WO2011029832A1

WO2011029832A1 - Novel thiazol and oxazol hepcidine antagonists

Info

Publication number: WO2011029832A1
Application number: PCT/EP2010/063146
Authority: WO
Inventors: Franz DÜRRENBERGER; Susanna Burckhardt; Peter Otto Geisser; Wilm Buhr; Felix Funk; Stefan Jaeger; Mark Slack; Christopher John Yarnold
Original assignee: Vifor (International) Ag
Priority date: 2009-09-09
Filing date: 2010-09-08
Publication date: 2011-03-17
Also published as: TW201111379A; AR078278A1

Abstract

The present invention relates to novel hepcidine antagonists of the general structural formula, pharmaceutical compositions comprising the same, and the use thereof as medications, particularly for treating iron metabolism disorders, such as in particular iron deficiency diseases and anemias, in particular anemias in conjunction with chronic inflammatory diseases (ACD, anemia of chronic disease, and AI, anemia of inflammation).

Description

NEW THIAZOL AND OXAZOLS PCI DIN ANTAGONISTS

DESCRIPTION:

INTRODUCTION;

The invention relates to new hepcidin-antagonists of the general formula (I), pharmaceutical compositions comprising them and their use for the treatment of iron metabolism disorders, in particular anemias in connection with chronic inflammatory diseases (ACD) and anemia of inflammation (AI)). or iron deficiency symptoms and iron deficiency anemia.

BACKGROUND:

Iron is an essential trace element for almost all living beings and is particularly relevant for growth and blood formation. The iron balance balance is primarily regulated at the level of iron recovery from hemoglobin from aging erythrocytes and the duodenal absorption of dietary iron. The released iron is taken up via the intestine in particular by specific transport systems (DMT-1, ferroportin, transferrin, transferrin receptors), transported into the bloodstream and passed on to the corresponding tissues and organs.

The element iron is of great importance in the human body for, among other things, oxygen transport, oxygen absorption, cell functions such as mitochondrial electron transport, and ultimately for the entire energy metabolism.

The human body contains on average 4 to 5 g of iron, which is present in enzymes, in hemoglobin and myoglobin, as well as depot or reserve iron in the form of ferritin and hemosiderin.

About half of this iron is about 2 g as heme iron bound in the hemoglobin of the red blood cells, since these erythrocytes only one limited lifespan (75-150 days), new ones must be constantly formed and old ones must be eliminated (over 2 million, erythrocytes are regenerated per second). This high capacity of neoplasms is achieved by macrophages by phagocytic uptake and lysing of the aging erythrocytes and thus to be able to recycle the contained iron for the iron balance. Thus, the amount of iron of about 25 mg needed daily for erythropoiesis is largely provided.

The daily iron requirement of an adult human is between 0.5 and 1.5 mg per day, in infants and women in pregnancy, the iron requirement is 2 to 5 mg per day. The daily loss of iron, for example, by exfoliation of skin and epithelial cells is relatively low, increased iron losses occur, for example, in the menstrual bleeding in women, in general, blood loss can reduce the iron budget considerably, since per 1 ml of blood lost about 1 mg of iron. The normal daily iron loss of about 1 mg is usually replaced by the daily food intake in an adult, healthy person. The iron metabolism is regulated by absorption, with the absorption rate of the iron present in the diet being between 6 and 12%; in the case of iron deficiency the absorption rate is up to 25%. The resorption rate is regulated by the organism depending on the iron demand and the iron storage size. The human organism uses both divalent and trivalent iron ions. Usually, iron (III) compounds are dissolved in the stomach at a sufficiently acidic pH and thus made available for absorption. The absorption of iron takes place in the upper small intestine by mucosal cells, Here, trivalent non-heme iron for absorption, for example, by Ferrireduktase (membrane-bound, duodenal cytochrome b) in the intestinal cell membrane initially reduced to Fe ²⁺ , then by the transport protein DMT1 (divalent In contrast, heme iron passes unchanged through the cell membrane into the enterocytes. In the enterocytes, iron is either stored in ferritin as depot iron or released into the blood by the transport protein ferroportin, bound to transferrin , In Hepcidin plays a central role in this process as it is the essential regulator of iron uptake. The divalent iron transported into the blood by ferroportin is converted into trivalent iron by oxidases (ceruloplasmin, hephaestin), which is then transported to the relevant sites in the organism by means of transferrin For example, "Balancing acts: molecular control of mammalian iron metabolism." MW Hentze, Cell 117, 200, 245-297.)

The regulation of the iron level is controlled or regulated by hepcidin,

Hepcidin is a peptide hormone that is produced in the liver. The predominant active form has 25 amino acids (s, for example: "Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation" T. Ganz Blood 102, 200, 783-8), although two forms shortened at the amino terminus , Hepcidin-22 and hepcidin-20, hepcidin acts on iron uptake via the intestine, via the placenta and on the release of iron from the reticuloendoteiiai system, in the body hepcidin is synthesized from the so-called pro-hepcidin in the liver, where pro-hepcidin is encoded by the so-called HAMP gene, If the organism is sufficiently supplied with iron and oxygen, hepcidin is increasingly formed, hepcidin binds in the small intestine mucosa cells and in the macrophages to ferroportin, through which usually iron from the cell interior is transported into the blood,

The transport protein ferroportin is a 571 amino acid membrane transport protein that is produced and localized in the liver, spleen, kidneys, heart, intestine and placenta. In particular, ferroportin is localized in the basolateral membrane of intestinal epithelial cells, the thus bound ferroportin causes this iron export into the blood. Ferroportin probably carries iron as Fe ^{2 +} , binds hepcidin to ferroportin, ferroportin is transported into the cell interior and degraded, whereby the iron release from the cells is then almost completely blocked Ferroportin inactivated via hepcidin and thus can not remove the iron stored in the mucosa cells, the iron is lost with the natural Zellabschilterung over the chair. This reduces the absorption of iron in the intestine by hepcidin. On the other hand, if the iron content in the serum is lowered, hepcidin production is reduced in hepatocytes of the liver so that less hepcidin is released and thus less ferroportin is inactivated, whereby an increased amount of iron can be transported to the serum.

In addition, ferroportin is strongly localized in the reticuloendothelial system (RES), which also includes macrophages.

Hepcidin plays an important role here in disturbed iron metabolism in the context of chronic inflammation, since in such inflammations in particular interleukin-6 is increased, which leads to an increase in the hepcidin-level. As a result, Hepcidn is increasingly bound to the ferroportin of the macrophages, resulting in a blockage of iron release, which ultimately leads to an inflammation-induced anemia (ACD or AI),

Since the mammalian organism can not actively excrete iron, the iron metabolism is essentially controlled by the hepcidin via the cellular release of iron from macrophages, hepatocytes and enterocytes,

Hepcidin thus plays an important role in functional anemia, in this case, despite filled iron stores, the iron requirement of the bone marrow for erythropoiesis is not sufficiently fulfilled. The reason for this is assumed to be an increased hepcidin concentration which, in particular, blocks the transport of iron from the macrophages by blocking the ferroportin and thus greatly reduces the release of phagocytic recycled iron,

A disturbance of the hepcidin regulatory mechanism thus has a direct effect on the iron metabolism in the organism For example, prevents hepcidin expression, for example, by a genetic defect, this leads directly to an overload of iron, which is known under the iron storage disease hemochromatosis.

In contrast, hepatitis in overexpression, for example, due to inflammatory processes, for example in chronic inflammation, directly in reduced serum iron levels, these may result in pathological cases to reduced content of hemoglobin, reduced erythrocyte production and thus to anemia.

The duration of use of chemotherapeutic drugs in carcinoma treatment can be significantly reduced by existing anemia, as the state of reduced red blood cell production, caused by the chemotherapeutic agents used, is compounded by existing anemia.

Other symptoms of anemia include fatigue, paleness, and decreased attention capacity. The clinical symptoms of anemia include low serum iron levels (hypoferremia), low hemoglobin levels, low hematocrit levels, and reduced red blood cell counts, reduced reticulocytes, elevated levels of soluble transferrin receptors.

Typically, iron deficiency or iron anemia is treated by iron. The substitution with iron takes place either by the oral route or by intravenous iron administration. In addition, to stimulate the formation of red blood cells, erythropoietin and other erythropoietin-stimulating substances may also be used in the treatment of anemias.

Anemias caused by chronic diseases, eg chronic inflammatory diseases, can not be adequately treated with such classic treatments. In particular, anemia that is based on chronic inflammatory processes plays Cytokines, in particular inflammatory cytokines, a special role. Hepcidin overexpression occurs particularly in such chronic inflammatory diseases and is known to result in reduced iron availability for the formation of red blood cells,

Hence, there is a need for an effective method of treatment of hepcidin-mediated herten or mediated anemias, especially those that can not be treated with classical iron substitutions, such as anemia caused by chronic inflammatory diseases (ACD and AI).

Anemia is due, inter alia, to such chronic inflammatory diseases as well as to malnutrition or low-iron diets. In addition, anemias occur due to reduced or poor iron absorption, for example due to gastrectomies or diseases such as Crohn's disease. Also, iron deficiency due to increased blood loss, e.g. due to injury, severe menstrual bleeding or blood donation. Also, an increased iron demand in the growth phase of adolescents and children and pregnant women is known because iron deficiency not only leads to a reduced formation of red blood cells, but also to a poor supply of the organism with oxygen, leading to the above symptoms such as fatigue Paleness and lack of concentration can lead to long-term negative effects on cognitive development, especially in adolescents, a particularly effective therapy is also of particular interest for this area in addition to the well-known classical substitution therapies,

Compounds which bind to hepcidin or to ferroportin and thus inhibit the binding of hepcidin to ferroportin, and thus in turn prevent inactivation of ferroportin by the hepcidin, or compounds which, although hepcidin bound to ferroportin, prevent the internalization of the hepcidin-ferroportin complex , and up In this manner, hepcidin can prevent inactivation of ferroportin, and may be commonly referred to as hepcidin-antagonists.

In addition, by using such hepcidin-antagonists, it is also generally possible to directly influence the regulation mechanism of hepcidin by, for example, inhibiting hepcidin expression or by blocking the hepcidin-ferroportin interaction, and thus blocking the isentransport pathway from tissue macrophages, liver cells and to prevent mucosal cells in the serum via the transport protein ferroportin. Thus, with such hepcidin antagonists or hepcidin expression inhibitors, substances are available which are suitable for the preparation of pharmaceutical compositions or medicaments in the treatment of anemias, in particular anemias in chronic inflammatory diseases. These substances can be used to treat such disorders and the resulting diseases as they directly affect the increase of macrophage release of recycled heme iron, as well as increase the iron absorption of food-released iron in the intestinal tract Such substances, hepcidin expression inhibitors or, hepcidin-antagonists, for the treatment of iron metabolism disorders such as iron deficiency diseases, anemias and anemia-related diseases usable, in particular, this includes such anemia caused by acute or chronic inflammatory diseases such as Osteoarticular diseases such as rheumatoid arthritis or diseases associated with inflammatory syndromes, Thus, such substances may be particularly in the indications cancer in particular colorectal cancer, multiple myeloma, ovarian and endometrial Kr ebs and prostate cancer, chronic kidney disease stage 3-5, CHF, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), STATE OF THE ART:

Hepcidin antagonists or compounds which inhibit or support the biochemical regulation pathways in iron metabolism are known in principle from the prior art,

Thus, for example, WO 2008/036933 describes double-stranded dsRNA which has an inhibiting effect on the expression of human HAMP genes in cells and thus in the iron metabolism signal pathway already at a very early stage the formation of hepcidin which is encoded by the HAMP gene , suppresses, thereby less hepcidin is formed, so that hepcidin is not available for the inhibition of ferroportin, so that the transport of iron from the cell into the blood by ferroportin can take place unhindered,

Further compounds which are aimed directly at reducing hepcidin expression are known from US 2005/020487, which describes compounds which have a stabilizing effect on HIF-α and thus lead to a reduction in hepcidin expression.

US 2007/004618 relates to siRNA, which acts directly inhibiting hepcidin mRNA expression.

Thus, all of these compounds or processes are those which begin in the iron metabolic pathway prior to the formation of hepcidin and already downregulate its general formation, However, also such substances and compounds are known and described in the prior art, the already formed Bind hepcidin in the body and thus inhibit its binding effect on the membrane transport protein ferroportin, so that inactivation of the ferroportin by hepcidin is no longer possible, Thus, such compounds are so-called hepcidin antagonists, from this group, in particular those based on Furthermore, such documents are also known in the art, the various mechanisms for action on hepcidin expression describe, for example, by antisense RNA or DNA molecules, ribozymes and anti-hepcidin antibodies. Such are described for example in EP 1 392 345.

