US20100240669A1 - New compounds - Google Patents

New compounds Download PDF

Info

Publication number
US20100240669A1
US20100240669A1 US12/711,716 US71171610A US2010240669A1 US 20100240669 A1 US20100240669 A1 US 20100240669A1 US 71171610 A US71171610 A US 71171610A US 2010240669 A1 US2010240669 A1 US 2010240669A1
Authority
US
United States
Prior art keywords
alkyl
denotes
group
substituted
fluorine atoms
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
US12/711,716
Other languages
English (en)
Inventor
Norbert Hauel
Angelo Ceci
Henri Doods
Ingo Konetzki
Juergen Mack
Henning Priepke
Annette Schuler-Metz
Rainer Walter
Dieter Wiedenmayer
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
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: HAUEL, NORBERT, CECI, ANGELO, KONETZKI, INGO, SCHULER-METZ, ANNETTE, WALTER, RAINER, MACK, JUERGEN, DOODS, HENRI, PRIEPKE, HENNING, WIEDENMAYER, DIETER
Publication of US20100240669A1 publication Critical patent/US20100240669A1/en
Priority to US13/742,175 priority Critical patent/US20130131075A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to the compounds of general formula I
  • n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are as defined hereinafter, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the medicaments containing the pharmacologically effective compounds, the preparation thereof and the use thereof.
  • One embodiment 2 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and denotes
  • An embodiment 3 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 4 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 5 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 6 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 7 of the present invention consists of the compounds of the above general formula I, wherein R 1 is defined as mentioned hereinbefore under embodiment 1, 2, 3, 4, 5 or 6 and
  • An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5 or 6 and
  • R 2 denotes H or CH 3 , the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
  • R 2 denotes H or CH 3 , the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 9 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
  • R 2 denotes H, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 10 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
  • R 3 and R 4 together with the carbon atom to which they are bonded denote a C 3-6 -cycloalkylene group wherein a —CH 2 — unit may be replaced by an oxygen atom, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 11 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
  • R 3 and R 4 together with the carbon atom to which they are bonded denote a group selected from
  • An embodiment 12 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 and
  • R 5 denotes H or CH 3 , the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 13 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 and
  • R 6 denotes H, F, Cl or methyl, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 14 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 and
  • An embodiment 15 of the present invention comprises the compounds of general formula Ia
  • An embodiment 16 of the present invention comprises the compounds of general formula Ia, wherein
  • An embodiment 17 of the present invention comprises the compounds of general formula Ia, wherein
  • An embodiment 18 of the present invention comprises the compounds of general formula Ia wherein
  • An embodiment 19 of the present invention comprises the compounds of general formula Ib
  • An embodiment 20 of the present invention comprises the compounds of general formula Ib, wherein
  • An embodiment 21 of the present invention comprises the compounds of general formula Ib, wherein
  • An embodiment 22 of the present invention comprises the compounds of general formula Ib, wherein
  • An embodiment 23 of the present invention comprises the compounds of general formula Ic
  • An embodiment 24 of the present invention comprises the compounds of general formula IC, wherein
  • An embodiment 25 of the present invention comprises the compounds of general formula Ic, wherein
  • An embodiment 26 of the present invention comprises the compounds of general formula Ic, wherein
  • An embodiment 27 of the present invention comprises the compounds of general formula Id
  • An embodiment 28 of the present invention comprises the compounds of general formula I, Ia, Ib, Ic or Id, wherein n, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are defined as described hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 and
  • a further embodiment of the present invention comprises the compounds of the above general formula II, wherein
  • a further embodiment of the present application relates to the use of the compounds of general formula II, wherein R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I, which have B1-antagonistic properties.
  • a further embodiment of the present invention comprises the compounds of the above general formula III, wherein
  • a further embodiment of the present application relates to the use of the compounds of general formula III, wherein R 2 , R 3 , and R 4 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I which have B1-antagonistic properties.
  • a further embodiment of the present invention comprises the compounds of the above general formula IV, wherein
  • a further embodiment of the present application relates to the use of the compounds of general formula IV, wherein R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I which have B1-antagonistic properties.
  • substituents are independent of one another. If for example there are a plurality of C 1-6 -alkyl groups as substituents in one group, in the case of three substituents C 1-6 -alkyl, one may represent methyl, one n-propyl and one tert-butyl.
  • Also included in the subject matter of this invention are the compounds according to the invention, including the salts thereof, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
