WO2013092674A1 - Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof - Google Patents

Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof Download PDF

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Publication number
WO2013092674A1
WO2013092674A1 PCT/EP2012/076101 EP2012076101W WO2013092674A1 WO 2013092674 A1 WO2013092674 A1 WO 2013092674A1 EP 2012076101 W EP2012076101 W EP 2012076101W WO 2013092674 A1 WO2013092674 A1 WO 2013092674A1
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alkyl
denotes
group
amino
phenyl
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PCT/EP2012/076101
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French (fr)
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Armin Heckel
Andreas Blum
Dieter Hamprecht
Joerg Kley
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Boehringer Ingelheim International Gmbh
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Priority to JP2014547960A priority Critical patent/JP6110872B2/en
Priority to EP12805685.0A priority patent/EP2794595B1/en
Publication of WO2013092674A1 publication Critical patent/WO2013092674A1/en

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    • 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
    • C07D401/12—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to compounds of general formula (I)
  • WO 08135557 discloses compounds of similar structure showing ENaC (Epithelial Sodium Channel) inhibitor activity.
  • the problem of the present invention is to prepare new compounds which may be used therapeutically for the treatment of pathophysiological processes treatable by the blockade of an epithelial sodium channel, particularly for the treatment of the lungs and airways.
  • the present invention therefore relates to a compound of formula (I),
  • R 1 denotes H or Ci -4 -alkyl
  • R 2 denotes H or Ci -4 -alkyl
  • R 3 denotes H or methyl
  • R 4 denotes H or methyl
  • R 5 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • H 2 C CH-CH 2 -0-, HC ⁇ C-CH 2 -0- and -NR 6'1 R 6'2 ,
  • R 6 - 1 denotes H, C 1-4 -alkyl-, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -,
  • R 6 2 denotes H or Ci -4 -alkyl-
  • R 7 is selected from the group consisting of
  • Ci -4 -alkyl- which is optionally substituted by one or more F atoms, HC ⁇ C-, OH, Ci -4 -alkyl-0-, HO-CH 2 -,
  • H 2 C CH-CH 2 -0-, HC ⁇ C-CH 2 -0-, -NR 7 I R 7 - 2 , H 2 N-C(NH)-, H 2 N-C(NH)NH-,
  • R 7 - 1 denotes H, C 1-4 -alkyl-, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -,
  • R 7'2 denotes H or Ci -4 -alkyl-
  • R 7'3 , R 7'4 independently from each other denote H or Ci -4 -alkyl, is selected from the group consisting of
  • Ci -4 -alkyl- which is optionally substituted by one or more F atoms, HC ⁇ C-, OH, Ci -4 -alkyl-0-, HO-CH 2 -,
  • H 2 C CH-CH 2 -0-, HC ⁇ C-CH 2 -0-, -NR 8 1 R 8 2 ,
  • Ci -4 -alkyl-COOH - Ci -4 -alkyl-COO- C 1-4 -alkyl, -OCH 2 -COOH, -OCH 2 -COO- C 1-4 -alkyl, -P(0)(OR 8 3 )(OR 8 - 4 ), -CH 2 -P(0)(OR 8 3 )(OR 8 - 4 ) and -B(OH) 2 ,
  • R 8 - 1 denotes H, C 1-4 -alkyl, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -,
  • R 8 2 denotes H or Ci -4 -alkyl
  • R 8'3 , R 8'4 independently from each other denote H or Ci -4 -alkyl
  • R 10 , R 8'5 independently from each other are selected from the group consisting of
  • R 10 , R 8 5 are not selected from the group consisting of B(OH) 2 , BF 3 and -S(0) 2 OH 8.5.1 denotes H, Ci -4 -alkyl, Ci -4 -alkyl-CO- or Ci -4 -alkyl
  • R 8 - 5 - 2 denotes H or C 1-4 -alkyl
  • R 8 - 5 - 3 denotes methyl or ethyl
  • R 9 denotes H or methyl
  • m, n independently from each other with the proviso that (m + n) ⁇ 4 , denote 0, 1 or 2
  • X denotes halogen
  • L 1 denotes a bond or is selected from the group consisting of
  • L 2 denotes a bond or is selected from the group consisting of -0-, -CH 2 -, -CH 2 -CH 2 -, -CH2O-, -CO-, -S-, -SO-, -S0 2 -, -S-CH 2 -, -SO-CH 2 - and -S0 2 -CH 2 -, L 2 denotes a bond or is selected from the group consisting of -0-, -CH 2 -, -CH 2 -CH 2 -,
  • L 3 , L 4 , L 5 independently from each other denote a bond or a linear chain of formula (m)
  • i denotes 0, 1 , 2, 3 or 4,
  • g1 , g2, g3 independently from each other denote 2, 3 or 4,
  • p1 , p3 independently from each other denote 0, 1 , 2, 3 or 4, p2 denotes 0 or 1 ,
  • the linear chain is consisting of 1 to 15 moieties selected from the group consisting of -CH 2 -, -O- and -NH- and with the proviso that the nitrogen atom of formula (m) is not directly linked to another nitrogen atom,
  • Y 1 denotes a bond, Y 1 '1 or -NR Y1 I -,
  • R Y1 '1 denotes L 3 -H or L 3 -NR Y1 '1 '1 R Y1 '1 '2 ,
  • R Y1 '1 '1 is selected from among
  • R Y1 - 1 - 2 denotes H or C 1-4 -alkyl-
  • R Y2.1.2 denotes H or Ci -4 -alkyl-
  • Y2. i .2 together with the nitrogen atom they are attached to form a heterocycle Y 3 , independently from each other denote a linker in form of a phenylene group optionally substituted by -L 5 R 10 , or
  • an optionally substituted heteroaromatic or heterocyclic moiety each containing at least one nitrogen atom denotes an optionally substituted 4-7-membered heterocycle containing at least one N-atom
  • the pharmacologically acceptable acid addition salts thereof preferably, the pharmacologically acceptable acid addition salts thereof.
  • Preferred compounds of formula (I) are those wherein
  • X denotes CI or Br
  • Y 1'1 , Y 2'1 independently from each other denote a bond or are selected from a group consisting of a linker of formula (a) to (k)
  • G denotes pyrrolidine or piperidine, each optionally substituted by up to two substituents independently selected from hydroxy or Ci -3 -alkoxy, or
  • Y denotes morpholine, piperazine, 4-methyl-piperazine, 4-ethyl-piperazine, 4-acetyl- piperazine or 4-propionyl-piperazine.
  • R 9 denotes H
  • L 1 denotes a bond, -CH 2 -, -CH 2 0- or -CO-, and
  • n independently from each other with the proviso that 0 ⁇ (m + n) ⁇ 4 , denote 0, 1 or 2, Y 3 denotes morpholine, 4-acetyl-piperazine or 4-propionyl-piperazine.
  • R 7 3 denotes H, R is selected from the group consisting of
  • H 2 C CH-CH 2 -0-, HC ⁇ C-CH 2 -0- and -NR 8 I R 8 - 2 ,
  • R 8 - 1 denotes H, C 1-4 -alkyl-, C ⁇ -alkyl-CO- or Ci -4 -alkyl-S0 2 -,
  • R 8 2 denotes H or Ci -4 -alkyl-
  • R 8 - 1 and R 8 2 together with the nitrogen atom they are attached to form a heterocycle Y 3 .
  • R 7 is selected from the group consisting of
  • R 7 3 , R 7 4 independently from each other denote methyl, ethyl or 2-propyl
  • R 8 is selected from the group consisting of
  • H 2 C CH-CH 2 -0-, HC ⁇ C-CH 2 -0- and -NR 8' R 8'2 ,
  • R 8 - 1 denotes H, C 1-4 -alkyl-, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -,
  • R 8 2 denotes H or Ci -4 -alkyl-
  • L 3 , L 4 independently from each other denote a bond, -CH 2 - or -CH 2 -CH 2 -,
  • R 8 denotes -L 2 -Y 1 -L 3 -Y 2 -L 4 -R 8 5 ,
  • R 8 - 5 denotes -NH 2 or -N + (R 8 - 5 - 3 ) 3 ,
  • R 8 - 5 - 3 denotes methyl or ethyl
  • R 10 denotes a hydrogen atom
  • L 2 denotes -CO- and Y 1 denotes -NR Y1 I -
  • L 2 denotes -CH 2 -CH 2 -
  • Y 1 denotes Y 1 - 1 ,
  • Y 1'1 is selected from a group consisting of linkers of formula (c), (d), (e), (f) and (k)
  • R 7 is selected from the group consisting of
  • R 8'5 is selected from the group consisting of H, OH, -C(CH 2 OH) 3 ,
  • L 2 denotes a bond, -CH 2 -CH 2 - or -0-CH 2 - ,
  • L 4 denotes a linear chain of formula (m.1):
  • i denotes 0, 1 , 2, or 3,
  • g1 denotes 2, or 3
  • p1 denotes 0, 1 or 2
  • R 8'5 denotes OH or Ci -4 -alkyl-0-
  • (i+ p1) >0
  • R 8'5 denotes H
  • p1 >0
  • the linear chain or formula (m.1) is consisting of no more than 8 moieties selected from the group consisting of -CH 2 - and -O- . denotes a bond
  • Y 2'1 is selected from a roup consistin of linkers of formula (c), (d), (e), (f) and (k)
  • L 3 , L 4 independently from each other denote a bond or a linear chain of formula (m)
  • i denotes 0, 1 , 2 or 3,
  • g1 denotes 2, 3 or 4,
  • g2 denotes 0,
  • g3 denotes 2, or 3
  • p1 denotes 0 or 1
  • p3 denotes 2, 3 or 4,
  • p2 denotes 0,
  • linear chain is consisting of 5 to 12 moieties selected from the group consisting of -CH 2 - and -O- , and
  • L 3 and L 4 together consist of at least eight -CH 2 - moieties and of at least four -O- moieties
  • Y 1 denotes Y 1 - 1 , wherein
  • ⁇ 1.1 denotes a linker of formula (e) or (f)
  • Y 2 denotes a bond
  • Y 2'1 , -Y 2 , -CONR Y2 - 1 - and -NR Y2 , -CO-Y 2 ⁇ R 8 - 5 denotes H, OH or -OCH 3 ,
  • R ⁇ R 2 , R 3 , R 4 , R 5 denote H
  • R 7 denotes H or halogen
  • R 9 denotes H
  • L 1 denotes a bond
  • L 2 denotes -CO- or -S0 2 -
  • R Y1 I denotes hydrogen
  • R ⁇ R 2 , R 3 , R 4 , R 5 denote H
  • R 7 denotes H or halogen
  • R 9 denotes H
  • L 1 denotes a bond
  • Y 1 denotes Y 1 - 1 ,
  • Y 1 - 1 is selected from a group consisting of linkers of formula (e) and (f)
  • a further embodiment of the current invention are compounds of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a further embodiment of the current invention are compounds of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways.
  • a further embodiment of the current invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a further embodiment of the current invention are medicament combinations which contain, besides one or more compounds of a compound according to the invention, as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR- inhibitors, dopamine agonists, H1 -antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-lnhibitors, iNOS-lnhibitors, SYK-lnhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations thereof, preferably VX-770 and VX-809, or double or triple combinations thereof.
  • CFTR cystic fibrosis transmembrane regulator
  • Ci -6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • radical attachment point(s) to the molecule from the free valences of the group itself.
  • the terminal bond indicates the radical attachment point, for example, the substituent "aryl-Ci -3 -alkyl-" means an aryl group which is bound to a Ci -3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • 3-carboxypropyl-group represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group.
  • the terms "1 -methylpropyl-", “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:
  • the asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. Many of the following terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, di- astereomers, E/Z isomers etc ..) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
  • lower- molecular groups regarded as chemically meaningful are groups consisting of 1 -200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds.
  • the groups may comprise:
  • Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may in turn be substituted by functional groups.
  • a number of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms which may be linked by one or more carbon chains, optionally interrupted by heteroatoms, optionally substituted by heteroatoms or other common functional groups.
  • prevention means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease.
  • the purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.
  • treatment means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof.
  • treatment of a disease means the management and care of a patient having developed the disease, condition or disorder.
  • the purpose of treatment is to combat the disease, condition or disorder.
  • Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carbox- ylic acids; and the like.
  • such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2'- iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N- ethyl-glucamine, hydrabamine, 1 H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)- morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2- dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulf
  • salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1 -19).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention e.g. trifluoro acetate salts, also comprise a part of the invention.
  • prodrug refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).
  • prodrug or “prodrug derivative” mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
  • prodrugs either have me- tabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups.
  • Most common prodrugs include esters and amide analogs of the parent compounds.
  • prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
  • Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991 , particularly Chapter 5: "Design and Applications of Prodrugs”; Design of Prodrugs, H.
  • pharmaceutically acceptable prodrug means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
  • aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
  • Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phe- nanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
  • heterocycle is intended to include all the possible isomeric forms.
  • heterocyclyl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • heteroaromatic means heteroaryl, monocyclic C 5 - 6 -heteroaryl, or monocyclic C 5- 6-heteroaryl.
  • heteroaryl is intended to include all the possible isomeric forms.
  • heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • monocyclic C 5 -7-heterocyclyl is intended to include all the possible isomeric forms.
  • monocyclic C 5 -7-heterocyclyl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • monocyclic C5- 6 - heteroaryl is intended to include all the possible isomeric forms.
  • monocyclic C 5 - 6 -heteroary includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • bicyclic C 8 -io-heterocyclyl is intended to include all the possible isomeric forms.
  • bicyclic C 8 -io-heterocyclyl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • annelated species of aryl or heterocyclyl as used herein, either alone or in combination with another substituent wherein the annelated species presents as an aryl-het (a), a het- aryl (b) or a het-het (c) annelation means a monovalent substituent derived by removal of one hydrogen from
  • an aromatic monocyclic system or aromatic multicyclic systems containing carbon atoms which is annelated to a five-, six- or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur or
  • a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur which is annelated to a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Suitable examples of a annelated species of aryl or het include: quinolinyl, 1-indoyl, 3-indoyl, 5-indoyl, 6-indoyl, indolizinyl, benzimidazyl or purinyl.
  • halogen as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.
  • Ci- n -alkyl wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • Ci -5 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2"CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-, H3C-CH2"CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-,
  • n is an integer 2 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms.
  • Ci -4 -alkylene includes -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH2-CH2-CH2-, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, -CH2-CH2-CH2-, -CH2"CH2-CH(CH3)-, -CH(CH3)-CH2-CH2", -CH2-CH(CH3)-CH2-,
  • C2- n -alkenyl is used for a group as defined in the definition for "Ci -n -alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
  • C 2 - n -alkenylene is used for a group as defined in the definition for "Ci -n -alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
  • C2- n -alkynyl is used for a group as defined in the definition for "Ci -n -alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
  • C 2 - n -alkynylene is used for a group as defined in the definition for "Ci -n -alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
  • Ci -6 -alkoxy (including those which are part of other groups) are meant branched and unbranched alkoxy groups with 1 to 6 carbon atoms and by the term “Ci -4 -alkoxy” are meant branched and unbranched alkoxy groups with 1 to 4 carbon atoms. Alkoxy groups with 1 to 4 carbon atoms are preferred.
  • Examples include: methoxy, ethoxy, propoxy, butoxy or pen- toxy.
  • the abbreviations OMe, OEt, OPr, etc. may optionally be used for the above-mentioned groups.
  • the definitions propoxy, butoxy and pentoxy include all the possible isomeric forms of the respective groups.
  • propoxy includes n-propoxy and / ' so-propoxy, butoxy includes / ' so-butoxy, sec-butoxy and ie f-butoxy etc.
  • C 3 - n -cycloalkyl wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
  • C 3- 7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl and cycloheptyl.
  • C 3 - n -cycloalkenyl wherein n is an integer 3 to n, either alone or in combination with another radical, denotes an cyclic, unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to n C atoms, at least two of which are bonded to each other by a double bond.
  • C 3- 7-cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl cycloheptadienyl and cyclohep- tatrienyl.
  • the substituent R 1 denotes H or Ci -4 -alkyl, preferably methyl or H, particularly preferred hydrogen.
  • the substituent R 2 denotes H or Ci -4 -alkyl, preferably methyl or H, particularly preferred hydrogen.
  • the substituent R 3 denotes H or methyl, preferably hydrogen.
  • the substituent R 4 denotes H or methyl, preferably hydrogen
  • the substituent R 5 is selected from the group consisting of
  • Ci -4 -alkyl-0-CO- and Ci -4 -alkyl particularly preferred H.
  • R 6 - 1 denotes H, C 1-4 -alkyl-, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -, preferably H, C 1-2 -alkyl-, Ci -2 -alkyl-CO- or Ci -2 -alkyl-S0 2 -, particularly preferred Ci -2 -alkyl-CO- or Ci -2 -alkyl-S0 2 -, R 6'2 denotes H or Ci -4 -alkyl-, preferably H or CH 3 -alkyl-, particularly preferred H.
  • the substituent R 7 is selected from the group consisting of
  • Ci -4 -alkyl-COOH - Ci -4 -alkyl-COO- C 1-4 -alkyl, -OCH 2 -COOH, -OCH 2 -COO- C 1-4 -alkyl,
  • R 7 - 1 denotes H, C 1-4 -alkyl-, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -, preferably H, C 1-2 -alkyl-, Ci -2 -alkyl-CO- or Ci -2 -alkyl-S0 2 -, particularly preferred Ci -2 -alkyl-CO- or Ci -2 -alkyl-S0 2 -, R 7'2 denotes H or Ci -4 -alkyl-, preferably H or CH 3 -alkyl-, particularly preferred H or
  • R 7'3 , R 7'4 independently from each other denote H or Ci -4 -alkyl, preferably H, methyl, ethyl or 2-propyl, particularly preferred H, methyl or ethyl.
  • the substituent R 8 is selected from the group consisting of
  • H particularly preferred H, halogen, CN, CH 3 -alkyl-, OH, CH 3 -alkyl-0-, -COOH, C 1-2 -alkyl- OCO-, CH 2 COOH, -(CH 2 ) 2 COOH, -CH 2 COO- C 1-2 -alkyl, -(CH 2 ) 2 COO- C 1-2 -alkyl, -OCH 2 - COOH and -OCH 2 -COO- C 1-2 -alkyl,
  • R 8 - 1 denotes H, C 1-4 -alkyl, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -, preferably H, C 1-2 -alkyl-,
  • Ci -2 -alkyl-CO- or Ci -2 -alkyl-S0 2 - particularly preferred Ci -2 -alkyl-CO- or Ci -2 -alkyl- S0 2 -,
  • R 8'2 denotes H or Ci -4 -alkyl preferably H or CH 3 -alkyl-, particularly preferred H or
  • H preferably H, methyl, ethyl or 2-propyl, particularly preferred H, methyl or ethyl,
  • R 8 - 5 - 1 denotes H, C 1-4 -alkyl, Ci -4 -alkyl-CO- or Ci -4 -alkyl-S0 2 -,
  • R 8'5'1 and R 8'5'2 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N-atom
  • pyrrolidine preferably pyrrolidine, piperidine, piperazine, 4-methylpiperazine, 4- acetylpiperazine or morpholine, particularly preferred piperazine, 4- methylpiperazine, 4-acetylpiperazine or morpholine,
  • R8.5.3 denotes methyl or ethyl, preferably methyl.
