NZ616045B2 - Fe(iii) complexes for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anaemias - Google Patents

Abstract

Disclosed are Fe(III) complexes with bidentate pyrimidine ligands (formula I) and pharmaceutical compositions for use in the treatment and prevention of iron dificency and anaema. In comparison to classical preparations of Fe(II) salts, the complexes have fewer side effects, lower toxicity, low molecular weight, high complex stability and do not lead to free Fe which catalyses the formation of reactive oxygen species that cause oxidative stress. cular weight, high complex stability and do not lead to free Fe which catalyses the formation of reactive oxygen species that cause oxidative stress.

Description

Fe(III) Complexes for the Treatment and Prophylaxis of Iron Defiency Symptoms and Iron Deficiency as AH26(9127889_1):SAK per second). This high regenerative capacity is achieved by macrophages phagocytizing the ageing erythrocytes, lysing them and thus recycling the iron thus ed for the iron metabolism. The amount of iron of about 25 mg required daily for erythropoiesis is thus provided for the main part.

The daily iron requirement of an adult human is between 0.5 to 1.5 mg per day, infants and women during pregnancy require 2 to 5 mg of iron per day. The daily iron loss, e.g. by desquamation of skin and lial cells, is low; increased iron loss occurs, for example, during menstrual hemorrhage in women. Generally, blood loss can significantly reduce the iron level since about 1 mg iron is lost per 2 ml blood. In a healthy human adult, the normal daily loss of iron of about 1 mg is usually replaced via the daily food . The iron level is regulated by I5 absorption, with the absorption rate of the iron present in food being n 6 and I2 %; in the case of iron deficiency, the absorption rate is up to 25%. The absorption rate is regulated by the organism depending on the iron requirement and the size of the iron store. in the process, the human organism utilizes both divalent as well as trivalent iron ions. Usually, iron[|||) compounds are dissolved in the stomach at a sufficiently acid pH value and thus made available for absorption. The absorption of the iron is carried out in the upper small intestine by mucosal cells. In the process, ent non-heme iron is first reduced in the intestinal cell membrane to FeIII) for absorption, for example by ferric reductase [membrane-bound duodenal cytochrome b), so that it can then be transported into the inal cells by means of the transport protein DMTI (divalent metal orter I). In contrast, heme iron enters the enterocytes through the cell membrane without any change. In the enterocytes, iron is either stored in ferritin as depot iron, or discharged into the blood by the ort protein ferroportin.

Hepcidin plays a central role in this process e it is the most important regulating factor of iron uptake. The divalent iron transported into the blood by ferroportin is converted into trivalent iron by oxidases [ceruloplasmin, stin), the trivalent iron then being transported to the relevant places in the organism by transferrin (see for example "Balancing acts: lar control of mammalian iron metabolism". M.W.

Hentze, Cell 117,2004,285-297.) Mammalian organisms are unable to actively discharge iron. The iron metabolism is ntially controlled by hepcidin via the cellular release of iron from macrophages, hepatocytes and enterocytes.

In pathological cases, a reduced serum iron level leads to a reduced hemoglobin level, reduced erythrocyte production and thus to anemia.

External ms of anemias include fatigue, pallor as well as reduced capacity for concentration. The al symptoms of an anemia include low serum iron levels [hypoferremia), low hemoglobin , low crit levels as well as a reduced number of erythrocytes, reduced i5 locytes and elevated levels of soluble transferrin receptors.

Iron deficiency symptoms or iron anemias are treated by ing iron.

In this case, iron substitution takes place either orally or by intravenous iron administration. Furthermore, in order to boost ocyte formation, erythropoietin and other erythropoiesis-stimulating substances can also be used in the treatment of anemias.

Anemia can often be traced back to malnutrition or low-iron diets or imbalanced nutritional habits low in iron. Moreover, anemias occur due to reduced or poor iron absorption, for e because of ectomies or diseases such as Crohn's disease. Moreover, iron deficiency can occur as a consequence of increased blood loss, such as because of an injury, strong menstrual bleeding or blood donation.

Furthermore, an increased iron requirement in the growth phase of 3O adolescents and children as well as in pregnant women is known. Since iron deficiency not only leads to a reduced erythrocyte formation, but thereby also to a poor oxygen supply of the organism, which can lead to the above-mentioned symptoms such as fatigue, pallor, reduced powers of concentration, and especially in adolescents, to long-term negative effects on cognitive pment, a highly effective and well tolerated therapy is of particular interest.

Through using The Fe(lll) complex compounds according To The invenTion, There is The possibliTy of TredTing iron ency sympToms and iron deficiency anemias ively by oral opplicaTion wiThouT having To accepT The large poTenTiaI for side effecTs of The classical preparaTions, The Fe(|i] iron salTs, such as FeSO4, which is caused by oxidaTive s’rress.

Poor compliance, which ofTen is The reason for The deficienT eliminaTion of The iron deficiency ion, is Thus avoided.

Prior arT: A mulTiTude of iron complexes for The TreaTmenT of iron deficiency ions is known from The prior arT.

A very large proporTion of These complex compounds consisTs of polymer sTrucTures. MosT of These x compounds are iron-polysaccharide complex nds [W020081455586, 062546, WO20040437865, U82003236224, EPi50085). IT is precisely from This area ThoT There are medicamenTs available on The morkeT (such as MalTofer, 2O Venofer, FeriniecT, Dexferrum, FerumoxyTol).

AnoTher large porTion of The group of The polymer complex compounds is comprised of The iron-pepTide x compounds (CNiOi 481404, EP939083, JP02083400].

There are also Fe complex compounds described in The IiTeroTure ThoT are sTrucTurally derived from macromolecules such as hemoglobin, phyll, curcumin and heparin (US474670, CNl687089, BiomeTols, 2009,22,7OT-710).

Moreover, low-molecular Fe complex compounds are also described in The IiTeraTure. A large number of These Fe complex compounds comprises carboxylic acid and amino acids as ligands. In This case, The focus is on asparTaTe (U82009035385) and ciTraTe [EP308362] as ligands.

Fe complex compounds containing derivatized phenylalanine groups as ligands are also described in this context (E82044777).

Hydroxypyrone and ypyridone Fe complex compounds are also described in the literature [EP159194, EP138420, EP107458). The corresponding 5-ring systems, the hydroxyfuranone Fe complex compounds, are also described in y thereto (WO2006037449). l particular, the hydroxypyridone Fe complex nds, however, have comparatively low water solubility, making them less suitable, especially for oral administration. rmore the hydroxypyridone Fe complex compounds have comparatively low iron utilization. er, iron-cyclopentadienyl complex nds are also described in the literature (GB842637).

Furthermore, oxy-4,o-dimethyl-2[1H]-pyrimidone are described in the literature as Fe(lil) ligands (Bull. Chem. Soc. Jpn., 66, 841 - 841 (1993), and as a possible structure of a corresponding iron[|||) complex the following structure is specified: (see also “Reviews On Heteroatom Chemistry", vol. 18., 1998, pages 87 to 118 from the same authors). A characterization of this complex was only carried out in solution. A solid form of this complex is not disclosed.

Furthermore, the iron complex compounds are not proposed or used as medicaments, such as especially for the treatment of iron deficiency ms. The same authors suggest only the use of hexadentate 1- hydroxy-lH-pyrimidine-2—one compounds as iron sequestering agents for treatment of iron overload conditions such as semia (J. Org. Chem. 1997, 62, 3618 — 3624). By the administration of hydroxy-pyrimidinone compounds to the body for the treatment of thalassemia iron might be removed — so no iron will be ed — as in the treatment of iron deficiency anemia by administration of iron complex nds in accordance with the present invention.

J. Am. Chem. Soc. 1985, 107, 6540 — 6546 describes tetradentate i— hydroxy-TH-pyridineone compounds as ligands and a binuclear iron complex compound therewith. The possibility to use the ligands for iron sequestering is mentioned, too. Similarly, lnorganico Chimica Acta, 135 (1987) T45 — 150 discloses the use of oxy-lH-pyridineones as agents for masking iron.

Iron salts (e.g. iron(|l) sulfate, iron(|l) fumarote, iron(lll) chloride, iron(|l) aspartate, iron(|l) ate] are another important constituent for the treatment of iron deficiency symptoms and iron deficiency anemias.

These iron salts are very problematic in that, in part, they are highly incompatible (up to 50%) in the form of nausea, vomiting, diarrhea and also obstipation and cramps. Moreover, free iron(|l) ions which catalyze the formation (inter alia Fenton on) of reactive oxygen s (ROS) occur during the use of these iron(|l) salts. These ROS cause damage to DNA, lipids, proteins and ydrates which has far- reaching effects in cells, tissue and organs. This complex of problems is known and, in the literature, is largely considered the cause for the high incompatibility and referred to as oxidative stress.

Therefore, iron(IIIJ-i-hydroxy-lH-pyrimidineone or pyrimidineoI-i- oxide complex compounds, respectively, have not been described in the prior art r as a medicament nor in particular for the use in the treatment and/or for prophylaxis of iron deficiency symptoms and iron deficiency anemia so far.

According to a first aspect of the present invention there is ed use of iron(III) pyrimidineoloxide complex compounds or pharmaceutically acceptable salts thereof, which contain at least one ligand of the formula (I): AH26(9820323_1):JIN wherein the arrows respectively represent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are ed from the group consisting of: - hydrogen, - alkyl, which may be substituted with cycloalkyl or with 1 to 3 substituents selected from the group consisting of o y, o aryl, which may be substituted with one or more substituents selected from  halogen,  hydroxy,  alkyl, as defined above and  alkoxy, as defined below, o heteroaryl, which may be substituted with one or more substituents selected from  halogen,  hydroxy,  alkyl, as defined above and  alkoxy, as defined above, o alkoxy (RO-), with R being alkyl as defined above, o alkoxycarbonyl (RO-CO-), with R being alkyl as d above, o acyl, o halogen, o amino ( -NH2) or a 5 or ered cyclic amino that may contain further hetero atoms selected from N, O, S, and which each may be substituted to form mono- or dialkylamino or AH26(9820323_1):JIN mono- or diarylamino, with aryl being aryl or heteroaryl, or mixed alkylarylamino groups, each with al kyl, aryl or heteroaryl as defined above, o aminocarbonyl, derived by adding a yl group to amino or a 5 or 6-membered cyclic amino, each as defined above, and o cyano, - halogen, - alkoxy, as defined above, - aryl, as defined above, - alkoxycarbonyl, as defined above, - amino, as defined above, and - aminocarbonyl, as defined above, or R1 and R2 or R2 and R3 er with the carbon atoms to which they are bonded, form an optionally substituted saturated or unsaturated 5 - or 6- membered ring, which may optionally contain one or more heteroatoms for the manufacture of a medicament medicament for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anemias and the symptoms associated therewith. ing to a second aspect of the t invention there is provided use of a composition containing iron(III) complex nds as defined in the first aspect, in combination with at least one further ment which acts on the iron metabolism for the preparation of medicaments for the treatment of iron deficiency anemia.

AH26(9820323_1):JIN therapeutic success in the treatment of iron ency anemia could be achieved. ally in comparison to iron salts, the complex compounds according to the invention ted a faster and higher utilization. Furthermore, these new systems have significantly reduced side effects than the classically used iron salts since there is no noteworthy occurrence of free iron irons in this case. The complex compounds according to the invention exhibit almost no oxidative stress since there is no formation of free radicals. Thus, significantly fewer side effects occur in the case of these complex compounds than in the case of the Fe salts known from the prior art. The x compounds exhibit good stability at various pH value ranges. Furthermore, the iron complex compounds have a very low toxicity and can therefore be administered in high dosages t side effects. Finally the complex compounds can be prepared well and are optimally suitable for the ation of medicaments. in particular for oral administration.

Thus, the subject matter of the invention are iron(|l|)-pyrimidineol-T- oxide complex compounds or their pharmaceutically acceptable salts for use as medicaments or synonymous for use in a method for therapeutic treatment of the human body, respectively.

The iron(|l|)-pyrimidineo|-T-oxide complex compounds as used in accordance with the present invention particularly include such nds with comprise the following structural t: N O ' \ 8\Fe wherein “W" respectively is a substituent saturating the free valence and the arrows respectively ent coordinate bonds to the iron atom.

Thus. the terms - “pyrimidineol-l -oxide”, - “pyrimidineol-i —oxide compounds” or - idineol-i oxide-“ligands occording To The invenTion include The corresponding y sTorTing compounds o'—N\O):j OS well as The corresponding deproTonoTed ligonds N+ , O-——N‘Nj \N / O/kl , Tively, which are presenT in The corresponding ironllll] complex compounds.

FurThermore, ing To The invenTion The oforemenTioned Terms do noT only comprise The respecTive bose body: Ho;-—N:’Nj or The ligand compound resulTing from deproTonoTing The underlying hydroxy compound 01—NO);/j , respecTiver buT as well Their represenToTives subsTiTuTed on The pyrimidine rings, resulTing from The replocemenT of one or more hydrogen dToms on The dine ring by other substituents. Accordingly, in context with the t invention the aforementioned terms refer to the entire class of “pyrimidine—2-ol-l-oxide” compounds and the deprotonated ligands, ing their representatives substituted on the pyrimidine ring.

Formally, a (deprotonated) pyrimidineol-l-oxide ligand according to the present invention carries a negative charge. This means, that in the case of three s per iron atom, the iron atom formally has the oxidation state +3. It is clear to the person skilled in the art that the shown formulas represent only one possible mesomeric formula and that there are several mesomeric formulas and that delocalisation of the electrons in the ligands or in the iron complex compound may be present, respectively, as shown hereinafter tically.

In the iron(lll) pyrimidineol—l-oxide complex compounds according to the invention, the coordination number of the iron atoms is generally six (6), with a coordinating atoms generally being arranged octahedrally.

Furthermore, mono- or polynuclear iron(lll) pyrimidineol-l-oxide complex compounds in which one or more (such as 2, 3 or 4) iron atoms are present are also comprised according to the ion.

Generally, 1—4 iron atoms and 2—1 0 ligands can be present in the iron(|ll} pyrimidineol-l-oxide complex compounds. Mononuclear iron[lll) pyrimidineol-l-oxide complex compounds with at least one preferably tri-, preferably bidentate dineol-l-oxide ligands are preferred.

