EP0734374A1 - N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents - Google Patents

N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents

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Publication number
EP0734374A1
EP0734374A1 EP95900893A EP95900893A EP0734374A1 EP 0734374 A1 EP0734374 A1 EP 0734374A1 EP 95900893 A EP95900893 A EP 95900893A EP 95900893 A EP95900893 A EP 95900893A EP 0734374 A1 EP0734374 A1 EP 0734374A1
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EP
European Patent Office
Prior art keywords
bis
hydroxybenzyl
ethylenediamine
formula
diacetate
Prior art date
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.)
Withdrawn
Application number
EP95900893A
Other languages
German (de)
French (fr)
Inventor
Fabrizio Gasparini
Thomas Leutert
David L. Farley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Novartis AG
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Filing date
Publication date
Application filed by Ciba Geigy AG, Novartis AG filed Critical Ciba Geigy AG
Priority to EP95900893A priority Critical patent/EP0734374A1/en
Publication of EP0734374A1 publication Critical patent/EP0734374A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/40—Vinylene carbonate; Substituted vinylene carbonates

Definitions

  • the invention relates to novel and systemically effective chelating agents embracing the derivatives of [N,N'-bis(2-hydroxybenzyl)ethylene diamine N,N'-diacetic acid] of the formula (I) as shown below, processes for their manufacture, pharmaceutical compositions containing such compounds, and the use of these derivatives.
  • the invention is also directed to alkali and alkaline earth metal salts of [N,N'-bis(2-hydroxybenzyl)ethylene diamine N,N'-diacetic acid] derivatives which represent valuable starting material and exhibit valuable therapeutical properties.
  • the invention relates especially to [N,N'-bis(2-hydroxybenzyl)ethylene diamine N.N'-diacetic acid] derivatives of the formula (I)
  • R represents -(CO)-! ⁇ , -O-(CO)-R 2 , -O-(CO)-O-R 3 or a. >°
  • Rj is -NR 4 R 5 or — N O ; whereby R 4 and R 5 are independent of each other C 1 -C 3 alkyl or C 3 -C 7 cycloalkyi or form together the group -(CH ⁇ n -, n is an integer from 3 to 6;
  • R 2 is C r C 6 alkyl, unsubstituted phenyl or phenyl substituted by one to four substituents selected from the group consisting of halogen and hydroxy;
  • R 3 is C r C 6 alkyl or C 3 -C 7 cycloalkyi
  • R is C j -C ⁇ alkyl; and salts thereof, processes for the manufacture of these compounds, pharmaceutical compositions containing such compounds and the use of these compounds.
  • the compounds of the formula (I) represent derivatives of HBED which is [N,N'-bis- (2-hydroxylbenzyl)ethylene diamine N,N diacetic acid] a product of the formula (II)
  • HBED is described as a chelating agent for the treatment of iron overload in U.S. patent US-4'528'196.
  • the major advantage of the compounds of the formula (I) over HBED is that the free molecules do not bind to heavy metal ions at all. Thus, they pass the intestinal tract without any loss. As free molecules they do not take up heavy metal ions but develop this metal binding properties surprisingly after their resorption when they circulate in the blood stream so that they can successfully be administered systemically to warm-blooded animals, most preferred orally or parenterally. Administered orally they even exhibit a significantly higher activity than HBED. Thus the present invention provide agents that are even effective chelators when administered systemically. Although the free molecules of the formula (I) do not bind to heavy metal ions they develop strong chelating properties in the animaTs blood.
  • a therapeutically preferred subgroup within the formula (I) consists of those representatives wherein R is defined as under Formula (I) and
  • R j is -NR 4 R5 whereby R and R 5 are independent of each other C -C 3 alkyl;
  • R 2 is C r C 3 alkyl
  • R 3 is Ci-C j alkyl or C 3 -C cycloalkyi; halogen is fluorine, chlorine or bromine; cycloalkyi is cyclohexyl;
  • R 4 is methyl; and salts thereof.
  • R represents -O-(CO)-R 2 and R 2 C r C 6 alkyl and preferably C r C 3 alkyl.
  • R represents -O-(CO)-R 2 and R 2 C r C 6 alkyl and preferably C r C 3 alkyl.
  • Cj-Cg alkyl stands for an unbranched or branched alkyl group characterized by the given number of carbon atoms.
  • Typical representatives are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, n-hexyl, 1-methyl-pentyl, 1,1 -dimethyl-butyl, 3,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2-methyl-pentyl, 3-methyl-pentyl, and 4-methyl-pentyl.
  • Halogen is, for example, fluorine, bromine or chlorine, preferably fluorine or chlorine.
  • C 3 -C 7 cycloalkyi represents a carbocyclic saturated ring with three to seven carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopentyl or cyclohexyl.
  • the compounds of the formula (I) are capable of forming salts.
  • the salts of the compounds according to the invention are, especially, pharmaceutically acceptable, non-toxic salts.
  • Such salts are especially metal salts and ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts as well as related 2+ salts such as zinc salts, and ammonium salts with ammonia or suitable organic amines, there coming into consideration for the salt formation especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, and also heterocyclic bases.
  • Such amines are, for example, lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkylammes, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzyl-ethylenediamine, also bases of the pyridine type, for example pyridine, collidine or quinoline.
  • lower alkylamines for example triethylamine
  • hydroxy-lower alkylamines for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxye
  • the compounds of the formula (I) can also form intermolecular (as opposed to intramolecular, i.e. zwitterionic) acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example methanesulfonic acid, or with amino acids, such as arginine and lysine.
  • inorganic acids such as hydrochloric acid, sulphuric acid or phosphoric acid
  • suitable organic carboxylic or sulphonic acids for example methanesulfonic acid
  • amino acids such as arginine and lysine.
  • the compounds of the formula I are transformed into a form that allows them to form stable complexes with metal ions, especially heavy metal ions.
  • metal ions especially heavy metal ions.
  • heavy metal ions there may be mentioned especially those in the 3+ oxidation state, such as Al 3+ or, most especially, Fe 3+ .
