U.S. patent application number 15/956640 was filed with the patent office on 2018-10-25 for solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses.
The applicant listed for this patent is Celgene Corporation. Invention is credited to Benjamin M. Cohen, William W. Leong, Ying Li, Hon-Wah Man, George W. Muller, Jean Xu.
Application Number | 20180305333 15/956640 |
Document ID | / |
Family ID | 45888486 |
Filed Date | 2018-10-25 |
United States Patent
Application |
20180305333 |
Kind Code |
A1 |
Muller; George W. ; et
al. |
October 25, 2018 |
SOLID FORMS OF
3-(5-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE,
AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES
Abstract
Solid forms comprising
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
compositions comprising the solid forms, methods of making the
solid forms and methods of their uses are disclosed.
Inventors: |
Muller; George W.; (Rancho
Santa Fe, CA) ; Man; Hon-Wah; (Princeton, NJ)
; Cohen; Benjamin M.; (Cranford, NJ) ; Li;
Ying; (Millburn, NJ) ; Xu; Jean; (Warren,
NJ) ; Leong; William W.; (Westfield, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Celgene Corporation |
Summit |
NJ |
US |
|
|
Family ID: |
45888486 |
Appl. No.: |
15/956640 |
Filed: |
April 18, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15670600 |
Aug 7, 2017 |
9969713 |
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15956640 |
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14975484 |
Dec 18, 2015 |
9751853 |
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15670600 |
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14317912 |
Jun 27, 2014 |
9249121 |
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14975484 |
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13417055 |
Mar 9, 2012 |
8802685 |
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14317912 |
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61451806 |
Mar 11, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/04 20130101;
A61P 35/00 20180101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; A61P 35/00 20060101 A61P035/00 |
Claims
1-64. (canceled)
65. A method of treating or managing a disease or disorder selected
from leukemia, lymphoma, myeloma, myelodysplastic syndrome, or
myeloproliferative disease comprising administering to a patient
having the disease or disorder a solid form of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione:
##STR00003## wherein the solid form has an X-ray powder diffraction
pattern comprising: peaks at approximately 14.6 .degree.2.theta.,
15.6 .degree.2.theta., 16.7 .degree.2.theta., 21.9 .degree.2.theta.
and 30.0 .degree.2.theta. as shown in FIG. 1; peaks at
approximately 10.6 .degree.2.theta., 14.7 .degree.2.theta., 19.1
.degree.2.theta. and 25.9 .degree.2.theta. as shown in FIG. 4;
peaks at approximately 10.8 .degree.2.theta., 15.1
.degree.2.theta., 25.1 .degree.2.theta. and 26.6 .degree.2.theta.
as shown in FIG. 7; peaks at approximately 16.7 .degree.2.theta.,
21.7 .degree.2.theta., 21.9 .degree.2.theta. and 25.8
.degree.2.theta. as shown in FIG. 10; peaks at approximately 7.3
.degree.2.theta., 14.6 .degree.2.theta., 22.0 .degree.2.theta.,
30.0 .degree.2.theta. and 37.0 .degree.2.theta. as shown in FIG.
13; or peaks at approximately 14.5 .degree.2.theta., 15.7
.degree.2.theta., 22.7 .degree.2.theta. and 29.9 .degree.2.theta.
as shown in FIG. 16.
66. The method of claim 65, wherein disease or disorder is leukemia
or lymphoma.
67. The method of claim 66, wherein the lymphoma is Hodgkin's
lymphoma.
68. The method of claim 66, wherein the lymphoma is Non-Hodgkin's
lymphoma.
69. The method of claim 68, wherein the Non-Hodgkin's lymphoma is
diffuse large B-cell lymphoma.
70. The method of claim 68, wherein the Non-Hodgkin's lymphoma is
cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large
B-cell lymphoma, Waldenstrom's macrogliobineima, mantle cell
lymphoma, or follicular lymphoma.
71. The method of claim 65, wherein the leukemia is chronic
lymphocytic leukemia, chronic myelocytic leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia, or acute
myeloblastic leukemia.
72. The method of claim 65, wherein the disease or disorder is
multiple myeloma, smoldering myeloma, or indolent myeloma.
73. The method of claim 72, wherein the disease or disorder is
multiple myeloma.
74. The method of claim 72, wherein the disease or disorder is
refractory or resistant multiple myeloma.
75. The method of claim 66, wherein the disease or disorder is
myelodysplastic syndrome or myeloproliferative disease.
76. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 14.6
.degree.2.theta., 15.6 .degree.2.theta., 16.7 .degree.2.theta.,
21.9 .degree.2.theta. and 30.0 .degree.2.theta. as shown in FIG. 1,
when analyzed using Cu K.alpha. X-ray radiation at 1.54 .ANG..
77. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 9.2
.degree.2.theta., 13.4 .degree.2.theta., 14.0 .degree.2.theta.,
14.6 .degree.2.theta., 15.6 .degree.2.theta., 16.7
.degree.2.theta., 18.5 .degree.2.theta., 21.9 .degree.2.theta.,
22.7 .degree.2.theta., 24.8 .degree.2.theta., 28.1
.degree.2.theta., 30.0 .degree.2.theta. and 37.0 .degree.2.theta.
as shown in FIG. 1, when analyzed using Cu K.alpha. X-ray radiation
at 1.54 .ANG..
78. The method of claim 76, wherein the solid form has a
differential scanning calorimetry plot comprising an endothermic
event with an onset temperature of approximately 282.degree. C.,
when heated from approximately 25.degree. C. to approximately
300.degree. C.
79. The method of claim 76, wherein the solid form has a thermal
gravimetric analysis plot comprising a mass loss of less than
approximately 6% when heated from approximately 25.degree. C. to
approximately 150.degree. C.
80. The method of claim 76, wherein the solid form exhibits a mass
increase of less than or equal to approximately 6% when subjected
to an increase in relative humidity from approximately 0% to
approximately 95% relative humidity.
81. The method of claim Error! Reference source not found.76,
wherein the solid form is hydrated.
82. The method of claim 81, wherein the crystal lattice of the
solid form comprises approximately one molar equivalent of water
per mole of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
83. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 10.6
.degree.2.theta., 14.7 .degree.2.theta., 19.1 .degree.2.theta. and
25.9 .degree.2.theta. as shown in FIG. 4, when analyzed using Cu
K.alpha. X-ray radiation at 1.54 .ANG..
84. The method of claim 65 wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 10.6
.degree.2.theta., 11.4 .degree.2.theta., 12.6 .degree.2.theta.,
13.7 .degree.2.theta., 14.7 .degree.2.theta., 19.1
.degree.2.theta., 20.3 .degree.2.theta., 20.9 .degree.2.theta.,
21.2 .degree.2.theta., 22.9 .degree.2.theta., 24.9
.degree.2.theta., 25.3 .degree.2.theta., 25.9 .degree.2.theta.,
26.9 .degree.2.theta., 29.5 .degree.2.theta. and 33.8
.degree.2.theta. as shown in FIG. 4, when analyzed using Cu
K.alpha. X-ray radiation at 1.54 .ANG..
85. The method of claim 83, wherein the solid form has a
differential scanning calorimetry plot comprising an endothermic
event with an onset temperature of approximately 279.degree. C.,
when heated from approximately 25.degree. C. to approximately
300.degree. C.
86. The method of claim 83, wherein the solid form has a thermal
gravimetric analysis plot comprising a mass loss of less than
approximately 0.1% when heated from approximately 25.degree. C. to
approximately 150.degree. C.
87. The method of claim 83, wherein the solid form exhibits a mass
increase of less than approximately 0.2% when subjected to an
increase in relative humidity from approximately 0% to
approximately 95% relative humidity.
88. The method of claim 83, wherein the solid form is
unsolvated.
89. The method of claim 83, wherein the solid form is substantially
nonhygroscopic.
90. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 10.8
.degree.2.theta., 15.1 .degree.2.theta., 25.1 .degree.2.theta. and
26.6 .degree.2.theta. as shown in FIG. 7, when analyzed using Cu
K.alpha. X-ray radiation at 1.54 .ANG..
91. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 10.8
.degree.2.theta., 11.9 .degree.2.theta., 15.1 .degree.2.theta.,
18.8 .degree.2.theta., 19.2 .degree.2.theta., 19.3
.degree.2.theta., 22.0 .degree.2.theta., 24.9 .degree.2.theta.,
25.1 .degree.2.theta., 26.6 .degree.2.theta. and 29.2
.degree.2.theta. as shown in FIG. 7, when analyzed using Cu
K.alpha. X-ray radiation at 1.54 .ANG..
92. The method of claim 90, wherein the solid form has a
differential scanning calorimetry plot comprising an endothermic
event with an onset temperature of approximately 281.degree. C.,
when heated from approximately 25.degree. C. to approximately
300.degree. C.
93. The method of claim 90, wherein the solid form has a thermal
gravimetric analysis plot comprising a mass loss of less than
approximately 0.1% when heated from approximately 25.degree. C. to
approximately 150.degree. C.
94. The method of claim 90, wherein the solid form exhibits a mass
increase of less than approximately 0.2% when subjected to an
increase in relative humidity from approximately 0% to
approximately 95% relative humidity.
95. The method of claim 90, wherein the solid form is
unsolvated.
96. The method of claim 90, wherein the solid form is substantially
nonhygroscopic.
97. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 16.7
.degree.2.theta., 21.7 .degree.2.theta., 21.9 .degree.2.theta. and
25.8 .degree.2.theta. as shown in FIG. 10, when analyzed using Cu
K.alpha. X-ray radiation at 1.54 .ANG..
98. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 10.6
.degree.2.theta., 14.0 .degree.2.theta., 14.6 .degree.2.theta.,
15.7 .degree.2.theta., 16.3 .degree.2.theta., 16.7
.degree.2.theta., 18.8 .degree.2.theta., 21.7 .degree.2.theta.,
21.9 .degree.2.theta., 24.8 .degree.2.theta., 25.1
.degree.2.theta., 25.8 .degree.2.theta., 28.1 .degree.2.theta. and
28.6 .degree.2.theta. as shown in FIG. 10, when analyzed using Cu
K.alpha. X-ray radiation at 1.54 .ANG..
99. The method of claim 97, wherein the solid form has a
differential scanning calorimetry plot comprising an endothermic
event with an onset temperature of approximately 283.degree. C.,
when heated from approximately 25.degree. C. to approximately
300.degree. C.
100. The method of claim 97, wherein the solid form has a thermal
gravimetric analysis plot comprising a mass loss of less than
approximately 4% when heated from approximately 25.degree. C. to
approximately 150.degree. C.
101. The method of claim 97, wherein the solid form exhibits a mass
increase of less than or equal to approximately 6% when subjected
to an increase in relative humidity from approximately 0% to
approximately 95% relative humidity.
102. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 7.3
.degree.2.theta., 14.6 .degree.2.theta., 22.0 .degree.2.theta.,
30.0 .degree.2.theta. and 37.0 .degree.2.theta. as shown in FIG.
13, when analyzed using Cu K.alpha. X-ray radiation at 1.54
.ANG..
103. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 7.3
.degree.2.theta., 9.3 .degree.2.theta., 12.2 .degree.2.theta., 14.0
.degree.2.theta., 14.6 .degree.2.theta., 15.7 .degree.2.theta.,
16.8 .degree.2.theta., 21.0 .degree.2.theta., 22.0
.degree.2.theta., 22.7 .degree.2.theta., 29.4 .degree.2.theta.,
30.0 .degree.2.theta. and 37.0 .degree.2.theta. as shown in FIG.
13, when analyzed using Cu K.alpha. X-ray radiation at 1.54
.ANG..
104. The method of claim 102, wherein the solid form has a
differential scanning calorimetry plot comprising an endothermic
event with an onset temperature of approximately 279.degree. C.,
when heated from approximately 25.degree. C. to approximately
300.degree. C.
105. The method of claim 102, wherein the solid form has a thermal
gravimetric analysis plot comprising a mass loss of less than
approximately 6% when heated from approximately 25.degree. C. to
approximately 150.degree. C.
106. The method of claim 102, wherein the solid form exhibits a
mass increase of less than approximately 0.5% when subjected to an
increase in relative humidity from approximately 0% to
approximately 95% relative humidity.
107. The method of claim 102, wherein the solid form is
hydrated.
108. The method of claim 102, wherein the solid form is
substantially nonhygroscopic.
109. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 14.5
.degree.2.theta., 15.7 .degree.2.theta., 22.7 .degree.2.theta. and
29.9 .degree.2.theta. as shown in FIG. 16, when analyzed using Cu
K.alpha. X-ray radiation at 1.54 .ANG..
110. The method of claim 65, wherein the solid form has an X-ray
powder diffraction pattern comprising peaks at approximately 7.2
.degree.2.theta., 9.1 .degree.2.theta., 14.5 .degree.2.theta., 15.7
.degree.2.theta., 16.8 .degree.2.theta., 18.3 .degree.2.theta.,
21.9 .degree.2.theta., 22.7 .degree.2.theta., 29.9 .degree.2.theta.
and 36.9 .degree.2.theta. as shown in FIG. 16, when analyzed using
Cu K.alpha. X-ray radiation at 1.54 .ANG..
111. The method of claim 109, wherein the solid form has a
differential scanning calorimetry plot comprising an endothermic
event with an onset temperature of approximately 267.degree. C.,
when heated from approximately 25.degree. C. to approximately
300.degree. C.
112. The method of claim 109, wherein the solid form is
hydrated.
113. The method of claim 65, wherein two or more of the solid forms
are administered.
114. The method of claim 65, wherein the solid form is administered
at a dose of about 1 mg to about 20 mg.
115. The method of claim 65, wherein a pharmaceutical composition
comprising the solid form and a pharmaceutical acceptable carrier,
diluent or excipient is administered.
116. The method of claim 115, wherein the composition is formulated
for oral, parenteral, or intravenous administration.
117. The method of claim 115, wherein the composition is formulated
as a single unit dosage form.
118. The method of claim 117, wherein the dosage form is a tablet
or capsule.
119. The method of claim 65, further comprising administering a
second active agent.
Description
[0001] The present application is a continuation of U.S. patent
application Ser. No. 15/670,600, filed Aug. 7, 2017, which is a
continuation of U.S. patent application Ser. No. 14/975,484, filed
Dec. 18, 2015, now U.S. Pat. No. 9,751,853, which is a continuation
of U.S. patent application Ser. No. 14/317,912, filed Jun. 27,
2014, now U.S. Pat. No. 9,249,121, which is a continuation of U.S.
patent application Ser. No. 13/417,055, filed Mar. 9, 2012, now
U.S. Pat. No. 8,802,685, which claims priority to U.S. Provisional
Patent Application No. 61/451,806, filed Mar. 11, 2011, the
entirety of each of which is incorporated herein by reference.
1. FIELD
[0002] Provided herein are solid forms of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
pharmaceutical compositions thereof, and methods of their uses for
the treatment of diseases or disorders.
2. BACKGROUND OF THE DISCLOSURE
[0003] 2.1 Pathobiology of Cancer and Other Diseases
[0004] Cancer is characterized primarily by an increase in the
number of abnormal cells derived from a given normal tissue,
invasion of adjacent tissues by these abnormal cells, or lymphatic
or blood-borne spread of malignant cells to regional lymph nodes
and to distant sites (metastasis). Clinical data and molecular
biologic studies indicate that cancer is a multistep process that
begins with minor preneoplastic changes, which may under certain
conditions progress to neoplasia. The neoplastic lesion may evolve
clonally and develop an increasing capacity for invasion, growth,
metastasis, and heterogeneity, especially under conditions in which
the neoplastic cells escape the host's immune surveillance. Roitt,
I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed.,
Mosby, St. Louis, Mo., 1993).
[0005] There is an enormous variety of cancers which are described
in detail in the medical literature. Examples include cancers of
the lung, colon, rectum, prostate, breast, brain, and intestine.
The incidence of cancer continues to climb as the general
population ages, as new cancers develop, and as susceptible
populations (e.g., people infected with AIDS or excessively exposed
to sunlight) grow. However, options for the treatment of cancer are
limited. For example, in the case of blood cancers (e.g., multiple
myeloma), few treatment options are available, especially when
conventional chemotherapy fails and bone-marrow transplantation is
not an option. A tremendous demand therefore exists for new methods
and compositions that can be used to treat patients with
cancer.
[0006] Many types of cancers are associated with new blood vessel
formation, a process known as angiogenesis. Several of the
mechanisms involved in tumor-induced angiogenesis have been
elucidated. The most direct of these mechanisms is the secretion by
the tumor cells of cytokines with angiogenic properties. Examples
of these cytokines include acidic and basic fibroblastic growth
factor (a,b-FGF), angiogenin, vascular endothelial growth factor
(VEGF), and TNF-.alpha.. Alternatively, tumor cells can release
angiogenic peptides through the production of proteases and the
subsequent breakdown of the extracellular matrix where some
cytokines are stored (e.g., b-FGF). Angiogenesis can also be
induced indirectly through the recruitment of inflammatory cells
(particularly macrophages) and their subsequent release of
angiogenic cytokines (e.g., TNF-.alpha., b-FGF).
[0007] A variety of other diseases and disorders are also
associated with, or characterized by, undesired angiogenesis. For
example, enhanced or unregulated angiogenesis has been implicated
in a number of diseases and medical conditions including, but not
limited to, ocular neovascular diseases, choroidal neovascular
diseases, retina neovascular diseases, rubeosis (neovascularization
of the angle), viral diseases, genetic diseases, inflammatory
diseases, allergic diseases, and autoimmune diseases. Examples of
such diseases and conditions include, but are not limited to,
diabetic retinopathy, retinopathy of prematurity, corneal graft
rejection, neovascular glaucoma, retrolental fibroplasia,
arthritis, and proliferative vitreoretinopathy.
[0008] Accordingly, compounds that can control angiogenesis or
inhibit the production of certain cytokines, including TNF.alpha.,
may be useful in the treatment and prevention of various diseases
and conditions.
[0009] 2.2 Methods of Treating Cancer
[0010] Current cancer therapy may involve surgery, chemotherapy,
hormonal therapy and/or radiation treatment to eradicate neoplastic
cells in a patient (see, e.g., Stockdale, 1998, Medicine, vol. 3,
Rubenstein and Federman, eds., Chapter 12, Section IV). Recently,
cancer therapy could also involve biological therapy or
immunotherapy. All of these approaches pose significant drawbacks
for the patient. Surgery, for example, may be contraindicated due
to the health of a patient or may be unacceptable to the patient.
Additionally, surgery may not completely remove neoplastic tissue.
Radiation therapy is only effective when the neoplastic tissue
exhibits a higher sensitivity to radiation than normal tissue.
Radiation therapy can also often elicit serious side effects.
Hormonal therapy is rarely given as a single agent. Although
hormonal therapy can be effective, it is often used to prevent or
delay recurrence of cancer after other treatments have removed the
majority of cancer cells. Biological therapies and immunotherapies
are limited in number and may produce side effects such as rashes
or swellings, flu-like symptoms, including fever, chills and
fatigue, digestive tract problems or allergic reactions.
[0011] With respect to chemotherapy, there is a variety of
chemotherapeutic agents available for treatment of cancer. A
majority of cancer chemotherapeutics act by inhibiting DNA
synthesis, either directly or indirectly by inhibiting the
biosynthesis of deoxyribonucleotide triphosphate precursors, to
prevent DNA replication and concomitant cell division. Gilman et
al., Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, Tenth Ed. (McGraw Hill, New York).
[0012] Despite availability of a variety of chemotherapeutic
agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol.
3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost
all chemotherapeutic agents are toxic, and chemotherapy causes
significant, and often dangerous side effects including severe
nausea, bone marrow depression, and immunosuppression.
Additionally, even with administration of combinations of
chemotherapeutic agents, many tumor cells are resistant or develop
resistance to the chemotherapeutic agents. In fact, those cells
resistant to the particular chemotherapeutic agents used in the
treatment protocol often prove to be resistant to other drugs, even
if those agents act by different mechanism from those of the drugs
used in the specific treatment. This phenomenon is referred to as
pleiotropic drug or multidrug resistance. Because of the drug
resistance, many cancers prove or become refractory to standard
chemotherapeutic treatment protocols.
[0013] Other diseases or conditions associated with, or
characterized by, undesired angiogenesis are also difficult to
treat. However, some compounds such as protamine, hepain and
steroids have been proposed to be useful in the treatment of
certain specific diseases. Taylor et al., Nature 297:307 (1982);
Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos.
5,001,116 and 4,994,443.
