WO2011104409A1 - Platinum complexes with trans geometry, comprising a sulphonamide ligand with antitumour activity - Google Patents

Platinum complexes with trans geometry, comprising a sulphonamide ligand with antitumour activity Download PDF

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WO2011104409A1
WO2011104409A1 PCT/ES2011/070117 ES2011070117W WO2011104409A1 WO 2011104409 A1 WO2011104409 A1 WO 2011104409A1 ES 2011070117 W ES2011070117 W ES 2011070117W WO 2011104409 A1 WO2011104409 A1 WO 2011104409A1
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formula
compound
compound according
compounds
cancer
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PCT/ES2011/070117
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Spanish (es)
French (fr)
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Carmen Navarro Ranninger
José Julián ALEMÁN LARA
Virginia DEL SOLAR FERNÁNDEZ
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Universidad Autónoma de Madrid
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention falls within the scope of the pharmaceutical industry and, in particular, relates to new compounds with antitumor activity, pharmaceutical compositions containing them and their use as antitumor agents.
  • cz ' s-platinum induces the formation of mono functional bonds to a single guanine and bifunctional of two types: to two adjacent GG guanines (50-60% of the total bound Pt) [Reedijk et al., Structure and Bonding (1987) 67, 53-89], and a guanine and an adenine of the same AG chain (20-30%).
  • cz ' s-platinum results in intercatenary junctions: GG (1%), GG separated by a third nucleobase (1%) and DNA-protein junctions (> 1%) [Rahmouni et al. , Biochemistry (1987) 26, 7229-7234].
  • GG 1%
  • GG separated by a third nucleobase
  • DNA-protein junctions > 1%)
  • polymerases [Vallan et al, Nuc ⁇ . Acids Res (1988) 16, 4407-4418; Lemaire et al, Proc. Nati Acad. Sci (1999) 88, 1982-85].
  • platinum complexes with trans geometry may also 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 [Montero, EI et al. J. Med. Chem. (1999) 42, 4264; 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.
  • trans- [PtCl 2 (dimethylamine) (isopropylamine)] complex exhibits antitumor activity in Latin cis-p resistant cells [Navarro -Ranninger, C. et al. Journal of Inorganic Biochemistry (1999), 77 (1-2), 37-42].
  • the inventors have surprisingly found that new platinum complexes of trans geometry and comprising a sulfonamide-type ligand are useful as antitumor agents.
  • the invention relates to a compound or complex of formula (I) (compound of the invention)
  • Ar represents aryl
  • A represents alkylidene or cycloalkylidene
  • X represents halogen
  • L represents a monodentate coordinating ligand
  • the invention relates to a process for obtaining said compound of formula (I) comprising: forming a cis- [PtX 2 L 2 ] complex of formula (II), where X and L have the previously indicated meaning; Y
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined above together with a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, prodrug or solvate thereof, for use as a medicament, in particular a medicament for preventing or treating cancer.
  • the invention relates to the use of said compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the preparation of a medicament for the prevention or treatment of cancer.
  • the invention is directed to a method of treatment or prevention of cancer which comprises applying to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as described above, or of a pharmaceutically acceptable drug, drug or solvate thereof.
  • Said patient refers to an animal, preferably a human being.
  • Figure 1 is a schematic drawing showing the resolution of the X-ray diffraction structure of compound 4 according to the present invention.
  • Alkylidene refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which preferably has from 1 to about 12 carbon atoms and which is attached to the rest of the molecule from the two ends by simple bonds. to both atoms of N.
  • One most preferred class of alkylidene groups has from 1 to about 5 carbon atoms, for example, methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), n-propylene (-CH 2 -CH 2 - CH 2 -), n-butylene (-CH 2 -CH 2 -CH 2 _CH 2 -), n-pentilén (-CH 2 -CH 2 -CH 2 -CH 2 - CH 2 -), etc.
  • alkylidene radicals may be optionally substituted by one or more substituents such as halogen, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio.
  • Cycloalkylidene refers to a cyclic hydrocarbon chain radical consisting of carbon and hydrogen atoms, which preferably has from 3 to about 12 carbon atoms and which is attached to the rest of the molecule by two simple bonds to both atoms of both N. Preferably, said single bonds start from adjacent carbons.
  • a more preferred class of alkylidene groups has from 5 to about 10 carbon atoms, such as the following radicals:
  • the carbons of the cycloalkylidene radical by which said radical is attached to the nitrogen can present any spatial configuration: (R, R), (S, S), (R, S) and (S, R). All these isomers are within the scope of the present invention.
  • Cycloalkylidene radicals may optionally be substituted by one or more substituents such as halogen, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio.
  • Aryl refers to an aromatic hydrocarbon radical such as phenyl, naphthyl or anthracil.
  • Suitable aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds containing separate and / or condensed aryl groups.
  • Typical aryl groups contain from 1 to 3 separate or condensed rings and from about 6 to about 18 ring carbon atoms.
  • Preferably the aryl groups contain from 6 to 10 ring carbon atoms.
  • aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl and substituted or unsubstituted antryl.
  • the aryl radical can be optionally substituted by one or more substituents such as halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio.
  • Halogen according to the present invention includes F, Cl, Br and I.
  • L represents in its most general sense a "monodentate coordinating ligand", that is, a molecule or ion that is directly (ie covalently) bound to platinum.
  • said coordinating ligand is a coordinating solvent such as an alcohol (for example, methanol, ethanol, etc.), an ether (for example, tetrahydrofuran (THF)) or an aprotic polar solvent (dimethylformamide (DMF), dimethylacetamide (DMA) , dimethylsulfoxide (DMSO), etc.).
  • the coordinating solvent L is DMSO.
  • the compounds of formula (I) may be in the form of salts, preferably pharmaceutically acceptable salts, in the form of solvates, preferably pharmaceutically acceptable solvates, or in the form of prodrugs.
  • Said pharmaceutically acceptable salts, solvates or prodrugs of the compound of formula (I), when administered to the recipient, can provide (directly or indirectly) a compound of formula (I) such as that described herein.
  • “Pharmaceutically acceptable” preferably refers to molecular compositions and entities that are physiologically tolerable and do not normally produce an allergic reaction or a similar unfavorable reaction, such as gastric disorders, dizziness and the like, when administered to a human or animal being.
  • pharmaceutically acceptable means that it is approved by a regulatory agency of a state or federal government or is included in the US Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans.
  • Pharmaceutically acceptable salts are also within the scope of the invention because they can be useful for preparing pharmaceutically acceptable salts. Salts, prodrugs and derivatives can be prepared by methods known in the state of the art.
  • solvate is to be understood as meaning any form of the active compound according to the invention having another molecule (most likely a polar solvent) attached thereto by non-covalent bond.
  • solvates include hydrates and alcoholates, for example methanolate.
  • the solvates are preferably pharmaceutically acceptable solvates.
  • salts and solvates can be carried out by methods known in the art.
  • pharmaceutically acceptable salts of compounds provided herein are synthesized from the original compound, which contains one or more basic moieties, by conventional chemical methods.
  • such salts are prepared, for example, by reacting the free base forms of these compounds with the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts examples include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate, etc., and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, etc.
  • inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate, etc.
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, etc.
  • a preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • the additional solvent and ionic residues must also be non-toxic.
  • the compounds of the invention can have different polymorphic forms, it is intended that the invention encompasses all these forms.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. Those skilled in the art would readily produce such derivatives, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, carbamates, amides, etc.
  • the compounds of the invention are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the substitution of a hydrogen for a deuterium or tritium, or the substitution of a carbon for a carbon enriched in 13 C or in 14 C or a nitrogen enriched in 15 N, are within the scope of this invention.
  • the compounds of the present invention represented by the formula (I) described above may include isomers such as enantiomers or diastereoisomers depending on the presence of chiral centers.
  • the unique isomers, enantiomers or diastereoisomers and mixtures thereof are within the scope of the present invention.
  • the compound of formula (I) is selected from a compound of formula (la) and a compound of formula (Ib)
  • Ar is preferably selected from phenyl and naphthyl, both substituted or unsubstituted.
  • Particularly preferred substituents for said aryl radicals include, without limitation, halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio.
  • the aryl is substituted by one or more alkyl groups, such as methyl, and / or by one or more dialkylamino groups, such as dimethylamino.
  • Ri is selected from methyl and dimethylamino.
  • the following radicals are selected: methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), n-propylene (-CH 2 - CH 2 -CH 2 -), n-butylene (-CH 2 -CH 2 -CH 2 -CH 2 -), n-pentilén (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -),
  • L preferably represents a coordinating solvent.
  • coordinating solvents useful according to the invention are methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO).
  • the coordinating solvent L is DMSO.
  • X is Chlorine or Iodine.
  • Particularly preferred compounds or complexes of the invention are the following:
  • the compounds of formula (I) of the present invention can be obtained by a process comprising:
  • a complex of formula (II) is carried out from a suitable Pt source such as K 2 PtCl 4 .
  • said source of Pt is in an aqueous solution, on which the coordinating ligand L is added.
  • a source to the reaction medium of said halogen, as per for example a fluorine, bromine or iodine salt, such as its potassium salt.
  • the reaction is carried out under stirring at about room temperature, for example, between 15 ° C and 25 ° C, typically around about 20 ° C-22 ° C, and in the absence of light.
  • the previously formed complex of formula (II) is reacted with the appropriate N-sulfonamide.
  • N-tosylcyclohexane-1,3-diamine is added
  • N- (l- (dimethylamino) naphthalen-5-ylsulfonyl is added
  • cyclohexane-1, 2-diamine is added
  • N- (3-aminopropyl) -2,4,6-trimethylbencenamine is added.
  • novel pharmaceutical compositions of compounds of general formula (I) comprising a compound of general formula (I) and a pharmaceutically acceptable carrier are provided.
  • vehicle refers to a diluent, adjuvant or excipient with which the active substance is administered.
  • Such pharmaceutical vehicles may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • water or aqueous solutions of saline solution and aqueous solutions of dextrose and glycerol are used as vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, 1995.
  • the vehicles of the invention are approved by the regulatory agency of a state or federal government or are listed in the United States Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans .
  • compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
  • the administration of the compounds or compositions of the present invention can be by any suitable method, such as intravenous infusion, oral preparations and intravenous and intraperitoneal administration. It is preferred that infusion times of up to 24 hours are used, more preferably 1-12 hours, with 1-6 hours being most preferred. Short infusion times that allow treatment to be carried out without a one-night hospital stay are especially desirable. However, the infusion can be 12 to 24 hours or even longer if needed. The infusion can be carried out at appropriate intervals of say 1 to 4 weeks. Pharmaceutical compositions containing compounds of the invention can be administered by encapsulation in liposomes or nanospheres, in sustained release formulations or by other usual means of administration.
