US20060142373A1 - Medicaments for the Treatment or Prevention of Fibrotic Diseases - Google Patents

Medicaments for the Treatment or Prevention of Fibrotic Diseases Download PDF

Info

Publication number
US20060142373A1
US20060142373A1 US11/275,223 US27522305A US2006142373A1 US 20060142373 A1 US20060142373 A1 US 20060142373A1 US 27522305 A US27522305 A US 27522305A US 2006142373 A1 US2006142373 A1 US 2006142373A1
Authority
US
United States
Prior art keywords
phenyl
methylene
indolinone
group
anilino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/275,223
Other languages
English (en)
Inventor
John Park
Gerald Roth
Armin Heckel
Nveed Chaudhary
Trixi Brandl
Georg Dahmann
Matthias Grauert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36602118&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20060142373(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GRAUERT, MATTHIAS, HECKEL, ARMIN, BRANDL, TRIXI, DAHMANN, GEORG, ROTH, GERALD JUERGEN, CHAUDHARY, NVEED, PARK, JOHN EDWARD
Publication of US20060142373A1 publication Critical patent/US20060142373A1/en
Priority to US12/645,151 priority Critical patent/US20100204211A1/en
Priority to US14/184,821 priority patent/US20140296217A1/en
Priority to US14/982,179 priority patent/US10154990B2/en
Priority to US16/167,567 priority patent/US20190038600A1/en
Priority to US16/921,043 priority patent/US20200330435A1/en
Priority to US18/363,779 priority patent/US20230372297A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to a new use of indolinones of general formula substituted in the 6 position, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof.
  • Remodeling is a normal response to tissue injury and inflammation that is observed in many tissues throughout the body. After resolution of the inflammation and repair of tissue damage, the tissue is generally returned to its original condition. Excessive uncontrolled tissue repair or the failure to stop remodeling when it is no longer required leads to condition known as fibrosis. Fibrosis is characterized by excessive deposition of extracellular matrix components and overgrowth of fibroblasts.
  • Fibrosis can occur in all tissues but is especially prevalent in organs with frequent exposure to chemical and biological insults including the lung, skin, digestive tract, kidney, and liver (Eddy, 1996, J Am Soc Nephrol, 7(12):2495-503; Dacic et al., 2003, Am J Respir Cell Mol Biol, 29S: S5-9; Wynn, 2004, Nat Rev Immunol, 4(8):583-94). Fibrosis often severely compromises the normal function(s) of the organ and many fibrotic diseases are, in fact, life-threatening or severely disfiguring, such as idiopathic pulmonary fibrosis (IPF), liver cirrhosis, scleroderma, or renal fibrosis. Treatment options for these diseases are often limited to organ transplantation, a risky and expensive procedure.
  • IPF idiopathic pulmonary fibrosis
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • TGFb transforming growth factor beta growth factor families in the induction or persistence of fibrosis
  • PDGF, EGF and FGF family members are potent mitogens for mesenchymal cells such as smooth muscle cells, myofibroblasts and fibroblasts (Benito et al., 1993, Growth Regul 3(3):172-9; Simm et al, 1998, Basic Res Cardiol, 93(S3):40-3; Klagsburn, Prog Growth Factor Res, 1989, 1(4):207-35; Kirkland et al., 1998, J Am Soc Nephrol, 9(8):1464-73), the very cells which supplant normal tissue in fibrosis and are believed to play a role in tissue remodeling (Abboud, 1995, Annu Rev Physiol., 57:297-309; Jinnin et al., 2004, J Cell Physiol, online; Martinet et al., 1996, Arch Toxicol 18:127-39; Desmouliere, Cell Biology International, 1995, 19:471-6; Jelaska et al., Springer Semin Immunopathol,
  • FGF1/FGF2-deficient mice show dramatically decreased liver fibrosis after chronic carbon tetrachloride (CCl4) exposure (Yu et al., 2003, Am J Pathol, 163(4):1653-62).
  • FGF expression is increased in human renal interstitial fibrosis where it strongly correlates with interstitial scarring (Strutz et al., 2000, Kidney Intl, 57:1521-38) as well as in a model of experimental lung fibrosis (Barrios et al., 1997, Am J Physiol, 273 (2 Pt 1):L451-8), again lending credence to the idea that fibrosis in various tissues has a common basis.
  • VEGF vascular endothelial growth factor
  • TGFb stimulates production of extracellular matrix proteins including fibronectin and collagens and is believed to play an important role in fibrosis in many tissues (Leask et al., 2004, FASEB J 18(7):816-27; Bartram et al., 2004, Chest 125(2):754-65; Strutz et al., 2003, Springer Semin Immunopathol, 24:459-76; Wynn, 2004, Nat Rev Immunol, 4(8):583-94). Inhibitors of TGFb production and signaling pathways are active in a number of fibrosis animal models (Wang et al., 2002, Exp Lung Res, 28:405-17; Laping, 2003, Curr Opin Pharmacol, 3(2):204-8).
  • the present invention thus relates to the use of the compounds of above general formula I for the preparation of a medicament for the treatment or prevention of specific fibrotic diseases.
  • the present invention also relates to a method for the treatment or prevention of specific fibrotic diseases, by administration to a patient in need thereof of a pharmaceutical composition comprising a compound of above general formula I, together with a pharmaceutically suitable carrier.
  • a pharmaceutical composition comprising a compound of above general formula I, together with a pharmaceutically suitable carrier.
  • patient is meant to comprise the mammalian animal body, preferably the human body.
  • the present invention further relates to a pharmaceutical composition for the treatment or prevention of specific fibrotic diseases which comprises a compound of above general formula I alone or in combination with one or more further therapeutic agents.
  • the compounds of above general formula I are the compounds in which
  • X denotes an oxygen or sulphur atom
  • R 1 denotes a hydrogen atom or a prodrug group such as a C 1-4 -alkoxycarbonyl or C 2-4 -alkanoyl group,
  • R 2 denotes a carboxy group, a straight-chain or branched C 1-6 -alkoxy-carbonyl group, a C 4-7 -cycloalkoxy-carbonyl or an aryloxycarbonyl group,
  • C 1-6 -alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C 1-3 -alkoxy-carbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,
  • an aminocarbonyl or methylaminocarbonyl group an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group,
  • R 3 denotes a hydrogen atom, a C 1-6 -alkyl, C 3-7 -cycloalkyl, trifluoromethyl or heteroaryl group,
  • a phenyl or naphthyl group a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C 1-3 -alkyl or C 2-3 -alkoxy group, whilst in the event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted
  • C 1-3 -alkylcarbonylamino N—(C 1-3 -alkyl)-C 1-3 -alkyl-carbonylamino, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, C 1-3 -alkyl-sulphonylamino, C 1-3 -alkylsulphonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino-C 1-3 -alkyl or aryl-C 1-3 -alkylsulphonylamino group,
  • R 4 denotes a C 3-7 -cycloalkyl group
  • methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,
  • R 6 a phenyl group substituted by the group R 6 , which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-5 -alkyl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, amino, acetylamino, C 1-3 -alkyl-sulphonylamino, aminocarbonyl, C 1-3 -alkyl-aminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, aminosulphonyl, C 1-3 -alkyl-aminosulphonyl, di-(C 1-3 -alkyl)-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein
  • R 6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom
  • a C 1-3 -alkoxy group a C 1-3 -alkoxy-C 1-3 -alkoxy, phenyl-C 1-3 -alkoxy, amino-C 2-3 -alkoxy, C 1-3 -alkylamino-C 2-3 -alkoxy, di-(C 1-3 -alkyl)-amino-C 2-3 -alkoxy, phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, N—(C 1-3 -alkyl) -phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, C 5-7 -cycloalkyleneimino-C 2-3 -alkoxy or C 1-3 -alkylmercapto group,
  • methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,
  • a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
  • the cycloalkylene moiety may be fused to a phenyl ring or one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl group and/or
  • the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino group or
  • R 7 denotes a C 3-7 -cycloalkyl group
  • a —(CH 2 ) 2 group may be replaced by a —CO—NH group
  • a —(CH 2 ) 3 group may be replaced by a —NH—CO—NH or —CO—NH—CO group or a —(CH 2 ) 4 group may be replaced by a —NH—CO—NH—CO group
  • a hydrogen atom bound to a nitrogen atom may be replaced by a C 1-3 -alkyl group
  • a hydroxy or C 1-3 -alkoxy group an amino, C 1-7 -alkylamino, di-(C 1-7 -alkyl) -amino, phenylamino, N-phenyl-C 1-3 -alkyl-amino, phenyl-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino or di-(phenyl-C 1-3 -alkyl)-amino group,
  • guanidino group wherein one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl group
  • R 8 denotes a hydrogen atom or a C 1-3 -alkyl group
  • n denotes one of the numbers 0, 1, 2 or 3 and
  • R 9 denotes an amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino,
  • R 10 denotes a hydrogen atom, a C 1-3 -alkyl group, a C 1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C 2-3 -alkyl-carbonyl, C 1-3 -alkylsulphonyl, arylsulphonyl or phenyl-C 1-3 -alkylsulphonyl group,
  • n denotes one of the numbers 1, 2, 3 or 4,
  • ⁇ denotes the number 1 or, if m denotes one of the numbers 2, 3 or 4, o may also denote the number 0 and
  • R 11 denotes an amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino, N—(C 1-4 -alkyl)-benzylamino, C 1-4 -alkoxy or C 1-3 -alkoxy-C 1-3 -alkoxy group, a di-(C 1-4 -alkyl)-amino-C 1-3 -alkylamino group optionally substituted in the 1 position by a C 1-3 -alkyl group or a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulph
  • the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C 1-3 -alkyl, C 1-3 -alkoxy or amino group, and/or
  • one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl group and/or
  • the methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy or C 1-3 -alkoxy-C 1-3 -alkyl group,
  • the methylene group in the 3 or 4 position of a 6- or 7-membered cycloalkyleneimino group may in each case be substituted by a hydroxy, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-C 2-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkyl-amino group or
  • sulphinyl, sulphonyl may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl-), —N(phenyl), —N(phenyl-C 1-3 -alkyl-), —N(C 1-3 -alkyl-carbonyl-), —N(C 1-4 -alkyl-hydroxy-carbonyl-), —N(C 1-4 -alkoxy-carbonyl-), —N(benzoyl-) or —N(phenyl-C 1-3 -alkyl-carbonyl-) group,
  • a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 7-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group,
  • R 6 denotes a C 1-4 -alkyl group which is substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group,
  • R 12 denotes a hydrogen atom, a C 1-6 -alkyl or C 3-7 -cycloalkyl group or a C 1-3 -alkyl group terminally substituted by a phenyl, heteroaryl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, aminocarbonyl, C 1-4 -alkylamino-carbonyl, di-(C 1-4 -alkyl)-amino-carbonyl, C 1-3 -alkyl-carbonyl, C 1-3 -alkyl-sulphonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkyl-sulphonylamino, C 1-3 -alkyl-aminosulphonyl or di-(C 1-3 -alkyl) -aminosulphonyl group and
  • p denotes one of the numbers 0, 1, 2 or 3 and
  • R 13 assumes the meanings of the abovementioned group R 7 , or, if p denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
  • R 14 denotes a hydrogen atom, a C 1-4 -alkyl group, a C 1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C 1-3 -alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C 1-3 -alkylcarbonyl, C 1-4 -alkylsulphonyl, arylsulphonyl, phenyl-C 1-3 -alkylsulphonyl, heteroarylsulphonyl or heteroaryl-C 1-3 -alkyl-sulphonyl group,
  • q denotes one of the numbers 1, 2, 3 or 4,