Furthermore, WO09 / 058797 discloses anti-hepcidin antibodies and their use for specific binding to human hepcidin-25 and thus their use for the therapeutic treatment of low iron contents, in particular of anemias,

Further compounds which act as hepcidin antagonists and are formed from the group of hepcidin antibodies are known from EP 1 578 254, WO08 / 097461, US2006 / 019339, WO09 / 044284 or WO09 / 027752,

In addition, antibodies are also known which bind to ferroportin-1 and thus activate ferroportin in order to support the transport of iron from the cell into the serum. Such ferroportin-1 antibodies are known, for example, from US2007 / 218055.

All of these described compounds, which act as hepcidin-antagonists or can exert an inhibitory effect on hepcidin expression, are compounds of high molecular weight, in particular those obtainable mainly by genetic engineering.

In addition, low molecular weight compounds that play a role in iron metabolism, and that can act both inhibiting or supporting, are known

Thus, WO08 / 109840 describes certain tricyclic compounds which can be used in particular for the treatment of disorders of iron metabolism such as, for example, ferroportin disorders, which compounds can act by regulation of DMT-1 in the form of inhibition or activation WO08 / 109840 described in particular as DMT-1 inhibitors, whereby they are preferably used in diseases with increased iron accumulation or iron storage diseases such as hemochromatosis.

Also known from WO08 / 121861 are low molecular weight compounds which have a regulating effect on the DMT-1 mechanism. In particular, certain pyrazole and pyrrole compounds are treated, the treatment of iron overload disorders being described here, for example, due to ferroportin disturbances ,

Furthermore, the subject matter of US2008 / 234384 are certain diaryl and di heteroaryl compounds for the treatment of disorders of iron metabolism, such as, for example, ferroportinal disorders, which can likewise be used by action as DMT-1 inhibitors, in particular for the treatment of disorders due to increased iron accumulation. However, this document generally mentions possible DMT-1 regulatory mechanisms that may be used to treat iron deficiency,

The same applies to WO08 / 151288, in which certain aromatic and heteroaromatic compounds are described with effect on the DMT-1 regulation and thus for the treatment of iron metabolism disorders.

Thus, the art-known low molecular weight compounds that act on iron metabolism are related to DMT-1 regulatory mechanisms and, in particular, disclosed for use as agents for treating iron accumulation disorders or iron overload syndromes such as hemochromatosis.

Structural chemical compounds of thiazolamides or oxazolamides have not previously been described in the context of the treatment of iron metabolism disorders. In addition, no low molecular weight chemical structures have been reported to date Effect as hepcidin antagonists and thereby are useful in the treatment of iron metabolism disorders.

The invention also provides novel thiazole and oxazolamide compounds of the general structural formula (I) according to the present invention,

WO 2007/056155 A1 describes specific heterocyclic compounds and their action as tyrosine kinase inhibitors. The compounds of the underlying general structural formulas (1) to (6) disclosed therein differ from the compounds of the present invention having the general structural formula (I). From the group of compounds of general formula (5):

there is disclosed a single concrete compound wherein the substituent X ^{B6 has} the meaning of substituted acyl having a structure corresponding to the general formula (I) of the present invention. Thus, although WO 2007/056155 A1 discloses the compound of the general structural formula

formally a single compound falling within the formula (I) of the present invention, however, the document does not give any indication of any particular effect of such a concrete structural element a possible effect of such specific compounds in the treatment of disorders of iron metabolism,

WO 2008/146774 A1 relates according to the English title and abstract Tetra hydroisochinollnon- derivatives and their use in the treatment of irritable bowel syndrome. Also, the compounds of the underlying general structural formulas (A), (B) and (C) disclosed herein differ in principle from the compounds of the present invention having the general structural formula (I). In this document, in a single concrete embodiment (Compound No. 238), there is disclosed a compound wherein a substituent has a structure corresponding to the general formula (I) of the present invention. Thus, WO 2008/146774 A1 does indeed disclose compound no. 238 having the general structural formula

however, formally a single compound falling within the formula (I) of the present invention, the document does not indicate either a particular effect of such a specific structural element nor a possible effect of such specific compounds in the treatment of iron metabolism disorders.

From "Preparation of carboxamide derivatives containing azole moiety as SGLT inhibitors"; Fukatsu, Kohji et al., Database Caplus Chemical Abstracts Service, STN, 2006) discloses some specific Ca boxa mid derivatives, processes for their preparation, and their use in treatment of Diabetes and Obesity, In particular, the following compounds are specifically disclosed therein:

2- [2 - [([l, 1'-biphenyl] -4-ylcarbonyl) -amino] -ethyl] -N- [2- (dl-phenylamino) -ethyl] -4-oxazolecarboxamide:

2- [2 - [([l, T-Bliphenyl] -4-ylcarbonyl) amino] ethyl] -N- [2- (4-morpholinyl) -3-phenoxypropyl] -4-Oxazolecarboxamide:

2- [2 - [([l, 1'-biphenyl] -4-ylcarbonyl) amino] ethyl] - N - [2- (4-morpholinyl) -3-phenoxypropyl] -4-thiazolecarboxamide:

2- [2 - [([l, 1'-biphenyl] -4-ylcarbonyl) amino] ethyl] -N- [2- (diphenylamino) ethyl] -4-thiazolecarboxamide:

2- (2-aminoethyl) -4-thiazolecarboxylic acid ethyl ester:

2- [2 - [[(1,1-dimethylethoxy) carbonyl] amino] ethyl] -4-oxazolecarboxylic acid

2- [2 - [([1,1'-biphenyl] -4-ylcarbonyl) at the ino] e † hyl] -4-thiazolecarboxylic acid

- (2-aminoethyl) -4-oxazolecarboxylic-methylester:

2- [2 - [([l, 1'-biphenyl] -4-ylcarbonyl) amino] ethyl] -4-oxazolecarboxylic acid

Therein, in each case the substituents in position R ² or R ³ corresponding to the general formula (I) of the present invention, the meaning of acyl (or, alkoxycarbonyl) or R ² and R ³ are the same and mean hydrogen. A compound wherein one of the substituents at position R ² or R ³ corresponding to the general formula (I) of the present invention has the meaning of optionally substituted alkyl is not disclosed herein. Moreover, this disclosure also fails to suggest any possible effect of the structural elements or compounds disclosed therein in the treatment of disorders of iron metabolism.

WO 2009/154739 A2 describes novel heterocyclic compounds and their action on the so-called Smo receptor, and their use in the treatment of cancer as well as in wound treatment and tissue regeneration. However, this document also discloses a specific compound (VI):

wherein the substituent R ² corresponding to the general formula (I) of the present invention has the meaning of substituted acyl (aroyl). Thus, although WO 2007/056155 A1 discloses formally with this specific compound a single compound which falls under the formula (I) of the present invention, the document does not give any indication of a particular effect of such a concrete structural element nor of a possible one Effect of such specific compounds in the treatment of iron metabolism disorders.

"Synthesis of fhiazole-based DNA targeting molecules aiming at guanine specificity" (Kobayashi Susumu et al., Synlett (1), 1992) describes processes for the preparation of thiazole derivatives and their use in DNA binding. Specifically, this document discloses the following compounds:

Compound 2a:

Compound 5a:

_ i 6 -

Compound όα;

in which the substituents in position R ² or R ³ , corresponding to the general formula (I) of the present invention, have the meaning of acyl (or alkoxycarbonyl). A compound wherein one of the substituents in the R ² and R \ positions corresponding to the general formula (I) of the present invention has the meaning of optionally substituted alkyl is not disclosed herein. Moreover, there is also no indication in this disclosure of any potential effect of the compounds disclosed therein in the treatment of iron metabolism disorders.

From "On the role of individual bleomycin thiazoles in oxygen activation and DNA cleavage" (Hamamishi Norimitsu et al., Journal of the American Chemical Society, 114 (16), 1992) are new bleomycins, as well as processes for their preparation and their role in DNA synthesis or DNA degradation described. Specifically, this document discloses the following compounds, which formally fall under the general formula (I) of the present invention:

with the meaning of R = Boc (Boc-protecting group) or H,

with the meaning of R = NPS (nitrophenylsulfonyl protecting group) or H,

with the meaning of R = Boc (Boc-protecting group) or H

and thus exclusively compounds in which the substituents in position R ² or R ³ , corresponding to the general formula (I) of the present invention, have the meaning of acyl (or Boc = alkoxycarbonyl) or sulfonyl (NPS = sulfonyl group). A compound in which one of the substituents at the position R ² or R 1 corresponding to the general formula (I) of the present invention has the meaning of optionally substituted alkyl is not disclosed herein. Moreover, there is no indication whatsoever from this disclosure of a possible effect of the compounds disclosed therein in the treatment of disorders of iron metabolism.

Synthesis and proton NMR spectral assignments of thiazoles amides related to bleomycin A2 (1) (Riordan et al., Database Caplus Chemical Abstracts Service, STN, 1982) are some specific Thiazolamide derivatives and processes for their preparation described According to STN Dafenbankauszug be specifically disclosed therein, in particular, the following compounds which formally fall under the general formula (I) of the present invention:

[3 - [[[2- [2- (Acetylamino) ethyl] -4-thiazolyl] carbonyl] amino] propyl] dimethylsulfonium chloride:

_{M e} _. _g l _, _{c H 2} jj ^~ ~ Ji | H ^"™ ~ I CI CH ₂ - Ctl _2" ^{* ™ 's} ^{"Ä C}

2- [2- (acetylamino) ethyl] -4-thiazolecarboxylic acid ethyl ester:

2- [2- (acetylamino) ethyl] -N- [3- (methylthio) propyl] -4-thiazolecarboxamide:

Therein, in each case the substituents in position R ² or R ³ , corresponding to the general formula (I) of the present invention, have the meaning of acyl (acetyl), a compound in which one of the substituents in position R ² or, R ³ , is not disclosed herein. Moreover, there is no indication whatsoever of medical use of the disclosed structural elements or compounds or even of a possible effect in this disclosure the treatment of disorders of iron metabolism,

In "A biomimetic synthesis of the bithiazole moiety of bleomycin" (McGowan et al., Journal of the American Chemical Society, 1977) are some specific bifhiazole units of bleomycin and methods for their preparation described. In addition, the document mentions the anticancer activity of bleomycins. In particular, the following compounds are disclosed concretely in this document, which formally fall under the general formula (I) of the present invention:

Connection 4

with the meaning of R = CH ₃ or phenyl and compound 5:

with the meaning of R =CH ₃ or phenyl and also R '= (C ₆ H ₅ ) ₃ C or H, in each case the substituents in position R ² or R ³ , corresponding to the general formula (I) of the present invention, the meaning of (optionally substituted) acyl (acetyl or benzoyl). A compound in which one of the substituents in position R ² or R ³ corresponding to the general formula (I) of the present invention has the meaning of optionally substituted alkyl is not disclosed herein. Moreover, there is no indication whatsoever of this disclosure to a possible effect of the compounds described in the treatment of disorders of iron metabolism,

In "Synthesis of 2 '- (2-aminoethyl) -2,4'-bi-hiazole-4-carboxylic acid, a component of the antitumor antibiotic bleomycin" (Zee-Cheng et al., Database Caplus Chemical Abstracts Service , STN, 1971) describes the synthesis of 2'2- (2-aminoethyl) -2,4'-bithiazole-4-carboxylic acid, according to STN In particular, the following compounds, which formally fall under the general formula (I) of the present invention, are also specifically disclosed therein:

2- [2- (benzoylamino) ethyl] -4-Thlazolcarbonsaure-e † † hyles he:

and

2- [2- (benzoylamino) ethyl] -4-thiazolecarboxamide:

Therein, each of the substituents in the position R ² or R ³ corresponding to the general formula (I) of the present invention has the meaning of acyl (benzoyl). A compound wherein one of the substituents at position R ² or R ³ corresponding to the general formula (I) of the present invention has the meaning of optionally substituted alkyl is not disclosed herein. Furthermore, there is no indication in this disclosure of any medicinal use of the disclosed compounds, or even of a potential effect in the treatment of iron metabolism disorders.

