US20120214803A1 - Novel Sulfonaminoquinoline Hepcidin Antagonists - Google Patents

Novel Sulfonaminoquinoline Hepcidin Antagonists Download PDF

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US20120214803A1
US20120214803A1 US13/364,566 US201213364566A US2012214803A1 US 20120214803 A1 US20120214803 A1 US 20120214803A1 US 201213364566 A US201213364566 A US 201213364566A US 2012214803 A1 US2012214803 A1 US 2012214803A1
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optionally substituted
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hydrogen
alkyl
heterocyclyl
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Inventor
Wilm Buhr
Susanna Burckhardt
Franz Dürrenberger
Felix Funk
Peter O. Geisser
Vincent A. Corden
Stephen M. Courtney
Graham Dawson
Tara Davenport
Mark Slack
Mark P. Ridgill
Chrostopher J. Yarnold
Susan Boyce
Albertus A. Ellenbroek
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Vifor International AG
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Vifor International AG
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Priority to US13/364,566 priority Critical patent/US20120214803A1/en
Priority to PCT/EP2012/052694 priority patent/WO2012110603A1/en
Priority to BR112013020916A priority patent/BR112013020916A2/pt
Priority to MX2013009522A priority patent/MX2013009522A/es
Priority to ES12704090.5T priority patent/ES2623229T3/es
Priority to CN201280018909.9A priority patent/CN103492028B/zh
Priority to JP2013553947A priority patent/JP5948352B2/ja
Priority to KR1020137025002A priority patent/KR20140009396A/ko
Priority to EP12704090.5A priority patent/EP2675526B1/en
Priority to RU2013142448/04A priority patent/RU2013142448A/ru
Priority to CA2826463A priority patent/CA2826463A1/en
Priority to AU2012217021A priority patent/AU2012217021A1/en
Priority to ARP120100551A priority patent/AR085283A1/es
Priority to TW101105292A priority patent/TW201302710A/zh
Assigned to VIFOR (INTERNATIONAL) AG reassignment VIFOR (INTERNATIONAL) AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RIDGILL, MARK P., GEISSER, PET O., CORDEN, VINCENT A., COURTNEY, STEPHEN M., DAVENPORT, TARA, DAWSON, GRAHAM, YARNOLD, CHRISTOPHER J., BURCKHARDT, SUSANNA, DURRENBERGER, FRANZ, FUNK, FELIX, BUHR, WILM, ELLENBROEK, ALBERTUS A., BOYCE, SUSAN, SLACK, MARK
Publication of US20120214803A1 publication Critical patent/US20120214803A1/en
Priority to ZA2013/06005A priority patent/ZA201306005B/en
Priority to US14/310,254 priority patent/US9102688B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to novel hepcidin antagonists of the general formula (I), pharmaceutical compositions comprising these and their use for treatment of iron metabolism disorders, in particular of anaemias in connection with chronic inflammatory diseases (anaemia of chronic disease (ACD) and anaemia of inflammation (AI)) or of iron deficiency symptoms and iron deficiency anaemias.
  • ACD chronic inflammatory diseases
  • AI anaemia of inflammation
  • Iron is an essential trace element for almost all organisms and in this context is relevant in particular for growth and blood formation.
  • the balance of iron metabolism in this context is primarily regulated at the level of recovery of iron from haemoglobin from ageing erythrocytes and duodenal absorption of iron bonded in food.
  • the iron released is absorbed via the intestine, in particular by way of specific transport systems (DMT-1, ferroportin, transferrin, transferrin receptors), transported into the blood stream and passed on by this means into the corresponding tissue and organs.
  • DMT-1 specific transport systems
  • the element iron is of great importance in the human body inter alia for oxygen transport, oxygen uptake, cell functions, such as mitochondrial electron transport, and finally for energy metabolism in total.
  • the body of a human contains on average 4 to 5 g of iron, this being present in enzymes, in haemoglobin and myoglobin and as depot or reserve iron in the form of ferritin and haemosiderin.
  • this iron about half of this iron, approx. 2 g, is present as haem iron bonded in the haemoglobin of red blood corpuscles. Since these erythrocytes have only a limited life (75-150 days), new ones must constantly be formed and old ones eliminated (over 2 million new erythrocytes are formed per second). This high regeneration capacity is achieved by macrophages, in that these absorb the ageing erythrocytes by phagocytosis, lyse them and in this way can recycle the iron contained in them for the iron metabolism. The amount of iron required daily for erythropoiesis of approx. 25 mg is thus mostly provided.
  • the daily iron requirement of an adult human is between 0.5 and 1.5 mg per day, and for infants and women in pregnancy the iron requirement is 2 to 5 mg per day.
  • Daily iron losses e.g. by exfoliation of skin cells and epithelial cells, is comparatively low, but increased iron losses occur, for example, in women during menstrual bleeding. Blood losses generally can considerably reduce iron metabolism, since about 1 mg of iron is lost per 2 ml of blood.
  • the normal daily iron loss of approx. 1 mg is conventionally replaced again by an adult, healthy human via the daily food intake.
  • Iron metabolism is regulated via absorption, the absorption rate of the iron present in food being between 6 and 12%, and in the event of iron deficiency the absorption rate is up to 25%.
  • the absorption rate is regulated by the organism as a function of iron requirement and the size of the iron store.
  • the human organism uses both divalent and trivalent iron ions.
  • Iron(III) compounds are conventionally dissolved in the stomach at a sufficiently acid pH and are thus made available for absorption. Absorption of the iron takes place in the upper small intestine by mucosa cells.
  • trivalent non-haem iron is first reduced to Fe 2+ e.g. by ferrireductase (duodenal cytochrome b at the membrane) in the membrane of intestinal cells, so that it can then be transported by the transport protein DMT1 (divalent metal transporter 1) into the intestinal cells.
  • DMT1 divalent metal transporter 1
  • haem iron enters into the enterocytes unchanged via the cell membrane.
  • iron is either stored as depot iron in ferritin or released into the blood by the transport protein ferroportin, bonded to transferrin.
  • Hepcidin plays a central role in this operation, since it is the essential regulation factor of iron uptake.
  • the divalent iron transported into the blood by the ferroportin is converted into trivalent iron by oxidases (ceruloplasmin, hephaestin), which is then transported to the relevant places in the organism by means of transferrin (see for example: “Balancing acts: molecular control of mammalian iron metabolism”. M. W. Hentze, Cell 117, 2004, 285-297.)
  • the regulation of the iron level in this context is controlled or regulated by hepcidin.
  • Hepcidin is a peptide hormone which is produced in the liver.
  • the prevailing active form has 25 amino acids (see for example: “Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation”. T. Ganz Blood 102, 2003, 783-8), although two forms shortened at the amino end, hepcidin-22 and hepcidin-20, have been found.
  • Hepcidin acts on iron uptake via the intestine, via the placenta and on the release of iron from the reticuloendothelial system.
  • hepcidin is synthesized from so-called pro-hepcidin in the liver, pro-hepcidin being coded by the so-called HAMP gene.
  • hepcidin If the organism is adequately supplied with iron and oxygen, increased hepcidin is formed. In the mucosa cells of the small intestine and in the macrophages, hepcidin binds to ferroportin, by means of which iron is conventionally transported out of the cell interior into the blood.
  • the transport protein ferroportin is a membrane transport protein comprising 571 amino acids which is formed and located in the liver, spleen, kidneys, heart, intestine and placenta.
  • ferroportin is located in the basolateral membrane of intestinal epithelial cells.
  • the ferroportin bound in this way effects export of iron into the blood here.
  • ferroportin very probably transports iron as Fe 2+ . If hepcidin is bound to ferroportin, ferroportin is transported into the cell interior and degraded, as a result of which the release of iron from the cells is then almost completely blocked.
  • ferroportin is inactivated via hepcidin, the iron stored in the mucosa cells therefore cannot be transported away, and the iron is lost with the natural exfoliation of cells via the stool. As a result, absorption of iron in the intestine is reduced by hepcidin. On the other hand, if the iron content in the serum is lowered, hepcidin production in the hepatocytes of the liver is reduced, so that less hepcidin is released and therefore less ferroportin is inactivated, as a result of which an increased amount of iron can be transported into the serum.
