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WO1993000327A1 - Hydroxamates lineaires, leur preparation et compositions pharmaceutiques les comportant pour le traitement de la surcharge en fer et en aluminium - Google Patents

Hydroxamates lineaires, leur preparation et compositions pharmaceutiques les comportant pour le traitement de la surcharge en fer et en aluminium Download PDF

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Publication number
WO1993000327A1
WO1993000327A1 PCT/EP1992/001473 EP9201473W WO9300327A1 WO 1993000327 A1 WO1993000327 A1 WO 1993000327A1 EP 9201473 W EP9201473 W EP 9201473W WO 9300327 A1 WO9300327 A1 WO 9300327A1
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WO
WIPO (PCT)
Prior art keywords
hydrogen
aryl
compound
heteroaryl
iron
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1992/001473
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English (en)
Inventor
Jacqueline Libman
Abraham Shanzer
Shneior Lifson
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Yeda Research and Development Co Ltd
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Yeda Research and Development Co Ltd
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Filing date
Publication date
Application filed by Yeda Research and Development Co Ltd filed Critical Yeda Research and Development Co Ltd
Publication of WO1993000327A1 publication Critical patent/WO1993000327A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to new linear hydroxamate derivatives, to a process for their preparation and to pharmaceutical compositions comprising them for sequestering iron (III) or aluminium (III) ions and thus removing these metal ions from blood, organs or tissues where they accumulate, or to remove iron (III) from mammalian cells and from iron-dependent pathogenic organisms in mammals, including humans.
  • Chronic iron overload is found in patients receiving regular blood transfusions, as in the case of genetic blood disease beta-thalassemia, sideroblastic anemia, autoimmune hemolytic anemia and other chronic anemias, or in idiopathic hemochromatosis patients and is associated with porphyria cutanea tarda.
  • iron (III) iron
  • Treatmenat of high levels of iron (III) and of aluminium overload comprises sequestering of the ions from the blood or tissues where they accumulate and their removal from the body. It is mainly performed today with desferrioxamine, a natural chelating agent of microbial origin, comprising three hydroxamate groups, which takes up iron (III), either free or bound to ferritin or hemosiderin, forming the complex ferrioxamine. It is also capable of mobilizing and chelating tissue-bound aluminium in the form of the complex aluminoxamine. Both complexes are completely excreted in the urine and feces, thus reducing pathological iron or aluminium deposits in the organism and the deleterious effects caused by them.
  • Desferrioxamine is usually administered by intravenous infusion over a 6-12 h period, thus requiring hospitalization of the patient. It may cause several side effects, including fever, nausea, anorexia and disturbances of vision and hearing. In addition, it may stimulate growth of pathogenic microorganisms, since it is a natural iron (III) carrier, thus promoting the development of severe infections in patients. Thus,several fatal cases have been reported of mucormycosis in patients on maintenance dialysis who were receiving desferrioxamine for the treatment of either aluminium overload or iron overload (Boelaert, J.R.
  • Mucormycosis is an opportunistic infection caused by fungi of the Mucorales order and the explanation is that desferrioxamine acts as a siderophore to the Mucorales fungi.
  • the invention relates to new compounds of the general formula R 1 R 2 N-X 1 -CONR 3 -X 2 -CONR 4 -X 3 -R 5 (I) wherein X 1 , X 2 and X 3 are the same or different moiety of the formula -CHR 6 -(CH 2 ) m - (CHR 7 ) p -CONOH-(CH 2 ) n - wherein m and n are zero or an integer from 1 to 7, n being possibly zero only in the X 3 moiety; p is zero or 1; R 1 and R 2 are the same or different and are hydrogen, alkyl, aryl, aralkyl, heteroaryl, YCOR 8 , YCOOR 8 , YCOSR 8 or YCONR 8 R 9 ; R 3 and R 4 are the same or different and are hydrogen, alkyl, aryl, aralkyl or heteroaryl; R 5 is hydrogen, alkyl, aryl, aralkyl
  • the moieties X 1 , X 2 and X 3 may be the same or different. In one of the preferred embodiments, X 1 , X 2 and X 3 are identical.
  • alkyl means a straight or branched alkyl group having 1-12, preferably a lower alkyl group of 1-6 carbon atoms.
  • aryl means a C 6 -C 10 carbocyclic aryl group unsubstituted or substituted by one or more halogen, nitro, alkyl, aryl, heteroaryl, OR 10 , SR 10 or NR 9 R 10 groups.
