CZ305411B6 - Platinum dichloride complexes containing kinetin derivatives, process for their preparation and their use as medicaments in antitumor therapy - Google Patents

Abstract

In the present invention, there are disclosed platinum dichloride complexes in the oxidation stage +II and crystalline solvates thereof comprising a structural motif (I) of the general formula (II) or (III) and expressed by structural formula cis-[PtCli2(L)i2] II or cis-[PtCli2(L)(L´)], wherein the symbols L and L´ represent kinetin (N6-furfuryladenine) and/or a derivative thereof of the general formula (IV) bound to a platinum atom via a nitrogen atom of adenine skeleton N7; a process for their preparation, a pharmaceutical composition containing thereof and their use in the treatment of tumor diseases.

Description

Technical field

The present invention in the field of platinum-based cancer drugs relates to cis-dichlorido complexes of platinum with kinetin (N6-furfuryladenine) and its derivatives, a process for their preparation starting from M ₂ [PtCl ₄ ], wherein M is Η, K, or Na , and their use in medical practice as medicaments and pharmaceutical compositions containing these complexes as an active ingredient for the treatment of cancer.

BACKGROUND OF THE INVENTION

The present platinum (II) complexes can be classified as structurally derived from cisplatin. Cisplatin, czs- [Pt (NH ₃ ) ₂ Cl ₂ ] (formula A), is a simple planar platinum complex in oxidation state II, to which two chloride, leaving in physiological environment and two ammin, ("carrier"), ligands. It is one of the longest and most commonly used platinum-based drugs as an active ingredient of pharmaceutical compositions in anticancer therapy. It is active mainly in the treatment of rapidly growing tumors and their cytostatic effects are used in medical practice mainly in the treatment of tumors of the urogenital tract and small cell lung cancer. Several thousands of cisplatin analogues have been synthesized and tested following the introduction of cisplatin in cancer practice in an attempt to increase the therapeutic index and suppress unwanted side effects, particularly nephrotoxic, neurotoxic and ototoxic. To date, however, only five substances in this group have completed clinical trials and have entered therapeutic practice, either globally or in some countries. These are platinum complexes:

diamino-1,1'-cyclobutanedicarboxylate platinum (complex carboplatin, formula B), (17?, 27?) - 1,2diaminocyclohexane oxalate platinum complex (oxaliplatin, formula C), czs-diammin glycollate platinum complex (nedaplatin ·, formula D , approved for therapeutic use only in Japan so far), [57- 4-2- (1R-trans)] (1,2-bis-aminomethylcyclobutane-N, N ') [hydroxypropaonato (2-) O, O '] platinum complex (lobaplatin, formula E, approved for therapeutic use only in South Korea so far), en.s-malonate - [(47?, 57?) - 4,5-bis (aminomethyl) -2-isopropyl-1] 3-dioxolane-TV, 7V '] platinum complex (heptaplatin, formula F, approved for therapeutic use in China only). Ongoing research into platinum complexes has clearly demonstrated that the presence of an analogous structural motif as in cisplatin is not enough to be useful and effective in the treatment of cancer. For a significant cytotoxicity of cisplatin derivatives, a suitable combination of the leaving (i.e. "ezzvzzzg") and the carrier N-donor (ligand) ligands is essential in their composition and structure. It should be emphasized that the qualitative, but also quantitative aspect of the interaction with the target nitrogenous bases of DNA (especially guanine and adenine) is not only related to the formation of a covalent bond between platinum ion (specifically {Pt (NH ₃ ) ₂ } ²⁺ for cisplatin) and nitrogen bases in DNA, but also with interactions of other nature (especially electrostatic interactions with other sites on the DNA strand and hydrogen bonds), which contribute significantly to the overall cytotoxic action of a particular platinum complex.

- 1 GB 305411 B6

NH4 (Cl2) m.p.

