WO2007006797A1

WO2007006797A1 - Use of 4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphtalen-1-ylamine for treating cancer

Info

Publication number: WO2007006797A1
Application number: PCT/EP2006/064155
Authority: WO
Inventors: Frédéric Revah; Fabrice Balavoine; Marius Tuijnder; Robert Amson; Adam Telerman
Original assignee: Anceris
Priority date: 2005-07-12
Filing date: 2006-07-12
Publication date: 2007-01-18
Also published as: NO20080722L; TNSN08010A1; WO2007006797A8; FR2888506A1; JP2009501193A; RU2008101268A; IL188685A0; MA29729B1; CN101222917A; ZA200800500B; AU2006268657A1; CA2614696A1; KR20080031748A; EP1904045A1

Abstract

The invention concerns the use of 4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-naphtalen-1-ylamine or any combination of enantiomers thereof or of one it its enantiomers for preparing a pharmaceutical composition for treating cancer, as well as for treating and preventing mestastases.

Description

USE OF 4- (3,4-DICHLOROPHENYL) -1,2,3,4-TETRAHYDRO-NAPHTHALEN-1-YLAMINE FOR THE TREATMENT OF CANCER

The present invention relates to the use of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine or one of its enantiomers or any combination thereof its enantiomers for the preparation of pharmaceutical compositions for the treatment of cancer, as well as the treatment and prevention of metastases. The annual number of new cancer cases has increased significantly over the last twenty years. The treatment of cancer is therefore a real public health problem. Whatever the type of cancer, treatment with chemotherapy is generally recommended, if only in adjuvant treatment. There is therefore a continuing need to develop new molecules for chemotherapy.

The inventors have studied 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and its enantiomers or any combination of its enantiomers, and have shown that these compounds possess a antiproliferative activity on many types of tumor cells, and that they can be used in the prevention or treatment of cancers.

The present invention therefore relates to the use of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine or one of its enantiomers selected from ((1S, 4S) 4- (3,4-Dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine, (1S, 4R) 4- (3,4-dichlorophenyl) -1, 2,3,4-tetrahydro-naphthalen-1-ylamine (1R, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and (1R , 4R) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine) or any combination of its enantiomers for the preparation of a pharmaceutical composition for the treatment cancer and the treatment and prevention of metastases By treatment of cancer or metastases is meant according to the present invention essentially the ability for a compound to selectively kill tumor cells without substantially reaching healthy cells, it being understood that this selectivity may be variable depending on the condition of the patient and the patient. type of cancer treated.

As will be seen in the examples below, the compounds according to the present invention possess a remarkable ability to destroy tumor cells. The results were particularly impressive with respect to the ability of these products to affect tumor cells from many different types of cancer.

According to the present invention, said cancer or said metastases are derived from a cancer selected from the group consisting of prostate cancer, osteosarcomas, lung cancer, non-small cell lung cancer, breast cancer, endometrial cancer or colon cancer, chronic or acute leukemia, solid tumors of the child, lymphocytic lymphoma, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the head and neck, uterine cancer, ovarian cancer, gynecological tumors, Hodgkin's disease, bone cancer, rectal cancer, cancer of the anal region, cancer of the uterus stomach, esophageal cancer, small bowel cancer, endocrine system cancer, soft tissue sarcomas, urethral cancer, penile cancer, bladder cancer, cancer of the kidney, cancer of the ureter, pediatric malignancies and of the central nervous system, particularly brain tumors. Preferably, said cancer or said metastases are derived from breast cancer. In another preferred manner, said cancer is leukemia.

In addition, the inventors have shown that 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine or one of its enantiomers or any combination of its enantiomers , administered in combination with at least one alkaloid, preferentially a vinca alkaloid, for example vincristine or vinblastine, has a synergy of specific cytotoxic activity against tumor cells.

Another aspect of the invention thus relates to the use of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine or one of its enantiomers or any combination of its enantiomers and at least one alkaloid for the preparation of a pharmaceutical composition for the treatment of cancer, as well as for the treatment and prevention of metastases. Preferably, the alkaloid is a vinca alkaloid. More preferably, the vinca alkaloid is selected from the group consisting of: vinblastine, vincristine, vindesine, and vinorelbine, preferably vincristine and / or vinblastine.

The term "alkaloid of vinca" is intended to mean, according to the present invention, the alkaloids of the periwinkle, Vinca rosea, and their derivatives obtained by chemical modification. They target tubulin achromatic spindle mitosis which they inhibit the polymerization. This tubulin also constituting the nerve fibers, the alkaloids of vinca have a nerve toxicity, especially sensitive, and induce a depressive tendency.

Another aspect of the invention relates to products comprising

4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine or one of its enantiomers or any combination of its enantiomers and at least one alkaloid, as a product combination for simultaneous, separate or time-course use in anti-cancer therapy.

Preferably, the alkaloid chosen is a vinca alkaloid. More preferably, the vinca alkaloid is selected from the group consisting of: vinblastine, vincristine, vindesine, and vinorelbine, preferably vincristine and / or vinblastine.

