TW201302191A - Fe(III) complex compounds for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anemias - Google Patents

Abstract

The invention relates to iron(III) complex compounds and pharmaceutical compositions comprising them for the use in the treatment and/or prophylaxis of iron deficiency symptoms and iron deficiency anemias.

Description

Fe(III) compound for the treatment and prevention of iron deficiency symptoms and iron deficiency anemia Field of invention Introduction:

The present invention relates to an iron(III)-2,4-dioxy-1-carbonyl(iron(III)-2,4-dioxo-1-carbonyl) compound which is used or administered as a medicament, respectively, and contains the same Pharmaceutical composition, which is particularly useful for the treatment and/or prevention of iron deficiency symptoms and iron deficiency anemia

Background of the invention

Iron is an essential trace element for almost all organisms and is particularly relevant for growth and blood formation. The balance of iron metabolism is mainly adjusted in the iron recovery level of hemoglobin of aged red blood cells and the absorption of iron duodenum in the diet. The released iron is absorbed through the intestine, in particular via a special transport system (DMT-1, transferrin, transferrin, transferrin receptor), transported into the circulation and thereby transported to appropriate tissues and organs. Inside.

In the human body, iron is important for oxygen transport, oxygen uptake, cellular function (eg, mitochondrial electron transport), and finally for overall energy metabolism.

The human body contains an average of 4 to 5 grams of iron, which is found in enzymes, heme and myoglobin, and stores or preserves iron in the form of ferritin and hemosiderin.

About half of this iron (about 2 grams) is a heme bound to red blood cells. The heme iron is present. Because these red blood cells have only a limited life span (75-150 days), the new born ones need to be continuously formed, and the old ones are removed (more than 2 million red blood cells per second are formed). This high regenerative capacity is achieved by macrophages, which phagocytize the aged red blood cells, dissolve them, and thus circulate the iron obtained for iron metabolism. The approximately 25 mg of iron required for daily red blood cell production thus provides the major portion.

The daily iron requirement for adults is between 0.5 and 1.5 mg per day, and young children and pregnant women need 2 to 5 mg of iron per day. Daily iron loss (for example, due to desquamation of skin cells and epithelial cells) is less; increased iron loss occurs, for example, in women during menstrual bleeding. In general, blood loss can significantly reduce the iron level because about 1 mg of iron is lost per 2 ml of blood. For healthy human adults, approximately 1 mg of normal daily iron loss is usually replaced by daily food intake. The iron level is regulated by absorption, and the absorption rate of iron present in food is between 6 and 12%; in the case of iron deficiency, the absorption rate is up to 25%. The rate of absorption is regulated by the organism depending on the iron demand and the iron reserve specification. In this process, human organisms use both bivalent and trivalent iron ions. The iron (III) compound is dissolved in the stomach of a pH sufficient for acid and is thus resorbable. The reabsorption of iron is carried out by mucosal cells in the upper small intestine. In this process, trivalent non-heme iron is firstly, for example, reduced to Fe(II) in the intestinal cell membrane by high-iron reductase (membrane-bound duodenal cytochrome b) for absorption, so that it can be The protein DMT1 (divalent metal transporter 1) is transported and transported into intestinal cells. In contrast, heme iron passes through the cell membrane unchanged into the intestinal cells. In intestinal cells, iron is stored in ferritin as stored iron, or released into the blood by transporting protein transferrin. Hepcidin plays a decisive role in this process because it is the most important regulator of iron absorption. The ferric iron transported to the blood by transferrin is converted into ferric iron by oxidase (blue cytosolic, ferrous iron oxide), which is transported to the organism by transferrin. Relevant location in the body (see for example: "Baltric acts:molecular control of mammalian iron metabolism". MWHentze, Cell 117, 2004 , 285-297).

Mammalian organisms are unable to actively excrete iron. Iron metabolism is essentially controlled by the release of hepcidin from macrophages, hepatocytes and intestinal cells via iron cells.

In pathological conditions, a reduced level of serum iron results in reduced hemoglobin content, reduced red blood cell production, and thus anemia.

External syndromes of anemia include fatigue, paleness, and reduced concentration. Clinical syndromes of anemia include low serum iron levels (low blood iron levels), low hemoglobin levels, low hematocrit levels, and reduced red blood cell counts, reduced reticulocytes, and increased soluble transferrin receptor levels. quasi.

Iron deficiency symptoms or iron anemia are treated by supplying iron. In this case, iron replacement occurs by oral administration or by intravenous administration of iron. Furthermore, in order to promote the formation of red blood cells, erythrocyte auxin and other substances that stimulate red blood cell production can also be used to treat anemia.

Anemia can often be traced back to nutritional habits that are malnourished or low-iron diets or iron imbalances. In addition, anemia also occurs due to reduced or poor iron absorption, for example, due to gastrectomy or diseases such as Crohn's disease. Also, iron deficiency can occur as a result of a large increase in blood loss. For example, because of injury, strong menstrual bleeding or blood donation. Furthermore, the increased iron demand for adolescent and child growth and pregnant women is known. Because iron deficiency not only leads to reduced red blood cell formation, but also to poor oxygen supply to the organism, which can lead to the above-mentioned syndromes, such as fatigue, paleness and low concentration, and especially among adolescents, leading to long-term cognitive development. Negative effects, a highly effective and well tolerated therapy, are of particular interest.

By using the Fe(III) complex compound according to the present invention, the possibility of iron deficiency symptoms and iron deficiency anemia can be effectively treated by oral administration without receiving the large side effects of the classical preparation, Fe(II) Iron salts, such as FeSO ₄ , which are caused by oxidative stress, are present. Thus avoiding poor compliance, which is often the cause of the elimination of disadvantages of iron deficiency conditions.

Previous skills:

Iron-missing compounds for the treatment of iron deficiency diseases are known in the prior art.

A very large proportion of such mis-synthesized compounds consist of a polymer structure. Most of these compounds are in the field of iron-polysaccharide complex compounds (WO20081455586, WO2007062546, WO20040437865, US2003236224, EP150085). It is indeed available from the market (eg Maltofer, Venofer, Ferinject, Dexferrum, Ferumoxytol).

Another group of most polymeric miscible compounds comprises iron-peptide mismatch compounds (CN101481404, EP939083, JP02083400).

Also described in the literature are Fe-missing compounds which are structurally derived from macromolecules such as heme, chlorophyll, curcumin and heparin (US474670, CN1687089, Biometals, 2009, 22, 701-710).

In addition, low molecular Fe complex compounds are also described in the literature. A large number of such Fe-missing compounds contain a carboxylic acid and an amino acid as a ligand. In this case, the focus is on aspartic acid (US2009035385) and citric acid (EP308362) as ligands. Amphetamine group Fe-described compounds containing a derivative as a ligand are also described herein (ES2044777).

Hydroxypyrone and hydroxypyridone Fe complex compounds are also described in the literature (EP159194, EP138420, EP107458). In a literature similar thereto (WO2006037449), the corresponding hydroxyfuranone Fe-described compound of the 5-ring system is also illustrated.

Hydroxypyrone and hydroxypyridone Fe complex compounds are also described in the literature (EP159194, EP138420, EP107458). In a literature similar thereto (WO2006037449), the corresponding hydroxyfuranone Fe-described compound of the 5-ring system is also illustrated.

Iron (III)-2,4-dioxy-1-carbonyl fused compound (JP-A-05271157 (JP 199270884), JP-A-04221391 (JP 199186727)) is also described in this patent document. The synthesis of several iron complexes is described in these patents, the patent application being directed solely to the problem of synthesis. There is no information on possible drug applications.

US-A-20060134227 discloses an iron-containing dietary supplement composition. As one of the iron compounds mentioned in the various compounds, an unspecified "acetylacetone iron complex salt" (Application No. 13). It is exactly which compound is still unknown. Various (acetylpyruvate) compounds are known. In addition to iron (II)-(acetylpyruvate) 2 (CAS 14024-17-0), the iron (III)-(acetylpyruvate) 3 is known, and its synthesis has also been disclosed, for example in Chaudhuri Mihir K ET AL: "Tri (acetylacetonato) iron (III) Novel synthesis method", JOURNAL OF THE CHEMICAL SOCIETY. DALTON TRANSACTIONS, ROYAL SOCIETY OF CHEMISTRY, 1 January 1983 (1983-01-01), pages 839-840, XP009150815, ISSN: 0300-9246. This compound has been validated in animal experiments, but the compound is very toxic (London, JE, Smith, DM, Preliminary toxicological study of ferric acetoacetate Report (1983) (LA-9627-MS, Order No. DE83007117), 7 pp. CAN 99:48652.AN 1983:448652 CAPLUS)), which appears to be currently not implemented in the human body for the treatment of iron deficiency anemia. The iron (acetamidine pyruvate) compound is a ß-diketone compound, but it has no additional carbonyl group at a position immediately adjacent to the ß-diketone structure. This is therefore not an iron (III)-2,4-dioxy-1-carbonyl conjugate compound as provided by the present invention.

WO 2005/074 899 A2 discloses salts of various quinoline compounds in which iron salts are also present. The structure of the salt is not shown. The salt form is the quinoline compound which is used for a long period of time to represent a pharmaceutically active ingredient. The quinoline compound is a treatment used in autoimmune diseases (U.S. 6,121,287). Further, the quinoline compound is not a 2,4-dioxy-1-carbonyl compound, and thus this is not a user as a complex ligand as in the present invention. Also, M Fiallo: "Metalanthracycline complexes as a new class of anthracycline derivatives", (Inorganica Chimica Acta, Vol 137, No. 1-2, 1 July 1987 (1987-07-01), pages 119-121, XP55003467, ISSN: 0020-1693, DOI: 10.1016/S0020-1693 (00) 87129-7) shows non-ferrous (III)-2,4-dioxy 1-carbonyl carbonyl compound and its use for the treatment of iron deficiency.

Further, an iron-cyclopentadienyl compound is also described in the document GB842637.

In addition, 1-hydroxy-4,6-dimethyl-2(1H)-pyrimidinone as a Fe(III) ligand is described in the literature as a Fe(III) ligand (Bull.Chem.Soc.Jpn) ., 66, 841-841 (1993)). It is recommended to use this as a chelating agent compound for the treatment of iron excess.

Iron salts (such as iron (II) sulfate, iron (II) butyrate, chloride (III), iron (II) aspartate, iron (II) succinate) are used to treat iron deficiency symptoms and Another important component of iron deficiency anemia.

These iron salts are extremely problematic because they are highly intolerant (up to 50%) in nausea, vomiting, diarrhea, and constipation and enthusiasm. Furthermore, free iron (II) ions that catalyze the formation of reactive oxygen species (ROS), especially the Fenton reaction, occur during the use of such iron (II) salts. These ROS cause damage to DNA, lipids, proteins and carbohydrates, which have profound effects on cells, tissues and organs. This problematic complex is known and is primarily believed in the literature to be responsible for the high degree of intolerance and is referred to as oxidative stress.

Iron(III)-2,4-dioxy-1-carbonyl fused compounds have not been mentioned in the prior art as a use for the treatment and/or prevention of iron deficiency symptoms and iron deficiency anemia.

Summary of invention Purpose of the invention:

The object of the present invention is to develop a novel therapeutically effective compound which can be used in an effective treatment for oral therapy which is preferably iron deficiency symptoms and iron deficiency anemia. In this case, these iron complexes are believed to exhibit significantly less side effects than the classically used Fe(II) salts. Furthermore, such iron complexes, if possible, should have a defined structure (stoichiometry) if possible and can be prepared by simple synthesis methods. Ultimately, the iron-missing compound should have very low toxicity and thus can be administered in very high doses. This goal is achieved by the development of novel Fe(III) complex compounds.

Furthermore, the new iron complex should be absorbed directly into the intestinal cells via the intestinal membrane so that the iron bound by its complex is directly released to ferritin or transferrin or the original complex is directly reached. blood. Because of their nature, these novel complexes should not actually cause high concentrations of free iron ions to appear. Because the free iron ions that cause ROS are the cause of the final side effects.

In order to be able to meet these necessary conditions, the inventors have developed new Fe(III) complex compounds which have a relatively small molecular weight, a medium lipophila and an optimum complex stability.

The inventors have surprisingly found that Fe(III) complex compounds having a 2,4-dioxy-1-carbonyl ligand are particularly suitable for use in the above requirements. This system may use To demonstrate that these Fe-missing compounds have high iron absorption, the success of rapid treatment for the treatment of iron deficiency anemia can be achieved. In particular, the compound of the present invention has a faster and higher utilization ratio than the iron salt. In addition, these new systems have significantly reduced side effects compared to the classically used iron salts, as there are noteworthy free irons in this case. The compounded compound of the present invention has almost no oxidative pressure because no free radicals are formed. Therefore, the mismatched compound of the present invention has significantly fewer side effects than the case of the Fe salt known in the prior art. The miscible compound has good stability and good solubility at various pH ranges. Furthermore, the iron-missing compound has very low toxicity and can therefore be administered in high doses without side effects. Finally, the compounded compound can be successfully prepared and is optimally suited for use in pharmaceutical compositions, particularly for oral administration.