  • the formulations can be prepared according to conventional methods such as those described in the Spanish, European or United States Pharmacopoeias, or in similar reference texts, for example "Galenic Pharmacy Treaty", by C. Faul ⁇ i Trillo, 10 Edition, 1993, Luzán 5, SA of Editions.
  • the correct dosage of the compounds will vary according to the particular formulation, the mode of application and the particular site, host and tumor being treated. Other factors such as age, body weight, sex, diet, administration time, excretion rate, host status, drug combinations, reaction sensitivities and disease severity should also be taken into account. Administration may be carried out continuously or periodically within the maximum tolerated dose.
  • the compounds and compositions of this invention can be used with other drugs to provide a combination therapy.
  • the other drugs may be part of the same composition, or they may be provided as a separate composition for administration at the same time or at a different time.
  • Antitumor activities of these compounds include, but are not limited to, lung cancer, colon cancer, breast cancer, ovarian cancer and cervical cancer.
  • Example 2 illustrates the antitumor activity of representative compounds of the present invention on different cell lines representative of various tumors (ovary, breast, cervix, endometrium, lung and colon).
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, pro-drug or solvate thereof, for use in the prevention and / or treatment of cancer.
  • the invention relates to the use of said compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the preparation of a medicament for prevention and / or cancer treatment.
  • said cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer and cervical cancer.
  • the invention relates to a method of treatment or prevention of cancer which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), or of a pharmaceutically acceptable salt, prodrug or solvate. acceptable of it.
  • said cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer and cervical cancer.
  • said patient is an animal, preferably a human being.
  • Step 1 Formation of cis complexes of formula cis- [PtX 2 (DMSO) 2 ]
  • X Cl.
  • aqueous solution of 1 g of K 2 PtCl 4 (2.4 mmol) in 2.5 mL of water is added 0.7 mL of DMSO (9.6 mmol) resulting in an orange solution. Said solution was left under stirring at room temperature in the absence of light. After 24 hours a yellow solid separates, washed with plenty of water and ethanol and finally with ether. The final result is a pale-yellow solid that is identified as cz ' s- [PtCl 2 (DMSO) 2 ] where the spectroscopic data coincide with those described in the literature (see Inorganic Syntheses (2002), 33, 189-196) .
  • X I.
  • Figure 1 which represents the resolution of the X-ray diffraction structure of compound 4, is in accordance with all the data described above.
  • the environment of the Pt atom is square plane, with the amine in trans position to the DMSO group.
  • the link length Pt-N 2,069 ⁇ , while the distance Pt-S is 2,213 ⁇ .
  • the distances Pt-Cl are in the range 2,286 (Pt-CU) and Pt-C12) is 2,307, according to other trans-type complexes [PtCl 2 LL '] where L and L' are different groups and in which the Chloride groups are in trans position from one another [Montero, EI et al. J. Med. Chem (1999), 42, 4264].
  • the antitumor activity was studied using the NCI protocol [PO Miranda, j. M. Padrón, j. I. Register, j. Villar, VS Mart ⁇ n, ChemMedChem 2006, 1, 323-329.].
  • the effect is measured as growth inhibition (GI 50 ), [PO Miranda, j. M. Padrón, j. I. Register, j.
  • A2780 human ovarian carcinoma cell line
  • HBL-1 00 human breast carcinoma cell line
  • HeLa human cervical carcinoma cell line
  • Ishikawa human endometrial adenocarcinoma cell line
  • SW1573 human lung carcinoma cell line
  • T-47D human breast carcinoma cell line
  • WiDr human colon carcinoma cell line

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Abstract

The invention relates to platinum complexes with trans geometry, comprising a sulphonamide ligand having formula (I), in which Ar is aryl, A represents alkylidene or cycloalkylidene, X is halogen, and L represents a monodentate coordinating ligand, which complexes can be used as antitumour agents.

Description

COMPLEJOS DE PLATINO CON GEOMETRÍA TRANS QUE COMPRENDEN UN LIGANDO SULFONAMIDA CON ACTIVIDAD ANTITUMORAL  PLATINUM COMPLEXES WITH TRANS GEOMETRY THAT INCLUDE A SULFONAMIDE LINK WITH ANTITUMORAL ACTIVITY
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La invención se encuadra en el ámbito de la industria farmacéutica y, en concreto, se refiere a nuevos compuestos con actividad antitumoral, composiciones farmacéuticas que los contienen y su uso como agentes antitumorales.  The invention falls within the scope of the pharmaceutical industry and, in particular, relates to new compounds with antitumor activity, pharmaceutical compositions containing them and their use as antitumor agents.
ANTECEDENTES DE LA INVENCIÓN BACKGROUND OF THE INVENTION
En la práctica oncológica la utilización y uso de complejos de platino tales como cz's-platino o carboplatino está ampliamente descrito en quimioterapia del cáncer en la bibliografía. Véase a modo de ejemplo: Cisplatin, Bernarhd Lipper Ed. Willey-VCH. 1999; Platinum-Based Drugs in Cáncer Therapy, Kelland, L. y Farrell, N. Humana Press 2000. In oncological practice the use and use of platinum complexes such as cz ' s-platinum or carboplatin is widely described in cancer chemotherapy in the literature. See an example: Cisplatin, Bernarhd Lipper Ed. Willey-VCH. 1999; Platinum-Based Drugs in Cancer Therapy, Kelland, L. and Farrell, N. Humana Press 2000.
Sin embargo, en algunas ocasiones con el tratamiento con cz's-platino surgen una gran variedad de efectos adversos conocidos, tales como nefrotoxicidad, pérdida de audición, ototoxicidad y mielosupresión. Otra de las desventajas más importantes en clínica es la resistencia adquirida por muchos tumores que se hacen inmunes a este fármaco. Por ello, a pesar de haberse utilizado en los últimos 40 años diversas variedades estructurales de cz's-platino, se siguen buscando nuevos fármacos que eviten los problemas mencionados, en particular, los dos principales: resistencia y nefrotoxicidad. However, on some occasions with treatment with cz ' s-platinum a wide variety of known adverse effects arise, such as nephrotoxicity, hearing loss, ototoxicity and myelosuppression. Another of the most important clinical disadvantages is the resistance acquired by many tumors that are made immune to this drug. Therefore, despite having used several structural varieties of cz ' s-platinum in the last 40 years, new drugs are still being sought to avoid the above-mentioned problems, in particular the two main ones: resistance and nephrotoxicity.
La actividad biológica del cz's-platino es consecuencia de su interacción covalente con el ADN . Así, el cz's-platino induce la formación de enlaces mono funcionales a una sola guanina y bifuncionales de dos tipos: a dos guaninas adyacentes GG (50-60% del total del Pt enlazado) [Reedijk y col., Structure and Bonding (1987) 67, 53-89], y a una guanina y a una adenina de la misma cadena AG (20-30%). También, pero en menor medida, el cz's-platino da lugar a uniones intercatenarias: GG (1%), GG separadas por una tercera nucleobase (1%) y uniones ADN-proteína (>1%) [Rahmouni y col., Biochemistry (1987) 26, 7229-7234]. Este tipo de lesiones en el ADN dan lugar a cambios conformacionales en la doble hélice, e incluso dichas lesiones pueden provocar la inhibición de la actividad de ADN polimerasas [Vallan y col, Nucí. Acids. Res (1988) 16, 4407-4418; Lemaire y col, Proc. Nati. Acad. Sci (1999) 88, 1982-85]. Recientemente se ha detectado también la unión con proteínas HMG [Lippard y col, Nature, (1999), 399, 708]. Aunque no está formalmente reconocida la verdadera razón que induce los efectos citotóxicos del cis- platino, parece lógico pensar, ante tantas posibles causas, que es atribuible a un efecto combinado de todas ellas. The biological activity of cz ' s-platinum is a consequence of its covalent interaction with DNA. Thus, cz ' s-platinum induces the formation of mono functional bonds to a single guanine and bifunctional of two types: to two adjacent GG guanines (50-60% of the total bound Pt) [Reedijk et al., Structure and Bonding (1987) 67, 53-89], and a guanine and an adenine of the same AG chain (20-30%). Also, but to a lesser extent, cz ' s-platinum results in intercatenary junctions: GG (1%), GG separated by a third nucleobase (1%) and DNA-protein junctions (> 1%) [Rahmouni et al. , Biochemistry (1987) 26, 7229-7234]. These types of lesions in the DNA give rise to conformational changes in the double helix, and even such lesions can cause inhibition of DNA activity. polymerases [Vallan et al, Nucí. Acids Res (1988) 16, 4407-4418; Lemaire et al, Proc. Nati Acad. Sci (1999) 88, 1982-85]. Recently, HMG protein binding has also been detected [Lippard et al., Nature, (1999), 399, 708]. Although the true reason that induces the cytotoxic effects of cisplatin is not formally recognized, it seems logical to think, given so many possible causes, that it is attributable to a combined effect of all of them.
Desde el punto de vista terapéutico se ha confirmado que sólo el isómero cis- [PtCl2(NH3)2] (cz's-platino) tiene actividad antitumoral, siendo el isómero trans inactivo. La causa parece ser que, una vez formado el aducto monofuncional del isómero trans con el ADN, se observa un entrecruzamiento con el glutation al que se ha atribuido la desactivación de la droga. En el caso del isómero trans, también se ha observado una interacción diferente frente al ADN: la formación de uniones intercatenarias GC [Leng, M. y Brabec, V. Proc. Nati. Acad. Sci., (1993), 90, 5345]. From the therapeutic point of view it has been confirmed that only the cis- [PtCl 2 (NH3) 2 ] (cz ' s-platinum) isomer has antitumor activity, the trans isomer being inactive. The cause seems to be that, once the monofunctional adduct of the trans isomer with the DNA is formed, a cross-linking with the glutathione to which the deactivation of the drug has been attributed is observed. 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. Nati Acad. Sci., (1993), 90, 5345].
