FIELD OF THE INVENTION

The current invention refers to a series of new all irans-diamino-dichloro-dihydroxy- platinum derivatives, their preparation and their application as anticancer agents.

BACKGROUND

A few c/s-diamino platinum complexes are widely used in cancer therapy. Antitumor properties of the first one, cisplatin, were discovered as early as 1965. Cisplatin was approved by FDA in 1978. Carboplatin and oxaliplatin were further approved by FDA in 1989 and 2002 respectively. Satraplatin and picoplatin are currently being reviewed for launching by FDA in some specific tumor settings. In cisplatin, carboplatin, oxaliplatin and picoplatin, the platinum atom, usually in the oxydation state II, is coordinated, with a cis geometry, to two amino ligands and to labile ligands which are either two chlorine atoms or one dicarboxylic organic acid, such as 1 ,1 -cyclobutanedicarboxylic acid (named "CBDCA") in the case of carboplatin, or oxalic acid in the case of oxaliplatin. In the case of picoplatin, the two nitrogen ligands are a-picoline and ammonia. Satraplatin is a platinum (IV) derivative c/s-coordinated to two amino ligands and two chlorine atom and linked to two irans-diaxial acetates.

These compounds are represented by the following formulae:

Cisplatin Carboplatin Oxaliplatin

Picoplatin Kalinowska-Lis et al., Coordination Chemistry Reviews (2008), 252(12-14), 1328-1345 gives a general review on trans geometry in Platinum anti-tumor compounds.

Gonzalez-Vadillo and al., Journal of Inorganic Biochemistry (2007), 101 (4), 551 -558 allows a more specific review on trans (II) and (IV) platinum compounds.

For many years, c/ ^' s geometry in bifunctional platinum complexes has been thought to be essential for the development of antitumor platinum-based drugs, since covalent binding to 7-nitrogen atoms of two adjacent guanines on the same strand of DNA was considered as responsible for antitumor activities. The discovery of the cytostatic activity of several analogs of Transplatin (trans isomer of Cisplatin) implied a very important change in the structure-pharmacological activity relationships for platinum compounds, as discussed by the groups of N. Farell (Metal Ions in Biological Systems, M. Dekker, 1996, 603-639), G. Natile (Metal Ions in Biological Systems, M. Dekker, 2004, 209-250) and C. Navarro-Ranninger (Crit. Rev. Oncol. Hematol., 2000, 35, 109- 120). C. Navarro-Ranninger and coworkers reported that all-irans-platinum (IV) complexes induce apoptosis in tumor cells resistant to Cisplatin (J. Med Chem 2007, 50, 2194-2199) and have slowed protein-binding kinetics and reactivities (Mol. Pharmacol, 2003, 63, 933-944).

ES 2214138 discloses the preparation and the antitumor activity of the all trans platinum (IV) complexes such as :

EP 0503830 A1 discloses the preparation and the antitumor activity of the all trans platinum (IV) complexes such as

BRIEF DESCRIPTION OF THE INVENTION

The authors of the present invention have unexpectedly found that all-irans-diamino- dichloro-dihydroxy-platinum (IV) complexes of formula (I) mentioned below have significantly improved antitumor activities. Thus, a first aspect of the present invention relates to new a\\-trans Platinu complexes of general formula (I):

(I)

where:

R1 and R2, identical or different, represent a hydrogen atom or a linear or branched C1 -C4 alkyl radical; provided that one of R1 and R2 is different from a hydrogen atom; R3 represents a bicyclic group of general formula (II):

(II)

X represents O or -CH ₂ - or -(CH ₂ )2-;

in the form of a free base, of an hydrate or of a solvate.

A second aspect of the present invention relates to a process for the preparation of a complex of formula (I), which comprises the reaction of a compound of formula (IV):

(IV)

where:

R1 , R2 and R3 are as defined above for formula (I),

with hydrogen peroxide in the darkness.

A third aspect of the present invention refers to the compound of formula (IV):

(IV)

where: R1 , R2 and R3 are as defined above for formula (I).

Another aspect of the present invention relates to a pharmaceutical composition which comprises a compound of formula (I), a hydrate or a solvate thereof, and at least one pharmaceutically acceptable excipient.

The invention also refers to the compound of formula (I) as defined above for its use as a medicament.