  • the substituent R 9 denotes H or methyl, preferably H.
  • X denotes halogen, preferably CI or Br, particularly preferred CI.
  • L 1 denotes a bond or is selected from the group consisting of
  • L 2 denotes a bond or is selected from the group consisting of -0-, -CH 2 -, -CH 2 -CH 2 -, -CH2-O-, -O-CH2-, -CO-, -CH2-CO-, -CO-CH2-, -S-, -SO-, -SO2- and -O-CO-, preferably a bond, -0-, -CH2-, -CH 2 -CH 2 -, -CH 2 -0-, -0-CH 2 -, -CO- and -S0 2 -, particularly preferred a bond, -CH2-, -CH 2 -CH 2 -, -CO - and -S0 2 -.
  • i denotes 0, 1 , 2, 3 or 4, preferably 0, 1 , 2, or 3, particularly
  • g1 , g2, g3 independently from each other denote 2, 3 or 4, preferably 2 or 3, particularly preferred 2,
  • p1 , p3 independently from each other denote 0, 1 , 2, 3 or 4, preferably 0,
  • P2 denotes 0 or 1 , preferably 0, with the provisio that the linear chain consists of 1 to 15 moieties, preferably 1 to 6, particularly preferred 1 to 3 moieties, selected from the group consisting of - CH 2 -, -O- and -NH- and with the proviso that the nitrogen atom of formula (m) is not directly linked to another nitrogen atom.
  • Y 1 denotes a bond, Y 1'1 or -NR Y1 I -,
  • R Y1 I denotes L 3 -H or L 3 -NR Y1 '1'1 R Y1 - 1 - 2 , preferably L 3 -H, particularly preferred H,
  • R Y1 '1'1 is selected from among
  • Ci-4-alkyh Ci -4 -alkyl-CO- and Ci -4 -alkyl-S0 2 - preferably H, C 1-2 -alkyl- Ci-2-alkyl-CO- and Ci-2-alkyl-S0 2 -, particularly preferred H, CH 3 -alkyl- CO- and CH 3 -alkyl-S0 2 -,
  • R Y1 I 2 denotes H or Ci -4 -alkyl-, preferably H or -CH 3 , particularly preferred H,
  • R Y1 '1'1 and R Y1 - 1 - 2 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N-atom, preferably pyrrolidine, piperidine, piperazine, 4- methylpiperazine, 4-acetylpiperazine and morpholine.
  • Y 2 denotes a bond
  • R Y2 I denotes L 3 -H or L 3 -NR Y2'1'1 R Y2 I - 2 , preferably L 3 -H,
  • R Y2'1'1 is selected from among
  • Ci-4-alkyh Ci -4 -alkyl-CO- and Ci -4 -alkyl-S0 2 - preferably H, C 1-2 -alkyl-, Ci -2 -alkyl-CO- and Ci -2 -alkyl-S0 2 -, particularly preferred H, CH 3 -alkyl-CO and CH 3 -alkyl-S0 2 -, Y2. i .2 (jgnotgg H or Ci-4-alkyl-, preferably H or CH 3 -alkyl-, particularly preferred H,
  • Y2. i .2 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N- atom, preferably selected from the group consisting of pyrrolidine, piperi- dine, piperazine, 4-methylpiperazine, 4-acetylpiperazine and morpholine,
  • Y 1'1 , Y 2'1 independently from each other denote a linker in the form of a phenylene group optionally substituted by -L 5 R 10 , preferably a linker in the form of an unsubstituted phenylene, or
  • Y 1'1 , Y 2'1 independently from each other are selected from a group consisting of a linker of formula (a) to (k)
  • linker of formula (a), (e), (f) or (k).
  • the compounds according to the invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. General methods for functional groups protection and deprotection steps are described e.g. in: Greene, T. W. and Wuts, P.G.M. (eds.): Protective Groups in Organic Synthesis, third edition 1999; John Wiley and Sons, inc.. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.
  • Compounds of general formula (I) can be prepared by reacting S-methylisothioureas of formula (II) with primary amines of formula (III) in a solvent like THF, acetonitrile or DMF or in a solvent mixture, preferably in the presence of a base, especially when the primary amine (III) is applied as an acid addition salt, preferably at r.t.( room temperature).
  • Compounds of general formula (II) can be prepared by reacting S-methylisothiourea (which may be generated in situ from its sulphuric acid salt by addition of base) with a 1 -(tert- butylcarbamoyl)prop1 -en-2-yl carboxylate of general formula (IV) in a solvent like DCM, THF, water or a mixture of these solvents, preferably at r.t.
  • Compounds of general formula (IV) can be prepared from the respective carboxylic acid of general formula (V) and a 2-tert-butyl-5- methyl-isoxazolium salt of general formula (VI), which can be applied as an isolated salt (e.g.
  • hexafluorophosphate salt PF 6
  • X PF 6
  • the latter reaction is preferably performed in a solvent like DMF or in a solvent mixture with the addition of triethylamine or another base, preferably while cooling to 0-10 °C.
  • Compounds of general formula (III) can be prepared from compounds of general formula (VII) by removal of the respective protecting group, preferably the BOC or FMOC protecting group which can be removed by standard acidic or basic conditions, respectively.
  • Compounds of general formula (VII) can be modified using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis, preferably by functional group protection or deprotection steps, esterifications, amidations, hydrogenations, or 1 ,3- dipolar cycloadditions of an azide to a terminal alkyne group or vice versa.
  • Compounds of general formula (I) can be converted into intermediates of general formula (XI) by BOC-protection.
  • Compounds of general formulas (I) or (XI) can be modified using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis, preferably by functional group protection or deprotection steps, esterifications, amida- tions, hydrogenations, or 1 ,3-dipolar cycloadditions of an azide to a terminal alkyne group or vice versa. After such modification steps, the BOC protecting group in compounds of general formula (XI) can be removed again by standard acidic deprotection conditions to yield modified compounds of general formula (I).
  • the compound may exist as a free base or a salt, depending on the synthesis conditions and the processes of workup and purification applied.
  • the skilled person will appreciate that the compound is not limited to the free base or a certain salt form.
  • the stoichiometry of the counterion is usually omitted.
  • the compound is not limited to the mono salt form and that it may exist as a disalt, trisalt or other compound:counterion
  • Methanesulphonyl chloride (426 ⁇ ; 5.50 mmol) is added carefully to a mixture of the trityl ether 1.1 (2.18 g; 5.00 mmol) and triethylamine (1 .85 ml; 13.2 mmol) in DCM (20 ml). The mixture is stirred for 2 h, then extracted with water. The organic layer is separated and evaporated. Aceto- nitrile (20 ml), the diphenol intermediate III.4 (780 mg; 2.20 mmol) and potassium carbonate (913 mg; 6.60 mmol) are added, and the mixture is refluxed overnight. Water is added and the mixture is extracted with DCM. The organic layer is separated, dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / (methanol : aqueous ammonia 9:1 ) 100:0 85:15 to yield the title compound.
  • Methanesulphonyl chloride (276 ⁇ ; 3.57 mmol) is added carefully to a mixture of the trityl ether intermediate 1.3 (1.00 g; 2.55 mmol) and triethylamine (715 ⁇ ; 5.60 mmol) in DCM (10 ml). The mixture is stirred overnight, then extracted with water. The organic layer is separated and evaporated. Acetonitrile (10 ml), triethylamine (715 ⁇ ; 5.60 mmol) and 1 -amino-1 1 -azido-3,6,9- trioxaundecane (850 mg; 3.90 mmol) is added and the mixture is refluxed for 4 h. The mixture is evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / (methanol : aqueous ammonia 9:1 ) 100:0 90:10 to yield the title compound.
  • Stage 1 A mixture of the halide methyl-4-(bromomethyl)-3-methoxy-benzoate (0.50 g; 1.93 mmol), the amine tert-butyl N-(piperidin-4-yl)carbamate (0.386 g; 1 .93 mmol) and triethylamine
  • Stage 2 (removal of BOC protecting group): A mixture of Methyl 4-[(4- ⁇ [(tert- butoxy)carbonyl]amino ⁇ piperidin-1 -yl)methyl]-3-methoxybenzoate and HCI in dioxane (4 mol/l;
  • the following compounds are prepared accordingly from starting materials as indicated.
  • the amine component applied is tert-butyl N-(piperidin-4-yl)carbamate.
  • the syntheses may yield a free base, a hydrochloride or dihy- drochloride salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
  • Stage 1 Methanesulphonyl chloride (0.929 ml; 12 mmol) is added to an ice-cold mixture of the alcohol (4-prop-2-ynyloxy-phenyl)-methanol (1.62 g; 10 mmol) and triethylamin (2.81 ml; 20 mmol) in DCM (20 ml). After stirring overnight, the amine tert-butyl N-(piperidin-4-yl)carbamate (4.01 g; 20 mmol) is added. After further stirring overnight, water is added. The organic phase is separated, dried with magnesium sulphate, filtered and evaporated.
  • Stage 2 The BOC protecting group is removed as described for compound X.1 to yield 1 - ⁇ [4- (prop-2-yn-1 -yloxy)phenyl]methyl ⁇ piperidin-4-amine as a hydrochloride salt.
  • the following compounds are prepared accordingly from starting materials as indicated. Unless stated otherwise, the amine component applied is tert-butyl N-(piperidin-4-yl)carbamate. Due to conditions applied, the syntheses may yield a free base, a hydrochloride or dihydrochloride salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
  • Stage 1 A mixture of the aldehyde methyl 3-formyl-5- ⁇ [2-(2-hydroxyethoxy)ethyl]-carbamoyl ⁇ - benzoate (4.51 g; 12.2 mmol) (which is prepared beforehand by amidation of Methyl 3-formyl-5- hydroxycarbonyl-benzoate with 2-(2-Hydroxyethoxy)-ethylamine using HATU as coupling reagent) and tert-butyl N-(piperidin-4-yl)carbamate (3.67 g; 18.3 mmol) in THF (50 ml) is refluxed for 3h. Glacial acetic acid (approx. 2 ml) is added to adjust at pH5.
  • the following compounds are prepared accordingly from starting materials as indicated. Unless stated otherwise, the amine component applied is tert-butyl N-(piperidin-4-yl)carbamate. Due to conditions applied, the syntheses may yield a free base, a hydrochloride or dihydrochloride salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
  • Stage 1 A mixture of 4-[(4- ⁇ [(tert-butoxy)carbonyl]amino ⁇ piperidin-1 -yl)methyl]benzoic acid (Intermediate XIII.1 ; 3.00 g; 8.97 mmol), TBTU (3.20 mg; 9.97 mmol) and triethylamine (1 .40 ml; 10.0 mmol) in DMF (50 ml) is stirred for 5 min. The amine 3-(2-aminoethyl)-pyridine (1 .06 ml; 9.00 mmol) is added. After further 3h stirring, the solvent is evaporated and the residue is taken up in DCM and washed with sodium carbonate solution. The organic layer is dried over sodium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography
  • Stage 2 The BOC protecting group is removed as described for intermediate X.1 to yield N-[1 - ( ⁇ 4-[(2-(3-pyridyl)-ethylamino)carbonyl]phenyl ⁇ methyl)piperidin-4-yl]amine.
  • the crude product is further purified by RP HPLC (modifier: TFA) to yield the title compound as a TFA salt.
  • the syntheses may yield a free base, a TFA salt or bis-TFA salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
  • the amine starting material is prepared by amidation of 4-(2- methoxyethoxy)benzoic acid with 2-[2-(2-aminoethoxy)ethoxy]ethan-1 -amine (TBTU coupling) and subsequent removal of the BOC protecting group using TFA in DCM.
  • Stage 1 To a solution of 4-(chloromethyl)benzoyl chloride (2.00 g; 10.6 mmol) in THF (30 ml) are added 5-hexyn-1 -ol (1.18 ml; 10.6 mmol) and DMAP (0.1 g; 0.82 mmol). The mixture is ref- luxed overnight with stirring. BOC-4-aminopiperidine (2.33 g; 1 1.6 mmol) and triethylamine (3.24 ml; 23.3 mmol) are added and the mixture is refluxed for further 3 h. Ethyl acetate (200 ml) and water (50 ml) are added.
  • Stage 2 The BOC protecting group is removed as described for intermediate X.1 to yield Hex-5- yn-1 -yl 4-[(4-aminopiperidin-1 -yl)methyl]benzoate as a hydrochloride salt.
  • Stage 1 A mixture of ⁇ 4-[(4- ⁇ [(tert-butoxy)carbonyl]amino ⁇ piperidin-1 -yl)methyl]phenyl ⁇ boronic acid (800mg; 2.39 mmol; prepared as described for the synthesis of intermediate X.7 without BOC deprotection step), ethyl 6-hydroxypyridine-3-carboxylate (420 mg; 2.51 mmol), copper(ll) acetate (250 mg; 1.38 mmol) and pyridine (210 ⁇ ; 2.60 mmol) in DCM (10 ml) is stirred overnight. The mixture is filtered and extracted with water. The organic layer is dried with sodium sulphate, filtered and evaporated.
  • Stage 1 To a mixture of 1 -azido-3,6,9-trioxaundecane-1 1 -ol (220 mg; 0.98 mmol) and triethy- lamine (550 ⁇ ; 3.92 mmol) in DCM (5 ml) is added methanesulphonyl chloride (250 ⁇ ; 3.23 mmol). After stirring for 2 h water is added. The organic layer is separated at evaporated.
  • Ace- tonitrile (5 ml), tert-butyl N- ⁇ 1 -[(4-hydroxyphenyl)methyl]piperidin-4-yl ⁇ carbamate (300 mg; 0.98 mmol; ; prepared as described for the synthesis of intermediate XII.4 without BOC deprotection step) and potassium carbonate (410 mg; 2.97 mmol) are added and the resulting mixture is ref- luxed overnight.
  • the mixture is evaporated to dryness, taken up in water and extracted with DCM.
  • the organic layer is dried with magnesium sulphate, filtered and evaporated.
  • Stage 2 The BOC protecting group is removed as described for XVI.1 (stage 2) to yield 1 - ⁇ [4- (5,8,1 1 -trioxa-1 ,2-diazatridec-1 -en-13-yloxy)phenyl]methyl ⁇ piperidin-4-amine as a TFA salt.
  • Stage 1 A mixture of 4-[(4- ⁇ [(9H-fluoren-9-ylmethoxy)carbonyl]amino ⁇ piperidin-1 - yl)methyl]benzoic acid (1.20 g; 2.63 mmol), TBTU (1 .01 g; 3.15 mmol) and DIPEA (1 .8 ml; 3.15 mmol) in DMF (10 ml) is stirred for 5 min.
  • tert-Butyl N- ⁇ 2-[2-(2- aminoethoxy)ethoxy]ethyl ⁇ carbamate (783 mg; 3.15 mmol) is added and the mixture is stirred overnight.
  • Stage 2 A mixture of 9H-fluoren-9-ylmethyl N-(1 - ⁇ [4-( ⁇ 2-[2-(2- ⁇ [(tert- butoxy)carbonyl]amino ⁇ ethoxy)ethoxy]ethyl ⁇ carbamoyl)phenyl]methyl ⁇ piperidin-4-yl)carbamate (240 mg; 0.314 mol) and piperidine (0.31 ml; 3.1 mmol) in THF (10 ml) is stirred overnight.
  • 3,5-diamino-6-bromopyrazine-2-carboxylic acid is prepared from methyl 3,5-diamino-6- bromopyrazine-2-carboxylate (which is prepared from methyl 3,5-diamino-6-chloropyrazine-2- carboxylate as described in J.Med.Chem. 10 (1967) 66-75) analogously to the procedure described for the synthesis of intermediate A.1
  • a e respect ve component see synt es s comment s escr e n t e terature an or commercially available.
  • Example 3.35 The trityl group is removed prior to chromatographic purification as described for the synthesis of example 5.1.
  • Trityl-protected compound example 3.23 (0.124 g; 0.123 mmol) and formic acid (1 .0 ml) in DCM (1 ml) is stirred at ambient temperature for 1 h. Volatiles are evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / (Methanol/aq. Ammonia 9:1 ) 95:5 70:30 to yield the title compound.
  • HPLC retention times are measured under the following parameters:
  • Solvent A Water + 0.1 % formic acid
  • Solvent B Acetonitrile + 0.1 % formic acid
  • Solvent A Water + 0.1% formic acid
  • Solvent B Acetonitrile + 0.1% formic acid
  • Solvent A Water + 0.1% formic acid
  • Solvent B Acetonitrile + 0.1% formic acid
  • Solvent A water + 0.1% TFA
  • Solvent B acetonitrile
  • the transepithelial electrical resistance (TEER) was determined by the application of voltage steps of ⁇ 5mV every 5 sec. Compounds were administered at a final concentration of 3 ⁇ or at increasing concentrations (1 -3-10 ⁇ ) to the apical solution. At the end of each experiment the amiloride sensitive l_SC was measured by adding 3 ⁇ amiloride to the apical compartment. Results are expressed as inhibition in percent of the amiloride effect or as IC 50 . With the example compounds given above, the following IC 50 values were determined in the Ussing Chamber assay:
  • the compounds of formula (I) are characterised by their wide range of applications in the therapeutic field. Particular mention should be made of those applications for which the compounds according to the invention of formula (I) are preferably suited on account of their pharmaceutical efficacy as ENaC inhibitors. Examples include respiratory diseases or complaints, or allergic diseases of the airways.
  • the present invention relates to the use of compounds of formula (I) for preparing a pharmaceutical composition for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory tract including the lungs, such as for example allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, , COPD, chronic bronchitis, chronic sinusitis and asthma.
  • inflammatory or obstructive diseases of the upper and lower respiratory tract including the lungs such as for example allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, , COPD, chronic bronchitis, chronic sinusitis and asthma.
  • the compounds of formula (I) for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, cystic fibrosis, particularly COPD, chronic bronchitis, asthma and cystic fibrosis.
  • the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
  • the compounds of formula (I) may be used on their own or in conjunction with other active substances of (I) according to the invention. If desired the compounds of formula (I) may also be used in combination with other pharmacologically active substances.
  • the invention further relates to medicament combinations which preferably contain, besides one or more compounds of formula (I), as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1 -antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-lnhibitors, iNOS- Inhibitors, SYK-lnhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators, or double or triple combinations thereof.
  • CFTR cystic fibrosis transmembrane regulator
  • betamimetics examples include Albuterole, Arformoterole, Bambuterole, Bitolterole, Broxaterole, Carbuterole, Clenbuterole, Fenoterole, Formoterole, Hexoprenaline, Ibuterole, Isoetharine, Isoprenaline, Levosalbutamole, Mabuterole, Meluadrine, Metaproterenole, Milveterol, Orciprenaline, Pirbuterole, Procaterole, Reproterole, Rimiterole, Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole, Terbutaline, Tiaramide, Tolubuterole, Zinterole, Nolomirole, and
  • salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hy- drosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
  • Examples of preferred anticholinergics which may be mentioned include Tiotropium salts, preferred the bromide salt, Oxitropium salts, preferred the bromide salt, Flutropium salts, preferred the bromide salt, Ipratropium salts, preferred the bromide salt, Aclidinium salts, preferred the bromide salt, Glycopyrronium salts, preferred the bromide salt, Trospium salts, preferred the chloride salt, Tolterodin.
  • the pharmacologically active part is the cation
  • possible anions are chloride, bromide, iodide, sulfate, phosphate, methansulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or
  • p-toluenesulfonate Further examples of preferred anticholinergics are selected from among
  • corticosteroids examples include Beclomethasone, Betamethasone, Budesonide, Butixocorte, Ciclesonide, Deflazacorte, Dexamethasone, Etipred- nole, Flunisolide, Fluticasone, Loteprednole, Mometasone, Prednisolone, Prednisone, Rofle- ponide, Triamcinolone, Tipredane, and
  • sodium or potassium salts sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroace- tates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.
  • PDE4-inhibtors examples include Enprofylline, Theophylline, Roflumilaste, Ariflo (Cilomilaste), Tofimilaste , Pumafentrine , Lirimilaste , Apremilaste, Arofylline, Atizorame, Oglemilastum, Tetomilaste and
  • LTD4-antagonists examples include Montelukast, Pranlukast, Zafirlukast, Masikulast , L-733321 (see compound 2ab of D. Guay et al, Bioorg. Med. Chem. Lett. 8 (1998) 453-458) and(E)-8-[2-[4-[4-(4-
  • Further examples for optionally preferred salts and derivatives are alkali salts, i.e.
  • EGFR-inhibitors examples include Cetuximab, Trastuzu- mab, Panitumumab Gefitinib, Canertinib, Erlotinib, Mab ICR-62 and

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Abstract

The present invention relates to compounds of general formula (I) and the tautomers and the salts thereof, particularly the pharmaceutically acceptable salts thereof with inorganic or organic acids and bases, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, the use thereof for the treatment of diseases, particularly diseases of the lungs and airways.

Description

Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof
1 . FIELD OF THE INVENTION
The present invention relates to compounds of general formula (I)
Figure imgf000002_0001
and the tautomers and the salts thereof, particularly the pharmaceutically acceptable salts thereof with inorganic or organic acids and bases, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, the use thereof for the treatment of diseases, particularly diseases of the lungs and airways.
2. BACKGROUND TO THE INVENTION
Amiloride type compounds are known from the prior art as active substances for example for the treatment of diseases of the lungs and airways (J.Med.C em. 49 (2006) 4098-4115). WO 08135557 discloses compounds of similar structure showing ENaC (Epithelial Sodium Channel) inhibitor activity.
The problem of the present invention is to prepare new compounds which may be used therapeutically for the treatment of pathophysiological processes treatable by the blockade of an epithelial sodium channel, particularly for the treatment of the lungs and airways.
3. DETAILED DESCRIPTION OF THE INVENTION It has surprisingly been found that the the problem mentioned above is solved by compounds of formula (I) of the present invention.
The present invention therefore relates to a compound of formula (I),
Figure imgf000003_0001
(I) wherein
R1 denotes H or Ci-4-alkyl,
R2 denotes H or Ci-4-alkyl,
R3 denotes H or methyl,
R4 denotes H or methyl, or
R3 and R4 together form an ethylene bridge,
R5 is selected from the group consisting of
H, d-4-alkyl-, Ci-4-alkyl-0-CO-, Ci-4-alkyl-0-CO-Ci-4-alkyl-,
Ci-4-alkyl-0-Ci-4-alkyl-, HO-CO- and HO-CO-Ci-4-alkyl-,
R6 is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl-, which is optionally substituted by one or more F atoms,
HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0- and -NR6'1R6'2,
wherein,
R6-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R6 2 denotes H or Ci-4-alkyl-,
R7 is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl-, which is optionally substituted by one or more F atoms, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR7 IR7-2, H2N-C(NH)-, H2N-C(NH)NH-,
H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-, -Ci-4-alkyl-COOH, -Ci-4-alkyl-COO-Ci-4- alkyl, -OCH2-COOH, -OCH2-COO-Ci-4-alkyl, -P(0)(OR7 3)(OR7-4), -CH2- P(0)(OR7 3)(OR7-4) and -B(OH)2, wherein,
R7-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R7'2 denotes H or Ci-4-alkyl-,
or
R7'3, R7'4 independently from each other denote H or Ci-4-alkyl, is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl- which is optionally substituted by one or more F atoms, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR8 1R8 2,
H2N-C(NH)-, H2N-C(NH)NH-, H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-,
- Ci-4-alkyl-COOH, - Ci-4-alkyl-COO- C1-4-alkyl, -OCH2-COOH, -OCH2-COO- C1-4-alkyl, -P(0)(OR8 3)(OR8-4), -CH2-P(0)(OR8 3)(OR8-4) and -B(OH)2,
or
denotes -L2-Y1-L3-Y2-L4-R8 5
wherein,
R8-1 denotes H, C1-4-alkyl, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R8 2 denotes H or Ci-4-alkyl,
or
R8'1 and R8'2 together with the nitrogen atom they are attached to form a heterocycle Y3,
R8'3, R8'4 independently from each other denote H or Ci-4-alkyl,
R10, R8'5 independently from each other are selected from the group consisting of
H, halogen, CN, N3, C1-4-alkyl, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-, H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR8-5 lR8-5-2
B(OH)2, BF3 ", -S(0)2OH, -0-C(C6H6)3, -C(CH2OH)3, -CH(CH2OH)2, -CH(OH)CH2OH and -N+(R8-5 3)3
With the proviso that
If at least one out of Y1 1 and Y2 1 is imidazole or pyridine then R10, R8 5 are not selected from the group consisting of B(OH)2, BF3 and -S(0)2OH 8.5.1 denotes H, Ci-4-alkyl, Ci-4-alkyl-CO- or Ci-4-alkyl
R8-5-2 denotes H or C1-4-alkyl,
or
R8'5'1 and R8'5'2 together with the nitrogen atom they are attached to form a heterocycle Y3,
R8-5-3 denotes methyl or ethyl, R9 denotes H or methyl, m, n independently from each other with the proviso that (m + n) < 4 , denote 0, 1 or 2, X denotes halogen,
L1 denotes a bond or is selected from the group consisting of
-CH2-, -CH2-CH2-, -CH2O-, -CO-, -S-, -SO-, -S02-, -S-CH2-, -SO-CH2- and -S02-CH2-, L2 denotes a bond or is selected from the group consisting of -0-, -CH2-, -CH2-CH2-,
-CH2-O-, -O-CH2-, -CO-, -CH2-CO-, -CO-CH2-, -S-, -SO-, -SO2- and -O-CO-,
L3, L4, L5 independently from each other denote a bond or a linear chain of formula (m)
-(CH2)i-[0-(CH2)g1]p1-[NH-(CH2)g2]p2-[0-(CH2)g3]p3- (m),
wherein
i denotes 0, 1 , 2, 3 or 4,
g1 , g2, g3 independently from each other denote 2, 3 or 4,
p1 , p3 independently from each other denote 0, 1 , 2, 3 or 4, p2 denotes 0 or 1 ,
with the provisio that the linear chain is consisting of 1 to 15 moieties selected from the group consisting of -CH2-, -O- and -NH- and with the proviso that the nitrogen atom of formula (m) is not directly linked to another nitrogen atom,
Y1 denotes a bond, Y1 '1 or -NRY1 I-,
wherein,
RY1 '1 denotes L3-H or L3-NRY1 '1 '1 RY1 '1 '2,
wherein
RY1 '1 '1 is selected from among
H, Ci-4-alkyh d-4-alkyl-CO- and Ci-4-alkyl-S02-,
RY1-1-2 denotes H or C1-4-alkyl-,
or
RY1 '1 '1 and RY1-1-2 together with the nitrogen atom they are attached to form a heterocycle, Y3,Y2 denotes a bond or
is selected from a group consisting of
Y2 \ -CO-, -NRY2 1-CO-, -CO-NRY2-1-, -Y2 1-CONRY2-1-, -Y2 1-CO- and -NRY2 1-CO-Y2 \ with the proviso that carbonyl moieties are not directly attached to nitrogen atoms of aromatic heterocycles,
wherein RY2.1
denotes -L3-H or -L3-NR Y2.1.1 R Y2.1.2
R Y2.1.1
is selected from among
H, d-4-alkyl-, Ci-4-alkyl-CO- and Ci-4-alkyl-S02-,
R Y2.1.2 denotes H or Ci-4-alkyl-,
or
Y2.i.i anc| Y2.i.2 together with the nitrogen atom they are attached to form a heterocycle Y3, independently from each other denote a linker in form of a phenylene group optionally substituted by -L5R10, or
an optionally substituted heteroaromatic or heterocyclic moiety each containing at least one nitrogen atom, denotes an optionally substituted 4-7-membered heterocycle containing at least one N-atom,
and optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, optionally in form of the hydrates, solvates or prodrugs thereof and optionally the pharmacologically acceptable acid addition salts thereof,
preferably, the pharmacologically acceptable acid addition salts thereof.
Preferred compounds of formula (I) are those wherein
X denotes CI or Br,
Y1'1, Y2'1 independently from each other denote a bond or are selected from a group consisting of a linker of formula (a) to (k)
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
(i) G) denotes pyrrolidine or piperidine, each optionally substituted by up to two substituents independently selected from hydroxy or Ci-3-alkoxy, or
Y denotes morpholine, piperazine, 4-methyl-piperazine, 4-ethyl-piperazine, 4-acetyl- piperazine or 4-propionyl-piperazine.
Particularly preferred are compounds of formula (I), wherein R\ R2, R3, R4, R5 denote H,
R9 denotes H,
X denotes CI,
L1 denotes a bond, -CH2-, -CH20- or -CO-, and
m, n independently from each other with the proviso that 0 < (m + n) < 4 , denote 0, 1 or 2, Y3 denotes morpholine, 4-acetyl-piperazine or 4-propionyl-piperazine.
Also particularly preferred are compounds of formula (I), wherein is selected from the group consisting of
-COOH, -CH2COOH, -(CH2)2COOH, -OCH2-COOH, -P(0)(OR7 3)(OR7-4),
-CH2-P(0)(OR7 3)(OR7-4) and -B(OH)2,
wherein
R7 3 denotes H, R is selected from the group consisting of
H, halogen, CN, C1-4-alkyl-, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0- and -NR8 IR8-2,
wherein
R8-1 denotes H, C1-4-alkyl-, C^-alkyl-CO- or Ci-4-alkyl-S02-,
R8 2 denotes H or Ci-4-alkyl-,
or
R8-1 and R8 2 together with the nitrogen atom they are attached to form a heterocycle Y3.
Also particularly preferred are compounds of formula (I), wherein
R7 is selected from the group consisting of
Ci-4-alkyl-OCO-, -C1-2-alkyl-COO-Ci.4-alkyl, -OCH2-COO-Ci-4-alkyl, -P(0)(OR7 3)(OR7-4), and -CH2-P(0)(OR7 3)(OR7-4),
wherein
R7 3, R7 4 independently from each other denote methyl, ethyl or 2-propyl,
R8 is selected from the group consisting of
H, halogen, CN, C1-4-alkyl-, HC≡C-, OH, C1-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0- and -NR8' R8'2,
wherein
R8-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R8 2 denotes H or Ci-4-alkyl-,
or
R8-1 and R8 2 together with the nitrogen atom they are attached to form a heterocycle Y3
Also particularly preferred are compounds of formula (I), wherein
L3, L4 independently from each other denote a bond, -CH2- or -CH2-CH2-,
R8 denotes -L2-Y1-L3-Y2-L4-R8 5,
wherein
R8-5 denotes -NH2 or -N+(R8-5-3)3,
R8-5-3 denotes methyl or ethyl, R 10 denotes a hydrogen atom
With the proviso that if YY22 ddeennotes a bond, then
L2 denotes -CO- and Y1 denotes -NRY1 I-
Also particularly preferred are compounds of formula (I), wherein
L2 denotes -CH2-CH2-,
Y1 denotes Y1-1,
wherein
Y1'1 is selected from a group consisting of linkers of formula (c), (d), (e), (f) and (k)
Figure imgf000009_0001
with the proviso that L3 is not a bond.
Especially preferred are compounds of formula (I), wherein
R7 is selected from the group consisting of
H, halogen, CN, C1-4-alkyl-, OH, d-4-alkyl-0- and HO-CH2-,
R8'5 is selected from the group consisting of H, OH,
Figure imgf000009_0002
-C(CH2OH)3,
-CH(CH2OH)2 and -CH(OH)CH2OH,
L2 denotes a bond, -CH2-CH2- or -0-CH2- ,
L3 denotes a bond,
L4 denotes a linear chain of formula (m.1):
-(CH2)r[0-(CH2)g1]p1 - (m.1),
wherein
i denotes 0, 1 , 2, or 3,
g1 denotes 2, or 3,
p1 denotes 0, 1 or 2, With the proviso that if R8'5 denotes OH or Ci-4-alkyl-0-, then (i+ p1) > 0, and with the proviso that if R8'5 denotes H, then p1 > 0, and with the provisio that the linear chain or formula (m.1) is consisting of no more than 8 moieties selected from the group consisting of -CH2- and -O- . denotes a bond,
denotes -CO-NH- or Y2 1,
wherein
Y2'1 is selected from a roup consistin of linkers of formula (c), (d), (e), (f) and (k)
Figure imgf000010_0001
Also especially preferred are compounds of formula (I), wherein
L2 denotes a bond,
L3, L4 independently from each other denote a bond or a linear chain of formula (m)
-(CH2)i-[0-(CH2)g1]p1-[NH-(CH2)g2]p2-[0-(CH2)g3]p3- (m), wherein
i denotes 0, 1 , 2 or 3,
g1 denotes 2, 3 or 4,
g2 denotes 0,
g3 denotes 2, or 3,
p1 denotes 0 or 1 ,
p3 denotes 2, 3 or 4,
p2 denotes 0,
with the provisio that the linear chain is consisting of 5 to 12 moieties selected from the group consisting of -CH2- and -O- , and
with the proviso that L3 and L4 together consist of at least eight -CH2- moieties and of at least four -O- moieties,
Y1 denotes Y1-1, wherein
γ1.1 denotes a linker of formula (e) or (f)
Figure imgf000011_0001
Y2 denotes a bond or
is selected from a group consisting of Y2'1, -Y2 ,-CONRY2-1- and -NRY2 ,-CO-Y2 \ R8-5 denotes H, OH or -OCH3,
Also preferred are compounds of formula (I), wherein
R\ R2, R3, R4, R5 denote H,
R7 denotes H or halogen,
R9 denotes H,
X denotes CI,
L1 denotes a bond,
m, n denote 1 ,
L2 denotes -CO- or -S02-
Y1 -NRY1 '1-,
wherein,
RY1 I denotes hydrogen,
Also preferred are compounds of formula (I), wherein
R\ R2, R3, R4, R5 denote H,
R7 denotes H or halogen,
R9 denotes H,
X denotes CI,
L1 denotes a bond,
m, n denote 1 ,
L2 denotes a bond,
Y1 denotes Y1-1,
wherein
Y1-1 is selected from a group consisting of linkers of formula (e) and (f)
Figure imgf000012_0001
A further embodiment of the current invention are compounds of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament.
A further embodiment of the current invention are compounds of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways.
Preferred are compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease selected from among chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), paediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alpha-1 -antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema and pneumonitis of different origins, preferably chronic bronchitis, acute bronchitis, bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), cystic fibrosis and paediatric asthma, preferably chronic bronchitis, COPD and cystic fibrosis.
A further embodiment of the current invention is a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
A further embodiment of the current invention are medicament combinations which contain, besides one or more compounds of a compound according to the invention, as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR- inhibitors, dopamine agonists, H1 -antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-lnhibitors, iNOS-lnhibitors, SYK-lnhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations thereof, preferably VX-770 and VX-809, or double or triple combinations thereof. 4. USED TERMS AND DEFINITIONS
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Ci-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
In general in single groups like HO, H2N, OS, 02S, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the terminal bond indicates the radical attachment point, for example, the substituent "aryl-Ci-3-alkyl-" means an aryl group which is bound to a Ci-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub- formulas to indicate the bond which is connected to the core molecule as defined.
For example, the term "3-carboxypropyl-group" represents the following substituent:
Figure imgf000013_0001
wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1 -methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups:
Figure imgf000013_0002
The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. Many of the following terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
Unless specifically indicated, according to the invention a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, di- astereomers, E/Z isomers etc ..) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
The term "substituted" as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
By the term "optionally substituted" is meant within the scope of the invention the above- mentioned group, optionally substituted by a lower-molecular group. Examples of lower- molecular groups regarded as chemically meaningful are groups consisting of 1 -200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds. For example the groups may comprise:
• Straight-chain or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted by rings, heteroatoms or other common functional groups.
• Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may in turn be substituted by functional groups.
• A number of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms which may be linked by one or more carbon chains, optionally interrupted by heteroatoms, optionally substituted by heteroatoms or other common functional groups.
The expressions "prevention", "prophylaxis", "prophylactic treatment" or "preventive treatment" used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or another disorder mentioned herein. Thus the expression "prevention of a disease" as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.
The expression "treatment" or "therapy" means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof. Thus the expression "treatment of a disease" as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carbox- ylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2'- iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N- ethyl-glucamine, hydrabamine, 1 H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)- morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2- dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, 1 -hydroxy-2- naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1 -19).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts,) also comprise a part of the invention.
As used herein the term "prodrug" refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).
The terms "prodrug" or "prodrug derivative" mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). Such prodrugs either have me- tabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups. Most common prodrugs include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991 , particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder ei a/. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc, 1975; Bioreversible Carriers in Drug Design, E.B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties.
The term "pharmaceutically acceptable prodrug" as used herein means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
The term "aryl" as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phe- nanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
The term "heterocyclyl" or "heterocycle" means a saturated or unsaturated mono- or polycyclic- ring systems including aromatic ring system containing one or more heteroatoms selected from N, O or S(0)r ,wherein r = 0, 1 or 2, consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term "heterocycle" is intended to include all the possible isomeric forms.
Thus, the term "heterocyclyl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
-18-
Figure imgf000020_0001
The term heteroaromatic means heteroaryl, monocyclic C5-6-heteroaryl, or monocyclic C5-6-heteroaryl.
The term "heteroaryl" means a mono- or polycyclic-ring systems containing one or more het- eroatoms selected from N, O or S(0)r, wherein r = 0, 1 or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term "heteroaryl" is intended to include all the possible isomeric forms.
Thus, the term "heteroaryl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000020_0002
Figure imgf000021_0001
The term " monocyclic C5-7-heterocyclyl" means a saturated or unsaturated non-aromatic mono- cyclic-ring systems containing one or more heteroatoms selected from N, O or S(0)r ,wherein r = 0, 1 or 2, consisting of 5 to 7 ring atoms. The term " monocyclic C5-7-heterocyclyl" is intended to include all the possible isomeric forms.
Thus, the term " monocyclic C5-7-heterocyclyl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000021_0002
Figure imgf000022_0001
The term " monocyclic C5-6-heteroaryl " means a monocyclic-ring systems containing one or more heteroatoms selected from N, O or S(0)r, wherein r = 0, 1 or 2, consisting of 5 or 6 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term "monocyclic C5-6- heteroaryl" is intended to include all the possible isomeric forms.
Thus, the term " monocyclic C5-6-heteroary includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000023_0001
The term " bicyclic C8-io-heterocyclyl " means a saturated or unsaturated bicyclic-ring systems including aromatic ring systems containing one or more heteroatoms selected from N, O or S(0)r ,wherein r = 0, 1 or 2, consisting of 8 to 10 ring atoms wherein the heteroatoms is optionally part of the aromatic ring. The term " bicyclic C8-io-heterocyclyl" is intended to include all the possible isomeric forms.
Thus, the term "bicyclic C8-io-heterocyclyl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
The term "annelated species of aryl or heterocyclyl" as used herein, either alone or in combination with another substituent wherein the annelated species presents as an aryl-het (a), a het- aryl (b) or a het-het (c) annelation means a monovalent substituent derived by removal of one hydrogen from
an aromatic monocyclic system or aromatic multicyclic systems containing carbon atoms, which is annelated to a five-, six- or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur or
a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, which is annelated to an aromatic monocyclic system or aromatic multicyclic systems containing carbon atoms or
a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, which is annelated to a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur. Suitable examples of a annelated species of aryl or het include: quinolinyl, 1-indoyl, 3-indoyl, 5-indoyl, 6-indoyl, indolizinyl, benzimidazyl or purinyl.
The term "halogen" as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.
The term "Ci-n-alkyl", wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term Ci-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2"CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2"CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-,
H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and
Figure imgf000026_0001
The term "Ci-n-alkylene" wherein n is an integer 2 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term Ci-4-alkylene includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2"CH2-CH(CH3)-, -CH(CH3)-CH2-CH2", -CH2-CH(CH3)-CH2-,
-CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)- , -CH(CH(CH3))2- and -C(CH3)(CH2CH3)-.
The term "C2-n-alkenyl", is used for a group as defined in the definition for "Ci-n-alkyl" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
The term "C2-n-alkenylene" is used for a group as defined in the definition for "Ci-n-alkylene" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
The term "C2-n-alkynyl", is used for a group as defined in the definition for "Ci-n-alkyl" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
The term "C2-n-alkynylene" is used for a group as defined in the definition for "Ci-n-alkylene" with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. By the term "Ci-6-alkoxy" (including those which are part of other groups) are meant branched and unbranched alkoxy groups with 1 to 6 carbon atoms and by the term "Ci-4-alkoxy" are meant branched and unbranched alkoxy groups with 1 to 4 carbon atoms. Alkoxy groups with 1 to 4 carbon atoms are preferred. Examples include: methoxy, ethoxy, propoxy, butoxy or pen- toxy. The abbreviations OMe, OEt, OPr, etc. may optionally be used for the above-mentioned groups. Unless stated otherwise, the definitions propoxy, butoxy and pentoxy include all the possible isomeric forms of the respective groups. Thus for example propoxy includes n-propoxy and /'so-propoxy, butoxy includes /'so-butoxy, sec-butoxy and ie f-butoxy etc.
The term "C3-n-cycloalkyl", wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl and cycloheptyl.
The term "C3-n-cycloalkenyl", wherein n is an integer 3 to n, either alone or in combination with another radical, denotes an cyclic, unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to n C atoms, at least two of which are bonded to each other by a double bond. For example the term C3-7-cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl cycloheptadienyl and cyclohep- tatrienyl.
In all cases of contradictions between structure and their naming, structure shall prevail. 5. PREFERRED EMBODIMENTS
The substituent R1 denotes H or Ci-4-alkyl, preferably methyl or H, particularly preferred hydrogen.
The substituent R2 denotes H or Ci-4-alkyl, preferably methyl or H, particularly preferred hydrogen.
The substituent R3 denotes H or methyl, preferably hydrogen.
The substituent R4denotes H or methyl, preferably hydrogen,
or
the substituents R3 and R4 together form an ethylene bridge, preferably if m = n = 1.
The substituent R5 is selected from the group consisting of
H, d-4-alkyl-, Ci-4-alkyl-0-CO-, Ci-4-alkyl-0-CO-Ci-4-alkyl-,
Ci-4-alkyl-0-Ci-4-alkyl-, HO-CO- and HO-CO-Ci-4-alkyl-,
preferably H, Ci-4-alkyl-0-CO- and Ci-4-alkyl, particularly preferred H.
The substituent R6 is selected from the group consisting of H, halogen, CN, N3, d-4-alkyl-, which is optionally substituted by one or more F atoms, HC≡C-, OH, Ci-4-alkyl-O-, HO-CH2-, H2C=CH-CH2-0-, HC≡C-CH2-0- and -NR6 IR6-2, preferably H, halogen, CN, C1-4-alkyl-, OH, Ci-4-alkyl-0-, HO-CH2-, and -NR6 IR6-2, particularly preferred H, halogen, CN, CH3-alkyl-, OH, and CH3-alkyl-0-,
wherein,
R6-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-, preferably H, C1-2-alkyl-, Ci-2-alkyl-CO- or Ci-2-alkyl-S02-, particularly preferred Ci-2-alkyl-CO- or Ci-2-alkyl-S02-, R6'2 denotes H or Ci-4-alkyl-, preferably H or CH3-alkyl-, particularly preferred H. The substituent R7 is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl- which is optionally substituted by one or more F atoms,
HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-, H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR7 IR7-2,
H2N-C(NH)-, H2N-C(NH)NH-, H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-,
- Ci-4-alkyl-COOH, - Ci-4-alkyl-COO- C1-4-alkyl, -OCH2-COOH, -OCH2-COO- C1-4-alkyl,
-P(0)(OR7 3)(OR7-4), -CH2-P(0)(OR7 3)(OR7-4) and -B(OH)2,
preferably H, halogen, CN, C1-4-alkyl-, OH, Ci-2-alkyl-0-, HO-CH2-, -NR7 IR7-2,
H2N-C(NH)-, H2N-C(NH)NH-, H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-, -
CH2COOH, -(CH2)2COOH, -CH2COO- C1-4-alkyl, -(CH2)2COO- C1-4-alkyl, -OCH2-COOH,
-OCH2-COO- Ci-4-alkyl, -P(0)(OR7 3)(OR7-4), -CH2-P(0)(OR7 3)(OR7-4) and -B(OH)2, particularly preferred H, halogen, CN, CH3-alkyl-, OH, CH3-alkyl-0-, H2N-C(NH)-, -
COOH, Ci-4-alkyl-OCO-, CH2COOH, -(CH2)2COOH, -CH2COO- C1-2-alkyl, -(CH2)2COO-
Ci-2-alkyl, -OCH2-COOH, -OCH2-COO- C1-2-alkyl, -P(0)(OR7 3)(OR7-4),
-CH2-P(0)(OR7 3)(OR7-4) and -B(OH)2,
wherein,
R7-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-, preferably H, C1-2-alkyl-, Ci-2-alkyl-CO- or Ci-2-alkyl-S02-, particularly preferred Ci-2-alkyl-CO- or Ci-2-alkyl-S02-, R7'2 denotes H or Ci-4-alkyl-, preferably H or CH3-alkyl-, particularly preferred H or
R7'3, R7'4 independently from each other denote H or Ci-4-alkyl, preferably H, methyl, ethyl or 2-propyl, particularly preferred H, methyl or ethyl.
The substituent R8 is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl- which is optionally substituted by one or more F atoms, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-, H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR8 1R8 2, H2N-C(NH)-, H2N-C(NH)NH-, H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-,
-Ci-4-alkyl-COOH, -Ci-4-alkyl-COO- C1-4-alkyl, -OCH2-COOH, -OCH2-COO- C1-4-alkyl, - P(0)(OR8 3)(OR8-4), -CH2-P(0)(OR8 3)(OR8-4) and -B(OH)2,
preferably H, halogen, CN, C1-4-alkyl-, OH, Ci-4-alkyl-0-, HO-CH2-, -NR8 1R8 2, H2N- C(NH)-, H2N-C(NH)NH-, H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-, CH2COOH, - (CH2)2COOH, -CH2COO- C1-4-alkyl, -(CH2)2COO- C1-4-alkyl, -OCH2-COOH and -OCH2- COO- Ci-4-alkyl,
particularly preferred H, halogen, CN, CH3-alkyl-, OH, CH3-alkyl-0-, -COOH, C1-2-alkyl- OCO-, CH2COOH, -(CH2)2COOH, -CH2COO- C1-2-alkyl, -(CH2)2COO- C1-2-alkyl, -OCH2- COOH and -OCH2-COO- C1-2-alkyl,
or
denotes -L2-Y1-L3-Y2-L4-R8 5
wherein,
R8-1 denotes H, C1-4-alkyl, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-, preferably H, C1-2-alkyl-,
Ci-2-alkyl-CO- or Ci-2-alkyl-S02-, particularly preferred Ci-2-alkyl-CO- or Ci-2-alkyl- S02-,
R8'2 denotes H or Ci-4-alkyl preferably H or CH3-alkyl-, particularly preferred H or
R8'1 and R8'2 together with the nitrogen atom they are attached to form a heterocycle Y3,
, preferably pyrrolidine, piperidine, piperazine, 4-methylpiperazine, 4-acetylpiperazine or morpholine, particularly preferred piperazine, 4-methylpiperazine, 4-acetylpiperazine or morpholine, independently from each other denote H or Ci-4-alkyl,
preferably H, methyl, ethyl or 2-propyl, particularly preferred H, methyl or ethyl,
independently from each other are selected from the group consisting of H, halogen, CN, N3, C1-4-alkyl, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-, H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR8-5 lR8-5-2
B(OH)2, BF3 ", -S(0)2OH, -0-C(C6H6)3, -C(CH2OH)3, -CH(CH2OH)2, -CH(OH)CH2OH and -N+(R8-5 3)3, preferably H, halogen, CN, C1-4-alkyl, OH, Ci-4-alkyl-0-, HO-CH2-, -NR8-5 lR8-5-2,
B(OH)2, BF3 ", -S(0)2OH, -C(CH2OH)3, -CH(CH2OH)2,
-CH(OH)CH2OH and -N+(R8-5 3)3, particularly preferred H, CN, C1-2-alkyl, OH, Ci-2-alkyl-0-, B(OH)2, BF3 ", -S(0)2OH, -C(CH2OH)3, -CH(CH2OH)2, - CH(OH)CH2OH and -N+(R8-5 3)3,
R8-5-1 denotes H, C1-4-alkyl, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
preferably H, Ci-2-alkyl-, Ci-2-alkyl-CO- or Ci-2-alkyl-S02-, particularly preferred Ci-2-alkyl-CO- or Ci-2-alkyl-S02 R8-5-2 denotes H or C1-4-alkyl,
preferably H or CH3-alkyl-, particularly preferred H, or
R8'5'1 and R8'5'2 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N-atom,
preferably pyrrolidine, piperidine, piperazine, 4-methylpiperazine, 4- acetylpiperazine or morpholine, particularly preferred piperazine, 4- methylpiperazine, 4-acetylpiperazine or morpholine,
R8.5.3 denotes methyl or ethyl, preferably methyl.
The substituent R9 denotes H or methyl, preferably H.
Variables m, n independently from each other with the proviso that (m + n) < 4 , denote
0, 1 or 2, preferably with the proviso that 0 < (m + n) < 4 denote 0, 1 or 2, particularly preferred denote m = n = 1 ,
The symbol X denotes halogen, preferably CI or Br, particularly preferred CI.
The symbol L1 denotes a bond or is selected from the group consisting of
-CH2-, -CH2-CH2-, -CH2O-, -CO-, -S-, -SO-, -S02-, -S-CH2-, SO-CH2- and -S02-CH2-, preferably bond, -CH2-, -CH20- and -CO-, particularly preferred a bond.
The symbol L2denotes a bond or is selected from the group consisting of -0-, -CH2-, -CH2-CH2-, -CH2-O-, -O-CH2-, -CO-, -CH2-CO-, -CO-CH2-, -S-, -SO-, -SO2- and -O-CO-, preferably a bond, -0-, -CH2-, -CH2-CH2-, -CH2-0-, -0-CH2-, -CO- and -S02-, particularly preferred a bond, -CH2-, -CH2-CH2-, -CO - and -S02-.
The symbols L3, L4, L5 independently from each other denote a bond
or a linear chain of formula (m),
-(CH2)i-[0-(CH2)g1]p1-[NH-(CH2)g2]p2-[0-(CH2)g3]p3-
(m)
wherein
i denotes 0, 1 , 2, 3 or 4, preferably 0, 1 , 2, or 3, particularly
preferred 1 or 2,
g1 , g2, g3 independently from each other denote 2, 3 or 4, preferably 2 or 3, particularly preferred 2,
p1 , p3 independently from each other denote 0, 1 , 2, 3 or 4, preferably 0,
1 , 2 or 3, particularly preferred 0 or 1 , P2 denotes 0 or 1 , preferably 0, with the provisio that the linear chain consists of 1 to 15 moieties, preferably 1 to 6, particularly preferred 1 to 3 moieties, selected from the group consisting of - CH2-, -O- and -NH- and with the proviso that the nitrogen atom of formula (m) is not directly linked to another nitrogen atom.
The symbol Y1 denotes a bond, Y1'1 or -NRY1 I-,
wherein,
RY1 I denotes L3-H or L3-NRY1 '1'1 RY1-1-2, preferably L3-H, particularly preferred H,
wherein
RY1 '1'1 is selected from among
H, Ci-4-alkyh Ci-4-alkyl-CO- and Ci-4-alkyl-S02-, preferably H, C1-2-alkyl- Ci-2-alkyl-CO- and Ci-2-alkyl-S02-, particularly preferred H, CH3-alkyl- CO- and CH3-alkyl-S02-,
RY1 I 2 denotes H or Ci-4-alkyl-, preferably H or -CH3, particularly preferred H,
or
RY1 '1'1 and RY1-1-2 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N-atom, preferably pyrrolidine, piperidine, piperazine, 4- methylpiperazine, 4-acetylpiperazine and morpholine.
The symbol Y2denotes a bond or
is selected from a group consisting of
Y2 \ -CO-, -NRY2 1-CO-, -CO-NRY2-1-, -Y2 1-CONRY2-1-, -Y2 1-CO- and -NRY2 1-CO-Y2 \ preferably bond or Y2 \ -NRY2 l-CO-, -CO-NRY2 \ and -Y2 1-CO-, particularly preferred bond or -NRY2 1-CO- and -CO-NRY2 1-,
with the proviso that carbonyl moieties are not directly attached to nitrogen atoms of aromatic heterocycles,
wherein
RY2 I denotes L3-H or L3-NRY2'1'1 RY2 I-2, preferably L3-H,
RY2'1'1 is selected from among
H, Ci-4-alkyh Ci-4-alkyl-CO- and Ci-4-alkyl-S02-, preferably H, C1-2-alkyl-, Ci-2-alkyl-CO- and Ci-2-alkyl-S02-, particularly preferred H, CH3-alkyl-CO and CH3-alkyl-S02-, Y2.i.2 (jgnotgg H or Ci-4-alkyl-, preferably H or CH3-alkyl-, particularly preferred H,
or
Y2.i.i anc| Y2.i.2 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N- atom, preferably selected from the group consisting of pyrrolidine, piperi- dine, piperazine, 4-methylpiperazine, 4-acetylpiperazine and morpholine,
Y1'1, Y2'1 independently from each other denote a linker in the form of a phenylene group optionally substituted by -L5R10, preferably a linker in the form of an unsubstituted phenylene, or
an optionally substituted heteroaromatic or heterocyclic moiety each containing at least one nitrogen atom,
preferably Y1'1, Y2'1 independently from each other are selected from a group consisting of a linker of formula (a) to (k)
Figure imgf000032_0001
particularly preferred selected from a group consisting of a linker of formula (a), (e), (f) or (k).
Any and each other of the substituents defined above may be combined with each other. 6. PREPARATION
The following methods are suitable for preparing compounds of general formula (I),
The compounds according to the invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. General methods for functional groups protection and deprotection steps are described e.g. in: Greene, T. W. and Wuts, P.G.M. (eds.): Protective Groups in Organic Synthesis, third edition 1999; John Wiley and Sons, inc.. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.
Compounds of general formula (I) can be prepared by reacting S-methylisothioureas of formula (II) with primary amines of formula (III) in a solvent like THF, acetonitrile or DMF or in a solvent mixture, preferably in the presence of a base, especially when the primary amine (III) is applied as an acid addition salt, preferably at r.t.( room temperature).
Scheme 1
Figure imgf000033_0001
(I)
Compounds of general formula (II) can be prepared by reacting S-methylisothiourea (which may be generated in situ from its sulphuric acid salt by addition of base) with a 1 -(tert- butylcarbamoyl)prop1 -en-2-yl carboxylate of general formula (IV) in a solvent like DCM, THF, water or a mixture of these solvents, preferably at r.t. Compounds of general formula (IV) can be prepared from the respective carboxylic acid of general formula (V) and a 2-tert-butyl-5- methyl-isoxazolium salt of general formula (VI), which can be applied as an isolated salt (e.g. the hexafluorophosphate salt; X = PF6) or generated in situ from tert-butanol, 5-methylisoxazole and trifluoromethanesulphonic acid. The latter reaction is preferably performed in a solvent like DMF or in a solvent mixture with the addition of triethylamine or another base, preferably while cooling to 0-10 °C.
Scheme 2
Figure imgf000034_0001
Figure imgf000034_0002
Compounds of general formula (III) can be prepared from compounds of general formula (VII) by removal of the respective protecting group, preferably the BOC or FMOC protecting group which can be removed by standard acidic or basic conditions, respectively. Compounds of general formula (VII) can be modified using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis, preferably by functional group protection or deprotection steps, esterifications, amidations, hydrogenations, or 1 ,3- dipolar cycloadditions of an azide to a terminal alkyne group or vice versa. Compounds of general formula (VII) can be prepared from secondary amines of general formula (VIII), preferably either by alkylation with a compound of general formula (IX) (wherein the leaving group LG is preferably CI, Br, OMesyl, or OTosyl), or by reductive amination with an aldehyde of general formula (X) (wherein R5 = H).
Scheme 3
Figure imgf000035_0001
Removal of the protecting group PG
Figure imgf000035_0002
Compounds of general formula (I) can be converted into intermediates of general formula (XI) by BOC-protection. Compounds of general formulas (I) or (XI) can be modified using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis, preferably by functional group protection or deprotection steps, esterifications, amida- tions, hydrogenations, or 1 ,3-dipolar cycloadditions of an azide to a terminal alkyne group or vice versa. After such modification steps, the BOC protecting group in compounds of general formula (XI) can be removed again by standard acidic deprotection conditions to yield modified compounds of general formula (I).
Scheme 4
Figure imgf000036_0001
BOC protection BOC deprotection
Figure imgf000036_0002
7. EXAMPLES
Where no salt forms of compounds are specified, the compound may exist as a free base or a salt, depending on the synthesis conditions and the processes of workup and purification applied. The skilled person will appreciate that the compound is not limited to the free base or a certain salt form. Where salt forms of compounds are specified, the stoichiometry of the counterion is usually omitted. The skilled person will appreciate that the compound is not limited to the mono salt form and that it may exist as a disalt, trisalt or other compound:counterion
stoichiometries. Furthermore, the skilled person will appreciate that such compound may unexpectedly exist as a free base or as a salt with a different counterion, depending on the synthesis conditions and the processes of workup and purification applied. Solely for the purpose of yield determination, an estimate of the nature of the counterion and of compound:counterion stoichieometry is made (as indicated by the formula given).
7.1 SYNTHESIS OF INTERMEDIATES
Intermediate 1.1 To a solution of tetra(ethylene glycol) (90 g; 463 mmol) in pyridine (100 ml) is added dropwise a solution of triphenylmethyl chloride (30,0 g; 108 mmol) in pyridine (100 ml). The mixture is stirred overnight and evaporated. Water is added and the aqueous layer is decanted, which is repeated for further two times. The residue is dissolved in diethyl ether, extracted with water and then with brine and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / methanol) 100:0 94:6 to yield the title compound.
Yield: 28.6 g (61 % of theory) C27H3205
ESI Mass spectrum: m/z = 454 [M+NH4]+; m/z = 435 [M-H]"
The following compounds are prepared analogously from the starting materials indicated:
Table 1
Figure imgf000037_0003
Intermediate 11.1
Figure imgf000037_0001
A mixture of 4-pentynoic acid (2.00 g; 20.4 mmol) and 4-methylmorpholine (2.24 ml; 20.4 mmol) in DCM (20 ml) is cooled to -5°C. Isobutyl chloroformate (2.68 ml; 20.4 mmol) is added, followed by DMF (10 ml). The resulting mixture is added in portions to a solution of diethanolamine (2.25 g; 21 .4 mmol) in DCM (10 ml). The resulting mixture is stirred overnight and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / methanol 100:0 82:18 to yield N,N-bis(2-hydroxyethyl)pent-4-ynamide.
Yield: 2.99 g (79% of theory) C9H15N03
ESI Mass spectrum: m/z = 186 [M+H]+
Figure imgf000037_0002
A mixture of the acid 3-propargyloxy-benzoic acid (0.245 g; 3.35 mmol), triethylamine (0.47 ml; 3.35 mmol) and TBTU (1 .08 g; 3.35 ml) in DMF (3 ml) is stirred at ambient temperature for 5 min. The amine 2-(2-hydroxyethoxy)-ethylamine (0.500 g; 4.76 mmol) and further triethylamine (0.47 ml; 3.35 mmol) is added. The mixture is stirred at ambient temperature for 6 h. Ice-water and sodium carbonate solution are added, and the mixture is extracted with ethyl acetate. The organic layer is separated, dried with magnesium sulphate, filtered and evaporated to yield the title compound.
Yield: 0.33 g (37% of theory) Ci4H17N04
ESI Mass spectrum: m/z = 264 [M+H]+; m/z = 262 [M-H]"; m/z = 308 [M+HCOO]"
The following compounds are prepared accordingly from the starting materials as indicated:
Table 2
Figure imgf000038_0002
Figure imgf000038_0001
To a solution of the alcohol intermediate 1.1 (3.49 g; 8.00 mmol) and triethylamine (1 .64 g; 16.0 mmol) in DCM (20 ml) is added slowly methanesulphonyl chloride (0.929 ml; 12.0 mmol). The mixture is stirred at ambient temperature for 1 h and then extracted with water. The organic layer is evaporated and the residue is taken up in acetonitrile (20 ml). The amine 3-amino-N- methyl-N-(prop-2-yn-1 -yl)propanamide hydrochloride (2.54 g; 10.1 mmol; prepared from Intermediate III.2 by BOC-deprotection with HCI in dioxane (4 mol/l)) and triethylamine (2.45 g; 24.0 mmol) are added and the mixture is stirred at 60 °C overnight. Water is added and the resulting mixture is extracted with extracted with DCM. The organic layer is dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / methanol 100:0 86:14 to yield the title compound.
Yield: 1 .1 1 g (25% of theory) C34H42N205
ESI Mass spectrum: m/z = 559 [M+H]+ ; m/z = 603 [M+HCOO]"
HPLC analytics: RT = 1 .38 min (HPLC method 4)
The following compounds are prepared analogously from the starting materials indicated:
Table 3
Figure imgf000039_0002
Intermediate V.1
Figure imgf000039_0001
A mixture of 5,5-bis(hydroxymethyl)-2-phenyl-1 ,3-dioxane (500 mg; 2.23 mmol), propargyl bromide (80% in toluene; 224 μΙ; 2.01 mmol) and NaH (60% in mineral oil; 85 mg; 2.22 mmol) in THF is stirred overnight at 50 °C. Water is added and the organic solvent is evaporated. Further water is added under stirring. The precipitate formed is filtered off and purified by silica gel column chromatography (gradient: DCM / methanol 100:0 90:10 to yield the title compound as a mixture of E/Z isomers.
Yield: 190 mg (32% of theory) Ci5H1804 ESI Mass spectrum: m/z = 263 [M+H]+
Intermediate VI.1
Figure imgf000040_0001
A mixture of 6-hydroxynicotinic acid (300 mg; 2.16 mmol) and CDI (420 mg; 2.59 mmol) in THF is stirred at ambient temperature for 30 min. 0,0'-Bis(TBDMS)-diethanolamine (720 mg; 2.16 mmol) is added and the mixture is stirred overnight at ambient temperature. Volatiles are evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / methanol 100:0 90:10 to yield the respective amide intermediate (750 mg; 76% of theory) which is further reacted as follows:
A mixture of the amide intermediate (710 mg; 1 .56 mmol), 4-bromo-1 -butyne (228 mg; 1.72 mmol) and cesium carbonate (712 mg; 2.19 mmol) in acetonitrile (10 ml) is stirred overnight at 70 °C. Further 4-bromo-1 -butyne (500 μΙ; 5.33 mmol) and cesium carbonate (712 mg; 2.19 mmol) are added and the mixture is stirred for one more day at 70°C. Volatiles are evaporated, water is added and the mixture is extracted with DCM. The organic layer is separated and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / methanol 100:0 70:30 to yield the title compound.
Yield: 315 mg (40% of theory) C26H46N2O4S12
ESI Mass spectrum: m/z = 507 [M+H]+; m/z = 551 [M+HCOO]"
Intermediate VII.
Figure imgf000040_0002
A mixture of the alcohol 1.2 (5.00 g; 9.53 mmol), methanesulphonyl chloride (1.1 1 ml; 14.3 mmol) and triethylamine (3.35 ml; 23.8 mmol) in DCM (50 ml) is stirred at ambient temperature for 1 h. Sodium azide (1 .86 g; 28.6 mmol) is added and the mixture is stirred overnight, then for 2 h at 50 °C. Further DCM is added and the mixture is extracted with sodium carbonate solution. The organic layer is separated, dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / methanol 100:0 70:30 to yield the title compound.
Yield: 4.39 g (84% of theory) C31 H39N3O6
ESI Mass spectrum: m/z = 567 [M+H]+; m/z = 594 [M+HCOO]"
The following compounds are prepared analogously from the starting materials indicated:
Table 4
Figure imgf000041_0001
Intermediate VIII.1
Figure imgf000041_0002
Methanesulphonyl chloride (426 μΙ; 5.50 mmol) is added carefully to a mixture of the trityl ether 1.1 (2.18 g; 5.00 mmol) and triethylamine (1 .85 ml; 13.2 mmol) in DCM (20 ml). The mixture is stirred for 2 h, then extracted with water. The organic layer is separated and evaporated. Aceto- nitrile (20 ml), the diphenol intermediate III.4 (780 mg; 2.20 mmol) and potassium carbonate (913 mg; 6.60 mmol) are added, and the mixture is refluxed overnight. Water is added and the mixture is extracted with DCM. The organic layer is separated, dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / (methanol : aqueous ammonia 9:1 ) 100:0 85:15 to yield the title compound.
Yield: 2.28 g (63% of theory) C69H82N4O14
ESI Mass spectrum: m/z = 1 191 [M+H]+; m/z = 594 [M+HCOO]"
The following compunds are prepared analogously from the starting materials indicated:
Table 5
Figure imgf000041_0003
Intermediate IX.1 IX.1
Methanesulphonyl chloride (276 μΙ; 3.57 mmol) is added carefully to a mixture of the trityl ether intermediate 1.3 (1.00 g; 2.55 mmol) and triethylamine (715 μΙ; 5.60 mmol) in DCM (10 ml). The mixture is stirred overnight, then extracted with water. The organic layer is separated and evaporated. Acetonitrile (10 ml), triethylamine (715 μΙ; 5.60 mmol) and 1 -amino-1 1 -azido-3,6,9- trioxaundecane (850 mg; 3.90 mmol) is added and the mixture is refluxed for 4 h. The mixture is evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / (methanol : aqueous ammonia 9:1 ) 100:0 90:10 to yield the title compound.
Yield: 910 mg (60% of theory) C33H44N4O6
ESI Mass spectrum: m/z = 593 [M+H]+
Intermediate X.1
Figure imgf000042_0001
Stage 1 : A mixture of the halide methyl-4-(bromomethyl)-3-methoxy-benzoate (0.50 g; 1.93 mmol), the amine tert-butyl N-(piperidin-4-yl)carbamate (0.386 g; 1 .93 mmol) and triethylamine
(0.538 ml; 3.86 mmol) in THF (10 ml) is stirred for 4 h. The solvent is evaporated. The residue is taken up in water and sodium carbonate solution and extracted with DCM. The organic layer is dried with Magnesium Sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / Methanol 100:0 92:8 to yield Methyl 4-[(4-{[(tert- butoxy)carbonyl]amino}piperidin-1 -yl)methyl]-3-methoxybenzoate.
Yield: 650 mg (89% of theory) C20H30N2O5
ESI Mass spectrum: m/z = 379 [M+H]+; m/z = 423 [M+HCOO]"
Stage 2 (removal of BOC protecting group): A mixture of Methyl 4-[(4-{[(tert- butoxy)carbonyl]amino}piperidin-1 -yl)methyl]-3-methoxybenzoate and HCI in dioxane (4 mol/l;
1 .82 ml; 7.27 mmol) in methanol (10 ml) is stirred overnight. Volatiles are evaporated and the resulting solid is suspended in ethyl acetate, filtered and evaporated again to yield Methyl (4- aminopiperidin-1 -yl)methyl-3-methoxybenzoate as a hydrochloride salt.
Yield: 480 mg (105% of theory calculated for the dihydrochloride salt)
Figure imgf000042_0002
The following compounds are prepared accordingly from starting materials as indicated. Unless stated otherwise, the amine component applied is tert-butyl N-(piperidin-4-yl)carbamate. Depending on conditions applied, the syntheses may yield a free base, a hydrochloride or dihy- drochloride salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
Table 6
Figure imgf000043_0001
Figure imgf000044_0001
* Intermediate X.3: The amidine is prepared from 4-bromomethyl-benzonitrile with ethanolic
HCI (Pinner reaction).
*b Purification by RP-HPLC (modifier: TFA) Intermediate XI.1
Figure imgf000044_0002
Stage 1 : Methanesulphonyl chloride (0.929 ml; 12 mmol) is added to an ice-cold mixture of the alcohol (4-prop-2-ynyloxy-phenyl)-methanol (1.62 g; 10 mmol) and triethylamin (2.81 ml; 20 mmol) in DCM (20 ml). After stirring overnight, the amine tert-butyl N-(piperidin-4-yl)carbamate (4.01 g; 20 mmol) is added. After further stirring overnight, water is added. The organic phase is separated, dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (DCM / Methanol 9:1 ) to yield tert-Butyl N-(1 -{[4-(prop-2-yn-1 - yloxy)phenyl]methyl}piperidin-4-yl)carbamate.
Yield: 1 .07 g (31 % of theory) C2oH28N203
ESI Mass spectrum: m/z = 345 [M+H]+
Stage 2: The BOC protecting group is removed as described for compound X.1 to yield 1 -{[4- (prop-2-yn-1 -yloxy)phenyl]methyl}piperidin-4-amine as a hydrochloride salt.
Figure imgf000045_0001
ESI Mass spectrum: m/z = 245 [M+H]+
The following compounds are prepared accordingly from starting materials as indicated. Unless stated otherwise, the amine component applied is tert-butyl N-(piperidin-4-yl)carbamate. Due to conditions applied, the syntheses may yield a free base, a hydrochloride or dihydrochloride salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
Table 7
Figure imgf000045_0002
Intermediate XII.1
Figure imgf000046_0001
Stage 1 : A mixture of the aldehyde methyl 3-formyl-5-{[2-(2-hydroxyethoxy)ethyl]-carbamoyl}- benzoate (4.51 g; 12.2 mmol) (which is prepared beforehand by amidation of Methyl 3-formyl-5- hydroxycarbonyl-benzoate with 2-(2-Hydroxyethoxy)-ethylamine using HATU as coupling reagent) and tert-butyl N-(piperidin-4-yl)carbamate (3.67 g; 18.3 mmol) in THF (50 ml) is refluxed for 3h. Glacial acetic acid (approx. 2 ml) is added to adjust at pH5. Sodium triacetoxyborohy- dride (5.18 g; 24.4 mmol) is added and the mixture is refluxed for further 2h. Ethyl acetate and water are added, the organic layer is separated, dried with Magnesium Sulphate, filtered and evaporated. The residue is purified first by silica gel column chromatography (gradient DCM / methanol 100:0 88: 12), then by RP HPLC (modifier: ammonia) to yield Methyl 3-[(4-{[(tert- butoxy)carbonyl]amino}piperidin-1 -yl)methyl]-5-{[2-(2-hydroxyethoxy)ethyl]carbamoyl}benzoate Yield: 915 mg (16% of theory) C24H37N3O7
ESI Mass spectrum: m/z = 480 [M+H]+
Stage 2: The BOC protecting group is removed as described for compound X.1 to yield Methyl 3-[(4-aminopiperidin-1 -yl)methyl]-5-{[2-(2-hydroxyethoxy)ethyl]carbamoyl}benzoate as a Hydrochloride
Figure imgf000046_0002
ESI Mass spectrum: m/z = 380 [M+H]+; m/z = 378 [M-H]"
The following compounds are prepared accordingly from starting materials as indicated. Unless stated otherwise, the amine component applied is tert-butyl N-(piperidin-4-yl)carbamate. Due to conditions applied, the syntheses may yield a free base, a hydrochloride or dihydrochloride salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
Table 8
Figure imgf000046_0003
Figure imgf000047_0001
H2N ^ ^ acetate Structure Aldehyde starting maSynthesis comment
Itnerterial applied
XII.14 3-Formyl-5-methoxy Purification of BOC- benzoic acid protected intermediate by
RP-HPLC only (modifier:
TFA).
XII.15 Methyl 2-(4- Amine applied: 3-tert- formylphenoxy)-acetate butoxycarbonyl-amino- azetidine
Figure imgf000048_0001
Intermediate XIII.1
Figure imgf000048_0002
XIII.1
A mixture of 4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-1 -yl)methyl]benzoic acid (BOC- protected intermediate from the synthesis of X.4 [without application of stage 2]; 3.80g; 10.5 mmol) and aqueous NaOH solution (4 mol/l; 4.0 ml) in ethanol (20 ml) is stirred overnight at 50 °C. Volatiles are evaporated and aqueous hydrochloric acid (4 mol/l; 4.0 ml) is added. The mixture is extracted three times with Ethyl Acetate. The combined organic layers are dried with sodium sulphate, filtered and avaporated to yield 4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-1 - yl)methyl]benzoic acid.
Yield: 1 .80 g (51 % of theory) C18H26N2O4
ESI Mass spectrum: m/z = 335 [M+H]+; m/z = 333 [M-H]"
Intermediate XIV.1
Figure imgf000048_0003
Stage 1 : A mixture of 4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-1 -yl)methyl]benzoic acid (Intermediate XIII.1 ; 3.00 g; 8.97 mmol), TBTU (3.20 mg; 9.97 mmol) and triethylamine (1 .40 ml; 10.0 mmol) in DMF (50 ml) is stirred for 5 min. The amine 3-(2-aminoethyl)-pyridine (1 .06 ml; 9.00 mmol) is added. After further 3h stirring, the solvent is evaporated and the residue is taken up in DCM and washed with sodium carbonate solution. The organic layer is dried over sodium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography
(gradient DCM / Methanol) to yield tert-Butyl N-[1 -({4-[(2-(3-pyridyl)- ethylamino)carbonyl]phenyl}methyl)piperidin-4-yl]carbamate
Yield: 3.36 g (85% of theory)
ESI Mass spectrum: m/z = 439 [M+H]+
Stage 2: The BOC protecting group is removed as described for intermediate X.1 to yield N-[1 - ({4-[(2-(3-pyridyl)-ethylamino)carbonyl]phenyl}methyl)piperidin-4-yl]amine. The crude product is further purified by RP HPLC (modifier: TFA) to yield the title compound as a TFA salt.
Yield: 3.91 g (90% of theory)
C2oH26N40 x 2TFA
ESI Mass spectrum: m/z = 339 [M+H]+
The following compounds are prepared accordingly from starting materials as indicated. Depending on conditions applied, the syntheses may yield a free base, a TFA salt or bis-TFA salt, a zwitterion or other salt forms which can be applied equally to the syntheses of example compounds as described above.
Table 9
Figure imgf000049_0001
Figure imgf000050_0001
*a Intermediate XIV.9: The amine starting material is prepared by amidation of 4-(2- methoxyethoxy)benzoic acid with 2-[2-(2-aminoethoxy)ethoxy]ethan-1 -amine (TBTU coupling) and subsequent removal of the BOC protecting group using TFA in DCM.
*b Intermediate XIV.10: The amine starting material is prepared analogously to the procedure described in Bioorganic and Medicinal Chemistry Letters 18 (2008) 1702-1707.
*c CDI is applied as amidation reagent instead of TBTU: 30 min at 40 °C, then addition of amidation reagent and 4h at 80°C. Trityl group removal occurs upon BOC removal.
*d The BOC-protected intermediate is purified by RP-HPLC (modifyer: TFA) without prior extraction.
*e CDI is applied as amidation reagent instead of TBTU: 30 min at 40 °C, then addition of amidation reagent and 4h at 80°C.
* BOC-Deprotection with TFA yields the resprective TFA-ester which is cleaved by stirring in MeOH / aq. NH3 at r.t. Intermediate XV.1
Figure imgf000051_0001
Stage 1 : To a solution of 4-(chloromethyl)benzoyl chloride (2.00 g; 10.6 mmol) in THF (30 ml) are added 5-hexyn-1 -ol (1.18 ml; 10.6 mmol) and DMAP (0.1 g; 0.82 mmol). The mixture is ref- luxed overnight with stirring. BOC-4-aminopiperidine (2.33 g; 1 1.6 mmol) and triethylamine (3.24 ml; 23.3 mmol) are added and the mixture is refluxed for further 3 h. Ethyl acetate (200 ml) and water (50 ml) are added. The organic layer is separated, washed with water and with brine and evaporated to dryness. The residue is purified by silica gel column chromatography (gradient cyclohexane / ethyl acetate 8:2 2:8) to yield 5-Hexyn-1 -yl 4-[(4-{[(tert- butoxy)carbonyl]amino}piperidin-1 -yl)methyl]-benzoate.
Yield: 3.1 1 g (71 % of theory) C24H34N204
ESI Mass spectrum: m/z = 415 [M+H]+
Stage 2: The BOC protecting group is removed as described for intermediate X.1 to yield Hex-5- yn-1 -yl 4-[(4-aminopiperidin-1 -yl)methyl]benzoate as a hydrochloride salt.
Figure imgf000051_0002
ESI Mass spectrum: m/z = 315 [M+H]+
Intermediate XVI.1
Figure imgf000051_0003
Stage 1 : A mixture of {4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-1 -yl)methyl]phenyl}boronic acid (800mg; 2.39 mmol; prepared as described for the synthesis of intermediate X.7 without BOC deprotection step), ethyl 6-hydroxypyridine-3-carboxylate (420 mg; 2.51 mmol), copper(ll) acetate (250 mg; 1.38 mmol) and pyridine (210 μΙ; 2.60 mmol) in DCM (10 ml) is stirred overnight. The mixture is filtered and extracted with water. The organic layer is dried with sodium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient DCM / methanol 98:2 94:4) to yield ethyl 1 -{4-[(4-{[(tert- butoxy)carbonyl]amino}piperidin-1 -yl)methyl]phenyl}-6-oxo-1 ,6-dihydropyridine-3-carboxylate Yield: 580 mg (53% of theory) C25H33N3O5
ESI Mass spectrum: m/z = 456 [M+H]+ Stage 2: The BOC protecting group is removed by stirring in TFA / DCM (1 :5) at r.t. to yield ethyl 1 -{4-[(4-aminopiperidin-1 -yl)methyl]phenyl}-6-oxo-1 ,6-dihydropyridine-3-carboxylate.
Figure imgf000052_0001
ESI Mass spectrum: m/z = 356 [M+H]+
Intermediate XVII.1
Figure imgf000052_0002
Stage 1 : To a mixture of 1 -azido-3,6,9-trioxaundecane-1 1 -ol (220 mg; 0.98 mmol) and triethy- lamine (550 μΙ; 3.92 mmol) in DCM (5 ml) is added methanesulphonyl chloride (250 μΙ; 3.23 mmol). After stirring for 2 h water is added. The organic layer is separated at evaporated. Ace- tonitrile (5 ml), tert-butyl N-{1 -[(4-hydroxyphenyl)methyl]piperidin-4-yl}carbamate (300 mg; 0.98 mmol; ; prepared as described for the synthesis of intermediate XII.4 without BOC deprotection step) and potassium carbonate (410 mg; 2.97 mmol) are added and the resulting mixture is ref- luxed overnight. The mixture is evaporated to dryness, taken up in water and extracted with DCM. The organic layer is dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient DCM / methanol 98:2 94:4) to yield tert-butyl N-(1 -{[4-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethoxy)phenyl]methyl}piperidin-4- yl)carbamate.
Yield: 84 mg (17% of theory) C25H4iN506
ESI Mass spectrum: m/z = 508 [M+H]+
Stage 2: The BOC protecting group is removed as described for XVI.1 (stage 2) to yield 1 -{[4- (5,8,1 1 -trioxa-1 ,2-diazatridec-1 -en-13-yloxy)phenyl]methyl}piperidin-4-amine as a TFA salt.
Figure imgf000052_0003
ESI Mass spectrum: m/z = 408 [M+H]+
Intermediate XVIII.1
Figure imgf000052_0004
XVIII.1
Stage 1 : A mixture of 4-[(4-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}piperidin-1 - yl)methyl]benzoic acid (1.20 g; 2.63 mmol), TBTU (1 .01 g; 3.15 mmol) and DIPEA (1 .8 ml; 3.15 mmol) in DMF (10 ml) is stirred for 5 min. tert-Butyl N-{2-[2-(2- aminoethoxy)ethoxy]ethyl}carbamate (783 mg; 3.15 mmol) is added and the mixture is stirred overnight. Volatiles are evaporated and the product is purified by RP-HPLC (modifyer: TFA) to yield 9H-fluoren-9-ylmethyl N-(1 -{[4-({2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl)phenyl]methyl}piperidin
Yield: 240 mg (13% of theory) C39H50N4O7
ESI Mass spectrum: m/z = 687 [M+H]+
Stage 2: A mixture of 9H-fluoren-9-ylmethyl N-(1 -{[4-({2-[2-(2-{[(tert- butoxy)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamoyl)phenyl]methyl}piperidin-4-yl)carbamate (240 mg; 0.314 mol) and piperidine (0.31 ml; 3.1 mmol) in THF (10 ml) is stirred overnight. Volatiles are evaporated and the product is purified by RP-HPLC (modifyer: TFA) to yield tert-butyl N-(2-{2-[2-({4-[(4-aminopiperidin-1 -yl)methyl]phenyl}formamido)ethoxy]ethoxy}ethyl)carbamate as a TFA salt.
Yield: 100 mg (37% of theory) C24H40N4O5 x 2 TFA
ESI Mass spectrum: m/z = 465 [M+H]+
Intermediate XIX.1
Figure imgf000053_0001
A mixture of the aryl halide component tert-butyl N-{1 -[(4-iodophenyl)methyl]piperidin-4- yl}carbamate (5.00 g; 12.0 mmol; prepared analogously to the procedure described for the synthesis of intermediate X.1 without BOC-deprotection.), the alkyne component 3-ethynylpyridine (2.48 g; 24.0 mmol), tris(dibenzylideneaceton)dipalladium(0) (0.55 mg; 0.60 mmol) and cop- per(l)iodide (229 mg; 1 ,20 mmol) in triethylamine (100 ml) is stirred under argon atmosphere at 70 °C for 3d. Volatiles are evaporated and the residue is taken up in DCM. The resulting mixture is filtered through celite and extracted with water. The organic layer is dried with magnesium sulphate and evaporated. The crude product is purified by silica gel column chromatography (gradient DCM / methanol 100:0 95:5) to yield the BOC-protected alkyne intermediate (3.50g; 8.98 mmol) which is hydrogenated with Raney-Nickel (0.70 g) in methanol (40 ml) under hydrogen pressure (50 psi). The catalyst is filtered off with suction and the resulting solution is evaporated to dryness to yield the title compound.
Yield: 3.52 g (93% of theory) C24H33N3O2
ESI Mass spectrum: m/z = 396 [M+H]+
The following compounds are prepared analogously from the starting materials indicated.
Table 10
Figure imgf000054_0001
methoxyethanol with sodium hydride in THF.
Intermediates XX.1 and XX.2
The following intermediates are prepared through BOC-deprotection analogously to the procedure described in the synthesis of intermediate X.1 from the starting material indicated. Due to conditions applied, the syntheses may yield a free base, a hydrochloride or dihydrochloride salt or other salt forms which can be applied equally to the syntheses of example compounds as described above.
Table 1 1
Figure imgf000054_0003
Intermediate XXI.1
Figure imgf000054_0002
To a mixture of [4-(2-azidoethyl)phenyl]methanol (2.66 g; 15.0 mmol) and triethylamine (6.5 ml; 46 mmol) in toluene (50 ml) is added dropwise POCI3 (0.67 ml; 7.34 mmol). The mixture is stirred for 5 d at r.t. Water (10 ml) is added and the mixture is stirred for further 2 h. Volatiles are evaporated. The residue is taken up in DCM and extracted with water. The aqueous layer is se- parated and evaporated. The residue is purified by silica gel column chromatography (gradient:
DCM / (Methanol/aq. Ammonia 9:1 ) 92:8 77:23 to yield the title compound (the counterion may be hydroxide but is not characterized).
Yield: 1 .20 g (31 % of theory) Ci5H25N4 + x HO"
ESI Mass spectrum: m/z = 261 [M]+; 351 [M+2HCOO]"
Intermediate XXII.1
Figure imgf000055_0001
A mixture of 6-hydroxynicotinic acid methyl ester (8.00 g; 52.2 mmol), 4-(chloromethyl)- phenylmethanol (9.00 g; 57.5 mmol) and cesium carbonate (34 g) in ACN (200 ml) is stirred overnight at r.t. and then filtered. The filtrate is evaporated and the residue is taken up in water and extracted three times with ethyl acetate. The combined organic layers are dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / methanol 100:0 90:10 to yield the title compound.
Yield: 4.79 g (34% of theory) Ci5H15N04
ESI Mass spectrum: m/z = 274 [M+H]+
Intermediate XXIII.1
Figure imgf000055_0002
XXIII.1
To a mixture of 4-(bromomethyl)-benzenesulphonyl chloride (1.00 g; 3.71 mmol) and triethyla- mine (2.08 ml; 14.8 mmol) in DCM (20 ml) is added slowly the amino reagent ethanolamine (0.224 ml; 3.71 mmol). The mixture is stirred for 1 hour at r.t., then tert-butyl N-(piperidin-4- yl)carbamate (892 mg; 4.45 mmol) is added. The mixture is stirred for 3 days at r.t., then water is added. The organic layer is separated and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / (methanol/aq. ammonia 9:1 ) 100:0 90:10 to yield the BOC protected intermediate which is deprotected as described for the synthesis of intermediate XVI.1 .
Yield: 240 mg (12% of theory, assuming a bis-TFA-salt is generated)
Figure imgf000055_0003
ESI Mass spectrum: m/z = 314 [M+H]+; m/z = 312 [M-H]" The following compounds are prepared analogously replacing ethanolamine by the amino reagent indicated:
Table 12
Figure imgf000056_0003
Intermediate XXIV.1
Figure imgf000056_0001
A mixture of 3-(chloromethyl)benzoic acid (1 .00 g; 5.86 mmol), tert-butyl N-(piperidin-4- yl)carbamate (1.17 g; 5.86 mmol), triethylamine (0.832 ml; 5.86 mmol) and ACN (10 ml) is stirred over night at 70 °C. The mixture is cooled to r.t., then 2-(2-aminoethoxy)ethanol (1.75 ml 17.6 mmol) and TBTU (1.98 g; 6.16 mmol) are added. The mixture is stirred for 3 days, then water is added and the mixture is extracted with ethyl acetate. The organic layer is dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / (Methanol/aq. Ammonia 9:1 ) 100:0 90:10 to yield the title compound.
Yield: 1 .13 g (46% of theory) C22H35N305
ESI Mass spectrum: m/z = 422 [M+H]+; m/z = 420 [M-H]"; m/z = 466 [M+HCOO]"
Intermediate XXV.1
Figure imgf000056_0002
Intermediate XXIV.1 (0.90 g; 2.14 mmol) is stirred in TFA / DCM (3:10; 13 ml) at r.t. for 2 hours.
The mixture is evaporated to yield the title compound.
Yield: 2.18 g (103% of theory, assuming a bis-TFA-salt is generated)
Ci9H26F3N304 x 2 C2HF3O2
ESI Mass spectrum: m/z = 418 [M+H]+
Intermediate A.1 3,5-diamino-6-chloropyrazine-2-carboxylic acid
Figure imgf000057_0001
A mixture of methyl 3,5-diamino-6-chloropyrazine-2-carboxylate (100 g; 494 mmol), methanol (1
I) and NaOH (6 mol/l in water; 240 mL; 1 .44 mol) is refluxed for 3 h. The mixture is allowed to cool to r.t. and then neutralized by addition of hydrochloric acid (6 mol/l in water; approx. 240 mL). Water (200 mL) is added. The precipitate formed is filtered off with suction, washed with water and dried at 60°C.
Yield: 99.6 g (107% of theory)
C5H5CIN402 ESI Mass spectrum: m/z = 189 [M+H]+; m/z = 187 [M-H]"
Intermediate A.2
3,5-diamino-6-bromopyrazine-2-carboxylic acid is prepared from methyl 3,5-diamino-6- bromopyrazine-2-carboxylate (which is prepared from methyl 3,5-diamino-6-chloropyrazine-2- carboxylate as described in J.Med.Chem. 10 (1967) 66-75) analogously to the procedure described for the synthesis of intermediate A.1
Intermediate B.1
-(fe/f-butylcarbamoyl)prop-1 -en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate
Figure imgf000057_0002
B.1
Stage 1 :
A mixture of ie f-butanol (21 .0 mL; 226 mmol) and 5-methylisoxazole (18.0 mL; 221 mmol) is cooled with an ice-bath. Trifluoromethanesulphonic acid (20.0 mL; 221 mmol) is added dropwise with continued cooling. The resulting mixture is stirred for 1 h without further cooling.
Stage 2:
To a solution or suspension of 3,5-diamino-6-chloropyrazine-2-carboxylic acid (Intermediate A.1 ; 14.0 g; 74.2 mmol) and triethylamine (31.0 mL; 222 mmol) in DMF (100 mL) is added the mixture prepared in stage 1 . The resulting mixture is stirred for 4 h at r.t.. Ice-water is added with stirring. The precipitate formed is filtered off with suction, washed with water and dried at 65°C to yield the title compound.
Yield: 18.2 g (75% of theory)
CisHisCINsOs ESI Mass spectrum: m/z = 328 [M+H]+; m/z = 326 [M-H]"
TLC (Silica; DCM/MeOH 9:1 ): Rf = 0.4 Intermediate B.2
-(2-methyl-2-butyl-carbamoyl)prop-1 -en-2-yl 3,5-diamino-6-bromopyrazine-2-carboxylate
Figure imgf000058_0001
B.2
Stage 1 :
A mixture of 2-methyl-2-butanol (5.75 mL; 51 mmol) and 5-methylisoxazole (4.42 mL; 51 mmol) is cooled with an ice-bath. Trifluoromethanesulphonic acid (4.84 mL; 54 mmol) is added drop- wise with continued cooling. The resulting mixture is stirred over night without further cooling. Stage 2:
To a solution or suspension of 3,5-diamino-6-bromopyrazine-2-carboxylic acid (Intermediate A.2; 5.00 g; 21.5 mmol) and triethylamine (7.48 mL; 54 mmol) in DMF (50 mL) cooled with an ice-bath is added dropwise the mixture prepared in stage 1. The resulting mixture is stirred for 4 h at r.t., then poured on ice-water. The precipitate formed is filtered off with suction, washed with water and dried at 50°C to yield the title compound.
Yield: 7.53 g (91 % of theory)
C-uHzoBrNsOs ESI Mass spectrum: m/z = 386 [M+H]+; m/z = 384 [M-H]"
Intermediate C.1
-diamino-6-chloro-/V-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide
Figure imgf000058_0002
To NaOH (1 mol/l in water; 9.2 mL; 9.2 mmol) is added S-methylisothiourea sulphate (1 .78 g; 6.1 mmol. The mixture is stirred until complete solution is achieved. TBME/THF (1 :1 ; 30 mL) and then 1 -(tert-butylcarbamoyl)prop-1 -en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate (Intermediate B.1 ; 2.00 g; 6.10 mmol) are added and the mixture is stirred at r.t. over night, then water (6 mL) is added. The precipitate formed is filtered off with suction, washed successively with water, methanol and then with diethyl ether and then dried at 50 °C to yield the title compound.
Yield: 1 .33 g (84% of theory)
C7H9CIN6OS ESI Mass spectrum: m/z = 261 [M+H]+; m/z = 259 [M-H]"
Intermediate C.2
3,5-diamino-6-bromo-/V-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide
Figure imgf000059_0001
To NaOH (1 mol/l in water; 30 mL; 30 mmol) is added S-methylisothiourea sulphate (5.42 g; 19.5 mmol. The mixture is stirred until complete solution is achieved. TBME/THF (1 :1 ; 100 mL) and then 1 -(2-methyl-2-butyl-carbamoyl)prop-1 -en-2-yl 3,5-diamino-6-bromopyrazine-2- carboxylate (Intermediate B.2; 7.52 g; 19.5 mmol) are added and the mixture is stirred at r.t. over night, then water (100 mL) is added. The precipitate formed is filtered off with suction, washed with THF/water (1 :2) and then dried at 50 °C to yield the title compound.
Yield: 5.44 g (92% of theory)
C7H9BrN6OS ESI Mass spectrum: m/z = 305 [M+H]+
7.2 SYNTHESIS OF EXAMPLES
Example 1.1
Figure imgf000059_0002
A mixture of 3,5-diamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide (Intermediate C.1 ; 0.35 g; 1 .34 mmol), the primary amine X.1 (0.48 g; 1 .37 mmol) and triethyla- mine (0.56 ml; 4.03 mmol) in THF (10 ml) is stirred overnight. Volatiles are evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / (methanol/aq. ammonia 9:1 ) 100:0 90:10. Product containing fractions are evaporated, suspended in ether, filtered off with suction and dried.
Yield: 293 mg (44% of theory) C2i H27CIN804
ESI Mass spectrum: m/z = 491 [M+H]+
HPLC analytics: RT = 1 ,26 min (HPLC method 1 )
The following compounds of general formula 1.A are prepared accordingly using the respective primary amine as indicated:
Table 13
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
a e respect ve component see synt es s comment s escr e n t e terature an or commercially available.
*c Examples 1 .51 , 1.60, 1 .62: The procedure described for example 1 .1 yields the respective tert-butylester which is converted into the title compound by stirring in TFA DCM at r.t. for 2h and subsequent purifiction by RP-HPLC (modifier: ammonia).
*d Example 1 .38: HPLC retention time not determined. Characterization by TLC (Silica; DCM / methanol / aq. ammonia 80:20:2): Rf = 0.55.
*e The BOC protecting group is removed by stirring in TFA/DCM 1 :3 at r.t. for 1 h prior to chromatographic purification.
* Purification by RP-HPLC (modifier: TFA)
*9 Purification by RP-HPLC (modifier: ammonia)
Also the following compounds of general formula 1.B are prepared accordingly using the respective primary amine as indicated:
Table 14
Figure imgf000064_0001
*a The respective component (see "synthesis comment") is described in the literature and/or commercially available.
*b The primary amino compound 1 -[(3-ethynylphenyl)methyl]piperidin-4-amine is prepared analogously to the procedure described for intermediate XI .4.
* Purification by RP-HPLC (modifier: TFA) Also the following compounds of general formula 1.C are prepared accordingly using the respective primary amine as indicated:
Table 15
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000066_0001
Figure imgf000067_0001
* The respective component (see "synthesis comment") is described in the literature and/or commercially available.
*c Examples 1 .51 , 1.60, 1 .62: The procedure described for example 1 .1 yields the respective tert-butylester which is converted into the title compound by stirring in TFA DCM at r.t. for 2h and subsequent purifiction by RP-HPLC (modifier: ammonia).
* Purification by RP-HPLC (modifier: TFA)
Also compound 1.68 is prepared accordingly (except that the reaction is carried out at 65 °C) from intermediate C.2 and intermediate 12.3
Figure imgf000067_0002
C2i H27BrN804 ESI Mass spectrum: m/z
RP-HPLC: Rt = 0.55 min (HPLC method 1 1 )
Example 2.1
Figure imgf000067_0003
A mixture of acid example 1 .51 (360 mg; 0.427 mmol), BOC-anhydride (247 mg; 1 .13 mmol) and triethylamin (230 μΙ; 1.17 mmol) in THF (100 ml) is stirred at 60 °C for 3d. Volatiles are eva- porated and the crude BOC-protected intermediate is further reacted without purification as follows:
A mixture of the intermediate, triethylamine (170 μΙ; 1 .23 mmol) and HATU (147 mg; 0.387 mmol) in DMF (6 ml) and ACN (6 ml) is stirred at ambient temperature for 30 min. The amino component 3-Amino-propylsulphonic acid (98 mg; 0.702 mmol) is added and the mixture is stirred overnight. The mixture is evaporated and the residue is purified by RP-HPLC (modifier: TFA) to yield the BOC-protected amide intermediate which is taken up in DCM and TFA and stirred overnight. Volatiles are evaporated and the residue is taken up in HCI in methanol and evaporated again. The latter is repeated for further two times to yield the title compound.
Yield: 31 mg (15% of theory) C22H3oCIN905S x 2 HCI
ESI Mass spectrum: m/z = 568 [M+H]+; m/z = 566 [M-H]"
RP-HPLC: Rt = 0.93 min (HPLC method 7)
The following compounds of general formula 2.A are prepared accordingly from starting materials as indicated:
Table 16
Figure imgf000068_0001
Figure imgf000068_0002
phonic acid
Figure imgf000069_0001
The respective amino component (see "synthesis comment") is described in the literature and/or commercially available.
Example 3.1
:
Figure imgf000069_0002
To a mixture of azide component example 1 .3 (0.80 g; 1.70 mmol) and the alkyne component 11.1 (0.564 ml; 2.37 mmol) in DMF (20 ml) is added a mixture of copper(ll) acetate (46 mg; 0.254 mmol) and sodium L-ascorbate (101 mg; 0.51 mmol) in water (2.0 ml). The mixture is stirred at 70°C overnight and then exaporated to dryness. The residue is purified by silica gel column chromatography (gradient: DCM / (methanol / ammonia 9:1 ) 95:5 70:30. The crude product is further purified by RP-HPLC (modifier: TFA) to yield the title compound as a TFA salt.
Yield: 0.401 g (36% of theory) C29H41 CIN 12O4 x 2 TFA
ESI Mass spectrum: m/z = 657 [M+H]+; m/z = 655 [M-H]"
RP-HPLC: Rt = 0.77 min (HPLC Method 4)
The following compounds of general formula 3.A, 3.B, 3.C, 3.D, 3.E, 3.F or 3.G are prepared accordingly from starting materials as indicated:
Table 17
Figure imgf000069_0003
Figure imgf000070_0001
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
*a The respective component (see "synthesis comment") is described in the literature and/or commercially available.
*b Examples 3.7 and 3.19: The procedure described for example 3.1 yields a benzylidene- protected intermediate which is deprotected by heating overnight in a mixture of hydrochloric acid (4 mol/l) and methanol. Purification by RP-HPLC (modifier: TFA). *c Example 3.16: The procedure described for example 3.1 yields a trityl-protected intermediate which is deprotected using the procedure described for the synthesis of example 5.1 .
*d Example 3.35: The trityl group is removed prior to chromatographic purification as described for the synthesis of example 5.1.
*e Alkyne component: 1 -(morpholin-4-yl)pent-4-yn-1 -one
* Alkyne component 1 -(4-acetylpiperazin-1 -yl)pent-4-yn-1 -one prepared as described for 1 - (morpholin-4-yl)pent-4-yn-1 -one
Example 4.1
Figure imgf000076_0001
A mixture of the BOC-protected compound example 3.5 (300 mg; 0.421 mmol), HCI in dioxan (4 mol/l; 2.0 ml; 8.0 mmol) and methanol (1.0 ml) is stirred at ambient temperature for 2h. The mixture is evaporated to dryness to the title compound as a hydrochloride salt.
Yield: 0.282 g (98% of theory) CZTHSSCIN
Figure imgf000076_0002
X 2 H CI
ESI Mass spectrum: m/z = 612 [M+H]+; m/z = 610 [M-H]"
RP-H PLC: RT = 0.72 min (H PLC Method 4)
The following compounds of general formula 3.C are prepared accordingly from starting materials as indicated:
Table 18
Figure imgf000076_0003
Example 5.1
Figure imgf000077_0001
OH 5.1
A mixture of Trityl-protected compound example 3.23 (0.124 g; 0.123 mmol) and formic acid (1 .0 ml) in DCM (1 ml) is stirred at ambient temperature for 1 h. Volatiles are evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / (Methanol/aq. Ammonia 9:1 ) 95:5 70:30 to yield the title compound.
Yield: 29 mg (31 % of theory) C33H50CIN 11O8
ESI Mass spectrum: m/z = 764 [M+H]+; m/z = 762 [M-H]"
HPLC analytics: RT = 1 ,28 min (HPLC method 7) The following compounds of general formula 3.A, 3.C, 3.D, 3.E or 3.F are prepared accordingly from starting materials as indicated:
Table 20
Figure imgf000077_0002
Elxampe
ESI mass
Z3
G fleneraormu- spectrum
3.E
1045 (M+H)+
5.7 3.34 1 .33 2
523 (M+H)++
3.D
1075 (M+H)+
5.8 3.25 1 .43 2
538 (M+2H)++
Tildtttryproece-
5.9 3.F -(CH2CH20)6H 3iittt. sarng maer37 734 (M+H)+ 0.83 6
l a
3.F
5.10 3.39 1045 (M+H)+ 1 .48 2
3.F HO 0 775 (M-H)-
5.1 1 3.40 C HPL Rt 0een¬.79 4
389 (M+2H)++ ()iii t tonmemn
3.F C HPLhdt meo
5.12 3.41 1 133 (M+H)+ 1 .43 3
Example 6.1
Figure imgf000078_0001
To a mixture of the TBS-protected compound example 3.17 (170 mg; 0.179 mmol) and tetrabu- tylammonium fluoride on silica (1.5 mmol/g; 0.30 g; purchased from Fluka) in THF (3 ml) is added aqueous hydrochloric acid (1 mol/l; 0.5 ml) and methanol (10 ml). The mixture is stirred at ambient temperature for 5 h. Volatiles are evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / (Methanol/aq. Ammonia 9:1 ) 100:0 70:30 to yield the title compound.
Yield: 71 mg (55% of theory) C32H4oCIN1305
ESI Mass spectrum: m/z = 722 [M+H]+; m/z = 720 [M-H]"
HPLC analytics: RT = 1 ,05 min (HPLC method 3)
Example 7.1
Figure imgf000079_0001
To the phosphonic ester example 1.8 (600 mg; 1.09 mmol) in DCM (5 ml) under argon atmosphere is added bromotrimethylsilane (2.87 ml; 21.8 mmol). The mixture is refluxed for 4 h, then methanol is added and the mixture is stirred for further 30 min at r.t. Volatiles are evaporated and the residue is purified by RP-HPLC (modifier: ammonia) to yield the title compound.
Yield: 300 mg (56% of theory) Ci9H26CIN804P
ESI Mass spectrum: m/z = 497 [M+H]+; m/z = 495 [M-H]"
HPLC analytics: RT = 1.09 min (Method 1 )
Example 8.1
Figure imgf000079_0002
To a solution of the ester compound example 1 .37 (150 mg; 0.218 mmol) in methanol (4 ml) is added aqueous NaOH solution (4 mol/l; 218 μΙ; 0.871 mmol). The mixture is stirred for 40 min at 50 °C, then neutralised by addition of aqueous hydrochloric acid. Volatiles are evaporated and the residue is purified by silica gel column chromatography (gradient: DCM / (Methanol/aq. Ammonia 9:1 ) 95:5 75:25 to yield the title compound.
Yield: 20 mg (19% of theory) Ci9H23CIN803
ESI Mass spectrum: m/z = 447 [M+H]+; m/z = 445 [M-H]"
HPLC analytics: RT = 0,73 min (HPLC method 6)
The following compounds of general formula 1.A or 1.B are prepared accordingly from starting materials as indicated: Table 21
Figure imgf000080_0001
Figure imgf000081_0001
Also the following compounds of general formula 1.C are prepared accordingly from starting materials as indicated:
Table 22 ESI
Elxampe
Synthesis commass
Y1
ment spectrum
Purification by
551
8.5 1 .53 RP-HPLC (mod0.72 4
(M+H)+
ifier: TFA)
* ttt eser saring 463
Purification by
(M+H)+
8.16 1 .4ilt maera2 RP-HPLC (mod0.69 4
461 (M- ifier: TFA)
H)-
*
Also compound 8.17 is prepared accordingly (Purification by RP-HPLC with modifier TFA) from example 1 .68. C HPL Rteen
Figure imgf000082_0001
()iii t tonmemn
C2oH25BrN804 ESI Mass spectrum: m/z
RP-HPLC: Rt = 0.51 min (HPLC method 1 1 ) C HPLhdt meo
Example 9.1
Figure imgf000082_0002
A mixture of the nitrile compound example 1.40 (1.00g; 2.34 mmol) and Raney-Nickel (500 mg) in methanolic ammonia solution (50 ml) is shaken under hydrogen (50 psi) for 8.5 h at 50 °C. The catalyst is filtered off with suction and the filtrate is evaporated. The residue is taken up in DMF (12 ml), insolubles are removed by filtration. The filtrate is evaporated and the crude product is purified by RP-HPLC (modifier: TFA), taken up in methanolic hydrochloric acid, and eva- porated to dryness to yield the title compound as a hydrochloride salt.
Yield: 28 mg (2% of theory) Ci9H26CIN90 x 4 HCI
ESI Mass spectrum: m/z = 432 [M+H]+; m/z = 430 [M-H]"
HPLC analytics: RT = 0.60 min (HPLC Method 4) Example 10.1
Figure imgf000083_0001
A mixture of the primary amine compound example 9.1 (25.0 mg; 0.043 mmol), 1 ,2,4-triazole-1 carboxamidine (10.0 mg; 0.068 mmol) and triethylamine (48.2 μΙ; 0.346 mmol) in DMF (2 ml) is stirred at 70 °C for 1 h. Volatiles are evaporated and the residue is purified by RP-HPLC (modifier: TFA). The product is taken up in methanolic hydrochloric acid and evaporated to yield the title compound as a hydrochloride salt.
Yield: 10 mg (40% of theory) CMHZBCIN HO X 3 H CI
ESI Mass spectrum: m/z = 474 [M+H]+; m/z = 472 [M-H]"
HPLC analytics: RT = 0.64 min (HPLC method 6)
8. ANALYTICAL METHODS AND PREPARATIVE CHROMATOGRAPHY
As a rule, "Ή-NMR and mass spectra have been obtained for the compounds prepared. Mass peaks given (e.g. (M+H)+, (M+HCOO)") refer to monoisotopic molecular weight. Rf values from TLC are determined using ready-made silica gel 60 TLC plates F254 (E. Merck, Darmstadt,
Item no. 1 .05714) without chamber saturation or using ready-made aluminium oxide 60 F254
TLC plates (E. Merck, Darmstadt, Item no. 1 .05713) without chamber saturation. The ratios given for the eluents relate to units by volume of the solvent in question. The units by volume for NH3 relate to a concentrated solution of NH3 in water. For silica gel chromatographic purifications, silica gel made by Millipore (MATREX™, 35-70 my) is used.
Preparative thin layer chromatochraphy (TLC):
Preparative TLC plates from Merck (PLC Silica gel 60 F254+366, 2 mm) are used. Product containing bands are scraped off and the resulting product-on-silica powder is extracted with DCM, methanol or a mixture thereof (depending on product solubility). Silica is filtered off and the filtrate is evaporated to dryness to yield the purified compound.
Preparative HPLC:
Stationary phase:
XBridge C18; 10 μηη or Sunfire C18; 10 μηη (both from waters, www.waters.com)
Mobile phase:
water/methanol gradient with addition of either TFA or ammonia as modifier as indicated. Analytical HPLC/MS Methods
The HPLC retention times given are measured under the following parameters:
HPLC method 1
Figure imgf000084_0001
HPLC method 2
Figure imgf000084_0002
Figure imgf000085_0001
HPLC method 5
Figure imgf000085_0002
HPLC method 6
Figure imgf000085_0003
HPLC method 7
Solvent A: Water + 0.1 % formic acid; Solvent B: Acetonitrile + 0.1 % formic acid
Gradient:
Figure imgf000085_0004
Column: X-terraI M MS C18 2,5 Mm 4,6 mm x 30 mm (Waters); Temperature: r.t. (ca. 25°C) HPLC method 8 Solvent A: Water + 0.1% formic acid; Solvent B: Acetonitrile + 0.1% formic acid Gradient:
Figure imgf000086_0001
Column: X-terra'M MS C182,5 m 4,6 mm x 30 mm (Waters); Temperature: r.t. (ca.25°C) HPLC method 9
Solvent A: Water + 0.1% formic acid; Solvent B: Acetonitrile + 0.1% formic acid
Gradient:
Figure imgf000086_0002
Column: X-terra'M MS C182,5 m 4,6 mm x 30 mm (Waters); Temperature: r.t. (ca.25°C) HPLC method 10
Solvent A: Water + 0.1% formic acid; Solvent B: Acetonitrile + 0.1% formic acid
Gradient:
Figure imgf000086_0003
Column: X-terra'M MS C182,5 m 4,6 mm x 30 mm (Waters); Temperature: r.t. (ca.25°C)
HPLC method 11
Solvent A: water + 0.1% TFA; Solvent B: acetonitrile
Figure imgf000086_0004
Figure imgf000087_0001
Column: Sunfire, 3 x 30 mm, 2.5 μηη (Waters)
The following abbreviations are used above and hereinafter:
ACN Acetonitrile
BOC tert-Butoxycarbonyl
CDI 1 ,1 '-Carbonyldiimidazole
DCM Methylene chloride
DIPEA Diisopropyl-ethylamine
DMF N,N-Dimethylformamide
ESI Electrospray ionization
HATU 0-(7-Azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
Ph Phenyl
r.t. ambient temperature (about 20°C)
TBS tert-Butyl-dimethylsilyl
TBTU 2-(1 H-Benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium-tetrafluoroborate
TEA Triethylamine
THF Tetrahydrofuran
Tr Triphenylmethyl
Fmoc 9H-Fluoren-9-yl-methoxycarbonyl
TFA Trifluoroacetic acid
TLC Thin layer chromatography
arrow and asterisk indicate the binding site, i.e. the point of attachment (here: atom "A") within a chemical entity (here exemplified by the group "A-R")
9. PHARMACOLOGICAL TEST METHOD
Ussing Chamber: Mouse kidney M-1 cells were cultivated in DMEM containing 5% FCS and 5μΜ dexamethasone for 10 to 12 days on polyester transwell filters. Filters were inserted into a teflon-coated well-plate which fit into the in-house ussing chamber system. Prior to measurement the medium of M-1 cells was replaced with Caco-2 transport buffer (Invitrogen, Germany). During measurements, the Ussing chamber temperature was kept at 37°C. Short circuit currents (l_sc) were measured in the voltage-clamp mode using an in-house built amplifier (Boe- hringer Ingelheim, Biberach) with the software package Lab View for data acquisition and analysis. The transepithelial electrical resistance (TEER) was determined by the application of voltage steps of ±5mV every 5 sec. Compounds were administered at a final concentration of 3μΜ or at increasing concentrations (1 -3-10μΜ) to the apical solution. At the end of each experiment the amiloride sensitive l_SC was measured by adding 3μΜ amiloride to the apical compartment. Results are expressed as inhibition in percent of the amiloride effect or as IC50. With the example compounds given above, the following IC50 values were determined in the Ussing Chamber assay:
Figure imgf000088_0001
Figure imgf000089_0001
10. INDICATIONS
As has been found, the compounds of formula (I) are characterised by their wide range of applications in the therapeutic field. Particular mention should be made of those applications for which the compounds according to the invention of formula (I) are preferably suited on account of their pharmaceutical efficacy as ENaC inhibitors. Examples include respiratory diseases or complaints, or allergic diseases of the airways.
Particular mention should be made of the prevention and treatment of diseases of the airways and of the lung which are accompanied by increased mucus production, inflammations and/or obstructive diseases of the airways. Examples include acute, allergic or chronic bronchitis, chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema, allergic or non- allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways, infectious bronchitis or pneumonitis, paediatric asthma, bronchiectases, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial oedema, pulmonary oedema, bronchitis, pneumonia or interstitial pneumonia triggered by various causes, such as aspiration, inhalation of toxic gases, or bronchitis, pneumonia or interstitial pneumonia as a result of heart failure, irradiation, chemotherapy, cystic fibrosis or mucoviscidosis, or al- phal -antitrypsin deficiency.
Particularly preferably the present invention relates to the use of compounds of formula (I) for preparing a pharmaceutical composition for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory tract including the lungs, such as for example allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, , COPD, chronic bronchitis, chronic sinusitis and asthma.
It is most preferable to use the compounds of formula (I) for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, cystic fibrosis, particularly COPD, chronic bronchitis, asthma and cystic fibrosis.
The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
1 1 . COMBINATIONS
The compounds of formula (I) may be used on their own or in conjunction with other active substances of (I) according to the invention. If desired the compounds of formula (I) may also be used in combination with other pharmacologically active substances.
Therefore the invention further relates to medicament combinations which preferably contain, besides one or more compounds of formula (I), as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1 -antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-lnhibitors, iNOS- Inhibitors, SYK-lnhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators, or double or triple combinations thereof.
Examples of preferred betamimetics which may be mentioned include Albuterole, Arformoterole, Bambuterole, Bitolterole, Broxaterole, Carbuterole, Clenbuterole, Fenoterole, Formoterole, Hexoprenaline, Ibuterole, Isoetharine, Isoprenaline, Levosalbutamole, Mabuterole, Meluadrine, Metaproterenole, Milveterol, Orciprenaline, Pirbuterole, Procaterole, Reproterole, Rimiterole, Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole, Terbutaline, Tiaramide, Tolubuterole, Zinterole, Nolomirole, and
• 1 -(2-chloro-4-hydroxyphenyl)-t-butylaminoethanole ,
• (-)-2-[7(S)-[2(R)-Hydroxy-2-(4-hydroxyphenyl)-ethylamino]-5,6,7,8-tetrahydro-2- naphthyloxy]-N,N-dimethylacetamide hydrochloride monohydrate ,
• 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)- benzyl-sulfonamide
• 5-[2-(5,6-Diethyl-indan-2-ylamino)-1 -hydroxy-ethyl]-8-hydroxy-1 H-quinoline-2-one
• 4-Hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)- benzothiazolone
• 1 -(2-Fluoro-4-hydroxyphenyl)-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylamino]ethanole
• 1 -[3-(4-Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1 -benzimidazolyl)-2-methyl-2- butylamino]ethanole
• 1 -[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl- 2-propylamino]ethanole
• 1 -[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2- propylamino]ethanole
• 1 -[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2- propylamino]ethanole • 1 -[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1 ,2,4-triazol-3- yl]-2-methyl-2-butylamino}ethanole
• 5-Hydroxy-8-(1 -hydroxy-2-isopropylaminobutyl)-2H-1 ,4-benzoxazin-3-(4H)-one
• 1 -(4-Amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanole
• 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-methoxy-phenyl)-1 ,1 -dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-one
• 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-phenoxy-acetic acid ethylester)-1 ,1 -dimethyl-ethylamino]- ethyl}-4H-benzo[1 ,4]oxazin-3-one
• 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-phenoxy-acetic acid)-1 ,1 -dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-one
• 8-{2-[1 ,1 -Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-one
• 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-hydroxy-phenyl)-1 ,1 -dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-one
• 6-Hydroxy-8-{1 -hydroxy-2-[2-(4-isopropyl-phenyl)-1 ,1 dimethyl-ethylamino]-ethyl}-4H- benzo[1 ,4]oxazin-3-one
• 8-{2-[2-(4-Ethyl-phenyl)-1 ,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-one
• 8-{2-[2-(4-Ethoxy-phenyl)-1 ,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-one
• 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3!4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-ethylamino]-2- methyl-propyl}-phenoxy)-butyric acid
• 8-{2-[2-(3,4-Difluor-phenyl)-1 ,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H- benzo[1 ,4]oxazin-3-one
• 1 -(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanole
• N-[2-Hydroxy-5-(1 -hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}- ethyl)-phenyl]-formamide
• 8-Hydroxy-5-(1 -hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)- 1 H-quinolin-2-one
• 8-Hydroxy-5-[1 -hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1 H-quinolin-2-one
• 5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1 -hydroxy- ethyl]-8-hydroxy-1 H-quinolin-2-one
• [3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5- methyl-phenyl]-urea • 4-(2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-he
phenole
• 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)- benzenesulfonamide
• 3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)- benzenesulfonamide
• 4-(2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1 -hydroxy-ethyl)-2- hydroxymethyl-phenole
• N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]- propyl}-phenyl)-acetamide
• (R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- (hydroxymethyl)phenole
• (R,S)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- (hydroxymethyl)phenole
• (R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- (hydroxy- methyl)phenole
• (R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- (hydroxymethyl)phenole
• (R,S)-5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1 -hydroxy-ethyl)-8- hydroxyquino- lin-2(1 H)-one
• (R!S)-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1 - hydroxyethyl]-2- (hydroxymethyl)phenole
• 4-(1 R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1 -hydroxyethyl)-2- (hydroxymethyl)phenol
• (R,S)-2-(Hydroxymethyl)-4-(1 -hydroxy-2-{[4,4,5l5-tetrafluoro-6-(3-phenylpropoxy)- hexyl]amino}ethyl)phenole
• (R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- hydroxy- phenyl]formamide
• (R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1 -hydroxyethyl]- 2- (hydroxymethyl)phenole
• (R, S)-N-[3-(1 ,1 -Difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]- ethyl}amino)hexyl]oxy}ethyl)phenyl]urea
• 3-[3-(1 ,1 -difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl}- amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione
• (R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1 -hydroxyethyl]-2- (hydroxymethyl)phenole • 5-((1 R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1 -hydroxyethyl)-8- hydroxyquinolin- 2(1 H)-one
• 4-((1 R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- (hydroxymethyl)phenole
• (R,S)-4-(2-{[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- (hydroxymethyl)phenole
• (R,S)-(2-{[6-(2!2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1 -hydroxyethyl)-2- (hydroxymethyl)phenole
• (R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1 -hydroxy ethyl)-2- (hydroxy- methyl)phenole
• 3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3- dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide
• N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)- ethylamino]-ethyl}-3-(2-naphthalen-1 -yl-ethoxy)-propionamide
• 7-[2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1 -hydroxy-ethyl]-4- hydroxy-3H-benzothiazol-2-one and 7-[(1 R)-2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]- propylsulfanyl}-ethylamino)-1 -hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one
optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hy- drosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
Examples of preferred anticholinergics which may be mentioned include Tiotropium salts, preferred the bromide salt, Oxitropium salts, preferred the bromide salt, Flutropium salts, preferred the bromide salt, Ipratropium salts, preferred the bromide salt, Aclidinium salts, preferred the bromide salt, Glycopyrronium salts, preferred the bromide salt, Trospium salts, preferred the chloride salt, Tolterodin. From the above mentioned salts the pharmacologically active part is the cation, possible anions are chloride, bromide, iodide, sulfate, phosphate, methansulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or
p-toluenesulfonate. Further examples of preferred anticholinergics are selected from among
• 2,2-Diphenylpropionic acid tropenole ester-methobromide
• 2,2-Diphenylpropionic acid scopine ester-methobromide
• 2-Fluor-2,2-Diphenylacetic acid scopine ester-methobromide
• 2-Fluor-2,2-Diphenylacetic acid tropenole ester-methobromide
• 3,3',4,4'-Tetrafluorbenzil acid tropenole ester-methobromide
• 3,3',4,4'-Tetrafluorbenzil acid scopine ester-methobromide
• 4,4'-Difluorbenzil acid tropenole ester-methobromide • 4,4'-Difluorbenzil acid scopine ester-methobromide
• 3,3'-Difluorbenzil acid tropenole ester-methobromide
• 3,3'-Difluorbenzil acid scopine ester-methobromide
• 9-Hydroxy-fluorene-9-carbon acid tropenole ester -methobromide
• 9-Fluor-fluorene-9-carbon acid tropenole ester -methobromide
• 9-Hydroxy-fluorene-9-carbon acid scopine ester -methobromide
• 9-Fluor-fluorene-9-carbon acid scopine ester methobromide
• 9-Methyl-fluorene-9-carbon acid tropenole estermethobromide
• 9-Methyl-fluorene-9-carbon acid scopine estermethobromide
• Benzil acid cyclopropyl tropine ester-methobromide
• 2,2-Diphenylpropionic acid cyclopropyl tropine ester-methobromide
• 9-Hydroxy-xanthene-9-carbon acid cyclopropyl tropine ester-methobromide
• 9-Methyl-fluorene-9-carbon acid cyclopropyl tropine ester-methobromide
• 9-Methyl-xanthene-9-carbon acid cyclopropyl tropine ester-methobromide
• 9-Hydroxy-fluorene-9-carbon acid cyclopropyl tropine ester -methobromide
• 4,4'-Difluorbenzil acid methylester cyclopropyl tropine ester-methobromide
• 9-Hydroxy-xanthene-9-carbon acid tropenole ester -methobromide
• 9-Hydroxy-xanthene-9-carbon acid scopine ester methobromide
• 9-Methyl-xanthene-9-carbon acid tropenole ester -methobromide
• 9-Methyl-xanthene-9-carbon acid scopine estermethobromide
• 9-Ethyl-xanthene-9-carbon acid tropenole ester methobromide
• 9-Difluormethyl-xanthene-9-carbon acid tropenole ester -methobromide
• 9-Hydroxymethyl-xanthene-9-carbon acid scopine ester -methobromide.
Examples of preferred corticosteroids which may be mentioned include Beclomethasone, Betamethasone, Budesonide, Butixocorte, Ciclesonide, Deflazacorte, Dexamethasone, Etipred- nole, Flunisolide, Fluticasone, Loteprednole, Mometasone, Prednisolone, Prednisone, Rofle- ponide, Triamcinolone, Tipredane, and
• {20R-16alpha,17alpha-[butylidenebis(oxy)]-6alpha,9alpha-difluoro-1 1 beta-hydroxy-17beta- (methylthio)androsta-4-en-3-one} ,
• 9-fluoro-1 1 beta, 17,21 -trihydroxy-16alpha-methylpregna-1 ,4-diene-3,20-dione 21 - cyclohexanecarboxylate 17-cyclopropanecarboxylate ,
• 16,17-butylidene dioxy-6,9-difluoro-1 1 -hydroxy-17-(methylthio)androst-4-en-3-one
• Flunisolide-21 -[4'-(nitrooxymethyl) benzoate]
• 6,9-Difluoro-17-[(2-furanylcarbonyl)oxy]-1 1 -hydroxy-16-methyl-3-oxo-androsta-1 ,4-dien-17- carbothion acid (S)-fluoromethylester , • 6,9-Difluoro-1 1 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1 ,4-dien-17-carbothion acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester, and
• 6alpha,9alpha-difluoro-1 1 beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2, 2,3,3- tertamethylcyclopropylcarbonyl)oxy-androsta-1 ,4-diene-17beta-carboxylic acid cyanomethyl ester optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Examples for preferred salts and derivatives are alkali salts, i.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroace- tates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.
Examples of preferred PDE4-inhibtors which may be mentioned include Enprofylline, Theophylline, Roflumilaste, Ariflo (Cilomilaste), Tofimilaste , Pumafentrine , Lirimilaste , Apremilaste, Arofylline, Atizorame, Oglemilastum, Tetomilaste and
• 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline
• 5-[N-(3,5-dichloro-1 -oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-quinoline
• N-(3,5-dichloropyrid-4-yl)-[1 -(4-fluorobenzyl)-5-hydroxy-indole-3-yl]glyoxyl acid amide ), 9-[(2- fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purine-6-amine 4-[(2R)-2-[3- (cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine ,
• N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1 -phenylpyrrolo[3,2,1 -jk][1 ,4]benzodiazepin-3-yl]- 4-Pyridinecarboxamide ,
• 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1 -naphthalenyl]-1 -(2-methoxyethyl)-2(1 H)-pyridinone
• 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1 -naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1 (2H)- Phthalazinone ,
• (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine ,
• beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1 ,3-dihydro-1 ,3-dioxo-2H-isoindole-2- propanamide ,
• 9-ethyl-2-methoxy-7-methyl-5-propyl- imidazo[1 ,5-a]pyrido[3,2-e]pyrazin-6(5H)-one
• 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl] (3S,5S)-2-piperidinone ,
• 4-[1 -[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1 -oxido-4-pyridinyl)ethyl]-alpha,alpha- bis(trifluoromethyl)-Benzenemethanol
• N-(3,5-Dichloro-1 -oxo-pyridine-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide
• (-)p-[(4aR*,106S*)-9-Ethoxy-1 ,2,3,4,4a, 10b-hexahydro-8-methoxy-2- methylbenzo[s][1 ,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid e
• (R)-(+)-1 -(4-Bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone
• 3-(Cyclopentyloxy-4-methoxyphenyl)-1 -(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2- pyrrolidone • cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carbon acid]
• 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 - one
• cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1 -ol]
• (R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate
• (S)-(-)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate
• 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3!4-c]-1 !2!4-triazolo[4,3- a]pyridine
• 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(iert-butyl)-9H-pyrazolo[3,4-c]-1 ,2,4-triazolo[4,3- a]pyridine optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hy- drosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
• Examples of preferred LTD4-antagonists which may be mentioned include Montelukast, Pranlukast, Zafirlukast, Masikulast , L-733321 (see compound 2ab of D. Guay et al, Bioorg. Med. Chem. Lett. 8 (1998) 453-458) and(E)-8-[2-[4-[4-(4-
Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1 H-tetrazole-5-yl)-4H-1 -benzopyran-4-one (MEN- 91507)
• 4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyric acid (MN-001 )
• 1 -(((R)-(3-(2-(6,7-Difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2- propyl)phenyl)thio)methylcyclopropane-acetic acid,
• 1 -(((1 (R)-3(3-(2-(2,3-Dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1 -hydroxy- 1 -methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid
• [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hy- drosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Further examples for optionally preferred salts and derivatives are alkali salts, i.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates. Examples of preferred EGFR-inhibitors which may be mentioned include Cetuximab, Trastuzu- mab, Panitumumab Gefitinib, Canertinib, Erlotinib, Mab ICR-62 and
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholine-4-yl)-1 -oxo-2-butene-1 -yl]amino}-7- cyclopropylmethoxy-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1 -oxo-2-butene-1 -yl]amino}-7- cyclopropylmethoxy-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 -yl]amino}-7- cyclopropylmethoxy-quinazoline
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(morpholine-4-yl)-1 -oxo-2-butene-1 -yl]amino}-7- cyclopentyloxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1 -oxo-2- butene-1 -yl]amino}-7-cyclopropylmethoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1 -oxo-2- butene-1 -yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4-yl)-1 -oxo- 2-butene-1 -yl]amino}-7-cyclopropylmethoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo-2- butene-1 -yl}amino)-7-cyclopropylmethoxy-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 -yl]amino}-7- cyclopentyloxy-quinazoline
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1 -oxo-2-butene-1 - yl]amino}-7-cyclopropylmethoxy-quinazoline
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1 -oxo-2-butene-1 - yl}amino)-7-cyclopropylmethoxy-quinazoline
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo-2-butene-1 - yl}amino)-7-cyclopropylmethoxy-quinazoline
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1 -oxo-2- butene-1 -yl}amino)-7-cyclopropylmethoxy-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 -yl]amino}-7- ((R)-tetrahydrofuran-3-yloxy)-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 -yl]amino}-7- ((S )-tetra hyd rof u ra n-3-y loxy )-q u i n azol i n e
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo-2- butene-1 -yl}amino)-7-cyclopentyloxy-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1 -oxo-2-butene-1 - yl]amino}-7-cyclopentyloxy-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 -yl]amino}-7- [(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 -yl]amino}-7- [(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino] quinazoline
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine
• 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 - yl]amino}-7-ethoxy-quinoline
• 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl- ethyl)amino]methyl}-furan-2-yl)quinazoline
• 4-[(R)-(1 -Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1 -oxo-2-butene-1 yl]amino}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholine-4-yl)-1 -oxo-2-butene-1 -yl]amino}-7- [(tetra hyd rof u ra n-2-y I )meth oxy]-q u i nazol i ne
• 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1 -oxo-2-butene-1 yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholine-4-yl)-1 -oxo-2-butene-1 - yl]amino}-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(R)- (tetrahydrofuran-2-yl)methoxy]-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-6-[(S)- (tetrahydrofuran-2-yl)methoxy]-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piperidin-1 -yl]-ethoxy}-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(tert.-butyloxycarbonyl)-piperidine-4-yloxy]-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexane-1 -yloxy)-7-methoxy- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexane-1 -yloxy)-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methyl-piperidine-4-yloxy)-7-methoxy-quinazolin
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(methoxymethyl)carbonyl]-piperidine-4-yloxy}-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(2-acetylamino-ethyl)-piperidine-4-yloxy]-7-methoxy- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexane- yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]-cyclohexane 1 -yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulfonylamino]-cyclohexane- 1 -yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methansulfonylamino- ethoxy)-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(piperidine-1 -yl)carbonyl]-piperidine-4-yloxy}-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -aminocarbonylmethyl-piperidine-4-yloxy)-7-methoxy- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl- amino}-cyclohexane-1 -yloxy)-7-methoxy quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}- cyclohexane-1 -yloxy)-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)sulfonyl]-N-methyl-amino}- cyclohexane-1 -yloxy)-7-methoxy- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexane-1 -yloxy)-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidine-4-yloxy)-7-ethoxy- quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidine-4-yloxy)-7-(2-methoxy- ethoxy)-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidine-4-yloxy]-7-(2-methoxy- ethoxy)-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexane-1 -yloxy)-7-methoxy- quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-[1 -(tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy- quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidine-1 -yl)carbonyl]-N-methyl-amino}- cyclohexane-1 -yloxy)-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1 -yl)carbonyl]-N-methyl amino}-cyclohexane-1 -yloxy)-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholine-4-yl)carbonylamino]-cyclohexane-1 yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[2-(2-oxopyrrolidine-1 -yl)ethyl]-piperidine-4-yloxy}-7- methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-(2- m et h oxy-et h oxy )-q u i n azo I i n e
• 4-[(3-Ethinyl-phenyl)amino]-6-(1 -acetyl-piperidine-4-yloxy)-7-methoxy-quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-(1 -methyl-piperidine-4-yloxy)-7-methoxy-quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-(1 -methansulfonyl-piperidine-4-yloxy)-7-methoxy-quinazolin
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methyl-piperidine-4-yloxy)-7(2-methoxy-ethoxy)- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -isopropyloxycarbonyl-piperidine-4-yloxy)-7-methoxy- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexane-1 -yloxy)-7-methoxy- chinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]- cyclohexane-1 -yloxy}-7-methoxy-quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-(piperidine-4-yloxy)-7-methoxy-quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-[1 -(2-methoxy-acetyl)-piperidine-4-yloxy]-7-methoxy- quinazoline
• 4-[(3-Ethinyl-phenyl)amino]-6-{1 -[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(cis-2,6-dimethyl-morpholine-4-yl)carbonyl]- piperidine-4-yloxy}-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{H
yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1 ]hept-5-yl)carbonyl]- piperidine-4-yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(N-methyl-N-2-methoxyethyl-amino)carbon
piperidine-4-yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -ethyl-piperidine-4-yloxy)-7-methoxy-quinazoli
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(^^
methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(3-methoxypropyl-amino)-carbonyl]-piperidi
yloxy}-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansutf^
1 -yloxy]-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N^
7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexane-1 -yloxy)-7-m
quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino
cyclohexane-1 -yloxy]-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-1 -yloxy)-^
methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl- amino}-cyclohexane-1 -yloxy)-7-methoxy-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(S)- (tetrahydrofuran-2-yl)methoxy]-quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidine-4-yloxy)-7-methoxy- quinazoline
• 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -cyano-piperidine-4-yloxy)-7-methoxy-quinazoline optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hy- drosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Examples of preferred dopamin antagonists which may be mentioned include Bromocriptine, Cabergoline, Alpha-Dihydroergocryptine, Lisuride, Pergolide, Pramipexole, Roxindole, Ropini- role, Talipexole, Terguride and Viozane, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hy- droacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydro- benzoate and hydro-p-toluenesulfonate.
Examples of preferred antiallergic agents which may be mentioned include Epinastine, Cetiriz- ine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Mizolastine, Ketotifene, Emedastine, Dimetindene, Clemastine, Bamipine, Cexchlorpheniramine, Pheniramine, Doxylamine, Chlor- phenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine, Ebastine, Olopatadine, De- sloratidine and Meclozine, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hy- droacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydro- benzoate and hydro-p-toluenesulfonate.
Examples of preferred PAF antagonists which may be mentioned include Lexipafante and
• 4-(2-Chlorphenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanone-1 -yl]-6H-thieno-[3,2-f]- [1 ,2,4]triazolo[4,3-a][1 ,4]diazepine
• 6-(2-Chlorphenyl)-8,9-dihydro-1 -methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta- [4,5]thieno-[3,2-f][1 ,2,4]triazolo[4,3-a][1 ,4]diazepine optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Examples of preferred MAP kinase inhibitors which may be mentioned include
• Bentamapimod (AS-602801 )
• Doramapimod (BIRB-796),
• 5-Carbamoylindole (SD-169),
• 6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridine carboxamide (VX-702), • alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazole acetonitrile (AS-601245),
• 9,12-Epoxy-1 H-diindolo[1 ,2,3-fg:3\2',1 '-kl]pyrrolo[3,4-i][1 ,6]benzodiazocine-10-Carboxylic acid (CEP-1347),
• 4-[3-(4-chlorophenyl)-5-(1 -methyl-4-piperidinyl)-1 H-pyrazole-4-yl]-pyrimidine (SC-409), optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hy- drosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Examples of preferred MRP4-lnhibitors which may be mentioned include /V-Acetyl-dinitrophenyl- Cysteine, cGMP, Cholate, Diclofenac, Dehydroepiandrosterone 3-glucuronide, Dehydroepian- drosterone 3-sulphate, Dilazep, Dinitrophenyl-S-glutathione, Estradiol 17-beta-glucuronide, Estradiol 3,17-disulphate, Estradiol 3-glucuronide, Estradiol 3-sulphate, Estrone 3-sulphate, Flurbiprofen, Folate, N5-formyl-tetrahydrofolate, Glycocholate, Glycolithocholic acid sulphate, Ibu- profen, Indomethacin, Indoprofen, Ketoprofen, Lithocholic acid sulphate, Methotrexate, (E)-3- [[[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]- propanoic acid alpha-Naphthyl-beta-D-glucuronide, Nitrobenzyl mercaptopurine riboside, Probenecid, Valspodar , Sildenafil, Sulfinpyrazone, Taurochenodeoxycholate, Taurocholate, Taurodeoxycholate, Taurolithocholate, Taurolithocholic acid sulphate, Topotecan, Trequinsin, Zaprinast and Dipyridamol, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Examples of preferred iNOS-lnhibitors which may be mentioned include S-(2- Aminoethyl)isothio-urea, Aminoguanidine, 2-Aminomethylpyridine, 5,6-dihydro-6-methyl-4H-1 ,3- thiazine-2-amine (AMT), L-Canavanin, 2-lminopiperidine, S-lsopropylisothiourea, S- Methylisothiourea, S-Ethylisothiourea, S-Methylthiocitrulline, S-Ethylthiocitrulline, L-NA (Ν - Nitro-L-arginin), L-NAME (N"-Nitro-L-argininmethylester), L-NMMA (N"-Monomethyl-L-arginin), L-NIO (N"-lminoethyl-L-ornithin), L-NIL (IsT-iminoethyl-lysin), (S)-6-Acetimidoylamino-2-amino- hexanoic acid (1 /-/-tetrazole-5-yl)-amide N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide , (S)-4-(2-acetimidoylamino-ethylsulfanyl)-2-amino-buturic acid ,2-[2-(4-Methoxy-pyridine-2-yl)- ethyl]-3H-imidazo[4,5-fc>]pyridine , 2-((R)-3-amino-1 -phenyl-propoxy)-4-chlor-5-fluorbenzonitrile, 2-((1 R,3S)-3-amino-4-hydroxy-1 -thiazole-5-yl-butylsulfanyl)-6-trifluoromethyl-nicotinonitrile, 2- ((1 R,3S)-3-amino-4-hydroxy-1 -thiazole-5-yl-butylsulfanyl)-4-chlor-benzonitrile, 2-((1 R,3S)-3- amino-4-hydroxy-1 -thiazole-5-yl-butylsulfanyl)-5-chlor-benzonitrile, (2S,4R)-2-amino-4-(2-chlor- 5-trifluoromethyl-phenylsulfanyl)-4-thiazole-5-yl-butane-1 -ol, 2-((1 R,3S)-3-amino-4-hydroxy-1 - thiazole-5-yl-butylsulfanyl)-5-chlor-nicotinonitrile, 4-((S)-3-amino-4-hydroxy-1 -phenyl- butylsulfanyl)-6-methoxy-nicotinonitrile and substituted 3-phenyl-3,4-dihydro-1 -isoquinolinamine as for instance 1 S,5S,6R)-7-Chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-ene-3-ylamin (4R,5R)-5- Ethyl-4-methyl-thiazolidine-2-ylideneamine,(1 S,5S,6R)-7-Chlor-5-methyl-2-aza- bicyclo[4.1.0]hept-2-ene-3-ylamin, (4R,5R)-5-Ethyl-4-methyl-thiazolidine-2-ylideneamine, (4R,5R)-5-Ethyl-4-methyl-selenazolidine-2-ylideneamine, 4-Aminotetrahydrobiopterine, (E)-3-(4- Chlor-phenyl)-/V-(1 -{2-oxo-2-[4-(6-trifluormethyl-pyrimidine-4-yloxy)-piperidine-1 -yl]- ethylcarbamoyl}-2-pyridine-2-yl-ethyl)-acrylamide , 3-(2,4-Difluor-phenyl)-6-[2-(4-imidazole-1 - ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine , 3-{[(Benzo[1 ,3]dioxol-5-ylmethyl)-carbamoyl]- methyl}-4-(2-imidazole-1 -yl-pyrimidine-4-yl)-piperazine-1 -carbon acid methylester , (R)-1 -(2- imidazole-1 -yl-6-methyl-pyrimidine-4-yl)-pyrrolidine-2-carbon acid (2-benzo[1 ,3]dioxol-5-yl- ethyl)-amide , optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethan- sulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Further examples of preferred iNOS-lnhibitors which may be mentioned include
antisense-Oligonucleotide, especially those antisense-Oligonucleotide bindung iNOS-coding nucleinic acids, examples therefore are disclosed in WO 01/52902.
Examples of preferred SYK-inhibitors which may be mentioned include
• 2-[(2-aminoethyl)amino]-4-[(3-bromophenyl)amino]-5-pyrimidinecarboxamide;
• 2-[[7-(3,4-dimethoxyphenyl)imidazo[1 ,2-c]pyrimidine-5-yl]amino]-3-pyridinecarboxamide;
• 6-[[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H- pyrido[3,2-b]-1 ,4-oxazin-3(4H)-one;
• N-[3-bromo-7-(4-methoxyphenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• 7-(4-methoxyphenyl)-N-methyl-1 ,6-naphthyridine-5-amine;
• N-[7-(4-methoxyphenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(2-thienyl)-1 ,6-naphthyridine-5-yl-1 ,3-propanediamine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,2-ethanediamine;
• N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1 ,6-naphthyridine-5-yl]- 1 ,3-propanediamine;
• N-[7-(4-methoxyphenyl)-3-phenyl-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-(7-phenyl-1 ,6-naphthyridine-5-yl)-1 ,3-propanediamine; • N-[7-(3-fluorophenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(3-chlorophenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[3-(trifluoromethoxy)phenyl]-1 ,6-naphthyridine-5yl]-1 ,3-propanediamine;
• N-[7-(4-fluorophenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(4-fluorophenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(4-chlorophenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(4'-methyl[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-1 ,3-propanediamine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(diethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(4-morpholinyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3- propanediamine;
• N-[7-(4-bromophenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(4-methylphenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(methylthio)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(1 -methylethyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• 7-[4-(dimethylamino)phenyl]-N-methyl-1 ,6-naphthyridine-5-amine;
• 7-[4-(dimethylamino)phenyl]-N,N-dimethyl-1 ,6-naphthyridine-5-amine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,4-butanediamine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,5-pentanediamine;
• 3-[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]oxy]-1 -propanole;
• 4-[5-(4-aminobutoxy)-1 ,6-naphthyridine-7-yl]-N,N-dimethyl-benzenamine;
• 4-[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]amino]-1 -butanole;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-N-methyl-1 ,3-propanediamine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-N'-methyl-1 ,3-propanediamine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-N,N'-dimethyl-1 ,3-propanediamine;
• 1 -amino-3-[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]amino]-2-propanole;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-2,2-dimethyl-1 ,3-propanediamine;
• 7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1 ,6-naphthyridine-5-amine;
• N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-amine;
• N-[7-[6-(dimethylamino)[1 ,1 '-biphenyl]-3-yl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[3-chloro-4-(diethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(diethylamino)phenyl]-3-methyl-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(3'-fluoro[1 ,1 '-biphenyl]-3-yl)-1 ,6-naphthyridine-5-yl]-1 ,2-ethanediamin,
• N-[7-(4-methoxyphenyl)-1 ,6-naphthyridine-5-yl]-1 ,6-naphthyridine-1 ,3-propanediamine;
• N,N'-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine; • N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-1 ,6-naphthyridine-5-yl]-1 ,6-naphthyridine-1 ,3- propanediamine;
• N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine;
• N-[7-(2-naphthalenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(2'-fluoro[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(3,4,5-trimethoxyphenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(3,4-dimethylphenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• 1 -amino-3-[[7-(2-naphthalenyl)-1 ,6-naphthyridine-5-yl]amino]-2-propanole;
• 1 -amino-3-[[7-(2'-fluoro[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-5-yl]amino]-2-propanole;
• 1 -amino-3-[[7-(4'-methoxy[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-5-yl]amino]-2-propanole;
• 1 -amino-3-[[7-(3,4,5-trimethoxyphenyl)-1 ,6-naphthyridine-5-yl]amino]-2-propanole;
• 1 -amino-3-[[7-(4-bromophenyl)-1 ,6-naphthyridine-5-yl]amino]-2-propanole;
• N-[7-(4'-methoxy[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-5-yl]-2,2-dimethyl-1 ,3- propanediamine;
• 1 -[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]amino]-2-propanole;
• 2-[[2-[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]amino]ethyl]thio]-ethanole;
• 7-[4-(dimethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-1 ,6-naphthyridine-5-amine;
• 7-[4-(dimethylamino)phenyl]-N-4-pyrimidinyl-1 ,6-naphthyridine-5-amine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-cyclohexane diamine;
• N,N-dimethyl-4-[5-(1 -piperazinyl)-1 ,6-naphthyridine-7-yl]-benzenamine;
• 4-[5-(2-methoxyethoxy)-1 ,6-naphthyridine-7-yl]-N,N-dimethyl-benzenamine;
• 1 -[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-4-piperidinole;
• 1 -[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-3-pyrrolidinole;
• 7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-1 ,6-naphthyridine-5-amine;
• 7-[4-(dimethylamino)phenyl]-N-[3-(1 H-imidazole-1-yl)propyl]-1 ,6-naphthyridine-5-amine;
• 1 -[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-4-piperidine carboxamide;
• 1 -[3-[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]amino]propyl]-2-pyrrolidinone;
• N-[3'-[5-[(3-aminopropyl)amino]-1 ,6-naphthyridine-7-yl][1 ,1 '-biphenyl]-3-yl]-acetamide;
• N-[7-(4'-fluoro[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[4'-[5-[(3-aminopropyl)amino]-1 ,6-naphthyridine-7-yl][1 ,1 '-biphenyl]-3-yl]-acetamide;
• N-[7-[4-(1 ,3-benzodioxol-5-yl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(2-thienyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(3-pyridinyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(1 ,3-benzodioxol-5-yl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(6-methoxy-2-naphthalenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• 7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1 ,6-naphthyridine-5-amine; • 3-[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]methylami
• 7-[4-(dimethylamino)phenyl]-N-[1 -(phenylmethyl)-4-piperidinyl]-1 ,6-naphthyridine-5-amine;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,2-cyclohexanediamin,
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,2-Cyclohexanediamine, (1 R,2S)- rel-.
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,2-benzene dimethanamine;
• N-[7-[4-(diethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,4-butanediamine;
• N-[7-[3',5'-bis(trifluoromethyl)[1 ,1 '-biphenyl]-4-yl]-1 ,6-naphthyridine-5-yl]-,3-propanediamine;
• N-[7-(3'-methoxy[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(3'-fluoro[1 ,1 '-biphenyl]-4-yl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• 4-[[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]oxy]-1 -butanole;
• N-[7-[4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]- 1 ,4-cyclohexanediamine;
• 7-[4-(dimethylamino)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-1 ,6-naphthyridine-5-amine;
• N-[7-[3-bromo-4-(dimethylamino)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(1 -methyl-1 H-indole-5-yl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[3-(trifluoromethyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-(trifluoromethyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-(3-bromo-4-methoxyphenyl)-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1 ,6-naphthyridine-5-yl]-1 ,4- cyclohexanediamine;
• N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1 ,6-naphthyridine-5-yl]-1 ,4- cyclohexanediamine;
• N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1 ,6-naphthyridine-5-yl]-1 ,4-cyclohexanediamine;
• N-[7-[4-(4-morpholinyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,4-cyclohexanediamine;
• N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,4-cyclohexanediamine;
• 4-[[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1 ,6-naphthyridine-5-yl]oxy]- cyclohexanole;
• N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1 ,6-naphthyridine-5-yl]-1 ,3-propanediamine;
• N,N-dimethyl-4-[5-(4-methyl-1 -piperazinyl)-1 ,6-naphthyridine-7-yl]-benzenamine;
• 4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1 ,6-naphthyridine-5-yl]oxy]- cyclohexanole;
• N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1 ,6-naphthyridine-5-yl]-1 ,4- butanediamin;
• [3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1 ,6-naphthyridine-2-yl]amino]propyl]- carbamic acid-1 ,1 -dimethylethyl ester, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydroni- trate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hy- drosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
Examples of preferred corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators which may be mentioned include, preferably VX-770 and VX-809
12. FORMULATIONS
Suitable forms for administration are for example inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.2 to 50 wt%, preferably 5 to 25 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.
Administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.
Preferably, therefore, pharmaceutical formulations are characterised in that they contain one or more compounds of (I) according to the preferred embodiments above.
It is also preferred if the compounds of formula (I) are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula (I) have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients.
Within the scope of the present invention, the term propellant-free inhalable solutions also include concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification.
Inhalable powders
If the active substances of formula (I) are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), di- saccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred. Methods of preparing the inhalable powders according to the invention by grinding and micronising and by finally mixing the components together are known from the prior art.
Propellant-containing inhalable aerosols
The propellant-containing inhalable aerosols which may be used according to the invention may contain a compound of formula (I) dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a
(1 ,1 ,1 ,2-tetrafluoroethane), TG227 (1 ,1 ,1 ,2,3,3, 3-heptafluoropropane) and mixtures thereof. The propellant-driven inhalation aerosols used within the scope of the use according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
Propel lant-free inhalable solutions
The compounds of formula (I) according to the invention are preferably used to prepare propel- lant-free inhalable solutions and inhalable suspensions. Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water on its own or a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, poly- oxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbi- tan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
For the treatment forms described above, ready-to-use packs of a medicament for the treatment of respiratory complaints are provided, containing an enclosed description including for example the words respiratory disease, COPD or asthma, a compound according to the invention and one or more combination partners selected from those described above.
The following example illustrates the present invention without restricting its scope:
Capsule for powder inhalation
1 capsule contains:
active substance 0.5 mg
lactose for inhalation 5.0 mg 5.5 mg
Preparation:
The active substance is mixed with lactose for inhalation. The mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg).
weight of capsule: 55.5 mg
size of capsule = 3

Claims

PATENT CLAIMS
1 . A compound of formula (I),
Figure imgf000112_0001
(I) characterized in that
R1 denotes H or Ci-4-alkyl,
R2 denotes H or Ci-4-alkyl,
R3 denotes H or methyl,
R4 denotes H or methyl, or
R3 and R4 together form an ethylene bridge,
R5 is selected from the group consisting of
H, d-4-alkyl-, Ci-4-alkyl-0-CO-, Ci-4-alkyl-0-CO-Ci-4-alkyl-,
Ci-4-alkyl-0-Ci-4-alkyl-, HO-CO- and HO-CO-Ci-4-alkyl-,
R6 is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl- which is optionally substituted by one or more F atoms,
HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0- and -NR6'1R6'2,
wherein,
R6-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R6 2 denotes H or Ci-4-alkyl-,
R7 is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl- which is optionally substituted by one or more F atoms, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR7 IR7-2,
H2N-C(NH)-, H2N-C(NH)NH-, H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-,
- Ci-4-alkyl-COOH, - Ci-4-alkyl-COO- C1-4-alkyl, -OCH2-COOH, -OCH2-COO- C1-4-alkyl,
-P(0)(OR7 3)(OR7-4), -CH2-P(0)(OR7 3)(OR7-4) and -B(OH)2 , wherein,
R7-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R7'2 denotes H or Ci-4-alkyl-,
R7'3, R7'4 independently from each other denote H or Ci-4-alkyl, is selected from the group consisting of
H, halogen, CN, N3, Ci-4-alkyl- which is optionally substituted by one or more F atoms, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR8 1R8 2,
H2N-C(NH)-, H2N-C(NH)NH-, H2N-C(NH)NH-CH2-, -COOH, Ci-4-alkyl-OCO-,
- Ci-4-alkyl-COOH, -Ci-4-alkyl-COO- C1-4-alkyl, -OCH2-COOH, -OCH2-COO- C1-4-alkyl, -P(0)(OR8 3)(OR8-4), -CH2-P(0)(OR8 3)(OR8-4) and -B(OH)2,
or
denotes -L2-Y1-L3-Y2-L4-R8 5
wherein,
R8-1 denotes H, C1-4-alkyl, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R8 2 denotes H or Ci-4-alkyl,
or
R8'1 and R8'2 together with the nitrogen atom they are attached to form a heterocycle Y3,
R8'3, R8'4 independently from each other denote H or Ci-4-alkyl,
R10, R8'5 independently from each other are selected from the group consisting of
H, halogen, CN, N3, C1-4-alkyl, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0-, -NR8-5 lR8-5-2
B(OH)2, BF3 ", -S(0)2OH, -0-C(C6H6)3, -C(CH2OH)3, -CH(CH2OH)2,
-CH(OH)CH2OH and -N+(R8-5 3)3
R8-5-1 denotes H, C1-4-alkyl, Ci-4-alkyl-CO- or C1-4-alkyl
R8-5-2 denotes H or C1-4-alkyl,
or
R8.5.1 „ a „nd^ 0 R8.5.2 together with the nitrogen atom they are attached to form a heterocycle Y3,
R8.5.3 denotes methyl or ethyl,
R9 denotes H or methyl, m, n independently from each other with the proviso that (m + n) < 4 , denote 0, 1 or 2, denotes halogen,
denotes a bond or is selected from the group consisting of
-CH2-, -CH2-CH2-, -CH20-, -CO-, -S-, -SO-, -S02-, -S-CH2-, SO-CH2- and -S02-CH2-, denotes a bond or is selected from the group consisting of -0-, -CH2-, -CH2-CH2-, -CH2-O-, -O-CH2-, -CO-, -CH2-CO-, -CO-CH2-, -S-, -SO-, -SO2- and -O-CO-,
L3, L4, L5 independently from each other denote a bond or a linear chain of formula (m)
-(CH2)i-[0-(CH2)g1]p1-[NH-(CH2)g2]p2-[0-(CH2)g3]p3- (m),
wherein
i denotes 0, 1 , 2, 3 or 4,
g1 , g2, g3 independently from each other denote 2, 3 or 4,
p1 , p3 independently from each other denote 0, 1 , 2, 3 or 4, p2 denotes 0 or 1 ,
with the provisio that the linear chain is consisting of 1 to 15 moieties selected from the group consisting of -CH2-, -O- and -NH- and with the proviso that the nitrogen atom of formula (m) is not directly linked to another nitrogen atom, denotes a bond, Y1 '1 or -NRY1 I-,
wherein,
RY1 '1 denotes L3-H or L3-NRY1 '1 '1 RY1 '1 '2,
wherein
RY1 '1 '1 is selected from among
H, Ci-4-alkyh d-4-alkyl-CO- and Ci-4-alkyl-S02-,
RY1-1-2 denotes H or C1-4-alkyl-,
or
RY1 '1 '1 and RY1-1-2 together with the nitrogen atom they are attached to form a
heterocycle Y3,
denotes a bond or
is selected from a group consisting of
Y2 \ -CO-, -NRY2 1-CO-, -CO-NRY2-1-, -Y2 1-CONRY2-1-, -Y2 1-CO- and -NRY2 1-CO-Y2 \ with the proviso that carbonyl moieties are not directly attached to nitrogen atoms of aromatic heterocycles,
wherein
RY2'1 denotes -L3-H or -L3-NRY2'1 '1 RY2'1 '2,
RY2'1 '1 is selected from among
H, Ci-4-alkyl-, Ci-4-alkyl-CO- and Ci-4-alkyl-S02-,
RY2-1-2 denotes H or C1-4-alkyl-, or
Υ2.ι.ι anc| Y2.i.2 together with the nitrogen atom they are attached to form a heterocycle Y3,
Y1'1, Y2'1 independently from each other denote a linker in form of a phenylene group optionally substituted by -L5R10, or
an optionally substituted heteroaromatic or heterocyclic moiety each containing at least one nitrogen atom,
Y3 denotes an optionally substituted 4-7-membered heterocycle containing at least one N-atom, and tautomers and optionally the pharmacologically acceptable acid addition salts thereof.
2. A compound of formula (I) according to claim 1 , characterized in that denotes CI or Br,
independently from each other denote a bond or are selected from a group consisting of a linker of formula (a) to (k)
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
Y3 denotes pyrrolidine or piperidine, each optionally substituted by up to two substi- tuents independently selected from hydroxy or Ci-3-alkoxy, or
Y3 denotes morpholine, piperazine, 4-methyl-piperazine, 4-ethyl-piperazine, 4- acetyl-piperazine or 4-propionyl-piperazine.
3. A compound of formula (I) according to claim 1 or 2, characterized in that
R\ R2, R3, R4, R5 denote H,
R9 denotes H,
X denotes CI,
L1 denotes a bond, -CH2-, -CH20- or -CO-, and
m, n independently from each other with the proviso that 0 < (m + n) < 4 , denote 0, 1 or 2, Y3 denotes morpholine, 4-acetyl-piperazine or 4-propionyl-piperazine.
4. A compound of formula (I) according to anyone of claims 1 to 3, characterized in that
R7 is selected from the group consisting of
-COOH, -CH2COOH, -(CH2)2COOH, -OCH2-COOH, -P(0)(OR7 3)(OR7-4),
-CH2-P(0)(OR7 3)(OR7-4) and -B(OH)2,
wherein
R7 3 denotes H,
R8 is selected from the group consisting of
H, halogen, CN, d-4-alkyl-, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0- and -NR8'1R8'2,
wherein
R8-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R8 2 denotes H or Ci-4-alkyl-,
or
R8'1 and R8'2 together with the nitrogen atom they are attached to form a heterocycle Y3.
5. A compound of formula (I) according to anyone of claims 1 to 3, characterized in that R7 is selected from the group consisting of
Ci-4-alkyl-OCO-, - Ci-2-alkyl-COO- C1-4-alkyl, -OCH2-COO- C1-4-alkyl, -P(0)(OR7 3)(OR7-4) and CH2-P(0)(OR7-3)(OR7-4),
wherein
R7 3, R7 4 independently from each other denote methyl, ethyl, or 2-propyl,
R8 is selected from the group consisting of
H, halogen, CN, C1-4-alkyl-, HC≡C-, OH, Ci-4-alkyl-0-, HO-CH2-,
H2C=CH-CH2-0-, HC≡C-CH2-0- and -NR8 IR8-2,
wherein
R8-1 denotes H, C1-4-alkyl-, Ci-4-alkyl-CO- or Ci-4-alkyl-S02-,
R8 2 denotes H or Ci-4-alkyl-,
or
R8-1 and R8 together with the nitrogen atom they are attached to form a heterocycle Y3.
6. A compound of formula (I) according to anyone of claims 1 to 3, characterized in that
L3, L4 independently from each other denote a bond, -CH2- or -CH2-CH2-,
R8 denotes -L2-Y1-L3-Y2-L4-R8 5,
wherein
R8-5 denotes -NH2 or -N+(R8-5-3)3,
R8-5-3 denotes methyl or ethyl,
R10 denotes hydrogen,
with the proviso that if Y2 denotes a bond, then
L2 denotes -CO- and Y1 denotes -NRY1 '1.
7. A compound of formula (I) according to anyone of claims 1 to 6, characterized in that
L2 denotes -CH2-CH2-,
denotes Y1 \
wherein γ1.1 is selected from a group consisting of linkers of formula (c), (d), (e), (f) and (k)
Figure imgf000118_0001
with the proviso that L3 is not a bond.
8. A compound of formula (I) according to anyone of claims 1 or 3, characterized in that
R7 is selected from the group consisting of
H, halogen, CN, C1-4-alkyl-, OH, Ci-4-alkyl-0- and HO-CH2-,
R8'5 is selected from the group consisting of H, OH,
Figure imgf000118_0002
-C(CH2OH)3,
-CH(CH2OH)2 and -CH(OH)CH2OH,
L2 denotes a bond, -CH2-CH2- or -0-CH2- ,
L3 denotes a bond,
L4 denotes a linear chain of formula (m.1):
-(CH2)r[0-(CH2)g1]p1 - (m.1),
wherein
i denotes 0, 1 , 2, or 3,
g1 denotes 2, or 3,
p1 denotes 0, 1 or 2, with the proviso that if R8'5 denotes OH, or Ci-4-alkyl-0-,
then ( i + p1 ) > 0,
and with the proviso that if R8'5 denotes H, then p1 > 0,
and with the provisio that the linear chain or formula (m.1) is consisting of no more than 8 moieties selected from the group consisting of -CH2- and -O- .
Y1 denotes a bond,
Y2 denotes -CO-NH- or Y2-1
wherein Y2'1 is selected from a roup consisting of linkers of formula (c), (d), (e), (f) and (k)
Figure imgf000119_0001
9. A compound of formula (I) according to anyone of claims 1 to 3, characterized in that
L2 denotes a bond,
L3, L4 independently from each other denote a bond or a linear chain of formula (m)
-(CH2)i-[0-(CH2)g1]p1-[NH-(CH2)g2]p2-[0-(CH2)g3]p3- (m),
wherein
i denotes 0, 1 , 2 or 3,
g1 denotes 2, 3 or 4,
g2 denotes 0,
g3 denotes 2 or 3,
p1 denotes 0 or 1 ,
p3 denotes 2, 3 or 4,
p2 denotes 0,
with the provisio that the linear chain is consisting of 5 to 12 moieties selected from the group consisting of -CH2- or -O- ,
with the proviso that L3 and L4 together consist of at least eight -CH2- moieties and of at least four -O- moieties, denotes Y1 \
wherein
Y1'1 denotes a linker of formula (e) or (f)
Figure imgf000119_0002
Y2 denotes a bond or
is selected from a group consisting of Y2'1, -Y2-1-CONRY2-1- and -NRY2-1-CO-Y2-1-, R8-5 denote H, OH or OMe.
10. A compound of formula (I) according to claims 1 , characterized in that
the compound is selected from the group consisting of:
a) 3-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmethyl}-benzoic acid,
Figure imgf000120_0001
b) 4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmethyl}-benzoic acid,
Figure imgf000120_0002
c) (4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmethyl}- phenoxy)-acetic acid,
Figure imgf000120_0003
d) (4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmethyl}- phenoxy)-acetic acid methyl ester,
Figure imgf000121_0001
e) (4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmethy phosphonic acid monoethyl ester,
Figure imgf000121_0002
f) 4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmethyl^ hydroxy-ethoxy)-ethyl]-benzamide,
Figure imgf000121_0003
g) N-[2-(4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmeth benzenesulfonylamino)-ethyl]-acetamide,
Figure imgf000121_0004
h) 3-Amino-N-[1 -(4-{4-[N'-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 - ylmethyl}-phenyl)-1 H-[1 ,2,3]triazol-4-ylmethyl]-N-methyl-propionamide,
Figure imgf000122_0001
Figure imgf000122_0002
j) N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'-{1 -[4-(1 -{2-[2-(2-hydroxy-ethoxy)-ethoxy]- ethyl}-1 H-[1 ,2,3]triazol-4-yl)-benzyl]-piperidin-4-yl}-guanidine,
.— OH
Figure imgf000122_0003
k) 3-{1 -[2-(4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1 -ylmethyl}- phenyl)-ethyl]-1 H-[1 ,2,3]triazol-4-yl}-N,N-bis-(2-hydroxy-ethyl)-propionamide
Figure imgf000122_0004
1 1. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use as a medicament.
12. A compound according to anyone of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways.
13. A compound according to anyone of claims 1 to 10 or a pharmaceutically acceptable salt thereof for for use in the treatment of a disease selected from among chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), paediat- ric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alpha-1 -antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema and pneumonitis of different origins.
14. A pharmaceutical composition comprising at least one compound according to anyone of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
15. Medicament combinations which contain, besides one or more compounds of a compound according to anyone of claims 1 to 10, as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1 - antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-lnhibitors, iNOS-lnhibitors, SYK- Inhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations thereof.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014177469A1 (en) * 2013-04-30 2014-11-06 Boehringer Ingelheim International Gmbh,M Diaminopyrazine compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof
WO2015003958A1 (en) * 2013-07-08 2015-01-15 Boehringer Ingelheim International Gmbh Amiloride-type compounds as inhibitors in epithelial sodium channels for the treatment of diseases of the lungs and airways
WO2015132228A1 (en) 2014-03-04 2015-09-11 Actelion Pharmaceuticals Ltd 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one derivatives and their use as antibacterial agents
EP2875001A4 (en) * 2012-07-18 2016-06-01 Sunshine Lake Pharma Co Ltd Nitrogenous heterocyclic derivatives and their application in drugs
JP2016529248A (en) * 2013-08-08 2016-09-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New pyrazinamide compounds
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
JP2017525677A (en) * 2014-07-07 2017-09-07 ジェネンテック， インコーポレイテッド Therapeutic compounds and methods of use thereof
WO2019220147A1 (en) 2018-05-18 2019-11-21 Enterprise Therapeutics Limited Compounds
US10759785B2 (en) 2016-06-21 2020-09-01 Enterprise Therapeutics Limited Compounds
US10941149B2 (en) 2016-11-22 2021-03-09 Enterprise Therapeutics Limited Substituted benzodiazoliums as ENaC inhibitors
US11091447B2 (en) 2020-01-03 2021-08-17 Berg Llc UBE2K modulators and methods for their use
US11370778B2 (en) 2017-10-17 2022-06-28 Enterprise Therapeutics Limited Bis(pentahydroxyhexyl)amino substituted 2-{[(3-amino-pyrazin-2-yl)formamido]methyl}-1H-1,3-benzodiazol-3-ium derivatives as ENaC inhibitors for treating respiratory diseases

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111492046B (en) * 2017-12-20 2022-09-09 亨斯迈石油化学有限责任公司 Aromatic-based polyetheramine alkoxylates

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052902A1 (en) 2000-01-24 2001-07-26 Isis Pharmaceuticals, Inc. Antisense modulation of inducible nitric oxide synthase expression
WO2008135557A1 (en) 2007-05-07 2008-11-13 Novartis Ag Organic compounds
WO2009138378A1 (en) * 2008-05-13 2009-11-19 Novartis Ag 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid derivatives and their use as epithelial sodium channel blockers for the treatment of arway diseases

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL6812003A (en) 1967-09-07 1969-03-11
US3953476A (en) 1971-12-27 1976-04-27 Merck & Co., Inc. 3-Amino-5-sulfonylbenzoic acids
KR20060037450A (en) * 2003-08-18 2006-05-03 패리온 사이언스 인코퍼레이티드 Cyclic pyrazinoylguanidine sodium channel blockers
GB0526244D0 (en) * 2005-12-22 2006-02-01 Novartis Ag Organic compounds
DK2723176T3 (en) 2011-06-27 2017-07-31 Parion Sciences Inc CHEMICAL AND METABOLIC STABLE DIPEPTIDE WITH POTENT SODIUM CHANNEL BLOCK ACTIVITY
AR086745A1 (en) 2011-06-27 2014-01-22 Parion Sciences Inc 3,5-DIAMINO-6-CHLORINE-N- (N- (4- (4- (2- (HEXIL (2,3,4,5,6-PENTAHYDROXIHEXIL)) AMINO) ETOXI) PHENYL) BUTIL) CARBAMIMIDOIL) PIRAZINA -2-CARBOXAMIDE

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052902A1 (en) 2000-01-24 2001-07-26 Isis Pharmaceuticals, Inc. Antisense modulation of inducible nitric oxide synthase expression
WO2008135557A1 (en) 2007-05-07 2008-11-13 Novartis Ag Organic compounds
WO2009138378A1 (en) * 2008-05-13 2009-11-19 Novartis Ag 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid derivatives and their use as epithelial sodium channel blockers for the treatment of arway diseases

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"A Textbook of Drug Design and Development", 1991, GORDON & BREACH, article "Design and Applications of Prodrugs"
"Bioreversible Carriers in Drug Design", 1987, ELSEVIER
"Burger's Medicinal Chemistry and Drug Discovery", vol. 1, 1995, JOHN WILEY & SONS, pages: 172 - 178,949-
"Design of Prodrugs", 1985, ELSEVIER
"Methods in Enzymology", vol. 42, 1985, ACADEMIC PRESS, pages: 309 - 396
"Pro-Drugs as Novel Delivery Systems", 1975, AM. CHEM. SOC.
"Prodrugs: Topical and Ocular Drug Delivery", 1998, MARCEL DEKKER
"Protective Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS, INC.
BERGE, S.M. ET AL.: "Pharmaceutical salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
D. GUAY ET AL., BIOORG. MED. CHEM. LETT., vol. 8, 1998, pages 453 - 458
E. MERCK, DARMSTADT, ITEM NO. 1.05713
HIRSH ANDREW J ET AL: "Design, Synthesis, and Structure-Activity Relationships of Novel 2-Substituted Pyrazinoylguanidine Epithelial Sodium Channel Blockers: Drugs for Cystic Fibrosis and Chronic Bronchitis", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 49, no. 14, 13 July 2006 (2006-07-13), pages 4098 - 4115, XP008122316, ISSN: 0022-2623, [retrieved on 20060613], DOI: 10.1021/JM051134W *
J.MED.CHEM., vol. 10, 1967, pages 66 - 75
J.MED.CHEM., vol. 49, 2006, pages 4098 - 4115
JH LI ET AL: "Stereoselective blockade of amphibian epithelial sodium channels by amiloride analogs", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, US, vol. 267, no. 3, 1 December 1993 (1993-12-01), pages 1081 - 1084, XP008093856, ISSN: 0022-3565 *

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