  • heteroaryl means a radical derived from a 5-6 membered aromatic heterocyclic ring containing one or more O, S and or N atoms, such as imidazolyl, indolyl, pyridyl, pyrimidyl, furyl, optionally substituted as the aryl group.
  • acyl means a carboxylic aliphatic, aromatic or heteroaromatic acyl group.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include but are not limited to inorganic salts, such as sodium, potassium, calcium, magnesium and the like, and organic salts with amines, such as dimethylamine, diethylamine and the like or with organic bases, such as piperidine, morpholine and the like.
  • the invention also encompasses the intermediate derivatives of the compounds of formula I wherein the hydroxamate groups are protected by conventional protecting groups, such as benzyloxy.
  • R 1 [HN-CHR 6 -(CH 2 ) m -CONOH-(CH 2 ) n -CO] 3 OR 11 (la) wherein R 1 is hydrogen or -COOR 8 and Re is preferably alkyl, most preferably t-butyl, m is zero, 1 or 2, n is 2 , R 11 is lower alkyl and R 6 is a radical such that the -HN-CHR 6 -(CH 2 ) m -CO- moiety is derived from a natural ⁇ -amino acid, such as glycine, alanine, leucine, isoleucine, aspartic acid, glutamic acid, glutamine, histidine, tryptophan, threonine, lysine, serine, cysteine, methionine, phenylalanine, tyrosine, proline, hydroxyproline.
  • R 1 is hydrogen or -COOR 8 and Re is preferably alkyl, most preferably t
  • the compounds have the formula Ib R 1 [HN-CHR 6 -(CH 2 ) m -CHNR 9 R 10 -CONOH- (CH 2 ) n CO] 3 OR 11 (Ib)
  • the compounds of formula la and lb are prepared by a several step process described in Schemes A and B herein, which comprises: (a) preparation of a N-protected amino acid residue such as (2); (b) coupling of the amino acid residue with a protected N-hydroxy amino acid, for example N-benzyloxy-3-amino-propionic acid (1) ethyl ester to the monomeric ester (4); (c) hydrolysis of the monomeric ester (4) to the monomeric amino acid (5), and (d) oligomerization of three monomeric acids (5) to the trimeric derivatives (6) by Merrifield solid phase synthesis.
  • These products are purified by column chromatography on silica gel and fully characterized by their spectroscopic properties.
  • removal of the protecting groups from (6) by hydrogenolysis provide the linear hydr ⁇ xamates (7). The latter are optionally purified by preparative thin layer chromatography and characterized by their spectra.
  • the process for the preparation of compounds of formula la comprises:
  • R 1 is H or Boc and R 6 is the residue of an ⁇ -amino acid.
  • step (d) a sequential oligomerization of the corresponding acids comprising the moieties X 3 , X 2 and X 1 is carried out in this sequence.
  • the compounds of the present invention are for use as active ingredients of pharmaceutical compositions for the treatment of chronic iron overload, acute iron poisoning, aluminium overload, and pathological disorders caused by iron (III)-dependent pathogenic organisms, such as Plasmodium falciparum, that causes malaria, Rhizopus fungi, or Pseudomonas, Candida or Streptomyces strains.
  • iron (III)-dependent pathogenic organisms such as Plasmodium falciparum, that causes malaria, Rhizopus fungi, or Pseudomonas, Candida or Streptomyces strains.
  • All conditions of chronic iron overload can be treated with the compounds of the invention, including beta-thalassemia, sideroblastic anemia, autoimmune hemolytic anemia and other chronic anemias of patients on regular blood transfusions, and iron overload associated with porphyria cutanea tarda.
  • the treatment for chronic aluminium overload includes treatment of patients on dialysis because of renal failure and of Alzheimer patients.
  • the compounds of formula I do not remove iron (III) from transferrin or from intraerythrocytic hemoglobin and thus the danger of causing concurrent anemia is negligible.
  • the synthetic compounds of the invention differ from desferrioxamine in that they may be composed of amino acid and N-hydroxy amino acid residues, rather than of diacid and N-hydroxy amino amine residues as desferrioxamine.
  • the compounds of the invention may be so designed such as to overcome the limitations of desferrioxamine.
  • the advantages of the present compounds relative to others used and proposed for the treatment of iron or aluminium overload are threefold.
  • the compounds described here may be tailored to either preferentially bind iron or aluminium ions, by lengthening or shortening the alkyl chains.
  • the compounds disclosed herein may be built from non-natural amino acids, and particularly enantiomers of the natural amino acids, thereby enhancing their resistance to metabolic degradation by hydrolytic enzymes. This is advantageous in providing compounds for per os administration.