Finally, the invention also refers to a compound of formula (I) as defined above for its use in the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION

The invention refers to a\\-trans Platinum (IV) complexes of general formula (I):

(I)

where:

R1 and R2, identical or different, represent a hydrogen atom or a linear or branched C1 -C4 alkyl radical; provided that one of R1 and R2 is different from a hydrogen atom; R3 represents a bicyclic group of general formula (II):

(II)

X represents O or -CH ₂ - or -(CH ₂ )2-;

in the form of a free base, of an hydrate or of a solvate.

In the context of the present invention, the term "C1 -C4 alkyl" refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl and t-butyl.

The compounds of formula (I) exist in the form of pure enantiomers or racemates. The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention.

A first sub-group of compounds is represented by the compounds of formula (I) where R1 is H and R2 represents a linear or branched C1 -4 alkyl radical. More preferably, R2 is an isopropyl group.

A second sub-group of compounds is represented by the compounds of formula (I) where R1 and R2 are both methyl.

A third sub-group of compounds is represented by the compounds of formula (I) where NH ₂ -R3 is the exo- or the enc/o-norbornylamine; the compound of formula (I) being either in the form of a racemate or of its pure levogyre or dextrogyre enantiomer.

A fourth sub-group of compounds is represented by the compounds of formula (I) where:

- R1 is H and R2 is isopropyl,

- NH ₂ -R3 is the exo- or the endo-norbornylamine,

the compound of formula (I) being either in the form of a racemate or of its pure levogyre or dextrogyre enantiomer.

A fith sub-group of compounds is represented by the compounds of formula (I) where:

- R1 and R2 are methyl,

- NH ₂ -R3 is the exo-norbornylamine,

the compound of formula (I) being either in the form of a racemate or of its pure levogyre or dextrogyre enantiomer.

Among the compounds of formula (I) which are the subject of the invention, the following compounds may be mentioned in particular:

- irans-irans-irans-{PtCl ₂ (OH) ₂ (isopropylamine)[(rac)-(exo)-norbornylamine]} ;

- irans-irans-irans-{PtCI ₂ (OH) ₂ (isopropylamine)[(rac)-(enc/o)-norbornylamine]} ;

- irans-irans-irans-{PtCI ₂ (OH) ₂ (dimethylamine)[(exo)-2- norbornylamine]}.

The complexes of formula (I) of the invention can be prepared by reacting a compound of formula (IV) :

(IV)

wherein R1 , R2 and R3 are as defined above in formula (I),

with hydrogen peroxide in the darkness.

Preferably, this reaction is performed by heating in an inactinic glassware.

In fact, compounds of formula (IV) represent another aspect of the present invention. These compounds are useful as intermediates in the synthesis of the complexes of formula (I).

The compound of formula (IV) can be prepared by reacting a compound of formula (III): where R1 and R2 are as defined above in formula (I),

with an amine of formula NH ₂ R3, where R3 is as defined above in formula (I), followed by a treatment with water and hydrochloric acid.

Accordingly, Pt(IV) complexes of formula (I) can be prepared following the next two step synthetic sequences illustrated in scheme 1 :

Scheme 1

(I)

(III) (IV)

In a first step, a compound of formula (III), where R1 and R2 are as defined above in formula (I), reacts with an amine of formula NH ₂ R3, where R3 is as defined above in formula (I), followed by a treatment with water and hydrochloric acid to give compound of formula (IV).

In a second step, the compound of formula (IV) reacts with hydrogen peroxide in the darkness, to give compound of formula (I).

In scheme 1 , the starting compounds and the reagents, when their mode of preparation is not described, are commercially available or are described in the literature, or they may be prepared according to methods described therein or which are known to persons skilled in the art. The present invention further provides pharmaceutical compositions comprising at least a novel compound of formula (I) of the present invention with a pharmaceutically acceptable excipient, for administration to a patient.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oral form. Suitable dose forms for oral administration may be tablets and capsules and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.

Administration of the novel compounds of formula (I) or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of many of the diseases to be treated.

The correct dosage of the compound of formula (I) will vary according to the particular formulation, the mode of application, and the particular site, host and tumour being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, other drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.

In the present application, by "cancer" it is meant to include tumors, neoplasias, and any other disease having as cause malignant tissue or cells.

The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.

Depending on the type of tumor and the development stage of the disease, anticancer effects of the treatments of the present invention include, but are not limited to, inhibition of tumor growth, tumor growth delay, regression of tumor, shrinkage of tumor, increased time to regrowth of tumor on cessation of treatment, slowing of disease progression, and prevention of metastasis. It is expected that when a treatment of the present invention is administered to a patient, such as a human patient, in need of such treatment, said treatment will produce an effect, as measured by, for example, the extent of the anticancer effect, the response rate, the time to disease progression, or the survival rate. In particular, the treatments of the invention are suited for human patients, especially those who are relapsing or refractory to previous chemotherapy. First line therapy is also envisaged.