  • C 1-3 -alkyl (including those that are part of other groups) are meant alkyl groups with 1 to 3 carbon atoms
  • C 1-4 -alkyl are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms
  • C 1-6 -alkyl are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms
  • C 1-8 -alkyl are meant branched and unbranched alkyl groups with 1 to 8 carbon atoms.
  • Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl.
  • the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. May optionally also be used for the above-mentioned groups.
  • the definitions propyl and butyl include all the possible isomeric forms of the groups in question.
  • propyl includes n-propyl and iso-propyl
  • butyl includes iso-butyl, sec-butyl and tert-butyl.
  • each methylene group may be substituted by up to two and each methyl group may be substituted by up to three fluorine atoms.
  • C 0-2 -alkylene are meant branched and unbranched alkylene groups with 0 to 2 carbon atoms, while a C 0 -alkylene group denotes a bond. Examples include: methylene, ethylene and ethane-1,1-diyl. Moreover the definitions mentioned previously also include those groups wherein each methylene group may be substituted by up to two fluorine atoms.
  • C 3-7 -cycloalkyl (including those that are part of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms and by the term “C 3-6 -cycloalkyl” are meant cyclic alkyl groups with 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • C 3-6 -cycloalkylene (including those that are part of other groups) are meant cyclic alkylene groups with 3 to 6 carbon atoms. Examples include: cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene. Unless otherwise stated, the cyclic alkylene groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • C 2-4 -alkynyl (including those that are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Examples include: ethynyl, propynyl or butynyl. Unless stated otherwise, the definitions propynyl and butynyl include all the possible isomeric forms of the groups in question. Thus for example propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-butynyl, 2-butynyl and 3-butynyl etc.
  • Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.
  • heterocyclic rings or “heterocyclic group” are meant stable 5- or 6-membered monocyclic ring systems, which may be both saturated and mono- or di-unsaturated and besides carbon atoms may carry one or two heteroatoms, which are selected from among nitrogen, oxygen and sulphur. Both nitrogen and sulphur heteroatoms may optionally be oxidised.
  • the previously mentioned heterocycles may be attached to the rest of the molecule via a carbon atom or a nitrogen atom. The following compounds are mentioned as examples:
  • Cyclic imides includes for example succinimides, maleimide and phthalimide.
  • aryl aromatic ring systems with 6 or 10 carbon atoms. Examples of these are phenyl, 1-naphthyl or 2-naphthyl; the preferred aryl group is phenyl.
  • the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.
  • heteroaryl are meant five- or six-membered heterocyclic aromatic groups, which may contain one, two, three or four heteroatoms, selected from among oxygen, sulphur and nitrogen, and additionally contain so many conjugated double bonds that an aromatic system is formed. These heteroaryls may additionally be benzo-condensed with a phenyl ring, so as to form nine- or ten-membered bicyclic heteroaryls.
  • heteroaryls mentioned previously may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.
  • any nitrogen atom present in the heteroaryl group may be oxidised, thereby forming an N-oxide.
  • oxo group an oxygen substituent at a carbon atom, which leads to the formation of a carbonyl group —C(O)—.
  • the introduction of an oxo group as substituent at a non-aromatic carbon atom leads to a conversion of a —CH 2 group into a —C(O)— group.
  • the introduction of an oxo group at an aromatic carbon atom leads to the conversion of a —CH— group into a —C(O)— group and may result in the loss of aromaticity.
  • compounds of general formula I may be converted, particularly for pharmaceutical use, into the physiologically acceptable salts thereof with inorganic or organic acids.
  • inorganic acids for this purpose include hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid
  • organic acids that may be used include malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid.
  • the compounds of general formula I may be converted into the physiologically acceptable salts thereof with inorganic or organic bases, particularly for pharmaceutical applications.
  • inorganic bases include alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides;
  • organic amines include diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.
  • the compounds according to the invention may be present as racemates, provided that they have only one chiral element, but may also be obtained as pure enantiomers, i.e. In the (R) or (S) form.
  • the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof, which are obtained if there is more than one chiral element in the compounds of general formula I, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up.
  • the compound prepared is not limited to one tautomeric form but includes all the tautomeric forms. This also applies particularly to nitrogen-containing heteroaryls:
  • the coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropyl carbodiimide
  • the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures.
  • solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures.
  • an auxiliary base such as diisopropylethylamine (DIPEA, Hünig base) is additionally used.
  • An alternative method of preparing compounds of general formula I consists in linking carboxylic acids of general formula V, wherein all the groups are as hereinbefore defined, with amines of general formula IV, wherein all the groups are as hereinbefore defined.