O

C

O

D

E

F

The present cis-dichloroid platinum complexes are linked to previously published platinum complexes of the general formula cis / [Pt (Bap) ₂ Cl ₂ ], in which N6-benzyladenine derivatives act as A-donor ligands (Bap) as described in Z publications. Travnicek et al., J. Inorg. Biochem. 94, 2003, 307-316; M. Maloň et al., J. Inorg. Biochem. 99, 2005, 2127-2138, L. Szucova et al., Bioorg. Copper. Chem. 14, 2006, 479-491; L. Sziičová et al., Polyhedron 27, 2008, 2710-2720, optionally for platinum complexes of the general composition czs- [Pt (Aza) ₂ Cl ₂ ], in which halogen-derivatives of 7- azaindole as described by P. Starha et al., J. Inorg. Biochem. 115, 2012, 57-63, and CZ 303560 and CZ 303417. The previously prepared cis-dichlorido complexes of platinum with various A-donor ligands published in the available patent literature are detailed in CZ 303417.

The present cA-dichlorido complexes of platinum with kinetin (N6-furfuryladenine) and its derivatives represent a completely new group of biologically active platinum complexes not previously described in the literature. These complexes are examples of cisplatin derivatives that differ from the parent compound by the use of carrier A-donor ligands with intrinsic biological activity that structurally replace both NH ₃ molecules in cisplatin. Kinetin itself is one of the plant hormones cytokinins that play key roles in various physiological processes, such as cell division, cell cycle regulation, or in response to plant stress or senescence. Kinetin was then found a number of effects, which are manifested in the human body. For example, kinetin has been shown to protect against oxidative damage to both DNA and proteins (A. Olsen et al. Biochem. Biophys. Res. Commun. 265,1999,499; P. Verbeke et al. Biochem. Biophys. Res. Commun. 276 , 2000, 1265), platelet damage in vitro and the formation of blood clots in vivo (G. Hsiao et al. Eur. J. Pharmacol. 465, 2003, 281). Especially due to its proven anti-aging effects, kinetin has found application as an active ingredient in various cosmetic products. It has been found to slow down aging not only in plants but also in the fruit fly Zaprionus paravittiger (SP Sharma et al. Biochem. Biophys. Res. Commun. 216, 1995, 1067-1071) and in particular in human fibroblasts (SIS Rattan, BFC Clark, Biochem Biophys Res Commun., 201, 1994, 665-672, SIS Rattan, J. Anni-Ageing Med. 5, 2002, 113-116, US 5371089). To date, a number of differently substituted kinetin derivatives have been prepared, as described, for example, in US 2008009508, CZ 303 054, and some exhibit more pronounced anti-aging activity of human fibroblasts than kinetin alone.

To date, no platinum complexes in the oxidation state +11 have been described in the literature that would contain a kinetin molecule and / or a derivative thereof in their structure. So far, only one Pt (IV) complex with a protonated kinetin molecule [PtCl ₅ (kinetinH *)] has been described (J. Vícha et al. Inorg. Chem. 51,2012, 1371).

-2 CZ 305411 B6

The present invention provides platinum complexes with kinetin and its derivatives that are cytotoxically active on a broad spectrum of human tumor lines in vitro, comparable or significantly more than the currently clinically used cisplatin drug. In addition, they are effective on both tumor sensitive and cisplatin resistant lines. Thus, the disclosed complexes may represent promising antitumor drugs that have been produced by combining antitumor inactive or low active components.

SUMMARY OF THE INVENTION

The present invention relates to the cis -dichlorido complexes of platinum in the oxidation stage +11 and their crystallosolvates comprising the structural motif (I) of formula (II) or (III) and represented by the formula cis [PtCl ₂ (L) ₂ ] or cis - [PtCl ₂ (L) (L ')], wherein L and L' are kinetin (N6-furfuryladenine) and its derivatives of formula (IV) bonded to a platinum atom via the nitrogen atom of the adenine backbone N7, wherein R1 is independently selected from the group :

- hydrogen, halogen, R2 is then independently selected from:

a hydrogen atom, a halogen, an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a functional group;

R 3 is independently selected from:

- a hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, functional group and an N-R'R 'group, wherein R 'and R' independently represent a hydrogen atom, an alkyl, a substituted alkyl, wherein the term:

- halogen represents a fluorine, chlorine, bromine or iodine atom,

- alkyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 18, in particular of 1 to 8 carbon atoms,

- alkenyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 18, in particular of 2 to 8, carbon atoms containing at least one carbon-carbon double bond,

- alkynyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 18, in particular of 2 to 8, carbon atoms containing at least one carbon-carbon triple bond,

-3 CZ 305411 B6

- cycloalkyl as such or as part of another group represents a cyclic hydrocarbon of 3 to 12, in particular of 3 to 8 carbon atoms, including fused cycles independently selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl,

- cycloheteroalkyl as such or as part of another group represents cycloalkyl having at least one carbon atom exchanged for a heteroatom selected from nitrogen, oxygen or sulfur,

- cycloalkenyl as such or as part of another group represents a cycloalkyl containing at least one carbon-carbon double bond,

- cycloheteroalkenyl as such or as part of another group represents cycloheteroalkyl containing at least one double bond between two carbon atoms, a carbon atom and a heteroatom, or two heteroatoms,

- the functional group as such or as part of another group represents amino, alkylamino, dialkylamino, alkenylamino, cycloalkylamino, cycloheteroalkylamino, cycloalkenylamino, cycloheteroalkenylamino, hydroxy, alkylhydroxy, alkoxy, carboxy, alkylcarboxy, carboxyalkyl,

substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloheteroalkyl, substituted cycloalkenyl, substituted cycloheteroalkenyl as such or as part of other groups represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, substituted substituents from halogen, alkyl , alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, and a functional group.

^L </ ^Cl Pt tS ^ Cl

III

-4GB 305411 B6

Another object of the invention are crystal-cz.s dichloride complexes of platinum, wherein within the general formula cž5- [PtCl ₂ (L) _2] or -xSolv c «- _[PtCl2 (L) (L ')] - xSolv indicates (in ) the number of crystal molecules, in particular 1 to 6, and (Solv) is a particular solvent molecule selected from water, primary alcohol, secondary alcohol, acetone, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, acetonitrile or diethyl ether and / or any of the reaction components, either alone or in combination of said solvate molecules.

The present invention also provides a process for the preparation of cis -dichloride platinum complexes, wherein the compound of formula (II) represented by formula cz's- [PtCl ₂ (L) ₂ ] or formula (III) represented by formula cz.s- [PtCl ₂ (L) (L ')] is prepared by reacting an alkali tetrachloridoplatinate or the corresponding acid of general formula M ₂ [PtCl ₄ ], wherein M comprises mainly H, k and Na, with kinetin or a derivative thereof.

In a preferred embodiment, a compound of formula (II) represented by formula cis- [PtCl ₂ (L) ₂ ] or formula (III) represented by formula czs- [PtCl ₂ (L) (L ')] is prepared by first reacting together two molar equivalents of kinetin or its derivative (L and / or L ') dissolved at 10 to 70 ° C in a solvent selected from the group of primary or secondary alcohols or acetone, with one molar equivalent of compound M ₂ [PtCl ₄ ], where M represents Η, K or Na, dissolved in distilled water at 10 to 90 ° C, then the reaction mixture is stirred for one to seven days at -20 to 70 ° C, after which the resulting product is filtered off, washed with the solvents used and dried .

An integral part of the invention is a pharmacological composition comprising a therapeutically effective amount of cis-dichlorido platinum complexes with one or more acceptable carriers and excipients for use in medicine for the preparation of a medicament for the treatment of cancer.

Clarification of drawings

Specific embodiments of the invention are illustrated by the accompanying drawings, in which:

- Figure 1 is an IR spectrum (400-4000 cm ^-1 measured by ATR technique) of the cis [PtCl ₂ (L ') ₂ ] -H ₂ O complex,

- Fig. 2 is an IR spectrum (region 250-600 cm ^-1 measured by the technique ATR) cz's- [PtCl2 (L ²⁾ 2] ₂ O -0,75H,

Fig. 3 is the molecular structure of the czs- [PtCl ₂ (L ¹ ) ₂ ] -H ₂ O complex solved using single crystal X-ray structure analysis, hydrogen atoms being shown only in the water molecule; they are not displayed in the complex molecule for clarity,