The pharmaceutical compositions and / or combination products according to the present invention can be administered orally, intravenously, enterally, parenterally, intramuscularly, intranasally, subcutaneously sublingually or topically. In general, we prefer to use oral or default injectables, in particular for the treatment of tumors. Remarkably, the inventors have demonstrated that the products of the present invention can be orally effective, unlike many anti-tumor products now available to patients (Goodman &Gilman's Pharmacological Basis of Therapeutics, Mc Graw HiIl Editor). ).

Daily dosages should take into account the condition of the patient but also the treated cancer, its stage and its progression.

The examples below are for illustrative purposes only and can not be construed as limiting the teaching of this specification.

LEGEND OF FIGURES

Figure 1: Study of the synergistic effect of combinations of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine on inhibition of proliferation U937 leukemia-like cells

Figure 2: Study of the synergistic effect of combinations of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine on inhibition of proliferation U937 leukemia-like cells

Figure 3: Study of the synergistic effect of combinations of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine on inhibition of proliferation breast cancer cells type MDA-MB231

Figure 4: Study of the synergistic effect of combinations of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine on inhibition of proliferation breast cancer cells type MDA-MB231 Figure 5: Evolution during treatment of the median volume of implanted tumors in SCID mice after chronic administration of Cis 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1 -ylamine intraperitoneally

Figure 6: Evolution during treatment of the median volume of implanted tumors in SCID mice after chronic administration of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro 1-naphthalen-1-ylamine intraperitoneally

EXAMPLES

By Cis 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine is meant the racemic mixture of the two enantiomers (1S, 4S) 4- (3, 4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and (1R, 4R) 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro- naphthalen-1-ylamine.

"Trans 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine" means the racemic mixture of the two enantiomers (1S, 4R) 4- (3, 4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and (1R, 4S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro- naphthalen-1-ylamine.

By "Cis / Trans 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine" is meant the racemic mixture of the four aforesaid enantiomers.

EXAMPLES 1 to 3:

In these examples, the inventors unexpectedly demonstrate the antitumor effect of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1. ylamine and its enantiomers or any combination of its enantiomers on tumor cell lines of various origin.

Example 1 Determination of IC ₅₀ on Leukemic U937-like Cells

The method described below was applied to determine the IC ₅₀ values of the following compounds on U937 cells:

• Cis / Trans 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

• Cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine • Trans 4- (3,4-dichlorophenyl) -1,2,3,4 -tetrahydro-naphthalen-l-ylamine

(1S, 4S) 4- (3,4-Dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

(1S, 4R) 4- (3,4-Dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

(IR, 4R) 4- (3,4-Dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

• (IR, 4S) 4- (3,4-Dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

The IC ₅₀ values are summarized in the table below (Table 1)

Table 1

These results show that 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine, combinations of its enantiomers and all its enantiomers have the property of inhibiting proliferation. U937 leukemic cells and therefore antitumor activity. The antitumor activities of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine, combinations of its enantiomers and all its enantiomers are equivalent to the extent that the values IC50 values are all between 3 μM and 12 μM. Accordingly, any combination of the enantiomers of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine has the property of inhibiting the proliferation of U937 leukemia-like cells. and therefore an antitumor activity Example 2: Determination of IC ₅₀ on breast cancer cells MDA-MB231

The method described hereinafter was applied to determine the IC ₅₀ values of the following compounds on MDA-MB231 cells:

• Cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

• Trans 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

The IC ₅₀ values are summarized in the table below (Table 2)

Table 2

These results show that 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and combinations of its enantiomers possess the property of inhibiting the proliferation of cancer cells. breast type MDA-MB231 and therefore antitumor activity. The antitumor activities of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and combinations of its enantiomers are equivalent insofar as the IC ₅₀ values obtained are all between 4 μM and 7 μM. As a result, all the enantiomers of 4- (3,4-dichlorophenyl) -1,2,3,4- Tetrahydro-naphthalen-1-ylamine and even any combination of these enantiomers possess the property of inhibiting the proliferation of MDA-MB231 type breast cancer cells and therefore antitumor activity.

Example 3: Determination of IC ₅₀ of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine on 30 tumor cell lines

The method described below was applied to determine the IC ₅₀ values of (1S, 4S) -4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1. ylamin on 30 cell lines derived from breast, colon, lung, ovarian, prostate, pancreatic, skin, brain and blood cancers.

Table 3 groups the IC ₅₀ values of (1S, 4S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine on 30 different tumor lines from haematological and solid tumors varied.

In this example the inventors unexpectedly demonstrate that (1S-4S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine has a broad spectrum of anti-tumor action and is capable of inhibiting the proliferation of tumor cells from all the cancers tested

Table 3

EXAMPLES 4-9:

In these examples, the inventors unexpectedly demonstrate the synergistic antitumor effect of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine and its enantiomers with alkaloids. of Vinca.