  • carboxylic acids of general formula V into carboxylic acid chlorides and then react these with amines of general formula IV.
  • Carboxylic acid chlorides are synthesised by methods known from the literature (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, vol. E5/1).
  • the reduction of a nitrile of general formula VI to an amine of general formula III, wherein the group R 2 at the amine nitrogen denotes hydrogen and all the other groups are as hereinbefore defined, may be carried out under standard conditions of catalytic hydrogenolysis with a catalyst such as Raney nickel, for example, in a solvent such as ammoniacal methanol or ethanol or with a reducing agent such as lithium aluminium hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of a Lewis acid such as aluminium chloride.
  • a catalyst such as Raney nickel
  • ketones obtained may also be converted into oximes.
  • the subsequent reduction of the oximes then yields compounds of general formula III.
  • CHO cells that express the cynomolgus BK1-receptor are cultivated in “HAM′S F-12 Medium”. The medium is removed from confluent cultures, the cells are washed with PBS buffer, scraped off or detached using Versene and isolated by centrifuging. Then the cells are homogenised in suspension, the homogenate is centrifuged and resuspended.
  • 200 ⁇ l of the homogenate (50 to 250 ⁇ g protein/assay) are incubated for 60-180 minutes at ambient temperature with 0.5 to 5.0 nM kallidine (DesArg10,Leu9), [3,4-Prolyl-3,43H(N)] and increasing concentrations of the test substance in a total volume of 250 ⁇ l.
  • the incubation is stopped by rapid filtration through GF/B glass fibre filters that have been pre-treated with polyethyleneimine (0.3%).
  • the radioactivity bound to the protein is measured with a TopCount NXT.
  • the radioactivity bound in the presence of 1.0 ⁇ M kallidine (DesArg10) is defined as non-specific binding.
  • the concentration binding curve may be analysed using computer-aided non-linear curve fitting to determine the corresponding K i value for the test substance.
  • novel compounds and their physiologically acceptable salts are suitable for treating diseases and symptoms of diseases caused at least to some extent by stimulation of bradykinin-B1 receptors, or in which antagonisation of the of bradykinin-B1 receptor can bring about an improvement in symptoms.
  • the present invention encompasses the compounds of the above-mentioned general formula I according to the invention for use as medicaments.
  • neuropathic pain such as for example painful neuropathies, pain of diabetic neuropathy, AIDS-associated neuropathic pain non-herpes-associated neuralgia,
  • the compounds are also suitable for treating
  • inflammatory complaints or phenomena caused by sunburn and burns inflammation of the gums, oedema after burns trauma, cerebral oedema and angiooedema, intestinal complaints including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory skin diseases (such as psoriasis and eczema), vascular diseases of the connective tissue, sprains and fracture, and musculoskeletal diseases with inflammatory symptoms such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, and also osteoarthritis, and inflammation of the connective tissue of other origins, and collagenoses of all origins such as systemic lupus erythematodes, scleroderma, polymyositis, dermatomyos
  • diabetic vasculopathy diabetic neuropathy, diabetic retinopathy
  • diabetic symptoms in insulitis for example hyperglycaemia, diuresis, proteinuria and increased renal excretion of nitrite and kallikrein
  • sepsis and septic shock after bacterial infections or after trauma for example hyperglycaemia, diuresis, proteinuria and increased renal excretion of nitrite and kallikrein
  • sepsis and septic shock after bacterial infections or after trauma (m) syndromes that cause itching and allergic skin reactions
  • neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease
  • osteoporosis epilepsy
  • vascular diseases such as panarteriitis nodosa, polyarthritis nodosa, periarteriitis nodosa, arteriitis temporalis, Wegner's granulomatosis, giant cell arteriitis, arteriosclerosis and erythema nodosum; inflammation of the gums;
  • the substances are suitable for causal treatment in the sense of slowing down or stopping the progress of chronically progressive diseases, particularly osteoarthritis, rheumatoid arthritis and spondylarthritis.
  • the present invention encompasses the use of the compounds of the above-mentioned general formula I according to the invention for preparing a medicament for therapeutic use in the above-mentioned indications.
  • the compounds of general formula I according to the invention are used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
  • treatment refers to a therapeutic treatment of patients with a manifest, acute or chronic indication, including on the one hand symptomatic (palliative) treatment to relieve the symptoms of the disease and on the other hand causal or curative treatment of the indication with the aim of ending the pathological condition, reducing the severity of the pathological condition or delaying the progression of the pathological condition, depending on the nature or gravity of the indication.
  • the present invention further relates to the use of a compound of general formula I for preparing a medicament for the acute and prophylactic treatment of acute pain, visceral pain, neuropathic pain, inflammatory/pain receptor-mediated pain, tumour pain, headache pain and pain of mixed causes and other diseases as mentioned above.
  • This use is characterised in that it comprises administering an effective amount of a compound of general formula I or a physiologically acceptable salt thereof to a patient requiring such treatment.
  • patient preferably refers to a human being.
  • these substances are also useful in the veterinary medical treatment of domestic pets, exotic animals and farmed animals.