  • r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it may also denote the number 0 and
  • R 15 assumes the meanings of the abovementioned group R 7 .
  • R 16 denotes a hydrogen atom or a C 1-4 -alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or N—(C 1-3 -alkyl)-trifluoromethyl-carbonyl-amino group and
  • R 17 denotes a C 1-3 -alkyl group
  • all the single-bonded or fused phenyl groups contained in the groups mentioned under R 6 may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-5 -alkyl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl, di-(C 1-4 -alkyl)-amino-carbonyl, aminosulphonyl, C 1-3 -alkyl-aminosulphonyl, di-(C 1-3 -alkyl)-aminosulphonyl, C 1-3 -alkyl-sulphonylamino, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group, and
  • R 5 denotes a hydrogen atom or a C 1-3 -alkyl group
  • an aryl group is meant a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C 1-3 -alkyl or C 1-3 -alkoxy group and
  • heteroaryl group a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C 1-3 -alkyl group in the carbon skeleton, wherein
  • the 6-membered heteroaryl group contains one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, an oxygen or sulphur atom or
  • an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or
  • a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused phenyl ring,
  • the saturated alkyl and alkoxy moieties with more than 2 carbon atoms which are present in the groups defined hereinbefore also include the branched isomers thereof, such as for example the isopropyl, tert.butyl, isobutyl group, unless otherwise stated, and
  • the hydrogen atom of any carboxy group present or a hydrogen atom bound to a nitrogen atom may each be replaced by a group which can be cleaved in vivo.
  • a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C 1-16 -alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C 1-16 -alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyl
  • R 6 denotes a C 1-8 -alkyl, C 5-7 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl group,
  • R f denotes a hydrogen atom, a C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl group and
  • R g denotes a hydrogen atom, a C 1-3 -alkyl or R e CO—O—(R f CR g )—O group wherein R e to R g are as hereinbefore defined,
  • amino group may be a phthalimido group
  • ester groups may also be used as a group which can be converted in vivo into a carboxy group
  • R 2 denotes a straight-chain or branched C 1-6 -alkoxy-carbonyl group, a C 4-7 -cycloalkoxycarbonyl or a aryloxycarbonyl group,
  • C 1-6 -alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,
  • R 2 denotes an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group,
  • R 4 denotes an R 7 -(C 1-4 -alkyl)-phenyl group, wherein
  • R 7 denotes an amino, C 1-7 -alkylamino, di-(C 1-7 -alkyl)-amino, phenylamino, N-phenyl-C 2-3 -alkyl-amino, phenyl-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino or di-(phenyl-C 1-3 -alkyl)-amino group,
  • Preferred compounds of general formula I are those wherein
  • R 1 and R 3 are as hereinbefore defined and X denotes an oxygen atom
  • R 2 denotes a carboxy group, a straight-chain or branched C 1-6 -alkoxy-carbonyl group, a C 5-7 -cycloalkoxycarbonyl or a phenoxycarbonyl group,
  • C 1-3 -alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,
  • an aminocarbonyl or methylaminocarbonyl group an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group,
  • R 4 denotes a C 3-7 -cycloalkyl group
  • methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,
  • R 6 a phenyl group substituted by the group R 6 , which may additionally be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C 1-3 -alkyl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, amino, acetylamino, aminocarbonyl, C 1-3 -alkyl-aminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein
  • R 6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom
  • a C 1-3 -alkoxy group an amino-C 2-3 -alkoxy, C 1-3 -alkylamino-C 2-3 -alkoxy, di-(C 1-3 -alkyl)-amino-C 2-3 -alkoxy, phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, pyrrolidino-C 2-3 -alkoxy, piperidino-C 2-3 -alkoxy or C 1-3 -alkylmercapto group,
  • a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
  • one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl group and/or
  • the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl) -phenyl-C 1-3 -alkylamino group or
  • sulphinyl may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH or —N(C 1-3 -alkyl) group,
  • R 7 denotes a C 5-7 -cycloalkyl group
  • methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be replaced by an —NH or —N(C 1-3 -alkyl) group or
  • a —(CH 2 ) 2 group may be replaced by a —CO—NH group
  • a —(CH 2 ) 3 group may be replaced by a —NH—CO—NH—
  • a —(CH 2 ) 4 group may be replaced by a —NH—CO—NH—CO group
  • a hydrogen atom bound to a nitrogen atom may be replaced by a C 1-3 -alkyl group
  • a ⁇ -hydroxy-C 2-3 -alkyl-amino N—(C 1-3 -alkyl)- ⁇ -hydroxy-C 2,3 -alkyl-amino, di-( ⁇ -hydroxy-C 2-3 -alkyl)-amino, di- ⁇ -(C 2-3 -alkoxy)-C 2-3 -alkyl)-amino or N-(dioxolan-2-yl)-C 1-3 -alkyl-amino group, a C 1-3 -alkylcarbonylamino-C 2-3 -alkyl-amino or C 1-3 -alkylcarbonylamino-C 2-3 -alkyl-N—(C 1-3 -alkyl)-amino group,
  • guanidino group wherein a hydrogen atom may be replaced by a C 1-3 -alkyl group
  • R 8 denotes a hydrogen atom or a C 1-3 -alkyl group
  • n denotes one of the numbers 0, 1, 2 or 3 and
  • R 9 denotes an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, phenylamino, benzylamino or C 1-4 -alkoxy group, a 5- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
  • R 10 denotes a hydrogen atom, a C 1-3 -alkyl group, a C 1-3 -alkylcarbonyl or C 1-3 -alkylsulphonyl group,
  • n denotes one of the numbers 1, 2 or 3,
  • ⁇ denotes the number 1 or, if m is one of the numbers 2 or 3, ⁇ may also denote the number 0 and
  • R 11 denotes an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, C 1-4 -alkoxy or C 1-3 -alkoxy-C 1-3 -alkoxy group or a 5- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group,
  • cycloalkylene moiety may be fused to a phenyl group or
  • one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl group and/or
  • the methylene group in position 3 of the pyrrolidino group may be substituted by a hydroxy or C 1-3 -alkoxy group
  • the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino group or
  • sulphinyl, sulphonyl may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(phenyl-C 1-3 -alkyl), —N(C 1-3 -alkyl-carbonyl), —N(C 1-4 -alkoxy-carbonyl), —N(benzoyl) or —N(phenyl-C 1-3 -alkyl-carbonyl) group,
  • a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 6-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group,
  • R 6 denotes a C 1-4 -alkyl group which is terminally substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group,
  • R 12 denotes a hydrogen atom, a C 1-3 -alkyl, C 5-7 -cycloalkyl, phenyl-C 1-3 -alkyl or heteroaryl-C 1-3 -alkyl group and
  • p denotes one of the numbers 0, 1, 2 or 3 and
  • R 13 assumes the meanings of the abovementioned group R 7 , or, if p denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
  • R 14 denotes a hydrogen atom, a C 1-4 -alkyl group, a C 1-3 -alkylcarbonyl, phenylcarbonyl, phenyl-C 2-3 -alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C 1-3 -alkylcarbonyl, C 1-4 -alkylsulphonyl, phenylsulphonyl, phenyl-C 1-3 -alkylsulphonyl-heteroarylsulphonyl or heteroaryl-C 1-3 -alkyl-sulphonyl group,
  • q denotes one of the numbers 1, 2, 3 or 4,
  • r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it may also denote the number 0 and
  • R 15 assumes the meanings of the abovementioned group R 7 .
  • R 16 denotes a hydrogen atom or a C 1-4 -alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or N—(C 1-3 -alkyl)-trifluoromethyl-carbonyl-amino group and
  • R 17 denotes a C 1-3 -alkyl group
  • phenyl groups contained in the groups mentioned under R 6 may be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C 1-3 -alkyl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkyl-aminocarbonyl, aminosulphonyl, C 1-3 -alkyl-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group, and
  • R 5 denotes a hydrogen atom or a C 1-3 -alkyl group
  • heteroaryl group as mentioned above is meant a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl or triazolyl group optionally substituted in the carbon skeleton by a C 1-3 -alkyl group wherein a hydrogen atom bound to a nitrogen atom may be replaced by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group and wherein the 5-membered heteroaryl groups containing at least one imino group are bound via a carbon or nitrogen atom,
  • a hydrogen atom bound to a nitrogen atom in the abovementioned groups may be replaced by a group which can be cleaved in vivo, particularly by an acetyl or tert.butoxycarbonyl group,
  • the carboxy groups contained in the abovementioned groups may each be substituted by a group which can be cleaved in vivo and may occur, for example, in the form of the tert.butoxycarbonyl group,
  • saturated alkyl and alkoxy moieties contained in the abovementioned groups which contain more than 2 carbon atoms, may be straight-chain or branched, unless otherwise stated,
  • R 2 denotes a straight-chain or branched Cl -alkoxy-carbonyl group, a C 3-7 -cycloalkoxycarbonyl or a phenoxycarbonyl group,
  • C 1-3 -alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a phenyl-carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,
  • a second sub-group of preferred compounds of general formula I deserving special mention comprises those wherein
  • R 2 denotes an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group,
  • a third sub-group of preferred compounds of general formula I deserving special mention comprises those wherein
  • R 4 denotes an R 7 -(n-C 1-4 -alkyl)-phenyl group, wherein
  • R 7 denotes an amino, C 1-6 -alkylamino, di-(C 1-6 -alkyl)-amino, phenylamino, N-phenyl-C 2-3 -alkyl-amino, phenyl-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino or di-(phenyl-C 1-3 -alkyl)-amino group,
  • X denotes an oxygen atom
  • R 1 denotes a hydrogen atom
  • R 2 denotes a carboxy group, a straight-chain or branched C 1-4 -alkoxycarbonyl group or a phenoxycarbonyl group,
  • C 1-3 -alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a phenyl, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,
  • an aminocarbonyl or methylaminocarbonyl group an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group,
  • R 3 denotes a C 1-4 -alkyl group or a phenyl group which may be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 1-3 -alkyl, hydroxy or C 1-3 -alkoxy group,
  • R 4 denotes a C 5-6 -cycloalkyl group
  • methylene group in position 4 of the cyclohexyl group may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,
  • a phenyl group a phenyl group disubstituted by C 1-3 -alkyl, C 1-3 -alkoxy or nitro groups, wherein the substituents may be identical or different, or
  • R 6 a phenyl group substituted by the group R 6 , which may additionally be substituted by a fluorine, chlorine or bromine atom or by an amino or nitro group, wherein R 6 denotes a fluorine, chlorine or bromine atom,
  • the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an —NH or —N(C 1-3 -alkyl) group,
  • R 7 denotes a C 5-7 -cycloalkyl group
  • a —(CH 2 ) 2 group may be replaced by a —CO—NH group
  • a —(CH 2 ) 3 group may be replaced by an —NH—CO—NH—
  • a —(CH 2 ) 4 group may be replaced by an —NH—CO—NH—CO group
  • a hydrogen atom bound to a nitrogen atom may be replaced by a C 1-3 -alkyl group
  • a phenyl or pyridinyl group or a pyrrolyl pyrazolyl, imidazolyl or triazolyl group bound via a carbon or nitrogen atom
  • the abovementioned heteroaromatic groups in the carbon skeleton may be substituted by a C 1-3 -alkyl group or a hydrogen atom bound to a nitrogen atom may be replaced by a C 1-3 -alkyl group
  • guanidino group wherein a hydrogen atom may be replaced by a C 1-3 -alkyl group