The following examples describe the preparation of some compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention.

Examples

Example 1 : Synthesis of complex I with R ¹ =H, R ² =/Pr and NH ₂ -R ³ = (rac)-(exo)- norbonylamine

Step 1 : Synthesis of irans-{PtCI ₂ (isopropylamine)[(rac)-(exo)-2- norbornylamine)]}):

A suspension of c/s-[PtCl ₂ (isopropylamine) ₂ ] (383mg, 1.04 mmol) in water (15 mL) was treated with (rac)-(exo )-norbonylamine (0.494 ml_, 4.16 mmol). The mixture was stirred at 80°C until most of the solid was dissolved and the slurry solution was maintained at the same temperature for 18 hours. The final solution obtained was filtered, washed with water and dried under reduced pressure. The solid obtained was dissolved in water (20 mL), treated with hydrochloric acid (10 mL) and heated at 90°C for 24h. After cooling down to room temperature, the product was collected by filtration as a yellow solid and washed with water (4x10 mL), obtaining 320 mg of pure compound, previous drying the yellow solid at 65°C under reduce pressure for 12 hours (5 mmHg).

irans-{PtCI ₂ (isopropylamine)[(rac)-(exo)-2-norbornylamine)]}. Yield: 70%.

Elemental analysis for Ci ₀ H ₂₂ N ₂ Cl ₂ Pt-3/2H ₂ O

Calculated C: 25.92, H: 5.44, N: 6.05

Found C: 25.82, H: 4.86, N: 6.30

1H NMR (CDCI ₃ )(ppm): 3.60-3.23 (m, 3H), 3.05 (m, 1 H), 2.46 (s, 1 H), 2.31 (s,

1 H), 1 .80 (ddd, J = 13.2, 7.8, 2.0 Hz, 1 H), 1.51 -1 .31 (m, 4H), 1.33 (d, J = 6.2 Hz, 6H), 1 .28-1 .15 (m, 2H), 1 .15-1.10 (m, 1 H).

Step 2: Synthesis of irans-irans-irans-{PtCI ₂ (OH) ₂ (isopropylamine)[(rac)-(exo)- norbornylamine]}

Example 1

The complex irans-{PtCI ₂ (isopropylamine)[(rac)-(exo)-2-norbornylamine]} (300mg, 0.685 mmol), prepared at step 1 , was suspended in water (20 ml) and hydrogen peroxide (35%, 1.0 ml) was added. The mixture was stirred and heated in the darkness at 70°C. After cooling, the product was collected by filtration as a pale yellow solid, washed with cold water and chloroform, and dried under reduced pressure.

7rans-irans-irans-{PtCl ₂ (OH) ₂ (isopropylamine)[(rac)-(exo)-norbornylamine]} Yield: 40%.

Elemental analysis for Ci ₀ H ₂₄ N ₂ Cl ₂ O ₂ Pt-H ₂ O-1 2KCI Calculated C: 22.85, H : 4.99, N: 5.33

Found C: 22.48, H : 4.60, N: 5.43

I R (cm ^"1 ): 3428 (broad signal), 2959, 1636, 1034, 798. Example 2: Synthesis of complexes I with R ¹ =H, R ² =/Pr and NH ₂ -R ³ = (rac)-

(endo)-norbonylamine

Step 1 : Synthesis of irans- PtCI ₂ (isopropylamine)[(rac)-(enc/o)-2-norbornylamine]}

To a solution of (rac)-(enc/o)-norbonylamine hydrochloride (767mg, 5.20 mmol) and KOH (583 mg, 10.4 mmol) in H ₂ 0 (50 mL) (previously cooled to 0°C for 15 min) was added a solution of c/ ^' s-[PtCI ₂ (isopropylamine) ₂ ] (500 mg, 1 .30 mmol) in water (5 mL). The mixture was stirred at 80°C until most of the solid was dissolved and the blur solution was maintained at the same temperature for 18 hours. The final solution was filtered, washed with water and dried under reduced pressure. The solid obtained was dissolved in water (20mL), treated with hydrochloric acid (10 mL) and heated at 90°C for 24h. After cooling down to room temperature, the product was collected by filtration and washed with water (4 x 10 mL), obtaining a yellow solid, previous drying at 65 °C under reduced pressure for 12 hours (5 mmHg).

