U.S. patent application number 16/986492 was filed with the patent office on 2020-11-26 for method of treating cancer using selective estrogen receptor modulators.
The applicant listed for this patent is Duke University. Invention is credited to Donald P. McDonnell, Erik R. Nelson, Suzanne E. Wardell.
Application Number | 20200368184 16/986492 |
Document ID | / |
Family ID | 1000005004633 |
Filed Date | 2020-11-26 |
View All Diagrams
United States Patent
Application |
20200368184 |
Kind Code |
A1 |
Wardell; Suzanne E. ; et
al. |
November 26, 2020 |
METHOD OF TREATING CANCER USING SELECTIVE ESTROGEN RECEPTOR
MODULATORS
Abstract
Disclosed herein are methods of treating subjects suffering from
estrogen receptor positive cancer of the brain by administering a
selective estrogen receptor degrader (SERM). Also disclosed are
methods of treating a cancer that is resistant to an estrogen
receptor modulator by administering a SERM.
Inventors: |
Wardell; Suzanne E.;
(Durham, NC) ; Nelson; Erik R.; (Champaign,
IL) ; McDonnell; Donald P.; (Chapel Hill,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Duke University |
Durham |
NC |
US |
|
|
Family ID: |
1000005004633 |
Appl. No.: |
16/986492 |
Filed: |
August 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16721329 |
Dec 19, 2019 |
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16986492 |
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16041416 |
Jul 20, 2018 |
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16721329 |
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15214187 |
Jul 19, 2016 |
10071066 |
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16041416 |
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14512061 |
Oct 10, 2014 |
9421264 |
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15214187 |
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61971627 |
Mar 28, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/137 20130101;
C07C 217/84 20130101; A61K 31/4535 20130101; A61K 31/138 20130101;
A61K 31/40 20130101; A61K 9/0019 20130101; C07C 217/78 20130101;
A61K 31/136 20130101; A61K 31/4196 20130101; A61K 45/06 20130101;
A61K 31/5685 20130101; A61K 31/565 20130101; A61K 2121/00
20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 45/06 20060101 A61K045/06; A61K 31/136 20060101
A61K031/136; C07C 217/78 20060101 C07C217/78; C07C 217/84 20060101
C07C217/84; A61K 31/138 20060101 A61K031/138; A61K 31/40 20060101
A61K031/40; A61K 31/4196 20060101 A61K031/4196; A61K 31/565
20060101 A61K031/565; A61K 31/5685 20060101 A61K031/5685; A61K
31/4535 20060101 A61K031/4535; A61K 9/00 20060101 A61K009/00 |
Goverment Interests
STATEMENT OF GOVERNMENT INTEREST
[0002] Not applicable.
Claims
1-23. (canceled)
24. A method of treating breast cancer brain metastasis in a
subject, the method comprising administering a compound of
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol, wherein the breast cancer brain
metastasis is resistant to an estrogen receptor modulator and is
estrogen receptor positive.
25. The method of claim 24, wherein an effective amount of the
compound is administered.
26. The method of claim 25, wherein the effective amount comprises
a high dosage.
27. The method of claim 26, wherein the high dosage is more than
about 20 mg/kg.
28. The method of claim 26, wherein the high dosage is about 20
mg/kg to about 100 mg/kg.
29. The method of claim 24, wherein the compound is administered by
oral administration, intravenous administration, intradermal
injection, intramuscular injection, or subcutaneous injection.
30. The method of claim 24, further comprising administering an
effective amount of at least one compound selected from the group
consisting of a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6
inhibitor), an antiestrogen, a ligand of retinoic acid or retinoxic
X receptor, an antiprogestin, an antiandrogen, vitamin D or
metabolite thereof, a farnesyl transferase inhibitor, a PPAR.alpha.
or gamma agonist and a MAP kinase inhibitor.
31. The method of claim 24, wherein the breast cancer brain
metastasis is de novo resistant to the estrogen receptor
modulator.
32. The method of claim 24, wherein the resistance to the estrogen
receptor modulator is acquired.
33. The method of claim 24, wherein the estrogen receptor modulator
is a selective estrogen receptor modulator (SERM).
34. The method of claim 33, wherein the SERM is tamoxifen,
idoxifene, raloxifene, or ICI 182,780.
35. The method of claim 24, wherein the estrogen receptor modulator
is an aromatase inhibitor.
36. The method of claim 35, wherein the aromatase inhibitor is
anastrozole, letrozole, or exemestane.
37. A method of treating breast cancer brain metastasis in a
subject, the method comprising administering a composition
comprising
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol, wherein the breast cancer brain
metastasis is resistant to an estrogen receptor modulator.
38. The method of claim 37, wherein the breast cancer brain
metastasis is estrogen receptor positive.
39. The method of claim 37, wherein an effective amount of the
composition is administered.
40. The method of claim 39, wherein the effective amount comprises
a high dosage.
41. The method of claim 40, wherein the high dosage is more than
about 20 mg/kg.
42. The method of claim 40, wherein the high dosage is about 20
mg/kg to about 100 mg/kg.
43. The method of claim 37, wherein the composition is administered
by oral administration, intravenous administration, intradermal
injection, intramuscular injection, or subcutaneous injection.
44. The method of claim 37, further comprising administering an
effective amount of at least one compound selected from the group
consisting of a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6
inhibitor), an antiestrogen, a ligand of retinoic acid or retinoxic
X receptor, an antiprogestin, an antiandrogen, vitamin D or
metabolite thereof, a farnesyl transferase inhibitor, a PPAR.alpha.
or gamma agonist and a MAP kinase inhibitor.
45. The method of claim 37, wherein the breast cancer brain
metastasis is de novo resistant to the estrogen receptor
modulator.
46. The method of claim 37, wherein the resistance to the estrogen
receptor modulator is acquired.
47. The method of claim 37, wherein the estrogen receptor modulator
is a selective estrogen receptor modulator (SERM).
48. The method of claim 47, wherein the SERM is tamoxifen,
idoxifene, raloxifene or ICI 182,780.
49. The method of claim 37, wherein the estrogen receptor modulator
is an aromatase inhibitor.
50. The method of claim 49, wherein the aromatase inhibitor is
anastrozole, letrozole, or exemestane.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/041,416, filed Jul. 20, 2018, which is a
continuation of U.S. patent application Ser. No. 15/214,187, filed
Jul. 19, 2016, now U.S. Pat. No. 10,071,066, which is a
continuation of U.S. patent application Ser. No. 14/512,061, filed
Oct. 10, 2014, which claims priority to U.S. Provisional
Application No. 61/971,627, filed Mar. 28, 2014, each of which is
incorporated by reference herein in its entirety.
TECHNICAL FIELD
[0003] The present invention relates to methods of treating
subjects suffering from estrogen receptor positive cancer of the
brain by administering a selective estrogen receptor modulator
(SERM) to the subject. The present invention also relates to
methods of treating subjects suffering from a cancer that is
resistant to an estrogen receptor modulator by administering a SERM
to the subject.
BACKGROUND
[0004] The estrogen receptor (ER) is a ligand dependent
transcription factor whose expression confers upon target cells the
ability to respond to estrogens. In the absence of an activating
ligand, ER resides in the cell in an inactive form within a large
inhibitory protein complex. Upon binding ligand, however, the
receptor undergoes an activating conformational change resulting in
its release from the inhibitory protein complex, spontaneous
dimerization and subsequent interaction with enhancers located
within target genes. Depending on the promoter context of the bound
receptor, and the co factors that are recruited to the receptor in
a particular cell, it can either positively or negatively regulate
target gene transcription. Thus, the same ER-ligand complex can
have very different activities in different cells, an observation
that explains how estrogens, generally considered to be
reproductive hormones, exhibit activities in bone, the
cardiovascular system and in brain that are unrelated to
reproductive function.
[0005] Whereas the molecular determinants of ER action differ
considerably between target cells, it has been anticipated that the
exploitation of this complexity will yield pharmaceuticals with
process or tissue selective activities. The first evidence in
support of this hypothesis came from studies that probed the
pharmacological activities of the `antiestrogen` tamoxifen.
Identified as a high affinity antagonist of ER and developed as a
treatment for ER-positive breast cancer, it soon became apparent
that whereas tamoxifen could oppose estrogen action in the breast
it exhibited agonist activity in the bone, uterus and in the
cardiovascular system. Reflecting this spectrum of activities,
tamoxifen was reclassified as a Selective Estrogen Receptor
Modulator (SERM).
[0006] The increasing incidence of breast cancer brain metastases
(BCBM) is an emerging challenge in the treatment of advanced breast
cancer patients. The growing success of improved treatments of
systemic disease has allowed the manifestation of BCBM that
previously would not have impacted the morbidity and mortality
associated with breast cancer. The privileged environment of the
brain, maintained by the relatively non-porous blood brain barrier,
presents a significant impediment to the successful targeting of
BCBM, leading to the use of gamma knife surgery and/or whole brain
radiation in an attempt to shrink or ablate brain lesions. The
benefit of these treatments must be carefully balanced with
neurological deficit as a result of treatment.
[0007] Although considerable advances have been made in targeting
the estrogen signaling axis for the treatment of breast cancer and
osteoporosis, similar progress has unfortunately not yet been
accomplished in the development of safe and effective treatments
for the climacteric conditions or vasomotor disturbances that are
associated with estrogen deprivation. There is considerable
interest in developing novel SERMs that can be used to treat
vasomotor symptoms but which do not exhibit mitogenic activities in
the breast or the uterus.
