ES2257178A1 - Set of platinum based anti tumor compounds consists of a halogen and amine ligands system - Google Patents

Abstract

The set of platinum-based anti-tumour compounds comprises trans-(PtCl2(isopropylamine)(4-hydroxymethyl)-pyridine)) and trans-(PtCl2(isopropylamine)(3-hydroxymethyl)-pyridine)). Also claimed is a process using the compounds. CLAIMED PROCESS - The process applies amine ligands (L',L), with a trans arrangement round the platinum atom. EMBODIMENT - The product has the formula PtX1L1>L2>, where X is a halogen.

Description

Platinum compounds of the formula trans - [PtCl2 (isopropylamine) (4- (hydroxymethyl) -pyridine)] and trans - [PtCl2 (isopro-
Pilamine) (3- (hydroxymethyl) -pyridine)] and its application as an antitumor drug.

Field of the Invention

The present invention comprises the trans platinum compounds of the general formula trans - [PtCl 2 (isopropylamine)
na) (3- (hydroxymethyl) -pyridine)] and trans - [PtCl2 (isopropylamine) (4- (hydroxymethyl) -pyridine)], the pharmaceutical compositions containing them, their method of preparation and their use for Preparation of a drug with antitumor activity.

Background of the invention

The use of platinum complexes in chemotherapy of cancer is widely described in the literature and accepted in cancer practice. [Cisplatin, Bernarhd Lipper Ed. Willey-VCH 1999; Platinum-Based Drugs in Cancer Therapy, Kelland, L. and Farrell, N. Humana Press 2000] Especially composed as cisplatin in treatment of ovarian, testicular and even some small cancers of lung

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Treatment with cisplatin often causes serious side effects such as nephrotoxicity, ototoxicity and myelosuppression. These are disadvantages that create an important clinical problem aggravated by the resistance acquired by many tumors that become immune to these drugs. There are three mechanisms of resistance to platinum compounds: 1) Repair of the lesions suffered in the DNA by the covalent attachment of the compounds. 2) High intracellular concentration of glutathione, which can be coordinated by the thiol group to Pt and decrease the amount of it that becomes bound to DNA. 3) Reduction of entry or increase

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Despite multiple attempts at synthesis in various laboratories, there is still a need to successfully obtain drugs that avoid the problem of acquired resistance and nephrotoxicity. From the therapeutic point of view it has been confirmed that only the cis - [PtCl 2 (NH 3) 2] (cisplatin) isomer has antitumor activity, the trans isomer being inactive. The cause seems to be that, once a monofunctional adduct with the DNA is formed, the trans isomer undergoes a cross-linking with the glutathione at a faster rate than the cis isomer resulting in the deactivation of the complex. In the case of the trans isomer, a different interaction against DNA has also been observed: the formation of GC intercatenary junctions [Leng, M. and Brabec, V. Proc. Natl Acad. Sci., (1993), 90, 5345].

In recent years, it has been published that platinum complexes with trans geometry exhibit cytotoxic activity; this is the case of monomers with aromatic ligands such as pyridines [Farrell et al. J. Med. Chem, (1989), 32, 51], with iminoethers [Coluccia et al. J. Med. Chem, (1993), 36, 510], with aliphatic amines [Pizarro, AM et al. Angew Chem. 2003, 115, 5497; Pérez, JM et al. J. Med. Chem. (2000) 43, 2411] and dimers and trimers that have resulted in numerous publications [Farrell, N. Comments Inorg.Chem. 1995, 16 373] and even some patents [WO 95/26968, US6,313,333-Multinuclear cationic platinum complexes with antitumor activity; US6,011,166-Trinuclear cationic platinum complexes having antitumor activity and pharmaceutical compositions containing them, US006,011,166-Water soluble transplatinum complexes with anticancer activity and method of using same].

