U.S. patent application number 15/594273 was filed with the patent office on 2018-04-05 for isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2,6-dione and methods of preparation thereof.
The applicant listed for this patent is Celgene Corporation. Invention is credited to William W. Leong, Hon-Wah Man.
Application Number | 20180093965 15/594273 |
Document ID | / |
Family ID | 49226507 |
Filed Date | 2018-04-05 |
United States Patent
Application |
20180093965 |
Kind Code |
A1 |
Man; Hon-Wah ; et
al. |
April 5, 2018 |
ISOTOPOLOGUES OF
3-(5-AMINO-2-METHYL-4-OXOQUINAZOLIN-3(4H)-YL)PIPERIDINE-2,6-DIONE
AND METHODS OF PREPARATION THEREOF
Abstract
Provided herein are deuterated isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
or enantiomers or mixtures of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, cocrystal or polymorph
thereof, and processes for making the same. Pharmaceutical
compositions comprising the isotopes-enriched compounds, and
methods of using such compounds are also provided.
Inventors: |
Man; Hon-Wah; (Princeton,
NJ) ; Leong; William W.; (Westfield, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Celgene Corporation |
Summit |
NJ |
US |
|
|
Family ID: |
49226507 |
Appl. No.: |
15/594273 |
Filed: |
May 12, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14425479 |
Mar 3, 2015 |
9682952 |
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PCT/US13/57786 |
Sep 3, 2013 |
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15594273 |
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61696727 |
Sep 4, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/00 20180101;
A61P 9/10 20180101; A61P 43/00 20180101; A61P 27/02 20180101; A61P
17/00 20180101; A61P 25/00 20180101; A61P 33/00 20180101; A61P
29/02 20180101; A61P 37/04 20180101; A61P 25/04 20180101; C07D
401/04 20130101; A61P 25/20 20180101; A61P 11/00 20180101; A61P
35/00 20180101; A61P 7/00 20180101 |
International
Class: |
C07D 401/04 20060101
C07D401/04 |
Claims
1-98. (canceled)
99. A method of treating, managing or preventing a disease or
disorder comprising administering to a patient a compound of
formula: ##STR00591## or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal or polymorph thereof, wherein at least
one of Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.6, Y.sup.7,
Y.sup.8, Y.sup.9, Y.sup.10, Y.sup.11, Y.sup.12, Y.sup.13, and
Y.sup.14, is a hydrogen that is isotopically enriched with
deuterium, and the others of Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4,
Y.sup.5, Y.sup.6, Y.sup.7, Y.sup.8, Y.sup.9, Y.sup.10, Y.sup.11,
Y.sup.12, Y.sup.13 and Y.sup.14 are non-enriched hydrogen atoms,
and 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 disorder, CNS injury, atherosclerosis or a related
disorder, dysfunctional sleep or a related disorder,
hemoglobinopathy or a related disorder, or a TNF.alpha. related
disorder.
100. The method of claim 1, wherein one of Y.sup.1, Y.sup.2,
Y.sup.3, Y.sup.4, Y.sup.6, Y.sup.7, Y.sup.8, Y.sup.9, Y.sup.10,
Y.sup.11, Y.sup.12, Y.sup.13 and Y.sup.14 is a hydrogen that is
isotopically enriched with deuterium, and the others of Y.sup.1,
Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, Y.sup.6, Y.sup.7, Y.sup.8,
Y.sup.9, Y.sup.10, Y.sup.11, Y.sup.12, Y.sup.13 and Y.sup.14 are
non-enriched hydrogen atoms.
101. The method of claim 99, wherein two, three, four, five, six,
seven, eight, nine, ten, eleven, twelve, or all of Y.sup.1,
Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.6, Y.sup.7, Y.sup.8, Y.sup.9,
Y.sup.10, Y.sup.11, Y.sup.12, Y.sup.13 and Y.sup.14 are hydrogen
atoms that are isotopically enriched with deuterium, and the others
of Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, Y.sup.6, Y.sup.7,
Y.sup.8, Y.sup.9, Y.sup.10, Y.sup.11, Y.sup.12, Y.sup.13 and
Y.sup.14 are non-enriched hydrogen atoms.
102. The method of claim 100, wherein Y.sup.1 is a hydrogen that is
isotopically enriched with deuterium.
103. The method of claim 100, wherein Y.sup.3 is a hydrogen that is
isotopically enriched with deuterium.
104. The method of claim 100, wherein Y.sup.6 is a hydrogen that is
isotopically enriched with deuterium.
105. The method of claim 100, wherein Y.sup.9 is a hydrogen that is
isotopically enriched with deuterium.
106. The method of claim 100, wherein Y.sup.10 is a hydrogen that
is isotopically enriched with deuterium.
107. The method of claim 100, wherein Y.sup.11 is a hydrogen that
is isotopically enriched with deuterium.
108. The method of claim 99, wherein the cancer is advanced
malignancy, amyloidosis, neuroblastoma, meningioma,
hemangiopericytoma, multiple brain metastase, glioblastoma
multiforms, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor, malignant glioma, recurrent malignant
giolma, 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, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large
B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma,
malignant mesothelioma, malignant pleural effusion mesothelioma
syndrome, peritoneal carcinoma, papillary serous carcinoma,
gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous
vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,
fibrodysplasia ossificans progressive, hormone refractory prostate
cancer, resected high-risk soft tissue sarcoma, unrescectable
hepatocellular carcinoma, Waldenstrom's macroglobulinemia,
smoldering myeloma, indolent myeloma, fallopian tube cancer,
androgen independent prostate cancer, androgen dependent stage IV
non-metastatic prostate cancer, hormone-insensitive prostate
cancer, chemotherapy-insensitive prostate cancer, papillary thyroid
carcinoma, follicular thyroid carcinoma, medullary thyroid
carcinoma, or leiomyoma.
109. The method of claim 108, wherein the cancer is non-Hodgkin's
lymphoma.
110. The method of claim 109, wherein the non-Hodgkin's lymphoma is
diffuse large B-cell lymphoma.
111. The method of claim 99, wherein the method comprises
administering a second active agent.
113. A method for preparing a compound of formula (I-A):
##STR00592## wherein Y.sup.12, Y.sup.13 and Y.sup.14 are
independently H or D, or an enantiomer or a mixture of enantiomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal or polymorph thereof, comprising the steps of: (a)
contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
with a base and an exchangeable deuterium source; (b) performing an
aqueous workup on the reaction mixture from step (a) to form a
compound of formula (I-A) or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, or polymorph thereof; and (c) optionally
obtaining enantiomers using chiral separation.
114. The method of claim 113, wherein the base is sodium C.sub.1-14
alkoxide, potassium C.sub.1-14 alkoxide, sodium hydride, potassium
hydride, calcium hydride. sodium hydroxide, lithium hydroxide,
potassium hydroxide, cesium hydroxide, cesium carbonate. lithium
hexamethyldisilazide (LiHMDS), lithium diisopropylamide (LDA),
2-tert-butyl-1,1,3,3-tetramethyl-guanidine (Barton's Base),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo(2.2.2)octane (DABCO), N,N-diisopropylethylamine
(DIPEA or Hunig's base, pyridine, 2,6-di-tert-butyl-pyridine,
2,6-lutidine. In lithium tetramethylpiperidide (LiTMP or harpoon
base, 7-methyl-1,5,7 triazabicyclo[4.4.0]dec-5-ene (MTBD),
1,2,2,6,6-pentamethylpiperidine (PMP),
2,2,6,6-tetramethylpiperidine (TMP), tributylamine,
2,4,6-tri-tert-butylpyridine, tris(trimethylsilyl)amine,
n-butyllithium, sec-butyllithium, tert-butyllithium, potassium
bis(trimethylsilyl)amide, sodium tert-butoxide, potassium
tert-butoxide, tert-butylimino-tris(dimethylamino)phosphorane and
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine.
115. The method of claim 113, wherein the exchangeable deuterium
source is selected from the group consisting of is D.sub.2O,
C.sub.1-14 alkyl-OD, C.sub.1-14 alkyl-COOD, aryl-OD, heteroaryl-OD,
aryl-SO.sub.3D, deuterium chloride, deuterium bromide, deuterium
iodide, sulfuric acid-d.sub.2 and nitric acid-d.sub.1.
116. A method for preparing a compound of formula I-B ##STR00593##
wherein Y.sup.12, Y.sup.13 and Y.sup.14 are independently H or D,
or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal or
polymorph thereof, comprising the steps of: (a) contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
or a salt thereof with an exchangeable deuterium source in a
solvent to form a compound of formula (I-B), or an enantiomer or a
mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, or polymorph thereof; and (b) optionally
obtaining enantiomers by chiral separation.
117. The method of claim 116, wherein the exchangeable deuterium
source is D.sub.2O, C.sub.1-14 alkyl-OD, C.sub.1-14 alkyl-COOD,
aryl-OD, heteroaryl-OD, aryl-SO.sub.3D, deuterium chloride,
deuterium bromide, deuterium iodide, sulfuric acid-d.sub.2 or
nitric acid-d.sub.1.
118. The method of claim 116, wherein the solvent is a hydrocarbon,
chlorinated hydrocarbon, alcohol, ether, ketone, ester, carbonate,
amide, nitrile, sulfoxide, sulfone, nitro compound, arene,
heteroarene, heterocycle, carboxylic acid, phosphoramide, carbon
sulfide or water.
Description
I. FIELD
[0001] Provided herein are isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
compositions comprising the isotopologues, methods of making the
isotopologues, and methods of their use for treatment or prevention
of diseases and conditions including, but not limited to,
inflammatory diseases, autoimmune diseases, and cancers.
II. BACKGROUND
[0002] Cancer is characterized primarily by an increase in the
number of abnormal cells derived from a given normal tissue,
invasion of adjacent tissues by these abnormal cells, or lymphatic
or blood-borne spread of malignant cells to regional lymph nodes
and to distant sites (metastasis). Clinical data and molecular
biologic studies indicate that cancer is a multistep process that
begins with minor preneoplastic changes, which may under certain
conditions progress to neoplasia. The neoplastic lesion may evolve
clonally and develop an increasing capacity for invasion, growth,
metastasis, and heterogeneity, especially under conditions in which
the neoplastic cells escape the host's immune surveillance. Roitt,
I., Brostoff, J., and Kale, D., Immunology, 17.1-17.12 (3rd ed.,
Mosby, St. Louis, Mo., 1993).
[0003] There is an enormous variety of cancers which are described
in detail in the medical literature. Examples include cancer of the
lung, colon, rectum, prostate, breast, brain, and intestine. The
incidence of cancer continues to climb as the general population
ages, as new cancers develop, and as susceptible populations (e.g.,
people infected with AIDS or excessively exposed to sunlight) grow.
However, options for the treatment of cancer are limited. For
example, in the case of blood cancers (e.g., multiple myeloma), few
treatment options are available, especially when conventional
chemotherapy fails and bone-marrow transplantation is not an
option. A tremendous demand therefore exists for new methods and
compositions that can be used to treat patients with cancer.
[0004] 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 a. Alternatively, tumor cells can release
angiogenic peptides through the production of proteases and the
subsequent breakdown of the extracellular matrix where some
cytokines are stored (e.g., b FGF). Angiogenesis can also be
induced indirectly through the recruitment of inflammatory cells
(particularly macrophages) and their subsequent release of
angiogenic cytokines (e.g., TNF a, b-FGF).
[0005] A variety of other diseases and disorders are also
associated with, or characterized by, undesired angiogenesis. For
example, enhanced or unregulated angiogenesis has been implicated
in a number of diseases and medical conditions including, but not
limited to, ocular neovascular diseases, choroidal neovascular
diseases, retina neovascular diseases, rubeosis (neovascularization
of the angle), viral diseases, genetic diseases, inflammatory
diseases, allergic diseases, and autoimmune diseases. Examples of
such diseases and conditions include, but are not limited to:
diabetic retinopathy; retinopathy of prematurity; corneal graft
rejection; neovascular glaucoma; retrolental fibroplasia;
arthritis; and proliferative vitreoretinopathy.
[0006] Accordingly, compounds that can control angiogenesis or
inhibit the production of certain cytokines, including TNF.alpha.,
may be useful in the treatment and prevention of various diseases
and conditions.
[0007] Current cancer therapy may involve surgery, chemotherapy,
hormonal therapy and/or radiation treatment to eradicate neoplastic
cells in a patient (see, e.g., Stockdale, 1998, Medicine, vol. 3,
Rubenstein and Federman, eds., Chapter 12, Section IV). Recently,
cancer therapy could also involve biological therapy or
immunotherapy. All of these approaches pose significant drawbacks
for the patient. Surgery, for example, may be contraindicated due
to the health of a patient or may be unacceptable to the patient.
Additionally, surgery may not completely remove neoplastic tissue.
Radiation therapy is only effective when the neoplastic tissue
exhibits a higher sensitivity to radiation than normal tissue.
Radiation therapy can also often elicit serious side effects.
Hormonal therapy is rarely given as a single agent. Although
hormonal therapy can be effective, it is often used to prevent or
delay recurrence of cancer after other treatments have removed the
majority of cancer cells. Biological therapies and immunotherapies
are limited in number and may produce side effects such as rashes
or swellings, flu-like symptoms, including fever, chills and
fatigue, digestive tract problems or allergic reactions.
[0008] With respect to chemotherapy, there are a variety of
chemotherapeutic agents available for treatment of cancer. A
majority of cancer chemotherapeutics act by inhibiting DNA
synthesis, either directly, or indirectly by inhibiting the
biosynthesis of deoxyribonucleotide triphosphate precursors, to
prevent DNA replication and concomitant cell division. Gilman et
al., Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, Tenth Ed. (McGraw Hill, New York).
[0009] Despite availability of a variety of chemotherapeutic
agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol.
3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost
all chemotherapeutic agents are toxic, and chemotherapy causes
significant, and often dangerous side effects including severe
nausea, bone marrow depression, and immunosuppression.
Additionally, even with administration of combinations of
chemotherapeutic agents, many tumor cells are resistant or develop
resistance to the chemotherapeutic agents. In fact, those cells
resistant to the particular chemotherapeutic agents used in the
treatment protocol often prove to be resistant to other drugs, even
if those agents act by different mechanism from those of the drugs
used in the specific treatment. This phenomenon is referred to as
pleiotropic drug or multidrug resistance. Because of the drug
resistance, many cancers prove or become refractory to standard
chemotherapeutic treatment protocols.
[0010] Other diseases or conditions associated with, or
characterized by, undesired angiogenesis are also difficult to
treat. However, some compounds such as protamine, heparin and
steroids have been proposed to be useful in the treatment of
certain specific diseases. (Taylor et al., Nature 297:307 (1982);
Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos.
5,001,116 and 4,994,443).
[0011] Still, there is a significant need for safe and effective
methods of treating, preventing and managing cancer and other
diseases and conditions, including for diseases that are refractory
to standard treatments, such as surgery, radiation therapy,
chemotherapy and hormonal therapy, while reducing or avoiding the
toxicities and/or side effects associated with the conventional
therapies.
[0012] Certain 4-oxoquinazoline compounds, including
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
have been reported to be capable of controlling angiogenesis or
inhibiting the production of certain cytokines, including
TNF-.alpha., and useful in the treatment and prevention of various
diseases and conditions. See U.S. Pat. No. 7,635,700, the
disclosure of which is incorporated herein by reference in its
entirety.
[0013] The molecule
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
which has the chemical structure:
##STR00001##
has been described in U.S. Pat. No. 7,635,700. A need still exists
for efficient and scalable processes for the preparation of
isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
or an enantiomer or a mixture of enantiomers thereof, or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal or
polymorph thereof. The compound
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dion-
e, its various isotopologues and compositions comprising the same
have utility for, inter alia, treatment of certain cancers (e.g.,
multiple myeloma, myelodyplastic syndrome, chronic lymphocytic
leukemia, and non-Hodgkin's lymphoma) and other various diseases
and disorders.
III. SUMMARY
[0014] Provided herein are isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
and methods for the preparation the isotopologues, or enantiomers
or mixtures of enantiomers thereof; or pharmaceutically acceptable
salts, solvates, hydrates, cocrystals or polymorphs thereof.
IV. DETAILED DESCRIPTION
[0015] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as those commonly understood by
one of ordinary skill in the art. All publications and patents
referred to herein are incorporated by reference herein in their
entireties.
A. Definitions
[0016] The descriptions of the terminology provided below apply to
the terms as used herein and unless otherwise specified.
[0017] The term "compound" includes salt, solvates (e.g.,
hydrates), cocrystals and polymorphs thereof.
[0018] The term "isotopic composition" refers to the amount of each
isotope present for a given atom, and "natural isotopic
composition" refers to the naturally occurring isotopic composition
or abundance for a given atom. Atoms containing their natural
isotopic composition may also be referred to herein as
"non-enriched" atoms. Unless otherwise designated, the atoms of the
compounds recited herein are meant to represent any stable isotope
of that atom. For example, unless otherwise stated, when a position
is designated specifically as "H" or "hydrogen," the position is
understood to have hydrogen at its natural isotopic
composition.
