WO1993000327A1

WO1993000327A1 - Linear hydroxamates, their preparation and pharmaceutical compositions comprising them for treatment of iron and aluminium overload

Info

Publication number: WO1993000327A1
Application number: PCT/EP1992/001473
Authority: WO
Inventors: Jacqueline Libman; Abraham Shanzer; Shneior Lifson
Original assignee: Yeda Research And Development Co., Ltd.
Priority date: 1991-06-30
Filing date: 1992-06-30
Publication date: 1993-01-07
Also published as: AU2194592A; IL98680A0

Abstract

Linear hydroxamate derivatives of the formula (I): R1R2N-X1-CONR3-X2-CONR4-X3-R5 wherein X1, X2 and X3 are the same or different moiety of the formula -CHR6-(CH2)m-(CHR7)8-CONOH-(CH2)n- and the -N-CHR6-(CH2)m-CO- moiety is preferably derived from a natural or non-natural α-amino acid, are disclosed as useful for treatment of acute iron poisoning, iron overload, aluminium overload and disorders caused by iron (III)-dependent pathogenic organisms, such as Plasmodium falciparum.

Description

LINEAR HYDROXAMATES, THEIR PREPARATION AND

PHARMACEUTICAL COMPOSITIONS COMPRISING THEM FOR TREATMENT OF IRON AND ALUMINUM OVERLOAD

Field of the Invention

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.

Background of the Invention

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. The accumulation of iron (III) in the blood and tissues causes serious impairment of heart and liver functions.

Chronic aluminium overload is found in patients with terminal renal failure on maintenance hemodialysis, causing aluminium-related bone disease, dialysis encephalopathy and/or aluminium - related anemia. High levels of aluminium are also associated with Alzheimer's disease.

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.

The treatment with desferrioxamine has, however, serious drawbacks. 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. et al., Clin.Nephrology (1988) 29: 261-266; Boelaert, J.R. et al. New England Journal of Medicine, 20.7.1989, pp. 190-191). 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.

Acylated derivatives of desferrioxamine B, said to be useful as oral forms of desferrioxamine for the treatment of high levels of iron and aluminium, are disclosed in US Patent No. 4,764,523.

There is a need to develop new drugs for efficient treatment of iron and/or aluminium overload that overcome the limitations and drawbacks of desferrioxamine.

Description of the Invention

It has now been found according to the present invention that certain linear compounds comprising three hydroxamate groups are useful as iron (III) and aluminium (III) chelating agents and may be used in the treatment of iron overload and aluminium overload.

The invention relates to new compounds of the general formula R₁R₂N-X₁-CONR₃-X₂-CONR₄-X₃-R₅ (I) wherein X₁, X₂ and X₃ are the same or different moiety of the formula -CHR₆-(CH₂)_m- (CHR₇)_p-CONOH-(CH₂)_n- wherein m and n are zero or an integer from 1 to 7, n being possibly zero only in the X₃ moiety; p is zero or 1; R₁ and R₂ are the same or different and are hydrogen, alkyl, aryl, aralkyl, heteroaryl, YCOR₈, YCOOR₈, YCOSR₈ or YCONR₈R₉; R₃ and R₄ are the same or different and are hydrogen, alkyl, aryl, aralkyl or heteroaryl; R₅ is hydrogen, alkyl, aryl, aralkyl or heteroaryl, when n in the X₃ moiety is zero, or R₅ is hydrogen, aryl , heteroaryl , COOR₈ , COSR₈ , CONR₈R₉ , OR₁₀, SR₁₀ or NR₉R₁₀ when n is different from zero; R₆ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, YCOR₈, YCOOR₈, YCONR₈R₉, NHC(NR₉R₁₀)=NR₉, lϊR₉R₁₀, OR₁₀ or SR₁₀ when p is zero or R₆ is hydrogen when p is 1; R₇ is NR₉R₁₀; R₈ and R₉ are hydrogen, alkyl, aryl, aralkyl or heteroaryl; R₁₀ is hydrogen, acyl, alkyl, aryl, aralkyl or heteroaryl; Y is a covalent bond or an alkylene radical; and each aryl or heteroaryl radical is optionally substituted by halogen, nitro, alkyl, aryl, heteroaryl, OR₁₀, SR₁₀ or NR₉R₁₀, and pharmaceutically acceptable salts of said compounds.

