NZ614424B2 - Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses - Google Patents
Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses Download PDFInfo
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- NZ614424B2 NZ614424B2 NZ614424A NZ61442412A NZ614424B2 NZ 614424 B2 NZ614424 B2 NZ 614424B2 NZ 614424 A NZ614424 A NZ 614424A NZ 61442412 A NZ61442412 A NZ 61442412A NZ 614424 B2 NZ614424 B2 NZ 614424B2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The disclosure relates to solid, crystalline forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (see abstract drawing), which may be the hydrochloride salt. The disclosure also relates to pharmaceutical compositions comprising the solid forms and their use to treat diseases and disorders. and disorders.
Description
SOLID FORMS OF 3-(5-AMINOMETHYLOXO-4H—QUINAZOLINYL)—
DINE-2,6-DIONE, AND THEIR PHARMACEUTICAL
ITIONS AND USES
The present application claims ty to US. Provisional Patent
Application No. ,806, filed March 11, 2011, the ty of which is incorporated
herein by reference.
1. FIELD
[002] Provided herein are solid forms of 3-(5-aminomethyloxo-4H—
quinazolinyl)-piperidine-2,6-dione, pharmaceutical compositions thereof, and
methods of their uses for the treatment of diseases or disorders.
2. BACKGROUND OF THE DISCLOSURE
2.1 PATHOBIOLOGY OF CANCER AND OTHER DISEASES
[003] 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 borne spread of malignant cells to regional lymph
nodes and to t sites (metastasis). Clinical data and molecular biologic studies
indicate that cancer is a multistep process that begins with minor preneoplastic changes,
which may under n 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 llance. Roitt, 1., Brostoff, J and Kale, D., Immunology, 7.12 (3rd
ed., Mosby, St. Louis, Mo., 1993).
[004] 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, s for the
treatment of cancer are limited. For example, in the case of blood cancers (e.g., multiple
myeloma), few treatment s 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.
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-(x. Alternatively, tumor cells can release
angiogenic peptides h the production ofproteases and the subsequent own
of the extracellular matrix where some nes 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-(x, b-
FGF).
A variety of other diseases and disorders are also associated with, or
terized by, red angiogenesis. For example, enhanced or unregulated
angiogenesis has been implicated in a number of diseases and l conditions
ing, but not limited to, ocular neovascular diseases, choroidal neovascular
diseases, retina neovascular diseases, is (neovascularization of the angle), viral
es, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune
diseases. Examples of such diseases and conditions include, but are not limited to,
ic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular
glaucoma, ental lasia, arthritis, and proliferative vitreoretinopathy.
Accordingly, compounds that can control angiogenesis or inhibit the
tion of certain cytokines, including TNFoc, may be useful in the treatment and
prevention of various diseases and conditions.
2.2 METHODS OF TREATING CANCER
[008] t 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 .
Radiation therapy is only effective when the stic 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
therapies are limited in number and may e side effects such as rashes or
swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems
or allergic ons.
With respect to chemotherapy, there is a variety of chemotherapeutic
agents available for treatment of cancer. A ty 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 ofTherapeutics, Tenth Ed. (McGraw Hill, New York).
Despite availability of a variety of chemotherapeutic agents,
herapy 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 p resistance to the chemotherapeutic agents. In fact, those cells
resistant to the particular chemotherapeutic agents used in the treatment protocol often
prove to be ant 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 ance. Because of the drug ance, many cancers
prove or become refractory to standard chemotherapeutic treatment protocols.
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 ed to be usefill in the ent of
certain specific es. 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.
Still, there is a significant need for safe and effective methods of treating,
preventing and managing cancer and other diseases and conditions, including for
es that are refractory to standard treatments, such as surgery, radiation therapy,
herapy and al therapy, while reducing or avoiding the toxicities and/or
side effects associated with the conventional therapies.
2.3 SOLID FORMS
The ation 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 cks in processing,
formulation, stability and bioavailability, among other important pharmaceutical
characteristics. Potential pharmaceutical solids e crystalline solids and amorphous
solids. Amorphous solids are characterized by a lack of long-range ural order,
whereas crystalline solids are characterized by structural periodicity. The desired class
of pharmaceutical solid depends upon the specific ation; amorphous solids are
sometimes selected on the basis of, e.g., an enhanced dissolution profile, while
lline solids may be desirable for properties such as, e.g., physical or al
stability (see, e.g., S. R. Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 4823-26; L.
Yu, Adv. Drug. Deliv. Rev., (2001) 42).
Whether crystalline or amorphous, potential solid forms of a
pharmaceutical compound include single-component and multiple-component solids.
Single-component solids t 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. Bym et 01]., Solid State Chemistry of Drugs, (1999) SSCI, West tte).
The importance of studying polymorphs was cored 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 ation 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).
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 ements for a pharmaceutical compound or
salt thereof include, e.g., hydrates, es, co-crystals and clathrates, among others
(see, e. g., S. R. Bym et 01]., Solid State Chemistry of Drugs, (1999) SSCI, West
tte). 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 pment of a safe, effective, stable and able
pharmaceutical compound.
Provided herein are embodiments addressing a need for solid forms of 3-
(5-aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-dione (“Compound A”).
Compound A was described in US. Pat. No. 7,635,700, the disclosure of which is
incorporated herein by reference in its entirety.
3. SUMMARY
This disclosure relates to methods of treating diseases and disorders
ing a solid form of 3-(5-aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-
dione or a stereoisomer thereof, or a pharmaceutically acceptable salt, e, hydrate,
co-crystal, clathrate, or polymorph thereof.
[0018] Provided herein are solid forms of minomethyloxo-4H—
quinazolinyl)—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 ment, 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 ment, the solid
form is crystalline Form F. In yet another ment, the solid form is a solid form of
a hydrochloride salt of 3-(5-aminomethyloxo-4H—quinazolinyl)—piperidine-2,6-
dione. In still another embodiment, the solid form is crystalline Form A1.
[0019] Further provided herein are pharmaceutical compositions, single unit
dosage forms, dosing regimens, and kits, which comprise a solid form of 3-(5-amino
methyloxo-4H—quinazolinyl)-piperidine-2,6-dione or a stereoisomer f, or a
pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph
f; and a pharmaceutically acceptable carrier.
[0020] 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-aminomethyloxo-4H—quinazolinyl)-
piperidine-2,6-dione or a stereoisomer thereof, or a pharmaceutically acceptable salt,
solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
Also ed herein are methods of preventing various diseases and
disorders, which comprise administering to a t a prophylactically effective amount
of a solid form of 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione
or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal
, clathrate, or polymorph thereof.
[0021A] In a related embodiment, provided herein is the use of a solid form of 3-
(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione or a stereoisomer
thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or
polymorph thereof, in the manufacture of a medicament for treating, ng or
preventing a disease or disorder, wherein the disease or disorder is cancer, a disorder
associated with angiogenesis, pain, macular degeneration or a related syndrome, a skin
disease, a pulmonary disorder, an asbestos-related disorder, a parasitic disease, an
immunodeficiency disorder, a CNS er, CNS injury, atherosclerosis or a related
disorder, dysfunctional sleep or a related er, hemoglobinopathy or a related
er, or a TNFα related disorder.
In certain embodiments, the solid forms are single-component crystal
forms of 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione. In
certain embodiments, the solid forms are multiple-component crystal forms of 3-(5-
aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione, including, but not
limited to, salts, co-crystals and/or solvates (including es) comprising 3-(5-amino-
2-methyloxo-4H-quinazolinyl)-piperidine-2,6-dione. In certain embodiments, the
solid forms are single-component amorphous forms of 3-(5-aminomethyloxo-4H-
quinazolinyl)-piperidine-2,6-dione. In certain embodiments, the solid forms are
multiple-component amorphous forms of 3-(5-aminomethyloxo-4H-quinazolin
yl)-piperidine-2,6-dione. Without intending to be d by any particular theory,
certain solid forms provided herein have particular advantageous physical and/or
al properties making them , e.g., for manufacturing, processing, ation
and/or storage, while also possessing particularly advantageous biological properties,
such as, e.g., bioavailability and/or ical activity.
In certain embodiments, solid forms provided herein include solid forms
comprising minomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione,
including, but not limited to, single-component and multiple-component solid forms
comprising minomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione. In
certain ments, solid forms provided herein include salts, polymorphs, solvates
(including hydrates), and co-crystals comprising 3-(5-aminomethyloxo-4H-
quinazolinyl)-piperidine-2,6-dione. Certain embodiments herein provide methods of
making, isolating and/or characterizing the solid forms provided herein.
40 [0024] The solid forms provided herein are useful as active pharmaceutical
ingredients for the preparation of formulations for use in patients. Thus, embodiments
herein ass the use of these solid forms as a final drug t. 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 ibility properties, among others, that are needed
for manufacturing, processing, formulation and/or storage of final drug products.
n embodiments herein provide pharmaceutical compositions comprising a singlecomponent
crystal form, a multiple-component crystal form, a single-component
amorphous form and/or a multiple-component amorphous form comprising 3-(5-amino-
2-methyloxo-4H-quinazolinyl)-piperidine-2,6-dione and a pharmaceutically
able 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
provides an X-ray Powder Diffraction (“XRPD”) pattern of Form
A of 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione.
[0025A] shows the solubility of Form A in DMSO:water as the relative
amount of DMSO is sed.
[0026] provides a Differential Scanning Calorimetry (“DSC”) plot of
Form A of 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione.
es a Thermal Gravimetric Analysis (“TGA”) plot of Form A
of 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione.
provides an XRPD pattern of Form B of 3-(5-aminomethyl
oxo-4H-quinazolinyl)-piperidine-2,6-dione.
es a DSC plot of Form B of 3-(5-aminomethyloxo-4H-
quinazolinyl)-piperidine-2,6-dione.
provides a TGA plot of Form B of 3-(5-aminomethyloxo-
4H-quinazolinyl)-piperidine-2,6-dione.
[0031] provides an XRPD pattern of Form C of 3-(5-aminomethyl
oxo-4H-quinazolinyl)-piperidine-2,6-dione.
provides a DSC plot of Form C of 3-(5-aminomethyloxo-4H-
quinazolinyl)-piperidine-2,6-dione.
provides a TGA plot of Form C of minomethyloxo-
nazolinyl)-piperidine-2,6-dione.
provides an XRPD pattern of Form D of 3-(5-aminomethyl
oxo-4H-quinazolinyl)-piperidine-2,6-dione.
provides a DSC plot of Form D of 3-(5-aminomethyloxo-
4H-quinazolinyl)-piperidine-2,6-dione.
provides a TGA plot of Form D of 3-(5-aminomethyloxo-
4H—quinazolinyl)-piperidine-2,6-dione.
provides an XRPD n of Form E of 3-(5-aminomethyl
oxo-4H—quinazolinyl)-piperidine-2,6-dione.
es a DSC plot of Form E of 3-(5-aminomethyloxo-
4H—quinazolinyl)-piperidine-2,6-dione.
provides a TGA plot of Form E of 3-(5-aminomethyloxo-
4H—quinazolinyl)-piperidine-2,6-dione.
provides an XRPD pattern of Form F of 3-(5-aminomethyl
oxo-4H—quinazolinyl)-piperidine-2,6-dione.
es a DSC plot of Form F of 3-(5-aminomethyloxo-
4H—quinazolinyl)-piperidine-2,6-dione.
provides an XRPD pattern of Form A1 of 3-(5-aminomethyl-
4-oxo-4H—quinazolinyl)-piperidine-2,6-dione hydrochloride.
[0043] provides a DSC plot of Form A1 of 3-(5-aminomethyloxo-
4H—quinazolinyl)-piperidine-2,6-dione hydrochloride.
provides a TGA plot of Form A1 of 3-(5-aminomethyloxo-
4H—quinazolinyl)-piperidine-2,6-dione hydrochloride.
provides a Dynamic Vapor Sorption (“DVS”) plot of Form A1 of
3-(5-aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-dione hydrochloride.
is a microscopic image of crystals of Form A1 of 3-(5-amino
methyloxo-4H—quinazolinyl)-piperidine-2,6-dione hydrochloride.
depicts interconversions between various solid forms of 3-(5-
2-methyloxo-4H-quinazolinyl)-piperidine-2,6-dione.
