The invention relates to the use of 3- (R) - [3- (2-
methoxyphenylthio) -2- (S) -methyl-propyll amino-3,4-
dihydro-2H-1,5-benzoxathiepine or any of the
pharmaceutically acceptable salts thereof in treating
5 cancer and particularly in preventing and/or treating
cancer metastases.
3- (R) - [3-( 2-methoxyphenylthio)- 2-( S)- methyl-propyl]
amino-3,4-dihydro-2H-13-benz~xathie~irneep resented by
the formula:
the pharmaceutically acceptable salts thereof and the
use thereof in treating angina, heart failure,
15 myocardial infarction and heart rhythm disorders are
described in the patent application WO 02/081464.
Cancer can be defined broadly as a disease
associated with the proliferation and uncontrolled
dissemination of the body's cells that have become
20 abnormal. It is one of the primary causes of mortality
in developed countries and the number of new cases is
constantly on the increase. However, due, among other
things, to progress in anticancer treatments, the
mortality rate due to cancer has decreased
25 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
5 cells while sparing the neighbouring healthy 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.
10 before metastasis has occurred, the prognosis is
relatively 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 radiotherapy;
15 patients may receive additional chemotherapy intended
to reduce the risks of recurrence and the onset of
secondary tumours, or metastases.
Many types of cancer are capable of forming
metastases which may be distant from the primary tumour
20 and may arise several years after treating a primary
tumour. This phenomenon can be explained by the
existence of pre-angiogenic micrometastases or cells
remaining without dividing for an extended period of
time at the secondary site(s). In cancerology, the term
25 metastases denotes secondary tumours forming due to the
spreading of cells from a primary tumour, whether
identified or not. The term micrometastases is used
when the size of these secondary tumours does not
exceed 2 mm.
30 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 formation of metastases is a
5 complex process, abbreviated herein as "metastatic
process1I, whereby cancer cells leave the primary tumour
and migrate to other parts of the body using the
lymphatic and/or blood system. The metastatic process
may be broken down into a plurality of steps: 1) the
10 cancer cells separate from the primary tumour and bind
with, simultaneously degrading, the proteins forming
the extracellular matrix separating the tumour from the
neighbouring tissue, 2) once there is a break in the
matrix, they infiltrate the surrounding tissue
15 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 extravasation, 4)
they bind to a tissue and proliferate after activating
the microenvironment and inducing angiogenesis to form
20 a metastasis.
The term angiogenesis 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
25 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
30 symptoms. In practice, systemic chemotherapy treatments
are however ineffective on metastases and have no
effect on the metastatic process per se.
A further strategy has been developed which does
not consist of destroying the metastases but rather
5 preventing the growth thereof beyond a few mm by
impeding tumour angiogenesis using substances
inhibiting the proliferation of cells from the vascular
endothelium.
The anti-angiogenic substances used in anticancer
10 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 thereof with VEGF receptors.
Sorafenib and sunitinib are non-selective inhibitors of
15 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
20 medicinal products nonetheless involve serious
drawbacks: 1) they reduce the density of tissue
microvessels and interfere with normal repair processes;
2) they worsen coronary disease, cause arterial
hypertension and thrombosis; 3) there are no predictive
25 factors of the response 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 suffering from cancer.
30 Furthermore, it would appear to be very desirable 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
5 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 Navl.5
voltage-gated sodium channel (Onkal and Djamgoz 2009,
Eur. J. Pharmacol. 625, 206-219). In the present
10 invention, the term "Navl.5" denotes the voltage-gated
sodium channels wherein the alpha subunit forming the
channel pore is coded by the SNC5A gene (also known as
HI) situated on chromosome 3. The alpha subunit may be
associated with one or a plurality of auxiliary
15 subunits (referred to as beta subunit(s)) coded by the
SNClB, SNC2B, SNC3B, SNC4B genes located on
chromosomes 11 and 19.