Accordingly, the present invention is directed to an iron(III)-2,4-dioxy-1-carbonyl conjugate compound for use or administration thereof for the treatment and prevention of iron deficiency symptoms and iron deficiency anemia, or a pharmaceutically acceptable compound thereof Accepted salts, each acting as a drug or - synonymous - used in therapeutic treatment of humans.

The iron(III)-2,4-dioxy-1-carbonyl conjugate compound used in the present invention particularly comprises a compound comprising the following structural components: Or its resonant structure A substituent that saturates the free valence, and the arrows each represent a coordinate bond to the iron atom.

The oxygen atoms (or each of the carbon atoms bonded to the oxygen atom) are thus each at the 1-, 2-, and 4-positions, wherein the oxygen atoms at the 2- and 4-positions are bonded to the 1-carbonyl group. Iron atom , although the de facto ligand is caused by the following corresponding enols:

(Because of the C=C double bond, the enol form can exhibit geometric isomers (cis/trans or E/Z)). This corresponding tautomerism is discussed in more detail below.

The 2,4-dioxy-1-carbonyl ligand below is also referred to as a 2,4-dioxycarbonyl ligand because the carbonyl group, which is usually in the basic structure of the ligand, is automatically assigned to The 1-position. In the context of the present invention, the terms "2,4-dioxy-1-carbonyl ligand" and "2,4-dioxycarbonyl ligand" are used synonymously or interchangeably.

The basic structure of the 2,4-dioxy-1-carbonyl ligand and the 2,4-dioxycarbonyl ligand according to IUPAC:

It is called 2-oxysuccinaldehyde (the enol form shown previously will therefore be each 2-hydroxybut-2-enedionaldehyde and 4-hydroxy-2-oxy-but-3-enal) . At this angle, the 2,4-dioxycarbonyl- and 2,4-dioxy-1-carbonyl ligands are each (optionally substituted) 2-oxysuccinaldehyde ligands. (formaldehyde form) or (optionally substituted) 2-hydroxybut-2-enedialdehyde ligand, and (optionally substituted) 4-hydroxy-2-oxy-but-3 - alkenyl ligand (enol form) which is in a deprotonated form during the mismatch (see description below).

For the sake of clarity, it should be noted that the numbering of carbon atoms positions the carbonyl group in the butane structure, which is selected for each of the 2,4-dioxy-1-carbonyl ligands or the 2,4-diox. A carbonyl group, and "1, 2, 4" is based on the basic structure. Depending on the R ₁ , R ₂ and R ₃ substituents, it is possible that the IUPAC chemical nomenclature will be given different numbers. Irrespective of this, and in this case as well, there are still 2,4-dioxy-1-carbonyl ligands or 2,4-dioxycarbonyl ligands within the definition of the invention. This is a well-characteristic feature of the ligand in the corresponding basic butane structure, wherein the two oxy groups are on the immediately adjacent carbon atom and one oxy group is in the ß-position for them.

After formally removing each of the 2,4-dioxycarbonyl ligands and one of the 2,4-dioxy-1-carbonyl ligands, a negative charge is thus present in the complex. Correspondingly, the iron of each ligand has a positive charge (ie, the metal has a +3 oxidation state in the form of three 2,4-dioxycarbonyl ligands or (III)). It is a matter of ordinary skill in the relevant art to further understand that the delocalization of the electron occurs in the 2,4-dioxycarbonyl ligand.

The invention also includes iron (III) 2,4-dioxycarbonyl fused compounds wherein the 2,4-dioxycarbonyl ligand forms a bridge between different iron atoms:

Particularly preferred in the present invention is a bidentate iron (III) 2,4-dioxycarbonyl ligand wherein the bond to the iron atom is produced via two oxygen atoms of the 2,4-dioxycarbonyl moiety. The present invention certainly includes a higher number of 2,4-dioxycarbonyl ligands, such as 2,4-dioxycarbonyl ligands of 3, 4, 5 or 6 teeth, but prefers their higher Mismatched stability (clamping effect), because the high misalignment stability may be insufficient for iron released in the body. Higher number of 2,4-dioxycarbonyl ligands, especially those having an additional functional group outside the two oxygen atoms of the 2,4-dioxycarbonyl group, such as a similar formula ( The additional carbonyl group of I), or which may be present in the substituents R ₁ to R ₃ as shown below. This may be, for example, an oxygen or nitrogen-containing functional group such as a hydroxyl group or an amine group.

The iron (III) 2,4-dioxycarbonyl-based compound of the present invention comprises, in particular, those compounds which contain at least one, preferably a 2,4-dioxycarbonyl ligand of a double tooth, i.e. as above The one shown is bonded to one or two iron atoms.

Preferably, it comprises only iron (III) 2,4-dioxycarbonyl conjugated compounds which are preferably the same or different bidentate 2,4-dioxycarbonyl ligands.

Particularly preferred is the same preferred double-dentate 2,4-dioxycarbonyl coordination A group of iron (III) 2,4-dioxycarbonyl miscible compounds.

The present invention however also includes those compounds having one or more (e.g., two or three) other identical or different monodentate or polydentate ligands other than the 2,4-dioxycarbonyl ligand, which Monodentate or polydentate ligands such as carboxylic acid or carboxylate ligands (R-COOH or RCOO-), alcohol-ligands (R-OH), such as carbohydrate ligands, primary or secondary amine groups Ligand (R-NH ₂ , R-NHR), amine ligand (R=NH), ruthenium ligand (R=N-OH), hydroxy ligand (OH or H ₂ O), ether a terminal group or a halogen ligand. These complexes may also be present as intermediates in the decomposition of the human body, particularly in aqueous solution, and then selectively present as a coordinating unsaturated intermediate.

In the iron(III)-2,4-dioxycarbonyl-based compound of the present invention, the coordination number of the iron atom is usually six (6), and the coordination atoms are usually arranged in an octahedron.

Furthermore, the invention includes the presence of one or more (e.g., 2, 3 or 4) iron atoms in a mono- or polynuclear iron (III)-2,4-dioxycarbonyl-based compound. Preferred, however, is a mononuclear iron (III)-2,4-dioxycarbonyl miscible compound having a central iron atom.

Usually, there are 1-4 iron atoms and 2-10 ligands in the iron(III)-2,4-dioxycarbonyl-based compound. Preferred is a mononuclear iron(III)-2,4-dioxycarbonyl group having at least 1, preferably 3, preferably a bis-coordinate pyrimidine-2-ol-1-oxyl ligand. Compound.

The iron (III)-2,4-dioxycarbonyl-based compound is present in a neutralized form. However, it also contains a salt of iron (III)-2,4-dioxycarbonyl-based compound, wherein the complex has a neutralized positive or negative charge, in particular by pharmaceutically compatible Anion that is essentially non-coordinating (for example, especially Such as a halide of chlorine or a cation (for example, especially an alkali or alkaline earth metal ion).

Preferably, the iron (III)-2,4-dioxycarbonyl conjugate compound has a molecular weight of less than 1000 g/mol, more preferably less than 800 g/mol (calculated by structural formula).

Particularly preferably, the iron(III)-2,4-dioxycarbonyl-based compound of the present invention comprises at least one of the ligands of formula (I):

Wherein each arrow represents a coordinate bond to one or a different iron atom, and R ₁ is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkoxy group, and an optionally substituted alkoxycarbonyl group. a group, R ₂ is selected from the group consisting of hydrogen, an optionally substituted alkyl group and a halogen, or R ₁ and R ₂ together with a carbon atom to which it is attached, represents an optionally substituted 5- or 6 - membered ring, which may optionally contain one or more hetero atoms, R ₃ is selected from consisting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino group and a hydroxyl group, or It is a pharmaceutically acceptable salt thereof.

Particularly preferred in the present invention is an iron (III)-2,4-dioxycarbonyl-substituted compound comprising at least one of the formula (I) wherein R ₃ is selected from an optionally substituted amine group.

A particular preferred embodiment of the invention is further characterized by an iron(III)-2,4-dioxycarbonyl conjugate compound containing at least one ligand of formula (I):

Wherein each arrow represents a coordinate bond to one or several iron atoms, and R ₁ is selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkoxy group, and an optionally substituted alkoxycarbonyl group. a group, R ₂ is selected from an alkyl group substituted by hydrogen or optionally, or R ₁ and R ₂ together with a carbon atom to which they are attached form an optionally substituted 5- or 6-membered ring, which may optionally containing one or more hetero atoms, R ₃ is selected from consisting of optionally substituted alkoxy, optionally substituted amino group and a hydroxyl group, or its pharmaceutically acceptable salts.

In the context of the present invention, the optionally substituted alkyl group (especially the R ₁ to R ₃ substituent) preferably comprises a linear or branched alkyl group having from 1 to 8, preferably 1 a 6-carbon atom; a cycloalkyl group having 3 to 8, preferably 5 or 6 carbon atoms; or an alkyl group having 1 to 4 carbon atoms, which is substituted by an alkyl group; wherein the alkyl group Selectively substituted.

The above alkyl group is preferably unsubstituted or substituted with 1 to 3 substituents.

The substituents of such alkyl groups are preferably selected from the group consisting of hydroxyl groups, especially the optionally substituted aromatic groups as defined below, especially the optionally substituted heteroaryl groups as defined below, An optionally substituted alkoxy group, especially an optionally substituted alkoxycarbonyl group, as defined below, especially an optionally substituted fluorenyl group, as defined below, especially a halogen as defined below, An optionally substituted amine group, particularly an optionally substituted aminocarbonyl group, as defined below. Particularly preferred substituents on the alkyl group are a hydroxyl group, a halogen, an alkoxy group, an alkoxycarbonyl group and an aminocarbonyl group.

As used herein and in the context of the present invention, the halogen comprises fluorine, chlorine, bromine and iodine, preferably fluorine.

The alkyl group optionally having one or more, more preferably 1 to 3 carbon atoms as defined above may be further substituted with a similar hetero group comprising nitrogen, oxygen or sulfur. This means that especially in the alkyl groups, for example one or more, preferably 1 to 3, and still more preferably one (1) mestenyl (-CH ₂ -) can be - NH-, -NR ₄ -, -O- or -S-substituted, wherein R ₄ is an optionally substituted alkyl group as defined above, preferably having 1 to 3 substituents such as fluorine, chlorine, hydroxyl, alkane Oxyl, alkyl (such as methyl, ethyl or i-propyl).

Examples of the alkyl residue having 1 to 8 carbon atoms include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl Base, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, 2-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethyl Butyl, 3,3-dimethylbutyl, 1-ethyl-methylpropyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl , 4-ethylpentyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1- Propyl butyl, n-octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl Base, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 5-ethylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-Dimethylhexyl, 4,4-dimethylhexyl, 5,5-dimethylhexyl, 1-propylpentyl, 2-propylpentyl, and the like. It is preferably one having 1 to 5 carbon atoms. Most preferred are methyl, ethyl, n-propyl and isopropyl.

A preferred example of the alkyl group produced by substituting one or more similar hetero groups (e.g., -O-, -S-, -NH- or -N(R4)-) is when an ether group is formed (e.g., methoxy) When methyl, ethoxymethyl, 2-methoxyethyl or the like is used, one or more of the alkenyl groups (-CH ₂ -) are substituted by -O-. Thus, the definition of alkyl includes an alkoxyalkyl group as defined below which is derived from the above alkyl group by the substitution of -O-. If the alkoxy group of the invention may additionally be an alkyl substituent, several ether groups may also be formed in this case (for example, -CH ₂ -O-CH ₂ -OCH ₃ - group). Thus, the polyether groups of the present invention may also be encompassed by the definition of alkyl groups. It is preferred that the alkyl group of the present invention is not substituted by a one or more similar heteroaryl groups (e.g., -O-, -S-, -NH- or -N(R ₄ )-)--CH ₂ - group produced.

The cycloalkyl group having 3 to 8 carbon atoms preferably contains a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like. Preferred are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be selectively Substituted with 1 to 2 substituents.