irans-{PtCI ₂ (isopropylamine)[(rac)-(enc/o)-2-norbornylamine]} Yield: 65%

Elemental analysis for Ci ₀ H ₂₁ N ₂ CI ₂ Pt- 1/3KCI-2/3H ₂ 0

Calculated C: 25.39, H : 4.97, N: 5.92

Found C: 25.35, H : 4.69, N: 6.24

¹ H N MR (CDCI ₃ )(ppm): 3.84-3.41 (bs, 3H), 3.36-3.22 (m, 1 H), 2.59 (s, 1 H), 2.21 (s, 1 H), 2.13-2.05 (m, 1 H), 1 ,67-1 .42 (m, 6H), 1 .33 (d, J = 6.4 Hz, 6H), 1 .24 (t, J = 9.1 Hz, 1 H), 1 .01 (dt, J = 13.0, 3.1 Hz, 1 H).

Step 2: Synthesis of irans-irans-irans-{PtCI ₂ (OH) ₂ (isopropylamine)[(rac)-(enc/o)- norbornylamine]}

Example 2

A solution of irans-{PtCI ₂ (isopropyl)[(rac)-(enc/o)-norbornylamine]} (80mg, 0.10 mmol), prepared at step 1 , was suspended in water (10 ml) and hydrogen peroxide (2 ml_, 18.3 mmol) was added. The mixture was stirred and heated, in the darkness, at 90 °C for 24 h. The residue solution was concentrated, acetone was added and the solution was left in the fridge for 12 hours. The obtained solid was washed with acetone and dried under reduced pressure.

7rans-irans-irans-{PtCl ₂ (OH) ₂ (isopropylamine)[(rac)-(enc/o)-norbornylamine]} Yield: 19%

Elemental analysis for

Calculated C: 23.72, H: 5.57, N: 5.53

Found C: 23.92, H: 4.84, N: 5.90

IR (cm ^"1 ): 3435 (bs), 2860, 1636, 616 Example 3: Synthesis of complex I with R ¹ = R ² = methyl and NH ₂ -R ³ = (exo)-2- norbonylamine

Step 1 : Synthesis of frans- PtCI ₂ (dimethylamine)[(exo)-2-norbornylamine]}:

A suspension of c/ ^' s-[PtCl2(dimethylamine)2] (Journal of the Chemical Society, Chemical Communications 1987 (6), 443-445) (425 mg; 1 .2 mmol) in water (25 mL) and (rac)-(exo)-2-norbornylamine (634 μΙ_; 5.3mmol) was stirred at 90 °C. A white precipitation was observed at 16 hours, and after 20h, the reaction was cooled down to room temperature and filtered. The milky solution was removed and the liquid was evaporated under reduced pressure. The white crystalline residue was suspended in water, treated with HCI (1.3ml_; 4.5 mmol) and heated at 100 °C for 72 hours. Then the reaction was cooled down to room temperature and the procedure explained before was repeated (HCI (1 .3ml_; 4.5mmol) addition and heated for 24h). After cooling at room temperature, the bright yellow solid was filtered and washed with cold water and acetone. The solid was then dissolved in chloroform and precipitated with hexane. The final solid was dried under vacuum.

frans-{PtCI ₂ (dimethylamine)[(exo)-2-norbornylamine]} Yield: 35%

Elemental analysis for C ₉ H2oN ₂ Cl2Pt-2,5% CH ₃ COCH ₃

Calculated C: 25.77, H: 4.79, N: 6.60

Found C: 26,28, H: 4,75, N: 6,33

¹ H NMR (CDCI ₃ )(ppm): 3.84-3.41 (bs, 1 H), 3.25-3.17 (m, 2H), 3.06 (s, 1 H), 2.66 (s, 3H), 2,64 (s, 3H) 2.45 (s, 1 H), 2.29 (s, 1 H), 1 .83 (ddd, J = 13.7, 7.6, 1 .9 Hz, 1 H), 1 .58-1 .42 (m, 3H), 1 .37-1.24 (m, 1 H), 1 .21 -1.10 ( m, 2H), 1 ,12-1 ,06 (m, 1 H).

1 ⁹⁵ Pt NMR (CDCI ₃ )(ppm): -2187,93

Step 2: Synthesis of irans-irans-irans-{PtCl ₂ (OH) ₂ (dimethylamine)[(exo)-2- norbornylamine]}

Example 3

A suspension of irans-[PtCl ₂ (dimethylamine)(exo)-2-norbornylamine] (158 mg; 0.37 mmol), prepared at step 1 , in water (12 mL) and hydrogen peroxide solution (1.0 ml_; 9 mmol) was stirred at 90 °C for 4 hours and overnight at room temperature in the dark. The yellow solid resulted from the reaction, was filtered and washed with water and finally dried under reduced pressure.

