WO2004016622A1 - Derives de 4-4'-bipyridil-2-2'-bisoxazoles et de 4-4'-bipyridil-2-2'-bisthiazoles utilises comme agents antineoplasiques - Google Patents

Derives de 4-4'-bipyridil-2-2'-bisoxazoles et de 4-4'-bipyridil-2-2'-bisthiazoles utilises comme agents antineoplasiques Download PDF

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Publication number
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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Prior art keywords
those
formula
compounds
compounds according
chemical compounds
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PCT/ES2003/000424
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English (en)
Spanish (es)
Inventor
Yolanda MARTÍN SÁNCHEZ-CANTALEJO
María Jesús VILLA HORMAECHE
Beatríz SAEZ PIZARRO
Javier Soto Romero
Miguel FERNÁNDEZ BRAÑA
Juan Carlos Lacal Sanjuan
Original Assignee
Consejo Superior De Investigaciones Científicas
Universidad Europea De Madrid
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Priority to AU2003260515A priority Critical patent/AU2003260515A1/en
Publication of WO2004016622A1 publication Critical patent/WO2004016622A1/fr

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dérivés de 4-4'-bipyridil-2-2'-bisoxazoles et de 4-4'-bipyridil-2-2'-bisthiazoles, représentés par la formule générale I, et possédant une activité d'inhibition de la prolifération cellulaire, en particulier, des cellules malignes comme HT-29. La présente invention concerne également le procédé de production industrielle desdits dérivés, ainsi que leur utilisation dans la mise au point de composés pharmaceutiques destinés à traiter des tumeurs humaines.
PCT/ES2003/000424 2002-08-16 2003-08-14 Derives de 4-4'-bipyridil-2-2'-bisoxazoles et de 4-4'-bipyridil-2-2'-bisthiazoles utilises comme agents antineoplasiques WO2004016622A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003260515A AU2003260515A1 (en) 2002-08-16 2003-08-14 Derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles as antineoplasic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP200201938 2002-08-16
ES200201938A ES2200706B1 (es) 2002-08-16 2002-08-16 Derivados de 4-4'-bipiridil-2-2'-bisoxazoles y 4-4'-bipiridil-2-2'-bistiazoles como agentes antineoplasicos.

Publications (1)

Publication Number Publication Date
WO2004016622A1 true WO2004016622A1 (fr) 2004-02-26

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AU (1) AU2003260515A1 (fr)
ES (1) ES2200706B1 (fr)
WO (1) WO2004016622A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2344780A1 (es) * 2009-03-03 2010-09-06 Universidad De Barcelona Compuestos bistiazolicos utiles para el tratamiento del cancer.
WO2012028757A1 (fr) 2010-09-02 2012-03-08 Universitat De Barcelona Tiazols fluorés utilisés pour le traitement du cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3148194A (en) * 1961-07-03 1964-09-08 Arapahoe Chemicals Inc Certain 1, 4-bis[2(4-substituted, 5-phenyloxazolyl)] benzenes
FR2066252A5 (en) * 1970-10-20 1971-08-06 Sumitomo Chemical Co Oxazolyl optical brighteners for textiles and plastics
DD260698A1 (de) * 1986-11-27 1988-10-05 Tech Hochschule C Schorlemmer Verfahren zur herstellung von bis-oxazoliumsalzen
JP2000318313A (ja) * 1999-05-07 2000-11-21 Mitsui Chemicals Inc 光記録媒体

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3148194A (en) * 1961-07-03 1964-09-08 Arapahoe Chemicals Inc Certain 1, 4-bis[2(4-substituted, 5-phenyloxazolyl)] benzenes
FR2066252A5 (en) * 1970-10-20 1971-08-06 Sumitomo Chemical Co Oxazolyl optical brighteners for textiles and plastics
DD260698A1 (de) * 1986-11-27 1988-10-05 Tech Hochschule C Schorlemmer Verfahren zur herstellung von bis-oxazoliumsalzen
JP2000318313A (ja) * 1999-05-07 2000-11-21 Mitsui Chemicals Inc 光記録媒体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RICE C. ET AL.: "New multidentate ligands for supramolecular coordination chemisttry: double and triple helical complexes of ligands containing pyridil and thiazol donor units", J. CHEM. SOCIETY, DALTON TRANSACTIONS, vol. 5, 2001, pages 550 - 559 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2344780A1 (es) * 2009-03-03 2010-09-06 Universidad De Barcelona Compuestos bistiazolicos utiles para el tratamiento del cancer.
WO2010100297A1 (fr) * 2009-03-03 2010-09-10 Universidad De Barcelona Composés bisthiazoliques utiles pour le traitement du cancer
WO2012028757A1 (fr) 2010-09-02 2012-03-08 Universitat De Barcelona Tiazols fluorés utilisés pour le traitement du cancer
US8680126B2 (en) 2010-09-02 2014-03-25 Universitat De Barcelona Fluorinated thiazoles for use in treating cancer

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Publication number Publication date
AU2003260515A1 (en) 2004-03-03
AU2003260515A8 (en) 2004-03-03
ES2200706B1 (es) 2005-06-01
ES2200706A1 (es) 2004-03-01

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