The definition of an optionally substituted alkyl group may also include an alkyl group substituted with a cycloalkyl group as described above, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

The heterocyclylalkyl group of the present invention is preferably formed by substituting a cycloalkyl-substituted methylene with a similar hetero group, and comprises, for example, a saturated 5 or 6-membered heterocyclic residue, the 5 or 6-membered heterocyclic residue The substituent is attached by a carbon atom or a nitrogen atom and preferably has 1 to 3, preferably 2, heteroatoms (particularly O, N), for example: tetrahydrofuran; tetrahydroindol-1-yl; substituted Tetrahydroanthracene, such as 3-hydroxyazetidine; tetrahydropyrrole, such as tetrahydropyrrolyl-1-yl; substituted pyrrolidinyl, such as 3-hydroxypyrrolidin-1-yl, 2-hydroxypyrrole Pyridin-1-yl, 2-methoxycarbonylpyrrolidin-1-yl, 2-ethoxycarbonylpyrrolidin-1-yl, 2-methoxypyrrolidin-1-yl, 2-ethoxypyrrole Pyridin-1-yl, 3-methoxycarbonylpyrrolidin-1-yl, 3-ethoxycarbonylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, 3-ethoxypyrrole Pyridin-1-yl; piperidinyl, for example piperidin-1-yl, piperidin-4-yl, substituted piperidinyl, for example 4-methyl-1-piperidinyl, 4-hydroxy-1- Piperidinyl, 4-methoxy-1-piperidinyl, 4-ethoxy-1-piperidinyl, 4-methoxycarbonyl-1-piperidinyl, 4-ethoxycarbonyl-1- Piperidinyl, 4-carboxy-1- Pyridyl, 4-ethenyl-1-piperidinyl, 4-methylindol-1-piperidinyl, 1-methyl-4-piperidinyl, 4-hydroxy-2,2,6,6- Tetramethyl-1-piperidinyl, 4-(dimethylamino)-1-piperidinyl, 4-(diethylamino)-1-piperidinyl, 4-amino-1-piper Pyridyl, 2-(hydroxymethyl)-1-piperidinyl, 3-(hydroxymethyl)-1-piperidinyl, 4-(hydroxymethyl)-1-piperidinyl, 2-hydroxy-1 - piperidinyl, 3-hydroxy-1-piperidinyl, 4-hydroxy-1-piperidinyl, morpholin-4-yl; substituted morpholinyl, for example 2,6-dimethylmorpholine 4- Piperazine, such as piperazin-1-yl; substituted piperazine, such as 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-ethoxycarbonylpiperazine a 1-yl group, a 4-methoxycarbonylpiperazin-1-yl group; or a tetrahydropyranyl group, such as a tetrahydropyran-4-yl group, which is optionally condensed with an aromatic ring, and which is The substituent is optionally substituted, for example, with 1 to 2 substituents such as a hydroxyl group, a halogen, a C1 to C6 alkyl group or the like. The definition of a selectively substituted alkyl group thus also includes an alkyl group substituted with a heterocyclic group as defined above, such as 3-(1-piperidinyl)propyl, 3-pyrrolidin-1-yl. Propyl, 3-morpholinylpropyl, 2-morpholinylethyl, 2-tetrahydropyran-4-ylethyl, 3-tetrahydropyran-4-ylpropyl, 3-(tetrahydrogen)吖唉-1-yl)propyl and the like.

Examples of a linear or branched alkyl group substituted with a halogen and having 1 to 8 (preferably 1 to 6) carbon atoms include: monofluoromethyl, difluoromethyl, trifluoromethyl Base, monochloromethyl, monochloromethyl, monotrichloromethyl, monobromomethyl, monodibromomethyl, tribromomethyl, mono-1-fluoroethyl, mono-1-chloroethyl, 1-Br-ethyl, 1-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,2-difluoroethyl, 1,2-dichloroethyl, one , 2-dibromoethyl, a 2,2,2-trifluoroethyl, a heptafluoroethyl, a 1-fluoropropyl, a 1-chloropropyl, a 1-bromopropyl, a 2- Fluoropropyl, 1-chloropropyl, 2-bromopropyl, 1-trifluoropropyl, 1-chloropropyl, 1-bromopropyl, 1-,2-difluoropropyl, one 1,2-dichloropropyl, 1,2-dibromopropyl, a 2,3-difluoropropyl, 2,3-dichloropropyl, a 2,3-dibromopropyl, a 3 , 3,3-trifluoropropyl, a 2,2,3,3,3-pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a 4- Fluoryl butyl, mono-4-chlorobutyl, mono-4-bromobutyl, a 4,4,4-trifluorobutyl, a 2,2,3,3,4,4,4-heptafluorobutyl, a perfluorobutyl group, a 2- Fluoryl, 1-chloropentyl, 2-bromopentyl, 5-pentylpentyl, 5-chloropentyl, 5-pentabromopentyl, monoperfluoropentyl, 2-fluorohexyl , 2-chlorohexyl, 2-bromohexyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, monofluorohexyl, 1-fluoroheptyl, 2-chloroheptyl, A 2-bromoheptyl group, a 7-fluoroheptyl group, a 7-chloroheptyl group, a 7-bromoheptyl group, a perfluoroheptyl group and the like.

Examples of the alkyl group substituted with a hydroxyl group include the above alkyl residue having 1 to 3 hydroxyl residues such as a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, and a 4-hydroxybutyl group. Wait.

The selectively substituted aryl group preferably contains 6 to 14 carbon atoms (no hetero atom in the cyclic aromatic ring system) according to the invention, for example, phenyl, naphthyl, phenanthryl, and anthracenyl. In each of the cases as explained above or below, the aforementioned aromatic group may preferably have one or more, preferably one substituent, particularly a halogen, a hydroxyl group, an alkyl group, an alkoxy group.

The selectively substituted aryl group according to the invention further comprises a selectively substituted heteroaryl group, i.e., a heteroaromatic group such as pyridinyl, pyridyl-N-oxide, pyrimidinyl, indole Base Base, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, anthracene Base, fluorenyl, benzo[b]thienyl, benzo[b]furanyl, oxazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl. It is preferably a 5- or 6-membered aromatic heterocyclic ring such as pyridyl, pyridyl-N-oxide, pyrimidinyl or anthracene. a base, a furyl group, and a thienyl group. In each case as explained above or as follows, the aforementioned heteroaromatic group may preferably have one or more, preferably one, a substituent, especially a halogen, a hydroxyl group, an alkyl group, an alkoxy group. Preferred examples of the alkyl (heteroarylalkyl) group substituted with a heteroaromatic group are methyl, ethyl or propyl substituted with a heteroaromatic group in each case, such as thiophene. Methyl, pyridylmethyl and the like.

According to the invention, the optionally substituted alkoxy group (RO-) comprises, for example, a linear or branched alkoxy group having up to 6 carbon atoms, such as monomethoxy, monoethoxy, a positive Propyloxy, monoisopropoxy, n-butoxy, monoisobutoxy, a second butoxy, a third butoxy, a n-pentyloxy, an isopentyloxy, a first Dipentyloxy, a third pentyloxy group, a 2-methylbutoxy group, a n-hexyloxy group, a monohexyloxy group, a third hexyloxy group, a second hexyloxy group, a 2-methyl group Pentyloxy, 3-methylpentyloxy, mono-1-ethylbutoxy, mono-2-ethylbutoxy, mono-1,1-dimethylbutoxy, a 2,2-dimethyl Butyloxy, -3,3-dimethylbutoxy, 1-ethyl-1-methylpropoxy, and the like. Monomethoxy, monoethoxy, mono-n-propoxy, mono-isopropoxy, mono-n-butoxy, mono-isobutoxy, a second butoxy, a third butoxy good. The alkoxy group may be optionally substituted with, for example, a substitutable group as described above for an alkyl group.

A preferred alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or a n-butoxy group.

The optionally substituted alkoxycarbonyl (RO-CO-) group is formally added by the above alkyl group to form an optionally substituted alkoxycarbonyl residue by adding an -OC(O) - derived from residues. In this regard, reference may be made to the definition of the alkyl group described above. Alternatively, an optionally substituted alkoxycarbonyl (RO-CO-) group is derived from the alkoxy group described above by the addition of a carbonyl group. Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, tert-butyloxycarbonyl, etc. Preferred alkoxycarbonyl groups, and the like, may all be substituted with an alkyl group as defined above.

The optionally substituted amine group according to the present invention preferably comprises an amine group (-NH ₂ ), an optionally substituted mono- or dialkylamino group (RHN-, (R) ₂ N), wherein The definition of the alkyl group can be referred to the above definition. Further comprising an optionally substituted mono- or diarylamino radical or a mixed optionally substituted alkylarylamino radical, wherein the definition of the optionally substituted alkyl or aryl group can be referred to the above definition. Further included are the optionally substituted mono or diarylamine groups, and the definitions of the optionally substituted alkyl or aryl groups can be referred to the above definitions.

Particularly in the definition of R ₃ , preferably at least one hydrogen atom, preferably two hydrogen atoms in the amine group (-NH ₂ ) are substituted. Particularly preferred in the definition of R ₃ is an optionally substituted amine-based optionally substituted mono- or diarylamine group (RHN-, (R) ₂ N-), especially the optionally substituted amine group. As defined above, it has up to 12 carbon atoms, or a cyclic amine group, wherein the nitrogen atom is a ring atom of a cyclic amine preferably having up to 6 ring carbon atoms as described below.

The alkyl or aryl group of the above substituted amino group may, for example, carry 1 to 3 substituents, such as, for example, a group of possible substituents selected from the above alkyl groups, such as a hydroxyl group, especially as defined above. Optionally substituted aryl, optionally substituted heteroaryl as defined above, especially an optionally substituted alkoxy group as defined above, especially an optionally substituted alkoxycarbonyl group as defined above, in particular An optionally substituted indenyl group, as defined above, in particular a halogen as defined above, in particular an optionally substituted amine group as defined below, in particular an optionally substituted amine carbonyl as defined below base. Particularly preferred substituents on the alkyl group are the hydroxy, halo, alkoxy, alkoxycarbonyl and aminocarbonyl groups as described above, respectively.

The cyclic amine group may also be substituted with 1 to 3 substituents as described above, wherein the cyclic amine group may be related to the substituent of the alkyl group of the above-mentioned amine group.

The amine groups include, for example, an unsubstituted amine group (-NH ₂ ), a methylamino group, a dimethylamino group, an ethylamino group such as 2-hydroxyethylamino group, N-(hydroxyethyl group). a hydroxyethylamine group such as -N-methylamino group, diethylamino group, phenylamino group or methylphenylamino group. The optionally substituted amine group further comprises an optionally substituted cyclic amine group such as a 5 or 6 membered cyclic amine group containing an additional optionally substituted hetero atom such as N, O, S (preferably O). Examples of the cyclic amine group include the above nitrogen-containing heterocyclic group bonded through a nitrogen, for example, piperidin-1-yl; 4-hydroxy-piperidin-1-yl; 4-alkoxy-piperidin-1-yl; , such as 4-methoxypiperidin-1-yl, piperazinyl, 4-methylpiperazinyl, 2-(methoxycarbonyl)pyrrolidin-1-yl, pyrrolidin-1-yl, morpholine Base-4-yl and the like.

Preferred optionally substituted amine groups in the definition of R ₃ are, in particular, an amine group (-NH ₂ ); an optionally substituted mono- or dialkylamino group, wherein the alkyl group may, for example, be substituted with a hydroxy group, in particular such as Dimethylamino, N-(hydroxyethyl)-N-methylamino; and ring, preferably 5 or 6 member, more preferably 6 membered cyclic amine, such as piperidino, pyrrole Pyrrolidino and morpholinyl, for example, substituted with an alkoxy group, such as 4-methoxypiperidin-1-yl.

In the context of the present invention, an optionally substituted indenyl group comprises an aliphatic and an aromatic mercapto group, wherein the aliphatic indenyl group is in particular a indenyl group and an optionally substituted alkylcarbonyl group, wherein the optionally substituted alkyl group Refer to the definition above. An aromatic quinone gene comprising an optionally substituted arylcarbonyl group, wherein With regard to the optionally substituted aryl group, reference is made to the above definition. Preferred aryl groups according to the invention are, for example, indolyl (-C(=O)H), ethyl hydrazino, propyl fluorenyl, butyl decyl, pentylene, hexyl thiol and the individual optical isomers thereof. , benzamidine. The substituent of the fluorenyl group includes the substituents of the above alkyl group and aryl group, and thus the substituents can be referred to.

The optionally substituted aminocarbonyl group in the context of the invention is formally derived from an optionally substituted amine group as defined above by the addition of a carbonyl residue ((R) ₂ NC(=O)-), so reference is made to The above definition of a substituted amine group. The examples thus comprise an amine formazan group (H ₂ NCO-), an optionally substituted mono- or dialkylaminocarbonyl group (RHNCO-, (R) ₂ NCO), wherein the definition of the optionally substituted alkyl group can be referred to above definition. Further comprising an optionally substituted mono- or diarylaminocarbonyl residue or a mixed optionally substituted alkylarylaminocarbonyl radical, wherein the definition of an optionally substituted alkyl or aryl group can be Refer to the above definition. Such groups include, for example, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, phenylaminocarbonyl, methylphenylaminocarbonyl, and the like.

The iron (III)-2,4-dioxy-1-carbonyl conjugate compound of the present invention comprising at least one of the following ligands of the formula (I) is preferably:

Wherein each arrow represents a coordinate bond of one or several iron atoms, and R ₁ is an alkyl group, which is optionally substituted with 1 to 3 substituents selected from the group consisting of: a hydroxyl group; Alkoxy as defined, for example especially methoxy, ethoxy, alkoxycarbonyl as defined above (for example especially methoxycarbonyl, ethoxycarbonyl) and aminocarbonyl as defined above, or R _{a 1} alkoxy group which is optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group and a C1-C6 alkoxy group, such as, in particular, a methoxycarbonyl group, an ethoxycarbonyl group. a propoxycarbonyl group or the like, or an R ₁ -based alkoxy group, which is optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, an alkoxy group and a halogen, respectively as described above definition.

