WO1992020227A1 - Chelateurs d'ions substitues efficaces par voie orale relatifs a la deferoxamine - Google Patents

Chelateurs d'ions substitues efficaces par voie orale relatifs a la deferoxamine Download PDF

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Publication number
WO1992020227A1
WO1992020227A1 PCT/US1992/003962 US9203962W WO9220227A1 WO 1992020227 A1 WO1992020227 A1 WO 1992020227A1 US 9203962 W US9203962 W US 9203962W WO 9220227 A1 WO9220227 A1 WO 9220227A1
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acyl
substituted
formula
groups
deferoxamine
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PCT/US1992/003962
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English (en)
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Donald E. Green
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Oral-D
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention is concerned with the preparation of compounds, compositions and methods which are useful for treating diseases in human beings which are a result, of a body tri-valent ion (i.e.
  • Iron overload diseases include thalassemia major, sideroachrestic anemia, Blackfan-Diamond anemia, aplastic anemia, sickle cell anemia, other hemolytic anemias, and a number of other diseases and conditions in which hemosiderosis (a focal or general increase in tissue iron stores without associated tissue damage) occurs.
  • hemosiderosis a focal or general increase in tissue iron stores without associated tissue damage.
  • One type of hemosiderosis occurs in most patients after multiple blood transfusions have occurred.
  • Another type of hemosiderosis occurs as the result of the treatment of an anemia found in kidney damaged patients where dialysis is used to remove toxic wastes. Treatment of these conditions has generally involved the administration of a chelating agent having a selective affinity for tissue Fe +++ ion which can then be excreted as the iron chelate.
  • the ideal chelating agent for the reduction of tissue metal ions e.g. iron, aluminum, gallium, ytterbium, indium and the like should have at least the following attributes:
  • deferoxamine a compound obtained from the microorganism strepotomyces pilosus.
  • Deferoxamine has the following structure:
  • Deferoxamine as the methanesulfonate salt
  • a portable infusion pump i.e., a battery powered syringe pump.
  • the present invention concerns certain acyl derivatives of deferoxamine which are effective ion, e.g. iron, aluminum, etc. chelators when administered orally.
  • R 1 may be an acyl group.
  • R groups are each acetyls, as intermediates in the production of their focus compounds.
  • Deferoxamine mesylate [DESFERAL R /Ciba-Geigy] (DFO) as an intraperitoneally administered iron-chelating agent is successfully marketed to facilitate the removal of iron in the treatment of acute iron intoxication and/or in chronic iron overload due to transfusion-dependent anemias and other related disease conditions.
  • the present invention concerns a group of di-, tri-, tetra-, penta-, hexa- and hepta-acylated
  • the invention is particularly useful in that its
  • this invention relates to compounds of the general formula: wherein:
  • R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are each selected from the group consisting of hydrogen and acyls of the formula:
  • R 5 is independently selected for each from the group consisting of alkyls, substituted alkyls, alkenyls, substituted alkenyls, cycloalkyls, substituted cycloalkyls, arylalkylenes, substituted arylalkylenes, alkylenecycloalkyls, alkylene substituted cycloalkyls, alkynyls, substituted alkynyls, aryls and substituted aryls.
  • Compounds of formula I are prodrug forms of deferoxamine which liberate deferoxamine in the body to complex and/or chelate ions, such as iron and/or aluminum, for subsequent excretion when administered to a human being, and are therefore useful in therapy in the treatment of diseases in which ion, e.g. iron, aluminum, levels in the body have elevated or toxic levels.
  • diseases for iron overload include, for example, thalassemia major, sideroachrestic anemia, Blackfan-Diamond anemia, aplastic anemia, sickle cell anemia, hemolytic anemias and hemosiderosis brought about by multiple blood transfusions or such condition when brought about by treatment of an anemia found in kidney-damaged patients undergoing renal dialysis.
  • Another aspect of the present invention relates to compounds of formula I as is described herein which liberate deferoxamine in the body to generally chelate any trivalent metal, such as iron, aluminum, chromium, gallium, ytterbium, indium and the like, for subsequent excretion, which is useful in the treatment of conditions (which is equivalent to
  • the compounds of formula I are useful as oral pharmaceuticals in the treatment of Alzheimer's and related diseases in which elevated aluminum levels have been found in the body, particularly the brain. Diseases or conditions having elevated aluminum body levels also include senile dementia and dialysis
  • compositions incorporating the compounds of formula I, dosage forms thereof and methods of treatment of the aforementioned conditions employing these preparations and/or dosage forms.
  • Another aspect of this invention is a process for the preparation of the compounds of formula I, as is described in greater detail hereinafter.