3.2. DEFINITIONS
As used herein, term “Compound A” refers to 3-(5-aminomethyl
oxo-4H—quinazolinyl)-piperidine-2,6-dione. The 1H NMR spectrum of Compound A
is substantially as follows: 6 (DMSO-dg): 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, .1: 8 Hz, 1H), 10.98 (s, 1H). The 13C NMR spectrum of
nd A is substantially as follows: 6 (DMSO-dg): 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.
Without being limited by theory, Compound A is believed to be 3-(5-
aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-dione, which has the
following structure:
O N 0
[005 0] As used herein, the term “patient” refers to a mammal, particularly a
human.
As used herein, the term “pharmaceutically able salt” refers to a salt
prepared from a pharmaceutically acceptable non-toxic acid or base, ing inorganic
acids and bases and organic acids and bases.
[0052] As used herein, term “adverse effects” includes, but is not limited to
gastrointestinal, renal and hepatic toxicities, leukopenia, ses in bleeding times due
to, e.g., thrombocytopenia, and gation of gestation, , vomiting, somnolence,
asthenia, dizziness, teratogenicity, extra-pyramidal symptoms, akathisia, cardiotoxicity
including vascular disturbances, inflammation, male sexual dysfunction, and
elevated serum liver enzyme levels. The term ointestinal 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.
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.
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 ure
is to be interpreted as encompassing all stereoisomers of it.
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 d
terms, when used herein to refer to nd A, refer to a physical form comprising
Compound A which is not predominantly in a liquid or a s state. Solid forms may
be crystalline, amorphous, or mixtures thereof. In ular 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 les, within the solid form. In n embodiments, a “multiple-
component” solid form comprising Compound A comprises a hydrochloride salt of
nd A. For example, in particular ments, a crystalline multiple-component
solid form comprising Compound A fiarther 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 e single-component and multiple-component
solid forms comprising Compound A. In particular embodiments, “solid forms
comprising nd A” and related terms include crystal forms comprising
Compound A, amorphous forms sing Compound A, and mixtures thereof.
As used herein and unless otherwise specified, the term “crystalline” and
related terms used herein, when used to describe a compound, substance, modification,
material, ent 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, 21St edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The
United States Pharmacopeia, 23rd ed., 1843-1844 (1995).
As used herein and unless ise 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 lar complexes. In certain embodiments, a crystal
form of a nce may be substantially free of amorphous forms and/or other crystal
forms. In certain embodiments, a crystal form of a substance may n 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.
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, les, and/or ions. Like different crystal
forms, different polymorphs may have different physical properties such as, e.g., melting
temperature, heat of , 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 e stability, compressibility and density (important in formulation and
product cturing), and dissolution rate (an important factor in bioavailability).
ences 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 (6.g. , tablets of one polymorph are
more susceptible to breakdown at high humidity). As a result of lity/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 (6.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).
As used herein and unless otherwise specified, the terms “solvate” and
“solvated,” refer to a crystal form of a substance which ns solvent. The terms
“hydrate” and “hydrated” refer to a solvate n the solvent comprises water.
“Polymorphs of solvates” refers to the existence of more than one l form for a
particular solvate composition. Similarly, “polymorphs of hydrates” refers to the
existence of more than one crystal form for a particular hydrate ition. The term
“desolvated solvate,” as used herein, refers to a l form of a substance which may be
ed by removing the solvent from a solvate.
As used herein and unless otherwise ied, the term “amorphous,”
“amorphous form,” and related terms used herein, mean that the substance, component or
product in question is not ntially lline 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 ous form of a substance may contain less than about
1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% ofone or
more other amorphous forms and/or crystal forms on a weight basis. In n
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.
Techniques for characterizing crystal forms and ous 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 oscopy,
solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical
microscopy, hot stage optical copy, scanning electron microscopy (SEM), electron
crystallography and quantitative analysis, particle size analysis (PSA), surface area
analysis, solubility measurements, dissolution measurements, elemental analysis, and
Karl r analysis. Characteristic unit cell parameters may be determined using one
or more techniques such as, but not limited to, X-ray diffraction and n diffraction,
including -crystal ction 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 sing more than one solid phase. Other methods usefiJl 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.
[0062] 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, 6.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 ; 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 able 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% ofthe recited value or range of
values.
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.
As used herein and unless ise specified, a sample or composition
that is antially free” of one or more other solid forms and/or other al
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.
As used herein, and unless otherwise specified, the terms “treat,”
“treating” and “treatment” refer to the eradication or amelioration of a disease or
er, or of one or more symptoms associated with the disease or disorder. In certain
embodiments, the terms refer to minimizing the spread or ing of the disease or
disorder resulting from the administration of one or more prophylactic or eutic
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.
[0066] As used herein, and unless ise specified, the terms “prevent,”
“preventing” and “prevention” refer to the tion of the onset, recurrence or spread
of a disease or disorder, or of one or more symptoms thereof. In certain ments,
the terms refer to the treatment with or administration of a compound provided ,
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
n embodiments. In addition, patients who have a y 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.”
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 ms thereof. Often, the
beneficial effects that a patient s from a prophylactic and/or therapeutic agent do
not result in a cure of the disease or er. In this regard, the term “managing”
encompasses treating a patient who had suffered from the particular e in an attempt
to t or minimize the recurrence of the disease.
[0068] 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 ment of a e or disorder, or to delay or ze 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 eutic 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.
[0069] As used , and unless otherwise specified, a “prophylactically
effective amount” of a compound is an amount ient to prevent a disease or disorder,
or prevent its ence. 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
ive amount” can encompass an amount that improves overall prophylaxis or
enhances the prophylactic efficacy of another prophylactic agent.
The term “composition” as used herein is intended to encompass a
product comprising the specified ingredients (and in the specified s, if indicated),
as well as any product which results, directly or indirectly, from combination of the
specified ingredients in the specified amounts. By “pharmaceutically able” 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. ED DESCRIPTION
This sure relates to solid forms of Compound A, which is 3-(5-
aminomethyloxo-4H—quinazolinyl)-piperidine-2,6-dione, and stereoisomers
f, 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, ate, or polymorph f. For example, the
present disclosure encompasses the in vitro and in viva 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.
4.1. SOLID FORMS OF COMPOUND A
In one embodiment, provided herein are solid forms of Compound A or a
stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal,
clathrate, or polymorph f.
Compound A is readily prepared using the methods as described in US.
Pat. No. 7,635,700, the disclosure of which is incorporated herein by reference in its
entirety.
Solid forms sing Compound A include single-component and
multiple-component forms, including crystal forms and amorphous forms, and including,
but not d 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 e multiple-component
amorphous forms sing 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.
[0075] Solid forms comprising nd 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 , 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, tallization on surfaces or templates such as, e.g., on rs,
recrystallization in the ce of additives, such as, e.g., co-crystal r-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, (6.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 llization solvent system, or by particle-size reduction
techniques, e.g., grinding, milling, izing or sonication.
[0076] 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, al stability, and chemical stability) affecting particular processes (e.g.,
yield, filtration, washing, drying, milling, , ing, 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.
n embodiments herein provide compositions sing 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 e
methods of using these itions in the treatment, prevention or management of
diseases and ers including, but not d to, the diseases and ers provided
herein.
Solid forms ed 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
(3H), iodine-125 (125I) sulfur-35 (35S), or carbon-14 (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
ions of Compound A, whether radioactive or not, are intended to be encompassed
within the scope of the embodiments provided herein.
4.1.1. FORM A OF COMPOUND A
[0079] n embodiments herein provide crystalline Form A of Compound A.
Form A may be crystallized from ater 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. Table 1 (shown in ) shows the
solubility of Form A in DMSO:water as the relative amount of DMSO is increased.
In n 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 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, , or thirteen of the following imate 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 2θ. 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 20. In n
embodiments, Form A of Compound A is characterized by an XRPD pattern which
matches the pattern exhibited in 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 entative Form A pattern provided herein.
In n 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
In certain embodiments, Form A is characterized by a DSC plot comprising an
endothermic event with an onset temperature of about 282 CC. 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 CC, and/or an
exothermic event with a peak temperature of about 161 CC. A representative TGA plot
for Form A of Compound A is shown in In certain ments, Form A is
characterized by a TGA plot sing 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 °C to about 110 CC. In one ment, 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 °C to about 110 CC. In certain embodiments, Form
A of Compound A contains either water or other solvent in the crystal lattice. In n
embodiments, the TGA mass loss event comprises the loss of water. In certain
embodiments, Form A is solvated. In certain ments, Form A is monohydrated.
In certain embodiments, the l lattice of Form A comprises about one molar
equivalent of water per mole of Compound A.
[0082] In certain embodiments, upon dehydration Form A is converted to Form
D of Compound A. In one embodiment, Form A is ted to Form D of Compound
A when dried at about 55 0C for 3 days. Form A of Compound A may be prepared from
Form D by slurrying Form D in water at 22 °C or 50 °C overnight.
In one embodiment, Form A of Compound A is physically and chemically
stable at 40 °C for 5 days under . In another embodiment, Form A of Compound
A is physically and chemically stable at 40 °C for 4 days under nitrogen atmosphere.
In certain embodiments, Form A of Compound A may be characterized
by re 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 sed back to about 0% RH.
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 ing, 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 sing nd A
hloride as provided herein. Certain embodiments herein provide Form A as a
mixture of solid forms comprising Compound A, including, e.g., a e 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.
4.1.2. FORM B OF COMPOUND A
[0086] 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 s 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 f at about
50°C.
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 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
imate positions: 10.6, 11.4, 12.6, 13.7, 14.7, 19.1, 20.3, 20.9, 21.2, 22.9, 24.9,
.3, 25.9, 26.9, 29.5 and 33.8 degrees 20. 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 20. In certain embodiments, Form B of Compound A is
terized by an XRPD pattern which s the pattern ted in 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.
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
In certain embodiments, Form B is characterized by a DSC plot sing an
endothermic event with an onset ature of about 279 CC. A entative TGA
plot for Form B of Compound A is shown in 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 °C to about 200 CC. In certain embodiments, Form B of
nd 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.
In certain embodiments, Form B of Compound A may be characterized by
moisture sorption analysis. In certain ments, 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
roscopic. In certain embodiments, the XRPD pattern of Form B material is
substantially ged following the adsorption/desorption is. In certain
embodiments, Form B is stable with respect to humidity.
Certain embodiments herein provide Form B of Compound A which is
ntially pure. Certain ments 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 ed 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 nd A as provided herein, and Form A1 and an amorphous solid form
comprising Compound A hydrochloride as provided herein.
4.1.3. FORM C OF COMPOUND A
n 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 s 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 , n-
butanol, tetrahydrofuran, or mixtures comprising two or more thereof, at about 50°C.
[0092] 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 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 s 20. In one embodiment, Form C of
nd A is characterized by XRPD peaks d at the following approximate
positions: 10.8, 15.1, 25.1 and 26.6 degrees 20. In certain ments, Form C of
Compound A is characterized by an XRPD pattern which matches the pattern exhibited
in 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.
In certain embodiments, Form C of Compound A may be terized by
thermal analysis. A representative DSC plot for Form C of Compound A is shown in
In certain embodiments, Form C is characterized by a DSC plot comprising an
ermic event with an onset temperature of about 281 CC. A representative TGA
plot for Form C of Compound A is shown in 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 0C to about 150 0C. In n embodiments, Form C of
Compound A does not n 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.
In certain ments, Form C of Compound A may be terized 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 tion is lost when the RH is
decreased back to about 0% RH. In certain embodiments, Form C is substantially
nonhygroscopic. In n 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.
[0095] Certain embodiments herein provide Form C of nd 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 ous solid form comprising Compound A
hydrochloride as provided herein. Certain embodiments herein provide Form C as a
mixture of solid forms sing 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 hloride as ed herein.
4.1.4. FORM D OF ND A
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°C.