R ₂ is selected from the group consisting of: -hydrogen, -alkyl, which is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, alkoxy, halogen, and Alkoxycarbonyl, each as defined above, -halogen, such as chloro, fluoro, particularly preferably fluoro, or R ₁ and R ₂ together with the carbon atom to which they are attached form a selectively substituted 5- or 6 a member ring, such as a ring of cyclopentane or a ring of cyclohexane, which may optionally have one or more, preferably one or two, heteroatoms, and additionally may preferably have 1 to 3 substituents such as the above: a hydroxyl group, an alkoxy group, an alkoxycarbonyl group and an aminocarbonyl group, and an R ₃ -based hydroxyl group, or an R ₃ -based alkyl group, which are optionally selected from 1 to 3 The substituents of the group consisting of are substituted with a hydroxyl group, an alkoxy group, respectively as defined above, or an R ₃ -based alkoxy group, which is selected from the group consisting of 1 to 3 selected from the group consisting of substituents: hydroxy, alkoxy, alkoxycarbonyl, respectively, as defined above, or R ₃ based group (-NH _2), which was based selectivity to 1-3 Substituted by substituents of the group consisting of: alkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl, as defined above, or the substituents together form an optional substitution of 5 or 6 members a ring (ie, a cyclic amine group as described above in this case), such as a ring of cyclopentane or a ring of cyclohexane which also optionally contains one or two heteroatoms, and may additionally carry The substituent of the alkyl group described above is preferably one to three, or a pharmaceutically acceptable salt thereof.

Particularly preferred is an iron (III) complex compound of the following formula (II): Wherein R ₁ , R ₂ and R ₃ are each as defined above, and are preferably as defined below.

Preferably, R ₁ of the preferred embodiment of the invention is selected from the group consisting of: -C1-6 alkyl, preferably as described above, optionally via a C1-4 alkoxy group as described above. Substituted, or optionally substituted with an alkoxycarbonyl group as described above, -C3-6 cycloalkyl, preferably as described above, -C3-6 cycloalkyl-C1-4 alkyl, preferably as above Description, a C1-4 alkoxy group, preferably as described above, a -hydroxy-C1-4 alkyl group, preferably as described above, and a -halo-C1-4 alkyl group, preferably as described above, or -C1 -4 alkoxycarbonyl group, preferably as described above.

More preferably R ₁ is C1-6 alkyl, preferably as described above, especially: methyl; ethyl; propyl, especially n-propyl and i-propyl; butyl, especially tert-butyl . Most preferred R ₁ is methyl, ethyl, i-propyl (isopropyl) and tert-butyl, which are optionally substituted with a C1-6 alkoxy group such as a methoxy group, or R ₁ is C1-4 alkoxycarbonyl, such as ethoxycarbonyl or especially methoxycarbonyl, or R ₁ is C1-4 alkoxy, preferably as previously discussed, in particular methoxy and ethoxy.

Preferably, the R ₂ of the preferred embodiment of the invention is selected from the group consisting of: -hydrogen, -halogen, preferably as described above, -C1-6 alkyl, preferably as described above.

More preferably, R ₂ is hydrogen and halogen as described above, more preferably R ₂ is hydrogen and fluorine, most preferably hydrogen, or R ₂ together with R ₁ forms a ring structure as shown below.

In a preferred embodiment of the invention, R ₁ and R ₂ together with the carbon atom to which they are attached form an optionally substituted 5 or 6 membered ring having one or more selectivity (e.g., specifically 2). Hetero atom. Then form a 2,4-dioxy-1-carbonyl ligand as shown below:

Wherein R ₃ is as described above or below. However, this particular embodiment is less preferred.

In this embodiment, R ₁ and R ₂ preferably together form a propyl group (-CH ₂ -CH ₂ -CH ₂ -) or a butyl group (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -). Wherein the methyl group (-CH ₂ -) is substituted by -O-, -NH- or -NR _{4 ,} respectively, wherein R ₄ is an optionally substituted alkyl group, and wherein the group formed by R ₁ and R ₂ The group is additionally substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, C1-4-alkoxy, amine and mono or di(C1-4-alkyl)amine. The following exemplary preferred ligands for this species: Wherein each R ₃ is as defined above.

In a preferred embodiment of the invention, R ₃ is selected from the group consisting of: - C1-6 alkyl, preferably as described above, which is optionally substituted with a C1-4 alkoxy group. As described above, or -hydroxyl, or -C1-4 alkoxy, preferably as described above, or - an amine group (NH ₂ ) as described above, which is preferably C1 as described above 1-6 alkyl or ring substituted, preferably a ring optionally substituted with a 5 or 6 membered cyclic amine, such as one or two heteroatoms, preferably containing an additional hetero atom in addition to the nitrogen atom to which R ₃ is attached. N or O, and the ring thereof may be substituted with, for example, a hydroxyl group or an alkoxy group. The following are exemplary cyclic amine residues R ₃ : Here, it is the binding site by which the radical R ₃ is attached.

Particularly preferred R ₃ is a hydroxyl group, an alkoxy group and an optionally substituted amine group, most preferably a hydroxyl group, a methoxy group, an ethoxy group, an amine group (-NH ₂ ), a dimethylamino group, and an N-(hydroxyl group). Base)-N-methylamino group: , piperidin-1-yl, 4-methoxypiperidin-1-yl, pyrrolidin-1-yl and morpholin-4-yl.

Those skilled in the art will understand the ligands of the present invention. It is produced from the corresponding 2,4-dioxy-1-carbonyl compound.

Among them, keto-enol tautomerism exists:

A and C of the mesomeric form are essentially indistinguishable by analysis. The only exception is when R ₁ and R ₃ are very different. The invention encompasses all forms in any case, but such ligands are generally only shown in the form of a ketone in the present invention.

Formally the ligand is obtained by isolating a proton from the corresponding 2,4-dioxy-1-carbonyl compound: It therefore has a single negative charge in its form. The iron-missing compound of the present invention exhibits only one of two local resonance formulas:

A further preferred embodiment of the invention comprises: R ₁ is selected from the group consisting of: -methyl-i-propyl (isopropyl)-t-butyl (tri-butyl)- Oxy-ethoxy-methoxycarbonyl, and -ethoxycarbonyl, and R ₂ are selected from the group consisting of: - hydrogen - methyl, and - fluoro, or R ₁ and R ₂ together Forming a propyl (-CH ₂ -CH ₂ -CH ₂ -)- or a butyl group (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -), and the R ₃ is selected from the group consisting of :-hydroxy, -methoxy, -ethoxy, -amino, -dimethylamino, -N-(hydroxyethyl)-N-methylamino-3-propylamino (n- Propylamino)-2-ethylamino (ethylamino)-morpholinyl(morpholin-4-yl)-piperidinyl(piperidin-1-yl)-pyrrolidinyl (pyrrolidine- 1-yl)- 4-hydroxypiperidinyl (4-hydroxypiperidin-1-yl)-4-methoxypiperidinyl (4-methoxypiperidin-1-yl). (In the present invention, In the number 1-6 of "1-6C" or "C1-6" or "1-4" in "1-4C" or "C1-4", etc., it means that the number is in the name of the hydrocarbon residue. The number of carbon atoms.)

The substituents as described above are particularly preferred. The 1-6C-alkyl group preferably contains a linear or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n - Hexyl, isohexyl and neohexyl.

The 3-6C-cycloalkyl group preferably contains a cycloalkyl group having 1 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. The 3-6C-cycloalkyl-1-4C-alkyl group preferably contains the above-mentioned alkyl group of 1-6C substituted with the above 3-6C cycloalkyl group. Examples of this may be cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The 1-3C-alkoxy-carbonyl-1-6C-alkyl group preferably contains the above 1-6C alkyl group which is bonded to a carbonyl group which is present as a carboxylic acid ester together with a 1-3C alkoxy group. Examples of this may be methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl and isopropoxycarbonylmethyl.

The 1-4C-alkoxy group preferably contains a 1-4C-alkoxy group having an oxygen atom bonded to a linear or branched alkyl chain having 1 to 4 carbon atoms. Examples of this may be methoxy, ethoxy, propoxy and isobutoxy.

The 1-4C-alkoxy-1-4C-alkyl group preferably contains the above 1-4C-alkoxy group which is bonded to the above 1-4C-alkyl group. An example of this may be methoxyethyl, ethoxypropyl, methoxypropyl, isobutoxymethyl. The hydroxy-1-4C-alkyl group includes the above 1-4C-alkyl group substituted with a hydroxy group. Examples herein may be hydroxyethyl, hydroxybutyl and hydroxyisopropyl.

The fluoro-1-4C-alkyl group includes the above 1-4C-alkyl group substituted with 1 to 3 fluorine atoms. Examples herein may be trifluoromethyl and trifluoroethyl.

Halogen is F, Cl, Br and I.

EXAMPLES Particularly preferred iron (III) complex compounds of formula (II) are described.

The invention further relates to a process for the preparation of the novel iron (II) complex compound comprising reacting an iron (III) salt with a 2,4-dioxycarbonyl compound.

The 2,4-dioxy-1-carbonyl compound comprises a group of formula (III): Wherein R ₁ to R ₃ are each as defined above, wherein this relates to a tautomeric resonance structure.

Examples of suitable iron (III)-salts include: iron (III)-chlorine, iron (III)-acetate, iron (III)-sulfate, iron (III)-nitrite, iron (III)- Ethyl ethoxide and iron (III)-acetamidine pyruvate, of which iron (III)-chloride is preferred.

The preferred method is shown in the following flow chart: Wherein R ₁ to R ₃ are each as defined above, X is an anion such as a halide (e.g., chlorine); a monocarboxylate such as acetate, sulfate; an alkoxy group such as an ethoxy group; nitrite And acetoacetate, and the base (V) which is optionally used is a conventional organic or baseless base.

Preferably, the 3-5 eq ligand (III) in the process of the invention is reacted under standard conditions using a suitable iron (III)-salt (IV) (wherein especially suitable for Fe(III)- Chlorine, Fe(III)-acetate, Fe(III)-ethanolate, Fe(III)-sulfate and Fe(III)-acetylpyruvate), to obtain the corresponding formula (II) Complex compound. This synthetic step is carried out herein under the optimum pH conditions for the complex formation system. This optimum pH condition is optionally adjusted by the addition of a base (V), which is particularly suitable here for the use of triethylamine, sodium carbonate, sodium hydrogencarbonate, sodium methoxide, sodium ethoxide, potassium carbonate, potassium bicarbonate or potassium methoxide.

The mismatched ligand (III) required for the preparation of the compound is commercially available or can be prepared by the following synthetic methods.

Can be achieved according to different synthetic paths. For a ligand of the formula R ₁ =methyl, R ₂ =H, R ₃ =NH ₂ or OH, R ₁ =methyl, R ₂ =H, R ₃ = in the form of a calcium salt are commercially available. NH ₂ , 2,4-dioxypentanoic acid ethyl ester, which is reacted with aqueous ammonia to give a ligand of the formula (III). (A. Ichiba et al, Journal of the Scientific Research Institute, Tokyo, 1948, 23, 23-29).

For 2,4-dioxyvaleric acid ethyl ester in the form of a copper complex, R ₁ =methyl, R ₂ =H, R ₃ =N(CH ₃ )CH ₂ CH ₂ OH, The methylaminoethanol is reacted to obtain a ligand of the formula (III).

For 2,4-dioxypentanoic acid ethyl ester of R ₁ =methyl, R ₂ =H, R ₃ =OH, which is subjected to alkali hydrolysis to give a ligand of the formula (III).

For the other ligand of the formula (III), an alkali condensation reaction is employed. (J. Wang et al, Can. J. Chem, 2009, 87, 328-334).

Wherein R ₁ to R ₃ are each as defined above, and R ₅ is an optionally substituted alkyl group, but preferably represents a methyl or ethyl group. Suitable bases include various condensed bases such as sodium ethoxide, potassium butoxide, sodium, sodium hydride or butyl lithium, preferably potassium butoxide.

The ligand of R ₃ -OH containing a free hydroxyl group can form a hemiacetal upon reaction with the carbonyl group of the main chain. In this case, the non-iron-bonded ligand of the formula (III) becomes the formula (VI):

It is apparent to the expert that the hemiacetal of the formula (VI) in solution is chemically balanced with the open-chain form of the formula (III), and when it is coordinated with iron, it always exhibits the coordination of the formula (I). base.

The iron (III) complex of the pharmaceutically acceptable salt of the compound of the present invention is formally positively charged, for example, a salt having a suitable anion such as a carboxylate, a sulfonate, a sulfate, a chloride, Bromide, iodide, phosphate, tartrate, methanesulfonate, isethionate, glycinate, maleic acid, propionate, fumarate, p-toluenesulfonate, benzenesulfonate a salt of a salt of acid, trifluoroacetate, 1,5-naphthalene disulfonate, salicylate, benzoate, lactate, hydroxysuccinate, 3-hydroxy-2-naphthoic acid-2, Citrate and acetate.

The iron (III) complex of the pharmaceutically acceptable salt of the compound of the present invention is formally present with a negative charge, such as a salt of a pharmaceutically acceptable base, such as, for example, an alkaline salt or Alkaline earth metal hydroxides such as NaOH, KOH, Ca(OH) ₂ , Mg(OH) _{2 ,} etc.; amine compounds such as ethylamine, diethylamine, triethylamine, diisopropylethylamine, ethanolamine, diethanolamine , triethanolamine, dicyclohexylamine, dimethylamine ethanol, procaine, diphenylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, 2-amine 2-methyl-propanol-(1), 2-amino-2-methyl-propanediol-(1,3), 2-amino-2-hydroxy-methyl-propanediol-(1,3 ) (TRIS) and so on.