The moieties X₁, X₂ and X₃ may be the same or different. In one of the preferred embodiments, X₁, X₂ and X₃ are identical. The term "alkyl" means a straight or branched alkyl group having 1-12, preferably a lower alkyl group of 1-6 carbon atoms. The term "aryl" means a C₆-C₁₀ carbocyclic aryl group unsubstituted or substituted by one or more halogen, nitro, alkyl, aryl, heteroaryl, OR₁₀, SR₁₀ or NR₉R₁₀ groups.

The term "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. The term "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.

One example of preferred compounds according to the invention is represented by the formula la R₁[HN-CHR₆-(CH₂)_m-CONOH-(CH₂)_n-CO]₃OR₁₁ (la) wherein R₁ is hydrogen or -COOR₈ and Re is preferably alkyl, most preferably t-butyl, m is zero, 1 or 2, n is 2 , R₁₁ is lower alkyl and R₆ is a radical such that the -HN-CHR₆-(CH₂)_m-CO- moiety is derived from a natural α-amino acid, such as glycine, alanine, leucine, isoleucine, aspartic acid, glutamic acid, glutamine, histidine, tryptophan, threonine, lysine, serine, cysteine, methionine, phenylalanine, tyrosine, proline, hydroxyproline.

in another preferred embodiment the compounds have the formula Ib R₁[HN-CHR₆-(CH₂)_m-CHNR₉R₁₀-CONOH- (CH₂)_nCO]₃OR₁₁ (Ib)

wherein m is 2 or 3, Rs is hydrogen and the moiety - HN-CHR₆-(CH₂)_m-CHNR₉R₁₀-CO- is derived from lysine or ornithine or derivatives thereof.

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. Finally, removal of the protecting groups from (6) by hydrogenolysis provide the linear hydrσxamates (7). The latter are optionally purified by preparative thin layer chromatography and characterized by their spectra.

In a preferred embodiment, the process for the preparation of compounds of formula la comprises:

(a) preparation of the t-butoxycarbonyl (Boc) N-protected amino acid of formula

Boc-NHCHR₆COOH ( 2 )

(b) coupling of compound (2) with N-benzyloxy (OBz)-3-aminopropionic acid ethyl ester (1) of the formula HNOBzCH₂CH₂COOC₂H₅ to produce an ester of formula

Boc-NHCHRCONOBzCH₂CH₂COOC₂H₅ (4)

(c) hydrolysis of the ester (4) to the corresponding acid of the formula

BocNHCHR₆CONOBzCH₂CH₂COOH (5)

(d) oligomerization of three molecules of the acid (5) by Merrifield solid phase synthesis and removal from the polymer to the trimeric derivative Boc(NHCHR₆CONOBzCH₂CH₂CO)₃OCH₃ (6), and

(e) hydrogenolysis of compound (6) to remove the protecting groups so as to provide the linear trihydroxamate of formula

R₁(NHCHR₆CONOHCH₂CH₂CO)₃OCH₃ (7)

wherein R₁ is H or Boc and R₆ is the residue of an α-amino acid.

All the compounds of formula I wherein X₁, X₂ and X₃ are identical moieties are prepared by the above process, only substituting the protected amino acid (2) by other suitable starting products. When R₅ is other than an ester group - COOR₈, the corresponding compound is obtained from the end product (7) by conventional methods, such as hydrolysis of the ester to produce the corresponding acid or coupling of the acid with nucleophiles HNR₈R₉ or HSR₈ to produce the corresponding amides or thioesters.

When X₁, X₂ and X₃ are different moieties, the compounds are prepared by the same process, wherein in step (d) a sequential oligomerization of the corresponding acids comprising the moieties X₃, X₂ and X₁ 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.

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. First, the compounds described here may be tailored to either preferentially bind iron or aluminium ions, by lengthening or shortening the alkyl chains. Secondly, 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. Thirdly, 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.

