U.S. patent application number 15/806254 was filed with the patent office on 2018-05-03 for 6-, 7-, or 8-substituted quinazolinone derivatives and compositions comprising and methods of using the same.
The applicant listed for this patent is Celgene Corporation. Invention is credited to Hon-Wah Man, George W. Muller.
Application Number | 20180118713 15/806254 |
Document ID | / |
Family ID | 40225265 |
Filed Date | 2018-05-03 |
United States Patent
Application |
20180118713 |
Kind Code |
A1 |
Muller; George W. ; et
al. |
May 3, 2018 |
6-, 7-, OR 8-SUBSTITUTED QUINAZOLINONE DERIVATIVES AND COMPOSITIONS
COMPRISING AND METHODS OF USING THE SAME
Abstract
Provided are quinazolinone compounds, and pharmaceutically
acceptable salts, solvates, clathrates, stereoisomers, and prodrugs
thereof. Methods of use, and pharmaceutical compositions of these
compounds are disclosed.
Inventors: |
Muller; George W.; (Rancho
Santa Fe, CA) ; Man; Hon-Wah; (Princeton,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Celgene Corporation |
Summit |
NJ |
US |
|
|
Family ID: |
40225265 |
Appl. No.: |
15/806254 |
Filed: |
November 7, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15415332 |
Jan 25, 2017 |
9834538 |
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15806254 |
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14749448 |
Jun 24, 2015 |
9586929 |
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15415332 |
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13928147 |
Jun 26, 2013 |
9096573 |
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14749448 |
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12238354 |
Sep 25, 2008 |
8492395 |
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13928147 |
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60995676 |
Sep 26, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/00 20180101;
A61P 35/02 20180101; A61P 11/00 20180101; A61P 25/04 20180101; A61P
7/00 20180101; C07D 401/04 20130101; A61P 29/00 20180101; A61P
35/00 20180101; A61P 9/10 20180101; A61P 25/20 20180101; A61P 17/00
20180101; A61P 37/00 20180101 |
International
Class: |
C07D 401/04 20060101
C07D401/04 |
Claims
1-30. (canceled)
31. A compound which is: ##STR00064## ##STR00065## or a
pharmaceutically acceptable salt, solvate, or stereoisomer
thereof.
32. A pharmaceutical composition comprising a compound of claim 31,
or a pharmaceutically acceptable salt, solvate, or stereoisomer
thereof
33. A method of treating, managing or preventing a disease or
disorder comprising administering to a patient a compound of claim
31, or a pharmaceutically acceptable salt, solvate, or stereoisomer
thereof, 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.
Description
[0001] This application claims priority to U.S. provisional
application No. 60/995,676, filed Sep. 26, 2007, the entirety of
which is incorporated herein by reference.
1. FIELD OF THE INVENTION
[0002] Provided herein are quinzolinone derivatives. Pharmaceutical
compositions comprising the compounds and methods for treating,
preventing and managing various disorders are also disclosed.
2. BACKGROUND OF THE INVENTION
2.1 PATHOBIOLOGY OF CANCER AND OTHER DISEASES
[0003] 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).
[0004] There is an enormous variety of cancers which are described
in detail in the medical literature. Examples includes 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.
[0005] Many types of cancers are associated with new blood vessel
formation, a process known as angiogenesis. Several of the
mechanisms involved in tumor-induced angiogenesis have been
elucidated. The most direct of these mechanisms is the secretion by
the tumor cells of cytokines with angiogenic properties. Examples
of these cytokines include acidic and basic fibroblastic growth
factor (a,b-FGF), angiogenin, vascular endothelial growth factor
(VEGF), and TNF-.alpha.. Alternatively, tumor cells can release
angiogenic peptides through the production of proteases and the
subsequent breakdown of the extracellular matrix where some
cytokines are stored (e.g., b-FGF). Angiogenesis can also be
induced indirectly through the recruitment of inflammatory cells
(particularly macrophages) and their subsequent release of
angiogenic cytokines (e.g., TNF-.alpha., b-FGF).
[0006] 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.
[0007] 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.
2.2 METHODS OF TREATING CANCER
[0008] 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.
[0009] 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).
[0010] 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.
[0011] Other diseases or conditions associated with, or
characterized by, undesired angiogenesis are also difficult to
treat. However, some compounds such as protamine, hepain and
steroids have been proposed to be useful in the treatment of
certain specific diseases. Taylor et al., Nature 297:307 (1982);
Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos.
5,001,116 and 4,994,443.
[0012] Still, there is a significant need for 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.
3. SUMMARY OF THE INVENTION
[0013] Provided herein are quinazolinone compounds, and
pharmaceutically acceptable salts, solvates (e.g., hydrates),
prodrugs, clathrates, or stereoisomers thereof.
[0014] Also provided are methods of treating and managing various
diseases or disorders. The methods comprise administering to a
patient in need of such treatment or management, or having such a
disease or disorder, a therapeutically effective amount of a
compound provided herein, or a pharmaceutically acceptable salt,
solvate, prodrug, clathrate, or stereoisomer thereof.
[0015] Also provided herein are methods of preventing various
diseases and disorders, which comprise administering to a patient
in need of such prevention, or at a risk of such a disease or
disorder, a prophylactically effective amount of a compound
provided herein, or a pharmaceutically acceptable salt, solvate,
prodrug, clathrate, or stereoisomer thereof.
[0016] Also provided herein are pharmaceutical compositions, single
unit dosage forms, dosing regimens and kits which comprise a
compound provided herein, or a pharmaceutically acceptable salt,
solvate, prodrug, clathrate, or stereoisomer thereof.
4. DETAILED DESCRIPTION OF THE INVENTION
[0017] In one embodiment, provided are quinazolinone compounds, and
pharmaceutically acceptable salts, solvates, prodrugs, clathrate,
and stereoisomers thereof.
[0018] In another embodiment, provided are methods of treating,
managing, and preventing various diseases and disorders, which
comprises administering to a patient a therapeutically or
prophylactically effective amount of a compound provided herein, or
a pharmaceutically acceptable salt, solvate, prodrug, clathrate, or
stereoisomer thereof. Examples of diseases and disorders are
described herein.
[0019] In other embodiments, a compound provided herein, or a
pharmaceutically acceptable salt, solvate, prodrug, clathrate, or
stereoisomer thereof, is administered in combination with another
drug ("second active agent") or treatment. Second active agents
include small molecules and large molecules (e.g., proteins and
antibodies), examples of which are provided herein, as well as stem
cells. Methods, or therapies, that can be used in combination with
the administration of compounds provided herein include, but are
not limited to, surgery, blood transfusions, immunotherapy,
biological therapy, radiation therapy, and other non-drug based
therapies presently used to treat, prevent or manage various
disorders described herein.
[0020] Also provided are pharmaceutical compositions (e.g., single
unit dosage forms) that can be used in the methods provided herein.
In one embodiment, pharmaceutical compositions comprise a compound
provided herein, or a pharmaceutically acceptable salt, solvate,
prodrug, clathrate, or stereoisomer thereof, and optionally a
second active agent.
4.1 COMPOUNDS
[0021] In one embodiment, the compounds provided herein for use in
the pharmaceutical compositions and methods have the formula
(I):
##STR00001##
and pharmaceutically acceptable salts, solvates, and stereoisomers
thereof, wherein: [0022] R.sup.1 is hydrogen; [0023] each of
R.sup.2, R.sup.3, R.sup.4 and is independently: hydrogen; halo;
--(CH.sub.2).sub.nOH; (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; (C.sub.1-C.sub.6)alkoxy,
optionally substituted with one or more halo; or [0024]
--(CH.sub.2).sub.nNHR.sup.a, wherein R.sup.a is: [0025] hydrogen;
[0026] (C.sub.1-C.sub.6)alkyl, optionally substituted with one or
more halo; [0027] --(CH.sub.2).sub.n-(6 to 10 membered aryl);
[0028] --C(O)--(CH.sub.2).sub.n-(6 to 10 membered aryl) or
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl), wherein the
aryl or heteroaryl is optionally substituted with one or more of:
halo; --SCF.sub.3; (C.sub.1-C.sub.6)alkyl, said alkyl itself
optionally substituted with one or more halo; or
(C.sub.1-C.sub.6)alkoxy, said alkoxy itself optionally substituted
with one or more halo; [0029] --C(O)--(C.sub.1-C.sub.8)alkyl,
wherein the alkyl is optionally substituted with one or more halo;
[0030] --C(O)--(CH.sub.2).sub.n-(C.sub.3-C.sub.10-cycloalkyl);
[0031] --C(O)--(CH.sub.2).sub.n--NR.sup.bR.sup.c, wherein R.sup.b
and R.sup.c are each independently: [0032] hydrogen; [0033]
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; [0034] (C.sub.1-C.sub.6)alkoxy, optionally substituted with
one or more halo; or [0035] 6 to 10 membered aryl, optionally
substituted with one or more of: halo; (C.sub.1-C.sub.6)alkyl,
itself optionally substituted with one or more halo; or
(C.sub.1-C.sub.6)alkoxy, itself optionally substituted with one or
more halo; [0036]
--C(O)--(CH.sub.2).sub.n--O-(C.sub.1-C.sub.6)alkyl; or [0037]
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl); or [0038] two of R.sup.1-R.sup.4 together can form a 5 or 6
membered ring, optionally substituted with one or more of: [0039]
halo; (C.sub.1-C.sub.6)alkyl, optionally substituted with one or
more halo; and (C.sub.1-C.sub.6)alkoxy, optionally substituted with
one or more halo; [0040] R.sup.5 is: hydrogen;
--(CH.sub.2).sub.nOH; phenyl; --O-(C.sub.1-C.sub.6)alkyl; or
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; [0041] R.sup.6 is: hydrogen; or (C.sub.1-C.sub.6)alkyl,
optionally substituted with one or more halo; and [0042] n is 0, 1,
or 2.
[0043] In another embodiment, provided herein are compounds of
formula (II):
##STR00002##
and pharmaceutically acceptable salts, solvates, and stereoisomers
thereof, wherein: [0044] R.sup.7 is: hydrogen; halo;
--(CH.sub.2).sub.nOH; (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; (C.sub.1-C.sub.6)alkoxy,
optionally substituted with one or more halo; or [0045]
--(CH.sub.2).sub.nNHR.sup.d, wherein R.sup.d is: [0046] hydrogen;
[0047] (C.sub.1-C.sub.6)alkyl, optionally substituted with one or
more halo; [0048] --(CH.sub.2).sub.n-(6 to 10 membered aryl);
[0049] --C(O)--(CH.sub.2).sub.n-(6 to 10 membered aryl) or
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl), wherein the
aryl or heteroaryl is optionally substituted with one or more of:
halo; --SCF.sub.3; (C.sub.1-C.sub.6)alkyl, itself optionally
substituted with one or more halo; or (C.sub.1-C.sub.6)alkoxy,
itself optionally substituted with one or more halo; [0050]
--C(O)--(C.sub.1-C.sub.8)alkyl, wherein the alkyl is optionally
substituted with one or more halo; [0051]
--C(O)--(CH.sub.2).sub.n--(C.sub.3-C.sub.10-cycloalkyl); [0052]
--C(O)--(CH.sub.2).sub.n--NR.sup.cR.sup.f, wherein R.sup.c and
R.sup.f are each independently: [0053] hydrogen; [0054]
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; [0055] (C.sub.1-C.sub.6)alkoxy, optionally substituted with
one or more halo; or [0056] 6 to 10 membered aryl, optionally
substituted with one or more of: halo; (C.sub.1-C.sub.6)alkyl,
itself optionally substituted with one or more halo; or
(C.sub.1-C.sub.6)alkoxy, itself optionally substituted with one or
more halo; [0057]
--C(O)--(CH.sub.2).sub.n--O--(C.sub.1-C.sub.6)alkyl; or [0058]
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl); [0059] R.sup.8 is: hydrogen; --(CH.sub.2).sub.nOH; phenyl;
--O--(C.sub.1-C.sub.6)alkyl; or (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; [0060] R.sup.9 is: hydrogen; or
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; and [0061] n is 0, 1, or 2.
[0062] In another embodiment, provided herein are compounds of
formula (III):
##STR00003##
and pharmaceutically acceptable salts, solvates, and stereoisomers
thereof, wherein: [0063] R.sup.10 is: hydrogen; halo;
--(CH.sub.2).sub.nOH; (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; or (C.sub.1-C.sub.6)alkoxy,
optionally substituted with one or more halo; [0064] R.sup.11 is:
hydrogen; --(CH.sub.2).sub.nOH; phenyl;
--O--(C.sub.1-C.sub.6)alkyl; or (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; [0065] R.sup.12 is: hydrogen; or
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; and [0066] n is 0, 1, or 2.
[0067] In one embodiment, R.sup.10 is hydrogen. In another
embodiment, R.sup.10 is halo. In another embodiment, R.sup.10 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo. In another embodiment, R.sup.10 is --(CH.sub.2).sub.nOH or
hydroxyl. In another embodiment, R.sup.10 is
(C.sub.1-C.sub.6)alkoxy, optionally substituted with one or more
halo.
[0068] In one embodiment, R.sup.11 is hydrogen. In another
embodiment, R.sup.11 is --(CH.sub.2).sub.nOH or hydroxyl. In
another embodiment, R.sup.11 is phenyl. In another embodiment,
R.sup.11 is --O--(C.sub.1-C.sub.6)alkyl, optionally substituted
with one or more halo. In another embodiment, R.sup.11 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo.
[0069] In one embodiment, R.sup.12 is hydrogen. In another
embodiment, R.sup.12 is (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo.
[0070] In one embodiment, n is 0. In another embodiment, n is 1. In
another embodiment, n is 2.
[0071] Compounds provided herein encompass any of the combinations
of R.sup.10, R.sup.11, R.sup.12 and n described above.
[0072] In one specific embodiment, R.sup.10 is halo. In another
embodiment, R.sup.10 is hydroxyl. In another embodiment, R.sup.10
is methyl.
[0073] In another specific embodiment, R.sup.11 is hydrogen. In
another embodiment, R.sup.11 is methyl.
[0074] In another specific embodiment, R.sup.12 is hydrogen. In
another embodiment, R.sup.12 is methyl.
[0075] Specific compounds include, but are not limited to:
##STR00004##
[0076] In another embodiment, provided herein are compounds of
formula (IV):
##STR00005##
and pharmaceutically acceptable salts, solvates, and stereoisomers
thereof, wherein: [0077] R.sup.g is: [0078] hydrogen; [0079]
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; [0080] --(CH.sub.2).sub.n-(6 to 10 membered aryl); [0081]
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered aryl) or
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl), wherein the
aryl or heteroaryl is optionally substituted with one or more of:
halo; --SCF.sub.3; (C.sub.1-C.sub.6)alkyl, itself optionally
substituted with one or more halo; or (C.sub.1-C.sub.6)alkoxy,
itself optionally substituted with one or more halo; [0082]
--C(O)--(C.sub.1-C.sub.8)alkyl, wherein the alkyl is optionally
substituted with one or more halo; [0083]
--C(O)--(CH.sub.2).sub.n--(C.sub.3-C.sub.10-cycloalkyl); [0084]
--C(O)--(CH.sub.2).sub.n--NR.sup.hR.sup.i, wherein R.sup.h and
R.sup.i are each independently: [0085] hydrogen; [0086]
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; [0087] (C.sub.1-C.sub.6)alkoxy, optionally substituted with
one or more halo; or [0088] 6 to 10 membered aryl, optionally
substituted with one or more of: halo; (C.sub.1-C.sub.6)alkyl,
itself optionally substituted with one or more halo; or
(C.sub.1-C.sub.6)alkoxy, itself optionally substituted with one or
more halo; [0089]
--C(O)--(CH.sub.2).sub.n--O--(C.sub.1-C.sub.6)alkyl; or [0090]
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl); [0091] R.sup.13 is: hydrogen; --(CH.sub.2).sub.nOH; phenyl;
--O--(C.sub.1-C.sub.6)alkyl; or (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; [0092] R.sup.14 is: hydrogen; or
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; and [0093] n is 0, 1, or 2.
[0094] In one embodiment, R.sup.g is hydrogen. In another
embodiment, R.sup.g is (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo. In another embodiment, R.sup.g
is --(CH.sub.2).sub.n-(6 to 10 membered aryl). In another
embodiment, R.sup.g is --C(O)--(CH.sub.2).sub.n-(6 to 10 membered
aryl) or --C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl),
wherein the aryl or heteroaryl is optionally substituted as
described above. In another embodiment, R.sup.g is
--C(O)--(C.sub.1-C.sub.8)alkyl, wherein the alkyl is optionally
substituted with one or more halo. In another embodiment, R.sup.g
is --C(O)--(CH.sub.2).sub.n--(C.sub.3-C.sub.10-cycloalkyl). In
another embodiment, R.sup.g is
--C(O)--(CH.sub.2).sub.n--NR.sup.hR.sup.i, wherein R.sup.h and
R.sup.i are as described above. In another embodiment, R.sup.g is
--C(O)--(CH.sub.2).sub.n--O-(C.sub.1-C.sub.6)alkyl. In another
embodiment, R.sup.g is
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl).
[0095] In one embodiment, R.sup.13 is hydrogen. In another
embodiment, R.sup.13 is --(CH.sub.2).sub.nOH or hydroxyl. In
another embodiment, R.sup.13 is phenyl. In another embodiment,
R.sup.13 is --O--(C.sub.1-C.sub.6)alkyl, optionally substituted
with one or more halo. In another embodiment, R.sup.13 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo.
[0096] In one embodiment, R.sup.14 is hydrogen. In another
embodiment, R.sup.14 is (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo.
[0097] In one embodiment, n is 0. In another embodiment, n is 1. In
another embodiment, n is 2.
[0098] Compounds provided herein encompass any of the combinations
of R.sup.g, R.sup.13, R.sup.14 and n described above.
[0099] In one specific embodiment, R.sup.g is hydrogen, and n is 0
or 1. In another embodiment, R.sup.g is
--C(O)--(C.sub.1-C.sub.6)alkyl. In another embodiment, R.sup.g is
--C(O)-phenyl, optionally substituted with one or more methyl,
halo, and/or (C.sub.1-C.sub.6)alkoxy.
[0100] In another specific embodiment, R.sup.13 is methyl. In
another embodiment, R.sup.14 is hydrogen.
[0101] Specific compounds include, but are not limited to:
##STR00006## ##STR00007## ##STR00008## ##STR00009##
[0102] In another embodiment, provided herein are compounds of
formula (V):
##STR00010##
and pharmaceutically acceptable salts, solvates, and stereoisomers
thereof, wherein: [0103] R.sup.15 is: hydrogen; halo;
--(CH.sub.2).sub.nOH; (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; (C.sub.1-C.sub.6)alkoxy,
optionally substituted with one or more halo; or [0104]
--(CH.sub.2).sub.nNHR.sup.j, wherein R.sup.j is: [0105] hydrogen;
[0106] (C.sub.1-C.sub.6)alkyl, optionally substituted with one or
more halo; [0107] --(CH.sub.2).sub.n-(6 to 10 membered aryl);
[0108] --C(O)--(CH.sub.2).sub.n-(6 to 10 membered aryl) or
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl), wherein the
aryl or heteroaryl is optionally substituted with one or more of:
halo; --SCF.sub.3; (C.sub.1-C.sub.6)alkyl, itself optionally
substituted with one or more halo; or (C.sub.1-C.sub.6)alkoxy,
itself optionally substituted with one or more halo; [0109]
--C(O)--(C.sub.1-C.sub.8)alkyl, wherein the alkyl is optionally
substituted with one or more halo; [0110]
--C(O)--(CH.sub.2).sub.n--(C.sub.3-C.sub.10-cycloalkyl); [0111]
--C(O)--(CH.sub.2).sub.n--NR.sup.kR.sup.l, wherein R.sup.k and
R.sup.l are each independently: [0112] hydrogen; [0113]
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; [0114] (C.sub.1-C.sub.6)alkoxy, optionally substituted with
one or more halo; or [0115] 6 to 10 membered aryl, optionally
substituted with one or more of: halo; (C.sub.1-C.sub.6)alkyl,
itself optionally substituted with one or more halo; or
(C.sub.1-C.sub.6)alkoxy, itself optionally substituted with one or
more halo; [0116]
--C(O)--(CH.sub.2).sub.n--O--(C.sub.1-C.sub.6)alkyl; or [0117]
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl); [0118] R.sup.16 is: hydrogen; --(CH.sub.2).sub.nOH; phenyl;
--O--(C.sub.1-C.sub.6)alkyl; or (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; [0119] R.sup.17 is: hydrogen; or
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; and [0120] n is 0, 1, or 2.
[0121] In one embodiment, R.sup.15 is hydrogen. In another
embodiment, R.sup.15 is halo. In another embodiment, R.sup.15 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo. In another embodiment, R.sup.15 is --(CH.sub.2).sub.nOH or
hydroxyl. In another embodiment, R.sup.15 is
(C.sub.1-C.sub.6)alkoxy, optionally substituted with one or more
halo.
[0122] In one embodiment, R.sup.15 is --(CH.sub.2).sub.nNHR.sup.j.
In one embodiment, wherein R.sup.15 is --(CH.sub.2).sub.nNHR.sup.j,
R.sup.j is hydrogen. In another embodiment, R.sup.j is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo. In another embodiment, R.sup.j is --(CH.sub.2).sub.n-(6 to 10
membered aryl). In another embodiment, R.sup.j is
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered aryl) or
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl), wherein the
aryl or heteroaryl is optionally substituted as described above. In
another embodiment, R.sup.j is --C(O)--(C.sub.1-C.sub.8)alkyl,
wherein the alkyl is optionally substituted with one or more halo.
In another embodiment, R.sup.j is
--C(O)--(CH.sub.2).sub.n-(C.sub.3-C.sub.10-cycloalkyl). In another
embodiment, R.sup.j is --C(O)--(CH.sub.2).sub.n--NR.sup.kR.sup.l,
wherein R.sup.k and R.sup.l are as described above. In another
embodiment, R.sup.j is
--C(O)--(CH.sub.2).sub.n--O--(C.sub.1-C.sub.6)alkyl. In another
embodiment, R.sup.j is
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl).
[0123] In one embodiment, R.sup.16 is hydrogen. In another
embodiment, R.sup.16 is --(CH.sub.2).sub.nOH or hydroxyl. In
another embodiment, R.sup.16 is phenyl. In another embodiment,
R.sup.16 is --O--(C.sub.1-C.sub.6)alkyl, optionally substituted
with one or more halo. In another embodiment, R.sup.16 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo.
[0124] In one embodiment, R.sup.17 is hydrogen. In another
embodiment, R.sup.17 is (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo.
[0125] In one embodiment, n is 0. In another embodiment, n is 1. In
another embodiment, n is 2.
[0126] Compounds provided herein encompass any of the combinations
of R.sup.15, R.sup.16, R.sup.17 and n described above.
[0127] In one specific embodiment, R.sup.15 is methyl. In another
embodiment, R.sup.15 is halo. In another embodiment, R.sup.15 is
--CF.sub.3. In another embodiment, R.sup.15 is
--(CH.sub.2).sub.nNHR.sup.j.
[0128] In one specific embodiment wherein R.sup.15 is
--(CH.sub.2).sub.nNHR.sup.j, R.sup.j is hydrogen, and n is 0 or 1.
In another embodiment wherein R.sup.15 is
--(CH.sub.2).sub.nNHR.sup.j, R.sup.j is
--C(O)--(O)--(C.sub.1-C.sub.6)alkyl.
[0129] In one specific embodiment, R.sup.16 is hydrogen. In another
embodiment, R.sup.16 is methyl. In another specific embodiment,
R.sup.17 is hydrogen or methyl.