Sin embargo, durante los últimos años, se ha publicado que complejos de platino con geometría trans también pueden presentar actividad citotóxica; este es el caso de monómeros con ligandos aromáticos,tales como piridinas [Farrell y col. J. Med. Chem, (1989), 32, 51], con iminoéteres [Coluccia y col. J. Med. Chem, (1993), 36, 510], con aminas alifáticas [Montero, E.I. y col. J. Med. Chem. (1999) 42, 4264; Pérez, J.M. y col. J. Med. Chem. (2000) 43, 2411], y dímeros y trímeros que han dado lugar a numerosas publicaciones [Farrell, N. Comments Inorg.Chem. 1995, 16 373] y documentos de patente [WO 95/26968, WO 96/16068, WO 99/01462]. Puesto que algunos de los complejos con geometría trans descritos muestran alta actividad in vitro e in vivo frente a células tumorales resistentes al cz's-platino, se cree que los efectos citotóxicos de los complejos trans deben de seguir patrones muy diferentes a los del cz's-platino. En este sentido, los propios inventores han observado que el complejo trans- [PtCl2(dimetilamina)(isopropilamina)] presenta actividad antitumoral en células resistentes al cis-p latino [Navarro -Ranninger, C. y col. Journal of Inorganic Biochemistry (1999), 77(1-2), 37-42]. Los datos más relevantes indican que dicho compuesto presenta actividad antitumoral en células Pam 212-ras, transformadas con el oncogén H-ras y que son resistentes a dicho fármaco, con un valor de IC50 de 6 μΜ frente a 164 μΜ del cz's-platino. Sin embargo, a pesar de los recientes avances en la quimioterapia y la radiación, el cáncer sigue siendo una de las principales causas de muerte a cualquier edad en todo el mundo. Se han hecho y se continúan realizando esfuerzos enormes con el fin de obtener nuevos agentes antitumorales activos y seguros para administrarlos a pacientes que tienen cáncer. Por tanto, la presente invención se enfrenta con el problema de proporcionar nuevos compuestos útiles en el tratamiento del cáncer. Preferiblemente, dichos nuevos compuestos deberían conservar o incluso mejorar la actividad citotóxica de los compuestos conocidos, siendo deseable que a su vez evitaran alguno de sus efectos secundarios adversos asociados. However, in recent years, it has been published that platinum complexes with trans geometry may also 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 [Montero, EI et al. J. Med. Chem. (1999) 42, 4264; 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 patent documents [WO 95/26968, WO 96/16068, WO 99/01462]. Since some of the trans geometry complexes described show high activity in vitro and in vivo against cz ' s-platinum resistant tumor cells, it is believed that the cytotoxic effects of trans complexes should follow very different patterns than those of cz ' s-platinum. In this regard, the inventors themselves have observed that the trans- [PtCl 2 (dimethylamine) (isopropylamine)] complex exhibits antitumor activity in Latin cis-p resistant cells [Navarro -Ranninger, C. et al. Journal of Inorganic Biochemistry (1999), 77 (1-2), 37-42]. The most relevant data indicate that said compound exhibits antitumor activity in Pam 212-ras cells, transformed with the H-ras oncogene and that they are resistant to said drug, with an IC 50 value of 6 μΜ versus 164 μΜ of the cz ' s -platinum. However, despite recent advances in chemotherapy and radiation, cancer remains one of the leading causes of death at any age worldwide. Huge efforts have been made and continue to be made in order to obtain new active and safe antitumor agents to administer to patients who have cancer. Therefore, the present invention faces the problem of providing new compounds useful in the treatment of cancer. Preferably, said new compounds should preserve or even improve the cytotoxic activity of the known compounds, it being desirable that they in turn avoid some of their associated adverse side effects.
COMPENDIO DE LA INVENCION SUMMARY OF THE INVENTION
Los inventores han encontrado sorprendentemente que nuevos complejos de platino de geometría trans y que comprenden un ligando de tipo sulfonamida son útiles como agentes antitumorales.  The inventors have surprisingly found that new platinum complexes of trans geometry and comprising a sulfonamide-type ligand are useful as antitumor agents.
Por tanto, en un aspecto, la invención se relaciona con un compuesto o complejo de fórmula (I) (compuesto de la invención)  Therefore, in one aspect, the invention relates to a compound or complex of formula (I) (compound of the invention)
Figure imgf000005_0001
Figure imgf000005_0001
(I)  (I)
donde  where
Ar representa arilo;  Ar represents aryl;
A representa alquilideno o cicloalquilideno;  A represents alkylidene or cycloalkylidene;
X representa halógeno; y  X represents halogen; Y
L representa un ligando coordinante monodentado;  L represents a monodentate coordinating ligand;
o una sal, un pro fármaco o un solvato del mismo. or a salt, a pro drug or a solvate thereof.
En otro aspecto, la invención se relaciona con un procedimiento para la obtención de dicho compuesto de fórmula (I) que comprende: formar un complejo cis-[PtX2L2] de fórmula (II), donde X y L tienen el significado previamente indicado; y In another aspect, the invention relates to a process for obtaining said compound of formula (I) comprising: forming a cis- [PtX 2 L 2 ] complex of formula (II), where X and L have the previously indicated meaning; Y
hacer reaccionar dicho complejo de fórmula (II) con una N-sulfonamida para obtener un compuesto de fórmula (I).  reacting said complex of formula (II) with an N-sulfonamide to obtain a compound of formula (I).
En otro aspecto, la invención se relaciona con una composición farmacéutica que comprende un compuesto de fórmula (I) como se ha definido anteriormente junto con un vehículo o excipiente farmacéuticamente aceptable.  In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above together with a pharmaceutically acceptable carrier or excipient.
La invención se refiere además a un compuesto de fórmula (I) como se ha definido anteriormente, o una sal, profármaco o solvato farmacéuticamente aceptable del mismo, para su uso como medicamento, en particular un medicamento para prevenir o tratar cáncer.  The invention further relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, prodrug or solvate thereof, for use as a medicament, in particular a medicament for preventing or treating cancer.
Asimismo, la invención se relaciona con el uso de dicho compuesto de fórmula (I), o una sal, profármaco o solvato farmacéuticamente aceptable del mismo, en la elaboración de un medicamento para la prevención o el tratamiento del cáncer.  Also, the invention relates to the use of said compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the preparation of a medicament for the prevention or treatment of cancer.
En un aspecto adicional, la invención se dirige a un método de tratamiento o prevención de cáncer que comprende aplicar a un paciente en necesidad de tal tratamiento una cantidad terapéuticamente eficaz de un compuesto de fórmula (I) tal como s e ha de s crito anteriormente, o de una s al , pro fármaco o so lvato farmacéuticamente aceptable del mismo. Dicho paciente se refiere a un animal, preferiblemente un ser humano.  In a further aspect, the invention is directed to a method of treatment or prevention of cancer which comprises applying to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as described above, or of a pharmaceutically acceptable drug, drug or solvate thereof. Said patient refers to an animal, preferably a human being.
BREVE DESCRIPCIÓN DE LAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
La Figura 1 es un dibujo esquemático que muestra la resolución de la estructura por difracción de rayos-X del compuesto 4 según la presente invención.  Figure 1 is a schematic drawing showing the resolution of the X-ray diffraction structure of compound 4 according to the present invention.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
En el contexto de la presente invención, lo siguientes términos tienen el significado indicado a continuación:  In the context of the present invention, the following terms have the meaning indicated below:
"Alquilideno" se refiere a un radical de cadena hidrocarbonada lineal o ramificada que consiste en átomos de carbono e hidrógeno, que preferiblemente tiene desde 1 hasta aproximadamente 12 átomos de carbono y que está unido al resto de la molécula desde los dos extremos mediante enlaces sencillos a ambos átomos de N. Una clase más preferida de grupos alquilideno tiene desde 1 hasta aproximadamente 5 átomos de carbono, como por ejemplo, metilén (-CH2-), etilén (-CH2-CH2-), n-propilén (-CH2-CH2-CH2-), n-butilén (-CH2-CH2-CH2_CH2-), n-pentilén (-CH2-CH2-CH2-CH2- CH2-), etc. Los radicales alquilideno pueden estar sustituidos opcionalmente por uno o más sustituyentes tales como halógeno, hidroxilo, alcoxilo, carboxilo, ciano, carbonilo, acilo, amino, dialquilamino, nitro, mercapto y alquiltio. "Alkylidene" refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which preferably has from 1 to about 12 carbon atoms and which is attached to the rest of the molecule from the two ends by simple bonds. to both atoms of N. One most preferred class of alkylidene groups has from 1 to about 5 carbon atoms, for example, methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), n-propylene (-CH 2 -CH 2 - CH 2 -), n-butylene (-CH 2 -CH 2 -CH 2 _CH 2 -), n-pentilén (-CH 2 -CH 2 -CH 2 -CH 2 - CH 2 -), etc. The alkylidene radicals may be optionally substituted by one or more substituents such as halogen, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio.
"Cilcloalquilideno" se refiere a un radical cíclico de cadena hidro carbonada que consiste en átomos de carbono e hidrógeno, que preferiblemente tiene desde 3 hasta aproximadamente 12 átomos de carbono y que está unido al resto de la molécula mediante dos enlaces sencillos a ambos átomos de N. Preferiblemente, dichos enlaces sencillos parten de carbonos adyacentes. Una clase más preferida de grupos alquilideno tiene desde 5 hasta aproximadamente 10 átomos de carbono, como por ejemplo los siguientes radicales:
Figure imgf000007_0001
"Cycloalkylidene" refers to a cyclic hydrocarbon chain radical consisting of carbon and hydrogen atoms, which preferably has from 3 to about 12 carbon atoms and which is attached to the rest of the molecule by two simple bonds to both atoms of both N. Preferably, said single bonds start from adjacent carbons. A more preferred class of alkylidene groups has from 5 to about 10 carbon atoms, such as the following radicals:
Figure imgf000007_0001
Tal como se puede apreciar los carbonos del radical cicloalquilideno mediante los cuales se une dicho radical a los nitrógenos pueden presentar cualquier configuración espacial: (R, R), (S, S), (R, S) y (S, R). Todos estos isómeros se encuentran dentro del alcance de la presente invención.  As can be seen the carbons of the cycloalkylidene radical by which said radical is attached to the nitrogen can present any spatial configuration: (R, R), (S, S), (R, S) and (S, R). All these isomers are within the scope of the present invention.
Los radicales cicloalquilideno pueden estar sustituidos opcionalmente por uno o más sustituyentes tales como halógeno, hidroxilo, alcoxilo, carboxilo, ciano, carbonilo, acilo, amino, dialquilamino, nitro, mercapto y alquiltio.  Cycloalkylidene radicals may optionally be substituted by one or more substituents such as halogen, hydroxy, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio.
"Arilo" se refiere a un radical hidrocarbonado aromático tal como fenilo, naftilo o antracilo. Grupos arilo adecuados en los compuestos de la presente invención incluyen compuestos de anillos únicos y múltiples, que incluyen compuestos de anillos múltiples que contienen grupos arilo separados y/o condensados. Los grupos arilo típicos contienen desde 1 hasta 3 anillos separados o condensados y desde aproximadamente 6 hasta aproximadamente 18 átomos de carbono de anillo. Preferiblemente los grupos arilo contienen desde 6 hasta 10 átomos de carbono de anillo . Los grupos arilo especialmente preferidos incluyen fenilo sustituido o no sustituido, naftilo sustituido o no sustituido, bifenilo sustituido o no sustituido, fenantrilo sustituido o no sustituido y antrilo sustituido o no sustituido. En este sentido, el radical arilo puede estar opcionalmente sustituido por uno o más sustituyentes tales como halógeno, hidroxilo, alcoxilo, carboxilo, ciano, carbonilo, acilo, amino, dialquilamino, nitro, mercapto y alquiltio. "Aryl" refers to an aromatic hydrocarbon radical such as phenyl, naphthyl or anthracil. Suitable aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds containing separate and / or condensed aryl groups. Typical aryl groups contain from 1 to 3 separate or condensed rings and from about 6 to about 18 ring carbon atoms. Preferably the aryl groups contain from 6 to 10 ring carbon atoms. Especially preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl and substituted or unsubstituted antryl. In this sense, the aryl radical can be optionally substituted by one or more substituents such as halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio.
