U.S. patent application number 17/108368 was filed with the patent office on 2021-03-25 for methods and use of compounds that bind to rela of nf-kb.
This patent application is currently assigned to Cedars-Sinai Medical Center. The applicant listed for this patent is Cedars-Sinai Medical Center. Invention is credited to Hirotaka KANZAKI, Ramachandran MURALI.
Application Number | 20210085649 17/108368 |
Document ID | / |
Family ID | 1000005251787 |
Filed Date | 2021-03-25 |
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United States Patent
Application |
20210085649 |
Kind Code |
A1 |
MURALI; Ramachandran ; et
al. |
March 25, 2021 |
METHODS AND USE OF COMPOUNDS THAT BIND TO RELA OF NF-KB
Abstract
The invention provides methods and agents that modulate RelA
activity. These methods and modulators of RelA activity can be used
to treat cancer progression of basal-like breast cancer, such as
triple-negative breast cancer.
Inventors: |
MURALI; Ramachandran;
(Beverly Hills, CA) ; KANZAKI; Hirotaka; (Okayama,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cedars-Sinai Medical Center |
Los Angeles |
CA |
US |
|
|
Assignee: |
Cedars-Sinai Medical Center
Los Angeles
CA
|
Family ID: |
1000005251787 |
Appl. No.: |
17/108368 |
Filed: |
December 1, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15828097 |
Nov 30, 2017 |
10881641 |
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17108368 |
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PCT/US2016/035318 |
Jun 1, 2016 |
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15828097 |
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62169466 |
Jun 1, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4164 20130101;
A61P 35/00 20180101; A61K 31/4174 20130101; A61K 31/04 20130101;
A61K 31/403 20130101; A61K 31/428 20130101; A61K 31/10 20130101;
A61K 31/5375 20130101; A61K 31/445 20130101; A61K 31/495
20130101 |
International
Class: |
A61K 31/4174 20060101
A61K031/4174; A61K 31/4164 20060101 A61K031/4164; A61K 31/495
20060101 A61K031/495; A61P 35/00 20060101 A61P035/00; A61K 31/04
20060101 A61K031/04; A61K 31/10 20060101 A61K031/10; A61K 31/403
20060101 A61K031/403; A61K 31/428 20060101 A61K031/428; A61K 31/445
20060101 A61K031/445; A61K 31/5375 20060101 A61K031/5375 |
Claims
1. A method for inhibiting or decreasing or reducing RelA activity
in a subject in need thereof, the method comprising administering
to the subject a therapeutically effective amount of: (a) a
compound of Formula I: ##STR00023## wherein: a is 0, 1, 2 or 3;
R.sup.11 and R.sup.12 can be same or different, and are
independently hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl,
heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; R.sup.13 is independently for
each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl,
cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted; R.sup.14 is hydrogen, alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; and
stereoisomers and pharmaceutically acceptable salts thereof, (b) a
compound of Formula (II): ##STR00024## wherein: b and g can be same
or different and are independently 0, 1, 2, 3, 4 or 5; d is 0, 1 or
2; f is 0, 1, 2, 3 or 4; R.sup.21, R.sup.24 and R.sup.25 can be all
same or all different or two same and one different, and
independently for each occurrence hydrogen, alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; R.sup.22 is
independently for each occurrence alkyl, alkenyl, alkynyl, halogen,
aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted, or two R.sup.22 together with
the carbon atoms they are attached to form an optionally
substituted 5-8 membered cyclyl, heterocylyl, aryl or heteroaryl;
R.sup.23 is hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl,
heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; and stereoisomers and
pharmaceutically acceptable salts thereof (c) a compound of Formula
(III): ##STR00025## wherein: h is 0, 1, 2, 3 or 4; j is 0, 1, 2, 3
or 4; k is 0, 1, 2, 3 or 4; R.sup.31, R.sup.32 and R.sup.33 can all
be same or all different or two are same, and are independently for
each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl,
cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted; and stereoisomers and pharmaceutically
acceptable salts thereof, (d) a compound of Formula (IV):
##STR00026## wherein: m is 0, 1, 2, or 3; n is 0, 1, 2, 3 or 4;
R.sup.41 is hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl,
heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; R.sup.42 is independently for
each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl,
cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted; R.sup.43 is hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted; R.sup.44, R.sup.45 and R.sup.46 can be same
or different, and are independently for each occurrence absent,
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,
heterocyclyl, aralkyl, sulfinyl, sulfonyl, carbonyl, carboxy,
thiocabonyl, thio, alkylthio, arylthio or CF.sub.3, each of which
can be optionally substituted, provided that at least one of
R.sup.44 and R.sup.46 is not absent; R.sup.47 is independently for
each occurrence alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl,
cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted; and stereoisomers and pharmaceutically
acceptable salts thereof, or (e) a compound of Formula (V):
##STR00027## wherein: p and q are same or different and are
independently 0, 1, 2, or 3; R.sup.51 is hydrogen, alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; R.sup.52 is
independently for each occurrence alkyl, alkenyl, alkynyl, halogen,
aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; R.sup.53, R.sup.54 and
R.sup.55 can be all same, all different or two are same, and are
independently for each occurrence hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, sulfinyl,
sulfonyl, carbonyl, carboxy, thiocabonyl, thio, alkylthio, arylthio
or CF.sub.3, each of which can be optionally substituted; R.sup.56
is independently for each occurrence alkyl, alkenyl, alkynyl,
halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy,
cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; and stereoisomers and
pharmaceutically acceptable salts thereof.
2. The method of claim 1, wherein the subject is need of treatment
for a cancer or a cancerous condition or a tumor.
3. The method of 1, wherein the compound is selected from the group
consisting of: ##STR00028##
4. The method of claim 2, further comprising the step of selecting
the subject having a cancer, a cancerous condition, or a tumor.
5. The method of claim 4, wherein the cancer is a breast cancer,
squamous cell cancer, lung cancer, a cancer of the peritoneum, a
hepatocellular cancer, a gastric cancer, a pancreatic cancer, a
glioblastoma, a cervical cancer, an ovarian cancer, a liver cancer,
a bladder cancer, a hepatoma, a colon cancer, a colorectal cancer,
an endometrial or uterine carcinoma, a salivary gland carcinoma, a
kidney or renal cancer, a prostate cancer, a vulval cancer, a
thyroid cancer, a head and neck cancer, a B-cell lymphoma, a
chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia
(ALL), a Hairy cell leukemia, or a chronic myeloblasts
leukemia.
6. The method of claim 5, wherein the cancer is a breast
cancer.
7. The method of claim 6 wherein the cancer is a triple negative
breast cancer.
8. The method of claim 2, further comprising administering one or
more additional anti-cancer therapies.
9. The method of claim 8, wherein the additional anti-cancer
therapy comprises surgery, radiation therapy, biotherapy,
immunotherapy, or chemotherapy.
10. The method of claim 2, further comprising administering one or
more anti-cancer therapeutic agents.
11. The method of claim 10, wherein the anti-cancer therapeutic
agent is a chemotherapeutic agent, a growth inhibitor agent, an
anti-angiogenesis agent, a cytotoxic agent, an anti-hormonal agent,
or a cytokine.
12. The method of claim 1, wherein the compound is formulated in a
pharmaceutical composition comprising the compound and a
pharmaceutically acceptable excipient or carrier.
13. The method of claim 1, wherein the compound is formulated in a
nanoparticle.
14. The method of claim 13, wherein the nanoparticle is formulated
in a pharmaceutical composition comprising the nanoparticle and a
pharmaceutically acceptable excipient or carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/828,097, filed Nov. 30, 2017, which is a continuation of PCT
Application No. PCT/US2016/035318, filed Jun. 1, 2016, which claims
benefit under 35 U.S.C. .sctn. 119(e) of U.S. Provisional Patent
Application Ser. No. 61/169,466 filed on Jun. 1, 2015, the contents
of each is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure relates generally to blocking
p65/RelA function of NF-kB, which prevents cancer progression of
basal-like breast cancer, such as triple-negative breast
cancer.
BACKGROUND
[0003] Chemotherapy is the standard treatment for patients with
Triple-negative breast cancer (TNBC). Although it improves the
prognosis, about 30% of the patients die due to resistance to
therapy and metastasis. There are no targeted therapies to improve
these patients. NF-kB is constitutively activated in several
cancers including triple-negative breast cancer, and is responsible
for resistance to therapy. This invention constitutes a new
targeted therapy for cancer, including but not limited to TNBC.
SUMMARY
[0004] Various aspects of the invention disclosed herein are based
on inventors' discovery of molecules that can block RelA transport
from cytoplasm into nucleus and thereby alter gene-expression
profiles. Accordingly, described herein are methods and molecules
for modulating, including but not limited to inhibiting, reducing
and/or decreasing, binding and/or function of RelA mediated gene
expression. In the various aspects describe herein, a compound that
modulates the binding and function of RelA can be of Formula I
##STR00001## [0005] wherein: [0006] a is 0, 1, 2 or 3; [0007]
R.sup.11 and R.sup.12 can be same or different, and are
independently hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl,
heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; [0008] R.sup.13 is
independently for each occurrence alkyl, alkenyl, alkynyl, halogen,
aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; [0009] R.sup.14 is hydrogen,
alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl,
heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy,
nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio,
arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino,
heteroarylamino or CF.sub.3, each of which can be optionally
substituted; and [0010] stereoisomers and pharmaceutically
acceptable salts thereof.
[0011] In the various aspects describe herein, a compound that
blocks or modulate RelA/p65 function can be of Formula II:
##STR00002## [0012] wherein: [0013] b and g can be same or
different and are independently 0, 1, 2, 3, 4 or 5; [0014] d is 0,
1 or 2; [0015] f is 0, 1, 2, 3 or 4; [0016] R.sup.21, R.sup.24 and
R.sup.25 can be all same or all different or two same and one
different, and independently for each occurrence hydrogen, alkyl,
alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl,
carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl,
sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; [0017]
R.sup.22 is independently for each occurrence alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted, or two
R.sup.22 together with the carbon atoms they are attached to form
an optionally substituted 5-8 membered cyclyl, heterocylyl, aryl or
heteroaryl; [0018] R.sup.23 is hydrogen, alkyl, alkenyl, alkynyl,
halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy,
cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; and stereoisomers and
pharmaceutically acceptable salts thereof.
[0019] In the various aspects describe herein, a compound that
blocks or modulate RelA/p65 function can be of Formula III:
##STR00003## [0020] wherein: [0021] h is 0, 1, 2, 3 or 4; [0022] j
is 0, 1, 2, 3 or 4; [0023] k is 0, 1, 2, 3 or 4; [0024] R.sup.31,
R.sup.32 and R.sup.33 can all be same or all different or two are
same, and are independently for each occurrence alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; and
stereoisomers and pharmaceutically acceptable salts thereof.
[0025] In the various aspects describe herein, a compound that
blocks or modulate RelA/p65 function can be of Formula IV:
##STR00004## [0026] wherein: [0027] m is 0, 1, 2, or 3; [0028] n is
0, 1, 2, 3 or 4; [0029] R.sup.41 is hydrogen, alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; [0030]
R.sup.42 is independently for each occurrence alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; [0031]
R.sup.43 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cyclyl, heterocyclyl, hydroxyl, alkoxy, aroxy, nitro, aralkyl,
sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; [0032]
R.sup.44, R.sup.45 and R.sup.46 can be same or different, and are
independently for each occurrence absent, hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, sulfinyl,
sulfonyl, carbonyl, carboxy, thiocabonyl, thio, alkylthio, arylthio
or CF.sub.3, each of which can be optionally substituted, provided
that at least one of R.sup.44 and R.sup.46 is not absent; [0033]
R.sup.47 is independently for each occurrence alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted; and [0034]
stereoisomers and pharmaceutically acceptable salts thereof.
[0035] In the various aspects describe herein, a compound that
modulates the binding and function of RelA can be of Formula V:
##STR00005## [0036] wherein: [0037] p and q are same or different
and are independently 0, 1, 2, or 3; [0038] R.sup.51 is hydrogen,
alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl,
heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy,
nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio,
arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino,
heteroarylamino or CF.sub.3, each of which can be optionally
substituted; [0039] R.sup.52 is independently for each occurrence
alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, cyclyl,
heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy, aroxy,
nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio,
arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino,
heteroarylamino or CF.sub.3, each of which can be optionally
substituted; [0040] R.sup.53, R.sup.54 and R.sup.55 can be all
same, all different or two are same, and are independently for each
occurrence hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cyclyl, heterocyclyl, aralkyl, sulfinyl, sulfonyl, carbonyl,
carboxy, thiocabonyl, thio, alkylthio, arylthio or CF.sub.3, each
of which can be optionally substituted; [0041] R.sup.56 is
independently for each occurrence alkyl, alkenyl, alkynyl, halogen,
aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted; and [0042] stereoisomers and
pharmaceutically acceptable salts thereof.
[0043] It is noted that the carbon to which N(R.sup.54)(R.sup.56)
is attached can be in the R or S configuration. Accordingly, in
some embodiments, the carbon to which N(R.sup.54)(R.sup.56) is
attached in the R configuration. In some other embodiments, the
carbon to which N(R.sup.54)(R.sup.56) is attached in the S
configuration.
[0044] In some embodiments of the various aspects described herein,
the compound that modulates the binding and/or function of RelA and
blocks nuclear translocalization is selected from the group
consisting of CRL1101, having the structure:
##STR00006##
CRL1102, having the structure:
##STR00007##
CRL11021, having the structure:
##STR00008##
CRL1103, having the structure:
##STR00009##
CRL1104, having the structure:
##STR00010##
and CRL11041, having the structure:
##STR00011##
[0045] In some aspects, described herein are methods of modulating
binding and/or function of RelA blocks nuclear translocation. The
method generally comprising contacting a compound of Formula I, II,
III, IV or V with the RelA.
[0046] In some aspects, described herein are methods of modulating,
e.g., inhibiting or reducing or decreasing, binding and/or function
of RelA blocks nuclear translocation in a subject in need thereof.
Such methods comprise administering to a subject a therapeutically
effective amount of a compound of Formula, I, II, III, IV or V.
[0047] In other aspects, described herein are methods of treating,
inhibiting, reducing severity of, slowing progression of and/or
preventing metastasis of a cancer or a cancerous condition by
modulating RelA activity. Such methods comprise administering to a
subject having a cancer or cancerous condition a therapeutically
effective amount of a compound of Formula I, II, III, IV or V
described herein.
[0048] In some embodiments of the various aspects described herein,
the methods further comprise the step of selecting the subject
having a cancer, a cancerous condition, or a tumor.
[0049] In some embodiments of these methods, the cancer is a breast
cancer, squamous cell cancer, lung cancer, a cancer of the
peritoneum, a hepatocellular cancer, a gastric cancer, a pancreatic
cancer, a glioblastoma, a cervical cancer, an ovarian cancer, a
liver cancer, a bladder cancer, a hepatoma, a colon cancer, a
colorectal cancer, an endometrial or uterine carcinoma, a salivary
gland carcinoma, a kidney or renal cancer, a prostate cancer, a
vulval cancer, a thyroid cancer, a head and neck cancer, a B-cell
lymphoma, a chronic lymphocytic leukemia (CLL); an acute
lymphoblastic leukemia (ALL), a Hairy cell leukemia, or a chronic
myeloblastic leukemia. In some such embodiments, the cancer is a
breast cancer. In some embodiments, the cancer is triple negative
breast cancer.
[0050] Some embodiments of these methods can further comprise
administration or treatment with one or more additional anti-cancer
therapies. In some such embodiments, the additional anti-cancer
therapy comprises surgery, radiation therapy, biotherapy,
immunotherapy, chemotherapy, or any combination thereof.
[0051] Some embodiments of these methods can further comprise
administration or treatment with one or more anti-cancer
therapeutic agents. In some such embodiments, the anti-cancer
therapeutic agent is a chemotherapeutic agent, a growth inhibitor
agent, an anti-angiogenesis agent, a cytotoxic agent, an
anti-hormonal agent, a prodrug, or a cytokine.
[0052] Also provided herein are pharmaceutical compositions
comprising a compound of Formula I, II, III, IV or V, and a
pharmaceutically acceptable excipient or carrier. Such
pharmaceutical composition can be used for blocking RelA/p65
function in a subject in need thereof.
[0053] In some aspects, pharmaceutical compositions comprising a
compound of Formula I, II, III, IV or V are provided for use in
treating, inhibiting, reducing severity of, slowing progression of
and/or preventing metastasis of a cancer or a cancerous condition
by blocking or modulating RelA/p65 function or activity.
[0054] In some embodiments of these aspects and all such aspects
described herein, the use further comprises the step of selecting
the subject having a cancer, a cancerous condition, or a tumor. In
some such embodiments, the cancer is a breast cancer, squamous cell
cancer, lung cancer, a cancer of the peritoneum, a hepatocellular
cancer, a gastric cancer, a pancreatic cancer, a glioblastoma, a
cervical cancer, an ovarian cancer, a liver cancer, a bladder
cancer, a hepatoma, a colon cancer, a colorectal cancer, an
endometrial or uterine carcinoma, a salivary gland carcinoma, a
kidney or renal cancer, a prostate cancer, a vulval cancer, a
thyroid cancer, a head and neck cancer, a B-cell lymphoma, a
chronic lymphocytic leukemia (CLL); an acute lymphoblastic leukemia
(ALL), a Hairy cell leukemia, or a chronic myeloblastic leukemia.
In some such embodiments, the cancer is a breast cancer.
[0055] In some embodiments of these aspects and all such aspects
described herein, the use further comprises one or more additional
anti-cancer therapies. In some such embodiments, the additional
anti-cancer therapy comprises surgery, radiation therapy,
biotherapy, immunotherapy, or chemotherapy.
[0056] In some embodiments of these aspects and all such aspects
described herein, the use further comprises one or more anti-cancer
therapeutic agents. In some such embodiments, the anti-cancer
therapeutic agent is a chemotherapeutic agent, a growth inhibitor
agent, an anti-angiogenesis agent, a cytotoxic agent, an
anti-hormonal agent, a prodrug, or a cytokine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0057] FIG. 1A shows TNBC Biological activity of CRL1101 in
triple-negative breast cancer cell lines. CRL1011 significantly
(IC50=20,uM) inhibited all the three TNBC cell line proliferation
as measured by calorimetric assay (MTT).
[0058] FIG. 1B shows the inhibition of tumor growth by anchorage
independent growth assay. The effects of CRL1101 on clonogenic
survival were analyzed. Base layers consisting of growth medium
containing 0.53% low-melting point agarose (Invitrogen) were poured
onto 6-well plates and allowed to solidify. Cells were seeded at
concentration of 10000/well in triplicate in top layers consisting
of growth medium containing 0.32% agarose. After 24 hours, 15,uM of
CRL1101 was added. Cells were incubated for 14 days to form visible
colonies. The colonies were fixed and stained by 0.05% Crystal
violet in 50% methanol.
[0059] FIG. 2 shows the nuclear localization of RelA in TNBC cell
lines by Immunofluorescent staining. Cells were grown in Dulbecco's
modified Eagle medium supplemented with 10% heat-inactivated fetal
calf serum and 1% (w/v) penicillin/streptomycin (all purchased from
Mediatech Inc, Manassas, Va., USA). Cells were treated with or
without 20 mM of CRL1101 in 1% DMSO. Forty five minutes after
treatment, cells were fixed with 4% formaldehyde for 10 min and
sequentially treated with 0.1% Triton X 100 for 10 min. Cells were
blocked in 1% BSA in PBS for 10 min. cells were incubated with
anti-Re/A(p65) antibody (1:150, Abeam, Cambridge, UK) in PBS with
1% BSA overnight at 4.degree. C. and a secondary antibody (1:1000
anti-rabbit Alexa 488, Invitrogen, Carlsbad, Calif., USA) for 1 hr
in the dark. Analyses were performed using a microscope (Nikon
ECLIPSE Ti-U, Nikon, Tokyo, JAPAN). Green signal shows RelA(p65),
blue signal shows DAPI.
[0060] FIG. 3 shows tumor growth mediated by MD-MBA-231 cells
assessed in athymic mice. Mice were administrated 25 mg/kg/day of
CRL1101 or vehicle IP, as indicated by arrows. Results are given as
mean tumor volume +-s.e. Tumor growth in animals treated with
CRL1101 was significant (p<0.001) compared to vehicle. N=6.
DETAILED DESCRIPTION
[0061] Described herein are compounds, compositions and methods
that modulate or block RelA/p65 function or activity. The inventors
have discovered small molecule compounds of Formula I, II, III, IV
and V that modulate RelA nuclear translocalization and can be used
to treat and inhibit proliferative disorders and metastasis such as
cancer.
[0062] RelA, also known as p65, is a REL-associated protein
involved in NF-.kappa.B heterodimer formation, nuclear
translocation and activation. NF-.kappa.B is an essential
transcription factor complex involved in all types of cellular
processes, including cellular metabolism, chemotaxis, etc.
Phosphorylation and acetylation of RELA are crucial
post-translational modifications required for NF-.kappa.B
activation. RELA has also been shown to modulate immune responses,
and activation of RELA in the nucleus is positively associated with
multiple types of cancer.
