WO2004016622A1 - Derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles as antineoplasic agents - Google Patents

Derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles as antineoplasic agents Download PDF

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WO2004016622A1
WO2004016622A1 PCT/ES2003/000424 ES0300424W WO2004016622A1 WO 2004016622 A1 WO2004016622 A1 WO 2004016622A1 ES 0300424 W ES0300424 W ES 0300424W WO 2004016622 A1 WO2004016622 A1 WO 2004016622A1
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Yolanda MARTÍN SÁNCHEZ-CANTALEJO
María Jesús VILLA HORMAECHE
Beatríz SAEZ PIZARRO
Javier Soto Romero
Miguel FERNÁNDEZ BRAÑA
Juan Carlos Lacal Sanjuan
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Consejo Superior De Investigaciones Científicas
Universidad Europea 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • Burguess et al Synthesis (1988), 36, p 199 synthesized 4,4'-trifluoromethyl-5,5'-fluor-2,2'-bisoxazole, and the corresponding bistiazole, with p-spacer phenyl among the heterocyclic rings, by treatment of 4,4-bis (trifluoromethyl) -hetero-1, 3- dienes with tin (II) chloride; also, K. Burguess et al Synthesis (1988), 36, p 194, describe the synthesis of other 5,5' symmetrical -bisoxazoles by coupling the 5--fluoroxazol preformed through a spacer.
  • B. et Helmreich to the United States Patent No.
  • the present invention presents new derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles of general formula I:
  • X can be oxygen or sulfur
  • Z may not exist or be 1,2-ethylidene, isopropylidene, p, p-biphenyl, p-phenyl, m-phenyl, 2,6-pyridylene, p, p-oxidiphenyl, p, p'-hexafluoroisopropylidendiphenyl
  • R may be hydrogen or substituents of those usual in organic chemistry, such as alkyls, alkylidenes, alkynes, aryls, or functional groups such as halogens, alcohols, thiols, ethers, thioethers, sulfoxides, sulfones, amines with or without substituents, nitro, aldehydes , ketones, nitrile, carboxylic acids and any of their derivatives, such as esters, amides, hydrazides, hydroxamic acids, with or without substituents, sulf
  • the mechanism of its industrial production is indicated in the present patent and forms part of the present invention.
  • the present patent describes the ability of these compounds to inhibit cell proliferation and, specifically, that of malignant cells such as HT-29, so they have application in anticancer therapy, and such use is part of the present invention. .
  • the present invention presents new derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles of general formula I:
  • HA compounds are directly transformed into VAT bisoxazoles by treatment with some fluorinated anhydrides, such as trifluoroacetic, pentafluoropropionic and heptafluorbutanoic anhydrides at different temperatures and in toluene as a solvent and using a base, such as pyridine.
  • fluorinated anhydrides such as trifluoroacetic, pentafluoropropionic and heptafluorbutanoic anhydrides at different temperatures and in toluene as a solvent and using a base, such as pyridine.
  • a complementary method is used via the anhydrobase IIIA, obtained by treatment of the corresponding HA diamide with ethyl chloroformate, using a base like triethylamine.
  • NIA compounds are generally obtained as insoluble solids within the reaction solvent (acetone) and are purified by conventional methods.
  • the subsequent oxazole formation reaction can be carried out successfully by working with the insoluble solid, which contains the triethylamine anhydrobase and hydrochloride in a 1: 5 ratio, as can be estimated based on its NMR- 1 spectra.
  • NIA anhydrobases are subsequently treated with different anhydrides or acid derivatives at different temperatures to obtain the bisoxazoles IVA, which give rise to the general structure IA by quaternization of the pyridine nitrogen with the corresponding alkyl derivative.
  • Both the IA and VAT products thus obtained are purified by conventional methods, and can be identified and characterized by the usual analytical procedures.
  • bistioamide is initially prepared and the previous sequence is continued as indicated in the scheme.
  • the corresponding thioamides IIB with different spacers (Z) are obtained by reacting the NA diamides with the Lawensson reagent at the reflux temperature of THF.
  • These HB compounds are directly transformed into IVB bistiazoles by treatment with some fluorinated anhydrides, for example, trifluoroacetic anhydride, under the conditions identical to those described for the transformation of HA amides into VAT bisoxazoles.
  • some fluorinated anhydrides for example, trifluoroacetic anhydride
  • the chemical compounds described in this patent can be used as anti-tumor active ingredients in human patients, and can be prepared and administered, according to the knowledge of the state of the art of galenic development, in different ways such as injectables, capsules, dragees or tablets, both as a free base as in the form of any of the salts mentioned, and all of them form part of the present invention.
  • solid forms are made in the presence of the necessary excipients, such as, among others, mannitol, polyvinylpyrrolidone, microcrystalline cellulose, silica gel, talcum, magnesium stearate, titanium oxide, USP grade dyes and antioxidants, and form part of the present invention.
  • reaction crude was extracted with ethyl acetate (3 x 15 mL) and the organic extracts were combined, washed with a saturated sodium chloride solution and dried with anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude obtained was purified by column chromatography (silica gel, ethyl acetate) and 2,2-bis [(5-trifluoromethyl-4- (4-pyridyl) -2] -oxazolyl)] propane (200 mg, 80%), as a yellow-beige solid, mp 126-128 S C (ethanol).
  • pyridine 0.35 ml, 4.32 mmol
  • the mixture was cooled to 0 Q C and then was added drop trifluoroacetic anhydride (0.31 mi, 2.16 mmol).
  • Example 8 Antitumor activity assays of the chemical compounds of the present patent.

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Abstract

The invention relates to novel derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles, having general formula I with antiproliferative activity and, more specifically, malignant cells such as HT-29. The invention also relates to the industrial production method for same and to the use thereof in the development of pharmaceutical compounds for the treatment of human tumours.

Description

TITULOTITLE
DERIVADOS DE 4-4'-BIPIRIDIL-2-2'-BISOXAZOLES Y 4-4'-BIPIRIDIL-2-2'- BISTIAZOLES COMO AGENTES ANTINEOPLÁSICOSDERIVATIVES OF 4-4'-BIPIRIDIL-2-2'-BISOXAZOLES AND 4-4'-BIPIRIDIL-2-2'- BISTIAZOLES AS ANTINEOPLASTIC AGENTS
SECTOR DE LA TÉCNICASECTOR OF THE TECHNIQUE
Compuestos químicos antitumorales. Síntesis química. Bisoxazoles y bistiazoles.Chemical anti-tumor compounds Chemical synthesis Bisoxazoles and bistiazoles.
ESTADO DEL ARTE Recientemente la síntesis de bis- y tris-oxazoles ha atraído mucha atención debido a la presencia de este heterociclo en varios productos naturales, tales como hennoxazoles como se describe en T. Ichiba et al J. Am. Chem. Soc. (1991), 113, p 3173, ulapualidas en J. A. Rosener et al J. Am. Chem. Soc. (1986), 108, p 846, y micalolidas en Panek etalJ. Am. Chem. Soc. (2000), 122, p 1235, todos ellos con actividad antifúngica. También la estructura de bistiazoles se encuentra en productos naturales como las micrococcinas según el trabajo de T. R. Kelly et al Tetrahedron Lett. (1995), 36, p 5319. En general, todos estos compuestos se caracterizan por la unión de los heterociclos correspondientes en posición 2,4', y su síntesis se aborda mediante la construcción secuencial de los anillos de oxazol o tiazol como se muestra en C. J. Moody et al Tetrahedron Lett. (1992), 33, p 7769, o bien mediante el acoplamiento cruzado de los heterociclos formados previamente como describen D. R. Williams et al Tetrahedron Lett (1998), 39, p 8023.STATE OF THE ART Recently the synthesis of bis- and tris-oxazoles has attracted a lot of attention due to the presence of this heterocycle in several natural products, such as hennoxazoles as described in T. Ichiba et al. J. Am. Chem. Soc. ( 1991), 113, p 3173, ulapualides in JA Rosener et al. J. Am. Chem. Soc. (1986), 108, p 846, and micalolides in Panek et al. Am. Chem. Soc. (2000), 122, p 1235, all of them with antifungal activity. The structure of bistiazoles is also found in natural products such as micrococcines according to the work of T. R. Kelly et al Tetrahedron Lett. (1995), 36, p 5319. In general, all these compounds are characterized by the binding of the corresponding heterocycles in 2.4 'position, and their synthesis is addressed by sequential construction of the oxazole or thiazole rings as shown in CJ Moody et al Tetrahedron Lett. (1992), 33, p 7769, or by cross-coupling the previously formed heterocycles as described by D. R. Williams et al Tetrahedron Lett (1998), 39, p 8023.
Los ejemplos de bisoxazoles o bistiazoles simétricos son muy escasos en la literatura, y menos frecuente aún es la formación simultánea de ambos anillos con unión 2,2'. R. Schróeder et al Liebigs. Ann. Chem. (1975), p 533, describen la síntesis del 5,5'-bifenil-2,2'-bisoxazol por acoplamiento de 5- feniloxazol-2-illitio con 2-tosiloxazol con rendimiento del 25%. Más tarde, K. Burguess et al Synthesis (1988), 36, p 199, sintetizan el 4,4'-trifluorometil-5,5'- fluor-2,2'-bisoxazol, y el correspondiente bistiazol, con espaciador p-fenilo entre los anillos heterocíclicos, por tratamiento de 4,4-bis(trifluorometil)-hetero-1 ,3- dienos con cloruro de estaño (II); también, K. Burguess et al Synthesis (1988), 36, p 194, describen la síntesis de otros 5,5 '-bisoxazoles simétricos mediante acoplamiento del anillo de 5-fluoroxazol preformado a través de un espaciador. En un trabajo posterior, B. Helmreich et al United States Patent Ns 5300625 (1994) utilizan la metodología desarrollada por Burguess para obtener polímeros con estructura de 2,2'-bisoxazol. No obstante lo anterior, no se han encontrado antecedentes sobre la utilización de bisoxazoles o bistiazoles en la terapia anticancerosa.Examples of bisoxazoles or symmetrical bistiazoles are very scarce in the literature, and less frequent is the simultaneous formation of both rings with 2,2 'junction. R. Schróeder et al Liebigs. Ann. Chem. (1975), p 533, describe the synthesis of 5,5'-biphenyl-2,2'-bisoxazole by coupling of 5-phenyloxazol-2-illitium with 2-tosyloxazole in 25% yield. Later, K. Burguess et al Synthesis (1988), 36, p 199, synthesized 4,4'-trifluoromethyl-5,5'-fluor-2,2'-bisoxazole, and the corresponding bistiazole, with p-spacer phenyl among the heterocyclic rings, by treatment of 4,4-bis (trifluoromethyl) -hetero-1, 3- dienes with tin (II) chloride; also, K. Burguess et al Synthesis (1988), 36, p 194, describe the synthesis of other 5,5' symmetrical -bisoxazoles by coupling the 5--fluoroxazol preformed through a spacer. In later work, B. et Helmreich to the United States Patent No. 5300625 s (1994) using the methodology developed by Burgess to obtain polymers with 2,2'-bisoxazole structure. Notwithstanding the foregoing, no background has been found on the use of bisoxazoles or bistiazoles in anticancer therapy.
DESCRIPCIÓN Descripción breveDESCRIPTION Brief Description
La presente invención presenta nuevos derivados de 4-4'-bipiridil-2-2'- bisoxazoles y 4-4'-bipiridil-2-2'-bistiazoles de fórmula general I:The present invention presents new derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles of general formula I:
Figure imgf000003_0001
Figure imgf000003_0001
I donde X puede ser oxígeno o azufre; Z puede no existir o bien ser 1 ,2-etilideno, isopropilideno, p,p-bifenilo, p-fenilo, m-fenilo, 2,6-piridileno, p,p-oxidifenilo, p,p'-hexafluoroisopropilidendifenilo; R pueden ser hidrógeno o sustituyentes de los habituales en la química orgánica, como alquilos, alquilidenos, alquinos, arilos, o grupos funcionales como halógenos, alcoholes, tioles, éteres, tioéteres, sulfoxidos, sulfonas, aminas con o sin sustituyentes, nitro, aldehidos, cetonas, nitrilo, ácidos carboxílicos y cualquiera de sus derivados, como esteres, amidas, hidrazidas, ácidos hidroxámicos, con o sin sustituyentes, ácidos sulfónicos y cualquiera de sus derivados equivalentes a los citados para los ácidos carboxílicos, etc, así como una sal, orgánica o inorgánica, farmacológicamente aceptable o profármacos de la misma, como sulfato, metanosulfonato, hidrocloruro, fosfato, nitrato, acetato, propionato, butirato, palmitato, oxalato, malonato, maleato, malato, fumarato, citrato, benzoato, etc; R' puede no existir o ser grupos alquilo; Y puede, a su vez, no existir, o ser sulfato, metanosulfonato, hidrocloruro, fosfato, nitrato, acetato, propionato, butirato, palmitato, oxalato, malonato, maleato, malato, fumarato, citrato, benzoato, etc. Por otro lado, se indica en la presente patente el mecanismo de su producción industrial y forma parte de la presente invención. Finalmente, en la presente patente se describe la capacidad de estos compuestos para inhibir la proliferación celular y, concretamente, la de células malignas como HT-29, por lo que tienen aplicación en la terapia anticancerosa, y dicho uso forma parte de la presente invención.I where X can be oxygen or sulfur; Z may not exist or be 1,2-ethylidene, isopropylidene, p, p-biphenyl, p-phenyl, m-phenyl, 2,6-pyridylene, p, p-oxidiphenyl, p, p'-hexafluoroisopropylidendiphenyl; R may be hydrogen or substituents of those usual in organic chemistry, such as alkyls, alkylidenes, alkynes, aryls, or functional groups such as halogens, alcohols, thiols, ethers, thioethers, sulfoxides, sulfones, amines with or without substituents, nitro, aldehydes , ketones, nitrile, carboxylic acids and any of their derivatives, such as esters, amides, hydrazides, hydroxamic acids, with or without substituents, sulfonic acids and any of their derivatives equivalent to those mentioned for carboxylic acids, etc., as well as a salt , organic or inorganic, pharmacologically acceptable or prodrugs thereof, such as sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate, etc .; R 'may not exist or be alkyl groups; And it can, in turn, not exist, or be sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate, etc. On the other hand, the mechanism of its industrial production is indicated in the present patent and forms part of the present invention. Finally, the present patent describes the ability of these compounds to inhibit cell proliferation and, specifically, that of malignant cells such as HT-29, so they have application in anticancer therapy, and such use is part of the present invention. .
Descripción detalladaDetailed description
La presente invención presenta nuevos derivados de 4-4'-bipiridil-2-2'- bisoxazoles y 4-4'-bipiridil-2-2'-bistiazoles de fórmula general I:The present invention presents new derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles of general formula I:
Figure imgf000004_0001
Figure imgf000004_0001
Por otro lado, en la presente patente se describe la síntesis química de los bisoxazoles objeto de esta patente se puede realizar según se indica en la Figura 1.On the other hand, the chemical synthesis of the bisoxazoles object of this patent can be described in this patent can be carried out as indicated in Figure 1.
Mediante una reacción de acilación de 4-aminometilpiridina con diferentes agentes acilantes, en forma de ácidos dicarboxílicos (HO2C-Z-CO2H) en presencia de un reactivo de condensación o derivados activados de los mismos, se obtienen diamidas NA con diferentes espaciadores (Z). Los compuestos HA se transforman directamente en los bisoxazoles IVA por tratamiento con algunos anhídridos fluorados, como los anhídridos trifluoracético, pentafluoropropiónico y heptafluorbutanoico a distintas temperaturas y en tolueno como disolvente y empleando una base, como la piridina.Through an acylation reaction of 4-aminomethylpyridine with different acylating agents, in the form of dicarboxylic acids (HO 2 CZ-CO 2 H) in the presence of a condensation reagent or activated derivatives thereof, NA diamides with different spacers are obtained ( Z). HA compounds are directly transformed into VAT bisoxazoles by treatment with some fluorinated anhydrides, such as trifluoroacetic, pentafluoropropionic and heptafluorbutanoic anhydrides at different temperatures and in toluene as a solvent and using a base, such as pyridine.
Para la introducción de otros grupos R se utiliza un método complementario vía la anhidrobase IIIA, obtenida por tratamiento de la correspondiente diamida HA con cloroformiato de etilo, empleando una base como la trietilamina. Los compuestos NÍA se obtienen en general como sólidos insolubles en el seno del disolvente de reacción (acetona) y se purifican por métodos convencionales. No obstante, la posterior reacción de formación de oxazoles se puede llevar a cabo con éxito trabajando con el sólido insoluble, que contiene la anhidrobase e hidrocloruro de trietilamina en relación 1 :5, según se puede estimar en base a sus espectros de RMN-1H. Así, las anhidrobases NÍA son tratadas posteriormente con distintos anhídridos o derivados de ácido a diferentes temperaturas para obtener los bisoxazoles IVA, los cuales dan lugar a la estructura general IA por cuaternización del nitrógeno piridínico con el derivado alquílico correspondiente. Tanto los productos IA como IVA así obtenidos se purifican por métodos convencionales, y pueden identificarse y caracterizarse por los procedimientos analíticos habituales.For the introduction of other R groups, a complementary method is used via the anhydrobase IIIA, obtained by treatment of the corresponding HA diamide with ethyl chloroformate, using a base like triethylamine. NIA compounds are generally obtained as insoluble solids within the reaction solvent (acetone) and are purified by conventional methods. However, the subsequent oxazole formation reaction can be carried out successfully by working with the insoluble solid, which contains the triethylamine anhydrobase and hydrochloride in a 1: 5 ratio, as can be estimated based on its NMR- 1 spectra. H. Thus, NIA anhydrobases are subsequently treated with different anhydrides or acid derivatives at different temperatures to obtain the bisoxazoles IVA, which give rise to the general structure IA by quaternization of the pyridine nitrogen with the corresponding alkyl derivative. Both the IA and VAT products thus obtained are purified by conventional methods, and can be identified and characterized by the usual analytical procedures.
Por otro lado, para la síntesis de bistiazoles se prepara inicialmente la bistioamida y se continúa la secuencia anterior de la forma que se indica en el esquema. Mediante reacción de las diamidas NA con el reactivo de Lawensson a la temperatura de reflujo del THF se obtienen las correspondientes tioamidas IIB con diferentes espaciadores (Z). Estos compuestos HB se transforman directamente en los bistiazoles IVB por tratamiento con algunos anhídridos fluorados, por ejemplo, anhídrido trifluoracético, en las condiciones idénticas a las descritas para la transformación de las amidas HA en bisoxazoles IVA. Para la introducción de otros grupos R se sigue una metodología análoga a la ya descrita para la síntesis de bisoxazoles.On the other hand, for the synthesis of bistiazoles, bistioamide is initially prepared and the previous sequence is continued as indicated in the scheme. The corresponding thioamides IIB with different spacers (Z) are obtained by reacting the NA diamides with the Lawensson reagent at the reflux temperature of THF. These HB compounds are directly transformed into IVB bistiazoles by treatment with some fluorinated anhydrides, for example, trifluoroacetic anhydride, under the conditions identical to those described for the transformation of HA amides into VAT bisoxazoles. For the introduction of other R groups, a methodology similar to that already described for the synthesis of bisoxazoles is followed.
En los siguientes ejemplos se describen la síntesis de compuestos derivados de la fórmula I, y finalmente los resultados de actividad antiproliferativa en células cancerosas HT29 (ver Ejemplo 8 y Tabla II) que indican que estos compuestos presentan una actividad antitumoral y por tanto son candidatos para el desarrollo de nuevos fármacos para el tratamiento de procesos cancerígenos humanos y dicho uso forma parte de la presente invención. Por otro lado, en la siguiente tabla (Tabla I) se indican más ejemplos de bisoxazoles y bistiazoles derivados de la fórmula general I, y forman parte de la presente invención. Tabla I. Compuestos químicos tipo bisoxazoles y bistiazoles derivados de la fórmula general IThe following examples describe the synthesis of compounds derived from formula I, and finally the results of antiproliferative activity in HT29 cancer cells (see Example 8 and Table II) that indicate that these compounds have an antitumor activity and are therefore candidates for The development of new drugs for the treatment of human carcinogenic processes and such use is part of the present invention. On the other hand, in the following table (Table I) more examples of bisoxazoles and bistiazoles derived from the general formula I are indicated, and form part of the present invention. Table I. Chemical compounds of bisoxazoles and bistiazoles derived from the general formula I
Figure imgf000006_0001
Figure imgf000006_0001
Los compuestos químicos descritos en esta patente pueden utilizarse como principios activos antitumorales en pacientes humanos pudiendo ser preparados y administrados, de acuerdo a los conocimientos existentes en el estado del arte del desaroollo galénico, de distintas formas como inyectables, cápsulas, grageas o tabletas, tanto como base libre como en forma de alguna de las sales citadas, y todas ellas forman parte de la presente invención. De igual forma, las formas sólidas se elaboran en presencia de los excipientes necesarios, como, entre otros, manitol, polivinilpirrolidona, celulosa microcristalina, silicagel, talco, estearato magnésico, óxido de titanio, colorantes y antioxidántes de calidad USP, y forman parte de la presente invención.The chemical compounds described in this patent can be used as anti-tumor active ingredients in human patients, and can be prepared and administered, according to the knowledge of the state of the art of galenic development, in different ways such as injectables, capsules, dragees or tablets, both as a free base as in the form of any of the salts mentioned, and all of them form part of the present invention. Similarly, solid forms are made in the presence of the necessary excipients, such as, among others, mannitol, polyvinylpyrrolidone, microcrystalline cellulose, silica gel, talcum, magnesium stearate, titanium oxide, USP grade dyes and antioxidants, and form part of the present invention.
A continuación se describen algunos ejemplos no limitativos del alcance del presente invento.Some non-limiting examples of the scope of the present invention are described below.
EJEMPLOSEXAMPLES
Ejemplo 1.- Preparación de 2,2-bis[(5-metil-4-(4-piridil)-2-oxazolil)]propanoExample 1.- Preparation of 2,2-bis [(5-methyl-4- (4-pyridyl) -2-oxazolyl)] propane
(Z= (CH3)2C; X = O; R = CH3).(Z = (CH 3 ) 2 C; X = O; R = CH 3 ).
Sobre una suspensión de /V,Λ/-bis(1-etoxicarbonil-1 ,4- dihidropiridilmetilen)-2,2-dimetilmalonamida con clorhidrato de trietilamina (218 mg, 0.48 mmol) en anhídrido acético (5 mi) mantenida bajo atmósfera de argón, se añadió tetracloruro de estaño (0.3 mi, 1M SnCI4, 0.3 mmol). La mezcla se calentó a reflujo durante 4 h y, a continuación, se eliminó el disolvente a presión reducida en el rotavapor. Sobre el crudo obtenido se añadió agua (3 mi) y se dejó un tiempo hasta que se pudo triturar el sólido resultante. Este sólido se filtró a vacío, se lavó sucesivamente con una solución de bicarbonato sódico al 5%, con agua, y finalmente, con acetona. El sólido que se recogió resultó ser el 2,2-bis[(5-metil-4-(4-piridil)-2-oxazolil)]propano (150 mg, 80%), como un sólido beige, p.f. > 3009C. 1H-RMN (δ, ppm) (DMSO-d6): 2.54 (s, 6H, CH3), 7.60 (d, 4H, J=6.0, Py); 8.57 (d, 4H, J=6.0, Py). 13C-RMN (δ, ppm) (DMSO-de): 11.83, 25.01 , 38.00, 120.27, 131.29, 138.79, 147.46, 149.98, 163.27. IR (crτϊ1) (KBr): 3432, 2987, 1621 , 1596, 1543, 1458, 1415, 1291. Em (m/z) (%): 360 (M+, 68), 345 (47), 317 (6), 201 (100), 159 (7), 106 (5), 69 (81). Análisis calculado para C2ιH2oN402: 69.98%C, 5.59%H, 15.55%N; exp. 69.87%C, 5.54%H, 15.49%N.On a suspension of / V, Λ / -bis (1-ethoxycarbonyl-1, 4-dihydropyridylmethylene) -2,2-dimethylmalonamide with triethylamine hydrochloride (218 mg, 0.48 mmol) in acetic anhydride (5 ml) kept under an atmosphere of Argon, tin tetrachloride (0.3 mL, 1M SnCI 4 , 0.3 mmol) was added. The mixture was heated at reflux for 4 h, and then the solvent was removed under reduced pressure on the rotary evaporator. Water (3 ml) was added to the crude obtained and a time was allowed until the resulting solid could be crushed. This solid was filtered under vacuum, washed successively with a 5% sodium bicarbonate solution, with water, and finally, with acetone. The solid that was collected was found to be 2,2-bis [(5-methyl-4- (4-pyridyl) -2-oxazolyl)] propane (150 mg, 80%), as a beige solid, mp> 300 9 C. 1 H-NMR (δ, ppm) (DMSO-d 6 ): 2.54 (s, 6H, CH 3 ), 7.60 (d, 4H, J = 6.0, Py); 8.57 (d, 4H, J = 6.0, Py). 13 C-NMR (δ, ppm) (DMSO-de): 11.83, 25.01, 38.00, 120.27, 131.29, 138.79, 147.46, 149.98, 163.27. IR (crτϊ 1 ) (KBr): 3432, 2987, 1621, 1596, 1543, 1458, 1415, 1291. Em (m / z) (%): 360 (M + , 68), 345 (47), 317 ( 6), 201 (100), 159 (7), 106 (5), 69 (81). Analysis calculated for C 2 ιH oN 2 4 0 2: 69.98% C, 5.59% H, 15.55% N; exp. 69.87% C, 5.54% H, 15.49% N.
Ejemplo 2.- Preparación de 2,2-bis[(5-trifluorometil-4-(4-piridil)-2- oxazolil)]propano (Z= (CH3)2C; X = O; R = CF3).Example 2.- Preparation of 2,2-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-oxazolyl)] propane (Z = (CH 3 ) 2 C; X = O; R = CF 3 ) .
Sobre una suspensión de Λ/,/V-bis(4-piridilmetilen)-2,2- dimetilmalonamida (190 mg, 0.6 mmol) en 15 mi de tolueno seco, mantenida bajo atmósfera de argón, se añadió piridina (0.6 mi, 7 mmol). La mezcla se enfrió a 0eC y, seguidamente, se añadió gota a gota anhídrido trifluoroacético (0.6 mi, 4.25 mmol). Se dejó que el conjunto alcanzara temperatura ambiente y se mantuvo la agitación durante 12 h. Al cabo de este tiempo, se eliminó el disolvente a presión reducida y se adicionó una disolución de carbonato sódico 5% (5 mi). El crudo de reacción se extrajo con acetato de etilo (3 x 15 mi) y los extractos orgánicos se combinaron, se lavaron con una disolución saturada de cloruro sódico y se secaron con sulfato sódico anhidro. Tras eliminar el disolvente a presión reducida, el crudo obtenido se purificó mediante cromatografía en columna (gel de sílice, acetato de etilo) y se obtuvo el 2,2- bis[(5-trifluorometil-4-(4-piridil)-2-oxazolil)]propano (200 mg, 80%), como un sólido amarillo-beige, p.f. 126-128 SC (etanol). 1H-RMN (δ, ppm) (CDCI3): 2.09 (s, 6H, CH3), 7.64 (d, 4H, J=6.0, Py), 8.73 (d, 4H, J=6.0, Py). 13C-RMN (δ, ppm) (CDCI3): 25.32, 39.83, 118.97, 120.75, 136.29, 137.56, 150.08, 150.34, 165.54. IR (cm"1) (KBr): 3447, 2992, 1701 , 1622, 1594, 1570, 1545, 1500, 1418, 1382. Em (m/z) (%): 468 (M+, 81), 453 (8), 255 (100), 189 (15), 158 (7), 63 (8). Análisis calculado para C2iHι4F6N4O : 53.86%C, 3.01 %H, 11.96%N; exp. 53.77%C, 2.97%H, 11.86%N.On a suspension of Λ /, / V-bis (4-pyridylmethylene) -2,2-dimethylmalonamide (190 mg, 0.6 mmol) in 15 ml of dry toluene, kept under argon, pyridine (0.6 mi, 7 was added mmol). The mixture was cooled to 0 e C and then trifluoroacetic anhydride (0.6 ml, 4.25 mmol) was added dropwise. The set was allowed to reach room temperature and stirring was maintained for 12 h. After this time, the solvent was removed under reduced pressure and a 5% sodium carbonate solution (5 ml) was added. The reaction crude was extracted with ethyl acetate (3 x 15 mL) and the organic extracts were combined, washed with a saturated sodium chloride solution and dried with anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude obtained was purified by column chromatography (silica gel, ethyl acetate) and 2,2-bis [(5-trifluoromethyl-4- (4-pyridyl) -2] -oxazolyl)] propane (200 mg, 80%), as a yellow-beige solid, mp 126-128 S C (ethanol). 1 H-NMR (δ, ppm) (CDCI 3 ): 2.09 (s, 6H, CH 3 ), 7.64 (d, 4H, J = 6.0, Py), 8.73 (d, 4H, J = 6.0, Py). 13 C-NMR (δ, ppm) (CDCI 3 ): 25.32, 39.83, 118.97, 120.75, 136.29, 137.56, 150.08, 150.34, 165.54. IR (cm "1 ) (KBr): 3447, 2992, 1701, 1622, 1594, 1570, 1545, 1500, 1418, 1382. Em (m / z) (%): 468 (M + , 81), 453 ( 8), 255 (100), 189 (15), 158 (7), 63 (8) Analysis calculated for C2iHι 4 F 6 N 4 O: 53.86% C, 3.01% H, 11.96% N; exp. 53.77% C, 2.97% H, 11.86% N.
Ejemplo 3.- Preparación de diyoduro de 4,4'-bis[(5-trifluorometil-4-(1-metil- 4-piridinio)-2-oxazolil)]bifenilo (Z = p-bifenilo; X = O; R = CF3, R'= CH3)Example 3.- Preparation of 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridinium) -2-oxazolyl)] biphenyl (Z = p-biphenyl; X = O; R = CF 3 , R '= CH 3 )
Sobre una disolución de 4,4'-bis[(5-trifluorometil-4-(4-piridil)-2- oxazolil)]bifenilo (40 mg, 0.07 mmol) en isopropanol seco (2 mi), mantenida bajo atmósfera de argón, se adicionó yoduro de metilo (2.5 mi, 40 mmol). La mezcla se calentó a reflujo durante 5h y al cabo de este tiempo, se enfrió, se añadió más yoduro de metilo (1 ml, 16 mmol) y se calentó a reflujo durante otras 12h. Al cabo de este tiempo, se enfrió la reacción y se evaporó el disolvente en el rotavapor, obteniéndose un crudo que fue identificado como el diyoduro de 4,4'-bis[(5-trifluorometil-4-(1-metil-4-piridinio)-2-oxazol¡l)]bifenilo (53 mg, 89 %). El crudo no fue purificado posteriormente. 1H-RMN (δ, ppm) (DMSO-d6): 4.21 (s, 6H, CH3), 8.09 (d, 4H, J= 7.9, Py), 8.27 (d, 4H, J= 8.5, Ph), 8.42 (d, 4H, J= 8.5, Ph), 9.14 (d, 4H, J=4.1 , Py). 13C-RMN (δ, ppm) (CDCI3): 48.06, 119.35, 123.50, 124.19, 124.27, 124.53, 126.09, 126.11 , 127.82, 127.95, 128.00, 135.3, 137.18, 142.05, 142.33, 142.37, 143.20, 146.45, 147.92, 161.95. IR (cm'1) (KBr): 3436, 3042, 2360, 1643, 1613, 1585, 1514, 1486, 1463, 1381 , 1293. Análisis calculado para C32H22F6I2N4O2: 44.57%C, 2.57%H, 6.50%N; exp. 44.60%C, 2.51 %H, 6.46%N.On a solution of 4,4'-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-oxazolyl)] biphenyl (40 mg, 0.07 mmol) in dry isopropanol (2 ml), kept under argon , methyl iodide (2.5 ml, 40 mmol) was added. The mixture was heated at reflux for 5h and after this time, cooled, more methyl iodide (1 mL, 16 mmol) was added and heated at reflux for another 12h. After this time, the reaction was cooled and the solvent was evaporated in the rotary evaporator, obtaining a crude which was identified as the 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-) diiodide pyridinium) -2-oxazolyl)] biphenyl (53 mg, 89%). The crude was not purified later. 1 H-NMR (δ, ppm) (DMSO-d 6 ): 4.21 (s, 6H, CH 3 ), 8.09 (d, 4H, J = 7.9, Py), 8.27 (d, 4H, J = 8.5, Ph ), 8.42 (d, 4H, J = 8.5, Ph), 9.14 (d, 4H, J = 4.1, Py). 13 C-NMR (δ, ppm) (CDCI 3 ): 48.06, 119.35, 123.50, 124.19, 124.27, 124.53, 126.09, 126.11, 127.82, 127.95, 128.00, 135.3, 137.18, 142.05, 142.33, 142.37, 143.20, 146.45, 147.92, 161.95. IR (cm '1 ) (KBr): 3436, 3042, 2360, 1643, 1613, 1585, 1514, 1486, 1463, 1381, 1293. Analysis calculated for C32H22F6I2N4O2: 44.57% C, 2.57% H, 6.50% N; exp. 44.60% C, 2.51% H, 6.46% N.
Ejemplo 4.- Preparación de diyoduro de 4,4'-bis[(5-pentafluoroetil-4-(1- metil-4-piridin¡o)-2-oxazolil)]b¡fenilo (Z = p-bifenilo; X = O; R = CF2CF3, R = CH3)Example 4.- Preparation of 4,4'-bis [(5-pentafluoroethyl-4- (1- methyl-4-pyridinyl) -2-oxazolyl)] b -phenyl (Z = p-biphenyl; X = O; R = CF 2 CF 3 , R = CH 3 )
Sobre una disolución de 4,4'-bis[(5-pentafluoroetil-4-(4-piridil)-2- oxazolil)]bifenilo (27 mg, 0.044 mmol) en isopropanol seco (2 mi), mantenida bajo atmósfera de argón, se adicionó yoduro de metilo en exceso (2.5 mi, 40 mmol). El conjunto se calentó a reflujo durante 5h y, al cabo de este tiempo, se enfrió, se añadió más yoduro de metilo (1ml, 16 mmol) y se calentó a reflujo durante otras 12h. Al cabo de este tiempo, se enfrió la reacción y se evaporó el disolvente en el rotavapor, obteniéndose el diyoduro de 4,4'-bis[(5- pentafluoroetil-4-(1-metil-4-piridinio)-2-oxazolil)]bifenilo (27 mg, rendimiento cuantitativo). El crudo no fue purificado posteriormente. 1H-RMN (δ, ppm) (DMSO-de): 4.42 (s, 6H, CH3), 8.10 (d, 4H, J= 6.7, Py), 8.26 (d, 4H, J= 8.5, Ph), 8.40 (d, 4H, J= 8.5, Ph), 9.14 (d, 4H, J=6.7, Py). 13C-RMN (δ, ppm) (DMSO-d6): 48.11 , 109.3, 118.4, 124.22, 126.48, 126.52, 127.96, 128.12, 130.12, 137.35, 142.50, 143.41 , 146.43, 162.97. IR (cm"1) (KBr): 3437, 2361 , 2342, 1717, 1684, 1646, 1616, 1559, 1541 , 1588, 1489, 1374, 1337, 1218, 1120. Análisis calculado para C34H22F10I2N-A.: 42.43%C, 2.30%H, 5.82%N; exp. 42.36%C, 2.27%H, 5.79%N.On a solution of 4,4'-bis [(5-pentafluoroethyl-4- (4-pyridyl) -2-oxazolyl)] biphenyl (27 mg, 0.044 mmol) in dry isopropanol (2 ml), kept under argon , excess methyl iodide (2.5 ml, 40 mmol) was added. The whole was heated at reflux for 5h and, after this time, cooled, more methyl iodide (1ml, 16mmol) was added and heated at reflux for another 12h. After this time, the reaction was cooled and the solvent was evaporated on the rotary evaporator, obtaining 4,4'-bis [(5- pentafluoroethyl-4- (1-methyl-4-pyridinium) -2-oxazolyl diiodide) )] Biphenyl (27 mg, quantitative yield). The crude was not purified later. 1 H-NMR (δ, ppm) (DMSO-de): 4.42 (s, 6H, CH 3 ), 8.10 (d, 4H, J = 6.7, Py), 8.26 (d, 4H, J = 8.5, Ph) , 8.40 (d, 4H, J = 8.5, Ph), 9.14 (d, 4H, J = 6.7, Py). 13 C-NMR (δ, ppm) (DMSO-d 6 ): 48.11, 109.3, 118.4, 124.22, 126.48, 126.52, 127.96, 128.12, 130.12, 137.35, 142.50, 143.41, 146.43, 162.97. IR (cm "1 ) (KBr): 3437, 2361, 2342, 1717, 1684, 1646, 1616, 1559, 1541, 1588, 1489, 1374, 1337, 1218, 1120. Analysis calculated for C34H22F10I2N-A .: 42.43% C, 2.30% H, 5.82% N; exp. 42.36% C, 2.27% H, 5.79% N.
Ejemplo 5.- Preparación de diyoduro de 4,4'-bis[(5-trifluorometil-4-(1-metil- 4-piridinio)-2-oxazolil)]hexafluoroisopropilidendifenilo (Z = Ph-(CF3)2C-Ph; X = O; R = CF3, R'= CH3) Sobre una disolución de 4,4'-bis[(5-trifluorometil-4-(4-piridil)-2- oxazolil)]hexafluoroisopropilidendifenilo (3 mg, 0.04 mmol) en isopropanol (4 mi) mantenida bajo atmósfera de argón, se adicionó yoduro de metilo en exceso (0.1 mi, 1.6 mmol) y la mezcla se calentó a reflujo durante 4h. Al cabo de este tiempo, se enfrió, se añadió más yoduro de metilo (0.1 mi, 1.6 mmol) y la mezcla se agitó a temperatura ambiente durante toda la noche. Se filtró el sólido obtenido que resultó ser el 4,4'-bis[(5-trifluorometil-4-(1-metil-4-pirid¡nio)- 2-oxazolil)] hexafluoroisopropididendifenilo (24 mg, 60%). El crudo no fue purificado posteriormente. 1H-RMN (δ, ppm) (DMSO-d6): 9.13 (d, 4H, J=7 Hz); 8.38 (d, 4H, J=6.69 Hz Pyr); 8.29 (d, 4H, J=8.55 Hz, Ph); 7.67 (d, 4H, J=7.92, Ph); 4.41 (s, 6H, Me). 13C-RMN (δ, ppm) (DMSO-d6): 48.12, 118.69, 124.04, 125.86, 126.14, 127.79, 130.95, 135.73, 136.47, 137.15, 143.09, 146.54, 161.29. IR (cm"1) (KBr): 3468, 1647, 1508, 1466, 1383, 1289, 1255, 1213, 1176, 1140. Análisis calculado para C35H22F12N4O2: 52%C, 2.19%H, 5.53%N; exp. 41.46%C, 2.13%H, 5.48%N.Example 5.- Preparation of 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridinium) -2-oxazolyl)] hexafluoroisopropylidenediphenyl (Z = Ph- (CF 3 ) 2 C- Ph; X = O; R = CF 3 , R ' = CH 3 ) On a solution of 4,4'-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-oxazolyl)] hexafluoroisopropylidenediphenyl (3 mg , 0.04 mmol) in isopropanol (4 ml) maintained under an argon atmosphere, excess methyl iodide (0.1 ml, 1.6 mmol) was added and the mixture was heated at reflux for 4 h. After this time, it was cooled, more methyl iodide (0.1 ml, 1.6 mmol) was added and the mixture was stirred at room temperature overnight. The solid obtained which was found to be 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridium) -2-oxazolyl)] hexafluoroisopropididenediphenyl (24 mg, 60%) was filtered. The crude was not purified later. 1 H-NMR (δ, ppm) (DMSO-d 6 ): 9.13 (d, 4H, J = 7 Hz); 8.38 (d, 4H, J = 6.69 Hz Pyr); 8.29 (d, 4H, J = 8.55 Hz, Ph); 7.67 (d, 4H, J = 7.92, Ph); 4.41 (s, 6H, Me). 13 C-NMR (δ, ppm) (DMSO-d 6 ): 48.12, 118.69, 124.04, 125.86, 126.14, 127.79, 130.95, 135.73, 136.47, 137.15, 143.09, 146.54, 161.29. IR (cm "1 ) (KBr): 3468, 1647, 1508, 1466, 1383, 1289, 1255, 1213, 1176, 1140. Analysis calculated for C35H22F12N4O2: 52% C, 2.19% H, 5.53% N; exp. 41.46 % C, 2.13% H, 5.48% N.
Ejemplo 6.- Preparación de 2,2-bis[(5-trifluorometil-4-(4-piridil)-2- tiazolil)]propano (Z= (CH3)2C; X = S; R = CF3). Sobre una suspensión de /V,Λ/'-bis(4-piridilmetilen)-2,2-dimetil-1 ,3- propanoditioamida (123 mg, 0.36 mmol) en 4 mi de tolueno seco, mantenida bajo atmósfera de argón, se añadió piridina (0.35 mi, 4.32 mmol). La mezcla se enfrió a 0QC y, seguidamente, se añadió gota a gota anhídrido trifluoroacético (0.31 mi, 2.16 mmol). Se dejó que el conjunto alcanzara temperatura ambiente y se mantuvo la agitación durante 12 h. Al cabo de este tiempo, se eliminó el disolvente a presión reducida y se adicionó una disolución de carbonato sódico 5% (5 mi). El crudo de reacción se extrajo con acetato de etilo (3 x 15 mi) y los extractos orgánicos se combinaron, se lavaron con una disolución saturada de cloruro sódico y se secaron con sulfato sódico anhidro. Tras eliminar el disolvente a presión reducida, el crudo obtenido se purificó mediante cromatografía en columna (gel de sílice, acetato de etilo:hexano 9:1) y se obtuvo el 2,2-bis[(5-trifluorometil-4-(4-piridil)-2-t¡azolil)]propano (Z= (CH3)2C; X = S; R = CF3) (36 mg, 25%), como un sólido amarillo. 1 H-RMN (δ, ppm) (DMSO-de): 1.96 (s, 6H, CH3 ); 7.61 (d, 4H, J=6.1 Hz, Py); 8.74 (d, 4H, J=6.1 Hz, Py). 13C-RMN (δ, ppm) (DMSO-d6): 117.23, 120.79, 122.38, 135.06, 135.69, 138.76, 138.79, 142.54, 150.44, 150.63, 165.78, 180.18. IR (cm"1) (KBr): 2928, 2360, 1829, 1733, 1717, 1653, 1647, 1623, 1594, 1570, 1546, 1506, 1457, 1419, 1383, 1373, 1337, 1250, 1208, 1182, 1147, 1103, 988. Análisis calculado para C2.Hι4F6N4S2: 50.40%C, 2.80%H, 11.20%N; exp. 50.27%C, 2.78%H, 11.15%N. Ejemplo 7.- Preparación de diyoduro de 4,4'-bis[(5-trifluorometil-4-(1-metil- 4-piridinio)-2-tiazolil)]-1.1 '-oxibisbenceno (Z= Ph-O-Ph; X = S; R = CF3, R = CH3)Example 6.- Preparation of 2,2-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-thiazolyl)] propane (Z = (CH 3 ) 2 C; X = S; R = CF 3 ) . On a suspension of / V, Λ / '- bis (4-pyridylmethylene) -2,2-dimethyl-1, 3- propanedithioamide (123 mg, 0.36 mmol) in 4 ml of dry toluene, kept under argon, added pyridine (0.35 ml, 4.32 mmol). The mixture was cooled to 0 Q C and then was added drop trifluoroacetic anhydride (0.31 mi, 2.16 mmol). The whole was allowed to reach room temperature and stirring was maintained for 12 h. After this time, the solvent was removed under reduced pressure and a 5% sodium carbonate solution (5 ml) was added. The reaction crude was extracted with ethyl acetate (3 x 15 mL) and the organic extracts were combined, washed with a saturated sodium chloride solution and dried with anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude obtained was purified by column chromatography (silica gel, ethyl acetate: hexane 9: 1) and 2,2-bis [(5-trifluoromethyl-4- (4 -pyridyl) -2-thiazolyl)] propane (Z = (CH 3 ) 2 C; X = S; R = CF 3 ) (36 mg, 25%), as a yellow solid. 1 H-NMR (δ, ppm) (DMSO-de): 1.96 (s, 6H, CH 3 ); 7.61 (d, 4H, J = 6.1 Hz, Py); 8.74 (d, 4H, J = 6.1 Hz, Py). 13 C-NMR (δ, ppm) (DMSO-d 6 ): 117.23, 120.79, 122.38, 135.06, 135.69, 138.76, 138.79, 142.54, 150.44, 150.63, 165.78, 180.18. IR (cm "1 ) (KBr): 2928, 2360, 1829, 1733, 1717, 1653, 1647, 1623, 1594, 1570, 1546, 1506, 1457, 1419, 1383, 1373, 1337, 1250, 1208, 1182, 1147, 1103, 988. Analysis calculated for C 2 .Hι 4 F 6 N 4 S2: 50.40% C, 2.80% H, 11.20% N; exp. 50.27% C, 2.78% H, 11.15% N. Example 7. Preparation of 4,4'-diiodide bis [(5-trifluoromethyl-4- (1-methyl - 4-pyridinio) -2-thiazolyl)] - 1.1 '-oxibisbenceno (Z = Ph-O-Ph ; X = S; R = CF 3 , R = CH 3 )
Sobre una disolución de 4,4'-bis[(5-trifluorometil-4-(4-piridil)-2-tiazolil)]- 1 ,1 '-oxibisbenceno (40 mg, 0.06 mmol) en una mezclaTo a solution of 4,4'-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-thiazolyl)] - 1, 1 '-oxibisbenceno (40 mg, 0.06 mmol) in a mixture
¡sopropanol:MeOH:EtOH 1 :1 :1 (4 mi) mantenida bajo atmósfera de argón, se adicionó yoduro de metilo en exceso (0.1 mi, 1.3 mmol) y la mezcla se calentó a reflujo durante 7h. Se adicionó más yoduro de metilo (0.1 mi) y se agitó a temperatura ambiente durante toda la noche. Se adicionó de nuevo yoduro de metilo (0.1 mi), se calentó a reflujo otras 7h y se mantuvo en agitación a temperatura ambiente durante toda la noche. El sólido obtenido se filtró a vacio y resultó ser el diyoduro de 4,4'-bis[(5-trifluorometil-4-(1-metil-4-piridinio)-2- tiazolil)]-1 ,1 '-oxibisbenceno (51 mg, 93%). 1H-RMN (δ, ppm) (DMSO-d6): 4.41 (s, 6H, CH3), 7.38 (d, 4H, J=9.1 , Ph), 8.22 (d, 4H, J=9.1 , Ph), 8.39 ( d, 4H, J=6.1 , Py), 9.12 ( d, 4H, J= 6.7, Py). 13C-RMN (δ, ppm) (CDCI3): 48.07, 119.93, 120.40, 120.60, 126.13, 126.16, 126.17, 129.80, 135.92, 137.14, 137.17, 143.28, 146.33, 146.63, 159.17, 161.92. IR (cm"1) (KBr): 3882, 3839, 3739, 3676, 2360, 1772, 1749, 1717, 1654, 1636, 160,6, 1559, 1541 , 1508, 1489, 1473, 1458, 1418, 1376, 1339, 1295. Análisis calculado para C32H22F6I2N4OS2: 42.19%C, 2.42%H, 5.15%N; exp. 42.21 %C, 2.38 %H, 5.13%N.Sopropanol: MeOH: EtOH 1: 1: 1 (4 mL) kept under argon, excess methyl iodide (0.1 mL, 1.3 mmol) was added and the mixture was heated at reflux for 7h. More methyl iodide (0.1 ml) was added and stirred at room temperature overnight. Methyl iodide (0.1 ml) was added again, refluxed for another 7 hours and kept stirring at room temperature overnight. The solid obtained was filtered in vacuo and was found to be 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridinium) -2-thiazolyl)] -1,1'-oxybisbenzene ( 51 mg, 93%). 1 H-NMR (δ, ppm) (DMSO-d6): 4.41 (s, 6H, CH 3 ), 7.38 (d, 4H, J = 9.1, Ph), 8.22 (d, 4H, J = 9.1, Ph) , 8.39 (d, 4H, J = 6.1, Py), 9.12 (d, 4H, J = 6.7, Py). 13 C-NMR (δ, ppm) (CDCI 3 ): 48.07, 119.93, 120.40, 120.60, 126.13, 126.16, 126.17, 129.80, 135.92, 137.14, 137.17, 143.28, 146.33, 146.63, 159.17, 161.92. IR (cm "1 ) (KBr): 3882, 3839, 3739, 3676, 2360, 1772, 1749, 1717, 1654, 1636, 160.6, 1559, 1541, 1508, 1489, 1473, 1458, 1418, 1376, 1339, 1295. Analysis calculated for C32H22F6I2N4OS2: 42.19% C, 2.42% H, 5.15% N; exp. 42.21% C, 2.38% H, 5.13% N.
Ejemplo 8.- Ensayos de actividad antitumoral de los compuestos químicos de la presente patente.Example 8.- Antitumor activity assays of the chemical compounds of the present patent.
Los productos descritos en los ejemplos anteriores han presentado una importante actividad antiproliferativa en células cancerosas HT29 valorada según se ha descrito anteriormente [Hernández-Alcoceba R., Saniger L., Campos J., Núñez M.C., Khaless F., Gallo M.A., Espinosa A., and Lacal J.C. (1997). Choline kinase inhibitors as a novel approach for antiproliferative drug design. Oncogene 15, 2289-2301 ; Hernández-Alcoceba R., Fernández F. and Lacal J.C. (1999). A novel mechanism for anticancer drug discovery:ln vivo antitumor activity by inhibition of phsphorylcholine production. Cáncer Research 59:3112-3118]. En la tabla siguiente (Tabla II) se indican las actividades de algunos de los ejemplos: Tabla II.- Nivel de IC50 de los compuestos químicos de los ejemplos anteriores.The products described in the previous examples have shown an important antiproliferative activity in HT29 cancer cells valued as described previously [Hernández-Alcoceba R., Saniger L., Campos J., Núñez MC, Khaless F., Gallo MA, Espinosa A ., and Lacal JC (1997). Choline kinase inhibitors as a novel approach for antiproliferative drug design. Oncogene 15, 2289-2301; Hernández-Alcoceba R., Fernández F. and Lacal JC (1999). A novel mechanism for anticancer drug discovery: ln vivo antitumor activity by inhibition of phsphorylcholine production. Cancer Research 59: 3112-3118]. The following table (Table II) shows the activities of some of the examples: Table II.- IC50 level of the chemical compounds of the previous examples.
Figure imgf000012_0001
Figure imgf000012_0001

Claims

REIVINDICACIONES
1.- Compuestos químicos derivados de 4-4'-bipiridil-2-2'-bisoxazoles y 4-4'- bipirid¡l-2-2'-bistiazoles de fórmula general I:1.- Chemical compounds derived from 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'- bipyrid¡l-2-2'-bistiazoles of general formula I:
Figure imgf000013_0001
I donde X puede ser oxígeno o azufre; Z puede no existir o bien ser 1 ,2-etilideno, isopropilideno, p,p-bifen¡lo, p-fenilo, m-fenilo, 2,6-piridileno, p,p'-oxidifenilo, p,p'-hexafluoroisopropilidendifen¡lo; R pueden ser hidrógeno o sustituyentes de los habituales en la química orgánica, como alquilos, alquilidenos, alquinos, arilos, o grupos funcionales como halógenos, alcoholes, tioles, éteres, tioéteres, sulfoxidos, sulfonas, aminas con o sin sustituyentes, nitro, aldehidos, cetonas, nitrilo, ácidos carboxílicos y cualquiera de sus derivados, como esteres, amidas, hidrazidas, ácidos hidroxámicos, con o sin sustituyentes, ácidos sulfónicos y cualquiera de sus derivados equivalentes a los citados, entre otros, para los ácidos carboxílicos, así como una sal, orgánica o inorgánica, farmacológicamente aceptable o profármacos de la misma, como sulfato, metanosulfonato, hidrocloruro, fosfato, nitrato, acetato, propionato, butirato, palmitato, oxalato, malonato, maleato, malato, fumarato, citrato, benzoato, etc; R' puede no existir o ser grupos alquilo; Y puede, a su vez, no existir, o ser, entre otros, sulfato, metanosulfonato, hidrocloruro, fosfato, nitrato, acetato, propionato, butirato, palmitato, oxalato, malonato, maleato, malato, fumarato, citrato, benzoato.
Figure imgf000013_0001
I where X can be oxygen or sulfur; Z may not exist or be 1,2-ethylidene, isopropylidene, p, p-biphenyl, p-phenyl, m-phenyl, 2,6-pyridylene, p, p'-oxidiphenyl, p, p'-hexafluoroisopropylidendiphen the; R may be hydrogen or substituents of those usual in organic chemistry, such as alkyls, alkylidenes, alkynes, aryls, or functional groups such as halogens, alcohols, thiols, ethers, thioethers, sulfoxides, sulfones, amines with or without substituents, nitro, aldehydes , ketones, nitrile, carboxylic acids and any of its derivatives, such as esters, amides, hydrazides, hydroxamic acids, with or without substituents, sulfonic acids and any of their derivatives equivalent to those mentioned, among others, for carboxylic acids, as well as a salt, organic or inorganic, pharmacologically acceptable or prodrugs thereof, such as sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate, etc .; R 'may not exist or be alkyl groups; And it can, in turn, not exist, or be, among others, sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate.
2.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que X es O. 2. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which X is O.
3.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que X es S. 3. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which X is S.
4.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es un enlace sencillo. 4. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is a single bond.
5.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es etano-1 ,2-diilo. 5. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is ethane-1,2-diyl.
6.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es propano-2,2-diilo. 6. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is propane-2,2-diyl.
7.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es m-fenilo. 7. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is m-phenyl.
8.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es p-fenilo. 8. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is p-phenyl.
9.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es p-bifenilo.9. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is p-biphenyl.
10.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es 4,4'-oxidifenilo. 10. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is 4,4'-oxidiphenyl.
11.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es 4,4'- (hexafluoñsopropiliden) difenilo.11. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is 4,4'- (hexafluoesopropylidene) diphenyl.
12.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que Z es piridin-2,6-diilo. 12. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is pyridin-2,6-diyl.
13.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R es metilo. 13. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is methyl.
14.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R es trifluormetilo. 14. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is trifluoromethyl.
15.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R es pentafluoroetilo. 15. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is pentafluoroethyl.
16.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R es heptafluoropropilo.16. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is heptafluoropropyl.
17.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R' es metilo. 17. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is methyl.
18.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R' es etilo. 18. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is ethyl.
19.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R' es /-propilo. 19. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is / -propyl.
20.- Compuestos químicos según la reivindicación 1 caracterizados porque los compuestos de fórmula I son aquellos en los que R' es n-butilo.20. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is n-butyl.
21.- Compuestos químicos según la reivindicación 1a, en que los compuestos de fórmula I preferidos son aquellos en los que R' es bencilo. Preferred 21. Compounds according to claim chemicals 1, in which the compounds of formula I are those wherein R 'is benzyl.
22.- Sales de compuestos químicos según una cualquiera de las reivindicaciones 1 a la 21 , farmacológicamente aceptables o profármacos de los mismos como, entre otros, sulfato, metanosulfonato, hidrocloruro, fosfato, nitrato, acetato, propionato, butirato, palmitato, oxalato, malonato, maleato, malato, fumarato, citrato y benzoato. 22. Salts of chemical compounds according to any one of claims 1 to 21, pharmacologically acceptable or prodrugs thereof such as, among others, sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate and benzoate.
23.- Un medicamento caracterizado porque alguno de sus principios activos es un compuesto químico según una cualquiera de las reivindicaciones 1 a la 22.23. A medicament characterized in that some of its active ingredients is a chemical compound according to any one of claims 1 to 22.
24.- El uso del medicamento según la reivindicación 23 en el tratamiento de procesos tumorales.24. The use of the medicament according to claim 23 in the treatment of tumor processes.
25.- Un método para la producción industrial de los compuestos químicos según una cualquiera de las reivindicaciones 1 a la 21 según un método cualquiera de los utilizados en la síntesis orgánica. 25. A method for the industrial production of the chemical compounds according to any one of claims 1 to 21 according to any method used in organic synthesis.
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