"Halógeno" según la presente invención incluye F, Cl, Br y I.  "Halogen" according to the present invention includes F, Cl, Br and I.
"L" según la presente invención representa en su sentido más general un "ligando coordinante monodentado", es decir, una molécula o ión que está unido directamente (es decir covalentemente) al platino. Preferiblemente dicho ligando coordinante es un disolvente coordinante tal como un alcohol (por ejemplo, metanol, etanol, etc.), un éter (por ejemplo, tetrahidrofurano (THF)) o un disolvente polar aprótico (dimetilformamida (DMF), dimetilacetamida (DMA), dimetilsulfóxido (DMSO), etc.). En una realización preferida, el disolvente coordinante L es DMSO.  "L" according to the present invention represents in its most general sense a "monodentate coordinating ligand", that is, a molecule or ion that is directly (ie covalently) bound to platinum. Preferably said coordinating ligand is a coordinating solvent such as an alcohol (for example, methanol, ethanol, etc.), an ether (for example, tetrahydrofuran (THF)) or an aprotic polar solvent (dimethylformamide (DMF), dimethylacetamide (DMA) , dimethylsulfoxide (DMSO), etc.). In a preferred embodiment, the coordinating solvent L is DMSO.
Los compuestos de fórmula (I) pueden estar en forma de sales, preferiblemente sales farmacéuticamente aceptables, en forma de solvatos, preferiblemente solvatos farmacéuticamente aceptables, o en forma de profármacos. Dichas sales, solvatos o profármacos farmacéuticamente aceptables del compuesto de fórmula (I), cuando se administran al receptor, pueden proporcionar (directa o indirectamente) un compuesto de fórmula (I) tal como el descrito en el presente documento. "Farmacéuticamente aceptable" se refiere preferiblemente a composiciones y entidades moleculares que son fisiológicamente tolerables y no producen normalmente una reacción alérgica o una reacción no favorable similar, tal como trastornos gástricos, mareo y similares, cuando se administra a un ser humano o animal. La expresión "farmacéuticamente aceptable" significa que está aprobado por una agencia reguladora de un gobierno de estado o federal o está incluido en la Farmacopea Estadounidense u otra farmacopea reconocida de modo general para su uso en animales, y de manera más particular en seres humanos. Las sales farmacéuticamente no aceptables también se encuentran dentro del alcance de la invención porque pueden ser útiles para preparar sales farmacéuticamente aceptables. Las sales, los profármacos y los derivados pueden prepararse por medio de métodos conocidos en el estado de la técnica.  The compounds of formula (I) may be in the form of salts, preferably pharmaceutically acceptable salts, in the form of solvates, preferably pharmaceutically acceptable solvates, or in the form of prodrugs. Said pharmaceutically acceptable salts, solvates or prodrugs of the compound of formula (I), when administered to the recipient, can provide (directly or indirectly) a compound of formula (I) such as that described herein. "Pharmaceutically acceptable" preferably refers to molecular compositions and entities that are physiologically tolerable and do not normally produce an allergic reaction or a similar unfavorable reaction, such as gastric disorders, dizziness and the like, when administered to a human or animal being. The term "pharmaceutically acceptable" means that it is approved by a regulatory agency of a state or federal government or is included in the US Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans. Pharmaceutically acceptable salts are also within the scope of the invention because they can be useful for preparing pharmaceutically acceptable salts. Salts, prodrugs and derivatives can be prepared by methods known in the state of the art.
El término "solvato" según esta invención ha de entenderse como que significa cualquier forma del compuesto activo según la invención que tiene otra molécula (lo más probablemente un disolvente polar) unida al mismo mediante enlace no covalente. Ejemplos de solvatos incluyen hidratos y alcoholatos, por ejemplo metanolato. Preferiblemente, los solvatos son, preferiblemente, solvatos farmacéuticamente aceptables. The term "solvate" according to this invention is to be understood as meaning any form of the active compound according to the invention having another molecule (most likely a polar solvent) attached thereto by non-covalent bond. Examples of solvates include hydrates and alcoholates, for example methanolate. Preferably, the solvates are preferably pharmaceutically acceptable solvates.
La preparación de sales y solvatos puede llevarse a cabo mediante métodos conocidos en la técnica. Por ejemplo, las sales farmacéuticamente aceptables de compuestos proporcionados en el presente documento se sintetizan a partir del compuesto original, que contiene uno o más restos básicos, mediante métodos químicos convencionales. En general, tales sales se preparan, por ejemplo, haciendo reaccionar las formas de base libre de estos compuestos con la base o ácido apropiados en agua o en un disolvente orgánico o en una mezcla de los dos. En general, se prefieren medios no acuosos como éter, acetato de etilo, etanol, isopropanol o acetonitrilo. Los ejemplos de las sales de adición de ácido incluyen sales de adición de ácido inorgánico tales como, por ejemplo, clorhidrato, bromhidrato, yodhidrato, sulfato, nitrato, fosfato, etc., y sales de adición de ácido orgánico tales como, por ejemplo, acetato, maleato, fumarato, citrato, oxalato, succinato, tartrato, malato, mandelato, metanosulfonato, p- toluenosulfonato, etc.  The preparation of salts and solvates can be carried out by methods known in the art. For example, pharmaceutically acceptable salts of compounds provided herein are synthesized from the original compound, which contains one or more basic moieties, by conventional chemical methods. In general, such salts are prepared, for example, by reacting the free base forms of these compounds with the appropriate base or acid in water or in an organic solvent or in a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of the acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate, etc., and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, etc.
Una forma farmacéuticamente aceptable preferida es la forma cristalina, incluyendo tal forma en una composición farmacéutica. En el caso de sales y solvatos, los restos de disolvente e iónicos adicionales también deben ser no tóxicos. Los compuestos de la invención pueden presentar diferentes formas polimórficas, se pretende que la invención englobe todas estas formas.  A preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates, the additional solvent and ionic residues must also be non-toxic. The compounds of the invention can have different polymorphic forms, it is intended that the invention encompasses all these forms.
Cualquier compuesto que es un profármaco de un compuesto de fórmula (I) se encuentra dentro del alcance de la invención. El término "profármaco" se usa en su sentido más amplio y engloba aquellos derivados que se convierten in vivo en los compuestos de la invención. Los expertos en la técnica producirían fácilmente tales derivados, e incluyen, dependiendo de los grupos funcionales presentes en la molécula y sin limitación, los siguientes derivados de los presentes compuestos: ésteres, ésteres de aminoácidos, ésteres de fosfato, carbamatos, amidas, etc.  Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. Those skilled in the art would readily produce such derivatives, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, carbamates, amides, etc.
Los compuestos de la invención también pretenden incluir compuestos que difieren sólo en presencia de uno o más átomos enriquecidos isotópicamente. Por ejemplo, compuestos que tienen las presentes estructuras, excepto para la sustitución de un hidrógeno por un deuterio o tritio, o la sustitución de un carbono por un carbono enriquecido en 13C o en 14C o un nitrógeno enriquecido en 15N, se encuentran dentro del alcance de esta invención. The compounds of the invention are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, except for the substitution of a hydrogen for a deuterium or tritium, or the substitution of a carbon for a carbon enriched in 13 C or in 14 C or a nitrogen enriched in 15 N, are within the scope of this invention.
Los compuestos de la presente invención representados por la fórmula (I) descrita anteriormente pueden incluir isómeros tales como enantiómeros o diastereoisómeros dependiendo de la presencia de centros quirales. Los isómeros únicos, enantiómeros o diastereoisómeros y mezclas de los mismos se encuentran dentro del alcance de la presente invención.  The compounds of the present invention represented by the formula (I) described above may include isomers such as enantiomers or diastereoisomers depending on the presence of chiral centers. The unique isomers, enantiomers or diastereoisomers and mixtures thereof are within the scope of the present invention.
Para dar una descripción más concisa, algunas de las expresiones cuantitativas dadas en el presente documento no se califican con el término "aproximadamente". Debe entenderse que, aunque el término "aproximadamente" se use explícitamente o no, cada cantidad dada en el presente documento pretende referirse al valor dado real, y también pretende referirse a la aproximación a tal valor dado que se inferirá razonablemente basándose en la experiencia habitual en la técnica, incluyendo equivalentes y aproximaciones debidos a las condiciones experimentales y/o de medición de tal valor dado.  To give a more concise description, some of the quantitative expressions given in this document are not qualified with the term "approximately". It should be understood that, although the term "approximately" is used explicitly or not, each quantity given in this document is intended to refer to the actual given value, and is also intended to refer to the approximation to that value given that it will be reasonably inferred based on usual experience. in the art, including equivalents and approximations due to the experimental and / or measurement conditions of such given value.
Según una realización particular, el compuesto de fórmula (I) se selecciona entre un compuesto de fórmula (la) y un compuesto de fórmula (Ib)  According to a particular embodiment, the compound of formula (I) is selected from a compound of formula (la) and a compound of formula (Ib)
O, Ar O, Ar O, Ar O, Ar
o=s o=s  o = s o = s
HN. HN,,  HN HN ,,
> A  > A
H2N H2N H 2 NH 2 N
X. / X. /  X. / X. /
Pt Pt  Pt Pt
L X L X  L X L X
Fórmula (la) Fórmula (Ib) donde Ar, A, X y L tienen los significados anteriormente indicados; o una sal, un pro fármaco o un solvato del mismo.  Formula (la) Formula (Ib) where Ar, A, X and L have the meanings indicated above; or a salt, a pro drug or a solvate thereof.
En compuestos de fórmula general (I), Ar se selecciona preferiblemente entre fenilo y naftilo, ambos sustituidos o no sustituidos. Sustituyentes particularmente preferidos para dichos radicales arilo incluyen, sin limitación, halógeno, hidroxilo, alcoxilo, carboxilo, ciano, carbonilo, acilo, amino, dialquilamino, nitro, mercapto y alquiltio. En una realización aún más particular, el arilo está sustituido por uno o más grupos alquílicos, como por ejemplo metilo, y/o por uno o más grupos dialquilamino, como por ejemplo dimetilamino. In compounds of general formula (I), Ar is preferably selected from phenyl and naphthyl, both substituted or unsubstituted. Particularly preferred substituents for said aryl radicals include, without limitation, halogen, hydroxyl, alkoxy, carboxyl, cyano, carbonyl, acyl, amino, dialkylamino, nitro, mercapto and alkylthio. In an even more particular embodiment, the aryl is substituted by one or more alkyl groups, such as methyl, and / or by one or more dialkylamino groups, such as dimethylamino.