[0097] 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 . In certain embodiments, Form D of Compound A
is characterized by an XRPD pattern which matches the pattern exhibited in . 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 ofthe 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 s 20. In one embodiment, Form D of
nd A is characterized by XRPD peaks located at the following approximate
positions: 16.7, 21.7, 21.9 and 25.8 s 20. 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.
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
. In certain embodiments, Form D is characterized by a DSC plot comprising an
ermic event with an onset temperature of about 283 CC. In certain embodiments, a
characteristic Form D DSC plot fiarther ses one additional event, such as, e.g., an
endothermic event with a peak temperature of about 114 CC. A representative TGA plot
for Form D of nd A is shown in . 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 °C to about 150 CC. 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.
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 ng mass of the sample. In certain ments, mass gained upon
adsorption is lost when the RH is decreased back to about 0% RH.
Certain embodiments herein provide Form D of Compound A which is
substantially pure. n 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 ous solid form comprising Compound A as provided
, and Form A1 and an amorphous solid form comprising Compound A
hydrochloride as ed herein. Certain embodiments herein provide Form D as a
mixture of solid forms comprising nd 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.
4.1.5. FORM E OF COMPOUND A
Certain embodiments herein provide the Form E l form of
Compound A. In certain embodiments, Form E of Compound A can be obtained from
various solvents, including, but not limited to, solvent s 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 tallization process at room temperature. Form E can also be
ed by an antisolvent recrystallization process by dissolving Compound A in DMF
or NMP and rapidly adding water as antisolvent.
In certain embodiments, Form E of Compound A may be characterized by
X-ray powder diffraction analysis. A representative XRPD n of Form E of
Compound A is provided in . 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 20. In one
embodiment, Form E of Compound A is characterized by XRPD peaks located at the
ing approximate positions: 7.3, 14.6, 22.0, 30.0 and 37.0 degrees 20. In n
embodiments, Form E of Compound A is characterized by an XRPD pattern which
matches the pattern exhibited in . 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.
In n 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
. In certain embodiments, Form E is characterized by a DSC plot sing an
endothermic event with an onset temperature of about 279 CC. 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 CC. A representative TGA plot
for Form E of Compound A is shown in . 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 0C to about 150 0C. In certain embodiments, the TGA mass loss
event ses the loss of water. In certain embodiments, Form E of Compound A is
ed. In n embodiments, Form E is hydrated.
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.
Certain embodiments herein e Form E of Compound A which is
substantially pure. Certain embodiments herein provide Form E of Compound A which
is ntially 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 ed
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 sing Compound A, ing, 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 hloride as provided herein.
4.1.6. FORM F OF COMPOUND A
Certain embodiments herein provide the Form F l 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 ments, Form F can be obtained using a slurry recrystallization process.
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
nd A is provided in . In n embodiments, Form F of Compound A
is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight,
nine or ten ofthe 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 20. In one embodiment, Form F of Compound A is
characterized by XRPD peaks d at the following approximate positions: 14.5, 15.7,
22.7 and 29.9 degrees 20. In certain embodiments, Form F of Compound A is
characterized by an XRPD n which matches the pattern exhibited in . In
certain embodiments, Form F of Compound A is terized 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.
In n embodiments, Form F of Compound A may be terized by
thermal analysis. A representative DSC plot for Form F of nd A is shown in
. In certain embodiments, Form F is characterized by a DSC plot comprising an
endothermic event with an onset temperature of about 267 CC. 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 CC. In certain embodiments,
Form F is solvated. In certain embodiments, Form F is hydrated.
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 e 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 ous solid form
comprising Compound A hydrochloride as provided .
4.1.7. FORM A1 OF COMPOUND A HLORIDE
Certain embodiments herein provide crystalline Form A1 of a
hydrochloride salt of nd A. In certain embodiments, Form A1 can be obtained
from various solvents, including, but not limited to, solvent systems comprising acetone,
itrile, 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 llization process. In certain embodiments, Form A1 can be obtained
using an antisolvent addition crystallization process.
Form A1 of Compound A hloride is a stable crystalline form. For
example, Form A1 found to be chemically stable upon e at room temperature,
exposed to air and light, for 6 weeks. Form Al was also found to be chemically stable
upon storage at 40 0C under vacuum. Form Al was also found to be chemically stable
upon storage at 40 °C under a en atmosphere. Form Al was also found to be
chemically stable upon storage at 40 °C and 75% relative humidity (RH). Form Al was
also found to be chemically stable upon storage at 60 0C 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).
In certain embodiments, Form A1 may be characterized by X-ray powder
diffraction analysis. A representative XRPD pattern of Form A1 is provided in .
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 20. In one embodiment,
Form A1 is terized by XRPD peaks located at the following approximate
positions: 8.6, 13.1, 20.5 and 26.3 degrees 20. In certain embodiments, Form A1 is
characterized by an XRPD pattern which matches the pattern exhibited in . 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.
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 . In certain embodiments, Form A1 is characterized by a DSC plot
comprising an endothermic event with an onset temperature of about 276 CC. In n
embodiments, Form A1 has a decomposition ature at about 276 CC. A
representative TGA plot for Form A1 of Compound A is shown in . 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 °C to about 150 CC. In certain embodiments, Form
A1 of nd 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 ous.
In certain embodiments, Form A1 may be characterized by moisture
sorption analysis. A representative moisture on isotherm plot is shown in .
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 .
In certain ments, mass gained upon adsorption is lost when the RH is sed
back to about 0% RH. Accordingly, in n 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 t to humidity.
In certain embodiments, Form A1 of a hydrochloride salt of nd 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
ts, and/or upon compression. In certain embodiments, for example, Form A1 is
stable following exposure to an environment of about 40 OC and about 75% RH
nment for about four weeks. In certain ments, 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
re to one or more solvent systems sing, 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 ydrofilran at about 50 °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.
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.
[001 17] Certain embodiments herein provide Form A1 Compound A which is
ntially pure. Certain embodiments herein provide Form A1 of a hydrochloride salt
of nd 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 ed herein. Certain embodiments herein provide
Form A1 as a mixture of solid forms sing 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.
[00118] Certain embodiments herein e 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.
4.2. METHODS OF TREATMENT
The disclosure encompasses methods of treating, preventing, and/or
ng various es 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 se administering a therapeutically or
prophylactically ive 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 .
t being limited by a particular theory, Compound A can control
angiogenesis or inhibit the production of n cytokines including, but not limited to,
TNF-(x, IL-1 [3, IL-12, IL-18, GM-CSF, and/or IL-6. t 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 nes such as, but not limited to, IL-12 and/or IFN—y. In
addition, Compound A can enhance the effects ofNK 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 s
diseases or disorders.
Examples of diseases or disorders include, but are not limited to, cancer,
disorders associated with angiogenesis, pain ing, but not limited to, Complex
Regional Pain Syndrome (“CRPS”), Macular Degeneration (“MD”) and d
syndromes, skin diseases, pulmonary disorders, os-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), TNFOL related disorders, and other s diseases and
disorders.
Examples of cancer and precancerous conditions include, but are not
limited to, those described in US. patent nos. 230 and 5,635,517 to Muller et al.,
in various US. patent publications to Zeldis, including publication nos.
2004/0220144A1, published er 4, 2004 (Treatment of Myelodysplastic
Syndrome); 2004/0029832A1, published February 12, 2004 (Treatment of Various
Types of ); and 2004/0087546, published May 6, 2004 (Treatment of
Myeloproliferative Diseases). Examples also include those described in WC
2004/103274, published December 2, 2004. All of these references are incorporated
herein in their entireties by reference.
Specific examples of cancer include, but are not limited to, cancers of the
skin, such as melanoma; lymph node; breast; cervix; uterus; intestinal tract; lung;
ovary; prostate; colon; ; mouth; brain; head and neck; throat; testes; kidney;
pancreas; bone; spleen; liver; bladder; larynx; nasal es; and AIDS-related cancers.
The compounds are also useful for ng cancers of the blood and bone marrow, such
as multiple myeloma and acute and c leukemias, for e, lymphoblastic,
myelogenous, lymphocytic, and myelocytic leukemias. The compounds provided herein
can be used for treating, preventing or ng either primary or metastatic tumors.
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, ant , recurrent malignant ,
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, dgkin’s
lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-
Cell lymphoma, low grade follicular lymphoma, atic melanoma (localized
ma, including, but not limited to, ocular melanoma), malignant elioma,
malignant pleural on mesothelioma me, 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
a, indolent myeloma, fallopian tube cancer, androgen independent prostate
cancer, androgen dependent stage IV non-metastatic prostate , hormone-
insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid
carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and oma.
In a specific embodiment, the cancer is metastatic. In another embodiment, the cancer is
refractory or resistance to chemotherapy or radiation.
In one embodiment, provided herein are methods of treating, preventing
or managing s forms of leukemias such as chronic lymphocytic leukemia, chronic
myelocytic leukemia, acute lymphoblastic leukemia, acute enous leukemia and
acute myeloblastic leukemia, including leukemias that are relapsed, refractory or
resistant, as disclosed in US. publication no. 2006/0030594, published February 9, 2006,
which is incorporated in its ty by nce.
[00126] The term “leukemia” refers malignant neoplasms of the blood-forming
tissues. The leukemia es, but is not limited to, chronic lymphocytic leukemia,
chronic myelocytic leukemia, acute lymphoblastic leukemia, acute enous
leukemia and acute myeloblastic ia. The leukemia can be relapsed, refractory or
resistant to conventional therapy. The term “relapsed” refers to a situation where
ts 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 ts, even after intensive ent, have
residual leukemia cells in their marrow.
In another embodiment, provided herein are methods of ng,
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 tic systems. “NHL” refers to malignant
onal proliferation of lymphoid cells in sites of the immune system, ing
lymph nodes, bone marrow, spleen, liver and gastrointestinal tract. Examples ofNHL
e, but are not d to, mantle cell lymphoma (MCL), lymphocytic lymphoma of
intermediate differentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorly
differentiated lymphocytic lymphoma (PDL), centrocytic lymphoma, diffilse small-
cleaved cell ma (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).
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). c examples of the
diseases and disorders associated with, or characterized by, undesired angiogenesis
include, but are not limited to, arthritis, triosis, Crohn’s disease, heart e,
advanced heart failure, renal ment, endotoxemia, toxic shock me,
osteoarthritis, retrovirus replication, wasting, meningitis, silica-induced fibrosis,
asbestos-induced fibrosis, veterinary disorder, malignancy-associated hypercalcemia,
stroke, circulatory shock, periodontitis, gingivitis, ytic anemia, refractory anemia,
and 5q-deletion syndrome.
Examples of pain include, but are not d to those described in US.
patent publication no. 203142, published September 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.
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.
Examples of neuropathic pain e, 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, ic neuropathy, post-stroke pain, luetic neuropathy, and other painful
neuropathic conditions such as those induced by drugs such as vincristine and velcade.
[00132] 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, r spontaneous or evoked, including allodynia
(painful se to a stimulus that is not usually painful) and hyperalgesia (exaggerated
response to a stimulus that is usually only mildly l); pain that is portionate to
the inciting event (6.g. of severe pain after an ankle sprain); al pain that is
, years
not limited to a single peripheral nerve distribution; and autonomic dysregulation (e.g.,
edema, alteration in blood flow and hyperhidrosis) associated with c skin changes
(hair and nail growth abnormalities and cutaneous ulceration).
Examples ofMD and related mes include, but are not limited to,
those described in US. patent publication no. 2004/0091455, hed May 13, 2004,
which is incorporated herein by reference. Specific examples include, but are not limited
to, ic (dry) MD, exudative (wet) MD, age-related pathy (ARM), choroidal
neovascularisation (CNVM), retinal pigment epithelium detachment (PED), and atrophy
of retinal pigment lium (RPE).
Examples of skin diseases include, but are not limited to, those described
in US. publication no. 2005/0214328A1, published September 29, 2005, which is
incorporated herein by reference. Specific examples include, but are not d to,
keratoses and related symptoms, skin es or ers characterized with
overgrowths of the epidermis, acne, and wrinkles.