[0014] Still, there is a significant need for safe and effective
methods of treating, preventing and managing cancer and other
diseases and conditions, including for diseases that are refractory
to standard treatments, such as surgery, radiation therapy,
chemotherapy and hormonal therapy, while reducing or avoiding the
toxicities and/or side effects associated with the conventional
therapies.
[0015] 2.3 Solid Forms
[0016] The preparation and selection of a solid form of a
pharmaceutical compound is complex, given that a change in solid
form may affect a variety of physical and chemical properties,
which may provide benefits or drawbacks in processing, formulation,
stability and bioavailability, among other important pharmaceutical
characteristics. Potential pharmaceutical solids include
crystalline solids and amorphous solids. Amorphous solids are
characterized by a lack of long-range structural order, whereas
crystalline solids are characterized by structural periodicity. The
desired class of pharmaceutical solid depends upon the specific
application; amorphous solids are sometimes selected on the basis
of, e.g., an enhanced dissolution profile, while crystalline solids
may be desirable for properties such as, e.g., physical or chemical
stability (see, e.g., S. R. Vippagunta et al., Adv. Drug. Deliv.
Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001)
48:27-42).
[0017] Whether crystalline or amorphous, potential solid forms of a
pharmaceutical compound include single-component and
multiple-component solids. Single-component solids consist
essentially of the pharmaceutical compound in the absence of other
compounds. Variety among single-component crystalline materials may
potentially arise, e.g., from the phenomenon of polymorphism,
wherein multiple three-dimensional arrangements exist for a
particular pharmaceutical compound (see, e.g., S. R. Byrn et al.,
Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The
importance of studying polymorphs was underscored by the case of
Ritonavir, an HIV protease inhibitor that was formulated as soft
gelatin capsules. About two years after the product was launched,
the unanticipated precipitation of a new, less soluble polymorph in
the formulation necessitated the withdrawal of the product from the
market until a more consistent formulation could be developed (see
S. R. Chemburkar et al., Org. Process Res. Dev., (2000)
4:413-417).
[0018] Additional diversity among the potential solid forms of a
pharmaceutical compound may arise, e.g., from the possibility of
multiple-component solids. Crystalline solids comprising two or
more ionic species may be termed salts (see, e.g., Handbook of
Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl
and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types
of multiple-component solids that may potentially offer other
property improvements for a pharmaceutical compound or salt thereof
include, e.g., hydrates, solvates, co-crystals and clathrates,
among others (see, e.g., S. R. Byrn et al., Solid State Chemistry
of Drugs, (1999) SSCI, West Lafayette). Moreover,
multiple-component crystal forms may potentially be susceptible to
polymorphism, wherein a given multiple-component composition may
exist in more than one three-dimensional crystalline arrangement.
The preparation of solid forms is of great importance in the
development of a safe, effective, stable and marketable
pharmaceutical compound.
[0019] Provided herein are embodiments addressing a need for solid
forms of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
("Compound A"). Compound A was described in U.S. Pat. No.
7,635,700, the disclosure of which is incorporated herein by
reference in its entirety.
3. SUMMARY
[0020] This disclosure relates to methods of treating diseases and
disorders utilizing a solid form of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
or a stereoisomer thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
[0021] Provided herein are solid forms of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
or a stereoisomer thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In
one embodiment, the solid form is crystalline Form A. In another
embodiment, the solid form is crystalline Form B. In yet another
embodiment, the solid form is crystalline Form C. In yet another
embodiment, the solid form is Form D. In yet another embodiment,
the solid form is crystalline Form E. In yet another embodiment,
the solid form is crystalline Form F. In yet another embodiment,
the solid form is a solid form of a hydrochloride salt of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
In still another embodiment, the solid form is crystalline Form
A1.
[0022] Further provided herein are pharmaceutical compositions,
single unit dosage forms, dosing regimens, and kits, which comprise
a solid form of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
or a stereoisomer thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof; and
a pharmaceutically acceptable carrier.
[0023] Additionally provided herein are methods of treating and
managing various diseases or disorders, which comprise
administering to a patient a therapeutically effective amount of a
solid form of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
or a stereoisomer thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
[0024] Also provided herein are methods of preventing various
diseases and disorders, which comprise administering to a patient a
prophylactically effective amount of a solid form of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
or a stereoisomer thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
[0025] In certain embodiments, the solid forms are single-component
crystal forms of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
In certain embodiments, the solid forms are multiple-component
crystal forms of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
including, but not limited to, salts, co-crystals and/or solvates
(including hydrates) comprising
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
In certain embodiments, the solid forms are single-component
amorphous forms of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
In certain embodiments, the solid forms are multiple-component
amorphous forms of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dio-
ne. Without intending to be limited by any particular theory,
certain solid forms provided herein have particular advantageous
physical and/or chemical properties making them useful, e.g., for
manufacturing, processing, formulation and/or storage, while also
possessing particularly advantageous biological properties, such
as, e.g., bioavailability and/or biological activity.
[0026] In certain embodiments, solid forms provided herein include
solid forms comprising
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
including, but not limited to, single-component and
multiple-component solid forms comprising
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
In certain embodiments, solid forms provided herein include salts,
polymorphs, solvates (including hydrates), and co-crystals
comprising
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
Certain embodiments herein provide methods of making, isolating
and/or characterizing the solid forms provided herein.
[0027] The solid forms provided herein are useful as active
pharmaceutical ingredients for the preparation of formulations for
use in patients. Thus, embodiments herein encompass the use of
these solid forms as a final drug product. Certain embodiments
provide solid forms useful in making final dosage forms with
improved properties, e.g., powder flow properties, compaction
properties, tableting properties, stability properties, and
excipient compatibility properties, among others, that are needed
for manufacturing, processing, formulation and/or storage of final
drug products. Certain embodiments herein provide pharmaceutical
compositions comprising a single-component crystal form, a
multiple-component crystal form, a single-component amorphous form
and/or a multiple-component amorphous form comprising
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
and a pharmaceutically acceptable diluent, excipient or carrier.
The solid forms and the final drug products provided herein are
useful, for example, for the treatment, prevention or management of
diseases and disorders provided herein.
3.1. BRIEF DESCRIPTION OF THE FIGURES
[0028] FIG. 1 provides an X-ray Powder Diffraction ("XRPD") pattern
of Form A of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-di-
one.
[0029] FIG. 2 provides a Differential Scanning Calorimetry ("DSC")
plot of Form A of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-di-
one.
[0030] FIG. 3 provides a Thermal Gravimetric Analysis ("TGA") plot
of Form A of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0031] FIG. 4 provides an XRPD pattern of Form B of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0032] FIG. 5 provides a DSC plot of Form B of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0033] FIG. 6 provides a TGA plot of Form B of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0034] FIG. 7 provides an XRPD pattern of Form C of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0035] FIG. 8 provides a DSC plot of Form C of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0036] FIG. 9 provides a TGA plot of Form C of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0037] FIG. 10 provides an XRPD pattern of Form D of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0038] FIG. 11 provides a DSC plot of Form D of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0039] FIG. 12 provides a TGA plot of Form D of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0040] FIG. 13 provides an XRPD pattern of Form E of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0041] FIG. 14 provides a DSC plot of Form E of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0042] FIG. 15 provides a TGA plot of Form E of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0043] FIG. 16 provides an XRPD pattern of Form F of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0044] FIG. 17 provides a DSC plot of Form F of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0045] FIG. 18 provides an XRPD pattern of Form A1 of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrochloride.
[0046] FIG. 19 provides a DSC plot of Form A1 of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrochloride.
[0047] FIG. 20 provides a TGA plot of Form A1 of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrochloride.
[0048] FIG. 21 provides a Dynamic Vapor Sorption ("DVS") plot of
Form A1 of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrochloride.
[0049] FIG. 22 is a microscopic image of crystals of Form A1 of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrochloride.
[0050] FIG. 23 depicts interconversions between various solid forms
of
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
[0051] FIG. 24 depicts the solubility of Form A of Compound A in
DMSO:water.
3.2. DEFINITIONS
[0052] As used herein, term "Compound A" refers to
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
The .sup.1H NMR spectrum of Compound A is substantially as follows:
.delta. (DMSO-d.sub.6): 2.10-2.17 (m, 1H), 2.53 (s, 3H), 2.59-2.69
(m, 2H), 2.76-2.89 (m, 1H), 5.14 (dd, J=6, 11 Hz, 1H), 6.56 (d, J=8
Hz, 1H), 6.59 (d, J=8 Hz, 1H), 7.02 (s, 2H), 7.36 (t, J=8 Hz, 1H),
10.98 (s, 1H). The .sup.13C NMR spectrum of Compound A is
substantially as follows: .delta. (DMSO-d.sub.6): 20.98, 23.14,
30.52, 55.92, 104.15, 110.48, 111.37, 134.92, 148.17, 150.55,
153.62, 162.59, 169.65, 172.57.
[0053] Without being limited by theory, Compound A is believed to
be
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
which has the following structure:
##STR00001##
[0054] As used herein, the term "patient" refers to a mammal,
particularly a human.
[0055] As used herein, the term "pharmaceutically acceptable salt"
refers to a salt prepared from a pharmaceutically acceptable
non-toxic acid or base, including inorganic acids and bases and
organic acids and bases.
[0056] As used herein, term "adverse effects" includes, but is not
limited to gastrointestinal, renal and hepatic toxicities,
leukopenia, increases in bleeding times due to, e.g.,
thrombocytopenia, and prolongation of gestation, nausea, vomiting,
somnolence, asthenia, dizziness, teratogenicity, extra-pyramidal
symptoms, akathisia, cardiotoxicity including cardiovascular
disturbances, inflammation, male sexual dysfunction, and elevated
serum liver enzyme levels. The term "gastrointestinal toxicities"
includes, but is not limited to, gastric and intestinal ulcerations
and erosions. The term "renal toxicities" includes, but is not
limited to, such conditions as papillary necrosis and chronic
interstitial nephritis.
[0057] As used herein and unless otherwise indicated, the phrases
"reduce or avoid adverse effects" and "reducing or avoiding adverse
effects" mean the reduction of the severity of one or more adverse
effects as defined herein.
[0058] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it.
[0059] As used herein and unless otherwise specified, the terms
"solid form" and related terms refer to a physical form which is
not predominantly in a liquid or a gaseous state. As used herein
and unless otherwise specified, the term "solid form" and related
terms, when used herein to refer to Compound A, refer to a physical
form comprising Compound A which is not predominantly in a liquid
or a gaseous state. Solid forms may be crystalline, amorphous, or
mixtures thereof. In particular embodiments, solid forms may be
liquid crystals. A "single-component" solid form comprising
Compound A consists essentially of Compound A. A
"multiple-component" solid form comprising Compound A comprises a
significant quantity of one or more additional species, such as
ions and/or molecules, within the solid form. In certain
embodiments, a "multiple-component" solid form comprising Compound
A comprises a hydrochloride salt of compound A. For example, in
particular embodiments, a crystalline multiple-component solid form
comprising Compound A further comprises one or more species
non-covalently bonded at regular positions in the crystal lattice.
Multiple-component solid forms comprising Compound A include
co-crystals, solvates (e.g., hydrates), and clathrates of Compound
A. In particular embodiments, the term "solid form comprising
Compound A" and related terms include single-component and
multiple-component solid forms comprising Compound A. In particular
embodiments, "solid forms comprising Compound A" and related terms
include crystal forms comprising Compound A, amorphous forms
comprising Compound A, and mixtures thereof.
[0060] As used herein and unless otherwise specified, the term
"crystalline" and related terms used herein, when used to describe
a compound, substance, modification, material, component or
product, unless otherwise specified, mean that the compound,
substance, modification, material, component or product is
substantially crystalline as determined by X-ray diffraction. See,
e.g., Remington: The Science and Practice of Pharmacy, 21.sup.st
edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005);
The United States Pharmacopeia, 23.sup.rd ed., 1843-1844
(1995).
[0061] As used herein and unless otherwise specified, the term
"crystal forms," "crystalline forms" and related terms herein refer
to solid forms that are crystalline. Crystal forms include
single-component crystal forms and multiple-component crystal
forms, and include, but are not limited to, salts (e.g., a
hydrochloride salt), polymorphs, solvates, hydrates, and/or other
molecular complexes. In certain embodiments, a crystal form of a
substance may be substantially free of amorphous forms and/or other
crystal forms. In certain embodiments, a crystal form of a
substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%,
8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or
more amorphous forms and/or other crystal forms on a weight basis.
In certain embodiments, a crystal form of a substance may be
physically and/or chemically pure. In certain embodiments, a
crystal form of a substance may be about 99%, 98%, 97%, 96%, 95%,
94%, 93%, 92%, 91% or 90% physically and/or chemically pure.
[0062] As used herein and unless otherwise specified, the terms
"polymorphs," "polymorphic forms" and related terms herein, refer
to two or more crystal forms that consist essentially of the same
molecule, molecules, and/or ions. Like different crystal forms,
different polymorphs may have different physical properties such
as, e.g., melting temperature, heat of fusion, solubility,
dissolution properties and/or vibrational spectra, as a result of
the arrangement or conformation of the molecules and/or ions in the
crystal lattice. The differences in physical properties may affect
pharmaceutical parameters such as storage stability,
compressibility and density (important in formulation and product
manufacturing), and dissolution rate (an important factor in
bioavailability). Differences in stability can result from changes
in chemical reactivity (e.g., differential oxidation, such that a
dosage form discolors more rapidly when comprised of one polymorph
than when comprised of another polymorph) or mechanical changes
(e.g., tablets crumble on storage as a kinetically favored
polymorph converts to thermodynamically more stable polymorph) or
both (e.g., tablets of one polymorph are more susceptible to
breakdown at high humidity). As a result of solubility/dissolution
differences, in the extreme case, some solid-state transitions may
result in lack of potency or, at the other extreme, toxicity. In
addition, the physical properties may be important in processing
(e.g., one polymorph might be more likely to form solvates or might
be difficult to filter and wash free of impurities, and particle
shape and size distribution might be different between
polymorphs).
[0063] As used herein and unless otherwise specified, the terms
"solvate" and "solvated," refer to a crystal form of a substance
which contains solvent. The terms "hydrate" and "hydrated" refer to
a solvate wherein the solvent comprises water. "Polymorphs of
solvates" refers to the existence of more than one crystal form for
a particular solvate composition. Similarly, "polymorphs of
hydrates" refers to the existence of more than one crystal form for
a particular hydrate composition. The term "desolvated solvate," as
used herein, refers to a crystal form of a substance which may be
prepared by removing the solvent from a solvate.
[0064] As used herein and unless otherwise specified, the term
"amorphous," "amorphous form," and related terms used herein, mean
that the substance, component or product in question is not
substantially crystalline as determined by X-ray diffraction. In
particular, the term "amorphous form" describes a disordered solid
form, i.e., a solid form lacking long range crystalline order. In
certain embodiments, an amorphous form of a substance may be
substantially free of other amorphous forms and/or crystal forms.
In other embodiments, an amorphous form of a substance may contain
less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45% or 50% of one or more other amorphous forms and/or crystal
forms on a weight basis. In certain embodiments, an amorphous form
of a substance may be physically and/or chemically pure. In certain
embodiments, an amorphous form of a substance be about 99%, 98%,
97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/or
chemically pure.
[0065] Techniques for characterizing crystal forms and amorphous
forms include, but are not limited to, thermal gravimetric analysis
(TGA), differential scanning calorimetry (DSC), X-ray powder
diffractometry (XRPD), single-crystal X-ray diffractometry,
vibrational spectroscopy, e.g., infrared (IR) and Raman
spectroscopy, solid-state and solution nuclear magnetic resonance
(NMR) spectroscopy, optical microscopy, hot stage optical
microscopy, scanning electron microscopy (SEM), electron
crystallography and quantitative analysis, particle size analysis
(PSA), surface area analysis, solubility measurements, dissolution
measurements, elemental analysis, and Karl Fischer analysis.
Characteristic unit cell parameters may be determined using one or
more techniques such as, but not limited to, X-ray diffraction and
neutron diffraction, including single-crystal diffraction and
powder diffraction. Techniques useful for analyzing powder
diffraction data include profile refinement, such as Rietveld
refinement, which may be used, e.g., to analyze diffraction peaks
associated with a single phase in a sample comprising more than one
solid phase. Other methods useful for analyzing powder diffraction
data include unit cell indexing, which allows one of skill in the
art to determine unit cell parameters from a sample comprising
crystalline powder.
[0066] As used herein and unless otherwise specified, the terms
"about" and "approximately," when used in connection with a numeric
value or a range of values which is provided to characterize a
particular solid form, e.g., a specific temperature or temperature
range, such as, e.g., that describing a DSC or TGA thermal event,
including, e.g., melting, dehydration, desolvation or glass
transition events; a mass change, such as, e.g., a mass change as a
function of temperature or humidity; a solvent or water content, in
terms of, e.g., mass or a percentage; or a peak position, such as,
e.g., in analysis by IR or Raman spectroscopy or XRPD; indicate
that the value or range of values may deviate to an extent deemed
reasonable to one of ordinary skill in the art while still
describing the particular solid form. For example, in particular
embodiments, the terms "about" and "approximately," when used in
this context and unless otherwise specified, indicate that the
numeric value or range of values may vary within 25%, 20%, 15%,
10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of
the recited value or range of values.
[0067] As used herein and unless otherwise specified, a sample
comprising a particular crystal form or amorphous form that is
"substantially pure," e.g., substantially free of other solid forms
and/or of other chemical compounds, contains, in particular
embodiments, less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%,
5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% percent by weight of
one or more other solid forms and/or of other chemical
compounds.
[0068] As used herein and unless otherwise specified, a sample or
composition that is "substantially free" of one or more other solid
forms and/or other chemical compounds means that the composition
contains, in particular embodiments, less than about 25%, 20%, 15%,
10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1%
percent by weight of one or more other solid forms and/or other
chemical compounds.
[0069] As used herein, and unless otherwise specified, the terms
"treat," "treating" and "treatment" refer to the eradication or
amelioration of a disease or disorder, or of one or more symptoms
associated with the disease or disorder. In certain embodiments,
the terms refer to minimizing the spread or worsening of the
disease or disorder resulting from the administration of one or
more prophylactic or therapeutic agents to a patient with such a
disease or disorder. In some embodiments, the terms refer to the
administration of a compound provided herein, with or without other
additional active agent, after the onset of symptoms of the
particular disease.
[0070] As used herein, and unless otherwise specified, the terms
"prevent," "preventing" and "prevention" refer to the prevention of
the onset, recurrence or spread of a disease or disorder, or of one
or more symptoms thereof. In certain embodiments, the terms refer
to the treatment with or administration of a compound provided
herein, with or without other additional active compound, prior to
the onset of symptoms, particularly to patients at risk of diseases
or disorders provided herein. The terms encompass the inhibition or
reduction of a symptom of the particular disease. Patients with
familial history of a disease in particular are candidates for
preventive regimens in certain embodiments. In addition, patients
who have a history of recurring symptoms are also potential
candidates for the prevention. In this regard, the term
"prevention" may be interchangeably used with the term
"prophylactic treatment."
[0071] As used herein, and unless otherwise specified, the terms
"manage," "managing" and "management" refer to preventing or
slowing the progression, spread or worsening of a disease or
disorder, or of one or more symptoms thereof. Often, the beneficial
effects that a patient derives from a prophylactic and/or
therapeutic agent do not result in a cure of the disease or
disorder. In this regard, the term "managing" encompasses treating
a patient who had suffered from the particular disease in an
attempt to prevent or minimize the recurrence of the disease.
[0072] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment or
management of a disease or disorder, or to delay or minimize one or
more symptoms associated with the disease or disorder. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment or management
of the disease or disorder. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or disorder, or
enhances the therapeutic efficacy of another therapeutic agent.
[0073] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease or disorder, or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of therapeutic agent, alone or in combination with other
agents, which provides a prophylactic benefit in the prevention of
the disease. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0074] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients (and in
the specified amounts, if indicated), as well as any product which
results, directly or indirectly, from combination of the specified
ingredients in the specified amounts. By "pharmaceutically
acceptable" it is meant that the diluent, excipient or carrier must
be compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
4. DETAILED DESCRIPTION
[0075] This disclosure relates to solid forms of Compound A, which
is
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,
and stereoisomers thereof, and pharmaceutically acceptable salts,
solvates, hydrates, co-crystals, clathrates, and polymorphs
thereof; as well as methods of using, and compositions comprising,
a solid form of Compound A or a stereoisomer thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal,
clathrate, or polymorph thereof. For example, the present
disclosure encompasses the in vitro and in vivo use of a solid form
of Compound A, and the incorporation of a solid form of Compound A
into pharmaceutical compositions and single unit dosage forms
useful in the treatment and prevention of a variety of diseases and
disorders.