Realizaciones preferidas de rupos arilo según la presente invención incluyen:  Preferred embodiments of aryl rupees according to the present invention include:
Figure imgf000011_0001
Figure imgf000011_0001
donde Ri se selecciona entre metilo y dimetilamino.  where Ri is selected from methyl and dimethylamino.
Realizaciones aún más preferidas de grupos arilo según la presente invención son las siguientes:  Even more preferred embodiments of aryl groups according to the present invention are the following:
Figure imgf000011_0002
Figure imgf000011_0002
En una realización particular, en los compuestos de fórmula (I) A se selecciona entre los siguientes radicales: metilén (-CH2-), etilén (-CH2-CH2-), n-propilén (-CH2- CH2-CH2-), n-butilén (-CH2-CH2-CH2-CH2-), n-pentilén (-CH2-CH2-CH2-CH2-CH2-),
Figure imgf000011_0003
In a particular embodiment, in the compounds of formula (I) A, the following radicals are selected: methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), n-propylene (-CH 2 - CH 2 -CH 2 -), n-butylene (-CH 2 -CH 2 -CH 2 -CH 2 -), n-pentilén (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -),
Figure imgf000011_0003
Tal como se ha definido anteriormente, en el contexto de la presente invención L representa preferiblemente un disolvente coordinante. Ejemplos, no limitativos, de disolventes coordinantes útiles según la invención son metanol, etanol, tetrahidrofurano (THF), dimetilformamida (DMF), dimetilacetamida (DMA), dimetilsulfóxido (DMSO). En una realización preferida, el disolvente coordinante L es DMSO. As defined above, in the context of the present invention L preferably represents a coordinating solvent. Non-limiting examples of coordinating solvents useful according to the invention are methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO). In a preferred embodiment, the coordinating solvent L is DMSO.
En los compuestos de fórmula (I), preferiblemente X es Cloro o Yodo. Compuestos o complejos particularmente preferidos de la invención son los siguientes: In the compounds of formula (I), preferably X is Chlorine or Iodine. Particularly preferred compounds or complexes of the invention are the following:
Figure imgf000012_0001
Figure imgf000012_0001
Los compuestos de fórmula (I) de la presente invención se pueden obtener mediante un procedimiento que comprende: The compounds of formula (I) of the present invention can be obtained by a process comprising:
- formar un complejo cz's-[PtX2L2] de fórmula (II), donde X y L tienen el significado previamente indicado; y - forming a cz ' s- [PtX 2 L 2 ] complex of formula (II), where X and L have the previously indicated meaning; Y
hacer reaccionar dicho complejo de fórmula (II) con una N-sulfonamida para obtener un compuesto de fórmula (I).  reacting said complex of formula (II) with an N-sulfonamide to obtain a compound of formula (I).
Dicho procedimiento es similar al método de síntesis descrito por Kukushkin, Vadim Yu.; Pombeiro, Armando J. L.; Ferreira, Cristina M. P.; Elding, Lars I.; Puddephatt, Richard J. Inorganic Syntheses (2002), 33, 189-196.  Said procedure is similar to the synthesis method described by Kukushkin, Vadim Yu .; Pombeiro, Armando J. L .; Ferreira, Cristina M. P .; Elding, Lars I .; Puddephatt, Richard J. Inorganic Syntheses (2002), 33, 189-196.
Así, la formación de un complejo de fórmula (II) se lleva a cabo a partir de una fuente de Pt adecuada como por ejemplo K2PtCl4. Típicamente, dicha fuente de Pt se encuentra en una disolución acuosa, sobre la que se adiciona el ligando coordinante L. Si el complejo de fórmula (I) que se pretende preparar contiene un halógeno distinto de Cl es necesario añadir al medio de reacción una fuente de dicho halógeno, como por ejemplo una sal de flúor, bromo o yodo, tal como su sal potásica. De manera conveniente, la reacción se lleva a cabo bajo agitación a aproximadamente temperatura ambiente, por ejemplo, entre 15°C y 25°C, típicamente alrededor de 20 °C-22 °C aproximadamente, y en ausencia de luz. Thus, the formation of a complex of formula (II) is carried out from a suitable Pt source such as K 2 PtCl 4 . Typically, said source of Pt is in an aqueous solution, on which the coordinating ligand L is added. If the complex of formula (I) to be prepared contains a halogen other than Cl it is necessary to add a source to the reaction medium of said halogen, as per for example a fluorine, bromine or iodine salt, such as its potassium salt. Conveniently, the reaction is carried out under stirring at about room temperature, for example, between 15 ° C and 25 ° C, typically around about 20 ° C-22 ° C, and in the absence of light.
Para preparar el complejo de fórmula (I), se hace reaccionar el complejo de fórmula (II) previamente formado con la N-sulfonamida adecuada. Por ejemplo, para formar los complejos 1 y 2 según la presente invención se añade N-tosilciclohexano- 1,3-diamina, para formar el complejo 3 según la presente invención se añade N-(l- (dimetilamino)naftalen-5-ilsulfonil)ciclohexano-l,2-diamina y para formar el complejo 4 según la presente invención se añade N-(3-aminopropil)-2,4,6-trimetilbencenamina.  To prepare the complex of formula (I), the previously formed complex of formula (II) is reacted with the appropriate N-sulfonamide. For example, to form complexes 1 and 2 according to the present invention N-tosylcyclohexane-1,3-diamine is added, to form complex 3 according to the present invention N- (l- (dimethylamino) naphthalen-5-ylsulfonyl is added ) cyclohexane-1, 2-diamine and to form complex 4 according to the present invention N- (3-aminopropyl) -2,4,6-trimethylbencenamine is added.
Una característica importante de los compuestos descritos anteriormente de fórmula (I) es su bioactividad y, en particular, su actividad citotóxica.  An important feature of the compounds described above of formula (I) is their bioactivity and, in particular, their cytotoxic activity.
Con esta invención, se proporcionan composiciones farmacéuticas novedosas de compuestos de fórmula general (I) que comprenden un compuesto de fórmula general (I) y un vehículo farmacéuticamente aceptable.  With this invention, novel pharmaceutical compositions of compounds of general formula (I) comprising a compound of general formula (I) and a pharmaceutically acceptable carrier are provided.
El término "vehículo" se refiere a un diluyente, adyuvante o excipiente con el que se administra el principio activo. Tales vehículos farmacéuticos pueden ser líquidos estériles, tales como agua y aceites, incluyendo aquellos de origen del petróleo, animal, vegetal o sintético, tales como aceite de cacahuete, aceite de soja, aceite mineral, aceite de sésamo y similares. Se emplean preferiblemente como vehículos agua o disoluciones acuosas de solución salina y disoluciones acuosas de dextrosa y glicerol, particularmente para las disoluciones inyectables. Vehículos farmacéuticos adecuados se describen en "Remington's Pharmaceutical Sciences" por E.W. Martin, 1995. Preferiblemente, los vehículos de la invención están aprobados por la agencia reguladora de un gobierno de estado o el federal o están enumerados en la Farmacopea Estadounidense u otra farmacopea reconocida en general para su uso en animales, y más particularmente en seres humanos.  The term "vehicle" refers to a diluent, adjuvant or excipient with which the active substance is administered. Such pharmaceutical vehicles may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Preferably water or aqueous solutions of saline solution and aqueous solutions of dextrose and glycerol are used as vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 1995. Preferably, the vehicles of the invention are approved by the regulatory agency of a state or federal government or are listed in the United States Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans .
Ejemplos de composiciones farmacéuticas incluyen cualquier composición sólida (comprimidos, pildoras, cápsulas, gránulos, etc.) o líquida (disoluciones, suspensiones o emulsiones) para la administración oral, tópica o parenteral.  Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
La administración de los compuestos o composiciones de la presente invención puede ser mediante cualquier método adecuado, tal como infusión intravenosa, preparaciones orales y administración intravenosa e intraperitoneal. Se prefiere que se usen tiempos de infusión de hasta 24 horas, más preferiblemente 1-12 horas, siendo de 1-6 horas lo más preferido. Son especialmente deseables los tiempos de infusión cortos que permiten que se lleve a cabo el tratamiento sin una estancia de una noche en el hospital. Sin embargo, la infusión puede ser de 12 a 24 horas o incluso más prolongada si se necesita. La infusión puede llevarse a cabo en intervalos adecuados de digamos de 1 a 4 semanas. Pueden administrarse composiciones farmacéuticas que contienen compuestos de la invención mediante encapsulación en liposomas o nanoesferas, en formulaciones de liberación sostenida o mediante otros medios de administración habituales. The administration of the compounds or compositions of the present invention can be by any suitable method, such as intravenous infusion, oral preparations and intravenous and intraperitoneal administration. It is preferred that infusion times of up to 24 hours are used, more preferably 1-12 hours, with 1-6 hours being most preferred. Short infusion times that allow treatment to be carried out without a one-night hospital stay are especially desirable. However, the infusion can be 12 to 24 hours or even longer if needed. The infusion can be carried out at appropriate intervals of say 1 to 4 weeks. Pharmaceutical compositions containing compounds of the invention can be administered by encapsulation in liposomes or nanospheres, in sustained release formulations or by other usual means of administration.
Las formulaciones se pueden preparar según métodos convencionales tales como los que se describen en las Farmacopeas Española, Europea o de Estados Unidos de América, o en textos de referencia similares, por ejemplo "Tratado de Farmacia Galénica", de C. Faulí i Trillo, 10 Edición, 1993, Luzán 5, S.A. de Ediciones.  The formulations can be prepared according to conventional methods such as those described in the Spanish, European or United States Pharmacopoeias, or in similar reference texts, for example "Galenic Pharmacy Treaty", by C. Faulí i Trillo, 10 Edition, 1993, Luzán 5, SA of Editions.
La dosificación correcta de los compuestos variará según la formulación particular, el modo de aplicación y el sitio, huésped y tumor particulares que se están tratando. También deben tenerse en cuenta otros factores como la edad, peso corporal, sexo, dieta, tiempo de administración, tasa de excreción, estado del huésped, combinaciones de fármacos, sensibilidades de reacción y gravedad de la enfermedad. Puede llevarse a cabo la administración de manera continua o periódica dentro de la dosis tolerada máxima.  The correct dosage of the compounds will vary according to the particular formulation, the mode of application and the particular site, host and tumor being treated. Other factors such as age, body weight, sex, diet, administration time, excretion rate, host status, drug combinations, reaction sensitivities and disease severity should also be taken into account. Administration may be carried out continuously or periodically within the maximum tolerated dose.
