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WO1986003745A1 - Nouveaux derives d'acides o-acylhydroxamiques - Google Patents

Nouveaux derives d'acides o-acylhydroxamiques Download PDF

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Publication number
WO1986003745A1
WO1986003745A1 PCT/CH1985/000174 CH8500174W WO8603745A1 WO 1986003745 A1 WO1986003745 A1 WO 1986003745A1 CH 8500174 W CH8500174 W CH 8500174W WO 8603745 A1 WO8603745 A1 WO 8603745A1
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Prior art keywords
desferrioxamine
acid
formula
compound according
radicals
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PCT/CH1985/000174
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German (de)
English (en)
Inventor
Bruno Fechtig
Heinrich Peter
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Ciba-Geigy Ag
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Publication of WO1986003745A1 publication Critical patent/WO1986003745A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids

Definitions

  • the invention relates to O-acyl derivatives of hydroxamic acids, in particular trihydroxamic acids, which are known under the name ferrioxamines as metabolites of microorganisms, in particular actinomycetes, and especially O-acylates of desferrioxamine B of the general formula
  • the invention also relates to processes for the preparation of the abovementioned compounds and pharmaceutical compositions containing these compounds and processes for their preparation; also the use of these compounds as chemical intermediates and therapeutic use of these compounds and pharmaceutical compositions containing them in warm-blooded animals, including humans.
  • Desferrioxamine B the base material of the O-acylates of the present invention
  • desferrioxamine B and its addition salts which are formed with one equivalent of acid, is the ability to form stable chelate-like metal complexes, especially with trivalent metal ions such as chromium (III) aluminum and primarily iron (III ) Ions to connect.
  • the broad therapeutic use of desferrioxamine B and its salts e.g.
  • methanesulfonate therefore generally extends to diseases and pathological conditions of the human body (as well as the body of other warm-blooded animals), which are associated with excessive exposure of the organism to iron (III) ions ( Fe +++ ions), such as thalassemia major, sickle cell anemia, sideroachrestic anemia, aplastic anemia and other anemic forms in which hemosiderosis (ie a local or general increase in iron stores in otherwise undamaged body tissues) plays a role.
  • This type also includes pathological conditions that develop in patients after repeated blood transfusions or repeated dialysis treatment in the absence or damage develop digestive kidney function.
  • the complex formation with other trivalent metals can also be used to remove them from the organism, for example to remove aluminum in dialysis encephalopathy and osteomalacia, and in Alzheimer's disease.
  • a serious disadvantage is the fact that desferrioxamine and its salts have little, inadequate activity when administered orally and require a parenteral administration form in all of the above-mentioned applications.
  • Recommended as a particularly effective method of administering the active ingredient by slow (8 to 12 hour) subcutaneous infusion which either involves hospitalization of the patient or, in the case of outpatient treatment, the use of a portable mechanical device such as one operated by an electric drive Infusion syringe, conditional.
  • such solutions are associated with high treatment costs, which severely limits their use, in particular, comprehensive treatment of thalassemia in the countries of the Mediterranean, the Middle East, India and Southeast Asia or sickle cell anemia in the African countries is impossible.
  • These widespread diseases continue to pose a serious health problem in these countries and make the search for a simpler and cheaper therapy, preferably by means of an orally active preparation, a priority in this area.
  • the present invention primarily relates to 0.0 ', 0 "-acylates of the formula I mentioned at the outset, in which Ac 1 , Ac 2 and Ac 3 are acyl radicals of carboxylic acids having 1-24 carbon atoms, and their salts.
  • the acyl radicals Ac 1 , Ac 2 and Ac 3 can be different from one another or, preferably, the same and correspond to the partial formula R-CO-, where R is a hydrogen atom or a hydrocarbyl having 1 to 23 carbon atoms (the acyl radical
  • R-CO- where R is hydrogen, is formyl
  • the hydrocarbyl radical R is a saturated or unsaturated acyclic, carbocyclic or carbocyclic-acyclic hydrocarbon radical which has at most 23, preferably at most 17 carbon atoms. It can be unsubstituted or substituted and can also carry atoms of other elements (heteroatoms), in particular oxygen, sulfur and nitrogen, but also, for example, phosphorus and silicon, instead of one, two or more carbon atoms, and thus, if these are in a cyclic Radical, form a heterocyclic radical (heterocyclyl) or a heterocyclic-acyclic radical.