  • the substances of the formula (I) exhibit valuable pharmacologically properties when administered systemically, especially after oral or percutaneous application.
  • the compounds of the formula (I) prevent, for example, the deposition of iron-containing pigments in the tissues and, in cases where iron has been deposited in the organism, bring about elimination of the iron, for example in haemochromatosis and haemosiderosis and also in cirrhosis of the liver. They can also be used for the elimination from the organism of other heavy metals, for example aluminium and also chromium and copper.
  • the compounds of the formula I can also be used in the case of dialysis encephalopathy, osteomalacia and Alzheimer's disease.
  • the compounds of the formula (I) according to the invention and salts thereof can be manufactured by chemical synthesis according to processes known per se. They are manufactured, for example, by adding under cooling sodium hydride or potassium hydrogene carbonate to the compound of the formula (II)
  • R in the formulae (III) and (IN) is defined as under formula (I) and Y represents halogen, preferably chlorine, bromine or iodine, most preferably bromine or iodine.
  • the compound of the formula (II) wherin X is hydrogen is HBED which is as mentiond above described in the U.S. patent US-4'528' 196.
  • the compound of the formula (II) wherin X is -CH 2 J can be prepared by reacting HBED with CH 2 C1J under suitable conditions. This type of reaction is described in the literature and well known to the skilled chemist.
  • the reaction is performed in a inert dipolar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylformamide (DMF), dimethylacetamide (DMA), tetrametylurea, dimethylsulfoxide (DMSO), tetrahydrothiophen- 1,1 -dioxide (sulfolane) or diether of ethylenglycole at relatively low temperatures preferably at temperatures arround 0°C, for example at about -10° to 30°C, and preferably under an inert gas atmosphere.
  • a inert dipolar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylformamide (DMF), dimethylacetamide (DMA), tetrametylurea, dimethylsulfoxide (DMSO), tetrahydrothiophen- 1,1 -dioxide (sulfolane) or diether of ethyleng
  • Salts of compounds of the formula (I) can be manufactured in a manner known per se.
  • acid addition salts of compounds of the formula (I) are obtained in customary manner, for example by treating with an acid or a suitable anion-exchange reagent.
  • Internal salts of compounds of the formula (I) can be formed, for example, by neutralising the compounds or salts, such as acid addtion salts, to the isoelectric point, for example with weak bases, or by treating with liquid ion-exchangers.
  • Salts can be converted in customary manner into the free compounds: metal and ammonium salts can be converted into the free compounds, for example, by treating with suitable acids, and acid addition salts, for example, by treating with a suitable basic agent.
  • the starting materials especially those of formula (II) and (HI) are available commercially and/or known or can be manufactured by known processes.
  • pharmacologically acceptable compounds of the present invention can be used, for example, for the manufacture of pharmaceutical compositions which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.
  • compositions according to the invention are those which are suitable for enteral, such as oral, administration and for parenteral, such as subcutaneous, administration to warm-blooded animals, especially humans, and which contain the pharmacological active substance on its own or together with a pharmaceutically acceptable carrier.
  • enteral such as oral
  • parenteral such as subcutaneous
  • contain the pharmacological active substance on its own or together with a pharmaceutically acceptable carrier The dosage of the active substance depends on the species of warm-blooded animal and on the age and individual condition, the illness to be treated and also on the mode of administration.
  • the novel pharmaceutical preparations contain from approximately 10 % to approximately 95 %, preferably from approximately 20 % to approximately 90 %, of the active substance.
  • Pharmaceutical compositions according to the invention can, for example, be in unit dose form, such as dragees, tablets, capsules, suppositories or ampoules, and contain from approximately 0.1 g to approximately 3.0 g, preferably from approximately 0.3 g to approximately 1.0 g, of the active ingredient.
  • the pharmaceutical compositions of the present invention are manufactured in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
  • compositions for oral use can be obtained by combining the active substance with one or more solid carriers, if desired granulating a resulting mixture and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, to form tablets or dragee cores. In so doing, they can also be incorporated into plastics carriers which release the active substances or allow them to diffuse in controlled amounts.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders such as starches, for example corn, wheat, rice or potato starch, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinyl- pyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked poly vinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate
  • binders
  • Adjuncts are especially flow-regulating and lubricating agents, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings that are, if desired, resistant to gastric juice, there being used, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the manufacture of coatings that are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl ⁇ methylcellulose phthalate. Colouring substances or pigments can be added to the tablets or dragee coatings, for example for the purpose of identification or for indicating different doses of active substance.
  • compositions are dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as corn starch, binders and/or glidants, such as talc or magnesium stearate, and optionally stabilisers.
  • fillers such as corn starch, binders and/or glidants, such as talc or magnesium stearate, and optionally stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids or wax-like substances, such as fatty oils, paraffin oil or polyethylene glycols, it being possible also for stabilisers to be added.
  • oral administration are, for example, syrups prepared in customary manner that contain the active ingredient in, for example, suspended form and in a concentration of approximately from 5 % to 20 %, preferably approximately 10 %, or in a similar concentration that provides a suitable single dose when administered, for example, in measures of 5 or 10 ml.