Example 4: Study of the synergistic effect of combinations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine on inhibition of proliferation U937 leukemia-like cells

The method described below for evaluating a synergistic effect of combinations of two products on the inhibition of U937 leukemia cell proliferation was applied with the following compounds:

• Cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

• Vincristine

The final 6 concentrations selected for testing cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine were 25, 13, 6.3, 3.1 and 1.6 micromolar (μM). The final 6 concentrations chosen for testing vincristine were 4000, 1000, 250, 63, and 16 picomolar (pM).

Incubation of U937 cells with different combinations of concentrations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine reveals the existence of synergy between the antiproliferative effects of two compounds.

The results are shown in Figure 1.

The antiproliferative activity (percent inhibition of proliferation of 73%) of a combination of vincristine (250 μM) and cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro naphthalen-1-ylamine (3.1 μM) is clearly superior to the effect of the only active agent (21% inhibition for vincristine at 250 μM). In addition, the antiproliferative effect observed with this combination is not a simple additivity of the separate effects of the two products given the positive value (+49) calculated for the excess over the additivity "Bliss". In conclusion, there is a synergistic effect of this combination of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine.

Example 5: Study of the synergistic effect of combinations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine on inhibition of proliferation U937 leukemia-like cells

The method described below to evaluate a synergistic effect of combinations of two products on the inhibition of U937 leukemia cell proliferation was applied with the following compounds: • cis 4- (3,4-dichlorophenyl) 1,2,3,4-tetrahydro-naphthalen-1-ylamine • Vinblastine

The final 6 concentrations selected for testing cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine were 25, 13, 6.3, 3.1 and 1.6 micromolar (μM). The final 6 concentrations chosen to test vinblastine were 4000, 1000, 250, 63, and 16 picomolar (pM).

Incubation of U937 cells with different combinations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine concentrations reveals the existence of synergy between the antiproliferative effects of two compounds. The results are shown in Figure 2.

Antiproliferative activity (percent inhibition of proliferation 54%) of a combination of vinblastine (250 μM) and cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro naphthalen-1-ylamine (3.1 μM) is clearly superior to the effect of the only active agent (19% inhibition for vinblastine at 250 μM). Moreover, the antiproliferative effect observed with this combination is not a mere additivity of the separate effects of the two products given the positive value (+31) calculated for the excess over the additivity "Bliss". In conclusion, there is a synergistic effect of this combination of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine. Example 6 Study of the Synergistic Effect of Combinations of (1S, 4S) 4- (3,4-Dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and Vincristine on the inhibition of U937 leukemia cell proliferation The method described below for evaluating a synergistic effect of combinations of two products on the inhibition of U937 leukemia cell proliferation was applied with the following compounds:

• (1S, 4S) 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

• Vincristine Incubation of U937 cells with different combinations of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and vincristine concentrations the existence of a synergy between the antiproliferative effects of two compounds. The observed antiproliferative effect of a combination of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine (3.1 μM) and vincristine does not add to the simple additivity of the separate effects of the two products given the positive value (+8) calculated for the excess over the additivity "Bliss". In conclusion, there is a synergistic effect of this combination of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and vincristine.

Example 7: Study of the synergistic effect of combinations of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and vinblastine on the inhibition of U937 leukemia cell proliferation

• (1S, 4S) 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

• Vinblastine Incubation of U937 cells with different combinations of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and vinblastine concentrations reveals that existence of a synergy between the antiproliferative effects of two compounds. The observed antiproliferative effect of a combination of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine (3.1 μM) and vinblastine is not a mere additivity of the separate effects of the two products given the positive value (+5) calculated for the excess over the additivity "Bliss". In conclusion, there is a synergistic effect of this combination of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and vinblastine.

Example 8: Study of the synergistic effect of combinations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine on inhibition of proliferation breast cancer cells type MDA-MB231

The method described below for evaluating a synergistic effect of combinations of two products on the inhibition of the proliferation of MDA-MB231 type breast cancer cells was applied with the following compounds: • Cis 4- (3, 4 -dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine • Vincristine

The final 6 concentrations selected for testing cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine were 25, 13, 6.3, 3.1 and 1.6 micromolar (μM). The final 6 concentrations chosen for testing vincristine were 4000, 1000, 250, 63, and 16 picomolar (pM). Incubation of MDA-MB231 cells with different combinations of concentrations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine reveals the existence of a synergy between the antiproliferative effects of two compounds.

The results are shown in Figure 3. Antiproliferative activity (percent inhibition of 59% proliferation) of a combination of vincristine (1000 μM) and cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro naphthalen-1-ylamine (3.1 μM) is clearly superior to the effect of the only active agent (25% inhibition for vincristine at 1000 μM). In addition, the antiproliferative effect observed with this combination is not a simple additivity of the separate effects of the two products given the positive value (+28) calculated for the excess over the additivity "Bliss". In conclusion, there is a synergistic effect of this combination of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vincristine.

