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

Abstract

The present invention relates to the use of 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 for treating cancer and particularly in preventing and/or treating cancerous metastases.

Claims

1. A method for treating cancer comprising the administration to a patient in need thereof of an effective amount of 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; wherein the patient suffers from breast, lung, prostate, colon, bladder, ovarian, testicular, skin, thyroid or stomach cancer.

2. The method according to claim 1, for preventing or treating cancer metastases.

3. The method according to claim 1, wherein the patient presents one or more cancerous tumours, the cells of which express, inter alia, the Nav1.5 voltage-gated sodium channel.

4. A method for treating cancer comprising the administration to a patient in need thereof of an effective amount of a pharmaceutical composition containing, 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; wherein the patient suffers from breast, lung, prostate, colon, bladder, ovarian, testicular, skin, thyroid or stomach cancer.

5. The method according to claim 4, for preventing or treating cancer metastases.

6. The method according to claim 4, wherein the patient presents one or more cancerous tumours, the cells of which express, inter alia, the Nav1.5 voltage-gated sodium channel.

7. The method according to claim 4, wherein the patient undergoes chemotherapy treatment.

8. The method according to claim 7, for the simultaneous, separate or staggered use of the pharmaceutical composition in relation to the chemotherapy treatment.

9. The method according to claim 4, wherein the patient undergoes radiotherapy and/or surgical treatment(s).

10. The method according to claim 9, for the simultaneous, separate or staggered use thereof in relation to the other radiotherapy and/or surgical treatment(s).

11. The method according to claim 4, wherein the patient undergoes chemotherapy treatment and radiotherapy and/or surgical treatment(s).

12. The method according to claim 11, for the simultaneous, separate or staggered use thereof in relation to the other chemotherapy treatment and radiotherapy and/or surgical treatment(s).

13. The method according to claim 4, wherein the pharmaceutical composition is administered orally or intravenously.

14. The method according to claim 4, wherein the pharmaceutical composition is in the form of a daily dosage unit of 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 between 1 and 1000 mg.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the measurement of the Voltage-dependent current I.sub.Na.

(2) Although the Nav1.5 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)-methyl-propyl]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 express, inter alia, the Nav1.5 channel.

(3) 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 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, detecting inhibitory properties of said current is thus equivalent to detecting anti-metastatic 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.

(4) The present invention relates to 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 for use as a medicinal product intended for treating cancer and more particularly for preventing or treating metastases thereof.

(5) In the present invention, the term pharmaceutically acceptable refers to molecular 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 pharmaceutically acceptable excipient includes any diluent, adjuvant or excipient, such as preservative 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 in the art.

(6) 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, phosphoric acid and similar or formed with organic 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, mandelic acid, methanesulphonic 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.

(7) The pharmaceutically acceptable salts also include the solvent addition forms (solvates) or crystalline (polymorphous) forms as defined herein, of the same acid addition salt.

(8) The invention also relates to the use of 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, in patients presenting one or more cancerous tumours wherein the cells express, inter alia, the Nav1.5 voltage-gated sodium channel.

(9) The present 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-1,5-benzoxathiepine or one of the pharmaceutically acceptable salts thereof 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, prostate, colon, bladder, ovarian, testicular, skin, thyroid or stomach cancer.

(10) 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 tumour, metastases, lymph nodes or blood and be analysed directly or cultured in vitro before being analysed.

(11) 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 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.

(12) The pharmaceutical compositions according to the 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 active ingredient may be administered in unitary dosage forms, mixed with conventional pharmaceutical carriers, 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, intramuscular, intravenous, intra-nasal or intraocular dosage forms, rectal dosage forms.

(13) 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 materials or may be treated so as to have a sustained or delayed activity and continuously release a predefined quantity of active ingredient.

(14) A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard capsules.

(15) A preparation in syrup or elixir form may contain the active ingredient in conjunction with a sweetener, an antiseptic, along with an agent providing flavour and a suitable colorant.

(16) Water-dispersible powders or granules may contain the active ingredient mixed with dispersion agents or wetting agents, or suspension agents, along with flavouring substances or sweeteners.

(17) For rectal administration, suppositories are used, which are prepared with binders melting at rectal temperature, for example cocoa butter or polyethylene glycols.

(18) 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.

(19) The active ingredient may also be formulated in microcapsule form, optionally with one or a plurality of additive carriers.

(20) Advantageously, the pharmaceutical composition according to the present invention is intended for oral or intravenous administration.

(21) The pharmaceutical composition according to the present invention may comprise further active ingredients resulting in an additional or optionally synergistic effect.

(22) The dosages of 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 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.

(23) The following example enables a clearer understanding of the invention without limiting the scope thereof.

(24) 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 potential 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 metastatic process. However, the inventors demonstrated by means of patch-clamp experiments in a whole cell configuration, conducted on MDA-MB-231 cells, that 3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine reduced the metastatic Nav1.5 current in a concentration-dependent fashion (IC.sub.50=1.5 M). For this reason, the inventors 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 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.

(25) Method

(26) Cell culture: the MDA-MB-231 cells are cultured in a Dulbecco'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 37 C., 100% moisture and 5% CO.sub.2.

(27) Electrophysiological measurements in whole cell configuration: the patch pipette (resistance 5-15 M) contains a solution of: 5 mM NaCl, 145 mM CsCl, 2 mM MgCl.sub.2, 1 mM CaCl.sub.2, 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 MgCl.sub.2, 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 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 record the maximum Nav channel activity.

(28) Two protocols were used: 1/ Voltage-dependent current I.sub.Na protocol for observing the maximum amplitude of I.sub.Na 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 FIG. 1). 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.

(29) Results

(30) 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 reversal potential at +30 mV (FIG. 1). The current is cancelled in the absence of Na.sup.+ ions in the medium, confirming that the current in question is a sodium current. The peak current inhibition with tetrodotoxin (Sigma) is merely partial: 307% at 1 M and 548% at 5 M, indicating that the current in question is tetrodotoxin-resistant.

(31) Moreover, the inventors demonstrated in vivo that 3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methyl-propyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine does not interfere with normal cardiac function even at high doses.

(32) The present invention is thus characterised: 1) in that 3-(R)-[3-(2-methoxyphenylthio)-2-(S)-methyl-propyl]amino-3,4-dihydro-2H-1,5-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-1,5-benzoxathiepine has a selective action on cancer cells without interfering, at anti-metastatic doses, with the other functions in which the Nav1.5 sodium channels are involved such as normal cardiac and vascular function.