Mononuclear iron(lll) dineol-l-oxide complex compounds with one [1) central iron atom and three (3) pyrimidineol-l-oxide ligands are particularly preferred.

The iron(|l|) pyrimidineol-l-oxide complex nds are generally present in neutral form. However, salt like iron(l|l] pyrimidineol-l-oxide complex compounds are also included, in which the complex has a ve or negative charge which is compensated, in particular, by pharmacologically compatible, substantially non-coordinating anions (such as, in particular, halogenides, such as chloride] or cations [such as, in particular, alkaline or alkaline-earth metal ions].

The iron[lll) pyrimidineol-l-oxide complex compounds according to the invention ularly include complex compounds, comprising at least one, preferably a bidentate pyrimidineol-l-oxide ligand of the formula lea/K if 0 9o\_\Fe wherein ”WW respectively is a substituent saturating the free valence of the ligands, which can, as shown above, bond to one or even two different iron atoms in the sense of bridging. lron[||l) pyrimidineol-l—oxide complex compounds are red which exclusively comprise preferably bidentate pyrimidineol-l -oxide ligands which may be the same or different. Furthermore, iron(lll) pyrimidineol- l-oxide complex compounds are particularly preferred which exclusively comprise the same pyrimidineol—l-oxide ligands and very particularly red are tris[pyrimidineol-l -oxide] |l) nds.

Preferably, the molecular weight of the ive iron [ll|)-pyrimidinol l- oxide-complex compounds is less than 1000 g / mol, more preferably less than 850 g / mol, still more preferably less than 700 g / mol (each determined from the structural formula).

In a ularly preferred embodiment the iron(lll) complex compounds according to the present invention comprise at least one, preferably three same or ent, preferably same ligands of the formula (l): R2 \ R3 3A0 @\ (1) wherein the arrows respectively ent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - hydrogen, - optionally substituted alkyl, - halogen, - optionally substituted alkoxy, - optionally substituted aryl, - optionally substituted alkoxycarbonyl, - optionally substituted amino, and - optionally substituted aminocarbonyl or R1 and R2 or R2 and R3 together with the carbon atoms to which they are bonded, form an ally substituted saturated or unsaturated 5- or 6- membered ring, which may optionally contain one or more heteroatoms, or pharmaceutically acceptable salts thereof.

The above-mentioned ring formation of the substituents I?1 and R2 or R2 and R3 is schematically shown in the ing formulas: 91 01 A preferred embodiment of the present invention relates to these lron(ll|) complex compounds containing at least one ligand of the formula [I]: 1 ska 0 \ @\ (I) wherein the arrows respectively represent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - hydrogen, - optionally substituted alkyl, - halogen, — ally substituted alkoxy, - ally substituted aryl, - optionally substituted alkoxycarbonyl, and - optionally substituted arbonyl or R1 and R2 or I?2 and R3 together with the carbon atoms to which they are bonded, form an optionally substituted saturated or unsaturated 5- or o- membered ring, which may optionally contain one or more heteroatoms, or pharmaceutically acceptable salts Thereof.

A preferred embodiment of the t invention relates to these ironilll) complex compounds containing at least one ligand of the formula (I): R2 \ R, iii/*0 @\ (I) wherein the arrows respectively represent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - hydrogen - optionally substituted alkyl, and — halogen.

Within the overall context of the invention, optionally substituted alkyl, in ular for the substituents R1 to R3, preferably includes: straight-chained or branched alkyl with i to 8, preferably i to 6 carbon atoms, cycloalkyl with 3 to 8, ably 5 or 6 carbon atoms, or alkyl with i to 4 carbon atoms, which is substituted with cycloalkyl, wherein these alkyl groups can be optionally substituted.

The above mentioned alkyl groups can be unsubstituted or substituted, preferably with i to 3 substituents. These substituents at the alkyl groups are preferably selected from the group consisting of: hydroxy, ally tuted aryl, in particular as d below, optionally tuted heteroaryl, in particular as defined below, optionally substituted alkoxy, in particular as defined below, optionally substituted alkoxycarbonyl, in particular as defined below, optionally substituted acyl, in particular as defined below, halogen, in ular as defined below, optionally substituted amino, in particular as defined below, optionally substituted aminocarbonyl, in particular as defined below, and cyano.

Halogen includes here and within to the t of the present invention, fluorine, chlorine, bromine and iodine, ably fluorine or chlorine.

In the above defined alkyl groups, ally one or more, more preferably 1 to 3 carbon atoms can furthermore be replaced with hetero-analogous groups that contain nitrogen, oxygen or sulphur. This means, in particular, that, for example, one or more, preferably 1 to 3, still more preferred one (i) ene group (-CH2-) can be replaced in the alkyl groups by —NH-, -NR4-, -O- or —S-, wherein R4 is optionally substituted alkyl as d above, preferably C1-C6 alkyl, such as methyl or ethyl, optionally substituted with i to 3 substituents, such as fluorine, ne, hydroxy or alkoxy.

Examples of alkyl residues having 1 to 8 carbon atoms include: a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyi group, an i-pentyi group, a sec-pentyl group, a t-pentyl group, a 2- methylbutyl group, an n-hexyl group, a i-methylpentyl group, a 2- methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a i-ethylbutyl group, a lbutyi group, a 3-ethylbutyl group, a i,i- dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a i-ethyI-i-methyipropyl group, an n-heptyl group, a i- methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4- methyihexyl group, a 5-methylhexyl group, a i-ethylpentyi group, a 2- ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a i,i- dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a 4,4-dimethylpentyl group, a i-propylbutyl group, an n-octyl group, a i-methyiheptyl group, a 2-methylheptyl group, a ylheptyl group, a 4-methylheptyl group, a 5-methylheptyi group, a 6-methylheptyl group, a l-ethylhexyl group, a 2-ethylhexyl group, a lhexyl group, a lhexyl group, a 5-ethylhexyl group, a l,l-dimethy|hexyl group, a 2,2—dimethylhexyl group, a methylhexyl group, a 4,4-dimethylhexyl group, a 5,5-dimethylhexyl group, a l-propylpentyl group, a 2- propylpentyl group, etc. Those with l to 6 carbon atoms are preferred.

Methyl, ethyl, n-propyl, isopropyl, sec-butyl and n-butyl are most preferred.

Examples of alkyl groups ed by replacement with one or more -analogous groups, such as —O—, —S—, —NH— or —N(R4)— are preferably such groups in which one or more methylene groups (-CH2-) are replaced with —0— while forming an ether group, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl etc. Therefore, the definition of alkyl also includes, for example, alkoxyalkyl groups as defined below, which are produced from the above-mentioned alkyl groups by replacement of a methylene group with -O-. If, according to the invention, alkoxy group are additionally permitted as substituents of alkyl, several ether groups can also be formed in this manner [such as a —CH2-O-CH2-OCH3-group]. Thus, according to the invention, polyether groups are also sed by the definition of alkyl.

Cycloalkyl groups with 3 to 8 carbon atoms preferably include: a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a ctyl group, etc. A cyclopropyl group, a cyclobutyl group, a Cyclopentyl group and a exyl group are preferred. The Cycloalkyl groups may optionally be substituted preferably with l to 2 substituents such as hydroxyl or C1-C6 alkoxycarbonyl.

The definition of the optionally substituted alkyl also includes alkyl groups which are substituted by the above mentioned cycloalkyl groups, such as ropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

Heterocyclic alkyl groups according to the invention are preferably those formed by the replacement of methylene with hetero-analogous groups from lkyl, and include, for example, saturated 5 or ered heterocyclic residues, which may be ed via a carbon atom or a nitrogen atom, and which preferably may have i to 3, preferably 2 heteroatoms, especially 0, N, such as tetrahydrofuryl, azetidine-l-yl, substituted inyl, such as 3-hydroxyazetidin—l-yl, pyrrolidinyl, such as pyrrolidin-l-yl, substituted pyrrolidinyl, such as oxypyrrolidin-l-yl, 2- hydroxypyrrolidin-l -yl 2-methoxycarbonylpyrrolidin-l -yl, 2- ethoxycarbonylpyrrolidin-l -yl, 2-methoxypyrrolidin-l -yl, 2-ethoxypyrrolidin- l-yl, 3-methoxycarbonylpyrrolidin-l-yl, 3-ethoxycarbonylpyrrolidin-l-yl, 3- methoxypyrrolidin-l-yl, 3-ethoxypyrrolidine-l-yl, piperidinyl, such as piperidin-l-yl, piperidinyl, substituted piperidinyl, such as 4-methyl-ipiperidyl , 4-hydroxy-l-piperidyl, oxy-l-piperidyl, 4-ethoxy-l- piperidyl, 4-methoxycarbonyI-l-piperidyl, 4-ethoxycarbonyl-l-piperidy|, 4- carboxy-l-piperidyl, 4-acetyl-l-piperidyl, 4-formyl-l-piperidyl, l-methyl piperidyl, 4-hydroxy-2,2,6,é-tetramethyl-l-piperidy|, 4-(dimethylamino]-l- piperidyl, 4-(diethylaminol-l-piperidyl, 4-amino-l-piperidyl, 2- (hydroxymethyl)-l -piperidyl, 3-(hydroxymethyl)-l idyl, 4- [hydroxymethyl)-l -piperidyl, 2—hydroxy-l -pi'peridyl, 3-hydroxy-l -piperidy|, 4-hydroxy-l-piperidyl, morpholin-A-yl, substituted morpholinyl, such as 2,6-dimethyl morpholinyl, piperazinyl, such as zin-l-yl, substituted piperazinyl, such as 4-methylpiperazin-l-yl, 4-ethylpiperazin- l-yl, 4-ethoxycarbonylpiperazin-i-yl, 4-methoxycarbonylpiperazin-l-yl, or ydropyranyl, such as tetrahydropyran-A-yl, and which can optionally be condensated with aromatic rings, and which may ally be substituted, such as with i to 2 substituents such as hydroxy, halogen, Cl-Cé-alkyl, etc. The definition of the optionally substituted alkyl groups thus includes also alkyl groups, which are substituted by the above-defined heterocyclic groups, such as 3-(l- dyl)propyl, 3-pyrrolidin-l -ylpropyl, 3-morpholinopropyl, 2- morpholinoethyl, 2-tetrahydropyranylethyl, 3-tetrahydropyran ylpropyl, 3-(azetidin-l -yl) propyl etc.

Examples of a linear or branched alkyl group substituted with halogen and having 1 to 8, preferably 1 to 6 carbon atoms include, in particular: a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyi group, a tribromomethyl group, a l-fluoroethyl group, a i-chloroethyl group, a i-bromoethyl group, a 2- fluoroethyl group, a roethyl group, a 2-bromoethyl group, a 1,2- difluoroethyl group, a 1,2-dichloroethyl group, a bromoethyl group, a 2,2,2-trifluoroethyl group, a heptafluoroethyl group, a l-tluoropropyl group, a ropropyl group, a l-bromopropyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 3-bromopropyl group, a 1,2- difluoropropyl group, a chloropropyl group, a l,2-dibromopropyl group, a 2,3-difluoropropyl group, a chloropropyl group, a 2,3- dibromopropyl group, a 3,3,3-trifluoropropyl group, a 2,2,3,3,3- pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyi group, a 2-bromobutyl group, a 4-fiuorobutyl group, a 4-chlorobutyl group, a 4- bromobutyl group, a 4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4- heptafluorobutyl group, a perfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a 2—bromopentyl group, a 5-fluoropentyl group, a ropentyl group, a 5-bromopentyl group, a perfluoropentyl group, a 2O 2-fluorohexyl group, a 2-chlorohexyl group, a 2-bromohexyl group, a 6- fluorohexyl group, a 6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a 2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptyl group, a 7-fluoroheptyl group, a roheptyl group, a 7-bromoheptyl group, a perfluoroheptyl group, etc..

Examples of an alkyl group substituted with hydroxy include the above- mentioned alkyl residues, which have i to 3 y residues, such as, for example hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4- ybutyl, 5-hydroxypentyl, b-hydroxyhexyl.

Optionally substituted aryl preferably includes according to the invention aromatic hydrocarbon residues with 6 to l4 carbon atoms (with no hetero atom in the aromatic ring system), for example: phenyl, naphthyl, phenanthrenyl and anthracenyl. The aforementioned aromatic groups may be unsubstituted or substituted. In case of substitution, they preferably preferably have one or more, preferably one (i) or two (2) substituents, in particular halogen, hydroxy, alkyl, alkoxy, in each case as explained above or below. A preferred aromatic group is phenyl. A preferred alkyl substituted with an aromatic group [arylalky|) is benzyl.

Optionally substituted aryl according to the present invention further includes optionally substituted heteroaryl, that is, heteroaromatic groups, such as for example: pyridyl, pyridyl-N-oxide, pyrimidyl, zinyl, pyrazinyl, thienyl, furyl, pyrrolyl, lyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, lyl, quinolyl, isoquinolyl, naphthyridinyl, qulnazolinyl. 5- or 6-membered aromatic heterocycles such as, for example pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl are red. The entioned heteroaromatic groups may be unsubstituted or substituted. In case of substitution, they preferably have one or more, preferably one (i) or two (2] substituents, in particular n, hydroxy, alkyl, alkoxy, in each case as ned above or below. Preferred examples of an alkyl substituted with a heteroaromatic group (hetarylalkyl) are methyl, ethyl, or propyl, in each case substituted with a heteroaromatic group, such as thienylmethyl, pyridylmethyl etc.

Optionally substituted alkoxy (RO-] is formally derived from the above mentioned optionally substituted alkyl residues by adding an oxygen atom and includes in t with the t invention, for e, linear or branched alkoxy groups with up to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an loxy group, a sec-butyloxy group, a t-butyloxy group, an n-pentyloxy group, an i-pentyloxy group, a sec- pentyloxy group, a t-pentyloxy group, a 2-methylbutoxy group, an n- hexyloxy group, an i-hexyloxy group, a t-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a l- ethylbutyloxy group, a 2-ethylbutyloxy group, a l,l-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a l- ethyl-l-methylpropyloxy group, etc. A methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an i- butyloxy group, a sec-butyloxy group, a t-butyloxy group, etc., are preferred. The alkoxy groups may optionally be substituted, such as with the above le substituents for alkyl.