[0019] The term "isotopically enriched" refers to an atom having an
isotopic composition other than the natural isotopic composition of
that atom. "Isotopically enriched" may also refer to a compound
containing at least one atom having an isotopic composition other
than the natural isotopic composition of that atom. As used herein,
an "isotopologue" is an isotopically enriched compound.
[0020] The term "isotopic enrichment" refers to the percentage of
incorporation of an amount of a specific isotope at a given atom in
a molecule in the place of that atom's natural isotopic
composition. For example, deuterium enrichment of 1% at a given
position means that 1% of the molecules in a given sample contain
deuterium at the specified position. Because the naturally
occurring distribution of deuterium is about 0.0156%, deuterium
enrichment at any position in a compound synthesized using
non-enriched starting materials is about 0.0156%.
[0021] The term "isotopic enrichment factor" refers to the ratio
between the isotopic composition and the natural isotopic
composition of a specified isotope.
[0022] With regard to the compounds provided herein, when a
particular atomic position is designated as having deuterium or
"D," it is understood that the abundance of deuterium at that
position is substantially greater than the natural abundance of
deuterium, which is about 0.015%. A position designated as having
deuterium typically has a minimum isotopic enrichment factor of, in
particular embodiments, at least 1000 (15% deuterium
incorporation), at least 2000 (30% deuterium incorporation), at
least 3000 (45% deuterium incorporation), at least 3500 (52.5%
deuterium incorporation), at least 4000 (60% deuterium
incorporation), at least 4500 (67.5% deuterium incorporation), at
least 5000 (75% deuterium incorporation), at least 5500 (82.5%
deuterium incorporation), at least 6000 (90% deuterium
incorporation), at least 6333.3 (95% deuterium incorporation), at
least 6466.7 (97% deuterium incorporation), at least 6600 (99%
deuterium incorporation), or at least 6633.3 (99.5% deuterium
incorporation) at each designated deuterium atom.
[0023] The isotopic enrichment and isotopic enrichment factor of
the compounds provided herein can be determined using conventional
analytical methods known to one of ordinary skill in the art,
including mass spectrometry and nuclear magnetic resonance
spectroscopy.
[0024] The term "alkyl" refers to a linear or branched saturated
monovalent hydrocarbon radical, wherein the alkyl is optionally
substituted with one or more substituents Q as described herein
elsewhere. For example, C.sub.1-6 alkyl refers to a linear
saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or
a branched saturated monovalent hydrocarbon radical of 3 to 6
carbon atoms. In certain embodiments, the alkyl is a linear
saturated monovalent hydrocarbon radical that has 1 to 20
(C.sub.1-20), 1 to 15 (C.sub.1-15), 1 to 10 (C.sub.1-10), or 1 to 6
(C.sub.1-6) carbon atoms, or branched saturated monovalent
hydrocarbon radical of 3 to 20 (C.sub.3-20), 3 to 15 (C.sub.3-15),
3 to 10 (C.sub.3-10), or 3 to 6 (C.sub.3-6) carbon atoms. As used
herein, linear C.sub.1-6 and branched C.sub.3-6 alkyl groups are
also referred as "lower alkyl." Examples of alkyl groups include,
but are not limited to, methyl, ethyl, propyl (including all
isomeric forms), n-propyl, isopropyl, butyl (including all isomeric
forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including
all isomeric forms), and hexyl (including all isomeric forms).
[0025] The term "alkenyl" refers to a linear or branched monovalent
hydrocarbon radical, which contains one or more, in one embodiment,
one to five, in another embodiment, one, carbon-carbon double
bond(s), wherein the alkenyl is optionally substituted with one or
more substituents Q as described herein elsewhere. The term
"alkenyl" embraces radicals having a "cis" or "trans" configuration
or a mixture thereof, or alternatively, a "Z" or "E" configuration
or a mixture thereof, as appreciated by those of ordinary skill in
the art. For example, C.sub.2-6 alkenyl refers to a linear
unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms
or a branched unsaturated monovalent hydrocarbon radical of 3 to 6
carbon atoms. In certain embodiments, the alkenyl is a linear
monovalent hydrocarbon radical of 2 to 20 (C.sub.2-20), 2 to 15
(C.sub.2-15), 2 to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon
atoms, or a branched monovalent hydrocarbon radical of 3 to 20
(C.sub.3-20), 3 to 15 (C.sub.3-15), 3 to 10 (C.sub.3-10), or 3 to 6
(C.sub.3-6) carbon atoms. Examples of alkenyl groups include, but
are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl,
butenyl, and 4-methylbutenyl.
[0026] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical, which contains one or more, in one embodiment,
one to five, in another embodiment, one, carbon-carbon triple
bond(s), wherein the alkynyl is optionally substituted with one or
more substituents Q as described herein elsewhere. For example,
C.sub.2-6 alkynyl refers to a linear unsaturated monovalent
hydrocarbon radical of 2 to 6 carbon atoms or a branched
unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
In certain embodiments, the alkynyl is a linear monovalent
hydrocarbon radical of 2 to 20 (C.sub.2-20), 2 to 15 (C.sub.2-15),
2 to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon atoms, or a
branched monovalent hydrocarbon radical of 3 to 20 (C.sub.3-20), 3
to 15 (C.sub.3-15), 3 to 10 (C.sub.3-10), or 3 to 6 (C.sub.3-6)
carbon atoms. Examples of alkynyl groups include, but are not
limited to, ethynyl (--C.ident.CH), propynyl (including all
isomeric forms, e.g., 1-propynyl (--C.ident.CCH.sub.3) and
propargyl (--CH.sub.2C.ident.CH)), butynyl (including all isomeric
forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including
all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl),
and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl).
[0027] The term "cycloalkyl" refers to a cyclic monovalent
hydrocarbon radical, wherein the cycloalkyl is optionally
substituted with one or more substituents Q as described herein
elsewhere. In one embodiment, cycloalkyl groups may be saturated or
unsaturated but non-aromatic, and/or spiro, and/or non-spiro,
and/or bridged, and/or non-bridged, and/or fused bicyclic groups.
In certain embodiments, the cycloalkyl has from 3 to 20
(C.sub.3-20), from 3 to 15 (C.sub.3-15), from 3 to 10 (C.sub.3-10),
or from 3 to 7 (C.sub.3-7) carbon atoms. Examples of cycloalkyl
groups include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl,
bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
[0028] The term "aryl" refers to a monovalent monocyclic aromatic
group and/or monovalent polycyclic aromatic group that contain at
least one aromatic carbon ring, wherein the aryl is optionally
substituted with one or more substituents Q as described herein
elsewhere. In certain embodiments, the aryl has from 6 to 20
(C.sub.6-20), from 6 to 15 (C.sub.6-15), or from 6 to 10
(C.sub.6-10) ring atoms. Examples of aryl groups include, but are
not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl,
phenanthryl, pyrenyl, biphenyl, and terphenyl. The term "aryl" also
refers to bicyclic or tricyclic carbon rings, where one of the
rings is aromatic and the others of which may be saturated,
partially unsaturated, or aromatic, for example, dihydronaphthyl,
indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
[0029] The term "aralkyl" or "arylalkyl" refers to a monovalent
alkyl group substituted with one or more aryl groups, wherein the
aralkyl or arylalkyl is optionally substituted with one or more
substituents Q as described herein elsewhere. In certain
embodiments, the aralkyl has from 7 to 30 (C.sub.7-30), from 7 to
20 (C.sub.7-20), or from 7 to 16 (C.sub.7-16) carbon atoms.
Examples of aralkyl groups include, but are not limited to, benzyl,
2-phenylethyl, and 3-phenylpropyl.
[0030] The term "heteroaryl" refers to a monovalent monocyclic
aromatic group and/or monovalent polycyclic aromatic group that
contain at least one aromatic ring, wherein at least one aromatic
ring contains one or more heteroatoms independently selected from
O, S, N, and P in the ring. Heteroaryl groups are bonded to the
rest of a molecule through the aromatic ring. Each ring of a
heteroaryl group can contain one or two O atoms, one or two S
atoms, one to four N atoms, and/or one or two P atoms, provided
that the total number of heteroatoms in each ring is four or less
and each ring contains at least one carbon atom. In certain
embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from
5 to 10 ring atoms. Examples of monocyclic heteroaryl groups
include, but are not limited to, furanyl, imidazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,
thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and
triazolyl. Examples of bicyclic heteroaryl groups include, but are
not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl,
benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl,
benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl,
imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl,
isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl,
naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl,
purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl,
quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of
tricyclic heteroaryl groups include, but are not limited to,
acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,
phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, and xanthenyl. In certain
embodiments, the heteroaryl is optionally substituted with one or
more substituents Q as described herein elsewhere.
[0031] The term "heterocyclyl" or "heterocyclic" refers to a
monovalent monocyclic non-aromatic ring system and/or monovalent
polycyclic ring system that contain at least one non-aromatic ring,
wherein one or more of the non-aromatic ring atoms are heteroatoms
independently selected from O, S, N, and P; and the remaining ring
atoms are carbon atoms. In certain embodiments, the heterocyclyl or
heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10,
from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Heterocyclyl
groups are bonded to the rest of a molecule through the
non-aromatic ring. In certain embodiments, the heterocyclyl is a
monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which
may be spiro, fused, or bridged, and in which nitrogen or sulfur
atoms may be optionally oxidized, nitrogen atoms may be optionally
quaternized, and some rings may be partially or fully saturated, or
aromatic. The heterocyclyl may be attached to the main structure at
any heteroatom or carbon atom which results in the creation of a
stable compound. Examples of such heterocyclic groups include, but
are not limited to, azepinyl, benzodioxanyl, benzodioxolyl,
benzofuranonyl, benzopyranonyl, benzopyranyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl,
benzoxazinyl, .beta.-carbolinyl, chromanyl, chromonyl, cinnolinyl,
coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,
dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl,
dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,
dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,
1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,
isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,
isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,
oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl,
thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In
certain embodiments, the heterocyclyl is optionally substituted
with one or more substituents Q as described herein elsewhere.
[0032] The term "alkene" refers to a linear or branched
hydrocarbon, which contains one or more, in one embodiment, one to
five, in another embodiment, one, carbon-carbon double bond(s),
wherein the alkene is optionally substituted with one or more
substituents Q as described herein elsewhere. The term "alkene"
embraces a compound having a "cis" or "trans" configuration or a
mixture thereof, or alternatively, a "Z" or "E" configuration or a
mixture thereof, as appreciated by those of ordinary skill in the
art. For example, C.sub.2-6 alkene refers to a linear unsaturated
hydrocarbon of 2 to 6 carbon atoms or a branched unsaturated
hydrocarbon of 3 to 6 carbon atoms. In certain embodiments, the
alkene is a linear hydrocarbon of 2 to 20 (C.sub.2-20), 2 to 15
(C.sub.2-15), 2 to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon
atoms, or a branched hydrocarbon of 3 to 20 (C.sub.3-20), 3 to 15
(C.sub.3-15), 3 to 10 (C.sub.3-10), or 3 to 6 (C.sub.3-6) carbon
atoms.
[0033] The term "cycloalkene" refers to a cyclic hydrocarbon, which
contains one or more, in one embodiment, one to five, in another
embodiment, one, carbon-carbon double bond(s), wherein the
cycloalkene is optionally substituted with one or more substituents
Q as described herein elsewhere. In one embodiment, the cycloalkene
may be non-aromatic, and/or spiro, and/or non-spiro, and/or
bridged, and/or non-bridged, and/or fused bicyclic. In certain
embodiments, the cycloalkene has from 3 to 20 (C.sub.3-20), from 3
to 15 (C.sub.3-15), from 3 to 10 (C.sub.3-10), or from 3 to 7
(C.sub.3-7) carbon atoms.
[0034] The term "arene" refers to a monocyclic aromatic compound
and/or polycyclic aromatic compound that contain at least one
aromatic carbon ring, wherein the arene is optionally substituted
with one or more substituents Q as described herein elsewhere. In
certain embodiments, the arene has from 6 to 20 (C.sub.6-20), from
6 to 15 (C.sub.6-15), or from 6 to 10 (C.sub.6-10) ring atoms. The
term "arene" also refers to bicyclic or tricyclic carbon rings,
where one of the rings is aromatic and the other(s) may be
saturated, partially unsaturated, or aromatic.
[0035] The term "heteroarene" refers to a monocyclic aromatic
and/or polycyclic aromatic compound that contain at least one
aromatic ring, wherein at least one aromatic ring contains one or
more heteroatoms independently selected from O, S, N, and P in the
ring. Each ring of a heteroarene can contain one or two O atoms,
one or two S atoms, one to four N atoms, and/or one or two P atoms,
provided that the total number of heteroatoms in each ring is four
or less and each ring contains at least one carbon atom. In certain
embodiments, the heteroarene has from 5 to 20, from 5 to 15, or
from 5 to 10 ring atoms. In certain embodiments, the heteroarene is
optionally substituted with one or more substituents Q as described
herein elsewhere.
[0036] The term "heterocycle" refers to a monocyclic non-aromatic
ring system and/or non-aromatic polycyclic ring system, wherein one
or more of the non-aromatic ring atoms are heteroatoms, each of
which is independently selected from O, S, N, and P; and the
remaining ring atoms are carbon atoms. In certain embodiments, the
heterocycle has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to
8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments,
the heterocycle is a monocyclic, bicyclic, tricyclic, or
tetracyclic ring system, which may be spiro, fused, or bridged, and
in which nitrogen or sulfur atoms may be optionally oxidized,
nitrogen atoms may be optionally quaternized, and some rings may be
partially or fully saturated. In certain embodiments, the
heterocycle is optionally substituted with one or more substituents
Q as described herein elsewhere.
[0037] The term "alcohol" refers to alkyl-OH, alkenyl-OH,
alkynyl-OH, cycloalkyl-OH, aryl-OH, aralkyl-OH, heteroaryl-OH or,
or heterocyclyl-OH, wherein the alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl are each as
defined herein. The term "carboxylic acid" refers to alkyl-COOH,
alkenyl-COOH, alkynyl-COOH, cycloalkyl-COOH, aryl-COOH,
aralkyl-COOH, heteroaryl-COOH, or heterocyclyl-COOH, wherein the
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and
heterocyclyl are each as defined herein.
[0038] The term "carboxylic acid ester" or "ester" refers to
alkyl-COOR', alkenyl-COOR', alkynyl-COOR', cycloalkyl-COOR',
aryl-COOR', aralkyl-COOR', heteroaryl-COOR', or heterocyclyl-COOR',
and each R' is independently wherein alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl; and
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl is as defined herein.
[0039] The term "optionally substituted" is intended to mean that a
group or substituent, such as an alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl group, may
be substituted with one or more substituents Q, each of which is
independently selected from, e.g., (a) oxo (.dbd.O), halo, cyano
(--CN), and nitro (--NO.sub.2); (b) C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl,
C.sub.7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is
further optionally substituted with one or more, in one embodiment,
one, two, three, or four, substituents Q.sup.a; and (c)
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c,
--C(NR.sup.a)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a,
--OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c,
--OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OS(O)R.sup.a,
--OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c,
--OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d,
--NR.sup.aC(O)NR.sup.bR.sup.c, NR.sup.aC(.dbd.NR)NR.sup.bR.sup.c,
--NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
--NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c,
--P(O)R.sup.aR.sup.d, --P(O)(OR.sup.a)R.sup.d,
--P(O)(OR.sup.a)(OR.sup.d), --SR.sup.a, --S(O)R.sup.a,
--S(O).sub.2R.sup.a, --S(O)NR.sup.bR.sup.c, and
--S(O).sub.2NR.sup.bR.sup.c, wherein each R.sup.a, R.sup.b,
R.sup.c, and R.sup.d is independently (i) hydrogen; (ii) C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl,
each of which is optionally substituted with one or more, in one
embodiment, one, two, three, or four, substituents Q.sup.a; or
(iii) R.sup.b and R.sup.c together with the N atom to which they
are attached form heteroaryl or heterocyclyl, each of which
optionally substituted with one or more, in one embodiment, one,
two, three, or four, substituents Q.sup.a. As used herein, all
groups that can be substituted are "optionally substituted," unless
otherwise specified.
[0040] In one embodiment, each Q.sup.a is independently selected
from the group consisting of (a) oxo, cyano, halo, and nitro; and
(b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl,
heteroaryl, and heterocyclyl; and (c) --C(O)R.sup.e,
--C(O)OR.sup.e, --C(O)NR.sup.fR.sup.g,
--C(NR.sup.e)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e,
--OC(O)OR.sup.e, --OC(O)NR.sup.fR.sup.g,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.h,
--NR.sup.eC(O)NR.sup.fR.sup.g,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eS(O)R.sup.h,
--NR.sup.eS(O)R.sup.h, --NR.sup.eS(O)NR.sup.fR.sup.g,
--NR.sup.eS(O).sub.2NR.sup.fR.sup.g, --P(O)R.sup.eR.sup.h,
--P(O)(OR.sup.e)R.sup.h, --P(O)(OR.sup.e)(OR.sup.h), --SR.sup.e,
--S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.fR.sup.g, and
--S(O).sub.2NR.sup.fR.sup.g; wherein each R.sup.e, R.sup.f,
R.sup.g, and R.sup.h is independently (i) hydrogen, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl,
C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl;
or (ii) R.sup.f and R.sup.g together with the N atom to which they
are attached form heteroaryl or heterocyclyl.