Example 9: Study of the synergistic effect of combinations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine on inhibition of proliferation The method described below for evaluating a synergistic effect of combinations of two products on the inhibition of the proliferation of leukemic U937-type cells has been applied with the following compounds:

• Cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine

• Vinblastine The final 6 concentrations chosen to test cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine were 25, 13, 6.3, 3, 1 and 1.6 micromolar (μM). The final 6 concentrations chosen to test vinblastine were 4000, 1000, 250, 63, and 16 picomolar (pM).

Incubation of MDA-MB231 cells with different combinations of concentrations of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine reveals the existence of a synergy between the antiproliferative effects of two compounds.

The results are shown in Figure 4. The antiproliferative activity (percent inhibition of proliferation 61%) of a combination of vinblastine (1000 μM) and cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro naphthalen-1-ylamine (1.6 μM) is clearly greater than the effect of the only active agent (33% inhibition for vinblastine at 1000 μM). In addition, the antiproliferative effect observed with this combination is not a simple additivity of the separate effects of the two products, given the positive value (+27) calculated for the excess over the additivity "Bliss". In conclusion, there is a synergistic effect of this combination of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine. Similarly, the antiproliferative activity (percent inhibition of proliferation 87%) of a combination of vinblastine (1000 μM) and cis 4- (3,4-dichlorophenyl) -1,2,3, 4-Tetrahydro-naphthalen-1-ylamine (3.1 μM) is clearly superior to the effect of the only active agent (33% inhibition for vinblastine at 1000 μM). In addition, the antiproliferative effect observed with this combination is not a simple additivity of the separate effects of the two products given the positive value (+47) calculated for the excess over the additivity "Bliss". In conclusion, there is a synergistic effect of this combination of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine cis and vinblastine.

EXAMPLES 10 and 11:

In these examples the inventors unexpectedly demonstrate the antitumor effect of 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and its enantiomers administered in the animal carrying a tumor.

Example 10: Study of the antitumor effect in the mice of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine after chronic administration by intrapertemal route

In this example, the inventors tested the antitumor effect in mice of Cis 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine, by applying the method described below. In order to test this effect, the inventors administered Cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine to mice which had previously been grafted with tumor cells. . They compared tumor growth in animals treated with Cis 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine with that of tumors in non-controlled animals. treated or treated only with the vehicle of the test substance. Remarkably the inventors have been able to show that the intraperitoneal administration of Cis 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine significantly slows tumor growth in the mice thus treated.

The inventors analyzed the average tumor size in subcutaneous tumor-bearing mice treated with Cis 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and compared it to that of the "control" mice bearing these tumors and treated with the vehicle of the test substance only.

Figure 5 represents the average volume of subcutaneous tumors carried by mice (in mm3) treated with Cis 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine as a function of time elapsed (in days) since the first day of treatment (50 mg / kg intraperitoneally), compared to the average volume of tumors carried by vehicle-treated mice.

The tumor volume of the mice treated with the compound of the invention is much lower than that of the untreated mice, which reveals a clear anti-tumor effect of Cis 4- (3,4-dichlorophenyl) -1, 2,3,4-Tetrahydronaphthalen-1-ylamine.

Example 11: Study of the anti-tumor effect in mice of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine after chronic administration intraperitoneally

In this example, the inventors tested the anti-tumor effect in mice of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalene-1 ylamine, using the method described below. In order to test this effect the inventors administered (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine to mice which had previously been grafted tumor cells. They compared tumor growth in animals treated with (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine with that of tumors in control animals which are untreated or treated only with the vehicle of the test substance. Remarkably the inventors have been able to show that the intraperitoneal administration of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine significantly slowed down tumor growth in the mice thus treated.

The inventors analyzed the average tumor size in subcutaneous tumor-bearing mice and treated with (1S, 4S) 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalene. l-ylamine and compared it to that of "control" mice bearing these tumors and treated with the vehicle of the test substance only.

Figure 6 shows the average volume of subcutaneous tumors carried by mice (in mm3) treated with (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalene. -l-ylamine as a function of the time elapsed (in days) since the first day of treatment (15 mg / kg twice daily intraperitoneally), compared to the average volume of tumors carried by vehicle-treated mice.

The tumor volume of the mice treated with the compound of the invention is much lower than that of the untreated mice, which reveals an obvious anti-tumor effect of (1S, 4S) 4- (3,4-dichlorophenyl) 1,2,3,4-tetrahydro-naphthalen-1-ylamine. EXAMPLES 12 and 13:

In these examples the inventors demonstrate remarkably that 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine and its enantiomers have the properties peculiar to their therapeutic use by oral route.

Example 12: Study of pharmacokinetic parameters (half-life, bioavailability) of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine in mice Pharmacokinetic studies were performed with (1S, 4S) -4-

(3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine in the rodent (CD1 mice). This compound was administered intravenously to animals at a dose of 1 mg / kg and orally at doses of 5, 10 and 20 mg / kg. The circulating levels of (1S, 4S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine in the blood of mice were measured by coupled liquid chromatography. mass spectrometry at different times between 5 and 480 minutes after intravenous administration and between 15 and 1440 minutes after oral administration. These measurements made it possible to show significant circulating doses of (1S, 4S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine in the treated animals.