CHALLENGES:

The object of the present invention was to provide in particular those compounds which can be used for the use of iron deficiency disorders or anemias, in particular ACD and AI and which act in particular in the iron metabolism as hepcidin-antagonists, and thus in the iron metabolism in the hepcidin-ferrino-porin interaction develop an antagonistic and over regulating effect. Furthermore, it was a particular object of the present invention Invention to provide compounds which are selected from the group of low molecular weight compounds and which can generally be prepared by simpler synthetic routes than the antagonistic or hepcidin-inhibiting compounds obtainable by genetic engineering methods, such as RNA, DNA or antibodies,

DESCRIPTION OF THE INVENTION:

The inventors found that certain compounds from the group of thiazolamides have an effect as hepcidin-antagonists.

The invention relates to compounds of the general structural formula

wherein

X is selected from: S or O;

R ^{1 is} selected from the group consisting of:

Hydrogen,

optionally substituted Amlno,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted alkenyl,

optionally substituted alkynyl,

optionally substituted aryl, or

optionally substituted heterocyclyl;

R ² and R ^{3 are the} same or different and are each selected from the group consisting of: Hydrogen,

optionally substituted alkyl, aryl or

heterocyclylsulfonyl,

optionally substituted acyl,

optionally substituted alkoxycarbonyl,

optionally substituted alkyl,

optionally substituted alkenyl,

optionally substituted alkynyl,

optionally substituted aryl, or

optionally substituted heterocyclyl; or pharmaceutically acceptable salts thereof,

In the context of the overall invention, the abovementioned substituent groups are defined as follows:

Optionally substituted alkyl preferably includes:

Straight-chain or branched alkyl having preferably 1 to 8, more preferably 1 to 6, particularly preferably 1 to 4 carbon atoms. In one embodiment of the invention optionally substituted straight-chain or branched alkyl may also include those alkyl groups in which preferably 1 to 3 carbon atoms are replaced by corresponding hetero analogues containing nitrogen, oxygen or sulfur or more methylene groups in said alkyl radicals may be replaced by NH, O or S,

Optionally substituted alkyl further includes cycloalkyl of preferably 3 to 8, more preferably 5 or 6, most preferably 6 carbon atoms,

Substituents of the above-defined optionally substituted alkyl preferably include 1 to 3 same or different substituents selected, for example, from the group consisting of: optionally substituted cycloalkyl as defined below, hydroxy, Halogen, cyano, alkoxy as defined below, optionally substituted aryloxy as defined below, optionally substituted heterocyclyloxy as defined below, carboxy, optionally substituted acyl as defined below, optionally substituted aryl as defined below, optionally substituted heterocyclyl as below defines optionally substituted amino as defined below, mercapto, optionally substituted alkyl, aryl or heterocyclysulfonyl (R-S0 ₂ -) as defined below.

Examples of alkyl radicals having 1 to 8 carbon atoms include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n- Pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, 2-methylbutyl group, n-hexyl group, 1-methylpentyl group, 2-methyl pentyl group, 3-methylpentyl group, 4-methyl pentyl group, one 1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group, an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylexyl group, a 1-ethylpentyl group, a 2-ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a 1 , 1-Dimethylpentylgruppe, a 2, 2 -Di methylpentyl group, a 3, 3-dimethylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutyi group, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group, a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a 1, 1-dimethylhexyl group, a 2, 2- Di methylhexylgruppe, a 3, 3 -Di methylhexylgruppe, a 4,4-di methylhexylgruppe, a 5, 5-Di methylhexylgruppe, a 1 - Propylpentylgruppe, a 2-propyl pentyl group, etc. Preferred are those having 1 to 6 carbon atoms , in particular methyl, ethyl, n-propyl and i- Propyl. Most preferred are C ₄ alkyl, such as in particular methyl.

Examples of alkyl groups resulting from exchange with one or more heteroanalogous groups, such as -O-, S- or -NH-, are preferably those in which one or more methyl groups are replaced by -O- to form an ether group, such as methoxymethyl , Ethoxymethyl, 2-methoxyethyl, etc. Also included in the invention are polyether groups such as poly (ethyleneoxy) groups of the definition of alkyl.

Cycloalkyl radicals having 3 to 8 carbon atoms preferably include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. Preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, particularly preferred is a cyclohexyl group.

Halogen in the context of the present invention includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine,

Examples of a halogen-substituted linear or branched alkyl radical having 1 to 8 carbon atoms:

a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a chloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 1-fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl group, a 2-fluoroethyl group, a 2- Chloroethyl group, a 2-bromoethyl group, a 1, 2-difluoroethyl group, a 1, 2-dichloroethyl group, a 1, 2-Di bromoethyl group, a 2, 2, 2-trifluoroethyl group, a

Heptafluoroethyl group, a 1-fluoropropyl group, a 1-chloropropyl group, a 1-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 1,2-dichloropropyl group, a 1,2-dibromopropyl group, a 2,3-difluoropropyl group, a 2,3-chloro-chloro-propyl group, a 2,3-dibromo-propyl group, a 3,3,3-trifluoropropyl group, a 2,2 , 3,3,3-pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a 4-fluorobutyl 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-fluorophenyl group, a 2-chloropentyl group, a 2-bromophenyl group, a 5-fluorophenyl group, a 5-chloropentyl group, a 5-bromophenyl group, a perfluoropentyl group, a 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-fluorohexyl group, a 7-chloro-phenyl group, a 7-bromohephenyl group, a perfluoroheptyl group, etc.

Examples of a halogen-substituted cycloalkyl radical having 3 to 8 carbon atoms include: a 2-fluorocyclopentyl group, a 2-

Chlorcyclopentyl group, a 2-bromocyclopentyl group, a 3-

Fluorocyclopentyl group, a 3-chlorocyclopentyl group, a 3-

Bromocyclopentyl group, a 2-fluorocyclohexyl group, a 2-

Chlorocyclohexyl group, a 2-bromocyclohexyl group, a 3-

Fluorocyclohexyl group, a 3-chlorocyclohexyl group, a 3-

Bromocyclohexyl group, a 4-fluorocyclohexyl group, a 4-

Chlorocyclohexyl group, a 4-bromocyclohexyl group, a di-

Fluorocyclopentyl group, a di-chlorocyclopentyl group, a di-

Bromocyclopentyl group, a di-fluorocyclohexyl group, a di-

Chlorocyclohexyl group, a di-bromocyclohexyl group, a tri-

Fluorocyclohexyl group, a tri-chlorocyclohexyl group, a tri-

Bromocyclohexyl group, etc. Examples of a hydroxy-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3 hydroxyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc.

Examples of an alkoxy-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3 alkoxy groups as defined below, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 3-methoxypropyl, etc., 2 Methoxyethylene, etc. Preferred is 2-methoxyethyl.

Examples of an aryloxy-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3 aryloxy groups as defined below, such as phenoxymethyl, 2-phenoxyethyl and 2- or 3-phenoxypropyl, etc. Preferred is 2-phenoxyethyl.

Examples of a heterocyclyioxy-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3 heterocyclyioxy groups as defined below, such as pyridin-2-yloxymethyl, -ethyl or -propyl, pyrldin-3-yloxymethyl, -ethyl or - propyl, thiophen-2-yloxymethyl, -ethyl or -propyl, thiophen-3-yloxymethyl, -propyl or -propyl, furan-2-yloxymethyl, -ethyl or -propyl, furan-3-yloxymethyl, -ethyl or -propyl.

Examples of an acyl-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3 acyl groups as defined below.

Examples of a cycloalkyl-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3, preferably an (optionally substituted) cycloalkyl group, such as: cyclohexylmethyl, 2-cyclohexylethyl, 2- or 3-cyclohexylpropyl, etc.,

Examples of an aryl-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3, preferably an (optionally substituted) aryl group as defined below, such as Example phenylmethyl (benzyl), 2-phenylethyl, 2- or 3-phenylpropyl, etc., phenylmethyl (benzyl) being preferred. Preference is furthermore given to alkyl groups as defined above which are substituted by substituted aryl, as defined below, in particular by halogen-substituted aryl, and more preferably 3-chloro-4-fluorophenylmethyl:

Examples of a heterocyclyl-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3, preferably an (optionally substituted) heterocyclic group as defined below, such as 2-pyridin-2-yl-ethyl, 2-pyridine 3-yl-ethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, 2-furan-2-yl-ethyl, 2-furan-3-yl-ethyl, furan-2-ylmethyl, Furan-3-yl-methyl, 2-thiophen-2-yl-ethyl, 2-thiophen-3-yl-ethyl, thiophen-2-yl-methyl, thiophen-3-yl-methyl, 2-morpholinyl-ethyl, as in 2 -Morpholin-4-yl-ethyl, morpholinyimethyl, such as morpholin-4-ylmethyl, 1H-imidazol-2-ylmethyl, each of which may still have fused benzene rings, such as 1H-benzoimidazol-2-ylmethyl:

(* = Binding site).

Particularly preferred are:

1H-benzoimidazol-2-ylmethyl;

(* = Binding site)

and -lmidazol-2-ylme † hyl:

(* = Binding site).

Examples of an amino-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3, preferably an (optionally substituted) amino group as defined below, such as methylaminomethyl, methylaminoethyl, methylaminopropyl, 2-ethylaminomethyl, 3-ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminoethyl, etc.

Optionally substituted alkoxy includes an optionally substituted alkyl-O group, wherein reference may be made to the above definition with respect to the definition of the alkyl group. Preferred alkoxy groups are linear or branched alkoxy groups having 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 i-butyloxy group, a sec-butyloxy group, a t-butyloxy group, n-pentyloxy group, i-pentyloxy group, sec-pentyloxy group, t-pentyloxy group, 2-methyl butoxy group, n-hexyloxy group, i-hexyloxy group, t-hexyloxy group, sec-hexyloxy group, 2-methylpentyloxy group a 3-methylpentyloxy group, a 1-ethylbutyloxy group, a 2-ethylbutyloxy group, a 1,1-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a 1-ethyl-1-methylpropyloxy group, and cycloalkyloxy groups such as a cyclopentyloxy group or a cyclohexyloxy group. Preferred are a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, a n-butyloxy group, an i-butyloxy group, a sec-butyloxy group, a t-butyloxy group. Particularly preferred is the methoxy group.

Optionally substituted alkenyl preferably includes throughout the scope of the invention: Straight chain or branched chain alkenyl of 2 to 8 carbon atoms and cycloalkenyl of 3 to 8 carbon atoms which may optionally be substituted by preferably 1 to 3 same or different substituents such as hydroxy, halogen or alkoxy, examples include vinyl, 1-ethylvinyl, allyl , 1-Butenyl, isopropenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. Preferred are vinyl or allyl.

Optionally substituted alkynyl preferably includes throughout the scope of the invention:

Straight-chain or branched-chain alkynyl having 2 to 8 carbon atoms and cycloalkynyl having 5 to 8 carbon atoms, which may be optionally substituted by preferably 1 to 3 identical or different substituents. With respect to the definition of the optionally substituted alkynyl, reference is made to the above definition of optionally substituted alkyl having more than one carbon atom wherein the optionally substituted alkynes comprise at least one C 1 -C 3 triple bond. Examples include ethynyl, propynyl, butynyl, pentynyl and optionally substituted substituted variants thereof as defined above. Preferred is ethynyl and optionally substituted ethynyl.

Optionally substituted aryl preferably includes throughout the scope of the invention:

Aromatic carbon hydrogen radicals having 6 to 14 carbon atoms (the carbon atoms of the possible substituents are not included), which may be mono- or bicyclic and which are preferably identical or different substituents selected from hydroxy, halogen, as defined above, cyano, optionally substituted amino as defined below, mercapto, optionally substituted alkyl as defined above, optionally substituted acyl as defined below, and optionally substituted alkoxy as defined above, optionally substituted aryloxy as defined above, optionally substituted heterocyclyloxy as defined above optionally substituted aryl, as defined herein, optionally substituted heterocyclyl, as defined below can. Aromatic carbon hydrogen radicals having 6 to 14 carbon atoms include, for example: phenyl, naphthyl, phenanthrenyl and anthracenyl, which may optionally be mono- or polysubstituted by identical or different radicals. Preference is given to phenyl and optionally substituted phenyl such as, in particular, mono- or poly-halogen-substituted phenyl.

Examples of an alkyl-substituted aryl group preferably include aryl as described above which is substituted with straight-chain or branched alkyl having 1 to 8, preferably 1 to 4, carbon atoms as described above. Preferred alkylaryl is toluyl.

Examples of a halogen-substituted aryl group preferably include aryl as described above which is substituted with halogen as described above.

Examples of a halogen-substituted aryl group having 3 to 8 preferably 6 carbon atoms in the aromatic ring system include a 2-fluorophenyl group, a 2-chlorophenyl group, a 2-bromophenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a 3-bromophenyl group, and the like 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 2,4-di-fluorophenyl group, a 2,4-di-chlorophenyl group, a 2,4-di-bromophenyl group, a 3,5-di-fluorophenyl group, a 3,5-di-chlorophenyl group, a 3,5-di-bromophenyl group, etc., a 2,4,6-tri-fluorophenyl group, a 2,4,6-tri-chlorophenyl group, a 2,4,6-tri Bromophenyl group, a 2-chloro-3-fluorophenyl group, a 3-chloro-4-fluorophenyl group, a 2-fluoro-3-chlorophenyl group, a 3-fluoro-4-chlorophenyl group, a 2,3-di-chloro-4- Fluorophenyl group, a 2, 4-di-chloro-3-fluorophenyl group, a 2-fluoro-3,4-di-chlorophenyl group, a 2,3-di-fluoro-4-chlorophenyl group, a 2,4-di-fluoro 3-Chlorph enyl group, a 2-chloro-3,4-di-fluorophenyl group, etc. Preferred is 2-fluorophenyl, 2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl and 4-chlorophenyl, and 2-chloro-3- Fluorophenyl, 3-chloro-4-fluorophenyl, 2-fluoro-3-chlorophenyl and 3-fluoro-4-chlorophenyl, especially preference is given to 3-chlorophenyl, 4-fluorophenyl and in particular 3-chloro-4-fluorophenyl,

Examples of a hydroxy-substituted aryl group preferably include: aryl, as described above, which is substituted with 1 to 3 hydroxy radicals, such as 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-di-hydroxyphenyl, 2, 5-Di-hydroxyphenyl, 2,6-di-hydroxyphenyl, 3,5-di-hydroxyphenyl, 3,6-di-hydroxyphenyl, 2,4,6-tri-hydroxyphenyl, etc. Preferred is 2-hydroxyphenyl, 3-hydroxyphenyl and 2,4-dihydroxyphenyl.

Examples of an alkoxy-substituted aryl group preferably include aryl, as described above, which is substituted with 1 to 3 alkoxy groups as described above, such as preferably 2-methoxyphenyl, 3-ethoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3 Ethoxyphenyl, 4-ethoxyphenyl, 2,4-di-methoxyphenyl, etc.

Optionally substituted heterocyclyl preferably includes throughout the scope of the invention:

Aliphatic, saturated or unsaturated heterocyclic 5 to 8 g cyclic radicals which have 1 to 3, preferably 1 to 2, heteroatoms selected from N, O or S, and which may optionally be substituted by 1 to 3 substituents, with respect to possible substituents reference can be made to the definition of the possible substituents of alkyl,

Preference is given to 5- or 6-membered saturated or unsaturated, optionally substituted heterocyclic radicals, such as tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl, tetrahydro-thiophen-3-yl, pyrrolidine-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, piperidin-1-yl, piperidin-2-yl , Piperidin-3-yl, piperidin-4-yl, piperazol-1-yl, plperazin-2-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, which optionally condenses with aromatic rings can be, etc. In addition, optionally substituted heterocyclyl includes in the entire scope of the invention heteroaromatic hydrocarbon radicals having 4 to 9 ring carbon atoms, which additionally preferably 1 to 3 identical or different heteroatoms from the series S, O, N in the ring, and thus preferably 5- to Form 12-membered heteroaromatic radicals, which may be preferably monocyclic but also bicyclic. Preferred aromatic heterocyclic radicals include for example: pyridinyl, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, pyridyl-N-oxide, pyrimidyl,

Pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolyncinyl, indolyl, benzo [b] thienyl, benzo [b] furyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl. 5- or 6-membered, mono- or bicyclic aromatic heterocycles such as pyridinyl, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, furyl and thienyl, and indolyl, benzimidazolyl, benzo [b] thienyl, benzothiazolyl or benzo [b] furyl. Particular preference is given to 1H-imidazolyl, such as 1H-imidazol-2-yl:

1H-imidazol-4-yl, or 3H-imidazol-4-yl and 1H-benzoimidazol-2-yl:

(^ each binding site).

The heterocyclyl radicals of the invention may be selected from preferably 1 to 3 identical or different substituents, for example, hydroxy, halogen as defined above, cyano, amino as defined below, mercapto, alkyl as defined above, acyl as defined below, and alkoxy as defined above, aryloxy as defined above, heterocyclyloxy as defined above, aryl as defined above, heterocyclyl as defined herein.

Heterocyclyl preferably includes: tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperidinyl or tetrahydropyranyl, pyridinyl, pyridyl-N-oxide, Pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyi, indolizinyl, indolyl, benzo [b] hienyl, benzo [b] furyl, indazolyl, benzimidazolyl, benzoxazolyl, benzo-hiazolyl, quinolyl , Isoquinolyl, naphthyridinyl, quinazolinyl, quinoxazolinyl. 5- or 6-membered, mono- or bicyclic aromatic heterocycles such as pyridinyl, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, furyl and thienyl, and indolyl, benzimidazolyl, benzo [b] hienyl, benzothiazolyl or benzo [b] furyl are preferred with imidazolyl and benzimidazolyl being particularly preferred,

Examples of an alkyl-substituted heterocyclyl group preferably include heterocyclyl as described above which is substituted with straight-chain or branched alkyl having 1 to 8, preferably 1 to 4, carbon atoms as described above. Preferred alkylheterocyclyl are methylimidazolyl, ethylimidazolyl, methylbenzimidazolyl as well as ethyl benzimidazolyl,

Examples of a hydroxy substituted heterocyclyl group preferably include heterocyclyl as described above which is substituted with 1 to 3 hydroxyl groups, such as 3-hydroxyimidazolyl, 3-hydroxybenzimidazolyl, 4-hydroxybenzimidazolyl, 3,4-dihydroxyimidazolyI, 3, 5-dihydroxybenzimidazolyl, 3,6-dihydroxybenzimidazolyl etc,

Examples of an alkoxy-substituted heterocyclyl group preferably include:

Heterocyclyl as described above which is substituted by 1 to 3 alkoxy radicals as described above, preferably 3-alkoxyimidazolyl, 3-alkoxybenzimidazolyl, 4-alkoxybenzimidazolyl, 3,4-di-alkoxyimidazolyl, 3,5-di-alkoxybenzimidazolyl, 3,6-di-alkoxybenzimidazolyl etc,

Optionally substituted acyl includes here and below: Optionally substituted aliphatic acyl (alkanoyl ----- alkyl-CO-, wherein with respect to the alkyl group can be referred to the above definition of optionally substituted alkyl), optionally substituted aromatic acyl (aroyl = aryl-CO-, in which, with respect to the aryl group, reference can be made to the above definition of optionally substituted aryl) or heterocyclic acyl heterocycloyl = heterocyclyl-CO-, wherein with respect to the heterocyclic group, reference can be made to the above definition of optionally substituted heterocyclyl ). Preferred is heterocyclic acyl (heterocyclyl-CO-).

Here, optionally substituted aliphatic acyl (alkanoyl) preferably includes: to C ₆ alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.

Examples of substituted aliphatic acyl include, for example: optionally aryl- or heterocyclyl-substituted C ₂ to C ₆ alkanoyl wherein reference may be made to the definitions above for aryl, heterocyclyl and C ₂ to C ₆ alkanoyl definitions such as phenylacetyl, thiophene -2-yl-acetyl, thiophen-3-yl-acetyl, furan-2-yl-acetyl, furan-3-yl-acetyl, 2- or 3-phenyl-propionyl, 2- or 3-thiophen-2-yl-propionyl , 2- or 3-thiophen-3-yl-propionyl, 2- or 3-furan-2-yl-propionyl, 2- or 3-furan-3-yl-propionyl.

Optionally substituted aromatic acyl (aroyl) includes in particular: C ₆ to C ₁₀ aroyl, such as benzoyl, toluoyl, xyloyl, etc.

Optionally substituted heterocyclic acyl (heterocycloyl) includes in particular: C ₆ to C ₁₀ heterocycloyl such as furanoyl, pyridinoyl, pyrrolidinoyl, piperidinoyl, tetrahydrofuranoyl such as tetrahydrofuran-2-oyl, etc.

Optionally substituted amino preferably includes throughout the scope of the invention; Amino, mono- or dialkylamino, mono- or diarylamino, (N-alkyl) (N-aryl) amino, mono- or diheterocyclylamino, (N-alkyl) (N-heterocyclyl) amino, (N-aryl) (N-heterocyclyl ) amino, mono- or diacylamino etc., wherein with respect to alkyl, aryl, heterocyclyl and acyl to the corresponding definition above for optionally substituted alkyl, optionally substituted aryl, optionally substituted Heterocyclyl and optionally substituted acyl can be referred,

Mono- or dialkylamino includes in particular: straight-chain or branched mono- or dialkylamino and mono- or dicycloalkylamino or (N-alkyl) (N-cycloalkyl) amino having 1 to 8, preferably 1 to 6, saturated or unsaturated, if appropriate as described above substituted carbon atoms in each alkyl group. In this case, (N-alkyl) (N-cycloalkyl) amino describes a substituted amino which is substituted in each case on the nitrogen atom by an alkyl radical and by a cycloalkyl radical. Examples of mono- or dialkylamino include methylamino, dimethylamino, ethylamino, cyclohexylamino or (N-methyl) (N-cyclohexyl) amino wherein the alkyl groups may each be substituted with preferably one substituent. Preference is given to monoalkylamino as well as iN-alkyl) (N-cycloalkyl) amino, particularly preferably substituted with (optionally substituted) aryl-substituted alkyl amino such as in particular benzyl methylamino and amino which carries substituted with halogen-substituted aryl alkyl as a substituent, such as 3-chloro -4- fluorophenyl methylamino. Particularly preferred are:

benzylamino:

*

(* = Binding site), or substituted benzylamino such as halogen-substituted benzylamino, such as:

(* = Binding site) and Dialkylamino, such as (cyclohexyl) (alkyl) amino, such as

(* = Binding site)

Mono- or diarylamino includes in particular: mono- or diarylamino having 3- to 8-, preferably 5- to 6-membered, optionally substituted as described above aryl radicals, in particular phenylamino or diphenylamino, wherein the aryl groups preferably substituted with one or two substituents could be,

(N-alkyl) (N-aryl) amlno describes in particular a substituted amino which is each substituted on the nitrogen atom by an alkyl radical and by an aryl radical, in particular (N-methyl) (N-phenyl) amino,

Mono- or diheterocyclylamino in particular includes mono- or diheterocyclylamino having 3- to 8-, preferably 5- to 6-membered, optionally substituted as described above heterocyclyl.

(N-alkyl) (N-heterocyclyl) amino particularly describes a substituted amino which is substituted in each case on the nitrogen atom by an alkyl radical and by a heterocyclyl radical,

(N-Aryl) (N-heterocyclyl) amino in particular describes a substituted amino which is in each case substituted on the nitrogen atom by an aryl radical and by a heterocyclyl radical,

Mono- or diacylamino in particular includes a substituted amino substituted with one or two acyl radicals, etc.

Furthermore, optionally substituted alkyl, aryl or heterocyclylsulfonyl (R-S0 ₂ -, wherein R is optionally substituted alkyl, aryl or heterocyclyl as defined above) is preferably methylsulfonyl, ethylsulfonyl, phenylsulfonyl, toylsulfonyi or benzylsulfonyl.

Optionally substituted alkoxycarbonyl (RO (O =) C) includes, with respect to the definition of alkoxy, the above-mentioned optionally substituted alkoxy,

PREFERRED EMBODIMENTS:

In a preferred embodiment, the compound of the formula (I) has the following substituent definitions:

X is selected from: S or O;

R ^{1 is} selected from the group consisting of:

Hydrogen,

optionally substituted amino,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted alkenyl,

optionally substituted alkynyl,

optionally substituted aryl, or

optionally substituted heterocyclyl;

R ² and R ³ are the same or different and each selected from the group consisting of:

Hydrogen,

optionally substituted alkyl or heterocyclylsulfonyl, optionally substituted alkyl,

optionally substituted alkenyl,

optionally substituted alkynyl,

optionally substituted aryl, or

optionally substituted heterocyclyl; with the proviso that in the case where R ^{1 is} selected from optionally substituted amino or optionally substituted alkoxy and R ² and R ^{3 are the} same, R ² and R ^{3 are} not hydrogen.

X is selected from: S or O;

R ¹ is selected from the group consisting of:

hydrogen

optionally substituted amino,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted aryl, or

optionally substituted heterocyclyl;

R ² and R ³ are the same or different and are each selected from the group consisting of:

Hydrogen,

optionally substituted acyl,

optionally substituted alkoxycarbonyl,

optionally substituted alkyl,

optionally substituted aryl, or

optionally substituted heterocyclyl,

In a more preferred embodiment, the compound of the formula (I) has the following substituent definitions:

X is S or O;

R ¹ is selected from the group consisting of: hydrogen

optionally substituted amino,

optionally substituted alkyl, and

Hydrogen,

optionally substituted alkyl,

optionally substituted aryl, or

n © n © benenfa !! ss

In a further more preferred embodiment, the compound of the formula (I) has the following substituent definitions:

X is S;

R ¹ is selected from optionally substituted amino; R ² is selected from optionally substituted alkyl; and R ³ is hydrogen.

In particularly preferred embodiments of the general formula (I), the individual substituents each have the following definitions:

1, X is S or O, wherein X is preferably S.

2. R ¹ is hydrogen, optionally substituted alkyl or

optionally substituted amino, wherein R ^{1 is} preferred

optionally substituted amino, as in particular with optionally substituted alkyl, as defined above,

More preferably, R ^{1 is} optionally substituted amino which is selected from monoalkylamino and from (N-alkyl) (N-cycloalkyl) amino, as with (optionally substituted) Aryl-substituted † alkyl substituted amino, in particular benzylmethylamino, and amino which bears substituents substituted by halogen-substituted aryl, such as 3-chloro-4-fluorophenylmethylamino,

3, R ² is hydrogen, optionally substituted alkyl,

optionally substituted aryl or optionally substituted heterocyclyl, wherein R ^{2 is} preferably optionally substituted alkyl, preferably with optionally substituted

Heterocyclyl, such as in particular selected from 5- to 10-membered mono- or bicyclic aromatic heterocycles such as preferably substituted (optionally substituted) imldazolyl or (optionally substituted) benzimidazolyl.

4. R ³ is hydrogen, optionally substituted alkyl,

optionally substituted aryl or optionally substituted heterocyclyl, wherein R ^{3 is} preferably hydrogen,

Particularly preferred compounds of the general formula (I) are shown in the following table;

H64806

Vifor (International) AG

and pharmaceutically acceptable salts thereof

In particular, the present invention also relates to novel compounds of the general formula (I) with the meaning of the substituents as described above, wherein one or more of the following compounds are excluded:

H64806

Vifor (international) AG

- 44 -

(Et = ethyl), i ^Me = ^meth V ' ^Bu = tert-butyl), _(Ph = _Ph eny !, Et = Ethyi)

H64806

Vifor (international) AG

- 45 -

(R = Boc († er † -Bu † oxycarbonyl) or H),

Methyl), (R = NPS (nitrophenylsulfonyl) or H

H64806

Vifor (international) AG

Vifor (international) AG

In principle, it is possible in the context of the present invention to combine the individual preferred, more preferred or particularly preferred meanings for the substituents R ¹ to R ³ with one another. That is, compounds of the general formula (I) are encompassed by the present invention in which, for example, the substituent R ^{1 has} a preferred or more preferred meaning and the substituents R ² and R ^{3 have} the general meaning or the substituent R ¹ has has a general meaning, and the substituents R ² and R ³ have a preferred or more preferred meaning, etc.,

The compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers) depending on their structure in the presence of asymmetric carbon atoms. The invention therefore includes the use of the enantiomers or diastereomers and their respective mixtures. The enantiomerically pure forms may optionally be obtained by conventional optical resolution methods such as by fractional crystallization of diastereomers therefrom by reaction with optically active compounds May involve forms, the present invention encompasses the use of all tautomeric forms,

The compounds provided by the invention may be prepared as mixtures of various possible isomeric forms, in particular stereoisomers, e.g. E and Z, syn and anti, and optical isomers are present, It is claimed both the E and the Z isomers, and the optical isomers, as well as any mixtures of these isomers.

The compounds of the general structural formula (I) according to the invention can in principle be obtained by the processes explained below, (α) Reaction of compounds of the formula (Ia):

wherein R ¹ and X are as defined above, with compounds of the formula

AR ² wherein R ^{2 is} as defined above, and A is a suitable leaving group which allows the substitution of H by R ² , such as

for example, a leaving group from the group of halogens, preferably chlorine, to compounds of the formula (Ib)

wherein R ¹ , R and X are as defined above.

Furthermore, the following implementation is possible:

(b) Reaction of the compound of the formula (Ib):

wherein R \ R ² and X are as defined above, with compounds of the formula

AR ³ wherein R ^{3 is} as defined above, and A is a suitable leaving group which allows the substitution of H by R ³ , such as

for example, a leaving group from the group of halogens, such as preferably chlorine, to obtain compounds of formula (I),

Furthermore, the following implementation is possible:

(c) reaction of compounds of the formula (Ic):

wherein R ² , R ³ and X are as defined above, and R ^{4 is} a C to C ₆ alkyl group, with compounds of the formula

HIM

R wherein R ⁵ and R ^{6 are the} same or different and are selected from the group consisting of:

Hydrogen,

optionally substituted alkyl,

optionally substituted aryl, and

optionally substituted heterocyclyl, or in which R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 3- to 6-membered ring which may optionally contain further heteroatoms in order to obtain compounds of the formula (Id):

wherein R ² , R ³ , R ⁵ and R ⁰ and X are as defined above and the compounds correspond to the general formula (I) in which R ^{1 represents} an optionally substituted amino group as defined above.

In particular, compounds according to the invention of the general formula (Id)

wherein X, R ² , R ³ , R ⁵ and R ^{6 are} as defined above, by the following

Procedure to be obtained:

Svntheseweg 1:

Starting point for the synthesis, the non-commercially available substances, the general formula (I), in which X is S and wherein R ^{1 is} selected from the group of optionally substituted Anninoverbindungen, is the commercially available N (tert-butoxycarbonyl) -ß-alanine of the general formula (II). This is initially transformed under standard conditions with 2-ethoxy-l - ethoxycarbonyl-1, 2-dlhydroquinoline (EEDQ) in the active ester, which is then reacted in situ with ammonium salts, preferably ammonium bicarbonate, to amide (III). Such amides according to formula (III) can then be transformed under standard conditions with the Lawesson reagent to the desired thioamide (IV) [see Bz .: O.Josse, Synthesis, 3, 1999, 404-406],

Subsequently, the thioamide (IV) is cyclized with commercial Brombrenztraubensäureethylester (V) under standard conditions familiar to the skilled worker to the thiazole (VI) [s, z. B.: K.Y. Zee-Cheng, Journal of Heterocyclic Chemistry, 7, 1970, 1439-1440; H. Sasaki, Heterocycles, 75, 2008, 1061-1074],

(IV) (V) (VI) This is followed by the reaction of the ester group of the thiazoles (VI) with amines of the general formula (VII) to give the corresponding amides. For this purpose, in principle, two alternative synthetic routes are available,

Synthetic route 1 a);

The reaction of the ester group of the thiazoles (Vi) with amines of the formula (VII) is carried out under standard conditions in the corresponding amides of the general formula (VIII) according to the following reaction scheme [s. z. B,: R.C. Larock, Comprehensive Organic Transformations, Wiley, NY, 1999, p., 1973-1976: A review for ester transformation into poverty]:

(VI) (VIII)

Synthesis path 1 b):

Alternatively, compound (VI) can be transformed by ester hydrolysis into the corresponding carboxylic acid (via) [s. z, BRC Larock, Comprehensive organic transformations, Wiley, NY, 1999, p. 1959-1968: A review for ester hydrolysis], which then under standard conditions [s, z. B. RC Larock, Comprehensive Organic Transformations, Wiley, NY, 1999, p. 1941-1949: A review for amide formation], with the corresponding amines (VII) are converted into the desired amides (VIII):

(Via) (VIII)

The thus-obtained amide (VIII) can then be further reacted to the objective compounds of the general formula (I) wherein R ^{1 is} optionally substituted amino and represented by the above-mentioned general formula (Id). For this purpose, the so-called BOC protecting group (tert-butyioxycarbonyi group) is acidic

Reaction conditions removed. The free amine of general formula (IX) thus obtainable can then be converted under standard conditions by alkylation [s, e. B.M. Smith, J. March, March ^'s Advanced Organic Chemistry, 5th. ed, Wiley, NY, 2001. 499-501: For a review of alkyation of aminogroups] or Acyclization [sz B.: MB, Smith, J. March, March ^'s advanced organic chemistry, 5th. ed, Wiley, NY, 2001, 506-512: For a review of acylatlon of aminogroups] to the object compound (Id) corresponding to general formula (I) wherein R ^{1 represents} an optionally substituted amino group. Here, A is a suitable leaving group which allows the substitution of H by R ² or by R ³ , such as a leaving group from the group of halogens, such as preferably chlorine and (Id) * is (Id) with X = S. ,

A-R

(IX) (ld) *

In order to obtain corresponding compounds of the formula (I) or (III) in which one of the substituents R ² or R ^{3 has} the meaning of hydrogen, the reaction of the compounds (IX) with the corresponding compound AR ² or AR ^{3 is} omitted accordingly .

According to the preparation process according to synthesis route 1 described here, particularly preferred compounds according to examples 1, 2 and 3 are obtainable.

For the preparation of compounds of general formula (I) wherein X is O and wherein R ^{1 is} selected from the group of optionally substituted amino compounds represented by general formula (ld) as appropriate, there is also another synthetic route 2, such as follows, available,

Synthesis path 2:

Starting point for the synthesis of the substances of the general formula (I) in which X = O and wherein R ^{1 represents} optionally substituted amino, is the commercially available acrylic acid amide (X), which under basic standard conditions with the commercially available Brombrenztraubensäureethylester (V) can become ΟχαζοΙ (XI) cycliser † [s. z, B,; F. Ahmed, Synthetic Communications, 33, 2003, 2685-2694],

(X) (V) (XI)

The oxazoie according to formula (XI) can then be converted into the corresponding nitro compounds (XII) via an additon reaction with hydrogen bromide and subsequent substitution reaction with sodium nitrite [s. z. B.: F. Ahmed, Synthetic Communications, 33, 2003, 2685-2694].

Subsequently, the nitrooxazole (XII) thus obtained can be reduced to the amino compound (XIII) under conventional standard conditions. Preferred reduction systems in this context are a) Pt / H ₂ or b) FeCl ₃ / C / H _2. The amine (XIII) obtainable in this way can be prepared by amination [see, for example: MB Smith, J. March, March ^'s advanced organic Chemistry, 5th, ed, Wiley, NY, 2001. 499-501: For a review of alkyation of aminogroups] or by acylation [eg: MB, Smith, J. March, March ^'s advanced organic chemistry, 5th. ed, Wiley, NY, 2001. 506-512: For a review of acylation of aminogroups] are converted to the compounds, the general formula (XI IIa) or (XIIIb), where A is a suitable leaving group, which is the substitution of H by R ² or, respectively, by R ³ , such as, for example, a leaving group from the group of the halogens, such as preferably chlorine and R ⁷ is selected from the group consisting of:

Hydrogen,

optionally substituted alkyl, optionally substituted aryl, and

optionally substituted heterocyclyl.

The compounds of the general formulas (XIIIa) or (XIIIb) can then be further derivatized by methods customary to the person skilled in the art.

Synthesis path 2a)

A preferred derivatization in this context is the conversion of the esters of the compounds (XIIIa) and (XIIIb) into the corresponding amides, corresponding to the general formulas (Id) and (XIV), respectively. Here, the ester group can be reacted under standard conditions with amines, the general formula (VII) to the corresponding target compounds [s, z. B. RC Larock, Comprehensive Organic Transformations, Wiley, NY, 1999, p. 1973-1976: A review for ester transformation into amides].

Synthesis path 2b)

Alternatively, the synthetic route described above can be carried out via the free carboxylic acids (XI IIa ') or (XIIIb') analogously to synthesis route 1 b), the active esters prepared in situ also being converted to the corresponding amides of the general by reaction with the amines Formulas (Id) and (XIV) lead.

In this case, (ld) ** corresponds to the compound (Id) with the meaning for X = G 1, which in turn corresponds to the compounds of the general formula (I) according to the invention in which R ^{1 is} selected from the group of optionally substituted amino. Compound (XIV) with the meaning for R ⁷ as defined above corresponds to compounds of the formula (I) in which X = Q and in which R ^{2 is} selected from the group of optionally substituted acyl,

In particular, processes according to the synthesis route 3) described in detail below are preferred, wherein the meaning of the substituents R ¹ to R ³ , and R ⁵ and R ⁶ corresponds to the above definitions and wherein R ^{8 is} the meaning of optionally substituted heterocyclyl as defined above, in particular preferably of (optionally substituted) imidazolyl or (optionally substituted) benzimidazolyl, and wherein the abbreviations used have the meaning as defined in the following preparation examples:

Process step 1

Verification step 2

Verification step 3

Process step 4

Process step 5

Process step 6 The reaction routes shown here represent known reaction types which can be carried out in a manner known per se. By reacting with a pharmaceutically acceptable base or acid, corresponding salts are obtained.