  • Ferroportin is moreover located to a high degree in the reticuloendothelial system (RES), to which the macrophages also belong.
  • RES reticuloendothelial system
  • Hepcidin plays an important role here in the event of impaired iron metabolism in the context of chronic inflammations, since interleukin-6 in particular is increased with such inflammations, which leads to an increase in the hepcidin level. Increased hepcidin is bound to the ferroportin of the macrophages by this means, as a result of which release of iron is blocked here, which in the end then leads to an inflammation-related anaemia (ACD or AI).
  • ACD inflammation-related anaemia
  • iron metabolism is essentially controlled via cellular release of iron from macrophages, hepatocytes and enterocytes by way of hepcidin.
  • Hepcidin thus plays an important role in functional anaemia.
  • the iron requirement of bone marrow for erythropoiesis is not met sufficiently.
  • the reason for this is assumed to be an increased hepcidin concentration, which in particular limits the transport of iron from the macrophages by blocking the ferroportin and thus greatly reduces the release of iron recycled by phagocytosis.
  • hepcidin for example due to inflammation processes, for example with chronic inflammations, results directly in reduced serum iron levels. In pathological cases this can lead to a reduced content of haemoglobin, reduced erythrocyte production and therefore to an anaemia.
  • the duration of use of chemotherapeutics in carcinoma treatments can be significantly reduced by an existing anaemia, since the state of reduced formation of red blood corpuscles caused by the chemotherapeutics employed is intensified still further by an existing anaemia.
  • anaemias include tiredness, pallor and reduced attention capacities.
  • the clinical symptoms of anaemia include low serum iron contents (hypoferraemia), low haemoglobin contents, low haematocrit level and a reduced number of red blood corpuscles, reduced reticulocytes and increased values of soluble transferrin receptors.
  • Iron deficiency symptoms or iron anaemias are conventionally treated by supplying iron.
  • substitution with iron takes place either by the oral route or by intravenous administration of iron.
  • Erythropoietin and other erythropoiesis-stimulating substances can moreover also be employed in the treatment of anaemias to give a boost to the formation of red blood corpuscles.
  • Anaemias which are caused by chronic diseases can be treated only inadequately with such conventional treatment methods.
  • Cytokines such as in particular inflammatory cytokine, in particular play a particular role in anaemias which are based on chronic inflammation processes.
  • An overexpression of hepcidin occurs in particular with such chronic inflammatory diseases and is known to lead to a reduced availability of iron for the formation of the red blood corpuscles.
  • Anaemia is to be attributed inter alia to those chronic inflammatory diseases mentioned, and to malnutrition or low-iron diets or unbalanced, low-iron eating habits. Anaemias moreover occur due to reduced or poor absorption of iron, for example due to gastrectomies or diseases such as Crohn's disease. An iron deficiency can also occur as a result of an increased blood loss, e.g. due to an injury, heavy menstrual bleeding or blood donation. An increased iron requirement in the growth phase of adolescents and children and in pregnant women is also known.
  • hepcidin antagonists Compounds which bind to hepcidin or to ferroportin and therefore inhibit the binding of hepcidin to ferroportin and therefore in turn prevent the inactivation of ferroportin by hepcidin, or compounds which, although hepcidin is bound to ferroportin, prevent the internalization of the hepcidin-ferroportin complex, and in this manner prevent the inactivation of the ferroportin by the hepcidin, can be called in general terms hepcidin antagonists.
  • hepcidin antagonists By using such hepcidin antagonists, there is moreover also generally the possibility, for example by inhibiting hepcidin expression or by blocking the hepcidin-ferroportin interaction, of acting directly on the regulation mechanism of hepcidin and therefore of preventing via this route blocking of the iron transport pathway from tissue macrophages, liver cells and mucosa cells into the serum via the transport protein ferroportin.
  • hepcidin antagonists or ferroportin expression inhibitors substances are therefore available which are suitable for the preparation of pharmaceutical compositions or medicaments in the treatment of anaemias, in particular anaemias with chronic inflammatory diseases.
  • Such substances can be employed for treatment of such disorders and the resulting diseases, since these have a direct influence on the increase in the release of recycled haem iron by macrophages and effect an increase in the iron absorption of iron released from food in the intestinal tract.
  • Such substances, inhibitors of hepcidin expression or hepcidin antagonists can therefore be used for treatment of iron metabolism disorders, such as iron deficiency diseases, anaemias and anaemia-related diseases.
  • iron metabolism disorders such as iron deficiency diseases, anaemias and anaemia-related diseases.
  • this also includes those anaemias which are caused by acute or chronic inflammatory diseases, such as, for example, osteoarticular diseases, such as rheumatoid polyarthritis, or diseases which are associated with inflammatory syndromes.
  • Such substances can therefore be of particular benefit in particular in the indications of cancer, in particular colorectal cancer, multiple myeloma, ovarian and endometrial cancer and prostate cancer, CKD 3-5 (chronic kidney disease stage 3-5) CHF (chronic heart failure), RA (rheumatoid arthritis), SLE (systemic lupus erythematosus) and IBD (inflammatory bowel disease).
  • cancer in particular colorectal cancer, multiple myeloma, ovarian and endometrial cancer and prostate cancer
  • CKD 3-5 chronic kidney disease stage 3-5
  • CHF chronic heart failure
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • IBD inflammatory bowel disease
  • Hepcidin antagonists or compounds which have an inhibiting or assisting action on the biochemical regulation pathways in iron metabolism are known in principle from the prior art.
  • WO 2008/036933 describes double-stranded dsRNA which has an inhibiting action on the expression of human HAMP genes in cells and therefore already suppresses the formation of hepcidin, which is coded by the HAMP gene, at a very early stage in the iron metabolism signal pathway. As a result, 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 unimpeded.
  • All these compounds or methods are therefore those which start in the iron metabolism pathway before formation of the hepcidin and already regulate its general formation downwards.
  • substances and compounds are known and described in the prior art which bind in the body to hepcidin which has already formed and therefore inhibit its binding action on the membrane transport protein ferroportin, so that an inactivation of ferroportin by hepcidin is no longer possible.
  • Such compounds are therefore so-called hepcidin antagonists, those based on hepcidin antibodies being known in particular from this group.
  • Such documents are furthermore known in the prior art which describe various mechanisms for action on hepcidin expression, for example by antisense RNA or DNA molecules, ribozymes and anti-hepcidin antibodies. Such mechanisms are described, for example, in EP 1 392 345.
  • WO2009/058797 furthermore discloses anti-hepcidin antibodies and the use thereof for specific binding to human hepcidin-25, and therefore the use thereof for therapeutic treatment of low iron contents, in particular of anaemias.
  • ferroportin-1 antibodies which bind to ferroportin-1 and therefore activate ferroportin in order to assist in the iron transport from the cell into the serum by this means are also known.
  • ferroportin-1 antibodies are known, for example, from US2007/218055.
  • All these compounds described which can act as hepcidin antagonists or can display an inhibiting action in hepcidin expression are compounds of higher molecular weight, in particular those which are chiefly obtainable by genetic engineering processes.
  • low molecular weight compounds which play a role in iron metabolism and which can have either an inhibiting or also an assisting action are also known.
  • WO2008/109840 thus describes certain tricyclic compounds which can be employed in particular for treatment of disorders in iron metabolism, such as, for example, ferroportin disorders, these compounds being able to act by regulation of DMT-1 in the form of inhibition or activation.
  • the compounds of this WO08/109,840 are described in particular as DMT-1 inhibitors, whereby they can preferably be employed on diseases with increased iron accumulation or iron storage diseases, such as haemochromatosis.
  • WO2008/121861 also discloses low molecular weight compounds which have a regulating action on the DMT-1 mechanism. Certain pyrazole and pyrrole compounds are dealt with here, treatment of iron overloading disorders, for example on the basis of ferroportin disorders, also being described here in particular.
  • US2008/234384 is furthermore certain diary and diheteroaryl compounds for treatment of disorders in iron metabolism, such as, for example, ferroportin disorders, which likewise by their action as DMT-1 inhibitors can be employed in particular for treatment of disorders on the basis of increased iron accumulation.
  • DMT-1 regulatory mechanisms which can be employed for use on iron deficiency symptoms are also mentioned quite generally.
  • the low molecular weight compounds described in the prior art which have an action on iron metabolism are therefore based on DMT-1 regulatory mechanisms and are disclosed in particular for use as agents for treatment of iron accumulation disorders or iron overloading syndromes, such as haemochromatosis.
  • Role of STAT1, NF-kappaB, and C/EBPbeta in the macrophage transcriptional regulation of Hepcidin by mycobacterial infection and IFN-gamma refers to the use of NFkB inhibitors as hepcidin antagonists but remains silent about the use of 8-sulfonaminoquinoline derivatives.
  • Hepcidin in human iron disorders Therapeutic implications” (Pietrangelo et al., Journal of Hepatology, 54 (1), 2011) refers to the use of hepcidin antagonists for treating iron metabolism disorders such as anaemia. Nevertheless, the publication remains silent about the use of 8-sulfonaminoquinoline derivatives in such indication.
  • Hepcidin Central-regulator of iron-metabolism
  • EP 726254 relates to N-(4-quinolylcarbonyl)guanidines as hydrogen ion-sodium antiporter inhibitors.
  • 8-sulfonaminoquinoline derivatives for use in the medical field are e.g.
  • WO2010/051064 A1, WO2008/074068 A1, US2007/254894 A1 or “Identification of N-(quinolin-8-yl)benzenesulfonamides as agents capable of down-regulating NfkappaB activity within two separate high-throughput screens of NfkappaB activation” Xie et al., Bioorganic & Medical Chemistry Letters, 18 (1), 2007
  • “Convenient preparation of N-8-quinolinyl benzenesultams as novel NF-kappaB inhibitors” Xie et al., Tetrahedron Letters, 49 (14), 2008
  • “Synthesis and in vitro evaluation of leishmanicidal and trypanocidal activities of N-quinolin-8-yl-arylsulfonamides” Da Silva et al., Bioorganic & Medical Chemistry, 15 (24), 2007).
  • WO2008/144011 A1 refers to the use of selected 8-sulfonaminoquinoline derivatives in the medical treatment of autoimmune deficiencies and inflammatory disorders such as e.g. aplastic anemia (automimmune attack on the bone marrow), pernicious anemia (anemia due to improper absorption of vitamin B12), systemic lupus erythematosus, or inflammatory bowel disease. Nevertheless, the document remains silent about the use of the selected 8-sulfonaminoquinoline derivatives in the treatment of iron metabolism disorders such as e.g. iron deficiency diseases or iron anaemia.
  • autoimmune deficiencies and inflammatory disorders such as e.g. aplastic anemia (automimmune attack on the bone marrow), pernicious anemia (anemia due to improper absorption of vitamin B12), systemic lupus erythematosus, or inflammatory bowel disease.
  • iron metabolism disorders such as e.g. iron deficiency diseases or iron anaemia
  • WO2009/134973 A1 refers to the use of selected 8-sulfonaminoquinoline derivatives in the medical treatment of e.g. aplastic anemia but remains silent about any use thereof in the treatment of iron metabolism disorders, especially of iron deficiency diseases or iron anaemia.
  • sulfonaminoquinolines in the formation of metal complexes is known, such as e.g. iron (III) complexes as described in “Fluorometric determination of iron using 5-(4-methoxyphenylazo)-8-(4-toluenesulfonamido)quinoline” (Zeng Zuotao and Jewsbury Roger A., Analyst, 125 (9), 1661-1665, 2000).
  • the object of the present invention was to provide in particular such compounds which can be employed for use for iron deficiency disorders or anaemias, in particular ACD and AI and which act in iron metabolism in particular as hepcidin antagonists and therefore display an antagonistic and via this a regulating action in the hepcidin-ferroportin interaction in iron metabolism. It was furthermore in particular an object of the present invention to provide in this context such compounds which are chosen from the group of low molecular weight compounds and which generally can be prepared by simpler synthesis routes than the antagonistic or hepcidin-inhibiting compounds obtainable by genetic engineering processes, such as RNA, DNA or antibodies.
  • the inventors have found that certain compounds from the group of sulfonaminoquinolines have an action as hepcidin antagonists.
  • the invention provides compounds of the general structural formula (I)
  • substituent X is preferably C.
  • 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.
  • optionally substituted straight-chain or branched alkyl can also include such alkyl groups in which preferably 1 to 3 carbon atom(s) are replaced by corresponding hetero-analogous groups which contain nitrogen, oxygen or sulfur. This means in particular that, for example, one or more methylene groups in the alkyl radicals mentioned can be replaced by NH, O or S.
  • Optionally substituted alkyl furthermore includes cycloalkyl having preferably 3 to 8, more preferably 5 or 6, particularly preferably 6 carbon atoms.
  • Substituents of the optionally substituted alkyl defined above preferably include 1 to 3 identical or different substituents which are chosen, for example, from the group which consists of: hydroxyl, halogen, cyano, alkoxy, as defined below, optionally substituted aryloxy, as defined below, optionally substituted heterocyclyloxy, as defined below, carboxyl, optionally substituted acyl, as defined below, optionally substituted aryl, as defined below, optionally substituted heterocyclyl, as defined below, optionally substituted amino, as defined below, mercapto, optionally substituted alkyl-, aryl- or heterocyclylsulfonyl (R—SO 2 —), as defined below.
  • substituents of the optionally substituted alkyl defined above preferably include 1 to 3 identical or different substituents which are chosen, for example, from the group which consists of: hydroxyl, halogen, cyano, alkoxy, as defined below, optionally substituted aryloxy
  • alkyl radicals having 1 to 8 carbon atoms include: a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a sec-pentyl group, a t-pentyl group, a 2-methylbutyl group, an -n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-di
  • C 1 to C 4 alkyl such as, in particular, methyl and ethyl and i-propyl, are most preferred.
  • alkyl groups which arise by replacement with one or more hetero-analogous groups, such as —O—, —S— or —NH—, are preferably those in which one or more methylene groups are replaced by —O— to form an ether group, such as methoxymethyl, ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl etc., 2-methoxyethyl, 3-methoxypropyl and 2-ethoxyethyl being particularly preferred.
  • polyether groups such as poly(ethylenoxy) groups, are also included in 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.
  • a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group are preferred.
  • a cyclopentyl group and a cyclohexyl group are particularly preferred.
  • halogen includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine or bromine.
  • Examples of a linear or branched alkyl radical having 1 to 8 carbon atoms and substituted by halogen include:
  • Examples of a cycloalkyl radical having 3 to 8 carbon atoms and substituted by halogen include: a 2-fluorocyclopentyl group, a 2-chlorocyclopentyl 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-chlorocycl
  • alkyl radical substituted by hydroxyl examples include the abovementioned alkyl radicals which contain 1 to 3 hydroxyl radicals, such as, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl etc. 2-hydroxyethyl being preferred.
  • alkyl radical substituted by alkoxy examples include the abovementioned alkyl radicals which contain 1 to 3 alkoxy radicals, as defined below, such as, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 3-methoxypropyl etc., 2-methoxyethylene etc. 2-Methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl are preferred.
  • alkyl radical substituted by aryloxy examples include the abovementioned alkyl radicals which contain 1 to 3 aryloxy radicals, as defined below, such as, for example, phenoxymethyl, 2-phenoxyethyl and 2- or 3-phenoxypropyl etc. Phenoxymethyl is preferred.
  • alkyl radical substituted by heterocyclyloxy examples include the abovementioned alkyl radicals which contain 1 to 3 heterocyclyloxy radicals, as defined below, such as, for example, pyridin-2-yloxymethyl, -ethyl or -propyl, pyridin-3-yloxymethyl, -ethyl or -propyl, thiophen-2-yloxymethyl, -ethyl or -propyl, thiophen-3-yloxymethyl, -ethyl or propyl, furan-2-yloxymethyl, -ethyl or -propyl, furan-3-yloxymethyl, -ethyl or -propyl etc.
  • heterocyclyloxy radicals such as, for example, pyridin-2-yloxymethyl, -ethyl or -propyl, pyridin-3-yloxymethyl, -ethyl or -propyl, thiophen
  • alkyl radical substituted by acyl examples include the above-mentioned alkyl radicals which contain 1 to 3 acyl radicals, as defined below.
  • alkyl group substituted by cycloalkyl examples include the abovementioned alkyl radicals which contain 1 to 3, preferably one (optionally substituted) cycloalkyl group, such as, for example: cyclohexylmethyl, 2-cyclohexylethyl, 2- or 3-cyclohexylpropyl etc.
  • alkyl group substituted by aryl examples include the above-mentioned alkyl radicals which contain 1 to 3, preferably one (optionally substituted) aryl group, as defined below, such as, for example, phenylmethyl, 2-phenylethyl, 2- or 3-phenylpropyl etc., phenylmethyl being preferred.
  • alkyl group substituted by heterocyclyl examples include the abovementioned alkyl radicals which contain 1 to 3, preferably one (optionally substituted) heterocyclyl group, as defined below, such as, for example, 2-pyridin-2-yl-ethyl, 2-pyridin-3-yl-ethyl, pyridin-2-yl-methyl, pyridin-3-yl-methyl, 2-furan-2-yl-ethyl, 2-furan-3-yl-ethyl, furan-2-yl-methyl, furan-3-yl-methyl, 2-thiophen-2-yl-ethyl, 2-thiophen-3-yl-ethyl, thiophen-2-yl-methyl, thiophen-3-yl-methyl, imidazol-1-yl-methyl, imidazol-2-yl-methyl, 2-imidazol-1-yl-ethyl, 2-imidazol-2-yl-ethyl, 2-morpholin
  • alkyl radical substituted by amino examples include the abovementioned alkyl radicals which contain 1 to 3, preferably one (optionally substituted) amino group, as defined below, such as, for example, methylaminomethyl, methylaminoethyl, methylaminopropyl, 2-methylaminomethyl (di-methylaminomethyl), 2-ethylaminomethyl (di-ethylaminomethyl), 3-ethylaminomethyl, 2-methylaminoethyl (di-methylaminoethyl), 2-ethylaminoethyl (di-ethylaminoethyl), 3-ethylaminoethyl etc. 2-methylaminomethyl (di-methylaminomethyl) being preferred.
  • 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, an n-pentyloxy group, an i-pentyloxy group, a sec-pentyloxy group, a t-pentyloxy group, a 2-methylbutoxy group, an n-hexyloxy group, an i-hexyloxy group, a t-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy group
  • a 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 are preferred.
  • the methoxy group, the ethoxy group and the i-propyloxy group are particularly preferred.
  • the methoxy group is most preferred.
  • substituted alkyl-O group in particular a difluoromethoxy (—OCHF 2 ) and a trifluoromethoxy group (—OCF 3 ) as well as a di-methylaminoethoxy group or a benzyloxy (Phenyl-CH 2 —O—) group.
  • Optionally substituted aryloxy includes an optionally substituted aryl-O group, wherein reference may be made to the following definition of optionally substituted aryl with respect to the definition of the aryl group.
  • Preferred aryloxy groups include 5- and 6-membered aryl groups, among which phenoxy, which can be optionally substituted, is preferred.
  • Optionally substituted heterocyclyloxy includes an optionally substituted heterocyclyl-O group, wherein reference may be made to the following definition of heterocyclyl with respect to the definition of the heterocyclyl group.
  • Preferred heterocyclyloxy groups include 5- and 6-membered heterocyclyloxy groups, among which pyridin-2-yloxy, pyridin-3-yloxy, thiophen-2-yloxy, thiophen-3-yloxy, furan-2-yloxy, furan-3-yloxy are preferred.
  • Optionally substituted alkenyl in the entire context of the invention preferably includes: straight-chain or branched-chain alkenyl having 2 to 8 carbon atoms and cycloalkenyl having 3 to 8 carbon atoms, which can optionally be substituted by preferably 1 to 3 identical or different substituents, such as hydroxyl, halogen or alkoxy.
  • substituents such as hydroxyl, halogen or alkoxy.
  • Examples include: vinyl, 1-methylvinyl, allyl, 1-butenyl, isopropenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. Vinyl or allyl are preferred.
  • Optionally substituted alkynyl in the entire context of the invention preferably includes:
  • Optionally substituted aryl in the entire context of the invention preferably includes: aromatic hydrocarbon radicals having 6 to 14 carbon atoms (the carbon atoms of the possible substituents not being included), which can be mono- or bicyclic and which can be substituted by preferably 1 to 3 identical or different substituents chosen from hydroxyl, halogen, as defined above, nitro, 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 alkoxycarbonyl as defined below, optionally substituted aryl, as defined here, optionally substituted heterocyclyl, as defined below.
  • Aromatic hydrocarbon radicals having 6 to 14 carbon atoms include, for example: phenyl, naphthyl, phenanthrenyl and anthracenyl, which can optionally be substituted once or several times by identical or different radicals.
  • Phenyl and optionally substituted phenyl such as, in particular, halogen-, nitro, cyano-, (optionally substituted) alkyl-, (optionally substituted) alkoxy-, (optionally substituted) alkoxycarbonyl- and (optionally substituted) amino-substituted phenyl, are preferred.
  • Examples of an aryl group substituted by alkyl preferably include: aryl, as described above, which is substituted by straight-chain or branched alkyl having 1 to 8, preferably 1 to 4 carbon atoms, as described above.
  • Preferred alkylaryl is toluoyl (2-, 3- or 4-toluoyl), trimethylphenyl and trifluoromethylbenzene (benzotrifluoride).
  • Examples of an aryl group substituted by halogen preferably include: aryl, as described above, which is substituted by one or more identical or different halogens, as described above.
  • Examples of an aryl radical having 3 to 8, preferably 6 carbon atoms in the aromatic ring system and substituted by halogen 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, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 2,3-di-fluorophenyl group, a 2,3-di-chlorophenyl group, a 2,3-di-bromophenyl group, a 2,4-di-fluorophenyl group, a 2,4-di-chlorophenyl group, a 2,4-di-bromophenyl group, a 2,4-di-bromophenyl group, a 2,4-di-brom
  • Examples of an aryl group substituted by a nitro group preferably include: aryl, as described above, which is substituted by 1 to 3 nitro radicals, such as, preferably, nitrophenyl, in particular 2-, 3- or 4-nitrophenyl, 2-nitrophenyl being particularly preferred.
  • Examples of an aryl group substituted by cyano preferably include: aryl, as described above, which is substituted by 1 to 3 cyano radicals, such as, preferably, benzonitrile (2-, 3- or 4-benzonitrile), in particular 2- or 3-benzonitrile.
  • Examples of an aryl group substituted by hydroxyl preferably include: aryl, as described above, which is substituted by 1 to 3 hydroxyl radicals, such as, for example, 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. 2-Hydroxyphenyl, 3-hydroxyphenyl and 2,4-di-hydroxyphenyl are preferred.
  • Examples of an aryl group substituted by alkoxy or a substituted alkoxy group preferably include:
  • aryl as described above, which is substituted by 1 to 3 alkoxy radicals, as described above, such as, preferably, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-propyloxyphenyl, 3-propyloxyphenyl, 4-propyloxyphenyl, 2-i-propyloxyphenyl, 3-i-propyloxyphenyl, 4-i-propyloxyphenyl, 2,4-di-methoxyphenyl etc., as well as 2-, 3- or 4-di-fluoromethoxy, 2-, 3- or 4-tri-fluoromethoxy. 2-methoxyphenyl, 4-methoxyphenyl 2-trifluoromethoxy, 3-trifluoromethoxy and 4-trifluoromethoxy being particularly preferred.
  • Examples of an aryl group substituted by alkoxycarbonyl preferably include: aryl, as described above, which is substituted by 1 to 3 alkoxycarbonyl radicals, as described below, such as, preferably, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl etc., methoxycarbonylphenyl, in particular 2-methoxycarbonylphenyl and 3-methoxycarbonylphenyl, being preferred.
  • Examples of an aryl group substituted by amino preferably include: aryl, as described above, which is substituted by an optionally substituted amino group, as described below.
  • Preferred aminoaryl is anilinyl (2-, 3- or 4-anilinyl), with 2-anilinyl and 3-anilinyl being preferred, and acylaminophenyl such as acetylaminophenyl, propionylaminophenyl, i-propionylaminophenyl and trifluoroacetylaminophenyl.
  • aryl groups substituted by at least two different substituents such as particularly 2-methyl-3-chlorophenyl, 2-methyl-3-fluorophenyl, 2-methyl-4-fluorophenyl, 2-nitro-4-fluorophenyl, 2-nitro-4-trifluoromethylphenyl, 2-nitro-4-methoxyphenyl, 4-methyl-2-anilinyl, 4-trifluoromethyl-2-anilinyl, 4-fluoro-2-anilinyl, 3-fluoro-4-methoxyphenyl, 4-methoxy-2-anilinyl, 3-carboxy-4-fluorophenyl, 2-acetylamino-4-trifluoro-methylphenyl, 2-i-propionylamino-4-trifluoromethylphenyl, 2-trifluoroacetyl-amino-4-trifluoromethylphenyl, 3-dimethylaminoethylaminomethyl-4-fluoro-phenyl, 3-N-morpholino
  • Optionally substituted heterocyclyl in the entire context of the invention preferably includes:
  • aliphatic, saturated or unsaturated heterocyclic 5- to 8-membered cyclic radicals which contain 1 to 3, preferably 1 to 2 hetero atoms chosen from N, O or S, and which can optionally be substituted, preferably by 1 to 3 substituents, wherein reference may be made to the definition of the possible substituents of aryl with respect to possible substituents.
  • heterocyclic radicals are preferred, such as tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl, tetrahydro-thiophen-3-yl, pyrrolidin-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, piperazin-1-yl, piperazin-2-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azepan-2-yl, azepan-3-yl,
  • optionally substituted heterocyclic radicals such as pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, optionally substituted with e.g. an alkyl group as defined above preferably with an amino-substituted alkyl group such as e.g. a dimethylaminoethyl group as preferably dimethylaminoethyl-piperazin:
  • Optionally substituted heterocyclyl in the entire context of the invention moreover includes heteroaromatic hydrocarbon radicals having 4 to 9 ring carbon atoms, which additionally preferably contain 1 to 3 identical or different hetero atoms from the series S, O, N in the ring, and which therefore preferably form 5- to 12-membered heteroaromatic radicals, which can preferably be monocyclic, but also bicyclic.
  • Preferred aromatic heterocyclic radicals include: pyridinyl, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, pyridyl N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl (thiophenyl), furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl.
  • 5- or 6-membered aromatic heterocyclyls such as e.g. pyridinyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, furyl and thienyl, are preferred, as well as quinolyl. Most preferred are pyrazolyl, pyridinyl, thienyl and quinolyl.
  • heterocyclyl radicals according to the invention can be substituted by preferably 1 to 3 identical or different substituents chosen, for example, from hydroxyl, 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 here.
  • Heterocyclyl preferably includes: tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperidinyl or tetrahydropyranyl, piperazinyl, diazepanyl, pyridinyl, pyridyl N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl (thiophenyl), furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, quinoxazolinyl.
  • 5- or 6-membered aromatic heterocyclyls such as e.g. pyridyl, pyridyl N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, furanyl and thienyl, as well as the bicyclyc aromatic heterocyclyl quinolyl are preferred.
  • Particularly preferred heterocyclyl includes: pyridinyl, with pyridin-2-yl:
  • pyrimidinyl with pyrimidin-2-yl:
  • thienyl with thien-2-yl:
  • quinolyl such as, preferably, quinol-3-yl:
  • heterocyclyl group substituted by alkyl preferably include: heterocyclyl, as described above, which is substituted by optionally substituted straight-chain or branched alkyl having 1 to 8, preferably 1 to 4 carbon atoms, as described above.
  • Preferred alkylheterocyclyl are methylpyridinyl, ethylpyridinyl, methylthienyl, ethylthienyl, methylquinolyl, ethylquinolyl, trifluoromethylpyridinyl, trifluoromethylthienyl, and trifluoromethylquinolyl, with trifluoromethylpyridinyl, in particular 6-trifluoromethyl-pyridin-3-yl:
  • heterocyclyl group substituted by halogen preferably include: heterocyclyl, as described above, which is substituted by one or more identical or different halogens, as described above.
  • heterocyclyl group substituted by cyano preferably include: heterocyclyl, as described above, which is substituted by a cyano group such as preferably 6-cyano-pyridin-3-yl:
  • heterocyclyl group substituted by halogen preferably include: heterocyclyl, as described above, which is substituted by halogen as described above.
  • Preferred halogen-substituted heterocyclyl groups are fluoropiperidinyl, chloropiperidinyl, bromopiperidinyl fluoropiperazinyl, chloropiperazinyl, bromopiperazinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, fluorothienyl, chlorothienyl, bromothienyl fluoroquinolyl, chloroquinolyl, bromoquinolyl, etc., with fluoropiperidinyl, chloropiperidinyl, bromopiperidinyl fluoropiperazinyl, chloropiperazinyl, bromopiperazinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, fluorothien
  • heterocyclyl group substituted by hydroxyl preferably include: heterocyclyl, as described above, which is substituted by 1 to 3 hydroxyl radicals, such as, for example, 3-hydroxypyridyl, 4-hydroxypyridyl 3-hydroxythienyl, hydroxyquinolyl etc.
  • heterocyclyl group substituted by alkoxy preferably include: heterocyclyl, as described above which is substituted by 1 to 3 alkoxy radicals, as described above, such as, preferably, 3-alkoxypyridyl, 4-alkoxypyridyl 3-alkoxythienyl, alkoxyquinolyl etc.
  • heterocyclyl group substituted by acyl preferably include: heterocyclyl, as described above, which is substituted by 1 to 3 acyl radicals, as described below.
  • Aliphatic acyl alkyl-CO—
  • optionally substituted aliphatic acyl preferably includes: C 1 to C 6 alkanoyl, such as formyl, acetyl, propionyl, iso-propionyl (1-propionyl), butyryl, Isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, cyclohexanoyl etc.
  • C 1 to C 6 alkanoyl such as formyl, acetyl, propionyl, iso-propionyl (1-propionyl), butyryl, Isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, cyclohexanoyl etc.
  • Formyl, acetyl and iso-propionyl are particularly preferred.
  • substituted aliphatic acyl examples include, for example: optionally halogen-substituted C 2 to C 6 alkanoyl and optionally heterocyclyl-substituted C 2 to C 6 alkanoyl, wherein reference may be made to the above definitions with respect to the definitions of halogen, heterocyclyl and C 2 to C 6 alkanoyl, such as particularly trifluoroacetyl and morpholinylacetyl:
  • Optionally substituted aromatic acyl includes in particular: C 6 to C 10 aroyl, such as benzoyl, toluoyl, xyloyl, alkoxybenzoyl etc.
  • Optionally substituted heterocyclic acyl includes in particular: C 6 to C 10 heterocycloyl, such as furanoyl, pyridinoyl, such as pyridin-2-oyl, pyrrolidinoyl, piperidinoyl, tetrahydrofuranoyl.
  • Optionally substituted amino in the entire context of the invention preferably includes: 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 reference may be made to the corresponding above definition for optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted acyl with respect to alkyl, aryl, heterocyclyl and acyl.
  • Mono- or dialkylamino in this context includes in particular: straight-chain or branched mono- or dialkylamino having 1 to 8, preferably 1 to 6, more preferably 1 to 4 saturated or unsaturated carbon atoms, optionally substituted as described above, in each alkyl group, in particular methylamino, dimethylamino, ethylamino, diethylamino, wherein the alkyl groups can be substituted by preferably one substituent such as e.g. by amino, alkoxy or heterocyclyl as defined herein.
  • Preferred is a mono- and dimethylamino group, a dieethylamino group, and an amino substituted alkyl-amino group such as dimethylaminoethylamino:
  • alkoxy substituted alkyl-amino group such as methoxyethylamino:
  • heterocyclyl substituted alkyl-amino group such as morpholinylethylamino:
  • Mono- or diarylamino in this context includes in particular: mono- or diarylamino with 3- to 8-, preferably 5- to 6-membered aryl radicals which are optionally substituted as described above, in particular phenylamino or diphenylamino, wherein the aryl groups can be substituted by preferably one or two substituents.
  • N-Alkyl)(N-aryl)amino describes in particular a substituted amino which is substituted in each case on the nitrogen atom by an alkyl radical and by an aryl radical.
  • Mono- or diheterocyclylamino includes in particular: mono- or diheterocyclylamino with 3- to 8-, preferably 5- to 6-membered heterocyclyl radicals which are optionally substituted as described above.
  • N-Alkyl(N-heterocyclyl)amino describes in particular 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 describes in particular a substituted amino which is substituted in each case on the nitrogen atom by an aryl radical and by a heterocyclyl radical.
  • Mono- or diacylamino includes in particular a substituted amino which is substituted by one or two (optionally substituted) acyl radicals, as defined above, such as, in particular, acetylamino, propionylamino, iso-propionylamino, trifluoroacetylamino etc.
  • Optionally substituted aminocarbonyl in the context of the entire invention represents optionally substituted amino-CO, wherein reference may be made to the above definition with respect to the definition of optionally substituted amino.
  • Optionally substituted aminocarbonyl preferably represents optionally substituted carbamoyl (H 2 NCO—), such as H 2 NCO—, mono- or dialkylaminocarbonyl (H(alkyl)N—CO— or (alkyl) 2 N—CO—), mono- or diarylaminocarbonyl (H(aryl)N—CO— or (aryl) 2 N—CO—) or mono- or diheterocyclylaminocarbonyl (H(heterocyclyl)N—CO— or (heterocyclyl) 2 N—CO—), wherein reference may be made to the above explanations for optionally substituted alkyl, aryl or heterocyclyl with respect to the definition of alkyl, aryl or heterocyclyl.
  • aminocarbonyl H 2 NCO—
  • alkylaminocarbonyl selected from monomethylaminocarbonyl (H(CH 3 )NCO—), dimethylaminocarbonyl ((CH 3 ) 2 NCO—), dimethylaminoethylaminocarbonyl:
  • Optionally substituted aminosulfonyl in the context of the entire invention furthermore represents optionally substituted amino-SO 2 —, wherein reference may be made to the above definition with respect to the definition of optionally substituted amino.
  • Optionally substituted sulfamoyl (H 2 N—SO 2 —) such as sulfamoyl (H 2 N—SO 2 —) or mono- or dialkylaminosulfonyl (alkyl) 2 N—SO 2 , are preferred, wherein reference may be made to the above explanations for optionally substituted alkyl with respect to the definition of alkyl.
  • Optionally substituted Sulfonyl (—SO 2 R), wherein R is a hydroxyl group (—OH or an optionally substituted alkyl, aryl or heterocyclyl as defined above) furthermore preferably represents a sulfonic acid residue, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, tolylsulfonyl or benzylsulfonyl. Methylsulfonyl is preferred.
  • Optionally substituted alkoxycarbonyl includes the optionally substituted alkoxy (—O-alkyl) mentioned above with respect to the definition of alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl etc.
  • pyrrolidinyloxycarbonyl such as pyrrolidin-3-yl-oxycarbonyl:
  • Optionally substituted acyloxy (—O—(C ⁇ O)-alkyl; —O—(C ⁇ O)-aryl; —O—(C ⁇ O)-heterocyclyl) includes the optionally substituted acyl mentioned above with respect to the definition of acyl.
  • the compound of the formula (I) has the following substituent definitions:
  • the compound of the formula (I) has the following substituent definitions:
  • At least one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is defined as in any one of the aforementioned embodiments.
  • Example Compound 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 321 323 324 325 326 327 328 329 330 331 332 333 334 3
  • the compounds of the general structural formula (I), (la) and (Ib) respectively, according to the present invention comprise pharmaceutically acceptable salts thereof.
  • a further aspect of the present invention is directed to the new compounds according to the general formula (Ib)
  • such new compounds are selected from the compounds as defined in the aforementioned table with the example compounds Nos. 113, 114, 115, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 398, 399, 401, 402, 403, 405, 407, 412, 413, 416, 424, 425, 426, 427, 428, and 429.
  • a further aspect of the present invention relates to the new compounds according to the generals formula (Ib) and preferably of the new compounds Nos. 113, 114, 115, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 398, 399, 401, 402, 403, 405, 407, 412, 413, 416, 424, 425, 426, 427, 428, and 429 as described herein for the use as a medicament.
  • the present invention includes compounds of the general formula (I), (la) and (Ib) respectively in which, for example, the substituents R 1 to R 5 and R 7 have the general meaning and the substituents R 6 and R 8 and X have a preferred meaning or the substituents R 1 to R 5 and R 7 have a preferred meaning and the substituents R 6 and R 8 and X have the general meaning etc.
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the use of the enantiomers or diastereomers and their particular mixtures.
  • the enantiomerically pure forms can optionally be obtained by conventional processes of optical resolution, such as by fractional crystallization of diastereomers therefrom by reaction with optically active compounds. If the compounds according to the invention can occur in tautomeric forms, the present invention includes the use of all the tautomeric forms.
  • the compounds provided according to the invention can be present as mixtures of various possible isomeric forms, in particular of stereoisomers, such as e.g. E and Z, syn and anti, and optical isomers. Both the E and the Z isomers and the optical isomers, and any desired mixtures of these isomers are claimed.
  • stereoisomers such as e.g. E and Z, syn and anti, and optical isomers.
  • substituent A being selected from a suitable aryl-substituent as defined in the present invention and with the substituent B being particularly selected from an alkyl-group to form a suitable acyl-, particularly a suitable acyl-amino group as defined in the present invention.
  • substituent A being selected from a suitable aryl-substituent as defined in the present invention and
  • substituent A being selected from a suitable aryl-substituent as defined in the present invention
  • substituent A being selected from a suitable aryl-substituent as defined in the present invention
  • substituent A′ being selected from a suitable amino-substituent as defined in the present invention
  • substituent X being C or preferably N with the substituent A′ being selected from a suitable alkyl- or amino-substituent, respectively, each as defined in the present invention
  • substituent A′ being selected from a suitable amino-substituent as defined in the present invention
  • substituent A′ being selected from a suitable amino-substituent as defined in the present invention
  • substituent A′ being selected from a suitable amino-substituent as defined in the present invention
  • substituent A′ being selected from a suitable amino-substituent as defined in the present invention
  • substituent A′ being selected from a suitable amino-substituent as defined in the present invention
  • reaction paths shown here are reaction types which are known per se and which can be carried out in a manner known per se.
  • reaction with a pharmaceutical acceptable base or acid By reaction with a pharmaceutical acceptable base or acid, corresponding salts are obtained.
  • the reaction of the various reaction partners can be carried out in various solvents, and in this respect is not subject to a particular limitation.
  • suitable solvents are thus water, methanol, ethanol, acetone, dichloromethane, dichloroethane, methylene chloride, dimethoxyethane, diglyme, acetonitrile, butyronitrile, THF, dioxane, ethyl acetate, butyl acetate, dimethylacetamide, toluene, chlorobenzene, dimethylsulfoxice (DMSO) etc.
  • Methanol, ethanol, acetone and methylene chloride are preferred, and in particular the solvents used in the preferred processes according to synthesis routes 1 to 65 as described herein.
  • the reaction according to the invention of the reaction partners is carried out, for example, at room temperature.
  • temperatures above room temperature for example up to 80 or 90° C.
  • temperatures below room temperature for example down to ⁇ 20° C. or less, can also be used.
  • the pH at which the reaction according to the invention of the reaction partners is carried out is suitably adjusted.
  • the pH adjustment is preferably carried out by addition of a base.
  • Both organic and inorganic bases can be used as bases.
  • inorganic bases such as, for example, LiOH, NaOH, KOH, Ca(OH) 2 , Ba(OH) 2 , Li 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , or organic bases, such as amines (such as, for example, preferably triethylamine (TEA, NEt 3 ), N,N-diisoproylethylamine (diethylisopropylamine), Bu 4 NOH, piperidine, morpholine, pyridine and alkylpyridines (4-Dimethylaminopyridine), are used.
  • amines such as, for example, preferably triethylamine (TEA, NEt 3 ), N,N-diisoproylethylamine (diethylisopropylamine), Bu 4 NOH, piperidine,
  • the pH adjustment can optionally also be carried out by means of acids.
  • Both organic and inorganic acids can be used as acids.
  • inorganic acids such as, for example, HCl, HBr, HF, H 2 SO 4 , H 3 PO 4 , or organic acids, such as CF 3 COOH, acetic acid (CH 3 COOH, AcOH), p-toluenesulfonic acid, and salts thereof are used.
  • HCl, H 2 SO 4 Organic acids, such as acetic acid (CH 3 COOH, AcOH), are particularly preferably used.
  • the pH adjustment is particularly preferably carried out by means of the pH-adjusting agents used in the preferred processes described herein according to synthesis routes 1 to 65.
  • a person skilled in the art is in a position here to choose the most suitable solvent and the optimum reaction conditions, in particular with respect to temperature, pH, catalyst and solvent, for the corresponding synthesis route or for the corresponding reaction step. In any case, the parameters as provided in the above presented synthesis routes 1 to 65 are preferred.
  • the present invention thus also provides novel intermediate products in accordance with the present invention, which are accessible with the preparation processes as described herein, such as, in particular, the intermediate products as described in the examples below and which are obtainable from the synthesis routes 1 to 65 as described herein.
  • the compounds provided by the present invention and represented by the general structural formula (I), (la) and (Ib) respectively show an action as a hepcidin antagonist and are therefore suitable for use as medicaments for treatment of hepcidin-mediated diseases and the symptoms accompanied by these or associated with these.
  • the compounds according to the invention are suitable in use for treatment of disorders in iron metabolism, in particular for treatment of iron deficiency diseases and/or anaemias, in particular ACD and AI.
  • the medicaments containing the compounds of the general structural formula (I), (la) and (Ib) respectively are suitable in this context for use in human and veterinary medicine.
  • the present invention thus provides new compounds according to the general structural formula (Ib) as well as the compounds of the general structural formula (I), (la) and (Ib) respectively according to the invention, each with the above substituent meanings, for use as medicaments, in particular for the use in the treatment of iron metabolism disorders.
  • the compounds according to the invention are therefore also suitable for the preparation of a medicament for treatment of patients suffering from symptoms of iron metabolism disorders, such as e.g. from an iron deficiency anaemia, such as, for example: tiredness, lack of drive, lack of concentration, low cognitive efficiency, difficulties in finding the correct words, forgetfulness, unnatural pallor, irritability, accelerated heart rate (tachycardia), sore or swollen tongue, enlarged spleen, pregnancy cravings (pica), headaches, loss of appetite, increased susceptibility to infections, depressive moods or suffering from ACD or AL.
  • an iron deficiency anaemia such as, for example: tiredness, lack of drive, lack of concentration, low cognitive efficiency, difficulties in finding the correct words, forgetfulness, unnatural pallor, irritability, accelerated heart rate (tachycardia), sore or swollen tongue, enlarged spleen, pregnancy cravings (pica), headaches, loss of appetite, increased susceptibility to infections, depressive moods or suffering
  • the compounds according to the invention are therefore also suitable for the preparation of a medicament for treatment of patients suffering from symptoms of an iron deficiency anaemia.
  • Administration can take place over a period of several months until the iron status improves, reflected, for example, by the haemoglobin value, the transferrin saturation and the ferritin value of the patient, or until the desired improvement is achieved in an impairment of the state of health caused by iron deficiency anaemia or by ACD or AI.
  • the preparation according to the invention can be taken by children, adolescents and adults.
  • the compounds of the present invention can furthermore also be used in combination with further active compounds or medicaments known in the treatment of disorders in iron metabolism and/or with active compounds or medicaments which are administered concomitantly with agents for treatment of diseases which are associated with disorders in iron metabolism, in particular with iron deficiency and/or anaemias.
  • agents for treatment of disorders in iron metabolism and further diseases associated with iron deficiency and/or anaemias which can be used in combination can include, for example, iron-containing compounds, such as e.g. 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 in this context either orally or parenterally, or the administration of the compounds according to the invention and of the compounds used in combination can take place by combination of the administration possibilities mentioned.
  • the compounds according to the invention and the combinations of the compounds according to the invention with further active compounds or medicaments can be employed in the treatment of disorders in iron metabolism, such as, in particular, iron deficiency diseases and/or anaemias, in particular anaemias with cancer, anaemia induced by chemotherapy, anaemia induced by inflammation (AI), anaemias with congestive cardiac insufficiency (CHF; congestive heart failure), anaemia with chronic renal insufficiency stage 3-5 (CKD 3-5; chronic kidney diseases stage 3-5), anaemia induced by chronic inflammation (ACD), anaemia with rheumatic arthritis (RA; rheumatoid arthritis), anaemia with systemic lupus erythematosus (SLE) and anaemia with inflammatory intestinal diseases (IBD; inflammatory bowel disease) or used for the preparation of medicaments for treatment of these diseases.
  • iron deficiency diseases and/or anaemias in particular anaemias with cancer, anaemia induced by chemotherapy,
  • the compounds according to the invention and the above-mentioned combinations of the compounds according to the invention with further active compounds or medicaments can be used in particular for the preparation of medicaments for treatment of iron deficiency anaemia, such as iron deficiency anaemias in pregnant women, latent iron deficiency anaemia in children and adolescents, iron deficiency anaemia as a result of gastrointestinal abnormalities, iron deficiency anaemia as a result of blood losses, such as by gastrointestinal haemorrhages (e.g.
  • iron deficiency anaemia as a result of ulcers, carcinomas, haemorrhoids, inflammatory disorders, intake of acetylsalicylic acid), menstruation, injuries, iron deficiency anaemia as a result of psilosis (sprue), iron deficiency anaemia as a result of reduced uptake of iron from the diet, in particular in selectively eating children and adolescents, weak immune system caused by iron deficiency anaemia, impaired cerebral performance caused by iron deficiency anaemia, restless leg syndrome.
  • the use according to the invention leads to an improvement in the iron, haemoglobin, ferritin and transferrin values which, especially in adolescents and children, but also in adults, are accompanied by an improvement in the short term memory test (STM), in the long term memory test (LTM), in the Raven's progressive matrices test, in the Wechsler adult intelligence scale (WAIS) and/or in the emotional coefficient (Baron EQ-i, YV test; youth version), or to an improvement in neutrophile levels, antibody levels and/or lymphocyte function.
  • STM short term memory test
  • LTM long term memory test
  • WAIS Wechsler adult intelligence scale
  • Baron EQ-i, YV test youth version
  • the present invention furthermore relates to pharmaceutical compositions comprising one or more compounds of the formula (I) according to the invention and optionally one or more further pharmaceutically active compounds and optionally one or more pharmacologically acceptable carriers and/or auxiliary substances and/or solvents.
  • the pharmaceutical carriers, auxiliary substances or solvents are conventional substances.
  • the pharmaceutical compositions mentioned are suitable, for example, for intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastral or intracutaneous administration and are present, for example, in the form of pills, tablets, tablets resistant to gastric juice, film-coated tablets, layered tablets, sustained release formulations for oral, subcutaneous or cutaneous administration (in particular as patches), depot formulation, sugar-coated tablets, small suppositories, gels, ointments, syrup, granules, suppositories, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, capsules resistant to gastric juice, powders, powders for inhalation, microcrystalline formulations, sprays for inhalation, dusting powders, drops, nasal drops, nasal spray
  • the compounds according to the invention and pharmaceutical compositions comprising such compounds are administered orally and/or parenterally, in particular intravenously.
  • the compounds according to the invention are preferably present in pharmaceutical compositions in the form of pills, tablets, tablets resistant to gastric juice, film-coated tablets, layered tablets, sustained release formulations for oral administration, depot formulations, sugar-coated tablets, granules, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, capsules resistant to gastric juice, powders, microcrystalline formulations, dusting powders, drops, ampoules, solutions, suspensions, infusion solutions or injection solutions.
  • the compounds according to the invention can be administered in a pharmaceutical composition which can comprise various organic or inorganic carrier materials and/or auxiliary materials such as are conventionally used for pharmaceutical purposes, in particular for solid medicament formulations.
  • excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonates
  • binders such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatine, gum arabic, polyethylene glycol, sucrose, starch
  • disintegrating agents such as starch, hydrolysed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl-starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate
  • lubricants and slip agents such as magnesium stearate, talc, sodium lauryl sulfate
  • a flavouring agent such as citric acid, menthol,
  • DTPA diethylenetriaminepentaacetic acid
  • suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminium stearate
  • dispersing agents such as diluents (such as water, organic solvents), beeswax, cacao butter, polyethylene glycol, white petrolatum etc.
  • Liquid medicament formulations such as solutions, suspensions and gels, conventionally contain a liquid carrier, such as water and/or pharmaceutically acceptable organic solvents. Such liquid formulations can furthermore also contain pH-adjusting agents, emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents, gelling agents (for example methylcellulose), colouring agents and/or aroma substances.
  • the compositions can be isotonic, that is to say these can have the same osmotic pressure as blood.
  • the isotonicity of the composition can be adjusted using sodium chloride or other pharmaceutically acceptable agents, such as, for example, dextrose, maltose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic soluble substances.
  • the viscosity of the liquid compositions can be adjusted using a pharmaceutically acceptable thickening agent, such as methylcellulose.
  • suitable thickening agents include, for example, xanthan, carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like. The preferred concentration of the thickening agent will depend on the agent chosen.
  • Pharmaceutically acceptable preservatives can be used to increase the life of the liquid composition. Benzyl alcohol may be suitable, although a large number of preservatives, including, for example, paraben, thimerosal, chlorobutanol or benzalkonium chloride, can likewise be used.
  • the active compound can be administered, for example, with 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.
  • the dosage can be increased or reduced, depending on the age, weight, condition of the patient, severity of the disease or nature of the administration.
  • a preferred embodiment relates to the use of the compounds according to the invention and of the compositions according to the invention comprising the compounds according to the invention and of the combination preparations according to the invention comprising the compounds and compositions according to the invention for the preparation of a medicament for oral or parenteral administration.
  • hepcidin-antagonistic action of the sulfonaminoquinoline compounds of the present invention was determined by means of the “ferroportin internalization assay” described in the following.
  • Fpn The internalization of Fpn was monitored by labelling these cells with fluorescent ligands (HaloTag®-TMR, tetramethylrhodamine) which join covalently on to the HaloTag reporter gene fused with the Fpn.
  • Imaging by confocal fluorescence microscopy showed a cell surface location of Fpn in the absence of hepcidin and the absence of Fpn surface staining in the presence of hepcidin.
  • Optimized image analysis algorithms were used to ascertain the cell surface and to quantify the corresponding membrane fluorescence associated with the Fpn-HaloTag fusion protein.
  • This assay allows a quantitative image-based analysis in order to quickly evaluate compounds which can block hepcidin-induced internalization of Fpn.
  • This assay is a direct in vitro pendant of the in vivo action mechanism proposed for medicament candidates and is therefore suitable as an initial assay with a high throughput for identifying compounds which counteract the action of hepcidin on its receptor
  • Flash silica gel chromatography was carried out on silica gel 230-400 mesh or on pre-packed silica cartridges.
  • Microwave reactions were carried out using a CEM Discover or Explorer focussed microwaves apparatus.
  • TFA or HCl salts Some compounds are isolated as TFA or HCl salts, which are not reflected by the chemical name.
  • the chemical name represents the compound in neutral form as well as its TFA salt or any other salt, especially pharmaceutically acceptable salt, if applicable.
  • Phosphorus pentachloride (3.0 g, 14.6 mmol) was added to a solution of 3-pyridinesulfonic acid (1.5 g, 9.42 mmol) dissolved in phosphoryl trichloride (2.45 g, 16.0 mmol) and the mixture heated to 130° C. for 3 h under argon. The mixture was concentrated in vacuo, the residue was quenched over ice and extracted with ether. The organic phase was washed with a saturated sodium bicarbonate solution and concentrated in vacuo to give the crude title compound (0.6 g, 36%) which was used immediately without purification.
  • Aqueous NaNO 2 (2.0 g, 29.5 mmol) was added dropwise to 4-methyl-2-nitroaniline (3.0 g, 19.7 mmol) dissolved in conc. HCl (15 ml) at 0° C. and the mixture was stirred for 45 min. The mixture was filtered and the filtrate added to a saturated solution of SO 2 gas in AcOH (10 ml), in the presence of CuCl 2 (800 mg, 6.0 mmol) at 50° C. The reaction was stirred for 5 h and the precipitate formed collected by filtration, dissolved in DCM, dried (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (950 mg, 67%). The structure was confirmed by 1 H NMR.
  • Benzenesulfonyl chloride 72 ⁇ l, 0.57 mmol was added to a solution of 5-bromoquinolin-8-ylamine hydrochloride (84 mg, 0.38 mmol) in pyridine (150 ⁇ l, 1.89 mmol) and DCM (5 ml) and the mixture was stirred at room temperature for 20 h. Water (5 ml) was added and the organic phase was separated. The aqueous phase was extracted with DCM and the combined organic phases were dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by trituration from DMSO/MeOH (1:2) to give the title compound (60 mg, 44%).
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US13/364,566 US20120214803A1 (en) 2011-02-18 2012-02-02 Novel Sulfonaminoquinoline Hepcidin Antagonists
RU2013142448/04A RU2013142448A (ru) 2011-02-18 2012-02-16 Новые сульфонаминохинолиновые антагонисты гепсидина
CA2826463A CA2826463A1 (en) 2011-02-18 2012-02-16 Novel sulfonaminoquinoline hepcidin antagonists
MX2013009522A MX2013009522A (es) 2011-02-18 2012-02-16 Nuevos antagonistas de hepcidina sulfonaminoquinolina.
ES12704090.5T ES2623229T3 (es) 2011-02-18 2012-02-16 Nuevos antagonistas de hepcidina de sulfonaminoquinolina.
CN201280018909.9A CN103492028B (zh) 2011-02-18 2012-02-16 磺氨基喹啉铁调素拮抗剂
JP2013553947A JP5948352B2 (ja) 2011-02-18 2012-02-16 新規なスルホンアミノキノリン系ヘプシジン拮抗薬
KR1020137025002A KR20140009396A (ko) 2011-02-18 2012-02-16 신규한 설폰아미노퀴놀린 헵시딘 길항제
EP12704090.5A EP2675526B1 (en) 2011-02-18 2012-02-16 Novel sulfonaminoquinoline hepcidin antagonists
PCT/EP2012/052694 WO2012110603A1 (en) 2011-02-18 2012-02-16 Novel sulfonaminoquinoline hepcidin antagonists
BR112013020916A BR112013020916A2 (pt) 2011-02-18 2012-02-16 compostos de fórmula geral, composição e preparação combinada
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AU2012217021A1 (en) 2013-08-22
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