The results of the pharmacokinetic parameters of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine in mice are reported in Table 4a and 4b below.

Table 4a

Pathway Rate Tl / 2 Cl AUCAU AUC (mg / kg) (min) (inL / inin / kg) (min * ng / mL) (min * ng / mL)

L V. Mouse 1 161 35 25057 28302 Table 4b

Pathway Dose Tmax Cmax Tl / 2 AUC AUCV AUG (mg / kg) (min) (ng / mL) (min) (min * ng / mL) (min * ng / mL) per os Mouse 5 120 49 379 30070 32255 per os Mouse 10 120 131 275 65769 67755 per os Mouse 20 120 254 316 151002 157847

With:

• T 1/2 = elimination at half life

• AUCaIl = area under the curve from the moment of administration (1 = 0) to the time of the last observation

• AUCESfF = area under the curve from the moment of administration (1 = 0) extrapolated to infinity.

• Tmax = Time of maximum observed concentration

• Cmax = Concentration corresponding to Tmax

• Cl = Total clearance

In addition, the ratio of areas under the curve (AUC) obtained during oral and intravenous (1S, 4S) -4- (3,4-dichlorophenyl) -1,2,3 , 4-tetrahydro-naphthalen-1-ylamine is used to measure a bioavailability factor, whose value according to the concentrations is between 24% and 30%. These experiments demonstrate that when (1S, 4S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine is administered orally, substantial doses of this compound are found in the circulation, with a significant bioavailability factor, which demonstrates that it is therefore well suited to oral treatment. Example 13: Study of the antitumor effect in mice of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine after chronic administration orally

In this example, the inventors tested the anti-tumor effect in mice of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine. By applying the method described below. In order to test this effect, the inventors administered (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine to mice which had previously been grafted tumor cells. They compared tumor growth in animals treated with (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine with that of tumors in control animals which are untreated or treated only with the vehicle of the test substance. Remarkably the inventors have been able to show that oral administration of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine slowed down significantly tumor growth in mice treated in this way.

Table 5 reports the median volumes (in mm ³ ) of subcutaneous tumors carried by SCID mice treated with (1S-4S) -4- (3,4-dichlorophenyl) -1,2,3,4- tetrahydro-naphthalen-1-ylamine as a function of elapsed time (in days) since the first day of treatment (80 mg / kg daily and oral) and median volumes of tumors carried by vehicle-treated mice on the same days. Days 5 and 18 correspond respectively to

day after the first day of treatment.

Table 5 below shows the median volumes of tumors implanted in SCID mice after chronic administration of (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro- naphthalen-l-ylamine orally Table 5

The median volume of tumors carried by the mice treated with the compound of the invention is significantly less (by almost half) the median volume of tumors carried by the vehicle-treated mice.

Therefore, (1S, 4S) -4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine administered orally has an anti-tumor effect in animal.

Example 14: Study of the cerebral penetration of (1S, 4S) 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine in mice

The activity of anti-tumors on tumors of the nervous system is often limited by their inability to cross the blood-brain barrier and thus to enter the brain. As shown in Table 3, (1S, 4S) -4- (3,4-dichloro-phenyl) -

1,2,3,4-Tetrahydro-naphthalen-1-ylamine is active in vitro on tumor lines derived from glioblastomas. Interestingly, the experiments reported below demonstrate that (1S, 4S) -4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine possesses the ability to cross the blood-brain barrier significantly, which is a major advantage of this compound for the treatment of brain tumors. (1S, 4S) -4- (3,4-Dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine was injected intravenously into a group of CD1 mice, at a rate of 1 mg / kg. Levels of (1S, 4S) -4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine in blood and brain were analyzed by liquid chromatography coupled with mass spectrometry.

The results of this study in mice (1S, 4S) 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine brain penetration are reported in the literature. Table 6 below.

Table 6

TIME (minutes) BRAIN PLASMA REPORT

CONCENTRATION CONCENTRATION BRAIN / PLASMA (ng / g brain) (ng / mL)

21 96 47 2

34 217 67 3

50 275 34 8

65 149 32 5

120 486 37 13

360,295 15,20

480 155 7 23

600 209 11 19

These experiments show that the concentrations of (1S, 4S) -4-

(3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine in the brain are more important than in plasma and the ratio of concentration of this compound between brain and blood increases with time (over the interval analyzed) thus showing the brain's capacity for accumulation.