[0130] Specific compounds include, but are not limited to:
##STR00011## ##STR00012##
[0131] In another embodiment, provided herein are compounds of
formula (VI):
##STR00013##
and pharmaceutically acceptable salts, solvates, and stereoisomers
thereof, wherein: [0132] R.sup.18 is: hydrogen; halo;
--(CH.sub.2).sub.nOH; (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; (C.sub.1-C.sub.6)alkoxy,
optionally substituted with one or more halo; or [0133]
--(CH.sub.2).sub.nNHR.sup.m, wherein R.sup.m is: [0134] hydrogen;
[0135] (C.sub.1-C.sub.6)alkyl, optionally substituted with one or
more halo; [0136] --(CH.sub.2).sub.n-(6 to 10 membered aryl);
[0137] --C(O)--(CH.sub.2).sub.n-(6 to 10 membered aryl) or
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl), wherein the
aryl or heteroaryl is optionally substituted with one or more of:
halo; --SCF.sub.3; (C.sub.1-C.sub.6)alkyl, itself optionally
substituted with one or more halo; or (C.sub.1-C.sub.6)alkoxy,
itself optionally substituted with one or more halo; [0138]
--C(O)--(C.sub.1-C.sub.8)alkyl, wherein the alkyl is optionally
substituted with one or more halo; [0139]
--C(O)--(CH.sub.2).sub.n--(C.sub.3-C.sub.10-cycloalkyl); [0140]
--C(O)--(CH.sub.2).sub.n--NR.sup.nR.sup.o, wherein R.sup.n and
R.sup.o are each independently: [0141] hydrogen; [0142]
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; [0143] (C.sub.1-C.sub.6)alkoxy, optionally substituted with
one or more halo; or [0144] 6 to 10 membered aryl, optionally
substituted with one or more of: halo; (C.sub.1-C.sub.6)alkyl,
itself optionally substituted with one or more halo; or
(C.sub.1-C.sub.6)alkoxy, itself optionally substituted with one or
more halo; [0145]
--C(O)--(CH.sub.2).sub.n--O--(C.sub.1-C.sub.6)alkyl; or [0146]
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl); [0147] R.sup.19 is: hydrogen; --(CH.sub.2).sub.nOH; phenyl;
--O--(C.sub.1-C.sub.6)alkyl; or (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; [0148] R.sup.20 is: hydrogen; or
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; and [0149] n is 0, 1, or 2.
[0150] In one embodiment, R.sup.18 is hydrogen. In another
embodiment, R.sup.18 is halo. In another embodiment, R.sup.18 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo. In another embodiment, R.sup.18 is --(CH.sub.2).sub.nOH or
hydroxyl. In another embodiment, R.sup.18 is
(C.sub.1-C.sub.6)alkoxy, optionally substituted with one or more
halo.
[0151] In one embodiment, R.sup.18 is --(CH.sub.2).sub.nNHR.sup.m.
In one embodiment, wherein R.sup.28 is --(CH.sub.2).sub.nNHR.sup.s,
R.sup.s is hydrogen. In another embodiment, R.sup.m is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo. In another embodiment, R.sup.m is --(CH.sub.2).sub.n-(6 to 10
membered aryl). In another embodiment, R.sup.m is
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered aryl) or
--C(O)--(CH.sub.2).sub.n-(6 to 10 membered heteroaryl), wherein the
aryl or heteroaryl is optionally substituted as described above. In
another embodiment, R.sup.s is --C(O)--(C.sub.1-C.sub.8)alkyl,
wherein the alkyl is optionally substituted with one or more halo.
In another embodiment, R.sup.m is
--C(O)--(CH.sub.2).sub.n--(C.sub.3-C.sub.10-cycloalkyl). In another
embodiment, R.sup.m is --C(O)--(CH.sub.2).sub.n--NR.sup.nR.sup.o,
wherein R.sup.n and R.sup.o are as described above. In another
embodiment, R.sup.m is
--C(O)--(CH.sub.2).sub.n--O--(C.sub.1-C.sub.6)alkyl. In another
embodiment, R.sup.m is
--C(O)--(CH.sub.2).sub.n--O--(CH.sub.2).sub.n-(6 to 10 membered
aryl).
[0152] In one embodiment, R.sup.19 is hydrogen. In another
embodiment, R.sup.19 is --(CH.sub.2).sub.nOH or hydroxyl. In
another embodiment, R.sup.19 is phenyl. In another embodiment,
R.sup.19 is --O--(C.sub.1-C.sub.6)alkyl, optionally substituted
with one or more halo. In another embodiment, R.sup.19 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo.
[0153] In one embodiment, R.sup.20 is hydrogen. In another
embodiment, R.sup.20 is (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo.
[0154] In one embodiment, n is 0. In another embodiment, n is 1. In
another embodiment, n is 2.
[0155] Compounds provided herein encompass any of the combinations
of R.sup.18, R.sup.19, R.sup.20 and n described above.
[0156] In one specific embodiment, R.sup.18 is methyl. In another
embodiment, R.sup.18 is halo. In another embodiment, R.sup.18 is
hydroxyl. In another embodiment, R.sup.18 is --CF.sub.3.
[0157] In one specific embodiment, R.sup.19 is hydrogen. In another
embodiment, R.sup.19 is methyl. In another specific embodiment,
R.sup.20 is hydrogen.
[0158] Specific compounds include, but are not limited to:
##STR00014##
[0159] In another embodiment, provided herein are compounds of
formula (VII):
##STR00015##
and pharmaceutically acceptable salts, solvates, and stereoisomers
thereof, wherein: [0160] R.sup.21 is hydrogen; [0161] R.sup.22,
R.sup.23, and R.sup.24 are each independently: halo;
--(CH.sub.2).sub.nOH; (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo; (C.sub.1-C.sub.6)alkoxy,
optionally substituted with one or more halo; or [0162] two of
R.sup.21-R.sup.24 together form a 5 to 6 membered ring, optionally
substituted with one or more of: [0163] halo;
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; and (C.sub.1-C.sub.6)alkoxy, optionally substituted with one
or more halo; [0164] R.sup.25 is: hydrogen; --(CH.sub.2).sub.nOH;
phenyl; --O--(C.sub.1-C.sub.6)alkyl; or (C.sub.1-C.sub.6)alkyl,
optionally substituted with one or more halo; [0165] R.sup.26 is:
hydrogen; or (C.sub.1-C.sub.6)alkyl, optionally substituted with
one or more halo; and [0166] n is 0, 1, or 2.
[0167] In one embodiment, two of R.sup.22-R.sup.24 are halo. In
another embodiment, two of R.sup.22-R.sup.24 are
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo. In another embodiment, two of R.sup.22-R.sup.24 are
(C.sub.1-C.sub.6)alkoxy, optionally substituted with one or more
halo.
[0168] In another embodiment, one of R.sup.22-R.sup.24 are is halo,
and another one of R.sup.22-R.sup.24 is (C.sub.1-C.sub.6)alkyl,
optionally substituted with one or more halo. In another
embodiment, one of R.sup.22-R.sup.24 is halo, and another one of
R.sup.22-R.sup.24 is (C.sub.1-C.sub.6)alkoxy, optionally
substituted with one or more halo. In another embodiment, one of
R.sup.22-R.sup.24 is (C.sub.1-C.sub.6)alkoxy, optionally
substituted with one or more halo, and another one of
R.sup.22-R.sup.24 is (C.sub.1-C.sub.6)alkyl, optionally substituted
with one or more halo.
[0169] In another embodiment, two of R.sup.22-R.sup.24 together
form a 5 to 6 membered ring. In one specific embodiment, R.sup.22
and R.sup.23 together form a 5 to 6 membered ring. In one specific
embodiment, R.sup.22 and R.sup.23 together form phenyl ring. In
another embodiment, the ring formed by R.sup.22 and R.sup.23 is
optionally substituted with one or more of: halo;
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo; and (C.sub.1-C.sub.6)alkoxy, optionally substituted with one
or more halo.
[0170] In one embodiment, R.sup.25 is hydrogen. In another
embodiment, R.sup.25 is --(CH.sub.2).sub.nOH or hydroxyl. In
another embodiment, R.sup.25 is phenyl. In another embodiment,
R.sup.25 is --O--(C.sub.1-C.sub.6)alkyl, optionally substituted
with one or more halo. In another embodiment, R.sup.25 is
(C.sub.1-C.sub.6)alkyl, optionally substituted with one or more
halo.
[0171] In one embodiment, R.sup.26 is hydrogen. In another
embodiment, R.sup.26 is (C.sub.1-C.sub.6)alkyl, optionally
substituted with one or more halo.
[0172] In one embodiment, n is 0. In another embodiment, n is 1. In
another embodiment, n is 2.
[0173] Compounds provided herein encompass any of the combinations
of R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, R.sup.26, and
n described above.
[0174] Specific compounds include, but are not limited to:
##STR00016##
[0175] As used herein, and unless otherwise specified, the term
"pharmaceutically acceptable salt" refers to salts prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
acids and organic acids. Suitable non-toxic acids include inorganic
and organic acids such as, but not limited to, acetic, alginic,
anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic,
glucorenic, galacturonic, glycidic, hydrobromic, hydrochloric,
isethionic, lactic, maleic, malic, mandelic, methanesulfonic,
mucic, nitric, pamoic, pantothenic, phenylacetic, propionic,
phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric,
tartaric acid, p-toluenesulfonic and the like. In one embodiment,
suitable are hydrochloric, hydrobromic, phosphoric, and sulfuric
acids.
[0176] As used herein, and unless otherwise specified, the term
"solvate" means a compound that further includes a stoichiometric
or non-stoichiometric amount of solvent bound by non-covalent
intermolecular forces. Where the solvent is water, the solvate is a
hydrate.
[0177] As used herein, and unless otherwise specified, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide the compound. Examples of prodrugs include,
but are not limited to, compounds that comprise biohydrolyzable
moieties such as biohydrolyzable amides, biohydrolyzable esters,
biohydrolyzable carbamates, biohydrolyzable carbonates,
biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
Other examples of prodrugs include compounds that comprise --NO,
--NO.sub.2, --ONO, or --ONO.sub.2 moieties. Prodrugs can typically
be prepared using well-known methods, such as those described in
Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982
(Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H.
Bundgaard ed., Elselvier, N.Y. 1985).
[0178] As used herein, and unless otherwise specified, the terms
"biohydrolyzable carbamate," "biohydrolyzable carbonate,"
"biohydrolyzable ureide" and "biohydrolyzable phosphate" mean a
carbamate, carbonate, ureide and phosphate, respectively, of a
compound that either: 1) does not interfere with the biological
activity of the compound but can confer upon that compound
advantageous properties in vivo, such as uptake, duration of
action, or onset of action; or 2) is biologically inactive but is
converted in vivo to the biologically active compound. Examples of
biohydrolyzable carbamates include, but are not limited to,
carbamates that include lower alkylamine, substituted
ethylenediamine, aminoacid, hydroxyalkylamine, heterocyclic and
heteroaromatic amine, and polyether amine moieties.
[0179] As used herein, and unless otherwise specified, the term
"stereoisomer" encompasses all enantiomerically/stereomerically
pure and enantiomerically/stereomerically enriched compounds
provided herein.
[0180] As used herein and unless otherwise indicated, the term
"stereomerically pure" means a composition that comprises one
stereoisomer of a compound and is substantially free of other
stereoisomers of that compound. For example, a stereomerically pure
composition of a compound having one chiral center will be
substantially free of the opposite enantiomer of the compound. A
stereomerically pure composition of a compound having two chiral
centers will be substantially free of other diastereomers of the
compound. A typical stereomerically pure compound comprises greater
than about 80% by weight of one stereoisomer of the compound and
less than about 20% by weight of other stereoisomers of the
compound, greater than about 90% by weight of one stereoisomer of
the compound and less than about 10% by weight of the other
stereoisomers of the compound, greater than about 95% by weight of
one stereoisomer of the compound and less than about 5% by weight
of the other stereoisomers of the compound, or greater than about
97% by weight of one stereoisomer of the compound and less than
about 3% by weight of the other stereoisomers of the compound.
[0181] As used herein and unless otherwise indicated, the term
"stereomerically enriched" means a composition that comprises
greater than about 55% by weight of one stereoisomer of a compound,
greater than about 60% by weight of one stereoisomer of a compound,
greater than about 70% by weight, or greater than about 80% by
weight of one stereoisomer of a compound.
[0182] As used herein, and unless otherwise indicated, the term
"enantiomerically pure" means a stereomerically pure composition of
a compound having one chiral center. Similarly, the term
"enantiomerically enriched" means a stereomerically enriched
composition of a compound having one chiral center.
[0183] As used herein, and unless otherwise indicated, the term
"alkyl" refers to a saturated straight chain or branched
hydrocarbon having a number of carbon atoms as specified herein.
Representative saturated straight chain alkyls include -methyl,
-ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while
saturated branched alkyls include -isopropyl, -sec-butyl,
-isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl,
3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and
the like. The term "alkyl" also encompasses cycloalkyl.
[0184] As used herein, and unless otherwise specified, the term
"cycloalkyl" means a specie of alkyl containing from 3 to 15 carbon
atoms, without alternating or resonating double bonds between
carbon atoms. It may contain from 1 to 4 rings. Examples of
unsubstituted cycloalkyls include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. A
cycloalkyl may be substituted with one or more of the
substituents.
[0185] As used herein, the term "aryl" means a carbocyclic aromatic
ring containing from 5 to 14 ring atoms. The ring atoms of a
carbocyclic aryl group are all carbon atoms. Aryl ring structures
include compounds having one or more ring structures such as mono-,
bi-, or tricyclic compounds as well as benzo-fused carbocyclic
moieties such as 5,6,7,8-tetrahydronaphthyl and the like.
Specifically, the aryl group is a monocyclic ring or bicyclic ring.
Representative aryl groups include phenyl, anthracenyl, fluorenyl,
indenyl, azulenyl, phenanthrenyl and naphthyl.
[0186] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it.
4.2 METHODS OF TREATMENT, PREVENTION AND MANAGEMENT
[0187] Provided herein are methods of treating, preventing, and/or
managing various diseases or disorders using a compound provided
herein, or a pharmaceutically acceptable salt, solvate (e.g.,
hydrate), prodrug, clathrate, or stereoisomer thereof. Without
being limited by a particular theory, compounds provided herein can
control angiogenesis or inhibit the production of certain cytokines
including, but not limited to, TNF-.alpha., IL-1.beta., IL-12,
IL-18, GM-CSF, and/or IL-6. Without being limited by a particular
theory, compounds provided herein can stimulate the production of
certain other cytokines including IL-10, and also act as a
costimulatory signal for T cell activation, resulting in increased
production of cytokines such as, but not limited to, IL-12 and/or
IFN-.gamma.. In addition, compounds provided herein can enhance the
effects of NK cells and antibody-mediated cellular cytotoxicity
(ADCC). Further, compounds provided herein may be immunomodulatory
and/or cytotoxic, and thus, may be useful as chemotherapeutic
agents. Consequently, without being limited by a particular theory,
some or all of such characteristics possessed by the compounds
provided herein may render them useful in treating, managing,
and/or preventing various diseases or disorders.
[0188] Examples of diseases or disorders include, but are not
limited to, cancer, disorders associated with angiogenesis, pain
including, but not limited to, Complex Regional Pain Syndrome
("CRPS"), Macular Degeneration ("MD") and related syndromes, skin
diseases, pulmonary disorders, asbestos-related disorders,
parasitic diseases, immunodeficiency disorders, CNS disorders, CNS
injury, atherosclerosis and related disorders, dysfunctional sleep
and related disorders, hemoglobinopathy and related disorders
(e.g., anemia), TNF.alpha. related disorders, and other various
diseases and disorders.
[0189] As used herein, and unless otherwise specified, the terms
"treat," "treating" and "treatment" refer to the eradication or
amelioration of a disease or disorder, or of one or more symptoms
associated with the disease or disorder. In certain embodiments,
the terms refer to minimizing the spread or worsening of the
disease or disorder resulting from the administration of one or
more prophylactic or therapeutic agents to a subject with such a
disease or disorder. In some embodiments, the terms refer to the
administration of a compound provided herein, with or without other
additional active agent, after the onset of symptoms of the
particular disease.
[0190] As used herein, and unless otherwise specified, the terms
"prevent," "preventing" and "prevention" refer to the prevention of
the onset, recurrence or spread of a disease or disorder, or of one
or more symptoms thereof. In certain embodiments, the terms refer
to the treatment with or administration of a compound provided
herein, with or without other additional active compound, prior to
the onset of symptoms, particularly to patients at risk of disease
or disorders provided herein. The terms encompass the inhibition or
reduction of a symptom of the particular disease. Patients with
familial history of a disease in particular are candidates for
preventive regimens in certain embodiments. In addition, patients
who have a history of reoccurring symptoms are also potential
candidates for the prevention. In this regard, the term
"prevention" may be interchangeably used with the term
"prophylactic treatment."
[0191] As used herein, and unless otherwise specified, the terms
"manage," "managing" and "management" refer to preventing or
slowing the progression, spread or worsening of a disease or
disorder, or of one or more symptoms thereof. Often, the beneficial
effects that a subject derives from a prophylactic and/or
therapeutic agent do not result in a cure of the disease or
disorder. In this regard, the term "managing" encompasses treating
a patient who had suffered from the particular disease in an
attempt to prevent or minimize the recurrence of the disease.
[0192] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment or
management of a disease or disorder, or to delay or minimize one or
more symptoms associated with the disease or disorder. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment or management
of the disease or disorder. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or disorder, or
enhances the therapeutic efficacy of another therapeutic agent.
[0193] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease or disorder, or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of therapeutic agent, alone or in combination with other
agents, which provides a prophylactic benefit in the prevention of
the disease. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0194] Examples of cancer and precancerous conditions include, but
are not limited to, those described in U.S. Pat. Nos. 6,281,230 and
5,635,517 to Muller et al., in various U.S. patent publications to
Zeldis, including publication nos. 2004/0220144A1, published Nov.
4, 2004 (Treatment of Myelodysplastic Syndrome); 2004/0029832A1,
published Feb. 12, 2004 (Treatment of Various Types of Cancer); and
2004/0087546, published May 6, 2004 (Treatment of
Myeloproliferative Diseases). Examples also include those described
in WO 2004/103274, published Dec. 2, 2004. All of these references
are incorporated herein in their entireties by reference.
[0195] Specific examples of cancer include, but are not limited to,
cancers of the skin, such as melanoma; lymph node; breast; cervix;
uterus; gastrointestinal tract; lung; ovary; prostate; colon;
rectum; mouth; brain; head and neck; throat; testes; kidney;
pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and
AIDS-related cancers. The compounds are also useful for treating
cancers of the blood and bone marrow, such as multiple myeloma and
acute and chronic leukemias, for example, lymphoblastic,
myelogenous, lymphocytic, and myelocytic leukemias. The compounds
provided herein can be used for treating, preventing or managing
either primary or metastatic tumors.
[0196] Other specific cancers include, but are not limited to,
advanced malignancy, amyloidosis, neuroblastoma, meningioma,
hemangiopericytoma, multiple brain metastase, glioblastoma
multiforms, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor, malignant glioma, recurrent malignant
glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,
neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D
colorectal cancer, unresectable colorectal carcinoma, metastatic
hepatocellular carcinoma, Kaposi's sarcoma, karotype acute
myeloblastic leukemia, chronic lymphocytic leukemia (CLL),
Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell
lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma,
low grade follicular lymphoma, metastatic melanoma (localized
melanoma, including, but not limited to, ocular melanoma),
malignant mesothelioma, malignant pleural effusion mesothelioma
syndrome, peritoneal carcinoma, papillary serous carcinoma,
gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous
vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,
fibrodysplasia ossificans progressive, hormone refractory prostate
cancer, resected high-risk soft tissue sarcoma, unrescectable
hepatocellular carcinoma, Waldenstrom's macroglobulinemia,
smoldering myeloma, indolent myeloma, fallopian tube cancer,
androgen independent prostate cancer, androgen dependent stage IV
non-metastatic prostate cancer, hormone-insensitive prostate
cancer, chemotherapy-insensitive prostate cancer, papillary thyroid
carcinoma, follicular thyroid carcinoma, medullary thyroid
carcinoma, and leiomyoma. In a specific embodiment, the cancer is
metastatic. In another embodiment, the cancer is refractory or
resistance to chemotherapy or radiation.
[0197] In one embodiment, provided herein are methods of treating,
preventing or managing various forms of leukemias such as chronic
lymphocytic leukemia, chronic myelocytic leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia and acute
myeloblastic leukemia, including leukemias that are relapsed,
refractory or resistant, as disclosed in U.S. publication no.
2006/0030594, published Feb. 9, 2006, which is incorporated in its
entirety by reference.
[0198] The term "leukemia" refers malignant neoplasms of the
blood-forming tissues. The leukemia includes, but is not limited
to, chronic lymphocytic leukemia, chronic myelocytic leukemia,
acute lymphoblastic leukemia, acute myelogenous leukemia and acute
myeloblastic leukemia. The leukemia can be relapsed, refractory or
resistant to conventional therapy. The term "relapsed" refers to a
situation where patients who have had a remission of leukemia after
therapy have a return of leukemia cells in the marrow and a
decrease in normal blood cells. The term "refractory or resistant"
refers to a circumstance where patients, even after intensive
treatment, have residual leukemia cells in their marrow.
[0199] In another embodiment, provided herein are methods of
treating, preventing or managing various types of lymphomas,
including Non-Hodgkin's lymphoma (NHL). The term "lymphoma" refers
a heterogenous group of neoplasms arising in the
reticuloendothelial and lymphatic systems. "NHL" refers to
malignant monoclonal proliferation of lymphoid cells in sites of
the immune system, including lymph nodes, bone marrow, spleen,
liver and gastrointestinal tract. Examples of NHL include, but are
not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma of
intermediate differentiation, intermediate lymphocytic lymphoma
(ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL),
centrocytic lymphoma, diffuse small-cleaved cell lymphoma (DSCCL),
follicular lymphoma, and any type of the mantle cell lymphomas that
can be seen under the microscope (nodular, diffuse, blastic and
mentle zone lymphoma).
[0200] Examples of diseases and disorders associated with, or
characterized by, undesired angiogenesis include, but are not
limited to, inflammatory diseases, autoimmune diseases, viral
diseases, genetic diseases, allergic diseases, bacterial diseases,
ocular neovascular diseases, choroidal neovascular diseases, retina
neovascular diseases, and rubeosis (neovascularization of the
angle). Specific examples of the diseases and disorders associated
with, or characterized by, undesired angiogenesis include, but are
not limited to, arthritis, endometriosis, Crohn's disease, heart
failure, advanced heart failure, renal impairment, endotoxemia,
toxic shock syndrome, osteoarthritis, retrovirus replication,
wasting, meningitis, silica-induced fibrosis, asbestos-induced
fibrosis, veterinary disorder, malignancy-associated hypercalcemia,
stroke, circulatory shock, periodontitis, gingivitis, macrocytic
anemia, refractory anemia, and 5q-deletion syndrome.
[0201] Examples of pain include, but are not limited to those
described in U.S. patent publication no. 2005/0203142, published
Sep. 15, 2005, which is incorporated herein by reference. Specific
types of pain include, but are not limited to, nociceptive pain,
neuropathic pain, mixed pain of nociceptive and neuropathic pain,
visceral pain, migraine, headache and post-operative pain.
[0202] Examples of nociceptive pain include, but are not limited
to, pain associated with chemical or thermal burns, cuts of the
skin, contusions of the skin, osteoarthritis, rheumatoid arthritis,
tendonitis, and myofascial pain.
[0203] Examples of neuropathic pain include, but are not limited
to, CRPS type I, CRPS type II, reflex sympathetic dystrophy (RSD),
reflex neurovascular dystrophy, reflex dystrophy, sympathetically
maintained pain syndrome, causalgia, Sudeck atrophy of bone,
algoneurodystrophy, shoulder hand syndrome, post-traumatic
dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer
related pain, phantom limb pain, fibromyalgia, chronic fatigue
syndrome, spinal cord injury pain, central post-stroke pain,
radiculopathy, diabetic neuropathy, post-stroke pain, luetic
neuropathy, and other painful neuropathic conditions such as those
induced by drugs such as vincristine and velcade.
[0204] As used herein, the terms "complex regional pain syndrome,"
"CRPS" and "CRPS and related syndromes" mean a chronic pain
disorder characterized by one or more of the following: pain,
whether spontaneous or evoked, including allodynia (painful
response to a stimulus that is not usually painful) and
hyperalgesia (exaggerated response to a stimulus that is usually
only mildly painful); pain that is disproportionate to the inciting
event (e.g., years of severe pain after an ankle sprain); regional
pain that is not limited to a single peripheral nerve distribution;
and autonomic dysregulation (e.g., edema, alteration in blood flow
and hyperhidrosis) associated with trophic skin changes (hair and
nail growth abnormalities and cutaneous ulceration).
[0205] Examples of MD and related syndromes include, but are not
limited to, those described in U.S. patent publication no.
2004/0091455, published May 13, 2004, which is incorporated herein
by reference. Specific examples include, but are not limited to,
atrophic (dry) MD, exudative (wet) MD, age-related maculopathy
(ARM), choroidal neovascularisation (CNVM), retinal pigment
epithelium detachment (PED), and atrophy of retinal pigment
epithelium (RPE).
[0206] Examples of skin diseases include, but are not limited to,
those described in U.S. publication no. 2005/0214328A1, published
Sep. 29, 2005, which is incorporated herein by reference. Specific
examples include, but are not limited to, keratoses and related
symptoms, skin diseases or disorders characterized with overgrowths
of the epidermis, acne, and wrinkles.