[0008] While tamoxifen and aromatase inhibitors have proven
effective in the treatment of estrogen receptor positive (ER+)
breast cancer, the incidence of resistance remains significant,
particularly in the advanced/metastatic breast cancer setting. An
additional class of estrogen receptor targeting therapy, selective
estrogen receptor degraders (SERDs), has recently come to
prominence. These agents have proven effective in pre-clinical
models of breast cancers that are resistant to tamoxifen or
aromatase inhibitors, leading to their evaluation in clinical
trials. However, these agents also do not readily pass the blood
brain barrier, suggesting that they will be ineffective in
targeting BCBM. It would be beneficial to have other treatment
options that can penetrate the blood brain barrier and/or
selectively target tissue specific activities responsive to ER
activation.
SUMMARY
[0009] The present invention is directed to a method of treating
estrogen receptor positive cancers of the brain in a subject. The
method comprises administering a compound represented by the
following formula I:
##STR00001## [0010] wherein [0011] TZ represents a C.sub.1-C.sub.4
alkylene group or --CR.sup.f'R.sup.g'--CH.sub.2--O-- wherein
R.sup.f' and R.sup.g' independently represent hydrogen or a C1-C6
alkyl group; [0012] A represents a 5- to 14-membered heteroarylene
group which may have a substituent or a C.sub.6-C.sub.14 arylene
group which may have a substituent; [0013] Y represents
--CH.sub.2--NR.sup.c-- wherein R.sup.c represents hydrogen or a
C.sub.1-C.sub.6 alkyl group which may have a substituent; [0014]
ring G represents the following formula:
[0014] ##STR00002## [0015] R' represents 1 to 4 substituents
independently selected from a hydrogen atom, a C.sub.1-C.sub.6
alkoxy group, and a hydroxyl group; [0016] a partial structure in
formula (I) represented by the following formula:
##STR00003##
[0016] is
##STR00004## [0017] R'' represents hydrogen, a hydroxyl group that
may be further protected by a protecting group or a C.sub.1-C.sub.6
alkoxy group which may have a substituent; and [0018] R.sup.a and
R.sup.b are the same as or different from each other and each
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may
have a substituent, or a C.sub.3-C.sub.8 cycloalkyl group which may
have a substituent, or when R.sup.a and R.sup.b are bonded
together, they may form, together with the nitrogen atom that is
adjacent to R.sup.a and R.sup.b, a 4- to 10-membered single ring
which may have a substituent; and [0019] L represents a single
bond, [0020] or a salt thereof.
[0021] The cancer may be Breast cancer brain metastases,
Astrocytoma, Atypical Teratoid Rhabdoid Tumor (ATRT),
Chondrosarcoma, Choroid Plexus Carcinoma, Craniopharyngioma,
Ependymoma, Germ Cell Tumor, Glioblastoma, Glioma, Hemangioma,
Juvenile Pilocytic Astrocytoma, Medulloblastoma, Meningioma,
Neurofibroma, Neuronal and Mixed Neuronal-Glial Tumors,
Oligoastrocytoma, Oligodendroglioma, Pineal Tumor, Pituitary Tumor,
PNET--(primitive neuroectodermal tumor), Schwannoma, and
Leptomeningeal metastases. R.sup.a and R.sup.b independently may
represent a hydrogen atom, a methyl group, an ethyl group, a
n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl
group, or a tert-butyl group. -T-Z-- may represents
--CH.sub.2CH.sub.2-- or --C(CH.sub.3).sub.2CH.sub.2O--. Y may
represents --CH.sub.2--N(CH.sub.2CH.sub.3)-- or
--CH.sub.2--N(CH.sub.2CH.sub.2OH)--. Each of R'' independently may
represents a hydrogen atom or a methoxy group. R'' may represents a
hydroxyl group. A may represents a phenylene group. The compound
may be
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol. An effective amount of the compound
may be administered. The effective amount may comprise a high
dosage. The high dosage may be more than about 20 mg/kg. The high
dosage may be about 20 mg/kg to about 100 mg/kg. The compound may
be administered by oral administration, intravenous administration,
intradermal injection, intramuscular injection or subcutaneous
injection. The method may further comprising administering an
effective amount of at least one compound selected from the group
consisting of a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6
inhibitor), an antiestrogen, a ligand of retinoic acid or retinoxic
X receptor, an antiprogestin, an antiandrogen, vitamin D or
metabolite thereof, a farnesyl transferase inhibitor, a PPAR.alpha.
or gamma agonist and a MAP kinase inhibitor.
[0022] The present invention is directed to a method of treating
breast cancer brain metastasis in a subject. The method comprises
administering a compound represented by the following formula
I:
##STR00005## [0023] wherein [0024] TZ represents a C.sub.1-C.sub.4
alkylene group or --CR.sup.f'R.sup.g'--CH.sub.2--O-- wherein
R.sup.f' and R.sup.g' independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; [0025] A represents a 5- to
14-membered heteroarylene group which may have a substituent or a
C.sub.6-C.sub.14 arylene group which may have a substituent; [0026]
Y represents --CH.sub.2--NR.sup.c-- wherein R.sup.c represents
hydrogen or a C.sub.1-C.sub.6 alkyl group which may have a
substituent; [0027] ring G represents the following formula:
[0027] ##STR00006## [0028] R' represents 1 to 4 substituents
independently selected from a hydrogen atom, a C.sub.1-C.sub.6
alkoxy group, and a hydroxyl group; [0029] a partial structure in
formula (I) represented by the following formula:
##STR00007##
[0029] is
##STR00008## [0030] R'' represents hydrogen, a hydroxyl group that
may be further protected by a protecting group or a C.sub.1-C.sub.6
alkoxy group which may have a substituent; and [0031] R.sup.a and
R.sup.b are the same as or different from each other and each
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may
have a substituent, or a C.sub.3-C.sub.8 cycloalkyl group which may
have a substituent, or when R.sup.a and R.sup.b are bonded
together, they may form, together with the nitrogen atom that is
adjacent to R.sup.a and R.sup.b, a 4- to 10-membered single ring
which may have a substituent; and [0032] L represents a single
bond, [0033] or a salt thereof.
[0034] R.sup.a and R.sup.b independently may represent a hydrogen
atom, a methyl group, an ethyl group, a n-propyl group, an
iso-propyl group, a n-butyl group, an iso-butyl group, or a
tert-butyl group. -T-Z-- may represents --CH.sub.2CH.sub.2-- or
--C(CH.sub.3).sub.2CH.sub.2O--. Y may represents
--CH.sub.2--N(CH.sub.2CH.sub.3)-- or
--CH.sub.2--N(CH.sub.2CH.sub.2OH)--. Each of R'' independently may
represents a hydrogen atom or a methoxy group. R'' may represents a
hydroxyl group. A may represents a phenylene group. The compound
may be
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol. An effective amount of the compound
may be administered. The effective amount may comprise a high
dosage. The high dosage may be more than about 20 mg/kg. The high
dosage may be about 20 mg/kg to about 100 mg/kg. The compound may
be administered by oral administration, intravenous administration,
intradermal injection, intramuscular injection or subcutaneous
injection. The method may further comprising administering an
effective amount of at least one compound selected from the group
consisting of a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6
inhibitor), an antiestrogen, a ligand of retinoic acid or retinoxic
X receptor, an antiprogestin, an antiandrogen, vitamin D or
metabolite thereof, a farnesyl transferase inhibitor, a PPAR.alpha.
or gamma agonist and a MAP kinase inhibitor.
[0035] The present invention is directed to a method of treating a
cancer in a subject, wherein the cancer is resistant to an estrogen
receptor modulator. The method comprises administering a compound
represented by the following formula I:
##STR00009## [0036] wherein [0037] TZ represents a C.sub.1-C.sub.4
alkylene group or --CR.sup.f'R.sup.g'--CH.sub.2--O-- wherein
R.sup.f and R.sup.g' independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; [0038] A represents a 5- to
14-membered heteroarylene group which may have a substituent or a
C.sub.6-C.sub.14 arylene group which may have a substituent; [0039]
Y represents --CH.sub.2--NR.sup.c-- wherein R.sup.c represents
hydrogen or a C.sub.1-C.sub.6 alkyl group which may have a
substituent; [0040] ring G represents the following formula:
[0040] ##STR00010## [0041] R' represents 1 to 4 substituents
independently selected from a hydrogen atom, a C.sub.1-C.sub.6
alkoxy group, and a hydroxyl group; [0042] a partial structure in
formula (I) represented by the following formula:
##STR00011##
[0042] is
##STR00012## [0043] R'' represents hydrogen, a hydroxyl group that
may be further protected by a protecting group or a C.sub.1-C.sub.6
alkoxy group which may have a substituent; and [0044] R.sup.a and
R.sup.b are the same as or different from each other and each
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may
have a substituent, or a C.sub.3-C.sub.8 cycloalkyl group which may
have a substituent, or when R.sup.a and R.sup.b are bonded
together, they may form, together with the nitrogen atom that is
adjacent to R.sup.a and R.sup.b, a 4- to 10-membered single ring
which may have a substituent; and [0045] L represents a single
bond, [0046] or a salt thereof.
[0047] The cancer may be de novo resistant to the estrogen receptor
modulator. The resistance to the estrogen receptor modulator may be
acquired. The estrogen receptor modulator may be a selective
estrogen receptor modulator (SERM). The SERM may be tamoxifen,
idoxifene, raloxifene or ICI 182,780. The cancer may be breast,
endometrial or ovarian cancer. The cancer may be breast cancer.