The reaction of the various reactants can be carried out in various solvents and is not particularly limited in this regard. Corresponding examples of suitable solvents are thus water, methanol, ethanol, acetone, dichloroethane, dichloromethane, trichloromethane, dimethoxyethane, diglyme, acetone tril, butyronitrile, THF (tetrahydrofuran), DMF (dimethylformamide), dioxane, ethyl acetate, butyl acetate, dimethylacetamide, toluene, chlorobenzene , Trimethylorthoformiat (TMOF), Preferred are ethanol, dioxane, THF, DMF, dichloromethane and trichloromethane, and in particular the solvents used in the preferred method according to Synthesis 3) described above.

Moreover, if the organic solvent is miscible with water, it is possible to carry out the reaction in a substantially homogeneous mixture of water and solvents.

However, temperatures above room temperature, for example up to 80 or 90 ° C or up to 100 or up to 130 ° C, and temperatures below room temperature, for example to -20 ° C or be applied less.

The pH at which the reaction of the reactants of the present invention is carried out is suitably adjusted.

The adjustment of the pH, in particular in the case of the basic conversion to the amides in synthesis route 1), is preferably carried out by adding a base. Both organic and inorganic bases can be used as bases be used. Preference is given to inorganic bases such as LiOH, NaOH, KOH, Ca (OH) ₂ , Ba (OH) ₂ , Li ₂ C0 ₃ , ₂ C0 ₃ , Na ₂ C0 ₃ , NaHC0 ₃ , NH ₄ HCO ₃ or organic bases such as amines (such as, for example, preferably triethylamine (TEA), diethylisopropylamine), Bu ₄ NOH, piperidine, morpholine, alkylpyridines used. Particular preference is given to using inorganic bases, very particularly preferably LiOH, NaOH, KOH and NH ₄ HC0 ₃ , and also TEA.

If appropriate, the adjustment of the pH can also be effected by means of acids, in particular in the removal of the BOC protective group in synthesis route 1). As acids both organic and inorganic acids can be used. Preference is given to using inorganic acids such as, for example, HCl, HBr, HF, H ₂ S0 ₄ , H ₃ P0 ₄ or organic acids such as CF ₃ COOH, acetic acid (CH ₃ COOH, AcOH), p-toluenesulfonic acid, and salts thereof. Particular preference is given to using inorganic acids such as HCl.

In particular, the pH adjusting agents used in the preferred method of Synthesis 3) described above are preferred.

A person skilled in the art is able here for the appropriate synthesis route or for the corresponding reaction step to select the most suitable solvent and the optimal reaction conditions, in particular with regard to temperature, pH, catalyst and solvent.

The present invention also relates to novel intermediates which are accessible with the preparation processes according to the invention, such as, in particular, the intermediates 1 to 9 specifically described in the preparation examples, which are obtainable from the process steps 1 to 5 described. The inventors have surprisingly found that the compounds which are the subject of the present invention and which are represented by the general structural formula (I), as well as (la), (Ib) and (Ic) show an activity as hepcidin-antagonist, and thus In particular, the compounds of the invention are useful in the treatment of iron metabolism disorders, especially for the treatment of iron deficiency disorders and / or anemias, in particular at ACD and AI,

The medicaments containing the compounds of general structural formula (I) are suitable for use in human and veterinary medicine.

The invention thus also relates to the compounds of the general structural formula (I) according to the invention with the above substituent meanings for use as medicaments.

In particular, those compounds of the general structural formula (I) according to the invention having the above substituent meanings are preferred for use as medicaments, in which one or more of the following compounds are excluded:

(E † = ethyl), t ^Me = Me yl, Bu-t = † er † -buty!), _{(Ph = Ph} enyL Et = Ethyi),

(Me = methyl), (R = Boc (ter † -Bu † oxycarbonyl) or H), (R = NPS (Nitropheny! Sulfonyi) or H),

CH 2 ^{- "CH} 2 ^- HH ^- C P h Ph = phenyl),

The compounds of the invention are thus also useful in the preparation of a medicament for the treatment of patients suffering from iron deficiency anemia symptoms such as: fatigue, lack of drive, lack of concentration, low cognitive efficiency, difficulties in finding the right words, forgetfulness, unnatural paleness, irritability, acceleration heart rate (tachycardia), sore or swollen tongue, enlarged. Spleen, Pregnancy cravings (Pica), Headache, Loss of appetite, Increased susceptibility to infection, Depressed mood or suffering from ACD or AI.

The compounds of the invention are therefore also suitable for the manufacture of a medicament for the treatment of patients suffering from symptoms of iron deficiency anemia.

The administration may be for a period of several months to the improvement of the iron status, reflected for example by the hemoglobin value, the transferrin saturation and the ferritin value of the patients, or to the desired improvement of iron deficiency anemia or ACD or AI induced impairment of the patient Health condition.

The preparation according to the invention can be taken by children, adolescents and adults.

In addition, the compounds of the present invention may also be used in combination with other agents or drugs known in the treatment of iron metabolism disorders and / or with agents or drugs concomitant with agents for the treatment of diseases associated with iron metabolism disorders, particularly iron deficiency and / or anemias are administered. Examples of such combination-applicable agents for the treatment of iron metabolism disorders and others with iron deficiency and / or anemia of associated diseases may include, for example, iron-containing compounds such as. For example, iron salts, iron carbohydrate complex compounds such as iron-maltose or iron-dextrin complex compounds, vitamin D and / or derivatives thereof.

The compounds used in combination with the compounds according to the invention can be administered either orally or parenterally, or the administration of the compounds according to the invention and the compounds used in combination can be effected by combining the stated administration possibilities.

The compounds according to the invention and the abovementioned combinations of the compounds according to the invention with further active compounds or medicaments can be used in the treatment of iron metabolism disorders, in particular iron deficiency disorders and / or anemias, in particular anemias in cancer, anemia triggered by chemotherapy, anemia triggered by infiltration (AI ), Congestive heart failure (CHF), stage 3 -5 chronic kidney disease (CKD 3-5) anemia, anemia caused by chronic infiltration (ACD), anemia in rheumatoid arthritis (Rheumatoid arthritis), systemic lupus erythematosus (SLE) anemia and inflammatory bowel disease (IBD) anemia, or are used to make medicaments for the treatment of these conditions.

The compounds according to the invention and the abovementioned combinations of the compounds according to the invention with other active substances or medicaments can be used in particular for the production of medicaments for the treatment of iron deficiency anemia, such as iron deficiency anemia in pregnant women, deficient iron deficiency anemia in children and adolescents, iron deficiency anemia as a result of gastrointestinal abnormalities , the iron deficiency anemia as a result of blood loss, such as through gastrointestinal Bleeding (eg, as a result of ulcers, carcinomas, hemorrhoids, inflammatory disorders, intake of acetylsalicylic acid), menstruation, injuries, iron deficiency anemia due to psilosis (sprue), iron deficiency anemia due to reduced dietary iron intake, especially to selectively eating children and adolescents, Immunodeficiency caused by iron deficiency anemia,

Impairment of brain function caused by iron deficiency anemia, restless leg syndrome.

The application according to the invention leads to an improvement in the iron, hemoglobin, ferritin and transferrin values, which are improved in the short-term memory test (STM), in the long-term memory test (LTM), in the test of the progressive matrices, in particular in adolescents and children but also in adults Raven, in the Welscher adult intelligence scale (WAIS) and / or in the emotional coefficient (Baron EQ-i, YV test, youth version), or to an improvement in neutrophil levels, antibody levels and / or lymphocyte function.

The present invention further relates to pharmaceutical compositions containing one or more of the compounds according to the invention of the formula (I), and optionally one or more further pharmaceutically active compound and optionally one or more pharmacologically acceptable carriers and / or excipients and / or solvents.

These are customary pharmaceutical carriers, excipients or solvents. Named pharmaceutical compositions are suitable, for example, for intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric or intracutaneous administration and are in the form of, for example, pills, tablets, enteric-coated tablets, film-coated tablets, coated tablets, oral, subcutaneous or cutaneous delayed-release formulations Administration (in particular as plaster), depot formulation, dragées, suppositories, gels, ointments, syrups, granules, suppositories, emulsions, dispersions, microcapsules, microformulations, nano-formulations, liposomal formulations, capsules, enteric-coated capsules, powders, inhalation powders, microcrystalline formulations, inhalation sprays, Powders, drops, nose drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, infusion solutions or injection solutions, etc.

The compounds according to the invention and pharmaceutical compositions containing such compounds orally and / or parenterally, in particular intravenously, are preferably used,

For this purpose, the compounds of the invention are preferably in pharmaceutical compositions in the form of pills, tablets, enteric tablets, film-coated tablets, shift tablets, sustained-release formulations for oral administration, depot formulations, dragees, granules, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, enteric-coated Capsules, powders, microcrystalline formulations, powders, drops, ampoules, solutions, suspensions, infusion solutions or injection solutions,

The compounds of the present invention may be administered in pharmaceutical composition which may contain various organic or inorganic carriers and / or adjuvant materials commonly used for pharmaceutical purposes, in particular for solid drug formulations, such as excipients (such as sucrose, starch, mannitol, sorbitol , Lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate), binders (such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch),

Disintegrant (such as starch, hydrolyzed starch,

Carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, Calcium phosphate †, calcium citrate), lubricants (such as magnesium stearate, talc, sodium lauryl sulfate), a flavoring agent (such as citric acid, menthol, glycine, orange powder), preservatives (such as sodium benzoate, sodium bisulfite, methylparaben, propylparaben), stabilizers (such as citric acid, Sodium citrate, acetic acid, and multicarboxylic acids from the Titriplex series such as diethylenetriaminepentaacetic acid (DTPA), suspending agents (such as methylcellulose, polyvinylpyrrolidone, aluminum stearate), dispersants, diluents (such as water, organic solvents), beeswax, cocoa butter, polyethylene glycol, white petrolatum, etc.

Liquid drug formulations, such as solutions, suspensions and gels, usually contain a liquid carrier, such as water and / or pharmaceutically acceptable organic solvents. Further, such liquid formulations may also include pH adjusting agents, emulsifying or dispersing agents, buffering agents, preservatives, wetting agents, gelling agents (For example, methyl cellulose), colorants and / or flavorings. The compositions may be isotonic, that is, they may have the same osmotic pressure as blood. The isotonicity of the composition may be adjusted by the use of sodium chloride or other pharmaceutically acceptable agents such as dextrose, maltose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic soluble substances. The viscosity of the liquid compositions may be determined using a pharmaceutically acceptable thickening agent such as Methyl cellulose can be adjusted. Other suitable thickening agents include, for example, xanthan, carboxymethyl cellulose,

Hydroxypropyl cellulose, carbomer and the like. The preferred concentration of thickening agent will depend on the agent selected. Pharmaceutically acceptable preservatives can be used to increase the shelf life of the liquid composition. Benzyl alcohol may be suitable, although a variety of preservatives including, for example, paraben, thimerosal, chlorobutanol or benzalkonium chloride may also be used. The active ingredient may be administered, for example, at a unit dose of from 0.001 mg / kg to 500 mg / kg of body weight, for example up to 1 to 4 times a day. However, the dosage may be increased or decreased depending on the age, weight, condition of the patient, severity of the disease or mode of administration,

A preferred embodiment relates to the use of the compounds according to the invention, as well as the compositions according to the invention containing the compounds according to the invention and the combination preparations according to the invention containing the compounds and compositions according to the invention for the preparation of a medicament for oral or parenteral administration,

The invention is further illustrated by the following examples. The examples are merely exemplifications, and those skilled in the art will be able to extend the specific examples to other claimed compounds.

EXAMPLES

PHARMACOLOGICAL ACTIVITIES:

The following materials were used:

The hepcidin-antagonistic activity of the thiazolamide-capping agents of the present invention was determined by the "Ferroportin Internalisation Assay" described below.

Principle of the "Ferroportin Internalisation Assays"

Low molecular weight organic compounds containing the

biochemical effects of hepcidin on its receptor, the iron-exporting ferroportin (Fpn), were identified on the basis of their ability to inhibit hepcidin-induced internalization of Fpn in living cells. For this purpose, a stable cell line (Madin Darby Canine Kidney, MDCK), the constitutively human ferroportin that is at its C-terminus with a fluorescent reporter protein

(HaloTag®, Promega Corp.) recombinantly fused. The Internalization of Fpn was monitored by labeling these cells with fluorescent ligands (HaloTag® TMR, tetramethyl rhodamine) which covalently attach to the Fpn-fused HaloTag reporter gene. Confocal fluorescence microscopy imaging revealed a cell surface localization of Fpn in the absence of

Hepcidin and the absence of FPN surface staining in the presence of hepcidin, optimized image analysis algorithms have been used to detect the cell surface and to quantify the corresponding, associated with the Fpn ^"Ha loTag- fusion protein membrane fluorescence This assay allows for quantitative image-based analysis to quickly

Evaluate compounds that can block hepcidin-induced internalization of Fpn. This assay is a direct in vitro counterpart of the drug-proposed in vivo mechanism of action, and thus is suitable as a high throughput initial assay for the

Identification of compounds that counteract the effect of hepcidin on its receptor, ferroportin,

Detailed procedure of the assay

• 7500 cells per well (MDCK-FPN-HaloTag) per well in 50 μM DMEM medium (Dulbecco's Modified Eagle medium with 10% fetal bovine serum (FBS) containing 1% penicillin, 1% streptomycin and 450 μg | m \ G-418) in 384-well microtiter plates (384 Cell Carrier Plates, Perkin Elmer, Cat., No. 6007430), followed by overnight incubation at 37 ° C / 5% Co ₂ ,

The volume of the medium was reduced to 10 μί and 10 μΐ of 5 μΜ Ha loTag ™ R ligands (Promega, Cat. No., G 8251) were added in DMEM medium to stain the Fpn-HaloTag fusion protein.

• 15 min incubation at 37 ° C / 5% 0O ₂

HaloTag TMR ligand was removed and cells were washed with

washed with fresh DMEM medium, and the volume was reduced to 20 μM DMEM medium, • 3 μί per well. a solution of the test compound (dissolved DMSO) added (10 μΐ final volume).

7 μί 43 μΜ hepcidin (Peptides International, cat. No. PLP-4392-s, 100 μΜ stock diluted in water in DMEM medium) was added per well to a final hepcidin concentration of 100 nM.

The cells were incubated overnight at 37 ° C / 5% C0 ₂ ,

The cells were fixed by adding paraformaldehyde (PFA, Electron

Microscopy Sciences, cat. No. 15710-S) was added directly to the cells to a final concentration of 4%, followed by a 15-20 minute incubation at room temperature.

The PFA solution was removed and the cells were washed with PBS (phosphate-buffered saline) with 30 μΙ remaining in the plate,

• 20 μί. DraqS (Biostatus, Cat. No. DR 51000) was added to a

final concentration of 2.5 μΜ was added to stain the cell nuclei, and the plates were sealed with plate seal of foil.

• The plates were mixed with the Opera Plate Imager (Opera Confocal Plate Imager, Perkin Elmer) at 7 frames per well; 440 ms

Exposure time per image, 1 μΜ focus height analyzed,

data analysis

Optimized algorithms have been used for image analysis to detect and quantify cell surface associated fluorescence as a measure of cell surface localization of Fpn HaloTag.

• The final reading was the percentage of cells that showed membrane fluorescence: wells treated with 100 nM hepcidin gave the lowest values (negative control reading = 0% inhibition of Fpn internalization) and wells that were not treated with hepcidin gave the maximum

Percentage of cells with membrane fluorescence (positive

Indicator 100% inhibition of Fpn internalization) • On each plate, the median value of the 6 positive and 6 negative control values was used to determine the percentage inhibition of the

Calculate compounds that have been tested according to the following formula:

I = 100 x -

n p v pos positive control display value (median) neg negative control display value (median)

^ Compound Display value of the examined connection

percentage inhibition of the respective

connection

• In dose-response experiments, dilution series (11

Concentrations, 1: 2 dilution steps) of the compounds (concentration range from 0.04 to 40 μΜ) and normalized signal values of replicated experiments (mean 6 titrations on independent plates) were fitted to curve fitting according to a robust standard dose-response model with four parameters (lower asymptote, upper asymptote, IC50, slope).

The following results were obtained:

PREPARATIONS:

I, purification by preparative HPLC and column chromatography

If appropriate, the following preparation examples were carried out according to the preparation process according to the invention, with subsequent purification by means of preparative HPLC and / or by column chromatography according to the following conditions:

1.1 Preparative HPLC (neutral conditions):

Method: Gilson semi-prep HPLC with 119 UV detector and 5.11 Unipoint control software

Stationary phase / column: Waters SunFire Prep Cl 8 OBD (5 μm 19 x 100 mm),

room temperature

Mobile phase A: water

B: acetonitrile

Flow rate: 20 ml / min

Injection volume: 1000 μ \

Detection: UV

eluent:

Time (minutes) solvent

0.0 to 2.0 5% B + 95% A

2.0 to 2.5 constant gradient to 10% B + 90% A

2.5 to 14.5 constant gradient to 100% B

14.5 to 16.5 100% B

16.5 to 16.7 constant gradient to 5% B + 95% A

16.7 to 17.2 5% B + 95% A Li! Preparative HPLC is acidic conditions):

Method: Gilson 215 Autosampier and fraction collector

Stationary phase / column: Waters SunFire Prep Cl 8 OBD (5 μm 19 × 100 mm),

room temperature

Mobile phase: A: 0.1% TFA / water

B: 0.1% TFA / acetonitrile

Flow rate: 26 ml / min

Injection volume: 1000 μ \

Detection: Waters Micromass Platform LCZ Single quadrupole mass spectrometer

Waters 600 solvent delivery module

Waters 515 ancillary pumps

Waters 2487 UV detector

eluent:

I.III Column Chromoaraphy:

"Flash" silica gel chromatography was performed using silica gel 230 to 400 mesh or prepacked silica gel. II. Analytical HPLC-MS

The detection and purity of the compounds was carried out in each case by HPLC MS (high performance liquid chromatography (High Performance Liquid Chromatography) with mass spectrometry (MS)) or by HPLC with UV detection (PDA, Photo Diode Array).

Method: MSI 9_7MIN_HIRES_POS / High resolution method

MS detection: TIC (Total Ion Count)

HPLC-MS system: Shimadzu LCMS 201 OEV system

Mass range: 100-1000 m / z

Scan speed: 2000 amu / sec

In particular, the following methods were used in particular: IM Method A

Stationary phase / column: Waters Atlantis dCl 8 (2, 1 x 100 mm, 3 m column);

40 ° C

Flow rate: 0.6 ml / min

Mobile phase: A; 0, 1% formic acid / water

B: 0, 1% formic acid / acetone tril

Flow rate: 0.6 ml / min

Injection volume 3 μΙ

Detection: UV; Wavelength 215 nm

eluent:

Gradient time organic

(min) Share (%)

0.00 5

5.00 100

5.40 100

5.42 5 Time (minutes) solvent

0 to 5 constant gradient from 95% A + 5% B to 100% B

5.0 to 5.4 100% B

5.4 to 5.42 constant gradient from 100% B to 95%

A + 5% B

5.42 to 7.0 95% A + 5% B

LLJJ method B

Stationary phase / column: Waters Atlantis dCl 8 (2.1 x 50 mm, 3 μηη)

Mobile phase: A: 0, 1% formic acid / water

B: 0, 1% formic acid / acetonitrile

Flow rate: 1 ml / min

Injection volume: 3 μ \

Detection: UV, wavelength 215 nm

eluent

Ii. III Method C

Stationary phase / column: Waters Atlantis dCl 8 (2.1 x 30 mm, 3 μm column) flow rate; 1 ml / min

Mobile phase: A: 0.1% formic acid / water

B: 0, 1% formic acid / acetonitrile

Injection volume: 3 μΙ De † † ek ion; UV; Wavelength 215 nm

eluent

MS detection: Waters LCT or LCT Premier or ZQ or ZMD

UV detection: Waters 2996 photodiode array or Waters 2787 UV or

Waters 2788 UV

III. Name of the compounds

Some of the compounds shown below were isolated as TFA or HCl salt, which is not reflected by the chemical names given. In the context of the present invention, the chemical names given refer to the corresponding compound in neutral form and its TFA salt or other salts, in particular pharmaceutically acceptable salts, where appropriate.

IV, abbreviations

Boc ₂ 0 di-tert-butyl dicarbonate

Day (s) / day (s)

DCM dichloromethane

DIPEA N, N-diisopropylethylamine

DMF N, N-dimethylformamide

EfOAc ethyl acetate

EtOH ethanol h Hour (s) / Hour (s)

HATU 1 - [bls (dimethylamino) methylene] -1H-l, 2,3-triazole [4,5-b] pyridinium

3-oxide hexafluorophosphate

HPLC High Performance Liquid Chromafography

MeCN acetonitrile

min min † e (s) / minu † e (n)

MW molecular weight

TEA triethylamine

TFA trifluoroacetic acid

TMOF trimethyl orthoformate

V. Manufacturing Label According to Syntheseweq 3)

V.l Intermediates to Svnthesewea 31

Intermediate 1: 2- (2-Amino-ethyl-thiazole-4-carboxylic acid ethyl ester (process step 1)

Ethyibromopyruvot (0.77 mL, 5.0 mmol) was added to a solution of he -sutyl / V- (3-amino-3-thioxopropyl) carbamate (1.02 g, 5.0 mmol) in EtOH (10 mL The mixture was concentrated in vacuo and the yield was triturated from diethyl ether and chloroform to give Intermediate 1 (1.16 g, 100%), which was used without further purification or characterization.

Intermediate 2: 2- (2-Fer-Butoxycarbonylaminoethyl) thiazole-4-carboxylic acid ethyl ester

(Process step 2)

TEA (6.4 mL, 46.0 mmol) and di-tert-butyl dicarbonate (3.0 g, 13.8 mmol) were added to a solution of 2- (2-amino-ethyl) -thlazole-4. ethyl carboxylic acid (Intermediate 1) (3.03g, 11.5mmol) in MeCN (150mL) and DMF (40mL) were added and the mixture was stirred at room temperature for 18 hours. The solvents were removed in vacuo and Yield dissolved in EtOAc (100 ml). The organic phase was washed with 2M HCl (x2) and the combined aqueous phases extracted with EtOAc (x3). The combined organic phases were washed with saturated NaHCO ₃ and brine, dried (MgSO 4) and concentrated in vacuo to give Intermediate 2 (3.57 g, 100%).

MW: 300.38

HPLCMS (method C): [m / z]: 323 (M + Na)

Intermediate 3: 2- (2-er / -Bu † oxycarbonylamino-e † hyl) - diazo-4-carboxylic acid

(Process step 3)

An aqueous solution of lithium hydroxide (2M, 14 mL, 28.4 mmol) was added to a solution of ethyl 2- (2-fero-butoxycarbonylamino-ethyl) thiazole-4-carboxylate (Intermediate 2) (1.71 g, 5.68 mmol) in THF / MeOH (60 ml / 40 ml) and the mixture stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the yield was separated between diethyl ether and water. The phases were separated and the aqueous phase acidified to pH -4 and extracted with EtOAc (x3). The combined EtOAc layers were dried (MgSO 4) and concentrated in vacuo to give Intermediate 3 (1.25 g, 81%).

MW: 272.33

HPLCMS (Method B): [m / z]: 294 (M + Na)

Intermediate 4: {2- [4- (cyclohexyl-me hyl †-carbamoyl) - † -thiazol-2-yl] - e †} hyi -carbamids0ure- erf ^"bu † † he yl-es

(Process step 4)

A solution of 2- (2-Fe-Butoxycarbonylamino-ethyl) -thiazole-4-carboxylic acid (Intermediate 3) (0.41 g, 1.5 mmol), HATU (0.67 g, 1.8 mmol) and N Methylcyclohexylamine (Intermediate 2) (0.24 mL, 1.8 mmol) in DMF (10 mL) was cooled to 0 ° C. DIPEA (0.78 ml, 4.5 mmol) was added and the mixture was stirred for 10 minutes at 0 ° C and for 1 hour at room temperature. The mixture was diluted with EtOAc (50 ml) and washed with ^"IM HCl (x2), saturated NaHCO _s and brine, the organic phase was dried (MgS0 ₄₎ and concentrated in vacuo. The crude yield was by column chromatography (MeOH / DCM 0-10%) as an eluent to give Intermediate 4 (0.57 g, 100%).

MW: 367.51

HPLCMS (Method B): [m / z]: 390 (M + Na), 368

Intermediate 5: {2- [4- (3-chloro-4-fluoro-benzylcarbamoyl) -thiazol-2-yl] -ethyl] -carbamic acid-fer-bu-yl-ether

The preparation was carried out analogously to intermediate 4 after process step 4 using:

2- (2-tert-Butoxycarbonylamino-ethyl) -thiazole-4-carboxylic acid (interm. 3) (0.41 g, 1.5 mmol), HATU (0.68 g, 1.8 mmol), DIPEA (0, 78 ml, 4.5 mmol) and 3-chloro-4-fluorobenzylamine (0.29 g, 1.8 mmol) to give intermediate 5 (0.41 g, 66%) after purification by column chromatography with MeOH / DCM ( 0 - 0.5%) as an egg.

MW: 413.90

HPLCMS (Method B): [m / z]: 436 (M + Na)

Intermediate 6: [2- (4-Benzyl-carbamoyl-thiazol-2-yl) -ethyl] -carbamic acid erf-butyl-ester

The preparation was carried out analogously to intermediate 4 after process step 4 using: 2- (2-Fer -Bu † oxycarbonylamino-ethyl) -hiazole-4-carboxylic acid (interm. 3) (0.62 g, 2.26 mmol), HATU (0.90 g, 2.38 mmol) , DIPEA (0.88 mL, 6.79 mmol) and benzylamine (0.26 mL, 2.38 mmol) to give Intermediate 6 (0.60 g, 73%) after purification by column chromatography with heptane / EtOAc (2 : 1) as eluent.

MW; 361, 47

HPLCMS (method B): [m / z]: 384 (M + Na)

Intermediate 7: 2- (2-amino-ethyl) -thiazole-4-carboxylic acid ~ cyclohexyl-methyl-amide

(Method step 5)

TFA (20% solution in DCM, 2 mL) was added to a solution of {2- [4- (cyclohexylmethyl-carbamoyl) -thiazol-2-yl] -ethyl} -carbamic acid-butyl-butylferride (inter 4) (0.56 g, 1.5 mmol) in DCM (8 mL) and the mixture stirred at room temperature for 1 h. The solvents were removed in vacuo and the yield was dissolved in EtOAc (30 ml). The mixture was washed with saturated NaHCO3, (x3) and brine, dried (MgSO4) and concentrated in vacuo The crude yield was purified by stirring a methanolic solution of the amine with carbonate resin for 30 minutes, filtering and concentrating the filtrate to give intermediate 7 ( 0, 12g, 30%).

MW: 267.40

HPLCMS (Method B): [m / z]: 268

Intermediate 8: 2 ~ (2-Amino-ethyl) -thiazole-4-carboxylic acid ~ 3-chloro-4-fluoro-benzylamide

The preparation was carried out analogously to intermediate product 7 after process step 5 using:

{2- [4- (3-Chloro-4-fluoro-benzylcarbamoyl) -thlazol-2-yl] -ethyl} -carbamic acid tert-butyl ester (Intermediate 5) (0.40 g, 0.96 mmol) and TFA (20% solution in DCM, 2 ml) to give intermediate 8 (207 mg, 69%) without further purification, MW: 313.78

HPLCMS (Method B); [m / z]: 314

Intermediate 9: 2- (2-amino-ethyl) -thiazole-4-carboxylic acid benzylamide

[2- (4-Benzylcarbamoyl-thiazol-2-yl) -ethyl] -carbamic acid-erf-butyl-ester (Intermediate 6) (0.59 g, 1.64 mmol) and TFA (20% solution in DCM, 2 ml) to give intermediate 9 (335 mg, 78%), without further purification.

MW: 261, 35

HPLCMS (Method B): [m / z]: 262

V.II Example Compounds by Synthesis 3)

Exemplary compound 3: 2- {2 - [(1H-Benzoimidazol-2-ylmethyl) amino] ethyl} -thigzole-4-carboxylic acid cyclohexylmethyl-gmid

(Method step 6)

1 H-Benzimidazole-2-carbaldehyde (67 mg, 0.46 mmol) was added to a solution of 2- (2-amino-ethyl) -triazole-4-carboxylic acid cyclohexyl-methyl-amide (intermediate 7) (0.12 g, 0.46 mmol) in MeOH (2 mL) and the mixture stirred at room temperature for 18 h. To increase imine formation, trimethyl orthoformate (0.5 ml) was added and stirring was continued for a further 2 hours. Sodium cyanoborohydride (34 mg, 0.55 mmol) was added and the mixture stirred for a further 18 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (neutral condition) to give Example Compound 3 (31.4 mg, 17%) .

EOAI3328876 VIT-1077

MW: 397.54 HPLCMS (Method A): [m / z]; 398

The result is shown in Figure 3,

Exemplary Compound 2: 2- {2 - [(1 H -imidazol-2-ylmethyl) amino] -ethyl] -hiazole-4-carboxylic acid 3-chloro-4-fluoro-benzylannide

The preparation was carried out analogously to example compound 3 according to process step 6 using:

2- (2-amino-ethyl) -thiazol-4-carboxylic acid 3-chloro-4-fluoro-benzylamide

(Intermediate 8) (0.20 g, 0.65 mmol), TMOF (1 mL), 1 H -imidazole-2-carbaldehyde (68.3 mg, 0.71 mmol) and sodium cyanoborohydride (44.7 mg, 0 , 71 mmol) to give Example Compound 2 (11.3 mg, 4%) after purification by preparative HPLC (neutral conditions).

EOAI3330064 VIT-1086

HP-AU001016-H10 (Manufacturer: TRIPOS)

MW: 393.87

HPLCMS (Method A): [m / z]: 394

The result is shown in Figures 2a and 2b.

Exemplary compound 1: 2- {2 - [(1H-Benzoimidazol-2-ylmethyl) amino] ethyl} -thiazole-4-carboxylic acid benzylamide

2- (2-Amino-ethyl) -thiazole-4-carboxylic acid benzylamide (interm. 9) (0.15 g, 0.59 mmol), TMOF (1 mL), 1 H-benzimidazole-2-carbaldehyde (95 mg , 0.65 mmol) and sodium cyanoborohydride (41.0 mg, 0.65 mmol) to give Example Compound 1 in the form of the TFA salt (43.7 mg, 12%) after purification by preparative HPLC (acidic condition).

EOAI3330486 VIT-1089

HP-AU001013-D01 (manufacturer: TRIPOS)

MW: 391, 5 or, 391, 49

HPLCMS (Method A): [m / z]: 392

The result is shown in Figures 1 a and 1 b. DESCRIPTION OF THE FIGURES

Figure 1 α and 1 b: HPLC-MS of Example Compound 1

Figure 2a and 2b: HPLC-MS of Example Compound 2

Figure 3: HPLC-MS of Example Compound 3

Claims

Patem ^ NSPRUCJiEi

1. Compounds of the general formula (I)

wherein

X is selected from: S or O;

R ^{1 is} selected from the group consisting of:

Hydrogen,

optionally substituted amino,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted alkenyl,

optionally substituted alkynyl,

optionally substituted aryl, or

optionally substituted heterocyclyl;

R ² and R ^{3 are the} same or different and are each selected from the group consisting of:

Hydrogen,

optionally substituted alkyl, aryl, heterocyclylsulfonyl,

optionally substituted acyl,

optionally substituted alkoxycarbonyl, optionally substituted alkyl,

optionally substituted alkenyl,

optionally substituted alkynes,

optionally substituted aryl, or optionally substituted heterocyclyl; or pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein

X is selected; S or O;

R ^{1 is} selected from the group consisting of;

Hydrogen,

optionally substituted amino,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted alkenyl,

optionally substituted alkynyl,

optionally substituted aryl, or

optionally substituted heterocyclyl;

Hydrogen,

optionally substituted alkenyl,

optionally substituted alkynyl,

optionally substituted aryl, or

optionally substituted heterocyclyl;

with the proviso that in the case where R ^{1 is} selected from optionally substituted amino or optionally substituted alkoxy and R ² and R ^{3 are the} same, R ² and R ^{3 are} not hydrogen, or pharmaceutically acceptable salts thereof. 3, compounds according to claim 1 or 2, wherein

X is selected from: S or O;

R ^{1 is} selected from the group consisting of;

hydrogen

optionally substituted Amlno,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted aryl, or

optionally substituted heterocyclyl;

Hydrogen,

optionally substituted acyl,

optionally substituted alkoxycarbonyl, optionally substituted alkyl,

optionally substituted aryl, or

optionally substituted heterocyclyl; or pharmaceutically acceptable salts thereof.

4. Compounds according to any one of claims 1 to 3, wherein

X is selected from: S or O;

R ^{1 is} selected from the group consisting of:

hydrogen

optionally substituted amino,

optionally substituted alkyl, R ² and R ^{3 are the} same or different and are each selected from the group consisting of:

Hydrogen,

optionally substituted alkyi,

optionally substituted aryl, or

optionally substituted heterocyclyl; or pharmaceutically acceptable salts thereof. Compounds according to any one of claims 1 to 4, wherein X represents S;

R ^{1 is} selected from optionally substituted amino;

R ^{2 is} selected from optionally substituted alkyl; and in which

R ^{3 is} hydrogen;

or pharmaceutically acceptable salts thereof, compounds according to one or more of claims 1 to 4 in which X has the meaning S, or pharmaceutically acceptable salts thereof,, compounds according to one or more of claims 1 to 6,

wherein R ^{1 is} selected from optionally substituted amino, or pharmaceutically acceptable salts thereof,, compounds according to one or more of claims 1 to 7,

wherein R ^{2 is} selected from optionally substituted alkyl, or pharmaceutically acceptable salts thereof, compounds according to one or more of claims 1 to 8,

wherein R ^{3 is} hydrogen, or pharmaceutically acceptable salts thereof,

10. Compounds according to one or more of claims 1 to 9 selected from:

or pharmaceutically acceptable salts thereof,

11. A process for the preparation of the compounds of the general formula (I) according to claim 1, which comprise:

(a) Reaction of compounds of the formula (ia):

wherein R ¹ and X are as defined above, with compounds of the formula

A - R ² wherein R ^{2 is} as defined above and A is a suitable leaving group which allows the substitution of H by R ² to give compounds of the formula (Ib)

in which R 1, R ² and X are as defined above, or (b) reaction of the compounds of the formula (Ib)

wherein R \ R ² and X are as defined above, with compounds of the formula

A -R ³ wherein R ^{3 is} as defined above and A is a suitable leaving group which allows the substitution of H by R ³ to obtain compounds of formula (I), or (c) reaction of the compound of the formula (Ic):

wherein R ² , R ³ and X are as defined above, and R ^{4 is} in particular a to C ₆ alkyl group, with compounds of the formula

to compounds of the formula (Id)

wherein R ² , R ³ and X are as defined above, and R ⁵ and R ^{6 are the} same or different and are selected from the group consisting of:

Hydrogen,

optionally substituted alkyl,

optionally substituted aryl, and

optionally substituted heterocyclyl, or wherein

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached, a saturated or unsaturated, optionally form substituted 3- to 6-membered ring, which may optionally contain further heteroatoms.

12. Compounds according to one or more of claims 1 to 10 for use as medicaments.

13. Compounds according to one or more of claims 1 to 10 for use in the treatment of Eisenmetabolismus- disorders, especially for the application of iron deficiency diseases and / or anemias, in particular anemia in cancer, anemia triggered by chemotherapy, anemia triggered by inflammation (AI ), Congestive heart failure (CHF), stage 3 -5 chronic kidney disease (CKD 3-5) anemia, anemia due to chronic inflammation (ACD), anemia in rheumatoid arthritis (Rheumatoid arthrltis), systemic lupus erythematosus (SLE) anemia, and inflammatory bowel disease (IBD) anemia.

14. A composition containing one or more of the compounds according to one or more of claims 1 to 10 and one or more pharmaceutical carriers and / or excipients and / or solvents.

15, combination preparation prepared containing one or more of the compounds according to one or more of claims 1 to 10 and at least one further pharmaceutically active compound, which is in particular a compound for the treatment of Eisenmetabolism us disorders and the associated symptoms, preferably an iron-containing compound is.

16, use of the compounds according to one or more of claims 1 to 10, the composition of claim 14 and of the combination preparation according to claim 15 for the preparation of a medicament for the treatment of hepcidin-mediated diseases and the associated symptoms, in particular for the treatment of iron metabolism disorders, in particular iron deficiency diseases and / or anemias, in particular ACD and AI, and the associated symptoms. Use of the compounds according to one or more of claims 1 to 10, the composition according to claim 14 and of the combination preparation according to claim 15 for the manufacture of a medicament for oral or parenteral administration.