[0207] As used herein, the term "keratosis" refers to any lesion on
the epidermis marked by the presence of circumscribed overgrowths
of the horny layer, including but not limited to actinic keratosis,
seborrheic keratosis, keratoacanthoma, keratosis follicularis
(Darier disease), inverted follicular keratosis, palmoplantar
keratoderma (PPK, keratosis palmaris et plantaris), keratosis
pilaris, and stucco keratosis. The term "actinic keratosis" also
refers to senile keratosis, keratosis senilis, verruca senilis,
plana senilis, solar keratosis, keratoderma or keratoma. The term
"seborrheic keratosis" also refers to seborrheic wart, senile wart,
or basal cell papilloma. Keratosis is characterized by one or more
of the following symptoms: rough appearing, scaly, erythematous
papules, plaques, spicules or nodules on exposed surfaces (e.g.,
face, hands, ears, neck, legs and thorax), excrescences of keratin
referred to as cutaneous horns, hyperkeratosis, telangiectasias,
elastosis, pigmented lentigines, acanthosis, parakeratosis,
dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,
cellular atypia, mitotic figures, abnormal cell-cell adhesion,
dense inflammatory infiltrates and small prevalence of squamous
cell carcinomas.
[0208] Examples of skin diseases or disorders characterized with
overgrowths of the epidermis include, but are not limited to, any
conditions, diseases or disorders marked by the presence of
overgrowths of the epidermis, including but not limited to,
infections associated with papilloma virus, arsenical keratoses,
sign of Leser-Trelat, warty dyskeratoma (WD), trichostasis
spinulosa (TS), erythrokeratodermia variabilis (EKV), ichthyosis
fetalis (harlequin ichthyosis), knuckle pads, cutaneous
melanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,
confluent and reticulated papillomatosis (CRP), acrochordons,
cutaneous horn, cowden disease (multiple hamartoma syndrome),
dermatosis papulosa nigra (DPN), epidermal nevus syndrome (ENS),
ichthyosis vulgaris, molluscum contagiosum, prurigo nodularis, and
acanthosis nigricans (AN).
[0209] Examples of pulmonary disorders include, but are not limited
to, those described in U.S. publication no. 2005/0239842A1,
published Oct. 27, 2005, which is incorporated herein by reference.
Specific examples include pulmonary hypertension and related
disorders. Examples of pulmonary hypertension and related disorders
include, but are not limited to: primary pulmonary hypertension
(PPH); secondary pulmonary hypertension (SPH); familial PPH;
sporadic PPH; precapillary pulmonary hypertension; pulmonary
arterial hypertension (PAH); pulmonary artery hypertension;
idiopathic pulmonary hypertension; thrombotic pulmonary
arteriopathy (TPA); plexogenic pulmonary arteriopathy; functional
classes I to IV pulmonary hypertension; and pulmonary hypertension
associated with, related to, or secondary to, left ventricular
dysfunction, mitral valvular disease, constrictive pericarditis,
aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous
pulmonary venous drainage, pulmonary venoocclusive disease,
collagen vasular disease, congenital heart disease, HIV virus
infection, drugs and toxins such as fenfluramines, congenital heart
disease, pulmonary venous hypertension, chronic obstructive
pulmonary disease, interstitial lung disease, sleep-disordered
breathing, alveolar hypoventilation disorder, chronic exposure to
high altitude, neonatal lung disease, alveolar-capillary dysplasia,
sickle cell disease, other coagulation disorder, chronic
thromboemboli, connective tissue disease, lupus including systemic
and cutaneous lupus, schistosomiasis, sarcoidosis or pulmonary
capillary hemangiomatosis.
[0210] Examples of asbestos-related disorders include, but not
limited to, those described in U.S. publication no. 2005/0100529,
published May 12, 2005, which is incorporated herein by reference.
Specific examples include, but are not limited to, mesothelioma,
asbestosis, malignant pleural effusion, benign exudative effusion,
pleural plaques, pleural calcification, diffuse pleural thickening,
rounded atelectasis, fibrotic masses, and lung cancer.
[0211] Examples of parasitic diseases include, but are not limited
to, those described in U.S. publication no. 2006/0154880, published
Jul. 13, 2006, which is incorporated herein by reference. Parasitic
diseases include diseases and disorders caused by human
intracellular parasites such as, but not limited to, P.
falcifarium, P. ovale, P. vivax, P. malariae, L. donovari, L.
infantum, L. aethiopica, L. major, L. tropica, L. mexicana, L.
braziliensis, T Gondii, B. microti, B. divergens, B. coli, C.
parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S.
haematobium, Trypanosoma ssp., Toxoplasma ssp., and O. volvulus.
Other diseases and disorders caused by non-human intracellular
parasites such as, but not limited to, Babesia bovis, Babesia
canis, Babesia Gibsoni, Besnoitia darlingi, Cytauxzoon felis,
Eimeria ssp., Hammondia ssp., and Theileria ssp., are also
encompassed. Specific examples include, but are not limited to,
malaria, babesiosis, trypanosomiasis, leishmaniasis, toxoplasmosis,
meningoencephalitis, keratitis, amebiasis, giardiasis,
cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,
ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,
toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,
filariasis, schistosomiasis, and dermatitis caused by animal
schistosomes.
[0212] Examples of immunodeficiency disorders include, but are not
limited to, those described in U.S. publication no. 2006/0188475,
published Aug. 24, 2006. Specific examples include, but not limited
to, adenosine deaminase deficiency, antibody deficiency with normal
or elevated Igs, ataxia-tenlangiectasia, bare lymphocyte syndrome,
common variable immunodeficiency, Ig deficiency with hyper-IgM, Ig
heavy chain deletions, IgA deficiency, immunodeficiency with
thymoma, reticular dysgenesis, Nezelof syndrome, selective IgG
subclass deficiency, transient hypogammaglobulinemia of infancy,
Wistcott-Aldrich syndrome, X-linked agammaglobulinemia, X-linked
severe combined immunodeficiency.
[0213] Examples of CNS disorders include, but are not limited to,
those described in U.S. publication no. 2005/0143344, published
Jun. 30, 2005, which is incorporated herein by reference. Specific
examples include, but are not limited to, include, but are not
limited to, Amyotrophic Lateral Sclerosis, Alzheimer Disease,
Parkinson Disease, Huntington's Disease, Multiple Sclerosis other
neuroimmunological disorders such as Tourette Syndrome, delerium,
or disturbances in consciousness that occur over a short period of
time, and amnestic disorder, or discreet memory impairments that
occur in the absence of other central nervous system
impairments.
[0214] Examples of CNS injuries and related syndromes include, but
are not limited to, those described in U.S. publication no.
2006/0122228, published Jun. 8, 2006, which is incorporated herein
by reference. Specific examples include, but are not limited to,
CNS injury/damage and related syndromes, include, but are not
limited to, primary brain injury, secondary brain injury, traumatic
brain injury, focal brain injury, diffuse axonal injury, head
injury, concussion, post-concussion syndrome, cerebral contusion
and laceration, subdural hematoma, epidermal hematoma,
post-traumatic epilepsy, chronic vegetative state, complete SCI,
incomplete SCI, acute SCI, subacute SCI, chronic SCI, central cord
syndrome, Brown-Sequard syndrome, anterior cord syndrome, conus
medullaris syndrome, cauda equina syndrome, neurogenic shock,
spinal shock, altered level of consciousness, headache, nausea,
emesis, memory loss, dizziness, diplopia, blurred vision, emotional
lability, sleep disturbances, irritability, inability to
concentrate, nervousness, behavioral impairment, cognitive deficit,
and seizure.
[0215] Other disease or disorders include, but not limited to,
viral, genetic, allergic, and autoimmune diseases. Specific
examples include, but not limited to, HIV, hepatitis, adult
respiratory distress syndrome, bone resorption diseases, chronic
pulmonary inflammatory diseases, dermatitis, cystic fibrosis,
septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis
syndrome, post ischemic reperfusion injury, meningitis, psoriasis,
fibrotic disease, cachexia, graft versus host disease, graft
rejection, auto-immune disease, rheumatoid spondylitis, Crohn's
disease, ulcerative colitis, inflammatory-bowel disease, multiple
sclerosis, systemic lupus erythrematosus, ENL in leprosy, radiation
damage, cancer, asthma, or hyperoxic alveolar injury.
[0216] Examples of atherosclerosis and related conditions include,
but are not limited to, those disclosed in U.S. publication no.
2002/0054899, published May 9, 2002, which is incorporated herein
by reference. Specific examples include, but are not limited to,
all forms of conditions involving atherosclerosis, including
restenosis after vascular intervention such as angioplasty,
stenting, atherectomy and grafting. All forms of vascular
intervention are contemplated herein, including diseases of the
cardiovascular and renal system, such as, but not limited to, renal
angioplasty, percutaneous coronary intervention (PCI), percutaneous
transluminal coronary angioplasty (PTCA), carotid percutaneous
transluminal angioplasty (PTA), coronary by-pass grafting,
angioplasty with stent implantation, peripheral percutaneous
transluminal intervention of the iliac, femoral or popliteal
arteries, and surgical intervention using impregnated artificial
grafts. The following chart provides a listing of the major
systemic arteries that may be in need of treatment, all of which
are contemplated herein:
TABLE-US-00001 Artery Body Areas Supplied Axillary Shoulder and
axilla Brachial Upper arm Brachiocephalic Head, neck, and arm
Celiac Divides into left gastric, splenic, and hepatic arteries
Common carotid Neck Common iliac Divides into external and internal
iliac arteries Coronary Heart Deep femoral Thigh Digital Fingers
Dorsalis pedis Foot External carotid Neck and external head regions
External iliac Femoral artery Femoral Thigh Gastric Stomach Hepatic
Liver, gallbladder, pancreas, and duodenum Inferior mesenteric
Descending colon, rectum, and pelvic wall Internal carotid Neck and
internal head regions Internal iliac Rectum, urinary bladder,
external genitalia, buttocks muscles, uterus and vagina Left
gastric Esophagus and stomach Middle sacral Sacrum Ovarian Ovaries
Palmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial Calf
Pulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach,
pancreas, and spleen Subclavian Shoulder Superior mesenteric
Pancreas, small intestine, ascending and transverse colon
Testicular Testes Ulnar Forearm
[0217] Examples of dysfunctional sleep and related syndromes
include, but are not limited to, those disclosed in U.S.
publication no. 2005/0222209A1, published Oct. 6, 2005, which is
incorporated herein by reference. Specific examples include, but
are not limited to, snoring, sleep apnea, insomnia, narcolepsy,
restless leg syndrome, sleep terrors, sleep walking sleep eating,
and dysfunctional sleep associated with chronic neurological or
inflammatory conditions. Chronic neurological or inflammatory
conditions, include, but are not limited to, Complex Regional Pain
Syndrome, chronic low back pain, musculoskeletal pain, arthritis,
radiculopathy, pain associated with cancer, fibromyalgia, chronic
fatigue syndrome, visceral pain, bladder pain, chronic
pancreatitis, neuropathies (diabetic, post-herpetic, traumatic or
inflammatory), and neurodegenerative disorders such as Parkinson's
Disease, Alzheimer's Disease, amyotrophic lateral sclerosis,
multiple sclerosis, Huntington's Disease, bradykinesia; muscle
rigidity; parkinsonian tremor; parkinsonian gait; motion freezing;
depression; defective long-term memory, Rubinstein-Taybi syndrome
(RTS); dementia; postural instability; hypokinetic disorders;
synuclein disorders; multiple system atrophies; striatonigral
degeneration; olivopontocerebellar atrophy; Shy-Drager syndrome;
motor neuron disease with parkinsonian features; Lewy body
dementia; Tau pathology disorders; progressive supranuclear palsy;
corticobasal degeneration; frontotemporal dementia; amyloid
pathology disorders; mild cognitive impairment; Alzheimer disease
with parkinsonism; Wilson disease; Hallervorden-Spatz disease;
Chediak-Hagashi disease; SCA-3 spinocerebellar ataxia; X-linked
dystonia parkinsonism; prion disease; hyperkinetic disorders;
chorea; ballismus; dystonia tremors; Amyotrophic Lateral Sclerosis
(ALS); CNS trauma and myoclonus.
[0218] Examples of hemoglobinopathy and related disorders include,
but are not limited to, those described in U.S. publication no.
2005/0143420A1, published Jun. 30, 2005, which is incorporated
herein by reference. Specific examples include, but are not limited
to, hemoglobinopathy, sickle cell anemia, and any other disorders
related to the differentiation of CD34+ cells.
[0219] Examples of TNF.alpha. related disorders include, but are
not limited to, those described in WO 98/03502 and WO 98/54170,
both of which are incorporated herein in their entireties by
reference. Specific examples include, but are not limited to:
endotoxemia or toxic shock syndrome; cachexia; adult respiratory
distress syndrome; bone resorption diseases such as arthritis;
hypercalcemia; Graft versus Host Reaction; cerebral malaria;
inflammation; tumor growth; chronic pulmonary inflammatory
diseases; reperfusion injury; myocardial infarction; stroke;
circulatory shock; rheumatoid arthritis; Crohn's disease; HIV
infection and AIDS; other disorders such as rheumatoid arthritis,
rheumatoid spondylitis, osteoarthritis, psoriatic arthritis and
other arthritic conditions, septic shock, septis, endotoxic shock,
graft versus host disease, wasting, Crohn's disease, ulcerative
colitis, multiple sclerosis, systemic lupus erythromatosis, ENL in
leprosy, HIV, AIDS, and opportunistic infections in AIDS; disorders
such as septic shock, sepsis, endotoxic shock, hemodynamic shock
and sepsis syndrome, post ischemic reperfusion injury, malaria,
mycobacterial infection, meningitis, psoriasis, congestive heart
failure, fibrotic disease, cachexia, graft rejection, oncogenic or
cancerous conditions, asthma, autoimmune disease, radiation
damages, and hyperoxic alveolar injury; viral infections, such as
those caused by the herpes viruses; viral conjunctivitis; or atopic
dermatitis.
[0220] In other embodiments, the use of compounds provided herein
in various immunological applications, in particular, as vaccine
adjuvants, particularly anticancer vaccine adjuvants, as disclosed
in U.S. Publication No. 2007/0048327, published Mar. 1, 2007, which
is incorporated herein in its entirety by reference, is also
encompassed. These embodiments also relate to the uses of compounds
provided herein in combination with vaccines to treat or prevent
cancer or infectious diseases, and other various uses of
immunomodulatory compounds such as reduction or desensitization of
allergic reactions.
[0221] Doses of a compound provided herein, or a pharmaceutically
acceptable salt, solvate, clathrate, stereoisomer or prodrug
thereof, vary depending on factors such as: specific indication to
be treated, prevented, or managed; age and condition of a patient;
and amount of second active agent used, if any. Generally, a
compound provided herein, or a pharmaceutically acceptable salt,
solvate, clathrate, stereoisomer or prodrug thereof, may be used in
an amount of from about 0.1 mg to about 500 mg per day, and can be
adjusted in a conventional fashion (e.g., the same amount
administered each day of the treatment, prevention or management
period), in cycles (e.g., one week on, one week off), or in an
amount that increases or decreases over the course of treatment,
prevention, or management. In other embodiments, the dose can be
from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,
from about 1 mg to about 200 mg, from about 10 mg to about 100 mg,
from about 0.1 mg to about 50 mg, from about 1 mg to about 50 mg,
from about 10 mg to about 50 mg, from about 20 mg to about 30 mg,
or from about 1 mg to about 20 mg.
4.3 SECOND ACTIVE AGENTS
[0222] A compound provided herein, or a pharmaceutically acceptable
salt, solvate, prodrug, clathrate, 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,
stereoisomer or prodrug thereof, can also work to alleviate adverse
effects associated with certain second active agents, and vice
versa.
[0223] 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).
[0224] 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).
[0225] Specific second active compounds that can be combined with
compounds provided herein vary depending on the specific indication
to be treated, prevented or managed.
[0226] 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.
[0227] 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.); O6-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.
[0228] Specific second active agents include, but are not limited
to, 2-methoxyestradiol, telomestatin, inducers of apoptosis in
multiple 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.
[0229] 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; and U.S. publication nos. 2004/0220144,
2004/0190609, 2004/0087546, 2005/0203142, 2004/0091455,
2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,
2006/0188475, 2006/0122228, and 2005/0143344.
[0230] Examples of second active agents that may be used for the
treatment, prevention and/or management of pain include, but are
not limited to, conventional therapeutics used to treat or prevent
pain such as antidepressants, anticonvulsants, antihypertensives,
anxiolytics, calcium channel blockers, muscle relaxants,
non-narcotic analgesics, opioid analgesics, anti-inflammatories,
cox-2 inhibitors, immunomodulatory agents, alpha-adrenergic
receptor agonists or antagonists, immunosuppressive agents,
corticosteroids, hyperbaric oxygen, ketamine, other anesthetic
agents, NMDA antagonists, and other therapeutics found, for
example, in the Physician's Desk Reference 2003. Specific examples
include, but are not limited to, salicylic acid acetate
(Aspirin.RTM.), celecoxib (Celebrex.RTM.), Enbrel.RTM., ketamine,
gabapentin (Neurontin.RTM.), phenytoin (Dilantin.RTM.),
carbamazepine (Tegretol.RTM.), oxcarbazepine (Trileptal.RTM.),
valproic acid (Depakene.RTM.), morphine sulfate, hydromorphone,
prednisone, griseofulvin, penthonium, alendronate, dyphenhydramide,
guanethidine, ketorolac (Acular.RTM.), thyrocalcitonin,
dimethylsulfoxide (DMSO), clonidine (Catapress.RTM.), bretylium,
ketanserin, reserpine, droperidol, atropine, phentolamine,
bupivacaine, lidocaine, acetaminophen, nortriptyline
(Pamelor.RTM.), amitriptyline (Elavil.RTM.), imipramine
(Tofranil.RTM.), doxepin (Sinequan.RTM.), clomipramine
(Anafranil.RTM.), fluoxetine (Prozac.RTM.), sertraline
(Zoloft.RTM.), naproxen, nefazodone (Serzone.RTM.), venlafaxine
(Effexor.RTM.), trazodone (Desyrel.RTM.), bupropion
(Wellbutrin.RTM.), mexiletine, nifedipine, propranolol, tramadol,
lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,
benzodiazepines, baclofen, tizanidine and phenoxybenzamine.
[0231] Examples of second active agents that may be used for the
treatment, prevention and/or management of macular degeneration and
related syndromes include, but are not limited to, a steroid, a
light sensitizer, an integrin, an antioxidant, an interferon, a
xanthine derivative, a growth hormone, a neutrotrophic factor, a
regulator of neovascularization, an anti-VEGF antibody, a
prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory
compound or an antiangiogenesis compound, or a combination thereof.
Specific examples include, but are not limited to, verteporfin,
purlytin, an angiostatic steroid, rhuFab, interferon-2.alpha.,
pentoxifylline, tin etiopurpurin, motexafin, lucentis, lutetium,
9-fluoro-11,21-dihydroxy-16,
17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,
latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and its
derivatives, rifamycin and its derivatives, macrolides,
metronidazole (U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein,
genistin, 6'-O-Mal genistin, 6'-O-Ac genistin, daidzein, daidzin,
6'-O-Mal daidzin, 6'-O-Ac daidzin, glycitein, glycitin, 6'-O-Mal
glycitin, biochanin A, formononetin (U.S. Pat. No. 6,001,368),
triamcinolone acetomide, dexamethasone (U.S. Pat. No. 5,770,589),
thalidomide, glutathione (U.S. Pat. No. 5,632,984), basic
fibroblast growth factor (bFGF), transforming growth factor b
(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen
activator factor type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals),
LY333531 (Eli Lilly), Miravant, and RETISERT implant (Bausch &
Lomb). All of the references cited herein are incorporated in their
entireties by reference.
[0232] 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.
[0233] Examples of second active agents that may be used for the
treatment, prevention and/or management of pulmonary hepertension
and related disorders include, but are not limited to,
anticoagulants, diuretics, cardiac glycosides, calcium channel
blockers, vasodilators, prostacyclin analogues, endothelin
antagonists, phosphodiesterase inhibitors (e.g., PDE V inhibitors),
endopeptidase inhibitors, lipid lowering agents, thromboxane
inhibitors, and other therapeutics known to reduce pulmonary artery
pressure. Specific examples include, but are not limited to,
warfarin (Coumadin.RTM.), a diuretic, a cardiac glycoside,
digoxin-oxygen, diltiazem, nifedipine, a vasodilator such as
prostacyclin (e.g., prostaglandin I2 (PGI2), epoprostenol (EPO,
Floran.RTM.), treprostinil (Remodulin.RTM.), nitric oxide (NO),
bosentan (Tracleer.RTM.), amlodipine, epoprostenol (Floran.RTM.),
treprostinil (Remodulin.RTM.), prostacyclin, tadalafil
(Cialis.RTM.), simvastatin (Zocor.RTM.), omapatrilat (Vanlev.RTM.),
irbesartan (Avapro.RTM.), pravastatin (Pravachol.RTM.), digoxin,
L-arginine, iloprost, betaprost, and sildenafil (Viagra.RTM.).
[0234] Examples of second active agents that may be used for the
treatment, prevention and/or management of asbestos-related
disorders include, but are not limited to, anthracycline, platinum,
alkylating agent, oblimersen (Genasense.RTM.), cisplatinum,
cyclophosphamide, temodar, carboplatin, procarbazine, gliadel,
tamoxifen, topotecan, methotrexate, taxotere, irinotecan,
capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,
liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,
vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic
acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate,
arsenic trioxide, vincristine, doxorubicin (Doxil.RTM.),
paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase,
mitomycin C, mepacrine, thiotepa, tetracycline and gemcitabine.
[0235] Examples of second active agents that may be used for the
treatment, prevention and/or management of parasitic diseases
include, but are not limited to, chloroquine, quinine, quinidine,
pyrimethamine, sulfadiazine, doxycycline, clindamycin, mefloquine,
halofantrine, primaquine, hydroxychloroquine, proguanil,
atovaquone, azithromycin, suramin, pentamidine, melarsoprol,
nifurtimox, benznidazole, amphotericin B, pentavalent antimony
compounds (e.g., sodium stiboglucuronate), interfereon gamma,
itraconazole, a combination of dead promastigotes and BCG,
leucovorin, corticosteroids, sulfonamide, spiramycin, IgG
(serology), trimethoprim, and sulfamethoxazole.
[0236] Examples of second active agents that may be used for the
treatment, prevention and/or management of immunodeficiency
disorders include, but are not limited to: antibiotics (therapeutic
or prophylactic) such as, but not limited to, ampicillin,
tetracycline, penicillin, cephalosporins, streptomycin, kanamycin,
and erythromycin; antivirals such as, but not limited to,
amantadine, rimantadine, acyclovir, and ribavirin; immunoglobulin;
plasma; immunologic enhancing drugs such as, but not limited to,
levami sole and isoprinosine; biologics such as, but not limited
to, gammaglobulin, transfer factor, interleukins, and interferons;
hormones such as, but not limited to, thymic; and other immunologic
agents such as, but not limited to, B cell stimulators (e.g.,
BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growth factors
(e.g., TGF-.alpha.), antibodies (e.g., anti-CD40 and IgM),
oligonucleotides containing unmethylated CpG motifs, and vaccines
(e.g., viral and tumor peptide vaccines).
[0237] Examples of second active agents that may be used for the
treatment, prevention and/or management of CNS disorders include,
but are not limited to: opioids; a dopamine agonist or antagonist,
such as, but not limited to, Levodopa, L-DOPA, cocaine,
.alpha.-methyl-tyrosine, reserpine, tetrabenazine, benzotropine,
pargyline, fenodolpam mesylate, cabergoline, pramipexole
dihydrochloride, ropinorole, amantadine hydrochloride, selegiline
hydrochloride, carbidopa, pergolide mesylate, Sinemet CR, and
Symmetrel; a MAO inhibitor, such as, but not limited to,
iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT
inhibitor, such as, but not limited to, tolcapone and entacapone; a
cholinesterase inhibitor, such as, but not limited to,
physostigmine saliclate, physostigmine sulfate, physostigmine
bromide, meostigmine bromide, neostigmine methylsulfate, ambenonim
chloride, edrophonium chloride, tacrine, pralidoxime chloride,
obidoxime chloride, trimedoxime bromide, diacetyl monoxim,
endrophonium, pyridostigmine, and demecarium; an anti-inflammatory
agent, such as, but not limited to, naproxen sodium, diclofenac
sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,
diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,
refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts,
Rho-D Immune Globulin, mycophenylate mofetil, cyclosporine,
azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid,
acetylsalicylic acid, methyl salicylate, diflunisal, salsalate,
olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac,
mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,
dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,
ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,
oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,
aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,
colchicine, allopurinol, probenecid, sulfinpyrazone and
benzbromarone or betamethasone and other glucocorticoids; and an
antiemetic agent, such as, but not limited to, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine,
acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride,
cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,
scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and a mixture thereof.
