NZ622728B2 - Use of 3-(r)-[3-(2-methoxyphenylthio)-2-(s)-methylpropyl]amino-3,4-dihydro- 2h-1,5-benzoxathiepine for treating cancer and in particular for preventing and/or treating cancer metastases - Google Patents
Use of 3-(r)-[3-(2-methoxyphenylthio)-2-(s)-methylpropyl]amino-3,4-dihydro- 2h-1,5-benzoxathiepine for treating cancer and in particular for preventing and/or treating cancer metastases Download PDFInfo
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- NZ622728B2 NZ622728B2 NZ622728A NZ62272812A NZ622728B2 NZ 622728 B2 NZ622728 B2 NZ 622728B2 NZ 622728 A NZ622728 A NZ 622728A NZ 62272812 A NZ62272812 A NZ 62272812A NZ 622728 B2 NZ622728 B2 NZ 622728B2
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- benzoxathiepine
- methoxyphenylthio
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- propyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/39—Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
Provided is the use of 3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine for treating cancer, and in particular preventing and/or treating cancer metastases.
Description
USE OF 3-(R)-[3-(2-METHOXYPHENYLTHIO)(S)-
PROPYL]AMINO-3,4-DIHYDRO- 2H-1,5-BENZOXATHIEPINE
FOR TREATING CANCER AND IN PARTICULAR FOR PREVENTING
AND/OR TREATING CANCER METASTASES
The invention relates to the use of 3-(R)-[3-(2-
methoxyphenylthio)(S)-methyl-propyl]amino-3,4-
dihydro-2H-1,5-benzoxathiepine or any of the
pharmaceutically acceptable salts thereof in treating
cancer and particularly in preventing and/or treating
cancer metastases.
3-(R)-[3-(2-methoxyphenylthio)(S)-methyl-propyl]
amino-3,4-dihydro-2H-1,5-benzoxathiepine represented by
the formula:
the pharmaceutically acceptable salts thereof and the
use thereof in treating angina, heart failure,
myocardial infarction and heart rhythm disorders are
bed in the patent application WO 02/081464.
Cancer can be d broadly as a disease
associated with the proliferation and uncontrolled
dissemination of the body's cells that have become
abnormal. It is one of the y causes of mortality
in developed countries and the number of new cases is
constantly on the se. However, due, among other
things, to progress in anticancer treatments, the
mortality rate due to cancer has decreased
significantly. Anticancer treatments include, according
to the type and degree of progression of the disease,
surgery, radiotherapy and chemotherapy. In most cases,
a combination of two or three approaches is required.
Radiotherapy is a locoregional treatment method
for cancer, using ionising radiation to destroy cancer
cells while sparing the ouring y tissue as
much as possible. Chemotherapy consists of the use of
substances liable to kill or limit the proliferation of
cancer cells.
When cancer is detected at an early stage, i.e.
before metastasis has occurred, the prognosis is
vely good. In practice, however, this only
represents approximately 30% of cases. The tumour,
known as the primary tumour, is then generally treated
locally by means of surgery and/or herapy;
patients may receive additional chemotherapy intended
to reduce the risks of recurrence and the onset of
secondary s, or ases.
Many types of cancer are capable of forming
metastases which may be distant from the primary tumour
and may arise several years after treating a primary
tumour. This phenomenon can be explained by the
nce of pre-angiogenic micrometastases or cells
remaining without dividing for an extended period of
time at the secondary site(s). In cancerology, the term
metastases denotes secondary tumours forming due to the
spreading of cells from a y tumour, whether
identified or not. The term micrometastases is used
when the size of these secondary tumours does not
exceed 2 mm.