As used herein, the term “keratosis” refers to any lesion on the epidermis
marked by the presence of scribed overgrowths of the horny layer, including but
not limited to actinic keratosis, seborrheic keratosis, keratoacanthoma, keratosis
follicularis (Darier disease), inverted follicular keratosis, palmoplantar derma
(PPK, keratosis is et plantaris), keratosis pilaris, and stucco keratosis. The term
“actinic keratosis” also refers to senile keratosis, keratosis senilis, verruca senilis, plana
senilis, solar sis, keratoderma or keratoma. The term “seborrheic sis” 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, es 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, osis, parakeratosis, atoses,
papillomatosis, hyperpigmentation of the basal cells, cellular atypia, mitotic figures,
abnormal cell-cell on, dense inflammatory infiltrates and small prevalence of
squamous cell carcinomas.
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, ing but not limited to,
infections associated with papilloma Virus, arsenical keratoses, sign of Leser-Tre’lat,
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 me), dermatosis papulosa nigra (DPN), epidermal nevus
syndrome (ENS), ichthyosis vulgaris, molluscum contagiosum, prurigo nodularis, and
acanthosis nigricans (AN).
Examples of pulmonary disorders include, but are not d to, those
described in US. publication no. 2005/0239842A1, hed October 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: y pulmonary ension (PPH); secondary
ary hypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonary
hypertension; pulmonary arterial hypertension (PAH); pulmonary artery hypertension;
idiopathic pulmonary ension; 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, ital 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 e, ar-capillary sia, sickle cell disease,
other coagulation disorder, chronic thromboemboli, connective tissue disease, lupus
including systemic and cutaneous lupus, schistosomiasis, sarcoidosis or pulmonary
capillary iomatosis.
Examples of asbestos-related disorders include, but not limited to, those
described in US. publication no. 100529, 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, l
plaques, pleural calcification, diffilse pleural thickening, rounded atelectasis, fibrotic
, and lung cancer.
[00139] Examples of parasitic diseases include, but are not limited to, those
described in US. publication no. 2006/0154880, published July 13, 2006, which is
incorporated herein by nce. Parasitic diseases include diseases and disorders
caused by human ellular parasites such as, but not d to, P. falcifarium, P.
ovale, P. vivax, P. malariae, L. donovari, L. um, L. aethiopica, L. major, L. tropica,
L. mexicana, L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C. parvum, C.
cayetanensis, E. ytica, I. belli, S. mansonii, S. haematobium, osoma ssp.,
asma ssp., and 0. valvulus. Other diseases and disorders caused by non-human
intracellular parasites such as, but not d to, Babesia bovis, Babesia canis, a
Gibsoni, Besnoitia darlingi, Cytauxzoonfelis, Eimeria ssp., Hammondia ssp., and
ria ssp., are also encompassed. Specific examples include, but are not limited to,
malaria, babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis, meningoencephalitis,
keratitis, amebiasis, giardiasis, sporidiosis, isosporiasis, cyclosporiasis,
microsporidiosis, ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis,
trichinosis, lymphatic filariasis, erciasis, filariasis, schistosomiasis, and dermatitis
caused by animal schistosomes.
Examples of immunodeficiency ers include, but are not limited to,
those described in US. application no. 11/289,723, filed November 30, 2005. Specific
examples e, but not limited to, adenosine deaminase deficiency, antibody
deficiency with normal or elevated Igs, ataxia-tenlangiectasia, bare lymphocyte
syndrome, common variable immunodeficiency, lg deficiency with hyper-IgM, Ig heavy
chain deletions, IgA deficiency, immunodeficiency with thymoma, reticular esis,
Nezelof syndrome, ive IgG subclass deficiency, transient hypogammaglobulinemia
of infancy, Wistcott—Aldrich syndrome, X-linked agammaglobulinemia, X-linked severe
combined immunodeficiency.
es of CNS disorders e, but are not limited to, those
described in US. publication no. 2005/0143344, published June 30, 2005, which is
incorporated herein by reference. Specific examples include, but are not limited to,
include, but are not limited to, Amyotrophic l Sclerosis, mer Disease,
Parkinson e, 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.
Examples of CNS injuries and related syndromes include, but are not
limited to, those described in US. publication no. 2006/0122228, published June 8,
2006, which is incorporated herein by reference. Specific examples e, 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,
diffiase axonal injury, head injury, concussion, post-concussion syndrome, cerebral
WO 25438
contusion and laceration, subdural hematoma, epidermal hematoma, post-traumatic
epilepsy, chronic vegetative state, te SCI, incomplete SCI, acute SCI, subacute
SCI, chronic SCI, central cord syndrome, Brown-Sequard syndrome, or cord
syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal
shock, d level of consciousness, headache, nausea, emesis, memory loss, dizziness,
diplopia, blurred vision, emotional lability, sleep disturbances, bility, inability to
concentrate, nervousness, behavioral impairment, ive , and seizure.
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 es, chronic
pulmonary inflammatory diseases, dermatitis, cystic fibrosis, septic shock, sepsis,
endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion
injury, itis, 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 y, radiation , cancer, asthma, or hyperoxic alveolar injury.
] Examples of atherosclerosis and d ions include, but are not
limited to, those disclosed in US. 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, lasty
with stent tation, peripheral aneous transluminal intervention of the iliac,
l or popliteal arteries, and surgical intervention using impregnated artificial grafts.
Examples of dysfunctional sleep and related syndromes include, but are
not limited to, those disclosed in US. publication no. 2005/0222209A1, hed
October 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 al Pain Syndrome, chronic
2012/028419
low back pain, musculoskeletal pain, arthritis, radiculopathy, pain ated with
cancer, flbromyalgia, chronic fatigue syndrome, visceral pain, bladder pain, c
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, inesia;
muscle rigidity; sonian tremor; parkinsonian gait; motion freezing; depression;
defective long-term memory, tein-Taybi syndrome (RTS); dementia; postural
instability; hypokinetic disorders; synuclein disorders; multiple system atrophies;
striatonigral degeneration; ontocerebellar 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;
inetic disorders; chorea; ballismus; dystonia tremors; Amyotrophic l
Sclerosis (ALS); CNS trauma and myoclonus.
Examples of hemoglobinopathy and related disorders include, but are not
limited to, those described in US. publication no. 2005/0143420Al, hed June 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.
Examples of TNFOL related disorders include, but are not limited to, those
described in WO 02 and WO 70, both of which are incorporated herein in
their entireties by nce. 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;
al 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, toid spondylitis, osteoarthritis, psoriatic arthritis and other tic
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 unistic infections in AIDS; disorders such as
septic shock, , endotoxic shock, hemodynamic shock and sepsis syndrome, post
ischemic reperfilsion injury, malaria, mycobacterial infection, meningitis, psoriasis,
tive heart failure, fibrotic disease, cacheXia, graft rejection, oncogenic or
ous conditions, , mune disease, radiation damages, and hyperoxic
alveolar injury; viral infections, such as those caused by the herpes viruses; viral
conjunctivitis; or atopic dermatitis.
In other embodiments, the use of Compound A in various immunological
applications, in particular, as vaccine adjuvants, particularly anticancer vaccine
adjuvants, as disclosed in US. Provisional ation No. 60/712,823, filed September
1, 2005, which is incorporated herein in its entirety by reference, is also encompassed.
These ments 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 ion or desensitization of allergic reactions.
Doses of a solid form of Compound A vary depending on factors such as:
ic 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 ), 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.
[00150] A solid form of Compound A ed herein can be combined with other
cologically active compounds (“second active agents”) in methods and
itions 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 e effects associated with certain second active
agents, and vice versa.
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
les).
Examples of large molecule active agents include, but are not limited to,
hematopoietic growth factors, cytokines, and monoclonal and onal antibodies.
Specific examples of the active agents are anti-CD40 monoclonal antibodies (such as, for
example, SGN—40); histone deacetlyase tors (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, nib and erlotinib
HCL); HER-2 dies (such as, for example, trastuzumab (Herceptin®) and
pertuzumab (OmnitargTM)); VEGFR antibodies (such as, for example, bevacizumab
(AvastinTM)); VEGFR inhibitors (such as, for example, flk-l specific kinase inhibitors,
SU5416 and /zk2225 84); P13K inhibitors (such as, for example, wortmannin); C-
Met tors (such as, for example, FHA-665752); monoclonal antibodies (such as, for
example, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab (Panorex®) and
G250); and anti-TNF-(x antibodies. es of small molecule active agents include,
but are not limited to, anticancer agents and otics (e.g., clarithromycin).
[00153] Specific second active nds that can be combined with a solid form
of nd A provided herein vary depending on the specific indication to be treated,
prevented or managed.
For instance, for the treatment, prevention or management of ,
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; in; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
sin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;
calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hloride;
carzelesin; cedefingol; xib; chlorambucil; cirolemycin; cisplatin; cladribine;
crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin;
daunorubicin hydrochloride; decitabine; dexormaplatin; anine; dezaguanine
mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hloride; droloxifene;
droloxifene citrate; dromostanolone propionate; duazomycin; xate; eflornithine
hydrochloride; trucin; enloplatin; enpromate; epipropidine; icin
hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide ate; etoprine; fadrozole
hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil;
flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;
yurea; icin hydrochloride; mide; sine; iproplatin; ecan;
irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole
hloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;
maytansine; mechlorethamine hydrochloride; rol acetate; melengestrol acetate;
melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; omide; mitocarcin; omin; mitogillin; mitomalcin; mitomycin;
mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;
nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; lfan; piroxantrone hydrochloride;
plicamycin; tane; porfimer ; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; cin hydrochloride; pyrazofurin; riboprine; safingol;
safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin;
spirogermanium hydrochloride; spiromustine; spiroplatin; onigrin; streptozocin;
sulofenur; talisomycin; lan sodium; taxotere; tegafur; teloxantrone hydrochloride;
temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; pa;
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; rosine
sulfate; lbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; vorozole; zeniplatin;
zinostatin; and zorubicin hydrochloride.
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 tors; apoptosis tors; apurinic acid; ara-CDP-DL-PTBA; arginine
deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; tatin
3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;
BCIUABL 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; rphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin
816; crisnatol; phycin 8; cryptophycin A derivatives; curacin A;
entanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliXimab; bine; dehydrodidemnin B; deslorelin; dexamethasone;
deXifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;
diethylnorspermine; dihydroazacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;
dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; lomab;
eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; stim; finasteride; ridol; flezelastine; fluasterone;
fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase
inhibitors; gemcitabine; hione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imatinib (Gleevec®), imiquimod; immunostimulant es; insulin-like
growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; j asplakinolide; kahalalide F; arin-N triacetate;
lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; ole; leukemia
inhibiting ; yte alpha interferon; lide+estrogen+progesterone;
leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic haride
peptide; lipophilic platinum compounds; linamide 7; lobaplatin; lombricine;
exol; 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; osine;
mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin
fibroblast growth factor-saporin; mitoxantrone; tene; 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;
ne+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin;
neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;
nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide; okicenone;
oligonucleotides; onapristone; ondansetron; etron; oracin; oral cytokine inducer;
ormaplatin; osaterone; latin; oxaunomycin; paclitaxel; paclitaxel analogues;
paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol;
panomifene; parabactin; pazelliptine; argase; peldesine; pentosan lfate
sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; rpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator
inhibitor; platinum complex; um compounds; um-triamine complex; porfimer
sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; some
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 famesyl protein
transferase tors; ras inhibitors; P inhibitor; retelliptine demethylated;
rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide;
roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; ine; ence derived inhibitor 1; sense
ucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium
borocaptate; sodium acetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin l; mine;
stipiamide; lysin inhibitors; sulfinosine; ctive 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;
oin; triacetyluridine; ibine; 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; rone; zeniplatin; zilascorb; and zinostatin stimalamer.