  • Figure 1 shows a comparison of iron excretion in response to deferoxamine derivatives administered intraperitoneally.
  • Figure 2 showsagraphic comparisonof iron excretion in response to deferoxamine derivatives administered orally .
  • Representative agents include, for example, acyl halides, acyl anhy- drides, mixed acyl anhydrides and mixtures thereof.
  • acylating agents When different acylating agents are employed herein they may include acylating agents which are in different catagories, e.g., alkyl acyl (acetyl chloride) and alkenyl acyl (methacryloyl chloride) or may include different acylating agents within the same category (e.g., acetyl chloride and propionyl chloride, etc.) or by substitution of one to three protons, e.g., propionyl chloride and 2-chloropropionyl chloride.
  • alkyl acyl acetyl chloride
  • alkenyl acyl methacryloyl chloride
  • Alkyl refers to a branched or unbranched saturated hydrocarbon containing 1 to 25 carbon atoms, such as, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-heptyl , i-heptyl , n-octyl, nonyl, decyl, undecyl, tridecyl, pentadecyl, heptadecyl, pentacosanyl and the like.
  • Substituted alkyl refers to an “alkyl” group, wherein at positions on the linear or branched structure one to three protons have been replaced by a group such as alkoxyl or halogen.
  • Alkenyl refers to a linear or branched unsaturated hydrocarbon group containing from 2 to 25 carbon atoms, such as, for example, ethenyl, propenyl, butenyl (1- and 2-), isobutenyl, hexenyl, heptenyl, nonenyl, undecenyl, dodecenyl, nonadecenyl, cosenyl, pentacosenyl and the like.
  • Substituted alkenyl refers to an "alkenyl” where at positions on the linear or branched structure, one to three protons have been replaced by a group such as alkoxyl or halogen.
  • Cycloalkyl refers to a cyclic alkyl structure containing 3 to 25 carbon atoms.
  • the cyclic structure may have alkyl substituents at any position.
  • Representative groups include cyclopropyl, 4-methylcyclohexyl, cyclooctyl, cyclohexadecyl, cyclopentacosanyl and the like.
  • Substituted cycloalkyl refers to a “cycloalkyl” where at positions on the group, one to three protons have been replaced by a group, such as
  • alkoxyl alkyl or halogen
  • -Arylalkylene refers to a group containing an "aryl” attached through an “alkylene.” Representative groups include benzyl (phenylmethylene), phenylethylene (phenethyl), phenyldecylene, naphthylmethylene, naphthyl-2-methylethylene and the like.
  • Substituted arylalkylene refers to an "arylalkylene” containing a “substituted aryl”
  • Representative groups include 2-methylphenylmethylene, 4-chlorophenylethylene, 4-bromophenylpropylene, 6-methoxynaphthylmethylene, 6-chloronaphthyldecylene and the like.
  • Representative groups include ethylenecyclopropyl, propylenecyclohexyl, 2-methylpropylenecyclodecyl, decylenecyclopentacosanyl and the like.
  • Alkylene substituted cycloalkyl refers to an alkylenecycloalkyl having a "substituted cycloalkyl” moiety. Representative groups include methylene-2-chlorocyclopropyl, ethylene-4-methylcyclohexyl, decylene-4-hydroxycyclodecyl, decylene-2-bromocyclopentacosanyl and the like.
  • Alkynyl refers to a branched or linear aliphatic hydrocarbon group having a -C ⁇ C- moiety which contains from 2 to 25 carbon atoms, such as for example, ethynyl, propynyl, isohexynyl, heptynyl, pentadecynyl, pentacosynyl and the like.
  • Substituted alkynyl refers to an “alkynyl” group, where at positions on the linear or branched structure, one to three protons have been replaced by a group such as alkoxy or halogen.
  • Halo or halogen refers to fluoro, chloro, bromo or iodo, usually as a substitutent replacing a hydrogen atom in an organic group.
  • Alkylene refers to a saturated linear or branched hydrocarbon structure containing 1 to 10 carbon atoms which has two points of attachment to other functional groups.
  • Representative “alkylenes” include methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -),
  • Aryl refers to a carbon-containing aromatic structure having 6 to 14 carbon atoms. Representative groups include phenyl, naphthyl, phenanthryl and the like. “Substituted aryl” refers to an “aryl” wherein at 1 to 3 positions on the aromatic ring, one to three protons have been replaced by another group, such as alkyl, alkoxyl or halogen.
  • deferoxamine N'-[5-[[4-[[-5-(acetylhydroxamino)
  • the 1-amino group when substituted by acyl (R 1 -), is designated as N-acyl (-N-R 1 ).