R.sup.a and R.sup.b independently may represent a hydrogen atom, a
methyl group, an ethyl group, a n-propyl group, an iso-propyl
group, a n-butyl group, an iso-butyl group, or a tert-butyl group.
-T-Z-- may represents --CH.sub.2CH.sub.2-- or
--C(CH.sub.3).sub.2CH.sub.2O--. Y may represents
--CH.sub.2--N(CH.sub.2CH.sub.3)-- or
--CH.sub.2--N(CH.sub.2CH.sub.2OH)--. Each of R'' independently may
represents a hydrogen atom or a methoxy group. R'' may represents a
hydroxyl group. A may represents a phenylene group. The compound
may be
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol. An effective amount of the compound
may be administered. The effective amount may comprise a high
dosage. The high dosage may be more than about 20 mg/kg. The high
dosage may be about 20 mg/kg to about 100 mg/kg. The compound may
be administered by oral administration, intravenous administration,
intradermal injection, intramuscular injection or subcutaneous
injection. The method may further comprising administering an
effective amount of at least one compound selected from the group
consisting of a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6
inhibitor), an antiestrogen, a ligand of retinoic acid or retinoxic
X receptor, an antiprogestin, an antiandrogen, vitamin D or
metabolite thereof, a farnesyl transferase inhibitor, a PPAR.alpha.
or gamma agonist and a MAP kinase inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 shows treatment with
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol ("RAD 1901") results in a dose
dependent reduction in ER expression and activity. (A) MCF7 breast
cancer cells were treated 4 hours as indicated prior to western
blot detection of ER and loading control cytokeratin (CK) 18. (B)
Ovariectomized mice bearing MCF7 xenograft tumors were treated
daily with RAD 1901 ("RAD") or tamoxifen ("Tam") in the context of
continued estrogen treatment.
[0049] FIG. 2 shows RAD1901 downregulates ER.alpha. expression.
FIG. 2A shows ER.alpha. protein expression in whole cell extracts
pre-treated with transcription or translation inhibitors before
treatment with RAD1901, analyzed by immunoblot. FIG. 2B shows
ER.alpha. mRNA expression in similarly treated cells.
[0050] FIG. 3 shows the interaction between ER and
conformation-specific peptides in mammalian two-hybrid system.
[0051] FIG. 4 shows RAD 1901 exhibits dose dependent
agonist/antagonist regulation of ER target genes.
DETAILED DESCRIPTION
[0052] The present disclosure provides a method of treating a
subject suffering from estrogen receptor positive cancer of the
brain, such as BCBM, or a cancer that is resistant to an estrogen
receptor modulator, such as tamoxifen resistant breast cancer. The
methods involve administering to the subject a SERM, such as RAD
1901. RAD 1901 exhibits desired pharmacological activities and
exhibits significant brain penetrance when evaluated in
post-menopausal women, in particular a unique dose response, with
lower doses of the drug being more effective at relieving hot
flashes. RAD 1901 induces hot flashes in healthy postmenopausal
women in a dose dependent manner, thus RAD 1901 may effectively
inhibit estrogen receptor action in the brain.
[0053] Turnover of ER.alpha. is significantly increased upon
binding RAD1901, an activity that is more pronounced at higher drug
concentrations (FIG. 1). This drug exhibits some of the
characteristics that are generally attributed to selective estrogen
receptor degraders (SERDs). Thus, at lower doses RAD1901 exhibits
partial agonist activity, i.e., SERM activity, allowing for relief
of hot flashes, but the SERD activity of the compound dominates
when the receptor is exposed to higher concentrations. The present
disclosure describes in vitro the mechanism by which RAD1901
impacts ER expression and investigates the possible result of such
action in vivo.
[0054] As exemplified below, RAD 1901 surprisingly has the ability
to degrade the estrogen receptor. Both in vitro and in vivo studies
have since shown that the antagonist activity of this ligand
correlates with estrogen receptor degradation in a dose dependent
manner. RAD 1901 also inhibits estrogen dependent growth of breast
cancer xenograft tumors and may be used to treat breast cancer,
such as tamoxifen resistant breast cancer.
[0055] RAD 1901 is unique among both SERMs and SERDs in that this
drug accumulates in the brain, an environment in which SERM
penetration has been historically regarded as quite low. Estrogen
receptor activity has been found to be important in the growth of
tumors resistant to aromatase inhibitors and/or tamoxifen, and
treatment with SERDs has been shown to have clinical benefit. While
the revelation that RAD 1901 exhibits SERD activity certainly
suggests potential utility in the treatment of progressing ER+
breast tumors, which was unappreciated prior to the present
disclosure, the targeting of ER activity for the treatment of ER+
brain cancers represents a new frontier for the use of both SERMs
and SERDs, as RAD 1901 represents the first SERM/SERD that can
sufficiently penetrate the brain to exhibit efficacy. Because BCBM
is generally diagnosed late in the disease progression of ER+
metastatic breast cancer, patients will in general have already
been treated with endocrine therapeutics (i.e., tamoxifen or
aromatase inhibitors). Thus, while SERMs such as tamoxifen have low
brain penetration and have exhibited efficacy in anecdotal cases of
BCBM that are detailed in the literature, the SERD activity of RAD
1901 becomes key to the therapeutic potential of this compound for
treatment of BCBM, as SERDs have been found to be effective in
breast cancers that are resistant to SERM or aromatase inhibitor
therapy.
1. DEFINITIONS
[0056] The terms "comprise(s)," "include(s)," "having," "has,"
"can," "contain(s)," and variants thereof, as used herein, are
intended to be open-ended transitional phrases, terms, or words
that do not preclude the possibility of additional acts or
structures. The singular forms "a," "and" and "the" include plural
references unless the context clearly dictates otherwise. The
present disclosure also contemplates other embodiments
"comprising," "consisting of" and "consisting essentially of," the
embodiments or elements presented herein, whether explicitly set
forth or not.
[0057] For the recitation of numeric ranges herein, each
intervening number there between with the same degree of precision
is explicitly contemplated. For example, for the range of 6-9, the
numbers 7 and 8 are contemplated in addition to 6 and 9, and for
the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6,
6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
[0058] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art. In case of conflict, the present
document, including definitions, will control. Preferred methods
and materials are described below, although methods and materials
similar or equivalent to those described herein can be used in
practice or testing of the present invention. All publications,
patent applications, patents and other references mentioned herein
are incorporated by reference in their entirety. The materials,
methods, and examples disclosed herein are illustrative only and
not intended to be limiting.
[0059] The term "administration" or "administering," as used herein
refers to providing, contacting, and/or delivery of the SERM by any
appropriate route to achieve the desired effect. These agents may
be administered to a subject in numerous ways including, but not
limited to, orally, ocularly, nasally, intravenously, topically, as
aerosols, suppository, etc. and may be used in combination.
[0060] "Aromatase inhibitor" as used herein refers to a compound
that targets aromatase, which is an enzyme involved in the
biosynthesis of estrogen. Aromatase inhibitors may block the
production of estrogen or block the action of estrogen on
receptors.
[0061] "Blood brain barrier" or "BBB" as used herein refers to a
highly selective permeability barrier that separates the
circulating blood from the brain extracellular fluid in the central
nervous system. The blood brain barrier may prevent the certain
drugs from entering brain tissue and is a limiting factor in the
delivery of many peripherally-administered agents to the central
nervous system.
[0062] "Breast cancer" as used herein refers to a type of cancer
that originates from and develops in the breast. "Metastatic breast
cancer" refers to breast cancer that spreads outside the breast to
the lymph nodes, bones, or other areas.
[0063] "Breast Cancer Brain Metastases" and "BCBM" as used
interchangeably herein refer to breast cancer that has metastasized
to the brain. BCBM may occur in up to 10-15% of breast-cancer
patients. BCBM may progress rapidly and can produce
life-threatening complications such as increased intracranial
pressure, herniation of the brain and seizures. Radiotherapy is a
treatment of BCBM as it halts tumor progression quickly and can
induce a response in the majority of patients.
[0064] "Cancer" as used herein refers to the uncontrolled and
unregulated growth of abnormal cells in the body. Cancerous cells
are also called malignant cells. Cancer may invade nearby parts of
the body and may also spread to more distant parts of the body
through the lymphatic system or bloodstream. Cancers include
Adrenocortical Carcinoma, Anal Cancer, Bladder Cancer, Brain Tumor,
Breast Cancer, Carcinoid Tumor, Gastrointestinal, Carcinoma of
Unknown Primary, Cervical Cancer, Colon Cancer, Endometrial Cancer,
Esophageal Cancer, Extrahepatic Bile Duct Cancer, Ewings Family of
Tumors (PNET), Extracranial Germ Cell Tumor, Intraocular Melanoma
Eye Cancer, Gallbladder Cancer, Gastric Cancer (Stomach),
Extragonadal Germ Cell Tumor, Gestational Trophoblastic Tumor, Head
and Neck Cancer, Hypopharyngeal Cancer, Islet Cell Carcinoma,
Kidney Cancer (renal cell cancer), Laryngeal Cancer, Acute
Lymphoblastic Leukemia, Leukemia, Acute Myeloid, Chronic
Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hairy Cell
Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Non-Small Cell
Lung Cancer, Small Cell Lung Cancer, AIDS-Related Lymphoma, Central
Nervous System (Primary) Lymphoma, Cutaneous T-Cell Lymphoma,
Hodgkin's Disease Lymphoma, Non-Hodgkin's Disease Lymphoma,
Malignant Mesothelioma, Melanoma, Merkel Cell Carcinoma, Metastasic
Squamous Neck Cancer with Occult Primary, Multiple Myeloma and
Other Plasma Cell Neoplasms, Mycosis Fungoides, Myelodysplastic
Syndrome, Myeloproliferative Disorders, Nasopharyngeal Cancer,
neuroblastoma, Oral Cancer, Oropharyngeal Cancer, Osteosarcoma,
Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Pancreatic
Cancer, Exocrine, Pancreatic Cancer, Islet Cell Carcinoma,
Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile
Cancer, Pituitary Cancer, Plasma Cell Neoplasm, Prostate Cancer,
Rhabdomyosarcoma, Rectal Cancer, Renal Cell Cancer (cancer of the
kidney), Transitional Cell Renal Pelvis and Ureter, Salivary Gland
Cancer, Sezary Syndrome, Skin Cancer, Small Intestine Cancer, Soft
Tissue Sarcoma, Testicular Cancer, Malignant Thymoma, Thyroid
Cancer, Urethral Cancer, Uterine Cancer, Unusual Cancer of
Childhood, Vaginal Cancer, Vulvar Cancer, and Wilms' Tumor.