Specific second active agents include, but are not limited to, 2-
methoxyestradiol, telomestatin, rs of apoptosis in e myeloma cells (such as,
for example, TRAIL), statins, semaxanib, cyclosporin, etanercept, doxycycline,
bortezomib, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan,
dexamethasone ron®), steroids, gemcitabine, cisplatinum, temozolomide,
etoposide, cyclophosphamide, temodar, carboplatin, bazine, gliadel, tamoxifen,
topotecan, rexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan,
xeloda, CPT-11, interferon alpha, pegylated interferon alpha (6.g. , PEG INTRON—A),
capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal ubicin,
cytarabine, doxetaxol, taxel, vinblastine, IL-2, GM-CSF, dacarbazine, Vinorelbine,
zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic
trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin,
estramustine sodium ate (Emcyt®), sulindac, and etoposide.
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: US. patent nos.
6,281,230 and 517; US. publication nos. 2004/0220144, 2004/0190609,
2004/0087546, 2005/0203142, 2004/0091455, 100529, 214328,
2005/0239842, 2006/0154880, 122228,and 2005/0143344; and US. provisional
application no. 60/631,870.
Examples of second active agents that may be used for the treatment,
tion and/or management of pain include, but are not limited to, conventional
therapeutics used to treat or prevent pain such as antidepressants, anticonvulsants,
pertensives, anxiolytics, m 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
nists, and other therapeutics found, for example, in the Physician ’s Desk
Reference 2003. Specific es include, but are not limited to, salicylic acid acetate
(Aspirin®), celecoxib rex®), Enbrel®, ketamine, gabapentin (Neurontin®),
phenytoin (Dilantin®), carbamazepine (Tegretol®), azepine (Trileptal®), valproic
acid (Depakene®), morphine sulfate, hydromorphone, prednisone, griseofillvin,
penthonium, alendronate, dyphenhydramide, guanethidine, ketorolac (Acular®),
thyrocalcitonin, dimethylsulfoxide (DMSO), clonidine (Catapress®), ium,
erin, reserpine, droperidol, ne, phentolamine, bupivacaine, lidocaine,
acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®), imipramine
(Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®), fluoxetine (Prozac®),
sertraline (Zoloft®), naproxen, nefazodone (Serzone®), venlafaxine (Effexor®), trazodone
(Desyrel®), bupropion (Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,
lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan, benzodiazepines, baclofen,
tizanidine and phenoxybenzamine.
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 d, a light izer, 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 giogenesis nd, or a
combination f Specific es include, but are not limited to, verteporfin,
purlytin, an angiostatic steroid, rhuFab, interferon-20L, pentoxifylline, tin etiopurpurin,
motexafin, is, lutetium, 9-fluoro-1 1,21-dihydroxy-16,
17methylethylidinebis(oxy)pregna-1 ,4-diene-3 ,20-dione, latanoprost (see U. S. Patent
No. 6,225,348), ycline and its derivatives, rifamycin and its derivatives, ides,
metronidazole (U.S. Patent Nos. 369 and 6,015,803), genistein, genistin, 6’-O-Mal
in, 6’-O-Ac genistin, daidzein, daidzin, 6’-O-Mal daidzin, 6’-O-Ac daidzin,
glycitein, glycitin, 6’-O-Mal glycitin, biochanin A, onetin (U.S. Patent No.
6,001,368), triamcinolone acetomide, dexamethasone (U.S. Patent No. 5,770,589),
thalidomide, glutathione (U.S. Patent No. 5,632,984), basic fibroblast growth factor
(bFGF), transforming growth factor b (TGF-b), brain-derived neurotrophic factor
(BDNF), nogen 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.
Examples of second active agents that may be used for the treatment,
prevention and/or ment of skin diseases include, but are not limited to,
keratolytics, retinoids, (x-hydroxy acids, otics, collagen, botulinum toxin,
interferon, steroids, and modulatory agents. Specific examples include, but are
not limited to, 5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lactic acid,
ammonium lactate, urea, tretinoin, tinoin, antibiotics, collagen, botulinum toxin,
interferon, corticosteroid, transretinoic acid and collagens such as human tal
collagen, animal placental collagen, Dermalogen, AlloDerm, Fascia, Cymetra,
Autologen, Zyderm, Zyplast, Resoplast, and Isolagen.
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, cyclin analogues, endothelin antagonists, phosphodiesterase
tors (e. g., PDE V inhibitors), endopeptidase tors, lipid lowering agents,
thromboxane tors, and other therapeutics known to reduce pulmonary artery
re. Specific examples include, but are not limited to, warfarin (Coumadin®), a
diuretic, a cardiac glycoside, digoxin-oxygen, diltiazem, nifedipine, a vasodilator such as
prostacyclin (e.g., prostaglandin 12 (PGIZ), epoprostenol (EPO, Floran®), treprostinil
(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine, epoprostenol
(Floran®), treprostinil (Remodulin®), prostacyclin, tadalafil (Cialis®), tatin
(Zocor®), omapatrilat (Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®),
digoxin, L-arginine, iloprost, betaprost, and sildenafil (Viagra®).
es 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®), cisplatinum,
cyclophosphamide, temodar, carboplatin, bazine, l, tamoxifen, topotecan,
rexate, taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,
carboplatin, liposomal daunorubicin, cytarabine, xol, pacilitaxel, vinblastine, IL-2,
GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan,
prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®),
paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine,
thiotepa, tetracycline and gemcitabine.
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, mycin,
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.
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 peutic or prophylactic) such as, but not limited to, llin,
tetracycline, penicillin, cephalosporins, streptomycin, kanamycin, and erythromycin;
antivirals such as, but not limited to, amantadine, rimantadine, acyclovir, and rin;
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; es such as, but not limited to,
thymic; and other immunologic agents such as, but not limited to, B cell stimulators
(e.g., BAFF/BlyS), nes (e.g., IL-2, IL-4, and IL-5), growth factors (e.g., ),
dies (e.g., anti-CD40 and IgM), oligonucleotides containing unmethylated CpG
, and vaccines (e.g., viral and tumor peptide es).
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 ne agonist or nist, such as, but not limited to, Levodopa, L-DOPA,
e, (x-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, ine,
fenodolpam mesylate, cabergoline, pramipexole dihydrochloride, ropinorole, amantadine
hydrochloride, selegiline hydrochloride, opa, 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, nim chloride, edrophonium chloride, tacrine,
pralidoxime chloride, ime chloride, trimedoxime e, diacetyl monoxim,
honium, pyridostigmine, and demecarium; an nflammatory 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, umab,
salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine,
alazine, acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate
sodium, in, ketorolac, fenac, flurbinprofen, oxaprozin, piroxicam,
meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,
nbutazone, antipyrine, aminopyrine, apazone, zileuton, aurothioglucose, gold
sodium thiomalate, auranofin, methotrexate, colchicine, allopurinol, ecid,
sulfinpyrazone and benzbromarone or betamethasone and other glucocorticoids; and an
antiemetic agent, such as, but not limited to, metoclopromide, domperidone,
prochlorperazine, promethazine, romazine, trimethobenzamide, ondansetron,
granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine,
dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,
oxypemdyl, zine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and a mixture f.
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, suppressive agents, antihypertensives,
anticonvulsants, fibrinolytic , antiplatelet agents, antipsychotics, antidepressants,
benzodiazepines, buspirone, amantadine, and other known or conventional agents used in
patients with CNS injury/damage and related syndromes. c examples e, 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, rexate, leflunomide, sulfasalazine, gold salts, RHo-D
Immune Globulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus,
basiliximab, daclizumab, lic acid, acetylsalicylic acid, methyl salicylate, diflunisal,
salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic
WO 25438
acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen, oxaprozin,
piroxicam, cam, ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,
oxyphenbutazone, antipyrine, aminopyrine, e, zileuton, aurothioglucose, gold
sodium thiomalate, auranofin, methotrexate, colchicine, rinol, probenecid,
sulfinpyrazone and benzbromarone; a CAMP analog including, but not limited to, db-
cAMP; an agent comprising a methylphenidate drug, which comprises l-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, ol, furosemide, glycerol,
and urea.
Examples of second active agent that may be used for the treatment,
tion and/or management of ctional sleep and related syndromes include, but
are not limited to, a lic antidepressant agent, a selective serotonin reuptake
inhibitor, an antiepileptic agent (gabapentin, pregabalin, carbamazepine, oxcarbazepine,
levitiracetam, topiramate), an antiaryhthmic agent, a sodium channel ng agent, a
selective inflammatory mediator tor, an opioid agent, a second immunomodulatory
compound, a combination agent, and other known or conventional agents used in sleep
therapy. c examples include, but are not limited to, tin, oxycontin,
morphine, topiramate, amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA,
cocaine, (x-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,
fenodolpam mesylate, oline, pramipexole dihydrochloride, ropinorole, amantadine
hydrochloride, selegiline hloride, carbidopa, pergolide mesylate, Sinemet CR,
Symmetrel, iproniazid, clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,
physostigmine saliclate, physostigmine sulfate, physostigmine bromide, meostigmine
bromide, neostigmine methylsulfate, ambenonim chloride, onium chloride,
tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide, diacetyl
monoxim, endrophonium, pyridostigmine, demecarium, naproxen sodium, diclofenac
sodium, diclofenac potassium, celecoxib, ac, zin, 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 late, 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, ecid, sulfinpyrazone,
omarone, betamethasone and other glucocorticoids, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron, hydroxyzine, acetylleucine hanolamine, alizapride,
azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine,
dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,
dyl, pipamazine, amine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and a mixture thereof
Examples of second active agents that may be used for the treatment,
prevention and/or management of obinopathy and d 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; HEMOXINTM (NIPRISANTM; see United States Patent No.
,800,819); Gardos channel nists such as clotrimazole and triaryl methane
derivatives; Deferoxamine; protein C; and transfusions of blood, or of a blood tute
such as HemospanTM or HemospanTM PS (Sangart).
stration 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 stration for the second active
agents or ingredients are known to those of ordinary skill in the art. See, e.g.,
Physicians ’ Desk Reference (60th ed., 2006).
[00170] 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
ic agent used, the type of disease being treated or d, the severity and stage
of disease, and the amount(s) of compounds provided herein and any optional additional
active agents concurrently administered to the t.
As discussed elsewhere herein, also encompassed is a method of
reducing, treating and/or preventing adverse or red effects associated with
conventional therapy including, but not limited to, surgery, chemotherapy, radiation
therapy, al therapy, ical 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 y.
In certain embodiments, the lactic 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. 6.,
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 s of one of the therapies, and/or improve
the efficacy of the treatment.
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 fiarther allows the frequency,
number, and length of dosing cycles to be increased. Thus, r 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 r number of cycles than would typically cause dose-
ng toxicity in a patient to whom a second active ingredient is not also being
stered.
[00174] 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.
In one ment, 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 s 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 ient is administered by intravenous on
over about 90 minutes every cycle.
Typically, the number of cycles during which the combination ent
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.
4.3. PHARMACEUTICAL COMPOSITIONS
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 , nasal, or vaginal), eral (including subcutaneous, intramuscular,
bolus injection, rterial, or intravenous), sublingual, transdermal, buccal, or topical
administration.
In n embodiments, pharmaceutical compositions and dosage forms
provided herein comprise one or more solid forms comprising Compound A. Certain
embodiments herein provide ceutical 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 hloride as provided herein,
wherein the solid form comprising Compound A substantially pure. n
embodiments herein provide pharmaceutical compositions and dosage forms comprising
a solid form comprising nd 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 sing 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 ed 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
ed herein typically also comprise one or more pharmaceutically acceptable
excipient, diluent or carrier.
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 onal therapeutic agents include, but
are not limited to: anti-cancer drugs and nflammation therapies including, but not
limited to, those provided herein.
Single unit dosage forms of the disclosure are suitable for oral, mucosal
(e.g., nasal, sublingual, l, buccal, or rectal), parenteral (e.g., subcutaneous,
enous, bolus injection, intramuscular, or intraarterial), or transdermal
administration to a patient. es of dosage forms include, but are not limited to:
tablets; caplets; capsules, such as soft elastic n capsules; cachets; troches; lozenges;
dispersions; suppositories; ointments; cataplasms (poultices); ; powders; dressings;
creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid
dosage forms suitable for oral or l administration to a t, 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 tituted to provide liquid dosage forms suitable for parenteral
administration to a patient.