[0076] 4.1. Solid Forms of Compound A
[0077] In one embodiment, provided herein are solid forms of
Compound A or a stereoisomer thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or
polymorph thereof.
[0078] Compound A is readily prepared using the methods as
described in U.S. Pat. No. 7,635,700, the disclosure of which is
incorporated herein by reference in its entirety.
[0079] Solid forms comprising Compound A include single-component
and multiple-component forms, including crystal forms and amorphous
forms, and including, but not limited to, salts, polymorphs,
solvates, hydrates, co-crystals and clathrates. Particular
embodiments herein provide single-component amorphous solid forms
of Compound A. Particular embodiments herein provide
single-component crystalline solid forms of Compound A. Particular
embodiments herein provide multiple-component amorphous forms
comprising Compound A. Particular embodiments herein provide
multiple-component crystalline solid forms comprising Compound A.
Multiple-component solid forms provided herein include solid forms
which may be described by the terms salt, co-crystal, hydrate,
solvate, clathrate and/or polymorph, and include solid forms which
may be described by one or more of these terms.
[0080] Solid forms comprising Compound A can be prepared by the
methods described herein, including the methods described in the
Examples below, or by techniques known in the art, including
heating, cooling, freeze drying, lyophilization, quench cooling the
melt, rapid solvent evaporation, slow solvent evaporation, solvent
recrystallization, antisolvent addition, slurry recrystallization,
crystallization from the melt, desolvation, recrystallization in
confined spaces such as, e.g., in nanopores or capillaries,
recrystallization on surfaces or templates such as, e.g., on
polymers, recrystallization in the presence of additives, such as,
e.g., co-crystal counter-molecules, desolvation, dehydration, rapid
cooling, slow cooling, exposure to solvent and/or water, drying,
including, e.g., vacuum drying, vapor diffusion, sublimation,
grinding (including, e.g., cryo-grinding, solvent-drop grinding or
liquid assisted grinding), microwave-induced precipitation,
sonication-induced precipitation, laser-induced precipitation and
precipitation from a supercritical fluid. The particle size of the
resulting solid forms, which can vary, (e.g., from nanometer
dimensions to millimeter dimensions), can be controlled, e.g., by
varying crystallization conditions, such as, e.g., the rate of
crystallization and/or the crystallization solvent system, or by
particle-size reduction techniques, e.g., grinding, milling,
micronizing or sonication.
[0081] While not intending to be bound by any particular theory,
certain solid forms are characterized by physical properties, e.g.,
stability, solubility and dissolution rate, appropriate for
pharmaceutical and therapeutic dosage forms. Moreover, while not
wishing to be bound by any particular theory, certain solid forms
are characterized by physical properties (e.g., density,
compressibility, hardness, morphology, cleavage, stickiness,
solubility, water uptake, electrical properties, thermal behavior,
solid-state reactivity, physical stability, and chemical stability)
affecting particular processes (e.g., yield, filtration, washing,
drying, milling, mixing, tableting, flowability, dissolution,
formulation, and lyophilization) which make certain solid forms
suitable for the manufacture of a solid dosage form. Such
properties can be determined using particular analytical chemical
techniques, including solid-state analytical techniques (e.g.,
X-ray diffraction, microscopy, spectroscopy and thermal analysis),
as described herein and known in the art.
[0082] Certain embodiments herein provide compositions comprising
one or more of the solid forms. Certain embodiments provide
compositions of one or more solid forms in combination with other
active ingredients. Certain embodiments provide methods of using
these compositions in the treatment, prevention or management of
diseases and disorders including, but not limited to, the diseases
and disorders provided herein.
[0083] Solid forms provided herein may also comprise unnatural
proportions of atomic isotopes at one or more of the atoms in
Compound A. For example, the compound may be radiolabeled with
radioactive isotopes, such as for example tritium (.sup.3H),
iodine-125 (.sup.125I) sulfur-35 (.sup.35S), or carbon-14
(.sup.14C). Radiolabeled compounds are useful as therapeutic
agents, e.g., cancer therapeutic agents, research reagents, e.g.,
binding assay reagents, and diagnostic agents, e.g., in vivo
imaging agents. All isotopic variations of Compound A, whether
radioactive or not, are intended to be encompassed within the scope
of the embodiments provided herein.
[0084] 4.1.1. Form A of Compound A
[0085] Certain embodiments herein provide crystalline Form A of
Compound A. Form A may be crystallized from DMSO:water at room
temperature, dissolving Compound A in 95:5 DMSO:water (v:v) and
crystallizing by adding water to reach 50:50 DMSO:water (v:v). A
wide screen of solvents resulted in the selection of DMSO:water,
with water being the anti-solvent. FIG. 24 shows the solubility of
Form A in DMSO:water as the relative amount of DMSO is
increased.
[0086] In certain embodiments, Form A of Compound A may be
characterized by X-ray powder diffraction analysis. A
representative XRPD pattern of Form A of Compound A is provided in
FIG. 1. In certain embodiments, Form A of Compound A is
characterized by XRPD peaks located at one, two, three, four, five,
six, seven, eight, nine, ten, eleven, twelve, or thirteen of the
following approximate positions: 9.2, 13.4, 14.0, 14.6, 15.6, 16.7,
18.5, 21.9, 22.7, 24.8, 28.1, 30.0 and 37.0 degrees 2.theta.. In
one embodiment, the Form A of Compound A is characterized by XRPD
peaks located at the following approximate positions: 14.6, 15.6,
16.7, 21.9 and 30.0, degrees 2.theta.. In certain embodiments, Form
A of Compound A is characterized by an XRPD pattern which matches
the pattern exhibited in FIG. 1. In certain embodiments, Form A of
Compound A is characterized by an XRPD pattern having 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12 or 13 peaks matching peaks in the
representative Form A pattern provided herein.
[0087] In certain embodiments, Form A of Compound A may be
characterized by thermal analysis. A representative DSC plot for
Form A of Compound A is shown in FIG. 2. In certain embodiments,
Form A is characterized by a DSC plot comprising an endothermic
event with an onset temperature of about 282.degree. C. In certain
embodiments, a characteristic Form A DSC plot further comprises one
or more additional events, such as, e.g., an endothermic event with
a peak temperature of about 145.degree. C., and/or an exothermic
event with a peak temperature of about 161.degree. C. A
representative TGA plot for Form A of Compound A is shown in FIG.
3. In certain embodiments, Form A is characterized by a TGA plot
comprising a mass loss of less than about 10%, less than about 8%,
or less than about 6%, e.g., about 5.9%, of the total mass of the
sample upon heating from about 40.degree. C. to about 110.degree.
C. In one embodiment, Form A is characterized by a TGA plot
comprising a mass loss of about 5 to about 6% of the total mass of
the sample upon heating from about 40.degree. C. to about
110.degree. C. In certain embodiments, Form A of Compound A
contains either water or other solvent in the crystal lattice. In
certain embodiments, the TGA mass loss event comprises the loss of
water. In certain embodiments, Form A is solvated. In certain
embodiments, Form A is monohydrated. In certain embodiments, the
crystal lattice of Form A comprises about one molar equivalent of
water per mole of Compound A.
[0088] In certain embodiments, upon dehydration Form A is converted
to Form D of Compound A. In one embodiment, Form A is converted to
Form D of Compound A when dried at about 55.degree. C. for 3 days.
Form A of Compound A may be prepared from Form D by slurrying Form
D in water at 22.degree. C. or 50.degree. C. overnight.
[0089] In one embodiment, Form A of Compound A is physically and
chemically stable at 40.degree. C. for 5 days under vacuum. In
another embodiment, Form A of Compound A is physically and
chemically stable at 40.degree. C. for 4 days under nitrogen
atmosphere.
[0090] In certain embodiments, Form A of Compound A may be
characterized by moisture sorption analysis. In certain
embodiments, when the relative humidity ("RH") is increased from
about 0% to about 95% RH, Form A exhibits a mass change ranging
from about 1% to about 10%, from about 2 to about 5%, or from about
3 to about 4% of the starting mass of the sample. In certain
embodiments, mass gained upon adsorption is lost when the RH is
decreased back to about 0% RH.
[0091] Certain embodiments herein provide Form A of Compound A
which is substantially pure. Certain embodiments herein provide
Form A of Compound A which is substantially free of other solid
forms comprising Compound A including, e.g., Forms B, C, D, E, and
F and/or an amorphous solid form comprising Compound A as provided
herein, and Form A1 and an amorphous solid form comprising Compound
A hydrochloride as provided herein. Certain embodiments herein
provide Form A as a mixture of solid forms comprising Compound A,
including, e.g., a mixture comprising one or more of the following:
Forms B, C, D, E, F, and an amorphous solid form comprising
Compound A as provided herein, and Form A1 and an amorphous solid
form comprising Compound A hydrochloride as provided herein.
[0092] 4.1.2. Form B of Compound A
[0093] Certain embodiments herein provide crystalline Form B of
Compound A. In certain embodiments, Form B of Compound A can be
obtained from various solvents, including, but not limited to,
solvent systems comprising acetone, acetonitrile, methanol, and
mixtures thereof. In certain embodiments, Form B can be obtained
using a slurry recrystallization process. In certain embodiments,
Form B is obtained using a slurry recrystallization process in
acetone, acetonitrile, methanol, or mixtures thereof at about
50.degree. C.
[0094] In certain embodiments, Form B of Compound A may be
characterized by X-ray powder diffraction analysis. A
representative XRPD pattern of Form B of Compound A is provided in
FIG. 4. In certain embodiments, Form B of Compound A is
characterized by XRPD peaks located at one, two, three, four, five,
six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,
fifteen or sixteen of the following approximate positions: 10.6,
11.4, 12.6, 13.7, 14.7, 19.1, 20.3, 20.9, 21.2, 22.9, 24.9, 25.3,
25.9, 26.9, 29.5 and 33.8 degrees 2.theta.. In one embodiment, Form
B of Compound A is characterized by XRPD peaks located at the
following approximate positions: 10.6, 14.7, 19.1 and 25.9 degrees
2.theta.. In certain embodiments, Form B of Compound A is
characterized by an XRPD pattern which matches the pattern
exhibited in FIG. 4. In certain embodiments, Form B of Compound A
is characterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15 or 16 peaks matching peaks in the
representative Form B pattern provided herein.
[0095] In certain embodiments, Form B of Compound A may be
characterized by thermal analysis. A representative DSC plot for
Form B of Compound A is shown in FIG. 5. In certain embodiments,
Form B is characterized by a DSC plot comprising an endothermic
event with an onset temperature of about 279.degree. C. A
representative TGA plot for Form B of Compound A is shown in FIG.
6. In certain embodiments, Form B is characterized by a TGA plot
comprising a mass loss of less than about 1%, less than about 0.5%,
less than about 0.1%, or less than 0.05% of the total mass of the
sample upon heating from about 25.degree. C. to about 200.degree.
C. In certain embodiments, Form B of Compound A does not contain
substantial amounts of either water or other solvent in the crystal
lattice. In certain embodiments, Form B is anhydrous. In certain
embodiments, Form B is unsolvated.
[0096] In certain embodiments, Form B of Compound A may be
characterized by moisture sorption analysis. In certain
embodiments, when the RH is increased from about 0% to about 95%
RH, Form B exhibits a mass change of less than about 1%, less than
about 0.5%, or less than about 0.2%, e.g., about 0.1%, of the
starting mass of the sample. In certain embodiments, mass gained
upon adsorption is lost when the RH is decreased back to about 0%
RH. In certain embodiments, Form B is substantially nonhygroscopic.
In certain embodiments, the XRPD pattern of Form B material is
substantially unchanged following the adsorption/desorption
analysis. In certain embodiments, Form B is stable with respect to
humidity.
[0097] Certain embodiments herein provide Form B of Compound A
which is substantially pure. Certain embodiments herein provide
Form B of Compound A which is substantially free of other solid
forms comprising Compound A including, e.g., Forms A, C, D, E, F,
and/or an amorphous solid form comprising Compound A as provided
herein, and Form A1 and an amorphous solid form comprising Compound
A hydrochloride as provided herein. Certain embodiments herein
provide Form B as a mixture of solid forms comprising Compound A,
including, e.g., a mixture comprising one or more of the following:
Forms A, C, D, E, F, and an amorphous solid form comprising
Compound A as provided herein, and Form A1 and an amorphous solid
form comprising Compound A hydrochloride as provided herein.
[0098] 4.1.3. Form C of Compound A
[0099] Certain embodiments herein provide crystalline Form C of
Compound A. In certain embodiments, Form C of Compound A can be
obtained from various solvents, including, but not limited to,
solvent systems comprising ethyl acetate, ethanol, 2-propanol,
methyl ethyl ketone, n-butanol, tetrahydrofuran, and mixtures
comprising two or more thereof. In certain embodiments, Form C can
be obtained using a slurry recrystallization process. In certain
embodiments, Form C is obtained using a slurry recrystallization
process in ethyl acetate, ethanol, 2-propanol, methyl ethyl ketone,
n-butanol, tetrahydrofuran, or mixtures comprising two or more
thereof, at about 50.degree. C.
[0100] In certain embodiments, Form C of Compound A may be
characterized by X-ray powder diffraction analysis. A
representative XRPD pattern of Form C of Compound A is provided in
FIG. 7. In certain embodiments, Form C of Compound A is
characterized by XRPD peaks located at one, two, three, four, five,
six, seven, eight, nine, ten or eleven of the following approximate
positions: 10.8, 11.9, 15.1, 18.8, 19.2, 19.3, 22.0, 24.9, 25.1,
26.6 and 29.2 degrees 2.theta.. In one embodiment, Form C of
Compound A is characterized by XRPD peaks located at the following
approximate positions: 10.8, 15.1, 25.1 and 26.6 degrees 2.theta..
In certain embodiments, Form C of Compound A is characterized by an
XRPD pattern which matches the pattern exhibited in FIG. 7. In
certain embodiments, Form C of Compound A is characterized by an
XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 peaks
matching peaks in the representative Form C pattern provided
herein.
[0101] In certain embodiments, Form C of Compound A may be
characterized by thermal analysis. A representative DSC plot for
Form C of Compound A is shown in FIG. 8. In certain embodiments,
Form C is characterized by a DSC plot comprising an endothermic
event with an onset temperature of about 281.degree. C. A
representative TGA plot for Form C of Compound A is shown in FIG.
9. In certain embodiments, Form C is characterized by a TGA plot
comprising a mass loss of less than about 1%, less than about 0.5%,
or less than about 0.1%, e.g., about 0.07%, of the total mass of
the sample upon heating from about 25.degree. C. to about
150.degree. C. In certain embodiments, Form C of Compound A does
not contain substantial amounts of either water or other solvent in
the crystal lattice. In certain embodiments, Form C is anhydrous.
In certain embodiments, Form C is unsolvated.
[0102] In certain embodiments, Form C of Compound A may be
characterized by moisture sorption analysis. In certain
embodiments, when the RH is increased from about 0% to about 95%
RH, Form C exhibits a mass change of less than about 1%, less than
about 0.5%, or less than about 0.2%, e.g., about 0.17%, of the
starting mass of the sample. In certain embodiments, mass gained
upon adsorption is lost when the RH is decreased back to about 0%
RH. In certain embodiments, Form C is substantially nonhygroscopic.
In certain embodiments, the XRPD pattern of Form C material is
substantially unchanged following the adsorption/desorption
analysis. In certain embodiments, Form C is stable with respect to
humidity.
[0103] Certain embodiments herein provide Form C of Compound A
which is substantially pure. Certain embodiments herein provide
Form C of Compound A which is substantially free of other solid
forms comprising Compound A including, e.g., Forms A, B, D, E, F,
and/or an amorphous solid form comprising Compound A as provided
herein, and Form A1 and an amorphous solid form comprising Compound
A hydrochloride as provided herein. Certain embodiments herein
provide Form C as a mixture of solid forms comprising Compound A,
including, e.g., a mixture comprising one or more of the following:
Forms A, B, D, E, F, and an amorphous solid form comprising
Compound A as provided herein, and Form A1 and an amorphous solid
form comprising Compound A hydrochloride as provided herein.
[0104] 4.1.4. Form D of Compound A
[0105] Certain embodiments herein provide Form D of Compound A. In
certain embodiments, Form D of Compound A can be obtained by drying
Form A of Compound A in an oven. In certain embodiments, Form D is
obtained by drying Form A in an oven at about 70.degree. C.
[0106] In certain embodiments, Form D of Compound A may be
characterized by X-ray powder diffraction analysis. A
representative XRPD pattern of Form D of Compound A is provided in
FIG. 10. In certain embodiments, Form D of Compound A is
characterized by an XRPD pattern which matches the pattern
exhibited in FIG. 10. In certain embodiments, Form D of Compound A
is characterized by XRPD peaks located at one, two, three, four,
five, six, seven, eight, nine, ten, eleven, twelve, thirteen or
fourteen of the following approximate positions: 10.6, 14.0, 14.6,
15.7, 16.3, 16.7, 18.8, 21.7, 21.9, 24.8, 25.1, 25.8, 28.1 and 28.6
degrees 2.theta.. In one embodiment, Form D of Compound A is
characterized by XRPD peaks located at the following approximate
positions: 16.7, 21.7, 21.9 and 25.8 degrees 2.theta.. In certain
embodiments, Form D of Compound A is characterized by an XRPD
pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14
peaks matching peaks in the representative Form D pattern provided
herein.
[0107] In certain embodiments, Form D of Compound A may be
characterized by thermal analysis. A representative DSC plot for
Form D of Compound A is shown in FIG. 11. In certain embodiments,
Form D is characterized by a DSC plot comprising an endothermic
event with an onset temperature of about 283.degree. C. In certain
embodiments, a characteristic Form D DSC plot further comprises one
additional event, such as, e.g., an endothermic event with a peak
temperature of about 114.degree. C. A representative TGA plot for
Form D of Compound A is shown in FIG. 12. In certain embodiments,
Form D is characterized by a TGA plot comprising a mass loss of
less than about 10%, less than about 8%, less than about 6%, less
than about 4%, e.g., about 3%, of the total mass of the sample upon
heating from about 25.degree. C. to about 150.degree. C. In certain
embodiments, the TGA mass loss event comprises the loss of water.
In certain embodiments, Form D of Compound A is solvated. In
certain embodiments, Form D is hydrated.
[0108] In certain embodiments, Form D of Compound A may be
characterized by moisture sorption analysis. In certain
embodiments, when the RH is increased from about 0% to about 95%
RH, Form D exhibits a mass change of less than about 5%, e.g.,
about 4%, of the starting mass of the sample. In certain
embodiments, mass gained upon adsorption is lost when the RH is
decreased back to about 0% RH.
[0109] Certain embodiments herein provide Form D of Compound A
which is substantially pure. Certain embodiments herein provide
Form D of Compound A which is substantially free of other solid
forms comprising Compound A including, e.g., Forms A, B, C, D, E,
F, and/or an amorphous solid form comprising Compound A as provided
herein, and Form A1 and an amorphous solid form comprising Compound
A hydrochloride as provided herein. Certain embodiments herein
provide Form D as a mixture of solid forms comprising Compound A,
including, e.g., a mixture comprising one or more of the following:
Forms A, B, C, E, F, and an amorphous solid form comprising
Compound A as provided herein, and Form A1 and an amorphous solid
form comprising Compound A hydrochloride as provided herein.
[0110] 4.1.5. Form E of Compound A
[0111] Certain embodiments herein provide the Form E crystal form
of Compound A. In certain embodiments, Form E of Compound A can be
obtained from various solvents, including, but not limited to,
solvent systems comprising acetonitrile or isopropanol, and
mixtures thereof. In certain embodiments, Form E can be obtained
using a slurry recrystallization process. In certain embodiments,
Form E can be obtained using a slurry recrystallization process at
room temperature. Form E can also be obtained by an antisolvent
recrystallization process by dissolving Compound A in DMF or NMP
and rapidly adding water as antisolvent.
[0112] In certain embodiments, Form E of Compound A may be
characterized by X-ray powder diffraction analysis. A
representative XRPD pattern of Form E of Compound A is provided in
FIG. 13. In certain embodiments, Form E of Compound A is
characterized by XRPD peaks located at one, two, three, four, five,
six, seven, eight, nine, ten, eleven, twelve or thirteen of the
following approximate positions: 7.3, 9.3, 12.2, 14.0, 14.6, 15.7,
16.8, 21.0, 22.0, 22.7, 29.4, 30.0 and 37.0 degrees 2.theta.. In
one embodiment, Form E of Compound A is characterized by XRPD peaks
located at the following approximate positions: 7.3, 14.6, 22.0,
30.0 and 37.0 degrees 2.theta.. In certain embodiments, Form E of
Compound A is characterized by an XRPD pattern which matches the
pattern exhibited in FIG. 13. In certain embodiments, Form E of
Compound A is characterized by an XRPD pattern having 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12 or 13 peaks matching peaks in the
representative Form E pattern provided herein.