[0041] The term "pharmaceutically acceptable salt(s)," as used
herein includes, but is not limited to, salts of isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
Basic moieties such as
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
are capable of forming a wide variety of salts with various
inorganic and organic acids. The acids that can be used to prepare
pharmaceutically acceptable acid addition salts of such basic
compounds are those that form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions. Suitable
organic acids include, but are not limited to, maleic, fumaric,
benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic,
tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic,
oleic, tannic, aspartic, stearic, palmitic, glycolic, glutamic,
gluconic, glucaronic, saccharic, isonicotinic, methanesulfonic,
ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamoic
(i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) acids, or
isotopically enriched analogues thereof. Suitable inorganic acids
include, but are not limited to, hydrochloric, hydrobromic,
hydroiodic, sulfuric, phosphoric, or nitric acids, or isotopically
enriched analogues thereof.
[0042] All of the compounds, functional groups and pharmaceutically
acceptable salts provided herein may have one or more isotopically
enriched hydrogen atom at one or more positions. Examples include,
but are not limited to, isotopically enriched alcohols, carboxylic
acids, carboxylic acid esters, or alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl groups,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,
heteroaryl, and heterocyclyl are each as defined herein. For
example, the term "alcohol" may include, but is not limited to
alkyl-OD, alkenyl-OD, alkynyl-OD, cycloalkyl-OD, aryl-OD,
aralkyl-OD, heteroaryl-OD, or heterocyclyl-OD, wherein the alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and
heterocyclyl are each as defined herein.
[0043] The term "solvate" refers to a complex or aggregate formed
by one or more molecules of a solute, e.g., a compound provided
herein, and one or more molecules of a solvent, which present in a
stoichiometric or non-stoichiometric amount. Suitable solvents
include, but are not limited to, water, methanol, ethanol,
n-propanol, isopropanol, and acetic acid. In certain embodiments,
the solvent is pharmaceutically acceptable. In one embodiment, the
complex or aggregate is in a crystalline form. In another
embodiment, the complex or aggregate is in a noncrystalline form.
Where the solvent is water, the solvate is a hydrate. Examples of
hydrates include, but are not limited to, a hemihydrate,
monohydrate, dihydrate, trihydrate, tetrahydrate, and
pentahydrate.
[0044] The term "polymorph" refers to solid crystalline forms of a
compound or complex thereof. Different polymorphs of the same
compound can exhibit different physical, chemical and spectroscopic
properties.
[0045] The term "about" or "approximately" means an acceptable
error for a particular value as determined by one of ordinary skill
in the art, which depends in part on how the value is measured or
determined. In certain embodiments, the term "about" or
"approximately" means within 1, 2, 3, or 4 standard deviations. In
certain embodiments, the term "about" or "approximately" means
within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,
0.5%, or 0.05% of a given value or range.
[0046] The term "substantially free" when referring to a
composition that is "substantially free" of a compound refers means
that the composition contains no greater than about 20% by weight,
no greater than about 10% by weight, no greater than about 5% by
weight, no greater than about 3% by weight, no greater than about
1% by weight, no greater than about 0.5% by weight, no greater than
about 0.2% by weight, no greater than about 0.1% by weight, no
greater than about 0.01% by weight, no greater than about 0.001% by
weight, or no greater than about 0.0001% by weight of the
compound.
[0047] The term "substantially pure" when referring to a compound
or composition means that the compound or composition has a purity
of no less than about 80% by weight, no less than about 90% by
weight, no less than about 95% by weight, no less than about 96% by
weight, no less than about 97% by weight, no less than about 98% by
weight, no less than about 99% by weight, no less than about 99.5%
by weight, no less than about 99.9% by weight, no less than about
99.95% by weight, no less than about 99.99% by weight, no less than
about 99.995% by weight, no less than about 99.999% by weight, no
less than about 99.9995% by weight, or no less than about 99.9999%
by weight.
[0048] The terms "process" and "method" are used interchangeably to
refer to a method disclosed herein for a compound preparation.
Modifications to the processes and methods disclosed herein (e.g.,
starting materials, reagents, protecting groups, solvents,
temperatures, reaction times, and/or purification) that are well
known to those of ordinary skill in the art are also encompassed by
the disclosure.
[0049] The terms "adding," "reacting," "contacting" and "mixing"
are used interchangeably to refer to contacting one reactant,
reagent, solvent, catalyst, or a reactive group with another
reactant, reagent, solvent, catalyst, or reactive group. Unless
otherwise specified, reactants, reagents, solvents, catalysts, and
reactive groups can be added individually, simultaneously, or
separately, and/or can be added in any order. They can be added in
the presence or absence of heat, and can optionally be added under
an inert atmosphere (e.g., N.sub.2 or Ar). In certain embodiments,
the term "reacting" can also refer to in situ formation or
intra-molecular reaction where the reactive groups are in the same
molecule.
[0050] The term "substantially complete" when referring to a
reaction means that the reaction contains no greater than about
50%, no greater than about 40%, no greater than about 30%, no
greater than about 20%, no greater than about 10%, no greater than
about 5%, no greater than about 4%, no greater than about 3%, no
greater than about 2%, no greater than about 1%, no greater than
about 0.5%, no greater than about 0.1%, or no greater than about
0.05% of a starting material left.
[0051] If the stereochemistry of a structure or a portion thereof
is not indicated, e.g., with bold or dashed lines, the structure or
portion thereof is to be interpreted as encompassing all
stereoisomers of the structure.
[0052] The phrase "an enantiomer or a mixture of enantiomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal or polymorph thereof" has the same meaning as the phrase
"an enantiomer or a mixture of enantiomers of the compound
referenced therein; a pharmaceutically acceptable salt, solvate,
hydrate, or polymorph of the compound referenced therein; or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal or
polymorph of an enantiomer or a mixture of enantiomers of the
compound referenced therein."
B. Compounds
[0053] Provided herein are isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
synthetic intermediates thereof, and metabolites thereof.
[0054] Isotopic enrichment (e.g., deuteration) of pharmaceuticals
to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and
toxicity profiles, has been demonstrated previously with some
classes of drugs. (See, e.g., Lijinsky et. al., Food Cosmet.
Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst.,
69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994);
Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al.,
Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388
(1986); Wade D, Chem. Biol. Interact. 117: 191 (1999)).
[0055] Without being limited by a particular theory, isotopic
enrichment of a drug can be used, for example, to (1) reduce or
eliminate unwanted metabolites, (2) increase the half-life of the
parent drug, (3) decrease the number of doses needed to achieve a
desired effect, (4) decrease the amount of a dose necessary to
achieve a desired effect, (5) increase the formation of active
metabolites, if any are formed, and/or (6) decrease the production
of deleterious metabolites in specific tissues and/or create a more
effective drug and/or a safer drug for combination therapy, whether
the combination therapy is intentional or not.
[0056] Replacement of an atom for one of its isotopes may often
result in a change in the reaction rate of a chemical reaction.
This phenomenon is known as the Kinetic Isotope Effect ("KIE"). For
example, if a C--H bond is broken during a rate-determining step in
a chemical reaction (i.e. the step with the highest transition
state energy), substitution of a deuterium for that hydrogen will
cause a decrease in the reaction rate and the process will slow
down. This phenomenon is known as the Deuterium Kinetic Isotope
Effect ("DKIE"). (See, e.g, Foster et al., Adv. Drug Res., vol. 14,
pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol.
77, pp. 79-88 (1999)).
[0057] The magnitude of the DKIE can be expressed as the ratio
between the rates of a given reaction in which a C--H bond is
broken, and the same reaction where deuterium is substituted for
hydrogen. The DKIE can range from about 1 (no isotope effect) to
very large numbers, such as 50 or more, meaning that the reaction
can be fifty, or more, times slower when deuterium is substituted
for hydrogen. Without being limited by a particular theory, high
DKIE values may be due in part to a phenomenon known as tunneling,
which is a consequence of the uncertainty principle. Tunneling is
ascribed to the small mass of a hydrogen atom, and occurs because
transition states involving a proton can sometimes form in the
absence of the required activation energy. Because deuterium has
more mass than hydrogen, it statistically has a much lower
probability of undergoing this phenomenon.
[0058] Tritium ("T") is a radioactive isotope of hydrogen, used in
research, fusion reactors, neutron generators and
radiopharmaceuticals. Tritium is a hydrogen atom that has 2
neutrons in the nucleus and has an atomic weight close to 3. It
occurs naturally in the environment in very low concentrations,
most commonly found as T.sub.2O. Tritium decays slowly
(half-life=12.3 years) and emits a low energy beta particle that
cannot penetrate the outer layer of human skin. Internal exposure
is the main hazard associated with this isotope, yet it must be
ingested in large amounts to pose a significant health risk. As
compared with deuterium, a lesser amount of tritium must be
consumed before it reaches a hazardous level. Substitution of
tritium ("T") for hydrogen results in yet a stronger bond than
deuterium and gives numerically larger isotope effects. Similarly,
substitution of isotopes for other elements, including, but not
limited to, .sup.13C or .sup.14C for carbon, .sup.33S, .sup.34S, or
.sup.36S for sulfur, .sup.15N for nitrogen, and .sup.17O or
.sup.18O for oxygen, may lead to a similar kinetic isotope
effect.
[0059] The animal body expresses a variety of enzymes for the
purpose of eliminating foreign substances, such as therapeutic
agents, from its circulation system. Examples of such enzymes
include the cytochrome P450 enzymes ("CYPs"), esterases, proteases,
reductases, dehydrogenases, and monoamine oxidases, to react with
and convert these foreign substances to more polar intermediates or
metabolites for renal excretion. Some of the most common metabolic
reactions of pharmaceutical compounds involve the oxidation of a
carbon-hydrogen (C--H) bond to either a carbon-oxygen (C--O) or
carbon-carbon (C--C) pi-bond. The resultant metabolites may be
stable or unstable under physiological conditions, and can have
substantially different pharmacokinetic, pharmacodynamic, and acute
and long-term toxicity profiles relative to the parent compounds.
For many drugs, such oxidations are rapid. These drugs therefore
often require the administration of multiple or high daily
doses.
[0060] Therefore, isotopic enrichment at certain positions of a
compound provided herein may produce a detectable KIE that affects
the pharmacokinetic, pharmacologic, and/or toxicological profiles
of a compound provided herein in comparison with a similar compound
having a natural isotopic composition. In one embodiment, the
deuterium enrichment is performed on the site of C--H bond cleavage
during metabolism.
[0061] In some embodiments, provided herein are isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
in which one or more atomic positions of the
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
molecule is/are isotopically enriched with deuterium. Certain
embodiments herein provide compounds of the following chemical
structure:
##STR00002##
in which one or more Y atoms (i.e., Y.sup.1, Y.sup.2, Y.sup.3,
Y.sup.4, Y.sup.5, Y.sup.6, Y.sup.7, Y.sup.8, Y.sup.9, Y.sup.10,
Y.sup.11, Y.sup.12, Y.sup.13, Y.sup.14) is/are hydrogen(s)
isotopically enriched with deuterium, and any remaining Y atom(s)
is/are non-enriched hydrogen atom(s). In particular embodiments,
one, two, three, four, five, six, seven, eight, nine, ten, eleven,
twelve, thirteen or all of the indicated Y atoms is/are
isotopically enriched with deuterium, and any remaining Y atom(s)
is/are non-enriched hydrogen(s).
[0062] In certain embodiments, one or more Y atoms on the
glutarimide portion of Compound I are deuterium-enriched. In
certain embodiments, one or more Y atoms on the oxoquinazoline
portion of Compound I are deuterium-enriched. In certain
embodiments, one or more Y atoms on both the glutarimide portion
and the oxoquinazoline portion of Compound I are
deuterium-enriched, i.e., any combination of deuteration shown
above for the glutarimide portion and the oxoquinazoline portion is
encompassed. For example, particular compounds provided herein
include the following listed compounds in Table 1, in which the
label "D" indicates a deuterium-enriched atomic position, i.e., a
sample comprising the given compound has a deuterium enrichment at
the indicated position(s) above the natural abundance of
deuterium:
TABLE-US-00001 TABLE 1 Deuterium enriched compounds of formula (I):
##STR00003## ##STR00004## ##STR00005## ##STR00006## ##STR00007##
##STR00008## ##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##
##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067##
##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072##
##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077##
##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082##
##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087##
##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092##
##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097##
##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102##
##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107##
##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112##
##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117##
##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122##
##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140##
##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145##
##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150##
##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155##
##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160##
##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165##
##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170##
##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175##
##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180##
##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185##
##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190##
##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195##
##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200##
##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205##
##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210##
##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215##
##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220##
##STR00221## ##STR00222## ##STR00223## ##STR00224## ##STR00225##
##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230##
##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235##
##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240##
##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245##
##STR00246## ##STR00247## ##STR00248## ##STR00249## ##STR00250##
##STR00251##
##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256##
##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261##
##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266##
##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271##
##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276##
##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281##
##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286##
##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291##
##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296##
##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301##
##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306##
##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311##
##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316##
##STR00317## ##STR00318## ##STR00319## ##STR00320## ##STR00321##
##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326##
##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331##
##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336##
##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341##
##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346##
##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351##
##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356##
##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361##
##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366##
##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371##
##STR00372## ##STR00373## ##STR00374## ##STR00375##
##STR00376##
##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381##
##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386##
##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391##
##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396##
##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401##
##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406##
##STR00407## ##STR00408## ##STR00409## ##STR00410## ##STR00411##
##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416##
##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421##
##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426##
##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431##
##STR00432## ##STR00433## ##STR00434## ##STR00435## ##STR00436##
##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441##
##STR00442## ##STR00443## ##STR00444## ##STR00445## ##STR00446##
##STR00447## ##STR00448## ##STR00449## ##STR00450## ##STR00451##
##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456##
##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461##
##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466##
##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471##
##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476##
##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481##
##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486##
##STR00487## ##STR00488## ##STR00489## ##STR00490## ##STR00491##
##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496##
##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501##
##STR00502##
##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507##
##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512##
##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517##
##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522##
##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527##
##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532##
##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537##
##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542##
##STR00543## ##STR00544## ##STR00545## ##STR00546## ##STR00547##
##STR00548## ##STR00549## ##STR00550## ##STR00551## ##STR00552##
##STR00553## ##STR00554## ##STR00555## ##STR00556## ##STR00557##
##STR00558## ##STR00559## ##STR00560## ##STR00561## ##STR00562##
##STR00563## ##STR00564## ##STR00565## ##STR00566##
[0063] Particular embodiments of the invention include variations
of the compounds listed in Table 1, wherein one, two or three of
the protons bound to nitrogen (i.e., Y.sup.12, Y.sup.13, Y.sup.14)
is/are hydrogen(s) isotopically enriched with deuterium.
[0064] It is understood that one or more deuteriums may exchange
with hydrogen under physiological conditions.
C. Methods of Preparation
[0065] Provided herein are methods for the preparation of
isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
or enantiomers or mixtures of enantiomers thereof; or
pharmaceutically acceptable salts, solvates, hydrates, cocrystals
or polymorphs thereof. In certain embodiments, the methods provided
herein are safe, efficient, cost effective, and/or readily
scalable. In certain embodiments, the methods provided herein are
suitable for the large scale or commercial production of
isotopologues of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione,
or enantiomers or mixtures of enantiomers thereof, or a
pharmaceutically acceptable salts, solvates, hydrates, cocrystals
or polymorphs thereof.
[0066] In some embodiments, provided herein is a method for
preparing a compound of formula (I-A):
##STR00567##
wherein Y.sup.12, Y.sup.13 and Y.sup.14 are independently H or D,
or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal or
polymorph thereof, comprising the steps of: (a) contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
with a base and an exchangeable deuterium source; (b) performing an
aqueous workup on the reaction mixture from step (a) to form a
compound of formula (I-A) or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal or polymorph thereof; and (c)
optionally obtaining enantiomers using chiral separation.
[0067] In certain embodiments, the base of step (a) (i.e.,
contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
with a base and an exchangeable deuterium source) is sodium
C.sub.1-14 alkoxide, potassium C.sub.1-14 alkoxide, sodium hydride,
potassium hydride, calcium hydride, cesium carbonate, lithium
hexamethyldisilazide (LiHMDS), lithium diisopropylamide (LDA),
2-tert-butyl-1,1,3,3-tetramethyl-guanidine (Barton's Base),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo(2.2.2)octane (DABCO), N,N-diisopropylethylamine
(DIPEA or Hunig's base), pyridine, 2,6-di-tert-butyl-pyridine,
2,6-lutidine, lithium tetramethylpiperidide (LITMP or harpoon
base), 7-methyl-1,5,7 triazabicyclo[4.4.0]dec-5-ene (MTBD),
1,2,2,6,6-pentamethylpiperidine (PMP),
2,2,6,6-tetramethylpiperidine (TMP), tributylamine,
2,4,6-tri-tert-butylpyridine, tris(trimethylsilyl)amine,
n-butyllithium, sec-butyllithium, tert-butyllithium, potassium
bis(trimethylsilyl)amide, sodium tert-butoxide,
tert-butylimino-tris(dimethylamino)phosphorane, or
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine. In a particular embodiment, the base is potassium
tert-butoxide.
[0068] In certain embodiments, the exchangeable deuterium source of
step (a) (i.e., contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
with a base and an exchangeable deuterium source) is D.sub.2O,
C.sub.1-14 alkyl-OD, C.sub.1-14 alkyl-COOD, aryl-OD, heteroaryl-OD,
aryl-SO.sub.3D, deuterium chloride, deuterium bromide, deuterium
iodide, sulfuric acid-d.sub.2, nitric acid-d.sub.1. In a particular
embodiment, the deuterium source is tert-butyl-OD.
[0069] In certain embodiments, the aqueous workup of step (b)
(i.e., performing an aqueous workup on the reaction mixture from
step (a) to form a compound of formula (I-A)) is performed under
acidic conditions. In certain embodiments, the acid selected for
the aqueous workup lacks isotopically enriched acidic protons. In
certain embodiments, the acid selected for the workup has one or
more isotopically enriched acidic proton. In a particular
embodiment, the aqueous workup comprising HCl. In another
particular embodiment, the aqueous workup comprises DCl.
[0070] In certain embodiments the method of chiral separation is
chiral column chromatography; in certain embodiments, the method of
chiral separation is chiral resolution.
[0071] In another embodiment, provided herein is a method for
preparing compounds of formula (I-B):
##STR00568##
wherein Y.sup.12, Y.sup.13 and Y.sup.14 are independently H or D,
or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal or
polymorph thereof, comprising the steps of: (a) contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
or a salt thereof with an exchangeable deuterium source in a
solvent to form a compound of formula (I-B), or an enantiomer or a
mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal or polymorph thereof; and (b)
optionally obtaining enantiomers by chiral separation.
[0072] In certain embodiments, the exchangeable deuterium source of
step (a) (i.e., contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
or a salt thereof with an exchangeable deuterium source in a
deuterated solvent to form a compound of formula (I-B), or an
enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal or
polymorph thereof, is one previously described herein elsewhere
above. In a particular embodiment, the exchangeable deuterium
source is D.sub.2O.
[0073] In certain embodiments, the solvent of step (a) (i.e.,
contacting
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
or a salt thereof with an exchangeable deuterium source in a
solvent to form a compound of formula (I-B), or an enantiomer or a
mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal or polymorph thereof) is a
hydrocarbon, chlorinated hydrocarbon, alcohol, ether, ketone,
ester, carbonate, amide, nitrile, sulfoxide, sulfone, nitro
compound, arene, heteroarene, heterocycle, carboxylic acid,
phosphoramide, carbon sulfide, water, or isotopically enriched
analogues thereof. In a particular embodiment, the solvent in step
(a) is DMSO-d.sub.6.
[0074] In a particular embodiment, the salt of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is the hydrochloride salt.
[0075] In certain embodiments the mode of chiral separation is
chiral column chromatography; in certain embodiments, the mode of
chiral separation is chiral resolution.
[0076] In other embodiments, provided herein is a method for
preparing a compound of formula (I-C):
##STR00569##
wherein Y.sup.12, Y.sup.13 and Y.sup.14 are independently H or D,
or an enantiomer or a mixture of enantiomers thereof; or a
pharmaceutically acceptable salt, solvate, hydrate, cocrystal or
polymorph thereof; comprising the steps of: (a) further contacting
a compound of formula I-B with a base and an exchangeable deuterium
source to form a compound of formula I-C or an enantiomer or a
mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal or polymorph thereof; and (b)
optionally obtaining enantiomers using chiral separation.
[0077] In certain embodiments, the base is one previously described
herein elsewhere above.
[0078] In certain embodiments, the exchangeable deuterium source is
one previously described herein elsewhere above.
[0079] In certain embodiments the method of chiral separation is
chiral column chromatography; in certain embodiments, the method of
chiral separation is chiral resolution.
[0080] In other embodiments, provided herein is a method for
preparing a compound of formula (I-D):
##STR00570##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, Y.sup.12,
Y.sup.13 and Y.sup.14 are independently H or D or an enantiomer or
a mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal or polymorph thereof; comprising
the steps of: (a) contacting
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with an isotopologue
of glutarimide having the structure:
##STR00571##
or a salt thereof, wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and
Y.sup.5 are independently H or D, in a solvent in the presence of a
coupling reagent to form compound of formula (XVII):
##STR00572##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5 and Y.sup.12
are independently H or D; (b) reducing XVII in a solvent to form a
compound of formula (I-D) or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal or polymorph thereof; and (c)
optionally obtaining enantiomers using chiral separation.
[0081] In some embodiments, one or more hydrogens of the
glutarimide ring (i.e. Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and
Y.sup.5) are enriched with deuterium through organic synthesis. In
certain embodiments, a deuterium-enriched glutamic acid is
converted to a N-Cbz protected deuterium-enriched glutamine using
methods known in the art. See e.g., Miller et al., Arch. Biochem.
Biophys., 35, 176 (1952); Hegedus, B., Helv. Chim. Acta 31, 737
(1948). The N-Cbz protected deuterium-enriched glutamine may then
subsequently be converted to an isotopologue of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
having a deuterium-enriched glutarimide ring. For example, in
particular embodiments, commercially available
CO.sub.2HCD.sub.2CD.sub.2CD(NH.sub.2)CO.sub.2H (formula 1) is
converted to N-Cbz protected derivative 2, which is subsequently
converted to compound I-D as shown in the following scheme
##STR00573##
[0082] In certain embodiments, compound XVI or a salt thereof in
step (a) (i.e., contacting
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and compound XVI or a
salt thereof to form XVII) is the free base compound XVI. In
certain embodiments, the compound XVI in step (a) is a salt of
compound XVI. In certain embodiments, the compound XVI or a salt
thereof in step (a) is the hydrochloride salt of compound XVI.
[0083] In certain embodiments, the coupling reagent in step (a)
(i.e., contacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and
compound XVI or a salt thereof to form compound XVII) is a
carbodiimide, 1,1'-carbonyldiimidazole (CDI),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP--Cl),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
(7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyAOP),
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP reagent),
N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (HBTU),
O-(benzotriazol-1-yl)-N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate (HBPyU),
O-(benzotriazol-1-yl)-N,N,N',N'-bis(pentamethylene)uronium
hexafluorophosphate, PCl.sub.3, PCl.sub.5, or 1-propanephosphonic
acid cyclic anhydride. In certain embodiments, the coupling reagent
in step (a) is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC
or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (EDC hydrochloride),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC
methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide
metho-p-toluenesulfonate, or 1,3-dicyclohexylcarbodiimide (DCC). In
certain embodiments, the coupling reagent in step (a) is PCl.sub.3,
PCl.sub.5, 1-propanephosphonic acid cyclic anhydride, POCl.sub.3,
or a mixture of POCl.sub.3 and water. In certain embodiments, the
coupling reagent in step (a) contains PCl.sub.3, PCl.sub.5,
1-propanephosphonic acid cyclic anhydride, acetic anhydride,
phosphoric acid, POCl.sub.3, or a mixture of POCl.sub.3 and water.
In certain embodiments, the coupling reagent in step (a) is
1-propanephosphonic acid cyclic anhydride. In certain embodiments,
the coupling reagent in step (a) contains acetic anhydride. In
certain embodiments, the coupling reagent in step (a) contains
acetic anhydride and phosphoric acid. In certain embodiments, the
coupling reagent in step (a) is a mixture of acetic anhydride and
phosphoric acid. In certain embodiments, the coupling reagent in
step (a) contains POCl.sub.3. In certain embodiments, the coupling
reagent in step (a) contains POCl.sub.3 and water. In certain
embodiments, the coupling reagent in step (a) is a mixture of
POCl.sub.3 and water. In certain embodiments, the molar ratio of
POCl.sub.3 versus water is ranging from about 0.5 to about 5; from
about 0.7 to about 4; or from about 1 to about 3. In certain
embodiments, the molar ratio of POCl.sub.3 versus water is about 1,
about 1.5, about 2, or about 3.
[0084] In certain embodiments, the solvent in step (a) (i.e.,
contacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and
compound XVI or a salt thereof to form XVII) is a hydrocarbon,
chlorinated hydrocarbon, alcohol, ether, ketone, ester, carbonate,
amide, nitrile, sulfoxide, sulfone, nitro compound, arene,
heteroarene, heterocycle, carboxylic acid, phosphoramide, carbon
sulfide, water, or a mixture thereof.
[0085] In certain embodiments, the solvent in step (a) (i.e.,
contacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and
compound XVI or a salt thereof to form XVII) is petroleum ether,
pentane, hexane(s), heptane, octane, isooctane, cyclopentane,
cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin,
cumene, dichloromethane (DCM), 1,2-dichloroethane,
1,1-dichloroethene, 1,2-dichloroethene, chloroform,
trichloroethane, trichloroethene, carbon tetrachloride,
chlorobenzene, trifluoromethylbenzene, methanol, ethanol,
isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol,
3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol,
ethyleneglycol, diethyl ether, diisopropyl ether, methyl t-butyl
ether (MTBE), diphenyl ether, 1,2-dimethoxyethane,
bi(2-methoxyethyl)ether, 1,1-dimethoxymethane,
2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl
ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl
isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl
acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl
acetate, ethylene carbonate, propylene carbonate, formamide,
N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile
(ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane,
nitrobenzene, N-methyl pyrrolindone, 2-methyl tetrahydrofuran,
tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid,
trichloroacetic acid, trifluoroacetic acid,
hexamethylphosphoramide, carbon sulfide, water; or a mixture
thereof.
[0086] In certain embodiments, the solvent in step (a) (i.e.,
contacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and
compound XVI or a salt thereof to form XVII) is a nitrile. In
certain embodiments, the solvent in step (a) is a carboxylic acid
ester. In certain embodiments, the solvent in step (a) is a mixture
of a nitrile and carboxylic acid ester. In certain embodiments, the
solvent in step (a) is an amide. In certain embodiments, the
solvent in step (a) is a cyclic amide. In certain embodiments, the
solvent in step (a) is 1-methyl-2-pyrrolidone (NMP), acetonitrile,
THF, or 2-methyl-THF. In certain embodiments, the solvent in step
(a) is NMP. In certain embodiments, the volume ratio of the nitrile
versus carboxylic acid ester is ranging from about 0.1 to about
100, from about 0.2 to about 50, from about 0.5 to about 25, from
about 1 to about 20, from about 1 to about 10, from about 1 to
about 5, or from about 1 to about 2. In certain embodiments, the
volume ratio of the nitrile versus carboxylic acid ester is ranging
from about 0.1 to about 100. In certain embodiments, the volume
ratio of the nitrile versus carboxylic acid ester is ranging from
about 0.2 to about 50. In certain embodiments, the volume ratio of
the nitrile versus carboxylic acid ester is ranging from about 0.5
to about 25. In certain embodiments, the volume ratio of the
nitrile versus carboxylic acid ester is ranging from about 1 to
about 20. In certain embodiments, the volume ratio of the nitrile
versus carboxylic acid ester is ranging from about 1 to about 10.
In certain embodiments, the volume ratio of the nitrile versus
carboxylic acid ester is ranging from about 1 to about 5. In
certain embodiments, the volume ratio of the nitrile versus
carboxylic acid ester is ranging from about 1 to about 2. In
certain embodiments, the volume ratio between acetonitrile and
ethyl acetate is about 1, about 1.1, about 1.2, about 1.3, about
1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or
about 2.
[0087] In certain embodiments, the solvent in step (a) (i.e.,
contacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and
compound XVI or a salt thereof to form XVII) is acetonitrile. In
certain embodiments, the solvent in step (a) is ethyl acetate. In
certain embodiments, the solvent in step (a) is a mixture of
acetonitrile and ethyl acetate. In certain embodiments, the volume
ratio of acetonitrile versus ethyl acetate is ranging from about
0.1 to about 100, from about 0.2 to about 50, from about 0.5 to
about 25, from about 1 to about 20, from about 1 to about 10, from
about 1 to about 5, or from about 1 to about 2. In certain
embodiments, the volume ratio of acetonitrile versus ethyl acetate
is ranging from about 0.1 to about 100. In certain embodiments, the
volume ratio of acetonitrile versus ethyl acetate is ranging from
about 0.2 to about 50. In certain embodiments, the volume ratio of
acetonitrile versus ethyl acetate is ranging from about 0.5 to
about 25. In certain embodiments, the volume ratio of acetonitrile
versus ethyl acetate is ranging from about 1 to about 20. In
certain embodiments, the volume ratio of acetonitrile versus ethyl
acetate is ranging from about 1 to about 10. In certain
embodiments, the volume ratio of acetonitrile versus ethyl acetate
is ranging from about 1 to about 5. In certain embodiments, the
volume ratio of acetonitrile versus ethyl acetate is ranging from
about 1 to about 2. In certain embodiments, the volume ratio of
acetonitrile versus ethyl acetate is about 1, about 1.1, about 1.2,
about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8,
about 1.9, or about 2.
[0088] In certain embodiments, the molar ratio of the coupling
reagent versus 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one in
step (a) (i.e., contacting
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and compound XVI or a
salt thereof to form XVII) is ranging from about 1 to about 10,
from about 1 to about 5, or from about 1 to about 3. In certain
embodiments, the molar ratio of the coupling reagent versus
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one is ranging from about
1 to about 10. In certain embodiments, the molar ratio of the
coupling reagent versus
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one is ranging from about
1 to about 5. In certain embodiments, the molar ratio of the
coupling reagent versus
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one is ranging from about
1 to about 3. In certain embodiments, the molar ratio of the
coupling reagent versus
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one is about 1, about
1.5, about 2, about 2.5 or about 3.
[0089] In certain embodiments, step (a) (i.e., contacting
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and compound XVI or a
salt thereof to form XVII) is conducted at a temperature ranging
from about 0 to about 150.degree. C., from about 25 to about
120.degree. C., from about 50 to about 100.degree. C., from about
60 to about 100.degree. C., from about 70 to about 90.degree. C.,
from about 70 to about 85.degree. C., or from about 75 to about
80.degree. C. In certain embodiments, step (a) is conducted at a
temperature from about 75 to about 80.degree. C.
[0090] In certain embodiments, the reduction of the nitro group of
compound XVII in a solvent to form a compound of formula I-D in
step is via a transfer hydrogenation. In certain embodiments, the
reduction in step (b) is via catalytic hydrogenation. In certain
embodiments, the reduction in step (b) is via catalytic
hydrogenation under a hydrogen atmosphere. In certain embodiments,
the reduction in step (b) is via catalytic hydrogenation in the
presence of hydrogen gas (H.sub.2). In certain embodiments, the
reduction in step (b) is performed via catalytic hydrogenation in
the presence of hydrogen gas and a palladium catalyst. In certain
embodiments, the reduction in step (b) is performed via catalytic
hydrogenation according to the procedures as described in U.S. Pat.
No. 7,635,700, the disclosure of which is incorporated by reference
in its entirety.
[0091] In one embodiment, the transfer hydrogenation is conducted
in the presence of a hydrogen donor. In another embodiment, the
transfer hydrogenation is conducted in the presence of a catalyst.
In yet another embodiment, the transfer hydrogenation is conducted
in the presence of a hydrogen donor and a catalyst.
[0092] In certain embodiments, the hydrogen donor is (i) a
C.sub.1-14 alcohol, C.sub.1-14carboxylic acid, C.sub.1-14
carboxylic acid salt, C.sub.1-14 carboxylic acid ester, C.sub.2-14
alkene, C.sub.3-14 cycloalkene, C.sub.6-14 arene, heteroarene, or
heterocycle, each of which is optionally substituted with one or
more substituents Q; or (ii) diazene (also known as diimine or
diimide), hydrazine, hydroxylamine, or NaH.sub.2PO.sub.2.
[0093] In certain embodiments, the hydrogen donor is a C.sub.1-14
alcohol, optionally substituted with one or more substituents Q. In
certain embodiments, the hydrogen donor is a primary or secondary
C.sub.1-14 alcohol, each optionally substituted with one or more
substituents Q. In certain embodiments, the hydrogen donor is a
primary C.sub.1-14 alcohol, optionally substituted with one or more
substituents Q. In certain embodiments, the hydrogen donor is a
secondary C.sub.1-14 alcohol, optionally substituted with one or
more substituents Q. In certain embodiments, the hydrogen donor is
methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol,
butan-2-ol, cyclopentanol, cyclohexanol, benzylalcohol, a menthol,
or a mixture thereof.
[0094] In certain embodiments, the hydrogen donor has one or more
isotopically enriched hydrogens. In certain embodiments, the
hydrogen donor is a C.sub.1-14 carboxylic acid, optionally
substituted with one or more substituents Q. In certain
embodiments, the hydrogen donor is a 2-hydroxy-C.sub.1-14
carboxylic acid, optionally substituted with one or more
substituents Q. In certain embodiments, the hydrogen donor is
formic acid, lactic acid, ascorbic acid, mandelic acid, or a
mixture thereof. In certain embodiments, the hydrogen donor is
formic acid. In certain embodiments, the hydrogen donor is formic
acid-d.sub.2.
[0095] In certain embodiments, the solvent in the transfer
hydrogenation is formic acid. In certain embodiments, the solvent
in the transfer hydrogenation is water. In certain embodiments, the
formic acid is isotopically enriched. In certain embodiments, the
water is isotopically enriched. In certain embodiments, both the
formic acid and water are isotopically enriched. In certain
embodiments, the formic acid is HCOOH. In certain embodiments, the
formic acid is DCOOD (formic acid-d.sub.2). In certain embodiments,
the formic acid is DCOOH. In certain embodiments, the formic acid
is HCOOD. In certain embodiments the formic acid is a combination
of two or more of HCOOH, DCOOD, DCOOH, and HCOOD.
[0096] In certain embodiments, the hydrogen donor is a C.sub.1-14
carboxylic acid salt, optionally substituted with one or more
substituents Q. In certain embodiments, the hydrogen donor is a
carboxylic acid amine salt, optionally substituted with one or more
substituents Q. In certain embodiments, the hydrogen donor is a
carboxylic acid amine salt, wherein the amine is an aromatic amine.
In certain embodiments, the hydrogen donor is a carboxylic acid
amine salt, wherein the amine is pyridine. In certain embodiments,
the hydrogen donor is a carboxylic acid amine salt, wherein the
amine is a non-aromatic amine. In certain embodiments, the hydrogen
donor is a carboxylic acid amine salt, wherein the amine is a
primary, secondary, or tertiary amine. In certain embodiments, the
hydrogen donor is a carboxylic acid amine salt, wherein the amine
is a primary amine. In certain embodiments, the hydrogen donor is a
carboxylic acid amine salt, wherein the amine is a secondary amine.
In certain embodiments, the hydrogen donor is a carboxylic acid
amine salt, wherein the amine is a tertiary amine. In certain
embodiments, the hydrogen donor is a carboxylic acid amine salt,
wherein the amine is a tri-(C.sub.1-6 alkyl)amine. In certain
embodiments, the hydrogen donor is a carboxylic acid amine salt,
wherein the amine is a trimethylamine, triethylamine,
di(isopropyl)ethylamine, pyridine, or a mixture thereof. In certain
embodiments, the hydrogen donor is a C.sub.1-14 carboxylic acid
ammonium salt. In certain embodiments, the hydrogen donor is
ammonium formate or potassium formate.
[0097] In certain embodiments, the hydrogen donor is a C.sub.1-14
carboxylic acid ester.
[0098] In certain embodiments, the hydrogen donor is C.sub.2-14
alkene, optionally substituted with one or more substituents Q. In
certain embodiments, the hydrogen donor is a terpene.
[0099] In certain embodiments, the hydrogen donor is C.sub.3-14
cycloalkene, optionally substituted with one or more substituents
Q. In certain embodiments, the hydrogen donor is cyclohexadiene,
cyclohexene, 1-methylcyclohexene, or a mixture thereof.
[0100] In certain embodiments the hydrogen donor is C.sub.6-14
arene, optionally substituted with one or more substituents Q. In
certain embodiments the hydrogen donor is tetralin.
[0101] In certain embodiments the hydrogen donor is a heteroarene,
optionally substituted with one or more substituents Q.
[0102] In certain embodiments the hydrogen donor is a heterocycle,
optionally substituted with one or more substituents Q. In certain
embodiments the hydrogen donor is dihydrofuran.
[0103] In certain embodiments, the hydrogen donor is diazene,
hydrazine, hydroxylamine, or NaH.sub.2PO.sub.2.
[0104] In certain embodiments, the hydrogen donor is methanol,
ethanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol,
cyclopentanol, cyclohexanol, benzylalcohol, a menthol, formic acid,
lactic acid, ascorbic acid, mandelic acid, ammonium formate,
potassium formate, cyclohexadiene, cyclohexene,
1-methylcyclohexene, tetralin, dihydrofuran, a terpene, diazene,
hydrazine, hydroxylamine, or NaH.sub.2PO.sub.2, or a mixture
thereof. In certain embodiments, the hydrogen donor is formic acid,
ammonium formate, potassium formate, cyclohexene,
1-methylcyclohexene, NaH.sub.2PO.sub.2, or a mixture thereof.
[0105] In certain embodiments, the catalyst is a hydrogenation
catalyst. In certain embodiments, the catalyst is a heterogeneous
hydrogenation catalyst. In certain embodiments, the catalyst is
Raney nickel, palladium, palladium black, palladium on carbon
(Pd/C), palladium oxide, Lindlar catalyst, palladium hydroxide on
carbon (also known as Pearlman's catalyst), platinum, platinum
black, platinum on carbon (Pt/C), or platinum dioxide (also known
as Adam's catalyst). In certain embodiments, the catalyst is a
homogeneous hydrogenation catalyst. In certain embodiments, the
homogeneous catalyst is an iridium-based catalyst. In certain
embodiments, the homogeneous catalyst is a palladium-based
catalyst. In certain embodiments, the homogeneous catalyst is a
platinum-based catalyst. In certain embodiments, the homogeneous
catalyst is a rhodium-based catalyst. In certain embodiments, the
homogeneous catalyst is chloro-tris(triphenylphosphine)rhodium(I)
(also known as Wilkinson's catalyst). In certain embodiments, the
homogeneous catalyst is an iridium-based catalyst. In certain
embodiments, the homogeneous catalyst is Crabtree's catalyst.
[0106] In certain embodiments, the catalyst is a precious metal
catalyst. In certain embodiments, the catalyst is an iridium,
palladium, platinum, rhodium, or ruthenium catalyst. In certain
embodiments, the catalyst is an iridium catalyst. In certain
embodiments, the catalyst is a palladium catalyst. In certain
embodiments, the catalyst is palladium, palladium black, palladium
on carbon (Pd/C), palladium oxide, Lindlar catalyst or palladium
hydroxide on carbon (also known as Pearlman's catalyst). In certain
embodiments, the catalyst is a platinum catalyst. In certain
embodiments, the catalyst is palladium. In certain embodiments, the
catalyst is palladium black. In certain embodiments, the catalyst
is palladium on carbon (Pd/C). In certain embodiments, the catalyst
is palladium oxide. In certain embodiments, the catalyst is Lindlar
catalyst. In certain embodiments, the catalyst is a platinum
catalyst. In certain embodiments, the catalyst is platinum,
platinum black, platinum on carbon (Pt/C), or platinum dioxide. In
certain embodiments, the catalyst is platinum. In certain
embodiments, the catalyst is platinum black. In certain
embodiments, the catalyst is platinum on carbon (Pt/C). In certain
embodiments, the catalyst is platinum dioxide. In certain
embodiments, the catalyst is a rhodium catalyst. In certain
embodiments, the catalyst is a ruthenium catalyst.
[0107] In certain embodiments, the catalyst is a non-precious metal
catalyst. In certain embodiments, the catalyst is a nickel
catalyst. In certain embodiments, the catalyst is Raney nickel.
[0108] In certain embodiments, the solvent in the transfer
hydrogenation is a hydrocarbon, chlorinated hydrocarbon, alcohol,
ether, ketone, ester, carbonate, amide, nitrile, sulfoxide,
sulfone, nitro compound, heteroarene, heterocycle, carboxylic acid,
phosphoramide, carbon sulfide, water, or a mixture thereof.
[0109] In certain embodiments, the solvent in the transfer
hydrogenation is petroleum ether, pentane, hexane(s), heptane,
octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane,
benzene, toluene, xylene, tetralin, cumene, dichloromethane (DCM),
1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene,
chloroform, trichloroethane, trichloroethene, carbon tetrachloride,
chlorobenzene, trifluoromethylbenzene, methanol, ethanol,
isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol,
3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol,
ethyleneglycol, diethyl ether, diisopropyl ether, methyl t-butyl
ether (MTBE), diphenyl ether, 1,2-dimethoxyethane,
bi(2-methoxyethyl)ether, 1,1-dimethoxymethane,
2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl
ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl
isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl
acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl
acetate, ethylene carbonate, propylene carbonate, formamide,
N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile
(ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane,
nitrobenzene, N-methyl pyrrolindone, 2-methyl tetrahydrofuran,
tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid,
trichloroacetic acid, trifluoroacetic acid,
hexamethylphosphoramide, carbon sulfide, water; or a mixture
thereof.
[0110] In certain embodiments, the solvent in the transfer
hydrogenation is a carboxylic acid. In certain embodiments, the
solvent in the transfer hydrogenation is a mixture of a carboxylic
acid and water. In certain embodiments, the volume ratio of the
carboxylic acid versus water is ranging from about 0.1 to about 10,
from about 0.2 to about 5, from about 0.5 to about 5, from about
0.5 to about 2, or from about 0.8 to about 1.5. In certain
embodiments, the volume ratio of the carboxylic acid versus water
is ranging from about 0.1 to about 10. In certain embodiments, the
volume ratio of the carboxylic acid versus water is ranging from
about 0.2 to about 5. In certain embodiments, the volume ratio of
the carboxylic acid versus water is ranging from about 0.5 to about
5. In certain embodiments, the volume ratio of the carboxylic acid
versus water is ranging from about 0.5 to about 2. In certain
embodiments, the volume ratio of the carboxylic acid versus water
is ranging from about 0.8 to about 1.5. In certain embodiments, the
volume ratio of the carboxylic acid versus water is about 0.5,
about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1,
about 1.2, about 1.3, about 1.4, or about 1.5. In certain
embodiments, the volume ratio of the carboxylic acid versus water
is about 0.8, about 0.9, about 1, about 1.1, or about 1.2. In
certain embodiments, the volume ratio of the carboxylic acid versus
water is about 0.8. In certain embodiments, the volume ratio of the
carboxylic acid versus water is about 0.9. In certain embodiments,
the volume ratio of the carboxylic acid versus water is about 1. In
certain embodiments, the volume ratio of the carboxylic acid versus
water is about 1.1. In certain embodiments, the volume ratio of the
carboxylic acid versus water is about 1.2.
[0111] In certain embodiments, the solvent in the transfer
hydrogenation is a mixture of formic acid and water. In certain
embodiments, the volume ratio of formic acid versus water is
ranging from about 0.1 to about 10, from about 0.2 to about 5, from
about 0.5 to about 5, from about 0.5 to about 2, or from about 0.8
to about 1.5. In certain embodiments, the volume ratio of formic
acid versus water is ranging from about 0.1 to about 10. In certain
embodiments, the volume ratio of formic acid versus water is
ranging from about 0.2 to about 5. In certain embodiments, the
volume ratio of formic acid versus water is ranging from about 0.5
to about 5. In certain embodiments, the volume ratio of formic acid
versus water is ranging from about 0.5 to about 2. In certain
embodiments, the volume ratio of formic acid versus water is
ranging from about 0.8 to about 1.5. In certain embodiments, the
volume ratio of formic acid versus water is about 0.5, about 0.6,
about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2,
about 1.3, about 1.4, or about 1.5. In certain embodiments, the
volume ratio of formic acid versus water is about 0.8, about 0.9,
about 1, about 1.1, or about 1.2. In certain embodiments, the
volume ratio of formic acid versus water is about 0.8. In certain
embodiments, the volume ratio of formic acid versus water is about
0.9. In certain embodiments, the volume ratio of formic acid versus
water is about 1. In certain embodiments, the volume ratio of
formic acid versus water is about 1.1. In certain embodiments, the
volume ratio of formic acid versus water is about 1.2.
[0112] In certain embodiments, the molar ratio of formic acid
versus compound XVII is ranging from about 1 to about 100, from
about 2 to about 50, from about 5 to about 50, from about 5 to
about 25, from about 10 to about 25, or from about 15 to about 25.
In certain embodiments, the molar ratio of formic acid versus
compound XVII is ranging from about 1 to about 100. In certain
embodiments, the molar ratio of formic acid versus XVII is ranging
from about 2 to about 50. In certain embodiments, the molar ratio
of formic acid versus compound XVII is ranging from about 5 to
about 50. In certain embodiments, the molar ratio of formic acid
versus
3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is ranging from about 5 to about 25. In certain embodiments, the
molar ratio of formic acid versus
3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is ranging from about 10 to about 25. In certain embodiments, the
molar ratio of formic acid versus
3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is ranging from about 15 to about 25. In certain embodiments, the
molar ratio of formic acid versus
3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is about 15, about 16, about 17, about 18, about 19, about 20,
about 21, about 22, about 23, about 24, or about 25.
[0113] In certain embodiments, the transfer hydrogenation is
performed at a temperature ranging from about 0 to about
100.degree. C., from about 5 to about 90.degree. C., from about 5
to about 80.degree. C., from about 10 to about 70.degree. C., or
from about 10 to about 60.degree. C.
[0114] In certain embodiments, when the hydrogen donor is formic
acid, the transfer hydrogenation further comprises the step of
hydrolyzing the isotopologue of
N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)-
formamide to form the free amine. In certain embodiments, the
hydrolysis step is performed in the presence of a deformylation
catalyst. In certain embodiments, the deformylation catalyst is an
acid. In certain embodiments, the deformylation catalyst is an
organic acid. In certain embodiments, the deformylation catalyst is
an inorganic acid. In certain embodiments, the deformylation
catalyst is hydrochloride.
[0115] In certain embodiments, the solvent in the deformylation
step is a hydrocarbon, chlorinated hydrocarbon, alcohol, ether,
ketone, ester, carbonate, amide, nitrile, sulfoxide, sulfone, nitro
compound, heteroarene, heterocycle, carboxylic acid, phosphoramide,
carbon sulfide, water, or a mixture thereof.
[0116] In certain embodiments, the solvent in the deformylation
step is petroleum ether, pentane, hexane(s), heptane, octane,
isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene,
toluene, xylene, tetralin, cumene, dichloromethane (DCM),
1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene,
chloroform, trichloroethane, trichloroethene, carbon tetrachloride,
chlorobenzene, trifluoromethylbenzene, methanol, ethanol,
isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol,
3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol,
ethyleneglycol, diethyl ether, diisopropyl ether, methyl t-butyl
ether (MTBE), diphenyl ether, 1,2-dimethoxyethane,
bi(2-methoxyethyl)ether, 1,1-dimethoxymethane,
2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl
ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl
isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl
acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl
acetate, ethylene carbonate, propylene carbonate, formamide,
N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile
(ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane,
nitrobenzene, N-methyl pyrrolindone, 2-methyl tetrahydrofuran,
tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid,
trichloroacetic acid, trifluoroacetic acid,
hexamethylphosphoramide, carbon sulfide, water; or a mixture
thereof.
[0117] In certain embodiments, the solvent in the deformylation
step comprises a C.sub.1-6 alcohol. Without being limited by any
theory, the alcohol acts as a reagent in the deformylation step. In
certain embodiments, the solvent in the deformylation step
comprises ethanol. In certain embodiments, the solvent in the
deformylation step comprises a C.sub.1-6 alcohol and water. In
certain embodiments, the solvent in the deformylation step
comprises ethanol and water. In certain embodiments, the solvent in
the deformylation step comprises formic acid, a C.sub.1-6 alcohol,
and water. In certain embodiments, the solvent in the deformylation
step comprises formic acid, ethanol, and water. In certain
embodiments, the solvent in the deformylation step comprises formic
acid, a C.sub.1-6 alcohol, and water. In certain embodiments, the
solvent in the deformylation step is a mixture formic acid, a
C.sub.1-6 alcohol, and water. In certain embodiments, the solvent
in the deformylation step is a mixture of formic acid, ethanol, and
water.
[0118] In certain embodiments, the deformylation step is performed
at a temperature ranging from about 50 to about 120.degree. C.,
from about 60 to about 100.degree. C., from about 60 to about
90.degree. C., from or about 65 to about 85.degree. C.
[0119] In certain embodiments, the reduction of compound XVII to
compound I-D is performed at a temperature ranging from about 0 to
about 100.degree. C., from about 5 to about 90.degree. C., from
about 5 to about 85.degree. C., from about 10 to about 90.degree.
C., or from about 10 to about 85.degree. C.
[0120] In certain embodiments provided herein, is a method for
preparing a compound of formula (I-E):
##STR00574##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, Y.sup.12,
Y.sup.13 and Y.sup.14 are independently H or D, or an enantiomer or
a mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal or polymorph thereof; comprising
the steps of: (a) further contacting compound I-D with an acid and
an exchangeable deuterium source in a solvent to give a compound of
formula (I-E); and (b) optionally obtaining enantiomers using
chiral separation.
[0121] In certain embodiments, the acid is C.sub.1-14 alkyl-COOD,
aryl-OD, heteroaryl-OD, C.sub.1-15 alkyl-SO.sub.3D and
aryl-SO.sub.3D. In certain embodiments, the acid deuterium bromide,
deuterium iodide, sulfuric acid-d.sub.2, nitric acid-d.sub.1 or
trifluoromethanesulfonic acid-d.sub.1. In a particular embodiment,
the acid is deuterium chloride.
[0122] In certain embodiments, the solvent is one previously
described herein elsewhere above. In a particular embodiment, the
solvent is DMSO-d.sub.6.
[0123] In other embodiments, provided herein is a method for
preparing a compound of formula (I-F):
##STR00575##
wherein Y.sup.2, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, Y.sup.12,
Y.sup.13 and Y.sup.14 are independently H or D, or an enantiomer or
a mixture of enantiomers thereof; or a pharmaceutically acceptable
salt, solvate, hydrate, cocrystal or polymorph thereof; comprising
the steps of: (a) contacting
2-(methyl-d.sub.3)-5-nitro-4H-benzo[d][1,3]oxazin-4-one with a
glutarimide of formula XVI or a salt thereof in a solvent in the
presence of a coupling agent to form a compound of formula
(XVIII):
##STR00576##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5 and Y.sup.12
are independently H or D; (b) reducing compound (XVIII) in the
presence of formic acid-d.sub.2 via transfer hydrogenation in a
solvent to form a compound of formula (I-F), wherein Y.sup.1,
Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, Y.sup.12, Y.sup.13 and Y.sup.14
are independently H or D, or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal or polymorph thereof; and (c)
optionally obtaining enantiomers using chiral separation.
[0124] In certain embodiments, deuterated
2-(methyl-d.sub.3)-5-nitro-4H-benzo[d][1,3]oxazin-4-one is prepared
by contacting 2-amino-6-nitrobenzoic acid with acetic
anhydride-d.sub.6.
[0125] In other embodiments, provided herein is a method for
preparing a compound of formula (I-G):
##STR00577##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are
independently H or D, or an enantiomer or a mixture of enantiomers
thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
cocrystal or polymorph thereof; comprising the steps of: (a)
contacting 2-amino-6-nitrobenzoic acid or a salt thereof with a
carbonyl equivalent in a solvent to form
5-nitro-1H-benzo[d][1,3]oxazine-2,4-dione; (b) contacting
5-nitro-1H-benzo[d][1,3]oxazine-2,4-dione with compound XIX:
##STR00578##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 are
independently H or D, and R is an alkyl, aryl or arylalkyl group as
previously described herein, in the presence of a base in a solvent
to form compound (XX):
##STR00579##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are
independently H or D; (c) contacting XX with an acetylating reagent
in the presence of an acid to form compound XXI:
##STR00580##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 are
independently H or D; (d) contacting compound XXI with a base in a
solvent followed by a workup to form compound XXII:
##STR00581##
wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 are
independently H or D; (e) reducing XXII in the presence of formic
acid-d.sub.2 via transfer hydrogenation in a solvent to form a
compound of formula (I-G) or an enantiomer or a mixture of
enantiomers thereof; or a pharmaceutically acceptable salt,
solvate, hydrate, cocrystal or polymorph thereof; and (f)
optionally obtaining enantiomers using chiral separation.
[0126] In a certain embodiment, the base in step (b) (i.e.
contacting 5-nitro-1H-benzo[d][1,3]oxazine-2,4-dione with compound
XIX, wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 are
independently H or D, in the presence of a base in a solvent to
form compound (XX)) is sodium bicarbonate, sodium carbonate, sodium
hydroxide, cesium carbonate, potassium carbonate, potassium
bicarbonate, triethylamine, diisopropylethylamine, tributylamine,
lithium hydroxide, potassium hydroxide, pyridine,
4-dimethylaminopyridine, 2,6-lutidine or
2,6-di-tert-butylpyridine.
[0127] In certain embodiments, the carbonyl equivalent is phosgene,
diphosgene, carbonyl diimidazole, or carbonyl
diimidazoledisuccinimidyl carbonate. In a particular embodiment,
the carbonyl equivalent is triphosgene.
[0128] In a certain embodiment, the acetylating agent is acetic
anhydride, acetic acid, acetyl chloride, or acetyl bormide. In a
certain embodiment, the acetylating agent is an orthoester. In a
particular embodiment, the orthoester is triethyl orthoacetate. In
a particular embodiment, the orthoester is triethylorthoacetate and
the acid isp-toluenesulfonic acid monohydrate (PTSA hydrate).
[0129] In certain embodiments, the base in step (d) (i.e.
contacting compound XXI with a base in a solvent followed by a
workup to form compound XXII) is potassium C.sub.1-14 alkoxide. In
certain embodiments, the base is sodium C.sub.1-14 alkoxide. In
certain embodiments, the base is sodium hydride. In certain
embodiments, the base is potassium hydride. In certain embodiments,
the base is calcium hydride. In certain embodiments, the base is
lithium hexamethyldisilazide (LiHMDS). In certain embodiments, the
base is lithium diisopropylamide (LDA). In certain embodiments, the
base is lithium tetramethylpiperidide (LiTMP or harpoon base). In
certain embodiments, the base is n-butyllithium. In certain
embodiments, the base is sec-butyllithium. In certain embodiments,
the base is tert-butyllithium. In certain embodiments, the base is
potassium bis(trimethylsilyl)amide, In certain embodiments, the
base is sodium tert-butoxide. In certain embodiments, the base is a
phosphazene base. In certain embodiments, the base is
tert-butylimino-tris(dimethylamino)phosphorane. In certain
embodiments, the base is
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine. In a particular embodiment, the base is potassium
tert-butoxide.
[0130] In a certain embodiment the transfer hydrogenation is
accomplished as described elsewhere herein.
D. Methods of Treatment
[0131] In certain embodiments, provided herein is a method of
treating, preventing, and/or managing an inflammatory disease,
disorder, or condition, comprising administering to a subject a
therapeutically effective amount of a treatment compound provided
herein.
[0132] In certain embodiments, the disease is lupus, scleroderma,
Sjogren syndrome, ANCA-induced vasculitis, anti-phospholipid
syndrome, or myasthenia gravis. In certain embodiments, the disease
is lupus or scleroderma.
[0133] In certain embodiments, provided herein is a method of
treating, preventing, and/or managing scleroderma or a symptom
thereof, comprising administering to a subject having scleroderma a
therapeutically effective amount of a treatment compound provided
herein. In certain embodiments, provided herein is a method of
treating, preventing, and/or managing scleroderma or a symptom
thereof, comprising administering to a subject having scleroderma
or at risk of having scleroderma a therapeutically effective amount
of a treatment provided herein.
[0134] In certain embodiments, the scleroderma is localized,
systemic, limited, or diffuse scleroderma.
[0135] In certain embodiments, the systemic scleroderma comprises
CREST syndrome (Calcinosis, Raynaud's syndrome, esophagaeal
dysfunction or dysmotility, sclerodactyly, and telangiectasia).
Scleroderma is also known as systemic sclerosis or progressive
systemic sclerosis.
[0136] In certain embodiments, the disease is Raynaud's disease. In
certain embodiments, systemic sclerosis comprises scleroderma lung
disease, scleroderma renal crisis, cardiac manifestations, muscular
weakness (including fatigue or limited CREST), gastrointestinal
dysmotility and spasm, and abnormalities in the central, peripheral
and autonomic nervous system (including carpal tunnel syndrome
followed by trigeminal neuralgia). It also includes general
disability, including depression, and impact on quality of
life.
[0137] In certain embodiments, limited scleroderma is limited to
the hands, the face, neck, or combinations thereof.
[0138] In certain embodiments, diffuse scleroderma comprises skin
tightening and also occurs above the wrists (or elbows). In certain
embodiments, the diffuse systemic sclerosis is sine scleroderma,
comprising internal organ fibrosis, but no skin tightening; or
familial progressive systemic sclerosis.
[0139] In one embodiment, scleroderma is not associated with
wasting, such as disease-related wasting.
[0140] In one embodiment, provided herein is a method for the
reduction, inhibition, or prevention of one or more of the
following symptoms of scleroderma: (i) gradual hardening,
thickening, and tightening of the skin (e.g., in extremities, such
as hands, face, and feet); (ii) skin discoloration; (iii) numbness
of extremities; (iv) shiny skin; (v) small white lumps under the
surface of the skin that erupt into a chalky white fluid; (vi)
Raynaud's esophagaeal dysfunction (pain, numbness, and/or color
changes in the hands caused by spasm of the blood vessels upon
exposure to cold or emotional stress); (vii) telangiectasia (red
spots on, e.g., the hands, palms, forearms, face, and lips); (viii)
pain and/or stiffness of the joints; (ix) swelling of the hands and
feet; (x) itching of the skin; (xi) stiffening and curling of the
fingers; (xii) ulcers (sores) on the outside of certain joints,
such as knuckles and elbows; (xiii) digestive problems, such as
heartburn, difficulty in swallowing, diarrhea, irritable bowel, and
constipation; (xiv) fatigue and weakness; (xv) shortness of breath;
(xvi) arthritis; (xvii) hair loss; (xviii) internal organ problems;
(xix) digital ulcers; or (xx) digital auto-amputation, comprising
administering a therapeutically effective amount of a treatment
provided herein to a subject in need thereof.
[0141] Without being bound to any particular theory, it is believed
that the treatment provided herein compounds provided herein
enhance Th1 immune response, and suppresses Th2 immune response,
which may result in anti-fibrotic effects in the skin.
[0142] In certain embodiments, provided herein is a method for
improving or reducing the skin thickness of a subject having
scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein. In one embodiment, the skin thickness is reduced by about
20%, about 25%, about 30%, about 40%, about 50%, about 60%, about
70% about 80%, about 90% or more.
[0143] In certain embodiments, provided herein is a method for
achieving one or more clinical endpoints in treating a subject with
scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein.
[0144] In certain embodiments, provided herein is a method for
increasing the overall survival, objective response rate, time to
progression, progression-free survival and/or time-to-treatment
failure of a subject having scleroderma, comprising administering
to the subject a therapeutically effective amount of a treatment
compound provided herein.
[0145] In certain embodiments, provided herein is a method for
decreasing mortality, respiratory mortality and/or respiratory
hospitalization of a subject having scleroderma, comprising
administering to the subject a therapeutically effective amount of
a treatment compound provided herein.
[0146] In certain embodiments, provided herein is a method for
improving the modified Rodnan skin score of a subject having
scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment provided herein. In
one embodiment, the improvement in modified Rodnan skin score is
about 5, about 10, about 15, or about 20 points or more.
[0147] In certain embodiments, provided herein is a method for
improving or reducing the skin thickness of a subject having
scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein. In one embodiment, the skin thickness is reduced by about
20%, about 25%, about 30%, about 40%, about 50%, about 60%, about
70% about 80%, about 90% or more.
[0148] In certain embodiments, provided herein is a method for
improving or reducing skin induration of a subject having
scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein.
[0149] In certain embodiments, provided herein is a method for
improving the dermatology quality of life index of a subject having
scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein.
[0150] In certain embodiments, provided herein is a method for
improving the pulmonary function of a subject having scleroderma,
comprising administering to the subject a therapeutically effective
amount of a treatment compound provided herein.
[0151] In certain embodiments, provided herein is a method for
improving the carbon monoxide diffusing capacity of a subject
having scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein. In one embodiment, the carbon monoxide diffusing capacity
of a subject is improved by an improvement in the diffusing
capacity of the lung for carbon monoxide (D.sub.Lco) of about 10%,
about 20%, about 25%, about 30%, about 40%, about 50%, about 60%,
about 70% about 80%, about 90% or more.
[0152] In certain embodiments, provided herein is a method for
improving the Mahler Dyspnea index of a subject having scleroderma,
comprising administering to the subject a therapeutically effective
amount of a treatment compound provided herein. In one embodiment,
the improvement in Mahler Dyspnea index is about 4, about 5, about
6, about 7, about 8, about 9, or about 10 points or more.
[0153] In certain embodiments, provided herein is a method for
improving the Saint George's Respiratory Questionnaire score of a
subject having scleroderma, comprising administering to the subject
a therapeutically effective amount of a treatment compound provided
herein. In one embodiment, the improvement in Saint George's
Respiratory Questionnaire score is about 4, about 8, about 12,
about 16, about 20, about 24, about 28, about 32, about 36, about
40, about 44, about 48, about 52 points or more.
[0154] In certain embodiments, provided herein is a method for
improving the UCLA scleroderma clinical trial consortium
gastrointestinal tract score of a subject having scleroderma,
comprising administering to the subject a therapeutically effective
amount of a treatment compound provided herein.
[0155] In certain embodiments, provided herein is a method for
treating or preventing digital ulcer of a subject having
scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein.
[0156] In certain embodiments, provided herein is a method for
improving flow-mediated dilatation of a subject having scleroderma,
comprising administering to the subject a therapeutically effective
amount of a treatment compound provided herein.
[0157] In certain embodiments, provided herein is a method for
improving or increasing the six minute walk distance of a subject
having scleroderma, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein. In one embodiment, the improvement in the six minute walk
distance is about 200 meters, about 250 meters, about 300 meters,
about 350 meters, about 400 meters or more.
[0158] In certain embodiments, provided herein is a method of
treating, preventing, and/or managing lupus erythematosus or a
symptom thereof, comprising administering to a subject having lupus
erythematosus a therapeutically effective amount of a treatment
compound provided herein.
[0159] In certain embodiments, provided herein is a method of
preventing lupus erythematosus or a symptom thereof, comprising
administering to a subject at risk of having lupus erythematosus a
therapeutically effective amount of a treatment compound provided
herein.
[0160] In certain embodiments, the disease is systemic lupus
erythematosus (SLE), cutaneous lupus erythematosus (CLE), or
drug-induced lupus.
[0161] The phrase "Systemic lupus erythematosus" is interchangeably
used herein with SLE and lupus and refers to all manifestations of
the disease as known in the art (including remissions and flares).
In SLE, abnormal hyperactivity of B lymphocytes and massive
abnormal production of immunoglobulin gamma (IgG) auto-antibodies
play a key role. This pathological process results in sequestration
and destruction of Ig-coated cells, fixation and cleaving of
complement proteins, and release of chemotaxins, vasoactive
peptides and destructive enzymes into tissues (Hahn BH. Systemic
Lupus Erythematosus. In: Kasper D L, Braunwald E, Fauci A S, Hauser
SL, Longo D L, Jameson, J L, editors. In: Harrison's Principles of
Internal Medicine (16th edition); New York (US): McGraw-Hill; 2005.
pp. 1960-1967).
[0162] Symptoms of SLE vary from person to person, and may come and
go. In most patients, the symptoms include joint pain and swelling.
Frequently affected joints are the fingers, hands, wrists, and
knees. Some patients develop arthritis. Other common symptoms
include: chest pain when taking a deep breath, fatigue, fever with
no other cause, general discomfort, uneasiness, or ill feeling
(malaise), hair loss, mouth sores, swollen lymph nodes, sensitivity
to sunlight, skin rash--a "butterfly" rash over the cheeks and
bridge of the nose affects about half of people with SLE, in some
patients, the rash gets worse in sunlight, and the rash may also be
widespread.
[0163] Other symptoms depend on what part of the body is affected,
and may include the following: [0164] Brain and nervous system:
headaches, numbness, tingling, seizures, vision problems,
personality changes, [0165] Digestive tract: abdominal pain,
nausea, and vomiting, [0166] Heart: abnormal heart rhythms
(arrhythmias), [0167] Lung: coughing up blood and difficulty
breathing, and [0168] Skin: patchy skin color, fingers that change
color when cold (Raynaud's phenomenon).
[0169] Some patients only have skin symptoms. This is called
discoid lupus.
[0170] In one embodiment, the disease is moderate, severe, or very
severe SLE. The term "severe SLE" as used herein refers to an SLE
condition where the patient has one or more severe or
life-threatening symptoms (such as hemolytic anemia, extensive
heart or lung involvement, kidney disease, or central nervous
system involvement).
[0171] In certain embodiments, provided herein is a method for
achieving one or more clinical endpoints in treating a subject with
SLE, comprising administering to the subject a therapeutically
effective amount of a treatment compound provided herein.
[0172] In certain embodiments, provided herein is a method for the
overall survival, objective response rate, time to progression,
progression-free survival and/or time-to-treatment failure of a
subject having SLE, comprising administering to the subject a
therapeutically effective amount of a treatment compound provided
herein.
[0173] In certain embodiment, certain treatment compounds provided
herein act as an inhibitor of primary human memory CD19+ B-cell
differentiation to the plasmablast stage. Without being bound to
any particular theory, it is believed that certain treatment
compounds provided herein block cells at a premature stage thereby
decreasing the numbers of plasmablasts that are capable of
producing high levels of immunoglobulin. A functional consequence
of this effect is reduced immunoglobulin G (IgG) and immunoglobulin
M (IgM) production in these differentiation cultures.
[0174] In certain embodiments, provided herein is a method for
treating, managing, or preventing an immune-related disease,
disorder, or condition, comprising administering to a subject a
therapeutically effective amount of a treatment compound provided
herein.
[0175] In certain embodiments, provided herein is a method of
treating a disease, disorder, or condition caused by, or is
associated with, an inappropriate or undesirable immune response,
comprising administering to a subject a therapeutically effective
amount of a treatment compound provided herein.
[0176] In certain embodiments, provided herein is a method of
treating a disease, disorder, or condition that can be treated
beneficially by immunosuppression, comprising administering to a
subject a therapeutically effective amount of a treatment compound
provided herein.
[0177] In certain embodiments, the immune-related disease, i.e., a
disease, disorder, or condition caused by, or is associated with,
an inappropriate or undesirable immune response, is Sjogren
syndrome, ANCA-induced vasculitis, anti-phospholipid syndrome,
myasthenia gravis, Addison's disease, alopecia areata, ankylosing
spondylitis, antiphospholipid antibody syndrome, antiphospholipid
syndrome (primary or secondary), asthma, autoimmune gastritis,
autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner
ear disease, autoimmune lymphoproliferative disease, autoimmune
thrombocytopenic purpura, Balo disease, Behcet's disease, bullous
pemphigoid, cardiomyopathy, celiac disease, Chagas disease, chronic
inflammatory demyelinating polyneuropathy, cicatrical pemphigoid
(e.g., mucous membrane pemphigoid), cold agglutinin disease, degos
disease, dermatitis hepatiformis, essential mixed cryoglobulinemia,
Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome,
Hashimoto's thyroiditis (Hashimoto's disease; autoimmune
thyroditis), idiopathic pulmonary fibrosis, idiopathic
thrombocytopenia purpura, IgA nephropathy, juvenile arthritis,
lichen planus, Meniere disease, mixed connective tissue disease,
morephea, narcolepsy, neuromyotonia, pediatric autoimmune
neuropsychiatric disorders (PANDAs), pemphigus vulgaris, pernicious
anemia, polyarteritis nodosa, polychondritis, polymyalgia
rheumatica, primary agammaglobulinemia, primary biliary cirrhosis,
Raynaud disease (Raynaud phenomenon), Reiter's syndrome, relapsing
polychondritis, rheumatic fever, Sjogren's syndrome, stiff-person
syndrome (Moersch-Woltmann syndrome), Takayasu's arteritis,
temporal arteritis (giant cell arteritis), uveitis, vasculitis
(e.g., vasculitis not associated with lupus erythematosus),
vitiligo, or Wegener's granulomatosis.
[0178] In certain embodiments, provided herein is a method for
treating and preventing cancer, comprising administering to a
subject a therapeutically effective amount of a treatment compound
provided herein.
[0179] In certain embodiments, provided herein is a method for
managing cancer, comprising administering to a subject a
therapeutically effective amount of a treatment compound provided
herein.
[0180] In certain embodiments, provided herein is a method for
treating or managing lymphoma, in one embodiment, non-Hodgkin's
lymphoma, comprising administering to a subject a therapeutically
effective amount of a treatment compound provided herein.
[0181] In certain embodiments, provided herein is a method for
treating or managing non-Hodgkin's lymphoma (NHL), including but
not limited to, diffuse large B-cell lymphoma (DLBCL), comprising
administering to a subject a therapeutically effective amount of a
treatment compound provided herein.
[0182] In certain embodiments, the subject is one who has been
previously treated for cancer, but is non-responsive to a standard
therapy. In certain embodiments, the subject is one who has not
previously been treated.
[0183] As used herein, the term "cancer" includes, but is not
limited to, solid tumors and blood born tumors. In certain
embodiments, the term "cancer" refers to disease of skin tissues,
organs, blood, and vessels, including, but not limited to, cancers
of the bladder, bone, blood, brain, breast, cervix, chest, colon,
endrometrium, esophagus, eye, head, kidney, liver, lymph nodes,
lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach,
testis, throat, and uterus.
[0184] In certain embodiments, the term "cancer" refers to advanced
malignancy, amyloidosis, neuroblastoma, meningioma,
hemangiopericytoma, multiple brain metastase, glioblastoma
multiforms, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor, malignant glioma, recurrent malignant
giolma, 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, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large
B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma,
malignant mesothelioma, malignant pleural effusion mesothelioma
syndrome, peritoneal carcinoma, papillary serous carcinoma,
gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous
vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,
fibrodysplasia ossificans progressive, hormone refractory prostate
cancer, resected high-risk soft tissue sarcoma, unrescectable
hepatocellular carcinoma, Waldenstrom's macroglobulinemia,
smoldering myeloma, indolent myeloma, fallopian tube cancer,
androgen independent prostate cancer, androgen dependent stage IV
non-metastatic prostate cancer, hormone-insensitive prostate
cancer, chemotherapy-insensitive prostate cancer, papillary thyroid
carcinoma, follicular thyroid carcinoma, medullary thyroid
carcinoma, and leiomyoma.
[0185] In certain embodiments, the cancer is a blood borne tumor.
In certain embodiments, the blood borne tumor is metastatic. In
certain embodiments, the blood borne tumor is drug resistant. In
certain embodiments, the cancer is myeloma or lymphoma.
[0186] In certain embodiments, the cancer is a solid tumor. In
certain embodiments, the solid tumor is metastatic. In certain
embodiments, the solid tumor is drug-resistant. In certain
embodiments, the solid tumor is hepatocellular carcinoma, prostate
cancer, ovarian cancer, or glioblastoma.
E. Second Active Agents
[0187] A compound provided herein, or a pharmaceutically acceptable
salt, solvate, prodrug, clathrate, cocrystal, polymorph or
stereoisomer thereof, can be combined with other pharmacologically
active compounds ("second active agents") in methods and
compositions provided herein. Certain combinations may work
synergistically in the treatment of particular types diseases or
disorders, and conditions and symptoms associated with such
diseases or disorders. A compound provided herein, or a
pharmaceutically acceptable salt, solvate, clathrate, cocrystal,
polymorph, stereoisomer or prodrug thereof, can also work to
alleviate adverse effects associated with certain second active
agents, and vice versa.
[0188] One or more second active ingredients or agents can be used
in the methods and compositions provided herein. Second active
agents can be large molecules (e.g., proteins) or small molecules
(e.g., synthetic inorganic, organometallic, or organic
molecules).
[0189] Examples of large molecule active agents include, but are
not limited to, hematopoietic growth factors, cytokines, and
monoclonal and polyclonal antibodies. Specific examples of the
active agents are anti-CD40 monoclonal antibodies (such as, for
example, SGN-40); histone deacetlyase inhibitors (such as, for
example, SAHA and LAQ 824); heat-shock protein-90 inhibitors (such
as, for example, 17-AAG); insulin-like growth factor-1 receptor
kinase inhibitors; vascular endothelial growth factor receptor
kinase inhibitors (such as, for example, PTK787); insulin growth
factor receptor inhibitors; lysophosphatidic acid acyltransrerase
inhibitors; IkB kinase inhibitors; p38MAPK inhibitors; EGFR
inhibitors (such as, for example, gefitinib and erlotinib HCL);
HER-2 antibodies (such as, for example, trastuzumab
(Herceptin.RTM.) and pertuzumab (Omnitarg.TM.)); VEGFR antibodies
(such as, for example, bevacizumab (Avastin.TM.)); VEGFR inhibitors
(such as, for example, flk-1 specific kinase inhibitors, SU5416 and
ptk787/zk222584); P13K inhibitors (such as, for example,
wortmannin); C-Met inhibitors (such as, for example, PHA-665752);
monoclonal antibodies (such as, for example, rituximab
(Rituxan.RTM.), tositumomab (Bexxar.RTM.), edrecolomab
(Panorex.RTM.) and G250); and anti-TNF-.alpha. antibodies. Examples
of small molecule active agents include, but are not limited to,
anticancer agents and antibiotics (e.g., clarithromycin).
[0190] Specific second active compounds that can be combined with
compounds provided herein vary depending on the specific indication
to be treated, prevented or managed.
[0191] For instance, for the treatment, prevention or management of
cancer, second active agents include, but are not limited to:
semaxanib; cyclosporin; etanercept; doxycycline; bortezomib;
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; amsacrine; anastrozole; anthramycin; asparaginase;
asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;
busulfan; cactinomycin; calusterone; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
cedefingol; celecoxib; chlorambucil; cirolemycin; cisplatin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine;
dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone;
docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene;
droloxifene citrate; dromostanolone propionate; duazomycin;
edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;
enpromate; epipropidine; epirubicin hydrochloride; erbulozole;
esorubicin hydrochloride; estramustine; estramustine phosphate
sodium; etanidazole; etoposide; etoposide phosphate; etoprine;
fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;
fludarabine phosphate; fluorouracil; flurocitabine; fosquidone;
fostriecin sodium; gemcitabine; gemcitabine hydrochloride;
hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;
iproplatin; irinotecan; irinotecan hydrochloride; lanreotide
acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; safingol; safingol hydrochloride; semustine; simtrazene;
sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur;
talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone
hydrochloride; temoporfin; teniposide; teroxirone; testolactone;
thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine;
toremifene citrate; trestolone acetate; triciribine phosphate;
trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole
hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin;
vinblastine sulfate; vincristine sulfate; vindesine; vindesine
sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine
sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine
sulfate; vorozole; zeniplatin; zinostatin; and zorubicin
hydrochloride.
[0192] Other second agents include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorlns;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene;
emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim;
finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imatinib (Gleevec.RTM.),
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
Erbitux, human chorionic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn;
oblimersen (Genasense.RTM.); 06-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;
peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0193] Specific second active agents include, but are not limited
to, 2-methoxyestradiol, telomestatin, inducers of apoptosis in
mutiple myeloma cells (such as, for example, TRAIL), statins,
semaxanib, cyclosporin, etanercept, doxycycline, bortezomib,
oblimersen (Genasense.RTM.), remicade, docetaxel, celecoxib,
melphalan, dexamethasone (Decadron.RTM.), steroids, gemcitabine,
cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar,
carboplatin, procarbazine, gliadel, tamoxifen, topotecan,
methotrexate, Arisa.RTM., taxol, taxotere, fluorouracil,
leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated
interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin,
thiotepa, fludarabine, carboplatin, liposomal daunorubicin,
cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,
dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,
busulphan, prednisone, bisphosphonate, arsenic trioxide,
vincristine, doxorubicin (Doxil.RTM.), paclitaxel, ganciclovir,
adriamycin, estramustine sodium phosphate (Emcyt.RTM.), sulindac,
and etoposide.
[0194] In another embodiment, examples of specific second agents
according to the indications to be treated, prevented, or managed
can be found in the following references, all of which are
incorporated herein in their entireties: U.S. Pat. Nos. 6,281,230
and 5,635,517; U.S. publication nos. 2004/0220144, 2004/0190609,
2004/0087546, 2005/0203142, 2004/0091455, 2005/0100529,
2005/0214328, 2005/0239842, 2006/0154880, 2006/0122228, and
2005/0143344; and U.S. provisional application No. 60/631,870.
[0195] Examples of second active agents that may be used for the
treatment, prevention and/or management of skin diseases include,
but are not limited to, keratolytics, retinoids, .alpha.-hydroxy
acids, antibiotics, collagen, botulinum toxin, interferon,
steroids, and immunomodulatory agents. Specific examples include,
but are not limited to, 5-fluorouracil, masoprocol, trichloroacetic
acid, salicylic acid, lactic acid, ammonium lactate, urea,
tretinoin, isotretinoin, antibiotics, collagen, botulinum toxin,
interferon, corticosteroid, transretinoic acid and collagens such
as human placental collagen, animal placental collagen, Dermalogen,
AlloDerm, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast,
and Isolagen.
[0196] Administration of a compound provided herein, or a
pharmaceutically acceptable salt, solvate, clathrate, cocrystal,
polymorph, stereoisomer or prodrug thereof, 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 compounds provided herein is oral. Routes of administration for
the second active agents or ingredients are known to those of
ordinary skill in the art. See, e.g., Physicians' Desk Reference
(60.sup.th ed., 2006).
[0197] In one embodiment, the second active agent is administered
intravenously or subcutaneously and once or twice daily in an
amount of from about 1 to about 1000 mg, from about 5 to about 500
mg, from about 10 to about 350 mg, or from about 50 to about 200
mg. The specific amount of the second active agent will depend on
the specific agent used, the type of disease being treated or
managed, the severity and stage of disease, and the amount(s) of
compounds provided herein and any optional additional active agents
concurrently administered to the patient.
[0198] As discussed elsewhere herein, also encompassed is a method
of reducing, treating and/or preventing adverse or undesired
effects associated with conventional therapy including, but not
limited to, surgery, chemotherapy, radiation therapy, hormonal
therapy, biological therapy and immunotherapy. Compounds provided
herein and other active ingredients can be administered to a
patient prior to, during, or after the occurrence of the adverse
effect associated with conventional therapy.
F. Pharmaceutical Compositions and Dosage Forms
[0199] Pharmaceutical compositions can be used in the preparation
of individual, single unit dosage forms. Pharmaceutical
compositions and dosage forms provided herein comprise a compound
provided herein, or a pharmaceutically acceptable salt, solvate,
stereoisomer, clathrate, cocrystal, polymorph or prodrug thereof.
Pharmaceutical compositions and dosage forms can further comprise
one or more excipients.
[0200] Pharmaceutical compositions and dosage forms provided herein
can also comprise one or more additional active ingredients.
Examples of optional second, or additional, active ingredients are
disclosed in Section 4.4, above.
[0201] Single unit dosage forms provided herein are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), topical (e.g., eye
drops or other ophthalmic preparations), transdermal or
transcutaneous administration to a patient. Examples of dosage
forms include, but are not limited to: tablets; caplets; capsules,
such as soft elastic gelatin capsules; cachets; troches; lozenges;
dispersions; suppositories; powders; aerosols (e.g., nasal sprays
or inhalers); gels; liquid dosage forms suitable for oral or
mucosal administration to a patient, including suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions,
or a water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
eye drops or other ophthalmic preparations suitable for topical
administration; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0202] The composition, shape, and type of dosage forms will
typically vary depending on their use. For example, a dosage form
used in the acute treatment of a disease 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. These and other ways in which
specific dosage forms are used will vary from one another will be
readily apparent to those skilled in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,
Easton Pa. (1990).
[0203] In one embodiment, pharmaceutical compositions and dosage
forms comprise one or more excipients. Suitable excipients are well
known to those skilled in the art of pharmacy, and non-limiting
examples of suitable excipients are provided herein. Whether a
particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form depends on a variety of
factors well known in the art including, but not limited to, the
way in which the dosage form will be administered to a patient. For
example, oral dosage forms such as tablets may contain excipients
not suited for use in parenteral dosage forms. The suitability of a
particular excipient may also depend on the specific active
ingredients in the dosage form. For example, the decomposition of
some active ingredients may be accelerated by some excipients such
as lactose, or when exposed to water. Active ingredients that
comprise primary or secondary amines are particularly susceptible
to such accelerated decomposition. Consequently, provided are
pharmaceutical compositions and dosage forms that contain little,
if any, lactose other mono- or di-saccharides. As used herein, the
term "lactose-free" means that the amount of lactose present, if
any, is insufficient to substantially increase the degradation rate
of an active ingredient.
[0204] Lactose-free compositions can comprise excipients that are
well known in the art and are listed, for example, in the U.S.
Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free
compositions comprise active ingredients, a binder/filler, and a
lubricant in pharmaceutically compatible and pharmaceutically
acceptable amounts. In one embodiment, lactose-free dosage forms
comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0205] Also provided are anhydrous pharmaceutical compositions and
dosage forms comprising active ingredients, since water can
facilitate the degradation of some compounds. For example, the
addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the
decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0206] Anhydrous pharmaceutical compositions and dosage forms can
be prepared using anhydrous or low moisture containing ingredients
and low moisture or low humidity conditions. Pharmaceutical
compositions and dosage forms that comprise lactose and at least
one active ingredient that comprises a primary or secondary amine
are preferably anhydrous if substantial contact with moisture
and/or humidity during manufacturing, packaging, and/or storage is
expected.
[0207] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are, in one embodiment,
packaged using materials known to prevent exposure to water such
that they can be included in suitable formulary kits. Examples of
suitable packaging include, but are not limited to, hermetically
sealed foils, plastics, unit dose containers (e.g., vials), blister
packs, and strip packs.
[0208] Also provided are pharmaceutical compositions and dosage
forms that comprise one or more compounds that reduce the rate by
which an active ingredient will decompose. Such compounds, which
are referred to herein as "stabilizers," include, but are not
limited to, antioxidants such as ascorbic acid, pH buffers, or salt
buffers.
[0209] 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. In one embodiment,
dosage forms comprise a compound provided herein in an amount of
from about 0.10 to about 500 mg. In other embodiments, dosage forms
comprise a compound provided herein in an amount of about 0.1, 1,
2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300,
350, 400, 450, or 500 mg.
[0210] In other embodiments, dosage forms comprise the second
active ingredient in an amount of 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. Of course, the specific amount of the second active
agent will depend on the specific agent used, the diseases or
disorders being treated or managed, and the amount(s) of a compound
provided herein, and any optional additional active agents
concurrently administered to the patient.
[0211] 1. Oral Dosage Forms
[0212] Pharmaceutical compositions that are suitable for oral
administration can be provided as discrete dosage forms, such as,
but not limited to, tablets (e.g., chewable tablets), caplets,
capsules, and liquids (e.g., flavored syrups). Such dosage forms
contain predetermined amounts of active ingredients, and may be
prepared by methods of pharmacy well known to those skilled in the
art. See generally, Remington's Pharmaceutical Sciences, 18th ed.,
Mack Publishing, Easton Pa. (1990).
[0213] Oral dosage forms provided herein are prepared by combining
the active ingredients in an intimate admixture with at least one
excipient according to conventional pharmaceutical compounding
techniques. Excipients can take a wide variety of forms depending
on the form of preparation desired for administration. For example,
excipients suitable for use in oral liquid or aerosol dosage forms
include, but are not limited to, water, glycols, oils, alcohols,
flavoring agents, preservatives, and coloring agents. Examples of
excipients suitable for use in solid oral dosage forms (e.g.,
powders, tablets, capsules, and caplets) include, but are not
limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0214] In one embodiment, oral dosage forms are tablets or
capsules, in which case solid excipients are employed. In another
embodiment, tablets can be coated by standard aqueous or nonaqueous
techniques. Such dosage forms can be prepared by any of the methods
of pharmacy. In general, pharmaceutical compositions and dosage
forms are prepared by uniformly and intimately admixing the active
ingredients with liquid carriers, finely divided solid carriers, or
both, and then shaping the product into the desired presentation if
necessary.
[0215] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0216] Examples of excipients that can be used in oral dosage forms
provided herein include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0217] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. An specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM.
[0218] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms provided herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions is, in one embodiment, present in from about 50 to
about 99 weight percent of the pharmaceutical composition or dosage
form.
[0219] Disintegrants may be used in the compositions to provide
tablets that disintegrate when exposed to an aqueous environment.
Tablets that contain too much disintegrant may disintegrate in
storage, while those that contain too little may not disintegrate
at a desired rate or under the desired conditions. Thus, a
sufficient amount of disintegrant that is neither too much nor too
little to detrimentally alter the release of the active ingredients
may be used to form solid oral dosage forms. The amount of
disintegrant used varies based upon the type of formulation, and is
readily discernible to those of ordinary skill in the art. In one
embodiment, pharmaceutical compositions comprise from about 0.5 to
about 15 weight percent of disintegrant, or from about 1 to about 5
weight percent of disintegrant.
[0220] Disintegrants that can be used in pharmaceutical
compositions and dosage forms include, but are not limited to,
agar-agar, alginic acid, calcium carbonate, microcrystalline
cellulose, croscarmellose sodium, crospovidone, polacrilin
potassium, sodium starch glycolate, potato or tapioca starch, other
starches, pre-gelatinized starch, other starches, clays, other
algins, other celluloses, gums, and mixtures thereof.
[0221] Lubricants that can be used in pharmaceutical compositions
and dosage forms include, but are not limited to, calcium stearate,
magnesium stearate, mineral oil, light mineral oil, glycerin,
sorbitol, mannitol, polyethylene glycol, other glycols, stearic
acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil
(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl
laureate, agar, and mixtures thereof. Additional lubricants
include, for example, a syloid silica gel (AEROSIL200, manufactured
by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of
synthetic silica (marketed by Degussa Co. of Plano, Tex.),
CAB--O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co.
of Boston, Mass.), and mixtures thereof. If used at all, lubricants
may be used in an amount of less than about 1 weight percent of the
pharmaceutical compositions or dosage forms into which they are
incorporated.
[0222] In one embodiment, a solid oral dosage form comprises a
compound provided herein, anhydrous lactose, microcrystalline
cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous
silica, and gelatin.
[0223] 2. Controlled Release Dosage Forms
[0224] Active ingredients provided herein can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos. 4,008,719,
5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476,
5,354,556, and 5,733,566, each of which is incorporated herein by
reference. Such dosage forms can be used to provide slow or
controlled-release of one or more active ingredients using, for
example, hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active agents provided herein. In one
embodiment, provided are 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.
[0225] In one embodiment, controlled-release pharmaceutical
products improve drug therapy over that achieved by their
non-controlled counterparts. In another embodiment, the use of a
controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0226] In another embodiment, the controlled-release formulations
are designed to initially release an amount of drug (active
ingredient) that promptly produces the desired therapeutic or
prophylactic effect, and gradually and continually release of other
amounts of drug to maintain this level of therapeutic or
prophylactic effect over an extended period of time. In one
embodiment, in order to maintain a constant level of drug in the
body, the drug can be released from the dosage form at a rate that
will replace the amount of drug being metabolized and excreted from
the body. Controlled-release of an active ingredient can be
stimulated by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0227] 3. Parenternal Dosage Forms
[0228] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. In some embodiments, administration of a parenteral
dosage form bypasses patients' natural defenses against
contaminants, and thus, in these embodiments, parenteral dosage
forms are sterile or capable of being sterilized prior to
administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0229] Suitable vehicles that can be used to provide parenteral
dosage forms are well known to those skilled in the art. Examples
include, but are not limited to: Water for Injection USP; aqueous
vehicles such as, but not limited to, Sodium Chloride Injection,
Ringer's Injection, Dextrose Injection, Dextrose and Sodium
Chloride Injection, and Lactated Ringer's Injection; water-miscible
vehicles such as, but not limited to, ethyl alcohol, polyethylene
glycol, and polypropylene glycol; and non-aqueous vehicles such as,
but not limited to, corn oil, cottonseed oil, peanut oil, sesame
oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[0230] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms. For example, cyclodextrin and its
derivatives can be used to increase the solubility of a compound
provided herein. See, e.g., U.S. Pat. No. 5,134,127, which is
incorporated herein by reference.
[0231] 4. Topical and Mucosal Dosage Forms
[0232] Topical and mucosal dosage forms provided herein include,
but are not limited to, sprays, aerosols, solutions, emulsions,
suspensions, eye drops or other ophthalmic preparations, 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.
[0233] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage
forms encompassed herein are well known to those skilled in the
pharmaceutical arts, and depend on the particular tissue to which a
given pharmaceutical composition or dosage form will be applied. In
one embodiment, excipients include, but are not limited to, water,
acetone, ethanol, ethylene glycol, propylene glycol,
butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral
oil, and mixtures thereof to form solutions, emulsions or gels,
which are non-toxic and pharmaceutically acceptable. Moisturizers
or humectants can also be added to pharmaceutical compositions and
dosage forms. Examples of 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).
[0234] The pH of a pharmaceutical composition or dosage form may
also be adjusted to improve delivery of one or more active
ingredients. Also, 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 alter the hydrophilicity or
lipophilicity of one or more active ingredients so as to improve
delivery. In other embodiments, stearates can serve as a lipid
vehicle for the formulation, as an emulsifying agent or surfactant,
or as a delivery-enhancing or penetration-enhancing agent. In other
embodiments, salts, solvates, prodrugs, clathrates, cocrystals,
polymorphs, or stereoisomers of the active ingredients can be used
to further adjust the properties of the resulting composition.
G. Kits
[0235] In one embodiment, active ingredients provided herein are
not administered to a patient at the same time or by the same route
of administration. In another embodiment, provided are kits which
can simplify the administration of appropriate amounts of active
ingredients.
[0236] In one embodiment, a kit comprises a dosage form of a
compound provided herein. Kits can further comprise additional
active ingredients such as oblimersen (Genasense.RTM.), melphalan,
G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere,
IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexamethasone,
IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic
acid, or a pharmacologically active mutant or derivative thereof,
or a combination thereof. Examples of the additional active
ingredients include, but are not limited to, those disclosed herein
(see, e.g., section 4.3).
[0237] In other embodiments, kits can further comprise devices that
are used to administer the active ingredients. Examples of such
devices include, but are not limited to, syringes, drip bags,
patches, and inhalers.
[0238] Kits can further comprise cells or blood for transplantation
as well as pharmaceutically acceptable vehicles that can be used to
administer one or more active ingredients. For example, if an
active ingredient is provided in a solid form that must be
reconstituted for parenteral administration, the kit can comprise a
sealed container of a suitable vehicle in which the active
ingredient can be dissolved to form a particulate-free sterile
solution that is suitable for parenteral administration. Examples
of pharmaceutically acceptable vehicles include, but are not
limited to: Water for Injection USP; aqueous vehicles such as, but
not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and
Lactated Ringer's Injection; water-miscible vehicles such as, but
not limited to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not
limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl myristate, and benzyl benzoate.
V. EXAMPLES
[0239] Certain embodiments are illustrated by the following
non-limiting examples. The discussion below is offered to
illustrate certain of the diverse methods available for use in
making the disclosed compounds and is not intended to limit the
scope of reactions or reaction sequences that can be used in
preparing the compounds provided herein.
Example 1
[0240] The gluarimide portion of the
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is enriched with deuterium as follows.
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione 3
is contacted with potassium tert-butoxide in tert-butyl alcohol and
allowed to stir at room temperature for 2 hours. The reaction is
subsequently treated with aqueous acid, concentrated and purified
to obtain deuterated
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione 4
as a mixture of enantiomers. The isotopically enriched products 5
and 6 are obtained by chiral separation.
##STR00582##
Example 2
[0241] The oxoquinazoline portion of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is enriched with deuterium as follows:
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
hydrochloride 3A is dissolved in DMSO-d.sub.6 and D.sub.2O and
allowed to stir at room temperature for ten hours to generate
compound 7 as a salt. The reaction mixture may optionally be
treated with aqueous sodium carbonate to generate the free base,
concentrated and purified to obtain deuterated
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
8. The isotopically enriched products 9 and 10 are obtained by
chiral separation.
##STR00583##
Example 3
[0242] The oxoquinazoline and gluarimide portions of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
are enriched with deuterium as follows:
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
hydrochloride 3A is dissolved in DMSO-d.sub.6 and D.sub.2O and
allowed to stir at room temperature. After two hours, the reaction
quenched, concentrated and purified to obtain 7. Compound 7 is
subsequently treated with potassium tert-butoxide in tert-butyl
alcohol and allowed to stir for an additional 2 hours. The reaction
mixture is then quenched, concentrated and purified to obtain
deuterated
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
11 as a mixture of enantiomers. The isotopically enriched products
12 and 13 are obtained by chiral separation.
##STR00584##
Example 4
[0243] Deuterated isotopologues 18 and 19 of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is prepared as follows. 2-amino-6-nitrobenzoic acid 14 is stirred
overnight in acetic anhydride under reflux to obtain
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one 15. The resulting
oxazinone is further contacted with
3,4,4,5,5-pentadeuteroglutarimide in the presence of
POCl.sub.3/H.sub.2O and diisopropylethylamine and refluxed in
N-methyl-2-pyrrolidinone (NMP) for 12 hours and subsequently
purified to give isotopologue 16 of
3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
Compound 16 is subsequently subjected to transfer hydrogenation
with DCOOD/D.sub.2O and 10% Pd/C; the catalyst is filtered off
through a celite pad and the filtrate is concentrated and purified
to obtain isotopologue 17 as a mixture of enantiomers. The
isotopically enriched products 18 and 19 are obtained by chiral
separation.
##STR00585##
Example 5
[0244] Deuterated isotopologues 22 and 23 of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is prepared as follows. 2-amino-6-nitrobenzoic acid 14 is stirred
overnight in acetic anhydride under reflux to obtain
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one 15. The resulting
oxazinone is further contacted with 3,4,5-trideuteroglutarimide in
the presence of POCl.sub.3/H.sub.2O and diisopropylethylamine and
refluxed in N-methyl-2-pyrrolidinone (NMP) for 12 hours and
subsequently purified to give isotopologue 20 of
3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
Compound 20 is subsequently subjected to transfer hydrogenation
with DCOOD/D.sub.2O and 10% Pd/C; the catalyst is filtered off
through a celite pad and the filtrate concentrated and purified to
obtain isotopologue 21 as a mixture of enantiomers. The
isotopically enriched products 22 and 23 are obtained by chiral
separation.
##STR00586##
Example 6
[0245] Deuterated isotopologue 27 and 28 of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
are prepared as follows. 2-amino-6-nitrobenzoic acid 14 is stirred
overnight in acetic anhydride-d.sub.6 under reflux to obtain
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one. The resulting
oxazinone 24 is further contacted with
3,4,4,5,5-pentadeuteroglutarimide in the presence of
POCl.sub.3/H.sub.2O and diisopropylethylamine and refluxed in
N-methyl-2-pyrrolidinone (NMP) for 12 hours. The subsequent
reaction mixture is cooled and purified to give oxoquinazoline 23.
The nitro-substituted quinazoline 25 is subjected to transfer
hydrogenation in the presence of DCOOD/D.sub.2O and 10% Pd/C; the
catalyst is filtered off through a celite pad and the filtrate
concentrated and purified to obtain isotopologue 26 as a mixture of
enantiomers. The isotopically enriched products 27 and 28 are
obtained by chiral separation.
##STR00587##
Example 7
[0246] Isotopologues 30 and 31 of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
are prepared as follows. 2-amino-6-nitrobenzoic acid 14 is stirred
overnight in acetic anhydride under reflux to obtain
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one 15. The resulting
oxazinone is further contacted with
3,4,4,5,5-pentadeuteroglutarimide in the presence of
POCl.sub.3/H.sub.2O and diisopropylethylamine and refluxed in
N-methyl-2-pyrrolidinone (NMP) for 12 hours and subsequently
purified to give the isotopologue 16 of
3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
Compound 16 is subsequently subjected to transfer hydrogenation
with DCOOD/D.sub.2O and 10% Pd/C; the catalyst is filtered off
through a celite pad and the filtrate concentrated and purified to
obtain isotopologue 15 as a mixture of enantiomers. Oxoquinazoline
17 is subsequently dissolved in DMSO-d.sub.6 and D.sub.2O, treated
with DCl, allowed to stir at room temperature for ten hours to
generate compound 29 as a mixture of enantiomers. The isotopically
enriched products 30 and 31 are obtained by chiral separation.
##STR00588##
Example 8
[0247] Isotopologue 36 of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
is prepared as follows. 2-Amino-6-nitrobenzoic acid 14 is stirred
overnight with triphosgene in THF, concentrated and purified to
obtain 5-nitro-1H-benzo[d][1,3]oxazine-2,4-dione 32. Dione 32 is
dissolved in acetonitrile, and deuterated glutamic acid methyl
ester and sodium bicarbonate are added. The reaction mixture is
stirred at 50.degree. C. for 4 hours, concentrated and purified to
give compound 33. Treatment of compound 33 with
triethylorthoacetate and PTSA hydrate in DMSO at 120.degree. C.
provides oxoquinazoline 34. Subsequent treatment of 34 with
potassium tert-butoxide in THF at -78.degree. C. affords
cyclization to glutarimide 35. Purification of the glutarimide 35
followed by transfer hydrogenation provides isotopologue 36 in
enantiomerically pure form.
##STR00589##
Example 9
[0248] Deuterated isotopologue 39 and 40 of
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
are prepared as follows. 2-amino-6-nitrobenzoic acid 14 is stirred
overnight in acetic anhydride-d.sub.6 under reflux to obtain
2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one 24. The resulting
oxazinone 24 is further contacted with 3-aminopiperidine-2,6-dione
in the presence of POCl.sub.3/H.sub.2O and diisopropylethylamine
and refluxed in N-methyl-2-pyrrolidinone (NMP) for 12 hours. The
subsequent reaction mixture is purified to give oxoquinazoline 37.
The nitro-substituted quinazoline 37 is subjected to transfer
hydrogenation in the presence of DCOOD/D.sub.2O and 10% Pd/C; the
catalyst is filtered off through a celite pad and the filtrate
concentrated and purified to obtain isotopologue 38 as a mixture of
enantiomers. The isotopically enriched products 39 and 40 are
obtained by chiral separation.
##STR00590##
[0249] While examples of certain particular embodiments are
provided herein, it will be apparent to those skilled in the art
that various changes and modifications may be made. Such
modifications are also intended to fall within the scope of the
appended claims.
* * * * *