[0238] Examples of second active agents that may be used for the
treatment, prevention and/or management of CNS injuries and related
syndromes include, but are not limited to, immunomodulatory agents,
immunosuppressive agents, antihypertensives, anticonvulsants,
fibrinolytic agents, antiplatelet agents, antipsychotics,
antidepressants, benzodiazepines, buspirone, amantadine, and other
known or conventional agents used in patients with CNS
injury/damage and related syndromes. Specific examples include, but
are not limited to: steroids (e.g., glucocorticoids, such as, but
not limited to, methylprednisolone, dexamethasone and
betamethasone); an anti-inflammatory agent, including, but not
limited to, naproxen sodium, diclofenac sodium, diclofenac
potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac,
meloxicam, ibuprofen, ketoprofen, nabumetone, refecoxib,
methotrexate, leflunomide, sulfasalazine, gold salts, RHo-D Immune
Globulin, mycophenylate mofetil, cyclosporine, azathioprine,
tacrolimus, basiliximab, daclizumab, salicylic acid,
acetylsalicylic acid, methyl salicylate, diflunisal, salsalate,
olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac,
mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,
dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,
ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,
oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,
aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,
colchicine, allopurinol, probenecid, sulfinpyrazone and
benzbromarone; a cAMP analog including, but not limited to,
db-cAMP; an agent comprising a methylphenidate drug, which
comprises 1-threo-methylphenidate, d-threo-methylphenidate,
d1-threo-methylphenidate, 1-erythro-methylphenidate,
d-erythro-methylphenidate, d1-erythro-methylphenidate, and a
mixture thereof; and a diuretic agent such as, but not limited to,
mannitol, furosemide, glycerol, and urea.
[0239] Examples of second active agent that may be used for the
treatment, prevention and/or management of dysfunctional sleep and
related syndromes include, but are not limited to, a tricyclic
antidepressant agent, a selective serotonin reuptake inhibitor, an
antiepileptic agent (gabapentin, pregabalin, carbamazepine,
oxcarbazepine, levitiracetam, topiramate), an antiaryhthmic agent,
a sodium channel blocking agent, a selective inflammatory mediator
inhibitor, an opioid agent, a second immunomodulatory compound, a
combination agent, and other known or conventional agents used in
sleep therapy. Specific examples include, but are not limited to,
Neurontin, oxycontin, morphine, topiramate, amitryptiline,
nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,
.alpha.-methyl-tyrosine, reserpine, tetrabenazine, benzotropine,
pargyline, fenodolpam mesylate, cabergoline, pramipexole
dihydrochloride, ropinorole, amantadine hydrochloride, selegiline
hydrochloride, carbidopa, pergolide mesylate, Sinemet CR,
Symmetrel, iproniazid, clorgyline, phenelzine, isocarboxazid,
tolcapone, entacapone, physostigmine saliclate, physostigmine
sulfate, physostigmine bromide, meostigmine bromide, neostigmine
methylsulfate, ambenonim chloride, edrophonium chloride, tacrine,
pralidoxime chloride, obidoxime chloride, trimedoxime bromide,
diacetyl monoxim, endrophonium, pyridostigmine, demecarium,
naproxen sodium, diclofenac sodium, diclofenac potassium,
celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,
ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate,
leflunomide, sulfasalazine, gold salts, RHo-D Immune Globulin,
mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus,
basiliximab, daclizumab, salicylic acid, acetylsalicylic acid,
methyl salicylate, diflunisal, salsalate, olsalazine,
sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic
acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac,
flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam,
droxicam, pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone,
antipyrine, aminopyrine, apazone, zileuton, aurothioglucose, gold
sodium thiomalate, auranofin, methotrexate, colchicine,
allopurinol, probenecid, sulfinpyrazone, benzbromarone,
betamethasone and other glucocorticoids, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine,
acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride,
cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,
scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,
thioproperazine, tropisetron, and a mixture thereof.
[0240] Examples of second active agents that may be used for the
treatment, prevention and/or management of hemoglobinopathy and
related disorders include, but are not limited to: interleukins,
such as IL-2 (including recombinant IL-II ("rIL2") and canarypox
IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon
alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon
alfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF;
hydroxyurea; butyrates or butyrate derivatives; nitrous oxide;
hydroxy urea; HEMOXIN.TM. (NIPRISAN.TM.; see U.S. Pat. No.
5,800,819); Gardos channel antagonists such as clotrimazole and
triaryl methane derivatives; Deferoxamine; protein C; and
transfusions of blood, or of a blood substitute such as
Hemospan.TM. or Hemospan.TM. PS (Sangart).
[0241] Administration of a compound provided herein, or a
pharmaceutically acceptable salt, solvate, clathrate, 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).
[0242] 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.
[0243] 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.
4.4 CYCLING THERAPY
[0244] In certain embodiments, the prophylactic or therapeutic
agents provided herein are cyclically administered to a patient.
Cycling therapy involves the administration of an active agent for
a period of time, followed by a rest (i.e., discontinuation of the
administration) for a period of time, and repeating this sequential
administration. Cycling therapy can reduce the development of
resistance to one or more of the therapies, avoid or reduce the
side effects of one of the therapies, and/or improve the efficacy
of the treatment.
[0245] Consequently, in one embodiment, a compound provided herein
is administered daily in a single or divided doses in a four to six
week cycle with a rest period of about a week or two weeks. Cycling
therapy further allows the frequency, number, and length of dosing
cycles to be increased. Thus, another embodiment encompasses the
administration of a compound provided herein for more cycles than
are typical when it is administered alone. In yet another
embodiment, a compound provided herein is administered for a
greater number of cycles than would typically cause dose-limiting
toxicity in a patient to whom a second active ingredient is not
also being administered.
[0246] In one embodiment, a compound provided herein is
administered daily and continuously for three or four weeks at a
dose of from about 0.1 mg to about 500 mg per day, followed by a
rest of one or two weeks. In other embodiments, the dose can be
from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,
from about 1 mg to about 200 mg, from about 10 mg to about 100 mg,
from about 0.1 mg to about 50 mg, from about 1 mg to about 50 mg,
from about 10 mg to about 50 mg, from about 20 mg to about 30 mg,
or from about 1 mg to about 20 mg, followed by a rest.
[0247] In one embodiment, a compound provided herein and a second
active ingredient are administered orally, with administration of
the compound provided herein occurring 30 to 60 minutes prior to
the second active ingredient, during a cycle of four to six weeks.
In another embodiment, the combination of a compound provided
herein and a second active ingredient is administered by
intravenous infusion over about 90 minutes every cycle.
[0248] Typically, the number of cycles during which the combination
treatment is administered to a patient will be from about one to
about 24 cycles, from about two to about 16 cycles, or from about
four to about three cycles.
4.5 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS
[0249] 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, or prodrug thereof. Pharmaceutical
compositions and dosage forms can further comprise one or more
excipients.
[0250] 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 4.3, above.
[0251] 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.
[0252] 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).
[0253] 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.
[0254] 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.
[0255] 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, N.Y., 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.
[0256] 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.
[0257] 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.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] 4.5.1 Oral Dosage Forms
[0262] 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).
[0263] 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.
[0264] 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.
[0265] 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.
[0266] 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.
[0267] 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.
[0268] 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.
[0269] 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.
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 4.5.2 Controlled Release Dosage Forms
[0274] 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 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.
[0275] 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.
[0276] 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.
[0277] 4.5.3 Parenteral Dosage Forms
[0278] 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.
[0279] 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.
[0280] 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.
[0281] 4.5.4 Topical and Mucosal Dosage Forms
[0282] 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.
[0283] 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).
[0284] 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, or
stereoisomers of the active ingredients can be used to further
adjust the properties of the resulting composition.
[0285] 4.6 Kits
[0286] 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.
[0287] 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), 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).
[0288] 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.
[0289] 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.
EXAMPLES
[0290] Certain embodiments of the invention are illustrated by the
following non-limiting examples.
5.1
3-(2,6-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00017##
[0292] To a stirred mixture of 2-amino-5-methylbenzoic acid (4.8 g,
32 mmol) and imidazole (2.6 g, 38 mmol) in acetonitrile (100 mL),
was added acetyl chloride (2.7 mL, 38 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(5.2 g, 32 mmol), imidazole (4.7 g, 70 mmol) and triphenyl
phosphite (9.9 mL, 38 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (100 mL). The suspension was filtered
and washed with water (2.times.100 mL), ethyl acetate (2.times.100
mL), sodium hydrogen carbonate (sat, 100 mL) and water (100 mL) to
give a white solid, which was stirred in DMF (40 mL) overnight. The
suspension was filtered and washed with DMF (5 mL) to give a white
solid. The solid was stirred in water (100 mL) at 60.degree. C. for
2 hours, then at room temperature overnight. The suspension was
filtered and washed with water (2.times.50 mL) to give
3-(2,6-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
white solid (3.4 g, 38% yield): HPLC: Waters Symmetry C.sub.18, 5
.mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 5.37 min (99.8%); mp: 270-272.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.10-2.22 (m, 1H, CHH), 2.43 (s, 3H,
CH.sub.3), 2.56-2.72 (m, 5H, CH.sub.3, 2CHH), 2.76-2.92 (m, 1H,
CHH), 5.24 (dd, J=6, 11 Hz, 1H, NCH), 7.52 (d, J=8 Hz, 1H, Ar),
7.64 (dd, J=2, 8 Hz, 1H, Ar), 7.82 (s, 1H, Ar), 11.02 (s, 1H, NH);
.sup.13C NMR (DMSO-d.sub.6) .delta. 20.76, 20.95, 23.34, 30.60,
56.47, 120.05, 125.20, 126.39, 135.96, 136.19, 144.87, 153.99,
160.40, 169.53, 172.62; LCMS: MH=286; Anal Calcd for
C.sub.15H.sub.15N.sub.3O.sub.3+2H.sub.2O: C, 56.07; H, 5.96; N,
13.08. Found: C, 55.73; H, 5.75; N, 13.01.
5.2
2-BENZYLOXY-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-
-OUINAZOLIN-6-YL]-ACETAMIDE
##STR00018##
[0294] Step 1: To a stirred mixture of 5-amino-isatoic anhydride
(1.0 g, 5.6 mmol) and triethyl amine (0.8 mL, 9.0 mmol) in
acetronitrile (15 mL), was added benzyloxyacetyl chloride (0.87 mL,
5.6 mmol) dropwise at room temperature. The mixture was kept at
room temperature overnight. To the mixture, was added triethylamine
(3.1 mL, 22 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride
(0.92 g, 5.6 mmol), and acetic acid (3.2 mL, 56 mmol). The mixture
was heated at 80.degree. C. for 8 hours. To the mixture, was added
water (75 mL). The suspension was filtered and washed with water
(75 mL) and ethyl acetate (75 mL) to give a dark solid, which was
purified with column chromatography (Silica Gel, methanol/methylene
chloride 0% to 10% in 15 min) to give
2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-yl)-benzamid-
e as a white solid (0.28 g, 12% yield): .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.92-2.18 (m, 2H, 2CHH), 2.50-2.55 (m, 1H, CHH), 2.72-2.84
(m, 1H, CHH), 4.03 (s, 2H, CH.sub.2), 4.61 (s, 2H, CH.sub.2),
4.68-4.77 (m, 1H, NCH), 6.19 (br, 2H, NH.sub.2), 6.68 (d, J=9 Hz,
1H, Ar), 7.30-7.42 (m, 6H, Ar), 7.62 (d, J=2 Hz, 1H, Ar), 8.43 (d,
J=8 Hz, 1H, NH), 9.44 (s, 1H, NH), 10.84 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 24.09, 30.96, 49.12, 69.37, 72.35, 114.27,
116.23, 121.11, 125.99, 126.13, 127.64, 127.77, 128.27, 137.68,
146.19, 167.28, 168.36, 172.35, 173.01.
[0295] Step 2: A solution of
2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-yl)-benzamid-
e (0.26 g, 0.6 mmol) and trimethyl orthoformate (2 mL) and
p-toluene sulfonic acid (60 mg) in acetonotrile (10 mL) was heated
to reflux for 21 hours. To the mixture, was added water (25 mL) and
ether (25 mL). The suspension was filtered and washed with water
(50 mL) and ethyl acetate (50 mL) to give
2-benzyloxy-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-qu-
inazolin-6-yl]-acetamide as a white solid (180 mg, 72% yield):
HPLC: Waters Symmetry C.sub.188, 5 .mu.m, 3.9.times.150 mm, 1
mL/min, 240 nm, 40/60 CH.sub.3CN/0.1% H.sub.3PO.sub.4, 2.87 min
(99.3%); mp: 248-250.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.
2.14-2.16 (m, 1H, CHH), 2.62-2.87 (m, 3H, CH.sub.2, CHH), 4.15 (s,
2H, CH.sub.2), 4.64 (s, 2H, CH.sub.2), 5.49-5.50 (m, 1H, NCH),
7.31-7.41 (m, 5H, Ar), 7.68 (d, J=9 Hz, 1H, Ar), 8.06-8.10 (m, 1H,
NH), 8.28 (s, 1H, CH), 8.55 (br, 1H, Ar), 10.24 (s, 1H, NH), 11.16
(s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 23.05, 31.48, 58
(br), 69.87, 72.92, 115.69, 122.15, 127.30, 128.16, 128.28, 128.34,
128.77, 137.98, 138.14, 144.06, 146.48, 160.10, 168.93, 170.43,
172.90; LCMS: MH=421; Anal Calcd for
C.sub.22H.sub.20N.sub.4O.sub.5: C, 62.85; H, 4.79; N, 13.33. Found:
C, 60.60; H, 4.29; N, 12.54.
5.3
3-(6-FLUORO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00019##
[0297] To a stirred mixture of 2-amino-5-fluorobenzoic acid (1.2 g,
7.8 mmol) and imidazole (0.63 g, 9.3 mmol) in acetonitrile (15 mL),
was added acetyl chloride (0.66 mL, 9.3 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(1.3 g, 7.7 mmol), imidazole (1.2 g, 17 mmol) and triphenyl
phosphite (2.2 mL, 8.5 mmol) and heated to reflux for 22 hours. The
suspension was filtered and washed with water (2.times.50 mL),
ethyl acetate (2.times.50 mL), and water (50 mL) to give
3-(6-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (1.2 g, 53% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 5.99 min (99.3%); mp:
273-275.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.13-2.23
(m, 1H, CHH), 2.57-2.71 (m, 5H, CH.sub.3, 2CHH), 2.75-2.95 (m, 1H,
CHH), 5.30 (dd, J=6, 11 Hz, 1H, NCH), 7.70-7.73 (m, 3H, Ar), 11.06
(s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.82, 23.31,
30.58, 56.63, 110.54 (d, J.sub.C-F=23 Hz), 121.40 (d, J.sub.C-F=8
Hz), 123.24 (d, J.sub.C-F=24 Hz), 129.47 (d, J.sub.C-F=8 Hz),
143.75, 154.45, 159.83 (d, J.sub.C-F=245 Hz), 159.86 (d,
J.sub.C-F=3 Hz), 169.37, 172.58; LCMS: MH=290; Anal Calcd for
C.sub.14H.sub.12N.sub.3O.sub.3F+1.3 H.sub.2O: C, 53.78; H, 4.71; N,
13.44. Found: C, 53.75; H, 4.61; N, 13.50.
5.4
3-(6-CHLORO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00020##
[0299] To a stirred mixture of 2-amino-5-chlorobenzoic acid (2.0 g,
12 mmol) and imidazole (1.0 g, 14 mmol) in acetonitrile (30 mL),
was added acetyl chloride (1.0 mL, 14 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(1.9 g, 12 mmol), imidazole (1.8 g, 26 mmol) and triphenyl
phosphite (3.7 mL, 26 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give
3-(6-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (2.9 g, 80% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 25/75
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 6.65 min (98.5%); mp:
276-278.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.15-2.24
(m, 1H, CHH), 2.58-2.71 (m, 5H, CH.sub.3, 2CHH), 2.78-2.92 (m, 1H,
CHH), 5.30 (dd, J=6, 11 Hz, 1H, NCH), 7.66 (d, J=9 Hz, 2H, Ar),
7.85 (dd, J=3, 9 Hz, 1H, Ar), 7.98 (d, J=2 Hz, 1H, Ar), 11.06 (s,
1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.79, 23.45, 30.57,
56.71, 121.47, 124.89, 128.89, 130.77, 134.87, 145.57, 155.67,
159.53, 169.31, 172.56; LCMS: MH=306, 308; Anal Calcd for
C.sub.14H.sub.12N.sub.3O.sub.3Cl+2H.sub.2O: C, 49.20; H, 4.72; N,
12.30; Cl, 10.37. Found: C, 49.34; H, 4.57; N, 12.20; Cl,
10.39.
5.5
3-(6-BROMO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00021##
[0301] Step 1: A stirred mixture of 5-bromo-isatoic anhydride (6.0
g, 25 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (4.1 g,
25 mmol), triethylamine (18 mL, 129 mmol), and acetic acid (15 mL,
262 mmol) in acetonitrile (60 mL) was heated at 90.degree. C. for
18 hours. The suspension was filtered and washed with acetonitrile
(2.times.80 mL), water (2.times.80 mL) and ethyl acetate
(2.times.80 mL) to give
2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide as a white
solid (5.8 g, 72% yield): LCMS: MH=326, 328. The sample was used in
the next step without further purification.
[0302] Step 2: A solution of
2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (1.0 g, 3
mmol) and trimethyl orthoacetate (1.6 mL) and p-toluene sulfonic
acid (250 mg) in acetonotrile (10 mL) was heated to reflux for 7
days. The suspension was filtered and washed with ethyl acetate (10
mL), methanol (5 mL) and ethyl acetate (10 mL) to give
3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an
off-white solid (108 mg, 10% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 5.17 min (98.7%); mp:
273-275.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.14-2.27
(m, 1H, CHH), 2.56-2.69 (m, 2H, 2CHH), 2.64 (s, 3H, CH.sub.3),
2.72-2.90 (m, 1H, CHH), 5.29 (dd, J=6, 11 Hz, 1H, NCH), 7.58 (d,
J=9 Hz, 1H, Ar), 7.98 (dd, J=2, 9 Hz, 1H, Ar), 8.12 (d, J=2 Hz, 1H,
Ar), 11.06 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.72,
23.42, 30.50, 56.64, 118.80, 121.77, 127.94, 128.95, 137.51,
145.76, 155.74, 159.32, 167.24, 172.49; LCMS: MH=350, 352; Anal
Calcd for C.sub.14H.sub.12N.sub.3O.sub.3Br: C, 48.02; H, 3.45; N,
12.00. Found: C, 48.02; H, 3.18; N, 11.76.
5.6
3-(6-HYDROXY-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00022##
[0304] To a stirred mixture of 2-amino-5-hydroxybenzoic acid (5.1
g, 33 mmol) and imidazole (5.0 g, 73 mmol) in acetonitrile (60 mL),
was added acetyl chloride (5.2 mL, 73 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(6.0 g, 37 mmol), imidazole (5.0 g, 73 mmol) and triphenyl
phosphite (10.5 mL, 40 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (100 mL) and conc HCl until pH
.about.1. The solvent was removed in vacuo. To the residue, was
added water (50 mL). The aqueous layer was extracted with ethyl
acetate (50 mL). To the aqueous layer, was added ethyl acetate (50
mL), and the mixture was stirred at room temperature to give a
suspension. The suspension was filtered to give a solid, which was
stirred in methanol (50 mL) overnight. The suspension was filtered
and washed with methanol (2.times.30 mL) and water to give
3-(6-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as an off-white solid (2.97 g, 31% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 5/95 grad
95/5 in 5 min CH.sub.3CN/0.1% H.sub.3PO.sub.4, 4.50 min (96.8%);
mp: 315-317.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.
2.13-2.18 (m, 1H, CHH), 2.58 (s, 3H, CH.sub.3), 2.62-2.71 (m, 2H,
2CHH), 2.78-2.91 (m, 1H, CHH), 5.22 (dd, J=6, 11 Hz, 1H, NCH),
7.24-7.32 (m, 2H, Ar), 7.49 (d, J=9 Hz, 1H, Ar), 10.07 (s, 1H, OH),
11.00 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.97,
23.10, 30.59, 56.36, 108.59, 121.24, 124.13, 128.19, 140.14,
151.39, 155.89, 160.24, 169.58, 172.63; LCMS: MH=288; Anal Calcd
for C.sub.14H.sub.13N.sub.3O.sub.4+1 H.sub.2O: C, 55.08; H, 4.95;
N, 13.76. Found: C, 54.82; H, 4.74; N, 13.54.
5.7 3-(6-CHLORO-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00023##
[0306] Step 1: A stirred mixture of 5-chloroisatoic anhydride (0.51
g, 2.5 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (0.42
g, 2.5 mmol), triethylamine (1.8 mL, 12.7 mmol), and acetic acid
(1.5 mL, 25.3 mmol) in acetonitrile (5 mL) was heated at
150.degree. C. in a microwave oven for 5 miutes. The suspension was
filtered and washed with water (50 mL) and ethyl acetate (20 mL) to
give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide as a
white solid (0.31 g, 42% yield): .sup.1H NMR (DMSO-d.sub.6) .delta.
1.91-2.12 (m, 2H, 2CHH), 2.50-2.56 (m, 1H, CHH), 2.72-2.80 (m, 1H,
CHH), 4.71-4.76 (m, 1H, NCH), 6.58 (brs, 2H, NH.sub.2), 6.74 (d,
J=8 Hz, 1H, Ar), 7.19 (dd, J=2, 9 Hz, 1H, Ar), 7.58 (t; J=2 Hz, 1H,
Ar), 8.62 (d, J=8 Hz, 1H, NH), 10.86 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 23.99, 30.89, 49.00, 114.62, 117.60, 118.04,
127.25, 131.63, 148.61, 167.37, 172.20, 172.93; LCMS: MH=282,
284.
[0307] Step 2: A solution of
2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide (0.31 g,
1.1 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic
acid (50 mg) was heated to 150.degree. C. in a microwave oven for
10 minutes. The suspension was filtered and washed with ethyl
acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give
3-(6-chloro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
white solid (230 mg, 74% yield): HPLC: Waters Symmetry C.sub.18, 5
.mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 4.01 min (100%); mp: 302-305.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.13-2.20 (m, 1H, CHH), 2.62-2.93 (m,
3H, CH.sub.2, CHH), 5.52 (br, 1H, NCH), 7.76 (d, J=9 Hz, 1H, Ar),
7.91 (dd, J=2, 9 Hz, 1H, Ar), 8.10 (d, J=2 Hz, 1H, Ar), 8.41 (s,
1H, CH), 11.19 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
22.39, 30.87, 56.29 (br), 122.56, 125.05, 129.47, 131.59, 134.82,
146.19, 147.75, 158.73, 169.68, 172.39; LCMS: MH=292, 294; Anal
Calcd for C.sub.13H.sub.10N.sub.3O.sub.3Cl: C, 53.53; H, 3.46; N,
14.41. Found: C, 53.43; H, 3.21; N, 14.27.
5.8 3-(6-BROMO-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00024##
[0309] Step 1: A stirred mixture of 5-bormo-isatoic anhydride (6.0
g, 25 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (4.1 g,
25 mmol), triethylamine (18 mL, 129 mmol), and acetic acid (15 mL,
262 mmol) in acetonitrile (60 mL) was heated at 90.degree. C. for
18 hours. The suspension was filtered and washed with acetonitrile
(2.times.80 mL), water (2.times.80 mL) and ethyl acetate
(2.times.80 mL) to give
2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide as a white
solid (5.8 g, 72% yield): LCMS: MH=326, 328. The sample was used in
the next step without further purification.
[0310] Step 2: A solution of
2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (0.51 g, 1.5
mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid
(150 mg) in acetonitrile (10 mL) was heated to reflux for 12 hours.
To the mixture, was added water (70 mL), and stirred at room
temperature for 2 hours. The suspension was filtered and washed
with ethyl acetate (10 mL). The solid in NMP (3 mL) was heated at
80.degree. C. To the solution, was added water (1.5 mL), and the
mixture was allowed to cool to room temperature. The suspension was
filtered and washed with NMP (1 mL) and ethyl acetate (10 mL) to
give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
white solid (350 mg, 68% yield): HPLC: Waters Symmetry C.sub.18, 5
.mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 4.18 min (99.9%); mp: 312-314.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.14-2.21 (m, 1H, CHH), 2.60-2.74 (m,
2H, 2CHH), 2.83-2.93 (m, 1H, CHH), 5.51 (brs, 1H, NCH), 7.68 (d,
J=9 Hz, 1H, Ar), 8.03 (dd, J=2, 9 Hz, 1H, Ar), 8.24 (d, J=2 Hz, 1H,
Ar), 8.42 (s, 1H, CH), 11.19 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 22.45, 30.93, 55.49, 119.83, 122.96, 128.23,
129.65, 137.61, 146.52, 147.94, 158.66, 169.75, 172.46; LCMS:
MH=336, 338; Anal Calcd for
C.sub.13H.sub.10N.sub.3O.sub.3Br+0.3H.sub.2O: C, 45.72; H, 3.13; N,
12.30; Br, 23.39. Found: C, 45.46; H, 2.75; N, 12.15; Br,
22.81.