[0113] In certain embodiments, Form E of Compound A may be
characterized by thermal analysis. A representative DSC plot for
Form E of Compound A is shown in FIG. 14. In certain embodiments,
Form E is characterized by a DSC plot comprising an endothermic
event with an onset temperature of about 279.degree. C. In certain
embodiments, a characteristic Form E DSC plot further comprises one
additional event, such as, e.g., an endothermic event with a peak
temperature of about 146.degree. C. A representative TGA plot for
Form E of Compound A is shown in FIG. 15. In certain embodiments,
Form E is characterized by a TGA plot comprising a mass loss of
less than about 10%, less than about 8%, less than about 6%, e.g.,
about 5.97%, of the total mass of the sample upon heating from
about 25.degree. C. to about 150.degree. C. In certain embodiments,
the TGA mass loss event comprises the loss of water. In certain
embodiments, Form E of Compound A is solvated. In certain
embodiments, Form E is hydrated.
[0114] In certain embodiments, Form E of Compound A may be
characterized by moisture sorption analysis. In certain
embodiments, when the RH is increased from about 0% to about 95%
RH, Form E exhibits a mass change of less than about 2%, less than
about 1%, or less than about 0.5%, e.g., about 0.4%, of the
starting mass of the sample. In certain embodiments, mass gained
upon adsorption is lost when the RH is decreased back to about 0%
RH. In certain embodiments, Form E is nonhygroscopic. In certain
embodiments, the XRPD pattern of Form E material is substantially
unchanged following the adsorption/desorption analysis. In certain
embodiments, Form E is stable with respect to humidity.
[0115] Certain embodiments herein provide Form E of Compound A
which is substantially pure. Certain embodiments herein provide
Form E of Compound A which is substantially free of other solid
forms comprising Compound A including, e.g., Forms A, B, C, D, F,
and/or an amorphous solid form comprising Compound A as provided
herein, and Form A1 and an amorphous solid form comprising Compound
A hydrochloride as provided herein. Certain embodiments herein
provide Form E as a mixture of solid forms comprising Compound A,
including, e.g., a mixture comprising one or more of the following:
Forms A, B, C, D, F, and an amorphous solid form comprising
Compound A as provided herein, and Form A1 and an amorphous solid
form comprising Compound A hydrochloride as provided herein.
[0116] 4.1.6. Form F of Compound A
[0117] Certain embodiments herein provide the Form F crystal form
of Compound A. In certain embodiments, Form F of Compound A can be
obtained from various solvents, including, but not limited to,
solvent systems comprising water. In certain embodiments, Form F
can be obtained using a slurry recrystallization process.
[0118] In certain embodiments, Form F of Compound A may be
characterized by X-ray powder diffraction analysis. A
representative XRPD pattern of Form F of Compound A is provided in
FIG. 16. In certain embodiments, Form F of Compound A is
characterized by XRPD peaks located at one, two, three, four, five,
six, seven, eight, nine or ten of the following approximate
positions: 7.2, 9.1, 14.5, 15.7, 16.8, 18.3, 21.9, 22.7, 29.9 and
36.9 degrees 2.theta.. In one embodiment, Form F of Compound A is
characterized by XRPD peaks located at the following approximate
positions: 14.5, 15.7, 22.7 and 29.9 degrees 2.theta.. In certain
embodiments, Form F of Compound A is characterized by an XRPD
pattern which matches the pattern exhibited in FIG. 16. In certain
embodiments, Form F of Compound A is characterized by an XRPD
pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks matching peaks
in the representative Form F pattern provided herein.
[0119] In certain embodiments, Form F of Compound A may be
characterized by thermal analysis. A representative DSC plot for
Form F of Compound A is shown in FIG. 17. In certain embodiments,
Form F is characterized by a DSC plot comprising an endothermic
event with an onset temperature of about 267.degree. C. In certain
embodiments, a characteristic Form F DSC plot further comprises one
additional event, such as, e.g., an exothermic event with a peak
temperature of about 170.degree. C. In certain embodiments, Form F
is solvated. In certain embodiments, Form F is hydrated.
[0120] Certain embodiments herein provide Form F of Compound A
which is substantially pure. Certain embodiments herein provide
Form F of Compound A which is substantially free of other solid
forms comprising Compound A including, e.g., Forms A, B, C, D, E,
and/or an amorphous solid form comprising Compound A as provided
herein, and Form A1 and an amorphous solid form comprising Compound
A hydrochloride as provided herein. Certain embodiments herein
provide Form F as a mixture of solid forms comprising Compound A,
including, e.g., a mixture comprising one or more of the following:
Forms A, B, C, D, E, and an amorphous solid form comprising
Compound A as provided herein, and Form A1 and an amorphous solid
form comprising Compound A hydrochloride as provided herein.
[0121] 4.1.7. Form A1 of Compound A Hydrochloride
[0122] Certain embodiments herein provide crystalline Form A1 of a
hydrochloride salt of Compound A. In certain embodiments, Form A1
can be obtained from various solvents, including, but not limited
to, solvent systems comprising acetone, acetonitrile, n-butanol,
ethanol, ethyl acetate, heptane, methanol, methylene chloride,
methyl ethyl ketone, methyl t-butyl ether, 2-propanol, toluene,
tetrahydrofuran, water, and mixtures thereof. In certain
embodiments, Form A1 can be obtained using a fast or slow cooling
crystallization process. In certain embodiments, Form A1 can be
obtained using an antisolvent addition crystallization process.
[0123] Form A1 of Compound A hydrochloride is a stable crystalline
form. For example, Form A1 found to be chemically stable upon
storage at room temperature, exposed to air and light, for 6 weeks.
Form A1 was also found to be chemically stable upon storage at
40.degree. C. under vacuum. Form A1 was also found to be chemically
stable upon storage at 40.degree. C. under a nitrogen atmosphere.
Form A1 was also found to be chemically stable upon storage at
40.degree. C. and 75% relative humidity (RH). Form A1 was also
found to be chemically stable upon storage at 60.degree. C. in a
closed container. Based on this data, Form A1 of Compound A was
determined to be suitably stable for large scale production
(Example 5.4.3.2).
[0124] In certain embodiments, Form A1 may be characterized by
X-ray powder diffraction analysis. A representative XRPD pattern of
Form A1 is provided in FIG. 18. In certain embodiments, Form A1 is
characterized by XRPD peaks located at one, two, three, four, five,
six, seven, eight, nine or ten of the following approximate
positions: 8.6, 11.3, 13.1, 15.3, 17.3, 20.5, 22.7, 23.6, 26.3 and
31.4 degrees 2.theta.. In one embodiment, Form A1 is characterized
by XRPD peaks located at the following approximate positions: 8.6,
13.1, 20.5 and 26.3 degrees 2.theta.. In certain embodiments, Form
A1 is characterized by an XRPD pattern which matches the pattern
exhibited in FIG. 18. In certain embodiments, Form A1 is
characterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10 peaks matching peaks in the representative Form A1 pattern
provided herein.
[0125] In certain embodiments, Form A1 of a hydrochloride salt of
Compound A may be characterized by thermal analysis. A
representative DSC plot for Form A1 is shown in FIG. 19. In certain
embodiments, Form A1 is characterized by a DSC plot comprising an
endothermic event with an onset temperature of about 276.degree. C.
In certain embodiments, Form A1 has a decomposition temperature at
about 276.degree. C. A representative TGA plot for Form A1 of
Compound A is shown in FIG. 20. In certain embodiments, Form A1 is
characterized by a TGA plot comprising a mass loss of less than
about 1%, less than about 0.5%, less than about 0.2%, less than
about 0.1%, less than about 0.05%, less than about 0.01%, e.g.,
about 0.0008%, of the total mass of the sample upon heating from
about 25.degree. C. to about 150.degree. C. In certain embodiments,
Form A1 of Compound A does not contain substantial amounts of
either water or other solvent in the crystal lattice. In certain
embodiments, Form A1 is unsolvated. In certain embodiments, Form A1
is anhydrous.
[0126] In certain embodiments, Form A1 may be characterized by
moisture sorption analysis. A representative moisture sorption
isotherm plot is shown in FIG. 21. In certain embodiments, when the
relative humidity ("RH") is increased from about 0% to about 95%
RH, Form A1 exhibits a mass change of less than about 1%, less than
about 0.5%, less than about 0.2% (e.g., about 0.15%) of the
starting mass of the sample. In certain embodiments, mass gained
upon adsorption is lost when the RH is decreased back to about 0%
RH. Accordingly, in certain embodiments, Form A1 is substantially
nonhygroscopic. In certain embodiments, the XRPD pattern of the
Form A1 material is substantially unchanged following the
adsorption/desorption analysis. In certain embodiments, Form A1 is
stable with respect to humidity.
[0127] In certain embodiments, Form A1 of a hydrochloride salt of
Compound A may be characterized by its stability profile. In
certain embodiments, Form A1 material is stable, e.g., its XRPD
pattern remains substantially unchanged, upon exposure to elevated
temperature, upon exposure to elevated humidity, upon exposure to
one or more solvents, and/or upon compression. In certain
embodiments, for example, Form A1 is stable following exposure to
an environment of about 40.degree. C. and about 75% RH environment
for about four weeks. In certain embodiments, for example, Form A1
is stable following exposure to an environment of room temperature
and about 95% RH environment for about four days. In certain
embodiments, Form A1 is stable following exposure to one or more
solvent systems comprising, e.g., acetone, acetonitrile, n-butanol,
ethanol, ethyl acetate, heptane, methanol, methylene chloride,
methyl ethyl ketone, methyl t-butyl ether, 2-propanol, toluene,
and/or tetrahydrofuran at about 50.degree. C. for at least about 24
hrs. In certain embodiments, Form A1 is stable upon compression at
about 2,000-psi pressure for about one minute.
[0128] In certain embodiments, Form A1 may be characterized by
particle analysis. In certain embodiments, a sample of Form A1
comprises particles having an acicular morphology.
[0129] Certain embodiments herein provide Form A1 Compound A which
is substantially pure. Certain embodiments herein provide Form A1
of a hydrochloride salt of Compound A, which is substantially free
of other solid forms comprising Compound A, including, e.g., an
amorphous solid form comprising a hydrochloride salt of Compound A
as provided herein, and Forms A, B, C, D, E, F, and/or an amorphous
solid form comprising Compound A as provided herein. Certain
embodiments herein provide Form A1 as a mixture of solid forms
comprising Compound A, including, e.g., a mixture comprising one or
more of the following: Forms A, B, C, D, E, F, and an amorphous
solid form comprising Compound A as provided herein, and an
amorphous solid form comprising Compound A hydrochloride as
provided herein.
[0130] Certain embodiments herein provide Form A1 of a
hydrochloride salt of Compound A, wherein the molar ratio of
Compound A and hydrochloride in Form A1 is ranging from about 0.1
to about 10, from about 0.2 to about 5, from about 0.5 to about 2,
from about 0.6 to about 1.5, from about 0.7 to about 1.3, from
about 0.8 to about 1.2, from about 0.9 to about 1.1, or from about
0.95 to about 1.05. In certain embodiments, the molar ratio of
Compound A and hydrochloride in Form A1 is about 0.5, about 0.6,
about 0.7, about 0.8, about 0.9, about 0.95, about 1, about 1.05,
about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5.
[0131] 4.2. Methods of Treatment
[0132] The disclosure encompasses methods of treating, preventing,
and/or managing various diseases or disorders using a solid form of
Compound A or a stereoisomer thereof, or a pharmaceutically
acceptable salt, solvate, hydrate, co-crystal, clathrate, or
polymorph thereof, which comprise administering a therapeutically
or prophylactically effective amount of one or more solid forms
comprising Compound A, such as, e.g., Form A, B, C, D, E, or an
amorphous form of Compound A, or Form A1 or an amorphous form of
Compound A hydrochloride as provided herein.
[0133] Without being limited by a particular theory, Compound A can
control angiogenesis or inhibit the production of certain cytokines
including, but not limited to, TNF-.alpha., IL-1.beta., IL-12,
IL-18, GM-CSF, and/or IL-6. Without being limited by a particular
theory, Compound A can stimulate the production of certain other
cytokines including IL-10, and also act as a costimulatory signal
for T cell activation, resulting in increased production of
cytokines such as, but not limited to, IL-12 and/or IFN-.gamma.. In
addition, Compound A can enhance the effects of NK cells and
antibody-mediated cellular cytotoxicity (ADCC). Further, Compound A
may be immunomodulatory and/or cytotoxic, and thus, may be useful
as chemotherapeutic agents. Consequently, without being limited by
a particular theory, some or all of such characteristics possessed
by Compound A may render them useful in treating, managing, and/or
preventing various diseases or disorders.
[0134] Examples of diseases or disorders include, but are not
limited to, cancer, disorders associated with angiogenesis, pain
including, but not limited to, Complex Regional Pain Syndrome
("CRPS"), Macular Degeneration ("MD") and related syndromes, skin
diseases, pulmonary disorders, asbestos-related disorders,
parasitic diseases, immunodeficiency disorders, CNS disorders, CNS
injury, atherosclerosis and related disorders, dysfunctional sleep
and related disorders, hemoglobinopathy and related disorders
(e.g., anemia), TNF related disorders, and other various diseases
and disorders.
[0135] Examples of cancer and precancerous conditions include, but
are not limited to, those described in U.S. Pat. Nos. 6,281,230 and
5,635,517 to Muller et al., in various U.S. patent publications to
Zeldis, including publication nos. 2004/0220144A1, published Nov.
4, 2004 (Treatment of Myelodysplastic Syndrome); 2004/0029832A1,
published Feb. 12, 2004 (Treatment of Various Types of Cancer); and
2004/0087546, published May 6, 2004 (Treatment of
Myeloproliferative Diseases). Examples also include those described
in WO 2004/103274, published Dec. 2, 2004. All of these references
are incorporated herein in their entireties by reference.
[0136] Specific examples of cancer include, but are not limited to,
cancers of the skin, such as melanoma; lymph node; breast; cervix;
uterus; gastrointestinal tract; lung; ovary; prostate; colon;
rectum; mouth; brain; head and neck; throat; testes; kidney;
pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and
AIDS-related cancers. The compounds are also useful for treating
cancers of the blood and bone marrow, such as multiple myeloma and
acute and chronic leukemias, for example, lymphoblastic,
myelogenous, lymphocytic, and myelocytic leukemias. The compounds
provided herein can be used for treating, preventing or managing
either primary or metastatic tumors.
[0137] Other specific cancers include, but are not limited to,
advanced malignancy, amyloidosis, neuroblastoma, meningioma,
hemangiopericytoma, multiple brain metastase, glioblastoma
multiforms, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor, malignant glioma, recurrent malignant
glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,
neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D
colorectal cancer, unresectable colorectal carcinoma, metastatic
hepatocellular carcinoma, Kaposi's sarcoma, karotype acute
myeloblastic leukemia, chronic lymphocytic leukemia (CLL),
Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell
lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma,
low grade follicular lymphoma, metastatic melanoma (localized
melanoma, including, but not limited to, ocular melanoma),
malignant mesothelioma, malignant pleural effusion mesothelioma
syndrome, peritoneal carcinoma, papillary serous carcinoma,
gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous
vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,
fibrodysplasia ossificans progressive, hormone refractory prostate
cancer, resected high-risk soft tissue sarcoma, unrescectable
hepatocellular carcinoma, Waldenstrom's macroglobulinemia,
smoldering myeloma, indolent myeloma, fallopian tube cancer,
androgen independent prostate cancer, androgen dependent stage IV
non-metastatic prostate cancer, hormone-insensitive prostate
cancer, chemotherapy-insensitive prostate cancer, papillary thyroid
carcinoma, follicular thyroid carcinoma, medullary thyroid
carcinoma, and leiomyoma. In a specific embodiment, the cancer is
metastatic. In another embodiment, the cancer is refractory or
resistance to chemotherapy or radiation.
[0138] In one embodiment, provided herein are methods of treating,
preventing or managing various forms of leukemias such as chronic
lymphocytic leukemia, chronic myelocytic leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia and acute
myeloblastic leukemia, including leukemias that are relapsed,
refractory or resistant, as disclosed in U.S. publication no.
2006/0030594, published Feb. 9, 2006, which is incorporated in its
entirety by reference.
[0139] The term "leukemia" refers malignant neoplasms of the
blood-forming tissues. The leukemia includes, but is not limited
to, chronic lymphocytic leukemia, chronic myelocytic leukemia,
acute lymphoblastic leukemia, acute myelogenous leukemia and acute
myeloblastic leukemia. The leukemia can be relapsed, refractory or
resistant to conventional therapy. The term "relapsed" refers to a
situation where patients who have had a remission of leukemia after
therapy have a return of leukemia cells in the marrow and a
decrease in normal blood cells. The term "refractory or resistant"
refers to a circumstance where patients, even after intensive
treatment, have residual leukemia cells in their marrow.
[0140] In another embodiment, provided herein are methods of
treating, preventing or managing various types of lymphomas,
including Non-Hodgkin's lymphoma (NHL). The term "lymphoma" refers
a heterogenous group of neoplasms arising in the
reticuloendothelial and lymphatic systems. "NHL" refers to
malignant monoclonal proliferation of lymphoid cells in sites of
the immune system, including lymph nodes, bone marrow, spleen,
liver and gastrointestinal tract. Examples of NHL include, but are
not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma of
intermediate differentiation, intermediate lymphocytic lymphoma
(ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL),
centrocytic lymphoma, diffuse small-cleaved cell lymphoma (DSCCL),
follicular lymphoma, and any type of the mantle cell lymphomas that
can be seen under the microscope (nodular, diffuse, blastic and
mentle zone lymphoma).
[0141] Examples of diseases and disorders associated with, or
characterized by, undesired angiogenesis include, but are not
limited to, inflammatory diseases, autoimmune diseases, viral
diseases, genetic diseases, allergic diseases, bacterial diseases,
ocular neovascular diseases, choroidal neovascular diseases, retina
neovascular diseases, and rubeosis (neovascularization of the
angle). Specific examples of the diseases and disorders associated
with, or characterized by, undesired angiogenesis include, but are
not limited to, arthritis, endometriosis, Crohn's disease, heart
failure, advanced heart failure, renal impairment, endotoxemia,
toxic shock syndrome, osteoarthritis, retrovirus replication,
wasting, meningitis, silica-induced fibrosis, asbestos-induced
fibrosis, veterinary disorder, malignancy-associated hypercalcemia,
stroke, circulatory shock, periodontitis, gingivitis, macrocytic
anemia, refractory anemia, and 5q-deletion syndrome.
[0142] Examples of pain include, but are not limited to those
described in U.S. patent publication no. 2005/0203142, published
Sep. 15, 2005, which is incorporated herein by reference. Specific
types of pain include, but are not limited to, nociceptive pain,
neuropathic pain, mixed pain of nociceptive and neuropathic pain,
visceral pain, migraine, headache and post-operative pain.
[0143] Examples of nociceptive pain include, but are not limited
to, pain associated with chemical or thermal burns, cuts of the
skin, contusions of the skin, osteoarthritis, rheumatoid arthritis,
tendonitis, and myofascial pain.
[0144] Examples of neuropathic pain include, but are not limited
to, CRPS type I, CRPS type II, reflex sympathetic dystrophy (RSD),
reflex neurovascular dystrophy, reflex dystrophy, sympathetically
maintained pain syndrome, causalgia, Sudeck atrophy of bone,
algoneurodystrophy, shoulder hand syndrome, post-traumatic
dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer
related pain, phantom limb pain, fibromyalgia, chronic fatigue
syndrome, spinal cord injury pain, central post-stroke pain,
radiculopathy, diabetic neuropathy, post-stroke pain, luetic
neuropathy, and other painful neuropathic conditions such as those
induced by drugs such as vincristine and velcade.
[0145] As used herein, the terms "complex regional pain syndrome,"
"CRPS" and "CRPS and related syndromes" mean a chronic pain
disorder characterized by one or more of the following: pain,
whether spontaneous or evoked, including allodynia (painful
response to a stimulus that is not usually painful) and
hyperalgesia (exaggerated response to a stimulus that is usually
only mildly painful); pain that is disproportionate to the inciting
event (e.g., years of severe pain after an ankle sprain); regional
pain that is not limited to a single peripheral nerve distribution;
and autonomic dysregulation (e.g., edema, alteration in blood flow
and hyperhidrosis) associated with trophic skin changes (hair and
nail growth abnormalities and cutaneous ulceration).