Although the metastatic cells originate from the
primary tumour, they are not exactly identical to the
cells thereof. Indeed, these cells need to acquire a
number of characteristics enabling the transition of
the cells from the cancerous to the metastatic
phenotype. However, the ion of metastases is a
complex process, abbreviated herein as "metastatic
process", whereby cancer cells leave the primary tumour
and e to other parts of the body using the
lymphatic and/or blood . The metastatic process
may be broken down into a ity of steps: 1) the
cancer cells separate from the primary tumour and bind
with, simultaneously degrading, the proteins forming
the extracellular matrix ting the tumour from the
neighbouring tissue, 2) once there is a break in the
matrix, they infiltrate the surrounding tissue
including lymph and/or blood vessels, 3) they then
survive in the circulation and are transported to the
secondary site(s) where they emerge by asation, 4)
they bind to a tissue and proliferate after activating
the microenvironment and inducing angiogenesis to form
a metastasis.
The term enesis denotes the set of processes
leading to the formation of new blood capillaries from
the pre-existing vascular system.
In most cases of cancer, the mortality is not due
to the primary tumour but to the metastases developing
and multiplying on one or a plurality of organs.
The treatment of metastatic forms of cancer is
essentially based on chemotherapy; radiotherapy and/or
surgery are generally used additionally to relieve some
symptoms. In practice, systemic chemotherapy treatments
are however ineffective on metastases and have no
effect on the metastatic s per se.
A further strategy has been developed which does
not consist of destroying the metastases but rather
preventing the growth thereof beyond a few mm by
impeding tumour angiogenesis using substances
inhibiting the proliferation of cells from the vascular
endothelium.
The ngiogenic substances used in anticancer
treatments include bevacizumab, sorafenib and sunitinib.
Bevacizumab is a monoclonal antibody that binds with
all the isoforms of vascular growth factor (VEGF) and
prevents the binding f with VEGF receptors.
Sorafenib and nib are lective inhibitors of
tyrosine kinase receptors, particularly those of VEGF.
Anti-angiogenic substances have an indirect antimetastatic
activity since they enhance the delivery of
the chemotherapeutic agents although they do not
interfere with the metastatic process per se. Said
medicinal products nonetheless e serious
drawbacks: 1) they reduce the density of tissue
microvessels and interfere with normal repair processes;
2) they worsen coronary disease, cause al
ension and thrombosis; 3) there are no predictive
factors of the se or the onset of resistance, and
4) the cost thereof is very high.
Given the limitations of current treatments, there
is a genuine medical need for substances capable of
preventing metastases in patients ing from cancer.
rmore, it would appear to be very ble for
the substances in question to have direct antimetastatic
properties, thus complementary to those of
existing medicinal products.
The ion channels have been described as being
involved in the invasion and migration mechanisms
necessary for the formation of metastases (Arcangeli et
al. 2009, Curr. Med. Chem. 16, 66-93). The channels
abnormally expressed in cancer cells include the Nav1.5
voltage-gated sodium l (Onkal and Djamgoz 2009,
Eur. J. Pharmacol. 625, 206-219). In the present
invention, the term "Nav1.5" denotes the voltage-gated
sodium channels wherein the alpha subunit forming the
l pore is coded by the SNC5A gene (also known as
H1) ed on chromosome 3. The alpha subunit may be
associated with one or a plurality of auxiliary
ts (referred to as beta subunit(s)) coded by the
SNC1B, SNC2B, SNC3B, SNC4B genes located on
chromosomes 11 and 19.
In this way, it has been demonstrated that the
expression of functional Nav1.5 channels in ovarian
cancer cells significantly increases the metastatic
potential thereof (Gao et al. 2010, Oncology Reports 23,
1293-1299). Similarly, functional Nav1.5 channels have
been detected in highly metastatic breast cancer
(Brisson et al. 2011, Oncogene 30, 076) or colon
cancer biopsies (House et al. 2010, Cancer Res. 70,
6957-6967) whereas they are not found in healthy cells
from the corresponding tissue or those of tumours with
little or no asis. Nav1.5 ls have also been
detected in a plurality of lung cancer biopsies and
tumour lines (Roger et al. 2007, Int. J. Biochem. Cell
Biol. 39, 774-786). Nav1.5 type l expression or
overexpression has further been proposed as a
diagnostic tool in respect of the metastatic potential
of cancer cells (Fraser et al. 2005, Clin. Cancer Res.