Therefore, (1S, 4S) -4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine is of major interest for the treatment of brain tumors. MATERIALS AND METHODS

I. Procedure for Determining a CI-n on U937 Leukemic-type Cells The test compound is dissolved in DMSO (100%) at a concentration of 1.10 ^-2 M (stock solution) and then 8 samples of 8 different concentrations are prepared by successive dilution with the complete cell culture medium (RPMI 1640 Cambrex + 10% FBS + 1% L-Glutamine + 40 μg / ml Gentamycin) For each sample, the dilution volume is adjusted to obtain an equal concentration at twice the final selected concentration C _x. for example, 1.10 microns, 5.10 ^"5 M, ^{2.5x10" 5} M, 1.3.10 ^"5 M, ^{6,3.10" 6} M, 3,1.10 ^{" 6} M, 1.6.10 ^"6 M and 7.8.10 ^{" 7} M is a standard range of 8 final concentrations. In parallel, 8 control samples are prepared by successive dilution of a solution of DMSO (100%) with the same cell culture medium (RPMI1640 Cambrex + 10% FBS + 1% L-Glutamine + 40 μg / ml of Gentamycin), the volumes selected dilution being strictly identical to those used for the preparation of samples of the test compound.

In a 96-well white non-transparent plate (fluoronunc 96F Nunclon Delta), 100 μl of a suspension of U937 cells at a concentration of 2.5 × 10 ⁴ cells / ml in RPMI1640 Cambrex medium + 10% FBS + 1% L-Glutamine + 40 μg / ml of Gentamycin are deposited in each well, ie 2500 cells per well. 100 μL of a 2 _x C _x sample are added (one sample per well) and the medium is homogenized. After 144h of incubation at 37 ° C. under one atmosphere (5% CO ₂ , 90-95% humidity), the quantification of the viability of the cells in culture is carried out by measuring the levels of ATP using the test. CellTiter-Glo ™ Luminescent Assay System supplied by Promega Corporation according to the supplier's instructions. The luminescence in each well is measured using a counter, VICTOR ₂ 1420 (Wallac, PerkinElmer, Courtaboeuf, France). For each final concentration C _x of the test compound, the percentage inhibition of cell proliferation (% Inh (C _x )) is obtained by applying the following formula:

[Lum. (Cx compound) - Lum. (White)]

% lnh. (Cx) = 100 x [1]

[Lum. (Check Cx control) - Lum. (White)] in which

• Lum. (Compound C _x ) = average of the luminescence measurements of three wells of the test sample at the final concentration C _x .

• Lum. (Control C _x ) = average luminescence measurements of three wells of the corresponding control sample • Lum. (white) = average luminescence measurements of eight wells comprising only 200 μl of cell culture medium (RPMI 1640 Cambrex + 10% FBS + 1% L-Glutamine + 40 μg / ml Gentamycin)

IC ₅₀ is the concentration of the compound required to achieve 50% inhibition of cell proliferation; these values are calculated with XLfit 3 software (ID Business Solutions Ltd., UK) from semi-logarithmic curves.

II. Procedure for determining a CI-n on MDA-MB231 breast cancer cells

The test compound is dissolved in DMSO (100%) at a concentration of 1.10 ^-2 M (stock solution) and then 8 samples of 8 different concentrations are prepared by successive dilution with the complete cell culture medium (E-MEM Cambrex + 10% FBS, + 1% non-essential amino acids + 1% Napyruvate + 1% L-Glutamine + 40μg / ml Gentamycin) For each sample, the dilution volume is adjusted to obtain a concentration equal to twice the final concentration C _x chosen, for example 1.1 O ^ M, 5.10 ^" 5M, 2.5.10 ^~ 5M, 1.3.10 ^" 5M, 6.3.10 ^" 6M, 3.1.10 ^" 6M, 1, 6.10 ^~ 6M and 7.8.10 ^~ 7M is a standard range of 8 final concentrations. In parallel, 8 control samples are prepared by diluting a solution of DMSO (100%) with even the cell culture medium (E-MEM Cambrex + 10% FBS, + 1% non-essential amino acids + 1% Napyruvate + 1% L-Glutamine + 40 μg / ml Gentamycin), the dilution volumes chosen being strictly identical to those used for the preparation of the samples of the test compound.

In a 96-well white non-transparent plate (fluoronunc 96F Nunclon Delta), 100 μl of a suspension of MDA-MB231 cells at a concentration of 1.25 × 10 ⁴ cells / ml in an E-MEM Cambrex medium + 10% FBS, + 1% of non-essential amino acids + 1% Napyruvate + 1% L-Glutamine + 40 μg / ml of Gentamycin are deposited in each well, ie 2500 cells per well. 100 μL of a 2 _x C _x sample are added (one sample per well) and the medium is homogenized. After 144h of incubation at 37 ° C. under one atmosphere (5% CO ₂ , 90-95% humidity), the quantification of the viability of the cells in culture is carried out by measuring the levels of ATP using the test. CellTiter-Glo ™ Luminescent Assay System supplied by Promega Corporation according to the supplier's instructions. The luminescence in each well is measured using a counter, VICTOR ₂ 1420 (Wallac, PerkinElmer, Courtaboeuf, France).