[0063] As the prototypical heterodimer complex member of the
NF-.kappa.B, together with p50, RELA/p65 interacts with various
proteins in both the cytoplasm and in the nucleus during the
process of classical NF-.kappa.B activation and nuclear
translocation. In the inactive state, RELA/p50 complex is mainly
sequestered by I.kappa.B.alpha. in the cytosol. TNF.alpha., LPS and
other factors serve as activation inducers, followed by
phosphorylation at residue 32 and 36 of I.kappa.B.alpha., leading
to rapid degradation of I.kappa.B.alpha. via the
ubiquitin-proteasomal system and subsequent release of RELA/p50
complex. RELA nuclear localization signal used to be sequestered by
I.kappa.B.alpha. is now exposed, and rapid translocation of the
NF-.kappa.B occurs. After NF-.kappa.B nuclear localization due to
TNF stimulation, p50/RELA heterodimer can function as a
transcription factor and bind to a variety of genes involved in all
kinds of biological processes, such as leukocyte
activation/chemotaxis, negative regulation of TNF/IKK pathway,
cellular metabolism, antigen processing, just to name a few.
Phosphorylation of RELA at different residues also enables its
interaction with CDKs and P-TEFb. Phosphorylation at serine 276 in
RELA allows its interaction with P-TEFb containing CDK-9 and cyclin
T1 subunits, and phospho-ser276 RELA-P-TEFb complex is necessary
for IL-8 and Gro-.beta. activation. Another mechanism is involved
in the activation of genes preloaded with Pol II in a RELA ser 276
phosphorylation independent manner.
[0064] NF-.kappa.B/RELA activation has been found to be correlated
with cancer development, suggesting the potential of RELA as a
cancer biomarker. Specific modification patterns of RELA have also
been observed in many cancer types. There is both a physical and a
functional association between RELA and aryl hydrocarbon receptor
(AhR), and the subsequent activation of c-myc gene transcription in
breast cancer cells. Prior art has also reported interactions
between estrogen receptor (ER) and NF-.kappa.B members, including
p50 and RELA. It has been shown that ER.alpha. interacts with both
p50 and RELA in vitro and in vivo, and RELA antibody can reduce
ER.alpha.:ERE complex formation.
[0065] RELA can also have a potential role as biomarker for breast,
prostate and pancreatic cancers progression and metastases, as
suggested by the association found between RELA nuclear
localization and prostate cancer aggressiveness and biochemical
recurrence. Strong correlation between nuclear localization of RELA
and clinicopathological parameters for papillary thyroid carcinoma
(PTC), has suggested a role for NF-.kappa.B activation in tumor
growth and aggressiveness in PTC. Nuclear localization of
NF-.kappa.B/RELA has been correlated with tumor micrometastases
into lymph and blood and negatively correlated with patient
survival outcome in patients with head and neck squamous cell
carcinoma (HNSCC).
[0066] Inventors have discovered modulators of RelA and have shown
that blocking RelA/p65 nuclear translocation using these compounds
can prevent cancer growth and metastasis. Thus, in embodiments of
the various aspects described herein, the compounds of Formula I,
II, III, IV or V can inhibit or reduce RelA nuclear localization
and thereby prevent transcription activation.
[0067] In embodiments of the various aspects disclosed herein, a
modulator of RelA function or activity can be a compound of Formula
I
##STR00012##
[0068] In compounds of Formula I, variable a can be 0, 1, 2, or 3.
In some embodiments of the various aspects described herein, a is
0.
[0069] In compounds of Formula I, R.sup.11 and R.sup.12 are
independently hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl,
heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted with 1, 2, 3, 4, or 5
substituents. Without limitations, R.sup.11 and R.sup.12 can be
same or different. In some embodiments, R.sup.11 and R.sup.12 are
same. In some other embodiments, R.sup.11 and R.sup.12 are
different.
[0070] In various embodiments, R.sup.11 and R.sup.12 can be
selected independently from hydrogen, halogen, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, acyl, thiol, hydroxyl,
carboxylic acid, trifluormethyl, amino, C.sub.1-C.sub.6alkylamino,
di(C.sub.1-C.sub.6alkyl)amino, or --CO.sub.2(C.sub.1-C.sub.6alkyl).
In some embodiments, R.sup.11 and R.sup.12 can be selected
independently from halogen, nitro, cyano, trifluoromethyl,
carboxylic acid, or amino.
[0071] In some embodiments, R.sup.11 is a halogen. Exemplary
halogens for R.sup.11 are fluoro, bromo or chloro. In one
embodiment, R.sup.11 is fluoro.
[0072] In various embodiments, R.sup.12 can be selected from
hydrogen, nitro, cyano, trifluoromethyl, carboxylic acid, amino,
C.sub.1-C.sub.6alkylamino, or C.sub.1-C.sub.6dialkylamino. In some
embodiments, R.sup.12 is nitro, cyano or trifluromethyl. In one
embodiment, R.sup.12 is nitro.
[0073] In some embodiments, R.sup.11 is halogen and R.sup.12 is
nitro. In one embodiment, R.sup.11 is fluoro and R.sup.12 is
nitro.
[0074] In various embodiments, R.sup.13 can be selected
independently for each occurrence from alkyl, alkenyl, alkynyl,
halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy,
cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted with 1, 2, 3, 4, or 5
substituents. In some embodiments, R.sup.13 is selected
independently for each occurrence from halo, nitro, cyano,
trifluoromethyl, amino, C.sub.1-C.sub.6alkylamino, or
di(C.sub.1-C.sub.6alkyl)amino.
[0075] The substituent R.sup.14 can be hydrogen, alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted with 1, 2, 3,
4 or 5 substituents. In some embodiments, R.sup.14 is a
C.sub.1-C.sub.6 alkyl group substituted with 1, 2, 3, 4 or 5
substituents. In some embodiments, R.sup.14 is a C.sub.1-C.sub.6
alkyl group substituted with 1 or 2 cyclyl, heterocyclyl, aryl, or
heteroaryl groups, each of which can be optionally substituted. In
some embodiments, R.sup.14 is a C.sub.1-C.sub.6 alkyl group
substituted with an optionally substituted heterocylyl. In some
embodiments, the optionally substituted heterocylyl is morpholine.
In one embodiment, R.sup.14 is 3-morpholinopropyl.
[0076] In some embodiments, a compound of Formula I is CRL1101,
having the structure:
##STR00013##
[0077] In various aspects described herein, a modulator of RelA
function or activity can be a compound of Formula II
##STR00014##
[0078] In compounds of Formula II, b and g are independently 0, 1,
2, 3, 4 or 5. In various embodiments, b can be 0, 1 or 2. In some
embodiments, b is 0. Likewise, g can be 0, 1 or 2 in the various
embodiments. In some embodiments, g is 0. Without limitations, b
and g can be same or different. In some embodiments, b and g are
same. In one embodiment, b and g are both 0.
[0079] Variable d in compounds of Formula II can be 0, 1 or 2. In
some embodiments, d is 0 or 1. In one embodiment, d is 0.
[0080] In compounds of Formula II, f can be 0, 1, 2, 3 or 4. In
various embodiments, f can be 0, 1 or 2. In some embodiments, f is
0 or 1. In one embodiment, f is 0.
[0081] In some embodiments, b, d, f and g are independently 0 or 1.
In one embodiment, b, d, f and g all are 0.
[0082] In compounds of Formula II, R.sup.21, R.sup.24 and R.sup.25
are independently for each occurrence hydrogen, alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted with 1, 2, 3,
4, or 5 substituents. In some embodiments, R.sup.21, R.sup.24 and
R.sup.25 are selected independently, for each occurrence, from
halogen, nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
acyl, thiol, hydroxyl, carboxylic acid, trifluormethyl, amino,
C.sub.1-C.sub.6alkylamino, di(C.sub.1-C.sub.6alkyl)amino, or
--CO.sub.2(C.sub.1-C.sub.6alkyl). Without limitations, R.sup.21,
R.sup.24 and R.sup.25, when present, can be same, all different, or
some same and some different.
[0083] In some embodiments, R.sup.21 and R.sup.24 are same. In some
embodiments, R.sup.21 and R.sup.25 are same. In some embodiments,
R.sup.24 and R.sup.25 are same. In some embodiments, R.sup.21 and
R.sup.24 are different. In some embodiments, R.sup.21 and R.sup.25
are different. In some embodiments, R.sup.24 and R.sup.25 are
different.
[0084] In various embodiments, each R.sup.22 can be selected
independently from alkyl, alkenyl, alkynyl, halogen, aryl,
heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted with 1, 2, 3, 4 or 5
substituents. In some embodiments, when d is 2, the two R.sup.22
groups with the carbon atoms they are attached to form a 5-8
membered cyclyl, heterocylyl, aryl or heteroaryl, each of which can
be optionally substituted with 1, 2, 3 or 4 substituents.
[0085] In compounds of Formula II, R.sup.23 can be selected from
hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl,
cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted with 1, 2, 3, 4, or 5 substituents. In some
embodiments, R.sup.23 can be selected from hydrogen, halogen,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, acyl,
thiol, hydroxyl, carboxylic acid, trifluormethyl, amino,
C.sub.1-C.sub.6alkylamino, di(C.sub.1-C.sub.6alkyl)amino, or
--CO.sub.2(C.sub.1-C.sub.6alkyl). In some embodiments, R.sup.23 is
hydrogen, hydroxyl or C.sub.1-C.sub.3alkoxy. In one embodiment,
R.sup.23 is hydroxyl.
[0086] In some embodiments of the various aspects described herein,
a compound of Formula II is CRL1102 having the structure:
##STR00015##
[0087] In various aspects described herein, a modulator of RelA can
be a compound of Formula III:
##STR00016##
[0088] In compounds of Formula III, h, j and k are independently 0,
1, 2, 3 or 4. Without limitations, h, j and k can all be same, all
different or two are same and the third is different. In some
embodiments, h is 0 or 1. In one embodiment, h is 0. In some
embodiments, j is 0 or 1. In one embodiment, j is 0. In some
embodiments, k is 0 or 1. In one embodiment, k is 0.
[0089] In some embodiments, h and j are independently 0, 1 or 2. In
some embodiments, h and k are independently 0, 1 or 2. In some
embodiments, j and k are independently 0, 1 or 2. In some
embodiments, h, j and k are independently 0 or 1. In one
embodiment, h, j and k all are 0.
[0090] In various embodiments, R.sup.31, R.sup.32 and R.sup.33 can
be selected independently for each occurrence from and are
independently for each occurrence alkyl, alkenyl, alkynyl, halogen,
aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy, cyano,
hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted with 1, 2, 3, 4, or 5
substituents. Without limitations, R.sup.31, R.sup.32 and R.sup.33
can all be same, all different or two are same and the third is
different. In some embodiments, R.sup.31 and R.sup.32 are same. In
some embodiments, R.sup.31 and R.sup.33 are same. In some
embodiments, R.sup.32 and R.sup.33 are same.
[0091] In some embodiments, R.sup.31 and R.sup.32 are different. In
some embodiments, R.sup.31 and R.sup.33 are different. In some
embodiments, R.sup.32 and R.sup.33 are different.
[0092] In some embodiments, R.sup.31, R.sup.32 and R.sup.33 can be
selected independently for each occurrence from halogen, nitro,
cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, acyl, thiol,
hydroxyl, carboxylic acid, trifluormethyl, amino,
C.sub.1-C.sub.6alkylamino, di(C.sub.1-C.sub.6alkyl)amino, or
--CO.sub.2(C.sub.1-C.sub.6alkyl). In some embodiments, R.sup.31,
R.sup.32 and R.sup.33 can be selected independently for each
occurrence from hydrogen, hydroxyl or C.sub.1-C.sub.3alkoxy.
[0093] In various embodiments, R.sup.34 can be selected
independently for each occurrence from alkyl, alkenyl, alkynyl,
cyclyl, heterocyclyl, aryl or heteroaryl, each of which can be
optionally substituted with 1, 2, 3, 4 or 5 substituents.
[0094] In some embodiments of the various aspects described herein,
a compound of Formula III is CRL11021 having the structure:
##STR00017##
[0095] In various aspects described herein, a modulator of RelA can
be a compound of Formula IV:
##STR00018##
[0096] In compounds of Formula IV, m is 0, 1, 2 or 3. In some
embodiments, m is 0 or 1. In one embodiment, m is 0.
[0097] In various embodiments, n can be selected from 0, 1, 2, 3 or
4. In some embodiments, n is 0 or 1. In one embodiment, n is 0.
[0098] In compounds of Formula IV, R.sup.41 can be selected from
hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl,
cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted with 1, 2, 3, 4, or 5 substituents. In some
embodiments, R.sup.41 can be selected from hydrogen, halogen,
nitro, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, acyl,
thiol, hydroxyl, carboxylic acid, trifluormethyl, amino,
C.sub.1-C.sub.6alkylamino, di(C.sub.1-C.sub.6alkyl)amino, or
--CO.sub.2(C.sub.1-C.sub.6alkyl). In some embodiments, R.sup.41 is
hydrogen, hydroxyl or C.sub.1-C.sub.3alkoxy. In one embodiment,
R.sup.41 is hydroxyl.
[0099] In various embodiments, R.sup.42 can be selected
independently for each occurrence from alkyl, alkenyl, alkynyl,
halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy,
cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted with 1, 2, 3, 4, or 5
substituents. In some embodiments, R.sup.42 is selected
independently for each occurrence from halo, nitro, cyano,
trifluoromethyl, amino, C.sub.1-C.sub.6alkylamino, or
di(C.sub.1-C6alkyl)amino.
[0100] In embodiments of the various aspects described herein,
R.sup.43 can be hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cyclyl, heterocyclyl, hydroxyl, alkoxy, aroxy, nitro,
aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio, alkylthio,
arylthio, amino, aminoalkyl, mono- or di-alkylamino, arylamino,
heteroarylamino or CF.sub.3, each of which can be optionally
substituted with 1, 2, 3, 4 or 5 substituents. In some embodiments,
R.sup.43 is hydrogen or C.sub.1-C.sub.6 alkyl, which can be
optionally substituted. In one embodiment, R.sup.43 is methyl,
ethyl propyl, butyl or t-butyl. In one embodiment, R.sup.43 is
methyl.
[0101] In compounds of Formula IV, R.sup.44 can be selected from
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl,
heterocyclyl, aralkyl, sulfinyl, sulfonyl, carbonyl, carboxy,
thiocabonyl, thio, alkylthio, arylthio or CF.sub.3, each of which
can be optionally substituted with 1, 2, 3, 4 or 5 substituents. In
some embodiments, R.sup.44 is hydrogen or C.sub.1-C.sub.6 alkyl,
which can be optionally substituted. In one embodiment, R.sup.44 is
methyl, ethyl propyl or butyl. In one embodiment, R.sup.44 is
methyl.
[0102] In compounds of Formula IV, R.sup.45 and R.sup.46 are
independently for each occurrence absent, hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, sulfinyl,
sulfonyl, carbonyl, carboxy, thiocabonyl, thio, alkylthio, arylthio
or CF.sub.3 with 1, 2, 3, 4 or 5 substituents. It is noted that
when either of R.sup.45 or R.sup.46 is present, the nitrogen to
which it is attached has a positive charge. Further, R.sup.45 and
R.sup.46 can be same or different. In some embodiments, R.sup.45
and R.sup.46 are independently absent, hydrogen or C.sub.1-C.sub.6
alkyl, which can be optionally substituted. In one embodiment,
R.sup.45 is hydrogen. In one embodiment, R.sup.46 is hydrogen. In
one embodiment, R.sup.45 and R.sup.46 both are hydrogen.
[0103] In various embodiments, R.sup.47 can be selected
independently for each occurrence from alkyl, alkenyl, alkynyl,
halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl, carboxy,
cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl, sulfonyl,
thiocabonyl, thio, alkylthio, arylthio, amino, aminoalkyl, mono- or
di-alkylamino, arylamino, heteroarylamino or CF.sub.3, each of
which can be optionally substituted with 1, 2, 3, 4 or 5
substituents.
[0104] In some embodiments of the various aspects described herein,
a compound of Formula IV is CRL1103 having the structure:
##STR00019##
[0105] In various aspects described herein, a modulator of RelA can
be a compound of Formula V:
##STR00020##
[0106] In compounds of Formula V, p and q are independently 0, 1, 2
or 3. In various embodiments, p and q can be same or they can be
different. In some embodiments, p is 0 or 1. In one embodiment, p
is 0. In some embodiments, q is 0 or 1. In one embodiment, q is 0.
In some embodiments, p and q are independently 0 or 1. In one
embodiment, p and q both are 0.
[0107] In various embodiments, R.sup.51 can be selected from
hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl,
cyclyl, heterocyclyl, carbonyl, carboxy, cyano, hydroxyl, alkoxy,
aroxy, nitro, aralkyl, sulfinyl, sulfonyl, thiocabonyl, thio,
alkylthio, arylthio, amino, aminoalkyl, mono- or di-alkylamino,
arylamino, heteroarylamino or CF.sub.3, each of which can be
optionally substituted with 1, 2, 3, 4, or 5 substituents. In some
embodiments, R.sup.51 can be selected from hydrogen, cyclyl,
heterocylyl, aryl, heteroaryl, halogen, nitro, cyano,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, acyl, thiol, hydroxyl,
carboxylic acid, trifluormethyl, amino, C.sub.1-C.sub.6alkylamino,
di(C.sub.1-C.sub.6alkyl)amino, or --CO.sub.2(C.sub.1-C.sub.6alkyl).
In some embodiments, R.sup.51 is an optionally substituted aryl or
heteroaryl. In some embodiments, R.sup.51 is optionally substituted
phenyl.
[0108] In compounds of Formula V, R.sup.52 and R.sup.56 can be
selected independently for each occurrence from alkyl, alkenyl,
alkynyl, halogen, aryl, heteroaryl, cyclyl, heterocyclyl, carbonyl,
carboxy, cyano, hydroxyl, alkoxy, aroxy, nitro, aralkyl, sulfinyl,
sulfonyl, thiocabonyl, thio, alkylthio, arylthio, amino,
aminoalkyl, mono- or di-alkylamino, arylamino, heteroarylamino or
CF.sub.3, each of which can be optionally substituted with 1, 2, 3,
4, or 5 substituents. Without limitations, R.sup.52 and R.sup.56
can be the same or different.
[0109] Without limitations, R.sup.53 can be hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl,
sulfinyl, sulfonyl, carbonyl, carboxy, thiocabonyl, thio,
alkylthio, arylthio or CF.sub.3, each of which can be optionally
substituted with 1, 2, 3, 4 or 5 substituents. In some embodiments,
R.sup.53 can be selected from hydrogen or C.sub.1-C.sub.6alkyl,
which can be optionally substituted. In one embodiment, R.sup.53 is
hydrogen.
[0110] In compounds of Formula V, R.sup.54 and R.sup.55 can be
independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cyclyl, heterocyclyl, aralkyl, sulfinyl, sulfonyl, carbonyl,
carboxy, thiocabonyl, thio, alkylthio, arylthio or CF.sub.3, each
of which can be optionally substituted with 1, 2, 3, 4 or 5
substituents. Without limitations R.sup.54 and R.sup.55 can be same
or different. In some embodiments, at least one of R.sup.54 and
R.sup.55 is hydrogen. In some embodiments, both of R.sup.54 and
R.sup.55 are hydrogen. In some embodiments, at least one of
R.sup.54 and R.sup.55 is not hydrogen. In some embodiments, both of
R.sup.54 and R.sup.55 are not hydrogen. In some embodiments, one of
R.sup.54 and R.sup.55 is hydrogen and the other is not
hydrogen.
[0111] In various embodiments, R.sup.54 can be selected from
hydrogen, C.sub.1-C.sub.6alkyl, cyclyl, heterocyclyl, aryl or
heteroaryl, each of which can be optionally substituted. In some
embodiments, R.sup.54 is hydrogen or C.sub.1-C.sub.6alkyl
optionally substituted with 1 or 2 substituents. In some
embodiments, R.sup.54 is a C.sub.1-C.sub.6alkyl substituted with a
hydroxyl, aryl, heteroaryl, alkoxy, or halogen. In some
embodiments, R.sup.54 is benzyl or 2-hydroxyethyl.
[0112] In various embodiments, R.sup.55 can be selected from
hydrogen, C.sub.1-C.sub.6alkyl, cyclyl, heterocyclyl, aryl or
heteroaryl, each of which can be optionally substituted. In some
embodiments, R.sup.55 is hydrogen or C.sub.1-C.sub.6alkyl
optionally substituted with 1 or 2 substituents. In some
embodiments, R.sup.55 is a C.sub.1-C.sub.6alkyl substituted with a
hydroxyl, aryl, heteroaryl, alkoxy, or halogen. In some
embodiments, R.sup.55 is benzyl or 2-hydroxyethyl.
[0113] In some embodiments of the various aspects described herein,
a compound of Formula V is CRL1104 having the structure:
##STR00021##
[0114] In some embodiments of the various aspects described herein,
a compound of Formula V is CRL11041 having the structure:
##STR00022##
[0115] It is noted that stereoisomers, pharmaceutically acceptable
salts, and prodrugs of compounds of Formula I, II, III, IV and V
are also provided herein.
[0116] In some embodiments, the compounds of Formula I, II, III, IV
and V are reversible inhibitors of RelA/p65 function or activity.
This is in contrast to the irreversible inhibitors known in the
art. The term "reversible inhibitor" is used herein to refer to a
compound that associates with RelA/p65 in such a way as to inhibit
the activity of the RelA/p65 while the RelA/p65 and inhibitor are
bound, but does not associate with RelA/p65 in such a way as to
inhibit the activity of the RelA/p65 when the RelA/p65 and
inhibitor are no longer bound.