In this way, it has been demonstrated that the
expression of functional Navl.5 channels in ovarian
20 cancer cells significantly increases the metastatic
potential thereof (Gao et al. 2010, Oncology Reports 23,
1293-1299). Similarly, functional Navl.5 channels have
been detected in highly metastatic breast cancer
(Brisson et al. 2011, Oncogene 30, 2070-2076) or colon
25 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 metastasis. Navl.5 channels have also been
detected in a plurality of lung cancer biopsies and
30 tumour lines (Roger et al. 2007, Int. J. Biochem. Cell
Biol. 39, 774-786) , Navl.5 type channel 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
5 beneficial effect of long-chain .unsaturated fatty acids
in breast, colon and prostate cancers could be
associated with the inhibitory properties thereof of in
respect of the Navl.5 sodium current, although the
mechanism of action thereof is not known (Gillet et al.
10 2011, Biochimie 93, 4-6). In vitro experiments indicate
that Navl.5 channel blockers such as tetrodotoxin or
polyclonal antibodies targeted against the neonatal
form of the Navl.5 channel attenuate the metastatic
potential in a plurality of cancer cell lines (Chioni
15 et al. 2005, J. Neurosci. Methods 147, 88-98).
A range of data thus indicates that the sodium
current produced by the Navl.5 channel plays a major
role in the metastatic process of cancer cells, at
least in some types of cancer, particularly breast,
20 lung, prostate, colon, bladder, ovarian, testicular,
skin, thyroid or stomach cancer. The mechanisms whereby
Navl.5 channels potentiate metastasis formation have
not been elucidated but a number of hypotheses have
been suggested such as, for example, adhesion
25 modification, proteolytic enzyme regulation. In
conclusion, the Navl.5 channel thus emerges as a
potential target for preventing metastasis formation.
Given the ubiquitous role of the Navl.5 channel,
the use thereof as a therapeutic target for developing
30 an anticancer and/or anti-metastatic agent is
nonetheless complex. Indeed, the Navl.5 channel is
widely distributed in the body notably in cardiac and
vascular cells (Goldin 2001, Annu. Rev. Physiol. 63,
In cardiomyocytes, opening the Navl.5 channel
5 triggers an incoming sodium current that can be
deactivated according to at least two modes, each
characterised by the channel closure kinetics: rapid
inactivation and slow inactivation. Rapid inactivation
induces the so-called llrapidllNa vl.5 current only
10 lasting a few milliseconds, whereas slow inactivation
generates the so-called "slowI1 current lasting several
tens of milliseconds. The rapid Navl.5 current plays a
fundamental role in normal heart function where it
activates and propagates cardiac action potential. On
15 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) .
20 Surprisingly, the inventors demonstrated that 3-
(R) - 13- (2-methoxyphenylthio)- 2-( S)- methyl-propyl]a mino-
3,4-dihydro-2H-1,5-benzoxathiepinweh ich is a selective
slow Navl.5 current inhibitor, also inhibits the sodium
current produced by the Navl.5 sodium channels found'in
25 cancer cells, abbreviated herein as I1metastatic Navl. 5
current l1 .
Based on this observation, it has emerged that the
metastatic Navl.5 current and the slow Navl.5 current
have sufficiently similar biophysical characteristics
30 to both be recognised by 3- (R) - [3- (2-
dihydro-2H-1,5-benzoxathiepine.
It has also emerged that the metastatic Navl.5
current and the rapid cardiac Navl.5 current are
5 actually dissociable. Indeed, the inventors have .
demonstrated that 3 - (R) - [3- (2-methoxyphenylthio)- 2-( S)-
methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine
does not affect normal cardiovascular system function
under the control of the rapid Navl. 5 current, even at
10 high doses. 3- (R)- [3-( 2-methoxyphenylthio)- 2-( S)-
methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine
thus has the selectivity of action required for the use
thereof as an anti-metastatic agent since it blocks the
metastatic Navl.5 current without interfering with the
15 rapid Navl.5 current essential for normal cardiac and
vessel function.
The Navl.5 channel inhibitors/blockers include
numerous non-Navl.5 selective compounds such as natural
toxins, therapeutic molecules (e.g. anaesthetic,
20 antiarrhythmic agents) and insecticides (Anger et al.
2001, J. Med. Chem. 44, 115-137). Only two medicinal
products are described as preferential slow cardiac
Navl.5 current blockers: ranolazine (RN 95635-55-5) and
riluzole (RN 1744-22-5), but they are relatively
25. ineffective and non-selective with respect to said
current. Furthermore, they interact with other
molecular targets than the Navl .5 channel.