Methoxy, ethoxy, n-propoxy, n-butoxy, etc. are red alkoxy.

Optionally substituted alkoxycarbonyl (RO-CO-] groups are ly derived from the above alkyl groups by adding a - e under formation of an optionally substituted alkyloxycarbonyl residue. In that regard reference can be made to the definition of the above-described alkyl groups. As an alternative optionally substituted alkoxycarbonyl (ROCO- ) groups are derived from the aforementioned alkoxy groups by the addition of a carbonyl group. Methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, n-butoxycarbonyl tert.-butoxycarbonyl etc. are preferred alkoxycarbonyl, which may all be substituted as the above defined alkyl groups.

Optionally substituted amino according to the invention includes preferably: amino (-NH2), optionally substituted mono- or dialkylamino (RHN-, (R)2N), wherein with respect to the definition of optionally substituted alkyl it can be referenced to the above definition. Further included are optionally substituted mono- or diarylamino radicals or mixed optionally substituted alkyl aryl amino radicals, wherein with respect to the definition of optionally substituted alkyl or aryl nce can be made to the above tion. Such groups include, for example, methylamino, dimethylamino, ethylamino, hydroxyethylamino, such as 2- hydroxyethylamino, lamino, phenylamino, methylphenylamino etc..

Particularly preferred is mino. ally substituted amino further includes an optionally substituted cyclic amino, such as optionally substituted 5 or 6-membered cyclic amino that may contain further hetero atoms such as N, O, S, preferably O. Examples of such cyclic amino groups include: the above-mentioned nitrogen-containing heterocyclic groups which are attached via a nitrogen atom, such as piperidin-i-yl, 4-hydroxy-piperidin-i-yl, hoxycarbonyi)pyrrolidin-i-y|, idin-l-yl, morpholinyl, etc. ally substituted amino carbonyl ing to the invention can be formally derived from ally substituted amino, as explained before, by adding a carbonyl residue [{R)2N-C[=O)-). Therein optionally substituted amino preferably includes according to the invention: amino (-NH2], optionally substituted mono- or dialkylamino (RHN-, (R)2N-] for which with regard to the definition of optionally tuted alkyl reference can be made to the above definition. Furthermore included are optionally substituted mono- or diarylamino groups or mixed optionally substituted alkylarylamino groups, for which as regards the definition of optionally substituted alkyl or aryI reference can be made to the above tions. Such groups include, for example methylamino, Dimethylamino, ethylamino, hydroxyethylamino, such as 2- hydroxyethlyamino, Diethylamino, phenylamino, methylphenylamino etc.

Optionally substituted amino further includes an optionally substituted cyclic amino, such as ally tuted 5 or 6-membered cyclic amino that may contain further hetero atoms such as N, O, 5, preferably 0. Examples of such cyclic amino groups include the above-mentioned nitrogen-containing heterocyclic groups bonded through a nitrogen atom, such as piperidin-l-yl, 4-hydroxy-piperidin-i-y|, 2- (methoxycarbonyl)pyrrolidin-i-y|, pyrrolidin-i—yl, Morpholinyl etc.

Examples of optionally substituted aminocarbonyl include therefore: Carbamoyl [HQNC(=O}-), ally substituted mono- or dialkylaminocarbonyl [RHNC(=O), [R)2NC(=O)-), wherein reference can be made to the above definition of optionally tuted alkyl.

Furthermore are included optionally substituted mono- or diarylaminocarbonyl residues or mixed, ally substituted alkylarylaminocarbonyl es, wherein reference can be made to the above definitions of optionally substituted alkyl and aryi. Preferred substituted aminocarbonyl groups comprise up to 14 carbon atoms.

Such groups include for example methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, phenylaminocarbonyl, diphenylaminocarbonyl, methylphenylamino- carbonyl etc.

In a preferred embodiment, R1 and R2 or R2 and R3 form together with the carbon atoms to which they are ed a 5- or b-membered carbocyclic ring.

Examples of the aforementioned ring formation of the substituents R1 and R2 or R2 and R3 as represented schematically by the following formulas: \N \N I l R3 32% 9% e in particular: compounds in which R1 and R2 or R2 and R3 together preferably ent a propylene (-CHQ-CHg-CHQ-l- or a butylene (-CHQ-CHQ-CHz-CHQ-l group, in which ally one methylene group [-CH2—] tively can be replaced with —O-, -NH- or —NR4-, wherein R4 is defined as mentioned above and wherein the groups formed by R1 and R2 or R2 or R3 optionally can furthermore respectively be substituted by one to three substituents selected from the group consisting of hydroxy, oxo, C1-C4 alkoxy, amino and mono- or di-(C1-C4-alkyIJamino.

Exemplary ligands are the following: \N \“ | to)?» l R3 @Xo 8\ 9\ wherein R1 and R3 are each as described above.

In another particularly preferred embodiment of iron [Ill] complex compounds according to the the invention R,, R2, R3 are identical or different and are selected from the group consisting of hydrogen and alkyl, with the proviso that at least one, preferably two of the substituents R1, R2, and R3 are alkyl. Alkyl is preferably as mentioned above, especially straight-chained or branched, preferably, unsubstituted alkyl having up to 6, preferably up to 4 carbon atoms. Still more preferred are iron (III) x compounds n R2 is hydrogen, and R1 and R3 are each the same or different and are selected from alkyl as mentioned above.

The ll) x compounds of the formula (ll) are particularly preferred: wherein R1, R2 and R3 are each defined as above or preferably as defined below.

Furthermore, preferably R1, R2 and I?3 are the same or ent and are selected from: - hydrogen, - Ci a|kyl, preferably as presented above, - halogen, preferably as presented above, - C3cycloalkyl, preferably as presented above, - ycloalkyI-Ci yl, preferably as presented above, - Ci a|i<oxy-Ci a|kyl, preferably as presented above, — Ci alkoxycarbonyl, ably as presented above, - Ci mono- or diaikylaminocarbonyl, ably as presented i5 above, - aminocarbonyl or carbamoyl [H2NC0-1 respectively, - hydroxy-Ci aiky|, preferably as presented above, and - halogen-Ci yl, preferably as presented above.

Particularly ably R], R2 and R3 are the same or different and are selected from: hydrogen, halogen and Ci-é-alkyl, preferably as presented above, in particular hydrogen, chlorine, methyl, ethyl and propyl, in particular i-propyi, butyl, especially tyi. Most preferably, R1, R2 and R3 are selected from: hydrogen, methyl and ethyl.

In a further embodiment of the invention there are provided the iron (III)- pyrimidinol i-oxide-compiex compounds in solid form. The term “solid form“ means here in particular in contrast to the dissolved form, in which the iron [II|)-pyrimidinoi i-oxide-complex compounds are present dissolved in a solvent such as water. The term ”solid form” means also that the iron (|i|)-pyrimidinol T-oxide-compiex compounds at room temperature [23 °C) are present in solid form. The iron (ll|)-pyrimidin-2—oi i-oxide-complex nds can be present in an amorphous, crystalline or partially crystalline form. Also, the iron [|l|)-pyrimidino| i— complex compounds of the invention may exist as hydrates, in particular as crystalline hydrates, such as the monohydrate, in particular as a crystalline monohydrate, It is clear to the person skilled in the art that the ligands ing to the invenfion R3 fik e9\ 0\ arise from the corresponding pyrimidineol-i -oxide compounds: R3 $A0H In the pyrimidineoI—i-oxide compounds there is a keto-enol- tautomerism, wherein the equilibrium state is determined by various factors.

R1 R1 R1 RUN“ R v..— RZPN EN/Ko 6/ 2|): R3 R3 N/|\OH v— R3 '7‘ 0 (5 ('3 OH e e The ligand is formally obtained by cleavage of a proton from the ponding pyrimidine-i -oxide compounds: R1 R1 R2 \ [- H+] R2 \N l i ———————-> l 69/ 69/ E) R3 l|\l OH R3 lIl o o o e 6 so formally carries a single negative charge.

Furthermore it is clear to a person skilled in the art that the pyrimidine oI-i-oxide compounds as used according to the present invention can be drawn by different notations (a, b and c}, but all include the same issue of the N-oxide.

R1 R1 R1 R2 \ R2 R2 / N I N NH R3 fiAOH R3 N’kori R3 \N/KO l l 9 (a) 0 (b) 0 (c).

The same applies for the corresponding deprotonated form of the pyrimidineol-i-oxide ligand compounds. Within the scope of the present invention all tautomeric forms are included, even if only one of the mesomeric formulas is drawn.

Depending on the substituent R1, R2, R3 they can also participate in the eric resonance ures in the pyrimidineol-i-oxide . By way of example, the 4-amino nds can be mentioned. For example: All such tautomers are included within the scope of the ion.

Optionally substituted amino preferably is in the position of R1, ie, in the 4-positlon of the pyrimidine ligand.

The iron(||l) pyrimidineoI-oxide complex compounds, in ular such as of the general a [H] or the corresponding pyrimidineol-i- oxide ligands, respectively, can be present in the form of various isomers or tautomers. Isomeric forms include, for example, regioisomers which differ in the position of the ligands relative to one another, including so- called optical s that have an image/mirror image relationship to one another. If asymmetric carbon atoms are present, the ligands can be present in the form of l isomers which have an image/mirror image relationship to one another, and include pure enantiomers, mixtures of the enantiomers, in particular racemates. Enantiomerically pure ligands can be obtained, as is known to the person skilled in the art, by optical resolution s, such as reaction with chiral reagents to form diastereomers, separation of the diastereomers and release of the enantiomers. Examples of tautomeric nce structures, which are also included according to the invention have been shown above as an example.

Furthermore, in particular the following are preferred embodiments of the invenfion: (In the t ion, the digits 1-6 in “l-éC” or “1-4” in “1 -4C” or “Cl- 4” etc. in each case signify the number of the carbon atoms of the subsequent arbon group designations].

R1, R2 and R3 are selected from the group consisting of: - hydrogen, - halogen, - mono- or di(i -6C-a|ky|)amino, - i—éC-alkyl, (i.e. alkyl with l to 6 carbon atoms), - 3-6C-cycloalkyl, - 3-6C-cycloalkyI-l -4C-a|kyl, - l-4C-alkoxy-i -4C-a|kyl, - hydroxy-l -4C-a|kyl, - fluoro-l-4C-alkyl; or I?1 and R2 together form a propylene (-CHQ-CHz-CH2], butylene [-CHQ- CH2—CH2-CH2-L azabutylene or oxabutylene group; or R2 and R3 together form a propylene (-CHz-CHz-CH2-]-, butylene (-CHQ- CHQ—CHQ-CHQ-l, azabutylene or oxabutylene group or R1 and R2 together with a carbon atom to which they are bonded, form an unsaturated ring, which may optionally contain one or more further hetero atoms, or R2 and R3 together with a carbon atom to which they are bonded, form an unsaturated ring, which may optionally contain one or more further hetero atoms, or pharmaceutically able salts thereof. ably, the aforementioned substituent groups are defined as follows: l-éC-alkyl preferably includes straight-chained or branched alkyl groups with l to 6 carbon atoms. Examples therefore can be methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl n-pentyl, iso- pentyl, neo-pentyl, n-hexyl, iso-hexyl and neo-hexyl. 3-6C-Cycloalkyl preferably includes cycloalkyl l to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. 3cycloalkyl-l-4C-alky| preferably includes a l-bC-alkyl group described above, tuted with a 3-éC-cycloalkyl group described above. Examples therefor can be a cyclopropylmethyl. cyclopentylmethyl and cyclohexylmethyl group. l-3C-alkoxy-carbonyl-l-6C-alky|, preferably es a l-éC-alkyl group described above, which is linked to a carbonyl group which is t with a l-3C alkoxy group as a carboxylic acid ester. es therefor can be methoxycarbonylmethyl, carbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl and isopropoxycarbonylmethyl. l-4C-alkoxy preferably includes a l-4C-alkoxy group, in which an oxygen atom is connected to a straight or branched alkyl chain with 1-4 carbon atoms. Examples of this group can be methoxy, ethoxy, propoxy and isobutoxy. l-4C-alkoxy-l-4C-alkyl preferably includes a l-4C-alkoxy group described above, which is substituted with a l-4C-alkyl group described above. Examples of this group can be methoxyethyl, propyl. methoxypropyl, isobutoxymethyl.

Hydroxy-l-4C-alkyl includes a lkyl group described above, which is substituted with a hydroxy group. es or can be hydroxyethyl, hydroxybutyl and hydroxyisopropyl.

Fluoro-l-4C-alkyl includes a l-4C-alkyl group described above, which is substituted with one to three fluorine atoms. Examples or can by trifluoromethyl and trifluoroethyl.

Halogen signifies F, Cl, Br, I.

Particularly preferred are: R1, R2 and R3 are selected from the group consisting of: - hydrogen, - halogen, - l-éC-alkyl, - l-4C-alkoxy-l-4C-alkyl, - hydroxy-l -AC-alkyl; or R1 and R2 together form a propylene (-CHz-CHQ-CHQ), butylen (-CHQ- CHQ-CHQ-CHz-l, azabutylene or oxabutylene group; 2O or R2 and R3 er form a propylene (-CHz-CH2-CH2), butylene (-CH2- CH2-CH2-CH2-), azabutylene or oxabutylene group, or R1 and R2 er with a carbon atom on which they are bonded, form an rated ring which may optionally contain further hetero atoms, or R2 and R3 together with a carbon atom to which they are , form an unsaturated ring which may optionally comprise further hetero atoms.

Particularly preferably: R1, R2 and R3 are selected from the group consisting of: - hydrogen, - i-éC-aikyl; - i-4C-alkoxy-l-4C-alkyl or R1 and R2 together form a propylene CHz-CHQ] or butylene (-CHQ-CHQ-CHz-CHQJ group; or R2 and R3 together form a ene (-CHz-CHQ-CHQJ or butylene (-CHQ-CHQ-CHz-CHQ-J group or R1 and R2 together with a carbon atom to which they are bonded form an unsaturated ring which may comprise one further nitrogen atom. or R2 and R3 together with a carbon atom to which they are bonded form an unsaturated ring which may comprise a further en atom.