Other patents related to the subject have been published several times, such as [ES2160466- trans - [PtCl2 (N, N-Dimethylamine) (Isopropylamine)]; ES2181603-Complexes for synthesis of the compounds of the general formula trans - [PtCl2 L (PPh3)] with antitumor activity; ES2181602-Pt (IV) complex with antineoplastic activity; trans - (PtCl 2 (OH) 2 (Dimethylamine) (Isopropylamine)] applicable as an antitumor; ES2214138- Trans platinum (IV) compounds of formula trans , trans , trans - [PtCl 2 (OH) 2 (amine)] with antitumor activity] More recently, the number of patents has grown considerably, such as, for example, platinum derivatives with piperidine and pyrrolidine ligand [WO, 03/017998], derivatives with adamantane ligands [WO99 / 674541] Even some existing patents have expanded their development in other countries [CA2366048-Water soluble transplatinum complexes with anticancer activity and method of using same].

The importance of these results is fundamental, since some of the previously mentioned compounds show high activity in vitro and in vivo against tumor cells resistant to cisplatin. Thus, it can be said that the cytotoxic effects of trans complexes must follow patterns very different from those of cisplatin.

Description of the invention

In the present invention, the synthesis and characterization of the new trans- and trans- [PtCl2 (isopropylamine) (4- (hydroxymethyl) -pyridine)] complexes is presented. These complexes have a high cytotoxicity in cisplatin resistant cell lines such as A2780 cisR and CH1 cisR.

Description of the drawings and tables

Figure 1.- represents the ORTEP diagram (Oak Ridge Thermal Ellipsoid Plot) obtained by diffraction of complex x-rays complex trans- [PtCl2 (isopropylamine) (3- (hydroxymethyl) -pyridine)] and its corresponding table with the most significant data referring to distances and angles.

Figure 2.- represents the ORTEP diagram obtained by X-ray diffraction of the trans- [PtCl2 (isopropyl-) complex
mine) (4- (hydroxymethyl) -pyridine)] and its corresponding table with the most significant data regarding distances and angles.

Preferred Embodiment of the Invention

Platinum compounds of general formula trans- [PtCl2 (isopropylamine) (3- (hydroxymethyl) -pyridine)] Y trans- [PtCl2 (isopropylamine) (4- (hydroxymethyl) -pyridine)], and its use for the preparation of an active medication antitumor, incorporate a synthesis procedure constituted to from the following:

1. Synthesis of the complexes trans- [PtCl2 (isopropylamine) (3- (hydroxymethyl) -pyridine)] and trans- [PtCl2 (isopropylamine) (4- (hydroxymethyl) pyridine)]

A suspension of cis - [PtCl 2 (isopropylamine) 2] (0.390 mmol, 150 mg) in water (3 mL) is treated with 4 equivalents of 3- (hydroxymethyl) -pyridine or 2 equivalents of 4- (hydroxymethyl) -pyridine. The mixture is stirred for 3 hours at 85 ° C, until the reaction mixture becomes a yellow solution. The yellow solution is cooled to room temperature. Hydrochloric acid (12 M, 0.5 mL) is added and the reaction is stirred for 48 hours at 85 ° C. After cooling this reaction to room temperature, the solution is dried under vacuum. Wash the resulting solid with CHCl3, dissolving the complex of interest. We remove the chloroform and add a small amount of water slowly appearing a yellow precipitate overnight. The solid is washed with cold water and then with ethyl ether.

trans- [PtCl2 (isopropylamine) (3- (hydroxymethyl) -pyridine)] . (Yield: 30%): ν (Pt-Cl): 340 cm -1, FAB-MS
434.236 Elemental analysis for C9 H16 {ON} {2} PtCl2 Calculated: C: 24.89, H: 3.71, N: 6.45. Found: C: 24.53, H: 3.72, N: 6.49. 1 H NMR (300 MHz, CDCl 3, 25 ° C) (ppm): 1.45 d 6H (CH 3), 2.08 t 1H (CH 2 O H ), 3.43 hp 1H (CH), 3.52 bs 2H (NH 2), 4.72 d 2H (C H 2 OH), 7.26 m 1H ( meta ), 8.78 m 1H ( para ), 8.89 m 2H ( ortho ). 13 C NMR (300 MHz, CDCl 3, 25 ° C) (ppm): 152.20 (C5), 151.70 (C4), 138.48 (C3), 136.49 (C2), 124.91 (C6), 61.57 ( C H_ {2} OH), 48.99 (CH), 23.99 (CH 3) 195 Pt NMR (300 MHz, CDCl 3, 25 ° C) (ppm): - 2091.7. ORTEP diagram and X-ray data in figure 1.