[0146] Examples of MD and related syndromes include, but are not
limited to, those described in U.S. patent publication no.
2004/0091455, published May 13, 2004, which is incorporated herein
by reference. Specific examples include, but are not limited to,
atrophic (dry) MD, exudative (wet) MD, age-related maculopathy
(ARM), choroidal neovascularisation (CNVM), retinal pigment
epithelium detachment (PED), and atrophy of retinal pigment
epithelium (RPE).
[0147] Examples of skin diseases include, but are not limited to,
those described in U.S. publication no. 2005/0214328A1, published
Sep. 29, 2005, which is incorporated herein by reference. Specific
examples include, but are not limited to, keratoses and related
symptoms, skin diseases or disorders characterized with overgrowths
of the epidermis, acne, and wrinkles.
[0148] As used herein, the term "keratosis" refers to any lesion on
the epidermis marked by the presence of circumscribed overgrowths
of the horny layer, including but not limited to actinic keratosis,
seborrheic keratosis, keratoacanthoma, keratosis follicularis
(Darier disease), inverted follicular keratosis, palmoplantar
keratoderma (PPK, keratosis palmaris et plantaris), keratosis
pilaris, and stucco keratosis. The term "actinic keratosis" also
refers to senile keratosis, keratosis senilis, verruca senilis,
plana senilis, solar keratosis, keratoderma or keratoma. The term
"seborrheic keratosis" also refers to seborrheic wart, senile wart,
or basal cell papilloma. Keratosis is characterized by one or more
of the following symptoms: rough appearing, scaly, erythematous
papules, plaques, spicules or nodules on exposed surfaces (e.g.,
face, hands, ears, neck, legs and thorax), excrescences of keratin
referred to as cutaneous horns, hyperkeratosis, telangiectasias,
elastosis, pigmented lentigines, acanthosis, parakeratosis,
dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,
cellular atypia, mitotic figures, abnormal cell-cell adhesion,
dense inflammatory infiltrates and small prevalence of squamous
cell carcinomas.
[0149] Examples of skin diseases or disorders characterized with
overgrowths of the epidermis include, but are not limited to, any
conditions, diseases or disorders marked by the presence of
overgrowths of the epidermis, including but not limited to,
infections associated with papilloma virus, arsenical keratoses,
sign of Leser-Trelat, warty dyskeratoma (WD), trichostasis
spinulosa (TS), erythrokeratodermia variabilis (EKV), ichthyosis
fetalis (harlequin ichthyosis), knuckle pads, cutaneous
melanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,
confluent and reticulated papillomatosis (CRP), acrochordons,
cutaneous horn, cowden disease (multiple hamartoma syndrome),
dermatosis papulosa nigra (DPN), epidermal nevus syndrome (ENS),
ichthyosis vulgaris, molluscum contagiosum, prurigo nodularis, and
acanthosis nigricans (AN).
[0150] Examples of pulmonary disorders include, but are not limited
to, those described in U.S. publication no. 2005/0239842A1,
published Oct. 27, 2005, which is incorporated herein by reference.
Specific examples include pulmonary hypertension and related
disorders. Examples of pulmonary hypertension and related disorders
include, but are not limited to: primary pulmonary hypertension
(PPH); secondary pulmonary hypertension (SPH); familial PPH;
sporadic PPH; precapillary pulmonary hypertension; pulmonary
arterial hypertension (PAH); pulmonary artery hypertension;
idiopathic pulmonary hypertension; thrombotic pulmonary
arteriopathy (TPA); plexogenic pulmonary arteriopathy; functional
classes I to IV pulmonary hypertension; and pulmonary hypertension
associated with, related to, or secondary to, left ventricular
dysfunction, mitral valvular disease, constrictive pericarditis,
aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous
pulmonary venous drainage, pulmonary venoocclusive disease,
collagen vasular disease, congenital heart disease, HIV virus
infection, drugs and toxins such as fenfluramines, congenital heart
disease, pulmonary venous hypertension, chronic obstructive
pulmonary disease, interstitial lung disease, sleep-disordered
breathing, alveolar hypoventilation disorder, chronic exposure to
high altitude, neonatal lung disease, alveolar-capillary dysplasia,
sickle cell disease, other coagulation disorder, chronic
thromboemboli, connective tissue disease, lupus including systemic
and cutaneous lupus, schistosomiasis, sarcoidosis or pulmonary
capillary hemangiomatosis.
[0151] Examples of asbestos-related disorders include, but not
limited to, those described in U.S. publication no. 2005/0100529,
published May 12, 2005, which is incorporated herein by reference.
Specific examples include, but are not limited to, mesothelioma,
asbestosis, malignant pleural effusion, benign exudative effusion,
pleural plaques, pleural calcification, diffuse pleural thickening,
rounded atelectasis, fibrotic masses, and lung cancer.
[0152] Examples of parasitic diseases include, but are not limited
to, those described in U.S. publication no. 2006/0154880, published
Jul. 13, 2006, which is incorporated herein by reference. Parasitic
diseases include diseases and disorders caused by human
intracellular parasites such as, but not limited to, P.
falcifarium, P. ovale, P. vivax, P. malariae, L. donovari, L.
infantum, L. aethiopica, L. major, L. tropica, L. mexicana, L.
braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C.
parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S.
haematobium, Trypanosoma ssp., Toxoplasma ssp., and O. volvulus.
Other diseases and disorders caused by non-human intracellular
parasites such as, but not limited to, Babesia bovis, Babesia
canis, Banesia Gibsoni, Besnoitia darlingi, Cytauxzoon felis,
Eimeria ssp., Hammondia ssp., and Theileria ssp., are also
encompassed. Specific examples include, but are not limited to,
malaria, babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis,
meningoencephalitis, keratitis, amebiasis, giardiasis,
cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,
ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,
toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,
filariasis, schistosomiasis, and dermatitis caused by animal
schistosomes.
[0153] Examples of immunodeficiency disorders include, but are not
limited to, those described in U.S. application Ser. No.
11/289,723, filed Nov. 30, 2005. Specific examples include, but not
limited to, adenosine deaminase deficiency, antibody deficiency
with normal or elevated Igs, ataxia-tenlangiectasia, bare
lymphocyte syndrome, common variable immunodeficiency, Ig
deficiency with hyper-IgM, Ig heavy chain deletions, IgA
deficiency, immunodeficiency with thymoma, reticular dysgenesis,
Nezelof syndrome, selective IgG subclass deficiency, transient
hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,
X-linked agammaglobulinemia, X-linked severe combined
immunodeficiency.
[0154] Examples of CNS disorders include, but are not limited to,
those described in U.S. publication no. 2005/0143344, published
Jun. 30, 2005, which is incorporated herein by reference. Specific
examples include, but are not limited to, include, but are not
limited to, Amyotrophic Lateral Sclerosis, Alzheimer Disease,
Parkinson Disease, Huntington's Disease, Multiple Sclerosis other
neuroimmunological disorders such as Tourette Syndrome, delerium,
or disturbances in consciousness that occur over a short period of
time, and amnestic disorder, or discreet memory impairments that
occur in the absence of other central nervous system
impairments.
[0155] Examples of CNS injuries and related syndromes include, but
are not limited to, those described in U.S. publication no.
2006/0122228, published Jun. 8, 2006, which is incorporated herein
by reference. Specific examples include, but are not limited to,
CNS injury/damage and related syndromes, include, but are not
limited to, primary brain injury, secondary brain injury, traumatic
brain injury, focal brain injury, diffuse axonal injury, head
injury, concussion, post-concussion syndrome, cerebral contusion
and laceration, subdural hematoma, epidermal hematoma,
post-traumatic epilepsy, chronic vegetative state, complete SCI,
incomplete SCI, acute SCI, subacute SCI, chronic SCI, central cord
syndrome, Brown-Sequard syndrome, anterior cord syndrome, conus
medullaris syndrome, cauda equina syndrome, neurogenic shock,
spinal shock, altered level of consciousness, headache, nausea,
emesis, memory loss, dizziness, diplopia, blurred vision, emotional
lability, sleep disturbances, irritability, inability to
concentrate, nervousness, behavioral impairment, cognitive deficit,
and seizure.
[0156] Other disease or disorders include, but not limited to,
viral, genetic, allergic, and autoimmune diseases. Specific
examples include, but not limited to, HIV, hepatitis, adult
respiratory distress syndrome, bone resorption diseases, chronic
pulmonary inflammatory diseases, dermatitis, cystic fibrosis,
septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis
syndrome, post ischemic reperfusion injury, meningitis, psoriasis,
fibrotic disease, cachexia, graft versus host disease, graft
rejection, auto-immune disease, rheumatoid spondylitis, Crohn's
disease, ulcerative colitis, inflammatory-bowel disease, multiple
sclerosis, systemic lupus erythrematosus, ENL in leprosy, radiation
damage, cancer, asthma, or hyperoxic alveolar injury.
[0157] Examples of atherosclerosis and related conditions include,
but are not limited to, those disclosed in U.S. publication no.
2002/0054899, published May 9, 2002, which is incorporated herein
by reference. Specific examples include, but are not limited to,
all forms of conditions involving atherosclerosis, including
restenosis after vascular intervention such as angioplasty,
stenting, atherectomy and grafting. All forms of vascular
intervention are contemplated herein, including diseases of the
cardiovascular and renal system, such as, but not limited to, renal
angioplasty, percutaneous coronary intervention (PCI), percutaneous
transluminal coronary angioplasty (PTCA), carotid percutaneous
transluminal angioplasty (PTA), coronary by-pass grafting,
angioplasty with stent implantation, peripheral percutaneous
transluminal intervention of the iliac, femoral or popliteal
arteries, and surgical intervention using impregnated artificial
grafts.
[0158] Examples of dysfunctional sleep and related syndromes
include, but are not limited to, those disclosed in U.S.
publication no. 2005/0222209A1, published Oct. 6, 2005, which is
incorporated herein by reference. Specific examples include, but
are not limited to, snoring, sleep apnea, insomnia, narcolepsy,
restless leg syndrome, sleep terrors, sleep walking sleep eating,
and dysfunctional sleep associated with chronic neurological or
inflammatory conditions. Chronic neurological or inflammatory
conditions, include, but are not limited to, Complex Regional Pain
Syndrome, chronic low back pain, musculoskeletal pain, arthritis,
radiculopathy, pain associated with cancer, fibromyalgia, chronic
fatigue syndrome, visceral pain, bladder pain, chronic
pancreatitis, neuropathies (diabetic, post-herpetic, traumatic or
inflammatory), and neurodegenerative disorders such as Parkinson's
Disease, Alzheimer's Disease, amyotrophic lateral sclerosis,
multiple sclerosis, Huntington's Disease, bradykinesia; muscle
rigidity; parkinsonian tremor; parkinsonian gait; motion freezing;
depression; defective long-term memory, Rubinstein-Taybi syndrome
(RTS); dementia; postural instability; hypokinetic disorders;
synuclein disorders; multiple system atrophies; striatonigral
degeneration; olivopontocerebellar atrophy; Shy-Drager syndrome;
motor neuron disease with parkinsonian features; Lewy body
dementia; Tau pathology disorders; progressive supranuclear palsy;
corticobasal degeneration; frontotemporal dementia; amyloid
pathology disorders; mild cognitive impairment; Alzheimer disease
with parkinsonism; Wilson disease; Hallervorden-Spatz disease;
Chediak-Hagashi disease; SCA-3 spinocerebellar ataxia; X-linked
dystonia parkinsonism; prion disease; hyperkinetic disorders;
chorea; ballismus; dystonia tremors; Amyotrophic Lateral Sclerosis
(ALS); CNS trauma and myoclonus.
[0159] Examples of hemoglobinopathy and related disorders include,
but are not limited to, those described in U.S. publication no.
2005/0143420A1, published Jun. 30, 2005, which is incorporated
herein by reference. Specific examples include, but are not limited
to, hemoglobinopathy, sickle cell anemia, and any other disorders
related to the differentiation of CD34+ cells.
[0160] Examples of TNF.alpha. related disorders include, but are
not limited to, those described in WO 98/03502 and WO 98/54170,
both of which are incorporated herein in their entireties by
reference. Specific examples include, but are not limited to:
endotoxemia or toxic shock syndrome; cachexia; adult respiratory
distress syndrome; bone resorption diseases such as arthritis;
hypercalcemia; Graft versus Host Reaction; cerebral malaria;
inflammation; tumor growth; chronic pulmonary inflammatory
diseases; reperfusion injury; myocardial infarction; stroke;
circulatory shock; rheumatoid arthritis; Crohn's disease; HIV
infection and AIDS; other disorders such as rheumatoid arthritis,
rheumatoid spondylitis, osteoarthritis, psoriatic arthritis and
other arthritic conditions, septic shock, septis, endotoxic shock,
graft versus host disease, wasting, Crohn's disease, ulcerative
colitis, multiple sclerosis, systemic lupus erythromatosis, ENL in
leprosy, HIV, AIDS, and opportunistic infections in AIDS; disorders
such as septic shock, sepsis, endotoxic shock, hemodynamic shock
and sepsis syndrome, post ischemic reperfusion injury, malaria,
mycobacterial infection, meningitis, psoriasis, congestive heart
failure, fibrotic disease, cachexia, graft rej ection, oncogenic or
cancerous conditions, asthma, autoimmune disease, radiation
damages, and hyperoxic alveolar injury; viral infections, such as
those caused by the herpes viruses; viral conjunctivitis; or atopic
dermatitis.
[0161] In other embodiments, the use of Compound A in various
immunological applications, in particular, as vaccine adjuvants,
particularly anticancer vaccine adjuvants, as disclosed in U.S.
Provisional Application No. 60/712,823, filed Sep. 1, 2005, which
is incorporated herein in its entirety by reference, is also
encompassed. These embodiments also relate to the use of Compound A
in combination with vaccines to treat or prevent cancer or
infectious diseases, and other various uses of immunomodulatory
compounds such as reduction or desensitization of allergic
reactions.
[0162] Doses of a solid form of Compound A vary depending on
factors such as: specific indication to be treated, prevented, or
managed; age and condition of a patient; and amount of second
active agent used, if any. Generally, a solid form of Compound A
provided herein may be used in an amount of from about 0.1 mg to
about 500 mg per day, and can be adjusted in a conventional fashion
(e.g., the same amount administered each day of the treatment,
prevention or management period), in cycles (e.g., one week on, one
week off), or in an amount that increases or decreases over the
course of treatment, prevention, or management. In other
embodiments, the dose can be from about 1 mg to about 300 mg, from
about 0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from
about 10 mg to about 100 mg, from about 0.1 mg to about 50 mg, from
about 1 mg to about 50 mg, from about 10 mg to about 50 mg, from
about 20 mg to about 30 mg, or from about 1 mg to about 20 mg.
[0163] A solid form of Compound A provided herein can be combined
with other pharmacologically active compounds ("second active
agents") in methods and compositions provided herein. Certain
combinations may work synergistically in the treatment of
particular types of diseases or disorders, and conditions and
symptoms associated with such diseases or disorders. A solid form
of Compound A provided herein can also work to alleviate adverse
effects associated with certain second active agents, and vice
versa.
[0164] One or more second active ingredients or agents can be used
in the methods and compositions provided herein. Second active
agents can be large molecules (e.g., proteins) or small molecules
(e.g., synthetic inorganic, organometallic, or organic
molecules).
[0165] Examples of large molecule active agents include, but are
not limited to, hematopoietic growth factors, cytokines, and
monoclonal and polyclonal antibodies. Specific examples of the
active agents are anti-CD40 monoclonal antibodies (such as, for
example, SGN-40); histone deacetlyase inhibitors (such as, for
example, SAHA and LAQ 824); heat-shock protein-90 inhibitors (such
as, for example, 17-AAG); insulin-like growth factor-1 receptor
kinase inhibitors; vascular endothelial growth factor receptor
kinase inhibitors (such as, for example, PTK787); insulin growth
factor receptor inhibitors; lysophosphatidic acid acyltransrerase
inhibitors; IkB kinase inhibitors; p38MAPK inhibitors; EGFR
inhibitors (such as, for example, gefitinib and erlotinib HCL);
HER-2 antibodies (such as, for example, trastuzumab
(Herceptin.RTM.) and pertuzumab (Omnitarg.TM.)); VEGFR antibodies
(such as, for example, bevacizumab (Avastin.TM.)); VEGFR inhibitors
(such as, for example, flk-1 specific kinase inhibitors, SU5416 and
ptk787/zk222584); P13K inhibitors (such as, for example,
wortmannin); C-Met inhibitors (such as, for example, PHA-665752);
monoclonal antibodies (such as, for example, rituximab
(Rituxan.RTM.), tositumomab (Bexxar.RTM.), edrecolomab
(Panorex.RTM.) and G250); and anti-TNF-.alpha. antibodies. Examples
of small molecule active agents include, but are not limited to,
anticancer agents and antibiotics (e.g., clarithromycin).
[0166] Specific second active compounds that can be combined with a
solid form of Compound A provided herein vary depending on the
specific indication to be treated, prevented or managed.
[0167] For instance, for the treatment, prevention or management of
cancer, second active agents include, but are not limited to:
semaxanib; cyclosporin; etanercept; doxycycline; bortezomib;
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; amsacrine; anastrozole; anthramycin; asparaginase;
asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;
busulfan; cactinomycin; calusterone; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
cedefingol; celecoxib; chlorambucil; cirolemycin; cisplatin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine;
dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone;
docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene;
droloxifene citrate; dromostanolone propionate; duazomycin;
edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;
enpromate; epipropidine; epirubicin hydrochloride; erbulozole;
esorubicin hydrochloride; estramustine; estramustine phosphate
sodium; etanidazole; etoposide; etoposide phosphate; etoprine;
fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;
fludarabine phosphate; fluorouracil; flurocitabine; fosquidone;
fostriecin sodium; gemcitabine; gemcitabine hydrochloride;
hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;
iproplatin; irinotecan; irinotecan hydrochloride; lanreotide
acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; safingol; safingol hydrochloride; semustine; simtrazene;
sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur;
talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone
hydrochloride; temoporfin; teniposide; teroxirone; testolactone;
thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine;
toremifene citrate; trestolone acetate; triciribine phosphate;
trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole
hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin;
vinblastine sulfate; vincristine sulfate; vindesine; vindesine
sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine
sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine
sulfate; vorozole; zeniplatin; zinostatin; and zorubicin
hydrochloride.
[0168] Other second agents include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorlns;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene;
emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim;
finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imatinib (Gleevec.RTM.),
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
Erbitux, human chorionic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn;
oblimersen (Genasense.RTM.); 06-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;
peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0169] Specific second active agents include, but are not limited
to, 2-methoxyestradiol, telomestatin, inducers of apoptosis in
mutiple myeloma cells (such as, for example, TRAIL), statins,
semaxanib, cyclosporin, etanercept, doxycycline, bortezomib,
oblimersen (Genasense.RTM.), remicade, docetaxel, celecoxib,
melphalan, dexamethasone (Decadron.RTM.), steroids, gemcitabine,
cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar,
carboplatin, procarbazine, gliadel, tamoxifen, topotecan,
methotrexate, Arisa.RTM., taxol, taxotere, fluorouracil,
leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated
interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin,
thiotepa, fludarabine, carboplatin, liposomal daunorubicin,
cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,
dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,
busulphan, prednisone, bisphosphonate, arsenic trioxide,
vincristine, doxorubicin (Doxil.RTM.), paclitaxel, ganciclovir,
adriamycin, estramustine sodium phosphate (Emcyt.RTM.), sulindac,
and etoposide.
[0170] In another embodiment, examples of specific second agents
according to the indications to be treated, prevented, or managed
can be found in the following references, all of which are
incorporated herein in their entireties: U.S. Pat. Nos. 6,281,230
and 5,635,517; U.S. publication nos. 2004/0220144, 2004/0190609,
2004/0087546, 2005/0203142, 2004/0091455, 2005/0100529,
2005/0214328, 2005/0239842, 2006/0154880, 2006/0122228, and
2005/0143344; and U.S. provisional application No. 60/631,870.
