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EP2467361A1 - Nouveaux antagonistes de chinoline-hepcidine - Google Patents

Nouveaux antagonistes de chinoline-hepcidine

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Publication number
EP2467361A1
EP2467361A1 EP10743174A EP10743174A EP2467361A1 EP 2467361 A1 EP2467361 A1 EP 2467361A1 EP 10743174 A EP10743174 A EP 10743174A EP 10743174 A EP10743174 A EP 10743174A EP 2467361 A1 EP2467361 A1 EP 2467361A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
hydrogen
group
compounds
iron
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10743174A
Other languages
German (de)
English (en)
Inventor
Franz DÜRRENBERGER
Susanna Burckhardt
Peter Otto Geisser
Wilm Buhr
Felix Funk
Vincent Anthony Corden
Tara Davenport
Stefan Jaeger
Mark Slack
Christopher John Yarnold
Wei Tsung Yau
Stephen Martin Courtney
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vifor International AG
Original Assignee
Vifor International AG
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Filing date
Publication date
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Priority to EP10743174A priority Critical patent/EP2467361A1/fr
Publication of EP2467361A1 publication Critical patent/EP2467361A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/32—Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to novel hepcidin antagonists of the general formula (I), to pharmaceutical compositions comprising them and to their use for the treatment of iron metabolism disorders, in particular of anemias in connection with chronic inflammatory diseases (ACD) and anemia of inflammation (A1)). or iron deficiency symptoms and iron deficiency anamies
  • Iron is an essential trace element for almost all living things and is particularly relevant for growth and blood formation.
  • the iron balance balance is primarily regulated at the level of iron recovery from hemoglobin of aging erythrocytes and duodenal absorption of dietary iron
  • the intestine is taken up by specific transport systems (DMT-I, 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 the transport of oxygen, the absorption of oxygen, cell functions such as mitochondrial electron transport and ultimately for the entire energy metabolism
  • the body of a human 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 hemoside Approximately half of this iron ca, 2 g is as urinary iron bound in the hemoglobin of the red blood cells, Since these erythrocytes have a limited life (75-1 50 days), constantly new formed and old must be eliminated (over 2 million, Erythrocytes are re-formed per second), this high neoplasm capacity is achieved by macrophages by phagocytic take up the aging erythrocytes, lyse, and thus can recycle the iron contained for the iron budget. Thus, the quantity of iron required for erylrophotesis of about 25 mg is largely provided,
  • the daily iron needs of an adult person 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 Elsenolde, z. B. by Absc Anlagenrung of skin and epithelial cells is relatively low, increased iron losses occur, for example, in menstrual bleeding in women.
  • blood loss can significantly reduce the iron balance, since about 1 mg of iron is lost per 2 ml of blood.
  • the normal iron loss of about 1 mg is usually replaced by the daily food intake in an adult, healthy person.
  • the iron balance is regulated by resorption , in which the absorption rate of the iron present in the food amounts to between 6 and 1 2%, with iron deficiency the absorption quota amounts to up to 25%,
  • the Resorpfionsquote is regulated by the organism depending on the iron requirement and the iron storage size, whereby the human organism uses both bivalent and Also trivalent iron ions, Usually iron (III) compounds are dissolved at sufficiently acidic pH in the stomach and thus made available for absorption. The absorption of iron takes place in the upper small intestine by mucosa cells. This trivalent is not urinary iron for absorption z. B.
  • the divalent iron transported into the blood by the ferroportin is transformed by oxidases (ceruloplasrnin, hephaestin) into trivalent iron, which is then transported by transferrin to the relevant sites in the organism (see, for example: “Balancing acts: molecular control of mammalian iron mefabolisrn "M, W. Hentze, Ce // 117, 2004, 285-297.)
  • 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 (see, for example: “Hepcidin, a key regulator of an iron metabolism and mediator of anemia of inflammation", T. Ganz B / ood 102, 2003, 783-8), although two at the amino terminus shortened forms, hepcidin-22 and hepcidin-20.
  • Hepcidin has an effect on iron uptake via the intestine, via the placenta and on the release of iron from the reticuloendotelial system, in the body hepcidin is released from the so-called pro-hepcidin in the liver If the organism is adequately supplied with iron and oxygen, hepcidin is increasingly formed and hepcidin binds to the small intestine mucosal cells and in the macrophages to ferroportin, through which iron is usually released 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. Ferroportin bound in this way causes iron to be exported to the blood. Ferroportin iron is most likely transported as Fe 2+ .
  • Binds hepcidin to ferroportin will F-erroportm transported into the cell interior and degraded, whereby the iron release from the cells is then almost completely blocked If the ferroportin inactivated by hepcidin and thus can not remove the stored iron in the mucosa cells, the iron is lost with the natural Zellabsc Anlagenrung through the chair This reduces the uptake of iron in the intestine by hepcidin. On the other hand, if the iron content in the serum is reduced, Hepcidm production is reduced in the hepatocytes of the liver so that less hepcidin is released and less ferroportin is inactivated, which causes an increased amount of iron in the serum can be transported
  • ferroportin is highly localized in the reticuloendotheous system (RES), which also includes the macrophages
  • Hepcidin plays an important role in disturbed metabolism of electrons 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 This causes Hepcidn is increasingly bound to the ferroportin of macrophages, making it here to a Blocking of iron release comes, which then leads to a inflammatory anemia (ACD or AI)
  • iron metabolism is primarily controlled by hepcidin via the cellular release of iron from macrophages, hepatocytes and enterocytes
  • Hepcidin thus plays an important role in functional anemia
  • Irotz filled iron stores the iron requirement of the bone marrow for erythropoiesis is not sufficiently fulfilled.