[0117] The compounds of described herein can be synthesized using
methods known in the art and available to one of ordinary skill in
the art. Some exemplary compounds of Formulas (I0-(IV) are also
available from commercial vendors, such as, ChemBridge Corporation,
San Diego, Calif.
[0118] In embodiments of the various aspects described herein, the
compounds of Formula I, II, III, IV or V can be formulated as
particles, e.g. nano- or microparticles. Formulation of the
compound into particles can be advantageous. As used herein, the
term "nanoparticle" refers to particles that are on the order of
10.sup.-9 or one billionth of a meter and below 10.sup.-6 or 1
millionth of a meter in size. The term "nanoparticle" includes
nanospheres; nanorods; nanoshells; and nanoprisms; and these
nanoparticles may be part of a nanonetwork. The term
"nanoparticles" also encompasses liposomes and lipid particles
having the size of a nanoparticle. The particles may be, e.g.,
monodisperse or polydisperse and the variation in diameter of the
particles of a given dispersion may vary, e.g., particle diameter
of between about 0.1 to 100's of nm. Without limitations, the
compounds of Formula I, II, III, IV or V can be formulated in any
type of nanoparticle, including, but not limited to, liposomes,
emulsions, microemulsions, nanoemulsions, self-microemulsifying
drug delivery systems (SMEDDS), polymeric nanoparticles,
solid-lipid nanoparticles, nano-structured liquid crystals, and the
like.
[0119] Generally there are at least seven types of nanoparticles
that can be formulated: (1) nanoparticles formed from a polymer or
other material to which a compound of Formula I, II, III, IV or V
absorbs/adsorbs or forms a coating on a nanoparticle core; (2))
nanoparticles formed from a core formed by the compound of Formula
I, II, III, IV or V, which is coated with a polymer or other
material; (3) nanoparticles formed from a polymer or other material
to which a compound of Formula I, II, III, IV or V is covalently
linked; (4) nanoparticles formed from compound of Formula I, II,
III, IV or V and other molecules; (5) nanoparticles formed so as to
comprise a generally homogeneous mixture of a compound of Formula
I, II, III, IV or V with a constituent of the nanoparticle or other
non-drug substance; (6) nanoparticles of a pure drug or drug
mixtures with a coating over a core of a compound of Formula I, II,
III, IV or V; and (7) nanoparticles composed entirely of a compound
of Formula I, II, III, IV or V.
[0120] In some embodiments, the nanoparticle is of size about 1 nm
to about 1000 nm, about 50 nm to about 500 nm, about 100 nm to
about 250 nm, or about 200 nm to about 350 nm. In one embodiment,
the nanoparticle is of about 100 nm to about 1000 nm. In another
embodiment, the nanoparticle is of size about 80 nm to about 200
nm. In one embodiment, nanoparticle is of size about 50 nm to about
500 nm. In some embodiments, nanoparticle is of size about 158 nm,
about 218 nm, or about 305 nm. In some embodiments, nanoparticle is
of size about 337 nm, about 526 nm, about 569 nm, about 362 nm,
about 476 nm, about 480 nm, about 676 nm, about 445 nm, about 434
nm, about 462 nm, about 492 nm, about 788 nm, about 463 nm, or
about 65 nm
[0121] Nanoparticles described herein usually have a narrow size
distribution as measured by Polydispersity Index (PdI). As used
herein, the term "polydispersity index" is a measure of the
distribution broadness of a sample, and is typically defined as the
relative variance in the correlation decay rate distribution, as is
known by one skilled in the art. See B J. Fisken, "Revisiting the
method of cumulants for the analysis of dynamic light-scattering
data," Applied Optics, 40(24), 4087-4091 (2001) for a discussion of
cumulant diameter and polydispersity. Generally, the polydispersity
of the nanoparticles described herein is less than about 0.8. In
some embodiments, the polydispersity of the nanoparticles is less
than about 0.5, less than about 0.4, less than about 0.3, less than
about 0.25, less than about 0.2, less than about 0.15, less than
about 0.1, or less than about 0.05. In some embodiments, the
polydispersity of the nanoparticles is about 0.072, about 0.1,
about 0.149, or about 0.236, about 0.165, about 0.221, about 0.177,
about 0.213, about 0.264, about 0.241, about 0.251, about 0.273,
about 0.211, about 0.181, about 0.249, about 0.298, about 0.348, or
about 0.282.
[0122] Without limitations, the nanoparticle can comprise other
components in addition to the compound of Formula I, II, III, IV or
V. For example, the nanoparticle can comprise one or more of
polymers, anionic polymers, cationic polymers, amphiphilic
polymers, surfactants, lipids, phospholipids, cationic lipids,
amphiphilic lipids, excipients and the like. If present in
nanoparticle, each of the additional component can be present in an
amount ranging from about 0.01% to about 90%, e.g., from about
0.01% to about 80%, from about 0.01% to about 70%, from about 0.01%
to about 60%, from about 0.01% to about 50%, from about 0.01% to
about 40%, from about 0.01% to about 30%, from about 0.01% to about
25%, of the total weight of the nanoparticle. It is to be
understood that amount of a component is independent from the
amount of a second component in the liposome or the emulsion.
[0123] A surfactant that can be added to the nanoparticle can be
any of anionic, cationic, ampholytic and nonionic surfactants.
Examples anionic surfactants include fatty esters such as sodium
stearate, potassium oleate and semicurable tallow fatty acid
sodium; alkyl sulfates such as sodium dodecyl sulfate,
tri(2-hydroxyethyl) ammonium dodecyl sulfate and sodium octadecyl
sulfate; benzensulfonates such as sodium nonyl benzanesulfonate,
sodium dodecyl benzenesulfonate, sodium otadecyl benzenesulfonate
and sodium dodecyl diphenylether disulfonate; naphthalenesulfonates
such as sodium dodecyl naphthalenesulfonate and naphthalenesulfonic
acid formalin condensates; sulfosuccinates such as sodium didodecyl
sulfosuccinate and sodium dioctadodecyl sulfosuccinate;
polyoxyethylene sulfates such as sodium polyoxyethylenedodecylether
sulfate, tri(2-hydroxyethyl) ammonia polyoxyethylene dodecylether
sulfate, sodium polyoxyethylene octadecylether sulfate and sodium
polyoxyethylene dodecylphenylether sulfate; and phosphates such as
potassium dodecyl phosphate and sodium octadecyl phosphate.
Examples of cationic surfactants include alkyl amine salts such as
octadecyl ammonium acetate and coconut oil amine acetate; and
fourth ammonia salts such as dodecyl trimethyl ammonium chloride,
octadecyl trimethyl ammonium chloride, dioctadecyl dimethyl
ammonium chloride and dodecyl benzyl dimethyl ammonium chloride.
Examples of ampholytic surfactants include alkyl betains such as
dodecyl betain and octadodecyl betain; and amine oxides such as
dodecyl dimethyl amine oxide. Examples of nonionic surfactants
include polyoxyethylene alkyl ethers such as polyoxyethylene
dodecyl ether, polyoxyethylene hexadecyl ether, polyoxyethylene
octadecyl ether and polyoxyethylene (9-octadecenyl) ether;
polyoxyethylene phenyl ethers such as polyoxyethylene octylphenyl
ether and polyoxyethylene nonylphenyl ether; oxirane polymers such
as polyethylene oxide and copolymer of ethylene oxide and propylene
oxide; sorbitan fatty esters such as sorbitan dodecanoic ester,
sorbitan hexadecanoic ester, sorbitan octadecanoic ester, sorbitan
(9-octadecenoic) ester, sorbitan (9-octadecenoic) triester,
polyoxyethylene sorbitan dodekanoic ester, polyoxyethylene sorbitan
hexadecanoic ester, polyoxyethylene sorbitan octadecanoic ester,
polyoxyethylene sorbitan octanoic triester, polyoxyethylene
sorbitan (9-octadecenoic) ester and polyoxyethylene sorbitan
(9-octadecenoic) triester; sorbitol fatty esters such as
polyoxyethylene sorbitol (9-octadecenoic) tetraester; glycerin
fatty esters such as glycerin octadecanoic ester and glycerin
(9-octadecenoic) ester; polyalkylene oxide block copolymers such
poloxomers (commercially available under the trademark
PLURONIC.RTM. (BASF)).
[0124] Suitable commercially available amphoteric surfactants
include, but are not limited to, MIRANOL.RTM. HMA sodium lauroampho
acetate (38% solids) and MIRANOL.RTM. ULTRA L32 sodium lauroampho
acetate available from Rhodia Novecare (Cranbury, N.J.). Suitable
commercially available linear alcohol ethoxylates include, but are
not limited to, SURFONIC.RTM. L12-6 six-mole ethoxylate of linear,
primary 10-12 carbon number alcohol available from Huntsman
Performance Products (The Woodlands, Tex.). Suitable commercially
available alkyl sulfates include, but are not limited to,
POLYSTEP.RTM. B-29 sodium octyl sulfate available from Stepan
Company (Northfield, 111.). Suitable commercially available
nonionic surfactants include, but are not limited to, oxo-alcohol
polyglycol ethers such as GENAPOL.RTM. UD 070 CI 1-oxo-alcohol
polyglycol ether (7 EO) available from Clariant Corporation
(Cranbury, N.J.). Suitable commercially available linear
alkylbenzene sulfonic acids and their salts include, but are not
limited to, NAXSOFT.RTM. 98S dodecyl Benzene Sulfonic Acid and
NAXSOFT.RTM. 40S Sodium dodecyl Benzene sulfonate available from
Nease Corporate (Cincinnati, Ohio).
[0125] In some embodiments, the compound of Formula I, II, III, IV
or V can be formulated in liposomes. As used herein, the term
"liposome" encompasses any compartment enclosed by a lipid layer,
which can be a monolayer or a bilayer. Liposomes may be
characterized by membrane type and by size. Liposomes are also
referred to as lipid vesicles in the art. In order to form a
liposome the lipid molecules comprise elongated non-polar
(hydrophobic) portions and polar (hydrophilic) portions. The
hydrophobic and hydrophilic portions of the molecule are preferably
positioned at two ends of an elongated molecular structure. When
such lipids are dispersed in water they spontaneously form bilayer
membranes referred to as lamellae or self arranged vesicles. The
lamellae are composed of two mono layer sheets of lipid molecules
with their non-polar (hydrophobic) surfaces facing each other and
their polar (hydrophilic) surfaces facing the aqueous medium. The
membranes formed by the lipids enclose a portion of the aqueous
phase in a manner similar to that of a cell membrane enclosing the
contents of a cell. Thus, the bilayer of a liposome has
similarities to a cell membrane without the protein components
present in a cell membrane.
[0126] The liposomes that are used in the present invention are
preferably formed from lipids which when combined form relatively
stable vesicles. An enormous variety of lipids are known in the art
which can be used to generate such liposomes. Preferred lipids
include, but are not limited to, neutral and negatively charged
phospholipids or sphingolipids and sterols, such as cholesterol.
The selection of lipids is generally guided by consideration of,
e.g., liposome size and stability in the personal care
composition.
[0127] Liposomes include unilamellar vesicles which are comprised
of a single lipid layer and generally have a diameter of 20 to 100
nanometers; large unilamellar vesicles (LUVS) are typically larger
than 100 nm, which can also be produced by subjecting multilamellar
liposomes to ultrasound. In some embodiments, liposomes have a
diameter in the range of 20 nm to 400 nm.
[0128] Liposomes can further comprise one or more additional lipids
and/or other components such as sterols, e.g., cholesterol.
Additional lipids can be included in the liposome compositions for
a variety of purposes, such as to prevent lipid oxidation, to
stabilize the bilayer, to reduce aggregation during formation or to
attach carriers onto the liposome surface. Any of a number of
additional lipids and/or other components can be present, including
amphipathic, neutral, cationic, anionic lipids, and programmable
fusion lipids. Such lipids and/or components can be used alone or
in combination.
[0129] Liposome compositions can be prepared by a variety of
methods that are known in the art. See e.g., U.S. Pat. Nos.
4,235,871; 4,737,323; 4,897,355 and 5,171,678; published
International Applications WO1996/14057 and WO1996/37194; Felgner,
P. L. et al., Proc. Natl. Acad. Sci., USA (1987) 8:7413-7417,
Bangham, et al. M. Mol. Biol. (1965) 23:238, Olson, et al. Biochim.
Biophys. Acta (1979) 557:9, Szoka, et al. Proc. Natl. Acad. Sci.
(1978) 75: 4194, Mayhew, et al. Biochim. Biophys. Acta (1984)
775:169, Kim, et al. Biochim. Biophys. Acta (1983) 728:339, and
Fukunaga, et al. Endocrinol. (1984) 115:757, content of all of
which is incorporated herein by reference.
[0130] In some embodiments, the compound of Formula I, II, III, IV
or V can be formulated in an emulsion. As used herein, "emulsion"
is a heterogenous system of one liquid dispersed in another in the
form of droplets. Emulsions are often biphasic systems comprising
two immiscible liquid phases intimately mixed and dispersed with
each other. Either of the phases of the emulsion can be a semisolid
or a solid, as is the case of emulsion-style ointment bases and
creams. The compound can be present as a solution in the aqueous
phase, oily phase or itself as a separate phase.
[0131] In some embodiments, the compositions are formulated as
nanoemulsions. The term "nanoemulsion" means an emulsion wherein
the particles are of sized in the nanometer scale. Nanoemulsions
also include thermodynamically stable, isotropically clear
dispersions of two immiscible liquids that are stabilized by
interfacial films of surface-active molecules. The application of
emulsion formulations via dermatological, oral and parenteral
routes and methods for their manufacture have been reviewed in the
literature, for example see Idson, in Pharmaceutical Dosage Forms,
Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New
York, N.Y., volume 1, p. 199; Rosoff, in Pharmaceutical Dosage
Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker,
Inc., New York, N.Y., volume 1, p. 245; and Block, in
Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.),
1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335,
content of all of which is herein incorporated by reference in its
entirety.
[0132] In some embodiments, the compound can be formulated in a
polymeric nanoparticle. As used herein, the term "polymeric
nanoparticle" refers to a carrier system in which the compound of
Formula I, II, III, IV or V is retained, encapsulated or adsorbed.
The term polymeric nanoparticles can be used to denote nanospheres
and nanocapsules. Nanospheres are constituted of a polymer matrix
in which the compound is retained, encapsulated or adsorbed.
Nanocapsules are constituted of a polymer container enclosing a
nucleus, in which the compound can be dissolved, retained, or
dispersed in the nucleus and/or adsorbed in the polymeric wall.
[0133] Overall, the production processes for polymer nanoparticles
can be classified among the methods of in situ polymerisation or
methods using pre-formed polymers. Polymers commonly used in the
preparation of nanoparticles are, for example poly (lactide), poly
(lactideglycolide), poly (glycolide), poly (caprolactone), poly
(amides), poly (anhydrides), poly (amino acids), poly (esters),
poly (cyanoacrylates), poly (phosphazines), poly (phosphoesters),
poly (esteramides), poly (dioxinones), poly (acetals), poly
(cetals), poly (carbonates), poly (orthocarbonates), degradable
poly (urethanes), chitins, chitosans, poly (hydroxybutyrates), poly
(hydroxyvalerates), poly (maleic acid), poly (alkylene oxalates),
poly (alkylene succinates), poly
(hydroxybutyrates-co-hydroxyvalerates), and copolymers,
terpolymers, oxidised cellulose, or combinations or mixtures of
these materials. Some polymers that prove to be especially
interesting are poly (e-caprolactone) (PCL; for example, poly
(E-caprolactone) 65 Kd-Sigma Aldrich); methacryllate acid
copolymers and methacryllate or acrylic esters (e.g.
EUDRAGITS.RTM.); poly (alkyl methacrylate); poly (methyl
methacryllate) (e.g. PMM).
[0134] Polymeric nanoparticles can be produced, for example, by the
methods (i) of in situ polymerisation of monomers (latex) or
dispersion of pre-formed polymers (pseudolatex or artificial latex)
as described in De Jaeghere F et al. Nanoparticles. In: Mathiowitz
E, ed. The Encyclopedia of Controlled Drug Delivery. New York,
N.Y.: Wiley and Sons Inc; 1999: 641-664 and Couvreur P, et al.
Controlled drug delivery with nanoparticles: Eur J Pharm Biopharm.
1995; 41: 2-13; (ii) method of emulsion-evaporation for
pharmaceutical use first proposed by Gurny R, Peppas N A,
Harrington D D, Banker G S. Development of biodegradable and
injectable lattices for controlled release of potent drugs. Drug
Dev Ind Pharm. 1981; 7: 1-25 based on patent U.S. Pat. No.
4,177,177, with the polymer being dissolved in a volatile organic
solvent immiscible in water. The organic solution is dispersed in
an aqueous phase containing emulsifier and oil/water emulsion
forming facilitators; and (iii) method of the interface deposit of
pre-formed polymers (nanoprecipitation) as described by Fessi et
al. in patent U.S. Pat. No. 5,049,322. Content of all references
cites in this paragraph is incorporated herein by reference.
[0135] The organic solvents that can be used for the preparation of
nanoparticles are: small chain alcohols (methanol, ethanol,
isopropanol, etc.), small chain ketones (acetone,
methyl-ethyl-ketone, etc.), light hydrocarbons or a mixture of
light hydrocarbons (hexane, petroleum ether, etc.), lightly
chlorated hydrocarbons (chloroform, methylene hydrochloride,
trihydrochlorideethylene, etc.), or other common light solvents
such as acetonitryl, dioxane, etc. Acetone is a particularly
interesting solvent.
[0136] Surfactants are commonly used to avoid the aggregation of
the particles when stored. Examples of surfactants that can be used
are: lecithins, synthetic, anionic (e.g. sodium lauryl sulphate),
cationic (e.g. quaternary ammonium) or non-ionic (e.g. sorbitan
monoesters, containing or not polyoxyethylene residues, ethers
formed from fatty alcohols and polyethylene glycol,
polyoxyethylene-polypropylene glycol, etc.). Particularly
interesting combinations include lipophilic surfactants with low
hydrophilic-lipophilic (EHL) balance values (e.g. sorbitan
esters--Span 20 or Span 60) and hydrophilic surfactants with high
EHL values (ethoxylated sorbitan esters-Tween 80) or, indeed,
merely a single non-ionic surfactant having a high EHL (such as
Tween 80).
[0137] In some embodiments, the compound of Formula I, II, III, IV
or V can be formulated in a self-microemulsifying drug delivery
system (SMEDDS). A self-microemulsifying drug delivery system can
be described as an optically isotropic system of oil, surfactant
and drug, which forms an oil in water microemulsion on gentle
agitation in the presence of water. A SMEDDS for pharmaceutical
application can thus be considered as a concentrate which is
rapidly dispersed when introduced to the body to form an
oil-in-water microemulsion.
[0138] In some embodiments, the compound of Formula I, II, III, IV
or V can be formulated in a solid lipid nanoparticle. Solid lipid
nanoparticles can be prepared in any manner conventional in the
art, such as, for example, as described in Stuchlik, M. and Zak, S.
(Lipid-Based Vehicle for Oral Delivery, Biomed. Papers 145 (2):
17-26, (2001)). The solid lipid nanoparticle can be prepared in a
hot homogenization process by homogenization of melted lipids at
elevated temperature. In this process, the solid lipid is melted
and the compound of Formula I, II, III, IV or V is dissolved in the
melted lipid. A pre-heated dispersion medium is then mixed with the
compound-loaded lipid melt, and the combination is mixed with a
homogenisator to form a coarse pre-emulsion. High pressure
homogenization is then performed at a temperature above the lipids
melting point to produce an oil/water-nanoemulsion. The
nanoemulsion is cooled down to room temperature to form solid lipid
nanoparticles.
[0139] Alternatively, the solid lipid nanoparticles can be prepared
in a cold homogenization process. In this process, the lipid is
melted and the compound of Formula I, II, III, IV or V is dissolved
in the melted lipid. The compound-loaded lipid is then solidified
in liquid nitrogen or dry ice. The solid compound-lipid is ground
in a powder mill to form 50-100 m particles. The lipid particles
are then dispersed in cold aqueous dispersion medium and
homogenized at room temperature or below to form solid lipid
nanoparticles.
[0140] Described herein are small molecule RelA modulators of
Formula I, II, III, IV and V for use in methods of treating a
subject having or at risk for developing a proliferative disorder,
such as a cancer. The compounds of Formula I, II, III, IV and can
be administered to a subject in need thereof by any appropriate
route which results in an effective treatment in the subject.
[0141] Accordingly, in some aspects, provided herein are methods of
modulating, e.g., inhibiting RelA/p65 activity or function in a
subject. Such methods comprise administering to a subject in need
thereof a therapeutically effective amount of a compound of Formula
I, II, III, IV or V.
[0142] In some aspects, provided herein are methods of treatment of
a subject having a cancer or a cancerous condition, or at risk for
cancer or a cancerous condition, the methods comprising
administering to a subject having a cancer or cancerous condition,
or at risk for cancer or a cancerous condition, a therapeutically
effective amount of a compound of Formula I, II, III, IV or V.
