U.S. patent application number 15/484844 was filed with the patent office on 2017-08-03 for polymorph of syk inhibitors.
The applicant listed for this patent is Gilead Connecticut, Inc.. Invention is credited to Tim G. Elford, Peter Chee-Chu Fung, Michael Laird Hurrey, Dimitrios Stefanidis, Dragos Vizitiu.
Application Number | 20170217967 15/484844 |
Document ID | / |
Family ID | 51301367 |
Filed Date | 2017-08-03 |
United States Patent
Application |
20170217967 |
Kind Code |
A1 |
Elford; Tim G. ; et
al. |
August 3, 2017 |
POLYMORPH OF SYK INHIBITORS
Abstract
Polymorphs of a bis-mesylate salt of a compound of Formula I:
##STR00001## or a hydrate thereof, are provided. The bis-mesylate
salt may also be depicted as a compound of Formula IA: ##STR00002##
Provided herein are also compositions thereof, methods for their
preparation and methods for such polymorphs.
Inventors: |
Elford; Tim G.; (Sherwood
Park, CA) ; Fung; Peter Chee-Chu; (San Mateo, CA)
; Hurrey; Michael Laird; (San Ramon, CA) ;
Stefanidis; Dimitrios; (Mountain View, CA) ; Vizitiu;
Dragos; (Edmonton, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Connecticut, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
51301367 |
Appl. No.: |
15/484844 |
Filed: |
April 11, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14446011 |
Jul 29, 2014 |
9657023 |
|
|
15484844 |
|
|
|
|
61860197 |
Jul 30, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/00 20180101;
C07C 309/04 20130101; A61P 35/02 20180101; A61P 25/02 20180101;
A61P 19/02 20180101; A61P 11/06 20180101; A61P 37/06 20180101; C07D
487/04 20130101; A61P 35/00 20180101; A61P 25/00 20180101; A61P
29/00 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1. A bis-mesylate salt of a compound of Formula I: ##STR00038## or
a hydrate thereof.
2. The bis-mesylate salt of claim 1, wherein the bis-mesylate salt,
or a hydrate thereof, is: a compound of Formula IB: ##STR00039## or
a compound of Formula IC: ##STR00040## or a compound of Formula ID:
##STR00041## wherein y is at least 0.5.
3. The bis-mesylate salt of claim 1, wherein the bis-mesylate salt,
or a hydrate thereof, is crystalline.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. application Ser.
No. 14/446,011 filed on Jul. 29, 2014 which claims the benefit of
U.S. Provisional Patent Application Ser. No. 61/860,197, filed Jul.
30, 2013, the disclosure of which is hereby incorporated herein by
reference in its entirety.
FIELD
[0002] The present disclosure relates to polymorphs and polymorph
pharmaceutical compositions of compounds that inhibit Spleen
Tyrosine Kinase (Syk) activity. The disclosure also relates to
methods of preparing such polymorphs and polymorph pharmaceutical
compositions, and the use of such polymorphs and pharmaceutical
compositions in treating subjects with various diseases, including
cancer and inflammatory conditions.
BACKGROUND
[0003] The inhibition of Spleen Tyrosine Kinase (Syk) activity may
be useful for treating certain types of cancer and autoimmune
diseases. One such compound that has been found to inhibit Syk
activity is represented by Formula I:
##STR00003##
or a pharmaceutically acceptable salt thereof. This compound and
its synthesis have been described in U.S. Pat. Nos. 8,450,321 and
8,455,493, which are hereby incorporated herein by reference in
their entirety, and are hereby incorporated by reference
specifically with reference to Examples 1 and 2.
[0004] Early clinical oral formulations have involved the use of a
mono-mesylate salt of the compound of Formula I. Various
challenges, however, have been observed in early clinical studies
when this oral formulation was administered to human subjects.
First, high inter-subject variability has been observed, which
could lead to variable pharmacodynamic responses in subjects.
Second, significant drug-drug-interaction and pH effect have been
observed with acid suppressants, and it is desired to minimize such
observed drug-drug-interaction. Third, a dose-dependent food effect
has been observed, and it is also desired to minimize such effect.
Fourth, it is desired to improve oral bioavailability.
[0005] What is desired in the art are physically stable forms of
the compound of Formula I, or a pharmaceutically acceptable salt
thereof, that address each of these challenges and facilitate
manufacturing processes.
SUMMARY
[0006] To overcome the reduced oral bioavailability of the
mono-mesylate salt of the compound of Formula I, a new compound was
investigated. A bis-mesylate salt of the compound of Formula I has
been chosen for further development. Such bis-mesylate salt may be
depicted in various ways. For example, the bis-mesylate salt may be
depicted as the compound of Formula IA, having the molecular
structure:
##STR00004##
One of skill in the art would understand that when the bis-mesylate
salt of the compound of Formula I is depicted as Formula IA above,
the ionic form (e.g., the cationic form of the compound of formula
I and the anionic form of the methanesulfonic acid) is
intended.
[0007] In some embodiments, a hydrate of the bis-mesylate salt of
the compound of Formula I is provided by this disclosure. In
certain embodiments, a monohydrate of the bis-mesylate salt of the
compound of Formula I is provided by this disclosure. In one
embodiment, certain polymorphic forms of the bis-mesylate salt of
the compound of Formula I, or a hydrate thereof, are provided by
this disclosure.
[0008] In one aspect, provided herein are polymorphs of a
bis-mesylate salt of the compound of Formula I (e.g., a compound of
Formula IA), or a hydrate thereof. In certain aspects, polymorphic
forms of a hydrate, bis-mesylate salt of the compound of Formula I
are provided. Specifically, in one aspect, polymorphic Forms 3 and
7 of the bis-mesylate salt of the compound of Formula I (e.g., a
compound of Formula IA) are provided. Methods of making and using
these polymorphic forms are also provided. Also provided are
polymorphic products obtained by the processes described herein
(e.g., obtained by the described methods of making). Pharmaceutical
compositions comprising one or more polymorphic forms of a
bis-mesylate salt of the compound of Formula I (e.g., a compound of
Formula IA), or a hydrate thereof, and a pharmaceutically
acceptable carrier are provided. Articles of manufacture and unit
dosage forms comprising one or more polymorphic forms of a
bis-mesylate salt of the compound of Formula I (e.g., a compound of
Formula IA), or a hydrate thereof, are provided. Kits comprising
one or more polymorphic forms of a bis-mesylate salt of the
compound of Formula I (e.g., a compound of Formula IA), or a
hydrate thereof, and instructions for use (e.g., instructions for
use in SYK-mediated disorder, such as cancer or an autoimmune
disease) are also provided. In some embodiments of the foregoing
methods of making and using the polymorphic forms, polymorphic
products, pharmaceutical compositions, articles of manufacture and
unit dosage forms, and kits provided herein, the bis-mesylate salt
of the compound of Formula I is a hydrate thereof. In certain
embodiments, the bis-mesylate salt of the compound of Formula I is
a monohydrate thereof. In one embodiment, the bis-mesylate salt of
the compound of Formula I or a hydrate thereof is polymorph Form 3
or polymorph Form 7, or a combination thereof.
[0009] In one aspect, provided is a bis-mesylate salt of a compound
of Formula I:
##STR00005##
or a hydrate thereof. In some embodiments, provided is a hydrate of
the bis-mesylate salt of the compound of Formula I. In certain
embodiments, provided is a monohydrate of the bis-mesylate salt of
the compound of Formula I. In some variations, the bis-mesylate
salt or a hydrate thereof is crystalline.
[0010] Provided herein is also a polymorph of the bis-mesylate salt
of the compound of Formula I, or a hydrate thereof. In some
embodiments, provided is a polymorph of a hydrate of the
bis-mesylate salt of the compound of Formula I. In certain
embodiments, provided is a polymorph of a monohydrate of the
bis-mesylate salt of the compound of Formula I. Polymorph Forms 3
and Form 7 are provided in this disclosure, as are methods of
making and using polymorph Form 3 and Form 7, and pharmaceutical
compositions, articles of manufacture, unit dosage forms and kits
comprising polymorph Form 3 or Form 7, or both.
[0011] In some embodiments, a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I is polymorph Form 3,
characterized by or having an X-ray diffraction pattern comprising
2.theta.-reflections (.+-.0.2 degrees) at 13.8, 16.9, 22.9, and
26.1. In further embodiments, a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I is polymorph Form 3,
characterized by or having an X-ray diffraction pattern comprising
2.theta.-reflections (.+-.0.2 degrees) at 7.7, 12.9, 17.7, and
18.1. In yet other embodiments a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I is polymorph Form 3,
characterized by or having an X-ray diffraction pattern comprising
2.theta.-reflections (.+-.0.2 degrees) at 7.7, 12.9, 13.8, 16.9,
17.7, 18.1, 22.9, and 26.1. When describing the
2.theta.-reflections in the X-ray diffraction pattern (e.g., of
polymorph Form 3, also referred to herein as "Form 3" or "Form
III"), it should be understood that .+-.0.2 degrees can also be
expressed as "plus or minus 0.2 degrees 2.theta.". In some
embodiments, a polymorph of a monohydrate, bis-mesylate salt of a
compound of Formula I is polymorph Form 3, characterized by or
having an X-ray diffraction pattern substantially as shown in FIG.
1A. In other embodiments, a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I is polymorph Form 3,
characterized by or having an X-ray diffraction pattern
substantially as shown in FIG. 1B.
[0012] In other embodiments, a polymorph of a hydrate, bis-mesylate
salt of a compound of Formula I is polymorph Form 7, characterized
by or having an X-ray diffraction pattern comprising
2.theta.-reflections at 4.9 (.+-.0.2 degrees), 9.8 (.+-.0.2
degrees), and 26.7 (.+-.0.4 degrees). In one variation, a polymorph
of a hydrate, bis-mesylate salt of a compound of Formula I is
polymorph Form 7, characterized by or having an X-ray diffraction
pattern comprising 2.theta.-reflections at 4.9 (.+-.0.2 degrees),
9.8 (.+-.0.2 degrees), and 26.7 (.+-.0.3 degrees). In certain
embodiments, a polymorph of a hydrate, bis-mesylate salt of a
compound of Formula I is polymorph Form 7, characterized by or
having an X-ray diffraction pattern comprising 2.theta.-reflections
(.+-.0.2 degrees) at 4.9, 9.8, and 26.7. In further embodiments, a
polymorph of a hydrate, bis-mesylate salt of a compound of Formula
I is polymorph Form 7, characterized by or having an X-ray
diffraction pattern comprising 2.theta.-reflections (.+-.0.2
degrees) at 15.0 and 18.0.
[0013] In one variation, a polymorph of a hydrate, bis-mesylate
salt of a compound of Formula I is polymorph Form 7, characterized
by or having an X-ray diffraction pattern comprising
2.theta.-reflections (.+-.0.2 degrees) at 4.9, 9.8, 15.0 and 18.0;
and 2.theta.-reflections (.+-.0.4 degrees) at 26.7. In one
variation, a polymorph of a hydrate, bis-mesylate salt of a
compound of Formula I is polymorph Form 7, characterized by or
having an X-ray diffraction pattern comprising 2.theta.-reflections
(.+-.0.2 degrees) at 4.9, 9.8, 15.0 and 18.0; and
2.theta.-reflections (.+-.0.3 degrees) at 26.7. In another
variation, a polymorph of a hydrate, bis-mesylate salt of a
compound of Formula I is polymorph Form 7, characterized by or
having an X-ray diffraction pattern comprising 2.theta.-reflections
(.+-.0.2 degrees) at 4.9, 9.8, 15.0, 18.0, and 26.7. In some
embodiments, a polymorph of a hydrate, bis-mesylate salt of a
compound of Formula I is polymorph Form 7, characterized by or
having an X-ray diffraction pattern substantially as shown in FIG.
2A. In other embodiments, a polymorph of a hydrate, bis-mesylate
salt of a compound of Formula I is polymorph Form 7, characterized
by or having an X-ray diffraction pattern substantially as shown in
FIG. 2B. When describing the 2.theta.-reflections in the X-ray
diffraction pattern (e.g., of polymorph Form 7, also referred to
herein as "Form 7" or "Form VII"), it should be understood that
.+-.0.2 degrees, .+-.0.3 degrees, and .+-.0.4 degrees can also be
expressed as "plus or minus 0.2 degrees 2.theta.", "plus or minus
0.3 degrees 2.theta.", and "plus or minus 0.4 degrees 2.theta.",
respectively.
[0014] In another aspect, provided is a hydrate of a bis-mesylate
salt of the compound of Formula I. In certain aspects, the hydrate,
bis-mesylate salt of the compound of Formula I is a polymorph
selected from the group consisting of Form 3 and Form 7; wherein
Form 3 is characterized by or has a differential scanning
calorimetry profile substantially as shown in FIG. 3A, 3B or 3C,
and/or a thermogravametrical analysis profile substantially as
shown in FIG. 3B or 3C; and Form 7 is characterized by or has a
differential scanning calorimetry profile substantially as shown in
FIG. 4A, 4B or 4C, and/or a thermogravametrical analysis profile
substantially as shown in FIG. 4B or 4C. It is understood that
"and/or", e.g., in reference to A and/or B intends and describes:
(i) embodiments wherein A is present; (ii) embodiments wherein B is
present; and (iii) embodiments wherein both A and B are present. In
a further embodiment that may be combined with any of the foregoing
embodiments related to Form 3, polymorph Form 3 is characterized by
or has an X-ray diffraction pattern substantially as shown in FIG.
1A or 1B. In another further embodiment that may be combined with
any of the foregoing embodiments related to Form 7, polymorph Form
7 is characterized by or has an X-ray diffraction pattern
substantially as shown in FIG. 2A or 2B.
[0015] In one aspect, provided is a compound of Formula IA:
##STR00006##
or a hydrate thereof. In some embodiments, the compound of Formula
(IA), or hydrate thereof, is crystalline.
[0016] In another aspect, provided is a polymorph of a monohydrate
of a compound of Formula IA:
##STR00007##
having an X-ray diffraction pattern comprising 2.theta.-reflections
(.+-.0.2 degrees) selected from the group consisting of Form 3:
13.8, 16.9, 22.9, and 26.1; and Form 7: 4.9, 9.8, and 26.7.
[0017] In some embodiments, an X-ray diffraction pattern of a
polymorph of a monohydrate of a compound of Formula IA comprises
2.theta.-reflections (.+-.0.2 degrees) characteristic of Form 3. In
some embodiments, an X-ray diffraction pattern of a polymorph of a
monohydrate of a compound of Formula IA comprises
2.theta.-reflections (.+-.0.2 degrees) characteristic of Form 7. In
some embodiments, an X-ray diffraction pattern of polymorph Form 3
is represented in FIG. 1A or 1B. In some embodiments, an X-ray
diffraction pattern of polymorph Form 7 is represented in FIG. 2A
or 2B.
[0018] In some embodiments, a polymorph of the compound of Formula
(IA) is a polymorph selected from the group consisting of Form 3
and Form 7; wherein Form 3 has a differential scanning calorimetry
profile represented in FIG. 3A, 3B or 3C, and Form 7 has a
differential scanning calorimetry profile represented in FIG. 4A,
4B or 4C. In some embodiments, a polymorph of the compound of
Formula (IA) is polymorph Form 3 having a differential scanning
calorimetry profile represented in FIG. 3A, 3B or 3C and/or an
X-ray diffraction pattern represented in FIG. 1A or 1B. In some
embodiments, a polymorph of the compound of Formula (IA) is
polymorph Form 7 having a differential scanning profile represented
in FIG. 4A, 4B or 4C and/or an X-ray diffraction pattern
represented in FIG. 2A or 2B.
[0019] In another aspect, provided is a polymorph of a compound of
Formula IA:
##STR00008##
or a hydrate thereof, wherein the polymorph is bioequivalent to the
polymorph of any of the foregoing embodiments.
[0020] In another aspect, provided is a method of preparing
polymorph Form 3 (which is a polymorph of a monohydrate,
bis-mesylate salt of the compound of Formula I), comprising adding
an amount of polymorph Form 3 seeds and a solvent to polymorph Form
7 (which is a polymorph of a hydrate, bis-mesylate salt of the
compound of Formula I) to form a mixture; wherein the method is
capable of producing polymorph Form 3. In another aspect, provided
is a method of preparing a production scale amount of polymorph
Form 3 (which is a polymorph of a monohydrate, bis-mesylate salt of
the compound of Formula I), comprising adding an amount of
polymorph Form 3 seeds and a solvent to polymorph Form 7 (which is
a polymorph of a hydrate, bis-mesylate salt of the compound of
Formula I) to form a mixture; wherein the polymorph Form 3 has an
X-ray diffraction pattern comprising 2.theta.-reflections (.+-.0.2
degrees) selected from the group consisting of A: 13.8, 16.9, 22.9,
and 26.1; B: 7.7, 12.9, 17.7, and 18.1; and C: 7.7, 12.9, 13.8,
16.9, 17.7, 18.1, 22.9, and 26.1; and wherein the polymorph Form 7
has an X-ray diffraction pattern comprising 2.theta.-reflections
(.+-.0.2 degrees) selected from the group consisting of A: 4.9,
9.8, and 26.7; B: 15.0 and 18.0; and C: 4.9, 9.8, 15.0, 18.0, and
26.7, and wherein the method is capable of producing a production
scale amount of polymorph Form 3. In one variation, the polymorph
Form 3 has an X-ray diffraction pattern comprising
2.theta.-reflections (.+-.0.2 degrees) selected from the group
consisting of A: 13.8, 16.9, 22.9, and 26.1; B: 7.7, 12.9, 17.7,
and 18.1; and C: 7.7, 12.9, 13.8, 16.9, 17.7, 18.1, 22.9, and 26.1;
and the polymorph Form 7 has an X-ray diffraction pattern
comprising 2.theta.-reflections (.+-.0.2 degrees) at 4.9, 9.8, and
26.7. In another variation, the polymorph Form 3 has an X-ray
diffraction pattern comprising 2.theta.-reflections (.+-.0.2
degrees) selected from the group consisting of A: 13.8, 16.9, 22.9,
and 26.1; B: 7.7, 12.9, 17.7, and 18.1; and C: 7.7, 12.9, 13.8,
16.9, 17.7, 18.1, 22.9, and 26.1; and the polymorph Form 7 has an
X-ray diffraction pattern comprising 2.theta.-reflections (.+-.0.2
degrees) at 4.9 and 9.8, and 2.theta.-reflections (.+-.0.4 degrees)
at 26.7. In yet another variation, the polymorph Form 3 has an
X-ray diffraction pattern comprising 2.theta.-reflections (.+-.0.2
degrees) selected from the group consisting of A: 13.8, 16.9, 22.9,
and 26.1; B: 7.7, 12.9, 17.7, and 18.1; and C: 7.7, 12.9, 13.8,
16.9, 17.7, 18.1, 22.9, and 26.1; and the polymorph Form 7 has an
X-ray diffraction pattern comprising 2.theta.-reflections (.+-.0.2
degrees) at 4.9 and 9.8, and 2.theta.-reflections (.+-.0.3 degrees)
at 26.7. In some embodiments, the method further comprises
isolating polymorph Form 3. In some embodiments, the solvent
comprises acetone. In some embodiments, the solvent comprises
acetone and water. In some embodiments, the ratio of water to
acetone is about 1:15 to about 1:40; or about 1:18 to about 1:22.
In some embodiments, the method further comprises agitating the
mixture; heating the mixture; and cooling the mixture to provide
polymorph Form 3. It is understood that the methods detailed herein
may also be carried out on a non-production scale, such as a method
of preparing a less than production scale amount of polymorph Form
3.
[0021] In yet another aspect, provided is a method of preparing a
production scale amount of polymorph Form 3, which is a polymorph
of a monohydrate of a compound of Formula IA:
##STR00009##
comprising adding an amount of polymorph Form 3 seeds and at least
one solvent to polymorph Form 7, which is a polymorph of a hydrate
of a compound of Formula IA, to form a mixture; and isolating
polymorph Form 3 produced. In some embodiments, the at least one
solvent is acetone. In some embodiments, the at least one solvent
further comprises water. In some embodiments, the at least one
solvent is acetone and further comprises water. In some
embodiments, the ratio of water to acetone is about 1:15 to about
1:40. In other embodiments, the ratio of water to acetone is about
1:18 to about 1:22. In some embodiments, the method further
comprises agitating the mixture; heating the mixture; and cooling
the mixture to provide polymorph Form 3.
[0022] In yet another aspect, provided is a method of preparing
polymorph Form 3, which is polymorph of a monohydrate, bis-mesylate
salt of a compound of Formula I, comprising: adding a solvent to a
compound of Formula I to form a mixture; adding an amount of
methanesulfonic acid to the mixture; heating the mixture; adding an
amount of polymorph Form 3 seeds to the mixture; and cooling the
mixture; wherein the method is capable of producing polymorph Form
3. In yet another aspect, provided is a method of preparing a
production scale amount of polymorph Form 3, which is a polymorph
of a monohydrate, bis-mesylate salt of a compound of Formula I,
comprising: adding a solvent to a compound of Formula I to form a
mixture; adding an amount of methanesulfonic acid to the mixture;
heating the mixture; adding an amount of polymorph Form 3 seeds to
the mixture; and cooling the mixture; wherein an X-ray diffraction
pattern of the polymorph Form 3 comprises 2.theta.-reflections
(.+-.0.2 degrees) selected from the group consisting of A: 13.8,
16.9, 22.9, and 26.1; B: 7.7, 12.9, 17.7, and 18.1; and C: 7.7,
12.9, 13.8, 16.9, 17.7, 18.1, 22.9, and 26.1. In some variations,
the mixture formed from adding solvent to the compound of Formula I
may be a heterogeneous mixture. In one embodiment, the method
further comprises isolating the polymorph Form 3. In another
embodiment, the amount of methanesulfonic acid is between 1.8 and
3.2 molar equivalents, between 1.8 and 3.0 molar equivalents,
between 1.95 and 3.0 molar equivalents, or between 2.0 and 2.4
molar equivalents with respect to one molar equivalent of the
compound of Formula I. It is understood that the methods detailed
herein may also be carried out on a non-production scale, such as a
method of preparing a less than production scale amount of
polymorph Form 3.