[0065] The term "effective dosage" as used herein means a dosage of
a drug effective for periods of time necessary, to achieve the
desired therapeutic result. An effective dosage may be determined
by a person skilled in the art and may vary according to factors
such as the disease state, age, sex, and weight of the individual,
and the ability of the drug to elicit a desired response in the
individual. This term as used herein may also refer to an amount
effective at bringing about a desired in vivo effect in an animal,
mammal, or human, such as reducing and/or inhibiting the function
of the estrogen receptor. A therapeutically effective amount may be
administered in one or more administrations (e.g., the agent may be
given as a preventative treatment or therapeutically at any stage
of disease progression, before or after symptoms, and the like),
applications or dosages and is not intended to be limited to a
particular formulation, combination or administration route. It is
within the scope of the present disclosure that the SERM may be
administered at various times during the course of treatment of the
subject. The times of administration and dosages used will depend
on several factors, such as the goal of treatment (e.g., treating
v. preventing), condition of the subject, etc. and can be readily
determined by one skilled in the art.
[0066] "Estrogen dependent cancer" or "estrogen receptor positive
cancer" as used interchangeably herein refers to a tumor that
contains estrogen receptor (ER) positive cells, i.e., cells that
have estrogen receptors, and respond to the presence of estrogen
with increased proliferation. Estrogen dependent cancers may
include breast cancer, ovarian cancer, or endometrial cancer.
"Estrogen receptor positive breast cancer" is a type of breast
cancer that is sensitive to estrogen.
[0067] "Estrogen receptor" or "ER" as used interchangeably herein
refers to a receptor that is activated by the hormone estrogen and
is a member of the nuclear hormone family of intracellular
receptors. There are two different isoforms of estrogen receptor,
referred to as a (also referred to as "ERa") and .beta. (also
referred to as "ERb"). ER.alpha. and ERb genes are encoded by ESR1
and ESR2 gene, respectively. Hormone-activated estrogen receptors
form dimers and may form homodimers or heterodimers. Both ERs are
widely expressed in different tissue types.
[0068] "Estrogen-receptor downregulators" as used herein refers to
a drug or compound which binds and down-regulates the expression of
an estrogen-receptor.
[0069] "Estrogen receptor negative breast cancer" or "Estrogen
independent breast cancer" as used interchangeably herein refers to
a tumor that does not contain estrogen receptor positive cells,
i.e., cells that lack estrogen receptors, and does not depend on
the presence of estrogen for ongoing proliferation.
[0070] "HER2 intervention drug" or "HER2 inhibitor" as used
interchangeably herein refers to a compound that targets human
Epidermal Growth Factor Receptor 2 (HER2). HER2 is a member of the
epidermal growth factor receptor family and is involved in the
development and progression of certain aggressive types of breast
cancer, such as estrogen dependent breast cancer. A HER2 inhibitor
may be a tyrosine kinase or a monoclonal antibody.
[0071] "Metastatic cancer" as used herein refers to a cancer that
has spread from the part of the body where it started (the primary
site) to other parts of the body.
[0072] "Progesterone receptor positive cancer" as used herein
refers to a tumor that contains progesterone receptor positive
(PR+) cells, i.e., cells that have progesterone receptors, which
respond to the presence of progesterone with increased
proliferation.
[0073] "Salt" as used herein is not limited as long as the salt is
formed with the compound according to the present invention, and is
pharmacologically acceptable; the preferred examples of the salt
include a hydrohalide salt (for instance, hydrochloride,
hydrobromide, hydroiodide and the like), an inorganic acid salt
(for instance, sulfate, nitrate, perchlorate, phosphate, carbonate,
bicarbonate and the like), an organic carboxylate salt (for
instance, acetate salt, maleate salt, tartrate salt, fumarate salt,
citrate salt and the like), an organic sulfonate salt (for
instance, methanesulfonate salt, ethanesulfonate salt,
benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt
and the like), an amino acid salt (for instance, aspartate salt,
glutamate salt and the like), a quaternary ammonium salt, an
alkaline metal salt (for instance, sodium salt, potassium salt and
the like), an alkaline earth metal salt (magnesium salt, calcium
salt and the like) and the like. In addition, hydrochloride salt,
sulfate salt, methanesulfonate salt, acetate salt, and the like are
preferred as "pharmacologically acceptable salt" of the compounds
according to the present invention. Further, when the compounds
according to the present invention are obtained in a free form,
they can be converted into a salt or a hydrate thereof by
conventional methods. In certain embodiments, the salt is a
hydrochloric acid salt of the compound of the following structural
formula:
##STR00013##
In one aspect, the salt is a hydrochloric acid salt of
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol.
[0074] "Selective estrogen receptor degraders" or "SERDs" as used
interchangeably herein refers to a compound that interacts with an
ER and induce a conformational change that results in the
degradation of the receptor.
[0075] "Selective estrogen receptor modulators" or "SERMs" as used
interchangeably herein refers to a compound that interacts with an
ER and whose relative agonist/antagonist activities are manifest in
a cell selective manner. The prevention of estrogen binding to the
estrogen receptor may lead to decreased proliferation of estrogen
dependent cancer cells.
[0076] The term "subject", "patient" or "subject in the method" as
used herein interchangeably, means any vertebrate, including, but
not limited to, a mammal (e.g., cow, pig, camel, llama, horse,
goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and
mouse, a non-human primate (for example, a monkey, such as a
cynomolgous or rhesus monkey, chimpanzee, etc.) and a human). In
some embodiments, the subject or subject may be a human or a
non-human. In some embodiments, the subject may be a human subject
at risk for developing or already suffering from cancer.
[0077] "Tamoxifen resistant breast cancer" as used herein refers to
a breast cancer that does respond to treatment with tamoxifen.
[0078] "Treat", "treating" or "treatment" are each used
interchangeably herein to describe reversing, alleviating, or
inhibiting the progress of a disease, or one or more symptoms of
such disease, to which such term applies. Depending on the
condition of the subject, the term also refers to preventing a
disease, and includes preventing the onset of a disease, or
preventing the symptoms associated with a disease. A treatment may
be either performed in an acute or chronic way. The term also
refers to reducing the severity of a disease or symptoms associated
with such disease prior to affliction with the disease. Such
prevention or reduction of the severity of a disease prior to
affliction refers to administration of the SERM to a subject that
is not at the time of administration afflicted with the disease.
"Preventing" also refers to preventing the recurrence of a disease
or of one or more symptoms associated with such disease.
"Treatment" and "therapeutically," refer to the act of treating, as
"treating" is defined above.
2. METHODS OF TREATING CANCER WITH A SERM
[0079] The present invention is directed to a method of treating
estrogen receptor positive cancers of the brain in a subject. The
method comprises administering a compound represented by the
following formula I:
##STR00014## [0080] wherein [0081] TZ represents a C.sub.1-C.sub.4
alkylene group or --CR.sup.f'R.sup.g'--CH.sub.2--O-- wherein
R.sup.f' and R.sup.g' independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; [0082] A represents a 5- to
14-membered heteroarylene group which may have a substituent or a
C.sub.6-C.sub.14 arylene group which may have a substituent; [0083]
Y represents --CH.sub.2--NR.sup.c-- wherein R.sup.c represents
hydrogen or a C.sub.1-C.sub.6 alkyl group which may have a
substituent; [0084] ring G represents the following formula:
[0084] ##STR00015## [0085] R' represents 1 to 4 substituents
independently selected from a hydrogen atom, a C.sub.1-C.sub.6
alkoxy group, and a hydroxyl group; [0086] a partial structure in
formula (I) represented by the following formula:
##STR00016##
[0086] is
##STR00017## [0087] R'' represents hydrogen, a hydroxyl group that
may be further protected by a protecting group or a C.sub.1-C.sub.6
alkoxy group which may have a substituent; and [0088] R.sup.a and
R.sup.b are the same as or different from each other and each
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may
have a substituent, or a C.sub.3-C.sub.8 cycloalkyl group which may
have a substituent, or when R.sup.a and R.sup.b are bonded
together, they may form, together with the nitrogen atom that is
adjacent to R.sup.a and R.sup.b, a 4- to 10-membered single ring
which may have a substituent; and [0089] L represents a single
bond, [0090] or a salt thereof.