trans- [PtCl2 (isopropylamine) (3- (hydroxymethyl) -pyridine)] . (Yield: 38%): ν (Pt-Cl): 339 cm -1, FAB-MS
434.236, Elemental analysis for C 9 H 16 ON 2 PtCl 2 Calculated: C: 24.89, H: 3.71, N: 6.45. Found: C: 24.52, H: 3.72, N: 6.47. 1 H NMR (300 MHz, CDCl 3, 25 ° C) (ppm): 1.45 d 6H (CH 3), 2.1 t 1H (CH 2 O H ), 3.45 hp 1H (CH), 3.48 bs 2H (NH 2), 4.76 d 2H (C H 2 OH), 7.26 m 2H ( meta ), 8.78 d 2H ( ortho ). 13 C NMR (300 MHz, CDCl 3, 25 ° C) (ppm): 152.53 (C3 and C5), 155.19 (C4), 122.62 (C2 and C6), 62.59 ( C H 2 OH), 48.69 (CH), 24.01 (CH 3). 195 Pt NMR (300 MHz, CDCl3, 25 ° C) (ppm): -2090.9. ORTEP diagram and X-ray data in figure 2.

2. Cytotoxicity test.

Cell death was assessed using a system. based on the tetrazolium MTT compound, which is reduced by living cells to produce a soluble formazan product that can be detected colorimetrically [Alley M. C. et al, Cancer Res. 48 (1988) 589; Ramos-Lima F. J. et al, Polyhedron 22 (2003) 3379-3381].

The first application of this invention relates to the discovery of the antitumor activity of the compounds trans - [PtCl 2 (isopropylamine) (3- (hydroxymethyl) -pyridine)] and trans- [PtCl 2 (isopropylamine) (4 - (hydroxymethyl) -pyridine)]. These complexes are capable of overcoming resistance to cis-DDP in the A2780 cisR and CH1 cisR cell lines, as well as showing some cytotoxicity in cell lines not resistant to the above, as can be seen in the IC 50 values represented in The following table:

A2780 A2780cisR CH1 CH1cisR Complex of Figure 1 12.4 \ pm 0.8 7.5 ± 0.4 23.4 ± 0.3 15.8 \ pm 0.3 Complex of Figure 2 11.6 \ pm one 8.4 ± 0.5 20.1 ± 0.3 15.9 ± 0.3 cis-DDP 2.2 \ pm 0.4 38 ± 4 6 ± 1 23 \ pm 3 trans-DDP > 300 > 300 > 300 > 300

Claims (5)

1. Trans platinum compound of the general formula trans - [PtCl2 (isopropylamine) (3- (hydroxymethyl) -pyridine)]. 2. Trans platinum compound of the general formula trans - [PtCl2 (isopropylamine) (4- (hydroxymethyl) -pyridine)]. 3. Pharmaceutical compositions containing the compounds of claims 1 and 2 in administration with a suitable diluent or pharmaceutical carrier. 4. Preparation of the compounds of claims 1 and 2 characterized by containing the following steps:

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A first step in which a reaction mixture is prepared at 85 ° C by the addition of 3- (hydroxymethyl) -pyridine or 4- (hydroxymethyl) -pyridine to a suspension of cis- [PtCl2 (isopropylamine) 2 ] which is under stirring in distilled water to form a yellow solution.

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A second stage in which acid is added to the yellow solution hydrochloric and the reaction is stirred for 48 hours at 85 ° C.

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A third stage in which the solution is dried under vacuum until obtaining a yellow precipitate which we dissolve with CHCl3, which subsequently removed in vacuo.

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A fourth stage in which we add a small amount of water a yellow precipitate slowly appearing.

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A fifth stage in which the yellow precipitate is washed with cold water and later with ethyl ether to finish drying it to room temperature.

5. Use of the compounds of the claims 1 and 2 to prepare a drug with antitumor activity.