  • the compounds described here may be tuned such as not to be recognized by microorganisms and thereby inhibit rather than stimulate their growth. Thus several compounds of the invention failed to promote growth of pathogenic Rhizopus fungi under conditions where desferrioxamine stimulates growth.
  • the invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a salt thereof as active ingredient, optionally together with a pharmaceutically acceptable carrier and/or without further additives.
  • the invention further relates to the use of the compounds of formula (I) or of a salt thereof for the treatment of acute iron poisoning or of conditions associated with high levels of iron (III) or of aluminium ions in the organism.
  • the compounds of formula I may be administered to the patients by intravenous or intramuscular injection.
  • the compounds may be presented in lyophilised form and the solution for injection is reconstituted therefrom.
  • the compounds may be presented in a form suitable for administration per os.
  • the dosage and mode of administration will depend on the patient's condition and the severity of the disease, as with desferrioxamine.
  • a dose of about 500 mg or less may be used at the beginning of the treatment and then it is increased until a plateau of iron excretion is achieved. Then, daily doses of 15-40 mg/kg body weight may be adequate.
  • a compound of formula I will be administered in a higher dose either per os or in a single intramuscular or intravenous dose.
  • doses between 500 mg to 5 g per week may be employed.
  • this dose can be reduced to 500 mg-1 g per week.
  • This synthesis depicted in Scheme B includes: (I) attachment to Merrifield solid phase resin P-C 6 H 5 -CH 2 Cl of the first unit of monomer [5]; (II) coupling of second and third units of monomer [5] and (III) release of trimer [7] from the resin by transesterification.
  • the beads are transferred to a shaker, 30 ml of a 1:1 solution of trifluoroacetic acid in methylene chloride are added, the mixture is shaken for 2 min, another 30 ml portion of a 1:1 solution of trifluoroacetic acid in methylene chloride are added and shaking is continued for 15 minutes.
  • the beads are then washed with methylene chloride (2x), chloroform-ethanol (3x), chloroform (3x), chloroform-triethylamine (lx), chloroform (3x) and dry chloroform (1x).
  • the beads are suspended in 100 ml anhydrous EtOH, treated with 15 ml triethylamine, stirred for 24 h at room temperature and filtered.
  • the beads are washed with at least 3 ⁇ 40 ml absolute MeOH and two portions of 40 ml CH 3 CN, and the filtrates are concentrated to give the trimer product [6] in 59% yield,
  • trimer (6) 200 mg (0.16 mmol) of trimer (6) are dissolved in 10 ml absolute EtOH, 80 mg of Pd/C 10% are added and the mixture hydrogenated at room temperature and atmospheric pressure for 2.5-3 h. Then the mixture is filtered, rinsed with absolute EtOH and concentrated to give the end product [7] in 98% yield.
  • the compound was characterized by IR and NMR spectra: IR (CHCl 3 ) 1636, 1732 cm -1 .
  • the anti-malarial activity of agents was assayed by adding them from concentrated stock solutions [in dimethyl sulfoxide (DMSO)] to microcultures (24 wells, Costar) containing infected erythrocytes (2.5% hematocrit and 2% parasitemia).
  • DMSO dimethyl sulfoxide
  • the cultures were usually synchronized (4- to 7-hr windows) by incubation in 300 mM alanine/10 mM Tris hydrochloride in conjunction with gelatin flotation and used either at the trophozoite (1-2% parasitemia) or at the ring stage (4-6% parasitemia) of the erythrocytic cycle.
  • the parasites used in this bioassay were P. falciparum strains as follows : ItG2G1 (Brazil, provided by L.H. Miller, National Institutes of Health, Bethesda, MO), D6 (West African, provided by A.J.M.
  • the IC 50 value for the compound MP14 shown in Example 2 as determined by this method was 20.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivés d'hydroxamate linéaire répondant à la formule R1R2N-X1-CONR3-X2-CONR4-X3-R5 dans laquelle X1, X2 et X3 représentent une même ou une autre fraction de la formule -CHR6-(CH2)m-(CHR7)8-CONOH-(CH2)n-, et la fraction -N-CHR6-(CH2)m-CO- est de préférence dérivée d'un acide α-amino naturel ou non. Lesdits dérivés sont utilisés pour le traitement de l'intoxication aiguë par le fer, de la surcharge en fer, de la surcharge en aluminium, et des troubles dus aux organismes pathogènes dépendant du fer (III), par exemple le Plasmodium falciparum.
PCT/EP1992/001473 1991-06-30 1992-06-30 Hydroxamates lineaires, leur preparation et compositions pharmaceutiques les comportant pour le traitement de la surcharge en fer et en aluminium Ceased WO1993000327A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL98680 1991-06-30
IL98680A IL98680A0 (en) 1991-06-30 1991-06-30 Hydroxamate derivatives and pharmaceutical compositions containing them