  • the hydroxamic acid hydrogen- at the 6-position, when substituted by acyl (R 2 -) is designated as O-acyl (-O-R 2 ).
  • the hydroxamic acid hydrogen at the 17-position, when substituted by acyl (R 3 -) is designated as O-acyl (-O-R 3 ).
  • hydroxamic acid hydrogen of the "27-(N-acetylhydroxylamino)" when substituted by acyl (R 4 -) is designated as (-O-R 4 ).
  • the second hydrogen on the 1-amino group and the hydrogens on the amide nitrogens at the 11 and 22 positions, when substituted by acyl, are also N- acyls designated by R 6 (-N-R 6 ), R 7 (-N-R 7 ) and
  • R 1 is isovaleryl
  • R 2 is acetyl (i.e., R 5 here is -CH 3 )
  • R 3 is butyryl (R 5 here is -CH 2 CH 2 CH 3 )
  • R 4 is n-octanoyl [R 5 here is -CH 2 (CH 2 ) 5 CH 3 ]
  • the compound name is N-isovaleryl-O,O,O-acetylbutyryl-n-octanoyldeferoxamine.
  • N-hydrogen N-H
  • -O-hydrogen -O-H
  • lower groups e.g., lower alkyl
  • intermediate groups e.g., lower alkyl
  • intermediate alkenyl contain 8 to 15 carbon atoms, and "higher" groups (e.g., higher alkyl)
  • Preferred compounds are those wherein R 6 , R 7 and R 8 are hydrogen.
  • Preferred groups include Compound
  • R 1 , R 2 , R 3 . R 4 , R 6 , R 7 and R 8 each contain the same number of carbon atoms or hydrogen. More
  • R 5 is alkyl, particularly lower alkyl and especially where R 5 is the same alkyl group. These compounds where R 5 is alkyl are preferred to be orally administered to treat the iron and aluminum related diseases described herein.
  • Preferred compounds of formula I also include those wherein up to five of R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen, more preferably the hydrogens are found on positions R 6 , R 7 and R 8 . See, for example. Table II.
  • this invention includes mixtures of compounds which would normally be expected in the reaction products described in the examples below. For instance, if an excess of acylating agent is used as shown in Table I, then a mixture of compounds such as 6, 6A, 6B, 6C and 6D may be
  • composition or method of treatment as a mixture of 2 or more isomers.
  • Another embodiment of the present invention includes those compounds of formula I as described herein, except that when R 1 is acyl of formula
  • R 5 is alkyl
  • a preferred compound is where R 1 is acetyl
  • R 2 , R 3 and R 4 are each acyl where R 5 is n-heptyl; and two of R 6 , R 7 and R 8 are hydrogen and the other is acyl where R 5 is n-heptyl.
  • Another embodiment of the present invention includes those compounds of formula I as described herein, except that when R 1 is acyl of formula
  • R 5 is alkenyl
  • compositions and for a method of treatment of ion, e.g. iron or aluminum, overload diseases are those where R6, R7 and R8 are each hydrogen.
  • An additional embodiment of the present invention describes a pharmaceutical composition useful for treating one or more diseases or conditions in a human being, related to excess iron in the blood and/or tissue, which comprises using a therapeutically effective amount of a compound of formula I in admixture with a pharmaceutically acceptable excipient.
  • R 5 contains 1 to 7 carbon atoms, particularly where R 5 is lower alkyl.
  • Preferred compounds include those where R 1 is acetyl and
  • R 5 is ethyl, n-propyl n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, or n-heptyl
  • R 6 , R 7 and R 8 are hydrogen.
  • Especially preferred compounds are N-acetyl-O,O,O-tri-n-octanoyldeferoxamine and
  • An additional embodiment of the present invention describes a method of treating a disease or condition in a human being, related to excess iron in the blood and/or tissue which method comprises administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula I.
  • Preferred embodiments include the method involving the compound of formula I wherein R 1 , R 2 R 3 , and R 4 are identical acyl groups. Particularly preferred are those compounds containing 2 to 8 carbon atoms per acyl, especially, acyls of the formula
  • An especially preferred compound is N-acetyl,O,O,O-tri-n-octanoyldeferoxamine.
  • Still another embodiment of the present invention describes a process for the preparation of the compounds of formula I which process comprises contacting the unsubstituted deferoxamine wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are each hydrogen with a suitable acylating agent in the presence of a strong base having a pK of about 9 to 11, treating the product with a weak base to form the N-acyl-O,O,O-trihydrogendeferoxamine; and treating this material with an excess of one or more different acylating agents to form the compound of formula I.
  • a particularly preferred embodiment is the process wherein R 5 of the first acylating agent contains one carbon atom; the weak base is ammonia; and in the different acylating agent R 5 contains 4 to 7 carbon atoms.
  • An especially preferred embodiment is the process wherein the first acylating agent is acetyl chloride or acetic anhydride; the base is anhydrous ammonia; and the
  • acylating agent is octanoyl chloride.
  • the reaction products of formula I may be separated using HPLC or equivalent means.
  • deferoxamine (la), as described by M. Windholz, Ed. in The Merck Index, published by Merck Co., Inc. of Rahway, New Jersey in 1976 (p. 374), is used as a starting material.
  • R 9 , R 10 and R 11 independently may be the same or different groups as is described herein for R 5 .
  • deferoxamine (la) may be tetra- up to and including hepta-acylated using an acyl halide.
  • Deferoxamine is suspended in a solution of water/solvent (i.e., water/dioxane, about 50/50) and the pH is adjusted to about 9 using a strongly basic solution, preferably 4 to 7N sodium hydroxide.
  • a strongly basic solution preferably 4 to 7N sodium hydroxide.
  • the acyl halide in a solvent, such as dioxane is added dropwise keeping the pH at about 9.
  • Water and a chlorinated solvent, such as chloroform may be needed to keep the reactants in solution. Strong agitation of the reaction mixture is necessary.
  • Step 2 the compound of formula Ic is obtained by dissolving the N-acyl-O,O,O-triacyl (to hepta-acyl) product of formula lb in an excess of an ethereal alcoholic solvent, such as methanol, and cooling to about -20°C to +20°C, preferably about 0°C, the reaction mixture is subsequently saturated with a base, preferably gaseous ammonia. After' maintaining the reaction mixture at about -20°C to +20°C,
  • the solvent is decanted and the product, usually as a solid, is recovered, washed twice with boiling hexane, and the resulting solid is and dried under reduced pressure. After recrystallization from alcohol/water solution, the product is recovered and air dried.
  • Step 3 compound Ic is suspended in a solution of water/solvent (i.e., water/chloroform about 50/50).
  • the solution is adjusted to about pH of 9 using strong base, preferably 3-7N sodium hydroxide solution.
  • strong base preferably 3-7N sodium hydroxide solution.
  • To this mixture is added dropwise a solution of the acyl halide, preferably the chloride, in a solvent such as chloroform.
  • the pH of the solution is continuously monitored and is maintained at pH of 9.
  • the layer of chlorinated solvent is removed, washed, dried, filtered, and evaporated in vacuo to produce an oily or waxy product, the compound of formula I.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, high pressure liquid chromatogrophy (HPLC), thin-layer chromatography or thick-layer chromatography, dry column chromatography or a combination of these procedures.
  • suitable separation and isolation techniques can be had by reference to the examples herein below. Other equivalent separation or isolation procedures, however, could also be used.
  • this invention includes mixtures of compounds of formula I wherein the groups, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen or acyl as is defined and as limited above.
  • the mixture of isomers is administered as part of a pharmaceutical composition to a person in the same manner that an essentially pure compound of formula I would be administered.
  • N-R 6 is formed first because it is the least steri- cally hindered of the three available amides.
  • the hypertransfused rat is one that closely mimics the situation in patients with transfusional iron overload.
  • heat-damaged rat erythrocytes are transfused intraperitoneally (i.p.) on a daily basis.
  • the iron in the red cells is processed by the reticuloendothelial system, and then transferred to parenchymal cells for storage throughout the body.
  • the highest concentration of iron is found in the liver and "spleen, during drug testing both "new” and “old” iron are available for sequestration and elimination, "new” iron being derived from recently catabolized red cells and "old” iron from parenchymal cells. This is identical to the situation in transfused (iron overload) thalassemia patients.
  • the hypertransfused rat has been used successfully to screen more than 600 drug candidates.
  • a related model, the hypertransfused mouse has also been used extensively with some success.
  • the animal models employing a variety of iron-containing compounds to produce iron overload have been investigated. None of the latter models have proved to be useful in systematically screening a wide variety of iron-chelating agents, in most cases, these models fail to overload the parenchymal and/or reticuloendothelial iron compartments. In vitro models are less useful and correlate poorly with results obtained in vivo, especially following oral drug administration.
  • Deferoxamine mesylate (DFO:Desferal) was obtained from the Ciba Pharmaceutical Company (Summit, New Jersey) as a lyophilized powder. For administration to the hypertranc fused rats, it was dissolved in physiological saline at a concentration of 10 mg/ml.