  • the compounds according to the invention For treating pain, it may be advantageous to combine the compounds according to the invention with stimulating substances such as caffeine or other pain-alleviating active compounds. If active compounds suitable for treating the cause of the pain are available, these can be combined with the compounds according to the invention.
  • Non-steroidal antirheumatics such as for example propionic acid derivatives which may be selected from among alminoprofen bucloxic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenic acid; acetic acid derivatives which may be selected from among indomethacin, acemetacin, alclofenac, isoxepac, sulindac and tolmetin; fenamic derivatives which may be selected from among meclofenamic acid, mefenamic acid and tolfenamic acid; biphenyl-carboxylic acid derivatives; oxicams which may be selected from among meloxicam, piroxicam and tenoxicam; salicylic acid derivatives which may be selected from among acetylsalicylic and sulphasalazine; pyr
  • Opiate receptor agonists which may for example be selected from among morphine, Darvon, tramadol and buprenorphine;
  • Cannabinoid agonists such as for example GW-1000;
  • Sodium channel blockers which may for example be selected from among carbamazepine, mexiletin, pregabalin, tectin and ralfinamide.
  • N-type calcium channel blockers such as for example ziconotide.
  • Serotonergic and noradrenergic modulators which may be selected from among for example duloxetine and amitriptyline.
  • Corticosteroids which may be selected from among for example betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
  • Histamine H1-receptor antagonists which may for example be selected from among bromopheniramine, chloropheniramine, dexchloropheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.
  • Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from among zafirlukast, montelukast, pranlukast and zileuton.
  • Local anaesthetics which may for example be selected from among ambroxol and lidocaine.
  • TRVP1 antagonists which may for example be selected from among AZD-1386, JTS-653 and PHE-377.
  • Nicotine receptor agonists such as for example A-366833.
  • P2X3-receptor antagonists such as e.g. A-317491.
  • anti-NGF antibodies and NGF antagonists which may for example be selected from among JNJ-42160443 and PPH 207.
  • NK1 and NK2 antagonists such as e.g. CP-728663.
  • NMDA antagonists which may for example be selected from among CNS-5161, AZ-756 and V-3381.
  • Potassium channel modulators such as e.g. CL-888.
  • GABA modulators such as e.g. baclofen.
  • Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan, naratriptan and eletriptan.
  • the compounds of general formula I may optionally also be used in conjunction with other pharmacologically active substances. It is preferable to use active substances of the type selected from among the betamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors, LTD4-receptor (CysLT1, CysLT2, CysLT3) antagonists, inhibitors of MAP kinases such as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, LTB4-receptor (BLT1, BLT2) antagonists, EGFR-inhibitors, H1-receptor antagonists, antihistamines, H4-receptor antagonists, PAF-antagonists and PI3-kinase inhibitors CXCR1 and/or CXCR2 receptor antagonists and anti-tussives.
  • the compounds of general formula I may also be used in the form of double or triple combinations thereof, such as for example combinations of compounds of formula I with one or two compounds selected from among
  • Betamimetics used according to the invention are preferably compounds selected from among arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterole, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol, reproterol, rimiterol, ritodrin, salmefamol, soterenol, sulphonterol, terbutalin, tiaramid, tolubuterol and zinterol or
  • Anticholinergics used according to the invention are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, Ipratropiumsalzen, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R)-1-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octane salts.
  • the cations are the pharmacologically active constituents.
  • the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while the chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions.
  • the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
  • anticholinergics may be selected from among
  • Corticosteroids used according to the invention are preferably compounds selected from among beclomethasone betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone and tipredane orpregna-1,4-dien-3,20-dione, 6-fluoro-11-hydroxy-16.17-[(1-methylethyliden)-bis(oxy)]-21-[[4-[(nitroxy)methyl]benzoyl]oxy], (6-alpha,11-beta,16-alpha)-(9Cl) (NCX-1024)
  • PDE4-inhibitors used according to the invention are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram, oglemilast and tetomilast or
  • LTD4-receptor antagonists used according to the invention are preferably compounds selected from among montelukast, pranlukast and zafirlukast, or (E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one (MEN-91507),
  • Histamine H1 receptor antagonists used according to the invention are preferably compounds selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadin, mizolastin, ketotifen, emedastin, dimetinden, clemastin, bamipin, cexchlorpheniramin, pheniramin, doxylamine, chlorophenoxamin, dimenhydrinat, diphenhydramin, promethazin, ebastin, olopatadine, desloratidin and meclozin, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
  • the acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
  • Histamine H4 receptor antagonists used according to the invention are preferably compounds such as for example (5-chloro-1H-indol-2-yl)-(4-methyl-1-piperazinyl)-methanone (JNJ-7777120), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