[00181] 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
ent 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 c
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 ceutical es, 18th
ed., Mack Publishing, Easton PA (1990).
WO 25438
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 .
Whether a particular excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of s 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.
[00183] Lactose-free compositions of the sure can comprise excipients that
are well known in the art and are , for example, in the US. Pharmocopia (USP) SP
(XXI)/NF (XVI). In general, lactose-free compositions comprise an active ient, a
binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically
able amounts. Preferred lactose-free dosage forms comprise an active ingredient,
rystalline cellulose, pre-gelatinized starch, and magnesium stearate.
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 on 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, nt, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms of the
disclosure can be prepared using anhydrous or low re containing ingredients and
low moisture or low humidity ions. Pharmaceutical itions and dosage
forms that comprise lactose and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial t with re and/or
humidity during manufacturing, packaging, and/or storage is expected.
An anhydrous ceutical 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 ary 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.
The disclosure fiarther encompasses pharmaceutical compositions and
dosage forms that comprise one or more compounds that reduce the rate by which an
active ient will decompose. Such compounds, which are referred to herein as
lizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH
buffers, or salt buffers.
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 g 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 y 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.
4.3.1. ORAL DOSAGE FORMS
Pharmaceutical compositions of the sure 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 ermined s of active ingredients, and may be
prepared by methods of pharmacy well known to those skilled in the art. See generally
Remington’s ceutical es, 18th ed., Mack Publishing, Easton PA (1990).
] 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 ents suitable for use in solid oral dosage forms (e.g.,
powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars,
crystalline cellulose, diluents, granulating agents, lubricants, binders, and
disintegrating agents.
] 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 ed 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 rs, or both,
and then shaping the t into the desired tation if necessary.
For e, 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 es, optionally mixed with an
ent. Molded s can be made by molding in a suitable machine a mixture of the
powdered compound ned with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the
disclosure include, but are not limited to, binders, s, 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 es, gelatin, natural and
synthetic gums such as , 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.
[00194] 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, ed cellulose, dextrates,
kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized , 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.
Suitable forms of microcrystalline cellulose e, but are not limited
to, the materials sold as AVICEL-PH-IOITM, AVICEL-PH-103TM, AVICEL RC-581TM,
AVICEL-PH-105TM (available from FMC Corporation, American Viscose Division,
Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a e of
microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL
RC-581TM. Suitable anhydrous or low moisture excipients or additives include
AVICEL-PH-103TM and Starch 1500 LMTM.
Disintegrants are used in the compositions of the sure to provide
tablets that disintegrate when exposed to an aqueous environment. Tablets that n
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 egrant 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 egrant.
[00197] Disintegrants that can be used in pharmaceutical itions and dosage
forms of the disclosure include, but are not limited to, agar-agar, c acid, calcium
carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, ilin
potassium, sodium starch glycolate, potato or a starch, pre-gelatinized starch, other
starches, clays, other algins, other celluloses, gums, and mixtures thereof
] 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 te, agar, and mixtures thereof Additional
lubricants include, for example, a syloid silica gel (AEROSIL 200TM manufactured by
W.R. Grace Co. of Baltimore, MD), a ated aerosol of synthetic silica (marketed by
Degussa Co. of Plano, TX), CAB-O-SILTM (a nic silicon dioxide product sold by
Cabot Co. of Boston, MA), 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 orated.
4.3.2. DELAYED RELEASE DOSAGE FORMS
WO 25438
Solid forms comprising Compound A as provided herein can be
administered by controlled e means or by delivery devices that are well known to
those of ry skill in the art. Examples include, but are not limited to, those
described in US. Patent Nos.: 3,845,770; 3,916,899; 809; 3,598,123; and
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 orated 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 ry 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.
All controlled-release pharmaceutical products have a common goal of
improving drug therapy over that achieved by their non-controlled counterparts. y,
the use of an optimally designed controlled-release preparation in medical treatment is
terized 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.
[00201] 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 ed period of time. In order to maintain
this constant level of drug in the body, the drug must be ed 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 s conditions
including, but not limited to, pH, temperature, enzymes, water, or other physiological
ions or compounds.
4.3.3. PARENTERAL DOSAGE FORMS
eral dosage forms can be administered to patients by various routes
including, but not d to, subcutaneous, intravenous (including bolus injection),
intramuscular, and intraarterial. Because their administration typically bypasses patients’
l es against contaminants, parenteral dosage forms are ably 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 ceutically acceptable vehicle for
injection, sions ready for injection, and emulsions.
[00203] Suitable vehicles that can be used to provide parenteral dosage forms of
the sure 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 ion, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium
Chloride ion, and ed Ringer’s Injection; water-miscible vehicles such as, but
not limited to, ethyl alcohol, polyethylene , 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.
Compounds that increase the solubility of one or more of the active
ingredients disclosed herein can also be incorporated into the eral dosage forms of
the disclosure.
4.3.4. TRANSDERMAL, TOPICAL, AND MUCOSAL DOSAGE
FORMS
Transdermal, topical, and mucosal dosage forms of the disclosure include,
but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments,
gels, solutions, ons, 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.
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 ular 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,
pyl palmitate, mineral oil, and mixtures thereof to form s, 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).
ing on the c 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 ls such as ethanol, oleyl, and ydrofuryl; alkyl
sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
hylene glycol; pyrrolidones such as nylpyrrolidone; Kollidon grades
(Povidone, Polyvidone); urea; and s soluble or insoluble sugar esters such as
Tween 80TM (polysorbate 80) and Span 60TM (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the tissue
to which the ceutical 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 ation, 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.
4.3.5. KITS
This disclosure encompasses kits which, when used by the medical
tioner, can simplify the administration of appropriate amounts of active ingredients
to a t.
A typical kit of the disclosure comprises a unit dosage form of compound
A, or a pharmaceutically able solid form or prodrug thereof, and a unit dosage
form of a second active ient. Examples of second active ingredients include, but
are not limited to, those listed herein.
Kits of the disclosure can fiarther comprise devices that are used to
administer the active ingredient(s). es of such devices include, but are not
limited to, syringes, drip bags, patches, and inhalers.
Kits of the disclosure can further comprise pharmaceutically acceptable
vehicles that can be used to administer one or more active ients. For example, if
an active ingredient is provided in a solid form that must be reconstituted for parenteral
administration, the kit can se a sealed container of a suitable vehicle in which the
active ingredient can be dissolved to form a particulate-free sterile on 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 opylene 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
.1. EXAMPLE 1: ASSAYS
.1.1. TNFa INHIBITION ASSAY IN PMBC
Peripheral blood mononuclear cells (PBMC) from normal donors are
obtained by Ficoll Hypaque (Pharmacia, Piscataway, NJ, USA) density centrifugation.
Cells are cultured in RPMI 1640 (Life Technologies, Grand , NY, USA)
mented with 10% AB+human serum (Gemini Bio-products, Woodland, CA,
W0 2012/125438
USA), 2 mM L-glutamine, 100 U/mL penicillin, and 100 ug/mL streptomycin (Life
Technologies).
PBMC (2 X 105 cells) are plated in l flat-bottom Costar tissue
culture plates (Corning, NY, 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 e 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 0C in 5 % C02, and supematants are then collected, diluted with e medium and
assayed for TNFOL levels by ELISA (Endogen, Boston, MA, USA). IC50s are calculated
using non-linear sion, 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 IC50 of 10 and 85 nM.
5.1.2. IL-2 AND MIP-3a TION BY T CELLS
PBMC are depleted of adherent tes by placing 1 X 108 PBMC in
mL te medium (RPMI 1640 mented with 10% heat-inactivated fetal
bovine serum, 2 mM L-glutamine, 100 U/mL penicillin, and 100 ug/mL streptomycin)
per 10 cm tissue culture dish, in 37°C, 5 % C02 tor 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 X 108 non-adherent PBMC: 0.3 mL Sheep anti-mouse IgG beads, 15 ML anti-
CD16, 15 ML anti-CD33, 15 ML anti-CD56, 0.23 mL anti-CD19 beads, 0.23 mL anti-
HLA class II beads, and 56 ML anti-CD14 beads. The cells and bead/antibody mixture is
rotated end-over—end for 30-60 minutes at 4°C. Purified T cells are removed from beads
using a Dynal magnet. Typical yield is about 50% T cells, 87-95% CD3+ by flow
try.
Tissue culture 96-well flat-bottom plates are coated with anti-CD3
antibody OKT3 at 5 ug/mL in PBS, 100 uL per well, incubated at 37 0C for 3-6 hours,
then washed four times with complete medium 100 uL/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 uM to about 0.00064 uM. A 10 mM stock of
nds provided herein is diluted 1:50 in complete for the first 20X dilution of 200
uM in 2 % DMSO and serially diluted 1:5 into 2 % DMSO. Compound is added at 10 ul
per 200 pl culture, to give a final DMSO concentration of 0.1 %. Cultures are incubated
at 37°C, 5 % C02 for 2-3 days, and supernatants analyzed for IL-2 and MIP-30t by
ELISA (R&D Systems). IL-2 and MIP-3oc levels are normalized to the amount produced
in the presence of an amount of a compound provided herein, and EC50s ated using
non-linear regression, sigmoidal dose-response, constraining the top to 100 % and
bottom to 0 %, allowing variable slope (GraphPad Prism v3.02).
.1.3. CELL PROLIFERATION ASSAY
] 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-l is obtained from the American Type Culture Collection (Manassas,
VA, USA). Cell proliferation as indicated by 3H-thymidine incorporation is measured in
all cell lines as follows.
[00218] 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
“M in a final concentration of about 0.25 % DMSO in triplicate at 37°C in a humidified
incubator at 5 % C02 for 72 hours. One microcurie of 3H-thymidine (Amersham) is then
added to each well, and cells are incubated again at 37°C in a humidified incubator at 5
% C02 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 uL/well) is added, and plates are analyzed in TopCount
NXT rd). Each well is counted for one . Percent inhibition of cell
proliferation is calculated by averaging all triplicates and normalizing to the DMSO
control (0 % tion). Each nd is tested in each cell line in three separate
experiments. Final IC50s are ated using non-linear regression, sigmoidal dose-
response, constraining the top to 100 % and bottom to 0 %, allowing variable slope.
(GraphPad Prism v3 .02).
.1.4. IMMUNOPRECIPITATION AND IMMUNOBLOT
[00219] Namalwa cells are d 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 ed and either precipitated 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 ular Dynamics).
.1.5. CELL CYCLE ANALYSIS
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 n Dickinson) according to manufacturer’s ol. Following
staining, cells are ed by a FACSCalibur flow cytometer using ModFit LT software
(Becton Dickinson).
5.1.6. APOPTOSIS ANALYSIS
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 ted with annexin-V binding protein and propidium iodide
(BD Biosciences) for 10 minutes. Samples are analyzed using flow cytometry.
5.1.7. LUCIFERASE ASSAY
Namalwa cells are transfected with 4 ug of ciferase (Stratagene)
per 1 X 106 cells and 3 ML Lipofectamine 2000 (Invitrogen) reagent ing 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
rase lysis buffer and substrate (Promega) and measured using a luminometer
r Designs).
.2. EXAMPLE 2: PREPARATION OF 3-(5-AMINO
OXO-4H-QUINAZOLINYL)-PIPERIDINE-
2,6-DIONE (COMPOUND A)
O E O
NH2 0 U
(:me/NJ\
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 CC. The
suspension was stirred at 0 0C for 3 hrs, and then heated to 30 0C for 3 hrs. To the
solution, was added HCl (100 mL, 6N). The resulting suspension was cooled to 0 0C for
1 hr. The suspension was filtered and washed with cold water (2 X 10 mL) to give 3-
nitro-phthalamic acid as a white solid (24.6 g, 90% yield): 1H NMR (DMSO-d6) 6 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); 13C NMR (DMSO-d6) 5
125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90, 167.31.