[0023] In one aspect, provided is a method of preparing a
production scale amount of polymorph Form 3, which is a polymorph
of a monohydrate, bis-mesylate salt of a compound of Formula I:
##STR00010##
comprising adding at least one solvent to the compound of Formula I
to form a mixture; adding an amount of methanesulfonic acid to the
mixture; heating the mixture; adding an amount of polymorph Form 3
seeds to the mixture; cooling the mixture; and recovering the
polymorph Form 3 produced. In some embodiments, the amount of
methanesulfonic acid is between 2.0 and 2.4 molar equivalents with
respect to one molar equivalent of the compound of Formula I. In
yet another aspect, provided is polymorph Form 3, which is a
polymorph of a monohydrate, bis-mesylate salt of a compound of
Formula I, prepared by a method of any of the foregoing
embodiments. In yet another aspect, provided is a production scale
amount of polymorph Form 3, which is a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I, prepared by a
production scale method of the foregoing embodiments.
[0024] In one aspect, provided is a method of preparing polymorph
Form 7, which is a polymorph of a hydrate, bis-mesylate salt of a
compound of Formula I:
##STR00011##
comprising adding at least one solvent to the compound of Formula I
to form a mixture; adding an amount of methanesulfonic acid to the
mixture; heating the mixture; and cooling the mixture to provide
polymorph Form 7. In some embodiments, the method further comprises
isolating polymorph Form 7. In yet another aspect, provided is
polymorph Form 7, which is a polymorph of a hydrate, bis-mesylate
salt of a compound of Formula I, prepared by a method of any of the
foregoing embodiments.
[0025] In another aspect, provided is a polymorph of a hydrate,
bis-mesylate salt of a compound of Formula I prepared by a method
of any of the foregoing embodiments. In another aspect, provided is
a polymorph of a monohydrate, bis-mesylate salt of a compound of
Formula I prepared by a method of any of the foregoing
embodiments.
[0026] In one aspect, provided is a polymorph of a bis-mesylate
salt of a compound of Formula I, or a hydrate thereof, wherein the
polymorph is bioequivalent to the bis-mesylate salt of a compound
of Formula I, or a hydrate thereof, of any of the foregoing
embodiments.
[0027] In another aspect, provided is polymorph Form 3, which is a
polymorph of a monohydrate of a compound of Formula IA:
##STR00012##
prepared by any of the foregoing methods.
[0028] In another aspect, provided is a pharmaceutical composition
comprising a bis-mesylate salt of a compound of Formula I, a
hydrate thereof, or a polymorph according to any of the foregoing
embodiments.
[0029] In yet another aspect, provided is an article of manufacture
comprising a bis-mesylate salt of a compound of Formula I, or a
hydrate thereof; or a polymorph or a pharmaceutical composition
according to any of the foregoing embodiments.
[0030] In one aspect, provided is a method of treating a condition
in a subject in need thereof, comprising administering to the
subject a bis-mesylate salt of a compound of Formula I, or a
hydrate thereof; or a polymorph of the bis-mesylate salt of a
compound of Formula I, or a hydrate thereof; or a pharmaceutical
composition comprising any of the foregoing embodiments, wherein
the condition is selected from the group consisting of cancer and
autoimmune disease. In some embodiments, the condition is selected
from the group consisting of acute lymphocytic leukemia (ALL),
acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL),
small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),
myeloproliferative disease (MPD), chronic myeloid leukemia (CML),
multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell
lymphoma (MCL), follicular lymphoma (FL), Waldestrom's
macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse
large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL),
and marginal zone lymphoma (MZL). In certain embodiments, the
condition is non-Hodgkin's lymphoma. In one variation, the NHL is
indolent non-Hodgkin's lymphoma (iNHL). In another variation, the
iNHL is refractory iNHL. In yet another variation, the iNHL is
non-FL iNHL. In other embodiments, the condition is selected from
the group consisting of asthma, rheumatoid arthritis, multiple
sclerosis, and lupus. In some of the foregoing embodiments, the
subject is human.
DESCRIPTION OF THE FIGURES
[0031] FIGS. 1A and 1B are exemplary X-ray powder diffraction
pattern (XRPD) patterns of polymorph Form 3.
[0032] FIGS. 2A and 2B are exemplary XRPD patterns of polymorph
Form 7. The XRPD pattern in FIG. 2B was obtained at 25.degree. C.
and 53% relative humidity (RH).
[0033] FIG. 3A is an exemplary differential scanning calorimetry
(DSC) plot of polymorph Form 3.
[0034] FIGS. 3B and 3C are exemplary DSC and thermal gravimetric
analysis (TGA) plots of polymorph Form 3.
[0035] FIG. 4A is an exemplary DSC plot of polymorph Form 7.
[0036] FIGS. 4B and 4C are exemplary DSC and TGA plots of polymorph
Form 7.
[0037] FIG. 5 shows the results of dynamic vapor sorption (DVS)
plot of (FIG. 5A) polymorph Form 3, and (FIG. 5B) polymorph Form
7.
[0038] FIGS. 5C and 5D show the results of a DVS plot of polymorph
Form 3 and polymorph Form 7, respectively.
[0039] FIG. 6 is an XRPD pattern of polymorph Form 3 before and
after DVS measurements.
[0040] FIG. 7 shows a comparison of dissolution rates between
polymorph Form 3 and the mono-mesylate (mono-MSA) salt of a
compound of Formula I at pH 6.8.
[0041] FIG. 8 shows a plot summarizing the results of a PK study of
mono- and bis-MSA salt form in dogs that have been pretreated with
either pentagastrin or famotidine (an acid suppressant).
[0042] FIG. 9 shows a simulated XRPD pattern of polymorph Form
3.
[0043] FIG. 10A shows a view of polymorph Form 3 from the crystal
structure showing the numbering scheme employed.
[0044] FIG. 10B illustrates the hydrogen bonding interactions of
polymorph Form 3.
[0045] FIG. 11 illustrates the infinite chains of polymorph Form 3,
mesylate and water molecules viewed down the crystallographic a
axis.
[0046] FIG. 12 illustrates the packing of polymorph Form 3 down the
crystallographic b axis.
[0047] FIG. 13 shows an exemplary proton NMR spectrum of polymorph
Form 3.
[0048] FIG. 14 shows an exemplary proton NMR spectrum of polymorph
Form 7.
DETAILED DESCRIPTION
[0049] The following examples are included to illustrate
embodiments of the disclosure, and are not intended to limit the
scope of the disclosure. It should be appreciated by those of skill
in the art that the techniques disclosed herein represent
techniques that apply in the practice of the disclosure. Those of
skill in the art would appreciate that, in light of the present
disclosure, changes can be made in the examples herein without
departing from the spirit and scope of the disclosure.
[0050] As used in the present specification, the following words
and phrases are generally intended to have the meanings as set
forth below, except to the extent that the context in which they
are used indicates otherwise.
[0051] Terms used in the singular will also include the plural. For
example, "a" means one or more unless indicated otherwise.
[0052] The use of the term "about" includes and describes the value
or parameter per se. For example, "about x" includes and describes
"x" per se. In some embodiments, the term "about" when used in
association with a measurement, or used to modify a value, a unit,
a constant, or a range of values, refers to variations of .+-.10%.
For example, "about 2:8" in some embodiments includes
1.8-2.2:7.2-8.8.
[0053] The use of the term "adding" does not limit the order,
method or how the materials being added are combined, unless
indicated otherwise. For instance, "adding A to B" may also
describe "adding B to A". Furthermore, "adding A and B to C" may
also describe the various other combinations such as "adding A to B
and C", "adding A and C to B", "adding B to A and C", "adding B and
C to A", and "adding C to A and B".
[0054] Provided are pharmaceutically acceptable salts of the
compound of Formula I:
##STR00013##
or a hydrate thereof. In some aspects, the pharmaceutically
acceptable salt of the compound of Formula I is a mesylate salt, or
a hydrate thereof. In one variation, the pharmaceutically
acceptable salt of the compound of Formula I is a bis-mesylate
salt, or a hydrate thereof.
[0055] In some embodiments, a bis-mesylate salt, or a hydrate
thereof, of a compound of Formula I is provided. It should be
understood that "bis-mesylate salt" may also be referred to herein
as "bis-MSA salt". In certain embodiments, a hydrate, bis-mesylate
salt of a compound of Formula I is provided. In another embodiment,
a monohydrate, bis-mesylate salt of a compound of Formula I is
provided. In yet another embodiment, a polymorph of any of the
foregoing is provided. In one variation, Form 3, which is a
polymorph of a monohydrate, bis-mesylate salt of a compound of
Formula I, is provided. In another variation, Form 7, which is a
polymorph of a hydrate, bis-mesylate salt of a compound of Formula
I, is provided.
[0056] The bis-mesylate salt of a compound of Formula I may be
depicted herein various ways. For example, in one variation, a
bis-mesylate salt may be represented by Formula IA:
##STR00014##
One of skill in the art would understand that when a bis-mesylate
salt of the compound of Formula I is depicted as Formula IA above,
the ionic form (e.g., the cationic form of the compound of formula
I and the anionic form of the methanesulfonic acid) is intended.
Without wishing to be bound by any theory, in another variation, a
bis-mesylate salt may be represented by Formula IB:
##STR00015##
[0057] In some embodiments, the bis-mesylate salt, as depicted by
Formula IA or IB, may be a hydrate thereof. For example, in one
embodiment, the bis-mesylate salt, as depicted by Formula IA or IB,
may be a monohydrate, bis-mesylate salt. Without wishing to be
bound by any theory, a monohydrate, bis-mesylate salt of a compound
of Formula I may also be represented by Formula IC:
##STR00016##
The monohydrate, bis-mesylate salt of a compound of Formula I has
increased solubility at higher pH compared to the mono-mesylate
salt of a compound of Formula I. It should be understood that
"mono-mesylate salt" may also be referred to herein as "mono-MSA
salt". The bis-mesylate salt of a compound of Formula I in
comparison to the mono-mesylate salt of a compound of Formula I
provides increased bioavailability and the ability to offset the
effect of acid reducing agents on the pharmacokinetic (PK) profile
of the compound of Formula I.
[0058] Without wishing to be bound by any theory, in other
embodiments, a hydrate of a bis-mesylate salt of a compound of
Formula I may be represented by Formula ID:
##STR00017##
wherein y is at least 0.5. In some variations, y is at least 1, at
least 1.5, at least 2, at least 2.5, at least 3, or at least 4, or
between 0.5 and 5, between 0.5 and 4, between 0.5 and 2, between
0.5 and 1.5, or about 0.5, about 1, about 1.5, about 2, about 3, or
about 4. In certain variations, y is an integer. For example, when
y is 1, the compound of Formula ID is a monohydrate, bis-mesylate
salt. When y is 2, the compound of Formula ID is a bis-hydrate,
bis-mesylate salt. Thus, variable "y" in Formula ID represents the
variability of the water content in the hydrate of the bis-mesylate
salt.
[0059] Without wishing to be bound by any theory, in another
variation, the hydrate, bis-mesylate salt may be represented by
Formula IE:
##STR00018##
wherein y is at least 0.5. In some variations, y is at least 1, at
least 1.5, at least 2, at least 2.5, at least 3, or at least 4, or
between 0.5 and 5, between 0.5 and 4, between 0.5 and 2, between
0.5 and 1.5, or about 0.5, about 1, about 1.5, about 2, about 3, or
about 4. In certain variations, y is an integer. For example, when
y is 2, the compound of Formula IE is a bis-hydrate, bis-mesylate
salt. In other variations, y is a non-integer.
[0060] In yet other embodiments, a hydrate of a bis-mesylate salt
of a compound of Formula I may have varying amounts of water.
[0061] Provided herein are polymorphs of a mesylate salt of a
compound of Formula I, or a hydrate thereof. In certain aspects,
provided are polymorphs of a bis-mesylate salt of a compound of
Formula I, or a hydrate thereof. In certain variations, provided
are polymorphs of a monohydrate, bis-mesylate salt of a compound of
Formula I. In one aspect, a polymorph of a compound of Formula IA
or IB, or a hydrate thereof, is provided. In another aspect, a
polymorph of a compound of Formula IC, ID or IE is provided. The
polymorphs described herein may be characterized by a variety of
solid state analytical data, including for example, by X-ray powder
diffraction pattern (XRPD), differential scanning calorimetry (DSC)
and thermal gravimetric analysis (TGA).
Polymorph Form 3
[0062] The therapeutic use and commercialization of a bis-mesylate
salt of a compound of Formula I, or a hydrate thereof (e.g., a
compound of Formula IA or IB, or a hydrate thereof; or a compound
of IC or ID) involves the development of a bioavailable and stable
compound. As one of skill in the art would appreciate, variations
in the crystal structure of a pharmaceutical drug substance may
affect the dissolution rate (which may affect bioavailability,
etc.), manufacturability (e.g., ease of handling, ability to
consistently prepare doses of known strength) and stability (e.g.,
thermal stability, shelf life, etc.) of a pharmaceutical drug
product, particularly when formulated in a solid oral dosage
form.
[0063] In one aspect, provided is polymorph Form 3, which is a
polymorph of a monohydrate, bis-mesylate salt of a compound of
Formula I. In certain variations, Form 3 is crystalline. Thus, in
certain aspects, provided is polymorph Form 3, which is a polymorph
of a monohydrate of a compound of Formula IA:
##STR00019##
In some embodiments, polymorph Form 3 is a crystalline form of a
monohydrate, bis-mesylate salt of Formula IA. One of skill in the
art would understand that when the bis-mesylate salt is depicted as
Formula IA above, the ionic form (e.g., the cationic form of the
compound of Formula I and the anionic form of the methanesulfonic
acid) is intended.
[0064] In other aspects, provided is polymorph Form 3, which is a
polymorph of a monohydrate of a compound of Formula IB:
##STR00020##
In some embodiments, polymorph Form 3 is a crystalline form of a
monohydrate, bis-mesylate salt of Formula IB.
[0065] In certain aspects, provided is polymorph Form 3, which is a
polymorph of a compound of Formula IC:
##STR00021##
In some embodiments, polymorph Form 3 is a crystalline form of a
monohydrate, bis-mesylate salt of a compound of Formula I.
[0066] In yet other aspects, provided is polymorph Form 3, which is
a polymorph of a compound of Formula ID:
##STR00022##
wherein y is 1 for a monohydrate of the bis-mesylate salt. In some
embodiments, polymorph Form 3 is a crystalline form of a
monohydrate, bis-mesylate salt of Formula ID.
[0067] In yet other aspects, provided is polymorph Form 3, which is
a polymorph of a compound of Formula IE:
##STR00023##
[0068] wherein y is 1 for a monohydrate of the bis-mesylate salt.
In some embodiments, polymorph Form 3 is a crystalline form of a
monohydrate, bis-mesylate salt of Formula IE. Throughout the
present disclosure, it is understood that reference to "polymorph
Form 3", "Form 3", "Form III", "bis-MSA salt of polymorph Form 3",
or "bis-MSA salt Form 3" refers to the polymorph Form 3, which is a
polymorph of a monohydrate, bis-mesylate salt of the compound of
Formula I. As discussed above, the bis-mesylate salt may be
depicted in various ways, including as a compound of Formula IA or
IB. Furthermore, the monohydrate, bis-mesylate salt may be depicted
by Formula IC, ID (wherein y is 1) or IE (wherein y is 1).
[0069] In some variations, polymorph Form 3 is characterized by or
has an X-ray powder diffraction (XRPD) pattern substantially as
shown in FIG. 1A or 1B. It should be understood, however, that
relative intensities and assignments of the peaks of polymorphic
forms depicted in the figures can vary depending on a number of
factors, including sample preparation, mounting, and the instrument
and analytical procedure and settings used to obtain the spectrum.
As such, the peaks observed in the figures and assignments listed
herein (including in FIGS. 1A and 1B for polymorph Form 3) are
intended to encompass variations of plus or minus 0.2 degrees
2.theta..
[0070] In other variations, polymorph Form 3 is characterized by or
has an X-ray diffraction (XRPD) pattern comprising
2.theta.-reflections (.+-.0.2 degrees): 13.8, 16.9, 22.9, and 26.1.
In some embodiments, polymorph Form 3 is characterized by or has an
X-ray diffraction (XRPD) pattern comprising at least one or more;
at least two or more; or at least three or more of the
2.theta.-reflections (.+-.0.2 degrees): 13.8, 16.9, 22.9, and 26.1.
In some embodiments, polymorph Form 3 is characterized by or has an
X-ray diffraction comprising 2.theta.-reflections (.+-.0.2
degrees): 7.7, 12.9, 17.7, and 18.1. In some embodiments, polymorph
Form 3 is characterized by or has an X-ray diffraction pattern
comprising 2.theta.-reflections (.+-.0.2 degrees) at 7.7, 12.9,
13.8, 16.9, 17.7, 18.1, 22.9, and 26.1. In some embodiments,
polymorph Form 3 is characterized by or has an X-ray diffraction
(XRPD) pattern comprising at least three or more; at least four or
more; or at least five or more of the 2.theta.-reflections (.+-.0.2
degrees): 7.7, 12.9, 13.8, 16.9, 17.7, 18.1, 22.9, and 26.1. When
describing the 2.theta.-reflections in the X-ray diffraction
pattern (e.g., of Form 3), it should be understood that .+-.0.2
degrees can also be expressed as "plus or minus 0.2 degrees
2.theta.".
[0071] In some embodiments, polymorph Form 3 is characterized by or
has a DSC plot substantially as shown in FIG. 3A, 3B or 3C.
[0072] In some embodiments, the term "substantially as shown in"
when referring to an X-ray powder diffraction pattern or a
differential scanning calorimetry profile means that a pattern or
profile that is not necessarily identical to those depicted herein,
but that falls within the limits of experimental error or
deviations, when considered by one of ordinary skill in the art,
would be encompassed.
[0073] In certain variations, polymorph Form 3 may also have one or
more, two or more, three or more, four or more, five or more, or
all of the following properties (i)-(vi):
[0074] (i) a unit cell as determined by crystal X-ray
crystallography of the following dimensions: a=8.7831(6) .ANG.;
b=11.8484(8) .ANG.; c=14.2485(10) .ANG.; .alpha.=98.108(6).degree.;
.beta.=100.955(6).degree.; and .gamma.=98.861(6).degree.;
[0075] (ii) a triclinic crystal system;
[0076] (iii) a P-1 space group;
[0077] (iv) a volume of 1416.05(17) .ANG..sup.3;
[0078] (v) a Z-value of 2; and
[0079] (vi) a density of 1.458 Mg/m.sup.3.
Polymorph Form 7
[0080] In another aspect, provided is polymorph Form 7, which is a
polymorph of a hydrate, bis-mesylate salt a compound of Formula I.
In some variations, provided is polymorph Form 7, which is a
polymorph of a hydrate of a compound of Formula IA:
##STR00024##
One of skill in the art would understand that when the bis-mesylate
salt is depicted as Formula IA above, the ionic form (e.g., the
cationic form of the compound of Formula I and the anionic form of
the methanesulfonic acid) is intended.
[0081] In other variations, provided is polymorph Form 7, which is
a polymorph of a compound of Formula IB:
##STR00025##
[0082] In some embodiments, polymorph Form 7 is a variable hydrate
of a bis-mesylate salt of a compound of Formula I. A variable
hydrate may have varying water content. For example, in one
embodiment, polymorph Form 7 is a polymorph of a bis-mesylate salt
having between 1.8% to 10% water. Various factors may affect the
water content of polymorph Form 7, including, for example, the
relative humidity conditions at which polymorph Form 7 is
characterized.
[0083] In some variations, polymorph Form 7 is a polymorph of a
hydrate, bis-mesylate salt that comprises at least two molecules of
water. In one variation, polymorph Form 7 may be depicted by
Formula ID:
##STR00026##
wherein y is at least 0.5. In some variations, y is at least 1, at
least 1.5, at least 2, at least 2.5, at least 3, or at least 4, or
between 0.5 and 5, between 0.5 and 4, between 0.5 and 2, between
0.5 and 1.5, or about 0.5, about 1, about 1.5, about 2, about 3, or
about 4. In certain variations, y is an integer. For example, when
y is 2, the compound of Formula ID is a bis-hydrate, bis-mesylate
salt. In other variations, y is a non-integer.
[0084] In some variations, polymorph Form 7 is a polymorph of a
hydrate, bis-mesylate salt that comprises at least two molecules of
water. In one variation, polymorph Form 7 may be depicted by
Formula IE:
##STR00027##
wherein y is at least 0.5. In some variations, y is at least 1, at
least 1.5, at least 2, at least 2.5, at least 3, or at least 4, or
between 0.5 and 5, between 0.5 and 4, between 0.5 and 2, between
0.5 and 1.5, or about 0.5, about 1, about 1.5, about 2, about 3, or
about 4. In certain variations, y is an integer. For example, when
y is 2, the compound of Formula IE is a bis-hydrate, bis-mesylate
salt. In other variations, y is a non-integer.
[0085] Throughout the application it is understood that reference
to "polymorph Form 7", "Form 7", "Form VII", "bis-MSA salt of
polymorph Form 7", or "bis-MSA salt Form 7" refers to the polymorph
Form 7, which is a polymorph of a hydrate, bis-mesylate salt of a
compound of Formula I. As discussed above, a bis-mesylate salt may
be depicted in various ways, including as a compound of Formula IA
or IB. Furthermore, a bis-mesylate salt having varying water
content may be depicted by Formula ID.
[0086] In some variations, polymorph Form 7 is characterized by or
has an X-ray diffraction (XRPD) pattern comprising
2.theta.-reflections (.+-.0.2 degrees) at 4.9 and 9.8, and
2.theta.-reflections (.+-.0.4 degrees) at 26.7. In certain
variations, polymorph Form 7 is characterized by or has an X-ray
diffraction (XRPD) pattern comprising 2.theta.-reflections (.+-.0.2
degrees) at 4.9 and 9.8, and 2.theta.-reflections (.+-.0.3 degrees)
at 26.7. In certain variations, polymorph Form 7 is characterized
by or has an X-ray diffraction (XRPD) pattern comprising
2.theta.-reflections (.+-.0.2 degrees): 4.9, 9.8, and 26.7.
[0087] In some variations, polymorph Form 7 is characterized by or
has an X-ray diffraction (XRPD) pattern comprising at least one or
more; or at least two or more of 2.theta.-reflections at 4.9
(.+-.0.2 degrees), 9.8 (.+-.0.2 degrees), and 26.7 (.+-.0.4
degrees). In some variations, polymorph Form 7 is characterized by
or has an X-ray diffraction (XRPD) pattern comprising at least one
or more; or at least two or more of 2.theta.-reflections at 4.9
(.+-.0.2 degrees), 9.8 (.+-.0.2 degrees), and 26.7 (.+-.0.3
degrees). In certain variations, polymorph Form 7 is characterized
by or has an X-ray diffraction (XRPD) pattern comprising at least
one or more; or at least two or more of 2.theta.-reflections
(.+-.0.2 degrees): 4.9, 9.8, and 26.7.