Particularly preferred complex compounds of the general formula (II) are described in the examples.

The ion further relates to a method for the preparation of the iron(|ll) complex compounds ing to the invention which comprises the reaction of a pyrimidineol-i-oxide of formula [Ill] with an iron(|||) salt.

PyrimidinoI-i-oxides as the starting compounds include in particular those of the formula (III): R3 WIAOH 6 (m) wherein R1, R2 and R3 are defined as above, to the tautomeric resonance structures of which it has been referred to. es of suitable ironilll) salts e: iron(|||] chloride, iron[i|l) acetate, iron(lll) sulfate, iron[|l|) e and ll) acetylacetonate, among which iron(|l|) chloride is preferred.

A preferred method is shown in the following scheme: R1 R FeXs 3 V» R3 I e \N (N) g\ l/OfiD/ERZ | EDAOH Fe Base R 0/ /| R 3 1 ('3 (V) X69 o e \N’e (Ill) WMRshi / wherein R,, R2 and R3 are as defined above, X is an anion such as halogenide, such as chloride, a carboxylate, such as acetate, sulphate, nitrate and acetylacetonate and base is a common organic or inorganic base. in the method according to the invention, preferably 3 eq pyrimidine ol-i-oxide (ill), using suitable ironilll} salts (IV) (in this case Fe(|l|) chloride, ) e, Fe(|||] sulphate and Feilll) acetylacetonate are particularly suitable), are reacted under standard conditions to form the corresponding complexes of the general formula [II]. In this case, the synthesis is carried out under the pH conditions optimal for complex 2O formation. The optimum pH value is set by adding a base (V); in this case, the use of sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium methanolate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate or potassium methanolate is particularly suitable.

The ligands (ill) required for the preparation of the complexes where prepared according to the following synthesis method (analogue tetrahedron 1967, 23, 353 — 357). For this purpose, the commercially available or synthesised l,3—dicarbonyl compounds of the l formula [N] were reacted under standard conditions with hydroxy urea [V] to form ligands of the general formula (III). When using unsymmetrical l- rbonyl compounds in this synthesis, this results almost always in the occurrence of the corresponding regioisomers , which can be separated by standard methods which are well known to a person skilled in the art. For n substitution patterns for R1, R2 and R3 [Illa] can also ent the main product and, in these cases, then is the synthesis access to the tive substitution patterns.

R2 R ° ° ————» R1 R3 l169/ 2'169/ acid R3 r]: OH R1 r}: OH (lV) (Ill) (Illa) l5 Analogously, it is also possible to use slightly modified synthesis routes for the preparation of the respective ligands of the general formula (III). l. e., in the synthesis of Ohkanda et al. (Bull. Chem. Soc. Jpn. 1993, 66, 841 — 847) the benzyl ted urea according to formula [V-Bn) is cyclized under rd conditions with the respective l,3-dicarbonyl compounds (IV) to form the corresponding benzyl protected product (lll- Bn], wherein the subsequent cleavage leads to the desired product (III).

In this alternative synthesis route it comes to the occurrence of (Illa), too. (iv) (lll-Bn) Bn = Hz/Pd (ill) For ligands in which one or both of the radicals R1 and R3 are hydrogen, a slightly modified synthesis was carried out. Herein the ponding protected i,3-dicarbonyl compounds such as for example those of the general formula (VI) have been reacted similarly with hydroxyurea (V) under acidic standard conditions. In this case R is preferably methyl or ethyl.

Herein too, the product ratio of the two forming pyrimidineol-l-oxides [lllc] and (llld) is controlled by the choice of the ls R1 and R2. The separation is then performed under standard conditions ar to those skilled in the art. )1 OH R o/R H2N N/ 1 H R1M3 ——___—»<v> l 0 HCI e/ko/ .19/ M) (We) (llld) In general, the preparation of the pyrimidineoI-oxide (III) can be as well carried out by other synthesis routes familiar to a d person. Thus, for example, there is the possibility to react the respective substituted pyrimidines (Vii) with suitable oxidizing agents, such as hydrogen peroxide or peroxycarboxylic acids, to form the desired ts of general formula (III) (e.g. analogous to Can. J. Chem. 1984, 62, 1176 — 1180).

R1 R1 R2 H O R2 | 1 —‘—’Z2 \N / or R3 N OH R3 (r? OH peroxycarboxylic o acids 9 (W) (m) es of the pyrimidineoI-l-oxide starting compounds (III) include particularly the following: hll DH EN”Am From These nds The ligands of The iron complex compounds according To The presenT invenTion are derived by simple deproTondTion CT The hydroxy group. ceutically acceptable salts of the compounds according to the invention in which the iron(lll) complex formally s a ve charge include, for example, salts with le anions, such as carboxylates, sultonates, sulfates, chlorides, bromides, iodides, phosphates, tartates, methanesulfonates, hydroxethanesulfonates, ates, maleates, propionates, fumarates, tulouenesulfonates, benzene sulfonates, trifluoroacetates, naphthalenedisulfonates-l,5, salicylates, benzoates, lactates, salts of malic acid, salts of 3-hydroxynaphthoic acid-2, citrates and acetates. ceutically acceptable salts of the compounds according to the invention in which the ll) complex formally carries a negative charge include, for example, salts with suitable pharmaceutically acceptable bases, such as, for e, salts with alkaline or alkaline-earth ides, such as NaOH, KOH, Ca(OH]2, Mg(OH)2 etc., amine compounds such as ethylamine, diethylamine, triethylamine, iisopropylamine, ethanolamine, diethanolamine, triethanolamine, methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidin, 2-aminomethyI-propanol-(l), 2-aminomethyl- propandioI-(l,3), 2-aminohydroxyI-methyl-propandioi-[l ,3) [TRIS] etc..

The water-solubility or the solubility in physiological saline solution and thus, optionally, also the efficacy of the compounds according to the invention can be significantly influenced by salt formation in general, specifically by the choice of the counterion.

Preferably, the compounds according to the ion constitute neutral complex compounds.

Advantageous pharmacological effects: Surprisingly, the inventors found that the iron(lll) pyrimidineoI-l-oxide complex compounds which are the subject matter of the present invention and which are represented, in particular, by the general structural formula (II), are stable bioavailable iron complexes and suitable for use as a medicament for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anemias the symptoms occompanying them.

The medicaments containing the compounds ing to the invention are suitable for use in human and veterinary medicine.

The compounds according to the invention are thus also suitable for TO preparing a medicament for the treatment of patients ing from ms of an iron deficiency anemia, such as, for example: e, listlessness, lack of concentration, low cognitive ency, difficulties in finding the right words, forgetfulness, unnatural pallor, irritability, acceleration of heart rate (tachycardia), sore or swollen tongue, enlarged spleen, desire for strange foods (pica), headaches, lack of appetite, increased susceptibility to infections or depressive moods.

The ll) complex compounds according to the invention are rmore suitable for the treatment of iron deficiency anemia in pregnant women, latent iron deficiency anemia in en and adolescents, iron deficiency anemia caused by gastrointestinal abnormalities, iron deficiency anemia due to blood loss, such as gastrointestinal hemorrhage (e.g. due to ulcers, carcinoma, hemorrhoids, inflammatory disorders, taking of salicylic acid), iron deficiency anemia caused by menstruation, iron deficiency anemia caused by injuries, iron deficiency anemia due to sprue, iron deficiency anemia due to reduced dietary iron uptake, in particular in selectively eating children and adolescents, immunodeficiency caused by iron deficiency anemia, brain function impairment caused by iron deficiency s, restless leg syndrome caused by iron ency anemias, iron deficiency anemias in the case of cancer, iron deficiency anemias caused by chemotherapies, iron deficiency anemias triggered by inflammation (Al), iron deficiency anemias in the case of congestive cardiac insufficiency (CHF; tive heart failure), iron deficiency anemias in the case of c renal insufficiency stage 3-5 (CDK 3-5; chronic kidney es sTage 3-5), iron deficiency anemias Triggered by c maTion (ACD), iron deficiency anemias in The case of rheumatoid arThriTis (RA), iron deficiency anemias in The case of sysTemic lupus eryThemaTosus [SLE) and iron deficiency anemias in The case of inflammaTory bowel diseases (IBD).

AdminisTraTion can Take place over a period of several monfhs unTil The iron sTaTus is improved, which is reflecfed, for e, by The obin level, Transferrin saTuraTion and The serum ferriTin level of The TO paTienTs, or unTil The desired emenT of The sTaTe of healTh affecTed by iron deficiency .

The preparaTion according To The invenTion can be Taken by children, adolescenTs and adulTs.

The applied compounds according To The invenTion can in This case be adminisTered boTh orally as well as parenTally. Oral sTraTion is preferred.

The compounds according To The ion and The aforemenfioned combinaTions of The compounds according To The invenTion wiTh oTher acTive subsTances or medicines can Thus be used, in parTicular, for The preparaTion of medicamenTs for The TreaTmenT of iron deficiency anemia, such as iron deficiency anemia in pregnanT women, laTenT iron deficiency anemia in children and adolescenTs, iron ency anemia caused by gasfroinTesTinal abnormalifies, iron deficiency anemia due To blood loss, such as gasTroinTesTinal hemorrhage [e.g. due To ulcers, carcinoma, hemorrhoids, inflammaTory disorders, Taking of aceTylsalicylic acid), mensTruaTion, injuries, iron deficiency anemia due To sprue, iron deficiency anemia due To reduced dieTary iron up’rake, in parTicular in selecTively eaTing children and adolescenTs, immunodeficiency caused by iron deficiency anemia, brain funcTion impairmenT caused by iron deficiency anemia, resTless leg syndrome.

The application according to the invention leads to an improvement of the iron, hemoglobin, ferritin and transferrin levels, which, in particular in children and adolescents, but also in adults, is accompanied by an improvement in short-term memory tests (STM), long-term memory tests (LTM), Ravens' progressive matrices test, in the Wechsler adult intelligence scale (WAIS) and/or in the emotional coefficient (Baron EQ-i, YV test, youth version), or to an improvement of the neutrophile level, the dy levels and/or lymphocyte function.

Furthermore, the present invention relates to pharmaceutical compositions comprising one or more of the compounds according to the invention, in particular according to the formula [II], as well as ally one or more further pharmaceutically effective compounds, as well as optionally one or more pharmacologically acceptable carriers and/or auxiliary substances and/or ts. The said pharmaceutical compositions contain, for e up to 99 weight-% or up to 90 weight-% or up to 80 weight-% of the compounds of the invention, the remainder being each formed by pharmacologically acceptable carriers and/or auxiliaries and/or ts.

These are common ceutical carriers, auxiliary substances or ts. The mentioned pharmaceutical compositions are suitable, for example, for intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragasteral or intracutaneous application and are provided, for example, in the form of pills, s, enteric-coated tablets, film tablets, layer tablets, sustained release formulations for oral, subcutaneous or cutaneous administration (in particular as a plaster), depot formulations, dragees, itories, 3O gels, solves, syrup, granulafes, suppositories, emulsions, dispersions, microcapsules, ormulations, nanoformulations, liposomal formulations, capsules, enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, epipastics, drops, nose drops, nose sprays, aerosols, ampoules, solutions, juices, suspensions, on solutions or injection solutions etc.

Preferably, the compounds according to the invention as well as pharmaceutical compositions ning such compounds are applied orally, gh other forms, such as parentally, in particUlar intravenously, are also possible.

For this purpose, the compounds according to the invention are ably provided in pharmaceutical compositions in the form of pills, tablets, enteric-coated tablets, film tablets, layer tablets, sustained e formulations for oral administration, depot formulations, dragees, granulates, emulsions, dispersions, apsules, microformulations, nanoformulations, liposomal formulations, capsules, enteric-coated capsules, powders, microcrystalline formulations, epipastics, drops, ampoules, solutions, suspensions, infusion solutions or injection solutions.

The compounds according to the invention can be administered in ceutical compositions which may contain various organic or inorganic r and/or auxiliary materials as they are customarily used for pharmaceutical purposes, in particular for solid medicament formulations, such as, for example, excipients [such as saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate, m carbonate), binding agents (such as cellulose, methylcellulose, hydroxypropylcellulose, polypropyl pyrrolidone, gelatine, gum , polyethylene glycol, saccharose, starch), disintegrating agents (such as starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl , sodium glycol starch, sodium onate, calcium phosphate, m citrate), lubricants (such as magnesium stearate, talcum, sodium laurylsulfate}, a flavorant [such as citric acid, menthol, glycin, orange powder), preserving agents (such as sodium benzoate, sodium bisulfite, methylparaben, proylparaben), stabilizers ( such as citric acid, sodium citrate, acetic acid and multicarboxylic acids from the titriplex series, such as, for example, diethylenetriaminepentaacetic acid [DTPA], suspending agents (such as methycellulose, nyl pyrrolidone, aluminum stearate], dispersing agents, diluting agents [such as water, organic solvents), beeswax, cocoa butter, polyethylene , white petroldtum, etc.

Liquid medicament formulations, such as solvents, suspensions and gels usually contain a liquid carrier, such as water and/or pharmaceutically acceptable organic solvents. Furthermore, such liquid formulations can also contain pH-adjusting agents, emulsifiers or dispersing agents, ing agents, preserving , wetting agents, gelatinizing agents (for example methylcellulose], dyes and/or flavouring agents. The TO compositions may be isotonic, that is, they can have the same osmotic pressure as blood. The isotonicity of the composition can be ed by using sodium chloride and other pharmaceutically acceptable agents, such as, for example, dextrose, maltose, boric acid, sodium tartrate, ene glycol and other inorganic or c soluble substances. The viscosity of the liquid compositions can be adjusted by means of a pharmaceutically able thickening agent, such as methylcellulose.

Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like.

The preferred concentration of the thickening agent will depend on the agent selected. Pharmaceutically acceptable preserving agents can be used in order to increase the storage life of the liquid composition.