  • Unsaturated radicals are those which contain one or more multiple bonds, ie double and triple bonds.
  • Cyclic radicals in which at least one 6-membered carbocyclic or 5- to 8-membered heterocyclic ring contains the maximum number of non-cumulative double bonds are termed aromatic.
  • Carbocyclic radicals in which at least one ring is present as a 6-membered aromatic ring (ie benzene ring) are referred to as aryl radicals.
  • acyclic radicals denoted “lower”, “medium” and “higher” in the present disclosure contain 1 to 5, 6 to 11 and 12 to 23 carbon atoms, respectively.
  • An acyclic hydrocarbyl is, for example, a straight or branched aliphatic radical which can also be mono- or polyunsaturated, e.g. Alkyl, alkenyl, alkadienyl, alkatrienyl or alkynyl.
  • An alkyl is, for example, a lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or isopentyl), a medium-length alkyl (such as hexyl, heptyl, octyl, nonyl, decyl and undecyl) or a higher alkyl (e.g. tridecyl, pentadecyl, heptadecyl and nonadecyl).
  • a lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or isopentyl
  • a medium-length alkyl such as hexyl, heptyl, octyl, nony
  • An alkenyl is, for example, vinyl, allyl, propenyl, isopropenyl, methallyl and 1-, 2- or 3-butenyl, also 9-decenyl and 8-heptadecenyl;
  • an alkadienyl is, for example, 1, 3-butadienyl, 1,3- or 2,4-pentadienyl and 8, 11-He ⁇ tadecadienyl;
  • an alkatrienyl is e.g. 8, 11, 14-He ⁇ tadecatrienyl, it being possible for individual double bonds in all such radicals to be independent of one another in the cis or trans configuration.
  • An alkynyl is e.g. Ethynyl, propargyl and 1-, 2- or 3-butynyl.
  • a carbocyclic hydrocarbon radical is in particular a mono-, bi- or polycyclic cycloalkyl, cycloalkenyl or cycloalkadienyl radical, or an aryl radical containing a corresponding aromatic ring. Residues with at most 12 ring carbon atoms and 3- to 8-, preferably 5- and / or 6-membered rings are preferred, wherein they also contain one or more acyclic residues, For example, the above, and especially the lower alkyl radicals, or can carry further carbocyclic radicals.
  • Carbocyclic-acyclic radicals are those in which an acyclic radical, in particular one with at most 7, preferably with 1 to 4 carbon atoms, bears one or more carbocyclic, optionally aromatic radicals of the above definition. Particularly noteworthy are cycloalkyl-lower alkyl and aryl-lower alkyl radicals, and their analogues which are unsaturated in the ring and / or side chain.
  • Cycloalkyl is e.g. Cyclopentyl and cycl ⁇ hexyl, as well as bicyclo [2,2, 2] octyl, 2-bicyclo [2, 2, 1] heptyl and adamantyl, also also 4,4-dimethylcyclohexyl and 2,4,4,6-tetramethylcyclohexyl; Cycloalkenyl is e.g. one of the cycloalkyl radicals already mentioned which carries a double bond in the 1-, 2- or 3-position, such as 1-, 2- or 3-cyclopentenyl and 1-, 2- or 3-cyclohexenyl. Cycloalkyl-lower alkyl or lower alkenyl is e.g.
  • An aryl radical is primarily a phenyl, furthermore a naphthyl, such as 1- or 2-Na ⁇ hthyl, a biphenylyl, such as in particular 4-blphenylyl, further also a tolyl, such as o-, m- and p-tolyl, and a xylyl.
  • Aryl lower alkyl and lower alkenyl radicals are e.g. Phenyl-lower alkyl or phenyl-lower alkenyl, e.g. Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (i.e. benzhydryl), trityl and 1- or 2-naphththylmethyl, or styryl or cinnamyl.
  • Heterocyclic residues including the heterocyclic-acyclic residues, are in particular monocyclic, but also bi- or polycyclic aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetrazacyclic residues of aromatic character, furthermore corresponding partially or completely saturated heterocyclic radicals of this type, such radicals optionally being able, for example as the abovementioned carbocyclic or aryl radicals, to carry further acyclic, carbocyclic or heterocyclic radicals and to be mono-, di- or polysubstituted.