In general, the formation of salts, especially the choice of counterions, can significantly affect the solubility of the compounds of the present invention in water or in physiological saline, and thus may also affect their efficacy.

Preferably, the compounds of the invention constitute a neutrally incompatible compound.

Advantageous Pharmacological Efficacy: Surprisingly, the inventors of the present invention have found that the subject matter of the present invention and the iron(III)-2,4-dioxycarbonylcarbonyl group represented by the general structural formula (II) The compound is a stable bioavailable iron complex and is suitable for use as a drug for treating and preventing symptoms of iron deficiency and symptoms associated with iron deficiency anemia.

The drug containing the compound of the present invention is suitable for use in human and animal drugs.

The compounds of the invention are thus also suitable for the preparation of a medicament for the treatment of patients suffering from symptoms of iron deficiency anemia, for example, fatigue, stenosis, lack of concentration, low cognitive efficiency, finding the correct word Difficulty, forgetfulness, unnatural paleness, irritability, rapid heartbeat (tachycardia), ulcer or tongue hypertrophy, splenomegaly, craving for strange foods (pica), headache, lack of appetite, increased infection Sexual or melancholy mood.

Iron (III) dysfunctional compound according to the invention and suitable for treating iron deficiency anemia in pregnant women, latent iron deficiency anemia in children and adolescents, iron deficiency anemia caused by gastrointestinal abnormalities, due to blood loss Iron deficiency anemia, for example, gastrointestinal bleeding (for example, due to duodenal ulcer, malignant tumor, hemorrhoids, inflammatory disease, salicylic acid application), iron deficiency anemia caused by menstruation, iron deficiency anemia caused by injury, due to Iron deficiency anemia caused by mouth sores, iron deficiency anemia caused by decreased dietary iron intake (especially children and adolescents with partial eclipse), immunodeficiency caused by iron deficiency anemia, caused by iron deficiency anemia Impaired brain function, restless leg syndrome caused by iron deficiency anemia, iron deficiency anemia of cancer, iron deficiency anemia caused by chemotherapy, iron deficiency anemia caused by inflammation, AI Iron deficiency anemia of ventricular dysfunction (CHF; congestive heart failure), iron deficiency in chronic renal insufficiency stage 3-5 (CDK 3-5; chronic kidney disease stage 3-5) Anemia, iron deficiency anemia (ACD) triggered by chronic inflammation, iron deficiency anemia of rheumatoid arthritis (RA), iron deficiency anemia of systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) The situation of iron deficiency anemia.

It can be administered continuously for several months until the state of iron is improved, which is reflected, for example, by the patient's hemoglobin value, transferrin saturation and serum ferritin levels, or to the state of health affected by iron deficiency anemia. Something improved.

The preparation of the present invention can be administered to children, adolescents and adults.

The compounds administered in the present invention can be administered orally and parenterally in this case. Preferably, it is administered orally.

The compounds of the present invention, as well as the aforementioned combinations of the compounds of the present invention and other active substances or drugs, may thus be particularly useful in the preparation of a medicament for the treatment of iron deficiency anemia, for example, iron deficiency anemia in pregnant women, latent iron deficiency in children and adolescents. Anemia, iron deficiency anemia caused by gastrointestinal abnormalities, iron deficiency anemia due to blood loss, for example gastrointestinal bleeding (for example, due to ulcers, cancer, acne, inflammatory disorders, ingestion of ethyl sulphate) , menstrual period, injury, iron deficiency anemia due to aphthous ulcer, iron deficiency anemia due to reduced dietary iron intake (especially in children and adolescents with partial eclipse), immunodeficiency caused by iron deficiency anemia, due to iron deficiency Impaired brain function caused by anemia, restless leg syndrome.

The application of the present invention results in an improvement in the levels of iron, heme, ferritin and transferrin, especially in children and adolescents, but also in adults, accompanied by short-term memory testing (STM), long-term memory testing ( LTM), Raven's progressive matrices, Wei's adult intelligence Improvements in the scale (WAIS) and/or mood coefficient (Baron EQ-i, YV test; youth version), or improvement in neutrophil levels, antibody levels, and/or lymphocyte function.

Furthermore, the invention relates to a pharmaceutical composition comprising one or more compounds of the invention, in particular one or more additional pharmaceutically effective compounds of formula (II) and optionally, and one or more pharmaceutically acceptable Accepted carrier and / or auxiliary substances and / or solvents. The pharmaceutical composition contains, for example, up to 99% by weight or up to 90% by weight or up to 80% by weight up to 70% by weight of a compound of the invention, each of which is a pharmaceutically acceptable carrier and / or an adjuvant and / or solvent formed.

These are common pharmaceutical carriers, auxiliary substances or solvents. The above pharmaceutical compositions are suitable for, for example, intravenous, intraperitoneal, intramuscular, intravaginal, buccal, transdermal, subcutaneous, mucosal, oral, rectal, transdermal , topical, intradermal, intragastric or intradermal, and are provided in the form of tablets, lozenges, enteric lozenges, film lozenges, tablets, for oral, subcutaneous or dermal Sustained release formulation (especially as a plaster), stored formula, dragee, suppository, gel, ointment, syrup, granules, suppositories, emulsions, dispersing agents, microcapsules, microformulations, nai Nanoformulations, liposome formulations, capsules, casing capsules, powders, inhaled powders, microcellulose formulations, inhalation sprays, epipastics, drops, nasal drops, nasal sprays, gas A sol, an ampoule, a solution, a juice, a suspension, an injection solution or an injection solution, and the like.

In a preferred embodiment of the invention, the iron-missing compound is It is administered in the form of an ingot or a capsule. These may for example be present in acid-resistant form or have pH-dependent coatings.

Preferably, the compounds of the invention and the pharmaceutical compositions containing the same are administered orally, although they may also be administered in other forms such as parenteral (especially intravenously).

For this purpose, the compounds of the invention are preferably provided in the pharmaceutical compositions in the form of pills, lozenges, enteric lozenges, film lozenges, layer tablets, sustained release formulations for oral administration, storage Formulations, dragees, granules, emulsions, dispersing agents, microcapsules, fine-tuning formulations, nano formulations, liposome formulations, capsules, casing capsules, powders, microcellulose formulations, dusting powders, drops, ampoules, Solution, suspension, infusion solution or injection solution.

The compounds according to the invention may be administered in the form of a pharmaceutical composition which may contain various organic or inorganic carriers and/or auxiliary materials conventionally used for pharmaceutical purposes, in particular for solid pharmaceutical formulations, for example, by way of example For the purposes of: excipients (eg, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate), binding agents (eg, cellulose, methyl cellulose, hydroxyl Propyl cellulose, propyl pyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch), disintegrant (for example, starch, hydrolyzed starch, carboxymethyl cellulose, calcium carboxymethyl cellulose) Salt, hydroxypropyl starch, sodium glycolate, sodium bicarbonate, calcium phosphate, calcium citrate), lubricants (eg, magnesium stearate, talc, sodium lauryl sulfate), flavoring agents (eg, citric acid, Menthol, glycerin, citrus powder), preservatives (eg, sodium benzoate, sodium bisulfite, methyl paraben, p-hydroxyl Propyl benzoate), stabilizers (eg, citric acid, sodium citrate, acetic acid, and tritriplex series of polycarboxylic acids, such as, for example, diethylenetriaminepentaacetic acid (DTPA), suspending agents (eg, , methylcellulose, polyvinylpyrrolidone, aluminum stearate), dispersant, diluent (for example, water, organic solvent), beeswax, cocoa butter, polyethylene glycol, white petrolatum, and the like.

Liquid pharmaceutical formulations (e.g., solutions, suspensions, and gels) typically contain a liquid carrier such as water and/or a pharmaceutically acceptable organic solvent. In addition, such liquid formulations may also contain pH adjusting agents, emulsifying or dispersing agents, buffering agents, preservatives, wetting agents, gelling agents (for example methylcellulose), dyes and/or flavoring agents. The composition may be isotonic, in other words, it may have the same osmotic pressure as blood. The iso-permeability of the present compositions can be adjusted using sodium chloride or other pharmaceutically acceptable formulations such as, for example, dextrose, maltose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic agents. Soluble matter. The viscosity of the liquid composition can be adjusted using a pharmaceutically acceptable thickening agent such as methyl cellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomers, and the like. The preferred concentration of the thickening agent will depend on the reagent selected. A pharmaceutically acceptable preservative can be used to increase the shelf life of the liquid composition. Benzyl alcohol may be suitable, although various preservatives including, for example, parabens, thimerosal, chlorobutanol or chlorinated benzalkonium chloride may also be used.

The active substance can be administered, for example, in a unit dose of 0.001 mg/kg to 500 mg/kg body weight and, for example, 1 to 4 times a day. However, the dosage may be increased depending on the age, weight and condition of the patient, the severity of the disease, or the type of administration or cut back.

Example

The nomenclature of this ligand was carried out in accordance with the IUPAC nomenclature using the program ACD/name 12.01 of Advanced Chemistry Development Inc.

Starting compound:

A. 2,4-dioxypentanoic acid ethyl ester

Product: a-Aldrich 232564

B. Methyl 2,4-dioxypentanoate

Product: Sigma-Aldrich 699675

C. 2,4-dioxypentamidine

100 g of calcium acetate monohydrate was dissolved in 250 ml of water and cooled in an ice bath. After 30 minutes, 185 g of 2,4-dioxypentanoic acid ethyl ester was added as a dropping funnel. The mixture was cooled in an ice bath and stirred with a mechanical stirrer for 2 small Time. The resulting precipitate was filtered off and washed thoroughly with 100 ml of ice water to remove acetic acid. The precipitate was dried to constant weight in an oven at 25 ° C, carefully ground in a mortar and dried again in an oven at 25 ° C overnight. Product: 178 g of a calcium salt of 2,4-dioxypentanoate as a white powder.

50 ml of ammonia methanol (7N) was added to 25 g of the calcium salt of 2,4-dioxypentanoic acid ethyl ester in a humidity-free atmosphere at room temperature, and stirred for 1 hour. Then, it was left to stand without stirring for 24 hours. The contents of the bottle are now fully cured. The white solid was filtered off in order to operate with stirring with 100 ml of methanol. It was dried at 40 ° C for 3 hours under vacuum. 15 g of the product of the calcium salt of 2,4-dimethoxyamylamine was obtained as a white solid.

20 g of this dried calcium complex was chopped into a fine powder in a bottle and cooled in a frozen mixture to release 2,4-dimethoxyamylamine. While stirring, 40 g of pre-cooled hydrochloric acid was added quickly and slowly. The mixture was stirred at an internal temperature of -10 ° C for 30 minutes until the pH of the suspension was fixed. The ice-cold suspension was quickly filtered, washed with a small amount of ice water and dried at room temperature under high vacuum. The crude product was recrystallized from ethanol. The product is 7 g of 2,4-dimethoxypentanylamine as a beige powder having a melting point of 130-132 ° C.

IR (solvent free, cm-1): 3417, 3290, 3195, 3119, 2773, 1677, 1579, 1378, 1220, 1108, 1022, 991, 933, 836, 798, 673.

Enol type

</ RTI> <RTIgt;

Ketone type

</ RTI> <RTIgt;

D. 2,4-dioxypentanoic acid

25 ml of acetone was added to 50.00 g (316 mmol) of 2,4-dioxypentanoate and cooled to 0 °C. Next, 126.5 ml of a 5 M sodium hydroxide solution was added at -3 to +5 ° C, and stirred at 0 ° C for 4 hours. 106.0 ml of 3 M sulfuric acid was added dropwise to the solution to maintain it in the temperature range of 0 to 5 °C. The mixture was filtered and the filtrate was transferred to a Kutscher-Steudel extractor and extracted with diethyl ether for 6.5 hours. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue was recrystallized from 15 ml of n-hexane / ethyl acetate (1:1). The crude product produced was placed in a sublimation apparatus and sublimed for 10.5 hours at 50-60 ° C, 6-10 mbar. 7.88 g of 2,4-dioxypentanoic acid were obtained as a white powder.

IR (solvent free, cm ^-1 ): 3186, 3114, 3033, 2935, 2577, 1756, 1736, 1586, 1380, 1296, 1237, 1194, 1129, 997, 901, 832, 792, 713, 561.

Enol type

¹ H-NMR (DMSO-d6, 400 MHz): δ [ppm] = 13.3 (1H), 6.27 (2H), 2.24 (3H).

Ketone type

¹ H-NMR (DMSO-d6, 400 MHz): δ [ppm] = 13.6 (1H), 3.96 (2H), 2.18 (3H).