Fig. 4 is a representation of the thermal decomposition of the cz's- [PtCl ₂ (L ² ) ₂ ] -0.75 H ₂ O complex by the methods of thermogravimetry (TG) and differential thermal analysis (DTA),

Fig. 5 is a graph of zzz vitro antitumor activity of [alpha] 5- [PtCl ₂ (L ¹ ) 2] -H 2 O (1), cis [PtCl ₂ (L ² ) 2] -0.7 H ₂ O (2) human breast adenocarcinoma tumor line (MCF7) and their comparison with cisplatin. L ¹ = 2-chloro-N 6 -furfuryl-9-isopropyladenine, L ² = 2-chloro-N 6 - (5-methylfurfuryl) -9-isopropyladenine,

Fig. 6 is a graph of zzz vitro antitumor activity of the cz'5- [PtCl ₂ (L ¹ ) 2] -H 2 O (1), cis [PtCl ₂ (L ² ) 2] 0.75H ₂ O (2) complexes against human tumor the osteosarcoma line (HOS) and their comparison with cisplatin; L ¹ = 2-chloro-N 6 -furfuryl-9-isopropyladenine, L ² = 2-chloro-N 6 - (5-methylfurfuryl) -9-isopropyladenine,

-5 CZ 305411 B6

Figure 7 is a graph of the in vitro antitumor activity of the czs- [PtCl ₂ (L ') ₂ ] -H ₂ O (1), cis [PtCl ₂ (L ² ) ₂ ] -0.75H ₂ O (2) complexes against human cancer cell line melanoma (G361) and their comparison with cisplatin · L ¹ = 2-chloro-N6-furfuryl-9-isopropyladenine L ² = 2-chloro-N6- (5-methylfurfuryl) 9-isopropyladenine,

Fig. 8 is a graph of in vitro anti-tumor activity of the czs- [PtCl ₂ (L ¹ ) 2] -H 2 O (1), cis [PtCl ₂ (L ² ) 2] -0.75 H ₂ O (2) complexes against the human tumor line. ovarian cancer (A2780) and their comparison with cisplatin; L ¹ = 2-chloro-N 6 -furfuryl-9-isopropyladenine, L ² = 2-chloro-N 6 - (5-methylfurfuryl) -9-isopropyladenine,

Fig. 9 is a graph of the in vitro antitumor activity of the czs- [PtCl ₂ (L ') ₂ ] -H ₂ O (1), cis [PtCl ₂ (L ² ) ₂ ] -0.75 H ₂ O (2) complexes against the human czs / z / zZzZzz-resistant ovarian carcinoma (A2780R) human tumor line and their comparison with cisplatin; L ¹ = 2-chloro-N 6 -furfuryl-9-isopropyladenine, L ² = 2-chloro-N 6 - (5-methylfurfuryl) -9-isopropyladenine.

DETAILED DESCRIPTION OF THE INVENTION

In the following, the invention is illustrated, but not limited, by specific examples thereof. The scope of the invention is then clearly limited by the claims.

In the examples below, the prepared compounds were characterized by the following physicochemical methods:

Elemental analysis (Flash 2000 CHNS, Thermo Scientific);

• infrared spectroscopy, where the regions 250 to 600 cm ^-1 (far-IR) and 400 to 4000 cm ^-1 (mid-1R) were performed by the ATR technique (Nexus 670 FT-IR, Thermo Nicolet), • nuclear magnetic resonance (NMR ) DMF0 complex solutions - * H, ¹³ C, ¹⁹⁵ Pt, Η- ¹ ! gs-COZY, ¹ H- ¹³ C gs-HMQC, 1 H- ¹³ C gs-HMBC experiments (400 MHz NMR spectrometer, Varian);

• thermal analysis with thermogravimetry (.TG) and differential thermal analysis (DTA) (Exstar TG / DTA 6200 thermal analyzer (Seiko Instruments));

• single crystal X-ray structure analysis (Xcalibur ™ 2 diffractometer, Sapphire2 CCD detector, MoΚδ radiation, Oxford Diffraction).