[0091] In certain embodiments, R.sup.a and R.sup.b independently
may represent a hydrogen atom, a methyl group, an ethyl group, a
n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl
group, or a tert-butyl group. -T-Z-- may represents
--CH.sub.2CH.sub.2-- or --C(CH.sub.3).sub.2CH.sub.2O--. Y may
represents --CH.sub.2--N(CH.sub.2CH.sub.3)-- or
--CH.sub.2--N(CH.sub.2CH.sub.2OH)--. Each of R'' independently may
represents a hydrogen atom or a methoxy group. R'' may represents a
hydroxyl group. In certain embodiments, the compound may be
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol. Examples of other SERMS are described
in U.S. Pat. No. 7,612,114, U.S. U.S. Pat. Nos. 7,960,412,
8,399,520, U.S. Patent Publication No. US 2009-0325930, and U.S.
Patent Publication No. US 2006-0116364, the contents of which are
incorporated by reference in their entirety. An effective amount of
the compound may be administered.
(a) Dosages
[0092] In general, the dosage of administered SERM will vary
depending upon such factors as the patient's age, weight, height,
sex, general medical condition, and previous medical history.
Typically, it is desirable to provide the recipient with a dosage
of SERM, which is in the range of from about 1 pg/kg to 10 mg/kg
(amount of agent/body weight of patient), although a lower or
higher dosage also may be administered as circumstances dictate.
Dosage regimens may be adjusted to provide the optimum desired
response (e.g., a therapeutic or prophylactic response). For
example, a single bolus may be administered, several divided doses
may be administered over time or the dose may be proportionally
reduced or increased as indicated by the exigencies of the
therapeutic situation. It is especially advantageous to formulate
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the mammalian subjects to be tested; each unit
containing a predetermined quantity of active compound calculated
to produce the desired therapeutic effect in association with the
required pharmaceutical carrier. The specification for the dosage
unit forms of the present invention are dictated by and directly
dependent on (a) the unique characteristics of the active compound
and the particular therapeutic or prophylactic effect to be
achieved and (b) the limitations inherent in the art of compounding
such an active compound for the treatment of sensitivity in
individuals.
[0093] An exemplary, non-limiting range for a therapeutically or
prophylactically effective amount of the SERM is a dose of between
0.1 and 200 mg/kg, for example between 0.1 and 10 mg/kg, or about
20 mg/kg to about 100 mg/kg. The therapeutically or
prophylactically effective amount of the SERM may be between 1 and
200 mg/kg, 10 and 200 mg/kg, 20 and 200 mg/kg, 50 and 200 mg/kg, 75
and 200 mg/kg, 100 and 200 mg/kg, 150 and 200 mg/kg, 50 and 100
mg/kg, 5 and 10 mg/kg, or 1 and 10 mg/kg. It is to be noted that
dosage values may vary with the type and severity of the condition
to be alleviated.
[0094] In some embodiments, the SERM can be administered to a
patient in an amount of about 10 mg/day to about 500 mg/day, about
10 mg/day to about 200 mg/day (e.g., 10, 20, 30, 40, 50, 60, 70,
80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200
mg/day), 20 mg/day to about 100 mg/day, 100 mg/day to about 200
mg/day, or about 200 mg/day to about 500 mg/day (e.g., 190, 200,
210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330,
340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460,
470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590,
600, 610, 620, 630, 640, 650, 660, 670, 680, 690, or 700 mg/day),
inclusive of any single or multi-dose daily administration regimen
that falls within that total daily dose range. In some embodiments,
the dose is from about 20 mg/day to about 100 mg/day. Additionally,
one of ordinary skill in the art would also know how to adjust or
modify variables such as dosage, dosage schedules, and routes of
administration, as appropriate, for a given subject.
[0095] Further, the SERM dose may be determined by a person skilled
in the art and may vary according to factors such as the disease
state, age, sex, and weight of the individual, and the ability of
the SERM to elicit a desired response in the individual. The dose
is also one in which toxic or detrimental effects, if any, of the
SERM are outweighed by the therapeutically beneficial effects. It
is to be further understood that for any particular subject,
specific dosage regimens should be adjusted over time according to
the individual need and the professional judgment of the person
administering or supervising the administration of the
compositions, and that dosage ranges set forth herein are exemplary
only and are not intended to limit the scope or practice of the
claimed composition.
(b) Rad 1901
[0096] The SERM may be RAD 1901. Although RAD 1901 may effectively
treat vasomotor symptoms, its pharmacology is complex. Treatment of
ER positive breast cancer cells with RAD 1901 in MCF7 and BT483
cells resulted in a pronounced dose dependent down regulation of
the receptor expression. RAD 1901 is a unique SERM in that it
apparently has a relative agonist/antagonist activity in the brain
that is determined by dose. At low doses RAD 1901, behaves as a
SERM as it exhibits estrogenic activity. At high doses, RAD 1901
may function as a SERD, reversing the response.
[0097] While targeting of the estrogen signaling axis has proven
effective in the treatment of breast cancer and osteoporosis,
implementing a safe therapy that mitigates the vasomotor. While
efforts are being made to address this unmet medical need using
tissue specific estrogen complexes (TSECs) that combine estrogens
and SERMs with the intention of inhibiting estrogen action only in
some tissues (i.e., breast and uterus), preliminary clinical data
suggest that RAD 1901 may accomplish the same medical goal without
exposing the patient to estrogen. The apparent dose dependent down
regulation of ER by RAD1901 suggest that at a therapeutic (low)
dose, RAD1901 may be mediating some level of agonist activity,
while a higher dose results in more extensive SERM activity and an
effective blockade in estrogen signaling, thereby exacerbating
vasomotor symptoms.
[0098] In some embodiments, a low dose of RAD 1901 may be about 0
mg/kg to about 25 mg/kg, about 0 mg/kg to about 20 mg/kg, about 0
mg/kg to about 15 mg/kg, about 0 mg/kg to about 10 mg/kg, about 0
mg/kg to about 5 mg/kg, about 1 mg/kg to about 25 mg/kg, about 1
mg/kg to about 20 mg/kg, about 1 mg/kg to about 15 mg/kg, about 1
mg/kg to about 10 mg/kg, about 1 mg/kg to about 5 mg/kg, about 2
mg/kg to about 25 mg/kg, about 2 mg/kg to about 20 mg/kg, about 2
mg/kg to about 15 mg/kg, about 2 mg/kg to about 10 mg/kg, about 2
mg/kg to about 5 mg/kg, about 3 mg/kg to about 25 mg/kg, about 3
mg/kg to about 20 mg/kg, about 3 mg/kg to about 15 mg/kg, about 3
mg/kg to about 10 mg/kg, about 3 mg/kg to about 5 mg/kg, about 4
mg/kg to about 25 mg/kg, about 4 mg/kg to about 20 mg/kg, about 4
mg/kg to about 15 mg/kg, about 4 mg/kg to about 10 mg/kg, about 4
mg/kg to about 5 mg/kg, about 5 mg/kg to about 25 mg/kg, about 5
mg/kg to about 20 mg/kg, about 5 mg/kg to about 15 mg/kg, about 5
mg/kg to about 10 mg/kg, about 5 mg/kg to about 7.5 mg/kg. In some
embodiments, a low dose of RAD 1901 may be less than about 25
mg/kg, about 24 mg/kg, about 23 mg/kg, about 22 mg/kg, about 21
mg/kg, about 20 mg/kg, about 19 mg/kg, about 18 mg/kg, about 17
mg/kg, about 16 mg/kg, about 15 mg/kg, about 14 mg/kg, about 13
mg/kg, about 12 mg/kg, about 11 mg/kg, about 10 mg/kg, about 9
mg/kg, about 8 mg/kg, about 7 mg/kg, about 6 mg/kg, about 5 mg/kg,
about 4 mg/kg, about 3 mg/kg, about 2 mg/kg, or about 1 mg/kg.
[0099] In some embodiments, a high dose of RAD 1901 may be about 15
mg/kg to about 500 mg/kg, about 15 mg/kg to about 250 mg/kg, about
15 mg/kg to about 200 mg/kg, about 15 mg/kg to about 150 mg/kg,
about 15 mg/kg to about 100 mg/kg, about 15 mg/kg to about 75
mg/kg, about 20 mg/kg to about 500 mg/kg, about 20 mg/kg to about
250 mg/kg, about 20 mg/kg to about 200 mg/kg, about 20 mg/kg to
about 150 mg/kg, about 20 mg/kg to about 100 mg/kg, about 20 mg/kg
to about 75 mg/kg, about 25 mg/kg to about 500 mg/kg, about 25
mg/kg to about 250 mg/kg, about 25 mg/kg to about 200 mg/kg, about
25 mg/kg to about 150 mg/kg, about 25 mg/kg to about 100 mg/kg, or
about 25 mg/kg to about 75 mg/kg. In some embodiments, a high dose
of RAD 1901 may be more than about 15 mg/kg, 20 mg/kg, about 25
mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45
mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65
mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85
mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 105
mg/kg, about 110 mg/kg, about 115 mg/kg, about 120 mg/kg, about 125
mg/kg, about 130 mg/kg, about 135 mg/kg, about 140 mg/kg, about 145
mg/kg, about 150 mg/kg, about 155 mg/kg, about 160 mg/kg, about 165
mg/kg, about 170 mg/kg, about 175 mg/kg, about 180 mg/kg, about 185
mg/kg, about 190 mg/kg, about 195 mg/kg, about 200 mg/kg, about 250
mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450
mg/kg or about 500 mg/kg.
[0100] In some embodiments, RAD1901 can be administered to a
patient in an amount of about 10 mg/day to about 500 mg/day, about
10 mg/day to about 200 mg/day (e.g., 10, 20, 30, 40, 50, 60, 70,
80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200
mg/day), 20 mg/day to about 100 mg/day, 100 mg/day to about 200
mg/day, or about 200 mg/day to about 500 mg/day (e.g., 190, 200,
210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330,
340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460,
470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590,
600, 610, 620, 630, 640, 650, 660, 670, 680, 690, or 700 mg/day),
inclusive of any single or multi-dose daily administration regimen
that falls within that total daily dose range. In some embodiments,
the dose is from about 20 mg/day to about 100 mg/day. Additionally,
one of ordinary skill in the art would also know how to adjust or
modify variables such as dosage, dosage schedules, and routes of
administration, as appropriate, for a given subject.
3. METHODS OF TREATING ESTROGEN RECEPTOR POSITIVE CANCER OF THE
BRAIN
[0101] The methods described above may be used to treat an estrogen
receptor positive cancer of the brain. In some embodiments, the
cancer may include subtypes of brain tumors that may express ER,
such as Breast Cancer Brain Metastases (BCBM), Astrocytoma,
Chondrosarcoma, Craniopharyngioma, Glioblastoma, Glioma,
Hemangioma, Medulloblastoma, Meningioma, Neurofibroma, Neuronal and
Mixed Neuronal-Glial Tumors, Oligoastrocytoma, Pituitary Tumor,
PNET--(primitive neuroectodermal tumor), Schwannomak, or
Leptomeningeal metastases. In some embodiments, the cancer may be
other cancers such as Atypical Teratoid Rhabdoid Tumor (ATRT),
Choroid Plexus Carcinoma, Ependymoma, Germ Cell Tumor, Juvenile
Pilocytic Astrocytoma, Oligodendroglioma, or Pineal Tumor.
(a) Breast Cancer Brain Metastases
[0102] The methods described above may be used to treat a subject
suffering from breast cancer brain metastases. 10-20% of breast
cancer patients ultimately experience breast cancer metastasis to
the brain, i.e., BCBM. 30-40% of BCBM express ER. ER expression is
retained in 50-65% of BCBM that arise from ER+/PR+ tumors, despite
treatment of the initial tumor with endocrine therapies. As many as
50% of BCBM express the estrogen receptor, and the brain is an
environment rich in aromatase activity, suggesting that estrogen
levels and signaling may be of importance in the establishment and
maintenance of BCBM. Therefore, the availability of the SERM, such
as RAD 1901 or a similar SERM with significant brain penetrance,
that can induce estrogen receptor turnover in BCBM may provide
therapeutic benefit in the treatment of BCBM.
(b) Astrocytoma
[0103] Astrocytoma is a type of cancer of the brain that originate
in astrocytes, which are a particular kind of glial cells,
start-shaped brains cells in the cerebrum. Low ERb expression has
been shown to be associated with the progression of
astrocytoma.
(c) Chondrosarcoma
[0104] Chondrosarcoma is a type of tumor that affects the bones and
joints. Chondrosarcoma grow from the types of cells that make
cartilage in the skull. In the head, these tumors grow inside the
bones at the base of the back part of the skull and may be very
close to the nerves and blood vessels around the brainstem. ER is
present and active in chondrosarcoma tumors.
(d) Craniopharyngioma
[0105] Craniopharyngioma is a benign tumor that develops near the
pituitary gland. ER may be present in craniopharyngioma and may be
associated with improved disease prognosis.
(e) Glioblastoma multiforme
[0106] Glioblastoma multiforme, also known as "glioblastoma," is
the most common and most aggressive malignant primary brain tumor
in humans, involving glial cells and accounting for 52% of all
functional tissue brain tumor cases and 20% of all intracranial
tumors. Glioblastoma may express both ERs, which may play a role in
etiology and treatment.
(f) Glioma
[0107] Glioma is a type of tumor that starts in the brain or spine
and arises from glial cells. Gliomas make up approximately 30% of
all brain and central nervous system tumors and 80% of all
malignant brain tumors. Glioma may express both ERs, which may play
a role in etiology and treatment. Glioma may be responsive to
tamoxifen treatment.
(g) Hemangioma
[0108] Hemangioma is a benign and usually self-involuting tumor
(swelling or growth) of the endothelial cells that line blood
vessels. Hemangioma is characterized by increased number of normal
or abnormal vessels filled with blood. Human vascular endothelial
cells express ER isoforms and are responsive to tamoxifen
treatment. Hemangioma may be intracranial hemangiomas or cutaneous
hemangiomas.
(h) Medulloblastoma
[0109] Medulloblastoma is a highly malignant primary brain tumor
that originates in the cerebellum or posterior fossa.
Medulloblastomas may originate from immature or embryonal cells at
their earliest stage of development. Medulloblastoma may express ER
isoforms. ER isoforms are associated with growth and migration of
these cells.
(i) Meningioma
[0110] Meningiomas are a diverse set of tumors arising from the
meninges, i.e., the membranous layers surrounding the central
nervous system. Meningioma may express both ER isoforms. Meningioma
may be responsive to tamoxifen treatment.
(j) Neurofibroma
[0111] Neurofibroma is a benign nerve sheath tumor in the
peripheral nervous system. Neurofibromas arise from
nonmyelinating-type Schwann cells that exhibit biallelic
inactivation of the NF1 gene that codes for the protein
neurofibromin. Neurofibroma may be ER positive.
(k) Neuronal & Mixed Neuronal-Glial Tumors
[0112] Neuronal & Mixed Neuronal-Glial Tumors are rare, benign
tumors that come from ganglion-type cells, i.e., groups of nerve
cells. ER may be present in these tumors.
(l) Oligoastrocytoma
[0113] Oligoastrocytomas are a subset of brain tumors that present
with an appearance of mixed glial cell origin, astrocytoma and
oligodendroglioma. Oligoastrocytoma may have a lasting response to
tamoxifen treatment.
(m) Pituitary Tumor
[0114] A pituitary tumor is an abnormal growth in the pituitary
gland. Both ERa and ERb may be detected in pituitary tumors.
(n) Primitive Neuroestodermal Tumor (PNET)
[0115] Primitive neuroestodermal tumor is a neural crest tumor. The
majority of the cells in the PNET are derived from neuroectoderm,
but have not developed and differentiated in the way a normal
neuron would, and so the cells appear "primitive. ERa may be
present and may increase metastatic potential via extracellular
signal-regulated Kinase (ERK) activation.
(o) Schwannoma
[0116] Schwannoma (also known as an "neurilemmoma," "neurinoma,"
"neurolemmoma," and "Schwann cell tumor") is a benign nerve sheath
tumor composed of Schwann cells, which normally produce the
insulating myelin sheath covering peripheral nerves. Schwannoma may
express ERa.
(p) Leptomeningeal Metastases
[0117] Leptomeningeal metastases is breast cancer metastasis to the
membranes (meninges) surrounding the brain and spinal cord. A
durable response has been observed in patient(s) treated with
aromatase inhibitors, which suggests possible responsiveness to ER
targeted therapies.
4. METHODS OF TREATING A CANCER THAT IS RESISTANT TO AN ESTROGEN
RECEPTOR MODULATOR
[0118] The methods described above may be used to treat a cancer
that is resistant to an estrogen receptor modulator. The resistance
to the estrogen receptor modulator may be acquired. The estrogen
receptor modulator may be a selective estrogen receptor modulator
(SERM). The SERM may be tamoxifen, idoxifene, raloxifene, or ICI
182,780. The cancer may be breast, endometrial or ovarian cancer.
The cancer may be tamoxifen resistant breast cancer.
5. MECHANISMS OF DELIVERY
[0119] The SERM may be formulated to be compatible with its
intended route of administration. Examples of routes of
administration include, but are not limited to, parenteral, e.g.,
intravenous, intradermal, subcutaneous, oral, intranasal (e.g.,
inhalation), transdermal (e.g., topical), transmucosal, and rectal
administration. In a specific embodiment, the SERM is formulated in
accordance with routine procedures as a pharmaceutical composition
adapted for intravenous, subcutaneous, intramuscular, oral,
intranasal, or topical administration to human beings. Typically,
compositions for intravenous administration are solutions in
sterile isotonic aqueous buffer. Where necessary, the composition
may also include a solubilizing agent and a local anesthetic such
as lignocaine to ease pain at the site of the injection.
[0120] Various delivery systems are known and can be used to
administer one or more SERMs or the combination of one or more
SERMs and a prophylactic agent or therapeutic agent useful for
preventing, managing, treating, or ameliorating a disorder or one
or more symptoms thereof, e.g., encapsulation in liposomes,
microparticles, microcapsules, receptor-mediated endocytosis (see,
e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), etc. Methods
of administering a prophylactic or therapeutic agent of the SERM
include, but are not limited to, parenteral administration (e.g.,
intradermal, intramuscular, intraperitoneal, intravenous and
subcutaneous), epidural administration, intratumoral
administration, and mucosal administration (e.g., intranasal and
oral routes).
6. COMBINATION TREATMENTS
[0121] The methods described above may include a combination
treatment of the compound of formula I with other drugs and/or
other conventional cancer therapies, such as hormone therapy.
(a) Combination Drugs
[0122] The methods may further include administering an effective
amount of at least one compound of a cyclin-dependent kinase 4 and
6 inhibitor (CDK4/6 inhibitor), an antiestrogen, a ligand of
retinoic acid or retinoic X receptor, an antiprogestin, an
antiandrogen, vitamin D or metabolite thereof, a farnesyl
transferase inhibitor, a PPAR.alpha. or gamma agonist and a MAP
kinase inhibitor.
(b) Conventional Cancer Therapies
[0123] Conventional cancer therapies may include surgery, radiation
therapy, chemotherapy, hormone therapy, and targeted therapy.
Examples of surgery include open craniotomy with maximal excision,
which may be followed by radiation therapy. Examples of radiation
therapy include whole-brain irradiation, fractionated radiotherapy,
and radiosurgery, such as stereotactic radiosurgery, e.g., Gamma
Knife radiosurgery. Examples of chemotherapy include
anthracyclines, such as doxorubicin (Adriamycin, Doxil), epirubicin
(Ellence), and daunorubicin (Cerubidine, DaunoXome), capecitabine
(Xeloda), carboplatin (Paraplatin), cisplatin, cyclophosphamide
(Cytoxan), eribulin (Halaven), fluorouracil (also called
5-fluorouracil or 5-FU; Adrucil), gemcitabine (Gemzar), ixabepilone
(Ixempra), methotrexate (Amethopterin, Mexate, Folex), mitoxantrone
(Novantrone), mutamycin (Mitomycin), taxanes, such as paclitaxel
(Taxol, Abraxane), and docetaxel (Taxotere), thiotepa (Thioplex),
vincristine (Oncovin, Vincasar PES, Vincrex), and vinorelbine
(Navelbine). Examples of targeted therapy include trastuzumab
(Herceptin), lapatinib (Tykerb), bevacizumab (Avastin), pertuzumab
(Perj eta), and everolimus (Afinitor).
i. Endocrine Therapy (Hormone Therapy)
[0124] Endocrine therapy, also known as hormonal therapy, hormone
therapy, and hormone treatment, is a treatment that adds, blocks,
or removes hormones. For example, hormones may be given to adjust
low hormone levels. Synthetic hormones or other drugs may be given
to block the body's natural hormones to slow or stop the growth of
certain cancers (such as prostate and breast cancer). Endocrine
therapy may also include surgery to remove the gland that makes a
certain hormones.
[0125] Examples of hormone therapy include selective estrogen
receptor modulators (SERMs), such as tamoxifen, raloxifene,
endoxifene, toremifene, lasofoxifene, pipendoxifene, bazedoxifene,
and ospemifene, aromatase inhibitors, such anastrozole, letrozole,
exemestane, formestane, fadrozole, aminoglutethimide, and
testolactone, a HER2 intervention drug, such as a HER2 inhibitor,
such as Herceptin (trastuzumab), pertuzumab, and lapatinib, and
estrogen-receptor downregulators, such as fulvestrant (ICI
182,780).
7. SUBJECT OR SUBJECT IN THE METHOD
[0126] The methods described above are directed to treating a
subject with a SERM. The subject treated by the methods described
above may be a subject or patient suffering from or at risk of
suffering from an estrogen receptor positive cancer of the brain,
such as BCBM, or a cancer that is resistant to an estrogen receptor
modulator, such as tamoxifen resistant breast cancer. The subject
may be diagnosed or identified as having or at risk of having
cancer using known methods and assays, such as a biopsy. The
subject may be treated with SERM alone or in combination with
another drug and/or conventional cancer therapy, as described
above. The subject may be treated with the SERM as a neoadjuvant
therapy or post-surgery. The present invention has multiple
aspects, illustrated by the following non-limiting examples.
8. EXAMPLES
[0127] The foregoing may be better understood by reference to the
following examples, which are presented for purposes of
illustration and are not intended to limit the scope of the
invention.
Example 1
In Vitro Analysis of ER Degradation
[0128] 48 hours prior to treatment, MCF7 cells were plated in
phenol red free DMEM/F12 media supplemented with 8% charcoal
stripped fetal bovine serum, non-essential amino acids, and sodium
pyruvate. After 20 hours of treatment with the indicated ligands,
i.e., estradiol ("E2"; Sigma-Aldrich), antiestrogen ICI 182,780
("ICI"; Sigma-Aldrich), and 4-hydroxytamoxifen ("4OHT";
Sigma-Aldrich), (0-1 .mu.M), cells were washed and lysed in RIPA
lysis buffer (50 mM Tris, pH 8, 150 mM NaCl, 1% IGEPAL, 0.02% SDS,
0.5% sodium deoxycholate, 1 mM EDTA). 50 .mu.g of cleared lysate
was resolved by SDS-PAGE and analyzed by immunoblot detection of
ER.alpha. or cytokeratin 18 (loading control), as illustrated in
FIG. 1A.
Example 2
In Vivo Analysis of RAD 1901 in MCF7 Xenograft Tumors
[0129] A total of 90 female Nu/Nu mice were ovariectomized and
implanted subcutaneous simultaneously with an estrogen pellet
(Innovative Research of America) releasing 0.72 mg estradiol (E2)
over 60 days. 2 days later an approximately 6 mm3 fragment of an
MCF7 xenograft tumor (isolated from a recently sacrificed estrogen
treated nu/nu mouse) was inserted subcutaneous into the axial
mammary gland. Tumor growth (by caliper measurement) and animal
body weight were monitored 3.times. weekly until tumor volume
reached .about.0.2 cm.sup.3. Mice (n.about.10) were randomized to
the following groups: estrogen control (corn oil vehicle), E2+RAD
1901 (20 mg/kg; Radius Health, Inc.), E2+Tamoxifen (20 mg/kg;
Sigma-Aldrich). Treatments were formulated in sterile corn oil and
were administered daily by subcutaneous injection. After 3 weeks of
treatments, animals were euthanized and serum and tissues saved for
analysis. FIG. 1B depicts tumor volume analyzed using non-linear
curve fit and exponential growth calculation (Graphpad Prism),
followed by two-way ANOVA and Bonferroni analysis.
Example 3
[0130] Mechanism by which RAD1901 Downregulates ER Expression
[0131] While the reduced levels of ER following treatment with
RAD1901 results in receptor degradation, whether the drug
influences the transcriptional activity of the gene encoding ER was
determined (FIG. 2). MCF7 cells were pre-treated with Vehicle (Veh)
or translation (cyclohexamide--CHX, 10 .mu.g/mL), proteasome
(MG132, 30 .mu.M) or transcription (Actinomycin D--Actin. D, 100
ng/mL) inhibitors for 2 hours prior to 6 hours of treatment with
RAD 1901 (0.1 or 1 .mu.M), or 0.1 .mu.M ICI 182,780 (ICI) or
raloxifene (Ral). FIG. 2A shows ER.alpha. protein expression in
whole cell extracts was analyzed by immunoblot, as in Example 1.
FIG. 2B shows cells treated, as indicated, were washed in PBS prior
to lysis. RNA isolation (BioRad) and reverse transcription
(iScript; BioRad) were performed per kit manufacturer's
instructions. qRT-PCR of cDNA was done using iQ SYBR Green Supermix
(Bio-Rad) per kit instructions and performed using the iCycler
optical system with associated software (Bio-Rad). mRNA abundance
was calculated using the .DELTA..DELTA.CT method to normalize
ER.alpha. mRNA expression to similarly detected housekeeping gene
36B4.
Example 4
Conformational Changes Induced in ER as a Consequence of Binding of
RAD1901
[0132] A series of short peptides whose ability to interact with
ER.alpha. is influenced by the nature of the bound ligand were
previously identified (see Chang et al. Methods Enzymol. (2003)
364:118-42; Huang et al. Mol Endocrinol. (2002) 16(8):1778-92;
Connor et al. Cancer Res. (2001) 61(7):2917-22; Chang et al. Mol
Cell Biol. (1999) 19(12):8226-39; and Norris et al. Science (1999)
285(5428):744-6). The interaction of these "conformational probes"
can be measured in vitro or within intact cells and thus enables
the definition of ligand induced conformational changes in the
receptor. This is significant, since differences in receptor
conformation facilitate the engagement of different coregulatory
proteins resulting in different pharmacological activities.
Application of this technology has led to the determination that
their impact on receptor structure is a distinguishing feature of
ER ligands.
[0133] FIG. 3 shows that Rad 1901 induces a unique conformation of
ER.alpha. as shown in the interaction between ER and
conformation-specific peptides in a mammalian two-hybrid system.
Triplicate wells of SKBR3 cells were transfected (Lipofectin per
manufacturer's instructions) with plasmids expressing ER.alpha.
fused to VP16 together with Gal4DBD alone (control) or fused to ER
interacting peptides noted on the horizontal axis. Cells were then
treated with Rad 1901 (1 nM-1 .mu.M) or the indicated ER ligands
(100 nM). Interaction of ER.alpha. with the Gal4DBD peptide
constructs was detected through activation of a Gal4 responsive
luciferase reporter construct and was normalized to detected
.beta.-galactosidase activity generated by a co-transfected
constitutive expression vector. Ligand classes recognized by each
probe are indicated below the graph.
Example 5
[0134] RAD1901 Possesses Dose Dependent Agonist and/or Antagonist
Potential
[0135] The complex pharmacological activities exhibited by RAD 1901
suggest that it will exhibit a unique gene expression profile in
target cells. A recent extensive microarray analysis has identified
"sentinel" subsets of ER-responsive genes that can differentiate
between ER agonists, SERMs and SERDs. For example, some of these
are responsive to only the SERM tamoxifen, while others display a
graded response to SERMs with varying agonist/antagonist potential,
and yet others are repressed by agonists or SERMs and are induced
only by SERDs. RAD1901 exhibits dose dependent agonist/antagonist
regulation of ER transactivation of target genes (FIG. 4). MCF7
breast cancer cells were treated 24 hours with RAD 1901 (0-1 .mu.M)
in the presence or absence of 17.beta.-estradiol (1 nM). RNA
isolation and the analysis of the expression of target genes
Anterior gradient protein 2 (AGR2) and KCNK6 was conducted as in
Example 3.
[0136] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
[0137] Various changes and modifications to the disclosed
embodiments will be apparent to those skilled in the art. Such
changes and modifications, including without limitation those
relating to the chemical structures, substituents, derivatives,
intermediates, syntheses, compositions, formulations, or methods of
use of the invention, may be made without departing from the spirit
and scope thereof.
[0138] For reasons of completeness, various aspects of the
invention are set out in the following numbered clauses:
[0139] Clause 1. A method of treating estrogen receptor positive
cancers of the brain in a subject, the method comprising
administering a compound represented by the following formula
I.
##STR00018## [0140] wherein [0141] TZ represents a C.sub.1-C.sub.4
alkylene group or --CR.sup.f'R.sup.g'--CH.sub.2--O-- wherein
R.sup.f' and R.sup.g' independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; [0142] A represents a 5- to
14-membered heteroarylene group which may have a substituent or a
C.sub.6-C.sub.14 arylene group which may have a substituent; [0143]
Y represents --CH.sub.2--NR.sup.c-- wherein R.sup.c represents
hydrogen or a C.sub.1-C.sub.6 alkyl group which may have a
substituent; [0144] ring G represents the following formula:
[0144] ##STR00019## [0145] R' represents 1 to 4 substituents
independently selected from a hydrogen atom, a C.sub.1-C.sub.6
alkoxy group, and a hydroxyl group; [0146] a partial structure in
formula (I) represented by the following formula:
##STR00020##
[0146] is
##STR00021## [0147] R'' represents hydrogen, a hydroxyl group that
may be further protected by a protecting group or a C.sub.1-C.sub.6
alkoxy group which may have a substituent; and [0148] R.sup.a and
R.sup.b are the same as or different from each other and each
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may
have a substituent, or a C.sub.3-C.sub.8 cycloalkyl group which may
have a substituent, or when R.sup.a and R.sup.b are bonded
together, they may form, together with the nitrogen atom that is
adjacent to R.sup.a and R.sup.b, a 4- to 10-membered single ring
which may have a substituent; and L represents a single bond, or a
salt thereof.
[0149] Clause 2. The method of clause 1, wherein the cancer is
Breast cancer brain metastases, Astrocytoma, Atypical Teratoid
Rhabdoid Tumor (ATRT), Chondrosarcoma, Choroid Plexus Carcinoma,
Craniopharyngioma, Ependymoma, Germ Cell Tumor, Glioblastoma,
Glioma, Hemangioma, Juvenile Pilocytic Astrocytoma,
Medulloblastoma, Meningioma, Neurofibroma, Neuronal and Mixed
Neuronal-Glial Tumors, Oligoastrocytoma, Oligodendroglioma, Pineal
Tumor, Pituitary Tumor, PNET--(primitive neuroectodermal tumor),
Schwannoma, and Leptomeningeal metastases.
[0150] Clause 3. A method of treating breast cancer brain
metastasis in a subject, the method comprising administering a
compound represented by the following formula I:
##STR00022## [0151] wherein [0152] TZ represents a C.sub.1-C.sub.4
alkylene group or --CR.sup.f'R.sup.g'--CH.sub.2--O-- wherein
R.sup.f' and R.sup.g' independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; [0153] A represents a 5- to
14-membered heteroarylene group which may have a substituent or a
C.sub.6-C.sub.14 arylene group which may have a substituent; [0154]
Y represents --CH.sub.2--NR.sup.c-- wherein R.sup.c represents
hydrogen or a C.sub.1-C.sub.6 alkyl group which may have a
substituent; [0155] ring G represents the following formula:
[0155] ##STR00023## [0156] R' represents 1 to 4 substituents
independently selected from a hydrogen atom, a C.sub.1-C.sub.6
alkoxy group, and a hydroxyl group; [0157] a partial structure in
formula (I) represented by the following formula:
##STR00024##
[0157] is
##STR00025## [0158] R'' represents hydrogen, a hydroxyl group that
may be further protected by a protecting group or a C.sub.1-C.sub.6
alkoxy group which may have a substituent; and [0159] R.sup.a and
R.sup.b are the same as or different from each other and each
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may
have a substituent, or a C.sub.3-C.sub.8 cycloalkyl group which may
have a substituent, or when R.sup.a and R.sup.b are bonded
together, they may form, together with the nitrogen atom that is
adjacent to R.sup.a and R.sup.b, a 4- to 10-membered single ring
which may have a substituent; and [0160] L represents a single
bond, [0161] or a salt thereof.
[0162] Clause 4. A method of treating a cancer in a subject,
wherein the cancer is resistant to an estrogen receptor modulator,
the method comprising administering a compound represented by the
following formula I:
##STR00026## [0163] wherein [0164] TZ represents a C.sub.1-C.sub.4
alkylene group or --CR.sup.f'R.sup.g'--CH.sub.2--O-- wherein
R.sup.f' and R.sup.g' independently represent hydrogen or a
C.sub.1-C.sub.6 alkyl group; [0165] A represents a 5- to
14-membered heteroarylene group which may have a substituent or a
C.sub.6-C.sub.14 arylene group which may have a substituent; [0166]
Y represents --CH.sub.2--NR.sup.c-- wherein R.sup.c represents
hydrogen or a C.sub.1-C.sub.6 alkyl group which may have a
substituent; [0167] ring G represents the following formula:
[0167] ##STR00027## [0168] R' represents 1 to 4 substituents
independently selected from a hydrogen atom, a C.sub.1-C.sub.6
alkoxy group, and a hydroxyl group; [0169] a partial structure in
formula (I) represented by the following formula:
##STR00028##
[0169] is
##STR00029## [0170] R'' represents hydrogen, a hydroxyl group that
may be further protected by a protecting group or a C.sub.1-C.sub.6
alkoxy group which may have a substituent; and [0171] R.sup.a and
R.sup.b are the same as or different from each other and each
represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group which may
have a substituent, or a C.sub.3-C.sub.8 cycloalkyl group which may
have a substituent, or when R.sup.a and R.sup.b are bonded
together, they may form, together with the nitrogen atom that is
adjacent to R.sup.a and R.sup.b, a 4- to 10-membered single ring
which may have a substituent; and [0172] L represents a single
bond, [0173] or a salt thereof.
[0174] Clause 5. The method of clause 4, wherein the cancer is de
novo resistant to the estrogen receptor modulator.
[0175] Clause 6. The method of clause 4, wherein the resistance to
the estrogen receptor modulator is acquired.
[0176] Clause 7. The method of clause 4, wherein the estrogen
receptor modulator is a selective estrogen receptor modulator
(SERM).
[0177] Clause 8. The method of clause 7, wherein the SERM is
tamoxifen, idoxifene, raloxifene or ICI 182,780.
[0178] Clause 9. The method of any one of clauses 4-8, wherein the
cancer is breast, endometrial or ovarian cancer.
[0179] Clause 10. The method of any one of clauses 4-9, wherein the
cancer is breast cancer.
[0180] Clause 11. The method of any one of clauses 1-10, wherein
R.sup.a and R.sup.b independently represent a hydrogen atom, a
methyl group, an ethyl group, a n-propyl group, an iso-propyl
group, a n-butyl group, an iso-butyl group, or a tert-butyl
group.
[0181] Clause 12. The method of any one of clauses 1-10, wherein
-T-Z-- represents CH.sub.2CH.sub.2-- or
--C(CH.sub.3).sub.2CH.sub.2O--.
[0182] Clause 13. The method of any one of clauses 1-10, wherein Y
represents --CH.sub.2--N(CH.sub.2CH.sub.3)-- or
--CH.sub.2--N(CH.sub.2CH.sub.2OH)--.
[0183] Clause 14. The method of any one of clauses 1-10, wherein
each of R'' independently represents a hydrogen atom or a methoxy
group.
[0184] Clause 15. The method of any one of clauses 1-10, wherein
R'' represents a hydroxyl group.
[0185] Clause 16. The method of any one of clauses 1-10, wherein A
represents a phenylene group.
[0186] Clause 17. The method of any one of clauses 1-10, wherein
the compound is
(R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7-
,8-tetrahydronaphthalen-2-ol.
[0187] Clause 18. The method of any one of clauses 1-10, wherein an
effective amount of the compound is administered.
[0188] Clause 19. The method of any one of clauses 1-10, wherein
the effective amount comprises a high dosage.
[0189] Clause 20. The method of clause 19, wherein the high dosage
is more than about 20 mg/kg.
[0190] Clause 21. The method of clause 19 or 20, wherein the high
dosage is about 20 mg/kg to about 100 mg/kg.
[0191] Clause 22. The method of any one of clauses 1-10, wherein
the compound is administered by oral administration, intravenous
administration, intradermal injection, intramuscular injection or
subcutaneous injection.
[0192] Clause 23. The method of any one of clauses 1-10, further
comprising administering an effective amount of at least one
compound selected from the group consisting of a cyclin-dependent
kinase 4 and 6 inhibitor (CDK4/6 inhibitor), an antiestrogen, a
ligand of retinoic acid or retinoxic X receptor, an antiprogestin,
an antiandrogen, vitamin D or metabolite thereof, a farnesyl
transferase inhibitor, a PPAR.alpha. or gamma agonist and a MAP
kinase inhibitor.
* * * * *