In addition,it is possibile to modify the molecules lipophilicity and overall size thus enabling the preparation of tailor-made analogs that can penetrate infected organs, possibly even the blood-brain barrier, and remove the metals accumulated in these organs.

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. In addition, 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.

For the treatment of acute iron poisoning, a compound of formula I will be administered in a higher dose either per os or in a single intramuscular or intravenous dose.

For treatment of aluminium overload in patients with renal failure on maintenance dialysis, doses between 500 mg to 5 g per week may be employed. For patients with moderate aluminium overload, this dose can be reduced to 500 mg-1 g per week.

The invention will now be illustrated by the following non-limiting examples.

Example 1

The compound designated [7] herein is prepared according to the following schemes [A] and [B]. First, the monomer [5] is prepared according to Scheme [A] and then the trimer is prepared by attachment of three monomer molecules to the Merrifield solid phase peptide resin, according to Scheme [B] shown below. Scheme A: Synthesis of Monomer

Scheme B: Preparation of Trimer

a. Synthesis of β-N-OBz-β-amino-propionic acid ethyl ester

[1]

To a solution of 0.5 mol ethylacrylate in 300 ml absolute EtOH is added dropwise a solution of 12.0 g (0.075 mol) of BzONHaHCl and 10.5 ml (0.075 mol) Et₃N in 300 ml absolute EtOH while cooling in a dry ice bath, and stirring. The mixture is stirred for 2-3 days at room temperature, then it is concentrated and suspended in a 1:1 hexane/ethylacetate (EtOAc) mixture and chromatographed on a column using hexane/EtOAc 1:1 as eluent. Yield: 40-50%. b. Synthesis of N-t-Boc-L-glutamic acid-α-diethylamide-ɣ-benzylester [2]

To a solution of 5.0 g (15.4 mmol) of N-t-Boc-L-glutamic acid-ɣ-benzylester in 15 ml CH₃CN are added 209 mg hydroxybenzotriazole (1.55 mmol) and the mixture is cooled, while stirring under argon, in an ice bath. 1.9 ml EtaNH and 2.6 ml (16.8 mmol) diisopropylcarbodiimide are added again under argon, the mixture is cooled for at least 1 h and then stirred for 1-2 days. After checking with TLC, the solution is concentrated and chromatographed on a column with hexane/EtOAc 1:1 as eluent. Yield: 52%.

c. Synthesis of N-t-Boc-L-glutamic acid-α-diethylamide [3] 1.5 g (38.2 mmol) of the benzylester [2] are dissolved in absolute EtOH and 200 mg Pd/C 10% are added thereto. The mixture is hydrogenated at room temperature and atmospheric pressure for 2.5-3 h while stirring. After checking with TLC the solution is filtered and concentrated, and chromatographed on a column with hexane/EtOAc 1:1 as eluent. Yield: 80-90%.

d. Synthesis of monomer ethylester [4]

1.0 g (3.3 mmol) of compound [3] is dissolved in about

4 ml dried CH₃CN and 47 mg (0.35 mmol) hydroxybenzotriazole are added thereto. The mixture is cooled in an ice bath and 770 mg (3.5 mmol) of compound [1] together with 0.59 ml (3.8 mmol) diisopropylcarbodiimide are added. The mixture is stirred for 2 days at room temperature, checked on TLC and concentrated. After dissolving the mixture in hexane/EtOAc 1:1 and separation on a column, compound [4] is obtained. Yield: 70-85%.

e. Synthesis of monomer [5]

2.5 g (4.9 mmol) of the compound [4]are dissolved in 60 ml MeOH and 5.1 ml (0.2 mmol excess) of 1 M NaOH/HaO are added. The solution is stirred for 1 h. Then, an additional amount of 5.1 ml 1M NaOH are added and the solution is stirred for 1 h. This procedure is repeated until the reaction is completed. The mixture is cooled and acidified with 1 M KHSO₄/H₂O to a pH of about 2. The mixture is concentrated, extracted with EtOAc and the EtOAc fraction is washed with water until neutral. The organic fraction is dried and concentrated after filtering to give compound [5]. Yield: 90-95%. The compound was characterized by IR and NMR spectra:

IR (CHCl₃) = 1711, 1636, 1169 cm^-1.