For each final concentration C _x of the test compound, the percentage inhibition of cell proliferation (% Inh (C _x )) is obtained by applying the following formula:

[Lum. (Cx compound) - Lum. (White)]

% lnh. (Cx) = 100 x [1]

[Lum. (Check Cx control) - Lum. (White)] in which

• Lum. (Compound C _x ) = average of the luminescence measurements of three wells of the test sample at the final concentration C _x . • Lum. (Control C _x ) = average of the luminescence measurements of three wells of the corresponding control sample

• Lum. (white) = average luminescence measurements of eight wells comprising only 200 μL of cell culture medium (E-MEM Cambrex + 10% FBS, + 1% non-essential amino acids + 1%

Napyruvate + 1% L-Glutamine + 40μg / ml Gentamycin)

III. A method for evaluating a synergistic effect of combinations of two products A and B on the inhibition of U937 leukemia cell proliferation

Each product is dissolved in DMSO (100%) at a concentration of 1.10 ^-2 M (stock solution) then, for each product, 6 samples of 6 different concentrations are prepared by successive dilution with the complete cell culture medium (RPMI 1640 Cambrex + 10% FBS + 1% L-Glutamine + 40μg / ml Gentamycin) For each sample, the dilution volume is adjusted to obtain a concentration equal to four times the final concentration chosen.

A cell suspension at 2.5 × 10 ⁴ cells / ml is prepared in complete medium, and 36 × 100 μl of this solution (ie 2500 cells / well) are distributed in 36 wells of a 96-well plate, white and non-transparent (fluoronunc 96F Nunclon). Delta). In each well containing 100 μl of cell suspension, are added 50 μl of a sample of product A concentrated four times and 50 μl of a sample of product B concentrated four times to obtain a final volume of 200 μl. Each sample of product A (6 concentrations Al, A2, A3, A4, A5, A6) is combined with each sample of product B (6 concentrations B1, B2, B3, B4, B5, B6). Concentrations A6 and B6 correspond to a zero concentration of product A and product B respectively.

The A6 / B6 combination therefore corresponds to a drug-free well and DMSO, which serves as a cell growth reference.

The contents of the 36 wells can be schematically represented as follows:

After 144h of incubation at 37 ° C. under one atmosphere (5% CO ₂ , 90-95% humidity), the quantification of the viability of the cells in culture is carried out by measuring the levels of ATP using the test. CellTiter-Glo ™ Luminescent Assay System supplied by Promega Corporation according to the supplier's instructions. The luminescence in each well is measured using a counter, VICTOR ₂ 1420 (Wallac, PerkinElmer, Courtaboeuf, France).

For each An / Bm combination, the percentage inhibition of cell proliferation (% Inh. (An / Bm)) is obtained by applying the following formula:

[Lum. M (An / Bm) - Lum.M (White)]

% lnh. (An / Bm) = 100 x ["l -

[Lum. M (A6 / B6) - Lum. M (White)] in which

• Lum.M (An / Bm) = average of two well luminescence measurements including the combination of An and Bm samples • Lum.M (A6 / B6) = average of two well luminescence measurements including the combination of samples A6 and B6

• Lum. (white) = average of 6-well luminescence measurements comprising only 200 μl of cell culture medium (RPMI 1640 Cambrex + 10% FBS + 1% L-Glutamine + 40 μg / ml of

gentamicin)

For each combination An / Bm, the excess over the single most active agent (E _aslpa (An / Bm)) is calculated by applying the following formulas:

• If% lnh. (An / B6)>% lnh. (A6 / Bm) then E _as , _pa (An / Bm) =% lnh. (An / Bm) -% lnh. (An / B6)

• If% lnh. (An / B6) <% lnh. (A6 / Bm) then E _as , _pa (An / Bm) =% lnh. (An / Bm) -% lnh. (A6 / Bm)

Finally, to differentiate the addition of the effects of the synergy, the percentage inhibition for each combination An / Bm is expressed as an excess with respect to the additivity "Bliss". The "Bliss" model predicts a combined response C for two active agents having a given effect A and B according to the formula: C = A + B - AB with A and B expressed as a fraction between 0 and 1.

FV. Method for Evaluating a Synergistic Effect of Two Products on Inhibition of MDA-MB231 Breast Cancer Cell Proliferation

The method used for MDA-MB231 breast cancer cells is similar to that used for U937 leukemia-type cells with the exception of the concentration of the cell suspension (1.25 × 10 ⁴ cells / ml for MDA-MB231 instead 2.5 × 10 ⁴ cells / ml for U937). The composition of the complete medium is also modified: E-MEM Cambrex + 10% FBS, + 1% non-essential amino acids + 1% Napyruvate + 1% L-Glutamine + 40 μg / ml Gentamycin. V. Procedure for Determining IC50 on Cell Lines Derived from Different Cancer Types

The cells were incubated in a final volume of 200 μl of a culture medium supplemented with 10% fetal bovine serum containing the test compound at 37 ° C. under an atmosphere containing 5% CO ₂ .