Los compuestos y composiciones de esta invención pueden usarse con otros fármacos para proporcionar una terapia de combinación. Los otros fármacos pueden formar parte de la misma composición, o pueden proporcionarse como una composición aparte para la administración al mismo tiempo o en un tiempo diferente.  The compounds and compositions of this invention can be used with other drugs to provide a combination therapy. The other drugs may be part of the same composition, or they may be provided as a separate composition for administration at the same time or at a different time.
Las actividades antitumorales de estos compuestos incluyen, pero no se limitan a, cáncer de pulmón, cáncer de colon, cáncer de mama, cáncer de ovario y cáncer de cuello uterino. El Ej emplo 2 ilustra la actividad antitumoral de compuestos representativos de la presente invención sobre distintas líneas celulares representativas de diversos tumores (ovario, mama, cuello de útero, endometrio, pulmón y colon).  Antitumor activities of these compounds include, but are not limited to, lung cancer, colon cancer, breast cancer, ovarian cancer and cervical cancer. Example 2 illustrates the antitumor activity of representative compounds of the present invention on different cell lines representative of various tumors (ovary, breast, cervix, endometrium, lung and colon).
En otro aspecto, la invención se relaciona con un compuesto de fórmula (I), o una sal, pro fármaco o solvato farmacéuticamente aceptable del mismo, para su uso en la prevención y/o el tratamiento del cáncer.Alternativamente, la invención se relaciona con el uso de dicho compuesto de fórmula (I), o una sal, profármaco o solvato farmacéuticamente aceptable del mismo, en la elaboración de un medicamento para la prevención y/o el tratamiento del cáncer. En una realización particular, dicho cáncer se selecciona entre cáncer de pulmón, cáncer de colon, cáncer de mama, cáncer de ovario y cáncer de cuello uterino. In another aspect, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, pro-drug or solvate thereof, for use in the prevention and / or treatment of cancer.Alternatively, the invention relates to the use of said compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the preparation of a medicament for prevention and / or cancer treatment. In a particular embodiment, said cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer and cervical cancer.
En otro aspecto, la invención se relaciona con un método de tratamiento o prevención del cáncer que comprende administrar a un paciente en necesidad de tal tratamiento una cantidad terapéuticamente eficaz de un compuesto de fórmula (I), o de una sal, profármaco o solvato farmacéuticamente aceptable del mismo. En una realización particular, dicho cáncer se selecciona entre cáncer de pulmón, cáncer de colon, cáncer de mama, cáncer de ovario y cáncer de cuello uterino. En otra realización particular, dicho paciente es un animal, preferiblemente un ser humano.  In another aspect, the invention relates to a method of treatment or prevention of cancer which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), or of a pharmaceutically acceptable salt, prodrug or solvate. acceptable of it. In a particular embodiment, said cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer and cervical cancer. In another particular embodiment, said patient is an animal, preferably a human being.
EJEMPLOS EXAMPLES
La presente invención se ilustra adicionalmente mediante los siguientes ejemplos, los cuales no pretenden ser limitativos de su alcance.  The present invention is further illustrated by the following examples, which are not intended to be limiting in scope.
Ejemplo 1 - Síntesis de los compuestos de la invención Example 1 - Synthesis of the compounds of the invention
El método de síntesis descrito por Kukushkin, Vadim Yu.; Pombeiro, Armando J. L.; Ferreira, Cristina M. P.; Elding, Lars I.; Puddephatt, Richard J. Inorganic Syntheses (2002), 33, 189-196, con ciertas modificaciones, fue el utilizado para sintetizar los compuestos 1-4 objeto de esta invención. El método de síntesis se describe detalladamente a continuación;  The synthesis method described by Kukushkin, Vadim Yu .; Pombeiro, Armando J. L .; Ferreira, Cristina M. P .; Elding, Lars I .; Puddephatt, Richard J. Inorganic Syntheses (2002), 33, 189-196, with certain modifications, was used to synthesize the compounds 1-4 object of this invention. The synthesis method is described in detail below;
Paso 1.- Formación de complejos cis de fórmula cis-[PtX2(DMSO) 2] Step 1.- Formation of cis complexes of formula cis- [PtX 2 (DMSO) 2 ]
X= Cl. A una disolución acuosa de 1 g de K2PtCl4 (2,4 mmol) en 2,5 mL de agua se le añade 0,7 mL de DMSO (9,6 mmol) resultando una disolución anaranjada. Dicha disolución se dej a en agitación a temperatura ambiente en ausencia de luz. Transcurridas 24 horas se separa un sólido amarillo, se lava con abundante agua y etanol y finalmente con éter. El resultado final es un sólido pálido-amarillo que se identifica como cz's-[PtCl2(DMSO)2] donde los datos espectroscópicos coinciden con los descritos en la bibliografía (véase Inorganic Syntheses (2002), 33, 189-196). X= I. A una disolución acuosa de 1 g de K2PtCl4 (2.4 mmol) en 5 mL de agua se le añade 3,984 g de KI (24 mmol) y, después de 1 hora en agitación a temperatura ambiente, se adicionan 0,7 mL de DMSO (9,6 mmol) resultando una disolución marrón. Dicha disolución se deja en agitación a temperatura ambiente en ausencia de luz. Transcurridas 24 horas se separa un sólido naranja, se lava con abundante agua y etanol y finalmente con éter. El resultado final es un sólido naranja que se identifica como cis- [PtI2(DMSO)2] donde los datos espectroscópicos coinciden con los descritos en la bibliografía (véase Transition Metal Chemistry (1998), 23, 403-406). X = Cl. To an aqueous solution of 1 g of K 2 PtCl 4 (2.4 mmol) in 2.5 mL of water is added 0.7 mL of DMSO (9.6 mmol) resulting in an orange solution. Said solution was left under stirring at room temperature in the absence of light. After 24 hours a yellow solid separates, washed with plenty of water and ethanol and finally with ether. The final result is a pale-yellow solid that is identified as cz ' s- [PtCl 2 (DMSO) 2 ] where the spectroscopic data coincide with those described in the literature (see Inorganic Syntheses (2002), 33, 189-196) . X = I. To an aqueous solution of 1 g of K 2 PtCl 4 (2.4 mmol) in 5 mL of water is added 3.984 g of KI (24 mmol) and, after 1 hour under stirring at room temperature, are added 0.7 mL of DMSO (9.6 mmol) resulting in a brown solution. Said solution is left under stirring at room temperature in the absence of light. After 24 hours an orange solid is separated, washed with plenty of water and ethanol and finally with ether. The final result is an orange solid that is identified as cis- [PtI 2 (DMSO) 2 ] where the spectroscopic data coincide with those described in the literature (see Transition Metal Chemistry (1998), 23, 403-406).
Paso 2.- Formación de los complejos trans-[PtX2DMSO(NH2ANH2S02Ar)] Complejo 1 Step 2.- Formation of trans- complexes [PtX 2 DMSO (NH 2 ANH 2 S0 2 Ar)] Complex 1
A una suspensión de 0,190 g. de cz's-PtI2(DMSO)2 en metanol, se le añaden 84,2 mg de N-tosilciclohexano-l,2-diamina y se deja en agitación a temperatura ambiente durante una noche. Transcurrido este tiempo se obtiene una suspensión marrón amarillenta que se filtra, lavando sucesivas veces con metanol. Acto seguido se lava con acetona, la disolución obtenida se concentra y enfría hasta la obtención de un sólido marrón-anaranj ado . At a suspension of 0.190 g. of cz ' s-PtI 2 (DMSO) 2 in methanol, 84.2 mg of N-tosylcyclohexane-1, 2-diamine are added and left under stirring at room temperature overnight. After this time a yellowish brown suspension is obtained, which is filtered, washing successively with methanol. It is then washed with acetone, the solution obtained is concentrated and cooled until a brown-orange solid is obtained.
Rendimiento: 61 % (complejo 1)  Yield: 61% (complex 1)
P.f.: 149-151°C.  Mp .: 149-151 ° C.
IR NujolXcm"1): v: 3260 (R-NH-R), 3002 (=CH- aromáticos), 2934, 2858 (C-H saturados), 1447 (-CH2-C=C), 1186 (C-N). IR NujolXcm "1 ): v: 3260 (R-NH-R), 3002 (= aromatic CH), 2934, 2858 (saturated CH), 1447 (-CH 2 -C = C), 1186 (CN).
Análisis elemental para Ci5H26I2N203PtS2 KC1: Elemental analysis for Ci 5 H 26 I 2 N 2 0 3 PtS 2 KC1:
calculado: C: 20,71, H: 3,01, N: 3,22, S: 7,37  calculated: C: 20.71, H: 3.01, N: 3.22, S: 7.37
encontrado: C: 20,76, H: 3,04, N: 3,54, S: 7,85  Found: C: 20.76, H: 3.04, N: 3.54, S: 7.85
1H RMN (acetona-d6)(ppm): 7,66 (d, J = 8,2 Hz, 2H), 7,29, (d, J = 8,1 Hz, 2H), 6,66 (d, J = 8,1 Hz, 1H), 4,63 (bs, 1H), 4,02 (bs, 1H), 3,66 (s, 3JPt_H = 10,2 Hz, 3H), 3,62-3,57 (m, 1H), 3,01-2,92 (m, 1H), 2,52-2,47 (m, 1H), 2,30 (s, 3H), 1,61-1,58 (m, 1H), 1,44-1,40 (m, 1H), 1,30-0,96 (m, 5H). 13C RMN (acetona-d6)(ppm): 144,4 (C), 139,3 (C), 130,6 (CH), 127,9 (CH), 61 ,7 (CH), 59,2 (CH), 51 ,7 (CH3), 33 ,9 (CH2), 32,3 (CH2), 25,5 (CH2), 25,3 (CH2), 21 ,4 (CH3). 1 H NMR (acetone-d 6 ) (ppm): 7.66 (d, J = 8.2 Hz, 2H), 7.29, (d, J = 8.1 Hz, 2H), 6.66 (d , J = 8.1 Hz, 1H), 4.63 (bs, 1H), 4.02 (bs, 1H), 3.66 (s, 3 J Pt _ H = 10.2 Hz, 3H), 3 , 62-3.57 (m, 1H), 3.01-2.92 (m, 1H), 2.52-2.47 (m, 1H), 2.30 (s, 3H), 1.61 -1.58 (m, 1H), 1.44-1.40 (m, 1H), 1.30-0.96 (m, 5H). 13 C NMR (acetone-d 6 ) (ppm): 144.4 (C), 139.3 (C), 130.6 (CH), 127.9 (CH), 61, 7 (CH), 59, 2 (CH), 51, 7 (CH 3 ), 33, 9 (CH 2 ), 32.3 (CH 2 ), 25.5 (CH 2 ), 25.3 (CH 2 ), 21, 4 (CH 3 ).