Publications (1)

Publication Number Publication Date
WO1993000327A1 true WO1993000327A1 (fr) 1993-01-07

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PCT/EP1992/001473 Ceased WO1993000327A1 (fr) 1991-06-30 1992-06-30 Hydroxamates lineaires, leur preparation et compositions pharmaceutiques les comportant pour le traitement de la surcharge en fer et en aluminium

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AU (1) AU2194592A (fr)
IL (1) IL98680A0 (fr)
WO (1) WO1993000327A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172064B1 (en) 1998-08-26 2001-01-09 Glaxo Wellcome Inc. Formamides as therapeutic agents
US6191150B1 (en) 1998-08-26 2001-02-20 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
US6329400B1 (en) 1998-08-26 2001-12-11 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
US6593339B1 (en) 1999-06-01 2003-07-15 Astrazeneca Ab Use of compounds as antibacterial agents
US7932326B2 (en) 2008-04-16 2011-04-26 The University Of Kentucky Research Foundation Chelating compounds and immobilized tethered chelators
WO2012104204A1 (fr) 2011-01-31 2012-08-09 Vifor (International) Ag Composés à base d'un complexe de fer-hydrate de carbone pour la thérapie intraveineuse du paludisme
EP2601947A1 (fr) 2011-12-05 2013-06-12 Abo Bakr Mohammed Ali Al-Mehdar Combinaison à dose fixe pour le traitement de maladies associées à Hélicobacter pylori
US9139456B2 (en) 2008-04-16 2015-09-22 The Curators Of The University Of Missouri Chelating compounds and immobilized tethered chelators
US9259670B2 (en) 2008-04-16 2016-02-16 The University Of Kentucky Research Foundation Flow-through filter to remove aluminum from medical solutions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985003290A1 (fr) * 1984-01-26 1985-08-01 Oral-D Chelateurs d'ions a efficacite orale apparentes a la deferoxamine
WO1986003747A1 (fr) * 1984-12-19 1986-07-03 Ciba-Geigy Ag Nouveaux esters d'acide carbonique
WO1986003745A1 (fr) * 1984-12-19 1986-07-03 Ciba-Geigy Ag Nouveaux derives d'acides o-acylhydroxamiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985003290A1 (fr) * 1984-01-26 1985-08-01 Oral-D Chelateurs d'ions a efficacite orale apparentes a la deferoxamine
WO1986003747A1 (fr) * 1984-12-19 1986-07-03 Ciba-Geigy Ag Nouveaux esters d'acide carbonique
WO1986003745A1 (fr) * 1984-12-19 1986-07-03 Ciba-Geigy Ag Nouveaux derives d'acides o-acylhydroxamiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOLOGY OF METALS vol. 4, no. 3, 1991, BERLIN, DE pages 186 - 191 I BERNER ET. AL. 'Chiral linear hydroxamates as biomimetric analogues of Ferrioxamine and Coprogen and their use in probing siderophore-receptor specificity in bacteria and fungi' *
PURE AND APPLIED CHEMISTRY vol. 62, no. 6, 1990, LONDOD, GB pages 1111 - 1114 A SHANZER ET. AL. 'Polytopic chiral binders' *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172064B1 (en) 1998-08-26 2001-01-09 Glaxo Wellcome Inc. Formamides as therapeutic agents
US6191150B1 (en) 1998-08-26 2001-02-20 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
US6329400B1 (en) 1998-08-26 2001-12-11 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
US6593339B1 (en) 1999-06-01 2003-07-15 Astrazeneca Ab Use of compounds as antibacterial agents
US7932326B2 (en) 2008-04-16 2011-04-26 The University Of Kentucky Research Foundation Chelating compounds and immobilized tethered chelators
US9139456B2 (en) 2008-04-16 2015-09-22 The Curators Of The University Of Missouri Chelating compounds and immobilized tethered chelators
US9259670B2 (en) 2008-04-16 2016-02-16 The University Of Kentucky Research Foundation Flow-through filter to remove aluminum from medical solutions
WO2012104204A1 (fr) 2011-01-31 2012-08-09 Vifor (International) Ag Composés à base d'un complexe de fer-hydrate de carbone pour la thérapie intraveineuse du paludisme
EP2601947A1 (fr) 2011-12-05 2013-06-12 Abo Bakr Mohammed Ali Al-Mehdar Combinaison à dose fixe pour le traitement de maladies associées à Hélicobacter pylori
EP2601938A1 (fr) 2011-12-05 2013-06-12 Abo Bakr Mohammed Ali Al-Mehdar Compositions pharmqaceutiques pour le traitement de maladies associées à Hélicobacter pylori

Also Published As

Publication number Publication date
IL98680A0 (en) 1992-07-15
AU2194592A (en) 1993-01-25

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