  • R 8 denotes a hydrogen atom or a C 1-3 -alkyl group
  • n denotes one of the numbers 0, 1, 2 or 3 and
  • R 9 denotes an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino or C 1-4 -alkoxy group, a 5- or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an —NH, —N(C 1-3 -alkyl) or —N(C 1-3 -alkyl-carbonyl) group, or, if n denotes one of the numbers 1, 2 or 3, R, may also denote a hydrogen atom,
  • R 10 denotes a hydrogen atom or a C 1-3 -alkyl group
  • n denotes one of the numbers 1, 2 or 3,
  • ⁇ denotes the number 1 or, if m is one of the numbers 2 or 3, ⁇ may also denote the number 0 and R 11 denotes an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, C 1-4 -alkoxy or methoxy-C 1-3 -alkoxy group or a 5- or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an —NH, —N(C 1-3 -alkyl) or —N(C 1-3 -alkyl-carbonyl) group,
  • the methylene group in position 3 of the pyrrolidino group may be substituted by a hydroxy group
  • the methylene group in position 4 of the piperidino group may be substituted by a hydroxy, hydroxy-C 1-3 -alkyl or C 1-3 -alkoxy group or
  • sulphinyl, sulphonyl may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl), —N(C 1-3 -alkyl-carbonyl), —N(benzoyl) or —N(phenyl-C 1-3 -alkyl-carbonyl) group,
  • a methylene group linked to an imino-nitrogen atom of the pyrrolidino, piperidino or piperazino group may be replaced by a carbonyl group
  • R 6 denotes a straight-chain C 1-3 -alkyl group which is terminally substituted by a carboxy or C 1-3 -alkoxy-carbonyl group
  • R 12 denotes a hydrogen atom, a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group
  • p denotes one of the numbers 0, 1 or 2 and
  • R 13 denotes an amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, benzylamino, N—(C 1-3 -alkyl) -benzylamino, C 1-3 -alkoxy-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-C 1-3 -alkoxy-C 1-3 -alkylamino, di-(2-methoxy-ethyl)-amino, di-( ⁇ -hydroxy-C 1-3 -alkyl)-amino or aminocarbonyl-methyl-N-(methyl)-amino group,
  • R 14 denotes a hydrogen atom, a C 1-4 -alkyl, C 2-3 -alkyl-carbonyl, phenylcarbonyl, phenyl-C 1-3 -alkylcarbonyl, furyl-carbonyl, pyridinyl-carbonyl, furyl-C 1-3 -alkylcarbonyl, pyridinyl-C 1-3 -alkylcarbonyl, C 1-4 -alkylsulphonyl, phenylsulphonyl or phenyl-C 1-3 -alkylsulphonyl group,
  • q denotes one of the numbers 1, 2 or 3,
  • r denotes the number 1 or, if q is one of the numbers 2 or 3, it may also denote the number 0 and
  • R 15 denotes an amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino or N—(C 1-4 -alkyl) -benzylamino group,
  • R 16 denotes a hydrogen atom or a C 1-3 -alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or N—(C 1-3 -alkyl)-trifluoromethyl-carbonyl-amino group and
  • R 17 denotes a C 1-3 -alkyl group
  • R 5 denotes a hydrogen atom
  • carboxy groups contained in the abovementioned groups may also be present in the form of the tert.butoxycarbonyl precursor group and
  • saturated alkyl and alkoxy moieties contained in the abovementioned groups which contain more than 2 carbon atoms, may be straight-chain or branched, unless otherwise stated,
  • R 2 denotes a straight-chain or branched C 1-4 -alkoxycarbonyl group or a phenoxycarbonyl group
  • C 1-3 -alkoxycarbonyl group which is terminally substituted in the alkyl moiety by a phenyl-carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group, or
  • R 4 denotes an R 7 -(n-C 1-3 -alkyl)-phenyl group, wherein
  • R 7 denotes an amino, C 1-6 -alkylamino, di-(C 1-4 -alkyl)-amino, ⁇ -hydroxy-C 2-3 -alkyl-amino,
  • a second subgroup of particularly preferred compounds of general formula I deserving special mention comprises those wherein
  • R 2 denotes an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group and
  • R 4 denotes a R 7 -(n-C 1-3 -alkyl)-phenyl group, wherein
  • R 7 denotes an amino, C 1-6 -alkylamino, di-(C 1-4 -alkyl)-amino, ⁇ -hydroxy-C 2-3 -alkyl-amino, N—(C 1-3 -alkyl)- ⁇ -hydroxy-C 2-3 -alkyl-amino, di-( ⁇ -hydroxy-C 2-3 -alkyl)-amino or di-( ⁇ -(C 1-3 -alkoxy)-C 2-3 -alkyl)-amino group,
  • X denotes an oxygen atom
  • R 1 and R 5 each denote a hydrogen atom
  • R 2 denotes a methoxycarbonyl, ethoxycarbonyl or aminocarbonyl group
  • R 3 denotes a phenyl group
  • R 4 denotes a phenyl group monosubstituted by the group R 6 , wherein
  • R 6 denotes an N-methyl-imidazol-2-yl group
  • R 12 denotes a C 1-3 -alkyl group
  • p denotes one of the numbers 1 or 2 and
  • R 13 denotes a di-(C 1-3 -alkyl)-amino group
  • R 14 denotes a C 1-3 -alkyl-carbonyl or C 1-3 -alkylsulphonyl group
  • q denotes one of the numbers 1, 2 or 3,
  • r denotes the number 1 or, if q is one of the numbers 2 or 3, r may also denote the number 0 and
  • R 15 denotes a di-(C 1-3 -alkyl)-amino group
  • saturated alkyl moieties contained in the abovementioned groups which contain more than 2 carbon atoms may be straight-chain or branched, unless otherwise stated,
  • R 2 denotes a methoxycarbonyl or ethoxycarbonyl group
  • R 4 denotes a di-(C 1-3 -alkyl)-amino-C 1-3 -alkylphenyl group or
  • Another subgroup of compounds of general formula I comprises those wherein
  • X denotes an oxygen or sulphur atom
  • R 1 denotes a hydrogen atom or a prodrug group such as a C 1-4 -alkoxycarbonyl or C 2-4 -alkanoyl group,
  • R 2 denotes a carboxy group, a straight-chain or branched C 1-6 -alkoxycarbonyl group, a C 5-7 -cycloalkoxycarbonyl or phenyl-C 1-3 -alkoxycarbonyl group, an aminocarbonyl or C 1-2 -alkylaminocarbonyl group or, if R 4 does not denote an aminosulphonyl-phenyl or N—(C 1-5 -alkyl)-C 1-3 -alkylaminocarbonyl-phenyl group, a di-(C 1-2 -alkyl)-aminocarbonyl group,
  • R 3 denotes a hydrogen atom, a C 1-6 -alkyl, C 3-7 -cycloalkyl, trifluoromethyl or heteroaryl group,
  • a phenyl or naphthyl group a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C 1-3 -alkyl or C 1-3 -alkoxy group, whilst in the event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted
  • C 1-3 -alkylcarbonylamino N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, C 1-3 -alkylsulphonylamino, C 1-3 -alkylsulphonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino-C 1-3 -alkyl or aryl-C 1-3 -alkylsulphonylamino group,
  • R 4 denotes a C 3-7 -cycloalkyl group
  • methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,
  • R 6 a phenyl group substituted by the group R 6 , which may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C 1-5 alkyl, trifluoromethyl, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, aminosulphonyl, nitro or cyano group, wherein
  • R 6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom
  • a C 1-3 -alkoxy group optionally unsubstituted by 1 to 3 fluorine atoms, a C 1-3 -alkoxy-C 1-3 -alkoxy, phenyl-C 1-3 -alkoxy, amino-C 2-3 -alkoxy, C 1-3 -alkylamino-C 2-3 -alkoxy, di-(C 1-3 -alkyl)-amino-C 2-3 -alkoxy, phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, C 5-7 -cycloalkyleneimino-C 2-3 -alkoxy or C 1-3 -alkylmercapto group,
  • a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
  • cycloalkylene moiety may be fused to a phenyl ring or
  • one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl group and/or
  • the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl) -aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino group or
  • sulphinyl may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group,
  • a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
  • the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C 1-3 -alkyl, C 1-3 -alkoxy or amino group or
  • one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl group and/or
  • the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl) -aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino group or
  • R 8 denotes a hydrogen atom or a C 1-3 -alkyl group
  • n denotes one of the numbers 0, 1, 2 or 3 and
  • R 9 denotes an amino, C 1-4 -alkylamino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino, N—(C 1-4 -alkyl)-benzylamino or di-(C 1-4 -alkyl)-amino group, a 4- to 7-membered cycloalkyleneimino group, whilst in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl,
  • sulphonyl —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
  • R 10 denotes a hydrogen atom, a C 1-3 -alkyl group, a C 1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C 1-3 -alkylcarbonyl, C 1-3 -alkylsulphonyl, arylsulphonyl or phenyl-C 1-3 -alkylsulphonyl group,
  • n denotes one of the numbers 1, 2, 3 or 4,
  • ⁇ denotes one of the numbers 0 or 1 and
  • R 11 denotes an amino, C 1-4 -alkylamino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino, N—(C 1-4 -alkyl)-benzylamino or di-(C 1-4 -alkyl)-amino group, a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group, a C
  • phenyl groups contained in the groups mentioned under R 6 may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-5 -alkyl, trifluoromethyl, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group, and
  • R 5 denotes a hydrogen atom or a C 1-3 -alkyl group
  • aryl group a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C 1-3 -alkyl or C 1-3 -alkoxy group and
  • heteroaryl group a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C 1-3 -alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1-3 -alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C 1-3 -alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms,
  • the saturated alkyl and alkoxy moieties present in the groups defined above which contain more than 2 carbon atoms also include the branched isomers thereof such as, for example, the isopropyl, tert.butyl or isobutyl group, unless otherwise stated, and
  • any carboxy, amino or imino group present may be substituted by a group which can be cleaved in viva,
  • TBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium-tetrafluoroborate
  • the aqueous phase is three times extracted with ethyl acetate and the combined organic phases are dried over sodium sulphate. After evaporation of the solvent the residue is purified over a silica gel column with methylene chloride/methanol (9:1) as eluant.
  • starting material VI 1-acetyl-3-(1-ethoxy-methylene)-6-methoxycarbonyl-2-indolinone (starting material VI) are dissoled in 150 ml of methanol and 86.4 ml of 1N sodium hydroxide solution are added. The mixture is refluxed for 8.5 hrs. After that time 86.4 ml of 1N hydrochloric acid are added. The residue is filtered off and dried at 90° C.
  • Tautomers, stereoisomers or physiologically acceptable salts of these compounds are also contemplated within the scope of the present invention, and may be obtained using the methods described in WO 01/27081, the content of which is herein incorporated by reference.
  • a particularly preferred compound is the monoethanesulphonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, disclosed for example in WO 04/13099, the content of which is incorporated herein by reference.
  • WO 04/13099 describes metabolites and prodrugs of the compound 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Window Of Vehicle (AREA)
US11/275,223 2004-12-24 2005-12-20 Medicaments for the Treatment or Prevention of Fibrotic Diseases Abandoned US20060142373A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US12/645,151 US20100204211A1 (en) 2004-12-24 2009-12-22 Medicaments for the treatment or prevention of fibrotic diseases
US14/184,821 US20140296217A1 (en) 2004-12-24 2014-02-20 Medicaments for the treatment or prevention of fibrotic diseases
US14/982,179 US10154990B2 (en) 2004-12-24 2015-12-29 Medicaments for the treatment or prevention of fibrotic diseases
US16/167,567 US20190038600A1 (en) 2004-12-24 2018-10-23 Medicaments for the treatment or prevention of fibrotic deiseases
US16/921,043 US20200330435A1 (en) 2004-12-24 2020-07-06 Medicaments for the treatment or prevention of fibrotic diseases
US18/363,779 US20230372297A1 (en) 2004-12-24 2023-08-02 Medicaments for the treatment or prevention of fibrotic diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04030770 2004-12-24
EP04030770 2004-12-24