Benzyl alcohol can be le, even though a plurality of preserving agents ing, for example, paraben, thlmerosal, chlorobutanol and benzalkonium chloride can also be used.

The active substance can be administered, for example, with a unit dose of 0.001 mg/kg to 500 mg/kg body weight, for example i to 4 times a day. However, the dose can be increased or reduced depending on the age, weight, condition of the patient, severity of the e or type of administration.

The designation of the ligands has been carried according to the IUPAC nomenclature with the program ACD/name, version 12.01 according to Advanced Chemistry Development Inc.

Abbreviations s singlet t triplet a doublet q quartet dd double doublet m mu lti plet [broad/superimposed) L ligand Starting compounds: A. Pyrimidineol-l -oxlde hydrochloride l QIAOH 0.261 mol (19.85 g] hydroxy urea have been dissolved in 390 ml T M HCI and 0.235 mol [51.77 g) i.i,3.3-tetraethoxypropane were added se under ice cooling, with the al ature being maintained at i — 2 °C. The solution was thawed in an ice bath to room temperature and d over night, then evaporated to dryness. The residue was suspended with 250 ml of e, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice- cold acetone. After drying, 24.5 g of crude product were obtained. The crude product was recrystallized with 460 ml of methanol from the boiling heat, cooled in an ice/ethanol bath, filtered off and dried. The mother liquor was concentrated on a rotary evaporator until again product started to precipitate, then a second fraction was crystallized rly. After drying 11.8 g (1. fraction) and 5.9 g (2. fraction) the title compound were ed.

IR (in substance, cm"): 3114, 3082, 2995, 2935, 2837, 2776,2718, 2467, 1734,1575,1492,1421,1363,1314,1232,1176,1123,1100,1073,911, 861, 773, 733, 689, 574 (2. fraction).

CN-elementary analysis: C, 32.29; N, 18.98 (1. fraction]; C, 32.41; N, 18.98 (2. fraction).

Chloride t: 24.6 % (m/m) (1. fraction], 23.6 % (m/m) (2. fraction) LC-MS:113[M+H). 1H-NMR (DMSO-dé, 400 MHz]. 8 [ppm] = 9.05 (dd, 1H), 8.55 (dd, 1H), 6.74 (t, 1H).

B. 4-Methylpyrimidineoloxld hydrochloride 0.10 mol (7.61 g] hydroxy urea were dissolved in 150 ml of 1 M HC1 and 0.11 mol [16.15 g, techn. 90 %] of 4,4,-dimethoxybutanone was added dropwise under ice cooling whereby the internal ature was maintained at 1 — 3 °C. The solution was thawed in an ice bath to room temperature and stirred over night, then filtered and evaporated to dryness. The residue was suspended with 100 ml of acetone, the mixture was cooled to —18 °C, the solid filtered off and washed with a little ice- cold acetone. After drying, 10.7 g or crude product were obtained. The crude product was recrystallized with 1750 ml ethanol from the boiling heat, cooled in an ice/ethanol bath, filtered off, washed with a little l and dried [fraction 1]. The mother liquor was concentrated on a 3O rotary evaporator until again product started to precipitate, cool stored and a second fraction isolated. After , 6.15 g (1. fraction) and 1.86 g (2. fraction) product was obtained. Both fractions were combined and recrystallized from the boiling heat with 230 mi 90 °/o ethanol (10 % water] similarly. After drying, 3.75 g (3. fraction) and 2.36 g (4. fraction] of the title compound were obtained.

IR (in substance, cm"): 3102, 3034, 2926, 2841, 2730, 2657, 2531, 1741, 1650,1602,1581,1518,1456,1374,1302,.1184,1131,1110,1037,977, . 888, 821, 780, 734, 697, 603 (3. fraction].

TO CHN-elementary analysis: C, 37.48; H, 4.33; N, 17.12 (3.Fraktion]; C, 37.12; H, 4.30; N, 17.08 (4. fraction).

LC-MS: 127 (M+H). 1H-NMR (DMSO-db, 400 MHz): 8 [ppm] = 8.97 (d, 1H), 6.73 (d, 1H], 2.49 (s, 3H).

C. 4,6-Dimethylpyrimidlneoloxide hydrochloride 0.40 mol (30.6 g) hydroxy urea was dissolved in 600 ml of 1 M HCI and 0.50 mol (50.06 g] acetyl e were added dropwise under ice g, maintaining the internal temperature at 1 — 3 °C. The solution was thawed to room temperature in an ice bath and stirred over night, then filtered off and evaporated to dryness. The residue was suspended with 400 ml of acetone, the mixture was cooled to -18 °C, the solid filtered off and washed with a little ice-cold acetone. After drying, 45,5 g of crude product were ed. The crude product was recrystallized with 4.0 I l from the boiling heat, cooled to —18 °C, filtered off and washed with little ethanol and dried (fraction 1). The mother liquor was concentrated on a rotary evaporator until product started to itate again, cool stored and a second fraction isolated. After drying 26.0 g (1. fraction, purity >98 %) and 11.0 g (2. fraction, contained 32 % NH4CI as by-product) of the titie compound was obtained.

IR (in substance, cm"): 3077, 3052, 2938, 2855, 2796, 2521, 1740, 1610, 1564,1509,1423,1368,1316,1215,1163,1141,1089,1049,1026,997, 975, 852, 775, 741, 695, 626, 601 (1. fraction].

CHN-elementary analysis: C, 40.74; H, 5.03; N, 15.78 [1. fraction]; C, 27.75; H, 5.87; N, 18.98 (2. fraction).

Chioride content: 19.9% (m/m) (1. fraction], 33.4% (m/m) (2. fraction) Lc-Ms: 141 [M+H). 1H-NMR (DMSO-db, 400 MHz): 8 [ppm] = 6.78 (s, 1H]: 2.53 (s, 3H); 2.43 (s, 3H] (1. fraction].

D. 4,6-Dlethylpyrimidlneol 1-oxid hydrochlorlde N OH 0.19 moi [14.45 g) hydroxy urea were dissolved in 300 ml 1 M HCI, 300 ml of methanol was added and 0.19 mol [24.35 g) of 3,5-heptandione was added se under ice cooling, maintaining the internal temperature at 1-2 °C. The on was thawed to room temperature in an ice bath and stirred over night, then evaporated to s. The residue was suspended with 200 ml of acetone, the mixture was cooled to below 0 °C in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying, 7.88 g of a product was obtained which contained 48 % of the title compound and 52 % ammonium de as by-product.

IR [in substance, cm"): 3116, 3024, 2804, 2687, 2628, 1996, 1746, 1603, 1572, 1512, 1443, 1394, 1297, 1213, 1156, 1082, 1061, 963, 901, 861. 814, 745, 700.

CHN-elementary analysis: C, 22.71; H, 6.94; N, 19.99.

Chloride content: 42.9% (m/m) LC-MS: 169 (M+H). 1H-NMR (DMSO-dé, 400 MHz): 8 [ppm] = 6.75 (s, 1H), 2.86 (q, 2H], 2.70 (q, 2H), 1.21 (t, 3H), 1.20 (t, 3H).

E. 4-Methyl(2-methylpropyl)pyrimldlne—2-oloxide hydrochloride E OH 0.20 mol (15.21 9] hydroxy urea were dissolved in 300 ml of M HCI, 300 ml of methanol were added, and 0.20 mol [28.44 g] 6-methyI-2,4- heptanedione were added dropwise while cooling at —1 2 to —10 °C. The solution was allowed to warm slowly to room Temperature and stirred over night, then evaporated to dryness. The e was suspended with 200 ml of acetone, the e cooled to below 0 °C in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying 7.23 g of a product was obtained, which contained 58 % of the title compound and 42 % of the by-product ammonium chloride.

IR (in substance, cm"): 3106, 3011, 2963, 2576, 1834, 1740, 1604, 1567, 1514, 1467, 1446, 1403, 1371, 1321, 1280, 1234, 1209, 1149, 1104, 1070, 1032, 1010, 915, 861, 820, 774, 750, 712, 680, 644, 615, 580.

CHN-elementary analysis: C, 28.68; H, 6.93; N, 18.33.

Chloride content: 37.6% [m/m] LC-MS: 183 (M+H]. 1H-NMR [DMSO-dé, 400 MHz]: 6 [ppm] = 6.76 (s, 1H), 2.72 (d, 2H), 2.44 (s, 3H], 2.13 (m, 1H), 0.91 (d, 6H]. From the NMR-spectrum was estimated that the product contained approximately 2 % of the regioisomere 6- (2-methylpropyl)pyrimidineoloxide hydrochloride.

F. 4.5,6-Trlmethylpyrlmldlneol-T —oxide hydrochlorlde 0.263 mol (20.0 9) hydroxy urea were dissolved in 263 ml 1 M HCl and 0.876 mol (100 g) 3-methyl-2,4-pentanedione (95 %, Alfa Aesar] were added dropwise under ice cooling. The two-phase-mixture was stirred for T h at room ature, and then it was extracted twice with 530 ml ethyl acetate. The combined c phases were dried with sodium sulphate and concentrated on a rotary evaporator to dryness. 86.6 g 3- methyl-2,4-pentanedione, depleted with acetyl acetone, were obtained. 0.758 mol [60.84 9) hydroxy urea were dissolved in 500 ml of 2 M HCI and 200 ml of methanol and 0.758 mol (86.56 g] 3-methyl-2,4- edione were added. The solution was stirred for i h at 50 °C, and then concentrated to dryness. The residue was suspended in 80 ml of acetone, the mixture was cooled to below 0 °C in an ice/ethanol bath, the solid filtered off, washed with a little ice-cold acetone and dried. 21.7 g of intermediate product were heated to boiling in 150 ml methanol, hot filtered from insoluble fractions and again evaporated to dryness. There were obtained 7.05 9 solid (1. fraction] which contained 9.6 % of the title nd and 90 % of the duct ammonium From the acetone mother liquor further solid precipitated which was filtered off, washed with a little acetone and dried. 2.50 g of the solid [2. fraction) contained 82 % of the title compound and T8 % of the by- product ammonium chloride.

IR (in substance, cm"): 3112, 2997, 2934, 2850, 2796, 2629, 2544, 1734, 1612, 1582, 1513, 1472, 1392, 1373, 1309, 1247, 1215, 1152, 1132, 1093, 1014, 945, 896, 803, 777, 742, 707, 630, 603, 558, 528, 500.

CHN-elementary analysis: C, 36.31; H, 6.16; N, 16.28 (2. fraction).

Chloride t: 25.9% (m/m) [2. fraction] LC-MS: 155 (M+H). 1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 2.56 (s, 3H), 2.47 (s, 3H), 2.05 (s. 3H]. From the NMR-spectrum was estimated that the product contained approximately 9 % 4,6-dimethylpyrimidine-2—oloxide hydrochloride as by-product.

G. 5-Chloro-4,6-dlmethylpyrlmldlneoloxide hydrochloride 0.20 mol (15.21 g) hydroxy urea were dissolved in 300 ml of 1 M HCI, 300 ml methanol were added and 0.20 mol (26.91 g) of 3-chloro-2,4- pentandedione were added dropwise under ice g at 1-2 °C. The two-phase-mixture was allowed to warm slowly to room temperature and stirred over night. The clear on was then evaporated to dryness. The residue was suspended with 200 ml of acetone, the mixture was cooled to below 0 °C in an ice/ethanol bath, the solid filtered off and washed with a little ice—cold acetone. The filtrate was trated to dryness, the residue was suspended in 20 ml of tetrahydrofuran, filtered off, washed with little ydrofuran and dried. 1.40 g of a product containing about 53 °/o of the title compound and 47 % of the byproduct ammonium chloride were obtained.

IR (in substance, cm"): 3115, 2900, 2667, 2516, 1745, 1577, 1505, 1378. 1310,1194,1135, 1102, 1049, 973, 900, 835, 737, 674, 578.

Chloride content: 40.1% [m/m] LC-MS: 175 (M+H]. 1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 2.49 (s, 3H), 2.37 (s, 3H).

H. lpyrlmldlneol-T -oxide hydrochlorlde 04—2 OH T,T-Dimethoxypentanon (T. Harayama, H. Cho and Y. Inubushi, Chem. Pharm. Bull. 1978, 26. 1201-12l4) Vk/ko/o In a multi-neck flask with internal thermometer and KPG-stirrer 0.96 mol TO [89 g) propionic acid chloride were charged and cooled with a salt/ice ng mixture. 0.82 mol (110 g) aluminium chloride was added portion wise and the mixture was stirred vigorously for 10 min and mixed with 50 ml of form. Then, within about i h 0.93 mol (TOO g) vinyl bromide was added in small portions (maximum internal temperature l4 °C). The mixture was stirred on ice for l h, and then the reaction mixture was poured onto 500 g ice and extracted several times with a total of l l of chloroform. The ed organic phases were washed 4 times with l l of water, dried with sodium sulphate and the chloroform was distilled off on a rotary evaporator. The residue was distilled in a rotary evaporator at 80 °C water bath temperature and 16 mbar (head temperature about 47 °C), which resulted in 118 g intermediate product (unstable, storage -18 °C). 118 g intermediate t were dissolved in 600 ml ous methanol and cooled on ice. 1.03 mol [55.65 g) natrium methoxid were dissolved in 360 ml anhydrous methanol and added dropwise within 30 min and the mixture was stirred at room temperature for further 18 h. The resulting salt was filtered off, washed with a small amount of dry methanol and the filtrate was concentrated on a rotary evaporator. The residue was led at a rotary ator at a water bath temperature of 75 °C and 4 mbar [head temperature 40 — 52 °C). 61.4 g of a product mixture containing 62 % (m/m] of the title compound sponding to 38 g) were obtained. 1H-NMR (DMSO-db, 400 MHZ]: 8 [ppm] = 4.74 (t, 1H], 3.23 (s, 6H), 2.70 (d, 2H), 2.45 (q, 2H), 0.90 (t, 3H) [title compound, 62% m/m in product mixture); 8 = 7.69 (d, 1H), 5.61 (d, 1H), 3.69 (s, 3H), 2.48 (q, 2H), 0.96 (t, 3H) ((1E)-l -methoxypent-l -enon, 38% in product mixture]. 4-Ethylpyrimidinoloxlde hydrochloride 0.388 mol (25.9 9) y urea were dissolved in 195 ml 2 M HCI, 80 ml of methanol were added and 0.388 mol (56.7 g) of 1,1- dimethoxypentane-B-on (62 % content in product mixture) were added dropwise under cooling with the internal temperature being maintained at —6 to —7 °C. The solution was thawed to room temperature in an ice bath and stirred for 1 h, then evaporated until dryness. The residue was suspended with 100 ml of acetone, the mixture was cooled to below 0 °C in an ice/ethanol bath, the solid filtered off and washed with little ice- cold acetone. After drying 32.6 g crude product were ed. The crude product was heated until bOiling with 200 ml ethanol, hot ed and slowly cooled to —18 °C. The precipitated solid was filtered off, washed with a little amount of ethanol and dried. 11.7 g of the title compound were obtained.