7rans-irans-irans-{PtCl ₂ (OH) ₂ (dimethylamine)[(exo)-2- norbornylamine]} Yield:

18%

Elemental analysis for C ₉ H ₂₂ N ₂ Cl ₂ 0 ₂ Pt

Calculated C: 23.72, H: 4.87, N: 6.13

Found C: 22.66, H: 4.61 , N: 5.85

¹ H NMR (CDCI ₃ )(ppm): 3.02 (bs, 1 H), 2.42-2.50 (m, 7H), 2.27 (bs, 1 H), 1.75-1.72 (m, 1 H), 1.54-1.48 (m, 4H), 1 ,22-1.14 (m, 3H). The in vitro and in vivo antitumor activities of compounds from the invention have been evaluated against a panel of cisplatin-sensitive and cisplatin-resistant cell lines and/or tumors, according to the following assay conditions: Cell lines and tumours:

- CCRF-CEM is a human T-cell leukemia cell line (DSMZ ref ACC 240), established in 1964 from peripheral blood of 3-years old young girl bearing a terminal- stage ALL (Foley et ai, Cancer 18: 522-529 (1965)).

- NCI-H460 is a human epidermoid lung tumour cell line, obtained from the NCI (NCI-Frederick. Tumor Bank).

- MX1 is a human mammary carcinoma tumour, harbouring BRCA1 mutation, obtained from NCI (NCI-Frederick. Tumor Bank).

In vitro antiproliferative assays:

Tumour cells were grown in appropriate culture medium, either RPMI-1640 or

DMEM, complemented with 10% calf-fetal serum and antibiotics.

Cell proliferation was evaluated by ¹⁴ C-thymidine uptake in DNA. Exponentially growing cells - from 5.10 ³ to 10 ⁴ per well in 180 μί culture medium - were introduced in a 96-wells microtitration Cytostar-T apparatus (GE Healthcare Bio-Sciences, Uppsala, Sweden). After 4 hours pre-incubation under C0 ₂ atmosphere at 37°C, compounds were added in 10 μί volume. After incubation for an additional 72 hours period, 0.1 μθί ¹⁴ C-thymidine was added in each well, C ¹⁴ -thymidine uptake was recorded 24 hours later on a scintillation counter (Perkin-Elmer Life Sciences, Boston, MA, USA). IC ₅₀ , defined as the dose which inhibits 50% of cell proliferation, were thus determined.

Table 1 summarizes the in vitro antiproliferative data obtained with compounds from the invention, in comparison with various reference compounds - cisplatin, oxaliplatin and satraplatin - and a compound representative from ES 2214138. Table 1

n.d means not determined.

In vivo antitumor evaluation of Example 1 in MX1 tumor model.

7 to 8 weeks-old female SCID mice, obtained from Charles River (L'Arbresle, Lyon , France) were acclimated for at least 1 week previous experiment.

Animals, placed under normal light cycle, had then ad libitum access to food and water. MX1 cells, 10 ⁷ cells per mouse initially grown in RPMI medium supplemented with 10% foetal-calf serum and antibiotics, were subcutaneously implanted in mice. When 1000 mg tumour volume was reached, fragments (2-3 mm diameter) were cut, placed in phosphate buffer (PBS), bilaterally implanted and further passaged in mice until tumour growth rate is stable, before starting the experiment. Tumors were measured with a caliper twice weekly until the tumor reached 2000 mm ³ or until the animal died (which ever come first). Tumor volumes were estimated from 2 dimensional measurements: Volume (in mm ³ ) = (a x b ² )/2, where a and b are the tumor length and width (mm) respectively. The variation from the baseline of the tumoral volume is calculated in the treated and control group. These values are used to calculate the median in the treated group (ΔΤ) and in the control group (AC). ΔΤ/AC, expressed as a percentage, is the ratio of median at a chosen day (the last day before it becomes necessary to sacrifice control mice owing to tumor size). ΔΤ/AC values can be translated into an activity rating, according to the Southern Research Institute (SRI) criteria:

SRI activity criteria ΔΤ/ΔΟ

Highly active - % <0

regression is dated

Very active <10%

Active 10%< <40% inactive >40% When ΔΤ/AC values are negative, the percentage of regression is evaluated. A

Partial regression (PR) is defined as a decrease in tumor volume greater than or equal to 50% of the tumor volume at start of treatment. A Complete regression (CR) is defined as a decrease in tumor volume below the limit of palpation (T=10mm ³ ). At the end of the study, the number of tumor free survivor (TFS) which correspond to mice without any detectable tumor is determined. Both drug-related deaths and maximum percent relative mean net body weight loss are also determined. A body weight loss (mean of group) of greater than 15% for more than 3 consecutive days or 20% weight loss for one day or 10% drug deaths are considered to indicate an excessively toxic dosage.