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/645,151 Continuation US20100204211A1 (en) 2004-12-24 2009-12-22 Medicaments for the treatment or prevention of fibrotic diseases

Publications (1)

Publication Number Publication Date
US20060142373A1 true US20060142373A1 (en) 2006-06-29

Family

ID=36602118

Family Applications (7)

Application Number Title Priority Date Filing Date
US11/275,223 Abandoned US20060142373A1 (en) 2004-12-24 2005-12-20 Medicaments for the Treatment or Prevention of Fibrotic Diseases
US12/645,151 Abandoned US20100204211A1 (en) 2004-12-24 2009-12-22 Medicaments for the treatment or prevention of fibrotic diseases
US14/184,821 Abandoned US20140296217A1 (en) 2004-12-24 2014-02-20 Medicaments for the treatment or prevention of fibrotic diseases
US14/982,179 Active 2026-01-08 US10154990B2 (en) 2004-12-24 2015-12-29 Medicaments for the treatment or prevention of fibrotic diseases
US16/167,567 Abandoned US20190038600A1 (en) 2004-12-24 2018-10-23 Medicaments for the treatment or prevention of fibrotic deiseases
US16/921,043 Abandoned US20200330435A1 (en) 2004-12-24 2020-07-06 Medicaments for the treatment or prevention of fibrotic diseases
US18/363,779 Pending US20230372297A1 (en) 2004-12-24 2023-08-02 Medicaments for the treatment or prevention of fibrotic diseases

Family Applications After (6)

Application Number Title Priority Date Filing Date
US12/645,151 Abandoned US20100204211A1 (en) 2004-12-24 2009-12-22 Medicaments for the treatment or prevention of fibrotic diseases
US14/184,821 Abandoned US20140296217A1 (en) 2004-12-24 2014-02-20 Medicaments for the treatment or prevention of fibrotic diseases
US14/982,179 Active 2026-01-08 US10154990B2 (en) 2004-12-24 2015-12-29 Medicaments for the treatment or prevention of fibrotic diseases
US16/167,567 Abandoned US20190038600A1 (en) 2004-12-24 2018-10-23 Medicaments for the treatment or prevention of fibrotic deiseases
US16/921,043 Abandoned US20200330435A1 (en) 2004-12-24 2020-07-06 Medicaments for the treatment or prevention of fibrotic diseases
US18/363,779 Pending US20230372297A1 (en) 2004-12-24 2023-08-02 Medicaments for the treatment or prevention of fibrotic diseases

Country Status (32)

Country Link
US (7) US20060142373A1 (cs)
EP (4) EP1830843B1 (cs)
JP (1) JP5122976B2 (cs)
KR (1) KR101235094B1 (cs)
CN (1) CN101087605B (cs)
AR (1) AR052177A1 (cs)
AU (1) AU2005318126B2 (cs)
BE (1) BE2015C038I2 (cs)
CA (1) CA2591083C (cs)
CY (3) CY1113766T1 (cs)
DK (2) DK2878297T3 (cs)
EA (1) EA015011B1 (cs)
ES (2) ES2399270T3 (cs)
FR (1) FR15C0046I2 (cs)
HR (1) HRP20130059T1 (cs)
HU (2) HUE050998T2 (cs)
IL (1) IL184125A (cs)
LT (2) LT2878297T (cs)
LU (1) LU92762I2 (cs)
ME (1) ME01493B (cs)
MY (1) MY148108A (cs)
NO (4) NO339784B1 (cs)
NZ (1) NZ556681A (cs)
PE (1) PE20060777A1 (cs)
PL (2) PL1830843T3 (cs)
PT (2) PT1830843E (cs)
RS (1) RS52653B (cs)
SI (2) SI2878297T1 (cs)
TW (1) TWI418351B (cs)
UA (1) UA94390C2 (cs)
WO (1) WO2006067165A2 (cs)
ZA (1) ZA200703601B (cs)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100233705A1 (en) * 2009-03-12 2010-09-16 Arao Tokuzo Method or system using biomarkers for the monitoring of a treatment
WO2010130758A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of cancer and fibrotic diseases
WO2010130757A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of oncological and fibrotic diseases
US20110178099A1 (en) * 2008-06-06 2011-07-21 Boehringer Ingelheim International Gmbh Pharmaceutical combination
US20110190318A1 (en) * 2008-06-06 2011-08-04 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US20150045395A1 (en) * 2013-08-09 2015-02-12 Acclaim BioMed USA LLC Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis
WO2018009854A1 (en) * 2016-07-08 2018-01-11 Arizona Board Of Regents On Behalf Of The University Of Arizona Indoline derivatives and method for using and producing the same
US9907756B2 (en) 2008-06-06 2018-03-06 Boehringer Ingelheim International Gmbh Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US20190070160A1 (en) * 2015-10-07 2019-03-07 Aiviva Holding Limited Compositions and methods of treating dermal fibrotic disorders
CN111278442A (zh) * 2017-10-23 2020-06-12 勃林格殷格翰国际有限公司 用于治疗进行性纤维化间质性肺病(pf-ild)的活性剂的新组合
US12138252B2 (en) 2017-02-12 2024-11-12 Aiviva Biopharma, Inc. Multikinase inhibitors of VEGF and TGF beta and uses thereof

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060154939A1 (en) * 2004-12-24 2006-07-13 Boehringer Ingelheim International Gmbh Medicaments for the Treatment or Prevention of Fibrotic Diseases
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
US20100184747A1 (en) * 2007-06-12 2010-07-22 Boehringer Ingelheim International Gmbh Indoline derivatives and their use in treating disease-states such as cancer
AU2008265104B2 (en) 2007-06-21 2013-09-12 Janssen Pharmaceutica Nv Indolin-2-ones and aza-indolin-2-ones
AU2015227503B2 (en) * 2008-06-06 2017-02-23 Boehringer Ingelheim International Gmbh Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
EA201100254A1 (ru) * 2008-07-29 2011-08-30 Бёрингер Ингельхайм Интернациональ Гмбх Новые соединения
US20120107304A1 (en) 2010-04-27 2012-05-03 Boehringer Ingelheim International Gmbh Combination therapy in treatment of oncological and fibrotic diseases
US8381108B2 (en) * 2010-06-21 2013-02-19 Microsoft Corporation Natural user input for driving interactive stories
WO2012021974A1 (en) 2010-08-20 2012-02-23 The Hospital For Sick Children Compositions and methods for treatment of cystic fibrosis and diseases associated with aberrant protein cellular processing
CN103102352B (zh) * 2011-11-15 2015-08-12 山东亨利医药科技有限责任公司 酪氨酸激酶抑制剂吲哚满酮衍生物
CN103130775B (zh) * 2011-11-22 2015-09-30 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的吲哚满酮衍生物
PL2807160T3 (pl) * 2012-01-26 2020-03-31 Angion Biomedica Corp. Związki przeciwzwłóknieniowe i ich zastosowania
CN103848814B (zh) * 2012-12-06 2016-08-17 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的取代吲哚满酮衍生物
US20140350022A1 (en) 2013-05-10 2014-11-27 Boehringer Ingelheim International Gmbh Efficacious treatment of NSCLC and predictive clinical marker of the responsiveness of a tumour to a treatment
CN104003925B (zh) * 2013-06-05 2016-03-30 四川大学 吲哚酮化合物或其衍生物及其用途
WO2015009889A1 (en) * 2013-07-18 2015-01-22 Concert Pharmaceuticals, Inc. Deuterated intedanib derivatives and their use for the treatment of proliferative disorders
ES3010397T3 (en) * 2013-07-31 2025-04-02 Avalyn Pharma Inc Aerosol tyrosine kinase inhibitor compounds and uses thereof
KR20160117596A (ko) 2014-02-07 2016-10-10 오스펙스 파마슈티칼스, 인코포레이티드 신규 제약 제제
CN106432042A (zh) * 2015-08-13 2017-02-22 南京华威医药科技开发有限公司 尼达尼布乙磺酸水合物的药物新晶型
BR112018013033A2 (pt) * 2015-12-24 2018-12-04 Respivert Ltd compostos de indolinonas e seu uso no tratamentod de doenças fibróticas
CN107019697A (zh) * 2016-02-02 2017-08-08 瑞阳(苏州)生物科技有限公司 预防或治疗纤维化疾病的药物组合物及其应用
CN109153666B (zh) 2016-03-08 2021-07-16 莱斯彼维特有限公司 吲哚衍生物及其作为蛋白激酶抑制剂的用途
JP2019511547A (ja) 2016-04-13 2019-04-25 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 結腸直腸癌を治療するためのニンテダニブ、トリフルリジンおよびチピラシルの医薬組合せ
EP3246029A1 (en) 2016-05-19 2017-11-22 Boehringer Ingelheim International Gmbh Pharmaceutical combination of nintedanib and capecitabine for the treatment of colorectal cancer
JP2019522638A (ja) 2016-05-27 2019-08-15 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 ニンテダニブ及びピルフェニドンによる治療開始を判定するためのｅｃｍバイオマーカーの使用
US20190275033A1 (en) 2016-06-01 2019-09-12 Boehringer Ingelheim International Gmbh Use of ecm biomarkers for determining the treatment onset with nintedanib and pirfenidone
CN108066343A (zh) * 2016-11-08 2018-05-25 瑞阳(苏州)生物科技有限公司 一种预防或治疗肾纤维化疾病的药物
EP3551187B1 (en) 2016-12-12 2021-02-17 Boehringer Ingelheim International GmbH Nintedanib for use in methods for the treatment of interstitial lung diseases by coadministration with olodaterol
CN106692150B (zh) * 2016-12-21 2019-08-20 中国人民解放军第三〇二医院 尼达尼布在制备预防和治疗肝纤维化与肝硬化的药物中的用途
CN110573161A (zh) 2017-03-28 2019-12-13 勃林格殷格翰国际有限公司 用于治疗肌营养不良的方法的尼达尼布
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
CN114748622B (zh) 2017-10-05 2024-09-24 弗尔康医疗公司 P38激酶抑制剂降低dux4和下游基因表达以用于治疗fshd
US10793564B2 (en) 2018-03-07 2020-10-06 Pliant Therapeutics, Inc. Amino acid compounds and methods of use
JP7061310B2 (ja) * 2018-04-05 2022-04-28 国立大学法人 大分大学 慢性脂肪性疾患の予防および治療用医薬
CA3101102A1 (en) 2018-04-23 2019-10-31 Tlc Biopharmaceuticals, Inc. Inhalable liposomal sustained release composition for use in treating pulmonary diseases
CN108358827A (zh) * 2018-05-07 2018-08-03 日照市普达医药科技有限公司 一种治疗牛皮癣的2-氧代-吲哚类衍生物及其制备方法
AU2019285066B2 (en) 2018-06-15 2024-06-13 Handa Pharmaceuticals, Inc. Kinase inhibitor salts and compositions thereof
CN109134431B (zh) * 2018-10-10 2021-06-04 成都理工大学 作为囊性纤维化跨膜传导调节因子抑制剂的氨基咪唑偶联吡啶酮衍生物
GB201905375D0 (en) 2019-04-16 2019-05-29 Mission Therapeutics Ltd Novel compounds
GB201905371D0 (en) 2019-04-16 2019-05-29 Mission Therapeutics Ltd Novel compounds
GB201912674D0 (en) 2019-09-04 2019-10-16 Mission Therapeutics Ltd Novel compounds
IL293474A (en) 2019-12-04 2022-08-01 Idorsia Pharmaceuticals Ltd Combination of an azetidine lpa1 receptor antagonist with pirfenidone and/or nintedanib for use in the treatment of fibrotic diseases
EP4125890A1 (en) 2020-04-01 2023-02-08 Boehringer Ingelheim International GmbH Use of biomarkers in the treatment of fibrotic conditions
EP4132925A1 (en) 2020-04-08 2023-02-15 Mission Therapeutics Limited N-cyanopyrrolidines with activity as usp30 inhibitors
GB202006079D0 (en) 2020-04-24 2020-06-10 Vicore Pharma Ab New composition
GB202006074D0 (en) 2020-04-24 2020-06-10 Vicore Pharma Ab New composition
MX2022014429A (es) 2020-05-28 2022-12-07 Mission Therapeutics Ltd N-cianopirrolidinas con actividad como inhibidores de usp30.
MX2022015254A (es) 2020-06-04 2023-01-11 Mission Therapeutics Ltd N-cianopirrolidinas con actividad como inhibidores de peptidasa especifica de ubiquitina 30.
FI4161929T3 (fi) 2020-06-08 2025-07-30 Mission Therapeutics Ltd 1-(5-(2-syaanipyridin-4-yyli)oksatsoli-2-karbonyyli)-4-metyyliheksahydropyrrolo[3,4-b]pyrroli-5(1h)-karbonitriili usp30-inhibiittorina käytettäväksi mitokondrioiden toimintahäiriön, syövän ja fibroosin hoitamisessa
GB202016800D0 (en) 2020-10-22 2020-12-09 Mission Therapeutics Ltd Novel compounds
EP4441044A1 (en) 2021-12-01 2024-10-09 Mission Therapeutics Limited Substituted n-cyanopyrrolidines with activity as usp30 inhibitors
WO2023161668A1 (en) 2022-02-28 2023-08-31 Nuformix Technologies Limited Compositions and methods for treatment of idiopathic pulmonary fibrosis
JP2025525881A (ja) 2022-08-16 2025-08-07 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 眼内使用するためのニンテダニブの医薬製剤
CN118772038B (zh) * 2023-01-03 2025-07-29 天津征程医药科技有限公司 2-吲哚酮衍生物及其用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6762180B1 (en) * 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases

Family Cites Families (177)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4460581A (en) 1982-10-12 1984-07-17 Boehringer Ingelheim Kg (1-Hydroxy-2-amino-alkyl)-substituted benzoxazinones and benzoxazolinones
WO1992012154A1 (en) 1990-12-31 1992-07-23 Fujisawa Pharmaceutical Co., Ltd. Imidazotriazine derivatives
GB9816837D0 (en) 1998-08-04 1998-09-30 Zeneca Ltd Amide derivatives
MX9300141A (es) 1992-01-13 1994-07-29 Smithkline Beecham Corp Compuestos de imidazol novedosos, procedimiento para su preparacion y composiciones farmaceuticas que lo contienen.
US5716972A (en) 1993-01-13 1998-02-10 Smithkline Beecham Corporation Pyridyl substituted imidazoles
US5656644A (en) 1994-07-20 1997-08-12 Smithkline Beecham Corporation Pyridyl imidazoles
GB9303993D0 (en) 1993-02-26 1993-04-14 Fujisawa Pharmaceutical Co New heterocyclic derivatives
US5593991A (en) 1993-07-16 1997-01-14 Adams; Jerry L. Imidazole compounds, use and process of making
US5593992A (en) 1993-07-16 1997-01-14 Smithkline Beecham Corporation Compounds
US5670527A (en) 1993-07-16 1997-09-23 Smithkline Beecham Corporation Pyridyl imidazole compounds and compositions
DK0672041T3 (da) 1993-10-01 2002-02-25 Novartis Ag Farmakologisk aktive pyridinderivater og fremgangsmåder til fremstilling deraf
CA2148931A1 (en) 1993-10-01 1995-04-13 Jurg Zimmermann Pyrimidineamine derivatives and processes for the preparation thereof
PT672042E (pt) 1993-10-01 2006-08-31 Novartis Ag Derivados de pirimidinoamina farmacologicamente activos e processos para a sua preparacao
US5543520A (en) 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives
GB9401182D0 (en) 1994-01-21 1994-03-16 Inst Of Cancer The Research Antibodies to EGF receptor and their antitumour effect
US5559137A (en) 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds
WO2000023072A1 (en) 1998-10-20 2000-04-27 Omeros Medical Systems, Inc. Irrigation solution containing mapk inhibitors and their use for treating pain and inflammation
WO1996030347A1 (en) 1995-03-30 1996-10-03 Pfizer Inc. Quinazoline derivatives
TW449590B (en) 1995-04-14 2001-08-11 Boehringer Ingelheim Kg New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds
US5739143A (en) 1995-06-07 1998-04-14 Smithkline Beecham Corporation Imidazole compounds and compositions
US5880141A (en) * 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
IL118544A (en) 1995-06-07 2001-08-08 Smithkline Beecham Corp History of imidazole, the process for their preparation and the pharmaceutical preparations containing them
CZ1598A3 (cs) 1995-07-06 1998-04-15 Novartis Ag Pyrrolopyrimidiny a způsoby jejich přípravy
AU702146B2 (en) 1995-10-06 1999-02-11 Merck & Co., Inc. Substituted imidazoles having anti-cancer and cytokine inhibitory activity
AU702887B2 (en) 1995-10-31 1999-03-11 Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use
AU7482396A (en) 1995-10-31 1997-05-22 Merck & Co., Inc. Substituted aryl pyrroles, compositions containing such compounds and methods of use
JP2000503302A (ja) 1996-01-11 2000-03-21 スミスクライン・ビーチャム・コーポレイション 新規置換イミダゾール化合物
AP9700912A0 (en) 1996-01-11 1997-01-31 Smithkline Beecham Corp Novel cycloalkyl substituted imidazoles
WO1997025047A1 (en) 1996-01-11 1997-07-17 Smithkline Beecham Corporation Novel cycloalkyl substituded imidazoles
ZA97175B (en) 1996-01-11 1997-11-04 Smithkline Beecham Corp Novel substituted imidazole compounds.
DE19608665A1 (de) 1996-03-06 1997-09-11 Boehringer Ingelheim Kg Neue Arylglycinamidderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen
WO1997033883A1 (en) 1996-03-13 1997-09-18 Smithkline Beecham Corporation Novel pyrimidine compounds useful in treating cytokine mediated diseases
JP2000507545A (ja) 1996-03-25 2000-06-20 スミスクライン・ビーチャム・コーポレイション Ｃｎｓ損傷についての新規な治療
JP2000507558A (ja) 1996-03-25 2000-06-20 スミスクライン・ビーチャム・コーポレイション Ｃｎｓ損傷についての新規な治療
EP0906099A4 (en) 1996-04-03 2001-02-07 Merck & Co Inc CANCER TREATMENT METHOD
EP0906307B1 (en) 1996-06-10 2005-04-27 Merck & Co., Inc. Substituted imidazoles having cytokine inhibitory activity
WO1998006715A1 (en) 1996-08-09 1998-02-19 Smithkline Beecham Corporation Novel piperazine containing compounds
WO1998007425A1 (en) 1996-08-21 1998-02-26 Smithkline Beecham Corporation Imidazole compounds, compositions and use
DE19633640C2 (de) 1996-08-21 1999-05-06 Ford Global Tech Inc Vorrichtung zur Winkelverstellung einer Welle gegenüber einem Antriebsrad
PT948495E (pt) 1996-11-19 2004-08-31 Amgen Inc Agentes anti-inflamatorios de pirrolo fundido substituidos em arilo e heteroarilo
AU730295B2 (en) 1996-11-20 2001-03-01 Merck & Co., Inc. Triaryl substituted imidazoles as glucagon antagonists
WO1998024782A2 (en) 1996-12-05 1998-06-11 Amgen Inc. Substituted pyrimidine compounds and their use
HUP0001140A3 (en) 1996-12-05 2002-05-28 Amgen Inc Thousand Oaks Substituted pyrimidinone and pyridone compounds and methods of use
ZA9711092B (en) 1996-12-11 1999-07-22 Smithkline Beecham Corp Novel compounds.
US6147080A (en) 1996-12-18 2000-11-14 Vertex Pharmaceuticals Incorporated Inhibitors of p38
WO1998028292A1 (en) 1996-12-23 1998-07-02 Smithkline Beecham Corporation Novel piperidine containing compounds
CN1127479C (zh) 1997-01-29 2003-11-12 辉瑞大药厂 磺酰脲衍生物及其在白介素－1活性的控制中的用途
WO1998047899A1 (en) 1997-04-24 1998-10-29 Ortho-Mcneil Corporation, Inc. Substituted pyrrolopyridines useful in the treatment of inflammatory diseases
WO1998047892A1 (en) 1997-04-24 1998-10-29 Ortho-Mcneil Corporation, Inc. Substituted imidazoles useful in the treatment of inflammatory diseases
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
CA2289102A1 (en) 1997-05-07 1998-11-12 Sugen, Inc. 2-indolinone derivatives as modulators of protein kinase activity
SK157899A3 (en) 1997-05-22 2000-08-14 Searle & Co Substituted pyrazoles as p38 kinase inhibitors, process for their preparation and pharmaceutical compositions
JP2002502380A (ja) 1997-05-22 2002-01-22 ジー．ディー．サール アンド カンパニー ｐ３８キナーゼ阻害剤としてのピラゾール誘導体
US5932576A (en) 1997-05-22 1999-08-03 G. D. Searle & Company 3(5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
AU7585498A (en) 1997-05-23 1998-12-11 Bayer Corporation Inhibition of p38 kinase activity by aryl ureas
EP0986382B1 (en) 1997-05-23 2008-06-25 Bayer Pharmaceuticals Corporation Raf kinase inhibitors
WO1998056788A1 (en) 1997-06-12 1998-12-17 Rhone-Poulenc Rorer Limited Imidazolyl-cyclic acetals
US20020156104A1 (en) 1997-06-13 2002-10-24 Jerry L. Adams Novel pyrazole and pyrazoline substituted compounds
US6093742A (en) 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
WO1999003837A1 (en) 1997-06-30 1999-01-28 Ortho-Mcneil Pharmaceutical, Inc. 2-substituted imidazoles useful in the treatment of inflammatory diseases
GB9713726D0 (en) 1997-06-30 1997-09-03 Ciba Geigy Ag Organic compounds
US5939421A (en) 1997-07-01 1999-08-17 Signal Pharmaceuticals, Inc. Quinazoline analogs and related compounds and methods for treating inflammatory conditions
EP1019396A1 (en) 1997-07-02 2000-07-19 SmithKline Beecham Corporation Novel cycloalkyl substituted imidazoles
TW517055B (en) 1997-07-02 2003-01-11 Smithkline Beecham Corp Novel substituted imidazole compounds
AR016294A1 (es) 1997-07-02 2001-07-04 Smithkline Beecham Corp Compuesto de imidazol sustituido, composicion farmaceutica que la contiene, su uso en la fabricacion de un medicamento y procedimiento para supreparacion
US5981710A (en) 1997-07-21 1999-11-09 Baxter International, Inc. Therapeutic hemoglobin composition having isotropically increased size
GB9718913D0 (en) * 1997-09-05 1997-11-12 Glaxo Group Ltd Substituted oxindole derivatives
EP1017378B1 (en) 1997-09-23 2002-12-11 AstraZeneca AB Amide derivatives for the treatment of diseases mediated by cytokines
US5975738A (en) 1997-09-30 1999-11-02 Lsi Logic Corporation Method for detecting failure in redundant controllers using a private LUN
US6362193B1 (en) 1997-10-08 2002-03-26 Smithkline Beecham Corporation Cycloalkenyl substituted compounds
ID24760A (id) 1997-11-14 2000-08-03 Sankyo Co Turunan-turunan piridilpirol
AU1924699A (en) 1997-12-19 1999-07-12 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositionsand uses
DE1041982T1 (de) 1997-12-22 2001-06-07 Bayer Corp., Pittsburgh HEMMUNG DER p38 KINASE AKTIVITÄT DURCH SUBSTITUIERTEN HETEROCYCLISCHEN HARNSTOFFEN
DE1043995T1 (de) 1997-12-22 2001-06-07 Bayer Corp., Pittsburgh INHIBIERUNG DER p38 KINASE-AKTIVITÄT DURCH DIE VERWENDUNG VON ARYL- UND HETEROARYLSUBSTITUIERTEN HARNSTOFFEN
IL136737A0 (en) 1997-12-22 2001-06-14 Bayer Ag Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
RS49779B (sr) 1998-01-12 2008-06-05 Glaxo Group Limited, Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze
AU759297B2 (en) 1998-02-26 2003-04-10 Ortho-Mcneil Pharmaceutical, Inc. Substituted pyrrolobenzimidazoles for treating inflammatory diseases
WO1999050238A1 (fr) 1998-03-26 1999-10-07 Santen Pharmaceutical Co., Ltd. Nouveaux derives d'uree
DE19815020A1 (de) 1998-04-03 1999-10-07 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19816624A1 (de) 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
YU67600A (sh) 1998-05-05 2003-07-07 F.Hofmann - La Roche Ag. Derivati pirazola kao inhibitori p-38 map kinaze
US6316466B1 (en) 1998-05-05 2001-11-13 Syntex (U.S.A.) Llc Pyrazole derivatives P-38 MAP kinase inhibitors
MY132496A (en) 1998-05-11 2007-10-31 Vertex Pharma Inhibitors of p38
EP1077971A1 (en) 1998-05-14 2001-02-28 G.D. SEARLE & CO. 1,5-DIARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
RU2205823C2 (ru) 1998-05-15 2003-06-10 Астразенека Аб Производные бензамида, способ их получения и фармкомпозиция на их основе
RU2215736C2 (ru) 1998-05-15 2003-11-10 Астразенека Аб Производные бензамида, способ их получения и фармакомпозиция на их основе
BR9910621A (pt) 1998-05-22 2001-01-30 Smithkline Beecham Corp Novos compostos de imidazol 2-alquil substituìdos
US6340685B1 (en) 1998-05-22 2002-01-22 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
WO1999061426A1 (en) 1998-05-22 1999-12-02 Scios Inc. Heterocyclic compounds and methods to treat cardiac failure and other disorders
US6589954B1 (en) 1998-05-22 2003-07-08 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
WO1999061440A1 (en) 1998-05-26 1999-12-02 Smithkline Beecham Corporation Novel substituted imidazole compounds
DE19824922A1 (de) * 1998-06-04 1999-12-09 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
EP1086085A1 (en) 1998-06-12 2001-03-28 Vertex Pharmaceuticals Incorporated INHIBITORS OF p38
AU4395399A (en) 1998-07-02 2000-01-24 Sankyo Company Limited Five-membered heteroaryl compounds
US6207687B1 (en) 1998-07-31 2001-03-27 Merck & Co., Inc. Substituted imidazoles having cytokine inhibitory activity
HUP0103019A3 (en) 1998-08-04 2002-01-28 Astrazeneca Ab Amide derivatives useful as inhibitors of the production of cytokines, process for producing them and pharmaceutical compositions containing them
CN1147469C (zh) 1998-08-05 2004-04-28 参天制药株式会社 带有芳香族含氮杂环的新型脲衍生物
CA2341370A1 (en) 1998-08-20 2000-03-02 Smithkline Beecham Corporation Novel substituted triazole compounds
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
CA2342251A1 (en) 1998-08-28 2000-03-09 Scios Inc. Use of piperidines and/or piperazines as inhibitors of p38-alpha kinase
JP4191825B2 (ja) 1998-09-10 2008-12-03 あすか製薬株式会社 ５−アミノイソキサゾール誘導体
AU762245B2 (en) 1998-09-18 2003-06-19 Vertex Pharmaceuticals Incorporated Inhibitors of p38
AR023659A1 (es) 1998-09-18 2002-09-04 Vertex Pharma Un compuesto inhibidor de p38, una composicion farmaceutica que lo comprende y el uso de dicha composicion en el tratamiento y prevencion de estados patologicos
DE19842833B4 (de) 1998-09-18 2005-04-14 Merckle Gmbh 2-Arylalkylthio-imidazole, 2-Arylalkenylthio-imidazole und 2-Arylalkinylthio-imidazole als Entzündungs-Hemmstoffe und Hemmstoffe der Cytokin-Freisetzung
WO2000018734A1 (de) 1998-09-25 2000-04-06 Boehringer Ingelheim Pharma Kg Neue substituierte indolinone mit inhibierender wirkung auf verschiedene kinasen und cyclin/cdk-komplexe
ID28267A (id) 1998-09-25 2001-05-10 Astrazeneca Ab Turunan benzamida dan penggunaannya sebagai inhibitor sitokina
JP2002526538A (ja) 1998-10-01 2002-08-20 アストラゼネカ アクチボラグ 化学化合物
AU6476599A (en) 1998-11-03 2000-05-22 Novartis Ag Anti-inflammatory 4-phenyl-5-pyrimidinyl-imidazoles
ES2212657T3 (es) 1998-11-04 2004-07-16 Smithkline Beecham Corporation Pirazinas sustituidas piridin-4-il o pirimidin-4-il.
WO2000031048A1 (en) 1998-11-19 2000-06-02 Warner-Lambert Company N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases
PT1131318E (pt) 1998-11-20 2004-07-30 Searle Llc Processo para a producao de pirazoles 5-substituidos utilizando ditietanos
US6350744B1 (en) 1998-11-20 2002-02-26 Merck & Co., Inc. Compounds having cytokine inhibitory activity
WO2000035911A1 (en) 1998-12-16 2000-06-22 Aventis Pharma Limited Heteroaryl-cyclic acetals
US6387641B1 (en) 1998-12-16 2002-05-14 Vertex Pharmaceuticals Incorporated Crystallized P38 complexes
DE69926542T2 (de) 1998-12-25 2006-04-27 Teikoku Hormone Mfg. Co., Ltd. Aminopyrazolderivate
WO2000041698A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
GB9904933D0 (en) * 1999-03-04 1999-04-28 Glaxo Group Ltd Compounds
MXPA01009077A (es) 1999-03-12 2002-03-27 Boehringer Ingelheim Pharma Composiciones heterociclicos aromaticos como agentes anti-inflamatorios.
EP1165516B1 (en) 1999-03-12 2004-10-06 Boehringer Ingelheim Pharmaceuticals Inc. Heterocyclic urea and related compounds useful as anti-inflammatory agents
DE60022328T2 (de) 1999-03-17 2006-06-01 Astrazeneca Ab Amid-derivate
KR100757282B1 (ko) 1999-03-17 2007-09-11 아스트라제네카 아베 아미드 유도체
GB9906566D0 (en) 1999-03-23 1999-05-19 Zeneca Ltd Chemical compounds
CO5170501A1 (es) 1999-04-14 2002-06-27 Novartis Ag AZOLES SUSTITUIDOS UTILES PARA EL TRATAMIENTO DE ENFERMEDADES MEDIADAS POR TNFa eIL-1 Y ENFERMEDADES DEL METABOLISMO OSEO
US6492516B1 (en) 1999-05-14 2002-12-10 Merck & Co., Inc. Compounds having cytokine inhibitory activity
CZ20014126A3 (cs) 1999-05-21 2002-03-13 Scios Inc. Indolové deriváty jako inhibitory p38 kinasy
DE19924401A1 (de) 1999-05-27 2000-11-30 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
IL147133A0 (en) 1999-06-21 2002-08-14 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof
US6403596B1 (en) 1999-06-28 2002-06-11 Merck & Co., Inc. Substituted pyridones having cytokine inhibitory activity
WO2001005745A1 (en) 1999-07-16 2001-01-25 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a)
AU769138B2 (en) 1999-07-16 2004-01-15 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Aminobenzophenones as inhibitors of IL-1beta and TNF-alpha
DE60014394T2 (de) 1999-07-16 2005-12-22 Leo Pharma A/S Aminobenzophenone als inhibitoren von il-1beta und tnf-alpha
CA2379293A1 (en) 1999-07-16 2001-01-25 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsa Ktieselskab) Aminobenzophenones as inhibitors of il-1.beta. and tnf-.alpha.
DK1202954T3 (da) 1999-07-16 2004-02-09 Leo Pharma As Nye aminobenzophenoner
ATE316527T1 (de) 1999-08-27 2006-02-15 Boehringer Ingelheim Pharma Substituierte indolinone als tyrosinkinase inhibitoren
WO2001027315A2 (en) 1999-10-13 2001-04-19 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) For substances acting on msk1 or msk2
UA75054C2 (uk) * 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу
GB9924092D0 (en) 1999-10-13 1999-12-15 Zeneca Ltd Pyrimidine derivatives
DE19949209A1 (de) 1999-10-13 2001-04-19 Boehringer Ingelheim Pharma In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
TR200201058T2 (tr) 1999-10-21 2002-07-22 F.Hoffmann-La Roche Ag P38 protein kinaz inhibitörleri olarak, alkilaminoyla ornatılmış bisiklik, azotlu heterosikller
HRP20020328A2 (en) 1999-10-21 2004-02-29 Hoffmann La Roche Heteroalkylamino-substited bicyclic nitrogen heterocycles as inhibitors of p38 protein kinase
HK1043591B (zh) 1999-11-10 2006-12-29 奥索-麦克尼尔药品公司 取代的2-芳基-3-(杂芳基)-咪唑并[1，2-a]嘧啶类化合物以及相关的药物组合物和方法
UA74803C2 (uk) 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. Стійкий поліморф гідрохлориду n-(3-етинілфеніл)-6,7-біс(2-метоксіетокси)-4-хіназолінаміну, спосіб його одержання (варіанти) та фармацевтичне застосування
ES2292488T3 (es) 1999-11-16 2008-03-16 Boehringer Ingelheim Pharmaceuticals Inc. Derivados de la urea, como agentes antiinflamatorios.
ATE305787T1 (de) 1999-11-23 2005-10-15 Smithkline Beecham Corp 3,4-dihydro-(1h)chinazolin-2-on-verbindungen als csbp/p39-kinase-inhibitoren
EP1248624A4 (en) 1999-11-23 2003-01-22 Smithkline Beecham Corp 3,4-DIHYDRO- (1H) -CHIRAZOLINE-2-ONES AND THE USE THEREOF AS CSBP / P38 KINASE INHIBITORS
WO2001038312A1 (en) 1999-11-23 2001-05-31 Smithkline Beecham Corporation 3,4-DIHYDRO-(1H)QUINAZOLIN-2-ONE COMPOUNDS AS CSBP/p38 KINASE INHIBITORS
EP1233951B1 (en) 1999-11-23 2005-06-01 SmithKline Beecham Corporation 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors
HUP0203300A3 (en) 1999-11-30 2003-10-28 Pfizer Prod Inc 2,4-diaminopyrimidine compounds useful as immunosuppressants, pharmaceutical compositions containing them and their use
CA2393312C (en) 1999-12-06 2011-07-12 Leo Pharma A/S Aminobenzophenones as inhibitors of il-1.beta. and tnf-.alpha.
US6602872B1 (en) 1999-12-13 2003-08-05 Merck & Co., Inc. Substituted pyridazines having cytokine inhibitory activity
ATE449764T1 (de) 1999-12-28 2009-12-15 Pharmacopeia Inc Cytokine, insbesondere tnf-alpha, hemmer
DE20002820U1 (de) 2000-02-16 2000-05-25 Igus Spritzgußteile für die Industrie GmbH, 51147 Köln Energieführungskette
US6537996B2 (en) 2000-02-23 2003-03-25 Iconix Pharmaceuticals, Inc. Modulators of p38 MAP kinase
AU2001241927A1 (en) 2000-02-28 2001-09-12 Scios Inc. Inhibitors of p38-alpha kinase
AR035851A1 (es) 2000-03-28 2004-07-21 Wyeth Corp 3-cianoquinolinas, 3-ciano-1,6-naftiridinas y 3-ciano-1,7-naftiridinas como inhibidoras de proteina quinasas
ATE350378T1 (de) 2000-04-08 2007-01-15 Boehringer Ingelheim Pharma Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
DE10042062A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Hertellung
DE10042060A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042058A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042059A1 (de) 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10051320A1 (de) 2000-10-17 2002-04-25 Boehringer Ingelheim Pharma Neue Neurokininantagonisten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen
DE10054019A1 (de) 2000-11-01 2002-05-23 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
US6638965B2 (en) 2000-11-01 2003-10-28 Boehringer Ingelheim Pharma Kg Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
DE10063435A1 (de) 2000-12-20 2002-07-04 Boehringer Ingelheim Pharma Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10117204A1 (de) 2001-04-06 2002-10-10 Boehringer Ingelheim Pharma In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
EP1492536B1 (de) 2002-03-30 2012-05-09 Boehringer Ingelheim Pharma GmbH & Co.KG 4- ( n-phenylamino ) -chinazoline/chinoline als tyrosinkinaseinhibitoren
DE10233500A1 (de) 2002-07-24 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel
DE10237423A1 (de) * 2002-08-16 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von LCK-Inhibitoren für die Behandlung von immunologischen Erkrankungen
US20040204458A1 (en) 2002-08-16 2004-10-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of Lck inhibitors for treatment of immunologic diseases
US7148249B2 (en) 2002-09-12 2006-12-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinones substituted by heterocycles, the preparation thereof and their use as medicaments
US20050043233A1 (en) 2003-04-29 2005-02-24 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
PE20061155A1 (es) 2004-12-24 2006-12-16 Boehringer Ingelheim Int Derivados de indolinona como agentes para el tratamiento o la prevencion de enfermedades fibroticas
US20060154939A1 (en) 2004-12-24 2006-07-13 Boehringer Ingelheim International Gmbh Medicaments for the Treatment or Prevention of Fibrotic Diseases
CA2726644C (en) 2008-06-06 2018-02-06 Boehringer Ingelheim International Gmbh Pharmaceutical combination comprising 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and pemetrexed, and use thereof in cancer treatment

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6762180B1 (en) * 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9907756B2 (en) 2008-06-06 2018-03-06 Boehringer Ingelheim International Gmbh Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
US20110178099A1 (en) * 2008-06-06 2011-07-21 Boehringer Ingelheim International Gmbh Pharmaceutical combination
US20110190318A1 (en) * 2008-06-06 2011-08-04 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US20130203773A1 (en) * 2008-06-06 2013-08-08 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US8802384B2 (en) 2009-03-12 2014-08-12 Boehringer Ingelheim International Gmbh Method or system using biomarkers for the monitoring of a treatment
US20100233705A1 (en) * 2009-03-12 2010-09-16 Arao Tokuzo Method or system using biomarkers for the monitoring of a treatment
WO2010130758A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of cancer and fibrotic diseases
WO2010130757A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of oncological and fibrotic diseases
EP2647375A1 (en) * 2009-05-14 2013-10-09 Boehringer Ingelheim International Gmbh Combination of vargatef and dabigatran for the treatment of oncological and fibrotic diseases
US20150045395A1 (en) * 2013-08-09 2015-02-12 Acclaim BioMed USA LLC Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis
US10450295B2 (en) * 2013-08-09 2019-10-22 Acclaim BioMed USA LLC Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis
US20190070160A1 (en) * 2015-10-07 2019-03-07 Aiviva Holding Limited Compositions and methods of treating dermal fibrotic disorders
US10736885B2 (en) * 2015-10-07 2020-08-11 Aiviva Biopharma, Inc. Compositions and methods of treating dermal fibrotic disorders
WO2018009854A1 (en) * 2016-07-08 2018-01-11 Arizona Board Of Regents On Behalf Of The University Of Arizona Indoline derivatives and method for using and producing the same
CN109476594A (zh) * 2016-07-08 2019-03-15 亚利桑那大学董事会 二氢吲哚衍生物及其使用和制备方法
US10654802B2 (en) 2016-07-08 2020-05-19 Arizona Board Of Regents On Behalf Of The Unversit Indoline derivatives and method for using and producing the same
US12138252B2 (en) 2017-02-12 2024-11-12 Aiviva Biopharma, Inc. Multikinase inhibitors of VEGF and TGF beta and uses thereof
CN111278442A (zh) * 2017-10-23 2020-06-12 勃林格殷格翰国际有限公司 用于治疗进行性纤维化间质性肺病(pf-ild)的活性剂的新组合