IR [in substance, cm”): 3115, 3038, 2936, 2678, 2518, 1753, 1606, 1585. 1516,1465,1403,1381,1301,1229,1184,1134,1109,1053,1002,896, 803, 769, 736, 680, 605, 540, 513, 494, 474.

CHN-elementary analysis: C, 40.72; H, 5.03; N, 15.32.

LC-MS: 141 [M+H). 1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 8.92 (d, 1H], 6.70 (d, 1H), 2.73 (q, 2H); 1.19 (t, 3H). From the NMR-spectrum was estimated that the product contained <3 % of the regioisomere 6—ethylpyrimidineol oxide hydrochloride.

I. 6-Ethylmethylpyrlmidlneoloxlde hydrochloride N OH 0.12 mol (9.13 g) hydroxy urea were dissolved in 50 ml 2 M HCI, 20 ml of methanol were added and 0.10 mol (11.41 g] 2,4-hexanedione were added dropwise under cooling by approximately —15 °C. Further 30 ml of water and 10 ml of methanol were added. The two-phase reaction mixture was allowed to warm up slowly to room temperature and was stirred at room ature for further 2 h, then ated until dryness.

The residue was suspended with 50 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice—cold acetone. After drying 7.88 g crude product were ed which were recrystallized from 45 ml ethanol wherefrom first an insoluble salt compound was hot filtered off and the product was subsequently recrystallized from the filtrate at —18 °C. 3.0 g product were obtained which were again recrystallized from 28 ml ethanol. Finally 2.26 g of the title compound were obtained.

IR (in substance, cm“): 3093, 2997, 2945, 2679, 2555, 1805, 1741, 1601, 1571, 1508, 1435, 1401, 1370, 1327, 1290, 1253, 1213, 1157, 1103, 1049, 903, 849, 811, 766, 742, 701, 669, 626, 607, 582, 512, 494.

LC-MS (m/Z]: 155.7 (M+H). 1H-NMR (DMSO-db, 400 MHz): 5 [ppm] = 6.78 (s, 1H), 2.88 (q, 2H], 2.46 (s, 3H), 1.21 (t, 3H). From the ectrum was estimated that the product contained imately 6.6 % of the regioisomer I methylpyrimidineoIoxide hydrochloride.

J. 4-Methyl-6,7-dihydro-5H-cyclopenta[dlpyrimldineoloxide hydrochloride 1‘ OH 0.20 mol (15.21 9) hydroxy urea was dissolved in 200 ml of 1 M HCI, 200 ml of methanol were added and 0.20 mol (25.23 g) 2- acetylcyclopentanone were added dropwise, 1 r hour stirred and then the solution was evaporated at the rotary evaporator until dryness.

The residue was suspended with 100 ml of acetone, the solid filtered off and washed with acetone. After drying 12.41 g crude product 1 were obtained which were solubilised in the g heat with 1200 ml isopropanol and hot filtered. The filtrate was evaporated until dryness and 8.49 g crude product 2 were obtained. This was lised in the boiling heat in 200 ml of ethanol and 200 ml of tetrahydrofuran were added. The precipitated solid was filtered off and dried. 5.63 g of a product were obtained which contained 91.5 % of the title nd and 8.5 % ammonium chloride. 1R (in substance, cm"): 3133, 3042, 2841, 2751, 2480, 1730, 1613, 1590. 1493, 1404, 1374, 1314, 1289, 1221, 1134, 1062, 1044, 1020, 972, 938, 894, 868, 822, 740, 707, 637, 575, 552, 525, 509.

LC-MS [m/z): 167.5 [M+H]. ementary analysis: C, 43.93; H, 6.07; N, 13.41.

Chloride content: 21.7% (m/m] lH-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 3.22 (t, 2H), 2.82 (t, 2H), 2.42 (s, 3H), 2.13 (quintett, 2H). From the MNR-spectrum was estimated that the product contained approximately 6 % of the regioisomere 4-methyI-6,7- dihydro-5H-cyc|openta[d]pyrimidineoIoxide hydrochloride.

K. 4-MethyI-5,6,7,8-tetrahydrochinazolineoIoxlde hydrochlorlde N OH 0.08 mol (6.08 9] y urea were dissolved in 40 ml of 2 M HCI, 40 ml of ol were added and 0.08 mol (11.21 g) 2-acetylcyclohexanone were added dropwise under cooling at approximately —1 5 °C, stirred one further hour and Thereby warmed up to 20 °C. This was carried out six times in total. The combined on mixtures were then evaporated at the rotary evaporator. The residue was suspended with acetone, the solid filtered off and washed with acetone. After drying 36.97 g crude product 1 were obtained which were suspended with 250 mi ethanol and hot filtered. The filtrate was evaporated until s and 20.87 g crude product 2 were obtained. This was solubilised in the g heat in 500 ml of ethanol, hot filtered, and the filtrate was combined with 800 ml tetrahydrofuran. The precipitated solid was filtered off and dried. 14.3 g of a product were ed which contained 87 % of the title compound and 13 % ammonium chloride.

IR [in substance, cm"): 3135, 3044, 2937, 2875, 2805, 2706, 2426, 1743, 1572, 1501, 1443, 1403, 1345, 1288, 1260, 1235, 1150, 1122, 1086, 1041, 908, 883, 824, 740, 707, 669, 643, 605, 546, 514.

CHN-elementary analysis: C, 43.63; H, 6.08; N, 14.66.

Chloride content: 22.2% (m/m) iH-NMR (DMSO-dé, 400 MHz): 8 [ppm] = 2.76 (m, 2H), 2.53 (s, 3H), 2.49 (m, 2H], 1.70 (m, 4H). From the NMR-spectrum was estimated that the product contained approximately 5 % of the regioisomere 4-methyl- ,6,7,8-tetrahydrochinazolinoloxide hydrochloride.

L. panyl)pyr|mldlneoloxlde hydrochloride lN/AOH 0.187 mol (14.22 g) hydroxy urea were dissolved in 200 ml of 1 M HCI and 0.187 mol [30 g) 1,1—dimethoxymethylpentaneon (E.E. Royals and K.C. Brannock, J. Am Chem. Soc. 1953, 75, 2050-2053) were added dropwise under cooling, with the al temperature being maintained at 0 — 1 °C. The two-phase mixture was thawed to room temperature in an ice bath and stirred for 12 h, then evaporated until dryness. The residue was suspended with 100 ml acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice- cold acetone. After drying 15.79 g crude product 1 were obtained. 11.04 g of crude t 1 were heated until boiling with 141 ml ethanol and precipitated solid was filtered off after cooling. The filtrate was again evaporated until dryness and 8.49 g crude product 2 were obtained which were heated until boiling in 80 ml ethanol and hot ed. The filtrate was cooled down slowly to room temperature and over night down to —18 °C. The precipitated solid was filtered off and after drying 2.18 g of the title compound were obtained.

IR (in substance, cm"): 2971, 2585, 1815, 1748, 1598, 1572, 1513, 1463, 1390, 1305, 1230, 1186, 1163, 1132, 1049, 986, 934, 901, 815, 773, 749, 719, 681, 616, 582, 518, 498, 484, 478.

CHN-elementary is: C. 43.54; H, 6.10; N, 14.50 LC-MS (m/z): 155.5 (M+H). 1H-NMR [DMSO-dé, 400 MHz): 8 [ppm] = 8.88 (d, 1H), 6.68 (d, 1H), 3.02 [heptett, 1H); 1.20 (d, 6H) M. 4-Ethylmethylpyrimidineol 1-oxlde hydrochlorlde 1N)OH Various mother liquors from recrystallization from the synthesis of the regioisomer 6-ethyImethyl-pyrimidineol 1-oxide hydrochloride [Example 1) were combined and ated to dryness. In total 22.14 grams of this product mixture, containing about 50% of the title compound, were heated in 140 ml of l to boiling, ed hot and evaporated to dryness. 20.96 g of the residue was recrystallized from 90 ml of l, in doing so first 0.82 g of an insoluble fraction were separated in the heat, and then it was slowly cooled down from the boiling point to -18 °C. 17.25 g of a precipitate were then recrystallized accordingly from 150 ml of ethanol / 70 ml of tetrahydrofuran, whereby 6.05 g of a solid predominantly containing 6-ethylmethyI-pyrimidine oi 1-oxide hydrochloride was separated. The filtrate was trated to dryness and 9.53 g of the residue were recrystallized from 180 ml of isopropanol. 7.57 g of a product mixture were obtained (63% enrichment) and recrystallized several times from isopropanol in a 2O corresponding manner. y there were obtained 0.69 g of the title compound.

IR (neat, cm"): 3077, 2853, 2685, 2550, 1745, 1608, 1568, 1514, 1461, 1416,1370,1323,1304,1249,1211,1160,1142,1104,1069,1028,994, 936,887, 849, 767, 746, 707, 685, 625, 599, 567, 525, 500.

LC—MS [m / z): 155 (M + H). 1H-NMR (DMSO-dé, 400 MHz): 6 [ppm] = 6.83 (s, 1H), 2.70 (q, 2H), 2.55 (s, 3H), 1.20 (t, 3H). From the NMR spectrum it was estimated that the product contained approximately 13% of the regioisomer 6—ethyl -pyrimidinol 1-oxide hydrochloride.

N. 4-tert-Butylpyrimidineol 1-oxlde hydrochlorlde The synthesis of the precursor 1,1-dimethoxy-4 ,4-dimethylpentaneone was performed in y to E.E. Royals and K.C. Brannock (J. Am. Chem Soc. 1953, 75, 2050-2053], wherein a mixture of about 20% of the desired precursor and 80% of the byproduct 1-methoxy-4,4— dimethylpent-l-en-S-one was obtained. To 32.8 g of this mixture were added 33.9 mmol (5.63 g) N-benzyloxy urea, 51 ml of methanol, 1.7 ml of water and 4.06 ml of sulfuric acid [analogous to M. Yamaguchi et al., J. Inorg. Biochemistry 2006, 100, 260-269). It was stirred at room temperature with portionwise addition of in total 153 mmol (25 g] N- benzyloxy urea for 5 h, untii N-benzyloxy urea could be detected in the reaction mixture (TLC hexane / ethyl acetate 2/1, 1% acetic acid]. The reaction mixture was evaporated to dryness, the residue taken up in water / romethane, the s phase was adjusted to pH 9.3 with saturated sodium carbonate solution and extracted three times with dichloromethane. The ed organic phases were washed with 2O water, dried over sodium sulfate and evaporated to dryness. 51.8 g of a crude product were obtained which was chromatographed with cyclohexane / ethyl acetate over silica gel. 46.4 mmol (12.0 g) purified intermediate product were obtained, which was dissolved in 240 ml of methanol and hydrogenated with 0.93 g of 10% Pd / C for 3.5 h with hydrogen. It was filtered over Celite, the filtrate was added with 50 mi of 1 M HCI and ated to dryness. The crude product was suspended in 100 ml of water, ed off from ble constituents and the filtrate was concentrated. After drying, 8.15 g [39.8 mmol, 5.0% yield over three steps) of the title compound were obtained. lR (neat, cm“): 2850, 2482, 1758, 1505, 1555, 1517, 1494, 1457, 1389, 1377,1310,1254,1190,1118,1085,887,828,751,730,703 1H-NMR (DMSO-db, 400 MHz]: 5 [ppm] = 8.55 (d, 1H), 5.51 (d, 1H), 1.27 (s, 9H] 0. 5,6-Dimethylpyrlmidineol i-oxlde hydrochlorlde The synthesis of the precursor 4,4-dimethoxymethylbutanone was performed in analogy to E.E. Royals and K.C. Brannock (J. Am. Chem., 1953, 75, 2050-2053) and d a mixture of 58% of the desired precursor, 24% of the byproduct 1,1-dimethoxy-pentanone and about 18% elimination t. 102 g of this mixture (0.405 mol of 4,4- dimethoxymethylbutanone) were ved in 30 ml of methanol and added dropwise to 0.698 mol of N-hydroxyurea in 400 ml of 2M HCI, while the internal temperature was ined at -10 to -4 °C. The solution was thawed to room temperature, stirred for 1 h, and then evaporated to dryness. The e was slurried with 200 ml of acetone, the solid filtered off and washed with little ice-cold acetone. After drying, the crude product was heated with 150 ml of ethanol to boiling, filtered hot, concentrated to 50 ml and cooled to -18 ° C. The precipitated solid was filtered off, washed with little ethanol and dried. 20 g of this solid was again recrystallized from 100 ml of ethanol, and finally 10 g (12% yield) of the title compound were obtained (content of 85% the title compound and 13% ammonium chloride].

IR (neat, cm"): 2569, 2539, 1726, 1628, 1589, 1503, 1453, 1378, 1336, 1255, 1220, 1157, 1141, 1120, 1021, 919, 828, 755, 734, 713 1H-NMR (DMSO-dé, 400 MHz]: 6 [ppm] = 8.98 (s, 1H); 2.50 [5, 3H]; 2.08 (s, 3H) P. 6—n-Propylpyrimidlneol 1-oxlde hydrochlorlde N OH The synthesis of the precursor 1,1 -dimethoxyhexaneone was performed in analogy to E.E. Royals and K.C. Brannock (J. Am. Chem. Soc. 1953, 75, 2050-2053) and yielded a mixture of 75% of the desired precursor, 13% of the byproduct 3-(dimethoxymethyl) pentanone and about 12% of elimination products. 29.2 g of this mixture [0.137 mol 1,1- dlmethoxyhexane-B-one) were mixed with 0.164 moles (27.3 g) N- benzyloxy urea, added with 150 ml of methanol and 20 ml of sulfuric acid [analogous to M. Yamaguchi et al., J. Inorg. Biochemistry 2006, 100, 260-269). The mixture was stirred at room temperature, then further 0.0164 mmol (2.73 g) of N-benzyloxy urea were added and it was heated for 1 h at 50 ° C. The mixture was evaporated to dryness, the residue was taken up in water / dichloromethane, the aqueous phase was adjusted to pH 11 with saturated sodium ate solution and extracted three times with dichloromethane. The combined organic phases were washed with water, dried over ium e and ated to dryness. 2O There were obtained 40.3 g of a crude product which was chromatographed with cyclohexane / ethyl acetate over silica gel. 0.026 mol (6.3 g) of the ed intermediate were ved in TOO ml of methanol and hydrogenated with 0.53 g of 10% Pd / C for 0.5 h with hydrogen. It was filtered off through Celite, the filtrate was concentrated to 50 ml added with 50 ml of 1 M HC1 and evaporated to dryness. The crude product was recrystallized from 50 ml of 2-propanol and 200 ml of diethyl ether. 3.46 g [18.2 mmol, 13% yield over 2 steps) of the title compound were obtained. 1R (neat, cm"): 2591, 2536, 2477, 1770, 1736, 1608, 1580, 1311, 1194, 3O 1185, 1130, 1115, 1082, 1001, 904, 892, 823, 787, 736, 680 1H-NMR dé, 400 MHz): 5 [ppm] = 8.98 (d, 1H), 6.75 (d, 1H), 2.74 (t, 2H), 1.69 [hextett, 2H), 0.93 (t, 3H) Iron com lex com ounds exam les Example 1 Tris-(pyrimidineoloxlde)-lron(|ll) complex I: O C)/we\o/k/ N/KN/o 114 mmol [16.93 g] pyrimidineoIoxide hydrochloride were ved in 150 ml of water and 38 mmol [10.27 g] FeC|3*6H20 ved in 15 ml water were added. The solution was adjusted to pH 6.3 with approximately 90 ml 2 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. 14.2 g of the title compound were obtained. 1R (in substance, cm"): 3082, 3054, 1596, 1506, 1431, 1366, 1278, 1197, 1136, 1108, 1055, 907, 798, 765, 613, 554, 513.

CHN-elementary analysis: C, 35.77; H, 2.78; N, 20.23.

ESI-MS: 278.3 [FeL2+); 390.4 (M+H+); 412.4 (M+Na+).

Fe-content: 13.61% [m/m] Example 2 Trls-(4-methylpyrlmldineol-oxlde)-lron(lll) complex 'N/k.

°\./°‘" \ NKN/o 21 mmol (3.76 9, approximately 90 % purity) 4-methylpyrimidineol oxide hydrochloride were dissolved in 15 ml water and 7.0 mmol (1.89 g) FeCla*6H20 ved in 5 ml water were added. The solution was adjusted to pH 5.85 with imately 44 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. 3.03 g of the title compound were obtained. 1R (in substance, cm"): 3400, 3074, 1602, 1545, 1503, 1425, 1378, 1339, 1249, 1201, 1145, 1110, 1032, 954, 805, 762, 645, 600.

CHN-elementary analysis: C, 38.42; H, 4.10; N, 18.11.

ESI-MS: 306.4 [FeL2+); 432.4 [M+H+).

Fe-content: 12.15% [m/m] Tris-(4,6-dlmethylpyrlmidineolox|de)-iron(ll|) complex 120 mmol (21.19 g] 4,6-dimethylpyrimidineoloxide hydrochloride were dissolved in 15 ml of water and 40 mmol (10.81 g) 6H20 dissolved in 10 ml water were added. The solution was adjusted to pH .90 with approximately 238 ml 1 M NdOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. 18.66 g of the title compound were obtained.

IR (in substance, cm"): 3596, 3441, 3077, 1604, 1551, 1511, 1441, 1393, 1380, 1360, 1320, 1153, 1097, 1029, 875, 856, 798, 651, 564, 524, 486.

CHN-elementory onolysis: C, 44.27; H, 4.22; N, 17.35.

ESI-MS: 334.4 [FeL2+); 474.5 (M+H+]; 496.6 (M+No+).

Fe-content: 11.33% [m/m] No melting point, at about 230 ° C exothermic decomposition stdrts.

Tris-(4,6-diethylpyrlmldlneoloxide)-lron(lll) complex o>1<l$ 14 mmol [6.1 9, approximately 48 % purity, 52 % ammonium chloride] 4,6-diethylpyrimidineoloxide hydrochloride were dissolved in 15 ml water and 4.67 mmol [1.26 g] FeC|3*6HQO dissolved in 2 ml water were added. The solution was adjusted to pH 5.85 with 27.7 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried at 50°C in a vacuum drying oven. 2.57 g of the title nd were obtained.

IR (in substance, cm"): 3593, 3378, 3087, 2969, 2934, 2880, 1602, 1549. 1510, 1460, 1406, 1328, 1255, 1235, 1146, 1108, 1073, 1027, 964, 903, 863, 807, 764, 701, 672, 645, 619, 578, 522.

CHN-elementary analysis: C, 49.23; H, 6.03; N, 14.43.

Fe-content: 10.05 % [m/m] Example 5 Tris-(4-methyl(2-methylpropyl)pyrlmld|noloxide)-iron(lll) complex mmol (5.74 g, imately 58 % purity, 42 % ammonium chloride] 4-methyl(2-methylpropyllpyrimidineoloxide hydrochloride were dissolved in 25 ml water and 5.0 mmol (1.35 g] FeC13*6HQO ved in 2 ml water were added. The solution was adjusted to pH 5.88 with 29.2 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. There was obtained 3.00 of the title compound.

IR (in substance, cm“): 2959, 2929, 2872, 1598, 1549, 1513, 1462, 1434, 1400, 1355, 1289, 1233, 1151, 1122, 1102, 1034, 990, 928, 879, 853, 799, 769, 701, 648, 606, 575.

CHN-elementary analysis: C, 53.71; H, 6.40; N, 13.92.

Fe-content: 9.29% [m/m] Example 6 Trls-(4,5,6-trlmethylpyrlmldlneoloxide)-iron(ll|) complex .2 mmol (2.38 9, approximately 82 °/o purity, 18 % um chloride) trimethylpyrimidineoloxide hydrochloride were dissolved in 5 ml water and 3.4 mmol (0.93 g) FeC|3*6H2O dissolved in 1 ml water were added. The solution was adjusted to pH 6.04 with 19 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. There were obtained 1.72 g of the title compound.

IR (in substance, cm"): 3424, 2925, 1593, 1510, 1439, 1377, 1234, 1188, 1160, 1109,'999, 935, 869, 803, 763, 720, 657, 613, 561.

CHN-elementory analysis: C, 45.43; H, 5.80; N, 14.12.

Fe-content: 10.68% [m/m] Example 7 Trls-(5-chloro-4,6-dimethylpyrlmldineoloxlde)-lron(lll) complex 6.73 mmol [3.8 9, approximately 37 % purity, 63 % ammonium chloride) and 0.77 mmol (0.31 9, imately 53 % , 47 % ammonium chloride) 5-chloro-4,6-dimethylpyrimidineoloxide hydrochloride were dissolved in 25 ml of water and 2.5 mmol (0.68 g] FeC13*6H20 dissolved in 2 ml water were added. The solution was adjusted to pH 5.96 with 14.8 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. There was obtained 1.37 g of the title compound.

IR (in substance, cm"): 2929, 2363, 1688, 1589, 1509, 1431, 1390, 1375, 1196, 1169, 1092, 1016, 968, 847, 759, 694, 667, 553.

CHN-elementary analysis: C, 37.01; H, 2.83; N, 14.47.

Fe-content: 9.88% [m/m] Example 8 Trls-(4-ethylpyrlmidineoloxlde)-lron(lll) complex 63 mmol (11.13 g] 4-ethylpyrimidineoIoxide hydrochloride were dissolved in 20 ml water and 21 mmol (5.68 g) FeC|3*6H20 dissolved in 5 ml water were added. The solution was adjusted to pH 6.17 with 125.6 mi 1 M NaOH and stirred for 0.5 h. The t was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. There was obtained 9.52 g of the title compound.

IR (in substance, cm"): 3083, 2974, 2936, 2876, 1596, 1543, 1511, 1460, 1428, 1313, 1249, 1194, 1143, 1107, 1079, 1056, 991, 948, 811, 770, 748, 696, 639, 598, 531, 502.

CHN-elementary analysis: C, 44.67; H, 4.52; N, 17.36.

Fe-content: 11.40% [m/m] Example 9 Tris-(6-ethylmethylpyrlmIdIn-2—o|oxlde)-Iron(|ll) x I .2» 3) 0‘ \/ / N \ Fe \ )l\ / 0 N 11.4 mmol (2.17 g) 6-ethyImethylpyrimidineoloxide hydrochlorid were dissolved in 5 ml water and 3.8 mmol (1.03 g] FeC13*6H20 dissolved in 2 ml water were added. The solution was ed to pH 6.3 with 22.7 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. There was obtained 1.89 g of the title compound.

IR (in substance, cm“): 3515, 3080, 2974, 2938, 1598, 1550, 1516, 1461, 1427, 1401, 1317, 1257, 1229, 1149, 1104, 1060, 1035, 985, 918, 851, 813, 768, 681, 651, 557, 522.

CHN-elementary analysis: C, 47.48; H, 5.44; N, 15.81.

Fe-content: r0.32% [m/m] Chloride-content: 0.0% [m/m] Example 10 Tris-(4—methyl-6,7-dihydro-5H-cyclopenta[d]pyrlmldInoloxide)-Iron(lll) complex 21 mmol (4.73 g) yI-6,7-dihydro-5H-cyclopenta[d]pyrimidineol— 1-oxide hydrochlorid (content approximately 90 %) were dissolved in 30 ml water and 7.0 mmol (1.89 g] FeC13*6H20 dissolved in 5 ml water were added. The solution was ed to pH 5.96 with 41.6 ml 1 M NaOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in a vacuum drying oven at 50 °C. There was obtained 3.8 g of the title compound. 1R (in substance, cm"): 2918, 2361, 2326, 1599, 1571, 1499, 1429, 1382, 1359, 1311, 1279, 1232, 1208, 1173, 1100, 1067, 1043, 1013, 970, 945. 904, 881, 836, 761, 733, 663, 566, 528, 499.

CHN-elementary analysis: C, 50.36; H. 4.98; N, 14.88.

Fe-content: 9.71% [m/m] Chloride-content: 1.05% [m/m] Example 1 1 4-methyl-5.6.7,8-tetrohydrochlnozollne—2-oloxide)-iron(lll) complex 55 mmol (14.3 g) 4-methyl-5,6,7,8-tetrohydrochindzolineoIoxide hydrochloride were dissolved in 30 ml water and 18.3 mmol [4.95 g] FeCI3*6H20 dissolved in 5 ml woter were added. The solution was adjusted to pH 6.19 with 110.7 ml 1 M NdOH and stirred for 0.5 h. The product was filtered off, washed with water and dried in or vacuum drying oven at 50 °C. There was obtained 10.7 g of the title nd.

IR (in substance, cm"): 2932, 2859, 1586, 1510, 1446, 1421, 1377, 1348, 1308, 1267, 1229, 1189, 1168, 1100, 1079, 1057, 1030, 969, 889, 846, 824, 762, 704, 654, 614, 571, 507.

CHN-elementory dnolysis: C, 53.25; H, 5.49; N, 13.76.

Fe-content: 9.03% [m/m] Chloride-content: 0.0% [m/m] Example 12 Trls-(4-propdneyl)pyrlmldlneoloxlde)-|ron(lll) complex 9.76 mmol (1.86 g] 4-(propdneyl)pyrimidineoloxide hlorid were dissolved in 5 ml water and 3.25 mmol (0.88 g) FeC|3*6H20 dissolved in 2 ml water were added. The solution was adjusted lo pH 6.04 wilh 18.5 ml 1 M NdOH and stirred for 0.5 h. The producl was filtered off, washed with water and dried in d vacuum drying oven at 50 °C. There was obtained 1.64 g of The title compound.

IR (in substance, cm“): 3071, 2965, 2930, 2871, 1594, 1540, 1510, 1467, 1428, 1373, 1309, 1239, 1204, 1152, 1132, 1108, 1049, 970, 931, 881, 834, 809, 777, 733, 712, 645, 599, 552, 514.

CHN-elemenldry onolysis: C, 47.53; H, 5.01; N, 15.84.

Fe-conleni: 10.86% [m/m] (ICP) Chloride-content: 0.60% [m/m] Example 13 Trls-(4-elhylmelhylpyrlmldlneol 1-oxlde)-lron(lll) complex 3.51 mmol (0.69 g] of 4-ethylmethylpyrimidineol 1-oxide hydrochloride were dissolved in 3 ml water and 1.17 mmol [0,316 g) FeCI3 * 6H20 were added. The solution was adjusted to pH 6.37 with 6.975 ml of 1 M NdOH and stirred further for 0.5 h. The product was filtered off, washed with water and dried at 50 °C in CI vacuum oven. This gave 0.63 g (92% Fe-yield) of the title compound.

IR (neat, cm"): 2970, 2936, 2876, 1750, 1685, 1601, 1552, 1511, 1462, 1441,1404,1386,1362,1308,1231,1196,1154,1106,1056,1034,984, 846, 807, 790, 770.

CHN elemental is: C, 42.43; H, 5.43; N, 14.03.