  • compounds such as for example (5-chloro-1H-indol-2-yl)-(4-methyl-1-piperazinyl)-methanone (JNJ-7777120), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
  • acid addition salts selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate are used.
  • MAP Kinase inhibitors used according to the invention are preferably compounds selected from among:
  • Neurokinin (NK1 or NK2) antagonists used according to the invention are preferably compounds selected from among: Saredutant, Nepadutant and Figopitant, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
  • Antitussive substances used according to the invention are preferably compounds selected from among hydrocodone, caramiphen, carbetapentane and dextramethorphane, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
  • Substances of preferred CXCR1 or CXCR2 antagonists used according to the invention are preferably compounds such as e.g. 3-[[3-[(dimethylamino)carbonyl]-2-hydroxyphenyl]amino]-4-[[(R)-1-(5-methylfuran-2-yl)propyl]amino]cyclobut-3-ene-1,2-dione (SCH-527123),
  • the dosage necessary for obtaining a pain-alleviating effect is, in the case of intravenous administration, expediently from 0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg, and, in the case of oral administration, from 0.1 to 8 mg/kg of body weight, preferably from 0.5 to 3 mg/kg, in each case 1 to 3 times per day.
  • the compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations being particularly suitable for inhalation.
  • customary pharmaceutical preparations such as tablets, coated tablets, capsules, powders, suspensions, solutions, metered-dose aerosols or suppositories, if appropriate together with one or more customary inert carriers and/or diluents, for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hardened fat, or suitable mixtures thereof.
  • customary inert carriers and/or diluents for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbito
  • the acid, base and salt solutions used for working up the reaction solutions are aqueous systems having the stated concentrations.
  • silica gel from Millipore 35 to 70 ⁇ m
  • Alox E. Merck, Darmstadt, Alumina 90 standardized, 63 to 200 ⁇ m, article No. 1.01097.9050
  • DMSO dimethylsulphoxide HATU 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate RP reverse phase R t retention time tert tertiary TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate TEA triethylamine THF tetrahydrofuran
  • Method 7 Column: YMC-Pack ODS-AQ, 3 ⁇ M, 4.6 ⁇ 75 mm
  • Method 8 Column: Zorbax Stable Bond C18, 1.8 ⁇ M, 3 ⁇ 30 mm
  • Method 11 Column: X Terra C18, 3.5 ⁇ M, 4.6 ⁇ 50 mm
  • Method 14 Column: Zorbax Stable Bond C18, 3.5 ⁇ M, 4.6 ⁇ 75 mm
  • the compounds of general formula I may be prepared from the following intermediates A, B and C:
  • AAV 3 Cleaving the Tert-Butyloxycarbonyl Protective Group
  • the nitrile group of the diphenylamine intermediate product thus obtained was then reduced to the aminomethyl group with the addition of Raney nickel at 55° C. and 3 bar excess hydrogen pressure and the product obtained was purified by chromatography.
  • the intermediate A with an alpha-alkylbenzyl group e.g. A1, A4, A5
  • the nitrile derivative (1 mol-equivalent) was dissolved in diethyl ether and at 0 to 5° C. it was added with stirring to a solution of alkylmagnesium bromide (4 mol-equivalents) in diethyl ether and then stirred for another 30 minutes approx.
  • the reaction mixture was then stirred into 1M hydrochloric acid at ⁇ 5° C. and the alkylketone thus obtained was isolated and purified by chromatography in the usual way.
  • Another possible way of reducing the oxime to the corresponding amine is by catalytic hydrogenation.
  • the oxime was hydrogenated in methanolic ammonia solution after the addition of Raney nickel at 50° C. and at an excess hydrogen pressure of 50 psi until the uptake of hydrogen had ended. If necessary, the amine thus obtained was purified by chromatography.
  • reaction is carried out under protective gas (argon).
  • a mixture of 2.39 g (12 mmol) 1-(4-bromophenyl)ethanone, 0.99 mL (8 mmol) 4-(difluoromethoxy)aniline, 2.21 g (16 mmol) potassium carbonate, 150 mg (0.8 mmol) copper iodide and 180 mg (1.6 mmol) L-proline in 12 mL DMSO was stirred for 72 hours at 95° C.
  • the reaction mixture was added to water, mixed with a little ammonia extracted twice with tert-butyl-methylether.
  • the combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo.
  • the residue was purified by column chromatography (silica gel, petroleum ether+30% ethyl acetate). The product was further reacted directly.
  • the aqueous phase was acidified with 4 molar hydrochloric acid and extracted three times with diethyl ether.
  • the combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo.
  • the residue was mixed with dichloromethane and the precipitate formed was suction filtered and dried in the circulating air dryer at 55° C.
  • reaction was carried out under protective gas (nitrogen). 860 mg (3.27 mmol) 5-(2-(trifluoromethyl)phenylamino)picolinic acid nitrile in 5 mL diethyl ether at ⁇ 10° C. were added dropwise to 9.34 mL (13.07 mmol) of a 1.4 molar solution of methylmagnesium bromide in toluene/THF (3:1) and the mixture was left for 15 minutes at this temperature with stirring. The reaction mixture was combined with saturated ammonium chloride solution, neutralised with 1 molar aqueous hydrochloric acid at ⁇ 5° C. and extracted with tert-butylmethylether. The organic phase was evaporated to dryness in vacuo.
  • Example (1d) Analogously to Example (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 41a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Psychology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
US12/711,716 2009-02-26 2010-02-24 New compounds Abandoned US20100240669A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/742,175 US20130131075A1 (en) 2009-02-26 2013-01-15 New compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP09153778.7 2009-02-26
EP09153778 2009-02-26