  • heterocyclic-acyclic radicals has, for example, the meaning given for the corresponding carbocyclic-acyclic radicals. They are primarily unsubstituted or substituted monocyclic monoaza, monothia or monooxacyclic radicals, such as aziridinyl, oxiranyl and thiiranyl, and in particular heterocyclic radicals of aromatic character, such as pyrryl, for example 2-pyrryl or 3-pyrryl, pyridyl, for example 2- 3- or 4-pyridyl, furthermore thienyl, for example 2- or 3-thienyl, or furyl, for example 2-furyl; bicyclic monoaza, monooxa or monothiacyclic radicals, such as indolyl, for example 2- or 3-indolyl, quinolinyl, for example 2- or 4-quinolinyl, isoquinolinyl, for example 1-isoquinolinyl, benzofuranyl, for example 2- or 3-benzo
  • radicals are, for example, tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, ryrrolidinyl, such as 2-pyrrolidinyl, tetrahydropyridyl, such as 1,2,3,4- or 1, 2, 3,6-tetrahydropyrid -2-yl, or piperidyl, such as 2-, 3- or 4-piperidyl, also also morpholinyl, thlomorpholinyl, piperazinyl and 2-N, N'-bis-lower alkyl-pyrerazinyl, such as in particular 2-N, N'-dimethylpiperazinyl.
  • tetrahydrothienyl such as 2-tetrahydrothienyl
  • tetrahydrofuryl such as 2-tetrahydrofuryl
  • ryrrolidinyl such as 2-pyrrolidinyl
  • radicals can also carry one or more acyclic, carbocyclic or heterocyclic radicals, in particular those mentioned above.
  • Hetercyclischacyclische residues are in particular of acyclischen residues with at most 7, preferably with 1 to 4 carbonates, for example derived from the above, and can carry one, two or more heterocyclic radicals, for example the above.
  • a hydrocarbyl (including a heterocyclyl) can be substituted by one, two or more identical or different substituents, e.g. Free or etherified hydroxyl groups, halogen atoms (such as chlorine, fluorine or bromine), keto groups, and free and functionally modified carboxyl groups (e.g. carbamoyl groups and esterified carboxyl groups) can be substituted.
  • substituents e.g. Free or etherified hydroxyl groups, halogen atoms (such as chlorine, fluorine or bromine), keto groups, and free and functionally modified carboxyl groups (e.g. carbamoyl groups and esterified carboxyl groups) can be substituted.
  • An etherified hydroxyl group present as a substituent in the hydrocarbyl is e.g. a lower alkoxy group, such as methoxy, ethoxy and tert-butoxy group, and a phenoxy, benzyloxy or phenethyloxy group optionally substituted by nitro, lower alkoxy, lower alkyl or halogens.
  • An esterified carboxyl group present as a substituent in the hydrocarbyl is in particular one in which the hydrogen has been replaced by one of the unsubstituted carbon radicals described above, especially a lower alkyl or phenyl-lower alkyl (e.g. methoxycarbonyl, ethoxycarbonyl and benzyloxycarbonyl).
  • Preferred acyl radicals Ac 1 , Ac 2 and Ac 3 are derived from unsubstituted and substituted monocarboxylic acids and dicarboxylic acids having 1 to 20 carbon atoms.
  • these include, in particular, residues of acyclic monocarboxylic acids, such as alkanoyl residues of lower alkane carboxylic acids (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl [2,2-dimethylpropanoyl] and hexanoyl [caproyl]), of alkane and alkene acids Length (e.g.
  • heptanoyl e.g., heptanoyl, octanoyl, decanoyl, undecanoyl, lauroyl or an alkenoyl such as 10-undecenoyl) and of higher alkane carboxylic acids (e.g.
  • myristoyl, palmitoyl and stearoyl or of their unsaturated analogs (alkenoyl, alkadienoyl, and alkatrienoyl residues , Elaidoyl, Linoleoyl [9,12-Octadecadienoyl] or Linolenoyl [9,12,15-Octadecatrienoyl]), all of these radicals also being substituted
  • substituents for example halogenated, such as chlorinated and brominated alkanoyl radicals (for example chloroacetyl, bromoacetyl and ⁇ -bromoisovaleryl), hydroxyalkanoyl radicals and their etherified analogs (for example lactoyl, ricinoleoyl [d-12-hydroxyoleoyl] or 2-methoxy- or 2-ethoxypropanoyl), ketoalkanoyl residues (e.g.