Also Published As

Publication number Publication date
NO342914B1 (no) 2018-08-27
DK2878297T3 (da) 2020-06-08
US20140296217A1 (en) 2014-10-02
ME01493B (me) 2014-04-20
NZ556681A (en) 2011-01-28
US20230372297A1 (en) 2023-11-23
AU2005318126A1 (en) 2006-06-29
NO20073831L (no) 2007-09-11
AR052177A1 (es) 2007-03-07
NO2017035I2 (no) 2017-07-28
CA2591083A1 (en) 2006-06-29
ES2797546T3 (es) 2020-12-02
EP2384751A1 (en) 2011-11-09
EP1830843A2 (en) 2007-09-12
ES2399270T3 (es) 2013-03-27
HRP20130059T1 (hr) 2013-02-28
CA2591083C (en) 2013-10-01
EP2878297A1 (en) 2015-06-03
US10154990B2 (en) 2018-12-18
US20160136133A1 (en) 2016-05-19
CY2015024I2 (el) 2016-04-13
DK1830843T3 (da) 2013-02-11
EP2878297B1 (en) 2020-03-25
MY148108A (en) 2013-02-28
CY1123050T1 (el) 2021-10-29
CY1113766T1 (el) 2016-04-13
UA94390C2 (ru) 2011-05-10
AU2005318126B2 (en) 2011-11-24
PL2878297T3 (pl) 2020-09-07
IL184125A (en) 2013-09-30
SI2878297T1 (sl) 2020-07-31
FR15C0046I1 (fr) 2015-08-28
FR15C0046I2 (fr) 2018-01-26
KR101235094B1 (ko) 2013-02-20
CN101087605B (zh) 2011-09-14
EA015011B1 (ru) 2011-04-29
EP3643309A1 (en) 2020-04-29
SI1830843T1 (sl) 2013-02-28
EA200701175A1 (ru) 2008-02-28
NO2017035I1 (no) 2017-07-28
EP1830843B1 (en) 2012-11-07
BRPI0519370A2 (pt) 2009-01-20
US20100204211A1 (en) 2010-08-12
PT1830843E (pt) 2013-02-06
LT2878297T (lt) 2020-07-10
PT2878297T (pt) 2020-06-25
JP2008525370A (ja) 2008-07-17
US20200330435A1 (en) 2020-10-22
PE20060777A1 (es) 2006-10-06
TW200635582A (en) 2006-10-16
TWI418351B (zh) 2013-12-11
BE2015C038I2 (cs) 2019-10-23
LTC1830843I2 (lt) 2017-03-10
NO339784B1 (no) 2017-01-30
US20190038600A1 (en) 2019-02-07
NO20170945A1 (no) 2007-09-11
HUE050998T2 (hu) 2021-01-28
LU92762I2 (fr) 2015-11-03
WO2006067165A3 (en) 2007-04-26
KR20070090038A (ko) 2007-09-04
IL184125A0 (en) 2007-10-31
HUS1500034I1 (hu) 2017-12-31
CN101087605A (zh) 2007-12-12
RS52653B (en) 2013-06-28
JP5122976B2 (ja) 2013-01-16
NO20161634A1 (no) 2016-10-12
EP2384751B1 (en) 2015-09-16
WO2006067165A2 (en) 2006-06-29
ZA200703601B (en) 2008-09-25
HK1110526A1 (en) 2008-07-18
PL1830843T3 (pl) 2013-03-29
CY2015024I1 (el) 2016-04-13
NO341591B1 (no) 2017-12-11

Similar Documents

Publication Publication Date Title
US20230372297A1 (en) Medicaments for the treatment or prevention of fibrotic diseases
US20140128409A1 (en) Medicaments for the treatment or prevention of fibrotic diseases
US20090048267A1 (en) Medicaments for the treatment or prevention of fibrotic diseases
HK1110526B (en) Medicaments for the treatment or prevention of fibrotic diseases
BRPI0519370B1 (pt) Emprego de indolinonas e seus sais na preparação de medicamentos para o tratamento ou prevenção de doenças fibróticas
HK1110521A (en) Medicaments for the treatment or prevention of fibrotic diseases

Legal Events

Date Code Title Description
AS Assignment

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PARK, JOHN EDWARD;ROTH, GERALD JUERGEN;HECKEL, ARMIN;AND OTHERS;REEL/FRAME:017200/0970;SIGNING DATES FROM 20060126 TO 20060131

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION