Uses of 4'-desferrithiocin analogs

a technology of desferrithiocin and analogs, applied in the field of 4'-desferrithiocin analogs, can solve problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems such as problems, and achieve high-effectiv

Inactive Publication Date: 2017-07-27
UNIV OF FLORIDA RES FOUNDATION INC
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  • Abstract
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  • Claims
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Benefits of technology

[0009]Various desferrithiocin analogs, including desferrithiocin polyether analogs, have been developed that effectively chelate and remove iron from biological systems. See International PCT Applications, PCT / US99 / 19691, filed Aug. 31, 1999; PCT / US2003 / 028304, filed Sep. 9, 2003; PCT / US2006 / 010945, filed Mar. 22, 2006; PCT / US2008 / 003433, filed Mar. 14, 2008; PCT / US2010 / 002336, filed Aug. 25, 2010; each of which is incorporated herein by reference. Therefore, the present invention applies the use of these analogs, which have been previously only suggested for use in the treatment of global metal overload, to diseases and conditions associated with focal iron overload, such as, but not limited to, macular degeneration, stroke, IBD, closed head injury, and reperfusion injury. In certain embodiments, the desferrithiocin analog useful in the present invention is of Formula (I):wherein R1-R9 are as defined here. In certain embodiments, desferrithiocin analogs with a polyether moiety at the 4′-position of the phenyl ring are used in the present invention (i.e., R2 is a polyether moiety). Such analogs have been found to be useful in treating diseases or conditions associated with focal iron overload, for example, where iron has been introduced into an organ, tissue, or space by bleeding or through an inflammatory response. In certain embodiments, such analogs have been found in the cerebral spinal fluid (CSF) and therefore may be useful in treating neurological diseases such as closed head injury or stroke. In certain embodiments, such analogs have been found to penetrate into the eye and may be useful in treating ophthalmologic diseases such as macular degeneration. All of these diseases are associated with free radical damage resulting from unmanaged or free iron in the respective tissue or organ. Therefore, the chelation and removal of the free iron in these tissues and organs would be effective in preventing or treating each of these diseases.

Problems solved by technology

Furthermore, superoxide anions or a biological reductant (e.g., ascorbic acid) can reduce the resulting Fe+3 ion back to Fe+2 for continued peroxide reduction, thus a problematic cycle.

Method used

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  • Uses of 4'-desferrithiocin analogs
  • Uses of 4'-desferrithiocin analogs
  • Uses of 4'-desferrithiocin analogs

Examples

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example 1

on of Sample Solutions

Synthesis of the Desferrithioncin (DFT) Analogs

[0173]The desferrithiocin (DFT) analogs and salts thereof useful in the present invention can be prepared from readily available starting materials using methods known in the art. For example, (S)-4′-(HO)-DADFT-norPE (III-A) and (S)-4′-(HO)-DADFT-PE (IV-A) may be synthesized using methods described in International PCT Applications, PCT / US2006 / 010945, filed Mar. 22, 2006, published as WO 2006 / 107626, PCT / US2010 / 002336, filed Aug. 25, 2010, published as WO2011 / 028255, and U.S. patent application U.S. Ser. No. 11 / 973,001, filed Oct. 4, 2007, each of which is incorporated herein by reference in its entirety.

Preparation of Sample Solutions Containing Monosodium Salts of the DFT Analogs

[0174]The DFT analogs useful in the inventive methods were converted from the free acid form to the monosodium salt form. Water followed by one equivalent of sodium hydroxide was added to the DFT analog as a free acid. The resulting slurr...

example 2

n of Acetic Acid-Induced Colitis by Deferrithiocin Analogs in a Rat Model

[0175]Induction of colitis. Male Sprague-Dawley rats (250-350 g) were anesthetized with sodium pentobarbital, 55 mg / kg intraperitoneally. The abdomen was shaved and prepared for surgery. A midline incision was made, and the cecum and proximal colon were exteriorized. A reversible suture was placed at the junction of the cecum and proximal colon. The colon was rinsed with saline (10 ml), and the fluid and intestinal contents were gently expressed out the rectum. A gum-based rectal plug was inserted. The compound of interest, or distilled water in the control animals (2 ml), was injected intracolonically just distal to the ligature. The cecum and proximal colon were returned to the abdominal cavity; the compound was allowed to remain in the gut for 30 min. Then, the cecum and proximal colon were exteriorized again. The rectal plug was removed, and the drug was gently expressed out of the colon. Acetic acid (4%, 2...

example 3

tion of DFT Analogs in Rat Plasma after PO (Oral) and SC (Subcutaneous) Dose

[0180]Male Sprague-Dawley rats (250-350 g) were given a single s.c. injection or an oral dose of the monosodium salt of deferitin, (S)-4′-(HO)-DADFT-norPE (III-A), or (S)-4′-(HO)-DADFT-PE (IV-A) at a dose of 300 μmol / kg. At times 0.5, 1, 2, 4, and 8 hours (n=3) rats per time point, the animals were euthanized by exposure to CO2 gas. Blood was obtained via cardiac puncture into vacutainers containing sodium citrate. The blood was centrifuged, and the plasma was separated for analysis. See FIGS. 2 and 3.

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Abstract

Macular degeneration, closed head injury, stroke, irritable bowel disease, and reperfusion injury are all associated with biological injury due to reactive oxygen species, probably due to focal iron overload in many instances. The present invention provides methods and pharmaceutical compositions for treating these diseases and conditions using desferrithiocin analogs of Formula (I). In certain embodiments, the analogs include a polyether moiety at the 4′-position of the phenyl ring of the compound.

Description

RELATED APPLICATIONS[0001]The present application is a continuation of and claims priority under 35 U.S.C. §120 to U.S. application Ser. No. 14 / 363,886, filed Jun. 9, 2014, which is a national stage filing under 35 U.S.C. §371 of international PCT application, PCT / US2012 / 069795, filed Dec. 14, 2012, which claims priority under 35 U.S.C. §119(e) to U.S. provisional patent application, U.S. Ser. No. 61 / 576,920, filed Dec. 16, 2011, each of which is incorporated herein by reference.GOVERNMENT SUPPORT[0002]This invention was made with U.S. Government support under grant number R37DK049108 awarded by National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The U.S. Government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Iron metabolism in primates is characterized by a highly efficient recycling process. Brittenham, “Disorders of Iron Metabolism: Iron Deficiency and Overload” In Hematology: Basic Principles and Practic...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/426
CPCA61K31/426C07D277/10A61P25/00
Inventor BERGERON, JR., RAYMOND J.
Owner UNIV OF FLORIDA RES FOUNDATION INC
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