195Pt (acetona-d6) (ppm): -4393,2. 1 95 Pt (acetone-d 6 ) (ppm): -4393.2.
Complejo 2 Complex 2
A una suspensión de 0, 1610 g de cz's-PtCl2(DMSO)2 en metanol, se le añaden 0, 1 023 g de N-tosilciclohexano-l ,2-diamina y se deja en agitación a temperatura ambiente durante una noche. Transcurrido este tiempo se obtiene una suspensión marrón amarillenta que se filtra, lavando sucesivas veces con metanol. El sólido obtenido de color amarillento, se deja secar a vacío. To a suspension of 0.1610 g of cz ' s-PtCl 2 (DMSO) 2 in methanol, 1.023 g of N-tosylcyclohexane-1, 2-diamine is added and allowed to stir at room temperature for a night. After this time a yellowish brown suspension is obtained, which is filtered, washing successively with methanol. The solid obtained yellowish, is allowed to dry under vacuum.
Rendimiento: 57 % (complejo 2)  Yield: 57% (complex 2)
P.f.: (descompone 189°C).  P.f .: (decomposes 189 ° C).
IR (NujolXcm"1): v: 3229 (R-NH-R), 3010 (=CH- aromáticos), 2936, 2860 (C-H saturados), 1448 (-CH2-C=C), 1 186 (C-N). IR (NujolXcm "1 ): v: 3229 (R-NH-R), 3010 (= CH-aromatic), 2936, 2860 (saturated CH), 1448 (-CH 2 -C = C), 1 186 (CN) .
M S (TOF ES+): [M+Na]+ calculado para Ci5H26Cl2N203PtS2 634,0302; experimental 634,0303. MS (TOF ES + ): [M + Na] + calculated for Ci 5 H 26 Cl 2 N 2 0 3 PtS 2 634.0302; Experimental 634,0303.
1H RMN (CDCl3)(ppm): 7,71 (d, J = 8,3 Hz, 2H), 7,27 (d, J = 8,0 Hz, 2H), 5,07 (d, J = 9,4 Hz, 1H), 4,71 (d, J = 10,7 Hz, 1H), 3,35 (s, 6H), 2,85-2,79 (m, 3H), 2,38 (s, 3H), 1 ,73-1 ,66 (m, 1H), 1 ,53-1 ,49 (m, 1H), 1 ,33-1 ,26 (m, 1H), 1 ,24-1 ,15 (m 2H), 1,04-0,96 (m 2H). 1 H NMR (CDCl 3 ) (ppm): 7.71 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 5.07 (d, J = 9.4 Hz, 1H), 4.71 (d, J = 10.7 Hz, 1H), 3.35 (s, 6H), 2.85-2.79 (m, 3H), 2.38 ( s, 3H), 1, 73-1, 66 (m, 1H), 1, 53-1, 49 (m, 1H), 1, 33-1, 26 (m, 1H), 1, 24-1, 15 (m 2H), 1.04-0.96 (m 2H).
13C RMN (CDCl3)(ppm): 144, 1 (C), 137,5 (C), 130, 1 (CH), 127,0 (CH), 58,9 (CH), 58,6 (CH), 44,2 (CH3), 43,9 (CH3), 32,6 (CH2), 32,3 (CH2), 24,9 (CH2), 24,2 (CH2), 21 ,6 (CH2). 13 C NMR (CDCl 3 ) (ppm): 144, 1 (C), 137.5 (C), 130, 1 (CH), 127.0 (CH), 58.9 (CH), 58.6 ( CH), 44.2 (CH 3 ), 43.9 (CH 3 ), 32.6 (CH 2 ), 32.3 (CH 2 ), 24.9 (CH 2 ), 24.2 (CH 2 ) , 21, 6 (CH 2 ).
195Pt (CDC13) (ppm): -31 12,7. 1 95 Pt (CDC1 3 ) (ppm): -31 12.7.
Complejo 3 Complex 3
A una suspensión de 0, 156 g de cz's-PtCl2(DMSO)2 en metanol, se le añaden 0, 1283 g de la correspondiente N-(l-(dimetilamino)naftalen-5-ilsulfonil)ciclohexano- 1 ,2-diamina y se dej a en agitación a temperatura ambiente durante una noche. Transcurrido este tiempo se obtiene una suspensión amarillenta que se filtra, lavando sucesivas veces con metanol. El sólido obtenido de color amarillento, se deja secar a vacío. To a suspension of 0.156 g of cz ' s-PtCl 2 (DMSO) 2 in methanol, 0.1283 g of the corresponding N- (l- (dimethylamino) naphthalen-5-ylsulfonyl) cyclohexane-1 are added, 2-diamine and allowed to stir at room temperature overnight. After this time a yellowish suspension is obtained, which is filtered, washing successive times with methanol. The solid obtained yellowish, is allowed to dry under vacuum.
Rendimiento: 76 % (complejo 3)  Yield: 76% (complex 3)
P.f.: (descompone 186 °C)  P.f .: (decomposes 186 ° C)
IR (NujolXcm"1): v: 3266 (R-NH-R), 3006 (=CH- aromáticos), 2938, 2861 (C-H saturados), 1452 (-CH2-C=C), 1185 (C-N). IR (NujolXcm "1 ): v: 3266 (R-NH-R), 3006 (= aromatic CH), 2938, 2861 (saturated CH), 1452 (-CH 2 -C = C), 1185 (CN).
Análisis elemental para C20H31Cl2N3O3PtS2- l/2 H20-1/2KC1: Elemental analysis for C 20 H 31 Cl 2 N 3 O 3 PtS 2 - l / 2 H 2 0-1 / 2KC1:
calculado: C: 32,55, H: 4,37, N: 5,69, S: 8,69  Calculated: C: 32.55, H: 4.37, N: 5.69, S: 8.69
encontrado: C: 32,28, H: 4,32, N: 5,65, S: 9,77  Found: C: 32.28, H: 4.32, N: 5.65, S: 9.77
1H RMN (CDCl3)(ppm): 8,91 (d, J = 8,7 Hz, 1H), 8,44 (d, J = 8,4 Hz, 1H), 8,35 (d, J= 6,9 Hz, 1H), 7,55 (t, J= 8,2 Hz, 1H), 7,47 (t, J= 7,9 Hz, 1H), 7,13 (d, J = 7,5 Hz, 1H), 4,28 (d, J = 9,1 Hz, 1H), 3,94 (t, J = 10,6 Hz, 1H), 3,51 (s, 3H), 3,48 (s, 3H), 3,31-3,17 (m, 2H), 2.85 (s, 3JPt.H = 14.0 Hz, 6H), 1,98-1,95 (m, 1H), 1,53-1,49 (m, 1H), 1,34-1,28 (m, 4H), 1,15-1,02 (m, 1H), 0,94-0,81 (m, 1H). 1 H NMR (CDCl 3 ) (ppm): 8.91 (d, J = 8.7 Hz, 1 H), 8.44 (d, J = 8.4 Hz, 1 H), 8.35 (d, J = 6.9 Hz, 1H), 7.55 (t, J = 8.2 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7, 5 Hz, 1H), 4.28 (d, J = 9.1 Hz, 1H), 3.94 (t, J = 10.6 Hz, 1H), 3.51 (s, 3H), 3.48 (s, 3H), 3.31-3.17 (m, 2H), 2.85 (s, 3 J Pt . H = 14.0 Hz, 6H), 1.98-1.95 (m, 1H), 1, 53-1.49 (m, 1H), 1.34-1.28 (m, 4H), 1.15-1.02 (m, 1H), 0.94-0.81 (m, 1H).
13C RMN (CDCl3)(ppm): 151,2 (C), 138,6 (C), 130,5 (C), 129,7 (C), 129,2 (CH), 129,0 (CH), 127,5 (CH), 122,9 (CH), 121,2 (CH), 114,9 (CH), 69,4 (CH3), 62,3 (CH3), 45,5 (CH3), 44,8 (CH), 44,7 (CH2), 33,3 (CH2), 31,7 (CH2), 24,9 (CH2), 24,6 (CH2). 13 C NMR (CDCl 3 ) (ppm): 151.2 (C), 138.6 (C), 130.5 (C), 129.7 (C), 129.2 (CH), 129.0 ( CH), 127.5 (CH), 122.9 (CH), 121.2 (CH), 114.9 (CH), 69.4 (CH 3 ), 62.3 (CH 3 ), 45.5 (CH 3 ), 44.8 (CH), 44.7 (CH 2 ), 33.3 (CH 2 ), 31.7 (CH 2 ), 24.9 (CH 2 ), 24.6 (CH 2 ).
195Pt (CDC13) (ppm): -3036,0. 1 95 Pt (CDC1 3 ) (ppm): -3036.0.
Complejo 4 Complex 4
A una suspensión de 0,209 g de cz's-PtCl2(DMSO)2 en metanol, se le añaden 0,1266 g de N-(3-aminopropil)-2,4,6-trimetillbencenamina y se deja en agitación a temperatura ambiente durante una noche. Transcurrido este tiempo se obtiene una suspensión naranja-amarillenta que se filtra, lavando sucesivas veces con metanol. El sólido obtenido de color amarillento, se deja secar a vacío. To a suspension of 0.209 g of cz ' s-PtCl 2 (DMSO) 2 in methanol, 0.1266 g of N- (3-aminopropyl) -2,4,6-trimethylbenzene amine are added and allowed to stir at temperature One night atmosphere. After this time an orange-yellow suspension is obtained, which is filtered, washing successively with methanol. The solid obtained yellowish, is allowed to dry under vacuum.
Rendimiento: 70 % (complejo 4)  Yield: 70% (complex 4)
P.f.: (descompone 166 °C).  P.f .: (decomposes 166 ° C).
IR (NujolXcm 1): v: 3280 (R-NH-R), 3006 (=CH- aromáticos), 2921 (C-H saturados), 1454 (-CH2-C=C), 1187 (C-N). M S (T O F E S+): [M+Na]+ calculado para Ci4H26Cl2N203PtS2 622,0302; experimental 622,0303. IR (NujolXcm 1 ): v: 3280 (R-NH-R), 3006 (= aromatic CH), 2921 (saturated CH), 1454 (-CH 2 -C = C), 1187 (CN). MS (TOFES + ): [M + Na] + calculated for Ci 4 H 26 Cl 2 N 2 0 3 PtS 2 622.0302; Experimental 622,0303.