NMR (CDCl₃)δ 4.82(s, CH₂Ph), 3.55 and 3.79 (m, NCH₂),

2.65 (m, CH₂CO), 3.29(m, CH₂NO), 2.58(m, CH₂CO), 2.04

(m, CH₂CH), and 4.55ppm (m, CαH). f. Synthesis of trimer [6] by trimerization of monomer [5]

This synthesis depicted in Scheme B includes: (I) attachment to Merrifield solid phase resin Ⓟ-C₆H₅-CH₂Cl 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.

I. To a solution of monomer [5] (1.63 g, 3.4 mmol) in absolute EtOH are added 0.43 ml of Et₃N, the resulting solution is stirred and 2.4 g resin ( chloromethylated Polystyrene, 2% crosslinked, Merck) are added thereto. The mixture is stirred very slowly for 72 h at 80°C and then filtered. The resin with attached monomer [5] is washed several times with CH₂Cl₂. Then 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).

II. To 0.96 g (2.0 mmol) of the monomer [5] dissolved in 10 ml of CH₃CN (dried) is added one equivalent (270 mg) of hydroxy- benzotriazole and the cold solution is treated with diisopropylcarbodiimide (0.30 ml, 1.1 eq. ) and allowed to react for 2h at ice temperature and for 1 h at room temperature. The mixture is added to the shaker containing the first monomer on the beads and shaken overnight. Then the material is washed, treated with methylene chloride and trifluoroacetic acid, washed again and procedure II repeated once more.

III. 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 CH₃CN, and the filtrates are concentrated to give the trimer product [6] in 59% yield,

g. Synthesis of free ligand [7] by hydrogenation of [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 (CHCl₃) 1636, 1732 cm^-1.

NMR (CDCl₃)δ 4.73 and 4.78 (s, CH₂Ph), 3.29 and 3.52 (m, NCH₂), 2.59 (m, CH₂CO), 3.19 (m,CH₂NO), 2.53 (m,CH₂CO), 2.05m (CH₂CH) and 4.55ppm (m,CαH).

Example 2

The following compounds were prepared by the same process described in Example 1:

R₁(NH-CHR₆-(CH₂)_m-CONOH-CH₂CH₂-CO)₃OCH₃

Code m Re R₁ Δ∈ (λ)*

P191 0 L-Me Boc -2.14 (420)

P178 0 L-iBu Boc -1.35 (420)

MP14 0 L-iBu H -1.00 (433) P239 0 D-iBu BOC +1.9 (428)

P238 0 L-CH₂CONEta Boc -2.65 (440)

AM8 2 L-CONEta Boc -4.5 (450)

P271 2 D-CONEta Boc +4.5 (450) * Cotton effects of the iron (III) complexes at the wavelength indicated in 0.3 mM solution of aqueous methanol (80-20).

All hydroxamates were fully characterized by their spectroscopic properties. They all were found to bind one equivalent of iron (III) and to form complexes of preferred Δ - configuration when L-amino acids were used, but preferred

- configuration when D-amino acids were used. However, the extent of chiral preference was found to depend on the nature of the amino acids used. While the chiral preference was rather modest with the ala (P191) and leu derivatives (P178, MP14, P239), it was significant with the asp derivative (P238)and the glu derivative.

Example 3

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). 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. After the indicated time of incubation with drug and either before or after washing three times with 100 vol of growth medium, the cells were supplemented with 6 μCi (1 Ci=37 GBq) of either [³H]hypoxanthine or [³H]isoleucine (Amersham) per well, and parasite growth was assessed after 24-48 hr by harvesting the labeled cells onto glass-fiber filters (Tamar, Jerusalem) and counting the radioactivity. 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. Oduola, Walter Reed Army Institute of Research, Washington), FCR-3 (Gambian, provided by J.B. Jensen, Michigan State University) and W2 (Indochina, provided by A.J.M. Oduola, Walter Reed Army Institute of Research, Washington). They were grown in culture flasks of human erythrocytes by a modified version of Trager and Jensen's method as described by Silfen et al. (1988) Biochem. Pharmcol. 37:4269-4276.