Step 2: To a mixture of 3-nitro-phthalamic acid (24.6 g, 117 mmol) and
ium 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 CC,
followed by on of a solution of potassium hydroxide (19.8 g, 351 mmol) in water
(350 mL). After 5 minutes at 0 CC, the mixture was heated in a 100 °C oil bath for 1 hr.
The reaction solution was cooled to room ature, and then, in an ice-water bath for
minutes. To the e, a solution of HCl (240 mL, 2N) was added dropwise at 0
OC, and the resulting mixture was kept for 1 hr. The supsension was filtered and washed
with water (5 mL) to give 2-aminonitro-benzoic acid as yellow solid (15.6 g, 73%
yield): HPLC: Waters ry C18, 5 pm, 3.9 x 150 mm, 1 mL/min, 240 nm,
CH3CN/0.1% H3PO4, 5% grad to 95% over 5 min, 5.83 min (85%); 1H NMR (DMSO-
d6) 6 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, N112); 13C NMR (DMSO-d6) 5 105.58, 110.14, 120.07,
131.74, 149.80, 151.36, ; LCMS: MH = 183.
[00225] Step 3: A mixture of 2-aminonitro-benzoic acid (1.5 g, 8.2 mmol) in
acetic anhydride (15 mL) was heated at 200 0C for 30 minutes in a microwave oven.
The e 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-methylnitro-
benzo[d][1,3]oxazinone as a light brown solid (1.4 g, 85% yield): HPLC: Waters
Symmetry C18, 5pm, 3.9 x 150 mm, 1 mL/min, 240 nm, CH3CN/0.1% H3PO4, 5% grad
95% in 5 min, 5.36 min (92%); 1H NMR (DMSO-d6) 6 2.42 (s, 3H, CH3), 7.79 (dd, J:
1, 8 Hz, 1H, Ar), 7.93 (dd, .1: 1, 8 Hz, 1H, Ar), 8.06 (t, .1: 8 Hz, 1H, Ar); 130 NMR
(DMSO-d6) 520.87, 107.79, 121.54, 128.87, 137.19, 147.12, 148.46, 155.18, 161.78;
LCMS: MH = 207.
Step 4: Two vials each with a suspension of 5-nitromethyl-
d][1,3]oxazinone (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 °C for 10
minutes in a microwave oven. The sion was filtered and washed with pyridine (5
2012/028419
mL). The filtrate was concentrated in vacuo. The ing 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 ol (50 mL) at room temperature ght. The
suspension was filtered and washed with methanol to give 3-(2-methyl-5 -nitrooxo-
4H-quinazolinyl)-piperidine-2,6-dione as a black solid (490 mg, 27% yield). The
solid was used in the next step without further purification.
Step 5: A mixture of 3-(2-methylnitrooxo-4H-quinazolinyl)-
piperidine-2,6-dione (250 mg) and Pd(OH)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-aminomethyloxo-4H-quinazolinyl)-
piperidine-2,6-dione as a white solid (156 mg, 69% yield): HPLC: Waters Symmetry
C18, 5pm, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, 3.52 min
(99.9%); mp: 293-295 0C; 1H NMR (DMSO-d6) 5 2.10-2.17 (m, 1H, CHH), 2.53 (s, 3H,
CH3), 2.59-2.69 (m, 2H, CH2), 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, NH2), 7.36 (t, J
= 8 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) 5 20.98, 23.14, 30.52, 55.92,
104.15, 110.48, 111.37, 134.92, 148.17, 150.55, , , 169.65, 172.57; LCMS:
MH = 287; Anal. Calcd. for C14H14N4O3 + 0.3 H20: C, 57.65; H, 5.05; N, 19.21. Found:
C, 57.50; H, 4.73; N, 19.00.
.3. EXAMPLE 3: PREPARATION OF ND A
HYDROCHLORIDE
[00228] In a stirred glass flask, approximately 19 g of Compound A (freebase)
was suspended in approximately 200 mL acetonitrile and 200 mL water. Approximately
mL 12 N hydrochloric acid was added, and the suspension was dissolved by heating
above 55 OC. The solution was cooled to approx 45 OC and seed crystals of Compound
A Form A1 (e. g. Hydrochloride) were added to the flask. Then 6 N hydrochloric acid
was added se causing further crystallization. The slurry was slowly . The
slurry was then filtered and the cake was washed with itrile. The product was then
dried in a vacuum oven. The resulting dry product was consistent with Compound A
Form A1.
.4. EXAMPLE 4: SOLID FORM SCREENING STUDIES
.4.1. EXPERIMENTAL METHODOLOGY
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 bed herein.
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
0C. If all of the solids appeared to be dissolved by visual inspection, the estimated
lities were calculated based on the total volume of solvent used to give a complete
on. The actual solubilities may be r 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.
[0023 l] 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 t. The resulting mixture was agitated for at least 24 hrs at
about 25 0C or about 50 OC. Upon reaching equilibrium, the saturated solution was
removed and allowed to evaporate slowly in an open vial under en at about 25 OC
and about 50 0C, respectively. The solids ing from the equilibration were filtered
and dried in the air.
Cooling Recrystallization: The selected solvents (THF/water,
MeCN/water, . lN HCl, and EtOH/0. lN HCl) were saturated with Compound A
hydrochloride at about 50-70 0C. Once the solids were completely dissolved, the
solution was rapidly cooled by placing into a refrigerator (about 0—5 OC). Solids were
isolated after 1 to 3 days.
] t/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 r cooled by placing into a refrigerator (about 0—
CC). The solids resulting from the recrystallization were filtered and air-dried.
Grinding Studies: Grinding experiments were med using a Wig-L-
Bug . About 50 mg of Compound A hydrochloride was added to a polystyrene
tube (1” X 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.
Humidity Studies: About 30 mg of Compound A hydrochloride was
placed in amber glass vials in duplicate. The vials were placed in 40 OC/75%RH
humidity r 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.
.4.2. CHARACTERIZATION METHODOLOGY
[0023 6] X-ray Powder Diffraction (XRPD): XRPD is was conducted on a
Thermo ARL X’TRATM X-ray powder diffractometer using Cu Ka radiation at 1.54 A.
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 ence 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 ed by a peltier-cooled Si(Li) solid-state detector. A theta-
two theta continuous scan at 2.40°/min (0.5 sec/0.02O step) from 1.5 020 to 40 020 was
used. A sintered alumina standard was used to check the peak position. In general,
positions ofXRPD peaks are expected to individually vary on a measurement-by-
ement basis by about ::0.2 020. 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, ining 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 d to, preferred orientation, phase
impurities, degree of llinity, 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.
[0023 7] Differential ng metry (DSC): DSC analyses were performed
on a TA Instruments 2000TM 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 °C/min from about 25 °C up to a final
ature of 300 CC. Melting points were reported as the extrapolated onset
temperatures.
Thermal Gravimetric Analyses (TGA): TGA analyses were performed on
a TA Instruments Q5000TM 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
OC/min up to a final temperature of about 300 0C.
[00239] Optical Microscopy: Morphology analysis of a sample was carried out on
an s microscope. Small amounts of a sample were dispersed in mineral oil on a
glass slide with cover slips and viewed with 20x magnification.
Dynamic Vapor Sorption (DVS): Hygroscopicity was determined on a
Surface ement 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.
lity 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 lity was measured after 1 hr of agitation.
.4.3. SOLID FORM SCREENING STUDY RESULTS
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, andI are ed herein as FIGS. 1 to 21.
1. SOLID FORMS OF COMPOUND A
Interconversions between various solid forms of nds A are
summarized in . The physical ties of Forms A, B, C, D, E, and F are
summarized in Table 2.
TABLE 2. Characteristics of Solid Forms of nd A
Form Morphology DSC Peaks TGA Loss Moisture
(°C) Sorption at
95% RH
Crystalline 145.3 (broad) . .
Irregular plate 161.2 (exo)
282.1 onset
Crystalline
Irre _ular shae
Crystalline
Irre _ular shae
Semi-crystalline 114.4 (broad) . Unstable
Irregular shape 283.3 (onset) dehydrated
form
lline 147.0 (broad) . Hydrate/solvate
Large irregular 279.4 (onset)
.late
266.5 onset
In a d 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 se and the batch further crystallized. The batch was then filtered. The
cake was washed with a 1:1 (vzv) 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.
[00245] 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 r crystallized. The batch was
then d. The cake was then washed with 1:1 (vzv) DMSO:water solution and neat
water. The wet cake was dried in a vacuum oven. The final dry product was tent
with Compound A Form A.
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 CC.
Upon reaching equilibrium, the solid was filtered and air dried.
] 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 CC. The
slurry ments 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 CC. Upon reaching equilibrium, the solid was d and air
dried.
Form D of Compound A was prepared from Form A Via drying Form A in
vacuum oven at about 80 - 90 0C.
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 panol. The ing mixture was agitated for at least 24
hours at room temperature. Upon reaching equilibrium, the solid was filtered and air
dried.
[00250] Form F of nd 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 ature. The solid was then filtered and air dried.
.4.3.2. SOLID FORM A1 OF COMPOUND A HCl
[00251] 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°C. The solution was cooled to 45°C and approx 3.3 mL 6 N
hydrochloric acid was added, causing crystallization. The slurry was then slowly cooled
and filtered. Tthe cake was washed with acetonitrile and then dried in a vacuum oven.
The ing dry product was consistent with Compound A Form Al.
Large Scale Process. Form Al was prepared on a large scale by
combining 100 g of Compound A hydrochloride, 960 mL itrile and 960 mL
deionized water in a reactor. The mixture was heated with agitation to 60 to 70 °C and
erred to a second reactor by an inline filter (0.45 um). The first reactor is rinsed
with 100 mL of acetonitrilezwater (1:1), which was transferred to the second reactor by
the inline filter. The temperature in the second reactor was maintained at 65 °C during
transfer. The second reactor was then cooled to 45 OC and seeded with 3 g Form Al
WO 25438
crystals. The batch began to crystallize and was aged at 45 °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 OC. The batch was aged at 45°C for 1.5 hours and cooled
to 0 °C in a linear ramp over 4 hours. The batch was then aged at 0 °C for 1 hour. The
supernatant was sampled for UPLC concentration. The concentration of Form A1 in the
atant was 5 mg/mL. The slurry was filtered through a fritted glass filter with
. The resulting cake was displacement washed with 2 x 300 mL acetonitrile
washes. The cake was dried in a vacuum oven at 40 0C until acetonitrile is < 400 ppm.
The dry cake of Form Al was a clean white/off-white .
[00253] It was discovered that acetonitrilezwater was the only solvent system
which afforded acceptable properties for scaleup, e.g., solubility greater than about
50g/mL product. Excess HCl was added to prevent formation of the free base of
nd A. In some cases it was found that the absence of HCl in the s resulted
in free base formation. Excess HCl was also thought to improve Form A1 yield during
crystallization.
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 ~280 0C, which is considered to be
decomposition (similar to the decomposition point of the freebase). Microscopy showed
long rod morphology.
Solubility Studies. The approximate solubility of Form A1 of nd
A hydrochloride in various solvents at about 25 0C was ined. Form Al 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,
CH2C12, THF, and water. Form Al 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 3.
TABLE 3. lity
Solubility (mg/mL)
Acetonitrile (AcCN) 0.02
Acetone 2.55
[0025 6] Slurry experiments were performed at room temperature and 50 0C using
Form A1 of Compound A hloride as starting material. The results are
summarized in Tables 4 and 5. 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 OC 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 4. Equilibration ments at Room Temperature.
eeeneee
WO 25438
Methanol Form Al
Methylene chloride Form Al
Methyl ethyl ketone Form Al
Methyl t-butyl ether Form Al
2-Pro o anol Form Al
Toluene Form Al
Tetrahydrofuran Form Al
Water Form A -- Form Al
Ethanol/Water (1:1) Form A -- Form Al
Acetonitrile /Water (1:1) Form A -- Form Al
Tetrahydrofuran /Water (1:1) Form A -- Form Al
TABLE 5. Euilibration Exoeriments at 50 °C
Solvent XRPD Result
Acetone Form Al
Acetonitrile Form Al
n-Butanol Form Al
Ethanol Form Al
Ethyl acetate Form Al
e Form Al
ol Form Al
Methyl ethyl ketone Form Al
2-Propanol Form Al
Toluene Form Al
Tetrahydrofuran Form Al
Water Form A -- Form Al
Ethanol/Water (1:1) Form A -- Form Al
Acetonitrile /Water (1:1) Form A -- Form Al
Tetrahydrofuran /Water (1:1) Form Al
Evaporation experiments were performed. The results are summarized in
Tables 6 and 7. For room temperature evaporations, solids obtained from water,
ater, and MeCN/water were confirmed to be Form Al. Partial or complete salt
dissociation were ed in MeOH, THF, and THF/water. For 50 OC evaporations,
solids obtained from MeOH, water, EtOH/water, and MeCN/water were confirmed to be
Form Al. Solid from THF/water was shown to be amorphous.