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/742,175 Continuation US20130131075A1 (en) 2009-02-26 2013-01-15 New compounds

Publications (1)

Publication Number Publication Date
US20100240669A1 true US20100240669A1 (en) 2010-09-23

Family

ID=42307969

Family Applications (3)

Application Number Title Priority Date Filing Date
US12/711,716 Abandoned US20100240669A1 (en) 2009-02-26 2010-02-24 New compounds
US13/031,895 Active 2031-04-02 US8372838B2 (en) 2009-02-26 2011-02-22 Compounds as bradykinin B1 antagonists
US13/742,175 Abandoned US20130131075A1 (en) 2009-02-26 2013-01-15 New compounds

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/031,895 Active 2031-04-02 US8372838B2 (en) 2009-02-26 2011-02-22 Compounds as bradykinin B1 antagonists
US13/742,175 Abandoned US20130131075A1 (en) 2009-02-26 2013-01-15 New compounds

Country Status (37)

Country Link
US (3) US20100240669A1 (zh)
EP (1) EP2401256B1 (zh)
JP (1) JP5629274B2 (zh)
KR (1) KR101660357B1 (zh)
CN (1) CN102414177B (zh)
AP (1) AP2011005808A0 (zh)
AR (1) AR075599A1 (zh)
AU (1) AU2010217606C1 (zh)
BR (1) BRPI1008779A2 (zh)
CA (1) CA2759126C (zh)
CL (1) CL2011002076A1 (zh)
CO (1) CO6430425A2 (zh)
CY (1) CY1114130T1 (zh)
DK (1) DK2401256T3 (zh)
EA (2) EA024656B1 (zh)
EC (2) ECSP11011304A (zh)
ES (1) ES2421630T3 (zh)
GE (1) GEP20135933B (zh)
HK (1) HK1164315A1 (zh)
HR (2) HRP20130666T1 (zh)
IL (1) IL214129A (zh)
MA (1) MA33238B1 (zh)
ME (1) ME01526B (zh)
MX (1) MX2011008553A (zh)
MY (1) MY153941A (zh)
NZ (1) NZ594674A (zh)
PE (1) PE20120360A1 (zh)
PL (1) PL2401256T3 (zh)
PT (1) PT2401256E (zh)
RS (2) RS52801B (zh)
SG (1) SG173698A1 (zh)
SI (1) SI2401256T1 (zh)
TN (2) TN2011000438A1 (zh)
TW (1) TW201041870A (zh)
UA (2) UA105923C2 (zh)
UY (2) UY32463A (zh)
WO (1) WO2010097372A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8372838B2 (en) * 2009-02-26 2013-02-12 Boehringer Ingelheim International Gmbh Compounds as bradykinin B1 antagonists
US8901127B2 (en) 2010-08-20 2014-12-02 Boehringer Ingelheim International Gmbh Pyridazin derivatives as antagonists of the bradykinin B1 receptor
US8916589B2 (en) 2007-08-29 2014-12-23 Boehringer Ingelheim International Gmbh Bradykinin B1-antagonists
US8937073B2 (en) 2010-08-20 2015-01-20 Boehringer Ingelheim International Gmbh Disubstituted tetrahydrofuranyl compounds and their use as B1-receptor antagonists