  • syrups prepared in customary manner that contain the active ingredient in, for example, suspended form and in a concentration of approximately from 5 % to 20 %, preferably approximately 10 %, or in a similar concentration that provides a suitable single dose when administered, for example, in measures of 5 or 10 ml.
  • powdered or liquid concentrates for preparing shakes, for example in milk. Such concentrates can also be packed in single-dose quantities.
  • Particularly suitable dosage forms for parenteral administration are sterile aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, or sterile aqueous injection suspensions which contain substances increasing the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally stabilisers.
  • the active ingredient, with or without adjuvants can also be in lyophilised form and brought into solution prior to parenteral administration by addition of suitable solvents.
  • compositions for diagnostic purposes that contain a suitable metal complex of a compound of the formula (I), preferably in the form of an aqueous solution or in the form of a dry preparation.
  • the invention relates also to a method of treatment of pathological conditions in a mammal, especially human, which, as has been described hereinbefore, are associated v/ith an excess of a trivalent metal cation such as aluminium or, especially, iron(III), in the body, which method comprises administering, preferably orally, a prophylactically or therapeutically effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof.
  • a daily dose of from approximately 25 mg kg to approximately 200 mg kg, preferably from approximately 20 mg kg to approximately 150 mg/kg, of a compound of the present invention being administered to a warm-blooded animal.
  • the dosage can be administered orally in several, for example three, individual doses.
  • systemic e.g. subcutaneous
  • administration the more water soluble salt forms of the compounds of the formula (I), e.g. the sodium salt, are preferred.
  • Most preferred mode of administration is orally.
  • An alternatively mode of administration is subcutaneously.
  • the invention concerns especially the compounds of the formula (I), the methods for their preparation as outlined above, pharmaceutical compositions containing as active ingredient a compound of the formula (I).
  • the invention further concerns a method of treatment of pathological conditions in a mammal that are associated with an excess of trivalent metal ions in the body, comprising administering systemically, most preferred orally, to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Example 1 Bis acetoxymethyl-rN,N'-bis(2-hvdroxybenzyl)]ethylenediamine- N,N'-diacetate
  • HBED (lg, 2.57 mMol) was dissolved in 15 ml of dimethylformamide, the resulting solution cooled to 0-4 C and kept under innert atmosphere. Sodium hydride (280 mg, 6.43 mMol, 55-60% suspension in oil) was added and the resulting suspension stirred 30 min. at 0-4 C.
  • the residue was purified on a chromatographic column containing 70g of silicagel and ethylacetate/hexane 1:1 v/v as eluting solvent. The fractions containing the pure compound were combined and concentrared in vacuo. The residue is recristallized from ethylacetate hexane to yield the desired compound as a white crystals, mp 100-101°C.
  • HBED (5.7g, 14.6 mMol) was dissolved in 100 ml DMF (N, N-dimethylformamide) and KHCO 3 (5.9g, 58.7 mMol) was added. The mixture was stirred for 50 min.
  • bromomethylpropionate (6.9ml, 61.67 mMol) was added and the mixture stirred for 18 h.
  • the reaction mixture was then poured in ethylacetate (100ml) and washed with water (2X200ml), brine (lX200ml) and dried over Na 2 SO 4 . After filtration the solution was concentrated in vacuo. The residue was recrystallized from ethylacetate/hexane yielding the desired compound with a melting point of 91-92 C.
  • HBED (lOOmg, 0.255 mMol) was dissolved in 5 ml of DMF, cooled at 0-4 C and kept under Ar. Sodium hydride (23mg, 0.52 mMol, 55-60% in oil) was added and the resulting mixture stirred for 18 h at 6-8 C.
  • reaction was diluted with ethylacetate (30ml) and washed with water (2X10ml), brine (IXlOml) and dried over Na 2 SO 4 . After filtration of the drying agent the solvent was evaporated in vacuo. The residue was purified on a chromatographic column and the fractions containing the pure compound were combined and evaporated in vacuo to give the desired product as a colorless oil.
  • HBED (200mg, 0.51 mMol) was dissolved in anhydrous DMF and cooled to 0-4 C under Ar. Sodium hydride (52mg, 1.2 mMol, 55-60 % in oil) was added and the resulting suspension was stirred for 30 min. Then 2-chloro-N,N-diethylacetamide (168ml, 1.23 mMol) and sodium iodide (18mg, 0.12 mMol) were added and the resulting suspension stirred for 24 h at room temperature.
  • reaction mixture was diluted with ethylacetate (50ml) and washed with sat. N ⁇ Cl (2X20ml), water (lX25ml), brine (lX20ml), dried with Na 2 SO 4 and filtrated.
  • the solvent was evaporated in vacuo and the reidue purified on a chromatographic column. The fractions containing the pure compound were combined and concentrated in vacuo to give the desired compound as a colorless oil.
  • HBED (200 mg, 0.51 mmol) was dissolved in anhydrous DMF (5ml) and cooled to 0-4 °C. NaH (50 mg, 1.12 mmol) was added and the suspension stirred for one hour. Then 2-bromo N-morpholinoacetamide was added and the reaction stirred for seven hours at room temperature.
  • reaction mixture was diluted with ethylacetate (30ml) washed with water (2 X 10 ml), brine (1 X 10 ml) dried over Na 2 SO . After filtration of the drying agent, the solvent was evaporated and the residue chromatographed on column. The fractions containing the pure compound were combined and the solvent evaporated in vacuo to yield the desired product as an oil.
  • Example 6 Bis(5-methyl- 1 ,3-dioxolan-2-one-4-yl)methoxy-rN,N'-bis(2-hvd-roxybenzyl)1- ethylenediamine-N,N ' -diacetate.
  • HBED-4H 2 O (1.31 g, 2.84 mmol) was dissolved in 40ml DMF (dimethylformamide).
  • KHCO 3 potassium bicarbonate
  • the solution was then cooled to 15 °C and 4-bromomethyl- -5-methyl-l,3-dioxolan-2-on 1.92 g, 9.94 mmol) in 10 ml DMF was added and the resulting solution stirred for two and a half hours at room temperature.
  • the pulverulent substances are forced through a sieve having a mesh width of 0.6 mm and mixed thoroughly to yield a total of 230 g. 1000 gelatine capsules are each filled with 330 mg of this mixture using a capsule filling machine.