[0171] Examples of second active agents that may be used for the
treatment, prevention and/or management of pain include, but are
not limited to, conventional therapeutics used to treat or prevent
pain such as antidepressants, anticonvulsants, antihypertensives,
anxiolytics, calcium channel blockers, muscle relaxants,
non-narcotic analgesics, opioid analgesics, anti-inflammatories,
cox-2 inhibitors, immunomodulatory agents, alpha-adrenergic
receptor agonists or antagonists, immunosuppressive agents,
corticosteroids, hyperbaric oxygen, ketamine, other anesthetic
agents, NMDA antagonists, and other therapeutics found, for
example, in the Physician's Desk Reference 2003. Specific examples
include, but are not limited to, salicylic acid acetate
(Aspirin.RTM.), celecoxib (Celebrex.RTM.), Enbrel.RTM., ketamine,
gabapentin (Neurontin.RTM.), phenytoin (Dilantin.RTM.),
carbamazepine (Tegretol.RTM.), oxcarbazepine (Trileptal.RTM.),
valproic acid (Depakene.RTM.), morphine sulfate, hydromorphone,
prednisone, griseofulvin, penthonium, alendronate, dyphenhydramide,
guanethidine, ketorolac (Acular.RTM.), thyrocalcitonin,
dimethylsulfoxide (DMSO), clonidine (Catapress.RTM.), bretylium,
ketanserin, reserpine, droperidol, atropine, phentolamine,
bupivacaine, lidocaine, acetaminophen, nortriptyline
(Pamelor.RTM.), amitriptyline (Elavil.RTM.), imipramine
(Tofranil.RTM.), doxepin (Sinequan.RTM.), clomipramine
(Anafranil.RTM.), fluoxetine (Prozac.RTM.), sertraline
(Zoloft.RTM.), naproxen, nefazodone (Serzone.RTM.), venlafaxine
(Effexor.RTM.), trazodone (Desyrel.RTM.), bupropion
(Wellbutrin.RTM.), mexiletine, nifedipine, propranolol, tramadol,
lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,
benzodiazepines, baclofen, tizanidine and phenoxybenzamine.
[0172] Examples of second active agents that may be used for the
treatment, prevention and/or management of macular degeneration and
related syndromes include, but are not limited to, a steroid, a
light sensitizer, an integrin, an antioxidant, an interferon, a
xanthine derivative, a growth hormone, a neutrotrophic factor, a
regulator of neovascularization, an anti-VEGF antibody, a
prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory
compound or an antiangiogenesis compound, or a combination thereof.
Specific examples include, but are not limited to, verteporfin,
purlytin, an angiostatic steroid, rhuFab, interferon-2a,
pentoxifylline, tin etiopurpurin, motexafin, lucentis, lutetium,
9-fluoro-11,21-dihydroxy-16,
17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,
latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and its
derivatives, rifamycin and its derivatives, macrolides,
metronidazole (U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein,
genistin, 6'-O-Mal genistin, 6'-O-Ac genistin, daidzein, daidzin,
6'-O-Mal daidzin, 6'-O-Ac daidzin, glycitein, glycitin, 6'-O-Mal
glycitin, biochanin A, formononetin (U.S. Pat. No. 6,001,368),
triamcinolone acetomide, dexamethasone (U.S. Pat. No. 5,770,589),
thalidomide, glutathione (U.S. Pat. No. 5,632,984), basic
fibroblast growth factor (bFGF), transforming growth factor b
(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen
activator factor type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals),
LY333531 (Eli Lilly), Miravant, and RETISERT implant (Bausch &
Lomb). All of the references cited herein are incorporated in their
entireties by reference.
[0173] Examples of second active agents that may be used for the
treatment, prevention and/or management of skin diseases include,
but are not limited to, keratolytics, retinoids, .alpha.-hydroxy
acids, antibiotics, collagen, botulinum toxin, interferon,
steroids, and immunomodulatory agents. Specific examples include,
but are not limited to, 5-fluorouracil, masoprocol, trichloroacetic
acid, salicylic acid, lactic acid, ammonium lactate, urea,
tretinoin, isotretinoin, antibiotics, collagen, botulinum toxin,
interferon, corticosteroid, transretinoic acid and collagens such
as human placental collagen, animal placental collagen, Dermalogen,
AlloDerm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast,
and Isolagen.
[0174] Examples of second active agents that may be used for the
treatment, prevention and/or management of pulmonary hepertension
and related disorders include, but are not limited to,
anticoagulants, diuretics, cardiac glycosides, calcium channel
blockers, vasodilators, prostacyclin analogues, endothelin
antagonists, phosphodiesterase inhibitors (e.g., PDE V inhibitors),
endopeptidase inhibitors, lipid lowering agents, thromboxane
inhibitors, and other therapeutics known to reduce pulmonary artery
pressure. Specific examples include, but are not limited to,
warfarin (Coumadin.RTM.), a diuretic, a cardiac glycoside,
digoxin-oxygen, diltiazem, nifedipine, a vasodilator such as
prostacyclin (e.g., prostaglandin 12 (PGI2), epoprostenol (EPO,
Floran.RTM.), treprostinil (Remodulin.RTM.), nitric oxide (NO),
bosentan (Tracleer.RTM.), amlodipine, epoprostenol (Floran.RTM.),
treprostinil (Remodulin.RTM.), prostacyclin, tadalafil
(Cialis.RTM.), simvastatin (Zocor.RTM.), omapatrilat (Vanlev.RTM.),
irbesartan (Avapro.RTM.), pravastatin (Pravachol.RTM.), digoxin,
L-arginine, iloprost, betaprost, and sildenafil (Viagra.RTM.).
[0175] Examples of second active agents that may be used for the
treatment, prevention and/or management of asbestos-related
disorders include, but are not limited to, anthracycline, platinum,
alkylating agent, oblimersen (Genasense.RTM.), cisplatinum,
cyclophosphamide, temodar, carboplatin, procarbazine, gliadel,
tamoxifen, topotecan, methotrexate, taxotere, irinotecan,
capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,
liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,
vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic
acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate,
arsenic trioxide, vincristine, doxorubicin (Doxil.RTM.),
paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase,
mitomycin C, mepacrine, thiotepa, tetracycline and gemcitabine.
[0176] Examples of second active agents that may be used for the
treatment, prevention and/or management of parasitic diseases
include, but are not limited to, chloroquine, quinine, quinidine,
pyrimethamine, sulfadiazine, doxycycline, clindamycin, mefloquine,
halofantrine, primaquine, hydroxychloroquine, proguanil,
atovaquone, azithromycin, suramin, pentamidine, melarsoprol,
nifurtimox, benznidazole, amphotericin B, pentavalent antimony
compounds (e.g., sodium stiboglucuronate), interfereon gamma,
itraconazole, a combination of dead promastigotes and BCG,
leucovorin, corticosteroids, sulfonamide, spiramycin, IgG
(serology), trimethoprim, and sulfamethoxazole.
[0177] Examples of second active agents that may be used for the
treatment, prevention and/or management of immunodeficiency
disorders include, but are not limited to: antibiotics (therapeutic
or prophylactic) such as, but not limited to, ampicillin,
tetracycline, penicillin, cephalosporins, streptomycin, kanamycin,
and erythromycin; antivirals such as, but not limited to,
amantadine, rimantadine, acyclovir, and ribavirin; immunoglobulin;
plasma; immunologic enhancing drugs such as, but not limited to,
levami sole and isoprinosine; biologics such as, but not limited
to, gammaglobulin, transfer factor, interleukins, and interferons;
hormones such as, but not limited to, thymic; and other immunologic
agents such as, but not limited to, B cell stimulators (e.g.,
BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growth factors
(e.g., TGF-.alpha.), antibodies (e.g., anti-CD40 and IgM),
oligonucleotides containing unmethylated CpG motifs, and vaccines
(e.g., viral and tumor peptide vaccines).
[0178] Examples of second active agents that may be used for the
treatment, prevention and/or management of CNS disorders include,
but are not limited to: opioids; a dopamine agonist or antagonist,
such as, but not limited to, Levodopa, L-DOPA, cocaine,
.alpha.-methyl-tyrosine, reserpine, tetrabenazine, benzotropine,
pargyline, fenodolpam mesylate, cabergoline, pramipexole
dihydrochloride, ropinorole, amantadine hydrochloride, selegiline
hydrochloride, carbidopa, pergolide mesylate, Sinemet CR, and
Symmetrel; a MAO inhibitor, such as, but not limited to,
iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT
inhibitor, such as, but not limited to, tolcapone and entacapone; a
cholinesterase inhibitor, such as, but not limited to,
physostigmine saliclate, physostigmine sulfate, physostigmine
bromide, meostigmine bromide, neostigmine methylsulfate, ambenonim
chloride, edrophonium chloride, tacrine, pralidoxime chloride,
obidoxime chloride, trimedoxime bromide, diacetyl monoxim,
endrophonium, pyridostigmine, and demecarium; an anti-inflammatory
agent, such as, but not limited to, naproxen sodium, diclofenac
sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,
diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,
refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts,
Rho-D Immune Globulin, mycophenylate mofetil, cyclosporine,
azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid,
acetylsalicylic acid, methyl salicylate, diflunisal, salsalate,
olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac,
mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,
dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,
ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,
oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,
aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,
colchicine, allopurinol, probenecid, sulfinpyrazone and
benzbromarone or betamethasone and other glucocorticoids; and an
antiemetic agent, such as, but not limited to, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine,
acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride,
cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,
scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and a mixture thereof.
[0179] Examples of second active agents that may be used for the
treatment, prevention and/or management of CNS injuries and related
syndromes include, but are not limited to, immunomodulatory agents,
immunosuppressive agents, antihypertensives, anticonvulsants,
fibrinolytic agents, antiplatelet agents, antipsychotics,
antidepressants, benzodiazepines, buspirone, amantadine, and other
known or conventional agents used in patients with CNS
injury/damage and related syndromes. Specific examples include, but
are not limited to: steroids (e.g., glucocorticoids, such as, but
not limited to, methylprednisolone, dexamethasone and
betamethasone); an anti-inflammatory agent, including, but not
limited to, naproxen sodium, diclofenac sodium, diclofenac
potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac,
meloxicam, ibuprofen, ketoprofen, nabumetone, refecoxib,
methotrexate, leflunomide, sulfasalazine, gold salts, RHo-D Immune
Globulin, mycophenylate mofetil, cyclosporine, azathioprine,
tacrolimus, basiliximab, daclizumab, salicylic acid,
acetylsalicylic acid, methyl salicylate, diflunisal, ssalalate,
olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac,
mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,
dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,
ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,
oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,
aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,
colchicine, allopurinol, probenecid, sulfinpyrazone and
benzbromarone; a cAMP analog including, but not limited to,
db-cAMP; an agent comprising a methylphenidate drug, which
comprises 1-threo-methylphenidate, d-threo-methylphenidate,
dl-threo-methylphenidate, l-erythro-methylphenidate,
d-erythro-methylphenidate, dl-erythro-methylphenidate, and a
mixture thereof; and a diuretic agent such as, but not limited to,
mannitol, furosemide, glycerol, and urea.
[0180] Examples of second active agent that may be used for the
treatment, prevention and/or management of dysfunctional sleep and
related syndromes include, but are not limited to, a tricyclic
antidepressant agent, a selective serotonin reuptake inhibitor, an
antiepileptic agent (gabapentin, pregabalin, carbamazepine,
oxcarbazepine, levitiracetam, topiramate), an antiaryhthmic agent,
a sodium channel blocking agent, a selective inflammatory mediator
inhibitor, an opioid agent, a second immunomodulatory compound, a
combination agent, and other known or conventional agents used in
sleep therapy. Specific examples include, but are not limited to,
Neurontin, oxycontin, morphine, topiramate, amitryptiline,
nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,
.alpha.-methyl-tyrosine, reserpine, tetrabenazine, benzotropine,
pargyline, fenodolpam mesylate, cabergoline, pramipexole
dihydrochloride, ropinorole, amantadine hydrochloride, selegiline
hydrochloride, carbidopa, pergolide mesylate, Sinemet CR,
Symmetrel, iproniazid, clorgyline, phenelzine, isocarboxazid,
tolcapone, entacapone, physostigmine saliclate, physostigmine
sulfate, physostigmine bromide, meostigmine bromide, neostigmine
methylsulfate, ambenonim chloride, edrophonium chloride, tacrine,
pralidoxime chloride, obidoxime chloride, trimedoxime bromide,
diacetyl monoxim, endrophonium, pyridostigmine, demecarium,
naproxen sodium, diclofenac sodium, diclofenac potassium,
celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,
ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate,
leflunomide, sulfasalazine, gold salts, RHo-D Immune Globulin,
mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus,
basiliximab, daclizumab, salicylic acid, acetylsalicylic acid,
methyl salicylate, diflunisal, salsalate, olsalazine,
sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic
acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac,
flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam,
droxicam, pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone,
antipyrine, aminopyrine, apazone, zileuton, aurothioglucose, gold
sodium thiomalate, auranofin, methotrexate, colchicine,
allopurinol, probenecid, sulfinpyrazone, benzbromarone,
betamethasone and other glucocorticoids, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine,
acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride,
cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,
scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and a mixture thereof.
[0181] Examples of second active agents that may be used for the
treatment, prevention and/or management of hemoglobinopathy and
related disorders include, but are not limited to: interleukins,
such as IL-2 (including recombinant IL-II ("rIL2") and canarypox
IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon
alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon
alfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF;
hydroxyurea; butyrates or butyrate derivatives; nitrous oxide;
hydroxy urea; HEMOXIN.TM. (NIPRISAN.TM.; see U.S. Pat. No.
5,800,819); Gardos channel antagonists such as clotrimazole and
triaryl methane derivatives; Deferoxamine; protein C; and
transfusions of blood, or of a blood substitute such as
Hemospan.TM. or Hemospan.TM. PS (Sangart).
[0182] Administration of a solid form of Compound A provided herein
and the second active agents to a patient can occur simultaneously
or sequentially by the same or different routes of administration.
The suitability of a particular route of administration employed
for a particular active agent will depend on the active agent
itself (e.g., whether it can be administered orally without
decomposing prior to entering the blood stream) and the disease
being treated. One of administration for a solid form of Compound A
provided herein is oral. Routes of administration for the second
active agents or ingredients are known to those of ordinary skill
in the art. See, e.g., Physicians' Desk Reference (60.sup.th ed.,
2006).
[0183] In one embodiment, the second active agent is administered
intravenously or subcutaneously and once or twice daily in an
amount of from about 1 to about 1000 mg, from about 5 to about 500
mg, from about 10 to about 350 mg, or from about 50 to about 200
mg. The specific amount of the second active agent will depend on
the specific agent used, the type of disease being treated or
managed, the severity and stage of disease, and the amount(s) of
compounds provided herein and any optional additional active agents
concurrently administered to the patient.
[0184] As discussed elsewhere herein, also encompassed is a method
of reducing, treating and/or preventing adverse or undesired
effects associated with conventional therapy including, but not
limited to, surgery, chemotherapy, radiation therapy, hormonal
therapy, biological therapy and immunotherapy. Compounds provided
herein and other active ingredients can be administered to a
patient prior to, during, or after the occurrence of the adverse
effect associated with conventional therapy.
[0185] In certain embodiments, the prophylactic or therapeutic
agents provided herein are cyclically administered to a patient.
Cycling therapy involves the administration of an active agent for
a period of time, followed by a rest (i.e., discontinuation of the
administration) for a period of time, and repeating this sequential
administration. Cycling therapy can reduce the development of
resistance to one or more of the therapies, avoid or reduce the
side effects of one of the therapies, and/or improve the efficacy
of the treatment.
[0186] Consequently, in one embodiment, a solid form of Compound A
provided herein is administered daily in a single or divided doses
in a four to six week cycle with a rest period of about a week or
two weeks. Cycling therapy further allows the frequency, number,
and length of dosing cycles to be increased. Thus, another
embodiment encompasses the administration of a compound provided
herein for more cycles than are typical when it is administered
alone. In yet another embodiment, a compound provided herein is
administered for a greater number of cycles than would typically
cause dose-limiting toxicity in a patient to whom a second active
ingredient is not also being administered.
[0187] In one embodiment, a solid form of Compound A provided
herein is administered daily and continuously for three or four
weeks at a dose of from about 0.1 mg to about 500 mg per day,
followed by a rest of one or two weeks. In other embodiments, the
dose can be from about 1 mg to about 300 mg, from about 0.1 mg to
about 150 mg, from about 1 mg to about 200 mg, from about 10 mg to
about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to
about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to
about 30 mg, or from about 1 mg to about 20 mg, followed by a
rest.
[0188] In one embodiment, a solid form of Compound A provided
herein and a second active ingredient are administered orally, with
administration of the compound provided herein occurring 30 to 60
minutes prior to the second active ingredient, during a cycle of
four to six weeks. In another embodiment, the combination of a
compound provided herein and a second active ingredient is
administered by intravenous infusion over about 90 minutes every
cycle.
[0189] Typically, the number of cycles during which the combination
treatment is administered to a patient will be from about one to
about 24 cycles, from about two to about 16 cycles, or from about
four to about three cycles.
[0190] 4.3. Pharmaceutical Compositions
[0191] Pharmaceutical compositions and single unit dosage forms
comprising one or more solid forms comprising Compound A are
provided herein. Also provided herein are methods for preparing
pharmaceutical compositions and single unit dosage forms comprising
one or more solid forms comprising Compound A. For example, in
certain embodiments, individual dosage forms comprising a solid
form provided herein or prepared using solid form provided herein
may be suitable for oral, mucosal (including rectal, nasal, or
vaginal), parenteral (including subcutaneous, intramuscular, bolus
injection, intraarterial, or intravenous), sublingual, transdermal,
buccal, or topical administration.
[0192] In certain embodiments, pharmaceutical compositions and
dosage forms provided herein comprise one or more solid forms
comprising Compound A. Certain embodiments herein provide
pharmaceutical compositions and dosage forms comprising a solid
form comprising Compound A, such as, e.g., Forms A, B, C, D, E, F
or an amorphous solid form comprising Compound A as provided
herein, or Form A1 or an amorphous solid form comprising Compound A
hydrochloride as provided herein, wherein the solid form comprising
Compound A substantially pure. Certain embodiments herein provide
pharmaceutical compositions and dosage forms comprising a solid
form comprising Compound A, such as, e.g., Forms A, B, C, D, E, F,
or an amorphous solid form comprising Compound A as provided
herein, or Form A1 or an amorphous solid form comprising Compound A
hydrochloride as provided herein, which is substantially free of
other solid forms comprising Compound A including, e.g., Forms A,
B, C, D, E, F, and/or an amorphous solid form comprising Compound A
as provided herein, and Form A1 and/or an amorphous solid form
comprising Compound A hydrochloride as provided herein. Certain
embodiments herein provide pharmaceutical compositions and dosage
forms comprising a mixture of solid forms comprising Compound A,
including, e.g., a mixture comprising one or more of the following:
Forms A, B, C, D, E, F, and an amorphous solid form comprising
Compound A as provided herein, and Form A1 and an amorphous solid
form comprising Compound A hydrochloride as provided herein.
Pharmaceutical compositions and dosage forms provided herein
typically also comprise one or more pharmaceutically acceptable
excipient, diluent or carrier.
[0193] A particular pharmaceutical composition encompassed by this
embodiment comprises one or more solid forms comprising Compound A
and at least one additional therapeutic agent. Examples of
additional therapeutic agents include, but are not limited to:
anti-cancer drugs and anti-inflammation therapies including, but
not limited to, those provided herein.
[0194] Single unit dosage forms of the disclosure are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), or transdermal
administration to a patient. Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as soft
elastic gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders;
dressings; creams; plasters; solutions; patches; aerosols (e.g.,
nasal sprays or inhalers); gels; liquid dosage forms suitable for
oral or mucosal administration to a patient, including suspensions
(e.g., aqueous or non-aqueous liquid suspensions, oil-in-water
emulsions, or a water-in-oil liquid emulsions), solutions, and
elixirs; liquid dosage forms suitable for parenteral administration
to a patient; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0195] The composition, shape, and type of dosage forms of the
disclosure will typically vary depending on their use. For example,
a dosage form used in the acute treatment of inflammation or a
related disorder may contain larger amounts of one or more of the
active ingredients it comprises than a dosage form used in the
chronic treatment of the same disease. Similarly, a parenteral
dosage form may contain smaller amounts of one or more of the
active ingredients it comprises than an oral dosage form used to
treat the same disease or disorder. These and other ways in which
specific dosage forms encompassed by this disclosure will vary from
one another will be readily apparent to those skilled in the art.
See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing, Easton Pa. (1990).