[0143] In some embodiments of the aspects described herein, the
methods of treating, inhibiting, reducing severity of, slowing
progression of and/or preventing metastasis of cancer or a
cancerous condition further comprise the step of selecting,
diagnosing, or identifying a subject having cancer or a cancerous
condition. In such embodiments, a subject is identified as having
cancer by objective determination of the presence of cancer cells
or a tumor in the subject's body by one of skill in the art. Such
objective determinations can be performed through the sole or
combined use of tissue biopsies, blood and platelet cell counts,
urine analyses, magnetic resonance imaging (MRI) scans, computed
tomography (CT) scans, liver function studies, chest X-rays and
bone scans in addition to the monitoring of specific symptoms
associated with a cancer.
[0144] The compounds of Formula I, II, III, IV or V can be
formulated, dosed, and administered in a fashion consistent with
good medical practice for use in the treatment of the cancers and
cancerous conditions described herein, such as breast cancer.
Factors for consideration in this context include the particular
disorder or type of disorder, e.g., cancer, being treated, the
particular subject being treated, the clinical condition of the
individual subject, the cause of the disorder, the site of delivery
of the agent, the method of administration, the scheduling of
administration, and other factors known to medical
practitioners.
[0145] Accordingly, the "therapeutically effective amount" of a
compound of Formula I, II, III, IV or V to be administered is
governed by such considerations, and, as used herein, refers to the
minimum amount necessary to prevent, ameliorate, or treat, or
stabilize, a disorder or condition, such as one mediated by binding
and/or function of RelA
[0146] In those aspects and embodiments relating to cancer or other
proliferative disorders, the therapeutically effective amount of a
compound of Formula I, II, III, IV or V described herein is the
minimum amount necessary to, for example, increase the time until
progression (duration of progression free survival), to inhibit or
prevent tumor invasion, or to treat or prevent the occurrence or
recurrence of a tumor, a dormant tumor, or a micrometastases. In
some such embodiments, a compound of Formula I, II, III, IV or V is
optionally formulated with one or more agents currently used to
prevent or treat cancer or a risk of developing a cancer. The
effective amount of such other agents depends on the amount of the
compound of Formula I, II, III, IV or V present in the formulation,
the type of disorder or treatment, and other factors discussed
herein, and as understood by one of skill in the art. These are
generally used in the same dosages and with administration routes
as used herein before or about from 1 to 99% of the heretofore
employed dosages.
[0147] An effective amount as used herein also includes an amount
sufficient to delay the development of a symptom of the cancer,
alter the course of a cancer (for example but not limited to, slow
the progression of a symptom of the cancer, such as growth of a
tumor), or reverse a symptom of the cancer or tumor. Thus, it is
not possible to specify the exact "effective amount". However, for
any given case, an appropriate "effective amount" can be determined
by one of ordinary skill in the art using only routine
experimentation.
[0148] Effective amounts, toxicity, and therapeutic efficacy can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD.sub.50 (the
dose lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dosage can
vary depending upon the dosage form employed and the route of
administration utilized. The dose ratio between toxic and
therapeutic effects is the therapeutic index and can be expressed
as the ratio LD.sub.50/ED.sub.50. Compositions and methods that
exhibit large therapeutic indices are preferred. A therapeutically
effective dose can be estimated initially from cell culture assays.
Also, a dose can be formulated in animal models to achieve a
circulating plasma concentration range that includes the IC.sub.50,
which achieves a half-maximal inhibition of symptoms as determined
in cell culture, or in an appropriate animal model. Levels in
plasma can be measured, for example, by high performance liquid
chromatography. The effects of any particular dosage can be
monitored by a suitable bioassay. The dosage can be determined by a
physician and adjusted, as necessary, to suit observed effects of
the treatment.
[0149] In various embodiments, the therapeutically or
prophylactically effective amount of a compound of Formula I, I,
III, IV or V for use with the methods described herein is any one
or more of about 0.01 to 0.05 .mu.g/kg/day, 0.05-0.1 .mu.g/kg/day,
0.1 to 0.5 .mu.g/kg/day, 0.5 to 5 .mu.g/kg/day, 0.5 to 1
.mu.g/kg/day, 1 to 5 .mu.g/kg/day, 5 to 10 .mu.g/kg/day, 10 to 20
.mu.g/kg/day, 20 to 50 .mu.g/kg/day, 50 to 100 .mu.g/kg/day, 100 to
150 .mu.g/kg/day, 150 to 200 .mu.g/kg/day, 200 to 250 .mu.g/kg/day,
250 to 300 .mu.g/kg/day, 300 to 350 .mu.g/kg/day, 350 to 400
.mu.g/kg/day, 400 to 500 .mu.g/kg/day, 500 to 600 .mu.g/kg/day, 600
to 700 .mu.g/kg/day, 700 to 800 .mu.g/kg/day, 800 to 900
.mu.g/kg/day, 900 to 1000 .mu.g/kg/day, 0.01 to 0.05 mg/kg/day,
0.05-0.1 mg/kg/day, 0.1 to 0.5 mg/kg/day, 0.5 to 1 mg/kg/day, 1 to
5 mg/kg/day, 5 to 10 mg/kg/day, 10 to 15 mg/kg/day, 15 to 20
mg/kg/day, 20 to 50 mg/kg/day, 50 to 100 mg/kg/day, 100 to 200
mg/kg/day, 200 to 300 mg/kg/day, 300 to 400 mg/kg/day, 400 to 500
mg/kg/day, 500 to 600 mg/kg/day, 600 to 700 mg/kg/day, 700 to 800
mg/kg/day, 800 to 900 mg/kg/day, 900 to 1000 mg/kg/day or a
combination thereof. Typical dosages of a compound of Formula I, I,
III, IV or V can be in the ranges recommended by the manufacturer
where known therapeutic compounds are used, and also as indicated
to the skilled artisan by the in vitro responses or responses in
animal models. Such dosages typically can be reduced by up to about
an order of magnitude in concentration or amount without losing
relevant biological activity. The actual dosage can depend upon the
judgment of the physician, the condition of the patient, and the
effectiveness of the therapeutic method based, for example, on the
in vitro responsiveness of relevant cultured cells or histocultured
tissue sample, such as biopsied malignant tumors, or the responses
observed in the appropriate animal models. In various embodiments,
a compound of Formula I, I, III, IV or V may be administered once a
day (SID/QD), twice a day (BID), three times a day (TID), four
times a day (QID), or more, so as to administer an effective amount
to the subject, where the effective amount is any one or more of
the doses described herein
[0150] Depending on the type and severity of the disease, about 1
.mu.g/kg to 100 mg/kg (e.g., 0.1-20 mg/kg) of a compound of Formula
I, I, III, IV or V is an initial candidate dosage range for
administration to the subject, whether, for example, by one or more
separate administrations, or by continuous infusion. A typical
daily dosage can range from about 1 .mu.g/kg to about 100 mg/kg or
more, depending on the factors mentioned above. For repeated
administrations over several days or longer, depending on the
condition, the treatment is sustained until the cancer is treated,
as measured by the methods described above or known in the art.
However, other dosage regimens can be useful. The progress of the
therapeutic methods described herein is easily monitored by
conventional techniques and assays, such as those described herein,
or known to one of skill in the art. In other embodiments, such
dosing regimen is used in combination with a chemotherapy regimen
as the first line therapy for treating, inhibiting, reducing
severity of, slowing progression of and/or preventing metastasis of
locally recurrent or metastatic breast cancer.
[0151] The duration of the therapeutic methods described herein can
continue for as long as medically indicated or until a desired
therapeutic effect (e.g., those described herein) is achieved. In
certain embodiments, administration of a compound of Formula I, II,
III, IV or V is continued for at least 1 month, at least 2 months,
at least 4 months, at least 6 months, at least 8 months, at least
10 months, at least 1 year, at least 2 years, at least 3 years, at
least 4 years, at least 5 years, at least 10 years, at least 20
years, or for at least a period of years up to the lifetime of the
subject.
[0152] The compounds of Formula I, II, III, IV or V can be
administered to a subject, e.g., a human subject, in accordance
with known methods, such as intravenous administration as a bolus
or by continuous infusion over a period of time, by intramuscular,
intraperitoneal, intracerobrospinal, subcutaneous, intra-articular,
intrasynovial, intrathecal, oral, topical, or inhalation routes.
Local administration can be used if, for example, extensive side
effects or toxicity is associated with the administered compound.
An ex vivo strategy can also be used for therapeutic
applications.
[0153] Exemplary modes of administration include, but are not
limited to, injection, infusion, inhalation (e.g., intranasal or
intratracheal), ingestion, rectal, and topical (including buccal
and sublingual) administration. The phrases "parenteral
administration" and "administered parenterally" as used herein,
refer to modes of administration other than enteral and topical
administration, usually by injection. As used herein, "injection"
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intraventricular, intracapsular,
intraorbital, intracardiac, intradermal, intraperitoneal,
transtracheal, subcutaneous, subcuticular, intraarticular, sub
capsular, subarachnoid, intraspinal, intracerebro spinal, and
intrasternal injection and infusion. The phrases "systemic
administration," "administered systemically", "peripheral
administration" and "administered peripherally" as used herein
refer to the administration of a compound of Formula I, II, III, IV
or V other than directly into a target site, tissue, or organ, such
as the lung, such that it enters the subject's circulatory system
and, thus, is subject to metabolism and other like processes.
[0154] In some embodiments, the compound of Formula I, II, III, IV
or V is administered by intravenous infusion or injection. In some
embodiments, where local treatment is desired, for example, at or
near a site of a tumor, such as a tumor in the breast in a subject
having breast cancer, the compound can be administered by
intralesional administration. Additionally, in some embodiments,
the compound can be administered by pulse infusion, particularly
with declining doses of the compound. Preferably the dosing is
given by injections, most preferably intravenous or subcutaneous
injections, depending in part on whether the administration is
brief or chronic.
[0155] In some embodiments, the compound of Formula I, II, III, IV
or V is administered locally, e.g., by direct injections, when the
disorder or location of the tumor permits, and the injections can
be repeated periodically. The compound can also be delivered
systemically to the subject or directly to the tumor cells, e.g.,
to a tumor or a tumor bed, following surgical excision of the
tumor, in order to prevent or reduce local recurrence or
metastasis, for example of a dormant tumor or micrometastases.
[0156] Therapeutic formulations of compounds of Formula I, II, III,
IV or V can be prepared, in some aspects, by mixing the compound
having the desired degree of purity with one or more
pharmaceutically acceptable carriers, excipients or stabilizers
(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.
(1980)), in the form of lyophilized formulations or aqueous
solutions. Such therapeutic formulations include formulation into
pharmaceutical compositions or pharmaceutical formulations for
parenteral administration, e.g., intravenous; mucosal, e.g.,
intranasal; enteral, e.g., oral; topical, e.g., transdermal;
ocular, or other mode of administration.
[0157] As used herein, the phrase "pharmaceutically acceptable"
refers to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio. The phrase "pharmaceutically acceptable
carrier" as used herein means a pharmaceutically acceptable
material, composition or vehicle, such as a liquid or solid filler,
diluent, excipient, solvent, media, encapsulating material,
manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc
stearate, or steric acid), or solvent encapsulating material,
involved in maintaining the activity of, carrying, or transporting
the compound of Formula I, II, III, IV or V, from one organ, or
portion of the body, to another organ, or portion of the body.
[0158] Some non-limiting examples of acceptable carriers,
excipients, or stabilizers that are nontoxic to recipients at the
dosages and concentrations employed, include pH buffered solutions
such as phosphate, citrate, and other organic acids; antioxidants,
including ascorbic acid and methionine; lubricating agents, such as
magnesium stearate, sodium lauryl sulfate and talc; excipients,
such as cocoa butter and suppository waxes; oils, such as peanut
oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil
and soybean oil; preservatives (such as octadecyldimethylbenzyl
ammonium chloride; hexamethonium chloride; benzalkonium chloride,
benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl
parabens such as methyl or propyl paraben; catechol; resorcinol;
cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less
than about 10 residues) polypeptides; proteins, such as serum
albumin, gelatin, HDL, LDL, or immunoglobulins; hydrophilic
polymers, such as polyvinylpyrrolidone; amino acids such as
glycine, glutamine, asparagine, histidine, arginine, or lysine;
monosaccharides, disaccharides, and other carbohydrates including
mannose, starches (corn starch or potato starch), or dextrins;
cellulose, and its derivatives, such as sodium carboxymethyl
cellulose, methylcellulose, ethyl cellulose, microcrystalline
cellulose and cellulose acetate; chelating agents such as EDTA;
sugars such as sucrose, glucose, lactose, mannitol, trehalose or
sorbitol; salt-forming counter-ions such as sodium; metal complexes
(e.g. Zn-protein complexes); glycols, such as propylene glycol;
polyols, such as glycerin; esters, such as ethyl oleate and ethyl
laurate; agar; buffering agents, such as magnesium hydroxide and
aluminum hydroxide; alginic acid; pyrogen-free water; isotonic
saline; Ringer's solution; polyesters, polycarbonates and/or
polyanhydrides; C2-C12 alcohols, such as ethanol; powdered
tragacanth; malt; and/or non-ionic surfactants such as TWEEN.TM.,
PLURONICS.TM. or polyethylene glycol (PEG); and/or other non-toxic
compatible substances employed in pharmaceutical formulations.
Wetting agents, coloring agents, release agents, coating agents,
sweetening agents, flavoring agents, perfuming agents, preservative
and antioxidants can also be present in the formulation.
[0159] In some embodiments, the therapeutic formulation comprising
a compound of Formula I, II, III, IV or V comprises a
pharmaceutically acceptable salt, typically, e.g., sodium chloride,
and preferably at about physiological concentrations. Optionally,
the formulations described herein can contain a pharmaceutically
acceptable preservative. In some embodiments, the preservative
concentration ranges from 0.1 to 2.0%, typically v/v. Suitable
preservatives include those known in the pharmaceutical arts.
Benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben
are examples of preservatives. Optionally, the formulations of the
invention can include a pharmaceutically acceptable surfactant at a
concentration of 0.005 to 0.02%.
[0160] In some embodiments of the aspects described herein, a
compound of Formula I, II, III, IV or V can be specially formulated
for administration of the compound to a subject in solid, liquid or
gel form, including those adapted for the following: (1) oral
administration, for example, drenches (aqueous or non-aqueous
solutions or suspensions), lozenges, dragees, capsules, pills,
tablets (e.g., those targeted for buccal, sublingual, and systemic
absorption), boluses, powders, granules, pastes for application to
the tongue; (2) parenteral administration, for example, by
subcutaneous, intramuscular, intravenous or epidural injection as,
for example, a sterile solution or suspension, or sustained-release
formulation; (3) topical application, for example, as a cream,
ointment, or a controlled-release patch or spray applied to the
skin; (4) intravaginally or intrarectally, for example, as a
pessary, cream or foam; (5) sublingually; (6) ocularly; (7)
transdermally; (8) transmucosally; or (9) nasally. Additionally,
the compounds described herein, e.g., a compound of Formula I, II,
III, IV or V, can be implanted into a patient or injected using a
drug delivery system. See, for example, Urquhart, et al., Ann. Rev.
Pharmacol. Toxicol. 24: 199-236 (1984); Lewis, ed. "Controlled
Release of Pesticides and Pharmaceuticals" (Plenum Press, New York,
1981); U.S. Pat. No. 3,773,919; and U.S. Pat. No. 35 3,270,960.
Examples of dosage forms include, but are not limited to: tablets;
caplets; capsules, such as hard gelatin capsules and soft elastic
gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders;
dressings; creams; plasters; solutions; patches; aerosols (e.g.,
nasal sprays or inhalers); gels; liquids such as suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions,
or water-in-oil liquid emulsions), solutions, and elixirs; and
sterile solids (e.g., crystalline or amorphous solids) that can be
reconstituted to provide liquid dosage forms.
[0161] In some embodiments, parenteral dosage forms of the compound
of Formula I, II, III, IV or V can be administered to a subject
with a cancer or at increased risk for cancer by various routes,
including, but not limited to, subcutaneous, intravenous (including
bolus injection), intramuscular, and intraarterial. Since
administration of parenteral dosage forms typically bypasses the
patient's natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
controlled-release parenteral dosage forms, and emulsions.
[0162] Suitable vehicles that can be used to provide parenteral
dosage forms described herein are well known to those skilled in
the art. Examples include, without limitation: sterile water; water
for injection USP; saline solution; glucose solution; 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 propylene 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.
[0163] In some embodiments, the compound of Formula I, II, III, IV
or V is formulated to be suitable for oral administration, for
example as discrete dosage forms, such as, but not limited to,
tablets (including without limitation scored or coated tablets),
pills, caplets, capsules, chewable tablets, powder packets,
cachets, troches, wafers, aerosol sprays, or liquids, such as but
not limited to, syrups, elixirs, solutions or suspensions in an
aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or
a water-in-oil emulsion. Such compositions contain a predetermined
amount of the pharmaceutically acceptable salt of the disclosed
compounds, 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).
[0164] Due to their ease of administration, tablets and capsules
represent the most advantageous solid oral dosage unit forms, in
which case solid pharmaceutical excipients are used. If desired,
tablets can be coated by standard aqueous or nonaqueous techniques.
These 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
ingredient(s) with liquid carriers, finely divided solid carriers,
or both, and then shaping the product into the desired presentation
if necessary.
[0165] Typical oral dosage forms of the compositions are prepared
by combining the pharmaceutically acceptable salt of a compound of
Formula I, II, III, IV or V 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 the composition 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, microcrystalline cellulose,
kaolin, diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0166] Binders suitable for use in the pharmaceutical formulations
described herein 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.
[0167] Examples of fillers suitable for use in the pharmaceutical
formulations described 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 described herein is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition.
[0168] Disintegrants are used in the oral pharmaceutical
formulations described herein to provide tablets that disintegrate
when exposed to an aqueous environment. A sufficient amount of
disintegrant that is neither too little nor too much to
detrimentally alter the release of the active ingredient(s) should
be used to form solid oral dosage forms of the compounds described
herein. The amount of disintegrant used varies based upon the type
of formulation, and is readily discernible to those of ordinary
skill in the art. Disintegrants that can be used to form oral
pharmaceutical formulations include, but are not limited to, agar,
alginic acid, calcium carbonate, microcrystalline cellulose,
croscarmellose sodium, crospovidone, polacrilin potassium, sodium
starch glycolate, potato or tapioca starch, other starches,
pre-gelatinized starch, clays, other algins, other celluloses,
gums, and mixtures thereof.
[0169] Lubricants that can be used to form oral pharmaceutical
formulations of the compound of Formula I, II, III, IV or V
include, but are not limited to, calcium stearate, magnesium
stearate, mineral oil, light mineral oil, glycerin, sorbitol,
mannitol, polyethylene glycol, other glycols, stearic acid, sodium
lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,
cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and
soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar,
and mixtures thereof. Additional lubricants include, for example, a
syloid silica gel (AEROSIL.RTM. 200, manufactured by W. R. Grace
Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica
(marketed by Degussa Co. of Piano, Tex.), CAB-O-SIL.RTM. (a
pyrogenic silicon dioxide product sold by Cabot Co. of Boston,
Mass.), and mixtures thereof. If used at all, lubricants are
typically used in an amount of less than about 1 weight percent of
the pharmaceutical compositions or dosage forms into which they are
incorporated.
[0170] In other embodiments, lactose-free pharmaceutical
formulations and dosage forms are provided, wherein such
compositions preferably contain little, if any, lactose or 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. Lactose-free compositions of the disclosure can
comprise excipients which are well known in the art and are listed
in the USP (XXI)/NF (XVI), which is incorporated herein by
reference.
[0171] The oral formulations of the compound of Formula I, II, III,
IV or V further encompass, in some embodiments, anhydrous
pharmaceutical compositions and dosage forms comprising the
compound as 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, 379-80 (2nd ed., Marcel Dekker, NY,
N.Y.: 1995). Anhydrous pharmaceutical compositions and dosage forms
described herein 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. Anhydrous compositions are preferably
packaged using materials known to prevent exposure to water such
that they can be included in suitable formulary kits. Examples of
suitable packaging include, but are not limited to, hermetically
sealed foils, plastics, unit dose containers (e.g., vials) with or
without desiccants, blister packs, and strip packs.
[0172] The compound of Formula I, II, III, IV or V can be
administered directly to the airways in the form of an aerosol or
by nebulization. Accordingly, for use as aerosols, in some
embodiments, the compound can be packaged in a pressurized aerosol
container together with suitable propellants, for example,
hydrocarbon propellants like propane, butane, or isobutane with
conventional adjuvants. In other embodiments, the compound can be
administered in a non-pressurized form such as in a nebulizer or
atomizer.
[0173] The term "nebulization" is well known in the art to include
reducing liquid to a fine spray. Preferably, by such nebulization
small liquid droplets of uniform size are produced from a larger
body of liquid in a controlled manner. Nebulization can be achieved
by any suitable means, including by using many nebulizers known and
marketed today. As is well known, any suitable gas can be used to
apply pressure during the nebulization, with preferred gases being
those which are chemically inert to the compound. Exemplary gases
include, but are not limited to, nitrogen, argon or helium.
[0174] In other embodiments, the compound of Formula I, II, III, IV
or V can be administered directly to the airways in the form of a
dry powder. For use as a dry powder, the compound can be
administered by use of an inhaler. Exemplary inhalers include
metered dose inhalers and dry powdered inhalers.
[0175] Suitable powder compositions include, by way of
illustration, powdered preparations of a compound of Formula I, II,
III, IV or V thoroughly intermixed with lactose, or other inert
powders acceptable for, e.g., intrabronchial administration. The
powder compositions can be administered via an aerosol dispenser or
encased in a breakable capsule which may be inserted by the subject
into a device that punctures the capsule and blows the powder out
in a steady stream suitable for inhalation. The compositions can
include propellants, surfactants, and co-solvents and may be filled
into conventional aerosol containers that are closed by a suitable
metering valve.
[0176] Aerosols for the delivery to the respiratory tract are known
in the art. See for example, Adjei, A. and Garren, J. Pharm. Res.,
1: 565-569 (1990); Zanen, P. and Lamm, J.-W. J. Int. J. Pharm.,
114: 111-115 (1995); Gonda, I. "Aerosols for delivery of
therapeutic and diagnostic agents to the respiratory tract," in
Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313
(1990); Anderson et al., Am. Rev. Respir. Dis., 140: 1317-1324
(1989)) and have potential for the systemic delivery of peptides
and proteins as well (Patton and Platz, Advanced Drug Delivery
Reviews, 8:179-196 (1992)); Timsina et al., Int. J. Pharm., 101:
1-13 (1995); and Tansey, I. P., Spray Technol. Market, 4:26-29
(1994); French, D. L., Edwards, D. A. and Niven, R. W., Aerosol
Sci., 27: 769-783 (1996); Visser, J., Powder Technology 58: 1-10
(1989)); Rudt, S. and R. H. Muller, J. Controlled Release, 22:
263-272 (1992); Tabata, Y, and Y. Ikada, Biomed. Mater. Res., 22:
837-858 (1988); Wall, D. A., Drug Delivery, 2: 10 1-20 1995);
Patton, J. and Platz, R., Adv. Drug Del. Rev., 8: 179-196 (1992);
Bryon, P., Adv. Drug. Del. Rev., 5: 107-132 (1990); Patton, J. S.,
et al., Controlled Release, 28: 15 79-85 (1994); Damms, B. and
Bains, W., Nature Biotechnology (1996); Niven, R. W., et al.,
Pharm. Res., 12(9); 1343-1349 (1995); and Kobayashi, S., et al.,
Pharm. Res., 13(1): 80-83 (1996), contents of all of which are
herein incorporated by reference in their entirety.
[0177] Topical dosage forms of the compound of Formula I, II, III,
IV or V are also provided in some embodiments, and include, but are
not limited to, creams, lotions, ointments, gels, shampoos, sprays,
aerosols, solutions, emulsions, and other forms known to one of
skill in the art. See, e.g., Remington's Pharmaceutical Sciences,
18th ed., Mack Publishing, Easton, Pa. (1990); and Introduction to
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,
Philadelphia, Pa. (1985). For non-sprayable topical dosage forms,
viscous to semi-solid or solid forms comprising a carrier or one or
more excipients compatible with topical application and having a
dynamic viscosity preferably greater than water are typically
employed. Suitable formulations include, without limitation,
solutions, suspensions, emulsions, creams, ointments, powders,
liniments, salves, and the like, which are, if desired, sterilized
or mixed with auxiliary agents (e.g., preservatives, stabilizers,
wetting agents, buffers, or salts) for influencing various
properties, such as, for example, osmotic pressure. Other suitable
topical dosage forms include sprayable aerosol preparations wherein
the active ingredient, preferably in combination with a solid or
liquid inert carrier, is packaged in a mixture with a pressurized
volatile (e.g., a gaseous propellant, such as Freon), or in a
squeeze bottle. Moisturizers or humectants can also be added to
pharmaceutical compositions and dosage forms if desired. Examples
of such additional ingredients are well known in the art. See,
e.g., Remington's Pharmaceutical Sciences, 18.sup.th Ed., Mack
Publishing, Easton, Pa. (1990) and Introduction to Pharmaceutical
Dosage Forms, 4th Ed., Lea & Febiger, Philadelphia, Pa. (1985).
Dosage forms suitable for treating mucosal tissues within the oral
cavity can be formulated as mouthwashes, as oral gels, or as buccal
patches. Additional transdermal dosage forms include "reservoir
type" or "matrix type" patches, which can be applied to the skin
and wom for a specific period of time to permit the penetration of
a desired amount of active ingredient.
[0178] Examples of transdermal dosage forms and methods of
administration that can be used to administer a compound of Formula
I, II, III, IV or V include, but are not limited to, those
disclosed in U.S. Pat. Nos. 4,624,665; 4,655,767; 4,687,481;
4,797,284; 4,810,499; 4,834,978; 4,877,618; 4,880,633; 4,917,895;
4,927,687; 4,956,171; 5,035,894; 5,091,186; 5,163,899; 5,232,702;
5,234,690; 5,273,755; 5,273,756; 5,308,625; 5,356,632; 5,358,715;
5,372,579; 5,421,816; 5,466; 465; 5,494,680; 5,505,958; 5,554,381;
5,560,922; 5,585,111; 5,656,285; 5,667,798; 5,698,217; 5,741,511;
5,747,783; 5,770,219; 5,814,599; 5,817,332; 5,833,647; 5,879,322;
and 5,906,830, each of which are incorporated herein by reference
in their entirety.
[0179] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal and mucosal
dosage forms of the inhibitors described herein are well known to
those skilled in the pharmaceutical arts, and depend on the
particular tissue or organ to which a given pharmaceutical
composition or dosage form will be applied. In addition, depending
on the specific tissue to be treated, additional components may be
used prior to, in conjunction with, or subsequent to treatment with
a compound of Formula I, II, III, IV or V. For example, penetration
enhancers can be used to assist in delivering the active
ingredients to or across the tissue.
[0180] In some embodiments of the aspects described herein, the
pharmaceutical formulations comprising the compound of Formula I,
II, III, IV or V can further comprise more than one active compound
as necessary for the particular indication being treated,
preferably those with complementary activities that do not
adversely affect each other. For example, in some embodiments, it
can be desirable to further provide antibodies which bind to EGFR,
VEGF, VEGFR, or ErbB2 (e.g., Herceptin.TM.) in the formulation
comprising the compound of Formula I, II, III, IV or V. In other
embodiments, the formulation comprising the compound of Formula I,
II, III, IV or can comprise a cytotoxic agent, cytokine, growth
inhibitory agent and/or VEGFR antagonist. Such molecules are
suitably present in combination in amounts that are effective for
the purpose intended.
[0181] In some embodiments, the active ingredients of the
formulations comprising the compound of Formula I, II, III, IV or V
can also be entrapped in microcapsules prepared, for example, by
coacervation techniques or by interfacial polymerization, for
example, hydroxymethylcellulose or gelatin-microcapsules and
poly-(methylmethacylate) microcapsules, respectively, in colloidal
drug delivery systems (for example, liposomes, albumin
microspheres, microemulsions, nano-particles and nanocapsules) or
in macroemulsions. Such techniques are disclosed in Remington's
Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
[0182] In some embodiments of these aspects, the compound of
Formula I, II, III, IV or V can be administered to a subject by
controlled- or delayed-release means. Ideally, the use of an
optimally designed controlled-release preparation in medical
treatment is characterized by a minimum of drug substance being
employed to cure or control the condition in a minimum amount of
time. Advantages of controlled-release formulations include: 1)
extended activity of the drug; 2) reduced dosage frequency; 3)
increased patient compliance; 4) usage of less total drug; 5)
reduction in local or systemic side effects; 6) minimization of
drug accumulation; 7) reduction in blood level fluctuations; 8)
improvement in efficacy of treatment; 9) reduction of potentiation
or loss of drug activity; and 10) improvement in speed of control
of diseases or conditions. (Kim, Cherng-ju, Controlled Release
Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.:
2000)). Controlled-release formulations can be used to control the
compound's duration of action, plasma levels within the therapeutic
window, and peak blood levels. In particular, controlled- or
extended-release dosage forms or formulations can be used to ensure
that the maximum effectiveness of the compound of Formula I, II,
III, IV or V is achieved while minimizing potential adverse effects
and safety concerns, which can occur both from under-dosing a drug
(i.e., going below the minimum therapeutic levels) as well as
exceeding the toxicity level for the drug.
[0183] A variety of known controlled- or extended-release dosage
forms, formulations, and devices can be adapted for use with the
compounds of Formula I, II, III, IV or V. 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; 4,008,719; 5,674,533; 5,059,595;
5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566;
and 6,365,185 B1; each of which is incorporated ins entirety herein
by reference. These dosage forms can be used to provide slow or
controlled-release of one or more active ingredients using, for
example, hydroxypropylmethyl cellulose, other polymer matrices,
gels, permeable membranes, osmotic systems (such as OROS.RTM. (Alza
Corporation, Mountain View, Calif. USA)), multilayer coatings,
microparticles, liposomes, or microspheres or a combination thereof
to provide the desired release profile in varying proportions.
Additionally, ion exchange materials can be used to prepare
immobilized, adsorbed salt forms of the disclosed compounds and
thus effect controlled delivery of the drug. Examples of specific
anion exchangers include, but are not limited to, Duolite.RTM. A568
and Duolite.RTM. AP143 (Rohm&Haas, Spring House, Pa. USA).
[0184] In some embodiments of the various aspects described herein,
the compound of Formula I, II, III, IV or V is administered to a
subject by sustained release or in pulses. Pulse therapy is not a
form of discontinuous administration of the same amount of a
composition over time, but comprises administration of the same
dose of the composition at a reduced frequency or administration of
reduced doses. Sustained release or pulse administrations are
particularly preferred in chronic conditions, such as cancer, as
each pulse dose can be reduced and the total amount of the compound
administered over the course of treatment to the patient is
minimized.
[0185] The interval between pulses, when necessary, can be
determined by one of ordinary skill in the art. Often, the interval
between pulses can be calculated by administering another dose of
the composition when the composition or the active component of the
composition is no longer detectable in the subject prior to
delivery of the next pulse. Intervals can also be calculated from
the in vivo half-life of the composition. Intervals may be
calculated as greater than the in vivo half-life, or 2, 3, 4, 5 and
even 10 times greater the composition half-life. Various methods
and apparatus for pulsing compositions by infusion or other forms
of delivery to the patient are disclosed in U.S. Pat. Nos.
4,747,825; 4,723,958; 4,948,592; 4,965,251 and 5,403,590.
[0186] In some embodiments, sustained-release preparations
comprising the compound of Formula I, II, II, IV or V can be
prepared. Suitable examples of sustained-release preparations
include semipermeable matrices of solid hydrophobic polymers
containing the compound, in which matrices are in the form of
shaped articles, e.g., films, or microcapsule. Examples of
sustained-release matrices include polyesters, hydrogels (for
example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),
polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic
acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl
acetate, degradable lactic acid-glycolic acid copolymers such as
the LUPRON DEPOT.TM. (injectable microspheres composed of lactic
acid-glycolic acid copolymer and leuprolide acetate), and
poly-D-(-)-3-hydroxybutyric acid.
[0187] The formulations comprising the compound of Formula I, II,
III, IV or V to be used for in vivo administration are preferably
sterile. This is readily accomplished by filtration through, for
example, sterile filtration membranes, and other methods known to
one of skill in the art.
[0188] One key advantage of the methods, uses and compositions
comprising the compound of Formula I, II, III, IV or V is the
ability of producing marked anti-cancer effects in a human subject
without causing significant toxicities or adverse effects. The
efficacy of the treatments described herein can be measured by
various parameters commonly used in evaluating cancer treatments,
including but not limited to, tumor regression, tumor weight or
size shrinkage, reduction in rate of tumor growth, the presence or
the size of a dormant tumor, the presence or size of metastases or
micrometastases, degree of tumor or cancer invasiveness, size or
number of the blood vessels, time to progression, duration of
survival, progression free survival, overall response rate,
duration of response, and quality of life. For example, tumor
shrinkage of greater than 50% in a 2-dimensional analysis is the
standard cut-off for declaring a response. However, in some
embodiments, the compositions comprising the compound of Formula I,
II, III, IV or V can be used to cause inhibition of metastatic
spread without shrinkage of the primary tumor, or can simply exert
a tumoristatic effect. In the case of cancers, the therapeutically
effective amount of the compositions comprising the compound of
Formula I, II, III, IV or V can reduce the number of cancer cells;
reduce the tumor size; inhibit (i.e., slow to some extent and
preferably stop) cancer cell infiltration into peripheral organs;
inhibit (i.e., slow to some extent and preferably stop) tumor
metastasis; inhibit, to some extent, tumor growth; and/or relieve
to some extent one or more of the symptoms associated with the
disorder. To the extent the compositions comprising the compound of
Formula I, II, III, IV or V can prevent growth and/or kill existing
cancer cells, it can be cytostatic and/or cytotoxic. For cancer
therapy, efficacy in vivo can, for example, be measured by
assessing the duration of survival, duration of progression free
survival (PFS), the response rates (RR), duration of response,
and/or quality of life.
[0189] In some embodiments, methods for increasing progression free
survival of a human subject susceptible to or diagnosed with a
cancer are described herein. "Time to disease progression," as used
herein, is defined as the time from administration of the drug
until disease progression or death. In a preferred embodiments, the
method of treatments described herein using the compound of Formula
I, II, III, IV or V, and, in some further embodiments, one or more
chemotherapeutic agents, significantly increases progression free
survival by at least about 1 month, at least about 2 months, at
least about 3 months, at least about 4 months, at least about 5
months, at least about 6 months, at least about 7 months, at least
about 8 months, at least about 9 months, at least about 10 months,
at least about 11 months, when compared to no treatment or a
treatment with chemotherapy alone.
[0190] In other embodiments, the methods of treatment described
herein significantly increase response rate in a group of human
subjects susceptible to or diagnosed with a cancer who are treated
with various therapeutics. "Response rate," as used herein, is
defined as the percentage of treated subjects who responded to the
treatment. In some such embodiments, the combination treatments
described herein comprising using a compound of Formula I, II, III,
IV or V and, in some further embodiments, one or more
chemotherapeutic agents, significantly increases response rate in
the treated subject group compared to an untreated group or a group
treated with chemotherapy alone.
[0191] In other embodiments of these methods, the administration of
a compound of Formula I, II, III, IV or V is used for increasing
duration of response in a human subject or a group of human
subjects susceptible to or diagnosed with a cancer. As used herein,
"duration of response" is defined as the time from the initial
response to disease progression. In some such embodiments, the
compound of Formula I, II, III, IV or V can be used for increasing
the duration of survival of a human subject susceptible to or
diagnosed with a cancer.
[0192] As used herein, the terms "treat," "treatment," "treating,"
or "amelioration" refer to therapeutic treatments, wherein the
object is to reverse, alleviate, ameliorate, inhibit, slow down or
stop the progression or severity of a condition associated with, a
disease or disorder. The term "treating" includes reducing or
alleviating at least one adverse effect or symptom of a condition,
disease or disorder associated with a chronic immune condition,
such as, but not limited to, a chronic infection or a cancer.
Treatment is generally "effective" if one or more symptoms or
clinical markers are reduced. Alternatively, treatment is
"effective" if the progression of a disease is reduced or halted.
That is, "treatment" includes not just the improvement of symptoms
or markers, but also a cessation of at least slowing of progress or
worsening of symptoms that would be expected in absence of
treatment. Beneficial or desired clinical results include, but are
not limited to, alleviation of one or more symptom(s), diminishment
of extent of disease, stabilized (i.e., not worsening) state of
disease, delay or slowing of disease progression, amelioration or
palliation of the disease state, and remission (whether partial or
total), whether detectable or undetectable. The term "treatment" of
a disease also includes providing relief from the symptoms or
side-effects of the disease (including palliative treatment).
[0193] For example, in some embodiments, the methods described
herein comprise administering an effective amount of the compound
of Formula I, II, III, IV or V to a subject in order to alleviate a
symptom of a cancer, or other such disorder. As used herein,
"alleviating a symptom of a cancer" is ameliorating or reducing any
condition or symptom associated with the cancer. As compared with
an equivalent untreated control, such reduction or degree of
prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%,
or 100% as measured by any standard technique. Ideally, the cancer
is completely cleared as detected by any standard method known in
the art, in which case the cancer is considered to have been
treated. A patient who is being treated for a cancer is one who a
medical practitioner has diagnosed as having such a condition.
Diagnosis can be by any suitable means. Diagnosis and monitoring
can involve, for example, detecting the level of cancer cells in a
biological sample (for example, a tissue or lymph node biopsy,
blood test, or urine test), detecting the level of a surrogate
marker of the cancer in a biological sample, detecting symptoms
associated with the specific cancer, or detecting immune cells
involved in the immune response typical of such a cancer
infections.
[0194] In some embodiments, the compositions and methods comprising
the compound of Formula I, II, III, IV or V further comprise
administration or treatment with one or more additional cancer
therapies. Examples of anti-cancer therapies include, without
limitation, surgery, radiation therapy (radiotherapy), biotherapy,
immunotherapy, chemotherapy, or a combination of these therapies.
In addition, cytotoxic agents, anti-angiogenic and
anti-proliferative agents can be used in combination with the
compounds of Formula I, II, III, IV or V.
[0195] For the treatment of cancer in such embodiments comprising
combination therapies, the appropriate dosage of a compound of
Formula I, II, III, IV or V will depend on the type of disease to
be treated, as defined above, the severity and course of the
disease, whether the compound is administered for preventive or
therapeutic purposes, previous therapy, the subject's clinical
history and response to the compound, and the discretion of the
attending physician. The compound can be suitably administered to
the subject at one time or over a series of treatments.
[0196] In those embodiments where a combination therapy regimen is
applied, the compound of Formula I, II, III, IV or V and one or
more anti-cancer therapeutic agents as described herein are
administered in a therapeutically effective or synergistic amount.
As used in such embodiments encompassing combination therapies, a
therapeutically effective amount is such that co-administration of
the compound of Formula I, II, III, IV or V, and one or more other
therapeutic agents, or administration of a therapeutic composition
or formulation comprising a compound of Formula I, II, III, IV or
V, results in reduction or inhibition of the cancer as described
herein. A "therapeutically synergistic amount" is that amount of
the compound of Formula I, II, III, IV or V, and one or more other
therapeutic agents necessary to synergistically or significantly
reduce or eliminate conditions or symptoms associated with a
particular cancer.
[0197] In some embodiments, a compound of Formula I, II, III, IV or
V, and one or more other therapeutic agents can be administered
simultaneously or sequentially in an amount and for a time
sufficient to reduce or eliminate the occurrence or recurrence of a
tumor, a dormant tumor, or a micrometastases. In some embodiments,
the compound of Formula I, II, III, IV or V, and one or more other
therapeutic agents can be administered as maintenance therapy to
prevent or reduce the likelihood of recurrence of the tumor.
[0198] As will be understood by those of ordinary skill in the art,
the appropriate doses of chemotherapeutic agents or other
anti-cancer agents will be generally around those already employed
in clinical therapies, e.g., where the chemotherapeutics are
administered alone or in combination with other chemotherapeutics.
Variation in dosage will likely occur depending on the condition
being treated. The physician administering treatment will be able
to determine the appropriate dose for the individual subject.
[0199] In addition to the above therapeutic regimes, the subject
can be subjected to radiation therapy.
[0200] The term "anti-cancer therapy" refers to a therapy useful in
treating, inhibiting, reducing severity of, slowing progression of
and/or preventing metastasis of cancer. Examples of anti-cancer
therapeutic agents include, but are limited to, e.g., surgery,
radiation therapy, chemotherapeutic agents, growth inhibitory
agents, cytotoxic agents, agents used in radiation therapy,
anti-angiogenesis agents, apoptotic agents, anti-tubulin agents,
and other agents to treat cancer, such as anti-HER-2 antibodies
(e.g., Herceptin.TM.), anti-CD20 antibodies, an epidermal growth
factor receptor (EGFR) antagonist (e.g., a tyrosine kinase
inhibitor), HER/EGFR inhibitor (e.g., erlotinib (Tarceva.TM.),
platelet derived growth factor inhibitors (e.g., Gleevec.TM.
(Imatinib Mesylate)), a COX-2 inhibitor (e.g., celecoxib),
interferons, cytokines, antagonists (e.g., neutralizing antibodies)
that bind to one or more of the following targets ErbB2, ErbB3,
ErbB4, PDGFR-beta, BlyS, APRIL, BCMA or VEGF receptor(s),
TRAIL/Apo2, and other bioactive and organic chemical agents, etc.
Combinations thereof are also included in the embodiments described
herein.
[0201] The term "cytotoxic agent" as used herein refers to a
substance that inhibits or prevents the function of cells and/or
causes destruction of cells. The term is intended to include
radioactive isotopes (e.g. At.sup.211, I.sup.131, I.sup.125,
Y.sup.90, Re.sup.186, Re.sup.188, Sm.sup.153, Bi.sup.212, P.sup.32
and radioactive isotopes of Lu), chemotherapeutic agents, and
toxins such as small molecule toxins or enzymatically active toxins
of bacterial, fungal, plant or animal origin, including fragments
and/or variants thereof.
[0202] As used herein, a "chemotherapeutic agent" is a chemical
compound useful in the treatment of cancer. Examples of
chemotherapeutic agents include, but are not limited to, alkylating
agents such as thiotepa and CYTOXAN.TM. cyclosphosphamide; alkyl
sulfonates such as busulfan, improsulfan and piposulfan; aziridines
such as benzodopa, carboquone, meturedopa, and uredopa;
ethylenimines and methylamelamines including altretamine,
triethylenemelamine, trietylenephosphoramide,
triethiylenethiophosphoramide and trimethylolomelamine; acetogenins
(especially bullatacin and bullatacinone); a camptothecin
(including the synthetic analogue topotecan); bryostatin;
callystatin; CC-1065 (including its adozelesin, carzelesin and
bizelesin synthetic analogues); cryptophycins (particularly
cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin
(including the synthetic analogues, KW-2189 and CB1-TM1);
eleutherobin; pancratistatin; a sarcodictyin; spongistatin;
nitrogen mustards such as chlorambucil, chlornaphazine,
cholophosphamide, estramustine, ifosfamide, mechlorethamine,
mechlorethamine oxide hydrochloride, melphalan, novembichin,
phenesterine, prednimustine, trofosfamide, uracil mustard;
nitrosureas such as carmustine, chlorozotocin, fotemustine,
lomustine, nimustine, and ranimnustine; antibiotics such as the
enediyne antibiotics (e.g., calicheamicin, especially calicheamicin
gamma II and calicheamicin omegaII (see, e.g., Agnew, Chem. Intl.
Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A;
bisphosphonates, such as clodronate; an esperamicin; as well as
neocarzinostatin chromophore and related chromoprotein enediyne
antiobiotic chromophores), aclacinomysins, actinomycin,
authramycin, azaserine, bleomycins, cactinomycin, carabicin,
caminomycin, carzinophilin, chromomycinis, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,
ADRIAMYCIN.TM., doxorubicin (including morpholino-doxorubicin,
cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and
deoxydoxorubicin), epirubicin, esorubicin, idarubicin,
marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,
quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,
ubenimex, zinostatin, zorubicin; anti-metabolites such as
methotrexate and 5-fluorouracil (5-FU); folic acid analogues such
as denopterin, methotrexate, pteropterin, trimetrexate; purine
analogs such as fludarabine, 6-mercaptopurine, thiamiprine,
thioguanine; pyrimidine analogs such as ancitabine, azacitidine,
6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,
enocitabine, floxuridine; androgens such as calusterone,
dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elformithine; elliptinium
acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
lentinan; lonidainine; maytansinoids such as maytansine and
ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine;
pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic
acid; 2-ethylhydrazide; procarbazine; PSK.TM., polysaccharide
complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;
sizofuran; spirogermanium; tenuazonic acid; triaziquone;
2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2
toxin, verracurin A, roridin A and anguidine); urethan; vindesine;
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;
gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa;
taxoids, e.g., TAXOL.TM., paclitaxel (Bristol-Myers Squibb
Oncology, Princeton, N.J.), ABRAXANE.TM., Cremophor-free,
albumin-engineered nanoparticle formulation of paclitaxel (American
Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE.TM.,
doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;
GEMZAR.TM. gemcitabine; 6-thioguanine; mercaptopurine;
methotrexate; platinum analogs such as cisplatin, oxaliplatin and
carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;
mitoxantrone; vincristine; NAVELBINE.RTM. vinorelbine; novantrone;
teniposide; edatrexate; daunomycin; aminopterin; xeloda;
ibandronate; irinotecan (Camptosar, CPT-11) (including the
treatment regimen of irinotecan with 5-FU and leucovorin);
topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);
retinoids such as retinoic acid; capecitabine; combretastatin;
leucovorin (LV); oxaliplatin, including the oxaliplatin treatment
regimen (FOLFOX); lapatinib (Tykerb.TM.); inhibitors of PKC-alpha,
Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva.TM..)) and VEGF-A that
reduce cell proliferation and pharmaceutically acceptable salts,
acids or derivatives of any of the above.
[0203] Also included in this definition are anti-hormonal agents
that act to regulate or inhibit hormone action on tumors such as
anti-estrogens and selective estrogen receptor modulators (SERMs),
including, for example, tamoxifen (including NOLVADEX.TM.
tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen,
trioxifene, keoxifene, LY17018, onapristone, and FARESTON
toremifene; aromatase inhibitors that inhibit the enzyme aromatase,
which regulates estrogen production in the adrenal glands, such as,
for example, 4(5)-imidazoles, aminoglutethimide, MEGASE.TM.
megestrol acetate, AROMASIN.TM. exemestane, formestanie, fadrozole,
RIVISOR.TM. vorozole, FEMARA.TM. letrozole, and ARIMIDEX.TM.
anastrozole; and anti-androgens such as flutamide, nilutamide,
bicalutamide, leuprolide, and goserelin; as well as troxacitabine
(a 1,3-dioxolane nucleoside cytosine analog); antisense
oligonucleotides, particularly those which inhibit expression of
genes in signaling pathways implicated in aberrant cell
proliferation, such as, for example, PKC-alpha, Ralf and H-Ras;
ribozymes such as a VEGF expression inhibitor (e.g., ANGIOZYME.TM.
ribozyme) and a HER2 expression inhibitor; vaccines such as gene
therapy vaccines, for example, ALLOVECTIN.TM. vaccine,
LEUVECTIN.TM. vaccine, and VAXID.TM. vaccine; PROLEUKIN.TM. rIL-2;
LURTOTECAN.TM. topoisomerase 1 inhibitor; ABARELIX.TM. rmRH; and
pharmaceutically acceptable salts, acids or derivatives of any of
the above.
[0204] The term "cytokine" is a generic term for proteins released
by one cell population which act on another cell as intercellular
mediators. Examples of such cytokines are lymphokines, monokines,
and traditional polypeptide hormones. Included among the cytokines
are growth hormone such as human growth hormone, N-methionyl human
growth hormone, and bovine growth hormone; parathyroid hormone;
thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein
hormones such as follicle stimulating hormone (FSH), thyroid
stimulating hormone (TSH), and luteinizing hormone (LH); epidermal
growth factor; hepatic growth factor; fibroblast growth factor;
prolactin; placental lactogen; tumor necrosis factor-alpha and
-beta; mullerian-inhibiting substance; mouse
gonadotropin-associated peptide; inhibin; activin; vascular
endothelial growth factor; integrin; thrombopoietin (TPO); nerve
growth factors such as NGF-alpha; platelet-growth factor;
transforming growth factors (TGFs) such as TGF-alpha and TGF-beta;
insulin-like growth factor-I and -II; erythropoietin (EPO);
osteoinductive factors; interferons such as interferon-alpha, -beta
and -gamma colony stimulating factors (CSFs) such as macrophage-CSF
(M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF
(G-CSF); interleukins (ILs) such as IL-1, IL-1alpha, IL-2, IL-3,
IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12; a tumor
necrosis factor such as TNF-alpha or TNF-beta; and other
polypeptide factors including LIF and kit ligand (KL). As used
herein, the term cytokine includes proteins from natural sources or
from recombinant cell culture and biologically active equivalents
of the native sequence cytokines.
[0205] A "growth inhibitory agent" when used herein refers to a
compound or composition which inhibits growth of a cell in vitro
and/or in vivo. Thus, the growth inhibitory agent may be one which
significantly reduces the percentage of cells in S phase. Examples
of growth inhibitory agents include agents that block cell cycle
progression (at a place other than S phase), such as agents that
induce G1 arrest and M-phase arrest. Classical M-phase blockers
include the vincas (vincristine and vinblastine), TAXOL.TM., and
topo II inhibitors such as doxorubicin, epirubicin, daunorubicin,
etoposide, and bleomycin. Those agents that arrest G1 also spill
over into S-phase arrest, for example, DNA alkylating agents such
as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin,
methotrexate, 5-fluorouracil, and ara-C. Further information can be
found in The Molecular Basis of Cancer, Mendelsohn and Israel,
eds., Chapter 1, entitled "Cell cycle regulation, oncogenes, and
antineoplastic drugs" by Murakami et al. (WB Saunders:
Philadelphia, 1995), especially p. 13.
[0206] By "radiation therapy" is meant the use of directed gamma
rays or beta rays to induce sufficient damage to a cell so as to
limit its ability to function normally or to destroy the cell
altogether. It will be appreciated that there will be many ways
known in the art to determine the dosage and duration of treatment.
Typical treatments are given as a one time administration and
typical dosages range from 10 to 200 units (Grays) per day.
Some Selected Definitions
[0207] For convenience, certain terms employed herein, in the
specification, examples and appended claims are collected herein.
Unless stated otherwise, or implicit from context, the following
terms and phrases include the meanings provided below. Unless
explicitly stated otherwise, or apparent from context, the terms
and phrases below do not exclude the meaning that the term or
phrase has acquired in the art to which it pertains. The
definitions are provided to aid in describing particular
embodiments, and are not intended to limit the claimed invention,
because the scope of the invention is limited only by the claims.
Further, unless otherwise required by context, singular terms shall
include pluralities and plural terms shall include the
singular.
[0208] Unless otherwise defined herein, scientific and technical
terms used in connection with the present application shall have
the meanings that are commonly understood by those of ordinary
skill in the art to which this disclosure belongs. It should be
understood that this invention is not limited to the particular
methodology, protocols, and reagents, etc., described herein and as
such can vary. The terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to
limit the scope of the present invention, which is defined solely
by the claims. Definitions of common terms in immunology, and
molecular biology can be found in The Merck Manual of Diagnosis and
Therapy, 18th Edition, published by Merck Research Laboratories,
2006 (ISBN 0-911910-18-2); Robert S. Porter et al. (eds.), The
Encyclopedia of Molecular Biology, published by Blackwell Science
Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.),
Molecular Biology and Biotechnology: a Comprehensive Desk
Reference, published by VCH Publishers, Inc., 1995 (ISBN
1-56081-569-8); Immunology by Werner Luttmann, published by
Elsevier, 2006. Definitions of common terms in molecular biology
are found in Benjamin Lewin, Genes IX, published by Jones &
Bartlett Publishing, 2007 (ISBN-13: 9780763740634); Kendrew et al.
(eds.), The Encyclopedia of Molecular Biology, published by
Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A.
Meyers (ed.), Maniatis et al., Molecular Cloning: A Laboratory
Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,
N.Y., USA (1982); Sambrook et al., Molecular Cloning: A Laboratory
Manual (2 ed.), Cold Spring Harbor Laboratory Press, Cold Spring
Harbor, N.Y., USA (1989); Davis et al., Basic Methods in Molecular
Biology, Elsevier Science Publishing, Inc., New York, USA (1986);
or Methods in Enzymology: Guide to Molecular Cloning Techniques
Vol. 152, S. L. Berger and A. R. Kimmerl Eds., Academic Press Inc.,
San Diego, USA (1987); Current Protocols in Molecular Biology
(CPMB) (Fred M. Ausubel, et al. ed., John Wiley and Sons, Inc.),
Current Protocols in Protein Science (CPPS) (John E. Coligan, et.
al., ed., John Wiley and Sons, Inc.) and Current Protocols in
Immunology (CPI) (John E. Coligan, et. al., ed. John Wiley and
Sons, Inc.), which are all incorporated by reference herein in
their entireties.
[0209] As used herein the term "comprising" or "comprises" is used
in reference to compositions, methods, and respective component(s)
thereof, that are essential to the invention, yet open to the
inclusion of unspecified elements, whether essential or not.
[0210] As used herein the term "consisting essentially of" refers
to those elements required for a given embodiment. The term permits
the presence of additional elements that do not materially affect
the basic and novel or functional characteristic(s) of that
embodiment of the invention.
[0211] The term "consisting of" refers to compositions, methods,
and respective components thereof as described herein, which are
exclusive of any element not recited in that description of the
embodiment.
[0212] The singular terms "a," "an," and "the" include plural
referents unless context clearly indicates otherwise. Similarly,
the word "or" is intended to include "and" unless the context
clearly indicates otherwise.
[0213] Other than in the operating examples, or where otherwise
indicated, all numbers expressing quantities of ingredients or
reaction conditions used herein should be understood as modified in
all instances by the term "about." The term "about" when used in
connection with percentages may mean.+-.5% of the value being
referred to. For example, about 100 means from 95 to 105. In some
embodiments, the term "about" when used in connection with
percentages may mean.+-.1% of the value being referred to
[0214] Although methods and materials similar or equivalent to
those described herein can be used in the practice or testing of
this disclosure, suitable methods and materials are described
below. The term "comprises" means "includes." The abbreviation,
"e.g." is derived from the Latin exempli gratia, and is used herein
to indicate a non-limiting example. Thus, the abbreviation "e.g."
is synonymous with the term "for example."
[0215] The terms "decrease", "reduced", "reduction", "decrease" or
"inhibit" are all used herein generally to mean a decrease by a
statistically significant amount. However, for avoidance of doubt,
"reduced", "reduction" or "decrease" or "inhibit" means a decrease
by at least 10% as compared to a reference level, for example a
decrease by at least about 20%, or at least about 30%, or at least
about 40%, or at least about 50%, or at least about 60%, or at
least about 70%, or at least about 80%, or at least about 90% or up
to and including a 100% decrease (e.g. absent level as compared to
a reference sample), or any decrease between 10-100% as compared to
a reference level.
[0216] The terms "increased", "increase" or "enhance" or "activate"
are all used herein to generally mean an increase by a statically
significant amount; for the avoidance of any doubt, the terms
"increased", "increase" or "enhance" or "activate" means an
increase of at least 10% as compared to a reference level, for
example an increase of at least about 20%, or at least about 30%,
or at least about 40%, or at least about 50%, or at least about
60%, or at least about 70%, or at least about 80%, or at least
about 90% or up to and including a 100% increase or any increase
between 10-100% as compared to a reference level, or at least about
a 2-fold, or at least about a 3-fold, or at least about a 4-fold,
or at least about a 5-fold or at least about a 10-fold increase, or
any increase between 2-fold and 10-fold or greater as compared to a
reference level.
[0217] The term "statistically significant" or "significantly"
refers to statistical significance and generally means at least two
standard deviation (2SD) away from a reference level. The term
refers to statistical evidence that there is a difference. It is
defined as the probability of making a decision to reject the null
hypothesis when the null hypothesis is actually true.
[0218] The term "modulate" in reference to a RelA modulator is used
consistently with its use in the art, e.g., meaning to cause or
facilitate a qualitative or quantitative change, alteration, or
modification in one or more biological processes, mechanisms,
effects, responses, functions, activities, pathways, or other
phenomena of interest. Accordingly, as used herein, modulate refers
to a qualitative or quantitative change, alteration, or
modification in one or more processes, mechanisms, effects,
responses, functions, activities or pathways mediated by RelA.
[0219] As used herein, the term "RelA modulator" refers to an agent
that causes or facilitates a qualitative or quantitative change,
alteration, or modification in one or more processes, mechanisms,
effects, responses, functions, activities or pathways mediated by
the RelA. Such changes mediated by an RelA modulator, such as an
inhibitor of the RelA described herein, can refer to a decrease or
an increase in the activity or function of the RelA, such as a
decrease in, inhibition of, or diversion of, constitutive activity
of the RelA. The terms "inhibitor of RelA" or "RelA inhibitor"
refers to an agent or compound that inhibits one or more
constitutive activity of RelA. For example, but not limited to, DNA
binding activity of RelA.
[0220] The terms "subject" and "individual" are used
interchangeably herein, and mean a human or animal. Usually the
animal is a vertebrate such as a primate, rodent, domestic animal
or game animal. Primates include chimpanzees, cynomologous monkeys,
spider monkeys, and macaques, e.g., Rhesus. Rodents include mice,
rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game
animals include cows, horses, pigs, deer, bison, buffalo, feline
species, e.g., domestic cat, canine species, e.g., dog, fox, wolf,
avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout,
catfish and salmon. Patient or subject includes any subset of the
foregoing, e.g., all of the above, but excluding one or more groups
or species such as humans, primates or rodents. In certain
embodiments, the subject is a mammal, e.g., a primate, e.g., a
human. The terms, "patient" and "subject" are used interchangeably
herein. The terms, "patient" and "subject" are used interchangeably
herein.
[0221] Preferably, the subject is a mammal. The mammal can be a
human, non-human primate, mouse, rat, dog, cat, horse, or cow, but
are not limited to these examples. Mammals other than humans can be
advantageously used as subjects that represent animal models of PH,
PAH, or fibrotic or fibroproliferative disease.
[0222] In addition, the methods described herein can be used to
treat domesticated animals and/or pets. Without limitations, a
subject can be male or female.
[0223] The terms "cancer" and "cancerous" refer to or describe the
physiological condition in mammals that is typically characterized
by unregulated cell growth or proliferation, which interferes with
the normal functioning of the bodily organs and systems.
Accordingly, the terms "cancer" or "tumor" as used herein refers to
an uncontrolled growth of cells which interferes with the normal
functioning of the bodily organs and systems, including cancer stem
cells and tumor vascular niches. A subject that has a cancer or a
tumor is a subject having objectively measurable cancer cells
present in the subject's body. Cancers which migrate from their
original location and seed vital organs can eventually lead to the
death of the subject through the functional deterioration of the
affected organs. Hematopoietic cancers, such as leukemia, are able
to out-compete the normal hematopoietic compartments in a subject,
thereby leading to hematopoietic failure (in the form of anemia,
thrombocytopenia and neutropenia) ultimately causing death.
Included in this definition are benign and malignant cancers, as
well as dormant tumors or micrometastases.
[0224] A "metastasis" refers to the spread of cancer from its
primary site to other places in the body. Cancer cells can break
away from a primary tumor, penetrate into lymphatic and blood
vessels, circulate through the bloodstream, and grow in a distant
focus (metastasize) in normal tissues elsewhere in the body.
Metastasis can be local or distant. Metastasis is a sequential
process, contingent on tumor cells breaking off from the primary
tumor, traveling through the bloodstream, and stopping at a distant
site. At the new site, the cells establish a blood supply and can
grow to form a life-threatening mass. Both stimulatory and
inhibitory molecular pathways within the tumor cell regulate this
behavior, and interactions between the tumor cell and host cells in
the distant site are also significant.
[0225] Metastases are most often detected through the sole or
combined use of magnetic resonance imaging (MRI) scans, computed
tomography (CT) scans, blood and platelet counts, liver function
studies, chest X-rays and bone scans in addition to the monitoring
of specific symptoms.
[0226] Accordingly, cancers that can be treated using the
compositions and methods described in the various aspects herein
include, but are not limited to, carcinoma, lymphoma, blastoma,
sarcoma, and leukemia. More particular examples of such cancers
include, but are not limited to, breast cancer; basal cell
carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain
and CNS cancer; cancer of the peritoneum; cervical cancer;
choriocarcinoma; colon and rectum cancer; connective tissue cancer;
cancer of the digestive system; endometrial cancer; esophageal
cancer; eye cancer; cancer of the head and neck; gastric cancer
(including gastrointestinal cancer); glioblastoma; hepatic
carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal
cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g.,
small-cell lung cancer, non-small cell lung cancer, adenocarcinoma
of the lung, and squamous carcinoma of the lung); lymphoma
including Hodgkin's and non-Hodgkin's lymphoma; melanoma; myeloma;
neuroblastoma; glioblastoma; oral cavity cancer (e.g., lip, tongue,
mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate
cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of
the respiratory system; salivary gland carcinoma; sarcoma; skin
cancer; squamous cell cancer; stomach cancer; testicular cancer;
thyroid cancer; uterine or endometrial cancer; cancer of the
urinary system; vulval cancer; as well as other carcinomas and
sarcomas; as well as B-cell lymphoma (including low
grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic
(SL) NHL; intermediate grade/follicular NHL; intermediate grade
diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic
NHL; high grade small non-cleaved cell NHL; bulky disease NHL;
mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's
Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute
lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic
myeloblastic leukemia; and post-transplant lymphoproliferative
disorder (PTLD), as well as abnormal vascular proliferation
associated with phakomatoses, edema (such as that associated with
brain tumors), and Meigs' syndrome.
[0227] In some embodiments, a cancer can be a solid tumor. As used
herein, a "solid tumor" refers to an abnormal mass of tissue that
usually does not contain cysts or liquid areas. Solid tumors can be
benign or malignant. Different types of solid tumors are named for
the type of cells that form them. Non-limiting examples of solid
tumors are sarcomas, carcinomas, and lymphomas. Leukemias and other
cancers of the blood generally do not form solid tumors and are not
hence encompassed by the term `solid tumor` as used herein.
[0228] In some embodiments, cancer is breast cancer. In some
further embodiments, cancer is triple negative breast cancer.
Triple-negative breast cancer refers to any breast cancer that does
not express the genes for estrogen receptor (ER), progesterone
receptor (PR) or Her2/neu. This makes it more difficult to treat
since most chemotherapies target one of the three receptors, so
triple-negative cancers often require combinatorial therapies.
Triple negative is sometimes used as a surrogate term for
basal-like; however, more detailed classification may provide
better guidance for treatment and better estimates for
prognosis.
[0229] Triple-negative breast cancers comprise a very heterogeneous
group of cancers. There is conflicting information over prognosis
for the various subtypes but it appears that the Nottingham
prognostic index is valid and hence general prognosis is rather
similar with other breast cancer of same stage, except that more
aggressive treatment is required. Some types of triple-negative
breast cancer are known to be more aggressive with poor prognosis,
while other types have prognosis very similar or better than
hormone receptor positive breast cancers. Pooled data of all
triple-negative subtypes suggest that with optimal treatment
20-year survival rates are very close to those of hormone positive
cancer.
[0230] Triple-negative breast cancers have a relapse pattern that
is very different from hormone-positive breast cancers: the risk of
relapse is much higher for the first 3-5 years but drops sharply
and substantially below that of hormone-positive breast cancers
after that. This relapse pattern has been recognized for all types
of triple-negative cancers for which sufficient data exists
although the absolute relapse and survival rates differ across
subtypes.
[0231] Triple-negative breast cancers are sometimes classified into
"basal-type" and other cancers. However, there is no standard
classification scheme. Basal type cancers are frequently defined by
cytokeratin 5/6 and EGFR staining. However, no clear criteria or
cutoff values have been standardized yet.
http://en.wikipedia.org/wiki/Triple-negative_breast_cancer-cite_note-Hudi-
s_2011-2 About 75% of basal-type breast cancers are triple
negative.
[0232] Some TNBC overexpresses epidermal growth factor receptor
(EGFR). Some TNBC over expresses transmembrane glycoprotein NMB
(GPNMB).
[0233] Upon histologic examination, triple-negative breast tumors
mostly fall into the categories of secretory cell carcinoma or
adenoid cystic types (both considered less aggressive); medullary
cancers and grade 3 invasive ductal carcinomas with no specific
subtype; and highly aggressive
[0234] The term "anti-cancer therapy" refers to a therapy or
therapeutic agent useful in treating, inhibiting, reducing severity
of, slowing progression of and/or preventing metastasis of cancer.
Examples of anti-cancer therapeutic agents include, but are limited
to, e.g., surgery, chemotherapeutic agents, growth inhibitory
agents, cytotoxic agents, agents used in radiation therapy,
anti-angiogenesis agents, apoptotic agents, anti-tubulin agents,
and other agents to treat cancer, such as anti-HER-2 antibodies
(e.g., Herceptin.TM.), anti-CD20 antibodies, an epidermal growth
factor receptor (EGFR) antagonist (e.g., atyrosine kinase
inhibitor), HER1/EGFR inhibitor (e.g., erlotinib (Tarceva.TM.),
platelet derived growth factor inhibitors (e.g., Gleevec.TM.
(Imatinib Mesylate)), a COX-2 inhibitor (e.g., celecoxib),
interferons, cytokines, antagonists (e.g., neutralizing antibodies)
that bind to one or more of the following targets ErbB2, ErbB3,
ErbB4, PDGFR-beta, BlyS, APRIL, BCMA or VEGF receptor(s),
TRAIL/Apo2, PARP inhibitors, HDAC inhibitors and other bioactive
and organic chemical agents, etc. Combinations thereof are also
included in the embodiments described herein.
[0235] Other than in the operating examples, or where otherwise
indicated, all numbers expressing quantities of ingredients or
reaction conditions used herein should be understood as modified in
all instances by the term "about." The term "about" when used in
connection with percentages can mean.+-.1%.
[0236] As used herein, the term "aliphatic" means a moiety
characterized by a straight or branched chain arrangement of
constituent carbon atoms and can be saturated or partially
unsaturated with one or more (e.g., one, two, three, four, five or
more) double or triple bonds.
[0237] As used herein, the term "alicyclic" means a moiety
comprising a nonaromatic ring structure. Alicyclic moieties can be
saturated or partially unsaturated with one or more double or
triple bonds. Alicyclic moieties can also optionally comprise
heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms
can be optionally quaternized or oxidized and the sulfur atoms can
be optionally oxidized. Examples of alicyclic moieties include, but
are not limited to moieties with C.sub.3-C.sub.8 rings such as
cyclopropyl, cyclohexane, cyclopentane, cyclopentene,
cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene,
cycloheptane, cycloheptene, cycloheptadiene, cyclooctane,
cyclooctene, and cyclooctadiene.
[0238] As used herein, the term "alkyl" means a straight or
branched, saturated aliphatic radical having a chain of carbon
atoms. C.sub.x alkyl and C.sub.x-C.sub.yalkyl are typically used
where X and Y indicate the number of carbon atoms in the chain. For
example, C.sub.1-C.sub.6alkyl includes alkyls that have a chain of
between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl,
butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl,
and the like). Alkyl represented along with another radical (e.g.,
as in arylalkyl) means a straight or branched, saturated alkyl
divalent radical having the number of atoms indicated or when no
atoms are indicated means a bond, e.g.,
(C.sub.6-C.sub.10)aryl(C.sub.0-C.sub.3)alkyl includes phenyl,
benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like.
Backbone of the alkyl can be optionally inserted with one or more
heteroatoms, such as N, O, or S.
[0239] In preferred embodiments, a straight chain or branched chain
alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30
for straight chains, C3-C30 for branched chains), and more
preferably 20 or fewer. Likewise, preferred cycloalkyls have from
3-10 carbon atoms in their ring structure, and more preferably have
5, 6 or 7 carbons in the ring structure. The term "alkyl" (or
"lower alkyl") as used throughout the specification, examples, and
claims is intended to include both "unsubstituted alkyls" and
"substituted alkyls", the latter of which refers to alkyl moieties
having one or more substituents replacing a hydrogen on one or more
carbons of the hydrocarbon backbone.
[0240] Unless the number of carbons is otherwise specified, "lower
alkyl" as used herein means an alkyl group, as defined above, but
having from one to ten carbons, more preferably from one to six
carbon atoms in its backbone structure. Likewise, "lower alkenyl"
and "lower alkynyl" have similar chain lengths. Throughout the
application, preferred alkyl groups are lower alkyls. In preferred
embodiments, a substituent designated herein as alkyl is a lower
alkyl.
[0241] Substituents of a substituted alkyl can include halogen,
hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl
(including phosphonate and phosphinate), sulfonyl (including
sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups,
as well as ethers, alkylthiols, carbonyls (including ketones,
aldehydes, carboxylates, and esters), --CF.sub.3, --CN and the
like.
[0242] As used herein, the term "alkenyl" refers to unsaturated
straight-chain, branched-chain or cyclic hydrocarbon radicals
having at least one carbon-carbon double bond. C.sub.x alkenyl and
C.sub.x-C.sub.yalkenyl are typically used where X and Y indicate
the number of carbon atoms in the chain. For example,
C.sub.2-C.sub.6alkenyl includes alkenyls that have a chain of
between 1 and 6 carbons and at least one double bond, e.g., vinyl,
allyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-methylallyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like).
Alkenyl represented along with another radical (e.g., as in
arylalkenyl) means a straight or branched, alkenyl divalent radical
having the number of atoms indicated. Backbone of the alkenyl can
be optionally inserted with one or more heteroatoms, such as N, O,
or S.
[0243] As used herein, the term "alkynyl" refers to unsaturated
hydrocarbon radicals having at least one carbon-carbon triple bond.
C.sub.x alkynyl and C.sub.x-C.sub.yalkynyl are typically used where
X and Y indicate the number of carbon atoms in the chain. For
example, C.sub.2-C.sub.6alkynyl includes alkynyls that have a chain
of between 1 and 6 carbons and at least one triple bond, e.g.,
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, isopentenyl,
1,3-hexa-diyn-yl, n-hexynyl, 3-pentynyl, 1-hexen-3-ynyl and the
like. Alkynyl represented along with another radical (e.g., as in
arylalkynyl) means a straight or branched, alkynyl divalent radical
having the number of atoms indicated. Backbone of the alkynyl can
be optionally inserted with one or more heteroatoms, such as N, O,
or S.
[0244] The terms "alkylene," "alkenylene," and "alkynylene" refer
to divalent alkyl, alkelyne, and alkynylene" radicals. Prefixes
C.sub.x and C.sub.x-C.sub.y are typically used where X and Y
indicate the number of carbon atoms in the chain. For example,
C.sub.1-C.sub.6alkylene includes methylene, (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), trimethylene
(--CH.sub.2CH.sub.2CH.sub.2--), tetramethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), 2-methyltetramethylene
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--), pentamethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the like).
[0245] As used herein, the term "alkylidene" means a straight or
branched unsaturated, aliphatic, divalent radical having a general
formula .dbd.CR.sub.aR.sub.b. C.sub.x alkylidene and
C.sub.x-C.sub.yalkylidene are typically used where X and Y indicate
the number of carbon atoms in the chain. For example,
C.sub.2-C.sub.6alkylidene includes methylidene (.dbd.CH.sub.2),
ethylidene (.dbd.CHCH.sub.3), isopropylidene
(.dbd.C(CH.sub.3).sub.2), propylidene (.dbd.CHCH.sub.2CH.sub.3),
allylidene (.dbd.CH--CH.dbd.CH.sub.2), and the like).
[0246] The term "heteroalkyl", as used herein, refers to straight
or branched chain, or cyclic carbon-containing radicals, or
combinations thereof, containing at least one heteroatom. Suitable
heteroatoms include, but are not limited to, O, N, Si, P, Se, B,
and S, wherein the phosphorous and sulfur atoms are optionally
oxidized, and the nitrogen heteroatom is optionally quaternized.
Heteroalkyls can be substituted as defined above for alkyl
groups.
[0247] As used herein, the term "halogen" or "halo" refers to an
atom selected from fluorine, chlorine, bromine and iodine. The term
"halogen radioisotope" or "halo isotope" refers to a radionuclide
of an atom selected from fluorine, chlorine, bromine and
iodine.
[0248] A "halogen-substituted moiety" or "halo-substituted moiety",
as an isolated group or part of a larger group, means an aliphatic,
alicyclic, or aromatic moiety, as described herein, substituted by
one or more "halo" atoms, as such terms are defined in this
application. For example, halo-substituted alkyl includes
haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like
(e.g. halosubstituted (C.sub.1-C.sub.3)alkyl includes chloromethyl,
dichloromethyl, difluoromethyl, trifluoromethyl (--CF.sub.3),
2,2,2-trifluoroethyl, perfluoroethyl,
2,2,2-trifluoro-1,1-dichloroethyl, and the like).
[0249] The term "aryl" refers to monocyclic, bicyclic, or tricyclic
fused aromatic ring system. C.sub.xaryl and C.sub.x-C.sub.yaryl are
typically used where X and Y indicate the number of carbon atoms in
the ring system. Exemplary aryl groups include, but are not limited
to, pyridinyl, pyrimidinyl, furanyl, thienyl, imidazolyl,
thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazinyl,
tetrazolyl, indolyl, benzyl, phenyl, naphthyl, anthracenyl,
azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl,
tetrahydronaphthyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,
quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl and xanthenyl, and the like. In some
embodiments, 1, 2, 3, or 4 hydrogen atoms of each ring can be
substituted by a substituent.
[0250] The term "heteroaryl" refers to an aromatic 5-8 membered
monocyclic, 8-12 membered fused bicyclic, or 11-14 membered fused
tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said
heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3,
1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or
tricyclic, respectively. C.sub.x heteroaryl and
C.sub.x-C.sub.yheteroaryl are typically used where X and Y indicate
the number of carbon atoms in the ring system. Heteroaryls include,
but are not limited to, those derived from benzo[b]furan, benzo[b]
thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline,
thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,
3-b]pyridine, indolizine, imidazo[1,2a]pyridine, quinoline,
isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine,
indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole,
benzothiazole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,
imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,
imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,
pyrrolo[2,3-b]pyridine, pyrrolo[2,3c]pyridine,
pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine,
pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo
[2,3-b]pyrazine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,
pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,
pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,
carbazole, acridine, phenazine, phenothiazene, phenoxazine,
1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine,
pyrido[1,2-a]indole, 2(1H)-pyridinone, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,
4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl,
tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl and xanthenyl. Some exemplary
heteroaryl groups include, but are not limited to, pyridyl, furyl
or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or
thienyl, pyridazinyl, pyrazinyl, quinolinyl, indolyl, thiazolyl,
naphthyridinyl, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,
tetrahydroisoquinolinyl, and the like. In some embodiments, 1, 2,
3, or 4 hydrogen atoms of each ring may be substituted by a
substituent.
[0251] The term "cyclyl" or "cycloalkyl" refers to saturated and
partially unsaturated cyclic hydrocarbon groups having 3 to 12
carbons, for example, 3 to 8 carbons, and, for example, 3 to 6
carbons. C.sub.xcyclyl and C.sub.x-C.sub.ycylcyl are typically used
where X and Y indicate the number of carbon atoms in the ring
system. The cycloalkyl group additionally can be optionally
substituted, e.g., with 1, 2, 3, or 4 substituents.
C.sub.3-C.sub.10cyclyl includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl,
cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, adamantan-1-yl,
decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,
2-oxobicyclo [2.2.1]hept-1-yl, and the like.
[0252] Aryl and heteroaryls can be optionally substituted with one
or more substituents at one or more positions, for example,
halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,
amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate,
phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,
ketone, aldehyde, ester, a heterocyclyl, an aromatic or
heteroaromatic moiety, --CF3, --CN, or the like.
[0253] The term "heterocyclyl" refers to a nonaromatic 5-8 membered
monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic
ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms
if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms
selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9
heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,
respectively). C.sub.xheterocyclyl and C.sub.x-C.sub.yheterocyclyl
are typically used where X and Y indicate the number of carbon
atoms in the ring system. In some embodiments, 1, 2 or 3 hydrogen
atoms of each ring can be substituted by a substituent. Exemplary
heterocyclyl groups include, but are not limited to piperazinyl,
pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, piperidyl,
4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl,
1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the
like.
[0254] The terms "bicyclic" and "tricyclic" refers to fused,
bridged, or joined by a single bond polycyclic ring assemblies.
[0255] The term "cyclylalkylene" means a divalent aryl, heteroaryl,
cyclyl, or heterocyclyl.
[0256] As used herein, the term "fused ring" refers to a ring that
is bonded to another ring to form a compound having a bicyclic
structure when the ring atoms that are common to both rings are
directly bound to each other. Non-exclusive examples of common
fused rings include decalin, naphthalene, anthracene, phenanthrene,
indole, furan, benzofuran, quinoline, and the like. Compounds
having fused ring systems can be saturated, partially saturated,
cyclyl, heterocyclyl, aromatics, heteroaromatics, and the like.
[0257] As used herein, the term "carbonyl" means the radical
--C(O)--. It is noted that the carbonyl radical can be further
substituted with a variety of substituents to form different
carbonyl groups including acids, acid halides, amides, esters,
ketones, and the like.
[0258] The term "carboxy" means the radical --C(O)O--. It is noted
that compounds described herein containing carboxy moieties can
include protected derivatives thereof, i.e., where the oxygen is
substituted with a protecting group. Suitable protecting groups for
carboxy moieties include benzyl, tert-butyl, and the like. The term
"carboxyl" means --COOH
[0259] The term "cyano" means the radical --CN.
[0260] The term, "heteroatom" refers to an atom that is not a
carbon atom. Particular examples of heteroatoms include, but are
not limited to nitrogen, oxygen, sulfur and halogens. A "heteroatom
moiety" includes a moiety where the atom by which the moiety is
attached is not a carbon. Examples of heteroatom moieties include
--N.dbd., --NR.sup.N--, --N.sup.+(O.sup.-).dbd., --O--, --S-- or
--S(O).sub.2--, --OS(O).sub.2--, and --SS--, wherein R.sup.N is H
or a further substituent.
[0261] The term "hydroxy" means the radical --OH.
[0262] The term "imine derivative" means a derivative comprising
the moiety --C(NR)--, wherein R comprises a hydrogen or carbon atom
alpha to the nitrogen.
[0263] The term "nitro" means the radical --NO.sub.2.
[0264] An "oxaaliphatic," "oxaalicyclic", or "oxaaromatic" mean an
aliphatic, alicyclic, or aromatic, as defined herein, except where
one or more oxygen atoms (--O--) are positioned between carbon
atoms of the aliphatic, alicyclic, or aromatic respectively.
[0265] An "oxoaliphatic," "oxoalicyclic", or "oxoaromatic" means an
aliphatic, alicyclic, or aromatic, as defined herein, substituted
with a carbonyl group. The carbonyl group can be an aldehyde,
ketone, ester, amide, acid, or acid halide.
[0266] As used herein, the term, "aromatic" means a moiety wherein
the constituent atoms make up an unsaturated ring system, all atoms
in the ring system are sp.sup.2 hybridized and the total number of
pi electrons is equal to 4n+2. An aromatic ring can be such that
the ring atoms are only carbon atoms (e.g., aryl) or can include
carbon and non-carbon atoms (e.g., heteroaryl).
[0267] As used herein, the term "substituted" refers to independent
replacement of one or more (typically 1, 2, 3, 4, or 5) of the
hydrogen atoms on the substituted moiety with substituents
independently selected from the group of substituents listed below
in the definition for "substituents" or otherwise specified. In
general, a non-hydrogen substituent can be any substituent that can
be bound to an atom of the given moiety that is specified to be
substituted. Examples of substituents include, but are not limited
to, acyl, acylamino, acyloxy, aldehyde, alicyclic, aliphatic,
alkanesulfonamido, alkanesulfonyl, alkaryl, alkenyl, alkoxy,
alkoxycarbonyl, alkyl, alkylamino, alkylcarbamoyl, alkylene,
alkylidene, alkylthiols, alkynyl, amide, amido, amino, amino,
aminoalkyl, aralkyl, aralkylsulfonamido, arenesulfonamido,
arenesulfonyl, aromatic, aryl, arylamino, arylcarbamoyl, aryloxy,
azido, carbamoyl, carbonyl, carbonyls (including ketones, carboxy,
carboxylates, CF.sub.3, cyano (CN), cycloalkyl, cycloalkylene,
ester, ether, haloalkyl, halogen, halogen, heteroaryl,
heterocyclyl, hydroxy, hydroxy, hydroxyalkyl, imino, iminoketone,
ketone, mercapto, nitro, oxaalkyl, oxo, oxoalkyl, phosphoryl
(including phosphonate and phosphinate), silyl groups, sulfonamido,
sulfonyl (including sulfate, sulfamoyl and sulfonate), thiols, and
ureido moieties, each of which may optionally also be substituted
or unsubstituted. In some cases, two substituents, together with
the carbon(s) to which they are attached to, can form a ring.
[0268] The terms "alkoxyl" or "alkoxy" as used herein refers to an
alkyl group, as defined above, having an oxygen radical attached
thereto. Representative alkoxyl groups include methoxy, ethoxy,
propyloxy, tert-butoxy, n-propyloxy, iso-propyloxy, n-butyloxy,
iso-butyloxy, and the like. An "ether" is two hydrocarbons
covalently linked by an oxygen. Accordingly, the substituent of an
alkyl that renders that alkyl an ether is or resembles an alkoxyl,
such as can be represented by one of --O-alkyl, --O-alkenyl, and
--O-alkynyl. Aroxy can be represented by --O-aryl or O-heteroaryl,
wherein aryl and heteroaryl are as defined below. The alkoxy and
aroxy groups can be substituted as described above for alkyl.
[0269] The term "aralkyl", as used herein, refers to an alkyl group
substituted with an aryl group (e.g., an aromatic or heteroaromatic
group).
[0270] The term "alkylthio" refers to an alkyl group, as defined
above, having a sulfur radical attached thereto. In preferred
embodiments, the "alkylthio" moiety is represented by one of
--S-alkyl, --S-alkenyl, and --S-alkynyl. Representative alkylthio
groups include methylthio, ethylthio, and the like. The term
"alkylthio" also encompasses cycloalkyl groups, alkene and
cycloalkene groups, and alkyne groups. "Arylthio" refers to aryl or
heteroaryl groups.
[0271] The term "sulfinyl" means the radical --SO--. It is noted
that the sulfinyl radical can be further substituted with a variety
of substituents to form different sulfinyl groups including
sulfinic acids, sulfinamides, sulfinyl esters, sulfoxides, and the
like.
[0272] The term "sulfonyl" means the radical --SO.sub.2--. It is
noted that the sulfonyl radical can be further substituted with a
variety of substituents to form different sulfonyl groups including
sulfonic acids (--SO.sub.3H), sulfonamides, sulfonate esters,
sulfones, and the like.
[0273] The term "thiocarbonyl" means the radical --C(S)--. It is
noted that the thiocarbonyl radical can be further substituted with
a variety of substituents to form different thiocarbonyl groups
including thioacids, thioamides, thioesters, thioketones, and the
like.
[0274] As used herein, the term "amino" means --NH.sub.2. The term
"alkylamino" means a nitrogen moiety having at least one straight
or branched unsaturated aliphatic, cyclyl, or heterocyclyl radicals
attached to the nitrogen. For example, representative amino groups
include --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NH(C.sub.1-C.sub.10alkyl), --N(C.sub.1-C.sub.10alkyl).sub.2, and
the like. The term "alkylamino" includes "alkenylamino,"
"alkynylamino," "cyclylamino," and "heterocyclylamino." The term
"arylamino" means a nitrogen moiety having at least one aryl
radical attached to the nitrogen. For example NHaryl, and
--N(aryl).sub.2. The term "heteroarylamino" means a nitrogen moiety
having at least one heteroaryl radical attached to the nitrogen.
For example --NHheteroaryl, and --N(heteroaryl).sub.2. Optionally,
two substituents together with the nitrogen can also form a ring.
Unless indicated otherwise, the compounds described herein
containing amino moieties can include protected derivatives
thereof. Suitable protecting groups for amino moieties include
acetyl, tertbutoxycarbonyl, benzyloxycarbonyl, and the like.
[0275] The term "aminoalkyl" means an alkyl, alkenyl, and alkynyl
as defined above, except where one or more substituted or
unsubstituted nitrogen atoms (--N--) are positioned between carbon
atoms of the alkyl, alkenyl, or alkynyl. For example, an
(C.sub.2-C.sub.6) aminoalkyl refers to a chain comprising between 2
and 6 carbons and one or more nitrogen atoms positioned between the
carbon atoms.
[0276] The term "alkoxyalkoxy" means --O-(alkyl)-O-(alkyl), such as
--OCH.sub.2CH.sub.2OCH.sub.3, and the like.
[0277] The term "alkoxycarbonyl" means --C(O)O-(alkyl), such as
--C(.dbd.O)OCH.sub.3, --C(.dbd.O)OCH.sub.2CH.sub.3, and the
like.
[0278] The term "alkoxyalkyl" means -(alkyl)-O-(alkyl), such as
--CH.sub.2OCH.sub.3, --CH.sub.2OCH.sub.2CH.sub.3, and the like.
[0279] The term "aryloxy" means --O-(aryl), such as --O-phenyl,
--O-pyridinyl, and the like.
[0280] The term "arylalkyl" means -(alkyl)-(aryl), such as benzyl
(i.e., --CH.sub.2phenyl), --CH.sub.2-pyrindinyl, and the like.
[0281] The term "arylalkyloxy" means --O-(alkyl)-(aryl), such as
--O-benzyl, --O--CH.sub.2-pyridinyl, and the like.
[0282] The term "cycloalkyloxy" means --O-(cycloalkyl), such as
--O-cyclohexyl, and the like.
[0283] The term "cycloalkylalkyloxy" means --O-(alkyl)-(cycloalkyl,
such as --OCH.sub.2cyclohexyl, and the like.
[0284] The term "aminoalkoxy" means --O-(alkyl)-NH.sub.2, such as
--OCH.sub.2NH.sub.2, --OCH.sub.2CH.sub.2NH.sub.2, and the like.
[0285] The term "mono- or di-alkylamino" means --NH(alkyl) or
--N(alkyl)(alkyl), respectively, such as --NHCH.sub.3,
--N(CH.sub.3).sub.2, and the like.
[0286] The term "mono- or di-alkylaminoalkoxy" means
--O-(alkyl)-NH(alkyl) or --O-(alkyl)-N(alkyl)(alkyl), respectively,
such as --OCH.sub.2NHCH.sub.3,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, and the like.
[0287] The term "arylamino" means --NH(aryl), such as --NH-phenyl,
--NH-pyridinyl, and the like.
[0288] The term "arylalkylamino" means --NH-(alkyl)-(aryl), such as
--NH-benzyl, --NHCH.sub.2-pyridinyl, and the like.
[0289] The term "alkylamino" means --NH(alkyl), such as
--NHCH.sub.3, --NHCH.sub.2CH.sub.3, and the like.
[0290] The term "cycloalkylamino" means --NH-(cycloalkyl), such as
--NH-cyclohexyl, and the like.
[0291] The term "cycloalkylalkylamino"-NH-(alkyl)-(cycloalkyl),
such as --NHCH.sub.2-cyclohexyl, and the like.
[0292] It is noted in regard to all of the definitions provided
herein that the definitions should be interpreted as being open
ended in the sense that further substituents beyond those specified
may be included. Hence, a C.sub.1 alkyl indicates that there is one
carbon atom but does not indicate what are the substituents on the
carbon atom. Hence, a C.sub.1 alkyl comprises methyl (i.e.,
--CH.sub.3) as well as --CR.sub.aR.sub.bR.sub.c where R.sub.a,
R.sub.b, and R.sub.c can each independently be hydrogen or any
other substituent where the atom alpha to the carbon is a
heteroatom or cyano. Hence, CF.sub.3, CH.sub.2OH and CH.sub.2CN are
all C.sub.1 alkyls.
[0293] Unless otherwise stated, structures depicted herein are
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structure except for the replacement of a hydrogen atom
by a deuterium or tritium, or the replacement of a carbon atom by a
.sup.13C- or .sup.14C-enriched carbon are within the scope of the
invention.
[0294] A "pharmaceutically acceptable salt", as used herein, is
intended to encompass any compound described herein that is
utilized in the form of a salt thereof, especially where the salt
confers on the compound improved pharmacokinetic properties as
compared to the free form of compound or a different salt form of
the compound. The pharmaceutically acceptable salt form can also
initially confer desirable pharmacokinetic properties on the
compound that it did not previously possess, and may even
positively affect the pharmacodynamics of the compound with respect
to its therapeutic activity in the body. An example of a
pharmacokinetic property that can be favorably affected is the
manner in which the compound is transported across cell membranes,
which in turn may directly and positively affect the absorption,
distribution, biotransformation and excretion of the compound.
While the route of administration of the pharmaceutical composition
is important, and various anatomical, physiological and
pathological factors can critically affect bioavailability, the
solubility of the compound is usually dependent upon the character
of the particular salt form thereof, which it utilized. One of
skill in the art will appreciate that an aqueous solution of the
compound will provide the most rapid absorption of the compound
into the body of a subject being treated, while lipid solutions and
suspensions, as well as solid dosage forms, will result in less
rapid absorption of the compound.
[0295] Pharmaceutically acceptable salts include those derived from
inorganic acids such as sulfuric, sulfamic, phosphoric, nitric, and
the like; and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isothionic, and the like. See, for example, Berge et al.,
"Pharmaceutical Salts", J. Pharm. Sci. 66:1-19 (1977), the content
of which is herein incorporated by reference in its entirety.
Exemplary salts also include the hydrobromide, hydrochloride,
sulfate, bisulfate, phosphate, nitrate, acetate, succinate,
valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,
phosphate, tosylate, citrate, maleate, fumarate, succinate,
tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts and the like. Suitable acids which are
capable of forming salts with the compounds of the disclosure
include inorganic acids such as hydrochloric acid, hydrobromic
acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid,
phosphoric acid, and the like; and organic acids such as
1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
2-naphthalenesulfonic acid, 3-phenylpropionic acid,
4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid,
4,4'-mefhylenebis(3-hydroxy-2-ene-1-carboxylic acid), acetic acid,
anthranilic acid, benzenesulfonic acid, benzoic acid,
camphorsulfonic acid, cinnamic acid, citric acid,
cyclopentanepropionic acid, ethanesulfonic acid, formic acid,
fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid,
glycolic acid, heptanoic acid, hydroxynaphthoic acid, lactic acid,
lauryl sulfuric acid, maleic acid, malic acid, malonic acid,
mandelic acid, methanesulfonic acid, muconic acid, naphthalene
sulfonic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid,
p-chlorobenzenesulfonic acid, propionic acid, p-toluenesulfonic
acid, pyruvic acid, salicylic acid, stearic acid, succinic acid,
sulfanilic acid, tartaric acid, tertiary butylacetic acid,
trifluoroacetic acid, trimethylacetic acid, and the like. Suitable
bases capable of forming salts with the compounds of the disclosure
include inorganic bases such as sodium hydroxide, ammonium
hydroxide, sodium carbonate, calcium hydroxide, potassium hydroxide
and the like; and organic bases such as mono-, di- and tri-alkyl
and aryl amines (e.g., triethylamine, diisopropyl amine, methyl
amine, dimethyl amine, N-methylglucamine, pyridine, picoline,
dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like), and
optionally substituted ethanol-amines (e.g., ethanolamine,
diethanolamine, triethanolamine and the like).
[0296] In some embodiments, the compounds described herein can be
in the form of a prodrug. The term "prodrug" as used herein refers
to compounds that can be converted via some chemical or
physiological process (e.g., enzymatic processes and metabolic
hydrolysis) to compound described herein. Thus, the term "prodrug"
also refers to a precursor of a biologically active compound that
is pharmaceutically acceptable. A prodrug can be inactive when
administered to a subject, i.e. an ester, but is converted in vivo
to an active compound, for example, by hydrolysis to the free
carboxylic acid or free hydroxyl. The prodrug compound often offers
advantages of solubility, tissue compatibility or delayed release
in an organism. The term "prodrug" is also meant to include any
covalently bonded carriers, which release the active compound in
vivo when such prodrug is administered to a subject. Prodrugs of an
active compound, as described herein, may be prepared by modifying
functional groups present in the active compound in such a way that
the modifications are cleaved, either in routine manipulation or in
vivo, to the parent active compound. Prodrugs include compounds
wherein a hydroxy, amino or mercapto group is bonded to any group
that, when the prodrug of the active compound is administered to a
subject, cleaves to form a free hydroxy, free amino or free
mercapto group, respectively. For example, a compound comprising a
hydroxy group can be administered as an ester that is converted by
hydrolysis in vivo to the hydroxy compound. Suitable esters that
can be converted in vivo into hydroxy compounds include acetates,
citrates, lactates, tartrates, malonates, oxalates, salicylates,
propionates, succinates, fumarates, formates, benzoates, maleates,
methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,
benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates,
quinates, esters of amino acids, and the like. Similarly, a
compound comprising an amine group can be administered as an amide,
e.g., acetamide, formamide and benzamide that is converted by
hydrolysis in vivo to the amine compound. See Harper, "Drug
Latentiation" in Jucker, ed. Progress in Drug Research 4:221-294
(1962); Morozowich et al, "Application of Physical Organic
Principles to Prodrug Design" in E. B. Roche ed. Design of
Biopharmaceutical Properties through Prodrugs and Analogs, APHA
Acad. Pharm. Sci. 40 (1977); Bioreversible Carriers in Drug in Drug
Design, Theory and Application, E. B. Roche, ed., APHA Acad. Pharm.
Sci. (1987); Design of Prodrugs, H. Bundgaard, Elsevier (1985);
Wang et al. "Prodrug approaches to the improved delivery of peptide
drug" in Curr. Pharm. Design. 5(4):265-287 (1999); Pauletti et al.
(1997) Improvement in peptide bioavailability: Peptidomimetics and
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content of all of which are herein incorporated by reference in its
entirety.
[0297] The term "protected derivatives" means derivatives of
compounds described herein in which a reactive site or sites are
blocked with protecting groups. Protected derivatives are useful in
the preparation of compounds or in themselves can be active. A
comprehensive list of suitable protecting groups can be found in T.
W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,
John Wiley & Sons, Inc. 1999.
[0298] "Isomers" mean any compound having identical molecular
formulae but differing in the nature or sequence of bonding of
their atoms or in the arrangement of their atoms in space. Isomers
that differ in the arrangement of their atoms in space are termed
"stereoisomers". Stereoisomers that are not mirror images of one
another are termed "diastereomers" and stereoisomers that are
nonsuperimposable mirror images are termed "enantiomers" or
sometimes "optical isomers". A carbon atom bonded to four
nonidentical substituents is termed a "chiral center". A compound
with one chiral center has two enantiomeric forms of opposite
chirality. A mixture of the two enantiomeric forms is termed a
"racemic mixture". A compound that has more than one chiral center
has 2.sup.n-1 enantiomeric pairs, where n is the number of chiral
centers. Compounds with more than one chiral center may exist as
ether an individual diastereomers or as a mixture of diastereomers,
termed a "diastereomeric mixture". When one chiral center is
present a stereoisomer may be characterized by the absolute
configuration of that chiral center. Absolute configuration refers
to the arrangement in space of the substituents attached to the
chiral center. Enantiomers are characterized by the absolute
configuration of their chiral centers and described by the R- and
S-sequencing rules of Cahn, Ingold and Prelog. Conventions for
stereochemical nomenclature, methods for the determination of
stereochemistry and the separation of stereoisomers are well known
in the art (e.g., see "Advanced Organic Chemistry", 4th edition,
March, Jerry, John Wiley & Sons, New York, 1992).
[0299] The term "enantiomer" is used to describe one of a pair of
molecular isomers which are mirror images of each other and
non-superimposable. Other terms used to designate or refer to
enantiomers include "stereoisomers" (because of the different
arrangement or stereochemistry around the chiral center; although
all enantiomers are stereoisomers, not all stereoisomers are
enantiomers) or "optical isomers" (because of the optical activity
of pure enantiomers, which is the ability of different pure
enantiomers to rotate planepolarized light in different
directions). Enantiomers generally have identical physical
properties, such as melting points and boiling points, and also
have identical spectroscopic properties. Enantiomers can differ
from each other with respect to their interaction with
plane-polarized light and with respect to biological activity.
[0300] The designations "R" and "S" are used to denote the absolute
configuration of the molecule about its chiral center(s). The
designations may appear as a prefix or as a suffix; they may or may
not be separated from the isomer by a hyphen; they may or may not
be hyphenated; and they may or may not be surrounded by
parentheses.
[0301] The designations or prefixes "(+)" and "(-)" are employed to
designate the sign of rotation of plane-polarized light by the
compound, with (-) meaning that the compound is levorotatory
(rotates to the left). A compound prefixed with (+) is
dextrorotatory (rotates to the right).
[0302] The term "racemic mixture," "racemic compound" or "racemate"
refers to a mixture of the two enantiomers of one compound. An
ideal racemic mixture is one wherein there is a 50:50 mixture of
both enantiomers of a compound such that the optical rotation of
the (+) enantiomer cancels out the optical rotation of the (-)
enantiomer.
[0303] The term "resolving" or "resolution" when used in reference
to a racemic mixture refers to the separation of a racemate into
its two enantiomorphic forms (i.e., (+) and (-); 65 (R) and (S)
forms). The terms can also refer to enantioselective conversion of
one isomer of a racemate to a product.
[0304] The term "enantiomeric excess" or "ee" refers to a reaction
product wherein one enantiomer is produced in excess of the other,
and is defined for a mixture of (+)- and (-)-enantiomers, with
composition given as the mole or weight or volume fraction F(+) and
F(-) (where the sum of F(+) and F(-)=1). The enantiomeric excess is
defined as *F(+)-F(-)* and the percent enantiomeric excess by
100x*F(+)-F(-)*. The "purity" of an enantiomer is described by its
ee or percent ee value (% ee).
[0305] Whether expressed as a "purified enantiomer" or a "pure
enantiomer" or a "resolved enantiomer" or "a compound in
enantiomeric excess", the terms are meant to indicate that the
amount of one enantiomer exceeds the amount of the other. Thus,
when referring to an enantiomer preparation, both (or either) of
the percent of the major enantiomer (e.g. by mole or by weight or
by volume) and (or) the percent enantiomeric excess of the major
enantiomer may be used to determine whether the preparation
represents a purified enantiomer preparation.
[0306] The term "enantiomeric purity" or "enantiomer purity" of an
isomer refers to a qualitative or quantitative measure of the
purified enantiomer; typically, the measurement is expressed on the
basis of ee or enantiomeric excess.
[0307] The terms "substantially purified enantiomer,"
"substantially resolved enantiomer" "substantially purified
enantiomer preparation" are meant to indicate a preparation (e.g.
derived from non-optically active starting material, substrate, or
intermediate) wherein one enantiomer has been enriched over the
other, and more preferably, wherein the other enantiomer represents
less than 20%, more preferably less than 10%, and more preferably
less than 5%, and still more preferably, less than 2% of the
enantiomer or enantiomer preparation.
[0308] The terms "purified enantiomer," "resolved enantiomer" and
"purified enantiomer preparation" are meant to indicate a
preparation (e.g. derived from non-optically active starting
material, substrates or intermediates) wherein one enantiomer (for
example, the R-enantiomer) is enriched over the other, and more
preferably, wherein the other enantiomer (for example the
S-enantiomer) represents less than 30%, preferably less than 20%,
more preferably less than 10% (e.g. in this particular instance,
the R-enantiomer is substantially free of the S-enantiomer), and
more preferably less than 5% and still more preferably, less than
2% of the preparation. A purified enantiomer may be synthesized
substantially free of the other enantiomer, or a purified
enantiomer may be synthesized in a stereo-preferred procedure,
followed by separation steps, or a purified enantiomer may be
derived from a racemic mixture.
[0309] The term "enantioselectivity," also called the enantiomeric
ratio indicated by the symbol "E," refers to the selective capacity
of an enzyme to generate from a racemic substrate one enantiomer
relative to the other in a product racemic mixture; in other words,
it is a measure of the ability of the enzyme to distinguish between
enantiomers. A nonselective reaction has an E of 1, while
resolutions with E's above 20 are generally considered useful for
synthesis or resolution. The enantioselectivity resides in a
difference in conversion rates between the enantiomers in question.
Reaction products are obtained that are enriched in one of the
enantiomers; conversely, remaining substrates are enriched in the
other enantiomer. For practical purposes it is generally desirable
for one of the enantiomers to be obtained in large excess. This is
achieved by terminating the conversion process at a certain degree
of conversion.
[0310] The disclosure is further illustrated by the following
examples which should not be construed as limiting. The examples
are illustrative only, and are not intended to limit, in any
manner, any of the aspects described herein. The following examples
do not in any way limit the invention.
EXAMPLES
[0311] Over 200,000 patients are likely to be diagnosed with breast
cancer in the United States (Jemal et al., Global cancer
statistics. CA Cancer J Clin., 2011, 61(2): p. 69-90). Although
triple-negative and basal-like tumors account for about 15% of all
invasive breast cancers, it disproportionally occurs in young Black
and Hispanic women. Also, women carrying a mutation in BRCA1 show
both phenotypes. So far, anti-EGFR therapeutic has proven to be
ineffective in treating the triple-negative breast cancer. Lately,
Poly-ADP ribose polymerase (PARP) inhibitors have proven to be
ineffective in a recent clinical trial (Guha, M., PARP inhibitors
stumble in breast cancer. Nat Biotechnol., 2011, 29(5): p.
373-4).
[0312] NF-.kappa.B is constitutively activated in several cancers
including breast cancer and plays an important role in cancer cells
survival (Nakshatri et al., Constitutive activation of NF-kappaB
during progression of breast cancer to hormone-independent growth.
Mol Cell Biol., 1997, 17(7): p. 3629-39 and Pratt et al., The
canonical NF-kappaB pathway is required for formation of luminal
mammary neoplasias and is activated in the mammary progenitor
population. Oncogene, 2009, 28(30): p. 2710-22). Activation of
NF-KB, a common molecular event that stems from a variety of
stimuli from inflammation, overexpression of growth factor
receptors and metabolic dysfunction, is critical for tumor survival
(Schmitz et al., NF-KB: A Multifaceted Transcription Factor
Regulated at Several Levels. ChemBioChem., 2004, 5(10): p.
1348-1358). Recently, breast cancer stem cells (BCSC) have been
implicated in resistance, recurrence and metastasis (Al-Ejeh et
al., Breast cancer stem cells: treatment resistance and therapeutic
opportunities. Carcinogenesis, 2011, 32(5): p. 650-8). More
importantly, activation of NF-KB is also critical for BCSC function
(Shostak et al., NF-kappaB, stem cells and breast cancer: the links
get stronger. Breast Cancer Res., 2011, 13(4): p. 214 and Zhou et
al., NF-kappaB pathway inhibitors preferentially inhibit breast
cancer stem-like cells, Breast Cancer Res Treat, 2011, 111(3): p.
419-27). Activation of NF-KB leads to nuclear localization of
RelA/p65, which has been implicated in chemoresistance (Benezra et
al., BRCA1 augments transcription by the NF-kappaB transcription
factor by binding to the Re! domain of the p65/Re/A subunit. J Biol
Chem., 2003, 278(29): p. 26333-41 and Jones et al., Nuclear
NF-kappaB/p65 expression and response to neoadjuvant chemotherapy
in breast cancer. J Clin Pathol., 2011, 64(2): p. 130-5). As shown
herein, blocking RelA/p65 nuclear translocation can prevent cancer
growth and metastasis.
[0313] The inventors used virtual screening to identify a small
molecule, CRL1101, to block RelA function. Briefly, the
three-dimensional structures of RelA dimer-DNA complexes (PBD code:
2RAM, INFI and 1VKX) were used to as template. Computational
analysis was performed at different temperature and simulation
times to identify critical sites to disrupt the nuclear
localization signal (NLS) region located nearby at the C-terminus.
Inventors have identified several chemical probes that potentially
disrupt NLS signaling. The calculations were performed on
Cedars-Sinai High performance computing Center facility.
[0314] In vitro biological activity of RelA inhibitor, CRL1101:
CRL1101 significantly inhibited cell proliferation (FIG. 1A),
colony formation (FIG. 1B) and nuclear localization in breast
cancer cells (FIG. 2).
[0315] Therapeutic efficacy of CRL101 in a pre-clinical breast
cancer mouse model: Therapeutic efficacy of CRL1101 was tested in
xenograft breast cancer model. Briefly, triple-negative breast
cancer cells, MDA-MB-231 were used to grow tumor in athymic mice.
Mice were treated with 25 mg/kg/day, IP for 4 weeks. The control
group was treated with vehicle. Mice treated with CRL1101 show
significant reduction in tumor growth (FIG. 3).
[0316] All patents and other publications identified in the
specification and examples are expressly incorporated herein by
reference for all purposes. These publications are provided solely
for their disclosure prior to the filing date of the present
application. Nothing in this regard should be construed as an
admission that the inventors are not entitled to antedate such
disclosure by virtue of prior invention or for any other reason.
All statements as to the date or representation as to the contents
of these documents is based on the information available to the
applicants and does not constitute any admission as to the
correctness of the dates or contents of these documents.
[0317] Although preferred embodiments have been depicted and
described in detail herein, it will be apparent to those skilled in
the relevant art that various modifications, additions,
substitutions, and the like can be made without departing from the
spirit of the invention and these are therefore considered to be
within the scope of the invention as defined in the claims which
follow. Further, to the extent not already indicated, it will be
understood by those of ordinary skill in the art that any one of
the various embodiments herein described and illustrated can be
further modified to incorporate features shown in any of the other
embodiments disclosed herein.
* * * * *
References