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Abstract

[N,N'-bis(2-hydroxybenzyl)ethylenediamine N,N'-diacetic acid] derivatives of formula (I) in which R represents -(CO)-R1, -O-(CO)-R2, -O-(CO)-O-R3 or (a) wherein R1 is -NR4R5 or (III); whereby R4 and R5 are independent of each other C1-C3 alkyl or C3-C7 cycloalkyl or form together the group -(CH2)n-, n is an integer from 3 to 6; R2 is C1-C6 alkyl, unsubstituted phenyl or phenyl substituted by one to four substituents selected from the group consisting of halogen and hydroxy; R3 is C1-C6 alkyl or C3-C7 cycloalkyl; R4 is C1-C3 alkyl; and salts thereof form chelate-type metal complexes with trivalent metal ions, especially iron (III), and can be used, for example, for the treatment of pathological conditions in warm-blooded animals that are associated with an excess of trivalent metal ions in the body.

Description

N,N ' -BIS (2-HYDROXYBENZYL) ETHYLENEDIA INE-N ,N ' -DIACETIC ACID DERIVATIVES AS CHELATING AGENTS
The invention relates to novel and systemically effective chelating agents embracing the derivatives of [N,N'-bis(2-hydroxybenzyl)ethylene diamine N,N'-diacetic acid] of the formula (I) as shown below, processes for their manufacture, pharmaceutical compositions containing such compounds, and the use of these derivatives. The invention is also directed to alkali and alkaline earth metal salts of [N,N'-bis(2-hydroxybenzyl)ethylene diamine N,N'-diacetic acid] derivatives which represent valuable starting material and exhibit valuable therapeutical properties.
The invention relates especially to [N,N'-bis(2-hydroxybenzyl)ethylene diamine N.N'-diacetic acid] derivatives of the formula (I)
R-CH2-0-( )-0-CH2-R
in which R represents -(CO)-!^, -O-(CO)-R2, -O-(CO)-O-R3 or a. >° wherein
Rj is -NR4R5 or — N O ; whereby R4 and R5 are independent of each other C1-C3 alkyl or C3-C7 cycloalkyi or form together the group -(CH^n-, n is an integer from 3 to 6;
R2 is CrC6 alkyl, unsubstituted phenyl or phenyl substituted by one to four substituents selected from the group consisting of halogen and hydroxy;
R3 is CrC6 alkyl or C3-C7 cycloalkyi;
R is Cj-C^ alkyl; and salts thereof, processes for the manufacture of these compounds, pharmaceutical compositions containing such compounds and the use of these compounds. The compounds of the formula (I) represent derivatives of HBED which is [N,N'-bis- (2-hydroxylbenzyl)ethylene diamine N,N diacetic acid] a product of the formula (II)
HO-(
HBED is described as a chelating agent for the treatment of iron overload in U.S. patent US-4'528'196. As tests in monkeys and human beings show, the major advantage of the compounds of the formula (I) over HBED is that the free molecules do not bind to heavy metal ions at all. Thus, they pass the intestinal tract without any loss. As free molecules they do not take up heavy metal ions but develop this metal binding properties surprisingly after their resorption when they circulate in the blood stream so that they can successfully be administered systemically to warm-blooded animals, most preferred orally or parenterally. Administered orally they even exhibit a significantly higher activity than HBED. Thus the present invention provide agents that are even effective chelators when administered systemically. Although the free molecules of the formula (I) do not bind to heavy metal ions they develop strong chelating properties in the animaTs blood.
A therapeutically preferred subgroup within the formula (I) consists of those representatives wherein R is defined as under Formula (I) and
Rj is -NR4R5 whereby R and R5 are independent of each other C -C3 alkyl;
R2 is CrC3 alkyl;
R3 is Ci-Cj alkyl or C3-C cycloalkyi; halogen is fluorine, chlorine or bromine; cycloalkyi is cyclohexyl;
R4 is methyl; and salts thereof.
Most preferred are however compounds of the formula (I) wherein R represents -O-(CO)-R2 and R2 CrC6 alkyl and preferably CrC3 alkyl. Within the scope of the present description, the definitions used hereinbefore and hereinafter have preferably the following meanings: Cj-Cg alkyl stands for an unbranched or branched alkyl group characterized by the given number of carbon atoms. Typical representatives are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, n-hexyl, 1-methyl-pentyl, 1,1 -dimethyl-butyl, 3,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2-methyl-pentyl, 3-methyl-pentyl, and 4-methyl-pentyl. Halogen is, for example, fluorine, bromine or chlorine, preferably fluorine or chlorine. C3-C7 cycloalkyi represents a carbocyclic saturated ring with three to seven carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopentyl or cyclohexyl.
Most preferred representatives within the scope of formula (I) are the following ones:
Bis N,N-diethylaminocarbonylmethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine
N,N'-diacetate;
Bis acetoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis n-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis iso-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N N'-diacetate;
Bis acetoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis tert-butoxymethyl- [N,N ' -bis(2-hydroxybenzyl)] ethylenediamine N,N ' -diacetate;
Bis n-pentoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis phenoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis ethoxycarbonyloxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine
N,N'-diacetate;
Bis cyclohexyloxycarbonyloxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine
N,N' -diacetate;
Bis (4-methyl-l,3-dioxolan-2-on-4-yl)methoxy-[N,N'-bis(2-hydroxybenzyl)]- ethylenediamine N,N' -diacetate; and
Bis N-morpholinocarbamoylmethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine
N,N' -diacetate.