  • ⁇ -carboxyalkanoyl residues especially ⁇ -lower alkoxycarbonylalkanoyl residues
  • ie monovalent acyl residues of aliphatic dicarboxylic acids e.g. amber, glutaric, adine, piperine, adipic, adipic, adipic, lainic acid, sebacic acid and erucic acid
  • lower alkanols such as methanol, ethanol or tert-butyl alcohol
  • optionally substituted benzyl alcohols optionally substituted benzyl alcohols.
  • Preferred acyl residues also include residues of carbocyclic and carbocyclic-acyclic carboxylic acids, in particular monocyclic and bicyclic arylcarbonyl (aroyl) residues (for example benzoyl, o-, m- and p-toluoyl, and 1- or 2-naphthoyl) and araliphatic residues such as aralkylcarbonyl and aralkenylcarbonyl (for example phenylacetyl, 1- and 2-phenylpropionyl or cinnamoyl), all of which can also carry 1-3 identical or different substituents in the aromatic ring, such as nitro (for example 4-nitrobenzoyl), halogen, in particular chlorine or fluorine (e.g.
  • hydroxyl e.g. salicyloyl or 4-hydroxybenzoyl
  • etherified hydroxyl especially lower alkoxy such as methoxy (e.g. anisoyl, veratroyl and piperonyloyl), and carboxyl (e.g. phthaloyl, isophthaloyl) and terephthaloyl , in particular in esterified form, for example as lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl.
  • Preferred acyl residues of heterocyclic carboxylic acids include, for example, 2-furoyl, 2-thenoyl, pyrrole-2-carbonyl, nicotinoyl and isonicotinoyl.
  • Mixed triacylates of the formula I ie those in which acyl radicals Ac 1 , Ac 2 and Ac 3 do not all have the same meaning, are particularly suitable those whose acyl radicals are derived from unsubstituted linear aliphatic monocarboxylic acids (fatty acids), for example the abovementioned ones. preferably at least one of which is a medium or higher aliphatic monocar is acid.
  • acyl radicals are derived from unsubstituted linear aliphatic monocarboxylic acids (fatty acids), for example the abovementioned ones. preferably at least one of which is a medium or higher aliphatic monocar is acid.
  • such mixed triacylates usually occur as a component of practically inseparable mixtures with other isomers in which the same 3 acyl radicals are present, but each of the symbols Ac 1 , Ac 2 and Ac 3 can represent any of these acyl radicals.
  • the name is a "0.0 ', 0" - (Ac 1 , Ac 2 , Ac 3 ) -Desferrioxamine B ", such as 0.0', 0" - (Lauroyl, Palmitoyl, Stearoyl) -, 0, 0 ', 0 "- (dibutyryl, octanoyl) -, 0.0', 0" - (diacetyl, oleoyl) - and 0.0 ', 0 "- (valeryl, bis-10-undecenoyl) desferrioxamine B, not to be understood only as a designation for an individual compound with an indefinite assignment of the acyl groups to individual 0 atoms, but as a collective term for the whole isomer structure containing all of the isomers
  • the individual components of such a mixture, as well as, after hydrolysis, the individual acyl residues can be qualitatively and quantitatively determined by modern analytical separation methods, such as gas chromatography (GLC) or high pressure liquid chromatography (HPLC), but classic analytical methods such as, for example, are often sufficient for general characterization are familiar in the technology of fat processing, such as the determination of the acid number, saponification number, hydrogenation number or iodine number etc.
  • GLC gas chromatography
  • HPLC high pressure liquid chromatography
  • Particularly preferred triacylates of the formula I are those in which Ac 1 , Ac 2 and Ac 3 each represent the same acyl radical, in particular one of the abovementioned, which is derived from an unsubstituted, preferably saturated, aliphatic monocarboxylic acid having at most 18 C atoms primarily those in which Ac 1 , Ac 2 and Ac 3 each represent acetyl, butyryl, pivaloyl, hexanoyl, octanoyl, palmitoyl or
  • triacylates of the formula I in which Ac 1 , Ac 2 and Ac 3 each represent a monocyclic aroyl or aryl-lower alkanoyl, especially benzoyl and phenylacetyl, these passing through in the ring
  • Methyl, methoxy, chlorine and / or nitro can be substituted, but are preferably unsubstituted.