  • acylated derivatives of DFO were prepared: PDP 3 : N-Propionyl-O,O,O-tripropionyl deferoxamine (# of acyl carbons-12),
  • BDB 3 N-Butyroyl-O,O,O-tributyryl deferoxamine (# of acyl carbons-16),
  • VDV 3 N-Valeroyl-O,O,O-trivaleroyl deferoxamine (# of acyl carbons-20),
  • MDP 3 N-Myristoyl-O,O,O-tripropionyl deferoxamine (# of acyl carbons-23).
  • a homogeneous solution of acylated derivative was obtained by dissolving the drugs in propylene glycol at a concentration of 30 mg/ml.
  • Sprague-Dawley rats 60-80g; Taconic Farms, Germantown, New York( were iron overloaded via daily (5 days/week) intraperitoneal injections of heat-damaged rat erythrocytes.
  • the red blood cells for infusion were purchased from Hilltop Lab Animals, Inc. (Scottsdale, Pennsylvania). They were obtained from retired breeders, the donor animals being exsanguinated via cardiac puncture under CO 2 anesthesia.
  • red cells Prior to infusion the red cells were slightly damaged by heating at 50°C for 15 minutes.
  • the recipient animals were infused with the heat-damaged red cells at one-tenth of their blood volume per day for 16 weeks at which time they had received eight blood volumes and were sufficiently iron overload to begin drug screening.
  • the animals were placed on a low iron diet (>10 ⁇ g of Fe/g) for one week prior to screening. Use of a low iron diet is necessary if one is to measure drug related excretion of stool iron.
  • a low iron diet is necessary if one is to measure drug related excretion of stool iron.
  • the compounds were administered either by gavage (orally) or by intraperitoneal injection 4 to 8 hours after the animals were transfused. The dose of each drug was 100 mg/kg/day for 5 days.
  • Urine and stool samples were collected approximately 24 hours after drug administration. They were placed in crucibles, dried at 110°C and then ashed at 550°C overnight. Following dissolution of the ash in 3N HCl, the iron content of the samples was determined by atomic absorption spectroscopy.
  • the iron-overloaded rats were divided into groups of six. Before testing any of the new compounds both positive and negative controls were evaluated. Baseline excretion of iron in the urine and stool of this series of hypertransfused rats was determined in the absence of drug administration (negative control). As a positive control, another group of six animals was given DFO intraperitoneally at a dose of 100 mg/kg (153 micromoles/kg). Since the thrust of these studies was to develop an orally- effective drug derived from DFO, a third group of animals was given DFO (100 mg/kg) orally. All of the drugs were evaluated both orally and intraperitoneally. The intraperitoneal effect was used to assess bioavailability.
  • Table 1 outlines the protocol followed for prodrug evaluation.
  • Table 2 gives the background iron excretion of the model, as well as that induced by oral and parenteral DFO.
  • DB 3 N-butyroyl-O,O,O-tributyroyldeferoxamine
  • VDV 3 The most effective oral drug studied, VDV 3 , induces a total iron excretion of 3.85 ⁇ g/kg/day/umole, which is 94% of the historically observed excretion induced by intraperitoneal deferoxamine, 4.09 ⁇ g/kg/day/umole.
  • VDV 3 is further enhanced by its lack of systemic toxicity.
  • the intraperitoneal LD 50 s of both DFO and VDV 3 were 800 mg/kg in Swiss-Webster mice.
  • VDV 3 has the most active derivative tested.
  • Oral VDV 3 has about 94% of the chronic iron excretory potency of i.p. DFO.
  • the present invention relates to a pharmaceutical composition for oral administration to a mammal to mitigate metal ion overload conditions of the structure:
  • R 6 , R 7 and R 8 are each -H
  • the total number of carbon atoms in groups R 1 , R 2 , R 3 and R 4 is between 12 and 28.
  • the pharmaceutical composition has R 1 , R 2 , R 3 and R 4 each selected from identical alkyl groups.
  • Another embodiment is the pharmaceutical composition wherein in groups R 5 and R 5a the alkyl group has 2 carbon atoms, ethyl.
  • Another embodiment is the pharmaceutical composition wherein in groups R 5 and R 5a the alkyl group has 3 carbon atoms, n-propyl or isopropyl.
  • Another embodiment is the pharmaceutical composition wherein in groups R 5 and R 5a the alkyl group has 4 carbon atoms, n-butyl, isobutyl sec-butyl or tert-butyl.
  • Another embodiment is the pharmaceutical composition wherein in groups R 5 and R 5a the alkyl group has 5 carbon atoms, n-pentyl or isopentyl.
  • Another embodiment is the pharmaceutical composition wherein in groups R 5 and R 5a the alkyl group has 6 carbon atoms, n-hexyl and isohexyl.
  • Another embodiment is the pharmaceutical composition wherein the ion is selected from iron +3 or aluminum +3 .
  • composition of the structure is a pharmaceutical composition of the structure:
  • R 1 myristoyl (the tetradecanoic acid ester) and R 2 , R 3 and R 4 are each acyl groups wherein the acyl group is propionyl.
  • the acyl halides and anhydrides, solvents, reagents and the like described herein are available according to Chemical Sources, published by
  • Administration of the compounds of this invention can be via any of the accepted modes of administration for therapeutic agents. These methods include oral, parenteral, transdermal, subcutaneous and other systemic modes. The preferred method of administration is oral.
  • the composition may be in many forms, for example, solid, semi- solid, or liquid dosage forms, including tablets, time release agents, pills, capsules, suspensions, solutions and the like.
  • the compositions will include a conventional pharmaceutical excipient and an active compound of formula I or the pharmaceutically acceptable salts thereof and may, in addition, include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
  • the amount of the active compound of formula I administered will, of course, be dependent on the molecular weight of selected compound, the subject being treated, the subject's weight, the severity of the affliction, the manner of the administration and the judgment of the prescribing physician.
  • an effective dose is in the range of about 25-200 mg/kg/day, preferably about 125 mg/kg/day.
  • those dosages would amount to about 1.5 to 14 g/day, or preferably about 9 g/day.
  • liquid pharmaceutically administratable compositions can be prepared by dissolving, dispersing, etc., a compound of formula I and optional pharmaceutical adjuvants in an excipient, such as, for example, water, glycerol, ethanol, vegetable oil and the like to form a
  • N-propionyl-O,O,O-tripropionyldeferoxamine N-butyryl-O,O,O-tributyryldeferoxamine
  • N-octanoyl-O,O,O-trioctanoyldeferoxamine N-dodecanoyl-O,O,O-tridodecanoyl- deferoxamine
  • N-palmitoyl-O,O,O-tripalmitoyldeferoxamine N-stearoyl-O,O,O-tristearoyldeferoxamine; or N-hexacosanoyl-O,O,O-tri(hexacosanoyl)- deferoxamine.
  • N-Acetyl-O,O,O-triacetyldeferoxamine (prepared in Example 1) (10.0 g) is taken up in 200 ml of methanol and 500 ml of ether, cooled to 0°C, and the solution is saturated with anhydrous gaseous ammonia. The reaction mixture is kept at 0°C tor 6 hr, and then at ambient temperature overnight (about 16 hr). The ammonia-containing methanol/ether is decanted and the resulting colorless crystalline solid is washed twice with boiling hexane and is dried in vacuum, crude yield 8.1 g.
  • N-propionyl-O,O,O-tripropionyldeferoxamine N-butyryl-O,O,O-tributyryldeferoxamine
  • N-octanoyl-O,O,O-trioctanoyldeferoxamine N-palmitoyl-O,O,O,-tripalmitoyldeferoxamine; or
  • N-propionyl-O,O,O-trihydrogendeferoxamine N-butyryl-O,O,O-trihydrogendeferoxamine
  • N-octanoyl-O,O,O-trihydrogendeferoxamine N-palmitoyl-O,O,O-trihydrogendeferoxamine; or
  • the reaction mixture is stirred for 1 hr, with periodic monitoring to maintain a pH of 9.
  • the reaction mixture is then diluted with 150 ml of water and 500 ml of chloroform, and centrifuged to separate the phases.
  • the white material present at the liquid interface is discarded.
  • the aqueous phase is separated and extracted twice with 250 ml of chloroform. Essentially no product is obtained upon removal of the chloroform.
  • the chloroform phase contained a white solid which is removed using additional centrifugation.
  • the combined chloroform layers are washed twice with saturated sodium bicarbonate solution, twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated using reduced pressure.
  • N-Acetyl-O,O,O-trihydrogendeferoxamine (from Example 2) (3.0 g) is suspended in a mixture of 100 ml of water and 150 ml of chloroform.
  • Step 1 Schotten-Baumann conditions
  • Deferoxamine mesylate 6.0g is suspended in 50 ml of water and 50 ml of dioxane. The suspension is adjusted to pH of 9 using 5N sodium hydroxide solution with strong agitation. In 10 ml portions, a solution of 13.0 g of octanoyl chloride in 60 ml of dioxane. The pH of the mixture is maintained at 9 by the dropwise addition of the 5N sodium hydroxide solution. After the addition of 40 ml of the octanoyl chloride/dioxane solution, the reaction mixture is treated with 50 ml of water and 200 ml of chloroform.