As depicted in Figure 1 (which shows the effect of example 1 compound, administered by IV route, in Scid mice bearing the MX1 tumor), compound from example 1 is highly active on MX1 , a human mammary tumour xenografted in SCID mice. Compound of example 1 administered by i.v. route daily during 5 days at 5 or 10 mg/kg (25 or 50 mg/kg total dose) from day 10 to day 15 post tumor implantation was highly active : a AT/AC<0 was observed at both dosages and 100% CR was observed. At 10 mg/kg, 2 TFS were noted at the end of the study. At these dosages, 4% and 12% body weight loss with no drug death was observed, indicating no significant toxicity. Administered at 20 mg/kg, compound of example 1 was detected to be toxic for mice, with 6/6 deaths detected respectively on days 17, 19, 20, 21 and 24 (2 mice). This suggests that 10 mg/kg can be considered as the maximal tolerated dose in this schedule of administration (daily for 5 days).

MX1 xenograft model is sensitive to platinums, and part of this sensitivity could be attributed to the dysfunction of DNA repair enzymes (Donawho CK et al Clin Cancer Res 2007; 13:2728-2737). MX1 has BRCA1 deletions and contains a BRCA2 mutation. These genes are important for DNA double-strand break repairs (Caldecott KW et al Nat Struct Mol Biol 2005; 12:387-388.) and these genetic alterations lead to a predisposition to breast and ovarian cancer (Weberpals et al J. Clin Oncol 2008; 19: 3259-3267; Futreal PA et al Science 1994;266:120-122; Freidman LS et al Nat Genet 1994; 8:399-404; Fedier A et al, Int J Oncol 2003; 22:1 169-1 173; Couch FJ et al N. Engl J Med 1997; 336:1409-1415; Yang Q et al Cancer 2001 ; 92:54-60; Hilton JL et al J Natl Cancer Inst 2002; 94:1396-1406). Thus, there is a rational to use the new platinum derivatives of the invention in BRCA-associated tumors, mainly breast and ovarian tumors. The new platinum derivatives of the invention may also be used in combination with PARP inhibitors in those pathologies.

The compounds according to the invention may therefore be used as medicaments or for the preparation of medicaments, in particular for the treatment of BRCA-associated tumors, such as breast and ovarian tumors.

Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or a hydrate or a solvate of the compound of formula (I).

These medicaments find use in therapy, in particular in the treatment of cancers. They are particularly active in the treatment of solid cancers such as breast and ovarian cancers.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, a hydrate or a solvate of the said compound, and at least one pharmaceutically acceptable excipient.

The said excipients are chosen, according to the pharmaceutical dosage form and the desired mode of administration, from the customary excipients which are known to persons skilled in the art.

In the pharmaceutical compositions of the present invention for subcutaneous, intramuscular or intravenous administration, the active ingredient of formula (I) above, or its possible solvate or hydrate, may be administered in unit dosage form, mixed with conventional pharmaceutical excipients, to animals and to human beings for the treatment of cancer diseases or disorders.

The appropriate unit dosage forms comprise the forms for parenteral, in particular subcutaneous, intramuscular or intravenous administration.

By way of example, a unit dosage form for a compound according to the invention in the form of a solution may comprise the following components:

Compound according to the invention 10 to 100 mg

Water for injection 2 to 20 ml

According to another embodiment of the invention, the compound may be provided in the form of a lyophilisate.

It is preferable to use the compounds according to the invention intravenously at doses of between 10 and 200 mg/m ² . There may be special cases where higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention. According to the usual practice, the dosage appropriate for each patient is determined by the doctor according to the mode of administration, the weight and the response of the said patient.

The present invention, according to another of its aspects, also relates to a method for treating the pathologies indicated above, which comprises the

administration, to a patient, of an effective dose of a compound according to the invention, in the form of a free base, of an hydrate or of a solvate.