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007034620A1 (de) * 2007-07-25 2009-01-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue B1-Antagonisten
WO2009028588A1 (ja) 2007-08-31 2009-03-05 Eisai R & D Management Co., Ltd. 多環式化合物
AU2010218667A1 (en) 2009-02-26 2011-07-21 Eisai R&D Management Co., Ltd. Salt of tetrahydrotriazolopyridine derivative and crystal thereof
CA2753696A1 (en) 2009-02-26 2010-09-02 Noritaka Kitazawa Nitrogen-containing fused heterocyclic compounds and their use as beta amyloid production inhibitors
CN103980258B (zh) * 2010-02-23 2016-09-07 贝林格尔.英格海姆国际有限公司 作为缓激肽b1拮抗剂的化合物
HUP1000598A2 (en) * 2010-11-05 2012-09-28 Richter Gedeon Nyrt Indole derivatives
US8912221B2 (en) * 2010-12-27 2014-12-16 Hoffmann-La Roche Inc. Biaryl amide derivatives
US8877766B2 (en) * 2013-02-15 2014-11-04 Peter F. Kador Neuroprotective multifunctional antioxidants and their monofunctional analogs
JP6072308B2 (ja) 2013-02-21 2017-02-01 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 ジヒドロプテリジノンｉｉ
US20160310477A1 (en) * 2013-12-20 2016-10-27 Biomed Valley Discoveries, Inc. Cancer treatments using combinations of mek type 1 and erk inhibitors
RU2690188C2 (ru) * 2017-05-26 2019-05-31 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Новый мультитаргетный препарат для лечения заболеваний у млекопитающих
WO2021198534A1 (en) 2020-04-04 2021-10-07 Oxurion NV Plasma kallikrein inhibitors for use in the treatment of coronaviral disease
GB202018412D0 (en) * 2020-11-23 2021-01-06 Exscientia Ltd Malt-1 modulators ii
WO2023148016A1 (en) 2022-02-04 2023-08-10 Oxurion NV Biomarker for plasma kallikrein inhibitor therapy response

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6689778B2 (en) * 2001-07-03 2004-02-10 Vertex Pharmaceuticals Incorporated Inhibitors of Src and Lck protein kinases
US20110263626A1 (en) * 2007-08-29 2011-10-27 Boehringer Ingelheim International Gmbh Novel bradykinin b1-antagonists
US20120142695A1 (en) * 2009-02-26 2012-06-07 Boehringer Ingelheim International Gmbh Compounds as bradykinin b1 antagonists

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003065789A2 (en) 2002-02-08 2003-08-14 Merck & Co., Inc. N-biphenylmethyl aminocycloalkanecarboxamide derivatives
US6919343B2 (en) * 2002-02-08 2005-07-19 Merck & Co., Inc. N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives
RU2005108667A (ru) * 2002-08-29 2005-08-27 Мерк энд Ко., Инк. (US) Производные n-биарилметиламиноциклоалканкарбоксамида
JP2007501790A (ja) * 2003-08-07 2007-02-01 メルク　エンド　カムパニー　インコーポレーテッド スルホニル置換ｎ−（ビアリールメチル）アミノシクロプロパンカルボキサミド
CA2557858A1 (en) * 2004-03-02 2005-09-15 Merck & Co., Inc. Amino cyclopropane carboxamide derivatives as bradykinin antagonists
MX2007013766A (es) 2005-05-11 2008-01-28 Nycomed Gmbh Combinacion de inhibidor pde4 de roflumilast y un derivado de tetrahidrobiopterina.
HUP0600808A3 (en) * 2006-10-27 2008-09-29 Richter Gedeon Nyrt New benzamide derivatives as bradykinin antagonists, process for their preparation and pharmaceutical compositions containing them
HUP0600809A3 (en) * 2006-10-27 2008-09-29 Richter Gedeon Nyrt New phenylsulfamoyl-benzamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6689778B2 (en) * 2001-07-03 2004-02-10 Vertex Pharmaceuticals Incorporated Inhibitors of Src and Lck protein kinases
US20110263626A1 (en) * 2007-08-29 2011-10-27 Boehringer Ingelheim International Gmbh Novel bradykinin b1-antagonists
US20120142695A1 (en) * 2009-02-26 2012-06-07 Boehringer Ingelheim International Gmbh Compounds as bradykinin b1 antagonists

