WO2003075905A1 - Utilisation de derives de phenols 2,4-disubstitues comme inhibiteurs de l'expression des l-selectines et de l'isoforme inductible de l'oxyde nitrique synthase - Google Patents

Utilisation de derives de phenols 2,4-disubstitues comme inhibiteurs de l'expression des l-selectines et de l'isoforme inductible de l'oxyde nitrique synthase Download PDF

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Publication number
WO2003075905A1
WO2003075905A1 PCT/ES2002/000119 ES0200119W WO03075905A1 WO 2003075905 A1 WO2003075905 A1 WO 2003075905A1 ES 0200119 W ES0200119 W ES 0200119W WO 03075905 A1 WO03075905 A1 WO 03075905A1
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terbutyl
isopropyl
phenyl
use according
methyl
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PCT/ES2002/000119
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English (en)
Spanish (es)
Inventor
Jesús LOPEZ-BELMONTE PASCUAL
Juan Lopez-Belmonte Pascual
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Bobel 246, S.L.
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Priority to PCT/ES2002/000119 priority Critical patent/WO2003075905A1/fr
Priority to AU2002246135A priority patent/AU2002246135A1/en
Publication of WO2003075905A1 publication Critical patent/WO2003075905A1/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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/055—Phenols the aromatic ring being substituted by halogen