TABLE 6. Evaporation Experiments at Room Temperature
Acetonitrile
Ethyl e
Ethanol/Water (1 1) Form A1
Acetonitrile /Water (1 : 1) Form A1
Tetrahydrofuran /Water (1:1) Form A + Form A1
TABLE 7. Evaporation Experiments at 50 °C
KY >>7/
Acetonitrile /Water (1 : 1) Form A1
Tetrahydrofilran /Water (1:1) Amorphous
Recrystallization experiments were med in several organic/aqueous
mixtures. The results are summarized in Table 8. Solids from MeCN/water,
MeOH/0.lN HCl, or EtOH/0. lN HCl were confirmed to be Form Al. Complete salt
dissociation was observed in ter.
Anti-solvent llization was also performed with MeCN/water as the
primary t system, and with acetone or IPA as antisolvent. Form Al was obtained
when acetone was used as antisolvent, and partial salt dissociation was observed when
IPA was used as lvent.
TABLE 8. Recrystallization without and with Antisolvents
Solvent Antisolvent Ratio. (Solvent XRPD Result
/Ant1solvent)
Grinding experiments were performed with and without addition of water,
as a further attempt to generate polymorphs. Form Al was found unchanged upon
grinding. The results are summarized in Table 9.
TABLE 9. ng Experiments
XRPD Result
Starting Form Test Conditions
Characterization of Form A1
Form A1 had a crystalline XRPD pattern as shown in and
ar l habit. TGA and DSC thermograms of Form A1 are shown in FIGS. 19
and 20, respectively. ible weight loss was observed prior to decomposition, the
onset temperature of which was about 276 0C as determined by DSC.
The moisture on/desorption behavior of Form Al was determined
by DVS and the results are summarized in . Form A1 exhibited a 0.15% mass
change ve 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.
Stability of Form Al was determined by exposing the sample to a
40°C/75%RH environment for four weeks or 95 %RH at room temperature for four days.
Solid form of the exposed al was not changed compared to the initial unexposed
sample (Table 10). Form Al was also found to be stable upon application of 2000-psi
re for about 1 minute.
TABLE 10. Grinding Experiments
Starting Form Test Conditions XRPD Result
40 CNS A) RH for0 0
Form A1 Form A1
4 weeks, open v1al
40 OC/75% RH f0?
Form A1 Form A1
4 weeks, closed v1al
Form A1 95%RH for 4 days Form A1
Based on these characterization studies, Form Al was found to be a stable
anhydrous and non-hygroscopic crystalline material.
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.
All of the patents, patent applications and publications referred to herein
are incorporated herein in their entireties. Citation or fication of any reference in
this application is not an admission that such reference is available as prior art to this
disclosure. The fill scope of the disclosure is better understood with reference to the
ed claims.
Claims (66)
1. A solid form of 3-(5-aminomethyloxo-4H-quinazolinyl)-piperidine-2,6-dione: 0 1‘31 0 Nlle U (5%N/J\ or a isomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, or clathrate thereof, wherein the solid form is crystalline.
2. The solid form of claim 1, which is a solid form of a hydrochloride salt of 3-(5-amino methyloxo-4H-quinazolinyl)-piperidine-2,6-dione.
3. The solid form of claim 2, having an X-ray powder diffiaction pattern substantially as shown in .
4. The solid form of claim 2, having an X—ray powder diffraction pattern comprising peaks at about 8.6, 13.1, 20.5 and 26.3 degrees 29.
5. The solid form of claim 2, having an X-ray powder diffraction pattern sing peaks at about 8.6, 11.3, 13.1, 15.3, 17.3, 20.5, 22.7, 23.6, 26.3 and 31.4 degrees 20.
6. The solid form of any one of claims 2-5, having a ential scanning calorimetry plot comprising an endothermic event with an onset temperature of about 276 °C.
7. The solid form of any one of claims 2-6, having a thermal gravimetric analysis plot comprising a mass loss of less than about 0.5% when heated from about 25 °C to about 150 °C.
8. The solid form of any one of claims 2-7, which is anhydrous.
9. The solid form of any one of claims 2-8, which exhibits a mass increase of less than about 0.5% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity.
10. The solid form of any one of claims 2-9, which is substantially nonhygroscopic.
11. The solid form of any one of claims 2-10, which is stable upon re to about 40 °C and about 75% ve humidity for about 4 weeks.
12. The solid form of any one of claims 2-11, wherein the molar ratio of 3-(5-amino methyloxo-4H-quinazolinyl)-piperidine-2,6-dione to hydrochloride is from about 0.1 to about 10.
13. The solid form of claim 1, having an X-ray powder diffraction pattern substantially as shown in
14. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 14.6, 15.6, 16.7, 21.9 and 30.0 degrees 2θ.
15. The solid form of claim 1, having an X-ray powder diffraction pattern sing peaks at about 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 2θ.
16. The solid form of any one of claims 13-15, having a differential scanning calorimetry plot comprising an endothermic event with an onset temperature of about 282 °C.
17. The solid form of any one of claims 13-16, having a thermal gravimetric analysis plot comprising a mass loss of less than about 6% when heated from about 25 °C to about 150 °C.
18. The solid form of any one of claims 13-17, which ts a mass increase of less than or equal to about 6% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity.
19. The solid form of any one of claims 13-18, which is hydrated.
20. The solid form of claim 19, which the crystal lattice of the solid form comprises about one molar equivalent of water per mole of 3-(5-aminomethyloxo-4H-quinazolinyl)- piperidine-2,6-dione.
21. The solid form of claim 1, having an X-ray powder diffraction pattern substantially as shown in
22. The solid form of claim 1, having an X-ray powder ction pattern comprising peaks at about 10.6, 14.7, 19.1 and 25.9 degrees 2θ.
23. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 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 2θ.
24. The solid form of any one of claims 21-23, having a ential scanning calorimetry plot comprising an endothermic event with an onset temperature of about 279 °C.
25. The solid form of any one of claims 21-24, having a thermal gravimetric analysis plot comprising a mass loss of less than about 0.1% when heated from about 25 °C to about 150 °C.
26. The solid form of any one of claims 21-25, which exhibits a mass increase of less than about 0.2% when subjected to an increase in relative humidity from about 0% to about 95% ve humidity.
27. The solid form of any one of claims 21-26, which is unsolvated.
28. The solid form of any one of claims 21-27, which is substantially roscopic.
29. The solid form of claim 1, having an X-ray powder diffraction pattern substantially as shown in
30. The solid form of claim 1, having an X-ray powder diffraction n comprising peaks at about 10.8, 15.1, 25.1 and 26.6 degrees 2θ.
31. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 10.8, 11.9, 15.1, 18.8, 19.2, 19.3, 22.0, 24.9, 25.1, 26.6 and 29.2 degrees 2θ.
32. The solid form of any one of claims 29-31, having a differential scanning calorimetry plot comprising an endothermic event with an onset temperature of about 281 °C.
33. The solid form of any one of claims 29-32, having a thermal gravimetric analysis plot comprising a mass loss of less than about 0.1% when heated from about 25 °C to about 150 °C.
34. The solid form of any one of claims 29-33, which exhibits a mass increase of less than about 0.2% when ted to an increase in relative humidity from about 0% to about 95% relative humidity.
35. The solid form of any one of claims 29-34, which is unsolvated.
36. The solid form of any one of claims 29-35, which is substantially roscopic.
37. The solid form of claim 1, having an X-ray powder diffraction pattern substantially as shown in .
38. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 16.7, 21.7, 21.9 and 25.8 degrees 2θ.
39. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 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 2θ.
40. The solid form of any one of claims 37-39, having a differential ng calorimetry plot comprising an endothermic event with an onset temperature of about 283 °C.
41. The solid form of any one of claims 37-40, having a thermal gravimetric analysis plot sing a mass loss of less than about 4% when heated from about 25 °C to about 150 °C.
42. The solid form of any one of claims 37-41, which exhibits a mass increase of less than or equal to about 6% when ted to an increase in relative humidity from about 0% to about 95% relative humidity.
43. The solid form of claim 1, having an X-ray powder diffraction pattern substantially as shown in .
44. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 7.3, 14.6, 22.0, 30.0 and 37.0 degrees 2θ.
45. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 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 2θ.
46. The solid form of any one of claims 43-45, having a differential scanning calorimetry plot comprising an ermic event with an onset temperature of about 279 °C.
47. The solid form of any one of claims 43-46, having a thermal gravimetric analysis plot comprising a mass loss of less than about 6% when heated from about 25 °C to about 150 °C.
48. The solid form of any one of claims 43-47, which exhibits a mass increase of less than about 0.5% when subjected to an increase in relative ty from about 0% to about 95% relative humidity.
49. The solid form of any one of claims 43-48, which is hydrated.
50. The solid form of any one of claims 43-49, which is substantially nonhygroscopic.
51. The solid form of claim 1, having an X-ray powder diffraction pattern substantially as shown in .
52. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 14.5, 15.7, 22.7 and 29.9 degrees 2θ.
53. The solid form of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 7.2, 9.1, 14.5, 15.7, 16.8, 18.3, 21.9, 22.7, 29.9 and 36.9 degrees 2θ.
54. The solid form of any one of claims 51-53, having a differential scanning calorimetry plot comprising an endothermic event with an onset temperature of about 267 °C.
55. The solid form of any one of claims 51-54, which is hydrated.
56. A mixture comprising two or more solid forms selected from the solid forms of claims 1-
57. A pharmaceutical ition comprising the solid form of any one of claims 1-55 and a pharmaceutical acceptable carrier, diluent or excipient.
58. The pharmaceutical composition of claim 57, wherein the composition is formulated for oral, parenteral, or intravenous administration.
59. The pharmaceutical composition of claim 57 or 58, n the composition is ated as a single unit dosage form.
60. The ceutical composition of claim 59, wherein the dosage form is a tablet or capsule.
61. Use of a solid form of any one of claims 1-55, a mixture of claim 56, or a composition of any one of claims 57-60, in the manufacture of a medicament for ng, managing or preventing a disease or disorder, wherein the disease or disorder is cancer, a disorder associated with angiogenesis, pain, macular degeneration or a related syndrome, a skin e, a pulmonary disorder, an asbestos-related er, a parasitic disease, an immunodeficiency disorder, a CNS disorder, CNS injury, atherosclerosis or a related disorder, dysfunctional sleep or a related disorder, hemoglobinopathy or a related disorder, or a TNFα related disorder.
62. The use of claim 61, n treating, ng or preventing comprises administering a second active agent.
63. A solid form according to claim 1, substantially as herein described or exemplified.
64. A mixture according to claim 56, substantially as herein described or exemplified.
65. A pharmaceutical composition according to claim 57, substantially as herein described or exemplified.
66. A use ing to claim 61, substantially as herein described or exemplified.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161451806P | 2011-03-11 | 2011-03-11 | |
US61/451,806 | 2011-03-11 | ||
PCT/US2012/028419 WO2012125438A1 (en) | 2011-03-11 | 2012-03-09 | Solid forms of 3-(5-amino-2methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ614424A NZ614424A (en) | 2016-01-29 |
NZ614424B2 true NZ614424B2 (en) | 2016-05-03 |
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