Example 1: Synthesis and characterization of cis-{dichlorido-bis (2-chloro-N6-furfuryl-9-isopropyladenine) platinum (II) cis- [PtCl ₂ (L ') ₂ ] H ₂ O:

0.5 mmol of K ₂ [PtCl ₂ ] was dissolved in a minimum volume of distilled water at room temperature and added to two molar equivalents (1 mmol) of 2-chloro-N 6 -furfuryl-9-isopropyladenine (L ¹ ) dissolved at room temperature. the minimum volume of acetone according to Scheme 1.

-6GB 305411 B6

Cl

Scheme 1

The reaction mixture was stirred for five days at room temperature. Light beige product, cis [PtCl ₂ (L ¹ ) 2] H ₂ O, depicted including the numbering of the atoms of Formula 1 formed during the reaction, was filtered, washed several times with distilled water, diethyl ether and then dried in a desiccator over P4O10 .

Formula 1

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂₆ H ₃₀ N ₁₀ Cl ₄ 0 ₃ Pt: C, 36.00 (35.58); H, 3.49 (3.15); N, 16.15 (15.83)%. far-IR (PXTR / cm &lt; -1 ^&gt; ): 335, 345, 404, 431, 484, 495, 527, 541. mid-IR (f _ATR / cm &lt; -1 &gt;): 520, 597, 635, 667, 737, 784, 813, 885.933, 1009, 1069, 1112, 1142, 1165, 1225, 1318, 1341, 1495, 1460, 1482, 1501, 1539, 1580, 1615, 2876, 2936, 2960, 3059, 3116, 3328. DMF-d _7, SiMe _4, ppm): δ 9.42 (bs. CBH, 1H); 9.27 (t, 7.2 Hz, N 6aH, 1H), 7.61 (s, CBH, 1H), 6.43 (mm, Cl 1.12H, 2H); 4.98 (bs, C 9 H,

2H); 4.82 (sep, 6.2 Hz, C 15 H, 1H); 1.58 (d, 6.5 Hz, C16, 17H, 6H). ¹³ C NMR (DMF-γ, SiMe ₄ , ppm): δ 154.50 (C6); 153.59 (CIO); 152.19 (C4); 149.49 (C2); 142.76 (03); 142.00 (C8); 115.96 (C5); 110.75 (02); 107.44 (CI); 49.16 (05); 38.24 (C9); 21.70 (06.17). ¹⁹⁵ PTNMR (DMF-4 K ₂ PtCl _4, ppm): δ -2020.55.

-7 GB 305411 B6

Example 2: Synthesis and characterization of cis-{dichlorido-bis (2-chloro-N6- (5-methylfurfuryl) -9-isopropyladenine)) platinum (II) cis- [PtCl ₂ (L ² ) ₂ ] -0.75H ₂ O:

0.5 mmol of K ₂ [PtCl ₄ ] was dissolved in a minimum volume of distilled water at room temperature and added to two molar equivalents (1 mmol) of 2-chloro-N 6 - (5-methylfurfuryl) -9-isopropyladenine (L ² ) dissolved at room temperature in a minimum volume of acetone. The reaction mixture was stirred for one day at room temperature. The light beige product, cz's- [PtCl ₂ (L ² ) 2] -0.75H ₂ O, depicted including the atom numbering of Formula 2 formed during the reaction, was filtered, washed several times with distilled water, diethyl ether and then dried in of desiccator over P ₄ Oi ₀ .