The IC₅₀ value for the compound MP14 shown in Example 2 as determined by this method was 20.

Claims

1. A compound of the general formula R₁R₂N-X₁-CONR₃-X₂-CONR₄-X₃-R₅ (I) wherein X₁, X₂ and X₃ are the same or different moiety of the formula -CHR₆-(CH₂)_m- (CHR₇)_p-CONOH-(CH₂)_n- wherein m and n are zero or an integer from 1 to 7, n being possibly zero only in the X₃ moiety; p is zero or 1; R₁ and R₂ are the same or different and are hydrogen, alkyl, aryl, aralkyl, heteroaryl, YCOR₈, YCOOR₈, YCOSR₈ or YCON₈N₉; R₃ and R₄ are the same or different and are hydrogen, alkyl, aryl, aralkyl or heteroaryl; R₅ is hydrogen, alkyl, aryl, aralkyl or heteroaryl, when n in the X₃ moiety is zero, or R₅ is hydrogen, aryl, heteroaryl, COOR₈, COSR₈, CONR₈R₉, OR₁₀, SR₁₀ or NR₉R₁₀ when n is different from zero; R₆ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, YCOR₈, YCOOR₈, YCONR₈R₉, NHC(NR₉R₁₀)=NR₉, NR₉R₁₀, OR₁₀ or SR₁₀ when p is zero or R₆ is hydrogen when p is 1; R? is NR₉R₁₀; Re and R₉ are hydrogen, alkyl, aryl, aralkyl or heteroaryl; R₁₀ is hydrogen, acyl, alkyl, aryl, aralkyl or heteroaryl; Y is a covalent bond or an alkylene radical; and each aryl or heteroaryl radical is optionally substituted by halogen, nitro, alkyl, aryl, heteroaryl, OR₁₀, SR₁₀ or NR₉R₁₀, and pharmaceutically acceptable salts of said compounds.

2. A compound as claimed in claim 1 wherein X₁, X₂ and

X₃ are identical moieties.

3. A compound as claimed in claim 2 of the formula

R₁[HN-CHR₆-(CH₂)_m-CONOH-(CH₂)₂-CO]₃OR₁₁ (la) wherein Rx is hydrogen or COOR₈, R₈ is lower alkyl, m is zero, 1 or 2, R₁₁ is lower alkyl and R₆ is a radical such that the -HN-CHR₆-(CH₂)_m-CO- moiety is derived from an α-amino acid.

4. A compound as claimed in claim 3, wherein the moiety -HN-CHR₆-(CH₂)_m-CO- is derived from a natural α-amino acid.

5. A compound as claimed in claim 3 , wherein the moiety -HN-CHR₆-(CH₂)_m-CO- is derived from a non-natural α- amino acid.

6. A compound as claimed in claim 3 wherein m is zero, Rx is hydrogen or t-butoxycarbonyl, R₆ is methyl, isobutyl or diethylaminocarbonylmethyl and R₁₁ is methyl.

7. A compound as claimed in claim 3 wherein m is 2, R₁ is hydrogen or t-butoxy-carbonyl, R₆ diethylaminocarbonyl and R₁₁ is methyl.

8. A compound as claimed in claim 2 of the formula

R₁[HN-CHR₆-(CH₂)_m-CHNR₉R₁₀-CONOH- (CH₂)_nCO]₃OR₁₁ (Ib) wherein m is 2 or 3, R₆ is hydrogen and the moiety -HN-CHR₆-(CH₂)_m-CHNR₉R₁₀-CO- is derived from lysine or ornithine or derivatives thereof.

9. A pharmaceutical composition comprising as active ingredient a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition as claimed in claim 9 for the treatment of acute iron poisoning or of conditions associated with high levels of iron (III) or of aluminium in the organism or disorders caused by iron (III)-dependent pathogenic organisms.

11. A pharmaceutical composition according to claim 10 for treatment of iron overload in patients.

12. A pharmaceutical composition according to claim 10 for treatment of malaria.

13. A pharmaceutical composition according to claim 10 fortreatment of aluminium overload in patients.