Interestingly, riluzole has been reported as having an
anti-metastatic activity in melanomas, however, this
30 activity involves other mechanisms than slow Navl.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 Navl.5 channel has been identified in
various types of metastatic cancer such as breast, lung,
prostate, or colon cancer, it is obvious that the use
of 3- (R) - [3-( 2-methoxyphenylthio)- 2-( S)- methylpropyl]
amino-3,4-dihydro-2H-1,5-benzoxathiepinei s not
limited to said forms of cancer but applies to all
forms of cancer wherein the cells express, inter alia,
the Navl.5 channel.
More specifically and by way of example, it is
demonstrated according to the invention that 3- (R) - [3-
(2-methoxyphenylthio)-2-(S)-methyl-propyl]amino-3,4-
dihydro-2H-1,5-benzoxathiepine or one of the
pharmaceutically acceptable salts thereof blocks the
metastatic Navl.5 current in a highly metastatic human
mammary cancer tumour line. Given the relationship
established between the current produced by the Navl.5
channels found in cancer cells and the tendency thereof
to form metastases, detecting inhibitory properties of
said current is thus equivalent to detecting antimetastatic
properties. Furthermore, the inventors
demonstrated that 3- (R)- [3-( 2-methoxyphenylthio)- 2-( S)-
methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine
was not cytotoxic.
The present invention relates to 3 - (R) - [ 3 - (2 -
methoxyphenylthio) -2 - (S) -methyl-propyl]a mino-3, 4-
dihydro-2H-1,5-benzoxathiepine or one of the
pharmaceutically acceptable salts thereof for use as a
5 medicinal product intended for treating cancer and more
particularly for preventing or treating metastases
thereof.
In the present invent ion, the term
llpharmaceutically acceptablel1 refers to molecular
10 entities and compositions not producing any adverse or
allergic effect or any other undesirable reaction when
administered to a human. When used herein, the term
upharmaceutically acceptable excipient" includes any
diluent, adjuvant or excipient, such as preservative
15 agents, filling agents, disintegrating, 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
20 in the art.
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
25 salts comprise: acid addition salts formed with mineral
acids such as hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid, phosphoric acid and
similar or formed with organic acids such as acetic
acid, benzenesulphonic acid, benzoic acid,
30 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, mandelic acid, methanesulphonic acid,
muconic acid, 2-naphthalenesulphonic acid, propionic
5 acid, salicylic acid, succinic acid, dibenzoyl-Ltartaric
acid, tartaric acid, p-toluenesulphonic acid,
trimethylacetic acid, trifluoroacetic acid and similar.
The pharmaceutically acceptable salts also include
the solvent addition forms (solvates) or crystalline
10 (polymorphous) forms as defined herein, of the same
acid addition salt.
The invention also relates to the use of 3- (R) - [3-
(2-methoxyphenylthio)-2-(S)-methyl-propyllamino-3,4-
dihydro-2H-1,5-benzoxathiepine or one of the
15 pharmaceutically acceptable salts thereof, in patients
presenting one or more cancerous tumours wherein the
cells express, inter alia, the Navl. 5 voltage-gated
sodium channel.
The present invention further relates to a
20 pharmaceutical composition containing, as an active
agent, 3- (R) - [3-( 2-methoxyphenylthio)- 2-( S)- methylpropyllamino-
3,4-dihydro-2H-1,5-benzoxathiepine or one
of the pharmaceutically acceptable salts thereof and at
least one pharmaceutically acceptable excipient, for
25 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, prostate, colon, bladder, ovarian,
30 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 Navl.5
channel. The presence of said channel in the patient's
5 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
10 (polymerase chain reaction), Western blot or in situ
hybridisation. The cells may be obtained from samples
taken from the primary tumour, metastases, lymph nodes
or blood and be analysed directly or cultured in vitro
before being analysed.
15 The pharmaceutical 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 surgical treatment,
or with a combination thereof. The administration may
20 then be simultaneous, 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 treatment.