Definitions

  • the present invention relates to the use in medicine and veterinary of certain derivatives of 2,4-disubstituted phenols which, due to a potent activity as an inhibitor of the inducible isoform of nitric oxide synthase (iNOS) and as an inhibitor of the expression of The adhesion molecule L-selectin on the surface of the plasma membrane of leukocytes, are very useful in the preparation of drugs for the treatment of therapeutic indications mediated by the action of iNOS, by the action of L expression -selectin or both.
  • iNOS inducible isoform of nitric oxide synthase
  • NO nitric oxide
  • NO is of a gaseous nature and is synthesized from the amino acid L-arginine thanks to the action of a cytosolic emzyme called nitric oxide synthase.
  • This enzyme belongs to the family of flavoproteins, has a certain homology with cytochrome P450 reductases and from it three different isoforms have been described: endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS).
  • Both eNOS and nNOS are expressed constitutively, are dependent on calcium and calmodulin and insensitive to the effects of glucocorticoids, release small amounts of NO intermittently for short periods, the constitutive NO acts as a mechanism of signal transduction in multiple physiological processes and is involved in the maintenance of vascular tone.
  • the biochemical characteristics of the constitutive NOS are similar, but they differ in their location and in the function performed by the NO produced by them.
  • the eNOS is preferentially located in renal endothelial cells, platelets and mesangial, osteoblasts and osteoclasts and is involved in the regulation of vascular homeostasis and platelet function.
  • the nNOS is of nerve location, both central and peripheral, and is a producer of a NO that acts as a central and peripheral neurotransmitter.
  • the iNOS is not calcium dependent and inflammatory stimuli of endotoxins (such as lipopolysaccharide) and certain cytokines (interleukin-1, tumor necrosis factor (TNF-alpha) or interferon gamma (INF-gamma)), induce the formation of iNOS in a variety of cells, including epithelial cells, macrophages and neutrophils. Inducible nitric oxide synthase produces much greater amounts of NO for long periods of time compared to the other isoforms.
  • endotoxins such as lipopolysaccharide
  • cytokines interleukin-1, tumor necrosis factor (TNF-alpha) or interferon gamma (INF-gamma)
  • the NO synthesized by the iNOS plays a fundamental role in the defense against external agents such as the cytotoxic molecule and is involved in vasodilation in inflammatory processes. It is known to those skilled in the art that large amounts of NO produced by iNOS have antimicrobial (J. Clin. Invest., 1989, 81: 1129-1136) and antitumor (Science, 1987, 235: 473-476) functions. The NO is involved in the elimination of parasites, bacteria, tumor cells and viruses. The high concentration of NO synthesized by iNOS explains the cytotoxic and cytostatic effects of this enzyme. Therefore, iNOS plays an important role in the immune response.
  • additional states in which there is an advantage of inhibiting the production of NO to Starting from L-arginine, by inhibiting the expression of iNOS include autoimmune and / or inflammatory joint and musculoskeletal states, inflammatory diseases of the gastrointestinal tract, cardiovascular ischemia, diabetes, hyperalgesia, cerebral ischemia, systemic hypotension associated with septic shock and / or toxic induced by a wide variety of agents, cytokine therapy, as an adjuvant for short-term immunosuppression in transplant therapy, as well as NO-mediated CNS disorders.
  • Inflammation is the response of vascularized tissues to aggressions.
  • the main objective of inflammation is to locate and eradicate irritation and repair surrounding tissue.
  • the inflammatory response involves 3 important stages: dilation of the capillaries to increase blood flow, microvascular structural changes and release of plasma proteins from the bloodstream, and thirdly leukocyte transmigration through the endothelium and accumulation in the damaged area.
  • Its regulation involves different humoral factors, such as prostaglandins, vasoactive amines, cytokines, etc., but in the last two decades it has been found that certain cytoplasmic membrane molecules present in both leukocytes and endothelial cells play an important role. in the regulation of leukocyte infiltration of inflamed tissues and, therefore, in the development and maintenance of the inflammatory response.
  • the leukocyte adhesion cascade is a sequence of adhesion and activation events that ends with the leukocyte extravasation. At least 5 steps appear to be necessary for the effective recruitment of leukocytes: capture, rotation, slow rotation, firm adhesion and transmigration. Blocking any of these steps can significantly reduce the accumulation of leukocytes in the tissue.
  • the recruitment of leukocytes to the foci of inflammation is directed by a series of adhesion molecules present both on the surface of the plasma membrane of the leukocytes themselves, as in the endothelial cells of the capillaries and venules of inflamed tissues.
  • the adhesion molecules involved in the inflammatory response belong mainly to 3 large families: selectins, integrins and the immunoglobulin superfamily.
  • Selectins are glycoproteins characterized by containing an amino terminal region with structural homology to calcium dependent lectins (LC), followed by another structure similar to epidermal growth factor (EGF); from 2 to 9 complement regulatory protein (SCR) regions; a transmembrane zone; and a cytoplasmic region.
  • LC calcium dependent lectins
  • EGF epidermal growth factor
  • SCR complement regulatory protein
  • L-selectin is constitutively expressed in virgin neutrophils, monocytes, T and B lymphocytes and in a subpopulation of K cells.
  • This adhesion molecule contributes greatly to the capture of leukocytes during the early stages of the adhesion cascade, demonstrating its involvement in said recruitment of leukocytes to foci of inflammation.
  • L-selectin is removed from the surface of the leukocytes, and released into the medium, in response to different activating stimuli, such as cytokines, calcium ionophore, forbol esters, etc. This mechanism of regulation of its expression is shared with other adhesion molecules or cytokine receptors.
  • the lectin-like region of L-selectin participates in the recognition of ligands; these domains bind L-selectin to ligands through a calcium-dependent interaction of the lectin-like amino-terminal region of L-selectin with complex carbohydrates (sialylated, sulphated and / or fucosylated) present in different glycoproteins of endothelial cells.
  • NK cells are lymphocytes of the innate immune system that recognize and induce lysis of a variety of cells, including virus-infected cells, tumor cells, and allogeneic cells without prior sensitization.
  • NK cells make a variety of cytokines such as interferon-gamma, tumor necrosis factor alpha (TNF-alpha), IL-l ⁇ , IL-10 and also produce chemokines such as RANTES, l ⁇ macrophage inflammatory protein and l ⁇ macrophage inflammatory protein, which are involved in the elimination of intracellular pathogens in vivo, as well as in the generation of antigen-specific immune response.
  • NK cells The differentiation of NK cells is accompanied by the expression on the cell surface of a glycoprotein (PEN5), which is a post-translational modification of the selectin P ligand (PSGL-1).
  • PEN5 glycoprotein
  • PSGL-1 selectin P ligand
  • the PEN5 epitope creates on PSGL-1 a single binding site for L-selectin.
  • the selectivity of PEN5 expression in NK cells, and their absence in antigen-specific T and B lymphocytes suggests that the specific functions of NK cells depend on the acquisition of this ligand for L-selectin. Therefore, the control of interactions of NK cells via PEN5 can have important implications for the induction and maintenance of immunity to tumor and infectious diseases, as well as amplifying the immune response to an inflammatory stimulus.
  • the present invention provides a group of products derived from 2,4-disubstituted phenols, known chemically in the literature. Of these 2,4-disubstituted phenols, their inhibitory activity of the inducible isoform of nitric oxide synthase, nor their ability to inhibit the expression of the adhesion molecule L-selectin on the membrane surface had never been described before. leukocyte plasma
  • Patent ES2087019 mentions the inhibitory activity of 5-lipoxygenase (5-LO) of the included products in the present invention, but at no time the possibility is mentioned that said products may exhibit inhibitory activity of the inducible isoform of nitric oxide synthase, nor of its ability to inhibit the expression of the adhesion molecule L-selectin in the surface of the plasma membrane of leukocytes.
  • 5-LO 5-lipoxygenase
  • the object of the present invention is the use of a 2,4-disubstituted phenol derivative of formula (I),
  • R2 is (C1-C4) -alkyl, (C1-C4) -acrylic, CF 3 , Cl, Br or I;
  • R3 is H, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -acrylic, (C 1 -C 4 ) -alkoxy, CF 3 / F, Cl, Br, phenyl, OH, SH, NH 2 or amino mono- or disubstituted by (Ci-C 3 ) -alkyl;
  • R4 is (C 1 -C 4 ) -alkyl, (C1-C4) -acrylic, CF 3 , F, Cl, Br, I, carboxyl, (C 1 -C 4 ) -alkoxycarboxyl, cyano, nitro or phenyl; Y
  • R6 is H, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -acrylic, CF 3 , Cl, Br or I;
  • R2 is (C 1 -C 4) -alkyl, CF 3 , Cl, Br or I
  • R3 is H, (C 1 -C 4 ) -alkyl, CF 3 , F, Cl, Br, phenyl, OH, SH, NH 2 or dimethylamino
  • R4 is (C 1 -C 4 ) -alkyl, CF 3 , F, Cl, Br, I, carboxyl, cyano, nitro or phenyl
  • R6 is H, (C1-C4) -alkyl, CF 3 , Cl, Br or I.
  • R2 is I;
  • R3 is H, methyl, ethyl, isopropyl, terbutyl, CF 3 , F, Cl, Br, phenyl or OH;
  • R4 is methyl, ethyl, isopropyl, terbutyl, CF 3 , F, Cl, Br, I, carboxyl or phenyl;
  • R6 is H, isopropyl, terbutyl, CF 3 , Cl, Br or I.
  • R3 is H, methyl, ethyl, isopropyl, terbutyl, CF 3 , Cl, Br or phenyl
  • R4 is isopropyl, terbutyl, CF 3 , Br, I, carboxyl or phenyl
  • R6 is H, isopropyl, terbutyl, CF 3 or I.
  • R3 is H; R4 is terbutyl, CF 3 , I or phenyl; and R6 is terbutyl, CF 3 or I. Still more preferred is that in which R4 and R6 are I.
  • a 2,4-disubstituted phenol derivative of formula (I) wherein: R2 is CF 3 or Br; R3 is H, methyl, ethyl, isopropyl, terbutyl, CF 3 , F, Cl, Br, phenyl or OH; R4 is methyl, ethyl, isopropyl, terbutyl, CF 3 , F, Cl, Br, I, carboxyl or phenyl; and R6 is H, isopropyl, terbutyl, CF 3 , Cl, Br or I.
  • R3 is H, methyl, ethyl, isopropyl, terbutyl, CF 3 , Cl, Br or phenyl
  • R4 is isopropyl, terbutyl, CF 3 , Br, I, carboxyl or phenyl
  • R6 is H, isopropyl, terbutyl, CF 3 or I.
  • R3 is H; R4 is terbutyl, CF 3 , I or phenyl; and R6 is terbutyl, CF 3 or I.
  • a 2,4-disubstituted phenol derivative of formula (I) wherein: R2 is isopropyl or terbutyl; R3 is H, methyl, ethyl, isopropyl, terbutyl, CF 3 , F, Cl, Br, phenyl or OH; R4 is methyl, ethyl, isopropyl, terbutyl, CF 3 , F, Cl, Br, I, carboxyl or phenyl; and R6 is H, isopropyl, terbutyl, CF 3 , Cl, Br or I.
  • R3 is H, methyl, ethyl, isopropyl, terbutyl, CF 3 , Cl, Br or phenyl
  • R4 is isopropyl, terbutyl, CF 3 , Br, I, carboxyl or phenyl
  • R6 is H, isopropyl, terbutyl, CF 3 or I.
  • R3 is H; R4 is terbutyl, CF 3 , I or phenyl; and R6 is terbutyl, CF 3 or I.
  • Some of the products of formula (I) have stereoisomers.
  • the use of these isomers, separately or mixed, as inhibitors of the inducible isoform of nitric oxide synthase and inhibitors of the expression of the L-selectin adhesion molecule on the surface of the plasma membrane of leukocytes, is also the subject of the present invention.
  • the products of formula (I) or their pharmaceutically acceptable salts or solvates are useful in the preparation of medicaments for the treatment of diseases mediated by the action of the inducible isoform of nitric oxide lasintase, by the action of L-selectin expression or both, with the preferences outlined above.
  • Derivatives of 2,4-disubstituted phenols or their pharmaceutically acceptable salts can be administered orally, parenterally or topically, in the form of injectables, tablets, dragees , syrups, lotions, shampoos, ointments, suppositories, eye drops, etc.
  • Example 1 Effect on the activity of nitric oxide synthase (NOS) in a model of TNB-induced ulcerative colitis in rats.
  • NOS nitric oxide synthase
  • TLB trinitrobenzene sulfonic acid
  • the animals were given different anti-inflammatory drugs, 24 hours after the administration of TNB.
  • the anti-inflammatory drugs that were used were: prednisolone (0.5mg kg "1 ), L-NAME (30mg kg " 1 ) and 2,4,6-triodophenol (BOBEL-24, l-25mg kg "1 ), administered orally for 3 consecutive days.
  • nitric oxide synthase activity in colonic tissue was carried out by means of the citrulline test, in which the conversion of monohydrochloric L- [14C] -argenine to [14C] -citrulline is measured, according to the method described by Knowles et al. (Biochem. Biophys. Res. Commun., 1990, v.172, 1042-1048).
  • Colonic tissue samples were obtained 24 hours after TNB administration and 2, 3 and 4 days after TNB administration. These tissues were homogenized in a buffer solution with HEPES, sucrose, DL-dithiothreitol, leupeptin, soy trypsin inhibitor and aprotinin. After centrifuging the homogenates, a sample of the supernatant was added to a tube containing 10 ⁇ l of preheated incubation buffer at 37 ° C which in turn contained potassium phosphate, L-valine, NADPH, MgCl 2 and CaCl 2 , L- argenine and L- [14C] -monohydric chloride and was incubated for 10min at 37 ° C.
  • the reaction was terminated by the addition of 500 ⁇ l of a mixture of H 2 0: Dowex-AG50.
  • the mixture of resin and incubated solution of the sample was dispersed and diluted by the addition of 860 ⁇ l of distilled water. After precipitation of the resin, 975 ⁇ l of supernatant was subtracted to count in a liquid scintillation counter (2ml of EcoScint H liquid; Packard).
  • BOBEL-24 prednisolone and L-NAME once a day for a period of 3 days, on the induced colonic damage after a single injection of trinitrobenzene sulfonic acid (TNB; 80 mg kg "1 administered on day 0), the results show the damage score as a function of the time elapsed after the administration of TNB.
  • TNB trinitrobenzene sulfonic acid
  • L-citrulline that can be inhibited by in vitro incubation with L-NMMA is taken as an index of NOS activity, expressed as nmol min "1 g " 1 of tissue.
  • cNOS constitutive NOS
  • iNOS inducible and independent form of calcium from NOS
  • Figure 2 shows the effect of BOBEL-24 treatment on the inhibition of the increase in total NOS activity. Finding a 68 + 7% inhibition of NOS activity.
  • Figure 3 shows the effect that treatment with BOBEL-24 produced on the activity of calcium-independent NOS (iNOS), which could be observed 2 and 4 days after the administration of TNB.
  • the inhibition of iNOS activity was 82 ⁇ 11% and 45 ⁇ 14% at 2 and 4 days after TNB administration, respectively.
  • Example 2 Study of the effect on the activity of polymorphonuclear leukocytes in vivo in the rat by intravital microscopy.
  • the objective of the study was to determine if the substance
  • mesenteric venules without branches of 25-40 ⁇ m in diameter, and their associated arterioles (15-25 ⁇ m) were selected for study.
  • polymorphonuclear leukocytes The activation of polymorphonuclear leukocytes was performed by administering a dose of 3mg kg "1 iv of endotoxin (LPS E. Coli 0.111: B4) to the animals once they have been anesthetized and prepared for intravital observation. To determine the effect of the test and reference substances on the activation of leukocytes, these were administered orally as a pre-treatment lh before the administration of endotoxin. The administration of endotoxin resulted in an increase in the number of adherent neutrophils determined in a section of lOO ⁇ m of venule over an observation period of 1 hour.
  • pre-treatment with BOBEL-24 also resulted in an inhibition of the reduction of endotoxin-induced neutrophil rolling, with an increase in the speed of rolling that is related to the dose of BOBEL. -24 administered (see Figure 5).

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Abstract

La présente invention concerne l'utilisation dans le domaine médical et vétérinaire de certains dérivés de phénols 2,4-disubstitués qui, en raison de leur puissante activité comme inhibiteurs de l'isoforme inductible de l'oxyde nitrique synthase (iNOS) et comme inhibiteurs de l'expression de la molécule d'adhésion L-sélectine sur la surface de la membrane cellulaire des leucocytes, sont utilisés avantageusement dans la préparation de médicaments destinés au traitement de pathologies induites par l'action de l'isoforme inductible de l'oxyde nitrique synthase, par l'action de l'expression de la L-sélectine, ou par l'action conjuguée de ces derniers.
PCT/ES2002/000119 2002-03-14 2002-03-14 Utilisation de derives de phenols 2,4-disubstitues comme inhibiteurs de l'expression des l-selectines et de l'isoforme inductible de l'oxyde nitrique synthase WO2003075905A1 (fr)

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PCT/ES2002/000119 WO2003075905A1 (fr) 2002-03-14 2002-03-14 Utilisation de derives de phenols 2,4-disubstitues comme inhibiteurs de l'expression des l-selectines et de l'isoforme inductible de l'oxyde nitrique synthase
AU2002246135A AU2002246135A1 (en) 2002-03-14 2002-03-14 Use of derivatives of 2,4-disubstituted phenols as inhibitors of the expression of l-selectins and of the isoform that is inducible from nitric oxide synthase

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1577289A1 (fr) * 2004-03-18 2005-09-21 Revotar Biopharmaceuticals AG Inhibiteurs de selectine a petites molecules non glycosylees/glycosidiques/peptidiques pour le traitement de troubles inflammatoires
ES2258415A1 (es) * 2006-04-12 2006-08-16 Fundacion Universitaria San Pablo Ceu Bobel-24(2,4,6-triyodofenol) para el tratamiento o prevencion de la cryptosporidiosis humana y animal.
EP1764093A1 (fr) * 2005-09-20 2007-03-21 Revotar Biopharmaceuticals AG Nouveaux composés aromatiques et leur application médical
US7851501B2 (en) 2005-09-20 2010-12-14 Revotar Biopharmaceuticals Ag Aromatic nitrocatechol compounds and their use for modulating processes mediated by cell adhesion molecules
US7919532B2 (en) 2005-09-20 2011-04-05 Revotar Biopharmaceuticals Ag Hydroxylated aromatic compounds

Citations (4)

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EP0147892A2 (fr) * 1983-12-16 1985-07-10 Bislak, S.A. Procédé pour la préparation et les applications thérapeutiques de 2,4,6-triiodophénol
WO1994025047A1 (fr) * 1993-05-03 1994-11-10 Genentech, Inc. Inhibition de l'adhesion des leucocytes
ES2087019A1 (es) * 1994-02-08 1996-07-01 Bobel246 S L Uso de derivados de fenoles 2,4-disubstituidos como inhibidores de la 5-lipoxigenasa.
WO1996030012A1 (fr) * 1995-03-24 1996-10-03 Defeudis Francis V Procedes de traitement de conditions associees a des excedents d'oxyde d'azote

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0147892A2 (fr) * 1983-12-16 1985-07-10 Bislak, S.A. Procédé pour la préparation et les applications thérapeutiques de 2,4,6-triiodophénol
WO1994025047A1 (fr) * 1993-05-03 1994-11-10 Genentech, Inc. Inhibition de l'adhesion des leucocytes
ES2087019A1 (es) * 1994-02-08 1996-07-01 Bobel246 S L Uso de derivados de fenoles 2,4-disubstituidos como inhibidores de la 5-lipoxigenasa.
WO1996030012A1 (fr) * 1995-03-24 1996-10-03 Defeudis Francis V Procedes de traitement de conditions associees a des excedents d'oxyde d'azote

Non-Patent Citations (3)

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Title
LEE C.S. ET AL.: "Inhibition of expression of P-selectine by antioxidant in cholesterol-fed rats", J. KOREAN MED. SCI., vol. 14, no. 1, 1999, pages 8 - 14 *
THERIAULT A. ET AL.: "Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes", ATHEROSCLEROSIS, vol. 160, January 2002 (2002-01-01), pages 21 - 30 *
XIA L. ET AL.: "A proteosome inhibitor, an antioxidant, or a salicylate but not a glucocorticoid blocks constitutive and cytokine-inducible expression of P-selectine in human endothelial cells", BLOOD, vol. 91, no. 5, 1998, pages 1625 - 1632 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1577289A1 (fr) * 2004-03-18 2005-09-21 Revotar Biopharmaceuticals AG Inhibiteurs de selectine a petites molecules non glycosylees/glycosidiques/peptidiques pour le traitement de troubles inflammatoires
WO2005090284A1 (fr) * 2004-03-18 2005-09-29 Revotar Biopharmaceuticals Ag Mimetiques psgl-1 de petites molecules non peptidiques/non glycosidiques/non glycosylees pour le traitement de troubles inflammatoires
US8367677B2 (en) 2004-03-18 2013-02-05 Revotar Biopharmaceuticals Ag Non-glycosylated/non-glycosidic/non-peptidic small molecule PSGL-1 mimetics for the treatment of inflammatory disorders
EP1764093A1 (fr) * 2005-09-20 2007-03-21 Revotar Biopharmaceuticals AG Nouveaux composés aromatiques et leur application médical
WO2007039113A1 (fr) * 2005-09-20 2007-04-12 Revotar Biopharmaceuticals Ag Nouveaux composes aromatiques et utilisation de ceux-ci dans des applications medicales
US7851501B2 (en) 2005-09-20 2010-12-14 Revotar Biopharmaceuticals Ag Aromatic nitrocatechol compounds and their use for modulating processes mediated by cell adhesion molecules
US7919532B2 (en) 2005-09-20 2011-04-05 Revotar Biopharmaceuticals Ag Hydroxylated aromatic compounds
US7923473B2 (en) 2005-09-20 2011-04-12 Revotar Biopharmaceuticals Ag Aromatic compounds and their use in medical applications
US8394835B2 (en) 2005-09-20 2013-03-12 Revotar Biopharmaceuticals Ag Aromatic compounds and their use in medical applications
US8461207B2 (en) 2005-09-20 2013-06-11 Revotar Biopharmaceuticals Ag Phloroglucinol derivatives having selectin ligand activity
ES2258415A1 (es) * 2006-04-12 2006-08-16 Fundacion Universitaria San Pablo Ceu Bobel-24(2,4,6-triyodofenol) para el tratamiento o prevencion de la cryptosporidiosis humana y animal.

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