1H RMN (acetona-d6)(ppm): 6,90 (d, J = 6,6 Hz, 2H), 6,33 (bs, 1H), 6, 15 (bs, 1H), 4,36 (bs, 1H), 3, 17 (s, 3JPt_H = 9,3 Hz, 3H), 2,95-2,90 (m, 2H), 2,79-2,73 (m, 2H), 2,51 (s, 3H), 2,45 (s, 3H), 2, 16 (s, 3H), l ,87-l ,83(m, 1H), 1,53-1,48 (m, 1H). 1H NMR (acetone-d 6 ) (ppm): 6.90 (d, J = 6.6 Hz, 2H), 6.33 (bs, 1H), 6, 15 (bs, 1H), 4.36 ( bs, 1H), 3, 17 (s, 3 J Pt _ H = 9.3 Hz, 3H), 2.95-2.90 (m, 2H), 2.79-2.73 (m, 2H) , 2.51 (s, 3H), 2.45 (s, 3H), 2, 16 (s, 3H), l, 87-l, 83 (m, 1H), 1.53-1.48 (m , 1 HOUR).
13C RMN (acetona-d6)(ppm): 141 ,7 (C), 138,8 (C), 134,8 (C), 131 ,8 (CH), 131,7 (CH), 42,7 (CH3), 39,7 (CH2), 39,4 (CH2), 30,3 (CH2), 22,2 (CH3), 22, 1 (CH3), 19,9 (CH3). 13 C NMR (acetone-d 6 ) (ppm): 141, 7 (C), 138.8 (C), 134.8 (C), 131, 8 (CH), 131.7 (CH), 42, 7 (CH 3 ), 39.7 (CH 2 ), 39.4 (CH 2 ), 30.3 (CH 2 ), 22.2 (CH 3 ), 22, 1 (CH 3 ), 19.9 ( CH 3 ).
195Pt (acetona-de) (ppm): -31 15,5. 195 Pt (acetone-de) (ppm): -31 15.5.
La Figura 1 , que representa la resolución de la estructura por difracción de rayos X del compuesto 4, está de acuerdo con todos los datos descritos anteriormente. El entorno del átomo de Pt es plano cuadrado, con la amina en posición trans al grupo DMSO. La longitud de enlace Pt-N =2,069 Á, mientras que la distancia Pt-S es 2,213 Á. Las distancias Pt-Cl están en el rango 2,286 (Pt-CU) y Pt-C12) es 2,307, de acuerdo con otros complejos tipo trans- [PtCl2LL'] donde L y L' son diferentes grupos y en los que los grupos cloruros se hallan en posición trans uno de otro [Montero, E.I. y col. J. Med. Chem (1999), 42, 4264]. Figure 1, which represents the resolution of the X-ray diffraction structure of compound 4, is in accordance with all the data described above. The environment of the Pt atom is square plane, with the amine in trans position to the DMSO group. The link length Pt-N = 2,069 Á, while the distance Pt-S is 2,213 Á. The distances Pt-Cl are in the range 2,286 (Pt-CU) and Pt-C12) is 2,307, according to other trans-type complexes [PtCl 2 LL '] where L and L' are different groups and in which the Chloride groups are in trans position from one another [Montero, EI et al. J. Med. Chem (1999), 42, 4264].
Ejemplo 2 - Estudios biológicos Example 2 - Biological studies
La actividad antitumoral fue estudiada utilizando el protocolo NCI [P. O. Miranda, j. M. Padrón, j. I. Padrón, j. Villar, V. S. Martín, ChemMedChem 2006, 1, 323-329.]. El efecto se mide como inhibición de crecimiento (GI50), [P. O. Miranda, j. M. Padrón, j. I. Padrón, j. Villar, V. S. Martín, ChemMedChem 2006, 1, 323-329.] determinándose con distintas líneas representativas de tumores sólidos en líneas celulares: A2780 (línea celular de carcinoma de ovario humano), HBL-1 00 (línea celular de carcinoma de mama humano), HeLa (línea celular de carcinoma de cuello de útero humano), Ishikawa (línea celular de adenocarcinoma endometrial humano), SW1573 (línea celular de carcinoma de pulmón humano) , T-47D (línea celular de carcinoma de mama humano), and WiDr (línea celular de carcinoma de colon humano). The antitumor activity was studied using the NCI protocol [PO Miranda, j. M. Padrón, j. I. Register, j. Villar, VS Martín, ChemMedChem 2006, 1, 323-329.]. The effect is measured as growth inhibition (GI 50 ), [PO Miranda, j. M. Padrón, j. I. Register, j. Villar, VS Martín, ChemMedChem 2006, 1, 323-329.] Determined with different representative lines of solid tumors in cell lines: A2780 (human ovarian carcinoma cell line), HBL-1 00 (human breast carcinoma cell line ), HeLa (human cervical carcinoma cell line), Ishikawa (human endometrial adenocarcinoma cell line), SW1573 (human lung carcinoma cell line), T-47D (human breast carcinoma cell line), and WiDr (human colon carcinoma cell line).
Los datos más relevantes indican que dichos compuestos presentan una actividad citotóxica notablemente superior al cisplatino, en distintas líneas celulares como A2780, HBL-100, HeLa, ISHIKAWA, SW1573, T-47D, WiDr con valores de GI50 [M] (véase Tabla 1). The most relevant data indicate that these compounds have a significantly higher cytotoxic activity than cisplatin, in different cell lines such as A2780, HBL-100, HeLa, ISHIKAWA, SW1573, T-47D, WiDr with values of GI 50 [M] (see Table 1).
Tabla 1. Diferentes valores GI50 [M] para los complejos 1-4.
Figure imgf000020_0001
Table 1. Different GI 50 values [M] for complexes 1-4.
Figure imgf000020_0001
nd= no determinado. Datos obtenidos a las 72 horas de incubación.  nd = not determined. Data obtained at 72 hours of incubation.

Claims

REIVINDICACIONES
1. Un compuesto de fórmula (I) 1. A compound of formula (I)
Figure imgf000021_0001
Figure imgf000021_0001
(I)  (I)
donde where
Ar representa arilo;  Ar represents aryl;
A representa alquilideno o cicloalquilideno;  A represents alkylidene or cycloalkylidene;
X representa halógeno; y  X represents halogen; Y
L representa un ligando coordinante monodentado;  L represents a monodentate coordinating ligand;
o una sal, un pro fármaco o un solvato del mismo. or a salt, a pro drug or a solvate thereof.
2. Compuesto según la reivindicación 1 , seleccionado entre un compuesto de fórmula (la) y un compuesto de fórmula (Ib) 2. Compound according to claim 1, selected from a compound of formula (la) and a compound of formula (Ib)
Figure imgf000021_0002
Figure imgf000021_0002
Fórmula (la) Fórmula (Ib)  Formula (la) Formula (Ib)
donde Ar, A, X y L tienen los significados definidos en la reivindicación 1.  wherein Ar, A, X and L have the meanings defined in claim 1.
3. Compuesto según cualquiera de las reivindicaciones 1 ó 2, en el que Ar se selecciona entre fenilo y naftilo, ambos sustituidos o no sustituidos. 3. A compound according to any one of claims 1 or 2, wherein Ar is selected from phenyl and naphthyl, both substituted or unsubstituted.
4. Compuesto según cualquiera de las reivindicaciones 1 a 3, en el que Ar se selecciona entre fenilo y naftilo sustituidos por uno o más grupos alquilo y/o por uno más grupos dialquilamino. 4. A compound according to any one of claims 1 to 3, wherein Ar is selected from phenyl and naphthyl substituted by one or more alkyl groups and / or by one or more dialkylamino groups.
5. Compuesto según cualquiera de las reivindicaciones 1 a 4, en el que Ar se selecciona entre 5. Compound according to any of claims 1 to 4, wherein Ar is selected from
Figure imgf000022_0001
Figure imgf000022_0001
6. Compuesto según cualquiera de las reivindicaciones 1 ó 2, en el que A se selecciona entre metilén, etilén, n-propilén, n-butilén, n-pentilén, 6. A compound according to any one of claims 1 or 2, wherein A is selected from methylene, ethylene, n-propylene, n-butylene, n-pentylén,
Figure imgf000022_0002
Figure imgf000022_0002
7. Compuesto según la reivindicación 6, en el que A se selecciona entre n- propilén
Figure imgf000022_0003
7. Compound according to claim 6, wherein A is selected from n-propylene
Figure imgf000022_0003
8. Compuesto según cualquiera de las reivindicaciones 1 ó 2, en el que L se selecciona entre metanol, etanol, tetrahidrofurano, dimetilformamida, dimetilacetamida y dimetilsulfóxido. 8. A compound according to any one of claims 1 or 2, wherein L is selected from methanol, ethanol, tetrahydrofuran, dimethylformamide, dimethylacetamide and dimethylsulfoxide.
9. Compuesto según la reivindicación 7, en el que L es dimetilsulfóxido. 9. A compound according to claim 7, wherein L is dimethylsulfoxide.
10. Compuesto según cualquiera de las reivindicaciones 1 ó 2, en el que X es cloro o yodo. 10. Compound according to any of claims 1 or 2, wherein X is chlorine or iodine.
11. Compuesto según cualquiera de las reivindicaciones 1 a 10, seleccionado entre: 11. Compound according to any of claims 1 to 10, selected from:
Figure imgf000023_0001
Figure imgf000023_0001
1  one
Figure imgf000023_0002
Figure imgf000023_0002
12. Un procedimiento para la preparación de un compuesto de fórmula (I) 12. A process for the preparation of a compound of formula (I)
Figure imgf000023_0003
Figure imgf000023_0003
(I)  (I)
donde where
Ar representa arilo;  Ar represents aryl;
A representa alquilideno o cicloalquilideno;  A represents alkylidene or cycloalkylidene;
X representa halógeno; y  X represents halogen; Y
L representa un ligando coordinante monodentado; que comprende: L represents a monodentate coordinating ligand; which includes:
- formar un complejo cz's-[PtX2L2] de fórmula (II), donde X y L tienen el significado arriba indicado; y hacer reaccionar dicho complejo de fórmula (II) con una N-sulfonamida para obtener un compuesto de fórmula (I). - forming a cz ' s- [PtX 2 L 2 ] complex of formula (II), where X and L have the meaning indicated above; and reacting said complex of formula (II) with an N-sulfonamide to obtain a compound of formula (I).
13. Una composición farmacéutica que comprende un compuesto de fórmula (I) según cualquiera de las reivindicaciones l a 11 y un excipiente farmacéuticamente aceptable. 13. A pharmaceutical composition comprising a compound of formula (I) according to any of claims 1 to 11 and a pharmaceutically acceptable excipient.
14. Compuesto de fórmula (I) según se ha definido en cualquiera de las reivindicaciones 1 a 11 para su uso en medicina. 14. Compound of formula (I) as defined in any of claims 1 to 11 for use in medicine.
15. Uso de un compuesto de fórmula (I) según cualquiera de las reivindicaciones 1 a l l, o una sal, profármaco o solvato farmacéuticamente aceptable del mismo, en la elaboración de una composición farmacéutica para la prevención o el tratamiento de cáncer. 15. Use of a compound of formula (I) according to any of claims 1 to 1, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in the preparation of a pharmaceutical composition for the prevention or treatment of cancer.
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