Tumor cells were incubated for 96 hours with final concentrations of the test compound (range of 1 x 10-4 to 4 x 10- ¹⁰ M). Each final concentration was assayed in quadriplicate. The vehicle of the tested compound At the end of the treatment period, the antiproliferative activity was evaluated by a colorimetric test using the tetrazolium salt MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxy phenyl) -2- (4-sulfophenyl) -2H-tetrazolium, Baltrop JA et al., Bioorg Med Chem, Lett, 1991, 1: 611-614).

At the end of the treatment of the cells, 40 μl of a solution freshly filtered at 0.22 μm of MTS (20 ml at 2 mg / ml, Ref Gl 111, Promega, Charbonnières,

France) and PMS (1 ml at 0.92 mg / ml, Ref P9625, Sigma) in Dulbecco's phosphate buffered saline (DPBS, Ref 17-513F, Cambrex) were added to each well. The culture plates were incubated for 2 hours at 37 ° C. The absorbance of each well was measured at 490 nm using a multi meter, VICTOR ₃ ™ 1420 (Wallac, PerkinElmer, Courtaboeuf,

France). The absorbance values correspond to the average of 4 experimental measurements

[Abs. Compound (Cx)]% lnh. (Cx) = 100 x [1]

[Abs. Control] in which • Abs. Compound (C _x ) = average of the absorbance measurements of the four wells of the sample to be tested at the final concentration C _x .

• Abs. Control = average of the absorbance measurements of the four control wells (no compound)

VI. Procedure for determining the in vivo antitumor effect of the products tested tumor induction

U937 viable cells in a volume of 200 .mu.l of RPMI culture medium are injected subcutaneously into the right flank of a SCID mouse. The injection of the cells is carried out 24 hours after the complete irradiation of the body with a γ source (1.8 Gy, Co ⁶⁰ , INRA BRETENIERE, Dijon,

France).

Treatment plan Treatment is initiated when the tumors have reached an average volume of about 50 mm ³ . The mice are randomly assigned to groups of 10 mice so that the mean tumor volume of each group is not statistically different from the other groups (variance analysis).

For each dose of test compound, an appropriate amount of product is suspended in Tween-20 (Ref P7949, Sigma). The suspensions are then diluted in water to achieve the desired concentration of the test compound and a final Tween-20 concentration of 1% (v / v). The mice received repeated intraperitoneal (IP) injections of the vehicle (Tween-1% (v / v) or the test compound at the dose and according to the chosen treatment plan (once daily or twice daily for 30 minutes). For oral treatments the products and the vehicle are administered by gavage.

Determination of tumor volume

The length and width of the tumor are measured twice a week using a caliper and the tumor volume is estimated by the formula: tumor volume = (width ² x length) / 2.

Claims

1. Use of 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydronaphthalen-1-ylamine, or any combination of its enantiomers or an enantiomer thereof for the preparation a pharmaceutical composition for the treatment of cancer, as well as the treatment and prevention of metastases.

2. Use according to claim 1 characterized in that the pharmaceutical composition further contains at least one alkaloid.

3. Use according to claim 2 characterized in that the alkaloid is a vinca alkaloid.

4. Use according to claim 3 characterized in that the vinca alkaloid is selected from the group consisting of: vinblastine, vincristine, vindesine, vinorelbine, or mixtures thereof, preferably vincristine and / or vinblastine.

5. Use according to one of claims 1 to 4, characterized in that said cancer is, or said metastases are derived from a cancer selected from the group consisting of prostate cancer, osteosarcomas, lung cancer, non-small cell lung cancer, breast cancer, endometrial cancer or colon cancer, chronic or acute leukemia, solid tumors of the child, lymphocytic lymphomas, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the head and neck, uterine cancer, ovarian cancer, gynecological tumors, Hodgkin's disease, bone cancer, cancer rectal cancer, anal cancer, stomach cancer, esophageal cancer, small bowel cancer, endocrine system cancer, soft tissue sarcomas, urethral cancer , penile cancer, bladder cancer, kidney cancer, cancer ureter, pediatric malignancies, and tumors of the central nervous system.

6. Use according to claim 5 characterized in that said cancer is breast cancer, or said metastases are derived from breast cancer.

7. Use according to claim 5 characterized in that said cancer is leukemia.

8. Use according to one of claims 1 to 7 characterized in that the pharmaceutical composition is administered orally, intravenously, enterally, parenterally, intramuscularly, intranasally, subcutaneously or sublingually.

9. A product comprising 4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-naphthalen-1-ylamine or at least one of its enantiomers or any combination of its enantiomers and at least one alkaloid, as a combination product for simultaneous, separate or time-course use in anti-cancer therapy.

10. Product according to claim 9 characterized in that the alkaloid is a vinca alkaloid.

11. Product according to claim 10 characterized in that the vinca alkaloid is selected from the group consisting of: vinblastine, vincristine, vindesine, vinorelbine, or mixtures thereof, preferably vincristine and / or vinblastine.