The compounds of the formula (I) are capable of forming salts. The salts of the compounds according to the invention are, especially, pharmaceutically acceptable, non-toxic salts. Such salts are especially metal salts and ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts as well as related 2+ salts such as zinc salts, and ammonium salts with ammonia or suitable organic amines, there coming into consideration for the salt formation especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly-amines, and also heterocyclic bases. Such amines are, for example, lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkylammes, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzyl-ethylenediamine, also bases of the pyridine type, for example pyridine, collidine or quinoline. The compounds of the formula (I) can also form intermolecular (as opposed to intramolecular, i.e. zwitterionic) acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, for example methanesulfonic acid, or with amino acids, such as arginine and lysine.
For isolation and purification, pharmaceutically unacceptable salts also can be used. Only the pharmaceutically acceptable, non-toxic salts are used for therapeutic application and, for that reason, they are preferred.
Taken up by the a warm-blooded animal, the compounds of the formula I are transformed into a form that allows them to form stable complexes with metal ions, especially heavy metal ions. Of the heavy metal ions, there may be mentioned especially those in the 3+ oxidation state, such as Al3+ or, most especially, Fe3+.
Thus, the substances of the formula (I) exhibit valuable pharmacologically properties when administered systemically, especially after oral or percutaneous application. Owing to their ability to form in the animal's body stable complexes with heavy metal ions, especially with those in the 3+ oxidation state, such as Al3+ or, most especially, with Fe3+, the compounds of the formula (I) prevent, for example, the deposition of iron-containing pigments in the tissues and, in cases where iron has been deposited in the organism, bring about elimination of the iron, for example in haemochromatosis and haemosiderosis and also in cirrhosis of the liver. They can also be used for the elimination from the organism of other heavy metals, for example aluminium and also chromium and copper. Thus, the compounds of the formula I can also be used in the case of dialysis encephalopathy, osteomalacia and Alzheimer's disease. The compounds of the formula (I) according to the invention and salts thereof can be manufactured by chemical synthesis according to processes known per se. They are manufactured, for example, by adding under cooling sodium hydride or potassium hydrogene carbonate to the compound of the formula (II)
wherin X stands for hydrogen or the group -CH2J and adding to the resultant solution either
(a) in those cases where X stands for hydrogen a compound of the formula (UI)
Y-CH2-R (m), or
(b) in those cases where X stands for the group -CH2J a compound of the formula (TV)
HO-C(O)-R (IN),
whereby R in the formulae (III) and (IN) is defined as under formula (I) and Y represents halogen, preferably chlorine, bromine or iodine, most preferably bromine or iodine.
The compound of the formula (II) wherin X is hydrogen is HBED which is as mentiond above described in the U.S. patent US-4'528' 196. The compound of the formula (II) wherin X is -CH2J can be prepared by reacting HBED with CH2C1J under suitable conditions. This type of reaction is described in the literature and well known to the skilled chemist.
The reaction is performed in a inert dipolar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylformamide (DMF), dimethylacetamide (DMA), tetrametylurea, dimethylsulfoxide (DMSO), tetrahydrothiophen- 1,1 -dioxide (sulfolane) or diether of ethylenglycole at relatively low temperatures preferably at temperatures arround 0°C, for example at about -10° to 30°C, and preferably under an inert gas atmosphere.
Salts of compounds of the formula (I) can be manufactured in a manner known per se. Thus, acid addition salts of compounds of the formula (I) are obtained in customary manner, for example by treating with an acid or a suitable anion-exchange reagent. Internal salts of compounds of the formula (I) (zwitterionic forms) can be formed, for example, by neutralising the compounds or salts, such as acid addtion salts, to the isoelectric point, for example with weak bases, or by treating with liquid ion-exchangers.
Salts can be converted in customary manner into the free compounds: metal and ammonium salts can be converted into the free compounds, for example, by treating with suitable acids, and acid addition salts, for example, by treating with a suitable basic agent.
The starting materials, especially those of formula (II) and (HI) are available commercially and/or known or can be manufactured by known processes.
The pharmacologically acceptable compounds of the present invention can be used, for example, for the manufacture of pharmaceutical compositions which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.
The pharmaceutical compositions according to the invention are those which are suitable for enteral, such as oral, administration and for parenteral, such as subcutaneous, administration to warm-blooded animals, especially humans, and which contain the pharmacological active substance on its own or together with a pharmaceutically acceptable carrier. The dosage of the active substance depends on the species of warm-blooded animal and on the age and individual condition, the illness to be treated and also on the mode of administration.