[0196] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms. The suitability of a particular
excipient may also depend on the specific active ingredients in the
dosage form.
[0197] Lactose-free compositions of the disclosure can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In
general, lactose-free compositions comprise an active ingredient, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise an active ingredient, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0198] This disclosure further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the
decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0199] Anhydrous pharmaceutical compositions and dosage forms of
the disclosure can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0200] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0201] The disclosure further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0202] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms provided herein lie within the range of from about 1 mg to
about 1,000 mg per day, given as a single once-a-day dose in the
morning but preferably as divided doses throughout the day. More
specifically, the daily dose is administered twice daily in equally
divided doses. Specifically, a daily dose range may be from about 5
mg to about 500 mg per day, more specifically, between about 10 mg
and about 200 mg per day. In managing the patient, the therapy may
be initiated at a lower dose, perhaps about 1 mg to about 25 mg,
and increased if necessary up to about 200 mg to about 1,000 mg per
day as either a single dose or divided doses, depending on the
patient's global response.
[0203] 4.3.1. Oral Dosage Forms
[0204] Pharmaceutical compositions of the disclosure that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0205] Typical oral dosage forms of the disclosure are prepared by
combining the active ingredient(s) in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0206] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0207] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0208] Examples of excipients that can be used in oral dosage forms
of the disclosure include, but are not limited to, binders,
fillers, disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0209] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the disclosure is typically present in from about
50 to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0210] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101.TM.,
AVICEL-PH-103.TM., AVICEL RC-581.TM., AVICEL-PH-105.TM. (available
from FMC Corporation, American Viscose Division, Avicel Sales,
Marcus Hook, Pa.), and mixtures thereof. A specific binder is a
mixture of microcrystalline cellulose and sodium carboxymethyl
cellulose sold as AVICEL RC-581.TM.. Suitable anhydrous or low
moisture excipients or additives include AVICEL-PH-103.TM. and
Starch 1500 LM.TM..
[0211] Disintegrants are used in the compositions of the disclosure
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
disclosure. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
specifically from about 1 to about 5 weight percent of
disintegrant.
[0212] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the disclosure include, but are
not limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, pre-gelatinized starch, other starches, clays, other
algins, other celluloses, gums, and mixtures thereof.
[0213] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the disclosure include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200.TM., manufactured by W.R. Grace Co. of Baltimore,
Md.), a coagulated aerosol of synthetic silica (marketed by Degussa
Co. of Plano, Tex.), CAB-O-SIL.TM. (a pyrogenic silicon dioxide
product sold by Cabot Co. of Boston, Mass.), and mixtures thereof.
If used at all, lubricants are typically used in an amount of less
than about one weight percent of the pharmaceutical compositions or
dosage forms into which they are incorporated.
[0214] 4.3.2. Delayed Release Dosage Forms
[0215] Solid forms comprising Compound A as provided herein can be
administered by controlled release means or by delivery devices
that are well known to those of ordinary skill in the art. Examples
include, but are not limited to, those described in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos.
4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543,
5,639,476, 5,354,556, and 5,733,566, each of which is incorporated
herein by reference. Such dosage forms can be used to provide slow
or controlled-release of one or more active ingredients using, for
example, hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the disclosure. The
disclosure thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0216] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0217] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0218] 4.3.3. Parenteral Dosage Forms
[0219] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0220] Suitable vehicles that can be used to provide parenteral
dosage forms of the disclosure are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0221] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the disclosure.
[0222] 4.3.4. Transdermal, Topical, and Mucosal Dosage Forms
[0223] Transdermal, topical, and mucosal dosage forms of the
disclosure include, but are not limited to, ophthalmic solutions,
sprays, aerosols, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th
eds., Mack Publishing, Easton Pa. (1980 & 1990); and
Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea &
Febiger, Philadelphia (1985). Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels. Further, transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active
ingredients.
[0224] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this disclosure are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied. With that fact in mind, typical
excipients include, but are not limited to, water, acetone,
ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures
thereof to form lotions, tinctures, creams, emulsions, gels or
ointments, which are non-toxic and pharmaceutically acceptable.
Moisturizers or humectants can also be added to pharmaceutical
compositions and dosage forms if desired. Examples of such
additional ingredients are well known in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990).
[0225] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the disclosure. For
example, penetration enhancers can be used to assist in delivering
the active ingredients to the tissue. Suitable penetration
enhancers include, but are not limited to: acetone; various
alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl
sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl
formamide; polyethylene glycol; pyrrolidones such as
polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea;
and various water-soluble or insoluble sugar esters such as Tween
80.TM. (polysorbate 80) and Span 60.TM. (sorbitan
monostearate).
[0226] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different solid forms comprising the
active ingredients can be used to further adjust the properties of
the resulting composition.
[0227] 4.3.5. Kits
[0228] This disclosure encompasses kits which, when used by the
medical practitioner, can simplify the administration of
appropriate amounts of active ingredients to a patient.
[0229] A typical kit of the disclosure comprises a unit dosage form
of compound A, or a pharmaceutically acceptable solid form or
prodrug thereof, and a unit dosage form of a second active
ingredient. Examples of second active ingredients include, but are
not limited to, those listed herein.
[0230] Kits of the disclosure can further comprise devices that are
used to administer the active ingredient(s). Examples of such
devices include, but are not limited to, syringes, drip bags,
patches, and inhalers.
[0231] Kits of the disclosure can further comprise pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous
vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
5. EXAMPLES
5.1. Example 1: Assays
5.1.1. TNF.alpha. Inhibition Assay in PMBC
[0232] Peripheral blood mononuclear cells (PBMC) from normal donors
are obtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA)
density centrifugation. Cells are cultured in RPMI 1640 (Life
Technologies, Grand Island, N.Y., USA) supplemented with 10%
AB+human serum (Gemini Bio-products, Woodland, Calif., USA), 2 mM
L-glutamine, 100 U/mL penicillin, and 100 .mu.g/mL streptomycin
(Life Technologies).
[0233] PBMC (2.times.10.sup.5 cells) are plated in 96-well
flat-bottom Costar tissue culture plates (Corning, N.Y., USA) in
triplicate. Cells are stimulated with LPS (from Salmonella abortus
equi, Sigma cat. no. L-1887, St. Louis, Mo., USA) at 1 ng/mL final
in the absence or presence of compounds. Compounds provided herein
are dissolved in DMSO (Sigma) and further dilutions are done in
culture medium immediately before use. The final DMSO concentration
in all assays can be about 0.25%. Compounds are added to cells 1
hour before LPS stimulation. Cells are then incubated for 18-20
hours at 37.degree. C. in 5% CO.sub.2, and supernatants are then
collected, diluted with culture medium and assayed for TNF.alpha.
levels by ELISA (Endogen, Boston, Mass., USA). IC.sub.50s are
calculated using non-linear regression, sigmoidal dose-response,
constraining the top to 100% and bottom to 0%, allowing variable
slope (GraphPad Prism v3.02). In two experiments, Compound A
demonstrated an IC.sub.50 of 10 and 85 nM.
[0234] 5.1.2. IL-2 and MIP-3A Production by T Cells
[0235] PBMC are depleted of adherent monocytes by placing
1.times.10.sup.8 PBMC in 10 mL complete medium (RPMI 1640
supplemented with 10% heat-inactivated fetal bovine serum, 2 mM
L-glutamine, 100 U/mL penicillin, and 100 .mu.g/mL streptomycin)
per 10 cm tissue culture dish, in 37.degree. C., 5% CO.sub.2
incubator for 30-60 minutes. The dish is rinsed with medium to
remove all non-adherent PBMC. T cells are purified by negative
selection using the following antibody (Pharmingen) and Dynabead
(Dynal) mixture for every 1.times.10.sup.8 non-adherent PBMC: 0.3
mL Sheep anti-mouse IgG beads, 15 .mu.L anti-CD16, 15 .mu.L
anti-CD33, 15 .mu.L anti-CD56, 0.23 mL anti-CD19 beads, 0.23 mL
anti-HLA class II beads, and 56 .mu.L anti-CD14 beads. The cells
and bead/antibody mixture is rotated end-over-end for 30-60 minutes
at 4.degree. C. Purified T cells are removed from beads using a
Dynal magnet. Typical yield is about 50% T cells, 87-95% CD3.sup.+
by flow cytometry.
[0236] Tissue culture 96-well flat-bottom plates are coated with
anti-CD3 antibody OKT3 at 5 .mu.g/mL in PBS, 100 .mu.L per well,
incubated at 37.degree. C. for 3-6 hours, then washed four times
with complete medium 100 .mu.L/well just before T cells are added.
Compounds are diluted to 20 times of final in a round bottom tissue
culture 96-well plate. Final concentrations are about 10 .mu.M to
about 0.00064 .mu.M. A 10 mM stock of compounds provided herein is
diluted 1:50 in complete for the first 20.times. dilution of 200
.mu.M in 2% DMSO and serially diluted 1:5 into 2% DMSO. Compound is
added at 10 al per 200 .mu.l culture, to give a final DMSO
concentration of 0.1%. Cultures are incubated at 37.degree. C., 5%
CO.sub.2 for 2-3 days, and supernatants analyzed for IL-2 and
MIP-3.alpha. by ELISA (R&D Systems). IL-2 and MIP-3.alpha.
levels are normalized to the amount produced in the presence of an
amount of a compound provided herein, and EC.sub.50s calculated
using non-linear regression, sigmoidal dose-response, constraining
the top to 100% and bottom to 0%, allowing variable slope (GraphPad
Prism v3.02).
[0237] 5.1.3. Cell Proliferation Assay
[0238] Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the
Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
(Braunschweig, Germany). The cell line KG-1 is obtained from the
American Type Culture Collection (Manassas, Va., USA). Cell
proliferation as indicated by .sup.3H-thymidine incorporation is
measured in all cell lines as follows.
[0239] Cells are plated in 96-well plates at 6000 cells per well in
media. The cells are pre-treated with compounds at about 100, 10,
1, 0.1, 0.01, 0.001, 0.0001 and 0 .mu.M in a final concentration of
about 0.25% DMSO in triplicate at 37.degree. C. in a humidified
incubator at 5% CO.sub.2 for 72 hours. One microcurie of
.sup.3H-thymidine (Amersham) is then added to each well, and cells
are incubated again at 37.degree. C. in a humidified incubator at
5% CO.sub.2 for 6 hours. The cells are harvested onto UniFilter
GF/C filter plates (Perkin Elmer) using a cell harvester (Tomtec),
and the plates are allowed to dry overnight. Microscint 20
(Packard) (25 .mu.L/well) is added, and plates are analyzed in
TopCount NXT (Packard). Each well is counted for one minute.
Percent inhibition of cell proliferation is calculated by averaging
all triplicates and normalizing to the DMSO control (0%
inhibition). Each compound is tested in each cell line in three
separate experiments. Final IC.sub.50s are calculated using
non-linear regression, sigmoidal dose-response, constraining the
top to 100% and bottom to 0%, allowing variable slope. (GraphPad
Prism v3.02).
[0240] 5.1.4. Immunoprecipitation and Immunoblot
[0241] Namalwa cells are treated with DMSO or an amount of a
compound provided herein for 1 hour, then stimulated with 10 U/mL
of Epo (R&D Systems) for 30 minutes. Cell lysates are prepared
and either immunoprecipitated with Epo receptor Ab or separated
immediately by SDS-PAGE. Immunoblots are probed with Akt,
phospo-Akt (Ser473 or Thr308), phospho-Gabl (Y627), Gabl, IRS2,
actin and IRF-1 Abs and analyzed on a Storm 860 Imager using
ImageQuant software (Molecular Dynamics).
[0242] 5.1.5. Cell Cycle Analysis
[0243] Cells are treated with DMSO or an amount of a compound
provided herein overnight. Propidium iodide staining for cell cycle
is performed using CycleTEST PLUS (Becton Dickinson) according to
manufacturer's protocol. Following staining, cells are analyzed by
a FACSCalibur flow cytometer using ModFit LT software (Becton
Dickinson).
[0244] 5.1.6. Apoptosis Analysis
[0245] Cells are treated with DMSO or an amount of a compound
provided herein at various time points, then washed with annexin-V
wash buffer (BD Biosciences). Cells are incubated with annexin-V
binding protein and propidium iodide (BD Biosciences) for 10
minutes. Samples are analyzed using flow cytometry.
[0246] 5.1.7. Luciferase Assay
[0247] Namalwa cells are transfected with 4 .mu.g of AP1-luciferase
(Stratagene) per 1.times.10.sup.6 cells and 3 .mu.L Lipofectamine
2000 (Invitrogen) reagent according to manufacturer's instructions.
Six hours post-transfection, cells are treated with DMSO or an
amount of a compound provided herein. Luciferase activity is
assayed using luciferase lysis buffer and substrate (Promega) and
measured using a luminometer (Turner Designs).
5.2. Example 2: Preparation of
3-(5-Amino-2-Methyl-4-Oxo-4H-Quinazolin-3-Yl)-Piperidine-2,6-Dione
(Compound A)
##STR00002##
[0249] Step 1: To a solution of potassium hydroxide (16.1 g, 286
mmol) in water (500 mL), was added 3-nitrophthalimide (25.0 g, 130
mmol) in portion at 0.degree. C. The suspension was stirred at
0.degree. C. for 3 hrs, and then heated to 30.degree. C. for 3 hrs.
To the solution, was added HCl (100 mL, 6N). The resulting
suspension was cooled to 0.degree. C. for 1 hr. The suspension was
filtered and washed with cold water (2.times.10 mL) to give
3-nitro-phthalamic acid as a white solid (24.6 g, 90% yield):
.sup.1H NMR (DMSO-d.sub.6) .delta. 7.69 (brs, 1H, NHH), 7.74 (t,
J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13 (dd, J=1, 8 Hz,
1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 125.33, 129.15, 130.25, 132.54, 136.72,
147.03, 165.90, 167.31.
[0250] Step 2: To a mixture of 3-nitro-phthalamic acid (24.6 g, 117
mmol) and potassium hydroxide (6.56 g, 117 mmol) in water (118 mL),
was added a mixture of bromine (6 mL), potassium hydroxide (13.2 g,
234 mmol) in water (240 mL) at 0.degree. C., followed by addition
of a solution of potassium hydroxide (19.8 g, 351 mmol) in water
(350 mL). After 5 minutes at 0.degree. C., the mixture was heated
in a 100.degree. C. oil bath for 1 hr. The reaction solution was
cooled to room temperature, and then, in an ice-water bath for 30
minutes. To the mixture, a solution of HCl (240 mL, 2N) was added
dropwise at 0.degree. C., and the resulting mixture was kept for 1
hr. The suspension was filtered and washed with water (5 mL) to
give 2-amino-6-nitro-benzoic acid as yellow solid (15.6 g, 73%
yield): HPLC: Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm,
1 mL/min, 240 nm, CH.sub.3CN/0.1% H.sub.3PO.sub.4, 5% grad to 95%
over 5 min, 5.83 min (85%); .sup.1H NMR (DMSO-d.sub.6) .delta. 6.90
(dd, J=1, 8 Hz, 1H, Ar), 7.01 (dd, J=1, 9 Hz, 1H, Ar), 7.31 (t, J=8
Hz, 1H, Ar), 8.5-9.5 (brs, 3H, OH, NH.sub.2); .sup.13C NMR
(DMSO-d.sub.6) .delta. 105.58, 110.14, 120.07, 131.74, 149.80,
151.36, 166.30; LCMS: MH=183.
[0251] Step 3: A mixture of 2-amino-6-nitro-benzoic acid (1.5 g,
8.2 mmol) in acetic anhydride (15 mL) was heated at 200.degree. C.
for 30 minutes in a microwave oven. The mixture was filtered and
washed with ethyl acetate (20 mL). The filtrate was concentrated in
vacuo. The solid was stirred in ether (20 mL) for 2 hrs. The
suspension was filtered and washed with ether (20 mL) to give
2-methyl-5-nitro-benzo[d][1,3]oxazin-4-one as a light brown solid
(1.4 g, 85% yield): HPLC: Waters Symmetry C.sub.18, 5 .mu.m,
3.9.times.150 mm, 1 mL/min, 240 nm, CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 5% grad 95% in 5 min, 5.36 min (92%); .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.42 (s, 3H, CH.sub.3), 7.79 (dd, J=1, 8 Hz,
1H, Ar), 7.93 (dd, J=1, 8 Hz, 1H, Ar), 8.06 (t, J=8 Hz, 1H, Ar);
.sup.13C NMR (DMSO-d.sub.6) .delta. 20.87, 107.79, 121.54, 128.87,
137.19, 147.12, 148.46, 155.18, 161.78; LCMS: MH=207.
[0252] Step 4: Two vials each with a suspension of
5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one (0.60 g, 2.91 mmol) and
3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol)
in pyridine (15 mL) were heated at 170.degree. C. for 10 minutes in
a microwave oven. The suspension was filtered and washed with
pyridine (5 mL). The filtrate was concentrated in vacuo. The
resulting mixture was stirred in HCl (30 mL, 1N), ethyl acetate (15
mL) and ether (15 mL) for 2 hrs. The suspension was filtered and
washed with water (30 mL) and ethyl acetate (30 mL) to give a dark
brown solid, which was stirred with methanol (50 mL) at room
temperature overnight. The suspension was filtered and washed with
methanol to give
3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a black solid (490 mg, 27% yield). The solid was used in the
next step without further purification.
[0253] Step 5: A mixture of
3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
(250 mg) and Pd(OH).sub.2 on carbon (110 mg) in DMF (40 mL) was
shaken under hydrogen (50 psi) for 12 hrs. The suspension was
filtered through a pad of Celite and washed with DMF (10 mL). The
filtrate was concentrated in vacuo and the resulting oil was
purified by flash column chromatography (silica gel,
methanol/methylene chloride) to give
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (156 mg, 69% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 10/90
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 3.52 min (99.9%); mp:
293-295.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.10-2.17
(m, 1H, CHH), 2.53 (s, 3H, CH.sub.3), 2.59-2.69 (m, 2H, CH.sub.2),
2.76-2.89 (m, 1H, CHH), 5.14 (dd, J=6, 11 Hz, 1H, NCH), 6.56 (d,
J=8 Hz, 1H, Ar), 6.59 (d, J=8 Hz, 1H, Ar), 7.02 (s, 2H, NH.sub.2),
7.36 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.98, 23.14, 30.52, 55.92, 104.15, 110.48,
111.37, 134.92, 148.17, 150.55, 153.62, 162.59, 169.65, 172.57;
LCMS: MH=287; Anal. Calcd. for
C.sub.14H.sub.14N.sub.4O.sub.3+0.3H.sub.2O: C, 57.65; H, 5.05; N,
19.21. Found: C, 57.50; H, 4.73; N, 19.00.
5.3. Example 3: Preparation of Compound A Hydrochloride
[0254] In a stirred glass flask, approximately 19 g of Compound A
(freebase) was suspended in approximately 200 mL acetonitrile and
200 mL water. Approximately 5 mL 12 N hydrochloric acid was added,
and the suspension was dissolved by heating above 55.degree. C. The
solution was cooled to approx 45.degree. C. and seed crystals of
Compound A Form A1 (e.g. Hydrochloride) were added to the flask.
Then 6 N hydrochloric acid was added dropwise causing further
crystallization. The slurry was slowly cooled. The slurry was then
filtered and the cake was washed with acetonitrile. The product was
then dried in a vacuum oven. The resulting dry product was
consistent with Compound A Form A1.
5.4. Example 4: Solid Form Screening Studies
5.4.1. Experimental Methodology
[0255] The methods described herein are illustrated with Compound A
hydrochloride. These methods can be used directly or with some
modification for other solids forms of Compound A as described
herein.
[0256] Solubility: A weighed sample of Compound A hydrochloride
(about 50 mg) was treated with a known volume of a test solvent.
The solvents used were either reagent or HPLC grade. The resulting
mixture was agitated for at least 24 hours at about 25.degree. C.
If all of the solids appeared to be dissolved by visual inspection,
the estimated solubilities were calculated based on the total
volume of solvent used to give a complete solution. The actual
solubilities may be greater than those calculated due to the use of
large amount of solvent or to a slow rate of dissolution. If solids
were present, the solubility was measured gravimetrically. A known
volume of filtrate was evaporated to dryness and the weight of the
residue was measured.
[0257] Equilibration/Slurry and Evaporation: Equilibration and
evaporation experiments were carried out by adding an excess of
Compound A hydrochloride to about 2 mL of a test solvent. The
resulting mixture was agitated for at least 24 hrs at about
25.degree. C. or about 50.degree. C. Upon reaching equilibrium, the
saturated solution was removed and allowed to evaporate slowly in
an open vial under nitrogen at about 25.degree. C. and about
50.degree. C., respectively. The solids resulting from the
equilibration were filtered and dried in the air.