E. Side oxygen (2-oxycyclopentyl) ethyl acetate

Product: Akos GmbH MSC-0387

F. side oxygen (2-oxycyclopentyl) ethyl acetate

Product: Akos GmbH MSC-0385

G. 5,5-Dimethyl-1-(piperidin-1-yl)hex-1,2,4-trione

14.0 g (164 mmol) of piperidine and 16.6 g (164 mmol) of triethylamine in 30 ml of dichloromethane were cooled to 0 °C. 20.1 g (164 mmol) of methyl chlorooxyacetate was added dropwise. The mixture was then stirred at room temperature for 16 hours. The reaction solution was washed with 1 N hydrochloric acid and then washed with a saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated to dryness on a rotary evaporator. 5 g of the remaining oil was combined with 2.93 g (29.3 mmol) of 3,3-dimethyl-2-butanone in 5 ml of anhydrous THF, and 6.89 g (61.4 mmol) of sodium t-butoxide was cooled in 40 minutes. Join in batches. The color of the reaction mixture changed from dark yellow to blueish yellow. Stirring was then continued at room temperature for an additional 3 hours. 6.32 g (105 mmol) of glacial acetic acid was added and the suspension was filtered. The filtrate was washed with a saturated NaCl solution and a 5% sodium hydrogen carbonate solution. The second cleaning is finally extracted with dichloromethane and ^. Combined with the filtrate. It was dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The crude product was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAc

LC / MS: m / z [ Da] = 240.5 [M + H] +, 262.3 [M + Na] +.

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 5.88 (1H), 3.6-3.4 (4H), 1.7-1.5 (6H), 1.17 (9H).

H. N,N,5,5-tetramethyl-2,4-dioxahexylamine

15 g (103 mmol) of N,N-dimethyloxalate ethyl ester were combined with 10.4 g (103 mmol) of 3,3-dimethyl-2-butanone in 40 ml of dry THF. 24.6 g (217 mmol) of potassium t-butoxide suspended in 200 ml of dry THF was added dropwise to the reaction mixture over 40 minutes. The color of the reaction mixture turned orange. It was then stirred at room temperature for 3 hours. 22.3 g (371 mmol) of glacial acetic acid was added and the suspension was filtered. The filtered solid was washed with 300 ml of dichloromethane and combined into the filtrate. The organic layer was washed with 100 ml of 5% sodium hydrogen carbonate solution and 100 ml of saturated NaCl solution, dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The crude product was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAc

LC/MS: m/z [Da] = 200.3 [M+H] +, 222.3 [M+Na]+.

Enol type

1H-NMR (DMSO-d6,400 MHz ): δ [ppm] = 5.92 (1H), 3.03 (3H), 2.94 (3H), 1.13 (9H).

Ketone type

1H-NMR (CDCl3, 400 MHz): δ [ppm] = 3.97 (2H), 3.06 (3H), 2.92 (3H), 1.11 (9H).

I. N,N,5-trimethyl-2,4-dioxyhexylamine

19.6 g (135 mmol) of N,N-dimethyloxalate ethyl ester together with 11.6 g (135 mmol) of 3-methyl-2-butanone in 50 ml of dry THF. 31.8 g (284 mmol) of potassium t-butoxide were suspended in 200 ml of dry THF and the reaction mixture was added dropwise over 40 minutes. The mixture was stirred at room temperature overnight. 29.2 g (486 mmol) of glacial acetic acid were added and the suspension was filtered. The filtered solid was washed with 300 ml of dichloromethane and combined with the filtrate. The organic layer was concentrated and dried by a rotary evaporator. The residual purple oil was dissolved in 67 ml of a 3M NaOH solution with a pH of 12. The basic aqueous layer was extracted 4 times with 100 ml of diethyl ether. The pH of the aqueous layer was then adjusted to 1-2 with hydrochloric acid. The aqueous layer was extracted 4 times with a mixture of diethyl ether / ethyl acetate (100 ml / 200 ml). The combined organic layers were dried over sodium sulfate and concentrated to dryness using a rotary evaporator. The crude product was purified by column chromatography (EtOAc,EtOAcEtOAcEtOAc

LC/MS: m/z [Da] = 186.7 [M+H] ⁺ , 208.7 [M+Na] ⁺ .

Enol type

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 5.87 (1H), 3.07 (3H), 2.98 (3H), 2.52 (1H), 1.16 (3H), 1.14 (3H).

Ketone type

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 3.96 (2H), 3.09 (3H), 2.96 (3H), 2.65 (1H), 1.12 (3H), 1.10 (3H).

J. diethyl 2-butanone ethyl ester

Product: TCI Europe O0073

K. 5-Methyl-1-(morpholin-4-yl)hex-1,2,4-trione

7.12 g (146 mmol) of morpholine and 14.8 g (146 mmol) of triethylamine were dissolved in 200 ml of dry diethyl ether and then cooled in an ice bath. 20 g (146 mmol) of ethyl chlorooxyacetate was added dropwise and allowed to warm to room temperature. The precipitated triethylamine hydrochloride was filtered and the filtrate was concentrated and dried using a rotary evaporator. 21.9 g of the remaining butter was combined with 10.1 g (117 mmol) of 3-methyl-2-butanone in 40 ml of dry THF. 27.6 g (245 mmol) of potassium t-butoxide was suspended in 200 m of anhydrous THF, and added dropwise to the reaction mixture over 40 minutes. In. It was then stirred at room temperature for a further 3 hours. 25.3 g (421 mmol) of glacial acetic acid were added and the suspension was filtered. The filtered solid was washed with 300 ml of dichloromethane and combined with the filtrate. The organic layer was washed with 250 ml of a 5% sodium hydrogen carbonate solution and 100 ml of a saturated NaCl solution. The organic layer was dried over sodium sulfate and concentrated to dryness using a rotary evaporator. The crude product was purified by column chromatography (EtOAc, ethyl acetate / petroleum ether = 1/3).

IR (solvent free, cm ^-1 ): 2971, 2929, 2859, 1702, 1641, 1601, 1461, 1439, 1386, 1364, 1328, 1274, 1256, 1204, 1156, 1112, 1070, 1026, 951, 915, 873, 842, 821, 780, 748, 655.

Enol type

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 5.88 (1H), 3.7-3.5 (8H), 2.50 (1H), 1.14 (3H), 1.12 (3H).

Ketone type

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 3.94 (2H), 3.7-3.5 (8H), 2.61 (1H), 1.09 (3H), 1.08 (3H).

L. 1-(morpholin-4-yl)penta-1,2,4-trione

26.1 g (300 mmol) of morpholine and 30.4 g (300 mmol) of triethylamine were dissolved in 300 ml of anhydrous diethyl ether and cooled in an ice bath. 41.0 g (300 mmol) of ethyl chlorooxyacetate was added dropwise and allowed to warm to room temperature. The precipitated triethylamine hydrochloride was filtered and concentrated to dryness on a rotary evaporator.

40.1 g of the remaining yellow oil was taken together with 12.4 g (214 mmol) of acetone in 80 ml of dry THF. 50.4 g (449 mmol) of potassium tert-butoxide was suspended in 200 ml of anhydrous THF and added dropwise to the reaction mixture over 40 minutes. It was then stirred for a further three hours at room temperature. 46.3 g (770 mmol) of glacial acetic acid were added and the suspension was filtered. The filtered solid was washed with 300 ml of dichloromethane and combined with the filtrate. The organic layer was washed with 250 ml of a 5% sodium hydrogen carbonate solution and 100 ml of a saturated NaCl solution. The organic layer was dried over sodium sulfate and concentrated to dryness using a rotary evaporator. The crude product was purified by column chromatography (EtOAc, ethyl acetate) and purified from diethyl ether. The product was 28.9 g of light brown crystals.

IR (solvent free, cm ^-1 ): 3092, 3001, 2969, 2921, 2901, 2858, 2774, 2720, 1615, 1485, 1426, 1371, 1304, 1269, 1214, 1151, 1107, 1067, 1031, 1004, 950,939,914,847,824,800,742,660.

Enol type:

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 5.93 (1H), 3.8-3.6 (8H), 2.15 (3H).

Ketone type

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 3.98 (2H), 3.8-3.6 (8H), 2.28 (3H).

M. 1-(pyrrolidin-1-yl)penta-1,2,4-trione

10.4 g (146 mmol) of pyrrolidine and 14.8 g (146 mmol) of triethylamine were dissolved in 200 ml of anhydrous diethyl ether and cooled in an ice bath. 20 g (146 mmol) of ethyl chlorooxyacetate was added dropwise and allowed to warm to room temperature. The precipitated triethylamine hydrochloride was filtered and concentrated to dryness on a rotary evaporator. 15.1 g of the remaining yellow oil and (5.1 g, 88 mmol) of acetone were added to 40 ml of anhydrous THF. 20.8 g (185 mmol) of potassium tert-butoxide was suspended in 200 ml of anhydrous THF and the reaction mixture was added dropwise over 40 minutes. It was then stirred for a further three hours at room temperature. 19.0 g (317 mmol) of glacial acetic acid was added and the suspension was filtered and filtered. The solid was washed with 300 ml of dichloromethane and combined with the filtrate. The organic layer was washed with 250 ml of a 5% sodium hydrogen carbonate solution and 100 ml of a saturated NaCl solution. The organic layer was dried over sodium sulfate and concentrated to dryness using a rotary evaporator. The crude product was purified by column chromatography (EtOAc,EtOAc)

IR (solvent free, cm ^-1 ): 3107, 2981, 2956, 2924, 2873, 1594, 1469, 1405, 1336, 1294, 1232, 1184, 1156, 1133, 1111, 1031, 1004, 982, 967, 917, 870, 844, 874, 710.

Enol type

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 6.18 (1H), 3.74 (2H), 3.56 (2H), 2.17 (3H), 2.0-1.85 (4H).

Ketone type

¹ H-NMR (CDCl 3 , 400 MHz): δ [ppm] = 3.95 (2H), 3.70 (2H), 3.50 (2H), 2.29 (3H), 2.0-1.85 (4H).

N. 1-(4-methoxypiperidin-1-yl)penta-1,2,4-trione

9.79 g (85.0 mmol) of 4-methoxypiperidine and 8.60 g (85.0 mmol) of triethylamine were dissolved in 50 ml of anhydrous diethyl ether and cooled in an ice bath. 11.6 g (85.0 mmol) of ethyl chlorooxyacetate was added dropwise to the cooled solution. The mixture was warmed to room temperature and filtered to remove the precipitated triethylamine hydrochloride. The filtrate was concentrated and dried by a rotary evaporator. A crude product of 10.8 g of dark oil was obtained. This was added to 80 ml of anhydrous THF in an unpurified state together with 2.90 g (50.0 mmol) of acetone. 11.8 g (105 mmol) of potassium t-butoxide in 200 ml of anhydrous THF was added dropwise to the reaction mixture. Stir at room temperature for 3 hours. 10.8 g (180 mmol) of glacial acetic acid was then added and the resulting suspension was filtered. The filter block was washed with 200 ml of dichloromethane. The combined organic layers were washed with aq.

The crude product was purified by column chromatography (gelatin, ethyl acetate/petroleum ether = 3/1), and the yield was 3.8 g as a yellow oil.

IR (solvent free, cm ^-1 ): 2931, 2826, 1708, 1637, 1442, 1362, 1309, 1273, 1245, 1205, 1140, 1094, 1076, 1022, 938, 889, 821, 785, 666.

¹ H-NMR (DMSO, 400 MHz): δ [ppm] = 5.7 (1H), 3.7 (1H), 3.5 (2H), 3.3 (3H), 3.2 (2H), 2.1 (3H), 1.7 (2H) , 1.4 (2H).

O. N -(2-hydroxyethyl)- N -methyl-2,4-dioxypentamidine

9.98 g (50.0 mmol) of copper acetate monohydrate was suspended in 80 ml of ethanol and heated to 50 °C. 15.8 g (100 mmol) of 2,4-dioxypentanoic acid ethyl ester were added and heated to 60 °C. Thereafter, 520 ml of ethanol was added, and the mixture was stirred at 60 ° C for 2 hours. The resulting copper complex was then filtered. The resulting copper complex is then filtered. After drying, 17.8 g of copper complex was obtained as a fine, fibrous solid.

17.8 g (47.0 mmol) of this copper complex and 21.2 g (283 mmol) of 2-methylaminoethanol were dissolved in 300 ml of cyanomethane. The reaction solution was slowly concentrated at 50 ° C, 30 mbar for 4 hours or more to remove the formed ethanol. After 4 hours, the reaction solution was completely concentrated and dried to obtain a crude product of dark green oil. For the operation, 200 ml of chloroform and 125 ml of 30% sulfuric acid were added to the crude product to decompose the copper complex. The layers were separated and the aqueous layer was extracted twice with 200 ml of chloroform. The combined organic layers were dried over sodium sulfate and evaporated to dryness. The product obtained is a pale yellow oil which is automatically crystallized as hemiacetal: IR (solvent free, cm ^-1 ): 3225, 3012, 2978, 2961, 2921, 1718, 1640, 1514, 1449, 1424, 1401, 1361, 1343, 1264, 1217, 1149, 1166, 1129, 1104, 1067, 1058, 957, 923, 902, 858, 800, 767, 702, 662.

Hemiacetal:

¹ H-NMR (DMSO, 400 MHz): δ [ppm] = 6.78 (1H), 4.10 (1H), 3.65 (1H), 3.50 (1H), 3.15 (1H), 3.08 (1H), 2.82 (3H) , 2.76 (1H), 2.03 (3H).

Pharmacological properties of iron-missing compounds: Iron utilization experimental method:

The excellent Fe utilization ratio which can be achieved by the iron complex of the present invention is measured using the following mouse model.