5.9 3-(6-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00025##
[0312] Step 1: A mixture of 2-amino-5-methylbenzoic acid (1.0 g,
6.6 mmol) and CDI (1.0 g, 6.1 mmol) in acetonitrile (15 mL) was
stirred at room temperature for 1.5 hours. To the suspension, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (1.0 g, 6.1
mmol) and sodium hydrogen carbonate (0.45 g, 3.6 mmol), and the
mixture was heated at 50.degree. C. for 21 hours. The suspension
was cooled to room temperature for 1 hour. The suspension was
filtered and washed with acetonitrile (20 mL), water (2.times.20
mL) and ethyl acetate (20 mL) to give
2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-methyl-benzamide as a blue
solid (1.1 g, 63% yield): .sup.1H NMR (DMSO-d.sub.6) .delta.
1.91-1.98 (m, 1H, CHH), 2.05-2.14 (m, 1H, CHH), 2.17 (s, 3H,
CH.sub.3), 2.50-2.56 (m, 1H, CHH), 2.73-2.85 (m, 1H, CHH),
4.69-4.77 (m, 1H, NCH), 6.20 (br, 2H, NH.sub.2), 6.63 (d, J=9 Hz,
1H, Ar), 7.00 (dd, J=2, 8 Hz, 1H, Ar), 7.34 (d, J=2 Hz, 1H, Ar),
8.43 (d, J=8 Hz, 1H, NH), 10.84 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 19.89, 24.13, 30.92, 48.93, 113.87, 116.48,
122.81, 127.87, 132.72, 147.40, 168.55, 172.40, 172.97.
[0313] Step 2: A solution of
2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-methyl-benzamide (0.45 g,
1.7 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic
acid (80 mg) was heated to 160.degree. C. in a microwave oven for 8
minutes. To the suspension, was added methanol (20 mL), methylene
chloride (20 mL), and Celite (5 mL). The solvent was removed in
vacuo. The reside was placed in a SIM and was purified with column
chromatography (Silca Gel, methanol/methylene chloride 0% gradient
10% in 15 min) to give as
3-(6-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
blue solid (50 mg, 9% yield): HPLC: Waters Symmetry C.sub.18, 5
.mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 2.78 min (96.1%); mp: 285-287.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.11-2.18 (m, 1H, CHH), 2.46 (s, 3H,
CH.sub.3), 2.56-2.74 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.48
(br, 1H, NCH), 7.61 (d, J=8 Hz, 1H, Ar), 7.70 (dd, J=2, 8 Hz 1H,
Ar), 7.94 (br, 1H, Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH);
.sup.13C NMR (DMSO-d.sub.6) .delta. 20.72, 22.51, 30.91, 57.00
(br), 121.09, 125.38, 127.00, 135.89, 137.07, 145.46, 146.45,
159.60, 169.88, 172.44; LCMS: MH=272; Anal Calcd for
C.sub.14H.sub.13N.sub.3O.sub.3: C, 61.99; H, 4.83; N, 15.49. Found:
C, 61.78; H, 4.57; N, 15.34.
5.10
3-(6-AMINO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00026##
[0315] Step 1: To a stirred mixture of 2-amino-5-nitrobenzoic acid
(5.0 g, 28 mmol) and imidazole (2.2 g, 33 mmol) in acetonitrile (50
mL), was added acetyl chloride (2.3 mL, 33 mmol) at room
temperature. The mixture was stirred at room temperature overnight.
To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen
chloride (4.5 g, 28 mmol), imidazole (4.1 g, 60 mmol) and triphenyl
phosphite (8.7 mL, 33 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give
3-(2-methyl-6-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as an off-white solid (5.3 g, 61% yield): .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.19-2.26 (m, 1H, CHH), 2.60-2.69 (m, 2H,
2CHH), 2.72 (s, 3H, CH.sub.3), 2.79-2.87 (m, 1H, CHH), 5.37 (dd,
J=5, 11 Hz, 1H, NCH), 7.83 (d, J=9 Hz, 1H, Ar), 8.56 (dd, J=3, 9
Hz, 1H, Ar), 8.74 (dt, J=3 Hz 1H, Ar), 11.12 (s, 1H, NH); .sup.13C
NMR (DMSO-d.sub.6) .delta. 20.69, 23.82, 30.57, 56.98, 119.46,
120.20, 122.21, 128.45, 128.74, 144.90, 150.85, 159.13, 159.78,
169.12, 172.53.
[0316] Step 2: A suspension of
3-(2-methyl-6-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
(4.1 g, 13 mmol) and 20% Pd(OH).sub.2/C (0.9 g) in cyclohexene (20
mL) and DMF (60 mL) was heated in a 125.degree. C. oil bath
overnight. The suspension was filtered thru a pad of Celite, and
washed with DMF (30 mL). The DMF solution and Charcoal (4 g) were
stirred at room temperature for 5 hours. The suspension was
filtered thru a pad of Celite. The solvent was removed in vacuo. To
the residue, was added DMF (20 mL), and then water (80 mL) to give
a suspension. The suspension was filtered and washed with water (50
mL), ethyl acetate (50 mL) and water (50 mL) to give a brown solid,
which was purified with preparative HPLC (C18 5/95 for 2 minutes
then gradient to 50/50 in 18 min CH.sub.3CN/H.sub.2O) to give
3-(6-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (1.15 g, 31% yield): HPLC: Waters Xterra C.sub.18,
5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1%
NH4HCO2, 5.31 min (99.8%); mp: 314-316.degree. C.; .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.08-2.14 (m, 1H, CHH), 2.54 (s, 3H,
CH.sub.3), 2.55-2.67 (m, 2H, 2CHH), 2.75-2.90 (m, 1H, CHH), 5.16
(dd, J=5, 11 Hz, 1H, NCH), 5.59 (brs, 2H, NH.sub.2), 7.04-7.08 (m,
2H, Ar), 7.31-7.34 (m, 1H, Ar), 10.97 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 21.06, 22.96, 30.62, 56.22, 105.89, 121.34,
122.61, 127.35, 137.89, 147.63, 149.24, 160.39, 169.68, 172.66;
LCMS: MH=287; Anal Calcd for
C.sub.14H.sub.14N.sub.4O.sub.3+1H.sub.2O: C, 55.26; H, 5.30; N,
18.41. Found: C, 54.99; H, 5.22; N, 18.35.
5.11
[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-
-YLMETHYL]-CARBAMIC ACID TERT-BUTYL ESTER
##STR00027##
[0318] Step 1: A mixture of 5-methyl-2-nitro-benzoic acid methyl
ester (93.95 g, 481.35 mmol), 1,3-dibromo-5,5-dimethylhydantoin
(75.70 g, 264.74 mmol), in methyl acetate (550 mL) was heated at
78.degree. C. for 40 minutes while stirred with a mechanical
stirrer. Then a solution of 2,2'-azobisisobutyro-nitrile (3.95 g,
24.07 mmol) in methyl acetate (80 mL) was added, and the mixture
was heated at about 75.degree. C. for 13 hours. The mixture was
allowed to cooled to 15.degree. C. and stirred for 2 hours to age
the precipitate. The suspension was filtered, washed with
10.degree. C. methyl acetate (2.times.50 mL) to give a brown
filtrate. To the filtrate, was added heptane (500 mL). The organic
layer was washed with 2% brine (2.times.500 mL) and water
(2.times.500 mL), and concentrated to about 2 volumes. To the
mixture, was added t-butyl methyl ether (or MTBE, 300 mL). The
mixture was heated at about 70.degree. C. for 15 minutes, cooled to
about 53.degree. C. over one hour, seeded with the product (about
250 mg, or simply re-crystallized) at 45.degree. C., then at
20.about.25.degree. C., while blowing nitrogen with a glass pipette
overnight. The resulting solid was filtered via a medium pore-sized
funnel, washed with a pre-cooled 10.degree. C. mixed solvent of
heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to
give 5-bromomethyl-2-nitro-benzoic acid methyl ester as an
off-white solid (58.3 g, 44.0% yield). The solid was used in the
next step without further purification.
[0319] Step 2: A stirred mixture of 5-bromomethyl-2-nitro-benzoic
acid methyl ester (50.5 g, 184 mmol), di-tert-butyl
iminodicarboxylate (40.15 g, 185 mmol), cesium carbonate (123.1 g,
377.7 mmol), and lithium iodide (1.23 g, 9.21 mmol) in 2-butanone
(556 mL) was heated to reflux in a 100.degree. C. oil bath for 12
hours while stirred with a mechanical stirrer. The mixture was
allowed to cool to room temperature. To the mixture, was added
brine (300 mL), water (300 mL), and ethyl acetate (750 mL), and the
mixture was stirred for 10 minutes. The suspension was filtered
through a pad of Celite. The two layers were separated, and the
organic layer was evaporated to a less volume. The aqueous layer
was extracted with ethyl acetate (2.times.150 mL). The combined
organic layers were washed with brine (500 mL), dried over
magnesium sulfate while de-colored at the same time by charcoal at
room temp with stirring for 30 minutes. The black mixture was
filtered through a pad of Celite. The filtrate was evaporated to
give 5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid
methyl ester as a brown oil (74.18 g, 98% yield). The product was
used in the next step without further purification.
[0320] Step 3: To a stirred brown solution of
5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl
ester (74.18 g, 180.7 mmol) in methylene chloride (700 mL) was
added trifluoroacetic acid (26.2 mL, 352.4 mmol), and the mixture
was stirred at room temp overnight. Sat. sodium bicarbonate (400
mL) was added to the solution, and the mixture was stirred for 10
minutes. The organic layer was separated, dried over magnesium
sulfate, and evaporated to give
5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl
ester as a brown oil (52.5 g, 94% crude yield). The product was
used in the next step without further purification.
[0321] Step 4: A mixture of
5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl
ester (52.5 g, 169.3 mmol), lithium hydroxide (4.86 g, 203.1 mmol)
in methanol (546 mL) and water (273 mL) was stirred with a
mechanical stirrer at room temp overnight. The methanol was
evaporated, and to the aqueous solution, was added 1 N HCl (270 mL)
to form the precipitate. Ether (350 mL) was added, and the mixture
was stirred at 0.degree. C. for 2 hours. The mixture was
evaporated. To the residue, was added water (500 mL). The aqueous
layer was extracted with methylene chloride (3.times.100 mL). The
combined organic layers were separated, dried over magnesium
sulfate, and concentrated to give
5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown
oil (21.0 g, 41% yield). The product was used in the next step
without further purification.
[0322] Step 5: A mixture of
5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid (21.0 g,
70.9 mmol) in methanol (210 mL) and palladium/carbon (2 g) was
hydrogenated with a Parr-shaker overnight at 51 psi. The black
mixture was filtered through a pad of Celite, and the filtrate was
evaporated to give a brown oil, which was stirred in ether (300 mL)
overnight. The ether slurry was filtered to give
2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brown
solid (9.3 g, 49% yield). The product was used in the next step
without further purification.
[0323] Step 6: To a stirred solution of
2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid (9.3 g,
34.9 mmol), imidazole (2.85 g, 41.9 mmol) in acetonitrile (120 mL),
was added acetyl chloride (3.0 mL, 41.9 mmol) and stirred at room
temp overnight. Then to the mixture, was added
3-amino-piperidine-2,6-dione hydrogen chloride (5.74 g, 34.9 mmol),
imidazole (4.76 g, 69.8 mmol) and triphenyl phosphite (11.0 mL,
41.9 mmol), and the mixture was heated to reflux for 6 hours. The
mixture was allowed to cool to room temperature, and water (about
400 mL) was added. The suspension was filtered, washed with water
(50 mL), ethyl acetate (20 mL), ether (50 mL), and suction dried to
give
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylm-
ethyl]-carbamic acid tert-butyl ester as an off-white solid (9.7 g,
70% yield): HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150
mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, grad.
to 95/5 in 5 min, kept 5 min, 5.95 min (96.7%); mp,
212.5-214.5.degree. C;.sup.IHNMR (DMSO-d.sub.6) 8 01.40 (s, 9H,
CMe.sub.3), 2.15-2.18 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH.sub.2,
CH.sub.3), 4.23 (d, J=6 Hz, 2H, CH.sub.2NH), 5.26 (dd, J=6, 11 Hz,
1H, CH), 7.52 (t, J=6 Hz, 1H, CH.sub.2NH), 7.56-7.88 (m, 3H, Ar),
11.03 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.92,
23.40, 28.20, 30.62, 42.97, 56.52, 77.94, 119.98, 123.50, 126.51,
133.74, 138.76, 145.75, 154.52, 155.79, 160.44, 169.47, 172.61.
LCMS MH=401; Anal Calcd For C.sub.20H.sub.24N.sub.4O.sub.5: C,
59.99; H, 6.04; N, 13.99. Found: C, 59.83; H, 5.98; N, 13.85.
5.12
3-(6-AMINOMETHYL-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DI-
ONEHYDROGEN CHLORIDE
##STR00028##
[0325] Step 1: To a stirred brown solution of
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylm-
ethyl]-carbamic acid tert-butyl ester (3.5 g, 8.7 mmol) in methanol
(36 mL) and methylene chloride (36 mL), was added 2 M HCl in ether
(102 mL), and the mixture was stirred overnight. The solvent was
evaporated, and the residue was stirred in ether (100 mL) for 2
hours. The suspension was filtered to give
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride as a light yellow solid (3.2 g, 109% crude
yield). The product was used in the next step without further
purification.
[0326] Step 2:
3-(6-Aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.95 g) was dissolved in water (100 mL). The
solution was washed with ethyl acetate (2.times.100 mL). The
aqueous layer was evaporated to give
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride as an off-white solid (0.79 g, 84% yield); HPLC,
Waters Xterra RP 18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm,
Waters LC Module 1, 05/95 CH.sub.3CN/0.1% (HCO.sub.2)NH.sub.4is
.degree. C.rat, 4.67 min (98.5%); mp, 299-301.degree. C.;
.sup.1HNMR (DMSO-d.sub.6) .delta. .quadrature.2.18-2.24 (m, 1H,
CHH), 2.59-2.89 (m, 6H, CHCH.sub.2, CH.sub.3), 4.14-4.19 (m, 2H,
ArCH.sub.2), 5.34 (dd, J=5, 11 Hz, 1H, CH), 7.71-8.20 (m, 3H, Ar),
8.54 (brs, 3H, ClNH.sub.3), 11.08 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.86, 22.97, 30.60, 41.61, 56.75, 119.85,
125.75, 126.83, 132.81, 135.80, 145.35, 156.51, 159.96, 169.23,
172.59. LCMS MH=301; Anal Calcd For C.sub.15H.sub.17N.sub.4O.sub.3
Cl+1.0 H.sub.2O and +0.8 HCl: C, 46.92; H, 5.20; N, 14.59; Cl,
16.62. Found: C, 46.72; H, 5.15; N, 14.29; Cl, 16.59.
5.13 HEPTANOIC ACID
[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-OUINAZOLIN-6-YLM-
ETHYL]-AMIDE
##STR00029##
[0328] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was
added heptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl
ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room
temp for one hour. The solvent was evaporated, and the residue was
purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give heptanoic acid
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylm-
ethyl]-amide as an off-white solid (349 mg, 58% yield); HPLC,
Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240
nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, gradient to 95/5 in 5
min, kept for 5 min, 6.12 min (96.3%); mp, 223-225.degree. C.;
.sup.1HNMR (DMSO-d.sub.6) .delta. .quadrature.0.84 (t, J=6 Hz, 3H,
CH.sub.3 of long chain), 1.24-2.20 (m, 11H,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, CHH), 2.57-2.86 (m, 6H,
CHCH.sub.2, CH.sub.3), 4.36 (d, J=6 Hz, 2H, CH.sub.2NH), 5.26 (dd,
J=6, 11 Hz, 1H, CH), 7.56-7.88 (m, 3H, Ar), 8.41 (t, J=6 Hz, 1H,
CH.sub.2NH), 11.03 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
13.86, 20.92, 21.95, 23.39, 25.23, 28.31, 30.61, 30.99, 35.33,
41.57, 56.51, 119.99, 123.79, 126.51, 133.96, 138.38, 145.74,
154.53, 160.40, 169.47, 172.25, 172.60. LCMS MH=413; Anal Calcd For
C.sub.22H.sub.28N.sub.4O.sub.4: C, 64.06; H, 6.84; N, 13.58. Found:
C, 63.76; H, 6.68; N, 13.42.
5.14 CYCLOPROPANECARBOXYLIC ACID
[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-OUINAZOLIN-6-YLM-
ETHYL]-AMIDE
##STR00030##
[0330] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was
added cyclopropanecarbonyl chloride (0.21 mL, 2.3 mmol) and N,
N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was
stirred at room temperature for one hour. The solvent was
evaporated, and the residue was purified by flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to
give cyclopropanecarboxylic acid
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylm-
ethyl]-amide as an off-white solid (233 mg, 42% yield); HPLC,
Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240
nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, gradient to 95/5 in 5
min, kept for 5 min, 5.01 min (98.4%); mp, 281-283.degree. C.;
.sup.1HNMR (DMSO-d.sub.6) .delta. .quadrature.0.64-0.74 (m, 4H,
CH.sub.2CH.sub.2 of cyclopropane ring), 1.57-1.66 (m, 1H, CH of
cyclopropane ring), 2.15-2.21 (m, 1H, CH), 2.57-2.89 (m, 6H,
CHCH.sub.2, CH.sub.3), 4.39 (d, J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd,
J=6, 11 Hz, 1H, CH), 7.57-7.89 (m, 3H, Ar), 8.68 (t, J=6 Hz, 1H,
CH.sub.2NH), 11.03 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
6.31, 13.55, 20.93, 23.40, 30.61, 41.77, 56.53, 120.01, 123.78,
126.58, 134.02, 138.34, 145.78, 154.55, 160.44, 169.47, 172.62,
172.70. LCMS MH=413; Anal Calcd For C.sub.19H.sub.20N.sub.4O.sub.4:
C, 61.95; H, 5.47; N, 15.21. Found: C, 61.86; H, 5.49; N,
15.04.
5.15
3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-OUINAZOLIN-
-6-YLMETHYL]-1,1-DIMETHYL-UREA
##STR00031##
[0332] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.50 g, 1.5 mmol) in acetonitrile (10 mL), was
added dimethyl carbamyl chloride (0.21 mL, 2.2 mmol) and
N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was
stirred at room temperature overnight. The solvent was evaporated,
and the residue was purified by flash column chromatography (Silica
gel, methanol/methylene chloride 4%/96%) to give
3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-1,1-dimethyl-urea as an off-white solid (290 mg, 52%
yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm,
1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, gradient
to 95/5 in 5 min, kept for 5 min, 4.66 min (98.7%); mp,
264-268.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.2.14-2.20 (m, 1H, CH), 2.56-2.86 (m, 12H,
N(CH.sub.3).sub.2, CHCH.sub.2, CH.sub.3), 4.31 (d, J=5 Hz, 2H,
CH.sub.2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.00 (t, J=5 Hz, 1H,
CH.sub.2NH), 7.54-7.89 (m, 3H, Ar), 11.03 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.95, 23.38, 30.61, 35.85, 43.20, 56.49,
119.88, 123.54, 126.30, 133.91, 139.98, 145.59, 154.27, 158.09,
160.50, 169.49, 172.62. LCMS MH=372; Anal Calcd For
C.sub.18H.sub.21N.sub.5O.sub.4+0.5 H.sub.2O: C, 56.83; H, 5.83; N,
18.41. Found: C, 56.71; H, 5.81; N, 18.18.
5.16
2-(4-CHLORO-PHENYL)-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3
4-DIHYDRO-OUINAZOLIN-6-YLMETHYL]-ACETAMIDE
##STR00032##
[0334] To a stirred solution of (4-chloro-phenyl)-acetic acid (0.30
g, 1.8 mmol) in DMF (8 mL) in a 40.degree. C. oil bath, was added
1.1' carbonyldiimidazole (0.31 g, 1.9 mmol), and the mixture was
stirred for one hour. Then
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.59 g, 1.7 mmol) was added, and the mixture was
stirred for 15 minutes. The solvent was evaporated, and the residue
was purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give
2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-di-
hydro-quinazolin-6-ylmethyl]-acetamide as a white solid (550 mg,
70% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150
mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, grad.
to 95/5 in 5 min, kept 5 min, 6.00 min (98.7%); mp,
229.5-231.5.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.2.15-2.21 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH.sub.2,
CH.sub.3), 3.50 (s, 2H, ArCH.sub.2), 4.37 (d, J=5 Hz, 2H,
CH.sub.2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.27-7.90 (m, 7H, Ar),
8.67 (t, J=5 Hz, 1H, CH.sub.2NH), 11.03 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.92, 23.40, 30.63, 41.39, 41.87, 56.53,
120.02, 123.99, 126.57, 128.13, 130.87, 131.09, 134.03, 135.21,
137.97, 145.81, 154.61, 160.38, 169.47, 169.85, 172.61. LCMS
MH=453, 455; Anal Calcd For C.sub.23H.sub.21N.sub.4O.sub.4Cl: C,
61.00; H, 4.67; N, 12.37; Cl, 7.83. Found: C, 60.88; H, 4.60; N,
12.27; Cl, 7.89.
5.17
1-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-OUINAZOLIN-
-6-YLMETHYL]-3-HEXYL-UREA
##STR00033##
[0336] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL,
2.1 mmol) in THF (12 mL) at 5.about.10.degree. C., was added hexyl
isocyanate (0.25 g, 1.9 mmol), and the mixture was stirred at room
temperature overnight. The mixture was quenched with methanol
(.about.1 mL), and the solvent was evaporated. The residue was
purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-hexyl-urea as an off-white solid (410 mg, 65% yield);
HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1
mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, grad. to
95/5 in 5 min, kept 5 min, 6.05 min (99.0%); mp, 220-222.degree.
C.; .sup.1HNMR (DMSO-d.sub.6) .delta. .quadrature.0.85 (t, J=6 Hz,
3H, CH.sub.3CH.sub.2CH.sub.2), 1.24-1.38 (m, 8H,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2), 2.15-2.20 (m, 1H, CHH),
2.56-3.03 (m, 6H, CHCH.sub.2, CH.sub.3), 4.30 (d, J=6 Hz, 2H,
ArCH.sub.2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 5.97 (t, J=5 Hz, 1H,
CH.sub.2NH), 6.40 (t, J=6 Hz, 1H, ArCH.sub.2NH), 7.55-7.89 (m, 3H,
Ar), 11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 13.88,
20.93, 22.05, 23.38, 26.03, 29.94, 30.63, 31.02, 39.35, 42.44,
56.51, 119.96, 123.46, 126.40, 133.81, 139.87, 145.64, 154.36,
157.99, 160.46, 169.47, 172.60. LCMS MH=428; Anal Calcd For
C.sub.22H.sub.29N.sub.5O.sub.4: C, 61.81; H, 6.84; N, 16.38. Found:
C, 61.50; H, 6.82; N, 16.23.
5.18
1-(4-CHLORO-PHENYL)-3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,-
4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-UREA
##STR00034##
[0338] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.47 g, 1.4 mmol) and triethylamine (0.27 mL,
2.0 mmol) in THF (8 mL) at 5.about.10.degree. C., was added
4-chlorophenyl isocyanate (0.28 g, 1.8 mmol), and the mixture was
stirred at room temperature overnight. The mixture was quenched
with methanol (.about.1 mL), and the solvent was evaporated. The
residue was purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give
1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3-
,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (400
mg, 63% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m,
3.9.times.150 mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, grad. to 95/5 in 5 min, kept 5 min, 6.18 min
(98.9%); mp, 225-227.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH.sub.2,
CH.sub.3), 4.41 (d, J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd, J=6, 11 Hz,
1H, CH), 6.81 (t, J=6 Hz, 1H, CH.sub.2NH), 7.23-7.95 (m, 7H, Ar),
8.80 (s, 1H, NH), 11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6)
.delta. 20.93, 23.38, 30.61, 42.33, 56.54, 119.23, 120.01, 123.67,
124.57, 126.53, 128.42, 133.95, 139.05, 139.37, 145.74, 154.53,
155.09, 160.46, 169.47, 172.60. LCMS MH=454, 456; Anal Calcd For
C.sub.22H.sub.20N.sub.5O.sub.4Cl+0.8H.sub.2O: C, 56.43; H, 4.65; N,
14.95; Cl, 7.57. Found: C, 56.45; H, 4.56; N, 14.87; Cl, 7.69.
5.19
1-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-
-6-YLMETHYL]-3-M-TOLYL-UREA
##STR00035##
[0340] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL,
2.1 mmol) in THF (12 mL) at 5.about.10.degree. C., was added
m-toluyl isocyanate (0.25 mL, 1.9 mmol), and the mixture was
stirred at room temperature overnight. The mixture was quenched
with methanol (.about.1 mL), and the solvent was evaporated. The
residue was purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazoli-
n-6-ylmethyl]-3-m-tolyl-urea as an off-white solid (437 mg, 68%
yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm,
1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, grad. to
95/5 in 5 min, kept 5 min, 5.95 min (99.0%); mp, 200-202.degree.
C.; .sup.1HNMR (DMSO-d.sub.6) .delta. .quadrature.2.07-2.24 (m, 4H,
ArCH.sub.3, CHH), 2.56-2.88 (m, 6H, CHCH.sub.2, CH.sub.3), 4.40 (d,
J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.70-7.95
(m, 8H, Ar and CH.sub.2NH), 8.54 (s, 1H, NH), 11.01 (s, 1H, NH);
.sup.13C NMR (DMSO-d.sub.6) .delta. 20.92, 21.19, 23.39, 30.61,
42.30, 56.53, 114.93, 118.27, 120.00, 121.87, 123.63, 126.53,
128.44, 133.94, 137.70, 139.23, 140.26, 145.73, 154.50, 155.22,
160.46, 169.48, 172.61. LCMS MH=434; Anal Calcd For
C.sub.23H.sub.23N.sub.5O.sub.4+1.4 H.sub.2O: C, 60.23; H, 5.67; N,
15.27. Found: C, 60.18; H, 5.44; N, 15.09.
5.20
1-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-
-6-YLMETHYL]-3-(4-TRIFLUOROMETHOXY-PHENYL)-UREA
##STR00036##
[0342] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.49 g, 1.5 mmol) and triethylamine (0.28 mL,
2.1 mmol) in THF (12 mL) at 5.about.10.degree. C., was added
trifluoromethoxy-phenyl isocyanate (0.29 mL, 1.9 mmol), and the
mixture was stirred at room temperature overnight. The mixture was
quenched with methanol (.about.1 mL), and the solvent was
evaporated. The residue was purified by flash column chromatography
(Silica gel, methanol/methylene chloride 4%/96%) to give
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-(4-trifluoromethoxy-phenyl)-urea as an off-white solid
(490 mg, 67% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m,
3.9.times.150 mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, grad. to 95/5 in 5 min, kept 5 min, 6.47 min
(98.6%); mp, 201-203.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.2.15-2.20 (m, 1H, CHH), 2.56-2.90 (m, 6H, CHCH.sub.2,
CH.sub.3), 4.42 (d, J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd, J=6, 11 Hz,
1H, CH), 6.84 (t, J=6 Hz, 1H, CH.sub.2NH), 7.21-7.96 (m, 7H, Ar),
8.88 (s, 1H, NH), 11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6)
.delta. 20.93, 23.39, 30.61, 42.33, 56.53, 118.81, 120.01, 120.17
(q, J.sub.C-F=255 Hz), 121.54, 123.66, 126.54, 133.93, 139.04,
139.69, 142.08, 145.76, 154.52, 155.12, 160.46, 169.48, 172.60.
LCMS MH=504; Anal Calcd For
C.sub.23H.sub.20N.sub.5O.sub.5F.sub.3+0.2 H.sub.2O: C, 54.48; H,
4.06; N, 13.81; F, 11.24. Found: C, 54.25; H, 4.00; N, 13.59; F,
11.24.
5.21
N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-
-6-YLMETHYL]-4-TRIFLUOROMETHYLSULFANYL-BENZAMIDE
##STR00037##
[0344] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.47 g, 1.4 mmol) in acetonitrile (10 mL), was
added 4-trifluoromethylthio-benzoyl chloride (0.35 mL, 2.1 mmol)
and N,N-diisopropyl ethylamine (0.58 mL, 3.5 mmol). The mixture was
stirred at room temperature for one hour. The solvent was
evaporated, and the residue was purified by flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to
give
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethyl-sulfanyl-benzamide as an off-white solid
(470 mg, 66% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m,
3.9.times.150 mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, gradient to 95/5 in 5 min, kept for 5 min, 6.63
min (96.8%); mp, 169-171.degree. C.; .sup.1HNMR (DMSO-d.sub.6)
.delta. .quadrature.2.15-2.20 (m, 1H, CHH), 2.56-2.86 (m, 6H,
CHCH.sub.2, CH.sub.3), 4.60 (d, J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd,
J=6, 11 Hz, 1H, CH), 7.59-8.03 (m, 7H, Ar), 9.35 (t, J=5 Hz, 1H,
CH.sub.2NH), 11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
20.89, 23.41, 30.60, 42.38, 56.52, 120.01, 123.90, 126.33, 126.64,
128.64, 129.46 (q, J.sub.C-F=307 Hz), 134.09, 135.91, 136.69,
137.86, 145.85, 154.64, 160.41, 165.28, 169.47, 172.62. LCMS
MH=505; Anal Calcd For C.sub.23H.sub.19N.sub.4O.sub.4F.sub.3S+0.8
H.sub.2O: C, 53.24; H, 4.00; N, 10.80; F, 10.98; S, 6.18. Found: C,
53.17; H, 3.83; N, 10.60; F, 10.74; S, 6.14.
5.22
1-(3-CHLORO-4-METHYL-PHENYL)-3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-
-4-OXO-3,4-DIHYDRO-OUINAZOLIN-6-YLMETHYL]-UREA
##STR00038##
[0346] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.46 g, 1.4 mmol) and triethylamine (0.27 mL,
1.9 mmol) in THF (10 mL) at 5-10.degree. C., was added
3-chloro-4-methyl-phenyl isocyanate (0.24 mL, 1.8 mmol), and the
mixture was stirred at room temperature overnight. The mixture was
quenched with methanol (.about.1 mL), and the solvent was
evaporated. The residue was purified by flash column chromatography
(Silica gel, methanol/methylene chloride 4%/96%) to give
1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-o-
xo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid
(450 mg, 70% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m,
3.9.times.150 mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, grad. to 95/5 in 5 min, kept 5 min, 6.38 min
(98.4%); mp, 186-188.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.2.15-2.23 (m, 4H, CHH and CH.sub.3Ar), 2.56-2.86 (m,
6H, CHCH.sub.2, CH.sub.3), 4.40 (d, J=6 Hz, 2H, CH.sub.2NH), 5.26
(dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=5 Hz, 1H, CH.sub.2NH),
7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH);
.sup.13C NMR (DMSO-d.sub.6) .delta. 18.71, 20.93, 23.39, 30.61,
42.34, 56.53, 116.45, 117.66, 120.01, 123.67, 126.54, 127.39,
130.99, 132.96, 133.95, 139.05, 139.58, 145.76, 154.51, 155.08,
160.47, 169.47, 172.60. LCMS MH=468, 470; Anal Calcd For
C.sub.23H.sub.22N.sub.5O.sub.4Cl+0.6 H.sub.2O: C, 57.71; H, 4.88;
N, 14.63; Cl, 7.41. Found: C, 57.63; H, 4.96; N, 14.50; Cl,
7.64.
5.23
4-CHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-O-
UINAZOLIN-6-YLMETHYL]-BENZAMIDE
##STR00039##
[0348] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.54 g, 1.6 mmol) in acetonitrile (10 mL), was
added 4-dichloro-benzoyl chloride (0.31 mL, 2.4 mmol) and
N,N-diisopropyl ethylamine (0.66 mL, 4.0 mmol). The mixture was
stirred at room temperature for 30 minutes. The solvent was
evaporated, and the residue was purified by flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to
give
4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quina-
zolin-6-ylmethyl]-benzamide as a white solid (298 mg, 42% yield);
HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1
mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, gradient to
95/5 in 5 min, kept for 5 min, 6.00 min (99.0%); mp,
267-269.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.2.15-2.18 (m, 1H, CHH), 2.57-2.85 (m, 6H, CHCH.sub.2,
CH.sub.3), 4.59 (d, J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd, J=6, 11 Hz,
1H, CH), 7.54-7.95 (m, 7H, Ar), 9.24 (t, J=5 Hz, 1H, CH.sub.2NH),
11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.91,
23.40, 30.60, 42.33, 56.52, 120.01, 123.89, 126.62, 128.44, 129.15,
132.84, 134.09, 136.16, 138.02, 145.83, 154.60, 160.43, 165.23,
169.45, 172.60. LCMS MH=439, 441; Anal Calcd For
C.sub.22H.sub.19N.sub.4O.sub.4Cl+0.3H.sub.2O: C, 59.48; H, 4.45; N,
12.61; Cl, 7.98. Found: C, 59.32; H, 4.10; N, 12.50; Cl, 7.99.
5.24
N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-OUINAZOLIN-
-6-YLMETHYL]-3-TRIFLUOROMETHYL-BENZAMIDE
##STR00040##
[0350] To a stirred solution of 3-trifluoromethyl-benzoic acid
(0.30 g, 1.6 mmol) in DMF (8 mL) in a 40.degree. C. oil bath, was
added 1.1' carbonyldiimidazole (0.28 g, 1.7 mmol), and the mixture
was stirred for one hour. Then
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.53 g, 1.6 mmol) was added, and the mixture was
stirred for 15 minutes. The solvent was evaporated, and the residue
was purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-trifluoromethyl-benzamide as an off-white solid (430 mg,
59% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150
mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, grad.
to 95/5 in 5 min, kept 5 min, 6.20 min (98.5%); mp, 220-222.degree.
C.; .sup.1HNMR (DMSO-d.sub.6) .delta. .quadrature.2.15-2.20 (m, 1H,
CHH), 2.56-2.91 (m, 6H, CHCH.sub.2, CH.sub.3), 4.62 (d, J=5 Hz, 2H,
CH.sub.2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.25 (m, 7H, Ar),
9.42 (t, J=5 Hz, 1H, CH.sub.2NH), 11.02 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.90, 23.41, 30.60, 42.45, 56.53, 120.02,
123.79 (q, J.sub.C-F=11 Hz), 123.79 (d, J.sub.C-F=3 Hz), 123.95 (q,
J.sub.C-F=275 Hz), 124.04, 126.67, 127.96 (d, J.sub.C-F=3 Hz),
129.19 (d, J.sub.C-F=32 Hz), 129.74, 131.38, 134.18, 134.88,
137.81, 145.88, 154.65, 160.43, 164.73, 169.45, 172.59. LCMS
MH=473; Anal Calcd For
C.sub.23H.sub.19N.sub.4O.sub.4F.sub.3+0.3H.sub.2O: C, 57.81; H,
4.13; N, 11.73; F, 11.93. Found: C, 57.77; H, 4.11; N, 11.69; F,
11.97.
5.25
N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-
-6-YLMETHYL]-4-TRIFLUOROMETHOXY-BENZAMIDE
##STR00041##
[0352] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.49 g, 1.4 mmol) in acetonitrile (10 mL), was
added 4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and
N,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was
stirred at room temperature for one hour. The solvent was
evaporated, and the residue was purified by flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to
give
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (500
mg, 71% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m,
3.9.times.150 mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, gradient to 95/5 in 5 min, kept for 5 min, 6.40
min (99.5%); mp, 165-167.degree. C.; .sup.1HNMR (DMSO-d.sub.6)
.delta. .quadrature.2.15-2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H,
CHCH.sub.2, CH.sub.3), 4.60 (d, J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd,
J=6, 11 Hz, 1H, CH), 7.458-8.04 (m, 7H, Ar), 9.28 (t, J=5 Hz, 1H,
CH.sub.2NH), 11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
20.90, 23.40, 30.60, 42.35, 56.53, 119.93 (q, J.sub.C-F =257 Hz),
120.01, 120.67, 123.87, 126.62, 129.56, 133.19, 134.17, 134.07,
137.97, 145.83, 150.35, 154.61, 160.43, 165.06, 169.45, 172.59.
LCMS MH=489; Anal Calcd For
C.sub.23H.sub.19N.sub.4O.sub.5F.sub.3+1.1H.sub.2O: C, 54.36; H,
4.20; N, 11.02; F, 11.21. Found: C, 54.40; H, 3.89; N, 10.67; F,
11.06.
5.26
3,4-DICHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYD-
RO-OUINAZOLIN-6-YLMETHYL]-BENZAMIDE
##STR00042##
[0354] To a stirred suspension of
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.45 g, 1.4 mmol) in acetonitrile (10 mL), was
added 3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and
N,N-diisopropyl ethylamine (0.54 mL, 3.2 mmol). The mixture was
stirred at room temperature for 15 minutes. The solvent was
evaporated, and the residue was purified by flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to
give
3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-q-
uinazolin-5-ylmethyl]-benzamide as an off-white solid (290 mg, 46%
yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150 mm,
1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, gradient
to 95/5 in 5 min, kept for 5 min, 6.45 min (99.6%); mp,
177-179.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.2.16-2.18 (m, 1H, CHH), 2.56-2.84 (m, 6H, CHCH.sub.2,
CH.sub.3), 4.59 (d, J=5 Hz, 2H, CH.sub.2NH), 5.26 (dd, J=5, 9 Hz,
1H, CH), 7.58-8.14 (m, 6H, Ar), 9.34 (t, J=5 Hz, 1H, CH.sub.2NH),
11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.91,
23.41, 30.61, 42.47, 56.54, 120.01, 124.04, 126.66, 127.56, 129.20,
130.77, 131.32, 134.17, 134.37, 137.71, 145.88, 154.65, 160.42,
164.00, 169.45, 172.60. LCMS MH=473, 475; Anal Calcd For
C.sub.22H.sub.18N.sub.4O.sub.4Cl.sub.2+1.0CH.sub.2Cl.sub.2: C,
53.78; H, 4.10; N, 11.40; Cl, 14.43. Found: C, 53.44; H, 4.11; N,
11.27; Cl, 14.80.
5.27
N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-OUINAZOLIN-
-6-YLMETHYL]-4-TRIFLUOROMETHYL-BENZAMIDE
##STR00043##
[0356] To a stirred solution of 4-trifluoromethyl-benzoic acid
(0.30 g, 1.6 mmol) in DMF (8 mL) in a 40.degree. C. oil bath, was
added 1.1' carbonyldiimidazole (0.29 g, 1.8 mmol), and the mixture
was stirred for one hour. Then
3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride (0.54 g, 1.6 mmol) was added, and the mixture was
stirred for 15 minutes. The solvent was evaporated, and the residue
was purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethyl-benzamide as an off-white solid (500 mg,
67% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m, 3.9.times.150
mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1% H.sub.3PO.sub.4, grad.
to 95/5 in 5 min, kept 5 min, 6.33 min (99.1%); mp, 221-223.degree.
C.; .sup.1HNMR (DMSO-d.sub.6) .delta. .quadrature.2.14-2.20 (m, 1H,
CHH), 2.56-2.88 (m, 6H, CHCH.sub.2, CH.sub.3), 4.62 (d, J=5 Hz, 2H,
CH.sub.2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.11 (m, 7H, Ar),
9.40 (t, J=5 Hz, 1H, CH.sub.2NH), 11.02 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.90, 23.41, 30.60, 42.41, 56.53, 120.03,
123.90 (q, J.sub.C-F=253 Hz), 123.95, 125.36 (d, J.sub.C-F=3 Hz),
125.45 (d, J.sub.C-F=3 Hz), 126.65, 128.14, 131.23 (d, J.sub.C-F=31
Hz), 134.11, 137.83, 145.87, 154.64, 160.42, 165.12, 169.45,
172.59. LCMS MH=473; Anal Calcd For
C.sub.23H.sub.19N.sub.4O.sub.4F.sub.3: C, 58.48; H, 4.05; N, 11.86;
F, 12.06. Found: C, 58.36; H, 3.96; N, 11.75; F, 11.84.
5.28
3-(2,7-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00044##
[0358] To a stirred mixture of 2-amino-4-methylbenzoic acid (2.0 g,
13 mmol) and imidazole (1.1 g, 16 mmol) in acetonitrile (20 mL),
was added acetyl chloride (1.1 mL, 16 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(2.2 g, 13 mmol), imidazole (2.0 g, 30 mmol) and triphenyl
phosphite (4.2 mL, 16 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give
3-(2,7-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
white solid (2.52 g, 67% yield): HPLC: Waters Symmetry C.sub.18, 5
.mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 5.13 min (99.9%); mp: 305.degree. C. (decomp);
.sup.1H NMR (DMSO-d.sub.6) .delta. 2.08-2.24 (m, 1H, CHH), 2.45 (s,
3H, CH.sub.3), 2.56-2.75 (m, 5H, CH.sub.3, 2CHH), 2.81-2.91 (m, 1H,
CHH), 5.24 (dd, J=6, 11 Hz, 1H, NCH), 7.32 (dd, J=1, 8 Hz 1H, Ar),
7.43 (s, 1H, Ar), 7.91 (d, J=8 Hz, 1H, Ar), 11.00 (s, 1H, NH);
.sup.13C NMR (DMSO-d.sub.6) .delta. 21.00, 21.35, 23.45, 30.61,
56.43, 117.94, 125.80, 126.10, 127.97, 145.21, 146.98, 154.96,
160.34, 169.56, 172.62; LCMS: MH=286; Anal Calcd for
C.sub.15H.sub.15N.sub.3O.sub.3: C, 63.15; H, 5.21; N, 14.73. Found:
C, 63.14; H, 5.21; N, 14.76.
5.29
3-(7-FLUORO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00045##
[0360] To a stirred mixture of 2-amino-4-fluorobenzoic acid (2.5 g,
16 mmol) and imidazole (1.3 g, 19 mmol) in acetonitrile (25 mL),
was added acetyl chloride (1.4 mL, 19 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(2.7 g, 16 mmol), imidazole (2.4 g, 36 mmol) and triphenyl
phosphite (5.1 mL, 19 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give
3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (2.5 g, 52% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 25/75
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 3.83 min (100%); mp:
243-245.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.15-2.22
(m, 1H, CHH), 2.58-2.71 (m, 5H, CH.sub.3, 2CHH), 2.79-2.86 (m, 1H,
CHH), 5.28 (dd, J=5, 11 Hz, 1H, NCH), 7.34-7.44 (m, 2H, Ar), 8.10
(dd, J=6, 9 Hz, 1H, Ar), 11.05 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.89, 23.50, 30.58, 56.59, 111.62 (d,
J.sub.C-F=22 Hz), 115.26 (d, J.sub.C-F=24 Hz), 117.32, 129.19 (d,
J.sub.C-F=11 Hz), 148.97 (d, J.sub.C-F=13 Hz), 156.65, 159.77,
165.83 (d, J.sub.C-F=252 Hz), 169.41, 172.59; LCMS: MH=290; Anal
Calcd for C.sub.14H.sub.12N.sub.3O.sub.3F: C, 58.13; H, 4.18; N,
14.53; F, 6.57. Found: C, 58.09; H, 4.08; N, 14.42; F, 6.72.
5.30
3-(7-CHLORO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00046##
[0362] To a stirred mixture of 2-amino-4-chlorobenzoic acid (5.0 g,
29 mmol) and imidazole (2.4 g, 35 mmol) in acetonitrile (50 mL),
was added acetyl chloride (2.5 mL, 35 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(4.8 g, 29 mmol), imidazole (4.4 g, 64 mmol) and triphenyl
phosphite (8.4 mL, 32 mmol) and heated to reflux for 22 hours. The
suspension was filtered and washed with acetonitrile (50 mL) and
water (2.times.50 mL) to give
3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (6.5 g, 73% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 4.36 min (99.9%); mp:
291-293.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.16-2.23
(m, 1H, CHH), 2.59-2.72 (m, 5H, CH.sub.3, 2CHH), 2.79-2.92 (m, 1H,
CHH), 5.29 (dd, J=5, 11 Hz, 1H, NCH), 7.53 (dd, J=2, 9 Hz, 1H, Ar),
7.69 (d, J=8 Hz, 1H, Ar), 8.03 (d, J=8 Hz, 1H, Ar), 11.07 (s, 1H,
NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.84, 23.53, 30.58,
56.65, 19.06, 125.70, 126.91, 128.07, 139.30, 147.89, 156.74,
159.89, 169.35, 172.58; LCMS: MH=306, 308; Anal Calcd for
C.sub.14H.sub.12N.sub.3O.sub.3Cl: C, 55.00; H, 3.96; N, 13.74; Cl,
11.60. Found: C, 55.24; H, 3.78; N, 13.74; Cl, 12.01.
5.31
3-(7-BROMO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00047##
[0364] To a stirred mixture of 2-amino-4-bromobenzoic acid (2.0 g,
9.3 mmol) and imidazole (0.8 g, 11 mmol) in acetonitrile (20 mL),
was added acetyl chloride (0.8 mL, 11 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(1.5 g, 9.3 mmol), imidazole (1.4 g, 20 mmol) and triphenyl
phosphite (2.9 mL, 11 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (30 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give
3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (2.4 g, 75% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 18.65 min (98.9%); mp:
315-317.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.08-2.22
(m, 1H, CHH), 2.62-2.79 (m, 5H, CH.sub.3, 2CHH), 2.80-2.91 (m, 1H,
CHH), 5.28 (dd, J=6, 11 Hz, 1H, NCH), 7.66 (dd, J=2, 8 Hz, 1H, Ar),
7.84 (d, J=2 Hz 2H, Ar), 7.95 (d, J=8 Hz, 1H, Ar), 11.05 (s, 1H,
NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.83, 23.53, 24.02,
30.58, 56.67, 119.36, 128.06, 128.29, 128.80, 129.67, 147.93,
156.69, 160.02, 169.33, 172.57; LCMS: MH=350, 352; Anal Calcd for
C.sub.14H.sub.12N.sub.3O.sub.3Br: C, 48.02; H, 3.45; N, 12.00; Br,
22.82. Found: C, 47.94; H, 3.17; N, 11.85; Br, 20.65.
5.32
3-(2-METHYL-4-OXO-7-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,-
6-DIONE
##STR00048##
[0366] To a stirred mixture of 2-amino-4-(trifluoromethyl)benzoic
acid (3.0 g, 15 mmol) and imidazole (1.2 g, 18 mmol) in
acetonitrile (30 mL), was added acetyl chloride (1.3 mL, 18 mmol)
at room temperature. The mixture was stirred at room temperature
overnight. To the mixture, was added 3-amino-piperidine-2,6-dione
hydrogen chloride (2.4 g, 15 mmol), imidazole (2.2 g, 32 mmol) and
triphenyl phosphite (4.6 mL, 18 mmol) and heated to reflux for 22
hours. To the mixture, was added water (100 mL). The suspension was
filtered and washed with water (2.times.50 mL), ethyl acetate
(2.times.50 mL), sodium hydrogen carbonate (sat, 50 mL) and water
(50 mL) to give a white solid, which was dissolved in DMSO (10 mL).
To the solution, was added water (3 mL) to give a suspension. The
suspension was filtered and washed with DMSO (2 mL) to give a white
solid. The solid was stirred in water (50 mL) at 60.degree. C. for
2hours, then at room temperature overnight. The suspension was
filtered and washed with water (2.times.50 mL) to give
3-(2-methyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-di-
one as a white solid (1.17 g, 24% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 8.14 min (99.9%); mp:
277-279.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.18-2.25
(m, 1H, CHH), 2.59-2.74 (m, 5H, CH.sub.3, 2CHH), 2.81-2.88 (m, 1H,
CHH), 5.34 (dd, J=6, 11 Hz, 1H, NCH), 7.80 (dd, J=2, 8 Hz, 1H, Ar),
7.96 (s, 1H, Ar), 8.24 (d, J=8 Hz, 1H, Ar), 11.09 (s, 1H, NH);
.sup.13C NMR (DMSO-d.sub.6) .delta. 20.73, 23.54, 30.57, 56.82,
122.30 (q, J.sub.C-F=3 Hz), 122.99, 123.45 (q, J.sub.C-F=273 Hz),
123.74 (q, J.sub.C-F=4 Hz), 127.85, 134.22 (q, J.sub.C-F=32 Hz),
146.84, 156.98, 159.80, 169.24, 172.56; LCMS: MH=340; Anal Calcd
for C.sub.15H.sub.12N.sub.3O.sub.3F.sub.3: C, 53.10; H, 3.57; N,
12.39; F, 16.80. Found: C, 52.55; H, 3.42; N, 12.21; F, 17.18.
5.33 3-(7-FLUORO-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00049##
[0368] Step 1: A mixture of 2-amino-4-fluorobenzoic acid (2.5 g, 16
mmol) and CDI (2.4 g, 15 mmol) in acetonitrile (30 mL) was stirred
at room temperature for 1.5 hours. To the suspension, was added
3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15 mmol) and
sodium hydrogen carbonate (1.6 g, 19 mmol), and the mixture was
heated at 50.degree. C. for 21 hours. The suspension was cooled to
room temperature for 1 hour. The suspension was filtered and washed
with acetonitrile (5 mL) and water (2.times.20 mL). The solid was
stirred in methanol (15 mL) overnight. The suspension was filtered
and washed with methanol (15 mL) to give
2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluorobenzamide as an
off-white solid (1.9 g, 45% yield): .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.91-1.96 (m, 1H, CHH), 2.04-2.18 (m, 1H, CHH), 2.50-2.56
(m, 1H, CHH), 2.73-2.85 (m, 1H, CHH), 4.67-4.76 (m, 1H, NCH), 6.35
(dt, J=2, 9 Hz, 1H, Ar), 6.48 (dd, J=2, 12 Hz, 1H, Ar), 6.76 (brs,
2H, NH.sub.2), 7.58 (dd; J=7, 8 Hz, 1H, Ar), 8.50 (d, J=8 Hz, 1H,
NH), 10.84 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 24.06,
30.91, 48.98, 101.30 (d, J.sub.C-F=23 Hz), 101.60 (d, J.sub.C-F=22
Hz), 110.60, 130.66 (d, J.sub.C-F=11 Hz), 152.16 (d, J.sub.C-F=12
Hz), 164.46 (d, J.sub.C-F=246 Hz), 167.80, 172.30, 172.94.
[0369] Step 2: A solution of
2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluoro-benzamide (0.9 g, 3.4
mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid
(110 mg) was heated to 160.degree. C. in a microwave oven for 15
minutes. To the mixture, was added methanol (10 mL), and the
mixture was stirred for 10 minutes. The suspension was filtered and
washed with methanol to give
3-(7-fluoro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
white solid (650 mg, 70% yield): HPLC: Waters Symmetry C.sub.18, 5
.mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 2.45 min (96.1%); mp: 296-298.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.13-2.19 (m, 1H, CHH), 2.63-2.73 (m,
2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.50 (br, 1H, NCH), 7.46 (dt,
J=3, 9 Hz, 1H, Ar), 7.53 (dd, J=3, 10 Hz, 1H, Ar), 8.22 (dd, J=6, 9
Hz, 1H, Ar), 8.42 (s, 1H, CH), 11.18 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 22.45, 30.88, 56.43, 112.3 (d, J.sub.C-F=22
Hz), 115.91 (d, J.sub.C-F=23 Hz), 118.38, 129.32 (d, J.sub.C-F=11
Hz), 148.71, 149.65 (d, J.sub.C-F=14 Hz), 159.00, 165.70 (d,
J.sub.C-F=252 Hz), 169.76, 172.41; LCMS: MH=276; Anal Calcd for
C.sub.13H.sub.10N.sub.3O.sub.3F: C, 56.73; H, 3.66; N, 15.27.
Found: C, 56.39; H, 3.60; N, 15.16.
5.34 3-(7-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00050##
[0371] Step 1: A mixture of 2-amino-4-methylbenzoic acid (2.0 g, 13
mmol) and CDI (2.0 g, 12 mmol) in acetonitrile (20 mL) was stirred
at room temperature for 1.5 hours. To the suspension, was added
3-amino-piperidine-2,6-dione hydrogen chloride (2.0 g, 12 mmol) and
sodium hydrogen carbonate (1.3 g, 16 mmol), and the mixture was
heated at 50.degree. C. for 21 hours. The suspension was cooled to
room temperature for 1 hour. The suspension was filtered and washed
with water (50 mL) and ethyl acetate (20 mL). The solid was dried
in a vacuum oven overnight to give
2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-methyl-benzamide as a white
solid (2.2 g, 69% yield): .sup.1H NMR (DMSO-d.sub.6) .delta.
1.90-1.96 (m, 1H, CHH), 2.05-2.14 (m, 1H, CHH), 2.18 (s, 3H,
CH.sub.3), 2.49-2.55 (m, 1H, CHH), 2.72-2.84 (m, 1H, CHH),
4.67-4.75 (m, 1H, NCH), 6.36 (dd, J=2, 8 Hz, 1H, Ar), 6.43 (br, 2H,
NHH, Ar), 6.51 (s, 1H, NHH), 7.43 (d, J=8 Hz, 1H, Ar), 8.38 (d, J=8
Hz, 1H, NH), 10.83 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
21.05, 24.21, 30.99, 48.97, 111.26, 115.74, 116.48, 128.09, 141.71,
149.96, 168.54, 172.50, 173.04; LCMS: MH=262.
[0372] Step 2: A solution of
2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-methyl-benzamide (1.0 g, 3.8
mmol) and trimethyl orthoformate (10 mL) and p-toluene sulfonic
acid (250 mg) was heated to 160.degree. C. in a microwave oven for
30 minutes. The suspension was filtered and washed with methanol
(20 mL), water (20 mL) and methanol (20 mL) to give
3-(7-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an
off-white solid (880 mg, 85% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 5.14 min (97.1%); mp:
313-315.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.11-2.18
(m, 1H, CHH), 2.48 (s, 3H, CH.sub.3), 2.61-2.74 (m, 2H, 2CHH),
2.82-2.92 (m, 1H, CHH), 5.46 (br, 1H, NCH), 7.41 (dd, J=1, 8 Hz,
1H, Ar), 7.53 (s, 1H, Ar), 8.03 (d, J=8 Hz, 1H, Ar), 8.33 (s, 1H,
CH), 11.15 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 21.23,
22.51, 30.91, 56.74, 118.95, 125.93, 126.74, 128.66, 145.27,
147.35, 147.59, 159.54, 169.88, 172.44; LCMS: MH=272; Anal Calcd
for C.sub.14H.sub.13N.sub.3O.sub.3+0.1H.sub.2O: C, 61.58; H, 4.87;
N, 15.39. Found: C, 61.41; H, 4.87; N, 15.15.
5.35
3-(7-AMINO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00051##
[0374] Step 1: To a stirred mixture of 2-amino-4-nitrobenzoic acid
(5.0 g, 28 mmol) and imidazole (2.2 g, 33 mmol) in acetonitrile (50
mL), was added acetyl chloride (2.3 mL, 33 mmol) at room
temperature. The mixture was stirred at room temperature overnight.
To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen
chloride (4.5 g, 28 mmol), imidazole (4.1 g, 60 mmol) and triphenyl
phosphite (8.7 mL, 33 mmol), and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give
3-(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as an off-white solid (4.8 g, 55% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 10/90
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 5.69 min (95.4%); .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.15-2.25 (m, 1H, CHH), 2.59-2.69 (m, 2H,
2CHH), 2.70 (s, 3H, CH.sub.3), 2.79-2.87 (m, 1H, CHH), 5.35 (dd,
J=6, 12 Hz, 1H, NCH), 8.20-8.29 (m, 2H, Ar), 8.34 (d, J=2 Hz, 1H,
Ar), 11.10 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.60,
23.53, 30.49, 56.85, 120.26, 121.58, 124.35, 128.30, 147.08,
151.30, 157.61, 159.52, 160.09, 172.48; LCMS: MH=317.
[0375] Step 2: A suspension of
3-(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
(4.8 g, 13 mmol) and 20% Pd(OH).sub.2/C (1.0 g) in cyclohexene (15
mL) and DMF (60 mL) was heated in a 125.degree. C. oil bath
overnight. The suspension was filtered thru a pad of Celite, and
washed with DMF (30 mL). To the filtrate, was added water (150 mL)
to give a suspension. The suspension was filtered and washed with
water (50 mL) to give
3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as an off-white solid (3.07 g, 71% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 5/95 grad
95/5 in 5 min CH.sub.3CN/0.1% H.sub.3PO.sub.4, 4.08 min (97.3%)
[sample was dissolved in 0.1% H3PO4]; mp: 305-307.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 2.05-2.16 (m, 1H, CHH), 2.53 (s,
3H, CH.sub.3), 2.58-2.69 (m, 2H, 2CHH), 2.75-2.86 (m, 1H, CHH),
5.10 (dd, J=6, 11 Hz, 1H, NCH), 6.11 (brs, 2H, NH.sub.2), 6.54 (d,
J=2 Hz, 1H, Ar), 6.68 (dd, J=2, 8 Hz, 1H, Ar), 10.93 (s, 1H, NH);
.sup.13C NMR (DMSO-d.sub.6) .delta. 21.36, 23.43, 30.63, 55.97,
106.12, 109.17, 114.70, 127.28, 148.95, 154.42, 154.61, 159.85,
169.87, 172.67; LCMS: MH=287; Anal Calcd for
C.sub.14H.sub.14N.sub.4O.sub.3: C, 58.74; H, 4.93; N, 19.57. Found:
C, 58.60; H, 4.83; N, 19.40.
5.36
[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-7-
-YLMETHYL]-CARBAMIC ACID TERT-BUTYL ESTER
##STR00052##
[0377] Step 1: To a stirred solution of 4-methyl-2-nitro-benzoic
acid methyl ester (108.5 g, 555.7 mmol) in acetonitrile (750 mL),
was added NBS (97.9 g, 550.1 mmol). The mixture was heated to a
gentle reflex with a 200 W light bulb on for 5.5 hours. The solvent
was evaporated, and the residue was dissolved in ethyl acetate
(1500 mL). The solution was washed with water (2.times.600 mL) and
brine (300 mL), dried over magnesium sulfate, and concentrated to
give a brown oil. To the oil, was added t-butyl methyl ether (300
mL). The mixture was heated at 70.degree. C. for 15 minutes. The
mixture was allowed to cool to about 53.degree. C. over one hour,
then to 45.degree. C., and then at 20.about.25.degree. C., while
blowing nitrogen with a glass pipette overnight. The suspension was
filtered via a medium pore-sized funnel. The solid was washed with
a pre-cooled 10.degree. C. mixed solvent of heptane/MTBE (1/2
vol/vol) and suction dried in hood overnight to give
4-bromomethyl-2-nitro-benzoic acid methyl ester as an off-white
solid (66 g, 43% yield). The solid was used in the next step
without further purification.
[0378] Step 2: A stirred mixture of 4-bromomethyl-2-nitro-benzoic
acid methyl ester (66.3 g, 241.9 mmol), di-tert-butyl
iminodicarboxylate (52.72 g, 242.6 mmol), cesium carbonate (161.58
g, 495.9 mmol), and lithium iodide (1.62 g, 12 mmol) in 2-butanone
(700 mL) was heated to reflux in a 100.degree. C. oil bath for 12
hours while stirred with a mechanical stirrer. The mixture was
allowed to cool to room temperature. To the mixture, was added
brine (300 mL), water (300 mL), and ethyl acetate (600 mL), and the
mixture was stirred for 10 minutes. The suspension was filtered
through a pad of Celite. The two layers were separated, and the
organic layer was evaporated to a less volume. The aqueous layer
was extracted with ethyl acetate (2.times.150 mL). The combined
organic layers were washed with brine (1.times.500 mL), dried over
magnesium sulfate while de-colored at the same time by charcoal at
room temperature with stirring for 30 minutes. The black mixture
was filtered through a pad of Celite, and the filtrate was
evaporated to give
4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl
ester as a brown oil (96.0 g, 96.7% yield). The product was used in
the next step without further purification.
[0379] Step 3: To a stirred brown solution of
4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl
ester (95.97 g, 233.8 mmol) in methylene chloride (800 mL), was
added trifluoroacetic acid (33.87 mL, 455.9 mmol), and the mixture
was stirred at room temperature overnight. Sat. sodium bicarbonate
(500 mL) was added to the solution, and the mixture was stirred for
10 minutes. The organic layer was separated, dried over magnesium
sulfate, and evaporated to give
4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl
ester as a brown oil (64.36 g, 88% crude yield). The product was
used in the next step without further purification.
[0380] Step 4: A mixture of
4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl
ester (64.36 g, 207.4 mmol), lithium hydroxide (5.96 g, 248.9 mmol)
in methanol (500 mL) and water (250 mL) was stirred with a
mechanical stirrer at room temperature overnight. The methanol was
evaporated, and to the aqueous solution, was added 1 N HCl (300 mL)
to form the precipitate. Ether (350 mL) was added, and the mixture
was stirred at 0.degree. C. for 2 hours. No desired precipitation
was formed. The mixture was evaporated. To the mixture, was added
water (500 mL). The aqueous layer was extracted with ethyl acetate
(5.times.120 mL). The combined organic layers were separated, dried
over magnesium sulfate, and concentrated to give
4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown
oil (56.69 g, 92% yield). The product was used in the next step
without further purification.
[0381] Step 5: A mixture of
4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid (56.57,
190.9 mmol) in methanol (250 mL) and palladium/carbon (5.66 g, 10%
weight) was hydrogenated with a Parr-shaker overnight at 51 psi.
The black mixture was filtered through a pad of Celite, and the
filtrate was evaporated to give a brown oil, which was stirred in
ether (300 mL) overnight. The ether slurry was filtered to give
2-amino-4-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brown
solid (42.0 g, 84% yield). The product was used in the next step
without further purification.
[0382] Step 6: To a stirred solution of
2-amino-4-(tert-butoxycarbonylamino-methyl)-benzoic acid (24.75 g,
92.94 mmol), imidazole (7.59 g, 111.53 mmol) in acetonitrile (300
mL), was added acetyl chloride (7.96 mL, 111.53 mmol), and the
mixture was stirred at room temperature overnight. To the mixture,
was added 3-amino-piperidine-2,6-dione hydrogen chloride (15.30 g,
92.94 mmol), imidazole (12.66 g, 185.89 mmol) and triphenyl
phosphite (29.23 mL, 111.53 mmol), and the mixture was heated to
reflux for 6 hours. The mixture was cooled to room temperature and
the brown mixture was filtered. The filtrate was evaporated and
then purified by flash column chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-7-ylm-
ethyl]-carbamic acid tert-butyl ester as a light yellow solid
(24.57 g, 66% yield); HPLC, Waters Symmetry C.sub.18, 5 .mu.m,
3.9.times.150 mm, 1 mL/min, 240 nm, 10/90 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, grad. to 95/5 in 5 min, kept 5 min, 5.97 min
(99.7%); mp, 240-242.degree. C.; .sup.1HNMR (DMSO-d.sub.6) .delta.
.quadrature.1.29 (brs, 1H, CH from the BOC group), 1.40 (s, 8H, 8CH
from the BOC group), 2.11-2.19 (m, 1H, CHH), 2.56-2.91 (m, 6H,
CHCH.sub.2, CH.sub.3), 4.26 (d, J=6 Hz, 2H, CH.sub.2NH), 5.25 (dd,
J=5, 11 Hz, 1H, CH), 7.35-7.99 (m, 4H, Ar and NHCH.sub.2), 11.02
(s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.97, 23.49,
28.19, 30.60, 43.22, 56.48, 78.00, 118.84, 123.99, 125.41, 126.00,
146.93, 147.55, 155.15, 155.81, 160.29, 169.51, 172.61. LCMS
MH=401; Anal Calcd For C.sub.20H.sub.24N.sub.4O.sub.5: C, 59.99; H,
6.04; N, 13.99. Found: C, 59.78; H, 5.78; N, 13.85.
5.37
3-(7-AMINOMETHYL-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DI-
ONE HYDROGEN CHLORIDE
##STR00053##
[0384] Step 1: To a stirred brown solution of
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-7-ylm-
ethyl]-carbamic acid tert-butyl ester (14.7 g, 36.8 mmol) in
methanol (200 mL) and methylene chloride (200 mL), was added 2 M
HCl in ether (320 mL), and the mixture was stirred overnight. The
solvent was evaporated, and the residue was stirred in ether (100
mL) for 2 hours. The suspension was filtered to give
3-(7-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride as a light yellow solid (13.2 g, 106% crude
yield). The product was used in the next step without further
purification.
[0385] Step 2:
3-(7-Aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydro-chloride (1.00 g) was dissolved in water (100 mL). The
solution was washed with ethyl acetate (2.times.100 mL). The
aqueous layer was evaporated to give
3-(7-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
hydrogen chloride as an off-white solid (0.86 g, 86% yield); HPLC,
Waters Xterra RP 18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm,
Waters LC Module 1, 05/95 CH.sub.3CN/0.1% (HCO.sub.2)NH.sub.4, 6.27
min (98.7%); mp, 313-315.degree. C.; .sup.IHNMR (DMSO-d.sub.6)
.delta. .quadrature.2.17-2.24 (m, 1H, CHH), 2.58-2.89 (m, 6H,
CHCH.sub.2, CH.sub.3), 4.20 (q, J=5 Hz, 2H, ArCH.sub.2), 5.34 (dd,
J=6, 11 Hz, 1H, CH, hiding under the water peak), 7.64-8.09 (m, 3H,
Ar), 8.72 (brs, 3H, ClNH.sub.3), 11.07 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.88, 22.97, 30.57, 41.69, 56.71, 119.61,
125.38, 126.42, 127.25, 141.34, 145.36, 156.66, 159.83, 169.25,
172.57. LCMS MH=301; Anal Calcd For
C.sub.15H.sub.17N.sub.4O.sub.3Cl+1.0H.sub.2O and +0.9HCl: C, 46.48;
H, 5.17; N, 14.45; Cl, 17.38. Found: C, 46.68; H, 5.15; N, 14.32;
Cl, 17.05.
5.38
3-(2,8-DIMETHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00054##
[0387] To a stirred mixture of 2-amino-3-methylbenzoic acid (3.0 g,
20 mmol) and imidazole (1.6 g, 24 mmol) in acetonitrile (30 mL),
was added acetyl chloride (1.7 mL, 24 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(3.3 g, 20 mmol), imidazole (3.0 g, 68 mmol) and triphenyl
phosphite (6.2 mL, 24 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.100 mL), ethyl acetate (2.times.100
mL), sodium hydrogen carbonate (sat, 100 mL) and water (100 mL) to
give a white solid, which was stirred in DMSO (20 mL) at 65.degree.
C. The mixture was polished filtered and washed with DMSO (10 mL).
To the filtrate, was added water (100 mL) to give a suspension. The
suspension was filtered and washed with water (2.times.50 mL) to
give 3-(2,8-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (3.2 g, 56% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 25/75
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 5.85 min (99.6%); mp:
296-298.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.12-2.24
(m, 1H, CHH), 2.51 (s, 3H, CH.sub.3), 2.48-2.74 (m, 2H, 2CHH), 2.66
(s, 3H, CH.sub.3), 2.76-2.91 (m, 1H, CHH), 5.27 (dd, J=6, 11 Hz,
1H, NCH), 7.38 (t, J=8 Hz, 1H, Ar), 7.67 (d, J=7 Hz, 1H, Ar), 7.86
(dd, J=0.6, 8 Hz, 1H, Ar), 11.02 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 16.91, 20.91, 23.80, 30.60, 56.51, 120.23,
123.59, 126.05, 134.72, 134.94, 145.25, 153.82, 160.71, 169.51,
172.62; LCMS: MH=286; Anal Calcd for
C.sub.15H.sub.15N.sub.3O.sub.3+0.2H.sub.2O: C, 62.36; H, 5.37; N,
14.54. Found: C, 62.21; H, 5.31; N, 14.43.
5.39
3-(8-FLUORO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00055##
[0389] To a stirred mixture of 2-amino-3-fluorobenzoic acid (3.0 g,
19 mmol) and imidazole (1.6 g, 23 mmol) in acetonitrile (30 mL),
was added acetyl chloride (1.7 mL, 23 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(3.2 g, 19 mmol), imidazole (2.9 g, 43 mmol) and triphenyl
phosphite (6.1 mL, 23 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give a white solid, which was purified
with preparative HPLC (C18 20/80 CH.sub.3CN/H.sub.2O) to give a
white solid. The white solid in DMSO (20 mL) was heated at
60.degree. C. for 30 minutes. To the solution, was added water (10
mL). The suspension was cooled to room temperature. The suspension
was filtered and washed with DMSO (4 mL) and water (20 mL) to give
3-(8-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (3.11 g, 67% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 4.7 min (99.7%); mp: 305.degree.
C. (decomp); .sup.1H NMR (DMSO-d.sub.6) .delta. 2.16-2.23 (m, 1H,
CHH), 2.43-2.76 (m, 5H, CH.sub.3, 2CHH), 2.79-2.92 (m, 1H, CHH),
5.32 (dd, J=6, 11 Hz, 1H, NCH), 7.46-7.53 (m, 1H, Ar), 7.67-7.73
(m, 1H, Ar), 7.84-7.94 (m, 1H, Ar), 11.06 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.80, 23.67, 30.58, 56.71, 120.04 (d,
J.sub.C-F=19 Hz), 121.71 (d, J.sub.C-F=4 Hz), 122.31, 126.91 (d,
J.sub.C-F=8 Hz), 136.04 (d, J.sub.C-F=12 Hz), 155.93 (d,
J.sub.C-F=254 Hz), 155.93, 159.62 (d, J.sub.C-F=3 Hz), 169.32,
172.57; LCMS: MH=290; Anal Calcd for
C.sub.14H.sub.12N.sub.3O.sub.3F: C, 58.13; H, 4.18; N, 14.53; F,
6.57. Found: C, 57.87; H, 3.94; N, 14.35; F, 6.91.
5.40
3-(8-CHLORO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00056##
[0391] To a stirred mixture of 2-amino-3-chlorobenzoic acid (2.2 g,
13 mmol) and imidazole (1.1 g, 16 mmol) in acetonitrile (30 mL),
was added acetyl chloride (1.1 mL, 16 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(2.3 g, 14 mmol), imidazole (1.9 g, 28 mmol) and triphenyl
phosphite (4.0 mL, 15 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give a white solid, which was stirred in
methanol (50 mL) overnight. The suspension was filtered and washed
with methanol (30 mL) and water (30 mL) to give
3-(8-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (1.5 g, 38% yield): HPLC: Waters Symmetry C18, 5
.mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 25/75 CH.sub.3CN/0.1%
H.sub.3PO.sub.4, 6.51 min (99.6%); mp: 290-292.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 2.16-2.23 (m, 1H, CHH), 2.59-2.69 (m,
5H, CH.sub.3, 2CHH), 2.79-2.87 (m, 1H, CHH), 5.32 (dd, J=5, 11 Hz,
1H, NCH), 7.48 (t, J=8 Hz, 1H, Ar), 7.96-8.02 (m, 2H, Ar), 11.07
(s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.68, 23.75,
30.51, 56.68, 121.87, 125.08, 126.91, 130.03, 134.69, 143.14,
156.14, 159.88, 169.23, 172.51; LCMS: MH=306, 308; Anal Calcd for
C.sub.14H.sub.12N.sub.3O.sub.3Cl: C, 55.00; H, 3.96; N, 13.74; Cl,
11.60. Found: C, 54.73; H, 3.96; N, 13.58; Cl, 11.03.
5.41
3-(8-BROMO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00057##
[0393] To a stirred mixture of 2-amino-3-bromobenzoic acid (1.0 g,
4.6 mmol) and imidazole (0.38 g, 5.5 mmol) in acetonitrile (10 mL),
was added acetyl chloride (0.6 mL, 8.3 mmol) at room temperature.
The mixture was stirred at room temperature overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride
(0.76 g, 4.6 mmol), imidazole (0.7 g, 10 mmol) and triphenyl
phosphite (1.5 mL, 5.6 mmol) and heated to reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered
and washed with water (2.times.50 mL), ethyl acetate (2.times.50
mL), and water (50 mL) to give
3-(8-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (0.34 g, 21% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 25/75
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 9.47 min (99.6%); mp:
307-309.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.16-2.23
(m, 1H, CHH), 2.58-2.67 (m, 2H, 2CHH), 2.68 (s, 3H, CH.sub.3),
2.76-2.92 (m, 1H, CHH), 5.31 (dd, J=5, 11 Hz, 1H, NCH), 7.41 (t,
J=8 Hz, 1H, Ar), 8.04 (dd, J=2, 8 Hz 1H, Ar), 8.15 (dd, J=1, 8 Hz
1H, Ar), 11.07 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
20.73, 23.85, 30.57, 56.76, 121.09, 121.82, 125.86, 127.47, 138.08,
144.23, 156.23, 159.97, 169.29, 172.58; LCMS: MH=350, 352; Anal
Calcd for C.sub.14H.sub.12N.sub.3O.sub.3Br: C, 48.02; H, 3.45; N,
12.00; Br, 22.82. Found: C, 47.74; H, 3.23; N, 11.85; Br,
22.42.
5.42
3-(8-HYDROXY-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00058##
[0395] To a stirred mixture of 2-amino-3-hydroxybenzoic acid (2.0
g, 13.1 mmol) and imidazole (2.0 g, 29.4 mmol) in acetonitrile (30
mL), was added acetyl chloride (2.0 mL, 28.7 mmol) at room
temperature. The mixture was stirred at room temperature overnight.
To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen
chloride (2.2 g, 13.1 mmol), imidazole (2.0 g, 29.4 mmol) and
triphenyl phosphite (4.11 mL, 15.7 mmol) and heated to reflux for
22 hours. To the mixture, was added water (60 mL) and conc HCl
until pH .about.1. The solvent was removed in vacuo. To the
residue, was added water (50 mL). The aqueous layer was extracted
with ethyl acetate (2.times.50 mL). To the aqueous layer, was added
sodium hydrogen carbonate (1.8 g) to pH=7-8, and the mixture was
stirred at room temperature to give a suspension. The suspension
was filtered to give
3-(8-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as an off-white solid (0.6 g, 16% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 3.03 min (99.3%); mp:
266-268.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.10-2.22
(m, 1H, CHH), 2.57-2.72 (m, 5H, CH.sub.3, 2CHH), 2.78-2.92 (m, 1H,
CHH), 5.25 (dd, J=5, 11 Hz, 1H, NCH), 7.19 (dd, J=1, 8 Hz, 1H, Ar),
7.30 (t, J=8 Hz, 1H, Ar), 7.45 (dd, J=1, 8 Hz, 1H, Ar), 9.65 (s,
1H, OH), 11.02 (s, 1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta.
20.92, 23.37, 30.59, 56.45, 115.62, 118.51, 121.19, 127.05, 135.91,
152.34, 153.09, 160.45, 169.52, 172.62; LCMS: MH=288; Anal Calcd
for C14H.sub.13N.sub.3O.sub.4+1H.sub.2O: C, 55.08; H, 4.95; N,
13.76. Found: C, 54.88; H, 4.97; N, 13.77.
5.43
3-(2-METHYL-4-OXO-8-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,-
6-DIONE
##STR00059##
[0397] To a stirred mixture of 2-amino-3-(trifluoromethyl)benzoic
acid (2.0 g, 9.8 mmol) and imidazole (0.8 g, 12 mmol) in
acetonitrile (20 mL), was added acetyl chloride (0.83 mL, 12 mmol)
at room temperature. The mixture was stirred at room temperature
overnight. To the mixture, was added 3-amino-piperidine-2,6-dione
hydrogen chloride (1.6 g, 9.8 mmol), imidazole (1.5 g, 22 mmol) and
triphenyl phosphite (3.1 mL, 12 mmol) and heated to reflux for 22
hours. To the mixture, was added water (60 mL). The suspension was
filtered and washed with water (2.times.50 mL), ethyl acetate
(2.times.50 mL), sodium hydrogen carbonate (sat, 50 mL) and water
(50 mL) to give
3-(2-methyl-4-oxo-8-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-di-
one as a white solid (0.32 g, 10% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 35/65
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 7.57 min (99.8%); mp:
351-353.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.19-2.26
(m, 1H, CHH), 2.59-2.70 (m, 5H, CH.sub.3, 2CHH), 2.81-2.93 (m, 1H,
CHH), 5.34 (dd, J=5, 11 Hz, 1H, NCH), 7.64 (t, J=8 Hz, 1H, Ar),
8.20 (d, J=8 Hz 1H, Ar), 8.31 (d, J=8 Hz, 1H, Ar), 11.09 (s, 1H,
NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 20.67, 24.05, 30.57,
56.84, 121.48, 123.52 (q, J.sub.C-F=274 Hz), 124.77 (q,
J.sub.C-F=30 Hz), 125.98, 130.74, 132.29 (q, J.sub.C-F=5 Hz),
144.20, 156.71, 159.68, 169.28, 172.58; LCMS: MH=340; Anal Calcd
for C15H.sub.12N.sub.3O.sub.3F.sub.3+0.3H.sub.2O+0.1CH.sub.3CN: C,
52.34; H, 3.72; N, 12.45; F, 16.34. Found: C, 52.71; H, 3.52; N,
12.31; F, 15.99.
5.44 3-(8-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00060##
[0399] Step 1: A mixture of 2-amino-3-methylbenzoic acid (2.1 g, 14
mmol) and CDI (1.9 g, 12 mmol) in acetonitrile (25 mL) was stirred
at room temperature for 5 hours. To the suspension, was added
3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol),
triethylamine (7.2 mL, 66 mmol) and acetic acid (8 mL, 132 mmol),
and the mixture was heated to reflux for 16 hours. To the mixture,
was added water (75 mL) and stirred at room temperature for 2
hours. The suspension was filtered and washed with water (50 mL)
and ethyl acetate (20 mL) to give
2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamide as a white
solid (1.9 g, 61% yield): .sup.1H NMR (DMSO-d.sub.6) .delta.
1.92-1.99 (m, 1H, CHH), 2.06 (s, 3H, CH.sub.3), 2.04-2.14 (m, 1H,
CHH), 2.51-2.56 (m, 1H, CHH), 2.73-2.85 (m, 1H, CHH), 4.69-4.78 (m,
1H, NCH), 6.22 (brs, 2H, NH.sub.2), 6.50 (t, J=8 Hz, 1H, Ar), 7.10
(d, J=8 Hz, 1H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H,
NH), 10.83 (s, 1H, NH); LCMS: MH=262.
[0400] Step 2: A stirred solution of
2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamide (0.9 g, 3.4
mmol) and trimethyl orthoformate (4.5 mL) and p-toluene sulfonic
acid (250 mg) in acetonitrile (20 mL) was heated to reflux for
17hours. To the mixture, was added water (75 mL) and stirred for 20
minutes. The suspension was filtered and washed with methanol (20
mL), water (20 mL) and ethyl acetate (20 mL) to give a purple
solid. The solid in NMP (4 mL) was heated at 80.degree. C. for 30
minutes. To the solution, was added water (1 mL), and the mixture
was allowed to cool to room temperature. The suspension was
filtered and washed with water (30 mL) to give
3-(8-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a
light purple solid (660 mg, 72% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 3.07 min (98.6%); mp:
290-292.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.11-2.19
(m, 1H, CHH), 2.56 (s, 3H, CH.sub.3), 2.62-2.93 (m, 3H, CH.sub.2,
CHH), 5.48 (br, 1H, NCH), 7.46 (t, J=8 Hz, 1H, Ar), 7.73 (d, J=8
Hz, 1H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.38 (s, 1H, CH), 11.16 (s,
1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 17.01, 22.53, 30.97,
56.22, 121.36, 123.79, 126.51, 126.86, 135.03, 135.47, 136.39,
145.96, 146.36, 159.97, 169.92, 172.52; LCMS: MH=272; Anal Calcd
for C.sub.14H.sub.13N.sub.3O.sub.3: C, 61.99; H, 4.83; N, 15.49.
Found: C, 61.70; H, 4.68; N, 15.40.
5.45
3-(6,7-DIMETHOXY-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DI-
ONE
##STR00061##
[0402] To a stirred mixture of 2-amino-4,5-dimethoxybenzoic acid
(5.0 g, 25 mmol) and imidazole (2.1 g, 30 mmol) in acetonitrile (50
mL), was added acetyl chloride (2.2 mL, 30 mmol) at room
temperature. The mixture was stirred at room temperature overnight.
To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen
chloride (4.2 g, 25 mmol), imidazole (3.8 g, 56 mmol) and triphenyl
phosphite (7.3 mL, 28 mmol) and heated to reflux for 22 hours. The
suspension was filtered and washed with acetonitrile (50 mL) and
water (2.times.50 mL) to give a solid. The solid was stirred in
sodium hydrogen carbonate (sat, 50 mL), and water (50 mL) for 1
hour. The suspension was filtered and washed with water (2.times.50
mL) and ethyl acetate (30 mL) to give
3-(6,7-dimethoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (5.7 g, 68% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 20/80
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 3.26 min (99.8%); mp: 325.degree.
C. (decomp); .sup.1H NMR (DMSO-d6) .delta. 2.15-2.19 (m, 1H, CHH),
2.56-2.88 (m, 6H, CH.sub.3, CH.sub.2, CHH), 3.85 (s, 3H, CH.sub.3),
3.90 (s, 3H, CH.sub.3), 5.22 (dd, J=5, 11 Hz, 1H, NCH), 7.09 (s,
1H, Ar), 7.35 (s, 1H, Ar), 10.99 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 21.12, 23.21, 30.62, 55.63, 55.97, 56.38,
104.98, 107.31, 113.27, 143.09, 148.40, 153.24, 154.83, 159.76,
169.61, 172.64; LCMS: MH=332; Anal Calcd for
C.sub.16H.sub.17N.sub.3O.sub.5: C, 58.00; H, 5.17; N, 12.68. Found:
C, 57.88; H, 5.06; N, 12.77.
5.46
3-(6,8-DICHLORO-2-METHYL-4-OXO-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIO-
NE
##STR00062##
[0404] To a stirred mixture of 2-amino-3,5-dichlorobenzoic acid
(5.0 g, 24 mmol) and imidazole (1.9 g, 28 mmol) in acetonitrile (60
mL), was added acetyl chloride (2.0 mL, 28 mmol) at room
temperature. The mixture was stirred at room temperature overnight.
To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen
chloride (3.9 g, 24 mmol), imidazole (3.5 g, 52 mmol) and triphenyl
phosphite (6.8 mL, 26 mmol) and heated to reflux for 22 hours. The
suspension was filtered and washed with acetonitrile (30 mL), water
(2.times.30 mL), and ethyl acetate (30 mL) to give
3-(6,8-dichloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
as a white solid (4.65 g, 58% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 40/60
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 4.78 min (100%); mp:
238-240.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta. 2.15-2.22
(m, 1H, CHH), 2.55-2.69 (m, 5H, CH.sub.3, 2CHH), 2.78-2.91 (m, 1H,
CHH), 5.33 (dd, J=6, 11 Hz, 1H, NCH), 7.96 (d, J=2 Hz, 1H, Ar),
8.15 (d, J=2 Hz, 1H, Ar), 11.09 (s, 1H, NH); .sup.13C NMR
(DMSO-d.sub.6) .delta. 20.63, 23.85, 30.54, 56.92, 122.55, 24.24,
130.51, 131.72, 134.38, 142.25, 156.80, 159.07, 169.12, 172.53;
LCMS: MH=340, 342; Anal Calcd for
C.sub.14H.sub.11N.sub.3O.sub.3Cl.sub.2: C, 49.43; H, 3.26; N,
12.35; Cl, 20.84. Found: C, 49.21; H, 3.11; N, 12.30; Cl,
19.43.
5.47
3-(2-METHYL-4-OXO-4H-BENZO[G]OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
##STR00063##
[0406] To a stirred mixture of 3-amino-2-naphtholic acid (5.4 g, 29
mmol) and imidazole (2 g, 29 mmol) in acetonitrile (60 mL), was
added acetyl chloride (2.1 mL, 29 mmol) at room temperature. The
mixture was stirred at room temperature overnight. To the mixture,
was added 3-amino-piperidine-2,6-dione hydrogen chloride (4 g, 25
mmol), imidazole (3.7 g, 54 mmol) and triphenyl phosphite (7.1 mL,
27 mmol) and heated to reflux for 22 hours. The suspension was
filtered and washed with acetonitrile (30 mL), water (2.times.30
mL), and ethyl acetate (30 mL) to give
3-(2-methyl-4-oxo-4H-benzo[g]quinazolin-3-yl)-piperidine-2,6-dione
as a pale white solid (6.3 g, 79% yield): HPLC: Waters Symmetry
C.sub.18, 5 .mu.m, 3.9.times.150 mm, 1 mL/min, 240 nm, 30/70
CH.sub.3CN/0.1% H.sub.3PO.sub.4, 4.59 min (99.7%); mp: 307.degree.
C. (decomp); .sup.1H NMR (DMSO-d6) .delta. 2.17-2.26 (m, 1H, CHH),
2.60-2.94 (m, 6H, CH.sub.3, CH.sub.2, CHH), 5.29 (dd, J=5, 11 Hz,
1H, NCH), 7.55-7.60 (m, 1H, Ar), 7.64-7.69 (m, 1H, Ar), 8.09 (d,
J=8 Hz, 1H, Ar), 8.18-8.20 (m, 2H, Ar), 8.75 (s, 1H, Ar), 11.06 (s,
1H, NH); .sup.13C NMR (DMSO-d.sub.6) .delta. 21.16, 23.60, 30.71,
56.45, 119.52, 123.86, 126.25, 127.47, 127.77, 128.58, 129.24,
129.53, 136.26, 142.20, 153.87, 160.97, 169.70, 172.68; LCMS:
MH=322; Anal Calcd for C.sub.18H.sub.15N.sub.3O.sub.3+0.1H.sub.2O:
C, 66.91; H, 4.74; N, 13.00. Found: C, 66.78; H, 4.76; N,
12.95.
5.48 ASSAYS
[0407] 5.48.1 TNF.alpha. Inhibition Assay in PMBC
[0408] Peripheral blood mononuclear cells (PBMC) from normal donors
are obtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA)
density centrifugation. Cells are cultured in RPMI 1640 (Life
Technologies, Grand Island, N.Y., USA) supplemented with 10%
AB+human serum (Gemini Bio-products, Woodland, Calif., USA), 2 mM
L-glutamine, 100 U/ml penicillin, and 100 .mu.g/ml streptomycin
(Life Technologies).
[0409] PBMC (2.times.10.sup.5 cells) are plated in 96-well
flat-bottom Costar tissue culture plates (Corning, N.Y., USA) in
triplicate. Cells are stimulated with LPS (from Salmonella abortus
equi, Sigma cat. no. L-1887, St. Louis, Mo., USA) at 1 ng/ml final
in the absence or presence of compounds. Compounds provided herein
are dissolved in DMSO (Sigma) and further dilutions are done in
culture medium immediately before use. The final DMSO concentration
in all assays can be about 0.25%. Compounds are added to cells 1
hour before LPS stimulation. Cells are then incubated for 18-20
hours at 37.degree. C. in 5% CO.sub.2, and supernatants are then
collected, diluted with culture medium and assayed for TNF.alpha.
levels by ELISA (Endogen, Boston, Mass., USA). IC.sub.50s are
calculated using non-linear regression, sigmoidal dose-response,
constraining the top to 100% and bottom to 0%, allowing variable
slope (GraphPad Prism v3.02).
[0410] 5.48.2 IL-2 and MIP-3.alpha. Production by T Cells
[0411] PBMC are depleted of adherent monocytes by placing
1.times.10.sup.8 PBMC in 10 ml complete medium (RPMI 1640
supplemented with 10% heat-inactivated fetal bovine serum, 2 mM
L-glutamine, 100 U/ml penicillin, and 100 .mu.g/ml streptomycin)
per 10 cm tissue culture dish, in 37.degree. C., 5% CO.sub.2
incubator for 30-60 minutes. The dish is rinsed with medium to
remove all non-adherent PBMC. T cells are purified by negative
selection using the following antibody (Pharmingen) and Dynabead
(Dynal) mixture for every 1.times.10.sup.8 non-adherent PBMC: 0.3
ml Sheep anti-mouse IgG beads, 15 .mu.l anti-CD16, 15 .mu.l
anti-CD33, 15 .mu.l anti-CD56, 0.23 ml anti-CD19 beads, 0.23 ml
anti-HLA class II beads, and 56 .mu.l anti-CD14 beads. The cells
and bead/antibody mixture is rotated end-over-end for 30-60 minutes
at 4.degree. C. Purified T cells are removed from beads using a
Dynal magnet. Typical yield is about 50% T cells, 87-95% CD3.sup.+
by flow cytometry.
[0412] Tissue culture 96-well flat-bottom plates are coated with
anti-CD3 antibody OKT3 at 5 .mu.g/ml in PBS, 100 .mu.l per well,
incubated at 37.degree. C. for 3-6 hours, then washed four times
with complete medium 100 .mu.l/well just before T cells are added.
Compounds are diluted to 20 times of final in a round bottom tissue
culture 96-well plate. Final concentrations are about 10 .mu.M to
about 0.00064 .mu.M. A 10 mM stock of compounds provided herein is
diluted 1:50 in complete for the first 20.times. dilution of 200
.mu.M in 2% DMSO and serially diluted 1:5 into 2% DMSO. Compound is
added at 10 .mu.l per 200 .mu.l culture, to give a final DMSO
concentration of 0.1%. Cultures are incubated at 37.degree. C., 5%
CO.sub.2 for 2-3 days, and supernatants analyzed for IL-2 and
MIP-3.alpha. by ELISA (R&D Systems). IL-2 and MIP-3.alpha.
levels are normalized to the amount produced in the presence of an
amount of a compound provided herein, and EC.sub.50s calculated
using non-linear regression, sigmoidal dose-response, constraining
the top to 100% and bottom to 0%, allowing variable slope (GraphPad
Prism v3.02).
[0413] 5.48.3 Cell Proliferation Assay
[0414] Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the
Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH
(Braunschweig, Germany). The cell line KG-1 is obtained from the
American Type Culture Collection (Manassas, Va., USA). Cell
proliferation as indicated by .sup.3H-thymidine incorporation is
measured in all cell lines as follows.
[0415] Cells are plated in 96-well plates at 6000 cells per well in
media. The cells are pre-treated with compounds at about 100, 10,
1, 0.1, 0.01, 0.001, 0.0001 and 0 .mu.M in a final concentration of
about 0.25% DMSO in triplicate at 37.degree. C. in a humidified
incubator at 5% CO.sub.2 for 72 hours. One microcurie of
.sup.3H-thymidine (Amersham) is then added to each well, and cells
are incubated again at 37.degree. C. in a humidified incubator at
5% CO.sub.2 for 6 hours. The cells are harvested onto UniFilter
GF/C filter plates (Perkin Elmer) using a cell harvester (Tomtec),
and the plates are allowed to dry overnight. Microscint 20
(Packard) (25 .mu.l/well) is added, and plates are analyzed in
TopCount NXT (Packard). Each well is counted for one minute.
Percent inhibition of cell proliferation is calculated by averaging
all triplicates and normalizing to the DMSO control (0%
inhibition). Each compound is tested in each cell line in three
separate experiments. Final IC.sub.50s are calculated using
non-linear regression, sigmoidal dose-response, constraining the
top to 100% and bottom to 0%, allowing variable slope. (GraphPad
Prism v3.02).
[0416] 5.48.4 Immunoprecipitation and Immunoblot
[0417] Namalwa cells are treated with DMSO or an amount of a
compound provided herein for 1 hour, then stimulated with 10 U/ml
of Epo (R&D Systems) for 30 minutes. Cell lysates are prepared
and either immunoprecipitated with Epo receptor Ab or separated
immediately by SDS-PAGE. Immunoblots are probed with Akt,
phospo-Akt (Ser473 or Thr308), phospho-Gab1 (Y627), Gab1, IRS2,
actin and IRF-1 Abs and analyzed on a Storm 860 Imager using
ImageQuant software (Molecular Dynamics).
[0418] 5.48.5 Cell Cycle Analysis
[0419] Cells are treated with DMSO or an amount of a compound
provided herein overnight. Propidium iodide staining for cell cycle
is performed using CycleTEST PLUS (Becton Dickinson) according to
manufacturer's protocol. Following staining, cells are analyzed by
a FACSCalibur flow cytometer using ModFit LT software (Becton
Dickinson).
[0420] 5.48.6 Apoptosis Analysis
[0421] Cells are treated with DMSO or an amount of a compound
provided herein at various time points, then washed with annexin-V
wash buffer (BD Biosciences). Cells are incubated with annexin-V
binding protein and propidium iodide (BD Biosciences) for 10
minutes. Samples are analyzed using flow cytometry.
[0422] 5.48.7 Luciferase Assay
[0423] Namalwa cells are transfected with 4 .mu.g of API-luciferase
(Stratagene) per 1.times.10.sup.6 cells and 3 .mu.l Lipofectamine
2000 (Invitrogen) reagent according to manufacturer's instructions.
Six hours post-transfection, cells are treated with DMSO or an
amount of a compound provided herein. Luciferase activity is
assayed using luciferase lysis buffer and substrate (Promega) and
measured using a luminometer (Turner Designs).
[0424] 5.48.8 Anti-Proliferation Assay
[0425] Day 1: The cells are seeded to 96-well plate with 50 ul/well
in 10% FBS RPMI (w/ Glutamine, w/o pen-strip) for overnight. The
following cells are used:
[0426] Colorectal cancer cell: Colo 205 3200 cells/well; positive
control irinotecan
[0427] Pancreatic cancer cell: BXPC-3 1200 cells/well; positive
control gemcitabine
[0428] Prostate cancer cell: PC3 1200 cells/well; positive control
docetaxel
[0429] Breast cancer cell: MDA-MB-231 2400 cells/well; positive
control paclitaxel
[0430] Day 2: The compounds are serially diluted from 0.00001
.mu.m-10 .mu.m (or 0.000001.about.1 .mu.M) with 50 .mu.l/well (of
2.times.) and added to the plates in duplicate with relative
positive control. The plates were then incubated at 37.degree. C.
for 72 hours.
[0431] Day 5: The results are detected by CellTiter Glo method. 100
.mu.l/well of CellTiter
[0432] Glo reagent is added to the plates and incubated for 10
minutes at room temperature, and then analyzed on the Top Count
reader. The IC.sub.50 of each compound is typically based on the
result of two or more individually experiments.
5.49 TNF.alpha. INHIBITION
[0433] Abilities of certain compounds for inhibiting TNF.alpha.
were determined using procedures substantially similar to those
described in Section 5.48.1, above.
[0434] The tested compounds included:
3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(2,7-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(6,7-dimethoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(8-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(8-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(2-methyl-4-oxo-8-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-di-
one; heptanoic acid
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylm-
ethyl]-amide; cyclopropanecarboxylic acid
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylm-
ethyl]-amide;
2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-di-
hydro-quinazolin-6-ylmethyl]-acetamide;
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-hexyl-urea;
1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-di-
hydro-quinazolin-6-ylmethyl]-urea;
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-m-tolyl-urea;
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3 -(4-trifluoromethoxy-phenyl)-urea;
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethyl-sulfanyl-benzamide;
1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-o-
xo-3,4-dihydro-quinazolin-6-ylmethyl]-urea;
4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quina-
zolin-6-ylmethyl]-benzamide;
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-trifluoromethyl-benzamide;
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethoxy-benzamide;
3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-q-
uinazolin-5-ylmethyl]-benzamide; and
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethyl-benzamide. From the tests, it was
determined that IC.sub.50 values of the tested compounds were in
the range of 0.01 to 25 .mu.M.
5.50 IL-2 PRODUCTION
[0435] Abilities of certain compounds for stimulating the
production of IL-2 were determined using procedures substantially
similar to those described in Section 5.48.2, above.
[0436] The tested compounds included:
3-(6-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(6-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-hexyl-urea; and 1-[3 -(2,6-dioxo-piperidin-3
-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluorometh-
oxy-phenyl)-urea. From the tests, it was determined that EC.sub.50
values of the tested compounds were in the range of 0.1 to 3.5
.mu.M.
5.51 CELL PROLIFERATION
[0437] Abilities of certain compounds for inhibiting proliferation
of Namalwa AG4 cells were determined using procedures substantially
similar to those described in Section 5.48.3, above.
[0438] The tested compounds included:
3-(6-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;
heptanoic acid
[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylm-
ethyl]-amide;
2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-di-
hydro-quinazolin-6-ylmethyl]-acetamide;
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-hexyl-urea;
1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-di-
hydro-quinazolin-6-ylmethyl]-urea;
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-m-tolyl-urea;
1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-(4-trifluoromethoxy-phenyl)-urea;
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethyl-sulfanyl-benzamide;
1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-o-
xo-3,4-dihydro-quinazolin-6-ylmethyl]-urea;
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-3-trifluoromethyl-benzamide;
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethoxy-benzamide;
3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-q-
uinazolin-5-ylmethyl]-benzamide; and
N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-y-
lmethyl]-4-trifluoromethyl-benzamide. From the tests, it was
determined that IC.sub.50 values of the tested compounds were in
the range of 0.01 to 5.5 .mu.M.
[0439] The embodiments of the invention described above are
intended to be merely exemplary, and those skilled in the art will
recognize, or will be able to ascertain using no more than routine
experimentation, numerous equivalents of specific compounds,
materials, and procedures. All such equivalents are considered to
be within the scope of the invention and are encompassed by the
appended claims.
[0440] All of the patents, patent applications and publications
referred to herein are incorporated herein in their entireties.
Citation or identification of any reference in this application is
not an admission that such reference is available as prior art to
this invention. The full scope of the invention is better
understood with reference to the appended claims.
* * * * *