11, 5381-5389). It has also been suggested that the
beneficial effect of long-chain rated fatty acids
in breast, colon and te cancers could be
associated with the inhibitory properties thereof of in
respect of the Nav1.5 sodium current, although the
mechanism of action thereof is not known (Gillet et al.
2011, Biochimie 93, 4-6). In vitro experiments indicate
that Nav1.5 channel blockers such as tetrodotoxin or
polyclonal antibodies targeted against the neonatal
form of the Nav1.5 channel attenuate the metastatic
potential in a plurality of cancer cell lines (Chioni
et al. 2005, J. Neurosci. Methods 147, .
A range of data thus indicates that the sodium
current produced by the Nav1.5 channel plays a major
role in the metastatic process of cancer cells, at
least in some types of cancer, particularly breast,
lung, prostate, colon, r, ovarian, testicular,
skin, d or stomach cancer. The mechanisms whereby
Nav1.5 channels potentiate metastasis formation have
not been elucidated but a number of hypotheses have
been suggested such as, for example, adhesion
modification, proteolytic enzyme regulation. In
conclusion, the Nav1.5 channel thus emerges as a
potential target for preventing metastasis formation.
Given the ubiquitous role of the Nav1.5 channel,
the use thereof as a therapeutic target for developing
an anticancer and/or anti-metastatic agent is
nonetheless complex. Indeed, the Nav1.5 channel is
widely distributed in the body y in c and
vascular cells n 2001, Annu. Rev. Physiol. 63,
871-894).
In myocytes, opening the Nav1.5 channel
triggers an ng sodium current that can be
deactivated according to at least two modes, each
characterised by the channel closure kinetics: rapid
inactivation and slow vation. Rapid inactivation
induces the so-called "rapid" Nav1.5 current only
lasting a few econds, whereas slow inactivation
generates the so-called "slow" current lasting several
tens of milliseconds. The rapid Nav1.5 current plays a
fundamental role in normal heart function where it
activates and propagates cardiac action potential. On
the other hand, that of the slow current does not seem
to be important in normal cardiac function and is only
produced or significantly amplified in cardiac and
vascular cells subjected to stress (Bocquet et al. 2010,
Br. J. Pharmacol. 161, 405-415).
Surprisingly, the inventors demonstrated that 3-
-(2-methoxyphenylthio)(S)-methyl-propyl]amino-
3,4-dihydro-2H-1,5-benzoxathiepine which is a selective
slow Nav1.5 current inhibitor, also inhibits the sodium
current produced by the Nav1.5 sodium channels found in
cancer cells, abbreviated herein as "metastatic Nav1.5
current".
Based on this ation, it has emerged that the
metastatic Nav1.5 current and the slow Nav1.5 current
have sufficiently similar biophysical characteristics
to both be recognised by 3-(R)-[3-(2-
methoxyphenylthio)(S)-methyl-propyl]amino-3,4-
dihydro-2H-1,5-benzoxathiepine.
It has also emerged that the metastatic Nav1.5
current and the rapid cardiac Nav1.5 current are
actually dissociable. Indeed, the inventors have
demonstrated that [3-(2-methoxyphenylthio)(S)-
-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine
does not affect normal cardiovascular system function
under the control of the rapid Nav1.5 current, even at
high doses. 3-(R)-[3-(2-methoxyphenylthio)(S)-
methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine
thus has the selectivity of action required for the use
thereof as an etastatic agent since it blocks the
metastatic Nav1.5 current without interfering with the
rapid Nav1.5 current essential for normal cardiac and
vessel on.
The Nav1.5 channel inhibitors/blockers e
numerous non-Nav1.5 selective compounds such as l
toxins, therapeutic molecules (e.g. anaesthetic,
antiarrhythmic agents) and insecticides (Anger et al.
2001, J. Med. Chem. 44, 115-137). Only two medicinal
products are described as preferential slow cardiac
Nav1.5 current blockers: ranolazine (RN 956355) and
riluzole (RN 17445), but they are relatively
ineffective and non-selective with respect to said
t. Furthermore, they interact with other
molecular targets than the Nav1.5 channel.
stingly, riluzole has been reported as having an
anti-metastatic activity in mas, however, this
activity involves other mechanisms than slow Nav1.5
sodium current inhibition (US 20100221246; Biechele et
al. 2010, Chemistry & Biology 17, 1177- 1182; Wu et al.
2009, NeuroToxicology 30, 677-685).
The present invention thus provides a novel means
for fighting cancer and more particularly for
preventing or treating metastases thereof, via direct
action on the metastatic process, which no existing
agent is capable of performing.
Although the Nav1.5 channel has been identified in
various types of metastatic cancer such as breast, lung,
te, or colon , it is obvious that the use
of 3-(R)-[3-(2-methoxyphenylthio)(S)-methylpropyl
]amino-3,4-dihydro-2H-1,5-benzoxathiepine is not
limited to said forms of cancer but applies to all
forms of cancer wherein the cells s, inter alia,
the Nav1.5 channel.
More specifically and by way of example, it is
demonstrated according to the invention that 3-(R)-[3-
(2-methoxyphenylthio)(S)-methyl-propyl]amino-3,4-
dihydro-2H-1,5-benzoxathiepine or one of the
pharmaceutically acceptable salts thereof blocks the
atic Nav1.5 current in a highly metastatic human
mammary cancer tumour line. Given the relationship
established between the current produced by the Nav1.5
channels found in cancer cells and the tendency thereof
to form metastases, ing inhibitory properties of
1001079487
said current is thus equivalent to detecting anti—
metastatic properties. Furthermore, the inventors
demonstrated that [3—(2—methoxyphenylthio)—2—(S)—
methyl—propyl]amino—3,4—dihydro—2H—l,5—benzoxathiepine
was not cytotoxic.
The present ion relates to 3—(R)—[3~(2—
methoxyphenylthio)—2—(S)—methyl—propyl]amino—3,4—
o—EH—l,5—benzoxathiepine or one of the
pharmaceutically acceptable salts thereof for use as a
medicinal product intended for treating cancer and more
particularly for preventing or ng metastases
thereof.
In one , the present invention provides use
of 3—(R)—[3—(2—methoxyphenylthio)—2—(S)—methyl—propyl]
amino—3,4—dihydro—2H—l,5—benzoxathiepine or one of the
pharmaceutically acceptable salts thereof, in the
preparation of a medicinal product for ng cancer.
In the present invention, the term
”pharmaceutically' acceptable" refers to molecular
2O entities and compositions not producing any adverse or
allergic effect or any other undesirable reaction when
administered. to a Ihumand When. used. herein, the term
"pharmaceutically acceptable excipient” includes any
diluent, adjuvant or excipient, such as gmeservative
agents, filling , egrating, wetting,
emulsifying, dispersing, antibacterial or antifungal
agents, or else agents suitable for delaying intestinal
and digestive absorption. and resorption. The use of
these media or vectors is well—known to those skilled
in the art.
1001079487
The term "pharmaceutically acceptable salts" of a
compound denotes salts which are pharmaceutically
acceptable, as defined herein. and. having the sought
pharmacological activity of the parent compound. Such
salts comprise: acid addition salts formed with mineral
acids such as hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid, oric acid and
similar (n: formed vfiiil c acids such as acetic
acid, benzenesulphonic acid, benzoic acid,
camphorsulphonic, citric acid, ethane—sulphonic acid,
fumaric acid, glucoheptonic acid, gluconic acid,
glutamic acid, glycolic acid, hydroxynaphthoic acid, 2—
hydroxyethanesulphonic acid, lactic acid, maleic acid,
malic acid, ic acid, esulphonic acid,
muconic acid, 2—naphthalenesulphonic acid, propionic
acid, salicylic acid, succinic acid, dibenzoyl—L—
tartaric acid, tartaric acid, p—toluenesulphonic acid,
trimethylacetic acid, trifluoroacetic acid and similar.
The pharmaceutically acceptable salts also e
the solvent. addition. forms (solvates) or crystalline
(polymorphous) forms as definedi herein, of the same
acid addition salt.
The invention also relates to the use of 3—(R)—[3—
(2—methoxyphenylthio)—2—(S)—methyl—propyl]amino—3,4—
dihydro—ZH—l,5—benzoxathiepine or one of the
pharmaceutically able salts thereof, in patients
ting one or more cancerous tumours wherein the
cells express, inter alia, the Navl.5 voltage—gated
sodium channel.
1001079487
In one aspect, the t invention provides use
of a pharmaceutical composition sing, as an
active agent, 3—(R)-[3—(2—methoxyphenylthio)—2—(S)—
methyl—propyl]amino-3,4—dihydro—2H—l,5—benzoxathiepine
or one of the pharmaceutically acceptable salts thereof
and at least one pharmaceutically acceptable excipient,
in the preparation of a medicinal product for treating
cancer.
The t invention further relates to a
pharmaceutical composition containing, as an active
agent, 3—(R)—[3—(2—methoxyphenylthio)~2—(S)—methyl—
propyl]amino—3,4—dihydro—2H—l,5—benzoxathiepine cut one
of the pharmaceutically acceptable salts f and at
least one pharmaceutically‘ acceptable excipient, for
the use thereof in treating cancer and more
particularly for preventing or treating cancer
metastases. Preferentially, the cancers concerned by
the composition according to the present invention are:
breast, lung, te, colon, bladder, ovarian,
testicular, skin, thyroid or stomach cancer.
Preferably, the pharmaceutical composition
according to the invention is intended for patients in
whom tumour cells express, inter alia, the Nav1.5
channel. The presence of said channel in the patient's
tumour cells may be detected by the presence of the
messenger RNA of the SCN5A gene and/or of the channel
protein per se. The messenger RNA and/or the protein
may be detected by means of techniques well-known to
those skilled in the art such as, for example, PCR
(polymerase chain reaction), Western blot or in situ
hybridisation. The cells may be obtained from samples
taken from the primary , ases, lymph nodes
or blood and be analysed directly or cultured in vitro
before being analysed.
The ceutical composition according to the
invention may be administered with one or more further
active agents, such as an anticancer agent, or in
association with a radiotherapy or al treatment,
or with a combination thereof. The administration may
then be aneous, separate or staggered in relation
to the other treatment(s). It may also be used for the
entire duration or for a shorter or longer period than
that of the other anticancer ent.
The ceutical compositions according to the
present invention are ated for administration to
humans. The compositions according to the invention may
be administered by the oral, sublingual, subcutaneous,
intramuscular, intravenous, transdermal, local or
rectal or also nasal route. In this case, the
active ingredient may be administered in unitary dosage
forms, mixed with conventional pharmaceutical rs,
to humans. Suitable unitary dosage forms include oral
forms such as tablets, capsules, powders, granules and
oral solutions or suspensions, sublingual and buccal
dosage forms, subcutaneous or transdermal, l,
intramuscular, enous, nasal or intraocular
dosage forms, rectal dosage forms.
When a solid composition in tablet form is
prepared, the main active ingredient is mixed with a
pharmaceutical vehicle such as gelatine, starch,
lactose, magnesium stearate, talc, gum arabic, silica
or equivalents. The tablets may be coated with sucrose
or other suitable als or may be treated so as to
have a sustained or delayed activity and continuously
release a predefined quantity of active ingredient.
A capsule preparation is obtained by mixing the
active ingredient with a diluent and pouring the
mixture obtained into soft or hard capsules.
A preparation in syrup or elixir form may contain
the active ingredient in conjunction with a sweetener,
an ptic, along with an agent ing flavour
and a suitable colorant.
Water-dispersible powders or granules may contain
the active ingredient mixed with dispersion agents or
wetting , or suspension agents, along with
flavouring substances or sweeteners.
For rectal administration, suppositories are used,
which are prepared with binders melting at rectal
temperature, for example cocoa butter or polyethylene
glycols.
For eral venous, intramuscular,
intradermal, subcutaneous), intra-nasal or intraocular
administration, aqueous suspensions, ic saline
solutions or sterile and injectable solutions
containing pharmacologically compatible dispersion
agents and/or wetting agents are used.
The active ient may also be formulated in
microcapsule form, optionally with one or a plurality
of additive carriers.
Advantageously, the pharmaceutical composition
according to the present invention is ed for oral
or intravenous administration.
The pharmaceutical composition ing to the
present invention may comprise further active
ingredients resulting in an additional or optionally
synergistic effect.
The dosages of 3-(R)-[3-(2-methoxyphenylthio)
thyl-propyl]amino-3,4-dihydro-2H-1,5-
benzoxathiepine or one of the pharmaceutically
acceptable salts thereof in the compositions according
to the invention may be adjusted to obtain a quantity
of substance which is effective for obtaining the
therapeutic response sought for a ular
composition with the administration method. The
effective dose of the compound according to the
invention varies according to numerous parameters such
as, for example, the selected administration route, the
, age, gender and sensitivity of the subject to
be treated. Consequently, the optimal dosage should be
determined by the relevant specialist according to the
ters deemed nt. Although the effective
doses can vary in large proportions, the daily doses
could range between 1 mg and 1000 mg per 24 hours, and
preferentially between 1 and 200 mg, for an adult with
an average weight of 70 kg, in one or more doses.
The following example enables a clearer
tanding of the invention without limiting the
scope thereof.
Merely as an illustration, the inventors chose to
use the MDA-MB-231 line, which is a highly metastatic
human mammary adenocarcinoma line, in the experiment.
Indeed, it has been demonstrated that said cells
express, inter alia, functional Nav1.5 voltage-gated
sodium channels and that blocking said channel using
various pharmacological tools reduced the metastatic
ial thereof (Brackenbury et al. 2007, Breast
Cancer Res. Treat. 101, 149-160). However, the
pharmacological tools in question are not suitable for
precise characterisation of the nature of the Nav1.5
sodium current involved in the atic process.
However, the inventors demonstrated by means of patchclamp
experiments in a "whole cell" configuration,
conducted on -231 cells, that 3-(R)-[3-(2-
methoxyphenylthio)(S)-methyl-propyl]amino-3,4-
dihydro-2H-1,5-benzoxathiepine reduced the metastatic
Nav1.5 current in a concentration-dependent fashion
(IC50 = 1.5 µM). For this reason, the inventors
consider that 3-(R)-[3-(2-methoxyphenylthio)(S)-
methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine
has anti-metastatic ties in relation to cancer
cells expressing the Nav1.5 channel. As such, it is
important to note that numerous types of metastatic
cancer have been reported as expressing the Nav1.5
channel.
Method
Cell culture: the MDA-MB-231 cells are cultured in
a Dulbecco's modified Eagle's medium, (Life
Technologies LTD, Paisley, UK) mented with 4 mM
L-glutamine and 10% foetal calf serum. The cells are
ated in 100 mm culture dishes and placed in an
incubator at 37°C, 100% moisture and 5% CO2.
Electrophysiological ements in "whole cell"
configuration: the patch pipette (resistance 5-15 MΩ)
contains a solution of: 5 mM NaCl, 145 mM CsCl, 2 mM
MgCl2, 1 mM CaCl2, 10 mM HEPES and 11 mM EGTA, the pH
is adjusted to 7.4 with CsOH. The reference electrode
is immersed in the extracellular medium consisting of a
solution of: 140 mM NaCl, 4 mM KCl, 2 mM MgCl2, 11 mM
glucose, 10 mM HEPES, the pH is adjusted to 7.4 with
NaOH. These two electrodes are connected to an Axopatch
200B amplifier (Axon Instrument). The ts are
filtered using a Bessel filter at a frequency of 5 kHz
and are sampled at a frequency of 5 kHz using the
Digidata interface (1200). The data acquisition and
analysis are performed using pClamp software (Axon
ment). The holding ial is set to -110 mV to
record the maximum Nav channel activity.
Two protocols were used:
1/ "Voltage-dependent current INa" ol for
observing the maximum amplitude of INa according
to the voltage d. Depolarisations in 5 mV
stages are performed at a frequency of 0.2 Hz,
from -110 to +60 mV. The depolarisation interval
lasts 600 ms (see Figure appended).
2/ "Repeated depolarisation" protocol for
measuring the effect of the test product on the
current amplitude. For this, depolarisations
at -20 mV are performed in sequence at a ncy
of 0.5 Hz. The depolarisation interval lasts 25 ms.
Results
The cells tested express a maximum amplitude
current in the order of 900 pA. The current activation
threshold is situated at -50 mV, the current peak
around -20 mV and the al potential at +30 mV
(Figure appended). The current is cancelled in the
absence of Na+ ions in the medium, confirming that the
current in question is a sodium current. The peak
current inhibition with tetrodotoxin (Sigma) is merely
partial: 30 ± 7% at 1 µM and 54 ± 8% at 5 µM,
indicating that the current in on is
otoxin-resistant.
Moreover, the inventors demonstrated in vivo that
[3-(2-methoxyphenylthio)(S)-methylpropyl
]amino-3,4-dihydro-2H-1,5-benzoxathiepine does
not interfere with normal cardiac function even at high
doses.
The present invention is thus characterised: 1) in
that 3-(R)-[3-(2-methoxyphenylthio)(S)-methyl-
1001079487
propyl]amino—3,4—dihydro—2H—l,5—benzoxathiepine has a
direct action on the metastatic process and, as such,
is complementary to existing treatments; 2) in that 3—
(R)—[3—(2—methoxyphenylthio)~2—(S)—methyl—propyl]amino—
3,4—dihydro—2H—l,5—benzoxathiepine has a selective
action on cancer cells without interfering, at anti—
metastatic doses, with the other functions in which the
Navl.5 sodium channels are involved such as normal
cardiac and vascular function.
Reference to any prior art in the specification is
not, and should not be taken as, an ledgment, or
any form of suggestion, that this prior art forms part
of the common general knowledge in New Zealand or any
other jurisdiction or that this prior art could
reasonably be expected to be ascertained, understood
and regarded as nt by a person skilled in the art.
As used herein, except where the t requires
otherwise, the term "comprise" and variations of the
term, such as "comprising", "comprises" and "comprised",
are not intended to e other additives, components,
integers or steps.
1001079487
THE
Claims (14)
1. Use of 3—(R)—[3—(2—methoxyphenylthio)—2—(S)—methyl— propyl] amino—3,4—dihydro—2H—l,5—benzoxathiepine or one of the pharmaceutically' acceptable salts thereof, in the preparation. of a medicinal t for treating cancer.
2. USe of 3—(R)—[3—(2—methoxyphenylthio)~2-(S)—methyl— propyl] amino—3,4—dihydro—2H—l,5—benzoxathiepine or one of the pharmaceutically able salts thereof, 10 according to claim 1, in the preparation of a medicinal product for preventing or treating cancer metastases.
3. Use of 3—(R)—[3—(2—methoxyphenylthio)—2—(S)—methyl— propyl] amino—3,4—dihydro—2H—l,5—benzoxathiepine or one 15 of the pharmaceutically able salts thereof, according t1) claim 1. or 2, in tflua preparation Ci a medicinal product for ts presenting one or more cancerous tumours, the cells of which express, inter alia, the Navl.5 voltage—gated sodium channel.
4. USe of 3—(R)—[3-(2—methoxyphenylthio)—2—(S)—methyl— propyl] amino—3,4—dihydro—2H—l,5—benzoxathiepine or one of the pharmaceutically acceptable salts thereof, according to any one of claims 1 to 3, in the 25 preparation of a nal product for patients suffering from breast, lung, prostate, colon, bladder, ovarian, testicular, skin, thyroid or stomach cancer. 1001079487
5. Use of a pharmaceutical composition comprising, as an active agent, 3—(R)—[3—(2—methoxyphenylthio)—2—(S)— methyl—propyl]amino—3,4—dihydro—2H—l,5—benzoxathiepine or one of the pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, in the preparation of a medicinal product for ng cancer.
6. Use of the pharmaceutical composition comprising, as 10 an active agent, 3—(R)—[3—(2—methoxyphenylthio)—2—(S)— methyl~propyl]amino—3,4—dihydro—2H—l,5—benzoxathiepine or one of the pharmaceutically acceptable salts f and at least one pharmaceutically acceptable excipient, according to claim 5, in the preparation of a medicinal 15 product for preventing or ng cancer metastases.
7. Use of the pharmaceutical composition comprising, as an active agent, 3—(R)—[3—(2—methoxyphenylthio)—2—(S)— methyl—propyl]amino—3,4—dihydro-2H—l,5—benzoxathiepine 20 or one of the pharmaceutically acceptable salts thereof and at least one pharmaceutically able excipient, ing' to clainl 5 or 6, in. the preparation. of a medicinal product for patients presenting one or more cancerous tumours, the cells of which express, inter 25 alia, the Navl.5 voltage—gated sodium channel.
8. Use of the pharmaceutical composition comprising, as an active agent, 3—(R)—[3—(2—methoxyphenylthio)—2—(S)— —propyl]amino-3,4—dihydro—2H—l,5—benzoxathiepine 3O or one of the pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, 1001079487 according to any one of claims 5 to 7, in the preparation of a medicinal product for patients suffering from breast, lung, prostate, colon, bladder, ovarian, testicular, skin, thyroid or stomach cancer.
9. Use of the ceutical composition comprising, as an active agent, 3—(R)—[3—(2-methoxyphenylthio)~2—(S)‘ methyl—propyl]amino—3,4—dihydro—2H—l,5—benzoxathiepine or one of the pharmaceutically acceptable salts thereof
10 and at least one pharmaceutically acceptable excipient, according to any one of claims 5 to 8, in the preparation of a medicinal product for ts undergoing chemotherapy treatment. 15 10. Use cfif the pharmaceutical composition comprising, as an, active agent, [3~(2—methoxyphenylthio)—2— (S)—methyl—propyl]amino—3,4—dihydro—2H—l,5— benzoxathiepine or one of the pharmaceutically acceptable salts thereof and at least one 2O pharmaceutically acceptable excipient, according to any one of claims 5 to 8, in the preparation of a medicinal product for patients undergoing herapy and/or surgical treatment. 25
11. Use according to claim 9 or claim 10, wherein the medicinal product is suitable for aneous, separate or staggered use in relation. to the other chemotherapy, radiotherapy and/or al treatment(s). 1001079487
12. Use according to any one of claims 5 to 11, wherein the medicinal product is suitable for oral or intravenous administration.
13. Use according to any one of claims 5 to 12, wherein the medicinal product is in the form of a daily dosage unit of 3—(R)—[3—(2—methoxyphenylthio)—2—(S)—methyl— propyl] 3,4~dihydro—2H—1,5—benzoxathiepine or one of the pharmaceutically acceptable salts thereof 10 between 1 and 1000 mg.
14. Use of 3—(R)—[3—(2—methoxyphenylthio)—2—(S)—methyl— propyl] amino—3,4—dihydro—2H—1,5—benzoxathiepine according to claim 1, ntially as hereinbefore 15 described.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1158148A FR2979823B1 (en) | 2011-09-13 | 2011-09-13 | USE OF 3- (R) - [3- (2-METHOXYPHENYLTHIO) -2- (S) -METHYL-PROPYL] AMINO-3,4-DIHYDRO-2H-1,5-BENZOXATHIEPINE FOR THE TREATMENT OF CANCER AND IN PARTICULAR FOR THE PREVENTION AND / OR TREATMENT OF CANCER METASTASES |
FR1158148 | 2011-09-13 | ||
PCT/EP2012/067780 WO2013037800A1 (en) | 2011-09-13 | 2012-09-12 | Use of 3-(r)-[3-(2-methoxyphenylthio)-2-(s)-methylpropyl]amino-3,4-dihydro- 2h-1,5-benzoxathiepine for treating cancer and in particular for preventing and/or treating cancer metastases |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ622728A NZ622728A (en) | 2015-08-28 |
NZ622728B2 true NZ622728B2 (en) | 2015-12-01 |
Family
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