Male NMRI (SPF) mice (approximately 3 weeks old) were fed a low iron diet (approx. 5 ppm iron) for approximately 3 weeks. The iron complex was then administered to the stomach tube (2 mg iron/kg body weight/day) twice daily for 5 days, interrupted for 2 days (days 1-5 and days 8-12). The utilization rate on the 15th day is calculated from the increase in hemoglobin and weight gain according to the following formula. =[(Hb _{2(3) *} BW ₉₍₁₄₎ -Hb _{1 *} BW ₄ ) _* 0.07 _* 0.0034-(Hb _{2(3) Control*} BW _{9(14) Control-} Hb _{1 Control*} BW _{4 Control} ) _* 0.07 _* 0.0034)] _* 100/Fe Dos. =[(Hb _{2(3) *} BW ₉₍₁₄₎ -Hb _{1 *} BW ₄ ) _* 0.000238-(Hb _{2(3) Control*} BW _{9(14) Control-} Hb _{1 Control*} BW _{4 Control} ) _* 0.000238] _* 100/Fe Dos. = (Hb _{2 (3) *} BW _{9 (14) -} Hb _{1 *} BW _{4 -} Hb _{2 (3) Control *} BW _{9 (14) Control} + Hb _{1 Control *} BW _{4 Control} ) _* 0.0238 / Fe Dos.

0.07=factor of 70 ml blood per kg body weight (BW)

0.0034=0.0034 g Fe/g factor of Hb

Hb ₁ = hemoglobin level on day 1 (g/l)

Hb ₂₍₃₎ = hemoglobin level (g/l) on day 8 (or 15)

BW ₄ = weight on day 1 (g)

BW ₉₍₁₄₎ = weight on day 8 (or 15) (g)

Hb _{1 control} = average hemoglobin level (g/l) on day 1 in the control group,

Hb _{2 (3) control} = average heme level (g/l) on day 8 (or 15) in the control group,

BW _{4 control} = average body weight (g) on day 1 in the control group,

BW _{9 (14) control} = average body weight (g) on day 8 (or 15) in the control group,

Fe Dos. = all iron (mg Fe) administered during 5 or 10 days,

Fe ut.=(Hb _{2(3) *} BW ₉₍₁₄₎ -Hb _{1 *} BW ₄ ) _* 0.07 _* 0.0034(mg Fe)

△ utilization = Fe tot. utilized (experimental group) - Fe ut. control group, used from food, (mg Fe)

The measured utilization values represent important parameters associated with the treatment of iron deficiency and iron deficiency anemia indications, as this parameter reflects not only iron absorption but also the relationship between body weight and iron intake, which is in animal models. Animals used in adolescence are especially important. If only the hemoglobin level of the degree of iron actually absorbed and used is considered, the part required for animal growth will not be included in the calculation. Thus the iron utilization rate is a more accurate measurement, although the iron utilization and hemoglobin values are usually associated with the individual. Less consideration is given to iron sera levels that can also be measured, because although it is an indicator of the amount of iron entering the body, it cannot tell how much it can be used by the body.

The test results show that the iron complex of the present invention has excellent iron utilization efficiency, and thus it can be used as a useful agent for treating iron deficiency anemia and related symptoms.

toxicity Compared to Fe(acac) ₃ toxicity

The toxicity of the novel iron-mismatched compound was compared to that of tris(acetonitrile)iron. Therefore, 6 Sprague-Dawley rats were administered orally in a single dose of this Example 3 (1400 mg/kg) and Example 1 (1600 mg/kg) of iron-missing compounds, each equivalent to 170 mg of iron. After 24 hours, all 6 animals survived and showed no toxicological findings at all. Six of the 10 experimental animals died compared to the administration of tris(acetonitrile) iron within 24 hours (Reference 1, see Table 1). The table below summarizes the results:

Experiment: Oral administration/single dose/spray of Sprague-Dawley rats 24 hours after administration

The results show that the iron-mismatched compound of the present invention actually shows no toxicological discovery compared to the highly toxic tris(acetonitrile) iron.

(Lit. 1: London, J. E.; Smith, D. M. Preliminary toxicological study of ferric acetylacetonate. Report (1983), (LA-9627-MS; Order No. DE83007117), 7 pp. CAN 99: 48652 AN 1983: 448652 CAPLUS)

Preparation example Example 1 Tris-(2,4-dioxypentanoate)-iron(III)-complex

25.0 g (158 mmol) of 2,4-dioxypentanoic acid ethyl ester was introduced into 50 ml of EtOH 92%, and 24.5 g of water-soluble iron(III)-chloride solution (12% w/w Fe, 53) Ment) was added at about 25 ± 5 ° C (micro-heating, cooling in an ice bath) for about 4 minutes. This was followed by stirring 21.8 g of NaOH (30% w/w, 164 mmol) in about 15 minutes at 25 ± 5 ° C (cooled in an ice bath). After 2 hours of reaction time, it was stirred while adding 240 ml of water at 25 ± 5 °C. The suspension was stirred at 0-5 ° C for two hours, filtered, and the filter cake was washed with 2×20 mL water. The product was dried at 50 ° C for 48 hours under high vacuum. The product was 23.0 g of a red solid.

IR (solvent free, cm ^-1 ): 3129, 2986, 1733, 1587, 1509, 1415, 1360, 1251, 1215, 1174, 1141, 1096, 1005, 948, 911, 863, 828, 793, 760, 634.

Elemental analysis: C 48.2%, H 5.0%.

Fe content: 10.4% [w/w].

Example 2 Tris-(2,4-dioxypentanoic acid methyl ester)-iron(III)-complex

6.49 g (40 mmol) of iron (III)-chlorine was dissolved in 100 ml of ethanol, and the solution was added dropwise to a solution of 17.30 g (120 mmol) of 2,4-dioxypentanoic acid methyl ester in 100 ml of ethanol. in. The solution turned from yellow to purple upon addition. The solution was stirred at RT for 30 minutes and then 16.80 g (200 mmol) sodium bicarbonate was added. The mixture was stirred at room temperature for 1 hour and then evaporated to dryness. The residue was dissolved in 100 ml of water (pH 6.5) and the pH was adjusted to 7.6 with sodium bicarbonate (about 3.36 g, 40 mmol). The mixture was stirred at RT for 2 hours, and the pad was filtered and dried in a vacuum oven at 45 °C. Next, 17.06 g of dark red powder was obtained.

IR (solvent free, cm ^-1 ): 3461, 3129, 2954, 2924, 2844, 2458, 2384, 2289, 2171, 2107, 1988, 1908, 1738, 1586, 1509, 1407, 1364, 1259, 1222, 1144, 1021,968,950,876,830,794,778,634.

Elemental analysis: C 44.3%, H 4.3%.

Fe content: 11.12% [w/w].

Example 3 Tris-(2,4-dimethoxyvaleramide)-iron(III)-complex

11.0 g (85.0 mmol) of 2,4-dimethoxyamylamine was dissolved in 730 ml of ethanol and heated to 40 °C. 4.60 g (28.3 mmol) of iron(III)-chloride dissolved in 46 ml of ethanol was added dropwise to the 2,4-dimethoxyammoniumamine solution. 11.8 ml (85.0 mmol) of triethylamine was added. The reaction solution was evaporated to dryness, and the mixture was applied to methylene chloride (2.3 L) and filtered. The bright red solid was dried at 50 ° C in a high vacuum overnight. This gave 6.2 g of product.

IR (solvent free, cm ^-1 ): 3430, 3293, 3161, 2969, 2927, 2884, 1682, 1587, 1512, 1427, 1356, 1231, 1145, 1091, 1035, 947, 885, 794, 690.

Fe content: 12.54% [w/w].

Example 4 Tris-(2,4-dioxypentanoic acid)-iron(III)-complex

A solution of 0.83 g (5.1 mmol) of iron (III)-chloride dissolved in 50 ml of ethanol was added dropwise to a solution of 2.00 g (15.4 mmol) of 2,4-dioxypentanoic acid in 50 ml of ethanol. The solution was stirred at room temperature for 30 minutes and then 3.32 g (15.4 mmol) of a 25% sodium methoxide solution was added. The mixture was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was dried in a vacuum oven at 50 °C. The product of 10.7 g of dark brown powder was obtained.

IR (solvent free, cm ^-1 ): 2920, 1713, 1586, 1517, 1358, 1234, 1157, 1010, 947, 909, 788, 725, 626, 589, 537, 495.

Fe content: 9.02% [w/w].

Example 5 Tris-(oxy(2-oxychloropentyl)ethyl acetate)-iron(III)-complex

0.81 g, (4.99 mmol) of iron (III) was dissolved in 20 ml of ethanol. 2.68 g (14.5 mmol) of ethyl oxy(2-oxychloropentyl)acetate was dissolved in 20 ml of ethanol, and the solution was added to the iron (III)-chloride solution. Upon addition, the color of the solution changed from yellow to dark red. The solution was stirred at room temperature for 5 minutes and then 1.26 g (15.0 mmol) sodium bicarbonate was added. The mixture was stirred at room temperature for 1 hour and then evaporated to dryness. The residue was dissolved in 100 ml of water, stirred at RT for 2 h (pH at 8.0) and extracted with ethyl acetate. The ethyl acetate was removed on a rotary evaporator. The residue was extracted with 100 ml of n-hexane, and the combined n-hexane portion was concentrated and dried. Obtained 2.6 g of a dark red solid.

IR (solvent free, cm ^-1 ): 2964, 1725, 1672, 1597, 1551, 1488, 1390, 1365, 1212, 1118, 1015, 917, 861, 839, 803, 771, 705, 634.

Fe content: 9.25% [w/w].

Example 6 Tris-(oxy(2-oxocyclohexyl)acetate)-iron(III)-complex

0.81 g (4.99 mmol) of iron (III)-chloro was dissolved in 20 ml of ethanol. 2.88 g (14.5 mmol) of ethyl oxy(2-oxycyclohexyl)acetate was added, and the reaction mixture was diluted with an additional 20 ml of ethanol. The solution turned from orange to dark red when added. The solution was stirred at room temperature for 10 minutes and then 3.23 g (15.0 mmol) sodium methoxide solution (25%) was added. The mixture was stirred at room temperature for 1 hour and evaporated to dryness. 90 ml of tert-butyl methyl ether was added to the residue and stirred at room temperature until overnight. The solid was filtered and dried under high vacuum. Obtained 2.8 g of a dark red solid.

IR (solvent free, cm ^-1 ): 2976, 2932, 2860, 1736, 1654, 1581, 1482, 1447, 1413, 1379, 1363, 1312, 1297, 1242, 1210, 1164, 1080, 1061, 1017, 972, 919, 827, 771, 726.

Elemental analysis: C 54.7%, H 6.9%.

Fe content: 8.27% [w/w].

Example 7 Tris-(5,5-dimethyl-1-(piperidin-1-yl)hexane-1,2,4-trione)-iron(III)-complex

3.50 g (1.39 mmol) of an iron (III) ethoxylate solution (ethanol, 2.22%) was dissolved in 8 ml of absolute ethanol. 1.00 g (4.18 mmol) of 5,5-dimethyl-1-(piperidin-1-yl)hexane-1,2,4-trione was added and the reaction solution was stirred overnight. The color of the solution changed from bright red to ruby upon addition. The solvent was removed on a rotary evaporator. The residue was completely dissolved in ethyl acetate and evaporated to dryness. The residue was dried at 50 ° C under high vacuum overnight. 1.21 g of a dark red solid was obtained.

IR (solvent free, cm ^-1 ): 3450, 2936, 2861, 1637, 1550, 1443, 1399, 1387, 1359, 1293, 1254, 1235, 1179, 1154, 1131, 1049, 1025, 1010, 964, 928, 895, 843, 810, 810, 780, 706.

Fe content: 7.5% [w/w].

Example 8 Tris-(N,N,5,5-tetramethyl-2,4-dimethoxyhexylamine)-iron(III)-complex

3.88 g (1.54 mmol) of an iron (III) ethoxylate solution (ethanol, 2.22%) was dissolved in 8 ml of absolute ethanol. 0.92 g (4.62 mmol) of N,N,5,5-tetramethyl-2,4-dimethoxyhexylamine was added, and the reaction solution was stirred overnight. The solvent was removed on a rotary evaporator. The residue was dried at 50 ° C under vacuum to overnight. Obtained 1.1 g of dark red oil.

IR (solvent free, cm ^-1 ): 2965, 2869, 1644, 1551, 1489, 1382, 1355, 1287, 1257, 1228, 1202, 1153, 1108, 1062, 1022, 969, 934, 840, 809, 780, 734, 706, 644.

Fe content: 8.7% [w/w].

Example 9 Tris-(N,N,5,-trimethyl-2,4-dimethoxyhexylamine)-iron(III)-complex

0.29 g (1.80 mmol) of iron (III)-chloro was dissolved in 10 ml of anhydrous THF. 1.00 g (5.40 mmol) of N,N,5-trimethyl-2,4-dimethoxyhexylamine was dissolved in 1 ml of anhydrous THF and the solution was added to an iron (III)-chloride solution. 0.56 g (5.58 mmol) of triethylamine was added to 2 ml of anhydrous THF and added dropwise to the reaction mixture. The mixture was stirred at room temperature for 15 minutes. 100 ml of diethyl ether was added and the resulting suspension was filtered. The filtrate was concentrated to dryness on a rotary evaporator, dissolved in 100 ml diethyl ether and filtered again. The filtrate was concentrated to dryness on a rotary evaporator and the residue was dried at 50 &lt;0&gt;C under high vacuum overnight. 0.84 g of a red vitreous solid was obtained.