  • the mixture separates into two phases which are agitated strongly. After the addition of all the acid chloride solution, the reaction mixture is agitated for 2 hr at pH of 9.
  • the reaction mixture is diluted with 500 ml of water and 1000 ml of chloroform and the aqueous phase is separated and extracted twice using 250 ml portions of chloroform.
  • the combined chloroform phases are washed twice with saturated sodium bicarbonate solution, twice with saturated sodium chloride solution and dried using anhydrous sodium sulfate.
  • the chloroform is removed under reduced pressure, and the waxy residue is dissolved in 500 ml of diethyl ether and hexane was added almost to turbidity. A sticky, granular product weighing 3.8g is obtained.
  • the infrared and proton magnetic resonance spectra are consistent with a structure of
  • N-propionyl-O,O,O-tripropionyldeferoxamine N-butyryl-O,O,O-tributyryldeferoxamine
  • N-acryloyl-O,O,O- butyrylbenzoylcyclohexyldeferoxamine; N- yclohexyl-O,O,O- benzoylacryloylbutyryldeferoxamine;
  • Products A, B and C also include other possible isomers of the groups described therein. Also, the position of the acyl groups on the nitrogen and oxygen is not yet known with certainity.
  • N-Octanoyl-O,O,O-trioctanoyldeferoxamine (3.5 g, from Example 4) is dissolved in 250 ml of ether, 100 ml of methanol and saturated at ambient temperature with ammonia gas. After stirring for 3 days (about 72 hr) at ambient temperature, the reaction mixture is evaporated to dryness using reduced pressure, and the solid residue is boiled five times with hexane to remove the octanoic acid amide. The remaining colorless crystalline product is recrystallized from n-propanol/water (66/34) to give 1.5g of N-octanoyl-O,O,O-trihydrogendeferoxamine, m.p. 185-137°. The infrared and nuclear magnetic resonance spectra are consistent with this structure. The product is sparingly soluble in water and ordinary organic solvents.
  • N-isovaleryl-O,O,O-trihydrogendeferoxamine N-dodecanoyl-O,O,O-trihydrogendeferoxamine
  • N-acryloyl-O,O,O-trihydrogendeferoxamine N-2-butenoyl-O,O,O-trihydrogendeferoxamine; N-2-pentenoyl-O,O,O-trihydrogendeferoxamine;
  • N-2-octenoyl-O,O,O-trihydrogendeferoxamine N-2-oleoyl-O,O,O-trihydrogendeferoxamine; or N-2-pentacosenoyl-O,O,O-trihydrogendeferoxamine.
  • Step 3 (a) N-Octanoyl-O,O,O-trihydrogen deferoxamine [1.5g, from Example 5(a)] is suspended in a solution of 50 ml of water and 50 ml of chloroform. The well-agitated suspension is adjusted to pH of 9 using 5N sodium hydroxide solution. To this mixture is added dropwise, a solution of 1.4g of butyryl chloride in 30 ml of chloroform. The pH of 9 of the mixture is maintained by the addition of a 5N sodium hydroxide solution as needed. After 20 ml of the butyryl chloride solution are added, 25 ml of water and 100 ml of chloroform are added to facilitate the mixing of the solution.
  • reaction mixture is stirred for 2 hours, with periodic adjustment to maintain a pH of 9.
  • the reaction mixture is then diluted with 50 ml of water and 200 ml of chloroform and centrifuged to separate the phases. Any white solid at the interface is removed and discarded.
  • the chloroform phase is washed twice with 100 ml of saturated sodium bicarbonate solution and twice with 100 ml of saturated sodium chloride solution, dried using anhydrous sodium sulfate, filtered and reduced to dryness using reduced pressure. About 2.0g of a crude waxy white solid is obtained, which is washed twice with ether and recrystallized from 60% ethanol.
  • N-propionyl-O,O,O-tributyryldeferoxamine N-butyryl-O,O,O-tributyryldeferoxamine
  • N-isovaleryl-O,O,O-tributyryldeferoxamine N-dodecanoyl-O,O,O-tributyryldeferoxamine; N-palmitoyl-O,O,O-tributyryldeferoxamine; or N-hexacosanoyl-O,O,O-tributyryldeferoxamine.
  • N-2-pentenoyl-O,O,O-tributyryldeferoxamine N-2-octenoyl-O,O,O-tributyryldeferoxamine; N-2-oleoyl-O,O,O-tributyryldeferoxamine; or N-2-pentacosenoyl-O,O,O-tributyryldeferoxamine.
  • N-(propynoyl)-O,O,O-tributyryldeferoxamine N-(2-hexynoyl)-O,O,O-tributyryldeferoxamine; N-(2-decynoyl)-O,O,O-tributyryldeferoxamine; or
  • N-(2-naphthyldecanoyl)-O,O,O-tributyryldeferoxamine N-(2-naphthyldecanoyl)-O,O,O-tributyryldeferoxamine.
  • N-octanoyl-O O, O- dioctanoylacryloyldeferoxamine; and C. N-octanoyl-O,O,O- butyryloctanoyIhydrogendeferoxamine;
  • N-octanoyl-O,O,O- hydrogenbutyryldeferoxamine N-octanoyl-O,O,O- hydrogenbutyryldeferoxamine.
  • the active ingredient is N-acetyl-O,O,O-trioctanoyldeferoxamine.
  • Other compounds of formula I may be substituted therein.
  • R 1 is lower acyl
  • R 2 , R 3 and R 4 are acyl (R 5 is lower alkyl) and R 6 , R 7 and R 8 are hydrogen
  • R 1 is acyl (R 5 is lower alkyl)
  • R 2 , R 3 and R 4 are acyl (R 5 is lower alkyl) and of R 6 , R 7 and R 8 , two are hydrogen and the remaining one is acyl (R 5 is lower alkyl).
  • Preferred is N-acetyl-O,O,O,N,H,H-tetraoctanoyldeferoxamine.
  • the above ingredients are thoroughly mixed/ granulated, and pressed into single scored tablets.

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Abstract

Composés de la formule générale (I), dans laquelle R1 représente acyle de la formule: -C(=O)-R5; R2, R3, R4, R6, R7 et R8 sont sélectionnés chacun dans le groupe constitué par de l'hydrogène et de l'acyle de la formule: -C(=O)-R5, dans laquelle R5 est choisi dans le groupe constitué d'alkyles, d'alcényles, de cycloalkyles, d'arylalkylènes, d'alkylènecycloalkyles, d'alkynyles et d'aryles substitués ou non-substitués; dans laquelle R2, R3 et R4 sont choisis de manière que R2 et/ou R3 et/ou R4 représentent un acyle. Lorsque R2, R3 et R4 comprennent un ou plusieurs acyles non identiques à l'acyle de R1, ces composés de la formule (I) sont nouveaux. L'invention concerne également des procédés de production des composés de la formule (I). Les composés de la formule (I) transforment en complexes et/ou chelates des ions tissulaires trivalents, notamment du fer et de l'aluminium (Fe?+++, Al+++¿), lorsqu'on les administre à l'homme, et par conséquent ils s'avèrent utiles en thérapie dans le traitement de maladies dans lesquelles les niveaux d'ions tissulaires dans le corps ont augmenté pour atteindre des niveaux toxiques.
PCT/US1992/003962 1991-05-13 1992-05-12 Chelateurs d'ions substitues efficaces par voie orale relatifs a la deferoxamine WO1992020227A1 (fr)

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Cited By (1)

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WO2002068379A2 (fr) * 2000-12-18 2002-09-06 Draximage, Inc. Nouveaux composes chelateurs bifonctionnels contenant des residus d'acide hydroxamique

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AU708115B2 (en) * 1991-10-04 1999-07-29 Sloan-Kettering Institute For Cancer Research Novel potent inducers of terminal differentiation and methods of use thereof
GB9211779D0 (en) * 1992-06-03 1992-07-15 Ciba Geigy Ag Amine salts

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US3247197A (en) * 1959-09-25 1966-04-19 Ciba Geigy Corp Tetrahydro-3:6-diodo-1:2-oxazines
US4671901A (en) * 1984-01-26 1987-06-09 Oral-D Orally effective ion chelators
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002068379A2 (fr) * 2000-12-18 2002-09-06 Draximage, Inc. Nouveaux composes chelateurs bifonctionnels contenant des residus d'acide hydroxamique
WO2002068379A3 (fr) * 2000-12-18 2003-02-13 Draximage Inc Nouveaux composes chelateurs bifonctionnels contenant des residus d'acide hydroxamique
US6623721B2 (en) 2000-12-18 2003-09-23 Draximage, Inc. Bifunctional chelating compounds containing hydroxamic acid residues
US7238339B2 (en) 2000-12-18 2007-07-03 Draxis Specialty Pharmaceuticals Inc. Bifunctional chelating compounds containing hydroxamic acid residues
EP2266953A1 (fr) * 2000-12-18 2010-12-29 Draximage, Inc. Nouveaux composés chélateurs bifunctionnels contenant des résidus d'acide hydroxamique
EP2266954A1 (fr) * 2000-12-18 2010-12-29 Draximage, Inc. Nouveaux composés chélateurs bifunctionnels contenant des résidus d'acide hydroxamique

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