[0088] In other embodiments, polymorph Form 7 is characterized by
or has an X-ray diffraction pattern comprising 2.theta.-reflections
(.+-.0.2 degrees): 15.0 and 18.0. In some embodiments, polymorph
Form 7 is characterized by or has an X-ray diffraction pattern
comprising 2.theta.-reflections (.+-.0.2 degrees) at 4.9, 9.8, 15.0
and 18.0, and 2.theta.-reflections (.+-.0.4 degrees) at 26.7. In
some embodiments, polymorph Form 7 is characterized by or has an
X-ray diffraction pattern comprising 2.theta.-reflections (.+-.0.2
degrees) at 4.9, 9.8, 15.0 and 18.0, and 20-reflections (.+-.0.3
degrees) at 26.7. In some embodiments, polymorph Form 7 is
characterized by or has an X-ray diffraction pattern comprising
2.theta.-reflections (.+-.0.2 degrees) at 4.9, 9.8, 15.0, 18.0, and
26.7.
[0089] In other embodiments, polymorph Form 7 is characterized by
or has an X-ray diffraction (XRPD) pattern comprising at least
three or more; at least four or more; or each of the
2.theta.-reflections at 4.9 (.+-.0.2 degrees), 9.8 (.+-.0.2
degrees), 15.0 (.+-.0.2 degrees), 18.0 (.+-.0.2 degrees), and 26.7
(.+-.0.4 degrees). In some embodiments, polymorph Form 7 is
characterized by or has an X-ray diffraction (XRPD) pattern
comprising at least three or more; at least four or more; or each
of the 2.theta.-reflections at 4.9 (.+-.0.2 degrees), 9.8 (.+-.0.2
degrees), 15.0 (.+-.0.2 degrees), 18.0 (.+-.0.2 degrees), and 26.7
(.+-.0.3 degrees). In some embodiments, polymorph Form 7 is
characterized by or has an X-ray diffraction (XRPD) pattern
comprising at least three or more; at least four or more; or each
of the 2.theta.-reflections (.+-.0.2 degrees) at 4.9, 9.8, 15.0,
18.0, and 26.7.
[0090] When describing the 2.theta.-reflections in the X-ray
diffraction pattern (e.g., of Form 7), it should be understood that
.+-.0.2 degrees, .+-.0.3 degrees, and .+-.0.4 degrees can also be
expressed as "plus or minus 0.2 degrees 2.theta.", "plus or minus
0.3 degrees 2.theta.", and "plus or minus 0.4 degrees 2.theta.",
respectively.
[0091] In some variations, polymorph Form 7 is also characterized
by or has an XRPD pattern substantially as shown in FIG. 2A or 2B.
It should be understood, however, that relative intensities and
assignments of the peaks of polymorphic forms depicted in the
figures can vary depending on a number of factors, including sample
preparation, mounting, and the instrument and analytical procedure
and settings used to obtain the spectrum. As such, the peak
observed in the figures and assignments listed herein (including in
FIGS. 2A and 2B for polymorph Form 7) are intended to encompass
variations of plus or minus 0.2 degrees 2.theta.. Further, in
certain instances, the XRPD pattern of polymorph Form 7 may be
moisture-dependent or vary based on the relative humidity at which
Form 7 is characterized. For example, the XRPD in FIG. 2B was
obtained at 25.degree. C. and 53% relative humidity (RH).
[0092] In some embodiments, polymorph Form 7 is provided as a
compound intermediate in the preparation of polymorph Form 3. In
some embodiments, polymorph Form 7 is provided in a reaction
mixture comprising polymorph Form 3. In some methods of making Form
3 from a compound of Formula I (which may also be referred to as
the free base of Formula I), Form 7 is an intermediate in the
reaction pathway.
Crystalline
[0093] The term "crystalline" refers to a solid phase in which the
material has a regular ordered internal structure at the molecular
level and gives a distinctive X-ray diffraction pattern with
defined peaks. Such materials when heated sufficiently will also
exhibit the properties of a liquid, but the change from solid to
liquid is characterized by a phase change, typically first order
(melting point).
[0094] For example, in one embodiment, polymorph Form 3 is
substantially crystalline. In some embodiments, a compound that is
substantially crystalline (e.g., polymorph Form 3) has greater than
50%; or greater than 55%; or greater than 60%; or greater than 65%;
or greater than 70%; or greater than 75%; or greater than 80%; or
greater than 85%; or greater than 90%; or greater than 95%, or
greater than 99% of the compound present in a composition in
crystalline form. In other embodiments, a compound that is
substantially crystalline (e.g., polymorph Form 3) has no more than
about 20%, or no more than about 10%, or no more than about 5%, or
no more than about 2% in the amorphous form. In yet other
embodiments, a compound that is substantially crystalline (e.g.,
polymorph Form 3) has no more than about 20%, or no more than about
10%, or no more than about 5%, or no more than about 2% in the
non-crystalline form.
Bioequivalents of the Polymorphs
[0095] Also provided herein are polymorphs that are bioequivalent
to polymorph Form 3. Also provided herein are polymorphs that are
bioequivalent to polymorph Form 7. In certain embodiments,
bioequivalence between two polymorphs refers to polymorphs having
substantially similar bioavailability, substantially similar
efficacy, substantially similar safety profiles, or a combination
thereof. In yet other embodiments, bioequivalence refers to
polymorphs that exhibit substantially similar pharmacokinetic (PK)
profiles or therapeutic effects. Bioequivalence may be demonstrated
through several in vivo and in vitro methods. These methods may
include, for example, pharmacokinetic, pharmacodynamic, clinical
and in vitro studies. In some embodiments, bioequivalence can be
demonstrated using any suitable pharmacokinetic measures or
combination of pharmacokinetic measures known in the art, including
loading dose, steady-state dose, initial or steady-state
concentration of drug, biological half-life, elimination rate, area
under the curve (AUC), clearance, the peak blood or plasma
concentration (C.sub.max), time to peak concentration (T.sub.max),
bioavailability and potency. In some embodiments, bioequivalence is
achieved with similar dosing amounts. In alternative embodiments,
bioequivalence is achieved with different dosing amounts.
Methods of Preparing Polymorph Form 3
[0096] In some embodiments, polymorph Form 3 described herein is
prepared by converting Form 7 into Form 3. Converting Form 7 into
Form 3 may be facilitated by adding an amount of polymorph Form 3
"seeds" to Form 7. In some embodiments, the methods of preparing
Form 3 require forming the polymorph Form 7 as a compound
intermediate.
[0097] In some embodiments, provided is a method of producing
polymorph Form 3, which is a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I, comprising:
[0098] adding polymorph Form 3 seeds and at least one solvent to
polymorph Form 7 (which is a polymorph of a hydrate, bis-mesylate
salt of a compound of Formula I) to form a mixture; and
[0099] producing polymorph Form 3 in the mixture.
In certain embodiments, the method further comprises isolating the
polymorph Form 3 from the mixture.
[0100] In some embodiments, provided is a method of preparing a
production scale amount of polymorph Form 3, which is a polymorph
of a monohydrate, bis-mesylate salt of a compound of Formula I,
comprising adding an amount of polymorph Form 3 seeds and at least
one solvent to polymorph Form 7 (which is a polymorph of a hydrate,
bis-mesylate salt of a compound of Formula I) to form a mixture;
and isolating polymorph Form 3.
[0101] In some embodiments of the methods provided above, the
amount of seed is an amount sufficient to initiate nucleation. In
some embodiments, the amount of seed is an amount that reduces the
time it takes to convert Form 7 to Form 3 compared to conversion
without the seed material. In some embodiments, adding an amount of
Form 3 seeds reduces Form 7 to Form 3 conversion time by about 10%
to about 20%; about 20% to about 50%; about 30% to about 60%; about
40% to about 75%; or about 50% to about 80%, compared to conversion
time without the addition of Form 3 seed. In some embodiments,
adding an amount of Form 3 seeds reduces Form 7 to Form 3
conversion time by at least about 10%; at least about 25%; at least
about 40%; at least about 50%; at least about 60%; at least about
75%; or at least about 80%, compared to conversion time without the
addition of Form 3 seeds.
[0102] In some embodiments, the methods provide adding an amount of
polymorph Form 3 seeds to Form 7. The amount of Form 3 seeds is
substantially smaller than the amount of Form 7 to be converted and
is also substantially smaller than the amount of Form 3 obtained by
the methods described herein. In some embodiments, the amount of
Form 3 seeds added to polymorph Form 7 is between 0.01 molar % and
5 molar %. In some embodiments, the amount of Form 3 seeds added to
polymorph Form 7 is between 0.01 molar % and 3 molar % of polymorph
Form 7. In some embodiments, the amount of Form 3 seeds added to
polymorph Form 7 is between 0.01 molar % and 2 molar % of polymorph
Form 7. In some embodiments, the amount of Form 3 seeds added to
polymorph Form 7 is between 0.01 molar % and 1 molar % of polymorph
Form 7. In some embodiments, the amount of Form 3 seeds added to
polymorph Form 7 is between 0.1 molar % and 2 molar % of polymorph
Form 7. In some embodiments, the amount of Form 3 seeds added to
polymorph Form 7 is between 0.1 molar % and 1 molar % of polymorph
Form 7. In some embodiments, the amount of Form 3 seeds added to
polymorph Form 7 is about 1 molar % of polymorph Form 7.
[0103] In some embodiments, the amount of Form 3 seeds added to
polymorph Form 7 is between 0.001 and 0.1 weight percent of
polymorph Form 7. In some embodiments, the amount of Form 3 seeds
added to polymorph Form 7 is between 0.01 and 0.1 weight percent of
polymorph Form 7. In some embodiments, the amount of Form 3 seeds
added to polymorph Form 7 is between 0.01 and 0.08 weight percent
of polymorph Form 7. In some embodiments, the amount of Form 3
seeds added to polymorph Form 7 is about 0.015 weight percent of
polymorph Form 7.
[0104] In one embodiment, however, one or more of the steps of the
method to prepare polymorph Form 3 from Form 7 may be omitted or
the order of the steps may be varied. For instance, in alternative
embodiments, the methods of making Form 3 do not require adding
seeds of Form 3 to Form 7. In some embodiments, the method
comprises the steps of heating and cooling the mixture. In some
embodiments, polymorph Form 7 is not isolated from the reaction
mixture but generated in situ and converted to Form 3.
[0105] In some embodiments, Form 3, including seeds thereof, is
obtained through alternative methods, for instance, the method
described in Example 11. In some embodiments, the method of
preparing Form 3 does not comprise adding seeds of Form 3.
[0106] In some embodiments, a production scale amount of polymorph
Form 3 is greater than 1 kg, 5 kg, 10 kg, 20 kg, 50 kg, 100 kg, 200
kg, or 500 kg. In some embodiments, a production scale amount of
polymorph Form 3 is between 1 kg and 500 kg. In some embodiments, a
production scale amount of polymorph Form 3 is between 10 kg and
300 kg. In some embodiments, a production scale amount of polymorph
Form 3 is between 50 kg and 500 kg.
[0107] In some embodiments, the mixture is heated to reflux. In
some embodiments, the mixture is heated to a temperature between
about 40.degree. C. and about 65.degree. C. In some embodiments,
the mixture is heated to a temperature between about 45.degree. C.
and about 65.degree. C. In some embodiments, the mixture is heated
to a temperature of about 55.degree. C.
[0108] In some embodiments, the mixture may be agitated. In some
embodiments, the mixture is agitated to facilitate the formation of
the Form 3 product. In some embodiments, agitation increases
dispersion of the components in a mixture. Well-dispersed
components in a mixture prevent high concentrations of certain
materials accumulating in a portion of the reaction mixture. For
instance, without agitation, adding a solvent to a solution in
order to precipitate a solid material, higher concentration of
acetone may accumulate in a portion of the solution causing
precipitation of solids in an uneven manner. A gummy form of the
solid or a solid with other undesirable character may result.
Agitation of the solution while adding the solvent, however, can
help prevent uneven distribution of the added solvent and prevent
undesirable forms of precipitated solid. Agitation speed can be
described in terms of revolutions per minute (RPM). In some
embodiments, agitation is greater than about 200 RPM, about 150
RPM, about 100 RPM, or about 50 RPM. In some embodiments, agitation
is between about 150 to about 250 RPM, about 100 to 200 RPM, 50 to
150 RPM. Agitation is particularly important in heterogeneous
mixtures (e.g., slurry). The agitation speed may vary depending on
the scale of the reaction volume with smaller reaction volumes
having higher RPM than larger reaction volumes. For instance,
maximum agitation speed in a production plant may reach about 100
to about 150 RPM. Maximum agitation speed in the laboratory setting
may reach over about 200 RPM. In some methods agitation is between
about 30 to about 60 RPM.
[0109] In some embodiments of the methods, a mixture is formed. In
some embodiments, the mixture is a homogeneous solution. In other
embodiments, the mixture is heterogeneous, wherein the mixture
comprises more than one phase, for instance a solid phase and a
liquid phase. In some embodiments the mixture is a slurry. In some
embodiments, a portion of the contents of a mixture may undergo
phase change over time. For instance, a homogenous solution mixture
may form solids over time and become a heterogeneous mixture,
wherein the mixture comprises a solid and liquid phase.
Alternatively, a heterogeneous mixture may become a homogenous
solution mixture, for instance when a solid material dissolves into
a solvent. In some embodiments the phase change occurs upon a
reaction event. For instance, a homogenous solution mixture may,
upon a reaction event, may become a heterogeneous mixture, and vice
versa. The reaction event may be a change in the conditions of the
reaction mixture, for instance, cooling or heating, addition of a
particular solvent, addition of a solid, or evaporation.
[0110] In some embodiments, provided is a method of producing
polymorph Form 3, which is a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I, comprising:
[0111] adding a compound of Formula I to methanesulfonic acid to
produce a bis-mesylate salt of the compound of Formula I; and
[0112] adding polymorph Form 3 seeds to the bis-mesylate salt to
convert the bis-mesylate salt into polymorph Form 3.
In certain embodiments, the method further comprises isolating the
polymorph Form 3 produced.
[0113] In other embodiments, provided is a method of preparing
polymorph Form 3 by adding the free base of a compound of Formula I
to methanesulfonic acid to form the bis-mesylate salt. The
bis-mesylate salt is added to an amount of polymorph Form 3 seeds
to convert the bis-mesylate salt to Form 3.
[0114] In certain embodiments of the methods described above, the
bis-mesylate salt is polymorph Form 7, which is isolated, then
further used to make Form 3. In other embodiments, the bis-mesylate
salt is Form 7, and is not isolated from the reaction mixture. The
amount of Form 3 seeds is substantially smaller than the amount of
free base used in the method to obtain Form 3, and is also
substantially smaller than the amount of Form 3 obtained by the
methods described herein. In some embodiments, the amount of Form 3
seed added to the bis-mesylate salt is between 0.01 molar % and 5
molar %; between 0.01 molar % and 3 molar %; between 0.01 molar %
and 2 molar %; between 0.01 molar % and 1 molar %; between 0.1
molar % and 2 molar %; or between 0.1 molar % and 1 molar %; about
1 molar % of the free base.
[0115] In some embodiments, the amount of Form 3 seeds added to the
bis-mesylate salt is between 0.001 and 0.1 weight percent; between
0.01 and 0.1 weight percent; or between 0.01 and 0.08 weight
percent; or about 0.015 weight percent of the free base.
[0116] In some embodiments, the amount of methanesulfonic acid is
between about 2.0 and about 2.5 molar equivalents; between about
2.0 and about 2.4 molar equivalents; between about 2.0 and about
2.2 molar equivalents; between about 2.0 and about 2.1 molar
equivalents; between about 2.0 and about 2.05 molar equivalents; or
about 2.05 molar equivalents with respect to one molar equivalent
of the compound of Formula I.
[0117] In practicing any of the methods disclosed herein, in some
embodiments, at least one solvent is added to the mixture.
Non-limiting examples of solvents include methanol, ethanol,
isopropanol, ethyl acetate, isopropyl acetate, acetone,
tetrahydrofuran, toluene, methyl-t-butyl ether, acetonitrile,
heptanes, hexanes, water, methyl ethyl ketone, dichloromethane,
2-methyl-tetrahydrofuran, and methyl isobutyl ketone. In preferred
embodiments, the solvent is acetone. In other embodiments, the
solvents are acetone and water. In some embodiments, the at least
one solvent is an organic solvent. In some embodiments, the at
least one solvent is an organic solvent, further comprising water.
Non-limiting examples of organic solvents include methanol,
ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone,
tetrahydrofuran, toluene, methyl-t-butyl ether, acetonitrile,
heptanes, hexanes, methyl ethyl ketone, dichloromethane,
2-methyl-tetrahydrofuran, and methyl isobutyl ketone. In some
embodiments, the at least one solvent further comprises a protic
solvent. Non-limiting examples of a protic solvent include water,
methanol, ethanol, isopropanol, propanol, and butanol. In some
embodiments, the at least one solvent is acetone, further
comprising water.
[0118] In some embodiments, the at least one solvent is an organic
solvent and water. In some embodiments, the concentration of water
in the water/organic solvent mixture is from about 1% to about
7.5%; from about 2% to about 5%; from about 4% to about 6%; or is
about 5%.
[0119] In some embodiments, the at least one solvent is acetone and
water, wherein the concentration of water in the acetone/water
solvent mixture is about 1% to about 7.0%; about 2% to about 5%;
about 4% to about 6%; or about 5%.
[0120] In some embodiments the ratio of water to acetone is about
1:15 to about 1:40; about 1:18 to about 1:22; about 1:19; or about
1:38.
[0121] In some of the foregoing embodiments, the method comprises
heating the mixture. In some embodiments, lower temperatures
require less water. For instance, while heating the mixture to
55.degree. C. might require a water concentration of about 5%,
heating the mixture to 35.degree. C. might require a water
concentration of about 4%.
[0122] In some embodiments, provided is a method of producing
polymorph Form 3 (which is a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I), comprising:
[0123] adding polymorph Form 3 seeds, acetone and water to
polymorph Form 7 (which is a polymorph of a hydrate, bis-mesylate
salt of a compound of Formula I) to form a mixture; and
[0124] producing polymorph Form 3 in the mixture.
In certain embodiments, the method further comprises isolating the
polymorph Form 3 produced from the mixture.
[0125] In some embodiments, provided is a method of preparing a
production scale amount of polymorph Form 3, which is a polymorph
of a monohydrate, bis-mesylate salt of a compound of Formula I,
such as a monohydrate of a compound of Formula IA
##STR00028##
comprising adding an amount of polymorph Form 3 seeds, acetone and
water to polymorph Form 7 to form a mixture; and isolating
polymorph Form 3 produced, wherein the ratio of water to acetone is
about 1:18 to about 1:22; optionally further comprising agitating
the mixture, and optionally further comprising heating and cooling
the mixture before isolating polymorph Form 3 produced. In some
embodiments, the mixture is heated to reflux and agitated. In some
embodiments, heating the mixture results in a faster conversion of
Form 7 to Form 3 compared to not heating the mixture. In some
embodiments, isolating polymorph Form 3 comprises filtering the
mixture to obtain solids. In some embodiments, the solids are
rinsed with a solvent and then dried.
[0126] In some embodiments, provided is a method of preparing a
production scale amount of polymorph Form 3, which is a polymorph
of a monohydrate, bis-mesylate salt of a compound of Formula I,
such as a monohydrate of a compound of Formula IA:
##STR00029##
comprising adding an amount of polymorph Form 3 seeds and at least
one solvent to polymorph Form 7 to form a mixture; and isolating
polymorph Form 3 produced, wherein polymorph Form 3 has an X-ray
diffraction (XRPD) pattern comprising at least two or more of the
2.theta.-reflections (.+-.0.2 degrees): 13.8, 16.9, 22.9, and 26.1;
and polymorph Form 7 has an X-ray diffraction (XRPD) pattern
comprising at least two or more 2.theta.-reflections (.+-.0.2
degrees): 4.9, 9.8, and 26.7.
[0127] In some embodiments, provided is a method of preparing a
production scale amount of polymorph Form 3, which is a polymorph
of a monohydrate, bis-mesylate salt of a compound of Formula I:
##STR00030##
comprising adding acetone and water to the compound of Formula I to
form a mixture, adding an amount of methanesulfonic acid to the
mixture, heating the mixture, adding an amount of polymorph Form 3
seeds to the mixture; cooling the mixture; and recovering the
compound of Formula I as polymorph Form 3, wherein the amount of
methanesulfonic acid is about 2.05 molar equivalents with respect
to one molar equivalent of the compound of Formula I. In certain
embodiments, the compound of Formula I, acetone, and water mixture
are under agitation, and methanesulfonic acid is added to the
agitated mixture. In some embodiments, the mixture is heated to
reflux and agitated.
Methods of Preparing Polymorph Form 7
[0128] In some embodiments, provided is a method of producing
polymorph Form 7, which is a polymorph of a hydrate, bis-mesylate
salt of a compound of Formula I, comprising:
[0129] adding a solvent to a compound of Formula I to form a
mixture;
[0130] adding an amount of methanesulfonic acid to the mixture;
[0131] heating the mixture; and
[0132] cooling the heated mixture to produce polymorph Form 7.
In some embodiments, the method further comprises isolating
polymorph Form 7 produced.
[0133] In some variations, the solvent comprises methanol, ethanol,
isopropanol, ethyl acetate, isopropyl acetate, acetone,
tetrahydrofuran, toluene, methyl-t-butyl ether, acetonitrile,
heptanes, hexanes, water, methyl ethyl ketone, dichloromethane,
2-methyl-tetrahydrofuran, and methyl isobutyl ketone. In one
variation, the solvent comprises acetone. In other embodiments, the
solvent comprises acetone and water. In some embodiments, the
solvent is an organic solvent. In some embodiments, the solvent is
an organic solvent, further comprising water. Non-limiting examples
of organic solvents include methanol, ethanol, isopropanol, ethyl
acetate, isopropyl acetate, acetone, tetrahydrofuran, toluene,
methyl-t-butyl ether, acetonitrile, heptanes, hexanes, methyl ethyl
ketone, dichloromethane, 2-methyl-tetrahydrofuran, and methyl
isobutyl ketone. In some embodiments, the solvent further comprises
a protic solvent. Non-limiting examples of a protic solvent include
water, methanol, ethanol, isopropanol, propanol, and butanol. In
some embodiments, the at least one solvent is acetone, further
comprising water.
[0134] In some embodiments, the mixture is heated to reflux. In
some embodiments, the mixture is heated to a temperature between
about 40.degree. C. and about 65.degree. C. In some embodiments,
the mixture is heated to a temperature between about 45.degree. C.
and about 65.degree. C. In some embodiments, the mixture is heated
to a temperature of about 55.degree. C.
[0135] In some embodiments, the heated mixture is cooled to room
temperature. In some embodiments, the heated mixture is cooled to a
temperature between about 0.degree. C. and about 30.degree. C., or
between about 10.degree. C. and about 30.degree. C., or between
about 10.degree. C. and about 25.degree. C., or between about
5.degree. C. and about 30.degree. C., or between about 10.degree.
C. and about 30.degree. C., or about 10.degree. C. and about
20.degree. C.
Deuterated Compounds
[0136] Any formula or structure given herein, including a compound
of Formula I and pharmaceutically acceptable salts thereof
(including, for example, the mono-mesylate and the bis-mesylate
salts), or a hydrate thereof, is also contemplated as an
isotopically labeled form of the compounds, or salts, or hydrates
thereof. Thus, although the unlabeled forms of compounds are
provided, it is understood that the present disclosure also
contemplates isotopically labeled compounds, even though such
isotopes are not explicitly depicted. Isotopically labeled
compounds, or salts, or hydrates thereof have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine and chlorine, such as, but not limited to
.sup.2H (deuterium, D), .sup.3H (tritium), .sup.11C, .sup.13C,
.sup.14C, .sup.15N, .sup.18F, .sup.31P, .sup.32P, .sup.35S,
.sup.36Cl and .sup.125I. For instance, isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such
as, but not limited to .sup.2H (deuterium, D), .sup.3H (tritium)
.sup.11C, .sup.13C, .sup.14C, .sup.15N, and .sup.35S may be
incorporated into a compound of formula I, including a salt (e.g. a
mesylate salt) of a compound of formula I, or a hydrate thereof.
Various isotopically labeled compounds, or salts, or hydrates
thereof of the present disclosure, for example those into which
radioactive isotopes such as .sup.3H, .sup.13C and .sup.14C are
incorporated. Such isotopically labeled compounds or salts thereof
may be useful in metabolic studies, reaction kinetic studies,
detection or imaging techniques, such as positron emission
tomography (PET) or single-photon emission computed tomography
(SPECT) including drug or substrate tissue distribution assays or
in radioactive treatment of subjects.
[0137] The disclosure also includes a compound of Formula I and
pharmaceutically acceptable salts thereof (including, for example,
the mono-mesylate and the bis-mesylate salts), or a hydrate
thereof, in which from 1 to n hydrogens attached to a carbon atom
is/are replaced by deuterium, in which n is the number of hydrogens
in the molecule. Such compounds may exhibit increased resistance to
metabolism and are thus useful for increasing the half life of a
compound of Formula I, or pharmaceutically acceptable salts
thereof, or hydrates thereof (including a bis-mesylate salt of
Formula IA or IB, or a hydrate thereof; or a hydrate, bis-mesylate
of Formula IC or ID) when administered to a mammal. See, for
example, Foster, "Deuterium Isotope Effects in Studies of Drug
Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such
compounds are synthesized by means well known in the art, for
example by employing starting materials in which one or more
hydrogens have been replaced by deuterium.
[0138] Deuterium labeled or substituted therapeutic compounds of
the disclosure (including salts or hydrates thereof) may have
improved DMPK (drug metabolism and pharmacokinetics) properties,
relating to absorption, distribution, metabolism and excretion
(ADME). Substitution with heavier isotopes such as deuterium may
afford certain therapeutic advantages resulting from greater
metabolic stability, for example increased in vivo half-life,
reduced dosage requirements and/or an improvement in therapeutic
index. An .sup.18F labeled compound may be useful for PET or SPECT
studies. Isotopically labeled compounds of this disclosure and
prodrugs thereof can generally be prepared by carrying out the
procedures disclosed in the schemes or in the examples and
preparations described below by substituting a readily available
isotopically labeled reagent for a non-isotopically labeled
reagent. It is understood that deuterium in this context is
regarded as a substituent in the compound of Formula I and
pharmaceutically acceptable salts thereof (including, for example,
the mono-mesylate and the bis-mesylate salts), or hydrates
thereof.
[0139] The concentration of such a heavier isotope, specifically
deuterium, may be defined by an isotopic enrichment factor. In the
compounds of this disclosure any atom not specifically designated
as a particular isotope is meant to represent any stable isotope of
that atom. Unless otherwise stated, when a position is designated
specifically as "H" or "hydrogen", the position is understood to
have hydrogen at its natural abundance isotopic composition.
Accordingly, in the compounds or salts thereof of this disclosure
any atom specifically designated as a deuterium (D) is meant to
represent deuterium.
Pharmaceutical Compositions
[0140] The mesylate salts described herein (including the
mono-mesylate and bis-mesylate salts of a compound of Formula I, or
a hydrate thereof), and any polymorphic forms thereof described
herein (e.g., Form 3 and/or Form 7), can be administered as the
neat chemical, but it is typical, and preferable, to administer the
compound, or salt or hydrate thereof, in the form of a
pharmaceutical composition or formulation. Provided are
pharmaceutical compositions comprising: (i) a bis-mesylate salt of
a compound of Formula I, or a hydrate thereof, or polymorph of the
foregoing, and (ii) a pharmaceutical carrier, excipient, adjuvant,
or vehicle. Pharmaceutical carrier, excipient, adjuvant, or vehicle
may also be referred to herein as pharmaceutically acceptable
carrier excipient, adjuvant or vehicle or as biocompatible
pharmaceutical carrier, excipient, adjuvant, or vehicle.
Accordingly, provided are pharmaceutical compositions that comprise
polymorph Form 3 and/or Form 7 and a biocompatible pharmaceutical
carrier, excipient, adjuvant, or vehicle. The composition can
include the bis-mesylate salt of a compound of Formula I, or a
hydrate thereof, or polymorphic forms described herein either as
the sole active agent or in combination with other agents, such as
oligo- or polynucleotides, oligo- or polypeptides, drugs, or
hormones mixed with one or more pharmaceutically acceptable
carriers or excipients. Carriers, excipients, and other ingredients
can be deemed pharmaceutically acceptable insofar as they are
compatible with other ingredients of the formulation and not
deleterious to the recipient thereof.
[0141] In one aspect, provided is a pharmaceutical composition,
comprising: a bis-mesylate salt of a compound of Formula I, or a
hydrate thereof and a pharmaceutical carrier, excipient, adjuvant,
or vehicle. In certain aspects, provided is a pharmaceutical
composition, comprising: a hydrate, bis-mesylate salt of a compound
of Formula I, and a pharmaceutical carrier, excipient, adjuvant, or
vehicle. In one aspect, provided is a pharmaceutical composition,
comprising: a monohydrate, bis-mesylate salt of a compound of
Formula I, and a pharmaceutical carrier, excipient, adjuvant, or
vehicle. In certain aspects, provided is a pharmaceutical
composition, comprising: a mesylate salt of Formula IA or IB, or a
hydrate thereof and a pharmaceutical carrier, excipient, adjuvant,
or vehicle. In other aspects, provided is a pharmaceutical
composition, comprising: a hydrate, mesylate salt of Formula IA or
IB; and a pharmaceutical carrier, excipient, adjuvant, or
vehicle.
[0142] For example, in some embodiments, provided herein is a
pharmaceutical composition comprising polymorph Form 3, and a
pharmaceutical acceptable carrier or other excipient. In one
embodiment of the pharmaceutical composition, the polymorph Form 3
in the composition is present in excess of other polymorphic forms.
For example, the weight ratio of polymorph Form 3 to other
polymorph forms in the pharmaceutical composition may be between 85
to 15, 90 to 10, 95 to 5, or 99 to 1. In one embodiment, the weight
ratio of polymorph Form 3 to other polymorph forms is between 90:1
and 99:1.
[0143] The term "carrier" refers to diluents, disintegrants,
precipitation inhibitors, surfactants, glidants, binders,
lubricants, and other excipients and vehicles with which the
compound is administered. Carriers are generally described herein
and also in "Remington's Pharmaceutical Sciences" by E. W.
Martin.
[0144] The pharmaceutical compositions can be formulated to contain
suitable pharmaceutically acceptable carriers, and optionally can
comprise excipients and auxiliaries that facilitate processing of
the polymorphic forms described herein into preparations that can
be used pharmaceutically. The mode of administration generally
determines the nature of the carrier. For example, formulations for
parenteral administration can include aqueous solutions of the
active compounds in water-soluble form. Carriers suitable for
parenteral administration can be selected from among saline,
buffered saline, dextrose, water, and other physiologically
compatible solutions. Preferred carriers for parenteral
administration are physiologically compatible buffers such as
Hanks's solution, Ringer's solution, or physiologically buffered
saline. For tissue or cellular administration, penetrants
appropriate to the particular barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art.
For preparations including proteins, the formulation can include
stabilizing materials, such as polyols (e.g., sucrose) and/or
surfactants (e.g., nonionic surfactants), and the like.
[0145] Alternatively, formulations for parenteral use can include
dispersions or suspensions of polymorphic forms described herein
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils, such as sesame
oil, and synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions can
contain substances that increase the viscosity of the suspension,
such as sodium carboxymethylcellulose, sorbitol, dextran, and
mixtures thereof. Optionally, the suspension also can contain
suitable stabilizers or agents that increase the solubility of the
compounds to allow for the preparation of highly concentrated
solutions. Aqueous polymers that provide pH-sensitive
solubilization and/or sustained release of the active agent also
can be used as coatings or matrix structures, e.g., methacrylic
polymers, such as the EUDRAGIT.TM. series available from Rohm
America Inc. (Piscataway, N.J.). Emulsions, e.g., oil-in-water and
water-in-oil dispersions, also can be used, optionally stabilized
by an emulsifying agent or dispersant (surface active materials;
surfactants). Suspensions can contain suspending agents such as
ethoxylated isostearyl alcohols, polyoxyethlyene sorbitol and
sorbitan esters, microcrystalline cellulose, aluminum
metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures
thereof.
[0146] Liposomes containing the polymorphic forms described herein
also can be employed for parenteral administration. Liposomes
generally are derived from phospholipids or other lipid substances.
The compositions in liposome form also can contain other
ingredients, such as stabilizers, preservatives, excipients, and
the like. Preferred lipids include phospholipids and phosphatidyl
cholines (lecithins), both natural and synthetic. Methods of
forming liposomes are known in the art. See, e.g., Prescott (Ed.),
Methods in Cell Biology, Vol. XIV, p. 33, Academic Press, New York
(1976).
[0147] In some embodiments, the polymorph, or composition thereof,
disclosed herein is formulated for oral administration using
pharmaceutically acceptable carriers well known in the art.
Preparations formulated for oral administration can be in the form
of tablets, pills, capsules, cachets, dragees, lozenges, liquids,
gels, syrups, slurries, elixirs, suspensions, or powders. To
illustrate, pharmaceutical preparations for oral use can be
obtained by combining the active compounds with a solid excipient,
optionally grinding the resulting mixture, and processing the
mixture of granules, after adding suitable auxiliaries if desired,
to obtain tablets or dragee cores. Oral formulations can employ
liquid carriers similar in type to those described for parenteral
use, e.g., buffered aqueous solutions, suspensions, and the
like.
[0148] Preferred oral formulations include tablets, dragees, and
gelatin capsules. These preparations can contain one or more
excipients, which include, without limitation: a) diluents, such as
microcrystalline cellulose and sugars, including lactose, dextrose,
sucrose, mannitol, or sorbitol; b) binders, such as sodium starch
glycolate, croscarmellose sodium, magnesium aluminum silicate,
starch from corn, wheat, rice, potato, etc.; c) cellulose
materials, such as methylcellulose, hydroxypropylmethyl cellulose,
and sodium carboxymethylcellulose, polyvinylpyrrolidone, gums, such
as gum arabic and gum tragacanth, and proteins, such as gelatin and
collagen; d) disintegrating or solubilizing agents such as
cross-linked polyvinyl pyrrolidone, starches, agar, alginic acid or
a salt thereof, such as sodium alginate, or effervescent
compositions; e) lubricants, such as silica, talc, stearic acid or
its magnesium or calcium salt, and polyethylene glycol; f)
flavorants and sweeteners; g) colorants or pigments, e.g., to
identify the product or to characterize the quantity (dosage) of
active compound; and h) other ingredients, such as preservatives,
stabilizers, swelling agents, emulsifying agents, solution
promoters, salts for regulating osmotic pressure, and buffers.
[0149] Examples of preferred carriers include, but are not limited
to, aluminum monostearate, aluminum stearate,
carboxymethylcellulose, carboxymethylcellulose sodium,
crospovidone, glyceryl isostearate, glyceryl monostearate,
hydroxyethylcellulose, hydroxymethylcellulose, hydroxyoctacosanyl
hydroxystearate, hydroxypropylcellulose,
hydroxypropylmethylcellulose, lactose, lactose monohydrate,
magnesium stearate, mannitol, microcrystalline cellulose, poloxamer
124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237,
poloxamer 407, povidone, silicon dioxide, colloidal silicon
dioxide, silicone, silicone adhesive 4102, and silicone emulsion.
It should be understood, however, that the carriers selected for
the pharmaceutical compositions provided in the present disclosure,
and the amounts of such carriers in the composition, may vary
depending on the method of formulation (e.g., dry granulation
formulation, solid dispersion formulation).
[0150] In certain variations, the pharmaceutical composition
comprises Form 3, and at least one pharmaceutically acceptable
carrier selected from the group consisting of
hydroxypropylmethylcellulose, mannitol, crospovidone, poloxamer,
colloidal silicon dioxide, microcrystalline cellulose, magnesium
stearate, and any mixtures thereof. In another variation, the
pharmaceutical composition comprises polymorph Form 3,
hydroxypropylmethylcellulose, and at least one additionally
pharmaceutically acceptable carrier selected from the group
consisting of mannitol, crospovidone, poloxamer, colloidal silicon
dioxide, microcrystalline cellulose, magnesium stearate, and any
mixtures thereof.
[0151] It should also be understood that the pharmaceutically
acceptable carriers described above may perform one or more
different functions in a given formulation, and may fall within one
or more functional classes of carriers (e.g., disintegrants,
lubricants, diluents).
[0152] It should further be understood that, in other embodiments,
the pharmaceutical composition may comprise one or more additional
carriers to improve flow, compression, hardness, taste, and tablet
performance.
[0153] In some embodiments, the pharmaceutical composition
comprises a) about 34% w/w of a mesylate salt (including, for
example, a mono-mesylate or bis-mesylate salt) of a compound of
Formula I; b) about 15% w/w HPMC; c) about 22% w/w mannitol; d)
about 10% w/w crospovidone; and e) about 1% w/w to about 3% w/w
poloxamer. In one variation, the pharmaceutical composition
comprises: a) about 34% w/w of a bis-mesylate salt of a compound of
Formula I, or a hydrate thereof; b) about 15% w/w HPMC; c) about
22% w/w mannitol; d) about 10% w/w crospovidone; and e) about 1%
w/w to about 3% w/w poloxamer. In another variation, the
pharmaceutical composition comprises: a) about 34% w/w of a
monohydrate, bis-mesylate salt of a compound of Formula I; b) about
15% w/w HPMC; c) about 22% w/w mannitol; d) about 10% w/w
crospovidone; and e) about 1% w/w to about 3% w/w poloxamer. In yet
another variation, the pharmaceutical composition comprises: a)
about 34% w/w of polymorph Form 3, polymorph Form 7, or a
combination thereof; b) about 15% w/w HPMC; c) about 22% w/w
mannitol; d) about 10% w/w crospovidone; and e) about 1% w/w to
about 3% w/w poloxamer.
Methods of Use
[0154] Provided is also the use of the pharmaceutical compositions
described in the present disclosure to selectively or specifically
inhibit Syk activity therapeutically or prophylactically. The
method comprises administering the pharmaceutical composition to an
individual in need thereof in an amount sufficient to inhibit Syk
activity. The method can be employed to treat subjects (e.g.,
humans) suffering from, or subject to, a condition whose symptoms
or pathology is mediated by Syk expression or activity.
[0155] In one aspect, provided is a method of treating a human in
need thereof, comprising administering a bis-mesylate salt of a
compound of Formula I, or a hydrate thereof, to the human. In
certain aspects, provided is a method of treating a human in need
thereof, comprising administering a hydrate, bis-mesylate salt of a
compound of Formula I to the human. In one aspect, provided is a
method of treating a human in need thereof, comprising
administering a monohydrate, bis-mesylate salt of a compound of
Formula I to the human. In certain aspects, provided is a method of
treating a human in need thereof, comprising administering a
mesylate salt of Formula IA or IB, or a hydrate thereof, to the
human. In other aspects, provided is a method of treating a human
in need thereof, comprising administering a hydrate, mesylate salt
of Formula IA or IB to the human. In one aspect, provided is a
method of treating a human in need thereof, comprising
administering polymorph Form 3 to the human. In one aspect,
provided is a method of treating a human in need thereof,
comprising administering polymorph Form 7 to the human.
[0156] "Treatment" or "treating" is an approach for obtaining
beneficial or desired results including clinical results.
Beneficial or desired clinical results may include one or more of
the following:
[0157] a) inhibiting the disease or condition (e.g., decreasing one
or more symptoms resulting from the disease or condition, and/or
diminishing the extent of the disease or condition);
[0158] b) slowing or arresting the development of one or more
clinical symptoms associated with the disease or condition (e.g.,
stabilizing the disease or condition, preventing or delaying the
worsening or progression of the disease or condition, and/or
preventing or delaying the spread (e.g., metastasis) of the disease
or condition); and/or
[0159] c) relieving the disease, that is, causing the regression of
clinical symptoms (e.g., ameliorating the disease state, providing
partial or total remission of the disease or condition, enhancing
effect of another medication, delaying the progression of the
disease, increasing the quality of life, and/or prolonging
survival.
[0160] "Prevention" or "preventing" means any treatment of a
disease or condition that causes the clinical symptoms of the
disease or condition not to develop. Compounds may, in some
embodiments, be administered to a subject (including a human) who
is at risk or has a family history of the disease or condition.
[0161] "Subject" refers to an animal, such as a mammal (including a
human), that has been or will be the object of treatment,
observation or experiment. The methods described herein may be
useful in human therapy and/or veterinary applications. In some
embodiments, the subject is a mammal. In one embodiment, the
subject is a human.
[0162] The term "therapeutically effective amount" of the
pharmaceutical composition means an amount sufficient to effect
treatment when administered to a subject, to provide a therapeutic
benefit such as amelioration of symptoms or slowing of disease
progression. For example, a therapeutically effective amount may be
an amount sufficient to decrease a symptom of a disease or
condition responsive to inhibition of Syk activity. The
therapeutically effective amount may vary depending on the subject,
and disease or condition being treated, the weight and age of the
subject, the severity of the disease or condition, and the manner
of administering, which can readily be determined by one or
ordinary skill in the art.
[0163] The term "inhibition" indicates a decrease in the baseline
activity of a biological activity or process. "Inhibition of
activity of Syk activity" refers to a decrease in activity of Syk
as a direct or indirect response to the presence of the
pharmaceutical composition, relative to the activity of Syk in the
absence of such pharmaceutical composition. In some embodiments,
the inhibition of Syk activity may be compared in the same subject
prior to treatment, or other subjects not receiving the
treatment.
[0164] In certain aspects, a bis-mesylate salt of a compound of
Formula I (including polymorphs of such bis-mesylate salt, such as
Form 3 and/or Form 7), or a hydrate thereof, and compositions
thereof described herein are used for treating a subject having
cancer, an allergic disorder and/or an autoimmune and/or
inflammatory disease, and/or an acute inflammatory reaction.
[0165] In one aspect, the pharmaceutical compositions provided in
the present disclosure may be used in the treatment of cancer. In
some embodiments, the polymorphs and compositions thereof described
herein can be employed in methods of inhibiting the growth or
proliferation of cancer cells of hematopoietic origin, such as
cancer cells. In some embodiments, the cancer cells are of lymphoid
origin, and in specific embodiments, the cancer cells are related
to or derived from B lymphocytes or B lymphocyte progenitors.
[0166] Cancers amenable to treatment using the method disclosed in
the present disclosure include, without limitation, lymphomas
(e.g., malignant neoplasms of lymphoid and reticuloendothelial
tissues, such as Burkitt's lymphoma, Hodgkins' lymphoma,
non-Hodgkins' lymphomas, lymphocytic lymphomas); multiple myelomas;
leukemias (e.g., lymphocytic leukemias, chronic myeloid
(myelogenous) leukemias). Other cancer cells, of hematopoietic
origin or otherwise, that express spleen tyrosine kinase (Syk) also
can be treated by administration of the polymorphs and compositions
thereof described herein.
[0167] In particular embodiments of the methods provided herein,
the cancer is leukemia or lymphoma. In certain embodiments, the
cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia
(AML), chronic lymphocytic leukemia (CLL), small lymphocytic
lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative
disease (MPD), chronic myeloid leukemia (CML), multiple myeloma
(MM), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL,
non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL),
follicular lymphoma (FL), Waldestrom's macroglobulinemia (WM),
T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma
(DLBCL), lymphoplasmacytic lymphoma (LPL), and marginal zone
lymphoma (MZL). In certain variations, the cancer is acute
lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL),
myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),
chronic myeloid leukemia (CIVIL), multiple myeloma (MM), indolent
non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's
lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma
(FL), Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell
lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one
embodiment, the cancer is T-cell acute lymphoblastic leukemia
(T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). The
non-Hodgkin lymphoma encompasses the indolent B-cell diseases that
include, for example, follicular lymphoma, lymphoplasmacytic
lymphoma, Waldenstrom macroglobulinemia, and marginal zone
lymphoma, as well as the aggressive lymphomas that include, for
example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL)
and mantle cell lymphoma (MCL). In one embodiment, the cancer is
indolent non-Hodgkin's lymphoma (iNHL). In yet another embodiment,
the cancer is non-FL iNHL.
[0168] In particular embodiments of the methods provided herein,
the cancer is a hematologic malignancy. In certain embodiments, the
hematologic malignancy is leukemia (e.g., chronic lymphocytic
leukemia) or lymphoma (e.g., non-Hodgkin's lymphoma). In some
variations, the cancer is MCL, DLBCL, iNHL, FL, MZL, LPL, SLL, or
WM. In other variations, the cancer is CLL, MCL, DLBCL, iNHL
(including, for example, non-FL iNHL), or FL.
[0169] In other embodiments, the cancer is a solid tumor cancer (or
solid cancer tumor). In certain embodiments the cancer is a solid
tumor and expresses spleen tyrosine kinase (Syk) activity. In other
embodiments, the solid tumor cancer is selected from the group
consisting of pancreatic cancer, lung cancer, colon cancer,
colo-rectal cancer, breast cancer, esophageal cancer,
adenocarcinoma, hepatocellular cancer. In one embodiment, the solid
tumor cancer is selected from the group consisting of pancreatic
cancer, lung cancer, colorectal cancer, ovarian cancer, and
hepatocellular cancer.
[0170] Any of the methods of treatment provided herein may be used
to treat cancer at an advanced stage. Any of the methods of
treatment provided herein may be used to treat cancer at locally
advanced stage. Any of the methods of treatment provided herein may
be used to treat early stage cancer. Any of the methods of
treatment provided herein may be used to treat cancer in remission.
In some of the embodiments of any of the methods of treatment
provided herein, the cancer has reoccurred after remission. In some
embodiments of any of the methods of treatment provided herein, the
cancer is progressive cancer.
[0171] In some embodiments, the conditions and diseases that can be
affected using the compounds and the compositions described herein,
include, but are not limited to: allergic disorders, including but
not limited to eczema, allergic rhinitis or coryza, hay fever,
bronchial asthma, urticaria (hives) and food allergies, and other
atopic conditions; autoimmune and/or inflammatory diseases,
including but not limited to psoriasis, ulcerative colitis, Crohn's
disease, irritable bowel syndrome, Sjogren's disease, tissue graft
rejection, and hyperacute rejection of transplanted organs, asthma,
systemic lupus erythematosus (and associated glomerulonephritis),
dermatomyositis, multiple sclerosis, scleroderma, vasculitis
(ANCA-associated and other vasculitides), autoimmune hemolytic and
thrombocytopenic states, Goodpasture's syndrome (and associated
glomerulonephritis and pulmonary hemorrhage), atherosclerosis,
rheumatoid arthritis, chronic obstructive pulmonary disease (COPD),
adult respiratory distress syndrome (ARDS), chronic Idiopathic
thrombocytopenic purpura (ITP), Addison's disease, Parkinson's
disease, Alzheimer's disease, diabetes, septic shock, and
myasthenia gravis; acute inflammatory reactions, including but not
limited to skin sunburn, inflammatory pelvic disease, inflammatory
bowel disease, urethritis, uvitis, sinusitis, pneumonitis,
encephalitis, meningitis, myocarditis, nephritis, osteomyelitis,
myositis, hepatitis gastritis, enteritis, dermatitis, gingivitis,
appendicitis, pancreatitis, and cholocystitis; polycystic kidney
disease.
[0172] In some embodiments, provided are also the use of the
compounds and compositions described herein the treatment of an
autoimmune disease. Certain embodiments of an autoimmune disease
include asthma, rheumatoid arthritis, multiple sclerosis, and
lupus.
[0173] In yet another aspect, provided are methods of treating an
individual having a Syk-mediated disorder by administering any of
the pharmaceutical compositions provided in the present disclosure
to the individual. Provided are also methods of modulating Syk in
an individual by administering any of the pharmaceutical
compositions provided in the present disclosure to the
individual.
[0174] In some of the foregoing methods, the pharmaceutical
compositions provided in the present disclosure may be administered
to the individual as unit dosage, for example in the form of a
tablet. In some variations, a mesylate salt (including, for
example, a mono-mesylate or bis-mesylate salt), or a hydrate
thereof, is administered in the form a tablet. In another
variation, polymorph Form 3, which is a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I (e.g., polymorph of a
monohydrate of the bis-mesylate salt of Formula IA) is used in the
spray dry preparation of the unit dosage, wherein the final unit
dosage does not substantially contain the polymorph Form 3.
[0175] Subjects
[0176] Any of the methods of treatment provided may be used to
treat a subject who has been diagnosed with or is suspected of
having a cancer, an allergic disorder and/or an autoimmune and/or
inflammatory disease, and/or an acute inflammatory reaction.
[0177] In some of the embodiments of any of the methods provided
herein, the subject is a human who is at risk of developing a
cancer (e.g., a human who is genetically or otherwise predisposed
to developing a cancer) and who has or has not been diagnosed with
the cancer. As used herein, an "at risk" subject is a subject who
is at risk of developing cancer (e.g., a hematologic malignancy).
The subject may or may not have detectable disease, and may or may
not have displayed detectable disease prior to the treatment
methods described herein. An at risk subject may have one or more
so-called risk factors, which are measurable parameters that
correlate with development of cancer, such as described herein. A
subject having one or more of these risk factors has a higher
probability of developing cancer than an individual without these
risk factor(s).
[0178] These risk factors may include, for example, age, sex, race,
diet, history of previous disease, presence of precursor disease,
genetic (e.g., hereditary) considerations, and environmental
exposure. In some embodiments, a subject at risk for cancer
includes, for example, a subject whose relatives have experienced
this disease, and those whose risk is determined by analysis of
genetic or biochemical markers. Prior history of having cancer may
also be a risk factor for instances of cancer recurrence.
[0179] Provided herein are also methods for treating a subject
(e.g., a human) who exhibits one or more symptoms associated with
cancer (e.g., a hematologic malignancy). In some embodiments, the
subject is at an early stage of cancer. In other embodiments, the
subject is at an advanced stage of cancer.
[0180] In some embodiments, the subject (e.g., a human) has a
cancer responsive to Syk activity. In another embodiment, the human
has a solid cancer tumor which expresses Syk. In some embodiments,
the human has a 17p deletion, a TP53 mutation, NOTCH1, a SF3B1
mutation, a 11q deletion, or any combination thereof. In one
embodiment, the human has a 17p deletion, a TP53 mutation, or a
combination thereof. In another embodiment, the human has NOTCH1, a
SF3B1 mutation, a 11q deletion, or any combination thereof.
[0181] Provided herein are also methods for treating a subject
(e.g., a human) who is undergoing one or more standard therapies
for treating cancer (e.g., a hematologic malignancy), such as
chemotherapy, radiotherapy, immunotherapy, and/or surgery. Thus, in
some foregoing embodiments, a bis-mesylate salt of a compound of
Formula I (including polymorphs of such bis-mesylate salt, such as
Form 3 and/or Form 7), or a hydrate thereof, and compositions
described herein is administered before, during, or after
administration of chemotherapy, radiotherapy, immunotherapy, and/or
surgery.
[0182] In another aspect, provided herein are methods for treating
a subject (e.g., a human) who is "refractory" to a cancer treatment
or who is in "relapse" after treatment for cancer (e.g., a
hematologic malignancy). A subject "refractory" to an anti-cancer
therapy means they do not respond to the particular treatment, also
referred to as resistant. The cancer may be resistant to treatment
from the beginning of treatment, or may become resistant during the
course of treatment, for example after the treatment has shown some
effect on the cancer, but not enough to be considered a remission
or partial remission. A subject in "relapse" means that the cancer
has returned or the signs and symptoms of cancer have returned
after a period of improvement, e.g. after a treatment has shown
effective reduction in the cancer, such as after a subject is in
remission or partial remission.
[0183] In some embodiments, the subject may be a human who is (i)
refractory to at least one anti-cancer therapy, or (ii) in relapse
after treatment with at least one anti-cancer therapy, or both (i)
and (ii). In some of embodiments, the subject is refractory to at
least two, at least three, or at least four anti-cancer therapy
(including, for example, standard or experimental
chemotherapies).
[0184] In certain embodiments, the subject is a human who is (i)
refractory to, and/or (ii) in relapse after treatment with at least
one therapy for chronic lymphocytic leukemia (CLL), mantle cell
lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular
lymphoma (FL), or non-FL indolent non-Hodgkin's lymphoma
(including, for example, lymphoplasmacytic lymphoma/Waldestrom's
macroglobulinemia (LPL/WM), small lymphocytic lymphoma (SLL), and
marginal zone lymphoma (MZL)).
[0185] In some variations, the subject is a human who (i) is
refractory to, and/or (ii) is in relapse after treatment with,
and/or (iii) has prior exposure to at least one therapy for a
non-FL indolent non-Hodgkin's lymphoma. In certain embodiments, the
non-FL indolent non-Hodgkin's lymphoma is lymphoplasmacytic
lymphoma/Waldestrom's macroglobulinemia (LPL/WM), small lymphocytic
lymphoma (SLL), or marginal zone lymphoma (MZL)). In another
variation, the subject is a human who (i) is refractory to, and/or
(ii) is in relapse after treatment with, and/or (iii) has prior
exposure to at least one therapy for follicular lymphoma (FL). In
another variation, the subject is a human who (i) is refractory to,
and/or (ii) is in relapse after treatment with, and/or (iii) has
prior exposure to at least one therapy for diffuse large B-cell
lymphoma (DLBCL). In another variation, the subject is a human who
(i) is refractory to, and/or (ii) is in relapse after treatment
with, and/or (iii) has prior exposure to at least one therapy for
mantle cell lymphoma (MCL). In yet another variation, the subject
is a human who (i) is refractory to, and/or (ii) is in relapse
after treatment with, and/or (iii) has prior exposure to at least
one therapy for chronic lymphocytic leukemia (CLL). In yet another
variation, the subject is a human who (i) is refractory to, and/or
(ii) is in relapse after treatment with, and/or (iii) has prior
exposure to a phosphatidylinositol 3-kinase (PI3K) inhibitor, a
bruton tyrosine kinase (BTK) inhibitor, or a B-cell receptor (BCR)
treatment for chronic lymphocytic leukemia (CLL).
[0186] In some embodiments, the subject is refractory to at least
one, at least two, at least three, or at least four anti-cancer
therapy (including, for example, standard or experimental
chemotherapy) selected from fludarabine, rituximab, obinutuzumab,
alkylating agents, alemtuzumab and other chemotherapy treatments
such as CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated
cyclophosphamide, vincristine, doxorubicin, dexamethasone,
methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM
(fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab,
fludarabine, cyclophosphamide, mitoxantrone); bortezomib and
rituximab; temsirolimus and rituximab; temsirolimus and
Velcade.RTM.; Iodine-131 tositumomab (Bexxar.RTM.) and CHOP; CVP
(cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);
ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE);
FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine,
rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin,
Adriamycin.RTM., cyclophosphamide, etoposide).
[0187] Other examples of chemotherapy treatments (including
standard or experimental chemotherapies) are described below. In
addition, treatment of certain lymphomas is reviewed in Cheson, B.
D., Leonard, J. P., "Monoclonal Antibody Therapy for B-Cell
Non-Hodgkin's Lymphoma" The New England Journal of Medicine 2008,
359(6), p. 613-626; and Wierda, W. G., "Current and Investigational
Therapies for Patients with CLL" Hematology 2006, p. 285-294.
Lymphoma incidence patterns in the United States is profiled in
Morton, L. M., et al. "Lymphoma Incidence Patterns by WHO Subtype
in the United States, 1992-2001" Blood 2006, 107(1), p.
265-276.
[0188] For example, treatment of non-Hodgkin's lymphomas (NHL),
especially of B-cell origin, include the use of monoclonal
antibodies, standard chemotherapy approaches (e.g., CHOP, CVP, FCM,
MCP, and the like), radioimmunotherapy, and combinations thereof,
especially integration of an antibody therapy with chemotherapy.
Examples of unconjugated monoclonal antibodies for Non-Hodgkin's
lymphoma/B-cell cancers include rituximab, alemtuzumab, human or
humanized anti-CD20 antibodies, lumiliximab, anti-TRAIL,
bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.
Examples of experimental antibody agents used in treatment of
Non-Hodgkin's lymphoma/B-cell cancers include ofatumumab, ha20,
PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab,
lumiliximab, apolizumab, milatuzumab, and bevacizumab. Examples of
standard regimens of chemotherapy for Non-Hodgkin's lymphoma/B-cell
cancers include CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), CVP
(cyclophosphamide, vincristine and prednisone), MCP (mitoxantrone,
chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP),
R-FCM (rituximab plus FCM), R-CVP (rituximab plus CVP), and R-MCP
(R-MCP). Examples of radioimmunotherapy for Non-Hodgkin's
lymphoma/B-cell cancers include yttrium-90-labeled ibritumomab
tiuxetan, and iodine-131-labeled tositumomab.
[0189] In another example, therapeutic treatments for mantle cell
lymphoma (MCL) include combination chemotherapies such as CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone), hyperCVAD
(hyperfractionated cyclophosphamide, vincristine, doxorubicin,
dexamethasone, methotrexate, cytarabine) and FCM (fludarabine,
cyclophosphamide, mitoxantrone). In addition, these regimens can be
supplemented with the monoclonal antibody rituximab (Rituxan) to
form combination therapies R-CHOP, hyperCVAD-R, and R-FCM. Other
approaches include combining any of the abovementioned therapies
with stem cell transplantation or treatment with ICE (iphosphamide,
carboplatin and etoposide). Other approaches to treating mantle
cell lymphoma includes immunotherapy such as using monoclonal
antibodies like Rituximab (Rituxan). Rituximab can be used for
treating indolent B-cell cancers, including marginal-zone lymphoma,
WM, CLL and small lymphocytic lymphoma. A modified approach is
radioimmunotherapy, wherein a monoclonal antibody is combined with
a radioisotope particle, such as Iodine-131 tositumomab
(Bexxar.RTM.) and Yttrium-90 ibritumomab tiuxetan (Zevalin.RTM.).
In another example, Bexxar.RTM. is used in sequential treatment
with CHOP. Another immunotherapy example includes using cancer
vaccines, which is based upon the genetic makeup of an individual
subject's tumor. A lymphoma vaccine example is GTOP-99)
(MyVax.RTM.). Yet other approaches to treating mantle cell lymphoma
includes autologous stem cell transplantation coupled with
high-dose chemotherapy, or treating mantle cell lymphoma includes
administering proteasome inhibitors, such as Velcade.RTM.
(bortezomib or PS-341), or antiangiogenesis agents, such as
thalidomide, especially in combination with Rituxan. Another
treatment approach is administering drugs that lead to the
degradation of Bcl-2 protein and increase cancer cell sensitivity
to chemotherapy, such as oblimersen (Genasense) in combination with
other chemotherapeutic agents. Another treatment approach includes
administering mTOR inhibitors, which can lead to inhibition of cell
growth and even cell death; a non-limiting example is Temsirolimus
(CCI-779), and Temsirolimus in combination with Rituxan.RTM.,
Velcade.RTM. or other chemotherapeutic agents.
[0190] Other recent therapies for MCL have been disclosed (Nature
Reviews; Jares, P. 2007). Such examples include Flavopiridol,
PD0332991, R-roscovitine (Selicilib, CYC202), Styryl sulphones,
Obatoclax (GX15-070), TRAIL, Anti-TRAIL DR4 and DR5 antibodies,
Temsirolimus (CCl-779), Everolimus (RAD001), BMS-345541, Curcumin,
Vorinostat (SAHA), Thalidomide, lenalidomide (Revlimid.RTM.,
CC-5013), and Geldanamycin (17-AAG).
[0191] Examples of other therapeutic agents used to treat
Waldenstrom's Macroglobulinemia (WM) include perifosine, bortezomib
(Velcade.RTM.), rituximab, sildenafil citrate (Viagra.RTM.),
CC-5103, thalidomide, epratuzumab (hLL2-anti-CD22 humanized
antibody), simvastatin, enzastaurin, campath-1H, dexamethasone, DT
PACE, oblimersen, antineoplaston A10, antineoplaston AS2-1,
alemtuzumab, beta alethine, cyclophosphamide, doxorubicin
hydrochloride, prednisone, vincristine sulfate, fludarabine,
filgrastim, melphalan, recombinant interferon alfa, carmustine,
cisplatin, cyclophosphamide, cytarabine, etoposide, melphalan,
dolastatin 10, indium In 111 monoclonal antibody MN-14, yttrium Y
90 humanized epratuzumab, anti-thymocyte globulin, busulfan,
cyclosporine, methotrexate, mycophenolate mofetil, therapeutic
allogeneic lymphocytes, Yttrium Y 90 ibritumomab tiuxetan,
sirolimus, tacrolimus, carboplatin, thiotepa, paclitaxel,
aldesleukin, recombinant interferon alfa, docetaxel, ifosfamide,
mesna, recombinant interleukin-12, recombinant interleukin-11,
Bcl-2 family protein inhibitor ABT-263, denileukin diftitox,
tanespimycin, everolimus, pegfilgrastim, vorinostat, alvocidib,
recombinant flt3 ligand, recombinant human thrombopoietin,
lymphokine-activated killer cells, amifostine trihydrate,
aminocamptothecin, irinotecan hydrochloride, caspofungin acetate,
clofarabine, epoetin alfa, nelarabine, pentostatin, sargramostim,
vinorelbine ditartrate, WT-1 analog peptide vaccine, WT1 126-134
peptide vaccine, fenretinide, ixabepilone, oxaliplatin, monoclonal
antibody CD19, monoclonal antibody CD20, omega-3 fatty acids,
mitoxantrone hydrochloride, octreotide acetate, tositumomab and
iodine 1-131 tositumomab, motexafin gadolinium, arsenic trioxide,
tipifarnib, autologous human tumor-derived HSPPC-96, veltuzumab,
bryostatin 1, and PEGylated liposomal doxorubicin hydrochloride,
and any combination thereof.
[0192] Examples of therapeutic procedures used to treat WM include
peripheral blood stem cell transplantation, autologous
hematopoietic stem cell transplantation, autologous bone marrow
transplantation, antibody therapy, biological therapy, enzyme
inhibitor therapy, total body irradiation, infusion of stem cells,
bone marrow ablation with stem cell support, in vitro-treated
peripheral blood stem cell transplantation, umbilical cord blood
transplantation, immunoenzyme technique, pharmacological study,
low-LET cobalt-60 gamma ray therapy, bleomycin, conventional
surgery, radiation therapy, and nonmyeloablative allogeneic
hematopoietic stem cell transplantation.
[0193] Examples of other therapeutic agents used to treat diffuse
large B-cell lymphoma (DLBCL) drug therapies (Blood 2005 Abramson,
J.) include cyclophosphamide, doxorubicin, vincristine, prednisone,
anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the
agents listed for Waldenstrom's, and any combination thereof, such
as ICE and R-ICE.
[0194] Examples of other therapeutic agents used to treat chronic
lymphocytic leukemia (CLL) (Spectrum, 2006, Fernandes, D.) include
Chlorambucil (Leukeran), Cyclophosphamide (Cyloxan, Endoxan,
Endoxana, Cyclostin), Fludarabine (Fludara), Pentstatin (Nipent),
Cladribine (Leustarin), Doxorubicin (Adriamycin.RTM.,
Adriblastine), Vincristine (Oncovin), Prednisone, Prednisolone,
Alemtuzumab (Campath, MabCampath), many of the agents listed for
Waldenstrom's, and combination chemotherapy and chemoimmunotherapy,
including the common combination regimen: CVP (cyclophosphamide,
vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide,
carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine,
cyclophosphamide, rituximab); and FR (fludarabine, rituximab).
[0195] In another aspect, provided is a method of sensitizing a
subject (e.g., a human) who is (i) refractory to at least one
chemotherapy treatment, or (ii) in relapse after treatment with
chemotherapy, or both (i) and (ii), wherein the method comprises
administering a bis-mesylate salt of a compound of Formula I
(including polymorphs of such bis-mesylate salt, such as Form 3
and/or Form 7), or a hydrate thereof, or a pharmaceutical
composition thereof, to the subject. A subject who is sensitized is
a subject who is responsive to the treatment involving
administration of a bis-mesylate salt of a compound of Formula I
(including polymorphs of such bis-mesylate salt, such as Form 3
and/or Form 7), or a hydrate thereof, and compositions thereof
described herein, or who has not developed resistance to such
treatment.
[0196] In another aspect, provided herein are methods for treating
a subject (e.g., a human) for a cancer, with comorbidity, wherein
the treatment is also effective in treating the comorbidity. A
"comorbidity" to cancer is a disease that occurs at the same time
as the cancer.
[0197] In some embodiments, provided herein are methods for
treating a subject (e.g., a human) for chronic lymphocytic leukemia
(CLL), with comorbidity, wherein the treatment is also effective in
treating the comorbidity. Many subjects with CLL will have one or
more other diseases, for example diseases affecting the blood
pressure system, vascular and heart systems, endocrine and
metabolic systems, genitourinary system, musculoskeletal system,
respiratory system, neurological system, upper and lower
gastrointestinal systems, psychiatric system, ear, nose and throat
systems, renal system, or liver system. Specific morbidities of CLL
include, but are not limited to, one or more other cancers (e.g.
breast, head and neck, lung, melanoma, non-Hodgkin's T-cell
lymphoma, prostate, colon, small intestine, gynecologic and urinary
tract), hypertension, hyperlipidemia, coronary artery disease,
peripheral vascular diseases, cardiomyopathy, vulvular heart
disease, atrial fibrillation, cerebrovascular disease (e.g.
transient ischemic attack, stroke), chronic obstructive pulmonary
disease, joint disease, peptic ulcer, inflammatory bowel disease,
psychiatric illness, thyroid disease, benign prostate hyperplasia,
diabetes mellitus, and osteoarthritis (Satram-Hoang et al., Journal
of Cancer Therapy, 2013; 4:1321-1329; Thurmes et al., Leukemia
& Lymphoma, 2008; 49(1):49-56).
[0198] In some embodiments, a method of treating a comorbidity of
CLL in a subject (e.g., a human), wherein the method comprises
administering a compound of Formula I, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition thereof,
to the subject. In some embodiments, the comorbidity is selected
from the group consisting of one or more other cancers (e.g.
breast, head and neck, lung, melanoma, non-Hodgkin's T-cell
lymphoma, prostate, colon, small intestine, gynecologic and urinary
tract), hypertension, hyperlipidemia, coronary artery disease,
peripheral vascular diseases, cardiomyopathy, vulvular heart
disease, atrial fibrillation, cerebrovascular disease (e.g.
transient ischemic attack, stroke), chronic obstructive pulmonary
disease, joint disease, peptic ulcer, inflammatory bowel disease,
psychiatric illness, thyroid disease, benign prostate hyperplasia,
diabetes mellitus, and osteoarthritis.
Monotherapy and Combination Therapies
[0199] Provided are methods of treatment in which the
pharmaceutical composition provided in the present disclosure is
administered to a subject (e.g., a human), such that the mesylate
salt (including, for example, a bis-mesylate salt) of a compound of
Formula I, or a hydrate thereof, is the only therapeutic agent
administered to the subject. Provided are also methods of treatment
in which the pharmaceutical composition provided in the present
disclosure administered to a subject (e.g., a human) is given to a
subject (e.g., a human) in combination with one or more additional
therapeutic agents or other therapies. Both monotherapy and
combination therapies are intended and described for use in the
methods detailed herein, such as in a method of treating any of the
diseases or conditions detailed herein and for use with any subject
detailed herein.
[0200] Monotherapy
[0201] In some embodiments, a method of treating cancer, an
allergic disorder and/or an autoimmune and/or inflammatory disease,
and/or an acute inflammatory reaction comprises administering to a
subject in need thereof an effective amount of a bis-mesylate salt
of a compound of Formula I (including polymorphs of such
bis-mesylate salt, such as Form 3 and/or Form 7), or a hydrate
thereof, wherein the subject is not undergoing therapy for the same
disease or condition with another agent or procedure.
[0202] In some embodiments where the bis-mesylate salt of a
compound of Formula I, (including polymorphs of such bis-mesylate
salt, such as Form 3 and/or Form 7), or a hydrate thereof, is
administered as a monotherapy to the subject who has been diagnosed
with or is suspected of having a cancer, the subject may be a human
who is (i) refractory to at least one anti-cancer therapy, or (ii)
in relapse after treatment with at least one anti-cancer therapy,
or both (i) and (ii). In some of embodiments, the subject is
refractory to at least two, at least three, or at least four
anti-cancer therapy (including, for example, standard or
experimental chemotherapies). For example, in some embodiments, the
subject may be a human who is (i) refractory to a therapy using an
anti-CD20 antibody, an alkylating agent (e.g., bendamustine), a
purine analog (e.g., fludarabine), an anthracycline, or any
combination thereof; (ii) in relapse after treatment with an
anti-CD20 antibody, an alkylating agent (e.g., bendamustine), a
purine analog (e.g., fludarabine), an anthracycline, or any
combination thereof, or both (i) and (ii).
[0203] A human subject who is refractory to at least one
anti-cancer therapy and/or is in relapse after treatment with at
least one anti-cancer therapy, as described above, may have
undergone one or more prior therapies. In some embodiments, such
subjects have undergone one, two, three, or four, or at least one,
at least two, at least three, at least four, or at least five, or
between one and ten, between one and nine, between one and eight,
between one and seven, between one and six, between one and five,
or between one and four, anti-cancer therapies prior to treatment
using the methods described herein (e.g., prior to the
administration of the compound of Formula I, or a pharmaceutically
acceptable salt thereof, as a monotherapy).
[0204] It should be understood that when a subject (e.g. a human)
is treated with the compound of Formula I, or a pharmaceutically
acceptable salt thereof, as a monotherapy, the subject may also
undergo one or more other therapies that are not anti-cancer
therapies.
[0205] In some embodiments, a method of treating a comorbidity of a
cancer, including but not limited to CLL, in a subject (e.g., a
human) who has been diagnosed with cancer, e.g. CLL, wherein the
method comprises administering a therapy to treat the comorbidity
in combination with of a bis-mesylate salt of a compound of Formula
I (including polymorphs of such bis-mesylate salt, such as Form 3
and/or Form 7), or a hydrate thereof, or a pharmaceutical
composition thereof, to the subject. In some embodiments, the
comorbidity is selected from the group consisting of one or more
other cancers (e.g. breast, head and neck, lung, melanoma,
non-Hodgkin's T-cell lymphoma, prostate, colon, small intestine,
gynecologic and urinary tract), hypertension, hyperlipidemia,
coronary artery disease, peripheral vascular diseases,
cardiomyopathy, vulvular heart disease, atrial fibrillation,
cerebrovascular disease (e.g. transient ischemic attack, stroke),
chronic obstructive pulmonary disease, joint disease, peptic ulcer,
inflammatory bowel disease, psychiatric illness, thyroid disease,
benign prostate hyperplasia, diabetes mellitus, and
osteoarthritis.
[0206] Combination Therapies
[0207] In some embodiments, a method of treating cancer, an
allergic disorder and/or an autoimmune and/or inflammatory disease,
and/or an acute inflammatory reaction comprises administering to a
subject (e.g., a human) in need thereof an effective amount of the
pharmaceutical composition described herein, together with one or
more additional therapies (e.g., one or more additional therapeutic
agents), which can be useful for treating a cancer, an allergic
disorder and/or an autoimmune and/or inflammatory disease, and/or
an acute inflammatory reaction.
[0208] In some embodiments, a method of treating cancer, an
allergic disorder and/or an autoimmune and/or inflammatory disease,
and/or an acute inflammatory reaction comprises administering to a
subject in need thereof an effective amount of a bis-mesylate salt
of a compound of Formula I (including polymorphs of such
bis-mesylate salt, such as Form 3 and/or Form 7), or a hydrate
thereof, together with a second active agent, which can be useful
for treating a cancer, an allergic disorder and/or an autoimmune
and/or inflammatory disease, and/or an acute inflammatory reaction.
For example the second agent may be an anti-inflammatory agent.
Treatment with the second active agent may be prior to, concomitant
with, or following treatment with a bis-mesylate salt of a compound
of Formula I (including polymorphs of such bis-mesylate salt, such
as Form 3 and/or Form 7), or a hydrate thereof. In some
embodiments, a bis-mesylate salt of a compound of Formula I
(including polymorphs of such bis-mesylate salt, such as Form 3
and/or Form 7), or a hydrate thereof, is combined with another
active agent in a single dosage form.
[0209] Provided herein are also methods of treatment in which a
bis-mesylate salt of a compound of Formula I (including polymorphs
of such bis-mesylate salt, such as Form 3 and/or Form 7), or a
hydrate thereof, is administered to a subject (e.g., a human) who
has been diagnosed with or is suspected of having a cancer is given
to the subject in combination with one or more additional
therapies, including one or more of the anti-cancer therapies
described above. Thus, in some embodiments, the method for treating
cancer in a subject (e.g., a human) in need thereof, comprises
administering to the subject a therapeutically effective amount of
a bis-mesylate salt of a compound of Formula I (including
polymorphs of such bis-mesylate salt, such as Form 3 and/or Form
7), or a hydrate thereof, or a pharmaceutical composition thereof,
together with one or more additional therapies, which can be useful
for treating the cancer. The one or more additional therapies may
involve the administration of one or more therapeutic agents.
[0210] In one aspect, provided is a method of treating cancer in a
human in need thereof, comprising administering a bis-mesylate salt
of a compound of Formula I (including polymorphs of such
bis-mesylate salt, such as Form 3 and/or Form 7), or a hydrate
thereof, and an additional therapeutic agent to the human. In
certain aspects, provided is a method of treating cancer in a human
in need thereof, comprising administering a hydrate, bis-mesylate
salt of a compound of Formula I to the human, and an additional
therapeutic agent to the human. In one aspect, provided is a method
of treating cancer in a human in need thereof, comprising
administering a monohydrate, bis-mesylate salt of a compound of
Formula I to the human, and an additional therapeutic agent to the
human. In certain aspects, provided is a method of treating cancer
in a human in need thereof, comprising administering a mesylate
salt of Formula IA or IB, or a hydrate thereof to the human, and an
additional therapeutic agent to the human. In other aspects,
provided is a method of treating cancer in a human in need thereof,
comprising administering a hydrate, mesylate salt of Formula IA or
IB to the human, and an additional therapeutic agent to the human.
In one aspect, provided is a method of treating cancer in a human
in need thereof, comprising administering polymorph Form 3 to the
human, and an additional therapeutic agent to the human. In another
aspect, provided is a method of treating cancer in a human in need
thereof, comprising administering polymorph Form 7 to the human,
and an additional therapeutic agent to the human. In any of the
foregoing embodiments, the treatment of cancer may include, for
example, leukemia, lymphoma and solid-cell tumors.
[0211] The additional therapeutic agent may be one or more agents.
In some embodiments, the one or more additional therapeutic agent
may be a phosphatidylinositol 3-kinase (PI3K) inhibitor, including
for example, Compounds A, B, C and D, whose structures are provided
below.
##STR00031##
[0212] In other embodiments, the one or more additional therapeutic
agent may be an inhibitors of lysyl oxidase-like 2 (LOXL2) or a
substance that binds to LOXL2, including for example, a humanized
monoclonal antibody (mAb) with an immunoglobulin IgG4 isotype
directed against human LOXL2. In yet other embodiments, the one or
more additional therapeutic agent may be an inhibitor of apoptosis
signal-regulating kinase (ASK-1) or a substance that binds to
ASK-1. In yet other embodiments, the one or more additional
therapeutic agent may be an inhibitor of a Janus kinase, such as
JAK1 or JAK2, or a substance that binds to a Janus kinase, such as
JAK1 or JAK2. In one embodiment, the one or more additional
therapeutic agent is momelotinib. In other embodiments, the one or
more additional therapeutic agent may be a Bruton's tyrosine kinase
(BTK) inhibitor. In yet other embodiments, the one or more
additional therapeutic agent may be a B-cell lymphoma (BCL)
inhibitor. In some variations, the BCL inhibitor is a BCL-2
inhibitor. In one variation, the BCL inhibitor is ABT-199.
[0213] In yet other embodiments, the one or more additional
therapeutic agent may be fludarabine, rituximab, obinutuzumab,
alkylating agents, alemtuzumab and other chemotherapy treatments
such as CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated
cyclophosphamide, vincristine, doxorubicin, dexamethasone,
methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM
(fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab,
fludarabine, cyclophosphamide, mitoxantrone); bortezomib and
rituximab; temsirolimus and rituximab; temsirolimus and
Velcade.RTM.; Iodine-131 tositumomab (Bexxar.RTM.) and CHOP; CVP
(cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);
ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE);
FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine,
rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin,
Adriamycin.RTM., cyclophosphamide, etoposide).
[0214] In other embodiments, the one or more additional therapeutic
agent may be a vinca-alkaloid. In one variation, the vinca-alkaloid
is selected from the group consisting of vincristine, vinblastine,
vindesine, vinorelbine, desoxyvincaminol, vincaminol, vinburnine,
vincamajine, and vineridine, and pharmaceutically acceptable salts
thereof. In certain variations, at least one vinca-alkaloid is
selected from the group consisting of vincristine, vinblastine,
vindesine, vinorelbine, desoxyvincaminol, vincaminol, vinburnine,
vincamajine, and vineridine and pharmaceutically acceptable salts
thereof. In some variations, the vinca-alkaloid is selected from
the group consisting of vincristine, vinblastine, vindesine, and
vinorelbine, and pharmaceutically acceptable salts thereof. In
other variations, the vinca-alkaloid is selected from the group
consisting of vincristine and vinblastine, and pharmaceutically
acceptable salts thereof. In one variation, the vinca-alkaloid is
vincristine and pharmaceutically acceptable salts thereof. In
another variation, the vinca-alkaloid is vinblastine and
pharmaceutically acceptable salts thereof. Thus, in one aspect,
provided is a method for treating cancer in a human in need
thereof, comprising administering to the human a bis-mesylate salt
of a compound of Formula I, or a hydrate thereof; and a
vinca-alkaloid, or a pharmaceutically acceptable salt thereof. In
certain aspects, provided is a method for treating cancer in a
human in need thereof, comprising administering to the human a
hydrate, bis-mesylate salt of a compound of Formula I; and a
vinca-alkaloid, or a pharmaceutically acceptable salt thereof. In
one aspect, provided is a method of treating cancer in a human in
need thereof, comprising administering a monohydrate, bis-mesylate
salt of a compound of Formula I; and a vinca-alkaloid, or a
pharmaceutically acceptable salt thereof. In certain aspects,
provided is a method of treating cancer in a human in need thereof,
comprising administering a mesylate salt of Formula IA or IB, or a
hydrate thereof and a vinca-alkaloid, or a pharmaceutically
acceptable salt thereof. In other aspects, provided is a method of
treating cancer in a human in need thereof, comprising
administering a hydrate, mesylate salt of Formula IA or IB; and a
vinca-alkaloid, or a pharmaceutically acceptable salt thereof.
[0215] In other embodiments, the one or more additional therapies
may be any monotherapy or combination therapy suitable for treating
leukemia, including, for example, chronic lymphocytic leukemia
(CLL), acute lymphocytic leukemia (ALL), and/or acute myeloid
leukemia (AML).
[0216] In other embodiments, the one or more additional therapeutic
agent may be an anti-inflammatory agent. Treatment with the one or
more additional therapeutic agent may be prior to, concomitant
with, or following treatment with the pharmaceutical composition
described herein. In some embodiments, the pharmaceutical
composition described herein is combined with another therapeutic
agent in a single dosage form. Suitable antitumor therapeutics that
may be used in combination with at least one chemical entity
described herein include, but are not limited to, chemotherapeutic
agents, for example mitomycin C, carboplatin, taxol, cisplatin,
paclitaxel, etoposide, doxorubicin, or a combination comprising at
least one of the foregoing chemotherapeutic agents.
Radiotherapeutic antitumor agents may also be used, alone or in
combination with chemotherapeutic agents.
[0217] The pharmaceutical composition described herein can be
useful as chemosensitizing agents, and, thus, can be useful in
combination with other chemotherapeutic drugs, in particular, drugs
that induce apoptosis.
[0218] A method for increasing sensitivity of cancer cells to
chemotherapy, comprising administering to a subject (e.g., human)
undergoing chemotherapy a chemotherapeutic agent together with the
pharmaceutical composition described herein an amount sufficient to
increase the sensitivity of cancer cells to the chemotherapeutic
agent is also provided herein. Examples of other chemotherapeutic
drugs that can be used in combination with chemical entities
described herein include topoisomerase I inhibitors (camptothesin
or topotecan), topoisomerase II inhibitors (e.g. daunomycin and
etoposide), alkylating agents (e.g. cyclophosphamide, melphalan and
BCNU), tubulin directed agents (e.g. taxol and vinblastine), and
biological agents (e.g. antibodies such as anti CD20 antibody, IDEC
8, immunotoxins, and cytokines).
[0219] In some embodiments, the pharmaceutical composition
described herein are used in combination with Rituxan.RTM.
(Rituximab) or other agents that work by selectively depleting
CD20+ B-cells.
[0220] Included herein are methods of treatment in which the
pharmaceutical composition described herein is administered in
combination with an anti-inflammatory agent. Anti-inflammatory
agents include but are not limited to NSAIDs, non-specific and
COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds,
corticosteroids, methotrexate, tumor necrosis factor receptor (TNF)
receptors antagonists, immunosuppressants and methotrexate.
Examples of NSAIDs include, but are not limited to ibuprofen,
flurbiprofen, naproxen and naproxen sodium, diclofenac,
combinations of diclofenac sodium and misoprostol, sulindac,
oxaprozin, diflunisal, piroxicam, indomethacin, etodolac,
fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine,
tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also
include COX-2 specific inhibitors (i.e., a compound that inhibits
COX-2 with an IC50 that is at least 50-fold lower than the IC50 for
COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib
and/or rofecoxib.
[0221] In a further embodiment, the anti-inflammatory agent is a
salicylate. Salicylates include but are not limited to
acetylsalicylic acid or aspirin, sodium salicylate, and choline and
magnesium salicylates. The anti-inflammatory agent may also be a
corticosteroid. For example, the corticosteroid may be chosen from
cortisone, dexamethasone, methylprednisolone, prednisolone,
prednisolone sodium phosphate, and prednisone. In some embodiments,
the anti-inflammatory therapeutic agent is a gold compound such as
gold sodium thiomalate or auranofin. In some embodiments, the
anti-inflammatory agent is a metabolic inhibitor such as a
dihydrofolate reductase inhibitor, such as methotrexate or a
dihydroorotate dehydrogenase inhibitor, such as leflunomide.
[0222] In some embodiments, combinations in which at least one
anti-inflammatory compound is an anti-C5 monoclonal antibody (such
as eculizumab or pexelizumab), a TNF antagonist, such as
entanercept, or infliximab, which is an anti-TNF alpha monoclonal
antibody are used.
[0223] In some embodiments, combinations in which at least one
therapeutic agent is an immunosuppressant compound such as
methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine,
or mycophenolate mofetil are used.
[0224] It should be understood that any combinations of the
additional therapeutic agents described above may be used, as if
each and every combination was individually listed. For example, in
certain embodiments, the additional therapeutic agents include a
PI3K inhibitor and a LOXL2 inhibitor.
Kits
[0225] Kits comprising a pharmaceutical composition comprising a
mesylate salt (including, for example, a bis-mesylate salt) of the
compound of Formula I, or a hydrate thereof, and at least one
pharmaceutical carrier, excipient, adjuvant, or vehicle (e.g., at
least one pharmaceutically acceptable polymer) are also
provided.
[0226] In one aspect, provided is a kit comprising a pharmaceutical
composition, comprising: a bis-mesylate salt of a compound of
Formula I, or a hydrate thereof; and a pharmaceutical carrier,
excipient, adjuvant, or vehicle. In certain aspects, provided is a
kit comprising a pharmaceutical composition, comprising: a hydrate,
bis-mesylate salt of a compound of Formula I, and a pharmaceutical
carrier, excipient, adjuvant, or vehicle. In one aspect, provided
is a kit comprising a pharmaceutical composition, comprising: a
monohydrate, bis-mesylate salt of a compound of Formula I, and a
pharmaceutical carrier, excipient, adjuvant, or vehicle. In certain
aspects, provided is a kit comprising a pharmaceutical composition,
comprising: a mesylate salt of Formula IA or IB, or a hydrate
thereof; and a pharmaceutical carrier, excipient, adjuvant, or
vehicle. In other aspects, provided is a kit comprising a
pharmaceutical composition, comprising: a hydrate, mesylate salt of
Formula IA or IB; and a pharmaceutical carrier, excipient,
adjuvant, or vehicle. In one aspect, provided is a kit comprising a
pharmaceutical composition, comprising: polymorph Form 3; and a
pharmaceutical carrier, excipient, adjuvant, or vehicle. In another
aspect, provided is a kit comprising a pharmaceutical composition,
comprising: polymorph Form 7; and a pharmaceutical carrier,
excipient, adjuvant, or vehicle.
[0227] In one variation, the mesylate salt is bis-mesylate salt of
Formula IA. In a particular variation, the mesylate salt is Form 3
of bis-mesylate salt of Formula IA, Form 7 of bis-mesylate salt of
Formula IA, or a mixture thereof. As described herein, Form 3 and
Form 7 are polymorphic forms of a bis-mesylate salt of a compound
of Formula I. For example, Form 3 is a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I.
[0228] In one aspect, the kit comprises instructions for use in the
treatment of cancer or inflammatory conditions. In a particular
variation, the instructions are directed to use of the
pharmaceutical composition for the treatment of cancer, including
for example, leukemia or lymphoma. In certain embodiments, the
cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia
(AML), chronic lymphocytic leukemia (CLL), small lymphocytic
lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative
disease (MPD), chronic myeloid leukemia (CML), multiple myeloma
(MM), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL,
non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL),
follicular lymphoma (FL), Waldestrom's macroglobulinemia (WM),
T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma
(DLBCL), lymphoplasmacytic lymphoma (LPL), and marginal zone
lymphoma (MZL). In certain embodiments, the cancer is acute
lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL),
myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),
chronic myeloid leukemia (CIVIL), multiple myeloma (MM), indolent
non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's
lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma,
Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell
lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one
embodiment, the cancer is T-cell acute lymphoblastic leukemia
(T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). In some
embodiments, the cancer is MCL, DLBCL, iNHL, FL, MZL, LPL, SLL, or
WM. In other embodiments, the cancer is CLL, MCL, DLBCL, iNHL
(including, for example, non-FL iNHL), or FL.
[0229] The non-Hodgkin lymphoma encompasses the indolent B-cell
diseases that include, for example, follicular lymphoma,
lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and
marginal zone lymphoma, as well as the aggressive lymphomas that
include, for example, Burkitt lymphoma, diffuse large B-cell
lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment,
the cancer is indolent non-Hodgkin's lymphoma (iNHL). In another
embodiment, the cancer is non-FL iNHL.
[0230] In a particular variation, the instructions are directed to
use of the pharmaceutical composition for the treatment of an
autoimmune disease. Certain embodiments of an autoimmune disease
include asthma, rheumatoid arthritis, multiple sclerosis, and
lupus.
[0231] Any pharmaceutical composition provided in the present
disclosure may be used in the kits, the same as if each and every
composition were specifically and individually listed for use a
kit. For example, in one embodiment a kit may comprise: a) about
34% w/w of a mesylate salt (including, for example, a mono-mesylate
or bis-mesylate salt) of a compound of Formula I; b) about 15% w/w
HPMC; c) about 22% w/w mannitol; d) about 10% w/w crospovidone; and
e) about 1% w/w to about 3% w/w poloxamer. In another embodiment, a
kit may comprise: a) about 34% w/w of a bis-mesylate salt of a
compound of Formula I, or a hydrate thereof; b) about 15% w/w HPMC;
c) about 22% w/w mannitol; d) about 10% w/w crospovidone; and e)
about 1% w/w to about 3% w/w poloxamer. In yet another embodiment,
a kit may comprise: a) about 34% w/w of a monohydrate, bis-mesylate
salt of a compound of Formula I; b) about 15% w/w HPMC; c) about
22% w/w mannitol; d) about 10% w/w crospovidone; and e) about 1%
w/w to about 3% w/w poloxamer. In yet another embodiment, a kit may
comprise: a) about 34% w/w of polymorph Form 3, polymorph Form 7,
or a combination thereof; b) about 15% w/w HPMC; c) about 22% w/w
mannitol; d) about 10% w/w crospovidone; and e) about 1% w/w to
about 3% w/w poloxamer.
Articles of Manufacture
[0232] Articles of manufacture comprising a container in which a
pharmaceutical composition comprising a mesylate salt (including,
for example, a bis-mesylate salt) of a compound of Formula I and at
least one pharmaceutically acceptable polymer are contained are
provided. The article of manufacture may be a bottle, vial,
ampoule, single-use disposable applicator, or the like, containing
the pharmaceutical composition provided in the present disclosure.
The container may be formed from a variety of materials, such as
glass or plastic and in one aspect also contains a label on, or
associated with, the container which indicates directions for use
in the treatment of cancer or inflammatory conditions.
[0233] In one aspect, provided is an article of manufacture
comprising a bis-mesylate salt of a compound of Formula I, or a
hydrate thereof. In certain aspects, provided is an article of
manufacture comprising a hydrate, bis-mesylate salt of a compound
of Formula I. In one aspect, provided is an article of manufacture
comprising a monohydrate, bis-mesylate salt of a compound of
Formula I. In certain aspects, provided is an article of
manufacture comprising a mesylate salt of Formula IA or IB, or a
hydrate thereof. In other aspects, provided is an article of
manufacture comprising a hydrate, mesylate salt of Formula IA or
IB. In one aspect, provided is an article of manufacture comprising
polymorph Form 3. In one aspect, provided is an article of
manufacture comprising polymorph Form 7. In any of the foregoing
embodiments, the article of manufacture may further comprise a
label containing instructions for use of the mesylate salt.
[0234] Unit dosage forms of the pharmaceutical composition
comprising a mesylate salt (including, for example, a mono-mesylate
or bis-mesylate salt) of a compound of Formula I and at least one
pharmaceutically acceptable polymer are also provided.
[0235] In one aspect, provided is a unit dosage comprising a
bis-mesylate salt of a compound of Formula I, or a hydrate thereof.
In certain aspects, provided is a unit dosage comprising a hydrate,
bis-mesylate salt of a compound of Formula I. In one aspect,
provided is a unit dosage comprising a monohydrate, bis-mesylate
salt of a compound of Formula I. In certain aspects, provided is a
unit dosage comprising a mesylate salt of Formula IA or IB, or a
hydrate thereof. In other aspects, provided is a unit dosage
comprising a hydrate, mesylate salt of Formula IA or IB. In one
aspect, provided is a unit dosage comprising polymorph Form 3. In
one aspect, provided is a unit dosage comprising polymorph Form 7.
In any of the foregoing embodiments, the unit dosage is a
tablet.
[0236] In some embodiments, the unit dosage form comprises from
about 10 mg to about 1800 mg, or about 10 mg to about 1500 mg, or
about 10 mg to about 1300 mg, or about 10 mg to about 1000 mg, or
about 10 mg to about 800 mg, or about 10 mg to about 600 mg, or
about 10 mg to about 300 mg, or about 10 mg to about 200 mg, or
about 10 mg to about 100 mg, or about 100 mg to about 800 mg, or
about 100 mg to about 600 mg, or about 100 mg to about 300 mg, or
about 100 mg to about 200 mg, or about 200 mg to about 350 mg, or
about 250 mg to about 300 mg, or about 200 mg to about 400 mg, or
about 400 mg to about 600 mg, or about 400 mg to about 800 mg, or
about 600 mg or about 800 mg, or about 800 mg to about 1200 mg, or
about 1200 mg to about 1600 of a mesylate salt of a compound of
Formula I, or a hydrate thereof; or in certain embodiments, of a
mono-mesylate or bis-mesylate salt of a compound of Formula I, a
hydrate thereof; or in one embodiment, of a monohydrate,
bis-mesylate salt of a compound of Formula I; or in another
embodiment, polymorph Form 3, polymorph Form 7, or a combination
thereof. In certain embodiments, the unit dosage form comprises
about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg,
about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450
mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about
800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg,
or about 1300 mg of a mesylate salt of a compound of Formula I, or
a hydrate thereof; or in certain embodiments, of a mono-mesylate or
bis-mesylate salt of a compound of Formula I, a hydrate thereof; or
in one embodiment, of a monohydrate, bis-mesylate salt of a
compound of Formula I; or in another embodiment, polymorph Form 3,
polymorph Form 7, or a combination thereof.
[0237] In some of the foregoing embodiments, the unit dosage form
further comprises at least one pharmaceutically acceptable
carrier.
[0238] The dosages for oral administration described above may be
administered once daily (QD) or twice daily (BID). In some
embodiments, a mesylate salt of a compound of Formula I, or a
hydrate thereof; or in certain embodiments, a mono-mesylate or
bis-mesylate salt of a compound of Formula I, a hydrate thereof; or
in one embodiment, a monohydrate, bis-mesylate salt of a compound
of Formula I; or in another embodiment, polymorph Form 3, polymorph
Form 7, or a combination thereof, or a pharmaceutical composition
of any of the foregoing, is administered orally at a unit dosage of
about 1 mg QD, about 2 mg QD, about 5 mg QD, about 10 mg QD, about
15 mg QD, about 20 mg QD, about 25 mg QD, about 30 mg QD, about 35
mg QD, about 40 mg QD, about 45 mg QD, about 50 mg QD, about 75 mg
QD, about 100 mg QD, about 125 mg QD, about 150 mg QD, about 175 mg
QD, about 200 mg QD, about 225 mg QD, about 250 mg QD, about 300 mg
QD, about 350 mg QD, about 400 mg QD, about 450 mg QD, about 500 mg
QD, about 550 mg QD, about 600 mg QD, about 650 mg QD, about 700 mg
QD, about 750 mg QD, about 800 mg QD, about 850 mg QD, about 900 mg
QD, about 950 mg QD, or about 1000 mg QD. In some embodiments, a
mesylate salt of a compound of Formula I, or a hydrate thereof; or
in certain embodiments, a mono-mesylate or bis-mesylate salt of a
compound of Formula I, a hydrate thereof; or in one embodiment, a
monohydrate, bis-mesylate salt of a compound of Formula I; or in
another embodiment, polymorph Form 3, polymorph Form 7, or a
combination thereof, or a pharmaceutical composition of any of the
foregoing, is administered orally at a unit dosage of about 1 mg
BID, about 2 mg BID, about 5 mg BID, about 10 mg BID, about 15 mg
BID, about 20 mg BID, about 25 mg BID, about 30 mg BID, about 35 mg
BID, about 40 mg BID, about 45 mg BID, about 50 mg BID, about 75 mg
BID, about 100 mg BID, about 125 mg BID, about 150 mg BID, about
175 mg BID, about 200 mg BID, about 225 mg BID, about 250 mg BID,
about 300 mg BID, about 350 mg BID, about 400 mg BID, about 450 mg
BID, about 500 mg BID, about 550 mg BID, about 600 mg BID, about
650 mg BID, about 700 mg BID, about 750 mg BID, about 800 mg BID,
about 850 mg BID, about 900 mg BID, about 950 mg BID, or about 1000
mg BID.
[0239] For example, in certain variations, provided is a tablet
comprising a mesylate salt of a compound of Formula I, or a hydrate
thereof; or in certain embodiments, a mono-mesylate or bis-mesylate
salt of a compound of Formula I, a hydrate thereof; or in one
embodiment, a monohydrate, bis-mesylate salt of a compound of
Formula I; or in another embodiment, polymorph Form 3, polymorph
Form 7, or a combination thereof, wherein the tablet is
administered orally to a human in need thereof at a unit dosage of
about 1 mg BID, about 2 mg BID, about 5 mg BID, about 10 mg BID,
about 15 mg BID, about 20 mg BID, about 25 mg BID, about 30 mg BID,
about 35 mg BID, about 40 mg BID, about 45 mg BID, about 50 mg BID,
about 75 mg BID, about 100 mg BID, about 125 mg BID, about 150 mg
BID, about 175 mg BID, about 200 mg BID, about 225 mg BID, about
250 mg BID, about 300 mg BID, about 350 mg BID, about 400 mg BID,
about 450 mg BID, about 500 mg BID, about 550 mg BID, about 600 mg
BID, about 650 mg BID, about 700 mg BID, about 750 mg BID, about
800 mg BID, about 850 mg BID, about 900 mg BID, about 950 mg BID,
or about 1000 mg BID. In one variation of the foregoing, the human
has a condition selected from the group consisting of
lymphoplasmacytic lymphoma/Waldestrom's macroglobulinemia (LPL/WM),
small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL),
follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL),
mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL),
or any combination thereof. In another variation of any of the
foregoing, the human is (i) refractory to, and/or (ii) in relapse
after treatment with at least one therapy for a non-FL indolent
non-Hodgkin's lymphoma. In certain embodiments, the non-FL indolent
non-Hodgkin's lymphoma is lymphoplasmacytic lymphoma/Waldestrom's
macroglobulinemia (LPL/WM), small lymphocytic lymphoma (SLL), or
marginal zone lymphoma (MZL)). In another variation, the human is
(i) refractory to, and/or (ii) in relapse after treatment with at
least one therapy for follicular lymphoma (FL). In another
variation, the human is (i) refractory to, and/or (ii) in relapse
after treatment with at least one therapy for diffuse large B-cell
lymphoma (DLBCL). In another variation, the human is (i) refractory
to, and/or (ii) in relapse after treatment with at least one
therapy for mantle cell lymphoma (MCL). In yet another variation,
the human is (i) refractory to, and/or (ii) in relapse after
treatment with at least one therapy for chronic lymphocytic
leukemia (CLL). In yet another variation, the human is (i)
refractory to, and/or (ii) in relapse after treatment with a
phosphatidylinositol 3-kinase (PI3K) inhibitor, a bruton tyrosine
kinase (BTK) inhibitor, or a B-cell receptor (BCR) treatment for
chronic lymphocytic leukemia (CLL).
[0240] Any pharmaceutical composition provided in the present
disclosure may be used in the articles of manufacture, the same as
if each and every composition were specifically and individually
listed for use an article of manufacture. For example, in one
embodiment, an article of manufacture may comprise: a) about 34%
w/w of a mesylate salt (including, for example, a mono-mesylate or
bis-mesylate salt) of a compound of Formula I; b) about 15% w/w
HPMC; c) about 22% w/w mannitol; d) about 10% w/w crospovidone; and
e) about 1% w/w to about 3% w/w poloxamer. In another embodiment,
an article of manufacture may comprise: a) about 34% w/w of a
bis-mesylate salt of a compound of Formula I, or a hydrate thereof
b) about 15% w/w HPMC; c) about 22% w/w mannitol; d) about 10% w/w
crospovidone; and e) about 1% w/w to about 3% w/w poloxamer. In yet
another embodiment, an article of manufacture may comprise: a)
about 34% w/w of a monohydrate, bis-mesylate salt of a compound of
Formula I; b) about 15% w/w HPMC; c) about 22% w/w mannitol; d)
about 10% w/w crospovidone; and e) about 1% w/w to about 3% w/w
poloxamer. In yet another embodiment, an article of manufacture may
comprise: a) about 34% w/w of polymorph Form 3, polymorph Form 7,
or a combination thereof; b) about 15% w/w HPMC; c) about 22% w/w
mannitol; d) about 10% w/w crospovidone; and e) about 1% w/w to
about 3% w/w poloxamer.
EXAMPLES
[0241] The following examples are included to illustrate preferred
embodiments of the disclosure. It should be appreciated by those of
skill in the art that the techniques disclosed herein represent
techniques that apply in the practice of the disclosure. Those of
skill in the art should, in light of the present disclosure,
appreciate that changes can be made in the and still obtain a like
or similar result without departing from the spirit and scope of
the disclosure.
[0242] The polymorphs described herein may be characterized by
various methods known in the art, such as X-ray powder diffraction
pattern (XRPD), differential scanning calorimetry (DSC), thermal
gravimetric analysis (TGA), dynamic vapor sorption (DVS), single
crystal X-ray diffraction, nuclear magnetic resonance (NMR, e.g.,
.sup.1H NMR), including, for example, the methods described in
Examples 4A, 4B, 4C, 5A, 5B, 6A, 6B and 11. With respect to
polymorph Form 3, exemplary XRPD patterns are provided in FIGS. 1A
and 1B; exemplary DSC and TGA profiles are provided in FIGS. 3A, 3B
and 3C; exemplary DVS plots are provided in FIGS. 5A and 5C; and an
exemplary .sup.1H NMR spectrum is provided in FIG. 13. With respect
to polymorph Form 7, representative XRPD patterns are provided in
FIGS. 2A and 2B; exemplary DSC and TGA data are provided in FIGS.
4A, 4B and 4C; exemplary DVS plots are provided in FIGS. 5B and 5D;
and an exemplary .sup.1H NMR spectrum is provided in FIG. 14.
[0243] In the following Examples, the term "X" refers to weight
equivalents, and "V" refers to volume equivalents. "RH" refers to
relative humidity.
Example 1: Synthesis of Polymorph Form 3
[0244] Methods for generally making various forms of the compound
of Formula I may be found in U.S. Pat. Nos. 8,450,321 and
8,455,493. The following is a method for producing polymorph Form
3, which is a polymorph of a monohydrate, bis-mesylate salt of a
compound of Formula I (and may also be described as a polymorph of
a monohydrate of the compound of Formula IA shown in the reaction
scheme below).
##STR00032##
[0245] A compound of Formula I (1.0.times.) was added to Reactor A.
Methanesulfonic acid (0.56.times., 2.40 eq), water (4.times., 4 V)
and acetone (3.2.times., 4 V) were added to Reactor B. The contents
of Reactor B were added to Reactor A while maintaining the
temperature in Reactor A below 35.degree. C. After the solids
dissolved, the contents of Reactor A were transferred to Reactor B.
Reactor A was rinsed with water (1.times., 1 V) and acetone
(0.8.times., 1 V), and transferred to Reactor B. The temperature of
Reactor B was adjusted to 19-25.degree. C. Under high agitation,
acetone (11.9.times., 15 V) was added to Reactor B. The temperature
of Reactor B was adjusted to 0-6.degree. C. and the contents of
Reactor B were mixed for 5 h, then filtered, and rinsed with
acetone (4.0.times., 5 V) to provide polymorph Form 7. Form 7 was
dried under vacuum at 60.degree. C. until constant weight was
achieved. Representative patterns of XRPD and DSC of polymorph Form
7 are shown in FIGS. 2A and 4A, respectively.
[0246] The isolated polymorph Form 7 was added to polymorph Form 3
seeds of a compound of Formula IA (0.01.times., 1 mol %) in Reactor
B. Acetone (15.4.times., 19.5 V), and water (0.5.times., 0.5 V)
were added to Reactor B and mixed at 19-25.degree. C. until
polymorph Form 7 was converted to Form 3. The conversion was
monitored by XRPD or DSC. The contents of Reactor B was filtered,
rinsed with acetone (2.4.times., 3 V) and dried under vacuum at
60.degree. C. until constant weight was achieved. Representative
patterns of XRPD and DSC of polymorph Form 3 of a compound of
Formula IA are shown in FIGS. 1A and 3A, respectively. Other
representative patterns of XRPD and DSC of polymorph Form 3 of a
compound of Formula IA are shown in FIGS. 1B and 3C,
respectively.
Example 2: Alternative Synthesis of Polymorph Form 3
[0247] The following is a method for producing polymorph Form 3, a
monohydrate, bis-mesylate salt of a compound of Formula I (which
may also be described as a polymorph of a monohydrate of the
compound of Formula IA shown in the reaction scheme below).
##STR00033##
[0248] Polymorph Form 7 was obtained as described in Example 1.
[0249] The isolated polymorph Form 7 was added to polymorph Form 3
seeds of a compound of Formula IA (0.01.times., 1 mol %) in Reactor
B. Acetone (15.0.times., 19.0 V), and water (1.0.times., 1.0 V)
were added to Reactor B. The contents of the Reactor B were heated
to reflux (about 55.degree. C.) until polymorph Form 7 was
converted to Form 3. The conversion was monitored by XRPD or DSC.
The contents of Reactor B was a slurry and was cooled to
19-25.degree. C., then filtered, rinsed with acetone (2.4.times., 3
V) and dried under vacuum at 60.degree. C. until constant weight is
achieved to provide the polymorph Form 3. Representative patterns
of XRPD and DSC of polymorph Form 3 of a compound of Formula IA are
shown in FIGS. 1A and 3A, respectively. Other representative
patterns of XRPD and DSC of polymorph Form 3 of a compound of
Formula IA are shown in FIGS. 1B and 3C, respectively.
Example 3: One-Pot Synthesis of Polymorph Form 3
[0250] The following is a method for producing polymorph Form 3, a
monohydrate, bis-mesylate salt of a compound of Formula I (which
may also be described as a polymorph of a monohydrate of the
compound of Formula IA shown in the reaction scheme below) from a
compound of Formula I (as a the free base). The described method
uses a single reactor in the conversion of a compound of Formula I
to polymorph Form 3, and does not require isolation of a compound
intermediate.
##STR00034##
[0251] A compound of Formula I (1.0.times.) was added to acetone
(14.2.times., 18V) in Reactor A and mixed. Water (0.8.times., 0.8V)
was added to Reactor A, followed by methanesulfonic acid,
(0.48.times., 2.05 eq). Acetone (0.9.times., 1.2 V) was pumped
through to rinse the lines forward to Reactor A with acetone. The
contents of Reactor A were heated to reflux (about 55.degree. C.)
for about 2 hours. Polymorph Form 3 seeds (0.015.times., 1 mol %)
were added to Reactor A and the contents mixed at reflux to convert
a compound of Formula IA to polymorph Form 3. The conversion was
monitored by XRPD. The contents of the reactor were cooled to
19-25.degree. C., filtered, rinsed with acetone (4.0.times., 5 V),
and dried under vacuum at 60.degree. C. Representative patterns of
XRPD and DSC of polymorph Form 3 of a compound of Formula IA are
shown in FIGS. 1A and 3A, respectively. Other representative
patterns of XRPD and DSC of polymorph Form 3 of a compound of
Formula IA are shown in FIGS. 1B and 3C, respectively.
Example 4A: Polymorph Form 3 and Polymorph Form 7 XRPD
Measurements
[0252] This example describes the experimental conditions and data
for XRPD measurements of polymorph Form 3 and polymorph Form 7.
Polymorph Form 3
[0253] XRPD patterns were collected with a PANalytical X'Pert PRO
MPD diffractometer using an incident beam of Cu radiation produced
using an Optix long, fine-focus source. An elliptically graded
multilayer mirror was used to focus Cu K.alpha. X-rays through the
specimen and onto the detector. Prior to the analysis, a silicon
specimen (NIST SRM 640d) was analyzed to verify the observed
position of the Si 111 peak is consistent with the NIST-certified
position. A specimen of the sample was sandwiched between
3-.mu.m-thick films and analyzed in transmission geometry. A
beam-stop, short antiscatter extension, and an antiscatter knife
edge were used to minimize the background generated by air. Soller
slits for the incident and diffracted beams were used to minimize
broadening from axial divergence. Diffraction patterns were
collected using a scanning position-sensitive detector
(X'Celerator) located 240 mm from the specimen and Data Collector
software v. 2.2b. The data acquisition parameters for each pattern
are displayed above the image in the Data section of this report
including the divergence slit (DS) before the mirror. Prominent
peaks are selected from observed peaks by identifying preferably
non-overlapping, low-angle peaks, with strong intensity.
[0254] An exemplary XRPD pattern of polymorph Form 3 is shown in
FIG. 1A. With reference to FIG. 1A, characteristic XRPD
2.theta.-reflections (.+-.0.2 degrees) for Form 3 are 13.75, 16.90,
22.88, and 26.06.
Polymorph Form 7
[0255] XRPD patterns were collected using a PANalytical X'Pert MPD
Pro Powder X-Ray Diffractometer configured with reflectance stage
with spinning, data acquisition range: 2-40 degrees 2.theta.,
Copper (Cu) anode; K.alpha.1/K.alpha.2 radiation; tube current 40
mA; tube tension 45 kV; automatic divergence and anti-scatter
slits. Samples were prepared for analysis by distributing solid
material as a thin layer on a silicon holder. Each holder was
mounted on a reflectance/transmittance stage and rotated during
data acquisition.
[0256] An exemplary XRPD pattern of polymorph Form 7 is shown in
FIG. 2A. With reference to FIG. 2A, characteristic XRPD
2.theta.-reflections (.+-.0.2 degrees) for Form 7 are 4.94, 9.82,
and 26.68.
Example 4B: Polymorph Form 3 and Polymorph Form 7 XRPD
Measurements
[0257] This example describes experimental conditions and data for
XRPD measurements of polymorph Form 3 and polymorph Form 7.
[0258] X-Ray Powder Diffraction (XRPD) patterns were collected on a
Bruker AXS C2 GADDS diffractometer using Cu K .alpha. 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).
[0259] 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 20 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 XP/2000 4.1.43 and the data were analysed
and presented using Diffrac Plus EVA v15.0.0.0.
[0260] Ambient conditions: 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.
[0261] Non-ambient conditions: Samples run under non-ambient
conditions were mounted on a silicon wafer with heat-conducting
compound. The sample was then heated to the appropriate temperature
at 20.degree. C./min and subsequently held isothermally for 1
minute before data collection was initiated.
Example 4C: Polymorph Form 3 and Polymorph Form 7 XRPD
Measurements
[0262] This example describes experimental conditions and data for
XRPD measurements of polymorph Form 3 and polymorph Form 7.
[0263] X-Ray Powder Diffraction (XRPD) patterns were collected on a
Bruker D8 diffractometer using Cu K .alpha. 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 v2.6.1 and the data were analysed and
presented using Diffrac Plus EVA v15.0.0.0.
[0264] 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:
Angular range: 2 to 42 .degree.2.theta. Step size: 0.05
.degree.2.theta. Collection time: 0.5 s/step
[0265] Samples run under non-ambient conditions: Approximately 40
mg of the sample was placed in a Ni-coated sample holder under
ambient conditions. The sample was loaded at 25.degree. C. The
sample was then heated to the appropriate temperature. The details
of the data collection are:
Angular range: 3 to 30 .degree.2.theta. Step size: 0.05
.degree.2.theta. Collection time: 0.5 s/step
Example 5A: Polymorph Form 3 and Polymorph Form 7 DSC
Measurements
[0266] This example describes the experimental conditions and data
for Modulated Differential Scanning calorimetry (mDSC) and Thermal
Gravimetric Analysis (TGA) measurements of polymorph Form 3 and
polymorph Form 7.
[0267] DSC was performed with approximately 2 to 5 mg of solid in
an aluminum pan with a pinhole, heated at 2.degree. C./min with a
modulation of .+-.0.8.degree. C. every 60 seconds under dried
nitrogen purge using TA instruments (New Castle, Del., USA) model
1000. TGA was performed with approximately 2 to 5 mg of solid
heated at a rate of 2 or 10.degree. C./min using TA Instruments
(New Castle, Del., USA) model 500.
Polymorph Form 3
[0268] The DSC thermogram and the overlay of the DSC and TGA
thermograms of polymorph Form 3 are shown in FIGS. 3A and 3B,
respectively. The characteristic DSC pattern of Form 3 was observed
to have three endotherms that onset at 109.degree. C., 206.degree.
C., and 255.degree. C. The major event in the DSC thermogram
observed was melting at 260.degree. C. with concurrent
decomposition. A minor endotherm was observed at .about.170.degree.
C. and a minor exotherm at .about.210.degree. C. the origins of
which were unknown. The TGA thermogram of Form 3 in this example
shows a step change of .about.3% between the temperature of
75.degree. C. and 100.degree. C. which could be due to loss of
residual solvent. Another step change around 200.degree. C. was
observed, which coincides with the small exotherm on the DSC
thermogram. The major decomposition was observed to start around
230.degree. C.
Polymorph Form 7
[0269] The DSC thermogram and the overlay of the DSC and TGA
thermograms of Form 7 are shown in FIGS. 4A and 4B, respectively.
Two small endotherms were observed at .about.110.degree. C. and
170.degree. C. prior to the onset of decomposition at
.about.280.degree. C. The reversing heat flow show a typical tg at
170.degree. C. which may indicate that the endotherm shown on the
total heat flow at the same temperature is not a melting event.
These thermal properties may be consistent with a liquid crystal
state. The TGA thermogram of Form 7 shows two step changes of
.about.1% each below 80.degree. C. which could be due to loss of
residual solvent. The onsite of decomposition was observed at
220.degree. C. which is similar to the DSC thermogram.
Example 5B: Polymorph Form 3 and Polymorph Form 7 DSC
Measurements
[0270] This example describes the experimental conditions and data
for Differential Scanning calorimetry (DSC) and Thermal Gravimetric
Analysis (TGA) measurements of polymorphs Form 3 and Form 7.
[0271] DSC data were collected on a Mettler DSC 823E equipped with
a 34 position auto-sampler. The instrument was calibrated for
energy and temperature 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 nitrogen
purge at 50 ml/min was maintained over the sample. The instrument
control and data analysis software was STARe v12.1. TGA data were
collected on a Mettler TGA/SDTA 851e equipped with a 34 position
auto-sampler. The instrument was temperature calibrated using
certified indium. Typically 5-30 mg of each sample was loaded onto
a pre-weighed aluminium crucible and was heated at 10.degree.
C./min from ambient temperature to 350.degree. C. A nitrogen purge
at 50 ml/min was maintained over the sample. The instrument control
and data analysis software was STARe v12.1.
[0272] Exemplary DSC and TGA thermograms of polymorph Form 3 and
polymorph Form 7 are shown in FIGS. 3C and 4C, respectively.
Example 6A: Hygroscopicity Studies of Polymorph Form 3 and
Polymorph Form 7
[0273] This example demonstrates the superior physical stability of
polymorph Form 3 compared to polymorph Form 7.
[0274] Hygroscopicity of polymorph Form 3 and polymorph Form 7 at
25.degree. C. was determined by dynamic vapor sorption (DVS) using
an automated vapor sorption balance (Q5000SA; TA instruments, New
Castle, Del.). Hygroscopicity was studied as a function of relative
humidity (RH) over the range of 0 to 90%. Approximately 10 mg of
solid sample was placed directly onto the 13 mm quartz DVS sample
cup and equilibrated at 0% relative humidity (RH) until a constant
weight was achieved. After equilibration, the RH was increased in
increments of 10% to reach 90%, and the water sorption was
monitored. For desorption, the relative humidity was deceased in a
similar manner to accomplish a full sorption/desorption cycle.
[0275] For all experiments, the instrument was operated in dm/dt
mode (mass variation over time) to determine when equilibrium was
reached. A fixed dm/dt value of 0.0010% min.sup.-1 was selected for
all RH segments. A maximum stage of 360 minutes and a minimum stage
of 60 minutes were selected for these experiments.
[0276] Polymorph Form 3 was not observed to be hygroscopic at 70%
RH and below. Above 70% RH, it was observed to absorb a large
amount of moisture. At 90%, the water adsorption was observed to
reach .about.28%. The water adsorption was observed to be
irreversible as indicated by the existence of a big hysteresis. At
the end of the DVS experiment, sample was collected and analyzed by
XRPD which showed the sample had converted to Form 7. See FIG.
6.
[0277] Polymorph Form 7 was observed to be highly hygroscopic. It
was observed to continuously adsorb water at all tested RH's. At
40% RH, the weight gain was observed to be nearly 10%. However, the
weight gain at 90% RH was observed to be .about.22% which is lower
than that of Form 3. As RH decreases, the sample loses weight and
the weight gain were observed to return to near zero at 0% RH.
[0278] In summary, at up to 70% RH, polymorph Form 3 was not
observed to be hygroscopic and exhibits increased stability
compared to Form 7 which adsorbs water below 70% RH.
Example 6B: Hygroscopicity Studies of Polymorphs Form 3 and Form
7
[0279] This example demonstrates the physical stabilities of
polymorph Form 3 and polymorph Form 7.
[0280] Sorption isotherms were obtained using a Hiden IGASorp
moisture sorption analyser, controlled by CFRSorp software. The
sample temperature was maintained at 25.degree. C. by a Huber
re-circulating water bath. The humidity was controlled by mixing
streams of dry and wet nitrogen, with a total flow rate of 250
ml/min. The relative humidity (RH) was measured by a calibrated
Vaisala RH probe (dynamic range of 0-95% 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 .+-.0.001 mg).
[0281] 10-20 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).
[0282] A moisture sorption isotherm was performed as outlined in
Table 1 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.
TABLE-US-00001 TABLE 1 Method Parameters for Hiden IGASorp
Experiments Parameters Values Adsorption - Scan 1 40-90
Desorption/Adsorption - Scan 2 85-Dry, Dry-40 Intervals (% RH) 10
Number of Scans 2 Flow rate (ml/min) 250 Temperature (.degree. C.)
25 Stability (.degree. C./min) 0.05 Minimum Sorption Time (hours) 1
Maximum Sorption Time (hours) 4 Mode AF2 Accuracy (%) 98
[0283] The software uses a least squares minimization procedure
together with a model of the mass relaxation, to predict an
asymptotic value. The measured mass relaxation value must be within
5% of that predicted by the software, before the next % RH value is
selected. The minimum equilibration time was set to 1 hour and the
maximum to 4 hours. Data analysis was carried out using IGASorp
Systems Software v 6.50.55. The sample was recovered after
completion of the isotherm and re-analyzed by XRPD.
[0284] In other cases, sorption isotherms were also obtained using
a SMS DVS Intrinsic moisture sorption analyser, controlled by DVS
Intrinsic Control software v1.0.1.2 (or v 1.0.1.3). 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).
[0285] 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 in Table 2 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 carried out using Microsoft Excel using DVS Analysis
Suite v6.2 (or 6.1 or 6.0). The sample was recovered after
completion of the isotherm and re-analyzed by XRPD.
TABLE-US-00002 TABLE 2 Method Parameters for SMS DVS Intrinsic
Experiments Parameter Value 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
[0286] Polymorph Form 3 was not observed to be hygroscopic at 70%
RH and below (FIG. 5C). However, Form 3 absorbs up to .about.20 wt.
% of water up to 90% RH at 25.degree. C. XRPD analysis of the
sample after DVS analysis shows that the material had converted to
Form 7.
[0287] Polymorph Form 7 was observed to be highly hygroscopic (FIG.
5D) picking up .about.21 wt. % of water up to 90% RH at 25.degree.
C. The form was found to be stable at room temperature between
30-60% RH. However, below this interval the material becomes
amorphous. In summary, up to 70% RH, polymorph Form 3 is not
hygroscopic and exhibits better stability compared to Form 7.
.sup.1H Nuclear Magnetic Resonance (NMR)
[0288] NMR spectra were collected on a Bruker 400 MHz instrument
equipped with an auto-sampler and controlled by a DRX400 console.
Automated experiments were acquired using ICON-NMR v4.0.7 running
with Topspin v1.3 using the standard Bruker loaded experiments. For
non-routine spectroscopy, data were acquired through the use of
Topspin alone.
[0289] Samples were prepared in DMSO-d.sub.6, unless otherwise
stated. Off-line analysis was carried out using ACD Spectrus
Processor 2012. FIGS. 13 and 14 are exemplary proton NMR spectra of
polymorph Form 3 and polymorph Form 7, respectively.
Example 7: Intrinsic Dissolution Studies of Polymorph Form 3 and a
Mono-MSA Salt of a Compound of Formula I
[0290] This example demonstrates the improved dissolution rate of
polymorph Form 3 (i.e., a polymorph of a monohydrate, bis-mesylate
salt of a compound of Formula I) compared to a mono-mesylate salt a
compound of Formula I.
[0291] Intrinsic dissolution rate experiments were conducted using
a rotating disk apparatus. Disks of drug substance were prepared by
directly compressing 100 mg of powder of polymorph Form 3 in a die
at a pressure of 2500 psi for 2 minutes using a hydraulic press
(Carver Press, Fred Carver, N.J., USA). The exposed surface area
for the resulting disk was 0.5 cm.sup.2. A regular USP dissolution
apparatus maintained at 37.+-.0.5.degree. C. was used for the
dissolution study. Each dissolution vessel contained 500 mL of
aqueous dissolution medium of 0.05 N HCl or pH 6.8 20 mM phosphate
buffer with 1% cetyltrimetrylammonium bromide (CTAB). The disk
holder (die) was half-immersed into the dissolution medium and
rotated at 100 rpm. Samples were withdrawn at specified time
intervals and analyzed by HPLC.
[0292] The dissolution rate (J) of solid per unit surface area may
be described by a diffusion model:
J = DA h ( C s - C b ) ( Equation 2 ) ##EQU00001##
[0293] Where D is the diffusion coefficient of the solute, h is the
diffusion layer thickness during dissolution at the surface of
solid, Cs is the saturation solubility of the solid in the
dissolution medium, and Cb is its concentration in the bulk medium.
Under sink condition (Cs>>Cb) Equation 2 is reduced to:
J = DA h ( C s ) ( Equation 3 ) ##EQU00002##
where dissolution rate is directly proportional to the saturated
solubility.
[0294] The intrinsic dissolution rates (IDR) of the free base
compound of Formula I, mono-MSA salt of the compound of Formula I,
and the polymorph Form 3 (a monohydrate, bis-MSA salt of the
compound of Formula I) are summarized in Table 3 below.
TABLE-US-00003 TABLE 3 polymorph Free Base, Form 3 Physicochemical
Compound of (monohydrate, Properties Formula I mono-MSA bis-MSA)
Solubility in water <0.00005 0.08 >100 (mg/mL) (final pH
(final 1.6) pH < 1.5) Intrinsic dissolution 0.00046 2.5 Not
determined rate in pH 1.3 0.05N HCl with 0.9% NaCl
(mg/min/cm.sup.2) Intrinsic dissolution Not determined 0.003 1.2
rate in pH 6.8 20 mM phosphate with 1% CTAB (mg/min/cm.sup.2)
[0295] The IDR of the anhydrous crystal form of the free base of
Formula I is 0.00046 mg/min/cm.sup.2 at pH 1.3. At pH 6.8 the
intrinsic dissolution rate could not be determined because no free
base was detectable in the dissolution medium.
[0296] The IDR of the crystal form of the mono-MSA compound of
Formula I showed high pH dependency. From pH 1.3 to 6.8, DR
decreased by about 1000 fold, from 2.5 to 0.003 mg/min/cm.sup.2. In
contrast, The DR of the crystal form of polymorph Form 3 showed
much higher IDR than the mono-MSA at pH 6.8. At 1.2
mg/min/cm.sup.2, the IDR of polymorph Form 3 is 400-fold higher
than mono MSA. In addition, FIG. 7 shows a graphical comparison of
the dissolution rate of the two compounds at pH 6.8.
[0297] Polymorph Form 3 has the unexpected and surprising result of
performing significantly better than the mono-MSA compound
increased pH conditions.
Example 8: PK Study in Dog Model
[0298] This example demonstrates the pharmacokinetic effects of
administering the mono-MSA salt or the bis-MSA salt (polymorph Form
3, which is a polymorph of a monohydrate, bis-MSA salt) of Formula
I to pentagastrin- or famotidine-pretreated dogs.
[0299] Pentagastrin pretreatment (6 .mu.g/kg intramuscular
injection 30 minutes prior to test formulation dosing) in fasted
dogs was used to simulate fasting gastric pH in humans. Famotidine
pretreatment (20 mg orally 1 hour prior to test formulation dosing)
in fasted dogs was used to simulate human gastric pH when acid
suppressant was co-dosed with test formulation. The tablets of the
mono-MSA salt or bis-MSA salt of a compound of Formula I
(conventional tablet and spray dried formulation) were orally
administered followed by a 30 mL water flush.
[0300] The exposure of the compound of Formula I in dogs dosed with
tablets containing the mono-MSA salt form is highly dependent on
gastric pH. As shown in Table 2, the area under the curve for 24
hours after dosing (AUC.sub.0-24) decreased by more than 100-fold
in famotidine-pretreated dogs compared to the AUC.sub.0-24 in
pentagastrin-pretreated dogs. These results are consistent with the
kinetic solubility profile of mono-MSA salt of a compound of
Formula I, where solubility decreases dramatically as pH increases
from 2 to 3.
[0301] When a similar tablet formulation containing Form 3 was
dosed in the famotidine-pretreated dogs, the AUC.sub.0-24
unexpectedly increased by more than 10-fold compared to the
mono-MSA salt formulation. A spray-dried formulation provides even
further increases in oral bioavailability over the conventional
tablet formulation. These surprising and unexpected results show
improved bioavailability and suggest that use of Form 3 reduces
drug-drug interactions with acid suppressants, compared to the
mono-mesylate salt. A graphical representation of the results is
shown in FIG. 8.
TABLE-US-00004 TABLE 4 F AUC.sub.0-24 C.sub.max T.sub.max Dog pre-
Compound (%) (.mu.M hr) (.mu.M) (hr) treatment of Formula I Mean
Mean SD Mean SD Mean SD pentagastrin mono-MSA salt, 34 11 1.8 1.6
0.2 2.4 1.2 famotidine conventional 0.2 0.06 0.01 0.02 0.002 1.7
0.6 tablet, 100 mg 20% drug load (clinical) pentagastrin Form 3 13
4.1 1.4 0.8 0.2 1.8 0.4 famotidine (monohydrate, 15 4.9 4.2 0.7 0.5
4.9 9.4 bis-MSA salt), conventional tablet, 100 mg 20% drug load
pentagastrin Form 3 18 6.1 1.8 1.1 0.1 2.3 0.8 famotidine
(monohydrate, 20 6.4 7.8 0.8 0.5 1.7 0.5 bis-MSA salt), 100 mg,
spray dried tablet 20% drug load
Example 9: Alternative Method of Obtaining Polymorph Form 3
[0302] This example describes an alternative method of obtaining
polymorph Form 3, wherein the method does not comprise adding seeds
of Form 3. Polymorph Form 3 is a polymorph of a monohydrate,
bis-mesylate salt of a compound of Formula I (and may also be
described is a polymorph of a monohydrate of the compound of
Formula IA shown in the reaction scheme below).
##STR00035##
[0303] Formic acid (3V, 3.6.times.) and ethyl acetate (2V,
1.8.times.) were added to Reactor A and adjusted to 19-25.degree.
C. The compound of Formula I (1.0.times.) was added to Reactor A
while maintaining the reactor temperature at 19-25.degree. C., and
mixed until the solids dissolved. The solution in Reactor A was
transferred to Reactor B. Formic acid (0.08V, 0.1.times.), ethyl
acetate (2V, 1.8.times.), and methanesulfonic acid (2.0 mol equiv.,
0.47.times.) were added to Reactor A. The solution in Reactor A was
transferred to Reactor B while maintaining a temperature of
19-25.degree. C. in Reactor B. Ethyl acetate (5V, 4.5.times.) was
added to Reactor A and then to Reactor B over a minimum of 1 hour.
The contents of Reactor B were agitated for about 16 h at
19-25.degree. C., then filtered rinsed with ethyl acetate (4V,
3.6.times.) and dried under vacuum at 60.degree. C.
[0304] The solids were transferred to Reactor A along with acetone
(18.9V, 15.0.times.) and water (0.5V, 0.5.times.). The pump and
lines were rinsed forward to Reactor A with acetone (0.9V,
0.7.times.). The contents of Reactor A were mixed at 19-25.degree.
C. The conversion was monitored by XRPD analysis. The reaction
mixture was filtered, rinsed with acetone (3V, 2.4.times.) and
dried under vacuum at 60.degree. C. to obtain polymorph Form 3.
Example 10: Synthesis of Polymorph Form 3
[0305] This example describes a method of obtaining polymorph Form
3, which is a polymorph of a monohydrate, bis-mesylate salt of a
compound of Formula I as depicted in the reaction scheme below.
##STR00036##
[0306] A mixture of methanesulfonic acid (0.56.times.) and water
(0.5.times.) were added to a mixture of compound of formula I
(1.0.times.), acetone (3.6.times.) and water (4.0.times.) while
maintaining a content temperature of below about 35.degree. C.
until solids dissolved. The solution was agitated for about 10
minutes and the content temperature was adjusted to about 19 to
25.degree. C. Under high agitation, acetone (11.9.times.) was added
over about 2 h. After this period, the content temperature was
adjusted to about 0 to 6.degree. C. The mixture was agitated for at
least about 5 h, filtered and the filter cake was rinsed with
acetone (4.0.times.). The wet cake was dried under vacuum at a
maximum of about 60.degree. C.
[0307] The dried solids were transferred back to a reaction vessel
and acetone (15.0.times.), water (0.5.times.) and acetone
(0.4.times.) were sequentially added. Polymorph Form 3 seeds
(0.0147.times., 1 mol %) were added and the contents were adjusted
to about 32 to 38.degree. C., and agitated until Form 7 to Form 3
conversion was deemed complete by XRD (about 24 to 60 h). The
slurry was cooled to about 19 to 25.degree. C. and filtered. The
filter cake was rinsed with acetone (2.4.times.). The wet cake was
dried under vacuum at a maximum of about 60.degree. C.
Example 11: Single Crystal X-Ray Structure of Polymorph Form 3
[0308] This example describes the single crystal X-ray structure of
polymorph Form 3 of a monohydrate, bis-mesylate salt of a compound
of Formula I.
[0309] The single crystal X-ray structure of polymorph Form 3 was
determined at RT in the triclinic system, space group P-1. There
was one cation of the compound of Formula I, 2 mesylate anions and
one water molecule in the asymmetric unit and the final R1
[I>2.sigma.(I)]=4.53%. An XRPD pattern was calculated from the
crystal structure to serve as a reference for this form (FIG.
9).
Structural Features
[0310] A crystal of sufficient size and quality for analysis by
single crystal X-ray diffraction was obtained by maturation between
50.degree. C. and RT on an eight hour cycle in isopropyl acetate.
The crystal was of block morphology with approximate dimensions
0.50.times.0.22.times.0.15 mm.
[0311] The structure of polymorph Form 3 was been determined as
depicted in FIGS. 10A, 10B, 11 and 12. Table 5 below summarizes the
sample and crystal data for polymorph Form 3.
TABLE-US-00005 TABLE 5 Crystallization method Maturation between RT
and 50.degree. C. Empirical formula C.sub.25H.sub.31N.sub.7OS.sub.2
Formula weight 621.69 Temperature 298(2) K Wavelength 1.54178 .ANG.
Crystal size 0.500 .times. 0.220 .times. 0.150 mm Crystal habit
Colourless Column Crystal system Triclinic Space group P-1 Unit
cell dimensions a = 8.7831(6) .ANG. .alpha. = 98.108(6).degree. b =
11.8484(8) .ANG. .beta. = 100.955(6).degree. c = 14.2485(10) .ANG.
.gamma. = 98.861(6).degree. Volume 1416.05(17) .ANG..sup.3 Z 2
Density (calculated) 1.458 Mg/m.sup.3 Absorption coefficient 2.239
mm.sup.-1 F(000)2 652
Example 12: Alternative Synthetic Route for Polymorph Form 3 Via
Mono-MSA Intermediate
[0312] This example provides a description of the synthesis of
polymorph Form 3 (which is a polymorph of a monohydrate, bis-MSA
salt of a compound of Formula I) from a mono-MSA salt of a compound
of Formula I.
[0313] Formic acid (3.7.times.) is charged to a reaction vessel and
combined with ethyl acetate (9.7.times.).
##STR00037##
The contents are agitated and adjusted to about 19 to 25.degree. C.
The mono-MSA compound of Formula I (1.0.times.) is charged
portion-wise while maintaining the content temperature at about 19
to 25.degree. C. The contents are agitated at about 19 to
25.degree. C. until all solids dissolve.
[0314] To the above contents is added a solution of ethyl acetate
(0.6.times.) and methanesulfonic acid (0.169.times., corrected for
MSA content and water present in the mono-MSA compound) prepared in
a separate reaction vessel. The resulting mixture is agitated at
about 19 to 25.degree. C. for about 24 h. The reaction mixture is
sampled and tested for MSA content by ion chromatography. Agitation
is continued until the desired range of MSA content is achieved.
Upon reaction completion, the contents of the reaction vessel are
filtered, rinsed with ethyl acetate (3.6.times.) and the wet filter
cake is dried under vacuum at about 60.degree. C. The dried solids
are transferred back to the reaction vessel.
[0315] To the dried solids was added acetone (15.0.times.) and the
resulting mixture is put under maximum agitation. Water
(0.50.times.) is added followed by acetone (0.70.times.). The
mixture is agitated at about 19 to 25.degree. C. until the form
conversion to polymorph Form 3 is complete as confirmed by XRPD
analysis. The solids are filtered, rinsed with acetone
(2.4.times.), and the wet cake is dried under vacuum at about
60.degree. C.
[0316] Throughout this specification, various patents, patent
applications and other types of publications (e.g., journal
articles) are referenced. The disclosure of all patents, patent
applications, and publications cited herein are hereby incorporated
by reference in their entirety for all purposes.
* * * * *