[0258] Cooling Recrystallization: The selected solvents (THF/water,
MeCN/water, MeOH/O. 1N HCl, and EtOH/0.1N HCl) were saturated with
Compound A hydrochloride at about 50-70.degree. C. Once the solids
were completely dissolved, the solution was rapidly cooled by
placing into a refrigerator (about 0-5.degree. C.). Solids were
isolated after 1 to 3 days.
[0259] Solvent/Anti-Solvent Recrystallization: The selected solvent
(MeCN/water) was saturated with Compound A hydrochloride at room
temperature. Once the solids were completely dissolved, an
anti-solvent (acetone or IPA) was added into the solution. The
mixture was stirred at room temperature overnight. If no
precipitation occurred, the vial was further cooled by placing into
a refrigerator (about 0-5.degree. C.). The solids resulting from
the recrystallization were filtered and air-dried.
[0260] Grinding Studies: Grinding experiments were performed using
a Wig-L-Bug shaker. About 50 mg of Compound A hydrochloride was
added to a polystyrene tube (1''.times.1/2'') with a Plexi bead
(3/8''). The vial was capped and placed on the shaker for about 50
s. For wet grinding, drops of water were added to the vial and a
wet paste was formed prior to placing on the shaker.
[0261] Humidity Studies: About 30 mg of Compound A hydrochloride
was placed in amber glass vials in duplicate. The vials were placed
in 40.degree. C./75% RH humidity chamber with one vial capped and
one vial open. The solids were tested by XRPD after four weeks. An
additional humidity stress experiment was performed by placing
about 10 mg of Compound A hydrochloride in a DVS instrument at 95%
RH and room temperature for four days.
5.4.2. Characterization Methodology
[0262] X-ray Powder Diffraction (XRPD): XRPD analysis was conducted
on a Thermo ARL X'TRA.TM. X-ray powder diffractometer using Cu
K.alpha. radiation at 1.54 .ANG.. The instrument was equipped with
a fine focus X-ray tube. The voltage and amperage of X-ray
generator were set at 45 kV and 40 mA, respectively. The divergence
slices were set at 4 mm and 2 mm and the measuring slices were set
at 0.5 mm and 0.2 mm. Diffracted radiation was detected by a
peltier-cooled Si(Li) solid-state detector. A theta-two theta
continuous scan at 2.40.degree./min (0.5 sec/0.02.degree. step)
from 1.5 .degree.2.theta. to 40 .degree.2.theta. was used. A
sintered alumina standard was used to check the peak position. In
general, positions of XRPD peaks are expected to individually vary
on a measurement-by-measurement basis by about +0.2
.degree.2.theta.. In general, as understood in the art, two XRPD
patterns match one another if the characteristic peaks of the first
pattern are located at approximately the same positions as the
characteristic peaks of the second pattern. As understood in the
art, determining whether two XRPD patterns match or whether
individual peaks in two XRPD patterns match may require
consideration of individual variables and parameters such as, but
not limited to, preferred orientation, phase impurities, degree of
crystallinity, particle size, variation in diffractometer
instrument setup, variation in XRPD data collection parameters,
and/or variation in XRPD data processing, among others. The
determination of whether two patterns match may be performed by eye
and/or by computer analysis.
[0263] Differential Scanning Calorimetry (DSC): DSC analyses were
performed on a TA Instruments Q2000.TM. differential scanning
calorimeter. Indium was used as a calibration standard. About 2-5
mg of a sample was placed in to a DSC pan. The sample was heated
under nitrogen at a rate of 10.degree. C./min from about 25.degree.
C. up to a final temperature of 300.degree. C. Melting points were
reported as the extrapolated onset temperatures.
[0264] Thermal Gravimetric Analyses (TGA): TGA analyses were
performed on a TA Instruments Q5000.TM. thermogravimetric analyzer.
Calcium oxalate was used for calibration. About 5-20 mg of an
accurately weighted sample was placed on a pan, and loaded into the
TGA furnace. The sample was heated under nitrogen at a rate of
about 10.degree. C./min up to a final temperature of about
300.degree. C.
[0265] Optical Microscopy: Morphology analysis of a sample was
carried out on an Olympus microscope. Small amounts of a sample
were dispersed in mineral oil on a glass slide with cover slips and
viewed with 20.times. magnification.
[0266] Dynamic Vapor Sorption (DVS): Hygroscopicity was determined
on a Surface Measurement Systems DVS. Typically, a sample of about
2-10 mg was loaded into the DVS instrument sample pan. The sample
was analyzed on a DVS automated sorption analyzer at room
temperature. The relative humidity was increased from 0 to 95% RH
at 10% RH step, then at 95% RH. The relative humidity was then
decreased in a similar manner to accomplish a full
adsorption/desorption cycle.
[0267] Solubility by HPLC: Solubility of Form A in selected aqueous
and organic solvents was determined by mixing solid with solvents
at room temperature. The samples were filtered after 24 hr of
agitation and quantified by an HPLC method, except for DMSO, for
which the solubility was measured after 1 hr of agitation.
5.4.3. Solid Form Screening Study Results
[0268] Solid forms comprising Compound A which were prepared during
the solid form screening studies included Form A, B, C, D, E, F,
and A1, and amorphous forms. Representative XRPD patterns, DSC
plots, TGA plots and DVS plots for Form A, B, C, D, E, F, and I are
provided herein as FIGS. 1 to 21.
[0269] 5.4.3.1. Solid Forms of Compound A
[0270] Interconversions between various solid forms of Compound A
are summarized in FIG. 23. The interconversion conditions as
depicted in FIG. 23 are:
[0271] 1. Slurry in MeOH at RT, or in acetone, MeCN, or MeOH at
50.degree. C.
[0272] 2. Slurry in EtOAC, EtOH, IPA, MEK, n-BuOH or THF at
50.degree. C.
[0273] 3. Dried in vacuum oven at .about.70.degree. C.
[0274] 4. Slurry in MeCN or IPA at RT
[0275] 5. Slurry in EtOH at RT
[0276] 6. Slurry in water at RT
[0277] 7. Slurry in organic solvents at RT or elevated
temperature
[0278] 8. Exposure to moisture at RT
[0279] 9. Slurry in water at RT
[0280] 10. Slurry in organic solvents at elevated temperature
[0281] 11. Slurry in water at RT
[0282] 12. Exposure to moisture in DVS
The physical properties of Forms A, B, C, D, E, and F are
summarized in Table 1.
TABLE-US-00001 TABLE 1 Characteristics of Solid Forms of Compound A
Moisture Sorption at DSC Peaks TGA Loss 95% RH Form Morphology
(.degree. C.) (wt %) (wt %) Comment A Crystalline 145.3 (broad)
5.87 3.19 Monohydrate Irregular plate 161.2 (exo) 282.1 (onset) B
Crystalline 279.0 (onset) 0.00 0.11 Anhydrate Irregular shape C
Crystalline 280.7 (onset) 0.07 0.17 Anhydrate Irregular shape D
Semi-crystalline 114.4 (broad) 3.04 4.11 Unstable Irregular shape
283.3 (onset) dehydrated form E Crystalline 147.0 (broad) 5.98 0.26
Hydrate/solvate Large irregular 279.4 (onset) plate F Crystalline
170.4 (exo) 266.5 (onset)
[0283] In a stirred glass flask, 3.5 g Compound A freebase was
dissolved in approx 14 mL DMSO and approx 0.7 mL water at room
temperature. Approx 2 mL water was added and crystals of Compound A
Form A began to form. Additional water was added dropwise and the
batch further crystallized. The batch was then filtered. The cake
was washed with a 1:1 (v:v) DMSO:water solution and neat water. The
wet cake was dried in a vacuum oven. The final dry product was
consistent with Compound A Form A.
[0284] Alternatively, Compound A Form A can be obtained by seeding.
In a stirred glass flask, 3.5 g Compound A freebase was dissolved
in approx 14 mL DMSO and approx 0.7 mL water at room temperature.
Approx 1.3 mL water was added, and seeds of Compound A Form A were
added, and the batch began to crystallize. Additional water was
added dropwise, and the batch further crystallized. The batch was
then filtered. The cake was then washed with 1:1 (v:v) DMSO:water
solution and neat water. The wet cake was dried in a vacuum oven.
The final dry product was consistent with Compound A Form A.
[0285] Form B of Compound A was prepared from Form A via slurry
recrystallization in methanol, acetone or acetonitrile. The slurry
experiments were carried out by adding an excess of Compound A to 2
mL of methanol, acetone or acetonitrile. The resulting mixture was
agitated for at least 24 hours at about 50.degree. C. Upon reaching
equilibrium, the solid was filtered and air dried.
[0286] Form C of Compound A was prepared from Form A via slurry
recrystallization in EtOAc, EtOH, IPA, MEK, n-BuOH, or THF at about
50.degree. C. The slurry experiments were carried out by adding an
excess of Compound A to 2 mL of EtOAc, EtOH, IPA, MEK, n-BuOH, or
THF. The resulting mixture was agitated for at least 24 hours at
about 50.degree. C. Upon reaching equilibrium, the solid was
filtered and air dried.
[0287] Form D of Compound A was prepared from Form A via drying
Form A in vacuum oven at about 80-90.degree. C.
[0288] Form E of Compound A was prepared from Form A via slurry
recrystallization in acetonitrile, ethanol or isopropanol at room
temperature. The slurry experiments were carried out by adding an
excess of Compound A to 2 mL of acetonitrile, ethanol or
isopropanol. The resulting mixture was agitated for at least 24
hours at room temperature. Upon reaching equilibrium, the solid was
filtered and air dried.
[0289] Form F of Compound A was prepared from Form B via slurry
recrystallization in water at room temperature. The slurry
experiment was carried out by adding an excess of Compound A to 2
mL of water. The resulting mixture was agitated for at least 16
hours at room temperature. The solid was then filtered and air
dried.
[0290] 5.4.3.2. Solid Form A1 of Compound A HCl
[0291] Form A1, a hydrochloride salt of Compound A was prepared by
the following process. In a stirred glass flask, 2 g Compound A
hydrochloride was mixed in a solvent mixture of approximately 20 mL
acetonitrile and 20 mL water and dissolved by heating to
>55.degree. C. The solution was cooled to 45.degree. C. and
approx 3.3 mL 6 N hydrochloric acid was added, causing
crystallization. The slurry was then slowly cooled and filtered.
The cake was washed with acetonitrile and then dried in a vacuum
oven. The resulting dry product was consistent with Compound A Form
A1.
[0292] Large Scale Process.
[0293] Form A1 was prepared on a large scale by combining 100 g of
Compound A hydrochloride, 960 mL acetonitrile and 960 mL deionized
water in a reactor. The mixture was heated with agitation to 60 to
70.degree. C. and transferred to a second reactor by an inline
filter (0.45 .mu.m). The first reactor is rinsed with 100 mL of
acetonitrile:water (1:1), which was transferred to the second
reactor by the inline filter. The temperature in the second reactor
was maintained at 65.degree. C. during transfer. The second reactor
was then cooled to 45.degree. C. and seeded with 3 g Form A1
crystals. The batch began to crystallize and was aged at 45.degree.
C. for 30 minutes. To the resulting slurry was added 171 mL 6 N HCl
by an inline filter over 1 hour, maintaining batch temperature at
about 45.degree. C. The batch was aged at 45.degree. C. for 1.5
hours and cooled to 0.degree. C. in a linear ramp over 4 hours. The
batch was then aged at 0.degree. C. for 1 hour. The supernatant was
sampled for UPLC concentration. The concentration of Form A1 in the
supernatant was 5 mg/mL. The slurry was filtered through a fritted
glass filter with vacuum. The resulting cake was displacement
washed with 2.times.300 mL acetonitrile washes. The cake was dried
in a vacuum oven at 40.degree. C. until acetonitrile is <400
ppm. The dry cake of Form A1 was a clean white/off-white
powder.
[0294] It was discovered that acetonitrile:water was the only
solvent system which afforded acceptable properties for scaleup,
e.g., solubility greater than about 50 g/mL product. Excess HCl was
added to prevent formation of the free base of Compound A. In some
cases it was found that the absence of HCl in the process resulted
in free base formation. Excess HCl was also thought to improve Form
A1 yield during crystallization.
[0295] The physical properties from the HCl salt are consistent
from batch to batch. TGA shows little residual solvent (also, by
NMR residual acetonitrile can be reduced to <400 ppm). DSC shows
a single event at .about.280.degree. C., which is considered to be
decomposition (similar to the decomposition point of the freebase).
Microscopy showed long rod morphology.
[0296] Solubility Studies.
[0297] The approximate solubility of Form A1 of Compound A
hydrochloride in various solvents at about 25.degree. C. was
determined. Form A1 was found to be most soluble (>25 mg/mL) in
MeCN/water (1:1) and THF/water (1:1). Form A1 was found to have
moderate solubility (3-10 mg/mL) in EtOH/water (1:1), MeOH,
CH.sub.2Cl.sub.2, THF, and water. Form A1 was found to have low
solubility (<3 mg/mL) in other organic solvents tested. The
solubility of Form A1 in selected solvents was also tested by HPLC
and results are shown in Table 2.
TABLE-US-00002 TABLE 2 Solubility Solvent Solubility (mg/mL) Water
1.71 0.9% NaCl 1.90 0.1N HCl 5.34 Acetate buffer (pH 4.0) 0.31
Phosphate buffer (pH 6.8) 0.03 Acetonitrile (AcCN) 0.02 Acetone
2.55 Methanol (MeOH) 0.27 Isopropanol (iPrOH) 0.02 Ethyl acetate
(EtOAc) <0.001 Tetrahydrofuran (THF) <0.005 Heptane <0.001
Toluene <0.005 Dimethyl Sulfoxide (DMSO) 21.88
[0298] Slurry experiments were performed at room temperature and
50.degree. C. using Form A1 of Compound A hydrochloride as starting
material. The results are summarized in Tables 3 and 4. All of the
solids isolated from pure organic solvents after 24 hrs of slurry
were confirmed to be Form A1 by XRPD. The solid isolated from
THF/water at 50.degree. C. slurry was also confirmed to be Form A1.
The solids isolated from other aqueous/organic or aqueous slurries
were shown be to mixtures of Form A1 and Compound A free base,
suggesting partial dissociation of the HCl salt.
TABLE-US-00003 TABLE 3 Equilibration Experiments at Room
Temperature. Solvent XRPD Result Acetone Form A1 Acetonitrile Form
A1 n-Butanol Form A1 Ethanol Form A1 Ethyl acetate Form A1 Heptane
Form A1 Methanol Form A1 Methylene chloride Form A1 Methyl ethyl
ketone Form A1 Methyl t-butyl ether Form A1 2-Propanol Form A1
Toluene Form A1 Tetrahydrofuran Form A1 Water Form A + Form A1
Ethanol/Water (1:1) Form A + Form A1 Acetonitrile/Water (1:1) Form
A + Form A1 Tetrahydrofuran/Water (1:1) Form A + Form A1
TABLE-US-00004 TABLE 4 Equilibration Experiments at 50.degree. C.
Solvent XRPD Result Acetone Form A1 Acetonitrile Form A1 n-Butanol
Form A1 Ethanol Form A1 Ethyl acetate Form A1 Heptane Form A1
Methanol Form A1 Methyl ethyl ketone Form A1 2-Propanol Form A1
Toluene Form A1 Tetrahydrofuran Form A1 Water Form A + Form A1
Ethanol/Water (1:1) Form A + Form A1 Acetonitrile/Water (1:1) Form
A + Form A1 Tetrahydrofuran/Water (1:1) Form A1
[0299] Evaporation experiments were performed. The results are
summarized in Tables 5 and 6. For room temperature evaporations,
solids obtained from water, EtOH/water, and MeCN/water were
confirmed to be Form A1. Partial or complete salt dissociation were
observed in MeOH, THF, and THF/water. For 50.degree. C.
evaporations, solids obtained from MeOH, water, EtOH/water, and
MeCN/water were confirmed to be Form A1. Solid from THF/water was
shown to be amorphous.
TABLE-US-00005 TABLE 5 Evaporation Experiments at Room Temperature
Solvent XRPD Result Acetone N/A Acetonitrile N/A n-Butanol N/A
Ethanol N/A Ethyl acetate N/A Heptane N/A Methanol Form A + Form A1
Methyl ethyl ketone N/A 2-Propanol N/A Toluene N/A Tetrahydrofuran
N/A Water Form A1 Ethanol/Water (1:1) Form A1 Acetonitrile/Water
(1:1) Form A1 Tetrahydrofuran/Water (1:1) Form A + Form A1
TABLE-US-00006 TABLE 6 Evaporation Experiments at 50.degree. C.
Solvent XRPD Result Acetone N/A Acetonitrile N/A n-Butanol N/A
Ethanol N/A Ethyl acetate N/A Heptane N/A Methanol Form A1 Methyl
ethyl ketone N/A 2-Propanol N/A Toluene N/A Tetrahydrofuran N/A
Water Form A1 Ethanol/Water (1:1) Form A1 Acetonitrile/Water (1:1)
Form A1 Tetrahydrofuran/Water (1:1) Amorphous
[0300] Recrystallization experiments were performed in several
organic/aqueous mixtures. The results are summarized in Table 7.
Solids from MeCN/water, MeOH/0.1N HCl, or EtOH/0.1N HCl were
confirmed to be Form A1. Complete salt dissociation was observed in
THF/water.
[0301] Anti-solvent crystallization was also performed with
MeCN/water as the primary solvent system, and with acetone or IPA
as antisolvent. Form A1 was obtained when acetone was used as
antisolvent, and partial salt dissociation was observed when IPA
was used as antisolvent.
TABLE-US-00007 TABLE 7 Recrystallization without and with
Antisolvents Ratio (Solvent/ Solvent Antisolvent Antisolvent) XRPD
Result THF/H.sub.2O NA NA Form A MeCN/H.sub.2O NA NA Form A1 + Form
A MeOH/0.1N HCl NA NA Form A1 EtOH/0.1N HCl NA NA Form A1
MeCN/H.sub.2O Acetone 1:5 Form A1 MeCN/H.sub.2O IPA 1:5 Form A1 +
Form A
[0302] Grinding experiments were performed with and without
addition of water, as a further attempt to generate polymorphs.
Form A1 was found unchanged upon grinding. The results are
summarized in Table 8.
TABLE-US-00008 TABLE 8 Grinding Experiments Starting Form Test
Conditions XRPD Result Form A Dry grinding Form A1 Form A Wet
grinding (paste) Form A1
[0303] Characterization of Form A1
[0304] Form A1 had a crystalline XRPD pattern as shown in FIG. 18
and acicular crystal habit. TGA and DSC thermograms of Form A1 are
shown in FIGS. 19 and 20, respectively. Negligible weight loss was
observed prior to decomposition, the onset temperature of which was
about 276.degree. C. as determined by DSC.
[0305] The moisture sorption/desorption behavior of Form A1 was
determined by DVS and the results are summarized in FIG. 21. Form
A1 exhibited a 0.15% mass change relative to the dry mass when the
relative humidity was increased from 0 to 95%, indicating that the
material is non-hygroscopic. After undergoing the full
adsorption/desorption cycle, the XRPD diffractogram of the sample
showed that the material was unchanged from the initial Form
A1.
[0306] Stability of Form A1 was determined by exposing the sample
to a 40.degree. C./75% RH environment for four weeks or 95% RH at
room temperature for four days. Solid form of the exposed material
was not changed compared to the initial unexposed sample (Table 9).
Form A1 was also found to be stable upon application of 2000-psi
pressure for about 1 minute.
TABLE-US-00009 TABLE 9 Grinding Experiments Starting Form Test
Conditions XRPD Result Form A1 40.degree. C./75% RH for Form A1 4
weeks, open vial Form A1 40.degree. C./75% RH for Form A1 4 weeks,
closed vial Form A1 95% RH for 4 days Form A1
[0307] Based on these characterization studies, Form A1 was found
to be a stable anhydrous and non-hygroscopic crystalline
material.
[0308] While the disclosure has been described with respect to the
particular embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made without
departing from the spirit and scope of the disclosure as defined in
the claims. Such modifications are also intended to fall within the
scope of the appended claims.
[0309] All of the patents, patent applications and publications
referred to herein are incorporated herein in their entireties.
Citation or identification of any reference in this application is
not an admission that such reference is available as prior art to
this disclosure. The full scope of the disclosure is better
understood with reference to the appended claims.
* * * * *