The novel pharmaceutical preparations contain from approximately 10 % to approximately 95 %, preferably from approximately 20 % to approximately 90 %, of the active substance. Pharmaceutical compositions according to the invention can, for example, be in unit dose form, such as dragees, tablets, capsules, suppositories or ampoules, and contain from approximately 0.1 g to approximately 3.0 g, preferably from approximately 0.3 g to approximately 1.0 g, of the active ingredient. The pharmaceutical compositions of the present invention are manufactured in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. Pharmaceutical compositions for oral use can be obtained by combining the active substance with one or more solid carriers, if desired granulating a resulting mixture and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, to form tablets or dragee cores. In so doing, they can also be incorporated into plastics carriers which release the active substances or allow them to diffuse in controlled amounts.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders such as starches, for example corn, wheat, rice or potato starch, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinyl- pyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked poly vinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating and lubricating agents, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that are, if desired, resistant to gastric juice, there being used, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the manufacture of coatings that are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl¬ methylcellulose phthalate. Colouring substances or pigments can be added to the tablets or dragee coatings, for example for the purpose of identification or for indicating different doses of active substance.
Other orally administrable pharmaceutical compositions are dry-filled capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as corn starch, binders and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids or wax-like substances, such as fatty oils, paraffin oil or polyethylene glycols, it being possible also for stabilisers to be added. Other forms of oral administration are, for example, syrups prepared in customary manner that contain the active ingredient in, for example, suspended form and in a concentration of approximately from 5 % to 20 %, preferably approximately 10 %, or in a similar concentration that provides a suitable single dose when administered, for example, in measures of 5 or 10 ml. Also suitable are, for example, powdered or liquid concentrates for preparing shakes, for example in milk. Such concentrates can also be packed in single-dose quantities.
Particularly suitable dosage forms for parenteral administration are sterile aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, or sterile aqueous injection suspensions which contain substances increasing the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally stabilisers. In addition, the active ingredient, with or without adjuvants, can also be in lyophilised form and brought into solution prior to parenteral administration by addition of suitable solvents.
The invention relates also to compositions for diagnostic purposes that contain a suitable metal complex of a compound of the formula (I), preferably in the form of an aqueous solution or in the form of a dry preparation.
The invention relates also to a method of treatment of pathological conditions in a mammal, especially human, which, as has been described hereinbefore, are associated v/ith an excess of a trivalent metal cation such as aluminium or, especially, iron(III), in the body, which method comprises administering, preferably orally, a prophylactically or therapeutically effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof. There are used for this purpose especially the above-mentioned pharmaceutical compositions, a daily dose of from approximately 25 mg kg to approximately 200 mg kg, preferably from approximately 20 mg kg to approximately 150 mg/kg, of a compound of the present invention being administered to a warm-blooded animal. The dosage can be administered orally in several, for example three, individual doses. For systemic, e.g. subcutaneous, administration the more water soluble salt forms of the compounds of the formula (I), e.g. the sodium salt, are preferred. Most preferred mode of administration is orally. An alternatively mode of administration is subcutaneously. The invention concerns especially the compounds of the formula (I), the methods for their preparation as outlined above, pharmaceutical compositions containing as active ingredient a compound of the formula (I). Preferred are pharmacetical compositions for systemic administration, as described generally and in the examples, and especially the oral dosage forms. The invention further concerns a method of treatment of pathological conditions in a mammal that are associated with an excess of trivalent metal ions in the body, comprising administering systemically, most preferred orally, to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The following examples serve to illustrate the invention but should not be construed as a limitation thereof. Temperatures are given in degrees Centigrade.
Example 1: Bis acetoxymethyl-rN,N'-bis(2-hvdroxybenzyl)]ethylenediamine- N,N'-diacetate
CH3(CO)-0-CH2-0-(CO) - N )-0-CH2-0-(CO)CH3
HBED (lg, 2.57 mMol) was dissolved in 15 ml of dimethylformamide, the resulting solution cooled to 0-4 C and kept under innert atmosphere. Sodium hydride (280 mg, 6.43 mMol, 55-60% suspension in oil) was added and the resulting suspension stirred 30 min. at 0-4 C.
Bromomethylacetate (656 ml, 6.7 mMol) was added and the reaction mixture stirred for 5 h at room temperature.The mixture was poured in ethylacetate (100 ml) and washed with water (3 X 50 ml), brine (lX50ml) dried with Na2SO , after filtration of the drying agent the solvent was evaporated under reduced pressure.
The residue was purified on a chromatographic column containing 70g of silicagel and ethylacetate/hexane 1:1 v/v as eluting solvent. The fractions containing the pure compound were combined and concentrared in vacuo. The residue is recristallized from ethylacetate hexane to yield the desired compound as a white crystals, mp 100-101°C.
% calc. for C^H^OK) : C 58.64
H 6.06 N 5.26 O 30.04
% found : C 58.52
H 6.12 N 5.18 O 29.91
JH-NMR (CDCU, 200 MHz) : 2.13 (s, 6H, 2 X H3CO-); 2.75 (s, 4H, N-CH2-CH2-N); 3.12 (s, 4H, 2 X N-CH2-CO-); 3.78 (s, 4H, 2 X -N-CH2-PH); 5.79 (s, 4H, 2 X O-CH2-O); 6.7-7.22 (m, 8H, 2 X Ph).
Example 2 : Bis propanoyloxymethyl fN,N'-bis(2-hvdroxybenzyl)]ethylene-diamine N,N'-diacetate
C2H5(CO)-0-CH2-0-( -0-CH2-0-(CO)C2H5
HBED (5.7g, 14.6 mMol) was dissolved in 100 ml DMF (N, N-dimethylformamide) and KHCO3 (5.9g, 58.7 mMol) was added. The mixture was stirred for 50 min.
After that period bromomethylpropionate (6.9ml, 61.67 mMol) was added and the mixture stirred for 18 h. The reaction mixture was then poured in ethylacetate (100ml) and washed with water (2X200ml), brine (lX200ml) and dried over Na2SO4. After filtration the solution was concentrated in vacuo. The residue was recrystallized from ethylacetate/hexane yielding the desired compound with a melting point of 91-92 C.
% calc. for : C 59.99
H 6.47 N 5.0 O 28.54
% found : C 60.1
H 6.6 N 5.0 O 28.2
Example 3 : Bis pivaloyloxymethyl r,N'-bis(2-hydroxybenzyl)1- ethylendiamine N,N'-diacetate
HBED (lOOmg, 0.255 mMol) was dissolved in 5 ml of DMF, cooled at 0-4 C and kept under Ar. Sodium hydride (23mg, 0.52 mMol, 55-60% in oil) was added and the resulting mixture stirred for 18 h at 6-8 C.
After that time the reaction was diluted with ethylacetate (30ml) and washed with water (2X10ml), brine (IXlOml) and dried over Na2SO4. After filtration of the drying agent the solvent was evaporated in vacuo. The residue was purified on a chromatographic column and the fractions containing the pure compound were combined and evaporated in vacuo to give the desired product as a colorless oil.
JH-NMR (CDCh, 200 MHz) : 1.2 (s, 9H, -(CH3)3); 2.75 (s, 4H, N-CH2-CH2-N); 3.32 (s, 4H, 2 X N-CH2-CO); 3.77 (s, 4H, N-CH2-Ph); 5.8(s, 4H, 2 X -CH2-Ph); 6.7-7.25(m, 8H, 2 X-Ph).
Example 4: Bis N,N-diethylaminocarbonylmethyl-rN,N'-bis(2-hvdroxybenzyl)l- ethylenediamine N,N' -diacetate
HBED (200mg, 0.51 mMol) was dissolved in anhydrous DMF and cooled to 0-4 C under Ar. Sodium hydride (52mg, 1.2 mMol, 55-60 % in oil) was added and the resulting suspension was stirred for 30 min. Then 2-chloro-N,N-diethylacetamide (168ml, 1.23 mMol) and sodium iodide (18mg, 0.12 mMol) were added and the resulting suspension stirred for 24 h at room temperature.
After that period the reaction mixture was diluted with ethylacetate (50ml) and washed with sat. N^Cl (2X20ml), water (lX25ml), brine (lX20ml), dried with Na2SO4 and filtrated. The solvent was evaporated in vacuo and the reidue purified on a chromatographic column. The fractions containing the pure compound were combined and concentrated in vacuo to give the desired compound as a colorless oil.
JH-NMR (CDC1,, 200 MHz) : 1-1.2 (m, 12H, 4X -CH3); 2.8 (s, 4H, N-CH2-CH2-N); 3.2 (q, 4H, 2X -CH?-CHQ; 3.3 (q, 4H, 2X -0^-0 ); 3.45 s, 4H, N-CH2-CO); 3.8 (s, 4H, N-CH2-Ph); 4.75 (s, 4H, -O-CH2-CO); 6.65-7.2 (m, 8H, 2X -Ph). Example 5: Bis-N-morpholinocarbonylmethyl-rN,N,-bis(2-hvdroxybenzyl)l-ethylene- diamine N,N'-diacetate
HBED (200 mg, 0.51 mmol) was dissolved in anhydrous DMF (5ml) and cooled to 0-4 °C. NaH (50 mg, 1.12 mmol) was added and the suspension stirred for one hour. Then 2-bromo N-morpholinoacetamide was added and the reaction stirred for seven hours at room temperature.
After that period the reaction mixture was diluted with ethylacetate (30ml) washed with water (2 X 10 ml), brine (1 X 10 ml) dried over Na2SO . After filtration of the drying agent, the solvent was evaporated and the residue chromatographed on column. The fractions containing the pure compound were combined and the solvent evaporated in vacuo to yield the desired product as an oil.
-NMR (CDC .200 MHz) : 2.81 (s, 4H, N-CH2-CH2-N); 3.42 (s, 4H, N-CH2-CO); 3.3-3.7 (m, 16H, 2 X N-CH2-CH2-O); 3.78 (s, 4H, 2 X N-CH2-Ph); 4.76 (s, 4H, 2 X O-CH2-CO); 6.7-7.2 (m, 8H, 2 X -Ph). Example 6: Bis(5-methyl- 1 ,3-dioxolan-2-one-4-yl)methoxy-rN,N'-bis(2-hvd-roxybenzyl)1- ethylenediamine-N,N ' -diacetate.
HBED-4H2O (1.31 g, 2.84 mmol) was dissolved in 40ml DMF (dimethylformamide). KHCO3 (potassium bicarbonate) (0.85 g, 8.5 mmol) was added and the reaction mixture was warmed to 65 °C for one hour. The solution was then cooled to 15 °C and 4-bromomethyl- -5-methyl-l,3-dioxolan-2-on 1.92 g, 9.94 mmol) in 10 ml DMF was added and the resulting solution stirred for two and a half hours at room temperature.
After that period the solution was diluted in 150 ml of ethylacetate and washed with water (4 X 80 ml). The water phases were extracted with ethylacetate (100 ml). The organic phases were combined, dried with Na2SO4 and evaporated in vacuo. The residue was purified on a chromatographic column and the fractions containing the pure compound were evaporated in vacuo. The residue was recrystallized from ethylacetate/hexane to yield the desired compound with a melting point of 111-113 °C.
% calc. for C30H32N2O12 : C 58.82
H 5.27 N 4.57 O 31.34
% found : C 58.7
H 5.2 N 4.6 O 31.4 Example 7: Pharmaceutical composition for oral administration
1000 gelatine capsules each containing 150 mg of active ingredient are manufactured as follows:
Composition:
150 g Bis acetoxymethyl-[N,N'-bis(2-hydroxybenzyl)]- ethylenediamine N,N'-diacetate
36 g talc
24 g wheat starch
16 g magnesium stearate
4 g lactose
The pulverulent substances are forced through a sieve having a mesh width of 0.6 mm and mixed thoroughly to yield a total of 230 g. 1000 gelatine capsules are each filled with 330 mg of this mixture using a capsule filling machine.

Claims

What we claim is:
1. A compound of the formula (I)
R-CH2-0-( )-0-CH2-R
in which R represents -(CO)-Rl5 -O-(CO)-R2, -O-(CO)-O-R3 or rin
R^ >° whee
Rx is -NR4R5 or — N O ; whereby R4 and R5 are independent of each other CrC3 alkyl or C3-C7 cycloalkyi or form together the group -(CH^-, n is an integer from 3 to 6; R2 is Cj-Cβ alkyl, unsubstituted phenyl or phenyl substituted by one to four substituents selected from the group consisting of halogen and hydroxy; R3 is C C6 alkyl or C3-C7 cycloalkyi; R is -C3 alkyl; and salts thereof.
2. A compound of the formula (I) according to claim 1 in which
Ri is -NR4R5 whereby -Rj and R5 are independent of each other -C3 alkyl;
R2 is CrC3 alkyl;
R3 is C!-C3 alkyl or C3-C7 cycloalkyi; halogen is fluorine, chlorine or bromine; cycloalkyi is cyclohexyl; and
R4 is methyl; and salts thereof.
3. A compound of the formula (I) according to claim 1 in which R represents -O-(CO)-R2 and R2 is Cj-Cg alkyl, preferably C C3 alkyl; and salts thereof.
4. A compound according to claim 1 selected from the group consisting of
Bis N,N'-diethylaminocarbonylmethyl-[N,N-bis(2-hydroxybenzyl)]ethylenediamine N,N' -diacetate; Bis acetoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis n-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis iso-propoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N N'-diacetate;
Bis acetoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis tert-butoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis n-pentoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis phenoxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine N,N'-diacetate;
Bis ethoxycarbonyloxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine
N,N' -diacetate;
Bis cyclohexyloxycarbonyloxymethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine
N,N'-diacetate;
Bis (4-methyl-l,3-dioxolan-2-on-4-yl)methoxy-[N,N'-bis(2-hydroxybenzyl)]- ethylenediamine N,N' -diacetate. and
Bis N-morpholinocarbamoylmethyl-[N,N'-bis(2-hydroxybenzyl)]ethylenediamine
N,N' -diacetate.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1.
6. A pharmaceutical composition according to claim 5 for systemic, preferably oral administration comprising a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 together with a carrier suitable for oral uptake.
7. A method of treatment of pathological conditions in a mammal that arc associated with an excess of trivalent metal ions in the body, comprising administering systemically to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1.
8. A method according to claim 7 comprising the oral administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 together with a carrier suitable for oral uptake.
9. Process for the production of a compound of the formula (I) according to claim 1 comprising adding under cooling sodium hydride or potassium hydrogene carbonat to the compound of the formula (II)
wherin X stands for hydrogen or the group -CH2J and adding to the resultant solution either
(a) in those cases where X stands for hydrogen a compound of the formula (III)
Y-CH2-R (HI), or
(b) in those cases where X stands for the group -CH2J a compound of the formula (IV)
HO-C(O)-R (IV),
whereby R in the formulae (III) and (IV) is defined as under formula (I) and Y represents halogen.
EP95900893A 1993-12-16 1994-12-05 N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents Withdrawn EP0734374A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP95900893A EP0734374A1 (en) 1993-12-16 1994-12-05 N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP93810886 1993-12-16
EP93810886 1993-12-16
EP95900893A EP0734374A1 (en) 1993-12-16 1994-12-05 N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents
PCT/IB1994/000388 WO1995016663A1 (en) 1993-12-16 1994-12-05 N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid derivatives as chelating agents

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EP0734374A1 true EP0734374A1 (en) 1996-10-02

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EP (1) EP0734374A1 (en)
JP (1) JPH09507473A (en)
CN (1) CN1137267A (en)
AU (1) AU1033495A (en)
CA (1) CA2179203A1 (en)
FI (1) FI962435A0 (en)
HU (1) HUT74457A (en)
NO (1) NO962307D0 (en)
WO (1) WO1995016663A1 (en)

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US6140305A (en) 1996-04-04 2000-10-31 Bio-Rad Laboratories, Inc. Hereditary hemochromatosis gene products
US7026116B1 (en) 1996-04-04 2006-04-11 Bio-Rad Laboratories, Inc. Polymorphisms in the region of the human hemochromatosis gene
WO1997044313A1 (en) * 1996-05-21 1997-11-27 Novartis Ag N,N'-Di(2-HYDROXYBENZYL)ETHYLENEDIAMINE-N,N'-DIACETIC ACID DERIVATIVES
US6849399B1 (en) 1996-05-23 2005-02-01 Bio-Rad Laboratories, Inc. Methods and compositions for diagnosis and treatment of iron misregulation diseases
DE69835519T2 (en) 1997-06-13 2007-04-05 Bio-Rad Laboratories, Inc., Hercules METHOD AND COMPOSITIONS FOR THE DIAGNOSIS AND THE TREATMENT OF DISEASES ASSOCIATED WITH IRON OXIDE OR IRON DEFICIENCY.
FR2768145B1 (en) * 1997-09-09 1999-10-08 Oreal NOVEL COMPOUNDS DERIVED FROM DI- OR TRI-ACETIC ALKYLENE DIAMINE ACID, PROCESS FOR THEIR PREPARATION, THEIR USE IN COSMETIC AND PHARMACEUTICAL COMPOSITIONS, AND COMPOSITIONS COMPRISING THE SAME
PT1052985E (en) * 1998-02-04 2005-04-29 Univ Florida N, N'-DIACEIC ACID N, N'-BIS (2-HYDROXYBENZYL) ETHYLENODIAMINO AND ITS SODIUM SALTS FOR IRON THICKNESS THERAPY
CA2394524A1 (en) * 1999-12-21 2001-06-28 Raymond J. Bergeron N,n'-bis(2-hydroxybenzyl)ethylenediamine-n,n'-diacetic acid in iron chelating therapy
CN109438517B (en) * 2018-12-27 2021-01-08 北京久杰净化工程技术有限公司 Complex of bifunctional linking agent coordinated with carbonyl metal core and preparation method thereof

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US4528196A (en) * 1981-02-23 1985-07-09 The United States Of America As Represented By The Department Of Health And Human Services Chelating agents for the treatment of iron overload
DE69023394T2 (en) * 1989-06-16 1996-07-04 Merck Frosst Canada Inc Chelate derivatives of atrial-natriurethic factor (ANF).

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See references of WO9516663A1 *

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HUT74457A (en) 1996-12-30
JPH09507473A (en) 1997-07-29
WO1995016663A1 (en) 1995-06-22
CN1137267A (en) 1996-12-04
FI962435A (en) 1996-06-12
AU1033495A (en) 1995-07-03
CA2179203A1 (en) 1995-06-22
NO962307L (en) 1996-06-04
HU9601658D0 (en) 1996-08-28
NO962307D0 (en) 1996-06-04
FI962435A0 (en) 1996-06-12

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