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8916589B2 (en) 2007-08-29 2014-12-23 Boehringer Ingelheim International Gmbh Bradykinin B1-antagonists
US8372838B2 (en) * 2009-02-26 2013-02-12 Boehringer Ingelheim International Gmbh Compounds as bradykinin B1 antagonists
US8901127B2 (en) 2010-08-20 2014-12-02 Boehringer Ingelheim International Gmbh Pyridazin derivatives as antagonists of the bradykinin B1 receptor
US8937073B2 (en) 2010-08-20 2015-01-20 Boehringer Ingelheim International Gmbh Disubstituted tetrahydrofuranyl compounds and their use as B1-receptor antagonists

Also Published As

Publication number Publication date
UY33238A (es) 2011-09-30
EP2401256A1 (de) 2012-01-04
ECSP12012161A (es) 2012-10-30
UY32463A (es) 2010-09-30
CY1114130T1 (el) 2016-07-27
UA105923C2 (uk) 2014-07-10
RS52801B (en) 2013-10-31
SI2401256T1 (sl) 2013-08-30
JP2012518672A (ja) 2012-08-16
WO2010097372A1 (de) 2010-09-02
HRP20130666T1 (en) 2013-10-11
AR075599A1 (es) 2011-04-20
HK1164315A1 (zh) 2012-09-21
MY153941A (en) 2015-04-15
TN2011000438A1 (en) 2013-03-27
TW201041870A (en) 2010-12-01
PT2401256E (pt) 2013-05-13
ME01526B (me) 2014-04-20
IL214129A0 (en) 2011-08-31
US20130131075A1 (en) 2013-05-23
NZ594674A (en) 2013-12-20
IL214129A (en) 2015-08-31
EA023437B1 (ru) 2016-06-30
GEP20135933B (en) 2013-10-10
EP2401256B1 (de) 2013-04-17
KR20110120913A (ko) 2011-11-04
EA024656B1 (ru) 2016-10-31
US8372838B2 (en) 2013-02-12
HRP20150167T1 (en) 2015-05-22
AU2010217606B2 (en) 2016-07-07
PL2401256T3 (pl) 2013-09-30
JP5629274B2 (ja) 2014-11-19
AP2011005808A0 (en) 2011-08-31
KR101660357B1 (ko) 2016-09-27
RS53710B2 (sr) 2018-07-31
EA201101209A1 (ru) 2012-04-30
AU2010217606C1 (en) 2017-01-19
TN2012000417A1 (en) 2014-01-30
SG173698A1 (en) 2011-09-29
PE20120360A1 (es) 2012-04-14
HRP20150167T4 (hr) 2018-04-20
BRPI1008779A2 (pt) 2020-12-22
MX2011008553A (es) 2011-09-09
CN102414177B (zh) 2014-07-02
CL2011002076A1 (es) 2012-02-17
UA108373C2 (xx) 2015-04-27
AU2010217606A1 (en) 2011-09-08
RS53710B1 (en) 2015-04-30
CO6430425A2 (es) 2012-04-30
CA2759126A1 (en) 2010-09-02
ES2421630T3 (es) 2013-09-04
CA2759126C (en) 2017-08-22
DK2401256T3 (da) 2013-06-03
EA201201167A1 (ru) 2013-04-30
MA33238B1 (fr) 2012-05-02
US20120142695A1 (en) 2012-06-07
CN102414177A (zh) 2012-04-11
ECSP11011304A (es) 2011-10-31

Similar Documents

Publication Publication Date Title
US20130131075A1 (en) New compounds
DK2539323T6 (en) Compounds as bradykinin B1 antagonists
US8937073B2 (en) Disubstituted tetrahydrofuranyl compounds and their use as B1-receptor antagonists
WO2010097374A1 (de) Verbindungen als bradykinin-b1-antagonisten
US8901127B2 (en) Pyridazin derivatives as antagonists of the bradykinin B1 receptor
AU2015271888B2 (en) Compounds as bradykinin B1 antagonists
WO2010097373A1 (de) Verbindungen als bradykinin b1 antagonisten
OA16324A (en) Disubstituted tetrahydrofuranyl compounds as antagonists of the bradykinin B1 receptor.

Legal Events

Date Code Title Description
AS Assignment

Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HAUEL, NORBERT;CECI, ANGELO;DOODS, HENRI;AND OTHERS;SIGNING DATES FROM 20100324 TO 20100415;REEL/FRAME:024339/0548

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE