X-Ray powder diffraction for Form D is displayed in FIG.
12. Characteristic peaks include 7.2.+-.0.1.degree. 2-Theta,
8.0.+-.0.1.degree. 2-Theta, 9.2.+-.0.1.degree. 2-Theta,
14.5.+-.0.1.degree. 2-Theta, 18.5.+-.0.1.degree. 2-Theta,
19.5.+-.0.1.degree. 2-Theta, 20.7.+-.0.1.degree. 2-Theta,
21.0.+-.0.1.degree. 2-Theta, 21.9.+-.0.1.degree. 2-Theta, and
22.4.+-.0.1.degree. 2-Theta.
[0584] XRPD on Form E
[0585] The X-Ray powder diffraction for Form E is displayed in FIG.
14. Characteristic peaks include 7.8.+-.0.1.degree. 2-Theta,
8.8.+-.0.1.degree. 2-Theta, 16.1.+-.0.1.degree. 2-Theta,
18.1.+-.0.1.degree. 2-Theta, 19.3.+-.0.1.degree. 2-Theta,
19.5.+-.0.1.degree. 2-Theta, 20.5.+-.0.1.degree. 2-Theta,
21.6.+-.0.1.degree. 2-Theta, and 25.2.+-.0.1.degree. 2-Theta.
[0586] XRPD on Form F
[0587] A simulated XRPD pattern was generated for Form F. The XRPD
simulated pattern was generated from the single crystal data
obtained from Example 3 (cif file) using Mercury CSD v3.1 (C. F.
Macrae et al. I Appl. Cryst. (2006), 39-3, 453-457) (XRPD pattern
settings: CuKa 1.54056; Start/End 2/43 2 .theta..degree.;
PWHW)(2.theta..degree. 0.1). The data was then saved as a raw file.
To generate the 20.degree. /Intensity (%) peak table the raw file
was treated using Diffrac Plus EVA v. 15,0,0,0.
[0588] The X-Ray powder diffraction simulated pattern for Form F is
displayed in FIG. 16. Characteristic peaks include
6.2.+-.0.1.degree. 2-Theta, 10.1.+-.0.1.degree. 2-Theta,
17.6.+-.0.1.degree. 2-Theta, 18.6.+-.0.1.degree. 2-Theta,
20.0.+-.0.1.degree. 2-Theta, 20.4.+-.0.1.degree. 2-Theta,
20.7.+-.0.1.degree. 2-Theta, 22.4.+-.0.1.degree. 2-Theta,
23.0.+-.0.1.degree. 2-Theta, 23.2.+-.0.1.degree. 2-Theta,
24.4.+-.0.1.degree. 2-Theta, 25.1.+-.0.1.degree. 2-Theta,
27.6.+-.0.1.degree. 2-Theta, 29.3.+-.0.1.degree. 2-Theta, and
29.7.+-.0.1.degree. 2-Theta.
Example 3
Single Crystal X-Ray Diffraction
[0589] Single crystal X-ray diffraction data was collected and
processed as follows:
TABLE-US-00005 Diffractometer SuperNova, Dual, Cu at zero, Atlas
Radiation source SuperNova (Cu) X-ray Source, CuK.alpha. Data
collection method omega scans Theta range for data collection 9.11
to 74.49.degree. Index ranges -11 .ltoreq. h .ltoreq. 12, -12
.ltoreq. k .ltoreq. 12, -18 .ltoreq. l .ltoreq. 18 Reflections
collected 22842 Independent reflections 9278 [R(int) = 0.0407]
Coverage of independent reflections 99.4% Variation in check
reflections N/A Absorption correction Semi-empirical from
equivalents Max. and min. transmission 1.00000 and 0.73583
Structure solution technique direct Structure solution program
SHELXS-97 (Sheldrick, 1990) Refinement technique Full-matrix
least-squares on F.sup.2 Refinement program SHELXL-97 (Sheldrick,
1997) Function minimized
.SIGMA.w(F.sub.o.sup.2-F.sub.c.sup.2).sup.2
Data/restraints/parameters 9278/3/660 Goodness-of-fit on F.sup.2
1.004 .DELTA./.sigma..sub.max 0.000 Final R indices 9185 data; I
> 2.sigma.(I) R1 = 0.0414, wR2 = 0.1144 all data R1 = 0.0417,
wR2 = 0.1149 Weighting scheme calc w = 1/[.sigma..sup.2
(F.sub.o.sup.2) + (0.0810P).sup.2 + 0.2800P] where P =
(F.sub.o.sup.2 + 2F.sub.c.sup.2)/3 Absolute structure parameter
-0.01(13) Extinction coefficient 0.0013(3) Largest diff. peak and
hole 0.320 and -0.285 e.ANG..sup.-3
[0590] Form F was characterized by unit cell unit cell parameters
approximately equal to the following at a temperature of
approximately 100(2) K:
TABLE-US-00006 Molecular formula C.sub.53H.sub.60N.sub.12O.sub.7
Molecular weight 977.13 Crystal system Triclinic Space group P1 a
9.6332(3) .ANG. .alpha. 105.762(3).degree. b 9.7536(4) .ANG. .beta.
95.132(2).degree. c 15.0592(4) .ANG. .gamma. 111.332(3).degree. V
1240.15(7) .ANG..sup.3 Z 1 Density 1.308 Mg/m.sup.3 (calculated)
Absorption 0.726 mm.sup.-1 coefficient Wavelength 1.54178 .ANG.
F(000) 518 T 100(2) K
Example 4
Fourier Transform--Infra-Red (FTIR)
[0591] Data were collected on a Perkin-Elmer Spectrum One fitted
with a universal Attenuated Total Reflectance (ATR) sampling
accessory. The data were collected and analysed using Spectrum
v5.0.1 software.
[0592] The infrared spectrum for Form A is displayed in FIG. 2.
Characteristic peaks observed in the infrared spectrum for Form A
include peaks at: 1584 cm.sup.-1, 1240 cm.sup.-1, 1147 cm.sup.-1,
1134 cm.sup.-1, 1099 cm.sup.-1, 1067 cm.sup.-1, 985 cm.sup.-1, and
953 cm.sup.-1.
[0593] The infrared spectrum for Form B is displayed in FIG. 6.
Characteristic peaks observed in the infrared spectrum for Form B
include peaks at: 1586 cm.sup.-1, 1573 cm.sup.-1, 1562 cm.sup.-1,
1229 cm.sup.-1, 1166 cm.sup.-1, 1141 cm.sup.-1, 1103 cm.sup.-1,
1056 cm.sup.-1, 1033 cm.sup.-1, and 982 cm.sup.-1.
Example 5
Differential Scanning Calorimetry (DSC) and Thermo-Gravimetric
Analysis (TGA)
[0594] DSC data were collected on a TA Instruments Q2000 equipped
with a 50 position autosampler. The calibration for thermal
capacity was carried out using sapphire and the calibration for
energy and temperature was carried out using certified indium.
Typically 0.5-3 mg of each sample, in a pin-holed aluminium pan,
was heated at 10.degree. C./min from 25.degree. C. to 300.degree.
C. A purge of dry nitrogen at 50 ml/min was maintained over the
sample, unless otherwise stated. Modulated temperature DSC was
carried out using an underlying heating rate of 2.degree. C./min
and temperature modulation parameters of .+-.0.318.degree. C.
(amplitude) every 60 seconds (period). The instrument control
software was Advantage for Q Series v2.8.0.392 and Thermal
Advantage v4.8.3 and the data were analysed using Universal
Analysis v4.4A.
[0595] TGA data were collected on a TA Instruments Q500 TGA,
equipped with a 16 position autosampler. The instrument was
temperature calibrated using certified Alumel and Nickel. Typically
3-10 mg of each sample was loaded onto a pre-tared aluminium DSC
pan and heated at 10.degree. C./min from ambient temperature to
350.degree. C. A nitrogen purge at 60 ml/min was maintained over
the sample, unless otherwise stated. The instrument control
software was
[0596] Advantage for Q Series v2.8.0.392 and Thermal Advantage
v4.8.3 and the data were analysed using Universal Analysis
v4.4A.
[0597] Form A
[0598] DSC and TGA thermograms for Form A are displayed in FIG. 3
and FIG. 4 respectively.
[0599] No weight loss was observed. Material is anhydrous.
[0600] In the DSC (rate of heating: 10.degree. C./min or 20.degree.
C./min) an endotherm was observed having an onset at about
154.degree. C. and a peak at about 157.degree. C. An exothermic
peak was observed at 159.degree. C.
[0601] Form B
[0602] DSC and TGA thermograms for Form B are displayed in FIG. 7
and FIG. 8 respectively.
[0603] No weight loss was observed. Material is anhydrous.
[0604] In the DSC (rate of heating: 10.degree. C./min or 20.degree.
C./min) an endotherm was observed having an onset at about
99-106.degree. C. and a peak at about 115-118.degree. C.
[0605] Form C
[0606] DSC and TGA thermograms for Form C are displayed in FIG. 10
and FIG. 11 respectively.
[0607] No weight loss was observed. Material is anhydrous.
[0608] In the DSC (rate of heating: 10.degree. C./min or 20.degree.
C./min) an endotherm was observed having an onset at about
134-135.degree. C. and a peak at about 137-139.degree. C.
[0609] Form D
[0610] A TGA thermogram for Form D is displayed in FIG. 13.
[0611] Total weight loss of 16.6-17.8%, equivalent to about one
mole of MIBK, was observed by TGA either as 1 step or as 2
steps.
[0612] Form E
[0613] DSC and TGA thermograms for Form E are displayed in FIG.
15.
[0614] A weight loss of 16.5% w/w was observed in TGA associated
with 2 endothermic events in DSC recorded at 85.degree. C. (onset)
and 151.degree. C. (onset) which could correspond to desolvation
phenomena.
Example 6
Gravimetric Vapour Sorption (GVS)
[0615] Sorption isotherms were obtained using a SMS DVS Intrinsic
moisture sorption analyser, controlled by DVS Intrinsic Control
software v1.0.0.30. The sample temperature was maintained at
25.degree. C. by the instrument controls. The humidity was
controlled by mixing streams of dry and wet nitrogen, with a total
flow rate of 200 ml/min The relative humidity was measured by a
calibrated Rotronic probe (dynamic range of 1.0-100% RH), located
near the sample. The weight change, (mass relaxation) of the sample
as a function of % RH was constantly monitored by the microbalance
(accuracy .+-.0.005 mg). Typically 5-20 mg of sample was placed in
a tared mesh stainless steel basket under ambient conditions. The
sample was loaded and unloaded at 40% RH and 25.degree. C. (typical
room conditions). A moisture sorption isotherm was performed as
outlined below (2 scans giving 1 complete cycle). The standard
isotherm was performed at 25.degree. C. at 10% RH intervals over a
0-90% RH range. Data analysis was undertaken in Microsoft Excel
using DVS Analysis Suite v6.0.0.7. The sample was recovered after
completion of the isotherm and re-analysed by XRPD.
TABLE-US-00007 TABLE 1 Method Parameters for SMS DVS Intrinsic
Experiments Parameters Values Adsorption - Scan 1 40-90
Desorption/Adsorption - Scan 2 90-0, 0-40 Intervals (% RH) 10
Number of Scans 2 Flow rate (ml/min) 200 Temperature (.degree. C.)
25 Stability (.degree. C./min) 0.2 Sorption Time (hours) 6 hour
time out
[0616] Form A
[0617] The mass change was <0.3% w/w between 0-90% RH. The
material is not hygroscopic. No significant changes were observed
in the XRPD after GVS analysis.
[0618] Form B
[0619] The mass change was 2.3% w/w between 0-90% RH. No hysteresis
was observed. No significant changes were observed in the XRPD
after GVS analysis.
Example 7
Thermodynamic Aqueous Solubility
[0620] Aqueous solubility was determined by suspending sufficient
compound in water to give a maximum final concentration of >10
mg/ml of the parent free-form of the compound. The suspension was
equilibrated at 25.degree. C. for 24 hours then the pH was
measured. The suspension was then filtered through a glass fibre C
filter. The filtrate was then diluted by an appropriate factor e.g.
101. Quantitation was by HPLC with reference to a standard solution
of approximately 0.25 mg/ml in DMSO. Different volumes of the
standard, diluted and undiluted sample solutions were injected. The
solubility was calculated using the peak areas determined by
integration of the peak found at the same retention time as the
principal peak in the standard injection.
TABLE-US-00008 TABLE 2 HPLC Method Parameters for Solubility
Measurements Type of method: Reverse phase with gradient elution
Column: Phenomenex Luna, C18 (2) 5 .mu.m 50 .times. 4.6 mm Column
Temperature (.degree. C.): 25 Standard Injections (.mu.l): 1, 2, 3,
5, 7, 10 Test Injections (.mu.l): 1, 2, 3, 10, 20, 50 Detection:
260, 80 Wavelength, Bandwidth (nm) Flow Rate (ml/min): 2 Phase A:
0.1% TFA in water Phase B: 0.085% TFA in acetonitrile Time (min) %
Phase A % Phase B Timetable: 0.0 95 5 1.0 80 20 2.3 5 95 3.3 5 95
3.5 95 5 4.4 95 5
[0621] Analysis was performed on an Agilent HP1100 series system
equipped with a diode array detector and using ChemStation software
vB.02.01-SR1.
[0622] The solubility of Form A in aqueous solution at different pH
is presented in Table 3.
TABLE-US-00009 TABLE 3 Form A Solubility in Aqueous Solution at
Different pH pH Conc. Found (mg/mL) 1.2 1.3 1.64 1.07 1.95 0.82 3
0.10 4 0.022 5 0.017 6 0.015 8 0.013 9 0.020 10 0.010
[0623] The thermodynamic aqueous solubility of norm B at pH of 7.42
was determined to be 0.0096 mg/ml.
Example 8
Chemical Purity Determination
[0624] HPLC analysis performed on an Agilent HP1100/1200 system
equipped with a diode array detector and using Chemstation software
using the method detailed below:
TABLE-US-00010 TABLE 4 Method Parameters Type of method: Reverse
phase with gradient elution Test sample make-up: ~0.1 mg/ml in
60:40 v/v H.sub.2O:ACN Column: Gemini-NX C18, 4.6 .times. 150 mm, 3
.mu.m Column temperature (.degree. C.): 40 Injection (.mu.l): 100
Detection: 260, scan from 210 to 500 nm Wavelength, Bandwidth (nm)
Flow Rate (ml/min): 1.5 Phase A: 0.1% TFA in water Phase B: 0.1%
TFA in acetonitrile Time (min) % Phase A % Phase B Timetable: 0 75
25 10 70 30 30 65 35 45 35 65 46 10 90 50 10 90 51 75 25 60 75 25
Retention time: ~20 min Needle wash: methanol:water (8:2)
[0625] In some embodiments, Form A is greater than 95% pure by HPLC
analysis. In some embodiments, Form A is greater than 96% pure by
HPLC analysis. In some embodiments, Form A is greater than 97% pure
by HPLC analysis. In some embodiments, Form A is greater than 98%
pure by HPLC analysis. In some embodiments, Form A is greater than
99% pure by HPLC analysis. In some embodiments, Form A is 99.8%
pure by HPLC analysis.
[0626] In some embodiments, Form B is greater than 95% pure by HPLC
analysis. In some embodiments, Form B is greater than 96% pure by
HPLC analysis. In some embodiments, Form B is greater than 97% pure
by HPLC analysis. In some embodiments, Form B is greater than 98%
pure by HPLC analysis. In some embodiments, Form B is greater than
99% pure by HPLC analysis. In some embodiments, Form B is 97.8%
pure by HPLC analysis. In some embodiments, Form B is 99.8% pure by
HPLC analysis.
[0627] In some embodiments, Form C is greater than 95% pure by HPLC
analysis. In some embodiments, Form C is greater than 96% pure by
HPLC analysis. In some embodiments, Form C is greater than 97% pure
by HPLC analysis. In some embodiments, Form C is greater than 98%
pure by HPLC analysis. In some embodiments, Form C is greater than
99% pure by HPLC analysis. In some embodiments, Form C is 99.4%
pure by HPLC analysis.
Example 9
Chiral Purity Determination
[0628] Chiral purity of Compound 1 was determined by using a Lux
Cellulose-1 chiral column by normal phase HPLC. The mobile phase is
composed of 20% isopropyl alcohol and 80% hexanes. The enantiomers
of
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-
din-1-yl)prop-2-en-1-one are detected at 260 nm. In one embodiment,
Compound 1 is dissolved in a mixture of Hexanes: IPA=(7:3) to
obtain a concentration of approximately 0.2 mg/mL and the chiral
purity of the sample is analyzed. The content of the R enantiomer
is determined by peak area normalization of the enantiomer peaks
and is expressed in weight to weight percent. In some embodiments,
a sample of Compound 1 includes less than 5.0%, less than 4.0%,
less than 3.0%, less than 2.0%, or less than 1.0%, of the
(S)-isomer. In some embodiments, a sample of Compound 1 includes
less than 1.0% of the (S)-isomer.
[0629] Solid Oral Dosage Forms
[0630] In some embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is formulated into a solid oral dosage
form. In some embodiments, the crystallinity of
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is maintained in the solid oral dosage
form. In some embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is formulated into tablets. In some
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is formulated into pills. In some
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is formulated into capsules. In some
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is placed into capsules without
excipients or with excipients. In any of these embodiments,
crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is Form A. In any of these
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is Form B. In any of these
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is Form C. In any of these
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is Form D. In any of these
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)pi-
peridin-1-yl)prop-2-en-1-one is Form E. In any of these
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is Form F. In any of these
embodiments, crystalline
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pi-
peridin-1-yl)prop-2-en-1-one is a mixture of two or more
crystalline forms selected from the group consisting of Form A,
Form B, Form C, Form D, Form E, and Form F.
Example 10
Capsule Formulations
[0631] In one embodiment, capsule formulations of Compound 1 for
administration to humans is prepared with the following
ingredients:
TABLE-US-00011 TABLE 5 Capsule Formulations 40 mg 140 mg 140 mg 200
mg Capsule Capsule Capsule Capsule mg/ mg/ mg/ mg/ Component w/w %
capsule w/w % capsule w/w % capsule w/w % capsule crystalline 29.6
40.0 60.9 140.0 42.4 140.0 74.1 200.0 Compound 1 Microcrystalline
57.4 77.5 23.0 53.0 45.9 151.4 8.5 23.0 cellulose NF Croscarmellose
10.0 13.5 10.0 23.0 7.0 23.0 10.0 27.0 sodium NF Sodium lauryl 3.0
4.0 6.1 14.0 4.2 14.0 7.4 20.0 sulfate NF Magnesium NA NA NA NA 0.5
1.6 NA NA stearate NF
[0632] In some embodiments, the manufacturing process includes the
following steps: weigh the indicated amount of the components, mix
together and add into an appropriate size capsule, and close
capsule. In some embodiments, the capsules are stored at room
temperature for an extended period of time until they are used.
Example 11
Immediate Release Tablets
[0633] In some embodiments, tablets are prepared with the
components set forth in Table 10.
TABLE-US-00012 TABLE 6 Components of Tablet Formulation Ingredient
Range crystalline Compound 1 5% to 50% Hypromellose 2% to 10%
Croscarmellose sodium 0% to 15% Microcrystalline cellulose 5% to
50% Lactose 10% to 75% Magnesium stearate 0.25% to 2.5% Total
Tablet weight range: 300 mg to 1000 mg
[0634] Manufacturing process will typically be granulation (dry,
wet or melt) or direct compression.
Example 12
Safety and Tolerability Study of Compound 1 in Chronic Lymphocytic
Leukemia
[0635] Purpose: The purpose of this study is to establish the
safety and optimal dose of orally administered Compound 1 (420
mg/day) in patients with B-cell chronic lymphocytic leukemia/small
lymphocytic lymphoma/diffuse well-differentiated lymphocytic
lymphoma.
[0636] Primary Outcome Measures: Safety and tolerability of
Compound 1 (frequency, severity, and relatedness of adverse
events).
[0637] Secondary Outcome Measures: Pharmacokinetic/Pharmacodynamic
assessments. Tumor response--overall response rate as defined by
recent guidelines on CLL and SLL (B cell lymphoma) and duration of
response.
[0638] Eligibility: 18 Years and older; both genders are
eligible.
[0639] Inclusion Criteria: 1. For treatment-naive group only: Men
and women.gtoreq.65 years of age with confirmed diagnosis of
CLL/SLL, who require treatment per NCI or International Working
Group guidelines11-14. 2. For relapsed/refractory group only: Men
and women.gtoreq.18 years of age with a confirmed diagnosis of
relapsed/refractory CLL/SLL unresponsive to therapy (ie,
failed.gtoreq.2 previous treatments for CLL/SLL and at least 1
regimen had to have had a purine analog [eg, fludarabine] for
subjects with CLL). 3. Body weight.gtoreq.40 kg. 4. ECOG
performance status of .ltoreq.2. 5. Agreement to use contraception
during the study and for 30 days after the last dose of study drug
if sexually active and able to bear children. 6. Willing and able
to participate in all required evaluations and procedures in this
study protocol including swallowing capsules without difficulty. 7.
Ability to understand the purpose and risks of the study and
provide signed and dated informed consent and authorization to use
protected health information (in accordance with national and local
subject privacy regulations).
[0640] Exclusion Criteria: 1. A life-threatening illness, medical
condition or organ system dysfunction which, in the investigator's
opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of Compound 1 PO, or put the study
outcomes at undue risk. 2. Any immunotherapy, chemotherapy,
radiotherapy, or experimental therapy within 4 weeks before first
dose of study drug (corticosteroids for disease-related symptoms
allowed but require 1-week washout before study drug
administration). 3. Central nervous system (CNS) involvement by
lymphoma. 4. Major surgery within 4 weeks before first dose of
study drug. 5. Creatinine>1.5.times.institutional upper limit of
normal (ULN); total bilirubin>1.5.times.ULN (unless due to
Gilbert's disease); and aspartate aminotransferase (AST) or alanine
aminotransferase (ALT)>2.5.times.ULN unless disease related. 6.
Concomitant use of medicines known to cause QT prolongation or
torsades de pointes. 7. Significant screening electrocardiogram
(ECG) abnormalities including left bundle branch block, 2nd degree
AV block type II, 3rd degree block, bradycardia, and QTc>470
msec. 8. Lactating or pregnant.
Example 13
Safety and Efficacy of Compound 1 in Subjects With
Relapsed/Refractory Mantle Cell Lymphoma (MCL)
[0641] The primary objective of this trial is to evaluate the
efficacy of Compound 1 in relapsed/refractory subjects with Mantle
Cell Lymphoma (MCL). The secondary objective is to evaluate the
safety of a fixed daily dosing regimen of Compound 1 (560 mg/day in
the form of capsules) in this population.
[0642] Primary Outcome Measures: To measure the number of
participants with a response to Compound 1.
[0643] Secondary Outcome Measures: To measure the number of
participants with adverse events as a measure of safety and
tolerability. To measure pharmacokinetics to assist in determining
how the body responds to the study drug. Patient reported outcomes
(to measure the number of participants reported outcomes in
determing the health related quality of life).
[0644] Eligibility: 18 Years and older; both genders are
eligible.
[0645] Inclusion Criteria: Men and women.gtoreq.18 years of age.
ECOG performance status of.ltoreq.2. Pathologically confirmed MCL,
with documentation of either overexpression of cyclin D1 or
t(11;14), and measurable disease on cross sectional imaging that
is.gtoreq.2 cm in the longest diameter and measurable in 2
perpendicular dimensions. Documented failure to achieve at least
partial response (PR) with, or documented disease progression
disease after, the most recent treatment regimen. At least 1, but
no more than 5, prior treatment regimens for MCL (Note: Subjects
having received.gtoreq.2 cycles of prior treatment with bortezomib,
either as a single agent or as part of a combination therapy
regimen, will be considered to be bortezomib-exposed.). Willing and
able to participate in all required evaluations and procedures in
this study protocol including swallowing capsules without
difficulty. Ability to understand the purpose and risks of the
study and provide signed and dated informed consent and
authorization to use protected health information (in accordance
with national and local subject privacy regulations).
[0646] Major exclusion criteria: Prior chemotherapy within 3 weeks,
nitrosoureas within 6 weeks, therapeutic anticancer antibodies
within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks,
radiation therapy within 3 weeks, or major surgery within 2 weeks
of first dose of study drug. Any life-threatening illness, medical
condition or organ system dysfunction which, in the investigator's
opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of Compound 1 capsules, or put the study
outcomes at undue risk. Clinically significant cardiovascular
disease such as uncontrolled or symptomatic arrhythmias, congestive
heart failure, or myocardial infarction within 6 months of
screening, or any Class 3 or 4 cardiac disease as defined by the
New York Heart Association Functional Classification. Malabsorption
syndrome, disease significantly affecting gastrointestinal
function, or resection of the stomach or small bowel or ulcerative
colitis, symptomatic inflammatory bowel disease, or partial or
complete bowel obstruction. Any of the following laboratory
abnormalities: 1. Absolute neutrophil count (ANC)<750 cells/mm3
(0.75.times.109/L) unless there is documented bone marrow
involvement. 2. Platelet count<50,000 cells/mm3 (50.times.109/L)
independent of transfusion support unless there is documented bone
marrow involvement. 3. Serum aspartate transaminase (AST/SGOT) or
alanine transaminase (ALT/SGPT)>3.0.times.upper limit of normal
(ULN). 4. Creatinine>2.0.times.ULN.
Example 14
Phase 2 Study of the Combination of Compound 1 and Rituximab in
High-Risk Chronic Lymphocytic Leukemia and Small Lymphocytic
Lymphoma Patients
[0647] Purpose: The goal of this clinical research study is to
learn if Compound 1 combined with rituximab can help to control
chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma
(SLL). The safety of this combination will also be studied.
[0648] Rituximab (375 mg/m.sup.2) given intravenously (IV) on Day
1, Day 8, Day 15, and Day 22, then continued once every 4 weeks
only on Days 1 during cycles 2-6. Compound 1 started on Day 2 of
cycle 1 at a dose of 420 mg (3.times.140-mg capsules) orally daily
and will be continued daily.
[0649] Primary Outcome Measures: Progression free survival (PFS)
[Time Frame: 3 months]--progression free survival defined as the
time interval from treatment to progressive disease or death,
whichever happens earlier. Patients in complete remission (CR),
partial remission (PR) or stable disease (SD) are all counted as
progression-free. Survival or times to progression functions
estimated using the Kaplan-Meier method.
[0650] Secondary Outcome Measures: Toxicity [Time Frame: 3
months]--toxicity reported by type, frequency and severity. Worst
toxicity grades per patient tabulated for selected adverse events
and laboratory measurements. Toxicity (grade 3 or 4) monitored
based on the Bayesian model (beta-binomial) by assuming a priori
probability of toxicity following beta(1,1).
[0651] Eligibility: 18 Years and older; both genders are
eligible.
[0652] Inclusion Criteria: 1. Patients must have a diagnosis of
high-risk CLL/SLL and be previously treated with up to 3 lines of
prior therapy. High-risk CLL and high-risk SLL is defined by the
presence of a 17p deletion or 11q deletion or TP53 mutation. Any
CLL and SLL patient who has a short remission duration of less than
3 years after prior first-line chemo-immunotherapy, such as the FCR
regimen, also fulfills criteria of high-risk CLL/SLL, regardless of
the presence or absence of cytogenetic abnormalities. 2. CLL and
SLL patients with 17p deletion or TP53 mutation will not be
required to have received any prior therapy, given the poor outcome
of CLL/SLL patients to standard frontline chemo-immunotherapy, such
patients will be eligible if they are untreated or if they have
received up to 3 lines of prior therapy. 3. Patients must have an
indication for treatment by 2008 IWCLL Criteria. 4. Patients
age>18 years at the time of signing informed consent. Understand
and voluntarily sign an informed consent. Be able to comply with
study procedures and follow-up examinations. 5. ECOG/WHO
performance status of 0-1. 6. Patients of childbearing potential
must be willing to practice highly effective birth control (e.g.,
condoms, implants, injectables, combined oral contraceptives, some
intrauterine devices [IUDs], sexual abstinence, or sterilized
partner) during the study and for 30 days after the last dose of
study drug. Women of childbearing potential include any female who
has experienced menarche and who has not undergone successful
surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or is not postmenopausal. Post menopause is
defined as follows: Amenorrhea>/=12 consecutive months without
another cause and a documented serum follicle stimulating hormone
(FSH) level>35 mIU/mL; a male of childbearing potential is any
male that has not been surgically sterilized. 7. Adequate renal and
hepatic function as indicated by all of the following: Total
bilirubin</=1.5.times.institutional Upper Limit of Normal (ULN)
except for patients with bilirubin elevation due to Gilbert's
disease who will be allowed to participate; an
ALT</=2.5.times.ULN; and an estimated creatinine clearance
(CrCl) of>30 mL/min, as calculated by the Cockroft-Gault
equation unless disease related. 8. Free of prior malignancies for
3 years with exception of currently treated basal cell, squamous
cell carcinoma of the skin, or carcinoma in situ of the cervix or
breast. 9. A urine pregnancy test (within 7 days of Day 1) is
required for women with childbearing potential
[0653] Exclusion Criteria: 1 .Pregnant or breast-feeding females.
2. Treatment including chemotherapy, chemo-immunotherapy ,
monoclonal antibody therapy, radiotherapy, high-dose corticosteroid
therapy (more than 60 mg Prednisone or equivalent daily), or
immunotherapy within 21 days prior to enrollment or concurrent with
this trial. 3 .Investigational agent received within 30 days prior
to the first dose of study drug or have previously taken Compound
1. If received any investigational agent prior to this time point,
drug-related toxicities must have recovered to Grade 1 or less
prior to first dose of study drug. 4. Systemic fungal, bacterial,
viral, or other infection not controlled (defined as exhibiting
ongoing signs/symptoms related to the infection and without
improvement, despite appropriate antibiotics or other treatment).
5. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or
autoimmune thrombocytopenia (ITP). 6. Patients with severe
hematopoietic insufficiency, as defined by an absolute neutrophil
count of less than 500/micro-L and/or a platelet count of less than
30,000/micro-L at time of screening for this protocol. 7. Any other
severe concurrent disease, or have a history of serious organ
dysfunction or disease involving the heart, kidney, liver or other
organ system that may place the patient at undue risk to undergo
therapy with Compound 1 and rituximab. 8. Significant
cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction
within 6 months of screening, or any Class 3 or 4 cardiac disease
as defined by the New York Heart Association Functional
Classification. 9. Significant screening ECG abnormalities
including left bundle branch block, 2nd degree AV block type II,
3rd degree block, bradycardia, and QTc>470 msec. 10. Any serious
medical condition, laboratory abnormality, or psychiatric illness
that places the subject at unacceptable risk if he/she were to
participate in the study. 11. History of stroke or cerebral
hemorrhage within 6 months. 12. Evidence of bleeding diathesis or
coagulopathy. 13. Major surgical procedure, open biopsy, or
significant traumatic injury within 28 days prior to Day 1,
anticipation of need for major surgical procedure during the course
of the study. 14. Minor surgical procedures, fine needle
aspirations or core biopsies within 7 days prior to Day 1. Bone
marrow aspiration and/or biopsy are allowed. 15. Serious,
non-healing wound, ulcer, or bone fracture. 16. Treatment with
Coumadin. Patients who recently received Coumadin must be off
Coumadin for at least 7 days prior to start of the study. 17. Any
chemotherapy (e.g., bendamustine, cyclophosphamide, pentostatin, or
fludarabine), immunotherapy (e.g., alemtuzumab, or ofatumumab),
bone marrow transplant, experimental therapy, or radiotherapy is
prohibited during therapy on this study. 18. Use of medications
known to prolong QTc interval or that may be associated with
Torsades de Pointes (refer to Appendix F) are prohibited within 7
days of starting study drug and during study-drug treatment.
[0654] The examples and embodiments described herein are
illustrative and various modifications or changes suggested to
persons skilled in the art are to be included within this
disclosure. As will be appreciated by those skilled in the art, the
specific components listed in the above examples may be replaced
with other functionally equivalent components, e.g., diluents,
binders, lubricants, fillers, and the like.
* * * * *