The pharmaceutical compositions according to the
25 present invention are formulated 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 intra-nasal route. In this case, the
30 active ingredient may be administered in unitary dosage
forms, mixed with conventional pharmaceutical carriers,
i 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, topical,
5 intramuscular, intravenous, intra-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,
10 lactose, magnesium stearate, talc, gum arabic, silica
or equivalents. The tablets may be coated with sucrose
or other suitable materials or may be treated so as to
have a sustained or delayed activity and continuously
release a predefined quantity of active ingredient.
15 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,
20 an antiseptic, along with an agent providing flavour
and a suitable colorant.
Water-dispersible powders or granules may contain
the active ingredient mixed with dispersion agents or
wetting agents, or suspension agents, along with
25 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.
30 For parenteral (intravenous, intramuscular,
intradermal, subcutaneous), intra-nasal or intraocular
administration, aqueous suspensions, isotonic saline
solutions or sterile and injectable solutions
containing pharmacologically compatible dispersion
agents and/or wetting agents are used.
The active ingredient 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 intended for oral
or intravenous administration.
The pharmaceutical composition according 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)- 2 -
(S)-methyl-propyllamino-3,4-dihydro-2H-l,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 particular
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
weight, age, gender and sensitivity of the subject to
be treated. Consequently, the optimal dosage should be
determined by the relevant specialist according to the
parameters deemed relevant. 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
understanding of the invention without limiting the
5 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
10. express, inter alia, functional Navl.5 voltage-gated
sodium channels and that blocking said channel using
various pharmacological tools reduced the metastatic
potential thereof (Brackenbury et al. 2007, Breast
Cancer Res. Treat. 101, 149-160) . However, the
15 pharmacological tools in question are not suitable for
precise characterisation of the nature of the Navl.5
sodium current involved in the metastatic process.
However, the inventors demonstrated by means of patchclamp
experiments in a "whole cellrr configuration,
20 conducted on MDA-MB-231 cells, that 3- (R) - [3- (2-
methoxyphenylthio) -2-( S)- methyl-propyl]a mino-3,4-
dihydro-2H-1,5-benzoxathiepine reduced the metastatic
Navl.5 current in a concentration-dependent fashion
(I'CtjO = 1.5 M . For this reason, the inventors
25 consider that 3- (R)- [3-( 2-methoxyphenylthio)- 2-( S) -
methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine
has anti-metastatic properties in relation to cancer
cells expressing the Navl.5 channel. As such, it is
important to note that numerous types of metastatic
30 cancer have been reported as expressing the Navl.5
channel.
Method
Cell culture: the MDA-MB-231 cells are cultured in
5 a Dulbeccol s modified Eagle's medium, (Life
Technologies LTD, Paisley, UK) supplemented with 4 mM
L-glutamine and 10% foetal calf serum. The cells are
inoculated in 100 mm culture dishes and placed in an
incubator at 37OC, 100% moisture and 5% C02.
10 Electrophysiological measurements in "whole cell1'
configuration: the patch pipette (resistance 5-15 MQ)
contains a solution of : 5 mM NaC1, 145 mM CsC1, 2 mM
MgC12, 1 mM CaC12, 10 mM HEPES and 11 mM EGTA, the pH
is adjusted to 7.4 with CsOH. The reference electrode
15 is immersed in the extracellular medium consisting of a
solution of : 140 mM NaC1, 4 mM KC1, 2 mM MgC12, 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 currents are
20 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
Instrument). The holding potential is set to -110 mV to
25 record the maximum Nav channel activity.
Two protocols were used:
1/ I1Voltage-dependent current INall protocol for
observing the maximum amplitude of INa according
to the voltage applied. 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 frequency
of 0.5 Hz. The depolarisation interval lasts 25 ms
Results
The cells tested express a maximum amplitude
10 current in the order of 900 PA. The current activation
threshold is situated at -50 mV, the current peak
around -20 mV and the reversal potential at +30 mV
(Figure appended). The current is cancelled in the
absence of ~ a i+on s in the medium, confirming that the
15 current in question is a sodium current. The peak
current inhibition with tetrodotoxin (Sigma) is merely
partial: 30 + 7% at 1 pM and 54 + 8% at 5 pM,
indicating that the current in question is
tetrodotoxin-resistant.
20
Moreover, the inventors demonstrated in vivo that
3- (R)- [3-( 2-methoxyphenylthio)- 2-( S)- methylpropyl]
amin0-3,4-dihydro-2H-1,5-benzoxathiepine does
not interfere with normal cardiac function even at high
25 doses.
The present invention is thus characterised: 1) in
that 3- (R)- [3-( 2-methoxyphenylthio)- 2-( S)- methylpropyl]
amino-3,4-dihydro-2H-1,5-benzoxathiepineh as a
direct action on the metastatic process and, as such,
30 is complementary to existing treatments; 2) in that 3-
(R)- [3-( 2-methoxyphenylthio)- 2-( S)- methyl-propylla mino3,4-
dihydro-2H-1,5-benzoxathiepine has a selective
action on cancer cells without interfering, at antimetastatic
doses, with the other functions in which the
Navl.5 sodium channels are involved such as normal
5 cardiac and vascular function.

WE CLAIM:
1. 3- (R) - [3-( 2-methoxyphenylthio)- 2-( S)- methyl-propyll
amino-3,4-dihydro-2H-1,5-benzoxathiepinoer one of the
pharmaceutically acceptable salts thereof, for use as a
medicinal product for treating cancer.
2. 3- (R)- [3 - (2-methoxyphenylthio)- 2-( S)- methyl-propyll
amin0-3,4-dihydro-2H-1,5-benzoxathiepineo r one of the
pharmaceutically acceptable salts thereof, for use as
claimed in claim 1, for preventing or treating cancer
10 metastases.
3. 3- (R)- [3 - (2-methoxyphenylthio)- 2-( S)- methyl-propyl]
amino-3,4-dihydro-2H-1,5-benzoxathiepinoer one of the
pharmaceutically acceptable salts thereof, for use as
15 claimed in claim 1 or 2, in patients presenting one or
more cancerous turnours, the cells of which express,
inter alia, the Navl.5 voltage-gated sodium channel.
4. 3- (R)- [3 - (2-methoxyphenylthio)- 2-( S)- methyl-propyll
20 amino-3,4-dihydro-2H-1,5-benzoxathiepinoer one of the
pharmaceutically acceptable salts thereof, for use as
claimed in any one of claims 1 to 3, in patients
suffering from breast, lung, prostate, colon, bladder,
ovarian, testicular, skin, thyroid or stomach cancer.
25
5. Pharmaceutical composition characterised in that it
contains, as an active agent, 3- (R) - [3- (2-
methoxyphenylthio)-2-(S)-methyl-propyl]amino-3,4-
dihydro-2H-1,5-benzoxathiepine or one of the
pharmaceutically acceptable salts thereof and at least
one pharmaceutically acceptable excipient, for use as a
medicinal product for treating cancer.
5 6. Pharmaceutical composition as claimed in claim 5,
for use for preventing or treating cancer metastases.
7. Pharmaceutical composition as claimed in claim 5 or
6, for use in patients presenting one or more cancerous
10 turnours, the cells of which express, inter alia, the
Navl.5 voltage-gated sodium channel.
8. Pharmaceutical composition as claimed in any one of
claims 5 to 7, for use in patients suffering from
15 breast, lung, prostate, colon, bladder, ovarian,
testicular, skin, thyroid or stomach cancer.
9. Pharmaceutical composition as claimed in any one of
claims 5 to 8, for use in patients undergoing
20 chemotherapy treatment.
10. Pharmaceutical composition as claimed in any one of
claims 5 to 9, for use ' in patients undergoing
radiotherapy and/or surgical treatment.
25
11. Pharmaceutical composition, as claimed in claim 9
or 10, for the simultaneous, separate or staggered use
thereof in relation to the other chemotherapy,
radiotherapy and/or surgical treatment (s) .
3 0
12. pharmaceutical composition as claimed in any one of
claims 5 to 11, for the oral or intravenous
administcation thereof..
5 13. pharmaceutical composition, as claimed in any one
of claims 5 to 12, characterised in that it is in the
form of a daily dosage unit of 3-(R)-[3-(2-
methoxyphenylthio) -2 - (S) -methyl-propyll amino-3,4-
dihydro-2H-1,5-benzoxathiepine or one of the
10 pharmaceutically acceptable salts thereof between 1 and
1000 mg.