Formula 2

Percentage of elements C, Η, N in the form: calculated value (found in parentheses) for C ₂₈ H ₃₃ , ₅ N ₁₀ O ₂ , ₇₅ Cl ₄ Pt: C, 37.74 (37.34); H, 3.79 (3.51); N, 15.72 (15.57)%. far-IR (λΑ / κ ¹ ): 219,314,335,343,410,427,493, 505,518, 546. mid-IR TyiR / cm ¹ ): 546, 619, 635, 670, 783, 812, 889, 932, 949, 1019, 1076, 1109, 1136 , 1164, 1225, 1261, 1318, 1340, 1373, 1406, 1462, 1484, 1538, 1581, 1615, 2681, 2936, 3061, 3112, 3291, 3345. 1 H NMR (DMF- d 7, SiMe 4, ppm): δ 9.43 (bs, C 8 H, 1H); 9.24 (t, 6.1 Hz, N 6aH, 1H); 6.28 (s, C 12 H, 1H); 6.01 (d, 2.8 Hz, C 11 H, 1H); 4.93 (bs, C 9 H, 2H); 4.81 (sep, 6.9 Hz, C 15 H, 1H); 2.29 (s, C 18 H, 3 H); 1.58 (d, 6.6 Hz, C16, 17H, 6H). ¹³ C NMR (DMF-? -, SiMe 4, ppm): δ 154.51 (C6); 153.55 (CIO); 151.49 (C13); 150.05 (C4); 149.44 (C2); 141.92 (C8); 115.93 (C5); 108.41 (Cl2); 106.62 (CI); 49.17 (Cl5); 38.39 (C9); 21.66 (Cl6.17); 13.03 (C18). ¹⁹⁵ Pt NMR (DMF- ₄₇ , K ₂ PtCl ₄ , ppm): δ-2021.65.

Example 3: In vitro cytotoxic activity of novel compounds on human tumor lines

Microtiter analysis using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) was used to determine the cytotoxic activity of the prepared complexes. Viable cells are detected by the assay and their number corresponds to the amount of reduced MTT. In vitro antitumor activity tests were performed on the following human tumor cell lines: breast adenocarcinoma (MCF7), osteosarcoma (HOS), malignant melanoma (G361), ovarian carcinoma (A2780), czsptozzz-resistant ovarian carcinoma (A2780R). The lines were maintained in plastic bottles in DMEM medium (5 g / L glucose, 2 mM glutamine, 100 U / ml penicillin, 100 µg / ml streptomycin, 10% fetal calf serum and sodium bicarbonate) for cell cultures. Cell suspensions (ca 1.25 χ 10 ⁵ cells ml ^-1 ) were pipetted at 80 µl onto ninety-six well microtiter plates. These were preincubated at 37 ° C in a CO ₂ atmosphere for 24 hours. Platinum (II) dichloride complexes and cisplatin tested were pre-dissolved in N-dimethylformamide, diluted to a concentration of 50.0 mM, and these served as stock solutions. For the experiment, the stock solutions were diluted 1 000x in the culture medium to a maximum concentration of 50.0 μΜ. After aspirating the culture medium, the mixture of individual test substances was added to the preincubated tumor cell suspension. The mixtures were then incubated for 24 h at 37 ° C, 100% humidity and CO ₂ . MTT solution was then added followed by incubation for 1 hour. MTT analysis was performed spectrophotometrically (TECAN, Schoeller Instruments LLC) at 540 nm.

The inhibitory concentrations of test complexes IC 50 (μΜ), corresponding to the concentration of test substances required to inhibit the growth of 50% of the inserted tumor cells, were calculated from the dose curves and are shown in Table 1.

Table 1 .: In vitro cytotoxicity results of prepared platinum dichloride complexes with kinetin derivatives (L ¹ , L ² ) expressed as inhibitory concentration IC 50 values (μΜ) and their comparison with cisplatin and uncoordinated organic molecules 2-chloro-N6-furfuryladenine (L ¹ ) and 2-chloro-N6- (5-methylfurfuryl) adenine (L ² )

Complex MCF7 HOS G361 A2780 A2780R czs- [PtCl ₂ (H ₂ ) -H ₂ O (1)] 18,013,5 14,614,7 3,810,2 4,510,3 3,910,8 CZ5- [PtCl ₂ (L ² ) ₂ ] -0.75H ₂ O (2) 23,414,9 12,215,0 4,010,6 5,611,0 2,710.6 Císplatína 20,014,8 29,115,5 5,812,4 15,112,1 28,715,4 L ¹ > 50 > 50 > 50 > 50 > 50 1? > 50 > 50 > 50 > 50 > 50

PATENT CLAIMS

Claims (6)