  • the reason for this is an increased hepcidin condensation, which limits the iron transport from the macrophages, in particular by blocking the ferroportin and thus greatly reducing the release of phagocytic recycled iron
  • a disturbance of the Hepcidm Regul ⁇ tionsmech ⁇ nismus thus shows a direct effect on the Elsenmetabolismus in the organism If, for example, the Hepcidm expression is prevented, for example, by a genetic defect, this leads to an unmeasurable overload to iron, which is known under the iron storage disease hamochromatosis
  • Hepcidm overexpression for example due to inflammatory processes, for example in chronic inflammations, results directly in reduced serum iron levels. These can lead to reduced levels of hemoglobin, reduced erythrocyte production and thus anemia in pathological cases
  • chemotherapeutic drugs in carcinoma treatments can be significantly reduced by existing anemia, since the condition of reduced formation of red blood cells, caused by the chemotherapeutic agents used by an existing anemia is further enhanced
  • anemia Other symptoms include fatigue, paleness, and decreased attention capacity
  • the clinical signs of anemia include low levels of serum iron (hypoferremia), low levels of hemoglobin, low levels of hamatoconstriction, reduced numbers of red blood cells, reduced reticulocytes, increased levels of soluble transferrin receptors
  • Iron deficiency or iron intakes are iron-treated. Iron substitution is either oral or by intravenous iron addition.
  • erythropoietin and other erythropoietin-stimulating substances may be used in the treatment of anemia to promote the formation of red blood cells
  • Anemias caused by chronic diseases may be inadequate Cytokines, such as in particular inflammatory cytokines, play a particular role in anemia that is based on chronic inflammatory piocences. Hepcidin overexpression particularly occurs in such chronic inflammatory diseases and, as is known, leads to reduced iron availability for the formation of the red blood cells
  • Anemia is attributed, among other things, to such chronic inflammatory diseases as well as to malnourished diets, low-iron diets or unbalanced, iron-poor feeding habits.
  • anemias occur due to reduced or poor iron absorption, for example due to gastrectomies or diseases such as Crohn's disease.
  • an iron deficiency due to increased blood loss z. B. by an injury, severe menstrual bleeding or blood donation occur.
  • iron deficiency leads not only 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 even in adolescents to long-term negative effects on cognitive development can lead to a particularly effective therapy in addition to the well-known classical substitution therapies of particular interest for this area.
  • hepcidin antagonists Compounds which bind to hepcidin or to ferroportin and thus inhibit the binding of hepcidin to ferroportin, and damil in turn prevent inactivation of ferroportin by hepcidin, or Compounds which, although hepcidin bound to ferroportin prevent the internalization of the hepcidin-ferroporfin complex and thus prevent inactivation of the ferroportin by the hepcidin, can be generally referred to as hepcidin antagonists
  • hepcidin antagonists it is also generally possible to directly influence the regulatory mechanism of hepcidin, for example by inhibiting hepcidin expression or by blocking the hepcidin-ferroporlin interaction, and thus block the iron transport pathway from tissue macrophages, liver cells, via this pathway and mucosa cells into the serum via the transport profil Ferroportin to prevent substances are available with such hepcidin antagonists or hepcidin expression inhibitors, which are suitable for the preparation of pharmaceutical compositions or medicaments in the treatment of anemia, in particular anemia in chronic inflammatory diseases These substances can be used to treat such disorders and the resulting diseases, as these have direct influence on increasing the release of reclaimed ham iron by macrophages, as well as a Thus, such substances, hepcidm expression inhibitors or hepcidin-antagonists, can be used for the treatment of iron metabolism disorders such as iron deficiency disorders, anemias and A ⁇ anhie-related diseases.
  • such substances may be particularly in the indications of cancer especially colorectal cancer, multiple myeloma, ova ⁇ al and endomet ⁇ al cancer, and prostate cancer, CKD 3, which are caused by acute or chronic inflammatory diseases such as osteoarticular diseases such as rheumatoid arthritis or diseases associated with inflammatory syndromes 5 (chronic kidney disease stage 3-5), CHF (chronic heart failure), RA (rheumatoid arthritis), SLE (systemic lupus erythomatosus) and IBD (inflammatory bowel diseases) may be of particular use STATE OF THE ART
  • WO 2008/036933 describes double-stranded dsRNA inhibiting the expression of human HAMP genes in cells and thus in the iron metabolism signal pathway at a very early stage the formation of hepcidin which is encoded by the HAMP gene. 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 unhindered
  • US 2007/004618 relates to siRNA, which has a direct inhibitory effect on hepcidin mRNA expression
  • WO08 / 109840 describes certain tricyclic compounds which can be used in particular for the treatment of disorders of the metabolism of metabolites, such as, for example, ferroportin preparations, wherein these Compounds can act by regulation of DMT-I in the form of inhibition or activation.
  • the compounds of this WO08 / 109840 are described in particular as DMT-I inhibitors, with which they are preferably used in diseases with increased iron accumulation or iron storage diseases such as hamochromatosis,
  • the low molecular weight compounds which are active in the iron metabolism described in the prior art are related to DMT-I regulatory mechanisms and in particular disclosed for use as agents for the treatment of iron accumulation disorders or iron overload syndromes such as hamochromatosis.
  • Hepcidin - Central-regulator of Iron-metabolism (Atanasiu Vale ⁇ u et al, European Journal of Haematolgy, 78 (1), 2007) gives an overview However, hepcidin and its funlelion do not give any indication of low molecular weight antagonists, especially such mi ⁇ quinoline structure
  • Structural chemical compounds of quinolines have thus far not been described in the context of the treatment of iron metabolism disorders.
  • no low-molecular-weight chemical structures which function as hepcidin antagonists and are thereby suitable for the treatment of iron metabolism disorders have not yet been synthesized. described
  • the invention also relates to novel quinone compounds of the general structural formula (I) according to the present invention
  • TNAP activators tissue-unspecific alkaline phosphatase (TNAP) activators, and their use for bone mineral resorption, in particular in the treatment of hypophosphatasia and osteoporosis.
  • the group of TNAP activators disclosed therein also comprises quinone compound 7 in particular - (Morphol ⁇ n-4-yl-pyr ⁇ d ⁇ n-2-yl-me1hyl) -ch ⁇ nol ⁇ n-8-ol, according to the
  • Example Compound 1 of the Present Invention an effect in the treatment of disorders of iron metabolism does not result
  • the object of the present invention was to provide in particular those compounds which are suitable for the use of
  • Iron deficiency disorders or anemias in particular ACD and AI can be used and act in iron metabolism in particular as hepcidin-antagonists, and thus exert an antagonistic and over regulating effect in iron metabolism in the hepcidin-ferroportin interaction, Furthermore, it was particularly an object of the present invention, thereby to provide those compounds which are selected from the group of low molecular weight compounds and which can generally be prepared by simpler synthesis routes than the antagonistic or hepcidin-inhibiting compounds obtainable by genetic engineering methods, such as RNA, DNA or antibodies.
  • the invention relates to compounds of the general structural formula (I) wherein
  • R 1 , R 2 and R 7 are the same or different and are each selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of
  • R 4 and R 6 are the same or different and are each selected from the group consisting of:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5- to 8-membered ring which may optionally contain further heteroatoms; or pharmaceutically acceptable salts thereof.
  • Optionally substituted alkyl preferably includes:
  • one or more, more preferably 1 to 3 carbon atoms may be replaced by hetero analogues containing nitrogen, oxygen or sulfur.
  • one or more methylene groups in the alkyl radicals may be replaced by NH, O or S.
  • one or more H atoms of a methyl group, preferably 1 to 3 H atoms, may be replaced by fluorine.
  • 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- A pentyl group, an i-pentyl group, a sec-pentyl group, a t-penfyl 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, 2-ethylbutyl group, 3-ethylbutyl group, 1, 1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylH-methylpropyl group, n-hept
  • 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-
  • Dimethylhexyl group a 3,3-dimethylhexyl group, a 4,4-dimethylhexyl group, a 5,5-dimethylhexyl group, a 1-propylpentyl group, a 2-propylpentyl group, etc.
  • Preferred are those having 1 to 6 carbon atoms, especially methyl, ethyl, n Propyl and i-propyl. Most preferred is methyl,
  • alkyl groups resulting from exchange with one or more heteroanalogous groups are preferably those in which one or more methylene groups are replaced by -O- to form an ether group, such as Methoxymethyl, ethoxymethyl, 2-methoxyethylene, etc.
  • polyether 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.
  • Preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • Heterocyclic alkyl radicals which are formed by exchange of methylene by heteroanalogical groups of cycloalkyl are, for example, 5- or 6-membered heterocyclic radicals, such as tetrahydrofuryl, pyrrolidinyl, morpholinyl, piperidinyl or tetrahydropyranyl, which may optionally be condensed with aromatic rings, etc.
  • examples of a halogen-substituted linear or branched alkyl radical having 1 to 8 carbon atoms include:
  • Trifluoromethyl group Trifluoromethyl group, a chloromethyl group, a dichloromethyl 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
  • Perfluoroheptyl group etc., in particular fluoroalkyl, difluoroalkyl and trifluoroalkyl should be mentioned.
  • 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.
  • a cycloalkyl-substituted alkyl group examples include the above-mentioned alkyl groups having 1 to 3, preferably an (optionally substituted) cycloalkyl or heterocyclyl group, such as For example, cyclohexyimethyl, 2-cyclohexylethyl, 2- or 3-cyclohexylpropyl, etc., or such as morpholinylalkyl, such as 2-morpholinylethyl, morpholinylmethyl, etc. Preferred is morpholinylmethyl,
  • Examples of an aryl or heteroaryl substituted alkyl group preferably include straight chain or branched alkyl of 1 to 8, preferably 1 to 4, carbon atoms as described above substituted with optionally substituted aryl and / or heteroaryl as described below.
  • Preferred arylalkyl and / or heteroarylalkyl are benzyl, alkoxybenzyl, in particular trimethoxybenzyl, pyridylmethyl, furylmethyl, pyrimidylmethyl and pyrrolylmethyl.
  • Optionally substituted aikoxy includes an optionally substituted alkyl-O group wherein reference may be made to the above definition with respect to the optionally substituted 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, i-propyloxy group, n-butyloxy group, i-butyloxy group, sec-butyloxy group, 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, 3-methylpentyloxy group, 1-ethylbutyl
  • Dimethylbufyloxy group Dimethylbufyloxy group, a 2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a 1-ethyl-1-methylpropyloxy group, etc.
  • Preferred are a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n Butoxy, an i-butyloxy group, a sec-butyloxy group, a t-butyloxy group.
  • Particularly preferred is the methoxy group.
  • Optionally substituted alkenyl includes throughout the scope of
  • Straight-chain or branched-chain alkenyl having 2 to 8 carbon atoms and cycloalkenyl having 3 to 8 carbon atoms which may be optionally substituted by preferably 1 to 3 same or different substituents, such as hydroxy, halogen or alkoxy.
  • substituents such as hydroxy, halogen or alkoxy.
  • Examples include vinyl, 1-methylvinyl, allyl, 1-butenyl, isopropenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl.
  • optionally substituted alkynyl With respect to the definition of the optionally substituted alkynyl, reference is made to the above definition of the optionally substituted alkyl wherein the optionally substituted alkynes comprise at least one C ⁇ C triple bond, examples include ethynyl, propynyl, butynyl, pentynyl and optionally substituted as defined above thereof, preferred is ethynyl and optionally substituted ethynyl,
  • Optionally substituted aryl preferably includes throughout the scope of the invention:
  • Aromatic hydrocarbon radicals having 6 to 1 4 carbon atoms (the carbon atoms of the possible substituents are not included), which may be mono- or bicyclic, and those which are preferably 1 to 3 identical or different substituents selected from hydroxy, halogen, as defined above, cyano, Amino, aminocarbonyl as defined below, mercapto, alkyl as defined above, acyl as defined below, and alkoxy as defined above may be substituted.
  • Aromatic hydrocarbon radicals having from 6 to 14 carbon atoms include, for example, phenyl, naphthyl, phenanthrenyl and anthracenyl, which may optionally be monosubstituted or polysubstituted by identical or different radicals. Preference is given to phenyl,
  • Optionally substituted heteroaryl preferably includes throughout the scope of the invention:
  • Heteroaromatic hydrocarbon radicals having 4 to 9 carbon atoms (wherein the carbon atoms of the substituents are not counted), which have 1 to 3 identical or different heteroatoms from the series S, O, N, and thus the 5- to 1 2-membered heteroaromatic radicals which may be mono- or di-cyclic and which are selected from preferably 1 to 3 identical or different substituents for example hydroxy, halogen as defined above, cyano, amino, mercapto, alkyl as defined above, acyl, as defined below, and Alkoxy can be substituted as defined above,
  • Heteroaryl includes, for example, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, 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 heterocycles such as, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furanyl and thienyl are preferred.
  • Preferred are pyridyl, pyrimidyl and furanyl.
  • heteroaryl includes: pyridyl, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, such as pyrimidin-2-yl and pyrimidin-5-yl, Pyrazine-2-yl, and imidazolyl such as imidazol-2-yl and imidazol-3-yl, furanyl such as furan-2-yl and furan-3-yl, and thienyl such as thien-2-yl and thien-3-yl .
  • pyridyl such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl
  • pyrimidinyl such as pyrimidin-2-yl and pyrimidin-5-yl
  • Pyrazine-2-yl and imidazolyl
  • imidazol-2-yl and imidazol-3-yl furanyl such as furan-2-yl
  • Examples of a halogen-substituted aryl group preferably include aryl as described above which is substituted with 1 to 3 halogen atoms, such as 2-chloro- or fluorophenyl, 3-chloro- or fluorophenyl, 4-chloro- or fluorophenyl, 2 , 4-di (chloro and / or fluoro) phenyl, 2,5-di (chloro and / or fluoro) phenyl, 2, ⁇ -di (chloro and / or fluoro) phenyl, 3,5 Di (chloro and / or fluoro) phenyl, 3,6-di- (chloro and / or fluoro) phenyl, 2,4,6-tri (chloro and / or fluoro) phenyl, etc. is preferred 2-chlorophenyl, A-chlorophenyl and 4-fluorophenyl.
  • Examples of an alkyl-substituted aryl or heteroaryl group preferably include aryl and / or heteroaryl as described above which is substituted with straight-chain or branched, optionally substituted alkyl of 1 to 8, preferably 1 to 4, carbon atoms as described above.
  • Preferred alkylaryl and / or Alkylheteroaryl are toluyl, methylpyridyl, methylfuryl, Mefhylpyrimidy! and methylpyrrolyl.
  • Examples of a substituted alkyl-substituted aryl or heteroaryl group preferably include aryl and / or heteroaryl as described above which is substituted with straight-chain or branched, substituted alkyl having 1 to 8, preferably 1 to 4, carbon atoms as described above,
  • a preferred substituted alkyl substituent includes, in particular: arylalkyl and / or heteroarylalkyl, such as in particular benzyl, alkoxybenzyl, in particular trimethoxybenzyl, pyridylmethyl, furylmethyl, pyrimidylmethyl and pyrrolylmethyl.
  • Preferred arylalkyl-substituted heteroaryls include benzylimidazolyl, benzylpyridyl, benzylfuryl, benzylpyrimidyl and methylpyrrolyl, with benzylimidazolyl being particularly preferred.
  • Examples of an alkoxy-substituted aryl and / or heteroaryl group preferably include aryl or heteroaryl as described above which is substituted with 1 to 3 alkoxy groups as described above, such as preferably 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl , 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2,4-di-methoxyphenyl, etc., as well as 2-alkoxypyridyl, 3-alkoxypyridyl, 4-alkoxypyridyl, 2-alkoxyfuryl, 3-alkoxyfuryl, 2-alkoxypyrimidyl, 4- Alkoxypyrimidyl, 5-alkoxypyrimidyl, 2-alkoxypyrrolyl, 3-alkoxypyrrolyl, 3,5-di-alkoxypyridin-2-yl, 2,5-diol
  • Alkoxypyrimidyl particular preference being given here to a methoxy group such as: 2-methoxypyridyl, 3-methoxypyridyl, 4-methoxypyridyl, 2-methoxyfuryl, 3-methoxyfuryl, 2-methoxypyrimidyl, 5-methoxypyrimidyl, 3-methoxypyrrolyl, 3.5- Di-Me1hoxypyridin-2-yl, 2,5-di-methoxypyrimidyl, etc.
  • Particularly preferred is 2-methoxyphenyl, 3-mefhoxyphenyl, A-methoxyphenyl and 2-methoxypyridyl, 3-methoxypyridyl and 4-methoxypyridyl,
  • Examples of an aminocarbonyl-substituted aryl and / or heteroaryl group preferably include aryl or heteroaryl as described above which is substituted with 1 to 3 aminocarbonyl radicals as described below, such as preferably benzylamide.
  • Examples of a cyano-substituted aryl and / or heteroaryl group preferably include aryl or heteroaryl, as described above, which is substituted with 1 to 3 cyano radicals, such as preferably benzonitrile.
  • Optionally substituted acyl includes here and below:
  • Optionally substituted amino includes within the scope of the invention preferably: amino, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, mono- or diacylamino, wherein with respect to alkyl, aryl and acyl to the corresponding above definition of optionally substituted alkyl, optionally substituted Aryl and optionally substituted acyl can be referred.
  • Mono or dialkylamino includes in particular: straight-chain or branched mono or dialkylamino having 1 to 8, preferably 1 to 4, saturated or unsaturated, optionally substituted as described above carbon atoms in each alkyl group, especially methylamines dimethylamino.
  • Optionally substituted aminocarbonyl is preferably carbamoyl (H 2 NCO) or mono- or dialkylaminocarbonyl (H (alkyl) N-CO- or (alkyl) 2 N-CO-) within the scope of the invention, wherein in terms of the definition of alkyl the above explanations for optionally substituted alkyl can be referred.
  • unsubstituted or substituted aminosulfonyl in the context of the entire invention in particular sulfamoyl (H 2 N-SO 2 -) or mono- or dialkylaminosulfonyl (alkyl) 2 N-SO 2 , wherein in terms of the definition of alkyl to the above explanations for optionally substituted alkyl can be referred.
  • R 1 is the three substituent positions (2, 3 and 4) of the quinoline skeleton indicated by the arrows
  • R 1 can be hydrogen, which means that the quinoline is unsubstituted at said positions, or R 1 can be used within the scope of Claim 1 definitions include one, two or three identical or different substitutions at said positions.
  • the compound of the formula (I) has the following substituent definitions:
  • R 1 , R 2 and R 7 are the same or different and are each selected from the group consisting of: - hydrogen,
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 4 and R 5 are the same or different and are each selected from the group consisting of:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5- to 8-membered ring which may optionally contain further heteroatoms,
  • the compound of the formula (I) has the following substituent definitions: R 1 , R 2 and R 7 are the same or different and are each selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 4 and R 5 are the same or different and are each selected from the group consisting of:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5- to 6-membered ring, which may optionally contain further Heferoatome.
  • the compound of the formula (I) has the following substituent definitions:
  • R 1 - hydrogen
  • R 4 and R 5 are the same or different and denote;
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 6-membered ring which may contain further heteroatoms;
  • the compound of the formula (I) has the following substituent definitions:
  • R 1 is hydrogen
  • R 2 is selected
  • R 3 is selected
  • R 4 and R 5 are the same or different and denote
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated, optionally substituted 6-glilene ring which contains a further heteroatom
  • R 6 means
  • R 7 is hydrogen
  • At least one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 of the compound of the formula (I) has the definition as in the two last-mentioned further preferred embodiments
  • a further preferred embodiment relates to compounds of the formula (I) having the following substituent definitions
  • R 1 , R 2 and R 7 are the same or different and are each selected from the group consisting of
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 4 and R 5 are the same or different and are each selected from the group consisting of:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5- to 6-membered ring which may optionally contain further heteroatoms,
  • the compound of the formula (I) has the following substituent definitions:
  • optionally substituted alkyl in particular optionally substituted aryl alkyl or optionally substituted heteroarylalkyl, or
  • optionally substituted acyl in particular optionally substituted aroyl or optionally substituted heteroaroyl;
  • R 4 and R 5 are the same or different and mean:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 6-membered ring which may contain further heteroatoms;
  • the compound of the formula (I) has the following substituent definitions:
  • R 1 is hydrogen
  • R 2 is selected from
  • R 3 is selected from
  • R 4 and R 5 are the same or different and mean:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated, optionally substituted 6-membered ring containing one or no further heteroatom;
  • R 7 is hydrogen
  • R 1 is preferably hydrogen (in all three positions as explained above),
  • R 2 is hydrogen or halogen, preferably chlorine
  • R 3 is hydrogen or optionally substituted acyl, especially optionally substituted aroyl or optionally substituted heteroaroyl, preferably [optionally substituted) furoyl or optionally substituted benzoyl, preferably alkoxy-substituted benzoyl, more preferably methoxy-substituted benzoyl, such as trimethoxybenzoyl
  • R 4 and R 5 are the same or different and denote
  • heteroaryl preferably pyridinyl, such as pyrrolidine or pyrrole-3-yl or
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted, 6-membered ring which may contain further heteroatoms selected from O, N, S, preferably O, preferably Morphino
  • R ⁇ is hydrogen, optionally substituted aryl, such as halogen-substituted phenyl, such as chlorophenyl, such as 4-chlorophenyl, or optionally substituted heteroaryl, such as Pyr ⁇ d ⁇ n-2-yl or Pyr ⁇ d ⁇ n-3-yl.
  • aryl such as halogen-substituted phenyl, such as chlorophenyl, such as 4-chlorophenyl, or optionally substituted heteroaryl, such as Pyr ⁇ d ⁇ n-2-yl or Pyr ⁇ d ⁇ n-3-yl.
  • R 7 is hydrogen
  • R 1 is preferably hydrogen (in all three positions as explained above)
  • R 2 is hydrogen or halogen, preferably chlorine, or morphohnylalkyl, such as preferably morpholinylmethyl
  • R 3 is hydrogen or optionally substituted Aikyi, in particular optionally substituted arylalkyl or heteroarylalkyl, preferably (optionally subsumed) benzyl, preferably alkoxy-substituted benzyl, preferred methoxy-substituted benzyl, such as trimethoxybenzyl, or R 3 is optionally substituted acyl, in particular optionally substituted aroyl or optionally substituted heteroaroyl; preferably (optionally substituted) furoyl or optionally substituted benzoyl; preferably alkoxy-substituted benzoyl, more preferably methoxy-substituted benzoyl, such as trimethoxybenzoyl,
  • R 4 and R 5 are the same or different and mean:
  • pyridinyl such as pyridin-2-yl or pyridin-3-yl or
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 6-membered ring which may contain further heteroatoms selected from O, N, S, preferably O. optionally mono- or polysubstituted by identical or different substituted morpholino, piperidine or piperazine, wherein with respect to the possible substituents of the heterocycles formed by R 4 and R 5 can be referred to the above substituent definitions, of which are particularly preferred (optionally substituted) alkyl, alkoxycarbonyl -, aryl and / or heteroaryl substituents.
  • Preferred alkyl substituents are, in particular, one or more methyl or ethyl groups, hydroxyalkyl, in particular hydroxyethyl, arylalkyl, in particular benzyl; preferred alkoxycarbonyl substituents are methoxycarbonyl or ethoxycarbonyl; preferred aryl substituents are optionally halogen-substituted phenyl, preferably chloro- or fluorophenyl; preferred heteroaryl substituents are pyridyl or pyridinyl.
  • R 4 and R 5 together with the nitrogen atom to which they are attached form morpholino, 2-, 4-dimethylmorpholino, piperidine, benzylpiperidine, Fluorophenylpiperidine, N-methylpiperazine, N-hydroxyethylpiperazole, N-benzylpiperazine, N-ethoxycarbonylpiperazine or N-pyridinylpiperazine,
  • R 6 is hydrogen, optionally substituted aryl, such as halo-substituted phenyl, such as fluorophenyl, such as 4-fluorophenyl or chlorophenyl, such as 2-chlorophenyl or 4-chlorophenyl, alkyl-substituted phenyl, such as toluyl, such as 2-folyl or 4-toluyl, alkoxy-substituted Phenyl, such as methoxyphenyl, such as 2-methoxyphenyl or 4-methylthoxyphenyl, aminocarbonyl-substituted phenyl, such as 4-benzamide, or cyano-substituted phenyl, such as benzonitrile, such as 4-benzonitrile, or optionally substituted heteroaryl, such as (optionally substituted) pyridin-2-yl or Pyridin-3-yl or pyridin-4-yl such as alkoxy-substitute
  • R 7 is hydrogen
  • the present invention also relates to novel compounds of general formula (I) with the meaning of the substituents as described above, wherein the following compounds are excluded,
  • the compounds according to the invention can exist in the presence of asymmetric carbon atoms in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the use of the enantiomers or diastereomers and their
  • the enantiomerically pure forms can optionally be obtained by conventional optical resolution methods, such as by fractionation of diastereomers thereof by reaction with optically active compounds. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses the use of all tautomeric forms
  • the asymmetric carbon atom may be present at the labeled position
  • the compounds provided according to the invention can be present as mixtures of various possible isomeric forms, in particular of stereoisomers, such as eg E- and Z-, syn and anti, as well as optical isomers. Both the E and the Z isomers, as well as the optical isomers , As well as any mixtures of these isomers claims
  • Product (V) may then optionally be derivatized under methods familiar to those skilled in the art, further to compounds of general formula (I) in which R 1 is hydrogen, in which the decomposition with R 3 ⁇ X may be carried out, for example in the presence of sodium hydride (NaH ) respectively ,
  • the substituents R 2 and R 7 of the general formula (I) are also hydrogen.
  • substituents R 2 and R 7 of the general formula (I) are also hydrogen.
  • substituted according to R 2 and / or R 7 substituted 8-hydroxyquinolines (II) are used as starting compounds or those described after Synthesis pathway compounds are then further reacted by suitable, generally known to those skilled methods to the corresponding R 2 - and / or R 7 -subsNtu faced compounds (I)
  • R 1 (mil R ' ⁇ H) substituted compounds (Ia) are exemplified by combination of a Doebner v. Miller Chinaldinsyni hese and the above Mannich reaction from Synthesis 1 accessible, the Doebner v.. Miller Chinaldinsynthese the Mannich reaction is preceded and provides the starting materials for the Mannich reaction.
  • the Friedées synthesis is based on an alkaline condensation of o-aminobenzaldehyde with the general structural formula (X) with aldehydes or ketones (XI) which have an active CH 2 group adjacent to the keto group [CCCheng, Org Rxs, 28, 1 982, 37] as shown in the reaction scheme below.
  • the Fried engineers synthesis can also be carried out acid catalylated. Especially in sterically demanding systems, this often leads to the desired product better.
  • substituted quinoline skeletons obtainable therewith can subsequently be converted into the compounds of the general structural formula (I) or, (Ia), (Ib) and (Ic) by suitable substitution reactions which are generally known to the person skilled in the art.
  • R 8 are inventively suitable and preferred substituents of the optionally substituted acyl group R 3 according to the invention, as defined in the context of the present invention, R 8 thus has the Meanings as defined above, in particular R 8 preferably has the meaning of (optionally substituted) alkyl, aryl or heteroaryl
  • the reaction routes shown here represent known reaction types, which can be carried out in a conventional manner by reacting with a pharmaceutical base or acid, corresponding salts are obtained
  • the reaction of the various reaction partners can be carried out in various solvents and is not particularly restricted in this respect.
  • suitable solvents are water, dichloroethane, dichloromethane, dimethoxyethane, diglyme, acetonitrile, butyronitrile, THF, dioxane, ethyl acetate, butyl acetate,
  • the erfmdungsgeande implementation of the reactants is carried out, for example, at room temperature. However, temperatures above room temperature, for example up to 50 0 C, and temperatures below room temperature, for example to -20 0 C or less can be applied.
  • the pH of the Doebner-Miller-Quinaldinsynthese preferably takes place by addition of an acid
  • acids can be used in principle both organic and inorganic acids are preferred inorganic acids such as HCl, HBr, HF, H 2 SO 4 , H 3 PO 4 or organic acids such as CF 3 COOH, CH 3 COOH, p-toluenesulfonic acid used.
  • inorganic acids very particularly preferably HCl and H 2 SO 4
  • It is expedient to adjust the pH in the F-terminal synthesis preferably by adding a base.
  • both organic and inorganic bases can be used as bases.
  • inorganic bases such as LiOH, NaOH, KOH, Ca (OH) 2 , Ba (OH) 2 , Li 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , NaH or organic bases such as amines (such as, for example, preferably trimethylamine (TEA), diethylisopropylamine), Bu 4 NOH, Pipe ⁇ din, Morphone, alkylpyridines used.
  • inorganic bases very particularly preferably LiOH, NaOH and KOH
  • the adjustment of the pH value is preferably carried out by adding an acid, such as preferably those mentioned above for the Doebner-V Miller's cholesterol synthesis
  • a person skilled in the art is able to select the most suitable solvent and the optimal reaction conditions, in particular with regard to temperature, pH and solvent, for the corresponding synthesis route.
  • the end product according to the invention is preferably obtained by means of preparative HPLC under neutral conditions and / or by column chromatography
  • the compounds which are the subject of the present invention and which are represented by the general structural formula (I) show an action as a hepcidin-initiator and thus for use as a medicament for the treatment of Hepcidm-mediated diseases and the concomitant or associated symptoms are particularly suitable.
  • the compounds according to the invention are suitable for use in the treatment of Iron metabolism disorders, especially for the treatment of iron deficiency diseases and / or anemias, especially in 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 for use as medicaments.
  • the compounds according to the invention are thus also suitable for the preparation of a medicament for the treatment of patients suffering from symptoms of iron deficiency such as fatigue, listlessness, lack of concentration, low cognitive efficiency, difficulty in finding the right words, forgetfulness, unnatural paleness, irritability, speeding up Heart rate (tachycardia), sore or swollen tongue, enlarged spleen, prurient pregnancy (pica), headache, loss of appetite, increased susceptibility to infection, depressive moods or suffering from ACD or AI
  • the compounds according to the invention are therefore also suitable for the preparation of a medicament for the treatment of patients who suffer from symptoms of iron deficiency
  • 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 Transfemn saturation and the Fer ⁇ tin value of the patients, or to the desired improvement of an induced by Eisenmangeianamie or by ACD or AI impairment of the Health condition
  • the preparation according to the invention can be taken by children, adolescents and adults
  • the compounds used in combination with the compounds according to the invention can be administered both orally and parenterally, or the administration of the compounds according to the invention and of the compounds used in combination can be effected by combining said 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-skeletal disorders such as, in particular, iron deficiency diseases and / or anemias, in particular anemias in cancer, anemia triggered by chemotherapy, anemia triggered by inflammation (AI).
  • iron-skeletal disorders such as, in particular, iron deficiency diseases and / or anemias, in particular anemias in cancer, anemia triggered by chemotherapy, anemia triggered by inflammation (AI).
  • Congestive heart failure (CHF), chronic kidney failure anemia, stage 3 -5 (CKD 3-5, chronic kidney diseases stage 3-5), anemia induced by chronic inflammation (ACD), anemia in rheumatoid arthritis (RA, rheumatoid arthritis), systemic lupus erythematosus (SLE, systemic lupus erythematosus) anemia, and inflammatory bowel disease (IBD) anemia, or used in the manufacture of medicaments for the treatment of these disorders
  • the compounds of the present invention can be used especially for the preparation of drugs for the treatment of iron deficiency anemia, such as iron deficiency anemia in pregnant women, latent iron deficiency anemia in children and adolescents, iron deficiency anemia due to gastrointestinal abnormalities, iron deficiency anemia of blood loss, such as gastrointestinal bleeding (eg due to ulcers, carcinomas, hemorrhoids,
  • the application according to the invention leads to an improvement of the iron, hemoglobin, ferritin and transfer values, which in particular in adolescents and children but also in adults with an improvement in short-term memory tests (STM), in long-term memory (LTM), in the test of progressive features Raven, in the Welscher Adult Concentration Scale (WAIS) and / or in the emotional coefficient (Baron EQ- ⁇ , YV-Test, youth version), or to an improvement of the neutrophil levels, the antibody levels and / or the
  • the present invention furthermore relates to pharmaceutical compositions containing one or more of the 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 excipients and / or solvents
  • Genannie pharmaceutical compositions are for example suitable for intravenous, ini rape ⁇ tonealen, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric or intracutaneous administration and are for example in the form of pills, tablets, enteric tablets, film-coated tablets, Schichttableiten, sustained release formulations for oral, subcutaneous or cutaneous administration (especially as a patch), depot formulation, dragees, suppositories, gels, ointments, syrups, granules, Supposito ⁇ en, emulsions, Dispersions, microcapsules, microformulations, nanoformulations,
  • the compounds of the invention and pharmaceutical compositions containing such compounds orally and / or parenterally, in particular administered intravenously.
  • the compounds of the invention are preferably in pharmaceutical compositions in the form of pills, tablets, enteric tablets, coated tablets, coated tablets, sustained-release formulations for oral administration, depot formulations, dragees, granules, emulsions, dispersions, microcapsules, microformulations, Nanoformuherept, hposomalen formulations, capsules, enteric Capsules, powders, microcrystalline formulations, 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 contain various organic or inorganic carriers and / or auxiliary substances, as customarily used for pharmaceutical purposes, in particular for solid Excipients (such as sucrose, starch, mannif, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate), binders (such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, Strength),
  • solid Excipients such as sucrose, starch, mannif, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate
  • binders such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, Strength
  • Disintegrant such as strong, hydrolyzed starch,
  • Carboxymethylcellulose calcium salt of carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate,
  • Liquid drug formulations such as solutions, suspensions and gels, usually contain a liquid carrier, water and / or pharmaceutically-acceptable organic solvents. Further, such liquid formulations may include pH adjuvants, emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents, gelling agents (e.g. Methylcellulose), colorants and / or flavorings.
  • the compositions may be isotonic, which may have the same osmotic pressure as blood. The isotonicity of the composition may be enhanced 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 viscose of the liquid compositions can be prepared by using a pharmaceutically acceptable thickening agent such as methylc
  • suitable thickeners include, for example, xanthan, carboxymethylcellulose,
  • 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 0.001 mg / kg to 500 mg / kg of body weight, for example up to 1 to 4 times a day, but the dosage may vary according to the age, weight, condition of the patient, severity of the disease or type of Administration be increased or decreased,
  • R 1 , R 2 and R 7 are the same or different and are each selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of
  • R 4 and R 5 are the same or different and are each selected from the group consisting of:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5- to 8-membered ring which may optionally contain further heteroatoms; or pharmaceutically acceptable salts thereof, 2, compounds according to embodiment 1, wherein
  • R 1 , R 2 and R 7 are the same or different and are each selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 4 and R 5 are the same or different and are each selected from the group consisting of:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5- to 8-membered ring which may optionally contain further heteroatoms; or pharmaceutically acceptable salts.
  • R 1 , R 2 and R 7 are the same or different and are each selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 4 and R 5 are the same or different and are each selected from the group consisting of:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 5- to 6-membered ring which may optionally contain further heteroatoms; or pharmaceutically acceptable salts thereof.
  • R 4 and R 5 are the same or different and mean:
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated or unsaturated, optionally substituted 6-membered ring which may contain further heteroatoms;
  • R 1 is hydrogen
  • R 2 is selected
  • R 3 is selected
  • R 4 and R 5 are the same or different and mean: - hydrogen
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a saturated, optionally substituted 6-membered ring containing one further heteroatom;
  • R 6 means'
  • R 7 is hydrogen, or pharmaceutically-acceptable salts thereof.
  • R 3 ⁇ X, wherein R 3 , as defined above, and X is an ordinary leaving group, such as halogen, to compounds of formula (I), , Compounds according to one or more of the embodiments 1 to 7 for use as medicaments, 0 Compounds according to one or more of the embodiments 1 to 7 for use in the treatment of Eisenrnetabolismus- disorders, especially for the application of iron deficiency diseases and / or anemias, in particular Anemia in cancer, anemia induced by chemotherapy, anemia triggered by inflammation (AI), anemia in congestive heart failure (CHF), anemia in chronic renal failure Stage 3 -5 (CDK 3-5) Anemia is caused by chronic inflammation (ACD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) anemia, and mflammatory bowel disease (IBD) anemia.
  • ACD chronic inflammation
  • RA rheumatoid arthritis
  • SLE systemic lupus erythemat
  • Arthurspraparat containing one or more of the compounds according to one or more embodiments 1 to 7 and at least one further pharmaceutically active compound, in particular a compound for the treatment of iron metabolism disorders and the associated symptoms, preferably an iron-containing compound.
  • hepcidin antagonist activity of the quinoline compounds of the present invention was determined by the "Ferroportin Internalization Assay" described below,
  • HaloTag® Promega Corp.
  • H ⁇ loT ⁇ g®-TMR fluorescent ligands
  • DMEM medium Dulbecco's Modified Eagle Medium with 10% fetal bovine serum (FBS) containing 1% penicillin, 1%
  • the volume of the medium was reduced to 10 ⁇ L, and 10 ⁇ L of 5 ⁇ M HaloTag TMR ligand (Promega, cat. No. G 8251) was added in DMEM medium to stain the Fpn-HaloTag fusion protein.
  • HaloTag TMR ligand was removed and cells were washed with
  • hepcidin (Peptides International, K ⁇ t No. PLP-4392-s, 100 ⁇ M stock solution diluted in water in DMEM medium) was added per well to a final hepcidin concentration of 100 nM
  • the cells were incubated overnight at 3 / ° C / 5% CO 2
  • the cells were fixed by adding paraformaldehyde (PFA, Electron
  • Microscopy Sciences, Cat. No. 1 571 0 S) was added directly to the cells to a final concentration of 4%, followed by incubation at room temperature for 1 5-20 min
  • Control indicator 1 00% inhibition of Fpn infernalization
  • HPLC MS high performance liquid chromatography (High Performance Liquid Chromatography) with mass spectrometry (MS)
  • HPLC with UV detection PDA, Photo Diode Array
  • UV detector 215nm (nominal)
  • Example Compound 4 was examined as a commercially available compound by analytical HPLC analogously
  • Example Compound 5 (298 mg, 78%).
  • example compound ⁇ was investigated as a commercially available compound by analytical HPLC analogously:
  • Example Compound 7 (18 mg, 11%).
  • Example Compound 10 (100 mg, 16%).
  • Example Compound 1 1 (64 mg, 10%).
  • Example Compound 1 2 (77 mg, 1 3%).
  • Example Compound 1 3 (1 8 mg, 2%).
  • Example Compound 1 4 (49 mg, 8%),
  • Example Compound 16 (270 mg, 43%).
  • Example Compound 17 (62 mg, 18%).
  • Example Compound 1 9 (200 mg, 33%)
  • Example Compound 21 (40 mg, 6%).
  • Example Compound 22 (237 mg, 5%).
  • Example Compound 23 (40 mg, 43%).
  • Example Compound 24 (24 mg, 57%).
  • FIG. 1 HPLC-MS of Example Compound 1 Figure 2: HPLC-MS of Example Compound 2 Figure 3: HPLC-MS of Example Compound 3 Figure 4 ⁇ and 4b: HPLC-MS of Example Compound 4 Figure 5: HPLC-MS of Example Compound 5 Figure 6 ⁇ and 6b: HPLC-MS of Example Compound 6 Figure 7: HPLC-MS of Example Compound 7 Figure 8: HPLC-MS of Example Compound 8 Figure 9: HPLC-MS of Example Compound 9 Figure 1 0: HPLC-MS of Example Compound 1 0 Figure 1 1 HPLC-MS of Example Compound 1 0 Figure 1 1 HPLC-MS of Example Compound 1 1 Figure 1 2: HPLC-MS of Example Compound 1 2 Figure 1 3: HPLC-MS of Example Compound 1 3 Figure 1 4: HPLC-MS of Example Compound 1 4 Figure 1 5: HPLC-MS of Example Compound 1 5 Figure 1 6: HPLC-MS of Example Compound 1 6 Figure 1 8: HPLC-MS of Example Compound 1 8 Figure 1 9: HPLC-MS of Example Com

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Abstract

La présente invention concerne de nouveaux antagonistes d'hepcidine de la formule (I), des compositions pharmaceutiques les contenant et leur utilisation comme médicament, notamment pour le traitement de troubles du métabolisme du fer, par exemple, des maladies liées au manque de fer et anémies, notamment des anémies dans le contexte de maladies inflammatoires chroniques (anémie de maladie chronique - ACD - et anémie de l'inflammation - AI- ).
EP10743174A 2009-08-20 2010-08-19 Nouveaux antagonistes de chinoline-hepcidine Withdrawn EP2467361A1 (fr)

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PCT/EP2010/062117 WO2011020886A1 (fr) 2009-08-20 2010-08-19 Nouveaux antagonistes de chinoline-hepcidine

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US8658170B2 (en) 2010-01-06 2014-02-25 Joseph P. Errico Combination therapy with MDM2 and EFGR inhibitors
CA2786277A1 (fr) * 2010-01-06 2011-07-14 Joseph P. Errico Methodes et compositions pour le developpement de medicaments cibles
US20150150869A1 (en) * 2012-06-20 2015-06-04 Eutropics Pharmaceuticals, Inc. Methods and compositions useful for treating diseases involving bcl-2 family proteins with quinoline derivatives
WO2014081953A1 (fr) 2012-11-21 2014-05-30 Richard David J Méthodes et compositions utiles dans le traitement de maladies faisant appel à des protéines de la famille bcl-2 et des dérivés d'isoquinoléine et de quinoléine
TR201802305T4 (tr) * 2012-12-24 2018-03-21 Cadila Healthcare Ltd Kinolon türevleri.
US10732182B2 (en) 2013-08-01 2020-08-04 Eutropics Pharmaceuticals, Inc. Method for predicting cancer sensitivity
JP6538044B2 (ja) 2013-10-30 2019-07-03 ユートロピクス ファーマシューティカルズ， インコーポレイテッド 化学療法感受性および化学毒性を判定する方法
HUP1500098A2 (hu) * 2015-03-09 2016-09-28 Avidin Kft 8-hidroxikinolin származékok új enantiomerjei és szintézisük
WO2020061476A1 (fr) * 2018-09-21 2020-03-26 Jnana Therapeutics, Inc. Petites molécules ciblant des protéines mutantes de mammifères
CN109797128A (zh) * 2019-01-14 2019-05-24 浙江大学 一种急性细胞铁过载模型的构建方法
WO2024073624A2 (fr) * 2022-09-28 2024-04-04 The Research Foundation For The State University Of New York Bases de betti antiprolifératives et promédicaments de celles-ci

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AR077892A1 (es) 2011-09-28
WO2011020886A1 (fr) 2011-02-24
TW201109324A (en) 2011-03-16
BR112012003701A2 (pt) 2019-09-24
US20120196853A1 (en) 2012-08-02
CN102574805A (zh) 2012-07-11

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