  • Salts of compounds of formula I above are acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts with inorganic acids, e.g. Hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acids, or with organic acids such as sulfonic acids such as aromatic sulfonic acids e.g. Benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid, or in particular aliphatic sulfonic acids, e.g.
  • inorganic acids e.g. Hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acids
  • organic acids such as sulfonic acids such as aromatic sulfonic acids e.g. Benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid, or in particular aliphatic sulfonic acids, e.g.
  • Methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid and ethane-1,2-disulfonic acid as well as carboxylic acids, e.g. Acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxy-benzoic acid, embonic acid, nicotinic acid or isonicotinic acid.
  • carboxylic acids e.g. Acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxy-benzoic acid, embonic acid, nicotinic acid or is
  • the compounds of the present invention have valuable properties, primarily pharmacological effects, by showing a physiological effect which is similar in nature to the action of desferrioxamine B. They can therefore be used in therapeutic indications similar to this, but with the essential advantage of oral administration, for example in particular for the treatment of functional disorders in which the concentration of trivalent iron (Fe 3+ ions) in body cells is abnormally high, such as in hemochromatosis and hemosiderosis.
  • By also binding aluminum ions in a similar manner, such as in dialysis encephalopathy, osteomalacia and Alzheimer's disease they can also be used successfully in these areas of indication. They can also serve as valuable intermediates for the production of other therapeutically valuable compounds.
  • 0.0'0 "-acylates of the formula I are prepared using conventional analogy processes, for example well known from peptide chemistry, in a corresponding compound having a protected amino group of the formula
  • Preferred amino protective groups X are derived from carbonic acid monoesters which correspond to the sub-formula R o -O-CO-, in which R o is a neutral and / or acidolytically removable hydrocarbyl.
  • Such a hydrocarbyl R o is, for example, a mono- or bicyclic ⁇ -aryl-lower alkyl R a (ie one in which the aryl and the oxygen atom of the oxycarbonyl group are bonded to the same carbon atom of the lower alkyl, with a simple heterocyclyl, such as 2-furyl, as the aryl ), in particular an ⁇ -phenyl-lower alkyl or ⁇ - (2-furyl)-lower alkyl, primarily benzyl or furfuryl.
  • a mono- or bicyclic ⁇ -aryl-lower alkyl R a ie one in which the aryl and the oxygen atom of the oxycarbonyl group are bonded to the same carbon atom of the lower alkyl, with a simple heterocyclyl, such as 2-furyl, as the aryl
  • Corresponding acyl radicals R a -O-CO- are, for example, benzyloxycarbonyl groups optionally substituted in the aromatic ring by halogen atoms, nitro groups, lower alkyl or lower alkoxy groups, such as unsubstituted benzyloxycarbonyl (ie carbobenzoxy), p-bromo- or p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- Methoxybenzyloxycarbonyl and p-tolyloxycarbonyl, or furfuryloxycarbonyl, as well as 2- (4-biphenylyl) -2-propyloxycarbonyl and similar aralkoxycarbonyl radicals.
  • benzyloxycarbonyl groups optionally substituted in the aromatic ring by halogen atoms, nitro groups, lower alkyl or lower alkoxy groups, such as unsubstituted benzyloxycarbonyl (ie
  • hydrocarbyl R o is a secondary or, preferably, tertiary alkyl or cycloalkyl R b , in particular one having at most 12 carbon atoms, as were also mentioned above.
  • a corresponding acyl radical R b -O-CO- is, for example, especially tert-butoxycarbonyl, or else an analogous radical, such as isopropyloxycarbonyl, tert-amyloxycarbonyl (ie 1,1-dimethylpropyloxycarbonyl), diisopropylmethoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, d-isobornyloxycarbonyl and Adamamtyloxycarbonyl. As will be described in more detail below, these residues can be split off primarily under acidic conditions (acidolytic).
  • hydrocarbyl R o is a ⁇ - (trihydrocarbylsilyl) ethoxycarbonyl radical R c which , in the ⁇ position, is a silyl group substituted by three unsubstituted C 1-6 hydrocarbon radicals, such as
  • they are stable under the conditions of acid hydrolysis and hydrogenolysis, they can be split off under very specific, very mild conditions by the action of fluoride ions, as will be described in more detail below.
  • Allyl should also be emphasized as hydrocarbyl R o .
  • the corresponding allyloxycarbonyl can be split off not only acidolytically, but especially also under very mild neutral conditions with dimedone or by the specific reductive action of tributyltin hydride under catalysis with palladium (O) tetrakis (triphenylphosphine) complex.
  • Suitable amino protecting groups X also include a methyl, methoxy, halogens and / or nitro substituted or, preferably, the unsubstituted trityl (triphenylmethyl) group which, under very mild conditions, such as with about 50% acetic acid, is solvolytically (acidolytically) removable.
  • Amino protecting groups X also include phenylsulfenyl groups substituted in the ring, in particular the 2-nitrophenylsulfenyl groups oO 2 NC 6 H 4 -S-; the latter is not only cleavable, for example, by acid-catalyzed solvolysis or acidolysis, in which pyridinium chloride is already sufficient as acid, but is also gently subject to mercaptolysis, for example with phenylmercaptan, under neutral conditions.
  • Formyl which can be cleaved not only under acidic conditions but also by oxidation with hydrogen peroxide, should also be mentioned as amino protecting group X.
  • the shortlist of the protective group X depends on the respective properties of the acyl groups, in particular on their stability under the reaction conditions for the removal of the protective group.
  • the protecting group X is split off in the generally known manner, with specific conditions for individual structure types being described in detail in the relevant literature (see, for example, Houben-Weyl, loc. Cit.).
  • Acidolysis is carried out, for example, with trifluoroacetic acid, hydrogen fluoride, hydrogen bromide and hydrogen chloride, if appropriate in the presence of water, such as with hydrochloric acid, and in the case of acid-sensitive protective groups also with a lower aliphatic carboxylic acid, such as formic acid and / or acetic acid, if appropriate in the presence of water and / or from a polyhalogenated lower alkanol or lower alkanone, such as 1,1,1,3,3,3-hexafluoropropan-2-ol or hexafluoroacetone.
  • the groups which can be split off neutrally are preferably hydrolytic, removed, for example, by hydrogenation with palladium catalysis.
  • the ß-silylethoxycarbonyl groups are preferably cleaved with fluoride ion-donating agents, for example with fluorides of quaternary organic bases, such as tetraethylammonium fluoride or tetrabutylammonium fluoride, in neutral organic solvents.
  • the end products of the formula I are obtained in the form of bases or acid addition salts.
  • the bases can be obtained from the acid addition salts in a manner known per se.
  • the latter in turn can be reacted with acids, e.g. with those which form the salts mentioned above, therapeutically usable acid addition salts.
  • X is an amino protecting group characterized above, acylated by conventional methods, in particular with a desired acid anhydride or acid chloride under basic conditions, to give the corresponding N-protected 0.0 ', 0 "triacylate of the formula II.
  • the invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate at any process stage and carries out the missing process steps, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative thereof, for example a salt .
  • the present invention also relates to pharmaceutical compositions which contain one of the new compounds of the formula I as active ingredient, in particular primarily compositions for enteral, in particular oral administration.
  • the preparations contain the active ingredient alone or preferably together with a pharmaceutically usable carrier material.
  • the dosage of the active ingredient depends on the disease to be treated, as well as on species, their age, weight and individual condition, and on the mode of administration.
  • compositions contain from about 5% to about 95% of the active ingredient, single dosage forms preferably from about 20% to about 90% and non-dosage forms preferably from about 5% to about 20% active ingredient;
  • Pharmaceutical preparations in unit dosage form such as coated tablets, tablets or capsules, contain from about 0.10 g to about 2 g, preferably from about 0.2 g to about 1 g, of the active ingredient.
  • compositions of the present invention are used in a manner known per se, e.g. produced by conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • pharmaceutical compositions for oral use can be obtained by combining the active ingredient with one or more solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired, optionally by adding additional auxiliaries, to tablets or coated tablets Cores processed.
  • Suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starches, e.g. Corn, wheat, rice or potato starch, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the above-mentioned starches, also carboxymethyl starch, cross-linked polyvinyl pyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional aids are primarily flow regulators and lubricants, e.g. Silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.
  • Dragees cores are provided with suitable, optionally gastric juice-resistant coatings, including concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, Lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, are used. Dyes or pigments can be added to the tablets or dragee coatings, for example for identification or for labeling different doses of active substance.
  • suitable, optionally gastric juice-resistant coatings including concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, Lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or
  • compositions which can be used orally are push-fit capsules made of gelatin, and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers, such as corn starch, binders and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.
  • Other oral forms of administration are e.g. Syrups prepared in the usual way, which e.g. in suspended form and in a concentration of about 5% to 20%, preferably about 10% or a similar concentration, e.g. when measuring 5 or 10 ml results in a suitable single dose.
  • Syrups prepared in the usual way, which e.g. in suspended form and in a concentration of about 5% to 20%, preferably about 10% or a similar concentration, e.g. when measuring 5 or 10 ml results in a suitable single dose.
  • the invention also relates to a method for the treatment of diseases in which, as has been described above, an excess of iron (III) or aluminum is present in the body, characterized in that a prophylactically or therapeutically effective amount of a compound of the formula I , preferably orally.
  • the pharmaceutical compositions mentioned above are primarily used, one being Warm-blooded animals of about 70 kg in weight are administered a daily dose of about 0.5 g to about 15 g, preferably from about 1.5 g to about 7.5 g, of a compound of the present invention.
  • Example 1 0.0 ', 0 "-Tri ⁇ ivaloyl-desferrioxamine B-hydrochloride.
  • a solution of 7.9 g (7.9 mmol) of N-tert-butoxycarbony1-0.0', 0" -tripivaloyl-desferrioxamine B in 80 ml of an anhydrous 0.5N solution of hydrogen chloride in methylene chloride are added to 80 ml of methylene chloride and the mixture is stirred at 22 ° for 2.5 hours.
  • the reaction mixture is diluted with 80 ml of ethyl acetate and largely concentrated in vacuo.
  • the starting material can be produced as follows:
  • N-tert-Butoxycarbony1-desferrioxamine B A suspension of 59.7 g (100 mmol) of desferrioxamine B hydrochloride in 900 ml of a mixture (v / v) of dioxane-water (2: 1) is mixed with 10.6 g (100 mmol) of anhydrous sodium carbonate and 26.6 ml (123 mmol) of di-tert-butyl dicarbonate were added and the mixture was stirred at 35-40 ° for 1.75 hours.
  • N-tert-Butoxycarbony1-0,0 ', 0 "-tripivaloyl-desferrioxamine B A solution of 9.9 g (15 mmol) of N-tert-butoxy-desferrioxamine B in 25 ml of absolute N, N-dimethylformamide and 8.9 ml (60 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene is mixed with 9.2 ml (75 mmol) of pivalic acid chloride at 0 ° and stirred for 4 hours at room temperature without further cooling is poured into a mixture of 300 ml of 0.3 molar aqueous dipotassium hydrogenphosphate solution and ethyl acetate with stirring.
  • Example 2 0.0 ', 0 "-triacetyl-desferrioxamine B-methanesulfonate.
  • the starting material can be produced as follows:
  • N-tert-butoxycarbonyl-desferrioxamine B (see Example 1a) is reacted with 7.5 mmol of acetyl chloride and the N-tert-butoxycarbonyl-0,0 ', 0 " -triacetyl-desferrioxamine B processed.
  • Thin layer chromatography (silica gel): R f : 0.40-0.45; Toluene-acetone (4: 6).
  • Example 3 0.0 ', 0 "-tribenzoyl-desferrioxamine B-hydrochloride
  • N-tert-butoxycarbonyl-0,0', 0" -tribenzoyl-desferrioxamine if the same equivalent amounts of N-tert-butoxycarbonyl-0,0', 0" -tribenzoyl-desferrioxamine are observed B reacted with hydrogen chloride and processed to the title compound above.
  • Thin layer chromatography sica gel: R f : 0.52-0.55; Chloroform-methanol (9: 1)
  • the starting material can be produced as follows:
  • N-tert-butoxycarbonyl-desferrioxamine B (see Example 1a) is reacted with 7.5 mmol of benzoyl chloride and to give N-tert-butoxycarbonyl-0,0 ', 0 "-tribenzoyl -Desferrioxamine B.
  • Thin layer chromatography (silica gel): R f : 0.40-0.45; toluene-acetone (4: 6).
  • Example 4 0.0 ', 0 "-trioctanoyl-desferrioxamine B-trifluoroacetate
  • the hydrochloride and the methanesulfonate of 0.0 ', 0 "-trioctanoyl-desferrioxamine B are obtained from the above-mentioned starting material with hydrogen chloride and with methanesulfonic acid.
  • the N-tert-butoxycarbonyl-0,0 ', 0 "- trioctanoyl-desferrioxamine B used as the starting material can be obtained as follows:
  • Example 5 Production of 1000 capsules with 260 mg of the active ingredient (e.g. 0.0 ', 0 "-trioctanol-desferrioxamine B) per capsule
  • the powdery substances are passed through a sieve with a mesh size of 0.6 mm and mixed thoroughly.
  • Each capsule filling machine uses 340 mg of this mixture to prepare gelatin capsules.
  • Example 6 Production of 1000 capsules containing 105 mg of the active ingredient (0.0 ', 0 "-Tri ⁇ ivaloyl-desferrioxarain B) per capsule
  • the ethyl cellulose and the stearic acid are dissolved in 120 ml of methylene chloride, the active ingredient is added, and the mass is passed through a sieve of 0.6 mm mesh size at a temperature of about 40 °, the methylene chloride evaporating. 111 mg of the granules obtained are filled into 0.5 ml gelatin capsules with the aid of a capsule filling machine.

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Abstract

Des desferrioxamines B de O,O',O''-triacyle ayant la formule (I), dans laquelle Ac1, Ac2 et Ac3 représentent indépendamment les uns des autres un acyle résiduel d'un acide carboxylique ayant entre 1 et 24 atomes de C, et leurs sels, peuvent être utilisés dans la thérapie de maladies liées à un excès de fer (III) ou d'aluminium dans le corps, par exemple l'hémochromatose et l'hémosidérose, voire la maladie d'Alzheimer. Ces composés peuvent être obtenus par des procédés analogiques courants, en clivant le groupe protecteur dans une composition correspondante avec un groupe amine protecteur en fin de chaîne.
PCT/CH1985/000174 1984-12-19 1985-12-13 Nouveaux derives d'acides o-acylhydroxamiques WO1986003745A1 (fr)

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Application Number Priority Date Filing Date Title
CH601584 1984-12-19
CH6015/84-0 1985-02-01

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WO1986003745A1 true WO1986003745A1 (fr) 1986-07-03

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JP (1) JPS62501146A (fr)
AU (1) AU5192086A (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0300966A3 (en) * 1987-07-23 1989-06-07 Ciba-Geigy Ag Process for the selective n-acylation of amino-hydraxamic and derivates and staiting compounds therefor
US4940811A (en) * 1986-12-09 1990-07-10 Ciba-Geigy Corporation N,N-disubstituted ureas and processes for their manufacture
WO1993000327A1 (fr) * 1991-06-30 1993-01-07 Yeda Research And Development Co., Ltd. Hydroxamates lineaires, leur preparation et compositions pharmaceutiques les comportant pour le traitement de la surcharge en fer et en aluminium

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1163337B (de) * 1960-10-11 1964-02-20 Ciba Geigy Verfahren zur Herstellung von Trihydroxamsaeuren

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1163337B (de) * 1960-10-11 1964-02-20 Ciba Geigy Verfahren zur Herstellung von Trihydroxamsaeuren

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4940811A (en) * 1986-12-09 1990-07-10 Ciba-Geigy Corporation N,N-disubstituted ureas and processes for their manufacture
EP0300966A3 (en) * 1987-07-23 1989-06-07 Ciba-Geigy Ag Process for the selective n-acylation of amino-hydraxamic and derivates and staiting compounds therefor
US4954634A (en) * 1987-07-23 1990-09-04 Ciba-Geigy Corporation Process for the selective N-acylation of aminohydroxamic acid derivatives and starting materials used therein
WO1993000327A1 (fr) * 1991-06-30 1993-01-07 Yeda Research And Development Co., Ltd. Hydroxamates lineaires, leur preparation et compositions pharmaceutiques les comportant pour le traitement de la surcharge en fer et en aluminium

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EP0205481A1 (fr) 1986-12-30
DD244976A5 (de) 1987-04-22
AU5192086A (en) 1986-07-22
JPS62501146A (ja) 1987-05-07

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