C ₂ -dichlorido complexes of platinum in the oxidation state + II and their crystallosolvates comprising the structural motif (I) of the general formula (II) or (III) and represented by the formula cz.?-[PtCl ₂ (L) ₂ ] or cis [PtCl ₂ (L) (L ')], wherein L and L' represent kinetin (N 6 -furfuryladenine) and its derivatives of general formula (IV) bonded to a platinum atom via a nitrogen atom N 7, (Cl L) Pt Pt Pt i / \; i ιΖ \: ι \ S \ ιι I II III Wherein R 1 is independently selected from: hydrogen, halogen; R2 is then independently selected from: a hydrogen atom, a halogen, an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a functional group; R 3 is independently selected from: - a hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, functional group and an N-R'R 'group, wherein R 'and R' independently represent a hydrogen atom, an alkyl, a substituted alkyl, wherein the term: - halogen represents a fluorine, chlorine, bromine or iodine atom, - alkyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 18, in particular of 1 to 8 carbon atoms, - alkenyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 18, in particular of 2 to 8, carbon atoms containing at least one carbon-carbon double bond, - alkynyl as such or as part of another group represents a branched or unbranched hydrocarbon chain of up to 18, in particular of 2 to 8, carbon atoms containing at least one carbon-carbon triple bond, - cycloalkyl as such or as part of another group represents a cyclic hydrocarbon of 3 to 12, in particular of 3 to 8 carbon atoms, including fused cycles independently selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, - cycloheteroalkyl as such or as part of another group represents cycloalkyl having at least one carbon atom exchanged for a heteroatom selected from nitrogen, oxygen or sulfur, - cycloalkenyl as such or as part of another group represents a cycloalkyl containing at least one carbon-carbon double bond, - 10GB 305411 B6 - cycloheteroalkenyl as such or as part of another group represents cycloheteroalkyl containing at least one double bond between two carbon atoms, a carbon atom and a heteroatom, or two heteroatoms, - the functional group as such or as part of another group represents amino, alkylamino, dialkylamino, alkenylamino, cycloalkylamino, cycloheteroalkylamino, cycloalkenylamino, cycloheteroalkenylamino, hydroxy, alkylhydroxy, alkoxy, carboxy, alkylcarboxy, carboxyalkyl, - substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloheteroalkyl, substituted cycloalkenyl, substituted cycloheteroalkenyl as such or as part of other groups represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, substituted halogen substituents, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, and a functional group. The crystalline solvates of the cis-dichloroid platinum complexes according to claim 1, wherein for compounds of the general formula cz's- [PtCl ₂ (L) ₂ ] -xSolv or cz's- [PtCl ₂ (L) (L ')] - xSolv indicates (x) the number and (Solv) is a particular solvent molecule selected from water, primary alcohol, secondary alcohol, acetone, on, Ν'-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, acetonitrile or diethyl ether and / or any of the reaction components, either alone or in combination of said solvate molecules. Process for the preparation of the cis-dichloroid platinum complexes according to claim 1, characterized in that the compound of formula (II) represented by formula czs- [PtCl ₂ (L) ₂ ] or of formula (III) represented by formula cz.s- [ PtCl ₂ (L) (L ')] is prepared by reacting an alkali tetrachloridoplatinate or the corresponding acid of general formula M ₂ [PtCl ₄ ], where M comprises in particular Η, K and Na, with kinetin or a derivative thereof. A process according to claim 3, characterized in that the compound of formula (II) represented by the formula cz's- [PtCl ₂ (L) ₂ or of formula (III) represented by the formula czs- [PtCl ₂ (L) (L) ')] prepared by first reacting two molar equivalents of kinetin or a derivative thereof dissolved at 10 to 70 ° C in a solvent selected from the group of primary or secondary alcohols or acetone, with one molar equivalent of compound M ₂ [PtCl ₄ ], M represents Η, K. or Na, dissolved in distilled water at 10 to 90 ° C, then the reaction mixture is stirred for one to seven days at -20 to 70 ° C, and then the resulting product is filtered off, washed with used solvents and dried. A pharmaceutical composition comprising a therapeutically effective amount of the cis-dichlorido complexes of platinum according to claim 1 with one or more acceptable carriers and excipients. Use of a pharmacological composition according to claim 5 for the preparation of medicaments for the treatment of cancer.