Fe content: 9.5% [w / w] Example 14 Trls-(5-ethyl-4,6-dlmethylpyrimidineol 1-oxide)-lron(lll) complex 6.68 mmol (1.44 g] 5-ethyl-4,6-dimethylpyrimidineol 1-oxide hydrochloride [Yomdguchi et 01., J. Inorg. Biochemistry 2006, 100, 260- 269) and 2.23 mmol [0.485 g) of FeCl3 * 6H20 were dissolved in 7 ml of water. The solution was adjusted with 1 M NoOH to pH 6.0 and stirred for 0.5 h. The product was filtered off, washed with water and dried at 50 ° C in o vacuum oven. This gave 0.98 g (75% Fe yield) of the title compound.

IR (neat, cm"): 2965, 1589, 1512, 1450, 1375, 1228, 1181, 1100, 1057, 1011, 958, 863, 768, 716, 685, 664.

CHN tal analysis: C, 49.67; H, 5.83; N, 14.52.

Fe-content: 9.54% [w / w] Chloride content: 0.0% [w / w] Example 15 4-tert-butylpyrimidineoi 1-oxlde)-Iron(ll|) complex O\Fe/O\N \ O/ \OiN/ AN,O .5 mmol (7.65 g) 4-tert-butylpyrimidineol 1-oxide hydrochloride were dissolved in 15 ml water and 11.84 mmol (3.20 g] FeC|3 * 6H20 were added. The suspension was ed to pH 6.1 with 69.4 ml of 1 M NdOH and d further for 0.5 h. The product was filtered off, washed with water and dried at 50 ° C in or vacuum oven. This gave 6.44 g [99% Fe- yield) of the title compound.

IR (neat, cm"): 2965, 1598, 1535, 1506, 1477, 1419, 1364, 1339, 1273. 1238,1217,1159,1122,1025, 967, 829, 810, 779, 717, 701.

Fe content: 10.15% [w / w] Chloride content: 0.65% [w / w] Example 16 Trls-(5,6-dimethylpyrlmldIneol 1-oxlde)-lron(|ll) complex 14.4 mmol (2.93 g) 5,6-dimethylpyrimidin—2-ol hydrochloride were dissolved in 20 ml water and 4.6 mmol FeCI3 [0.76 9] dissolved in 10 ml of water were added. The solution was adjusted with 6.26 ml of 1 M NaOH to pH 5.8 and stirred for 0.5 h. The product was filtered off, washed with water and dried at 50 ° C in a vacuum oven. This gave 2.22 g (92% Fe-yield) of the title compound.

IR (neat, cm"): 3409, 1613, 1518, 1443, 1403, 1361, 1241, 1221, 1202, 1177, 1094, 1007, 880, 762, 714.

TO CHN tal analysis: C, 40.77; H, 4.95; N, 15.85.

Fe content: 10.68% [w / w] Chloride content: 1.1% [w / w] Example 17 Trls—(6-n-propyipyrimidineol 1-oxlde)-Iron(lll) complex NpTAO \ /°‘~ \ O/ \O/K/ N/KN/0 15 mmol (2.97 g] 6-n-propylpyrimidineol 1-oxide hydrochloride and 5 mmol (1.334 g) FeC|3 * 6H20 were dissolved in 42 ml water and 18 ml of ethanol and maintained at 50 °C. 30% sodium hydroxide solution was added to pH 5.2 and the suspension was cooled to room temperature.

The product was filtered off, washed with water and dried at 50 °C in a vacuum oven. This gave 2.2 g [85% Fe-yield] of the title nd.

IR (neat, cm"): 3072, 2961, 1594, 1541, 1507, 1460, 1426, 1380, 1337, 1246, 1141, 1108, 1088, 979, 870, 838, 799, 768, 733, 691.

Fe content: 10.74% [w / w] Chloride content: 0.0% [w / w] Example 18 4-(ethylomlno)pyrimidineol 1-oxlde)-lron(||l) complex ' A. eye0/ \OiN/ N/\ A ,o 3 mmol (0.602 g] 4-[ethyldmino]—pyrimidine—2-o| 1-oxide hydrochloride (Yomoguchi et 01, J. Inorg Biochemistry 2006, 100, 260-269) were dissolved in 20 ml water, and 1 mmol (0.27 g] FeCl3 * 6H20 dissolved in 2 ml of water were added. The on was adjusted with 1 M NoOH to pH .7 and stirred for another 15 min. The product was filtered off, washed with water and dried at 50 °C in o vacuum oven. This gave 0.43 g [85% Fe-yield] of the title compound.

IR (neat, cm"): 3287, 2975, 1620, 1588, 1531, 1490, 1448, 1381, 1344, 1283, 1254, 1178, 1156, 1096, 1066, 1014, 826, 784, 754, 708 Fe-content: 11.03% [w / w] Chloride content: 0.47% [w / w] Pharmacological testing method: The excellent Fe utilizations that can be accomplished through the Fe complexes according to the invention were measured by means of 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 complexes were then stered to them by means of a stomach tube [2 mg iron/kg body weight/day) for 2 times 5 days, with an interruption of 2 days (days i - 5 and 8 - l2). Utilization on day 15 was ated from the hemoglobin increase and the body weight increase in accordance with the formula Airon ation * 100 ut.—Fe ut. Control) * 100 Utilization [%) = _ (Fe FeDos. FeDos.

[(Hb2[3] BW9H4) _ Hb] BW4] _ * * * 0.07 9r 0.0034 (Hb2[3] Control * BW9[14] _ Hbi Control Control * BWA l) * 007 * 00034)] * 100/ Fe DOS' [(Hb2lsl " (Hb2lsl * BW9l14)_ Hbl * 3W4) * 0-000238 Control * BW9['l4| Control “ Hbt Comm .. BW4 Como.) * 0.000238] * 100 / Fe DOS.

(HD2131 — * BW9[14)— Hbl * BW4 Hbzlal Control * BW9(14] Control + Hbi Control * BW4 Como.) . 0.0238 / Fe DOS. 0.07 = Factor for 70 ml blood per kg body weight (BW) 0.0034 = Factor for 0.0034 g Fe/g Hb Hb1 = Hemoglobin level (g/I) on day l Hbm, = Hemoglobin level (g/I) on day 8 [or 15] 3O BW4 = body weight [g] on day l BWWA, = body weight [g] on day 8 (or 15) Hb1 Como. = e hemoglobin level (g/l) on day l in the control group, Hbmmontrol = average hemoglobin level (g/I) on day 8 (or 15) in the control group, BW4 Comm. = average body weight (g) on day l in the control group, BWWMmomm. = average body weight (g) on day 8 (or 15) in the control group, Fe Dos. = entire stered iron [mg Fe] over 5 or to days, Fe ut. = (Hbm, * BW9r141— Hb1 , 8W4) * 0.07 * 0.0034 (mg Fe) A Utilization = Fe tot. utilized (examined group) — Fe ut. Control group, utilized from food, [mg Fe) Table i - iron utilizations: Example-No. ation n 15 d (abs. %) not determined comparative example* * Comparative example: As a ative example the tris(pyridinoneol-i-oxide)-iron(lll) i5 complex compound of the formula: 04lFem)O—N\ ONOO//\\ / was ed according to EP 0138420 and tested to demonstrate the influence of the heterocyclic base body. EP 0138420 discloses in example 7 only trislpyridinonoi-i-oxide]-iron(|l|] x compounds which carry a further substituent on the pyridine ring. Unsubstituted tris[pyridinoneol-i-oxide)-iron(l|l) complex compounds as used in the present comparative example are not disclosed therein. As can be seen from the results in the above-mentioned table the corresponding pyrimidine compound of example 1 according to the present invention exhibits significantly improved iron ation compared to the comparative pyridine nd according to EP Ol 38420.

Claims (13)

WE CLAIM:

1. Use of iron(III) pyrimidineoloxide complex nds or pharmaceutically acceptable salts thereof , which contain at least one ligand of the formula (I): wherein the arrows respectively represent a coordinate bond to one or ent iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - hydrogen, - alkyl, which may be tuted with cycloalkyl or with 1 to 3 substituents ed from the group consisting of o hydroxy, o aryl, which may be substituted with one or more substituents selected from  halogen,  hydroxy,  alkyl, as defined above and  alkoxy, as defined below, o heteroaryl, which may be substituted with one or more substituents selected from  halogen,  hydroxy,  alkyl, as defined above and  alkoxy, as defined above, AH26(9820323_1):JIN o alkoxy (RO-), with R being alkyl as defined above, o alkoxycarbonyl (RO-CO-), with R being alkyl as defined above o acyl, o halogen, o amino ( -NH2) or a 5 or 6 -membered cyclic amino that may contain further hetero atoms selected from N, O, S, and which each may be substituted to form mono- or dialkylamino or monoor diarylamino, with aryl being aryl or heteroaryl, or mixed alkylarylamino groups, each with alkyl, aryl or heteroaryl as defined above, o arbonyl, derived by adding a carbonyl group to amino or a 5 or 6-membered cyclic amino, each as defined above, and o cyano, - n, - , as defined above, - aryl, as defined above, - alkoxycarbonyl, as defined above, - amino, as defined above, and - aminocarbonyl, as defined above, or R1 and R2 or R2 and R3 together with the carbon atoms to which they are bonded, form an optionally substituted ted or unsaturated 5 - or 6- membered ring, which may optionally contain one or more heteroatoms for the manufacture of a medicament for the treatment and prophylaxis of iron deficiency symptoms and iron deficiency anemias and the symptoms associated therewith.

2. The use according to claim 1, wherein the iron(III) complex compounds or pharmaceutically acceptable salts thereof n at least one ligand of the formula (I): AH26(9820323_1):JIN wherein the arrows respectively represent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - en, - alkyl, as defined in claim 2, - halogen, - alkoxy, as defined in claim 2, - aryl, as d in claim 2, - alkoxycarbonyl, as defined in claim 2, and - aminocarbonyl, as defined in claim 2 or R1 and R2 or R2 and R3 together with the carbon atoms to which they are bonded, form an optionally substituted saturated or unsaturated 5 - or 6- membered ring, which may optionally contain one or more heteroatoms.

3. The use according to any one of claims 1 or 2, wherein the iron(III) complex compounds or pharmaceutically able salts thereof contain at least one ligand of the formula (I): AH26(9820323_1):JIN wherein the arrows respectively represent a coordinate bond to one or different iron atoms, and R1, R2, R3 may be the same or different and are selected from the group consisting of: - hydrogen - alkyl, as defined in claim 2, and - n or R1 and R2 or R2 and R3 together with the carbon atoms to which they are bonded form a 5- or ered carbocyclic ring.

4. The use according to any one of claims 1 to 3, wherein the iron(III) complex compounds or pharmaceutically acceptable salts thereof cont ain at least one ligand of the formula (I): the arrows tively represent a coordinate bond to one or different iron atoms, R1, R2, R3 may be the same or different and are selected from the group consisting of hydrogen, alkyl which may optionally be substituted by alkoxy, and halogen, or R1 and R2 or R2 and R3 form together a propylene ( -CH2-CH2-CH2-), a butylene (-CH2-CH2-CH2-CH2-), azabutylene or oxabutylene group. AH26(9820323_1):JIN

5. The use according to any one of claims 1 to 4, wherein R1, R2, R3 are identical or ent and are selected from the group ting of hydrogen and alkyl, with the proviso that at least one of the substituents R 1, R2, and R3 is alkyl.

6. The use according to any one of claims 1 to 5, wherein wherein R2 is hydrogen, and R1 and R3 are each the same or different and are selected from alkyl.

7. The use according to any one of claims 1 to 6, wherein the iron(III) complex compounds are of the formula: wherein R1, R2, R3 may be the same or different and are defined as above, and pharmaceutically acceptable salts thereof.

8. The use according to any one of claims 1 to 7, n the symptoms include: fatigue, listlessness, lack of concentration, low cognitive efficiency, difficulties in finding the right words, forgetfulness, unnatural pa llor, irritability, acceleration of heart rate (tachycardia), sore or swollen tongue, ed spleen, desire for strange foods (pica), headaches, lack of appetite, sed susceptibility to infections, depressive moods.

9. The use according to any one of claims 1 to 7 for the ent of iron deficiency anemia in pregnant women, latent iron deficiency anemia in children and adolescents, iron deficiency anemia caused by gastrointestinal AH26(9820323_1):JIN abnormalities, iron deficiency anemia due to blood loss, s uch as gastrointestinal hemorrhage (e.g. due to ulcers, carcinoma, hemorrhoids, inflammatory disorders, taking of acetylsalicylic acid), iron deficiency anemia caused by menstruation, iron deficiency anemia caused by injuries, iron deficiency anemia due to psilosis (sprue), iron deficiency anemia due to reduced dietary iron uptake, in particular in selectively eating children and adolescents, immunodeficiency caused by iron deficiency anemia, brain function impairment caused by iron deficiency anemias, rest less leg syndrome caused by iron deficiency anemias, iron deficiency anemias in the case of cancer, iron ency anemias caused by chemotherapies, iron ency anemias triggered by inflammation (AI), iron deficiency anemias in the case of congestive c insufficiency (CHF; congestive heart failure), iron deficiency anemias in the case of chronic renal insufficiency stage 3 -5 (CKD 3-5; chronic kidney es stage 3-5), iron deficiency anemias red by chronic inflammation (ACD), iron deficiency s in the case of rheumatoid arthritis (RA), iron deficiency anemias in the case of systemic lupus erythematosus (SLE) and iron deficiency anemias in the case of inflammatory bowel diseases (IBD).

10. The use according to any one of the claims 1 to 9, n the medicament is formulated for oral stration.

11. The use according to claim 10, wherein a solid formulation such as pills, tablets, enteric-coated tablets, film tablets, layer tablets, sustained release ations, depot formulations, dragees, suppositories, granulates, apsules, microformulations, nanoformulations, capsules, enteric -coated capsules and powders, or a liquid formulation including a drinkable formulation such as a syrup, elixir, solution, suspension, juice is for administration.

12. The use according to any one of claims 1 to 11, wherein the medicament further comprises at least one physiological compatible carrier or excipient.

13. Use of a composition containing iron(III) complex compounds as defined in any one of claims 1 to 7, in ation with at least one further AH26(9820323_1):JIN medicament which acts on the iron lism for the preparation of medicaments for the treatment of iron deficiency anemia. Vifor (International) AG By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(9820323_1):JIN