IR (solvent free, cm ^-1 ): 2968, 2932, 2873, 1649, 1555, 1491, 1389, 1338, 1261, 1224, 1149, 1112, 1094, 1060, 966, 944, 883, 814, 796, 784, 752, 719, 677, 654.

Fe content: 7.48% [w/w].

Example 10 Tris-(2-butyric acid diethyl ester)-iron(III)-complex

0.65 g (4.00 mmol) of iron (III)-chloro was dissolved in 25 ml of anhydrous THF, and 2.26 g (12.0 mmol) of diethyl 2-butanone was added. After stirring for 30 minutes, 1.21 g (12.0 mmol) of triethylamine dissolved in 12.5 ml of anhydrous THF was added dropwise to the blue reaction solution, and stirring was continued for 30 minutes at room temperature. The reaction solution, which is now red, is diluted with 30 ml of water THF. Then 12.5 g of a 6.4% sodium methoxide solution (11.8 mmol) diluted in 12.5 ml of anhydrous THF was added dropwise. The precipitated salts were filtered and concentrated to dryness on a rotary evaporator. The residue was dried at 50 ° C under vacuum. The crude product was dissolved in 200 ml of diethyl ether, filtered, and then filtered and evaporated. This gave 2.3 g of dark red resin.

IR (solvent free, cm ^-1 ): 2983, 2938, 1790, 1726, 1597, 1537, 1476, 1446, 1389, 1367, 1260, 1229, 1131, 1094, 1032, 989, 946, 859, 822, 785, 685.

Fe content: 8.93% [w/w].

Example 11 Tris-(5-methyl-1-(morpholin-4-yl)hexane-1,2,4-trione)-iron(III)-complex

0.24 g (1.48 mmol) of iron (III)-chloro was dissolved in 0.60 g (4.40 mmol) of sodium acetate in 10 ml of water. 1.00 g (4.40 mmol) of 5-methyl-1-(morpholin-4-yl)hexane-1,2,4-trione was added and the solution was stirred for 5 minutes. 0.37 g (4.49 mmol) of sodium hydrogencarbonate was dissolved in a minimum amount of water and added dropwise to the reaction mixture. The reaction mixture was extracted with EtOAc, dried over sodium sulfate and evaporated. The residue was dried at 50 ° C under high vacuum overnight. A 0.8 g red vitreous solid was obtained.

IR (solvent free, cm ^-1 ): 2968, 2927, 2858, 1643, 1556, 1520, 1434, 1406, 1359, 1298, 1274, 1252, 1202, 1165, 1150, 1111, 1065, 1028, 965, 944, 916, 878, 842, 815, 783, 748.

Fe content: 7.48% [w/w].

Example 12 Tris-(1-(morpholin-4-yl)pentane-1,2,4-trione)-iron(III)-complex

4.12 g (21.3 mmol) of iron(III)-acetate was suspended in 190 ml of 13.1 g (66.0 mmol) of 1-(morpholin-4-yl)pentane-1,2,4-trione dissolved in ethyl acetate. Stir at 60 ° C for 60 minutes. The insoluble components were then filtered off and the product was crystallized from the reaction mixture at 4 °C. The crystal precipitate was filtered, dissolved in acetone, and evaporated to dryness on a rotary evaporator. The residue was dried at 50 ° C under vacuum to overnight. 11.0 g of a red solid was obtained.

IR (solvent free, cm ^-1 ): 2979, 2918, 2855, 1644, 1559, 1523, 1437, 1390, 1357, 1300, 1283, 1269, 1248, 1224, 1169, 1111, 1067, 1036, 953, 919, 852, 823, 807, 790, 760.

Fe content: 8.05% [w/w].

Example 13 Tris-(1-(pyrrolidin-1-yl)pentane-1,2,4-trione)-iron(III)-complex

0.54 g (3.30 mmol) of iron (III)-chloro was dissolved in 1.36 g (10.0 mmol) of sodium acetate in 20 ml of water. 1.83 g (10.0 mmol) of 1-(pyrrolidin-1-yl)pentane-1,2,4-trione was dissolved in 40 ml of ethyl acetate, and the solution was added to the reaction mixture while stirring. The pH of the water soluble layer was adjusted to 6.5 with a saturated sodium bicarbonate solution. After removing the ethyl acetate, the water-soluble layer was extracted three times with ethyl acetate (200 ml), dried over sodium sulfate and evaporated to dryness. 1.5 g of a red solid was obtained.

IR (solvent free, cm ^-1 ): 2969, 2877, 1701, 1633, 1562, 1520, 1427, 1361, 1250, 1225, 1187, 1159, 1113, 1014, 980, 951, 917, 870, 824, 783, 718.

Fe content: 8.19% [w/w].

Example 14 Tris-(1-(4-methoxypiperidin-1-yl)pentane-1,2,4-trione)-iron(III)-complex

0.56 g (2.90 mmol) of iron was suspended in 2.04 g (9.00 mmol) of 1-(4-methoxypiperidin-1-yl)pentane-1,2,4-trione dissolved in 30 ml of ethyl acetate. III)-acetate, stirred at 60 ° C for 60 minutes. The insoluble portion was then filtered, and the filtrate was concentrated and dried by a rotary evaporator. 80 ml of toluene was added and concentrated again by a rotary evaporator. Repeat this process three times. The residue was dried at 50 ° C under vacuum to overnight. This gave 1.9 g of a red amorphous solid.

IR (solvent free, cm ^-1 ): 2930,2825,1637,1561,1527,1445,1393,1358,1318,1282,1260,1221,1185,1162,1094,1075,1020,955,939,889,834,820,782,735,698,671.

Fe content: 7.06% [w/w].

Example 15 Tris-( N- (2-hydroxyethyl) -N -methyl-2,4-dimethoxypentanylamine)-iron(III)-complex

0.26 g (1.62 mmol) of iron (III)-acetate and 1.00 g (5.61 mmol) of N-(2-hydroxyethyl)-N-methyl-2,4-dimethoxypentanylamine were dissolved in 10 ml. In water, stir at room temperature for 1 hour. 0.59 g (4.35 mmol) of sodium acetate trihydrate was added and stirred at room temperature for 10 minutes. Then 0.21 g (2.52 mmol) of sodium hydrogencarbonate was added, after which the reaction mixture was lyophilized immediately. The residue was dissolved in 50 ml of ethanol and the insoluble salts were filtered. The filtrate was evaporated to dryness and the residue was takenjjjjjjjjj More insoluble salts were filtered off and the filtrate was concentrated again and dried. Excess ligand was removed by cooking with 50 ml of diethyl ether and the remaining complex was dried in vacuo. This gave 0.8 g of a red solid.

IR (solvent free, cm ^-1 ): 3388, 2931, 1626, 1593, 1484, 1389, 1290, 1113, 1048, 1018, 956, 923, 864, 835, 771.

Fe content: 7.7% [w/w].

Claims (13)

An iron(III)-2,4-dioxy-1-carbonyl conjugate compound or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of iron deficiency symptoms and iron deficiency anemia. An iron (III) complex compound as claimed in claim 1 which comprises at least one of the ligands of formula (I): Wherein each arrow represents a coordinate bond of one or different iron atoms, and R ₁ is selected from the group consisting of: an optionally substituted alkyl group, an optionally substituted alkoxy group, and a selectivity a substituted alkoxycarbonyl group, the R ₂ group being selected from the group consisting of: -hydrogen, -optionally substituted alkyl, and -halogen, or R ₁ and R ₂ together with a carbon atom to which they are attached A selectively substituted saturated or unsaturated 5- or 6-membered ring, the 5- or 6-membered ring optionally containing one or more heteroatoms, and the R ₃ is selected from the group consisting of: An optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted amine group, and a -hydroxy group, or a pharmaceutically acceptable salt thereof. An iron (III) complex compound for use as described in claim 2, wherein R ₃ is an optionally substituted amine group. An iron (III) complex compound for use as claimed in claim 2, wherein R ₁ is selected from the group consisting of: -alkyl, which is selected from 1 to 3 The substituents of the group consisting of freely substituted are: a hydroxyl group, an alkoxy group, an alkoxycarbonyl group, and an aminocarbonyl group, an alkoxycarbonyl group, which is selected from the group consisting of 1 to 3 selected from the group consisting of Substituent substituents of the group: hydroxy and alkoxy, -alkoxy, which are optionally substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, alkoxy and halogen. R ₂ is selected from the group consisting of: -hydrogen, -alkyl, which is optionally substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, alkoxy, halogen, and An alkoxycarbonyl group, a halogen, selected from chlorine or fluorine, or R ₁ and R ₂ together with a carbon atom to which they are attached form a selectively substituted 5- or 6-membered ring, 5- or 6 The member ring may optionally contain one or more heteroatoms and may have from 1 to 3 substituents selected from the group consisting of hydroxyl, alkoxy, alkoxycarbonyl and amine groups. The carbonyl group, and the R ₃ group are selected from the group consisting of: -hydroxy-alkyl groups, which are optionally substituted with from 1 to 3 substituents selected from the group consisting of: hydroxy, alkoxy, An alkoxycarbonyl group and an aminocarbonyl group, an alkoxy group, which is optionally substituted with 1 to 3 substituents selected from the group consisting of a hydroxyl group, an alkoxy group and an alkoxycarbonyl group, and An amine group optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxy and alkoxycarbonyl, Its pharmaceutically acceptable salts. An iron (III) complex compound for use as claimed in any one of claims 2 to 4 wherein R ₁ is selected from the group consisting of: -methyl, -isopropyl, - uncle Butyl, -methoxy, -ethoxy, -methoxycarbonyl, and -ethoxycarbonyl. R ₂ is selected from the group consisting of: -hydrogen, -methyl, and -fluoro, or R ₁ and R ₂ together form a propyl (-CH ₂ -CH ₂ -CH ₂ -)- or butyl The group of (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -), and the group of R ₃ are selected from the group consisting of: -hydroxy, -methoxy, -ethoxy, -amino, - Dimethylamino, 3-propylamino, 2-ethylamino, -morpholinyl, -piperidine, and 4-hydroxypiperidine, or a pharmaceutically acceptable salt thereof. An iron (III) complex compound for use as claimed in any one of claims 1 to 5, which has the following formula Wherein R ₁ , R ₂ and R ₃ , respectively, may be the same or different and are as defined above, as well as pharmaceutically acceptable salts thereof. An iron (III) complex compound for use as claimed in any one of claims 1 to 6, wherein the symptoms associated with iron deficiency symptoms and iron deficiency anemia include: fatigue, stenosis, lack of concentration Strength, low cognitive efficiency, difficulty finding the correct word, forgetfulness, unnatural paleness, irritability, rapid heartbeat (tachycardia), ulcer or tongue hypertrophy, splenomegaly, craving strange food (pica) , headache, lack of appetite, increased vulnerability to infection, depression. An iron (III) complex compound for use as claimed in any one of claims 1 to 7 for use in the treatment of iron deficiency anemia in pregnant women, potential iron deficiency anemia in children and adolescents, Iron deficiency anemia caused by gastrointestinal abnormalities, iron deficiency anemia caused by blood loss (such as gastrointestinal bleeding, for example, due to duodenal ulcer, malignant tumor, acne, inflammatory disease, administration of salicylic acid), iron deficiency caused by menstruation Iron deficiency, iron deficiency anemia caused by injury, iron deficiency anemia caused by intestinal lepidemia, iron deficiency anemia caused by reduced dietary iron intake (especially picky children and youth) Year), immunodeficiency caused by iron deficiency anemia, brain function damage caused by iron deficiency anemia, restless leg syndrome caused by iron deficiency anemia, iron deficiency anemia of cancer, iron deficiency caused by chemotherapy Iron deficiency anemia caused by anemia, inflammation (AI), iron deficiency anemia (CHF, congestive heart failure), chronic renal insufficiency, stage 3-5 (CDK 3-5, chronic Iron deficiency anemia in chronic kidney disease (3-5), iron deficiency anemia caused by chronic inflammation (ACD), iron deficiency anemia in rheumatoid arthritis (RA), iron deficiency in systemic lupus erythematosus (SLE) Anemia and iron deficiency anemia of inflammatory bowel disease (IBD). The iron (III) complex compound used as described in any one of claims 1 to 8 is for oral administration. An iron (III) complex compound according to any one of claims 9 to 9, wherein a solid preparation or a liquid preparation is administered, for example, a pill, a lozenge, an enteric lozenge, a film. Tablets, layering agents, sustained release formulations, stored formulations, dragees, stoppers, granules, microcapsules, fine-tuning formulations, nano-formulations, capsules, casing capsules and powders, the liquid formulation comprising: Drinkable formulations such as syrups, elixirs, solutions, suspensions, juices. An agent comprising an iron (III) complex compound as defined in any one of claims 1 to 6. An agent comprising an iron (III) complex compound as defined in any one of claims 1 to 6 and at least one physiologically compatible carrier or excipient. A composition comprising an iron (III) complex compound as defined in any one of claims 1 to 6 and at least one additional agent acting on iron metabolism in combination therewith.